Risk-stratification for treatment de-intensification in WNT-pathway medulloblastoma: finding the optimal balance between survival and quality of survivorship

ABSTRACT

Introduction

Advances in molecular biology have led to consensus classification of medulloblastoma into four broad molecular subgroups – wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4, respectively. Traditionally, children >3 years of age, with no/minimal residual tumor (<1.5 cm²) and lack of metastasis were classified as average-risk disease with >80% long-term survival. Younger age (<3 years), large residual disease (≥1.5 cm²), and leptomeningeal metastases either alone or in combination were considered high-risk features yielding much worse 5-year survival (30–60%). This clinico-radiological risk-stratification has been refined by incorporating molecular/genetic information. Contemporary multi-modality management for non-infantile medulloblastoma entails maximal safe resection followed by risk-stratified adjuvant radio(chemo)therapy. Aggressive multi-modality management achieves good survival but is associated with substantial dose-dependent treatment-related toxicity prompting conduct of subgroup-specific prospective clinical trials.

Areas covered

We conducted literature search on PubMed from 1969 till 2023 to identify putative prognostic factors and risk-stratification for medulloblastoma, including molecular subgrouping. Based on previously published data, including our own institutional experience, we discuss molecular risk-stratification focusing on WNT-pathway medulloblastoma to identify candidates suitable for treatment de-intensification to strike the optimal balance between survival and quality of survivorship.

Expert opinion

Prospective clinical trials and emerging biological information should further refine risk-stratification in WNT-pathway medulloblastoma.

KEYWORDS:

• De-intensification
• medulloblastoma
• molecular
• risk-stratification
• survival
• WNT

Article highlights

• Medulloblastoma is a heterogeneous disease comprising of four broad molecular subgroups (WNT, SHH, Group 3 and Group 4)

• Molecular/genetic information is now incorporated in the WHO classification as well as contemporary risk-stratification of medulloblastoma.

• WNT-subgroup medulloblastoma has the best long-term survival (>95%) with no/minimal impact of traditional risk factors (extent of resection and/or metastatic disease)

• Aggressive multi-modality treatment is associated with substantial burden of dose-dependent treatment-related toxicities, particularly in long-term survivors.

• Systematic attempts at treatment de-intensification in WNT-pathway medulloblastoma aim to strike the optimal balance between survival and quality of survivorship.

• Prospective clinical trials and emerging biological information should further refine risk-stratification of WNT-activated medulloblastoma.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors acknowledge the Brain Tumor Foundation (BTF) India.

Additional information

Funding

This paper was not funded.