New Lessons From “Old” Chemotherapy in Colorectal Cancer

The standard of care in the treatment of metastatic colorectal cancer has seen a rapid evolution over the past 10 years. In clinical practice, combination regimens consisting of a fluoropyrimidine plus either irinotecan or oxaliplatin now commonly form the backbone for the addition of a biologic agent. In the first-line setting, this biologic agent is routinely bevacizumab; in subsequent lines of therapy, antibodies against the epidermal growth factor receptor (EGFR) are introduced, again mainly in combination with conventional cytotoxic chemotherapy. Presently ongoing clinical trials focus almost exclusively on defining the best strategy to integrate these biologic agents into palliative (or adjuvant) treatment algorithms, or on biomarkerdriven patient selection (eg, by using KRAS mutations to select a patient population with a greater likelihood of responding to EGFRtargeted approaches). Based on this current generation of ongoing trials, one might think that all pertinent questions related to conventional chemotherapy in colorectal cancer have been solved, and that it is time to move on beyond the nonselective, one-size-fits-all treatment decisions to a more sophisticated approach toward colorectal cancer. Indeed, the past 10 years have seen a plethora of definitive results from clinical trials which have shaped our current standard treatment approaches. We have learned that infusional fluorouracil (FU) is a much more appropriate backbone for the addition of irinotecan and/or oxaliplatin than bolus FU. We have seen that capecitabine can serve as substitute for FU in combination regimens with oxaliplatin, but that combinations with irinotecan can be problematic. Eventually, we have recognized that with all treatment options available, one particular treatment sequence is not superior to another, but that within clinical trials, the overall survival of patients with metastatic colorectal cancer is tightly correlated with the percentage of patients who are treated with all three active agents, fluoropyrimidine, irinotecan, and oxaliplatin. In view of all this knowledge on conventional chemotherapy, what could a trial of second-line irinotecan alone versus irinotecan plus oxaliplatin (IROX) after failure of FU/leucovorin (LV) tell us about palliative treatment algorithms in colorectal cancer in 2008? Currently, at least in the United States, few patients are treated with FU/LV alone as first-line therapy, and definitive first-line results with IROX are available from the pivotal phase III N9741 trial in which it was found to be inferior to FOLFOX4, but superior to IFL (bolus FU/LV plus irinotecan). In this issue of Journal of Clinical Oncology, Haller et al present the results of a phase III trial in advanced colorectal cancer which 628 patients who had shown tumor progression FU/LV were randomly assigned to either irinotecan or IROX. It is important to note that the time of patient accrual (January 2001 to April 2004) largely predates the era of biologics in colorectal cancer, and even oxaliplatin was not routinely available everywhere during that time. Haller et al report that IROX was found to be the superior second-line therapy with regard to overall survival, time to tumor progression, response rate, and improvement in tumor-related symptoms. In fact, the median overall survival for both arms was in the upper range of expectation, with 11.1 months and 13.4 months for irinotecan and IROX, respectively. The incremental gain in median progression-free survival (2.5 months) achieved with IROX over irinotecan alone translated almost exactly into the same incremental gain in overall survival. This finding is notable given the relatively high percentage of patients (46%) in the irinotecan arm who subsequently received an oxaliplatin-based therapy, although almost half of these patients received oxaliplatin as single agent in third-line therapy which is know to have very limited activity. The results of the Haller et al trial are very similar to the findings of N9841, a phase III trial which randomly assigned 491 patients in second-line after FU/LV failure to either irinotecan or FOLFOX4 with optional cross-over in third-line therapy. The overall survival for both arms was remarkably long but not statistically different (14.7 months for irinotecan, 13.5 months for FOLFOX4), conceivably due to the high rate of cross-over (51% for FOLFOX4, 38% for irinotecan). These results again highlight the sequence-independent overall survival effect of utilizing all three active cytotoxic agents in the course of therapy. The clinical relevance of the findings of Haller et al are strengthened by their inclusion of a standardized assessment of tumorrelated symptoms (TRS) in their study to provide information on patient benefit. This assessment recorded a combined metric of patient-reported variables (self-assessed pain intensity, patientassessed performance status), objectives measures (weight, analgesic use by diaries), and investigator-assessed performance status. Patients on IROX experienced an improvement in TRS compared with irinotecan alone, a result which nicely complements—and goes beyond— the tumor-related parameters demonstrating superiority of IROX. The trial convincingly shows the feasibility and added value by using patient-reported outcome measures in study designs. The trial results raise the question of whether IROX should now be considered the optimal second-line therapy after FU/LV JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 28 OCTOBER 1 2008