Boron Neutron Capture Therapy - A Literature Review

Boron Neutron Capture Therapy (BNCT) is a radiation science which is emerging as a hopeful tool in treating cancer, by selectively concentrating boron compounds in tumour cells and then subjecting the tumour cells to epithermal neutron beam radiation. BNCT bestows upon the nuclear reaction that occurs when Boron-10, a stable isotope, is irradiated with low-energy thermal neutrons to yield α particles (Helium-4) and recoiling lithium-7 nuclei. A large number of 10 Boron (10B) atoms have to be localized on or within neoplastic cells for BNCT to be effective, and an adequate number of thermal neutrons have to be absorbed by the 10B atoms to maintain a lethal 10B (n, α) lithium-7 reaction. The most exclusive property of BNCT is that it can deposit an immense dose gradient between the tumour cells and normal cells. BNCT integrates the fundamental focusing perception of chemotherapy and the gross anatomical localization proposition of traditional radiotherapy.

There is an increase in oral cancer burden day by day. The mainstream treatment modalities in treating cancer are surgery, chemotherapy and radiotherapy. Surgical annihilation is highly efficient in primary tumours, but it is limited to surgically sizeable and approachable tumours and thus cancer cells may not be wholely evacuated. Chemotherapy is the use of chemical drugs to fight cancer. The systemically administrated drugs circulate in the body to kill cells that divide rapidly, especially cancer cells. It commonly has significant side effects due to drug toxicity to normal cells and is subject to the development of resistance by the cancer cells. Radiation utilizes high energy ionization particles like X-rays, gamma rays or electrons, to damage cells at molecular level and is often used as an integral approach, to exterminate remaining cancer cells after surgery. But, it can cause destruction to the lively/healthy tissues neighbouring the cancer cells or in the lane of radiation beam.

Boron Neutron Capture Therapy (BNCT) is a technique that selectively aims to treat tumour cells sparring the normal cells using Boron compound. Gordon Locher was the first one to propose the principle of BNCT in 1936 and hypothesized that if boron could be selectively concentrated in a tumour mass and the volume then exposed to thermal neutrons, a higher radiation dose to the tumour relative to adjacent normal tissue would be produced [1].

BNCT depends on the following nuclear reaction [2]:

Non-radioactive isotope 10B atoms absorb low-energy (<0.5 eV) thermal neutrons and subsequently breaks up into an α particle (Helium-4) and a recoiled lithium nucleus (7 Li) [Table/Fig-1]. Resultant is the high Linear Energy Transfer (LET) alpha particle, ≈150 keV/μm, 7Li ion, ≈175 keV/μm [3].

[Table/Fig-1]:

Nuclear reaction.

10B + n→7Li + 4He

These particles provide high energy along their very brief pathway (<10μm), Hence, their energy deposition is limited to the diameter of a single cell. Thus, only neoplastic cells with 10B are ravaged following thermal neutron irradiation. Hypothetically, any normal cells abutting the cancer cells are saved from high LET irradiation by 4 He and 7 Li particles [Table/Fig-2].

[Table/Fig-2]:

How BNCT eliminates tumour cells.

Targeting is primarily achieved by precisely establishing the boron drugs in the tumour rather than by aiming the beam, which provides the explanation for the clinical application of the concept of BNCT.

BNCT integrates the fundamental focusing perception of chemo-therapy and the gross anatomical localization proposition of traditional radiotherapy. The unique outstanding feature of BNCT, is its ability to deposit an immense dose gradient between the tumour cells and normal cells [4]. This serves as the rationale for its clinical implementation in treating malignant cells, thus sparing normal healthy cells.

Historical Milestones in BNCT

The credit of discovery of neutron is attributed to Chadwick in 1932 [5]. Locher in 1936 proposed the principal behind the neutron capture reaction, thus the foundation for BNCT evolved from then [1]. The very first attempt of BNCT was performed in a patient diagnosed with Malignant Glioma in 1951, using the nuclear research reactor presently available in Brookhaven Graphite Research Reactor [6].

