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.
Highlights
Optimization of chemotherapy effectiveness in metastatic colorectal cancers is a major endpoint to enhance the possibility of curative intent surgery
For patients diagnosed with metastatic disease or relapsing after oxaliplatin-based adjuvant therapy, optimization of chemotherapy effectiveness is a major endpoint to enhance the possibility of curative intent surgery
Two primary tumor resections were performed before enrolment due to a symptomatic disease and one resection was performed after enrolment due to an occlusion (Table 1)
Summary
Optimization 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. For patients diagnosed with metastatic disease or relapsing after oxaliplatin-based adjuvant therapy, optimization of chemotherapy effectiveness is a major endpoint to enhance the possibility of curative intent surgery. For those patients, CPT-11 (irinotecan)-containing chemotherapies are an available option, when combined with biotherapies. In first-line mCRC patients, the addition of irinotecan (180 mg/m2) to LV5FU2 (FOLFIRI) conferred a significant survival advantage over LV5FU2 alone (leucovorin (LV) 200 mg/m2 day 1, 5-fluorouracil (5FU) bolus 400 mg/m2 day 1 followed by a 46 hours-5FU continuous infusion 2400 mg/m2) [4]. The clinical benefit of irinotecan was demonstrated in patients whose disease had progressed after first-line 5FU [6,7]
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