Long-term Outcome of the Milano-Hyperfractionated Accelerated Radiotherapy Strategy for High-Risk Medulloblastoma, Including the Impact of Molecular Subtype
Long-Term Outcomes of High-Risk Medulloblastoma Treatment
Background
Medulloblastoma is one of the most common malignant brain tumors in children. Despite advancements in treatment, the prognosis for high-risk medulloblastoma patients remains poor. High-risk medulloblastoma typically includes patients with metastatic disease, TP53 mutations, MYC/MYCN gene amplification, or large cell/anaplastic (LC/A) histological subtypes. The treatment strategies for these patients are complex, and long-term survival rates are low. Therefore, finding more effective treatment options to improve the prognosis of these patients is a critical area of research in neuro-oncology.
This study, led by Maura Massimino and her team from the Fondazione IRCCS Istituto Nazionale dei Tumori in Italy, aimed to evaluate the long-term efficacy of a treatment strategy known as the “Milano Strategy,” which combines high-dose chemotherapy with hyperfractionated accelerated radiotherapy (HART) in high-risk medulloblastoma patients. The study particularly focused on the impact of molecular subtypes on prognosis, especially the prognosis of Sonic Hedgehog (SHH) subtype medulloblastoma.
Source of the Paper
The study was led by Maura Massimino and her team from the Fondazione IRCCS Istituto Nazionale dei Tumori in Italy, with collaboration from institutions such as the Princess Máxima Center in the Netherlands and the Hopp Children’s Cancer Center in Germany. The paper was published online in advance on September 27, 2024, in the journal Neuro-Oncology, with the DOI 10.1093/neuonc/noae189.
Research Process and Results
Research Process
Patient Inclusion and Treatment Strategy
The study included 89 high-risk medulloblastoma patients treated at the Fondazione IRCCS Istituto Nazionale dei Tumori between 1998 and 2021. All patients underwent surgical tumor resection, followed by staging and histo-biological analysis. The treatment regimen included sequential high-dose chemotherapy (HD-MTX, HD-VP16, HD-Cyclo, HD-Carbo) and hyperfractionated accelerated radiotherapy (HART). The radiotherapy dose was adjusted based on the patient’s age and response to chemotherapy: patients under 10 years old who achieved complete response (CR) or partial response (PR) after chemotherapy received 31.2 Gy, while other patients received 39 Gy. An additional 9 Gy boost was administered to the posterior fossa or metastatic lesions.Molecular Subtype Analysis
Molecular subtype analysis was performed on tumor samples from 66 patients, revealing 15 SHH subtype cases, 15 Group 3 cases, and 29 Group 4 cases. Among the SHH subtype patients, 2 carried TP53 mutations.Long-Term Follow-Up and Statistical Analysis
Patients were followed for a median of 136 months, and overall survival (OS) and event-free survival (EFS) were assessed. Survival curves were plotted using the Kaplan-Meier method, and multivariate analysis was conducted using the Cox proportional hazards model to evaluate the impact of factors such as age, molecular subtype, and response to chemotherapy and radiotherapy on prognosis.
Key Results
Survival Rates
The 5-year and 15-year overall survival (OS) rates were 75.9% and 66.5%, respectively, while the event-free survival (EFS) rates were 68.2% and 65.3%, respectively. Patients with the SHH subtype had the worst prognosis, with a 15-year EFS of 45.7%, significantly lower than that of Group 3 and Group 4 subtype patients (69.8%).Response to Chemotherapy and Radiotherapy
Response to chemotherapy and radiotherapy was significantly correlated with prognosis. Patients who experienced disease progression (PD) after chemotherapy or stable disease (SD) or progression (PD) after radiotherapy had a poorer prognosis (p < 0.001).Radiotherapy Dose Adjustment
Among patients under 10 years old, 31 patients had their radiotherapy dose reduced (to 31.2 Gy) based on their response to chemotherapy, without compromising their survival rates.
Conclusions and Significance
The study confirmed the long-term efficacy of the “Milano Strategy” in high-risk medulloblastoma patients, particularly in SHH subtype patients, whose prognosis remains poor but may be improved through optimized chemotherapy and radiotherapy strategies. The study also demonstrated that adjusting radiotherapy doses based on chemotherapy response is feasible and does not affect long-term survival. These findings provide new insights into the treatment of high-risk medulloblastoma and offer important references for the design of future clinical trials.
Research Highlights
Long-Term Follow-Up Data
The study provided long-term follow-up data with a median of 136 months, offering reliable evidence for assessing the long-term prognosis of high-risk medulloblastoma.Molecular Subtype Analysis
The study systematically analyzed the impact of molecular subtypes on prognosis in high-risk medulloblastoma patients for the first time, particularly focusing on the prognosis of the SHH subtype.Radiotherapy Dose Adjustment
The study confirmed the feasibility of adjusting radiotherapy doses based on chemotherapy response, providing a basis for reducing radiotherapy-related side effects.
Additional Valuable Information
The study also reported that 20% of long-term survivors developed secondary tumors, with 3 patients dying as a result. This finding highlights that, although treatment has improved survival rates, the risk of secondary tumors must be closely monitored during long-term follow-up.