Ten years to the month Sunnybrook researchers used a novel technique to non-invasively open the blood-brain barrier for the first time in history, the results of a new study Sunnybrook co-led shows its 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 (FUS) to open the blood-brain barrier (BBB) to improve delivery of chemotherapy to the tumour site in patients with brain cancer,” says Dr. Nir Lipsman, senior investigator of the multi-site clinical trial and one of the neurosurgeons at Sunnybrook Health Sciences Centre to lead the world-first technique over a decade ago.

With the pioneer of this FUS technique at the helm – Dr. Kullervo Hynynen – and a team of Sunnybrook researchers made history on November 5, 2015 when they were the first in the world to use the approach he developed to non-invasively and temporarily breach the BBB to more effectively deliver chemotherapy into the brain tumour of a patient with glioblastoma. The Sunnybrook 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,” adds Dr. Lipsman, also the Harquail Chair in Neuromodulation at Sunnybrook and University of Toronto’s Temerty Faculty of Medicine, and Chief for 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.”

Published in The Lancet Oncology, the landmark trial of 34 patients evaluated the role of adding and combining repeated microbubble-enhanced FUS treatments (to open the BBB) immediately before standard chemotherapy was administered (six monthly infusions of the drug temozolomide) in individuals with high-grade glioma who were initially treated with surgery to remove their brain tumour. The trial participants were matched to a rigorously-selected control group of 185 glioblastoma patients with similar characteristics who received the standard dose of the chemotherapy drug temozolomide, without receiving FUS.

The results show that the 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, on average, lived for more than 30 months 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 currently an ongoing multi-centre pivotal trial exploring the potential to investigate FUS with a liquid biopsy strategy).

Dr. Hynynen and his team have collaborated with industry partner Insightec for nearly two decades to develop and refine the focused ultrasound technology used in this groundbreaking approach. Together, they advanced the platform from early research to clinical implementation, continually improving its precision, safety, and effectiveness through years of joint innovation and testing.

“We are proud that Insightec’s incisionless focused ultrasound technology played a role in enabling this monumental breakthrough,” said Maurice R. Ferré, MD, Chairman 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 Dr. Hynynen, Vice President of Research at Sunnybrook Research Institute (SRI) and a professor with University of Toronto’s Temerty Faculty of Medicine. 

While temozolomide is the standard chemotherapy drug used in the treatment for glioblastoma, studies show that less than 20 percent reaches the brain in patients. This study did not determine the exact amount of temozolomide 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. Ongoing studies are working to confirm and expand upon this research. 

“Breaching this barrier and now seeing the success of this clinical trial suggests that adding microbubble-enhanced FUS 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 Dr. Neal Kassell, chairman 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 of America, as part of the growing ReFOCUSED Consortium: Sunnybrook Health Sciences Centre (SRI 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 (NIH), Insightec Inc., Harquail Centre for Neuromodulation, and the Midas Touch Foundation.