CA Pancreas

Disease-a-Month 59 (2013) 368 402
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Disease-a-Month
journal homepage: www.elsevier.com/locate/disamonth
Pancreatic cancer: A comprehensive review and update

Thiruvengadam Muniraj, MD, PhD, MRCP(UK), Priya A. Jamidar, MBChB, FACG, FASGE, Harry R. Aslanian, MD, AGAF, FASGE
1. Introduction The term pancreatic cancer encompasses both exocrine and endocrine tumors of the pancreas. More than 90% of pancreatic tumors originate from ductal epithelium and this review will focus only on pancreatic ductal adenocarcinoma, which is commonly referred to as pancreatic cancer. The aim of this review is to update the primary practitioner on the epidemiology, genetics, risk factors, potential for screening, etiology, clinical presentation, diagnosis, and current medical and surgical management of pancreatic cancer. 1.1. Epidemiology In the United States, pancreatic cancer is the tenth most common cancer diagnosis in men and ninth most common in women. Despite its relatively low incidence, pancreatic cancer is the fourth leading cause of cancer deaths in both men and women and is predicted to become the second leading cause of cancer-related death in the U.S. by 2020.1 The American Cancer Society estimates that in 2013 about 45,220 people will be diagnosed with pancreatic cancer in the United States, and about 38,460 people will die from it this year (Fig. 1). Pancreatic cancer accounts for about 7% of all cancer deaths. The estimated lifetime risk for developing a pancreatic cancer is 1 in 78 (1.47%) and this risk increases with age, with a mean age of onset in the seventh and eighth decades of life.2 The 5-year relative survival rate remains very dismal (approximately 6% for all stages combined) and least among all the cancers3,4 (Fig. 2). When compared to other cancers, the survival rate for the disease has not improved substantially since the passage of the National Cancer Act over 40 years ago. Since 1975, the 5-year relative survival rate for pancreatic cancer has only improved from 2% to 6%, whereas in the same time frame the overall 5-year relative survival rate for all cancer sites has improved from 49% to 68% and some cancer survival rates are 90% or above5 (Fig. 4). 1.2. Are there geographic differences in pancreatic cancer in the US? The age-adjusted death rate per 100,000 for pancreatic cancer in the US from 2005 to 2009 was 10.85. Despite substantial international variation, within the US, pancreatic cancer incidence
0011-5029/$ - see front matter & 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.disamonth.2013.08.001
T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402
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Fig. 1. Ten leading cancer types for the estimated new cancer cases and deaths by sex, United States, 2013.2
Fig. 2. Five-year survival rate of pancreatic cancer and other cancers.3
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Fig. 3. Age-adjusted death rates in pancreatic cancer, state wise.3
and mortality rates vary only slightly between states. The pancreatic cancer death rate is highest in the North-East, with Connecticut (12.13) having the 3rd highest death rate after DC and Louisiana3 (Fig. 3). 1.3. Pancreatic cancer is a systemic disease from the onset More than 90% of pancreatic cancer patients have overt metastasis at the time of development of clinical symptoms and diagnosis. The overall 5-year survival rate in all patients (all stages included) is only 6% (Fig. 6) and that has not signicantly changed over the past 5 decades. Cure is rare and largely seen in only surgically resectable patients, which encompass approximately 1015% of all patients at presentation. Most patients die within 2 years of diagnosis.
Fig. 4. Five-year survival rate for major cancers.3
T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402 Table 1 Risk factors for pancreatic cancer. Risk factors Modiable Cigarette smoking Obesity High intake of animal fat Occupational exposure (Nickel, Cl-hydrocarbons from petroleum products and wood pulp) Partial gastrectomy Diabetes mellitus of recent onset Non-modiable
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Age Sex Positive family history Chronic pancreatitis (Tropical/familial/chronic) Inherited genetic predisposition Non-O blood group
2. Is pancreatic cancer preventable? The etiology of pancreatic cancer is not well understood; however, there are several factors known to increase the risk. The modiable risk factors include cigarette smoking, obesity, and high intake of animal fat. Non-modiable risk factors include chronic pancreatitis and an inherited genetic predisposition as part of a family history of pancreatic cancer or known inherited syndromes. Use of aspirin has been suggested in some studies to reduce the risk of pancreatic cancer.6 The relationship between diabetes and pancreatic cancer remains controversial and is discussed below (Tables 1 and 2). 2.1. Age Pancreatic cancer incidence and death rates increase with advancing age, with a steep increase after the age of 50 years. Around 9 in 10 pancreatic cancer patients are at least 55 years old and the average age at the time of diagnosis is 71 years. Approximately half of all patients with pancreatic cancer, had developed cancer after the age of 71 years, and pancreatic cancer rarely develops before the age of 45 years5 (Fig. 5). 2.2. Gender Pancreatic cancer is about 30% more common in men than in women. During 20052009, the age-adjusted incidence rate (per 100,000 persons) of pancreatic cancer was 13.6 for men and 10.5 for women, with age-adjusted death rate of 12.5 for men and 9.5 for women.3 This could partly be due to increased use of tobacco in men. The lifetime risk of developing pancreatic cancer is about 1.5% for both men and women.
Table 2 Strategies that could potentially decrease risk of pancreatic cancer. What can I do to decrease my risk of developing pancreatic cancer? Maintain BMI below 25 kg/m2 Quit or Do not smoke cigarettes Exercise regularly and maintain daily physical activity Ensure adequate sunlight exposure to increase Vit D levels Avoid high animal fat Drink Alcohol beverages in moderation Consume fresh fruits rich in antioxidants
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Fig. 5. Age and race with pancreatic cancer. Data for Whites and African-Americans from 1975 to 2009 and for Asian/ Pacic Islanders, American Indians/Alaska Natives and Hispanics from 1992 to 2009.3
2.3. Race African-Americans have the highest incidence rate of pancreatic cancer, which is 3266% greater than other groups. This racial difference in pancreatic cancer rates is likely largely due to racial variation in the prevalence of established risk factors, such as cigarette smoking, obesity, and diabetes.3,7 The lowest rates of pancreatic cancer are noted in Asian Americans/Pacic Islanders. Between 2005 and 2009, the incidence rate (per 100,000 persons) was 15.3 for African-Americans, 11.6 for whites, and 8.8 for Asian Americans/Pacic Islanders3 (Fig. 6). 2.4. Obesity and physical inactivity Obesity, a modiable risk factor, has been consistently shown to be linked to pancreatic cancer. Individuals who are obese have a 20% greater risk of developing pancreatic cancer than those with normal body weight.810 Obesity, particularly abdominal obesity, has been associated with earlier age of onset of pancreatic cancer.1012 Physical activity has been shown to reduce pancreatic cancer risk; however, results differ between several studies.1315 2.5. Alcohol use The relationship between alcohol use and pancreatic cancer is unsettled. A pooled analysis of 14 prospective cohort studies showed a modest increase in the risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day.16 Some studies show positive association, whereas a few studies did not nd any link.16 A recent meta-analysis showed that consumption of three or more drinks of alcohol per day is associated with a 2030% increased risk of pancreatic cancer.17 2.6. Smoking and pancreatic cancer Smoking is a risk factor for both chronic pancreatitis and pancreatic cancer, emphasizing the importance of smoking cessation in the prevention of both diseases. Smokers have a 75% increase in the risk of pancreatic cancer compared to nonsmokers, and this risk persists for a minimum of 510 years after smoking cessation. It is estimated that 20% of pancreatic cancers
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Fig. 6. SEER US incidence and death rates due to pancreatic cancer adjusted for race. Data for Whites and AfricanAmericans from 1975 to 2009 and for Asian/Pacic Islanders, American Indians/Alaska Natives and Hispanics from 1992 to 2009.3
are attributable to cigarette smoking.46,47 In a recent large pooled-data analysis by Bosetti, from 12 casecontrol studies including 6507 pancreatic cases and 12,890 controls, it was conrmed that current cigarette smoking is associated with 2.2-times increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and the duration of smoking. They observed that the risk level reaches that of never-smokers only approximately 20 years after smoking cessation.48 The evidence of second-hand smoking causing pancreatic cancer is inconclusive.49
2.7. Vitamin D and pancreatic cancer Several studies have shown lower pancreatic cancer death rates with sun exposure, suggesting a protective role of vitamin D. One study found an inverse relationship between UV-B radiation and 25-hydroxy Vit D levels and pancreatic cancer.18 Two large population studies showed a lower risk of pancreatic cancer with higher 25-hydroxy Vit D levels.19 A Harvard study group observed that poor vitamin D status, which is relatively more common in African-Americans, contributes to their higher incidence and mortality from various malignancies, including pancreatic cancer.20