Followed by 3 series of treatment process using BNCT was carried out in 40 patients using simple boron compounds, but they were reported with serious side effects like radio-dermatoses of scalp and deep ulcerations [7]. Saltkin mentioned that the outcome of BNCT was similar to traditional radiotherapy, causing cerebral oedema and intractable shock in patients [8]. Sweet WH et al., in 1963 from the reactors of Massachusetts Institute of Technology treated 18 patients using Disodium decahydrodecarborate, which was considered to be less toxic, but was capable of delivering more boron compounds to the cell [9]. Asbury AK et al., noted severe brain necrosis in patients undergoing BNCT [10]. Keeping in mind the potential side effect and toxicity caused by BNCT and the potential harm of using nuclear reactors, USA halted the progress of BNCT in 1961.

Hiroshi Hatanaka in 1968 re-instigated clinical application of BNCT in Japan using Borocaptate Sodium (BSH) by directly exposing the beam to surgically exposed intracranial tumour bed and reported with impressive results of achieving 58% of 5 year survival rate [11–13]. Hatanaka and co-workers reconsidered and revamped the clinical application of BNCT in USA and Europe [3]. In 1987 Mishima from Japan applied BNCT for malignant melanoma using Boronophenylalanine (BPA) as boron compound, this chiselled the clinical implementation of BNCT in treating tumours outside the central nervous system [14]. Slowly and steadily the rebirth of BNCT took place, but was predominantly limited to countries having research reactor facilities capable of delivering epithermal neutron beam, which had better tissue penetration.

BNCT evolved through 60 years of research and clinical progress, but faced n-number of problems including lack of controlled, prospective trials, need of nuclear research reactors for clinical irradiation and disappointment regarding the evolution of ideal boron compounds. The re-emergence of BNCT took pace in the 1990s in USA at Brookhaven [15] and Cambridge, MA [16], then in Europe at Petten [17], in Finland [18], Sweden[19], the Czech Republic [20] and Japan [21,22], and finally in Argentina [23] and Taiwan [24].

Procedure of BNCT:

The procedure is illustrated in [Table/Fig-3].

[Table/Fig-3]:

Block diagram representing the procedure for BNCT.

Ideal Properties of Boron compounds: Low systemic toxicity, normal tissue uptake with high tumour uptake, high tumour/brain and tumour/blood concentration ratios (>3-4:1), tumour concentrations of 20-35mg10B/g tumour [25], rapid clearance from blood and normal tissues and persistence in tumour during BNCT.

There are three generation boron compounds presently and there has been a constant refinement in each generation of these boron delivery agents, so that these boron compounds achieve more selective targeting of the tumour cell and provide reasonably low toxicity in the living system.

a) 1^st Generation Boron Compounds: Boric acid and some of its derivatives were used as delivery agents in the clinical trials in 1950s and early 1960s. They were elementary chemical compounds, non-discriminatory, had meagre tumour retention, and obtained low tumour/brain ratios.

b) 2^nd Generation Boron Compounds: BPA and BSH were two other boron compounds that had emerged out in 1960s. These had significantly lesser toxicity, persisted longer in animal tumours compared with related molecules, and the tumour/brain as well as tumour/blood boron ratios were >1. These compounds are currently being used in many researches and clinical trials.

c) 3^rd Generation Boron Compounds: These are stable boron group or cluster connected via a hydrolytically stable linkage with a tumour targeting component or moiety (Boron Carriers). Low and high molecular weight biomolecules such as mitochondria, lysosomes, endoplasmic reticulum, golgi apparatus, nucleoside, sugars (BPA-fructose), porphyrins, liposome and monoclonal antibodies (mAb) have been used as the tumour targeting moiety. These 3^rd generation boron compounds tend to work more specifically towards the targeted tumour cell i.e., the tumour cell nucleus and DNA are alluring targets to these agents, also the amount of boron required to produce a lethal effect may be considerably reduced if it is localized within or near the nucleus. These agents are still under research process. BPA-fructose complex was used to treat patients with BNCT in 1994 for treating glioblastoma [26].

