according to research published in the .
Investigators conducted a prospective trial of 87 children diagnosed with nonmetastatic medulloblastoma before the age of 4 years who were treated from 2001-2011.
At 5 years after diagnosis, the 42 DMB/MBEN patients had a 93% progression-free survival (PFS) rate, a 100% overall survival (OS) rate, and a 93% craniospinal irradiation (CSI)–free survival rate.
“Our results suggest that ... poor outcomes of patients treated with systemic chemotherapy alone can be improved by the addition of intraventricular [methotrexate],” wrote Martin Mynarek, MD, of the University Medical Center Hamburg-Eppendorf (Germany), and colleagues.
However, it was a different story for the 45 patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (CLA), in which outcomes are historically worse. At 5 years, the PFS was 37%, the OS was 62%, and the CSI-free survival was 39% in these patients.
In 2006, the CMB and CLA patients started receiving local radiotherapy in addition to chemotherapy and intraventricular methotrexate, but the radiotherapy did not seem to help with their disease.
“Because data suggest no effects, or even adverse effects, of local radiotherapy, additional development of this approach does not seem justified,” the investigators wrote.
“Interestingly, almost all patients with CMB/LCA had distant or combined relapses after local radiotherapy,” they added. “One might speculate that local radiotherapy reduced disease burden of the primary tumor and subclinical metastasis in the posterior fossa, leading to a survival advantage of distant subclinical metastasis over local residues.”
The 87 patients were enrolled in the BIS4 arm of the HIT 2000 trial (), which was designed to test six protocols and identify the optimal approach for treating young patients with medulloblastoma, supratentorial primitive neuroectodermal tumor, or ependymoma.
Patients started “HIT-SKK” chemotherapy within 2-4 weeks of surgery. They received three cycles of intravenous cyclophosphamide, vincristine, methotrexate (followed by leucovorin rescue after 42 hours), carboplatin, and etoposide, with concomitant intraventricular methotrexate, for a duration of 6 months ().
Among patients who achieved a complete remission, treatment was ended after two additional cycles of chemotherapy. For other patients, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended.
Starting in 2006, DMB and MBEN patients without complete remissions, as well as those with CMB or LCA, received 54 Gy of focal radiotherapy to the tumor bed after the first three treatment cycles.
SHH-I vs. SHH-II DMB/MBEN
DNA methylation profiling was available for 50 of the 87 patients in this analysis, 28 of whom had infantile sonic hedgehog (SHH)–activated DMB/MBEN. Data from these 28 patients – and 71 patients in a validation cohort – revealed no significant difference in 5-year PFS or OS based on methylation subtype.
The 5-year PFS was 73% in SHH-I patients and 83% in SHH-II patients (P = .25). The 5-year OS was 88% and 97%, respectively (P = .099).
“This suggests that the higher risk of relapse in the less favorable [SHH-I subtype] can be abrogated by the addition of intraventricular [methotrexate] to systemic chemotherapy,” the investigators wrote.
The results suggest SHH-I patients “markedly benefit” from the addition of intraventricular chemotherapy, according to the authors of a, Giles Robinson, MD, and Amar Gajjar, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
“However, cross-trial comparison of PFS among the SHH-II subtype does not suggest that SHH-II patients derive the same benefit,” the editorialists wrote.
These data divide SHH medulloblastoma into SHH-I, which benefits from chemotherapy with intraventricular methotrexate, and SHH-II, which can be cured without intraventricular methotrexate, high-dose chemotherapy, or focal radiotherapy, according to the editorialists.
This new information might prompt investigation of a risk-adapted approach. SHH-II patients would receive a reduced-intensity regimen with systemic chemotherapy only, and SHH-I patients would receive systemic chemotherapy combined with intraventricular methotrexate. This could avoid exposing young children to “more intensive therapy than necessary,” according to the editorialists.