Neutron capture therapy of cancer
Neutron Capture Therapy (NCT) is a noninvasive therapeutic modality for treating locally invasive malignant tumors such as primary brain tumors and recurrent head and neck cancer. It is a two step procedure: first, the patient is injected with a tumor localizing drug containing a non-radioactive isotope that has a high propensity or cross section (σ) to capture slow neutrons. The cross section of the capture agent is many times greater than that of the other elements present in tissues such as hydrogen, oxygen and nitrogen. In the second step, the patient is radiated with epithermal neutrons, which after losing energy as they penetrate tissue, are absorbed by the capture agent which subsequently emits high-energy charged particles, thereby resulting in a biologically destructive nuclear reaction (Fig.1).
All of the clinical experience to date with NCT is with the non-radioactive isotope boron-10, and this is known as Boron Neutron Capture Therapy (BNCT). At this time, the use of other non-radioactive isotopes, such as gadolinium, has been limited, and to date, it has not been used clinically. BNCT has been evaluated clinically as an alternative to conventional radiation therapy for the treatment of malignant brain tumors (gliomas), and more recently, recurrent, locally advanced head and neck cancer.
- 1 Boron neutron capture therapy
- 2 Basic Principles
- 3 Radiobiological considerations
- 4 Clinical dosimetry
- 5 Boron delivery agents
- 6 Gadolinium neutron capture therapy (Gd NCT)
- 7 Neutron sources
- 8 Clinical studies of BNCT for brain tumors
- 9 Clinical Studies of BNCT for extracranial tumors
- 10 Conclusions
- 11 See also
- 12 References
- 13 External links
Boron neutron capture therapy
After the initial discovery of the neutron in 1932 by Sir James Chadwick, H. J. Taylor in 1935 showed that boron-10 nuclei could capture thermal neutrons. Neutron capture resulted in fission of the boron-11 nuclei into helium-4 (alpha particles) and lithium-7 ions. In 1936, G.L. Locher, a scientist at the Franklin Institute in Pennsylvania, realized the therapeutic potential of this discovery and suggested that neutron capture could be used to treat cancer. W. H. Sweet first suggested the technique for the most malignant brain tumors in 1951, and a trial of the therapy against glioblastoma multiforme using borax as the boronating agent was reported first in a collaboration between Brookhaven National Laboratory and Massachusetts General Hospital in 1954.
In neutron capture therapy, a binary system uses two separate components for a therapeutic effect. Each component in itself is non-tumoricidal, but when combined together they produce highly lethal effect. As development on neutron capture therapy continued, radioactive isotopes such as uranium-235 were investigated. However, studies in the late 1950s by Lussenhop et al. showed that the amounts of uranium needed for successful neutron capture therapy was too toxic for human use.
Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which makes up approx 20% of natural elemental boron, is irradiated with neutrons of the appropriate energy to yield high energy alpha particles ("stripped" down 4He nuclei) and high energy lithium-7 (7Li) nuclei. The nuclear reaction is:
- 10B + nth → [11B] → α + 7Li + 2.31 MeV.
Both the alpha particles and the lithium ions produce closely spaced ionizations in the immediate vicinity of the reaction, with a range of approximately 5-9 µm, or approximately the diameter of one cell. Their lethality is limited to boron containing cells. BNCT, therefore, can be regarded as both a biologically and a physically targeted type of radiation therapy. The success of BNCT is dependent upon the selective delivery of sufficient amounts of 10B to the tumor with only small amounts localized in the surrounding normal tissues. Thus, normal tissues, if they have not taken up boron-10, can be spared from the nuclear capture and fission reactions. Normal tissue tolerance is determined by the nuclear capture reactions that occur with normal tissue hydrogen and nitrogen.
A wide variety of boron delivery agents have been synthesized, but only two of these currently are being used in clinical trials. The first, which has been used primarily in Japan, is a polyhedral borane anion, sodium borocaptate or BSH (Na2B12H11SH), and the second is a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or BPA. The latter has been used in clinical trials in the United States, Europe, Japan and more recently, Argentina and Taiwan. Following administration of either BPA or BSH by intravenous infusion, the tumor site is irradiated with neutrons, the source of which has been specially modified nuclear reactors. Up to 1994, low-energy (< 0.5 eV) thermal neutron beams were used primarily in Japan, 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, have been used in clinical trials in the United States, Europe, and Japan.
In theory BNCT is a highly selective type of radiation therapy that can selectively target the tumor at the cellular level without causing radiation damage to the adjacent normal cells and tissues. Doses up to 60–70 Gy can be delivered to the tumor cells in one or two applications compared to 6–7 weeks for conventional external beam photon irradiation. However, the effectiveness of BNCT is dependent upon a relatively homogeneous distribution of 10B within the tumor, and this is still one of the key stumbling blocks that have limited its success.
