Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters

Abstract

Purpose To assess an intensified treatment in the context of clinical and biologic risk factors in metastatic medulloblastoma. Patients and Methods Patients (4 to 21 years old, diagnosed between 2001 and 2007) received induction chemotherapy, dose-escalated hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy. Subgroup status and other biologic parameters were assessed. Results In 123 eligible patients (median age, 8.2 years old; median follow-up, 5.38 years), 5-year event-free survival (EFS) and overall survival (OS) were 62% (95% CI, 52 to 72) and 74% (95% CI, 66 to 82), respectively. OS was superior compared with the precedent HIT '91 trial. The 5-year EFS and OS were both 89% (95% CI, 67 to 100) for desmoplastic/nodular (n = 11), 61% (95% CI, 51 to 71) and 75% (95% CI, 65 to 85) for classic (n = 107), and 20% (95% CI, 0 to 55) and 40% (95% CI, 0 to 83) for large-cell/anaplastic (n = 5) medulloblastoma ( P < .001 for EFS; P = .001 for OS). Histology (hazard ratio, 0.19 for desmoplastic/nodular and 45.97 for large-cell/anaplastic medulloblastoma) and nonresponse to the first chemotherapy cycle (hazard ratio, 1.97) were independent risk factors (EFS). Among 81 (66%) patients with tumor material, 5-year EFS and OS differed between low-risk (wingless [WNT], n = 4; both 100%), high-risk ( MYCC/ MYCN amplification; n = 5, both 20%), and intermediate-risk patients (neither; n = 72, 63% and 73%, respectively). Survival rates were different between molecular subgroups (WNT, n = 4; sonic hedgehog [SHH; n = 4]; group 4 [n = 41]; group 3 with [n = 3] or without [n = 17] MYCC/MYCN amplification; P < .001). All cases showed p53 immuno-negativity. There was no association between patients with nonresponding tumors to induction chemotherapy and WNT ( P = .143) or MYCC/MYCN status ( P = .075), histologic subtype ( P = .814), or molecular subtype ( P = .383), as assessed by Fisher's exact test. Conclusion This regimen was feasible and conferred overall favorable survival. Our data confirm the relevance of subgroup status and biologic parameters (WNT/ MYCC/ MYCN status) in a homogeneous prospective trial population, and show that metastatic group 3 patients do not uniformly have poor outcomes. Biologic subgroup, MYCC/ MYCN status, response to induction chemotherapy, and histologic subtype may serve for improved treatment stratification.

Surveillance imaging for high‐grade childhood brain tumors: What to do 10 years after completion of treatment?

“…We found no recurrence of the primary brain tumor, either local or distant, 10 years or more after the end of treatment in the reviewed literature . After combining the latency period from all relapses, median time to relapse was 13.7 months; average minimal latency time was 3.3 months and a maximum of 49.0 months.…”

“…Tumor recurrence rate was between 18.7‐40% . No relapse occurred more than 10 years after diagnosis.…”

Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study

“…High-risk clinical factors (metastatic disease [M+]; large-cell, anaplastic [LCA] pathology; incomplete surgical resection [R+]; and MYC / MYCN amplification), which are currently used to stratify risk in medulloblastoma in children aged 3 years or older, were derived from cohort-wide investigations before discovery of the consensus subgroups, and thus did not consider their effect 15, 16, 20, 21…”

Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series

“…(SKK is an abbreviation of the German phrase “Säuglinge und Kleinkinder,” meaning “infants and toddlers.”) For patients <4 years of age, primary intensified chemotherapy treatment with the intention of high‐dose chemotherapy was allowed. For induction treatment either etoposide/carboplatin (until 2005) or modified Head Start treatment (after the 2005 amendment) was used, followed by tandem high‐dose chemotherapy (carboplatin/etoposide, cyclophosphamide/thiotepa) in patients with response to induction treatment . For children older than 4 years at diagnosis, hyperfractionated craniospinal irradiation (CSI) was intended, with 2 × 1 Gy fractions per day and dose prescription of 40 Gy to the craniospinal axis and boost up to 68 Gy to the primary tumor region, or 72 Gy to residual tumor and 50 Gy to metastatic deposits.…”

“…Depending on the treatment arm and response to initial chemotherapy, maintenance chemotherapy was foreseen after irradiation, with either vincristine/lomustine/cisplatin, mSKK, or temozolomide .…”