In a phase II trial (SJYC07) reported in The Lancet Oncology, Robinson et al found that risk-adapted treatment did not improve event-free survival in young children with medulloblastoma. Analysis by methylation status showed superior outcome in the sonic hedgehog (SHH) subgroup.
The study enrolled 81 children aged < 3 years with newly diagnosed medulloblastoma or children aged 3 to 5 years with newly diagnosed nonmetastatic medulloblastoma without any high-risk features between November 2007 and April 2017 at 6 sites in the US and Australia. Eligible patients were required to start therapy within 31 days from definitive surgery and had not received previous radiotherapy or chemotherapy. Patients were categorized postsurgery on clinical and histology criteria as low- (n = 23), intermediate- (n = 32), or high-risk (n = 26); accrual to the low-risk group was suspended after interim analysis in December 2015 indicated that 1-year event-free survival was below the stopping rule boundary.
All patients received induction chemotherapy with methotrexate, vincristine, cisplatin, and cyclophosphamide, with high-risk patients receiving additional vinblastine. Risk-adapted consolidation consisted of cyclophosphamide, etoposide, and carboplatin for two 4-week cycles in low-risk patients, focal radiation therapy (54 Gy, clinical target volume 5 mm over 6 weeks) in intermediate-risk patients, and targeted intravenous topotecan plus cyclophosphamide (days 1–5) in high-risk patients. All patients received maintenance treatment with cyclophosphamide, topotecan, and erlotinib.
The coprimary endpoints were event-free survival and methylation profiles associated with progression-free survival.
After median follow-up of 5.5 years, 5-year event-free survival was 31.3% in the entire population, 55.3% in the low-risk group, 24.6% in the intermediate-risk group (hazard ratio [HR] vs low risk = 2.50, P = .016), and 16.7% in the high-risk group (HR vs low risk = 3.55, P = .0011; overall P = .0021).
Progression-free survival at 5 years according to methylation subgroup was 51.1% in the SHH subgroup (n = 42), 8.3% in the group 3 subgroup (n = 24), and 13.3% in the group 4 subgroup (n = 10). In two distinct methylation subtypes found in the SHH subgroup, 5-year progression-free survival was 27.8% in the infant (i)SHH-I group (n = 21) and 75.4% in the iSHH-II group (n = 21), including 22.2% vs 90.9% among low-risk patients (n = 11, n = 12) in the 2 groups.
Overall, the most common grade 3 or 4 adverse events were febrile neutropenia (59%), neutropenia (26%), infection with neutropenia (25%), leukopenia (19%), vomiting (19%), and anorexia (16%). No treatment-related deaths were observed.
The investigators concluded, “The risk-adapted approach did not improve event-free survival in young children with medulloblastoma. However, the methylation subgroup analyses showed that the SHH subgroup had improved progression-free survival compared with the group 3 subgroup. Moreover, within the SHH subgroup, the iSHH-II subtype had improved progression-free survival in the absence of radiation, intraventricular chemotherapy, or high-dose chemotherapy compared with the iSHH-I subtype. These findings support the development of a molecularly driven, risk-adapted, treatment approach in future trials in young children with medulloblastoma.”
The study was supported by the American Lebanese Syrian Associated Charities, St Jude Children’s Research Hospital, National Cancer Institute, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.
Giles W. Robinson, MD, of the Department of Oncology at St. Jude Children’s Research Hospital, is the corresponding author for The Lancet Oncology article.
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