Late effects of high-dose methotrexate in childhood cancer survivors: a Swiss single centre observational study

Springer Science and Business Media LLC - Tập 15 Số 1
Kevin Brunold1, Maria Otth2, Katrin Scheinemann2
1Faculty of Medicine, University of Zurich, Zurich, Switzerland
2Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland

Tóm tắt

Abstract Importance Childhood cancer survivors (CCS) are at risk for late effects of different organ systems. The currently available screening recommendations for those treated with high-dose methotrexate (HD-MTX) are not uniform and the available literature is limited. Objective We aim to assess the prevalence and severity of late effects in CCS treated with HD-MTX at a single centre in Switzerland. We focus on organ systems defined at risk by the long-term follow-up care guidelines of the children’s oncology group (COG), because this guideline has a holistic approach, is evidence based, and up to date. Methods We used the modified Common Terminology Criteria for Adverse Events (CTCAE) to assess late effects in 15 different organ systems. Eligible were CCS diagnosed with cancer younger than 18 years and treated with HD-MTX, defined as at least 1 g per body surface area (≥ 1 g/m2). Results We analysed 32 CCS with a median follow-up of 12.1 years. The endocrine system was most frequently affected by adverse events (69%), followed by the musculoskeletal (57%) and neuropsychological (38%) systems. The hepatobiliary (9%) and immunological (6%) systems were the least affected ones. Within the endocrine system, overweight/obesity was the most frequent and severe diagnosis. Conclusion Late effects in CCS treated with HD-MTX are frequent. Our findings could add to the COG guidelines, where only screening for the musculoskeletal, neuropsychological, and hepatobiliary systems are recommended. More patient data need to be collected and analysed using the suggested standardised approach, to increase the quality of evidence for future screening recommendations.

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Tài liệu tham khảo

Childhood Cancer Registry (KiKR). Annual Report 2023 https://www.kinderkrebsregister.ch/statistiken-und-berichte/jahresberichte/. Accessed 5 Jul 2023

Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, et al. Childhood cancer survival in Europe 1999–2007: results of EUROCARE-5–a population-based study. Lancet Oncol. 2014;15(1):35–47.

Winther JF, Kenborg L, Byrne J, Hjorth L, Kaatsch P, Kremer LC, et al. Childhood cancer survivor cohorts in Europe. Acta oncologica (Stockholm, Sweden). 2015;54(5):655–68.

Schindler M, Belle FN, Grotzer MA, von der Weid NX, Kuehni CE, et al. Childhood cancer survival in Switzerland (1976–2013): Time-trends and predictors. Int J Cancer. 2017;140(1):62–74.

Erdmann F, Frederiksen LE, Bonaventure A, Mader L, Hasle H, Robison LL, et al. Childhood cancer: survival, treatment modalities, late effects and improvements over time. Cancer Epidemiol. 2021;71(Pt B): 101733.

Bhakta N, Liu Q, Ness KK, Baassiri M, Eissa H, Yeo F, et al. The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE). Lancet Oncol. 2017.

Hudson MM, Ness KK, Gurney JG, Mulrooney DA, Chemaitilly W, Krull KR, et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA. 2013;309(22):2371–81.

Gibson TM, Mostoufi-Moab S, Stratton KL, Leisenring WM, Barnea D, Chow EJ, et al. Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970–99: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 2018;19(12):1590–601.

Childrens Oncology Group (COG). Long Term Follow-Up guidelines Version 5.0 2018 http://www.survivorshipguidelines.org/pdf/2018/COG_LTFU_Guidelines_v5.pdf. Accessed 6 Jul 2023.

United Kingdom Children's Cancer Study Group. Therapy based long term follow-up - Practice Statement 2005. https://www.cclg.org.uk/write/MediaUploads/Member%20area/Treatment%20guidelines/LTFU-full.pdf. Accessed 6 Jul 2023.

SKION DCOGD. Guidelines for follow-up in survivors of childhood cancer 5 years after diagnosis. 2010. https://www.skion.nl/voor-patienten-en-ouders/late-effecten/533/richtlijn-follow-up-na-kinderkanker/. Accessed 5 Aug 2010.

van Atteveld JE, Mulder RL, van den Heuvel-Eibrink MM, Hudson MM, Kremer LCM, Skinner R, et al. Bone mineral density surveillance for childhood, adolescent, and young adult cancer survivors: evidence-based recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Diabetes Endocrinol. 2021;9(9):622–37.

Daetwyler E, Bargetzi M, Otth M, Scheinemann K. Late effects of high-dose methotrexate treatment in childhood cancer survivors-a systematic review. BMC Cancer. 2022;22(1):267.

Cooper SL, Brown PA. Treatment of pediatric acute lymphoblastic leukemia. Pediatr Clin North Am. 2015;62(1):61–73.

Pollack IF, Agnihotri S, Broniscer A. Childhood brain tumors: current management, biological insights, and future directions. J Neurosurg Pediatr. 2019;23(3):261–73.

Ehrhardt MJ, Dixon SB, Belsky J, Hochberg J. Late effects and frontline treatment selection for children with non-Hodgkin lymphoma. Best Pract Res Clin Haematol. 2023;36(1): 101443.

Ackland SP, Schilsky RL. High-dose methotrexate: a critical reappraisal. J Clin Oncol. 1987;5(12):2017–31.

Hudson MM, Ehrhardt MJ, Bhakta N, Baassiri M, Eissa H, Chemaitilly W, et al. Approach for classification and severity grading of long-term and late-onset health events among childhood cancer survivors in the St. Jude lifetime cohort. Cancer Epidemiol Biomark Prev. 2017;26(5):666–74.

Howell CR, Bjornard KL, Ness KK, Alberts N, Armstrong GT, Bhakta N, et al. Cohort Profile: The St. Jude Lifetime Cohort Study (SJLIFE) for paediatric cancer survivors. Int J Epidemiol. 2021;50(1):39–49.

Otth M, Drozdov D, Hügli C, Scheinemann K. Young Survivors at KSA: registry for standardised assessment of long-term and late-onset health events in survivors of childhood and adolescent cancer-a study protocol. BMJ Open. 2021;11(12): e053749.

Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95: 103208.

Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81.

den Hoed MA, Klap BC, te Winkel ML, Pieters R, van Waas M, Neggers SJ, et al. Bone mineral density after childhood cancer in 346 long-term adult survivors of childhood cancer. Osteoporos Int. 2015;26(2):521–9.

Lequin MH, van der Shuis IM, Van Rijn RR, Hop WC, Huevel-Eibrink MM, MuinckKeizer-Schrama SM, et al. Bone mineral assessment with tibial ultrasonometry and dual-energy X-ray absorptiometry in long-term survivors of acute lymphoblastic leukemia in childhood. J Clin Densitom. 2002;5(2):167–73.

Tillmann V, Darlington AS, Eiser C, Bishop NJ, Davies HA. Male sex and low physical activity are associated with reduced spine bone mineral density in survivors of childhood acute lymphoblastic leukemia. J Bone Miner Res. 2002;17(6):1073–80.

van der Sluis IM, van den Heuvel-Eibrink MM, Hählen K, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density, body composition, and height in long-term survivors of acute lymphoblastic leukemia in childhood. Med Pediatr Oncol. 2000;35(4):415–20.

Verwaaijen EJ, Ma J, de Groot-Kruseman HA, Pieters R, van der Sluis IM, van Atteveld JE, et al. A validated risk prediction model for bone fragility in children with acute lymphoblastic leukemia. J Bone Miner Res. 2021;36(12):2290–9.

Inaba H, Cao X, Han AQ, Panetta JC, Ness KK, Metzger ML, et al. Bone mineral density in children with acute lymphoblastic leukemia. Cancer. 2018;124(5):1025–35.

Jarfelt M, Fors H, Lannering B, Bjarnason R. Bone mineral density and bone turnover in young adult survivors of childhood acute lymphoblastic leukaemia. Eur J Endocrinol. 2006;154(2):303–9.

Wilson CL, Liu W, Yang JJ, Kang G, Ojha RP, Neale GA, et al. Genetic and clinical factors associated with obesity among adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Cancer. 2015;121(13):2262–70.

Nam GE, Kaul S, Wu YP, Nelson RE, Wright J, Fluchel MN, et al. A meta-analysis of body mass index of adolescent and adult survivors of pediatric acute lymphoblastic leukemia. J Cancer Surviv. 2015;9(3):412–21.

Swiss Federal Office for Statistics. Health determinants - Overweight 2022. https://www.bfs.admin.ch/bfs/de/home/statistiken/gesundheit/determinanten/uebergewicht.html. Accessed 26 Nov 2023.

Swiss monitoring system for addiction and non-communicable diseases (MonAM). Overweight and obesity (age: 6–12) 2017. https://ind.obsan.admin.ch/indicator/monam/uebergewicht-und-adipositas-alter-6-12. Accessed 26 Nov 2023.

Krull KR, Cheung YT, Liu W, Fellah S, Reddick WE, Brinkman TM, et al. Chemotherapy pharmacodynamics and neuroimaging and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia. J Clin Oncol. 2016;34(22):2644–53.

Cheung YT, Sabin ND, Reddick WE, Bhojwani D, Liu W, Brinkman TM, et al. Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis. Lancet Haematol. 2016;3(10):e456–66.

Cohen IJ. Neurotoxicity after high-dose methotrexate (MTX) is adequately explained by insufficient folinic acid rescue. Cancer Chemother Pharmacol. 2017;79(6):1057–65.

Sadeh M, Toledano H, Cohen IJ. A comprehensive review of neuropsychologic studies supports the concept that adequate folinic acid rescue prevents post methotrexate neurotoxicity. J Pediatr Hematol Oncol. 2023;45(1):1–11.

Skärby TV, Anderson H, Heldrup J, Kanerva JA, Seidel H, Schmiegelow K. High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia. 2006;20(11):1955–62.

Mateos MK, Marshall GM, Barbaro PM, Quinn MCJ, George C, Mayoh C, et al. Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia. Haematologica. 2022;107(3):635–43.

Liberman PHP, Goffi-Gomez MVS, Schultz C, Jacob PL, de Paula CAA, Sartorato EL, et al. Contribution of the GSTP1 c.313A>G variant to hearing loss risk in patients exposed to platin chemotherapy during childhood. Clin Transl Oncol. 2019;21(5):630–5.

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