Summary: A fully implantable pump system can safely bypass the blood-brain barrier to deliver chemotherapy directly into the brain, showing biological activity against glioblastoma in a first-in-patient study.
Source: Columbia University
Treating brain cancer is complicated not only by the tumor but by the brain’s protective anatomy.
The blood-brain barrier is a vital defense that shields the brain from toxins, pathogens, and circulating substances, but it also blocks most systemic therapies from reaching brain tumors in effective concentrations. Researchers have explored nanoparticles, focused ultrasound, and novel chemistries to penetrate this barrier, but a team of neurosurgeons at Columbia University and NewYork-Presbyterian has pursued a more direct solution: an entirely implantable pump that continuously delivers chemotherapy through a catheter placed precisely in the brain.
In a phase 1 clinical trial, this implantable pump system was tested in patients with recurrent glioblastoma. The study demonstrates that chronic, convection-enhanced delivery of chemotherapy directly into brain tissue can saturate tumor regions, reduce actively dividing tumor cells, and be delivered safely without major neurological complications.
Results from the single-center, first-in-patient trial involving five patients with recurrent glioblastoma were published in Lancet Oncology (November issue).
“This delivery approach could change how we treat brain tumors by overcoming a major barrier to drug access,” says Jeffrey Bruce, MD, Edgar M. Housepian Professor of Neurological Surgery Research at Columbia University Vagelos College of Physicians and Surgeons and a senior author of the study. He notes that additional testing is needed in patients with earlier-stage disease and with other drugs.
Why glioblastoma is hard to treat
Standard care for glioblastoma begins with surgery to remove as much tumor as possible, followed by radiation and systemic chemotherapy. Because the blood-brain barrier limits drug penetration, clinicians cannot safely increase systemic chemotherapy doses without causing toxic side effects elsewhere in the body. As a result, the concentrations that reach the brain are often inadequate to eliminate tumor cells, and recurrence is common.
Median survival after initial treatment for glioblastoma remains poor—just over 12 months—and when tumors recur, expected survival typically falls to only a few months. New delivery strategies that raise local drug levels while minimizing systemic toxicity are therefore a high priority in neuro-oncology.
An implantable pump to breach the barrier
Over the past decade, the Columbia team developed a pressurized, implantable pump and catheter system designed for chronic convection-enhanced delivery (CED). Earlier versions used external pumps and required short, inpatient treatment windows, increasing infection risk and restricting repeated dosing. The new design eliminates external components: a compact pump is implanted beneath the skin of the abdomen and connected to a thin, flexible catheter tunneled to a precisely targeted brain region using stereotactic imaging.
Delivered very slowly—at a few drops per hour—the drug is pushed under slight pressure, allowing it to penetrate surrounding brain tissue. Laboratory and animal studies showed that this method produces brain concentrations of drug up to 1,000 times higher than those achievable with systemic administration, while keeping systemic exposure and side effects low.
The implanted pump technology is analogous to established devices used to deliver pain medication to the spinal cord: pumps can remain implanted for extended periods, be accessed percutaneously for refills, and be controlled wirelessly to set on/off cycles and flow rates so the drug infuses at an optimal, slow rate without leaking.
“Delivering drugs continuously and locally lets us maintain therapeutic levels in the tumor zone without the systemic toxicity that limits traditional chemotherapy,” says Bruce. The system also enables the possibility of switching drugs over time, testing agents that would be ineffective if given systemically but potent when concentrated directly in the brain.
Phase 1 trial: safety and biological activity
In the reported trial, five patients with recurrent glioblastoma received stereotactic placement of catheters into the glioma-infiltrated, peritumoral brain and subcutaneous implantation of pumps filled with topotecan, a drug active against rapidly dividing cells. Gadolinium was co-infused as a tracer to monitor distribution by MRI.
Treatment consisted of four cycles over one month: each week the pump infused for 48 hours at a controlled flow rate (200 μL/h of 146 μM topotecan), followed by a 5–7 day washout period. Patients went home between infusions and maintained normal daily activities while therapy continued.
All five patients completed the prescribed infusions without substantial treatment-related complications. No serious neurological adverse events attributable to the drug infusions occurred; the only grade 3 adverse event related to treatment was a transient intraoperative supplemental motor area syndrome in one patient. MRI confirmed that the infusions produced predictable drug distribution in and around the tumor regions.
Importantly, paired tissue analysis—comparing pre-treatment and post-treatment biopsies—showed a marked reduction in proliferating tumor cells in all patients, while normal brain cells were spared. Though the small cohort precludes conclusions about survival benefit, these tissue-based biological effects indicate that chronic CED of topotecan reached and impacted tumor tissue.
Next steps and patient-centered benefits
The authors plan additional studies to evaluate safety and efficacy in patients with newly diagnosed glioblastoma and to test other drugs using this delivery platform. Because many recurrent tumors become more treatment-resistant, delivering chemotherapy earlier—when tumor burden and resistance are lower—may produce stronger responses.
This implantable, refillable pump offers a patient-focused approach: it allows outpatient treatment, preserves quality of life during therapy, and provides a flexible platform to test drugs that require high local concentrations but cause unacceptable systemic toxicity when given orally or intravenously.
Funding: The study was supported by grants from the US National Institutes of Health (R01CA161404, R01NS103473, P30CA013696, 5P30CA013696-43, 5UG1CA189960-04, P41EB028741, UL1TR001873, U54 CA210180), the William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Khatib Foundation, the Gary and Yael Fegel Foundation, and the Michael Weiner Glioblastoma Research Into Treatment Fund.
About this brain cancer research news
Author: Helen Garey
Source: Columbia University
Contact: Helen Garey – Columbia University
Image: The image is in the public domain
Original Research: Closed access. “Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial” by Jeffrey Bruce et al., Lancet Oncology.
Abstract
Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial
Background
Topotecan is cytotoxic to glioma cells but has limited clinical benefit when given systemically because of poor brain penetrance and systemic toxicity. Convection-enhanced delivery has been restricted historically to brief, single treatments. To address these limitations, the authors engineered a subcutaneously implanted pump-catheter system capable of repeated, chronic (pulsatile) CED of topotecan directly into brain tissue and assessed its safety and biological effects in recurrent glioblastoma patients.
Methods
This single-center, open-label, phase 1b trial enrolled patients aged 18 or older with solitary, histologically confirmed recurrent glioblastoma that progressed after standard surgery, radiotherapy, and chemotherapy, and with Karnofsky Performance Status ≥70. Five patients had stereotactically placed catheters targeting glioma-infiltrated peritumoural brain connected to subcutaneous pumps. Pumps delivered 146 μM topotecan at 200 μL/h for 48 hours, followed by a 5–7 day washout; this cycle was repeated four times. After the fourth infusion the pump was removed and the tumor resected. The primary endpoint was safety, assessed by serious adverse events. The trial is registered as NCT03154996.
Findings
Between Jan 22, 2018, and July 8, 2019, all five patients completed chronic CED without major treatment-related complications. The only grade 3 adverse event attributed to treatment was a transient intraoperative supplementary motor area syndrome in one patient; there were no grade 4 treatment-related events. Median follow-up was 12 months (IQR 10–17) after pump explant. Post-treatment tissue analysis demonstrated a significant reduction in proliferating tumor cells in all patients.
Interpretation
In this small cohort, chronic CED of topotecan appears potentially safe and biologically active against recurrent glioblastoma. The approach overcomes key delivery limitations and provides a tissue-based measure of response without requiring large patient numbers. The platform could be adapted for other anti-glioma agents or CNS diseases; larger studies are needed to determine clinical outcome benefits.
Funding
US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.