Robinson GW, et al. - Researchers investigated event-free survival and molecular characteristics related to progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure. No improvement in event-free survival was brought about by the risk-adapted approach. In the methylation subgroup analyses, improved progression-free survival was found in the sonic hedgehog (SHH) subgroup vs the group 3 subgroup. Moreover, within the SHH subgroup, improved progression-free survival was seen in the iSHH-II subtype vs the iSHH-I subtype in the absence of radiation, intraventricular chemotherapy, or high-dose chemotherapy.

Methods

• For this multicentre, phase 2 trial including children younger than 3 years with newly diagnosed medulloblastoma at six centres in the USA and Australia, children aged 3–5 years with newly diagnosed, non-metastatic medulloblastoma without any high-risk features were also eligible.
• To be eligible, patients were required to start therapy within 31 days from definitive surgery, had a Lansky performance score of at least 30, and did not receive previous radiotherapy or chemotherapy.
• Using clinical and histological criteria, patients were stratified postoperatively into low-risk, intermediate-risk, and high-risk treatment groups.
• Identical induction chemotherapy (methotrexate, vincristine, cisplatin, and cyclophosphamide) was given to all patients, with high-risk patients also receiving an additional five doses of vinblastine.
• Risk-adapted consolidation therapy was received following induction: cyclophosphamide (1500 mg/m² on day 1), etoposide (100 mg/m² on days 1 and 2), and carboplatin (area under the curve 5 mg/mL per min on day 2) for two 4-week cycles was received by low-risk patients; focal radiation therapy (54 Gy with a clinical target volume of 5 mm over 6 weeks) to the tumour bed was received by intermediate-risk patients; and chemotherapy with targeted intravenous topotecan (area under the curve 120–160 ng-h/mL intravenously on days 1–5) and cyclophosphamide (600 mg/m² intravenously on days 1–5) was received by high-risk patients.
• Maintenance chemotherapy with cyclophosphamide, topotecan, and erlotinib was administered to all patients following consolidation.
• Event-free survival and patterns of methylation profiling associated with progression-free survival were considered as coprimary endpoints.
• Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy); including all patients with tissue available for methylation profiling, biological analyses were carried out.

Results

• Enrollment of 81 patients with histologically confirmed medulloblastoma was carried out between Nov 27, 2007, and April 19, 2017.
• Following an interim analysis on Dec 2, 2015, accrual to the low-risk group was suspended when the 1-year event-free survival was estimated to be below the stopping rule boundary.
• A median follow-up of 5·5 years (IQR 2·7–7·3) revealed 5-year event-free survival to be 31·3% (95% CI 19·3–43·3) for the whole cohort, 55·3% (95% CI 33·3–77·3) in the low-risk cohort (n=23) vs 24·6% (3·6–45·6) in the intermediate-risk cohort (n=32; hazard ratio 2·50, 95% CI 1·19–5·27; p=0·016) and 16·7% (3·4–30·0) in the high-risk cohort (n=26; 3·55, 1·66–7·59; p=0·0011; overall p=0·0021).
• By methylation subgroup, the reported 5-year progression-free survival was 51·1% (95% CI 34·6–67·6) in the sonic hedgehog (SHH) subgroup (n=42), 8·3% (95% CI 0·0–24·0%) in the group 3 subgroup (n=24), and 13·3% (95% CI 0·0–37·6%) in the group 4 subgroup (n=10).
• Researchers identified iSHH-I and iSHH-II as two distinct methylation subtypes within the SHH subgroup.
• For iSHH-I and for iSHH-II, the observed 5-year progression-free survival was 27·8% (95% CI 9·0–46·6; n=21) and 75·4% (55·0–95·8; n=21), respectively.
• The adverse events that were most commonly reported were: grade 3–4 febrile neutropenia (48 patients [59%]), neutropenia (21 [26%]), infection with neutropenia (20 [25%]), leucopenia (15 [19%]), vomiting (15 [19%]), and anorexia (13 [16%]).
• No occurrence of treatment-related deaths was reported.