Focused ultrasound combined with chemotherapy prolongs survival for people with deadly brain cancer

Ten years after Toronto researchers used a novel technique to non-invasively open the blood-brain barrier for the first time, the results of a new multi-site clinical trial show the technique’s success not only in aiding medication to the brain of patients with glioblastoma, but also a 40 per cent increase in survival time.

“This is the first time we have been able to demonstrate a potential survival benefit from using microbubble-enhanced focused ultrasound to open the blood-brain barrier (BBB) to improve delivery of chemotherapy to the tumour site in patients with brain cancer,” says senior investigator Nir Lipsman, a neurosurgeon at Sunnybrook Health Sciences Centre and Dan Family Chair in the division of neurosurgery at the University of Toronto’s Temerty Faculty of Medicine, who helped develop technique over a decade ago.

Focused ultrasound pioneer Kullervo Hynynen, senior scientist at Sunnybrook Research Institute and professor of medical biophysics at Temerty Medicine, was at the helm — joined by the researchers who first used the approach to breach the BBB and more effectively deliver chemotherapy to a glioblastoma patient’s brain tumour. The team has since led intensive multi-site research over the past decade, testing for the safety and feasibility of the technique.

“Patients with glioblastoma have had really no effective treatment options that can significantly prolong survival; there is an urgent need to improve drug delivery and treatment efficacy early on in treatment,” says Lipsman, who is also the Harquail Chair in Neuromodulation at Sunnybrook and Temerty Medicine, and leads the Hurvitz Brain Sciences Program at Sunnybrook. “One of the most frustrating realities for individuals with these devastating brain tumours, and for us as their clinicians, is knowing there may be promising drugs but they just can’t get through the BBB effectively nor sufficiently enough to make a significant or lasting impact.

“The findings of this trial now give reason to suggest we may have found a possible solution to bypass that barrier. This is significant not only for advancing treatments for brain cancers, but other devastating conditions of the brain, including Alzheimer’s disease and ALS,” Lipsman says.

The 34-patient trial, published in Lancet Oncology, evaluated the role of adding and combining repeated microbubble-enhanced focused ultrasound treatments to open the BBB immediately before administering standard chemotherapy. Clinicians delivered the drug temozolomide in six monthly chemotherapy infusions, in individuals with high-grade glioma who were initially treated with surgery to remove their brain tumour.

Trial participants were matched to a rigorously selected control group of 185 glioblastoma patients with similar characteristics who received the standard dose of temozolomide, without receiving focused ultrasound.

The results show that trial participants had nearly 14 months of median progression-free survival, compared to eight months in the control group. In terms of overall survival, trial participants lived for more than 30 months on average, compared to 19 months in the control group.

The study also showed an increased clearance of neurotoxins in the brain, anti-tumour immune activation and enhanced shedding of brain tumour markers in the circulating bloodstream that could be detected. There is an ongoing multi-centre pivotal trial exploring the potential to investigate focused ultrasound with a liquid biopsy strategy.

Hynynen worked with industry partner InSightec for almost two decades to develop the technology and bring it to a clinic-ready state in 2015. With his lab team, he also did an additional decade of intensive research to test the technique’s safety and feasibility, while fine tuning and adapting it.

“We are proud that Insightec’s incisionless focused ultrasound technology played a role in enabling this monumental breakthrough,” said Maurice R. Ferré, MD, Chair and CEO of Insightec. “This collaboration exemplifies how partnerships between academia, industry, and clinical teams can accelerate advances that give new hopes to patients. Seeing focused ultrasound help extend life for people with glioblastoma underscores its potential to transform how we treat brain disorders.” 

“Learning that this therapeutic approach has been shown not only to be safe for individuals with high-grade glioma, but also to extend their lives, is deeply rewarding for the many research personnel who have contributed to this project over the years. We are humbled and gratified to be part of this work and to witness its potential impact on patients and their families,” says Hynynen, who is also vice president of research at Sunnybrook Research Institute and holds the Temerty Chair in Focused Ultrasound Research at Sunnybrook and U of T.

While temozolomide is the standard chemotherapy drug used to treat glioblastoma, studies show that less than 20 percent reaches the brain in patients. This study did not determine the exact amount of the drug to reach the brain in each patient, but earlier studies have shown that opening the BBB before delivering chemotherapy can dramatically increase the amount that gets to the original tumour site. Studies are underway to confirm and expand upon this research.

“Breaching this barrier and now seeing the success of this clinical trial suggests that adding microbubble-enhanced focused ultrasound to monthly upfront chemotherapy is a promising combination therapeutic approach for individuals with high-grade glioma. We are encouraged by these results and look forward to accelerating continued testing of targeted therapies for glioblastoma and other brain conditions to see whether they may offer further life-extending benefits,” says Neal Kassell, chair of the Focused Ultrasound Foundation.

This phase 1/2 clinical trial was conducted between October 2018 and March 2022, at sites in Canada and the United States participating in the ReFOCUSED Consortium: Sunnybrook Health Sciences Centre (Sunnybrook Research Institute and University of Toronto), Montreal Neurological Institute and Hospital, University of Maryland Medical Center (University of Maryland School of Medicine), Harvard University, University of Virginia, West Virginia University, McGill University, Brigham and Women’s Hospital, Johns Hopkins University School of Medicine, Massachusetts College of Pharmacy and Health Sciences University, Columbia University and Harvard Medical School.

This trial was funded by the National Institutes of Health, InSightec Inc., the Harquail Centre for Neuromodulation and the Midas Touch Foundation.