It is a two-step process: first, the patient is injected with a tumor-localizing drug containing the stable isotope boron-10 (10B), which has a high propensity to capture low energy "thermal" neutrons.

Locher, a scientist at the Franklin Institute in Philadelphia, Pennsylvania, recognized the therapeutic potential of this discovery and suggested that this specific type of neutron capture reaction could be used to treat cancer.

[8] Since then, clinical trials have been done in a number of countries including Japan, the United States, Sweden, Finland, the Czech Republic, Taiwan, and Argentina.

BNCT is based on the nuclear capture and decay reactions that occur when non-radioactive boron-10, which makes up approximately 20% of natural elemental boron, is irradiated with neutrons of the appropriate energy to yield excited boron-11 (11B*).

[9] The first, which has mainly been used in Japan, is a polyhedral borane anion, sodium borocaptate or BSH (Na2B12H11SH), and the second is a dihydroxyboryl derivative of phenylalanine, called boronophenylalanine or BPA.

Until 1994, low-energy (< 0.5 eV) thermal neutron beams were used in Japan[10] and the United States,[6][7] but since they have a limited depth of penetration in tissues, higher energy (> .5eV < 10 keV) epithermal neutron beams, which have a greater depth of penetration, were used in clinical trials in the United States,[11][12] Europe,[13][14] Japan,[15][16] Argentina, Taiwan, and China until recently when accelerators replaced the reactors.

Doses up to 60–70 grays (Gy) can be delivered to the tumor cells in one or two applications compared to 6–7 weeks for conventional fractionated external beam photon irradiation.

High-LET, heavier charged alpha particles (stripped down helium [4He] nuclei) and lithium-7 ions, released as products of the thermal neutron capture and decay reactions with 10B [10B(n,α)7Li].

However, the possibility of incorporating gadolinium into biologically active molecules is very limited and only a small number of potential delivery agents for Gd NCT have been evaluated.

The poor tissue-penetrating properties of the thermal neutron beams necessitated reflecting the skin and raising a bone flap in order to directly irradiate the exposed brain, a procedure first used by Sweet and his collaborators.

However, the survival data were no worse than those obtained by standard therapy at the time, and there were several patients who were long-term survivors, and most probably they were cured of their brain tumors.

Included in the research team were Otto Harling at MIT and the Radiation Oncologist Paul Busse at the Beth Israel Deaconess Medical Center in Boston.

[12] Shin-ichi Miyatake and Shinji Kawabata at Osaka Medical College in Japan[15][16] have carried out extensive clinical studies employing BPA (500 mg/kg) either alone or in combination with BSH (100 mg/kg), infused intravenously (i.v.)

[38] The clinical regimen consisted of intravenous administration of boronophenylalanine two hours before neutron irradiation at the Kyoto University Research Reactor Institute in Kumatori, Japan.

[40] The technological and physical aspects of the Finnish BNCT program have been described in considerable detail by Savolainen et al.[44] A team of clinicians led by Heikki Joensuu and Leena Kankaanranta and nuclear engineers led by Iro Auterinen and Hanna Koivunoro at the Helsinki University Central Hospital and VTT Technical Research Center of Finland have treated approximately 200+ patients with recurrent malignant gliomas (glioblastomas) and head and neck cancer who had undergone standard therapy, recurred, and subsequently received BNCT at the time of their recurrence using BPA as the boron delivery agent.

This was based on experimental animal studies in glioma bearing rats demonstrating enhanced uptake of BPA by infiltrating tumor cells following a 6-hour infusion.

If this improved survival data, obtained using the higher dose of BPA and a 6-hour infusion time, can be confirmed by others, preferably in a randomized clinical trial, it could represent a significant step forward in BNCT of brain tumors, especially if combined with a photon boost.

The single most important clinical advance over the past 15 years[52] has been the application of BNCT to treat patients with recurrent tumors of the head and neck region who had failed all other therapy.

A very heterogeneous group of patients with a variety of histopathologic types of tumors have been treated, the largest number of which had recurrent squamous cell carcinomas.

Kankaanranta et al. have reported their results in a prospective Phase I/II study of 30 patients with inoperable, locally recurrent squamous cell carcinomas of the head and neck region.

As previously indicated in the section on neutron sources, all clinical studies have ended in Finland, for variety of reasons including economic difficulties of the two companies directly involved, VTT and Boneca.

The original studies were carried out in Japan by the late Yutaka Mishima and his clinical team in the Department of Dermatology at Kobe University[55] using locally injected BPA and a thermal neutron beam.

It is important to point out that it was Mishima who first used BPA as a boron delivery agent, and this approach subsequently was extended to other types of tumors based on the experimental animal studies of Coderre et al. at the Brookhaven National Laboratory.

[58] The In-Hospital Neutron Irradiator (IHNI) in Beijing has been used to treat a small number of patients with cutaneous melanomas with a complete response of the primary lesion and no evidence of late radiation injury during a 24+-month follow-up period.

Finally, Yanagie and his colleagues at Meiji Pharmaceutical University in Japan have treated several patients with recurrent rectal cancer using BNCT.

Alphabeam 7Li(p,n)7Be Tandem Electrostatic Treatment of Recurrent Malignant Gliomas The single greatest advance in moving BNCT forward clinically has been the introduction of cyclotron-based neutron sources (c-BNS) in Japan.

[75] These patients ranged in age from 20 to 75 years, and all previously had received standard treatment consisting of surgery followed by chemotherapy with temozolomide (TMZ) and conventional radiation therapy.

They received an intravenous infusion of a proprietary formulation of 10B-enriched boronophenylalanine ("Borofalan," StellaPharma Corporation, Osaka, Japan) prior to neutron irradiation.

[75] As a result of this trial, the Sumitomo accelerator was approved by the Japanese regulatory authority having jurisdiction over medical devices, and further studies are being carried out with patients who have recurrent, high-grade (malignant) meningiomas.

[77] Based on this Phase II clinical trial, the authors suggested that BNCT using Borofalan and c-BENS was a promising treatment for recurrent head and neck cancers, although further studies would be required to firmly establish this.