Pancreatic Cancer : Treatment, Incidence and Etiology

Pancreatic Cancer
Over 90% of pancreatic cancers are ductal adenocarcinomas of the exocrine pancreas. These tumors occur twice as frequently in the pancreatic head compared to the rest of the organ, and tend to be aggressive, often presenting when locally inoperable or after distal metastases have occurred. Patients with pancreatic cancer have a poor prognosis, with a 5-year survival of only 5%. The discussion of pancreatic cancer here will be limited to ductal adenocarcinomas. Other types of pancreatic neoplasms include islet cell tumors and neuroendocrine tumors.

Incidence and Etiology

The lifetime risk of being diagnosed with pancreatic cancer in the United States is 1.27%. In the United States, it is estimated that approximately 37,170 people will be diagnosed with pancreatic cancer in 2007. Consistent with its associated poor prognosis, 33,370 are expected to die from this disease in the same year, making it the fourth leading cause of cancer-related death. The median age of diagnosis of pancreatic cancer is 72 years, with the peak incidence of diagnosis between the ages of 65 and 84; it is rarely diagnosed in those below the age of 50. The incidence is slightly higher in men than women, and it is also higher in African Americans than in Caucasians.

Cigarette smoking, obesity, and nonhereditary chronic pancreatitis appear to be risk factors for the development of pancreatic cancer. With smoking, the risk seems to increase with the number of cigarettes consumed and decreases with smoking cessation. Less clear, and sometimes conflicting associations, have been observed for other environmental factors such as diet, coffee and alcohol consumption, previous partial gastrectomy or cholecystectomy, and Helicobacter pylori. An epidemiologic association between diabetes mellitus and pancreatic cancer has also been demonstrated; however, it is uncertain if diabetes is a precedent of, or consequence of, pancreatic cancer.
Genetic Considerations
Five to 10% of patients with pancreatic cancer also have an affected first-degree relative, suggesting that in some cases genetic factors are involved. These patients seem to present earlier than sporadic cases. The risk of pancreatic cancer is increased in certain syndromes, whether directly or indirectly, such as hereditary chronic pancreatitis, Peutz-Jeghers syndrome, Von Hippel-Lindau syndrome, familial atypical multiple-mole melanoma syndrome, ataxia-telangiectasia, Gardner's syndrome [a variant of familial adenomatous polyposis (FAP)] and Lynch syndrome II, a subtype of hereditary nonpolyposis colorectal cancer (HNPCC). Heavy smokers who also have homozygous deletions of the gene for glutathione-S transferase T1 (GSTT1), a carcinogen metabolizing enzyme, may be at particular risk. Activating mutations in the K-ras oncogene are found in nearly all pancreatic cancer. Loss-of-function mutations in several tumor suppressor genes occur in this disease, including p53, CDKN2A gene (also called multiple tumor suppressor-1 gene, leading in many cases to loss of function of p16), DPC4, and BRCA2. A feature almost unique to pancreatic cancer is the combination of K-ras and CDKN2A mutations.

Clinical Features

Presenting Features
Common presenting features of pancreatic cancer include pain (present in more than 80% of patients with locally advanced or metastatic disease), obstructive jaundice, weight loss, and anorexia. Patients with jaundice may also have pruritus, pale stools, and dark urine; they often have tumors in the pancreatic head, and tend to be diagnosed earlier and with earlier stage disease. Other symptoms tend to be more insidious, so that in the absence of jaundice, the interval between onset and diagnosis can be prolonged. Pain, for example, is often more of a problem in patients with lesions in the body or tail of the pancreas where the primary tumor is more likely to become quite large or to invade adjacent structures (such as the splanchnic nerves) before becoming manifest; these patients frequently have inoperable disease. When present, pain is often felt as a dull ache in the upper abdomen and may radiate to the back, and characteristically may improve upon leaning forward. It may initially be intermittent, and may worsen with meals. These patients may suffer from marked weight loss, which may result from a combination of anorexia, early satiety, malabsorption or diarrhea/steatorrhea. Other less common presenting features include the diagnosis of glucose intolerance (particularly within 2 years of cancer diagnosis), previous pancreatitis, migratory superficial thrombophlebitis (Trousseau's syndrome), gastrointestinal hemorrhage from varices, and splenomegaly.

