N0147: A Randomized Phase III Trial of Oxaliplatin plus 5-Fluorouracil/Leucovorin with or Without Cetuximab After Curative Resection of Stage III Colon Cancer

Abstract

Rationale For many years, adjuvant therapy for resected stage III colon cancer consisted of 5-fluorouracil (5-FU) and leucovorin (LV) administered on one of several different schedules. More recently, oxaliplatin was introduced into the treatment of patients with colorectal cancer, and a trial or adjuvant therapy demonstrated a significant benefit with the use of this drug when added to 5-FU/LV. In the pivotal MOSAIC trial, patients received the LV5FU2 regimen (bolus 5-FU/LV followed by infusional 5-FU on days 1 and 2) or the FOLFOX4 regimen, which is the LV5FU2 regimen with the addition of oxaliplatin on day 1.1 As recently reported, the 3year disease-free survival (DFS) rate improved from 73% to 78%, for a 23% reduction in the risk of recurrence. Recognizing that further significant gains in DFS with chemotherapy alone are unlikely, the focus of current national and international trials is to access the potential added benefit of biologic agents to chemotherapy. Recently, 2 monoclonal antibodies targeting specific molecular characteristics of malignant tumors, bevacizumab and cetuximab, have been approved for use in metastatic colorectal cancer. Of these antibodies, cetuximab exerts a direct tumor-targeted effect by binding to the transmembranous epidermal growth factor receptor (EGFR) on the surface of tumor cells with documented single-agent activity in the salvage setting.2,3 This activity is enhanced in combination with conventional cytotoxic chemotherapy. In the pivotal randomized trial that led to the Food and Drug Administration’s approval of cetuximab, cetuximab/irinotecan produced higher response rates and longer times to tumor progression than cetuximab alone.2 Although the experience with cetuximab as a component of first-line therapy is limited, recent results of phase II studies demonstrate high activity when cetuximab is added to FOLFOX regimens (oxaliplatin/5-FU/LV).4,5 Cetuximab’s potential use in the adjuvant setting appears promising with the ability of monoclonal antibodies to directly target tumor cells and thereby target micrometastatic disease in which angiogenesis has not yet occurred. The North Central Cancer Treatment Group N0147 study is a phase III US Intergroup trial to assess the potential benefit of adding cetuximab to a modified FOLFOX6 regimen as adjuvant therapy in patients with completely resected stage III colon cancer.