Survival Benefit From Up-Front Fluorouracil, Leucovorin, and Irinotecan/Cetuximab in Metastatic Colorectal Cancer: Is It Just a Now-or-Never Result?

Abstract

TO THE EDITOR: I read with interest the updated analysis of the overall survival results according to tumor KRAS and BRAF mutational status from the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial. 1 Thestudydemonstratedastatisticallysignificantandclinicallymeaningful increase of 3.5 months of life in patients with KRAS wild-type tumorstreatedwithinitialfluorouracil,leucovorin,andirinotecan(FOLFIRI)/cetuximab.However,wasthisafunctionoftheuseofcetuximab in first-line therapy or simply a result of the use of anti‐epidermal growthfactorreceptor(EGFR)monoclonalantibodiessomewherein the course of the disease? Earlier trials in metastatic colorectal cancer clearly demonstrated that the initial use of multiple drugs in combination was no better from a survival perspective than the sequential useofthesamedrugs. 2,3 Also,theNationalCancerInstituteofCanada CO17trial 4 revealedthatsingle-agentcetuximabadded4.7monthsof survival benefit in individuals with KRAS wild-type tumors when given after all standard chemotherapy failed. Because only approximately30%ofpatientsintheFOLFIRIcontrolarminthecurrenttrial ever received an anti-EGFR drug in the course of their illness, it is difficult to attribute the survival gain to the addition of cetuximab to first-line FOLFIRI chemotherapy. It is equally plausible that the survival benefit was simply a function of the fact that all patients in the