The Economic and Clinical Prospect of Proton
and Neutron Radiation in Cancer Treatment

What if cancer patients could shorten radiotherapy to one or two sessions, avoid serious side effects, and lower the chance of relapse? Neutron Radiation in Cancer Treatment holds promise for that reality.

In our current day and time, the most recommended cancer treatment involves surgical resection of tumors and subsequently, radiotherapy with x-rays and/or chemotherapy (Debela 2021). Together irradiation, chemotherapy, and surgery form the three pillars of conventional cancer treatment. Depending on the size and spread of the tumor and whether or not it’s surgically excisable, the goals of radiochemotherapy in the treatment of cancer include:

• Curative: eliminating all cancer in the body

• Adjuvant: attacking leftover cancerous cells in the body after surgery to prevent relapse

• Neoadjuvant: shrinking tumors to prepare for possible surgery

• Palliative: relieving symptoms when it’s no longer possible to remove all tumor cells

However, all types of radiochemotherapy share the goal of stopping or slowing the growth of cancer cells by inhibiting their uncontrolled cell division. Accordingly, chemotherapy drugs contain cytostatic agents that slow or stop the spread of cancer by, depending on their specific mechanism of action, interfering with cell division in different ways. The only problem is cytostatics cannot specifically target malicious cells, but rather have a systemic effect. Cancer cells tend to grow abnormally fast and chemo drugs are engineered to kill fast-growing cells, but because cytostatic agents in the drugs do not have a local effect on specific parts of the body, the drugs can affect normal, healthy cells that are growing very fast (Nurgali). This is what causes the extensive side effects most severely impacting the digestive tract, hair follicles, blood-forming cells in the bone marrow, the mouth, and the reproductive system (Pietrangelo 2022).

Consequently, despite emerging improvements in efficiency and survival rate, the long-term sequelae and side effects of chemotherapy remain a major source of concern for physicians. Though efforts have been made to engineer drugs or other approaches to counteract the adverse effects of chemotherapy, they have been largely ineffective and have often even caused other side effects, further exacerbating patient discomfort (Nurgali 2018).

Thus, researchers have turned to emergent therapies that can more precisely attack cancerous cells while preserving the healthy ones; Boron (or Gadolinium) Neutron Capture Therapy has shown promise in the management of locally advanced unresectable radioresistant tumors (Fleurette). The use of the non-radioactive isotope gadolinium (Gd) has been limited to experimental animal studies and has not been used clinically like Boron-10. Boron Neutron Capture Therapy (BNCT) has been evaluated clinically as an alternative to conventional radiation therapy for the treatment of 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 frequently, superficial melanomas primarily involving the skin and genital region.

Neutron capture therapy is a two-step radio-therapeutic modality for treating locally invasive malignant tumors first involving the administration of a tumor-localizing drug containing the non-radioactive isotope boron-10 (10B) which has a high propensity to capture low energy "thermal" neutrons. Then, the patient is irradiated with epithermal neutrons from accelerators which penetrate tissue and are captured by the boron atoms. The resulting decay reaction yields high-energy alpha particles that kill the cancer cells that have taken up sufficient quantities of 10B (Sauerwein). The boron-10 is 3-5 times more likely to be in a cancerous cell than in a healthy cell, which limits damage to surrounding healthy tissue (TAE Life Science).

Thus, BNCT is proving a better alternative to radiation, chemotherapy, or other current cancer treatments because of its ability to deliver highly effective and cell-localized radiation therapy to treat tumors with minimal impact on the patient’s quality of life.

With the promise BNCT has shown, one might wonder why it isn’t more widely known and available. The answer lies in the treatment’s novelty and feasibility.

There are only two boron delivery agents in clinical use, L-boronophenylalanine (BPA) and sodium borocaptate (BSH) though investigators have been trying for decades to develop more drugs that are more effective (Nature). However, until there are new drugs, the effectiveness and the dosing and delivery of BPA and BSH need to be improved (Barth).

Like most innovations, the cost of implementing BNCT seems exorbitant and needs to be weighed against the impact its use will have. Though the treatments in clinical trials conducted in collaboration with Boneca Ltd and Helsinki University Central Hospital patients showed improved tumor control and survival, this radiotherapy service ended in the bankruptcy of Boneca Ltd, the not-for-profit which organized the treatments, in January 2012, with just over 300 patient irradiations (Airila). Thus, nuclear reactor-based BNCT has ended except for its use in the China mainland and Taiwan.

Since then, the technology has changed (namely, neutron sources have become accelerator based), but still cost-benefit analyses have shown that at current rates, BNCT technologies are not economically competitive with present recovery rates; yet, investing in BNCT technologies still holds immediate nonmonetary benefits now including those of humanitarian value like lowering the risk of death or dependency and improving the quality of life of patients. Indirect economic benefits also exist considering that innovation is a benefit in its own right, that often new technologies lend themselves to spillover benefits in other fields or further applications in the same field, and that, over time, technologies develop to become not only cheaper but also more efficient (Kulvik).

