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Children with high-risk medulloblastoma have relatively poor survival rates, with few studies demonstrating durable treatment responses, despite aggressive multimodality therapy. As such, improved therapy for high-risk medulloblastoma represents an urgent unmet clinical need in pediatric neuro-oncology. In this issue of JAMA Oncology, Leary et al1 describe the results of a phase 3 randomized clinical trial that meets that need. The addition of carboplatin to traditional high-risk therapy specifically benefited molecularly unfavorable patients with group 3 medulloblastoma, including those with metastatic disease. Over the past decade, research has helped to inform pathologic and molecular differences between the 4 noted subtypes: WNT, sonic hedgehog (SHH), group 3, and group 4. However, many challenges remain in widely implementing this therapy in patients who will benefit most. Despite multiple treatment options intent on influencing survival curves, in retrospective analyses, only WNT medulloblastoma, the least common subgroup, has shown high treatment responsivity and lower rates of recurrence. Historically, treatments for high-risk medulloblastoma given in addition to radiotherapy and surgery have ranged from use of standard DNA intercalator/alkylator-based chemotherapies to high-dose myeloablative chemotherapy requiring autologous stem-cell rescue to adjunctive biologic and/or immunologic therapies.2,3 Poor success in achieving statistically significant increases in survival within this high-risk group has necessitated intelligent consortium trials that evaluate treatment options based on pathologic, radiologic, and molecular classifications.
This multi-institutional pediatric consortium study specifically evaluated therapy intensification with carboplatin as a radiosensitizer and isotretinoin as a proapoptotic/differentiation agent in children with newly diagnosed high-risk medulloblastoma.1 High-risk features were defined as metastasis, residual disease, and/or histologic diffuse anaplasia. Following the results of a phase 1/2 trial, patients were randomized to receive 36-Gy craniospinal radiation with or without daily low-dose carboplatin, 35 mg/m2, and weekly vincristine.4 Induction therapy was followed by 6 cycles of maintenance chemotherapy: cisplatin, cyclophosphamide, and vincristine with or without 12 cycles of isotretinoin, 80 mg/m2, twice daily during and following maintenance therapy. Isotretinoin randomization was closed early owing to futility; however, significant findings were that carboplatin improved 5-year event-free survival by 19% (73% vs 54%) only in children with high-risk group 3 medulloblastoma. In addition, this trial demonstrated nearly 100% survival of patients with high-risk medulloblastoma with (1) WNT subtype without metastatic disease, (2) group 4 subgroup with chromosome 11 loss and/or chromosome 17 gain, and (3) group 3 subgroup with localized disease with histologic diffuse anaplasia, regardless of randomization. This high survival rate indicates that some patients within the high-risk group may have excellent prognosis with modern therapy. Of note, the presence of a TP53 mutation in the SHH subtype, which has been associated with a poor prognosis in retrospective studies, was not prognostically significant in this cohort.1
Therapy intensification with carboplatin was associated with increased adverse effects, particularly hematologic, including febrile neutropenia, underscoring the importance of correctly identifying patients who could benefit from this intervention and avoid unnecessary toxic effects. The authors correctly identified difficulty in separating group 3 from group 4 medulloblastoma, and this study raises the issue of how this distinction will be widely implemented for patients outside of clinical trials.1 In 2011, Ellison et al5 pioneered an immunohistochemical approach to subtype analysis that was adopted by the World Health Organization in 2016 owing to its ability to be performed in almost any laboratory around the world.6 Yet, DNA methylation and other advanced testing methods used to separate groups 3 and 4 in this study are not available at most Children’s Oncology Group member institutions, let alone globally. In this study, retrospective central pathologic review found 5% discordance with anaplastic histologic findings, emphasizing the continued nuance of defining anaplasia in medulloblastoma and the potential pitfall of overtreating some patients.1 Before this study, the only proven method of therapy intensification had been to increase craniospinal radiation to 36 Gy from 23.4 Gy. The toxicity of high-risk radiation to 36 Gy and the excellent response of patients with nonmetastatic disease on this study led the authors to suggest a critical evaluation of diffuse anaplasia as an independent high-risk criterion, depending on other molecular features. Advantageously, current Children’s Oncology Group central nervous system studies require prospective rapid central pathologic review, which should further facilitate accurate anaplasia identification and link contextual interpretations to future multi-institutional trials.
