TY - JOUR
T1 - Cetuximab in the first-line treatment of K-ras wild-type metastatic colorectal cancer
T2 - The choice and schedule of fluoropyrimidine matters
AU - Ku, Geoffrey Y.
AU - Haaland, Benjamin A.
AU - De Lima Lopes, Gilberto
N1 - Funding Information:
Acknowledgments BAH is supported by Singapore National Medical Research Council grant IRG10nov006; GYK and GLL are supported by the Johns Hopkins Singapore Research Fund; BAH is supported by Singapore National Medical Research Council grant IRG10nov006, NUS Initiative to Improve Health in Asia-Global Asia Institute grant, and Ministry of Health grant HSRG10nov002.
PY - 2012/8
Y1 - 2012/8
N2 - Background 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 wildtype (WT) tumors. Methods 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. Results 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. Conclusion 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.
AB - Background 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 wildtype (WT) tumors. Methods 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. Results 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. Conclusion 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.
KW - Cetuximab
KW - Chemotherapy
KW - Colorectal cancer
KW - Fluoropyrimidine
KW - Meta-analysis
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U2 - 10.1007/s00280-012-1898-7
DO - 10.1007/s00280-012-1898-7
M3 - Article
C2 - 22699811
AN - SCOPUS:84866529371
SN - 0344-5704
VL - 70
SP - 231
EP - 238
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -