Summary of treatment of pancreatic cancer

Epidemiology & Etiology:

• Data regarding coffee and excess alcohol consumptions are conflicting; therefore, they cannot be considered true etiologic factors.
• There is an association between pancreatic cancer and diabetes; however, it is more likely that diabetes is an early manifestation of cancer and not necessarily a predisposing factor.
• Selective mutations of BRCA2, and, to a lesser degree, BRCA1 have been associated with familial pancreatic cancer.
• Approximately 10% to 20% of patients are thought to have a familial predisposition.
• Pancreatic adenocarcinomas arise from ductal epithelial cells.
• Pancreas cancer has the highest lethality of all the gastrointestinal malignancies.

Diagnosis:

• Diagnostic tests used for pancreas cancer are CT scan, MRI, EUS, and endoscopic retrograde cholangiopancreatography.
• Diagnostic tests, such as PET and EUS, may play a role in distinguishing cancer from other abnormalities and most importantly are used to adequately stage the disease, but do not replace a biopsy (e.g., EUS-guided) as a definitive diagnostic test.

Treatment:

• For patients with tumors that appear resectable, which includes only approximately 20% to 25% of all pancreatic cancers, surgery remains the only potentially curative treatment option.
• In order to determine the resectability of a pancreatic mass, a detailed evaluation of its spatial relationship to critical vascular structures, in particular, the superior mesenteric artery and celiac axis, has to be performed.
• The 5-year survival rate for the minority of patients who are able to undergo resection is 5% to 25%.
• Adjuvant therapy:
• Based on a small randomized study (43 patients) conducted in the United States, approximately 30 years ago in which a significantly larger number of patients in the combined-modality group were alive at 1 year compared with the surgery-alone group, postoperative chemoradiotherapy with bolus fluorouracil became the standard of care in the United States.
• Since then, the role of radiation in this context has been repeatedly challenged by European investigators.
• A German phase III trial (CONKO-1) including 364 patients demonstrated the superiority of adjuvant chemotherapy with gemcitabine compared with surgery alone for patients with resected pancreas cancer, regardless of whether a tumor-free resection margin could be obtained. An update of this study demonstrated a significant improvement in 5-year overall survival of 20.7% (95% CI 14.7%, 26.6%) for gemcitabine compared with 10.4% (95% CI 5.9%, 15.0%) for surgery alone, and 10-year overall survival of 12.2%.
• A large phase III trial mainly conducted in the United Kingdom, the ESPAC-3 trial, compared weekly gemcitabine to bolus 5-FU/LV (Mayo Clinic regimen) as adjuvant therapy in 1,088 patients with resected pancreas cancer. Median survival was almost identical in both groups (5-FU/LV: 23.0 months vs. gemcitabine: 23.6 months, p = 0.39). More mucositis/stomatitis and diarrhea were seen with bolus 5-FU/LV; patients assigned to gemcitabine had more thrombocytopenia. Based on these data, both adjuvant gemcitabine or bolus 5-FU/LV can be considered as appropriate adjuvant chemotherapy
• Most recently, at the 2013 ASCO Annual Meeting data from a randomized phase III comparison of gemcitabine with S-1, an oral fluoropyrimidine not available in the United States but commonly used in Japan, in 385 patients with resected pancreas cancer were presented. Although S-1 and gemcitabine had previously shown similar results in the advanced setting, adjuvant S-1 was found to be superior to gemcitabine in preliminary analysis with a substantial improvement of overall survival (2-year overall survival rate 53% vs. 70%, HR 0.54, p < 0.0001) and relapse-free survival (median 11.2 vs. 23.2 months, HR 0.57, p < 0.0001). In Japan, S-1 has since emerged as the standard of care in adjuvant therapy of pancreas cancer. It is unclear if these results can be extrapolated to the population of Western countries in which, at this point in time, adjuvant gemcitabine remains the adjuvant standard of care.
• To expand on the potential role of radiation therapy, a U.S. trial (Radiation Therapy Oncology Group, RTOG 9704) involving 451 patients documented an improved outcome for patients with pancreas head cancers (but not cancers of the pancreas body or tail) who received adjuvant gemcitabine followed by chemoradiotherapy with continuous infusion of fluorouracil (50.4 Gy, 5-FU at 250 mg/m2/day) and subsequent gemcitabine monotherapy compared with postoperative fluorouracil-based chemoradiotherapy. Patients with pancreas head tumors (388 patients) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group compared with a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (HR 0.82, 95% CI 0.65, 1.03; p = 0.09). By design, this trial was not able to verify if radiation therapy is an essential component of adjuvant therapy in resected pancreas cancer. Thus, for the foreseeable future, the standards of care might differ between the United States and Europe, with adjuvant gemcitabine-based chemotherapy without radiation favored in Europe and combined-modality approaches favored in the United States. It should be noted, however, that the data from the CONKO-1 trial (with a more than doubling of long-term overall survival) have made inroads into U.S. practice standards.
• Chemotherapy and Radiation for Locally Advanced Pancreas Cancers:
• For patients with initially unresectable cancers a “conversion approach” of chemotherapy with or without radiation is tolerable, with occasional tumor responses allowing subsequent surgical resection. No randomized trial has been conducted yet, so it is unclear if this approach is associated with a survival advantage. In addition, no clear definition of “borderline resectable” pancreas cancer has been established; although most surgeons consider abutment of major upper abdominal blood vessels the main criterion.
• For patients with locally advanced, unresectable disease, there are two treatment strategies: primary chemoradiotherapy or systemic chemotherapy.
• Chemoradiotherapy might be preferred for patients with poorly controlled pain from local tumor invasion in view of the well-documented analgesic effect of radiation therapy.
• Other palliative means to treat patients in this setting include biliary stenting, intraoperative or external beam radiation therapy, and celiac axis nerve blocks.
• It is noteworthy that in this context the routine preoperative placement of biliary stents in patients with biliary obstruction and operable pancreas head cancers was associated with an increase in surgical complications when compared with upfront surgery without prior biliary drainage. Thus, routine preoperative biliary drainage in patients undergoing subsequent surgery for cancer of the pancreas head is not recommended.

