Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance

Abstract

Purpose: We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance.

Patients and methods: We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD).

Results: Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001).

Conclusion: Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.

Fig 1.

CONSORT diagram.

Fig 2.

Kaplan-Meier plots. (A) Progression-free survival and (B) overall survival for patients treated with FOLFIRI + B. The 1-year and 2-year survivals were 93% (95% CI, 98% to 80%) and 65% (95% CI, 78% to 48%), respectively. (C) Progression-free survival for patients with interleukin-8 levels above and below the median value of 3.7 pg/mL.

Fig 3.

Cytokine values at baseline, after a single dose of bevacizumab, after a single dose of fluorouracil, leucovorin, irinotecan, and bevacizumab (FOLFIRI + B), before progression, and at the time of progression. (*) Significantly different after multiple comparison correction, with significance defined by local false discovery rate q less than 0.05. ULN, upper limit of normal.

Fig A1.

Cumulative time to radiographic response by Response Evaluation Criteria in Solid Tumors, demonstrating continued accumulation of response after extended treatment. Dashed lines represent 95% CIs for cumulative response rate.

Fig A2.

Correlation of baseline cytokine and angiogenic factor levels and tumor volume by sum of tumor unidimensional measurement according to Response Evaluation Criteria in Solid Tumors (RECIST) methodology.

Fig A3.

Unsupervised clustering analysis of cytokines and angiogenic factors before progression (log base 2 change from baseline without normalization or centering).

Fig A4.

Cytokine values at baseline, after single dose of bevacizumab, after a single dose of fluorouracil, leucovorin, irinotecan, and bevacizumab (FOLFIRI + B), before progression, and at the time of progression for factors associated with myeloid cell recruitment. (*) Significantly different after multiple comparison correction, with significance defined by local false discovery rate q less than 0.05. ULN, upper limit of normal.