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Richard C. E. Anderson, Benjamin Kennedy, Candix L. Yanes, James Garvin, Michael Needle, Peter Canoll, Neil A. Feldstein and Jeffrey N. Bruce

Convection-enhanced delivery (CED) for the treatment of malignant gliomas is a technique that can deliver chemotherapeutic agents directly into the tumor and the surrounding interstitium through sustained, low-grade positive-pressure infusion. This allows for high local concentrations of drug within the tumor while minimizing systemic levels that often lead to dose-limiting toxicity. Diffuse intrinsic pontine gliomas (DIPGs) are universally fatal childhood tumors for which there is currently no effective treatment. In this report the authors describe CED of the topoisomerase inhibitor topotecan for the treatment of DIPG in 2 children.

As part of a pilot feasibility study, the authors treated 2 pediatric patients with DIPG. Stereotactic biopsy with frozen section confirmation of glial tumor was followed by placement of bilateral catheters for CED of topotecan during the same procedure. The first patient underwent CED 210 days after initial diagnosis, after radiation therapy and at the time of tumor recurrence, with a total dose of 0.403 mg in 6.04 ml over 100 hours. Her Karnofsky Performance Status (KPS) score was 60 before CED and 50 posttreatment. Serial MRI initially demonstrated a modest reduction in tumor size and edema, but the tumor progressed and the patient died 49 days after treatment. The second patient was treated 24 days after the initial diagnosis prior to radiation with a total dose of 0.284 mg in 5.30 ml over 100 hours. Her KPS score was 70 before CED and 50 posttreatment. Serial MRI similarly demonstrated an initial modest reduction in tumor size. The patient subsequently underwent fractionated radiation therapy, but the tumor progressed and she died 120 days after treatment.

Topotecan delivered by prolonged CED into the brainstem in children with DIPG is technically feasible. In both patients, high infusion rates (> 0.12 ml/hr) and high infusion volumes (> 2.8 ml) resulted in new neurological deficits and reduction in the KPS score, but lower infusion rates (< 0.04 ml/hr) were well tolerated. While serial MRI showed moderate treatment effect, CED did not prolong survival in these 2 patients. More studies are needed to improve patient selection and determine the optimal flow rates for CED of chemotherapeutic agents into DIPG to maximize safety and efficacy. Clinical trial registration no.: NCT00324844.

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Randy S. D’Amico, Justin A. Neira, Jonathan Yun, Nikita G. Alexiades, Matei Banu, Zachary K. Englander, Benjamin C. Kennedy, Timothy H. Ung, Robert J. Rothrock, Alexander Romanov, Xiaotao Guo, Binsheng Zhao, Adam M. Sonabend, Peter Canoll and Jeffrey N. Bruce

OBJECTIVE

Intracerebral convection-enhanced delivery (CED) has been limited to short durations due to a reliance on externalized catheters. Preclinical studies investigating topotecan (TPT) CED for glioma have suggested that prolonged infusion improves survival. Internalized pump-catheter systems may facilitate chronic infusion. The authors describe the safety and utility of long-term TPT CED in a porcine model and correlation of drug distribution through coinfusion of gadolinium.

METHODS

Fully internalized CED pump-catheter systems were implanted in 12 pigs. Infusion algorithms featuring variable infusion schedules, flow rates, and concentrations of a mixture of TPT and gadolinium were characterized over increasing intervals from 4 to 32 days. Therapy distribution was measured using gadolinium signal on MRI as a surrogate. A 9-point neurobehavioral scale (NBS) was used to identify side effects.

RESULTS

All animals tolerated infusion without serious adverse events. The average NBS score was 8.99. The average maximum volume of distribution (Vdmax) in chronically infused animals was 11.30 mL and represented 32.73% of the ipsilateral cerebral hemispheric volume. Vdmax was achieved early during infusions and remained relatively stable despite a slight decline as the infusion reached steady state. Novel tissue TPT concentrations measured by liquid chromatography mass spectroscopy correlated with gadolinium signal intensity on MRI (p = 0.0078).

CONCLUSIONS

Prolonged TPT-gadolinium CED via an internalized system is safe and well tolerated and can achieve a large Vdmax, as well as maintain a stable Vd for up to 32 days. Gadolinium provides an identifiable surrogate for measuring drug distribution. Extended CED is potentially a broadly applicable and safe therapeutic option in select patients.