Approach to Chemotherapy and Radiation Therapy

185

AJCC (see Appendix D). Several modifications were included in the recentlyedited AJCC classification. Smooth metastatic nodules in the pericolonic or perirectal
fat are defined as lymph node metastases. Irregularly-contoured metastatic nodules in the
peritu- moral fat are considered vascular invasion. Stage II is subdivided into IIA (T3
lesions) and IIB (T4 lesions) based on the depth of invasion. Stage III disease is
further subdi- vided into IIIA (T1-2N1), IIIB (T3-4N1), or IIIC (TanyN2)
depending on the depth of invasion and the level of involvement of lymph node. The
importance of cooperation among the different medical specialties is emphasized
also by the Joint Committee. Surgeons are encouraged to score the completeness of
the resection as R0 (the complete resection with all margins negative of cancer), R1
(incomplete resection with micro- scopic involvement of a margin), and R2
(incomplete resection with gross residual of cancer).
For stage I colorectal cancer, the cure rate exceeds 90% following surgery
alone. However, once a tumor invades through the bowel wall (stage II), survival at
5 years decreases to 60% to 80%. If the pericolonic or perirectal lymph nodes are
found to be involved with cancer (stage III), 5-year survival falls to 30% to 60%, with
the lower sur- vival associated with an increasing number of lymph node
metastases.3,4 The overall prognosis of patients with distant metastases is poor,
although the survival rate has been improved dramatically in past several years because
of the development of new cytotox- ic chemotherapy agents and novel molecular
oriented agents. The most frequent site of metastasis for colorectal cancer is the liver,
followed by lung and intra-abdominal sites.
Other clinical and pathologic features such as perforation, obstruction, adherence or
invasion of the tumor to other organs, radial (lateral) margin involvement,
lymphatic and vascular invasion, and degree of tumor differentiation may also increase
the risk of recurrence in those patients with localized diseases.5 Elevation of
preoperative CEA level may predict for prognosis, especially in patients with nodepositive disease.6 The change of CEA level is frequently used as a surrogate indicator
of response in patients having chemotherapy for their metastatic diseases. The
elevation of CEA may be an early warn- ing sign of recurrence and/or metastasis of
the disease in those patients with localized colorectal cancer with or without adjuvant
therapy. A number of biological and molec- ular characteristics (such as mutations of
p53 and p21, K-ras mutation, chromosome
18q loss of heterozygosity [LOH], MSI-related germline mismatch repair gene mutations, and high expression of thymidylate synthase [TS]) have been identified that may
be of prognostic importance,7-10 although none has yet been validated in
prospective clinical trials.

TREATMENT

OF

PATIENTS WITH METASTATIC DISEASES

The chemotherapy of metastatic colorectal cancer has greatly advanced in the past
several years because of the development of new cytotoxic and novel molecularoriented agents. The paradigm of treatment has changed. Physicians should encourage
all suitable patients to enter clinical studies for understanding the disease better,
improving the treatment further, and achieving potentially the best outcome for
enrolled patients.
For some selected patients with metastatic colorectal cancer (mainly those with
lim- ited hepatic and pulmonary lesions), there is a potential of having their diseases
cured after surgical resection (metastasectomy). It is important to evaluate the
resectability first for patients with metastatic colorectal cancer (Figure 11-1). The
data have shown that surgical resection is safe and may achieve a long-time survival

Approach to Chemotherapy and Radiation Therapy

185

depending on the size and number of the metastases, the disease-free interval, the
lymph node status of the primary

Approach to Chemotherapy and Radiation Therapy

185

Figure 11-1. Strategies

for advanced/metastatic
colorectal cancer (stage
IV).

Metastases Disease

Resectability Assessment

Resectable

Neoadjuvant

Unresectable

Surgery

Chemotherapy

Postoperation Chemotherapy

Table 11-1

SURVIVAL AFTER RESECTION

OF

Clinical Risk Score (Points)

HEAPTIC METASTASES
5-Year Overall Survival

0 to 1
52%
2 to 3
23%
4 to 5
11%
Each of the following factors is assigned as 1 point:
1. The largest tumor is >5 cm.
2. Number of tumors in liver is >1.
3. The disease-free interval <12 months.
4. Node-positive in the primary tumor.
5. CEA >200 ng/mL.

tumor, and the level of CEA11 (Table 11-1). The advantage of systemic
chemotherapy with 5-FU/LV after resection of metastases has been demonstrated in
both 5-year dis- ease free survival (DFS) and 5-year overall survival (OS).12 Until now,
surgical resection of metastatic lesions followed by further chemotherapy for those
with respectable dis- eases was accepted at most situations (see Figure 11-1).
Preoperative chemotherapy with new agents has been investigated lately. This
approach may help to select patients who will benefit from curative resection if
they have good responses to the systemic chemotherapy and to avoid unnecessary
surgical procedure for those patients with no response to chemotherapy or even
with their diseases progressed during treatment. Successful down-staging of the
disease, even with complete histologic response, has been achieved in some patients
with initially unresectable metastases.13,14 It has been report- ed that the
postmetastasectomy outcome in patients whose disease responded to neoad- juvant

