P-0210 - A Phase II Study of Bevacizumab Combined with Modified Optimox-1 as First-Line Treatment for Patients with Metastatic Colorectal Cancer

Abstract

Background: Combination of bevacizumab (BV) and oxaliplatin (L-OHP) is widely used for treatment of metastatic colorectal cancer (mCRC) all over the world. But most mCRC patients cannot continue to use L-OHP because of a sever neurotoxicity. In addition, it is often pointed out that continuous adverse effects worsen patients' quality of life and motivation for treatment after stopping L-OHP treatment, The OPTIMOX-1 trial (JCO 2006), which was conducted to evaluate L-OHP stop-and-go strategy, has reported that its strategy prolong duration of disease control (DDC) and decrease neurotoxicities. In this trial, L-OHP was not often reintroduced, which was reported to affect survival improvement. Therefore, we considered it necessary to improve the L-OHP reintroduction rate and conducted a phase II study of BV and modified OPTIMOX-1 (which modifies original L-OHP dose form 100mg/m2 to 85mg/m2) as first-line treatment of patients with mCRC. Methods: Enrollment criteria was previously untreated unresectable mCRC, other criteria were as same as OPTIMOX-1 trial. Patients were treated with 6 cycles of modified FOLFOX6 (L-OHP 85 mg/m2, l-LV 200 mg/m2, 5-FU 400 mg/m2 bolus, 5-FU 2400 mg/m2 46h continuous infusion) plus BV (5 mg/kg) q2wks, followed by maximum 12 cycles of sLV5FU2 (omit L-OHP 85 mg/m2 from mFOLFOX6) plus BV q2wks. After that, L-OHP reintroduction was planned (mFOLFOX6 plus BV q2wks was continued until disease progression). Primary endpoint was DDC (defined as the PFS, or, if mFOLFOX6 + BV was reintroduced, defined as the addition of the initial PFS and the PFS of the reintroduction in case of no progression at the first evaluation on reintroduction). Secondary endpoints were overall survival (OS), overall response rate (ORR), Disease control rate (DCR), L-OHP reintroduction rate (RR), and safety. CT scans were done every 8wks and assessed on the basis of RECIST ver1.1 and WHO criteria. Toxicities were graded according to CTCAE ver 3.0. Results: Between June 2008 and June 2011, 40 patients were enrolled. The median follow-up time was 40.8 months. Median DDC was 11.7months. Median OS was 23.1 months. In both RECIST and WHO criteria, ORR and DCR (CR + PR + SD) were 51.3% and 92.3%, respectively. One patient achieved CR. L-OHP reintroduction rate was 76.9% (Nine patients could not have reintroduction because of chemotherapy-related toxicity (55.6%), early progression (11.1%). Grade 3/4 toxicities were neutropenia (32.5%), hypertension (17.5%) and neurotoxicity (10.0%). As specific toxicities related to BV and L-OHP, gastrointestinal perforation, obstruction and allergy was observed in each 2 patients, respectively. 31 patients (79.5%) received post-protocol treatment, FOLFIRI-based regimen (22 patients) with or without anti-EGFR antibodies (13 patients). Conclusion: Modified OPTIMOX-1 combined with BV was well tolerated and effective. L-OHP reintroduction rate was 76.9%, which was higher compared with the original trial. This suggests that modified OPTIMOX-1 combined with BV can be one of good option for mCRC patients. We conclude that it requires further examination.