Upgradation in Boron Enhancements: There must be sufficient number of boron molecules embedded or incorporated into the tumour cells for their lysis. Thus, to enhance the uptake of boron compounds changes were brought about in the infusion route and rate, for instances in the infusion method intravenous, intra-arterial or direct infusion into the internal carotid artery [27] were tried. Combination of boron with other drugs like mannitol was done [28]. The most promising route that has evolved during the test of time is using tumour targeting moiety and nanoscale drug delivery using liposome and nanoparticles [3].

Neutron Source for BNCT: Neutrons for BNCT must not only be delivered with a high flow rate, but also should have the right amount of energy. The radiation beam which is directed into the tumour bed should have minimal contaminants. The neutron source for epithermal radiation is generated from Nuclear Reactors and Accelerator-Based Neutron Sources (ABNS). Most of these nuclear reactors have already been shut down, or at the verge of closure or have ceased their activities for BNCT trials, only a few are open. Thus, the ultimate hope of BNCT relies on ABNS, which was proposed two decades ago, for BNCT application. ABNS ranging from low-energy electrostatic machines to higher energy cyclotrons and much higher energy Linacs or synchrotrons have been used [3]. The neutron beam produced by ABNS has a low intensity flux compared to nuclear reactor sources, but there exists a possibility of delivering the neutron sources with the desired intensities by many accelerators. Moreover, ABNS is compact and less expensive compared to nuclear reactors. Radiotherapy departments in hospitals are quiet well experienced with accelerators for many years.

Development in Imaging: An important factor that is often marked as a drawback in BNCT is the heterogeneous boron distribution within the tumour, which causes ambiguity in the calculated dose distributions.

Positron Emission Tomography (PET) [29–31] is capable of quantifying boron uptake. In recent years to follow the pharmacological and chemical behaviour of the boron carrier using PET has become an additional stimulus for BNCT. Already 18F-BPA-PET scan images have been routinely used clinically to assess the distribution of boron molecules in patients by many investigators. In fact PET with 18F-labelled BPA is used for patient selection in Japan [32]. In Europe and Finland the use of 18F-BPA and PET was part of the inclusion criteria for BNCT patients [33].

The incidence and mortality rates of head and neck cancer are increasing day by day. Aggressive and combined local treatment including surgery and chemo-radiation has been applied to advanced head and neck cancer, but the prognosis for patients with recurrent disease is generally poor. BNCT is emerging as a hopeful tool in treating cancer, by selectively concentrating Boron compounds in tumour cells and then subjecting the tumour cells to epithermal neutron beam radiation which selectively destroys the tumour cells. The unique property of BNCT is that it can deposit a large dose gradient between the tumour cells and normal cells. During the earlier days failure of treatment with BNCT were primarily attributable to; (a) inadequate tumour specificity of boron used as capture agents; (b) insufficient tissue penetrating properties of the thermal neutron beams and (c) high blood boron concentrations that resulted in excessive damage to normal brain vasculature and to the scalp [34,35].

The concept of BNCT though had evolved in 1936, there has been a steady improvement in knowing and understanding the science behind it, working out with the clinical trials and putting it to clinical use. Though may be for now BNCT may not have gained its popularity, but definitely in near future BNCT will be a milestone in the field of radiotherapy for treating cancers.

