This special collection, Guest Edited by Robert J. Gilliard (University of Virginia), Rosario Núñez (Institut de Ciència de Materials de Barcelona) and Caleb Martin (Baylor University), covers all areas of boron chemistry with an emphasis on synthesis and reactivity. This includes small molecules, boron clusters, frustrated Lewis pairs, borylation, catalysis, and ligand development.
Neutron capture therapy (NCT) is a type of radiotherapy for treating locally invasive malignant tumors such as primary brain tumors, recurrent cancers of the head and neck region, and cutaneous and extracutaneous melanomas. 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. The neutron cross section of 10B (3,837 barns) is 1,000 times more than that of other elements, such as nitrogen, hydrogen, or oxygen, that occur in tissue. In the second step, the patient is radiated with epithermal neutrons, the sources of which in the past have been nuclear reactors and now are accelerators that produce higher energy epithermal neutrons. After losing energy as they penetrate tissue, the resultant low energy "thermal" neutrons are captured by the 10B atoms. The resulting decay reaction yields high-energy alpha particles that kill the cancer cells that have taken up enough 10B.
All clinical experience with NCT to date is with boron-10; hence this method is known as boron neutron capture therapy (BNCT). Use of another non-radioactive isotope, such as gadolinium, has been limited to experimental animal studies and has not been done clinically. BNCT has been evaluated as an alternative to conventional radiation therapy for malignant brain tumors such as glioblastomas, which presently are incurable, and more recently, locally advanced recurrent cancers of the head and neck region and, much less often, superficial melanomas mainly involving the skin and genital region.
James Chadwick discovered the neutron in 1932. Shortly thereafter, H. J. Taylor reported that boron-10 nuclei had a high propensity to capture low energy "thermal" neutrons. This reaction causes nuclear decay of the boron-10 nuclei into helium-4 nuclei (alpha particles) and lithium-7 ions. In 1936, G.L. 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. William Sweet, a neurosurgeon at the Massachusetts General Hospital, first suggested the possibility of using BNCT to treat malignant brain tumors to evaluate BNCT for treatment of the most malignant of all brain tumors, glioblastoma multiforme (GBMs), using borax as the boron delivery agent in 1951. A clinical trial subsequently was initiated by Lee Farr using a specially constructed nuclear reactor at the Brookhaven National Laboratory in Long Island, New York, U.S.A. Another clinical trial was initiated in 1954 by Sweet at the Massachusetts General Hospital using the Research Reactor at the Massachusetts Institute of Technology (MIT) in Boston.
Biological weighting factors have been used in all of the more recent clinical trials in patients with high-grade gliomas, using boronophenylalanine (BPA) in combination with an epithermal neutron beam. The 10B(n,α)7Li part of the radiation dose to the scalp has been based on the measured boron concentration in the blood at the time of BNCT, assuming a blood: scalp boron concentration ratio of 1.5:1 and a compound biological effectiveness (CBE) factor for BPA in skin of 2.5. A relative biological effectiveness (RBE) or CBE factor of 3.2 has been used in all tissues for the high-LET components of the beam, such as alpha particles. The RBE factor is used to compare the biologic effectiveness of different types of ionizing radiation. The high-LET components include protons resulting from the capture reaction with normal tissue nitrogen, and recoil protons resulting from the collision of fast neutrons with hydrogen. It must be emphasized that the tissue distribution of the boron delivery agent in humans should be similar to that in the experimental animal model in order to use the experimentally derived values for estimation of the radiation doses for clinical radiations. For more detailed information relating to computational dosimetry and treatment planning, interested readers are referred to a comprehensive review on this subject.
aThe delivery agents are not listed in any order that indicates their potential usefulness for BNCT. None of these agents have been evaluated in any animals larger than mice and rats, except for boronated porphyrin (BOPP) that also has been evaluated in dogs. However, due to the severe toxicity of BOPP in canines, no further studies were carried out.bSee Barth, R.F., Mi, P., and Yang, W., Boron delivery agents for neutron capture therapy of cancer, Cancer Communications, 38:35 (doi: 10.1186/s40880-018-0299-7), 2018 for an updated review.cThe abbreviations used in this table are defined as follows: BNCT, boron neutron capture therapy; DNA, deoxyribonucleic acid; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; MoAbs, monoclonal antibodies; VEGF, vascular endothelial growth factor.
