Austin Duffy, Christopher Ryan Heery, and Tim F. Greten
EPIDEMIOLOGY
■In 2012, an estimated 43,920 new cases of pancreatic cancer were diagnosed with 37,390 individuals dying from this disease.
■Pancreatic cancer remains the fourth leading cause of cancer death in the United States.
■There is a slight male predominance (1.3:1) and a variation in risk according to both race and family history. African Americans are at a higher risk for developing pancreatic cancer and have higher mortality rates. It is estimated that between 3% and 16% of cases have a familial component.
■Cigarette smoking is perhaps the most important environmental risk factor. The risk decreases following cessation. Other risk factors are chronic pancreatitis, heavy alcohol intake, diabetes, obesity, and physical inactivity. Data regarding diet type and intake of coffee or NSAID medication are inconclusive.
■The peak incidence of pancreatic cancer occurs in the seventh and eight decades of life.
Pathophysiology
The pancreas performs both endocrine and exocrine functions. Most pancreatic malignancies arise from the ductal epithelium of the exocrine pancreas. K-ras mutations are present in over 90% of pancreatic cancer, a molecular event which is believed to occur early in tumorigenesis. Other frequent molecular findings comprise loss of the tumor suppressor genes DPC4 and p16. Other primary pancreatic tumors are listed in Table 9.1. Intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms follow a more indolent course in general. Patients with IPMN are at increased risk of developing invasive adenocarcinoma and may also be at risk for the development of extra-pancreatic malignancies.
Clinical Features
■The majority of pancreatic ductal adenocarcinomas arise from the head of the pancreas, frequently presenting with biliary obstruction and jaundice necessitating stent placement. Pain caused by localized disease is classically described as mid to upper back pain resulting from tumor invasion of the celiac and mesenteric plexi. This can be palliated effectively by celiac axis block.
■Many patients develop some degree of pancreatic insufficiency leading to fat malabsorption and require replacement with exogenous enzymes at mealtime. Anorexia and weight loss are perhaps the most frequent symptoms in pancreatic cancer and nutritional support and supplementation is extremely important. Small bowel obstruction can occur with bulky head of pancreas tumors, often requiring surgical bypass. Glucose intolerance is also a frequent development.
STAGING
The American Joint Committee for Cancer/International Union Against Cancer (AJCC/UICC) staging classification of pancreatic cancer is the most widely used staging system. The practical importance of accurate staging is to discriminate between three categories: (1) operable or potentially operable disease; (2) inoperable but localized disease; and (3) metastatic disease. It is noted that in pancreatic cancer—unlike other solid tumors—stage III disease is by definition inoperable.
DIAGNOSIS
■Screening tests: There are no approved screening tests for pancreatic cancer.
■Tumor markers: CA 19-9 is the most useful and frequently measured tumor marker. However, it is relatively nonspecific, being elevated in the presence of jaundice and other upper GI cancers. In addition, between 10% and 30% of patients will never manifest an elevation in this marker. The CA 19-9 may have utility for surveillance following surgery or in the setting of advanced disease; however, changes or trends during treatment are complimentary to management and should not be used to alter therapy.
■Imaging techniques: Imaging techniques include chest radiographs, triphasic abdominal computerized tomography (CT) (with oral water contrast for enhanced imaging), ultrasound, endoscopic retrograde cholepancreatography (ERCP), and endoscopic ultrasound (EUS).
■EUS is excellent for tumor and nodal staging, and also for detecting the presence of portal vein invasion, although it is operator dependent. A major advantage of EUS is the ability to perform fine-needle aspiration (FNA). Hepatic lesions can also be visualized and potentially sampled.
■Pathologic diagnosis may be achieved with ERCP, laparoscopy, peritoneal cytology, or CT-guided biopsy.
MANAGEMENT
For the management of patients with pancreatic cancer the most important considerations relate to both the tumor stage and performance status of the patient. Following either surgical or radiological staging, the patient’s disease can be deemed (1) resectable or potentially resectable; (2) locally advanced, inoperable; or (3) metastatic.
