Bifractionated CPT-11 with LV5FU2 infusion (FOLFIRI-3) in combination with bevacizumab: clinical outcomes in first-line metastatic colorectal cancers according to plasma angiopoietin-2 levels

Abstract

BackgroundOptimization of chemotherapy effectiveness in metastatic colorectal cancers (mCRC) is a major endpoint to enhance the possibility of curative intent surgery. FOLFIRI3 has shown promising results as second-line chemotherapy for mCRC patients previously exposed to oxaliplatin. The clinical efficacy of FOLFIRI3 was never determined in association with bevacizumab in non-previously treated mCRC patients.MethodsWe conducted a phase II clinical trial to characterize the response rate and toxicity profile of FOLFIRI3-bevacizumab as initial treatment for mCRC. Sixty-one patients enrolled in 3 investigation centers were treated with FOLFIRI3-bevacizumab (median of 10 cycles) followed by a maintenance therapy combining bevacizumab and capecitabine. Levels of plasma angiopoietin-2 (Ang-2) were measured by enzyme-linked immunosorbent assay at baseline.ResultsOverall response rate (ORR) was 66.7% (8% of complete and 58% of partial responses). The disease control rate was 91.7%. After a median time of follow-up of 46.7 months, 56 patients (92%) had progressed or died. The median progression free survival (PFS) was 12.7 months (95% confidence interval (CI) 9.7-15.8 months). The median overall survival (OS) was 24.5 months (95% CI: 10.6-38.3 months). Twenty-one patients underwent curative intent-surgery including 4 patients with disease initially classified as unresectable. Most common grade III-IV toxicities were diarrhea (15%), neutropenia (13%), asthenia (10%), and infections (4%). Hypertension-related medications needed to be increased in 3 patients. In multivariate analysis, surgery of metastases and Ang-2 levels were the only independent prognostic factors for PFS and OS. Indeed, baseline level of Ang-2 above 5 ng/mL was confirmed as an independent prognostic factor for progression free survival (HR = 0.357; 95% CI: 0.168-0.76, p = 0.005) and overall survival (HR = 0.226; 95% CI: 0.098-0.53, p = 0.0002).ConclusionsAs front-line therapy, FOLFIRI-3-bevacizumab is associated with an acceptable toxicity and induced promising objective response rates. However, unfavorable clinical outcomes were observed in patients with high levels of angiopoietin-2.

Prognostic value of baseline seric Syndecan‐1 in initially unresectable metastatic colorectal cancer patients: a simple biological score

“…We used a prospective phase II clinical trial as an additional fully external validation cohort set to assess CD138 independent prognostic value identified in the final multivariate Cox model of the development set and to validate the discrimination ability of the CD138-LDH score. 20 Finally, in an exploratory approach, we first investigated the correlation between CD138 and Ang-2 expression in a continuous and binary approach, with Spearman correlation coefficient and v 2 test, respectively. Then, the potential independent Ang-2 association with survival among the staging system issued from CD138 analysis was assessed by a Cox modelization.…”

“…All patients had unresectable liver metastases in this development set . The validation set enrolled 51 patients between October 2007 and October 2009 treated by FOLFIRI‐3/bevacizumab, in a pilot, single‐arm, multicenter, phase II trial . In this cohort, surgery of metastases was allowed after six cycles of treatment (see Supporting Information Methods).…”

Prognostic Value of Angiopoietin-2 for Death Risk Stratification in Patients with Metastatic Colorectal Carcinoma

“…Tumor responses were assessed every 8 weeks by spiral CT until progression. As the main objective was to assess the tumor response rate, surgery of metastases was allowed after 6 cycles of treatment, and the precise timing left at discretion of investigators (18). This phase II study was funded by the University Hospital of Besançon (Besançon, France), and registered on ClinicalTrials.gov (study NCT00544011, approved by the French Ethical Committee on February 1, 2007).…”

“…Cancer Epidemiology, Biomarkers & Preventionpreviously treated patients with mCRC (17,18). The main interest of Ang-2 as a biomarker is its ability to predict OS when measured at diagnosis, before treatment initiation.…”

“…In a cohort of 51 patients with mCRC treated by FOLFIRI-3 and bevacizumab, we have also recently observed an association between baseline Ang-2 plasmatic levels, OS and progression-free survival (PFS; ref. 18). Other exploratory studies pointed out its potential prognostic value by the description of an association between Ang-2 and OS or PFS, in small cohorts of patients (19,20).…”