Approach to Chemotherapy and Radiation Therapy

chemotherapy is much better than those whose disease did not.15

185

Majority of patients with metastatic colorectal cancer are not candidates for
metas- tasectomy, and surgical procedures are performed only for bypassing
obstructive and hemorrhagic lesions. The palliative systemic chemotherapy is the
only maneuver for their treatment. The median survival (MS) of individuals with
metastatic disease has dramatically improved in the past several years. As a main
component of chemotherapy,
5-FU is administered intravenously either with LV as bolus fashions or as
continuous infusion. The combinations of 5-FU with oxaliplatin (a
diaminocyclohexane platin that inhibits DNA replication and transcription through
the formation of intra- and inter- strand DNA adducts) or irinotecan (a
topoisomerase I inhibitor) are the new standard treatments for metastatic colorectal
cancer.16-19 Various regimens are available with dif- ferent doses and schedules (Figure
11-2). The question of which combination (irinote- can with 5-FU/LV or oxaliplatin
with 5-FU/LV) is more effective is unknown, but pre- liminary data suggest a rough
equivalency in efficacy of each combination in first- or sec- ond-line treatment, with
differences in toxicity patterns.20 It appears that the combina- tion of irinotecan with
bolus 5-FU may be more toxic, particularly in the elderly and patients with poor
performance status. It is important for physicians to realize that patients with
reasonable good performance should be treated with all 3 effective med- ications
during their treatment courses. Capecitabine, an oral fluoropyrimidine carba- mate
derivative, has also been approved by the FDA as first-line therapy for patients with
metastatic colorectal cancer who are not candidates for combination therapy.
Capecitabine was shown to be as effective as a standard bolus 5-FU/LV regimen in 2
ran- domized trials.21,22 Based on continuous dosing, capecitabine may hold the
potential to replace infusional 5-FU in combination with irinotecan and oxaliplatin.
Although phase II trials of capecitabine in combination with irinotecan and
oxaliplatin appear promis- ing, equivalence to standard intravenous infusional therapy
needs to be proven by ongo- ing phase III studies.
Many novel biological agents are now being tested. These new agents target the
EGFR, VEGF, and other molecular markers. Significant improvements in median survival, progression-free survival, and overall response rates have been demonstrated when
bevacizumab, a recombinant humanized monoclonal antibody against VEGF, is
added to irinotecan/5-FU/LV (IFL)23 (Table 11-2). The results of the combination
of beva- cizumab with oxaliplatin/5-FU/LV are expected in 2005. Encouraging results
have also been shown from phase II studies with cetuximab (C225), a monoclonal
humanized antibody directly against EGFR in previous-treated metastatic
colorectal cancer patients.24
Postmetastectomy hepatic artery infusion (HAI) of floxuridine (FUDR) with
sys- temic 5-FU/LV chemotherapy may improve survival compared with systemic 5FU/LV alone25 (Table 11-3). However, with more effective systemic chemotherapy
regimens available, the potential contribution of HAI needs to be tested further.
Many other hepatic-directed treatments have been proposed for metastases of
colorectal cancer, including radiofrequency ablation (RFA), hepatic artery
chemoembolization (HACE), cryotherapy, and percutaneous ethanol injection.26-28 All
of these procedures have their limits, and local availability and expertise vary widely.
While no survival benefit has been proven to date, trials are underway comparing
chemotherapy alone to chemotherapy plus either HACE or RFA.

IFL (Weekly, 2 weeks on and 2 weeks off)

Day 1

Irinolecan 125 mg/m2

IV over 90 mins

5-FU 500 mg/m2

IV bolus
LV 200 mg/m2
IV over 2 hours

5-FU 500 mg/m2

IV bolus

Day 1
Irinolecan 250 mg/m2
IV over 90 mins

LV 200 mg/m2
IV over 2 hours

Day 2

5-FU 600 mg/m2 over 22 hours

FOLFOX 4 (Every 14 days)

Day 1
LV 200 mg/m2
IV over 2 hours
Ox 85 mg/m2
IV over 2 hours

5-FU 400 mg/m2

IV bolus
5-FU 600 mg/m2 over 22 hours

Day 2
LV 200 mg/m2
IV over 2 hours

LV 200 mg/m2
IV over 2 hours

5-FU 400 mg/m2

IV bolus
5-FU 600 mg/m2 over 22 hours

5-FU 400 mg/m2

IV bolus
5-FU 600 mg/m2 over 22 hours

FOLFOX 6 (Every 14 days)

Day 1

5-FU 400 mg/m2

IV bolus

LV 400 mg/m2
IV over 2 hours
Ox 100 mg/m2
IV over 2 hours

5-FU 2400 to 3000 mg/m2 over 46 hours

FOLFOX 7 (Every 14 days)

Day 1
5-FU 2400 to 3000 mg/m2 over 46 hours

Figure 11-2. Schema of common chemotherapy regimens in treatment of metastatic colorectal cancer.

