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Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children.

ABSTRACT: 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.

SUBMITTER: Anderson RC

PROVIDER: S-EPMC7227321 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children.

Anderson Richard C E RC Kennedy Benjamin B Yanes Candix L CL Garvin James J Needle Michael M Canoll Peter P Feldstein Neil A NA Bruce Jeffrey N JN

Journal of neurosurgery. Pediatrics 20121214 3

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 ...[more]

PMID: 23240851

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Project description:Abstract INTRODUCTION While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single dose drug infusions, agents for oncologic therapy require repeated or chronic infusions to maintain therapeutic concentrations. Repeat/chronic CED infusions have rarely been described for oncologic purposes. We report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma (DIPG). METHODS Patients were enrolled in a phase I single center clinical trial using 124I-8H9 monoclonal antibody (124I-Omburtamab, Y-mAbs Therapeutics) administered by CED (NCT01502917). Retrospective chart review was used to assess demographic data, CED infusion data, and post-operative neurologic and surgical outcomes. MRI scans were analyzed using iPlan® Flow software (Brainlab AG, Munich, Germany) for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the Clearpoint imaging software (Clearpoint®, MRI Interventions Inc. Irvine, USA). RESULTS Seven patients underwent two or more sequential CED infusions. No patients experienced deficits Clinical Terminology Criteria for Adverse Events (CTCAE) grade 3 or greater. One patient had persistent grade 2 cranial nerve deficit after a second infusion. No patients experienced hemorrhage or stroke post-operatively. There was a statistically significant decrease in radial error (p= 0.005) and absolute tip error (p=0.008) for infusion two compared to the initial infusion. Sequential infusions did not result in significantly different distribution capacity between the first and second infusion (Vd:Vi ratio: 2.66 ± 0.35 versus 2.42 ± 0.75; p=0.45). CONCLUSIONS This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural work flow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncologic purposes.

Project description:BackgroundDiffuse intrinsic pontine glioma is one of the deadliest central nervous system tumours of childhood, with a median overall survival of less than 12 months. Convection-enhanced delivery has been proposed as a means to efficiently deliver therapeutic agents directly into the brainstem while minimising systemic exposure and associated toxic effects. We did this study to evaluate the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen in children with diffuse intrinsic pontine glioma.MethodsWe did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients were aged 3-21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Karnofsky (patients ≥16 years) performance score of at least 50 at study entry; a minimum weight of 8 kg; and had completed external beam radiation therapy (54·0-59·4 Gy at 1·8 Gy per fraction over 30-33 fractions) at least 4 weeks but no more than 14 weeks before enrolment. Seven dose-escalation cohorts were planned based on standard 3 + 3 rules: patients received a single infusion of 9·25, 18·5, 27·75, 37, 92·5, 120·25, or 148 MBq, respectively, at a concentration of about 37 MBq/mL by convection-enhanced delivery of the radiolabelled antibody [124I]-8H9. The primary endpoint was identification of the maximum tolerated dose. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full planned dose of treatment), and all patients who received any dose of study treatment were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01502917, and is ongoing with an expanded cohort.FindingsFrom April 5, 2012, to Oct 8, 2016, 28 children were enrolled and treated in the trial, of whom 25 were evaluable for the primary endpoint. The maximum tolerated dose was not reached as no dose-limiting toxicities were observed. One (4%) of 28 patients had treatment-related transient grade 3 hemiparesis and one (4%) had grade 3 skin infection. No treatment-related grade 4 adverse events or deaths occurred. Estimated volumes of distribution (Vd) were linearly dependent on volumes of infusion (Vi) and ranged from 1·5 to 20·1 cm3, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq 124I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200.InterpretationConvection-enhanced delivery in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be a rational and safe therapeutic strategy. PET-based dosimetry of the radiolabelled antibody [124I]-8H9 validated the principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure. This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma.FundingNational Institutes of Health, The Dana Foundation, The Cure Starts Now, Solving Kids' Cancer, The Lyla Nsouli Foundation, Cookies for Kids' Cancer, The Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center.

Project description: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 μM), 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.

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Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children.

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Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children.

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