Clinical and pharmacogenetic determinants of 5-fluorouracyl/leucovorin/irinotecan toxicity: Results of the PETACC-3 trial.

Details

Serval ID
serval:BIB_BEFEC6CAADF3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Clinical and pharmacogenetic determinants of 5-fluorouracyl/leucovorin/irinotecan toxicity: Results of the PETACC-3 trial.
Journal
European journal of cancer
Author(s)
Tejpar S., Yan P., Piessevaux H., Dietrich D., Brauchli P., Klingbiel D., Fiocca R., Delorenzi M., Bosman F., Roth A.D.
ISSN
1879-0852 (Electronic)
ISSN-L
0959-8049
Publication state
Published
Issued date
08/2018
Peer-reviewed
Oui
Volume
99
Pages
66-77
Language
english
Notes
Publication types: Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Irinotecan (CPT-11) in combination with 5-fluorouracil (5FU) is widely used in the treatment of colorectal cancer. We assessed potential clinical variables that may predict toxicity and more specifically the role of UGT1A1 polymorphisms associated with irinotecan toxicity. We used data from the PETACC3 trial, which randomised patients in adjuvant setting to 6 months of leucovorin (LV) and 5FU (LV5/FU2) or LV5/FU2 + irinotecan.
Clinical and toxicity data were available for 2982 patients, DNA was available for 1200 (40%) of these patients. We genotyped the polymorphisms UGT1A1*28 and UGT1A1-3156G > A. Risk factors for neutropenia and diarrhoea were assessed by univariable and multivariable analyses.
In univariable analysis, UGT1A*28 genotype was associated with an increased incidence of grade III-IV neutropenia (incidence: 44% versus 26%; odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.4-3.7). In multivariable analysis, the most important predictors (ordered in terms of contribution to R <sup>2</sup> ) were baseline neutrophil count (OR for 1-unit (10 <sup>9</sup> /l) decrease: 1.8, 95% CI: 1.3-1.7), female sex (OR: 1.8, 95% CI: 1.1-3.0), body surface area (OR for 0.1-unit increase: 0.8, 95% CI: 0.7-1.0), UGT1A1 (OR: 2.8, 95% CI: 1.6-5.0), age (OR per 10 years: 1.3, 95% CI: 1.1-1.6) and poor performance status (OR: 1.6, 95% CI: 1.0-2.6). The main predictors for grade IV neutropenia were sex, age, performance score and UGT1A1. The main predictors for diarrhoea were sex and age.
We found that a complex of risk factors is involved in the development of toxicity, including UGT1A1. Parameters that are readily available in clinical practice, notably sex, age and performance status, are stronger predictors than the UGT1A1*28 genotype. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the determinants of toxicity risk, notably in females.
Keywords
Adult, Age Factors, Aged, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Biomarkers, Pharmacological/blood, Body Surface Area, Colorectal Neoplasms/blood, Colorectal Neoplasms/drug therapy, Colorectal Neoplasms/genetics, Colorectal Neoplasms/pathology, Diarrhea/chemically induced, Diarrhea/epidemiology, Female, Fluorouracil/adverse effects, Glucuronosyltransferase/genetics, Humans, Incidence, Irinotecan/adverse effects, Leucovorin/adverse effects, Leukocyte Count, Male, Middle Aged, Neoplasm Staging, Neutropenia/blood, Neutropenia/chemically induced, Neutropenia/epidemiology, Neutropenia/genetics, Neutrophils, Sex Factors, Treatment Outcome, Young Adult, Colon cancer, FOLFIRI, Toxicity, UGT1A1
Pubmed
Web of science
Create date
19/06/2018 8:10
Last modification date
20/08/2019 15:33
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