Resectable Disease
Surgical removal of locally confined disease is the only realistic curative option. Even in that circumstance, however, the relapse rate is high such that surgical resection (with adjuvant chemotherapy) is viewed by many as deferring rather than eliminating recurrence. Less than 20% of patients with pancreatic cancer have disease that is considered resectable at diagnosis, meaning that the tumor is confined to the pancreas and not encasing the celiac axis or SMA and, at many institutions, not involving the superior mesenteric vein–portal vein confluence. A Whipple or modified, pylorus-sparing procedure is the surgical procedure of choice for pancreatic head tumors. The stomach (distal third), gallbladder, cystic and common bile ducts, duodenum, and proximal jejunum are 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 to 4 cm of the SMA) by inking the margin and sectioning the tumor perpendicular to the margin. For tumors in the tail of the pancreas, distal pancreatectomy is performed.
Adjuvant chemotherapy: The current standard of care adjuvant chemotherapy for pancreatic cancer consists of either 5-fluorouracil (5-FU) or gemcitabine for 6 months. The major studies which have led to this are as follows:
–The ESPAC-1 trial (Neoptolemos et al. 2004) evaluated four groups of postsurgical patients treated with (1) surgery alone, (2) chemotherapy alone, (3) chemoradiation alone, or (4) chemoradiation followed by chemotherapy. The chemotherapy consisted of 5-FU/leucovorin and the median survival was 20.1 months (95% CI 16.5 to 22.7 months) for those who received chemotherapy and 15.5 months (95% CI 13.0 to 17.7 months) for those who did not receive chemotherapy (HR for death 0.71). Two-year and 5-year survival estimates were 40% and 21%, respectively, among patients who received chemotherapy compared to 30% and 8%, respectively, among patients who received no chemotherapy.
–The RTOG 9704 trial compared gemcitabine and 5-FU in a 442 patient study, all of whom also received adjuvant 5-FU-based chemoradiation. There was a suggested benefit to gemcitabine for patients with tumors in the head of the pancreas for whom the median and 3-year survival was 20.5 months and 31% respectively compared to 16.9 months and 22% in the fluorouracil group (HR 0.82; 95% CI 0.65 to 1.03; P = 0.09).
–The CONKO-1 study was a straightforward comparison of gemcitabine versus observation. Estimated disease-free survival at 3 and 5 years was 23.5% and 16.0% in the gemcitabine group versus 8.5% and 6.5% in the observation group, respectively. Gemcitabine significantly improved median overall survival (22.8 months vs. 20.2 months; P = 0.005). Estimated survival at 3 and 5 years was 36.5% and 21.0% for the gemcitabine-treated group compared to 19.5% and 9.0% for the observation group.
–The European Study Group for Pancreatic Cancer (ESPAC)-3 trial directly compared 5-FU and gemcitabine in resected disease and found that there was no difference in survival (23 months vs. 23.6 months; P = 0.39).
Adjuvant chemoradiation: The role of radiation postpancreatectomy is controversial given the systemic nature of the disease when it recurs. A potential role for radiation is argued for the high risk of locoregional recurrence and the attendant morbidity of this. The data are conflicting however and derive mainly from older studies:
–The Gastrointestinal Study Group (GITSG) trial randomized patients to chemoradiation with maintenance chemotherapy (n = 21) versus surgery alone (n = 22). The chemoradiation arm consisted of split-course 4,000 cGy radiation in combination with bolus 5-FU. The chemotherapy was subsequently administered for up to 2 additional years. A significantly prolonged median survival of 20 months for the patients treated with chemoradiation versus 11 months for controls was observed.
–The European Organization for Research and Treatment of Cancer (EORTC) randomly assigned 218 patients with pancreatic or ampullary tumors to adjuvant 5-FU-based chemoradiotherapy (but no maintenance chemotherapy) or surgery alone. Although there was a trend toward a survival benefit for the treatment arm with median survivals of 17 and 13 months in the treatment and observation groups, respectively, and 5-year survival estimates of 23% and 10%, respectively, this was not statistically significant.
–The design of the ESPAC-1 study, mentioned above, allowed for a comparison of patients who received adjuvant chemoradiation and those who did not. There was no benefit for those patients who underwent chemoradiation, and in fact chemoradiation appeared to be detrimental. The median survival was 15.9 months (95% CI 13.7 to 19.9) among the 145 patients who were assigned to chemoradiotherapy and 17.9 months (95% CI 14.8 to 23.6) among the 144 patients who were not assigned to receive chemoradiotherapy (HR for death 1.28; 95% CI 0.99 to 1.66; P = 0.05). Two-year and 5-year survival estimates were 29% and 10%, respectively, among patients who received chemoradiotherapy, and 41% and 20%, respectively, among those who did not receive chemoradiotherapy. There have been a number of criticisms of this conclusion, however, especially with regard to the quality control of the radiation delivered.
Locally Advanced Pancreatic Cancer
For disease that is clearly unresectable the major modality of treatment is systemic chemotherapy. The role of radiation therapy (RT) has grown increasingly controversial—as in the adjuvant setting—largely due to a fuller appreciation of the tendency in pancreatic cancer for early systemic progression. An important exception to this, however, is for patients who have pain related to the loco-regional extent of their disease and for whom a definite palliative benefit exists with the use of chemoradiation. The majority of studies evaluating systemic therapy in metastatic disease also include locally advanced, nonmetastatic disease. The major studies evaluating chemoradiation in locally advanced pancreatic cancer (LAPC) are as follows:
–A number of small older clinical trials suggested a possible survival benefit for (5-FU-based) chemoradiation compared to radiotherapy alone in this patient population. For example, a trial by the GITSG suggested a benefit for chemoradiation plus chemotherapy compared to chemotherapy alone. The chemotherapy consisted of streptozocin, mitomycin, and 5-FU, and the 1-year survival benefit was 41% compared to 19%.
–In an attempt to address this question in the modern clinical trial era the FFCD–SFRO (Fédération Francophone de Cancérologie Digestive–Société Française de Radiothérapie Oncologique) performed a phase III study—the first for nearly 20 years to address this question—directly comparing chemotherapy and chemoradiation. In this study, 119 patients (of a planned 176) were randomized to undergo induction chemoradiation (with 5-FU 300 mg/m2/24 h as a continuous infusion, days 1 to 5 every week and cisplatin, 20 mg/m2/day, days 1 to 5 at weeks 1 and 5) followed by gemcitabine, or straight to chemotherapy with gemcitabine. The study was stopped prior to its full enrollment due to an inferior survival in the chemoradiation group (median survival 8.6 vs. 13 months; P = 0.014).
–Recently a similar study was presented comparing gemcitabine alone (1,000 mg/m2 weekly × 3 every 4 weeks for seven cycles) to chemoradiation (RT 50.4 GY in 28 fractions plus gemcitabine 600 mg/m2weekly × 6) followed by five cycles of gemcitabine alone (1,000 mg/m2 weekly × 3 every 4 weeks). The trial was stopped early due to slow accrual (N = 74, out of a planned 316). The median survivals were 9.2 months (95% CI 7.8 to 11.4) and 11.0 months (95% CI 8.4 to 15.5) for the two arms respectively (P = 0.044).
–The Groupe Coordinateur Multidisciplinaire en Oncologie (GERCOR) performed a retrospective analysis of 181 patients with locally advanced PAC who had been entered on prior prospective GERCOR studies and who had been offered chemoradiation (at the discretion of the investigator), but only if they had remained metastasis-free after a 3-month period. For those patients who were metastasis-free after initial chemotherapy, there was a survival advantage if they proceeded to chemoradiation compared to those who continued with chemotherapy alone (median OS 15.0 and 11.7 months, respectively; P = 0.0009). These data suggest that chemoradiation may offer a survival benefit in selected patients who have disease that remains localized after a test of time.
Metastatic Disease
The majority of patients present with advanced disease and for these patients systemic therapy is the major modality of treatment. Compared to best supportive care, chemotherapy has been shown to prolong survival in patients with advanced pancreatic cancer, a conclusion based on a meta-analysis of over 50 studies. The major consideration in the management of metastatic disease is the performance status of the patient which has been shown in multiple studies and meta-analyses to be in itself a powerful predictor of outcome. While progress has been slow there have been a few developments of note and the narrative pertaining to these is as follows:
–Gemcitabine is a nucleoside analog whose cornerstone role in pancreatic cancer was established in 1997 following a phase III study which demonstrated an improvement in clinical benefit and survival (a secondary endpoint in the study) compared to 5-FU in patients with advanced pancreatic cancer who had received no prior treatment. More patients treated with gemcitabine had an improvement in clinical benefit response—a composite measure of clinical improvement based on three factors: pain, performance status, and weight change—compared to those treated with 5-FU. There were also (modest) gains in survival (median survival 5.65 vs. 4.41; P = 0.0025; and 1-year survival 18% vs. 2% in favor of gemcitabine).
