scholarly journals Repeat convection-enhanced delivery for diffuse intrinsic pontine glioma

2020 ◽  
Vol 26 (6) ◽  
pp. 661-666
Author(s):  
Evan D. Bander ◽  
Alexander D. Ramos ◽  
Eva Wembacher-Schroeder ◽  
Iryna Ivasyk ◽  
Rowena Thomson ◽  
...  
Keyword(s):  
Demographic Data ◽  
Absolute Error ◽  
Volume Of Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Therapeutic Drug ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Technical Application ◽  
Drug Concentrations ◽  
Radial Depth

OBJECTIVEWhile the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single-dose drug infusions, agents for oncological therapy may require repeated or chronic infusions to maintain therapeutic drug concentrations. Repeat and chronic CED infusions have rarely been described for oncological purposes. Currently available CED devices are not approved for extended indwelling use, and the only potential at this time is for sequential treatments through multiple procedures. The authors 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.METHODSPatients in this study were enrolled in a phase I single-center clinical trial using 124I-8H9 monoclonal antibody (124I-omburtamab) administered by CED (clinicaltrials.gov identifier NCT01502917). A retrospective chart and imaging review were used to assess demographic data, CED infusion data, and postoperative neurological and surgical outcomes. MRI scans were analyzed using iPlan Flow software 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.RESULTSSeven patients underwent 2 or more sequential CED infusions. No patients experienced Clinical Terminology Criteria for Adverse Events grade 3 or greater deficits. One patient had a persistent grade 2 cranial nerve deficit after a second infusion. No patient experienced hemorrhage or stroke postoperatively. There was a statistically significant decrease in radial error (p = 0.005) and absolute tip error (p = 0.008) for the second infusion compared with the initial infusion. Sequential infusions did not result in significantly different distribution capacities between the first and second infusions (volume of distribution determined by the PET signal/volume of infusion ratio [mean ± SD]: 2.66 ± 0.35 vs 2.42 ± 0.75; p = 0.45).CONCLUSIONSThis series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural workflow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncological purposes.

scholarly journals SURG-24. REPEAT CONVECTION-ENHANCED DELIVERY FOR DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii208-ii209
Author(s):  
Evan Bander ◽  
Alexander Ramos ◽  
Eva Wembacher-Schroeder ◽  
Iryna Ivasyk ◽  
Rowena Thomson ◽  
...  
Keyword(s):  
Demographic Data ◽  
Retrospective Chart Review ◽  
Absolute Error ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Technical Application ◽  
Radial Error ◽  
Radial Depth ◽  
Mri Scans

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.

8 Convection enhanced delivery of carboplatin for the treatment of diffuse intrinsic pontine glioma: the pharmacist’s perspective

2018 ◽  
Vol 103 (2) ◽  
pp. e2.48-e2
Author(s):  
Rebekah Rogers
Keyword(s):  
Extracellular Fluid ◽  
Intrathecal Chemotherapy ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Therapeutic Drug ◽  
List Type ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Safe Delivery ◽  
Department Of Health ◽  
The Brain