[1]. Locher GL, Biological effects and therapeutic possibilities of neutrons Am J Roentgenol Radium Ther 1936 36(1):1-13.  [Google Scholar]

[2]. International Atomic Energy Agency. IAEA in Austria.2001. Available from: http://www-pub.iaea.org/MTCD/publications/PDF/te_1223_prn.pdf [Last Date of access-11/11/2016]  [Google Scholar]

[3]. Moss RL, Critical review, with an optimistic outlook, on Boron Neutron Capture [3] Therapy (BNCT) Appl Radiat Isotopes [Internet] 2014 Available from: http://dx.doi.org/10.1016/j.apradiso.2013.11.109 [Last Date of access-11/11/2016]  [Google Scholar]

[4]. Suzuki M, Kato I, Aihara T, Hiratsuka J, Yoshimura K, Niimi M, Boron neutron capture therapy outcomes for advanced or recurrent head and neck cancer Journal of Radiation Research 2014 55(1):146-53.  [Google Scholar]

[5]. Chadwick J, The existence of a neutron Proc R Soc Lond 1932 A136:692-708.  [Google Scholar]

[6]. Farr LE, Sweet WH, Locksley HB, Robertson JS, Neutron capture therapy of gliomas using boron-10 Trans Am Neurol Assoc 1954 79:110-13.  [Google Scholar]

[7]. Archambeau JO, The effect of increasing exposures of the 10B(n,a)7Li reaction on the skin of man Radiology 1970 94:178-87.  [Google Scholar]

[8]. Slatkin DN, A history of boron neutron capture therapy of brain tumours Brain 1991 114:1609-29.  [Google Scholar]

[9]. Sweet WH, Soloway AH, Brownell GL, Boron-slow neutron capture therapy of gliomas Acta Radiol Stockholm 1963 1:114-21.  [Google Scholar]

[10]. Asbury AK, Ojeman RG, Nielsen SL, Sweet WH, Neuropathological study of fourteen cases of malignant brain tumor treated by boron-10 slow neutron capture radiation J Neuropathol Exp Neurol 1972 31(2):278-303.  [Google Scholar]

[11]. Hatanaka H, Boron-neutron capture therapy for tumors. Preface In: Boron- Neutron capture therapy for tumors 1986 NiigataNishimura Co. Ltd.  [Google Scholar]

[12]. Hatanaka H, Clinical results of boron neutron capture therapy Basic Life Sci 1990 54(15):15-21.  [Google Scholar]

[13]. Hatanaka H, Sweet WH, Sano K, Ellis F, The present status of boron- neutron capture therapy for tumors Pure Appl Chem 1991 63(3):373-74.  [Google Scholar]

[14]. Mishima Y, Ichihashi M, Hatta S, Honda C, Yamamura K, Nakagawa T, First human clinical trial of melanoma neutron capture. Diagnosis and therapy Strahlenther Onkol 1989 165(2–3):251-54.  [Google Scholar]

[15]. Chanana AD, Capala J, Chadha M, Coderre JA, Diaz AZ, Elowitz EH, Boron neutron capture therapy for glio- blastoma multiforme: nterim results from the phase I/II dose-escalation studies Neurosurgery 1999 44(6):1182-93.  [Google Scholar]

[16]. Busse PM, Harling OK, Palmer MR, KigerIII W S, Kaplan J, Kaplan I, A critical examination of the results from the Harvard-MITNCT program phase I clinical trial of neutron capture therapy for intracranial disease J Neurooncol 2003 62(1–2):111-21.  [Google Scholar]

[17]. Sauerwein W, Zurlo A, The EORTC boron neutron capture therapy group: Achievements and future perspectives Eur J Cancer 2002 38(4):S31-34.  [Google Scholar]

[18]. Joensuu H, Kankaanranta L, Seppala T, Auterinen I, Kallio M, Kulvik M, Boron neutron capture therapy of brain tumors: Clinical trials at the Finnish facility using boronophe-nylalanine J Neurooncol 2003 62(1–2):123-34.  [Google Scholar]

[19]. Capala J, Stenstam BH, Sköld K, Rosenschold PM, Giusti V, Persson C, Boron neutron capture therapy for glioblastoma multiforme: Clinical studies in Sweden J Neurooncol 2003 62(1–2):135-44.  [Google Scholar]

