Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group

Author:

Schwab Matthias1,Zanger Ulrich M.1,Marx Claudia1,Schaeffeler Elke1,Klein Kathrin1,Dippon Jürgen1,Kerb Reinhold1,Blievernicht Julia1,Fischer Joachim1,Hofmann Ute1,Bokemeyer Carsten1,Eichelbaum Michel1

Affiliation:

1. From the Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and Department of Mathematics, University of Stuttgart, Stuttgart; University of Tuebingen and Department of Internal Medicine II, University Medical Center, Tuebingen; Epidauros Biotechnology AG, Bernried; and Department of Internal Medicine II (Oncology, Hematology, Bone marrow transplantation, Pneumology), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Abstract

Purpose To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase (DPYD ), thymidylate synthase (TYMS ), and methylene tetrahydrofolate reductase (MTHFR ) and of nongenetic factors for severe leukopenia, diarrhea, and mucositis related to fluorouracil (FU) treatment. Patients and Methods A multicenter prospective clinical trial included 683 patients with cancer treated with FU monotherapy. Toxicity was documented according to World Health Organization grades. DPYD, TYMS, and MTHFR genotypes were determined, and DPYD was resequenced in patients with severe toxicity. Results Grade 3 to 4 toxicity occurred in 16.1% of patients. The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% (95%CI, 0.02 to 0.11), with a positive predictive value of 0.46 (95% CI, 0.19 to 0.75; P = .01). Inclusion of additional DPYD variants improved prediction only marginally. Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia, whereas TYMS was associated with diarrhea. Genotype, female sex, mode of FU administration, and modulation by folinic acid were identified as independent risk factors by multivariable analysis. A previously unrecognized significant interaction was found between sex and DPYD, which resulted in an odds ratio for toxicity of 41.8 for male patients (95% CI, 9.2 to 190; P < .0001) but only 1.33 (95% CI, 0.34 to 5.2) in female patients. Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold (95% CI, 1.08 to 2.22; P = .02). Conclusion DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

Reference34 articles.

1. Lamont EB, Schilsky RL: The oral fluoropyrimidines in cancer chemotherapy. Clin Cancer Res 5:2289,1999-2296,

2. Systemic Therapy for Colorectal Cancer

3. Four Decades of Continuing Innovation With Fluorouracil: Current and Future Approaches to Fluorouracil Chemoradiation Therapy

4. Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. Meta-Analysis Group In Cancer.

5. Heggie GD, Sommadossi JP, Cross DS, et al: Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 7:2203,1987-2206,

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3