, Volume 70, Issue 2, pp 231-238
Date: 15 Jun 2012

Cetuximab in the first-line treatment of K-ras wild-type metastatic colorectal cancer: the choice and schedule of fluoropyrimidine matters

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Cetuximab, a monoclonal antibody against the epidermal growth factor receptor, inconsistently improves response rates (RR), progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced colorectal cancer patients with K-ras wild-type (WT) tumors.


We performed a meta-analysis of four trials where K-ras WT Pts received a fluoropyrimidine (infusional vs. bolus 5-fluorouracil (5-FU) vs. capecitabine) and oxaliplatin or irinotecan with and without cetuximab (CRYSTAL, OPUS, COIN and NORDIC VII trials) and two trials, where K-ras WT and mutant patients received cetuximab and a fluoropyrimidine (capecitabine in a German AIO study and infusional 5-FU in the CECOG study) with oxaliplatin versus irinotecan. We sought to determine whether the choice of fluoropyrimidine or of oxaliplatin versus irinotecan affects the response to cetuximab. Meta-analysis was performed in the context of a mixed effects model with a random effect for each study.


Only patients treated with infusional 5-FU-based chemotherapy derived benefit from cetuximab. Relative to infusional 5-FU, patients treated with capecitabine/bolus 5-FU-based doublet chemotherapy had a 42 % (95 % CI 21–58 %; p < 0.001) decrease in response probability and a 52 % (95 % CI 20–93 %; p < 0.001) and 33 % (95 % CI 7–65 %; p = 0.012) increase, respectively, in risk of progression and death. The choice of oxaliplatin or irinotecan did not affect benefit from cetuximab.


The lack of benefit for cetuximab with capecitabine/bolus 5-FU regimens is unexpected. Cetuximab should only be used with infusional 5-FU regimens in the first-line treatment of K-ras WT colorectal cancer patients. Further study is urgently needed to elucidate the basis of this observation.

Geoffrey Y. Ku and Benjamin A. Haaland authors are contributed equally to the manuscript.