Avastin Enhances FOLFOX Efficacy

March 2, 2005

This special “annual highlights” supplement to Oncology News International (ONI)is a compilation of selected news on important advances in the management ofgastrointestinal cancers over the past year, as reported in ONI. Guest Editor, Dr.James L. Abbruzzese, comments on the reports included herein and discussesdevelopments in the clinical management of GI cancers, with a look at the impactof targeted agents with cytotoxic chemotherapy, first-line and adjuvant therapies foradvanced disease, and the role of statins and COX-2 inhibitors in prevention.

HOLLYWOOD, Florida-Bevacizumab(Avastin) increases the efficacyof oxaliplatin (Eloxatin)-basedsecond-line therapy in colorectalcancer, according to results of the EasternCooperative Oncology Group(ECOG) study E3200. The data wereeagerly awaited after the National CancerInstitute released a preliminaryreport of the study, based on the recommendationof the trial's data monitoringcommittee, late last year (seeONI January 2005, page 2).The study results, presented as alate-breaking abstract at the 2005Gastrointestinal Cancers Symposium(abstract 169a), showed that addinghigh-dose bevacizumab to the oxaliplatin-based combination FOLFOX4significantly lengthens overall survivalin patients with advanced colorectalcancers. Previous studies had shown asimilar benefit from the addition ofbevacizumab to irinotecan (Camptosar)-based regimens."These data suggest that the additionof bevacizumab to a treatmentstrategy that incorporates all three activechemotherapy agents [oxaliplatin,leucovorin, fluorouracil] is likely toextend patient survival to beyond amedian of 2 years," said Bruce J. Giantonio,MD, of the Abramson CancerCenter, University of Pennsylvania,who reported the results on behalf ofthe E3200 investigators.The study enrolled 828 patientswho had metastatic colorectal cancerthat had been previously treated witha fluoropyrimidine and with an irinotecan-based regimen, used either aloneor in combination. Patients were initiallyrandomized among three treatmentarms: bevacizumab alone (10mg/kg every 2 weeks), FOLFOX4alone, or FOLFOX4 plus bevacizumab.DosagesFOLFOX4 dosages were as follows:oxaliplatin 85 mg/m2 on day 1, leucovorin200 mg/m2 IV, and fluorouracil400 mg/m2 IV bolus, followed by fluorouracil600 mg/m2 by continuousIV for 22 hours on days 1 and 2.Dr. Giantonio pointed out that thedose of bevacizumab used in this studyis higher than that used in previousstudies of the agent.He said that the bevacizumab-onlytreatment arm was discontinued earlybecause the data safety and monitoringcommittee found that mortalityon that arm was approaching predefinedlimits for stopping treatment.Overall SurvivalThis report included data for 290patients randomized to FOLFOX4 plusbevacizumab and 289 patients randomizedto FOLFOX4 alone. The primaryendpoint was overall survival.Dr. Giantonio reported that medianoverall survival was 12.5 months withFOLFOX4 plus bevacizumab vs 10.7months with FOLFOX4 alone (P =.0024, HR = 0.74). "This is the firsttime bevacizumab has been shown tobe effective in a second-line setting incolorectal cancer," Dr. Giantonio said.Prior studies found improved outcomeswith bevacizumab plus irinotecan,compared with irinotecan alone."Our study adds to existing experiencethat suggests that bevacizumab'sbenefit in colorectal cancer may beindependent of the particular chemotherapygiven," Dr. Giantonio concluded.

Adding bevacizumab to FOLFOX4also increased the rates of grade 3 or 4hypertension and grade 3 sensory neuropathy(see Table 1).Dr. Giantonio said that the treatment-related hypertension was controllablewith conventional antihypertensivetherapy. He told ONI that theinvestigators suspect this problem isdue to bevacizumab inhibition of nitricoxide synthase (NOS). This moleculenormally contributes to vasodilatoryresponses, he said. Without it,vascular constriction results, sometimesleading to elevations in bloodpressure measurements.Sensory NeuropathyThe management and preventionof oxaliplatin-related sensory neuropathiesare currently under study. Theincrease in sensory neuropathy seenin patients treated with FOLFOX4 andbevacizumab is probably due to thelonger time those individuals spent ontreatment, Dr. Giantonio said.In commenting on the study, RobertJ. Mayer, MD, director, Center forGastrointestinal Oncology, Dana-FarberCancer Institute, said, "This justifiesgiving bevacizumab with FOLFOX,an approach that had beenquestionable before."