Validation of an effective implantable pump-infusion system for chronic convection-enhanced delivery of intracerebral topotecan in a large animal model

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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.

ABBREVIATIONS CED = convection-enhanced delivery; FVd = final volume of distribution; FVi = final volume infused; GBM = glioblastoma; LCMS = liquid chromatography mass spectroscopy; NBS = neurobehavioral scale; TPT = topotecan; Vd = volume of distribution; Vdmax = maximal volume of distribution; Vi = volume of infusion.

Article Information

Correspondence Randy S. D’Amico: Columbia University Medical Center, New York, NY. rd2398@cumc.columbia.edu.

ACCOMPANYING EDITORIAL DOI: 10.3171/2019.4.JNS19614.

INCLUDE WHEN CITING Published online August 2, 2019; DOI: 10.3171/2019.3.JNS1963.

P.C. and J.N.B. contributed equally to this work.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    A: Animals were sedated, intubated, and placed prone with their heads secured with rigid fixation where subsequent scalp registration with the Brainlab frameless stereotactic system was performed. B: The proximal catheter was stereotactically guided to its target using the VarioGuide neuronavigation system. C: A microinfusion pump was implanted subcutaneously in the ipsilateral flank, and a silastic lumbar catheter was primed with infusate and tunneled from the flank to the cranium. D: The pump-catheter system, consisting of a single proximal tapered SmartFlow Flex ventricular catheter (0.5-mm internal diameter) connected via a silastic lumbar catheter to a Synchromed II pump. Figure is available in color online only.

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    The cytotoxic effects of TPT are not affected by the presence of gadolinium (gado). At 48 hours, there was no difference in OD490 between U87 cells plated in media with or without gadolinium (2.13 vs 2.10, p = 0.69). Addition of TPT (146 µM) resulted in a significant reduction in OD490 at 48 hours in media with and without 1:100 gadolinium (1.28 vs 2.10 and 1.35 vs 2.13, p < 0.01, respectively; data not shown). The addition of 1:100 gadolinium to media already containing TPT (146 µM) did not alter the OD490 at 48 hours (1.35 vs 1.32, p = 0.48). Bars represent the mean and error bars, SD.

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    A: Preoperative (left) and final (right) axial T1-weighted MR images obtained in pig 5, demonstrating infusion volume confined to the right posterior hippocampus. The blue circle on the preoperative image represents the final location of the catheter tip. B: Final axial T1-weighted MR images obtained in pigs 1 and 2, demonstrating extravasation of infusate into the right lateral ventricle. Figure is available in color online only.

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    Linear regression of TPT concentration within biopsied tissue as determined by LCMS analysis versus absolute gadolinium signal intensity of the biopsy site as determined by T1-weighted MRI in pigs that underwent short-term CED (p = 0.008). TPT concentration is represented on a logarithmic scale.

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    A: Serial axial T1-weighted MR images obtained in pig 4, demonstrating a progressively increasing volume of distribution with continuous short-term infusion of TPT/gadolinium. Importantly, “priming” with a lower initial infusion rate avoided intraventricular extravasation and facilitated a large Vd. B: Vd as determined by the measurement of the gadolinium signal on T1-weighted MR images on each postoperative day (POD) for individual short-term pigs. Pigs 1 and 2 suffered from intraventricular extravasation of infusate. Pigs 3 and 4 had ideal placement of the catheter tip within the white matter of the posterior centrum semiovale. Pig 5 had placement of the catheter within the posterior hippocampus. C: The ratio of volume of distribution as determined by identification of gadolinium on MRI to volume of drug infused (Vd/Vi) on each POD for pigs that underwent short-term infusions. D: Linear regression of average Vd/Vi versus POD for short-term pigs with optimal catheter placement (pigs 3 and 4, p = 0.01).

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    A: Representative sequence of serial MR images demonstrating evolving Vd during 32 days of chronic TPT-gadolinium infusion. Axial T1-weighted MR images demonstrated unambiguous hyperintense gadolinium signal during all scans performed during active infusion. The blue circle on the preoperative image represents the target for catheter tip placement within the posterior white matter of the centrum semiovale. B: Vd as determined by identification of gadolinium on MRI on each postoperative day for individual pigs undergoing long-term infusion. C: The ratio of Vd as determined by identification of gadolinium on MRI to volume of drug infused (Vd/Vi) on each POD for pigs undergoing chronic CED. D: Linear regression of average Vd/Vi versus POD for all long-term animals (p < 0.01). Figure is available in color online only.

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    Comparison of the volume of the ipsilateral cerebral hemisphere (Vh), Vdmax, FVd, and pericatheter signal hypointensity (FVt) for each pig undergoing long-term infusion.

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