What is the typical treatment for medulloblastoma?

Treatment of Medulloblastoma

Maximal Safe Surgical Resection Followed by Risk-Stratified Multimodal Therapy

The standard treatment for medulloblastoma consists of maximal safe surgical resection followed by risk-stratified craniospinal irradiation with concurrent and maintenance chemotherapy, with specific radiation doses and chemotherapy regimens determined by molecular subtype, extent of resection, and metastatic status. 1

Initial Surgical Management

• Pursue maximal safe resection (gross total resection) as the primary surgical goal while minimizing neurologic deficits 2, 1
• Surgery serves multiple critical functions: maximal cytoreduction, relief of hydrocephalus, reduction of tumor-associated mass effect, and obtaining adequate tissue for both histologic and molecular classification 2, 1
• Obtain postoperative MRI ideally within 24-48 hours after surgery to confirm extent of resection 2
• Collect tissue for molecular genetic characterization at initial surgery, including assessment for WNT activation, SHH activation with TP53 status, and Group 3/4 classification, which is critical for risk stratification 1
• Refer patients to fertility preservation counseling before initiating chemotherapy, given the young age at diagnosis 2, 1

Molecular Subtype-Based Risk Stratification

The molecular subtype fundamentally determines prognosis and should guide treatment intensity:

• WNT-activated medulloblastoma (10% of cases): Excellent prognosis with long-term survival rates >90%, most common in children aged 7-14 years 2, 1
• SHH-activated, TP53-wild-type: Intermediate prognosis; however, TP53-mutant and/or MYCN amplification confers very poor prognosis, worse than TP53 mutation alone 2, 1
• Group 3 medulloblastoma (25% of cases): Poor prognosis with 5-year survival rates 20-30% 2, 1
• Group 4 medulloblastoma (35% of cases): Better prognosis with survival rates 75-90% 2, 1

Risk-Stratified Treatment Protocols

Average-Risk Patients

Average-risk patients should receive reduced-dose craniospinal irradiation (23.4 Gy) with involved field boost to 54 Gy, plus adjuvant/maintenance systemic therapy. 1

• Administer weekly vincristine during the 6-week radiation period 1, 3
• Follow with maintenance chemotherapy using either:
  • St. Jude protocol: vincristine, cisplatin, and cyclophosphamide 1, 3
  • COG protocol (alternative regimen) 1
• Do not interchange or mix protocols mid-treatment, as the COG and St. Jude maintenance regimens differ significantly and are not interchangeable 3
• The reduced CSI dose of 23.4 Gy combined with chemotherapy maintains efficacy while lessening long-term neurocognitive side effects 2, 4

High-Risk Patients

High-risk patients require high-dose craniospinal irradiation (36 Gy) with involved field boost to 54-55.8 Gy, plus adjuvant/maintenance systemic therapy. 1

• High-risk features include: large cell or anaplastic histology, disease dissemination (M+ disease), unresectable tumors, or residual tumors >1.5 cm² post-surgery 2
• Use St. Jude protocol or ACNS0332 protocol for maintenance chemotherapy 1
• Consider stem cell collection before radiation for potential future autologous stem cell reinfusion at disease progression 2

Very High-Risk Patients (MYC Amplification)

Very high-risk patients with MYC amplification should receive high-dose CSI 36 Gy with involved field boost to 54-55.8 Gy, and carboplatin prior to each radiation fraction as a radiosensitizer. 1

• This approach improved event-free survival by 19% in high-risk Group 3 medulloblastoma 1

Critical Treatment Timing and Age Considerations

• Radiation therapy should begin within one month postoperatively 3
• **Radiation therapy is not recommended for patients <3 years of age**, though radiation-avoiding strategies may be considered for patients >3 years at the treating physician's discretion 1, 3
• Treatment of children <3 years is complex and requires specialized protocols not covered in standard guidelines 2

Toxicity Monitoring During Treatment

• Monitor closely for vincristine-associated peripheral neuropathy throughout treatment, as this is a common dose-limiting toxicity requiring intervention 1, 3
• Monitor for cisplatin-associated ototoxicity, which can be severe and permanent 1, 3
• Do not cap vincristine at 1 mg; the protocol specifies 1.4 mg/m² with a 2 mg maximum 3
• Myelosuppression occurs in approximately 38-45% of patients but is usually manageable 2, 5

Treatment of Recurrent or Progressive Disease

Recurrent/progressive medulloblastoma after first-line therapy occurs in approximately one-third of patients and carries survival rates <10%. 1

• For recurrence after 3-5 years, rebiopsy the tumor to distinguish between recurrent medulloblastoma and secondary malignancy, and to identify actionable molecular findings 1
• Treatment options include:
  • Targeted therapy based on molecular alterations: dabrafenib/trametinib or vemurafenib for BRAF V600E-mutated tumors; larotrectinib or entrectinib for TRK fusion-positive tumors; nivolumab or pembrolizumab for hypermutant tumors; lorlatinib or alectinib for ALK rearrangement-positive tumors 2
  • Reirradiation if feasible 2, 1
  • Reresection for single, focal posterior fossa recurrence 1
  • High-dose chemotherapy with autologous stem cell rescue for patients showing no evidence of disease after resection or conventional reinduction chemotherapy 2
  • Palliative/best supportive care for poor performance status, including oral etoposide, bevacizumab, or nitrosoureas (lomustine or carmustine) 2, 1

Surveillance Strategy

• Perform brain MRI every 3 months for the first 2 years, then biannual brain MRI for the next 3 years, then yearly 2
• Use MRI with gadolinium contrast for surveillance, including spine MRI, which is superior to other modalities for detecting leptomeningeal dissemination 1
• If recurrent disease is detected, CSF sampling is required 2
• FDG-PET/CT can be useful for evaluating metastatic disease and prognosis when MRI findings are equivocal 1

Special Considerations for Adult Patients

• Adults with medulloblastoma should be referred to specialized centers or "centers of excellence" with expertise in diagnosis and treatment, as treatment at academic centers and high-volume facilities is associated with longer survival rates 1
• Routinely conduct DNA methylation testing for diagnosis and molecular subgrouping in adult patients 1

Common Pitfalls to Avoid

• Do not use low-dose CSI (<23.4 Gy) in average-risk patients, as this may compromise outcomes 3
• Do not delay radiation therapy beyond one month postoperatively 3
• Do not switch between protocols mid-treatment (St. Jude vs. COG), as they are not interchangeable 3
• Do not modify the initial empiric treatment based solely on persistent symptoms if the patient remains clinically stable during the treatment course 2
• Be aware that treatment-related late toxicity, particularly reduction in IQ ranging from 8-21%, represents a significant long-term morbidity in survivors 5