[20]. Dbaly V, Tovarys F, Honova H, Petruzelka L, Prokes K, Burian J, Contemporary state of neutron capture therapy in Czech Republic (Part 2) Cesaslov Neurol Neurochir 2002 66-99(1):60-63.  [Google Scholar]

[21]. Nakagawa Y, Pooh K, Kobayashi T, Kageji T, Uyama S, Matsumura A, Clinical review of the Japanese experience with boron neutron capture therapy and a proposed strategy using epithermal neutron beams J Neurooncol 2003 62(1–2):87-99.  [Google Scholar]

[22]. Ono K, Ueda S, Oda Y, Nakagawa Y, Miyatake S, Osawa M, Boron neutron capture therapy for malignant glioma at Kyoto University reactor. In: Larsson B, Crawford J, Weinreich R. (Eds.) Advances in Neutron Capture Therapy 1997 vol.IAmsterdamElsevier Science:39-45.  [Google Scholar]

[23]. González SJ, Bonomi MR, Santa Cruz GA, Blaumann HR, Calzetta Larrieu OA, Menéndez P, First BNCT treatment of a skin melanoma in Argentina: Dosimetric analysis and clinical outcome Appl Radiat Isot 2004 61(5):1101-05.  [Google Scholar]

[24]. Liu YWH, Huang TT, Jiang SH, Liu HM, Renovation of epithermal neutron beam for BNCT at THOR Appl Radiat Isot 2004 61:1039-43.  [Google Scholar]

[25]. Barth RF, Soloway AH, Fairchild RG, Brugger RM, Boron neutron capture therapy for cancer, realities and prospects Cancer 1992 7:2995-3007.  [Google Scholar]

[26]. Diaz AZ, Assessment of the results from the phase I/II boron neutron capture therapy trials at the brookhaven national laboratory from a clinician’s point of view J Neurooncol 2003 62:101-09.  [Google Scholar]

[27]. Sköld K, Stenstam BH, Diaz AZ, Giusti V, Pellettieri L, Hopewell JW, Boron neutron capture therapy for glioblastoma multiforme: Advantage of prolonged infusion of BPA-f Acta Neurol Scand 2010 (122):58-62.  [Google Scholar]

[28]. Barth RF, Yang W, Rotaru JH, Moeschberger ML, Boesel CP, Soloway AH, Boron neutron capture therapy of brain tumors: Enhanced survival and cure following blood–brain barrier disruption and intracarotid injection of sodium borocaptate and boronophe-nylalanine Int J Radiat Oncol Biol Phys 2003 47:209-18.  [Google Scholar]

[29]. Kabalka GW, Smith GT, Dyke JP, Reid WS, Longford CP, Roberts TG, Evaluation of fluorine-18-BPA-fructose for boron neutron capture treatment planning J Nucl Med 1997 38:1762-67.  [Google Scholar]

[30]. Nariai T, Ishiwata K, Analysis and imaging: PET. In: Sauerwein WAG, Wittig A, Moss R, Nakagawa H. (Eds.) Neutron capture therapy: Principles and applications 2012 HeidelbergSpringer-Verlag  [Google Scholar]

[31]. Wittig A, Sauerwein WAG, In: Sauerwein WAG, Wittig A, Moss R, Nakagawa H. (Eds.) Neutron capture therapy: Principles and applications 2012 HeidelbergSpringer-Verlag  [Google Scholar]

[32]. Yamamoto T, Nakai K, Kageji T, Kumada H, Endo K, Matsuda M, Boron neutron capture therapy for newly diagnosed glioblastoma Radiother Oncol 2009 91(1):80-84.  [Google Scholar]