The radiation doses delivered to tumor and normal tissues during BNCT are due to energy deposition from three types of directly ionizing radiation that differ in their linear energy transfer (LET), which is the rate of energy loss along the path of an ionizing particle: 1. low LET gamma rays, resulting primarily from the capture of thermal neutrons by normal tissue hydrogen atoms [1H(n,γ)2H]; 2. high LET protons, produced by the scattering of fast neutrons and from the capture of thermal neutrons by nitrogen atoms [14N(n,p)14C]; and 3. high LET, heavier charged alpha particles(stripped down 4He nuclei) and lithium-7 ions, released as products of the thermal neutron capture and fission reactions with 10B [10B(n,α)7Li]. Since both tumor and surrounding normal tissues are present in the radiation field, even with an ideal epithermal neutron beam, there will be an unavoidable, nonspecific background dose, consisting of both high and low LET radiation. However, a higher concentration of 10B in the tumor will result in it receiving a higher total dose than that of adjacent normal tissues, which is the basis for the therapeutic gain in BNCT. The total radiation dose (Gy) delivered to any tissue can be expressed in photon-equivalent units as the sum of each of the high LET dose components multiplied by weighting factors (Gyw), which depend on the increased radiobiological effectiveness of each of these components.
Biological weighting factors have been used in all of the recent clinical trials in patients with high grade gliomas, using boronophenylalanine (BPA) in combination with an epithermal neutron beam. The 10B(n,α)7Li component 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) 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 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 "Gray" (Gy) 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.
Boron delivery agents
The development of boron delivery agents for BNCT began approximately 50 years ago and is an ongoing and difficult task of high priority. A number of boronated pharmaceuticals using boron-10, have been prepared for potential use in BNCT. The most important requirements for a successful boron delivery agent are: 1. low systemic toxicity and normal tissue uptake with high tumor uptake and concomitantly high tumor: to brain (T:Br) and tumor: to blood (T:Bl) concentration ratios (> 3-4:1); 2. tumor concentrations in the range of ~20 µg 10B/g tumor; 3. rapid clearance from blood and normal tissues and persistence in tumor during BNCT. However, it should be noted that at this time no single boron delivery agent fulfills all of these criteria. With the development of new chemical synthetic techniques and increased knowledge of the biological and biochemical requirements needed for an effective agent and their modes of delivery, a number of promising new boron agents has emerged (see examples in Table 1).
|*Boronophenylalanine ("BPA")||*Sodium borocaptate ("BSH")|
|Dodecaborate cluster lipids and cholesterol derivatives||Carboranyl nucleosides|
|"GB10" (Na2B10H10)||Carboranyl porphyrins|
|Cholesteryl ester mimics||Boronated EGF and anti-EGFR mAbs|
|Boronated DNA metallo-intercalators||Boron-containing nanoparticles|
|Transferrin–polyethylene glycol (TF–PEG) liposomes||Carboranyl porphrazines|
|Unnatural amino acids||Boronated cyclic peptides|
|Dodecahyrdo-closo-dodecaborate clusters||Boron carbide particles|
*These are the only two boron delivery agents that have been used clinically.
The major challenge in their development has been the requirement for selective tumor targeting in order to achieve boron concentrations sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. The selective destruction of brain tumor (glioma) cells in the presence of normal cells represents an even greater challenge compared to malignancies at other sites in the body, since malignant gliomas are highly infiltrative of normal brain, histologically complex and heterogeneous in their cellular composition. In principle, NCT is a radiation therapy that could selectively deliver lethal doses of radiation to tumor cells while sparing adjacent normal cells.
Gadolinium neutron capture therapy (Gd NCT)
There also has been interest in the possible use of gadolinium-157 (157Gd) as a capture agent for NCT for the following reasons: First, and foremost, has been its very high neutron capture cross section of 254,000 barns. Second, gadolinium compounds, such as Gd-DTPA (gadopentetate dimeglumine Magnevist®), have been used routinely as contrast agents for magnetic resonance imaging (MRI) of brain tumors and have shown high uptake by brain tumor cells in tissue culture (in vitro). Third, gamma rays and internal conversion and Auger electrons are products of the 157Gd (n,γ)158Gd capture reaction (157Gd + nth (0.025eV) → [158Gd] → 158Gd + γ + 7.94 MeV).
Although the gamma rays have long pathlengths, orders of magnitude greater depths of penetration compared with the other radiations, the other radiation products (internal conversion and Auger electrons) have pathlengths of approximately one cell diameter and can directly cause DNA damage. Therefore, it would be highly advantageous for the production of DNA damage if the 157Gd were localized within the cell nucleus. 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 studied.
The gadolinium studies in cells and animals may be compared to the relatively large number of boron containing compounds (Table 1) have been synthesized and evaluated in vitro and in experimental animals (in vivo). Although in vitro activity has been demonstrated using the Gd-containing MRI contrast agent Magnevist® as the Gd delivery agent, there are very few studies demonstrating the efficacy of Gd NCT in experimental animal tumor models, and Gd NCT has to date never been used clinically (i.e., in humans).