2.8. Diabetes and pancreatic cancer The relationship between diabetes and pancreatic cancer is complex.
2.8.1. Prevalence of diabetes in pancreatic cancer patients Frank diabetes or impaired glucose tolerance is present in more than two-third of pancreatic cancer patients at the time of diagnosis. A study by Permert et al.21 using glucose tolerance tests in patients with newly diagnosed pancreatic cancer showed that 75% of patients met the criteria for diabetes. Pannala et al.22 used fasting blood glucose values or previous use of anti-diabetic medications to dene diabetes in patients with pancreatic cancer (N 512) and age-matched control non-cancer subjects attending primary care clinics (N 933) (Fig. 7). They reported a nearly seven-fold higher prevalence of diabetes in pancreatic cancer patients compared to
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Fig. 7. Distribution of fasting blood glucose among pancreatic cancer cases and controls. (Adapted with permission from Pannala et al.22)
controls (47% vs. 7%). In a retrospective study using similar criteria, Chari et al.23 found the prevalence of diabetes in pancreatic cancer patients to be 40%.
2.8.2. Risk of pancreatic cancer in diabetic patients There have been numerous epidemiologic studies, both cohort and casecontrol, on the association between diabetes and pancreatic cancer, which have consistently shown a modest increase in the risk of pancreatic cancer in type 2 diabetes, with an inverse relationship to duration of disease. A recent meta-analysis by Ben et al.24 included 35 casecontrol and nested casecontrol studies from 1966 to 2010 (Fig. 8) and concluded that diabetes was associated with two fold increased risk of pancreatic cancer (RR 1.94). Subjects 4 50 years of age with new-onset diabetes are at a higher risk of having pancreatic cancer.
2.8.3. Late-onset DM precedes pancreatic cancer In nearly all studies, the relative risk of pancreatic cancer inversely correlated with the duration of diabetes and the highest risk was found among patients who had been diagnosed with diabetes within less than 1 year (Table 3).
2.8.4. Do anti-diabetic agents inuence the risk of pancreatic cancer? Recent studies suggest that anti-diabetic medications may modulate the risk of pancreatic cancer in type 2 diabetes. Numerous studies report the protective effect of metformin on overall cancer mortality including a recent meta-analysis by Ben et al. Li et al.25 in a casecontrol study of 973 patients with pancreatic cancer (259 of whom had diabetes) and 863 controls (109 diabetic patients) observed that diabetic patients who had taken metformin had a signicantly lower risk of pancreatic cancer compared with those who had not (odds ratio0.38). Diabetic patients who had taken insulin or insulin secretagogues were found to have a signicantly higher risk of pancreatic cancer. However, a subsequent study by Bodmer et al.26 did not nd any association between metformin use and pancreatic cancer. At this time, a denitive conclusion on a potential protective role for metformin cannot be drawn Table 4.
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Fig. 8. Relationship between type 2 diabetes and risk of pancreatic cancer in casecontrol and nested casecontrol studies. Diamond: point estimate representing study-specic relative risks or summary relative risks with 95% CIs. Horizontal lines: represent 95% condence intervals (CIs). Test for heterogeneity among studies: P o 0.001, I2 93.6%. (1) cohort studies (N 27) use incidence or mortality rate as the measurements of relative risk; (2) cohort studies (N 8) use standardized incidence/mortality rate as the measurement of relative risk. (Adapted with permission from Ben et al.17)
2.8.5. Newer agentsGLP-1 agonists role in pancreatic cancer Both the pancreatic ducts as well as the pancreatic islets have abundant expression of GLP-1 receptors. GLP-1-based therapies that stimulate Beta cells may also affect the exocrine pancreatic cells. In response to GLP-1 therapy, the pancreatic acinar and duct cells proliferate, causing an increase in pancreatic weight.27 Gier et al.28 demonstrated in a chronic pancreatitis-prone KRASG12Dmouse model that treatment with GLP-1 analog will induce focal proliferation in pancreatic exocrine cells, promote chronic pancreatitis, and accelerate the formation and growth of dysplastic intraepithelial neoplasia (PanIN) lesions. PanIN leisons are one of the precursor leisons of pancreatic cancer, commonly present in up to 50% of the middle-aged population,
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T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402 Table 3 Relative risk of pancreatic cancer by duration of diabetes. Duration of diabetes o 1 year 14 years 59 years 4 10 years Number of studies 3 5 4 4 Relative risk (95% CI) 5.38 1.95 1.49 1.47
although relatively few actually progress to cancer.29 GLP-1 agents are known to be carcinogens and may stimulate dysplastic lesions, possibly promoting cancer formation. 2.8.6. Is this pancreatic cancer-induced diabetes, type 2 or type 3 diabetes or something else? According to the American Diabetic Association, diabetes occurring in exocrine and endocrine diseases of the pancreas (such as chronic pancreatitis) are dened as Type 3c pancreatogenous DM or a pancreatic DM. With exception of pancreatic cancer, other causes of pancreatogenous Type 3c DM occurs due to extensive damage and brosis of pancreatic tissue. In contrast, in pancreatic cancer, diabetes frequently improves after the resection of the tumor, suggesting a possible paraneoplastic phenomenon. Patients with pancreatic cancer-induced diabetes may present with weight loss rather with obesity and abdominal fat deposition, which are more characteristic of type 2 DM patients. Thus, new-onset diabetes after the age of 50 years with weight loss might be a heralding clue for pancreatic cancer. However, to screen new-onset diabetes for pancreatic cancer, additional markers are needed that can distinguish pancreatic cancer-associated diabetes from type 2 diabetes. From a population-based study of 2122 subjects, it is estimated that 0.85% of new cases of diabetes in individuals over the age of 50 years are due to underlying pancreatic cancer.30 2.9. Pancreatitis and pancreatic cancerInammation and cancer Pancreatitis is a well-known risk factor for pancreatic cancer. From a meta-analysis of 6 cohort studies, pooled relative risk estimate for chronic pancreatitis patients to get pancreatic cancer is found to be 13.3. The relative risk is particularly high when pancreatitis develops at an early age, such as hereditary pancreatitis (RR 69) and tropical pancreatitis, (RR 100), with at least 50-fold greater rates of pancreatic cancer vs. the general population.31,32 Hereditary pancreatitis patients have a cumulative risk of 44.0% at 70 years from the onset of symptom.33,34 Chronic pancreatitis is also a predisposing risk factor for pancreatic cancer. However, over a period of 20 years pancreatic cancer develops in about 5% or less of all chronic pancreatitis patients.
Table 4 Anti-diabetic agents and pancreatic cancer risk. Type of therapy Insulin Never Ever Insulin secretagogues Never Ever Metformin Never Ever TZDs Never Ever No. of cases/no. of controls Adjust OR (95% CI)/P value
147/88 112/21 171/84 84/22 138/32 117/74 204/87 51/19
1.0 5.04 (2.3810.7)/ o 0.001 1.0 1.74 (0.803.77)/0.160 1.0 0.41 (0.190.87)/0.020 1.0 1.65 (0.713.87)/0.245
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Fig. 9. Forest plot of individual PanC4 studiesodds ratios (ORs) and 95% condence intervals (CIs) for pancreatitis (diagnosed 4 2 years before) and risk of pancreatic cancer.42 Forest plot of individual PanC4 studiesodds ratios (ORs) and 95% condence intervals (CIs) for pancreatitis (diagnosed 4 2 years before) and risk of pancreatic cancer. Studyspecic ORs adjusted for age, sex, race/ethnicity, education, body mass index, tobacco smoking, alcohol intake, and history of diabetes. Squares indicate study-specic OR; size of the square denotes weight given to this study (inverse of the variance of the log OR). Horizontal lines indicate study-specic CI; diamond indicates summary pooled OR adjusted for age, sex, study, race/ethnicity, education, body mass index, tobacco smoking, alcohol intake, and history of diabetes. Solid vertical line denotes OR of 1. Dashed vertical line denotes summary OR.
Therefore, screening of all patients with chronic pancreatitis for pancreatic cancer is not recommended at the present time (Fig. 10). The exact mechanism for development of pancreatic cancer in patients with pancreatitis is not completely understood. KRAS activity inuences most pancreatic diseases.35 Ras mutations are present in nearly all pancreatic cancers and may contribute to malignant transformation. Researchers from MD Anderson proposed a new model in which Ras activity in the acinar cell is the direct link between inammatory conditions and malignancy.36 Several studies have shown that KRAS mutations in pancreatic tissue sampled by endoscopic ultrasound-guided ne-needle biopsy (EUS-FNB) and pancreatic juice analysis in chronic pancreatitis patients might help identify those with increased risk.3740 Pancreatic stellate cells have also been implicated in promoting inammation-associated carcinogenesis (Fig. 9).41 2.10. Blood type Genome-wide association study (GWAS) and other epidemiologic studies have shown that non-O blood-type individuals have an increased risk of pancreatic cancer. When compared with blood group O, subjects with blood types AO, AA, BO, or BB had odds ratios for pancreatic cancer ranging from 1.3 to 2.4. The actual mechanism of this association is unclear. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 when compared with nonsmokers of blood type O.4345