• Metastatic pancreatic cancer:
• In the mid-1990s, gemcitabine was tested against single-agent IV fluorouracil (administered without leucovorin as short-term infusion, thus not optimally administered) in a randomized clinical trial with 126 patients. Gemcitabine was found to be superior to fluorouracil regarding clinical benefit, with more patients (24% vs. 5%) experiencing a reduction of pain as well as improvements in appetite and weight. There were few clinical responses in either arm (less than 10%), but the median survival (5.65 vs. 4.4 months  and the 1-year survival rate (18% vs. 2%) were better for patients treated with gemcitabine.
• Two phase III trials showed small survival benefits of similar magnitude when another agent was used in combination with gemcitabine. In the first trial, the combination of gemcitabine with erlotinib, an EGFR tyrosine kinase inhibitor, was found to significantly increase progression-free survival albeit only with a median overall survival improvement of about 2 weeks.
• A new standard of care was defined by the results of a French study of 342 patients comparing gemcitabine with FOLFIRINOX, a combination of standard modified FOLFOX6, a well-known regimen established in colorectal cancer with full-dose irinotecan (180 mg/m2) in an every-2-week schedule.104 The median overall survival was an unprecedented 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group. Median progression-free progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group. The objective response rate was 31.6% for FOLFIRINOX compared with 9.4% for the gemcitabine group.
• A potentially competing standard first-line therapy to FOLFIRINOX in patients with good performance status was established when the addition of nab-paclitaxel to gemcitabine was found to be superior to gemcitabine alone in a phase III trial of 861 patients with metastatic pancreas cancer.112 The median overall survival was 8.5 months in the nab-paclitaxelgemcitabine group compared with 6.7 months in the gemcitabine group. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group compared with 3.7 months in the gemcitabine group. the response rate according to independent review was 23% compared with 7% in the two groups.
• It could be reasonable to establish a three-tier approach toward metastatic pancreas cancer:
• Otherwise healthy, younger patients in good performance status could preferentially be treated with FOLFIRINOX first-line and potentially nab-paclitaxel-gemcitabine second-line.
• Patients with poor performance status, advanced age, and significant comorbidities could still be considered candidates for gemcitabine as a single agent.
• In between these extremes lies a group of patients who could be considered for nab-paclitaxel-gemcitabine as first line therapy.
• The role of second-line therapies after failure of gemcitabine-based first-line approaches is not very well validated.
• German phase III trial randomly assigned 46 patients with advanced pancreas cancer who had received first-line gemcitabine to weekly infusional 5-FU/LV with biweekly oxaliplatin or best supportive care. The oxaliplatin-based therapy was able to confer a significant overall survival benefit 4.8 vs. 2.3 months, HR 0.45.