[33]. Kankaanranta L, Seppälä T, Koivunoro H, Saarilahti K, Atula T, Collan J, Boron neutron capture therapy in the treatment of locally recurred head-and-neck cancer: Final analysis of a phase I/II trial Int J Radiat Oncol Biol Phys 2012 (82):e67-75.  [Google Scholar]

[34]. Barth RF, Coderre JA, Vicente MG, Blue TE, Boron neutron capture therapy of cancer: Current status and future prospects Clin Cancer Res 2005 11:3987-4002.  [Google Scholar]

[35]. Barth RF, Graca M, Vicente H, Harling OK, Kiger WS, Riley KJ, Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer Radiat 2012 (7):146-67.  [Google Scholar]

[36]. Kankaanranta L, Kiovunoro H, Seppälä T, et al. 2008. Outcome of the first twelve patients with locally recurred inoperable head and neck cancer treated in the Finnish head and neck cancer BNCT trial. In: Proceedings of the13^th International Congress on Neutron Capture Therapy Florence, Italy, 2012; November2–7, pp. 21–25  [Google Scholar]

[37]. Fuwa N, Suzuki M, Sakurai Y, Nagata K, Kinashi Y, Masunaga S, Treatment results of boron neutron capture therapy using intra-arterial administration of boron compounds for recurrent head and neck cancer Br J Radiol 2008 (81):749-752.  [Google Scholar]

[38]. Kawabata S, Miyatake S, Nonoguchi N, Hiramatsu R, Iida K, Miyata S, Survival benefit from boron neutron capture therapy for the newly diagnosed glioblastoma patients Appl Radiat Isot 2009 67(7–8):S15-18.  [Google Scholar]

[39]. Kawabata S. Boron neutron capture therapy for the patients with malignant meningioma. In presented at the15^th international congresson neutron capture therapy, Tsukuba, Japan. September 10–14  [Google Scholar]

[40]. Kawabata S, Miyatake S, Boron neutron capture therapy for malignant meningiomas. In: Sauerwein WAG, Wittig A, Moss R, Nakagawa H.(Eds.) Neutron capture therapy: Principles and applications 2012 HeidelbergSpringer-Verlag  [Google Scholar]

[41]. Kankaanranta L, Saarilahti K, Makitie A, Valimaki P, Tenhunen M, Joensuu H, Boron neutron capture therapy (BNCT) followed by intensity modulated chemoradiotherapy as primary treatment of large head and neck cancer with intracranial involvement Radiother Oncol 2011 99:98-99.  [Google Scholar]

[42]. Kato I, Ono K, Sakurai Y, Ohmae M, Maruhashi A, Imahori Y, Effectiveness of BNCT for recurrent head and neck malignancies Applied Radiation and Isotopes 2004 61:1069-73.  [Google Scholar]

[43]. Haginomori S, Miyatake S, Inui T, Araki M, Kawabata S, Takamaki A, Planned fractionated boron neutron capture therapy for a patient with recurrent squamous cell carcinoma in the temporal bone: A case report Head Neck 2009 31:412-18.  [Google Scholar]

[44]. Yanagie H, Higashi S, Seguchi K, Ikushima I, Oyama K, Nonaka Y, et al. Pilot clinical study of boron neutron capture therapy for recurrent hepatic cancer and gastric cancer. In: Presented at the 15^th international congress on neutron capture therapy, Tsukuba, Japan, 2012. September 10–14  [Google Scholar]

[45]. Suzuki M et al. Reirradiation for locally recurrent lung cancer in the chest wall with boron neutron capture therapy (BNCT): A case report. In: Presented at the15^th international congress on neutron capture therapy. Tsukuba, Japan, 2012. September. 10–14  [Google Scholar]

[46]. Sasaoka S. The first clinical trial of boron neutron captures therapy using 10B-para-boronophenylalanine for treating extra-mammary Paget’s disease. In: Presented at the 15^th International Congress on Neutron Capture Therapy, Tsukuba, Japan, 2012.September, 10–14  [Google Scholar]