3. Genetic vs. sporadic pancreatic cancer Genetic syndromes contribute only 5% of all pancreatic cancer, while 95% are sporadic (Fig. 11).
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Fig. 10. Study-specic and summary risk estimates with 95% condence intervals for the association between different types of pancreatitis and pancreatic cancer risk.31
3.1. Genetic alterations and mutational load Virtually all pancreatic cancers present with multiple mutations. However, the mutational load may vary among different groups (Fig. 12).
3.2. Pancreatic cancer genetics A recent GWAS study ne-mapped common pancreatic cancer susceptibility regions and identied 3 loci chromosomes 13q22.1, 1q32.1, and 5p15.33 that are identied with pancreatic risk.51 Some of the genes known to be involved in pancreatic cancer are shown in Table 5.
3.3. Familial syndromes Familial syndromes that confer an increased risk in pancreatic cancer include the following: FAMMM (p16), HNPCC, BRCA2, PeutzJeghers, and Ataxia Telangiectasia. Most of these genetic syndromes are autosomal dominant and have high risk of developing pancreatic cancer (see Table 6).
Fig. 11. Sporadic cancer in red; Genetic cancer syndrome in blue.
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Fig. 12. Total mutational load in pancreatic cancer compared to pancreatitis and normal subjects. Individual cases (arrayed along the x axis) are presented by increasing total mutational load values (y axis). The total mutational load parameter derived from the MLDA proles separates the three groups of subjects with a narrow band of overlap between pancreatitis and cancer. The increase in total mutational load can be interpreted as a reection of progressive genetic instability.50
4. Other conditions associated with pancreatic cancer Cystic brosis is associated with an increased risk of developing pancreatic cancer.52 Cholecystectomy53 and partial gastrectomy54 have also been associated with an increased risk of developing pancreatic cancer.
Table 5 Pancreatic cancer gene alterations. Gene Oncogene KRAS Tumor suppressor p16 p53 DPC4 BRCA2 LKB1 MKK4 Genome maintenance b MSH2, b MLH1 Frequency (%)
90 95 5075 55 7 4 5 4
Table 6 Hereditary syndromes with pancreatic cancer risk. Syndrome PeutzJeghers syndrome Family X Hereditary pancreatitis FAMMM Familial breast CA2 HNPCC (Lynch syndrome) Familial adenomatous polyposis (FAP) Inheritance AD AD AD AD AD AD AD Gene location STK11 Palladin PRSS1 p16/CDKN2A BRCA2 MSH2, MLH1 APC, 5q21 Gene type Tumor suppressor Cationic trypsinogen Tumor suppressor Tumor suppressor Mismatch repair Tumor suppressor Est. relative risk 140 4 100 60 20 10 Unknown 5
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Some studies have suggested a link between chronic infections, including hepatitis B virus, hepatitis C virus, and Helicobacter pylori,55 and pancreatic cancer; however this remains inconclusive.56,57
5. Pathogenesis As mentioned above, pancreatic cancer involves multiple mutations that trigger the tumor progression cascade (Fig. 13). Normal duct epithelium progresses to inltrating cancer (left to right) through a series of histologically dened precursors (PanINs). The overexpression of HER-2/neu and point mutations in the KRAS gene occur early, inactivation of the p16 gene at an intermediate stage and the inactivation of p53, DPC4, and BRCA2 occur relatively late.58 5.1. Pancreatic cysts as precursors to pancreatic cancer The precursors to pancreatic adenocarcinoma are cystic lesions, such as pancreatic intraepithelial neoplasia (PanIN), intra-ductal papillary mucinous neoplasms (IPMN), and mucinous cystic neoplasms (MCN), and solid pseudo-papillary tumors. Non-neoplastic cysts, such as serous cystadenomas and lymphoepithelial cysts, have nearly no malignant transformation risk. The most prevalent type of precursor lesions are PanIN, which arise from ductal epithelial cells. PanIN leions are not detectable on imaging such as CT, MRI, or EUS. It is presumed that these lesions follow a pathway of progression from no dysplasia, to moderate dysplasia, to high-grade dysplasia (carcinoma in situ), to invasive carcinoma. There is an increased frequency of multiple genetic alterations as the atypia progresses. Pancreatic cysts are increasingly detected because of the widespread use of abdominal imaging done for evaluation of abdominal symptoms or screening for other conditions. Approximately 10% of individuals over 75 years of age have a pancreatic cyst.59 Unlike PanIN leisons, CT, MRI, and EUS often detect IPMNs and MCNs. The most common lesion incidentally detected is a branch duct IPMN. Although only responsible for a minority of pancreatic cancers (less than 15%), IPMNs and MCNs offer an opportunity to identify a potential premalignant lesion, and surveillance guidelines have recently been updated (Ref Sendai Consensus guidelines 2012).60 Ductal adenocarcinoma is associated with a dense, desmoplastic reaction surrounding a compact mass of hard pancreatic tissue that can invade surrounding mesenteric vessels,
Fig. 13. Progression from normal to dysplasia and cancer.58
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peri-neuronal tissue, and lymphatic channels or nodes. This hard desmoplasia prevents chemotherapeutic agents penetration into the cancer tissue. In recent years, cells which promote this stroma have been identied and targeted during therapy. Activated pancreatic stellate cells (PaSCs), which promote brosis during the development of chronic pancreatitis, were found to produce the extracellular matrix (ECM) proteins that comprise the pancreatic tumor stroma.61 Pancreatic cancer cells closely interact with the PaSCs causing an increase in extracellular matrix (ECM) and brosis.61 PaSCs, in turn, stimulate cancer cell proliferation and inhibit cancer cell apoptosis. PaSCs are believed to be involved in the resistance of tumors to chemotherapy and radiotherapy. In a mouse model, gemcitabine was found to be sequestered in the stroma of the pancreatic tumors, and was not able to reach some cancer cells.62 This nding led to a new treatment target aiming at inhibition of the Hedgehog cellular signaling pathway, which thereby depletes tumor-associated stromal tissue and causes a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine (Fig. 14). Pancreatic cancer cells recruit PaSCs to their immediate vicinity and promote brogenic responses in PaSCs. PaSCs reciprocate by facilitating cancer cell growth as well as local invasion.63 Inammatory markers, including IL-6 are increased in patients with pancreatic ductal adenocarcinoma (PDAC). Tumor-associated macrophages are the main source of IL-6 in pancreatic cancer tissue. Chronic pancreatitis is a risk factor for pancreatic cancer, but most cases of pancreatic cancer develop in patients without clinical evidence of chronic pancreatitis, yet there is evidence of inammation in tissue samples. Risk factors described earlier, such as smoking, alcohol, antioxidants, and diet, likely confer a major portion of attributable risk via the injury-inammation-cancer pathway.64 Activation of KRAS in pancreatic cells has been shown in mice models to promote inammatory signaling and development of precancerous lesions.65 Subsequently, the inammatory stimulus activates PaSCs in the periacinar area, leading to recruitment of inammatory cells (monocytes, T cells, neutrophils, macrophage, and mast cells). These cells produce IL-6, which activate signal transducer and activator of transcription 3 (STAT3) to promote development of PanIN and PDAC in susceptible tissue (Fig. 15). 5.2. KRAS and pancreatic cancer The KRAS gene is mutated to an oncogenic form (most commonly K-RASG12D) in most pancreatic tumors.66 As part of aging, people acquire oncogenic mutations in KRAS in the lung, pancreas, colon, and other tissues.67,68 The existence of KRAS mutation in non-cancer cells as well, is the major reason for KRAS not serving as a good biomarker for cancer.69 5.2.1. If most normal healthy aged people have KRAS mutation, why do few people develop pancreatic cancer? Oncogenic KRAS is not always in the active state.70 The presence of a KRAS oncogenic mutation is not sufcient to transform the cell to cancer. It requires additional genetic or
Fig. 14. Close relationship between pancreatic cancer cells and PaSCs.
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environmental factors that raise the threshold of KRAS activity and remove barriers to carcinogenesis. Furthermore, for a pancreatic cell to progress to a metastatic pancreatic cancer cell, multiple steps are required, each of which requires changes in gene expression. In early, PanIN lesions, KRAS mutation is present, but additional genetic alterations are absent.71,72 Oncogenic KRAS may contribute to pancreatic cancer initiation by protecting cells from entering a state of permanent growth arrest, but further progression requires inactivation of tumor suppressor gene, such as p16 and p53.73,74 A high level of sustained KRAS activity is required for pancreatic tumorigenesis. KRAS regulates the factors that produce active stroma around the tumor, including Sonic hedgehog, interleukin-6 (IL-6), and prostaglandin E. Sonic hedgehog signaling regulates the dense desmoplastic stroma, which makes the cancer resistant to chemo- and radiotherapies.74 Pancreatic tumors create a hypoxic microenvironment; they are not well vascularized and the large amounts of desmoplasia contribute to the low levels of oxygen.75 The cancer cells adapt to the hypoxic environment. Changes in cell metabolism, such as shifting to glycolytic pathways
