A New Direction for Pancreatic Cancer Treatment: FOLFIRINOX in Context.

Since 1996, the cornerstone of chemotherapy for advanced pancreatic cancer has been gemcitabine, which has a genuine, but modest effect on survival and quality of life. It has been remarkably difficult to improve on these outcomes. Many phase III studies of gemcitabine doublets have been uniformly negative, with the exception of a trial of gemctabine plus erlotinib, which provided only marginal benefit. In 2010, the FOLFIRINOX regimen (bolus and infusional 5-fluorouracil, irinotecan, and oxaliplatin) emerged as a major treatment advance for patients with metastatic pancreatic cancer. In a trial with 342 patients, FOLFIRINOX yielded a longer median overall survival (11.1 vs. 6.8 months, hazard ratio [HR] 0.57, p < 0.001), a superior progression-free survival (6.4 vs. 3.3 months, HR 0.47, p < 0.001), a higher objective response rate (31.6% vs. 9.4%, p < 0.001), and a significant increase in time until definitive deterioration in quality of life, compared with gemcitabine. FOLFIRINOX is also more cost-effective than gemcitabine. Because of higher rates of grade 3 to 4 neutropenia (46% vs. 21%), febrile neutropenia (5% vs. 1%), and diarrhea (13% vs. 2%) with FOLFIRINOX, vigilant patient selection, education, and monitoring are essential. Retrospective single-institution series confirm the substantial activity of FOLFIRINOX in metastatic, locally advanced, and previously-treated patients; demonstrate its safety in individuals with biliary stents; and elucidate how physicians routinely modify drug doses without clear evidence or guidelines. Ongoing and planned studies will prospectively evaluate FOLFIRINOX in the adjuvant, locally advanced, and borderline resectable settings, will add targeted agents to FOLFIRINOX, and will evaluate how to adjust doses to ameliorate toxicity.