Abstract
Simple SummaryMedulloblastoma is a rare brain tumor that affects children and adults. Treatment with surgery, radiation, and chemotherapy currently cures most patients; however, ~30% of all patients have poor clinical outcomes despite treatment. Prospective clinical trials have historically excluded older patients, while recent advances in molecular diagnostics have enhanced our understanding of tumorigenesis. The aim of this literature review is to discuss the history of clinical trials in medulloblastoma and to argue in favor of prioritizing molecular drivers of disease as trial inclusion features rather than an arbitrary age cutoff.Medulloblastoma is a rare malignant brain tumor that predominantly affects children but also occurs in adults. The incidence declines significantly after age 15, and distinct tumor molecular features are seen across the age spectrum. Standard of care treatment consists of maximal safe surgical resection followed by adjuvant radiation and/or chemotherapy. Adjuvant treatment decisions are based on individual patient risk factors and have been informed by decades of prospective clinical trials. These trials have historically relied on arbitrary age cutoffs for inclusion (age 16, 18, or 21, for example), while trials that include adult patients or stratify patients by molecular features of disease have been rare. The aim of this literature review is to review the history of clinical trials in medulloblastoma, with an emphasis on selection criteria, and argue in favor of rational and inclusive trials based on molecular features of disease as opposed to chronological age. We performed a scoping literature review for medulloblastoma and clinical trials and include a summary of those results. We also discuss some of the significant advances made in understanding the molecular biology of medulloblastoma within the past decade, most notably the identification of four distinct subgroups based on gene expression profiling. We will also cite the recent experiences of childhood leukemia and the emergence of tissue-agnostic therapies as examples of successes of rationally designed, inclusive trials translating to improved clinical outcomes for patients across the age spectrum. Despite the prior trial history and recent molecular advances outcomes remain poor for ~30% of medulloblastoma patients. We believe that defining patients by the specific molecular alterations their tumors harbor is the best way to ensure they can access potentially efficacious therapies on clinical trials.
Highlights
Given the toxicities associated with cycles of multi-drug cytotoxic chemotherapy regimens and the lack of randomized data showing benefit in adult patients, adults with non-disseminated disease were typically recommended treatment with surgery followed by craniospinal radiation (CSI) alone
At present both children and adults are recommended to receive systemic chemotherapy, the regimens and doses vary based on risk stratification and individual patient factors [19]
The observation that adolescent and young adults with acute lymphoblastic leukemia have improved outcomes when treated on “pediatric” chemotherapy regimens supports the hypothesis that selecting patients for clinical trials based on arbitrary age cutoffs is an inefficient and potentially harmful way to identify optimal regimens
Summary
The term medulloblastoma was first used in 1925 by Drs Cushing and Bailey, who reviewed a series of ~400 cases of gliomas and identified 29 cerebellar tumors occurring mainly in children (ages 2–28, median 8 years) [1] Their series included five patients who were 18 years or older. Further research led to a reclassification system proposed by Dr Rorke in 1983 that grouped medulloblastomas with other histologically similar primary CNS neoplasms composed of undifferentiated neuroepithelial cells and occurring primarily in infancy and childhood [2]. These lesions were given the name “primitive neuroectodermal tumors” (PNET). This series included patients, ofof which were adults [9][9]
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