Implantable pump safely delivers chemotherapy to the brain in patients with glioblastoma
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When administering chemotherapy to a patient with recurrent glioblastoma, physicians must overcome the blood-brain barrier, an immunologic feature of the central nervous system.
Theoretically, IV or oral administration of higher doses of chemotherapy may surmount the blood-brain barrier; however, these increased doses are generally not well-tolerated.
“The reason these drugs haven’t worked is not because they aren’t good drugs — it is a drug delivery problem,” Jeffrey N. Bruce, MD, the Edgar M. Housepian professor of neurological surgery at Columbia University Vagelos College of Physicians and Surgeons and neurosurgeon at New York-Presbyterian/Columbia University Irving Medical Center, told Healio. “The only way you can overcome it is to give higher doses of your chemotherapy drug, and then you develop all kinds of toxicity. So, it’s a very limiting factor in treating brain tumors.”
To address this obstacle, Bruce and his colleagues at Columbia have developed an implantable, pressurized pump to circumvent the blood-brain barrier and direct chemotherapy to the tumor location. The researchers published results of a first-in-patient, single-arm, phase 1b trial of this innovation in The Lancet Oncology.
Bruce spoke with Healio about the complexities of treating recurrent glioblastoma and how the implant can provide less toxic, more targeted chemotherapy.
Healio: What inspired you to develop this implant?
Bruce: Brain tumors are unlike other cancers. In most cancers, people die of metastatic disease. Glioblastoma is different; these tumors don’t metastasize but grow back in the same spot. So, when a tumor is initially diagnosed, it is treated with surgery to remove it, then radiation and finally with [temozolomide]. That keeps the tumor under control for a while. Inevitably, though, the tumors grow back, and usually in only a short period of time. At that point, the only treatments available are experimental.
Many drugs have been developed and tested, but none have really worked because when you give a drug intravenously or orally, the drug has to travel through the entire body to get to the brain. Then the blood-brain barrier prevents it from getting into the brain.
Local drug delivery, more formally called convection-enhanced delivery, is a somewhat counterintuitive concept. The idea is to implant a simple catheter in the tumor or in the brain, connect it through tubing to a pump and slowly pump the drug into the brain. If you pump it very slowly, delivering several drops an hour, it sets up a pressure gradient at the catheter tip that pushes the drug through the brain tissue.
The initial way this was done was through an externalized system with a pump at the patient’s bedside. With that setup, we can only deliver the drugs for a few days before we have to start worrying about it causing an infection. That limits us to just a single treatment over a few days before we have to remove the catheter. To be effective, chemotherapy has to be given multiple times, because at any given time, only a small fraction of tumor cells are vulnerable to the chemotherapy.
Healio: How is the implant you developed different?
Bruce: We used an implantable pump currently used to deliver pain medications into the spine. It’s about the size of a hockey puck, and you can implant it in the abdomen and tunnel the tubing under the skin up to the catheter in the brain. These pumps have a wireless technology that allows you to turn them on or off or change the flow rate. They have a little diaphragm in them, so you can take a needle and syringe and empty the drug reservoir and refill it.
We tested this for the first time to deliver chemotherapy to a group of patients with brain tumors who had already failed standard treatment. We used topotecan, which is primarily used for lung cancer. However, most chemotherapies would probably work with our delivery method. We were able to show that we could deliver the drug through the pump over the course of a month. Because it was the first trial of its kind, we limited it to a month and only to a small number of patients. We were also able to deliver drugs multiple times — we would turn the pump on for 2 days and then turn it off for 5 days, and we did that four times. We were able to show that this concept was safe and effective — you could deliver drugs for months or potentially years at a time. There’s no reason the drugs can’t be delivered indefinitely.
Healio: What else did this study reveal?
Bruce: We gained several other insights from this research. When we delivered the drug, we delivered gadolinium, a contrast used in MRI scans. This allowed us to see the volume of distribution and where the drug was going in the brain in relation to the tumor itself.
Additionally, we wanted to have a way of telling whether the drug was working or not. If you only have five patients, that’s hard to do. When we surgically implanted the catheter, we took multiple stereotactic-guided biopsies at the same time. With MRI imaging, we could be very precise in terms of where we were taking our biopsy. We biopsied the tumor and the surrounding brain where the drug was to be infused. We had all this brain and tumor tissue from before treatment, and then we implanted the catheter and pump. At the end of the month of treatment, we removed the pump and catheter, and then the tumor itself. So, we had tissue both from before and after treatment, which we were able to analyze histologically, as well as with very advanced RNA sequencing to look at genomic changes. We were able to show that we were killing tumor cells, but not damaging normal brain cells. We don’t have to wait to see how patients do on a long-term basis — we showed proof of principle that the drug is working, and that we can look at how it is affecting the rest of the brain.
Healio: What is next in terms of your research on this?
Bruce: This was the first trial to show safety and feasibility. Going forward, we can potentially optimize delivery, perhaps by adding another catheter or increasing the amount of time the pump is implanted. We need to do a bigger trial to show that there is a survival advantage.
For more information:
Jeffrey N. Bruce, MD, can be reached at Columbia University Irving Medical Center, 710 W. 168th St., Suite 4-434, New York, NY 10032; email: jnb2@cumc.columbia.edu.
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