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Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump.

ABSTRACT: Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), with or without topotecan (136 ?M), was infused at 0.7 mL/24 h for 3 or 10 days. Pigs underwent magnetic resonance imaging before and at 6 times points after surgery. Enhancement and FLAIR+ volumes were calculated in a semi-automated fashion. Magnetic resonance spectroscopy-based topotecan signature was also investigated. Brain histology was analyzed by hematoxylin and eosin staining and with immunoperoxidase for a microglial antigen. CED of topotecan/gadolinium was well tolerated in all cases (n = 6). Maximum enhancement volume was reached at day 3 and remained stable if CED was continued for 10 days, but it decreased if CED was stopped at day 3. Magnetic resonance spectroscopy revealed a decrease in parenchymal metabolites in the presence of topotecan. Similarly, the combination of topotecan and gadolinium infusion led to a FLAIR+ volume that tended to be larger than that seen after the infusion of gadolinium alone. Histological analysis of the brains showed an area of macrophage infiltrate in the ipsilateral white matter upon infusion with topotecan/gadolinium. Intracerebral topotecan CED is well tolerated in a large animal brain for up to 10 days. Intracerebral long-term CED can be achieved with a subcutaneously implanted pump and provides a stable volume of distribution. This work constitutes a proof of principle for the safety and feasibility for prolonged CED, providing a means of continuous local drug delivery that is accessible to the practicing neuro-oncologist.

SUBMITTER: Sonabend AM

PROVIDER: S-EPMC3145467 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump.

Sonabend Adam M AM Stuart R Morgan RM Yun Jonathan J Yanagihara Ted T Mohajed Hamed H Dashnaw Steven S Bruce Samuel S SS Brown Truman T Romanov Alex A Sebastian Manu M Arias-Mendoza Fernando F Bagiella Emilia E Canoll Peter P Bruce Jeffrey N JN

Neuro-oncology 20110712 8

Intracerebral convection-enhanced delivery (CED) of chemotherapeutic agents currently requires an externalized catheter and infusion system, which limits its duration because of the need for hospitalization and the risk of infection. To evaluate the feasibility of prolonged topotecan administration by CED in a large animal brain with the use of a subcutaneous implantable pump. Medtronic Synchromed-II pumps were implanted subcutaneously for intracerebral CED in pigs. Gadodiamide (28.7 mg/mL), wit ...[more]

PMID: 21750007

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Project description: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.

Project description:BackgroundTopotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma.MethodsWe did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 μM topotecan 200 μL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996.FindingsBetween Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients.InterpretationIn this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes.FundingUS National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

Dataset Information

Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump.

Publications

Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump.

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