Gastrointestinal Oncology.2011 PDF

Gastrointestinal Oncology
Charles D. Blanke Claus Rdel

Mark S. Talamonti
(Editors)
Gastrointestinal Oncology
A Practical Guide
Editors
Charles D. Blanke
Division of Medical Oncology
University of British Columbia
West 10th Avenue 600
V5Z 4E6 Vancover, BC
Canada
cblanke@bccancer.bc.ca
Claus Rdel
Department of Radiotherapy and Oncology
Johann Wolfgang Goethe-University
Frankfurt,
Theodor-Stern-Kai 7
60590 Frankfurt am Main
Germany
claus.roedel@kgu.de
Mark S. Talamonti
Pritzker School of Medicine
University of Chicago
Chicago, IL
USA
and
Department of Surgery
NorthShore University Health System
Northwestern University
Evanston Northwestern Healthcare
Ridge Avenue 2650
60201 Evanston, JL
USA
mtalamonti@enh.org
ISBN 978-3-642-13305-3
e-ISBN 978-3-642-13306-0
DOI 10.1007/978-3-642-13306-0
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Preface
Gastrointestinal oncology practitioners aim to establish effective prevention and treatment

strategies for patients with malignancies involving the GI tract, ultimately leading to a
reduction in morbidity and mortality from GI cancers. GI tumours arise from a number of
distinct anatomic sites and may or may not share underlying biologic similarities; however, they differ in their required radiotherapeutic or surgical approaches for limited, curable disease, as well as their chemosensitivity and treatment patterns in the advanced or
metastatic settings. The best therapeutic approach to these cancers is usually multidisciplinary, involving medical, surgical, and radiation oncologists, with strong input from
pathologists, gastroenterologists, and specialists in diagnostic imaging. Making major
strides in future GI cancer control will certainly involve both expert clinicians and researchers, specializing in areas including new drug development, clinical trial design, biostatistics, experimental and molecular therapeutics, and molecular pathology.
This edition of Gastrointestinal Oncology: A Practical Guide features chapters devoted
to each of the major GI anatomic sites, as well as sections on diagnostic imaging, interventional GI oncology, practical correlative science, and non-site specific tumours such as
neuroendocrine cancers and gastrointestinal stromal tumours. The emphasis of this text is
to furnish useful, evidence-based clinical advice, highlighting the multidisciplinary nature
of GI oncology practice. This remains an incredibly exciting time in medicine. The knowledge leaps in molecular oncology in general and characterization and treatment of GI
malignancies specifically have been prodigious. We hope you find the information in this
text useful, guiding your everyday practice and stimulating thought regarding potential
future advances.
Vancouver, Canada
Frankfurt, Germany
Evanston, USA
Charles D. Blanke
Claus Rdel
Mark S. Talamonti
Contents
1 Imaging in Gastrointestinal Cancer.....................................................................

Minsig Choi and Anthony F. Shields
2 Interventional Gastrointestinal Oncology........................................................... 21

Jennifer Chennat and Irving Waxman
3 Practical Gastrointestinal Oncology Correlative Science.................................. 43
Kay Washington and Christopher L. Corless
4 Esophageal Cancer................................................................................................ 67
Florian Lordick and Arnulf Hlscher
5 Gastric Cancer....................................................................................................... 101
John S. Macdonald, Scott Hundahl, Stephen R. Smalley,
Denise ODea, and Edith P. Mitchell
6 Gastrointestinal Stromal Tumors......................................................................... 139
John R. Zalcberg, Desmond Yip, Christine Hemmings,
Bruce Mann, and Charles D. Blanke
7 Multimodality Management of Localized and Borderline
Resectable Pancreatic Adenocarcinoma.............................................................. 173
Michael B. Ujiki, William Small, Robert Marsh, and Mark S. Talamonti
8 Unresectable Pancreatic Cancer........................................................................... 205
Daniel Renouf, Laura A. Dawson, and Malcolm Moore
9 Liver Cancer........................................................................................................... 225
Joseph D. Thomas, George A. Poultsides, Timothy M. Pawlick,
and Melanie B. Thomas
10 Carcinoma of the Biliary Tract............................................................................. 251
Sean P. Cleary, Jennifer Knox, and Laura Ann Dawson
vii
viii
Contents
11 Neuroendocrine Cancers....................................................................................... 301

John A. Jakob, Carlo Mario Contreras, Eddie K. Abdalla,
Alexandria Phan, and James C. Yao
12 Colon Cancer.......................................................................................................... 325
Sharlene Gill, Carl Brown, Robert Miller, and Oliver Bathe
13 Rectal Cancer......................................................................................................... 379
Claus Rdel, Dirk Arnold, and Torsten Liersch
14 Anal Cancer............................................................................................................ 423
Rob Glynne-Jones and Suzy Mawdsley
Index ............................................................................................................................. 451
Imaging in Gastrointestinal Cancer
Minsig Choi and Anthony F. Shields
1.1
Introduction
Imaging has been an essential part of oncology since the discovery and use of X-rays by
Roentgen. Gastrointestinal (GI) oncology has made extensive use of a number of imaging
approaches which utilize X-rays, including plain films, contrast placed in the intestinal
tract for barium swallows, upper gastrointestinal (UGI) series, barium enemas (BE), and in
the last three decades, the extensive use of computed tomography (CT). A number of other
techniques are now routinely employed including ultrasound (US), magnetic resonance
imaging (MRI), and positron emission tomography (PET). Most imaging modalities provide adequate anatomic and structural images of cancer patients. Recent technological
advances in functional imaging bring new insights to cancer staging and early monitoring
of treatment response. This chapter concentrates on some of the new approaches to imaging and the application of older approaches where active research is being done in screening, diagnosis and staging, monitoring treatment, and surveillance in GI cancers. It also
focuses on PET and PET-CT scans and novel ways of utilizing these methodologies to
improve the clinical outcomes in GI cancer patients.
1.2
Screening
Screening of GI cancers has most commonly been done using endoscopic procedures, since
one can visualize the tumors, biopsy the lesions, and even remove small lesions at the same
time. This approach has been the standard of practice in the upper GI tract in populations
M. Choi
Karmanos Cancer Institute, Wayne State University School of Medicine
A.F. Shields (*)
Karmanos Cancer Institute, Wayne State University School of Medicine,
4100 John R Street, HW04HO, Detroit, MI 48201-2013, USA
e-mail: shieldsa@karmanos.org
C.D. Blanke et al. (eds.), Gastrointestinal Oncology,
DOI: 10.1007/978-3-642-13306-0_1, Springer-Verlag Berlin Heidelberg 2011
M. Choi and A.F. Shields
and patients with high risk of esophageal and stomach cancers. In the lower GI tract, colorectal cancer screening has employed a number of techniques including fecal blood testing, stool DNA analysis, colonoscopy, X-rays with BE, and more recently, CT
colonography.
1.2.1
Colon Cancer Screening
In recent years, colonoscopy has almost completely replaced BE for screening the entire
colon, since colonoscopy has a higher sensitivity for cancer (95 and 82.9% in colonoscopy
and BE, respectively) and more readily detects polyps (Rex et al. 1997; Rockey et al.
2004). Furthermore, an abnormal barium study generally requires a subsequent colonoscopy to obtain a biopsy or remove small polyps. The advent of CT colonography (also
called virtual colonoscopy) may change the routine screening paradigm once again, but
this remains an area of very active research. CT colonography allows one to obtain highresolution images of the colon that include the usual cross-sectional images and, in addition, one can obtain three-dimensional endoluminal views. A number of studies have
analyzed the sensitivity and specificity of CT colonography and a meta-analysis of 24
studies with 4,181 patients, published between 1994 and 2003, found a sensitivity of 93%
(95% confidence interval [CI]: 73%, 98%) and specificity of 97% (95% CI: 95%, 99%) for
lesions >1 cm (Halligan et al. 2005). Another meta-analysis of 30 studies, published
between 1997 and 2005, found that CT colonography had a sensitivity of 82% for polyps
over 10mm (95% CI: 7688%) (Rosman and Korsten 2007).
It should be noted that these meta-analyses included older studies and the methods used
for CT colonography have been evolving over time with continuous software improvement. In fact, most of the studies in these meta-analyses primarily used 2D reconstruction
for the initial evaluation. Furthermore, these studies took the optical colonoscopy as the
gold standard. A study by Iannaccone etal. (2005) involved 88 patients who initially
underwent CT colonography and standard colonoscopy on the same day, where the observers were unaware of the results of the other studies. The patients then underwent a repeat
colonoscopy within two weeks by an endoscopist who had knowledge of the first examinations and this final evaluation served as the reference. On a per-polyp basis, for lesions
6mm, the sensitivities of CT colonography and colonoscopy were 86 and 84%, respectively. On a per-patient basis the sensitivities of CT colonography and colonoscopy were
84 and 90%, respectively. While lesions less than 6 mm were difficult to detect by CT
colonography, for lesions 6mm the two approaches were comparable.
CT colonography is now regularly reimbursed for patients who have incomplete
colonoscopies in the United States. For routine screening, payment by Medicare was
denied in 2009 because of concern that most of the comparative studies were conducted in
patients under the age of 65. While the cost of CT colonography is less than a colonoscopy,
the fact that an abnormal CT colonography study mandates colonoscopy lessens the advantage somewhat. In the study by Johnson etal., 17 and 12% of patients had lesions 5 or 6
mm, respectively, and would require colonoscopy depending on the chosen threshold.
With the CT colonography threshold set at 5mm, the positive predictive value for the test
1 Imaging in Gastrointestinal Cancer
was 0.45 for adenomas 5mm or cancer. Concerns about the radiation dose have also been
raised, along with the cost and complications associated with the evaluation of extracolonic findings of unknown significance found on the CT scans. Overall 66% of the patients
had extracolonic findings, but fortunately most were not thought to require further evaluation. The evaluation of extracolonic findings, which were needed in 16% of subjects in the
study by Johnson etal. (2008), will lead to added costs and patient anxiety.
One of the continuing issues is the need for complete bowel cleansing before CT
colonography, as it is done before colonoscopy. To decrease the number of false positive
CT colonography studies, patients are regularly given oral contrast after purging to help
differentiate retained stool from polyps (Johnson et al. 2008). Similar approaches have
been studied using minimal bowel preparation and combined fecal tagging. When compared to full preparation, these methods had sensitivities of 97 and 88%, respectively, for
polyps 6mm (Nagata etal. 2009). Investigators are working on software filters to improve
lesion detection and hence decrease the need for bowel cleansing (Oda et al. 2009). In
summary, CT colonography is already finding routine use, but further testing and refinement are in order. New techniques may allow for limited bowel preparation, which is
preferred by patients (Jensch etal. 2009).
1.2.2
Diagnosis and Staging
CT has been the standard for the diagnosis and staging of GI cancers over the last 30 years.
The CT scan has a sensitivity of 7590%, and a specificity of 8090% (McAndrew and
Saba 1999; Pasanen etal. 1992), and can elucidate important abdominal structures. CT
angiography can assess the relationship of the tumor to the neighboring major vessels.
MRI adds little information after conventional CT scans except for the hepatobiliary system. Its use has been defined in the individual disease chapters and is excluded from this
chapter.
1.2.3
PET Imaging: The Basics
PET scans are a noninvasive imaging modality utilizing positron emitting radioisotopes to
label molecules and create different images depending on the tissue concentrations.
18
F-Fluorodeoxyglucose (18F-FDG), an analog of glucose, is the most commonly used tracer
and accumulates more specifically in metabolically active cells like cancer. It capitalizes on
the distinctive feature of cancer, which has a higher glycolytic index known as the Warburg
(1956) phenomenon. Aside from high glucose utilization, most cancer cells have a higher
expression of the glucose transporter Glut-1 than normal cells (Aloj etal. 1999; Tohma etal.
2005). Inside the cell FDG is phosphorylated by hexokinase, but further glucose metabolism is prevented by the fluorine atom. Thus, FDG preferentially accumulates in the tumor
cells as illustrated in Fig.1.1. Detectors surrounding the patient during a PET scan capture
the degree of tumoral 18F-FDG. Its avidity is expressed using a standardized uptake value
Fig.1.1 When glucose enters the cell, hexokinases phosphorylate glucose into glucose-6-phosphate.
Glucose can undergo glycolysis producing CO2, water and energy. 18F-Fluorodeoxyglucose
(18F-FDG) follows the same pathway as glucose, but, after phosphorylation, 18F-FDG is not further
metabolized. Hence, FDG can preferentially accumulate in the tumor cells
(SUV). SUV is a semiquantitative measure of 18F-FDG uptake from PET images comparing
it to the normal physiologic distribution. SUVs are dependent on several parameters: blood
glucose level, tumor size, time after 18F-FDG injection, and spatial resolution of the images.
Although kinetic parameters of 18F-FDG-PET can be expressed using Patlak and compartmental modeling, the need for prolonged imaging and the complexity of such modeling has
limited most routine clinical studies to SUV quantitation to measure the activity of 18F-FDG
in cancer (Gjedde and Diemer 1983; Patlak etal. 1983).
18
F-FDG became a useful radiotracer since it has a longer half-life of 110min as compared to other radioisotopes. There are no pharmacologic adverse effects of the radiolabelled
FDG since it uses an extremely low amount of tracer (less than a micromole). The high sensitivity and specificity of PET imaging makes it a useful tool in the diagnosis and staging of
cancer patients (Bombardieri etal. 2001; Facey etal. 2007; Fletcher etal. 2008). Its reproducibility for quantitative metabolic measurements has been validated in malignant tumors
using FDG-PET (Minn etal. 1995; Weber etal. 1999). PET is now approved for use in the
United States for the initial staging of many cancers. Its use for restaging and assessment of
treatment response has not been approved for reimbursement for GI cancers originating in
the stomach, liver, pancreas, biliary tree, and small intestine, as well as neuroendocrine
cancers (http://www.cancerpetregistry.org/indications_facilities.htm) (National Oncology

PET Registry (NOPR) 2009; Avril etal. 2005; Avril and Weber 2005). Although the spatial
resolution for PET scans continues to improve, current resolution is approximately 0.5cm
and low-contrast dose can limit the detection of lesions two to four times larger. Hence, the
ability to detect subcentimeter lesions in oncology remains a challenge. Another limitation of
PET is its lack of ability to distinguish infectious or inflammatory conditions from cancer.
These acute conditions attract metabolically active granulocytes and monocytes that can lead
to false positive findings, particularly after surgery and radiation therapy. Additionally, physiologic 18F-FDG uptake by normal tissues can lead to false positive findings. Brain and heart
tissues in particular may have avid uptake (shortly after tracer injection) while moderate
uptake may be seen in the liver, spleen, and GI tract. Finally, the FDG is excreted by the
urinary system. Some other areas that can have increased physiologic uptake include muscles
and brown fat and lymphatic tissues. The sensitivity of these areas may often be suboptimal
when the patient has recently exercised stimulating muscles, or has had an infectious or
inflammatory condition leading to activity in lymphatic tissues.
The emergence of PET-CT has improved the confidence and accuracy of PET imaging
because it can delineate clear anatomic relationships in areas with FDG activity.
Increasingly, PET-CT is replacing dedicated PET devices in the United States and currently almost all of the new units being sold are combined PET-CT machines. Other advantages of PET-CT are its ability to perform both tests at a single convenient time point, and
better-resolution images are provided as compared to fused images. Due to its recent emergence, clinical outcome using long-term survival data are not available for patients who
were staged using PET-CT.
1.2.4
PET in Staging GI Cancers
At this point, PET is only routinely done for staging prior to surgery in GI oncology
patients with esophageal cancer. For other GI cancers, PET is regularly employed as a
problem-solving tool to assist in staging when other clinical or imaging studies suggest
that the patient may have more widespread disease. The role for PET scans in staging
esophageal cancer is derived from multiple studies demonstrating changes in the clinical
decision in patients planned for surgical intervention (Flamen etal. 2000; Kato etal. 2005;
van Westreenen et al. 2004). As esophagectomy has an operative mortality of 410%,
avoiding surgical intervention in patients with distant metastasis who will not benefit from
surgery is paramount (Enzinger and Mayer 2003). However, PET scans are noted to be
inferior to endoscopic ultrasound (EUS) in local and regional lymph node (LN) staging
with a sensitivity of 51% and specificity of 84%. Sensitivity for PET in detecting distant
metastasis is 67% and specificity of 97% (van Westreenen etal. 2004). PET is regularly
used in conjunction with CT scans and endoscopic US for staging esophageal cancer.
PET-CT has been shown to improve sensitivity, specificity, and accuracy in staging esophageal cancer patients. Recent data show a sensitivity of 93.9%, specificity of 92%, and
accuracy of 92% in patients with locally advanced squamous esophageal cancer (Yuan
etal. 2006). In most of the recent clinical studies, PET can detect unsuspected metastatic
disease in 1520% of patients, consequently changing the management approach to those

patients (Flamen etal. 2000; Kato etal. 2005; van Westreenen etal. 2004).
Staging of gastric carcinoma using PET is complicated by the high physiologic uptake
of FDG in normal gastric mucosa. Sensitivity of primary tumors varies from 58 to 94%
with specificity of 78100% (Dassen etal. 2009). The wide ranges of sensitivity and specificity may be related to the location and tumor histology. Proximal gastric cancers behave
like esophageal cancer and are easily detected with PET while tumors in the distal stomach
have a low sensitivity. Tumor histology can also affect the PET sensitivity; tumors with
diffuse subtype and mucinous adenocarcinoma have a low sensitivity due to the small
concentration of active cancer cells compared to its background. Up to 30% of gastric
cancers may not be assessed with PET (Ott etal. 2008; Stahl etal. 2003). Overall, locoregional staging using PET is poor with a sensitivity of 28% as compared to CT scan with a
sensitivity of 68%, but with a higher specificity of 96% (Dassen etal. 2009). Limited studies done on PET for gastric cancer distant staging shows a sensitivity of 6785% and
specificity of 7488% (Yoshioka etal. 2003).
PET has a limited role in the initial staging of patients with colorectal cancer and currently
is not routinely used if metastatic disease is not suspected based on CT or other studies. The
benefit and risk ratio for surgical intervention in colorectal cancer is high and the morbidity is
low. Additionally, precancerous adenomatous polyps also demonstrate higher FDG uptake
and PET is not sensitive for locoregional staging. It is a useful test for patients with potentially
resectable hepatic metastasis and in those with recurrent disease. PET can detect additional
systemic metastasis and can be helpful in preventing futile laparotomies. Figure1.2 illustrates
Fig.1.2 Fused positron emission tomography/computed tomography (PET/CT) scans (a, c) and
PET alone (b, d) of a patient with a lesion seen in the rectum (images c, d) and in the liver (images
a, b). Because of an elevated creatinine the routine CT scan was done without contrast and did not
show this liver lesion, although a larger lesion in the dome was visualized (not shown)
a patient with recurrent rectal cancer with three liver lesions. The sensitivity of PET for hepatic
lesions is 92% and specificity is high at 96% while CT has a sensitivity of 83% and specificity
of 84% (Wiering etal. 2005). PET also has a sensitivity of 91% and specificity of 98% in
detecting extrahepatic lesions as compared to 61 and 91% for CT. In a number of clinical studies, PET has been shown to alter therapeutic management in 2032% of patients with potentially resectable metastatic disease. These changes include avoidance of surgery, initiation of
palliative chemotherapy, or change in the extent of surgical interventions. PET is not helpful
in detecting lesions less than 1cm and in patients with peritoneal carcinomatosis. A recent
randomized trial was done to compare the outcome in patients with potentially resectable liver
metastases. Patients underwent routine staging with or without PET prior to planned surgery.
Overall PET was found to decrease the number of futile surgeries by 38%. With routine CT
evaluation of 75 patients who went to surgery, 34 (45%) were found to have unresectable
disease or recurred within 6 months. When PET was included 21 of 75 (28%) patients had
unnecessary surgery (Wiering etal. 2005; Ruers etal. 2009). Compared to the use of dedicated
PET devices, data on the utilization of PET-CT are evolving; PET-CT in most clinical scenarios leads to a change in patient management in 1121% (Lubezky etal. 2007; Rappeport
etal. 2007; Selzner etal. 2004).
In pancreatic cancer, even pancreaticoduodenectomy (Whipple procedure) cures only a
tiny fraction of patients. This procedure has a high surgical and postoperative mortality of up
to about 5%. Overall evidence shows that PET can be beneficial, mostly by avoiding futile
surgeries. PETs sensitivity is 91% and its specificity is 86% (BCBS 2000). PET is also a
useful tool in the initial work-up of pancreatic masses of unknown origin (Heinrich etal.
2005; Sperti etal. 2007). Masses with increased FDG retention are more likely to be cancer,
but inflammatory conditions can also be visualized with PET. On the other hand, PET can
miss some mucinous tumors and those with extensive fibrosis. Table1.1 summarizes the
sensitivity and specificity of PET scan in staging for different GI cancers.
In liver and hepatobiliary cancers, FDG-PET is not helpful in staging and surveillance.
Hepatocellular cancer (HCC) shows poor uptake of FDG due to a high level of glucose6-phosphatase, which is responsible for dephosphorylating 18F-FDG (Garcea etal. 2009).
Only 3060% of primary HCC have avid FDG uptake (Okazumi etal. 1992). PET still
Table1.1 Sensitivity and specificity of positron emission tomography (PET) scan in gastrointestinal
cancers
Site
Staging
Sensitivity
Specificity
References
Esophagus
Locoregional
Distant
51% (3469)
67% (5876)
84% (7691)
97% (90100)
van Westreenen etal. (2004)
Stomach
Locoregional
Distant
27.5% (1846)
6785%
96% (91100)
7488%
Dassen etal. (2009)
Liver
Whole body
61%
NA
Park etal. (2008)
Colorectum
Hepatic lesion
Extrahepatic
88% (8595)
92%
96%
95%
Wiering etal. (2005)
Colon
Whole body
85%
90%
Wiering etal. (2005)
Pancreas
Whole body
91%
86%
BCBS (2000)
may be useful in patients at risk for HCCs who have a rising alpha-fetoprotein. In such
patients liver scarring and regeneration may hide a growing tumor on routine CT and
MRI. A positive PET scan may help direct biopsies, but a negative scan does not rule out
cancer. A recent Korean study shows that FDG-PET has a sensitivity of 61%, which could
be improved to 83% using dual tracer imaging using 11C-acetate (Park et al. 2008).
However, performance of PET remained poor in small and well-differentiated tumors.
Future studies with dual tracer imaging may prove to be valuable in PET for primary
hepatobiliary tumors.
1.3
Monitoring Response to Treatment
The recent advances in targeted therapy for cancer have led to individualized therapy for
cancer patients based on molecular and other biomarkers. Monitoring such therapies itself
may affect the clinical outcome. Normal CT and MRI scans measure anatomic changes to
current treatment and such changes have been monitored through either the World Health
Organization (WHO) classification or response evaluation criteria in solid tumors
(RECIST) (Miller et al. 1981; Therasse et al. 2000). WHO classification defines tumor
measurement by utilizing the product of two perpendicular diameters (bidimensional) as
criteria for measurement. It groups response into four different categories: complete
response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).
Complete radiologic disappearance without any new lesions was considered CR. A 50%
decrease in size is considered PR while a 30% increase in size was deemed progression of
disease. Anything that does not meet the above criteria is considered SD (Miller et al.
1981). RECIST uses unidimensional measurement to simplify the monitoring and has
been validated in recent clinical studies (Therasse etal. 2006). When multiple measurable
tumors are noted, each measurement is added. Response is reported as PR if there is more
than a 30% decrease in unidimensional diameter and PD if more than 20% growth is noted
(Therasse etal. 2000). The RECIST working group reviewed 6,500 patients and more than
18,000 lesions to find out how the criteria affect patients and overall outcome. In 2009, the
group came up with RECIST 1.1, decreasing the number of maximum target lesions from
10 to 5 (five to two per organ) and defined criteria for measuring LNs using the short axis.
RECIST 1.1 also adds new lesions on FDG-PET as PD, incorporating new technology to
the RECIST (Eisenhauer etal. 2009).
Both WHO criteria and RECIST offer simple approaches to determine anatomic size
and tumor changes during a therapeutic treatment as an indicator of response. Although
RECIST has been validated to correlate with clinical outcome, these responses have
been correlated to neither pathologic response nor survival outcome in certain GI cancers. In pancreatic cancer, for example, use of doublet therapy produces a higher
response rate than does the use of gemcitabine alone, but no difference in overall survival is noted in multiple phase III trials (Oettle etal. 2005; Rocha Lima etal. 2004).
Most trials in pancreatic cancer continue to use survival as the primary endpoint.
Similarly, studies demonstrate that RECIST cannot accurately demonstrate clinical
benefit in patients with GI stromal tumors (GIST) treated with imatinib (Benjamin etal.
2007; Choi etal. 2007).
Cellular degradation and reconstruction of tumor tissue is the final step in treatment,
making early monitoring difficult using anatomic images. The recent use of targeted therapies has led to other cutoffs to evaluating response, since tumor shrinkage may not be seen
and disease stabilization is more common. Studies of drug development now include
waterfall plots where the change in tumor size at a specified time or greatest change in size
may be plotted (Arnold et al. 2008; Ratain et al. 2006). Instead of categorizing tumor
response to arbitrary categories, waterfall plots measure change in tumor size as a continuous variable. Patients with limited tumor growth are considered to benefit from such a
treatment even in the absence of major tumor shrinkage. Further improvements in both
morphologic and functional imaging are clearly needed for better monitoring of patients
with GI cancers.
Early treatment monitoring is crucial to avoid toxicity and the costs associated with
ineffective therapy. Furthermore, improved measurements may provide for the earlier use
of alternate therapies to impact clinical outcome. PET data suggest the amount of FDG
uptake in tumor cells is correlated with the number of viable cancer cells. Hence, decline
in FDG-PET avidity is hypothesized to represent a decrease in the number of viable cancer
cells, though it might also represent a transport phenomenon. This concept has been tested
for PET in early assessment of cancer treatment in esophageal, breast, and head and neck
cancers (Juweid and Cheson 2006). Wahl et al. recently reported new response criteria
incorporating PET for monitoring cancer treatment, naming the system PET evaluation
criteria in solid tumors (PERCIST) (Wahl et al. 2009). Actual usage of PERCIST will
require validation studies in GI cancer and its treatments. If further studies could refine the
use of PET in monitoring and correlate its results to clinical outcome, such progress will
improve the current concept of individualizing therapy.
1.3.1
Use of FDG-PET in Monitoring Early Response to Treatment
1.3.1.1
Esophageal Cancer
Recent clinical trials have shown that the use of neoadjuvant chemotherapy and chemoradiotherapy for locally advanced gastroesophageal cancer improves overall survival.
Monitoring early response to therapy is important in this disease since patients responding
to neoadjuvant therapy have better clinical outcomes than nonresponding patients. Weber
et al. studied 37 patients with locally advanced gastroesophageal cancer who received
neoadjuvant chemotherapy. FDG-PET was done at baseline and on day 14 of the first cycle
of chemotherapy. The percentage change in SUV was more prognostic than the absolute
value of SUV. Patients with more than a 35% decrease in SUV were considered PET
responders while those who had less were considered nonresponders. The two-year survival and overall survival rates of PET responders were 49% and >48 months, respectively, as compared to 9% and 20 months, respectively, for nonresponders (p=0.04).
10
Thesame group assessed 44 patients with locally advanced gastric cancer. A similar outcome was noted; PET responders had survival of >48 months while nonresponders had 17
months (p=0.001) (Weber et al. 2001). Nine patients did not have PET activity in the
baseline and were excluded from further analysis. Wieder etal. evaluated 27 patients with
neoadjuvant chemoradiotherapy and used 30% SUV changes as criteria for PET response.
PET responders had median overall survival of >38 months as compared to 18 months for
nonresponders (Wieder et al. 2004). Other similar studies assessing treatment response
using PET for gastroesophageal cancer are listed in Table1.2.
A multi-institutional study testing the feasibility of PET-guided therapy in gastroesophageal cancer was conducted by Lordick etal. This study enrolled 110 patients with gastroesophageal cancer and the PET scan was done at 2 weeks after induction chemotherapy was
used to identify patients with metabolic response. Metabolic responders were predefined
as patients with SUV decrease of more than 35% from baseline. Patients who were metabolic responders continued to receive chemotherapy for 12 weeks while nonresponders
discontinued chemotherapy and immediately had surgical resection. The median overall
survival for metabolic responders was not reached, whereas median overall survival for
nonresponders was 25.8 months (p=0.015) (Lordick etal. 2007). The study also demonstrated a correlation of metabolic responders and pathologic response. Major histopathologic regression (Ia or Ib) was seen in 59% of patients who were metabolic responders but
no histopathologic regression was seen in PET nonresponders. These findings may enable
future clinical trials to utilize PET scans to tailor multimodality therapy for gastroesophageal cancers.
1.3.1.2
Colorectal Cancer
There have been several small studies assessing PET in monitoring patients with colorectal
cancers. Findlay etal. monitored 18 patients with colon cancer and liver metastasis who were
treated with infusional 5FU and interferon. Although the tumorliver ratio and SUV did not
correlate with treatment response at 12 weeks, more than 15% decrease in tumorliver ratio
at 45 weeks was able to predict the ultimate response as measured by CT (done later in treatment) with a sensitivity of 100% and specificity of 90% (Findlay etal. 1996). No survival data
were available for responders vs. nonresponders. Most of the other small studies investigated
2030 patients who received chemoradiotherapy for rectal cancer and investigated different
PET parameters and pathologic response. Guillem etal. reported a long-term outcome of 15
patients with locally advanced rectal cancer treated with 5FU-based chemoradiotherapy and
usage of PET monitoring. An SUV change from baseline and at 5 weeks after chemoradiotherapy of less than 62.5% was predictive of disease recurrence (Guillem etal. 2004). Capirci
etal. conducted the largest study, which investigated 81 patients with stage II and III rectal
cancer who received neoadjuvant chemoradiotherapy. PET done at 1 month after completion
of CRT had a sensitivity of 45% in detecting patients with complete pathologic response and
specificity of 78% (Capirci etal. 2004). PET accuracy was only 56% and there were no survival data for comparison. Table 1.3 lists recent investigations using PET for response in
colorectal cancer. Overall, utilization of PET for colorectal cancer treatment is still in the
preliminary stage and further experimental trials are needed to further elucidate its usage.
37
36
17
27
35
110
Weber etal. (2001)
Flammen etal. (2000)
Downey etal. (2003)
Wieder etal. (2004)
Ott etal. (2003)
Lordick etal. (2007)
Chemotherapy
Chemotherapy
Neoadjuvant
chemoradiotherapy
Chemoradiotherapy
Chemoradiotherapy
Chemotherapy
Table1.2 Treatment response using FDG-PET for gastroesophageal cancer

References
Treatment
n
35
35
30
52
80
35
Criterion
(change in
SUV) (%)
>48
>48
>38
22.5
16.3
>48
Responder
(months)
25.8
17
18
6.7
6.4
20
Nonresponder
(months)
0.015
0.001
0.011
0.001
0.02
0.04
p Value

11
12
Table1.3 Treatment response using FDG-PET for colorectal cancer

References
Treatment
Criterion
n
Comments
Amthauer etal. (2004)
20
Chemoradiotherapy
with regional
hyperthermia
36% reduction
in SUV
Correlated with
tumor response
Calvo etal. (2004)
25
CRT
SUV max
change
SUV max correlated

to survival at 3 years
Capirci etal. (2004)
81
CRT
Five point
visual scale
Sensitivity = 45%
Specificity = 79%
DimitrakopoulouStrauss etal. (2003)
28
FOLFOX
chemotherapy
SUV not helpful
Fractal dimension
of time activity with
SUV was helpful
Guillem etal. (2004)
15
CRT
62.5% change
in SUV
p=0.08
Melton (2007)
21
Neoadjuvant
treatment
75% reduction
in SUV
Multiple parameters
including CT
volume changes
1.3.1.3
GI Stromal Tumors
GISTs are mesenchymal neoplasms that generally express CD117, the product of the KIT
proto-oncogenes. GISTs have high metabolic activity related to increased glycolysis and
have been noted to have extremely high FDG-avidity. In patients treated with imatinib,
PET can show changes as early as 24h after the treatment (Abbeele 2001). Stroobants
etal. studied 21 patients with sarcomas treated with imatinib and found that PET responders (SUV change >25%) after eight days of treatment had longer progression-free survival compared to nonresponders (92 vs. 12% at 1 year p=0.001) (Stroobants et al.
2003). Antoch et al. studied 20 patients with advanced GIST and demonstrated that
PET-CT correctly characterized the ultimate tumor response in 95% at 1 month as compared to 44% using CT scan (Antoch etal. 2004). In these limited studies, combining
both morphologic and functional imaging provides additional information in patients
with advanced GIST.
For a variety of reasons, RECIST used in monitoring systemic treatment for GIST does
not correlate well with clinical outcome. These include actual enlargement of tumors with
successful therapy (related to cystic change) and subsequent long delays in achieving
actual shrinkage. Choi etal. reviewed 40 patients with metastatic GISTs treated with imatinib and proposed newer criteria including both anatomic and tumor density criteria to
improve the sensitivity of monitoring patients. The group demonstrated that a 10% decrease
in unidimensional tumor size and 15% decrease in tumor density can better predict time to
tumor progression than RECIST criteria (Choi etal. 2007). This was further validated by
an additional 58 patients treated with imatinib in advanced GIST patients (Benjamin etal.
2007). Since newer CT criteria have similar findings compared with PET in advanced
13
GIST patients, the relative merits of PET are unclear. But in patients with borderline resectable GIST and in patients with extensive tumor burden, early assessment of therapy with
PET may provide an earlier opportunity to offer alternative therapy in these patients.
1.4
Surveillance
1.4.1
Surveillance After Potentially Curative Resection
The role of surveillance studies in patients with resected cancer is to detect early recurrences of the original disease, which may be curatively resected, to detect systemic recurrence, which may benefit from drug therapy while metastatic burden is still relatively
small, and to detect new primary cancers, which are amenable to curative resection. These
simple goals must be kept in mind when choosing the best evaluation scheme for following
such patients, particularly for said middle group. Few data exist to demonstrate that the
early detection of asymptomatic, advanced cancer leads to significant improvement in
survival, in GI or other solid malignancies. However, passive monitoring, especially without radiographic surveillance, is often difficult to explain to patients.
Colorectal cancer surveillance has been found to be useful in some studies because
patients may develop metastatic disease, particularly to the liver or lungs, which is amenable to resection for cure. Local recurrence in the bowel or second cancers in the colon
may also be detected and these can also be removed with curative intent. Standard guidelines now indicate that CT evaluation of the chest and abdomen be done yearly for the first
3 years after resection (Desch etal. 2005). This guideline is based on three separate metaanalyses, which demonstrated that CT surveillance produced a 2033% decrease in death
rates (Figueredo etal. 2003; Jeffery etal. 2002; Renehan etal. 2002). A study by Chau
etal. (2004) demonstrated that CT scans complemented testing for carcinoembryonic antigen (CEA). While the optimal scheme for surveillance continues to evolve, physicians are
generally adopting a reasonable scheme to detect treatable, recurrent disease.
Future studies may also examine the use of PET combined with routine CT in the surveillance of patients with resected colorectal cancer. One small study randomized 130
patients to routine imaging, which included US every 3 months, chest X-ray every 6
months and abdominal CT at 9 and 15 months. To this series of tests, the investigators
added PET (not PET/CT) at 9 and 15 months after resection (Sobhani etal. 2008). Patients
in the PET group had recurrence detected earlier (12.13.6 months) than in the control
group (15.44.9 months) (p=0.01). The patients with recurrence in the PET group underwent surgery with curative intent in 10 of 23 cases while only 2 of 21 had such surgery
after routine evaluation (p<0.01). Further study of this approach is warranted.
The role of imaging in the routine surveillance after resection of esophageal, gastric,
biliary, and pancreatic cancers is not well defined since there is lack of objective data. For
gastric cancer, the National Comprehensive Cancer Network (NCCN) guidelines only suggest imaging when clinically indicated. On the other hand, the NCCN guidelines suggest
14
Fig.1.3 CT scan of a patient with recently diagnosed large gastric gastrointestinal stromal tumors
(GIST) and liver metastases (a). The patient underwent resection of the stomach lesion due to
bleeding and was then started on imatinib. A repeat CT scan about 11 months later (b) shows that
the largest lesion has remained stable in size, but decreased in density and other low-density lesions
have become apparent elsewhere in the liver consistent with a response to treatment
that pancreatic cancer patients, after potentially curative resections, may have CT scans
every 36 months for 2 years and then annually. Given the low likelihood that any detectable disease would be amenable to surgery with curative intent, this approach is expected to
produce little clinical benefit.
Patients with extensive disease metastases not eligible for curative approaches, no longer need to have other follow-up tests. For example, patients with extensive liver metastases may continue to have regular CT scans and CEA levels drawn to monitor treatment
response, but tests directed at finding new primary cancers, such as colonoscopies, are no
longer necessary. Similarly, patients with other life-limiting diseases, be they cardiac dysfunction, severe chronic obstructive lung disease, dementia, or another metastatic cancer
will not benefit from surveillance for their cancers and do not require extensive testing
with imaging or serum markers (Fig.1.3).
1.5
Summary
Routine and innovative imaging approaches are used for screening, diagnosis and staging, monitoring treatment, and surveillance in GI cancers. While screening endoscopy
has been the standard for diagnosing most GI tumors, noninvasive CT colonography
has evolved and is beginning to find routine use in practice. The sensitivity and specificity of CT colonography are 93% (7398%) and 97% (9599%), respectively, for
lesions >1 cm. The main limitation for CT colonography is that an abnormal CT
colonography study mandates colonoscopy. Further testing in the elderly group and
refinement in technology would make CT colonography more useful in general
practice.
15
For diagnosis and staging, the CT scan has been the backbone of imaging over the last
30 years. Functional imaging modalities, such as PET scans, are now employed as an
added tool to assist in the diagnosis and staging of GI cancers. PET helps detect more
widespread disease so futile surgical interventions can be avoided. In most of the recent
clinical studies, PET can detect unsuspected metastatic disease in 1520% of esophageal
cancer patients, consequently changing the management approach to those patients. These
changes include avoidance of surgery or initiation of palliative chemotherapy. Similar
findings were noted for some studies of colorectal and pancreatic cancers. With these data,
PET has been adopted for routine staging for esophageal cancers and data are evolving in
other GI cancers.
Clinical trials data using functional imaging for early treatment monitoring for GI cancers are limited. The best data are in esophageal cancer, where a multi-institutional study
showed that PET done at 2 weeks after induction chemotherapy could be used to identify
patients with metabolic response. The PET responders had improvement in overall survival and pathologic response at the time of surgery. Another area of utility for early treatment monitoring could be in patients with borderline resectable GIST with extensive tumor
burden. PET may provide an earlier opportunity to offer alternative therapy in these
patients. Future clinical trials using functional imaging may enable clinicians to provide
rapid adjustments to therapy for each patient.
The role of surveillance in patients with resected cancer is to detect early recurrence,
which is amenable to curative resections. In three separate meta-analyses, CT surveillance
for colorectal cancer patients produced a 2033% improvement in overall survival. CT
scans complement testing with CEA. Hence, for high-risk patients with stage II and III
colorectal cancer who underwent surgical resection, an annual CT, along with regular
serum CEA and colonoscopy is recommended. PET CT may be more useful in this setting;
however, data are evolving and further studies using PET CT in surveillance are warranted. Ultimately, the proper application of all available imaging technology will render
improved clinical outcomes in GI cancer patients.
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Interventional Gastrointestinal Oncology
Jennifer Chennat and Irving Waxman
2.1
Endoscopic Mucosal Resection
Endoscopic mucosal resection (EMR), initially developed in Japan to treat early gastric
cancer, has evolved into a minimally invasive alternative treatment approach for early
cancers throughout the upper and lower gastrointestinal tract. This endoscopic technique
involves removal of affected mucosal tissue, in most cases with the use of preresection
saline injection lifting of the target lesion to separate it from the submucosal layer. The
lesion is most often removed with an endoscopic snare that applies electrocautery. The
advantage of EMR is the added information provided by deeper en-bloc resection specimens for histological analysis.
The standard treatment of Barretts esophagus (BE) with high-grade dysplasia (HGD)
has been esophagectomy, due to the previously estimated 40% pooled risk of harboring
occult invasive adenocarcinoma (Ferguson and Naunheim 1997; Pellegrini and Pohl 2000).
However, more recent analysis of the literature points toward a much lower rate of invasive cancer at 12% (Konda etal. 2008). Intramucosal cancer (IMC) in the setting of BE has
also traditionally been treated by esophagectomy, despite a relatively low incidence of
lymph node metastasis of less than 1%, associated with noninvasive, T1a disease (Buskens
etal. 2004; Pech etal. 2008; Stein etal. 2005). The use of EMR to treat focal areas of BE
with HGD/IMC has been reported in several prior studies. However, focal resection solely
of neoplastic areas has been associated with a high rate of synchronous and recurrent
lesions noted by various groups, ranging from 14 to 47%, and increasing with longer
observation times (Ell etal. 2000; Nijhawan and Wang 2000; May etal. 2002a, b; Pech
etal. 2003; Larghi etal. 2005; Mino-Kenudson etal. 2005). With these issues in mind,
circumferential endoscopic resection of BE has been utilized with promising results by
J. Chennat
Assistant Professor of Medicine, The Center for Endoscopic Research & Therapeutics (CERT),
Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center,
5758 S. Maryland Avenue, MC 9028, Chicago, IL 60637, USA
e-mail: jchennat@medicine.bsd.uchicago.edu
I. Waxman ()
Center for Endoscopic Research and Therapeutics (CERT), University of Chicago
Medical Center, 5758 S. Maryland Avenue, MC 9028, Chicago, IL 60637, USA
e-mail: iwaxman@medicine.bsd.uchicago.edu
21
22
J. Chennat and I. Waxman
select groups with the curative intention to eradicate all Barretts epithelium thereby reducing or eliminating metachronous lesion development (Peters et al. 2006; Seewald etal.
2003; Giovannini etal. 2004; Larghi etal. 2007). EMR is the only endoscopic modality
which serves the dual function of curative potential and provision of more accurate histological staging. In our institution, EMR resulted in a 45% rate of upstaging or downstaging
of final BE neoplasia histology when comparing pre-EMR biopsies with resection specimens (Chennat etal. 2009) (Figs.2.1 and 2.2).
With respect to esophageal squamous cell carcinoma (SCC), EMR has been shown to
have similar rates of survival in patients with m3 or sm1 disease as compared to those who
underwent surgery (Kodama and Kakegawa 1998). Thus, EMR may be an acceptable
alternative particularly in patients at higher surgical risk (Shimizu etal. 2002). Follow-up
intervals for surveillance after esophageal EMR have not been clearly defined to date, and
should be performed in a protocol fashion.
The absolute indications for gastric EMR include well or moderately differentiated
mucosal adenocarcinoma without ulceration or with an ulcer scar smaller than 2cm for
Fig.2.1 Long segment Barretts esophagus with

high-grade dysplasia
Fig.2.2 Postendoscopic mucosal resection

(EMR) of long segment Barretts esophagus
with high-grade dysplasia
2 Interventional Gastrointestinal Oncology
23
superficially elevated lesions. These lesions have a negligible risk of lymph node metastasis. Poorly differentiated or signet ring cell morphology are contraindications to EMR
regardless of lesion size (Larghi and Waxman 2007). EMR has also been applied to early
neoplastic gastric lesions, with acceptable long-term outcomes, demonstrating a 1.9%
recurrence rate in a pooled series analysis of documented complete resections (Kojima
etal. 1998). However, the recurrence rate has been noted to be 18% in another series when
incomplete resection occurred (Ono etal. 2001).
The use of EMR for neoplastic duodenal lesions has been reported with less frequency
in the literature. Outcomes of larger series have demonstrated complete resection without
major complications in the setting of duodenal nonampullary adenomas with HGD or carcinoma (Ahmad etal. 2002; Oka etal. 2003) (Figs.2.3 and 2.4). The data on endoscopic
removal of ampullary early neoplastic adenomatous lesions generally recommend the
assessment of these lesions with endoscopic ultrasound (EUS) and endoscopic retrograde
cholangiopancreatography to exclude invasive or biliary/pancreatic ductal involvement
(Binmoeller etal. 1993). Long-term success rates of EMR of these lesions have been documented in the range of 7080%, but careful endoscopic surveillance is still mandated for
follow-up (Catalano etal. 2004).
Colonic polypoid and nonpolypoid lesions with evidence of HGD or intramucosal carcinoma have been shown by various studies to be successfully treated by EMR technique,
with recurrence rates ranging from zero to 15% (Caputi Iambrenghi etal. 2009; Kudo1993;
Fig.2.3 Duodenal adenoma
Fig.2.4 Postendoscopic mucosal resection of

duodenal adenoma
24
Fig.2.5 Tubulo-villous adenoma in the

rectum
Fig.2.6 Postendoscopic mucosal resection of

tubulo-villous adenoma in the rectum
Kudo etal. 2000) (Figs.2.5 and 2.6). Lateral spreading tumors of the colorectum, which
have different clinicopathologic features, have also been successfully addressed by EMR
techniques (Hurlstone etal. 2004; Tanaka etal. 2001). Procedure-related complications
such as bleeding and even perforation in certain cases can be successfully managed endoscopically (Raju 2009).
2.2
Endoscopic Submucosal Dissection
Due to concern about incomplete lesion resection via EMR, endoscopic submucosal dissection (ESD) has been developed and utilized particularly by the Japanese for more complete and extensive endoscopic resections (Figs.2.72.10). Although the risk of perforation
is higher with ESD vs. EMR, the safety profile and efficacy of ESD in patients with
advanced age or poor performance status has been published (Hirasaki etal. 2005). ESD
also has been utilized successfully in scenarios where prior EMR has been incomplete,
leaving residual neoplasia in place. However, the use of ESD in locations where prior
EMR has been attempted can be technically more challenging and less feasible due to tissue fibrosis formation (Yokoi etal. 2006).

Fig.2.7 Intramucosal gastric cancer (T1)
involving the pylorus
Fig.2.8 Marking of desired endoscopic resection

margins
Fig.2.9 Postendoscopic submucosal dissection

(ESD) with pylorus preservation
25
26
Fig.2.10 Surveillance endoscopy 3 months

after ESD with expectant scar and no residual
cancer seen
2.3
Endoscopic Ultrasound
EUS and EUS-guided fine-needle aspiration (EUS-FNA) have together evolved into useful diagnostic and therapeutic modalities. Clinical management has been significantly
affected by the addition of FNA technique to this procedure. The overall complication rate
from EUS-FNA is less than 1% (Dye and Waxman 2002).
The accuracy and direct clinical impact of EUS-FNA is largely related to the availability of on-site cytopathology services. The clinical impact of on-site cytopathology in the
evaluation of EUS-FNA for suspected malignancy cases has been previously studied by
our center. A confirmatory diagnosis of positive or negative malignancy status was made
more frequently if on-site cytopathology interpretation was present, decreasing the likelihood of an inadequate specimen or need for repeat procedure. Resources for on-site cytopathology evaluation should be allocated by all EUS centers (Klapman etal. 2003).
2.3.1
Pancreatic Adenocarcinoma
The role of EUS-FNA has become increasingly prominent in the diagnosis and treatment
management of pancreatic adenocarcinoma (Figs.2.11 and 2.12). Larger series have found
that pancreatic adenocarcinoma EUS accuracy ranges from 78 to 94% for T stage disease
andfrom 64 to 82% for N stage disease (Varadarajulu and Eloubeidi 2005). Chang etal.
found that for pancreatic lesions, EUS-FNA had a sensitivity of 92%, specificity of 100%,
and diagnostic accuracy of 95% for pancreatic lesions and 83, 100, and 88% for lymph
nodes, respectively. Thus, with this level of accuracy, EUS-FNA peripancreatic N staging
has had a direct impact on the reduction of unwarranted surgical procedures for these cancer
patients, whom some authorities deem incurable by surgical resection (Chang etal. 1997).
EUS-FNA confers an added advantage over computed tomography (CT)-guided FNA
of pancreatic lesions regarding two aspects. Through its direct ultrasound visualization,
27
Fig.2.11 Pancreatic head

mass measuring 5.1 cm
visualized on endoscopic
ultrasound (EUS) imaging
Fig.2.12 EUS-guided fine

needle aspiration (FNA) of
pancreatic mass
EUS-FNA can safely target pancreatic lesions that are in close proximity to surrounding
vascular structures. EUS also characterizes lesions considered too small to be detected by
CT or magnetic resonance imaging (MRI) (Fig.2.1). EUS-FNA offers a valuable role as a
salvage diagnostic modality when CT-guided percutaneous FNA or endoscopic retrograde
cholagiopancreatography (ERCP) cytology brushing samples are negative, but a strong
clinical suspicion of pancreatic cancer persists (Fig.2.2) (Gress etal. 2001).
2.3.2
Pancreatic Cystic Lesions
Pancreatic mucinous cystic neoplasms have malignant potential, and therefore require a
differing management algorithm, often involving surgical resection. EUS-FNA derived
28
cytologic specimens in combination with cystic fluid tumor markers such as CEA (carcinoembryonic antigen) level help identify these lesions (Figs.2.13 and 2.14). In a study
which compared EUS-FNA diagnoses with final surgical pathology, FNA made an accurate diagnosis in 10/11 cases of pancreatic cystic lesions, with sensitivity and specificity
for detection of malignancy of 100 and 89%, respectively, while the accuracy for identification of mucinous cystic neoplasms was 100% (Moparty etal. 2007).
EUS-FNA cystic CEA levels have been purported to be the most accurate (79%) diagnostic method for mucinous cystic lesions of the pancreas (Brugge etal. 2004). A multivariate analysis study found that the strongest predictor of mucinous neoplasia is the
presence of identifiable mucin, followed by a CEA level greater than 300ng/mL. Presence
of extracellular mucin in cystic fluid. The determination of cystic fluid extracellular mucin
presence has also been recommended in the work-up of mucinous lesions (Shami etal.
2007). Despite the ongoing controversies surrounding which type of marker is the optimal
cystic diagnostic sample, EUS-FNA still serves an integral role in obtaining pancreatic
cystic fluid for analysis.
Fig.2.13 Intraductal papillary

mucinous neoplasm (IPMN)
seen on EUS
Fig.2.14 Characteristic major papilla

endoscopic fish eye appearance in the setting
of IPMN
29
2.3.3
Hepatobiliary Neoplasms
Recent studies have shown that EUS-FNA may have an adjunctive diagnostic role in the
work up of hepatobiliary cancers. In one study, 27 of 28 total patients had nondiagnostic
or equivocal sampling of their biliary lesions via ERCP, percutaneous transhepatic cholangiogram (PTC), and/or CT-guided biopsy. EUS-FNA demonstrated a positive impact
on management in 84% of total patients, by avoiding surgery for tissue diagnosis in
patients with inoperable disease, facilitating surgery in patients with unidentifiable cancer by other modalities, and avoiding surgery in benign disease (Eloubeidi etal. 2004).
In addition, EUS-FNA has an ancillary role in establishing M-stage disease in hepatic
metastasis states. When a lesion, particularly in the left hepatic lobe, is not amenable to
CT-guided or percutaneous biopsy, it oftentimes can been accessed transgastrically
(Nguyen etal. 1999).
2.3.4
Submucosal Gastrointestinal Lesions
The ability of EUS to differentiate the five-layer gastrointestinal wall anatomy is the fundamentally unique aspect of this modality (Figs.2.15 and 2.16). With the availability of
miniprobe EUS, lesions in the right colon can be assessed also via a standard colonoscope.
The accuracy rate for EUS-FNA of submucosal lesions is high (80%), and thus, potentially
affects clinical decision making (Arantes et al. 2004). Distinguishing true leiomyomas
from gastrointestinal stromal tumors (GISTs) has significant implications, as the two neoplasms have different prognoses and treatment options. Immunohistochemical findings
that define these lesions can be derived readily from cell block material obtained by EUSguided FNA (Stelow etal. 2003).
Fig.2.15 Gastric gastrointestinal stromal tumor

(GIST) seen in fundus on endoscopy exam
30
Fig.2.16 Gastric GIST with

characteristic submucosal
splitting seen on EUS exam
2.3.5
Gastric Cancer
EUS has an overall 80% accuracy for T staging and 70% for N staging, and has been found
to be superior to CT (Xi etal. 2003; Javaid etal. 2004). The major impact EUS-FNA has
on gastric cancer management comes from the novel technique of endoscopic ultrasound
guided paracentesis (EUS-P) of ascites to determine M staging. One study found that aspiration through EUS-FNA of a mean volume of 6.8mL of ascites has a sensitivity, specificity, positive predictive value, and negative predictive value of 94, 100, 100, and 89%,
respectively, for diagnosing malignant ascites. Accordingly, the finding of malignant
ascites has significant impact on patient management, rendering a poorer prognosis
(Kaushik etal. 2006).
2.3.6
Esophageal Neoplasms
As a complementary exam, EUS is used in conjunction with CT and positron emission
tomography (PET) scanning in the staging of esophageal carcinoma. EUS vs. EUS-FNA
for lymph node staging has been shown to have a sensitivity of 63 vs. 93% (p=0.01),
specificity 81 vs. 100% (not significant), and accuracy 70 vs. 93% (p=0.02), respectively
(Vazquez-Sequeiros etal. 2001). Celiac lymph node M1a disease confirmation via EUSFNA has been found to be superior to CT scanning. As celiac lymph node involvement
carries a poorer prognosis, and is usually treated with nonsurgical methods, this determination is critical (Parmar etal. 2002).
In cases of early-stage esophageal neoplastic disease, where minimally invasive procedures such as EMR can be considered for potentially curative treatment, EUS-FNA
31
has impacted management. Detecting unsuspected malignant lymphadenopathy via conventional endosonography and EUS-FNA dramatically changed the course of management in 20% of patients referred to our center for endoscopic therapy of BE with
high-grade dysplasia or intramucosal carcinoma. Based on these results, we believe that
conventional endosonography and EUS with FNA when nodal disease is suspected
should be performed routinely in all patients referred for endoscopic therapy in this setting (Shami etal. 2006).
Subcarinal and supracarinal lymph node metastases proves critical in selection of transthoracic or transhiatal esophagectomy surgical strategy for distal esophageal carcinomas.
In patients with a resectable distal esophageal carcinoma and subcarinal and/or supracarinal lymph nodes visualized on preoperative EUS, Fockens etal. prospectively studied the
impact of EUS-FNA on surgical decision making. If EUS-FNA sampling of lymph nodes
was positive for malignancy, then transthoracic resection was offered. Patients without
demonstrated lymph node metastases were offered a transhiatal resection. Out of the
48patients included in the study, lymph node metastases were found in 23% with EUSFNA. Out of the 13 patients who had lymph nodes which were suspicious for malignancy
on EUS, 31% had their diagnosis status changed to nonmalignant nodes with FNA confirmation. Conversely, EUS-FNA proved lymph node malignancy presence in 9% of 35
patients who had nonsuspicious-appearing nodes on EUS. Therefore, EUS-FNA has considerable impact on clinical decision management in distal esophageal carcinoma cases
when transhiatal resection was presumptively planned (Marsman etal. 2006).
2.3.7
Colorectal Carcinoma
Recently, locoregional stage-focused colorectal cancer therapy has been given higher
emphasis. EUS-FNA colorectal cancer N-staging, especially nonjuxtatumoral lymph
nodes, has been shown to have clinical impact on decision making. This technique also
aids in detecting disease recurrence (Shami etal. 2004). In the setting of re-staging after
chemoradiation therapy, EUS has virtually no role, due to posttreatment induced local
inflammation. However, when recurrence is not present intralumenally, and is suspected in
the face of rising CEA levels, EUS-FNA can be helpful (Dye and Waxman 2002).
2.3.8
Lung Malignancy
The posterior mediastinum can be accessed for FNA through the esophageal wall, for staging of lung cancer. Sensitivity, specificity, and accuracy for EUS-FNA in mediastinal analysis have been reported as 91, 100, and 93%, respectively. Certain experts advocate
EUS-FNA as the initial diagnostic procedure for suspected lung cancer with enlarged
mediastinal lymphadenopathy, to possible reduce the number of surgical staging procedures (Annema etal. 2005; Micames etal. 2007).
32
2.3.9
Therapeutic Applications of EUS-FNA
The following section will highlight EUS-FNA-based interventional applications with
specific targeted therapies.
2.3.9.1
Celiac Plexus Blockade
Refractory pain management via celiac plexus neurolysis (CPN) through EUS guidance
for inoperable pancreatic cancer has become an increasingly utilized modality. EUS utilizes an anterior approach to the celiac axis, so that the risk of resultant paraplegia is theoretically negligible, while posterior percutaneous approach confers a 1% risk (Raj and
Chen 2006). In a large prospective study, 78% of patients had lower pain score at 2 weeks
after EUS-CPN, with a sustained response of up to 24 weeks, independent of narcotic
usage or adjuvant therapy (Gunaratnam etal. 2001).
2.3.9.2
EUS-Guided Pancreatico-Biliary Access/Drainage
When achieving selective ductal drainage through standard ERCP is unsuccessful, EUSguided pancreatic or biliary access of the desired duct has been effectively performed as an
alternative to surgery or percutaneous drainage (Figs.2.17 and 2.18). EUS-FNA puncture
is performed into an obstructed and dilated biliary or main pancreatic duct. After fluoroscopic guidewire access is established via the FNA needle, a transenteric fistula is created,
through which stent placement in the desired duct can be performed, either directly or via
a rendezvous ERCP. At qualified high-volume EUS/ERCP centers, this technique can
Fig.2.17 EUS-guided pancreatic ductal access

with contrast injection under fluoroscopy
33
Fig.2.18 Pancreatic stent placed after

EUS-guided pancreatic ductal access for
rendezvous procedure
serve as an alternative salvage approach to difficult pancreatico-biliary access cases, with

acceptable success and complication rates (Shami and Kahaleh 2007).
2.3.9.3
EUS-Guided Fine Needle Injection
A concept known as EUS-guided fine-needle injection (EUS-FNI) has evolved from using
EUS-FNA as a portal to introduce various agents with therapeutic capabilities. Chang
etal. have reported on injection of allogeneic mixed lymphocytic culture into unresectable
pancreatic tumors. However, the study was terminated early when survival was determined
to be less favorable in the lymphocytic culture recipients compared with the patient group
receiving gemcitabine (Chang et al. 2000). Feasible injection of a replication-deficient
adenovector into unresectable pancreatic tumors, with well-tolerated and fair responses
has also been reported by the same investigator (Raju 2009).
2.4
Endoscopic Management of Malignant Gastrointestinal Obstruction
2.4.1
Malignant Esophageal Obstruction
The palliation of malignant esophageal obstruction has been enhanced by the development
of self-expanding metallic covered or uncovered stents (SEMS) (Figs. 2.19 and 2.20).
These devices offer relief from dysphagia, poor nutrition, and weight loss. A host of alternate nonstent therapies have been utilized such as argon plasma coagulation, photodynamic therapy, laser, brachytherapy, local injection of alcohol, and antineoplastic drugs.
However, they have lost popularity due to lack of efficacy or expense, precluding logistical
34
Fig.2.19 Nonoperable malignant esophageal

stenotic obstruction
Fig.2.20 Postesophageal stent prosthesis

placement for relief of dysphagia
usage. The use of chemoradiation adjunctively with stent placement can be a strategy for
malignant dysphagia relief, though the acute local inflammation from the chemoradiation
can make tissue more friable and irritated temporarily (Fleischer and Sivak 1985;
Christiaens et al. 2008; Okunaka et al. 1990; Homs et al. 2005; Wadleigh et al. 2006;
Burris et al. 1998). It has been shown that covered metal stents help prevent tumor in
growth without substantially raising migration rates, when compared to uncovered ones
(Vakil etal. 2001). However, stent migration still presents itself as a significant complication particularly in distal esophageal obstructions (Verschuur etal. 2008).
The use of SEMS as sole therapy for patients with inoperable disease who have not
already received, or are unfit for, chemoradiotherapy has been studied. Thousand stents
were placed in 951 patients. Long-term follow-up was obtained for 35% with a median
survival of 250 days (IQR 130431, 95% CI 217301). Mean dysphagia scores improved
from 3.3 (SD 0.6) pre-SEMS to 1.0 (SD 1.3) for 78 patients still alive and 1.8 (SD 1.2) at
35
time of death of 165 patients. SEMS-related mortality was 0.3%, demonstrating that SEMS
can effectively palliate inoperable esophageal cancer (White etal. 2009).
2.4.2
Malignant Gastro-Duodenal Obstruction
Endoscopic palliation of gastro-duodenal malignant obstruction can help obviate the need for
otherwise invasive surgery in patients with limited life expectancy with unresectable cancer. In
a study where 81 stents were inserted into 75 patients, the technical and clinical success rates
were 98 and 87%, respectively. The median stent patency was 55 days (95% CI 4070 days).
The median survival was 79 days (95% CI 58123 days). Stent occlusion caused by tumor
ingrowth or overgrowth occurred in 31%. Use of covered stents (odds ratio 0.29, 95% CI
0.110.76; p=0.01) and chemotherapy after stent placement (odds ratio 0.34, 95% CI 0.13
0.91; p=0.03) were significant prognostic factors for ongoing stent patency after a multivariate
analysis. This study found that endoscopic stenting is a safe and effective palliation treatment
for malignant gastric outlet obstruction and a covered stent and chemotherapy are significant
prognostic factors for stent patency (Cho etal. 2009). Successful stent placement in otherwise
endoscopically inaccessible regions of the small bowel has been described for malignant
obstruction using double-balloon-enteroscopy-assisted techniques (Ross etal. 2006).
2.4.3
Malignant Colorectal Obstruction
Colorectal obstruction expandable metallic stent placements for either palliation or preoperatively as a bridge to surgery have become mainstays of therapy (Figs. 2.212.23).
Studies have shown that for acute colonic obstruction, outcomes of SEMS placement are
more favorable to surgery with the respect of overall medical cost and mortality. Risks of
stent placement include tumor ingrowth, migration, and tenesmus/pain if stent placement
is close to the anal verge (Dekovich 2009; Siddiqui etal. 2007).
Fig.2.21 Malignant obstruction at the ileocecal

valve with guidewire for future stent
placement
36
Fig.2.22 Endoscopic view after ileocolonic

stent placement across malignant
stenosis
Fig.2.23 Fluoroscopic view after ileocolonic

stent placement across malignant stenosis
2.4.4
Malignant Biliary Obstruction
Malignant biliary obstructions often result from intrinsic biliary tract cancers or extrinsic
compression from pancreatic tumors or surrounding lymphadenopathy. The onset of jaundice portends greater morbidity and mortality in these patient populations, who also may
be immunosuppressed by adjuvant or palliative chemotherapy. In cases of operable disease, ERCP plastic biliary stenting will provide temporary therapeutic relief of jaundice
prior to surgery. The plastic stent variety has a three-month patency as advocated by industry, and will require repeat future stent exchanges. In an effort to reduce the need for repeat
procedures, and enhance longer stent patency, SEMS have been developed for the biliary
tract for inoperable cases.
Cross-sectional imaging (preferably magnetic resonance cholangiopancreatography
[MRCP]) is often utilized preprocedurally to determine the appropriateness of endoscopic
stent therapy and to guide stent placement. Hilar cholangiocarcinomas particularly benefit
from the preprocedure mapping provided by 3-D reconstructive MRCP imaging, so as
to avoid blind contrast injection into otherwise undrainable hepatic systems.
37
Fig.2.24 24 Hilar malignant biliary obstruction

cholangiogram via endoscopic retrograde
cholangio-pancreatography (ERCP)
Fig.2.25 Postbilateral self-expanding metal

stent placement across malignant hilar biliary
obstruction
Self-expanding metal stents are preferred over plastic stents for their cost effectiveness
if patient survival is estimated to be greater than 6 months. Photodynamic therapy is a
treatment option for local but inoperable cholangiocarcinoma which is capable of prolonging survival (Stern and Sturgess 2008) (Figs.2.24 and 2.25).
2.5
Conclusion
The field of interventional gastrointestinal endoscopy is transforming into a robust specialty
that can offer a wide array of minimally invasive nonsurgical alternatives for diagnostic and
therapeutic objectives in gastrointestinal oncology patients. The outcomes of these techniques
are often favorable to surgical approaches. Development of improved endoscopic imaging
and ancillary devices will enhance the fields progress and further enable physicians to accomplish previously incomprehensible techniques for hopefully better quality of patient care.
38
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Practical Gastrointestinal Oncology

Correlative Science
Kay Washington and Christopher L. Corless
3.1
The Molecular Bases of Gastrointestinal Cancer
Gastrointestinal (GI) cancers, like other human malignancies, are characterized by the
accumulation of a variety of genetic alterations, including mutations that lead to inactivation of tumor suppressor genes or activation of oncogenes. These genetic and epigenetic
changes can be used to classify tumors on the molecular level, and form the basis for
development of new prognostic and predictive markers. While a number of molecular
prognostic factors in GI cancers have been recognized or postulated (Table3.1), few have
been validated in large data sets to date and their utilization is not yet considered a standard
of care. The essential prognostic factors for carcinomas across all GI sites remain the anatomic stage as classified, using TNM categories, lymphovascular invasion, and achievement of margin-negative surgical resection in potentially curable neoplasms. However,
with the development of therapies targeted to specific molecular pathways involved in
tumorigenesis, characterization of molecular alterations in individual GI malignancies has
become important for prediction of response to therapy and thus may be used in some situations to guide selection of treatment options. Currently, the two most prominent examples
are colorectal carcinoma and gastrointestinal stromal tumors (GISTs), for which molecular
testing for prediction of response to therapy has become widely applied in certain clinical
settings, such as KRAS mutational testing prior to treatment with cetuximab in high stage
colorectal carcinoma.
K. Washington (*)
Department of Pathology, Vanderbilt University Medical Center,
C-3321 MCN, Nashville, TN 37232, USA
e-mail: kay.washington@vanderbilt.edu
C.L. Corless
Department of Pathology, Oregon Health & Science University and Knight Cancer Institute,
Portland, OR, USA
43
44
K. Washington and C.L. Corless
Table3.1 Potential molecular markers for colorectal carcinoma

Category
Marker
Application/comments
Microsatellite
instability
RT-PCR, IHC
Testing for hereditary non-polyposis colon

cancer (HNPCC); prognostic marker;
possibly predictive for response to 5-FU
based therapies
Allelic imbalances/
LOH
18q
Prognostic marker; unclear if predictive
Chromosomal
instability
DNA ploidy
Prognostic marker
Methylation
Genome-wide or
specific
Defines CIMP+ subset of colorectal cancers
Oncogene expression
Ras, myc
No clinical application as biomarker

at present in GI cancers
Loss of tumor
suppressor gene
Bcl-2, p21, p27, p53

Proliferation/apoptosis
Bcl-2, bax, ki67

Angiogenesis
VEGF

Inflammation
Cox-2

Cell adhesion
Ecad, b-catenin,
CD44
No clinical application at present in GI

cancers
Predictive markers
EGFR, TS, VEGF,

KRAS mutation
KRAS mutation predicts lack of response to

cetuximab and is recommended prior to
treatment with anti-EGFR antibody therapy
TS may have utility as predictive marker
but is not recommended for clinical use
at present time
EGFR testing is not recommended
at present
3.2
Molecular Pathways of Colorectal Carcinoma
In terms of molecular profiling, colorectal carcinoma is arguably the most extensively characterized human malignancy, for a number of reasons: high prevalence, accessibility of
precursor lesions (adenomas) for study, and recognition of well-defined familial syndromes
(familial adenomatous polyposis coli and Lynch syndrome) that led to break-through
observations identifying causative molecular factors. Two major pathways of carcinogenesis
3 Practical Gastrointestinal Oncology Correlative Science
45
for colorectal carcinomas are recognized: chromosomal instability and microsatellite instability (MSI). Chromosomal instability, present in roughly 85% of colorectal carcinomas, is
characterized by accumulation of genomic abnormalities such as widespread chromosomal
gains and losses and translocations, and aneuploidy. MSI accounts for 1015% of colorectal carcinomas and is characterized by genome-wide alterations in the size of repetitive
DNA sequences known as microsatellites. This variability in microsatellite sequences is a
consequence of defective DNA mismatch repair and may be due to germline mutation in a
gene involved in the mismatch repair mechanism, or epigenetic mechanisms such as gene
hypermethylation in sporadic cases. A third mechanism of tumorigenesis in colorectal carcinomas, referred to as CpG island methylator phenotype or CIMP+, has been recently
described; in these colorectal tumors, epigenetic changes due to widespread DNA methylation, particularly that of CpG islands in the promoter regions of genes, leads to inactivation
of tumor suppressor genes. CIMP-high tumors have been described as demonstrating a
distinct clinicopathologic profile, such as association with proximal tumor location, high
grade histology, high levels of MSI, high BRAF mutation rate, and low TP53 mutation rate
(Samowitz etal. 2005; Weisenberger etal. 2006; Shen etal. 2007).
3.2.1
Chromosomal Instability Pathway
Colorectal carcinomas characterized by chromosomal instability are usually characterized by
mutations in APC, the tumor suppressor gene mutated in individuals with familial adenomatous polyposis coli. In sporadic colorectal cancers, the APC mutation is somatic, occurring
very early in the adenoma-carcinoma sequence, and the chromosomal instability observed in
very small early adenomas and dysplastic aberrant crypt foci is likely related to defective
chromosome segregation association with APC inactivation. In FAP, affected individuals
inherit one mutant copy of APC that is functionally inactive, or the mutation arises as a spontaneous germline mutation in approximately 25% of affected individuals (Bisgaard et al.
1994). Clinical consequences of chromosomal inactivation include worsening prognosis with
increasing number of allelic changes (Kern etal. 1989), which may be reflected in aneuploidy
(Sinicrope etal. 2006). These tumors often show p53 mutations associated with loss of 17p,
which occurs at the transition from non-invasive adenoma to the appearance of carcinoma.
KRAS mutation, another early event in colorectal carcinogenesis, occurs later, as evidenced
by its presence in only 20% of adenomas with APC mutation (Tsao and Shibata 1994).
Regulation of b-catenin by APC appears to be the key to its tumor suppressor activity.
3.2.2
Microsatellite Instability Pathway
Defects in the DNA mismatch system lead to colorectal carcinoma in two settings: Lynch
syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC), and in sporadic carcinomas. Lynch syndrome, accounting for 14% of colorectal carcinoma, is an autosomal
dominant disorder caused by mutation in one of several genes involved in mismatch repair,
46
such as MLH1, MSH2, MSH6, and PMS2. Defects in the functioning of the mismatch
repair system lead to DNA replication errors in simple short tandem DNA repeat sequences
of one to six bases, called microsatellites, which are scattered throughout the genome. MSI
is a change in length of microsatellites due to insertion or deletion of repeating units during
DNA replication, secondary to failure of the DNA replication system to correct these
errors. Genetic instability occurs in the repetitive sequences of microsatellites because the
replication machinery slips more frequently on repetitive sequences than on non-repetitive
sequences. High levels of MSI in sporadic colorectal carcinomas are due to somatic hypermethylation of the MLH1 promoter, leading to inactivation of the MLH1 gene and loss of
expression of the gene product.
MSI in colon cancer was discovered in 1993, and was recognized as the genetic basis for
the pathogenesis of many cases of HNPCC. In mismatch repair-deficient cells, genes that
contain microsatellites in the coding region are more prone to frameshift mutations. One
example is frameshift mutations in TGFbRII, found in colorectal but not endometrial cancer. Two of the DNA mismatch repair genes, MSH3 and MSH6, themselves contain coding
microsatellites that can be mutated in MSI-H cancers and are thus mutational targets.
The original Bethesda guidelines for the identification of individuals with HNPCC proposed a panel of five markers (BAT25, BAT26, D2S123, D5S346, D17S250) (Boland etal.
1998) for detection of MSI. If two or more microsatellite sequences are mutated the tumor
is considered to show high levels of MSI (MSI-H); if only one is mutated, then the tumor is
classified as showing low levels of MSI (MSI-L) and additional testing with other microsatellite sequences is recommended for definitive classification. Tumors showing no microsatellite mutations are considered microsatellite stable (MSS). Because mononucleotide
markers are more sensitive than di- or trinucleotide microsatellites, the revised Bethesda
guidelines following a 2002 NCI workshop recommended that a secondary panel of mononucleotide markers such as BAT-40 be used to exclude MSI-L cases in which only the dinucleotide repeats are mutated (Umar etal. 2004). Revised guidelines are effective in identifying
MLH1/MSH2 mutation carriers with a sensitivity of ~82% and specificity of ~98%. In general, 50% or more of the microsatellites will have mutations in the tumor cells.
3.2.2.1
Specific Genetic Alterations in the MIS Pathway
Inactivation of the TGFb signaling pathway is common in MSI-H carcinomas, with 90%
of such tumors showing mutation of the TGFbRII gene and the remaining 10% showing
mutations within IGFIIR. Other mutations include BAX, mutated in ~50% of MSI-H cancers, and activating mutations in b-catenin, found in ~25% of MSI-H cancers (MirabelliPrimdahl etal. 1999). APC mutation is rare in MSI-H cancers.
3.2.2.2
Practical Applications of MSI Testing
Detection of defects in mismatch repair in colorectal carcinomas is important for detection
of Lynch syndrome, and examination of the tissue for defective DNA mismatch repair is
47
recommended if any of the criteria in the revised Bethesda guidelines (Umar etal. 2004)
are met. These guidelines recommend testing for MSI in the following situations:
Colorectal carcinoma in a patient younger than 50 years of age

Synchronous or metachronous colorectal or other HNPCC-related tumors, such as
endometrial, small bowel, gastric, ovarian, pancreatic, biliary, ureteral or renal pelvis
carcinomas, brain tumors, sebaceous gland adenomas, and keratoacanthomas, in a
patient of any age
Colorectal carcinoma with histologic features associated with MSI-H status (medullary,
mucinous or signet ring cell differentiation, presence of numerous tumor infiltrating
lymphocytes, or presence of Crohns disease-like peritumoral lymphocytic reaction)
(Alexander etal. 2001; Greenson etal. 2003), in a patient less than 60 years of age
Colorectal carcinoma in one or more first-degree relatives with an HNPCC-associated
tumor, with one of the cancers being diagnosed under age 50 years
Colorectal cancer in two or more first-or second-degree relatives with HNPCC-related
tumors, regardless of age
Pre-symptomatic detection of carriers could lead to increased surveillance and potentially
reduce morbidity and mortality from colorectal carcinomas and other cancers in these
patients. The specificity of MSI testing can be increased by using primarily on at risk
populations such as colorectal cancer patients under the age of 50 or patients with a strong
family history of HNPCC associated tumors (e.g., colorectal, endometrial, gastric, or upper
urinary tract urothelial carcinoma) (Umar etal. 2004).
MSI in colorectal carcinomas has been associated with a more favorable prognosis in
many (Halling etal. 1999; Benatti etal. 2005; French etal. 2008) but not all (Kim etal.
2007; Lamberti et al. 2007) retrospective case studies and a population based study
(Samowitz et al. 2001) compared to tumors with intact mismatch repair, and a recent
pooled analysis of randomized clinical trials (Sargent etal. 2008) showed a 49% reduction
in disease-free survival in patients not receiving chemotherapy who had MSS tumors,
compared to those with MSI-H colorectal carcinomas. Factors that may account for these
reported differences in prognostic impact (reviewed in Sinicrope and Sargent 2009) include
insufficient sample size, given that MSI-H tumors represent roughly 15% of colorectal
carcinomas, and the relatively modest magnitude of the effect of MSI status on outcome.
In addition, emerging data suggest that high levels of MSI may serve as a predictor of
response to 5-FU based chemotherapy (Ribic etal. 2003; Sargent etal. 2008; Jover etal.
2009), in that MSI-H tumors show relative resistance to these regimens. Although MSI
testing for prognostic and predictive purposes is not clearly established and has not yet
been accepted as standard of care, use of MSI testing to influence treatment decisions for
stage II colon cancer patients is therefore advocated by some investigators (Sinicrope and
Sargent 2009).
PCR-based techniques for MSI testing can be used to screen at risk colorectal cancer
patients for possible HNPCC cost-effectively; immunohistochemistry for detection of loss
of expression of gene products associated with mismatch repair may also be used to determine tumor mismatch repair status. Because patients with an MSI-H phenotype may have
a heritable germline mutation in one of several DNA MMR genes, appropriate genetic
counseling prior to testing is indicated. Follow-up germline testing for HNPCC after
48
determination of MSI-status may help in making a definitive diagnosis of the disorder and
aid in the pre-symptomatic detection of carriers in at risk individuals.
PCR-based MSI testing is generally performed with at least five microsatellite markers,
generally mononucleotide or dinucleotide repeat markers. Because dinucleotide repeats
may have lower sensitivity and specificity for identifying MSI-H tumors, currently used
panels often include more mononucleotides and fewer dinucleotides. Many laboratories
now use a commercially available kit for MSI testing that utilizes five mononucleotide
markers.
Both PCR-based MSI testing (Fig.3.1) and immunohistochemistry for mismatch repair
proteins (Fig.3.2) use formalin-fixed, paraffin-embedded tissue sections, which are usually readily available from routinely processed tissue submitted for examination through
90
110
130
150
170
190
110
130
150
170
190
6300
4200
2100
0
90
6300
4200
2100
0
Fig.3.1 Polymerase chain reaction-based testing for microsatellite instability (MSI) shows variation in size of microsatellites in the colorectal carcinoma (bottom) compared to normal colonic
mucosa (top) in a case showing high levels of MSI. Figure courtesy of Dr. Cindy Vnencak-Jones,
Vanderbilt University Medical Center
Fig.3.2 Immunohis
tochemistry for MSH2
shows retention of nuclear
expression in normal
colonic crypts and loss of
expression in the adenocarcinoma (arrows) in this case
of colorectal carcinoma
arising in a Lynch syndrome
patient
49
the pathology laboratory. The detection of MSI in a tumor by microsatellite analysis

requires that the DNA used for the analysis be extracted from a portion of the tumor that
contains approximately 40% tumor cells and is thus dependent upon tumor cellularity. If
the results of DNA MMR IHC and MSI testing are discordant, (e.g., MSI-H phenotype
with normal IHC or abnormal IHC with MSS phenotype) then the laboratory should make
sure that the same sample was used for MSI and IHC testing and that there was no sample
mix-up.
Examination of expression of MLH1, MSH2, MSH6, and PMS2 is the most common
IHC testing method used for suspected MSI-H cases; antibodies to these mismatch repair
proteins are commercially available. Any positive reaction in the nuclei of tumor cells is
considered as intact expression (normal), and it is common for intact staining to be somewhat patchy. Intact expression of all four proteins indicates that mismatch repair enzymes
tested are intact but does not entirely exclude Lynch syndrome, as approximately 5% of
families may have a missense mutation (especially in MLH1) that can lead to a nonfunctional protein with retained antigenicity. Rarely, defects in lesser-known mismatch repair
enzymes may also lead to a similar result. Loss of expression of MLH1 may be due to
Lynch Syndrome or methylation of the promoter region (as occurs in sporadic MSI colorectal carcinoma). Genetic testing is ultimately required for this distinction, although a
specific BRAF mutation is present in many sporadic cases, but not familial cancers. Loss
of MSH2 expression essentially always implies Lynch syndrome. PMS2 loss is often associated with loss of MLH1 and is only independently meaningful if MLH1 is intact. MSH6
is similarly related to MSH2.
Analysis for somatic mutations in the V600E hot spot in BRAF may be indicated for
tumors that show high levels of MSI, as this mutation has been found in sporadic MSI-H
tumors but not in HNPCC-associated cancers (Domingo etal. 2005). Use of BRAF mutational analysis as a step before germline genetic testing in patients with MSI-H tumors may
be a cost-effective means of identifying patients with sporadic tumors for whom further
testing is not indicated (Bessa etal. 2008).
3.3
Molecular Alterations in GI Cancers with Current Clinical Applications
3.3.1
KRAS
KRAS, a small G-protein that functions as a signal transducer and integrator downstream of
the epidermal growth factor receptor (EGFR), is a key component in the EGFR signaling
cascade. Activating mutations in KRAS serve to isolate this signaling pathway from the
effects of EGFR and render EGFR inhibition ineffective. In sporadic colorectal carcinomas,
activating KRAS mutations involving codons 12, 13, or 61 have been detected in roughly
4050% of tumors (Vogelstein etal. 1988; Karapetis etal. 2008); the mutation is usually a
50
missense mutation involving codon 12. Interestingly, KRAS mutation is associated with exophytic tumors, and is not found in flat adenomas or flat carcinomas (Yashiro etal. 2001).
Cetuximab, a monoclonal antibody therapy directed against the extracellular domain of
EGFR, was originally approved only for patients whose colorectal carcinomas expressed
EGFR. However, it was observed that some patients with EGFR-negative tumors received
therapeutic benefit from anti-EGFR treatment, and recent advances have shown that only
tumors with wild-type KRAS show significant response to these agents. Accumulating data
from both randomized and non-randomized studies (Lievre etal. 2006; Amado etal. 2008;
Bokemeyer et al. 2008; Karapetis et al. 2008; Van Cutsem et al. 2009b), reviewed by
Jimeno etal. (2009), suggest that colorectal cancer patients whose tumors show KRAS
mutations should not receive EGFR-targeting monoclonal antibody therapy. These findings may partially explain the lack of correlation of immunohistochemical evidence of
EGFR expression in tumors with efficacy of anti-EGFR therapies.
While the predictive value of KRAS mutations regarding monoclonal antibody-based antiEGFR therapy is now well established, the prognostic value of KRAS mutation independent
of treatment remains controversial. A large series of over 3,400 colorectal cancers patients
found that only the glycine to valine mutation on colon 12, found in 8.6% of all cases, had a
significant impact on disease free survival and overall survival (Andreyev etal. 2001). This
mutation appeared to have a more significant negative impact on patients with Stage III disease, compared to those with Stage II tumors. However, several retrospective subset analyses
from large randomized studies have failed to confirm this finding, including studies in which
no difference relative to KRAS mutational status was observed in among patients treated with
best supportive care (Ince etal. 2005; Amado etal. 2008; Karapetis etal. 2008).
3.3.1.1
Practical Applications of KRAS Mutational Analysis
While clinical guidelines for KRAS mutational analysis in colorectal cancer are evolving,
current provisional recommendations from the American Society for Clinical Oncology
are that all patients with stage IV colorectal carcinoma, who are candidates for anti-EGFR
antibody therapy, should have their tumors tested for KRAS mutations (http://www.asco.
org/portal/site/ASCO/). Anti-EGFR antibody therapy is not recommended for patients
whose tumors show mutation in KRAS codons 12 or 13.
Testing for KRAS mutational status is generally initiated by the treating physician in most
medical centers, although some institutions have implemented reflex testing for stage III or
stage IV colorectal cancers. Polymerase chain reaction-based methods remain the cornerstone for KRAS mutational analysis; several commercial kits based upon allele-specific
assays are available but none has been approved to date by the Federal Drug Administration.
Refinements in DNA extraction techniques from formalin-fixed paraffin-embedded tissue
blocks have increased sensitivity of DNA testing and eliminated the need for fresh or frozen
tissue samples. Careful selection of the tumor block by the pathologist is necessary to minimize dilution of tumor DNA by contaminating normal cells such as fibroblasts, endothelial
cells, and inflammatory cells; a target of at least 70% tumor cells is recommended. The most
appropriate tissue for analysis appears to be the primary tumor, although testing of metastases
51
is acceptable if the primary tumor is not available. Insufficient data exist to support recommendation of dual testing of primary and metastatic tumor (Conlin etal. 2005).
3.3.2
Allelic Imbalance in 18q
Allelic loss of chromosome 18q is common in colorectal carcinomas, and is reported in
50% to almost 75% of tumors (Jen etal. 1994; Watanabe etal. 2001). Chromosome 18q21
contains several genes implicated in colorectal carcinogenesis, including DCC (deleted in
colon cancer gene), as well as SMAD4 and SMAD2, involved in transforming growth factor signaling, although it remains unclear which genes on chromosome 18q play the most
important roles in colorectal carcinoma tumorigenesis. While the preponderance of published studies support allelic imbalance in 18q as a poor prognostic marker, not all studies
have been able to confirm this finding (Choi etal. 2002; Popat and Houlston 2005; Popat
etal. 2007). Overall, Stage II colorectal carcinomas with 18q allelic imbalance appear to
behave as poorly as average stage III carcinoma. Whether 18q allelic imbalance is a predictive factor for response to chemotherapy is unknown. For these reasons, current testing
guidelines recommend that testing for 18q status in colorectal cancer be performed only in
the clinical trial setting (Locker etal. 2006; Duffy etal. 2007).
3.3.3
Other Molecular Abnormalities
Loss of p53 is a late event in colorectal carcinomas, occurring in about 5075% of cancers
(Vogelstein etal. 1988, 1989). Mutational status of TP53 has not been shown to have major
prognostic or predictive value, however, and clinical testing is not recommended for GI
carcinomas (Locker etal. 2006; Duffy etal. 2007).
High tumor levels of thymidylate synthase (TS), the major target for 5-FU based therapies, have been associated with more advanced disease and poor response to adjuvant
therapy in some but not all retrospective studies (Lenz etal. 1998; Paradiso etal. 2000;
Allegra etal. 2002; Johnston etal. 2003). However, no standardized assay is available, and
controversy exists regarding the best testing method and determination of a threshold
value for resistance to 5-FU based therapy (Popat etal. 2004).
3.4
Molecular Testing in Other GI Cancers
For GI cancers other than colorectal carcinoma and GI stromal tumors, tissue-based testing
for potentially prognostic or predictive biomarkers is not currently recommended as standard
of care. However, recent data from the ToGA trial demonstrate improved survival in locally
advanced, recurrent, or metastatic gastroesophageal and gastric adenocarcinomas in patients
whose tumors were positive for human epidermal growth factor receptor 2 (HER2) and were
52
treated with trastuzumab added to standard chemotherapy (Van Cutsem etal. 2009a). These
results suggest that testing gastric cancers for over-expression of HER2, as currently performed for breast cancers, should be considered, especially for patients with metastatic
disease. For small bowel carcinomas, testing for defects in mismatch repair is important for
detection of Lynch syndrome. Examination of the tissue for defective DNA mismatch
repair should be considered in small intestinal carcinomas regardless of patient age (Umar
etal. 2004), if other predisposing conditions such as familial adenomatous polyposis coli
are absent. In addition, emerging data suggest that the frequency of MSI (18%) in small
intestinal carcinomas is roughly equal to that of colon cancer (Planck etal. 2003) and may
be associated with better survival (Brueckl etal. 2004). However, this latter indication for
testing is not clearly established and has not been accepted as standard of care.
3.5
Summary of Recommendations for Molecular Testing in GI Carcinomas
For colorectal carcinoma, testing for MSI and BRAF V600E mutational status is currently
recommended for detection of Lynch syndrome and should be considered for stage II cancers in which microsatellite status would influence choice of therapy. Given the association
between Lynch syndrome and small bowel adenocarcinomas, testing of these tumors for
microsatellite status is also recommended. KRAS mutational analysis is indicated for colorectal cancers before treatment with anti-EGFR antibody therapy. Given results of the
recent Phase III clinical trial in advanced gastric cancer, testing for overexpression of HER2
in these tumors should be performed if treatment with trastuzumab is a therapeutic option.
3.6
Gastrointestinal Stromal Tumor (GIST)
GISTs are the most common mesenchymal neoplasms of the GI tract. GISTs may arise
anywhere in the GI tract, but they most commonly occur in the stomach (50%), followed
by the small bowel (25%) and colon/rectum (10%) (Brainard and Goldblum 1997; Tworek
etal. 1997, 1999a, b; DeMatteo etal. 2000; Miettinen etal. 2000a, b, 2003, 2005b, 2006b).
GISTs can also develop within the mesentery, omentum, retroperitoneum, and pelvis
(Miettinen etal. 1999; Reith etal. 2000).
3.6.1
Pathology
GISTs have a wide range of histologic appearances, from spindle cell to epithelioid, and
immunohistochemistry is strongly recommended to verify the diagnosis (Kindblom
etal. 1998; Sarlomo-Rikala etal. 1998; Fletcher etal. 2002). The tumors usually express
53
KIT/CD117 (95%), DOG1 (98%), and CD34 (6070%), and may show varying degrees
of staining for smooth muscle actin (3040%), S100 (5%), desmin (12%), and keratin
(12%) (Kindblom et al. 1998; Sarlomo-Rikala et al. 1998; Fletcher et al. 2002).
Approximately 5% of GISTs are KIT-negative and a subset of these cases may benefit
from KIT-targeted therapy (Fletcher etal. 2002). Therefore, it is recommended that KITnegative GISTs be reviewed by a reference pathologist.
GISTs range in size from small nodules less than 1 cm in diameter to large masses
upwards of 35cm (median 5cm) (Demetri etal. 2004). GISTs share a number of electron
microscopic and immunophenotypic features with the interstitial cells of Cajal (ICC)
(Ramon y Cajal 1893; Thuneberg 1982; Sanders 1996; Kindblom et al. 1998; Kluppel
etal. 1998). ICC are innervated cells associated with Auerbachs plexus that have autonomous pacemaker function and coordinate peristalsis throughout the GI tract. It is widely
hypothesized that GISTs either arise from ICC or share a common stem cell with them.
3.7
Oncogenic Kinase Mutations in GISTs
Approximately 7580% of GISTs have oncogenic mutations in the KIT gene (Hirota
et al. 1998; Rubin et al. 2001; Heinrich et al. 2003a; Wardelmann et al. 2003). Most
involve the juxtamembrane domain (exon 11) and consist of in-frame deletions or insertions, missense mutations, or combinations thereof. Mutations also occur in the extracellular domains of KIT (exons 8 and 9), as well as in the kinase I and II domains (exons 13
and 17) (Fig.3.3).
Among the 2025% of GISTs that lack KIT gene mutations, approximately one third
(8% of all GISTs) have mutations in a homologous receptor tyrosine kinase, platelet-derived
growth factor receptor alpha (PDGFRA) (Heinrich etal. 2003b; Hirota etal. 2003). Sitesof
KIT and PDGFRA Mutations in GISTs

Genotyping of 1581 Cases
Wild-type (18.6%)
KIT
PDGFRA
Exon 8 (1 case)
Exon 9 (9.9%)
Fig.3.3 KIT and plateletderived growth factor

receptor alpha (PDGFRA)
mutations in gastrointestinal
(GI) stromal tumors
Exon 11(60%)
Exon 12 (1.2%)
Exon 13 (2%)
Exon 14 (0.5%)
Exon 17 (1.3%)
Exon 18 (6.4%)
CL Corless & MC Heinrich, unpublished
54
mutations in this kinase parallel those in KIT (Fig.3.3). KIT and PDGFRA mutations are
mutually exclusive. Altogether, 8590% of GISTs have a mutation in one or the other of
these kinase genes (Fig.3.3).
Binding of KIT ligand (stem cell factor) results in dimerization of two KIT receptors,
activation of their respective kinase domains, and phosphorylation of a variety of signaling
substrates known to promote cell growth and survival (Blume-Jensen et al. 1991). The
most common mutations affect the juxtamembrane region of KIT (exon 11), which, based
on structural studies, normally serves to inhibit KIT dimerization in the absence of KIT
ligand (Mol etal. 2004). Disruption of this domain promotes spontaneous kinase activation (Fig.3.3) (Kitayama etal. 1995; Ma etal. 1999; Chan etal. 2003). Mutations in the
kinase II domain, which are the most common type of mutation in PDGFRA, alter the socalled activation loop, which conformationally regulates the ATP-binding pocket.
Through these and probably other mechanisms, mutations of KIT and PDGFRA promote
continuous oncogenic signaling in GISTs.
The importance of kinase mutations in GISTs is supported by a number of observations.
KIT mutations are common in small (1cm), incidentally discovered GISTs, indicating
that they occur very early in development (Corless etal. 2002; Agaimy etal. 2007). GIST
extracts contain activated (phosphorylated) KIT or PDGFRA. Inhibition of KIT by kinase
inhibitors blocks the growth of GIST cell lines (Tuveson etal. 2001; Nakatani etal. 2005;
Heinrich etal. 2006; Tarn etal. 2006). Similarly, introduction of KIT shRNA into these
cell lines also inhibits their growth (Heinrich etal. 2006). Expression of mutant KIT in
transgenic knock-in mice results in KIT-positive spindle cell tumors that morphologically resemble GIST (Sommer etal. 2003; Rubin etal. 2005). Finally, GIST tumors that
initially respond to the KIT/PDGFRA inhibitor imatinib mesylate (Gleevec/Glivec,
Novartis) often become secondarily resistant through the acquisition of new mutations in
KIT or PDGFRA that interfere with drug binding, which indicates a continued dependence
on signaling from these kinases (Chen etal. 2004; Antonescu etal. 2005; Debiec-Rychter
etal. 2005; Heinrich etal. 2006).
3.8
Molecular Classification of GISTs
Subclassification of GISTs according to their kinase mutation status has both biological and
clinical implications (Table3.2). Whereas KIT exon 9-mutant GISTs arise almost exclusively
in the small intestine and colon, GISTs with a PDGFRA D842V substitution (the single most
common PDGFRA mutation), are limited to the stomach and omentum. In addition, GISTs
with KIT exon 9 mutations are often high-risk or overtly malignant, suggesting an inherently
more aggressive biology (Lasota etal. 1999; Sakurai etal. 2001; Corless etal. 2004). In
contrast, PDGFRA-mutant tumors may be less aggressive overall than KIT-mutant GISTs
(Lasota etal. 2004). GISTs with juxtamembrane mutations of KIT or PDGFRA, as well as
wild-type GISTs, occur at all locations in the GI tract. As detailed below, the molecular
subtypes of GIST differ greatly in their response to treatment with kinase inhibitors.
55

Table3.2 Molecular classification of gastrointestinal stromal tumors (GISTs)
Objective
Genotype
Approximate
Familial
In vitro
frequency (%)
examples
sensitivity responsesa
to imatinib (CR+PR by
RECIST)
KIT mutation
Exon 8
Exon 9
Exon 11
Exon 13
80
<1
10
67
1
None
None
10 Kindreds
2 Kindreds
Yes
Yes
Yes
Yes
Exon 17
2 Kindreds
Yes
PDGFRA
mutation
Exon 12
58
1
2 Kindreds
Yes
Exon 14
Exon 18
<1
5
None
None
Yes
D842V is
resistant
NR
3440%
6567%
(Responses
reported)
(Responses
reported)
(Responses
reported)
NR
(Responses
reported)
Progressive
diseasea
NR
17%
3%
NR
Yes D842V
Most
others are
sensitive
Wild-type
1215
2340%
19%
NR no cases reported
a
Data combined from EORTC-AustralAsian phase III trial and North American SWOG phase III
trial (Sinicrope etal. 2006)
3.8.1
GIST Variants
Familial GIST is related to heritable mutations in KIT or PDGFRA (Hirota etal. 2000,
2002; Isozaki etal. 2000; Beghini etal. 2001; Maeyama etal. 2001; Chompret etal. 2004;
Carballo etal. 2005; Hartmann etal. 2005; Ince etal. 2005; Kim etal. 2005; ORiain etal.
2005; Lasota and Miettinen 2006). In kindred with such mutations, affected members
develop multiple GISTs of the stomach and small bowel as early as age 18; diffuse ICC
hyperplasia is often evident in the adjacent gut wall. Additional findings may include pigmented macules involving the skin of the perineum, axilla, hands and face, as well as
evidence of skin mastocytosis (urticaria pigmentosa). Testing for germline KIT and
PDGFRA mutations is clinically available and should be sought in the context of appropriate genetic counseling.
Pediatric GIST are rare but have been divided into two subgroups: those with tumors that
harbor a KIT or PDGFRA mutation similar to adult GISTs, and those with non-mutant tumors.
Interestingly, the latter group dominates, being comprised almost exclusively of females presenting with gastric GIST by 20 years of age (Miettinen etal. 2005a; Prakash etal. 2005).
56
Many of these cases overlap with Carney triad, a non-hereditary syndrome in which patients
develop gastric GIST, paraganglioma and/or pulmonary chondroma (Carney 1999).
GISTs in Type I Neurofibromatosis (NF1, von Recklinghausens neurofibromatosis)
arise primarily in the small intestine. Approximately 7% of NF1 patients, will develop one
or more GISTs, which tend to follow an indolent course (Zoller etal. 1997). The tumors
are strongly KIT-positive by immunohistochemistry, yet they are generally negative for
KIT mutations (Kinoshita etal. 2004; Andersson etal. 2005; Takazawa etal. 2005; Yantiss
etal. 2005; Miettinen etal. 2006a).
3.9
Kinase Genotype and Treatment with Imatinib Mesylate
Metastatic GIST typically presents with tumors isolated to the peritoneal cavity and/or the
liver. Historically, the median survival of patients with advanced GIST was only 1824
months, because these tumors respond poorly to conventional cytotoxic chemotherapy
agents and probably radiation therapy (Shiu etal. 1982; Ng etal. 1992a, b; DeMatteo etal.
2000; Demetri etal. 2006). Imatinib mesylate is a small molecule tyrosine kinase inhibitor
with activity against KIT, PDGFRA, PDGFRB, ABL and BCR-ABL (Buchdunger etal.
2000). It mimics ATP structurally and binds competitively to the ATP binding sites of its
target kinases thereby shutting down signaling activity.
A number of phase I/II and III clinical trials have demonstrated the efficacy of imatinib
in the treatment of metastatic GIST (Heinrich etal. 2003b, 2008; Debiec-Rychter etal.
2004, 2006). Disease control is observed in 7085% of patients and the median progression free survival is in the range of 2024 months. Imatinib is approved by the U.S. FDA
for the treatment of unresectable and metastatic GIST.
Two randomized, multi-center phase III trials were conducted in Europe/AustralAsia and
North America to compare the relative efficacy of 400mg vs. 800mg of imatinib (DebiecRychter etal. 2006; Heinrich etal. 2008) (additional details available in Chap. 6). These
trials served to establish two important differences between the various genotypic subtypes
of GIST. First, progression free and overall survivals were significantly better for patients
with KIT exon 11-mutant GIST as compared those with exon 9-mutant tumors, tumors lacking a KIT or PDGFRA mutation (wild-type tumors), and tumors with a PDGFRA D842V
mutation (which is inherently imatinib resistant). Second, the progression free survival of
patients with exon 9-mutant tumors was better on the 800mg arm as compared with the
400mg arm in the Europe/AustralAsia study. This trend was also seen in the North American
trial (Heinrich etal. 2008). In contrast, exon 11-mutant and WT tumors responded equally
well to 400 and 800mg of imatinib (Debiec-Rychter etal. 2006; Heinrich etal. 2008).
3.9.1
Adjuvant Imatinib and Kinase Genotype
A large randomized trial of 12 months of adjuvant imatinib vs. placebo for fully resected
GISTs 3cm or larger showed a clear benefit of drug treatment in regard to progression free
57
survival, leading to FDA approval of adjuvant therapy (Dematteo etal. 2009). Correlative
genotyping studies conducted in this trial will be completed in 20092010.
3.10
Imatinib Resistance
Although imatinib has dramatically improved the quality of life and survival of patients
with advanced GIST, the majority of patients are not cured (Benjamin etal. 2003; Heinrich
etal. 2003a; Verweij etal. 2004). Resistance to the drug can be divided into two categories.
A minority of patients (1015%) have tumors that do not respond to treatment within the
first 6 months of treatment. KIT exon 9-mutant and wild-type tumors are over-represented
in this group (Heinrich etal. 2003a; Debiec-Rychter etal. 2004). However, most patients
develop one or more sites of disease progression after more than 6 months of clinical
response. Such secondary resistance is almost invariably related to the acquisition (orselection) of new kinase mutations in KIT (or PDGFRA) that interfere with imatinib activity
(Fletcher et al. 2003; Chen et al. 2004; Tamborini et al. 2004; Antonescu et al. 2005;
Debiec-Rychter etal. 2005; Heinrich etal. 2006). In all likelihood, the emergence of these
secondary mutations is due to a population of GIST cells for which imatinib is cytostatic
rather than cytocidal. As with other cancers, medical cure of GIST may require eradication
of the transformed stem cells that give rise to the tumor.
3.10.1
Sunitinib
Sunitinib (Sutent, Pfizer) is FDA-approved for the treatment of patients with imatinib-resistant
GIST. In addition to targeting KIT, sunitinib has antiangiogenic effects through inhibition of
vascular endothelial growth factor receptor. In the pivotal, double-blind, placebo-controlled
phase III trial of this drug, the median time to progression was 6.3 months vs. 1.5 months on
placebo (Demetri etal. 2006). Interestingly, analysis of a phase I/II trial revealed that patients
with KIT exon 9-mutant GIST, or wild-type GIST, had better and more durable responses to
sunitinib than those with KIT exon 11-mutant tumors (Maki etal. 2005). This is probably
because exon 11-mutant tumors have a higher frequency of secondary resistance mutations,
many of which confer cross-resistance to sunitinib. Screening for secondary resistance mutations to predict the benefit of sunitinib therapy has been proposed, but there is remarkable
inter- and intra-tumoral heterogeneity of these mutations, making it impractical to assess disease status on the basis of limited biopsy material.
3.10.2
Other Tyrosine Kinase Inhibitors
Other kinase inhibitors being tested for the treatment of imatinib-resistant GIST include
dasatinib (Sprycel, Bristol Myers Squibb), sorafenib (Nexavar, Bayer) and nilotinib
58
(Tasigna, Novartis). There are as yet no data on whether kinase genotyping will have a role
in predicting benefit from these drugs in either the pre- or post-imatinib setting.
3.11
Recommendations for GIST Genotyping
Based on the data from the phase III trials, kinase genotyping is recommended by the
NCCN for all newly diagnosed high-risk and malignant GISTs (Demetri et al. 2007).
Mutation status can be used to predict the likelihood of benefit from imatinib therapy and
to determine the optimal dose for treatment. At a minimum, gastric tumors should be
screened for KIT exon 11 mutations, which predict for the best overall imatinib response
and survival. Small and perhaps large intestinal GISTs should be screened for mutations in
KIT exons 11 and 9, as the latter appear to respond better to higher dose imatinib (800mg/
day). For tumors lacking an exon 11 or 9 mutation, additional screening to rule out mutations in KIT (exons 13 and 17) and PDGFRA (exons 12, 14 and 18) is necessary to establish a WT genotype, which is associated with a significantly shorter PFS on imatinib. This
additional screening can identify PDGFRA mutations that are responsive to imatinib as
opposed to the inherently resistant substitution D842V.
GIST genotyping is sometimes used in the setting of disease progression on imatinib
to help determine whether dose escalation should be pursued or a switch should be
made to sunitinib or another kinase inhibitor. Patients with KIT exon 9-mutant GIST
may benefit from a higher dose of imatinib, while those with exon 11-mutant or WT
GISTs are more likely to respond to another inhibitor. As discussed above, screening
for specific imatinib-resistant mutations in progressing patients is not recommended
due to the remarkable heterogeneity of such mutations between individual tumor
nodules.
3.12
Summary
This chapter has discussed current recommendations for molecular testing of GI carcinomas and stromal tumors, emphasizing selection of tests that impact clinical decisionmaking. However, as we move into the era of individualized medicine, recommendations
and practice patterns are rapidly changing as tumor molecular characteristics predictive
of response to available therapies are identified. For instance, KRAS mutational status
as a predictor of response to monoclonal antibody-based anti-EGFR therapy has emerged
as new and powerful tool in selection of therapy in advanced colorectal cancer.
Correlative science from retrospective studies and from prospective clinical trials will
remain critically important in further advances in tailoring treatment options for the
individual patient.
59
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Esophageal Cancer
Florian Lordick and Arnulf Hlscher
4.1
Epidemiology
In contrast to gastric cancer incidence, which is decreasing worldwide, the incidence and
prevalence of esophageal carcinoma is rising at an alarming rate worldwide (Pohl 2005).
This rise is due primarily to an increase in the rate of adenocarcinoma of the distal esophagus (Kamangar etal. 2006). At many institutions in the world, adenocarcinomas of the
esophagus now outnumber squamous cell esophageal cancers. Because of marked differences in the pathogenesis, tumor location, tumor biology, and characteristics of the affected
patients (Table 4.1), squamous cell carcinoma and adenocarcinoma of the esophagus
should be treated as separate entities to a certain extent. This differentiation is frequently
not made when treatment results for esophageal cancer are reported.
Esophageal cancer is the ninth most common cancer in the world. Esophageal cancer is
a disease of mid to late adulthood (6070 years). There is a marked variation in its incidence according to sex, geographical area, and racial and economical background. The
annual age-adjusted incidence rate among males varies from less than 5 cases per 100,000
population among whites in the United States to 18.726.5 per 100,000 cases in some
regions of France, with up to 100 cases per 100,000 in Linxian (China) or the Caspian
region of Iran. In most countries, esophageal cancer is two to four times more frequent in
men than in women. In China and Iran, this cancer is almost as frequent in women as in
men. Esophageal squamous cell carcinoma occurs five times more often among blacks
than whites; this excess is greater at younger ages. Esophageal cancer is one of the most
common malignancies among black men younger than 55. In China, the country with the
F. Lordick (*)
Third Medical Department, Klinikum Braunschweig, Hannover Medical School,
Celler Strae 38, 38104 Braunschweig, Germany
e-mail: medklinik3@klinikum-braunschweig.de
A. Hlscher
Department of Surgery and Centre of Integrated Oncology (CIO), University of Cologne,
Cologne, Germany
67
68
F. Lordick and A. Hlscher
Table4.1 Comparison of patient characteristics for those with squamous cell esophageal cancer and
adenocarcinoma of the distal esophagus
Adenocarcinoma of
Squamous cell
p Value
the distal esophagus
esophageal
carcinoma
Median age
53.4 years
62.6 years
<0.001
Male-to-female ratio
7:1
8:1
NS
Profession (prevalence)
Academic
White collar
Blue collar
20.8%
27.2%
52.2%
52.9%
27.7%
20.2%
<0.001
Alcohol abuse
(prevalence)
69.7%
42.3%
<0.001
Smoking (prevalence)
69.3%
51.9%
<0.05
Malnutrition
(prevalence)
24.1%
1.9%
<0.001
Pulmonary function
(mean FEV1,% of
normal)
82.5%
93.7%
<0.05
Cardiovascular risk
factors (prevalence)
19.5%
34.8%
<0.01
Impaired liver function

(prevalence)
35.3%
24.9%
<0.05
FEV1 forced expiratory volume in 1s; NS not significant