Physical Findings
Patients with early disease may not have any significant abnormalities detectable on physical examination. Jaundice may be a presenting feature in some; in these patients a palpable, nontender gallbladder (Courvoisier's sign) may be palpated under the right costal margin. Patients with more advanced disease may have an abdominal mass, hepatomegaly, splenomegaly, or ascites. The left supraclavicular lymph node (Virchow's node) may be involved with tumor, or widespread peritoneal disease may be palpable on rectal examination in the pouch of Douglas.

Diagnostic Procedures

Imaging Studies
(Fig. 89-1) Ultrasound is often used as an initial investigation for patients with jaundice, or with less-specific symptoms such as upper abdominal discomfort, and is able to assess the biliary tract, gall bladder, pancreas, and liver. Computed tomography (CT) scanning is preferable to ultrasound even though it is more costly, as it is less operator-dependent, more reproducible, and less susceptible to interference from intestinal gas. The sensitivity and specificity of CT is markedly improved by the use of pancreatic protocol scanning on modern multislice scanners. CT may show a pancreatic mass, dilatation of the biliary system or pancreatic duct, or distal spread to the liver, regional lymph nodes, or peritoneum (and/or associated ascites). When helical CT is combined with the use of intravenous contrast, it may also help determine resectability by providing information on the involvement of important vascular structures such as the celiac axis, superior mesenteric or portal vessels. Endoscopic retrograde cholangiopancreatography (ERCP) is also widely used in the diagnosis of pancreatic cancer, particularly when CT and ultrasound fail to show a mass lesion, and may reveal either stricture or obstruction in either the pancreatic or common bile duct. ERCP can also be used to obtain brushings of a stricture for cytology or for placing stents in order to relieve obstructive jaundice. Endoscopic ultrasound (EUS) may be useful in the diagnosis of small lesions (less than 2–3 cm in diameter) and, in some cases, for local staging as well as evaluating invasion of major vascular structures. EUS-guided fine-needle aspiration may also be used to obtain cytology for confirming the diagnosis, particularly in patients with potentially operable disease (see below). While magnetic resonance imaging (MRI) does not offer any advantages over CT in the routine evaluation of patients with possible pancreatic cancer, magnetic resonance cholangiopancreatography (MRCP) may be better than CT for defining the anatomy of the pancreatic duct and biliary tree, being able to image the ducts both above and below a stricture. The sensitivity of MRCP is comparable to ERCP, but does not require contrast administration to the ductal system, so that there is less associated morbidity. MRCP may be useful when cannulation of the pancreatic duct by ERCP has been unsuccessful or may be difficult, such as when normal anatomy is changed by surgery. Positron-emission tomography with 18F-fluoro-2deoxyglucose (FDG-PET) may be useful for excluding occult distal metastasis in patients with localized disease who are being worked up for surgery or in patients with unresectable localized disease being considered for chemoradiotherapy.

Figure 89-1
Carcinoma of the pancreas. A. Sonogram showing pancreatic carcinoma (P), dilated intrahepatic bile ducts (d), dilated portal vein (pv), and inferior vena cava (IVC). B. Computed tomography scan showing pancreatic carcinoma (dark arrows). C. Endoscopic retrograde showing abrupt c utoff of the duct of Wirsung (arrow). D. Magnetic resonance cholangiopancreatography showing obstruction (Obs) in the pancreatic duct (PD). The gallbladder (GB), hepatic duct (HD), and common bile duct (CBD) are labeled.

