NS-21MULTI-CATHETER INTERMITTENT CONVECTION-ENHANCED DELIVERY OF CARBOPLATIN AS A TREATMENT FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): PRE-CLINICAL RATIONALE AND EARLY CLINICAL EXPERIENCE

Abstract

Treatment failure inDIPGis in part due to poorCNSpenetration of systemic chemotherapy at non‐toxic doses. Convection‐enhanced delivery (CED) of carboplatin to the paediatric brainstem through surgically placed microcatheters overcomes the limitations of systemic treatment. Carboplatin is cytotoxic to ex‐vivo patient derived DIPG cells in vitro in a dose‐dependant manner, with calculated area under the concentration/time curve values (AUC‐50) of 4.18‐58.9 mg/ml x min after a 360 minute drug exposure. This AUC can be achieved with direct intra‐tumoural infusion of drug, but would be toxic at corresponding systemic doses. 8 children (ages 4‐12 years) have been treated in a compassionate treatment program of carboplatin CED for radiological or biopsy proven DIPG using a multi‐catheter intermittent regime of carboplatin CED via a bone anchored transcutaneous port. All children underwent robot‐assisted stereotactic MRI guided implantation of 4 recessed step catheters using trans‐frontal and trans‐cerebellar trajectories. Carboplatin at a concentration of 0.18mg/ml was infused on two consecutive days for up to 9 cycles in an intermittent regime. Infusions were well tolerated. Neurological side effects due to the infusion and drugwere seen mostcommonly during the first cycle of treatment and resolved before further infusions. Survival has exceeded 15 months from diagnosis in 3 patients. 7 of the 8 children treated remain alive and 6 continue to receive therapy.CED of carboplatin to the paediatric brainstem is well tolerated and could potentially represent a paradigm shift in the treatment of DIPG. A phase II clinical trial is planned.