Overview of Boron Neutron Capture Therapy in Medical 

Cancer is an abnormal growth of cell due to loosing ability to control and maintain its proliferation, differentiation and apoptosis cycle. There are several method to treat cancer, one of them is boron neuron capture therapy. Boron Neutron Capture Therapy (BNCT) is radiation modality by deliver high radiation dose to tumor cell with lower damage to surrounding normal tissue. This modality has been used widely as treatment to several cancer cases e.g Head and neck cancer, breast cancer, liver cancer, etc.

BNCT is using BSH and BPA as delivery agent. Then, tumor cell will be irradiated by thermal radiation. This method has a big prospect to be a main cancer therapy in the future, and thus will reduce the adverse effect of conventional cancer therapy.

INTRODUCTION

Cancer is an abnormal growth of cells. The cells lost its ability to control and maintain cell number normally. A Normal cell divide, differentiate into another cell or do apoptosis constantly through regular cellular signal.

As the cell loosing its ability to maintain normal life cycle, this uncontrolled cells grow and proliferate continuously. In advanced stage, cancer cells can migrate to another site of body and invade normal tissue.

There are common changes in cell physiology that results in cancer. Normal cells have a finite lifespan. Cancer cell have oncogenes that trigger the cell to keep dividing by producing protein that stimulate proliferation cells. Even though there is antigrowth signal mechanism, through tumor suppressor gene, that can regulate this proliferation; Cancer cell has the ability to override this mechanism resulting on avoidance of apoptosis.

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Cancer cells can bypass apoptosis in many ways. The most common method is by inactivating of p53 protein. The mutation of p53 tumor suppressor gene cause reduction of proapoptotic regulator drastically. Neovascularization occurs when tumor cells releasing pro-angiogenic factor. This substance will stimulate endothelial cells to activate formation of new blood vessel. This vessel will give tumor cell another nutrient supply.

Cancerous cells can develop from any tissue within the body. It develops over several years and has many causes. The risk factor divided into two large groups, which are internal factor and external factor. The external factor refers to environmental factors. In United States, the exposure to wide variety of natural and man-made substances in the environment leads to two-thirds all cases of cancer (National Institute of Health, 2003). Lifestyle plays a big role in this factor; such as cigarette smoking, excessive alcohol consumption, poor diet, lack of exercise, radiation, exposure to certain medical drugs, excessive of sunlight, certain viruses etc. High environmental exposures are linked to specific kind of cancer. For example, hyper exposure to asbestos may be linked to lung cancer. In the other hand, internal factor are certain factor inside the body that make people more likely to develop cancer than others.

Some people have abnormality to transcript normal genes resulting to alter genes in body cells, abnormal hormone level in the blood stream, or weakened immune system. This abnormality can be inherited from their predecessor. People become more susceptible to cancer due to this factor. Cancer rates are increased by the number of risks and by lowering exposure to these risks factor, some leading cancer could be suppressed. For example, the majority of lung cancer deaths are caused by tobacco use (71%). By avoiding tobacco use, people reduce their possibility to be threatened by lung cancer. The combination of environmental and behavioral risks (e.g. high body mass index, low fruit and vegetable intake, physical inactivity, unsafe sex etc) – are responsible for the increasing of cancer deaths. (WHO,2009)

According to GLOBOCAN 2012, there were approximately 14.1 million cancer cases and 8.2 million cancer-related deaths occurred in 2012 (Ferlay, 2015). The most commonly diagnosed cancers worldwide were lung cancer (13% of the total), breast cancer (11.9 %) and colorectum cancer (9.7%). Nowadays, Cancer is on the top three disease that kill patients at the most, followed by coronary heart disease and all kind of strokes. In Indonesia, There are 195.300 deaths caused by cancer in 2014 (WHO,2014). Based on Cancer Mortality Profile by WHO, Trachea, bronchus , and lung cancer was in the top rank on male mortality cases caused by cancer and breast cancer was the first cause of cancer mortality on female.

There are several treatment modalities in treating cancer such as surgery, chemotherapy and radiotherapy. Surgical treatment is efficient in primary tumors, but it is limited to surgically sizeable and approachable tumors. Chemotherapy is the use of chemical substance in certain dosage to fight cancer. The drug circulates through blood vessel to kill malignant cells. It has significant side effects due to drug toxicity to normal cells and is subject to the development of resistance by the cancer cells. Radiation is a physical agent, which is used to destroy cancer cells. A high energy ionization particle, e.g. X-rays, gamma rays or electrons, are utilized during radiotherapy treatment. This high energy can kill cancer cell or cause genetic changes resulting in cancer cell death (Baskar, 2012).

