Current Progress in Targeted Therapy for Colorectal Cancer

Jose Ortega, MD; Carlos E. Vigil, MD; Catherine Chodkiewicz, MD

Disclosures

Cancer Control. 2010;17(1):7-15. 

In This Article

Bevacizumab in Metastatic Colon Cancer

Bevacizumab, a humanized monoclonal antibody targeting VEGF-A, has been approved by the FDA for first-and second-line treatment of metastatic colorectal cancer. Bevacizumab was expected to have activity as a single agent by reducing the blood vessel density within tumors. In fact, when used as a single agent, bevacizumab provided only modest response rates, whereas it demonstrated significant efficacy when used in combination with conventional chemotherapy compared to chemotherapy alone.[5] These clinical observations led to the hypothesis that perhaps by destroying some of the tumor vasculature, the compound might make the remaining vasculature more organized and less tortuous, thus improving tumor blood flow and raising oxygen levels in the tumor and thereby resulting in better chemotherapy delivery to the tumor.[6]

Bevacizumab and Irinotecan Combinations

A 2004 pivotal trial that gained approval of bevacizumab in the United States in first-line treatment of metastatic colorectal cancer showed that the addition of bevacizu mab to a bolus 5-fluorouracil (5-FU) leucovorin, and ir ino tecan regimen (IFL) compared to IFL alone significantly improved response rates (45% vs 35%), time to progression (11 months vs 6 months), and overall survival (20 months vs 16 months).[7] The IFL regimen proved later, in the BICC-C trial, to be inferior and is no longer used.

The BICC-C trial randomized patients to IFL vs FOLFIRI (a protracted infusion of 5-FU/irinotecan) vs capecitabine/irinotecan (CAPIRI) with or without celecoxib vs placebo.[8,9] In January 2005, safety concerns regarding celecoxib led to the discontinuation of the drug in all study patients. Following the approval of bevacizumab in 2004, the study was amended to include bevacizumab in all treatment arms; the CAPIRI arm was discontinued due to significant toxicities. Of the 430 patients accrued to the study, 117 received bevacizumab. The median survival of patients receiving FOLFIRI with bevacizumab was significantly superior to that of patients receiving IFL/bevacizumab (28 months vs 19.2 months).

Bevacizumab and Oxaliplatin Combinations

In the first-line metastatic setting (N016966 trial[10]) in association with either FOLFOX or capecitabine/oxaliplatin (CAPOX), bevacizumab failed to increase response rates (38% in both arms) or survival (19.9 months vs 21.3 months compared with either combination alone), although a progression-free survival (PFS) benefit was observed in the trial (9.4 months vs 8.0 months). However, the magnitude of the benefit recorded with bevacizumab was smaller than expected; patients treated with bevacizumab had discontinued treatment early because of toxicity rather than disease progression. Premature discontinuation of bevacizumab before disease progression occurred may explain the less impressive (although statistically significant) difference in terms of PFS (hazard ratio [HR] = 0.83; 97.5% confidence interval [CI], 0.72–0.95, P=.0023) between the two treatment arms.

In an Eastern Cooperative Oncology Group trial (ECOG 3200),[11] the use of bevacizumab with FOLFOX in second-line treatment of metastatic colon cancer resulted in significantly improved PFS (7.3 months vs 4.7 months) and median survival (12.9 vs 10.8 months) compared with FOLFOX alone. Based on these results, bevacizumab was approved for second-line use in metastatic colorectal cancer.

Bevacizumab and 5-FU Combination

There is an added benefit to the use of bevacizumab with 5-FU/leucovorin in the in first-line treatment of metastatic disease. A combined analysis of the results from three different studies showed that the combination resulted in longer median survival compared with 5-FU alone (17.9 months vs 14.6 months) and in longer median PFS (8.8 months vs 5.6 months) compared with 5-FU/leucovorin.[12]

Bevacizumab-related Toxicities

The most common side effect seen with bevacizumab across trials is hypertension, which occurs in approximately 25% of patients and requires medical treatment in about 10% of cases. Other more serious but less frequent complications include gastrointestinal perforations, wound-healing complications, and thromboembolic events (strokes or myocardial infarction). The BEAT study[13] (conducted in Europe) and the BRiTE study[14] (conducted in the United States) were two open-label phase IV registry studies. The purpose of both studies was to evaluate the incidence of toxicities in a more diverse patient population receiving bevacizumab in combination with any of the approved chemotherapy regimens for colon cancer. Rates of toxicities were comparable to those seen in the pivotal trial that gained the drug approval ( Table 1 ).

Interestingly, patients in the BRiTE registry who continued chemotherapy with bevacizumab past first disease progression had an improvement in median survival compared with those who received chemotherapy only or no treatment at all. Yet, the use of bevacizumab beyond progression remains controversial and is not considered standard of care in the United States.[15]

Bevacizumab in the Adjuvant Setting

Full results from the NSABP C-08 trial were presented in 2009.[16] In this study, patients with stage II and III colon cancer were randomly assigned to receive FOLFOX or FOLFOX plus bevacizumab for 24 weeks followed by maintenance bevacizumab for an additional 24 weeks in the experimental arm. The study did not reach its primary objective of improving disease-free survival at 3 years, with a modest improvement of 2% with the use of bevacizumab over that of FOLFOX alone. Interestingly, the trial showed a significant benefit for the bevacizumab arm in the first year of the trial when most patients were exposed to bevacizumab. However, that benefit became insignificant over time, suggesting that bevacizumab may have delayed recurrence but did not increase the cure rate. Results from another adjuvant study, the AVANT trial, are expected in 2010.[15]

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