BNCT of patients with brain tumors was resumed in the United States in the mid-1990s by Chanana, Diaz, and Coderre and their co-workers at the Brookhaven National Laboratory using the Brookhaven Medical Research Reactor (BMRR) and at Harvard/Massachusetts Institute of Technology (MIT) using the MIT Research Reactor (MITR). For the first time, BPA was used as the boron delivery agent, and patients were irradiated with a collimated beam of higher energy epithermal neutrons, which had greater tissue-penetrating properties than thermal neutrons. A research group headed up by Zamenhof at the Beth Israel Deaconess Medical Center/Harvard Medical School and MIT was the first to use an epithermal neutron beam for clinical trials. Initially patients with cutaneous melanomas were treated and this was expanded to include patients with brain tumors, specifically melanoma metastatic to the brain and primary glioblastomas (GBMs). 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. A total of 22 patients were treated by the Harvard-MIT research group. Five patients with cutaneous melanomas were also treated using an epithermal neutron beam at the MIT research reactor (MITR-II) and subsequently patients with brain tumors were treated using a redesigned beam at the MIT reactor that possessed far superior characteristics to the original MITR-II beam and BPA as the capture agent. The clinical outcome of the cases treated at Harvard-MIT has been summarized by Busse. Although the treatment was well tolerated, there were no significant differences in the mean survival times (MSTs)of patients that had received BNCT compared to those who received conventional external beam X-irradiation.
Shin-ichi Miyatake and Shinji Kawabata at Osaka Medical College in Japan 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.) over 2 h, followed by neutron irradiation at Kyoto University Research Reactor Institute (KURRI). The Mean Survival Time (MST) of 10 patients with high grade gliomas in the first of their trials was 15.6 months, with one long-term survivor (>5 years). Based on experimental animal data, which showed that BNCT in combination with X-irradiation produced enhanced survival compared to BNCT alone, Miyatake and Kawabata combined BNCT, as described above, with an X-ray boost. A total dose of 20 to 30 Gy was administered, divided into 2 Gy daily fractions. The MST of this group of patients was 23.5 months and no significant toxicity was observed, other than hair loss (alopecia). However, a significant subset of these patients, a high proportion of which had small cell variant glioblastomas, developed cerebrospinal fluid dissemination of their tumors. Miyatake and his co-workers also have treated a cohort of 44 patients with recurrent high grade meningiomas (HGM) that were refractory to all other therapeutic approaches. The clinical regimen consisted of intravenous administration of boronophenylalanine two hours before neutron irradiation at the Kyoto University Research Reactor Institute in Kumatori, Japan. Effectiveness was determined using radiographic evidence of tumor shrinkage, overall survival (OS) after initial diagnosis, OS after BNCT, and radiographic patterns associated with treatment failure. The median OS after BNCT was 29.6 months and 98.4 months after diagnosis. Better responses were seen in patients with lower grade tumors. In 35 of 36 patients, there was tumor shrinkage, and the median progression-free survival (PFS) was 13.7 months. There was good local control of the patients' tumors, as evidenced by the fact that only 22.2% of them experienced local recurrence of their tumors. From these results, it was concluded that BNCT was effective in locally controlling tumor growth, shrinking tumors, and improving survival with acceptable safety in patients with therapeutically refractory HGMs.
The technological and physical aspects of the Finnish BNCT program have been described in considerable detail by Savolainen et al. 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. The median time to progression in patients with gliomas was 3 months, and the overall MeST was 7 months. It is difficult to compare these results with other reported results in patients with recurrent malignant gliomas, but they are a starting point for future studies using BNCT as salvage therapy in patients with recurrent tumors. Due to a variety of reasons, including financial, no further studies have been carried out at this facility, which has been decommissioned. However, a new facility for BNCT treatment has been installed using an accelerator designed and fabricated by Neutron Therapeutics. This accelerator was specifically designed to be used in a hospital, and the BNCT treatment and clinical studies will be carried out there after dosimetric studies have been completed in 2021. Both Finnish and foreign patients are expected to be treated at the facility. 2b1af7f3a8