Boron neutron capture therapy in clinical application:Progress and prospect

Boron neutron capture therapy (BNCT) is an emerging radiotherapeutic modality aimed at selectively concentrating boron compounds in tumor cells and then subjecting the tumor cells to neutron beam radiation. Treatment with BNCT is based on the nuclear capture and fission reactions that occur when nonradioactive boron-10 (¹⁰B) is irradiated with neutrons to yield an alpha particle (helium, ⁴He) and a recoiling lithium-7 (⁷Li) nuclei. The ⁴He particle has a range of 9 μm and the ⁷Li particle 5 μm in tissue. In theory, the short range of this reaction limits the damage to malignant cells while sparing adjacent normal cells. The development of BNCT is still constrained by the progress in developing boron delivery agents with a high tumor uptake, low normal tissue uptake, and optimizing the dosing paradigms and quantitative estimation of the ¹⁰B concentrations. It is widely recognized that the second generation boron-containing agents, sodium borocaptate (BSH) and boronophenylalanine (BPA), are less than ideal. New and more effective boron-containing agents are urgently required for clinical use to deliver the requisite amounts of boron to tumor cells. The delivery of boron-containing agent can also be optimized to improve cancer cell uptake and subcellular distribution. Additionally, it is crucial to design high intensity neutron sources and establish hospital-based BNCT. Compared with nuclear reactors, accelerator-based neutron sources are more realistic to be applied in clinical practice. In future, the critical issues regarding novel boron-containing agents, the appropriate delivery strategies, and neutron sources of BNCT for clinical use must be addressed. Two clinical trials with newly diagnosed glioblastoma have been reported, BNCT alone after surgery provided a mean survival time of 17.7 and 19.5 months respectively. The survival outcomes were good as compared to the current standard of care which is post-operation fractionated radiotherapy with concomitant and adjuvant TMZ. Several clinical studies of BNCT in the treatment of recurrent head and neck cancer have been reported, with high response rate and acceptable toxicity. To date, BNCT has been clinically evaluated as an alternative to conventional radiotherapy for the treatment of several tumor types, including newly diagnosed glioblastoma, recurrent glioma, recurrent head and neck tumors, meningioma, malignant melanoma, and liver metastasis. Recently, accelerator-based neutron source has been used in clinical trials for recurrent malignant gliomas and head & neck cancers. Although initial results with BNCT are promising, high-quality prospective clinical trials are still lacking. Well-designed phase II/III clinical research is necessary to define the efficacy and safety of BNCT in various tumor types. Meanwhile, studies comparing the outcomes of BNCT with other standards of care are needed for the further development of BNCT. Based on the previous studies, the BNCT clinical trials in glioblastoma can be initiated with newly diagnosed glioblastoma patients. For other tumor types, late-stage patients with recurrent or metastatic disease after the first-line treatment might be recruited. Last but not the least, in the era of comprehensive treatment for malignant tumor, it is necessary to explore the combined treatment mode of BNCT. For the future research, BNCT may be coupled with a variety of anti-tumor modalities, including traditional photon radiotherapy, immunotherapy, targeted therapy and chemotherapy. It is also possible to explore a variety of drug delivery methods to improve the uptake of boron-containing agents by tumor sites. Multidisciplinary model is needed to jointly promote BNCT to become a routine clinical treatment modality.