Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience

We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin-fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatin + capecitabine (Xelox, 41%), 102 received OxMdG + cetuximab (OxMdG + C, 13%) and 166 Xelox + cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdG + C and Xelox + C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xelox + cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P = 0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P = 0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen.