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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3322-3324 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.6118
Turning Point for Colorectal Cancer Clinical TrialsFox Chase Cancer Center, Philadelphia, PA The recent introduction of therapeutic antibodies for the treatment of patients with colorectal cancer has garnered well-deserved attention and excitement.1-4 However, it is notable that traditional cytotoxics remain the backbone of systemic therapy for this disease. The benefits of both bevacizumab and cetuximab are augmented by concurrent administration of chemotherapy.2,3 In fact, both of these targeted therapeutics may be appropriately viewed as chemotherapy sensitizers. Therefore, efforts to refine understanding and optimize the clinical use of available cytotoxics remain important. In this issue, Goldberg et al5 report outcomes for a subset of patients enrolled onto North Central Cancer Treatment Group trial 9741, a North American intergroup study of initial therapy for patients with metastatic colorectal cancer. The latest data from this rich clinical resource continue to answer relevant clinical questions, while highlighting those that remain. In addition, the design and conduct of this trial illustrate how the world of clinical research in colorectal cancer has evolved over the past decade. North Central Cancer Treatment Group trial 9741 was the first phase III cooperative group study to move beyond the question of how best to deliver fluorouracil (FU).6 It was designed at a time when irinotecan and oxaliplatin were new to our armamentarium. Whereas irinotecan was commercially available at the initiation of this trial, oxaliplatin was not. The study began as a six-arm trial. Bolus FU/leucovorin (LV) was the control arm, with two irinotecan plus FU/LV schedules, two oxaliplatin plus FU/LV schedules, and a nonfluoropyrimidine irinotecan plus oxaliplatin arm.7 After the study was initiated, emerging data showed improved survival for irinotecan/FU/LV compared with FU/LV, and a new standard treatment for patients with metastatic colorectal cancer was established. Consequently, the FU/LV control arm was deleted. In addition, the arms containing a daily times five bolus schedule of FU/LV with either oxaliplatin or irinotecan, which were regimens that had not undergone extensive previous clinical testing, proved too toxic and were also discontinued. The initial inclusion of these arms represented a new level of confidence by the GI intergroup in the ability to successfully monitor toxicity in real time and react rapidly with appropriate protocol modification if needed. Thus, 9741 was reduced to the following three arms: weekly irinotecan/FU/LV (IFL), biweekly oxaliplatin/bolus plus infusional FU/LV (FOLFOX4), and 3-weekly irinotecan plus oxaliplatin. Approximately 1 year after the three-arm design was implemented, real-time toxicity monitoring identified an excessive frequency of toxic deaths on the IFL arm (4.6% 60-day mortality rate),8,9 and the study was once again amended, with a reduction of the starting doses of irinotecan and FU on the IFL arm (rIFL). The logistics involved in each of these modifications were complex, requiring coordination and commitment by investigators, the National Cancer Institute, the US Food and Drug Administration, local institutional review boards, industry sponsors, and patients. The reward for this commitment has been the rich data set of clinical and laboratory material derived from N9741. The current report of Goldberg et al5 considers the 305 patients randomly assigned to receive either rIFL or FOLFOX4. As anticipated, the reduced starting doses of irinotecan and FU were associated with reduced toxicity. However, the rIFL regimen proved inferior to FOLFOX4 in time to progression (5.5 v 9.7 months, respectively; P < .0001), response rate (32% v 48%, respectively; P = .006), and overall survival (16.3 v 19.0 months, respectively; P = .026). The findings are similar to those previously reported when comparing FOLFOX4 with standard-dose IFL before the protocol modification in N9741.6 Have we learned anything other than that rIFL is better tolerated than IFL but remains inferior to FOLFOX4 on all efficacy measures? I believe the answer is yes. It was initially hoped that N9741 would determine the comparative efficacy of irinotecan and oxaliplatin. However, the arms differed in how FU was administered, potentially biasing the comparison in favor of the infusional FOLFOX4 regimen.10 Furthermore, given that oxaliplatin was not widely available at the time the original cohort was enrolled, there was a significant imbalance in subsequent therapy received, with 60% of patients on the FOLFOX4 arm ultimately receiving irinotecan but only 24% of the patients on the IFL arm receiving subsequent oxaliplatin.6 This imbalance would tend to favor improved survival in the FOLFOX4 arm.11 This study helps clarify the relative contribution of subsequent therapy because an equivalent proportion of patients in both the rIFL and FOLFOX4 arms was able to obtain cross-over treatment (approximately 55% to 60%) because of the commercial availability of oxaliplatin during this time period. Because the survival benefit for FOLFOX4 was preserved, these data (in conjunction with other randomized data showing equivalence of oxaliplatin and irinotecan when administered with an identical infusional FU regimen12) provide additional support for the hypothesis that infusional FU is a superior platform than bolus FU for the addition of other agents, contributing to improved response rate and several months of progression-free and overall survival. Therefore, when irinotecan is selected for initial therapy of metastatic colorectal cancer, it should be combined with infusional (eg, folinic acid, FU, and irinotecan [FOLFIRI]12) rather than bolus (IFL or rIFL) FU. Furthermore, the consistent finding in other studies that bevacizumab benefits patients with colorectal cancer receiving a variety of chemotherapy regimens1,3,13 lends credence to its routine inclusion in front-line therapy with folinic acid, FU, and irinotecan or FOLFOX.
Although FOLFOX4 is superior to rIFL in time to progression, there was no difference between these treatments in time to treatment discontinuation. Although not reported by Goldberg et al,5 this finding suggests that more patients may have discontinued FOLFOX4 before disease progression because of toxicity. Neurotoxicity and neutropenia were the only N9741 signifies a turning point in the design and conduct of large-scale cooperative group clinical trials in colorectal cancer. Although this was an initial effort to move beyond FU modulation, it is ironic that a significant conclusion from this study is that FU delivery schedule is a likely basis for the observed results. Although not an anticipated goal, this study demonstrated that an intergroup effort can be nimble, reacting to new findings from without and within. This has enabled the next generation of studies to accelerate development of new agents, asking bold questions and proceeding with the knowledge that a phase III clinical trial is a living entity and is able to react, develop, and bear unanticipated fruit. Author's Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
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Goldberg RM, Sargent DJ, Morton RF, et al: Randomized controlled trial of reduced-dose bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and oxaliplatin in patients with previously untreated metastatic colorectal cancer: A North American intergroup trial. J Clin Oncol 24:3347-3353, 2006 6. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 7. Goldberg RM, Sargent DJ, Morton RF, et al: Early detection of toxicity and adjustment of ongoing clinical trials: The history and performance of the North Central Cancer Treatment Group's real-time toxicity monitoring program. J Clin Oncol 20:4591-4596, 2002 8. Sargent DJ, Niedzwiecki D, O'Connell MJ, et al: Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. 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Kabbinavar FF, Hambleton J, Mass RD, et al: Combined analysis of efficacy: The addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 23:3706-3712, 2005 14. Tournigand C, Cervantes A, Figer A, et al: OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—A GERCOR study. J Clin Oncol 24:394-400, 2006 15. Webster RG, Brain KL, Wilson RH, et al: Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels. Br J Pharmacol 146:1027-1039, 2005[CrossRef][Medline] 16. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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grade 3 adverse events more common with FOLFOX4. Grade 3 paresthesias occurred in 14.4% of patients treated with FOLFOX4. This is a key concern for oxaliplatin therapy, given that neurotoxicity may be irreversible. An empirical approach recently undertaken has been an intermittent scheduling of FOLFOX, in which oxaliplatin is discontinued after a predefined number of cycles of FOLFOX and reinitiated at the time of disease progression.
