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Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses

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Abstract

Purpose

Methotrexate chemotherapy is associated with various toxicities which can result in the interruption or discontinuation of treatment and a subsequently raised risk of relapse. This umbrella systematic review was conducted to synthesize the results of all existing systematic reviews that investigate the pharmacogenetics of methotrexate-induced toxicity, with the aim of developing a comprehensive reference for personalized medicine.

Methods

Databases searched were PubMed, Embase, JBI Database of Systematic Reviews and Implementation Reports, DARE, and ProQuest. Papers were critically appraised by two reviewers, and data were extracted using a standardized tool.

Results

Three systematic reviews on methotrexate-induced toxicity were included in the review. Meta-analyses were reported across Asian, Caucasian, pediatric and adult patients for the MTHFR C677T and A1298C polymorphisms. Toxicity outcomes included different forms of hematologic, ectodermal and hepatic toxicities. Results varied considerably depending on the patient groups and subgroups investigated in the different systematic reviews, as well as the genetic models utilized. However, significant associations were found between the MTHFR C677T allele and; hepatic toxicity, myelosuppression, oral mucositis, gastrointestinal toxicity, and skin toxicity. Additionally, limited evidence suggests that the MTHFR A1298C polymorphism may be associated with decreased risk of skin toxicity and leukopenia.

Conclusion

This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of methotrexate toxicity. The next step in making personalized medicine for methotrexate therapy a clinical reality is research on the effectiveness and cost-effectiveness of MTHFR genotype testing to enable the close monitoring of at-risk patients for the timely initiation of rescue therapies.

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Acknowledgments

No grants or other funding were received for this project.

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Authors and Affiliations

  1. The Joanna Briggs Institute, Faculty of Health Science, University of Adelaide, 115 Grenfell Street, Adelaide, SA, Australia

    Jared M. Campbell, Matthew D. Stephenson & Micah D. J. Peters

  2. School of Medicine, Faculty of Health Science, University of Adelaide, Frome Road, Adelaide, Australia

    Emma Bateman, Joanne M. Bowen & Dorothy M. Keefe

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  1. Jared M. Campbell
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Correspondence to Jared M. Campbell.

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Campbell, J.M., Bateman, E., Stephenson, M.D. et al. Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Cancer Chemother Pharmacol 78, 27–39 (2016). https://doi.org/10.1007/s00280-016-3043-5

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  • DOI: https://doi.org/10.1007/s00280-016-3043-5

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