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.

Figures

FIG. 1.

Artist’s rendering of CED. Drawing superimposed on an axial T1-weighted MR image showing bilateral catheters stereotactically placed through the cerebellar peduncles into the brainstem of a patient with a DIPG. Catheters are placed into the tumor with the tips approximately 1 cm apart, avoiding the fourth ventricle to minimize loss of drug to CSF. Catheters are tunneled subcutaneously to prevent migration and CSF leakage. Drug is distributed throughout the tumor via convection (yellow shading). Inset depicts sagittal orientation of patient with catheters in place.

FIG. 2.

Case 1. Axial MR images. A and B: T2-weighted (A) and contrast-enhanced T1-weighted (B) images obtained at the time of diagnosis showing enlargement of the pons without contrast enhancement. C: Contrast-enhanced T1-weighted image obtained after radiation treatment at the time of recurrence showing new patchy enhancement. D: FLAIR image obtained immediately after surgery demonstrating bilateral catheters within the tumor. E and F: FLAIR (E) and contrast-enhanced T1-weighted (F) images obtained after treatment (6.04 ml infusion volume) showing effects of drug infusion within the tumor. G and H: T2-weighted (G) and contrast-enhanced T1-weighted (H) images obtained 1 month posttreatment demonstrating tumor progression.

FIG. 3.

Case 2. Axial MR images. A and B: Preoperative T2-weighted (A) and contrast-enhanced T1-weighted (B) images showing enlargement of the pons with 2 small areas of mild contrast enhancement. C: T1-weighted image obtained immediately after surgery demonstrating bilateral catheters within the tumor. D and E: T2-weighted images obtained mid-treatment (3.09 ml infusion volume [D]) and immediately posttreatment (5.30 ml total infusion volume [E]) showing increasing area of drug distribution within the tumor. F: Contrast-enhanced T1-weighted image obtained 1 month after treatment demonstrating stable tumor. G and H: T2-weighted (G) and contrast-enhanced T1-weighted (H) images obtained nearly 4 months posttreatment demonstrating tumor progression.

FIG. 4.

Case 2. Results of histological and immunohistochemical analysis of recurrent tumor at autopsy showing tumor progression. A: Hemotoxylin and eosin staining of the tumor in the pons showing the histological features of glioblastoma, with marked nuclear pleomorphism and areas of pseudopallisading necrosis (N). B and C: Immunoperoxidase staining for p53 showing strong nuclear staining (brown) in a subset of the tumor cells (B) and scattered p53+ tumor cells invading the cerebellar cortex (C). Original magnificatio×100.