Adding Bevacizumab to IFL Combination Does Not Significantly Alter IFL Toxicity

PHILADELPHIA—Bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), was well tolerated in preliminary analyses of two Eastern Cooperative Oncology Group (ECOG) studies, according to Bruce J. Giantonio, MD, assistant professor of medicine, University of Pennsylvania Medical Center, Philadelphia.

Combination therapy with irinotecan (CPT-11, Camptosar), fluorouracil (5-FU), leucovorin (IFL) required reduction of irinotecan doses from 125 mg/m² to 100 mg/m² and of 5-FU from 500 mg/m² to 400 mg/m² in combination therapy, but bevacizumab did not increase the risk of thrombosis. The reductions of the starting doses of irinotecan and 5-FU were enacted as a result of the toxicity analyses conducted on other trials using IFL and not as a result of toxicities seen in this trial (E2200).

The phase II study enrolled patients with histologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum. Patients had no prior therapy for advanced disease, but prior 5-FU adjuvant therapy was allowed if it had occurred more than 1 year before study entry. Patients were treated with IFL every week for 4 weeks and with bevacizumab (10 mg/kg IV) every 14 days. Accrual was suspended at 92 patients in February 2002. Dr. Giantonio reported toxicity data on 60 patients, including 19 accrued prior to the dosage reduction.

Toxicity Profile Unaltered

"Gastrointestinal toxicities were common and not unexpected," Dr. Giantonio said. "Diarrhea was mostly grade 1 or 2 (67%); 15% of patients had grade 3 diarrhea; and there was no grade 4 diarrhea. Grade 1 or 2 vomiting occurred in 18% of patients, grade 3 in 12%, and grade 4 in 2%. Grade 1 or 2 nausea occurred in 59%, and grade 3 in 12%. Dehydration was grade 1 in 2% of patients, grade 3 in 5%, and grade 4 in 2%."

Neutropenia was the worst hematologic toxicity. Grade 1 or 2 neutropenia occurred in 43% of patients, grade 3 in 15%, and grade 4 in 18%. Grade 3 febrile neutropenia occurred in 5% of patients and infection with grade 3 or grade 4 neutropenia in 2%.

Thrombocytopenia was relatively rare, with grade 1 or 2 occurring in 20% of patients. "There were 21 bleeding events reported, 19 of which were grade 1 and predominantly epistaxis. Only one event required transfusions," Dr. Giantonio said. There were no treatment-related deaths in trial E2200.

"The addition of bevacizumab to irinotecan, leucovorin, and fluorouracil does not alter the toxicity profile for that regimen. Bleeding has been manageable and not life threatening. Reduced starting doses of irinotecan and fluorouracil are better tolerated," Dr. Giantonio said.

Phase III Trial

The other ECOG trial (E3200) was a phase III trial of bevacizumab, oxaliplatin (Eloxatin) 5-FU, and leucovorin, compared to oxaliplatin, 5-FU, leucovorin, or to bevacizumab alone in previously treated patients with advanced colorectal cancer. The trial enrolled patients with histologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum. All patients must have received a 5-FU-based regimen and an irinotecan-based regimen, but no prior oxaliplatin or bevacizumab.

The study included a planned suspension to conduct a toxicity analysis once 50 patients had been accrued in each arm. Dr. Giantonio said that 208 patients had been accrued at the time of the suspension and that 122 adverse events had been reported in 39 patients. "There have been no grade 4 hemorrhage events, although we do anticipate seeing some," Dr. Giantonio said. Thus far adverse events have been approximately the same on all three treatment arms. The only grade 4 thrombotic event occurred on the non-bevacizumab arm.

"Addition of bevacizumab does not significantly alter the toxicity profile and does not appear to increase the risk of thrombosis," Dr. Giantonio concluded.