Problems and prospects of clinical trials of boron neutron capture therapy

Abstract

<p indent="0mm">Boron neutron capture therapy (BNCT) is an intracellular radiotherapy that exploits the neutron capture and fission reaction of the boron isotope, ¹⁰B. As a binary targeted tumor therapy based on intracellular radiotherapy, BNCT brings new hope to cancer patients. In 2012, the team from the Third Xiangya Hospital of Central South University, together with Prof. Yongmao Zhou’s team, started the clinical trial of BNCT in China based on the in-hospital neutron irradiator-1 (IHNI-1), and completed the first trial of BNCT in September 2014. The following is the summarization of the clinical trial: The first patient, a <sc>53 years</sc> old man with black plaque found on the left anterior palmar <sc>7 years</sc> ago, was diagnosed as malignant melanoma after pathological examination. The patient completed boron phenylalanine (BPA) drug uptake test and neutron irradiation in September 2014. After irradiation, no tumor tissue was indicated by PET-CT and pathological examination. The team continued to complete drug uptake tests and/or neutron irradiation for a total of 20 cases, including 2 cases of early malignant melanoma, who survived in the <sc>5 years</sc> of follow-up. The rest 17 patients were in advanced cancer stage, among which 8 patients had local tumor shrinkage and 9 patients were not suitable for irradiation because ¹⁰B in tumor tissue did not reach the required concentration for treatment. The trial validated the safety of IHNI-1 and boron-containing agent, and the anti-tumor effects of BNCT. However, the board application of BNCT is limited by the lack of targeted boron delivery agent. Currently available boron-containing agents cannot concentrate in tumor lesions of some patients at an early stage, resulting in the impracticable status of BNCT for these patients. Even though some difference was observed in the concentration of ¹⁰B between tumor and normal tissues in some cancer patients at an advanced stage, the difference is not large enough for in the safe application of total body irradiation by IHNI-1. On the other hand, patients at advanced stage can only enjoy little survival benefits when local radiotherapy was accomplished. We highly recommend metastatic and recurrent tumors, and advanced tumors insensitive to current chemotherapy and radiotherapy as the major indications of BNCT. The pivotal task of BNCT research is to develop targeted boron delivery agent which can achieve sufficiently high boron concentration in tumor tissue against normal tissue (<italic>T</italic>/<italic>N</italic>). Based on the clinical trial and clinical experience mentioned above, we propose that a boron drug achieving a <italic>T</italic>/<italic>N</italic> ratio higher than 10, combined with large area or whole-body neutron irradiation, might be a sign of the maturity of BNCT technology. The current available boron drugs are mainly composed of small molecules of amino acid derivatives such as BPA, which are concentrated in tumor tissues through the high metabolic mechanism of tumor tissues. The shortcomings of these drugs include off-target effects and low concentration in the tumor tissue. Deoxy glucose isotope is a tracer widely used in tumor screening; nanotechnologies such as nanosphere technology also shows good application in tumor drug concentration, and drugs assembled by antibodies and small molecule targeting ligands are becoming increasingly mature. These might be the potential directions for future boron drug development. In addition, the study and parameter design of neutron irradiation can be adjusted according to the development of boron drugs. However, neutron sources should consider irradiation area and depth to meet the requirements of large area or whole-body neutron irradiation, as the major application scenario of BNCT is to treat metastatic and recurrent tumors, and advanced tumors. Ultimately, well-designed clinical studies can be used to validate the efficiency of the newly developed boron drugs and neutron irradiation related techniques, and to give feedback for the improvement of these drugs and techniques.