Tissue Diagnosis and Cytology
Patients with disease that is potentially curable by surgery, and in whom a highly suspicious lesion is seen on imaging, are often taken directly to surgery without prior tissue confirmation of cancer. This is because of theoretical concerns that a percutaneous fine-needle aspiration may result in dissemination of cancer intraperitoneally or along the track of the biopsy needle. In addition, negative cytology may not be sufficient evidence to avoid surgery, particularly with small lesions. EUS-guided fine-needle aspiration is increasingly being used, even in patients with potentially resectable disease, as there is less risk of intraperitoneal spread of cancer. Other methods of obtaining specimens for cytological analysis include sampling of pancreatic juices or brushings of ductal lesions obtained by ERCP.

Serum Markers
The most widely used serum marker in pancreatic cancer is cancer-associated antigen 19-9 (CA 19-9). It has a reported sensitivity and specificity of about 80–90%, and is suggestive, rather than confirmatory, of the diagnosis of pancreatic cancer. Serum levels of CA 19-9 can be elevated in patients with jaundice without pancreatic cancer present. The level of CA 19-9 may have prognostic implications, with very high levels sometimes found in patients with inoperable disease. In advanced disease, patients treated with chemotherapy who had high pretreatment levels of CA 19-9 have also been found to have a worse survival, whereas those patients whose levels of marker fell with treatment had a better outcome. In patients with cancers with elevated CA 19-9, serial evaluation of this marker is useful for monitoring responses to treatment. In patients with completely resected tumors, follow-up with CA 19-9 is useful for detecting recurrence.

In pancreatic cancer, which has a poor prognosis, the value of detailed clinical staging is limited. The most clinically relevant distinction to make is between patients with disease that may be resected with curative intent, and those with advanced disease in whom treatment is palliative (Table 89-1).
Table 89-1 Staging of Pancreatic Carcinoma
Stage Grouping
TNM Staginga
Localized resectable
T1–2 N0 M0
T3 N0 M0 or T1–3 N1 M0
Locally advanced
T4 N(any) M0
T(any) N(any) M1

aTNM, tumor, nodes, metastasis.
Note: T1, tumor limited to pancreas, 2 cm; T2, tumor limited to pancreas, more than 2 cm; T3, tumor extends beyond the pancreas but without involvement of celiac axis or superior mesenteric artery; T4, tumor involves celiac axis or the superior mesenteric artery (unresectable primary tumor); N0, no regional lymph node metastasis (regional lymph nodes are the peripancreatic lymph nodes, including the lymph nodes along the hepatic artery, celiac axis and pyloric/splenic regions); N1, regional lymph node metastasis; M0, no distal metastasis; M1, distal metastasis.

Surveillance in High-Risk Individuals
Routine screening for pancreatic cancer is not recommended due to a high false-positive rate of the available tests. However, screening may be reasonable in certain high-risk individuals, such as those with strong family histories, although the optimal timing, frequency, and method of screening is unknown. One recommendation is to commence screening at the age of 35 in patients with hereditary pancreatitis, or 10 years before the age of the youngest diagnosis of pancreatic cancer in those with a significant family history using spiral CT, followed by EUS when CT results have been indeterminate.

Pancreatic Cancer: Treatment
Symptoms and the associated impaired performance status are significant issues in the management of patients with pancreatic cancer, as they can have a marked negative impact on the ability to safely deliver chemotherapy or perform curative surgery. For example, patients with malabsorption secondary to pancreatic insufficiency may be treated with pancreatic enzyme supplementation. Indeed effective symptom management is as important a therapeutic goal as survival prolongation.

