From concept to clinic: past and present of boron neutron capture therapy


An illustration that features Dr. William Herbert Sweet, a pioneer of BNCT, and a lily, which was surprisingly and inspiration for BNCT
The idea to use boron to treat cancer came to BNCT pioneer Dr. William Herbert Sweet (pictured) from an unlikely source — a study about the effects of radiation on lily bulbs

The concept of boron neutron capture therapy was conceived in the early 20th century as a method for treating solid tumors. Over the past nearly 100 years, research and clinical development in boron neutron capture therapy, or BNCT as it’s known, has been marked by steady progress in the U.S. and in many other countries, particularly in Japan.

But it is only recently that we have seen a convergence of advanced science and technology that has the potential to make this promising modality widely available to patients in need.

Early ideas

Using neutrons to kill cancer cells was first conceived in the 1930s by American astrophysicist Gordon Locher. In an article titled “Biological Effects and Therapeutic Possibilities of Neutrons,” published in 1936 in The American Journal of Roentgenology and Radium Therapy, Locher hypothesized that the interaction between neutrons released from radium and captured by beryllium could be used as a form of cancer treatment.

“The facility with which neutron pass through matter, and penetrate and disrupt atomic nuclei, of which they are now believed to be fundamental constituents, give them an importance in some fields of atomic physics which is not equaled by alpha, beta or gamma rays,” Locher wrote. “This naturally reflects on the various fields of biological applications of corpuscular and quantum radiations.”

It wasn’t until nearly two decades later, however, that the concept was taken further, this time by Dr. William Herbert Sweet, a neurosurgeon at Massachusetts General Hospital, with boron added to the equation.

In an interview with the American Association of Neurological Surgeons, Dr. Sweet recounts how he came up with the idea that boron might have the right characteristics for use in combination with neutrons. His idea came from an unlikely place — a study he read about the effects of radiation on lily bulbs.

“One day I came across an article pointing out that all of the radiation injury in a lily bulb that ensues when it’s bombarded with slow neutrons is because of the trace amounts of boron in the lily bulb,” Dr. Sweet said. “I said, by gosh, that’s what we’re after. We’re after something that converts an innocuous substance into a lethal substance.”

Dr. William Herbert Sweet discusses how he came up with the idea that alpha particles released from boron could be used to kill cancer cells.

Into the clinic

In 1951, Dr. Sweet and physicist Gordon Lee Brownell of MIT conducted the first clinical trial of boron neutron capture therapy for patients with brain tumors at Brookhaven National Laboratory using a reactor. Additional experiments were conducted later in the 1950s, but the lack of suitable boron delivery agents, and the difficulty of generating neutrons safely, limited the effectiveness and practicality of BNCT.

A portrait of Dr. Hiroshi Hatanaka wearing a suit and tie
Dr. Hiroshi Hatanaka (source)

In the late 1960s, interest in BNCT shifted from the U.S. to Japan. Dr. Hiroshi Hatanaka, who studied with Dr. Sweet at Mass General, began a clinical program on BNCT in Japan after returning home, according to a review article published in 2022 by Dr. Will H. Jin of the Department of Radiation Oncology, Jackson Memorial / Sylvester Comprehensive Care Center, University of Miami Health Systems.

Dr. Hatanaka remained the prime champion of BNCT for years. There were few significant advancements in the field until the early 1990s. Clinical studies Dr. Hatanaka led demonstrated extremely promising results using what are known as “second-generation boron compounds,” which exhibited greater tumor selectivity compared to first-generation compounds that were used in the earliest clinical trials.

Dr. Hatanaka’s and his colleagues’ studies showed benefits for patients with astrocytoma and glioblastoma, forms of brain cancers, reporting a median survival of 21.3 months. At the time of Dr. Jin’s review, the current standard of care resulted in a median survival of 14.6 months.

These impressive results were likely due to the improved pharmacokinetics of the drug, sodium borocaptate. This drug exhibited “tumor to normal brain ratio was as high as 40 to 1,” Dr. Jin notes. Yet while these initial results were promising in terms of selective tumor destruction, there were still challenges with targeting the boron compound and with side effects from radiation.

Dr. Hatanaka continued to study BNCT until his death in 1994.

First approval and recent innovations

In the past few decades, interest in BNCT has grown internationally, with countries like Finland, China, Italy, Israel and Argentina developing their own BNCT programs and constructing research reactors or other neutron sources specifically designed for BNCT.

In 2020, Steboronine, developed by Stella Pharmaceuticals, was approved in Japan for the treatment of unresectable locally advanced or locally recurrent head and neck cancer, marking the first drug approval for BNCT.

Accelerator technology has advanced considerably in the past decade as well, including innovations by our partner Neutron Therapeutics with their nuBeam® system, which has made it possible to produce the required neutron flux with the use of particle accelerators instead of nuclear reactors, facilitating wider adoption of BNCT in hospitals and research institutions.

Indeed, the International Atomic Energy Agency recently noted in an in-depth report on BNCT published earlier this year that the development of this new class of neutron accelerators has increased interest in the modality around the world.

New boron delivery agents are also being developed, such as boronated biologics that are designed to increase the uptake of boron into tumor cells. Efforts are being made to standardize treatment protocols and to conduct larger international clinical trials to assess the efficacy and safety of BNCT for various types of cancers.

The history of BNCT reflects a gradual progression of scientific understanding, improvements in technology and a commitment to overcoming the clinical challenges associated with this complex form of cancer therapy.

We believe BNCT has reached an inflection point due to the tireless commitment to innovation and care that researchers and physicians have brought to their work. Looking back on the history of the modality, we are honored to build on our predecessors’ discoveries and hope to continue their legacy.