Avastin Enhances FOLFOX Efficacy

HOLLYWOOD, Florida-Bevacizumab (Avastin) increases the efficacy of oxaliplatin(Drug information on oxaliplatin) (Eloxatin)-based second-line therapy in colorectal cancer, according to results of the Eastern Cooperative Oncology Group (ECOG) study E3200. The data were eagerly awaited after the National Cancer Institute released a preliminary report of the study, based on the recommendation of the trial's data monitoring committee, late last year (see ONI January 2005, page 2). The study results, presented as a late-breaking abstract at the 2005 Gastrointestinal Cancers Symposium (abstract 169a), showed that adding high-dose bevacizumab(Drug information on bevacizumab) to the oxaliplatin- based combination FOLFOX4 significantly lengthens overall survival in patients with advanced colorectal cancers. Previous studies had shown a similar benefit from the addition of bevacizumab to irinotecan (Camptosar)- based regimens. "These data suggest that the addition of bevacizumab to a treatment strategy that incorporates all three active chemotherapy agents [oxaliplatin, leucovorin, fluorouracil(Drug information on fluorouracil)] is likely to extend patient survival to beyond a median of 2 years," said Bruce J. Giantonio, MD, of the Abramson Cancer Center, University of Pennsylvania, who reported the results on behalf of the E3200 investigators. The study enrolled 828 patients who had metastatic colorectal cancer that had been previously treated with a fluoropyrimidine and with an irinotecan(Drug information on irinotecan)- based regimen, used either alone or in combination. Patients were initially randomized among three treatment arms: bevacizumab alone (10 mg/kg every 2 weeks), FOLFOX4 alone, or FOLFOX4 plus bevacizumab. Dosages FOLFOX4 dosages were as follows: oxaliplatin 85 mg/m² on day 1, leucovorin 200 mg/m² IV, and fluorouracil 400 mg/m² IV bolus, followed by fluorouracil 600 mg/m² by continuous IV for 22 hours on days 1 and 2. Dr. Giantonio pointed out that the dose of bevacizumab used in this study is higher than that used in previous studies of the agent. He said that the bevacizumab-only treatment arm was discontinued early because the data safety and monitoring committee found that mortality on that arm was approaching predefined limits for stopping treatment. Overall Survival This report included data for 290 patients randomized to FOLFOX4 plus bevacizumab and 289 patients randomized to FOLFOX4 alone. The primary endpoint was overall survival. Dr. Giantonio reported that median overall survival was 12.5 months with FOLFOX4 plus bevacizumab vs 10.7 months with FOLFOX4 alone (P = .0024, HR = 0.74). "This is the first time bevacizumab has been shown to be effective in a second-line setting in colorectal cancer," Dr. Giantonio said. Prior studies found improved outcomes with bevacizumab plus irinotecan, compared with irinotecan alone. "Our study adds to existing experience that suggests that bevacizumab's benefit in colorectal cancer may be independent of the particular chemotherapy given," Dr. Giantonio concluded. Adding bevacizumab to FOLFOX4 also increased the rates of grade 3 or 4 hypertension and grade 3 sensory neuropathy (see Table 1). Dr. Giantonio said that the treatment- related hypertension was controllable with conventional antihypertensive therapy. He told ONI that the investigators suspect this problem is due to bevacizumab inhibition of nitric oxide synthase (NOS). This molecule normally contributes to vasodilatory responses, he said. Without it, vascular constriction results, sometimes leading to elevations in blood pressure measurements. Sensory Neuropathy The management and prevention of oxaliplatin-related sensory neuropathies are currently under study. The increase in sensory neuropathy seen in patients treated with FOLFOX4 and bevacizumab is probably due to the longer time those individuals spent on treatment, Dr. Giantonio said. In commenting on the study, Robert J. Mayer, MD, director, Center for Gastrointestinal Oncology, Dana-Farber Cancer Institute, said, "This justifies giving bevacizumab with FOLFOX, an approach that had been questionable before."