Background: Children diagnosed with medulloblastoma (MB) that are refractory to upfront therapy or experience recurrence have very poor prognoses. Reports of phase I and II studies for these children exist, but bear significant treatment related morbidity and mortality. Methods: A retrospective review of children diagnosed with a pediatric MB from 2002-2015 from the McMaster Pediatric Brain Tumour Study Group (PBTSG) captured a number of pediatric recurrent MB. Results: Over the 13-year period, 31 children with a histological diagnosis of MB were treated. At two years, 21 (67.7%) of 31 patients were free of recurrence and 25 (80.6%) survived. Thirteen children had recurrent or treatment refractory MB. mean time to recurrence was 14.6 months. The mean follow-up for survivors of recurrent MB was 4.0 years. In 3 recurrent MB, the disease had significantly progressed and the patients palliated. For the remaining children, therapy offered included surgery, radiation, and chemotherapy agents either in isolation or in varying combinations. Conclusions: Recurrent MB in our cohort carried a poor prognosis despite administration of salvage therapy. Though there is standardization of the upfront treatment exists, we observed great heterogeneity in the treatment of our 13 patients experiencing recurrence. A greater understanding of the biology of recurrent MB has the potential to guide salvage therapy.

BACKGROUND: Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy agents and clearing reactive oxygen species formed by radiation. In this study, we explored the relationship between the host GSTP1-105 polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1-105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events. METHODS: The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children’s Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and tumor GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and multivariable logistic regression for toxicity comparisons. RESULTS: Patients with a GSTP1-105 AG/GG genotype or who had received a higher dose of craniospinal radiation (median 36 Gy) had a greater risk of requiring hearing aids than their respective counterparts (OR 4.0, 95%CI 1.2 - 13.6, and OR 3.1, 95%CI 1.1 - 8.8, respectively). Additionally, there was a statistically significant interaction between the two variables. Compared with the lowest risk group (GSTP1-105 AA-lower dose radiation) patients with a GSTP1-105 AG/GG genotype who received a higher dose radiation were 8.4 times more likely to require hearing aids (95%CI 1.4 - 49.9, p-trend ¼ 0.005). When adjusted for age, gender, and amifostine use, the association remained. CONCLUSIONS: The GSTP1-105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. A possible mechanism for this finding is that the GSTP1-105 G-allele leads to reduced GSTpi free radical detoxification in the setting of multimodality therapy including cisplatin and radiation. Patients with this allele should be considered for clinical trials employing radiation dose modifications and more targeted cytoprotectant strategies than are currently being used with amifostine.