Over the past decade, new cytotoxic and biologic therapies beyond the old standard-of-care, biomodulated fluorouracil (5-FU), have become available for the treatment of metastatic colorectal cancer (mCRC). The introductions of irinotecan (Camptosar), oxaliplatin (Eloxatin), and bevacizumab (Avastin) have prolonged survival, but the optimal use of these new therapies remains to be determined. Issues remain regarding management of toxicities, treatment of elderly patients or those with poor performance status, and the duration of treatment with front-line therapy. This article reviews recent and ongoing studies of newer therapies in an effort to determine the best use of these drugs in the treatment of mCRC. Current data support the front-line use of bevacizumab added to either 5-FU/leucovorin alone or 5-FU/leucovorin in combination with oxaliplatin (FOLFOX/bevacizumab) or irinotecan (FOLFIRI/bevacizumab). If oxaliplatin is used in first-line therapy, oxaliplatin should be discontinued before the development of severe neurotoxicity and be reintroduced or replaced with irinotecan on disease progression. Definitive conclusions on the sequence and duration of front-line therapy and the most effective strategy to ameliorate toxicity await results of ongoing prospective clinical trials.
The past decade has been a dynamic era in the treatment of metastatic colorectal cancer (mCRC). A host of new cytotoxic and biologic therapies have become available, some of which have completely changed our approach to treating mCRC. Still others are being investigated. The agents with the greatest impact in the first-line treatment of mCRC are bevacizumab (Avastin), oxaliplatin (Eloxatin), and irinotecan (Camptosar). In clinical studies, when combined with fluorouracil (5-FU) and leucovorin (LV), these agents have been shown to prolong time to disease progression (FOLFIRI), progression-free survival (bevacizumab, FOLFOX, FUFOX) and overall survival (bevacizumab, FOLFIRI), compared to 5-FU/LV alone. Agents that have been shown to be efficacious in second-line treatment are irinotecan, bevacizumab, cetuximab (Erbitux), and the newly approved drug panitumumab (Vectibix), which has shown promising activity as a single agent in clinical trials.
It is important that oncologists recognize that the optimal use of these new agents—in particular, their sequencing—remains to be determined. Several challenges are associated with using these new therapies, including (1) minimizing toxicity, especially with oxaliplatin-containing regimens, (2) determining the appropriate adjustments in elderly patients and patients with poor performance status, (3) deciding how long to administer front-line chemotherapy, and (4) understanding which is the most meaningful clinical endpoint—particularly with bevacizumab, which has a primarily cytostatic rather than cytotoxic mechanism of action. This article reviews the data that support the current standard of care, addresses these challenges, and, in the absence of conclusive clinical trials, suggests a treatment strategy based on the currently available data.
Current Standard of Care
A number of significant milestones in the past 2 decades have shaped the management of mCRC mainly through the introduction of new, active agents beyond 5-FU in this disease (Table 1). With regard to 5-FU, most clinicians have accepted that a protracted infusion plus biomodulation with LV is the preferred method of administration, especially in combination regimens with oxaliplatin (FOLFOX) and irinotecan (FOLFIRI).
Oxaliplatin- and Irinotecan-Based Regimens
In the first few years of the 21st century, a total of six phase III trials clearly demonstrated that combination regimens using irinotecan or oxaliplatin plus 5-FU/LV (preferentially administered as infusional 5-FU) are superior to 5-FU/LV alone.[1,3,6-8] This superior efficacy manifested itself in increased response rate and prolonged progression-free survival, but did not necessarily translate into a significant improvement in overall survival, presumably due to the confounding effects of crossover therapies and subsequent second- and third-line therapies.
Although the ill-fated—and now obsolete—IFL regimen (weekly bolus 5-FU/LV/irinotecan) claimed the status of standard of care from April 2000 to April 2002, the results of Intergroup trial N9741 clearly showed that FOLFOX4 (bolus/infusional 5-FU/LV plus oxaliplatin) is superior to IFL in terms of toxicity and efficacy. Inevitable imbalances in second-line therapies during this time when irinotecan, but not oxaliplatin, was readily available for patients on study conceivably contributed to the fact that the difference in overall survival was perhaps more pronounced than that expected from progression-free survival and response rate results. However, this does not negate the fact that FOLFOX established itself as superior to IFL.
