Abstract
With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years). From these cases, molecular subgrouping of primary medulloblastomas with available tissue (n = 5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). The estimated cumulative incidence of DIPG after post-treatment medulloblastoma ranged from 0.3–3.9%. Posterior fossa radiation exposure (including brainstem) was greater than 53.0 Gy in all cases with available details. Tumor/germline exome sequencing of three radiation-associated DIPGs revealed an H3 wild-type status and mutational signature distinct from primary DIPG with evidence of radiation-induced DNA damage. Mutations identified in the radiation-associated DIPGs had significant molecular overlap with recurrent drivers of adult glioblastoma (e.g. NRAS, EGFR, and PTEN), as opposed to epigenetic dysregulation in H3-driven primary DIPGs. Patients with radiation-associated DIPG had a significantly worse median overall survival (median 8 months; range 4–17 months) compared to patients with primary DIPG. Here, it is demonstrated that DIPG occurs as a not infrequent complication of radiation therapy in survivors of pediatric medulloblastoma and that radiation-associated DIPGs may present as a poorly-prognostic distinct molecular subgroup of H3 wild-type DIPG. Given the abysmal survival of these cases, these findings provide a compelling argument for efforts to reduce exposure of the brainstem in the treatment of medulloblastoma. Additionally, patients with radiation-associated DIPG may benefit from future therapies targeted to the molecular features of adult glioblastoma rather than primary DIPG.
Highlights
Medulloblastoma is the most common malignant pediatric brain tumor, and standard treatment includes surgical resection followed by adjuvant external beam radiation therapy (EBRT) and systemic chemotherapy [14]
All patients diagnosed with primary medulloblastoma from age 0–21 years who were subsequently diagnosed with brainstem glioma were included
Twelve patients who developed diffuse intrinsic pontine glioma (DIPG) after radiation treatment for primary pediatric medulloblastoma were identified. Six of these cases were acquired from the IDIPGR, and six were extracted from literature review, reported primarily in results from medulloblastoma cooperative group trials: COG A9961 (n = 2), HIT’91 (n = 1), HIT-SIOP-PNET4 (n = 1), and CCG 9892 (n = 1) [12, 30, 31, 36, 42, 46]
Summary
Medulloblastoma is the most common malignant pediatric brain tumor, and standard treatment includes surgical resection followed by adjuvant external beam radiation therapy (EBRT) and systemic chemotherapy [14]. The elevated risk of SMNs in medulloblastoma survivors may be due to high doses of EBRT. The risks of glioma, the most common SMN reported after primary medulloblastoma, increase linearly with radiation dose [9, 19, 31, 42]. Radiation dosing for medulloblastoma varies based on clinical and molecular risk stratification, and standard treatment involves craniospinal irradiation (CSI) with a posterior fossa boost. No previous studies have assessed the risk of the development of radiation-associated DIPG in medulloblastoma survivors, which could impact the future dose and modality of radiation therapy in future clinical trials
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