OS02.1 Multicenter pilot study of radio-chemotherapy as first-line treatment for adults with medulloblastoma - the NOA-07 trial

Abstract

Abstracts iii3NEURO-ONCOLOGY • MAY 2017 of the prognostic significance of MGMT promoter methylation relative to IDH and 1p/19q status is ongoing as well as efforts to increase sample size. FUNDING: U10CA180868, U10CA180822, and U24CA196067 (NCI). Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and the Ohio State University CCC (all to AC). BACKGROUND: Medulloblastoma in adult patients has a low incidence, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. In contrast to children, no prospective data on the feasibility of radio-chemotherapy in adults exists. The German Neuro-Oncology Working Group (NOA) performed a prospective multicenter single-arm Phase II trial to evaluate the feasibility and toxicity of radio-chemotherapy in this population. METHODS: The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by a maximum of eight cycles of cisplatin, lomustine and vincristine. Adverse events, imaging and progression patterns, combined histological and genetic markers, health-related quality of life (HRQoL) and cognition were evaluated prospectively. The primary endpoints were the rate of toxicity-related treatment terminations after four cycles of chemotherapy, and the toxicity profile. FINDINGS: Thirty patients were evaluable. Fifty percent of patients showed classic, and 50% desmoplastic-nodular histology. Sixty-eight percent of patients were genetically classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13.6% in wingless (WNT), and 17.7% in Non-WNT/Non-SHH (Group 4). Four cycles of chemotherapy were feasible in the majority of patients (n=21; 70.0%). Leukopenia was the major toxicity, with 79 events of CTC grade 3 and 4 in 17 patients. Polyneuropathy and ototoxicity were the only grade 3 or 4 non-haematological toxicities during the active treatment phase and occurred 12 times in eight patients and one time in one patient, respectively. Events were also calculated per cycle and showed an increase of toxicity over treatment time. Feasibility appeared to be age-dependent, leading to application of four cycles of chemotherapy in 72.7% of patients below age 45 and 62.5% of patients 45 or above. Testing for all eight adjuvant cycles revealed that 45.5% of all patients younger than 45 years completed eight cycles, whereas only 12.5% of patients over 45 years received all cycles. Severe adverse events were significantly more frequent in patients older than 45 years of age (p = 0.040). We observed no treatment-related deaths. During the active treatment period, HRQoL showed clinically relevant improvements in several domains. Verbal fluency also improved. The 3-year EFS rate was 66.6% at the time of databank lock. INTERPRETATION: This is a prospective trial in a homogenous population of adults with medulloblastoma. Radio-chemotherapy was safe and tolerable throughout the active treatment phase and generated improvements of HRQoL and cognition. However, toxicity was ...

Management and Long-term Outcomes of Adults With Medulloblastoma

“…Many guiding studies were published before widespread molecular subgroup classification in clinical practice, which will be important to incorporate into future clinical trials. 10,11,20,45,46 The main strength of our study is a large and well-characterized sample, given the rarity of this diagnosis. We provide patientspecific demographic, management, and outcome data with known molecular subgroup classification in a majority of the cohort.…”

“…Prior prospective and retrospective reports in adults have used various techniques such as radiation therapy (RT) type/dose, chemotherapy, or a combination of therapy after surgical resection. [6][7][8][9][10] Recently, the molecular characterization of medulloblastoma elucidated 4 distinct molecular subgroups-sonic-hedgehog (SHH or SHH-activated), wingless (WNT or WNTactivated), and non-WNT/non-SHH (group 3 and group 4). 1,11 SHH-activated is further categorized based on TP53 status as SHH-TP53 wild-type (wt) or SHH-TP53 mutant (mut), with a worse prognosis in the latter.…”

Neurocognitive dysfunction in adult cerebellar medulloblastoma

“…Emerging evidence supports the use of upfront chemotherapy for both high-risk and low-risk adult MB, 29 but consideration of the increased toxicity associated with radiochemotherapy in this population remains warranted. 30 Platinum agents, lomustine, cyclophosphamide, topoisomerase inhibitors, and vinca alkaloids often are a part of the regimens employed. While the neurocognitive sequelae of all of these agents are not entirely elucidated, many have been associated with impaired NCF in prior studies.…”

“…Chemotherapy was a significant contributor to NCF. Emerging evidence supports the use of upfront chemotherapy for both high‐risk and low‐risk adult MB, but consideration of the increased toxicity associated with radiochemotherapy in this population remains warranted . Platinum agents, lomustine, cyclophosphamide, topoisomerase inhibitors, and vinca alkaloids often are a part of the regimens employed.…”