Nowadays, there is another branch of radiotherapy that can be used as an alternative methods to treat cancer called Nuclear Medicine. This therapeutic modality utilizes radiobiologic burden to harm the lesions. There are two things that always should be noticed while prescribing dosage, they are maximal tolerable dose/MTD of organ and maximal tolerable activity/MTA of individual. In oncology, the doses must be within MTDs of limiting organ and the administered activities must not exceed MTA of individual patients. It is fundamental for personalized medicine. The administration of therapeutic radiopharmaceutical may be given directly to the lesions or systematically to lesions (through intravenous, oral).

One of its modalities that can be used as cancer treatment is Boron Neutron Capture Therapy (BNCT). This therapeutic modality is a promising way to treat patients with cancer. In this method, Boron (Bo-10) is initially carried to a tumor by its oncotropic vector, then the tumor is irradiated with thermal neutron beams producing Li-7 and He-4 ion of 2,3 MeV (Pranoto,2016). A dense ionization is produced by He-4 and α particle along its path. This radiation has lethal energy to kill cancer cell. The oncotropic vector may be BSA, BPA, curcuma or NPs loaded with targeting agents.

METHOD

This study used library research method and process primary data only Data sources were obtained from journals, articles, books, and documentations. Relevant cases were used as reference and processed into new information. The literature was conducted using Pubmed, elsevier, ncbi, Science Direct and google scholar to search for research studies published between 2000 and 2018. The keyword used included cancer, radiation, BNCM, boron or a combination of these terms. This study clearly describe an overview of using Boron Neutron Capture Therapy/BNCT in medical field based on the previous researches and studies. The objective of this study was to know the benefit using BNCT as cancer treatment furthermore and to see its potency as treatment modality.

DISCUSSION

Boron neutron capture therapy/BNCT is a noninvasive therapeutic modality for treating locally malignant tumor. BNCT based on two phenomena. First, tumor tissue would be injected with non radioactive boron drag, after that, patient was irradiated with epithermal neutron until the normal tissue dose limit is reached. Boron has an advantage as delivery agent, where it has large section (3840 barn) for slow thermal neutron. When the non radioactive boron atom capture the thermalised neutron, there will be decaying process where the thermalised neutron decays through short range α-particle and recoiling Li-7 nucleus. These emitted charged particles can travel only a short distance (10µm), have a high linear energy transfer and an associated high relative biological effectiveness. This energy has an ability to destroy the cancer tissue locally that containing the boron drag without harming the healthy tissue around the tumor cell. To reach a good result, there are two parameters that should be considered, those are boron concentration and neutron beam.

Boron is delivery agent that has a fundamental part on BNCT method. Good agents, are those that can be high concentrated in tumor cell while leaving a small residue in normal tissue. There are three main requirements to meet a successful delivery agent, which are (a) low systemic toxicity and normal tissue uptake with high tumor uptake, (b) tumor concentration of 20 µg10 B/g tumor, (c) rapid clearance from blood and normal tissues and persistence during BNCT (Baskar, 2012). Two boron compound that have been used for BNCT is BSH (sodium boroncaptate) and BPA (boron Phenylamine). Both compounds have accumulated different place when inserted into the body. BSH will accumulate in the cell membrane while the BPA will accumulate in the nucleus of cells. BSH can pass through the disrupted blood brain barrier easily and boron can be internalized into cells in endocytic pathways after binding to the plasma membrane. In the other side, BPA is inserted into tumor cells via metabolism pathway of amino acids (Savalainen, 2012).

Neutrons are classified three types according its energy as thermal neutron (energy 10keV). Boron Neutron Capture reaction use thermal neutron as it can be very effective for treatment of tumors. Reactors are the most suitable type for neutron source because of it provides correct energy spectrum and adequate thermal high intensity neutron flux. Neutron sources providing an epithermal spectrum ranging from 0.4 eV to 10 keV are being considered for clinical use for the treatment of deep-seated tumors such as gliomas (Barth, 2012).

There are a lot of benefit using BNCT as cancer treatment modality, since BNCT is biologically targeted type of radiation treatment. BNCT provides a way to deliver curative dose to the tumor. Compared to the conventional radiotherapy, BNCT targeting tumor selectively while radiotherapy using external radiation that irradiate not only tumor cell but also normal cell. High-energy radiation damages genetic material (deoxyribonucleic acid) of cells and thus blocking their ability to multiply and proliferate. In Radiotherapy, Ionizing radiation deposit energy in the cells of the tissues it passes through, which means it is not only damaging cancer cell but also normal cell tissues surrounding.

