Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5

Abstract

Background: High-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5-19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5.

Methods: All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1-3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy).

Results: Fifty-one patients (median age, 8 y; range, 5-19) were enrolled. The median follow-up was 7.1 years (range: 3.4-9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65-88) and 76% (63-86), and the 3 and 5-year OS were 84% (72-92) and 76% (63-86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated.

Conclusions: This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.

Keywords: children; high-risk medulloblastoma; phase II trial.

Fig. 1

Trial profile. *The trial profile presents the treatments that were actually received by the patients, based on the results of the tumor assessments provided by local radiologists. A progression was identified by the central review on the post VP16-Carboplatin assessment of a third patient. The local radiologist identified this progression later, after the patient has received the second course of thiotepa.

Fig. 2

Overall and progression-free survival.

Fig. 3

Progression-free survival (A) by histological subtype; (B) by molecular subgroup; (C) by tumor response after VP16-Carboplatin and (D) by tumor response after high-dose chemotherapy. DNB, desmoplastic/nodular medulloblastoma; MB NOS, medulloblastoma not otherwise specified; CMB, classic medulloblastoma; LCA, large cell/anaplastic medulloblastoma; WNT, Wingless; SHH, Sonic hedgehog.