- In 2008, approximately 37,680 new cases of pancreatic cancer were diagnosed and 34,290 patients died from this disease (1).
- Pancreatic cancer remains the fourth leading cause of cancer death in the United States.
- The 5-year survival of patients with pancreatic cancer is less than 5%.
- Men and African Americans are at a higher risk for developing pancreatic cancer and have higher mortality rates.
- Incidence of pancreatic cancer increases at the age of 50 and peaks in the seventh decade (Table 9.1).
- Pain caused by localized disease is usually described as mid to upper back pain resulting from tumor invasion of the celiac and mesenteric plexi.
TABLE 9.1. Risk factors Environmental Cigarette smoking N-nitrosoamines may increase risk by twofold to threefold. Accounts for roughly 30% of pancreatic cancers. Dietary factors Decreased risk with fruits and vegetables, increased risk with fat and meat. No caffeine association, and alcohol link is controversial. Disease states Diabetes mellitus Maximal risk at time of diagnosis of diabetes and for the subsequent 5 years. Chronic pancreatitis Relative risk as high as 16-fold. Genetic FAMM p16 mutation, 13- to 22-fold increased risk Hereditary pancreatitis PRSS1 or cationic trypsinogen gene, 20-fold increased risk HNPCC Lynch syndrome II BRCA2 10-fold risk Peutz-Jeghers syndrome Manifested by hamartomatous gastrointestinal polyps and perioral pigmented spots, mutation of serine-threonine kinase (STK) (11) Occupational Chemicals Petrochemical products, benzidine, and β-naphthylamine
Fig. 9.1. Neoplastic progression model—pancreatic intraepithelial neoplasia (PanIN-1 through PanIN-3). (Used with permission from Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Can Res 2000;6:2969-2972.) - Most patients develop glucose intolerance and some degree of pancreatic insufficiency. An analysis of 512 pancreatic cancer patients and 933 age-matched controls revealed diabetes mellitus to be more prevalent (47% vs. 7%; P < 0.001) and of recent, <2-year onset (74% vs. 53%; P = 0.002) in the cancer cases (2).
- K-ras mutations are common in pancreatic cancer (Fig. 9.1).
- Intraductal papillary mucinous neoplasm and mucinous cystic neoplasm are relatively benign lesions, but the presence of severe dysplasia or invasion warrant further investigation and probable resection (3). Lesions that are 2 cm or less can be followed as there is low risk for development of invasive cancer over 5 to 10 years. Incidental cysts that enlarge over time to greater than 3 cm and/or a change in morphology (presence of solid component) should be considered for resection. Despite the evolution of malignant clones within these lesions, the overall survival is better than with ductal adenocarcinoma.
- Screening tests: There are no approved screening tests for pancreatic cancer. CA 19-9, a sialated Lewis antigen, is elevated in 70% to 90% of patients with pancreatic cancer; however, it is not useful as a screening test because of low specificity. A recent analysis of resected patients revealed that 34% of patients were Lewis-antigen-negative (5). The CA 19-9 may have greater utility for surveillance in detecting recurrent or advanced disease. Changes or trends during treatment should not be used to alter therapy.
- Imaging techniques: Imaging techniques include chest radiographs, abdominal computerized tomography (CT), ultrasound, endoscopic retrograde cholepancreatography (ERCP), and endoscopic ultrasound (EUS)
TABLE 9.2. American Joint Committee for Cancer/International Union Against Cancer staging classification (2002) Primary tumor TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor limited to the pancreas ≥2 cm T2 Tumor limited to the pancreas 2 cm T3 Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery (SMA) T4 Tumor involves the celiac axis or the SMA (unresectable primary tumor) Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage grouping Stage 0 Tis N0 M0 Stage IA T1 N0 M0 Stage IB T2 N0 M0 Stage IIA T3 N0 M0 Stage IIB T1-3 N1 M0 Stage III T4 Any N M0 Stage IV Any T Any N M1 Source: From Exocrine Pancreas. In: American Joint Committee on Cancer. AJCC Cancer Staging Manual, sixth edition. New York, NY: Springer, 2002, 157-164. - Dual-phase contrast, helical CT: Its sensitivity is 67% for lesions <1.5 cm and almost 100% for tumors >1.5 cm; it has a 95% positive predictive value in defining resectability if major vessel tumor encasement is present.
