Randomized Phase III Study to Assess Efficacy and Safety of Adjuvant CAPOX with or without Bevacizumab in Patients after Resection of Colorectal Liver Metastases: HEPATICA study

Abstract

Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF). Recurrence after resection of colorectal liver metastases (CRLMs), presumably caused by VEGF-mediated outgrowth of micrometastases, might decrease when VEGF is inhibited. This study examines the efficacy and safety of adding bevacizumab to an adjuvant regimen of CAPOX in patients undergoing radical resection for their CRLMs. Patients with resected CRLMs were randomized after surgery to receive CAPOX and bevacizumab (arm A) or CAPOX alone (arm B) as adjuvant treatment. CAPOX was given in both arms for a total of eight cycles. Bevacizumab was administered for 16 cycles. The primary end point was disease-free survival (DFS). Secondary outcomes were overall survival (OS), toxicity, and quality of life (QoL). In total, 79 patients were randomized. At the time of analysis, 23 events were encountered in arm A and 20 in arm B. One-year DFS rate was 79% [95% confidence interval (CI): 68%-93%] and 68% (95% CI: 55%-85%) for arm A and B, respectively (P = .89). Toxicity was evaluated for 75 patients. No significant differences in toxicity between the two arms were found. QoL scores were higher in arm A, of which emotional functioning and global QoL scores were significant. Adding bevacizumab to a CAPOX regimen in patients undergoing a resection for their CLM is safe and showed higher QoL scores compared with CAPOX alone. Because of premature closure of the study, conclusions about the effect on DFS of additional VEGF inhibition in this setting could not yet be made.

Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…211 The randomized phase III HEPATICA trial, which closed prematurely due to poor accrual, found that global quality of life scores were higher in patients receiving CAPEOX plus bevacizumab than those receiving CAPEOX alone after resection of liver metastases, but no conclusions could be drawn regarding the primary endpoint of DFS. 212 Furthermore, data regarding the lack of efficacy of bevacizumab in the adjuvant setting in stage II and III colon cancer 213,214 have prompted some to reconsider the role of bevacizumab in the adjuvant setting of resectable colorectal metastases. However, the panel does not recommend the use of bevacizumab in the perioperative stage IV setting.…”

The Role of Systemic Therapy in Resectable Colorectal Liver Metastases: Systematic Review and Network Meta-Analysis

“… 12 Slow accrual was noted in most trials leading to early study termination in 5 trials. 7 , 8 , 12 , 13 , 21 Most of the trials included patients with synchronous and metachronous liver metastases. The characteristics of the included RCTs are outlined in Supplementary Table S1 .…”

Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials

“…Bevacizumab was investigated in 72 trials 8 – 79 and ramucirumab was investigated in 13 trials. 80 – 92 All of the studies included 21 colorectal cancer, 8 – 26 , 85 , 86 15 breast cancer, 27 – 39 , 87 , 88 16 lung cancer, 40 – 52 , 80 – 82 three renal cell cancer, 53 , 54 two pancreatic cancer, 55 , 56 five ovarian cancer, 57 – 61 six gastric or gastroesophageal junction adenocarcinoma, 62 – 65 , 89 – 91 three glioblastoma, 66 – 68 one lymphoma, 69 one lymphocytic leukemia, 70 two melanoma, 71 , 72 two malignant mesothelioma, 73 , 74 one prostate cancer, 75 one cervical cancer, 76 one leiomyosarcoma, 77 two urothelial carcinoma, 83 , 84 two hepatocellular carcinoma, 78 , 92 and one soft tissue sarcoma. 79 In addition, 35 trials 9 , 10 , 12 – 20 , 22 – 26 , 46 , 49 , 52 , 55 , …”