SituationTo ensure safe delivery of carboplatin by convection enhanced delivery (CED) for the treatment of diffuse intrinsic pontine glioma (DIPG).BackgroundCED describes a method of direct drug delivery to the brain parenchyma through surgically placed microcatheters, completely bypassing the blood brain barrier (BBB)1 Drug is infused with precisely controlled low infusion rates that create a pressure gradient that displaces the brain extracellular fluid with infusate.2DIPG is a malignant high grade brain tumour of children. The median survival is only 9 months1 and no systemic treatment to date has been effective.1 This is likely due to the fact that the majority of systemic therapies do not cross the BBB to achieve a therapeutic concentration within the tumour.1 CED overcomes these limitations and has the potential to achieve a therapeutic drug concentration within the tumour without causing any systemic toxicity.1The unique surgical technology developed in our department, allows repeated infusions of drug without the need for further surgery. The challenges faced by pharmacy were to ensure that an appropriate policy and register was developed to ensure that all professionals involved in the handling, prescription, preparation and administration of carboplatin by CED are appropriately trained and informed, and that patients receiving this therapy are safe. This follows the Department of Health guidance on the safe administration of intrathecal chemotherapy.3 This also had to be reflected on the prescription chart that was designed specifically for CED. It was necessary to ensure that carboplatin was stable at differing concentrations in the diluent used, artificial cerebrospinal fluid, and to determine the shelf life.OutcomeCED of carboplatin has been administered to 8 patients (ages 4–12 years) under compassionate use.4Patients were infused with up to 9 cycles of carboplatin for two consecutive days at a concentration of 0.18 mg/ml which were well tolerated, with neurological side effects most commonly seen during the first cycles.4 The process of safe prescribing and administration of carboplatin administered by this novel method is the first of its kind worldwide, and has the potential to revolutionise the treatment of malignant brainstem tumours.ReferencesBarua NU, Lowis SP, Woolley M, et al. Robot-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma. Acta Neurochirurgica2013;155:1459–65.Bobo RH, Laske DW, Akbasak A, et al. Convection-enhanced delivery of macromolecules in the brain. Proc Natl AcadSci U S A1994;91:2076–80.Department of Health. HSC 2008/001 Updated national guidance on the safe administration of intrathecal chemotherapy2008.Singleton WGB, Barua N, Morgan J, et al. Multi-catheter intermittent convection enhanced delivery of carboplatin as a treatment for Diffuse Intrinsic Pontine Glioma (DIPG): Pre-clinical rationale and early clinical experience. Proceedings of the International Symposium of Paediatric Neurooncology (ISPNO), Neuro-Oncology June 2016;18:131.

A phase I study of convection-enhanced delivery of 124I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma: An update with dose-response assessment.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2008-2008 ◽  
Author(s):  
Mark M. Souweidane ◽  
Kim Kramer ◽  
Neeta Pandit-Taskar ◽  
Zhiping Zhou ◽  
Pat Zanzonico ◽  
...  
Keyword(s):  
Dose Level ◽  
Therapeutic Strategy ◽  
Absorbed Dose ◽  
Volume Of Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Overall Survival Rate ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
The Mean ◽  
The Brain

2008 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for efficiently distributing therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard phase I dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion of radiation therapy. Seven dose levels of a single injection of 124I-8H9 (Omburtamab) (range 0.25 to 4.0 mCi) were studied. Results: 37 children were treated with 34 evaluable for primary and secondary endpoints. The median age at enrollment was 6.8 years old (range 3.2 - 17.9). There was no dose limiting toxicity (DLT). Among adverse events that were at least possibly related to the treatment, there were no grade 4 or 5 events, and only 4 reversible grade 3 events in 4 patients (2 hemiparesis, 1 skin infection and 1 anxiety). Estimations of distribution volumes based on T2-weighted imaging were dose dependent and ranged from 1.5 to 20.8 cm3, and for dose level 7, 10.5 - 19.0 cm3. The mean volume of distribution/volume of infusion ratio (Vd/Vi) was 3.4 ±1.1, and for dose level 7, 3.5 ± 1.0. The mean lesion absorbed dose was 33.3 ± 25.9 Gy, and for dose level 7, 50.1 ± 22.9 Gy. The mean ratio of lesion-to-whole body absorbed dose was 910. The mean volume of distribution/tumor volume ratio on dose level 7 was 82.5%, but the mean tumor overlap was 40.5%. No death occurred as a result of the treatment. Median survival was 15.3 months (n = 29, 95% CI 12.7 - 17.4). Median follow-up time of the 5 surviving patients is 27.2 months (range 11.5 - 72.4). Overall survival rate at 12 months was 64.7% (22/34, 4 alive), and overall survival rate at 24 months 14.7% (5/34, 3 alive). Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. An infusion volume of 4,000 mcl appears to be a reasonable single dose for a target distribution volume but enhanced tumor coverage is likely needed. There seems to be a survival benefit using this therapeutic strategy and outcomes might be dependent on dosimetry and distribution patterns. Clinical trial information: NCT01502917.

