Efficacy of intrathecal methotrexate in children with high-risk medulloblastoma over three years: a retrospective study from a single center

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Abstract

Purpose

Chemotherapy is commonly used for treatment in children over three years old with high-risk medulloblastoma(MB). However, little is currently known about the therapeutic benefits and side effects of intrathecal methotrexate(MTX), warranting further research.

Methods

In this retrospective study, patients who received intrathecal MTX during chemotherapy were included in the MTX group (n = 32), and patients that only underwent cerebrospinal fluid (CSF) cytology analysis were assigned to the control group (n = 14).

Results

In the MTX group, 27(84.38%) patients had metastatic disease, 3(9.38%) had diffuse anaplasia, and 3(9.38%) had residual disease greater than 1.5 cm ². Molecular subgroup classification was available for 28(87.5%) patients. In the control group, 8(57.14%) patients had metastatic disease, 3(27.27%) had diffuse anaplasia, and 6(42.86%) had residual disease greater than 1.5 cm ². Molecular subgroup classification was available for 6(42.86%) patients. The 5-year progression-free survival was 70.99% and the 5-year overall survival was 72.99% for the MTX group, and the corresponding values were 41.67% and 50% for the control group, respectively. 6 (18.75%) patients in the MTX group with group 4 disease developed MTX-related acute leukoencephalopathy and one of them died.

Conclusions

Our findings support the addition of intrathecal MTX during chemotherapy as the optimal management for children with group 3 and SHH high-risk MB. However, it is not recommended for group 4 MB patients, especially in resource-limited regions.

Trial registration number

: Retrospective registered No.(2020 − 117).

Supplementary Information

The online version contains supplementary material available at 10.1007/s11060-023-04388-2.

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Most cited references 27

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The 2007 WHO Classification of Tumours of the Central Nervous System

David N Louis, Hiroko Ohgaki, Otmar Wiestler … (2007)

The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO ‘Blue Book’, the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.

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Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial.

Amar Gajjar, Murali Chintagumpala, David P Ashley … (2006)

Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. After resection, patients were classified as having average-risk medulloblastoma ( 1.5 cm2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

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Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma.

Roger Packer, Amar Gajjar, Gilbert Vezina … (2006)

To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.

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Author and article information

Contributors

Yu-Tong Zhang:

ORCID: http://orcid.org/0000-0002-6259-7880

zhanglaodi@jlu.edu.cn

Yu Wang: wangyu1@jlu.edu.cn

Xiao-dan Zhong: zhongxd@jlu.edu.cn

Jian Chang:

ORCID: http://orcid.org/0000-0002-3442-6881

changjian@jlu.edu.cn

Journal

Journal ID (nlm-ta): J Neurooncol

Journal ID (iso-abbrev): J Neurooncol

Title: Journal of Neuro-Oncology

Publisher: Springer US (New York )

ISSN (Print): 0167-594X

ISSN (Electronic): 1573-7373

Publication date (Electronic): 20 July 2023

Publication date PMC-release: 20 July 2023

Publication date (Print): 2023

Volume: 164

Issue: 1

Pages: 117-125

Affiliations

GRID grid.430605.4, ISNI 0000 0004 1758 4110, Department of Pediatric Oncology, , the First Hospital of Jilin University, ; Changchun, Jilin 130021 China

Author information

Yu-Tong Zhang http://orcid.org/0000-0002-6259-7880

Jian Chang http://orcid.org/0000-0002-3442-6881

Article

Publisher ID: 4388

DOI: 10.1007/s11060-023-04388-2

PMC ID: 10462507

PubMed ID: 37474745

SO-VID: 37fcc3a7-bd13-45bb-a803-1addee120b70

Copyright © © The Author(s) 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 12 June 2023

Date accepted : 4 July 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100007847, Natural Science Foundation of Jilin Province;

Award ID: YDZJ202201ZYTS128

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: medulloblastoma,high risk,intrathecal methotrexate,leukoencephalopathy

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: medulloblastoma, high risk, intrathecal methotrexate, leukoencephalopathy

Efficacy of intrathecal methotrexate in children with high-risk medulloblastoma over three years: a retrospective study from a single center

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Karger: Oncology

Most cited references 27

The 2007 WHO Classification of Tumours of the Central Nervous System

Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial.

Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma.

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