FOLFIRINOX: A Small Step or a Great Leap Forward?

Clinical trials in advanced pancreatic cancer during the last couple of decades have almost uniformly yielded disappointing results. To date, the paradigm for almost all phase III studies has been to compare the long-time reference standard, gemcitabine, with a gemcitabinebased combination regimen. Agents evaluated in combination with gemcitabine have been myriad; these have included both cytotoxic drugs (platinum analogs, fluoropyrimidines, and camptothecins) and targeted therapies (inhibitors of farnesyl transferase, matrix metalloproteinase, vascular endothelial growth factor, and epidermal growth factor receptor, to name a few). With the exception of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib—which produced a modest incremental improvement when added to gemcitabine—none of these individual trials demonstrated a statistically significant survival benefit in favor of doublet therapy, although some have shown improvement in secondary outcome measures such as response rate and time to tumor progression. The continued use of multidrug regimens, in fact, has been guided more by a bias in oncology practice that combination therapy is better than monotherapy, meta-analyses that indicate a survival advantage with certain combinations, particularly in patients who retain a good performance status, and practice guidelines, rather than by compelling prospective randomized phase III data. With this as background, the results of the ACCORD4/Partenarait de Recherche en Oncologie Digestive (PRODIGE) 11 trial, first presented by Conroy et al at the 2010 annual meeting of the American Society of Clinical Oncology and recently published in the May 12, 2011, issue of the New England Journal of Medicine, are nothing short of eye opening. In this phase II/III trial conducted at 48 centers throughout France, 342 patients with previously untreated metastatic pancreatic cancer were randomly assigned to receive either gemcitabine monotherapy or a nongemcitabine-based regimen called FOLFIRINOX (biweekly bolus plus infusional fluorouracil, leucovorin, irinotecan, and oxaliplatin). There was a statistically significant improvement for the FOLFIRINOX arm in terms of the primary end point, overall survival (median of 11.1 v 6.8 months; P .001; hazard ratio for death, 0.57). Additionally, more patients on the FOLFIRINOX arm were alive at specified landmark time points; patients on this arm demonstrated a 1-year survival rate of 48.4% compared with 20.6% on the gemcitabine arm. Other secondary end points, including median progression-free survival (6.4 v 3.3 months) and objective response rate (31.6% v 9.4%), were likewise significantly in favor of the FOLFIRINOX regimen. A median survival of close to 1 year in a purely metastatic cohort has never before been approached in any phase III study of this disease. As such, the immediate question arises as to whether FOLFIRINOX should become the newly adopted standard of care for the front-line treatment of patients with metastatic pancreatic cancer, at least in those with preserved performance status. (Notably, patients enrolled onto this trial were required to have an Eastern Cooperative Oncology Group performance status of 0-1; there was also an upper-limit age cutoff at 76 years.) The authors offer an appropriately measured conclusion, noting in their final statement that FOLFIRINOX represents “a first-line option” (as opposed to the new gold standard) in this patient population. 3(p1824) Why is it prudent for us to follow this lead, tempering our enthusiasm with an appropriate degree of caution? First of all, not surprisingly, the FOLFIRINOX regimen was associated with higher rates of grade 3 and 4 toxicities than gemcitabine, including febrile neutropenia (5.4%), diarrhea (12.7%), and sensory neuropathy (9.0%). The incidence of severe toxicities is of paramount concern when weighing the risks and benefits of various therapies to determine which to offer patients in a noncurative setting. Additional measures that need to be accounted for but are not reported in this article include the frequency of less severe (grade 1 or 2) toxicities and hospitalization rates. Other practical considerations, such as the minor inconvenience associated with infusional pump therapy and central catheters, also factor into medical decision making. Importantly, despite the aforementioned toxicities, the time to definitive quality of life (QOL) degradation (as measured by a biweekly European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30) was superior in patients who received FOLFIRINOX compared with gemcitabine, presumably because of a delay in disease progression that was associated with this treatment arm. Especially in pancreatic cancer, such QOL measures are an absolutely essential component of assessing the risk/benefit ratio of any new therapeutic option, given patients’ short survival duration and the pain, anorexia, and inanition that so often accompanies the underlying disease process. (Recall, for instance, that clinical benefit response was used as the primary efficacy measure in the pivotal trial that led to the approval of gemcitabine for this disease.) Thus, inclusion of these QOL data are reassuring. Perhaps even more so, one needs to ask whether the absolute magnitude of survival benefit that is conferred by FOLFIRINOX is clinically meaningful and worth the added risks and toxicities. The modest improvement in median survival of 0.33 months in the PA.3 trial (A Randomized Placebo Controlled Study of OSI-774 [TARCEVA] Plus Gemcitabine in Patients With Locally Advanced, Unresectable or Metastatic Pancreatic Cancer), for example, helps explain why the combination of gemcitabine plus erlotinib has not gained more widespread traction for this disease indication. By comparison, an absolute incremental improvement in median survival of JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 29 NUMBER 28 OCTOBER 1 2011