Neutron sources for NCT have been limited to nuclear reactors and in the present section we only will summarize information that is described in more detail in a recently published review. Reactor derived neutrons are classified according to their energies as thermal (En <0.5 eV), epithermal (0.5 eV <En <10 keV) or fast (En >10 keV). Thermal neutrons are the most important for BNCT since they usually initiate the 10B(n,α)7Li capture reaction. However, because they have a limited depth of penetration, epithermal neutrons, which lose energy and fall into the thermal range as they penetrate tissues, are now preferred for clinical therapy.
A number of reactors with very good neutron beam quality have been developed and used clinically. These include:
- Kyoto University Research Reactor (KURR) in Kumatori, Japan;
- the RA-6 CNEA reactor in Bariloche, Argentina, the High Flux Reactor (HFR) at Petten in the Netherlands and the Massachusetts Institute of Technology Research Reactor (MITR).
- the FiR1 (Triga Mk II) research reactor at VTT Technical Research Centre, Espoo, Finland.
The neutron irradiation facility at the MITR currently represent the state of the art in epithermal beams for NCT with the capability of completing a radiation field in 10–15 minutes with close to the theoretically maximum ratio of tumor to normal tissue dose. Unfortunately, however, no clinical studies currently are being carried out at the HFR, MITR and the BMRR. The operation of the BNCT facility at the Finnish FiR1 research reactor (Triga Mk II), treating patients since 1999, was terminated in 2012 due to the BNCT operating company's bankruptcy. A new operator for the BNCT facility has not emerged, and consequently the owner of FiR1 (VTT Technical Research Centre of Finland) is planning to decommission the reactor in 2015.
Finally, a low power "in-hospital" compact nuclear reactor has been designed and built in Beijing, China, and it has been undergoing performance evaluation over the past several years, but it is uncertain when and if it could ever be used for clinical BNCT.
Accelerators also can be used to produce epithermal neutrons and accelerator-based neutron sources(ABNS) are being developed in a number of countries. Interested readers are referred to the recently published Proceedings of the 14th International Congress on Neutron Capture Therapy for information on this subject. For ABNSs, one of the more promising nuclear reactions involves bombarding a 7Li target with high energy protons. An experimental BNCT facility, using a thick lithium solid target, has been in use since the early 1990s at the University of Birmingham in the UK. This facility makes use of a high current Dynamitron accelerator originally supplied by Radiation Dynamics.
Recently, a prototypic Cyclotron-Based Neutron Source (C-BENS) has been developed by Sumitomo Heavy Industries in Japan. It has been installed at KURRI and should be ready for clinical use in 2013. A second one has been constructed by Mitsubishi Heavy Industries for use at Tsukuba University in Japan, and similarly should be ready for clinical use in 2013. A third one is being built by Hitachi for use in Tokyo. Finally, a fourth one is under construction by Mitsubishi Heavy Industries Mechatoronic Systems/Sumitomo Corporation. This one will have a liquid lithium-7 target, designed by Osaka University, and it will be evaluated by a consortium of institutions, including Osaka University, as a demonstration project.
Once clinical trials have been initiated, it will be important to determine how these ABNS compare to BNCT that has been carried out in the past using nuclear reactors as the neutron source.
Clinical studies of BNCT for brain tumors
Early studies in the U.S.A. and Japan
It was not until the 1950s that the first clinical trials were initiated by Farr at the Brookhaven National Laboratory (BNL) in New York and by Sweet and Brownell at the Massachusetts General Hospital (MGH) using the Massachusetts Institute of Technology (MIT) nuclear reactor (MITR) and several different low molecular weight boron compounds (such as borate) as the boron containing drug. However, the results of these studies were disappointing, and no further clinical trials were carried out in the United States, until the 1990s.
Following a two-year fellowship in Sweet's laboratory, clinical studies were started by Hiroshi Hatanaka in Japan in 1967. He used a low energy thermal neutron beam, which has low tissue penetrating properties and sodium borocaptate (BSH). This had been developed as a boron delivery agent by Albert Soloway at the MGH. In Hatanaka’s procedure, as much of the tumor was surgically removed as possible ("debulking"), and at some time thereafter, sodium borocaptate (BSH) was administered by a slow infusion, usually intra-arterially, but later intravenously. Twelve to 14 hours later, BNCT was carried out at one or another of several different nuclear reactors using low energy thermal neutron beams. The less 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.
Approximately 200+ patients were treated by Hatanaka, and subsequently by his associate, Nakagawa. Due to the heterogeneity of the patient population, in terms of the microscopic diagnosis of the tumor ("grade"), and its size, and the age and the ability of the patient to carry out normal daily activities ("performance status"), it was not really possible to come up with definitive conclusions about therapeutic efficacy, as measured by a prolongation in the mean survival time (MST). 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.