Data are for patients treated at the Department of Surgery, Klinikum rechts der Isar, Technische
Universitt Mnchen, 19822000
highest mortality rate due to this disease, incidence rates have been decreasing since the
1970s, probably as a consequence of a diet with higher contents of foods rich in proteins,
carotene, vitamins C and E, and riboflavin. At the same time, more cases of squamous cell
carcinoma are due to an increase in the consumption of tobacco and alcohol, reflecting the
economic changes in these areas.
4.2
Etiologic Factors
4.2.1
Squamous Cell Cancer
Both alcohol consumption and smoking increase risk, typically in a synergistic manner. In a study made on a French population, among heavy smokers and heavy drinkers
4 Esophageal Cancer
69
the relative incidence risk was >100-fold. Risk is five times higher among cigarette
smokers than nonsmokers. The risk depends mainly on the duration of consumption: a
moderate intake during a long period carries a higher risk than a high intake during a
shorter period (Launoy et al. 1997). Among drinkers of alcohol, the risk appeared
increased and related to the amount consumed (2050-fold), with former and current
consumption having similar effects. A very low risk is associated with a low alcohol
intake. Smoking and drinking are independent risk factors. Racial differences may
account for the excessive risk of esophageal cancer in black men. In countries with the
highest esophageal cancer rates (some parts of China, Iran, South Africa), micronutrient deficiencies (beta-carotene, several B vitamins, vitamin C, magnesium, zinc, and
certain minerals) prevail. Some dietary habits have been associated with increased
risk: pickled vegetables and other foods that may become moldy or fermented, very
hot drinks and foods, diets rich in cereals but with low intake of fruit and vegetables.
Randomized trials investigating the effects of supplementation with vitamins and minerals on esophageal cancer risk have recently been reported from China where, after 5
years of supplementation, death rates from cancer were significantly lower (by 13%)
among those who received the combination of beta-carotene, vitamin E, and selenium.
Another effect of the supplements was a greater proportion of dysplasia regression
(Qiao etal. 2009). From these results, it appears likely that improved nutrition may
help lower the incidence of esophageal cancer among individuals at high risk. Other
factors that may play a minor role are occupational exposures to asbestos, vulcanization combustion products, and several types of metal dust (chromium, nickel, beryllium). Ionizing radiations may also increase the risk. Several reports have described
the occurrence of esophageal carcinoma after thoracic radiation. Radiation therapy for
breast cancer may increase the risk for developing esophageal squamous cell carcinoma 10 or more years after radiation therapy (Ahsan 1998). Genetic predisposition to
the malignancy is uncommon (Dhillon et al. 2001). Ninety-five percent of patients
with congenital palmar and plantar keratosis (tylosis) develop an esophageal cancer
before the age of 65 (Moodley et al. 2007). Predisposing conditions to esophageal
carcinoma are chronic inflammation, achalasia, caustic injury, and Plummer-Vinson
syndrome (Kamangar et al. 2009). Predisposing agents act as inducers of dysplasia
which is recognized as a preneoplastic situation. Human papillomavirus (HPV) infection, notably HPV types 16 and 18, may play an important role in the pathogenesis of
squamous cell carcinoma in high-incidence areas, including China and South Africa.
HPV infection occurs infrequently in association with squamous cell carcinoma in
patients from low-risks areas (He etal. 1997; Rugge etal. 1997; Turner etal. 1997).
An elevated risk of esophageal carcinomas following tobacco-related malignancies
has been reported (Kesting etal. 2009; Yokoyama etal. 2008).
4.2.2
Adenocarcinoma
The increase in esophageal and esophagogastric junction adenocarcinomas is not yet completely understood. Adenocarcinoma preferentially develops in metaplastic epithelium of
70
the distal esophagus which occurs as a sequela of chronic gastroesophageal reflux disease
(Lagergren etal. 1999). Obesity is a predisposition that facilitates gastroesophageal reflux
disease and has been identified to be associated with esophageal adenocarcinoma.
Consumption of lower esophageal sphincter relaxing drugs has been identified as another
risk factor while the presence of Helicobacter pylori infection as well as high fruit and
vegetable intake have been associated with a protective effect (Lagergren 2005). These
risk factors seem to have differential effects in the male and female populations (Lfdahl
etal. 2008). Eighty-five percent of patients presenting with adenocarcinoma of the distal
esophagus have a history of reflux symptoms (Leers et al. 2005; Witzig et al. 2006).
According to the person who first described this transformation in 1953, this metaplasia is
called Barretts epithelium (Thompson etal. 1983). The tumor that develops in this epithelium is called Barretts carcinoma. An esophageal columnar metaplasia can be found in
more than 90% of patients with adenocarcinoma of the esophagus. Persons with Barretts
esophagus have a 125-fold lifetime risk to develop an adenocarcinoma of the esophagus.
Predisposing lesions are low-grade and high-grade intraepithelial dysplasias which are
triggered by a variety of genetic mutations and epigenetic events (Hao etal. 2006; Tischoff
and Tannapfel 2008; Wiech etal. 2009). The risk for developing cancer is significantly
higher for a long- vs. a short-segment esophagus but even in short-segment metaplasia
(<3cm of length), the risk for developing cancer seems to be elevated at least in some
studies (Rudolph etal. 2000; Thomas etal. 2007). Several chemopreventive strategies for
populations at risk have been postulated, among which low-dose intake of aspirin is probably the most promising one (Neumann etal. 2009). The Aspect trial is currently recruiting
patients; first interim results are awaited in 2011 (Das etal. 2009).
4.3
Classification and Pathology
4.3.1
Squamous Cell Carcinoma
Squamous cell carcinoma has been the most common histotype among esophageal malignancies. Macroscopically it can be classified into vegetating, infiltrating, and ulcerated
tumors. Most of them appear histologically as well-differentiated neoplasms. Poorly differentiated cancers may be composed of polyhedral cells, sometimes simulating a glandular-like epithelium. In other cases, either small cells or giant cells may be present in
poorly differentiated squamous cancers. In advanced cancers, histology frequently demonstrates areas of necrosis. Tumor grading does not seem to be a significant prognostic
parameter. Verrucous carcinoma is a rare variant of well-differentiated squamous cancers.
Spindle cell carcinoma is a variant of poorly differentiated squamous cancers; it may be
mistaken for a sarcoma or carcinosarcoma. Basaloid squamous cell carcinoma is a recently
recognized variant of poorly differentiated squamous cancers; after surgery the prognosis
is similar to that of patients with typical squamous cell carcinoma.
4 Esophageal Cancer
71
4.3.2
Adenocarcinoma
Adenocarcinoma is now the most common histotype of esophageal cancers in most regions
with a more Western-type lifestyle. It is formed by a glandular epithelium, with papillary
and/or tubular structure. Most esophageal adenocarcinomas originate from areas of Barretts
epithelium, or glandular metaplasia of the esophageal mucosa. Adenocarcinoma has a site
predilection for the distal third of the esophagus. Macroscopic characteristics of these tumors
are similar to those of squamous cancers. Other sites of origin of adenocarcinomas are islands
of heterotopic gastric mucosa or cardiac glands and esophageal glands in the submucosa.
4.3.3
Precancerous Lesions
Dysplasia is an epithelial precancerous lesion. Histologically it is characterized by nuclear
enlargement and hyperchromaticity with increased mitotic activity. Dysplasia in the esophagus can be either squamous or glandular. Squamous cell dysplasia is found preceding or
combining with squamous carcinoma. Glandular dysplasia is associated with adenocarcinoma complicating Barretts esophagus; dysplasia develops more frequently in the intestinal
than in the gastric type of mucosa. Increasing grades of dysplasia, from mild to severe, appear
to be associated with increasing risk of cancer. In China, when dysplasia was histologically
evaluated, the cumulative incidence of squamous cell carcinoma is reported to be 30% for
moderate dysplasia and 65% for severe dysplasia or carcinoma in situ in a 3.5-year observation period (Lightdale 1996). High-grade dysplasia is described as carcinoma in situ. Natural
history of high-grade glandular dysplasia is not well defined, since high-grade dysplasia can
remain stable without progressing, or it can even disappear. High-grade dysplasia in Barretts
esophagus may be associated with invasive cancer in one third of patients (Spechler 1994).
4.3.4
Differential Pathologic Diagnosis
Experienced pathologists may differ in the interpretation of microscopic specimens: an
87% interobserver agreement was found in distinguishing intra-mucosal carcinoma and
high-grade dysplasia from lesser degrees of dysplasia or no dysplasia. Pathologists who are
less regularly confronted with the assessment of esophageal dysplasia may have difficulties
in making this differentiation. If an esophageal resection for a high-grade dysplasia is
planned, it is recommended that a second experienced pathologist confirms the diagnosis.
4.3.5
Specific Histotypes
Rare histotypes are found in only 4% of esophageal malignancies.
72
Other epithelial cancers are adenosquamous carcinoma, mucoepidermoid carcinoma,

adenoid cystic carcinoma, small cell carcinoma, undifferentiated carcinoma, and pseudosarcomatous carcinoma.
Non-epithelial cancers are leiomyosarcoma and Kaposi sarcoma. Miscellaneous tumors
are carcinosarcoma, malignant melanoma, carcinoid, and malignant lymphoma.
4.3.6
Lymphatic Spread
Lymphatic spread depends on the location of the primary tumor and does primarily concern the locoregional lymph nodes. Correspondingly, squamous cell cancer often causes
lymph node metastases of the mediastinum while adenocarcinoma more often metastasizes to the paracardiac and perigastric regions along the lower curvature. Nevertheless,
especially in advanced stages, both subtypes also often metastasize from the upper parts of
the mediastinum down to the pericoeliac region.
The rate of lymph node metastases correlates with the T stage and is relevant for therapy planning and for the assessment of the prognosis. Regarding early detection of esophageal cancer and the potential of endoscopic therapy in early stages, the rate and dissemination
of lymph node metastases in early stages is of particular interest (Bollschweiler etal. 2006;
Liu etal. 2005; Westerterp etal. 2005). A differentiation between mucosal and submucosal
cancer and the corresponding thirds according to the Japanese classification (sm-1, sm-2,
sm-3) has gained importance. When compared according to these stages, there seem to be
no major differences in the rates of affected lymph nodes between adenocarcinoma and
squamous cell cancer. The critical step for lymph node spread is the infiltration of the submucosal layer. sm-1 cancers can cause lymph node metastases in up to 1020% while sm-3
cancers may cause lymph node metastases in up to 5060% (Hlscher and Vallbhmer
2007). Reports about a significantly more frequent prevalence of lymph node metastases
in squamous cell carcinoma compared with adenocarcinoma in T1 stages can be explained
by a significantly more frequent infiltration of the submucosal layers (particularly sm-3) of
squamous cell cancers in these series (Bollschweiler etal. 2006). Stage-adapted comparisons between T2 and higher-staged tumors also reveal no significant differences between
the squamous cell and adenocarcinoma subtypes.
4.3.7
Distant Metastases
Distant metastases are most frequently localized in the liver, in the peritoneum, and in the
lung. Distant lymph node metastases are associated with a poor prognosis similar to that of
hematogenous distant metastases but involvement of coeliac lymph nodes (formerly classified M1a) is in the range of involvement of other locoregional lymph node groups
(Hofstetter etal. 2007).
73
4 Esophageal Cancer
4.3.8
Anatomic Classification
Of therapeutic relevance is also the topographic relationship of the esophagus to the tracheo-bronchial system. As a result of their proximity in the upper mediastinum and cervical
region the risk of infiltration of the trachea or bronchi by wall-penetrating esophageal tumors
is high. This is not the case in the lower mediastinum. Consequently, esophageal cancers are
often classified as tumors of the upper, the middle, and the lower mediastinum.
Another important classification is Siewerts classification concerning tumors located at
the gastroesophageal junction (Fig.4.1) (Siewert and Stein 1998). Type I adenocarcinoma
of the esophagogastric junction are primarily cancers occurring in Barretts esophagus.
Those cancers are surgically treated by esophagectomy while for type II and type III cancers
many centers prefer extended gastrectomy according to Siewerts recommendations.
Currently, the TNM classification has been renewed. Tables4.2 and 4.3 give an overview of the latest version of the TNM classification and staging system of the International
Union of Cancer Classification (Sobin etal. 2009).
4.4
Symptoms
The major symptom leading to diagnosis of esophageal cancer is dysphagia. Less frequently, patients complain about odynophagia, which means pain on swallowing food and
fluids (Leers etal. 2005; Witzig etal. 2006). In most patients, dysphagia is a symptom
occurring in advanced disease. Other symptoms associated with more advanced tumors are
hematemesis, hoarseness which is due to recurrent nerve paralysis, respiratory symptoms
Anatomic
Cardia
Type I
Type II
Type III
Fig.4.1 Adenocarcinoma
of the esophagogastric
junction (AEG type IIII)
according to Siewerts
classification
74
Table4.2 TNM stages of esophageal cancer according to the UICC TNM classification system, 7th
edn (Sobin etal. 2009)
Tis
Carcinoma in situ /high-grade dysplasia
T1
Lamina propria or submucosa
T1a
Lamina propria or muscularis mucosae
T1b
Submucosa
T2
Muscularis propria
T3
Adventitia
T4
Adjacent structures
T4a
Pleura, pericardium, diaphragm, or adjacent

peritoneum
T4b
Other adjacent structures, e.g., aorta, vertebral body,

trachea
N0
No regional lymph node metastasis
N1
12 regional lymph nodes
N2
36
N3
>6 (N1 was site dependent)
Distant metastasis
M1
Distant metastasis (M1a,b were site dependent)
Table4.3 Anatomical stage groups of esophageal cancer according to the UICC TNM classification
system, 7th edn (Sobin etal. 2009)
Stage IA
T1
N0
M0
Stage IB
T2
N0
M0
Stage IIA
T3
N0
M0
Stage IIB
T1, T2
N1
M0
Stage IIIA
T4a
T3
T1, T2
N0
N1
N2
M0
M0
M0
Stage IIIB
T3
N2
M0
Stage IIIC
T4a
T4b
Any T
N1, N2
Any N
N3
M0
M0
M0
Stage IV
Any T
Any N
M1
75
4 Esophageal Cancer
due to esophago-tracheal fistula, weight loss, and swelling of cervical lymph nodes. A history of heartburn is typical for many patients with Barretts cancer. According to a recent
study, the delay between onset of alarming symptoms and diagnosis was 2.2 months
(Witzig etal. 2006). In the Western world, early cancers are mainly diagnosed on the basis
of surveillance endoscopies in case of Barretts esophagus or when upper gastrointestinal
endoscopy is performed for the clarification of nonspecific abdominal symptoms.
4.5
Clinical Diagnostics
An effective diagnostic workflow is subdivided into the primary diagnosis and staging
(Table4.4). The crucial investigation for the primary diagnosis is upper gastrointestinal
tract endoscopy with biopsy. This investigation is necessary to prove malignancy and to
allocate the malignancy to one of the histologic subtypes. At the same time, endoscopy
will provide information about the location and local extent of the tumor.
An accurate staging is necessary for all treatment decisions. The exclusion or proof of
distant metastases is of paramount interest, as in case of distant metastases the goals of
treatment are palliative. The most important investigation for the exclusion of distant
metastases is computed tomography (CAT scan) of the neck, thorax and abdomen. Magnetic
resonance tomography does not augment the accuracy of diagnosis and is not a routine
procedure in the diagnostic workflow of esophageal cancer. Sonography of the abdomen is
a useful and sensitive investigation, especially for the detection of liver metastases, but it
cannot replace computed tomography. According to the current literature, the diagnostic
Table4.4 Clinical diagnostics in esophageal cancer
Diagnostics
Aim
(a) Primary diagnostics
Endoscopy+biopsy
Endosonography
Multisclice CT of the
neck+thorax+abdomen
3D reconstruction of CT images
Histologic verification, localization

Depth of infiltration, uT-category (uN with less
accuracy)
Distant metastases, infiltration of adjacent organs,
pleural effusion, ascites
Localization of the primary tumor with regard to
the tracheobronchial system
(b) Supplementary diagnostics depending on results from (a)

Bronchoscopy+Biopsie
Infiltration of the trachea or the main bronchi
Laparoscopy+biopsy+laparoscopic
Peritoneal carcinomatosis and liver metastases
ultrasound
Thoracoscopy
Pleural carcinomatosis, lung metastases
PET
Distant metastases
76
benefit of whole-body positron emission tomography (PET) is limited after state-of-the-art

staging, and so broad implementation in daily clinical practice is questionable. However,
before indicating neoadjuvant therapy and esophagectomy in locally advanced tumors,
PET should be performed to increase the sensitivity for exclusion of distant metastases
(van Westreenen et al. 2007). Bone scans are not part of routine staging procedure and
should be limited to patients with specific bone-associated symptoms or findings. In case
of ascites, laparoscopy should be performed to exclude peritoneal carcinomatosis.
Following the exclusion of distant metastases, sophisticated staging of the primary
tumor is of interest as clinical treatment is based on the categorization of the primary tumor
(Fig.4.2).
Locoregional staging is most reliably performed by means of endoscopic ultrasound
(Hardwick and Williams 2002; Kelly etal. 2001). Its average accuracy for T staging is
84% (range 6090%) and for nodal staging 77% (range 5090%) (Rsch 1995). If the
tumor cannot be passed endoscopically and accordingly cannot be investigated with endoscopic ultrasound, a T3 or T4 category must be assumed. In proximal and mid-esophageal
tumors, tracheobronchoscopy, with multiple biopsies and brush and washing cytology
examinations, is recommended to rule out tumor infiltration, indicating that the tumor is
not resectable and (possibly) indicating an enhanced risk of esophagotracheal fistula after
radiation therapy (Riedel etal. 1998, 2001).
With regard to patient perception of clinical diagnostics, significant but small differences were observed in patient burden for imaging tests to evaluate esophageal cancer. The
perceived burden of PET was lower than that of endoscopic ultrasound, but higher than the
burden of computed tomography. However, absolute values were low for all tests and
therefore patient burden will not be a key feature for the construction of an optimal staging
algorithm for esophageal cancer EC (Westerterp etal. 2008).
4.6
Preoperative Risk Assessment
Abdominothoracic esophagectomy implies a significant risk of postoperative morbidity and
mortality. This may even be higher after neoadjuvant chemoradiation. Many of the patients
presenting with esophageal cancer have concomitant diseases associated with alcohol or
tobacco consumption in squamous cell cancer and with obesity and other cardiovascular
risk factors in adenocarcinoma. The preoperative assessment of risk factors is of paramount
interest. Several scores have been developed (Bartels etal. 1998, 2000; Bollschweiler etal.
2000; Steyerberg et al. 2006). An evaluation of pulmonary, cardiac, renal, hepatic, and
endocrine functions is essential for the exclusion of excessive perioperative risks. Patients
with a high-risk score have been recommended to be excluded from esophagectomy and to
be offered alternative treatment options (Bartels et al. 2000) (Fig. 4.2). Cirrhosis of the
liver, current alcohol misuse, and irreversible severe pulmonary impairment are regarded as
absolute contraindications against esophagectomy. Cardiac risk, especially coronary heart
disease must be carefully evaluated and treated by coronary angioplasty if indicated. All
this must be done before any neoadjuvant treatment is started.
Any TN M1b
uT3/T4-Nx M0/M1a
uT1sm/2-Nx M0/M1a
uT1m Nx M0
ECOG-PS < 2
ECOG-PS > 2
nicht
resektabel
resectable
Chemotherapy
Best supportive Care
RCTx
Fig.4.2 Therapy of esophageal cancer according to staging
Resection
Preoperative therapy
(CTx or RCTx)
RCTx
Abdomino-thoracic esophagectomy
Rtx bei T1sm
EMR
Esophagectomy or limited
esophagectomy (Merendino)
EMR
RCTx
Normal surgical risk
High surgical risk
High surgical risk
High surgical risk
Primary treatment
CTx: chemotherapy; ECOG-PS: performance status according to Eastern Cooperativ Group; EMR: Endoscopic mucosal resection; RTx: radtiation; RCTx: radichemoradiation
In resectable tumors
surgical risk
assessment
including
ECG
echocardiography
stress test
coronary
angiography if
indicated
spirometry
renal, hepatic and
endocrine function
PET-CT before
neoadjuvant
therapy
Computed
tomography
neck, thorax,
abdomen
Endosonography
Abdominal
sonography
Biopsy/
Histology
Endoscopy
Clinical
Diagnostics
Postop. RTx
may be
considered in
R1 resected
patients
No routine
adjuvant
treatment
indicated
Adjuvant
therapy
4 Esophageal Cancer
77
78
4.7
Indications and Selection of Treatment Modalities
The goals of curative treatment of esophageal cancer are the radical resection with a low
risk of perioperative mortality and the minimization of a recurrence risk. The algorithm is
individualized and is mainly based on the preoperative TNM classification of the tumor
and the individual oncological and medical risk profile (Fig.4.2).
Endoscopic mucosal resection (EMR) has its proven indications and is an important
therapeutic approach in T1 mucosal cancer (Pech and Ell 2009a).
Radical transthoracic esophagectomy is the operation of choice, having shown a prog-
nostic advantage over subradical transhiatal esophagectomy in a prospective randomized controlled trial in the Netherlands (Hulscher etal. 2002).
A resection of the distal esophagus and reconstruction, according to Merendino, with
limited lymphadenectomy is indicated in adenocarcinoma of the distal esophagus, limited to the mucosal layer (Stein etal. 2007).
Radical resection after neoadjuvant therapy is warranted in locally advanced stages.
There are positive results from meta-analyses for neoadjuvant chemotherapy in locally
advanced adenocarcinoma and for neoadjuvant chemoradiation in squamous cell cancer and adenocarcinoma (Gebski etal. 2007).
Definitive chemoradiation may replace surgical resection in patients with co-morbidities or in patients who are not willing to take the risks of radical esophagectomy; but
local tumor control is significantly better with resection and survival has a strong trend
to favor surgery (Stahl etal. 2005).
4.8
Endoscopic Therapy
Centers now have an experience of more than 10 years with EMR in early esophageal
cancer (Ell etal. 2000). Criteria for an EMR with curative intention are as follows:
Infiltration restricted to the mucosal layer (T1a)

Tumor diameter 2cm
No ulcerative tumor
Histopathologic grading G1 or G2
No lymphatic and no vascular invasion (L0, V0)
The most commonly used techniques for endoscopic therapy are EMR and endoscopic
submucosal dissection (ESD) (Inoue etal. 2010).
While smaller lesions with a diameter up to 1 cm can be removed by EMR, bigger
lesions traditionally required a piecemeal resection which made the histopathological
4 Esophageal Cancer
79
assessment of resection margins difficult, if not impossible. With current ESD techniques,
lesions of >1cm can also be resected en bloc.
There are more data for endoscopic resection in early Barretts cancer than in T1
squamous cell cancer. Compared to surgery, there are significantly less R0 resections with
endoscopic resection (74.5% vs. 100%) (Vieth etal. 2004). However, the clinical success
rate seems to be very high according to the results of Ell and co-workers. In experienced
centers, the five-year survival rate after endoscopic mucosa resection for early Barretts
cancer is equivalent to that after surgical resection (Pech and Ell 2009b). A major debate
is around the question as to how the remaining Barretts epithelium after endoscopic resection of the neoplasia should be treated. There are competing approaches, e.g., surveillance,
photodynamic therapy, radiofrequency ablation, and resection. Prospective comparative
trials are missing thus far. EMR has also been performed for early squamous cell cancer.
Most results come from Japanese centers (Higuchi et al. 2009), but there is also some
experience in Western centers. According to current results, early squamous cell cancers
of the esophagus can also be treated endoscopically. The recurrence rate is about 26%,
especially in cancers with multifocal characteristics; but in case of local recurrence, salvage procedures can be performed successfully (Pech etal. 2007).
4.9
Surgical Therapy
The goal of oncological surgery in esophageal cancer is a radical (R0) resection together
with an adequate lymphadenectomy.
4.9.1
Procedures
Transthoracic en-bloc esophagectomy with radical mediastinal lymphadenectomy and
abdominal lymphadenectomy (so-called two-field lymphadenectomy) followed by

reconstruction with high intrathoracic or cervical anastomosis after gastric pull-up or
colon interposition. This procedure can be extended by a three-field lymphadenectomy
(Hlscher etal. 2003; Hlscher and Vallbhmer 2007) (Fig.4.3).
Transhiatal/cervical (synonym: transmediastinal) esophagectomy with lymphadenectomy of the lower mediastinum and abdominal lymphadenectomy followed by reconstruction with cervical anastomosis of a gastric pull-up or colon interposition
Distal esophagectomy with lymphadenectomy of the lower mediastinum and partial
abdominal lymphadenectomy and reconstruction by jejunal interposition (Merendino
procedure) (Gutschow etal. 2004; Stein etal. 2007) (Fig.4.4).
Resection of the cervical esophagus with regional lymphadenectomy and reconstruction
by a free jejunal interposition with microvascular anastomosis (Ott etal. 2009b) (Fig.4.5).
80
Fig.4.3 Transthoracic en-bloc
esophagectomy with radical mediastinal
lymphadenectomy and abdominal
lymphadenectomy
Fig.4.4 Limited cardia resection with jejunal interposition
4 Esophageal Cancer
81
Fig.4.5 Resection of the

cervical esophagus with
regional lymphadenectomy
and reconstruction by a free
jejunal interposition with
microvascular anastomosis
The procedure of choice for T1b tumors in squamous cell cancer of the distal esophagus as well as for Barretts cancer is a transthoracic en-bloc esophagectomy with a twofield lymphadenectomy and a high intrathoracic anastomosis. In a randomized controlled
trial there was no significant overall survival benefit for this approach. However, compared with limited transhiatal resection, extended transthoracic esophagectomy for type I
esophageal adenocarcinoma showed an ongoing trend toward better five-year survival.
Moreover, patients with a limited number of positive lymph nodes in the resection specimen seem to benefit from an extended transthoracic esophagectomy (Hulscher 2002;
Omloo etal. 2007).
Apart from the results of the randomized controlled trial, the rationale for this choice is
as follows: In all esophageal cancers of category T1sm or higher, the rate of lymph node
metastases is at least 30% or more. Affected lymph nodes can be localized in the mediastinum or in the locoregional abdominal lymph nodes. According to the current literature
(Stein et al. 2005; Feith et al. 2003), there seems to be a preferred lymphatic drainage
according to the location of the primary tumor but bidirectional lymphatic spread is also
possible. A clear preoperative distinction between affected and non-affected lymph nodes
82
is not possible. Sentinel-node techniques are currently not sufficiently established outside
clinical trials, although results from experienced centers are interesting (Burian etal. 2004;
Grotenhuis etal. 2009; Natsugoe etal. 2009; Piert etal. 2007; Takeuchi etal. 2009). In limited transhiatal/cervical procedures the lymph nodes of the middle and upper mediastinum
cannot be completely resected which limits the radicality of this surgical approach. Due to
these considerations, limited transhiatal/cervical resection is no more the procedure of choice
but can be used as an alternative approach in patients with limited pulmonary function for
avoiding thoracotomy and unilateral pulmonary ventilation in selected patients with distal
adenocarcinoma of the esophagus. Another attempt to limit the surgical trauma and to reduce
postoperative complications that are associated with laparotomy is laparoscopic ischemic
conditioning of the stomach for esophageal replacement (Hlscher etal. 2007).
Most esophageal cancers are located in the distal and middle third of the esophagus and
can be resected with safe margins by transthoracic esophagectomy and intrathoracic
transection allowing for a high intrathoracic anastomosis. Preparation of the cervical
esophagus can thereby be avoided which limits the morbidity of the procedure. Only in
carcinomas located above the tracheal bifurcation, a cervical transection and cervical anastomosis should be performed in order to ensure a sufficient radicality.
The high intrathoracic anastomosis has a similar mortality but a lower insufficiency rate
compared to cervical esophagogastrostomy and leads to a good swallowing function.
Leakage, strictures, and subsequent stenosis are more frequently found with cervical anastomosis (Hlscher etal. 2003; Ott etal. 2009a).
With a limited distal esophagectomy and reconstruction according to Merendino the
extent of lymphadenectomy is even more limited (Gutschow etal. 2004; Stein etal. 2007).
The lymph nodes of the middle and upper third of the mediastinum are left behind and a
lymphadenectomy of the lesser gastric curvature is limited at least when the vagal nerve is not
resected. Consequently, this procedure should be limited to patients without suspicion of
extended lymphatic spread, especially mucosal cancers in Barretts esophagus and is an alternative to endoscopic resection. Merendinos procedure cannot be recommended for T1sm
(submucosal) cancer, because the risk for lymphatic spread is 30% in this patient population
(Bollschweiler etal. 2006; Liu etal. 2005). Merendinos procedure can also not be recommended in very long Barretts metaplasia segments, because then neoplastic lesions would be
left behind which limits the curative intention of this approach (Westerterp etal. 2005).
For squamous cell cancer of the cervical esophagus, a limited cervical resection via
a cervical and sternal approach and reconstruction with a free jejunal interposition can
be performed. In the largest prospective series with this approach, the complete R0
resection rate was 72.5%. Median overall survival was 34.3 months; one-, three- and
five-year survival rates were 83.8, 47.0, and 47.0%, respectively. Despite high complication and reoperation rates, the mortality rate was low, even after preoperative chemoradiation. But randomized comparisons with definitive chemoradiation are lacking thus
far (Ott etal. 2009b).
4.9.2
Perioperative Morbidity and Mortality
Diagnostic and therapy of postoperative complications are listed in Table4.5.
83
4 Esophageal Cancer
Table4.5 Diagnostic and therapy of postoperative complications following esophagectomy
Complication
Diagnostic
Therapy
Recurrent nerve palsy
Clinical, bronchoscopy
Respiratory support,
tracheotomy, logopedics
Tracheobronchial lesions
Bronchoscopy
Spontaneous ventilation,
tracheotomy, stent
Anastomotic leakage
Contrast enhanced X-ray

endoscopy
Thoracic: Stent, re-thoracotomy

Cervical: Wound incision,
drainage
Necrosis of the interposition
Endoscopy
Resection of the interposition
Interposition
retention/pylorospasm
Endoscopy
Dilatation
Erythromycin
Anastomotic stenosis

endoscopy
Dilatation
Chylothorax
Pleurocentesis
Conservative, ligature
The most frequent general complications following esophagectomy comprise bronchopneumonia, delirium tremens in alcoholics, and cardiac dysrhythmia, especially atrial
fibrillation, which all have to be treated accordingly, usually in intensive care units. It has
always to be kept in mind that general symptoms can be associated with or superimposed
to surgical complications (Stippel etal. 2005).
For reaching good results in esophageal surgery, all procedures must be highly standardized. Not only the surgeons but also the whole team including anesthetists, intensive
care physicians, radiologists, pathologists etc., must be trained. The postoperative mortality is clearly reduced in centers with a high case load (Birkmeyer etal. 2002; Hlscher
etal. 2004). According to the German literature analysis, 20 esophagectomies per year are
necessary in order to achieve a hospital mortality rate of <5%. Also long-term outcome
seems to be better in high-volume centers (Birkmeyer etal. 2007).
4.9.3
Long-Term Surgical Outcome
The crucial prognostic factor in esophageal surgery is a resection with tumor-free margins
(R0) (Hlscher etal. 1995; Roder etal. 1994). Survival analysis demonstrates that almost
all patients with macroscopic tumor residuals or with microscopically involved margins
die within two years, while in patients with tumor-free margins the five-year survival rate
is 40%. Due to a variety of reasons the survival rate of patients with squamous cell cancer
of the esophagus is lower than for patients with adenocarcinoma (Siewert etal. 2001). Best
surgical results are achieved with radical transthoracic esophagectomy (Hulscher et al.
2002; Omloo etal. 2007).
T category and N category are both very strong and independent prognostic factors. The
outcome of patients presenting with N1 disease depends on the ratio of invaded vs. resected
84
lymph nodes. The smaller this ratio is kept, the better the prognosis (Hlscher etal. 1995;
Roder etal. 1994).
Improvements in prognosis can be achieved with preoperative therapy. Response to preoperative treatment has been shown to be an independent prognostic factor (Brcher etal.
2006; Brcher etal. 2009; Javeri etal. 2008; Schneider etal. 2005; Siewert etal. 2001).
Concerning quality of life, even after 3 years, patients who underwent esophagectomy suffered persistent problems with physical function and specific symptoms. These findings may
be used to inform patients of the long-term consequences of surgery (Lagergren etal. 2007a).
4.10
Perioperative Treatment
Despite the optimization of surgical treatment as delineated above, long-term outcome in
locally advanced stages is still poor with surgical therapy alone. This is why neoadjuvant and
adjuvant therapies have been tested in randomized controlled trials. Adjuvant treatment following esophagectomy is difficult to deliver due to the relatively high complication rate,
morbidity, weight loss, and digestive disorders associated with esophagectomy. Current retrospective data suggest that postoperative radiation therapy may be beneficial in selected cases
(Schreiber etal. 2010). However, controlled randomized trials could not establish a role for
adjuvant radiation therapy in resected esophageal cancer. The same is true for postoperative
chemotherapy, for which randomized controlled trials could show only moderate benefit in
subgroups of patients (Ando etal. 1997, 2003). After these unsatisfying results regarding the
role of any postoperative treatment, the research focus was directed to neoadjuvant preoperative treatment which theoretically may have several advantages. Neoadjuvant therapy may
shrink the tumor and thus enable R0 resection in cases with marginally resectable tumors. It
also may improve the systemic relapse rate by eliminating hematogenous metastases early in
the course of treatment. Finally, it allows for response monitoring invivo by conventional
and investigational imaging technologies (Lordick etal. 2004; Lordick 2009).
4.10.1
Neoadjuvant Radiation
Neoadjuvant radiation without chemotherapy has been investigated in five fully published
randomized controlled trials. Clinical response to neoadjuvant radiation was reported in
about two thirds of patients. But a significant survival advantage was reported in only one
study (Nygaard etal. 1992). Two studies reported a worse outcome with neoadjuvant radiation. In a recent meta-analysis including 1,147 patients from five randomized controlled
trials, the investigators conclude that neoadjuvant radiation leads to a relative risk reduction for the endpoint death with a hazard ratio (HR) of 0.89, 95% confidence interval (CI)
0.781.01. The survival difference is 3% after 2 years and 4% after 5 years. This is not
statistically significant (p=0.062) (Arnott et al. 2005). Preoperative radiation alone is
therefore not indicated for esophageal cancer.
4 Esophageal Cancer
85
4.10.2
Neoadjuvant Chemotherapy
Nine randomized controlled trials have been performed investigating the role of preoperative chemotherapy. Seven studies enrolled patients with squamous cell cancer only; two
studies allowed for the inclusion of squamous cell and adenocarcinoma (Allum etal. 2009;
Kelsen etal. 1998; Medical Research Council 2002). Only the newest study organized by
the United Kingdom Medical Research Council could demonstrate a small, although significant survival advantage for patients receiving neoadjuvant chemotherapy (Allum etal.
2009). In contrast to other randomized studies, the proportion of patients with adenocarcinoma of the esophagus in the British study was >60%. In the subgroup analysis of patients
with adenocarcinoma a significant survival advantage was found.
Several older meta-analyses could demonstrate improved R0 resection rates but only
marginally improved survival rates for patients treated with neoadjuvant chemotherapy in
resectable esophageal cancer. Of note, most patients who were analyzed had squamous cell
cancers (Urschel etal. 2002; Malthaner and Fenlon 2003).
There is no significant increase in the postoperative complication rate or mortality rate
following neoadjuvant chemotherapy. However, severe (grade 3) and life-threatening
(grade 4) toxicities are observed in 32 patients treated neoadjuvantly with cisplatin and
5-fluorouracil and a death rate of 1.62.1% has been reported (Urschel et al. 2002;
Malthaner and Fenlon 2003).
A recently published meta-analysis of over 1,724 patients enrolled in 11 randomized
controlled trials showed a significant survival advantage for patients treated with neoadjuvant chemotherapy with a relative risk reduction of 10% and a two-year survival difference
of 7%. This meta-analysis presented subgroup analyses according to the histopathologic
subtype. While the difference was nonstatistically significant for squamous cell cancer (HR
0.87; 95% KI 0.751.03, p=0.12), the difference was statistically significant for adenocarcinoma of the esophagus (HR 0.78; 95% KI 0.640.95, p=0.014) (Gebski etal. 2007).
In summary, it has been shown that neoadjuvant chemotherapy improves the prognosis
of patients with locally advanced adenocarcinoma of the esophagus without increasing the
postoperative mortality rate.
4.10.3
Neoadjuvant Chemoradiation
Neoadjuvant chemoradiation has been the most frequently studied neoadjuvant treatment
modality for locally advanced esophageal cancer within the last years. Most studies included
patients regardless of the histopathologic subtype of their cancer. One study included patients
with adenocarcinoma only (Walsh etal. 1996); three other studies included a majority of
patients with adenocarcinoma (Urba etal. 2001; Burmeister 2005; Tepper etal. 2008).
Meta-analyses come to the result that neoadjuvant chemoradiation leads to a significantly improved survival rate and an improved locoregional tumor control rate (Fiorica
etal. 2004; Gebski etal. 2007; Greer etal. 2005; Urschel and Vasan 2003). But postoperative mortality was also found to be increased after neoadjuvant chemoradiation. This effect
86
was less marked when studies using single doses of >2Gy were excluded from the metaanalysis (Fiorica etal. 2004). The deleterious effects of neoadjuvant chemoradiation are
not sufficiently understood thus far. Neoadjuvant chemoradiation with higher doses leads
to an impaired alveolar diffusion capacity and therefore to impaired pulmonary gas
exchange. In patients undergoing previous chemoradiation, there is an increased rate of
postoperative respiratory complications (Abou-Jawde etal. 2005). With regard to cellular
immunity, neoadjuvant chemoradiation seems to suppress T-lymphocytes which leads to
an increased risk of encountering postoperative septic complications (Heidecke et al.
2002). A significant decline in the postoperative complication rate and mortality rate following neoadjuvant chemoradiation was achieved with the introduction of a two-stage
operation which means that reconstruction of the intestinal passage is done >7 days after
esophagectomy (Stein etal. 2001).
In the most recent meta-analysis (Gebski etal. 2007), 1,209 patients who were enrolled
in ten randomized studies were analyzed. The HR for survival after neoadjuvant chemoradiation vs. surgery alone was 0.81 (95% CI 0.700.93; p=0.002) corresponding to a difference in the two-year-survival rate of 13%. This was in the same range for adenocarcinoma
and for squamous cell cancer of the esophagus.
A small randomized trial that was finished prematurely due to low accrual randomized
patients to receiving an unusual preoperative chemotherapy regimen (18 weeks of
cisplatin/5-fluorouracil) vs. an investigational chemoradiation regimen (12 weeks of
cisplatin/5-fluorouracil followed by cisplatin/etoposide plus radiation, dose 30Gy) (Stahl
etal. 2009). Due to the exploratory character of this study comparing two experimental
arms and the limited number of enrolled patients, no major conclusions can be drawn. The
study showed a similar R0 resection rate in both arms. The study also showed a trend
toward an improved survival rate in the chemoradiation arm with an HR of 0.67 (95% CI
0.411.07) and a trend toward an increased postoperative mortality rate (10.2% after
chemoradiation vs. 3.8% after chemotherapy alone).
In summary, the survival rates are significantly better after neoadjuvant chemoradiation, even though postoperative mortality may be increased in comparison to surgery
alone. This is true for adenocarcinoma and for squamous cell carcinoma of the esophagus,
albeit for adenocarcinoma the benefit seems to be in the same range as for chemotherapy
without radiation.
Patients with clinically staged uT3/T4 tumors and/or with lymph node involvement
(stages II and III) are candidates for neoadjuvant treatment (Fig.4.2).
4.10.4
Quality of Life
Esophagectomy has a negative influence on health-related quality of life (HRQL) during
the first postoperative year. A recent study examined HRQL during preoperative chemotherapy/chemoradiotherapy treatment and compared postoperative recovery of HRQL in
patients undergoing combined treatment with patients undergoing surgery alone.
Deterioration in most aspects of HRQL occurred during preoperative chemotherapy.
4 Esophageal Cancer
87
Patients proceeding to concomitant radiotherapy further deteriorated with specific problems with reflux symptoms and role function (difference between means >15, p<0.01).
After neoadjuvant treatment, but before surgery, HRQL returned to baseline levels. Six
weeks after surgery, patients reported marked reductions in physical, role, and social function (difference between means >30, p<0.01) and increase in fatigue, nausea and emesis,
pain, dyspnea, appetite loss, and coughing (difference between means >15, p<0.01).
Recovery of HRQL was not hampered by preoperative treatment, and fewer problems with
postoperative nausea, emesis, and dysphagia were reported by patients who had undergone
neoadjuvant treatment compared with patients who had undergone surgery alone. In conclusion, preoperative chemotherapy or chemoradiotherapy had a negative impact on
HRQL that was restored in patients proceeding to surgery. Recovery of HRQL after
esophagectomy was not impaired by neoadjuvant treatment. These results supported the
use of neoadjuvant treatment before surgery (Blazeby etal. 2004). A new quality of life
questionnaire has been developed by the European Organization of Research and Treatment
of Cancer. The QLQ-OG25 is recommended to supplement the EORTC QLQ-C30 when
assessing HRQL in patients with esophageal, junctional or gastric cancer (Lagergren etal.
2007b).
4.10.5
Treatment Protocols
4.10.5.1
Chemotherapy
In the largest trial showing a significant survival advantage for neoadjuvant chemotherapy,
patients received two preoperative cycles of cisplatin 80mg/m2 on day 1 (over 4h, as usually given in the United Kingdom, 1 h in many other countries) plus 5-fluorouracil
1,000mg/m2/day on days 14 (24-h-infusion), to be repeated after 3 weeks (Allum etal.
2009; Medical Research Council 2002).
4.10.5.2
Chemoradiation
In view of the many and heterogenous schedules that have been investigated and the conflicting results that exist, it is not possible to identify an optimal neoadjuvant chemoradiation regimen.
Outside clinical trials, radiation should be conventionally fractionated. Single doses
should not exceed 2Gy. Limited experience exists with hyperfractionated or accelerated
protocols which should not be used outside of clinical trials. Doses that have been investigated in randomized trials were between 20 and 45Gy with a trend to higher response rates
with higher doses but also more pulmonary toxicity. A total dose of 45 Gy with single
doses of 1.8Gy has been established as standard of care in many experienced institutions.
88
Cisplatin and continuous infusions with 5-fluorouracil are usually given as concomitant
chemotherapy. To avoid the typical toxicities associated with cisplatin, oxaliplatin was
tested with reasonable results in phase II, but randomized studies are lacking (Khushalani
etal. 2002; Lorenzen etal. 2008). Therefore, oxaliplatin may serve as a substitute for cisplatin in patients presenting with contraindications against cisplatin infusions.
Esophagitis is the dose limiting toxicity of mediastinal radiotherapy. 5-Fluorouracil
may augment this specific adverse effect. Therefore, 5-fluorouracil-free regimens have
been developed. The combinations of cisplatin plus paclitaxel or cisplatin plus docetaxel
or cisplatin plus irinotecan have yielded interesting results (Brenner etal. 2004; Ilson etal.
2003; Ruhstaller etal. 2009). But the superiority of these newer regimes vs. cisplatin plus
5-fluorouracil has not been proven in a randomized controlled trial.
The interval between the end of concomitant chemoradiation and surgery should usually be 46 weeks. This standard which is based on expert knowledge and some theoretical
considerations has never been tested in a clinical trial. While recovery from acute skin and
mucosal toxicities usually takes place within the first 6 weeks following chemoradiation,
it is also known that within this time frame there is the greatest risk for developing radiation induced pneumonitis (Mehta 2005). In our own experience, a time interval of 48
weeks between the end of radiation and surgery has proved to be of value.
4.10.6
Response Evaluation and Response Prediction
A couple of recent trials investigated the significance of response during and after neoadjuvant therapy. Histopathologic remission has been shown to be an important prognostic
factor (Berger etal. 2005; Brcher etal. 2006; Rohatgi etal. 2005; Schneider etal. 2005;
Swisher etal. 2005). Histological type of esophageal cancer might affect response to neoadjuvant chemoradiation and subsequent prognosis (Bollschweiler etal. 2009). Response
evaluation by established clinical methods like endoscopy, re-biopsy, and endoscopic
ultrasound does not accurately predict histopathologic response. Post-treatment endoscopic biopsy is a poor predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer and the American Joint Committee on Cancer
staging system does not accurately predict survival in patients receiving multimodality
therapy for esophageal adenocarcinoma (Rizk etal. 2007).
Often, conventional clinical assessment cannot distinguish between tumor and fibrous
tissue or post-radiation edema. Of note, post-treatment endoscopic biopsy is a poor predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal
cancer (Sarkaria etal. 2009). Supplementary information is provided by Fluordeoxyglucosepositron emission tomography (FDG-PET). FDG-PET is a preferred method in clinical
studies to assess post-therapeutic response and to predict survival (Swisher etal. 2004;
Flamen etal. 2002; Downey etal. 2003; Wieder etal. 2004, 2007). However, FDG-PET is
not able to predict histopathologic complete response (Vallbhmer etal. 2009). Therefore
minimal residual disease cannot be excluded by post-therapeutic FDG-PET and therefore
this assessment should not be used outside of clinical trials to exclude patients from surgery or to delay surgery.
4 Esophageal Cancer
89
Meanwhile, it has become clear that patients who do not respond to neoadjuvant treatment have a very poor prognosis that is even worse than the prognosis for patients who do
not receive neoadjuvant chemotherapy or neoadjuvant chemoradiation (Kelsen etal. 2007;
Bollschweiler etal. 2009). These patients are probably no good candidates for neoadjuvant
treatment. FDG-PET signals have been used to identify patients who do not respond to
neoadjuvant treatment and should be offered alternative treatment options. Higher glucose
uptake as measured by FDG-PET seems to correlate with a better chance for responding to neoadjuvant therapy (Javeri etal. 2009; Lordick etal. 2007; Rizk etal. 2009).
Data for early response evaluation by monitoring tumor glucose uptake during neoadjuvant chemotherapy by FDG-PET are particularly interesting and promising. An insufficient decrease of the FDG uptake after only 14 days of neoadjuvant chemotherapy indicates
patients who have a very poor chance of responding to further chemotherapy (Ott etal.
2006; Weber etal. 2001). An interventional study showed that early response monitoring
by FDG-PET can be integrated into a clinical treatment algorithm and can help to guide
neoadjuvant treatment (Lordick etal. 2007).
4.11
Definitive Chemoradiotherapy
4.11.1
Randomized Studies
In randomized studies, primary simultaneous chemoradiation has proved to be superior
compared with conventionally fractionated radiotherapy with regard to local tumor control, relapse-free survival, and overall survival. One-year survival is improved by about
9% and two-year survival by about 8% (Herskovic etal. 1992; Kleinberg etal. 2007). It is
crucial that chemotherapy and radiotherapy are given simultaneously.
To clarify the optimal dose of radiotherapy given in combination with cisplatin
and 5-fluorouracil, a randomized trial compared 50.4 with 64.8Gy (Minsky etal.
2002). The higher radiation dose failed to show superiority with regard to local
tumor control, relapse-free survival, and overall survival. In contrast, acute side
effects and therapy-associated deaths were increased. Therefore, the regimen as
published by the Radiation Therapy Oncology Group (RTOG 8506) with a radiation dose of 50.4Gy (conventional fractionation of 1.82.0Gy/day) with concomitant cisplatin (75mg/m day 1) and 5-fluorouracil (1,000mg/m days 14, repeated
week 5) has remained a standard of care. Radiation split-course regimes are less
effective in achieving local tumor control and should not be used (Crehange etal.
2007). Only when there are absolute contraindications against chemotherapy or
when the treatment goal is clearly palliative, patients should be treated with radiotherapy alone.
90
4.11.2
Chemoradiation vs. Surgery
Recent randomized studies compared definitive chemoradiation with neoadjuvant chemoradiation followed by esophagectomy in locally advanced esophageal cancer. Of note, no
such comparison is available for adenocarcinoma of the esophagus (Lordick etal. 2006).
Briefly, these studies could not show a statistically significant survival advantage for
surgical resection vs. definitive chemoradiation in locally advanced squamous cell carcinoma of the esophagus. However, in the German multicenter study, a difference in threeyear survival of 7% favoring resection was seen. But as the endpoint of this study was
planned to show non-inferiority of chemoradiation, this difference failed to be statistically
significant (Stahl etal. 2005). Local tumor control was significantly better after surgery.
Subgroup analyses suggest a benefit of surgery especially for those patients who do not
respond to neoadjuvant chemoradiation. Of note, in both large European randomized trials,
the postoperative mortality rate was >10% (Stahl etal. 2005; Bedenne etal. 2007). Surgery
and continuation of chemoradiation had the same impact on quality of life in patients with
locally advanced, resectable esophageal cancer although a significantly greater decrease in
quality of life was observed in the postoperative period (Bonnetain etal. 2006).
In conclusion, resection should be offered to all fit patients presenting with locally
advanced esophageal squamous cell cancer who are willing to undergo surgery and who
are able to understand the advantages and limitations and risks of a surgical procedure. In
patients with increased surgical risks and in patients who are not consenting to a surgical
resection, definitive chemoradiation is an alternative which leads to comparable survival
results. It should be emphasized that only few data exist for the definitive chemoradiation
of esophageal adenocarcinoma. In this respect, surgery remains the unchallenged standard
of care for R0 resectable localized esophageal adenocarcinoma.
4.12
Treatment of Metastatic Disease
4.12.1
Chemotherapy
Distant metastases are found in approximately 50% of patients newly diagnosed with
esophageal cancer. Additionally, in about 50% of patients with resected esophageal cancer
distant metastases occur as metachronous lesions.
The indication for palliative chemotherapy is based on individual factors and preferences and on the patients motivation. Randomized studies comparing best supportive care
with or without chemotherapy have not been performed in esophageal cancer. In a recently
published analysis of a large database of patients treated in randomized trials coordinated
by the Royal Marsden Hospital, no significant differences were demonstrated on multivariate analyses in overall survival, response rate, and toxic effects among patients with
35
71
Cisplatin 30mg/m2 weekly 4/6 weeks

Irinotecan 65mg/m2 weekly 4/6 weeks
Ilson etal. (1999)
Cisplatin 80mg/m2 d1 Vinorelbine

25mg/m2 d1, 8, qd22 (Conroy etal. 2002)
SCC
SCC/AC
SCC
34%
(95% CI: 2346%)
57%
(95% CI: 4173%)
35%
(95% CI: 2054%)
Response rate
3.6 months
(PFS)
27 weeks
(TTP)
TTP/PFS
6.8 months
4.2 months
40 weeks
Duration of
response
AC adenocarcinoma; CI confidence interval; PFS progression-free survival; SCC squamous cell cancer; TTP time to progression
44
Cisplatin 100mg/m2 d1
5-FU 1,000mg/m2 d15, qd22
Bleiberg etal. (1997)
Table4.6 Phase II studies for the treatment of advanced esophageal cancer

Histology
n
6.8 months
14.6 months
33 weeks
Median survival
4 Esophageal Cancer
91
92
Table4.7 Chemotherapy regimens for the treatment of advanced esophageal cancer
First-line therapy
Cisplatin/5-FU
(modified Bleiberg etal. 1997)
Cisplatin/Vinorelbin
(Conroy etal. 2002)
Cisplatin 80mg/m2 day 1

5-FU 1,000mg/m2 days 14,
repeated day 22
Cisplatin 80mg/m2 day 1
Vinorelbin 25mg/m2 days
1+8, repeated day 22
Second-line therapya
Capecitabine/Docetaxel
(Lorenzen etal. 2005)
Capecitabine 1,000mg/m2
days 114
Docetaxel 75mg/m2 day 1,
repeated day 22
May also be used in first line, when there are contraindications against the use of cisplatin
advanced esophageal, esophagogastric junction, and gastric adenocarcinoma (Chau etal.

2009). Therefore, patients with metastatic adenocarcinoma of the esophagus should be
treated with the same chemotherapy regimen as patients with advanced gastric adenocarcinoma. Whether this is also true for new biologically targeted drugs remains to be
shown.
Combination chemotherapy consisting of cisplatin plus 5-fluorouracil or another combination partner has achieved 2550% tumor remissions (mostly partial responses)
(Table4.6).
In more recent studies, chemotherapeutic drugs of the newer generation were investigated. For patients with progression after platin-based first-line chemotherapy, no standards are available thus far. The combination of docetaxel every 3 weeks and the oral
fluoropyrimidine capecitabine yielded interesting response rate and may be considered
after failure of platin-containing chemotherapy (Lorenzen etal. 2005). Interesting chemotherapy regimens for the treatment of advanced esophageal cancer are found in Table4.7.
The current clinical research is focused on the characterization of new therapeutic targets and evaluation of biologically targeted drugs. The epidermal growth factor receptor
(EGFR) family seems to be of particular interest for testing new treatments in esophageal
cancer. First clinical studies investigating the value of anti-EGFR-directed therapy have
been published (Dragovich etal. 2004; Lorenzen etal. 2009). Other targets may also play
a role in the near future.
4.12.2
Local Treatment
Treatment of tumor stenosis which is often found associated with advanced tumor stages
is primarily endoscopic. Endoscopic dilation of the esophagus can lead to immediate patency and relief of symptoms. As these effects usually are of short duration, dilatation often
is stabilized by the insertion of a stent, by thermic (radiofrequency) ablation, or by insertion of a percutaneous endoscopic gastrostomy (PEG).
Exophytic tumors can be effectively treated with Nd-YAG laser or with an argon plasma
beamer. These methods are technically limited in long-segment tumor stenosis; moreover,
4 Esophageal Cancer
93
palliative effects are usually of short duration because tumor regrowth may lead to recurrent stenosis after 46 weeks.
Radiotherapy does also effectively provide relief from symptoms caused by tumor
stenosis. Stents that are inserted before the start of radiation should be extractable in case
of tumor remission. Esophagotracheal or esophagobronchial fistula constitute a contraindication against endoscopic laser or beamer therapy. In this situation, covered stents should
be inserted.
It should be kept in mind that besides some early complications of stenting, especially
pain in 40% of patients, late complications may occur in about a third of endoscopically
stented patients. These are stent migration or dislocation or restenosis in the stent by tumor
growth. This may necessitate further treatment like the insertion of another stent or thermic
ablation within the stent.
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Gastric Cancer
John S. Macdonald, Scott Hundahl, Stephen R. Smalley, Denise ODea,

and Edith P. Mitchell
5.1
Epidemiology
Gastric cancer represents a challenging health problem around the world. It is the fourth
most common cancer behind lung, breast, and colon and rectum cancers. An analysis of the
worldwide incidence and mortality from gastric cancer had estimated that 691,432 new
cases among men and 375,111 cases among women would occur in 2007 (Garcia et al.
2007). It was also estimated that approximately 800,000 patients would die of this disease
annually (Garcia etal. 2007). In the United States, it was estimated that 21,000 new cases
of gastric cancer would occur in 2010, with 10,570 deaths expected (Jemal etal. 2010).
There are significant geographic variations in the incidence of gastric cancer. Nearly
70% of new cases of gastric cancer occur in developing countries (Garcia etal. 2007). An
estimated 42% of all cases occur in China alone. This disease is far more common in geographic areas such as East Asia, Eastern Europe, Costa Rica, and parts of Central and
South America than it is in the United States or Western Europe (Parkin etal. 2005). In
most countries, the incidence and death rates for men are twice as high as those for women.
In high-incidence countries (Jemal etal. 2010; Parkin etal. 2005), the intestinal form of
J.S. Macdonald ()
Aptium Oncology Inc, 8201 Beverly Boulevard, Los Angeles, CA 90048, USA
e-mail: jmacdonald@aptiumoncology.com
S. Hundahl
VA Northern California Health Care System, Mather, CA 95655, USA and
U.C. Davis, Sacramento, CA 95817, USA
S.R. Smalley
Olathe Regional Oncology Center, Olathe, KS, USA
D. ODea
Mount Sinai Medical Center New York, New York, USA
E.P. Mitchell
Thomas Jefferson University, Philadelphia, PA, USA
101
102
J.S. Macdonald et al.
gastric cancer associated with intestinal metaplasia and Helicobacter pylori (H. pylori)
mediated gastritis is significantly more common than the diffuse form.
Japan is the only country demonstrating a moderately good survival rate for patients
diagnosed with stomach cancer. This finding is likely due to earlier diagnosis secondary to
mass screening, including the use of newer endoscopic techniques such as photofluoroscopy (Parkin etal. 2005). Most patients with gastric cancer in the U.S. are symptomatic at
the time of diagnosis and have locally advanced or metastatic disease. In North America,
survival is improving secondary to greater numbers of endoscopic examinations for various upper abdominal symptoms, leading to earlier diagnosis of cancer.
A small percentage of gastric cancers are hereditary, but the vast majority of cases are
related to environmental, socioeconomic, and dietary risk factors. A steady decline in gastric cancer rates in developed countries has been observed over the past 50 years with rates
dropping by more than 80% (Garcia etal. 2007). The decline may be due to improvements
in food storage and preservation as well as lifestyle changes. Increased availability of fresh
fruits and vegetables and the decreased use of salted and preserved foods have also contributed to the decline (Garcia etal. 2007). Changes in the prevalence of H. pylori may also
play a role, with H. pylori infection becoming less prevalent in relatively wealthy western
countries. Decrease in H. pylori infection is due to better sanitation, increased use of antibiotics, and increased screening in developed countries.
5.2
Etiology
The great majority of malignant tumors of the stomach are adenocarcinomas (Macdonald
et al. 1992). The histology of gastric adenocarcinoma falls into two broad subtypes: the
intestinal and diffuse types. The intestinal type is the form of gastric cancer seen in countries
with high incidence rates, and it is also referred to as the endemic form of stomach cancer.
The intestinal type arises in the antrum or antral-corpus junction. The histologic type varies
with tumor location in the stomach. Diffuse-type cancers involve the corpus, and intestinaltype cancers may be seen in the gastroesophageal junction (Hundahl etal. 2006).
In high-incidence countries, the most common gastric cancers are the intestinal-antral
types, which are usually associated with pre-existing intestinal metaplasia, atrophic
gastritis, and chronic H. pylori infections. The remaining types of gastric cancers in highincidence countries are diffuse-type tumors. Diffuse-type gastric cancers may also be
associated with the presence of H. pylori but generally do not develop on the background
of intestinal metaplasia. In high-incidence countries, these diffuse-type cancers occur in
geographic locations where a high prevalence of H. pylori exists. The relationship of
H. pylori infection to the etiology of diffuse-type cancers is not as clear as the bacterias
role in intestinal-type cancers. Diffuse-type cancers are more common in younger patients
and may be associated with brisk mucosal inflammatory infiltrates that may in some cases,
be related to H. pylori infection (Hundahl etal. 2006).
Intestinal-type cancers of the proximal stomach and gastroesophageal junction are
less common in high-incidence countries. These are usually associated with gastro
esophageal reflux disease (GERD). These GERD-associated tumors occur most commonly
5 Gastric Cancer
103
in middle-aged white men, and, although the distal esophagus is most commonly involved,
the cardioesophageal junction also frequently exhibits tumors. It becomes difficult to determine whether these cancers are gastroesophageal junction stomach tumors or distal esophageal malignancies. The tumors associated with GERD also appear to be more common in
obese men who drink alcohol and smoke cigarettes. It is considered possible that all three
factors (drinking, smoking, and obesity) decrease the tone of the gastroesophageal sphincter
mechanism and thus favor GERD (Parkin et al. 2005; Macdonald et al. 1992; van den
Brandt and Goldbohm 2006).
Gastric malignancies other than adenocarcinomas account for <10% of gastric cancers
(Berlin and Washington 2006). These tumors of the stomach include undifferentiated gastric carcinomas with lymphoid stroma, hepatoid carcinomas, adenoacanthomas, adenosquamous and squamous cell carcinoma, parietal cell carcinoma, oncocytic gastric
carcinoma, carcinoid tumors, and gastrointestinal stromal tumors (GIST) (Berlin and
Washington 2006). GIST tumors are discussed elsewhere in this book. Choriocarcinomas,
teratomas, and yolk sac tumors all occur as primary gastric tumors; although these germ
cell neoplasms are very uncommon, the stomach is the most common site of nongonadal,
nongestational germ cell tumors (Berlin and Washington 2006). Lymphoma occurs in the
gastrointestinal (GI) tract, and the stomach is the most common site for GI lymphomas.
Most gastric lymphomas are of the non-Hodgkins type, with the majority classified as
B-cell lymphomas (Berlin and Washington 2006). Mucosa-associated lymphatic tissue
(MALToma) neoplasms are low-grade neoplastic processes associated with H. pylori colonization and occur in the stomach. These neoplastic B-cell proliferations appear to initially
develop as polyclonal proliferations, which may be successfully treated with antibiotic
therapy directed at eradication of H. pylori before the MALToma has evolved to a monoclonal, truly malignant neoplasm (Berlin and Washington 2006; Wotherspoon etal. 1993;
Manson 2006).
5.3
Environmental Risks and Prevention
A number of epidemiologic studies have examined various factors associated with the
development of gastric cancer. Low socioeconomic class and low education level have
been associated with a higher incidence of gastric cancer. A higher incidence has also been
seen in those who work in coal, nickel, and asbestos mining and in the processing of timber
and rubber (Wu-Williams etal. 1990). Blood group A, gastric ulcer, ionizing radiation, and
previous gastric resection are also associated risk factors (Hundahl etal. 2006).
Dietalso plays a role in the development of gastric cancer. Diets with a high intake of
smoked and cured meats, as well as diets with a high intake of salt or salt-preserved foods,
have been associated with gastric cancer (van den Brandt and Goldbohm 2006). Diets
deficient in raw vegetables and fruits, vitamin C, and antioxidants also are associated with
gastric cancer. Obesity has been linked to approximately 2540% of gastric cancers
(NCCN). Smoking and alcohol consumption have been associated with gastroesophageal
junction tumors. Dietary and lifestyle changes may play a modest role in the prevention of
gastric cancer (van den Brandt and Goldbohm 2006).
104
Evidence linking H. pylori infection to gastric cancer was considered sufficient for the
International Agency for Research on Cancer to classify it as carcinogenic in humans
(Parkin etal. 2005). The role of H. pylori infection in carcinogenesis is probably indirect,
with the bacteria serving as a factor in causing gastritis. This chronic gastritis may lead to
dysplasia and eventually carcinoma. The infection is acquired in childhood, and prevalence is related to socioeconomic status. The primary prevention strategy for reducing the
risk of gastric cancer includes reducing the prevalence of H. pylori infection by improving
hygienic conditions and increasing the use of antibiotics to eradicate H. pylori in cases
harboring the bacteria.
5.3.1
Genetic Risk
Approximately 13% of gastric cancers are associated with an inherited gastric cancer
syndrome (NCCN guidelines). The lifetime risk for diffuse gastric cancer in individuals
with the gene mutation is approximately 67% for men and 83% for women.
Hereditary diffuse gastric cancer (HDGC) is strongly associated with an autosomal
dominant susceptibility to develop diffuse gastric cancers. These diffuse cancers are poorly
differentiated adenocarcinomas that infiltrate the stomach wall, causing thickening of the
wall without forming a distinct mass (Kaurah and Huntsman 2004). Most cases of HDGC
occur before the age of 40, with an average onset age of 38 years. Germline mutations in
the E-cadherin gene, CDH1, have been identified in families with HDGC. The CHD1 gene
is the only gene known to be associated with HDGC (Kaurah and Huntsman 2004).
In 1999, the International Gastric Cancer Linkage Consortium defined HDGC as the
presence of two or more documented cases of diffuse gastric cancer in first- or seconddegree relatives, with at least one case diagnosed before age 50 or three or more documented
cases of diffuse gastric cancer in first- or second-degree relatives, regardless of age of onset
(Kaurah and Huntsman 2004). Genetic testing was recommended for individuals falling into
these categories. In 2004, the criteria for consideration of genetic testing were revised. The
six criteria for consideration of CDH1 molecular genetic testing are outlined in Table5.1.
Due to the broad nature of the recommendations, it may not be practical for use in regions of
high gastric cancer incidence, such as Japan (Kaurah and Huntsman 2004). Other cancers
reported in family members of patients with HDGC are lobular breast cancer and colorectal
cancer. Patients with these neoplasms in HDGC families have not, at this point, been recommended as candidates for genetic testing (Kaurah and Huntsman 2004).
Management options for carriers of CDH1 germline mutations include prophylactic
gastrectomy or intensive surveillance for early detection and treatment of gastric cancer
(Blair etal. 2006). Current methods of surveillance use chromogastroscopy. The use of
newer sophisticated endoscopic techniques (Berlin and Washington 2006), such as spectroscopy and autofluorescence, have not been studied in HDGC. Small studies of prophylactic gastrectomy have shown that they can be performed safely and prevent cancers in
carriers of CDH1 germ-line mutations (Newman and Mulholland 2006). Prophylactic gastrectomy and surveillance remain controversial and require further study to fully understand the risks and benefits of these approaches.
5 Gastric Cancer
105
Table5.1 Criteria for consideration of CDH1

Molecular genetic testing
Two or more cases of gastric cancer in a family, with at least one diffuse gastric cancer
diagnosed before age 50 years
Three or more cases of gastric cancer in a family, diagnosed at any age, with at least one
documented case of diffuse gastric cancer
An individual diagnosed with diffuse gastric cancer before 45 years of age
An individual diagnosed with both diffuse gastric cancer and lobular breast cancer
(no other criteria met)
One family member diagnosed with diffuse gastric cancer and another family member
diagnosed with lobular breast cancer (no other criteria met)
One family member diagnosed with diffuse gastric cancer and another family member
diagnosed with signet ring colon cancer (no other criteria met)
5.4
Diagnosis and Workup
Early diagnosis of gastric cancer often is not possible because patients are asymptomatic
during the initial stages of gastric cancer. The symptoms of stomach cancer frequently are
vague and nonspecific. They include complaints such as weight loss, epigastric discomfort, nausea, vomiting, fatigue, anorexia, and early satiety. Dysphagia is common in
patients with GE junction/distal esophageal cancers and early satiety is seen in patients
with more distal cancers. In low-incidence countries, upper GI symptoms or positive fecal
occult blood testing may trigger endoscopic investigation. In Japan, mass screening with
upper GI contrast studies and endoscopy has proven successful in obtaining early diagnosis (Hundahl etal. 2006). Mass screening is expensive and not practical in other high-risk
countries without the resources to support the technology and logistics involved.
Although the double barium upper GI series may still be helpful in defining a gastric
abnormality, the most common diagnostic test used at initial evaluation is upper endoscopy.
While barium studies may identify gastric lesions, negative studies may be seen in a substantial minority of cases (Dooley, 1984). However in the infiltrative submucosal form of typically poorly differentiated gastric cancers, endoscopy can be negative because of lack of
mucosal abnormalities. In such cases demonstrating the linitis plastica variant of stomach
cancer, an area of the stomach without peristalsis on the barium study may be a strong indication that cancer is present. Endoscopy can be helpful in providing information about tumor
location, distance from the esophagogastric junction, and extent of mucosal involvement.
Biopsies for tissue diagnosis can be performed during this test. Endoscopic ultrasound
examination is useful to evaluate depth of tumor, penetration of the wall, and assessment of
gross lymph node enlargement. This is a reliable way of assessing patients preoperatively
(Hundahl etal. 2006). Diagnostic/therapeutic laparoscopy is useful in identifying cases with
disseminated and/or technically unresectable disease and, therefore, may spare patients full
106
laparotomy. The extent of disease at laparotomy usually is greater than predicted preoperatively. Computed tomography (CT) scanning provides additional information for staging
purposes before laparotomy and assists in decision making regarding curative vs. palliative
resections. CT scanning is helpful in detecting distant metastatic disease, extraregional adenopathy, and signs of locally advanced disease (Hundahl et al. 2006). Positron-emission
tomography (PET) scanning is being used in patients receiving preoperative neoadjuvant
therapy to indicate the possibility of disseminated cancers before curative resection is
attempted. PET scanning is also being used to detect recurrent disease and distant organ
metastases. However, PET scanning has not proved as useful in gastric cancers as in other
tumors. Primary tumor uptake is only seen in approximately 75% of cases. Neither mucuscontaining tumors nor diffuse-type tumors, particularly poorly differentiated scirrhous
tumors, image well in PET scans (Hundahl etal. 2006). PET scanning, however, may be a
useful means to assess the benefit of chemoradiation therapy in the management of welldifferentiated adenocarcinomas of the esophagus. Currently, no reliable serum tumor markers exist in gastric cancer. CEA and CA19-9 have been noted to be elevated in approximately
4050% of patients with disseminated disease (Macdonald etal. 1992).
Comprehensive physical examination is imperative in the workup of gastric cancer.
Common physical findings in surgically incurable patients include palpable lymph node
metastases in the left supraclavicular area (Virchow node) or left axilla (Irish node).
Periumbilical nodules (Sister Joseph nodes) represent peritoneal dissemination of tumor.
Hepatomegaly or ascites may be present. Epigastric mass or pelvic masses due to
Krukenberg tumor (ovarian metastases) or pelvic peritoneal drop metastases (Blumer
shelf) may be detected on physical examination, and a careful pelvic/rectal examination
should be part of the initial evaluation of all gastric cancer cases.
5.5
Staging
There are two major classification systems currently in use for gastric carcinoma. The
Japanese classification system is based on the location of positive lymph nodes. The other
staging system was developed jointly by the American Joint Committee on Cancer (AJCC)
and the International Union Against Cancer (UICC) and is used in countries in the western
hemisphere (Sayegh etal. 2004a). This system is based on tumor/node/metastasis classification (Table5.2).
5.6
Surgical Treatment
In contrast to other parts of the GI tract, the stomachs relationships to adjacent key structures and the highly complicated lymphatic network, combined with the risk associated with
various surgical treatment options, have rendered description of a truly optimal oncologic
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Table5.2 American Joint Committee on Cancer (AJCC) staging

Primary tumor (T)
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria
T1: Tumor invades lamina propria or submucosa
T2: Tumor invades the muscularis propria or the subserosa
T2a: Tumor invades muscularis propria
T2b: Tumor invades subserosa
T3: Tumor penetrates the serosa (visceral peritoneum) without invading adjacent structures
T4: Tumor invades adjacent structures
Regional lymph nodes (N)
NX: Regional lymph node(s) cannot be assessed
N0: No regional lymph node metastasis*
N1: Metastasis in 16 regional lymph nodes
N2: Metastasis in 715 regional lymph nodes
N3: Metastasis in more than 15 regional lymph nodes
Distant metastasis (M)
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
Stage groupings
Stage 0
Tis, N0, M0
Stage IA
T1, N0, M0
Stage IB
T1, N1, M0
T2a, N0, M0
T2b, N0, M0
Stage II
T1, N2, M0
T2a, N1, M0
T2b, N1, M0
T3, N0, M0
Stage IIIA
T2a, N2, M0
T2b, N2, M0
T3, N1, M0
T4, N0, M0
Stage IIIB
T3, N2, M0
Stage IV
T4, N1, M0
T4, N2, M0
T4, N3, M0
(continued)
108
Table5.2 (continued)
T1, N3, M0
T2, N3, M0
T3, N3, M0
Any T, any N, M1
*At least 15 lymph nodes must be examined and free of tumor for a case to be considered N0
approach elusive. The topic of optimal gastric cancer surgery has remained controversial for
over 70 years. Fortunately, results from prospective, randomized surgical trials conducted
over the past two decades have pointed to some clear answers. Today, the historical onesize-fits-all approach has been largely abandoned in favor of customized surgery appropriate to both the extent and location of the cancer, and the condition of the patient.
5.6.1
Extent of Organ Resection (Subtotal vs. Total Gastrectomy and Margins)
Several prospective randomized clinical trials address the potential value of routine total
gastrectomy vs. subtotal gastrectomy for distal cancers, which can be potentially cleared
by either procedure (Gouzi etal. 1989; Bozzetti etal. 1997, 1999; Robertson etal. 1994).
The trials consistently fail to show any survival advantage for routine total gastrectomy,
and, indeed, a Hong Kong Trial (Robertson etal. 1994) that included the addition of an
extended node dissection to the total gastrectomy arm showed worse survival when routine
total gastrectomy was selected. A trend to higher 30-day mortality with total gastrectomy
(up to 3% with total gastrectomy) was also documented.
Intraoperative frozen section analysis of organ margins fails to solve the issue of margin
adequacy. Most have confronted a situation in which a frozen-section-negative margin
proves involved on permanent section. Further guidance concerning margin adequacy can be
gleaned from series addressing rates of margin positivity and distance between edge of resection and tumor. In a series by Bozetti and colleagues, with 285 proximal margins assessed, the
positive margin rate was 5% if the margin was 35.9cm and 0% if the margin was 6cm or
greater. Subset analysis revealed that if a tumor had not invaded deeper than the muscularis
propria, a margin of 3cm was also safe (Bozzetti etal. 1982). United States experts generally
agree with this advice, and, paralleling Japanese recommendations (Japanese Gastric Cancer
Association 1998), note that a margin of 3 cm for an intestinal-type cancer with a well-
circumscribed edge (i.e., Borrmann I or II), and not invading the serosa, is quite safe.
5.6.2
Endoscopic Mucosal Resection (EMR)
For selected superficial or noninvasive early gastric cancer (i.e., Tis or T-1 tumor),
EMR has emerged as a reasonable option (Ono etal. 2001; Pathirana and Poston 2001;
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109
Sanoetal. 2000; Sasako 1997; Hiki 1996; Kobayashi etal. 2003). In the classic technique
of EMR, a submucosal injection of saline floats the area of tumor-bearing mucosa off the
underlying muscularis propria and the lesion is resected with a special cautery snare with
hooks to preserve specimen orientation for margin analysis. The procedure can be technically challenging, but innovations such as the use of incision endo-forceps (Yamamoto
etal. 2001), aspiration mucosectomy (Yoshikane etal. 2001), a stabilizing distal magnetic
anchor (Kobayashi et al. 2004), and double endoscope resection techniques (Kuwano
etal. 2004) can facilitate it. Laparoscopic resection is another option, but the potential
risk of intra-abdominal seeding and/or port site tumor implantation in node-negative T-1
tumors otherwise suitable for EMR, make EMR the appropriate choice for such lesions
(Kobayashi etal. 2003).
Selection of cases suitable for EMR hinges on the absence of disease in the regional
lymphatics. A combined series of 5,265 surgically treated T-1 cases from the National
Cancer Center Hospital and the Cancer Institute Hospital in Tokyo offers unsurpassed guidance (Gotoda etal. 2000). For intramucosal tumors, none of the 1,230 well-differentiated
cancers of less than 30-mm diameter, regardless of ulceration findings, were associated
with metastases (95% confidence interval (CI), 00.3%). Regardless of tumor size, none of
929 cancers without ulceration were associated with nodal metastases (95% CI, 00.4%).
For submucosal cancers, there was a significant correlation between tumor size larger than
30mm and lymphatic-vascular involvement with an increased risk of nodal involvement.
None of the 145 well-differentiated adenocarcinomas of less than 30-mm diameter without
lymphatic or venous permeation were associated with nodal involvement, provided that the
lesion had invaded less than 500mm into the submucosa (95% CI, 02.5%) (Gotoda etal.
2000).
In an 11-year, 445-case series by Ono and colleagues (2001) from the National Cancer
Center Hospital in Tokyo, there were no gastric cancer-related deaths during a median
follow-up period of 38 months (3120 months). Although bleeding and perforation
occurred in 5%, there were no treatment-related deaths (Japanese Gastric Cancer
Association 1998). For selected superficial T-1 cancers, EMR performed by experienced
personnel can generate superb results and can certainly be recommended, especially since
local recurrences can be addressed with salvage gastrectomy.
5.6.3
Lymphadenectomy and D-Level Trials
Lymphadenectomy for gastric cancer is mandatory for tumors not fitting EMR criteria.
The extent of lymphadenectomy in gastric cancer has been historically defined according
to (several variations of) Japanese-defined nodal treatment. Such definitions reflect mandates contained in various editions of Japanese standardized treatment/staging rules, dating from 1963 to the present (Sayegh etal. 2004b; Kajitani 1981; Japanese Classification
of Gastric Carcinoma 1995; Degiuli etal. 1998). The Japanese treatment and classification
system has, since its inception, included numeric designations for various lymph node stations and sub-stations around the stomach, 31 at last count (Degiuli etal. 1998). Definitions
110
for various nodal levels, originally N1 through N4, are expressed in terms of groupings of
these numbered anatomically-defined nodal stations for tumors in various positions within
the stomach. The N groupings have changed considerably over time. Current definitions
include only node levels from N1 thorough N3 (i.e., no N4). With the 13th edition of the
Japanese classification system, circa 1997, which has been translated into English (Japanese
Gastric Cancer Association 1998), several major changes were instituted. For example,
one major change involves the designation of node involvement at perigastric short gastric
(#4a) and left paracardial (#2) sites as distant metastatic disease sites (M1) when they
occur in the setting of an antral primary tumor. The same stations are N1 disease or N3
disease for other primary sites within the stomach. The reader should appreciate that the
Japanese system bears scant relation to the more familiar UICC/AJCC TNM system
described earlier (Greene etal. 2002).
Japanese mandates for node dissection are classified according to the D-level system.
Definitions for extent of lymphadenectomy in all but one of the trials we will discuss follow the Japanese mandates. According to the Japanese system, a D1 lymphadenectomy
encompasses all anatomically defined N1 node stations for a given location of tumor, a
D2 all N2 nodes stations, and a D3 all N3 node stations. To make matters still more
confusing, all but one of the trials we shall discuss use D-level definitions based on pre1997 editions.
Table 5.3 summarizes prospective randomized trials of various Japanese-defined
lymphadenectomy schemes. Given the aforementioned changing definitions and resulting
confusion, surgeons might consider themselves fortunate that the trials are largely
negative.
For the two large European trials, the MRC Trial (Cuschieri etal. 1996, 1999) and the
Dutch Trial (Bonenkamp et al. 1995, 1999; Hartgrink et al. 2004) in-hospital surgical
Table 5.3 Prospective, randomized trials addressing extent of lymphadenectomy, as defined by

D-level (note: changing definitions over time)
TRIAL
N
Rand.
Survival P Value
1. South African, 88
Dent etal., Br J Surg 1988; 75: 110112
43 pts
D1 vs D2 p = n.s.
2. M.R.C., 98
Cushieri etal., Br J Cancer 1998; 79:
15221530
400 pts
D1 vs D2 p = n.s.
3. Dutch, 99
Bonenkamp etal., NEJM 1999; 340: 908914
711 pts
D1 vs D2 p = n.s.
4. Taipei Veterans, 06
221 (intent)
D2 vs. D3 p = 0.041
Wu CW etal., Lancet Oncol 2006; 7: 309315 156 (per protocol)
p = 0.056
523
5. Japanese JCOG9501, 06
Sasako etal, JCO 2006; 24(18s): 934s (abstract)
Sasako etal. Scan J Surg 2006; 95: 232235
Sasako M., Sano T, etal. NEJM 2008; 359:
453462
D2 vs. D3 p = n.s.
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111
mortality rates for the D2 groups were quite high: 13 and 10%, respectively. Both trials
showed higher mortality when pancreatic-splenic resection was performed, and this somewhat confounded the D-level question since, at the time of these trials, these were mandated procedures for the D-2 group when tumors were in the middle third or proximal third
of the stomach. In the Dutch Trial, restricting subgroup analysis to patients who did not
undergo pancreatic or splenic resection (a post-hoc, selected analysis), survival was higher
for the D-2 group (59% for the D-1 group vs. 71% for the D-2 group, p=0.02) (Hartgrink
etal. 2004). An 11-year follow-on report for this trial indicates that of the 12% of cases
with pathologic N-2 disease (N=89 out of 711 total), there were nine 10-year survivors,
and eight of the nine were in the D-2 group (p=0.01 for this post-hoc analysis of the N-2
subgroup) (Hartgrink etal. 2004). Subgroup analysis notwithstanding, both European trials were negative. Whatever was supposedly gained as a result of D-2 lymphadenectomy
was lost as a result of higher surgical mortality. In the borderline-positive, single-institution Wu Trial, conducted in Taiwan, surgical mortality was zero in both D-2 and D-3
groups.
The confounding influence of pancreatectomy and splenectomy deserve mention. In the
mid-1990s, as a result of key work by Maruyama and others (Maruyama et al. 1995;
Kasakura etal. 2000; Uyama etal. 1996), Japanese surgeons abandoned the routine pancreaticsplenic resection, unless it was required to achieve a negative-margin resection.
Recommendations for D2/D3 resections were changed accordingly, but too late for the
aforementioned trials. Both the MRC and Dutch Trials verified the wisdom of this change
(Cuschieri etal. 1996, 1999; Hartgrink etal. 2004).
5.6.4
Low Maruyama Index Lymphadenectomy is Associated with Improved Survival
In the late 1980s, Keiichi Maruyama and colleagues at the National Cancer Center Hospital
in Tokyo created a computer program (known as the Maruyama Program) which
searched a meticulously-maintained 3,843-patient database of gastric cancer cases treated
by extensive lymphadenectomy. The program is designed to match cases with characteristics similar to a given case, and report observed nodal dissemination risk, survival, and
other information. With seven demographic and clinical inputs, all identifiable preoperatively or intraoperatively, the program predicts the statistical likelihood of nodal disease
for each of the 16 main nodal stations around the stomach. Maruyama Program predictions
have been assessed in Japanese, German, and Italian populations and found to be highly
accurate (Kampschoer etal. 1989; Bollschweiler etal. 1992; Guadagni etal. 2000). The
Maruyama Program is designed (Hundahl 2005) to be used by surgeons preoperatively or
intraoperatively, as a convenient means of rationally planning a more data-driven extent of
lymphadenectomy for a given patient. Since the late 1980s, the program has been used in
exactly this way by many gastric cancer surgeons around the world. In an effort to expand
use of this computerized tool, a CD-ROM with expanded case volume was prepared in
2000 (Siewert etal. 2000).
In a prospectively planned surgical analysis of a large adjuvant chemoradiation trial in
the U.S. (SWOG 9008, Intergroup 0116), the extent of surgical treatment was specifically
112
assessed and prospectively coded. The prospectively planned surgical analysis of survival
made use of a novel means of quantifying the adequacy of lymphadenectomy relative to
the likely extent of nodal disease, the Maruyama Index of Unresected Disease (MI). MI
was defined (by the author, SH) as the sum of Maruyama Program predictions for those
Japanese-defined regional node stations (stations #1#12) left in situ by the surgeon
(Hundahl etal. 2002). On the basis of the trials entry criteria and the definition of MI,
every case registered could have had an MI of zero; this variable was under the surgeons
control. Median overall survival for the MI <5 subgroup was 91 months vs. 27 months for
others (p=0.005). By multivariate analysis, adjusting for treatment, T-stage and number of
nodes positive, MI proved an independent predictor of survival (p=0.0049).
To further assess of the utility of the MI as a prognostic tool, the Dutch D1 vs. D2 Trial
has been re-analyzed (Peeters etal. 2005). Blinded to survival and eliminating cases with
incomplete information, 648 of the 711 patients treated with curative intent had MI
assigned. Median MI was 26 (vs. median of 70 for the Macdonald Trial). Overall trial findings with respect to D-level were not affected by the absence of the 63 cases with incomplete data. In contrast to D level, MI <5 proved a strong predictor of survival by both
univariate and multivariate analysis (see Fig. 5.1). MI was an independent predictor of
both overall survival (p=0.016, HR=1.45, 95% CI 1.071.95) and relapse risk (p=0.010,
HR=1.72, 95% CI 1.142.60). Strong dose-response with respect to MI and survival
was also observed, and the effect was profound. Thus, the Dutch Trial findings with respect
to MI largely confirmed what was observed in the Macdonald Trial.
Based on results from these two trials, it appears that surgeons might better impact on
patient survival by pursuing a low Maruyama Index operation instead of relying on D-level
Overall survival and DFS by

Maruyama Index of Unresected
Disease (MI) quartiles
Overall survival
1,0
8
1,0
P < 0.01
P < 0.01
(logrank)
(logrank)
>70 (n = 61)
>26 70 (n = 159)
5 26 (n = 164)
MI in quartiles
Cum Survival
Cum Survival
MI in quartiles
6
6
4
<=5 (n = 164)
0,0
2 4 6 8 10 12 14
survival since surgery (yrs)
Disease-specific survival
>70 (n = 61)
>26 70 (n = 159)
5 26 (n = 164)
<=5 (n = 164)
0,0
0 2 4 6 8 10 12 14
disease free period since surgery (yrs)
Fig. 5.1 In the absence of adjuvant treatment, the impact of Maruyama Index of Unresected
Disease (MI) is profound. This graph depicts the relationship between MI quartiles and survival.
Lower MI is associated with higher survival (Peeters et al., 2005)
5 Gastric Cancer
113
guidance. By using the Maruyama Program to prospectively plan a given patients lymphadenectomy, achieving a low Maruyama Index operation is relatively straightforward.
The compelling dose-response effect observed for MI also suggests it can also be viewed
as a quantitative yardstick for the adequacy of lymphadenectomy in a given case of gastric
cancer. As such a quantitative yardstick, it might someday be used to perhaps identify
patients at greater or lesser risk of locore gional recurrence, and perhaps influence decisions
on postoperative adjuvant therapy. At a minimum, we feel that strong consideration should
be given to explicitly calculate and report MI for every patient who is entered into a future
postoperative adjuvant trial.
5.7
Radiotherapy
5.7.1
Palliative Radiotherapy
Radiotherapy is an effective palliative modality of local gastric cancer symptoms. Gastric
outlet obstruction, pain from local tumor extension and/or lymph node encasement of
celiac nerves, bleeding, and biliary obstruction are not infrequent problems confronting
those afflicted with gastric cancer. These symptoms interfere with the tolerance of systemic therapy and certainly impact quality of life. Radiotherapy to symptomatic sites of
disease will cause tumor reduction in the vast majority. Symptomatic relief is achieved in
6580% (Moertel etal. 1964; Tey etal. 2007; Kim etal. 2008a, b; Hashimoto etal. 2009)
of patients. The MD Anderson Group reported the results of palliative radiotherapy in 37
gastric patients (Kim etal. 2008b). Two-thirds received concurrent chemoradiation therapy. Bleeding, obstruction, and pain were controlled in 70, 80, and 86%, respectively.
Furthermore, these symptoms were controlled without additional interventions for the
patients remaining life expectancy in 70, 81, and 49%, respectively. Those who received
concomitant chemotherapy had a trend towards improved median survival. Retrospective
evaluations suggest that more moderate doses of radiotherapy (4045Gy) result in a higher
palliative rate and longer duration of palliation (Kim etal. 2008b; Hashimoto etal. 2009).
Certainly, decisions regarding duration of radiotherapy and concomitant systemic chemotherapy, with palliative radiation therapy, need to be individualized, based on clinical
judgment.
5.7.2
Role of Radiotherapy in Potentially Curative Gastric Cancer
5.7.2.1
Patterns of Failure
The role and implementation of radiotherapy in curative gastric cancer therapy largely
flows from a consideration of failure patterns following gastric resection. Locoregional
114
failure is defined as disease recurrence in the tumor bed, anastomosis, regional nodes, or,
rarely, the operative wound. Autopsy series document locoregional failure in 8393%
(Horn 1955; McNeer etal. 1957; Stout 1943; Thomson and Robins 1952). Clinical series
have also observed a significant incidence of locoregional failure. Among 130 patients
receiving curative gastric resection at the Massachusetts General Hospital, locoregional
failure was observed in 38%. There were 16% who developed locoregional failure alone
as the sole site of identifiable disease relapse at the time of first failure (Landry et al.
1990). Finally, the University of Minnesota reoperative series provides important insight
into failure following gastric resection (Gunderson and Sosin 1982; Gunderson 2002).
There were 107 patients who had planned single or multiple reoperations following curative gastric resection. Locoregional relapse occurred in 67% of the entire cohort; and,
importantly, 23% of the entire cohort failed only in the locoregional areas, without any
other documented site of failure. In these patterns of failure analyses, the sites of relapse
are quite consistent. Failure in the gastric bed occurs in 2050%. Failure in the anastomosis or stump occurs in approximately 25%, and failure in the regional lymphatics occurs
in 40% of the re-operative series and 50% of the autopsy series. These sites (tumor bed;
anastomosis/stump; lymph nodes) constitute the target volumes treated in either preoperative (obviously excluding anastomosis considerations) or postoperative adjuvant
radiotherapy trials. In view of the consistent risk of recurrence in the anastomosis and
stump, as well as in the tumor bed, it is not surprising that efforts to increase dissection
of lymph node stations alone have less than a dramatic impact on locoregional recurrence
and overall survival. For example, in the Dutch randomized study of D1 vs. D2 lymph
node dissection, locoregional recurrence occurred in 58% of the D1 group as well as fully
in 45% of the D2 group at 11 years (Hartgrink et al. 2004; Jansen et al. 2005). The
University of Minnesota reoperative series employed increasingly more extensive nodal
dissection during the course of the series without clinically apparent impact on reduction
of locoregional failure (Gunderson and Sosin 1982; Gunderson 2002). Anastomotic and/
or stump recurrence is felt to likely be a result of the propensity of gastric carcinoma to
spread longitudinally along the submucosal and subserosal lymphatic systems. Tumor
bed failure is related in large part to the instance of involved surgical margins seen in
multiple surgical series. Eight series evaluating this issue report 260 of 1074 (24%) with
positive surgical margins (Smalley and Gunderson 1996). It is important to note that the
serosal investiture of the stomach is incomplete. The cardia, in particular, has incomplete
serosal investiture and extension of tumor to inked radial margins in this location represents a true positive margin in the vast majority. The inferoposterior portion of the stomach (inferioroposterior to the antrum and pylorus) also has either no serosal lining or
incomplete serosal lining; and careful communication between surgeons and pathologists
is imperative in the evaluation of margin status. The University of Bologna (Mattioli
etal. 2001) reported positive radial margins of excision in 32% of gastric cardia lesions
out of 116 patients evaluated. Positive radial margins were associated with increased
locoregional failure and decreased overall survival. The consistently observed locoregional failures of patients resected for gastric cancer in the tumor bed, anastomosis/
stump, and lymph node areas provide rationale for adjuvant radiotherapy either prior to
or following surgery.
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115
5.7.3
Postoperative Adjuvant Radiation
Three methodologically flawed but suggestive randomized phase III studies observed
improved outcomes with postoperative adjuvant radiation. Takahashi and Abe (1986) randomly assigned patients to surgery alone vs. surgery plus intraoperative radiotherapy. Fiveyear survival was statistically improved by 1520% in those with stages IIIII disease, but
randomization was susceptible to bias, and failed to stratify for important prognostic factors
(Landry etal. 1990). Moertel and associates prospectively randomized 62 high-risk patients
to receive surgery alone vs. surgery followed by postoperative external beam radiotherapy
plus bolus 5-fluorouracil (5-FU). Those randomized to therapy had statistically significant
improvements in relapse-free and overall survival. Overall survival was 23% with adjuvant therapy vs. 4% with surgery alone (p=0.05). However, there were also methodologic
problems with interpretation of this study (Moertel et al. 1969). The British Stomach
Cancer Group randomized gastric cancer patients to receive surgery only vs. 5-FU, doxorubicin, and mitomycin-C chemotherapy alone vs. irradiation alone. Locoregional failure
was substantially reduced with radiotherapy vs. the other two treatment arms, but no overall survival benefit was seen; and there were, again, substantial methodologic problems
(Hallissey etal. 1994).
The consistently observed locoregional failure following stomach resection as well as
the intriguing phase III randomized trials discussed above set the stage for the Intergroup
0116 trial. There were 603 patients registered on this U.S.Canadian study from 1991 to
1998 (Macdonald etal. 2001, 2009). Patients had to have complete margin-negative resection of a gastric cancer with either extension full-thickness through the muscularis propria
and/or positive regional lymph nodes. There was no requirement for the performance of
either a D1 or D2 resection. Complete resection was defined by the presence of tumor-free
resection margins along with the operating surgeons report of no unresected cancer. Lymph
nodes were positive for metastatic cancer in 85% of patients and 20% arose in the gastric
cardia. Patients were randomized to either surgery alone vs. adjuvant radiochemotherapy.
Radiation consisted of 45Gy to the anastomosis/stump, regional lymphatics, and original
tumor bed. Bolus 5-FU and leucovorin were given 4 weeks before radiation, during weeks
one and five of radiation, as well as following radiation. Significantly, all radiotherapy
fields were centrally reviewed and approved before radiotherapy initiation. Therapy produced significant acute morbidity (Kassem et al. 2005), but only 1% overall mortality as a
result of therapy. With over 10 years of median follow-up, disease-free survival (p<0.001)
as well as overall survival (p=0.004) favor chemoradiotherapy. Multiple subset analyses
were performed, including demographic, TNM-stage, D-level of resection, and tumor origin. Chemoradiotherapy benefitted all subsets, with the exception of those with diffuse
histology. The use of postoperative adjuvant radiotherapy increased significantly after the
release of this information. The SEER database documented a doubling in the use of postoperative radiotherapy after the results of Intergroup 0116 were published, with statistically significant improvement in overall survival (Kozak and Moody 2008; Coburn etal.
2007). The benefit of adjuvant postoperative radiochemotherapy for gastric cancer has
been observed in other series (Besa et al. 2006; Fiorica et al. 2007; Kim et al. 2005).
116
Kim and others (2005) reported a large South Korean experience of 544 patients who
received postoperative chemoradiotherapy. The outcomes in these patients were compared
to outcomes in 446 patients matched for prognostic factors who received surgery alone in
South Korea during the same time period. All patients underwent extensive D2 lymph node
dissection. Radiochemotherapy was administered similar to Intergroup 0116. Relapse-free
and overall survival was statistically significantly improved with radiochemotherapy in
this large group, all of whom received D2 nodal dissection. Quality of life (QOL) was
assessed in a Canadian trial of postoperative radiochemotherapy. As expected, radiochemotherapy was associated with clinical significant worsening in global and function scales at
completion of radiation therapy. However, by 612 months post-therapy, none of the subscales showed clinically or statistically significant differences from baseline, on average.
5.7.4
Local Unresectable/Postoperative Residual Local Disease
Fewer than half of patients with newly diagnosed gastric cancer are candidates for curative
surgical resection and effective adjuvant therapy. Some present with no clinically evident
metastatic disease, but with primary tumors that are too large to resect with curative intent.
Increasingly, carefully planned multimodality therapy is being implemented to afford a
minority the possibility of true cure, while simultaneously providing effective palliation to
the majority. The MD Anderson group reported 39 patients with potentially resectable
disease who received preoperative radiochemotherapy in anticipation of eventual curative
resection. These patients failed to proceed to surgery usually because of development of
distant metastases (primarily peritoneal) or other clinical contraindications. Median follow-up was 8 months and median and 1-year clinical local disease control were 11 months
and 46%, respectively (Kim etal. 2008a). The majority, therefore, despite not being able
to complete potentially curative surgery, were effectively palliated with respect to local
symptoms, for the remainder of their lives (median survival 10 months).
5.7.5
Definitive Radiochemotherapy
Several series (Moertel etal. 1969; Schein and Novak 1982; Holbrook 1974; Haas etal.
1983) have documented a small minority of cases with low-volume locally unresectable
gastric cancer in the range of 510% who achieve long-term survival with a combination of moderate-dose radiotherapy and concomitant systemic chemotherapy. The Mayo
Clinic evaluated concomitant 5-FU with radiation in a phase III trial of locally unresectable gastric adenocarcinomas. Patients received 4540Gy and were randomized to receive
either 5-FU via bolus or saline placebo on the same schedule. Overall survival was substantially improved in the 5-FU group, with 12% of the 5-FU group surviving five years
vs. none in the placebo arm (Holbrook 1974; Childs etal. 1968). The EORTC trial randomized 115 patients to receive radiotherapy alone vs. concomitant radiotherapy and 5-FU
during radiotherapy alone vs. radiotherapy plus concomitant and post-radiotherapy 5-FU.
117
5 Gastric Cancer
An overall survival advantage was present in those receiving both 5-FU and irradiation
(p=0.04). Additionally, among those with incompletely resected tumors, all long-term
survivors received combined modality therapy (Bleiberg et al. 1989). Finally, the
Gastrointestinal Tumor Study Group (GTSG) performed a randomized trial in locally
unresectable gastric cancer. Ninety patients were randomized to receive either chemotherapy alone (5-FU and methyl-CCNU (MeCCNU)) or external beam radiotherapy
(50 Gy) combined to the same chemotherapy. Combined radiochemotherapy produced
excessive morbidity and mortality during the first 26 weeks after randomization. However,
with longer follow-up, those who received combined modality therapy had statistically
significant improvement in long-term survival, with approximately 20% alive at follow-up
after five years. Those who had prior debulking surgery but were left with residual local
unresectable disease had improved outcome when compared to those who were not debulked prior to randomization (Schein and Novak 1982).
5.7.6
Neoadjuvant Chemotherapy for Locally Unresectable Gastric Cancer
Table 5.4 summarizes several series (Yano et al. 2002; Menges et al. 2003; GallardoRincn et al. 2000; Melcher et al. 1996; Cascinu et al. 2004; Verschueren et al. 1988;
Wilke etal. 1989) of locally unresectable, nonmetastatic gastric cancer treated with neoadjuvant chemotherapy. A variety of 5-FUbased chemotherapy regimens have been
employed. Those displaying substantial clinical regression of disease have been explored,
with some capable of undergoing potential curative resection. Several themes emerged
from the data available to date. The rate of pathologic complete remission is, in most
series, 5%. Outcome is clearly improved in those who undergo significant cytoreduction
to allow R0 resections. Only a few series have evaluated locoregional failure in those
presenting with locally unresectable disease downsized sufficiently to allow resection.
However, in these series, locoregional relapse occurs in >50%. This highlights the potential
role of adjuvant radiotherapy prior to or following surgical resection for those presenting
Table 5.4 Phase II trials of preoperative chemotherapy

Series (ref)
#
pCR
Operated
0%
Resected
R0
resections
42%
24%
64%
52%
8%
Yano (33)
34
Menges (34)
25
Gallardo-Rincon (35)
60
2%
18%
Melcher (36)
10
0%
10%
Cascinu (37)
82
5%
45%
Verschueren (38)
19
Wilke (39)
34
80%
15%
74%
37%
59%
53%
LRF
71%
44%
50%
118
with locally unresectable tumors without clinically apparent metastases. Furthermore, as

neoadjuvant chemotherapy is increasingly utilized, it is important to identify those in
whom neoadjuvant chemotherapy alone is unlikely to permit an R0 resection, or those
who receive an R0 resection, but manifest features associated with high risk of development of subsequent locoregional failure. Both of these subsets deserve consideration of
the use of radiochemotherapy to increase the likelihood of R0 resection and/or decrease
the risk of locoregional failure.
5.7.7
Preoperative Radiotherapy with/without Chemotherapy
Preoperative radiotherapy as a component of neoadjuvant treatment has increasingly been
explored in both unresectable but nonmetastatic gastric cancer as well as resectable, poorprognosis presentations. This is certainly not surprising in view of the substantial locoregional failure problem with gastric cancer. Other GI sites, such as the esophagus and
rectum, have had more formal evaluations of neoadjuvant radiotherapy. Skoropad and others (2000) randomized 112 gastric cancer patients whose cancer was resectable but nonmetastatic to receive either surgery alone or preoperative and intraoperative radiation
therapy. Overall, there was no survival benefit; but, among those at greatest risk of locoregional failure (either positive nodes or T3T4 primary tumors), survival benefit was suggested on subset analysis. Zhang and colleagues (1998) prospectively randomized 370
patients with adenocarcinoma of the gastric cardia to receive surgery alone vs. preoperative radiotherapy as monotherapy to the primary tumor site and regional lymphatics.
Overall survival was improved at 5 and 10 years in those receiving preoperative radiotherapy. Failure-site analysis was performed on all sites of failure occurring at any time in
the patients follow-up after randomization. Tumor bed failure and regional lymphatic
failure was dramatically reduced with preoperative treatment (p<0.02 for both failure
sites). Distant metastases were similar between the groups, occurring in 24.3% with preoperative radiotherapy vs. 24.7% with surgery alone.
Several phase II trials of either neoadjuvant radiochemotherapy alone or induction
chemotherapy followed by neoadjuvant radiochemotherapy have been reported and are
summarized in Table5.5 (Allal etal. 2005; Ajani etal. 2004a, b, 2005, 2006; Reed etal.
2008; Lowy et al. 2001; Safran et al. 2000; Saikawa et al. 2008). These series include
those who have operable but poor-prognosis features evident preoperatively (Allal etal.
2005; Ajani etal. 2004a, b, 2005, 2006; Reed etal. 2008; Lowy etal. 2001) as well as
those with nonmetastatic but unresectable tumors (Safran etal. 2000; Saikawa etal. 2008).
Many of these series indicate that substantial pathologic evidence of tumor regression is
powerfully associated with a reduction in locoregional failure (Reed etal. 2008) or with
an improvement in overall survival (Ajani etal. 2004a, b, 2005). Ajani and others at the
MD Anderson Cancer Center have defined a pathologic partial response (pPR) as <10%
of residual cancer in the stomach. In the series cited above, this dramatic cytoreduction
was also associated with very favorable overall survival outcome. Series utilizing only
neoadjuvant radiochemotherapy (Allal etal. 2005; Lowy etal. 2001) seem to have a lower
rate of pCR than those treated with induction chemotherapy followed by neoadjuvant
119
5 Gastric Cancer
radiochemotherapy. The approach of neoadjuvant induction chemotherapy followed by

radiochemotherapy has been associated with pCR rates of 2030% and R0 resection rates
in excess of 70%. While these are unarguably excellent results, these regimens are toxic,
and further evaluation in the setting of randomized control studies is important. The limited data addressing locally unresectable but nonmetastatic tumors (Safran et al. 2000;
Saikawa et al. 2008) demonstrate that a meaningful minority can undergo significant
cytoreduction without evidence of metastatic disease to allow R0 resections. While it is
impossible to compare the phase II trials of preoperative chemotherapy alone (Table5.4)
vs. preoperative radiochemotherapy trials (Table5.5), future trials will appropriately be
careful to evaluate not only pCR and pPR rates, but also R0 resections and locoregional
failure following primary tumor excision.
Table 5.5. Phase II trials of preoperative radiochemotherapy

Series (ref) #
pCR Operated Resected RO
resections
LRF regimen
Neoadjuvant Radiochemotherapy for Resectable Gastric Cancer

Allal (42)
19
5%
18%
Ajani (43)
33
30%
85%
Reed (44)
146
23%
Ajani (45)
43
Ajani (46)
18%
11%
Induction CDDP, 5-FU,

LV then CDDP, 5-FU,
LV + XRT
70%
9%
Induction 5-FU, LV,

CDPP X 2; then 45 Gy
XRT + 5-FU pvi
various preoperative
XRT regimens
75%
70%
13%
26%
83%
77%
Induction 5-FU, LV,

CDDP 2; then 45 Gy
XRT + 5-FU pvi,
paclitaxel
41
20%
98%
78%
Induction 5-FU,
paclitaxel, CDDP 2;
then 45 Gy XRT +
5-FU pvi, paclitaxel
Ajani (47)
43
26%
91%
Induction CPT-11,
CDDP; then 45 Gy
XRT + 5-FU, paclitaxel
Lowy (48)
24
8%
Neoadjuvant 5-FU pvi

+ XRT
Neoadjuvant Radiochemotherapy for Unresectable Gastric Cancer

Safran (49)
27
4%
Saikawa
(50)
29
13%
48%
34%
37%
Neoadjuvant paclitaxel
+ XRT
34%
XRT + S-1; CDDP

followed by S-1:
CDDP
120
5.8
Systemic Therapy in Advanced Disease
Gastric cancer is a common disease worldwide. With approximately 800,000 new cases
diagnosed annually throughout the world, gastric cancer is the second most common cancer diagnosed globally. In the United States, more than 21,000 new cases of gastric cancer
are diagnosed each year, with approximately 35% having metastatic disease at the time of
diagnosis (Garcia etal. 2007; Parkin etal. 2005). At the time of diagnosis, gastric cancers
are localized in approximately 50% of patients, and primary management is based on surgical resection of the primary tumor. When the cancer is localized to the stomach, an early
lesion with minimal invasion is detected with negative lymph nodes, and the cancer is
confined to the mucosa or submucosa, surgical cure rates may exceed 80% (Parkin etal.
2005; Sue-Ling etal. 1993); however, as few patients have symptoms, the detection of
early gastric cancer is rare in the United States and other Western countries. Gastric cancer
is more commonly locally advanced at diagnosis, with tumor extension through the gastric
wall and direct extension into other organs, with or without metastatic involvement of perigastric lymph nodes (Sasako etal. 1997; Siewert etal. 1993; Earle and Maroun 1999). In
these circumstances, fewer than 30% of patients are cured by surgical means.
Because many patients present with metastatic disease at the time of diagnosis, and this
results in poor outcomes after surgery, with a significant number of patients having relapse
of the disease, there has been interest in treating patients with systemic chemotherapy. In
the setting of metastatic gastric cancer, many chemotherapeutic agents have resulted in
positive response when used alone as monotherapy or in combination with other agents,
that has resulted in improvement in overall survival rates, although the duration of response
has remained limited (Fig.5.2). Advances in systemic chemotherapy may predict response
and guide treatment in metastatic gastric cancer.
Fig.5.2 Progress in treatment of advanced gastric/esophagogastric cancer. FAM, 5-FU, doxorubicin, and mitomycin C; FAMTX, 5-FU, doxorubicin, leucovorin, and methotrexate; ECF, epirubicin, cisplatin, and 5-FU
5 Gastric Cancer
121
5.8.1
Single-Agent Chemotherapy
Traditional chemotherapy agents used as monotherapy have resulted in variable response
rates in patients with advanced or metastatic gastric cancer (Table5.5). Single-agent chemotherapy has resulted in response rates from 10 to approximately 2.5% and included
5-FU; mitomycin C, doxorubicin, epirubicin, cisplatin, and carmustine (BCNU); methotrexate; etoposide; chlorambucil; hydroxyurea; docetaxel; irinotecan; and paclitaxel.
Initial studies with 5-FU vs. best supportive care (BSC) established the role of chemotherapy in demonstrating objective responses and impact on progression and overall survival. 5-FU has been the most extensively studied chemotherapy agent in patients with
metastatic gastric cancer. Reported response rates vary, but are up to 21%. Earlier trials
used schedules with daily 5-FU administration by intravenous bolus injection for 5 consecutive days. Treatments using 5-FU by continuous infusion for several days up to several
weeks have been reported. Although the response rates to infusional chemotherapy with
5-FU are similar to those of bolus 5-FU, the toxicity profiles are different. The major side
effects of bolus 5-FU are neutropenia and diarrhea, and erythroderma of the palms and
soles (handfoot syndrome). The oral fluorinated pyrimidines ftorafur and uracil (UFT),
S1, and capecitabine have also demonstrated significant efficacy as single agents in the
treatment of metastatic gastric cancer.
5.8.2
Combination Chemotherapy
Many phase II trials of combination chemotherapy were based on promising activity
observed with a variety of single agents. Table5.6 lists several combinations of recently
published trials. Many of these regimens resulted in less activity and/or greater toxicities
in subsequent phase II and phase III trials (Tables5.7 and 5.8).
5.8.3
Nitrosourea Combinations
The combination of a nitrosourea, such as BCNU or MeCCNU, with 5-FU represents one
of the earlier approaches to combination chemotherapy in the treatment of metastatic gastric cancer. Although earlier response rates, up to 41%, were promising, the median duration of survival for the combination was 7.7 months, which was not significantly improved
over each of the drugs when used alone (Ajani etal. 1998). Subsequent trials with combinations of BCNU and 5-FU showed lower response rates (Kovach etal. 1974). MeCCNU
was also evaluated with 5-FU. In a randomized study comparing MeCCNU combined with
5-FU to 5-FU alone, the combination produced a 40% response rate and superior survival
(Jamieson and Gill 1981), but subsequent studies with nitrosoureas failed to confirm these
results (Moertel 1976). Nitrosourea compounds have the potential for causing significant
severe toxicities and are no longer used in gastric cancer therapy.
122
Table5.6 Phase II trials of new agents in gastric cancer