187

LV 400 mg/m2
IV over 2 hours
Ox 100 mg/m2
IV over 2 hours

Approach to Chemotherapy and Radiation Therapy

FOLIRI (Every 14 days)

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189

Table 11-2

EFFICACY AND TOXICITY OF IFL/BEVACIZUMAB

IFL/Placebo
(N=412)
Median survival
(months)
Progression-free survival
(months)
Overall response rate
(CR+PR,
Duration %)
of response
(months)
Grade 3/4 bleeding (%)
Thromboembolism (%)
Grade 3 proteinuria (%)
Grade 3 hypertension (%)

IFL/BV
(N=403)

15.
6
6.24
35
7.1
2.5
16.1 1
0.8
2.3

20.
3
10.
6
45
10.
4
3.
1
9.
3
0.
8
10.
9

p-value
0.00003
<0.00001
0.0029
0.0014
NS
NS
NS

IFL=irinotecan, 5-FU (fluorouracil), LV (leucovorin); BV=bevacizumab

Table 11-3

BENEFIT OF SYSTEMIC CHEMOTHERAPY WITH AND

WITHOUT HEPATIC ARTERY INFUSION (HAI) POST
LIVER METASTASECTOMY
No. of
Patients

5-Year DFS

5-Year OS

5-FU/LV (5-FU: 370 mg/m2, LV:

49%
200 mg/m2) daily, 5
days/4 weeks for 6 cycles

82

34%

5-FU/LV (5-FU: 325 mg/m2, LV:

61%
200 mg/m2) daily, 5 days/4 weeks
plus
HAI (FUDR 0.25 mg/kg/day,
20 mg dexamethasone, and
50,000 U heparin through
pump), 14 days/
3 weeks for 6 cycles

74

40%

FUDR=floxuridine, or fludeoxyuridine

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189

Table 11-4

COMMON 5-FU-BASED REGIMENS

Regimen
Roswell Park
weeks, repeat-

Dosing

Schedule

LV 500mg/m2 IV over
2 hours
5-FU 500mg/m2 IV push
1 hour after LV
infusion started

Weekly for 6
ed every 8 weeks

Mayo Clinic
LV 20mg/m2 IV push
consecutive days,
5-FU 425mg/m2 IV push
weeks
de Gramont
days every
(LV5FU2)

Daily for 5
repeated every 4

LV 200 mg/m2 2 hours IV

infusion; followed by 5-FU
IV bolus of 400 mg/m2; then
5-FU 600 mg/m2 IV 22hour continuous
infusion

Two consecutive
14 days

LV=leucovorin; 5-FU=fluorouracil

ADJUVANT CHEMOTHERAPY

FOR

COLON CANCER

The benefit of adjuvant chemotherapy for colorectal cancer has become well
estab- lished over the past 2 decades.29-33 The final results of Intergroup 0089 and
National Surgical Adjuvant Breast and Bowel Project (NSABP) C-04 studies
confirmed that
5-FU-based therapy significantly improves disease-free and overall survival for patients
with stage III colon cancer.33,34 Neither study showed the addition of levamisole
(LEV) to 5-FU/LV providing any additional benefits. The combination of 5-FU with
LV for 6 to 8 months is still the standard therapy for stage III (Dukes C) colon
cancer as adju- vant setting by the time this article was written, given by a variety of
different doses and schedules that have demonstrated comparable efficacy (Table
11-4). In the United States, the Roswell Park regimen and the Mayo Clinic regimen
are commonly used with somewhat different toxicity profiles. More leukopenia and
stomatitis are associated with the Mayo regimen, and more grade 3 to 4 diarrhea is
seen in the Roswell Park regimen, which is usually manageable with aggressive
antidiarrhea medications. The infusional regimen, LV5FU2 (also called de Gramont
regimen) was compared with a bolus regime for toxicity and efficacy in patients with
stage II and III colorectal cancer.35 There was no significant difference in disease-free
or overall survival between the treatment arms; however, toxicities were
significantly lower in the infusion group (p<0.001). Capecitabine, as an oral
fluoropyrimidine, has been studied as an adjuvant treatment for patients with resected

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189

Dukes C colon cancer (the X-ACT trial). Preliminary safety data showed 60-day allcause and treatment-related mortality was similar to the Mayo Clinic Regimen at
~0.5%. Capecitabine causes significantly less diarrhea, nausea, vomiting, stomatitis,
and alopecia compared to bolus 5-FU/LV, but more hand-foot syndrome.36
The efficacy data are expected soon.