More recent clinical studies in the U.S.A. and Japan
BNCT of patients with brain tumors and a few with cutaneous melanoma was resumed in the United States in the mid-1990s at the Brookhaven National Laboratory 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. This was well tolerated, but there were no significant differences in the MSTs compared to patients that had received conventional therapy.
In Japan, Miyatake and Kawabata have initiated several protocols employing the combination of BPA (500 mg/kg) and BSH (100 mg/kg), infused i.v. over 2 hrs, followed by neutron irradiation at Kyoto University Research Reactor Institute(KURRI). The MST of 10 patients 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). These results suggest that the combination of BNCT with X-irradiation deserves further evaluation in a larger group of patients. In another Japanese trial, carried out by Yamamoto et al., BPA and BSH were infused over 1 hr, followed by BNCT at the Japan Research Reactor (JRR)-4 reactor. Patients subsequently received an X-ray boost after completion of BNCT. The overall median survival time (MeST) was 27.1 months, and the 1 year and 2 year survival rates were 87.5 and 62.5%, respectively. Based on the reports of Miyatake, Kawabata, and Yamamoto, it appears that combining BNCT with an X-ray boost can produce a significant therapeutic gain. Further studies are needed to optimize this combined therapy, and to evaluate it using a larger patient population.
Clinical studies in Finland
The team of clinicians and physicists at the Helsinki University Central Hospital and VTT Technical Research Center of Finland have treated a large number of patients with 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 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. Over 100 patients with recurrent head and neck cancers and brain tumors have been treated in Finland with BNCT using the Otaniemi nuclear reactor which, as previously indicated, has been closed down.
|Reactor Facility*||No. of patients & duration of trial||Delivery agent||Median survival time (months)||Reference no.|
|BMRR, U.S.A||53 (1994–1999)||BPA 250–330 mg/kg||12.8|||
|MITR, MIT, U.S.A.||20 (1996–1999)||BPA 250 or 350 mg/kg||11.1|||
|KURRI, Japan||40 (1998-2008)||BPA 500 mg/kg||23.5 (primary + X-ray)|||
|JRR4, Japan||15 (1998-2007)||BPA 250 mg/kg + BSH 5 g||10.8 (recurrent), 27.1 (+ X-ray)|||
|R2-0, Studsvik Medical AB, Sweden||30 (2001–2007)||BPA 900 mg/kg||17.7 (primary)|||
|FiR1, Finland||50 (1999-2012)||BPA 290–400 mg/kg||11.0 - 21.9 (primary), 7.0 (recurrent)|||
|HFR, Netherlands||26 (1997–2002)||BSH 100 mg/kg||10.4 - 13.2|||
|* A more comprehensive compilation of data relating to BNCT clinical trials can be found in Radiation Oncology 7:146-167, 2012|
Clinical studies in Sweden
Finally, to conclude this section, the following is a brief summary of a clinical trial that was carried out in Sweden using BPA and an epithermal neutron beam, which had greater tissue penetration properties than the thermal beams originally used in Japan. This study differed significantly from all previous clinical trials in that the total amount of BPA administered was increased (900 mg/kg), and it was infused i.v. over 6 hours. The longer infusion time of the drug was well tolerated by the 30 patients who were enrolled in this study. All were treated with 2 fields, and the average whole brain dose was 3.2-6.1 Gy (weighted), and the minimum dose to the tumor ranged from 15.4 to 54.3 Gy (w). There has been some disagreement among the Swedish investigators who carried out this study in terms of evaluation of the results. Based on incomplete survival data, the MeST was reported as 14.2 months and the time to tumor progression was 5.8 months. Another group had the complete survival data and concluded that the MeST was 17.7 months compared to 15.5 months that has been reported for patients who received standard therapy of surgery, followed by radiotherapy (RT) and the drug temozolomide (TMZ). Furthermore, the frequency of adverse events were lower after BNCT (14%) than after RT alone (21%) and both of these were lower than those seen following RT in combination with TMZ. 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.
Clinical Studies of BNCT for extracranial tumors
Head and neck cancers
The single most important clinical advance over the past 8 years in BNCT has been the application of BNCT to treat patients with recurrent tumors of the head and neck region who had failed all other therapy. These studies were first initiated by Kato et al. and subsequently followed by several other groups in Japan and by Kankaanranta and her co-workers in Finland. All of these studies employed BPA as the boron delivery agent, either alone or in combination with BSH. 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. Kato et al. have reported on a series of 26 patients with far-advanced cancer for whom there were no further treatment options. Either BPA + BSH or BPA alone were administered by a 1 or 2 hr intravenous (i.v.) infusion, and this was followed by BNCT using an epithermal beam. In this series, there were complete regressions in 12 cases, 10 partial regressions, and progression in 3 cases. The MST was 13.6 months, and the 6-year survival was 24%. Significant treatment related complications ("adverse" events) included brain necrosis, osteomyelitis, transient mucositis, and alopecia.
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. Patients received either two or, in a few cases, one BNCT treatment using BPA (400 mg/kg), administered i.v. over 2 hours, followed by neutron irradiation. Of 29 evaluated patients, there were 13 complete and 9 partial remissions, with an overall response rate of 76%. The most common adverse event was oral mucositis, oral pain, and fatigue. Based on the clinical results, it was concluded that BNCT was effective for the treatment of inoperable, previously irradiated patients with head and neck cancer. Some responses were durable but progression was common, usually at the site of the previously recurrent tumor. As indicated in the section on neutron sources, all clinical studies have ended in Finland, based on economic difficulties of the two companies directly involved, VTT and Boneca.
Other types of tumors
Other extracranial tumors that have been treated include malignant melanomas which was carried out in Japan by Yutaka Mishima and his clinical team using BPA and a thermal neutron beam. Local control was achieved in almost all patients, but none were cured of their disease. Recently, several patients with cutaneous melanomas also have been treated in Argentina. The first clinical trial of BNCT in Argentina was performed on 9 October 2003.
Two patients with colon cancer, which had spread to the liver, have been treated by Zonta et al. in Italy. The first was treated in 2001 and the second in mid-2003. The patients received an i.v. infusion of BPA, followed by removal of the liver (hepatectomy). This was treated out side of the body (extracorporeal) by BNCT and then re-transplanted into the patient. The first patient did remarkably well and survived for over 4 years after treatment, but the other died within a month of cardiac complications. Clearly, this is a very challenging approach for the treatment of hepatic metastases, and it is unlikely that it will ever be widely used. Nevertheless, the good clinical results in the first patient established proof of principle.
As described in the proceedings of the 14th International Conference on Neutron Capture Therapy, there have been several recent reports describing the possible use of BNCT to treat other solid tumors, including sarcomas of the extremities, primary lung cancer, mesothelioma, and spinal tumors, and melanoma, but the future of these studies is in part dependent upon additional clinical studies confirming and extending the use of BNCT to treat head and neck cancer.
BNCT represents a joining together of nuclear technology, chemistry, biology, and medicine to treat malignant gliomas and recurrent head and neck cancers. Sadly, the lack of progress in developing more effective treatments for these tumors has been part of the driving force that continues to propel research in this field. BNCT may be best suited as an adjunctive treatment, used in combination with other modalities, including surgery, chemotherapy and external beam radiation therapy for those malignancies, whether primary or recurrent, for which there are no effective therapies. Clinical studies have demonstrated the safety of BNCT. The challenge facing clinicians and researchers is how to move forward. Advantages of BNCT include the potential ability to selectively deliver a radiation dose to the tumor with a much lower dose to surrounding normal tissues. This is an important feature that makes BNCT particularly attractive for salvage therapy of patients with a variety of malignancies who already have been heavily irradiated. Second, although it may be only palliative, it can produce striking clinical responses, as evidenced by the experiences of several groups treating patients with recurrent, therapeutically refractory head and neck cancers.
Problems with NCT and BNCT that need to be solved include:
- The development of more tumor-selective boron delivery agents for BNCT. Similar problems are seen with Gd-NCT and other NCTs that require delivery of a specific neutron-absorbing nuclide selectively to tumor, but not surrounding tissues.
- Accurate, real time dosimetry to better estimate the radiation doses delivered to the tumor and normal tissues.
- Evaluation of recently constructed accelerator-based neutron sources as an alternative to nuclear reactors.
For a more detailed discussion of these problems and their solutions in BNCT, readers are referred to the published proceedings of the 13th and 14th International Congresses on Neutron Capture Therapy (2009 and 2011) and a recently published review on the current status of BNCT of high grade gliomas and recurrent cancers of the head and neck region. If the problems enumerated above can be solved BNCT could have an important role in twenty-first century cancer treatment of those malignancies that are loco-regional and that are presently incurable by other therapeutic modalities.
- Barth, Rolf F.; Soloway, Albert H.; Fairchild, Ralph G. (1990). "Boron Neutron Capture Therapy for Cancer". Scientific American 263 (4): 100–3, 106–7. Bibcode:1990SciAm.263d.100B. doi:10.1038/scientificamerican1090-100. PMID 2173134.
- Locher, G. L. (1936). "Biological effects and therapeutic possibilities of neutrons". Am. J. Roentgenol 36 (1): 1–13.
- Sweet, William H. (1951). "The Uses of Nuclear Disintegration in the Diagnosis and Treatment of Brain Tumor". New England Journal of Medicine 245 (23): 875–8. doi:10.1056/NEJM195112062452301. PMID 14882442.