Agents
Response rate (%)
Pac-5-FU
56
Pac-Cis-5-FU
53
CPT-Cis
50
UFT-Cis
51
Cape-Cis
55
5-FU-Oxal
48
FOLFOX-4
45
DCF
54
Table5.7 Phase III trials in gastric cancer

Agents
ELF vs
Response rate
9%
FAMTX vs
12%
Cis-5-FU
20%
FAMTX vs.
21%
E-Cis-5-FU
45%
Mito-Cis-5-FU vs
44%
E-Cis-5-FU
43%
EAP vs
20%, more toxic
FAMTX
33%
DCF vs
36%
CF
26%
CF cisplatin and fluorouracil; DCF docetaxel, cisplatin and 5-FU; Cis-5-FU cisplatin and 5-fluorouracil; E etoposide; EAP etoposide, doxorubicin, cisplatin; ELF etoposide, leucovorin, 5-FU;
FAMTX 5-FU, doxorubicin, and methotrexate; Mito mitomycin
5.8.4
Mitomycin Regimens
With single-agent therapy demonstrating activity of mitomycin C and doxorubicin, the
triple-drug combination of 5-FU, doxorubicin, and mitomycin C (FAM) underwent phase
II and III evaluations (Moertel and Lavin 1979). Initial studies demonstrated a 42%
123
5 Gastric Cancer
Table5.8 Response rates to single-agent chemotherapy in patients with advanced and metastatic
gastric adenocarcinoma
Drug
Number of patients
Response rate (%)
Antimetabolites
Fluorouracil
416
21
Methotrexate
28
11
Gemcitabine hydrochloride
15
Oral antimetabolites
UFT
188
28
S1
51
45
Capecitabine
31
28
Hydroxyurea (oral)
31
19
Tegafur (oral)
19
19
Mitomycin C
211
30
Doxorubicin hydrochloride
141
17
80
19
139
30
41
17
Antibiotics
Epirubicin hydrochloride
Heavy metals
Cisplatin
Carboplatin
Taxanes
Paclitaxel
3h
24h
Docetaxel
98
17
22
123
21
Irinotecan hydrochloride
66
23
Topotecan hydrochloride
33
Camptothecins
Targeted therapies
Gefitinib
1.5
Erlotinib
UFT uracil and tegafur
response rate; however, subsequent phase III trials failed to demonstrate the response rate
or a survival benefit (Schein etal. 1978). In a randomized trial of 5-FU, 27% to FA, and
38% to FAM, survival among the groups was similar, with 27 weeks for FA and 30 weeks
for the other two regimens (Cullinan etal. 1985).
124
5.8.5
5-Fluorouracil, Doxorubicin, Leucovorin, and Methotrexate
Biochemical modulation of 5-FU by methotrexate and leucovorin led to the development
of a regimen combining 5-FU, doxorubicin, leucovorin, and methotrexate (FAMTX). This
combination was evaluated in metastatic gastric cancer, with responses exceeding 50%
(Douglass et al. 1984; Klein et al. 1982). When compared to FAM, FAMTX showed a
superior response rate with BSC (Cullinan etal. 1985). Subsequently FAMTX has been
replaced by cisplatin-containing regimens.
5.8.6
Cisplatin-Based Combinations
The invitro synergy between cisplatin and 5-FU and the single-agent antitumor activity of
cisplatin in metastatic gastric cancer led to the development of phase II studies of cisplatincontaining regimens (Fig.5.3). In a phase II study, the response rate of the combination of
5-FU, doxorubicin, and cisplatin (FAP) was 35% (Moertel etal. 1986). A phase III study did
not show an advantage of FAP compared to 5-FU (Cullinan etal. 1994). Cunningham etal.
(1990) utilized epirubicin, cisplatin, and 5-FU (ECF), with response rates in phase II trials
of 3771%. In a randomized trial, the response rate of ECF was superior to FAMTX (46%
vs. 21%, p=0.0002), and median survival was longer (8.7 months vs. 6.1 months, p=0.0009)
(Cunningham etal. 1990; Waters etal. 1999). With the exception of emesis and alopecia,
ECF demonstrated an overall better toxicity profile. At two years of follow-up, 14% of the
ECF patients remained alive while only 5% of the FAMTX patients did likewise.
Etoposide was added to cisplatin and doxorubicin (EAP), with a response rate of
approximately 50% but with a mortality rate in the range of 1014% (Preusser etal. 1989).
50
RR %
45
Median survival (months)
40
36
30
26
21
20
10
5.7
8.9
8.6
9.2
0
FAMTX
Epirubicin-CF
CF
Docetaxel-CF
Fig.5.3 Metastatic gastric cancer: phase III. Adding a third drug to 5-fluorouracil (F) and cisplatin
(C). FAMTX, 5-FU, doxorubicin, leucovorin, and methotrexate
5 Gastric Cancer
125
In a randomized study, similar response rates were demonstrated with FAMTX, but it also
showed less toxicity (Kelsen etal. 1991). To decrease toxicity from the EAP regimen, this
group developed a subsequent regimen of etoposide, leucovorin, and 5-FU (ELF), with a
response rate of 53% and a median survival rate of 11 months (Wilke etal. 1990).
In a phase III trial by the European Organization for Research and Treatment of Cancer,
FAMTX was compared to ELF and to infusional 5-FU and cisplatin. There were differences
in response rates and median survival rates (Vanhoefer etal. 2000).
5.8.7
Taxane-Based Regimen
Several phase II studies demonstrated activity of docetaxel in metastatic gastric cancer.
The Swiss Group for Clinical Cancer Research conducted a randomized phase II study
comparing docetaxel and cisplatin (DC), docetaxel, cisplatin and 5-FU (DCF), and ECF in
119 chemotherapy-nave patients that resulted in an ORR of 18.5, 36, and 25% respectively (Roth etal. 2007). In the phase III V325 study, 158 patients with metastatic gastric
cancer received either DC or DCF, showing a higher response rate of 43% while DC
resulted in ORR of 26%. The combination of docetaxel, cisplatin, and 5-FU (DCF) has
been compared to cisplatin/5-FU, with DCF demonstrating a significantly longer time to
tumor progression (5.6 months vs. 3.7 months), higher response rate (36% vs. 26%), longer time on therapy (19 months vs. 16 months), and marginal, but significantly longer,
overall survival, as well as greater 1- and 2-year survival. Toxicity, however, was also
greater in the DCF group, with more neutropenia (82% vs. 57%), neutropenic fever without granulocyte colony-stimulating factor (30% vs. 12%), diarrhea (19% vs. 8%), and
lethargy (19% vs. 14%). The conclusion was that DCF improved clinical end points, but
with greater toxicity (Moiseyenko etal. 2002). On the basis of these results, docetaxel in
combination with cisplatin and 5-FU was approved by the FDA as a first-line treatment of
patients with advanced gastric cancer.
5.8.8
Irinotecan-Based Therapy
Multiple studies have demonstrated the activity of irinotecan with phase II response rates
of irinotecan combinations in metastatic gastric cancer. The combination of irinotecan and
bolus 5-FU demonstrated a response rate of 22% (Blanke etal. 2001). The combination of
irinotecan and cisplatin has been reported in several phase II studies, with responses ranging from 30 to 60% (Baker etal. 2001; Ilson etal. 1999a, b). With infusional 5-FU, several
phase II reports demonstrate responses of 3540% (Hawkins etal. 2003; Moehler etal.
2003; Bouche et al. 2003). A recent phase III trial randomized patients to irinotecan,
weekly infusional 5-FU, and leucovorin (IF), or conventional cisplatin and 5-FU. Although
the response rate, time to tumor progression, and overall survival were all improved in the
IF group, statistical significance was not reached. Toxicity was likewise less in the IF arm
except for diarrhea (Dank etal. 2005).
126
5.8.9
Epirubicin-Based Combinations
In a phase II randomized trial, REAL-2, 1,002 patients with gastric cancer were assigned
chemotherapy with one of four epirubicin-based regimens. The first was epirucibin, 5-FU,
and cisplatin; the second, epirubicin, cisplatin, and capecitabine; third, epirubicin, oxaliplatin, and 5-FU (EOF); and fourth, epirubicin oxaliplatin, and capecitabine (EOX). The
primary endpoint was noninferiority in overall survival for triplet therapeutic regimens
containing oxaliplatin compared to cisplatin, and for those containing capecitabine compared to 5-FU. The median OS in the ECF, ECX, EOF, and ECF were demonstrated to be
9.9, 9.9, 9.3, and 11 months, respectively. Toxicities for both fluoropyrimidines, capecitabine and 5-FU, were quite similar. Higher incidences of grade 3 or 4 diarrhea and neuropathy were observed in oxaliplatin-treated patients compared to those treated with
cisplatin. Although ORR, PFS, and median OS did not differ significantly among the four
groups, median OS was longer with EOX compared to ECF (p=0.02). The conclusions
from this trial demonstrated that oxaliplatin is as effective as cisplatin and capecitabine as
effective as 5-FU when given according to these gastric cancer regimens.
5.8.10
Chemotherapy vs. Best Supportive Care
Because of debate over whether chemotherapy offered any advantages for patients with
advanced gastric cancer, randomized trials were conducted in which patients with metastatic gastric cancer were assigned to receive chemotherapy or BSC (Table5.9). There was
variability in when chemotherapy was initiated, with treatment beginning at the time of
symptomatic or objective progression or at the discretion of the physician. Although the
studies were different, results consistently showed that patients randomized to receive chemotherapy immediately had better survival rates than those randomized to BSC, even if
they received chemotherapy later.
In one study of 40 patients with advanced gastric cancer receiving either BSC or an
induction course of 5-FU, methotrexate, cyclophosphamide, and vincristine followed by
weekly 5-FU and mitomycin C. The median survival in both groups was 2 months (Rake
et al. 1976). The West Midlands group reported on 193 patients randomized to 5-FU/
MeCCNU or no treatment. For patients who received the minimum of one 6-week course
of chemotherapy, the survival time was 25 weeks, compared to 22-week survival in control
subjects. Median survival estimates for all patients, including early deaths, was in the 8- to
10-week range with no apparent difference between the two groups. A QOL analysis did
favor the patients treated with chemotherapy (Kingston etal. 1978).
In a group of 76 patients with T4 or M1 disease who were randomized to no treatment,
localized radiotherapy, and thiotepa, median survival for all three groups was approximately 19 weeks (Dent etal. 1979). However, in another randomized trial in which patients
were assigned to treatment with a modified FAMTX regimen or supportive care, the trial
was stopped and all patients were assigned to treatment because of a significantly better
outcome in those who received treatment. Median survival was 10 months for patients who
were treated, vs. 3 months for the untreated controls (p=0.001) (Murad etal. 1993).
127
5 Gastric Cancer
Table5.9 Chemotherapy for advanced gastric cancer vs. best supportive care (BSC)
Regimen
FMCV/FM
BSC
FU/MeCCNU
25
BSC
22
Thiotepa
19
BSC
19
FAMTX
10
BSC
FEMTX
3.1
BSC
3.0
ELF/FU-LV
BSC
FAM
(1 year=34.1%)
BSC
(1 year=22.5%)
CV cisplatin and vinorelbine; ELF etoposide, leucovorin, 5-FU; FAM 5-FU, doxorubicin, and mitomycin
C; FAMTX 5-FU, doxorubicin, and methotrexate; FEMTX 5-FU, epirubicin, and methotrexate; FM
fludarabine and mitoxantrone; FU fluorouracil; LV leucovorin; MeCCNU, methyl-CCNU
In another trial, 41 patients were randomized to receive 5-FU, epirubicin, and methotrexate (FEMTX) plus vitamins A and E, vs. the same vitamins and BSC. Median time to
progression was 5.4 months and 1.7 months (p=0.0013), and median survival time was 3.1
months vs. 3.0 months, favoring treatment with FEMTX (Pyrhonen etal. 1995).
In a study of 61 patients randomized between chemotherapy with lactoferrin or 5-FU/
leucovorin compared to BSC, survival was superior in the treatment group, with 8 months
median survival vs. 5 months in the untreated patients (p=0.003). The QOL also favored
the treated patients (p<0.05) (Glimelius etal. 1977).
In the final trial, a retrospective study of 409 patients treated with FAM and 207 patients
untreated, the 1-year survival rate was 34.1% in the treated patients vs. 22.5% in the
untreated group (Park etal. 1997).
5.8.11
Targeted Therapy
Research into the molecular biology of gastric cancer cells has revealed genetic and
molecular targets that are being evaluated as predictive and prognostic markers in stomach
cancer. Knowledge of molecular targets also allow for the development of targeted therapeutic interventions.
128
5.8.12
Monoclonal Antibodies and Tyrosine Kinase Inhibitors
Newer targeted therapies, such as the anti-HER2 monoclonal antibody, trastuzumab; the
anti-vascular endothelial growth factor (VEGF) drug, bevacizumab; the anti-epidermal
growth factor (EGF) receptor drugs, cetuximab and matuzumab; and signal transduction
inhibitors, such as erlotinib and gefitinib, are currently being evaluated in gastric cancer.
Cetuximab is being evaluated in the Cancer and Leukemia Group B 80403 trial,
combining monoclonal antibody with chemotherapy as first-line treatment in a phase II
trial of metastatic gastric cancer. As planned, this will be a randomized phase III trial of
three different chemotherapy regimens combined with cetuximab: ECF; oxaliplatin,
5-FU, and leucovorin; and irinotecan with cisplatin (CALGB Clinical Trials (www.
calgb.org)) Multiple phase II trials of chemotherapy combined with targeted therapies
are ongoing. Promising outcomes from these studies will undoubtedly be tested in future
phase III trials.
Trastuzumab, a recombinant monoclonal antibody against HER2 plus chemotherapy
has recently demonstrated benefit in patients with metastatic gastric cancer. In a prospective, randomized controlled phase III trial, 3,807 patients with recurrent, locally advanced,
or metastatic gastroesophageal and gastric adenocarcinoma were evaluated. Tumor tissue
was tested for HER2 status and 22.1% of tested cancers were found to be positive for
HER2 expression. Patients were randomly assigned standard chemotherapy with 5-FU or
capecitabine plus cisplatin or this standard chemotherapy plus trastuzumab. Trastuzumab
was given until disease progression. The primary endpoint was OS; secondary endpoints
included overall response rate, PFS, time to disease progression, duration of response, and
safety. Compared with standard chemotherapy, trastuzumab plus standard chemotherapy
resulted in increased OS, 13.8 months vs. 11.11 months (HR=0.74; 95% CI, 0.600.91).
Additionally, trastuzumab plus chemotherapy was associated with an improved response
rate, 47.3% vs. 34.5% p=0.0017). Both regimens were tolerated well with no unusual
toxicities or adverse events. The conclusions from this study suggested that this regimen
offered another option for patients after testing for HER2 status based on protein expression or fluorescent in situ hybridization (VanCutsen etal. 2009, Bang 2010). However, an
amended Hercept Test scoring system should be used to determine HER2 positivity in
gastric cancer since there are differences between the results in stomach cancer and in
breast cancer (Hofman 2008).
5.8.13
Chemotherapy in Resectable Gastric Cancer
The use of chemotherapy in patients with resectable or potentially resectable gastric cancer
should be considered in two clinical scenarios. The first is as postoperative adjuvant chemotherapy after resection in patients at risk for recurrence. The second clinical scenario in
which chemotherapy is used is as perioperative treatment. In this situation chemotherapy
is used both before and after gastrectomy.
5 Gastric Cancer
129
There has until recently been no convincing evidence that the postoperative use of
cytotoxic chemotherapy benefits patients after gastrectomy with curative intent (Earle and
Maroun 1999; Mari etal. 2000). The use of postoperative cytotoxic therapy has never been
adopted as a standard of care in North America. In late 2007, the study of Sakuramoto and
colleagues (2007) was published in the New England Journal of Medicine. This large
(greater than 1,000 cases) phase III study of adjuvant chemotherapy in resected gastric
cancer compared 1 year of postoperative therapy with the fluorinated pyrimidine S-1 to
cases treated with surgical resection alone. Follow-up data showed that the 3-year overall
survival rates were 80.1% in the S-1 group and 70.1% in the surgery-only group. The hazard ratio for death in cases receiving S-1 compared to that in the surgery-only group was
0.68 (0.520.87). The log rank p value was 0.003. S-1 was well tolerated with grade 3 or
grade 4 adverse events occurring in less than 10% of cases.
There was no question that the clinical trial of Sakuramoto etal. was well designed,
well powered, and well executed. The benefit seen for S-1 therapy was highly statistically
significant. However, when looked at from the perspective of western oncologists, there
was concern that the S-1 results were not applicable to the gastric cancer cases seen in the
United States and Europe. The striking finding of a 70% 3-year survival in the surgeryonly cases was very much higher than the 2545% survivals seen in western studies of
surgical resection alone (Macdonald etal. 2001). Although the Japanese cases had some
better prognostic factors (more T2 and fewer T3 tumors and somewhat less nodal involvement) than seen in western series, a 70% 3-year survival is well beyond what could be
attributed to differences in prognostic factors. In summary, although all agree that the S-1
study demonstrates benefit for the Japanese gastric cancer population, it appears that
monotherapy with S-1 is not appropriate for western gastric cancer patients.
Perioperative chemotherapy does have a role in the management of surgically resectable stomach cancer. In 2006, the results of a European phase III trial testing perioperative
chemotherapy with the combination chemotherapy regimen ECF (epirubicin, cisplatin and
5-FU) was reported (Cunningham et al. 2006). The study (acronym: the MAGIC trial)
reported by Cunningham etal. accrued patients with potentially resectable gastroesophageal cancer to surgery alone or perioperative chemotherapy. The chemotherapy consisted
of pre- and postoperative ECF. The results of the trial convincingly demonstrated a benefit
from the use of the ECF regimen. Five-year overall survival was 36% in the perioperativechemotherapy group and 23% in the surgery-only group (p=0.008 by the log-rank test).
This improvement in survival of 13% points corresponds to a 25% relative reduction in the
risk of death. Progression-free survival also was improved by chemotherapy. Perioperative
chemotherapy appeared to influence other outcomes. Encouraging trends, such as decreased
tumor size and reduction in the extent of nodal metastases were noted in the ECF patients.
There were significant toxicities, as would be expected, in the patients receiving ECF.
These toxicities were manageable, and well over 90% of cases randomized to chemotherapy were able to receive preoperative chemotherapy. However, it is significant that, for a
variety of reasons including chemotherapy toxicity, less than 50% of cases completed all
the postoperative chemotherapy.
The MAGIC study of Cunningham and colleagues is a significant step forward in the
treatment of gastric cancer. As the INT0116 study (Macdonald et al. 2001) defined
130
chemoradiation as a standard of care for patients identified postoperatively, MAGIC has

now defined perioperative chemotherapy strategies as appropriate approaches for patients
presenting with resectable gastric cancer.
5.8.14
Supportive Care
Because a large percentage of patients with metastatic gastric cancer have experienced
significant weight loss, supportive care with attention to obstruction, nutrition support, and
pain control are important to enhance the ability of the patient to undergo chemotherapy
(Table5.10). Gastric outlet obstruction can often be treated with endoluminal stent or with
laser therapy for exophytic tumor masses. Nutritional support can be achieved through
feeding jejunostomy or percutaneous endoscopic gastrostomy tube placement or through
parenteral alimentation. Pain management, including selective use of palliative radiation
for bone metastases or obstructing or bleeding tumors, may also be necessary.
5.9
Conclusion
Gastric cancer is a common disease worldwide, occurring in greater than 800,000 persons
each year. The epidemiology, molecular carcinogenesis, diagnosis, and therapy of stomach
cancer represent complex multifactorial problems. There is still a great deal to learn about
this neoplasm. This chapter emphasized clinical aspects of the management of gastric
cancer patients. There are several themes of importance. First, as is the case in all oncology
at the start of the twenty-first century, an increasing understanding of the molecular biology and molecular genetics of carcinogenesis and tumor growth is beginning to supply
clinicians with rationales for targeted approaches to be tested in clinical trials. Understanding
some of the important factors in the biology of gastric carcinogenesis has led to strategies
of disease prevention such as the elimination of H. pylori in high-risk populations. Targeted
therapies and effective prevention strategies hold real promise for the future control of
Table5.10 Supportive care: symptom management
Obstruction
Endoluminal stent
Endoscopic laser
Nutritional support
Feeding jejunostomy
Percutaneous endoscopic gastrostomy (PEG)
Parenteral alimentation
Pain control
Palliative irradiation
5 Gastric Cancer
131
stomach cancer. However, the major theme in the management of this neoplasm that has
been communicated by this chapter is the importance of multispecialty care. The advances
that have been demonstrated in the recent past have been the result of committed oncologists of various disciplines working together. The surgeon, radiation oncologist, and medical oncologist working together have led to perioperative and postoperative treatment
strategies that have improved patient survival and have been widely adopted as standards
of care. The accomplishments of teamwork in the multimodality management of gastric
cancer are impressive. However, more impressive is the promise that this well-established
clinical teamwork, melded with rapidly developing advances in translational science,
holds for continued improvement in the treatment of stomach cancer.
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Gastrointestinal Stromal Tumors
John R. Zalcberg, Desmond Yip, Christine Hemmings,

Bruce Mann, and Charles D. Blanke
6.1
Epidemiology
6.1.1
Demographics
Gastrointestinal stromal tumors (GISTs) are the commonest mesenchymal tumors of the
gastrointestinal tract. Although they most frequently arise in the stomach (around 60% of
cases) and small intestine (3035%), GISTs can occur anywhere in the tubular organs of
the gastrointestinal tract, though they uncommonly arise from colorectum and appendix
(5%) and esophagus (<1%) (Miettinen and Lasota 2006b). Extraintestinal examples
(e.g., omental, mesenteric or retroperitoneal tumors) also occur, but metastasis from an
intestinal primary should be considered in these cases; it is thought that true primary
extra-intestinal disease represents less than 1% of all GISTs. Rare examples have been
reported in the gallbladder (Mendoza-Marin etal. 2002; Park etal. 2004). The overall
incidence of GISTs has been estimated at anywhere from 10 to 20 per million if small,
J.R. Zalcberg (*)

Division of cancer medicine,
Peter MacCallum Cancer Centre and Dept of medicine University of Melbourne,
Melbourne, VIC, Australia
e-mail: john.zalcberg@petermac.org
D. Yip
Medical Oncology Unit, The Canberra Hospital, ANU Medical School, Australian National
University, Canberra, ACT, Australia
C. Hemmings
ACT Pathology, The Canberra Hospital, ANU Medical School, Australian National University,
Canberra, ACT, Australia
B. Mann
Peter MacCallum Cancer Center, Melbourne, VIC, Australia
C.D. Blanke
Division of Medical Oncology, UBC, Vancouver, BC, Canada
139
140
J.R. Zalcberg et al.
incidentally discovered tumors are included. Sporadic GIST most commonly arises in the
fifth and sixth decades, with a slight male preponderance, at least in terms of malignant
tumors (Miettinen and Lasota 2006b). Recent autopsy series suggest around 20% of the
general population harbor micro-GISTs, though only a small fraction will develop clinically significant tumors (Kawanowa etal. 2006).
While GISTs are relatively rare tumors, their incidence has apparently increased in
recent times, in part because of better recognition due to the characteristic CD117 immunohistochemical staining for the c-KIT receptor that is expressed on the majority of GISTs.
An additional reason for the apparent higher incidence is the increased attention and
research interest due to the recognition of the key role of oncogenic KIT gain-of-function
mutations first recognized and described by Hirota (1998), coupled with the availability of
novel targeted therapies such as imatinib for the condition.
Finally, these tumors in the past have been misclassified as other soft tissue sarcomas
such as leiomyosarcomas, leiomyomas or leimyoblastomas (Miettenen etal. 2002). For
example a Dutch National Pathology Registry study found an incidence of 2.1 per million
inhabitants in 1995 and one of 12.7 per million in 2003 (Goettsch etal. 2005). Similarly
US SEER cancer registry data have documented an increase in cases from 2.8 per million
population in 1992 to 6.9 per million in 2002. These changes are mainly due to reclassification of smooth muscle tumors as GIST, but there are also a noticeably increased number
of cases of mesenchymal tumors diagnosed since 1992. Histopathological review of all
cases of patients with potential GIST in western Sweden diagnosed between 1983 and
2000 determined an incidence of 14.5 per million (Nilsson etal. 2005). A similar Icelandic
histopathological review of all gastrointestinal mesenchymal tumors diagnosed in the
country between 1990 and 2003 has found an annual incidence of 11 per million
population.
6.1.2
Special Types and Associations
6.1.2.1
Pediatric GIST
Fewer than 1% of GISTs occur in children, and these tumors have a strong predilection for
the stomach. In contrast to sporadic GIST in adults, tumors arising in children show a striking female preponderance (around 75%), with a median age of 12; they are also more
commonly multifocal and have a tendency to involve regional lymph nodes more frequently. The majority of tumors have an epithelioid phenotype. Despite the majority of
tumors expressing CD117 immunohistochemically, only around 15% show KIT mutations
(Janeway etal. 2007). Pediatric GISTs have been shown to have a distinct transcriptional
signature, with overexpression of BAALC, PLAG1, IGF1R, FGF4, and NELL1 (Agaram
etal. 2008a). Most are wild type in mutational profile and invitro studies show that kinase
inhibitors such as nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib. Association with Carney triad (see below) seems infrequent, despite demographic
and histologic similarities (Miettinen etal. 2005a).
6 Gastrointestinal Stromal Tumors
141
6.1.2.2
Familial GIST
Familial GIST is a rare autosomal dominant condition arising as a result of germline KIT
or PDGFR mutations and is characterized by multiple tumors arising throughout the gastrointestinal tract, often in association with interstitial cell of Cajal (ICC) hyperplasia.
These tumors tend not to arise until middle age, and their behavior varies from indolent to
malignant. Other manifestations of KIT activation including mastocytosis and increased
cutaneous pigmentation may be seen (Miettinen and Lasota 2006b).
6.1.2.3
Syndromic GIST
GIST cases are mostly sporadic but may also occur as part of a syndromic association such
as Carneys triad where GIST can be associated with extra-adrenal paragangliomas and
pulmonary chondromas, typically affecting young females (Carney 1999). In these cases,
the tumors are typically gastric in location, epithelioid in morphology and arise in girls or
young women. The majority of these tumors are indolent, with prolonged survival even
after the development of liver metastases (Miettinen and Lasota 2006b; Miettinen etal.
2005a). There is also an autosomal dominant familial inherited association with paraganglioma alone affecting both males and females, which is thought to be a separate syndrome
(Carney and Stratakis 2002). These pediatric and syndromic GISTs tend to be wild type
and have a more indolent clinical course (Miettinen etal. 2005b).
GIST is relatively common in patients with neurofibromatosis, Type 1, accounting for
around 5% of GIST cases (Miettinen etal. 2006). These tumors typically have a spindled
morphology with few mitoses and lack CD117 expression but express CD34. They most
often arise in the small intestine and are typically multiple and small (Miettinen and Lasota
2006a). They are often associated with diffuse ICC hyperplasia, and generally lack both
KIT and PDGFR mutations (Miettinen and Lasota 2006b). Although they tend to be clinically indolent, in malignant examples primary imatinib resistance is common (Mussi etal.
2008b).
6.1.2.4
Other Associations
GIST may also occur in patients with other tumors, either synchronously or metachronously
and indeed many GISTs are discovered incidentally during investigation of unrelated disease. The frequency of second tumors reportedly ranges from 4.5 to 33%, when Carney
triad and neurofibromatosis are excluded. Gastric GISTs are the ones most often associated
with other tumors, reflecting their overall high frequency. The commonest second malignancies in one series were gastrointestinal tract carcinoma (47%), hematologic malignancies (7%), and carcinoma of prostate (9%), breast (7%), kidney (6%), lung (5%) or female
genital tract (5%). Others included carcinoid tumor (3%), sarcoma (3%), melanoma (2%)
142
and seminoma (2%). An association has been seen with myeloid leukemia (Miettinen etal.
2008). Collision tumors and metastases of carcinoma or sarcoma into GIST have also been
reported (Agaimy etal. 2006).
6.2
Pathology
6.2.1
Gross Pathology
GISTs are believed to originate from ICC, or their stem-cell like precursors. ICC have both
myoid and neural features and function as gut pacemakers, regulating GI motility. They
are KIT-dependent cells located around the myenteric plexus and in the muscularis propria
throughout the GI tract. ICC may differentiate into smooth muscle cells if KIT signaling is
disrupted (Torihashi etal. 1999).
GISTs most often arise as intramural tumors, centered on muscularis propria. Tumor
may erode overlying mucosa, classically producing a smooth nodule with central umbilication from which devastating hemorrhage may occur. GISTs vary widely in size, varying
from less than 1cm when discovered incidentally, to 30cm or more (Hemmings, unpublished data). There is often relative constriction of tumor growth within muscularis propria, with bulging of larger tumors into submucosal and subserosal connective tissue,
producing a dumbbell configuration. The cut surface of the tumor varies from myxoid to
smooth, homogeneous, pale tumor with a soft fleshy texture, to firm and more fibrous, or
more variegated with areas of hemorrhage and necrosis. Foci of calcification may produce
a gritty texture on slicing.
6.2.2
Light Microscopy
6.2.2.1
Morphology
The commonest histologic pattern is that of a moderately cellular spindle-cell neoplasm,
typically centered on muscularis propria but often extending into submucosa and/or subserosa (Fig.6.1). The cells recapitulate the ICCs to varying degrees. Indeed, ICC hyperplasia may be identifiable in subjects with familial GIST. The degree of cellularity may vary
considerably, as does the mitotic rate. Necrosis is an inconsistent finding but may be
extensive.
A subset of GIST has a more epithelioid morphology (Fig.6.2), which may be seen
exclusively or intermingled with areas of spindle cells. Some tumors, particularly those
harboring PDGFR mutations, have abundant myxoid stroma (Fig.6.3), which may appear
chondroid and, on occasion, include true cartilaginous differentiation (Fig.6.4). Metaplastic
143
Fig.6.1 Typical appearance

of a spindle-cell GIST
(H & E, original
magnification 200)
Fig.6.2 Less commonly,

the cells have a more
epithelioid morphology
(H& E, original
magnification 1,000)
osteoid or true ossification may also be seen (Fig.6.5). Other less common findings include
signet-ring, oncocytic or rhabdoid cells. Rhabdomyosarcomatous differentiation has been
described following tyrosine kinase inhibitor therapy (Liegl etal. 2009).
6.2.2.2
Immunohistochemistry
CD117
Most GISTs (approximately 95%) express KIT protein, and a mainstay of diagnosis in GIST
has been immunoperoxidase staining for CD117, a cell surface antigen on the extracellular
domain of KIT (Croom and Perry 2003). CD117 staining is typically strong and diffuse in
most GISTs, though some KIT negative tumors may still harbor KIT gene mutations, strongly
144
Fig.6.3 Some tumors,

particularly those harboring
PDGFR mutations, exhibit
abundant myxoid stroma
(H & E, original
magnification 100)
Fig.6.4 The stroma may

appear chondroid and,
on occasion, show true
cartilaginous differentiation
(H & E, original
magnification 200)
suggesting that KIT is still involved in tumorigenesis. Many KIT-negative GISTs harbor
PDGFR mutations. In some intestinal tumors the staining may be patchy, and a minority label
as paranuclear dots only (Miettinen and Lasota 2006b).
Despite its relatively high sensitivity, CD117 staining should not be taken as definite
evidence of GIST a number of other tumors will show weak or focal positivity (particularly if antigen retrieval is employed; this should not be performed to reduce the risk of
false positive staining). Particularly in unusual sites, other diagnoses such as solitary
fibrous tumor (which is also typically positive for CD34) should be considered.
CD34
CD34 is a hemopoietic progenitor cell antigen which is also expressed in endothelial cells,
some fibroblasts, and various mesenchymal neoplasms. Perhaps 70 (Miettinen and Lasota
145
Fig.6.5 Heterologous
elements such as
metaplastic osteoid or true
ossification may also be
seen (H & E, original
magnification 200)
2006b) to 85% (Miettinen and Lasota 2006a) of GIST express CD34, with almost universal positivity in tumors of the esophagus and rectum, whereas in the stomach epithelioid or
sarcomatoid GIST may be negative.
PDGFR
It has been suggested that immunohistochemical staining for PDGFR has diagnostic value,
particularly in KIT-negative GIST (Rossi et al. 2005), however the currently available
antibodies appear to be unreliable on paraffin-embedded tissue (Miettinen and Lasota
2006a), and its use is not widespread. Furthermore, PDGFR may also be expressed in a
subset of abdominal fibromatosis (desmoid tumor) and is therefore not entirely specific
(Rossi etal. 2005).
Protein Kinase C Theta

Protein kinase C (PKC) theta is a downstream effector in the KIT signaling pathway and
has been suggested as an immunohistochemical marker as well as a potential further therapeutic target in GIST, often staining KIT-negative tumors as well (Lee et al. 2008).
Positivity in GIST is reported to range from perhaps 85100% of tumors (Miettinen and
Lasota 2006b) however, a number of other mesenchymal tumors also react with the antibody (Lee etal. 2008), which is again said to be difficult in everyday laboratory applications and has not gained widespread use for routine diagnosis.
DOG-1
Gene expression profiling found that the gene FLJ10261 Discovered On GIST-1 (DOG-1)
was specifically expressed in GIST. Immunoreactivity was subsequently demonstrated in
146
Fig.6.6 Immunoperoxidase
staining for DOG-1 is
usually positive in GIST,
including those that are
negative for CD117.
Mutational analysis of this
case confirmed the presence
of a PDGFR mutation,
whereas kit was wild type
(same case as Fig.6.3).
(DOG-1, original magnification 200)
the vast majority of GIST, including in KIT-negative and PDGFR-mutant tumors. Very
few non-GIST mesenchymal tumors have been shown to react with DOG-1 (West etal.
2004), which also appears to stain fewer cases of carcinoma, melanoma and seminoma
than does CD117 (Espinosa etal. 2008). This antibody is now commercially available and
provides a useful additional diagnostic tool in cases where CD117 staining is focal, weak
or negative (Fig.6.6).
6.2.2.3
Other Markers
Other markers which may be expressed in GISTs include the myoid markers smooth
muscle actin (SMA) (2035%) and heavy-caldesmon (80%), whereas desmin is only
occasionally positive (<5%). Perhaps surprisingly, expression of S-100 protein is relatively unusual in GIST, being rare in the stomach but somewhat more common (perhaps 14%) in the small intestine. Most GISTs express nestin, but this is of limited
value clinically as it is also expressed in gastrointestinal schwannoma, whereas GFAP
is negative in GIST. Keratin positivity (generally focal) may be observed, particularly
with antibodies reacting to keratin 18, whereas CK7 and CK20 are generally negative
(Miettinen and Lasota 2006a).
6.2.3
Electron Microscopy
There are no diagnostic ultrastructural features specific to GISTs, and the appearances may
vary somewhat according to anatomic location. Overall, gastric and omental tumors tend to
have better developed myoid features than their intestinal counterparts. Cytoplasmic filaments and intercellular junctions are common, with filaments often forming paranuclear
147
Fig.6.7 Skeinoid fibers

(bottom right, below the
nucleus) are most often seen
in small intestinal tumors
(EM, original magnification
20,000)
aggregates in epithelioid tumors. The cells tend to have surface filopodia and interdigitating
cell processes, but these are often short in gastric and omental tumors whereas in the intestine they tend to be long and complex. External lamina is often poorly formed, and tends to
be absent altogether in intestinal tumors. Pinocytotic vesicles are variable in frequency but
tend to occur at all anatomic locations, whereas microtubules are more common in intestinal
tumors but rare in the stomach or omentum. Skeinoid fibers occur in around one-third of
small intestinal tumors, and appear to be largely confined to that location (Yantiss et al.
2002) see Fig.6.7.
6.2.4
Molecular Biology and Mutational Analysis
6.2.4.1
KIT
The majority of GISTs (perhaps 85%) harbor mutations in the gene encoding the transmembrane receptor tyrosine kinase KIT. These mutations cause functional changes in KIT
protein, usually leading to ligand-independent dimerization and constitutive activation of
KIT signaling and thereby activation of downstream effectors. These processes commonly
involve signal transduction via the transfer of ATP to tyrosine residues on substrate proteins, by tyrosine kinase enzymes. The end result is to stimulate cellular proliferation and
impede apoptosis, thereby culminating in neoplasia. KIT mutations most often arise in the
juxtamembrane position at exon 11 (around 67% of GISTs, arising at all anatomic sites),
with exons 9 (extracellular domain, 10%, occurring in a higher percentage of intestinal
GISTs), 13 (kinase 1 domain, 1%) and 17 (activation loop, 1%) being less commonly
affected (Miettinen and Lasota 2006b).
148
6.2.4.2
PDGFR
Most GISTs lacking KIT mutations are wild type (~10%), or have PDGFRA mutations
(57%). KIT and PDGFR are highly homologous receptor tyrosine kinases. Both genes are
located at 4q12, suggesting a common ancestral gene (Miettinen and Lasota 2006b).
PDGFR mutations most often occur in exons 12 (juxtamembrane, approximately 1% of
GISTs) or 18 (activation loop, 6%), and are commoner in gastric tumors, often having a
myxoid and epithelioid phenotype (see Fig. 6.5). Activation loop mutations at D842V
(5%) are often associated with extraintestinal location (mesentery and omentum), and imatinib resistance. KIT and PDGFR mutations appear to be mutually exclusive (Miettinen
and Lasota 2006b).
Thus molecular analysis for KIT and PDGFR mutations may be useful in establishing
a diagnosis of GISTs in challenging cases, and should be performed at diagnosis in highrisk or metastatic GISTs, when it may serve to guide therapy (see below). Fully resected,
low-risk GISTs need not be routinely tested.
6.2.4.3
IGF-1
IGF-1 and -2 bind to the IGF-1 receptor and lead to activation of MAPK and PI3K cascades. Braconi etal. (2008) found IGF-1R to be overexpressed in all 94 GISTs analyzed in
a series. Strong IGF-1 expression correlated with higher mitotic index, larger size, and a
higher risk of relapse and metastasis. IGF-1 and -2 expression both correlated with reduced
disease-free survival, which was improved if both IGF-1 and -2 were negative.
Immunohistochemistry, quantitative polymerase chain reaction (qPCR) and fluorescent in
situ hybridization (FISH) of GISTs have demonstrated significant overexpression of
IGF-1R and amplification of the IGFR1 gene in wild type or pediatric GIST compared to
mutant types (Godwin etal. 2008). Inhibition of IGF-1R activity using NVP-AEW541 has
been shown to result in cytotoxicity and induce apoptosis in GIST cell lines, via AKT and
MAPK signaling (Tarn etal. 2008) suggesting that IGF-1 drives pathogenesis in the subset
of GISTs which do not have KIT or PDGFR mutations, and offers another potential therapeutic target.
6.2.4.4
BRaf V600E
A small subset of tumors studied by Agaram etal., (2008b) were found to harbor BRaf
mutations at exon 15 (V600E). These tumors all arose in the small intestine and were classified as high risk and occurred in women aged 4955 years, raising the possibility of a
distinct subset of GISTs, providing an alternative mechanism of imatinib resistance and
potentially offering another therapeutic target for some patients.
149
6.2.4.5
Other
As stated above, 20% of the population has micro-GISTs, with only a few becoming
malignant. KIT gene mutation is known to be a very early event in tumor genesis, and it
is felt additional alterations are necessary for progression to high-risk disease (e.g., loss
of chromosomes 1p, 14q, 22q; telomerase reactivation, and microsatellite instability)
(Kawanowa etal. 2006).
6.2.5
Behavior and Prognosis
6.2.5.1
Patterns of Metastasis
GISTs most often metastasize within the abdomen, either intraperitoneally or hematogenously to the liver. Metastasis to extra-abdominal sites is rare, but distant metastases can
occur in unusual sites including brain (Hughes etal. 2004), testis (Doric etal. 2007) or soft
tissues (Pasku etal. 2008).
6.2.5.2
Prediction of Behavior
Histology is an imperfect predictor of clinical behavior, which also varies according to
primary site. Primary esophageal GISTs are rare, but most are malignant. Gastric tumors
are commonest, with fundic tumors being more often malignant than those arising in the
antrum. Small intestinal GISTs are more often malignant and although rare, primary
colorectal GISTs frequently metastasize (around 50%) and often follow an aggressive
clinical course. In comparison with gastric tumors, intestinal GIST tend to be larger at
diagnosis, but even when controlling for size and mitotic count, intestinal tumors tend
to be more aggressive, also reflected in differing gene expression profiles. Be that as it
may, the two best-documented early criteria for assessment of biologic potential were
size and mitotic count. NIH-consensus risk-group stratification criteria for risk of GIST
recurrence following resection were published in 2002 (Fletcher etal. 2002) but these
did not reflect the importance of location in predicting behavior or of the negative
impact of tumor rupture (Joensuu 2008). More recently, the Armed Forces Institute of
Pathology (AFIP) (Miettinen and Lasota 2006a) attempted to refine the criteria in terms
of location as well as size and mitotic count, although data for rare sites such as esophagus and rectum are still limited. Gastric GISTs <10cm and with five mitotic figures (mf)
per 50 high-power fields (hpf) have a low risk for metastases, whereas those with >5
mf/50 hpf are at high risk. In contrast, intestinal GISTs >5cm have at least a moderate
risk of metastasis, and those with >5 mf/50 hpf are at high risk. Intestinal GISTs <5cm
or <5 mf/50 hpf are relatively at low risk. See Table6.1.
150
Table6.1 Risk stratification of primary GIST by mitotic index, size and site (based on Miettinen
and Lasota 2006a)
Mitoses per 50
Size
Gastric
Duodenal
Distal small
Colorectal
high-power fields
bowel
<5/50
<2cm
25cm
510cm
>10
None
Very low
Low
Moderate
None
Low
Moderate
High
None
Low
ID
High
None
Low
ID
High
>5/50
<2cm
25cm
510cm
>10
Nonea
Moderate
High
High
Higha
High
High
High
ID
High
ID
High
High
High
ID
High
ID insufficient data
Small numbers
Furthermore, gastric GISTs may be subclassified histologically, which improves estimation of biologic potential. Sclerosing spindle cell GISTs are usually small, mitotically
inactive and relatively paucicellular tumors with abundant collagenous matrix which may
calcify. The prognosis of this subtype is excellent. Palisading spindle cell tumors reminiscent of schwannoma typically have a low mitotic rate but may attain larger size, despite
which the prognosis is generally favorable. Hypercellular spindle cell GISTs without
nuclear palisading tend to have more frequent mitoses (often >5 mf/50 hpf), and carry a
moderate risk of metastasis. Sarcomatoid spindle cell GIST have diffuse atypia and
increased mitoses (often >20 mf/50 hpf), and a greater tendency to metastasize. In the
epithelioid group, sclerosing tumors with a somewhat syncytial appearance tend to have
few mitoses and a low risk of metastasis. Dyshesive tumors with clearly defined cell borders are intermediate in behavior, whereas hypercellular and sarcomatoid tumors are more
aggressive (Miettinen and Lasota 2006a).
Other morphologic factors which may have adverse prognostic significance include
the presence of multiple peritoneal nodules and fat infiltration (regardless of primary
site), coagulative necrosis and/or ulceration, mucosal invasion (Miettinen and Lasota
2006a), serosal involvement (Goh etal. 2008), the presence of metastases at diagnosis,
and tumor rupture (Joensuu 2008, Takahashi etal. 2007). On the other hand, nuclear
palisading is statistically favorable in both gastric and intestinal GISTs (Miettinen and
Lasota 2006a). Immunohistochemically, loss of p16 expression is common (perhaps
50% of cases), does not correlate with age, sex, histologic subtype, or the presence of
necrosis, but appears to be an independent predictor of poor prognosis (Schneider-Stock
etal. 2005).
Although metastases may resemble the primary tumor histologically, they are often
genetically heterogeneous, harboring a variety of secondary mutations not seen in the primary (Wardelmann etal. 2006). Response to targeted therapy may therefore vary between
different tumor deposits (Cameron etal. 2009).
151
6.3
6.3.1
Clinical Presentation
GISTs have a predilection for adults older than 50 years, with a peak at around 60 years.
They arise slightly more commonly in men (Miettinen etal. 2005c). GISTs may have a
variety of presentations. They may be incidentally detected at gastroscopy, abdominal
imaging or laparotomy for unrelated conditions (Miettinen etal. 2005c). The most common
presentation is with bleeding, which may manifest as iron deficiency anemia due to chronic
blood loss, or as an acute gastrointestinal hemorrhage from the primary causing hematemesis or melena. Rarely rupture of the primary or a metastasis into the peritoneal cavity may
produce hemoperitoneum. Obstructive symptoms may occur depending on the location of
the primary. For example dysphagia may occur with esophageal GISTs and altered bowel
habits in rectal primaries. Advanced disease may present with ascites and a palpable mass.
Patients may have considerable disease bulk at initial diagnosis, though this occurs less
commonly in modern series. The most common sites of spread are into the liver and the
peritoneum. Lung, cutaneous, intracerebral, and bony involvement occur less commonly.
6.3.2
Investigations
Incidental submucosal lesions may be encountered during endoscopy and a biopsy using
forceps may be difficult to conduct. Endoscopic ultrasound (EUS) may be used to detect
the component of the gastric wall from where the lesion is arising and also to determine
echogenicity, which may allow lipomas to be distinguished (these are intensely hyperechoic and arise from the submucosa). Lesions may be observed if small and non-suspicious. If lesions are symptomatic or intramural and hypoechoic, then these are suspicious
for malignancy and should be referred for resection (Hwang etal. 2006).
Small bowel GISTs may be more difficult to detect. An abnormality may be found on a
barium follow-through examination. Active bleeding sites in the small bowel may be
localized by mesenteric angiography however video wireless capsule endoscopy is a more
accurate way of diagnosing intraluminal small bowel lesions than conventional imaging
modalities (Mazzarolo and Brady 2007).
If lesions are deemed to be easily resectable, preoperative percutaneous biopsy may not
be advisable due to the risk of tumor rupture or dissemination (The NCCN Clinical Practice
Guidelines in Oncology 2008). A tissue diagnosis is always required however, before
instituting neoadjuvant therapy or placing a patient onto a clinical trial.
If GIST is suspected or confirmed, computed tomography (CT) with contrast of the
chest, abdomen and pelvis is important in staging the patient to determine the local extent
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of disease as well as presence of metastases, with respect to planning further management.

MRI imaging of the pelvis for rectal GISTs can give more anatomical information than CT
scanning. Functional imaging with fluorodeoxyglucose-positron emission tomography
(FDG-PET) scanning is a very useful modality for initial staging as well as monitoring of
treatment response to therapy and is complementary to CT imaging.
6.4
Clinical Management
Similarly to other gastrointestinal malignancies, the management of GISTs is multidisciplinary, involving a number of different specialties.
6.4.1
Surgical Management
The technical aspects of the surgery for GIST follow general surgical oncological principles
with nuances specific to this tumor type. This means, surgeons with site-specific or diseasespecific expertise should be involved with elective surgical treatment. When GISTs present
with acute bleeding, perforation, or obstruction and require emergency laparotomy by a
general surgeon, pathological material should be available to guide further management.
6.4.1.1
Resectable Primary GIST
Resection without definitive biopsy material is appropriate when the diagnosis of GIST is
likely, except as discussed above. Endoscopic biopsy is often unable to definitively diagnose GIST, as a common result is normal overlying mucosa. EUS-guided fine-needle aspiration is usually inadequate to provide a definitive diagnosis (American Gastroenterological
Association Institute 2006; Pidhorecky et al. 2000). Transperitoneal core biopsy in a
patient with apparently resectable disease risks tumor rupture and seeding (Demetri etal.
2007; Gold and Dematteo 2006; Pidhorecky etal. 2000). A difficulty is when radiological
imaging has GIST as one of a number of differential diagnoses, with lymphoma being
another. These cases must be decided on an individual basis.
All GISTs are considered potentially malignant, and resection should be considered
even for small intramural lesion (2cm) (Blackstein etal. 2006; Blay etal. 2005; Corless
etal. 2002). Most treatment guidelines mandate removal of lesions 2cm in size of larger
(Demetri etal. 2007).The decision to observe or remove will depend on the features of the
tumor and also its location and the age and fitness of the patient. Small tumors that are not
resected should be monitored with periodic EUS or computerized tomography (CT).
The objective of GIST surgery is to remove the primary tumor with negative microscopic margins. This may require en bloc resection of adjacent organs and structures such
as the spleen, tail of pancreas, diaphragmatic crus, etc. for gastric GISTs. Tumor handling
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should be minimized since tumor rupture is associated with poor outcome (Blackstein
etal. 2006; Eisenberg and Judson 2004; Gold and Dematteo 2006; Pidhorecky etal. 2000).
Open surgery has been standard, but, there is little evidence for avoiding laparoscopic
resection of lesions (Everett and Gutman 2008).The principals of laparoscopic surgery are
similar to those of open surgery-macroscopic tumor resection, minimal tumor handling,
and protection from port-site implantation by the use of a specimen retrieval bag.
As lymphatic spread is rare and nodal metastasis indicates advanced disease, lymphadenectomy is not part of standard surgery for GIST (Blackstein etal. 2006; Eisenberg and Judson
2004; Gold and Dematteo 2006). Clinically or radiologically involved nodes should be resected
when feasible as part of the primary operation, but if there is nodal involvement, systemic
disease is likely and preoperative systemic therapy would be appropriate. Postoperatively,
patients with intermediate- or high-risk primary GIST should be considered for adjuvant imatinib therapy or for entry into an adjuvant trial (see Adjuvant imatinib therapy).
6.4.1.2
Borderline Resectable Disease
Though highly likely to be GIST on imaging (or proven on biopsy) a disease of borderline
resectability definitely requires referral to a surgeon with interest and experience in the
field and consideration in an appropriate multidisciplinary setting. Options include
attempted resection (which may include biopsy for confirmation if unresectable) or nonoperative biopsy and subsequent imatinib treatment.
The role of preoperative imatinib is not clearly defined; however, in many patients the
disease becomes resectable after response to imatinib. Situations where neoadjuvant therapy might be considered include: potentially resectable GIST where surgery would cause
functional impairment (e.g., rectal GIST requiring abdominoperitoneal resection) or loss
of organ function (e.g., total gastrectomy), or where a tumor is large and truly locally
advanced (Blay etal. 2005).Close monitoring for possible tumor progression on treatment
is necessary, though it would be unusual to worsen on short-term therapy. The surgical and
medical oncologists should decide the optimal timing of the surgery. As 75% of responding patients achieved their maximal response by 23 weeks in clinical trials, the optimal
time to operative after neoadjuvant treatment is at about 6 months (Blanke etal. 2008a).
Surgery after treatment with imatinib follows similar principles as primary surgery. The
tumor is usually quite soft, which may increase the risk of rupture; however, the vascularity
may be reduced, which may facilitate surgery. Imatinib should be continued in patients
who have had tumor resection following response to imatinib, and the patient may resume
taking drug as soon as oral intake is feasible (Blay etal. 2005).
6.4.1.3
Surgery for Recurrence
Before effective systemic therapy evolved, resection of recurrent disease in the liver and/
or peritoneal cavity was the only potential treatment and was routinely considered. While
apparent complete resection was sometimes possible, the disease inevitably recurred, and
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so the role of surgery in metastatic GIST is uncertain. Resection may be considered in

patients with disease responding to imatinib in whom the disease is apparently completely
resectable, and in otherwise stable oligo- or multi-focal disease where one tumor mass is
growing (clonal escape) and resection is feasible (Demetri etal. 2007; Eisenberg 2006).
One report details a progression-free survival rate of 33% at 1 year with such an approach
(Raut etal. 2006).The true impact of this approach on disease outcome is the subject of at
least two ongoing or proposed clinical trials. Surgery in patients with evidence of generalized progression is associated with poor outcomes and is not recommended.
Occasionally surgery may be useful for palliation of a particular lesion that is bleeding
or obstructing. Such surgery is often difficult and potentially morbid, and should only be
undertaken after consideration of other options, such as hepatic embolization.
6.4.2
Medical Management
6.4.2.1
Chemotherapy
Historically conventional chemotherapy treatments have not been very successful in the
treatment of GISTs. Cytotoxic agents active in soft tissue sarcomas have formerly been
employed. A Mayo Clinic study compared patients with leiomyosarcomas with those with
GIST treated with a schedule of dacarbazine, mitomycin, doxorubicin and cisplatin plus
GM-CSF support. There was a one response seen in 21 patients with GISTs while a 67%
(12/18) response rate was seen in leiomyosarcomas. Reviews of the MD Anderson Cancer
Center experience of treatment of gastrointestinal leiomyosarcomas (most of which would
be GISTs) found a response rate of 3.3% using doxorubicin containing regiments in 120
patients treated between 1948 and 1989 (Plager etal. 1991) and of 13.3% in 30 patients
treated with ifosfamide between 1985 and 1989 (Patel etal. 1991). A more recent phase II
trial by the same group found no responses to temozolamide in a group of 18 patents with
GIST (Trent etal. 2003).
6.4.2.2
Imatinib mesylate (Glivec, Gleevec, (STI571) Novartis)
Imatinib mesylate is an oral phenylaminopyrimidine tyrosine kinase inhibitor that inhibits
the PDGFR receptor, KIT kinase, BCR-ABL and ABL kinases. Developed for its activity
against the PDGFR receptor, it was also found to be effective against chronic myeloid
leukemia. In vitro experiments found the drug to be a potent inhibitor of KIT and also of a
GIST cell line (Tuveson etal. 2001). Imatinib selectively inhibits the tyrosine kinase activity associated with KIT, which forms the rationale for its use in GIST (Croom and Perry
2003). The proof of principle came with the treatment of a Finnish woman in 2000 with
rapidly progressive advanced GIST refractory to chemotherapy (Joensuu et al. 2001).
After a month of starting treatment there was a 52% reduction in tumor diameters in the
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liver on MRI imaging and loss of FDG uptake on PET scanning. Fine needle biopsy of the
liver metastases showed decreased density of tumor cells as well as development of myxoid degeneration.
This single case study led to the commencement of two early phase studies. The EORTC
conducted a phase I study of imatinib with doses ranging from 300 to 1,000mg/day in soft
tissue sarcoma patients (van Oosterom etal. 2001). Thirty six patients with GIST were
enrolled and dose limiting toxicity was seen at a dose of 500mg bd with doses at 400mg
bd and below being more manageable in terms of side effects and less need for dose reduction. Most patients were seen to have major and rapid improvements in symptoms and
performance status. Twenty-five patients had an objective response to treatment, with 19
of these being partial remissions.
The USFinland B2222 study conducted at the same time randomized 147 patients to
receive either 400 or 600mg/day of imatinib (Demetri etal. 2002). A partial response was
seen in 53.7% of these patients with 27.9% having stable disease in the initial publication.
PET imaging was again found to be a sensitive and rapid indicator of response or resistance to imatinib. An update of this study with a median of 63 months follow-up (and 71
months maximum follow-up) has found an overall response rate of 68% with two cases of
complete remission seen (Blanke etal. 2008a). The median time to progression was 24
months. This gives an estimated 5-year survival of 57% with no differences in either overall response, time to progression, response duration or overall survival between the two
doses. Twenty eight percent of the cohorts were still taking imatinib at the last follow-up,
suggesting that long-term survival, even with advanced disease, is possible.
The North American Sarcoma Intergroup S0033 phase III trial randomized 746 patients
to two dose levels (400 vs. 800mg) of imatinib (Blanke etal. 2008b). Crossover to the
higher dose level was allowed on disease progression. At a median follow-up of 4.5 years,
no difference was seen in the overall response rate in either arm of 45%. The median progression-free survivals were 18 and 20 months, respectively, and median overall survivals
55 and 51 months, respectively; neither of which were statistically different. A third of the
patients on the standard arm who crossed over to the higher dose achieved an objective
response or stabilization of their disease. Serious adverse events and possible treatment
related deaths were higher on the 800-mg arm.
The EORTC, Italian Sarcoma Group (ISG) and Australasian Gastrointestinal Trials
Group (AGITG) conducted a parallel randomized study which enrolled 946 patients with
advanced GIST to 400 vs. 400-mg bd of imatinib (Verweij et al. 2004). After approximately 25-months median follow-up, 56% of patients in the 400mg arm were found to
have disease progression compared to 50% in the higher dose arm (P=0.026). However,
at the 40-month median follow-up, there was no statistical difference in the progressionfree survivals of each arm (Casali etal. 2005). No differences were seen in the response
rates in either arm and in total for the group there was a 5% complete remission rate, 47%
partial remission and 32% stable disease. As expected there were a higher number of dose
reductions (60 vs. 16%) and dose interruptions (64 vs. 40%) in the higher dose arm due to
toxicity compared to the lower dose arm. Patients on this study were also allowed to cross
over to the higher dose on progression if they were on the standard dose to start with. Fiftyfour percent of the patients who met protocol criteria for crossover (113/241) went over to
the higher dose and only 17% required a subsequent dose reduction (Zalcberg etal. 2005).
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The partial response rate with dose escalation was 2 and 27% with stable disease. Eighteen
percent were progression-free at 12 months following crossover.
The licensed starting dose of imatinib for metastatic GIST is 400600 mg/day. The
EORTC-ISG-AGITG and the North American Intergroup S0033 trials both compared two
dose levels of imatinib (400 vs. 800mg/day). The studies were designed so that data could
be combined in a preplanned meta-analysis, the MetaGIST project (Van Glabbeke etal.
2007). With a median follow-up of 45 months no difference in overall survival was seen in
the arms but there was a small improvement in progression-free survival with the high
dose arm (HR 0.89, P=0.04). Multivariate analyses were carried out to determine whether
there were any factors that influenced survival and to find subgroups that benefitted from
the higher dose. Adverse prognostic factors were found to be male sex, poor performance
status, bowel origin, low baseline hemoglobin and high baseline neutrophil counts. Exon
mutational analysis was available from 47% of the cohort. This confirmed that exon 11
mutations had a better PFS and overall survival (26 and 60 months) than either exon 9 (13
and 31 months), wild type (16 and 43 months) and other mutations (16 vs. 34 months). The
only factor that showed a benefit to high dose imatinib in improved PFS was exon 9 mutation status (HR 0.58, P=0.017) but this did not translate into improved overall survival
(numbers were small, however). This would support a strategy of using an imatinib starting dose of 800 mg/day (Casali et al. 2008). Where licensing restrictions prevent this,
patients with the mutation may be able to start on 600mg/day or alternatively they need
closer monitoring for evidence of lack of disease control on the 400mg dose so that dose
escalation can be implemented on progression.
Tumors with exon 11 mutations are often aggressive but tend to respond to imatinib
because the mutation results in a conformational change in KIT which allows a better fit
of the imatinib molecule into the ATP-binding pocket in the intracellular domain of the
KIT molecule. Tumors with exon 11 duplication may be associated with better survival.
Exon 9 mutations are more often seen in intestinal tumors rather than gastric, and are associated with aggressive behavior. Higher dose imatinib is indicated in these tumors (DebiecRychter etal. 2006).
Many patients who initially respond to imatinib ultimately develop progressive disease.
This secondary imatinib resistance often arises after around 2 years of therapy in primary
exon 11 mutations (Heinrich etal. 2008) and is usually associated with secondary KIT or
PDGFR mutations. Several distinctive secondary point mutations have been identified,
generally affecting the same allele as the primary mutation (Antonescu et al. 2005).
Furthermore, after mutated receptors are switched off, heterologous wild-type tyrosine
kinase receptors may become an important means of maintaining signaling activation in
imatinib-exposed GIST (Negri etal. 2009).
6.4.2.3
Toxicity of Imatinib
The toxicities of imatinib mesylate are generally manageable (Harrison and Goldstein
2006). In many clinical trials gastrointestinal hemorrhage either into the gut or into the
abdominal cavity has been observed in a small number of patients. This may be a result of
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direct mucosal disruption or of tumor response. The latter tends to affect patients with high
tumor bulk and emergency surgical intervention may be indicated. In the USFinland trial
hemorrhage occurred in 5.4% of patients (Demetri etal. 2002). The S0033 trial reported
significant bleeding in 5% of the low dose arm and 11% of the higher dose with four
patients in the higher dose dying from the hemorrhage (Blanke etal. 2008b).
Hematological toxicities are common and usually mild not requiring any treatment. It
is dose related and on the clinical trials where a higher dose is used significant anemia,
neutropenia and thrombocytopenia is observed which may require treatment interruption
and dose reductions.
The most commonly described nonhematological side effects are gastrointestinal, especially nausea and vomiting. These may respond to splitting the dose or taking the tablets
with food and water or at night. Diarrhea may occur and respond to anti-diarrheal agents.
An erythematous and pruritic maculopapular rash can occur which responds to treatment interruption and dose reduction as well as topical steroids and antihistamines.
Superficial edema of the legs as well as in the periorbital region is common and usually
does not required specific treatment. Severe cases may require use of diuretics.
Liver function abnormalities can occur uncommonly and may be managed again by
dose interruption and reduction; rarely systemic steroids are needed.
Investigators from the EORTC-ISG-AGITG study have analyzed the relationship of
toxicities to imatinib and pretreatment factors to see which are prognostic ones (Van
Glabbeke etal. 2006). Anemia was found to correlate with dose and baseline hemoglobin,
while neutropenia was found to correlate with baseline neutrophil count and hemoglobin
level but was not dose dependent. Nonhematological toxicities were also dose related.
High toxicity rates were found in female sex (edema, nausea and diarrhea), older age
(edema, rash, fatigue), poor performance status (fatigue and nausea), prior cytotoxic treatment (fatigue), small lesions (rash) and identified gastrointestinal origin tumor (diarrhea).
A predictive spreadsheet calculator incorporating this model has been validated on a separate dataset and is available from www.eortc.be/tools/imatinibtoxicity.
6.4.2.4
Dosing of Imatinib Mesylate
The pharmacokinetics of imatinib may vary between individuals due to factors such as
body weight, loss of absorptive surface of the small bowel due to resection, cytochrome
P450 3A4 polymorphisms, P glycoprotein polymorphisms, OCT1 efflux pump activity,
albuminemia and alpha1 acid glycoprotein binding (Gurney etal. 2007; White etal. 2006;
Widmer etal. 2006). Over time serum levels in individual patients may also vary due to
drug interactions (especially those that interact with cytochrome P450 3A4) and medication
non-compliance. It has been found that there is a trend towards increased imatinib clearance with long-term exposure (Judson et al. 2005). Low plasma imatinib trough levels
have been found to correlate with a lower overall response rate and time to progression in
a subset of patients treated on the B2222 study where pharmacokinetic monitoring was
carried out (von Mehren etal. 2008). Maintaining imatinib trough levels above 1110ng/
mL may help to optimize dosing of the drug for therapeutic effect (Demetri etal. 2008).
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Excessively high plasma levels may provide an explanation for treatment toxicities and
support implementation of dose reduction without an expected loss of efficacy.
6.4.2.5
Duration of Imatinib Therapy
Imatinib may produce striking responses in metastatic GISTs, with marked tumor shrinkage and loss of functional tracer uptake on PET imaging. However, serial biopsies of
responding lesions have shown that despite the development of myxoid degeneration there
continued to be viable tumor cells present (Joensuu et al. 2001). The French Sarcoma
Group BFR14 study attempted to assess the effect of treatment interruption of patients on
imatinib vs. continuation (Blay etal. 2007). This trial enrolled 182 patients with advanced
GIST and 58 of the 98 patients who had received a year of imatinib and were stable or
responding were randomized to treatment interruption or discontinuation. At the date of
analysis 8 of 26 patients in the continuation arm had progressed while 26 of 32 patients had
progressed on the interruption arm. There were no differences observed in the quality of
life, overall survival or the rate of resistance to reintroduction of imatinib. The trial has
continued with another randomization of 50 patients (excluding patients who were interrupted at 1 year) who were still responding at 3 years (Adenis etal. 2008). Again it was
found that there was a high rate of progression with 1 year PFS in the interruption arm
being 23.7 vs. 87.7% for continuation. Another randomization is ongoing at the 5-year
mark (Duffaud etal. 2009). All progressing patients were salvaged on reintroduction of
imatinib and no impact on overall survival was seen. No difference so far has been seen in
the time to development of secondary resistance on either arms of the study, and reintroduction of imatinib leads to reinduction of response in 93% of subjects (Duffaud et al.
2009). This study thus indicates that discontinuation of imatinib is associated with a high
relapse rate and that maintenance treatment is recommended.
6.4.2.6
Management of Progression on Imatinib
Isolated areas of tumor progression indicating the development of resistant clones may be
treated by surgery or ablative procedures such as radiofrequency ablation whilst continuing imatinib to maintain control of sensitive clones. This is aimed at eliminating the drug
resistant clones and may be associated with prolonging progression-free survival (Raut
etal. 2006). See above Sect.6.4.1.3.
Generalized or multifocal progression should be first treated by dose escalation of imatinib to 400 mg bd if patients are already on the 400 mg/day dose. This may establish
tumor control in about a third of patients (Verweij etal. 2004). Dose escalation is associated with increased side effects, but the rate of dose reduction required within 6 months
with dose escalation from 400 to 800mg/day is less if patients are initially started on the
higher dose (17 vs. 50%) (Zalcberg etal. 2005). The median duration of benefit in dose
escalation is estimated at 11.6 weeks (Zalcberg etal. 2005).
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If dose escalation is ineffective then use of the multi-kinase inhibitor sunitinib should
be implemented outside of a clinical trial setting (see below). Continuation of imatinib
until alternative therapy is started is recommended to prevent a flare response of the imatinib sensitive clones on withdrawal of the medication which may cause rapid clinical
deterioration.
6.4.2.7
Sunitinib (Sutent (SU11248) Pfizer)
Sunitinib is an oral multikinase inhibitor which blocks a number of targets including KIT,
PDGFR, VEGFR, RET and CSF-1R. In a randomized phase III registration study, 312
advanced GIST patients with imatinib resistance or intolerance received either sunitinib
or placebo in a 2:1 allocation in a 4-weeks on and 2-week off schedule of 50 mg/day
(Demetri etal. 2006). Crossover of the placebo arm was allowed on tumor progression.
The trial was unblinded early when planned interim analysis revealed a prolongation in
time to progression with sunitinib. Median time to progression was 27.3 vs. 6.4 weeks
with placebo. An overall response rate of 7% was seen with sunitinib and 0% with placebo. Stable disease lasting at least 22 weeks was seen in 17%. Despite the crossover
overall survival was better in the upfront sunitinib group (HR 0.49, P=0.007). As a result
sunitinib is licensed for second line therapy of advanced GIST in the 4 week on and 2
week off schedule.
Continuous daily dosing of sunitinib at 37.5mg/day either in the evening or in the
morning has been shown be safe and efficacious in a phase II study in patients with
imatinib resistant or intolerant GIST (George et al. 2009). There were no other new
toxicities seen and response rates as well as toxicity were similar to those reported in
the 4 weeks on 2 weeks off schedule. Constant serum levels were maintained with no
accumulation over time. Twenty-three percent of patients still required dose reductions
to 25mg daily.
Sunitinib is associated with side effects of nausea, fatigue, diarrhea, mucositis, handfoot syndrome, and skin discoloration. The drug may also cause hematological toxicity in
terms of anemia and neutropenia. These side effects were generally mild and manageable
by dose delay or reduction. Hypertension may occur due to its anti-VEGF effect, and initiation or titration of an antihypertensive may be required. Hypothyroidism is well recognized as a complication of sunitinib therapy. In a series of 42 patients with advanced GIST
treated with the drug, 62% exhibited TSH abnormalities with 38% becoming hypothyroid
(Desai et al. 2006). Some patients were noted to have a transient fall in the TSH level
before developing hypothyroidism and two patients were found to have absent thyroid tissue on neck ultrasound, suggesting that the mechanism for this is the induction of a destructive thyroiditis. It is thus important to measure monitor thyroid functioning and initiate
thyroid replacement therapy if necessary.
The effect of primary and secondary kinase genotypes in sunitinib response has been
studied in a series of 97 patients with imatinib refractory GIST (Heinrich etal. 2008). The
clinical benefit of sunitinib observed on patients with primary exon 9 or wild type mutations were higher than those with exon 11 mutations (58 vs. 56% vs. 34%). Similarly the
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overall response was higher in exon 9 than exon 11 (37 vs. 5%, P=0.02). Longer median
progression-free survivals were seen with exon 9 (19.4 months, P=0.005) and wild type
(19.0 months, P=0.0356) compared to exon 11 (5.1 months). This translated into higher
median overall survivals of exon 9 (26.9 months, P=0.012) and wild type GISTs (30.5
months, P=0.0132) compared to exon 11 (12.3 months). Secondary kinase mutations were
seen more commonly in the primary exon 11 patients compared to exon 9 (73 vs. 19%) and
no secondary mutations were observed in wild type GISTs on imatinib. Patients with
acquired exon 13 or 14 mutations which encode the receptor ATP binding pocket had a
median progression-free survival of 7.8 months compared to exon 17 or 18 which encode
the activating loop (2.3 months, P=0.0157) correlating with higher clinical benefit (61 vs.
15%, P=0.011) with sunitinib. This is supported by invitro autophosphorylation studies
indicating that exon 13 and 14 mutations were sensitive to sunitinib while secondary exon
17 and 18 mutations were resistant.
6.4.3
Assessing Response to Therapy
CT scan imaging may be used to monitor response to therapy. Scans should be performed
with oral contrast (to outline bowel) and in triple phase (to detect hypervascular liver
metastases). Conventional measurement of response to treatment in solid tumors is with
the use of the response evaluation criteria in solid tumors (RECIST) criteria (Therasse
etal. 2000). This relies on measuring change in maximal tumor diameters. However, a
number of factors in GIST serve to make RECIST a less than ideal methodology for
response measurement. Increase in tumor size may occur due to intratumoral hemorrhage
or cystic changes developing due to myxoid degeneration in lesions as a result of treatment
response. Localized intratumoral progression may occur with resistant clones causing a
new nodule within a mass to develop without increasing the size of the preexisting lesion
(Shankar etal. 2005). Choi etal. (2007) have proposed a new set of CT scan criteria to
measure response in GIST which incorporates changes in tumor density (quantified by
change in Hounsfield units) and smaller changes in tumor sizes. This has been found to
correlate well with functional response measured with PET scans. These criteria have been
validated in a independent dataset (Benjamin etal. 2007).
FDG-PET is useful in detecting early response to biological therapy if the tumors are
FDG avid to begin with. A marked reduction in metabolic activity may be seen within days
of initiation of therapy much earlier than can be detected on CT imaging (Stroobants etal.
2003). Changes in tumor density can cause apparently new lesions to appear on CT imaging on response to therapy and PET may determine these are hypofunctioning and not due
to tumor progression. Conversely this modality is useful in detecting tumor relapse or
progression. See Fig.6.8.
Dynamic contrast-enhanced Doppler ultrasound (DCE-US) is currently being developed as a functional imaging method of monitoring response of GIST to therapy. It involves
the measurement of uptake of ultrasound microbubble contrast agents by tumor (Lamuraglia
etal. 2006). This may become a less expensive method and more widely used functional
imaging modality once validated.
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Fig.6.8 FDG-PET/CT imaging of patient with metastatic GIST shows a baseline study with several
metabolically-active peritoneal deposits. Highlighted are two pelvic lesions in the pelvis as visualized on volume-rendered PET/CT above and coronal PET images below. There is a larger and more
intense abnormality at baseline (red arrow) and smaller, less intense lesion (blue arrow). One month
following imatinib there was a complete metabolic response in all lesions. By 12 months there had
been significant CT regression of most lesions except the left pelvic lesion. PET demonstrated
recrudescent activity in the small right pelvic lesion as well as intense uptake in the previously lowgrade left pelvic lesion. These images emphasize the heterogeneity that can exist in biology at
baseline evaluation and a variable response to therapy, suggesting clonal mutational variations
6.4.4
Radiotherapy
There is paucity of data in the literature regarding the utility of radiotherapy in GIST. The
location of GISTs and their pattern of spread usually make it difficult to deliver adequate
doses of radiotherapy without causing toxicity to surrounding organs.
There are some isolated reports of its use as adjuvant therapy after resection. In a prospective series of 50 patients from Toronto ten patients with small intestinal GIST were
162
given adjuvant radiotherapy (Crosby etal. 2001). All the patients who received radiation
subsequently relapsed with three of the cases being within the radiotherapy field and six
outside the field. In the remaining patient it was not possible to determine where the recurrence was relative to the field. There is a case report of a rectal GIST patient with probable
microscopic positive margins who remained disease free on 2-year follow-up after receiving radical radiotherapy (50.5Gy) to the tumor bed (Pollock etal. 2001). A more recent
series of 39 patients with primary or recurrent rectal or pararectal space, GISTs identified
6 patients who received radiotherapy. One patient achieved stabilization of disease after
imatinib failure and out of five where post operative radiotherapy was received, only one
developed a further recurrence (Mussi etal. 2008a).
The consideration of use of palliative radiotherapy in symptomatic areas such as bony
or cutaneous metastases would be reasonable, but data as to effectiveness are lacking.
6.4.5
Adjuvant Therapy for Resected Gastrointestinal Stromal Tumor
Despite complete surgical resection of the primary GISTs, recurrence or metastases may
occur in 4090% of cases (Eisenberg and Judson 2004). The five-year survival rate from a
series of patients who achieved gross resection of GIST from the Memorial Sloan Kettering
Cancer Centre was 54% (DeMatteo etal. 2000). The risk of recurrence may be determined
by stratification of patients on the basis of tumor characteristics such as the size and mitotic
rate (Fletcher etal. 2002). A number of studies have been conducted on the use of imatinib
in adjuvant systemic therapy of resected GISTs.
The American College of Surgeons Oncology Group (ACOSOG) Z9001 study randomized patients with completely resected c-KIT positive GISTs measuring greater than
or equal to 3cm to placebo or imatinib 400mg daily for 1 year (DeMatteo etal. 2007a).
On relapse patients were allowed to crossover to the drug if on placebo or double the
dose of imatinib if already on it. The trial was stopped early when interim analysis
showed a significant advantage in reduction in relapse with the imatinib. One-year
relapse free survival with imatinib vs. placebo was 97 vs. 83% and 2 year relapse free
survival 90 vs. 71%. After unblinding, the placebo arm patients were allowed to go onto
imatinib for a year. The patients had been stratified on the basis of tumor size only (with
no consideration of mitotic rate) and the group that obtained the most benefit was the
>10cm group; however, patients with GISTs of all sizes statistically obtained improved
results. No difference in overall survival has yet been seen. This may be due to the short
period of follow-up or possibly that imatinib may be successfully reserved for salvage of
relapsed disease.
An earlier adjuvant study performed by the ACOSOG was the phase II Z9000 trial of
imatinib 400 mg/day for 1 year in c-KIT positive patients with high risk resected GIST
(DeMatteo etal. 2008). High risk was defined as tumors 10cm, ruptured or multifocal. At
3 years median follow-up relapse free survival at 1, 2, and 3 years have been reported as 94,
73, and 61% respectively. Overall survivals for the same time periods are 99, 97, and 97%.
Nilsson has reported a small pilot series of 23 patients with high-risk resected GIST
patients who were also treated for 1 year with imatinib (Nilsson etal. 2007). With a mean
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follow-up of 40 months only 1 (4%) of the patients has relapsed. This was compared to a
matched historical control group of 48 patients derived from a population based series
(Nilsson etal. 2005) where 32 patients (67%) relapsed. Mutational analysis was performed
and interestingly the relapse in the pilot study was in a wild type pediatric GIST case.
Another small multicentre single armed study has been reported early results from China
where 57 patients with high risk GIST were enrolled to receive imatinib for at least 12
months (Zhan and China Gastrointestinal Cooperative, 2007). With about 75% of patients
completing 12 months of treatment only two relapses have been seen.
There are two other large phase III trials of adjuvant imatinib in resected GIST which
have completed enrollment but are yet to report results. The first is the EORTC 62024 trial
which randomized 750 patients with resected intermediate and high risk GIST to either
observation or 2 years of imatinib 400mg daily. The primary endpoint of this study was
overall survival but this was subsequently amended to time to secondary resistance.
Another trial the Scandinavian Sarcoma Group SSGXVIII trial enrolled 400 patients and
compares 12 vs. 36 months of imatinib in high and very risk patients with the main endpoint being recurrence free survival.
In summary, 12 months of imatinib mesylate does seem to reduce early recurrences.
Longer follow-up will be required along with the results of ongoing randomized studies
to determine whether this is sustained and whether this may translate into an overall survival benefit. The appropriate duration of adjuvant therapy will also be partly answered
by these studies.
6.4.6
Neoadjuvant Therapy for Locally Advanced GISTs
The use of neoadjuvant systemic biological therapy for locally advanced GISTs may be
justified if the aim is to render initially inoperable tumors resectable by shrinkage (socalled conversion therapy) or if it allows preservation of organ function by allowing a less
radical operation by shrinkage of the disease. A number of retrospective series have
described this approach. A Polish series (Rutkowski etal. 2006) analyzed surgical resection of 32 out of 141 patients with inoperable or metastatic GIST who were treated with
imatinib. Surgery was carried out either for residual disease after response (24 patients,
17%) or for salvage (eight patients) after progression on imatinib. In those patients who
achieved complete remission after resection of downstaged tumor and did not continue
imatinib the early relapse rate was high. Subsequent patients were continued on imatinib
post surgery and more durable remissions were achieved. Despite the continuation of imatinib the results of salvage surgery was not good with five patients relapsing. A French
paper (Bonvalot et al. 2006) reported surgery in 22 (12%) out of 180 advanced GIST
patients treated with imatinib. Of these five patients, emergency operations were due to
tumor rupture. The rest were planned resections either for the primaries or metastases. The
observed progression-free survivals for downstaged tumors were however similar to that
of nonoperated patients. An Italian series (Fiore etal. 2009) of 15 patients found that all
patients responded to imatinib and underwent surgery with a 77% 3-year progression-free
survival from commencement of imatinib. The recently published RTOG 0132 phase II
164
trial examined the use of preoperative imatinib 600 mg daily in 63 patients potentially
resectable GIST (Eisenberg etal. 2009). These were a mix of primary GIST and recurrent
GIST. An additional 24 months of adjuvant imatinib was given post operatively. Operative
complications and toxicity of therapy were found to be minimal. Likewise a Memorial
Sloan Kettering Cancer Centre series described 40 patients who received tyrosine kinase
therapy before proceeding to resection after a median of 15 months (DeMatteo et al.
2007b). All but one patient initially had disease stabilization or partial response. In the 20
patients who were responding at the time of resection, the 2-year progression-free survival
and overall survival were 61 and 100%, respectively. Of the 13 patients who had surgery
for focal progression the median time to progression was 12 months and the 2-year overall
survival 36%. Multifocal disease progression was associated with poor outcomes with
surgery in seven patients. The median time to progression was 3 months with 1-year survival of 36%. This would suggest that surgery in the context of multifocal progression is
not indicated.
The German APOLLO study is a phase II study to examine the benefit of neoadjuvant
imatinib in locally advanced GIST. The primary endpoints are radiological and histological response, and secondary endpoints are achievement of R0 resection and organ preservation. The EORTC is conducting a randomized trial of surgery or no surgery in patients
with locally advanced GIST who are downstaged to potential resectability.
6.4.7
Other Agents in Development
6.4.7.1
Nilotinib (AMN107, Tasigna, Novartis)
Nilotinib is a second generation tyrosine kinase inhibitor with activity against KIT, PDFR
and BCR-ABL. It achieves 710 times the intracellular concentration as imatinib. In vitro
studies show some activity in imatinib resistant cell lines and also some synergy with
imatinib. A phase I dose escalation study was conducted in 53 patients with imatinib
refractory GIST (Von Mehren etal. 2007). Eighteen patients received nilotinib alone and
35 received it in combination with imatinib. The maximal tolerated dose (MTD) was
established as being nilotinib 400mg bd with imatinib 400mg daily. In the monotherapy
cohort of 18 patients 1 partial remission and 13 stable disease were seen (tumor control
rate of 78%) with median duration of disease control being 158 days. In the MTD cohort
of 16 patients 1 partial remission and 9 patients had stable disease (tumor control rate 62%)
with median duration of control being 259 days (Blay etal. 2008). A retrospective analysis
has been conducted for 42 patients with imatinib and sunitinib resistant GIST enrolled
onto a multicountry European compassionate access program of nilotinib at a dose of
400mg bd. Four partial remissions and 15 stable disease response were seen giving a clinical benefit of 45%. Toxicity led to cessation of the medication in 12%. The median overall
survival was 211 days. A phase III study of third line nilotinib vs. best supportive care has
been completed and results are awaited. A frontline phase III study of imatinib vs. nilotinib
has also been initiated.
165
6.4.7.2
Sorafenib (BAY 43 1006, Nexavar, Bayer)
Sorafenib is an oral multikinase inhibitor that inhibits KIT, VEGFR, PDGFR and Raf
kinases. In vitro inhibition of imatinib resistance GIST cell lines have been observed (Guo
etal. 2007). Preliminary results of a phase II trial of sorafenib in patients with imatinib
resistant and both imatinib and sunitinib resistant advanced GIST patients have shown
activity of the drug (Wiebe etal. 2008). Three out of 24 patients have had a partial remission and 14 stable disease with disease control rate 71%. Median progression-free survival
was 5.3 months and median survival 13 months. A European series has reported preliminary data on 24 GIST patients treated with sorafenib in the fourth line setting following
failure of imatinib, sunitinib and nilotinib) (Gelderblom etal. 2009). Twenty percent have
achieved partial remission and 50% stable disease. Half the patients had a clinical benefit
in terms of improvement in performance status or symptoms.
6.4.7.3
Retaspimycin Hydrochloride (IPI-504, Infinity Pharmaceuticals)
Retaspimycin is a water soluble heat shock protein 90 (HSP90) inhibitor. HSP90 is a protein chaperone that is responsible for the folding, stability and localization of mutated
client proteins such as c-KIT and PDGFR. In vitro experiments have shown that HSP90
inhibition has inhibitory effects on imatinib sensitive and imatinib resistant GIST cell line
KIT oncoproteins (Bauer etal. 2006). A phase I study has determined a dosing schedule of
400mg twice weekly for 2 weeks out of three (Wagner etal. 2008). Forty-five patients
with GIST were treated and 32 assessable for response. At 6 weeks the partial remission
rate was 3% and stable disease 67% (70% disease control rate). The median progressionfree survival was 12 weeks. Commonly seen side effects were fatigue, headache, nausea,
diarrhea, myalgia and first-degree heart block. A phase III double blind, placebo controlled
study of retaspimycin (RING trial) in refractory GIST commenced enrolment of patients
who have previously been treated with at least imatinib and sunitinib. This study was
halted in April 2009 when early review of data found a higher than expected mortality in
the study arm.
6.4.7.4
Everolimus (RAD001, Afinitor, Novartis)
Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor. It has been
found that in imatinib resistance that downstream kinase signaling pathways which
include the AKT/mTOR and MAP kinase pathways remain activated (Fletcher et al.
2003). Synergism has been found between imatinib and everolimus in GIST cell lines
leading to the conduct of a phase I/II trial of this combination in imatinib resistant GIST
(van Oosterom etal. 2005). This established a safe tolerable dose of imatinib 600mg and
everolimus 2.5mg daily. In the phase I part of this study 31 patients were treated in dif-
166
ferent everolimus dose cohorts. Stable disease was observed in eight patients and two
experienced partial remissions. The phase II part of the study enrolled patients in two
strata; those following one line of prior therapy, and those who were second line failures
(Dumez etal. 2008). Four-month progression-free survival was 17.4% in 23 evaluable
out of 28 patients in the first stratum while it was 37.1% in the 35 of 47 evaluable patients
in the second cohort. Common side effects included mild fatigue, diarrhea, vomiting,
nausea, anemia, headache and rash.
6.4.7.5
Motesanib Diphosphate (AMG706, Amgen)
Motesanib is an oral small molecule multi-kinase inhibitor targeting c-KIT, PDGFR and
VEGFR13. Two phase II clinical trials have been performed with this agent in advanced
imatinib refractory GIST patients. The first multinational study enrolled 139 patients of
whom 120 were eligible on the basis of confirmed prestudy disease progression (Benjamin
etal. 2006). The response rate on RECIST criteria was 3% with 46% of patients having
stable disease as the best response. Durable stable disease of more than 22 weeks was
seen in 24%. Median progression-free survival was 16 weeks and median overall survival
was 14.8 months. FDG PET imaging was performed at 8 weeks and in the 89 patients
who had baseline and week 8 scans the response was 30%. Choi criteria was also used to
evaluate responses at week 8 and of the 96 patients evaluable for efficacy the response
rate was 33% on the basis of reduced tumor density and/or tumor size. The second study
was conducted in Japan and reported on the initial 35 patients who had received more
than one dose of motesanib (Yamada etal. 2008). There was one partial response and
seven patients had stable disease for more than 24 weeks. Median progression-free survival was 113 days.
6.5
Conclusion
Great progress has been made in the understanding of the biological basis behind the
pathogenesis of GISTs in the last 10 years. This understanding has translated directly into
clinical breakthroughs in the management of this rare disease, which in the past had no
effective therapies except surgery. These developments in targeted biological therapies
have come at a rapid rate and made an enormous difference in the survival and quality of
life of patients with advanced disease. The management of GIST is necessarily multidisciplinary and involves coordinated care of patients spanning gastroenterologists, surgeons,
pathologists, scientists, radiologists, nuclear physicians and medical oncologists. Further
advances in the understanding of the tumor biology will lead to progression of new agents
from the laboratory to the clinic, thereby providing further therapeutic options for patients
in the future.
167
Acknowledgments The authors would acknowledge the assistance of Mark Koina of the Electron Microscopy Unit at ACT Pathology, The Canberra Hospital in supplying the electron microscopy image and Rod Hicks from the Centre for Molecular Imaging, Peter MacCallum Cancer
Centre for providing the PET/CT images.
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Multimodality Management of Localized

and Borderline Resectable Pancreatic
Adenocarcinoma
Michael B. Ujiki, William Small, Robert Marsh, and Mark S. Talamonti
7.1
Introduction
Adenocarcinoma of the pancreas continues to be a daunting clinical challenge, with approximately 42,000 deaths per year in the United States (Jemal etal. 2009). It is a disease characterized by its late presentation, rapid demise thereafter, and relatively ineffective systemic
therapies. Despite this grim prognosis, appreciable progress has been made in the identification of patients with localized disease who may be candidates for potentially curative resections and in the understanding of the technical nuances and efficacy of aggressive surgical
procedures. Following initial reports in the 1930s of successful resections for periampullary
tumors, the technique known as the Whipple procedure, or pancreaticoduodenectomy,
underwent several technical modifications and revisions (Brunschwig 1937; Halsted 1899;
Whipple etal. 1935). With time also has come a better understanding of the considerable
physiologic impact and sequelae of the procedure and its potential, albeit limited, for cure.
The high in-hospital mortality rate during the first several decades after the development of
the operation led some to propose that it be abandoned, with risks not sufficiently justified
by the low overall survival rates (Crile 1970; Shapiro 1975). By the late 1980s and early
M.B. Ujiki
Pritzker School of Medicine, University of Chicago, Chicago, IL, USA and
Minimally Invasive Surgery, NorthShore University Health System, Evanston, IL 60201, USA
W. Small
Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago,
IL, USA
R. Marsh
Gastrointestinal Oncology Section, NorthShore University Health System, Evanston, IL, USA
M.S. Talamonti (*)
Department of Surgery, NorthShore University Health System, Evanston, IL, USA
e-mail: mtalamonti@enh.org
173
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1990s, series from experienced centers indicated that an aggressive surgical approach to
periampullary tumors, of which pancreatic cancer is the most common, was justified.
Morbidity and mortality rates dramatically improved and median survival rates began to
significantly exceed the expected survival times of nonoperative treatment options (Crist
et al. 1987; Trede et al. 1990). Today, the overall five-year survival rate is 1525% for
patients who undergo resection, compared with 15% for those who do not receive cancerdirected treatment (Bilimoria etal. 2007; Alexakis etal. 2004).
7.2
Clinical Staging and Preoperative Management
From a surgical perspective, the first objective in the management of suspected or confirmed
pancreatic cancer is to determine the potential for resection. Routine exploratory laparotomy
for the purpose of operatively determining resectability has been diminished by modern
three-dimensional radiographic imaging along with effective and sustainable nonoperative
methods of palliation. Contrast-enhanced computed tomography (CT) accurately predicts
resectability in 8090% of patients (McCarthy etal. 1998; Chong etal. 1998; Vedantham
etal. 1998; Roche etal. 2003; Gulliver etal. 1992; Freeny etal. 1993; Fuhrman etal. 1994).
Careful correlation between preoperative CT findings and surgical results has better defined
CT criteria for resectability. The critical aspects that need to be evaluated in a thorough radiographic assessment are: the presence or absence of peritoneal or hepatic metastases; the patency of the superior mesenteric vein (SMV) and portal vein and the relationship of these
vessels and their tributaries to the tumor; the relationship of the tumor to the superior mesenteric artery, celiac axis, hepatic artery, and gastroduodenal artery; and the presence of any
aberrant vascular anatomy (Wayne etal. 2002). Magnetic resonance imaging does not appear
to have an advantage over CT except for revealing smaller hepatic metastases and for use in
patients who cannot undergo contrast-enhanced CT (Ichikawa etal. 1997; Megibow etal.
1995). Unequivocal radiographic findings contraindicating resection include distant metastases, major venous thrombosis of the portal vein or SMV extending for several centimeters,
and circumferential encasement of the superior mesenteric, celiac, or proximal hepatic arteries (Fuhrman etal. 1994). Patients without distant metastases and with slightly more advanced
but still potentially localized disease may now be categorized as borderline resectable.
Criteria for this group of patients include encasement of a short segment of the hepatic artery,
without evidence of tumor extension to the celiac axis; tumor abutment of the superior mesenteric artery involving less than 180 of the artery circumference; and short-segment occlusion of the SMVportal vein confluence beneath the neck of the pancreas. Whether these
patients would benefit from an initial approach with chemoradiation, repeat staging studies,
and subsequent exploration remains an area of investigation and will be discussed subsequently (Varadhachary etal. 2006).
A recent consensus conference with representation from the Society of Surgical
Oncology, the American Society of Clinical Oncology, and the American HepatoPancreatico-Biliary Association attempted to define reproducible and clinically relevant
criteria to better categorize resection classifications for nonmetastatic pancreatic cancer
7 Multimodality Management of Localized and Borderline Resectable Pancreatic Adenocarcinoma
175
(Callery etal. 2009). These classifications are listed below and are crucial if the efficacy of
surgery and neoadjuvant strategies are to be carefully assessed and determined based on
extent of disease.
1. Tumors considered localized and resectable should demonstrate the following:
(a) No distant metastases
(b)No radiographic evidence of SMV and portal vein abutment, distortion, tumor
thrombus, or venous encasement
(c) Clear fat planes around the celiac axis, hepatic artery, and SMA (Fig.7.1)
2. Tumors considered borderline resectable include the following:
(a) No distant metastases
(b)Venous involvement of the SMV/portal vein demonstrating tumor abutment with or
without impingement and narrowing of the lumen, encasement of the SMV/portal
vein but without encasement of the nearby arteries, or short-segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel
proximal and distal to the area of vessel involvement, allowing for safe resection
and reconstruction
(c)Gastroduodenal artery encasement up to the hepatic artery with either short-segment encasement or direct abutment of the hepatic artery, without extension to the
celiac axis
(d)Tumor abutment of the SMA not to exceed 180 of the circumference of the vessel
wall (Figs.7.2 and 7.3)
In patients without significant major comorbidities and in the absence of radiographic findings to suggest metastatic disease or locally advanced unresectable disease as outlined
above, surgical resection should be considered feasible and likely to be achievable.
Fig.7.1 (a) Cross-sectional and (b) sagittal images of a localized, potentially resectable pancreatic
cancer seen as a low-density lesion sparing the superior mesenteric vein (SMV) (arrow) and superior mesenteric artery
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Fig.7.2 Borderline resectable pancreatic cancer with partial involvement of the SMV, and abutment but not encasement of the mesenteric artery (arrow). Patient underwent successful pancreaticoduodenectomy but required segmental resection of the involved vein and reconstruction using
an internal jugular vein graft
360
Fig.7.3 Coronal image of a locally advanced, unresectable pancreatic cancer demonstrating 360
encasement of the superior mesenteric artery (arrow)
Positron emission tomography (PET) is an evolving technology, which as of yet does

not have a specifically defined role in the evaluation of patients with suspected pancreatic
cancer. PET may be useful for preoperative diagnosis of pancreatic carcinoma in patients
with suspected cancer in whom CT fails to identify a discrete mass or in whom fine-needle
aspiration (FNA) is nondiagnostic (Delbeke and Martin 2010). It does not appear to significantly alter the clinical approach in most patients staged by helical CT. It is also limited
by the fact there is a relatively high rate of glucose intolerance in patients with pancreatic
disease, which could contribute to a higher false negative rate (Diederichs etal. 1998).
PET imaging is useful for M staging and restaging by detecting CT occult metastatic disease, allowing noncurative resection to be avoided in this group of patients. PET can differentiate post-therapy changes from recurrence and holds promise for monitoring
neoadjuvant chemoradiation treatment responses. The technique is less useful in periampullary carcinoma and marginally helpful in staging except for M staging. PET should be
177
considered complementary to morphologic imaging with CT (Delbeke and Martin 2010;

Diederichs etal. 1998).
Endoluminal ultrasonography (EUS) has become a powerful tool in the diagnostic evaluation of suspected pancreatic tumors. It is remarkably sensitive for detecting small pancreatic tumors and clarifying suspected vascular invasion (Owens and Savides 2010). EUS
has also been shown to be accurate in the evaluation of peripancreatic adenopathy and
ascites when combined with EUS-guided FNA (Rosch etal. 2000; Rosch 1995; Raut etal.
2003). With the development of neoadjuvant protocols for borderline resectable pancreatic
cancer, preoperative tissue diagnosis is required to differentiate adenocarcinoma from neuroendocrine tumors and chronic pancreatitis. EUS is currently the procedure of choice for
obtaining a tissue biopsy prior to the commencement of treatments. Furthermore, there is
a theoretical oncologic advantage over percutaneous biopsy because the needle tract is
contained in the eventual surgical specimen. The major limitation of EUS is the dependence on a skilled and experienced gastroenterologist to perform the procedure.
Endoscopic retrograde cholangiopancreatography (ERCP) has both diagnostic and
therapeutic roles in the evaluation of patients with suspected pancreatic cancers. ERCP
provides suggestive evidence of malignancy when irregular, tight strictures are seen in the
distal common bile duct and main pancreatic duct. Brush biopsies of such strictures are not
particularly sensitive (60%), but they are highly specific when positive (98%) (Stewart
etal. 2001). ERCP is applicable in the evaluation of patients with suspected intraductal
papillary mucinous neoplasms of the pancreas. The procedure can accurately detect the
presence of mucin in the pancreatic duct and may be helpful in localizing the extent of
disease to the head, body, or tail of the pancreas (Tanaka 2004). ERCP is most valuable
when decompression of biliary obstruction is required before surgery.
Placement of a biliary stent preoperatively is controversial. Some reports have demonstrated increased morbidity and mortality rates when resection is performed following preoperative drainage (van der Gaag etal. 2010). These reports have not clearly delineated the
differences between percutaneous biliary drainage vs. endoscopic stent placement, nor has
the experience or the expertise of the unit performing the drainage procedures been accounted
for on a regular basis. Other reports have found no significant effect on outcome except for a
slight increase in the incidence of wound infections (Pisters etal. 2001a; Sewnath etal. 2001;
Sohn etal. 2000). The expected decrease in serum bilirubin levels, increases in albumin and
protein levels, and improvements in performance status have similarly not led to better surgical outcomes. Most studies regarding this issue have been retrospective, and therefore meaningful conclusions are difficult to draw. Most would agree that preoperative biliary
decompression is not necessary if timely surgical therapy is anticipated and there are no
significant metabolic or nutritional deficits. All patients presenting with obstructive jaundice
and entered into a neoadjuvant trial do require biliary decompression. Most surgeons routinely prefer that this be done with endoscopic stent placement. In general, stents placed in
patients with potentially resectable cancers should be plastic, not metal.
CA 19-9 is a tumor-associated antigen frequently elevated in patients with pancreatic cancer (Ritts and Pitt 1998). Studies have attempted to evaluate its role in establishing the diagnosis of malignancy in a clinically suspicious presentation. Controversy exists regarding the
correct cutoff used to establish the threshold level for malignancy. Forsmark etal. found accuracy rates of 85 and 95% in the diagnosis of pancreatic malignancy when levels were greater
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than 90U/mL and greater than 200U/mL, respectively (Forsmark etal. 1994). In combination
with CT, a positive predictive value of 99% can be achieved when levels are greater than
120U/mL (Ritts etal. 1994). Schlieman etal. found that CA 19-9 levels may be potentially
useful as a marker for resectability (Schlieman et al. 2003). When a threshold level of
150U/mL was used, the positive predictive value for determination of unresectable pancreatic
cancer was 88%. Their recommendation was for additional staging modalities, such as diagnostic laparoscopy, in patients with abnormally high serum levels of CA 19-9. Katz found that
levels greater than 680U/mL were a significant prognostic predictor of overall survival (Katz
etal. 1998). Most physicians caring for patients with pancreatic cancer use CA 19-9 levels as
supportive evidence of malignancy in equivocal cases, as a parameter of therapeutic response,
and as an indicator of recurrence. It should be noted that 515% of patients, who are Lewis a
antigen negative, are incapable of expressing CA19-9 and may, therefore, have a falsely negative reading. Equally, a high bilirubin may falsely elevate the value.
Some centers still routinely employ laparoscopy as part of the preoperative evaluation for
patients with potentially resectable tumors. Early reports from high-volume centers demonstrated
a 1525% incidence of occult metastatic disease detected at the time of staging laparoscopy
(Warshaw et al. 1986, 1990; Conlon et al. 1996). More recent series, using modern, contrastenhanced helical CT scans, have found a lower incidence (415%) of occult metastatic disease
detected by laparoscopy (Friess etal. 1998; Barreiro etal. 2002; Pisters etal. 2001b; Jimenez etal.
2000; Nieveen van Dijkum etal. 2003). Differences also exist in its utility for tumors located in the
head of the pancreas vs. those in the body and tail of the pancreas. The latter are associated with a
higher incidence of occult metastatic disease (Barreiro etal. 2002). Rather than apply diagnostic
laparoscopy in all patients, most surgeons now use it selectively. Laparoscopy is recommended
prior to laparotomy for tumors larger than 5cm, patients with preoperative CA 19-9 levels greater
than 680mg/dL, or tumors in the body or tail of the pancreas (Katz etal. 1998; Montgomery etal.
1997). Laparoscopy is also useful when CT suggests the presence of hepatic, peritoneal, or omental
nodules that are too small to characterize or biopsy. Additionally, laparoscopic ultrasound may help
identify vascular invasion, as well as hepatic metastases (John etal. 1995).
7.3
Principles of Surgical Management and Current Controversies
The fundamental objectives of pancreatic cancer surgery are total extirpation of the primary
tumor with microscopically clear resection margins, complete regional lymphadenectomy
of appropriate peripancreatic nodal groups, and reconstruction of the gastrointestinal tract
so as to facilitate early and sustained return of normal physiologic function. Subtotal pancreatic resection can be carried out as either a left (distal) or right pancreatectomy. The latter
is also described as a pancreaticoduodenectomy or Whipple procedure. A standard pancreaticoduodenectomy involves resection of the distal stomach, distal common bile duct, gall
bladder, duodenum, pancreatic head, uncinate process, proximal jejunum, and regional
lymph nodes (Evans et al. 2001). More recent modifications include preservation of the
distal stomach and proximal duodenum, the so-called pyloric-preserving Whipple. Most
adenocarcinomas of the pancreas occur in the head of the gland and their resection requires
pancreaticoduodenectomy.
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7.3.1
Extent of Regional Lymphadenectomy
Given the high incidence of lymph node metastasis in patients with pancreatic cancer, there
continues to be interest in the extent of lymphadenectomy done during pancreaticoduodenectomy. Data from Asia and Japan have suggested a survival benefit for extended lymph node
dissections for esophageal and gastric cancers. Retrospective reviews of surgical experiences
have shown a wide range in the number and location of lymph nodes removed during a routine pancreas resection with no definitive conclusions regarding the impact of nodal dissection on survival. Two recent surgical trials have attempted to address this issue. Neither
showed any survival advantage to extended dissections that included more aggressive clearance of retroperitoneal soft tissues and nodes. Yeo etal. reported no significant difference in
one-, three-, or five-year survival rates and median survival when comparing standard pancreaticoduodenectomy to more radical resection, but did find that complication rates were
increased in the radical group (Yeo etal. 2002). In the most recent update of this trial, now
with a median live patient follow-up of 5.3 years, the one- and five-year survival rates in the
standard group were 75 and 13%, respectively, compared with 73 and 29% in the radical
group (p=0.13) (Riall etal. 2005). Pedrazzoli etal. also found that overall survival did not
differ according to the magnitude of lymphadenectomy (Pedrazzoli etal. 1998). Predictors
of long-term survival were tumor differentiation, tumor size, presence of lymph node metastases, and need for blood transfusions (Pedrazzoli etal. 1998).
Standard lymph node basins resected in a typical pancreaticoduodenectomy include
nodes along the common bile duct, nodes along the hepatic artery back toward the
celiac trunk, posterior, and anterior pancreaticoduodenal nodes, and nodes along the
superior mesenteric artery. Lymph nodes not routinely resected in the standard Whipple
procedure include nodes at or above the bifurcation of the common hepatic duct, celiac
axis nodes and the left gastric and splenic branch nodes, aortocaval nodes, and nodes
along the distal superior mesenteric artery (Fig. 7.4). Complications resulting from
extended lymphadenectomy may include exacerbated dumping syndromes and debilitating diarrhea (Yeo etal. 2002; Riall etal. 2005; Pedrazzoli etal. 1998). Results of
clinical trials thus far suggest that nodal metastases are a strong predictor of subsequent
systemic failure and that radical removal of regional nodes is unlikely to favorably
impact overall survival. Outside the setting of a clinical trial, extended lymphadenectomy cannot be justified because of increased complication rates and lack of any convincing survival advantage.
7.3.2
Role of Vascular Resection
The critical need for a complete margin-negative resection (R0) is highly evident when
examining survival data. Most series suggest similar survival rates for margin-positive
resections compared to nonoperative local-regional therapies in patients with locally
advanced disease (Trede etal. 1990; Varadhachary etal. 2006; Evans etal. 2001). Data
from the surgical group at the M.D. Anderson Cancer Center have demonstrated the
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CHD
CBD
Hepatic
artery
Celiac Axis
&
Branches
APD
&
PPD
SMV
&
R-SMA
Aorto-Caval
&
Distal SMA
Fig.7.4 Extent of lymphadenectomy during pancreaticoduodenectomy. Nodal basins designated in

green represent those removed in a standard Whipple procedure. Nodal basins designated in red
represent those not typically removed in a Whipple procedure but which may be part of an extended
nodal dissection and are usually included in standard radiation treatment volumes. CBD common
bile duct; APD anterior pancreaticoduodenectomy nodes; PPD posterior pancreaticoduodenal
nodes; SMV superior mesenteric vein; R-SMA right lateral wall of the superior mesenteric artery;
CHD common hepatic duct; celiac axis and branches celiac trunk at origin from aorta and splenic
artery and left gastric artery branches; aorta-caval nodes between the inferior vena cava and
abdominal aorta; distal SMA nodes along the distal superior mesenteric artery at the root of the
small bowel mesentery
safety and utility of venous resection in highly selected patients with localized headof-pancreas cancers in which a margin-negative resection could only be accomplished
by the addition of venous resection. Perioperative morbidity was low and ultimate survival rates were comparable to those of patients undergoing R0 resection without vein
resection (Bold etal. 1999). The operative mortality rate was 1.6% and the overall complication rate was 22%. Median survival in both groups was approximately 22 months.
CT scanning predicted the need for vein resection and reconstruction in approximately
85% of patients. This is critical since preoperative awareness of vascular involvement
will facilitate intraoperative technical approaches and minimize the potential danger of
adding a vascular procedure to the already formidable task at hand. Technical options for
reconstruction include primary end-to-end repair, lateral venorrhaphy with vein patch
from the saphenous or inferior mesenteric vein, or internal jugular vein interposition
grafting, usually with splenic vein preservation (Fig.7.5). Although superior mesenteric
artery or hepatic artery encasement is a contraindication to resection, if gross tumor-free
margins can be achieved, venous resection of the portal vein or SMV appears to be justified. In experienced hands, venous resection is not associated with reduced survival or
increased complications (Bachellier et al. 2001; Sasson et al. 2002; Nakagohri et al.
2003; van Geenen et al. 2001). Since survival is improved relative to microscopic
(R1 resection) or macroscopic (R2 resection) margin involvement, venous resection
should be strongly considered if it would result in a margin negative resection (R0)
(Bold etal. 1999; Harrison and Brennan 1998).
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Fig.7.5 Intraoperative picture of vascular reconstruction of the superior mesenteric, splenic vein,
and portal vein confluence using an internal jugular vein graft and facial vein side branch
7.3.3
Standard Gastrectomy vs. Pyloric-Preserving Whipple
Conflicts regarding the use of the standard Whipple operation with distal gastrectomy vs. a
pylorus-preserving Whipple procedure stem from concerns over the oncologic completeness of resection when preserving the pylorus and first portion of the duodenum vs. the
potential physiologic side effects of gastric resection (Thomas and Ahmad 2010; Lin and
Lin 1999). Sequelae of distal gastrectomy may include dumping syndromes, bile reflux, and
marginal anastomotic ulcerations. Others have suggested that the incidence of delayed gastric emptying is higher after pyloric preservation and may result in longer postoperative
length of stay. Suffice to say, no study has shown a markedly improved quality of life after
either procedure, and more recent studies, with large cohorts, have shown the incidence of
serious physiologic complications or clinically significant delayed gastric emptying to be
equally common after either operation (Tran etal. 2004; Lerut etal. 1984). No significant
differences have been observed in local recurrence rates, and overall survival between the
two techniques also appears equivalent (Tran etal. 2004). The authors tend to use a selective approach to gastric resection and reconstruction. In patients undergoing the Whipple
procedure for ampullary lesions, benign cystic neoplasms of the pancreas, and islet cell
tumors, pyloric-preserving resections are chosen. If the resection is being done after neoadjuvant radiation or if postoperative radiation is anticipated, then a standard Whipple with
distal gastrectomy and antecolic gastrojejunostomy is preferred. The advantage of this
reconstruction is the location of the anastomosis in the left mid-abdomen and a reduction in
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the incidence of radiation gastritis and radiation jejunal strictures. Truncal vagotomy is no
longer routinely done and pharmacologic acid suppression is usually sufficient to minimize
the risk of marginal ulceration at the gastrojejunostomy.
7.3.4
Techniques for Pancreatic Reconstruction
For several decades, the most feared complication after the Whipple procedure was the
development of a pancreatic leak from the pancreatic-enteric anastomosis. Mortality rates
secondary to a pancreatic leak have been reported to be as high as 40% (Lerut etal. 1984;
Herter etal. 1982; Aston and Longmire 1973). Death was usually secondary to overwhelming sepsis or delayed hemorrhage. Mortality secondary to a pancreatic leak has markedly
diminished with CT-guided drainage of abdominal fluid collections, advanced antibiotics,
and nutritional support; however, improved outcomes are most likely due to better attention
to technical factors affecting the integrity of the anastomosis. Technical approaches regarding reconstruction of the pancreatic-enteric anastomosis have included anatomic variations
of the anastomosis such as a pancreaticogastrostomy instead of the traditional pancreaticojejunostomy. Retrospective studies have shown a slightly higher pancreatic leak rate and mortality rate in patients when a pancreaticojejunostomy was performed (Schlitt etal. 2002).
However, randomized prospective studies have shown no difference in leak rates when a
pancreaticogastrostomy or pancreaticojejunostomy is performed (Yeo et al. 1995). Other
technical considerations include the type of pancreatic to intestinal anastomosis done with
variations of an invagination technique (end of pancreas invaginated into either the end or
side of the jejunum) vs. a duct-to-mucosa technique between the main pancreatic duct and
the jejunal mucosa. All have proven to be safe and effective with no clear advantage of one
over another (Sikora and Posner 1995). Randomized prospective trials have shown no difference in duct-to-mucosa or end-to-side anastomosis in patients who have a pancreaticojejunostomy after pancreaticoduodenectomy (Bassi etal. 2003). Anastomotic stents have also
been used in the pancreatic duct but do not seem to affect fistula rates (Sikora and Posner
1995; Balcom etal. 2001). Prophylactic pharmacologic approaches employing somatostatin
analogs have been used in Europe and the United States with conflicting results (Bassi etal.
2000; Yeo etal. 2000). Two recent prospective clinical trials from the M.D. Anderson Cancer
Center and Johns Hopkins Hospital have failed to show any benefit for prophylactic octreotide therapy (Yeo etal. 2000; Lowy etal. 1997). Topical agents with sealants such as fibrin
glue have not justified the extra costs with appreciable reductions in leak rates. Factors most
likely associated with increased leak rates include the type of primary tumor and texture of
the pancreatic gland remnant. Anastomotic leaks are, in general, more likely in patients with
ampullary and primary duodenal neoplasms compared to those with primary pancreatic cancers. The latter are thought to induce a fibrotic, sclerosing reaction in the substance of the
gland and therefore actually make the anastomotic suture lines more secure. Regardless of
which technique is used, most pancreatic surgeons now pay careful attention to preserving
the blood supply around the end of the pancreas and performing anastomosis with meticulous fine suture techniques. In patients receiving neoadjuvant or adjuvant chemoradiation,
anastomotic complications are not significantly increased. However, these patients are at risk
183
for the subsequent development of pancreatic enzyme insufficiency and require periodic
clinical evaluations to avoid the potential metabolic consequences of malabsorption and steatorrhea (Ohtsuka etal. 2001).
7.3.5
Surgical Morbidity and Mortality
Several studies have assessed the impact of referral to high-volume centers on morbidity
and mortality after pancreaticoduodenectomy (Raval et al. 2010). The development of
regional referral centers, with a high volume of procedures (>40 resections per year) performed by surgeons specializing in this operation is one of the main reasons for the decrease
in mortality noted in recent series. In high-volume centers, perioperative mortality rates
are 14%. Systemic, rather than surgical, complications now cause the majority of perioperative deaths. Predictors of surgical mortality include intraoperative blood loss, preoperative serum bilirubin level, diameter of the main pancreatic duct, and postoperative
complications (Bilimoria etal. 2008). Not only postoperative mortality but also morbidity,
hospital stay, and cost are reduced in high-volume centers. Most complications respond to
nonoperative treatment; however, complications that require reoperation are still associated with a mortality rate of 2367%. Resection rates in explored patients and overall
survival rates are also significantly higher at high-volume centers.
The most common complication following pancreatic resection is delayed gastric
emptying, with an incidence of 5070%. Although other complications, such as pancreatic leak, can predispose to delayed gastric emptying, it can occur without other morbidity. Intravenous erythromycin can reduce the incidence of delayed gastric emptying by up
to 37%. The incidence of postoperative pancreatic fistula is 224%. However, the definition of a fistula varies (Ujiki and Talamonti 2005). Low-output fistulas, defined as fistulas
of a volume less than 100mL/day, even with elevated fluid amylase levels, are probably
of little clinical significance. These problems rarely delay the resumption of normal oral
intake and should not significantly delay discharge or adjuvant treatments. High-output
fistulas with volumes greater than 100 cc/day and with amylase levels greater than
1,000U/dL may require a period of conservative management with bowel rest, octreotide
therapy, and nutritional support. In the absence of a complete dehiscence of the pancreatic-jejunal anastomosis, reoperation is rarely required. The mortality rate can be as high
as 28% and the usual cause of death is retroperitoneal sepsis or hemorrhage. Most series
have not identified a risk factor that predisposes to leakage; however, some report that
soft pancreatic parenchyma, small pancreatic duct diameter, ampullary carcinoma, and
the anastomotic method used are predisposing factors. Intra-abdominal abscess following
pancreatic resection occurs in 112% of patients. The usual cause is a leak from the
pancreatic-enteric anastomosis. CT usually diagnoses the abscess, and image-guided
drainage is usually successful.
Postoperative hemorrhage occurs in 215% of patients after pancreatic resection (Ujiki
and Talamonti 2007). Bleeding within the first 24h postoperatively is usually a result of
inadequate intraoperative hemostasis or hemorrhage from one of the enteric anastomoses.
Anastomotic hemorrhage can usually be treated conservatively; however, hemorrhage into
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the peritoneum requires re-exploration. Hemorrhage later in the postoperative period is

usually due to stress ulceration or erosion of a retroperitoneal vessel from an anastomotic
leak, the latter being much more serious with a mortality rate of up to 58%. In some cases,
embolization alone may suffice as treatment; otherwise more dramatic measures such as
re-exploration and revision of the anastomosis or, in the worse-case scenario, completion
total pancreatectomy may be required.
The impact of these complications has significant treatment implications. Delay in postoperative adjuvant therapy due to prolonged recovery is frequent following surgical complications (Bilimoria et al. 2009). Decline in general performance status and in the
parameters used to measure nutritional status is the rule rather than the exception in patients
with severe complications. Indeed, most clinical trials to assess the impact of adjuvant
chemoradiation after pancreaticoduodenectomy find that 2025% of patients are unable to
complete a full course of planned therapy, secondary to the debilitating effects of operative
complications.
7.4
Adjuvant Therapy for Pancreatic Adenocarcinoma
Despite improved perioperative outcomes after surgical resection and improved estimated
five-year survival rates after potentially curative surgery, the vast majority of patients
experience recurrence. Significant risk factors for recurrence after surgical resection for
pancreatic adenocarcinoma include lymph node-positive disease and involved surgical
margins. Outcomes for these patients are significantly worse than those for patients with
negative resection margins and lymph node-negative disease. Unfortunately, over 75% of
resected specimens will demonstrate nodal metastases, microscopic margin involvement,
or both, underscoring the imperative need for an effective adjuvant therapy.
Results from the several published prospective and retrospective series evaluating the
role of adjuvant chemoradiation are shown in Table 7.1. In the United States, adjuvant
chemoradiation has been considered to be the standard of care for more than 20 years by
many clinicians. The rationale for this, however, lies in the findings of the randomized
Gastrointestinal Tumor Study Group (GITSG) study initially published in 1985 (Kalser
and Ellenberg 1985). This trial, which randomized a total of 49 patients between 1974 and
1982, enrolled only patients with negative surgical margins and who had pancreatic adenocarcinoma confirmed by histology (excluding patients with periampullary carcinoma, islet
cell carcinoma, or cystadenocarcinoma). Patients were randomized after resection to
receive 5-fluorouracil (5-FU) chemotherapy plus radiotherapy or observation alone.
Patients were stratified at the time of randomization by the type of surgical procedure,
degree of differentiation, stage of disease, and location of primary tumor. Ninety-five percent of patients had primary cancer of the head of pancreas, and 28% had node-positive
disease. Radiotherapy was given in two courses of 20Gy each, separated by a two-week
interval, for a total of 40Gy. Chemotherapy with 5-FU (500mg/m2 intravenous bolus) was
administered at the beginning of each course of radiotherapy for three consecutive days
and then continued on a once-weekly basis for two years or until disease recurrence was
Pancreas only
289
Multi-institutional,
22 factorial/
randomized, no
therapy vs.
chemotherapy vs.
chemoradiotherapy
randomized therapy
vs. no therapy
218
EORTC (Klinkenbijl Pancreatic head

etal. 1999)
(55%) or/
periampullary
cancer
ESPAC-1
(Neoptolemos etal.
1997, 2001, 2004,
2009a)
Single-institution,
prospective
nonrandomized
therapy vs. intensive
therapy vs. no
therapy
174
Pancreas only
(head, neck, or
uncinate)
Johns Hopkins
(Yeo etal. 1997)
randomized therapy
vs. no therapy
43
Pancreas only
(95% head)
GITSG (Kalser and