Fig. 15. Role of inammation in progression of pancreatic cancer.63
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from the Krebs cycle, are a hallmark of pancreatic cancer.76,77 KRAS regulates changes in cancer cell metabolism, and hence targeted agents that inhibit KRAS would impair their ability to amplify the glycolytic pathway, thereby causing cell death.77,78
6. Clinical presentation Early stage pancreatic cancer is usually asymptomatic. When symptoms do occur, the tumor has usually spread to surrounding tissues or distant organs. Symptoms may widely vary based on the location of the tumor. The majority of tumors are located in the head of the pancreas and these often present earlier due to biliary obstruction. Tumors in the body and tail, however, can remain asymptomatic until late in disease stage. Common symptoms include abdominal pain, jaundice, pruritus, unexplained weight loss, new-onset diabetes mellitus, and depression (Fig. 16). Later symptoms are related to liver metastasis and/or invasion or compression of adjacent organs (stomach and colon) or of the peritoneal cavity (ascites). Peripancreatic edema or a large tumor itself may compress the duodenum or the stomach, causing gastric outlet obstruction or delayed gastric emptying, with associated nausea and early satiety. Pancreatic cancers other than ductal adenocarcinoma, such as islet cell tumors or lymphomas, tend to be softer and less brotic and thus tend to cause distortion rather than encasement or compression of adjacent structures. Occasionally, patients present with acute pancreatitis, migratory thrombophlebitis,79 hypoglycemia, or hypercalcemia. A study of prospectively recruited exocrine pancreatic cancer patients, newly diagnosed at ve general hospitals in Eastern Spain over 5 years (n 185) showed clinical features as shown in Table 7.80 Any of the above symptoms in the presence of late-onset diabetes should strongly alert the physician to the possibility of pancreatic cancer. Patients over the age of 50 years with newonset diabetes have an eight times increased risk of developing pancreatic cancer within 3 years of the diagnosis compared to the general population.81 Interestingly, in a Mayo clinic study with 2122 new-onset diabetes patients, 18 patients had pancreatic cancer (0.85%). Approximately 50% were diagnosed 4 6 months after rst meeting criteria for diabetes. Probability of having cancer or of not being diagnosed was more pronounced among those 4 70 years of age.30
Fig. 16. Site of pancreatic cancer and clinical presentation.
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Table 7 Clinical features in pancreatic cancer.80 Symptom Asthenia86% Weight loss85% Anorexia83% Abdominal pain79% Epigastric pain71% Dark urine59% Jaundice56% Nausea51% Back pain49% Diarrhea44% Vomiting33% Steatorrhea25% Thrombophlebitis3% Sign Jaundice55% Hepatomegaly39% Right upper quadrant mass15% Cachexia13% Courvoisiers sign (nontender but palpable distended gallbladder at the right costal margin)13% Epigastric mass9% Ascites5%
Abdominal pain is one of the most frequent symptoms and may be present, even with small (o 2 cm) pancreatic cancers.82 The pain is usually of insidious onset, with a gnawing visceral quality, and predominantly epigastric, with radiation to the sides and/or back. It may sometimes mislead, by being intermittent and made worse by eating and frequently worse at night and when supine. Severe back pain, with no jaundice should raise suspicion for a tumor arising in the body and tail of the pancreas. Rarely, the patient may present with acute onset pain, as a result of an episode of acute pancreatitis due to occlusion of the pancreatic duct.83
7. Diagnosis Transabdominal ultrasound is frequently utilized in the initial evaluation of the jaundiced patient. Cross-sectional imaging with computed tomography (CT) scan and MRI are important diagnostic and staging tests. Endoscopic ultrasound (EUS)-guided FNA, has become the preferred method for tissue diagnosis. Blood tests and cancer markers are of use when combined with clinical and imaging data. 7.1. Blood tests The complete blood count may reveal anemia, or reactive thrombocytosis. With obstruction of the bile duct, elevation of alkaline phosphatase, Gamma Glutamyl Transferase (GGT), Bilirubin, and AST/ALT levels may be seen. Metastasis to the liver alone, without CBD obstruction does not always produce marked elevations in ALP or bilirubin. 7.2. Role of tumor markers Several serum markers have been studied for detecting pancreatic cancer. They are CEA, carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1), CA 19-9, SPan-1, DUPAN-2, macrophage inhibitory cytokine 1 (MIC-1), alpha4GnT, PAM4, pancreatic juice DNA methylation, and fecal KRAS; however the most useful and widely adopted is the cancerassociated antigen 19-9 (CA 19-9). 7.2.1. CA 19-9 CA 19-9 is an epitope of blood group antigen Sialis Lewis antigen, which is absent in up to 10% of Caucasians, precluding its use as a tumor marker in these individuals.84 As a screening test, CA 19-9 has sensitivity and specicity rates for pancreatic cancer, which range from 70% to 92% and 6892% respectively. The sensitivity is limited for small-sized cancers.85,86 CA 19-9 has a very
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low positive predictive value of only 0.50.9% in the general population, which renders it not useful as a screening test. It is falsely elevated in several pancreaticobiliary disorders, most often obstructive jaundice, which may cause marked elevation of CA 19-9, as it is partly excreted through bile. Benign conditions, such as acute and chronic pancreatitis, pancreatic abscess, and pseudocysts, may also cause elevation of CA 19-9. In pancreatic cancer patients with CA 19-9 elevation, it may be used as a predictor of prognosis, overall survival, and in monitoring treatment response to surgery and chemotherapy.87 Preoperative CA 19-9 levels correlate with cancer stage and therefore, can be used indirectly as a marker for tumor resectability. Sugiura et al.88 studied 154 patients undergoing surgical resection and showed that a preoperative CA 19-9 value Z 100 U/mL was a signicant predictor of early recurrence and a poor prognosis after resection for pancreatic adenocarcinoma. Preoperative CA 19-9 serum levels provide useful prognostic information as patients with normal levels (o 37 U/mL) have a prolonged median survival (3236 months) compared to patients with elevated levels (4 37 U/mL) (1215 months).89 An Australian study involving 260 patients noted that patients with postresection CA 19-9 levels less than 90 U/mL appeared to benet from adjuvant chemotherapy and normalization of CA 19-9 levels may be associated with an excellent outcome.90 A recent German study concluded that baseline CA 19-9 and CA 19-9 kinetics had prognostic value with advanced pancreatic cancer patients during rst-line chemotherapy.91
8. Imaging in pancreatic cancer Imaging techniques currently used for the diagnosis and preoperative staging of pancreatic cancer include abdominal ultrasound (US), contrast-enhanced computed tomography (CT), Magnetic Resonance Imaging (MRI), MR Cholangiopancreatography (MRCP), Endoscopic Retrograde CholangioPancreatography (ERCP), and Endoscopic Ultrasound (EUS). Crosssectional radiologic imaging plays a critical role in determining surgical resectability based on local vascular staging in the absence of metastatic disease. 8.1. Abdominal ultrasound Abdominal ultrasound is safe, non-invasive, and inexpensive. It is sensitive in detecting bile duct dilation (as a general rule, 4 7 mm or 4 10 mm if previous cholecystectomy) and more marked pancreatic duct dilation. The double duct sign, which is the dilation of the pancreas duct and bile duct may be an indicator of an obstructing pancreas head mass. Abdominal Ultrasound is not as sensitive as computed tomography in imaging the pancreas, and small tumors (less than 3 cm) will frequently be missed. Furthermore, overlying intestinal bowel gas frequently obscures complete visualization of the pancreas. Pancreatic cancers typically appear as a focal hypoechoic, hypovascular solid mass with irregular margins. The utilization of echoenhanced power Doppler sonography may increase sensitivity (87%) and specicity (94%) with respect to diagnosing pancreatic cancer; however, the results are highly operator dependent and not widely available.92 8.2. CT abdomen CT scan is a comprehensive initial imaging modality, which is most commonly used for diagnosis and staging.93,94 8.3. Non-contrast CT Most pancreatic tumors are hypovascular and can be best visualized with contrast imaging. Non-contrast CT scans have poor sensitivity and specicity. In patients with renal failure or contrast allergy, EUS can play an important role in pancreas imaging.
