Summary: A new implantable pump system efficiently crosses the blood-brain barrier to deliver chemotherapy drugs to patients with glioblastoma brain cancer.

Source: Columbia University

The biggest obstacle to treating brain cancer is not the cancer, but the brain itself.

The blood-brain barrier is an important part of the brain’s blood vessels that prevents toxins, viruses, and bacteria from entering the brain through the bloodstream—but it also blocks most healing substances.

Nanoparticles, focused ultrasound, smart chemistry and other new ideas are being tried to overcome the barrier and deliver therapies to the brain. Now, neurosurgeons at Columbia University and New York-Presbyterian are taking a more direct approach: a fully implantable pump that continuously delivers a chemical through a tube inserted directly into the brain.

A novel approach that effectively kills brain tumor cells and offers a safe way to treat patients with brain cancer is the first study to examine an implantable pump in patients with brain cancer.

Results from the study, a phase 1 trial involving five patients with recurrent glioblastoma, were published in November 2015. Lancet Oncology.

“This new approach has the potential to transform the treatment of patients with brain cancer, where survival prospects are poor, although further testing is needed in patients with earlier-stage tumors and different types of chemotherapy,” said Jeffrey Bruce, MD. Edgar M. Hauspian Research Professor of Neurological Surgery at Columbia University Vagelos College of Physicians and Surgeons, New York-Presbyterian/Columbia University Irving Medical Center, and senior author of the study.

Brain cancer is resistant to treatment

Patients with brain cancer are treated with surgery to remove as much of the tumor as possible, followed by radiation and chemotherapy.

In theory, doctors could give patients high doses of chemotherapy—in pills or intravenously—to cross the blood-brain barrier and get more chemo into the brain. But at higher doses, the drugs cause too many side effects on other parts of the body, and patients cannot tolerate them.

As a result, the amount of chemotherapy that can be safely given to patients with brain tumors is not always effective.

“The tumors inevitably grow back,” said Bruce, director of the Bartoli Brain Tumor Research Laboratory at Columbia University’s Vagelos College of Physicians and Surgeons. “And there’s no proven treatment for them when they grow up.”

Median survival for patients treated for glioblastoma is more than 12 months. After the patient’s tumors are restored, their prognosis is usually only around four or five months.

A new system breaks the brain barrier

Over the past decade, Bruce and his team have been working on a pressurized pump to deliver chemotherapy across the blood-brain barrier and direct it to the area of ​​the brain where the tumor is located.

But early prototypes, which involved an external pump attached to a catheter in the skull, allowed for only one treatment, limited to a few days before the risk of developing the disease became apparent. Patients must stay in the hospital while connected to the pump.

To overcome this limitation, Bruce’s team designed a new prototype that has no external components and can last as long as needed. A small pump is surgically implanted in the abdomen and connected to a thin flexible catheter under the skin. Stereotactic imaging guides the surgical placement of the catheter precisely in the area of ​​the brain where the tumor and any remaining cancer cells are located.

“The drug penetrates the brain tissue very slowly, literally in several drops over an hour,” says Bruce, who first tested the method in animal models.

“The concentration of a drug that ends up in the brain is 1,000 times greater than anything you can get intravenously or orally.”

Similar implantable pumps are available to deliver pain medication to the spine and can last for years. The pump can be refilled or injected. Wireless technology is used to turn the pump on and off and control the flow rate, which ensures that the drug is slowly absorbed and saturates the tumor without leaking around the tube.

“Most drugs are more effective if you can give them for a long time without side effects,” says Bruce.

“The pump can stay in place for a long time, so we can deliver high doses of chemotherapy directly to the brain without the side effects of oral or intravenous chemotherapy.”

The study demonstrates the safety and feasibility of an implantable pump

In the new study, the pumps were implanted in recurrent glioblastoma patients and filled with topotecan, a chemotherapy drug used to treat lung cancer, and gadolinium, a tracer agent to monitor the drug’s distribution.

(Previous research in Bruce’s lab has shown that local delivery of topotecan, which stimulates actively dividing cells, may be more effective than current glioblastoma treatments.)

Patients had four treatments over a period of one month; Every week the pumps are off for two days and five days. While the treatment continues, patients carry out their normal activities at home, drip with drops.

This shows the shape of the head
A novel approach that effectively kills brain tumor cells and offers a safe way to treat patients with brain cancer is the first study to examine an implantable pump in patients with brain cancer. The image is in the public domain.