Ellenberg 1985)
5-FU 425mg/m2 plus

FA 20mg/m2/day for 5
days every 28 days6
(continued)
Median overall survival:

chemoRT vs. no chemoRT
15.9 vs. 17.9 months p=not
reported
Chemotherapy vs. no chemo
20.1 vs. 15.5 months p=not
reported
40Gy split course 5-FU 500mg/m2 for 3

20Gy2, 2
days with each course
weeks apart
of RT or/
Median overall survival,

therapy vs. none:
19.5 vs. 13.5 months
p=0.003
intensive vs. regular: 17.5 vs.
21 months p=NS
therapy vs. none: 24.5 vs.
19.0 months p=0.208
17.1 vs. 12.6 months
p=0.099 (head of pancreas
only)
5-FU 500mg/m2 for 3

days each, and then
weekly for 4 months
(std) vs.
5-FU 200mg/m2 plus
FA 5mg/m2 5/7 days CI
for 4 months (intense)

therapy vs. none: 21 vs. 11
months p=0.03
2 year survival: 43 vs. 19%
Results
40Gy split course 5-FU 25mg/kg for 35

days by CI with each
20Gy2, 2
course of RT only
weeks apart
4045Gy split
course (std) vs.
5057Gy
continuous, plus
2327Gy to the
liver (intense)
40Gy split course 5FU 500mg/m2 for 3

20Gy2, 2
days with each course
weeks apart
of RT and then weekly
for 2 years
Table7.1 Results from recent prospective and retrospective series of adjuvant therapy for resected pancreatic cancer
Study
Disease sites
Number of Design
Radiation therapy Chemotherapy
patients

185
randomized, 5FU
plus FA vs. GEM
randomized, 5-FU
vs. GEM used
pre- and post-5-FU/
RT
1,088
451 (388
head)
616
Pancreas only
Pancreas only,
all sites and
head only
ESPAC-3
(Neoptolemos etal.
2009b)
RTOG 97-04
(Regine etal. 2008)
Johns Hopkins
Pancreas only
(Herman etal. 2008)
Single institution,
retrospective
analysis of adjuvant
chemoRT vs. none
randomized therapy
vs. no therapy
368
Pancreas only
CONKO-001
(Neuhaus etal.
2008; Neoptolemos
etal. 2009b)
Design
Number of
patients
Disease sites
Study
5-FU 425mg/m2 plus

FA 20mg/m2 days 15
every 28 days GEM
1,000mg/m2
Days 1, 8, and 15
every 4 weeks, both
6 months
5-FU 250mg/m2 CI
throughout RT (both
arms)
None
45Gy by
continuous
fractionation to
tumor bed and
nodes, with boost
to 50.4Gy tumor
bed
Varied. Majority
received 50Gy
by continuous
fractionation
GEM 1,000mg/m2
days 1, 8, and 15 every
4 weeks for 6 months
None
Varied. Majority
received CI 5FU with
RT followed by 5FU
for 26 months
5-FU 250mg/m2 CI;

GEM 1,000mg/m2
Days 1, 8, and 15
every 4 weeks, both
3 weeks before and
3 months after RT
Chemotherapy
Radiation therapy

chemoRT vs. none: 21.2 vs.
14.4 months, p<0.001
Median overall survival: no

difference at 5 years; planned
subset analysis of head of
pancreas only, GEM vs.
5-FU: 20.5 vs. 16.9 months
p=0.09
Log-rank analysis=0.7,
p=0.39
HR (gem) = 0.94

5-FU/FA vs. GEM: 23.0 vs.
23.6 months

therapy vs. none: 22.8 vs.
20.2 months p=0.005
Median DFS, therapy vs.
none: 13.4 vs. 6.9 months
p<0.001
Results
186
M.B. Ujiki et al.
Pancreas
head only
ACOSOG Z05031
(Picozzi etal. 2008)
89
472 466
eligible
Multi-institutional
phase II study
Single institution,
retrospective
analysis of adjuvant
chemoRT vs. none
50.4Gy by
continuous
fractionation
Varied. 93% of
patients received
4555Gy, median
50.4Gy

chemoRT vs. none: 25.2 vs.
19.2 months p=0.001
Median overall survival: 27.1

months (95% confidence
interval 23.433.6 months)
31.8 months if all treatment
cycles begun
Varied. 98% received

concurrent fluorouracil
with RT and 10.4%
received additional
chemotherapy
Cisplatin 30mg/m2
weekly 6, 5FU
175mg/m2 CI days
138, INT 3 million
units MWF during RT;
chemoRT chemotherapy plus radiation therapy; Gy gray; CI continuous infusion; HR hazard ratio; DFS disease free survival; INT interferon alpha; FA folinic
acid; NS not significant; 5FU 5 fluorouracil; RT radiation therapy
Pancreas only
Mayo Clinic
(Corsini etal. 2008)

187
188
M.B. Ujiki et al.
noted. With 43 patients in the final analysis, median survival was improved (21 vs.
11 months) with the addition of adjuvant therapy, and this did meet statistical significance
(p=0.035). This trial has been extensively criticized because of its small numbers, slow
accrual, the use of outdated split course radiation, and a delay of more than 10 weeks in
starting adjuvant therapy in 25% of patients.
The only other prospective study in the United States that compared adjuvant chemoradiation with surgical resection alone for pancreatic adenocarcinoma is a nonrandomized
study from Johns Hopkins (Yeo et al. 1997). Patients were allowed to choose between
standard therapy (similar to that used in the GITSG study), intensified therapy (intensified
radiation therapy to pancreatic bed and liver with infusional 5-FU), or observation alone.
The majority of patients chose standard therapy and those that received adjuvant chemoradiation showed an improvement in overall survival (19.5 months vs. surgery, 13.5 months,
p=0.003), with no difference seen between the two chemoradiation arms.
The Gastrointestinal Tract Cancer Cooperative Group of the European Organization for
Research and Treatment of Cancer (EORTC) published a phase III trial comparing radiotherapy plus 5-FU with observation alone in the adjuvant setting (Klinkenbijl etal. 1999).
Two hundred eighteen patients were randomized from 1987 to 1995, to receive either
observation alone or a combination of 5-FU as a continuous infusion (CI) concomitantly
with radiotherapy. After chemoradiation was completed, patients were followed and
received no more chemotherapy unless they relapsed. The median survival was 19 months
for the observation group and 24.5 months for the treatment group, but this result was not
statistically significant (p=0.208) and was further confounded by the inclusion in this trial
of patients with periampullary tumors, who made up almost half of the cohort. In a subset
analysis, there was a nonsignificant trend toward improved survival in the pancreatic cancer cohort when adjuvant therapy was given (17.1 vs. 12.6 months, p=0.099) (Klinkenbijl
etal. 1999).
More recent data from European trials show a significant role for adjuvant systemic
chemotherapy, but have raised considerable controversy regarding the role for adjuvant
chemoradiation in pancreatic adenocarcinoma. The European Study Group for Pancreatic
Cancer (ESPAC-1) trial was designed to answer several questions about adjuvant therapy
for pancreatic cancer (Neoptolemos et al. 1997). This complex trial was initially constructed with a 22 factorial design to compare adjuvant chemoradiation, 6 months of
adjuvant chemotherapy, and a combination of these, with an additional observation control
arm. The results of this trial were published sequentially over the course of several years
(Neoptolemos etal. 1997, 2001, 2004, 2009a). In the chemoradiation group, a course of
40Gy was given with 5-FU as a sensitizing agent, using the same schedule and doses as
were used in the GITSG trial. In the chemotherapy arm, patients received folinic acid with
bolus 5-FU at a dose of 425mg/m2 for five consecutive days every 28 days for six cycles.
Patients randomized to both treatment arms were to receive chemoradiation first, followed
by the full course of chemotherapy. Patients were stratified by margin status at initial randomization. For the overall group, the two-year survival for those receiving chemotherapy was 40% and for those not receiving chemotherapy, 30% (no p value reported). The
two-year survival rate for patients receiving chemoradiation was 29%, compared with
40% for those not receiving chemoradiation. For chemotherapy randomization, a secondary end-point analysis demonstrated that the hazard ratio (HR) for death was statistically
189
significantly improved in patients receiving chemotherapy compared with those not receiving chemotherapy (HR = 0.71, p=0.0009), and median survival for the chemotherapy arm
was 20.1 vs. 15.5 months for the no-chemotherapy arm, with no p values reported. The
same analysis was performed in the chemoradiation arm, and this analysis suggested worse
outcomes for patients receiving chemoradiation, with an HR for death of 1.28 (p=0.05).
Median survival was 15.9 months for patients receiving chemoradiation and 17.9 months
for patients who did not receive chemoradiation. Five-year survival rate was 21% among
patients who received chemotherapy and 8% among patients who did not receive chemotherapy (p=0.009), and it was 10% among patients randomized to receive chemoradiation
and 20% among patients who did not receive chemoradiation (p=0.05). Patients in the
22 factorial design who received adjuvant chemoradiation actually fared significantly
worse than those undergoing surgery alone. In contrast, however, those who received adjuvant systemic chemotherapy had an increased overall survival compared with those who
underwent surgery alone. When both the 22 factorial arm and single randomization arms
were analyzed for prognostic factors, the benefit of chemotherapy appeared most pronounced in patients with well-differentiated tumors, lymph node-positive disease, and
margin-negative resections. The detrimental effects of chemoradiation in Europe aside,
this study has been widely criticized in the United States because of its complicated design,
the lack of statistical power in the 22 design, and the lack of radiation quality controls
(Backlund etal. 2010).
The Charite Onkologie (CONKO)-001 is a multicenter trial based in Germany comparing adjuvant chemotherapy with gemcitabine (GEM) vs. observation alone following pancreatic resection. Patients were randomized on a 1:1 basis and stratified for resection status
(R0 vs. R1), T status (T12 vs. T34), and nodal status (N-positive vs. N-negative). Patients
in the GEM group received three weekly infusions of GEM at a dose of 1,000mg/m2 for
three weeks on and one week off, for a total of six cycles. The primary endpoint of the trial
was disease-free survival, with a secondary endpoint of overall survival. Estimated disease-free survival was 13.4 months in the GEM group compared with 6.9 months in the
control group (p<0.001), and this benefit was seen regardless of margin status, tumor size,
or nodal involvement (Oettle etal. 2007). At the time of initial publication, there was no
statistically significant benefit seen in overall survival numbers, but a subsequent update
demonstrated that patients receiving adjuvant GEM had a median survival rate of 22.8
months vs. 20.2 months for patients receiving observation alone (p=0.005). Estimated
five-year survival for the GEM arm was 21% compared with 9% for the observation arm
(Neuhaus etal. 2008).
The ESPAC-3 trial evaluated the use of adjuvant 5-FU and leucovorin (425 and
20mg/m2, respectively, daily for five days per month) vs. GEM (1,000mg/m2 weekly for
three out of four weeks), both for six months in an attempt to clarify the optimal agent in
the adjuvant setting (Neoptolemos et al. 2009b). Thousand hundred and eighty-eight
patients were randomized and at 34 months, there was no statistical difference in the
median survival (23 vs. 23.6 months). There was, however, more toxicity in the 5-FU/
leucovorin arm (10% vs. 0% grade 34 toxicity) and this suggests that GEM, when used
as a single agent, is the superior therapy on the basis of similar results but less toxicity.
The largest multigroup trial in the United States to address chemotherapy and chemoradiation was the Radiation Therapy Oncology Group (RTOG) Trial 97-04. RTOG 97-04
190
M.B. Ujiki et al.
was a large intergroup trial conducted by the RTOG, the Eastern Cooperative Oncology
Group (ECOG), and the Southwest Oncology Group, inclusive of Canadian affiliates
(Regine et al. 2008). This trial included 451 patients with pancreatic adenocarcinoma,
with 75% of patients having T3 and T4 disease and approximately 66% of patients having
node-positive disease. One-third of patients had positive margins. Randomization was
performed after surgery and was stratified by tumor diameter (<3cm or 3cm) and surgical margins (33% of patients had positive surgical margins). Patients were randomly
assigned to either 5-FU (group 1) or GEM (group 2). Chemotherapy before chemoradiation in group 1 consisted of CI 5-FU (250mg/m2) daily for 3 weeks, and in group 2 consisted of a 30-min infusion of GEM (1,000mg/m2) once weekly for three weeks. Within
the next two weeks, both groups began identical chemoradiation regimens (50.4Gy with
CI of 250mg/m2 of 5-FU daily through the course of radiotherapy). An additional phase
of chemotherapy was initiated 35 weeks after the completion of chemoradiation, with
group 1 receiving three months of infusional 5-FU daily for the next three months (four
weeks on and two weeks off for two cycles) and group 2 receiving three months of GEM
(three weeks on and one week off). Prospective quality assurance procedures were used,
including central review of preoperative CT scans and radiation therapy fields, before the
initiation of chemoradiation. For the final analysis, 451 evaluable patients were included,
and there was found to be no difference in the overall or disease-free survival rates among
treatment groups. As part of the second primary objective study, a subgroup analysis of
patients with tumors in the head of the pancreas was performed, and these patients had a
median survival of 20.5 months and a three-year survival rate of 31% in the GEM group
compared with 16.9 months and 22% in the 5-FU group (HR = 0.82, p=0.09). However,
after adjusting for prespecified stratification variables of nodal status, tumor diameter,
and surgical margin status, the treatment effect yielded an HR of 0.80 (p=0.05). Although
complicated by crossover to treatment with GEM when recurrence developed, this study
suggests a mild advantage for GEM over 5-FU in the adjuvant setting for tumors in the
head of the pancreas (Regine etal. 2008).
Recently, large retrospective series from Johns Hopkins and Mayo Clinic have suggested that the use of adjuvant 5-FU-based chemoradiation significantly improves overall
survival compared with that in patients undergoing surgery alone (Corsini et al. 2008;
Herman etal. 2008). In the study from Johns Hopkins, analysis of 616 patients showed that
the benefit of chemoradiation was independent of several risk factors including tumor size,
grade, margin, and nodal status. Adjuvant chemoradiation improved survival for both
margin-negative and margin-positive patients (median 21.2 vs. 14.4 months, p<0.001). In
addition, lymph node-positive patients appeared to have significant benefit with adjuvant
chemoradiation, and lymph node-negative patients did not. But by multivariate analysis,
the interaction between nodal status and treatment was not significant (Herman etal. 2008).
The recently reported Mayo Clinic experience of 472 patients who underwent R0 resection
also showed a significant survival benefit with the use of adjuvant 5-FU based chemoradiation (median 25.2 vs. 19.2 months, p=0.001). This benefit was present for both lymph
node-positive and lymph node-negative disease (Picozzi etal. 2010). Although both these
trials support the findings of a benefit of adjuvant chemoradiation, they were nonrandomized single-institution studies.
191
A multi-institutional phase II study which provoked considerable interest was the

recently reported ACOSOG study based on the adjuvant use of 5-FU (175mg/m2 CI daily),
interferon alpha (3 million units three times a week) and cisplatinum (30mg/m2 weekly6
doses) with concurrent RT (50.4Gy) (Picozzi etal. 2010). This was intended to be a confirmatory study based on an earlier single-institution evaluation of this regimen which had
proven remarkably effective but also quite toxic. The original regimen was modified by
decreasing the 5-FU and interferon dose, but study accrual was nonetheless terminated
after accrual of 89 out of an intended 93 patients owing to excessive toxicity. Provocatively,
at two years median follow-up, 67% of patients were alive 18 months from study registration. Median survival was 27.1 months overall (CI 23.433.6 months) and 31.8 months if
all treatment cycles had been begun.
The challenges in the study of adjuvant therapy after pancreaticoduodenectomy are
readily apparent in the analysis of the above studies. Patient accrual is slow, and selection
criteria are inconsistent and often poorly defined. Stratification criteria often inhibit adequate numbers of patients to enrollment and thus preclude sufficient power to determine
significance between patient subgroups. Crossover treatment after recurrence prevents
clear delineation between 5-FU vs. GEM-based protocols. Nonetheless, certain conclusions can probably be drawn from the above-mentioned studies, albeit with more than a
modicum of restraint. Adjuvant therapy after potentially curative pancreatic resection
appears warranted though the most effective form of therapy (chemotherapy alone vs.
chemoradiation) remains to be determined. The benefit of local-regional control with
added radiation therapy for patients at lower risk for early disseminated disease, but with
concern for local recurrence, may justify the potential added morbidity of combined
modality therapy. There does not appear to be a marked advantage to GEM over 5-FU as
the best radiation sensitizer. Systemic therapy with full-dose GEM as the early or initial
treatment for patients at risk for early distant recurrence appears warranted and probably
has some survival advantage, though small, over surgery alone. Future trials will need to
address the controversy of chemotherapy alone as the adjuvant therapy of choice vs.
chemoradiation with or without systemic therapy before or after radiation. GEM should be
considered the more effective baseline systemic chemotherapeutic agent by which to compare other treatment arms (Backlund etal. 2010).
7.5
Neoadjuvant Therapy for Localized and Borderline Resectable Pancreas Cancer
The rationale for neoadjuvant therapy in pancreatic cancer is multifold. Preoperative
chemotherapy or radiation may theoretically downstage disease by (1) sterilizing
peripheral extent of tumor infiltration, resulting in fewer R1 margin-positive resections,
(2) decreasing tumor volume such that borderline-resectable disease may become more
easily resectable, and (3) minimizing regional nodal disease/tumor burden such that
locoregional recurrence is reduced. Furthermore, patients who receive neoadjuvant
therapy are more likely to complete their full course of chemotherapy and radiation
192
M.B. Ujiki et al.
when compared to patients given postoperative chemoradiation; between 21 and 30%

of patients undergoing pancreaticoduodenectomy may not complete adjuvant chemoradiation due to postoperative morbidity or patient refusal (Spitz etal. 1997). Additionally,
chemoradiation administered to undissected, well-oxygenated tissue may maximize
any cytotoxic benefit gained from treatment. Perhaps most importantly, patients who
exhibit disease progression during their neoadjuvant therapy self-select themselves as
poor responders who are least likely to gain benefit from resection and may forego the
morbidity of pancreatic resection. Lastly, preliminary analysis of the cost effectiveness of a neoadjuvant vs. adjuvant approach suggests that the neoadjuvant approach
may be superior in this regard. Each of these clinical justifications is relevant in pancreatic cancer, as the aggressive and unforgiving nature of this disease leaves little
margin for mismanagement or over/under treating (Abbott etal. 2010).
7.5.1
Resectable Disease
Patients with clinically localized disease who undergo successful resection and on pathologic review are found to have clear resection margins (R0) and no evidence of nodal
metastases have a relatively favorable prognosis compared to patients with either marginpositive resections (R1 or R2) or nodal and regional disease. Thus, those patients with
limited disease found on noninvasive imaging are those most likely to survive, with a
corollary that these patients are most likely to benefit further from advances in neoadjuvant
therapies. There is a growing body of literature examining neoadjuvant strategies in this
selected subgroup of patients who by definition have no imaging evidence of nodal disease, disruption of local planes, or extension of tumor outside the pancreas (Spitz etal.
1997; Abbott etal. 2010; Yeung etal. 1993; Hoffman etal. 1998; Moutardier etal. 2004;
White and Tyler 2004; Mornex etal. 2006; Evans etal. 2008; Talamonti etal. 2006).
In 1997, Spitz etal. reported the MD Anderson Cancer Center experience, providing
preoperative 5-FU-based chemoradiation to patients with potentially resectable tumors
based on high-quality imaging and comparing outcomes with those receiving postoperative combined modality therapy (Spitz etal. 1997). Of the 91 patients in the neoadjuvant
therapy cohort, 26% exhibited disease progression during therapy and were not offered
operative intervention. Of the remaining 67 patients, 41 were treated according to study
protocol (chemoradiation followed by resection). Median survival in this cohort was 19.2
months compared to 22 months in the postoperative adjuvant cohort, despite postoperative
therapy patients more frequently having a microscopically positive margin and positive
regional lymph nodes on final histologic examination. This lack of survival benefit in the
neoadjuvant cohort may be explained by bias in their selection criteria; to be included in
this treatment arm, patients were required to have histologically proven pancreatic adenocarcinoma and a hypodense mass in the pancreatic head; those without CT evidence of a
mass or biopsy-proven pancreatic cancer were given postoperative chemoradiation.
Because the two treatment arms were neither matched nor randomized, it is difficult to
derive definitive conclusions regarding efficacy from these data. Certainly, the study did
confirm the feasibility and safety of a neoadjuvant approach. Of note, this study also
193
detailed the high GI toxicity of standard 5.5-week radiation therapy (32% of patients
required hospital admission) and the better tolerated two-week, rapid fractionation that
evolved from this finding.
Lowy, in his recent review of adjuvant and neoadjuvant therapy for pancreatic cancer,
outlined twelve studies published between 1993 and 2006 that evaluate a variety of preoperative chemoradiation regimens (Lowy 2008). As noted, early studies were largely 5-FU-based,
with or without mitomycin-C, while more recent investigations either added, or replaced
5-FU with, GEM. Radiation schema usually delivered between 30 and 50.4Gy with fairly
wide treatment fields including prophylactic regional nodal radiation. Primary outcomes
reported include percent of patients resected following neoadjuvant therapy (range 3885%)
and median survival (range 1236 months). No correlation between dose of preoperative
radiation and resectability or survival has been demonstrated, nor was the addition of mitomycin-C to chemotherapeutic regimens related to increased survival. It is noteworthy that
two of the three studies that added cisplatin to their 5-FU-based neoadjuvant therapy demonstrated survival at the higher end of the twelve-study range (23 and 27 months) (Moutardier
etal. 2004; White and Tyler 2004). Furthermore, the use of GEM in the preoperative protocol
of three studies was associated with 20-, 26-, and 34-month median survival, again much
longer survival than most 5-FU-based reports (Evans et al. 2008; Talamonti et al. 2006;
Lowy 2008; Meszoely etal. 2004). Talamonti reported 20 patients in a multicenter trial utilizing 36Gy of limited field radiation and full-dose GEM (1, 000mg/m2) (Talamonti etal.
2006). This trial reported an 85% resectability rate and a median survival of 26 months.
These data are consistent with earlier Phase I trials and animal models which demonstrate
that GEM is an excellent radiosensitizer (when compared to 5-FU) and that its use may portend increased survival for patients who are operative candidates.
A large series from the MD Anderson Cancer Center expanded on these outcomes
using GEM-based neoadjuvant chemoradiation. In 2008, Evans etal. described the administration of GEM (7 weeks, 400mg/m2) and rapid-fraction radiation therapy (30Gy over
2 weeks) in patients with resectable pancreatic cancer (Evans etal. 2008). While 26% of
patients either exhibited disease progression or were deemed unresectable at surgery, a full
74% of patients underwent successful resection. Median survival for these patients was
34 months compared to only 7 months for patients who had unresectable disease. This
substantial median survival compares very favorably to nearly all other neoadjuvant
regimes, demonstrating the best median survival for patients undergoing neoadjuvant therapy for resectable pancreatic cancer.
Varadhachary etal. reported outcomes in a cohort of patients who received four doses
of GEM-cisplatin in addition to the standard preoperative GEM and rapid fractionation,
30-Gy radiation therapy (GEM 400mg/m2 weekly 4 concomitant with RT, and GEM
750mg/ m2 with cisplatin 30mg/m2 every 2 weeks 4 prechemoRT) (Varadhachary etal.
2008). This extra treatment period did not adversely affect tumor progression, though
patients did require more durable biliary decompression. In the 88% of patients who completed chemoradiation, 66% underwent resection. The median survival in resected patients
was 31 months vs. only 10.5 months in the unresected group. The authors conclusions,
when comparing median survival to the similar cohort described by Evans et al. (34
months) (Evans etal. 2008), were that the addition of GEM-cisplatin to GEM-based neoadjuvant chemoradiation was not efficacious in extending survival.
194
M.B. Ujiki et al.
The omission of radiation therapy and the accentuation of neoadjuvant chemotherapy is

a novel strategy with recent support (Heinrich etal. 2008). Heinrich etal demonstrated the
feasibility of delivering GEM with cis-platinum and no radiation therapy in a recent phase
II trial. The regimen was well tolerated, graded histologic tumor responses were comparable to chemoradiation protocols, and there was no added surgical morbidity. This strategy of neoadjuvant chemotherapy alone for resectable pancreas cancer is under investigation
in a current American College of Surgeons Oncology Group clinical trial, Z5041, which is
examining GEM plus erlotinib both pre and postsurgery.
In examining these data on neoadjuvant therapy for resectable pancreatic cancer on the
whole, it is important to note that there are no randomized, prospective trials evaluating
either 5-FU- or GEM-based chemoradiation in a neoadjuvant setting. Despite this shortcoming, many researchers have noted a median survival that exceeds traditionally recognized survival for operable pancreatic cancer and this should serve as the paradigm on
which further clinical trials are based.
7.5.2
Borderline Resectable Strategies
Most studies that address neoadjuvant chemoradiation for borderline resectable or locally
advanced tumors prior to 2005 include patients who have visceral vessel abutment or
encasement (again a vague distinction for study purposes) with relatively low subsequent
resection rates ranging from 1 to 29% (Snady etal. 2000; Kim etal. 2002). In these reports,
there was significant variability in treatment regimens, at times including the use of some
or all of the following agents: external beam radiation therapy (EBRT), 5-FU, streptozotocin, cisplatin, mitomycin-C, leucovorin, and dipyridamole. Utilizing a variety of preoperative chemoradiation strategies, median survival ranged from 10 to 32 months depending
on patient cohort and inclusion criteria used (Pipas et al. 2005; Kamthan et al. 1997;
Ammori etal. 2003; Aristu etal. 2003; Joensuu etal. 2004).
There are a number of more recent studies that have helped to refine our understanding
of optimal neoadjuvant treatment strategies for borderline resectable disease. Two studies
from Japan highlight their experience with preoperative chemoradiation for borderline
resectable pancreatic cancer. In the first, 32 patients with <50% of SMA encasement and
no cavernous transformation or thrombosis of the SMVportal vein confluence were
treated with EBRT (40Gy) and either 5-FU/cisplatin- or GEM (400mg/m2)-based chemotherapy (Takai etal. 2008). Twenty-four of the 32 patients underwent definitive resection, with median survival of 26 and 20 months for 5-FU/cisplatin and GEM treatment
strategies, respectively (p=NS). A caveat in interpreting this study is the lack of clarity
in the study arm, as patients may belong to either resectable or borderline resectable
according to expert consensus criteria highlighted above. The second study from the same
group retrospectively examined 68 patients with pancreatic adenocarcinoma who were
initially found to have extra-pancreatic disease (T3/4 by AJCC staging) or borderline
disease by previous NCCN criteria (Satoi etal. 2009). Utilizing the same neoadjuvant
regimen described in their previous study (40Gy EBRT with 5-FU/cisplatin or GEM at
400 mg/m2), 35 patients (19 potentially resectable and 16 locally advanced) received
195
preoperative chemoradiation without adjuvant therapy. Following neoadjuvant therapy,

79% of patients underwent surgical resection. Median survival was 24.5 months in the
resected group in the neoadjuvant arm compared to 18.5 months in a historical control
surgery-alone group.
A retrospective review from MD Anderson, published in 2008, details the preoperative classification, administration of therapy, and subsequent response (with or without
the addition of surgery) in 160 patients (Katz etal. 2008). Many were deemed to have
borderline resectable disease (proximity/abutment/encasement of visceral vessels
Group A). However, the authors submitted that two additional subsets of patients exist;
those with questionable metastatic disease (Group B) and those who display either a
suboptimal performance status or have prohibitive medical comorbidities and who are
not initially surgical candidates (Group C). All 160 patients received either chemotherapy, chemoradiation, or both. This primarily consisted of either 50.4 or 30Gy of EBRT
with radiosensitizing doses of either 5-FU, paclitaxel, GEM, or capecitabine. Resection
rates following neoadjuvant therapy were 38, 50, and 38% in groups A, B, and C, respectively. Furthermore, resected patients in groups A, B, and C exhibited 40/29/39-month
median survivals compared with 15/12/13-month median survivals for unresected
patients, respectively. This important study certainly does not demonstrate an obvious
benefit of one treatment regimen vs. another, but does clearly make two salient points.
Firstly, patients with stringently defined borderline resectable disease who respond to
neoadjuvant therapy and undergo definitive surgical therapy have a significant survival
advantage compared to patients with unresectable disease. Secondly, and perhaps more
provocatively, there are further subsets of patients, not encompassed by traditional AJCC
criteria, who may equally benefit from a trial of neoadjuvant chemotherapy or chemoradiation therapy. Further studies will need to be done to validate these findings, but the
notion of expanding the indications for neoadjuvant therapy for this disease warrants
further investigation.
Two small retrospective studies with a similar design examined the use of GTX (GEM,
Taxotere, capecitabine) chemotherapy alone for three cycles followed by either 5-FU, or
capecitabine plus/minus oxaliplatin, combined with RT prior to surgery in borderline
resectable disease (Takai etal. 2008; Satoi etal. 2009). In the first study, 9 of 17 patients
were able to undergo surgery, and 8 of 9 had an R0 resection. In the second, 14 of 16 completed a pancreaticoduodenectomy and 12 of 14 had an R0 resection. The numbers are too
small to draw any meaningful conclusions about survival, but the results show that an
intensive neoadjuvant approach is both feasible and safe and that selected patients with
initially borderline resectable disease may have an R0 resection by this approach.
It is fairly apparent that the optimal management of borderline resectable disease is less
clearly defined than that of resectable disease, as evidenced by both relatively fewer studies addressing the issue as well the wider variability in treatment regimens and outcomes.
Most importantly, the lack of consistency in defining study participants makes interpretation particularly dangerous. Certainly as treatment strategies become more disease-stage
specific, efficacious, tolerable, and consistent, better data will exist to guide ongoing management. Many high-volume centers will now accept radiographic findings of a borderline
resectable tumor as an indication for a neoadjuvant treatment strategy based on the possible survival benefits vs. a primary surgical approach for these patients. There does not yet
196
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exist consensus agreement as to the optimal treatment schema for neoadjuvant therapy in
borderline resectable disease, though most investigators would now agree on a GEMbased regimen.
7.6
Summary
The management of localized pancreatic cancer has progressed from a nearly purely surgical approach to increasingly effective multimodality treatment strategies. State-of-theart care now involves coordination of exquisite staging by radiology, appropriate use of
interventional gastroenterology, optimized surgical outcomes, and individualized applications of chemotherapy and radiation oncology predicated upon prognosis and risk for
recurrence. For the patient presenting with signs and symptoms of pancreatic cancer,
initial staging studies should include high-quality three-dimensional radiologic imaging
with either CT or MRI. There now exist definable and objective radiographic criteria to
accurately categorize a nonmetastatic tumor as localized and potentially resectable, or
surgically borderline based on limited vascular involvement, vs. locally advanced and
unresectable with extensive regional involvement that would preclude complete resection
of all gross disease. Surgical treatment with improved outcomes has probably been the
most significant contribution to these patients in the last 25 years. Surgical advances
include a more refined understanding of the importance of the regional lymphadenectomy, the imperative need to achieve an R0 or R1 resection margin near the vascular
structures, and the necessity to optimize long-term quality of life issues with more functional resections and reconstructions such as the pyloric-preserving Whipple. Adjuvant
chemotherapy with a GEM-based regime should now be considered the standard of care
for postoperative patients with a sufficient performance status after a reasonable recovery
period. The role of adjuvant radiation therapy remains one of the most controversial
debates in gastrointestinal oncology. Data from several large European trials demonstrate
that most patients do not derive marked benefit from adjuvant chemoradiation and may
actually suffer a diminution in quality and length of life. Conversely, data from US trials
and single-institution series suggest there are certain patients with relatively lower risk of
early distant disease who would benefit from radiation for improved local and regional
control. Developing criteria for these patients and defining the roles of adjuvant chemotherapy and chemoradiation will be the challenge and mandate for future trials. Patients
with surgically borderline tumors as described in previous sections would most likely
require advanced surgical techniques such as vascular resection and reconstructions if a
complete resection is to be achieved. These are optimal candidates for novel neoadjuvant
strategies that may improve resectability rates and the margin status of these surgical
specimens. The impact of such aggressive strategies appears to be justified by currently
available reports. Clearly, pancreatic cancer remains one of the most formidable challenges in medicine today. Advances have been made, but future improvements will come
only with well-designed clinical trials addressing the roles of combined treatment strategies and the development of more effective biologic and chemotherapeutic agents.
197
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White RR, Tyler DS (2004) Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg
Oncol Clin N Am 13(4):675684, ixx
Yeo CJ, Cameron JL, Maher MM, Sauter PK, Zahurak ML, Talamini MA etal (1995) A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy. Ann Surg 222(4):580588; discussion 892
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Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH et al (1997) Pancreati
coduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation
improves survival. A prospective, single-institution experience. Ann Surg 225(5):621633; discussion 3336
Yeo CJ, Cameron JL, Lillemoe KD, Sauter PK, Coleman J, Sohn TA etal (2000) Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Results of a prospective randomized placebo-controlled trial. Ann Surg
232(3):419429
Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK et al (2002)
Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal
lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg 236(3):355366; discussion 6668
Yeung RS, Weese JL, Hoffman JP, Solin LJ, Paul AR, Engstrom PF etal (1993) Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A phase II study. Cancer 72(7):21242133
Unresectable Pancreatic Cancer
Daniel Renouf, Laura A. Dawson, and Malcolm Moore
8.1
Introduction
Pancreatic adenocarcinoma is the fourth leading cause of cancer death in North America,
with approximately 35,000 deaths annually (Jemal etal. 2008). Advanced pancreatic cancer is an aggressive and lethal disease; the median survival without treatment is less than
3 months and one-year survival is less than 5% (Glimelius etal. 1996). The disease is relatively resistant to cytotoxic chemotherapy; even with treatment, median survival is approximately 6 months and one-year survival is 2025% (Moore etal. 2007).
The majority of patients with pancreatic cancer are diagnosed with locally advanced or
metastatic disease. Around 1520% of patients have localized disease amenable to surgical resection, though even with successful surgery, the disease usually recurs. A major
improvement in outcome can only come through better systemic therapy or earlier detection. Screening programs are being studied but show little promise.
Locally advanced pancreatic cancer (LAPC) includes tumors that invade into or are
adherent to adjacent structures, such as the celiac and superior mesenteric vasculature, and
are thus difficult to resect with negative margins. Borderline resectable tumors are often
defined as having focal tumor abutment of the vasculature (Katz etal. 2008). The treatment
of borderline resectable tumors may still involve surgery (with or without preoperative
systemic and radiation therapy), and is addressed in the previous chapter on resectable
disease, while this chapter focuses on truly unresectable tumors. The treatment modalities
for LAPC evaluated include systemic therapy, radiation therapy, systemic therapy given
concurrently with radiation (chemoradiotherapy), or a combination of both approaches.
D. Renouf and M. Moore (*)

Department of Medical Oncology, Princess Margaret Hospital, 5-708,
610 University Avenue, Toronto, ON, M5G 2M9, Canada
e-mail: malcolm.moore@uhn.on.ca
L.A. Dawson
Department of Radiation Oncology, Princess Margaret Hospital,
5-708, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
205
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D. Renouf et al.
Metastatic pancreatic cancer refers to tumors that have spread beyond the pancreas and
regional lymph nodes. The main treatment modality for metastatic pancreatic cancer is
systemic therapy. This chapter reviews the current data on local and systemic therapies in
unresectable pancreatic adenocarcinoma and discusses future directions for the treatment
of this challenging disease. Given the unsatisfactory results of therapy for all stages of
pancreatic cancer, clinical research is a critical part of the approach to these patients.
8.2
Locally Advanced Pancreatic Cancer
8.2.1
Radiation and Chemoradiotherapy
There is evidence from small older studies that treatment of LAPC improves outcomes
compared with best supportive care. Shinchi etal. (2002) compared chemoradiotherapy
(with 5-FU and radiation therapy) to best supportive care. This was a randomized study of
only 31 patients, and treatment with chemoradiotherapy improved median survival, from
6.4 to 13.2 months.
Several studies have compared radiotherapy alone with chemoradiotherapy for the
treatment of LAPC. Moertel etal. 1981) randomized 194 patients to receive radiotherapy
(to a total dose of 60Gy) or radiotherapy (to a total dose of 40 or 60Gy) given with 5-FU.
Overall survival was significantly better in the chemoradiotherapy arms, and there was no
difference between the higher and lower doses of radiation. A second study compared
radiotherapy and chemoradiotherapy, in which the chemotherapy used was 5-FU and mitomycin C. In this trial no significant difference was noted between the two arms, although
there was a trend toward improved survival in the chemoradiotherapy arm (Cohen etal.
2005). The method of 5-FU administration (intermittent high dose rather then continuous
infusion), and the use of mitomycin C may have contributed to the poor outcomes in the
chemoradiotherapy arm.
Two meta-analyses have been performed, using the data from these two trials, as
well as also data from previous smaller studies (Yip etal. 2006; Sultana 2007). Both
concluded that chemoradiotherapy significantly improved survival, compared with
radiation therapy alone. This conclusion was further supported by a retrospective study
of 1,700 elderly patients with LAPC derived from the Medicare/SEER database which
found an adjusted mean survival for patients who had undergone chemoradiotherapy of
47 weeks, vs. 29 weeks for those who had undergone radiation therapy alone
(Krzyzanowska etal. 2003). Selection bias may have contributed to these results as it
was not a randomized trial.
A recent systemic review (Huguet etal. 2009) concluded that chemoradiotherapy with
5-FU and radiotherapy to a total dose of 50 Gy increases survival and quality of life in
patients with LAPC compared with best supportive care (level of evidence C); that chemoradiotherapy increases overall survival compared with radiotherapy alone (level of evidence
B1); and that chemoradiotherapy is more toxic then radiotherapy (level of evidence A).
8 Unresectable Pancreatic Cancer
207
8.2.2
Different Chemoradiotherapy Protocols
8.2.2.1
Radiotherapy Protocols
Modifications of radiation dose and technique have been tested in an attempt to improve
the efficacy of chemoradiotherapy. A recent review concluded that the optimal dose of
radiotherapy is unclear, and the association between dose and local control and survival
has not been evaluated prospectively. The maximum tolerable dose of radiation depends
on the dose, schedule, and drug given concurrently. When radiation is given with 5-FU,
5054Gy is usually given in standard fractionation (over 56 weeks) (Huguet etal. 2009).
The volume irradiated is also important and older studies have included regional nodal
irradiation. As toxicity is related to the volume of normal tissues irradiated, there is movement towards a more involved field approach. When strong potent sensitizers are used
concurrently with radiation therapy (e.g., gemcitabine or targeted agents), smaller volume
irradiation is recommended (to include the gross primary and nodal targets without extensive elective nodal radiation therapy).
Original studies of radiation therapy used 2D radiation therapy. CT-based 3D conformal
therapy is now widely available and allows a reduced exposure to normal tissues. Other
modern radiation therapy techniques include intensitymodulated radiation therapy (IMRT)
where the fluence patterns of photons varies across each beam angle, allowing more flexibility regarding where dose is deposited (and sparing normal tissues).
Stereotactic body radiotherapy (SBRT), allows high-dose conformal radiation therapy
to be delivered to small volumes in far fewer fractions than standard radiation therapy.
Image guidance and breathing motion management need to be used with SBRT to ensure
that the doses are delivered to the tumor as planned. Studies of SBRT in LAPC (Hoyer
etal. 2005; Chang etal. 2009) have been disappointing with substantial toxicity and unimpressive median survivals. This is in part due to doses delivered to tumors involving or
directly adjacent to the duodenum (a common situation), causing an increase in duodenal
bleeding. Lower-dose SBRT may be an option for palliation of pancreatic cancer.
Intraoperative radiation (IORT) allows for the delivery of high-dose radiation directly
to areas of tumor and thus potentially may reduce side effects of the radiation. Results have
been inconclusive and at this time this technique is not routinely used outside of clinical
trials. (Ruano-Ravina 2008).
8.2.2.2
Chemotherapy Given Concurrently
Fluoropyrimidines, either bolus or infusional 5-FU, or more recently the oral agent capecitabine, have been the standard chemotherapy given with radiation therapy. Gemcitabine,
active in advanced pancreatic cancer, is a potent radiosensitizer even at lower doses.
Studies have demonstrated the feasibility of combining radiation with weekly or biweekly
gemcitabine with doses ranging from 40 to 1,000 mg/m2 (Blackstock et al. 2003).
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Asmallcomparative study by Li and colleagues compared gemcitabine (600mg/m2/week)

with 5-FU, both given concurrently with radiotherapy, and demonstrated a survival benefit
for the gemcitabine arm (14.5 vs. 6.7 months) although the confidence limits are wide due
to the small sample size (Li etal. 2003). Wilkowski etal. (2009) conducted a larger randomized phase II trial that revealed no difference in survival between chemoradiotherapy
with gemcitabine and cisplatin or 5-FU-based chemoradiotherapy.
In the absence of any phase III trials to compare gemcitabine or 5-FU-based chemoradiotherapy, a recent review concluded that 5-FU remains the reference chemotherapy to be
given in combination with radiotherapy in LAPC (level of evidence B1) (Huguet et al.
2009). There are data from several studies to support capecitabine as a potential replacement for infusional 5-FU, as a radiation sensitizer (Saif etal. 2005; Schneider etal. 2005).
An ongoing large phase III study comparing capecitabine-based chemoradiotherapy vs.
5-FU based chemoradiotherapy in rectal cancer will more clearly define the role of capecitabine in this setting (Hofheinz etal. 2009).
More intensive chemoradiotherapy strategies have been or are currently being explored.
The Eastern Cooperative Oncology Group (ECOG) performed a phase I/II trial of 5-FU,
gemcitabine (50100mg/m2/week), plus radiotherapy that closed early due to excess toxicity (Talamonti et al. 2000). The treatment volumes included elective regional nodes,
which contributed to the high toxicity observed. This study provides further support for the
use of smaller radiation fields when radiation therapy is used concurrently with gemcitabine or combination chemotherapy. This combination, but with lower radiation dose and
volumes (50.4 vs. 59.4Gy), was evaluated in a phase II study conducted by the Cancer and
Leukemia Group B (CALGB). There was acceptable toxicity and a median survival of
11.4 months (Mamon etal. 2005). The Radiation Therapy Oncology Group (RTOG) evaluated paclitaxel 50mg/m2/week with concurrent radiotherapy in 122 patients with LAPC.
There were seven clinically complete responses, 28 partial responses, and a median survival of 11.2 months (Rich etal. 2004).
8.2.3
Chemotherapy Alone
Several large studies have compared chemoradiotherapy to chemotherapy alone in LAPC
(Table8.1). Earlier studies found no difference in survival between 5-FU-based chemoradiotherapy and 5-FU-based chemotherapy alone (Hazel etal. 1981; Klaassen etal. 1985).
The gastrointestinal tumor study group (GITSG) compared chemotherapy with 5-FU,
streptomycin, and mitomycin vs. chemoradiotherapy with 5-FU followed by 5-FU, streptomycin, and mitomycin. The chemoradiotherapy arm had a trend towards improved
median survival (10.5 vs. 8 months) that did not reach statistical significance, and a statistically significant improvement in one-year survival (41 vs. 19%, p<0.02) (Gastrointestinal
Tumor Study Group 1988).
More recent studies have used gemcitabine as the chemotherapy platform for comparison
with chemoradiotherapy. Chauffert etal. (2000) conducted a randomized phase III trial comparing chemoradiotherapy with 5-FU and cisplatin followed by maintenance gemcitabine,
vs. gemcitabine alone. The patients who received gemcitabine alone had a significantly
209
Table 8.1 Selected trials comparing chemoradiotherapy vs. chemotherapy for locally advanced
unresectable pancreatic cancer
Reference
Treatment
Median survival
(months)
Hazel etal. (1981)
5-FU chemoradiotherapy
followed by Methyl CCNU vs. 5-FU and
Methyl CCNU
7.8 vs. 7.3 (p=NS)
Klaassen etal. (1985)
5-FU chemoradiotherapy vs. 5-FU alone
8.3 vs. 8.2 (p=NS)
Gastrointesinal tumor
study group (1988)
5-FU chemoradiotherapy
followed by streptozocin, mitomycin,
and 5-FU vs. streptozocin, mitomycin,
and 5-FU
10.5 vs. 8 (p=NS)
Chauffert etal. (2000)
5-FU and cisplatin chemoradiotherapy

followed by maintenance gemcitabine vs.
gemcitabine alone
8.6 vs. 13 (p=0.03)
Loehrer etal. (2008)
Gemcitabine chemoradiotherapy
followed by maintenance gemcitabine
vs. gemcitabine alone
11 vs. 9.2 (p=0.044)
longer overall survival than those receiving chemoradiotherapy (13 vs. 8.6 months). The
high dose of radiation therapy used (60Gy compared to more usual 54Gy), and the concurrent cisplatin led to increased toxicity and likely contributed to the poor outcome of the
chemoradiotherapy arm.
At the 2008 American Society of Clinical Oncology (ASCO) meeting, Loehrer etal.
(2008) presented the results of a phase III trial comparing chemoradiotherapy with gemcitabine followed by maintenance gemcitabine, vs. gemcitabine alone. This trial closed early
due to poor accrual, but results were reported on the 74 patients who were randomized.
The chemoradiotherapy arm had an improved overall survival compared with chemotherapy alone (11 vs. 9.2 months; p=0.044). Higher rates of grade 4 toxicity were observed
with chemoradiotherapy (41.2 vs. 5.7%).
A meta-analysis that included most of the aforementioned trials (but not Loehrers
study) concluded that there is no significant difference in overall survival between chemoradiotherapy vs. chemotherapy alone (Sultana 2007). A systematic review (Huguet etal.
2009) recently concluded that concurrent chemoradiotherapy is not superior to chemotherapy alone in terms of survival (level of evidence B1) and increases treatment-related
toxicity (level of evidence A).
Until recently, clinical trials evaluating systemic therapy for advanced pancreatic cancer included patients with both metastatic and locally advanced disease. This demonstrates
that many investigators consider systemic therapy alone an appropriate option. LAPC has
a better survival rate than metastatic disease and the results of a study can be influenced by
the proportion of patients with LAPC included; it has ranged from 10 to 40% in recent
trials. This practice has inhibited the study of LAPC as a unique subset of pancreatic cancer, and in the future, metastatic disease and LAPC will be studied separately by most
expert groups.
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8.2.4
Chemotherapy Followed by Chemoradiotherapy
A popular current approach to LAPC is induction chemotherapy followed by chemoradiotherapy. This strategy screens out those patients with rapidly growing systemic disease,
and allows selection of patients with true localized disease who may receive a greater
benefit from local control. Ko etal. (2007) treated 25 LAPC patients with induction chemotherapy with gemcitabine and cisplatin for six cycles, followed by capecitabine with
radiotherapy. They found a median survival of 13.5 months for all patients, and 17 months
for the 12 patients who completed the two phases of treatment.
Two retrospective studies evaluated induction chemotherapy followed by chemoradiotherapy, in LAPC. Krishnan et al. (2007) examined a regimen consisting of induction
chemotherapy with gemcitabine or gemcitabine and cisplatin, followed by gemcitabinebased chemoradiotherapy. Median overall survival was significantly longer in patients
who received chemotherapy followed by chemoradiotherapy. Huguet et al. (2007) also
retrospectively examined the efficacy of a regimen consisting of induction chemotherapy
followed by chemoradiotherapy and found that patients who received chemoradiotherapy
had a significant improvement in median progression-free survival (10.8 vs. 7.4 months),
and overall survival (15 vs. 11.7 months). These results have to be interpreted with caution
as these were not derived from randomized studies.
A systemic review concluded that induction chemotherapy before concurrent chemoradiotherapy improves survival in patients with LAPC (level of evidence C) (Huguet etal.
2009). This method also potentially spares patients with rapidly progressive disease from
potentially toxic radiotherapy, and may help to define which patients benefit from chemoradiotherapy. The Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) LAP07
phase III trial will test this therapeutic strategy. Patients with LAPC will initially receive
induction chemotherapy (gemcitabine vs. gemcitabine and erlotinib) for four cycles, and
those with a controlled tumor will be randomly assigned between two additional cycles of
chemotherapy vs. chemoradiotherapy (conformal radiation therapy with a total dose of
54Gy and concomitant capecitabine). At the end of this second phase patients who received
erlotinib during induction will continue erlotinib as maintenance treatment until progression.
The GERCOR study highlights much of the uncertainty that exists about the optimal management of locally advanced disease in 2010. These include fundamental questions such as
whether local therapy has any role, what the optimal timing would be, and the role of maintenance therapy. As trials move toward exclusively being performed in the locally advanced
population, these issues should be answered, and therapy will become better defined.
8.2.5
Targeted Therapy
A number of the newer targeted agents can function as radiosensitizers. Epidermal
growth factor receptor (EGFR) tyrosine kinase inhibitors have activity in advanced pancreatic cancer (Sect.8.2.5). There is preclinical evidence that inhibiting EGFR may sensitize
tumor cells to ionizing radiation, through increasing the proportion of cells in the G1 phase
211
of the cell cycle (Huang and Harari 2000), restoration of apoptosis (Ciardiello etal. 2001;
Baumann etal. 2007), or potentially antiangiogenic mechanisms (Baumann etal. 2007).
There is also clinical data from the head and neck literature that combining EGFR inhibitors with radiation improves outcomes vs. radiotherapy alone (Bonner etal. 2006).
The EGFR tyrosine kinase inhibitor gefinitib given in combination with chemoradiotherapy was found to be associated with significant toxicity and minimal efficacy (Czito
etal. 2006; Maurel etal. 2006). Toxicity was also seen when the anti-EGFR monoclonal
antibody cetuximab was given with IMRT and gemcitabine, but there was also promising
efficacy, with one study finding a rate of complete plus partial response of 35.5% (Munter
etal. 2008).
A phase II study tested escalating doses of erlotinib with gemcitabine, paclitaxel, and
radiation followed by maintenance erlotinib in locally advanced and margin positive
patients (Iannitti et al. 2005). In this study the partial response rate was 46% and the
median survival was 14 months. Another study, performed by Duffy and colleagues,
assessed escalating doses of erlotinib with radiation and biweekly gemcitabine, followed
by weekly maintenance gemcitabine and erlotinib (Duffy etal. 2008). The results of this
study were also encouraging, with 53% of patients having stable disease, 35% having
partial responses, and a median survival of 18.7 months emerging.
The incorporation of targeted agents into current chemoradiotherapy protocols is an
area that requires more study. Whether these efforts should be restricted to agents that have
established activity in advanced disease is unknown. One critical aspect of these trials will
be correlative studies to define molecular predictive and prognostic markers (Chang and
Saif 2009).
8.2.6
Summary and Future Directions
Despite close to 10,000 patients in North America a year presenting with LAPC limited progress has been made, and clinical trial activity lags behind what is ongoing in metastatic disease. One may conclude, however, that chemoradiotherapy is superior to radiotherapy alone
and that fluoropyrimidines combined with radiation therapy represent a reasonable current
standard for chemoradiotherapy, but not that chemoradiotherapy clearly adds to what can be
achieved using chemotherapy alone. A reasonable approach would be to start with chemotherapy alone for 26 months and proceed to chemoradiotherapy in patients without progressive disease. This selects patients who have a higher likelihood of benefit from local therapy.
As discussed previously, at this time there is a move toward separating patients with
locally advanced disease from those with metastatic disease for ongoing clinical trials (traditionally these were grouped together). If chemoradiotherapy is not shown to have incremental benefit in the GERCOR study, then the current approach of separating LAPC and
metastatic disease could stop and both could be combined in studies of systemic therapies.
If chemoradiotherapy has benefits, then the challenge will be how to develop and evaluate new protocols, particularly those incorporating targeted agents. At present there is no
agreed-upon methodology for doing this, and the heterogeneity of this population limits
the conclusions that can be drawn from phase II studies.
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8.3
Metastatic Pancreatic Cancer
8.3.1
Chemotherapy
Many cytotoxic agents have been studied in advanced pancreatic cancer (Table8.2). Early
studies used response as a primary endpoint, although this is unreliable and few drugs were
able to reproducibly demonstrate meaningful rates of tumor response. Fluorouracil (5-FU)
was considered the best of these drugs (Glimelius etal. 1996; Palmer etal. 1994; Mallinson
etal. 1980; Crown etal. 1991) and many subsequent studies evaluated 5-FU combinations.
Until gemcitabine was approved, no drug or combination had clearly demonstrated an
improvement in survival or quality of life in advanced disease over 5-FU alone. In 1997
the results of a landmark trial in 126 patients comparing gemcitabine with 5-FU were
reported (Burris etal. 1997). Both drugs were given weekly and the gemcitabine arm had
an improvement in clinical benefit (a composite of measurements of pain, analgesic usage,
Table 8.2 Selected trials comparing chemotherapy regimens for unresectable and metastatic
pancreatic cancer
Reference
Treatment
Burris etal. (1997)
Gemcitabine vs. 5-FU
5.7 vs. 4.4 (p=0.0025)
Poplin etal. (2009)
Gemcitabine vs. gemcitabine

FDR vs. gemcitabine and
oxaliplatin
4.8 vs 6.2 (p=0.04)

vs. 5.7 (p=0.22)
Heinemann etal. (2006)

and cisplatin
6 vs. 7.5 (p=NS)
Colucci etal. (2009)

and cisplatin
8.3 vs. 7.2 (p=NS)
Louvet etal. (2002)

and oxaliplatin
7.1 vs. 9 (p=NS)
Herrmann etal. (2007)

and capecitabine
7.2 vs. 8.4 (p=NS)
Cunningham etal. (2009)

and capecitabine
6.2 vs. 7.1 (p=NS)
Rocha Lima etal. (2004)

and irinotecan
6.3 vs. 6.6 (p=NS)
Stathopoulous etal. (2004)

and irinotecan
6.4 vs. 6.5 (p=NS)
Oettle etal. (2005)

and pemetrexed
6.3 vs. 6.2 (p=NS)
OReilly etal. (2004)

and exatecan
6.2 vs. 6.7 (p=NS)
213
and performance status), and survival when compared with 5-FU. The response rate to
gemcitabine was less than 10%, there was an overall disease control rate (PR+SD) of 45
vs. 19% with 5-FU, the time to progression doubled from 1.9 to 3.8 months, the median
survival increased from 4.4 to 5.7 months, and the one-year survival improved from 2 to
18% (p<0.002). While clinical benefit was the primary endpoint, it was the improvement
in one-year survival that was most impressive and led to the approval of gemcitabine as
first-line treatment of metastatic pancreatic cancer in many jurisdictions. Gemcitabine has
since been regarded as the standard backbone of systemic therapy for pancreatic cancer.
Subsequent trials focused on modulation of gemcitabine, and on combinations of gemcitabine with various cytotoxic or targeted agents. The standard dose of gemcitabine is
1,000 mg/m2 given over 30 min at an infusion rate of 33 mg/m2/min. Gemcitabine is
metabolized intracellularly to its active metabolite (dFdCTP), a rate limited process saturated at infusion rates of 10mg/m2/min. Gemcitabine by fixed dose rate infusion (FDR)
involved giving gemcitabine at 10mg/m2/min for 150180min to increase intracellular
levels of the active metabolite (Hochster 2003). Pharmacological studies demonstrated
that the FDR dosing strategy did increase intracellular dFdCTP. Initial studies showed
greater toxicity but also suggested a greater efficacy when compared to the standard 30-min
infusion (Touroutoglou et al. 1998; Tempero and Plunkett 2003). However, when FDR
gemcitabine was evaluated in a large phase III study it did not meaningfully improve survival compared to standard-dose gemcitabine and its use has been largely abandoned
(Poplin etal. 2009).
Numerous phase II and III trials have evaluated cytotoxic agents in combination with
gemcitabine. The most commonly evaluated agents were fluoropyrimidines and the platins
(cisplatin and oxaliplatin). The results have been generally disappointing. Several phase II
studies of gemcitabine plus cisplatin showed early promise (Brodowicz et al. 2000;
Heinemann etal. 2000; Philip etal. 2001; Cascinu etal. 2003). Two underpowered phase
III trials of gemcitabinecisplatin demonstrated higher response rates and a trend towards
an improvement in survival with the combination arm and a meta-analysis suggested benefit in the good performance status population (Heinemann etal. 2006, 2007; Colucci etal.
2002). However, in 2009, Colucci and colleagues presented results from a randomized
phase III trial comparing gemcitabinecisplatin in over 450 patients (Colucci etal. 2009).
There was no improvement in overall or progression-free survival for all patients, and even
in the good performance status subset, no improvements were seen. Quality of life was
somewhat worse on the gemcitabine-cisplatin arm.
A phase II study of gemcitabine with oxaliplatin reported a response rate of 30.6% and
a promising median survival of 9.2 months (Alberts etal. 2003; Louvet etal. 2002). The
survival results were probably influenced by the high proportion of patients with locally
advanced disease included in the study. This led to two randomized trials to evaluate the
addition of oxaliplatin to gemcitabine (Poplin etal. 2006; Louvet etal. 2005). Louvet and
colleagues demonstrated a nonsignificant trend for an improvement in the median survival
in a study of over 300 patients that did not reach statistical significance (Klaassen etal.
1985). A larger study conducted by ECOG compared standard gemcitabine to FDR gemcitabine and to FDR gemcitabine plus oxaliplatin in over 800 patients (Blackstock etal.
2003). Neither FDR gemcitabine nor gemcitabine+oxaliplatin improved overall survival
beyond that achieved with gemcitabine alone. One potential problem with the combination
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D. Renouf et al.
of gemcitabine+oxaliplatin is the overlapping myelotoxicity, which often leads to a reduction in dose for both drugs.
For the fluoropyrimidines, all studies using intravenous 5-FU with gemcitabine have
been negative. One combination that showed initial promise was capecitabine and gemcitabine. In 2003, Hess and colleagues reported the results of a phase I/II study demonstrating
that this combination is tolerable and has promising activity (Hess etal. 2003). Scheithauer
etal. (2003) also reported on a randomized phase II study that showed this combination to
be well tolerated, and found a trend towards improved survival benefit. This stimulated the
conduct of two large phase III randomized controlled trials comparing gemcitabine alone
with gemcitabine in combination with capecitabine (Cunningham 2005; Herrmann etal.
2007; Cunningham etal. 2009). The first study published by Hermann and colleagues did
not meet its primary endpoint of an overall improvement in survival but reported a trend
towards better survival, especially in patients with good performance status (Herrmann
etal. 2007). The second study used a higher dose of capecitabine and was initially presented as a positive study by Cunningham and colleagues at the European Cancer
Conference in 2005. At the final analysis and reporting, the trial was no longer positive for
survival (7.4 vs. 6 months with gemcitabine alone: HR 0.86 (0.721.02), p=0.08)
(Cunningham etal. 2009). A meta-analysis combining data from the two phase III studies
and the prior phase II data did demonstrate a modest survival benefit over gemcitabine
alone (hazard ratio of 0.86 (0.750.98), p=0.02).
Numerous other cytotoxic agents (Rocha Lima etal. 2004; Oettle etal. 2005; OReilly
et al. 2004; Shepard et al. 2004; Stathopoulos et al. 2006) including irinotecan, pemetrexed, exatecan, and docetaxel have not shown benefit when combined with gemcitabine.
A Cochrane meta-analysis of studies in advanced pancreatic cancer did not find a significant difference in one-year survival between gemcitabine combinations and gemcitabine
alone. It is reasonable to conclude that single-agent gemcitabine is equivalent to combination chemotherapy and remains a standard of care in clinical trials. There may be benefit
from combination therapy in selected patients, but the characteristics of this population
have not been determined. If benefit can only be shown in meta-analyses done on thousands of patients, then the absolute benefits of combination therapy are quite small and
probably not justifiable given the incremental toxicity of combination chemotherapy.
8.3.2
Targeted Therapy
A better understanding of the biology of pancreatic cancer has led to the identification of
pathways that are potential targets for drug therapy. There is now a wealth of preclinical
data demonstrating growth inhibition by drugs that inhibit these targets. The majority of
early phase trials in pancreatic cancer now evaluate these targeted therapies either alone or
in combination with traditional cytotoxic agents, and there have been numerous phase II
and phase III trials examining the efficacy of targeted agents in metastatic pancreatic cancer (Table8.3).
The EGFR pathway is important in pancreatic tumorigenesis and preclinical data suggest that it may be activated in patients with pancreatic cancer. Anti-EGFR agents have
215
Table 8.3 Selected trials comparing chemotherapy vs. biological therapychemotherapy for
unresectable and metastatic pancreatic cancer
Reference
Treatment
Median survival
(months)
Moore etal. (2003)

and erlotinib
5.9 vs. 6.2 (p=0.038)
Philip etal. (2007)

and cetuximab
6 vs. 6.5 (p=NS)
Cascinu etal. (2008)
Gemcitabine and cisplatin

vs. gemcitabine, cisplatin,
and cetuximab
7.5 vs. 78 (p=NS)
Kindler etal. (2008)

and bevacizumab
5.7 vs. 6 (p=NS)
Kindler etal. (2008)
Gemcitabine, bevacizumab
and erlotinib vs. gemcitabine,
bevacizumab, and cetuximab
7.2 vs. 7.8 (p=NS)
Van Cutsem etal. (2004)
Gemcitabine and erlotinib vs.

gemcitabine, erlotinib and
bevacizumab
6 vs. 7.1 (p=NS)
Van Cutsem etal. (2004)

and tipifarnib
6.1 vs. 6.4 (p=NS)
Bramhall etal. (2002)

and marimastat
5.5 vs. 5.5 (p=NS)
Moore etal. (2003)
Gemcitabine vs. BAY 12-9566
6.7 vs. 3.7 (p<0.001)
been successfully used in the treatment of colon and lung cancer (Jonker etal. 2007; Van
Cutsem etal. 2007a; Shepherd 2005). The NCIC.PA.3 trial compared the EGFR tyrosine
kinase inhibitor erlotinib plus gemcitabine vs. gemcitabine alone (Moore etal. 2007). Five
hundred and sixty-nine patients were randomized and while median survival in the erlotinib-gemcitabine arm was modestly improved (6.24 vs. 5.91 months with gemcitabine
alone) the overall survival (HR 0.82, p=0.038) (Fig.8.1), and the one-year survival, which
improved from 17 to 23% (p=0.023) were significantly better. The major toxicities were
an increase in the incidence of grade 3 and 4 skin rashes (6 vs. 1%) and diarrhea (6 vs. 2%).
The incidence of interstitial lung disease was 2%. Progression-free survival was longer in
the erlotinib arm (HR 0.77, p=0.004) and the disease control rate (response rate+stable
disease) increased from 49 to 59%.
The presence of EGFR expression in tumor specimens did not predict for a benefit from
erlotinib, but the patients who experienced a grade 2 or greater skin rash had a median
survival of 10.3 months and a one-year survival of 43%. A molecular analysis of KRAS
mutation status and EGFR expression using fluorescent in situ hybridization (FISH) was
conducted in a subset of patients who had specimens available. The hazard ratio for gemcitabine+erlotinib in the 21% of patients who had wild type KRAS was 0.66 as compared
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D. Renouf et al.
Fig. 8.1Overall survival-Gemcitabine vs Gemcitabine + Erlotinib in advanced pancreatic cancer
to 1.07 in the KRAS mutants. This is consistent with data in colorectal cancer where EGFR
inhibitors have no effect in the presence of a KRAS mutation. The relationship suggested
between rash and activity of EGFR inhibitors in pancreatic cancer (Moore et al. 2007;
Xiong etal. 2004), and also in other cancers treated with EGFR inhibitors is being further
explored (Van Cutsem etal. 2007b). Smoking status may also play a role in metabolism of
these drugs, as Hughes and colleagues demonstrated that maximum tolerated dose for
erlotinib is higher in smokers than nonsmokers, possibly due to induction of the
CYP1A1/1A2 enzymes involved in erlotinib metabolism (Hughes etal. 2009). The concept of erlotinib dose escalation to rash is being tested in the ongoing first-line RACHEL
study (comparing dose-escalated erlotinib (to rash) in combination with gemcitabine vs.
standard dose erlotinib with gemcitabine).
Cetuximab, a monoclonal antibody to EGFR, was studied in combination with gemcitabine in a phase II study in patients whose tumors had immunohistochemical evidence of
EGFR expression (Xiong et al. 2004). The disease control rate was 76% (12% partial
response and 64% disease stabilization) with a median overall survival of 7.1 months and
a one-year survival of 32%. Cascinu et al. (2008) evaluated gemcitabine and cisplatincetuximab in a phase II study. There were no significant differences noted in response
rate, progression-free survival, or median overall survival (7.5 vs. 7.8 months). A randomized phase III trial compared gemicitabinecetuximab in 735 patients with advanced pancreatic cancer. The addition of cetuximab did not significantly improve objective response
rate, progression-free survival, or overall survival (Philp etal. 2007).
Pancreatic cancer is not a vascular tumor but as with other solid tumors such as colorectal
and lung cancers, a number of trials targeting the vascular endothelial growth factor (VEGF)
pathway were undertaken (Hurwitz etal. 2004; Sandler etal. 2006). The final results have
been universally negative and some excess toxicity was seen. A phase II study of bevacizumab, a monoclonal antibody against VEGF, plus gemcitabine as first-line therapy in 52
217
advanced pancreatic cancer patients at the University of Chicago looked promising with
21% with partial response, 46% with stable disease, a median progression-free survival
of 5.4 months and a median survival of 8.8 months (Kindler etal. 2005). The CALGB then
conducted a randomized phase III study comparing bevacizumab and gemcitabine to gemcitabine alone. Six hundred and two patients were enrolled, and based on a protocol-specified interim analysis the study data were released because a futility boundary was crossed
(Kindler etal. 2007). The results revealed no benefit of the addition of bevacizumab to gemcitabine. The promising phase II data was likely due to a high percentage of ECOG performance status 0 and 1 patients being included, plus other exclusion criteria that then selected
out a population of patients with a more favorable biology.
A randomized phase II study of gemcitabineaxitinib (an orally active selective inhibitor of VEGF 1, 2, and 3) did show a trend favoring the combination (Spano etal. 2008),
and a randomized phase III trial was conducted. In early 2009 it was announced that this
trial had also crossed a futility boundary and was negative. Aflibercept or VEGF-trap is a
soluble VGF receptor and acts as a potent antiangiogenic agent. A phase III study of gemcitabineaflibercept was also recently announced to be negative.
Given the molecular complexity of pancreatic cancer, there is strong rationale for combining targeted agents to achieve greater efficacy. Kindler and colleagues recently presented the results of a phase II study examining the efficacy of gemcitabine, bevacizumab,
and erlotinib vs. gemcitabine, bevacizumab, and cetuximab (Kindler et al. 2008). The
median survival was 7.2 months in the erlotinib arm and 7.8 months in the cetuximab arm.
The AVITA study was a large randomized phase III trial exploring the efficacy of adding
bevacizumab to gemcitabine and erlotinib (Van Cutsem et al. 2009). Six hundred and
seven patients with previously untreated metastatic pancreatic cancer were randomly
assigned to gemcitabine and erlotinib and either bevacizumab or placebo. While the addition of bevacizumab to gemcitabine/erlotinib improved Progression-Free Survival (PFS)
(4.6 vs. 3.6 months), there was no improvement in overall survival. Further studies of
antivascular therapy do not seem justified at this point.
Other targeted therapies with biological rationale and preclinical activity that have been
inactive in human testing include the mTOR inhibitor RAD001 (everolimus) (Wolpin etal.
2009), the NF-kB inhibitor curcumin (Dhillon etal. 2008), the farnesyltransferase inhibitor tipifarnib (Van Cutsem etal. 2004), and the matrix metalloproteinase inhibitors marimastat (Bramhall etal. 2002) and BAY 12-9566 (Moore etal. 2003).
8.3.3
Second-Line Therapy
Once patients have progressed after gemcitabine-based chemotherapy, there is minimal
evidence to suggest a benefit from further systemic therapy. Additionally, many patients
will not be of adequate performance status to receive further therapy. A small randomized study with a combination of 5-FU and oxaliplatin demonstrated a modest survival
benefit from treatment and further studies of this combination are under way (Pelzer
et al. 2008). Small studies have also suggested that single-agent erlotinib may have
218
D. Renouf et al.
modest activity in this setting, and the results of correlative studies to define the molecular features of those who achieve disease control are awaited (Kulke etal. 2007; Tang
etal. 2009). Kulke and colleagues demonstrated a response rate of 10%, and a median
survival of 6.5 months in a phase II study of erlotinib and capecitabine in 30 patients.
Paradoxically, the survival in second-line studies was comparable to or greater than that
seen in first line, likely due to selection of a better group of patients who maintain a
decent performance status despite failing first-line therapy. Patients with adequate performance status who have progressed after first-line therapy should certainly be considered for clinical trials.
8.3.4
Summary and Future Directions
Despite a high level of clinical trial activity over the past decade, effective therapies for
advanced metastatic pancreatic cancer remain elusive. Almost all the phase III studies
conducted were negative, suggesting that better clinical trial methodologies and criteria for
the phase II/III transition are required. Standard options for first-line treatment include
gemcitabine alone, or gemcitabine combined with erlotinib. 5-FU with oxaliplatin demonstrated a survival benefit in one study in the second-line setting. Patients with reasonable
performance status should be enrolled onto clinical trials if feasible.
While it has been a discouraging decade for new therapeutics development in pancreatic cancer, there is cause for some optimism. A greater understanding of the genetic
complexity and heterogeneity of the disease is emerging. The International Genome
Sequencing Consortium will characterize the entire genome of 500 human pancreatic
cancers and create xenografts for preclinical testing of new therapies. This will be an
invaluable resource to better understand the development and progression of this disease.
Jones and colleagues from Johns Hopkins sequenced over 20,000 protein coding genes in
24 pancreatic cancers (Jones etal. 2008). The average number of genetic mutations was
63 and while there was marked heterogeneity in the pathways affected and the mutations
in those pathways, they were clustered into abnormalities in 12 core signaling pathways.
These were apoptosis, K-ras signaling, DNA damage control, hedgehog signaling, regulation of G1/S transition, integrin signaling, homophilic cell adhesion, JNK signaling,
regulation of invasion, TGF-b signaling, Wnt/Notch signaling and non K-ras GTPase
dependent signaling. The pathways are important clues to unlocking the mystery of pancreatic cancer and drugs targeting most of these key pathways are now coming into phase
I and II testing. The clinical trials need to be linked to the genetics and biology of pancreatic cancer. Tissue collection to define predictive markers needs to be included in these
studies as has been done with EGFR inhibitors in colorectal cancer (Jones etal. 2008;
Lynch et al. 2004; Karapetis et al. 2008; Peeters et al. 2009). This will provide better
therapeutic and economic efficiency (Van Cutsem etal. 2007c). Given the genetic complexity, it seems likely that effective control of pancreatic cancer will require combinations of targeted agents and a personalized approach to treatment based on the individual
genotype and phenotype.
219
8.4
Summary
Pancreatic cancer is a common and deadly disease. Most patients present with unresectable locally advanced or metastatic disease and the median survival is 69 months. For
LAPC, standard approaches include gemcitabine-based chemotherapy alone or in combination with 5-FU-based chemoradiotherapy. Treatments under investigation include induction chemotherapy followed by chemoradiotherapy, and the use of biological therapy with
radiotherapy in locally advanced disease. For metastatic pancreatic cancer the standard
treatments include systemic therapy with gemcitabine or gemcitabine combined with the
EGFR tyrosine kinase inhibitor erlotinib. Ongoing and future trials are assessing novel
targeted agents alone or in combination.
There have been significant advances in the understanding of pancreatic cancer biology
but these are yet to translate to better therapies at the bedside. Important areas of future
research will include attempts to better understand the link between tumor biology and the
clinical course of the disease, and to develop clinical and molecular predictive models that
better define therapy for the individual patient.
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Van Cutsem E, van de Velde H, Karasek P etal (2004) Phase III trial of gemcitabine plus tipifarnib
compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol
22:14301438
Van Cutsem E, Peeters M, Siena S etal (2007a) Open-label phase III trial of panitumumab plus
best supportive care compared with best supportive care alone in patients with chemotherapyrefractory metastatic colorectal cancer. J Clin Oncol 25:16581664
Van Cutsem E, Humblet Y, Gelderblom H etal (2007) Cetuximab dose-escalation study in patients
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Van Cutsem E, Vervenne WL, Bennouna J etal (2009) Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol
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Wilkowski R, Boeck S, Ostermaier S et al (2009) Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs
chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic
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gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol 27:193198
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Yip D, Karapetis C, Strickland A et al (2006) Chemotherapy and radiotherapy for inoperable
advanced pancreatic cancer. Cochrane Database Syst Rev 3:CD002093
Liver Cancer
Joseph D. Thomas, George A. Poultsides,

Timothy M. Pawlick, and Melanie B. Thomas
9.1
Introduction
The most common primary malignancy of the liver in adults is hepatocellular carcinoma
(HCC). It is currently the fifth most common solid tumor worldwide, and the third leading
cause of cancer-related death (Jemal etal. 2005). HCC is a particularly lethal disease, as
evidenced by roughly equal annual incidence and mortality rates (Jemal etal. 2004). A
majority of HCC patients have underlying cirrhosis and hepatic dysfunction, which significantly complicates patient care. HCC is a highly heterogeneous malignancy and due to this
prevalence of cirrhosis, HCC patients present the challenges of one patient with two diseases. Multidisciplinary management of HCC patients is critical to safely and effectively
optimizing the available treatment options for HCC patients. Encouraging progress has
been made in several aspects of HCC management, such as improved treatment of viral
hepatitis, increased screening of patients at high-risk for developing HCC, improved
patient selection for liver transplantation and surgical resection, and approval of the oral
anti-cancer agent sorafenib for treatment of advanced HCC.
9.2
Epidemiology and Risk Factors
The prevalence of HCC varies greatly depending on geographic location, but 80% of
new HCC cases occur in developing countries, principally in Eastern Asia and SubSaharan Africa (Bosch et al. 2004). The incidence of HCC is rising in economically
developed regions, including Japan, Western Europe, and the United States. In the United
J.D. Thomas, G.A. Poultsides, T.M. Pawlick, and M.B. Thomas (*)
Hollings Cancer Center, A National Cancer Institute Designated Cancer Center, Medical
University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
e-mail: thomasmb@musc.edu
225
226
J.D. Thomas et al.
States, an estimated 22,620 new cases of primary liver cancer are expected in 2009
(El-Serag 2002). This incidence is predicted to rise significantly in ensuing years due to
the estimated 4,000,000 hepatitis-C virus exposed individuals in the U.S (El-Serag and
Rudolph 2007; NIH 2002).
In addition to variations in HCC by geographical location, the incidence of HCC has
been shown to differ based on age, gender, and race. Men are typically affected two to
three times as often as women, Asians are affected twice as often as African Americans,
and Caucasians are affected two to three times less than African Americans. There has also
been a recent shift in incidence off HCC from the elderly population to younger patients.
The mean age of patients diagnosed with HCC in the US is 65, with the peak incidence
between 70 and 75 years (El-Serag 2002). However, recent trends show the greatest
increase in incidence has now shifted to men between the ages of 40 and 60.
The primary risk factor for HCC is hepatic cirrhosis, but a moderate number of
patients develop HCC in the absence of cirrhosis. HCC is most commonly associated
with chronic viral hepatitis (HBV and HCV). Worldwide, the hepatitis B virus is the
most frequent underlying cause of HCC, and case control studies have estimated that
chronic HBV carriers were at a 515 times increase risk of and it has been estimated that
the risk of HCC could be increased up to 17 times in an HCV infected patient (Chu and
Liaw 2006). Other diseases that result in liver cell injury and lead to fibrosis also increase
the risk of HCC. HCC has been demonstrated in alpha 1 antitrypsin deficiency, hereditary tyrosinemia, Wilsons disease, and Primary Biliary Cirrhosis, each with variable
risk. Hemochromatosis is a significant risk factor for HCC with an increased relative
risk of 200 times that of the normal population. Other risk factors identified include
nonalcoholic fatty liver disease, excessive alcohol consumption, and environmental toxins such as aflatoxin B1 a carcinogenic mycotoxin ubiquitous to contaminated food in
the developing world. The combination of insulin resistance, hypertension, and hypercholesterolemia, termed metabolic syndrome, along with diabetes, obesity, steroid
abuse, and long-term use of estrogen-containing drugs have been identified as risk factors as well (Smedile and Bugianesi 2005; Oh etal. 2005; El-Serag etal. 2006; Nissen
and Martin 2002).
9.3
Clinical Presentation
The clinical presentation of HCC varies greatly depending on both time of diagnosis, as
well as geographical region of the world (Bialecki and Di Bisceglie 2002, 2005). In developed countries such as the US, HCC is rare before age 40, and is usually found as a part of
routine screening tests of high-risk individuals, or as a result of hepatic decompensation
and clinical deterioration. However, in high risk areas such as Africa, patients often present with large painful masses in their early 20s and 30s.
Several studies have acknowledged a difference in presentation, depending on whether
the HCC presents in the setting of cirrhosis. Cirrhotic patients often present with hepatic
decompensation, which leads to ascites, encephalopathy, jaundice, and variceal bleeding.
9 Liver Cancer
227
Noncirrhotic patients are more likely to present with more constitutional symptoms such
as weight loss, anorexia, or malaise. Abdominal pain is the most frequent complaint of
both noncirrhotic and cirrhotic patients, while cirrhotic patients are more likely to have
hepatomegaly on physical exam, and noncirrhotics are more likely to have abdominal
distension. Other symptoms at time of presentation include paraneoplastic syndromes,
hypoglycemia, diarrhea, nausea or vomiting, painless jaundice secondary to obstruction,
cholangitis, fever, and in rare cases peritonitis from tumor rupture. Other patients are relatively asymptomatic, and they are diagnosed as a result of a screening test or radiological
exam for another condition.
9.4
Liver Disease and HCC
A majority of HCC (6080%) arise in a background of chronic hepatitis and cirrhosis,
which is characterized by inflammatory cell infiltration, hepatocyte regeneration, necrosis,
and parenchymal remodeling. Liver injury triggers activation of hepatic stellate cells
(SCs), which are resting fibroblasts and a major storage site in the liver for retinoids and
extracellular matrix. SC activation results in release of chemotactic cytokines, inflammatory cell recruitment and infiltration, growth factor upregulation, and release of proteases.
Residual hepatocytes are stimulated to proliferate, and eventually, there is remodeling of
the hepatic sinusoids and subdivision of liver parenchyma by fibrous septae, resulting in
cirrhosis (Hino etal. 2002).
Cirrhosis can have a profound impact on tolerance and efficacy of anticancer drug therapy. The liver is central to the metabolism of virtually every foreign and endogenous substance in the body. Hepatic metabolism involves oxidative pathways, primarily via the
CYP450 enzyme system, and additional metabolic steps, which include conjugation to a
glucuronide, a sulfate, or glutathione. In cirrhosis, the total liver cell mass is reduced and
distortion of the microcirculation of the liver and collagen deposition leads to impaired
sinusoidal transport and reduced extraction of protein-bound substances. Hepatic cirrhosis
not only decreases drug metabolizing enzyme activity, but it also alters the absorption,
plasma protein binding, distribution, and renal excretion of drugs. Intrahepatic vascular
shunts that develop as a consequence of cirrhosis, allow drugs to be routed around hepatocytes, thus decreasing their first-pass extraction. However, all routes of hepatic metabolism
are not equally impaired. As hepatic dysfunction progresses in cirrhotic patients, reduced
synthesis of albumin occurs that leads to a decrease in plasma protein binding of drugs. For
drugs that are more than 90% protein-bound, this increase in the free drug fraction may be
substantial and may have clinical consequences. The CYP3A4 subfamily, the most common
hepatic enzyme in adult humans, oxidizes over 50% of currently used drugs. Several studies
have shown significant decreases in the CYP3A protein levels in patients with cirrhosis,
although contradictory data does exist. Therefore, it is difficult to predict the disposition of
a drug in liver disease, and each agent must be studied individually to provide a rationale
for adjusting doses (Elbekai etal. 2004).
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J.D. Thomas et al.
9.5
With the varying clinical presentations of HCC, several imaging modalities can assist in the
diagnosis of HCC. Ultrasound and serum alpha-fetoprotein (AFP) levels are most often
used as screening tests in high risk individuals, while imaging studies such as computed
tomography (CT) scan and MRI have become the diagnostic procedures of choice (Befeler
and Di Bisceglie 2002). The development of tri-phasic CT scanning and improved MRI
equipment has led to greater sensitivity and specificity in diagnosis and many patients are
now being diagnosed at an asymptomatic stage. Core biopsy of the liver is also used as a
histological means to confirm the diagnosis, but is not being performed as routinely as it was
in the past because of the increasing availability of advanced radiological techniques.
9.6
Alpha Fetoprotein
Serum AFP is most commonly used as a screening test; however it has been shown to have a
poor positive predictive value, as well as a low sensitivity and specificity (Gambarin-Gelwan
etal. 2000; Nakamura etal. 2006). AFP levels can be normal in up to 30% of patients at time
of diagnosis. Serum AFP levels of 400500 mg/mL are considered diagnostic for HCC,
although elevations of AFP can also be seen in other diseases such as germ cell tumors, gastric
cancer, lung cancer, as well as chronic inflammatory states such as viral hepatitis. Several
studies have demonstrated that significantly elevated levels of AFP related to HCC correlate
with tumor size, aggressiveness, and a worsening prognosis with a lower median survival rate.
AFP can also be useful as a way to monitor tumor progression, the response to treatment, or
detecting the recurrence of disease. AFP has a short half-life and the level will change within
a few days after proliferation, removal or destruction of tumor cells (Sassa etal. 1999).
9.6.1
Ultrasound
Ultrasound of the abdomen is a noninvasive, safe imaging modality that is commonly used
for screening individuals at risk for developing HCC, due to its relatively high sensitivity
to detect very small intrahepatic lesions (Liao etal. 2008). Abdominal US with the addition of Doppler are frequently used for the assessment of vascular invasion of HCC, and
can differentiate tumor invasion into the portal vein from a bland or non-tumor thrombus.
US also can visualize the biliary structures, ductal dilatation, as well as detect hilar adenopathy, which is helpful in the staging process. The role of US in diagnosis of HCC is
limited however, because of the improvement and wide availability of CT and MRI, as
well as a low sensitivity and predictive value of US in the setting of cirrhosis. US is an
imaging option for patients in whom iodinated contrast media is contraindicated.
9 Liver Cancer
229
9.6.2
MRI
The use of MRI in the diagnosis of HCC has increased substantially with the development
and improvement of MRI scanners, software, and techniques. For some physicians, MRI
has become the preferred diagnostic procedure because of its ability to detect and characterize hepatic lesions. Gadolinium enhancement of HCC during various stages of hepatic
circulation, help improve characterization of HCC, and because of its ability to detect
vascular invasion, it is the best tool to differentiate HCC from hepatic hemangioma (Secil
etal. 2008). MRI sensitivity is lowest when evaluating small tumors less than 2cm, but
overall it is more accurate than CT or US in detecting HCC and estimating actual tumor
size. It is also more effective than CT in detecting HCC in patients with cirrhosis.
9.6.3
CT
In addition to MRI, CT scanning is another advanced imaging technique used for the diagnosis and staging of HCC. Evaluation for HCC has improved greatly with the use of spiral
CT scanners and advanced imaging protocols. Spiral scanners allow for very rapid imaging of the liver, while the use of triphasic imaging provides images during three different
phases of contrast administration. HCC is typically supplied with blood from the hepatic
artery while the surrounding liver parenchyma receives both arterial and portal venous
blood. Therefore, triphasic CT scanning is able to differentiate tumor cells from normal
tissue utilizing images before contrast, during the arterial phase, as well as the portal
venous phase. HCC is a hypervascular tissue and tends to enhance during the first 240s
of contrast administration, or the arterial phase, while the liver parenchyma enhances most
notably at 5090s after contrast administration, or during the portal venous phase. HCC
frequently can be found with satellite nodules surrounding the primary lesion, and typically appears heterogeneous on CT, secondary to the fibrotic and/or necrotic characteristics of the tumor tissue (Shinmura etal. 2008; Kitamura etal. 2008).
9.6.4
Liver Biopsy
Liver biopsy is still the gold standard when diagnosing HCC, as histological examination is the
only true way to confirm the diagnosis. It is superior to any other diagnostic test in sensitivity
and specificity, and is a safe, efficient, and an effective confirmatory test. A fine needle aspiration biopsy is performed most frequently with CT or US guidance, but depending on the circumstances, an open surgical biopsy can also be performed. Recently, liver biopsy has become
somewhat controversial because of case reports of HCC being spread along biopsy needle
tracks. These case reports are rare, but with the increasing availability of CT and MRI, some
specialists argue that when patients can potentially be cured by liver transplantation or resection, biopsy is unnecessary after a thorough radiological, clinical, and laboratory evaluation.
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9.7
Staging and Prognostic Systems in HCC
HCC staging is an important prognostic tool that provides a classification framework, to
help guide and plan treatment. Over the years, various staging systems have been developed, none of which is universally adopted. HCC is more difficult to stage and prognosticate than other solid tumors, because most HCC patients have underlying liver dysfunction
in addition to a tumor burden. The amount of liver dysfunction and degree of cirrhosis is
one of the most important variables in predicting survival, and helps determine what treatment can be offered. Knowledge of the various HCC staging systems is important to
understanding the heterogeneity of HCC patients, and as a basis for treatment decision
making.
The Okuda classification for HCC is the most widely used classification system and has
been in place for over a decade It is a point based system based on bilirubin, albumin,
ascites, and tumor size (>50%, <50%). It was the first classification system to account for
both severity of liver dysfunction as well as tumor burden. One of the limitations of the
system, however, is that it has a very narrow definition of tumor size, and does not include
other factors which have prognostic significance such as vascular invasion, or multifocality. It has also been shown to have lower predictive capacity, when compared to some of
the newer staging systems.
The ChildsPugh and TMN staging systems are uni-dimensional prognostic systems
that only account for one of the two prognostic variables of HCC. TMN only addresses the
tumor itself, while ChildsPugh only accounts for degree of hepatic dysfunction. Childs
Pugh uses ascites, encephalopathy, serum bilirubin, serum albumin, and prothrombin time
as variables, but despite its limitations, has been shown to offer significant prognostic
information. The TMN system, as modified in 2002, describes tumor morphology, vascular invasion, and metastasis, but does not account for any abnormalities in liver functional
status. This limitation has restricted its use, which is often limited to the surgical setting.
The Chinese University Prognostic Index (CUPI) considers six variables and divides
patients into three stages. The tumor itself is evaluated by the TNM staging system and
AFP level, while liver function is evaluated on the basis of ascites, bilirubin, alkaline phosphatase, and fibrosis. It is one of the newer staging systems that has shown promise when
compared to the Okuda and Cancer of the Liver Italian Program (CLIP) staging systems,
but it is now as widely accepted as some of the other staging systems while still being
validated.
The Barcelona Clinic Liver Cancer Staging System (BCLC) is a four stage system that
links variables related to tumor stage, liver functional status, physical status, and cancer
related symptoms, into a complex treatment algorithm. It is currently the only staging
system to account for the patients performance status, and is clinically useful because of
its treatment algorithm.
CLIP is a seven stage classification system based upon four variables. It uses the
ChildsPugh class to evaluate hepatic dysfunction, but also addresses tumor characteristics including tumor morphology, portal vein thrombosis, and alpha- fetoprotein (AFP)
levels (Tables9.1 and 9.2).
231
9 Liver Cancer
Table9.1 Staging and prognostic systems in HCC
System
Features
Okuda
Three stage system, based on four variables

(1) Bilirubin:
<3 (0 points)
>3 (1 point)
(2) Albumin:
>3 (0 points)
<3 (1 point)
(3) Ascites:
Absent (0 points)
Present (1 point)
(4) Tumor Size on cross section:
<50% (0 points)
>50% (1 point)
Stage 1: 0 total points
ChildsPugh
Classification system divided into

Class A, B, C, based on a score that is calculated
from five variables
(1) Ascites:
Absent (1 point)
Mild/diuretic responsive (2 points)
Severe/diuretic resistant (3 points)
(2) Encephalopathy:
None (1 point)
Grade 12 (2 points)
Grade 34 (3 points)
(3) Bilirubin:
<2mg/dL (1 point)
23mg/dL (2 points)
>3mg/dL (3 points)
(4) International normalized ratio (INR):
<1.7 (1 point)
1.72.3 (2 points)
>2.3 (3 points)
(5) Albumin:
>3.5g/dL (1 point)
2.83.5g/dL (2 points)
<2.8g/dL (3 points)
Class A: 56 total points
Class B: 79 total points
Class C: 1015 total points
Cancer of the
Liver Italian program
(CLIP)
Seven Stage Score (06) based on four variables

(1) ChildsPugh:
A (0 points)
B (1 point)
C (2 points)
References
Okuda etal.
(1985)
The Cancer
of the Liver
Italian
Program (CLIP)
Investigators
(2000)
(continued)
232
System
J.D. Thomas et al.
Features
References
(2) Alpha fetoprotein (AFP):

<400ng/dL (0 points)
>400ng/dL (1 point)
(3) Portal vein thrombosis:
Yes (0 points)
No (1 point)
(4) Tumor extension/morphology:
Uninodular and extension less than
or equal to 50% (0 points)
Multinodular and extension less than
or equal to 50% (1 point)
Massive or extension >50% (2 points)
Leung etal.
(2002)
Chinese University
Prognostic Index
(CUPI)
Three stage system group into three risk groups,

low, intermediate and high
(1) TMN stage
I and II (3 points)
IIIa and IIIb (1 points)
IVa and IVb (0 points)
(2) Serum bilirubin (mmol/L)
<34 (0 points)
3451 (3 points)
52 (4 points)
(3) Serum alkaline phosphatase
200 (3 points)
(4) Serum AFP
500ng/dL (2 points)
(5) Ascites
Yes (3 points)
(6) Asymptomatic on presentation
Yes (4 points)
Low risk: Score 1
Intermediate risk: Score 27
High risk: Score 8
American Joint
Committee on
Cancer (AJCC)
TNM
Categorical staging system with stages IIV based on Vauthey etal.

(2002)
tumor size and number (T), lymph nodes involved
(N), and presence of metastasis (M), does not use
any laboratory values or account for cirrhosis
T (primary tumor size, number and location)
T0
No evidence of primary tumor
T1
Solitary tumor 2cm without vascular
invasion
T2
Solitary tumor 2cm with vascular
invasion OR
Multiple tumors in 1 lobe 2cm without
vascular invasion OR
Solitary tumor >2cm without vascular
invasion
233
9 Liver Cancer
System
Features
T3
Solitary tumor >2cm with vascular invasion OR
Multiple tumors in one lobe 2cm with
vascular invasion OR
Multiple tumors in one lobe >2cm with or
without vascular invasion
T4
Multiple tumors in more than one lobe OR
Invasion of a major branch of hepatic or portal
vein OR
Invasion of adjacent organs other than the
gallbladder OR
Perforation of visceral peritoneum
N (nodal metastasis)
N0
N1
Regional lymph node metastasis
M (distant metastasis)
M0
No distant metastasis
M1
distant metastasis
Fibrosis score (F)a
F0 Fibrosis score 04 (none to moderate fibrosis)
F! Fibrosis score 56 ( severe fibrosis or cirrhosis)
Stages
Stage I
T1N0M0
Stage II
T2N0M0
Stage IIIA
T3N0M0
Stage IIIB
T1N1M0 or T2N1M0 or T3N1M0
Stage IVA
T4, any N, M1
Stage IVB
Any T, any N, M1
Barcelona Cancer
Liver Clinic (BCLC)
Four stage (AD) categorical staging

system, only staging system to account
for performance status
Stage A: all criteria need to be met
Stage B: all criteria need to be met
Stage C: Must include either Performance Status
12, or extrahepatic spread/vascular invasion
Stage D: Must include either Performance
Status 34 or Okuda III/ ChildsPugh C
(Llovet etal. 1999a)
Fibrosis score as defined by Ishak (Ishak H hepatol 1995)
References
234
J.D. Thomas et al.
Table9.2 Barcelona Cancer of the Liver Clinic Staging System

Stage
Performance Tumor stage
Okuda Liver functional status
status
Stage A: early HCC
A1
Single, <5cm
Bilirubin normal and

no portal hypertension
A2
Single, <5cm
Bilirubin normal
and portal
hypertension
A3
Single, <5cm
Bilirubin increased
and portal
hypertension
A4
Three nodules <3cm III
ChildPugh
class A or B
Stage B: intermediate 0
HCC
Multinodular
III
ChildPugh
class A or B
Stage C: advanced
HCC
12
Vascular invasion
or extrahepatic
spread
III
ChildPugh
class A or B
Stage D: end-stage
HCC
34
Any
III
ChildPugh class C
9.8
Treatment of HCC
The optimal management of patients with HCC requires multidisciplinary care, including
potential input from surgical oncology, liver transplantation, diagnostic imaging, interventional radiology, anatomic pathology, and medical oncology. Many academic centers have
established multidisciplinary liver clinics and/or liver conferences which can address this
important need. Since as discussed previously, there are several staging and prognostic
systems for HCC, but at present not one that has been validated across a wide spectrum of
HCC patients, nor universally accepted, the evidence-based management of HCC patients
follows a treatment algorithm at many institutions (Fig.9.1).
9.9
Surgical Resection
The standard surgical management for HCC consists of resection or liver transplantation.
However, of patients initially presenting with HCC only 1030% will be eligible for surgery (Choi et al. 2006). Patients with cirrhosis may be candidates for limited surgical
235
9 Liver Cancer
Assess tumor size, location

? extrahepatic metastases
Potentially
resectable
Assess serverity
of liver disease
Unresectable
Child-pugh C
Liver transplant
candidate?
Yes
No
Child-pugh A/B*
Optimize medical
therapy,
consider PVE
Intraoperative
evaluation
Resect
Evaluate
for
transplant
Liver
only
Tumor Size,
number
>5 cm
Systemic
therapy
Unresectable
Single
5 cm
Consider intraopertive
ETOH injetion,
RFA, cryoablation
RFA
PEI/cryoblation, TACE,
stereotactic radiotheraphy,
or radiotherapeutic
microspheres may be
alternatives depending
on tumor charcteristics,
location, and
local expertise
Consider
bridging
therapy,eg,
TACE
Extrahepatic
mets
Multiple
5 cm
>4 lesions
4 lesions
Fig. 9.1 General treatment algorithm for hepatocellular carcinoma (HCC) (Clark et al. 2005);
(Palavecino etal. 2009). PVE portal vein embolization; RFA radiofrequency ablation; PEI percutaneous ethanol injection; TACE transarterial chemoembolization. * Suitability of patients with
ChildPugh B cirrhosis for surgical resection is highly controversial. Systemic therapy options
include participation in a clinical trial (preferred) or sorafenib
resection, liver transplantation, or locoregional ablative treatment, depending on the severity of the cirrhosis. In general, the treatment of HCC is predicated on not only the extent of
underlying tumor, but also the level of hepatic dysfunction. Specifically, in patients with
236
J.D. Thomas et al.
no evidence of cirrhosis, hepatic resection has been the mainstay of surgical treatment. In
patients with severely cirrhotic livers (ChildPugh class B or C) transplantation is optimal
therapy for HCC, as it addresses simultaneously the neoplasm and the underlying liver
dysfunction. The ideal treatment strategy for small HCC in patients with mild cirrhosis
may involve resection or transplantation, and is more controversial. However, due to lack
of organ availability as well as cultural and economic reasons, surgical resection is the
primary therapy for many patients with HCC worldwide.
The selection of patients for surgical resection is based on several criteria, including the
absence of extrahepatic disease, the degree of hepatic dysfunction, and technical considerations such as the adequacy of the Future Liver Remnant (FLR), and tumor involvement
of major vascular structures, such as the portal vein or vena cava. Patients with normal
liver parenchyma are usually eligible for extensive resection, whereas patients with compensated cirrhosis may be candidates for minor or major hepatectomy in selected cases.
Surgery in patients with underlying cirrhosis can be associated with substantial morbidity
and mortality. Although perioperative mortality can be as high as 3050% in patients who
are ChildTurcottePugh B or C, ChildTurcottePugh A patients have an associated surgical mortality of only 510%. Pawlik etal. (2005a) have reported a series of patients who
underwent resection of HCC >10cm with a perioperative mortality of 5%. Ng etal. (2005)
evaluated 40 patients with small (<5 cm) and 380 patients with large or multinodular
tumors and noted a similar morbidity (27 and 23%, respectively) and mortality (2.4 and
2.7%, respectively) between the two groups studied. More recently, with the combination
of better patient selection, as well as better preoperative optimization, peri-operative mortality has further decreased following hepatic resection in well-compensated cirrhotics.
Factors limiting the safety of resection include preexisting portal hypertension and
decreased hepatic reserve. A potentially severe complication of resection is exacerbation
of portal hypertension, which may result in a precipitous decline in hepatic function. In
1999, Llovet etal. (1999b) reported the importance of portal hypertension as a prognostic
indicator in cirrhotic patients undergoing resection of HCC. The 5-year survival of resection patients without portal hypertension was 74%, compared to 25% in those with clinically relevant hypertension. The model for end-stage liver disease (MELD) has recently
been shown to be a very accurate and easy way to predict accurately postoperative liver
failure and mortality. The calculated MELD is based on the patients age, serum creatinine,
serum bilirubin, and international normalized ratio (INR) levels. Patients with MELD
score <9 had a reported mortality rate of zero in two recent large institutional series of
patients undergoing resection of HCC (Cucchetti etal. 2006; Teh etal. 2005).
For patients with cirrhosis being considered for surgical resection, CT volumetry can be
helpful. Accurate identification of patients with an inadequate FLR may allow for subsequent utilization of portal vein embolization (PVE) and offer a safer resection in a subset
of patients (Tu etal. 2007). In general, PVE is advocated for patients with underlying cirrhosis who have an FLR less than 4050% of the total liver volume. PVE in this subset of
patients may allow for preoperative hypertrophy of the remnant liver, thereby decreasing
the risk of liver insufficiency and failure in the postoperative period. These advancements
in patient selection and preoperative optimization have resulted in contemporary perioperative rates of 05% for patients with compensated cirrhosis who undergo resection of
early HCC (Ng etal. 2005; Pawlik etal. 2005b; Fan etal. 1999; Katz etal. 2009).
9 Liver Cancer
237
In addition to being safe, surgical resection can be an efficacious therapy for early HCC.
In most series, surgical resection of early HCC reported 5-year survival rates of 4550%,
compared with 6570% for transplantation (Cunningham etal. 2009). However, direct comparison of resection vs. transplantation survival data can be difficult to interpret. The better
results with transplantation may reflect in part the more stringent selection of patients. In
fact, investigators from both the United States (Cha etal. 2003) and Asia (Poon etal. 2002)
have reported that partial hepatectomy in patients with early HCC, who were otherwise eligible for transplantation, was associated with a 5-year overall survival rate of 6970%,
which is comparable to that reported for liver transplantation. Other data have similarly
confirmed that certain patients with early HCC can have durable long term survival following surgical resection. For example, Izumi etal. (1994) reported a 5-year survival of more
than 75% in patients with a solitary HCC tumor without vascular invasion following hepatic
resection. In aggregate, these data serve to emphasize that certain subsets of patients can
enjoy excellent long-term prognosis following hepatic resection.
Some patients with HCC who undergo resection may have smaller and solitary tumors
with low histologic grade and no associated vascular invasion (Cho etal. 2008; Nathan
et al. 2009; Pawlik et al. 2005c). Unlike transplantation which requires strict tumorspecific criteria for eligibility (e.g., solitary tumor 5cm or three tumors, the largest being
3cm), patients being considered for resection, however, may also have more advanced
tumor characteristics. Specifically, some patients with advanced HCC who otherwise
would not be candidates for transplantation may sometimes be considered for surgical
resection. Pawlik etal. (2005a) reported on 300 patients who underwent hepatic resection
for HCC 10cm or larger. In this study, median overall survival was 20 months, and the
5-year actuarial survival rate was 27%. Perhaps more importantly, those patients with large
HCC that was solitary and had no vascular invasion had a 5-year survival of greater than
45%. In a separate study, Ng etal. (2005) reported that patients with large or multinodular
HCC had a 5-year survival rate of 39%. In contrast, while hepatic resection for HCC with
major vascular invasion has been reported to be associated with median survival exceeding
historical survival in patients not treated surgically, the 5-year survival rate following
resection is only 10% (Pawlik etal. 2005c).
Unlike advanced HCC, early HCC (e.g., solitary tumor 5cm or three tumors, the largest being 3 cm) may often be treated surgical with either resection or transplantation.
Resection of early HCC may offer several advantages over transplantation, including more
immediate therapy, the availability of pathologic analysis of the resected tumor to better
guide the appropriateness of liver transplantation, and, in cases of eventual transplantation,
a delay of exposure to the morbidity and mortality of transplantation and immunosuppression. For those patients who have disease progression after resection, salvage transplantation may be a potential treatment option. Reporting on over 450 patients who underwent
resection of early HCC, Poon etal. (2002) noted that 80% of patients who recurred had a
transplantable recurrence using the same criteria as for primary transplantation. In addition, Belghiti etal. (2003) reported that salvage liver transplantation was as safe and efficacious as primary liver transplantation. Specifically, in this series, global morbidity and
perioperative mortality were comparable between primary and salvage liver transplantation. In addition, primary vs. salvage liver transplantation was associated with similar
long-term survival rates (59% vs. 61% at 5 years) (Belghiti et al. 2003). The use of
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J.D. Thomas et al.
different therapeutic approaches that incorporate hepatic resection or transplantation

should be dictated by the clinical situation (Kim and Hemming 2009; Pawlik 2009). It is
important to note that the exact proportion of patients who may qualify for salvage transplantation remains unclear. Whereas some studies (Poon etal. 2002) have estimated that
salvage transplantation may be feasible in up to 7580% of patients with recurrence following hepatic resection, other studies (Del Gaudio etal. 2008; Facciuto etal. 2008) have
reported a significantly lower salvage rate in the range of 20%. Further studies will be
needed to define the true applicability of salvage transplantation for patients who recur
following hepatic resection.
9.10
Liver Transplantation
A major pattern of failure after surgical resection for HCC is recurrence with the development of denovo intrahepatic disease. It has been suggested that the hepatic fibrosis, as well
as chronic active hepatitis, is responsible for the tendency of the remaining liver to generate new HCCs. As such, while 5-year overall survival rates following resection may be
close to 70% following resection of early, transplantable HCC, disease-free survival
rates have been reported to be low as 3648% at 5 years (Cha etal. 2003; Poon etal. 2002).
For this reason, liver transplantation has been proposed as definitive treatment for HCC, to
treat both the tumor as well as the damaged liver parenchyma at risk.
Initial results for orthotopic liver transplantation (OLT) for all stage HCC were associated with high early recurrence (18%) and lower 5-year survival rates (40%) as compared to other indications for OLT (Ringe etal. 1991). As a result of these discouraging
experiences, HCC was considered a contraindication to OLT in many transplantation centers in the early 1990s. Subsequently, on examination of liver explants, it was observed
that incidental small HCC, not detected by preoperative imaging, had no adverse impact
on the posttransplantation outcome. This observation led to the formulation of the Milan
criteria (Bismuth 2000; Mazzaferro etal. 1996). Patients with HCC meeting these criteria
(a single tumor less than 5cm in diameter, or two to three tumors each less than 3cm) had
similar posttransplant survival compared with patients without HCC, with 4-year and
recurrence-free survival rates of 75 and 83%, respectively (Mazzaferro etal. 1996). These
results have been corroborated by multiple centers and have led to the acceptance of liver
transplantation for HCC in cirrhotic patients who fit these criteria. While there exists an
interest in expanding the criteria for liver transplantation of patients with HCC to include
patients with larger and more numerous tumors (Silva etal. 2008; Yao etal. 2001; Takada
etal. 2007), these criteria have not been universally accepted or adopted.
One major deterrent to the widespread application of liver transplantation for early
HCC is organ availability. In one series, cumulative probabilities for dropout from the liver
transplantation list (due to death or the appearance of contraindications) were 7.3, 25.3,
and 43.6% at 6, 12, and 24 months, respectively (Yao etal. 2002). Furthermore, in a study
of 347 patients from the University of Toronto, although survival associated with liver
transplantation was better than resection when measured from the time of surgery, survival
9 Liver Cancer
239
from time of listing or hepatic resection (intention-to-treat analysis) was not different
between the two groups (Shah etal. 2007).This group also noted that patients who waited
longer than 4 months for transplantation had over a twofold higher risk of death (Shah
etal. 2007). One proposed method of ameliorating the prolonged wait times has been the
introduction of live-donor liver transplantation (LDLT); largely pioneered in Asia, where
adult-to-adult right lobe liver transplantation is performed more frequently than in the
United States or Europe. Although recent studies have reported favorable outcomes for
LDLT (Todo etal. 2004), it remains unclear whether these outcomes will be equivalent to
that of deceased-donor liver transplantation (DDLT) (Lo etal. 2007).
9.11
Nonresectional Locoregional Therapies
For selected patients with HCC confined to the liver, whose disease is not amenable to
resection or transplantation, nonresectional locoregional therapies can be considered.
These include percutaneous ethanol injection (PEI), cryotherapy, radiofrequency ablation
(RFA), and transarterial chemoembolization (TACE). While nonresectional locoregional
therapies are generally not considered potentially curative, these approaches do allow
for destruction of tumors while preserving nontumorous liver parenchyma, and the potential to serve as a bridge to more definitive therapy, such as liver transplantation, or as salvage treatment for postresection recurrence.
PEI and cryotherapy have been largely replaced by RFA, secondary to their decreased
efficacy (Lin etal. 2005), and associated risks of cholangitis and myoglobinuria-related
renal failure, respectively. RFA uses radio waves delivered via an electrode directly
inserted into a tumor to create a zone of thermal necrosis to destroy the tumor. Using US
or CT guidance, a needle electrode is inserted into the tumor and delivers a high-frequency alternating current, generating rapid vibration of ions, which leads to frictional
heat, and eventually coagulative tissue necrosis. RFA can be performed percutaneously,
laparoscopically, or through an open incision and is most effective in tumors <3cm in
diameter. Larger tumors generally require multiple overlapping ablations or the use of
multiple-array probes. RFA can be an alternative to resection for small resectable HCC,
but the equivalence of RFA to surgery has not been consistently supported. Traditionally,
RFA (and any ablative technique) has been limited by the inability to accurately evaluate
treatment margins in all three dimensions. In fact, in a nonrandomized comparative study
of 148 patients with solitary, small (<4cm) HCC, the rate of local (near the margin of
ablation) recurrence was found to be as high as 7.3% after RFA, compared with 0% after
surgery (Hong et al. 2005). However, in a recent prospective randomized trial of 180
patients with a solitary HCC <5cm, percutaneous RFA and surgical resection were associated with similar overall (68% vs. 64%) and disease-free (46 and 52%) survival rates at
4 years (Chen et al. 2006).It has been suggested that RFA may be more effective in
patients with cirrhosis, because the fibrotic liver can act as insulation and confine the heat
to the tumor, creating the so-called oven effect (Livraghi et al. 1999). Nevertheless,
there is no consensus regarding the efficacy of RFA as first-line treatment for HCC, andto
240
J.D. Thomas et al.
date this technique is generally accepted as the best treatment for small HCC in the patient
whose tumor cannot be resected safely, as a means of preventing tumor progression prior
to liver transplantation, or as salvage treatment for patients who have tumor recurrence
after surgical treatment.
TACE is another form of locoregional therapy that combines intraarterially infused
chemotherapy and hepatic artery embolization. It is based on the fact that HCCs larger
than 2cm predominantly receive their blood supply from the hepatic arterial circulation.
Chemotherapy agents may be either infused into the liver before embolization or impregnated in the gelatin sponges used for the embolization. Lipiodol has also been used in
conjunction with TACE because this agent will remain selectively in HCCs for an
extended period, allowing the delivery of locally concentrated therapy. Transarterial
(bland) embolization (TAE) can also be performed omitting the chemotherapeutic agent.
The superiority of TACE compared to best supportive care has been established in two
randomized control trials. The first study from the University of Hong-Kong randomized
80 patients with advanced HCC to TACE with an emulsion of cisplatin in lipiodol and
gelatin-sponge particles or conservative management (Lo etal. 2002). Two-year survival
rates were significantly higher for TACE compared with the control group (31% vs. 11%,
p=0.006). In the second trial performed by the BCLC group, the TACE group received
doxorubicin combined with lipiodol and gelfoam (Llovet etal. 2002).The 112 nonsurgical
candidates with HCC in this trial had more favorable characteristics than the Hong-Kong
study, but again, the 2-year survival rates were significantly better for the TACE than the
symptomatic control group (63% vs. 27%, p=0.009). Morbidity rates have been reported
to be as high as 23% after TACE especially among patients with HCCs >10cm in diameter. Moreover, postembolization syndrome, including fever, nausea, and pain, is common. Other complications, such as fatal hepatic necrosis and liver failure, have rarely
been reported. TACE is generally contraindicated in patients with ascites (Choi et al.
2006). Given that it is well-tolerated and has proven efficacy over best-supportive care,
TACE has secured a role as standard of care for HCC patients who are not candidates for
resection or transplantation.
9.12
Systemic Therapy
Until recently there has been no published evidence that systemic chemotherapy improves
overall survival in any subset of HCC patients. HCCs are clinically chemotherapy-resistant tumors; this observation is supported by low response rates (RR) across a wide variety
of cytotoxic chemotherapy agents (Simonetti etal. 1997; Watanuki etal. 2002; Anna etal.
1994; Chan and Lung 2004). The most widely used agent has been adriamycin, both as a
single agent and in chemotherapeutic combinations. A pivotal phase III trial of adriamycin
vs. combination chemotherapy (cisplatinum, interferon, adriamycin, and 5-fluorouracil,
PIAF) showed a statistically significant difference in RR favoring PIAF, but no survival
difference (Yeo etal. 2005). Over the course of the last several decades, numerous clinical
trials of a wide variety of chemotherapeutic and hormonal agents has shown little or no
9 Liver Cancer
241
activity in this complex malignancy (Table 9.3), and a sense of skepticism of ever
developing effective systemic therapy for HCC, pervaded the field.
A large Phase II, single arm trial of sorafenib in advanced HCC patients conducted by
Abou-Alfa and colleagues, indicated that this novel oral agent did not induce tumor
responses (RR 2.2%), however the median overall survival was 9.3 months, which was
very favorable compared to historical controls. These encouraging results led to an international placebo-controlled international phase III trial of sorafenib in HCC patients with
ChildsPugh A cirrhosis. The SHARP (Sorafenib Hepatocellular Carcinoma Assessment
Randomized Protocol) trial showed superior survival in the sorafenib arm compared to
placebo (10.7 months vs. 7.9 months, p=0.00058) (Llovet etal. 2008). Sorafenib is a multikinase inhibitor with activity against Raf kinase and several other cellular receptors including vascular endothelial growth factor 2 (VEGF2), platelet-derived growth factor receptor
(PDGFR), FLT3, and c-Kit. In HCC cell lines sorafenib inhibits proliferation and induces
apoptosis (Liu etal. 2006). The approval of the oral agent sorafenib for the treatment of
patients with HCC in 2007 in both the United States and the European Union represents a
true paradigm shift in the treatment of advanced HCC, and a significant step forward in
providing effective therapeutic options for the many individuals with advanced HCC.
Despite the fact that sorafenib does not yield radiographic tumor shrinkage, the traditional
measure of anti-tumor activity, it clearly does impact carcinogenic activity in HCC, based
on prolongation of both time to tumor progression and overall survival. The demonstration
of improved patient outcome of a targeted chemotherapeutic agent in this very challenging
malignancy has also generated renewed enthusiasm in the field, and an explosion of clinical
research efforts worldwide. Sorafenib also provides a platform on which to build future
comparative, adjuvant, and combination clinical trials, to further improve patient outcome.
The challenge going forward is to identify those agents that in combination with sorafenib
have the greatest potential for improved efficacy while maintaining patient safety.
Several other novel targeted or biologic agents are now being tested in HCC patients.
Hepatocarcinogenesis is a complex multistep, process, which results in a large number of
heterogeneous molecular abnormalities, and thus numerous potential targets for existing
therapeutic agents. There are several molecular pathways that represent rational targets in
HCC for novel therapies, summarized below.
The MAPK (mitogen-activated protein kinase) which is responsible for cellular proliferation and differentiation (Ito et al. 1998; McKillop et al. 1997; Feng et al. 2001).
Therapeutic agents that target this pathway include sorafenib (targets both raf and vascular
endothelial growth factor receptor (VEGFR)) and farnesyltransferase inhibitors (targeting
ras). The MAPK pathway involves a cascade of phosphorylation of four major cellular
kinases; ras, raf, MAP and Erk (MAP, MAPK; ERK, extracellular-signal-regulated kinase),
which is responsible for cellular proliferation and differentiation. These intermediates are
found to be elevated in both HCC cell lines and human specimens. Therapeutic agents that
target this pathway include sorafenib (targets both raf and VEGFR) and farnesyltransferase inhibitors (targeting ras). A Phase II trial of sorafenib demonstrated antitumor activity in advanced HCC patients. This study did not meet its primary endpoint of response
based on WHO criteria, with limited RR of 2.2%. However, many patients (33.6%) had stable disease for at least 4 months, with many showing central tumor necrosis. Based on the
encouraging overall survival of 9.2 months reported in the phase II trial, a placebo-controlled
242
J.D. Thomas et al.
international phase III trial was conducted in HCC patients with ChildsPugh A cirrhosis
(Llovet etal. 2008).
The PI3K/Akt/mTOR pathway (Phosphoinositide-3 kinase/Protein Kinase B/mammalian target of rapamycin) is a kinase cascade responsible for cellular proliferation and
apoptosis, and is closely linked to cell cycle. PI3K is associated with cell surface growth
factor receptors, and upon ligand binding can trigger formation of PIP3, which in turn
activates Akt and leads to a number of downstream events (mTOR being one of the
targets). PI3K is associated with cell surface growth factor receptors, and upon ligand
binding can trigger formation of PIP3, which in turn activates Akt and leads to a number
of downstream events (mTOR being one of the targets). This pathway is known to be
up-regulated in a subset of HCC patients. Molecular targeted therapy such as rapamycin, a naturally occurring mTOR inhibitor, showed promising results in HCC cell lines
(Sahin etal. 2004; Treiber 2009; Villanueva etal. 1983; Tam etal. 2009). However, no
published results from clinical trials of any agents that target mTOR in HCC patients are
available.
9.13
Growth Factors as Therapeutic Targets in Hepatocellular Carcinoma
Both the EGFR (epidermal growth factor receptor) and VEGFR families of growth factors
are upregulated in HCC (Fausto 1991; Hisaka etal. 1999).The EGFR is frequently expressed
in human hepatoma cells and EGF may be one of the mitogens that are needed for the growth
of hepatoma cells. Several agents the inhibit EGF signaling are clinically available, including
gefitinib, cetuximab, erlotinib and panitumumab. Erlotinib is an orally active and selective
inhibitor of the EGFR/HER1-related tyrosine kinase enzyme. EGFR/HER1 expression was
detected in 88% of the patients in a phase II study of erlotinib. In two phase II studies of this
agent, the RR was less than 10% but the disease control rate was more than 50%, and median
survival times were 10.75 and 13 months, respectively (Thomas et al. 2007; Philip et al.
2005). Other studies of anti-EGFR agents in HCC are summarized in Table9.3.
HCCs are generally hypervascular, and vascular endothelial growth factor (VEGF)
promotes HCC development and metastasis (Yamaguchi et al. 2006; Li et al. 1999).
Various agents targeting the VEGF circulating ligand or transmembrane receptor,
including bevacizumab (Avastin), sorafenib (Nexavar), and TSU-68, have been studied in patients with HCC. Bevacizumab, a monoclonal antibody inhibitor of VEGF
ligand, has been investigated in phase II studies alone or combination with other agents.
These studies showed a high disease control rate of over 80% and a median PFS of
more than 6 months. Sorafenib, an oral multikinase inhibitor, blocks tumor cell proliferation mainly by targeting Raf/MEK/ERK signaling at the level of Raf kinase, and
exerts an antiangiogenic effect by targeting VEGFR-2/-3. TSU-68 is an oral antiangiogenesis compound that blocks VEGFR-2, PDGFR (platelet-derived growth factor
receptor), and FGFR (fibroblast growth factor receptor); a phase I/II study has been
conducted in Japan.
Gefitinib
ODwyer etal. (2006)
Combination cytotoxic+biologic therapy

Sun etal. (2007)
Capecitabine, oxaliplatin,
bevacizumab
Zhu etal. (2006)
GEMOX+bevacizumab
Sorafenib vs. placebo

Sorafenib
Erlotonib
Erlotonib
Bevacizumab+erlotonib
Cetuximab
Targeted biologic therapy

Llovet etal. (2008)
Abou-Alfa etal. (2006)
Philip etal. (2005)
Thomas etal. (2007)
Thomas etal. (2009)
Zhu etal. (2007)
30
33
II
31
602
137
38
40
34
30
94/94
37/17
169/170
444
37
35
Sample size
II
II
III
II
II
II
II
II
III
II
II/III
III
II
II
Cytotoxic chemotherapy
Yeo etal. (2005)
Mok etal. (2002)
Gish etal. (2007)
Gish etal. (2007)
Patt etal. (2005)
Pastorelli etal. (2006)
PIAF vs. adriamycin

Nolatrexed vs. adriamycin
TI38067 vs. adriamycin
Nolatrexed vs. adriamycin
Thalidomide
Pegylated
adriamycin+gemcitabine
Phase
Table9.3 Selected clinical trials in patients with advanced HCC

Study
Regimen
20
11%
3%
2.3%
2.2
9%
0%
20.6%
0%
20.9 vs. 10.5

0
NA
1.4 vs. 4.0
6%
23%
Response rate
(RR) %
9.6
PFS 5.4 months
10.7 vs. 7.9 (p=0.00058)

9.3
13
10.75
19 (PFS 9 months)
PFS 6 weeks; OS 22
weeks
PFS 2.8 months; OS 6.5
months
8.6 vs. 6.83

4.9 vs. 3.7
5.7 vs. 5.6
5.5 vs. 8 (p=0.0068)
6.8
8.8 months
Median survival
(months)
9 Liver Cancer
243
244
J.D. Thomas et al.
9.14
Summary and Conclusions
As noted previously, the availability in the clinic of several novel biologic agents and the
urgent need for effective therapies for the majority of HCC with advanced HCC has led to
the evaluation of many of these agents in HCC, principally in phase II trials. The efficacy
and safety of sorafenib in patients with poorer performance status and more advanced
hepatic dysfunction, is yet to be established. A key objective for future clinical trials in
HCC is to continue assessing new biologic agents in combination with sorafenib, across
the broad spectrum of HCC patients seen in the clinic. The traditional approach is to evaluate new agents in single arm phase II studies and use classic radiological response criteria
such as WHO or RECIST as a measure of activity and thereby identify promising agents
to take forward into phase III clinical trial testing against an appropriate control group.
This approach, however, is being questioned because traditional radiographic tumor
responses may not occur with biologic agents although they may cause other anticancer
effects that may lead to meaningful patient benefit. This is especially true in HCC where
radiological assessment is notoriously difficult due to poor delineation of tumors in the
liver and tumor necrosis may occur without any change in overall tumor dimensions. Many
investigators are evaluating novel radiological imaging techniques that assess changes in
blood flow as criteria by which to assess biologic activity of antiangiogenic therapies.
Conducting controlled clinical trials of systemic chemotherapy regimens in HCC patients
is challenging. Obstacles include the multiple comorbidities of patients with cirrhosis, the
intrinsic chemo-resistance of HCC, the advanced nature of HCC at presentation in a majority of patients, the pharmacotherapeutic challenges of treating a cancer that arises in an
already-damaged liver, and the distribution of the majority of patients primarily in developing nations where multidisciplinary treatment of HCC may not be available.
Hepatocellular cancer is a heterogeneous disease in terms of its etiology, underlying associations, and biologic and clinical behavior, which further complicates clinical trial design.
The need for newer effective systemic therapies for HCC patients remains evident, and
making continued progress in this disease requires the collaboration and expertise of all of
the medical disciplines involved in the care of HCC patients.
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Carcinoma of the Biliary Tract
10
Sean P. Cleary, Jennifer Knox, and Laura Ann Dawson
10.1
Introduction
The gallbladder and bile ducts share a common embryologic origin and are lined with a
simple columnar epithelium. Most malignancies of the biliary tract are adenocarcinomas
that arise from the malignant transformation of this columnar epithelium. Adenocarcinomas
of the bile ducts are often referred to as cholangiocarcinomas. Malignant transformation
can occur anywhere along the biliary system from the ampulla of Vater to the terminal
intrahepatic bile ducts. Gallbladder cancers arise from the epithelium of the gallbladder or
cystic duct. Intrahepatic cholangiocarcinoma (ICC) develops in bile ducts within the liver
and proximal to the lobar hepatic ducts and hepatic duct confluence. Extrahepatic bile duct
cancer develops in the biliary tree from the ampulla of Vater to the hepatic duct confluence.
Extrahepatic bile duct tumors can be further subdivided into intrapancreatic cholangiocarcinoma, which are managed similarly to other periampullary malignancies (and are not
discussed here), and proximal or hilar cholangiocarcinoma.
Adenocarcinomas of the bile ducts and gallbladder have traditionally been associated with
a poor prognosis. The malignancies often present late as locally advanced or metastatic disease due to the lack of early symptoms and effective screening strategies. The management of
these cancers is hampered by the complexity of the hepatic, vascular and biliary anatomy; the
traditionally high morbidity and mortality of hepatobiliary resection and lack of proven adjuvant treatment. As an uncommon malignancy, the majority of experience in the management
L.A. Dawson (*)

Department of Radiation Oncology, University Health Network, Princess Margaret Hospital,
610 University Ave, Toronto, ON, M5G 2M9, Canada
e-mail: laura.dawson@rmp.uhn.on.ca
S.P. Cleary
Division of General Surgery, Department of Surgery, University Health Network, Toronto
General Hospital, Toronto, ON, Canada
J. Knox
Department of Medical Oncology, University Health Network, Princess Margaret Hospital,
Toronto, ON, Canada
251
252
S.P. Cleary et al.
of these cancers has generally been limited to few high-volume centers. Over the last two
decades, enhanced understanding of hepatic and biliary anatomy, improved radiologic assessment, the development of adjunctive interventional radiologic techniques such as biliary
drainage and portal vein embolization, and improved peri-operative care have all combined to
increase the safety of hepatic and biliary resections. This improvement in perioperative outcomes has permitted the application of an increasingly aggressive surgical approach towards
these cancers that has paralleled improvements in long-term survival observed over time.
While cancers of the gallbladder and bile duct share a common embryologic origin and many
similarities; the natural history, diagnosis and management of cancers from different regions
of the biliary tree are dissimilar enough that they are highlighted separately.
10.2
Gallbladder Cancer
10.2.1
Gallbladder cancer is a rare malignancy in North America affecting 12 people per 100,000
with approximately 2,0005,000 cases diagnosed each year (Jemal etal. 2006). It is the
fifth most common cancer of the gastrointestinal tract (Canadian Cancer Society/National
Cancer Institute of Canada 2008). The incidence of gallbladder cancer shows a substantial
gender, geographic and ethnic variation. High incidence areas include East Asia, Northern
India and Pakistan, Eastern Europe and South America (Randi etal. 2006). Gallbladder
cancer is more common in females with a female: male ratio of 23:1, with a more apparent gender discrepancy in India and South America vs. Asia and Eastern Europe (Randi
etal. 2006). By comparison, North America is a low incidence area in this disease, with
increased risk seen among Hispanics and Native Americans.
The most commonly cited risk factor for gallbladder cancer is gallstones. Between 60
and 100% of patients with gallbladder cancer also have gallstones (Perpetuo etal. 1978),
and gallstones are associated with a 47-fold increase in the risk of cancer (Lowenfels
etal. 1985, 1999); this risk may be higher for patients with symptomatic gallstone disease,
those with large stones, and in high risk geographic regions or ethnic groups (Lowenfels
etal. 1989; Diehl 1980; Zatonski etal. 1997). The mechanistic link between gallstones and
cancer is poorly understood but likely involves longstanding chronic inflammation leading
to dysplasia and neoplastic changes in the mucosa either alone or in combination with
other factors (Serra and Diehl 2002; Wistuba and Gazdar 2004). Similarly, longstanding
inflammation leading to dysplastic changes may be implicated in the association between
chronic infections with Salmonella (S. typhi and S. paratypi) (Shukla etal. 2000; Dutta
etal. 2000; Nath etal. 1997) and possibly Helicobacter (H. pylori and H. bilis) species
(Bulajic etal. 2002) and gallbladder malignancy. Finally, endocrine and metabolic factors
associated with gallbladder cancer include increasing parity and gravidity (Zatonski etal.
1997; Pandey and Shukla 2003) and obesity (Calle etal. 2003; Moller etal. 1994; Serra
etal. 2002; Strom etal. 1995).
10 Carcinoma of the Biliary Tract
253
10.2.2
Pathology of Gallbladder Cancer
Since gallbladder cancer is often diagnosed at an advanced stage and associated with an
overall poor prognosis, there is considerable interest in identifying premalignant lesions
and defining the malignant progression in this disease. To date, gallbladder adenomas and
dysplasia have been identified as premalignant lesions, while adenomyomatosis as well as
cholesterol and inflammatory polyps are not believed to be associated with cancer risk.
Up to 1% of cholecystectomy specimens will contain an adenoma; these lesions may
resemble normal gallbladder mucosa or show evidence of pyloric gland metaplasia or
intestinal metaplasia (Koga etal. 1988; Kozuka etal. 1982). Malignant changes have been
identified in 39% of adenomas, and 19% of carcinomas contain adjacent adenomatous elements. Furthermore, a correlation between polyp size and risk of malignancy may exist
with benign histology in virtually all polyps <1cm, with malignant features in some adenomas >1.2cm, and invasive cancers in some polyps >3cm (Koga etal. 1988; Kozuka
etal. 1982). As a result the risk of malignancy in a gallbladder polyps is thought to be
negligible in lesions <1cm.
Dysplasia is considered as a premalignant gallbladder lesion that is often flat with
poorly defined borders, may have a villous or granular appearance, and may be solitary or
multifocal. These lesions may demonstrate varying degrees of pseudostratification, nuclear
atypia, loss of polarity and mitotic figures without evidence of invasion. Dysplastic
mucosal areas are often difficult to identify on gross examination, as a result there is a wide
range in estimates of the frequency of these lesions varying from 0.4 to 33.8% (Sasatomi
etal. 2000). Dysplasia can be graded as mild, moderate to severe, with dysplasia and carcinoma-in situ often found adjacent to, or in continuity with invasive cancer (Nakajo etal.
1990; Yamaguchi and Enjoji 1988; Roa et al. 2006). Indirect estimates of the time for
progression from dysplasia-to-carcinoma-in situ-to-carcinoma indicate that invasive cancer may develop over a period of 1015 years (Roa etal. 2006).
Ninety-eight percent of carcinomas of the gallbladder are of epithelial origin, with over
90% identified as adenocarcinomas. Nonepithelial tumors include sarcomas, lymphomas,
carcinoid tumors and metastases; other epithelial types include adenosquamous, squamous
and small-cell carcinomas (Henson etal. 1992). Histologic subtypes of adenocarcinoma
include papillary, intestinal, mucinous, signet-cell and clear cell variants (Henson etal.
1992). The papillary subtype of adenocarcinoma is noteworthy since these lesions tends to
be exophytic with fibrovascular stalks that fill the gallbladder lumen before invading
through the gallbladder wall and are associated with more indolent biologic behavior and
favorable long-term prognosis (Albores-Saavedra etal. 2005).
On gross examination, about 60% of cancers arise in the fundus of the gland, with 30%
developing in the body and 10% in the neck (Levy etal. 2001), and they develop as an
asymmetric thickening of the gallbladder wall with diffuse infiltration of surrounding
structures. Based on macroscopic characteristics, cancers can be categorized into infiltrative, nodular, papillary or mixed forms. Infiltrative tumors are most common and exhibit
early and extensive infiltration of the subserosal plane leading to involvement of the entire
gallbladder wall. Nodular tumors are characterized by early invasion through the gallbladder wall into adjacent organs and liver. The growth of papillary tumors is predominantly
254
S.P. Cleary et al.
intraluminal, resulting in a polypoid or cauliflower-like lesion. These tumors are less prone
to local invasion and lymph node metastases and are therefore associated with a better
prognosis (Sumiyoshi etal. 1991).
Gallbladder carcinomas spread via lymphatic, vascular, perineural, intraperitoneal and
intraductal routes as well as by direct invasion; understanding these modes of spread is
important in considering an approach to surgical resection of these tumors. Lymphatic
drainage from the gallbladder occurs first into the cystic duct node followed by lymph
nodes along the common bile duct, in the pancreaticoduodenal region, posterior to the
portal vein and along the common hepatic artery. From there, lymphatic drainage proceeds
to the celiac, superior mesenteric and para-aortic lymph nodes (Fahim etal. 1962). The
next most common site of spread is to the adjacent liver via direct invasion or by invasion
of veins which drain from the gallbladder into the adjacent liver segments, particularly
segments IVb and V (Fahim etal. 1962; Misra etal. 2003). Intraductal spread is commonly
seen in papillary cancers, and perineural spread often follows the course of the arterial
anatomy of the region. Direct invasion of the cancers can also occur along the hilar plate
and Glissons capsule towards the liver hilum; this mode of spread is particularly challenging when considering surgical resection and can often render tumors unresectable based on
early hepatic vascular invasion. Other organs which can become involved by direct invasion include the anterior abdominal wall, duodenum, colon, diaphragm and hepatic ducts.
10.2.3
Diagnosis of Gallbladder Cancer
The diagnosis of gallbladder cancer can be challenging due to the lack of specific signs and
symptoms of early disease, particularly in the elderly that are most commonly affected in
this disease. The clinical manifestation of gallbladder malignancy can often overlap with
gallstone disease and other benign upper gastrointestinal disorders. As a result, most cases
are not diagnosed until the disease is advanced. The most common symptom for patients
with gallbladder cancer is right upper quadrant pain, followed by weight loss, anorexia,
nausea and vomiting. Chronic or recurring pain may be due to associated gallstone disease
or can be the result of locally invasive disease. A palpable mass, jaundice, gastrointestinal
obstruction and the development of constitutional symptoms such as anorexia and weight
loss are all indicators of advanced disease. Alternatively, malignancy may be detected in
cases of complicated gallstone disease such as chronic cholecystitis, Mirrizzis syndrome
or even as an incidental finding after cholecystectomy performed for presumed benign
indications (Misra etal. 2003; Liu etal. 1997; Redaelli etal. 1997).
Radiologic investigations play a critical role in the detection and staging of gallbladder
malignancies. Ultrasound (U/S) is the most common imaging modality used to investigate
biliary tract symptoms. Thickening of the gallbladder wall can be seen in both benign
inflammation and malignancy, but findings of discontinuous thickening or diffuse thickening >12mm can be suggestive of cancer. The observation of a mass protruding into the
gallbladder lumen, a fixed mass, mural calcifications and loss of the normal interface
between the gallbladder and the liver parenchyma can all be indicators of malignancy seen
on U/S (Wibbenmeyer et al. 1995a; Pandey et al. 2000). The diagnostic sensitivity of
255
conventional U/S for the detection of cancer approaches 80% and can reliably detect
hepatic parenchymal invasion; the addition of duplex vascular assessment can improve
this sensitivity by demonstrating vascular flow within lesions and enhance the ability to
detect vascular involvement (Bach etal. 1998; Chijiiwa etal. 1991). Contrast-enhanced
computed tomography (CT) has a high sensitivity (90%) for detecting more advanced
tumors (>T2) but its utility in detecting early lesions is uncertain (Yoshimitsu etal. 2002;
Ohtani etal. 1996). Gallbladder cancers usually appear as a low-attenuation mass or eccentric thickening of the gallbladder wall. CT is the predominant imaging modality for staging
gallbladder cancer and determining resectability and is highly accurate in determining
local extent, vascular involvement, invasion of adjacent structures as well as detecting the
presence of metastatic disease. Magnetic resonance imaging (MRI) can provide similar
information to CT, although current image resolution of this technique limits its detection
of small early lesions. Gallbladder cancers appear hypointense on T1-weighted images and
hyperintense on T2-weighted images. The role of positron emission tomography (PET)
and PET-CT has not been fully established in this disease, although recent reports suggest
a promising role for this imaging modality in the detection of the primary tumor and metastatic disease (Petrowsky etal. 2006; Rosenbaum etal. 2006).
The use of biochemical serum markers to improve the diagnostic accuracy in gallbladder
cancer has been investigated. In a series comparing patients undergoing upper abdominal surgery to patients with gallbladder cancer, a serum carcino-embryonic antigen (CEA) level
>4.0ng/mL had a specificity of 93% but had a limited sensitivity of 50%. A CA19-9 level
>20U/mL had a sensitivity and specificity of 80%. The use of both CEA and CA19-9 either in
parallel or in series did not improve the diagnostic yield (Strom etal. 1990; Ritts etal. 1994).
10.2.4
Staging of Gallbladder Cancer
The original staging system for gallbladder cancer was proposed by Nevin etal. (1976) but
has been largely replaced by the TNM system proposed by the International Union Against
Cancer (UICC) and the American Joint Committee on Cancer (AJCC) 5th edition in 1997
(Fleming etal. 1997) and revised in the 6th edition in 2002 (Greene etal. 2002). The UICC/
AJCC 6th edition was designed to be clinically relevant with T3 tumors considered to be
locally invasive but potentially resectable tumors and T4 tumors as unresectable in most
cases. Stage 2 is divided into locally advanced resectable tumors (stage 2a), and tumors with
lymph node metastases (stage 2b). Stage 3 tumors are considered unresectable in most
cases, whereas stage 4 represents distant metastatic disease (Tables10.1 and 10.2).
10.2.5
Surgical Resection of Gallbladder Cancer
Surgical resection is the only potentially curative treatment modality for gallbladder cancer.
Until recently, surgery for this disease has been hampered by high peri-operative complication rates and poor long-term results. Widespread reviews of surgical cases from the 1970s
256
S.P. Cleary et al.
Table10.1 UICC/AJCC staging system for gallbladder cancer

6th edition 2002
T stage
T0 no evidence of primary tumor
Tis carcinoma in situ
T1 tumor invades lamina propria or muscle layer
T1a tumor invades lamina propria
T1b tumor invades muscle layer
T2 tumor invades perimuscular connective tissue
w/no extension beyond serosa or into liver
T3 tumor perforates serosa (visceral peritoneum)
And/or directly invades liver
And/or invades adjacent or structure such as
Duodenum, stomach, colon, pancreas, omentum
Or bile ducts
T4 tumor invades main portal vein or hepatic artery
Or multiple extrahepatic organs or structures
N stage
Nx regional lymph nodes cannot be assessed
N0 no regional lymph node metastasis
N1 regional lymph node metastasis
M stage
Mx distant metastases cannot be assessed
M0 no distant metastases
M1 distant metastases
Table10.2 Gallbladder cancer tumor stage
Stage 0
Tis
N0
M0
Stage 1A
T1
N0
M0
Stage 1B
T2
N0
M0
Stage 2A
T3
N0
M0
Stage 2B
T13
N1
M0
Stage 3
T4
Any N
M0
Stage 4
Any T
Any N
M1
and 1980s demonstrated that few cases underwent potentially curative resections and 5-year
survival rates of 517% (Cubertafond etal. 1994; Piehler and Crichlow 1978; Wilkinson
1995). Since those reports, developments in preoperative evaluation, intraoperative technique and postoperative care have substantially reduced the rates of peri-operative morbidity and mortality with an associated increase in long-term survival. Developments in imaging
have permitted better staging and improved operative planning. Improvements in surgical
technique, intraoperative anesthesia, and postoperative care have enabled the performance
of more complex resections while reducing the perioperative mortality rate to <5%.
257
The surgical resection of gallbladder cancers must take into account the anatomic and
pathologic characteristics of this disease and include hepatic resection with regional
lymphadenectomy and potentially resection of the biliary system. Malignancies of the
gallbladder invade the liver through local extension or via the venous drainage of the gallbladder into segments IVB and V. As a result, these segments are the most common site of
hepatic involvement, but tumors may extend further into segment IVa or the right and
caudate lobes (Sumiyoshi etal. 1991; Nimura etal. 1991). In conservative series, early
tumors with no obvious intrahepatic extension have been managed with resection of the
gallbladder with a rim of 23cm of liver tissue around the gallbladder bed. For tumors
with limited liver invasion, some centers have advocated resection of segments IVb and V
as a formal anatomic resection with vascular control of the portal inflow along the umbilical fissure and segmental portal vein branch, respectively, and ligation of the middle
hepatic vein at the apex of the resection. Segmental resection of segments IVb and V is
limited in its ability to achieve an adequate radial margin while preserving the integrity of
the remaining right hemi-liver by the proximity of the gallbladder neck to the bifurcation
of the right portal pedicle, which can be as little as 2mm (Yamaguchi etal. 1998). As a
result, many centers have argued that improved oncologic clearance can be obtained by
extended right hepatectomy with resection of segments IVb, VVIII (Nimura etal. 1991;
Nakamura etal. 1989, 1994; Todoroki etal. 1999a).
In addition to hepatic invasion, gallbladder cancers can invade the hepatoduodenal ligament into or along bile ducts (intraductal or periductal invasion) and spread along the
lymphatic channels in the porta hepatis (Kaneoka etal. 2003). Invasion of the biliary ducts
is often associated with jaundice; however periductal spread occurs via perineural invasion
and may not cause biliary obstruction. The role of resection of the extrahepatic biliary tree
in gallbladder cancer is the subject of considerable debate (Pawlik etal. 2007; Shimizu
etal. 2004). The rate of lymph node metastases appears to correlate with the depth of primary tumor invasion (T-stage) and can range from 10 to 62% (Misra etal. 2003; Ogura
etal. 1991; Fong etal. 1998; Shirai etal. 1992a; Bartlett 2000).
The overall objective in the surgical management of gallbladder cancer is the complete
resection of all macro- and microscopic disease and achievement of an R0 resection. While
a standardized operation may not be beneficial for all cases and patients (DAngelica etal.
2009), the surgical approach should be tailored to the clinical setting in which cancer is
identified, the extent of the tumor, and the operative risk in each individual patient. Due to
the rarity of these tumors, these cases are best managed at high-volume hepatobiliary surgical oncology centers.
10.2.5.1
Management of Known Gallbladder Cancer
Malignancies of the gallbladder can remain asymptomatic until they have reached an
advanced stage. As a result, most lesions diagnosed on the development of symptoms or
detected on imaging investigations tend to be T3 lesions or greater and many of these lesions
are unresectable at presentation. Although unusual, early T1/2 lesions can be detected preoperatively on imaging as an incidental finding or on investigations for associated gallstone
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S.P. Cleary et al.
disease. The management of lesions detected preoperatively should be determined by the

stage and location of the tumor.
The challenge in managing early gallbladder cancers without adjacent organ involvement (T1 or T2 lesions) is differentiating these lesions from chronic inflammatory changes
in the gallbladder and properly staging these lesions. The dissection for simple cholecystectomy proceeds along the subserosal plane; while cholecystectomy alone may be sufficient
treatment for Tis and T1a lesions, it should be avoided in cases where malignancy is suspected. For early T1 and T2 lesions, cholecystectomy with resection of the adjacent liver
parenchyma has been established as the minimum treatment required to reliably obtain an
R0 radial margin. The extent of liver resection is the subject of some debate and may depend
on the individual case. Options include: cholecystectomy with a wedge of hepatic parenchyma which may be adequate for an early T1 lesions in the fundus, formal resection of
segments IVb and V for early T1/2 lesions in the fundus, to extended right hepatectomy
which may be necessary for T2 lesions in the neck of the gallbladder. A conservative
approach to hepatic resection can be considered in cancers exhibiting an expansive or nodular growth pattern but avoided in cases of infiltrative tumors where more extensive resection
is required (Ogura etal. 1998). Since lymph node metastases can be seen in up to 10% of
T1b lesions and 60% of T2 lesions, resection of even early malignancies should include
regional lymphadenectomy of the nodes in the porta hepatis (Misra etal. 2003; Ogura etal.
1991; Fong etal. 1998; Shirai etal. 1992a; Bartlett 2000). The role of bile duct resection in
these cases is controversial with some centers advocating routine biliary resection (Nakamura
etal. 1989; Shimizu etal. 2004), while others advocate a selected approach where bile duct
resection is performed in cases with jaundice or a positive cystic duct margin (Pawlik etal.
2007; DAngelica etal. 2009). Five year survival rates of 60100% has been documented
for T2 lesions treated with cholecystectomy, hepatic resection with lymphadenectomy and
possible biliary resection compared to 1950% for cholecystectomy alone (Dixon et al.
2005; Matsumoto etal. 1992; Shirai etal. 1992b; de Aretxabala etal. 1997).
Aggressive resection is indicated in T3 tumors and selected T4 cancers, where resection
of all macro and microscopic disease is feasible. For many tumors an extended right hepatectomy, portal lymphadenectomy and possible bile duct resection is required for R0 resection.
This aggressive approach has been enabled by the increasing safety of hepatobiliary surgery,
has led to an increasing use of extended resections, and has improved overall survival at
many Asian and North American centers; 5 year survival rates for stage III and IV disease
now approach 69 and 25%, respectively (Nimura etal. 1991; Nakamura etal. 1989, 1994;
Todoroki etal. 1999a; Dixon etal. 2005; Kondo etal. 2002). For selected T3 tumors that
invade the pancreas or have extensive periductal invasion, several centers have reported
combined hepatectomy, bile duct resection and pancreaticoduodenectomy with 5-year survival rates of up to 30% (Kaneoka etal. 2003; Kondo etal. 2002; Todoroki etal. 1999b;
Chijiiwa and Tanaka 1994; Sasaki etal. 2006). These improved peri-operative and long-term
results have significantly improved the outlook for patients diagnosed with gallbladder cancer. While some may advocate a dogmatic approach to routine formalized extended resection, recent publications have stressed that negative margins status (R0), and not the extent
of resection, is predictive of survival and proposed that the surgical treatment of gallbladder
cancers be tailored in each individual case to obtain complete macro and microscopic disease clearance (Pawlik etal. 2007; DAngelica etal. 2009; Pawlik and Choti 2009).
259
10.2.5.2
Management of Incidental Gallbladder Cancer
Laparoscopic cholecystectomy is a common surgical procedure performed with increasing
frequency for benign gallbladder conditions. The unexpected findings of malignancy in a
laparoscopic cholecystectomy may occur during the procedure or, more commonly, as a
finding on histopathologic examination of the gallbladder specimen. Due to the subserosal
plane of dissection in a standard cholecystectomy, the incidental finding of cancer presents
a unique and challenging clinical dilemma. Intraoperatively, the index of suspicion for
malignancy should be raised in cases of a thickened gallbladder wall, or when the tissue
planes are obscured and dissection is difficult, particularly in an older patient.
Malignancy can be an unexpected finding on pathologic examination of the specimen
in 0.32% of cases (Misra etal. 2003). This finding should prompt a thorough pathologic
review including the determination of radial and cystic duct margin status, depth of tumor
invasion (T-stage), presence of perineural/vascular/lymphatic invasion, and presence/status of the cystic duct node. The presence of gallbladder injury and bile spillage are associated with increased rates of local, peritoneal and port-site recurrence (Wibbenmeyer etal.
1995b; Wakai etal. 2002; Weiland etal. 2002; Suzuki etal. 1998). Once the specimen has
been thoroughly reviewed, the subsequent management of incidental gallbladder cancers
is determined by the T-stage and other pathologic characteristics of the tumor.
T1a lesions, that invade the lamina propria only, have a very good prognosis with a
5-year survival of 90100% when treated with simple cholecystectomy (Wakai etal. 2002;
Shirai etal. 1992b; Toyonaga etal. 2003). Perineural, vascular and lymphatic invasion is
extremely rare in T1a lesions and more extensive resections do not improve outcome
(Ogura etal. 1991; Taner etal. 2004; Ouchi etal. 2002). The management of incidental
T1b tumors is somewhat controversial. Two series report excellent survival for T1b cancer
with an 8590% 10-year survival, and no benefit to radical resection (Shirai etal. 1992b;
Wakai et al. 2001). In comparison, many groups have recommended reexploration and
radical reresection for incidental T1b lesions with reports of 5-year survival rates of
72100% (Ouchi etal. 1994; Ogura etal. 1991; Matsumoto etal. 1992). Supporters of
reexploration cite the 15% incidence of lymph node metastases, 10% incidence of residual
disease in the gallbladder fossa and a 37% incidence of any residual disease upon reexploration as evidence to support the role for exploration and extended resection in these
cases (Pawlik etal. 2007; Ogura etal. 1991; de Aretxabala etal. 1992).
The management of more advanced incidental lesions, T2 or greater, is less controversial as these tumors are associated with a 2062% incidence of lymph node metastases and
4076% incidence of residual disease at reexploration (Misra etal. 2003; Fong etal. 1998;
Shirai etal. 1992a; Bartlett 2000; de Aretxabala etal. 1992). For this reason, several series
have demonstrated a significant survival benefit with extended resection compared to
cholecystectomy alone for T2 lesions (Fong etal. 1998; Shirai etal. 1992a; de Aretxabala
etal. 1997; Wakai etal. 2002; Chijiiwa etal. 2001). Cases undergoing reresection have
been associated with 5-year survival rates of 7080% and 3045% for T2 and T3 lesions,
respectively (Shirai etal. 1992a; Fong etal. 2000; Suzuki etal. 2004; Oertli etal. 1993).
Initial reports on high rates of port-site recurrences led many to advocate abdominal wall
resection of port sites at reexploration (Wakai etal. 2002; Schaeff etal. 1998; Paolucci
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S.P. Cleary et al.
2001; Lundberg and Kristoffersson 1999), but more recent series have shown no increase
risk in abdominal wall recurrences compared to open surgery (Paolucci et al. 2003;
Lundberg and Kristoffersson 2000).
In summary, in cases where cancer is found incidentally on examination of a specimen
after simple cholecystectomy, patients with tumors T1b or greater should be considered for
reexploration and extended resection. Surprisingly, there is no evidence that survival in
patients treated with cholecystectomy and reexploration is inferior to those who undergo
primary extended resection (Fong etal. 2000; Suzuki etal. 2000). Despite this evidence,
population-based studies show that only the minority of patients with potentially curable
gallbladder tumors undergo extended resection (Paolucci etal. 2003; Coburn etal. 2008).
10.2.6
Radiation Therapy in Gallbladder Cancer
The historical role of radiation therapy (RT) in gallbladder cancer has been palliative.
Reasons for the limited historical experience in using RT as adjuvant, neoadjuvant or
definitive therapy include challenges in defining the extent of tumor, the proximity of sensitive normal tissues to the biliary system, and technical demands with delivery of precise
high dose radiation to the biliary targets that move with breathing. Specialized techniques
including transcatheter brachytherapy, intraoperative radiation therapy (IORT), conformal
radiation therapy (CRT), and intensity modulated radiation therapy (IMRT) allow tumorcidal doses to be delivered safely to some gallbladder and biliary cancers.
IORT is most often delivered using electrons intraoperatively, immediately after resection, while the abdominal cavity is open. Brachytherapy is often delivered using 192-Iridium
within biliary catheters placed in malignant bile ducts. Advantages of IORT and brachytherapy are that the high dose radiation falls off quickly, however this advantage also limits the
utility to superficial targets. IORT and brachytherapy have often been used in addition to
external beam RT to increase the dose to the highest risk regions. The delivery of high
radiation doses that conform around the tumor is now possible with external beam RT,
delivered using CRT or IMRT, combined with strategies to reduce organ motion and imaging at the time of radiation delivery to ensure it is targeted appropriately.
There are no randomized trials of RT in gallbladder cancer. Most retrospective and
prospective series include heterogeneous patient populations (bile duct and gall bladder),
treated with heterogeneous therapy (external beam RT, IORT and/or brachytherapy, with
or without chemotherapy or surgery). This heterogeneity and the potential for selection
bias makes it impossible to accurately quantify the benefits of RT.
10.2.6.1
Adjuvant Radiation Therapy for Gallbladder Cancer
Although there is an increased propensity for metastases to develop following resection for
gallbladder cancer vs. bile duct cancer, several series suggest a benefit to adjuvant local
regional RT. In most series, adjuvant RT has consisted of 4555 Gy delivered over
261
45 weeks using conventional external beam, RT delivered to the gallbladder fossa, adjacent liver and regional nodal areas. Vaittenim etal. found an improved median survival
following surgery and adjuvant RT compared to no adjuvant therapy (median survival 63
vs. 29 months) for gallbladder cancer (Vaittenim 1970). However, surgery most often consisted of a simple cholecystectomy. Todoroki etal. found a significant improvement of 5
year survival in 85 patients with stage IV gallbladder carcinoma following resection and
adjuvant RT (n=47) compared to resection alone (8.9 vs. 2.9%, p=0.002) (Todoroki etal.
1999b). Local control was also improved from 36 to 59% (p=0.05). Long term survival
was observed in patients with microscopic residual disease after surgery who were treated
with RT (p=0.003). Kresl et al. reported improved survival in patients with complete
resection vs. microscopic and gross residual disease (median survival 5.1, 1.4, and
0.6 years, respectively, p=0.02) in patients who received 5-FU-based chemotherapy and
RT following surgery (Kresl et al. 2002). Radiotherapy doses greater than 54 Gy were
associated with improved local control. Bosset etal. reported that five of seven resected
gallbladder cancer patients were without recurrence 558 months following 46Gy, followed by 9Gy to the high risk volume (Bosset etal. 1989). Czito etal. observed a median
survival of 1.9 years and local control of 65% in 22 patients with resected gallbladder
cancer who received adjuvant RT (median dose 45Gy) and concurrent 5-FU chemotherapy (n=18) (Czito etal. 2005). Morrow etal. reported an improved median survival from
3 to 4.5 months for patients receiving adjuvant chemotherapy or RT or both compared to
those treated with surgery alone, demonstrating how patient selection can greatly alter
outcomes (Morrow etal. 1983). In a national cancer database review of 2,500 patients with
gallbladder cancer treated between 1989 and 1990, patients who underwent surgery, RT
and chemotherapy had better survival than those who underwent surgery alone (hazard
ratio 0.625, 95% CI 0.520.75) (Donohue etal. 1998).
10.2.6.2
Radiation Therapy for Unresectable Gallbladder Cancer
RT can palliate bleeding or pain from locally advanced gallbladder cancer. Moderate dose
RT for locally advanced gallbladder cancer is generally well tolerated, and some series
have suggested improved survival with RT compared to palliative resection, although survival remains poor (median survival 68 months) (Houry etal. 1989; Uno etal. 1996). In
one series, in patients in whom complete resection was not feasible, there was a trend
toward improved survival with the addition of RT (13 vs. 8 months, p<0.10) (Vaittenim
1970). In another series, patients with unresectable gallbladder cancer treated with RT had
an improvement in their symptoms (Mahe etal. 1994).
Fuller et al. showed the possibility for escalating doses to gallbladder cancers with
image guided IMRT (median dose 60Gy, range 5470Gy) in ten patients with no prior
surgery (Randi et al. 2006), cholecystectomy with (Canadian Cancer Society/National
Cancer Institute of Canada 2008) or without (Lowenfels etal. 1985) hepatoduodenectomy;
two of the seven resected patients had R1 resections. Five received concurrent 5FU chemotherapy. One patient developed grade 3 gastrointestinal toxicity. Median survival was 16.7
months (Fuller etal. 2006). Others have also delivered doses up to 70Gy to gallbladder
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cancers (Silk etal. 1989). There are rare case reports of long term survivors following RT
for locally advanced gallbladder cancer (Sugimoto etal. 2005; Montemaggi etal. 1996).
10.3
Carcinoma of the Extrahepatic Bile Duct
10.3.1
Carcinomas of the extrahepatic biliary tree, commonly known as Klatskin tumors, are rare
malignancies that account for up to 3% of all gastrointestinal cancers. At an incidence rate
of 0.52 cases per 100,000, it is estimated that there are between 2,500 and 4,000 new
cases per year in the United States (Strom etal. 1995; Khan etal. 2005; Rajagopalan etal.
2004). Of all cholangiocarcinomas, approximately 2/3 are hilar or extrahepatic, 2030%
are distal or intrapancreatic, and 510% are intrahepatic (Nakeeb etal. 1996). The management of intrapancreatic cholangiocarcinoma is better addressed within the description
of pancreatic malignancies and ICC will be discussed in a subsequent section.
There are several recognized risk factors for cholangiocarcinoma, although the vast
majority of cancers are seen in patients with no readily identifiable predisposing condition.
Primary sclerosing cholangitis (PSC) is an autoimmune condition that causes bile duct
inflammation resulting in scarring and fibrosis. This chronic inflammation is thought to
lead dysplastic and ultimately neoplastic changes in the bile ducts. The risk of cholangiocarcinoma in patients with PSC is thought to be over a 1,000-fold higher than the general
population, and is thought to be 0.51% per year or 1040% lifetime risk (Burak etal.
2004). There does not appear to be a relationship between the duration of disease or the
concomitant presence of inflammatory bowel disease and the risk of cancer in PSC
(Chalasani etal. 2000; Broome etal. 1996).
Congenital cystic dilatations of the biliary ducts, or choledochal cysts, have a risk of
developing cancer that is proportional to the duration of disease or age of the patient. The
mechanism of cancer development in these cysts is not certain but is likely related to bile
stasis and infection as well as reflux of pancreatic secretions leading to chronic inflammation, dysplasia and cancer. The median age of cancer diagnosis in patients with these
lesions is 3035 years old, compared to the overall peak incidence of 7075 years of age
of sporadic cases (Shaib and El-Serag 2004). The risk of cancer is thought to be <1% per
year in these lesions with an overall lifetime cancer incidence of 28% if cysts are left
untreated (Lipsett etal. 1994; Chijiiwa and Koga 1993). Other known risk factors for cholangiocarcinoma include exposure to thorium dioxide found in Thorotrast, a radiologic
contrast agent used in the 1950s, liver fluke Opisthorcis viverrini infections (Shaib and
El-Serag 2004; Watanapa and Watanapa 2002; Chaimuangraj etal. 2003; Thamavit etal.
1978), and inherited BRCA2 mutations (The Breast Cancer Linkage Consortium 1999).
Epidemiologic studies have suggested associations between Clonorchis sinensis infection,
dioxide exposure, cirrhosis and cancer but the evidence supporting these is not as strong
(Shaib and El-Serag 2004; Lipshutz etal. 2002).
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10.3.2
Pathology of Extrahepatic Bile Duct Cancer
The vast (>90%) majority of Klatskin tumors are adenocarcinomas; occasionally adenosquamous or squamous carcinomas may be seen in cases of choledochal cysts or common bile duct stones (Rossi etal. 1987). Histologically and macroscopically they can be
further classified as nodular, sclerosing and papillary subtypes (Weinbren and Mutum
1983). The papillary subtype is characterized by intraluminal growth of papillary projections of tumor. These papillary growths are often friable so that some cases will present
with intermittent jaundice due to transient bile duct obstruction due to either tumor debris
or mucin produced by these lesions. Papillary tumors have a lower propensity to invade
through the duct wall into adjacent structures and are therefore associated with a better
prognosis (Lim and Park 2004; Lim etal. 2003). The sclerosing subtype is characterized
by intraductal and periductal tumor growth with significant associated desmoplastic reaction causing obstruction of the affected bile ducts with little or no perceptible mass on
imaging, while the nodular subtype often is seen as a mass that arises from and obstructs
the bile duct lumen (Lim and Park 2004; Choi etal. 2004).
10.3.3
Diagnosis of Extrahepatic Bile Duct Cancer
The present symptoms and the stage at which the disease presents, is dependent on the
location and extent of the tumor. As a result, the anatomic relationships between the tumor
and bile duct as well as its pattern of invasion and spread, impact not only the stage at
which the disease is recognized but also the treatment strategy and outcomes. The most
common presenting sign for Klatskin tumors is obstructive jaundice which is often accompanied by pruritus, acholic stool and dark urine; for this to occur the tumor must occlude
the common hepatic duct or the hepatic ducts bilaterally. In a patient with normal liver
function, unilateral hepatic duct obstruction will not result in jaundice but may cause
abnormalities in hepatic transaminases or alkaline phosphatase which may be picked up
incidentally. Serum tumor markers such as CEA, Ca-125 and Ca19-9 are of limited use in
the initial diagnosis due to low sensitivity and specificity. Elevated Ca19-9 levels can be
seen in benign biliary tract disease, but a Ca19-9 level >100 U/mL has some utility in
detecting cancer in patients with PSC (Nichols etal. 1993; Patel etal. 2000). Symptoms of
cholangitis such as fever and sepsis are unusual as initial symptoms unless there has been
prior manipulation of the biliary tree. RUQ pain, weight loss, nausea, and fatigue are nonspecific symptoms which are often seen in these cases, particularly among those with
advanced disease (Malhi and Gores 2006).
The radiologic assessment of Klatskin tumors should include the delineation of the
location and extent of biliary ductal involvement, an assessment of local invasion of liver,
vascular structures and adjacent organs, the assessment of liver volumes including the
presence of hepatic hypertrophy or atrophy, and the identification of local and distant metastatic disease. Endoscopic U/S is a commonly used imaging modality in the assessment
of patients with obstructive jaundice. U/S is useful in determining the proximal level of
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S.P. Cleary et al.
biliary ductal dilatation and obstruction as well as ruling out benign causes of jaundice
such as gallstone disease. U/S may be limited in its ability to define the distal level of
ductal involvement, the detection of mass component or differentiate between benign and
malignant strictures. Doppler U/S can be very reliable in detecting vascular involvement
in the porta hepatis (Choi etal. 2004; Bach etal. 1996; Hann etal. 1996). Cholangiography
can be invaluable in delineating the extent of biliary tract involvement and can be performed
though either a percutaneous (PTC) or endoscopic approach (ERCP). Both techniques have
the advantage of determining the proximal and distal extent of malignant obstruction but
also provide an opportunity to establish biliary decompression and drainage as well as
obtaining samples for cytologic diagnosis (Brugge 2005). MR cholangiography (MRCP)
has largely replaced endoscopic and percutaneous procedures for diagnostic purposes in
many centers and has the distinct advantage of providing three dimensional reconstructions
of the biliary tree and accurately depicting its relationship to vascular structures (Manfredi
etal. 2004; Zidi etal. 2000; Hekimoglu etal. 2008). Extensive experience with the use of
18
FDG-PET and PET-CT in the staging of Klatskin tumors is limited. PET may identify not
only the primary tumor, but also sites of extrahepatic disease that may be missed on conventional imaging (Petrowsky etal. 2006). The sensitivity and specificity of PET may approach
80% and may be more useful in nodular tumors compared to mucinous or sclerosing cancers, as these are more 18FDG avid (Kluge etal. 2001; Anderson etal. 2004). False positive
PET findings can be seen in regions of acute inflammation such as PSC and following biliary stent insertion (Keiding etal. 2000).
10.3.4
Staging Extrahepatic Bile Duct Cancer
The original classification system for cancers of the extrahepatic bile duct was proposed by
Bismuth and Corlette (1975), and describes the location and extent of bile duct involvement.
Type 1 tumors are midbile duct lesions that are proximal to the bifurcation. Type 2 tumors
extend up to the hepatic duct confluence but do not involve either the right or left hepatic
ducts. Type 3 tumors occlude the common hepatic duct as well as its confluence and extend
into the right (Type 3A) or left (Type 3B) hepatic ducts. Type 4 tumors are classified as
tumors that occlude the hepatic duct, its confluence and extend into both the left and right
hepatic ducts, or tumors with multifocal duct involvement. It is possible that in early series,
many Type 1 tumors were actually gallbladder cancers with periductal involvement that were
misclassified as arising from the bile duct. The Bismuth-Corlette classification system has
endured and is still used today because of its simplicity, and utility in predicting the extent of
biliary and hepatic resection likely required to achieve complete tumor clearance, but does
not account for issues such as local invasion, resectability and long-term outcome.
The AJCC 6th edition (Greene etal. 2002) staging system for extrahepatic bile duct
cancer is shown in Table10.3; this system describes the extent of local invasion, the presence of lymph node or distant metastases and begins to address issues of resectability since
T3 tumors may be resectable whereas, most T4 tumors would be considered unresectable.
While the AJCC 6th edition staging has not been validated in terms of clinical outcomes,
lack of associations between the AJCC 5th edition staging and resectability or survival led
265

Table10 3 AJCC 6th edition (Greene etal. 2002) TNM staging for bile duct cancer
AJCC 6th edition TNM
Description
T stage
T0
Tis
T1
T2
T3
T4
N stage
N0
N1
M stage
M0
M1

Carcinoma in situ
Tumor confined to the bile duct histologically
Tumor invades beyond the bile duct wall
Tumor invades the liver, gallbladder, pancreas and/or unilateral
branches of the portal vein or hepatic artery
Tumor invades any of the following: main portal vein or its
branches bilaterally, common hepatic artery or adjacent structures
(colon, stomach, duodenum, abdominal wall)
No regional lymph node metastases
Regional lymph node metastases
No distant metastases
Distant metastases
Table10.4 AJCC 6th edition (Greene etal. 2002) stage grouping for bile duct cancer
AJCC 6th edition stage
Definition
Stage 0
Tis
N0
M0
Stage 1A
T1
N0
M0
Stage 1B
T2
N0
M0
Stage 2A
T3
N0
M0
Stage 2B
T13
N1
M0
Stage 3
T4
Any N
M0
Stage 4
Any T
Any N
M1
Jarnagin etal. (2001) to suggest a new staging system (see Tables10.4 and 10.5) which
introduced the incorporation of lobar atrophy into the staging of bile duct cancers. Lobar
atrophy can occur due to prolonged biliary obstruction or vascular occlusion; its presence
indicates that removal of the lobe is required for tumor clearance and may be associated
with improved perioperative outcomes by inducing hypertrophy of the contralateral lobe
(Jarnagin and Shoup 2004). The system proposed by Jarnagin associated with resectability
and overall survival in the original series of patients, (Jarnagin etal. 2001) but was not
associated with outcome in other series (Hemming etal. 2005) (Table10.6).
10.3.5Surgical Resection of Extrahepatic Bile Duct Cancer

The surgical management of Klatskin tumors is extremely challenging; extensive experience in the treatment of this disease is limited to a few high-volume hepatobiliary oncology
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Table 10.5 Criteria for unresectability proposed by Jarnagin et al. (2001), Jarnagin and Shoup
(2004), and Sicklick and Choti (2005)
Criteria of unresectability for hilar cholangiocarcinoma
Patient factors
Medically unfit or otherwise unable to tolerate a major operation
Hepatic cirrhosis
Insufficient remnant liver volume to maintain adequate hepatic function
Local tumor-related factors
Tumor extension to secondary (2) biliary radicles bilaterally
Encasement or occlusion of main portal vein or its bifurcationa
Atrophy of one hepatic lobe with contralateral portal vein branch encasement or occlusiona
Atrophy of one hepatic lobe with contralateral tumor extension to 2 biliary radicles
Unilateral tumor extension to 2 biliary radicles with contralateral portal vein branch
encasement or occlusion
Metastatic disease
Histologically proven metastases in N2 lymph nodesb
Lung, liver or peritoneal metastases
onsidered relative contraindications in centers with experience in portal vein resection and
C
reconstruction
b
N2 lymph nodes are defined as the peripancreatic, periduodenal, celiac, superior mesenteric or
posterior pancreaticoduodenal lymph nodes in the AJCC 5th edition staging system. Metastases
to N1 lymph nodes (cystic duct, pericholedochal, hilar or portal nodes) are considered resectable
a
Table10.6 Clinical T-stage criteria proposed by Jarnagin etal. (2001)

Clinical stage
Criteria
T1
Tumor involving biliary confluence unilateral extension

into 2 biliary radicles
T2
Tumor involving biliary confluence unilateral extension

into 2 biliary radicles and ipsilateral portal vein involvement
ipsilateral hepatic lobar atrophy
T3
Tumor involving biliary confluence + bilateral extension into

2 biliary radicles, unilateral extension into 2 biliary radicles
with contralateral portal vein involvement, unilateral
extension into 2 biliary radicles with contralateral hepatic
lobar atrophy, or main portal vein involvement
centers. Early surgical experiences were hampered by high perioperative morbidity and
mortality as well as low rates of R0 resection (Cameron etal. 1990; Gerhards etal. 2000).
Increasing safety of hepatic resection and an aggressive approach to resection have improved
peri-operative and long-term results in this disease. Thorough preoperative imaging and
staging is crucial to proper preoperative planning as approximately 30% of tumors will be
unresectable at diagnosis and a further 3050% will be deemed unresectable at laparotomy
with a high correlation between tumor stage and resectability (Jarnagin etal. 2001; Hemming
etal. 2005; Mansfield etal. 2005; Launois etal. 1999). Preoperative laparoscopy may be
267
useful in detecting peritoneal spread or intrahepatic metastases but has limited utility in
determining local factors affecting resectability (Weber etal. 2002).
The role of preoperative biliary drainage of the future remnant liver (FRL) using percutaneous transhepatic cholangiography (PTC) is the subject of some debate. While PTC has
largely been replaced by MRCP as a diagnostic modality, preoperative biliary drainage of
the FRL has the potential advantage of relieving biliary obstruction and controlling infection. This may not only improve hepatic function and patients nutritional status prior to
surgery, but may also improve renal function and liver hypertrophy thus reducing the risk
of postoperative liver failure and morbidity. While preoperative biliary drainage is advocated by many centers, its benefits have not been conclusively demonstrated (Ebata etal.
2003; Smith et al. 1985; Wig et al. 1999; Hatfield et al. 1982; McPherson et al. 1984;
Laurent etal. 2008; Nimura 2008). The preoperative assessment of patients with hilar cholangiocarcinoma should include an evaluation of the volume of the FRL. Since many cases
require extensive hepatic resection, FRL volumes of <20% of total liver volume are associated with higher rates of postoperative liver failure and complications (Abdalla 2001; Shoup
2003). Preoperative embolization of the contralateral portal vein and segment four branches
can induce hypertrophy of the FRL and increase the safety of extensive hepatic resections
(Madoff etal. 2003; Abdalla etal. 2002a; Palavecino etal. 2009).
An aggressive surgical approach to Klatskin tumors to improve R0 resection rates was
pioneered by Japanese centers (Nishio et al. 2005; Kosuge et al. 1999; Miyazaki et al.
1999) and has gained acceptance throughout North America (Jarnagin and Shoup 2004;
Hemming etal. 2005; Ito etal. 2008) and Europe (Neuhaus etal. 1999). Resection of the
extrahepatic bile duct combined with portal lymphadenectomy and extended hepatectomy
including caudate lobe resection can achieve complete microscopic tumor clearance (R0
resection) in 5080% and 5-year survival in 3050% of cases with a perioperative mortality rate of 510% and is considered the standard of care for surgical resection of hilar
cholangiocarcinoma (Jarnagin and Shoup 2004; Hemming etal. 2005; Nishio etal. 2005;
Kosuge etal. 1999; Miyazaki etal. 1999; Ito etal. 2008; Neuhaus etal. 1999; Tsao etal.
2000). Routine resection of the caudate lobe has been advocated due to its variable biliary
drainage pattern, its proximity to the hepatic duct confluence and the observation that the
caudate is a common site of tumor recurrence (Tsao et al. 2000; Abdalla et al. 2002b;
Parikh etal. 2005; Nimura etal. 1990; Ogura etal. 1993). In selected cases with extensive
intra and periductal tumor extension into the intrapancreatic bile duct, combined hepatic
resection and pancreaticoduodenectomy (Whipple procedure) may be performed to achieve
complete tumor clearance in appropriate patients (Sasaki etal. 2006; Jarnagin etal. 2001;
Nishio etal. 2005). Due to its proximity to the bile duct, tumor invasion of the portal vein
is commonly seen and was previously considered to be a contraindication to resection due
to high complication rates associated with complex vascular resections and reconstruction.
Resection of the portal vein to achieve an R0 resection has been performed safely and
effectively in many centers; cases where portal vein resection is performed appear to have
similar long-term outcomes with minimal increases in peri-operative morbidity and mortality compared to cases resected without vascular involvement (Ebata etal. 2003; Nishio
etal. 2005; Neuhaus etal. 1999; Hemming etal. 2006).
While controversial, liver transplantation has been suggested as a treatment option in
selected cases of cholangiocarcinoma that are deemed unresectable due to the presence of
268
S.P. Cleary et al.
bilateral liver involvement, extensive vascular invasion or preexisting liver disease such as
PSC. Transplantation can achieve complete tumor clearance in cases where the disease is
confined to the liver and porta hepatis and allows complete inflow vascular resection and
reconstruction (Iwatsuki etal. 1998). Initial reports of transplantation in unresectable or
incidental cholangiocarcinoma were hampered by early tumor recurrence and poor overall
survival (Robles etal. 2004; Shimoda etal. 2001; Zheng etal. 2002) even when transplantation was combined with pancreaticoduodenectomy to improve tumor clearance
(Cherqui et al. 1995; Jonas et al. 1998; Anthuber et al. 1996). Recently, neoadjuvant
chemotherapy with external beam RT brachytherapy followed by liver transplantation
has been shown in selected centers to be associated with 5-year survival of up to 80%
(Rea etal. 2005; Sotiropoulos etal. 2004; Sudan etal. 2002). As a result of these recent
results, several centers are reevaluating the potential role of transplantation in the management of cholangiocarcinoma.
10.3.6
Radiation Therapy in Bile Duct Cancer
Cholangiocarcinomas tend to spread along the bile duct system and locally via direct
extension into adjacent structures (more common in intrahepatic and perihilar tumors),
regionally to pericholedochal, peripancreatic, hilar, and cystic lymph nodes and distantly
to the liver and peritoneum. In contrast to gallbladder cancers, most recurrences following
resection of extrahepatic cholangiocarcinoma are locoregional within the liver, tumor bed,
and regional lymph nodes in the porta hepatic or pancreaticoduodenal system and the
celiac axis, providing stronger rationale for adjuvant RT for biliary cancers vs. gallbladder
cancers. In general, the potential benefits of RT to distal bile duct cancers are less than
those to proximal bile duct cancers, in part due to the challenges in delivering tumorcidal
doses to more distal cancers and in part due to the proximity to the duodenum and other
luminal gastrointestinal tissues.
Similar to gallbladder cancer, most experience with radiotherapy for biliary cancer has
been with conventional (nonconformal) adjuvant RT (4055Gy), to a large volume, sometimes with chemotherapy (Kim et al. 2002a; Morganti et al. 2003). CRT, IORT or
brachytherapy are sometimes used to increase the doses to the highest risk regions (to
6066Gy).
10.3.6.1
Adjuvant Radiation Therapy for Perihilar Cholangiocarcinomas
The majority of series suggest a benefit to adjuvant RT in bile duct cancers. The European
Organization for Research and Treatment of Cancer (EORTC) reported improved survival
(median 19 vs. 8.3 months, p=0.0005) in 38 patients with Klatskin tumors after curative
resection, external beam RT and brachytherapy vs. 17 patients who underwent surgery
alone (Gonzalez etal. 1990). Gerhards etal. also observed improved survival in 71 patients
with resected hilar cholangiocarcinoma who received adjuvant radiotherapy (external
269
beam and brachytherapy) compared with 20 who had resection alone (24 vs. 8 months)
(Gerhards etal. 2000). Complications such as cholangitis were more common in patients
receiving brachytherapy vs. no radiation or external beam RT alone (63 vs. 40 vs. 32%,
respectively, p=0.03). Improved survival was also seen in 28 Japanese patients with stage
IV Klatskin tumor treated with external beam RT, IORT or both compared with 19 patients
who had resection alone (33.9 vs. 13.5%, p=0.014) (Todoroki etal. 2000). Locoregional
control was improved from 31 to 80% with postoperative RT. No change in survival was
seen following adjuvant radiotherapy in the patients without lymph node involvement and
negative margins. For 24 patients with positive lymph nodes, survival was better in patients
treated with external beam RT plus IORT compared to IORT alone (Kurosaki etal. 1999).
In another series, locoregional recurrences were seen in 47% of 91 patients with extrahepatic bile duct cancer treated with postoperative RT (4045Gy over 45 weeks), with or
without concurrent 5-FU chemotherapy (Kim etal. 2002b). Twenty-five patients had positive resection margins and 12 had gross residual tumor following surgery. Five year survival was approximately 30% in patients with negative margins and positive margins,
suggesting a benefit to postoperative RT used more often in patients with microscopic
residual tumor (Kim etal. 2002b).
Borghero etal. compared outcomes of 42 high risk patients with resected extrahepatic
cholangiocarcinoma (with microscopically positive resection margins or pathologically
involved nodes) who received adjuvant chemo-RT to those of 21 lower risk patients (with
negative resection margins and negative nodes) who did not receive adjuvant RT. Survival
and local recurrence rates were similar in both groups (5 year survival 36 vs. 42%, p=0.6;
5 year locoregional recurrence rate 38 vs. 37%, p=0.13, for adjuvant and no adjuvant
therapy groups respectively). The lack of a significant difference in outcomes suggests that
adjuvant chemo-RT may have benefited patients with higher risk extrahepatic cholangiocarcinoma (Borghero etal. 2008). In contrast to the above series, other studies have failed
to show a benefit of RT following surgery (Lillemore and Cameron 2000; Zlotecki etal.
1998). In a matched control study, Pitt etal. found no survival difference in patients with
perihilar cholangiocarcinoma treated with or without postoperative RT (median survival
18.4 vs. 20.1 months) (Pitt etal. 1995).
Selection bias plays a role in the above series in that patients with better performance
status and recovery from surgery are more likely to be offered RT. It is also likely that
patients with worse prognostic factors would be more likely to be offered adjuvant therapy.
Overall, most series suggest a benefit to adjuvant RT, with most marked differences seen
in patients with positive margins or involved nodes.
10.3.6.2
Neoadjuvant Radiation Therapy for Cholangiocarcinomas
Neoadjuvant therapy for cholangiocarcinoma may benefit borderline resectable cancers by
making them resectable. Also, the volume irradiated in the neoadjuvant setting is smaller,
with less risk of toxicity. McMasters etal. reported that preoperative chemo-RT was well
tolerated in nine patients who went on to have R0 resections. In contrast, margin-negative
resections were only seen in 54% of patients who did not receive preoperative therapy
270
S.P. Cleary et al.
(p<0.01). Six unresectable patients became resectable following preoperative therapy,

three with a pathologic complete response (McMasters etal. 1997). Three minor wound
infections were seen postoperatively. No anastomotic leaks or serious complications were
observed. None of the five patients with proximal bile duct cancers recurred, and one was
disease free at 32 months. Gerhards etal. evaluated the role of preoperative RT (3.5Gy3)
in minimizing the risk of implantation metastases in 21 patients who underwent resection
of proximal cholangiocarcinomas (Gerhards etal. 2000). With a follow-up time of 279
months, no patient developed implantation metastases, compared to 20% of patients who
did following endoscopic biliary drainage in a prior study.
10.3.6.3
Radiation Therapy for Unresectable Cholangiocarcinoma
Extrahepatic cholangiocarcinoma and portal or pancreaticoduodenal lymph node metastases may precipitate biliary obstruction and jaundice. Palliative low dose RT to this region
may alleviate biliary obstruction in some patients. As edema and precipitation of obstruction is possible following RT, it is most successful in conjunction with a bypass procedure
or percutaneous stent. Cameron etal. found that 1 year survival was improved in patients
treated with RT in addition to palliative stenting (38 vs. 9%, p<0.05), suggesting a palliative benefit to RT (Cameron etal. 1990).
In addition to palliation of symptoms, several studies have suggested improved outcomes with RT with or without chemotherapy for unresectable cancers. The median survival of patients with locally advanced bile duct cancers treated with RT alone or
chemotherapy ranges from 7 to 24 months, with a suggestion that outcomes are better with
more intense treatment (Monson etal. 1992). Ben-David etal. reviewed 81 patients with
extrahepatic cholangiocarcinomas and gallbladder carcinoma treated with RT (52 unresectable or with gross residual disease) and concurrent chemotherapy in 50% of patients. The
median survival and progression-free survival rates were 13.1 and 7.9 months, respectively (Ben-David etal. 2006). Grove etal. reported significantly increased median survival in patients with unresectable extrahepatic bile duct cancer receiving RT vs. those
who underwent surgical decompression alone (12.2 vs. 2.2 months, p=0.05) (Grove etal.
1991). Tollenaar etal. also found increased survival with RT following surgical decompression compared to surgical decompression alone (16 vs. 3 months, p<0.001) in 55
patients (Tollenaar etal. 1991). In a study by Crane etal, 1-year survival in 52 unresectable
patients undergoing primarily RT was 44% (Crane etal. 2002). Local control was improved
with higher doses. In another study of 31 patients with extrahepatic bile duct cancer treated
with external beam RT alone (median 50.5Gy over 5 weeks, n=17) or with brachytherapy
(5Gy3, n=14), higher doses were also associated with a longer time to recurrence (9 vs.
5 months, p=0.06) and survival (21 vs. 0% 2 year survival, p=0.015) (Shin etal. 2003).
Others have also seen improved outcomes following higher RT doses and occasional long
term survivors (Foo etal. 1984; Grove etal. 1991), but this has not been a universal finding
(Flickinger etal. 1991) (Table10.8).
271
Although brachytherapy is an attractive strategy to increase RT dose, it has been associated with an increased risk of cholangitis, duodenal ulcer and duodenal stenosis.
Brachytherapy likely has the most value in unresectable hilar cholangiocarcinomas where
the irradiated segment is at a distance of at least 2cm from the duodenum. A metal stent
can be placed across the obstructed segment following brachytherapy and can help prevent scarring and reduce the risk of cholangitis. IORT has also been used to boost the
highest risk regions (by 1025Gy) (Kurosaki etal. 1999). Toxicity is more likely with a
combination of external RT and IORT with a 1325% risk of serious toxicity in the original IORT series.
Various chemotherapy regimens (mostly 5 FU based) have been used as radiation sensitizers (Minsky etal. 1990; Morganti etal. 2000). When RT (45Gy) was combined with
doxifluridine (600mg/m2) daily, intravenous paclitaxel (50mg/m2) weekly (before RT) in
19 patients with unresectable extrahepatic bile duct cancer, the local response rate was
90% with a median survival time of 14 months. One case of gastrointestinal bleeding was
seen (Park etal. 2006). RT and gemcitabine have also been investigated in the setting of
local-regional radiotherapy for distal biliary malignancies. As the volume of tissue required
to be irradiated increases, the maximal dose of weekly gemcitabine should be reduced
(e.g., to 250mg/m2) (Morganti etal. 2003).
Overall, the use of external beam RT with or without brachytherapy, IORT or chemotherapy results in a median survival of 1214 months in patients with unresectable cholangiocarcinoma. Long-term survival is possible, reported in up to 10% of selected patients
with unresectable or recurrent biliary malignancies (Gonzalez et al. 1990; Grove et al.
1991; Minsky etal. 1990; Fogel and Weissberg 1984; Veeze-Kuijpers etal. 1990; Fritz
etal. 1994; Alden and Mohiuddin 1994; Kopelson etal. 1977) (Fig.10.1).
Baseline CT
3 months post RT
Change due to RT
2 years post RT
Fibrosis due to high

dose RT
Fig. 10.1 (a) Intrahepatic cholangiocarcinoma refractory to chemotherapy (gemcitabine and

capecitabine), treated with conformal RT (CRT) (33Gy in six fractions). (b) Three months following RT, there is hypodense change in liver within the high dose irradiated volume. (c) Two years
following RT, the tumor remains stable with less enhancement
272
S.P. Cleary et al.
10.4
Intrahepatic Cholangiocarcinoma
10.4.1
ICC are adenocarcinomas arising from the epithelial cells of the intrahepatic (second order
and higher) bile ducts. ICC have also been referred to as peripheral cholangiocarcinomas due to their origin from the higher order biliary ducts and location within the liver
parenchyma. After hepatocellular cancer (HCC), ICC is the second most common primary
liver malignancy accounting for 1020% of liver cancers (Shaib and El-Serag 2004; Welzel
etal. 2006; Yamasaki 2003). ICC is a somewhat enigmatic cancer as it is often a diagnosis
of exclusion once secondary malignancies are excluded and is often classified along with
HCC in cancer registries, though its genetic origin and biologic behavior is vastly different
from either HCC or metastases. With an increasing appreciation for this malignancy, studies from multiple continents have shown a consistent increase in the incidence and mortality of ICC beyond what would be expected by increased detection and improved
classification alone, and has an incidence of approximately 0.85 per 100,000 in the United
States (Patel 2002; Khan etal. 2002a; Wood etal. 2003; Shaib and El-Serag 2004).
Traditional risk factors for ICC include PSC, ulcerative colitis, choledochal cysts, liver
fluke infection, thorium dioxide exposure hepatolithiasis and cholodocholithiasis; as well
as viral (B and C) hepatitis, alcoholic liver disease, cirrhosis are also risk factors for extrahepatic cholangiocarcinoma and HCC, respectively (Sorensen et al. 1998). Combined,
these risk factors suggest that chronic biliary ductal inflammation and/or chronic liver
disease and cirrhosis lead to the development of ICC. It is possible that research on the
progenitor cells of HCC, ICC and an intermediary tumor cholangiolocarcinoma may yield
further incites into the origin of the cancer, and whether common and/or distinct oncologic
pathways exist for HCC and ICC. Furthermore, recent studies have suggested that smoking, diabetes, obesity, peptic ulcer disease, chronic pancreatitis, and HIV infection may be
additional risk factors for ICC (Welzel etal. 2007; Shaib etal. 2005); the increase in prevalence of these predisposing conditions may partially explain the increasing worldwide
incidence of ICC (Welzel etal. 2007).
10.4.2
Pathology of Intrahepatic Cholangiocarcinoma
ICCs are adenocarcinomas containing tubular or papillary patterns of duct structures surrounded by an abundance of desmoplastic stroma. Tumors can be classified as scirrhoustype or nonscirrhous type based on the amount of desmoplastic reaction seen on histologic
examination (Kajiyama etal. 1999). Based on macroscopic appearances and behavior, the
Liver Cancer Study Group of Japan (LCSGJ) classified ICCs into mass-forming, periductal infiltrating, and intraductal infiltrating types (Liver Cancer Study Group of Japan
2003). The mass-forming subtype is seen as a well defined mass with distinct margins in
273
the hepatic parenchyma; this subtype demonstrates a nodular, exophytic or expansive

growth pattern and has a lower propensity to infiltrate along biliary ducts towards the porta
hepatis. The mass forming subtype is prone to invasion of the portal venous system and as
a result is at higher risk of intrahepatic recurrence after resection. The periductal infiltrating subtype forms a more poorly defined mass that has a sclerosing growth pattern and
infiltrates along the biliary ducts and may invade both the hepatic parenchyma and portal
vascular structures. The intraductal infiltrating type is characterized by a prominent papillary growth within the bile duct lumen that extends proximally towards the porta hepatis
with limited superficial extraductal extension (Weinbren and Mutum 1983; Liver Cancer
Study Group of Japan 2003; Nakajima etal. 1988; Sasaki etal. 1998).
10.4.3
Diagnosis of Intrahepatic Cholangiocarcinoma
Unlike hilar cholangiocarcinomas which commonly presents early, with jaundice, ICC can
progress to a very advanced stage before they become symptomatic. Most curable lesions
are detected incidentally by identification of abnormal liver enzymes or a mass on imaging
studies. When symptoms do develop, vague abdominal pain, fatigue, weight loss and
weakness are the most common complaints (Chen etal. 1999; DeOliveira etal. 2007; Paik
et al. 2008). Tumor markers CEA and Ca19-9 are most commonly evaluated in ICC
patients. Ca19-9 is elevated in 29% of ICC cases and, when abnormal have a sensitivity of
89% and a specificity of 86%. The use of Ca19-9 as a diagnostic tool is limited by fact that
the sensitivity of this test drops to 53% in cases with concomitant PSC and the enzyme
may be elevated in cholangitis, chronic liver disease and other GI malignancies. Significant
elevations of Ca19-9 may be indicative of advanced unresectable disease (Nichols etal.
1993; Patel etal. 2000; Paik etal. 2008; Levy etal. 2005) (Fig.10.2).
Radiologic assessment of ICC often requires the utilization of multiple complementary
noninvasive imaging techniques. U/S can detect and localize suspected masses and color
Post op conformal RT plan

50Gy
Fig.10.2 Example of a CRT

plan for a pT3N1 R1 hilar
cholangiocarcinoma treated
with hepatectomy and biliary
reconstruction. Fifty gray in 25
fractions was delivered with
concurrent 5FU chemotherapy,
followed by oral capecitabine.
The patient remains alive with
no evidence of recurrence 4.5
years following surgery
274
S.P. Cleary et al.
Doppler can identify associated vascular compression or invasion. Proximal biliary dilatation can be difficult to identify with peripheral lesions but may be easily detected by U/S
on more central lesions arising in more proximal regions of the biliary tree. On CT ICCs
appear as hypodense lesions on venous phase with occasional peripheral arterial rim
enhancement. CT can be valuable in detecting intrahepatic metastases, vascular invasion,
lymphadenopathy, and may be used in the assessment of liver volumetry prior to resection.
However, CT may underestimate the extent of infiltrative cancers, particularly periductal
infiltrating lesions, due to the poorly defined borders of these tumors and the sclerosis and
fibrosis in surrounding hepatic parenchyma (Zhang etal. 1999; Khan etal. 2002b). MRI
and MRCP have the ability to define the malignant mass in relation to the biliary system.
The ability to accurately visualize strictures within the bile ducts may be particularly useful when evaluating patients with PSC. With enhanced abilities to discriminate tissue characteristics, MRI and MRCP may be able to provide insight into the extent of infiltrative
lesions but can still under-stage lesions (Manfredi etal. 2004; Braga etal. 2001; Zidi etal.
2000; Peterson etal. 1998). There is limited data on the use of FDG-PET and PET/CT in
ICC. PET-based imaging appears to reliably detect mass forming ICC >1cm in diameter
with a sensitivity and specificity similar to contrast-CT (Petrowsky etal. 2006). PET may
have higher specificity in diagnosing malignant lymphadenopathy and may be more sensitive in detecting distant metastases than the traditional CT and MRI (Anderson etal. 2004;
Kim etal. 2008).
The need for percutaneous needle biopsy is relatively common in cases of ICC vs. other
hepatic lesions, due to the similarities in radiographic appearance between ICC and either
metastatic lesions or HCC with cholangiohepatoma features. The diagnostic yield of percutaneous biopsy must always be weighed against the risk of bleeding, needle track seeding, and inconclusive pathologic examination. Immunohistochemical examination of ICC
usually demonstrates staining with CK7, CK19 and CEA with variable staining of CK20;
staining with Hepatocyte-1 would indicate a hepatocellular differentiation (Endo et al.
2008). A search for primary malignancies including upper and lower endoscopy, CT chest
and abdomen as well as mammography for females is undertaken to rule out metastatic
disease in cases of ICC where either radiologic or histologic examination is inconclusive.
10.4.4
Staging of Intrahepatic Cholangiocarcinoma
The appropriate staging system for ICC has been the subject of considerable debate in
North America and Asia. The AJCCUICC 6th edition TNM staging system (Greene etal.
2002) for ICC was based on prognostic data derived from patients with HCC, not cholangiocarcinoma. Due to the etiologic and prognostic differences between these two malignancies, it was felt that this staging system might not provide an accurate prediction of
survival in ICC. As a result, three alternate staging systems have been proposed by two
groups in Japan as well as one group in North America (Nathan etal. 2009) based on ICC
cases in the respective region; a comparison of these staging systems can be seen in
Table10.7. In 2001, Okabayashi etal. (2001) modified and simplified the AJCC system
and developed a staging system for mass-forming ICC based on clinical, diagnostic and
Regional lymph node

metastases
3C-any T N1
Any T any N M1
Direct invasion of adjacent

organs (other than
gallbladder)
Perforation of visceral
peritoneum
3B-T4N0
Multiple tumors >5cm

Tumor invading main
portal or hepatic vein
branch
3A-T3N0
Metastatic disease
Solitary tumor with

vascular invasion
Multiple tumors, all <5cm
T2N0
Solitary tumor without

vascular invasion
T1N0
Metastatic disease
4A-T4N0-meets 0/4
requirements
Any T N1-lymph node
metastases
4B-any T any N
M1-Metastatic disease
Any T any N
M1 metastatic disease
T3N0 tumors with

extrahepatic extension
Any T N1 lymph node
metastases
T3N0 meets 1/3

requirements
3A-multiple tumors
with or without vascular
invasion
3B-regional lymph
node metastases
T2N0 tumors with

vascular invasion
and/or multiple tumors
T1N0 single tumor without

vascular invasion
Nathan etal. (2009)
T2N0 meets 2/3

requirements
T1N0 meets three

requirements
Single nodule
Tumor 2cm
No venous or serous
membrane invasion
Liver cancer study

group of Japan
Solitary tumor with

vascular invasion
Solitary tumor without

vascular invasion
Table10.7 Comparison of staging systems for intrahepatic cholangiocarcinoma

Stage
AJCC
Okabayashi

275
276
S.P. Cleary et al.
pathologic features of 60 cases of resected ICC. In multivariate analysis multiple tumors,

vascular invasion and lymph node metastases were independent predictors of survival and
were incorporated into the staging system. The LCSGJ proposed a staging system for mass
forming ICC based on three factors: solitary vs. multiple tumors, size 2 cm, portal or
hepatic venous invasion and serosal invasion (Liver Cancer Study Group of Japan 2003).
Nathan etal. (2009) attempted to validate the AJCC and Japanese staging systems on 598
histologically confirmed resected cases of ICC obtained through the United States SEER
database. In this analysis, tumor size did not predict survival and as a result the AJCC
T-stage system failed to accurately differentiate patients prognosis. Multiple tumors, vascular invasion and lymph node metastases were all predictive of survival in their analysis.
While the Okabayashi staging system had an improved ability over AJCC to discriminate
between T2 and T3 lesions, due to the elimination of size criteria, there was no difference
in survival according to stage using LCSGJ system.
10.4.5
Surgical Resection of Intrahepatic Cholangiocarcinoma
Complete resection with negative microscopic margins (R0 resection) offers the best
chance of cure in patients with ICC. Noncurative resection with macroscopic (R2) or
microscopic (R1) positive margins are frequently associated with rapid tumor recurrence
within months (median=3 months), poor long-term survival (5-year survival <7%), and
offer little to no improvement in survival over conservative or palliative management
(Khan etal. 2005; Yamamoto etal. 1992, 2001; Ohashi etal. 1994). Curative resection in
ICC is hampered by the often advanced stage of disease at which the disease is discovered,
with many series reporting resectability rates are commonly <40% (DeOliveira etal. 2007;
Endo etal. 2008; Yang and Yan 2008). Furthermore, infiltrating tumors often have poorly
defined borders which presents a challenge in planning and achieving a resection with an
adequate margin. Therefore, the surgical approach to ICC includes hepatectomy that
achieves complete tumor resection with negative microscopic margins, which leaves an
adequate functioning liver remnant offers the best opportunity for curative resection. In
general, an adequate liver remnant consists of two contiguous liver segments which constitute at least 20% of the total liver volume and have adequate vascular inflow/outflow and
biliary drainage (Pawlik etal. 2004; Vauthey etal. 2000). There are many factors which
impact remnant liver function, its assessment and the actual volume required including
preexisting liver disease and chemotherapy (Clavien etal. 2007). If an inadequate liver
remnant is anticipated, hypertrophy of these segments can be induced by preoperative
portal vein embolization with both the final remnant volume and the degree of hypertrophy
associated with improved peri-operative outcomes (Ribero etal. 2007).
The vast majority of publications on surgical resection of ICC consist of small (most
<60 patients) single-center experiences. While there is some variability between these
series, aggressive curative resection is associated with a perioperative mortality rate of
<5%, and 1-year survival rates of 5075% and 5-year survival rates of 4060% (Nakeeb
etal. 1996; Chen etal. 1999; DeOliveira etal. 2007; Paik etal. 2008; Endo etal. 2008;
Okabayashi etal. 2001; Yamamoto etal. 1992). Since lymphatic spread is common in this
277
disease, the role of lymphadenectomy with hepatic resection for ICC is the subject of some
debate. Routine hilar lymphadenectomy is more commonly practiced in Asia while many
North American centers perform a lymphadenectomy on a selected basis in cases where
lymphatic spread is suspected or in highly advanced lesions (Endo etal. 2008; Yang and
Yan 2008). At this time there is little evidence that routine lymphadenectomy improves
survival as most recurrences occur in the remnant liver (Chu and Fan 1999; Shimada etal.
2001). Further extension of surgery for ICC to include routine vascular resection and/or
pancreaticoduodenectomy has not yielded improvements in outcome (Yamamoto et al.
1999; Urahashi etal. 2007). Liver transplantation has been suggested as a treatment modality for ICC in cases deemed unresectable due to tumor extent and invasion or underlying
liver disease. Initial experience of transplantation for ICC was hampered by early recurrences and poor outcomes (Pichlmayr etal. 1995), since then several centers have reported
5-year survival rates of approximately 20%. However, two recent studies by Robles etal.
(2004) and Becker et al. (2008) reporting 5-year survival rates of up to 40% following
transplantation and the experience of in hilar tumors (Rea etal. 2005; Rosen etal. 2008)
may lead to an expansion of the role of transplantation in this disease.
10.4.6
Radiation Therapy for Intrahepatic Cholangiocarcinoma
Unresectable ICC has been treated with CRT, delivered in a variety of fractionations. At
the University of Michigan, hyperfractionated RT, delivered in 1.5Gy twice daily, with
concurrent FuDR, was used to treat patients with ICC. Individualized prescription doses
were used, and up to 90Gy was delivered, dependent on the volume of liver irradiated. The
median survival of 46 cholangiocarcinoma patients was 13 months (Ben-Josef etal. 2005).
At the Princess Margaret Hospital in Toronto, ten ICC patients were treated with individualized hypofractionated RT delivered in six fractions (median dose 32.5 Gy, range
2848Gy) (Hekimoglu etal. 2008). Two patients developed transient biliary obstruction
following the first few fractions, leading to a policy of pretreatment steroids for subsequent
patients with central tumors. No other serious treatment-related toxicity was seen. The
median survival was 15.0 months (95% CI 6.529.0). Local control was common, but
recurrences outside the irradiated fields were frequent, providing rationale for combining
RT with systemic therapy.
10.5
Systemic Therapy in Biliary Cancers
10.5.1
Metastatic Disease
While surgical resection of the primary tumor is potentially curative therapy, less than 25%
of patients will be resectable at presentation and amongst those, relapse rates are high
278
S.P. Cleary et al.
(Oertli etal. 1993; Alexander etal. 1984; Wade etal. 1997; de Groen etal. 1999). Those
with unresectable or metastatic disease will receive variable palliative therapy with a
median survival most often less than 1 year. Biliary bypass or decompression stenting is
crucial if chemotherapy metabolized or cleared by the hepatobiliary system is contemplated. Once adequate biliary drainage is achieved, there must be no evidence of infection
at the start of each cycle of chemotherapy.
Generally there has not been an accepted standard chemotherapy regimen in advanced
biliary cancer. Data from a recent phase III trial evaluating a gemcitabine-cisplatin doublet (Valle etal. 2010). Historically, chemotherapy has had limited proven impact on the
natural history of this disease. This is due in part to the absence of agents with substantial activity compared with chemotherapy in other solid tumors, limited data on the
optimal therapeutic approach and the overall morbidity of treatment for this patient
population. Practices vary considerably between institutions and regions, and range
from no chemotherapy offered, due to concern over lack of efficacy and detrimental
toxicity, to offering patients multiple-drug, potentially toxic regimens without demonstrated efficacy. Clinical trials in cholangiocarcinomas and gallbladder cancer have suffered from the relative rarity of these tumors and the inclination to lump them with other
difficult and anatomically related cancers such as pancreas or hepatocellular carcinomas. In addition the difficulty in obtaining a histological diagnosis, the propensity to not
always have measurable disease and the generally morbidity of this older patient population have made standard chemotherapy trials more difficult to complete. While many
small studies have been completed, more multicenter cooperation is required for larger
randomized trials.
Carcinomas of the biliary tract and gallbladder may have biologic sufficient differences
leading to different sensitivities to chemotherapy. However, most studies to date show
similar response rates. A shorter median survival for gallbladder cancer patients is seen
compared with cholangiocarcinomas. This probably reflects a more aggressive biology of
gallbladder cancer. Due to their relative rarity it may not be practical to separate the biliary
cancers in chemotherapy clinical trials, but planned randomized studies should include
biliary tumor type in the stratification strategy.
10.5.1.1
Early Chemotherapy Studies
Fluoropyrimidines have been considered the basis of palliative chemotherapy despite
response rates (seen in small phase III trials) in the range of 010% (Falkson etal. 1984;
Takada etal. 1994; Kajanti and Pyrhonen 1994). Older combination chemotherapy including 5-FU, has not demonstrated a clear superiority over single agent 5-FU but resulted in
added toxicity (Table10.8). However, Glimelius etal. (1996) showed there was improved
quality of life for biliary cancer patients treated with 5-FU-based chemotherapy vs. bestsupportive care.
Cisplatin; the platinum analog, is a drug that has had an important impact on many solid
tumors. It synergizes with other drugs and is rarely used as a single agent. Regimens containing cisplatin, often combined with gemcitabine or 5-FU, evaluated in phase II studies
279

Table10.8 Randomized chemotherapy trials in advanced biliary cancer
References
Treatment
ORR (%) Median
n
survival
(months)
QOL
Falkson (1984)
87
5-FU vs.
5-FU + STZ vs.
5-FU + MeCCNU
10
12
10
2.55
NS
NR
Takada (1994)
36
5-FU vs.
FAM
NR
NR
5-FU/LV
Etoposide vs.
BSC
11
0
6.5
2.5
NS
33%
vs. 5%
p<0.01
Glimelius (1996) 37
Rao (2005)
54
ECF vs.
FELV
19
15
9
12
NS
Symptomatic
relief both arms
Valle (2010)
410
Gemcitabine vs.
Cisplatin/Gem
15
26
8.1
11.7
p<0.001,
HR 0.62
Pending
STZ streptozocin; MeCCNU methyl CCNU; LV leucovorin; FAM 5-FU, doxorubicin, and mitomycin; NR not reported; BSC best supportive care; NS not significant; ECF epirubicin, cisplatin, and
infused 5-FU; FELV bolus 5-FU, etoposide, leukovorin
of biliary cancer have in general reported higher response rates than those seen previously
(2045%), but also have more toxicity (2050% grade 3 toxicity) which may limit their
general applicability in this patient population (Reyes-Vidal etal. 2003; Doval etal. 2004;
Taieb etal. 2002; Mitry etal. 2002; Patt etal. 2001; Rao etal. 2005). Rao etal. (2005)
compared two triplet chemotherapy regimens in a small phase III trial, designed primarily
to evaluate if a cisplatin containing regimen improved survival over a regimen without
cisplatin. Epirubicin, cisplatin and infused 5-FU (ECF) was compared to the bolus 5-FU,
etoposide and leukovorin (FELV) combination. The primary endpoint of overall survival
was 9 months for ECF and 12 months for FELV (p=0.20). While this study of 54 patients
was underpowered to detect small differences in efficacy, it did show that the ECF regimen
may actually have been better tolerated than FELV. The authors concluded that both arms
achieved good symptomatic relief for patients with advanced disease. Many other small
studies evaluating cisplatin combined with gemcitabine are discussed below.
10.5.1.2
The Newer Chemotherapy Agents
Numerous small phase II trials in biliary cancer reflects not only the lack of consensus on
the best treatment but also an increase in research interest to evaluate new therapeutics in
biliary cancer. What has emerged with some newer chemotherapeutic agents is a level of
chemosensitivity which was not previously seen. Gemcitabine (Reyes-Vidal etal. 2003;
280
S.P. Cleary et al.
Doval etal. 2004; Gallardo etal. 2001; Kubicka etal. 2001; Penz etal. 2001; Raderer etal.
1999; Gebbia et al. 2001; Hsu et al. 2004; Knox et al. 2004, 2005; Riechelmann et al.
2007), newer 5-FU regimens (Raderer etal. 1999; Gebbia etal. 2001; Hsu etal. 2004),
capecitabine (Lozano etal. 2000; Kornek etal. 2004; Nehls etal. 2003) and platinum analogs (Reyes-Vidal etal. 2003; Doval etal. 2004; Taieb etal. 2002; Mitry etal. 2002; Patt
etal. 2001; Rao etal. 2005; Nehls etal. 2003; Sanz-Altamira etal. 1998) all appear to be
active, and perhaps more so in combinations. Larger phase II trials report objective radiological response rates (ORRs) ranging from 15 to 45%. Median survivals in general are
over 1 year, which appear superior to older series. Significant differences in response rates
between gallbladder and cholangiocarcinoma have not been seen, however, some series
report poorer overall survival for patients with gallbladder cancer compared to cholangiocarcinoma (Reyes-Vidal etal. 2003; Doval etal. 2004; Knox etal. 2005). Many of these
investigators have also reported preliminary data correlating the tumor marker; CA-19-9
with clinical response.
The nucleoside analog gemcitabine is a chemotherapeutic agent with a favorable therapeutic profile. It has been established as the standard agent in advanced pancreas cancer,
and has activity in a number of other solid cancers. Gallardo etal. (2001) showed promising single agent activity in gallbladder cancer with a response rate of 35%. Other series
have shown ORRs ranging from 15 to 30% in mixed biliary cancers, with gemcitabine
appearing consistently active and well-tolerated as a single agent (Kubicka et al. 2001;
Penz et al. 2001; Gebbia et al. 2001). It has been studied in patients with preserved or
decompressed livers and does not appear to contribute to any permanent liver damage. To
quantitate the impact on overall survival, a prospective trial with best supportive care as
the comparator arm is required but that trial is not likely to be done. A pooled analysis of
104 chemotherapy trials involving over 1,300 advanced biliary cancer patients conducted
between the years 1999 and 2006 (Eckel and Schmid 2007) concludes that gemcitabine
appears to be the most active single systemic agent. A second large review (Yonemoto
etal. 2007) also supported gemcitabine as a potential standard chemotherapy despite the
lack of phase III data. Both these reviews also concluded gemcitabine combined with a
platinum containing agent has shown consistently higher ORRs than other regimens.
Similarly, the gemcitabine-capecitabine (GemCap) couplet also looked very promising
when compared to other combinations (ORRs of 30%, median survivals of over a year and
mild toxicity) (Knox etal. 2005; Townsley and Knox 2005; Cho etal. 2005; Iyer etal.
2005; Koeberle etal. 2008). Whether Gemcitabine used in combination with other active
agents improves patient outcomes further required evaluation in a phase III trial. Mounting
a large phase III trial in biliary cancer has been difficult. Two large, well-designed phase
III trials were planned in the early 2000s and are described below.
One of the earliest trials planned was led by the National Cancer Institute of Canada
(NCIC)s Clinical Trials Group to evaluate the GemCap combination in a phase III trial
with single agent gemcitabine as the comparator arm and overall survival as the primary
endpoint. This design is stratified for gallbladder vs. bile duct cancer as well as performance status and extent of disease. This trial suffered from multiple delays to activate and
reluctance of international partners to join a trial of a relatively rarer tumor type. It finally
opened in late 2008 but closed in 2009 when new data from the British ABC-02 suggested
the control arm of single agent gemcitabine may no longer be adequate.
281
The National Cancer Research Network in Great Britain recently conducted a successful randomized trial of gemcitabine vs. a gemcitabine-cisplatin doublet (ABC-02) (Valle
etal. 2010). This is the largest randomized chemotherapy clinical trial in biliary cancer to
date. The control arm of single agent gemcitabine was delivered at a standard 1,000mg/m2
days 1, 8, 15 q 28 days (Takahashi etal. 2004), while the experimental doublet combined
gemcitabine 1,000mg/m2 day 1, eight with low dose cisplatin at 25mg/m2 dL, d8 all q 21
days (CisGem). A preliminary analysis at 86 patients showed both arms to be active but
with a trend to improved responses time-to-progression and 6 month progression-free survival in the combination arm. An increase in toxicity, especially lethargy was seen with the
combination (Valle et al. 2006). A preplanned expansion continued to accrue over 400
patients in order to have 80% power to detect an increase in median overall survival from
8 to 11 months (2-sided a at 5% level). Patients were randomized 1:1 and stratified by
primary site of disease, center enrolled, performance status and disease extent. Three hundred and twenty-four patients were accrued between May 2005 and September 2008. The
initial 86 patients in the preliminary study were included in the final analysis for a total of
410 patients evaluated with intention-to-treat analysis. Eligible patients for ABC-02 had
histologically or cytologically verified nonresectable or recurrent/metastatic cholangiocarcinoma, gallbladder or ampullary carcinoma and receiving first-line systemic therapy.
They required ECOG performance status of 02, adequate biliary drainage and were free
of infection at enrollment. Screening biochemistry included total bilirubin <1.5 the upper
limit of normal (ULN) and AST, ALT and ALP <3 ULN. The trial met its primary endpoint demonstrating a median overall survival of 11.7 months for the CisGem doublet over
8.1 months for gemcitabine alone (p<0.001, HR 0.64 (0.520.8)). This is the first clear
demonstration of an overall survival advantage with chemotherapy in biliary cancer, representing a 36% risk reduction in death. Exploratory sub-group analysis favored CisGem
across all stratified groups including primary site, extent of disease and performance status. Progression-free survival was 8.4 months vs. 6.5 also favoring CisGem (p<0.001, HR
0.63 (0.510.77)), and objective response rates were 26 vs. 15% (Table10.8). Quality of
life analysis is pending (Fig. 10.3).
ABC-02 toxicity to date has been reported as grade 3/4 adverse events on study and
was very similar and modest between the two arms. Myelosuppression by gemcitabine vs.
CisGem (% grade 3/4) was as follows: neutropenia; 17 vs. 25, thrombocytopenia; 7 vs. 9,
anemia; 3 vs. 8, infection with neutropenia; 7 vs. 10. Other notable toxicity (Gem vs.
CisGem (% grade 3/4)) included: lethargy; 17 vs. 19, nausea and vomiting; 9 vs. 9. Overall
no significant serious toxicity differences were noted between the two arms. There may
be significant differences in <grade 3 toxicity rates that have not yet been reported.
The results of the ABC-02 trial taken in its entirety should place the CisGem regimen
as the new standard of care for first line chemotherapy in selected patients with preserved
performance status and organ function. The relative ease of administration and general
availability of the gemcitabine and cisplatin as agents should position this regimen as the
control arm or backbone for additional studies. It is important to emphasize that this relatively late advancement for advanced biliary cancer patients only occurred because of a
concerted multiinstitutional collaboration in this rare tumor site.
Oxaliplatin is a third generation platinum agent with a generally better toxicity profile
and different spectrum of activity than cisplatin. It has been established as a standard of
282
Valle etal. 2010)
100
Overall Survival (%)
Fig. 10.3 ABC-001 survival

curve and progression-free
survival (Figure courtesy of
S.P. Cleary et al.
Hazard ratio for death,

