Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07)

Abstract

Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy.

Methods: The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy.

Results: Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock.

Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.

Fig. 1

Histological and genetic distribution in NOA-07. (A) Clustering of samples based on the 5000 most differentially methylated cytosine-phosphate-guanine probes (standard deviation), with DNA methylation values shown from unmethylated (blue) to methylated (red). SHH-activated, WNT-activated, and non-WNT/non-SHH (Group 4) tumors are clearly distinct. DNMB, desmoplastic/nodular medulloblastoma; CMB classic medulloblastoma. (B) Summary of copy number profiles per molecular subgroup. Log₂ copy number ratios (tumor: normal) are displayed on a scale from loss (red) to gain (green). Notable changes include monosomy 6 in one WNT-activated sample, loss of 9q in a subset of SHH-activated tumors, and iso(17q) in all 3 non-WNT/non-SHH (Group 4) tumors.

Fig. 2

HRQoL evaluation (main categories). Scores over time for the 3 preselected scales: (A) role functioning, (B) cognitive functioning, and (C) social functioning, with the number of patients with HRQoL data at each time point.