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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2015; 21(43): 12234-12248
Published online Nov 21, 2015. doi: 10.3748/wjg.v21.i43.12234
Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer
Ken-ichi Fujita, Yutaro Kubota, Hiroo Ishida, Yasutsuna Sasaki
Ken-ichi Fujita, Yasutsuna Sasaki, Institute of Molecular Oncology, Showa University, Tokyo 1428555, Japan
Yutaro Kubota, Hiroo Ishida, Yasutsuna Sasaki, Department of Medical Oncology, Showa University School of Medicine, Tokyo 1428666, Japan
Author contributions: All authors contributed to write this paper.
Conflict-of-interest statement: We have no conflict of interest to disclose.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ken-ichi Fujita, PhD, Professor, Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 1428555, Japan. k.fujita@med.showa-u.ac.jp
Telephone: +81-3-37848146 Fax: +81-3-37842299
Received: April 29, 2015
Peer-review started: May 8, 2015
First decision: August 31, 2015
Revised: September 5, 2015
Accepted: October 23, 2015
Article in press: October 26, 2015
Published online: November 21, 2015
Processing time: 202 Days and 17.8 Hours
Abstract

Irinotecan hydrochloride is a camptothecin derivative that exerts antitumor activity against a variety of tumors. SN-38 produced in the body by carboxylesterase is the active metabolite of irinotecan. After irinotecan was introduced for the treatment of metastatic colorectal cancer (CRC) at the end of the last century, survival has improved dramatically. Irinotecan is now combined with 5-fluorouracil, oxaliplatin and several molecularly-targeted anticancer drugs, resulting in the extension of overall survival to longer than 30 mo. Severe, occasionally life-threatening toxicity occurs sporadically, even in patients in relatively good condition who have a low risk of chemotherapy-induced toxicity, often causing the failure of irinotecan-based chemotherapy. Clinical pharmacological studies have revealed that such severe toxicity is related to exposure to SN-38 and genetic polymorphisms in UDP-glucuronosyltransferase 1A1 gene. The large inter- and intra-patient variability in systemic exposure to SN-38 is determined not only by genetic factors but also by physiological and environmental factors. This review first summarizes the roles of irinotecan in chemotherapy for metastatic CRC and then discusses the optimal dosing of irinotecan based on the aforementioned factors affecting systemic exposure to SN-38, with the ultimate goal of achieving personalized irinotecan-based chemotherapy.

Keywords: Irinotecan; Metastatic colorectal cancer; Survival advantage; Personalized chemotherapy; Dosing; Severe renal failure

Core tip: Irinotecan is a key anticancer drug for the treatment of metastatic colorectal cancer. By combining irinotecan with 5-fluorouracil, oxaliplatin, and a molecularly-targeted drug, overall survival of longer than 30 mo has been achieved. Exposure to SN-38, the active metabolite of irinotecan, shows large inter- and intra-patient variability and can cause severe irinotecan-related toxicities. Many studies have recommended the dose reduction of irinotecan for patients with UDP-glucuronosyltransferase 1A1 polymorphisms and liver dysfunction. Surprisingly, dose reduction may be required in patients with severe renal failure, even though irinotecan is predominantly eliminated via the liver.