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8.4. Multidetector CT with IV contrast MDCT with IV contrast provides very thin slice cuts with high image resolution and fast image acquisition. MDCT scanning (spiral CT) is generally accepted to be the rst line of investigation in a patient with suspected pancreatic cancer. Pancreatic cancer enhances poorly compared to the surrounding pancreatic parenchyma in the early phase of dynamic CT and gradually enhances with delayed images. As a result, on contrast-enhanced CT, pancreatic cancer is typically seen as a hypoattenuating area. Apart from the mass, indirect secondary signs of a pancreatic cancer include a pancreatic duct cutoff, dilatation of the pancreatic duct or common bile duct, parenchymal atrophy, and contour abnormalities.95 Ductal dilatation occurs in 58% of patients. Among patients with ductal dilatation, 75% have dilation of both the pancreatic ducts and the biliary ducts (double duct sign).96
8.5. Pancreatic protocol triple-phase contrast CT (CT angiography) A proper pancreatic protocol MDCT has four critical components: (1) neutral oral contrast administration to distend the stomach and duodenal sweep, (2) intravenous contrast injection via a rapid bolus, (3) optimized biphasic MDCT scan acquisition, and (4) post-processing with a combination of two-dimensional (2D) and 3D volumetric image displays to highlight extrapancreatic extension along blood vessels and peripancreatic tissues. Triple-phase IV contrast CT scan, preceded by non-contrast CT, is a good technique for detecting and staging pancreatic neoplasms with a sensitivity of 8997% and may detect masses less than 2 cm.9799 To start, the patient drinks 7501000 mL of a neutral oral contrast, such as water, to distend the stomach and duodenum. Gastroduodenal distension allows better depiction of invasion of these structures and also highlights the region of the ampulla of Vater. It is important to not miss an underlying ampullary carcinoma or misdiagnose it as a ductal adenocarcinoma. Ampullary tumors have a better survival rate than pancreas adenocarcinoma (40%, 5-year survival). Following the oral neutral contrast, 150 mL of nonionic contrast is given as rapid intravenous bolus. This rapid bolus causes intense enhancement of the normal pancreas, which will highlight the differences in vascular perfusion between the typically hypovascular brotic ductal adenocarcinoma and the normal pancreatic parenchyma. A late arterial-phase scan acquisition, typically 30 s from the onset of IV contrast injection, shows the underlying pancreatic lesions and their hypervascular liver metastasis and enhances the celiac axis, superior mesenteric artery, and peripancreatic arteries, thereby enabling the detection of subtle perivascular inltration of the underlying cancer.100 In 9095% of patients with pancreatic cancer, a hypoattenuating mass will be identied on an image acquired during this phase. The remaining 510% of pancreatic cancers may be isodense or small lesions, which may not be seen as a mass, but the only clue may be upstream uniform dilation of the main pancreatic duct. The portal venous phase, which is obtained at 6070 s after the start of the contrast injection, provides better enhancement of the superior mesenteric vein, splenic, and portal veins as well as the pancreas itself and any liver metastases if present. Disadvantages of CT include radiation exposure and the potential for contrast-induced nephropathy.
8.6. CT ndings mimicking pancreatic cancer Occasionally, both focal and autoimmune pancreatitis may cause a discrete mass of lesions, which may mimic ductal pancreatic cancer and also cause dilatation of the pancreatic or common bile ducts, making it indistinguishable without biopsy.101
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8.7. Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) MRI with intravenous gadolinium is the most useful for imaging pancreas masses. At present, contrast MRI and contrast-enhanced CT have similar test characteristics (sensitivity of 86% on CT vs. 84% on MRI).102 The choice of MRI vs. CT often depends upon local expertise and availability. Gadolinium-based contrast agents have been known to cause debilitating Nephrogenic Systemic Fibrosis (NSF) or Nephrogenic Fibrosing Dermopathy (NFD) in patients who have End-Stage Renal Disease (ESRD). NSF patients develop large areas of hardened skin with brotic nodules and plaques. In its most severe form, NSF may cause severe systemic brosis affecting internal organs, including the lungs, heart and liver, deep pain in the hip bones or ribs and muscle weakness are also observed.103 MRCP is frequently performed in conjunction with abdominal MRI and does not require IV contrast. MRCP provides a three-dimensional image of the pancreaticobiliary tree, liver parenchyma, and vascular structures. MRCP is better than CT for dening the anatomy of the biliary tree and pancreatic duct, and to assess for bile duct stones. It is an alternative to diagnostic ERCP and avoids the potential complication of ERCP-induced pancreatitis. 8.8. Positron emission tomography (PET) PET scan with tracer 18-uorodeoxyglucose (FDG) is based on functional changes in the metabolically active pancreatic cancer cells caused by enhanced glucose utilization, making them FDG-avid. Most benign lesions do not accumulate FDG, with the exception of inammatory lesions, such as chronic pancreatitis.104 Several studies have shown that PET scan has similar accuracy to MDTCT or MRI in staging pancreatic cancer.105,106 8.9. Endoscopic ultrasound (EUS) EUS utilizes a small ultrasound transducer attached to the end of the usual upper endoscope (echoendoscope) and it permits the acquisition of highly detailed images of the pancreas and surrounding blood vessels. Since the retrospective study by Yasuda et al.107 which compared transcutaneous ultrasonography (US), computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and angiography with EUS for the evaluation of pancreatic tumors, EUS has emerged as one of the most sensitive techniques for detecting pancreatic masses. Staging of pancreatic malignancy is done according to the American Joint Committee for Cancer (AJCC) Staging TNM classication, which describes the tumor extension (T), lymph node (N), and distant metastases (M) of tumors. EUS has a high accuracy rate that varies from 78% to 94% for T staging and 6482% for N staging, and overall sensitivity to detect pancreatic mass ranges from 85% to 100%.108110 EUS ne-needle aspiration (EUS-FNA) is the preferred method for tissue diagnosis of pancreas masses.111 Several studies have compared EUS with CT, MRI, PET, and angiography for evaluation of resectability.112116 EUS is very useful in diagnosing pancreatic cancer without denitive masses on CT scan or MRI, especially when the tumor is less than 2 cm.117,118 DeWitt et al. compared EUS with CT and observed that EUS detects more tumors (97 % vs. 73%). A tissue diagnosis is always needed in unresectable tumors (representing the majority of tumors) before chemo/radiotherapy. Although adenocarcinoma is most common, rarely lymphoma, a metastatic tumor or neuroendocrine tumor is detected, which would redirect therapy. Many institutions prefer to have tissue conrmation of diagnosis prior to surgical resection as well. EUS-FNA has a high accuracy and low complication rate. The sensitivity and diagnostic accuracy of EUS-FNA for solid pancreatic lesions is correlated with tumor size, with a decrease seen for tumors smaller than 1 cm.119 Interventional EUS is emerging as a new therapeutic tool for malignancy in pancreatic cancer. EUS-guided celiac plexus neurolysis is a chemical splanchnicectomy of the celiac plexus, which
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decreases thereby decreases the pain transmission and this technique is utilized in palliation of pancreatic cancer pain. EUS-guided anti-tumor therapy with injection of immunologic and chemotherapeutic agents into tumor to ablate the tumor tissue has been reported. 8.10. Endoscopic retrograde cholangiopancreatography (ERCP) Endoscopic retrograde cholangiopancreatography (ERCP) is a highly sensitive tool for visualization of the biliary tree and pancreatic duct. An early meta-analysis showed a sensitivity of 92% and specicity of 96% for diagnosing cancer of the pancreas by ERCP.120 ERCP aids in tissue sample collection through forceps biopsy or brush cytology of the intrapancreatic bile duct, although EUSFNA is much more sensitive.121 ERCP is currently predominantly utilized as a therapeutic modality for patients who present with jaundice due to tumor obstruction of the biliary system and require placement of a biliary stent. ERCP has a 510% risk of signicant complications including pancreatitis, and gastrointestinal or biliary perforation, and is therefore usually reserved for such therapy of obstructive jaundice with a plastic or metal biliary stent. Resectable patients undergoing prompt surgical resection may not require biliary decompression of the bile ducts.122
9. Who should be screened for pancreatic cancer? Ninety-ve percent of pancreatic cancers are sporadic with unclear risk factors and only the rest are genetic. Screening for sporadic pancreatic cancer has so far been considered unrealistic as the incidence in the general population is low.81 Screening trials utilizing a combination of EUS, CT, and MRI imaging have focused on high-risk populations (Section 5). Pancreas parenchymal changes have been commonly identied in these groups with a small number of early malignancies identied. (Canto, M. and Brentnall, T.). The utility of screening or surveillance remains debatable. 9.1. Candidates for pancreatic cancer surveillance123

In the same lineage, Z 3 rstdegree, seconddegree, or thirddegree relatives with PC. Known mutation carrier for BRCA1, BRCA2, or p16, with at least one rstdegree or second degree relative with pancreatic cancer. A member, ideally a veried germline carrier, of a PJS kindred. Two relatives in the same lineage (directly connected) affected with pancreatic cancer, at least one a rstdegree relative of the candidate. An affected individual with hereditary pancreatitis.
A study group from Vermont, enrolled 546 patients who are all rst-degree relatives of pancreatic cancer patients and measured CA 19-9. CA 19-9 was elevated in 27 patients, who underwent EUS, pancreatic adenocarcinoma was detected in 1 patient, and the cost to detect one pancreatic adenocarcinoma was $41,133.124 Several studies have shown that late new-onset diabetes could be a heralding sign of pancreatic cancer. The cohort of subjects with new-onset diabetes (as above) provides an intriguing opportunity to explore the possibility of screening for pancreatic cancer in these patients (Fig. 17). 9.2. Can we diagnose pancreatic cancer early? EUS is currently the most sensitive test for early stage pancreatic cancer. When EUS is targeted to high-risk populations, it is cost effective, with an incremental cost-effectiveness ratio of $16,885/life-year saved. This is comparable with mammogram $22,000/life-year saved and colonoscopy $10,00040,000/life-year saved.126 Numerous promising technologies are being developed for early diagnosis, including cyst uid biomarkers, genomic proling, nano-particle imaging, spectroscopy, and circulating pancreatic cells.
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Fig. 17. Model for screening in general population.125
10. Staging of pancreatic cancer Pancreatic cancer is staged according to the most recent seventh edition of the American Joint Committeeon on Cancer tumornodemetastasis classication, which is based on assessment of resectability by means of helical CT. T1, T2, and T3 tumors are potentially resectable, whereas T4 tumors, which involve the superior mesenteric artery or celiac axis, are unresectable (Table 8). Cancer involving the superior mesenteric veins, portal veins, or splenic veins are classied as T3, since these veins can be resected and reconstructed, when they are patent.
10.1. Staging of pancreatic cancer often by clinical rather than formal TNM classication 10.1.1. National Comprehensive Cancer Network (NCCN)s clinical staging of pancreatic cancer127 Resectable Absence of extrapancreatic disease, no evidence of direct tumor extension to the Superior mesenteric artery (SMA) or celiac axis (presence of fat plane between the tumor and these vessels), patent Superior mesenteric, and Portal vein (SMPV). Borderline resectable (Potentially resectable) Absence of extrapancreatic disease, SMA encasement o 1801 SMV/portal impingement, short segment SMV occlusion, celiac encasement o 1801 (tail), abutment/encasement of hepatic artery. Locally advanced/unresectable Absence of extrapancreatic disease, SMA encasement 4 1801, un-reconstru-ctable SMV/ portal vein occlusion; any celiac abutment (head) or celiac encasement 4 1801 (body/tail), aortic invasion or encasement, lymph node metastases beyond eld of resection. Metastatic The specic radiographic criteria that dene unresectable disease include signicant involvement or encasement of the superior mesenteric artery or the celiac trunk. With short segment involvement of the portal vein or the superior mesenteric vein, it is possible with reconstruction to perform a successful cancer operation on these patients, but for longer segment involvements or occlusion at the SMV portal vein conuence, resection is technically prohibitive (Fig. 18).
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Table 8 TNM staging for pancreatic cancer.a Stage Tumor grade Nodal status Distant metastases Median survivalb (months) 24.1 20.6 15.4 Characteristics
IA IB IIA
T1 T2 T3
N0 N0 N0
M0 M0 M0
IIB III
T1, T2, or T3 T4
N1 N0 or N1
M0 M0
12.7 10.6
IV
a b
T1, T2, T3, or T4 N0 or N1
M1
4.5
Tumor limited to the pancreas, r 2 cm in longest dimension Tumor limited to the pancreas, 4 2 cm in longest dimension Tumor extends beyond the pancreas but does not involve the celiac axis or superior mesenteric artery Regional lymph-node metastasis Tumor involves the celiac axis or the superior mesenteric artery (unresectable disease) Distant metastasis
N denotes regional lymph nodes, M denotes distant metastases, and T denotes primary tumor. Data are from Bilimoria et al.45
Fig. 18. Practical staging of pancreatic cancer. Tumors of head of pancreas are those arising to right of portal vein superior mesentric vein conuence. Ref.: www.medivisuals.com.
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Unfortunately, only approximately 1020% of patients are resectable at the time of diagnosis.128 Even among those patients who undergo resection for pancreatic cancer and have tumor-free R0 margins, the 5-year survival rate after resection is only 1025% with the median survival of 1519 months.128 A locally advanced stage is identied in 2535% of patients and is associated with a median survival of 610 months. The vast majority of these patients develop metastatic disease within the rst year of therapy. At presentation, 4555% of patients are in metastatic or advanced stage. The prognosis of patients with advanced disease remains extremely poor, with a median survival of 6 months. Borderline resectable disease is a newer sub-class that helps separate patients who initially may not be operable but, with some cytoreduction with chemotherapy and/or radiation, may be able to be taken to surgery vs. those who are very unlikely to become operative candidates. 11. Management of resectable and locally advanced pancreatic cancer Patients with pancreatic cancer are best managed by a multidisciplinary team that include surgeons, medical and radiation oncologists, radiologists, gastroenterologists, nutritionists, and pain specialists, and several supportive staff.129 If the tumor is resectable, surgery remains the treatment of choice.130 Depending on the location of the tumor, the operative procedures may involve pancreatoduodenectomy (the Whipple procedure), distal pancreatectomy, or total pancreatectomy.131 The surgery involves extensive lymph-node resection, i.e., at least 1215 nodes to be removed with the aim of achieving a tumor-free R0 margin. Studies show that the outcomes of vein resection and vascular reconstruction in patients with limited involvement of the superior mesenteric vein and portal vein are similar to the outcomes in patients without vein involvement.132 Poor prognostic factors include lymph-node metastases, a high tumor grade, a large size tumor, high levels of serum CA 19-9, persistently elevated postoperative levels of CA 19-9, and positive microscopic resection margins (R1). Recent studies have identied several prognostic markers as seen in Table 9. There is controversy existing on microscopically positive margin (R1) on patterns of disease recurrence and survival after pancreaticoduodenectomy (PD) when compared to negative margin (R0). While some studies showed that the survival rate of patients with positive margins after resection is almost similar to locally advanced stage who never underwent surgery. In a recent study, Massachusetts investigators observed that patients undergoing an R1 resection still have an improved survival compared with patients with locally advanced unresectable pancreatic adenocarcinoma. They also concluded that R0 resections have an improved survival compared with R1 resections, but this survival benet is lost when the tumor is within 1 mm of the resection margin.133
Table 9 Prognostic markers in pancreatic cancer.
Higher levels of CA 19-9 in a resected pancreatic cancer patient suggests micrometastases CA 19-9 is a highly signicant predictor of overall survival in patients with resected pancreatic cancer SMAD4 (DPC4) is a predictive biomarker in patients with localized pancreatic cancer VEGF is a prognostic marker in resected pancreatic cancer miR-10b is a predictive marker of response to neo-adjuvant therapy in pancreatic cancer REG4 protein overexpression is an unfavorable response to preoperative chemoradiotherapy in patients with pancreatic cancer Alpha 1-antichymotrypsin (AACT) may be a useful prognostic marker in patients with advanced stage pancreatic cancer Human equilibrative nucleoside transporter 1 (hENT1) and deoxycytidine kinase (dCK) are useful predictive markers to response to gemcitabine in patients with pancreatic cancer EGFR and KRAS mutation status were not identied as markers predictive of a survival benet from the combination of erlotinib with gemcitabine for the rst-line treatment of advanced pancreatic cancer
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These ndings emphasis the need for universal use of postoperative adjuvant treatment with either gemcitabine alone or gemcitabine with 5-FU, based chemo-radiation, which is currently adopted as the standard of care. As a recent strategy, use of Neo-adjuvant chemotherapy was studied in a few RCTs, suggesting that this approach is at least as effective as postoperative treatment and may decrease the rate of local failures and positive resection margins after surgery.134 This is especially when the tumor is borderline resectable.
12. Adjuvant therapy for resectable disease Kalser et al.135 studied a group of 43 patients and showed an improvement in median survival in the group of patients with resected pancreatic cancer who received split course radiation with concurrent 5-FU, followed by 5-FU for an additional 2 years thereafter, compared to patients who received no adjuvant therapy. ESPAC-1 was a European trial where patients were randomized in a 2-by-2 factorial design to observation, chemotherapy with bolus 5-FU or 5-FU-based radiation, or 5-FU-based chemoradiation, followed by more 5-FU chemotherapy. The study showed that adjuvant chemotherapy has a signicant survival benet in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.128 The take-home message was a clear benet from chemotherapy with 5-FU; however, the study was much critiqued as the patients on the 2 arms of this study who received radiation treatment seemed to do less well than those who did not receive radiation, which raised the question of whether radiation is necessary, or whether it might even be deleterious in patients in the postoperative setting. Ottle et al. conducted the German CONKO-001 trial that established a 6-month course of gemcitabine as an appropriate standard of care. Patients did have improvements in disease-free and overall survival compared to those who received no adjuvant treatment. This study did not include radiation as part of the adjuvant therapy.136 In the United States, RTOG 9704 study was designed by Regine et al. and both arms received 5-FU and radiation, but one arm received pre- and post-radiation 5-FU as continuous infusion, while the other arm received gemcitabine. This large trial ultimately showed, at least in patients with pancreatic head tumors, a slight benet of gemcitabine over 5-FU. As both arms received radiation, the study did not address the question about the necessity of radiation in this adjuvant setting (see Table 10).137 The ESPAC-3 trial was a direct comparison of gemcitabine vs. 5-FU/leucovorin. No radiation was used and, there was no difference whatsoever in patients receiving either gemcitabine or 5-FU.138
Table 10 Randomized trials and chemo/radiation in pancreatic cancer.137
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Fig. 19. Median survival duration with gemcitabine therapy.139
Over more than the past 20 years, the median survival in resectable disease with adjuvant therapy has remained around 20 months.
13. Management of advanced and systemic disease 13.1. Gemcitabine as the mainstay of treatment Burris et al. in 1997, studied 126 patients with advanced pancreatic cancer, who were randomized to receive either gemcitabine or bolus 5-FU (Source: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78245, USA.).139 This was the pivotal study dening the role for gemcitabine as rst-line treatment for patients with advanced pancreatic cancer (Fig. 19). Gemcitabine vs bolus 5-FU Median survival: 5.65 vs. 4.41 months. 1-year survival: 18% vs. 2% Clinical benet: 23.8% vs. 4.8% Response rate: 5.4% vs. 0%
These data are probably familiar to many as they led to the approval of gemcitabine, more than a decade ago, as the mainstay of treatment for patients with advanced pancreatic cancer. A recent meta-anaylsis by Heinmennan studied various studies on gemcitabine combinations in advanced pancreatic cancer, and this study factored in several characteristics typical of patients with pancreatic cancer, namely their degree of pain and their opioid analgesic requirements, their performance status, and degree of weight loss, and the results highlighted the fact that approximately a quarter of patients receiving gemcitabine in any combination had a signicant clinical benet (Table 11).140 A meta-analysis looked at gemcitabine plus a second drug categorized by mechanism of action, for example, gemcitabine plus a platinum analog like cisplatin or oxaliplatin. By pooling all of the studies together the improvement in overall survival became statistically signicant with a hazard ratio of 0.85. Similarly, gemcitabine plus a uoropyrimidine like 5-FU or capecitabine produced a statistically signicant improvement, which was not the case with gemcitabine plus any of the
394 Table 11 Gemcitabine-based studies.140 Regimen Gemcitabine platinum analog vs gemcitabine Gemcitabine uoropyrimidine vs gemcitabine Gemcitabine other vs. gemcitabine
Studies/patients (n) 5/1248 6/1813
Examples Cisplatin and oxaliplatin Bolus 5-FU, infusional 5-FU, and capecitabine Pemetrexed, irinotecan, and exatecan
Improvement in OS? HR P HR P 0.85 0.010 0.90 0.03
4/1404
HR 0.99 P 0.80
other agents that were studied in previous phase III trials. All the phase III trials showed no survival benet for gemcitabine combination vs. monotherapy (targeted agents were excluded) (Table 12). Another study led by Heinemann and colleagues from Eastern Cooperative Oncology Group (ECOG) pooled the data from 5 separate studies of gemcitabine plus a platinum analog. None of the individual studies was positive, but by pooling them together, there was a statistically signicant improvement in overall survival (Table 13).140 As seen in the above two scenarios, the difference in performance status may inuence the choice of treatment, especially for a patient with a marginal performance status and that patient is unlikely to benet from a combination regimen of say, a Gemcitabine-based doublet, or certainly FOLFIRINOX. Patients with an ECOG performance status of 0 or 1 do benet from some form of combination therapy, whereas those with a performance status of 2 do not and are probably best suited to receive monotherapy with gemcitabine alone. Meta-analysis of randomized trials conrms that performance status is the critical factor in determining who is more likely to benet from combination chemotherapy.140 14. FOLFIRINOX: Recent standard treatment for metastatic pancreatic cancer In a well-executed multicenter, randomized, phase II/III trial, Conray et al. from France, compared gemcitabine with FOLFIRINOX (Fluorouracil, Leucovorin, Oxaliplatin, Irinotecan) in 342 patients with metastatic pancreatic cancer with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Unlike the US population, more patients had tumors located in the pancreatic body and tail (59%) than in the pancreatic head (38%). Patients were randomized and received either gemcitabine (1000 mg/m2 weekly for 7 of 8 weeks followed by weekly therapy for 3 of 4 weeks) or Folrinox (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and uorouracil 400 mg/m2 followed by 2400 mg/m2 over 46 h every 2 weeks). Folrinox was superior to gemcitabine in all outcome measures, including overall survival (11.1 months vs. 6.8 months), 1-year survival (48.4% vs. 20.6%), progression-free survival (PFS; 6.4 months vs. 3.3 months), antitumor response rate (31.6% vs. 9.4%), and less degradation in global healthrelated quality of life (31% vs. 66%). Diarrhea, sensory neuropathy, neutropenia, thrombocytopenia,
Table 12 Gemcitabine-based studies. Regimen Gemcitabine Gemcitabine Gemcitabine Gemcitabine Gemcitabine Gemcitabine Gemcitabine vs. vs. vs. vs. vs. vs. vs. (gem (gem (gem (gem (gem (gem (gem cisplatin) oxaliplatin) 5-FU) capecitabine) pemetrexed) irinotecan) exatecan) Pts (n) 192 313 322 533 565 360 349 Control arm (months) 6.0 7.1 5.4 6.2 6.2 6.6 6.2 Study arm (months) 7.6 9.0 6.7 7.1 6.3 6.3 6.7
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and febrile neutropenia were more common with Folrinox than gemcitabine. These results suggest there may be benet to the prophylactic use of growth factor support in patients receiving Folrinox. Despite the high rates of toxicity, QoL evaluation favored the Folrinox arm.141
FOLFIRINOX study: Take-home messages
All the patients in this trial had good performance status - FOLFIRINOX may be a 1st line for metastatic pancreatic cancer with good performance score. This study population is representative of majority nonhead tumors. (Only 40% located in head.) Signicant neutropenia caused by therapy may place patients requiring biliary stenting for jaundice at risk of biliary sepsis.

15. Nab-paclitaxel plus gemcitabineNew emerging standard for metastatic pancreatic cancer Nab-paclitaxel (Nano-albumin-bound paclitaxel) is currently FDA approved for use in metastatic breast cancer as well as locally advanced or metastatic non-small cell lung cancer. It is known that poor drug delivery is one of the key reasons why the currently available treatments for pancreatic cancer have failed and there have been suggestions that nab-paclitaxel may aid in drug delivery.142 In preclinical models of pancreatic cancer, nab-paclitaxel showed activity as a single agent and in combination with gemcitabine. The combination also showed promise in a previous phase 1/2 study in 2011 that included patients with metastatic pancreatic cancer. The response rate was an impressive 48% with a median 12.2 month overall survival.143 The initial results of the Phase III trial MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study were presented at ASCO June 2013, by Von Hoff and colleagues, with 861 patients, from 5 countries (median age, 63 years; range, 2788) with metastatic disease and a Karnofsky performance status Z 70.
Table 13 Gemcitabine/platinum doublets for advanced pancreatic cancer (phase III), combined analysis: gemcitabine/platinum results in signicant improvement in OS (HR 0.85; P 0.01).140 Treatment PFS (months) Median survival (months) 5 7.5 6.0 7.5 7.1 9.0 4.9 5.9 6.7 8.0
Gruppo Oncologia dellItalia meridionale study (N 107) German multicentre study (N 190) GERCOR/GISCAD intergroup study (N 313)
ECOG 6201 (N 833) Third arm FDR gem Viret et al. (N 83)
Gemcitabine Gemcitabine/cisplatin Gemcitabine Gemcitabine/cisplatin Gemcitabine Gemcitabine/ oxaliplatin Gemcitabine Gemcitabine/ oxaliplatin Gemcitabine Gemcitabine/cisplatin
2 5 3.1 5.3 3.7 5.8 N/A N/A 2.5 2.2
396
The median duration of treatment was 3.9 months among patients assigned to combination arm and 2.8 months among those who were in Gemcitabine alone arm. The primary end point was Overall Survival (OS) and the secondary endpoints included progression free survival (PFS), time to treatment failure, and overall response rate. The patients in the combination arm had longer median OS (8.5 months vs. 6.7 months) and longer PFS (5.5 months vs. 3.7 months). The overall response rate was 23% among patients assigned to nab-paclitaxel plus gemcitabine compared with 7% among patients assigned to gemcitabine alone. Also, as expected the toxicity prole was more with the combination arm (Table 14).144,145 Based on this MPACT study, On Sept. 6 2013, the U.S. Food and Drug Administration (FDA) approved nab-paclitaxel (brand name Abraxane) plus gemcitabine as a rst-line treatment for patients with metastatic advanced pancreatic cancer patients. 16. Sequence of chemotherapy and radiation Pancreatic cancer is often a systemic disease at presentation and patients who do not have overt evidence of metastatic disease likely have micrometastatic disease. A principal focus of therapy is to try to eradicate the micrometastatic disease with the optimal systemic regimen. The additional benet of radiation therapy remains uncertain.
Radiation First, Chemotherapy Later Chemotherapy First, Radiation Later
Greatest imperative is to eradicate micrometastatic disease. Better likelihood of cytoreduction to downstage a patient for potential surgery. Restricts XRT to subgroup of patients whose tumors do not spread and are well controlled with a period of up-front Importance of obtaining optimal local systemic therapy. control. Better palliation of symptoms.
Table 14 Grade 3/4 adverse events in the MPACT study. Toxicity Neutropenia Fatigue Diarrhea Febrile neutropenia Peripheral neuropathya Nab-paclitaxel plus gemcitabine (%) 38 17 6 3 17 Gemcitabine alone (%) 27 7 1 1 1
a Peripheral neuropathy improved (downgraded to a grade 1 or less) on average in 29 days with 44% of patient able to tolerate resumption of nab-paclitaxel treatment.
T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402 Table 15 Targeted therapy in pancreatic cancer.147
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There are mixed data from various studies on giving concurrent chemoradiation as a rst step in a patients with locally advanced disease. Thus sequencing of chemoradiation, and whether it is necessary at all, remains a debate. Huquet et al. showed that patients who continued with chemotherapy did less well than those who received induction chemotherapy and then moved on to chemoradiation.146
17. Targeted therapy While targeted or personalized therapies have shown promise in some areas, those who studied pancreatic cancer have not shown signicant benet thus far, including matrix metalloproteinase inhibitors and farnesyl transferase inhibitors that ostensibly inhibit RAS signaling. Recent studies have utilized Erlotinib, Bevacizumab, Cetuximab; however, only Erlotinib has shown a modest improvement in median survival thus far (Table 15).145,147
18. Conclusion Despite extensive research, the survival rates in pancreatic cancer still remains dismal. Surgery is the only curative option. Adjuvant therapies with chemotherapy and radiation, though improves the disease to some extent, are not yet optimal. Newer molecular targeted agents and agents which inhibit desmoplasia surrounding the cancer may play an important role in improving the overall survival in patients with pancreatic cancer. References
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Contents lists available at ScienceDirect

Pancreatic cancer: A comprehensive review and update

T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402

Fig. 2. Five-year survival rate of pancreatic cancer and other cancers.3

T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402

Fig. 3. Age-adjusted death rates in pancreatic cancer, state wise.3

Fig. 4. Five-year survival rate for major cancers.3

T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402

T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402

T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402

T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402

147/88 112/21 171/84 84/22 138/32 117/74 204/87 51/19

T. Muniraj et al. / Disease-a-Month 59 (2013) 368 402

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Fig. 11. Sporadic cancer in red; Genetic cancer syndrome in blue.

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Fig. 13. Progression from normal to dysplasia and cancer.58

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Fig. 15. Role of inammation in progression of pancreatic cancer.63

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Fig. 16. Site of pancreatic cancer and clinical presentation.

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Fig. 17. Model for screening in general population.125

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T1, T2, T3, or T4 N0 or N1

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Fig. 19. Median survival duration with gemcitabine therapy.139

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Studies/patients (n) 5/1248 6/1813

Improvement in OS? HR P HR P 0.85 0.010 0.90 0.03

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FOLFIRINOX study: Take-home messages

2 5 3.1 5.3 3.7 5.8 N/A N/A 2.5 2.2

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