- Endoscopic ultrasound is excellent for tumor and nodal staging, and also for detecting the presence of portal vein invasion; fine-needle aspiration (FNA) provides tissue for pathologic diagnosis with minimal risk of tumor seeding; hepatic lesions can be visualized and sampled; limitations include assessment of blood vessel encasement or superior mesenteric artery (SMA) invasion.
- Pathologic diagnosis may be achieved with ERCP, laparoscopy, peritoneal cytology, or CT-guided biopsy.
resected, with resultant pancreatico-, choledocho-, and gastrojejunostomy. The peripancreatic, superior mesenteric, and hepatoduodenal lymph nodes are also staged. Pathologic review of the surgical margins must include assessment of the retroperitoneal margin (space directly adjacent to the proximal 3-4 cm of the SMA) by inking the margin and sectioning the tumor perpendicular to the margin.
Fig. 9.2. Resectable disease, locally advanced disease, metastatic disease. |
Fig. 9.3. Staging studies should include computerized tomography (CT) (spiral with contrast preferred) or magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), as well as laparoscopy for potentially respectable cancers. (*) indicates that for CT-guided FNA there is a controversy about tumor seeding in potentially curable (i.e., resectable) disease, and in some centers patients undergo a planned Whipple procedure to obtain tissue at the time of surgery. Adj CRT, adjuvant chemoradiation; FNA, fine needle aspiration; ERCP, endoscopic retrograde cholangio-pancreatography. |
performance status (PS) patients, 5FU is typically used as the radiosensitizing agent (500 mg/m2/day for days 1-3 and last 3 days or continuous infusion 250 g/m2/day). Median survival is approximately 10 months with treatment. Use of gemcitabine as a radiation-sensitizing agent has been evaluated. Initial studies of gemcitabine at a dose of 400 to 600 mg/m2/week and 5,040 cGy irradiation reported tolerability (mainly gastrointestinal toxicity and myelosuppresion) and objective responses in patients. Alternatively, in an effort to maximize the systemic effects of gemcitabine, a full dose of 1,000 mg/m2 every week has been combined with a maximally tolerated 4,200 cGy radiation (administered as 280-cGy fractions over 3 weeks). A recently presented study (n = 74 patients) compared gemcitabine to combined- modality therapy with gemcitabine as the radiosensitizer (10). Median survival was superior in the gemcitabineradiation arm versus the gemcitabine alone arm (11.0 vs. 9.2 months, P = 0.034) with manageable toxicity observed. Subset analyses from recent U.S. phase 3 trials support the approximately 9-month survival seen with chemotherapy alone Several studies have evaluated the use of preoperative chemotherapy-radiation in an effort to convert unresectable patients to resectable state. Despite reports of improvements, this approach is limited with only 8% to 13% of patients able to achieve a complete resection. Intriguing results with neoadjuvant approaches (11) have been reported in patients with “borderline resectable disease” as defined by the following tumor-vessel relationships: SMV-PV confluence that can be reconstructed (i.e., a suitable portal vein above, and SMV below the area of occlusion); tumor abutment of the SMA of <180 degrees; or short segment encasement of the hepatic artery amenable to resection and reconstruction (usually at the origin of the gastroduodenal artery). Metastatic Disease Approximately 50% of newly diagnosed pancreatic cancer patients have metastasis, and palliative treatment with systemic chemotherapy should be offered to patients with a good PS (Eastern Cooperative Oncology Group [ECOG] 0-1). Gemcitabine is the first-line standard treatment in patients with metastatic pancreatic cancer (12). This is based on a study in which 126 untreated patients were randomized to receive gemcitabine, 1,000 mg/m2 intravenously weekly for 3 of 4 weeks, or single-agent 5-FU, 600 mg/m2 intravenous bolus weekly. Despite an objective response rate of less than 10%, a benefit in quality-of-life scores (clinical benefit response 23.8% vs. 4.8%, [P = 0.0022]) and median survival (5.7 vs. 4.4 months, P = 0.0025) was observed with the gemcitabine therapy. The 1-year survival also favored the gemcitabine arm (18% vs. 2%). Several clinical trials attempting to surpass survival outcomes with