Dr. Hiroshi Hatanaka (pictured) was one of the pioneers of boron neutron capture therapy and was a key figure in the advancement of the therapy in Japan. Last year, Aviko’s partner Neutron Therapeutics installed their next-generation compact neutron accelerator at Shonan Kamakura General Hospital (pictured) in Kamakura City, Kanagawa Prefecture, Japan.
After years of research and clinical trials, boron neutron capture therapy, which was conceived as a method for treating solid tumors in the United States, is helping patients live longer, healthier lives.
Though many countries have contributed to BNCT’s advancement throughout the world, Japan has been the center for the modality for decades. The late Japanese neurosurgeon Hiroshi Hatanaka is one reason why.
Boston to Tokyo
After studying in the U.S. as a Fulbright Scholar in the mid-1960s, including four years under the tutelage of BNCT clinical pioneer Dr. William Herbert Sweet at Massachusetts General Hospital, Dr. Hatanaka returned home to Japan with the goal of further advancing BNCT for clinical use.
The timing was complicated. While support for civilian nuclear power was growing in Japan, funding for cancer-related research with boron was scarce. But Dr. Hatanaka was determined to bring the modality he studied with Dr. Sweet in Boston to his native country.
“Unwilling to accept these refusals as final he appealed with success for governmental financial support for this research to none other than the prime minister of the Japanese nation,” Dr. Sweet wrote in a remembrance penned after his protégé’s death in 1994.1
“No other visiting scientist spent as much time with us, and no other scientist on return to his home base devoted himself to a sustained major effort to bring the concept of boron neutron capture therapy of intracranial tumors to fruition,” Dr. Sweet wrote.
In 1968, Dr. Hatanaka became the first researcher to successfully use BNCT for brain tumors using borocaptate sodium (BSH), a boron-carry compound that he developed through joint research with Dr. A.H. Soloway while at Massachusetts General Hospital. In these studies, Dr. Hatanaka and colleagues applied these compounds and radiation directly to surgically exposed tumors.
Over the next three decades, Hatanaka treated some 120 patients with brain tumors using a combination of surgery and BSH-mediated BNCT, according to the International Society for Neutron Capture Therapy. Post-treatment survival rates — more than five years in some cases — continued to astonish peers.
An ecosystem of innovators
Among Dr. Hatanaka’s most enduring accomplishments was helping to create the academic, government and industry collaborations needed to ignite Japan’s BNCT ecosystem.
BNCT is an interdisciplinary method that combines several scientific fields, including biology, chemistry, radiation oncology, surgery, pharmacology and physical engineering — fields that don’t often intersect.
But again, Dr. Hatanaka was unphased by the challenge of bringing experts from different fields together. “The complexity of the tasks requiring the expertise of the usually unrelated fields of nuclear physics, the little-known chemistry of boron … the special problems of pharmacokinetics of the normal vs. neoplastic brain tissue, and finally, the problems peculiar to surgery of the brain did not prevent Hiroshi from seeking collaborators in all of these relatively unrelated fields,” Dr. Sweet wrote in his dedication.
By the late 1980s, other Japanese doctors were also advancing BNCT. In 1987, Dr. Yutaka Mishima, a professor of dermatology at Kobe University Medical School, reported that p-boronophenylalanine (BPA), an amino acid derivative of boron, could be used to treat malignant melanoma.
Then, in 2001, Dr. Koji Ono and colleagues at the Kyoto University Research Reactor Institute reported the first successful application of BNCT to treat head and neck cancer after standard therapies had failed. In a 2018 interview, Dr. Ono conceded that even he was amazed by the results. “The patient was a middle-aged woman, and she had a big tumor in her face … She was suffering from the pain and continuous bloody exudate from the lesion,” he recalled.
“After applying BNCT, two or three days later, I visited her at the hospital. I was very surprised because she was not suffering from any pain after the treatment. One month later, I applied the BNCT on her again, and finally, such a huge size tumor completely disappeared.”
Emulating Japan’s success
There are currently 33 boron neutron capture therapy facilities in the world, with 21 being hospital-based systems, according to the International Atomic Energy Agency. Nearly a third are in Japan. Other countries that have invested in BNCT include China, with five centers, Argentina with three centers, and Russia, South Korea and the United Kingdom, each with two.
Dr. Mitsunori Kirihata, director of the BNCT research center at Osaka Prefecture University, says establishing Japan’s BNCT ecosystem required solving two bottlenecks in the therapy’s clinical application.
The first bottleneck related to boron. To test and deliver BNCT treatments, doctors need a steady supply of boron-10, which requires specialized enrichment. Early on in Japan’s BNCT research, the isotope was imported from the U.S. a few grams at a time. But in the late 1990s, Kirihata had a chance encounter with an employee at Stella Chemifa, a chemical manufacturer based outside Tokyo that was enriching boron-10 “by the ton” as a neutron absorber for nuclear power generation. The proximity of a reliable boron source supercharged research in Kirihata’s lab and beyond.
The second bottleneck was the neutron source. Transporting patients to large nuclear reactors wasn’t feasible or scalable, and hospital-based solutions were needed. The first accelerator-based neutron source for BNCT research, the C-BENS facility in Kyoto, was built in 2010. A decade later, Sumitomo Heavy Industries, in partnership with Kyoto University, received approval from the Japanese Pharmaceuticals and Medical Devices Agency to start routine BNCT for head and neck cancer using a cyclotron accelerator.
Around this time, Aviko’s partner Neutron Therapeutics entered the Japanese market with an agreement to install an accelerator-based neutron source at Shonan Kamakura General Hospital and successfully generated a neutron beam at that facility in 2023.
The geographic concentration of industrial and academic prowess combined with government support — a combination Dr. Kirihata credits to “heavenly timing” — has enabled BNCT in Japan to flourish.
Similar efforts are underway to return BNCT’s clinical capacities to its conceptual and clinical birthplace in the U.S. In collaboration with Leo Cancer Care and Neutron Therapeutics, Aviko is working with partners across government, industry and academia to build a BNCT ecosystem in the United States.
“Early innovators like Sweet, Soloway, and Hatanaka saw the potential of BNCT,” said Noah Smick, Neutron Therapeutics’ president and chief operating officer. “We see it, too, and we’re committed to ensuring that patients everywhere can access this revolutionary cancer treatment.”
This post is the second in our series on the history of BNCT and is authored by Michael Fiore, a veteran healthcare services executive who has focused for the last 40 years on physician and hospital joint ventures and multi-site operations. Michael has an interest in BNCT and how it can be used for patients with difficult to treat cancers. He was previously chairman, CEO and co-founder of Vantage Oncology, a developer and operator of multi-specialty oncology treatment centers and a cancer care management company, which was acquired by McKesson. Michael is a business advisor to Aviko Radiopharmaceuticals.
- Dr. Yutaka Mishima edited the book, Cancer Neutron Capture Therapy, in which this remembrance appears. Dr. Mishima is also listed as the author of the remembrance on the publication webpage. However, in the back matter of the book, available here, Dr. Sweet is credited as the author of the dedication to Dr. Hatanaka.