Since IFL and FOLFOX use different 5-FU/LV backbones, a fairer comparison between optimized oxaliplatin- and irinotecan-based combination regimens can be seen in the trial conducted by Tournigand and colleagues. In this relatively small trial, 220 evaluable patients with advanced colorectal cancer were randomized to either FOLFOX6 or FOLFIRI with a planned crossover option on progression. The key result of this trial was that all pertinent efficacy parameters (response rate, progression-free survival, and overall survival) revealed no appreciable difference between these two arms. These findings were recently confirmed by a slightly larger phase III trial conducted in Italy. Thus, the key criterion in choosing between FOLFOX and FOLFIRI as the most suitable first-line therapy is the difference in expected toxicities associated with each regimen.
Notably, patients who are exposed to each of 5-FU/LV, oxaliplatin, and irinotecan at some time during treatment have the longest reported overall survival in trials evaluating cytotoxic agents. In trial populations where more than 50% of patients have been treated with all three treatments, median overall survival ranges from 17.4 to 21.5 months; in those with 50% or fewer who have been treated with all three agents, median overall survival ranges from 13.9 to 17.5 months.[12,13] In addition, overall survival appears to be influenced more by the percentage of patients treated with all the available drugs at some time in their treatment than by the sequence and combinations that were used.
Furthermore, in multivariate analysis, the availability of all active agents was more important than the use of irinotecan- or oxaliplatin-based doublets as first-line therapy. However, because patients who are treated with first-line chemotherapy doublets ultimately have a greater chance of receiving all three active agents, these data support using combination therapy as a first-line approach.
The question of whether capecitabine (Xeloda) can serve as an equipotent and more convenient substitute for infusional 5-FU in combination regimens is currently being addressed in phase III trials. As a single agent, capecitabine is reportedly at least as active and better tolerated than bolus 5-FU/LV, except for a higher rate of hand-foot-syndrome.[14,15] The results from a phase III trial that compared capecitabine plus weekly oxaliplatin (CAPOX) with weekly 5-FU/LV/oxaliplatin (FUFOX) in 476 patients with advanced colorectal cancer showed no significant difference in overall response rates (48% and 54%, P = .70) or median overall survival (both ≥ 17.3 months, hazard ratio [HR] = 1.16) but slightly shorter median progression-free survival (7.1 vs 8.0 months, HR = 1.23) with CAPOX. Toxicity was comparable, with the exception of more hand-foot syndrome associated with CAPOX.
The recently presented, Roche-sponsored NO16966 phase III trial did indeed show noninferiority of XELOX to FOLFOX4. The trial was first designed as a direct comparison between XELOX and FOLFOX4 as palliative first-line treatment in advanced colorectal cancer. When bevacizumab was approved as a component of 5-FU-based first-line therapy, the trial was amended to a 2 × 2 design to test XELOX and FOLFOX plus bevacizumab or placebo. Eventually, 1,017 patients were randomized to a XELOX-based arm (XELOX or XELOX plus placebo or XELOX plus bevacizumab), and 1,018 patients received a FOLFOX-based treatment. In a pooled analysis, XELOX-based therapy was not inferior to FOLFOX4 in terms of the primary endpoint of the trial, progression-free survival (XELOX, 8.0 months; FOLFOX4, 8.5 months, HR = 1.04; 95% confidence interval = 0.93-1.16). On the basis of these data, XELOX and FOLFOX4 should be regarded as equally effective first-line combination regimens in this setting.
When compared to capecitabine/oxaliplatin or 5-FU/LV/irinotecan, the combination of capecitabine/irinotecan has led to a higher incidence of severe diarrhea.[7,18] When capecitabine is combined with either irinotecan or oxaliplatin, toxicity is related to the dose of capecitabine. Clearly, in studies conducted in the United States, dose reductions reduce the toxicity and, in the Three Regimens of Eloxatin Evaluation (TREE)-2 study, actually increased overall responses and outcomes. When using a capecitabine-based regimen, close attention must be paid to this issue of optimal dose.
Dr. Grothey has received honoraria for consulting from Amgen, Bristol-Myers Squibb, Pfizer, Genentech, and Roche. Dr. Marshall has received research support and honoraria from Pfizer, Sanofi, Genentech, Roche, Bristol-Myers Squibb, Amgen, and Boehringer Ingelheim.
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