scholarly journals DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii294-iii295
Author(s):  
Jovana Pavisic ◽  
Chankrit Sethi ◽  
Chris Jones ◽  
Stergios Zacharoulis ◽  
Andrea Califano
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Treatment Options ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Low Grade ◽  
Precision Oncology ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Master Regulator

Abstract Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with no effective drugs to date. Mutation-based precision oncology approaches are limited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease drivers—master regulator proteins (MRs)—in DIPG to expand treatment options. Using the metaVIPER algorithm, we interrogated an integrated low grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective in murine proneural gliomas in which TOP2 was identified as a MR while RRM2—targetable by drugs such as cladribine—has been shown to be a positive regulator of glioma progression whose knock-down inhibits tumor growth. We also prioritized drugs by their ability to reverse MR-activity signatures using a large drug-perturbation database. Patients clustered by predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which have early evidence in treating gliomas. We will refine this analysis in a multi-institutional study of >100 patient gene expression profiles to define MR signatures driving known biological/molecular disease subtypes, use DIPG cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.

scholarly journals A novel magnetic resonance imaging segmentation technique for determining diffuse intrinsic pontine glioma tumor volume

2016 ◽  
Vol 18 (5) ◽  
pp. 565-572 ◽  
Author(s):  
Ranjodh Singh ◽  
Zhiping Zhou ◽  
Jamie Tisnado ◽  
Sofia Haque ◽  
Kyung K. Peck ◽  
...  
Keyword(s):  
Confidence Limit ◽  
Interobserver Agreement ◽  
Tumor Volume ◽  
Correlation Coefficients ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Subjective Judgment ◽  
Low Degree ◽  
Picture Archiving And Communication

OBJECTIVE Accurately determining diffuse intrinsic pontine glioma (DIPG) tumor volume is clinically important. The aims of the current study were to 1) measure DIPG volumes using methods that require different degrees of subjective judgment; and 2) evaluate interobserver agreement of measurements made using these methods. METHODS Eight patients from a Phase I clinical trial testing convection-enhanced delivery (CED) of a therapeutic antibody were included in the study. Pre-CED, post–radiation therapy axial T2-weighted images were analyzed using 2 methods requiring high degrees of subjective judgment (picture archiving and communication system [PACS] polygon and Volume Viewer auto-contour methods) and 1 method requiring a low degree of subjective judgment (k-means clustering segmentation) to determine tumor volumes. Lin's concordance correlation coefficients (CCCs) were calculated to assess interobserver agreement. RESULTS The CCCs of measurements made by 2 observers with the PACS polygon and the Volume Viewer auto-contour methods were 0.9465 (lower 1-sided 95% confidence limit 0.8472) and 0.7514 (lower 1-sided 95% confidence limit 0.3143), respectively. Both were considered poor agreement. The CCC of measurements made using k-means clustering segmentation was 0.9938 (lower 1-sided 95% confidence limit 0.9772), which was considered substantial strength of agreement. CONCLUSIONS The poor interobserver agreement of PACS polygon and Volume Viewer auto-contour methods highlighted the difficulty in consistently measuring DIPG tumor volumes using methods requiring high degrees of subjective judgment. k-means clustering segmentation, which requires a low degree of subjective judgment, showed better interobserver agreement and produced tumor volumes with delineated borders.

scholarly journals ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma

Neurosurgery ◽  
2019 ◽  
Vol 86 (5) ◽  
pp. 742-751 ◽  
Author(s):  
Vadim Tsvankin ◽  
Rintaro Hashizume ◽  
Hiroaki Katagi ◽  
James E Herndon ◽  
Christopher Lascola ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Kinase Inhibitor ◽  
Mutant Cell ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
P Glycoprotein ◽  
Magnetic Resonance Imaging Mri

Abstract BACKGROUND An impermeable blood–brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). OBJECTIVE To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. METHODS The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. RESULTS Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305). CONCLUSION ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.