“The patients were walking, talking, eating—doing all their daily activities. They didn’t even know if the pump was on or not,” says Bruce.

None of the patients had severe neurological complications. And an MRI scan showed that the chemotherapy had filled the space in and around the tumor.

Although the number of patients was too small to detect an overall survival benefit, an exclusive analysis of pretreatment and posttreatment biopsies was conducted by Peter Cannoll, MD, PhD, director of neuropathology at New York-Presbyterian/Columbia University Irving Medical Center and senior author of the study. The chemotherapy showed that it was working: the actively dividing tumor cells were significantly reduced, while normal brain cells were not affected.

watch out

This shows a large man wearing a face mask.

A patient-centered approach to treating brain cancer

New studies are planned to determine whether the treatment is safe for patients with newly diagnosed glioblastoma and can improve survival.

“When the first treatments fail, a lot has happened to make the tumor difficult to treat, so we think the pump will work better with newly diagnosed patients,” says Bruce.

“This approach allows us to change the treatment over time and use other types of chemotherapy, which are less effective if given systemically, but may be more effective when delivered directly to the brain.”

Financial support ጥናቱ የተደገፈው ከብሔራዊ የጤና ተቋማት (R01CA161404፣ R01NS103473፣ P30CA013696፣ 5P30CA013696-43፣ 5UG1CA189960-04፣ P41EB028741፣ UL17TR0013696-43፣ 5UG1CA189960-04፣ P41EB028741፣ UL17TR001 EB028741 ፣ UL17TR001013696 ፣ ሉዊልያም ጂ ኤል 13TR00 የጋሪ እና ያኤል ፌጌል ፋውንዴሽን፣ እና ማይክል ዌይነር Glioblastoma Research on the Cure Fund.

So brain cancer research news

Author: Helen Gary
Source: Columbia University
Contact: Helen Gary – Columbia University
Image: The image is in the public domain.

Preliminary study: Closed access.
Chronic convection-enhanced delivery of topotecan in patients with recurrent glioblastoma: a patient-first, single-center, single-arm, phase 1b trial.” by Jeffrey Bruce et al Lancet Oncology


Draft

Chronic convection-enhanced delivery of topotecan in patients with recurrent glioblastoma: a patient-first, single-center, single-arm, phase 1b trial.

Background

Topotecan is cytotoxic to glioma cells but lacks clinical efficacy due to limited drug availability. Systemic delivery is limited by toxicity and insufficient brain penetration, and to date, convection-enhanced delivery (CED) has been limited to a single regimen. To address this problem, we developed a subcutaneous catheter-pump system, delivered repeated, chronic (long, pulsatile) CED topotecan to the brain and tested its safety and biological effects in patients with recurrent glioblastoma.

Methods

We conducted a single-center, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically proven recurrent glioblastoma showing radiographic progression and a Karnofsky performance status of at least 70 after surgery, radiation therapy, and chemotherapy. And connected to subcutaneous pumps, 146 μM topotecan 200 μL/h for 48 hours, followed by a 5-7-day washout period before the next infusion, with four total treatments. After the fourth discharge, the pump was removed and the tumor was fixed. The primary endpoint of the study was the safety of the treatment regimen as defined by the presence of serious adverse events. Analyzes were performed on all treated patients. The trial is closed, and registered at ClinicalTrials.gov, NCT03154996.

Findings

Between January 22, 2018 and July 8, 2019, chronic topotecan CED was successfully completed in all five patients, and was well tolerated without complications. The only grade 3 adverse event was treatment-related surgical accessory motor area syndrome (a [20%] Five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to the surgical treatment and not the study treatment. Median follow-up from pump explant was 12 months (IQR 10–17). Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumor cells in all five patients.

Interpretation

In this small cohort of patients, we demonstrated that chronic topotecan CED is a safe and active treatment for recurrent glioblastoma. Our analysis provided a tissue-specific assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan in patients with glioblastoma overcomes the limitations of delivery and treatment response evaluation and may be applied to other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the impact of this drug delivery approach on clinical outcomes.

Financial support

The US National Institutes of Health, the William Rhodes and Louise Tilzer Rhodes Globoblastoma Center, the Michael Weiner Glioblastoma in Cure Fund, the Gary and Yael Feigel Foundation, and the Khatib Foundation.

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