Effect of Bevacizumab in Combination With Standard Oxaliplatin-Based Regimens in Patients With Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Avallone, Antonio; Piccirillo, Maria C.; Nasti, Guglielmo; Rosati, Gerardo; Carlomagno, Chiara; Di Gennaro, Elena; Romano, Carmela; Tatangelo, Fabiana; Granata, Vincenza; Cassata, Antonino; Silvestro, Lucrezia; De Stefano, Alfonso; Aloj, Luigi; Vicario, Valeria; Nappi, Anna; Leone, Alessandra; Bilancia, Domenico; Arenare, Laura; Petrillo, Antonella; Lastoria, Secondo

Key Points: Question: Does sequential scheduling of bevacizumab administration in combination with chemotherapy improve treatment efficacy in patients with metastatic colorectal cancer in keeping with the tumor vascular normalization hypothesis? Findings: In this phase 3 randomized clinical trial of 230 patients, the primary end point objective response rate did not significantly differ between the sequential and the concomitant schedule of bevacizumab administration in combination with standard oxaliplatin-based regimens. However, the sequential schedule of bevacizumab administration was associated with longer overall survival, fewer adverse effects, and better health-related quality of life. Meaning: Sequential bevacizumab scheduling plus chemotherapy might be relevant to optimize therapeutic efficacy and to explore antiangiogenic combination treatments with innovative perspectives. This randomized clinical trial compares outcomes of concomitant and sequential administration of bevacizumab in combination with standard oxaliplatin-based regimens in untreated or single line–treated patients with metastatic colorectal cancer. Importance: Although bevacizumab is a standard of care in combination treatments for metastatic colorectal cancer (mCRC), its clinical benefit has been limited. Objective: To determine whether sequential scheduling of bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with mCRC, in keeping with the tumor vascular normalization hypothesis. Design, Setting, and Participants: This open-label, randomized clinical phase 3 trial was conducted from May 8, 2012, to December 9, 2015, at 3 Italian centers. Patients aged 18 to 75 years with unresectable, previously untreated, or single line–treated mCRC were recruited. Follow-up was completed December 31, 2019, and data were analyzed from February 26 to July 24, 2020. Interventions: Patients received 12 biweekly cycles of standard oxaliplatin-based regimens (modified FOLFOX-6 [levo–folinic acid, fluorouracil, and oxaliplatin]/modified CAPOX [capecitabine and oxaliplatin]) plus bevacizumab administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm). Main Outcomes and Measures: The primary end point was the objective response rate (ORR) measured with Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival, overall survival, safety, and quality of life (QOL). Results: Overall, 230 patients (136 men [59.1%]; median age, 62.3 [interquartile range, 53.3-67.6] years) were randomly assigned to the standard arm (n = 115) or the experimental arm (n = 115). The median duration of follow-up was 68.3 (95% CI, 61.0-70.0) months. No difference in ORR (57.4% [95% CI, 47.8%-66.6%] in the standard arm and 56.5% [95% CI, 47.0-65.7] in the experimental arm; P =.89) or progression-free survival (10.5 [95% CI, 9.1-12.3] months in the standard arm and 11.7 [95% CI, 9.9-12.9] months in the experimental arm; P =.15) was observed. However, the median overall survival was 29.8 (95% CI, 22.5-41.1) months in the experimental arm compared with 24.1 (95% CI, 18.6-29.8) months in the standard arm (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.99; P =.04). Moreover, the experimental arm was associated with a significant reduction in the rate of severe diarrhea (6 [5.3%] vs 19 [16.5%]; P =.006) and nausea (2 [1.8%] vs 8 [7.0%]; P =.05) and improved physical functioning (mean [SD] change from baseline, 0.65 [1.96] vs −7.41 [2.95] at 24 weeks; P =.02), and constipation scores (mean [SD] change from baseline, −17.2 [3.73] vs −0.62 [4.44]; P =.003). Conclusions and Relevance: In this randomized clinical trial, sequential administration of bevacizumab plus chemotherapy did not improve ORR, the primary end point. However, the overall survival advantage, fewer adverse effects, and better health-related QOL associated with sequential bevacizumab administration might provide the basis for exploring antiangiogenic combination treatments with innovative perspectives. Trial Registration: EudraCT Identifier: 2011-004997-27; ClinicalTrials.gov Identifier: NCT01718873

DIARRHEA prevention; PATIENT aftercare; CONFIDENCE intervals; NAUSEA; CONSTIPATION; ANTINEOPLASTIC agents; METASTASIS; CANCER patients; COLORECTAL cancer; RANDOMIZED controlled trials; FLUOROURACIL; ANTIMETABOLITES; TREATMENT effectiveness; SURVIVAL analysis (Biometry); QUALITY of life; CHI-squared test; KAPLAN-Meier estimator; OXALIPLATIN; BEVACIZUMAB; STATISTICAL sampling; PATIENT safety

JAMA Network Open, 2021, Vol 4, Issue 7, pe2118475

2574-3805

Academic Journal

10.1001/jamanetworkopen.2021.18475