Predictive factors for 6 vs 12 cycles of Folfiri-Bevacizumab in metastatic colorectal cancer.

Vincenzo Formica,Gianfranco Filippelli,Giacomo Vessia,Giuseppe Barberis,Livio Blasi,Bruno Massidda,Luigi Maiorino,Donato Natale,Maria Teresa Ionta,Anna Russo,Ettore Greco,Rossana Casaretti,Liberato Di Lullo,Mario Roselli,Sergio Mancarella,Enrico Barbato

doi:10.18632/oncotarget.23355

Abstract

Early switching to de-intensified maintenance regimen is still a matter of debate in metastatic colorectal cancer (mCRC).The MARTHA trial, a S.I.C.O.G. phase III randomized trial, compared FOLOFIRI+bevacizumab (B) for 12 cycles (6 months) followed by B for up to 12 months (FOLFIRI +B*12 arm) vs FOLFIRI+B for 6 cycles (3 months) followed by capecitabine+B for 4 cycles followed by B for up to 12 months (FOLFIRI+B*6 arm). Chemotherapy-naïve mCRC patients were randomized, primary endpoint was progression free survival (PFS), with overall survival (OS) as a secondary endpoint. A novel analysis, the Death Pace Analysis (DPA), was performed to identify patients who benefited from a specific treatment.No PFS difference was seen in 198 enrolled patients (101 in FOLFIRI+B*12, 97 in FOLFIRI+B*6). A non-significant superior OS was observed for FOLFIRI+B*6 (HR 0.74, p 0.098). The DPA demonstrated that 14% of patients were identifiable as FOLFIRI+B*6-benefiting patients. According to a logistic regression analysis including 23 clinicopathological variables, baseline Hb was the only independent predictor of DPA-defined FOLFIRI+B*6-benefit status. Among patients with Hb ≤ 11.1 gr/dL a statistically significant prolonged OS was observed for FOLFIRI+B*6 over FOLFIRI+B*12 (median OS: 20.7 vs 12.6 months, respectively, HR 0.54, p 0.048). No survival difference was observed between arms in patients with Hb > 11.1.mCRC patients with low baseline Hb levels are better treated with FOLFIRI+B*6 first-line strategy. Possible biological explanations for this finding are being investigated.

Highlights

Inoperable metastatic colorectal cancer is an incurable disease for which the main objective of systemic treatment is to stabilize or reduce the tumor burden, prolonging survival while maintaining quality of life [1].In the last two decades the therapeutic armamentarium has broadened significantly, and median overall survival has passed from 10 months with the sole use of fluorouracil in 1980s-1990s to the current 32-40 months with the use of several novel biologic and chemotherapeutic agents [2]
No significant difference was observed between the two arms for the primary endpoint of progression free survival (PFS) (Figure 2A), with a median PFS of 10.8 and 10.5 months, in FOLFIRI+B*12 arm and FOLFIRI+B*6 arm, respectively, Hazard Ratio (HR) 0.9282, p 0.661
Www.impactjournals.com/oncotarget treated patients (20% and 12%, respectively), chi-square p values 0.04 and 0.01, respectively. In this randomized multicentre phase III trial, the MARTHA (Maintenance and Reduction Chemotherapy With Avastin in Metastatic Colon Cancer) trial, a clinical study designed to compare 12 cycles vs 6 cycles of firstline FOLFIRI+bevacizumab, with both arms followed by de-intensified maintenance therapies, we were not able to demonstrate the superiority of a standard strategy of FOLFIRI+Bevacizumab given for approximately six months as compared to a short duration, three months, full treatment schedule

Summary

Introduction

Inoperable metastatic colorectal cancer (mCRC) is an incurable disease for which the main objective of systemic treatment is to stabilize or reduce the tumor burden, prolonging survival while maintaining quality of life [1].In the last two decades the therapeutic armamentarium has broadened significantly, and median overall survival has passed from 10 months with the sole use of fluorouracil in 1980s-1990s to the current 32-40 months with the use of several novel biologic and chemotherapeutic agents [2]. Inoperable metastatic colorectal cancer (mCRC) is an incurable disease for which the main objective of systemic treatment is to stabilize or reduce the tumor burden, prolonging survival while maintaining quality of life [1]. A simple clinical feature, the primary tumour location (right vs left colon), has been demonstrated to have a significant impact on prognosis, and perhaps on the efficacy of anti-EGFR agents, in wild type colorectal cancer patients [4]. Possible molecular and microenviromental differences between right-sided and left-sided tumours have been put forth to explain this clinical finding [5]. The focus on safeguarding quality of life over a prolonged time of treatment exposure (up to > 40 months) has increasingly gained attention [6]

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Results

Conclusion