RTHP-19. DIFFUSE INTRINSIC PONTINE GLIOMA AS A LATE COMPLICATION OF MEDULLOBLASTOMA THERAPY

Radiation therapy has been associated with increased risk of secondary gliomas in survivors of childhood medulloblastoma. Despite this clear association, no studies have specifically addressed the risk of diffuse intrinsic pontine glioma (DIPG) after craniospinal irradiation in medulloblastoma survivors. We performed a systematic review of patients enrolled in the DIPG Registry and Repository as well as a literature review of studies reporting recent cooperative group medulloblastoma trials in order to identify cases of DIPG occurring after radiation therapy for pediatric medulloblastoma. Eleven cases of secondary DIPG in patients with primary medulloblastoma were identified from the DIPG Registry (n=5) and literature review (n=6). Patients were diagnosed with primary medulloblastoma between the ages of 2-9 years. All patients underwent surgical resection followed by craniospinal photon irradiation (range 18-36 Gy) and posterior fossa boost (range 19.8-36 Gy). For cases with dosimetric information available, mean brainstem exposure was 50.1-54.0 Gy. Median time to diagnosis of secondary DIPG was 7.4 years (range 2-11 years). Patients died of secondary DIPG a median of 8 months after diagnosis (range 4-17 months). We performed germline and tumor DNA and RNA sequencing of secondary DIPGs at autopsy, when available, which revealed no germline cancer predisposition syndromes and mutations associated with DIPG and non-brainstem high-grade glioma (TP53 loss, PTEN loss, and NRAS mutation). The incidence of DIPG as a secondary malignancy after medulloblastoma ranged from 0.3-2.6% between the involved institutions and reported studies. In conclusion, we report that survivors of pediatric medulloblastoma are at increased risk for the development of secondary DIPG. While treatment varied for the patients in our cohort, all cases resulted in death within 2 years of diagnosis. This risk highlights the importance of radiation field and modality in the treatment of children with medulloblastoma, and provides a compelling argument for efforts to reduce brainstem exposure.