Therefore, the radiotherapy is used because it is still able to control the growth of cancer cells. Effective means cancer cell receiving optimum dosage of radiation so that it can treat and control the growth adequately. Moreover, effectiveness itself cannot be separated from the safe limit (Sardjono,2016). BNCT has a potency to more effectively target multicentric deposits of tumors than is possible with radiosurgery to patients with primary and metastatic brain tumors. Although it may be only palliative treatment, it shows good clinical responses, as evidenced by the experience of several groups treating patients with cancer (Barth,2012).

In some clinical trials and investigations, there was improvement in cancer patients with BNCT. This method can be used in fresh cancer cases and also recurrent cases. Kankaanranta L et al., reported 22 patients with recurrent glioblastoma multiforme, who had recurrence following standard treatment, were treat with BNCT using BPA. It was concluded that BNCT can be used as therapy in patients with recurrent tumors.

In the first decade of 2000s, some clinical studies of BNCT for newly diagnosed malignant gliomas were reported. It showed a quite impressive result, where the mean survival time in each studies was approximately 13 months. Combination BNCT and X Ray Therapy as cancer treatment showed a significant improvement. A better result was showed in patients with combination of BNCT and X Ray Therapy.The mean survival time (MST) to patients with combination BNCT and X Ray Therapy was 23.5 months (Miyatake,2016).

Clinical interest in BNCT has focused primarily on high grade gliomas and recently on patients with recurrent tumors of head and neck (HN) region who have not significant improvement health status using conventional cancer therapy. Miyatake et. al initiated their studies on the treatment of brain tumors in 2002 to 140 patients of BNCT. They have treated 58 patients with newly diagnosed high grade gliomas, 50 with recurrent tumors and 32 patients with recurrent high grade meningiomas. The results are summarized as follows. L-BPA and BSH was used as boron delivery agents in 50 patients with recurrent high grade gliomas. Two thirds of the patients who had contrast-enhanced regions by magnetic resonance imaging (MRI), showed a decrease in their tumor size during the follow up period. There was a significant prolongation in mean survival time of 9.1 months following BNCT versus 4.4 months for those that had received other type of therapy in 22 patients with recurrent gliomas.

Figure 3. A 25-year-old woman who had recurrent rhabdoid meningioma was treated with BNCT. Tumor size was reduced gradually in 4 month after BNCT. A. One week prior to BNCT; B : Two weeks after BNCT; C : Four months after BNCT. BCT : Boron Neutron Capture Therapy (Miyatake,2016)

Another report by Kawabata said that, there was reduction in tumor mass after BNCT. Nineteen patients with recurrent malignant meningioma were subjected to BNCT. There was more than 50% reduction in tumor mass in 18 out of 19 cases, within observation period. The median survival time post BNCT was reported to be 14.1 months. BNCT provides a better option to treat malignancy successfully. This report shows that there a big potency using BNCT as first line therapy in the future or combined with other therapies.

Patients with recurrent tumors of HN region had been treated using BNCT in several countries e.g. Japan, Taiwan and Finland. Most of them are those who had done surgery treatment, combined with chemo-radiation with doses that have reached normal tissue tolerance. Although the total number of patients treated by BNCT are relative small, they show some very impressive result. Wang et. al reported there was high responses in patients with recurrent HN tumors (12 out of total 17 patients) who received BNCT using BPA-F as boron delivery. Suddenly, recurrence within or near the treatment site was common. This could be caused by non-homogenous uptake of BPA-F with poor distribution in some part of tumors (Barth, 2018). To improve the response and cure rates, further evaluation and research are needed to optimize the dosage and better distribution of agent delivery. Biodistribution studies and pretreatment biopsies other recurrent tumor sites could be very useful for improving therapeutic result.

The Research on boron neutron capture therapy (BNCT) give a great result in clinical studies, even though it progressed slowly. The development of BNCT agent is focused on specific target on certain cancer cells. Biomarker become a modality to develop better agents since every cancer cell has its own specific biomarker.

To reach an optimal clinical application for patients with cancer, the development of BNCT need a huge attention from many aspect. Further research is needed to develop and invent more selective and efficient delivery agents (boron), to calculate accurate dosage of agents, and to improve BNCT implementation through randomized clinical trial. The improvements will definitely bring this method to be ready competing with others cancer treatment modalities.

CONCLUSION

Boron Neutron Capture Therapy is a good method of other form of therapy to destroy malignant tumor specifically. This method can be an alternatives way to treat cancer beside surgery, chemotherapy or external radiation. There are a lot of report that show improvement to patient cancer after receive therapy with BNCT. This Method can be used as therapy to treat primary or recurrent cancer. Even though, BNCT is still new i medical world as cancer therapy, it has promising step in the future. Further evaluation and research should be done to improve therapeutic result.