Abstract B27: Toxicity of convection-enhanced delivery with doxorubicin to treat pediatric brain-tumors depends on anatomical location
Authors: Sewing A. Charlotte P. , Veringa Susanna J.E. , Lagerweij Tonny , Noske David P. , Vuurden Dannis G. van , Kaspers Gertjan J.L. , Hulleman Esther 
Published: May 2016

Abstract
Introduction and Aim: Diffuse Intrinsic Pontine Glioma (DIPG) and pediatric High Grade Glioma (pHGG) are primary pediatric brain tumors that have a very high mortality and morbidity. Especially tumors that are not (DIPG) or only partially (midline pHGG) eligible for surgical resection have a very poor prognosis. Systemic chemotherapy regimens have failed to deliver satisfactory results but convection enhanced delivery (CED) is a promising technique that delivers chemotherapeutics directly to the tumor. Determining the best agent to deliver via CED is a challenge. Doxorubicin has shown to be highly effective when delivered via CED in preclinical glioma models, and against pHGG and DIPG cells in vitro. Liposomal doxorubicin is thought to improve distribution, bio-availability and subsequent efficacy of CED in glioma models. This preclinical study aims to determine the feasibility of performing CED with free doxorubicin or pegylated liposomal doxorubicin (PLD) in the brainstem and thalamus, and to study the efficacy of PLD and free doxorubicin when treating preclinical DIPG and pHGG models.
Methods: Preclinical CED was performed with 15μl doxorubicin in the brainstem and thalamus of 6-week-old nude mice. Maximal tolerated dose was determined by treating mice with doxorubicin concentrations ranging from 2 mg/ml to 0.02 mg/ml. The efficacy study was performed with the highest possible dose and using the orthotopic diffusely growing E98-FM-DIPG model in the brainstem. Mice (n=12) were treated at day 9 after injection of cells. Follow-up consisted of BLI measurements, and determination of body weight and clinical symptoms.
Results: Maximal tolerated dose was 0.02 mg/ml in the brainstem and 0.2 mg/ml in the thalamus for both free doxorubicin and PLD. Clinical toxicity after CED with higher concentrations consisted of weight loss and neurological deficits including paresis and loss of balance. Symptoms occurred after three (free doxorubicin) or six days (PLD). E98FM-DIPG bearing mice treated with 0.02 mg/ml of free doxorubicin, or PL-doxorubicin via CED did not show any survival benefit compared to vehicle treated animals. 0.2 mg/ml has previously shown to be effective in treating preclinical glioma models.
Conclusions: Local drug delivery of concentrations that are safe in the thalamus show severe toxicity when delivered to the brainstem. No therapeutic window existed for treating orthotopic brainstem tumors in mice. However, therapeutic concentrations could be reached in the thalamus. This data suggest that anatomical location of the tumor is of vital importance when considering the best drugs to deliver via CED.
Citation Format: A. Charlotte P. Sewing, Susanna J.E. Veringa, Tonny Lagerweij, David P. Noske, Dannis G. van Vuurden, Gertjan J.L. Kaspers, Esther Hulleman. Toxicity of convection-enhanced delivery with doxorubicin to treat pediatric brain-tumors depends on anatomical location. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B27.