- Farr, LE; Sweet, WH; Robertson, JS; Foster, CG; Locksley, HB; Sutherland, DL; Mendelsohn, ML; Stickley, EE (1954). "Neutron capture therapy with boron in the treatment of glioblastoma multiforme". The American journal of roentgenology, radium therapy, and nuclear medicine 71 (2): 279–93. PMID 13124616.
- Luessenhop, AJ; Gallimore, JC; Sweet, WH; Struxness, EG; Robinson, J (1958). "The toxicity in man of hexavalent uranium following intravenous administration". The American journal of roentgenology, radium therapy, and nuclear medicine 79 (1): 83–100. PMID 13487894.
- Barth, R. F.; Coderre, JA; Vicente, MG; Blue, TE (2005). "Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects". Clinical Cancer Research 11 (11): 3987–4002. doi:10.1158/1078-0432.CCR-05-0035. PMID 15930333.
- Vicente, M. (2006). "Boron in Medicinal Chemistry". Anti-Cancer Agents in Medicinal Chemistry 6 (2): 73. doi:10.2174/187152006776119162.
- Nakagawa, Yoshinobu; Pooh, K; Kobayashi, T; Kageji, T; Uyama, S; Matsumura, A; Kumada, H (2003). "Clinical review of the Japanese experience with boron neutron capture therapy and a proposed strategy using epithermal neutron beams". Journal of Neuro-Oncology 62 (1–2): 87–99. doi:10.1023/A:1023234902479. PMID 12749705.
- Diaz, Aidnag Z. (2003). "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". Journal of Neuro-Oncology 62 (1–2): 101–9. doi:10.1023/A:1023245123455. PMID 12749706.
- Busse, Paul M.; Harling, Otto K.; Palmer, Matthew R.; Kiger, W. S.; Kaplan, Jody; Kaplan, Irving; Chuang, Cynthia F.; Goorley, J. Tim et al. (2003). "A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease". Journal of Neuro-oncology 62 (1–2): 111–21. doi:10.1007/BF02699938. PMID 12749707.
- Kankaanranta, Leena; Seppälä, Tiina; Koivunoro, Hanna; Välimäki, Petteri; Beule, Annette; Collan, Juhani; Kortesniemi, Mika; Uusi-Simola, Jouni et al. (2011). "L-Boronophenylalanine-Mediated Boron Neutron Capture Therapy for Malignant Glioma Progressing After External Beam Radiation Therapy: A Phase I Study". International Journal of Radiation Oncology • Biology • Physics 80 (2): 369–76. doi:10.1016/j.ijrobp.2010.02.031. PMID 21236605.
- Kankaanranta, Leena; Seppälä, Tiina; Koivunoro, Hanna; Saarilahti, Kauko; Atula, Timo; Collan, Juhani; Salli, Eero; Kortesniemi, Mika et al. (2012). "Boron Neutron Capture Therapy in the Treatment of Locally Recurred Head-and-Neck Cancer: Final Analysis of a Phase I/II Trial". International Journal of Radiation Oncology • Biology • Physics 82 (1): e67–75. doi:10.1016/j.ijrobp.2010.09.057. PMID 21300462.
- Kawabata, Shinji; Miyatake, Shin-Ichi; Kuroiwa, Toshihiko; Yokoyama, Kunio; Doi, Atsushi; Iida, Kyoko; Miyata, Shiro; Nonoguchi, Naosuke et al. (2009). "Boron Neutron Capture Therapy for Newly Diagnosed Glioblastoma". Journal of Radiation Research 50 (1): 51–60. doi:10.1269/jrr.08043. PMID 18957828.
- Miyatake, Shin-Ichi; Kawabata, Shinji; Yokoyama, Kunio; Kuroiwa, Toshihiko; Michiue, Hiroyuki; Sakurai, Yoshinori; Kumada, Hiroaki; Suzuki, Minoru et al. (2008). "Survival benefit of Boron neutron capture therapy for recurrent malignant gliomas". Journal of Neuro-Oncology 91 (2): 199–206. doi:10.1007/s11060-008-9699-x. PMID 18813875.
- Coderre, JA; Morris, GM (1999). "The radiation biology of boron neutron capture therapy". Radiation research 151 (1): 1–18. doi:10.2307/3579742. PMID 9973079.
- Nigg, David W. (2003). "Computational dosimetry and treatment planning considerations for neutron capture therapy". Journal of Neuro-Oncology 62 (1–2): 75–86. doi:10.1023/A:1023241022546. PMID 12749704.
- "Overview of neutron capture therapy pharmaceuticals".[unreliable source?]
- Cerullo, N.; Bufalino, D.; Daquino, G. (2009). "Progress in the use of gadolinium for NCT". Applied Radiation and Isotopes 67 (7–8): S157–60. doi:10.1016/j.apradiso.2009.03.109. PMID 19410468.
