Surgically Resectable Disease
For tumors confined to the pancreas and not involving vital vascular structures such as the celiac trunk or superior mesenteric artery, surgical excision is generally performed. In some centers, neoadjuvant chemotherapy and radiation are given to patients prior to surgery. If surgery is performed primarily, adjuvant chemotherapy with gemcitabine, with or without radiation is generally performed, regardless of nodal involvement. Adjuvant therapy generally lasts 6 months in duration.
For tumors generally limited to the pancreatic area but involving sufficient structures or tissue that precludes surgical resection, several therapies are employed. Radiation with chemotherapy sensitization such as 5-fluorouracil, capecitabine, or gemcitabine is often performed with a limited success in converting patients to resectability. Sometimes, systemic therapies such as FOLFIRINOX or gemcitabine-based therapy are given until progression of the malignancy.
For metastatic pancreatic adenocarcinoma, therapeutic options range from FOLFIRINOX (most aggressive, but highest side effect profile) to gemcitabine (fewer side effects) with or without erlotinib, to palliative care alone. Participation in a clinical trial if available is strongly encouraged, as current options are limited.
Since its approval in 1997 gemcitabine has been the standard of care for advanced pancreatic adenocarcinoma. Gemcitabine is generally well tolerated with side effects primarily limited to cytopenias and fatigue; more substantial side effects are uncommon. However, multiple gemcitabine-based combinations have failed to show a substantial survival benefit over gemcitabine alone, which still remains the mainstay of therapy for many patients. In 2010, a phase III study performed in Europe showed a substantial survival benefit from the aggressive combination of FOLFIRINOX (oxaliplatin, irinotecan, 5-FU, and leucovorin) over gemcitabine therapy. However given the substantial toxicity of this combination, including neutropenia and gastrointestinal side effects, FOLFIRINOX is primarily used in patients with good performance scores and few comorbidities. Gemcitabine is still utilized in the second-line setting, either alone or in combination with other agents such as erlotinib. For patients receiving gemcitabine-based therapy in the first-line setting there is data showing a benefit to oxaliplatin, 5-FU, and leucovorin (OFF) over best supportive care. The majority of practitioners have used the FOLFOX schedule (which includes the same drugs as OFF, but in a slightly different schedule) in the second-line setting after gemcitabine failure. It is not known if FOLFIRINOX is more active than FOLFOX in any line of therapy.
The only currently approved target therapy for pancreatic adenocarcinoma is erlotinib, a small molecule inhibitor of epidermal growth factor receptor (EGFR). The efficacy of this agent was demonstrated in a National Cancer Institute of Canada (NCIC) study in combination with gemcitabine, where the erlotinib arm had a longer survival than the gemcitabine alone arm. However this was a modest survival benefit, with a median difference in survival of less than 2 weeks, with the improvement in 1-year survival from 7% to 15%. Diarrhea and skin rash were prominent side effects in the combination arm; side effect profile along with the cost has limited the use of erlotinib in pancreatic cancer patients. Many other targeted agents are under investigation for therapy and pancreatic cancer but have not yet demonstrated survival benefit.