0.64 (95% CI, 0.520.80)
P<0.001
75
Cisplatingemcitabine
50
Gemcitabine
25
0
0
12
16
20
24
28
32
3
8
2
2
Months since Randomization

No. at Risk
Gemcitabine
206
Cisplatingem- 204
citabine
151
167
97
120
53
76
28
51
15
28
4
17
Progression-free Survival (%)
100
Hazard ratio for disease progression,
0.63 (95% CI, 0.510.77)
P<0.001
75
50
Cisplatingemcitabine
25
Gemcitabine
0
0
No. at Risk
Gemcitabine
206
Cisplatingem- 204
citabine
12
16
20
24
28
32
1
1
1
1
Months since Randomization

115
140
56
95
18
36
4
18
3
10
1
4
care in colon cancer. In combination with either gemcitabine (GEMOX) (Andre et al.
2004) or capecitabine (XELOX) (Nehls etal. 2003) promising response rates were seen in
phase II trials, with encouraging median survivals ranging from 9 to 15 months. GEMOX
was further evaluated in a 70 patient multicenter phase II trial of both intra and extrahepatic cholangiocarcinomas and gallbladder cancers (Andre etal. 2006). ORR persisted in
the 30% range, overall survival was 8.3 months. Toxicity was moderate but quite manageable. At this time it is not clear whether GEMOX offers an advantage over gemcitabinecisplatin regimens.
10.5.1.3
Targeted Therapies
Many advances are being made with targeted therapy in various solid tumor adenocarcinomas. Strategies include blockade of angiogenesis-related signaling, Akt survival pathways
283
or the epidermal growth factor receptor (EGFR) signaling. While evaluating these strategies in biliary cancer are barely underway, it is likely that lessons learned from more common cancers will translate eventually into cholangiocarcinomas and gallbladder cancers.
Philip etal. evaluated the oral EGFR tyrosine kinase inhibitor; erlotinib, in advanced
biliary cancer (Philip etal. 2006). Over half of the patients had received one prior chemotherapy. EGFR expression by immunohistochemistry was detected in 81% of the patients
tumors. Three patients had partial responses (7%) and 17% of patients were progression
free at 6 months. These results suggest a therapeutic benefit to EGFR blockade with erlotinib in some patients with biliary cancer. Activity of EGFR inhibition should be reevaluated in biliary cancer in light of emerging data of influence of k-ras mutation and lack of
response to EGFR inhibitors seen in colon cancer. It may be possible to identify a more
susceptible subpopulation.
Recent focus on the Raf and MAPK/Erk kinase (Hemming etal. 2006) pathway in
drug development may advance biliary cancer. A MEK 1/2 inhibitor, AZD 6244 showed
promise in a phase II trial of advanced biliary patients who had failed prior chemotherapy. ORRs and potentially prolonged PFS were reported in abstract form (Bekaii-Saab
etal. 2009). This and other MEK targeted agents warrant priority investigation in biliary
cancers.
10.5.2
Adjuvant Systemic Therapy
In any cancer, where the cure rates with resection are poor and at least modestly effective
metastatic systemic therapy is available, a strong argument for adjuvant therapy can be
made. The current paradigm of developing such a treatment starts first with establishing a
safe, well-tolerated regimen that prolongs life in the advanced disease. Development of
adjuvant therapy in biliary cancer has been hindered by the lack of consensus as to what
chemotherapy standard for advanced disease, should be brought forward for adjuvant
evaluation. The recent data on the CisGem regimen should change that. It is also a rare
tumor, where relatively few patients are resectable at presentation, and so it would be difficult to complete a large randomized adjuvant trial.
The data surrounding adjuvant chemotherapy are very limited. The largest trial to date
was conducted in Japan by Takada etal. and published in 2002 (Takada etal. 2002). This
phase III multicenter randomized trial accrued patients with resected pancreaticobiliary
cancers to postoperative chemotherapy consisting of mitomycin C and 5-FU given IV at
surgery followed by oral 5-FU until progressive disease (MF arm) vs. surgery alone.
Patients were stratified by tumor site and whether R0 resection was achieved. The trial
accrued 118 patients with bile duct cancers, 112 patients with gallbladder cancer and 48
patients with carcinoma of the ampulla of Vater. The 5-year survival rate in gallbladder
cancer in per protocol analysis was significantly better on the MF arm than the control arm
(26 vs. 14%, p=0.0367). This was not statistically different in the intention-to treat analysis. There were no significant differences between patients with bile duct or ampulla of
Vater carcinomas between the MF and control arms (5-year survival MF vs. control: 27 vs.
24% in bile duct cancer and 34 vs. 28% in the ampullary cancers). A third to one half of
patients on study did not have a R0 resection, and so this trial did not ask a pure adjuvant
284
S.P. Cleary et al.
question. It makes sense that adjuvant chemotherapy might impact on gallbladder cancer
due to its high rate of metastatic spread. A confirmatory trial in gallbladder cancer has not
been done.
Further adjuvant chemotherapy data specific to distal bile duct cancers may be forthcoming from the European Study Group for Pancreatic Cancer-3 trial (ESPAC-3), a large
intergroup randomized adjuvant pancreas cancer trial. There is a planned subset analysis
of distal bile duct cancers resected with pancreaticoduodenectomy with clear margins and
randomized to 5-FU or gemcitabine or no therapy. This trial completed accrual but the
analysis has not been presented to date. At this time the literature does not support routine
adjuvant chemotherapy in biliary cancer, although it is often offered to patients with high
risk disease and a good performance status.
As previously discussed, there have been numerous series of adjuvant or neo-adjuvant
chemo-RT with differing conclusions and no level I evidence to mandate adjuvant therapy
as a standard practice (see Sects.3.6.1 and 3.6.2 for further discussion). A recently activated South Western Oncology Group (SWOG)-led phase II study of adjuvant therapy for
80 resected extrahepatic biliary and gallbladder cancer patients should provide insight
regarding outcomes, toxicity and feasibility of a multidisciplinary standardized adjuvant
treatment regimen (12 weeks of Gemcitabine/capecitabine followed by CRT or IMRT
(5229Gy) delivered over 6 weeks with concurrent capecitabine) in these patients.
10.6
Conclusions and Future Work
Gallbladder and bile duct cancers are challenging cancers to treat with an overall poor
prognosis. Treatment should be multidisciplinary and limited to tertiary centers. Supportive
care and appropriate use of biliary stents are crucial for all patients with biliary cancers as
biliary decompression is often a priority. Aggressive surgery to obtain negative microscopic margins (R0 resection) offers the best option for cure in biliary tract and gallbladder
cancer. Extended hepatic resection with portal lymphadenectomy and biliary tract resection is the current standard of care for resection of hilar cholangiocarcinoma. The extent of
surgery required for to reliably obtain an R0 resection in gallbladder cancer remains the
subject of some debate and research, and may depend on the stage and clinical presentation. Hepatic resection remains the mainstay for treatment of ICC, but the role of lymphadenectomy and bile duct resection remain controversial and may depend on the stage and
macroscopic tumor subtype. Vascular resection and multivisceral resection can now be
performed safely with good long-term outcome and have permitted a surgical approach to
more advanced tumors. Recent results have led to a reappraisal of the use of transplantation with neoadjuvant chemoradiotherapy in hilar and intrahepatic cholangiocarcinoma;
patient selection appears to be of critical importance and requires further study. There is
rationale for increased use of RT and chemotherapy, in combination with surgery, as outcomes remain poor overall. Advanced RT techniques allow higher doses to be delivered
safely, and improved outcomes following RT and chemotherapy in the adjuvant setting
and for unresectable disease have been suggested, especially for patients without R0 resections or with positive nodes.
285
With the completion of the large randomized phase III trial (ABC-02), a new chemotherapy standard of care has been established for advanced, unresectable biliary cancer.
The cisplatin/gemcitabine couplet was demonstrated to improve overall survival over
single agent gemcitabine, with a hazard ratio of 0.64 (Valle etal. 2010). Toxicity appears
acceptable for this patient population. It is expected that this Cis/Gem doublet will
be adapted as a first-line chemotherapy globally in suitable patients. It is also expected
that with this success more clinical research aimed at defining the most optimal management of biliary subtypes, evaluating combinations with targeted therapy or in the
second-line setting and with RT will gain support. A safe and effective standard in
advanced disease should spur on prospective adjuvant and neoadjuvant studies. Future
ambitious proposals will require multiinstitutional and international collaboration to
accrue sufficient numbers of patients, continued support from clinical trial cooperative
groups and the ongoing commitment from industry to help develop treatments for this
orphan tumor site.
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Neuroendocrine Cancers
11
John A. Jakob, Carlo Mario Contreras, Eddie K. Abdalla,

Alexandria Phan, and James C. Yao
Abbreviations
5-HIAA
5-HT
5-HTP
ACTH
CGA
CGH
CHD
CT
DOTA
DTPA
EGF
FAS
FDG
HACE
HAE
IFN a
LOH
MEN1
MRI
mTOR
NCCN
NET
NF1
5-Hydroxyindoleacetic acid
5-Hydroxytryptophan
5-Hydroxytryptamine
Adrenocorticotropic hormone
Chromogranin A
Comparative genomic hybridization
Carcinoid heart disease
Computed tomography
Tetraazacyclo-dodecanetetra-acetic acid
Diethylenetriamine pentaacetic acid
Epidermal growth factor
5-Fluorouracil, doxorubicin, and streptozocin
2-Fluoro-2-deoxy-D-glucose
Hepatic artery chemoembolization
Hepatic artery embolization
Interferon a
Loss of heterozygosity
Multiple endocrine neoplasia type 1
Magnetic resonance imaging
Mammalian target of rapamycin
National comprehensive cancer network
Neuroendocrine tumor
Neurofibromatosis type 1
J.A. Jakob, A. Phan, and J.C. Yao (*)

Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
e-mail: jyao@mdanderson.org
C.M. Contreras and E.K. Abdalla
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center,
1515 Holcombe Blvd, Houston, TX 77030, USA
301
302
NSE
NYHA
PDGF
PET
PFS
RFA
SEER
SNP
TGF b
TSC2
TTP
VEGF
VHL
VIP
ZES
J.A. Jakob et al.
Neuron-specific enolase
New York Heart Association
Platelet-derived growth factor
Positron emission tomography
Progression-free survival
Radiofrequency ablation
Surveillance, Epidemiology, End Results
Single nucleotide polymorphism
Transforming growth factor b
Tuberous sclerosis complex 2
Time to progression
Vascular endothelial growth factor
von HippelLindau syndrome
Vasoactive intestinal peptide
Zollinger-Ellison syndrome
11.1
Introduction
Neuroendocrine tumors (NETs) originate from neuroendocrine cells which are located
throughout the body. This chapter focuses on low- to intermediate-grade NETs of the gastrointestinal tract, though the term neuroendocrine tumor can also denote other diseases
such as small-cell carcinoma of pulmonary and extrapulmonary origins, thyroid medullar
carcinoma, neuroblastoma, and Merkel cell tumors.
Islet cell carcinomas, also known as pancreatic endocrine tumors, pancreatic NETs, or pancreatic carcinoid, arise from the islets of Langerhans. Low- to intermediate-grade NETs arising from other sites are generally called carcinoids and are most commonly localized in the
gastrointestinal tract and bronchopulmonary tree. Both of these tumor groups share the capacity for hormone production and usually have indolent clinical courses. Presenting symptoms,
when present, are caused by excess hormones, local tumor growth, and metastasis. Surgical
resection is the curative approach for localized disease. In unresectable, metastatic disease, the
introduction of somatostatin analogs such as octreotide have significantly improved quality of
life, and the potential tumor stabilization properties of newer, targeted agents are the subject of
ongoing phase III trials. Nonetheless, advanced NETs remain largely incurable and often
require the concerted efforts of a multidisciplinary team for effective palliation.
11.2
Epidemiology
The incidence of NETs varies with gender, age, and race. The overall incidence in
the United States is estimated at 5.25 cases per 100,000 (Yao etal. 2008a). Most NETs
progress slowly and may remain undiagnosed for many years. Carcinoid tumors were
303
11 Neuroendocrine Cancers
Table11.1 Organ distribution of neuroendocrine tumors (carcinoids and pancreatic islet cell tumors)
Distribution (%)
Pulmonary
27
Gastrointestinal
Stomach
Small intestine
Appendix
Colon
Rectum
Pancreas
58
6
17
3
4
17
6
Unknown/other
15
Adapted from analysis of SEER 17 registry, 20002004 in Yao etal. (2008a).
found in 0.651.2% patients during unselected small intestine necropsy (Moertel et al.
1961; Berge and Linell 1976). These tumors are usually diagnosed in the sixth and seventh
decades. NETs have been described as more common among African Americans owing to
a higher incidence of rectal carcinoid (Modlin etal. 2003; Yao etal. 2008a).
The gastrointestinal tract is the most common primary site of NETs. It accounts for 58%
of all carcinoid tumors (Yao et al. 2008a). The distribution of NETs is illustrated in
Table11.1.
11.3
Prognosis
The overall prognosis of patients with NETs varies by histologic grade, extent of disease,
and site of primary tumor. High-grade NETs have high metastatic potential and an aggressive growth pattern. Treatment strategy is similar to that for small cell carcinoma of the
lung. Most low- to intermediate-grade NETs have a more favorable prognosis than adenocarcinoma of the same primary site. The median overall survival of patients with localized
low- to intermediate-grade NETs is 223 months, according to a recent analysis of the
Surveillance Epidemiology and End Results (SEER) database of patients registered from
1973 to 2004. For those patients with regional disease, defined as involvement of regional
lymph nodes or extension to adjacent tissue or both, median overall survival is 111 months.
For metastatic disease, median overall survival plummets to 33 months (Yao etal. 2008a).
The prognoses of NETs by anatomical site will be discussed in Sects.11.7 and 11.8.
11.4
Pathogenesis and Molecular Biology
NETs may occur sporadically or in the context of an inherited disorder. Little is known
about the pathogenesis of sporadic NETs. The multiple endocrine neoplasia type 1 (MEN1)
gene, mutated in Multiple Endocrine Neoplasia, type I, whose germline mutation
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J.A. Jakob et al.
p redisposes to inherited islet cell carcinomas does manifest mutation (20%) and loss of
heterozygosity (LOH) (70%), in sporadic islet cell carcinomas (Toumpanakis and Caplin
2008). Menin, the protein product of the MEN1 gene, appears to exert its tumor suppressor
action via multiple mechanisms, including transcription regulation/chromatin remodeling
via interaction with histone methyltransferases, direct regulation of cell cycle progression
via interaction with the genetic loci of the cyclin-dependent kinase inhibitors p18ink4c, and
p27kip1, as well as facilitation of apoptosis by increased production of caspase 8 (Yang and
Hua 2007).
Interestingly, the two most frequently mutated tumor suppressors in human cancer, p53
and PTEN, are not altered in NETs of the gastroenteropancreatic system. p53 mutations
have been reported in atypical pulmonary carcinoids (Schnirer etal. 2003). PTEN protein
expression was not altered in a limited sample size of nine assayed carcinoid lesions,
although expression was lost in poorly differentiated neuroendocrine carcinomas (Wang
etal. 2002).
The elevated expression of various angiogenesis and tumor growth factors, such as
vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming
growth factor (TGF), platelet-derived growth factor (PDGF), and their receptors, is found
in carcinoid tumors (Terris etal. 1998; Krishnamurthy and Dayal 1997; Chaudhry etal.
1992). In addition, somatostatin receptors are expressed in the majority of carcinoids.
Investigators have employed positional cloning techniques to identify novel candidate
tumor suppressor or oncogene loci for sporadic NETs, without finding specific candidate
genes. In a series of 12 foregut tumors (mostly islet cell carcinomas) and 14 midgut tumors
(mostly carcinoids of the ileum), comparative genomic hybridization (CGH) identified gain
of chromosome arm 20q as the most common chromosome imbalance in the foregut tumors
(58%), and gain of 17p and 19q as the most common imbalance in midgut tumors (57%
each). This study also demonstrated loss of chromosome arm 18q in 43% of midgut carcinoid tumors (Tonnies etal. 2001). A separate investigation of 18 midgut carcinoids with
CGH revealed loss of 18q22-qter as the most common chromosomal abnormality (Kytola
et al. 2001). Higher-resolution, single-nucleotide polymorphism (SNP)-based array technology has recently confirmed frequent loss of chromosome 18 (34%) (Kim etal. 2008). As
of early 2009, however, no oncogene or tumor suppressor candidates unique to sporadic
NETs have been identified via positional cloning or related technologies.
A significant minority of NETs, 510%, occur in the context of multiple endocrine neoplasia, type I (MEN1), an autosomal dominant disorder characterized by pituitary tumors,
hyperparathyroidism, and islet cell carcinomas. MEN1 syndrome-related NET disease differs from sporadic disease insofar as it consists of a unique pattern of symptomatic and
nonsymptomatic lesions. Symptomatic lesions include duodenal gastrinomas, which are
the cause of Zollinger-Ellison syndrome, a condition that afflicts nearly 60% of MEN1
patients with peptic ulcers, gastroesophageal reflux, and diarrhea. Characteristic nonsymptomatic lesions include small, duodenal foci of somatostatin expression and pancreatic
microadenomas and macroadenomas. These pancreatic lesions tend to be asymptomatic
and express glucagon or pancreatic polypeptide (PP). Roughly 20% of MEN1-associated
pancreatic macroadenomas are insulinomas, causing hyperinsulinemic hypoglycemic
syndrome. Of note, approximately 10% of pancreatic islet cell carcinomas are associated
with MEN1 syndrome (Anlauf etal. 2007).
305
Other inherited disorders, such as neurofibromatosis type 1 (NF1), von HippelLindau

syndrome (VHL), and tuberous sclerosis complex 2 (TSC2), predispose to NETs.
Carcinoids of the ampulla of Vater, mediastinum, and duodenum are seen in roughly 1%
of patients with NF1; islet cell carcinomas are associated with 517% and <1% of VHL
and TSC2 patients, respectively. These diseases account for far less NET disease burden
then sporadic and MEN1-related tumors (Anlauf etal. 2007).
11.5
Pathologic Classification
NETs are derived from neuroectodermal cells and are characterized by monotonous sheets
of small round cells with uniform nuclei and cytoplasm (Fig.11.1). Neuroendocrine cells
store endocrine or paracrine substances in membrane-bound vesicles, releasing them by a
process of exocytosis. Typical carcinoid cells have minimal mitotic activity, cytological
atypia, or nuclear polymorphism. Pulmonary carcinoid with more than two mitoses per ten
high power fields are considered atypical and are more likely to metastasize and recur.
Tumors with high mitotic activity or necrosis are called poorly differentiated, anaplastic,
Fig.11.1 Histologic appearance of neuroendocrine tumors (NETs). Microscopic appearance of low

grade NET. (a) Standard microscopy showing few mitoses, no necrosis, and large number of tumor
vessels. (b) Immunohistochemical staining for chromogranin A
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J.A. Jakob et al.
or high-grade neuroendocrine carcinoma. They have a behavior similar to small cell carcinoma of the lung and have a poor prognosis. If tumor grade cannot be determined based on
available tumor specimen, a repeat core needle biopsy is recommended because the results
may determine treatment options.
11.6
Clinical Presentation of NETs and Diagnostic Work Up
The classic symptoms associated with hormonal production such as flushing and diarrhea
in carcinoid syndrome are typically present in the setting of metastases. These symptoms
can be insidious in onset and present years before diagnosis. Symptoms of local and
regional carcinoid and islet cell carcinoma disease, with the exception of hypoglycemia
in insulinoma, tend to be vague. Symptoms often occur secondary to acute obstruction
from primary tumor, mesenteric fibrosis, or ischemia secondary to mesenteric vascular
involvement.
Multiple diagnostic procedures are frequently performed, including computed tomography (CT) of the abdomen and pelvis, esophagogastroduodenoscopy, and colonoscopy,
sometimes without achieving a definitive diagnosis. This situation is particularly frustrating when clinical suspicion of carcinoid syndrome is great; fortunately, serum and
urine laboratory markers, described below in Sect.11.6.1, are frequently performed in
parallel with more invasive testing and can confirm the diagnosis, if not localize the
primary lesion.
11.6.1
Neuroendocrine Tumor Laboratory Tests and Markers
Frequently measured tumor markers in carcinoid disease include serum chromogranin A
(CGA) and 5-hydroxyindoleacetic acid (5-HIAA) levels in a 24-h urine sample. Tryptophanrich food should be avoided during urine collection for 5-HIAA levels (Feldman and Lee
1985). False-positive results occur with the consumption of serotonin-rich foods such as
plantains, pineapples, bananas, kiwifruit, plums, tomatoes, butternuts, walnuts, shagbark
hickory nuts, mockernut, pecans, and sweet pignuts. Common medications that affect urinary 5-HIAA levels include guaifenesin, acetaminophen, and salicylates.
Serum CGA level is a very sensitive, but nonspecific, marker for all NETs. Elevations
are frequently seen among patients on proton pump inhibitors or with poor renal function.
Urine 5-HIAA and serum CGA may also serve as biochemical markers for monitoring the
disease progression and the treatment response. Immunohistochemical markers used to
confirm a carcinoid diagnosis on actual tumors include neuron-specific enolase (NSE),
CD56, CGA and synaptophysin (summarized in Table11.2).
In addition to the above markers, NETs also synthesize many bioactive amines and
peptides such as 5-hydroxytryptamine (5-HTP), 5-hydroxytryptophan (5-HT), serotonin,
307
Table11 2 Immunohistochemical markers of neuroendocrine carcinoma
Marker
Significance
Neuron-specific enolase
Cytoplasmic glycolytic enzyme, neuroendocrine

marker
Synaptophysin
Presynaptic vesicle membrane glycoprotein,

present on normal and neoplastic
neuroendocrine cells
Chromogranin A
Acidic protein, universal marker for

neuroendocrine tissue
CD56
Neural adhesion molecule
insulin, gastrin, glucagon, somatostatin, vasoactive intestinal polypeptide (VIP), growth

hormone, adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone, PP,
calcitonin, substance P, pancreastatin, and various growth factor such as transforming
growth factor-b, (TGF-b) and PDGF (Schnirer etal. 2003).
11.6.2
Imaging
11.6.2.1
Endoscopy
Endoscopic techniques are designed to localize tumors and to facilitate biopsy retrieval.
Upper endoscopy can often locate gastric and duodenal carcinoid tumors. Colonoscopy is
used in the identification of colorectal carcinoids. Conventional endoscopy is generally not
useful in patients with jejunal or ileal tumors. Instead, double-balloon enteroscopy and capsule endoscopy are emerging techniques that could play a prominent role for tumors in these
locations. The disadvantages of endoscopy include the requirement for patient sedation and
the difficulty in visualizing small, submucosal lesions. Endoscopic ultrasound is useful in
the assessment, visualization, and biopsy of pancreatic and some small duodenal NETs.
11.6.2.2
Computed Tomography and Magnetic Resonance Imaging
Both CT and magnetic resonance imaging (MRI) can be used for diagnostic workup. The
utility of CT and MRI imaging for diagnosis of a typical small bowel carcinoid of the ileum
is limited at best; usually the presence of such lesions can only be inferred by the presence
of luminal narrowing, adenopathy, and mesenteric fibrosis. CT and MRI technologies are
far more useful in the detection of hepatic metastases, which frequently present more convenient sites for biopsy to confirm diagnosis.
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J.A. Jakob et al.
CT and MRI technologies are more adept in the detection of primary pancreatic islet
cell carcinomas; sensitivities of CT and MRI are 6482% and 74100%, respectively
(Tamm etal. 2007).
11.6.2.3
OctreoScan
Somatostatin receptor scintigraphy has improved the visualization of NETs. OctreoScan utilizes a somatostatin analog, 111In-labeled diethylenetriamine penta-acetic acid octreotide
(DTPA-D-Phe1-octreotide) to visualize somatostatin receptor-positive tumors. Compared with
routine CT or MRI, OctreoScan detects additional metastases in about one third of patients. In
addition, OctreoScan may help to identify insulinoma and gastrinoma when conventional
scans are negative. The overall sensitivity of OctreoScan is 8090% (Krenning etal. 1994).
11.6.2.4
Positron Emission Tomography (PET)
There is little experience with positron emission tomography (PET) imaging in the evaluation of NETs. Because 2-fluoro-2-deoxy-D-glucose (FDG) PET scan only identifies
tumors with moderate to high proliferative activity, false-positive and false-negative results
are common. 11C-labeled 5-HT PET is used to image tryptophan metabolism and is superior to routine FDG PET or CT scan (Eriksson etal. 1993, 2002). Currently, 11C-labeled
5-HT PET is not available in North America.
11.6.2.5
Other Nuclear Scintigraphy Techniques
Metaidobenzyguanidine (MIBG) is absorbed by carcinoid tumor cells. 131Iodine-labeled
MIBG (131I-MIBG) has an overall sensitivity of 5570% (Krenning etal. 1994; Vinik etal.
1989; Feldman 1989; Hanson et al. 1989). Although 131I-MIBG is less sensitive than
OctreoScan, it may be used in patients who are treated by long-acting octreotide.
11.7
Carcinoid Clinical Behavior by Site
11.7.1
Gastric Carcinoid
Gastric carcinoid tumors are divided into three distinct groups. Group one (75%) is associated with chronic atrophic gastritis, group two (510%) with Zollinger-Ellison syndrome
(510%); and group three (1525%) is sporadic gastric carcinoid tumors (Nilsson 1996).
Group three has the worse prognosis of the subtypes, frequently presenting with metastatic
309
Table11 3 The clinical features of gastric carcinoid by group
Clinical
Clinical feature
Tumor size
feature
(cm)
Metastasis
Prognosis
Group 1
Chronic gastritis
<1
10 %
Good
Group 2
ZES, gastrinoma
<1.5
25%
Intermediate
Group 3
Atypical carcinoid
>1
Frequent
Poor
ZES, Zollinger Ellison syndrome.
disease. Analysis of the SEER database demonstrates a median overall survival of just 13
months for patients with metastatic gastric carcinoid (Yao etal. 2008a). Clinical features
of the three types of gastric carcinoids are summarized in Table11.3.
11.7.2
Small Intestine Carcinoid
Small intestine carcinoid tumors, the carcinoid most frequently associated with typical
symptoms of carcinoid syndrome, are usually found in the distal ileum within 60cm of the
ileocecal valve. At diagnosis, multiple putative primary lesions tend to be present in
multiple sites. Analysis of SEER data from 1973 to 2004 demonstrates that jejunum and
ileum carcinoids (30%) were far more likely then rectal (5%) or appendiceal (9%) lesions
to be diagnosed with distant metastases. Of note, only 9% of duodenal carcinoids present
with distant metastases. The median overall survival for duodenal and jejunum/ileum carcinoids is 107 and 111 months, respectively, in localized disease and 57 and 56 months,
respectively, with metastases (Yao etal. 2008a).
11.7.3
Appendiceal Carcinoid
Carcinoid tumors are found incidentally in 1 out of 200300 appendectomies in young adults.
For appendiceal carcinoid of less than 1cm in diameter, surgical resection is sufficient. For
tumors >2cm in diameter, a significantly higher risk of metastasis exists and a right hemicolectomy is recommended. The optimal treatment of lesions between 1 and 2 cm is controversial,
but right hemicolectomy is recommended if high risk features such as vascular invasion are
observed. (Stinner and Rothmund 2005). Median overall survival of disease restricted to the
appendix is greater than 360 months; individuals with metastatic disease at diagnosis fare far
worse, with a median overall survival of only 27 months (Yao etal. 2008a).
11.7.4
Rectal Carcinoid
Rectal carcinoids occur most frequently in middle-aged adults. These tumors are found incidentally in approximately 1 in 2,500 proctoscopies as a small yellow-gray submucosal nodule in the walls of the rectum. The majority of rectal carcinoids are less than 1cm in diameter
and do not metastasize, whereas 6080% of lesions larger than 2cm do. Local excision is
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adequate for rectal carcinoids <1cm. Lesions measuring 11.9cm without evidence of highrisk features such as muscularis, lymphovascular, or perineural invasion can also be excised
locally (Kwaan etal. 2008). Patients with tumors displaying any of these high-risk features
should prompt consideration of a more aggressive segmental rectal resection, sphincter-sparing if possible. In patients with metastatic rectal carcinoid at diagnosis, excision is generally
performed with palliative, not curative intent (Wang and Ahmad 2006). The median overall
survival of patients with metastatic rectal carcinoid is just 22 months (Yao etal. 2008a).
11.8
Clinical Features of Islet Cell Tumors
11.8.1
Insulinomas
Insulinomas are the most common type of islet-cell tumor. The peak incidence of insulinomas occurs in patients between 30 and 60 years of age, and these tumors are more frequent
in women. These tumors are usually benign (90%), intrapancreatic (nearly 100%), solitary,
and small (<2cm). About 5% of these tumors are associated with the MENI syndrome;
screening of the family members of an MEN1 index case should be considered (Toumpanakis
and Caplin 2008). Hyperinsulinism causes obesity and neurological or psychiatric disturbances in many patients. A recent series of four patients demonstrated efficacy of everolimus, whose frequent side effect is hyperglycemia, in the treatment of the hypoglycemia of
advanced, progressive insulinoma (Kulke etal. 2009).
The insulinoma diagnosis is made with detection of inappropriately high concentrations
of both insulin and C peptide in the blood at a blood glucose level of less than 50mg/dL
together with symptoms of hypoglycemia. Conventional CT, transabdominal ultrasonography, and selective arteriography fail to localize an insulinoma in about 40% of cases, though
>90% sensitivity can be achieved with combinations of MRI, thin-section pancreatic protocol CT scan, and endoscopic ultrasound. OctreoScan is another noninvasive modality available to assist in the localization of insulinoma. Portal venous sampling and arterial calcium
stimulation are technically demanding, invasive procedures that are not widely available.
When preoperative studies fail to definitively localize the insulinoma, surgical exploration
with intraoperative ultrasonography can be considered (Tucker etal. 2006). At the authors
institution, radiologic innovations have rendered blind surgical exploration unnecessary.
11.8.2
Gastrinomas
Gastrinomas cause Zollinger-Ellison syndrome and their clinical hallmark is multiple recurrent peptic ulcers. Most gastrinomas are located in the gastrinoma triangle, which encompasses the duodenum, pancreatic head, and hepatoduodenal ligament. Gastrinomas of the
duodenum are often small submucosal tumors and can easily be missed during routine
311
upper gastrointestinal endoscopy; gastrinomas of the pancreas can exceed 1 cm in size

(Fendrich etal. 2007).
The diagnostic workup for gastrinoma often involves two steps. An elevated concentration of gastrin in a blood sample from a fasting patient and increased basal gastric acid output (>15mEq/h) suggest the presence of gastrinoma. A secretin stimulation test is required
to differentiate gastrinomas from other causes of gastrin elevation. Octreotide scan has 77%
sensitivity for gastrinoma. Fifty percent of gastrinomas have metastases at diagnosis. Their
median survival time is between 3 and 6 years. Roughly one fifth of gastrinomas occur in the
context of MEN1 syndrome (Fendrich etal. 2007).
11.8.3
Glucagonomas
Glucagonomas are rare alpha-cell tumors of the pancreas that occur in people between 50
and 70 years of age. These tumors are primarily located within the pancreas; most are
malignant. They penetrate the pancreatic capsule and invade the regional lymph nodes.
Symptoms may not appear until the tumor is larger than 5cm in diameter. At diagnosis,
5080% of tumors have metastasized to liver. Serum glucagon levels are usually quite
elevated (>1,000pg/mL; normal range, 150200pg/mL) and assist in diagnosis.
Mild glucose intolerance is the most common feature. A characteristic skin rash called
necrolytic erythema migrans may precede the diagnosis by at least 5 years. The initial lesion
consists of red papules or pale brown macules on the face, abdomen, groin, perineum, or
extremities. The erythematous areas form superficial bullae that eventually break down and
become encrusted. Anemia, thromboembolic disease with venous thrombosis or pulmonary
emboli, and psychiatric disturbances are other clinical features of glucagonoma. Anticoagulation
therapy is recommended in individuals with glucagon excess (Doherty 2005).
11.8.4
Somatostatinoma
Somatostatinoma is very rare. Most are found in the pancreas or duodenum. Patients often
present with diabetes mellitus, cholelithiasis, diarrhea, steatorrhea, hypochlorhydria, anemia, and weight loss. These tumors are generally malignant and are usually diagnosed late
in their course. Metastases to lymph nodes, liver, and bone may be found at diagnosis
(Doherty 2005).
11.8.5
VIPoma
VIPoma is characterized by symptoms of watery diarrhea of >3L/day, hypokalemia, and
achlorhydria; symptoms are mediated by VIP as well as other peptides secreted by malignant islet cells. VIPomas are located in the pancreas in adults and in extrapancreatic sites
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J.A. Jakob et al.
in children. They are often metastatic at diagnosis. The stool is essentially isotonic, and the
diarrhea persists even during fasting with nasogastric suction. Large amounts of potassium
and bicarbonate are lost in the stool, leading to hypokalemia and metabolic acidosis.
Diagnosis is made by typical clinical presentation, presence of large pancreatic mass per
imaging, and elevated plasma VIP levels. Somatostatin analogs are effective in the control
of hormonal syndrome (Schonfeld etal. 1998).
11.8.6
Pancreatic Polypeptidomas
PP is synthesized and released from PP cells in the normal pancreas. Pancreatic polypeptideomas are often found unexpectedly in patients with symptoms produced by metastases
to the liver and bone (Sakai etal. 1993).
11.9
Carcinoid Syndrome, Carcinoid Heart Disease, and Carcinoid Crisis
11.9.1
Carcinoid Syndrome
Carcinoid syndrome is often observed in patients with metastatic disease or when the
primary tumor site allows secreted amines to escape into the enterohepatic circulation
(Table 11.4). Common symptoms include flushing, diarrhea, abdominal cramping, and
less frequently wheezing, heart valve dysfunction, and pellagra, all of which result from
synergistic interactions between 5-HTP metabolites, kinins and prostaglandins. The
Table11.4 Symptoms of carcinoid syndrome
Symptom
Frequency
Characteristics
(%)
Involved mediators
Flushing
8590
Foregut: long-lasting,
purple
Midgut: short-lasting,
pink
Killirein, 5-HTP, histamine,

substance P, prostaglandins
Diarrhea
70
Secretory
Gastrin, 5-HTP, histamine,

prostaglandins, VIP
Abdominal pain
35
Progressive
Small bowel obstruction,

hepatomegaly, ischemia
Telangiectasia
25
Face
Unknown
Bronchospasm
15
Wheezing
Histamine, 5-HTP
Pellegra
Dermatitis, diarrhea,
dementia
Niacin deficiency
313
i ncidence of carcinoid syndrome ranges from 10% in localized carcinoid to 4050% in

advanced tumors. As we will discuss in more detail in Sect.11.12.1, somatostatin analogs
such as octreotide are the mainstay of medical therapy for carcinoid syndrome.
11.9.2
Carcinoid Heart Disease
Carcinoid heart disease (CHD) is due to fibrosis of endocardium of the right heart and occasionally leads to tricuspid regurgitation and right heart failure. However, the relationship
between CHD and frank heart failure in the somatostatin analog era is unclear. A recent
study of 150 patients with carcinoid syndrome and midgut lesions described a 20% prevalence of carcinoid valve disease as determined by echocardiography. Of those with valve
disease by echocardiogaphy, 53% were assessed clinically as New York Heart Association
(NYHA) heart failure class I or II. Surprisingly, 27% of the patients with moderate or severe
valvular disease by echocardiography were NYHA class I, or essentially asymptomatic.
Notably, more than 70% of all patients in the study were maintained on somatostatin analogs, though there was no relationship demonstrated between somatostatin analog use and
the presence of CHD or heart failure. Patients with CHD did exhibit increased urine 5-HIAA
and serum CGA levels, supporting a role for these metabolites in pathogenesis (Bhattacharyya
etal. 2008). Currently, the United States National Comprehensive Cancer Network (NCCN)
guidelines suggest echocardiography of patients with carcinoid syndrome and clinical signs/
symptoms of heart failure or in whom major surgery is planned (NCCN 2009).
11.9.3
Carcinoid Crisis
Carcinoid crisis is caused by a massive release of bioactive products to the systemic blood,
and is characterized by profuse hypotension, watery stools, and abdominal cramps.
Characteristic symptoms such as itching, palpitations, and facial edema are related to large
amounts of histamine, kinins, and prostaglandins. Carcinoid crisis is often precipitated by
a surgery or procedure; treatment consists of prompt intravenous delivery of octreotide,
with initiation of octreotide infusion at 50100mg/h as needed. Premedication of carcinoid
patients with additional octreotide, in subcutaneous or intravenous form is often used to
prevent or mitigate carcinoid crises caused by interventions (Dierdorf 2003).
11.10
General Approach to Treatment of Localized
and Advanced Neuroendocrine Tumors
The indolent features and lack of response to existing chemotherapy complicate treatment
decisions for patients with NETs. Localized NETs should be surgically excised whenever
possible. In asymptomatic or mildly symptomatic patients with advanced NETs, that is,
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J.A. Jakob et al.
those with lesions that are surgically unresectable or metastatic, treatment should be
delayed and patients should be monitored every 36 months. For advanced, well to moderately differentiated, and asymptomatic NETs of the midgut, we recommend surgical
resection of all gross disease that can be reasonably removed.
There are multiple indications for palliative surgical interventions for advanced NETs.
These indications extend beyond the commonly appreciated complications of refractory
intestinal obstruction and bleeding. Patients with locally advanced tumors are often associated with bulky mesenteric lymphadenopathy; these nodes can cause mesenteric vascular
compromise manifesting as visceral ischemia. Surgical intervention can also alleviate
symptomatic, refractory hormone-mediated symptoms. In addition, surgical resection of a
pancreatic NET can prevent pancreatitis and/or biliary obstruction. Ideally, the palliative
resections include excision of primary tumor mass and removal of mesenteric nodal burden. Intestinal bypass is another strategy, but this does not address bulky mesenteric
lymphadenopathy.
The mainstays of medical treatment for symptomatic advanced carcinoid and VIPoma
are somatostatin analogs. When carcinoid syndrome symptoms persist with somatostatin
analog therapy, or mass effect symptoms worsen, debulking or ablation surgery, as discussed in the above paragraph and in Sect.11.12.1, may be used to reduce tumor load and
provide effective palliation. Interferon a (IFN a) can also offer palliation after somatostatin
analog failure. For patients with unresectable disease confined to the liver, liver-directed
therapy, such as hepatic artery embolization and radiofrequency ablation (RFA) (discussed
at length in Sects.11.12.4 and 11.12.5, respectively) should be considered for bulky disease,
progression, or symptom palliation. A general approach for the therapy of unresectable
disease is depicted in Fig.11.2.
In general, NETs respond poorly to conventional chemotherapy. However, two situations are appropriate for the initiation of conventional cytotoxic therapy. High-grade
NETs, because of their rapid rate of growth and likely responsiveness to platinum-based
chemotherapy, are reasonable candidates for prompt initiation of systemic treatment.
The second situation appropriate for cytotoxic therapy in advanced NETs is progressive,
symptomatic, metastatic, or unresectable islet cell carcinoma. The University of Texas
M. D. Anderson Cancer Center has noted radiographic response rates of nearly 40% in
a series of 84 such patients, using a regimen of 5-fluorouracil, doxorubicin, and streptozocin (FAS). Importantly, several patients with radiographic responses in this series
became surgical candidates for potentially curative resection after chemotherapy
(Kouvaraki etal. 2004).
11.11
Treatment of Resectable Neuroendocrine Tumors
Surgery is the only treatment for NETs offering definitive cure. The surgical management
of gastrointestinal NETs is dependent on multiple factors. The most important considerations are the site and histology of the primary tumor, the extent of the detectable disease,
315
High grade
Platinum-based chemotherapy
FAS chemotherapy
or
clinical trials
Islet cell
NET
Low volume,
asymptomatic
Observation
or
clinical trials
Carcinoid
High volume
or symptomatic
octreotide+/-IFN a
or
HAE/HACE
or
clinical trials
or
targeted therapy,
off protocol
Progression
Low grade
octreotide+/-IFN a
or
HAE/HACE
or
clinical trials
or
targeted therapy,
off protocol
Fig.11.2 Approach for the therapy of advanced NETs. NET, neuroendocrine tumor. Islet cell, islet
cell carcinoma of pancreas. Carcinoid, pulmonary or gastrointestional carcinoid. FAS chemotherapy, 5-fluouroracil, doxorubicin, streptozocin systemic chemotherapy. IFN a interferon a; HAE
hepatic artery embolization; HACE hepatic artery chemoembolization. Targeted therapy, see
Sect.11.12.9, Targeted therapy for specific single- and double-agent regimens. Modified from
Talamonti etal. (2004)
and the clinical presentation of the patient. Types I and II gastric carcinoids measuring
less than 2cm can be removed endoscopically while gastrectomy should be considered
for patients with tumors >2cm. Type III gastric carcinoids have a more aggressive course
with a five-year survival less than 50%. Small intestine carcinoids should be managed
with resection of the intestinal segment and its associated mesentery due to the risk of
nodal involvement even with small tumors. The rest of the intestinal tract should be carefully examined, as 20% of these tumors are accompanied by a second primary malignancy (Memon and Nelson 1997). Appendiceal carcinoid tumors measuring <2cm can
be treated with appendectomy provided they do not display any high-risk features. As
discussed in Sect. 11.7.3, larger lesions should be treated with right hemicolectomy.
Similarly, carcinoid tumors of the colon and rectum are successfully treated with a formal
hemicolectomy adhering to the usual techniques of mesenteric lymphadenectomy as with
colon adenocarcinoma. The surgical approach of rectal carcinoids is outlined in
Sect. 11.7.4. Noncarcinoid colon NETs (i.e., small cell and large cell neuroendocrine
carcinoma) are rare and aggressive and have a worse outcome than colonic adenocarcinomas; patients with these lesions have a median survival of approximately 10 months
(Bernick etal. 2004). As such, these patients rarely benefit from resection and are usually
treated with chemotherapy.
316
J.A. Jakob et al.
11.12
Treatment of Advanced Neuroendocrine Tumors
The current goal of treatment of advanced NETs, that is, unresectable or metastatic tumors,
is the amelioration of hormone-related symptoms. The reduction of tumor burden is also
desirable, but the ultimate aim is palliation of the symptoms. The current standard of care
for hormone-related symptom control remains a somatostatin analog, with or without
adjunct IFN a. Other therapeutic methods, including systemic chemotherapy, hepatic
artery embolization or hepatic artery chemoembolization, and an emerging technology,
peptide receptor radionuclide therapy, are occasionally useful. Identifying targeted therapies with the potential to alter the natural history of advanced NET and extend survival
remains a key research effort.
11.12.1
Surgical Resection of Hepatic Metastases
There are several important considerations in the evaluation of a patient with isolated
hepatic metastases of an NET. In general, liver metastases are resectable if two basic criteria are satisfied: (a) all tumors in the liver can be completely resected and (b) an adequate
volume (20% of the standardized total liver volume) of liver with adequate biliary drainage, arterial inflow, and venous outflow can be preserved. If the locoregional and hepatic
tumor burden is completely resectable, then this is the preferred management of metastatic
NETs whether functional or nonfunctional. Hepatic resection is most effective for patients
with low-grade NETs (Cho etal. 2008).
Unique to functional NETs is the concept of incomplete resection, or debulking.
Debulking at least 90% of the hepatic tumor burden in patients with functional metastases
prolongs survival and improves endocrinopathy-related symptoms (Que et al. 1995).
Patients with unresectable hepatic NET metastases may benefit from liver-directed therapies such as RFA (alone or in combination with resection), hepatic artery infusion, bland
hepatic artery embolization or hepatic artery chemoembolization; the latter two interventions are discussed in depth in Sect. 11.12.4. Of note, hepatic artery embolization and
surgical resection are equally effective in ameliorating pain and symptoms of hormonal
excess (Chamberlain etal. 2000).
11.12.2
Somatostatin Analogs
Somatostain analogs such as octreotide, depot octreotide, and lanreotide are the front-line
medications for symptom control of advanced/nonresectable, symptomatic carcinoid and
VIPoma; these agents may also have tumor stabilization properties in NETs. Octreotide is an
intermediate-acting somatostatin analog that can be administered subcutaneously every
612h. It provides a complete resolution or partial relief of flushing or diarrhea in about 85%
317
of patients with carcinoid syndrome, and produces a biochemical response rate of up to 72%
(Schnirer etal. 2003). The dose of octreotide varies from 50 to 500mg, three times a day.
Long-acting somatostatin analogs have obviated the need for multiple daily injections in most patients. Depot octreotide (10, 20, and 30 mg) is given intramuscularly
once a month (Rubin etal. 1999). An intermediate-acting somatostatin analog should be
used to supplement long-acting agents until a steady state is reached. Rarely, sinus bradycardia and cardiac conduction abnormalities have been observed. Caution should be
observed in patients with preexisting cardiac disease. Gallbladder stones and sludge may
develop with chronic use of somatostatin analogs. Hypoglycemia and, more commonly,
hyperglycemia may occur especially among patients with brittle diabetes. Steatorrhea
may also occur but can be managed with the use of pancreatic enzymes. Lanreotide is a
somatostatin analog more frequently used in Europe than in the United States, and in
extended release form, is administered subcutaneously once a month in doses of 60, 90,
and 120mg.
Somatostatin analogs may also have cytostatic activity. Stabilization of growing NETs
has been reported in nonrandomized phase II studies (Saltz etal. 1993; Arnold etal. 1993).
Interim analysis of a phase III, randomized trial of depot octreotide 30 mg monthly in
untreated, metastatic carcinoids of the midgut demonstrated significantly increased time to
progression (TTP) in treated patients vs. placebo (14.3 vs. 6 months, p<0.001), though
this benefit was restricted to patients with less than 10% hepatic volume replaced by tumor
(Arnnold etal. 2009). In addition, an international phase III trial is now under way to test
the effect of lanreotide (120 mg, every 28 days) on progression-free survival (PFS) in
patients with nonfunctioning NETs. Secondary end points include overall survival at 48
and 96 weeks (Clincaltrials.gov 2006a).
11.12.3
Biotherapy
IFN a can induce biochemical response in most patients with carcinoid syndrome
(Schnirer etal. 2003). In addition, the combination of octreotide and IFN a may have a
synergistic effect on symptom control and biochemical responses in NETs (Janson etal.
1992a, b, 1993; Frank etal. 1999). However, IFN a is much more toxic than somatostatin
analogs. Fatigue, fever, anorexia, psychiatric side effects, and weight loss are common.
The use of IFN a is usually reserved for patients with symptoms refractory to somatostatin analog-only therapy.
11.12.4
Hepatic Artery Embolization and Hepatic Artery Chemoembolization
The liver is the most common metastatic site of NETs, making hepatic artery embolization
(HAE) and hepatic artery chemoembolization (HACE) feasible approaches to improve symptom control and reduce metastatic disease burden. These percutaneous catheter-based
approaches can also be useful in reducing the volume or hormonal function of liver metastases
318
J.A. Jakob et al.
with the intent of then performing a potentially curative resection in a patient who initially
presents with unresectable disease, or particularly when hormone syndrome depresses performance status such that resection is not feasible on this basis alone. Common embolization
agents include gelfoam or polyvinyl alcohol particles; when performed without chemotherapy
agents, this process is referred to as bland embolization. Chemoembolization employs traditional cytotoxic agents such as cisplatin or doxorubicin along with the above-mentioned
nonchemotherapy agents for embolization of arterial flow. To prevent carcinoid crisis, somatostatin analogs should be given before these procedures, which are performed in the inpatient
setting. Many patients experience a transient postembolization syndrome, which can include
severe abdominal pain, nausea, fever, fatigue, elevation of liver enzymes, and even death.
Other major complications are gastrointestinal bleeding, gastric or duodenal ulceration,
hepatic abscesses, ischemic necrosis of gallbladder and small intestine, sepsis, renal failure,
portal vein thrombosis, arterial thrombosis, and arrhythmias.
The efficacies of HAE and HACE for symptom and disease-burden control in metastatic NETs are commonly evaluated in nonrandomized, retrospective studies because of
the invasive nature and palliative goals of these procedures. In addition, these studies generally include a significant proportion of patients who have undergone prior systemic chemotherapy as well as previous, concurrent, and subsequent octreotide treatment, further
complicating assessment of the clinical benefit of HACE and HAE. In a retrospective,
nonrandomized analysis of 81 patients undergoing HAE or HACE at the authors institution (The University of Texas M.D. Anderson Cancer Center), radiographic response rate
was 67%, median PFS was 19 months, and median overall survival was 31 months. Of
note, 63% of patients experienced symptomatic relief post procedure (Gupta etal. 2003).
Other series have observed similar results, though sometimes with a higher frequency of
symptom control (Bloomston etal. 2007; Ho etal. 2007).
The clinical benefit of HACE vs. HAE in metastatic NETs has not been studied in randomized trials. However, a retrospective, nonrandomized analysis of 123 HAE- and
HACE-treated patients in follow-up to the study described in the above paragraph demonstrated decreased response rate in carcinoid patients treated with HACE vs. HAE (44 vs.
81%, p<0.003); differences observed in overall survival (33.8 vs. 33.2 months) and PFS
(23.9 vs. 20.9 months) were not statistically significant. However, the same analysis
reported statistically insignificant trends toward improved overall survival (31.5 vs. 18.2
months) and radiographic response (50 vs. 25%) in HACE vs. HAE treated islet cell carcinomas (Gupta etal. 2005).
11.12.5
Radiofrequency Ablation
RFA involves the application of microwaves to eradicate diseased tissue, or in the case of
a patient with advanced NET, specific metastases of the liver. This technique can be applied
percutaneously or intraoperatively under ultrasound guidance. RFA has demonstrated
some effectiveness in reducing hepatic metastases of less than 4 cm in NET patients
(Hellman etal. 2002).
319
11.12.6
Additional Symptom Control Methods
Carcinoid symptoms may also be controlled or even eliminated by avoiding stress, minimizing tryptophan-rich foods, and supplementing dietary nicotinamide. Medical management of carcinoid symptoms can include bronchodilator for bronchospasm, loperamide or
diphenoxylate for frequent, loose bowel movements, and diuretics for fluid overload secondary to valvular dysfunction. A proton pump inhibitor should be used for managing
gastric hypersecretion in patients of gastrinoma.
11.12.7
Chemotherapy
11.12.7.1
Effectiveness of Chemotherapy in Carcinoids
Carcinoids are resistant to conventional cytotoxic chemotherapy (Strosberg etal. 2008).
11.12.7.2
Effectiveness of Chemotherapy Islet Cell Carcinomas
As discussed above in Sect.11.10, triple agent therapy with FAS has activity in islet cell
carcinomas (Kouvaraki etal. 2004). The FAS regimen is typically employed when islet
cell carcinoma patients become symptomatic despite octreotide therapy. Scant data exist to
support the use of FAS in metastatic carcinoid.
11.12.8
Biochemotherapy
The combination of chemotherapy (streptozocin and doxorubicin or 5FU) plus IFN a does
not improve response rate in NETs (Saltz etal. 1994; Janson etal. 1992a, b).
11.12.9
Peptide Receptor Radionuclide Therapy
Lutetium-labeled octreotate (a derivative of octreotide) via tetraazacyclo-dodecanetetraacetic acid (DOTA) has shown promise in the treatment of advanced NETs. A recent Dutch
study of 310 advanced NET patients with significant uptake on [111In-DTPA0octreotide]
scintigraphy demonstrated an impressive PFS of 33 months for all patients treated with
[177Lu-DOTA0,Tyr3]octreotate (Kwekkeboom etal. 2008).
320
J.A. Jakob et al.
11.12.10
Targeted Therapy
The identification of effective, molecularly targeted therapy for NETs is an active area of
research. Phase II trials of modern molecular targeted therapies as single agents are summarized in Table11.5; response rates have generally been as low as single-agent trials of
older therapies. A study comparing VEGF inhibitor bevacizumab and monthly depot octreotide vs. pegylated IFN a and depot octreotide in 44 patients with metastatic carcinoid
demonstrated 95% PFS at 18 weeks in the former vs. 68% in the latter. In addition, an 18%
radiographic response was observed in the bevacizumab/depot octreotide arm as compared
to no responses in the IFN a depot octreotide arm (Yao etal. 2008b). Inhibition of the
VEGF receptor by sunitinib has also shown promise in a recent phase II trial. Kulke etal.
reported a 16% overall response rate in advanced islet cell carcinoma as well as a median
TTP of 7.7 and 10.2 months in advanced islet cell carcinomas and carcinoids respectively
(Kulke etal. 2008).
Everolimus or RAD001, an inhibitor of the mammalian target of rapamycin (mTOR),
has proven efficacious when combined with octreotide depot. In a recent phase II study of
advanced carcinoid and islet cell carcinoma patients, overall response rates of 22% and
PFS of 60 weeks were observed (Yao etal. 2008c).
Current, ongoing multicenter phase III studies of modern targeted agents effect on PFS
include: bevacizumab/octreotide vs. IFN a octreotide in advanced carcinoid patients
(Clincaltrials.gov 2007a), sunitinib vs. placebo in islet cell carcinoma (Clincaltrials.gov
2007b), everolimus/octreotide vs. placebo/octreotide in advanced carcinoid (Clincaltrials.
gov 2006b), and everolimus vs. placebo in islet cell carcinoma (Clincaltrials.gov 2007c).
Table 11.5 Phase II trials of targeted, molecular agents in advanced carcinoid and islet cell
carcinoma
Agent(s)
Number
Median PFS
CR/PR/OR
References
of patients
Bevacizumab +
octreotide LAR
22
66 weeks
0/18/18%
Yao etal.( 2008b)
Bortezomib
16
N/A
0/0/0%
Shah etal. (2004)
Everolimus +
octreotide LAR
60
60 weeks
0/22/22%
Yao etal. (2008c)
Gefitinib
37
30% at 6 months
(carcinoid)
14% at 6 months
(islet cell)
0/4/4%
Hobday etal. (2006)
Imatinib
27
24 weeks
0/3/3%
Yao etal. (2007)
Sunitinib
107
10.2 months,
carcinoid (TTP)
7.7 months, islet
cell (TTP)
0/11/11%
Kulke etal. (2008)
6 months (TTP)
0/5.5/5.5%
Temsirolimus
36
Islet cell:
0/16.7/16.7%
Duran etal. (2006)
321
11.13
Conclusion
The multidisciplinary approach to effective, efficient diagnosis and treatment of patients
with localized and advanced NETs is paramount. The care of the patient with localized
NET disease requires the expertise of both the surgeon and the pathologist. The advanced
NET patient presents the physician with different challenges, and interventional radiologists in addition to medical oncologists have a role to play in symptom control.
Unfortunately, the options presently available to the medical oncologist to halt or prolong the natural history of advanced NET disease are limited. However, several ongoing
phase III trials address the effectiveness of newer and promising targeted therapies to delay
the progression of disease in advanced NET patients. Specific targets include VEGF (bevacizumab), the VEGF receptor (sunitinib), and mTOR (everolimus). Noteably, the clinical
utility of several targeted agents is being evaluated both as single-agent therapy and in
combination with depot octreotide. In addition, the potential of somatostatin analogs alone
to alter the natural history of advanced NETs is the subject of ongoing clinical investigation. This research will hopefully produce an evidence-based strategy, possibly employing
targeted therapy and/or somatostatin analogs, to prolong overall survival in patients with
advanced NETs.
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Colon Cancer
12
Sharlene Gill, Carl Brown, Robert Miller, and Oliver Bathe
12.1
Introduction
Cancers of the colon represent the third leading cause of neoplasia-related morbidity and mortality in the United States and Canada (Committee CCSS 2009; Jemal etal. 2009). The lifetime
risk for colon cancer is estimated to be 1 in 20 persons, with a median age of diagnosis of 71
years (Jemal etal. 2009). Over the past three decades, the overall incidence of colon cancer has
diminished slightly by 2.2% in women and 2.8% in men (Jemal etal. 2008), yet there has been
an increasing relative incidence of proximal, particularly cecal, colonic adenocarcinoma (Troisi
etal. 1999). While this is partly explained by increased endoscopic screening, the etiology of
this proximal shift is not entirely understood. Encouragingly, 5-year survival rates have notably
improved over this time period, from 52% in 1975 to 65% in 2004 (Jemal etal. 2009).
In metastate disease, 5-year survival has improved from 9% in 2000 to 19% in 2006
(Kopetz etal. 2009)
12.2
Pathogenesis, Pathology and Prognosis
Four major anatomic divisions of the colon have been defined: (1) the right colon, subdivided into the cecum (intraperitoneal and measuring about 69 cm) and the ascending
S. Gill (*)
Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver,
BC V5Z 4E6, Canada
e-mail: sgill@bccancer.bc.ca
C. Brown
Colorectal Surgery, St. Pauls Hospital, Vancouver, BC, Canada
R. Miller
Radiation Oncology, Mayo Clinic, Rochester, MN, USA
O. Bathe
Surgical Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada
325
326
S. Gill et al.
Table12.1 World Health Organization classification of colorectal carcinoma

Adenocarcinoma
Medullary carcinoma
Mucinous (colloid) adenocarcinoma (>50% mucinous)
Signet ring cell carcinoma (>50% signet ring cells)
Squamous cell (epidermoid) carcinoma
Adenosquamous carcinoma
Small-cell (oat cell) carcinoma
Undifferentiated carcinoma
Other (e.g., papillary carcinoma)
colon (retroperitoneal and measuring 1520cm long); (2) the middle (transverse) colon;
(3) the left (descending) colon, and (4) the sigmoid colon, originating at the mesosigmoid
and terminating at the rectum (Compton 2003).
The overwhelming majority of colon cancers are adenocarcinomas with other histologies rarely occurring (Table12.1). Based upon limited data, signet ring cell and small-cell
histologies are considered unfavorable, and medullary and mucinous carcinomas are considered favorable, but the true independent prognostic impact of histology subtype alone
remains unclear. In addition, the presence of tumor lymphatic or vascular invasion has been
associated with poor prognosis on univariate analysis; however, in multivariate analyses,
the significance has been uncertain (Compton etal. 2000a, b). On the other hand, histologic
grade has been shown to have stage-independent prognostic value in a number of analyses
(Compton etal. 2000b; Gill etal. 2004) with high-grade disease (defined as poorly differentiated or undifferentiated), associated with inferior outcomes. Likewise, the presence of
perineural invasion is a significant adverse prognostic feature but, unfortunately, this is
often inconsistently reported in colon cancer pathology reports (Liebig etal. 2009).
Of increasing interest in recent years is the evaluation of molecular determinants of prognosis. The multistep progression of colon carcinogenesis from an adenoma to a carcinoma,
as originally defined by Fearon and Vogelstein (1990), is characterized by the development
of genomic instability wherein DNA integrity is compromised. The major known mechanisms of genomic instability are chromosomal and microsatellite. The pathway of chromosomal instability (CIN), also known as the suppressor pathway, represents the more
common pathway of genomic instability and is characterized by sequential inactivation of
tumor-suppressor genes, such as APC (located on chromosome 5q), p53 (chromosome 17p),
and DCC (chromosome 18q) through widespread loss of heterozygosity (LOH) and by
gain-of-function mutations, resulting in activation of oncogenes such as RAS (Kinzler and
Vogelstein 1996; Lengauer etal. 1997). The less common second pathway of microsatellite
instability (MSI), also known as the mutator pathway, is observed in 1520% of colon
cancers and is associated with defects in DNA mismatch repair. This can be due to germline
mutations in genes involved the mismatch repair genes (hMLH1, hMSH2, hMSH6, or
PMS2) which characterize hereditary Lynch syndrome (previously known as Hereditary
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327
Nonpolyposis Colon Cancer or HNPCC), or, more commonly, may arise in sporadic colon
cancers from inactivation of hMLH1 due to a CpG Island Methylator Phenotype (CIMP)
associated with epigenetic instability from aberrant promoter hypermethylation with consequent transcriptional silencing (Liu etal. 1995, 1996; Lynch and Smyrk 1996; Goel etal.
2003). Sporadic CRCs with evidence of hMLH1 promoter hypermethylation have also been
found to commonly carry a V600E mutation in the BRAF gene (Bessa etal. 2008).
Clinicopathologic differences have been identified in the phenotypes of these two pathways. Tumors with high levels of microsatellite instability-high (MSI-H) are more likely
to arise from the proximal colon, are more common in females and, pathologically, associated with poor differentiation, mucinous features, node-negative status and prominent
lymphocytic infiltration (Rodriguez-Bigas etal. 1997; Thibodeau etal. 1993).
Elucidation of these pathways has led to the identification of a number of putative prognostic molecular markers in colon cancer. Unfortunately, these advances have yielded few
clinically validated biomarkers which may be used in practice to inform current-day
treatment decision making. One such potential marker is 18q LOH, which has been implicated as a negative prognostic feature, particularly in stage II. However, results from
several retrospective analyses have been inconsistent, and its use as a prognostic marker is
not presently recommended outside of clinical trials (Jen etal. 1994; Popat etal. 2005,
2007; Ogino et al. 2009a). Likewise, mutation of the KRAS oncogene was previously
believed to be associated with a poor prognosis however, recent studies have failed to
demonstrate any prognostic utility to KRAS status (Ogino etal. 2009b; Roth etal. 2010).
In contrast, MSI-H has been demonstrated as an independent favorable prognostic feature
in early stage colon cancer in a number of retrospective studies (Thibodeau etal. 1993;
Popat etal. 2005; Watson etal. 1998). A systematic review of 32 studies including 1,277
colorectal cancers with MSI found a combined hazard ratio (HR) estimate for overall survival (OS) of 0.65 (95% confidence interval [CI], 0.590.71) (Popat etal. 2005). Despite
the interest in MSI status as a prognostic marker, the 2006 American Society of Clinical
Oncology guidelines update on the use of tumor markers for gastrointestinal cancers do
not endorse the use of MSI as a prognostic marker in clinical practice, citing the largely
retrospective nature of the available data (Locker etal. 2006). The use of biomarkers as
predictive factors to determine efficacy of treatment is discussed later in this chapter.
12.3
Risk Factors for Colon Cancer
12.3.1
Inherited Predisposition
Family history of CRC in a first-degree relative is an important risk factor and accounts for
up to 20% of all affected patients. The relative risk (RR) associated with a single firstdegree relative with adenomas is 1.74 (95% CI 1.242.45) over that of the general population (Ahsan et al. 1998). Fewer than 10% of colon cancers are associated with a true
inherited polyposis-related predisposition. The most common hereditary colorectal cancers
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S. Gill et al.
are Lynch syndrome and familial adenomatous polyposis (FAP). Less well-known are the
hamartomatous polyposis syndromes, including Peutz-Jeghers syndrome, Cowden syndrome and Juvenile Polyposis. Management of inherited syndromes must not only address
the management and surveillance of an affected individual but also the identification and
management of family members not yet affected.
Lynch Syndrome is an autosomal dominant syndrome caused by a germline mutation in
one of the genes involved in DNA mismatch repair and accounts for up to 3% of all CRC. It
is molecularly characterized by MSI and clinically characterized by early-onset proximal
colon cancers (median age 45 years), and extracolonic neoplasms such as endometrial, transitional cell carcinoma of the ureter and renal pelvis, small bowel, gastric, ovarian, pancreatic
and biliary cancers (Lynch etal. 2009). The accepted clinical criteria for diagnosis are known
as the Amsterdam Criteria (Vasen etal. 1999) and the criteria to identify affected high-risk
individuals who may benefit from MSI testing are known as the Bethesda Guidelines (Laghi
etal. 2004) (Table12.2). Immunohistochemistry for protein expression of the MMR gene
products (particularly for MSH2 and MLH1) have demonstrated high sensitivity and specificity for the MSI phenotype and are widely accepted as an initial step for Lynch screening
(Lindor etal. 2002). Patients who fulfill Bethesda guidelines with MSI-H tumors would be
offered genetic counseling and germline testing for MMR gene mutations (Lynch etal. 2007).
Subtotal colectomy is recommended in affected mutation-carriers undergoing surgical resection of a colorectal cancer but the role of prophylactic colectomy in unaffected mutationcarriers is controversial (Lindor etal. 2006). Prophylactic hysterectomy and oophorectomy,
on the other hand, is supported by the available evidence (Schmeler etal. 2006).
Table12.2 Lynch syndrome clinical criteria
Amsterdam II criteria for diagnosis (Vasen etal. 1999)
At least three relatives with an hereditary nonpolyposis colorectal cancer (HNPCC)-associated
cancer (colorectal cancer, endometrial, stomach, ovary, ureter/renal pelvis, brain, small bowel,
hepatobiliary tract, and skin [sebaceous tumors]):
One is a first-degree relative of the other two

At least two successive generations affected
At least one of the syndrome-associated cancers should be diagnosed at <50 years of age
FAP should be excluded in any colorectal cancer cases
Tumors should be verified whenever possible
Bethesda guidelines for tumor MSI testing (Laghi etal. 2004)

Colorectal cancer diagnosed in a patient who is <50 years of age
Presence of synchronous or metachronous colorectal, or other syndrome-associated tumorsa
regardless of age
Colorectal cancer with microsatellite instability-high (MSI-H) histology diagnosed in a
patient who is <60 years of age
Colorectal cancer or syndrome-associated tumor diagnosed under age 50 years in at least
one first-degree relative
Colorectal cancer or syndrome-associated tumor diagnosed at any age in two first- or
second-degree relatives
(HNPCC)-associated tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter
and renal pelvis, biliary tract, gliomas (in Turcots syndrome) sebaceous gland adenomas and keratoacanthomas (in Muir-Torre syndrome), and carcinoma of the small bowel
a
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FAP is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene and accounts for less than 1% of all CRCs. It is characterized by literally thousands of early-onset colorectal polyps with 100% penetrance for
colorectal cancer, in addition to extracolonic manifestations of hypertrophy of the retinal
pigment epithelium, osteomas, sebaceous and epidermoid cysts, and desmoids tumors
(Gardners syndrome) (Kinzler and Vogelstein 1996). FAP carries an increased risk of
adenocarcinomas of the duodenum, jejunum, pancreas and biliary tree in addition to thyroid cancers and gliomas (associated with Turcots syndrome) (Offerhaus et al. 1992).
Variants include an attenuated, later-onset variant of FAP (AFAP) and a recessively inherited MUTYH-associated polyposis (MAP). Guidelines recommend APC genetic testing
for FAP in all patients with clinical evidence of greater than 100 colorectal adenomas, and
for all first-degree relatives of FAP patients (Giardiello etal. 2001). The surgical management of FAP is dictated by prophylactic total colectomy. Chemoprevention with COX2
inhibitors may play a role in preventing the progression of duodenal adenomas (Phillips
et al. 2002). Peutz-Jeghers syndrome is a rare autosomal dominant disorder involving
mutations in a gene encoding STK-11, a serine threonine kinase, and is characterized by
multiple hamartomatous polyps throughout the gastrointestinal tract, and hyperpigmented
lesions affecting the buccal mucosa and lips. It is associated with increased risk of multiple
cancers including the colorectum, small intestine, stomach, pancreas, breast, lung, ovary,
and endometrium (Giardiello etal. 2000). Management is directed at intensive screening
for at-risk first-degree relatives and surveillance for affected patients (Giardiello and
Trimbath 2006).
12.3.2
Inflammatory Bowel Disease
The association between inflammatory bowel disease, particularly ulcerative colitis, and
CRC is well accepted. Based upon retrospective cohort analyses, left-sided disease is associated with a threefold increase in cancer risk and pan-colitis renders an almost 15-fold
increase in risk beginning about 8 years after initial diagnosis (Ekbom et al. 1990;
Greenstein etal. 1979). This risk is further magnified in the presence of primary sclerosing
cholangitis (Brentnall etal. 1996) and pseudopolyps (Velayos etal. 2006). A similar magnitude increased risk is implicated for Crohns colitis but this is a much less common
presentation (Gillen etal. 1994). Annual surveillance colonoscopy with random biopsies
has been recommended after 8 years of colitis, with colectomy recommended in the presence of high grade dysplasia (Winawer etal. 2003).
12.3.3
Acquired Risk Factors
Sporadic colon cancer accounts for over 65% of all new diagnoses. There is a 25-fold
variation in the incidence of colon cancers worldwide with lower incidences in Asia and
Africa relative to North America, Western Europe and Australia (Parkin etal. 2005). This
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S. Gill et al.
geographic variability has fueled interest in the role of dietary and lifestyle factors in colon
carcinogenesis. The available evidence supporting the role of diet patterns and physical
activity is largely retrospective and hence ascertainment of a causative role has been problematic. The association between a Western diet, namely a diet low in fruits and vegetables
and high in red meat and animal fat, has been the subject of numerous cohort studies yet
remains contentious. In a pooled analysis including over 14 studies with more than 750,000
participants, fruit and vegetable intake was associated with a 26% relative reduction in risk
of distal colon cancers, but not with overall colon cancer risk (Koushik et al. 2007).
Similarly, high intake of red and processed meat has been associated with an increased risk
of distal colon cancers (Larsson etal. 2005; Chao etal. 2005) but these findings have not
been consistently reproducible.
Dietary fiber has been postulated to be protective by absorbing fecal carcinogens, altering bile acid metabolism and reducing colonic transit time (Kritchevsky 1995). Despite
cohort studies supporting an association, a systematic review of five randomized trials
evaluating dietary fiber for prevention of colorectal cancers demonstrated no evidence of
reduced risk of colorectal adenomas with increased fiber intake (Asano and McLeod 2002).
Folic acid, a water-soluble vitamin of the B family, is essential for DNA synthesis and
DNA methylation. Since it cannot be endogenously synthesized, it must be provided in the
diet with major sources including citrus fruits, dark-green vegetables and dried beans. In a
Nurses Health Study, folate intake exceeding 400mg/day (from supplements and food)
was associated with a 31% reduced risk for colon cancer this reduction became statistically significant after 15 years of use (Giovannucci etal. 1998). However, two subsequent
controlled trials unfortunately failed to demonstrate a reduced risk of colorectal adenomas
with an intervention of folic acid supplementation and, in fact, one study suggested an
increased risk of adenomas (Cole etal. 2007; Logan etal. 2008).
The epidemiologic evidence supporting the benefit of physical activity and reduced risk
of colon cancer is more robust. The biologic rationale is underscored by the mitogenic
potential of hyperinsulinemia which is directly related to lack of physical activity, central
adiposity and high body mass index (Giovannucci 1995). Moreover, insulin-like growth
factors have also been linked to cellular proliferative and antiapoptotic effects (Aaronson
1991). In a metaanalysis of 52 studies examining physical activity in primary prevention
of colorectal cancer, there was a 24% RR reduction of colon cancer when comparing the
most vs. the least active individuals across all studies (RR 0.76, 95% CI 0.720.81) (Wolin
etal. 2009).
12.4
Screening
Symptoms of colon cancer (i.e., bleeding, obstruction) typically occur in the later stages of
the natural history of the disease, particularly in proximal colon cancer. Furthermore, colon
cancer mortality is mostly influenced by the stage of the disease at diagnosis; 5-year mortality in stage I disease is less than 10%, whereas stage IV colon cancer has a greater than
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331
90% 5-year mortality. Thus, identifying colon cancers prior to the development of symptoms is critical in reducing mortality.
Conventional principles of screening encompass the following:
Natural history, where the disease can be identified at an earlier, more easily treatable
stage
Safe, cost effective and acceptable screening measures that is sensitive and specific
Treatment must be acceptable to most patients
Disease must have a prevalence that is significant
In colon cancer, all of these principles apply.
Currently, there are two different classes of screening modalities for identifying colon
cancers and advanced adenomas: indirect and direct. Indirect modalities include fecal
occult blood testing (FOBT) and fecal immunochemistry tests (FIT). Direct modalities
include flexible sigmoidoscopy (FS), colonoscopy, double contrast barium enema (DCBE),
and computed tomography colonography (CTC).
12.4.1
Fecal Occult Blood Test
The conceptual basis of the FOBT is that a colon cancer (or advanced polyp) is more likely
to bleed than healthy mucosa. While there are several variants of the FOBT, they are all
guaiac-based tests that test for peroxidase activity. Other substances with peroxidase or
pseudoperoxidase (e.g., red meat, some fruits) can cause false positive test results. Similarly,
common drugs that can cause mucosal irritation and bleeding, like nonsteroidal antiinflammatory drugs (NSAIDs) can also lead to a false positive test. Vitamin C can interfere with
peroxidase activity, leading to the possibility of false negative tests in patients consuming
large amounts of vitamin C.
As cancers may bleed intermittently, the sensitivity of the test can be increased by taking more than a single sample over time. Typically, two samples are taken from three
consecutive bowel movements. The sensitivity increases with each additional sample
tested. Furthermore, the chances of finding an advanced neoplastic polyp are 23% with one
positive test and over 50% with three positive tests (Lieberman and Weiss 2001).
FOBT is recommended as either a yearly or biennial screening test in patients over age
50 years old. Hewitson etal. performed a metaanalysis of four randomized controlled trials comparing screening with annual FOBT with no screening and concluded that this
strategy results in a 16% reduction in CRC mortality (RR 0.84, 95% CI 0.780.90)
(Hewitson etal. 2008). Similarly, there was a 15% RR reduction (RR 0.85, 95% CI 0.78
0.92) in CRC mortality for studies that used biennial screening. Furthermore, when
adjusted for only those individuals who attended at least one round of screening, there was
a 25% RR reduction (RR 0.75, 95% CI 0.660.84). However, there was no difference in
all-cause mortality (RR 1.00, 95% CI 0.991.02) or all-cause mortality excluding CRC
(RR 1.01, 95% CI 1.001.03).
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12.4.2
Fecal Immunochemistry Tests
FIT tests are antibody based tests that are designed to identify human hemoglobin, globin
or other blood components. Thus, dietary restrictions are unnecessary. Furthermore, some
of these tests use automated devices to interpret the tests, eliminating human error.
A recent review evaluated nine cohort studies and estimated the sensitivity of FIT for an
advanced neoplasia to be 6191% and specificity 9198% (Whitlock etal. 2008). While the
sensitivity is better than conventional FOBT (2538%), the specificity of FIT is a little lower
than the 9899% reported for most guaiac based tests. However, optimized FOBT with specimen rehydration appears to have similar sensitivity and specificity as FIT (Levin etal. 2008).
In summary, FIT may have better test characteristics than guaiac based FOBTs. Even
though it has not been tested in large randomized controlled studies, it can be considered a
reasonable alternative to FOBT.
12.4.3
Barium Enema
While single contrast barium enema may detect tumors, it is substantially less sensitive than
DCBE and should not be recommended. Patients must have complete colon preparation prior
to the procedure. The radiologist uses a flexible rectal catheter to infuse barium followed by
pressurized air to coat the bowel wall with barium. The test can take up to 1h to complete
and can be uncomfortable for the patient. The risk of colonic perforation is 1 in 25,000.
Current literature would suggest the sensitivity of DCBE to identify lesions 1 cm
ranges from 48 to 70% (Canon 2008). All DCBE tests that demonstrate a suspicious finding mandate a subsequent colonoscopy for confirmation of a lesion, polyp removal and/or
biopsy. False positive tests, caused by large haustral folds or retained stool, occur in up to
10% of patients.
DCBE does not evaluate the very distal rectum well, because of the infusion catheter
placement and difficulties in imaging the low pelvis. Thus, it is often recommended in the
combination with FS for screening purposes. This strategy for CRC screening has never
been tested in a controlled trial for mortality reduction.
In the era of CTC, the role of DCBE has been questioned. Currently, DCBE is used
predominantly in patients who have an incomplete colonoscopy rather than screening
(Ferrucci 2006). Furthermore, radiologists are more confident interpreting CTC than
DCBE. Thus, as CTC becomes more available, DCBE will likely be abandoned.
12.4.4
CT Colonography
CTC, also known as virtual colonoscopy, involves thin slice (~1mm) CT scanning of the
abdomen. The patient must perform full bowel preparation prior to the procedure and the
radiologist must infuse air via a flexible rectal catheter to distend the colon for evaluation.
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333
Whitlock et al. summarized the results of two recent large studies evaluating 3,751
patients (Whitlock etal. 2008). They demonstrated that pooled sensitivity for large adenomas (1.0cm) in these two studies was 92% (CI, 8796%), with no statistical heterogeneity detected between the studies (I2=0%; p=0.42). A metaanalysis of CTC (n=6,393)
demonstrated a slightly lower sensitivity of 85% (CI, 7991%) for polyps >9 mm and
specificity of 97% (CI, 9697%) (Mulhall et al. 2005). This is similar to sensitivities
reported for colonoscopic examination.
The risk of bowel perforation from air infusion is likely similar to DCBE. The risk of
radiation in these patients is unclear, but in patients over 50 years old undergoing CTC for
surveillance the risk of radiation related malignancy is certainly less than 0.1%. CTC can
demonstrate unexpected extracolonic findings in up to 50% of patients. While this may
lead to early treatment of diseases unrelated to colon cancer, it is also possible that the
investigation of these abnormalities may lead to complications (e.g., bleeding after percutaneous biopsy).
While there are no controlled clinical trials demonstrating reduced disease specific or
overall mortality with CTC, it is likely to supplant DCBE as a colon cancer screening
modality.
12.4.5
Flexible Sigmoidoscopy
FS is the simplest direct method for screening of colon cancer. The patient prepares for the
test by utilizing one or two packages of phospha-soda enemas, instilled per rectum and the
test requires no sedation. The endoscopist then inserts the colonoscope and advances it to
at least 40cm from the anal verge to be considered a complete FS. However, depending
on the length of the colon, this may reach as far as the distal transverse colon, or as distal
as the proximal sigmoid colon.
Sensitivity of FS has been estimated at 70% for detection of all adenomas (Hakama
etal. 2005). This implies that approximately 20% of adenomas occur in the proximal colon
and up to 10% of polyps would be missed with either FS or colonoscopy. Two large trials
have demonstrated an increased risk of proximal adenoma that warrants colonoscopic
evaluation in all patients discovered to have a distal adenoma (Lieberman and Weiss 2001;
Imperiale etal. 2000). In a population-based study, Rabenek etal. identified 39,762 patients
who had an FS for apparent screening. The authors demonstrated a significantly lower
incidence of colorectal cancer for up to 7 years after the investigation when compared to a
similar unscreened population (Rabeneck et al. 2008). Similarly, Lieberman and Weiss
demonstrated that FOBT and FS in combination can detect 75.8% of patients with an
advanced adenoma or cancer (Lieberman and Weiss 2001). Most recently, in the UK, FS
randomized controlled screening trial, a single FS offered between the ages of 55 and 64
years reduced the incidence of CRC by 23% (HR 0.77, 95% CI 0.700.84) and remarkably
reduced the mortality by 31% (HR 0.69, 95% CI 0.590.82) (Atkin etal. 2010).
While FS is more sensitive than FOBT alone, it is also riskier (1 in 20,000 risk of bowel
perforation). Furthermore, patient attendance in several large studies has ranged from 40
to 49%, implying that it is less acceptable to patients than FOBT.
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12.4.6
Colonoscopy
Colonoscopy involves direct endoscopic evaluation of the entire colon, from the cecum to
the anus. It is the only screening modality that allows evaluation, prevention (via endoscopic polypectomy), and diagnosis (via biopsy) for CRC. A complete bowel cleansing is
required the evening prior to the test and sedation is typically used.
Colonoscopy is the gold standard by which other screening modalities are measured, so
determining the sensitivity of colonoscopy is a challenge. However, two studies of patients
undergoing back to back colonoscopies suggest that polyps bigger than 1cm can be missed
in 614% of patients (Heresbach etal. 2008; Rex etal. 1997). However, the miss rate of
invasive cancer is considered to be much lower than 10%. There is evidence to suggest that
prolonging the withdrawal time by at least 6min during colonoscopy can improve neoplasia detection rates (Barclay etal. 2006). Furthermore, there are several technical maneuvers that can reduce miss rates (Rex 2006). Thus, colonoscopy screening should be
performed by experienced surgeons and gastroenterologists in a center where there are
clear performance benchmarks.
Despite the possibility of missed lesions, a completed colonoscopy has been demonstrated to reduce the risk of death from colon cancer by nearly 50% in large case controlled
studies (Baxter etal. 2009; Mulier etal. 2005). However, no prospective trials have been
conducted to confirm this mortality benefit.
Colonoscopy has the highest risk of complication among the available screening
modalities. A recent population based study of 97,091 colonoscopies in patients 5075
years old demonstrated the risk of bleeding was 1.64 per 1,000 and the risk of perforation
was 0.85 per 1,000 (Rabeneck etal. 2008). The risk of death was 1 in 14,000.
12.4.7
Current Screening Recommendations
In 2008, the American Cancer Society, in collaboration with the US Multi Society Task
Force on Colorectal Cancer and the American College of Radiology, updated their guidelines for screening and surveillance for colorectal cancer and adenomatous polyps (see
Table12.3) (Levin etal. 2008). Presently, less than 30% of eligible patients in the United
States are being screened for colorectal cancer (Klabunde etal. 2007). Clearly, physician
and patient education initiatives are necessary to ensure that patients have access to this
potentially life-saving practice.
12.5
Staging
Colonoscopy remains the most commonly utilized diagnostic evaluation. It offers the
opportunity to identify and biopsy colonic lesions, as well as to identify synchronous
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Table12 3 Current guidelines for colorectal cancer screening
Risk category
Recommended
Average risk
Interval
FOBT
FIT
Flexible sigmoidoscopy to
40cm or splenic flexure
DCBE
CT colonography
Colonoscopy
Annual
Annual
Every 5 years
Colonoscopy
Colonoscopy
510 years
3 years
Colonoscopy
Colonoscopy
<3 years
36 months
Previous history of colon cancer

Perioperative
Colonoscopy
Postoperative
Colonoscopy
Prior to surgery or
within 6 months
after surgery
1 year after
perioperative
colonoscopy
Subsequent
evaluations should
be at 3 years and
then 5 years, if all
evaluations are
normal
Every 5 years
Every 5 years
Every 10 years
Increased risk
Previous history of polyp
12 small tubular adenomas
310 small adenomas or
1 adenoma >1cm or
Polyp with villous or high
grade dysplasia
>10 adenomas
Sessile adenomas removed piecemeal
Family history of colorectal cancer or adenomatous polyps

One first degree relative who developed Colonoscopy at
neoplasia <60 years old, or
2 first degree relatives who developed 40 years old or
neoplasia at any age
10 years younger than the
One first degree relative who developed
neoplasia 60 years old, or
2 second degree relatives who
developed cancer at any age
High risk
Genetic or suspected diagnosis of FAP
youngest relative with

colorectal cancer
Any screening modality
used in patients with
average risk
Flexible sigmoidoscopy
at 1012 years old
5 years
5 years
Annual
(continued)
336
Risk category
Genetic or suspected
diagnosis of HNPCC
Chronic ulcerative colitis

or Crohns disease
S. Gill et al.
Recommended
Interval
Colonoscopy
Age 2025 years old or
10 years younger than
youngest family member
at diagnosis
Colonoscopy with biopsies
for dysplasia
Annual or Biennial
Annual or Biennial
FOBT fecal occult blood test; FIT fecal immunochemistry test; DCBE double contrast barium
enema; FAP familial adenomatous polyposis; HNPCC hereditary nonpolyposis colorectal cancer
malignancies or polyps. Once the diagnosis is confirmed, an accurate staging assessment

is required. Stage of disease at diagnosis remains the strongest predictor of CRC survival
and defines the clinical management strategy. The tumor, node, metastasis (TNM) staging
system of the American Joint Committee on Cancer (AJCC) is the recognized standard for
CRC staging and is widely used at the bedside and by regional and national tumor registries in the US and Canada. The application of a uniform staging assessment allows for the
evaluation of population-based treatment effects and outcomes. In the TNM system, pathologic staging (designated with the prescript p) is derived from resection specimens of the
primary tumor, and is considered the most accurate assessment of local disease. Clinical
classification (designated by the prescript c) is based upon clinical evaluation which may
include physical examination, radiologic imaging and surgical exploration. The AJCC
released the seventh edition of the Staging Manual in 2010 (AJCC 2010). As illustrated in
Table12.4, notable changes from the sixth edition included the further subdivision of stage
II and III colon cancer, based upon new survival and relapse data (Gunderson etal. 2010),
subclassification of M1 disease to differentiate single vs. multiple metastatic sites and a
recommendation to include expanded reporting of pathologic and molecular prognostic
features including the presence of perineural invasion, MSI and KRAS gene analysis.
12.6
Clinical Management
12.6.1
Malignant Polyps
Adenomatous polyps occur in close to 20% of adults over the age of 60 years old who live
in western countries (Correa 1978). Most of these premalignant adenomatous polyps are
amenable to endoscopic removal for definitive treatment. Colonoscopic removal of these
polyps has been shown to reduce the risk of colon cancer. However, up to 5% of polyps
that appear grossly benign will contain invasive cancer (OBrien etal. 1990). The risk of
cancer correlates to the size of the polyp (see Table12.5).
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Table12.4 TNM staging classification for cancers of the colon and rectum, AJCC (2010)
Primary tumor (T)
Tx
T0
Tis
T1
T2
T3
T4a
T4b
Primary tumor cannot be assessed

Carcinoma in situ: intraepithelial or invasion of lamina propria
Tumor invades submucosa
Tumor invades muscularis propria
Tumor invades through the muscularis propria into pericolorectal
tissues
Tumor penetrates to the surface of the visceral peritoneum
Tumor directly invades or is adherent to other organs or structures

NX
Regional lymph nodes cannot be assessed
N0
N1a
Metastasis in one regional lymph node
N1b
Metastasis in 23 regional lymph nodes
N1c
Tumor deposit(s) in the subserosa, mesentery or nonperitonealized
pericolic or perirectal tissues without regional nodal metastasis
N2a
Metastasis in 46 regional lymph nodes
N2b
Metastasis in seven or more regional lymph nodes
M0
M1
Distant metastasis
M1a
Metastasis confined to one organ or site (e.g., liver, lung, ovary,
nonregional node)
M1b
Metastases in more than one organ/site or the peritoneum
Staging classification
0
I
IIA
IIB
IIC
IIIA
IIIB
IVA
IVB
Tis
T1T2
T3
T4a
T4b
T1T2
T1
T4a
T3T4a
T4b
Any T
Any T
N0
N0
N0
N0
N0
N1aN1c
N2a
N2a
N2b
N1N2
Any N
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1a
M1b
Pathologically, a malignant polyp is defined by adenocarcinoma that invades into (but no

deeper than) the submucosal layer of the bowel wall. By definition, a malignant polyp is a
T1 colon cancer. It is important to distinguish a malignant polyp from a polyp with carcinoma in situ or high grade dysplasia. These entities have no appreciable metastatic potential
and are cured by polypectomy if the pathologic assessment is adequate and the specimen
can be removed in total.
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Table12.5 Risk of invasive adenocarcinoma in an adenomatous polyp

Study
Size of polyp
<1.0cm
1.02.0cm
>2.0cm
Muto (1975) (n=2,489)
1%
9%
46%
Shinya (1979) (n=18,286)
0.5%
5%
11%
Hermanek (1987) (n=6,793)
0.3%
7%
53%
Odom (2005) (n=4,443)
0.07%
2%
19%
In a malignant polyp that has been removed with negative margins, the main reason to
proceed with a formal segmental resection is to harvest the associated lymph nodes in the
mesentery. The risk of lymph node metastasis in malignant polyps is 815% (Hassan etal.
2005; Robert 2007). This is a relatively low risk, and in some patients this risk approaches
the mortality associated with colon resection.
In 1985, Haggitt proposed a classification of malignant polyps designed to predict
lymph node metastasis (Haggitt etal. 1985). In 64 patients who had a malignant polyp,
Haggitt demonstrated that polyps with invasive cancer at the base of a pedunculated polyp
or any sessile polyp had a 25% risk of lymph node involvement, while all other polyps had
<5% risk of lymphatic spread. While the role of Haggitts classification has been superceded by other important pathologic features, this study represents an important early
attempt to delineate patients who might be spared major surgery.
In 2004, Ueno et al. evaluated 292 patients with malignant polyps who subsequently
underwent either segmental colonic resection or close clinical follow up for recurrent cancer
(Ueno etal. 2004). The authors evaluated Haggitt level, tumor grade, depth of submucosal
invasion, tumor budding and lymphovascular invasion and found that the three features most
predictive of adverse outcomes (lymph node metastasis or recurrence with clinical follow up)
were tumor grade, tumor budding and lymphovascular invasion. In the absence of any of
these features, the risk of adverse outcome is less than 1%. However, if the malignant polyp
had any one of these features, the risk of adverse outcome was 20%. If the polyp had two or
more of these features, the risk of adverse outcomes increased to 36%. Prospective evaluation
of this scoring system may better define patients who can be spared major surgery.
Presently, the American College of Gastroenterology guidelines (Bond 2000) state that
malignant polyps may be treated with endoscopic removal and close surveillance when:
The polyp is completely excised.

The polyp can be accurately assessed with respect to the depth of invasion, grade of
differentiation, and completeness of excision of the carcinoma.
The cancer is not poorly differentiated.
There is no vascular or lymphatic involvement.
The margin of excision is not involved.
All other malignant polyps should be considered for surgical resection. However, even
with some high risk features, patients with malignant polyps and serious medical comorbidities are best managed with close surveillance and nonsurgical treatment.
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12.6.2
Early-Stage Colon Cancer (Stage IIII Disease)
12.6.2.1
Surgical Management of the Primary Tumor
There are three primary objectives in the surgical treatment of colon cancer: to cure, to stage
and to palliate. Despite advances in adjuvant therapy, surgical removal of primary cancer and
all macroscopic disease is necessary to achieve cure. In most cases, this involves removing the
involved colon, its lymphatic basin, and any adjacent structures that are directly invaded by the
tumor. Removing the entire lymph node basin is critical to cure the disease, as lymph nodes
with tumor deposits are likely to grow and cause local recurrence. Furthermore, adequate
lymphadenectomy is critical to accurately distinguish patients with early stage (I or II) disease
from patients with stage III colon cancer. Palliation, or the relief of symptoms, is usually associated with surgery for incurable disease. However, many patients with colon cancer present with
symptoms of either bleeding or obstruction. Thus, palliation is an important but often overlooked objective in the surgical treatment of patients, regardless of whether cure is possible.
Segmental resection of the colon is the preferred treatment of most colon cancers. At
the time of initial surgery, intramural spread of the tumor rarely exceeds 2cm from the
edge of the gross lesion (Hughes etal. 1983; Williams etal. 1983). Thus, gross margins of
5cm or more are generally recommended (Hida etal. 2005). Furthermore, removal of the
entire lymph node basin is critical in removing all gross disease, preventing recurrence and
providing adequate tissue for lymph node assessment. Lymphatic drainage of the colon
follows the same pattern as the arterial blood supply and venous outflow (see Figs.12.1
and 12.2). Thus, proximal ligation of the segmental blood supply of the colon and removal
of the mesenteric fat is the accepted oncologic strategy for harvesting lymph nodes.
Surgical Procedures for Colon Cancer

