The importance of sequence in rescheduling bevacizumab and chemotherapy administration in the first-line treatment of metastatic colorectal carcinoma (mCRC).

Abstract

617 Background: One of the proposed mechanisms of action for bevacizumab is by reducing the interstitial fluid pressure (IFP) allowing an increased penetration and uptake of chemotherapy agents in tumors. Clinical and laboratory data suggest that the decrease of IFP occurs after a few days of bevacizumab administration and intratumoral delivery of chemotherapy increase when bevacizumab precedes chemotherapy. We hypothesized that altering the schedule of BEV/FOLFOX regimen would improve the efficacy of the regimen and increase objective response rate. Methods: Patients (pts) with mCRC or locally advanced colorectal cancer, with ECOG PS 0-2 were eligible. The treatment schedule was Bevacizumab 5mg/Kg on day 1, standard FOLFOX-4 regimen on days 8-9 at cycles repeated every 14 days. Prior 5-FU/oxaliplatin adjuvant treatment was allowed. The pts were treated for 6 months or until reaching a plateau of response. Standard RECIST v1.1 response evaluation criteria were used. Primary endpoint of the study was the percentage of objective response rate, PR+CR (ORR), secondary end points were PFS, OS and toxicity. A Simon two step, minimax, statistical design was used: the minimum accepted ORR was 45% (p0) and the estimated ORR was 65% (p1). Results: Thirty (n=30) pts were enrolled. The median age was 69.5 years, the performance status was 0 (40%), 1 (40%), 2 (20%), the median follow up was 20.75 months and the K-RAS status was wild type for 63.5% and mutant for 36.5%. Seven pts (23.3%) had received prior adjuvant chemotherapy. Five pts had convertible metastatic disease. Four CR (13.33%), 18 PR (60%), 7 SD (23.33%), and one PD (3.3%) were observed for a total ORR of 73.3% and disease control rate (CR+PR+SD) of 96.7%. Four out of five (80%) pts with convertible disease achieved a R0 resection. The PFS was 12.8 months and OS has not been reached yet. One patient experienced a grade 4 event (febrile neutropenia). The study met its primary endpoint and therefore is considered positive. Conclusions: Delivering bevacizumab before chemotherapy in the first-line treatment of mCRC represents a very effective and promising schedule which warrants further investigation in randomized clinical trials.