Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan;83(1):123-129.
doi: 10.1007/s00280-018-3711-8. Epub 2018 Oct 30.

Dose adjustment of irinotecan based on UGT1A1 polymorphisms in patients with colorectal cancer

Hironori Fujii  1 , Yunami Yamada  2 , Daichi Watanabe  2 , Nobuhisa Matsuhashi  3 , Takao Takahashi  3 , Kazuhiro Yoshida  3 , Akio Suzuki  2
Affiliations

Dose adjustment of irinotecan based on UGT1A1 polymorphisms in patients with colorectal cancer

Hironori Fujii et al. Cancer Chemother Pharmacol. 2019 Jan.

Abstract

Purpose: Irinotecan is effective for metastatic colorectal cancer (mCRC). SN-38 is an active metabolite of irinotecan, which is formed by carboxylesterase and inactivated by UDP-glucuronyltransferase (UGT) 1A1. The UGT enzyme activity is reduced in patients with homozygous mutation in UGT1A1 genes (*6/*6, *28/*28 and *6/*28); thus dose reduction is required for prevention of severe adverse events associated with irinotecan. The present study was designed to investigate the relationship between UGT1A1 polymorphisms and the incidence of adverse events or the therapeutic effect in mCRC patients who received irinotecan.

Methods: Sixty-three mCRC patients who received irinotecan during January 2014 and May 2018 were the subjects of this study. The incidence of adverse events, including diarrhea and neutropenia, and the therapeutic effect of irinotecan were compared among homozygous group, heterozygous group and wild-type group. The initial dose of irinotecan was 150 mg/m2 in the heterozygous group and wild-type group, while the dose was reduced by 20% (120 mg/m2) in the homozygous group.

Results: The UGT1A1 polymorphisms occurred in 15.9%, 33.3%, and 50.8% for homozygous group, heterozygous group, and wild-type group, respectively. The average dose of irinotecan during overall cycles was not significantly different among three groups, despite the reduction of initial dose in homozygous group. There were no significant differences in the incidence rates of adverse events, tumor response, or time to treatment failure among three groups.

Conclusion: The present study demonstrated that dose reduction by 20% ensured safety and efficacy of irinotecan in mCRC patients with homozygous mutation in UGT1A1 genes.

Keywords: Adverse events; Dose adjustment; Irinotecan; Metastatic colorectal cancer; Time to treatment failure; UGT1A1 polymorphisms.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

K. Yoshida has received grants, personal fees, and nonfinancial support from Chugai Pharmaceutical Co., Ltd. during the conduction of this study; grants and personal fees from Taiho Pharmaceutical Co., Ltd.; grants and personal fees from Pfizer Inc.; grants and personal fees from Yakult Honsha Co., Ltd.; grants from Bristol-Myers Squibb; grants from Kyowa Hakko Kirin Co., Ltd., outside the submitted work; and honoraria from Taiho Pharmaceutical Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., and Yakult Honsha Co., Ltd.; and had a consultant or advisory relationship with Taiho Pharmaceutical Co., Ltd. and La Roche, Ltd. T. Takahashi has received honoraria for lectures from Takeda Pharmaceutical Co., Ltd. Other authors have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Figures

Fig. 1
Fig. 1
Kaplan–Meier plots comparing time to treatment failure (TTF) among patients with UGT1A1 polymorphisms who received irinotecan in combination with or without other chemotherapeutic drugs for colorectal cancer. Median TTF values were statistically compared by log-rank test
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Shimada Y, Yoshino M, Wakui A, et al. Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group. J Clin Oncol. 1993;11:909–913. doi: 10.1200/JCO.1993.11.5.909. - DOI - PubMed
    1. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041–1047. doi: 10.1016/S0140-6736(00)02034-1. - DOI - PubMed
    1. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229–237. doi: 10.1200/JCO.2004.05.113. - DOI - PubMed
    1. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25:4779–4786. doi: 10.1200/JCO.2007.11.3357. - DOI - PubMed
    1. Yamazaki K, Nagase M, Tamagawa H, et al. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G) Ann Oncol. 2016;27:1539–1546. doi: 10.1093/annonc/mdw206. - DOI - PubMed

MeSH terms