Conventional procedures for solitary colon cancers are illustrated in Fig.12.2. For most
colon cancers, segment resection is the most appropriate surgical treatment.
In patients with synchronous colon cancers, surgeons must decide between two separate segment resections, subtotal colectomy and ileorectal anastomosis, and total proctocolectomy and permanent ileostomy or ileal pouch anal reconstruction (see Fig.12.3). In
elderly patients, those with marginal fecal continence and those with frequent bowel movements, two segmental resections, are usually favored. However, this approach does increase
the risk of anastomotic leak, a complication that has a high mortality. In younger patients,
the perception of increased risk of metachronous lesions and the known capacity for bowel
adaptation often leads to the recommendation of subtotal or total colectomy.
Patients with underlying conditions (e.g., ulcerative colitis, Crohns colitis, FAP,
HNPCC) that predispose to colon cancer are offered more extensive surgery to remove
colon risk. In ulcerative colitis and FAP, the procedure of choice is proctocolectomy and
ileal pouch anal anastomosis. In patients with Crohns colitis, ileo-anal reconstruction is
not an option, so the extent of colectomy is determined by the minimal surgery required to
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Fig.12.1 Lymphatic drainage

of the colon
resect the colon involved by the cancer and colitis. Often, this can only be achieved by a
proctocolectomy and permanent ileostomy. In patients with HNPCC, segmental colectomy, subtotal colectomy, and ileorectal anastomosis or proctocolectomy and ileal pouch
anal anastomosis are all options for the treatment of a cancer or advanced polyp. In these
patients, balancing the ongoing risk of metachronous cancer and the possible functional
consequences of extensive colectomy are the primary considerations and must be individualized in discussions between the surgeon and the patient.
Lymphadenectomy
There is controversy regarding the importance of extended lymphadenectomy and its impact
on the oncologic outcomes in colon cancer. Chang etal. conducted a systematic review of
retrospective studies evaluating the impact of lymph node harvest on 5-year survival (Chang
etal. 2007a). The authors analyzed two nested cohort studies, five population-based studies,
and ten single institution case series. In 16 of 17 studies evaluating patients with stage II
colon cancer, increased lymph node retrieval/identification was associated better survival.
This improved survival can be partially attributed to stage migration. Stage migration is the
phenomenon whereby the distribution of stage in a particular cancer is influenced by either a
change in staging system or a technical improvement that facilitates more accurate identification of spread of the disease. In this case, better lymph node harvest leads to fewer patients
with undiagnosed stage III cancer being erroneously considered to have stage II disease.
Johnson etal. used Surveillance, Epidemiology and End Results (SEER) data to analyze
the impact of the number of disease-free lymph nodes harvested on survival in patients with
stage III colon cancer (Johnson et al. 2006). In 20,702 patients with stage III disease,
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Fig.12.2 Arterial blood supply of the colon
patients with >13 negative lymph nodes had better survival than patients with fewer than
three negative lymph nodes. Furthermore, in patients with stage IIIB and IIIC colon cancer,
there was a statistically significant reduction in survival with fewer lymph nodes retrieved.
These data suggest that lymph node harvest impacts more than just staging accuracy.
Improved survival in stage III patients with better lymph node retrieval and identification
may be related to better surgery and pathology. However, this association may be explained
by the biology of the cancer and its interaction with the host immune system; in other
words, patients with larger, more easily identified lymph nodes may be experiencing a more
robust immune response to the cancer, leading to locoregional containment of the disease.
In a randomized controlled trial enrolling 260 patients (Rouffet etal. 1994), very high
ligation (i.e., ligation at takeoff from the aorta) of the arterial blood supply of the colon did
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Fig.12.3 Standard surgical resections for colon cancer. (a) Oncologic resection of cecal and ascending colon carcinoma. (b) Oncologic resection of hepatic flexure carcinoma, in which the distance
between the tumor and left branch of the middle colic vessels is greater than 10 cm. (c) Shown is
oncologic resection of proximal transverse colon carcinoma, in which the distance between the
tumor and the left branch of the middle colic vessels is less than 10 cm. (d) Depicted are two
options for resection of transverse colon carcinoma: transverse colectomy (A) and extending right
hemicolectomy (A plus B). (e) Depicted are two options for resection of splenic flexure carcinoma:
splenic flexure resection (A) and left hemicolectomy (A plus B). (f) Oncologic resection of
descending colon carcinoma. (g) Oncologic resection of sigmoid colon carcinoma
not result in improved 5-year survival when compared to a slightly less proximal vascular
ligation. However, all procedures were performed by experienced cancer surgeons who
were performing wide mesenteric excisions, even in the control arm of the study.
The College of American Pathologists recommend that a minimum of 12 lymph nodes
should be identified after segmental resection for colon cancer (Compton 2006). Baxter
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etal. reviewed SEER data from all stage IIII colon cancer patients between 1988 and
2001 (Baxter etal. 2005). They found that only 37% of patients had 12 or more lymph
nodes assessed. Furthermore, only 41% of patients with stage II colon cancer had adequate
lymph node staging. These data suggest many patients with colon cancer might have had
inadequate surgery and inadequate adjuvant therapy based on poor staging.
Fortunately, there is evidence that colon cancer surgery can be improved. Wright etal.
performed a study where community surgeons were exposed to a standardized lecture
regarding surgical technique to optimize lymph node retrieval (Wright etal. 2008). The
authors demonstrated a significant improvement in lymph node harvest after the intervention. Surgeons performing surgery for colon cancer need to monitor the lymph node harvest in patients with colon cancer and work closely with pathologists to maintain the
minimum standard of 12 lymph node assessment.
Laparoscopic Surgery
While laparoscopy has revolutionized selected major abdominal surgeries, the impact on
colon surgery has been less extreme. While operating times are longer with the laparoscopic approach, hospital stay and postoperative pain are consistently better with minimally invasive surgery (Brown and Raval 2008). A recent Cochrane review evaluated 12
trials in which 3,346 patients were randomized to either open or laparoscopic surgery
(Kuhry et al. 2008). At minimum 2-year follow-up, there was no difference in cancer
related mortality (OR 0.84, 95% CI 0.761.06).
Presently, not every general surgeon who performs surgery for colon cancer is qualified to
perform laparoscopic colon resection. Specific training in laparoscopic colon surgery and a
minimum of 20 laparoscopic colon resections for benign disease are recommended before proceeding with laparoscopic colon cancer surgery. As laparoscopic surgery is integrated into residency and fellowship training, laparoscopic colon cancer surgery will become more common.
12.6.3
Radiotherapy Considerations in Resected High-Risk Colon Cancer
In contrast to rectal cancer, neoadjuvant and adjuvant radiotherapy has no proven role in
the treatment of colon cancer. The anatomical constraints of operating in the lower pelvis
and pattern of lymphatic drainage of the rectum are largely absent for colon malignancies
and the addition of radiotherapy as adjuvant therapy for resectable colon cancer as a whole
has not demonstrated a significant benefit in prolonging survival or reducing local or
regional relapses. However, the select use of radiotherapy, both external beam radiotherapy (EBRT) given with radiosensitizing 5-fluorouracil (5-FU) as well as EBRT with 5-FU
in conjunction with intraoperative electron beam radiotherapy (IOERT) has been proposed
in situations where the advanced stage of the primary tumor or its anatomic location might
compromise resection and lead to a higher risk of local or regional recurrence than is normally seen in colon carcinoma. These would include T4NxM0 tumors, T3N1-2M0 tumors
of the proximal ascending, distal descending, and sigmoid colon, and locally extensive
tumors arising in the setting of a fistula or abscess where en bloc surgical extirpation is
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difficult. This approach has been based on patterns of failure data from the University of
Minnesota reoperation series which demonstrated a high rate of local and regional recurrence following surgery alone for high risk colon cancers (Gunderson etal. 1985) and a
single institution study that suggested a benefit to postoperative radiotherapy and 5-FU
chemotherapy in high risk colon cancer (Willett etal. 1993). However, the single phase III,
multiinstitutional randomized clinical trial to have been performed to date (INT 013) failed
to show a benefit of postoperative radiochemotherapy in high risk colon cancer patients
randomized to 45.050.4Gy of EBRT with 5-FU and levamisole vs. 5-FU and levamisole
alone (5-year OS 58% vs. 62%, p>0.50). This study closed after accruing only 222 of a
planned 700 patients, leaving it underpowered to evaluate its primary endpoint. Additionally,
this study was performed without the benefit of modern imaging and radiotherapy treatment planning in a significant number of patients (Martenson etal. 2004).
In summary, although no level I evidence supports the routine use of radiochemotherapy as neoadjuvant or adjuvant therapy for resectable colon cancer, some investigators
have supported its use in situations for locally advanced tumors of the very proximal and
distal colon, as well as for T4NxM0 tumors or those arising from abscesses or fistuli. In
such situations, a typical treatment regimen would include careful radiotherapy treatment
planning using CT-based simulation to delineate the gross tumor or preoperative tumor
volume and normal anatomic and lymphatic structures at risk for tumor adherence or
involvement. Intensity modulated radiotherapy may offer a benefit in delivering therapeutic doses of radiotherapy to structures at risk while sparing the considerable small bowel
volumes that traditionally would receive high dose radiotherapy during EBRT for colon
cancer. Radiotherapy doses have traditionally been limited to 45.050.4Gy in 1.8Gy/day
fractions because of the limits of small bowel tolerance. 5-FU given either as a bolus at the
beginning and end of EBRT or as a continuous infusion through EBRT, has typically been
employed as a radiosensitizing agent (Gunderson etal. 1994).
In unresectable, nonmetastatic colon cancers where potentially curative surgical
resection is a consideration but where a concern exists regarding the radial margin status
because of local extension of the tumor into an unresectable structure, the combination
of EBRT and chemotherapy, followed by maximal resection and IOERT, has been
employed. Patients at the Mayo Clinic who present with primary or recurrent colon carcinoma who are unresectable at cure because of involvement by the primary or malignant
lymphadenopathy of critical, unresectable structures such as the inferior vena cava or
root of the mesentery. Patients typically receive maximal systemic therapy, followed by
neoadjuvant EBRT (median dose of 50.4 Gy) with radiosensitizing 5-FU, and then
undergo restaging at approximately 4 week after completion of EBRT. Following maximal resection of the tumor, IOERT to doses of 10.020.0Gy (median dose 12.5Gy) are
delivered to the site of adherence and/or residual tumor following close consultation
between the radiation oncologist, colorectal surgeon, and pathologist. In 40 primary
colon carcinoma patients receiving such therapy, OS was approximately 52% and disease-free survival was 49% at 5 years, with 13% of patients (in a combined analysis of
colon and rectal cancer patients) demonstrating local failure (Mathis etal. 2008). A similar approach has been used to salvage primary and nodal failures of colon cancer. Patients
with isolated pelvic and retroperitoneal nodal failures of colonic primaries treated with
irradiation, complete resection, and IORT had a median OS of 53 months and 5-year
survival of 49% (Haddock etal. 2001, 2003).
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12.6.4
Adjuvant Chemotherapy for Resected High-Risk Colon Cancer
Patients with early-stage colon cancer (stage I) have a very high cure rate with surgery
alone and are rarely, if ever, considered for adjuvant systemic therapy. Patients with stage
II or greater tumors may be offered additional testing and/or therapy.
12.6.4.1
5-FU Monotherapy
In the preadjuvant chemotherapy era over two decades ago, when surgery alone was the
standard of care, only 50% of stage III colon cancer patients remained recurrence-free at 3
years (Moertel etal. 1990). In current day, with the routine use of adjuvant therapy, patients
with stage III colon cancer have 75% likelihood that they will be disease-free at 3 years and,
most will be cured of their disease (Andre etal. 2004). The first definitive data supporting
adjuvant chemotherapy came from parallel trials performed by the North Central Cancer
Treatment Group (NCCTG) and the National Surgical Adjuvant Breast and Bowel Project
(NSABP) initiated in the late 1970s. NSABP investigators showed that treatment with the
combination of methyl-CCNU, vincristine, and 5-FU (MOF) led to a clinically and statistically significant disease-free (DFS) and overall 5-year survival (OS) advantage (59%) for
Stage III patients over surgery alone (50%) (Wolmark etal. 1988). A similar improvement
was seen using 5-FU modulated by either levamisole or leucovorin (Moertel etal. 1995).
5-FU and leucovorin subsequently became the standard of care in the next generation of
studies (OConnell etal. 1997; Wolmark etal. 1993). The largest American study to date,
Intergroup 0089, randomized 3,759 patients with stage II and III colon cancer to 5-FU plus
levamisole for 12 months, 5-FU plus high-dose leucovorin (HDLV) administered weekly
for 6 of 8 weeks for 4 cycles (the Roswell Park Regimen), 5-FU plus low-dose leucovorin
(LDLV) administered daily for 5 days every 45 weeks for 6 cycles (the Mayo regimen) and
5-FU plus LDLV plus levamisole (Haller etal. 2005). This study showed that either 5-FU +
HDLV or 5-FU + LDLV led to a survival advantage for patients with stage III colon cancer,
and that levamisole added toxicity without incremental benefit. More importantly, this study
demonstrated six to be as effective as 12 months of adjuvant therapy. The overall relative
benefit of adjuvant 5-FU-based monotherapy for all patients with stage II and III colon
cancer and for substages based on T and N characteristics, was estimated in a pooled individual patient data analysis including seven adjuvant trials with surgery alone control arms
(Gill etal. 2004). In this metaanalysis, adjuvant therapy with modulated 5-FU for stage II
and III colon cancer decreased the risk of recurrence by 30% (HR, 0.70; range, 0.630.78)
and decreased the risk of death by 26% at 5 years (HR 0.74; range, 0.660.83).
While bolus regimens remained the preferred 5-FU platform in North America, the
combination of both a bolus loading dose of 5-FU followed by 5-FU infusion was pursued
by European investigators, in part because 5-FU is cell cycle specific in its action and
appears to have a dual mechanisms of action related to inhibition of thymidylate synthetase and incorporation of the abnormal pyrimidine into RNA (Sobrero etal. 1997). The
LV5-FU2 regimen initiated by de Gramont and colleagues admistered LV 200 mg/m2,
5-FU 400 mg/m2 bolus followed by 600 mg/m2 infused continuously for 22 h with
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treatment repeated on days 1 and 2 of every 2 weeks was compared again at the Mayo
Clinic regimen, and was found to have comparable efficacy (Andre et al. 2003).
Convenience would make an oral fluoropyrimidine an attractive alternative to either bolus
or infusional 5-FU, if equivalent efficacy could be assured. Capecitabine is an oral prodrug
that undergoes a series of enzymatic conversions to 5-FU (Schuller et al. 2000). The
X-ACT trial compared capecitabine at a dose of 1,250mg/m2 b.i.d. to the Mayo Clinic
regimen in resected stage III colon cancer (Twelves etal. 2005). The HR for 3-year DFS
of 0.87 (95% CI 0.751.00) met the primary endpoint for noninferiority and established
capecitabine as a preferred option for patients receiving adjuvant 5-FU monotherapy.
12.6.4.2
5-FU and Oxaliplatin
MOSAIC was the pivotal first trial to evaluate the combination of oxaliplatin with 5-FU/LV
(FOLFOX4) to LV5-FU2 and enrolled 2,246 patients with stages II and III colon cancer
(Andre etal. 2004). FOLFOX4 adds biweekly oxaliplatin at a dose of 85mg/m2/day to the
LV5-FU2 backbone as described previously. In the final analysis, the addition of oxaliplatin
significantly improved 5-year DFS (73.3 vs. 67.4%, p=0.003) and 6-year OS (78.5 vs. 76%,
p=0.046) (Andre etal. 2009). In stage III disease, 5-year DFS improved by 7.5% (66.4 vs.
58.9%, p=0.005) and 6-year OS improved by 4.2% (72.9 vs. 68.7%, p=0.023). Oxaliplatin
caused significantly more peripheral sensory neuropathy, neutropenia, thrombocytopenia,
nausea and vomiting, and allergic reactions (Andre etal. 2004). Out of the 12% of patients
who developed sensory neuropathy interfering with function, only 1% of patients continued
to have residual severe neuropathy 1 year later. NSABP C-07 which randomized 2,492
patients with stages II and III colon cancer to receive the Roswell Park regimen of bolus 5-FU/
LV with or without oxaliplatin (FLOX), confirmed these findings (Kuebler etal. 2007). Three
year DFS increased from 71.8 to 76.1% (HR for DFS 0.79). Grade 3 or greater side effects
were observed in 51% of patients on 5-FU/LV compared with 61% of patients receiving
FLOX. Of note the FLOX regimen prescribes approximately 2/3 of the cumulative oxaliplatin
dose specified by the FOLFOX4 regimen suggesting that less exposure to oxaliplatin than the
cumulative dose of 1,020mg/m2 delivered through the administration of 12 fortnightly doses
of FOLFOX4 may be sufficient to achieve the same benefit. MOSAIC and NSABP C-07 have
solidly shifted the standard of care to adjuvant oxaliplatin plus 5-FU/LV for patients with
resected high-risk colon cancer. The subsequent XELOXA randomized study validated the
efficacy of oxaliplatin in the adjuvant setting when combined with capecitabine (XELOX) vs.
5-FU/LV (3-year DFS in stage III 70.9 vs. 66.5%, p=0.0045) (Haller etal. 2010).
12.6.4.3
Negative Trials in Adjuvant Colon Cancer
It is worthwhile to acknowledge that irinotecan has no proven role in the adjuvant setting.
The Cancer and Leukemia Group B (CALGB) chaired a U.S. Intergroup study comparing
the bolus 5-FU based IFL regimen to bolus 5-FU/LV (Saltz etal. 2004). Accrual of C89803
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was discontinued prematurely and outcomes were reported earlier than planned after a
protocol specified interim analysis indicated that IFL could not be proven superior to 5-FU/
LV. In the Pan European Trial in Adjuvant Colon Cancer (PETACC)-3, the addition of
irinotecan to infusional 5-FU/LV favored but did not significantly improve 3-year DFS
(p=0.091) (Van Cutsem etal. 2009a). The third study examining the potential benefits of
adjuvant irinotecan was the French ACCORD2 trial (Ychou etal. 2009). This study limited its enrollment to 400 stage III patients with high risk of recurrence because of N2
disease or N1 disease with concomitant perforation or obstruction. Again the irinotecan
plus 5-FU arm failed to provide a benefit over 5-FU/LV. Irinotecan-based regimens should
not be administered to patients in the adjuvant setting.
Perhaps even more disappointing is the lack of incremental efficacy observed in recently
completed trials evaluating the combination of FOLFOX and targeted therapies with demonstrated efficacy in the advanced setting. Bevacizumab is a monoclonal antibody (mAb)
to vascular endothelial growth factor (VEGF) and has been shown to improve survival
when combined with 5-FU based chemotherapy for the treatment of metastatic disease
(see later Sect.12.6.6.2). In NSABP C-08, a randomized trial of FOLFOX and bevacizumab vs. FOLFOX alone for resected stage II and III colon cancer, no significant improvement in DFS was observed (Wolmark et al. 2009). Confirmatory trials are pending. A
similar negative finding has been reported with cetuximab, a mAb to the epidermal growth
factor receptor (EGFR) which has survival efficacy in the metastatic setting when used in
previously treated patients with tumors with a wild-type KRAS status (see later
Sect. 12.6.6.2). The NCCTG-led N0147 trial of FOLFOX and cetuximab vs. FOLFOX
alone in wild-type KRAS stage III colon cancer failed to reach its primary endpoint of DFS
(Alberts etal. 2010). At present, an understanding of why biologic therapies have failed to
improve outcomes in the adjuvant setting is lacking. Further studies including a careful
evaluation of molecular determinants of response and outcomes, will be required to better
elucidate the reasons for these disappointing findings.
12.6.4.4
Considerations in Stage II Colon Cancer
While adjuvant treatment is clearly the standard of care for patients with stage III colon
cancers, the treatment benefit for stage II disease remains the subject of debate. As most
adjuvant studies enroll relatively fewer stage II patients, these studies have been underpowered to detect statistically significant benefits in this node-negative subgroup. Pooled analyses have been the typical methodology employed to judge the benefits of therapy in this
group. The stage II controversy was initially fueled by two conflicting pooled analyses
from the late 1990s: the NSABP pooled analysis of four trials reported a 30% reduction in
mortality for stage II (Mamounas etal. 1999), whereas the International Multicentre Pooled
Analysis of B2 Colon Cancer Trials (IMPACT B2) failed to demonstrate a statistically
significant benefit for stage II tumors (International Multicentre Pooled Analysis of B2
Colon Cancer Trials (IMPACT B2) Investigators 1999). These data as well as a literaturebased metaanalysis (Figueredo et al. 2004) led a panel convened by ASCO in 2004 to
conclude that routine administration of adjuvant therapy in stage II colon cancers was not
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recommended, but that patients should discuss their case on an individual basis with their
physicians (Benson etal. 2004). The British QUASAR investigators (Quick and Simple
and Reliable) enrolled 3,238 patients, 91% of whom were Dukes B and 71% of whom had
colon cancer in one out of three 5-FU treatment arms or to observation (Gray etal. 2004).
The study demonstrated significant improvement in DFS, and an analysis of the stage II
patients (n=2,948) indicated that there was a 34% absolute improvement in OS at 5 years
for the treatment vs. control arm (p=0.04). Interpretation of this study is confounded by the
inclusion of patients with rectal cancer, a disease with higher stage-specific rates of recurrence. These results have been interpreted by some as evidence that adjuvant chemotherapy
should be offered to all stage II patients with a clear description of the risks and benefits, so
that the individual patient might make an informed choice. In addition, subgroup analyses
from the MOSAIC trial demonstrate no significant interaction between stage of disease and
treatment, supporting the position that FOLFOX benefited both stage II and stage III colon
cancer patients compared to LVS-FU2 (Andre et al. 2004). Based upon these data, the
question has been redirected from whether or not we should treat stage II patients, to
whether we can select stage II patients who might benefit most from treatment.
The ASCO expert panel that provided recommendations for adjuvant therapy of stage
II colon cancer concluded that treatment may be considered for patients with higher than
average risk, including those with inadequately sampled nodes (<13), T4 primary lesions,
perforation, obstruction, lymphovascular invasion or poorly differentiated tumors but
should not be administered as a matter of routine (Benson etal. 2004). Additional molecular markers of interest have since emerged to support this risk-adapted approach to adjuvant therapy in stage II disease. As previously discussed, MSI-H tumors are associated
with a more favorable prognosis. In addition, recent studies have indicated that MSI-H
tumors may be less responsive to 5-FU chemotherapy (Ribic etal. 2003). Most commonly
cited among these is a retrospective pooled correlative analysis by Sargent etal. which
found that patients with MSI-H tumors (deficient MMR) treated with 5-FU had a 5-year
DFS which was similar to patients treated with surgery alone (70 vs. 67%, p=0.30)
(Sargent etal. 2010). In an ongoing stage II trial led by the Eastern Cooperative Oncology
Group (ECOG 5202), a strategy of risk stratification by MSI and 18qLOH status to determine need for adjuvant chemotherapy is now being prospectively evaluated. In the meantime, the development and validation of a gene signature to predict recurrence in stage II
colon cancer may have promising clinical utility in the near future. A recurrence score
based upon a 7-gene RT-PCR assay has been validated as an independent predictor of
recurrence beyond conventional pathologic features and MSI status (Kerr etal. 2009).
12.6.4.5
Adjuvant Therapy in the Elderly
Over half of all newly diagnosed, cases of colon cancer are over the age of 70 years. The
degree to which age may influence benefit from adjuvant chemotherapy remains an active
topic. In 2001, the findings from a trial-based individual patient data analysis evaluating age
as a predictive factor for adjuvant 5-FU chemotherapy were published in the New England
Journal of Medicine (Sargent etal. 2001). Sargent etal. demonstrated that patients older than
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70 years received the same proportional benefit from 5-FU adjuvant therapy as their younger
counterparts, without a noticeable increase in toxicity. The standard of care for adjuvant chemotherapy then switched from 5-FU to 5-FU plus oxaliplatin based upon the MOSAIC and
NSABP C-07 findings (Andre etal. 2009; Kuebler etal. 2007). ACCENT is a multinational
collaborative effort to pool individual patient data from phase 3 adjuvant colon cancer trials.
In 2009, the ACCENT study group presented an analysis of older age on the efficacy of using
new therapies beyond 5-FU alone (Mcleary etal. 2009). With 15% of 4,680 trial subjects over
age 70, a somewhat surprising significant negative interaction of age by treatment effect was
observed for disease-free survival and OS in the trials evaluating oxaliplatin-based adjuvant
therapy. This was not observed for the endpoint of time to colon cancer recurrence (where
deaths without recurrence are censored at the time of death, p=0.21) suggesting interplay with
competing risks. These data imply that adjuvant oxaliplatin does not translate into a survival
benefit in patients over 70 years of age. Unfortunately, the ACCENT database does not capture
toxicity and comorbidity data. Contradictory to these findings, an age-by-treatment analysis of
the XELOXA study (Haller etal. 2010) showed no detrimental impact of age on oxaliplatinbased treatment effect. Thus, the clinical implications of these age-by-treatment analyses
remain debatable. Ultimately, age alone cannot be the sole arbitrator of treatment decision
making. Patient functional status, comorbidities, support and preferences must be carefully
considered when determining the optimal adjuvant strategy for an individual patient.
12.6.5
Advanced Colon Cancer (Stage IV Disease)
12.6.5.1
Management of the Primary Tumor in Metastatic Colon Cancer
The management and prognosis of patients with metastatic colon cancer has changed significantly over the past 10 years. Median survival has nearly doubled and subsets of
patients with resectable metastatic disease may be cured with aggressive surgical and medical management. Management of the primary tumor in patients with stage IV disease is
dependent on whether the cancer is symptomatic or asymptomatic. In patients with symptoms, surgical intervention is generally recommended for palliation. The most common
symptom is bowel obstruction, occurring in nearly 30% before death. Except in patients
whose life expectancy is very short, the preferred choice in this situation is resection of the
primary tumor. In patients with unresectable colon cancer due to local invasion of critical
structures, surgical bypass (anastomosis of proximal bowel to colon distal to obstructing
lesion) may be possible. While restoration of gastrointestinal continuity is preferred, this
may not be advisable in patients with a significant intraabdominal tumor burden. Thus, a
colostomy or ileostomy may be necessary.
In patients with short life expectancy and/or high surgical risk, colonic stenting is an
option in centers with appropriate expertise. In a pooled analysis of case series including
791 patients stented for palliation, technical success was achieved in a median of 96% of
patients (interquartile range 77100%) (Sebastian etal. 2004). The majority of these patients
had left colon obstruction, and most technical failures occurred proximal to the splenic
350
S. Gill et al.
flexure. In the overall group of patients treated with stents (n=1,198), 7.3% developed a
recurrent obstruction in a median of 24 weeks (IQ 152 weeks) after stent placement. Of
these, 72% were managed with either argon beam ablation of tumor ingrowth or repeat stent
placement for relief of obstruction and managed to avoid major abdominal surgery. The risk
of perforation and death with the procedure was 3.8 and 0.6%, respectively.
The role of surgery for patients with asymptomatic colon cancer and unresectable metastatic disease is less clear. Surgical resection is often recommended to avoid subsequent
obstruction, which may occur at a time when both the primary tumor and the metastatic
disease has progressed and the patient is less fit to survive surgical intervention. Furthermore,
there is data to suggest that patients with metastatic disease may have a survival advantage
with resection of the primary tumor. Ruo etal. reported 127 patients who were asymptomatic when they had their primary tumor resected, and compared them to 103 of patients who
did not have their primary tumor resected between 1996 and 1999 (Ruo etal. 2003). It is
unknown what proportion of patients in the nonresected group had symptoms. At baseline,
the two groups had important differences; the resection group had fewer patients with two
or more sites of distant metastases (32 vs. 47%), fewer patients with left sided and rectal
tumors (54 vs. 72%) and less tumor burden in their liver (percentage of patients with >25%
burden was 41 vs. 55%), and slightly more patients with comorbidities (32 vs. 20%).
Nonetheless, the median survival was 16 months in the resection group compared to 9
months (p<0.001) in the no resection group. These data are often used to justify resection
in patients with incurable disease.
However, there are emerging data suggesting that improvements in chemotherapy that
have led to longer median survival may also affect the primary tumor. Armbrust et al.
reported on four patients with stage IV colon cancer treated with systemic chemotherapy
and no surgical intervention and the primary tumor remained stable at reevaluation 6, 23,
26, and 48 months later, respectively (Armbrust etal. 2007). Furthermore, Benoist etal.
reported on 27 patients with incurable stage IV colon cancer treated with chemotherapy
alone and compared them to 32 patients matched for important determinants of cancerspecific and overall mortality (Benoist etal. 2005). The authors demonstrated no significant difference in 2-year actuarial survival (41 vs. 44%, p=0.75). Of the 27 unresected
patients, only four patients developed bowel obstruction requiring surgery.
The role of palliative surgery in asymptomatic patients remains unclear. While patients
are living longer with improved systemic therapies, there is insufficient data to determine
if the antitumor effects of chemotherapy will adequately suppress the growth of the primary tumor to prevent future obstruction. Thus, the potential risks, benefits and alternatives of surgical resection must be discussed with the patient and treatment individualized
based on patient preference and the estimated risk of impending bowel obstruction.
12.6.5.2
Locoregional Management of Liver-Limited Metastatic Colon Cancer
Colon cancer has a propensity to spread to liver and, about 25% of the time, only liver
metastases are apparent. Untreated, liver metastases are almost uniformly fatal at 5 years
(Bengtsson et al. 1981; Wagner et al. 1984). In recent years, treatment options have
12 Colon Cancer
351
expanded dramatically as a consequent of advances in ablative technologies as well as

systemic therapies. Liver resection for colorectal cancer was once controversial, but has
been shown to be cost effective (Gazelle etal. 2003) and is now considered standard of
care. Because of the segmental anatomy of the liver, it is technically possible to remove
multiple lesions from different regions of the liver. Technical surgical advances including
improved techniques for obtaining vascular control, development of new technologies for
parenchymal dissection, and anesthetic advances, have made liver resection much safer. In
institutions in which high volumes of liver surgery are performed, liver resections for colorectal metastases are associated with mortalities of <5% (Fernandez et al. 2004; Fong
etal. 1997; Gayowski etal. 1994; Jarnagin etal. 2002; Pawlik etal. 2006). A SEER-based
analysis of the last two decades has confirmed profound improvements in the outcome of
patients with metastatic CRC directly correlated to sequential increases in the use of
hepatic resection, in conjunction with advances in systemic therapy (Kopetz etal. 2009).
Candidates for resection must be of sufficiently good health to tolerate major surgery,
particularly surgery in which hemodynamic fluctuations and major blood loss is a risk. In
general, it must be technically possible to remove all gross disease. For this reason, the
presence of extrahepatic disease represents a contraindication for resection. Exceptions to
that tenet may include patients with synchronous primary tumors as well as highly selected
patients with synchronous lung metastases (Lee et al. 2008). Finally, the residual liver
must have sufficient functional reserve. While cirrhosis is rare in this patient population,
the effects of chemotherapy on liver function must be considered (Karoui et al. 2006;
Kooby etal. 2003; Vauthey etal. 2006) as discussed below.
The diagnostic work-up for proper selection of candidates focuses on identifying contraindications to resection. Total bilirubin, liver enzymes, albumin and INR are required
for assessment of liver function. A colonoscopy is required (if not recently done) to ensure
that the primary tumor is controlled. A triphasic CT scan or a liver MRI will define the
extent of the intrahepatic disease and the technical feasibility of resection. A CT of the
chest, abdomen and pelvis are required to evaluate for extrahepatic disease. Recently,
FDG-PET has been advocated as a more sensitive and comprehensive way of ruling out
extrahepatic disease (Fernandez etal. 2004; Zealley etal. 2001).
With resection of hepatic metastases alone, the median survival is 3046 months and
5-year survival is 3038% (Fong et al. 1997; Gayowski et al. 1994; Doci et al. 1991;
Seifert etal. 2000). A number of investigations have attempted to identify prognostic factors which may guide the selection of patients for resection. Perhaps the most commonly
cited prognostic factors are the factors that comprise the Clinical Risk Score, described by
Fong (see Table12.6): nodal status of the primary tumor, disease-free interval, number of
metastases, size of the largest metastasis, and preoperative CEA (Fong etal. 1999). Several
independent investigators have confirmed the prognostic value of this Clinical Risk Score
(Arru etal. 2008; Mala etal. 2002; Mann etal. 2004). A high Clinical Risk Score correlates with an increased likelihood of identifying extrahepatic disease with FDG-PET
(Schussler-Fiorenza etal. 2004) and with diagnostic laparoscopy (Jarnagin etal. 2001).
However, additional factors have also been reported as prognostic including tumor grade
(Arru etal. 2008; Rees etal. 2008; Tan etal. 2008). In a large series reported by Pawlik
etal., disease-free interval and nodal status of the primary tumor were not found to be
prognostic on multifactorial analysis (Pawlik etal. 2005) Recent data suggest that a more
352
Table12.6 Clinical risk score
forrecurrence after hepatic
resection (Fong etal. 1999)
S. Gill et al.
Score
5-year survival (%)
60
44
40
20
25
14
One point each for: node positive primary, disease-free interval

<12 months, >1 tumor, size >5cm, CEA>200ng/mL
exuberant host inflammatory response to the tumor may portend a worse prognosis (Gomez
etal. 2008; Ishizuka etal. 2007; Neal etal. 2009). In practice, while it is desirable to identify patients who will most likely benefit from resection, most hepatobiliary surgeons do
not exclude patients for liver resection on the basis of any prognostic index alone. On the
other hand, it is possible that patients with worse prognostic factors should be more
strongly encouraged to receive perioperative systemic therapy, although the rationale for
this has never been supported by experimental evidence.
Some groups have taken a particularly aggressive approach at resecting colorectal liver
metastases. Even before the advent of more effective systemic therapies, resection of four
or more metastases was associated with a 5-year survival of 2437% (Fong etal. 1997;
Bolton and Fuhrman 2000; Minagawa et al. 2000). Extensive resections in which it is
anticipated that the residual liver mass is less than 25% may benefit from portal vein embolization, in which the portal vein flow is eliminated in the segments containing tumor in an
effort to induce hypertrophy in the uninvolved hepatic remnant (Covey etal. 2005, 2008).
Alternatively, two-stage liver resections can be undertaken, whereby the diseased segments are removed in two separate operations (Adam et al. 2007; Mentha et al. 2009;
Wicherts et al. 2008). During the course of a staged resection, the portal vein may be
ligated, which has similar effects on the hepatic remnant as portal vein embolization
(Capussotti etal. 2008). Finally and with increasing occurrence, chemotherapy has been
administered to patients with extensive intrahepatic disease in an effort to downstage to a
point where all gross disease is technically resectable. With contemporary multiagent chemotherapy regimens, unresectable disease can be converted to a resectability in 523%
(Table12.7). In series where resection was accomplished following chemotherapy for the
purpose of downstaging, 5 year survival rates were 3340% (Adam et al. 2001, 2004;
Bismuth etal. 1996). The current emphasis is to evaluate the role of biologics in combination with chemotherapy to achieve resection in patients with initially unresectable or borderline-resectable liver metastases. In a recent randomized phase 2 trial of combination
chemotherapy with cetuximab (CELIM study), response rates of 5768% were observed
with an encouraging 60% hepatic resectability rate (Folprecht etal. 2010).
A number of ablative technologies have emerged that enable the ablation of liver lesions
without surgery. These include cryoablation, radiofrequency ablation, microwave coagulation
therapy, and laser-induced thermotherapy. Cryoablation has largely been supplanted by
353
12 Colon Cancer
Table 12.7 Incidence of successful hepatic metastasectomy in first-line chemotherapy trials for
c olorectal cancer
References
Agents
RP (%)
% Liver
n
resection
Levi (1999)
5-FU, LV, oxaliplatin
90
66
23
De Gramont (2000)
210
54
Giacchetti (2003)
100
53
32
Scheithauer (2003)
Capecitabine, oxaliplatin
89
48
Teufel (2004)
5-FU, LV, CPT-11
35
31
Tournigand etal. (2004)
FOLFIRI? FOLFOX
109
56
Tournigand etal. (2004)
FOLFOX? FOLFIRI
111
54
22
Sorbye (2004)
82
62
11
Bajetta (2004)
Capecitabine, CPT-11
140
46
Cassidy (2004)
Capecitabine, oxaliplatin
96
55
Kohne (2005)
5-FU, LV, CPT-11
214
62
Falcone etal. (2007)
FOLFIRI
FOLFOXIRI
122
122
41
66
6
15
Taberno (2007)
FOLFOX + cetuximab
43
72
23
thermal ablation because of the adverse systemic effects associated with cryotherapy (Pearson
etal. 1999). Radiofrequency ablation is the most widely available technology. The general
indications for ablation are similar to those for liver resection. Selected patients typically
include those who cannot tolerate surgery; those who have prohibitive anatomy or small
hepatic remnants from previous resections (Elias etal. 2002); and those with bilateral disease
(in which case RFA may be used in conjunction with resection) (Abdalla etal. 2004; Elias
etal. 2005). Technical success rates and local recurrence rates vary widely in the literature for
colorectal liver metastases (Table12.8). Large tumors and lesions directly adjacent to large
vessels are associated with particularly high risks of local recurrence (Mulier et al. 2005;
Machi etal. 2001). While outcomes for selected patients undergoing ablation are promising,
local recurrences are much more likely with ablation, and the data are not yet available to
suggest that ablation is equivalent to resection. In 2009, ASCO convened a panel to evaluate
the utility of radiofrequency ablation for hepatic metastases from CRC (Wong etal. 2009).
The panel acknowledged that evidence supports a survival benefit with hepatic resection, with
wide variability in recurrence and survival rates across ablation studies and reported a compelling need for more research to determine the efficacy and utility of ablation to improve
survival outcomes in this setting.
Incremental improvements in survival following resection of liver metastases may be
attributed to several factors. The wide availability of FDG-PET scan to exclude extrahepatic
disease may enhance the proper selection of individuals who would benefit from resection.
Fernandez etal. described a cohort of 100 consecutive patients who were selected using
354
S. Gill et al.
Table12.8 Outcomes following radiofrequency ablation for colorectal liver metastases

Series
Number of Number of Local recurrence Survival
patients
lesions
rate (%)
Solbiati etal. (2001)
117
Machi etal. (2001)
179
39.1
130
9.2
46% (3 years)
Bowles etal. (2001)
39
39
30.8
25 months (median)
Kosari etal. (2002)
76
76
6.6
Bleicher etal. (2003)
59
59
18.3
Aloia etal. (2006)
30
30
37
27% (5 years)
Abdalla etal. (2004)
57
110
22% (4 years)
FDG-PET as part of the diagnostic work-up (Fernandez etal. 2004). The 5-year survival
was 58%. While this was attributed to the superior capability of FDG-PET to select patients
without extrahepatic disease, results from a definitive study of the influence of FDG-PET on
survival are still unavailable. Likely of greater import are the temporal in systemic therapy
for advanced colon cancer. In practice, the majority of patients who undergo resection of
colorectal liver metastases have received chemotherapy at some time in the perioperative
period. At present, it is unknown whether neoadjuvant chemotherapy or adjuvant chemotherapy is the optimal approach. There are rationales for each approach, and each approach
has its advantages and disadvantages. Administering chemotherapy after resection more
closely resembles the practices associated with treatment of the primary tumor, in which
adjuvant therapy has consistently been shown to provide a survival advantage in reducing
risk of recurrence. This approach also is less likely to detrimentally impact on the conduct
of liver surgery. Unfortunately, this practice is largely based upon extrapolation from adjuvant studies and the evidence from adjuvant chemotherapy for resected liver metastases is
sparse (Power and Kemeny 2010). Perhaps the most compelling data are derived from a trial
by Portier etal., which was stopped prematurely due to slow accrual (Portier etal. 2006).
A total of 171 patients were randomized to receiving 5-FU/LV or observation. Median
disease-free survival was significantly greater in patients who received adjuvant chemotherapy (24.4 vs. 17.6 months), but OS was not significantly improved. In addition to this
trial, a retrospective evaluation of outcomes from 792 liver resections from two major
centers revealed an improved survival in patients who had received 5-FU-based adjuvant
chemotherapy compared to patients who had not received chemotherapy, even after controlling for Clinical Risk Score (Parks etal. 2007). Administration of chemotherapy was
associated with a median survival of 47 months, whereas the median survival in the cohort
which had not received chemotherapy was 36 months. Further studies are required to elucidate the benefits of a postoperative adjuvant therapy approach after resection of colorectal cancer liver metastases, although it is unlikely that a trial employing a no
chemotherapy arm will be feasible.
Administration of chemotherapy prior to resection of otherwise resectable hepatic
metastases has a number of potential advantages. It provides measurable information on
the invivo chemosensitivity of a given tumor. One might argue that progression during
12 Colon Cancer
355
preoperative chemotherapy is a relative contraindication to postoperative treatment with

the same agents and this has been associated with a less favorable prognosis (Abdalla etal.
2004; Gruenberger etal. 2008a; Small etal. 2009). The rationale for neoadjuvant chemotherapy has spurred a number of trials, mostly phase II trials. In sum, these trials have
demonstrated that it is feasible and safe to administer chemotherapy prior to liver resection
in a setting in which there is good multidisciplinary collaboration (Chua etal. 2010). The
European Organization for Research and Treatment of Cancer (EORTC)-led EPOC study
wherein 364 patients with four or less resectable liver metastases were randomized to
perioperative FOLFOX or surgery alone (Nordlinger etal. 2008). Perioperative chemotherapy was associated with an 8.1% improvement in progression-free survival at 3 years,
but no significant improvement in OS was observed. While this result was compelling, it
did not demonstrate a definitive advantage to perioperative chemotherapy. Another limitation in the interpretation of the results is that the trial included mostly patients with favorable prognostic factors. Therefore, it is difficult to extrapolate the potential effects of
chemotherapy on patients with worse prognostic factors. In addition, preoperative chemotherapy is not without risk. Chemotherapy is associated with alterations in the hepatic
parenchyma such as sinusoidal dilatation, hyperbilirubinemia, steatosis, and steatohepatitis (Karoui et al. 2006; Vauthey et al. 2006). Irinotecan-containing regimens have been
implicated with a relatively greater risk of steatosis (Vauthey etal. 2006), which is associated with increased surgical morbidity (Kooby etal. 2003). The use of portal vein embolization in tandem with administration of chemotherapy has been considered to prevent
postoperative liver failure (Covey etal. 2008). While an increase in adverse events was not
seen in an institutional series (Reddy etal. 2008), a phase II trial of preoperative XELOX
and bevacizumab when surgery was performed more than 5 weeks after the last dose of
systemic therapy (Gruenberger etal. 2008b), it will be important to continue to evaluate
the safety of antiVEGF agents in this setting.
As more than 50% of recurrences following resection of colorectal liver metastases
appear in the liver (Ballantyne and Quin 1993), it has been reasoned that exposing the liver
to a high dose of chemotherapy would be beneficial following hepatic resection. Hepatic
artery infusion (HAI) represents an attempt at providing regional chemotherapy. The rationale for this approach is that liver metastases derive their blood supply from the hepatic
arteries and normal hepatocytes derive most of their blood supply from the portal vein
(Ackerman 1974). This gained attention when Kemeny etal. reported on a survival advantage in patients who received HAI (Kemeny etal. 1999). At the time of resection of colorectal liver metastases, 156 patients were randomly assigned to HAI with floxuridine and
dexamethasone plus intravenous 5-FU/LV or systemic 5-FU/LV alone. At 2 years, the
actuarial survival was 86% in the group which received HAI and 72% in the control group,
which was significant. Clancy etal. performed a metaanalysis of trials in an attempt to
better delineate the value of HAI following liver resection (Clancy etal. 2005). Seven trials met the inclusion criteria, and six of those consisted of randomized controlled trials.
There was considerable heterogeneity in the chemotherapy administered, as well as in the
control arms of the studies included in the metaanalysis. A small but statistically insignificant survival advantage was seen in the group that had received HAI. The authors concluded that adjuvant HAI could not be routinely recommended following resection of
colorectal liver metastases, but further study was warranted. Since the development of
356
S. Gill et al.
numerous systemic chemotherapy regimens and drug combinations that include biological
agents with high response rates, HAI is now infrequently administered, particularly in the
setting of resectable liver metastases.
12.6.5.3
Stereotactic Body Radiotherapy
In recent years, stereotactic body radiotherapy (SBRT), also referred to as radiosurgery, has
become increasingly used as a noninvasive means of controlling isolated liver metastases
arising from colorectal carcinoma primaries. Interest arose in developing a noninvasive
treatment for liver metastases following publication of successful surgical excision of liver
metastases. SBRT relies on delivering very high doses of radiotherapy to small treatment
volumes with high precision, relying on recent developments in image-guided radiotherapy
for accuracy. The combination of shortened treatment times, usually delivered in one to
five fractions of SBRT, higher doses, and ability to avoid excess radiotherapy to normal
tissues, such as the liver, combine to permit an ablative dose of radiotherapy to be focused
on a small tumor within the liver with little risk of toxicity and a high likelihood of local
control (Timmerman etal. 2007; Olsen etal. 2009). Additionally, advances in diagnostic
imaging, such as positron emission scanning, allow for appropriate selection of patients
with oligometastatic disease that might be appropriate for locally aggressive therapy in the
setting of liver metastases (Kavanagh etal. 2006a; MacDermed etal. 2008).
A number of investigators have reported excellent long term local control in patients
undergoing SBRT for liver metastases (Blomgren etal. 1995). Although early reports have
included liver metastases treated with SBRT arising from a number of primary sites,
colonic primaries have predominated. Treatment of liver metastases is complicated by
respiratory motion of the liver, which can be accounted for with abdominal compression,
respiratory gating, breath holding techniques, and other methods. The University of
Heidelberg has reported the results of a phase I/II trial of liver tumors treated with SBRT
in which 30 of 60 tumors were liver metastases. Eligibility criteria included unresectable
liver tumors less than 6cm in maximum dimension that were at least 6mm from the GI
tract in patients with a Karnofsky performance status greater than 80%. Patients received
doses from 14 to 26Gy in a single fraction. Toxicity was minimal and local control was
81% at 5 years in last 54 patients treated (Herfarth etal. 2001). Wulf etal. have reported
similar findings using a hypofractionated regimen consisting of three fractions of 10.0
12.5Gy, four fractions of 7.0Gy, and one fraction of 26.0Gy (Wulf etal. 2006). Twenty
four of 51 treated lesions in the series were colorectal metastases. Local control was
improved in the higher effective dose regimens, with half of patients receiving 10Gy failing locally. In the high dose group, three fractions 12.012.5Gy or one fraction of 26.0Gy,
local control was 82% at 2 years. OS was 22% at 3 years and freedom from progression
was 19% at 2 years. Toxicity was also minimal. The University of Colorado reported the
results of a phase I/II trial treating 36 patients with 13 liver metastases 6cm in size with
three fractions of 20.0Gy in the phase II component of the trial. Local control was 93% in
the 28 patients evaluable after 6 months (Kavanagh etal. 2006b). A report from Rotterdam
utilizing three fractions of 12.5Gy for liver metastases, 14 of 17 patients from colorectal
12 Colon Cancer
357
primaries, found an 86% rate of local control at 2 years for metastatic patients (Mendez
Romero et al. 2006). A reanalysis of data on liver metastases treated with SBRT at
Heidelberg suggested that colorectal metastases treated with SBRT who previously had
received oxaliplatin and/or CPT-11 had a worse outcome in relation to other histologies,
although a similar analysis by Romero did not confirm this (Mendez Romero etal. 2006;
Herfarth and Debus 2005).
12.6.6
Unresectable Metastatic Disease
12.6.6.1
Radiotherapy Considerations to Palliate Advanced Unresectable Disease
Radiotherapy can be used palliatively for control of bone metastasis pain and for treatment of spinal cord compression. Some degree of pain relief is noted in approximately
two-thirds of patients treated and complete pain relief in approximately one-quarter, with
maximum pain reduction being reached over a period of weeks after treatment is complete. Typical EBRT courses range from 8Gy in 1 fraction to 30Gy in 10 fractions to
40Gy in 20 fractions. No single regimen has proven superior to others in terms of dose
and fractionation (Chow etal. 2007; Brown etal. 1999; Fairchild and Chow 2007). In
previously irradiated patients with spinal metastases, stereotactic body radiosurgery may
be an option for treatment (Yin etal. 2004; Chang and Timmerman 2007; Chang etal.
2007b). For patients with disseminated bone metastases that demonstrated activity on a
technetium-99 nuclear bone scan, radiopharmaceutical treatment with strontium-89 and
samarium-153 may be options to treat multiple sites of pain causing metastases (Bauman
etal. 2005).
Brain metastases in the setting of colon cancer are relatively less common and tend to
occur later in the course of the illness in comparison to brain metastases arising from
other primary sites. In a series of 916 patients with brain metastases from Freiburg,
median time from primary diagnosis to diagnosis for brain metastases from colorectal
cancer was 22.6 vs. 8.0 months for metastases arising from other sites. Additionally,
patients with gastrointestinal primaries had fewer metastases at diagnosis compared with
nongastrointestinal primary tumors (Bartelt et al. 2004). Options for treatment and
expected survival depend on the numbers of metastases, presence of active systemic
malignant disease outside the central nervous system, patient age, and performance status. Treatment is typically whole brain radiotherapy, administered over a periods weeks.
However, for patients with solitary brain metastases, good performance status, and controlled systemic disease, surgical resection or stereotactic radiosurgery may be considered an option in addition to whole brain radiotherapy. If reversible edema-induced
neurological symptoms are present, reaction may be the treatment of choice patients
treated, but OS remains poor for most patients after a diagnosis of brain metastases from
colonic origin. No dose fractionation regimen for whole brain radiotherapy has been
demonstrated to be superior to any other (Bartelt etal. 2004; Amichetti etal. 2005; Tsao
etal. 2005a, b).
358
S. Gill et al.
12.6.6.2
Systemic Therapy for Advanced Unresectable Colon Cancer
While selected patients with liver and/or lung limited oligometastases may be amenable to
curative-intent resection, systemic therapy remains the mainstay treatment. Recent
improvements in the survival of patients with advanced disease have been significant and
meaningful, with median survivals approaching up to 2 years on treatment (Grothey etal.
2004) compared to an estimated survival of 6 months with best supportive care alone. The
current armamentarium of cytotoxic agents with demonstrable efficacy which will be
reviewed here include: fluoropyrimidines (intravenous 5-FU or oral capecitabine), oxaliplatin and irinotecan. While 5-FU and irinotecan have single agent efficacy, oxaliplatin is
best used in combination with 5-FU. In a review of phase 3 trials over the last 10 years,
access to all three active agents is strongly correlated with improved survival (Grothey and
Sargent 2005). Chemotherapy regimens referred to in this section are summarized in
Table12.9. In addition, two classes of biologic agents will be discussed: the antiVEGF
mAb, bevacizumab, and the antiEGFR mAbs: cetuximab and panitumumab.
First and Second-Line Chemotherapy

N9741 was an Intergroup trial comparing three random-assignment allocations: FOLFOX4,
IROX, and IFL, the standard first-line regimen for metastatic CRC at the time of this study
(Goldberg etal. 2004). FOLFOX4 was associated with superior time to progression (TTP)
(8.7 vs. 6.9 months, p=0.0014), response rate (RR) (45 vs. 31%, p=0.002) and median
survival (19.5 vs. 14.8 months, p=0.0001) compared to IFL. IFL also resulted in more diarrhea, vomiting, nausea and febrile neutropenia while patients on FOLFOX4 experienced
higher rates of paresthesias. The use of IFL as an irinotecan-5-FU doublet has been replaced
by irinotecan with infusional 5-FU (FOLFIRI). In a French intergroup (GERCOR) study,
two hundred and twenty patients with metastatic CRC were randomly assigned to a sequence
of FOLFIRI followed by FOLFOX6 or the reverse (Tournigand etal. 2004). Both strategies
(FOLFOX6-FOLFIRI or FOLFIRI-FOLFOX6) achieved impressive equivalent first-line
RRs (54 and 56%, respectively) and median survivals (20.6 and 21.5 months). Equivalent
RR efficacy was also demonstrated in the randomized trial of first-line FOLFOX4 (36%)
vs. FOLFIRI (34%) reported by Colucci etal. (2005). In both trials, toxicity varied with
nausea, mucositis, and alopecia more frequent with FOLFIRI, and neutropenia and paresthesias more frequent with FOLFOX. Hence, the most widely accepted cytotoxic strategy
is to employ FOLFOX or FOLFIRI in the first-line with a planned switch to the alternate
regimen at progression or treatment intolerance. This switch to a second-line regimen will
occur in the majority but not all patients. Ultimately, this will be influenced by toxicity
concerns, performance status and patient preference.
With no new classes of cytotoxics on the horizon, multiple strategies to optimize the use
of available chemotherapies have been evaluated. To address the question of upfront doublets vs. sequential therapy, the UK MRC FOCUS randomized trial (Seymour etal. 2007)
and the Dutch CAIRO trial (Koopman etal. 2007) demonstrated that a sequential approach
359
12 Colon Cancer
Table12 9 Description of commonly used chemotherapy regimens
Regimen
Agents and doses
(given IV unless specified)
Cycle frequency
LV5-FU2
Leucovorin 400mg/m2 on day 1 with

bolus 5-FU 400mg/m2 bolus followed by
a 46h infusion of 5-FU 2,4003,000mg/m2
Every two weeks
IFL
Irinotecan 125mg/m2 with bolus 5-FU

500mg/m2 and leucovorin 20mg/m2 on
days 1, 8, 15, and 22
Every 6 weeks
IROX
Oxaliplatin 85mg/m2 on day 1 with bolus

5-FU 400mg/m2 and leucovorin 200mg/m2
followed by a 22h infusion of 5-FU
600mg/m2 on days 1 and 2
Every 2 weeks
FOLFOX4
Oxaliplatin 85mg/m2 on day 1 with

bolus 5-FU 400mg/m2 and leucovorin 200mg/
m2 followed by a 22h infusion
of 5-FU 600mg/m2 on days 1 and 2
Every 2 weeks
FOLFOX6
Oxaliplatin 100mg/m2 with bolus 5-FU 400mg/

m2 and leucovorin 400mg/m2 followed by a
46h infusion of 5-FU 2,400mg/m2
Every 2 weeks
mFOLFOX6
Oxaliplatin 85mg/m2 with bolus 5-FU 400mg/

Every 2 weeks
FOLFOX7
Oxaliplatin 130mg/m2, leucovorin

400mg/m2 and a 46h infusion
of 5-FU 2,400mg/m2
Every 2 weeks
FOLFIRI
Irinotecan 180mg/m2 with bolus 5-FU 400mg/

Every 2 weeks
FUFOX
Oxaliplatin 50mg/m2 with leucovorin 500mg/

m2 and a 24h infusion of 5-FU 2,000mg/m2
on days 1, 8, 15, and 22
Every 5 weeks
FOLFOXIRI
Irinotecan 165mg/m2, oxaliplatin 85mg/m2 and

leucovorin 200mg/m2 followed
by a 48h infusion of 5-FU 3,200mg/m2
Every 2 weeks
CAPIRI
Capecitabine 1,000mg/m2 p.o. b.i.d.

days 114 plus irinotecan 80mg/m2
on days 1 and 8
Every 3 weeks
CAPOX
Capecitabine 1,000mg/m2 p.o. b.i.d. days 114

oxaliplatin 70mg/m2 days 1 and 8
Every 3 weeks
XELIRI

plus irinotecan 250mg/m2 on day 1
Every 3 weeks
XELOX

plus oxaliplatin 130mg/m2 on day 1
Every 3 weeks
360
S. Gill et al.
did not compromise OS although first-line response rates were inferior. Of concern in both
these studies was the lower than expected survival for all treatment arms, suggesting an
overall poorer prognosis study cohort. While upfront doublets remain the preferred standard, FOCUS and CAIRO do suggest that a sequential approach, particularly in patients
not well suited for doublet therapy, is not unreasonable. The amelioration of treatmentrelated toxicity is also a priority. The major dose-limiting toxicity of oxaliplatin is cumulative neuropathy. The OPTIMOX1 trial (Tournigand etal. 2006) randomly assigned patients
to FOLFOX4 until progression or to OPTIMOX1, a strategy of six cycles of modified
FOLFOX7 followed by maintenance LV5-FU2 for 12 cycles. For patients with nonprogressive disease, FOLFOX7 was then reintroduced. Overall RR, PFS and survival were
similar despite the decreased use of oxaliplatin in the OPTIMOX1 arm. The OPTIMOX2
study aimed to evaluate a chemotherapy-free interval with no maintenance LV5-FU2
(Chibaudel et al. 2009). PFS (8.6 vs. 6.6 months) and duration of disease control were
superior with the maintenance strategy confirming that while oxaliplatin-free intervals are
feasible, caution and close follow-up must be exercised when considered complete chemotherapy holidays. The next generation of OPTIMOX trials will examine the integration of
molecular targeted therapies (OPTIMOX3). Finally, the use of an oral fluoropyrimidine
backbone in lieu of infusional 5-FU may also improve patient acceptability and tolerability. In a phase III trial designed to demonstrate equivalence of XELOX vs. FOLFOX, the
PFS of XELOX was shown to be noninferior to FOLFOX (median 8.0 vs. 8.5 months)
(Cassidy etal. 2008).
Recognizing that exposure to all three active chemotherapy agents extends survival
(Grothey etal. 2004) and that a proportion of patients may not be suitable for second-line
therapy, the strategy of combining oxaliplatin, irinotecan and 5-FU in a single first-line
regimen can be of interest. In an Italian randomized trial of FOLFOXIRI vs. FOLFIRI, the
triplet combination yielded superior RR (60 vs. 34%, p<0.0001), PFS (9.8 vs. 6.9 months,
p=0.0006) and OS (22.6 vs. 16.7 months, p=0.03) (Falcone et al. 2007). A combined
analysis of triplet regimen studies reaffirms improved response rates, PFS, OS and hepatic
resection rates compared to FOLFIRI therapy, but at the expense of increased toxicity,
notably diarrhea, vomiting and neutropenia (Montagnani etal. 2010).
First and Second-Line Targeted Therapies in Advanced Disease

Table 12.10 summarizes the key trials assessing the combination of available biologic
therapies with first- and second-line chemotherapies. These trials are discussed below.
Bevacizumab
Bevacizumab is a humanized mAb to the VEGF-A ligand, thus halting the VEGF signaling
pathway. Available evidence suggests that the efficacy of bevacizumab is mediated by antiVEGF induced vascular normalization which may alleviate hypoxia and improve delivery
of the chemotherapy backbone to the tumor (Jain 2005). The pivotal trial was a randomized
comparison of first-line IFL plus placebo with IFL plus bevacizumab 5mg/kg every 2 weeks
(Hurwitz etal. 2004). Median survival was increased from 15.6 to 20.3 months (p<0.001)
with the addition of bevacizumab, as were TTP (10.6 vs. 6.2 months, p<0.001) and RR (45
361
12 Colon Cancer
Table 12.10 Selected first and second-line phase 3 studies of biologics in combination with
chemotherapy
Study-Author
Chemotherapy
Biologic
Primary efficacy
endpoint
First-line
AVF2107g,
Hurwitz etal. (2004)
IFL
Bevacizumab
Second-line
E3200, Giantonio etal. (2007)
FOLFOX
Bevacizumab
EPIC, Sobrero etal. (2008)
Irinotecan
181, Peeters etal. (2010)
FOLFIRI
NO16966, Saltz etal. (2008)

CRYSTAL,
Van Cutsem etal. (2009b)
PRIME, Siena etal. (2010)
Median OS 20.3 vs.

15.6 months
HR 0.66, p<0.001
FOLFOX/XELOX Bevacizumab Median PFS 9.4 vs.
8.0 months
HR 0.83, p=0.0023
FOLFIRI
Cetuximab
Median PFS 9.3 vs.
8.7 months (wtKRAS)
HR 0.68, p=0.02
FOLFOX
Panitumumab Median PFS 9.6 vs.
8.0 months (wtKRAS)
HR 0.80, p=0.02
Median OS 12.9 vs.
10.8 months
HR 0.75, p=0.0011
Cetuximab
Median OS 10.7 vs.
9.9 months
HR 0.975, p=0.71
Panitumumab Median PFS 5.9 vs.
3.9 months (wtKRAS)
HR 0.73, p=0.004
vs. 35%, p=0.004). Notable and expected toxicity with bevacizumab was limited to grade 3
hypertension (10.3 vs. 2.3%), increased risk of arterial thrombo-embolic events, and rare
reports of gastrointestinal perforation and wound dehiscence. Bevacizumab in combination
with first-line 5-FU/LV monotherapy has been evaluated in two phase II trials (Kabbinavar
etal. 2003, 2005a) and as a third treatment arm of the Hurwitz trial which was discontinued
after a planned interim analysis established acceptable safety for the IFL plus bevacizumab
arm (Hurwitz etal. 2005). In a combined efficacy analysis of these three cohorts, the addition of bevacizumab to 5-FU/LV resulted in an improvement in survival (17.9 vs. 14.6
months, p=0.008), TTP (8.8 vs. 5.6 months, p<0.0001) and RR (34 vs. 24%, p=0.019)
(Kabbinavar etal. 2005b). NO16966 was a randomized phase III 2X2 factorial trial of firstline FOLFOX vs. XELOX with or without bevacizumab (Saltz etal. 2008). While the primary endpoint of superior PFS was met in this study, the magnitude of benefit was lower
than anticipated. This was partly attributed to methodologic concerns pertaining to treatment
discontinuations in the absence of progressive disease, and variability in the definition of the
primary PFS endpoint. When compared to the Hurwitz/IFL findings, a differential efficacy
of bevacizumab with an irinotecan vs. oxaliplatin backbone has also been speculated. Despite
these issues, the use of bevacizumab in combination with either FOLFOX or FOLFIRI
remains the current standard of care for first-line therapy.
362
S. Gill et al.
To investigate the role of bevacizumab in second-line, a randomized trial of FOLFOX

with or without bevacizumab was conducted in patients with IFL-refractory metastatic
CRC (Giantonio et al. 2007). Survival, TTP and RR with FOLFOX plus bevacizumab
(10 mg/kg every 2 weeks) was superior to FOLFOX alone (respectively 12.9 vs. 10.8
months, p=0.0018, 7.2 vs. 4.8 months, p<0.001 and 22 vs. 9%, p<0.001). No meaningful
activity was seen with single-agent bevacizumab (RR 3%). The addition of bevacizumab to
second-line chemotherapy is therefore an appropriate option in bevacizumab-nave patients.
In clinical reality, this represents a minority of patients. In fact, there exists considerable
interest in evaluating the role of continued bevacizumab therapy beyond progression of
first-line chemotherapy. This is sparked primarily from the results of the phase IV bevacizumab registry study (BRiTE) which reported a remarkable 31.8 month survival in patients
who went to receive postprogression chemotherapy with continued bevacizumab (Grothey
etal. 2008). While impressive, this strategy requires prospective, controlled validation.
C etuximab and Panitumumab

Cetuximab is a chimeric mAb against the extracellular domain of EGFR. Panitumumab is
a fully human mAb against the same EGFR target. Both agents have demonstrated singleagent efficacy and approved indications in the chemotherapy-refractory setting with lack
efficacy in tumors with mutated KRAS, as discussed in the next section. The initial investigation of the role of antiEGFR therapy in treatment-nave disease focused on the strategy of combining cetuximab or panitumumab to the current standard of chemotherapy
plus bevacizumab. Unfortunately, this dual-antibody approach yielded negative outcomes
and was promptly abandoned in light of evidence of harm in two large phase 3 trials: the
PACCE trial (Hecht etal. 2009) (HR for PFS 1.27; 95% CI, 1.061.52 with the addition
of panitumumab) and the CAIRO2 trial (Tol et al. 2009) (HR for PFS 1.22; 95% CI,
1.041.43 with the addition of cetuximab). A number of randomized trials evaluating the
combination of first-line chemotherapy with cetuximab or panitumumab compared to
chemotherapy alone have been completed within the last 2 years (see Table12.10). These
phase 3 trials have consistently demonstrated enhanced response rates and improved PFS
with the addition of cetuximab or panitumumab in tumors with wild type (wild-type
KRAS) (Bokemeyer etal. 2009; Siena etal. 2010; Van Cutsem etal. 2009b). Ongoing
randomized trials including a phase 3 CALGB/SWOG-led by North American Intergroup
trial (C80405) are presently directly comparing the efficacy of doublet chemotherapy
with cetuximab or panitumumab to a standard of chemotherapy plus bevacizumab in the
first-line treatment of unresectable, metastatic wild-type KRAS colorectal cancer.
12.6.7
Management of Chemotherapy-Refractory Disease
Therapeutic options are limited once a patient has exhausted 5-FU, irinotecan, oxaliplatin
and bevacizumab. The BOND trial was a UK MRC randomized (2:1 assignment) phase II
trial of irinotecan plus cetuximab (400mg/mg2 loading dose then weekly 250mg/m2) or
cetuximab alone in irinotecan-refractory metastatic CRC (Cunningham etal. 2004). Over
60% of enrolled patients had also previously progressed on oxaliplatin. Response rates
12 Colon Cancer
363
(primary endpoint), TTP and survival were respectively 23%, 4.1 and 8.6 months for irinotecan plus cetuximab and 11%, 1.5 and 6.9 months for cetuximab alone. Cetuximab use was
associated with an acneiform rash. Despite the lack of phase III survival data, cetuximab
was approved in 2004 in the US and European Union for second or subsequent-line therapy
in patients with EGFR-positive, irinotecan-refractory metastatic CRC, recognizing that this
was an area of an unmet medical need. The National Cancer Institute of Canada Clinical
Trials Group Study CO-17 randomized patients with chemotherapy-refractory disease
between cetuximab and best supportive care (Jonker etal. 2007). A modest but statistically
significant improvement in OS was observed with cetuximab (median survival 6.1 vs. 4.6
months, HR 0.77, p=0.005). A study in a similar population was performed with panitumumab (Van Cutsem et al. 2007) which demonstrated an improved PFS (HR 0.54,
p<0.0001) but was unable to prove an OS benefit as this endpoint was confounded by a
76% cross-over rate. During this time, retrospective analyses emerged which led to the
breakthrough of KRAS status as a determinant of treatment benefit with antiEGFR therapy
(Benvenuti etal. 2007; Lievre etal. 2006). The KRAS-RAF-MAPK signaling pathway is
activated downstream of EGFR. Mutation of KRAS causes constitutive oncogenic activation of this downstream cascade resulting in cell proliferation, antiapoptotic effect and
angiogenesis (Bardelli and Siena 2010). The consequent independence from upstream signaling results in a failure to respond to blockade of the transmembrane EGFR receptor
vis--vis cetuximab or panitumumab. KRAS mutation, specifically a mutation in codons 12
or 13, is observed in up to 40% of CRC. While no longer felt to unequivocally be a marker
of poor prognosis, the negative predictive value of mutant KRAS has been confirmed in
multiple KRAS correlative reanalyses of cetuximab and panitumumab phase 2 and 3 clinical
trials. Notably, the CO.17 KRAS analysis demonstrated an extraordinary 4.7 month improvement in OS with the use of third-line cetuximab in the wtKRAS subset (median survival 9.5
vs. 4.8 months, HR 0.55, p<0.001) (Karapetis etal. 2008). In accordance with the 2009
ASCO guidelines for KRAS testing, if KRAS mutation in codon 12 or 13 is detected, then
patients should not receive antiEGFR antibody therapy (Allegra etal. 2009).
The demonstration of the predictive utility of KRAS has heralded an era of intense
investigation for additional genetic determinants to further tailor therapies for colon cancer. KRAS and BRAF mutations are mutually exclusive in CRC. Mutations in the BRAF
V600E allele may account for up to 15% of wt KRAS nonresponders, based upon an initial
retrospective study of 113 cases treated with antiEGFR therapy (Di Nicolantonio et al.
2008) and later studies with similar results (Laurent-Puig etal. 2009; Loupakis etal. 2009).
Based upon these findings, evaluation of BRAF status in addition to KRAS mutational
status is now recommended by the 2010 National Comprehensive Cancer Network
(NCCN) Clinical Practice Guidelines for the management of colon cancer. However,
recent re-analyses confirm the negative prognostic value of BRAF mutations but fail to
confirm that it is a negative predictive marker for antiEGFR theraphy (Bokemeyer 2010).
Hence, it is not clear that patients whos tumors harbor BRAF mutations do not benefit
from therapy with cetuximab or panitumumab.
The last decade has witnessed remarkable strides in the management of patients with
advanced colorectal cancer. The optimal approach is continually being redefined with previous distinct lines of therapy now blurred into individualized treatment strategies which employ
locoregional and surgical therapies where appropriate, in combination with tailored systemic
364
S. Gill et al.
and targeted chemotherapies. A personalized approach to cancer management with rational

selection of therapies will hopefully continue to improve as advances are made in our understanding of the molecular predictors of prognosis and treatment efficacy in colon cancer.
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Radiographics 21 Spec No:S55S69
Rectal Cancer
13
Claus Rdel, Dirk Arnold, and Torsten Liersch
13.1
Introduction
The treatment of rectal cancer is as variable as its clinical presentations. It can occur as an
early tumor suitable for local excison, a locally advanced tumor that requires major surgery plus (neo)adjuvant therapy, one invading adjacent organs with no evidence of distant
metastases, and lastly, one presenting with distant metastases. New data have been collected and progress has been made both in surgery as well as in radiotherapy and chemotherapy. Better knowledge of radial microscopic lymphatic spread within the so-called
mesorectum has led to the use of total mesorectal excision (TME). With this type of surgery, local control rates have been markedly increased and local failure rates above 15%
are now no longer acceptable. Technical advances in radiotherapy and improvements in
the sequencing of radiotherapy, chemotherapy, and surgery allow a further increase in the
therapeutic ratio. Moreover, additional agents, for example, capecitabine, oxaliplatin, or
irinotecan as well as targeted therapies, are currently incorporated into multimodality concepts. In addition, advances in both pathology and imaging have further contributed to the
multidisciplinary management.
C. Rdel ()
Department of Radiotherapy and Oncology, Johann Wolfgang Goethe-University Frankfurt,
Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
e-mail: claus.roedel@kgu.de
D. Arnold
Department of Haematology and Oncology, University Halle-Wittenberg, Halle, Germany
T. Liersch
Department of General Surgery, University of Gttingen, Gttingen, Germany

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13.2
Epidemiology
Colorectal cancer is the third most frequently diagnosed cancer in men and women in
Europe and the U.S.A., with an estimated 40,840 new cases diagnosed in the U.S.A. in
2009 (Jemal et al. 2009). High incidence rates are found in North America, Western
Europe, and Australia (4045 cases/100,000 population), and intermediate rates in
Eastern Europe (26/100,000), with the lowest rates found in Africa (38/100,000).
Approximately two-thirds of cases occur in the colon and one-third in the rectum. Within
the U.S.A., little difference in incidence exists among whites, African Americans, and
Asian Americans. The occurrence of sporadic colorectal cancer increases continuously
above the age of 4550 years for both genders and peaks in the seventh decade. Subgroups
of patients, including those with inherited syndromes, such as familial adenomatous
polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), or hamartomatous
polyposis conditions (e.g., the PeutzJeghers syndrome), can experience colorectal cancer at a much earlier age.
13.3
Etiology
The etiology appears to be multifactorial in origin and includes both environmental factors
and a genetic component. Approximately 7585% of colorectal cancers are sporadic;
1520% develop in those with either a positive family history or a personal history of
colorectal cancer or polyps (Learn and Kahlenberg 2009). The remaining cases occur in
people with certain genetic predispositions, such as HNPCC (47%) or FAP (1%), or in
people with inflammatory bowel disease, particularly chronic ulcerative colitis (1%).
The fundamental role of environmental factors is supported by observations in migrant
populations. Generally, migrants from low-incident regions in Africa and Asia to the highincident regions of North America or Australia assume the incidence of the host country
within one generation (Whittemore etal. 1990). Specifically, a high-fat, low-fiber diet is
implicated in the development of colorectal cancer. Conversely, the ingestion of a highfiber diet and fish appears to be protective against colorectal cancer. Fiber causes the formation of a soft, bulky stool that dilutes out carcinogens; it also decreases colonic transit
time, allowing less time for carcinogenic substances to contact the mucosa. The more
sedentary lifestyle in western countries, prolonged cigarette smoking, and alcohol consumption also appear to be linked with the risk of colorectal neoplasia (Norat etal. 2005;
Cho etal. 2004).
Most colorectal cancers arise from benign, adenomatous polyps lining the wall of the
bowel, with those that grow to a large size (>2cm) and have villous appearance or contain dysplastic cells being most likely to progress to cancer. This progression from adenoma to carcinoma is associated with an accumulation of genetic alterations, including
the activation of oncogenes and inactivation of tumor suppressor genes (Leslie et al.
13 Rectal Cancer
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2002). One of the early steps in this process is the interruption of the APC/b-catenin/
TCF-4 pathway allowing unchecked cellular replication at the crypt surface. This can
occur in the germline of FAP patients with the second allele being inactivated somatically or in sporadic cancers for which both alleles are somatically inactivated. At least
two pathways exist to develop colorectal cancer: chromosomal instability (CIN) and
microsatellite instability (MSI). CIN is the genetic reason for tumor formation in about
8085% of colorectal cancer and the mechanism operative in FAP. It is typically coupled with mutations in K-ras and p53, ultimately leading to loss of heterozygosity of
p53 and malignant transformation. MSI is found not only in >90% of HNPCCs that
carry a germline inactivation in DNA mismatch repair genes, but also in 15% of sporadic cancer, in which epigenetic hypermethylation silences gene transcription of
hMLH1 (Grady and Carethers 2008). With MSI, multiple frameshift mutations at microsatellite sequences occur, including those in exon coding sequences of the transforming growth factor b receptor II, the proapoptotic gene BAX, and DNA mismatch repair
genes (hMSH3 and hMSH6). Clinically, tumors with MSI are located preferentially in
the right colon, tend to be diploid, exhibit a mucinous histology with a lymphoid reaction around the tumor, and have a more favorable stage-matched prognosis compared
with non-MSI tumors.
13.4
Prevention and Early Detection
13.4.1
Primary Prevention
Primary prevention involves the identification and elimination of factors which cause or
promote colorectal cancer or interfere with adenoma-to-carcinoma cascade. Dietary and
lifestyle approaches employ higher-fiber/lower-fat components and increased physical
activity. Other dietary components, such as selenium, carotenoids, and vitamins A, C,
and E, may also have protective effects by scavenging free-oxygen radicals. Folic acid,
a component of fresh fruits and green vegetable, supplies methyl groups necessary for
nucleotide synthesis and gene regulation. Prospective studies generally support an
inverse association between folate intake and colorectal cancer risk (Lashner et al.
1997). Chemopreventive strategies are based on population-based studies that strongly
support an inverse relationship between use of nonsteroidal anti-inflammatory drugs
(NSAIDs), such as aspirin, sulindac, or the new selective COX-2 inhibitors, and the risk
of colorectal adenomas or carcinomas (Williams etal. 1999). COX-2 is commonly overexpressed in more than 50% of adenoma and 8085% of adenocarcinoma. The protective role of aspirin and NSAIDs, however, has to be counterpoised with the adverse
effects of these drugs that preclude any recommendation that they should be commonly
used for chemoprevention. Currently under way are trials that focus on FAP patients,
those with resection of early-stage colorectal carcinoma and those with a history of
adenomatous polyps.
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13.4.2
Screening for Early Detection
The process of malignant transformation from adenoma to carcinoma takes several years.
The goal of screening is to prevent rectal cancer mortality through the detection and treatment of benign or premalignant lesions and curable-stage cancer. For the average-risk
population, screening should begin at age 50 and should follow one of the following testing options: colonoscopy (preferably) every 10 years, or fecal occult blood testing every
year and flexible sigmoidoscopy every 5 years, or double-contrast barium enema every 5
years. If there is an affected first-degree relative, a family history of FAP or HNPCC, or a
personal history of adenomatous polyps, colorectal cancer, or chronic inflammatory bowel
disease, screening should begin earlier and/or such patients should undergo screening
more often than the average-risk group. Two promising but investigational approaches of
screening tools include virtual colonoscopy and molecular stool testing. The first employs
virtual reality technology from cross-sectional CT or MRI scans, the second is based on
the molecular detection of neoplasm-specific DNA from exfoliated cancer cells (Huerta
2008; Yee 2009).
13.5
Clinical Manifestations
Rectal cancer is usually symptomatic prior to diagnosis. Common symptoms include gross
red blood in stool (mixed or covering stool, or by itself, sometimes accompanied by the
passage of mucus) and a change in bowel habits such as unexplained constipation, diarrhea, or reduction in stool caliber. Hemorrhoidal bleeding should always be a diagnosis of
exclusion. Obstructing rectal cancers frequently present with diarrhea rather than constipation. In cases of locally advanced rectal cancer with circumferential growth and extensive
transmural penetration, urgency, inadequate emptying, and tenesmus is seen. Urinary
symptoms and buttock or perineal pain from posterior extension are grave signs.
13.6
Diagnostic Evaluation and Imaging
13.6.1
Pretreatment Staging
The standard workup for rectal cancer is seen in Table13.1. The pretreatment evaluation
of a patient with rectal cancer should include a careful history and physical examination.
Through digital rectal examination (DRE; the average finger can reach approximately
8cm above the anal verge), tumors can be assessed for size, ulceration, and fixation to
surrounding structures. DRE also permits a cursory evaluation of the patients sphincter
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Table13.1 Workup for rectal cancer
History
Including family history of colorectal cancer or polyps
Physical exam
Including assessment of size, minimum diameter of the lumen,

mobility, distance from the anal verge, and cursory evaluation
of sphincter function
Rigid rectoscopy
Including assessment of mobility, minimum diameter of the

lumen, and distance from the anal verge. Allows diagnostic
biopsy of the primary tumor (preferably performed after or
1 week before rectal ultrasound to avoid false positive
classification of lymph nodes in the mesorectal compartment)
Colonoscopy or Enema
To detect possible synchronous neoplasm; barium

is only allowed if there is no stenotic tumor. In cases
of stenotic tumor enema with water soluble contrast is favored
Endorectal ultrasound
Considering a local excision or preoperative therapy; allows

determination of the infiltration depth into the rectal wall and LN
status, offers the surgeon, who should perform the ERUS, the
possibility to clarify the surgical strategy (low anterior resection
with sphincter preservation or coloanal anastomosis, APR)
Pelvic CT or MRI
To assess the extent of the primary tumor and lymph node

involvement (for accuracy of transrectal ultrasound,
CT, MRI for T and N staging, see Table13.2)
Abdominal/lung-CT
To detect possible metastatic disease
CEA
To obtain baseline CEA level (a prognostic factor

and important for follow-up)
Complete blood count
Anemia secondary to bleeding
function, which is critical when determining whether a patient is a candidate for a sphincter-sparing procedure. Additionally, anal manometry should be used to quantify the function of the internal and external sphincters. The anal pressures can be measured at 1-cm
intervals, first in the resting state and then during periods of voluntary contraction of the
external anal sphincter. In normal adults, intra-anal pressure is usually doubled during
voluntary contraction. For the assessment of the anal pressure profile, the recording probe
must be withdrawn from the rectum continuously at a constant rate. This continuous pullthrough technique allows an appropriate assessment of the anal pressure profile and functional sphincter length. As determined by this method the length of the high-pressure zone
varies between 2.5 and 5cm. Rigid proctosigmoidoscopy allows direct visualization of the
lesion and provides an estimation of the size of the lesion and degree of obstruction. This
procedure is used to obtain biopsies and gives an accurate measurement of the distance of
the lesion from the anal verge and the linea dentata. A complete evaluation of the large
bowel, preferably by colonoscopy, should also be done to rule out synchronous intraluminal neoplasms.
The primary imaging modalities to assess the extent of the primary tumor are endorectal
ultrasound (ERUS), multidetector 416 slice CT, and phased array MRI. ERUS is the most
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Table13.2 Estimates of sensitivity and specificity for pelvic CT, MRI and ERUS: a meta-analysis
by Bipat etal. (2004), encompassing 90 studies from 1985 to 2002
Stage
Imaging modality
Sensitivity (%) Specificity (%)
Muscularis propria invasion
ERUS
MRI
CT
94
94
NA
86
69
NA
Perirectal tissue invasion
ERUS
MRI
CT
90
82
79
75
76
78
Adjacent organ invasion
ERUS
MRI
CT
70
74
72
97
96
96
Lymph node involvement
ERUS
MRI
CT
67
66
55
78
76
74
accurate tool in predicting T stage of rectal cancers, especially T1 vs. T2 (Table13.2; Fig.13.1)
(Bipat etal. 2004; Puli etal. 2009). Thus, ERUS has been recommended as the investigation
of choice in selection of potentially curative local excision which should be restricted to
patients with T1 (sm1/sm2) tumors without further risk factors, as well as in the selection of
patients with early T3 tumors (vs. T2) for neoadjuvant treatment. ERUS cannot be reliably
used in patients with high or stenosing tumors. Noteably, overestimation of staging with this
technique occurs more often than understaging. In the German CAO/ARO/AIO-94 study,
18% of patients in the immediate surgery arm clinically staged by ERUS to have T3 and/or
N+ disease had lymph node negative tumors confined to the rectal wall (pT1/2 pN0) on
Mass
Fig.13.1 Endorectal ultrasound (ERUS) visualizes the rectal wall as alternating hyperechoic and
hypoechoic layers of tissue. The first layer is the hyperechoic water-filled balloon or mucosal
interface, which is bounded by the hypoechoic mucosa and muscularis mucosa, the hyperechoic
submucosa, the hypoechoic muscularis propria, and, finally, the hyperechoic muscularis propria or
perirectal fat interface. Depth of penetration is determined by identifying which of these layers is
disrupted by the tumor. The figure shows a mass infiltrating beyond the muscularis propria (thick
arrow) into the perirectal fat (bright area in the lower part), indicating a uT3-rectal tumor
385
13 Rectal Cancer
pathologic assessment of the resected specimen (Sauer etal. 2004). This probably is due to the
inflammatory and desmoplastic processes caused by the tumor (or by tumor biopsy taken
within 1 week before ERUS was performed), but is also operator dependent. Endorectal coil
MRT is an alternative to ERUS but appears not to be superior to ERUS for T staging.
Because of limited acoustic penetration by ERUS, invasion of bulky tumors into the
perirectal fat and adjacent organs and pelvic side walls is better evaluated by multislice-CT
scan and phased array MRI. The involvement of the anal sphincter and levator ani muscles
cannot be truly seen on CT scans, whereas high-resolution MRI techniques using phasedarray coils have led to better spatial resolution and particularly have been shown to identify
the anal sphincter, puborectalis, and particularly the mesorectal fascia (Beets-Tan and Beets
2008) (Fig.13.2a, b). This latter is an important feature to predict negative circumferential
margins between the tumor and the mesorectal fascia, and makes phase array MRI superior
to CT especially for lower third rectal tumors. Moreover, substaging of T3 tumors (T3a/b
with tumor spread 5mm into the mesorectal compartment) has been validated prospectively by the MERCURY Study Group (2007) and has shown direct agreement between
pretreatment imaging and corresponding pathology.
The identification of positive lymph nodes is more difficult. Involvement is mainly
assessed by size criteria (>8mm), although enlarged lymph nodes are not pathognomonic
of tumor involvement, and morphological features such as the presence of mixed signal
intensity and irregularity of the borders of the lymph nodes may be more reliable. The
overall accuracy in detecting positive lymph nodes with the above techniques is approximately 6075% (Table13.2). The accuracy of MRI is similar to CT; however, it may be
male, 65 years,
cT3 cN+ rectal caner,
G
H
C
C
B
D
Fig.13.2 (a) MRI scan of the pelvis: Rectal cancer of the lower third of the rectum. A bladder, B os
pubis, C rectal cancer of the lower third of the rectum, uT3 uN+, D sphincter area, E mesorectum,
F ossis coccygeus, G glandulae spermaticae, H venae of the pelvis. (b) MRI scan of the pelvis:
Rectal cancer of the upper third of the rectum. A bladder, B os pubis, C rectal cancer of the lower
third of the rectum, uT3 uN+, D sphincter area, E mesorectum, F ossis coccygeus, G glandulae
spermaticae, H venae of the pelvis
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male, 74 years,
cT3 cN+ rectal cancer,
E
A
C
E
B
D
Fig.13.2 (continued)
further enhanced with the use of superparamagnetic iron oxide particles (Lahaye et al.
2008). Likewise, the accuracy of ERUS for the detection of involved perirectal lymph
nodes may be augmented if combined with fine needle aspiration. However, adequate
clinical detection of lymph node involvement remains a challenge that is critically important with respect to the increasing use of preoperative treatment strategies.
Screening for distant metastatic disease is accomplished routinely by chest X-ray and
abdominal contrast-enhanced CT or MRI. Thoracic CT is recommended for high-risk
rectal cancer and suspicious findings on chest X-ray. Bone scan and brain imaging are
required for clinical symptoms only. The major advantage of a positron emission tomography (PET) scan is to differentiate between recurrent tumor and scar tissue by measuring tissue metabolism of an injected glucose-based substance. Scar tissue is inactive,
whereas tumor generally is hypermetabolic. This test generally is not used in a routine
preoperative metastatic workup.
13.6.2
Imaging After Radio(Chemo)therapy
Although ERUS, CT, and MRI can be used to assess downstaging of the tumor after neoadjuvant multimodal treatment, it is not accurate in distinguishing between ypT0, ypT1, ypT2
or ypT3 residual cancers. Overstaging is common, especially when there is a fibrotic thickening of the rectal wall. A reasonably high level of accuracy has been observed by phased
array MRI for differentiating ypT02 vs. ypT3 (Barbaro etal. 2009). Diffusion-weighted
MRI has been investigated to monitor therapy response and to predict outcome to preoperative therapy; however, further studies are needed. For the identification of responders to
neoadjuvant therapy, 18FDG (18F fluoro-2-deoxy-d-glucose)-PET has a larger role (Fig.13.3).
Many studies have reported a significant decrease in standardized uptake values (SUV) on
postradiation FDG-PET in responders when compared to nonresponders, but the clinical
value of this information remains to be determined (Calvo etal. 2004).
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Fig.13.3 [18F]FDG-PET for response prediction in rectal cancer treated with preoperative chemoradiotherapy (CRT). (a) Whole-body (focused on the pelvis) [18F]FDG-PET scan with 300MBq
prior to preoperative 5-FU-based CRT: enhanced uptake in cUICC-III rectal cancer. (b) [18F]
FDG-PET with 300MBq after 3 weeks of ongoing preoperative 5-FU-based CRT: there was only
a physiological uptake in the rectum; no signs for viable cancer were detectable and the patient was
classified as a complete responder. After surgery the FDG-PET result was confirmed by histopathological findings (ypT0 ypN0 M0)
13.7
Pathology
13.7.1
Anatomy and Pathway of Spread
The rectum is approximately 16cm in length. Because of differences in treatment and prognosis the rectum is subdivided into three parts according to the distance of the lower margin
of the tumor from the anal verge (assessed by rigid rectoscopy): upper third 1216 cm,
middle third 6 to 12cm, and lower third <6cm. In reporting results, it should be stated
whether the reference point is the anal verge (i.e., lowermost portion of the anal canal), the
dentate line, or the anorectal ring. Distances measured from the anal verge are approximately 2cm greater than distances from the dentate line. The anorectal ring is at the level
of the puborectalis sling and levators, representing the pelvic floor from within the pelvis.
The anterior peritoneal reflection represents the point at which the rectum exits the peritoneal
cavity and becomes retroperitoneal (approximately 812cm from the anal verge, extremely variable between females and males). Below this level there is a mesorectal, or circumferential,
resection margin all around the rectum. While distal intramural spread usually extends no more
than some millimeters beyond the grossly recognizable margin of the tumor, microscopic tumor
nodules, so-called satellites, are found in the mesorectum predominantly in the radial direction,
but also distal, some centimeters from the lower tumor margin (Quirke etal. 1986; Hermanek
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etal. 2003). A layer of visceral fascia (fascia propria) encloses both rectum and mesorectum and
thus forms a separate compartment within the pelvis. With TME, this entire package is removed
by sharp retroperitoneal dissection within the anatomically defined avascular (holy) plane
between the visceral and parietal pelvic fascia. The sharp dissection is performed under direct
vision between the fascia propria of the mesorectum and the fascia presacralis (Waldeyers fascia). Anteriorly, the Denonvilliers fascia (in men) or the rectovaginal septum (in women) should
be used as the standard plane of dissection, unless an anterior or circumferential tumor dictates a
wider resection margin (en bloc resection), such as resection of the posterior vaginal wall The
dissection is performed until the levator muscles are visible laterally and posteriorly to the rectum (Fig.13.4a, b).
The major portion of the lymphatic drainage of the rectum passes along the superior
hemorrhoidal arterial trunk toward the inferior mesenteric artery. Only a few lymphatics
follow the inferior mesenteric vein. The pararectal nodes above the level of the middle
rectal valve drain exclusively along the superior hemorrhoidal lymphatic chain. Below this
level (approximately 78cm above the anal verge), some lymphatics pass to the lateral
rectal pedicle. These lymphatics are associated with nodes along the middle hemorrhoidal
artery, obturator fossa, and hypogastric and common iliac arteries. Extensive lymphatics
are also present contiguous with the rectovaginal septum in women, and along Denonvilliers
fascia in men. The venous drainage of the upper rectum is to the inferior mesenteric vein
via the superior hemorrhoidal and then to the portal system, whereas the lower rectum can,
in addition, drain to the internal iliac veins and inferior vena cava. Therefore, either liver
or lung metastases or both can occur with rectal cancers.
13.7.2
Histopathology
The vast majority (over 90%) of colorectal cancers are adenocarcinoma. Mucinous and
signet ring carcinoma are both variants of adenocarcinoma and account for some 10% of
all colorectal cancer. This subdivison appears to confer no independent prognostic value.
Other histologic types are rare and include carcinoid tumors, leiomyosarcomas, lymphomas, and squamous cell cancers. The grading system used for adenocarcinomas refers to
the degree of differentiation and anaplasticity (good, moderate, poor) of the untreated primary. Despite substantial inter- and intraobserver variability in tumor grading, poorly differentiated tumors have consistently been found to be associated with a worse prognosis in
multivariate analysis.
13.7.3
TNM Classification System
In 1988, the American Joint Commission on Cancer (AJCC) and the Union Internationale
Contre le Cancer (UICC) proposed a joint TNM staging system. This was based on the fifth
edition of the AJCC TNM staging system. The sixth edition of the AJCC TNM staging
system is seen in Table13.3. There are four major changes from the fifth edition. These
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ventral view
dorsal view
A. mesenterica
inferior
A. mesenterica
inferior
Peritoneal
fold
Distal resection margin with Contour-stapler
b
Plexus hypogastricus sinister
Left ureter
Cavity of sacrum
Promontorium
Plexus hypogastricus dexter
Fig.13.4 (a) Total mesorectal excision (TME) specimen after preoperative CRT and perioperatively performed staining with methylenblue via A. mesenterica inferior. (b) Situs after TME. The
task for surgeons: to perform an extended oncological R0 resection and to preserve organs and
their function
include the following: (1) A revised description of the anatomy of the colon and rectum
which better delineates the data regarding the boundaries between the colon, rectum, and
anus is provided. (2) Smooth metastatic nodules in the pericolic or perirectal fat are considered nodal metastasis. In contrast, irregularly contoured metastatic nodules in the peritumoral fat are considered vascular invasion and are coded as a subcategory of the T stage as
V1 (microscopic vascular invasion) if microscopically visible or V2 (macroscopic vascular
Regional nodes cannot be assessed

No regional nodes
Metastasis to 13 regional lymph nodes
Metastasis to >4 regional lymph nodes
Distant metastasis cannot be assessed
Distant metastasis
Cannot be assessed
No lymphatic vessel invasion
Lymphatic vessel invasion present
Cannot be assessed
No venous invasion
Microscopic venous invasion present
Macroscopic venous invasion present

Mx
M0
M1
Lymphatic vessel invasionf

Lx
L0
L1
Venous invasion (V)f

Vx
V0
V1
V2
Primary tumor cannot be assessed

Carcinoma in situ: intraepithelial or invasion of the lamina propriaa
Tumor invades submucosab
Tumor invades muscularis propria
Tumor invades through the muscularis propria into the subserosa, or into nonperitonealized
pericolic or perirectal tissuesc
Tumor directly invades other organs or structures, and/or perforates the visceral peritoneumd,e

Nx
N0
N1
N2
T4
Primary tumor (T)

Tx
T0
Tis
T1
T2
T3
Table13.3 American Joint Commission on Cancer (AJCC) TNM staging system for colorectal cancer (sixth edition)
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C. Rdel et al.
T
Tis
T12
T3
T4
T12
T34
Tany
Tany
N
N0
N0
N0
N0
N1
N1
N2
Nany
M
M0
M0
M0
M0
M0
M0
M0
M1
Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the
muscularis mucosa into the submucosa
b
T1 Classification modified by Nivatvongs (2000): Sm1: invasion only into the upper third of the submucosa, Sm2: invasion into middle third of submucosa;
Sm3: invasion into lower third of submucosa
c
Additional classification by the UICC 2001: T3a: invasion 1mm, T3b: invasion >15mm, T3c: invasion >515mm, T3d: invasion >15mm (Wittekind etal
2001)
d
Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma
of the cecum
e
Tumor that is adherent to other organs or structures, macroscopically, is classified as T4. However, if no tumor is present in the adhesion, microscopically, the
classification should be pT3. The V and L substaging should be used to identify the presence or absence of vascular or lymphatic invasion
f
A tumor nodule in the pericolonic adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule is classified in the
pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, it should
be classified in the T category and also coded as V1 (microscopic venous invasion) or as V2 (if it was grossly evident), because there is a strong likelihood that
it represents venous invasion
g
Additional descriptors: Although they do not effect the stage grouping, additional prefixes are used which indicate the need for additional analysis. Suffix vs.
Reason: m the presence of multiple primary tumors in a single site and is recorded in parenthesis: pT(m)NM; y When classification is performed during or
following initial radiation and/or chemotherapy and is based on the amount of tumor present at the time of the examination, and not an estimate of tumor prior
to therapy: ycTNM or ypTNM; r indicates recurrent tumor: rTNM; a indicates the stage at autopsy: aTNM
Stage groupingsg
Stage
0
I
IIA
IIB
IIIA
IIIB
IIIC
IV
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C. Rdel et al.
invasion) if grossly visible. (3) Stage group II is subdivided into IIA (pT3 pN0 M0 disease)
and IIB (pT4 pN0 M0 disease). (4) Stage group III is subdivided into IIIA (pT12 pN1 M0
disease), IIIB (pT34 pN1 M0 disease), and IIIC (pTany pN2 M0 disease). The prognostic
validity of this latter change was supported by both the pooled analysis of Intergroup and
NSABP postoperative trials and the retrospective analysis of the American College of
Surgeons (National Cancer Database (NCDB)) database (Gunderson etal. 2004; Greene
etal. 2004). The five-year survival by stages IIIA, IIIB, and IIIC in the pooled analysis was
81, 57, and 49%, and in the NCDB database was 55, 35, and 25%, respectively. Recently,
however, concerns regarding the use of the sixth edition of the TNM staging system have
been expressed, especially with respect to the definitions of lymph nodes and venous invasion, that may be associated with marked interobserver variations in defining stage II and
III disease (Quirke etal. 2007).
13.7.4
Circumferential Resection Margin
Surgeons create margins that can be involved by tumor spread at a variety of sites. The
most well known are the proximal and distal margins of a resection. However, only
12% of cases in randomized trials show involvement of these margins. By far the most
important margin is that created around the mesorectum (circumferential resection margin, CRM). This margin is under threat not only by direct involvement but also by the
incomplete removal of lymph nodes that lie just under the mesorectal fascia, and any
small deviation from the correct surgical plane could enter them, potentially compromising cure (Fig.13.5). Studies by Quirke and others have shown that local recurrence is
greatly increased and survival halved when tumor can be visualized at or within 1mm
from the radial surgical plane of resection (CRM+) (Quirke etal. 1986; Nagtegaal and
Quirke 2008).
CRM
Fig.13.5 Mesorectum and

circumferential resection
margin (CRM). This margin
is under threat by direct
tumor (TU) involvement but
also by the incomplete
removal of lymph nodes
(LN) that lie just under the
mesorectal fascia
TU
Mesorectum
LN
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13.7.5
Recording of Surgical Quality
The recording of the frequency of involvement of the surgical CRM and the plane of surgery is important as an indicator of the quality of surgery and of prognosis for the patient.
Quirke first introduced the concept of pathological audit of the quality of surgery in the
MRC CLASSIC and CR07 studies (Table13.4). The concept was also adopted in the Dutch
TME trial. In the latter trial, despite extensive surgical training, only 57% of cases were
judged to be good/complete excisions, with nearly one quarter of all cases (24%) assessed
as a poor/incomplete excision with early evidence of prognostic value (Nagtegaal and
Quirke 2008). In the recently published MRC CR07 trial, the plane of surgery achieved
was classified as good (mesorectal) in 52% of 1,156 included patients, intermediate
(intramesorectal) in 34%, and poor (muscularis propria plane) in 13% (Table13.5) (Quirke
etal. 2009). The plane of surgery achieved was significantly associated with the risk of
local recurrence both in univariate and multivariate analysis, and should therefore be
assessed and reported routinely. Moreover, the assessment of the abdominoperineal excision specimens to measure the amount of tissue removed at the anorectal junction and to
determine whether levator muscle is included in the resection is also strongly recommended
Table13.4 Grading of surgical TME specimen (M.E.R.C.U.R.Y. criteria)

Good (grade 1): intact mesorectum with only minor irregularities of a smooth mesorectal
surface; no defects larger than 5mm; no coning on specimen; smooth CRM on slicing
Moderate (grade 2): moderate bulk to mesorectum but irregularity of the mesorectal surface;
moderate coning of the specimen towards the distal margin; at no site is the muscularis propria
visible with the exception of the area of insertion of levator muscles; moderate irregularity of
the CRM
Poor (grade 3): little bulk of mesorectum with defects down into muscularis and/or very
irregular CRM
Table13.5 Local failure rates of the British MRC (Medical Research Council) CR07-trial for rectal
cancer according to TME quality grading
Grading
Three-year local recurrence rates
N
of TME-specimen
preop. RT
Surgery (+post.
+surgery (%)
CRT if pCRM+) (%)
Poor plane of surgery: Defects
down onto muscularis propria
154 (13%)
10
16
Moderate plane of surgery:

Intramesorectal excision
398 (34%)
10
Good plane of surgery: Intact

mesorectum
604 (52%)
Patients either received preoperative 55Gy (arm 1) or selective postoperative CRT only in case
of a positive circumferential resection margin (CRM+, defined as tumor within 1mm from the
CRM) (Sebag-Montefiore etal. 2009)
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C. Rdel et al.
(West etal. 2008). Guidelines of the Royal College of Pathologists in the United Kingdom
for dissection and reporting of rectal cancer specimens are available at http://www.rcpath.
org/resources/pdf/colorectalcancer.pdf.
13.7.6
Tumor Regression
There is good evidence that neoadjuvant radio(chemo)therapy is able to induce T-level
downsizing and UICC or nodal downstaging in locally advanced rectal cancers. In approximately 530% of cases, this can lead to complete disappearance of tumor cells, i.e., a pathological complete response (pCR, ypT0 ypN0), and patients with pCR have consistently been
shown to have better outcomes (Rdel etal. 2005; Capirci etal. 2008). Variation in sampling
protocols may explain some of the differences in reporting pCR-rates. Moreover, various
tumor regression grading systems (TRG), based on the relative amount of tumor cells and
fibrotic reactions, have been proposed. These classifications were often derived from esophageal or gastric cancer, and little information on the extent of inter- and intraobserver variability in defining TRG has been published. Recently, a four-point scale has been proposed
(0=complete histomorphologic regression, 1=major histomorphologic regression with few
hard to find scattered microscopic foci <2mm, 2=minor histomorphologic regression with
fibrosis outweighing residual cancer cells, 3=minimal histomorphologic regression with no/
negligible evidence of any tumor response) (Glynne-Jones and Anyemene 2009). This classification system needs to be prospectively tested on multiple datasets to validate the predictive value in terms of long-term outcome, and its reproducibility in the wider setting.
13.8
Surgery
During the last two decades, locoregional tumor control in rectal cancer surgery has changed
dramatically. On the basis of improved interdisciplinary pretherapeutical staging procedures,
the development of very differentiated concepts in oncological surgery started with the introduction of new techniques like Transanal Endoscopic Microsurgery (TEM) and more precise, but extended surgical procedures following embryonic planes in the pelvic organ
(TME). Considerable progress has been made not only in the treatment of small tumors
without an endosonographically verified spread into the rectal wall but also in the treatment
of locally advanced rectal cancer with broad invasion into the mesorectal compartment.
13.8.1
Local Excision: pT1-Low Risk Rectal Cancer
Early rectal cancer is limited to the rectal wall (c/pT1 N0 M0) and represents accompanied
35% of rectal cancers. So-called low-risk pT1 cancers comprise small mobile tumors
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Fig.13.6 Transanal endoscopic microsurgery (TEM) procedure. Since the optic of the operative
rectoscope has an angle of 400, the tumor should always be in 6 o`clock lithotomy position on the
operating table. For TEM the patient was positioned according to the location of the tumor and
after gentle extension of the sphincter, the TEM equipment (Wolff, Knittlingen, Germany) was
inserted (a). Under continuous distension of the rectal cavity by pressure-controlled CO2 insufflation, the lesion was identified centrally with an attempted macroscopically tumor-free margin of
1cm (b). The resection was performed as full thickness excision (c). The wound was closed transversely with a single continuous suture of polyglactin (not shown). The completely resected tumor
has been fixed to a cork board for specific evaluation of the resection margins (d)
without prognostic adverse histopathological parameters, such as high-grade differentiation (G3G4), blood or lymphatic vessel invasion (V1, L1), invasion into the lower third
of submucosa (sm3), or colloid histology. These low-risk pT1 (sm1, sm2; G1/2) cancers
can be cured by local removal of the full thickness of the rectal wall, accomplished either
by TEM (Fig.13.6) for lesions localized 516cm above the anal verge or with transanal
excision alone (05cm above anal verge) (Guerrieri etal. 2008; Langer etal. 2003). In
general, local excison is associated with less anorectal and genitourinary dysfunction and
better quality of life compared with radical transabdominal surgery.
These methods are limited, however, to non-obstructing tumors with a dimension of
less than half of the lumen and/or a size of <4cm in diameter. The resected full wall specimen (no piecemeal procedures!) has to be examined meticulously by the pathologist to
evaluate its integrity, the depth of tumor invasion into the rectal wall, the absence of margin infiltration both laterally and deeply, and the presence of other adverse pathological
parameters, like high-grade differentiation and blood and/or lymphatic vessel invasion. In
cases of high-risk pT1 and pT2 cancers, there is a substantial risk of positive lymphatic
nodes, ranging from 10% in pT1 and up to 20% in pT2 rectal cancers. Therefore, local
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C. Rdel et al.
excision alone is oncologically not appropriate, and these patients require transabdominal
resection, performed either as (low) anterior resection or as an abdominoperineal excision.
Only in cases where major surgery is contraindicated or refused by the patient, local excision for high-risk T1 or T2 tumors can be performed on the basis of the patients decision,
preferably then accompanied with combined multimodal treatment (Borschitz etal. 2008;
Lezoche etal. 2008).
13.8.2
Standard Resection (Including Total Mesorectal Excision):
High-Risk pT1- and pT2-Rectal Cancer
In high-risk pT1 and pT2 rectal cancer, the standard transabdominal resection (anterior or
low anterior resection and abdominoperineal resection (APR)), including TME, is the
adequate treatment of choice. Provided the lymph nodes are negative (pN0) as a result of
histopathological workup of the resected specimen, no further adjuvant treatment is
required. In cases of positive lymph nodes (pN+, UICC stage III), postoperative 5-fluorouracil (5-FU)-based radio-chemotherapy (RCT) is indicated.
13.8.3
Surgical Treatment in Locally Advanced Rectal Cancer (UICC Stages II and III)
From the clinical point of view, intermediate tumor stages are defined as neoplasms extending beyond the rectal wall into the mesorectal compartment but without unresectable infiltration to surrounding organs (c/pT34 or N12 M0). After TME alone for pT34 pN12
rectal cancers in the middle and lower third of the rectum, local recurrence rates range
between 15 and 21% in randomized trials (Peeters et al. 2007; Sebag-Montefiore et al.
2009). It is well known that the efficacy of the TME procedure is closely related to the
training and volume of cases per year of the individual surgeon. Thus, the surgeon represents one of the major prognostic factors for the treatment of rectal cancer patients
(Martling etal. 2002). According to surgical standard procedures, the surface features of
the resected mesorectum should be photodocumented during surgery and later analyzed
pathologically. A further improvement of the quality of TME can be achieved by stain
marking of the mesorectum (Sterk etal. 2000), which allows the surgeon to test intraoperatively for lesions in mesorectal fascia and the mesorectum itself. Such lesions bear the risk
of locoregional relapse.
It is generally accepted that by using low anterior resection with TME, radical surgery
with negative margins can be achieved also for distal lesions since rectal cancer rarely
grows more than a few millimeters distally from the macroscopic margin in the bowel
wall. This indicates that a distal resection margin of 1cm will probably be sufficient for
local cure in terms of intramural spread. If such an approach is considered, frozen section
(during the surgical intervention) is mandatory to decide if an abdominoperineal excison is
necessary or not. To avoid a conversion of the surgical strategy intraoperatively, and to
provide oncological safety, preoperative staging procedures should have allowed a definite
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decision about an initially planned sphincter preservation. If the tumor is felt to impinge on
the puborectalis muscle, this patient is not a candidate for a sphincter-preserving operation.
On the other hand, coloanal anastomosis is reserved for a highly defined group of patients.
After complete TME transabdominally, this procedure consists of a perianally primary
hand-sewn anastomosis and is usually performed with interrupted sutures of 20 or 30
vicryl including the internal anal sphincter. In all the cases of coloanal anastomosis, a
diverting ileostomy or colostomy is performed in anticipation of poor immediate functional results with severe perineal irritation and excoriation (Cavaliere etal. 1995).
Population-based registries have demonstrated that improvements in outcome after
TME procedure occur mainly in patients <75 years of age. The 6-month postoperative
mortality after TME is significantly increased in elderly patients (>75 years of age) and
should be restricted to those patients with good physical and mental status and low comorbidity (Rutten etal. 2008). Furthermore, TME may be associated with an increased risk of
anastomotic leakage with increased morbidity and mortality in the postoperative period
(den Dulk etal. 2009). Based on an associated decreased local tumor control and survival
(Law etal. 2007), the rate of anastomotic leakage has been considered as one of the important quality indicators of surgical performance. Recently, a multicenter analysis (pooled
data from the Swedish Rectal Cancer Trial, Dutch TME trial, German CAO/ARO/AIO-94
trial, EORTC 22921 trial, and the Polish Rectal Cancer Trial) of oncological and survival
outcomes following anastomotic leakage after rectal cancer surgery showed that, in multivariate analysis, cancer-specific survival was not reduced significantly by leakage but was
overall survival (den Dulk etal. 2009). In summary, anastomotic leakage cannot be completely avoided in rectal cancer surgery, but its life-threatening consequences can be limited by a diverting stoma and/or pelvic drain (Matthiessen etal. 2007). From the clinical
point of view, prompt diagnosis and immediate surgical re-intervention is mandatory for
an effective treatment of anastomotic leakage in order to reduce morbidity and mortality in
rectal cancer patients.
The TME procedure is recommended for patients with locally advanced rectal cancer
localized in the middle (6 to 12cm from anal verge) and lower third (<6cm) of the rectum. It is known that metastatic involvement of lymph nodes and other tumor deposits can
be found in the mesorectal compartment up to 4cm distally from the lower pole of the
rectal cancer. Therefore, complete removal of the mesorectum is always indicated for
these tumor locations (Heald and Ryall 1986), and should be further extended in cases of
sphincter infiltration as wide abdominoperineal excision (West et al. 2008; Holm et al.
2007). Recently pathological studies of the CRM at the level of the anorectal junction and
anal sphincters showed a high risk of tumor involvement (Nagtegaal et al. 2005). The
quality of surgery in the levator/anal canal area below the mesorectum varies between
surgeons who may operate in different surgical planes: intrasphincteric/submucosal plane,
sphincteric plane, and levator plane. With an APR, there are two planes: one for the
mesorectum and one for the anal canal. It is crucial to have the correct strategy when an
APR is performed. The dissection from above has to be stopped from entering the levator
plane. The next step is to dissect from below outside the sphincteric plane and by doing so
finally divide the levators from below. With this technique, or an apple core just at the
place of the tumor can be avoided to prevent the specimen from having positive CRM
(Fig.13.7a, b).
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Ventral view after perioperative

staining of the resected specimen
via A. mesenterica inferior
Dorsal view after perioperative

staining of the resected specimen
Peritoneal fold
Mesorectum with nonviolated surface, only

one punctual ink
leakage (white arrow)
Perineal fat tissue
and partially resected
M. levator ani
Anus and canalis analis,
yellow: intersphincteric
resection line
perineal tissue
b
peritoneal fold
anal canal
staining via A. mesenterica

inferior
TU
apple core phenomenon
Fig.13.7 (a) Wide abdominoperineal resection (APR) for a low-lying tumor. (b) APR for a lowlying tumor with the so-called apple core phenomenon that should be avoided to reduce the risk
of a positive circumferential resection margin
13.8.4
Partial Mesorectal Excision
In rectal cancer of the upper third of the rectum (1216cm), a partial mesorectal excision
(PME) extending 5cm below the lower tumor margin (as measured intraoperatively) is
feasible while sparing the distal part of the mesorectum. As shown in Figs.13.8 and 13.9,
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Ventral view
Dorsal view
peritoneal fold
TU
TU
TU
PME
5 cm
TME
distal resection margin
surface of distal dorsal mesorectum
Fig.13.8 Resection margins: partial vs. total mesorectal excision (PME, TME)
uterus
lower third of the rectum

with resection margin
tube
ovary
residual mesorectum
ureter sinister
Fig.13.9 PME residual

mesorectum
plexus hypogastricus sinister
for TME the mesorectum is completely excised downwards to the pelvic floor, whereas for
PME the mesorectum is transected at a right angle to the rectal wall at a distance of 5cm
beyond the gross distal margin of the tumor. Corresponding to this in situ situation, adequate PME requires a distal clearance to the tumor site of 3cm when measured on fresh
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non-stretched resection specimen. It is important to avoid coning with the remaining

mesorectal tissue, because this could contain cancer clusters or satellites. The transection
therefore needs to be performed at the same distance from the distal tumor margin in both
the outer and inner parts of the mesorectum and in the rectal muscular wall. In both TME
and PME, circumferential excision needs to be performed in an anatomically defined plane
(including the mesorectal fascia), and with a sharp dissection. From the oncological point
of view, PME is considered sufficient for the treatment of rectal carcinomas of the upper
third (distal margin of the tumor is 12cm or more from anal verge), provided the surgeon
avoids coning and the pathologist can confirm this practise (Lopez-Kostner etal. 1998).
Actually the definite evidence for this procedure is investigated by the ongoing German
GAST-05 trial (ISRCTN35198481).
13.8.5
Total Pelvic Exenteration
T4 cancers are defined as lesions extending beyond the rectal wall with infiltration to surrounding organs or structures, and/or perforation of the visceral peritoneum (c/p T4 N02 M0).
In these cases, the evaluation of resectability depends on the extent of the operation the surgeon is able to perform as well as the degree of morbidity the patient is willing to accept. It
is mandatory for the surgeon to recognize preoperatively the extent of tumor invasion into
other organs and/or the pelvic sidewall for documentation prior to preoperative chemoradiotherapy (CRT) and to establish a plan for en bloc resection (Ishiguro etal. 2009). From both
the surgical as well as the oncological point of view, histologically confirmed R0 resection
represents the most important parameter to achieve the best long-term outcome in T4 rectal
cancer. In specialized centers there is a minimum consensus that when the trigone of the
bladder or the prostate is involved by rectal cancer, a total pelvic exenteration (TPE) is recommended for all patients, irrespective of the response to preoperative multimodal treatment. The TPE involves the removal of the rectum, bladder, lower ureters, internal genital
organs, and bilateral internal iliac vessels en bloc to achieve tumor-free resection margins
and a complete clearance of lymphatics (Moriya etal. 2003). A TPE achieving clear resection margins (R0) is potentially curative and results in five-year overall survival rates of
5260%, but it is accompanied by high morbidity (>50%; e.g., pelvic abscess or fistulas,
sepsis, anastomotic leak, perineal wound infection, intestinal obstruction, and pulmonary
disease) and impaired quality of life (Yamada etal. 2002). Furthermore, surgery extended to
lateral pelvic nodes is associated with significant morbidity (Watanabe etal. 2008).
13.9
Radiotherapy and Chemotherapy
The last decades have witnessed the development of a variety of preoperative and postoperative radiotherapy (RT) and CRT schedules designed to optimize the sequence of treatment modalities and the most appropriate scheduling of irradiation and 5-fluorouracil-based
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chemotherapy. On the basis of the same evidence from studies, these modalities are used
differently in different parts of the world (Valentini etal. 2009).
13.9.1
Randomized Trials of Postoperative CRT
Historically, the combination of postoperative RT and 5-FU-based chemotherapy has been
shown in several randomized trials to reduce local recurrence rates and to improve overall
survival compared with (conventional, i.e., non-TME) surgery alone or surgery plus postoperative RT (Table13.6). In the early GITSG 7175 trial, the best local control was achieved
with combined CRT (local relapse rate of 11% vs. 20% with RT alone), while no impact on
local control was noted with chemotherapy as single adjuvant treatment (local relapse rate
of 27% vs. 24% with surgery alone) (Gastrointestinal Tumor Study Group 1985). Although
rates of distant metastases were slightly lower in the two arms that contained chemotherapy,
no single arm had a significant impact on distant failure. Thus, the survival advantage
achieved with combined CRT appeared to relate primarily to the marked reduction in local
relapse rates. These results were later confirmed by a trial conducted by the Norwegian
Adjuvant Rectal Cancer Project Group (Tveit etal. 1997). Again, the local relapse rate was
significantly decreased from 30 to 12% by combined postoperative CRT compared with
surgery alone, an effect which also translated into an improvement in five-year survival,
though no significant impact on distant metastases was achieved. The more recent NSABP
R-02 also showed that combined CRT resulted in a significantly reduced local failure rate
compared with chemotherapy alone (8% vs. 13%); however, this rather small absolute
reduction did no longer translate into a difference in overall survival (Wolmark etal. 2000).
Evidently, in all these trials, the effect of concomitant 5-FU-chemotherapy was primarily
mediated through its radiosensitization properties rather than through its own systemic efficacy. This conclusion is further strengthened by a recent Italian study that showed no significant effect on local control and survival when postoperative RT and chemotherapy was
applied sequentially rather than concomitantly (Cafiero etal. 2003).
The NCCTG 794751 trial was the first to integrate a course of full-dose chemotherapy
before as well as after combined CRT in an attempt to exploit both the radiosensitization
properties of 5-FU and its potential to reduce the incidence of distant metastases (Krook
et al. 1991). Indeed, this was also the first trial in which both local relapse and distant
metastasis rates were significantly reduced in the experimental arm. The NCI Consensus
Conference concluded in 1990 that combined CRT was the standard adjuvant treatment for
patients with TNM stages II and III rectal cancer (NIH consensus conference 1990).
13.9.2
Randomized Trials to Optimize 5-FU-Based Postoperative CRT
Further trials by the GITSG (7180) and NCCTG (864751) investigated the need for methylCCNU in the chemotherapy regimen and found that it added no benefit to the 5-FU regimen (Table 13.7) (Gastrointestinal Tumor Study Group 1992; OConnell et al. 1994).
Surgery+RT
Surgery+RT+5-FU/MeCCNU
Surgery
Surgery+RT+5-FU
Surgery+CTa
Surgery+CRT
Surgery+RT
Surgery+5-FU/LEV+RT+5-FU/LEV
(RT and CT applied sequentially)
NCCTG/Mayo 794751
(Krook etal. 1991)
Norway trial (Tveit etal. 1997)
NSABP R-02
(Wolmark etal. 2000)
Italy trial (Cafiero etal. 2003)
39%
33%
29%
31%
30%; p=0.01
12%
13%; p=0.02
8%
38%
27%
46%; p=0.01
29%
25%; p=0.04
13.5%
20%
22%
34%
30%
27%
26%
24%
20%; p=0.08
27%
11%
Male patients received MOF (MeCCNU, Vincristin, 5-FU) or 5-FU/LV; female patients only 5-FU/LV
Surgery
Surgery+RT
Surgery+5-FU/MeCCNU
Surgery+RT+5-FU/MeCCNU
GITSG 7175 (Gastrointestinal

Tumor Study Group 1985)
59%
43%
64%
64%
50%; p=0.05
64%
48%; p=0.025
58%
45%
52%; p<0.05
56%
59%
Table13.6 Randomized trials of postoperative radiation (RT), chemotherapy (CT), or combined CRT for locally advanced rectal cancer (UICC II and III)
Series
Treatment
Local failure
Distant failure
Five-year-survival
402
C. Rdel et al.
403
13 Rectal Cancer
Table13 7 Randomized trials of postoperative combined CRT in locally advanced rectal cancer
Series
Postoperative treatment
DFS
OS
GITSG 7180
(Gastrointestinal
Tumor Study Group
1992)
CRT bolus 5-FU+bolus

5-FU (6 cycles,
escalating 5-FU)
CRT bolus 5-FU+bolus
5-FU/MeCCNU
(12 months treatment)
68% (3y)
75% (3y)
54% (3y); p=0.20
66% (3y); p=0.58
NCCTG 864751
(OConnell etal. 1994)
2 cycles of bolus 5-FU

(MeCCNU)+CRT bolus
5-FU+2 cycles of bolus
5-FU (MeCCNU)
2 cycles of bolus 5-FU
(MeCCNU)+CRT PVI
5-FU+2 cycles of bolus
5-FU (MeCCNU)
53% (4y)
60% (4y)
63% (4y); p=0.01
70% (4y);
p=0.005
2 cycles bolus 5-FU+

CRT bolus 5-FU+2
cycles bolus 5-FU
2 cycles bolus 5-FU/
LV+CRT bolus 5-FU/
LV+2 cycles bolus
5-FU/LV
2 cycles bolus 5-FU/
LEV+CRT bolus
5-FU+2 cycles bolus
5-FU/LEV
2 cycles bolus 5-FU/LV/
LEV+CRT bolus 5-FU/
LV+2 cycles bolus 5-FU/
LV/LEV
54% (all)
64% (all)
No significant
difference
No significant
difference
INT 0114
(Tepper etal. 2002)
INT 0144
(Smalley etal. 2006)
2 cycles bolus 5-FU+CRT 6869% (3y)

PVI 5-FU+2 cycles bolus
5-FU
PVI 5-FU+CRT PVI
No significant
5-FU+PVI 5-FU
difference
2 cycles bolus 5-FU/LV/
LEV+CRT bolus 5-FU/
LV+2 cycles bolus 5-FU/
LV/LEV
8183% (3y)
No significant
difference
Thus, this compound is no longer used for adjuvant CRT in rectal cancer. NCCTG (864751)
also tested the best method of administering 5-FU during radiotherapy: Bolus 5-FU
(500mg/m for 3 days during weeks 1 and 5 of RT) was compared with continuous infusion (225mg/m during the whole course of RT): A 10% disease-free and overall survival
advantage was achieved with continuous infusion 5-FU during RT (OConnell etal. 1994).
The INT 0144 trail tested the question whether additional continuous infusion 5-FU instead
of bolus 5-FU before and after CRT (or modulation of 5-FU through addition of leucovorin
404
C. Rdel et al.
and levamisole) may further increase tumor control (Tepper et al. 2002). There was no
significant difference in local control or survival. Results of a four-arm intergroup trial,
INT 0114, also showed no significant differences in local control and survival among
patients receiving bolus 5-FU, bolus 5-FU+folinic acid, bolus 5-FU+levamisole, or bolus
5-FU+folinic acid+levamisole. However, gastrointestinal toxicity was higher in folinic
acidcontaining regimens (Smalley etal. 2006). Only one randomized phase III trial, performed by the Hellenic Cooperative Oncology Group, compared concurrent postoperative
RT with combination chemotherapy including 5-FU/folinic acid plus irinotecan vs. 5-FU/
folinic acid alone (Kalofonos etal. 2008). There were no differences between the arms in
three-year overall, disease-free and local relapse-free survival, whereas the incidence of
severe leucopenia was significantly higher in the irinotecan containing arm.
Given all these results, the standard design of postoperative CRT is to deliver 6 cycles
of 5-FU chemotherapy with concurrent radiation therapy during cycles 1 and 2 or 3 and 4.
During RT continuous infusion 5-FU regimens are recommended. The main advantage
with the postoperative approach is the better selection of the patients based on pathologic
staging. The primary disadvantages include an increased toxicity related to the amount of
small bowel in the radiation field, a potentially more radio-resistant hypoxic postsurgical
bed and, if the patient has undergone an APR, the radiation field has to be extended to
include the perineal scar.
13.9.3
Preoperative Radiation
The potential advantages of the preoperative approach include decreased tumor seeding
during surgery, less acute and chronic toxicity, increased radiosensitivity due to more oxygenated cells, and according to some, a potential for sphincter preservation. The main
disadvantage is related to possible overtreatment of patients with early stages (pT12N0)
or undetected metastatic disease. This disadvantage becomes less important because imaging modalities (ERUS and high-resolution phased-array magnetic resonance imaging)
allow better preoperative staging.
There are more than 15 randomized trials of preoperative RT without concurrent chemotherapy for clinically resectable rectal cancer. All used low to moderate doses of RT and
most showed a decrease in local recurrence. The Swedish Rectal Cancer Trial (1997) is the
only one out of eight studies with more than 500 patients, which reported a survival advantage for the total treatment group. Two meta-analyses report conflicting results. While both
revealed a decrease in local recurrence, the analysis by Camma etal. reported a survival
advantage, whereas the Colorectal Cancer Collaborative Group did not (Colorectal Cancer
Collaborative Group 2001; Camma et al. 2000). The Swedish Council of Technology
Assessment in Health Care performed a systematic review of RT trials. They analyzed data
from 42 randomized trials and 3 meta-analyses, 36 prospective studies, 7 retrospective
studies, and 17 other articles, for a total of 25,351 patients (Glimelius etal. 2003). The
main conclusion was that preoperative RT at biologically effective doses above 30 Gy
decreases the relative risk of local failure by 5070%, and by 3040% for postoperative
RT at doses that are usually higher than those used preoperatively, and that survival is
13 Rectal Cancer
405
improved by about 10% using preoperative RT. In recent years, therefore, preoperative
therapy has gained a wide acceptance as the standard therapy for rectal cancer.
After standardization of TME there is, however, no evidence of overall survival benefit
in the so-called Dutch TME trial. This trial randomized 1,861 patients with resectable
rectal cancer (stage IIII) between TME alone or TME preceded by 55 Gy. With a
median follow-up of surviving patients of 6.1 years, there was a significant reduction of the
five-year local recurrence risk (5.6% in the 55 arm vs. 10.9% for TME alone, p<0.001)
(Peeters etal. 2007; Kapiteijn etal. 2001). Subgroup analyses reported a significant effect
of RT in reducing local recurrence risk for patients with nodal involvement, for patients
with lesions 510cm from the anal verge, and for patients with uninvolved CRM. Overall
survival at five years was 64.2 and 63.5% (p=0.9), respectively, indicating that the absolute reduction in local failure rates was too small to translate into a survival benefit.
13.9.4
Randomized Trials to Optimize the Sequence
Until recently, the only randomized trial that directly compared preoperative to postoperative RT (both without chemotherapy) in rectal cancer has been the Uppsala trial, which
was carried out between 1980 and 1985 in Sweden (Frykholm etal. 1993). In the preoperative arm, patients received intensive short-course radiation (five fractions of 5.1Gy to a
total dose of 25.5Gy in 1 week), postoperatively conventional radiation therapy (2Gy to
a total of 60Gy with a two-week split after 40Gy) was applied. Preoperative radiation
significantly decreased local failure rate (13% vs. 22%, p=0.02), however, there was no
significant difference in five-year survival rates (42% vs. 38%).
Prospective randomized trials comparing the efficacy of preoperative with standard
postoperative CRT in UICC-stage II and III rectal cancer were initiated both in the U.S.A.
through the Radiation Therapy Oncology Group (RTOG 9401) and the NSABP (R-03) as
well as in Germany (Protocol CAO/ARO/AIO-94). Unfortunately, both U.S. trials suffered from lack of accrual and were closed prematurely. The NSABP R-03 trial reported
results from 254 (of intended 900) patients after median follow-up for surviving patients
of 8.4 years: The five-year disease-free and overall survival rates for preoperative patients
were 64.7 and 74.5% vs. 53.4 and 65.6% for postoperative patients, respectively (p=0.011,
p=0.065). The five-year cumulative incidence of locoregional recurrence was 10.7% for
each arm; sphincter-saving surgery was 47.8% for preoperative patients and 39.2% for
postoperative patients (p=0.23) (Roh etal. 2009). The German study (CAO/ARO/AIO94) could be completed with more than 820 patients included (Sauer et al. 2004). The
design of this trial and the treatment schedule is depicted in Fig.13.10. Five-year results
were reported in 2004 (Table13.8): Compared with postoperative CRT, the preoperative
combined modality approach was superior in terms of local control, downstaging, acute
and chronic toxicity, and sphincter preservation in those patients judged by the surgeon to
require an APR. Given these advantages preoperative CRT is now the preferred adjuvant
treatment for patients with locally advanced rectal cancer. However, it needs to be emphasized that, with a median follow-up of 46 months, there was no difference in five-year
disease-free and overall survival rates between both treatment arms.
406
C. Rdel et al.
Arm I:
5-FU
5 x 1000 mg/m2
120h-infusion
5-FU
5 x 1000 mg/m2
120h-infusion
4 cycles of adjuvant chemotherapy with

5-FU 500 mg/m2/d i.v. bolus for 5 days
3 weeks break.
OP
RT: 50.4 Gy + 5.4 Gy Boost
Arm II:
5-FU
5 x 1000 mg/m2
120h-infusion
5-FU
5 x 1000 mg/m2
120h-infusion
4 cycles of adjuvant chemotherapy with

5-FU 500 mg/m2/d i.v. bolus for 5 days
3 weeks break.
OP
RT: 50.4 Gy
Fig.13.10 Design of the German CAO/ARO/AIO-94 study comparing postoperative (arm I) with
preoperative radiochemotherapy (RCT) (arm II) in locally advanced rectal cancer
Table13.8 German Rectal Cancer Study Group randomized trial of preoperative compared with
postoperative CRT for rectal cancer (Sauer etal. 2004)
Five-year outcome
Preoperative
Postoperative
p Value
CRT (%)
CRT (%)
Locoregional recurrence rate
13
0.006
Distant recurrence rate
36
38
0.84
Disease-free survival
68
65
0.32
Overall survival
74
76
0.80
Any grade 3/4-acute toxicity
27
40
0.001
Any grade 3/4-late toxicity
14
24
0.01
Sphincter preservation rate
39
19
0.004
In patients deemed to require abdominoperineal resection by the surgeon before randomization
The most recent UK Medical Research Council Trial MRC C07 randomized 1,350
patients with clinical stage IIII rectal cancer to preoperative 55Gy or selective postoperative CRT (45Gy with concurrent 5-FU), which was applied only for patients with a
histologic CRM <1 mm (12% of all patients with immediate surgery). Results after a
median follow-up of 4 years showed local recurrence rates at 3 years of 4.4 and 10.6%
(p<0.0001), and an absolute difference in disease-free survival at 3 years of 6.0% (77.5%
13 Rectal Cancer
407
vs. 71.5%, p=0.013), both significantly favoring the unselected preoperative treatment
approach (Sebag-Montefiore etal. 2009).
13.9.5
Concomitant Chemotherapy with Preoperative RT?
The concurrent use of chemotherapy as part of the preoperative regimen is another important point. For the treatment of primarily unresectable, fixed T4 rectal cancer, several
institutions have applied preoperative RT and CRT. The goal is to convert (downsize) a
tumor, which is clinically not amenable to curative resection at presentation, to a resectable
status. Minsky etal. (1992) compared preoperative RT (50.4Gy) with or without 5-FU/
folinic acid and showed that initially unresectable tumors were converted to resectable
lesions in 90% of the patients by preoperative combined therapy as compared with only
64% of those who received RT alone. Moreover, a complete pathologic response was
found in 20% of patients receiving combined modality therapy as compared to 6% receiving RT alone, indicating an enhancement of radiation-induced downstaging by concomitant 5-FU-based CRT. In a recent randomized phase III study comparing RT (50Gy) alone
(n=109) with combined 5-FU-based CRT (n=98) for primarily unresectable T4 rectal
cancer or local recurrences, Braendengen etal. (2008).could demonstrate that the addition
of chemotherapy to RT significantly improved R0 resection rates, local control, time to
treatment failure, and cancer-specific survival
A Polish randomized trial compared preoperative short-course irradiation (55Gy)
and immediate surgery with conventionally fractionated CRT (1.850.4Gy plus 5-FU/
folinic acid) and delayed surgery in 316 patients with locally advanced (T3/T4) low
rectal cancer (Bujko et al. 2004). The primary endpoint of the trial was the rate of
sphincter-preserving surgery. Despite a significant increase in tumor response in the
CRT group (pathologic complete remission, 16% vs. 1%; mean largest tumor diameter
on the operative specimen, 29mm vs. 48mm), the rate of sphincter preservation was
61% in the immediate surgery group and 58% in the delayed group, indicating a strong
commitment of the surgeons in this trial not to change their choice whatever the tumor
response was after neoadjuvant CRT. The actuarial four-year overall survival was 67%
in the short-course group and 66% in the chemoradiation group; no significant differences were found in disease-free survival, incidence of local recurrence, and severe late
toxicity (Bujko et al. 2006). Two other (ongoing) phase III studies (from the Berlin
Cancer Society in Germany, and Trans-Tasmania group in Australia) are currently evaluating short-course RT with 55Gy and immediate surgery vs. long-course CRT. Data
from the Uppsala group in T4 rectal cancer patients have shown that short-course RT and
delayed surgery also result in downsizing and possibly R0 resections (Radu etal. 2008).
A three-arm ongoing study in Sweden (Stockholm III trial) is evaluating the role of
short-course RT with immediate vs. delayed surgery vs. long-course RT in resectable
rectal cancer patients.
Two randomized trials have examined whether chemotherapy improves the results of
preoperative, conventionally fractionated RT in patients with cT3/4 rectal cancer
(Table13.9). The EORTC 22921 was a four-arm randomized trial of preoperative 45Gy
408
C. Rdel et al.
Table13.9 Preoperative conventionally fractionated radiotherapy with or without 5-FU/LV-based

chemotherapy
Five-year outcome
Preoperative RT
Preoperative CRT
p Value
EORTC 22921 (n=1011)
pCR rate
ypN0
Tumor size (median)
Sphincter preserved
Local failure
Overall survival
5.3%
60.5%
30mm
50.5%
17%
64.8%
13.7%
71.9%
25mm
52.8%
8%
65.6%
<0.001
<0.001
<0.0001
0.47
0.002
0.79
FFCD 9203 (n=762)

pCR rate
Sphincter preserved
Grade 3+4 toxicity
Local failure
Overall survival
3.6%
54.4%
2.7%
8.1%
67.9%
11.4%
52.4%
14.6%
16.5%
67.4%
<0.05
0.68
<0.0001
<0.05
0.68
Results of EORTC 22921 and FFCD 9203 randomized trials (Bosset etal. 2006; Gerard etal. 2006)
with or without concurrent bolus 5-FU/leucovorin followed by surgery with or without

four cycles of postoperative 5-FU/leucovorin. A significant decrease in local recurrence
was observed in three chemotherapy groups: 8.8, 9.6, 8.0%, respectively, with preoperative
CRT, postoperative chemotherapy and both, vs. 17.1% without (p=0.002) (Bosset etal. 2006).
Five-year overall survival was not affected by chemotherapy at the median follow-up of
5.4 years: 65.6% vs. 64.8% (p=0.79) for preoperative CRT vs. preoperative RT and 67%
vs. 63% (p=0.132) for postoperative chemotherapy vs. no postoperative chemotherapy. An
increased rate of ypT0 (13.7% vs. 5.3%, p <0.0001) was observed, but no difference in
sphincter-saving surgery (52.8% vs. 50.5%, p=0.47); 42.9% of patients received planned
adjuvant chemotherapy. The authors stated that in view of the benefit of preoperative CRT
and the bad compliance of postoperative chemotherapy, preoperative CRT should be preferred. The second trial (FFCD 9203) compared preoperative 45Gy with or without bolus
5-FU/leucovorin, and all patients received postoperative chemotherapy. An improvement
in the pCR rate was observed (11.4% vs. 3.6%, p=0.0001), and local recurrence was lower
with preoperative CRT: 8.1% vs. 16.5% of preoperative RT (p=0.004) (Gerard etal. 2006).
Overall survival at 5 years was the same (67%). A recent systematic review and metaanalysis, including four relevant randomized trials, also confirmed that, compared with
preoperative RT alone, preoperative 5-FU-based CRT improves local control, but does not
benefit long-term survival (Ceelen etal. 2009).
13.9.6
Adjuvant Chemotherapy After Neoadjuvant RT/CRT
There are no sufficient data on adjuvant postoperative chemotherapy after preoperative treatment with RT or CRT. In the EORTC 22921 trial postoperative chemotherapy had a nonsignificant influence with improvement of relapse-free and overall survival. Exploratory
13 Rectal Cancer
409
post-hoc subgroup analyses suggest that only good-prognosis patients with downstaging of
cT34 to ypT02 benefit from adjuvant chemotherapy (Collette et al. 2007). In patients
treated with 55Gy preoperative radiation, postoperative chemotherapy has not been evaluated so far but is currently investigated in a randomized trial (SCRIPT, Simply Capecitabine
in Rectal cancer after Irradiation Plus TME). Another randomized trial (CHRONICLE) that
investigated postoperative chemotherapy with capecitabine and oxaliplatin vs. observation
only after preoperative 5-FU-based CRT has unfortunately been closed due to poor accrual.
13.9.7
Integrating Combination Chemotherapy into the Combined Modality Program
Given that with optimized local treatment, including preoperative RT/CRT and TME surgery, distant metastasis is by far the predominant pattern of tumor failure in rectal cancer
today, the current challenge is to integrate more effective systemic therapy into the multimodal concepts for this disease. Novel chemotherapeutic agents such as capecitabine,
oxaliplatin, and irinotecan, which have improved results of patients treated in the adjuvant
or metastatic setting for colorectal cancer, have been incorporated into preoperative phase
I/II combined modality programs for rectal cancer as well (Rodel and Sauer 2007). All
suggest higher pCR rates compared with preoperative 5-FU-CRT alone. However, for
some agents, with this increased pCR rate is an associated increase in acute toxicity.
Clearly, phase III trials are needed to determine if these regimens offer an advantage compared with 5-FU-based combined modality regimen. These studies have now been started
in Europe and the US (Table13.10). Interestingly, early results from the ACCORD and
STAR trials did not confirm a significant improvement of early endpoints (such as the pCR
rate) with the addition of oxaliplatin (Aschele etal. 2009; Gerard etal. 2009). Long-term
results are awaited.
Given the fact that (1) in previous 5-FU-based phase III trials concomitant as well as
adjuvant cycles of chemotherapy were applied and (2) the cumulative doses of the new
drugs reached during RT are substantially lower than in adjuvant colon cancer trials, a
multicenter phase II trial of the German Rectal Cancer Study Group has investigated the
feasibility of preoperative concomitant CRT with capecitabine and oxaliplatin (XELOX)
plus 4 cycles of adjuvant XELOX chemotherapy (Rodel etal. 2007). The most important
result of this trial was that only 60% of the entire cohort of 103 operated patients were able
to complete all 4 postoperative XELOX cycles (with or without dose reduction); 27% did
not for different reasons receive any adjuvant chemotherapy. Thus, it is evident that
preoperative CRT, surgical complications, and the fact that a substantial part of patients
will have pCR or yTNM stage I and II tumors due to downstaging effects or initial clinical
staging error, compromise the possibility and willingness of patients to tolerate postoperative chemotherapy. This is, however, true not only for patients treated with more active
protocols, such as XELOX-RT, but also for standard 5-FU-CRT: In three recent large phase
III trial of preoperative 5-FU-CRT plus postoperative 5-FU chemotherapy, the EORTC
22921, the FFCD 9293, and CAO/ARO/AIO-94 trial, a total of 25, 23, and 20%, respectively, did not start postoperative chemotherapy (Sauer et al. 2004; Bosset et al. 2006;
Gerard etal. 2006).
RT 50.4Gy+5-FU PVI vs.

