by Katsumi Hirose
In clinical practice of boron neutron capture therapy (BNCT), its therapeutic effect is subject to various uncertainties. BNCT is recognized to be a difficult treatment modality with many inherent error factors, such as the inability to evaluate boron accumulation into tissues correctly when treating patients, and the fact that intense of biological effects on the reaction of boron and neutrons, which is expressed as a CBE factor, vary from tumor to tumor, or tissue to tissue. Furthermore, neutrons have difficulty in reaching deep into tumors over 7-8-cm depth, and track of neutron transfer has no linearity and widely diffuse in air and tissues. Therefore, it requires a high skill to position and align the planned treatment site close to a beam aperture. Operation for achieving this requirement is not easy.
Based on the recent development of accelerator-based neutron irradiation system and sorbitol formulation of boronophenylalanine with highly concentrated 10B, clinical trials of BNCT were conducted for head and neck cancer and recurrent brain tumor [1,2]. The JHN002 trial for recurrent and locally advanced head and neck cancer was designed based on the results of a phase I safety evaluation conducted by Kawasaki Medical College and Kyoto University Research Reactor Institute (KURRI), and was based on Japanese expertise in reactor BNCT clinical research. With full cooperation of KURRI, we prepared for the JHN002 study with acquiring basic knowledge and skills of BNCT. The most important and realistic goal was to ensure at least the clinical efficacy of BNCT proven at nuclear reactors, which had already been reported. But the method to ensure reproducibility during simulation, treatment planning, and treatment had not been well established before. In most cases of head and neck cancer, treatment in the sitting position is superior to that in the supine position for making the treatment site closer to the beam aperture in the points that neutrons can be delivered and treatment can be performed more efficiently. Therefore, we developed a method to setup the patient in a sitting position without so large deviation as the neutron fluence given to the patient’s tissue would not deviate from the calculated results, and we implemented in the study. The sitting positioning and the reproduction of the body position in the supine CT were realized through multiple trials and errors. Misalignment of the beam entry and exit points on skin to be held were controlled within 3 mm for most cases between setup with sitting positioning, CT imaging with supine positioning, and treatment with sitting position.
Patients enrolled in the JHN002 study included 8 patients with recurrent squamous cell carcinoma (R-SCC) and 13 patients with locally advanced non-squamous cell carcinoma (LA-NSCC, including 1 patient with malignant melanoma). Irradiation was performed until the maximum dose to the mucosa of the pharynx, larynx, and oral cavity was 12 Gy-Eq, and tumor doses were passively determined. The median tumor minimum, mean, and maximum doses (interquartile) were 31.1 (26.1–34.3), 44.7 (42.9–50.6), and 56.6 (51.3–62.2) Gy-Eq. The response rate for all patients was 71%, of which 24% were CR. For safety, 15% of the patients developed symptomatic Grade 3 adverse events, which included brain abscess due to intracranial infection, mucositis, and dermatitis. There was no grade 4 or 5 toxicity. Distinguished by histology, the CR rate for the 13 LA-NSCC, was 13%, which was lower than and contradicted previous reports, but for the 8 R-SCC, the response rate was high with 4 cases of CR (50%). Subsequent follow-up of these cases was conducted as part of the JHN002 Lookup study, which showed a median progression-free survival of 11.5 months for R-SCC. Of course, the efficacy of R-SCC is still far from satisfactory, but when combined with its good safety profile, it is a very significant treatment option for R-SCC cases. As well as treatment outcomes, the course and profile of adverse events of the treatment and the ways to treat them have been clarified and published, and are available to all oncologists .
