Advances in Risk Stratification and Treatment Strategies for Medulloblastoma

Background

Medulloblastoma is a common malignant brain tumor in children, with significant differences in treatment and prognosis depending on its molecular subtypes. In recent years, advances in molecular biology have revealed that medulloblastoma can be further divided into four distinct molecular subtypes, each with unique cellular origins, molecular characteristics, and clinical outcomes. This discovery has provided new directions for risk stratification and optimization of treatment strategies for medulloblastoma. However, although radiation therapy remains the most effective treatment for medulloblastoma, its long-term impact on neurocognitive and neuroendocrine functions remains a significant clinical concern. Therefore, reducing radiation doses without compromising efficacy has become a key focus of current research.

This article, authored by Nicholas G. Gottardo and Amar Gajjar from Perth Children’s Hospital in Australia and St. Jude Children’s Research Hospital in the USA, respectively, was published in Neuro-Oncology on October 25, 2024. It explores the progress in risk stratification for medulloblastoma and its implications for treatment strategies.

Key Content of the Paper

1. Progress in Risk Stratification

The article begins by reviewing the historical progress in risk stratification for medulloblastoma. Since the discovery of its four molecular subtypes, researchers have further subdivided the Sonic Hedgehog (SHH) subtype into four subgroups and the Group 3 and Group 4 subtypes into eight subgroups using methylation profiling. These molecular subtypes have provided more precise tools for risk stratification. Through advanced genomic technologies, researchers have been able to define risk features associated with patient outcomes in multiple prospective clinical trials, offering a basis for optimizing treatment strategies.

2. Long-Term Outcomes of the Milano-HART Strategy

The article highlights the long-term outcomes of the Milano-Hyperfractionated Accelerated Radiotherapy (HART) strategy proposed by Massimino et al. This strategy targets high-risk medulloblastoma patients over 3 years old, employing multiagent high-dose chemotherapy combined with adjusted HART, followed by thiotepa-based chemotherapy and autologous stem cell rescue. The initial study included 33 patients with metastatic disease, reporting a 5-year event-free survival (EFS) rate of 70% ± 8%. In the latest update, the study expanded to 89 patients, incorporating molecular features such as large cell/anaplastic histology, TP53 mutations, and MYC/MYCN amplification. The results showed a 5-year EFS of 68.2%, consistent with the initial findings. The study also found that response to neoadjuvant chemotherapy was the primary determinant of survival, while factors such as metastatic disease, MYC/MYCN amplification, and post-surgical residual disease had no significant impact on survival.

3. Complexity of Risk Features

The article further discusses the complexity of risk features. Risk features depend not only on the molecular characteristics of the tumor but also on the treatment strategy. Currently, the World Health Organization (WHO) recommends diagnostic methods including histopathological examination, methylation profiling, tumor sequencing (whole exome or panel sequencing), and germline sequencing. These technologies have made the diagnosis and risk stratification of medulloblastoma more precise. However, due to differences in treatment strategies across studies, the interpretation of risk features requires caution. For example, in North America, radiation therapy is typically delivered upfront, followed by alkylator-based maintenance chemotherapy, which differs from the Milano-HART strategy.

4. Future Directions and Challenges

The article concludes by noting that risk stratification and treatment strategies for medulloblastoma will continue to evolve as treatment modalities and molecular biology technologies advance. Future clinical trials will increasingly incorporate molecular data and detect minimal residual disease (MRD) through cerebrospinal fluid (CSF) analysis, providing a basis for adjusting treatment plans. Additionally, the ongoing high-risk medulloblastoma clinical trial (SIOP-HR-MB) by the International Society of Paediatric Oncology Europe (SIOP-E) will further validate the efficacy of the Milano-HART strategy.

Significance and Value of the Paper

By analyzing the long-term outcomes of the Milano-HART strategy, this article highlights the importance of neoadjuvant chemotherapy response in the treatment of medulloblastoma. Although the findings differ from previous large cohort studies, they offer new insights into the treatment of high-risk medulloblastoma. Furthermore, the article emphasizes the critical role of molecular features in risk stratification and calls for cautious clinical implementation of modified risk stratification strategies.

Key Highlights

1. Refinement of Molecular Subtypes: Methylation profiling and genomic technologies have further subdivided medulloblastoma molecular subtypes, providing more precise tools for risk stratification.
2. Long-Term Outcomes of the Milano-HART Strategy: This strategy demonstrated stable 5-year event-free survival rates in high-risk medulloblastoma patients, offering strong evidence for the use of neoadjuvant chemotherapy.
3. Complexity of Risk Features: The article underscores that risk features depend not only on tumor molecular characteristics but also on treatment strategies, highlighting the need for cautious interpretation of risk stratification results in clinical practice.
4. Future Directions: Future clinical trials will increasingly incorporate molecular data and MRD detection, providing a basis for individualized treatment adjustments.

This article provides significant theoretical support and clinical guidance for risk stratification and optimization of treatment strategies for medulloblastoma, offering high scientific value and clinical application prospects.