RT 50.4Gy+5-FU+Oxaliplatin
RT 50.4Gy+5-FU vs.
RT 50.4Gy+5-FU+Oxaliplatin vs.
RT 50.4Gy+Capecitabine vs.
RT 50.4Gy+Capecitabine+Oxaliplatin
RT 4055.8Gy+Chemotherapy according to
NSABP-04 or 5-FU PVI/CapecitabinOxaliplatin or
5-FU+Leucovorin
RT 50.4Gy+5-FU vs.
RT 50.4Gy+5-FU+Oxaliplatin
RT 45Gy+5-FULeucovorin or Capecitabine
RT 45Gy+Capecitabine vs.
RT 45Gy+Capecitabine+Oxaliplatin
RT 25Gy/1 week
STAR
NSABP R-04
ECOG-E 5204
CAO/ARO/AIO-04
CHRONICLE
PETACC 6
SCRIPT
TME
TME
TME
TME
TME
Observation vs.
Capecitabine
Capecitabine vs.
Capecitabine+Oxaliplatin
Observation vs.
Capecitabine+Oxaliplatin
5-FU vs.
5-FU+Oxaliplatin
Oxaliplatin+5-FU/Leucovorin vs.
Oxaliplatin+5-FU/Leucovorin+Bevacizumab
TME
TME
TME
TME
patients may enter ECOG-E5204
5-FU based CT
5-FU based CT
Postop CT free in each institution

Postop CT free in each institution
Postoperative treatment
TME
TME
TME
TME
TME
TME
TME
TME
Surgery
RT radiotherapy; TME total mesorectal excision; CT chemotherapy; PVI protracted venous infusion; ACCORD Actions Concertes dans les Cancers Colorectaux
et Digestifs; STAR Studio nazionaleTerapia neoAdiuvante Retto; NSABP National Surgical Adjuvant Breast and Bowel Project; SCRIPT Simply Capecitabine
in Rectal Cancer after Irradiation Plus TME; CAO/ARO/AIO Chirurgische Arbeitsgemeinschaft fr Onkologie/Arbeitsgemeinschaft Radiologische Onkologie/
Arbeitsgemeinschaft Internistische Onkologie; CHRONICLE Chemotherapy or no chemotherapy in clear margins after neoadjuvant CRT in locally advanced
rectal cancer; ECOG Eastern Cooperative Oncology Group; PETACC Pan-European Trials in Alimentary Tract Cancer
RT 45Gy+Capecitabine vs.
RT 50Gy+Capecitabine+Oxaliplatin
ACCORD 12
Table13.10 Ongoing phase III trials with novel agents for rectal cancer patients
Preoperative treatment
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C. Rdel et al.
13 Rectal Cancer
411
In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver neoadjuvant chemotherapy prior to preoperative CRT rather
than adjuvant chemotherapy (Chau etal. 2006; Calvo etal. 2006). This strategy avoids the
problems of postoperative chemotherapy, but may also be associated with its own caveats,
such as selection of radio-resistance clones, possibly reduced compliance to CRT, and
substantial delay of definitive surgery (Glynne-Jones etal. 2006). Thus, the strategy currently adopted by most groups that have designed phase III comparisons of standard 5-FU
vs. more intense CRT protocols is to stick to the concept of preoperative CRT plus adjuvant chemotherapy and simply accept that a certain percentage of patients will not receive
protocol-conformal postoperative chemotherapy (Table13.10).
13.9.8
Integrating Targeted Agents into the Combined Modality Program
The epidermal growth factor receptor (EGFR) is a promising target of antitumor treatment
because it participates in cell division, inhibition of apoptosis, and angiogenesis. EGFR
overexpression has been associated with a more aggressive phenotype and poor prognosis
in many human cancers, including rectal cancer. Preclinical investigations have linked
EGFR expression with radioresistance both invitro and invivo. Moreover, recent clinical
studies have established EGFR expression as an independent predictor of poor tumor
response and prognosis in rectal cancer patients treated with preoperative RT or CRT
(Marquardt etal. 2009).
Clinical studies of preoperative CRT have now been initiated to evaluate EGFR inhibitors as radiosensitizers in rectal cancer (Table13.11). Machiels etal. (2007) have reported
the safety and efficacy of combining preoperative RT with capecitabine and cetuximab in
a phase I/II trial. This combination was associated with no unexpected toxicity, and full
doses of RT, CT, and cetuximab could be applied. However, only two of 37 patients (5%)
achieved a pCR, and a total of 25/37 patients (68%) had only moderate or minimal tumor
regression. The German Rectal Cancer Study Group conducted a multicenter phase I/II
study to determine the tolerability and efficacy of adding cetuximab to preoperative RT
with capecitabine and oxaliplatin (Rodel etal. 2008). Again, only four of the 45 operated
patients (9%) had pCR in the resected specimen, and 53% of patients had only moderate,
minimal, or no tumor regression at all. As shown in Table13.11, the disappointingly low
rate of pCR rates achieved by the combination of CRT plus cetuximab has now been confirmed in several phase II studies (Horisberger etal. 2009; Bertolini etal. 2009; Debucquoy
etal. 2009). Several mechanisms may contribute to the apparently subadditive interaction
between CRT and cetuximab, including upregulation of cycline-dependent kinase p27 and
G1 cell cycle arrest, the redundancy of EGFR pathways, K-ras mutation status, as well as
sequence dependencies (Debucquoy et al. 2009). As molecular targeted therapies exert
their efficacy predominantly as cytostatic rather than cytotoxic agents, it is also well conceivable that the benefit may be manifested not as an increase in early tumor regression but
rather as an arrest in tumor progression. Thus, longer follow-up (and finally randomized
trials) is needed to draw any firm conclusions with respect to local and distant failure rates
as well as toxicity.
50
40
41
Horisberger etal. (2009)
Bertolini etal. (2009)
Debucquoy etal. (2009)
Preop. RT: 1.845Gy

Capecitabine 825mg/m during RT
Cetuximab 400mg/m loading dose (d-7)
followed by 250mg/m (d1, 8, 15, 22, 29)
Preop. RT: 2.050Gy

5-FU: 225mg/m continuous infusion
Cetuximab 400mg/m loading dose, followed
by 250mg/m weekly, three times, followed
weekly concomitantly with CRT
Preop. RT: 1.850.4Gy

Capecitabine 500mg/m bid d138
Irinotecan 40mg/m d1 ,8, 15, 22, 29
Cetuximab 400mg/m loading dose (d1)
followed by 250mg/m (d8, 15, 22, 29)
Grade 3 diarrhea 15%

Grade 4: myocardial infarction (1),
pulmonary embolism (1), sepsis (1)
Grade 3 acneiform rash 15%, no

grade 4 toxicity
Grade 34 leukopenia 4%
Grade 3 diarrhea: 30%
5%
8%
8%
9%
48
Rdel etal. (2008)

Capecitabine 825mg/m bid d114 an d2235
Oxaliplatin 50mg/m d1,8,22,29
Cetuximab 400mg/m loading dose (d-7)
followed by 250mg/m (d1,10, 8, 15, 22, 29)
pCR
Table13.11 Selected phase II studies of preoperative of CRT for rectal cancer with epidermal growth factor receptor (EGFR)-inhibition
Series
Concurrent CRT
Toxicity
N
412
C. Rdel et al.
13 Rectal Cancer
413
Angiogenesis is necessary for the survival and growth of tumors; however, tumor blood
vessels are often characterized by a disorganized architecture that contributes to intratumoral regions of intermittent or chronic hypoxia. Preclinical data have suggested that
proangiogenic factors, especially the vascular endothelial growth factor (VEGF), are
upregulated in tumors in response to RT and may increase resistance to RT. These findings
are now supported by clinical data in rectal cancer patients, such that VEGF expression has
been linked to a worse prognosis (Marquardt etal. 2009). VEGF-targeted therapy may lead
to a normalization of the tumor vasculature, thereby leading to greater tumor oxygenation and drug penetration. When combined with RT, antibodies against VEGF-induced
additive to supraadditive tumor growth delay and cell death in colon cancer models.
Willett etal. have reported on a phase I study of preoperative bevacizumab, 5-FU, and
radiation therapy for clinical T3 or T4 rectal cancer. Preliminary data indicate safety of this
regimen and significant activity (six of seven evaluable patients demonstrated only microscopic disease in the surgical specimen 7 weeks after completion of neoadjuvant treatment) (Willett etal. 2004). In a meticulous analysis of the first six patients performed 12
days after the first bevacizumab infusion, this group revealed a significant decrease in
tumor blood perfusion and blood volume, and a significant decrease in tumor microvessel
density. This was accompanied by an increase in pericyte coverage of tumor vessels and a
decrease of the interstitial fluid pressure, indicating that a normalization of the tumor
vasculature by anti-VEGF treatment may contribute to the high efficacy of bevacizumab
in this and further trials with combined CRT and VEGF inhibition (Table13.12) (Willett
etal. 2009; DiPetrillo etal. 2008; Marijnen etal. 2008; Crane etal. 2009). Clearly the
toxicity pattern (radiation-induced enteritis, perforations) and surgical complications
(wound healing, fistula, bleeding) observed in at least some of the clinical studies warrants
further investigations of the interaction of RT with VEGF-inhibition, both for tumor and
normal tissues.
13.9.9
Treatment Toxicity and Quality of Life
Complications of pelvic RT are a function of the volume of the radiation field, overall
treatment time, fraction size, RT energy, total dose, technique and sequence of RT, and
combination with concurrent chemotherapy. Acute side effects such as diarrhea, proctitis,
and dysuria are common during treatment. These conditions are usually transient and
resolve within a few weeks following the completion of RT or CRT. Positioning devices,
such as the bellyboard, can be used to reduce small-bowel toxicity. Management usually
involves the use of antispasmodic and/or anticholinergic medications. Dietary counseling
is also useful in the management of diarrhea.
Delayed complications occur less frequently but are substantially more serious. The
initial symptoms commonly occur 618 months following completion of RT or CRT.
Complications include: persistent diarrhea, increased bowel frequency and impairment of
sphincter function, proctitis and strictures at the anastomotic site, small-bowel obstruction,
perineal/scrotal tenderness, delayed perineal wound healing, urinary incontinence, and
bladder atrophy/bleeding. Injury to the vascular and supporting stromal tissues as well as
23
23
32
25
Marijnen etal. (2008)
DiPetrillo etal. (2008)
Willett etal. (2009)
Crane etal. (2009)

Capecitabine 900mg/m bid M-F
Bevacizumab: 5mg/m d1,15,29
Surgery 611 weeks (median 7.3) after RT

5-Fluorouracil: 225mg/m continuous
infusion
Bevacizumab: 5 or 10mg/m d-14,1,15,29
Surgery: 79 weeks after completion of RT
Two biweekly courses of bevacizumab

5mg/m and modified FOLFOX6 followed
by bevacizumab 5mg/m biweekly,
oxaliplatin 50mg/m weekly (subsequently
reduced to 40mg/m due to grade 3
diarrhea), 5-FU 200mg/m continuous
infusion concurrent with 50.4Gy pelvic
irradiation
Surgery 48 weeks after completion of RT
Preop. RT: 2.050Gy

Capecitabine 825mg/m bid
Bevacizumab: 5mg/m d-14, 1, 15, 8 ,29
Surgery 610 weeks thereafter
16% (ypT0)
32%
No patients had grade 3 GI or hematologic
toxicity.
Surgical: three wound complications that
required surgical intervention
25%
Grade 3 during CRT: 75%

Grade 4: neutropenia (1 patient), diarrhea (1
patient)
No acute grade 4
Postoperative complications: wound
infection (3), delayed healing (2), presacral
abscess (2), pelvic hematoma (2), ileus (2)
9%
pCR
Grade 3: skin (4), diarrhea (2),

Grade 4: anal mucositis (1);Grade 5:
enteritis with uncontrollable bleeding (1),
Postop: 2/23 small-bowel perforations, 1
rectal wall perforation, surgical: perineal
dehiscence (1), rectovaginal fistula (2),
bleeding 5500 cc (1)
Table13.12 Selected phase II studies of preoperative CRT for rectal cancer with VEGF (vascular endothelial growth factor)-inhibition
Series
Concurrent CRT
Toxicity
N
414
C. Rdel et al.
13 Rectal Cancer
415
to autonomic nerves is the presumed pathophysiology. The most common delayed severe
complications are due to small-bowel damage and include small-bowel enteritis, adhesions, and small-bowel obstruction requiring surgical intervention. These complications
occur more often after postoperative compared with preoperative RT/CRT (Sauer et al.
2004). The incidence of small-bowel obstruction requiring surgery following postoperative
pelvic RT/CRT for rectal cancer is 412% in modern series, but was as low as 2% in the
preoperative CRT arm of the recent German Rectal Cancer Study (CAO/ARO/AIO-94).
As with surgery, RT has been shown to lead to increased sexual dysfunction, with longterm deterioration of ejaculatory and erectile function in men, and vaginal dryness and
diminished sexual satisfaction in women. In the Polish randomized trial, the incidence of
long-term toxicity was similar for preoperative short-course RT and 5-FU-based longcourse CRT (Bujko etal. 2006). Some evidence from long-term analysis of the Swedish
trials indicate an increased risk of second cancers in organs within or adjacent to the RT
volume (Birgisson etal. 2005).
13.10
Future Perspectives
As depicted in Fig.13.11, there have been two major developments in neoadjuvant treatment of rectal cancer over the past two decades. The first one has been to apply RT and CT
as early as possible. Since 2004, CRT is set before surgery, and the most recent studies
even incorporated neodjuvant chemotherapy prior to preoperative CRT. As a consequence,
surgery has been gradually postponed. Indeed, the need for radical surgery is now challenged by series of definitive CRT that report excellent outcomes in patients with clinical
complete response (Habr-Gama and Perez 2009). The second major development has been
to integrate combination chemotherapy with preoperative RT (Rodel and Sauer 2007). The
most recent series used triple combinations, including RT, combination chemotherapy, and
targeted therapies (Marquardt etal. 2009). Phase III trials are needed to determine if these
novel combination regimens offer an advantage compared with 5-FU-based combined
modality.
Moreover, better knowledge of microscopic lymphatic spread within the mesorectum
has led to the use of TME for mid and low rectal cancer. With this optimized surgery,
local control rates have been markedly increased and local failure rates above 1015% are
now no longer acceptable. Technical advances in RT, including tumor-optimized and radiobiologically optimized fractionation and image-guided and intensity-modulated radiation
therapy will further allow application of more sophisticated treatment volume to reduce
irradiation of normal tissue and increase the therapeutic index (Valentini etal. 2008).
Evidently, the monolithic approaches, established by studies more than a decade ago, to
either apply the same schedule of preoperative or postoperative 5-FU-based CRT to all
patients with TNM stage II/III rectal cancer or to give preoperative intensive short-course
RT according to the Swedish and Dutch concept for all patients with resectable rectal cancer irrespective of tumor stage and location, need to be questioned. The inclusion of different multimodal treatments into the surgical oncological concept, adapted to the tumor
416
C. Rdel et al.
GITSG 7175 and NCCTG/Mayo 794751:

Superiority of combined CRT over surgery
1992 alone or adjuvant RT and CT alone.
GITSG 7180: Six cycles of bolus 5-FU, RT with
3./4.cycle. Methyl-CCNU plus 5-FU not superior
to 5-FU alone.
5-FU
Bolus
5-FU continuous infusion

S
NCCTG 864751: 5-FU continuous

infusion during RT superior to bolus 5-FU for
1994 disease-free and overall survival (not
confirmed by the more recent INT 0144).
Modulation of 5-FU through addition of folinic
acid, levamisol, or of both, not superior to
bolus 5-FU alone (INT 0114).
2002 Korean Trial: Start of RT together with 1./2.
versus 3./4. cycle of 5-FU/folinic acid
improved disease-free survival.
German Rectal Cancer study (CAO/ARO/AIO94): Preop. superior to postop. CRT for
2004/ local control, sphincter preservation, toxicity.
EORTC 22921; FFCD 9203: Preoperative
2006 RCT with 5-FU/folinic acid superior to
preoperative RT alone for local control. None of
the 3 trials showed improved survival.
Oxaliplatin or Irinotecan
Capecitabin or 5-FU
Several phase I/II-studies incorporated novel

chemotherapy combinations into
2004/ preoperative RCT:
2006 pCR-rates 9-36%; increased, but manageable
acute toxicity (for review: Rdel C, Sauer R 2007).
The question of
postoperative chemotherapy was not
addressed.
2006 Multicenter phase II trial of the German Rectal
Cancer Study Group: Preoperative RCT
active and feasible (pCR-rate 16%,
compliance 96%). Only 60% of patients
received all four cycles of chemotherapy.
Oxaliplatin
Cape
Oxaliplatin
Cape
Capecitabine
2006 Integration of neoadjuvant

chemotherapy prior to RCT for MRI-defined
poor risk rectal cancer.
Cetuximab or Bevacizumab
Oxaliplatin or Irinotecan
S
Capecitabin or 5-FU
Intergration of targeted therapy (cetuximab

and bevacizumab) into combined modality
2007/ programs for rectal cancer
2008
Fig. 13.11 Major developments in (neo-) adjuvant treatment of rectal cancer over the past two decades
location and stage and to individual patients risk factors is mandatory. Clearly, future
developments will aim at identifying and selecting patients for the ideal treatment alternatives. Thus, clinicopathological and molecular features as well as accurate preoperative
imaging and postoperative surgical quality control will take an important and integrative
part in multimodality treatment of rectal cancer.
13 Rectal Cancer
417
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14
Anal Cancer
Rob Glynne-Jones and Suzy Mawdsley
Conflict of Interest Statement

Rob Glynne-Jones has received honoraria for lectures and advisory boards and has been
supported in attending international meetings by Merck, Pfizer, Sanofi-Aventis and Roche.
He has also received unrestricted grants for research from Merck-Serono, Sanofi-Aventis
and Roche.
Suzy Mawdsley: No conflicts of interest
14.1
Incidence
Squamous cell cancer (SCC) of the anus is rare and accounts for only 24% of all lower
alimentary tract malignancies. The annual incidence is approximately 1 in 100,000
(approximately 900 cases per year in the UK, and 5,000 in the USA), and has been increasing over the past three decades (Frisch etal. 1993; Johnson etal. 2004; Bilimoria etal.
2009; Jemal etal. 2008). Anal cancers are more common in women than men (Bilimoria
etal. 2009; Jemal etal. 2008) and patients are often elderly. An indolent natural history and
a low rate of distant metastases (Jemal etal. 2008; Boman etal. 1984; UKCCCR Anal
Cancer Working Party 1996) mean that anal cancer is usually amenable to loco-regional
treatment. The relative five-year survival rate in the US for anal cancer diagnosed 1983
1990 was 62% (Miller etal. 1973), and has changed little for patients treated in the last two
decades (Bilimoria etal. 2009; Jemal etal. 2008) (Table14.1).
R. Glynne-Jones (*)
Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, UK and
Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex HA6 2RN, UK
e-mail: rob.glynnejones@nhs.net
S. Mawdsley
Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex HA6 2RN, UK
423
72
283
Newman etal. 1992)
Friberg etal. 1998)

Anal canal
6064
50Gy/20f
4562
222
Not stated
55
55/72 T1=100
T1/T2=84
T1/T2=77
Papillon and
Montbarbon (1987)
6
20% late
complications
63.95
35
Doggett etal. 1988)
12
T1/T2=91
T1/T2=90
6569
14
T1/T2=56
33
6065
67
San Francisco, Cantril

etal. (1983)
64
Institut Gustave Roussy
6567
Local control (%)
T3=76
21
Cutuli etal. 1988)

(margin)
6575
Complications
needing surgery %
Eschwege etal. 1985)
158
Institut Curie
Salmon etal. 1984)
Table14.1 Results of historical studies with radiotherapy alone

Series
Number
Dose Gy
60
66
65
92
79
46
55
59 (70% for<4cm)
5-Year survival (%)
58
74
Not stated
77 Surgical
definition
78
74
45
73 for <4cm
Functioning anus (%)
424
R. Glynne-Jones and S. Mawdsley
14 Anal Cancer
425
This chapter will limit its discussion to SCC arising in the anal canal and margin, and
ignore other biologically distinct anal tumours such as melanoma, neuroendocrine tumours,
adenocarcinomas, lymphomas and GIST tumours.
14.2
Aetiology and Risk Factors
Human papilloma virus (HPV) infection is closely correlated with squamous cell anal
carcinoma (Williams etal. 1996). Using polymerase chain reaction (PCR), the presence of
the HPV genome has been identified in 8085% of cases (Frisch etal. 1997; Crook etal.
1991). This parallels the prevalence seen in cervical and vulval carcinoma in women
(Bosch etal. 1995). In one study 331 patients were examined and 84% demonstrated HPV
in the malignant tissue. HPV 16 made up 87% of these (Frisch etal. 1999a). The role of
HPV has therapeutic implications, as patients with HPV positive tumours in some tumour
sites appear to be more radiosensitive (Licitra etal. 2006).
Immuno-suppression is a further important risk factor, particularly in renal and cardiac
transplant recipients (Penn 1986). Even before the current HIV epidemic an excess risk of
4050 times was observed in the homosexual population for anal cancer (Daling et al.
1982; Daling and Weiss 1987). Currently HIV is a recognised risk factor (Melbye etal.
1994), but the precise relationship is difficult to separate from the prevalence of HPV.
Anal cancer is strongly associated with cigarette smoking (Holly etal. 1989; Daling
etal. 1992; Tseng etal. 2003; Frisch etal. 1999b). In a casecontrol study current cigarette
smoking was a major risk factor in both sexes, with relative risk 7.7 in women and 9.4 in
men (Daling et al. 1992). There is no clear association with dietary habits and chronic
inflammatory diseases and the presence of haemorrhoids do not appear to predispose to
anal cancer development (Frisch etal. 1994; Frisch and Johansen 2000).
14.3
Pathology and Biology
The neoplastic process in the anus can be divided into intra-epithelial neoplasia (AIN) and
invasive disease.
14.4
Intra-Epithelial Neoplasia
AIN can be graded from one to three in severity. The incidence of AIN in homosexual men
is >36% (Clark etal. 1986; Daling etal. 2004). The natural history of progression from
AIN3 to invasive malignancy in anal cancer is generally poorly documented. It appears
426
low in immuno-competent patients (Schofield etal. 2005). In contrast, progression is more

likely in systemically immuno-suppressed patients (Lacey etal. 1999), and is influenced
by HIV seropositivity, low CD4 count and serotype of HPV infection (Zbar etal. 2002;
Abbasakoor and Boulos 2005).
14.5
Histological Types
In terms of histological appearances, colorectal type mucosa is found about 1cm above the
dentate line. Between this level and the dentate line is a transitional zone with epithelial
variants of columnar and cuboidal cells and areas of colorectal crypts above and squamous
epithelium below. Terms such as basaloid transitional or spheroidal and cloacogenic have
a similar natural history and patterns of spread, and have been replaced by SCC.
14.6
Tumour Grade
Tumours of the anal canal are often poorly differentiated SCC, but grading is subject to
considerable inter-observer variability, and considerable heterogeneity in larger tumours.
Hence, although high-grade tumours are generally accepted to have a worse prognosis, this
has not been confirmed in multivariate analysis (Shepherd etal. 1990).
14.7
Anatomy
The anal canal measures approximately 4 cm in length. The anatomical definition and
terminology used to describe the anal canal are often confused and imprecise. We would
define the anal canal as that part of the large intestine beginning at the anorectal junction,
passing through the anorectal ring and ending where true skin is found at the anal margin.
Because the dentate line is the most easily identified landmark in the mucosa of the anal
canal, many have suggested that the canal is divided into infra dentate and supra dentate
regions (Wendell-Smith 2000).
The anal margin reflects that region of pigmented skin with skin folds surrounding the
anus. Although the lateral border of the anal margin has not been defined, tumours of the perianal skin within a radius of approximately 5cm from the anal orifice are usually considered as
anal margin cancer.
14 Anal Cancer
427
14.8
Lymphatic Drainage
The most proximal portion of the anal canal drains to perirectal nodes and nodes along the
superior rectal vessels to the inferior mesenteric system, and then to the para-aortic nodes.
There is also drainage to the internal iliac and obturator nodes (Hill etal. 2003). The canal
above the dentate line drains to internal pudendal nodes and to the internal iliac system.
Venous drainage of the upper half of the canal is mainly by the superior rectal vein to inferior mesenteric vein, while drainage of the lower half is by the inferior rectal vein, to the
internal pudendal vein and internal iliac vein. Hence, metastases may occur to either liver
via the portal system or lung via the systemic circulation, depending on tumour position.
The canal below the dentate line drains to the medial group of superficial inguinal nodes
with some communication with femoral nodes and to external iliac nodes.
Involved nodes are often palpable, but historical pathology studies, using a clearing
technique, demonstrated that almost half of all involved lymph nodes were smaller than
5mm in diameter (Wade etal. 1986). The inguinal, femoral and iliac lymph nodes are the
most frequent sites for nodal metastases (Greenall etal. 1985; Beahrs and Wilson 1976;
Stearns etal. 1980; Greene etal. 2002).
14.9
Presentation
The initial and most common symptom is bleeding and occurs in approximately 50% of
patients, and 25% present with an obvious mass and discomfort (Stearns et al. 1980).
Pruritus and discharge are found in 25% (Stearns etal. 1980) and less commonly, patients
may present with faecal incontinence or a rectovaginal fistula. Diagnosis can be made on
rectal examination. Small, early cancers often cause few symptoms, and are sometimes
diagnosed serendipitously with the removal of anal tags. Suspicious lesions should always
be biopsied.
14.10
Staging and Risk Assessment
The American Joint Committee on Cancer (AJCC) in 2002, tumour node metastases staging system (Greene etal. 2002) is based on size (T stage), regional lymph node involvement (N) and spread to different sites (M). Data from surgical studies prior to the use of
chemoradiation suggest that small tumours <2cm were associated with five-year survival
in the range of 6080%, but this figure fell to 2455% when tumours were >5cm (Boman
etal. 1984; Greenall etal. 1985; Sato etal. 2005). A cut off of 4cm has been proposed as
428
the size, which distinguishes good and poor prognosis (Touboul etal. 1994). Because currently few cancers are surgically resected, this classification is now based on clinical
examination and imaging studies. Nodal status is based on distance from the primary site
rather than the number of nodes involved, as this has more prognostic significance, and the
definition is different for cancers in the anal canal and margin.
14.11
Pre-Treatment Assessment
Patients should be assessed for performance status, renal function and medical co-morbidity.
Patients should also be tested for relevant infections and other malignancies.
Clinical examination and digital rectal examination (DRE) remain a valuable method
for assessing TNM staging. Imaging can provide information such as tumour length,
degree of circumferential extent, involvement of adjacent structures and extension above
the dentate line and below the anal margin. Direct proctoscopy is often difficult in more
advanced lesions because of pain. Hence, examination under anaesthetic (EUA) may be
required for biopsy. Vaginal examination is essential in female patients to assess extension
into the post vaginal wall or even breaching of the vaginal mucosa. Currently, a cervical
smear is also recommended for younger patients in whom the cervix can be accessed.
The assessment of inguino-femoral lymph nodes remains controversial. In a retrospective surgical series 30% of patients had involvement of their inguinal nodes; however, in the early T1/T2 tumours the incidence was only 12% (Stearns etal. 1980; Pyper
and Parks 1985; Clark etal. 1986). Involvement is usually unilateral and occasionally
bilateral but not usually contralateral to the tumour. Involved nodes can be imaged on
MRI (Roach etal. 2005), but clinically suspicious nodes should be assessed by biopsy
where possible, as only 50% will contain tumour; the remainder are enlarged due to
secondary infection.
14.12
Radiological Staging
Given that definitive chemoradiation is currently the standard of care, there are few data to
confirm the accuracy of staging, as there can be no histopathological correlation. MRI is
favoured for assessing loco-regional disease extent (Salerno etal. 2006) as this provides
good contrast resolution and multiplanar anatomical detail. The intermediate to high signal
intensity tumour is well delineated on T2 and STIR-weighted sequences and primary
tumour extent into surrounding structures (Koh et al. 2008). Endo-anal ultrasound
(Magdeburg etal. 1999; Giovannini etal. 2001; Berton etal. 2008; Otto etal. 2009) and
computed tomography (CT) may also provide useful information. Endoscopic ultrasound
may be superior to MRI for detecting small superficial tumours. However, magnetic resonance imaging appears more effective for N staging.
14 Anal Cancer
429
Carcinoma of the anus has a low rate of distant metastasis (Boman etal. 1984; Kuehn
etal. 1968). Haematogenous spread at presentation is noted in less than 5% of cases and
predominantly involves lung or liver. CT of the thorax and abdomen is therefore preferred
to a chest radiograph and liver ultrasound for assessing metastatic disease due to its higher
sensitivity.
Prediction of lymph node involvement by size alone is inaccurate, as 44% of all involved
lymph nodes are smaller than 5mm in diameter (Wade etal. 1986). More recently, staging
by virtue of positron emission tomography/CT with 18-F fluorodeoxyglucose (FDG-PET/
CT) has been advocated, because positive lymph nodes may be more easily identified than
with other imaging modalities (Trautmann and Zuger 2005; Cotter etal. 2006). FDG-PET/
CT is recommended in the current National Comprehensive Cancer Network treatment
guidelines (Engstrom etal. 2008). More accurate staging of lymph nodes is important as
treatment is potentially influenced in terms of the radiation fields and the need for a boost
to these sites.
The use of MR lymphangiography with ultra-small superparamagnetic iron oxide particles (USPIO) to improve specificity and sensitivity of the nodes remains investigational
(Koh etal. 2004).
14.13
Other Investigations/Procedures
HIV testing is recommended in any patient with an at-risk lifestyle. HIV status has major implications both in terms of excess treatment toxicity and the development of infection. Optimisation
of anti-retroviral treatment is therefore essential. Sperm banking should be discussed prior to
the commencement of treatment with male patients, who wish to preserve fertility. It is assumed
that scattered doses of radiation to the testes will invariably induce permanent sterility.
A defunctioning colostomy should be considered prior to treatment in patients with significant
faecal incontinence or in female patients with transmural vaginal involvement at risk of development of an anorectal-vaginal fistula, due to marked tumour regression following chemoradiation (CRT). Smoking may worsen acute toxicity during treatment and lead to a poorer
outcome in terms of disease-free and colostomy-free survival (Mai etal. 2007). Every effort
should be made to ensure that patients quit smoking prior to therapy.
14.14
Predictive Factors
The association of response with tumour T stage has been noted previously in anal carcinomas (Gerard etal. 1998). In a study of chemoradiation (Doci etal. 1996), a 100% complete response rate was reported in T1/2 tumours and 60% in T3 tumours. The Intergroup
and EORTC trials (Bartelink etal. 1997; Flam etal. 1996) also reported a higher complete
response rate on univariate analysis by tumour size.
430
14.15
Prognostic Factors
Analysis of prognostic factors in anal cancer has only been reported from the smallest of
the four published randomised studies (Bartelink etal. 1997), which suggested that skin
ulceration as well as gender and nodal status were important, but not tumour size.
Retrospective analyses with all their inherent limitations have highlighted gender, nodal
status and tumour size (Greenall etal. 1985; Sato etal. 2005; Touboul etal. 1994; Longo
etal. 1994; Peiffert etal. 1997; Das etal. 2007; Myerson etal. 2001) as prognostic factors.
Tumour size has also been supported in multivariate analyses (Constantinou etal. 1997;
Papillon and Montbaron 1987; Schlienger etal. 1989). In a series of 118 patients treated
by external beam and brachytherapy there was an increase in local failure with increasing
T stage (T1, 11%; T2, 24%; T3, 45% and T4, 43%) and a corresponding decrease in fiveyear survival Peiffert etal. 1997). The level of tumour regression (>80%) after primary
chemoradiation may be predictive of colostomy-free and disease-free survival Chapet
etal. 2005). A basaloid rather than squamous histological subtype has also been shown to
have a higher risk of developing metastatic disease (Das etal. 2007).
The impact of treatment factors has also been analysed. External beam (rather than
iridium implant) to deliver boost radiotherapy and overall treatment time greater than or
equal to 75 days, have been associated with poorer local control, but these factors did not
remain significant in multivariate analysis (Allal etal. 1998). Others have not found any
relationship between local control rates and total radiation dose, overall treatment time or
irradiation technique in 270 patients treated with radiotherapy (Touboul etal. 1994).
14.16
Biological Markers
Anal carcinomas appear to have a high proliferative index (Allal etal. 1998; Noffsinger
etal. 1995). However, only two studies have shown prognostic significance. Nilsson demonstrated that a high cyclin A expression was prognostic for an improved tumour-specific
survival, overall survival (OS), and loco-regional failure rate (Nilsson etal. 2006). In a
very small study of just 30 patients, Ki67 expression correlated significantly with diseasefree survival (DFS) (Ajani etal. 2008). In contrast, the family of cyclin-dependent kinases
(cyclin E and D1), which regulate transition through the cell cycle appear to have no significant prognostic effect (Allal etal. 2004). A high proliferative index may also be predictive of treatment response and in the ACT I series, of 240 patients, a higher expression of
cyclin A predicted for an improved response to irradiation (Mawdsley etal. 2004).
Over-expression of p53 is common in anal carcinomas (Ogunbiyi etal. 1993; Jakate
and Saclarides 1993). Alterations in p53 protein function may result from either mutations
in its gene or sequestration by other cellular proteins such as the E6 viral oncoprotein of
the HPV virus (Gangopadhyay etal. 1997). HPV E6 protein has a direct effect on p53 in
the basal layers of the anal epithelium, allowing the continuous proliferation of the host
14 Anal Cancer
431
cells and increasing their risk of mutation (Zwerschke and Jansen-Durr 2000). Several
studies have looked at the association of p53 and HPV. P53 nuclear accumulation has been
found to be associated with the presence of HPV without an effect on clinical outcome.
However, in other studies p53 was not found to be associated with HPV and coexpression
of p53 and the HPV E6 oncoprotein was uncommon (Ogunbiyi etal. 1993; Jakate and
Saclarides 1993; Tanum etal. 1993).
In a recent analysis of 240 patients in the UKCCR ACT I anal cancer trial, p53 predicted for a poorer cause-specific survival (Mawdsley etal. 2004). In a smaller study of
(Wong etal. 1999) 49 patients, p53 expression predicted for a poorer DFS. Other studies
however, have been contradictory (Tanum et al. 1993). The RTOG study (Bonin et al.
1999) of 64 patients found there was a trend for patients whose tumours over-expressed
p53 to have an inferior outcome. In a further small study of 18 patients, p53 had no prognostic impact and the authors concluded that p53 gene over-expression may simply confer
a more aggressive growth pattern (Indinnimeo etal. 1998).
The apoptotic marker Bcl-2 has been analysed extensively. In a study of 98 anal carcinoma patients, 51 of whom received combined modality treatment, lack of bcl-2 expression was associated with lower local control and OS. This association remained significant
on multivariate analysis (Allal etal. 2003). Patients with a positive bcl-2 and negative p53
tumour had a significantly higher five-year local control compared to patients with negative bcl-2 and positive p53 (93 vs. 53%).
There is little data on the potential role of angiogenic markers. A study of CD31
(Indinnimeo etal. 2001), a platelet endothelial cell adhesion molecule, showed no correlation with neoplastic relapse but there was a significant correlation with the depth of tumour
invasion, supporting the concept that tumour growth is angiogenesis-dependent. Increasing
micro-vessel density has also been demonstrated to correlate with increasing grade of intraepithelial anal neoplasia (Litle etal. 2000), suggesting that angiogenesis is a pre-malignant
event. In the ACT I analysis (Mawdsley etal. 2004), decreasing CD34 was significantly
associated with a poorer relapse-free survival (RFS), in multivariate analysis. This may
reflect that those tumours with low vessel counts are more hypoxic and will therefore
respond less well to treatment.
In the ACT I series (Mawdsley etal. 2004) the markers of 5-fluorouracil (5-FU) metabolism, i.e. dihydropyrimidine dehydrogenase and thymidylate synthase expression, failed
to correlate with survival. Thymidine phosphorylase expression did however correlate
with a poorer RFS, although this observation could reflect the dual role of its direct involvement in angiogenesis.
14.17
Tumour Markers
Squamous cell carcinoma antigen (SCCAg) is expressed by several epidermoid tumours,
including carcinoma of the anal canal. In small historical studies, SCCAg levels have not
been demonstrated to be of prognostic value in anal carcinoma (Petrelli etal. 1988), or
useful in follow-up (Petrelli etal. 1992). In a series of 66 patients, the SCCAg correlated
432
with nodal invasion (p<0.05), but did not offer any prognostic value (Fontana etal. 1991).
In another study with 60 patients, actuarial survival analyses for patients with normal vs.
elevated SCCAg concentrations showed that the projected five-year OS was 81% for those
with a normal level and 43% for those with an elevated level (p=0.004), and for tumourspecific survival the figures were 83 vs. 45% respectively (p=0.004) (Goldman et al.
1993). More recently a larger retrospective study from the UK suggests that the initial
SCCAg level prior to treatment appears to be related to tumour stage and/or nodal status,
and may assist in guiding planning target volumes (Swampillai etal. 2009).
14.18
Surgery as Primary Treatment for Anal Cancer
Up until the mid 1980s surgery was the cornerstone of treatment for this disease (Boman
et al. 1984; Stearns et al. 1980; OBrien et al. 1982). Local resection was usually performed for cancer of the anal margin, which behaves in a similar fashion to skin cancer,
and rarely it was used for smaller lesions of the anal canal. Abdomino-perineal resection
was recommended as the best method of achieving adequate resection margins for most
cancers in the anal canal. Inguinal node dissection was originally performed electively, but
fell out of fashion because of concerns regarding morbidity (Golden and Hosley 1976).
Some authors also advocated full pelvic node dissection; however, this aggressive surgical
strategy failed to show any improvement in survival. Surgical treatment was associated
with local failure in up to half of cases (Boman etal. 1984; Stearns etal. 1980), and fiveyear survival rates in the region of 5070%.
Local excision may be appropriate for small well-differentiated carcinomas of the anal
margin (T1 N0), i.e. <2cm in diameter, if there is no evidence of disease within the anal
canal, there is no evidence of nodal spread clinically or on imaging and if clear lateral and
deep margins are likely to be obtained. Further excision can be undertaken if the margins
are not satisfactory (<3mm). In contrast, local excision of a lesion in the anal canal may
compromise sphincter function and an incomplete excision can severely impair long-term
sphincter function from both the surgical procedure and from the additional CRT. Hence,
there is no evidence to support a debulking approach prior to chemoradiation.
14.19
Non-Surgical Treatment
The initial studies of Nigro (Nigro 1974, Nigro etal. 1983; Vaitkevicius etal. 1974) demonstrated high rates of local control with the use of approximately 30Gy of irradiation with
concurrent mitomycin C (MMC) and 5-FU. Cummings (1991) reported a series of 190
patients treated with radiotherapy (RT) or CRT using seven sequential regimens and concluded retrospectively that CRT and the addition of MMC to 5-FU improved local control.
14 Anal Cancer
433
Subsequently, randomised controlled studies in Europe have confirmed that synchronous chemoradiation (SCRT), as the primary modality, is superior to radiotherapy alone in
the treatment of anal cancer (UKCCCR Anal Cancer Working Party 1996; Doci et al.
1996). The RTOG phase III study (Flam etal. 1996; Bartelink etal. 1997) has also helped
to confirm the value of adding MMC to 5-FU-based CRT (Table14.2).
Together with sequential phase II studies Cummings etal. 1991; Cummings 1993; Rich
etal. 1993; Martenson and Lipsitz 1995; John etal. 1996; Friberg etal. 1998), these randomised trials have helped to refine techniques of radiotherapy and the efficacy of relatively low total radiation doses. However, the optimal schedules, radiation dose, technique,
duration of gap and chemotherapy choice have been repeatedly questioned and remain in
some cases the subject of ongoing clinical trials.
The established European philosophy of treatment has usually relied on split-course
radiotherapy with high total doses, and the use of interstitial implants based on the tradition of Papillon and Montbaron (1987). Anal cancers regress slowly and the perineal skin
reactions take about four weeks to heal. Several authors suggested that it was impossible
to deliver either an immediate perineal boost with external beam radiotherapy (EBRT) or
an I-192 wire implant (Schlienger etal. 1989; Eschwege etal. 1985) and studies of continuous CRT in anal cancer confirmed that unscheduled breaks in treatment for up to two
weeks were commonly required to allow severe skin and anorectal reactions to settle (Flam
etal. 1996; Tanum etal. 1991). Therefore the rationale of this gap has been to allow the
acute toxicity of skin and mucosal surfaces to resolve, to allow sufficient time for the bulk
of the tumour to shrink and hence facilitate both an effective assessment of tumour response
and the delivery of high doses of radiation using an interstitial implant to the smallest possible volume. This practice also minimises the risk of necrosis in the high-dose area. In
addition, the long gap allows the selection of patients who fail to respond after the initial
phase of treatment to proceed to surgical resection.
The early randomised European trials advocated a six-week gap in treatment following
wide-field pelvic chemoradiotherapy to a dose of 45Gy prior to embarking on a more localised boost (UKCCCR Anal Cancer Working Party 1996; Bartelink etal. 1997). In contrast, the American view has opted for large shrinking field techniques with higher initial
total doses in the region of 4850 Gy in conjunction with synchronous chemotherapy,
which avoid interruptions in the radiotherapy (Flam etal. 1996).
However, evidence from the two cohorts in the RTOG 92-08 anal trial implies that even
a short gap is detrimental to outcome. When the cohort with a two-week mandated gap is
compared to those with similar initial characteristics in the RTOG-04 trial, where a median
initial dose of 45Gy was prescribed (Flam etal. 1996), OS, DFS and Colostomy free survival (CFS) all fared worse (Konski etal. 2008). In contrast, patients with no mandated
break had similar outcomes to those in the RTOG 87-04 study. Small patient numbers and
non-randomised comparisons make the study difficult to interpret.
More recent sequential EORTC trials have integrated infusional 5-FU and reduced the
gap to 2 weeks (Bosset etal. 2003; Crehange etal. 2006), allowing the overall treatment
time to be within 65 days. This practice also allows two doses of mitomycin to be delivered. However, the use of any planned gap defies standard radiotherapy principles regarding
overall treatment time, breaks in treatment and the concept of repopulation.
42 months
110
291
644
EORTC 22861
(Bartelink etal.
1997)
RTOG 87-04/
ECOG (Flam etal.
1996)
RTOG 98-11
(Ajani etal. 2008)
2.51 years
42 months
585
ACT 1 (UKCCCR
Anal Cancer
Working Party
1996)
CRT with MMC

vs. NACT and
CRT with cisplatin
CRTMMC
9Gy salvage CRT
for biopsy proven
residual post CRT
RT vs. CRT
RT vs. CRT
Table14.2 Designs of randomised phase III trials in anal cancer

Trial
No.
Median FU Randomisation
5-FU 1,000
mg/m2 D14,
2932
Cisplatin 75mg/
m2 D1 and 29
No
No
No
NACT
No
M Chemo
4559Gy
5-FU 1,000mg/m2 D14, 2932
MMC 10mg/m2 D1 and 29
Or
5-FU 1,000mg/m2 D5760,
8588
Cisplatin 75mg/m2 D57and 85
5-FU 1,000mg/m
D14, 2932
MMC 10mg/m2 D1 and 29

If residual disease
9Gy boost/5-FU/cisplatin
100mg/m2
4550.4Gy
No
No
45Gy/25F
No
5-FU 750mg/m2
D15, 2933
MMC 15mg/m2 D1
6 week gap 15Gy (CR) or 20Gy
boost (PR)
45Gy/2025F5-FU 1,000
mg/m2 D14, 2932
MMC 10mg/m2 D1
CRT schedule
OS
DFS
DFS
Local control
Colostomy
free survival
Local failure
(disease or
complications
of treatment)
Primary
endpoint
434
940
ACT II (James
etal. 2009)
36 months
43 months
22 factorial CRT
cisplatin and
maintenance CT
cisplatin
No
50.4Gy/28F
5-FU 1,000mg/m2 D14, 2932
MMC 12mg/m2 D1
Or
5-FU 1,000mg/m2 D14, 2932
Cisplatin 60mg/m2 D1 and 29
5-FU 800mg/m2/ 45Gy/25F

day
5-FU 800mg/m2 D14, 2932
NACT and CRT
D14, 2932
Or
(5-FU/Cisplatin)
5-FU 800mg/m2 D5760, 8588
HDRT
Cisplatin 80mg/m2 D57 and85
15Gy boost
22 Factorial
DFS
OS
5-FU 1,000
mg/m2 D14
Cisplatin 60
mg/m2 D1
Every 3 weeks
Colostomyfree survival
OS
DFS
Two cycles
No
Anal cancer phase III trials. CRT chemoradiation; RT radiotherapy; NACT neoadjuvant chemotherapy; MMC mitomycin C; HDRT high dose radiotherapy; NR
not reported; M Chemo maintenance chemotherapy
307
ACCORD 03
(Conroy etal.
2009)
14 Anal Cancer
435
436
14.20
T1/T2 Tumours
14.21
The Use of Radiation Alone
For small tumours, some investigators have used high dose EBRT alone, followed by a small
volume boost with either photons or electrons, or interstitial implantation. In addition, interstitial implantation has been advocated as a sole modality (Papillon and Montbaron 1987;
Newman etal. 1992). Scandinavian retrospective series (Glimelius and Pahlman 1987) have
also described the use of high doses in the region of 60Gy EBRT with results that compare
favourably in terms of local control with the randomised trials of chemoradiotherapy.
High rates of local control after radiotherapy alone have been observed in a retrospective series from the Institut Gustave Roussy (91% for T1/T2 tumours). Salmon and colleagues (Salmon etal. 1984) found that tumour size was significantly related to survival,
in which radiation therapy alone was the primary treatment. In addition, in a study from
San Francisco, node-negative patients with T1/T2 tumours had a five-year survival rate of
92%. For this reason, it has been suggested that small volume T1 and early T2 tumours
(<4cm) can be treated with radiation alone to achieve a high cure rate. Nevertheless, the
20% long-term complication rate in the series treated with radiotherapy alone from San
Francisco (Doggett etal. 1988) raises a note of caution. Although EBRT alone without
chemotherapy is an acceptable alternative (Martenson and Lipsitz 1995), randomised trials
have shown that chemoradiation is more effective even for T1 cancers (UKCCCR Anal
Cancer Working Party, 1996; Northover etal. 1997).
Initial data from Nigro (Nigro etal. 1983; Vaitkevicius etal. 1974) prompted Papillon
(1990) to use chemoradiation rather than radiation alone, and local control for T3 tumours
improved from 70% with radiotherapy alone to 90% with chemoradiation. Nigro showed
that tumours under 5cm in size could usually be controlled with 30Gy in combination
with chemotherapy. It is entirely possible that 4550Gy in combination with 5-FU/mitomycin is sufficient for local control of a large proportion of anal cancers, particularly those
with stage T1 and T2. However, it remains unclear whether, in such early tumours, the
optimal dose for RT alone is 4550Gy or 6065Gy. Most of the studies using RT alone
used a tolerance dose of 6065Gy. It might be expected that late morbidity would be more
common and more pronounced with a higher radiation dose.
Cummings also noted an improvement in local control for T2T4 tumours but not for
T1 cancers (Cummings etal. 1991). In contrast, the UKCCR Anal Cancer Trial (ACT 1)
demonstrates that even T1/T2 lesions appear to obtain the benefit from the addition of
chemotherapy (UKCCCR Anal Cancer Working Party, 1996; Northover etal. 1997).
The randomised trials confirm that more than 75% of patients will suffer at least one
grade 3 or higher toxicity during modern chemoradiotherapy regimens. There is an exacerbation of acute toxicity with chemoradiation compared to radiation alone, but there is no
clear increase in late effects, although accurate information on quality of life (QOL) and
14 Anal Cancer
437
late morbidity from these studies is sparse. In the Accord-03 study, assessment two months
after completion of treatment did not show that induction chemotherapy and high-dose
radiotherapy either alone or in combination had any negative impact on QOL (TournierRangeard etal. 2008).
Approximately 10% of patients suffer severe long-term toxicity after chemoradiation, and
5% require a subsequent colostomy for treatment-related problems (chronic diarrhoea,
incontinence of faeces, pain on defecation and anorectal stenosis) rather than tumour recurrence (Ajani etal. 2008). Therefore it would seem logical to use chemoradiation even if there
is only a small benefit in local control for small tumours by the addition of chemotherapy.
Some studies have demonstrated a low risk of relapse in the inguinal region even for
higher-stage lesions (Newman etal. 1992; Ferrigno etal. 2005), and many Europeans have
a conservative approach to treating the inguinal region. The inguinal lymph node region is
included in the fields only when the primary tumour is located in the canal <1cm from the
anal orifice, or if there is actual invasion of the anal orifice, or in case of clinical involvement of pelvic lymph nodes (on CT or MRI criteria). Some suggest that a conservative
approach, avoiding elective groin irradiation, might be possible for all T1 and T2 tumours,
but most authors still advocate formal groin irradiation for more advanced tumours (Das
etal. 2007). A recent study (TROG 99-02) closed early because of an unacceptable rate of
inguinal node relapse (Matthews 2005).
14.22
The Boost
If required, a radiotherapy boost can be delivered by interstitial Iridium-192 implant to a
dose of 20Gy at a dose rate of 10Gy per day according to the techniques of Papillon and
Montbarbon (1987), delivering a dose to the 85 % reference isodose of the Paris system.
A crescent-shaped template can ensure regular spacing of the radioactive sources, and is
advocated in many centres. However, the experience and skills required for performing
interstitial implants are not widespread, and the risks of necrosis are not insubstantial.
14.23
Treatment for Late Stage (T3/T4)
Studies have demonstrated that the higher the stage of tumour, the lower the response to
treatment and likelihood of achieving a complete response (Salmon etal. 1984; Touboul
etal. 1994; Gerard etal. 1998; Bartelink etal. 1997; Flam etal. 1996; Constantinou etal.;
1997; Schlienger etal. 1989). Response rates for T3 and T4 tumours have been reported to
be between 45 and 60% (Doci etal. 1996; Peiffert etal. 1997).
For patients with locally advanced disease (stages T2N1, T3 and T4 (which is over 50%
of cases), there is a high risk of recurrence. Patients with >5-cm tumour and N1 status have
only 30% chance of being disease-free at three years (Ajani et al. 2009). The most
438
favourable prognostic subgroup in the RTOG is patients with <5-cm diameter, clinically
node-negative tumours with three- and five-year DFS of 74 and 66%, respectively, and
three and five-year OS of 86 and 80%. The worst prognoses for DFS are for patients with
tumour >5-cm diameter and clinically positive nodal status (approximately 25% of all
patients) with three-year DFS of only 30% and four-year OS of 48%.
A recent retrospective study suggested that doses >50Gy are associated with improved
local control (Ferrigno etal. 2005). Although higher radiation dose appears to improve
outcome in some studies (Constantinou etal. 1997; Rich etal. 1993; Hughes etal. 1989),
it remains unclear if increasing the radiation dose in patients with locally advanced anal
cancer receiving combined modality therapy, will improve the results compared with doses
of 4550Gy (John etal. 1996). Radiotherapy dose escalation to improve local control may
not be the most appropriate strategy with standard planning techniques, because the risk of
late adverse effects is related to the total radiotherapy dose (Allal etal. 1997). However,
intensity modulated radiotherapy (IMRT) may be more practical.
Most current radiation protocols for T3/T4 tumours use techniques that employ an initial
wide field of radiotherapy, treating the whole of the lower pelvis and including the inguinal
lymph nodes and the posterior pelvic lymph nodes in continuity with the primary cancer.
Subsequent field reductions aim to encompass the primary treatment plus a margin.
14.24
Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy (NACT) has been associated with high response rates in chemotherapy nave anal cancer (Gerard etal. 1998). However, despite this very high response rate,
the addition of NACT prior to chemoradiation has not improved either local regional or
distant control (Ajani etal. 2008; Conroy etal. 2009). The Intergroup RTOG 98-11 accrued
a total of 682 patients between 1998 and 2005. Randomisation was between the standard
arm of concurrent chemoradiation with 5-FU and mitomycin, and the novel arm of neoadjuvant 5-FU and cisplatin for two cycles prior to chemoradiation with concurrent 5-FU and
cisplatin. NACT with cisplatin followed by 5-FU/cisplatin-based chemoradiation failed to
improve OS, DFS, loco-regional control and distant relapse when compared to the standard
of concurrent 5-FU with mitomycin chemoradiation. In fact, trends favoured the control arm
of mitomycin. The cumulative rate of the requirement for a colostomy was significantly
higher for the cisplatin arm compared to the standard of mitomycin (19 vs. 10%; p=0.02).
In a further recent phase 3 study, the Intergroup/ACCORD 03 trial, patients were randomised in a 22 factorial manner to moderate dose vs. high dose RT, and induction chemotherapy with 5-FU/cisplatin prior to CRT (Conroy etal. 2009). The aim of the study was
to assess the benefit on the colostomy-free survival of two cycles of induction chemotherapy and an increase of the dose of irradiation delivered to the primary, from 60 to 6570Gy.
Interim analysis suggested that this study would be underpowered to show a significant
difference for NACT. More recent updated results after a mean follow-up of three years
showed an 88% local control rate but did not show any benefit of the RT dose intensification group or NACT compared to standard treatment (Conroy et al. 2009). In fact,
14 Anal Cancer
439
three-year actuarial local control was equivalent in the NACT and the standard arm 88
and 90% respectively.
14.25
Consolidation Chemotherapy
It has been argued that OS will only improve if there are both improvements in local
regional control from chemoradiation and more effective systemic chemotherapy, which
can decrease the risk of distant metastases. To date neither cisplatin in the chemoradiotherapy phase nor 5-FU and cisplatin in the maintenance or consolidation phase has been
shown to improve outcome (James etal. 2009).
The co-operation of additional effective drugs should be investigated in both the chemoradiotherapy and consolidation settings. Various groups are attempting to integrate capecitabine (Glynne-Jones etal. 2008), oxaliplatin (Eng etal. 2009) or cetuximab (RTOG). We
have also not yet begun to identify molecular predictive and prognostic factors, and the
new targeted therapies have yet to be integrated.
14.26
Biological Agents
Biological therapy could be integrated into the chemoradiation component, or as a consolidation manoeuvre following the completion of chemoradiation, at a point when the cancer
appears to express high levels of both vascular endothelial growth factor and epidermal
growth factor. There are no data on the efficacy of biologicals combined with chemoradiation
although several trials are currently in progress (RTOG Trials). A phase I study from Brazil
reported efficacy and safety at ASCO 2008 in 10 patients with cetuximab added to CRT
(Olivatto etal. 2008). Anal cancers commonly over-express epidermal growth factor receptor
(EGFR) (Le etal. 2005; Van Damme etal. 2008). In addition, radiation itself induces EGFR
activation, which contributes, at least in part, to the mechanism of accelerated proliferation,
and which can be expected to increase the capacity for DNA damage repair. Over-expression
of EGFR has been linked to radio-resistance (Miyaguchi etal. 1991); hence, one of the most
promising recent additional avenues of treatment has been to target the EGFR pathway.
14.27
Radiotherapy Technique and Treatment Fields
There are significant differences in approach to radiotherapy fields and techniques within
Europe, but in general, treatment should aim to encompass the primary tumour and any
sites of nodal involvement within the high-dose volume.
440
The inguinal nodes are usually included in the radiation fields in the majority of
cases, even in the absence of clearly demonstrable involvement. The incidence of nodal
involvement increases with increasing primary tumour size and is at least 20% in patients
with T3 disease. Some clinicians may decide to treat clinically uninvolved inguinal
nodes only in certain circumstances (e.g. T34 primary disease, location of primary
tumour within the canal, 1cm from the anal orifice, or if there is involvement of pelvic
lymph nodes (on CT or MRI criteria). The results of the ACT II trial should clarify the
optimum strategy.
14.28
Post-Operative Adjuvant Treatment
Post-operative chemoradiation should be considered in patients in whom completeness of
excision cannot be guaranteed, when the resection margin is involved or in the case of narrow margins. Some authors argue that smaller fields can be treated, and the total dose can
be lowered to 30Gy for microscopic disease (Hu etal. 1999; Hatfield etal. 2008).
Some patients may undergo initial abdominoperineal excision as definitive treatment of
their anal cancer. This sometimes results from a small poorly differentiated biopsy, which
is not recognised as squamous histology, and treated as a low rectal cancer. Post-operative
chemoradiation should be considered when there is evidence of involvement of the circumferential resection margin (deep or lateral resection margins 1 mm), or numerous
involved mesorectal lymph nodes.
14.29
Toxicity and Supportive Care During Radiotherapy
CRT (particularly if Mitomycin C is used) is associated with high risks of G3 and G4 haematological toxicity (Ajani et al. 2008). The EORTC trial had no toxic deaths. In the
UKCCR ACT I trial there were six treatment-related deaths in the first 116 patients; after
amending the protocol to provide antibiotic cover during treatment, there were no more
septicaemic deaths. In the RTOG study 20% of patients experienced G4/G5 toxicity with
5-FU MMC vs. 7% of those on 5-FU alone. There were four (3%) treatment-related deaths
in the MMC arm. In the recent ACT II trial all patients were given prophylactic antibiotic
cover during CRT.
Tolerance to treatment can be maximised with the use of simple anti-emetics, analgesia,
skin care, advice regarding nutrition and psychological support. Expected acute side effects
include diarrhoea, proctitis, urinary frequency and dysuria, loss of pubic hair and erythema, lymphoedema and moist desquamation of the skin in the groins and perineum. Skin
effects rapidly disappear within 23 weeks after treatment is completed. The use of vaginal
dilators in sexually active females is recommended.
14 Anal Cancer
441
14.30
Patterns of Relapse
Recognition of the patterns of loco-regional failure after definitive chemoradiation is a
crucial aspect in the management of anal cancer. Cancer can recur either at the primary
tumour site, in the regional lymph nodes or very occasionally, at distant sites such as liver
and lung (Boman etal. 1984; Kuehn etal. 1968). Patients tend to relapse in the local region
rather than at distant sites, although loco-regional failure is quite commonly followed by
distant failure.
In the UKCCCR ACT I trial only 21 of 285 patients (7%) treated with chemoradiation
developed metastatic disease outside the pelvis in the absence of evidence of pelvic
recurrence (UKCCCR Anal Cancer Working Party 1996). Long-term follow-up of this
study, with a median follow-up of 11.5 and 13.5 years in the RT and CMT groups respectively, shows that 239 of 560 patients had a local relapse (153 radiotherapy, 86 CMT).
Only four of these patients had a distant relapse before their first recorded local relapse
(James etal. 2009).
14.31
Chemoradiotherapy Salvage
Salvage chemoradiotherapy using cisplatin and radiation to a dose of 9 Gy has been
reported to salvage up to 50% of patients not responding to the first phase of chemoradiation (Flam etal. 1996), although others have not proved this strategy so successful (Longo
etal. 1994). Slow or late response could also play a part in these favourable results.
14.32
Surgical Salvage
Patients who have persistent or progressive disease following chemoradiation or local
recurrence should be considered for surgical salvage with an abdomino-perineal resection.
However, biopsy and restaging for metastatic disease is recommended first. Outcomes
from surgical salvage are variable with five-year survival rates ranging from 24 to 64%
(Longo etal. 1994; Zelnick etal. 1992; Pocard etal. 1998; Smith etal. 2001; Renehan
etal. 2005). Close follow-up of patients after completion of chemoradiation and a proactive approach to salvage surgery appears more successful (Renehan et al. 2005).
Achievement of negative resection margins appears crucial to subsequent outcome
(Sunesen etal. 2009). Persistent or progressive disease in the inguinal lymph nodes should
be considered for radical groin dissection.
442
14.33
Treatment of Recurrent and/or Metastatic Anal Cancer
Fit patients with metastatic or recurrent disease not amenable to surgery should receive
chemotherapy usually with a combination of cisplatin and 5-FU, which offers approximately a 50% response rate. Responses are rarely complete and usually of short duration.
In these circumstances, therapy is aimed at palliation.
14.34
Late Sequelae
Long-term morbidity includes ulceration of the anal/rectal area, necrosis, small bowel
obstruction, uretheral obstruction and fistula formation. Pelvic and hip fractures are also
more common (Baxter etal. 2005). All such late effects should be carefully documented.
No differences in late toxicity were observed between radiotherapy and chemoradiation in
the EORTC and UKCCR trials. However, no formal assessments of QOL have been performed on patients within the randomised trials.
14.35
Follow-Up and Surveillance
Follow-up relies on DRE and palpation of the inguinal lymph nodes. MRI can complement clinical assessment. Patients should be evaluated clinically between 8 and 12
weeks following the completion of chemoradiation. Evidence of major residual tumour
or progression should be considered for biopsy. Patients in complete remission at eight
weeks should be evaluated every 36 months for a period of two years, and 612
monthly until five years. Patients tend to relapse loco-regionally rather than at distant
sites, and given that distant relapse are uncommon without relapse at the primary site,
the scheduling of regular CT scans for metastatic surveillance outside trials remains
controversial.
The level of tumour regression (>80%) after primary chemoradiation may be predictive of colostomy-free and disease-free survival Chapet et al. 2005). Early studies
assessed with biopsy at 68 weeks, and positive biopsy findings led to an APER
(Martenson and Lipsitz 1995). Some prospective studies have examined clinical response
at four weeks (Glynne-Jones etal. 2008) and six weeks following completion of CRT
(UKCCCR Anal Cancer Working Party 1996). Complete clinical response at two months
predicted DFS (Gerard etal. 1998; Derniaud-Alexandre etal. 2003). Hence response by
RECIST criteria at 68 weeks has been suggested to be a highly relevant endpoint, which
allows phase II trials to explore novel treatments and chemoradiation combinations.
14 Anal Cancer
443
Therecent national UK trial (ACT II) has collected additional data on clinical response
at 18 and 26 weeks.
Other authors suggest that cell death from radiotherapy can continue up to 12 weeks
following the completion of CRT (Cummings etal. 1991), suggesting that salvage surgery
should present an option only after 12 weeks. Hence, most authors recommend that patients
should be evaluated clinically between 8 and 12 weeks following the completion of chemoradiation. The skin reaction should have settled by this time, and failure to achieve complete response, major residual tumour or progression on digital rectal examination, should
be considered for biopsy (Tanum etal. 1993). It may take 36 months for complete resolution to occur, and during this period ulceration can cause concerns (Schlienger etal. 1989;
Borzomati etal. 2005).
14.36
Conclusions
In anal cancer, a multidisciplinary approach is essential with close co-operation and communication required between surgeon, radiologist, medical oncologist, radiation oncologist, pathologist and nursing specialists. The results of five randomised phase III trials in
anal cancer confirm that the paradigm of external beam radiation therapy with concurrent
5-FU and mitomycin remains the standard of care.
The endpoint of colostomy-free survival is probably the best measure of the success of
chemoradiation in preserving the anal sphincter in anal cancer. However, we need much
more data regarding severe complication rates and proportion of patients who maintain a
functioning anus.
As anal cancer is a rare tumour, it is in the interest of all patients to be offered participation in a clinical trial. National and international trials in this disease site are ongoing
throughout Europe.
14.37
Guidelines
Engstrom PF, Amoletti JP, Benson AB, et al., NCCN Practice Guidelines: Anal Cancer Version
2. 2009 (08/19/09). Available at www.nccn.org/professionals/physician (last accessed
September 27 2009)
Guidelines for the management of Colorectal cancer issued by the Association of Colopro
ctology of Great Britain and Ireland; 3rd Edition 2007.
Fleshner PR, Chalasani S, Chang GJ et al., Practice parameters for anal squamous neoplasms.
Dis Colon Rectum 2008;51:29.
Glynne-Jones R, Northover J, Oliveira J. ESMO Guidelines Working Group. Anal cancer:
ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;
20(4):5760.
444
14.38
Reviews
Poggi MM, Suh WW, Saltz L et al (2007) ACR Appropriateness Criteria on treatment of anal
cancer. J Am Coll Radiol 4:448456
Uronis HE, Bendell JC (2007) Anal cancer: an overview. The Oncologist 12(5):524534
Das P, Crane C, Ajani J (2007) Current treatment of localized anal carcinoma. Curr Opin Oncol
19:396400
Fleshner PR, Chalasani S, Chang GJ et al (2008) Practice parameters for anal squamous neoplasms. Dis Colon Rectum 51:29
Czito BG, Willett CG (2009) Current management of anal canal cancer. Curr Oncol Rep
11(3):186192
Buchs NC, Allal AS, Morel P, Gervaz P (2009) Prevention, chemoradiation and surgery for anal
cancer. Expert Rev Anticancer Ther 9(4):483489
Eng C, Pathak P (2008) Treatment options in metatstatic squamous cell carcinoma of the anal
canal. Curr treat Options Oncol 9 (46):400407
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Index
A
Abdominoperineal resection (APR), 396
Abdominothoracic esophagectomy, 76
Adenocarcinoma
classification and pathology, 71
etiologic factors, 6970
glandular dysplasia, 71
Siewerts classification, 73
Adenomatous polyposis coli (APC), 329
Adjuvant therapy
borderline resectable pancreatic
adenocarcinoma
CONKO-001, 189
EORTC, 188
ESPAC-3 trial, 189
multi-institutional phase II study, 191
prospective and retrospective series,
185187
RTOG 97-04, 189190
colon cancer, 348349
gastrointestinal stromal tumors, 162163
Alpha-fetoprotein (AFP)
CT, 229
liver biopsy, 229
MRI, 229
ultrasound, 228
American Joint Committee on Cancer (AJCC)
colorectal cancer, 390391
gallbladder cancer, 255, 256
gastric cancer, 106108
American Society of Clinical Oncology
(ASCO), 209
Anal cancer
aetiology and risk factors, 425
anatomy, 426
biological
agents, 439
markers, 430431
boost response, 437
chemoradiation, 443
clinical presentation, 427
consolidation chemotherapy, 439
histological types, 426
history, 423424
HIV testing, 429
lymphatic drainage, 427
non-surgical treatment
mitomycin C (MMC), 432
phase III trials, 433435
radiotherapy, 433
pathology, 425
predictive factors, 429
pre-treatment, 428
prognostic factors, 430
radiation therapy, 436437
radiological staging, 428429
recurrent/metastatic, 442
relapse, patterns, 441
salvage chemoradiotherapy, 441
sequelae, 442
staging and risk assessment, 427428
surgery, 432
surgical salvage, 441
surveillance, 442443
toxicity and supportive care, 440
treatment
late stage (T3/T4), 437438
post-operative adjuvant, 440
radiotherapy, 439440
tumour
grade, 426
markers, 431432
APC. See Adenomatous polyposis coli
B
Barium enema, 332
Barretts esophagus, 21, 22
Best supportive care (BSC), 126128
451
452
Biliary tract carcinoma
extrahepatic bile duct cancer
diagnosis, 263264
epidemiology, 262
pathology, 263
risk factors, 262
staging, 264266
surgical resection, 265268
gallbladder cancer
diagnosis, 254255
epidemiology, 252
pathology, 253254
risk factors, 252
staging, 255, 256
intrahepatic cholangiocarcinoma
diagnosis, 273274
epidemiology, 272
pathology, 272273
risk factors, 272
staging, 274276
systemic therapy
adjuvant, 283284
metastatic disease, 277283
Borderline resectable pancreatic
adenocarcinoma
adjuvant therapy
CONKO-001, 189
EORTC, 188
ESPAC-3 trial, 189
multi-institutional phase II study, 191
prospective and retrospective series,
185187
RTOG 97-04, 189190
clinical staging and preoperative
management
CA 19-9, 177
coronal image, 176
cross-sectional and sagittal images, 175
endoluminal ultrasonography, 177
positron emission tomography,
176177
surgery and neoadjuvant strategies, 175
neoadjuvant therapy
MD Anderson Cancer Center, 192, 193
median survival, 192
radiation schema, 193
resectable strategies, 194196
surgical management
pancreatic reconstruction, 182183
Index
regional lymphadenectomy, 179, 180
standard gastrectomy vs. pyloricpreserving Whipple operation,
181182
surgical morbidity and mortality,
183184
vascular resection, 179181
C
Cancer and leukemia group B
(CALGB), 346
Carcinoid heart disease (CHD), 313
Celiac plexus neurolysis (CPN), 32
CGH. See Comparative genomic hybridization
Chemoradiotherapy
esophageal cancer
perioperative treatment, 8586
treatment protocols, 8788
locally advanced pancreatic cancer
vs. chemotherapy, 209
Eastern Cooperative Oncology Group,
208
radiotherapy protocols, 207
Chemotherapy
adjuvant, 408409
biliary cancers
ABC-001 survival curve, 282
ABC-02 trial, 281
GEMOX, 282
National Cancer Institute of Canada,
280
nucleoside analog gemcitabine, 280
randomized trials, 279
EORTC 22921, 407408
esophageal cancer
chemoradiation vs. surgery, 90
metastatic disease treatment, 9092
perioperative treatment, 85
randomized studies, 89
treatment protocols, 87
gastric cancer
vs. best supportive care, 126128
single-agent, 121
GTX, 195
American Society of Clinical Oncology,
209
vs. chemoradiotherapy, 209
gastrointestinal tumor study group, 208
radiation, 206
metastatic pancreatic cancer, 212214
modality program, 409411
Cholangiocarcinoma
hilar malignant biliary obstruction, 37
453
Index
intrahepatic (see Intrahepatic
cholangiocarcinoma)
Chromogranin A (CGA), 306
Chromosomal instability (CIN), 45, 326
Circumferential resection margin (CRM), 392
Colon cancer
adjuvant therapy, 348349
chemotherapy-refractory disease,
362364
5-FU
monotherapy, 345346
oxaliplatin, 346
laparoscopic surgery, 343
liver-limited metastatic
chemotherapy, 354
clinical risk, 351, 352
diagnosis, 351
incidence, 352, 353
outcome, 353, 354
prognostic factor, 355
propensity, 350
radiofrequency ablation, 353
lymphadenectomy
biology, 341
mesenteric excision, 342
stage migration, 340
surgical technique, 343
lymphatic drainage, 339, 340
malignant polyps
classification, 338
definition, 337
endoscopic removal, 338
invasive adenocarcinoma, 336, 338
metastasis, 349350
negative trials, 346347
pathology
biomarkers, 327
classification, 326
prognosis, 326327
suppressor, mutator pathway, 326
radiotherapy considerations, 343344
risk factors
acquired, 329330
inflammatory bowel disease, 329
inherited predisposition, 327329
screening
barium enema, 332
colonoscopy, 334
conventional principles, 331
CT colonography, 332333
current guidelines, 334336
fecal immunochemistry tests, 332
fecal occult blood test, 331
flexible sigmoidoscopy, 333
staging
classification, 336, 337
diagnostic evaluation, 334
stage II considerations, 347348
stereotactic body radiotherapy,
356357
surgical procedures
arterial blood supply, 339, 341
proctocolectomy, 340
segment resection, 339
standard surgical resection, 339, 342
Colorectal carcinoma
molecular pathways
chromosomal instability, 45
microsatellite instability, 4549
potential molecular markers, 44
Combined modality program
adjuvant chemotherapy, 411
angiogenesis, 413
CRT and VEGF inhibition, 413, 414
EGFR, 411
phase III trials, 409, 410
preoperative CRT, 411, 412
Comparative genomic hybridization (CGH),
304
Computed tomography colonography (CTC),
23, 331
CpG Island methylator phenotype
(CIMP), 327
D
Digital rectal examination (DRE), 428
Discovered On GIST-1 (DOG-1), 145146
Disease free survival (DFS), 430
Distal esophagectomy, 79
Double contrast barium enema (DCBE), 331
Doxorubicin, 124
Dynamic contrast-enhanced Doppler
ultrasound (DCE-US), 160
E
Eastern Cooperative Oncology Group
(ECOG), 208
Electron microscopy, 146147
EMR. See Endoscopic mucosal resection
Endoluminal ultrasonography (EUS), 177
Endorectal ultrasound (ERUS), 383
Endoscopic mucosal resection (EMR)
Barretts esophagus, 21, 22
colorectum, 24
duodenal adenoma, 23
HGD/IMC, 21
histological staging, 22
454
indications, 78
neoplastic duodenal lesion, 23
tubulo-villous adenoma, rectum, 2324
Endoscopic retrograde cholangiopancre
atography (ERCP), 177
Endoscopic submucosal dissection (ESD)
endoscopic resection margins, 24, 25
endoscopy, surveillance, 24, 26
intramucosal gastric cancer, pylorus, 24, 25
pylorus preservation, 24, 25
Endoscopic therapy, 7879
Endoscopic ultrasound (EUS)
celiac plexus blockade, 32
colorectal carcinoma, 31
esophageal neoplasms, 3031
EUS-guided fine-needle injection, 33
gastric cancer, 30
hepatobiliary neoplasms, 29
lung malignancy, 31
pancreatic adenocarcinoma, 2627
pancreatic cystic lesions, 2728
pancreatico-biliary access/drainage, 32, 33
submucosal gastrointestinal lesions, 29, 30
Epidermal growth factor receptor (EGFR), 411
ERCP. See Endoscopic retrograde
cholangiopancreatography
ESD. See Endoscopic submucosal dissection
Esophageal cancer
chemoradiotherapy
chemoradiation vs. surgery, 90
randomized studies, 89
classification and pathology
adenocarcinoma, 71
differential pathologic diagnosis, 71
distant metastases, 72
lymphatic spread, 72
precancerous lesions, 71
Siewerts classification, 73
specific histotypes, 7172
squamous cell carcinoma, 70
UICC TNM classification system,
73, 74
clinical diagnostics, 7576
endoscopic therapy, 7879
epidemiology, 6768
etiologic factors
adenocarcinoma, 6970
squamous cell cancer, 6869
indications and selection, 78
metastatic disease
chemotherapy, 9092
local treatment, 9293
monitoring, FDG-PET, 911
perioperative treatment
Index
neoadjuvant chemoradiation, 8586
neoadjuvant chemotherapy, 85
neoadjuvant radiation, 84
protocols, 8788
quality of life, 8687
response evaluation and response
prediction, 8889
preoperative risk assessment, 7677
staging GI cancers, 5
surgical therapy
cervical esophagus, 79, 81
distal esophagectomy, 79, 80
high intrathoracic anastomosis, 82
long-term surgical outcome, 8384
perioperative morbidity and mortality,
8283
transhiatal/cervical esophagectomy, 79
transthoracic en-bloc esophagectomy,
79, 80
symptoms, 73, 75
European Organization for Research and
Treatment of Cancer (EORTC),
188, 268
European Study Group for Pancreatic Cancer
(ESPAC-1), 188
EUS. See Endoluminal ultrasonography
EUS-guided fine-needle injection
(EUS-FNI), 33
Examination under anaesthetic (EUA), 428
External beam radiotherapy (EBRT), 343, 433
Extrahepatic bile duct cancer
diagnosis, 263264
epidemiology, 262
pathology, 263
radiation therapy
adjuvant, 268269
neoadjuvant, 269270
unresectable cholangiocarcinoma,
270271
risk factors, 262
staging
AJCC 6th edition, 265
Bismuth-Corlette classification system,
264
clinical T-stage criteria, 266
surgical resection
future remnant liver, 267
percutaneous transhepatic
cholangiography, 267
F
Familial adenomatous polyposis (FAP),
328, 380
Fecal immunochemistry tests (FIT), 331
Index
Fecal occult blood testing (FOBT), 331
Flexible sigmoidoscopy, 333
Fluordeoxyglucose-positron emission
tomography (FDG-PET), 88, 89
Future remnant liver (FRL), 267
G
Gallbladder cancer
diagnosis, 254255
epidemiology, 252
pathology, 253254
radiation therapy
adjuvant, 260261
unresectable, 261262
risk factors, 252
staging, 255, 256
surgical resection
incidental management, 259260
laparoscopic cholecystectomy, 259
T1 and T2 lesions, 258
Gastric cancer
diagnosis and workup, 105106
environmental risks and prevention,
103105
epidemiology, 101102
etiology, 102103
radiotherapy
local unresectable/postoperative
residual local disease, 116117
palliative, 113114
patterns of failure, 114115
postoperative adjuvant radiation,
115116
preoperative, 119120
radiochemotherapy, 117
staging, 106108
surgical treatment
D-level trials, 109111
endoscopic mucosal resection, 108109
low Maruyama Index, 111113
lymphadenectomy, 109111
subtotal vs. total gastrectomy and
margins, 108
systemic therapy
best supportive care, 126128
cisplatin-based combinations,
124125
combination chemotherapy, 121123
doxorubicin, 124
epirubicin-based combinations, 126
5-fluorouracil, 124
INT0116 study, 130
irinotecan-based therapy, 125126
455
leucovorin, 124
MAGIC study, 130
methotrexate, 124
mitomycin regimens, 124
monoclonal antibodies, 128
nitrosourea combinations, 122123
single-agent chemotherapy, 121
symptom management, 130
targeted therapy, 128
taxane-based regimen, 125
tyrosine kinase inhibitors, 128
Gastroesophageal reflux disease (GERD),
102103
Gastrointestinal (GI) cancer
allelic imbalance, 18q, 51
doublet therapy, 8
KRAS, 4951
molecular abnormalities, 51
molecular bases, 4344
molecular testing, 5152
monitoring, FDG-PET
colorectal cancer, 10, 12
esophageal cancer, 911
GISTs (see Gastrointestinal stromal
tumor)
RECIST (see Response evaluation criteria
in solid tumors)
screening
colon cancer, 23
diagnosis and staging, 3
endoscopic procedure, 1
PET imaging, 35
PET, staging, 58
surveillance, curative resection, 1314
Gastrointestinal stromal tumor (GIST)
behavior and prognosis
patterns of metastasis, 149
prediction of behavior, 149150
clinical management
borderline resectable disease, 153
recurrence, 153154
resectable primary, 152153
diagnosis and staging
investigations, 151152
electron microscopy, 146147
epidemiology
demographics, 139140
familial, 141
pediatric, 140
syndromic, 141
everolimus, 165166
FDG-PET/CT imaging, 160, 161
456
gross pathology, 142
imatinib resistance
sunitinib, 57
kinase genotype and imatinib mesylate,
5657
light microscopy
immunohistochemistry, 143146
markers, 146
morphology, 142145
medical management
chemotherapy, 154
imatinib mesylate, 154159
sunitinib, 159160
metabolic activity, 12
molecular biology and mutational analysis
BRaf V600E, 148
IGF-1, 148
KIT, 147
PDGFR, 148
molecular classification
biological and clinical implications,
54, 55
familial, 55
pediatric, 5556
type I neurofibromatosis, 56
motesanib diphosphate, 166
neoadjuvant therapy, 163164
nilotinib, 164
oncogenic kinase mutations, 5354
pathology, 5253
recommendations, 58
retaspimycin hydrochloride, 165
sorafenib, 165
submucosal gastrointestinal lesions, 29, 30
GIST. See Gastrointestinal stromal tumor
Glandular dysplasia, 71
Groupe Cooperateur Multidisciplinaire en
Oncologie (GERCOR), 210
H
Health-related quality of life (HRQL), 8687
Hepatic artery chemoembolization (HACE),
317318
Hepatic artery infusion (HAI), 355
Hepatocellular carcinoma (HCC)
CYP3A4, 227
diagnosis, 228
FDG-PET, 78
growth factors, 242243
incidence, 225226
staging and prognostic systems, 230234
Index
treatment, 234, 235
Hereditary diffuse gastric cancer
(HDGC), 104
Hereditary nonpolyposis colorectal cancer
(HNPCC), 380
High-grade dysplasia (HGD), 21
Human papilloma virus (HPV), 425
5-Hydroxyindoleacetic acid (5-HIAA), 306
I
Ileocolonic stent placemen, 35, 36
Imatinib resistance, 5758
Inflammatory bowel disease, 329
Intensity modulated radiotherapy
(IMRT), 438
International Union Against Cancer (UICC),
255, 256
Intraductal papillary mucinous neoplasm
(IPMN), 28
Intra-epithelial neoplasia (AIN), 425426
Intrahepatic cholangiocarcinoma (ICC)
diagnosis
Ca19-9, 273
PET-based imaging, 274
staging, 274276
epidemiology, 272
pathology, 272273
risk factors, 272
Intramucosal cancer (IMC), 21
Intraoperative electron beam radiotherapy
(IOERT), 343
Intraoperative radiation therapy (IORT), 260
Irinotecan-based therapy, 125126
Islet cell tumors
gastrinomas, 310311
glucagonomas, 311
insulinomas, 310
pancreatic polypeptidomas, 312
somatostatinoma, 311
VIPoma, 311312
K
KRAS mutational analysis, 5051
L
Leucovorin, 124
Light microscopy
immunohistochemistry
CD34, 144145
CD117, 143144
DOG-1, 145146
457
Index
PDGFR, 145
protein kinase C theta, 145
markers, 146
morphology, 142143
Liver cancer
alpha fetoprotein
CT, 229
liver biopsy, 229
MRI, 229
ultrasound, 228
diagnosis and staging, 228
HCC
CYP3A4, 227
growth factors, 242243
staging and prognostic systems,
230234
treatment, 234, 235
liver transplantation, 238239
nonresectional locoregional therapies
percutaneous ethanol injection, 239
transarterial chemoembolization, 240
risk factors, 225226
surgical resection
hepatic resection, 237
model for end-stage liver disease, 236
portal vein embolization, 236
systemic therapy
MAPK, 241
PI3K/Akt/mTOR pathway, 242
SHARP, 241
Locally advanced pancreatic cancer (LAPC)
209
chemoradiotherapy vs. chemotherapy, 209
Eastern Cooperative Oncology
Group, 208
5-FU, 208
gemcitabine, 207
Groupe Cooperateur Multidisciplinaire en
Oncologie, 210
radiation, 206
Radiation Therapy Oncology Group, 208
radiotherapy protocols, 207
Locally advanced rectal cancer
apple core, 397, 398
neoplasm, 396
pathology, 397
TME procedure, 396
Loss of heterozygosity (LOH), 326
Lymphadenectomy
biology, 341
colon cancer
biology, 341
and D-level trials, 109111
low Maruyama Index, 111113
regional, 179, 180
Lynch syndrome, 328
M
Magnetic resonance imaging (MRI), 307
Malignant gastrointestinal obstruction
biliary obstructions, 36, 37
colorectal obstruction, 35, 36
gastro-duodenal obstruction, 35
malignant esophageal obstruction,
3335
Metaidobenzyguanidine (MIBG), 308
Metastatic pancreatic cancer
chemotherapy, 212214
second-line therapy, 217218
targeted therapy
anti-EGFR agents, 214215
AVITA study, 217
CALGB, 217
fluorescent in situ hybridization, 215
smoking status, 216
Methotrexate, 124
Microsatellite instability (MSI)
genetic alterations, 46
guidelines, 47
IHC testing, 49
immunohistochemistry, 48
PCR-based techniques, 4748
pre-symptomatic detection, 47
Mitogen-activated protein kinase
(MAPK), 241
Mitomycin C (MMC), 432
Model for end-stage liver disease
(MELD), 236
Multimodality management
clinical staging, 174178
neoadjuvant therapy, 191196
preoperative management, 174178
surgical management, 178184
Multiple endocrine neoplasia type 1
(MEN1), 303
458
N
National Cancer Institute of Canada
(NCIC), 280
National Comprehensive Cancer Network
(NCCN), 313, 363
Neoadjuvant chemotherapy (NACT),
438439
Neuroendocrine tumor (NET)
advanced treatment
biochemotherapy, 319
biotherapy, 317
chemotherapy, 319
control methods, 319
hepatic artery embolization, 317318
hepatic metastases, 316
peptide receptor radionuclide
therapy, 319
somatostatin analog, 316317
carcinoid
appendiceal, 309
crisis, 313
gastric, 308309
heart disease, 313
rectal, 309310
small intestine, 309
syndrome, 312313
clinical symptom, diagnosis
CT and MRI, 307308
endoscopy, 307
nuclear scintigraphy techniques, 308
octreoscan, 308
PET, 308
test and markers, 306307
islet cell tumors
gastrinomas, 310311
glucagonomas, 311
insulinomas, 310
pancreatic polypeptidomas, 312
somatostatinoma, 311
VIPoma, 311312
medical oncologist, 321
pathogenesis and molecular biology,
303305
pathologic classification, 305306
prognosis, 303
surgical interventions, 314
therapy, 314, 315
Nonresectional locoregional therapies
percutaneous ethanol injection, 239
transarterial chemoembolization, 240
Index
Nonsteroidal anti-inflammatory drugs
(NSAIDs), 331, 381
O
Orthotopic liver transplantation
(OLT), 238
Oxaliplatin, 346
P
Palliative radiotherapy, 113114
Pancreatic adenocarcinoma, 2627
Partial mesorectal excision (PME), 398
Percutaneous ethanol injection (PEI), 239
Percutaneous transhepatic cholangiography
(PTC), 267
Perioperative treatment, esophageal cancer
evaluation and prediction, 8889
neoadjuvant
chemoradiation, 8586
chemotherapy, 85
radiation, 84
protocols, 8788
quality of life, 8687
Platelet-derived growth factor receptor alpha
(PDGFRA), 5354
Portal vein embolization (PVE), 236
Positron emission tomography (PET)
advantage, 386
imaging
accuracy, PET-CT, 5
FDG phosphorylation,
hexokinase, 3, 4
18
F-FDG uptake, 35
malignant tumors, metabolic
measurements, 4
Warburg phenomenon, 3
NETs evaluation, 308
staging GI cancers
colorectal cancer, 6
esophageal cancer, 5
gastric carcinoma, 6
HCC (see Hepatocellular carcinoma)
pancreatic cancer, 7
recurrent rectal cancer, liver lesions,
67
sensitivity and specificity, 6, 7
therapeutic management, 7
Practical correlative science
colorectal carcinoma
chromosomal instability pathway, 45
microsatellite instability pathway,
4549
gastrointestinal cancer
Index
allelic imbalance, 18q, 51
KRAS, 4951
molecular abnormalities, 51
molecular bases, 4344
molecular testing, 5152
GIST
imatinib resistance, 5758
kinase genotype, 5657
molecular classification, 5456
oncogenic kinase mutations, 5354
pathology, 5253
recommendations, 58
Primary sclerosing cholangitis (PSC), 262
Progression-free survival (PFS), 317
Protein kinase C (PKC), 145
Q
Quality of life (QoL), 8687, 436
R
Radiation therapy (RT)
extrahepatic bile duct cancer
adjuvant, 268269
neoadjuvant, 269270
unresectable cholangiocarcinoma,
270271
gallbladder cancer
adjuvant, 260261
unresectable, 261262
gastric cancer
local unresectable/postoperative
residual local disease, 116117
palliative, 113114
patterns of failure, 114115
postoperative adjuvant radiation,
115116
preoperative, 119120
radiochemotherapy, 117
intrahepatic cholangiocarcinoma, 277
Radiation Therapy Oncology Group (RTOG)
trial 97-04, 189190
Radiochemotherapy (RCT), 117
Radiofrequency ablation (RFA), 239
Rectal cancer
anatomy, 387389
apple core, 397, 398
chemotherapy
adjuvant, 408409
combination, 409411
concomitant, 407408
clinical manifestations, 382
CRM, 392
epidemiology, 380
459
etiology, 380381
5-FU-based postoperative CRT, 401404
histopathology, 388
neoadjuvant treatment, 415, 416
neoplasm, 396
optimized surgery, 415
partial mesorectal excision, 398400
partial vs. total mesorectal excision, 399
pathology, 397
PET, 386
postoperative CRT, 401
preoperative radiation, 404405
pretreatment staging
anal manometry, 383
ERUS, 384
MRI scan, 385386
sensitivity and specificity, 384
standard workup, 382, 383
primary prevention, 381
screening, 382
sequence optimization, 405407
surgery
local excision, 394396
standard resection, 396
surgical quality, 393394
targeted agents, 411413
TEM, 394
TME procedure, 396
TNM classification, 389392
total pelvic exenteration, 400
toxicity
side effects, 413
small-bowel obstruction, 415
tumor regression, 394
Relapse-free survival (RFS), 431
Resectable neuroendocrine tumor, 314315
Response evaluation criteria in solid tumors
(RECIST), 8
S
Self-expanding metallic covered/uncovered
stents (SEMS), 3335
Single-agent chemotherapy, 121, 123
Sorafenib Hepatocellular Carcinoma
Assessment Randomized Protocol
(SHARP), 241
Squamous cell carcinoma (SCC)
classification and pathology, 70
etiologic factors, 6869
Standardized uptake value (SUV), 34
Stereotactic body radiotherapy (SBRT),
356357
Superior mesenteric vein (SMV), 174176
460
Surveillance epidemiology and end results
(SEER), 303
Systemic therapy
biliary cancer
adjuvant, 283284
metastatic disease, 277283
targeted therapies, 282283
gastric cancer
chemotherapy vs. best supportive care,
126128
cisplatin-based combinations, 124125
combination chemotherapy, 121123
doxorubicin, 124
epirubicin-based combinations, 126
5-fluorouracil, 124
INT0116 study, 130
irinotecan-based therapy, 125126
leucovorin, 124
MAGIC study, 130
methotrexate, 124
mitomycin regimens, 124
monoclonal antibodies, 128
nitrosourea combinations, 122123
single-agent chemotherapy, 121
symptom management, 130
taxane-based regimen, 125
T
Time to progression (TTP), 358
Total mesorectal excision (TME), 379, 389
Total pelvic exenteration (TPE), 400
Transanal endoscopic microsurgery
(TEM), 394
Index
Transarterial chemoembolization
(TACE), 240
Transhiatal/cervical esophagectomy, 79
Transthoracic en-bloc esophagectomy, 79
Tumor node metastasis (TNM), 336
Tumor regression grading (TRG), 394
U
Unresectable metastatic disease
radiotherapy considerations, 357
systemic therapy
bevacizumab, 360362
cetuximab and panitumumab, 362
description, 358, 359
first and second-line, 358360
phase 3 study, 360, 361
Unresectable pancreatic cancer
209
chemoradiotherapy protocols,
207208
meta-analysis, 209
radiation and chemoradiotherapy, 206
systemic review, 210
metastatic pancreatic cancer
chemotherapy, 212214
second-line therapy, 217218
V
Vascular endothelial growth factor (VEGF),
347, 413

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Gastrointestinal Oncology

Charles D. Blanke Claus Rdel

Gastrointestinal oncology practitioners aim to establish effective prevention and treatment

1 Imaging in Gastrointestinal Cancer.....................................................................

2 Interventional Gastrointestinal Oncology........................................................... 21

11 Neuroendocrine Cancers....................................................................................... 301

Imaging in Gastrointestinal Cancer

Minsig Choi and Anthony F. Shields

M. Choi and A.F. Shields

1 Imaging in Gastrointestinal Cancer

M. Choi and A.F. Shields

1 Imaging in Gastrointestinal Cancer

cancers (http://www.cancerpetregistry.org/indications_facilities.htm) (National Oncology

M. Choi and A.F. Shields

disease in 1520% of patients, consequently changing the management approach to those

1 Imaging in Gastrointestinal Cancer

van Westreenen etal. (2004)

Dassen etal. (2009)

Park etal. (2008)

Wiering etal. (2005)

Wiering etal. (2005)

M. Choi and A.F. Shields

1 Imaging in Gastrointestinal Cancer

M. Choi and A.F. Shields

Weber etal. (2001)

Flammen etal. (2000)

Downey etal. (2003)

Wieder etal. (2004)

Ott etal. (2003)

Lordick etal. (2007)

Table1.2 Treatment response using FDG-PET for gastroesophageal cancer

1 Imaging in Gastrointestinal Cancer

M. Choi and A.F. Shields

Table1.3 Treatment response using FDG-PET for colorectal cancer

Amthauer etal. (2004)

Calvo etal. (2004)

SUV max correlated

Capirci etal. (2004)

DimitrakopoulouStrauss etal. (2003)

SUV not helpful

Guillem etal. (2004)

1 Imaging in Gastrointestinal Cancer

M. Choi and A.F. Shields

1 Imaging in Gastrointestinal Cancer

M. Choi and A.F. Shields

Antoch G, Kanja J, Bauer S, Kuehl H, Renzing-Koehler K, Schuette J, Bockisch A, Debatin JF,

1 Imaging in Gastrointestinal Cancer

Enzinger PC, Mayer RJ (2003) Esophageal cancer. N Engl J Med 349:22412252

M. Choi and A.F. Shields

1 Imaging in Gastrointestinal Cancer

M. Choi and A.F. Shields

Interventional Gastrointestinal Oncology

Jennifer Chennat and Irving Waxman

J. Chennat and I. Waxman

Fig.2.1 Long segment Barretts esophagus with

Fig.2.2 Postendoscopic mucosal resection

2 Interventional Gastrointestinal Oncology

Fig.2.3 Duodenal adenoma

Fig.2.4 Postendoscopic mucosal resection of

J. Chennat and I. Waxman

Fig.2.5 Tubulo-villous adenoma in the

Fig.2.6 Postendoscopic mucosal resection of

2 Interventional Gastrointestinal Oncology