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.
•Bevacizumab—In the same year that the N9741 trial was reported, results from another landmark study were published, which evaluated bevacizumab, a humanized antibody to vascular endothelial growth factor (VEGF). This trial compared IFL/bevacizumab, weekly bolus 5-FU/LV/bevacizumab, and IFL/placebo, with treatment continuing until disease progression.[19,20] Compared to IFL/placebo, IFL/bevacizumab resulted in a higher response rate (45% vs 35%, P < .05), prolongation of median progression-free survival by 4.4 months (10.6 vs 6.2 months, P < .001) and median overall survival by 4.7 months (20.3 vs 15.6 months, P < .001). It is important to note that patients who were treated with first-line IFL/placebo could not cross over to second-line bevacizumab; thus, the difference in progression-free survival was translated 1:1 into overall survival.
Once the safety of IFL/bevacizumab had been established in the phase III trial, the FU/LV/bevacizumab arm of the trial was discontinued with 110 patients enrolled. The results in this relatively small patient sample were later published, showing similar overall and progression-free survival for 5-FU/LV/bevacizumab and IFL/placebo with a trend in favor of the bevacizumab-containing arm. The results of adding bevacizumab to 5-FU/LV alone (without irinotecan or oxaliplatin) are important for patients who cannot tolerate or do not wish to be treated with the newer cytotoxic agents. A combined analysis of three randomized trials (N = 500) of bevacizumab added to 5-FU/LV alone showed significantly greater overall survival and progression-free survival (more than 3.3 and 3.2 months), compared with the combined control group of chemotherapy without bevacizumab (5-FU/LV alone, 5-FU/LV/placebo, or IFL/placebo). As the front-line use of IFL is (fortunately) diminishing, the efficacy and safety of bevacizumab had to be assessed in combination with oxaliplatin-containing regimens and with FOLFIRI.
For the TREE studies, two sequential randomized trials compared three oxaliplatin-based regimens with bevacizumab (TREE-2) or without bevacizumab (TREE-1). In each trial, oxaliplatin was paired with either infusional 5-FU/LV (mFOLFOX6, Table 2), bolus 5-FU/LV (bFOL), or capecitabine (XELOX). Results of TREE-1 and TREE-2 were recently presented together at the American Society of Clinical Oncology (ASCO) annual meeting (Table 3). Comparisons across trials indicate that bevacizumab enhances the efficacy of each treatment in terms of response rate, time to progression, and overall survival (Table 2). At a median follow-up of 27 months, overall survival for all bevacizumab-containing regimens combined (TREE-2) was 24.4 months, compared with 18.2 months without bevacizumab (TREE-1). The addition of bevacizumab did not increase the median time to treatment failure, a composite endpoint of efficacy and toxicity. The lack of effect of bevacizumab on this endpoint is conceivably due to the cumulative toxicity associated with oxaliplatin, which typically does not allow patients to remain on therapy for more than 6 months.
Most recently, a large randomized, placebo-controlled phase III trial (NO16966) investigated the addition of bevacizumab to XELOX or FOLFOX. This trial clearly demonstrated that bevacizumab increases progression-free survival when added to an oxaliplatin-based regimen in the first-line therapy of mCRC. The results of this trial and its implications for current clinical practice are discussed further below.
In a design similar to that of the TREE trials, the Bolus, Infusion, or Capecitabine with Camptosar ± Celecoxib (BICC-C) studies investigated the optimal fluoropyrimidine backbone for the addition of irinotecan in first-line treatment of mCRC. When bevacizumab was approved, the trial was amended to eventually compare modified IFL/bevacizumab (n = 60) with FOLFIRI/bevacizumab (n = 57) at a phase II level. These data were most recently presented at the 2007 ASCO Gastrointestinal Cancers Symposium; the median overall survival (not yet reached vs 19.2 months, P = .007) and progression-free survival (11.2 vs 8.3 months, P = .28) were greater with FOLFIRI plus bevacizumab than with bevacizumab plus mIFL. Of note, 1-year survival was markedly higher with FOLFIRI plus bevacizumab than with bevacizumab plus mIFL (87% vs 61%). Response rates were similar (54% and 53%) with the two regimens.
Bevacizumab has also been investigated in the second-line setting combined with oxaliplatin-based regimens. In the Eastern Cooperative Oncology Group (ECOG) E3200 phase III trial of FOLFOX4 plus bevacizumab (10 mg/kg) involving patients in whom irinotecan-based therapy had failed, FOLFOX4/bevacizumab significantly increased median progression-free survival (7.2 vs 4.8 months, P < .0001) and median overall survival (12.9 vs 10.8 months, P < .002) compared to FOLFOX4 alone. This trial included a bevacizumab-only arm, in which progression-free survival was inferior to FOLFOX4 alone (2.7 vs 4.8 months, P < .0001). Based on these data, bevacizumab in combination with intravenous 5-FU-based therapies received US Food and Drug Administration (FDA) approval for use in the second-line setting. These results highlight the benefit of combining bevacizumab with a cytotoxic agent such as conventional chemotherapy or, alternatively, with cetuximab, as discussed below. In contrast, the single-agent activity of bevacizumab in mCRC appears to be marginal at best.
•EGFR Antibodies—The other biologic strategy with proof-of-efficacy in mCRC is to target the extracellular domain of the epidermal growth factor receptor (EGFR) with monoclonal antibodies. The first antibody developed and eventually FDA-approved was cetuximab. The only currently published randomized trial of this agent for mCRC was conducted in the salvage setting of irinotecan-refractory disease. The addition of cetuximab to irinotecan compared to cetuximab alone in irinotecan-refractory patients significantly improved response (22.9% vs 10.8%) and time to progression (4.1 vs 1.5 months). Bevacizumab appears to increase the therapeutic benefit in an irinotecan-refractory population as well. When the combination of bevacizumab/cetuximab/irinotecan was evaluated in the BOND-2 trial and compared to historical controls receiving cetuximab/irinotecan alone in this setting, time to progression and response rate were greater in those receiving bevacizumab.[24,25]
More recently, very promising results have been presented for the monoclonal anti-EGFR antibody panitumumab. Unlike cetuximab, which is a chimeric IgG1 antibody, panitumumab is a fully human monoclonal IgG2 antibody. The pivotal trial was conducted in the third-line setting. Patients with mCRC who had failed oxaliplatin and irinotecan received either panitumumab plus best supportive care or best supportive care alone. Those receiving panitumumab experienced a 46% reduction in tumor progression compared to best supportive care alone (P < .000000001). As of early 2007, only limited data exist on the combination of panitumumab with modern cytotoxic combination regimens such as FOLFIRI. Therefore, panitumumab was approved as a single-agent salvage therapy option in patients with mCRC refractory to 5-FU, irinotecan, and oxaliplatin.
Based on the available clinical data, FOLFIRI, FOLFOX, and XELOX are appropriate chemotherapy backbones in the first-line therapy of mCRC, to which bevacizumab should be added to maximize efficacy. 5-FU/LV plus bevacizumab is an alternative for patients not considered candidates for irinotecan- or oxaliplatin-based combination therapy.
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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