New trial of convection enhanced drug delivery (CED) in DIPG- applying the SIOPe DIPG survival prediction model for power calculation.

Abstract

Abstract Background In diffuse intrinsic pontine glioma (DIPG) drug resistance is in part due to inadequate penetration of blood-brain barrier (BBB) by systemically administered drugs. Convection-enhanced drug delivery (CED) techniques have been established to bypass BBB. Trial design to measure efficacy requires evidence to justify power calculation. Aims To apply SIOPe DIPG registry survival prediction tool to pilot cohort of children with DIPG treated with CED of carboplatin and sodium valproate. Methods Case note and imaging review of 9 children with typical DIPG on imaging who were treated on compassionate basis with CED intra-tumoural infusions of carboplatin (0.12 mg/ml) and sodium valproate (14.4 mg/ml), after radiotherapy (n=9) and chemotherapy (n=4). Each had Renishaw device placed with 4 micro-catheters located within tumour mass. Up to 8 treatment cycles of CED infusions delivered through 2 pairs of catheters on 2 days to encompass pontine tumour volume. Survival prediction was performed using clinical criteria: age, sex, duration of symptoms, prior chemotherapy; and radiological criteria: absence of distant metastases; disease involving more than 50% of, and confined to, pons, ring enhancement at diagnosis. Results Cases were categorized as intermediate or high-risk using SIOPe risk scoring with predicted median overall survival (OS) of 9.7, and 7.0 months, respectively. Four patients, categorized as high-risk, had median overall survival (OS) of 14.2 months. Five children, categorized as standard-risk, had median OS of 16.0 months. Conclusions Results justify a phase 2 trial of CED carboplatin and sodium valproate powered to detect at least 4-month prolongation of survival.