Aims: Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemotherapy. We conducted a pragmatic prospective cohort study to establish the relevance of UGT1A1 variants in the prediction of severe diarrhea and neutropenia in patients with colorectal cancer receiving irinotecan in a routine clinical setting. Materials & methods: Genotyping of UGT1A1*28 and c.-3156G>A was undertaken in an unselected, prospective cohort of 96 individuals treated with irinotecan at a single major UK oncology centre. Data on cytotoxic drugs received, and toxicity for all irinotecan treatment cycles were collected from case notes. Over 95% (92/96) of patients received an intermediate dose of irinotecan (180 mg/m², twice weekly). Irinotecan was given in combination with other cytotoxic drugs in 93/96 subjects and Grade 3 or 4 toxicity occurred in 23% of subjects. Results: No association was found between UGT1A1*28 or c.-3156G>A and neutropenia. However, individuals carrying two copies of UGT1A1*28 (p = 0.04; OR: 14; 95% CI: 1.1–185) or c.-3156G>A (p = 0.03) had a significantly increased risk of diarrhea over all cycles. Conclusion: Our findings indicate that UGT1A1 genotyping is not a good predictor of hematological toxicity in patients treated with intermediate irinotecan doses. However, it may be useful in the identification of patients at risk of severe diarrhea.

Keywords:

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

Bibliography

1 National Institute for Health and Clinical Excellence: Irinotecan, oxaliplatin and ralitrexad for the treatment of advanced colorectal cancer. Review of Technology Appraisal33,1–159 (2005).
Google Scholar
2 Innocenti F, Ratain MJ: Pharmacogenetics of irinotecan: clinical perspectives on the utility of genotyping. Pharmacogenomics7,1211–1221 (2006).
CASGoogle Scholar
3 Grothey AD, Sargent R, Goldberg M, Schmoll HJ: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J. Clin. Oncol.22,1209–1214 (2004).
Medline CASGoogle Scholar
4 Rivory LP, Robert J: Identification and kinetics of a β-glucuronide metabolite of SN-38 in human plasma after administration of the camptothecin derivative irinotecan. Cancer Chemother. Pharmacol.36,176–179 (1995).
Medline CASGoogle Scholar
5 Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K: Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res.51,4187–4191 (1991).
Medline CASGoogle Scholar
6 Bosma PJ, Chowdhury JR, Bakker C et al.: The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N. Engl. J. Med.333,1171–1175 (1995).
Medline CASGoogle Scholar
7 Ando Y, Saka H, Ando M et al.: Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res.60,6921–6926 (2000).▪ First report of association between UGT1A1 and irinotecan toxicity.
Medline CASGoogle Scholar
8 Innocenti F, Undevia SD, Iyer L et al.: Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J. Clin. Oncol.22,1382–1388 (2004).▪▪ Prospective study demonstrating an association between UGT1A1 and severe neutropenia.
Medline CASGoogle Scholar
9 Rouits E, Boisdron-Celle M, Dumont A et al.: Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin. Cancer Res.10,5151–5159 (2004).
Medline CASGoogle Scholar
10 Marcuello E, Altes A, Menoyo A et al.: UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br. J. Cancer91,678–682 (2004).
Medline CASGoogle Scholar
11 Carlini LE, Meropol NJ, Bever J et al.: UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin. Cancer Res.11,1226–1236 (2005).
Medline CASGoogle Scholar
12 Cote JF, Kirzin S, Kramar A et al.:UGT1A1 polymorphism can predict haematologic toxicity in patients treated with irinotecan. Clin. Cancer Res.13,3269–3275 (2007).
Medline CASGoogle Scholar
13 Font A, Sanchez M, Taron E et al.: Weekly regimen of irinotecan/docetaxel in previously treated non-small cell lung cancer patients and correlation with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism. Invest. New Drugs21,435–443 (2003).
Medline CASGoogle Scholar
14 Massacesi CS, Terrazzino F, Marcucci MB et al.: Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy. Cancer106,1007–1016 (2006).
Medline CASGoogle Scholar
15 Toffoli GE, Cecchin G, Corona A et al.: The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J. Clin. Oncol.24,3061–3068 (2006).
Medline CASGoogle Scholar
16 Kweekel D, Guchelaar HJ, Gelderblom H: Clinical and pharmacogenetic factors associated with irinotecan toxicity. Cancer Treat. Rev.34,656–669 (2008).
Medline CASGoogle Scholar
17 Liu JY, Qu K, Sferruzza AD, Bender RA: Distribution of the UGT1A1*28 polymorphism in Caucasian and Asian populations in the US: a genomic analysis of 138 healthy individuals. Anticancer Drugs18,693–696 (2007).
Medline CASGoogle Scholar
18 Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL:UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J. Natl Cancer Inst.99,1290–1295 (2007).▪▪ Meta-analysis of studies considering UGT1A1 and irinotecan toxicity.
Medline CASGoogle Scholar
19 Seymour MT, Maughan TS, Ledermann JA et al.: Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet370,143–152 (2007).
Medline CASGoogle Scholar
20 Kweekel DM, Gelderblom H, van der Straaten T, Antonioni NF, Punt CJA, Guchelaar H-J: UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group Study. Br. J. Cancer99,275–282 (2008).▪ Large study demonstrating an association between UGT1A1 variants and febrile neutropenia.
Medline CASGoogle Scholar
21 Liu CY, Chen PM, Chiou TJ et al.: UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma. Cancer112,1932–1940 (2008).
Medline CASGoogle Scholar
22 Ruzzo A, Graziano F, Loupakis F et al.: Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first line FOLFIRI chemotherapy. Pharmacogenetics J.8,278–288 (2008).
Medline CASGoogle Scholar
23 Rouits E, Charasson V, Pétain A et al.: Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients. Br. J. Cancer99,1239–1245 (2008).
Medline CASGoogle Scholar
101 Common toxicity criteria, version 2.0. National Cancer Institute. Accessed October 2008 http://ctep.cancer.gov/forms/CTCv20_4–30–992.pdf
Google Scholar
103 R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria (2007) www.R-project.org
Google Scholar

Vol. 10, No. 5

Metrics

Downloaded 452 times

History

Published online 18 May 2009

Published in print May 2009

Information

Keywords

Acknowledgements

We thank Del McEntee, Lisa Dixon and Rubiena Miah for assistance with project coordination. We thank Dr Roger Mountford, Regional Molecular Genetics Laboratory, Liverpool Women’s NHS Foundation Trust, Liverpool, UK for UGT1A1 primers and details of assay conditions.

Financial & competing interests disclosure

The study was supported by the NIHR Manchester Biomedical Research Centre. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

PDF download

UGT1A1*28 genotype predicts gastrointestinal toxicity in patients treated with intermediate-dose irinotecan

Abstract

Bibliography

UGT1A128* genotype predicts gastrointestinal toxicity in patients treated with intermediate-dose irinotecan