Neutron Therapeutics Inc. and the Helsinki University Hospital are collaborating to launch the first European hospital-based BNCT facility (Porra). Johanna Mattson, Senior Medical Director at the Helsinki University Hospital Comprehensive Cancer Center, said: "Providing BNCT with the most sophisticated accelerator-based device will enable Finnish clinicians to treat patients with some of the most obstinate cancers and remain globally at the forefront of oncology. We are working hand in hand with our industry partners, Neutron Therapeutics and Cosylab, to bring the full clinical potential of BNCT to patients in Helsinki as soon as 2023(Business Wire)." Ergo, the future of BNCT is dependent on positive results from the ongoing Japanese Phase II clinical trials and the upcoming trials in Finland (Barth).

Boron Neutron Capture Therapy continues to grow: treatment of malignant glioma treatments was followed by more successful head and neck treatments, novel carriers of boron-10 are approaching clinical trials, and the era of accelerator-based neutron beams has just begun. Despite the number of problems that must be addressed, further BNCT clinical studies are occurring and displaying promise. If the results obtained from these clinical trials are adequate, then BNCT will have a clear path to the future to improve the lives of patients previously inaccessible by current treatments.

References

Airila, M. I., Auterinen, I., Kotiluoto, P., Vanttola, T., & Vilkamo, O. (2015, December 22).

The glow of Finland’s first reactor fades. Nuclear Engineering International.

Barth, R.F., Zhang, Z. & Liu, T. A realistic appraisal of boron neutron capture therapy

as a cancer treatment modality. Cancer Commun 38, 36 (2018).

https://doi.org/10.1186/s40880-018-0280-5

Debela, D. T., Muzazu, S. G., Heraro, K. D., Ndalama, M. T., Mesele, B. W., Haile, D. C.,

Kitui, S. K., & Manyazewal, T. (2021). New approaches and procedures for cancer treatment: Current perspectives. SAGE open medicine, 9, 20503121211034366.

https://doi.org/10.1177/20503121211034366

First simulated patient treatment carried out in the first hospital-based BNCT facility in

Europe. Business Wire. (2022, May 11). Retrieved August 24, 2022, from

https://www.businesswire.com/news/home/20220511005192/en/First-Simulated-Patient-Treatment-Carried-Out-in-the-First-Hospital-Based-BNCT-Facility-in-Europe

Fleurette, F., & Charvet-Protat, S. (1996). Proton and neutron radiation in cancer

treatment: clinical and economic outcomes. Bulletin du cancer. Radiotherapie : journal de la Societe francaise du cancer : organe de la societe francaise de radiotherapie oncologique, 83 Suppl, 223s–7s. https://doi.org/10.1016/0924-4212(96)84918-8

Hiratsuka, J., Kamitani, N., Tanaka, R., Yoden, E., Tokiya, R., Suzuki, M., Barth, R. F., &

Ono, K. (2018). Boron neutron capture therapy for vulvar melanoma and genital

extramammary Paget's disease with curative responses. Cancer communications (London, England), 38(1), 38. https://doi.org/10.1186/s40880-018-0297-9

Kulvik M, Hermans R, Linnosmaa I, Shalowitz J. An economic model to assess the cost-

benefit of BNCT, Appl Radiat Isot, 2015; 106: 3–9. Pmid:26365901

https://doi.org/10.1016/j.apradiso.2015.08.021

Liisa Porra, Tiina Seppälä, Lauri Wendland, Hannu Revitzer, Heikki Joensuu, Paul Eide,

Hanna Koivunoro, Noah Smick, Theodore Smick & Mikko Tenhunen (2022) Accelerator-based boron neutron capture therapy facility at the Helsinki University Hospital, Acta Oncologica, 61:2, 269-273, DOI: 10.1080/0284186X.2021.1979646

Nurgali, K., Jagoe, R. T., & Abalo, R. (2018). Editorial: Adverse Effects of Cancer

Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae?. Frontiers in pharmacology, 9, 245. https://doi.org/10.3389/fphar.2018.00245

Pietrangelo, A. (2022, January 4). The Effects of Chemotherapy on Your Body. Healthline.

https://www.healthline.com/health/cancer/effects-on-body

Sauerwein W, Wittig A, Moss R, Nakagawa K. Neutron Capture Therapy: Principles and

Applications. London: Springer Heidelberg New York Dordrecht (2012).

TAE Life Science. (2021, March 1). Developing targeted drugs for boron neutron capture

therapy to treat refractory cancers. Nature.

https://www.nature.com/articles/d43747-021-00008-y