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DIPG-37. INFLUENCE OF AN INTRA-TUMORAL CYST ON DRUG DISTRIBUTION BY CONVECTION ENHANCED DELIVERY

ABSTRACT: Abstract INTRODUCTION: Convection-enhanced delivery (CED) employs positive pressure to induce convective flow of molecules and maximize drug distribution. Concerns have been raised about the effect of cystic structures on uniform drug distribution with CED. We describe a patient with diffuse intrinsic pontine glioma (DIPG) with a large cyst and examine the effect on drug distribution after CED with a radiolabeled antibody. METHODS: The patient was treated according to protocol with CED of 124I-8H9 to the pons for non-progressive DIPG after radiation therapy as part of a Phase I trial (NCT01502917). Care was taken to avoid the cystic cavity in the planned catheter tract and target point. Co-infusion with Gd-DTPA was performed to assess drug distribution. Infusate distribution was examined by MRI immediately following infusion and analyzed using iPlan Flow software (Brainlab, Inc). RESULTS: Analysis of post-infusion MR images demonstrates convective distribution around the catheter tip and an elongated configuration of the drug distribution that is consistent with the superior-inferior corticospinal fiber orientation in the brainstem. This indicates that the catheter was functioning and a pressure gradient was established. No infusate entry into the cystic region could be identified on T2 FLAIR or T1-weighted images. CONCLUSION: The effects of ependymal and pial surfaces on drug delivery using CED in brainstem tumors remain controversial. Drug distribution is a critical component of effective application of CED to neurosurgical lesions. This case suggests that cyst cavities may not always behave as fluid “sinks” for drug distribution. We observed that infusate was not lost into the cyst cavity, suggesting that lesions with cystic components can be treated by CED without significant alterations to target and infusion planning.

SUBMITTER: Ivasyk I

PROVIDER: S-EPMC5475003 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Project description:Abstract INTRODUCTION: Convection enhanced delivery (CED) has recently been explored as a therapeutic strategy for children with diffuse intrinsic pontine glioma (DIPG). An anterior or supratentorial approach for catheter positioning risks conflict with descending white matter bundles where they become concentrated in the internal capsule and crural pyramid. We describe our experience planning catheter trajectories in the context of eloquent structures and outcomes this patient population. METHODS: As part of a Phase 1 clinical trial using CED with 124I-8H9, a radiolabeled monoclonal antibody (NCT01502917), a flexible step-design infusion catheter (Brainlab Flexible Catheter, BrainLab, Munich, Germany) was surgically placed via a supratentorial approach. Surgical planning was conducted based on 3D T1, T2, and SWI sequences. A fully compatible MR-guidance platform was used for trajectory planning catheter deployment. A neurologic exam was performed immediately post-procedure, prior to initiating infusion, to assess for procedure-related deficits. Intra- and post-procedural MR images were analyzed for the anatomic position of catheter trajectories. Conflicts between the catheter tract and the posterior limb of the internal capsule and the pyramid of the crus cerebri were recorded. Correlation between motor deficits and the catheter path was evaluated. RESULTS: Thirty-three catheter insertions were performed for 28 children with DIPG. One patient experienced a slight worsening of an existing ipsilateral facial palsy likely related to the course of facial nerve fibers in the brainstem. The posterior limb of the internal capsule and the pyramid of the crus cerebri frequently overlapped the catheter tract without incident. CONCLUSIONS: Transgression of descending corticospinal motor tracts by catheters for intracranial infusion is acceptable. We observed that a supratentorial approach to the brainstem crossing eloquent fibers resulted in one neurologic deficit. There does not appear to be a functional risk requiring a need for avoidance of the dominant motor fiber tracts during trajectory planning.

Project description:Abstract BACKGROUND: Median survival from DIPG is less than one year. In a phase 1 dose escalation study (clinicaltrials.gov NCT01502917) 124I-omburtamab targeting B7-H3 was administered intratumorally using CED. METHODS: CED was performed between 4-14 weeks post radiation therapy. Using a 3 + 3 design, 124I-omburtamab was escalated from 0.25-10.0 mCi and infusion volumes (Vi) from 250-10,000 µl with serial 124I PET/CT performed up to ~1 week post-administration. Toxicities were assessed for 30 days. Dose escalation safety was evaluated. Survival was calculated using Kaplan-Meier statistics. RESULTS: 46 children were treated and evaluable for toxicity and survival;4 patients received partial doses and were evaluable for toxicity only. Three patients experienced dose limiting toxicities. Eleven patients had transient treatment related grade 3 toxicities with no grade 4 or 5 toxicities. Grade 3 nervous system toxicities included: muscular weakness(n=8), dysarthria(n=4), ataxia(n=3), dysphagia(n=3), and gait disturbance(n=1). Lesion absorbed doses ranged from 1,000-1,500cGy/mCi, with lesion-to-whole body radiation absorbed-dose ratios of ~900. A dose of 8mCi and infusion volume of 8,000 µl is safe and may provide a distribution volume up to 20cm3. Median survival was 15.3 months (n =46, 95% CI 12.7, 17.3). Survival rate estimates (95% CI) at 1, 2, 3 and 5 years were 0.67 (0.55;0.82); 0.18 (0.09;0.35); 0.10 (0.04;0.26); and 0.05 (0.01;0.20). Four patients survived >3 years; two remain alive (61+ and 106+ months);two have died (44 and 53 month) with distant CNS disease and one with extra-CNS metastasis. CONCLUSION: Administration of escalating doses and volumes of 124I-omburtamab via CED was a viable option for this patient subgroup. The median overall survival was increased 3-4 months compared to historical controls. Anecdotal long-term survival if validated with a planned phase 2 trial would support the concept of whole neuroaxis treatment in combination with CED in a subset of DIPG patients.

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DIPG-37. INFLUENCE OF AN INTRA-TUMORAL CYST ON DRUG DISTRIBUTION BY CONVECTION ENHANCED DELIVERY

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