- Yasui, Linda S.; Andorf, Christine; Schneider, Linda; Kroc, Thomas; Lennox, Arlene; Saroja, K. R. (2008). "Gadolinium neutron capture in glioblastoma multiforme cells". International Journal of Radiation Biology 84 (12): 1130–9. doi:10.1080/09553000802538092. PMID 19061138.
- Nemoto, Hisao; Cai, Jianping; Nakamura, Hiroyuki; Fujiwara, Masaru; Yamamoto, Yoshinori (1999). "The synthesis of a carborane gadolinium–DTPA complex for boron neutron capture therapy". Journal of Organometallic Chemistry 581: 170–5. doi:10.1016/S0022-328X(99)00049-2.
- Tokumitsu, Hiroyuki; Hiratsuka, Junichi; Sakurai, Yoshinori; Kobayashi, Tooru; Ichikawa, Hideki; Fukumori, Yoshinobu (2000). "Gadolinium neutron-capture therapy using novel gadopentetic acid–chitosan complex nanoparticles: In vivo growth suppression of experimental melanoma solid tumor". Cancer Letters 150 (2): 177–82. doi:10.1016/S0304-3835(99)00388-2. PMID 10704740.
- De Stasio, G.; Rajesh, D; Ford, JM; Daniels, MJ; Erhardt, RJ; Frazer, BH; Tyliszczak, T; Gilles, MK et al. (2006). "Motexafin-Gadolinium Taken Up in vitro by at Least 90% of Glioblastoma Cell Nuclei". Clinical Cancer Research 12 (1): 206–13. doi:10.1158/1078-0432.CCR-05-0743. PMID 16397044.
- Geninatti-Crich, Simonetta; Alberti, Diego; Szabo, Ibolya; Deagostino, Annamaria; Toppino, Antonio; Barge, Alessandro; Ballarini, Francesca; Bortolussi, Silva et al. (2011). "MRI-Guided Neutron Capture Therapy by Use of a Dual Gadolinium/Boron Agent Targeted at Tumour Cells through Upregulated Low-Density Lipoprotein Transporters". Chemistry 17 (30): 8479–86. doi:10.1002/chem.201003741. PMID 21671294.
- Harling, Otto K. (2009). "Fission reactor based epithermal neutron irradiation facilities for routine clinical application in BNCT—Hatanaka memorial lecture". Applied Radiation and Isotopes 67 (7–8): S7–11. doi:10.1016/j.apradiso.2009.03.095. PMID 19428265.
- Yiguo, L, Pu X, Xiao, W, et al (October 25–29, 2010). "Start-up of the first in-hospital neutron irradiator (IHNI-1) & Presentation of the BNCT development status in China". New Challenges in Neutron Capture Therapy 2010: Proceedings of the 14th International Congress on Neutron Capture Therapy. Buenos Aires. pp. 371–4.
- Mitsumoto,T, Yajima, S, Tsutsui, H, et al (October 25–29, 2010). "Cyclotron-based neutron source for BNCT". New Challenges in Neutron Capture Therapy 2010: Proceedings of the 14th International Congress on Neutron Capture Therapy. Buenos Aires. pp. 519–22.
- Sweet WH (1983). "Practical problems in the past in the use of boron-slow neutron capture therapy in the treatment of glioblastoma multiforme". Proceedings of the First International Symposium on Neutron Capture Therapy. pp. 376–8.
- Hatanaka, Hiroshi; Nakagawa, Yoshinobu (1994). "Clinical results of long-surviving brain tumor patients who underwent boron neutron capture therapy". International Journal of Radiation Oncology • Biology • Physics 28 (5): 1061–6. doi:10.1016/0360-3016(94)90479-0. PMID 8175390.
- Barth, Rolf F; Grecula, John C; Yang, Weilan; Rotaru, Joan H; Nawrocky, Marta; Gupta, Nilendu; Albertson, Brent J; Ferketich, Amy K et al. (2004). "Combination of boron neutron capture therapy and external beam radiotherapy for brain tumors". International Journal of Radiation Oncology • Biology • Physics 58 (1): 267–77. doi:10.1016/S0360-3016(03)01613-4. PMID 14697448.
- Yamamoto, T.; Nakai, K.; Nariai, T.; Kumada, H.; Okumura, T.; Mizumoto, M.; Tsuboi, K.; Zaboronok, A. et al. (2011). "The status of Tsukuba BNCT trial: BPA-based boron neutron capture therapy combined with X-ray irradiation". Applied Radiation and Isotopes 69 (12): 1817–8. doi:10.1016/j.apradiso.2011.02.013. PMID 21393005.
- http://www.boneca.fi/medical-info/referrals/17[full citation needed][dead link]
- Henriksson, Roger; Capala, Jacek; Michanek, Annika; Lindahl, Sten-Åke; Salford, Leif G.; Franzén, Lars; Blomquist, Erik; Westlin, Jan-Erik et al. (2008). "Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA)". Radiotherapy and Oncology 88 (2): 183–91. doi:10.1016/j.radonc.2006.04.015. PMID 18336940.