Convection Enhanced Delivery of carmustine in diffuse intrinsic pontine glioma

2013 ◽  
Vol 81 (S1) ◽  
pp. 113-113
Author(s):  
S.E.M. Veldhuijzen van Zanten ◽  
M.H.A. Jansen ◽  
D.G. van Vuurden ◽  
E. Hulleman ◽  
T. Lagerweij ◽  
...  
Keyword(s):  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery

scholarly journals The intersect of neurosurgery with diffuse intrinsic pontine glioma

2019 ◽  
Vol 24 (6) ◽  
pp. 611-621 ◽  
Author(s):  
Claudia M. Kuzan-Fischer ◽  
Mark M. Souweidane
Keyword(s):  
Drug Delivery ◽  
Tumor Biology ◽  
Scientific Research ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Therapeutic Drug ◽  
Tissue Sampling ◽  
75Th Anniversary ◽  
Pontine Glioma

An invited article highlighting diffuse intrinsic pontine glioma (DIPG) to celebrate the 75th Anniversary of the Journal of Neurosurgery, a journal known to define surgical nuance and enterprise, is paradoxical since DIPG has long been relegated to surgical abandonment. More recently, however, the neurosurgeon is emerging as a critical stakeholder given our role in tissue sampling, collaborative scientific research, and therapeutic drug delivery. The foundation for this revival lies in an expanding reliance on tissue accession for understanding tumor biology, available funding to fuel research, and strides with interventional drug delivery.

scholarly journals Phase I trial of convection-enhanced delivery of IL13-Pseudomonas toxin in children with diffuse intrinsic pontine glioma

2019 ◽  
Vol 23 (3) ◽  
pp. 333-342 ◽  
Author(s):  
John D. Heiss ◽  
Aria Jamshidi ◽  
Smit Shah ◽  
Staci Martin ◽  
Pamela L. Wolters ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Disease Progression ◽  
Performance Status ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Antitumor Effects ◽  
Radiographic Findings ◽  
Long Term Treatment

OBJECTIVEIn this clinical trial report, the authors analyze safety and infusion distribution of IL13-Pseudomonas exotoxin, an antitumor chimeric molecule, administered via intratumoral convection enhanced delivery (CED) in pediatric patients with diffuse intrinsic pontine glioma (DIPG).METHODSThis was a Phase I single-institution, open-label, dose-escalation, safety and tolerability study of IL13-PE38QQR infused via single-catheter CED into 5 pediatric DIPG patients. IL13-PE38QQR was administered to regions of tumor selected by radiographic findings. Two escalating dose levels were evaluated: 0.125 µg/mL in cohort 1 and 0.25 µg/mL in cohort 2. Real-time MRI was performed during intratumoral infusions, and MRI and MR spectroscopy were performed before and after the infusions. Clinical evaluations, including parent-reported quality of life (QOL), were assessed at baseline and 4 weeks post-infusion.RESULTSDirect infusion of brainstem tumor with IL13-PE using the CED technique in patients with DIPG produced temporary arrest of disease progression in 2 of 5 patients, both of whom subsequently received a second infusion. All 5 patients showed signs of disease progression by 12 weeks after initial infusion. Two patients experienced transient cranial nerve deficits and lethargy after infusion, and these deficits resolved with corticosteroid treatment in both cases. No patient had radiographic evidence of acute or long-term treatment toxicity. Parent-reported QOL was consistent with medical outcomes.CONCLUSIONSEven though IL13-PE delivered by CED did not reach the entire MRI-defined tumor volume in any patient, short-term radiographic antitumor effects were observed in 2 of the 5 patients treated. The patients’ performance status did not improve. Drug delivery using multiple catheters may produce improved outcomes.Clinical trial registration no.: NCT00088061 (clinicaltrials.gov)

Sign in / Sign up

Export Citation Format

Share Document