Worse Progression-Free Survival With Addition of Cetuximab to Chemotherapy in Patients With Resectable Colorectal Liver Metastasis
Surgery for liver metastasis from colorectal cancer is associated with overall survival of approximately 40% at 5 years, and progression-free survival is increased with the addition of oxaliplatin and fluorouracil (5-FU). The addition of cetuximab (Erbitux) to chemotherapy has produced a survival benefit in advanced KRAS exon 2 wild-type disease. In the New EPOCH trial reported in The Lancet Oncology, Primrose et al found that the addition of cetuximab to standard chemotherapy in patients with KRAS exon 2 wild-type resectable colorectal liver metastasis resulted in shorter progression-free survival. The investigators stated that further study is needed to identify the molecular basis for the unexpected interaction.
Study Details
In this open-label trial, patients with KRAS exon 2 wild-type resectable or suboptimally resectable colorectal liver metastases were randomly assigned between February 2007 and November 2012 to receive chemotherapy with (n = 129) or without (n = 128) cetuximab before and after liver resection. Treatments consisted of intravenous oxaliplatin at 85 mg/m2 over 2 hours and 5-FU bolus at 400 mg/m2 over 5 minutes followed by a 46-hour infusion of 5-FU at 2,400 mg/m2 every 2 weeks with (n = 87) or without (n = 87) cetuximab at 500 mg/m2 every 2 weeks; or oxaliplatin at 130 mg/m2 over 2 hours and oral capecitabine at 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks with (n = 24) or without (n = 27) cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly. Patients who had received adjuvant oxaliplatin could receive irinotecan at 180 mg/m2 over 30 minutes with 5-FU instead of oxaliplatin with (n = 15) or without (n = 11) cetuximab at 500 mg/m2 every 2 weeks. The primary endpoint was progression-free survival.
For the chemotherapy/cetuximab and chemotherapy groups, median age was 63 and 64 years, 71% and 63% were male, 98% and 100% had WHO performance status of 0 or 1, primary tumors were T3 or T4 in 84% in both, N1 or N2 in 60% and 64%, poorly differentiated in 12% and 8%, and unresected in 14% and 10%, 75% and 80% had one to three liver metastases, 53% and 47% had synchronous metastases, 26% and 24% had carcinoembryonic antigen > 30 ng/L, and 5% and 2% had extrahepatic disease
Worse Progression-Free Survival
Overall, 119 patients in the chemotherapy/cetuximab group and 117 in the chemotherapy-alone group were included in the primary analysis. The trial was closed after interim analysis, through November 1, 2012, showed that protocol-defined futility criteria had been met. After median follow-up of 20.7 months and occurrence of 123 (58%) of 212 required events, median progression-free survival was significantly shorter in the chemotherapy/cetuximab group (14.1 vs 20.5 months, hazard ratio [HR] = 1.48, P = .030). Median overall survival was 39.1 months vs not reached (HR = 1.49, P = .16).
Adverse Events
For the chemotherapy/cetuximab vs chemotherapy-alone groups, the most common grade 3 or 4 adverse events were preoperative (4% vs 11%) and postoperative (8% vs 4%) neutropenia, preoperative (6% vs 4%) and postoperative (3% vs 2%) embolic events, preoperative (1% vs 4%) and postoperative (4% vs 2%) peripheral neuropathy, preoperative (4% vs 3%) and postoperative (2% vs 4%) nausea/vomiting, and preoperative (15% vs 1%), and postoperative (8% vs 0%) skin rash.
Three deaths in the chemotherapy/cetuximab group, due to interstitial lung disease and pulmonary embolism, bronchopneumonia, and pulmonary embolism, and one in the chemotherapy-alone group, due to heart failure, were considered possibly related to study treatment.
The investigators concluded, “Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended.”
John Primrose, MD, of Southampton General Hospital, is the corresponding author for The Lancet Oncology article.
The study was funded by Cancer Research UK. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