gemcitabine alone have been reported. In the National Cancer Institute-Canada phase 3 trial PA.3, 569 patients were randomly assigned to receive standard gemcitabine and erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo (13). The primary end point, overall survival, was significantly longer with erlotinib/gemcitabine (median 6.24 vs. 5.91 months, HR 0.82 (95% CI, 0.69-0.99); P = 0.038). One-year survival (23% vs. 17%; P = 0.023) and progression-free survival (HR of 0.77; P = 0.004) were also improved with the combination. Exploratory analyses revealed that patients who developed ≥ grade 2 skin rash had better survival (10.5 months) while trends for improved outcome were seen with wild-type k-ras status and EGFR negativity as measured by FISH. The combination of gemcitabine and capecitabine (GEM-CAP) was evaluated by the National Cancer Research Institute of the United Kingdom (14). Although only presented as an interim analysis (70% of the expected events), survival (median—GEM-CAP 7.4 vs. Gem 6.0 months; 1-year—GEM-CAP 26% vs. Gem 19%) was improved with the combination. Capecitabine was given as 1,660 mg/m2/day for 21 consecutive days of a 4-week cycle while gemcitabine 1000 mg/m2 was administered weekly 3 times every 4 weeks. Responses were also higher with GEM-CAP (14.2% vs. 7.1%, P = 0.008). Presentation of the final results is awaited prior to declaring this the new chemotherapy standard although the regimen may be considered for patients with good PS. The role of combination chemotherapy in the treatment of metastatic patients has been explored using two- and three-drug regimens. Unfortunately despite signs of early promise in small, single institution studies with selected patient populations, the regimens proved inferior to gemcitabine alone upon formal phase 3 testing. Noteworthy combinations include gemcitabine and platinums or gemcitabine
with fluoropyrimidines. Several meta-analyses have been performed that support these combinations in patients with good PS. For example, with the gemcitabine-platinum combination, a HR of 0.85 (P = 0.010) is detected and with gemcitabine-fluoropyrimidine the HR is 0.90 (P = 0.030). In the subgroup with a Karnofsky PS of 90% to 100% or ECOG 0-1, survival benefits are more pronounced (HR = 0.76, P < 0.001) with combination chemotherapy (15). Another meta-analysis reported a consistent survival benefit (HR = 0.83, 95% CI, 0.72-0.96) with the combination of gemcitabine and capecitabine (16). Unfortunately, more detailed analysis derived from pooled individual patient data has not been presented. Targeted agents such as bevacizumab (Avastin) and cetuximab (Erbitux) have been evaluated in combination with gemcitabine in pancreatic cancer.
Gemcitabine in combination with cetuximab (loading dose 400 mg/m2 followed by 250 mg/m2 weekly) was evaluated in a phase 3 trial (17) by SWOG with a nonstatistically significant, yet similar to erlotinib, 2-week benefit being detected (6.4 vs. 5.9 months gemcitabine, HR 1.09 [0.93-1.27], P = 0.14).
Despite significant activity in a phase 2 trial, the CALGB study with gemcitabine with and without Avastin (10 mg/kg every 2 weeks) failed to demonstrate any survival advantage with the combination (5.8 vs. 6.1 months gemcitabine, HR = 1.03, P = 0.78). Trials with EGFR inhibitors (erlotinib or cetuximab) and bevacizumab have also failed to demonstrate any significant activity with the combined biologic approach.
5-FU, 225 to 250 mg/m2/day continuous infusion concomitantly with radiation or 5-FU, 500 mg/m2/day by intravenous bolus for the first 3 days and last 3 days of radiotherapy (total dose per 3-day course of fluorouracil, 1,500 mg/m2), or capecitabine 825 mg/m2 BID Monday through Friday, followed by
gemcitabine, 1,000 mg/m2/week intravenously weekly for 3 weeks (days 1, 8, and 15) followed by 1 week without gemcitabine for 4 to 6 months.
Gemcitabine, 1,000 mg/m2/week intravenous weekly for 3 weeks (days 1, 8, and 15), followed by 1 week rest. Treatment cycles are repeated every 28 days.
Gemcitabine-erlotinib 100 mg/day continuous
Gemcitabine-capecitabine 1,660 mg/m2/day days 1 to 21, 1-week rest of a 4-week cycle
Gemcitabine (either standard or prolonged infusion 10 mg/m2/min) given every 2 weeks with oxaliplatin 100 mg/m2 every 2 weeks of a 4-week cycle
Gemcitabine and cisplatin 50 mg/m2 given every 2 weeks of a 4-week cycle
