In a single-center, small phase Ib trial reported in The Lancet Oncology, Spinazzi et al found that repeated and prolonged convection-enhanced delivery of topotecan prior to surgery was feasible in patients with recurrent glioblastoma and resulted in significant reduction in proliferating tumor cells.
As stated by the investigators, “Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) convection-enhanced delivery of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma.”
Study Details
Five patients were enrolled into the study at Columbia University Irving Medical Center between Jamuary 2018 and July 2019. Patients had catheters stereotactically implanted into the glioma-infiltrated peritumoral brain, which were connected to subcutaneously implanted pumps that infused 146 μM topotecan at 200 μL/h for 48 hours, followed by a 5- to 7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumor was resected.
Key Findings
Chronic convection-enhanced delivery was successfully completed safely in all five patients, was well tolerated, and was not associated with substantial complications. The most common adverse events of any grade (all grade 1–2) were pain at incision site (100%), fatigue (60%), and headache (40%). One patient had a grade 3 adverse event related to treatment, consisting of intraoperative supplemental motor area syndrome. No grade 4 adverse events were observed. Other observed serious adverse events were related to surgical resection, not convection-enhanced delivery of topotecan.
Posttreatment tissue analysis showed that topotecan significantly reduced proliferating tumor cells in all five patients. The SOX2 labeling index was significantly reduced in post– vs pre–convection-enhanced delivery biopsies (18.5% vs 25.8%, P = .031), as was the Ki67 labeling index (1.4% vs 3.9%, P = .0090). Positron-emission tomography–fluorodeoxyglucose (PET-FDG) imaging in three patients showed reductions in glucose metabolism of 17.2%, 12.7%, and 6.2%; an inverse exponential correlation between Ki67 proliferation labeling index and PET-FDG uptake was observed (P = .0020).
The investigators concluded, “In this small patient cohort, we showed that chronic convection-enhanced delivery of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other antiglioma drugs or other central nervous stystem diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes.”
Jeffrey N. Bruce, MD, of the Department of Neurological Surgery, Columbia University Irving Medical Center, New York, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the National Institutes of Health, William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, Michael Weiner Glioblastoma Research Into Treatment Fund, and others. For full disclosures of the study authors, visit thelancet.com.
