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

Abstract

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 þ capecitabine (Xelox, 41%), 102 received OxMdG þ cetuximab (OxMdG þ C, 13%) and 166 Xelox þ 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 þ C and Xelox þ C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xelox þ cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P ¼ 0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P ¼ 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.

Rash Rates with EGFR Inhibitors: Meta-Analysis

“…One study included in the analysis evaluated the efficacy and safety of panitumumab. Seven publications provided information on the incidence of all grades of rash (Table iii) 9, 16,17,19,23,25,27 . The difference between egfris and non-egfris in overall incidence rate for all severity grades of rash was 0.74 (95% ci: 0.68 to 0.81; p < 0.01; chi-square: 42.21, p < 0.001).…”

“…For the sensitivity analysis related to rashes overall, we examined rash rate differences in mcrc patients (five studies 9,18,19,23,25 ), in studies with active comparators (five studies 16,17,19,23,25 ), and in studies with best supportive care as the comparator (two studies 9,18 , Table v).…”

“…For the sensitivity analysis related to grades 3 and 4 rashes, we examined the rash differences in studies reporting grade 4 reactions (seven studies 9,17,19,20,[23][24][25] ), in studies with active comparators (eleven studies 16,17,[19][20][21][22][23][24][25][26][27] ), in studies with best supportive care as the comparator (two studies 9,18 ), in studies evaluating crc patients only (seven studies 9,18,19,23,[25][26][27] ), in studies evaluating nsclc patients only (three studies 17,21,22 ), and in studies with best supportive care as a comparator (two studies 9,18 , Table v). …”

Evaluating Many Treatments and Biomarkers in Oncology: A New Design

“…Finally, new agents are used on their own or in novel-novel combinations, after standard treatment, thereby avoiding unpredictable negative pharmacologic or toxicity interactions with conventional chemotherapy, which has been seen repeatedly in colorectal cancer chemotherapy. [39][40][41][42] Consequently, randomization occurs in a treatment window of opportunity or treatment break, which is a clinically reasonable and safe strategy on the basis of randomized data from the COIN (Continuous or Intermittent) trial. 38 Although this strategy is somewhat unusual in colorectal cancer, there are many settings in the management of other tumors in which periods of observation of patients off treatment are standard and could be used for such window-of-opportunity trials.…”

Balancing the efficacy and toxicity of chemotherapy in colorectal cancer

“…Evidence from randomized trials is lacking in this disease setting and clinical trials assessing this subgroup of patients are required. An important consideration in the intensification of treatment in this patient population is the increased toxicity associated with three-drug combination regimens of either doublet chemotherapy plus mAb [Adams et al 2009a;Hecht et al 2009] or triplet combination chemotherapy [Falcone et al 2007;Souglakos et al 2006]. These regimens pose a risk of increased rates of severe toxicity and may not be tolerated by a significant proportion of patients.…”