Collectively, these study findings demonstrate the complexity of diagnosing high-risk medulloblastoma while balancing treatment responsivity.7 As such, multiple research teams have sought to elucidate medulloblastoma molecular classifications, as well as identify optimal targeted therapies for adjunctive use. Specifically, Hovestadt et al8 reviewed all medulloblastoma molecular profiling studies to date. Their review collated DNA methylation analysis or combined DNA methylation and gene expression analysis, detailing that, although molecular profiling identified only 1 WNT subtype, SHH subgroup could be divided into 4 subtypes and both group 3 and group 4 subgroups had 4 subtypes with overlap of expression and mutational burden. Resultantly, molecular profiling with all 13 subtypes may be useful with histologic characterization, selection of targeted therapy based on tumor heterogeneity, and prognosticating treatment response, when evaluated at the time of trial enrollment.
Although more molecular data may assist with risk stratification, many clinicians, clinician-scientists, and researchers may question what all these data provide in the context of treatment options. In addition, with only group 3 demonstrating an increased event-free survival with carboplatin, we wonder why the benefits are limited to this subgroup. One potential reason for the limitation is both carboplatin’s radiosensitizing effect and its inhibitory role in DNA damage repair. These carboplatin qualities likely prove doubly helpful in group 3 medulloblastoma with high MYC and MYCN amplification; the proto-oncogenes of these genes feed on replicative stress to enable proliferation and migration, but the exact molecular mechanism remains to be determined. Other radiosensitizing agents and/or cell cycle inhibitors should be considered for evaluation in this MYC and MYCN high-amplification group 3 subgroup, such as suberoylanilide hydroxamic acid, temozolomide, or WEE1 inhibitors. In addition, the SJMB12 study is evaluating the addition of pemetrexed and gemcitabine for patients with high-risk group 3 and group 4 medulloblastoma. Each of these agents has been shown to increase survival in preclinical medulloblastoma models, alone or in combination with standard chemotherapy.
Despite the pediatric neuro-oncology community’s desire to decrease the toxic effects of medulloblastoma therapy by de-escalating treatment accordingly, only the regimen that increased therapy intensification has been proven to be successful to date. ACNS0331 attempted to reduce craniospinal radiation doses from 23.4 to 18 Gy for standard-risk medulloblastoma in patients aged 3 to 7 years, but increased rates of disease recurrence were seen and molecular subgroup distinctions had not yet been established. Resultantly, ACNS1422 is testing this hypothesis with 18-Gy craniospinal radiation along with reduced chemotherapy cycles. A bolder pilot study sought to eliminate radiotherapy completely for treatment of WNT medulloblastoma, using the ACNS0331 chemotherapy backbone, but met stopping criteria after enrolling just 6 patients owing to high rates of recurrent disease.
The outcomes of these studies reflect the complex biologic characteristics of these tumors and the difficulty in translating molecular phenotypes to the clinic. The study by Leary et al1 provides us with glimmers of hope for the survival of children with high-risk group 3 medulloblastoma and that the treatment paradigm for all patients with high-risk disease can be improved through incorporation of detailed molecular analyses. The trial also presents a window into the behavior of high-risk group 3 medulloblastoma with a nod to future treatment options for more treatment-responsive, favorable high-risk patients.
Corresponding Author: Sadhana Jackson, MD, 10 Center Dr, Room 7D45, Bethesda, MD 20814 (firstname.lastname@example.org).
Published Online: July 22, 2021. doi:10.1001/jamaoncol.2021.2084
Conflict of Interest Disclosures: Dr Martin reported owning shares in Celgene that were sold in 2019. No other disclosures were reported.
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Martin AM, Jackson S. High-risk Medulloblastoma—Balancing the High Stakes of Molecular Profiling to Enhance Treatment Responsivity. JAMA Oncol. 2021;7(9):1322–1323. doi:10.1001/jamaoncol.2021.2084
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