Incidence and relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5- fluorouracil: a meta-analysis of published trials Roberto Iacovelli, 1,2 Filippo Pietrantonio, 1 Antonella Palazzo, 1,2 Claudia Maggi, 1,2 Francesca Ricchini, 1 Filippo de Braud 1 & Maria Di Bartolomeo 1 1 Department of Meical Oncology, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy and 2 PhD Program, Department of Radiology Oncology and Human Pathology, Sapienza University of Rome, Rome, Italy Correspondence Dr Roberto Iacovelli MD, Fondazione IRCCS, Istituto Nazionale Tumori. Via G. Venezian 1, 20133 Milan, Italy. Tel.: +3902 2390 2882 Fax: +3902 2390 2149 E-mail: roberto.iacovelli@istitutotumori.mi.it ----------------------------------------------------------------------- The Principal Investigator of this work is Dr Roberto Iacovelli. ----------------------------------------------------------------------- Keywords 5-fluorouracil, breast cancer, capecitabine, colorectal cancer, diarrhoea, gastric cancer ----------------------------------------------------------------------- Received 23 April 2014 Accepted 17 June 2014 Accepted Article Published Online 24 June 2014 AIM Capecitabine is an oral fluoropyrimidine that can effectively replace infusional 5-fluorouracil (5-FU) for treatment of colorectal, gastric and breast cancer. This study aims to analyze the incidence and the relative risk of grade 3 and 4 diarrhoea in patients treated with capecitabine or 5-FU in randomized clinical trials (RCTs). METHODS MEDLINE and Cochrane Library were reviewed for RCTs that compared capecitabine with 5-FU for treatment of solid malignancies. The incidence and relative risk (RR) of grade 3/4 diarrhoea were estimated for each arm in the overall population and in colorectal cancer (CRC) patients RESULTS Twenty-three studies and 15 761 patients were included. Among these 8303 and 7458 patients received capecitabine or 5-FU based therapies, respectively. In the overall populations severe diarrhoea was reported in 16.6% (95% CI 15.8, 17.4) and in 12.7% (95% CI 11.9, 13.4) of patients treated with capecitabine or 5-FU-based therapies, respectively. The RR was 1.39 (95% CI 1.14, 1.69, P = 0.0010). In 14 899 CRC patients, the incidence of severe diarrhoea was 17.0% (95% CI 16.2, 17.9) and 12.9% (95% CI 12.1, 13.7), respectively, with a RR of 1.46 (95% CI 1.18, 1.81, P < 0.0001). In CRC patients treated with combined chemotherapy, the RR was 1.40 (95% CI 1.07, 1.82; P = 0.01) for patients receiving oxaliplatin and 2.35 (95% CI 1.76, 3.13; P < 0.0001) for patients receiving irinotecan. CONCLUSIONS Treatment with capecitabine is characterized by an increased risk of severe diarrhoea, mainly in patients affected by CRC and treated with polichemotherapy. Combination treatment with irinotecan doubles the risk over 5-FU. Introduction Capecitabine is an orally administered fluoropyrimi- dine which constitute a systemic prodrug of 5′-deoxy-5- fluorouridine (5′-DFUR). Several enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo, and both normal and tumour cells metabolize 5-FU to 5- fluoro-2′-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites are able to bind the thymidylate synthase whose products British Journal of Clinical Pharmacology DOI:10.1111/bcp.12449 1228 / Br J Clin Pharmacol / 78:6 / 1228–1237 © 2014 The British Pharmacological Society