Advanced Pancreatic Cancer
These patients have metastatic or locally advanced inoperable disease and are the majority with newly diagnosed disease. Debulking surgery or partial resections have no role, as these procedures are associated with the same risks as a curative resection but are unlikely to improve survival. Many patients may, however, benefit from endoscopic biliary or duodenal stenting, and some patients from nerve plexus blocks or ablation. Less frequently, intestinal bypass surgery is required.
The deoxycytidine analogue gemcitabine, given as a single agent (gemcitabine 1000 mg/m2 weekly for 7 weeks followed by 1 week rest, then weekly for 3 weeks every 4 weeks thereafter), has been the preferred treatment for these patients since it was shown to yield clinical benefit (a composite parameter for evaluating symptomatic benefit of treatment used in some trials of this disease) and improved survival compared to 5-fluorouracil. The median survival observed with single-agent gemcitabine in randomized trials is about 6 months, with a 12-month survival of approximately 18%. Furthermore, two randomized trials have shown improved survival from the addition of either the oral fluoropyrimidine, capecitabine (gemcitabine 1000 mg/m2 days 1, 8, and 15 plus capecitabine 1660 mg/m2 days 1–21, repeated every 28 days), or the tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), erlotinib (standard gemcitabine plus erlotinib 100 mg daily). The survival improvement observed with both of these combinations appears similar, and the addition of capecitabine to gemcitabine in this regimen does not appear to increase the toxicity above single-agent gemcitabine. Either combination should, therefore, be considered as options for treating these patients. Second-line treatment options in pancreatic cancer are limited although there may be an emerging role for oxaliplatin-based chemotherapy; fit patients who have failed first-line treatment should be offered entry into clinical trials. On-going clinical trials are evaluating the potential benefits of incorporating other novel targeted agents into the treatment of pancreatic cancer, usually together with gemcitabine.
In patients with locally advanced unresectable disease, external beam chemoradiotherapy may be useful, either as initial treatment or as consolidation after induction chemotherapy.

Operable Disease
Complete surgical resection in patients with localized disease (stage I or II disease), with distal metastases excluded by prior CT scan of the abdomen and pelvis, and CT of the chest or chest x-ray, is potentially curative. However, such surgery is only possible in 10–15% of patients, many of whom will suffer from recurrences of their disease. Indeed, the 5-year survival reported in randomized trials with surgery alone is approximately 10%, although modern series have improved on these results. Outcomes tend to be more favorable in patients with lymph node–negative disease, smaller tumors (less than 3 cm), negative resection margins and well-differentiated tumors. Despite a dismal long term outcome, these patients still have a better survival with surgery than with other palliative measures.
Surgery is usually preceded by laparoscopy in order to exclude peritoneal metastases not seen on other staging investigations. Pancreaticoduodenectomy, also known as the Whipple procedure, is the standard operation for cancers of the head or uncinate process of the pancreas. The procedure involves resection of the pancreatic head, duodenum, first 15 cm of the jejunum, common bile duct, and gallbladder, and a partial gastrectomy, with the pancreatic and biliary anastomosis placed 45 to 60 cm proximal to the gastrojejunostomy. Perioperative mortality rates have fallen to less than 5%, reflecting greater experience with the surgery and perioperative management of these patients. However, this type of surgery is highly specialized and should ideally only occur in dedicated centers with a high volume of these cases and specialized surgeons.
Adjuvant treatment for patients with curatively resected pancreatic cancer is controversial, with divergent treatment approaches preferred in the United States and in Europe, based on the results of different randomized trials conducted on both sides of the Atlantic. In the United States, fluoropyrimidine-based postoperative chemoradiotherapy followed by adjuvant chemotherapy is preferred. In Europe, because a large randomized trial (the European Study Group for Pancreatic Cancer 1 or ESPAC1 trial) showed a survival benefit for adjuvant chemotherapy with 5-fluorouracil (5FU) (Fig. 89-2), this approach is more common practice.
Survival by adjuvant chemotherapy. Kaplan-Meier estimates of survival from the European Study Group for Pancreatic Cancer 1 (ESPAC1) trial for the comparison of adjuvant chemotherapy versus no adjuvant chemotherapy (CT) in patients with resected pancreatic cancer (hazard ratio for death, 0.71; 95% confidence interval, 0.55 to 0.92; p = .009). (Reprinted with permission from JP Neoptolemos, DD Stocken, H Friess, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.
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