Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses
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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.
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.
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.
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.
KeywordsMethotrexate Chemotherapy Toxicity Cancer Personalized medicine Pharmacogenetics
No grants or other funding were received for this project.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113. doi:10.1038/ng0595-111 CrossRefPubMedGoogle Scholar
- 5.Studies N-NWGoRiA, Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, Hunter DJ, Thomas G, Hirschhorn JN, Abecasis G, Altshuler D, Bailey-Wilson JE, Brooks LD, Cardon LR, Daly M, Donnelly P, Fraumeni JF Jr, Freimer NB, Gerhard DS, Gunter C, Guttmacher AE, Guyer MS, Harris EL, Hoh J, Hoover R, Kong CA, Merikangas KR, Morton CC, Palmer LJ, Phimister EG, Rice JP, Roberts J, Rotimi C, Tucker MA, Vogan KJ, Wacholder S, Wijsman EM, Winn DM, Collins FS (2007) Replicating genotype-phenotype associations. Nature 447(7145):655–660. doi:10.1038/447655a CrossRefGoogle Scholar
- 11.Imanishi H, Okamura N, Yagi M, Noro Y, Moriya Y, Nakamura T, Hayakawa A, Takeshima Y, Sakaeda T, Matsuo M, Okumura K (2007) Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma. J Hum Genet 52(2):166–171. doi:10.1007/s10038-006-0096-z CrossRefPubMedGoogle Scholar
- 12.Seidemann K, Book M, Zimmermann M, Meyer U, Welte K, Stanulla M, Reiter A (2006) MTHFR 677 (C→T) polymorphism is not relevant for prognosis or therapy-associated toxicity in pediatric NHL: results from 484 patients of multicenter trial NHL-BFM 95. Ann Hematol 85(5):291–300. doi:10.1007/s00277-005-0072-2 CrossRefPubMedGoogle Scholar
- 17.Campbell JM, Peters MDJ (2014) The association of chemotherapy-induced toxicities with germline polymorphisms: an umbrella review of systematic reviews and meta-analyses. JBISRIR 12(10):40–46Google Scholar
- 20.Hagleitner MM, Coenen MJH, Aplenc R, Patino-Garcia A, Chiusolo P, Gemmati D, De Mattei M, Ongaro A, Krajinovic M, Hoogerbrugge PM, Vermeulen SHHM, Te Loo DMWM (2014) The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer. Pharmacogenomics J 14(2):115–119CrossRefPubMedGoogle Scholar
- 23.Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS (2011) Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood 118(2):243–251. doi:10.1182/blood-2010-12-322909 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Salazar J, Altes A, del Rio E, Estella J, Rives S, Tasso M, Navajas A, Molina J, Villa M, Vivanco JL, Torrent M, Baiget M, Badell I (2012) Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia. Pharmacogenomics J 12(5):379–385. doi:10.1038/tpj.2011.25 CrossRefPubMedGoogle Scholar
- 25.Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, Gluud C, Martin RM, Wood AJG, Sterne JAC (2008) Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. Br Med J 336(7644):601–605. doi:10.1136/bmj.39465.451748.AD CrossRefGoogle Scholar
- 29.D’Angelo V, Ramaglia M, Iannotta A, Crisci S, Indolfi P, Francese M, Affinita MC, Pecoraro G, Napolitano A, Fusco C, Oreste M, Indolfi C, Casale F (2011) Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol 68(5):1339–1346. doi:10.1007/s00280-011-1665-1 CrossRefPubMedGoogle Scholar
- 30.Chiusolo P, Giammarco S, Bellesi S, Metafuni E, Piccirillo N, De Ritis D, Marietti S, Federica S, Laurenti L, Fianchi L, Hohaus S, Giuseppe L, Sica S (2012) The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue. Cancer Chemother Pharmacol 69(3):691–696. doi:10.1007/s00280-011-1751-4 CrossRefPubMedGoogle Scholar