Convection-enhanced delivery (CED) uses 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. The authors describe the case of a patient with a diffuse intrinsic pontine glioma (DIPG) with a large cyst and examine its effect on drug distribution after CED with a radiolabeled antibody. The patient was treated according to protocol with CED of 124I-8H9 to the pons for nonprogressive DIPG after radiation therapy as part of a Phase I trial (clinical trial registration no. NCT01502917, clinicaltrials.gov). Care was taken to avoid the cystic cavity in the planned catheter track 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. Analysis of postinfusion MR images demonstrated convective distribution around the catheter tip and an elongated configuration of drug distribution, consistent with the superoinferior 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-weighted FLAIR or T1-weighted images. 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. The authors 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.
Iryna Ivasyk, Peter F. Morgenstern, Eva Wembacher-Schroeder, and Mark M. Souweidane
Evan D. Bander, Karima Tizi, Eva Wembacher-Schroeder, Rowena Thomson, Maria Donzelli, Elizabeth Vasconcellos, and Mark M. Souweidane
In the brainstem, there are concerns regarding volumetric alterations following convection-enhanced delivery (CED). The relationship between distribution volume and infusion volume is predictably greater than one. Whether this translates into deformational changes and influences clinical management is unknown. As part of a trial using CED for diffuse intrinsic pontine glioma (DIPG), the authors measured treatment-related volumetric alterations in the brainstem and ventricles.
Enrolled patients underwent a single infusion of radioimmunotherapy. Between 2012 and 2019, 23 patients with volumetric pre- and postoperative day 1 (POD1) and day 30 (POD30) MRI scans were analyzed using iPlan® Flow software for semiautomated volumetric measurements of the ventricles and pontine segment of the brainstem.
Children in the study had a mean age of 7.7 years (range 2–18 years). The mean infusion volume was 3.9 ± 1.7 ml (range 0.8–8.8 ml). Paired t-tests demonstrated a significant increase in pontine volume immediately following infusion (p < 0.0001), which trended back toward baseline by POD30 (p = 0.046; preoperative 27.6 ± 8.4 ml, POD1 30.2 ± 9.0 ml, POD30 29.5 ± 9.4 ml). Lateral ventricle volume increased (p = 0.02) and remained elevated on POD30 (p = 0.04; preoperative 23.5 ± 15.4 ml, POD1 26.3 ± 16.0, POD30 28.6 ± 21.2). Infusion volume had a weak, positive correlation with pontine and lateral ventricle volume change (r2 = 0.22 and 0.27, respectively). Four of the 23 patients had an increase in preoperative neurological deficits at POD30. No patients required shunt placement within 90 days.
CED infusion into the brainstem correlates with immediate but self-limited deformation changes in the pons. The persistence of increased ventricular volume and no need for CSF diversion post-CED are inconsistent with obstructive hydrocephalus. Defining the degree and time course of these deformational changes can assist in the interpretation of neuroimaging along the DIPG disease continuum when CED is incorporated into the treatment algorithm.
Evan D. Bander, Alexander D. Ramos, Eva Wembacher-Schroeder, Iryna Ivasyk, Rowena Thomson, Peter F. Morgenstern, and Mark M. Souweidane
While 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.
Patients 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.
Seven 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).
This 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.
Eva Wembacher-Schroeder, Nicole Kerstein, Evan D. Bander, Neeta Pandit-Taskar, Rowena Thomson, and Mark M. Souweidane
With increasing use of convection-enhanced delivery (CED) of drugs, the need for software that can predict infusion distribution has grown. In the context of a phase I clinical trial for pediatric diffuse intrinsic pontine glioma (DIPG), CED was used to administer an anti-B7H3 radiolabeled monoclonal antibody, iodine-124–labeled omburtamab. In this study, the authors retrospectively evaluated a software algorithm (iPlan Flow) for the estimation of infusate distribution based on the planned catheter trajectory, infusion parameters, and patient-specific MRI. The actual infusate distribution, as determined on MRI and PET imaging, was compared to the distribution estimated by the software algorithm. Similarity metrics were used to quantify the agreement between predicted and actual distributions.
Ten pediatric patients treated at the same dose level in the NCT01502917 trial conducted at Memorial Sloan Kettering Cancer Center were considered for this retrospective analysis. T2-weighted MRI in combination with PET imaging was used to determine the distribution of infusate in this study. The software algorithm was applied for the generation of estimated fluid distribution maps. Similarity measures included object volumes, intersection volume, union volume, Dice coefficient, volume difference, and the center and average surface distances. Acceptable similarity was defined as a simulated distribution volume (Vd Sim) object that had a Dice coefficient higher than or equal to 0.7, a false-negative rate (FNR) lower than 50%, and a positive predictive value (PPV) higher than 50% compared to the actual Vd (Vd PET).
Data for 10 patients with a mean infusion volume of 4.29 ml (range 3.84–4.48 ml) were available for software evaluation. The mean Vd Sim found to be covered by the actual PET distribution (PPV) was 77% ± 8%. The mean percentage of PET volume found to be outside the simulated volume (FNR) was 34% ± 10%. The mean Dice coefficient was 0.7 ± 0.05. In 8 out of 10 patients, the simulation algorithm fulfilled the combined acceptance criteria for similarity.
iPlan Flow software can be useful to support planning of trajectories that produce intraparenchymal convection. The simulation algorithm is able to model the likely infusate distribution for a CED treatment in DIPG patients. The combination of trajectory planning guidelines and infusion simulation in the software can be used prospectively to optimize personalized CED treatment.