Based on these results, now in Japan head and neck cancer patients can receive the treatment under national health insurance system. More than hundred patients were treated at Southern Tohoku BNCT Research Center until December 2021. As an initial treatment results under the insurance system, the response rate was 70% in the first 27 evaluable patients who had been observed for more than 3 months, of which 50% were CR. Of the patients who achieved CR, 70% were relapse-free at 6 months, and future results are expected. Although these data is just given by a preliminary analysis, we believe this represents the actual real-world data for accelerator-BNCT. Official results will be published in the near future. These results are almost comparable to those of JHN002 trials. These good results may depend on the continuous institutional efforts to improve techniques of patient setup and treatment to cover a wide range of tumor locations and patient conditions. The techniques can be presented by a well-sophisticated BNCT team constituted by radiation oncologists, medical physicists, radiological technologists, and radiation oncology nurses. Currently, an on-demand video broadcast on NHK world that offers a glimpse into the technical aspects of our facility is available on the web.
On the other hand, however, patient characteristics and tumor factors that may reduce the effectiveness of BNCT, as well as factors that should be considered non-indications, are gradually becoming clear. For example, many cases in which the tumor is located to the mucosa show a fairly good response, but tumors with non-contrast areas that suggest necrosis or decreased blood flow on imaging studies often show a poor response to treatment. In addition, patients with cognitive decline or those who are elderly and have a marked decline in physical fitness often have difficulty with positional maneuvers and do not achieve the required treatment quality. Patients with claustrophobia may panic and engage in risky behavior when positional fixation is performed. How to treat these patients effectively and safely remains a challenge for the future.
18F-FBPA-PET, which is now performed as a clinical trial in conjunction with BNCT under the insurance system, is one of useful test for preliminary evaluation of tumor boron concentration. However, physicians should be aware that tumor conditions (tumor size, homogeneity, etc.) that ensure quantification of 18F-FBPA accumulation vary depending on the specifications of the PET/CT system used. For example, it is common knowledge that the quantification of 18F-FBPA is impaired in superficial thin and flat tumors in terms of tumor size, and the clinician should not use the tumor dose derived from this PET parameter to determine the indication for treatment. The same is also true in cases of high contrast heterogeneity of tumors or tumors with polycystic growth and lack of uniform full tissue areas. Tumor RBE doses derived from PET parameters without any mention of the performance of the PET/CT equipment should be questioned as to their quantitativeness.
Expanding the range of indications for BNCT in clinical practice is one of the greatest challenges. To make this possible, however, requires a deeper consideration of how BNCT should be used in oncology practice. It is of course important to develop new basic technologies that will enhance the effectiveness of BNCT over the decades. However, it is desirable that BNCT will be introduced in a way that compensates for the advantages and disadvantages of other treatment modalities based on a comprehensive view of current oncology practice.
Katsumi Hirose, M.D., Ph.D.
Department of Radiation Oncology, Southern Tohoku BNCT Research Center
Hirosaki University Graduate School of Medicine
You will find the references in our repository:
 Hirose K, Konno A, Hiratsuka J, Yoshimoto S, Kato T, Ono K, Otsuki N, Hatazawa J, Tanaka H, Takayama K, Wada H, Suzuki M, Sato M, Yamaguchi H, Seto I, Ueki Y, Iketani S, Imai S, Nakamura T, Ono T, Endo H, Azami Y, Kikuchi Y, Murakami M, Takai Y. Boron neutron capture therapy using cyclotron-based epithermal neutron source and borofalan(10B) for recurrent or locally advanced head and neck cancer (JHN002): An open-label phase II trial. Radiother Oncol. 2021;155:182-7.
 Kawabata S, Suzuki M, Hirose K, Tanaka H, Kato T, Goto H, Narita Y, Miyatake S. Accelerator-based BNCT for patients with recurrent glioblastoma: a multicenter phase II study. Neuro-Oncol Adv. 2021;3:1-9.
 Hirose K, Sato M, Kato T, Takayama K, Suzuki M, Yamaguchi H, Seto I, Kikuchi Y, Murakami M, Takai Y. Profile analysis of adverse events after boron neutron capture therapy for head and neck cancer: a sub-analysis of the JHN002 study. J Radiat Res. 2022: 1–9.