–Following this, efforts focused on combining with other cytotoxics, the majority of which resulted in negative studies. A meta-analysis of randomized trials, however, has indicated a significant survival benefit for combination regimens when gemcitabine was either combined with platinum agents (HR 0.85; 95% CI 0.76 to 0.96; P = 0.010) or fluoropyrimidines (HR 0.90; 95% CI 0.81 to 0.99; P = 0.030). In a subgroup analysis patients with a good performance status appeared to benefit from cytotoxic combinations (HR = 0.76; 95% CI 0.67 to 0.87; P < 0.0001), whereas patients with a poor performance status seem to have no survival benefit from combination chemotherapy.
–The first trial to show a survival benefit for any combination therapy in pancreas cancer and which led to FDA approval of this combination in the front-line treatment of pancreas cancer in 2005 was a study by Moore et al., in which 569 patients with untreated locally advanced or metastatic pancreas cancer were randomized to receive gemcitabine with either erlotinib or placebo. There was a very modest but statistically significant improvement in progression-free (HR 0.77; 95% CI 0.64 to 0.92; P = 0.004) 1-year survival (23% vs. 17%; P = 0.023) and median overall survival (6.24 months vs. 5.91 months, HR 0.82; 95% CI 0.69 to 0.99; P = 0.038) favoring the erlotinib arm. As has been the experience with EGFR inhibitors in other cancer types, the occurrence of a rash was associated with an improved outcome. The median survival rates for patients with grade 0, 1, and 2+ rashes were 5.3, 5.8, and 10.5 months, respectively, suggesting that although the benefit for the entire cohort is small, a specific subpopulation of patients may benefit significantly from the addition of erlotinib.
–Recently the combination of gemcitabine with albumin-bound paclitaxel formulation demonstrated activity in phase II studies and preliminary phase III results have been reported to be positive for survival.
–In 2011 the standard of care initial management for patients with good performance status changed with the publication of a phase III trial comparing gemcitabine with an intensive polychemotherapy regimen combining oxaliplatin, irinotecan, and 5-FU/leucovorin (FOLFIRINOX). Although there was increased toxicity with the experimental regimen it was associated with an impressive response rate (31.6% vs. 9.4%) and survival advantage (11.1 vs. 6.8 months) compared with gemcitabine.
REVIEW QUESTIONS
1.A 62-year-old male presents to his physician following the onset of jaundice. A CT scan reveals a 3 cm mass in the head of the pancreas with no evidence of metastatic disease. After referral to a surgeon the patient undergoes a Whipple resection. Pathology reveals a moderately differentiated T3 adenocarcinoma of the pancreas. Zero of 14 lymph nodes showed evidence of malignancy. The patient is recovering well. Which statement is TRUE regarding further management?
A.Adjuvant chemotherapy is not indicated as the patient’s lymph node resection was negative.
B.Adjuvant chemotherapy is indicated to improve quality of life but it has not been shown to prolong survival in randomized studies.
C.Adjuvant chemotherapy is indicated based on randomized studies showing a small survival benefit compared to placebo.
2.The following is a standard of care treatment consideration for a newly diagnosed patient of good performance status with metastatic pancreatic cancer to the liver:
A.Gemcitabine alone
B.FOLFIRINOX
C.Gemcitabine and erlotinib.
D.All of the above
3.Which of following statements about Ca-199 is TRUE?
A.Ca-199 is a useful screening tool in pancreatic cancer because it is noninvasive.
B.Ca-199 is particularly useful in patients with jaundice who are suspected of having pancreatic cancer.
C.A rising Ca-199 following surgery for pancreatic cancer should be treated with early chemotherapy in order to prolong survival, even if the CT scan is negative for metastatic disease.
D.Ca-199 has been shown to have prognostic value in both the pre- and postoperative settings.
Suggested Readings
1.Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-2413.
2.Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-1825.
3.Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer. 2008;8(1):82.
4.Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960-1966.
5.Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304(10):1073-1081.
6.Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-1210.
7.Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297(3):267-277.
8.O’Reilly EM. Adjuvant therapy for pancreas adenocarcinoma. J Surg Oncol. 2013;107(1):78-85.
9.Varadhachary G, Tamm E, Abbruzzese J, et al. Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol. 2006;13(8):1035-1046.