- Sköld, K.; Gorlia, T.; Pellettieri, L.; Giusti, V.; H-Stenstam, B.; Hopewell, J. W. (2010). "Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: An assessment of clinical potential". British Journal of Radiology 83 (991): 596–603. doi:10.1259/bjr/56953620. PMC 3473677. PMID 20603410.
- Wittig, A., Hideghety, K., Paquis, P., et al (2002). Sauerwein, W; Mass, R; Wittig, A, eds. "Current clinical results of the EORTC – study 11961". Research and Development in Neutron Capture Therapy Proc. 10th Intl. Congress on Neutron Capture Therapy. pp. 1117–22.
- Barth, Rolf F; H Vicente, M Graca; Harling, Otto K; Kiger, WS; Riley, Kent J; Binns, Peter J; Wagner, Franz M; Suzuki, Minoru et al. (2012). "Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer". Radiation Oncology 7: 146. doi:10.1186/1748-717X-7-146. PMC 3583064. PMID 22929110.
- Stupp, Roger; Hegi, Monika E; Mason, Warren P; Van Den Bent, Martin J; Taphoorn, Martin JB; Janzer, Robert C; Ludwin, Samuel K; Allgeier, Anouk et al. (2009). "Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial". The Lancet Oncology 10 (5): 459–66. doi:10.1016/S1470-2045(09)70025-7. PMID 19269895.
- Kato, Itsuro; Fujita, Yusei; Maruhashi, Akira; Kumada, Hiroaki; Ohmae, Masatoshi; Kirihata, Mitsunori; Imahori, Yoshio; Suzuki, Minoru et al. (2009). "Effectiveness of boron neutron capture therapy for recurrent head and neck malignancies". Applied Radiation and Isotopes 67 (7–8): S37–42. doi:10.1016/j.apradiso.2009.03.103. PMID 19409799.
- Wang, L.W.; Wang, S.J.; Chu, P.Y.; Ho, C.Y.; Jiang, S.H.; Liu, Y.W.H.; Liu, Y.H.; Liu, H.M. et al. (2011). "BNCT for locally recurrent head and neck cancer: Preliminary clinical experience from a phase I/II trial at Tsing Hua Open-Pool Reactor". Applied Radiation and Isotopes 69 (12): 1803–6. doi:10.1016/j.apradiso.2011.03.008. PMID 21478023.
- Mishima, Yutaka (1996). "Selective Thermal Neutron Capture Therapy of Cancer Cells Using their Specific Metabolic Activities—Melanoma as Prototype". In Mishima, Yutaka. Cancer Neutron Capture Therapy. pp. 1–26. doi:10.1007/978-1-4757-9567-7_1. ISBN 978-1-4757-9569-1.
- "The BNCT Project at the National Atomic Energy Commission (CNEA)". Comision Nacional de Energia Atomica.
- Zonta, A.; Pinelli, T.; Prati, U.; Roveda, L.; Ferrari, C.; Clerici, A.M.; Zonta, C.; Mazzini, G. et al. (2009). "Extra-corporeal liver BNCT for the treatment of diffuse metastases: What was learned and what is still to be learned". Applied Radiation and Isotopes 67 (7–8): S67–75. doi:10.1016/j.apradiso.2009.03.087. PMID 19394837.
- Zonta, A; Prati, U; Roveda, L; Ferrari, C; Zonta, S; Clerici, Am; Zonta, C; Pinelli, T et al. (2006). "Clinical lessons from the first applications of BNCT on unresectable liver metastases". Journal of Physics: Conference Series 41 (1): 484–95. Bibcode:2006JPhCS..41..484Z. doi:10.1088/1742-6596/41/1/054.
- Kreiner, A.J. "Special Issue: 14th International Conference on Neutron Capture Therapy" Applied Radiation and Isotopes 69:1631-1939, 2011
- Altieri, Saverio; Bortolussi, Silva; Barth, Rolf F.; Roveda, Laura; Zonta, Aris (2009). "Thirteenth International Congress on Neutron Capture Therapy". Applied Radiation and Isotopes 67 (7–8): S1–2. doi:10.1016/j.apradiso.2009.03.009. PMID 19395267.
- Barth, Rolf F. (2009). "Boron neutron capture therapy at the crossroads: Challenges and opportunities". Applied Radiation and Isotopes 67 (7–8): S3–6. doi:10.1016/j.apradiso.2009.03.102. PMID 19467879.
- Helsinki University Central Hospital and Technical Research Centre of Finland BNCT Project
- Boron and Gadolinium Neutron Capture Therapy for Cancer Treatment
- MIT Nuclear Reactor Lab overview of BNCT
- Washington State University Nuclear Radiation Center BNCT Overview