Evaluation of sodium borocaptate (BSH) and boronophenylalanine (BPA) as boron delivery agents for neutron capture therapy (NCT) of cancer: an update and a guide for the future clinical evaluation of new boron delivery agents for NCT

Abstract

Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the nuclear capture and fission reactions that occur when boron-10, a stable isotope, is irradiated with neutrons of the appropriate energy to produce boron-11 in an unstable form, which undergoes instantaneous nuclear fission to produce high-energy, tumoricidal alpha particles. The primary purpose of this review is to provide an update on the first drug used clinically, sodium borocaptate (BSH), by the Japanese neurosurgeon Hiroshi Hatanaka to treat patients with brain tumors and the second drug, boronophenylalanine (BPA), which first was used clinically by the Japanese dermatologist Yutaka Mishima to treat patients with cutaneous melanomas. Subsequently, BPA has become the primary drug used as a boron delivery agent to treat patients with several types of cancers, specifically brain tumors and recurrent tumors of the head and neck region. The focus of this review will be on the initial studies that were carried out to define the pharmacokinetics and pharmacodynamics of BSH and BPA and their biodistribution in tumor and normal tissues following administration to patients with high-grade gliomas and their subsequent clinical use to treat patients with high-grade gliomas. First, we will summarize the studies that were carried out in Japan with BSH and subsequently at our own institution, The Ohio State University, and those of several other groups. Second, we will describe studies carried out in Japan with BPA and then in the United States that have led to its use as the primary drug that is being used clinically for BNCT. Third, although there have been intense efforts to develop new and better boron delivery agents for BNCT, none of these have yet been evaluated clinically. The present report will provide a guide to the future clinical evaluation of new boron delivery agents prior to their clinical use for BNCT.

Keywords: Boron neutron capture therapy (BNCT); boronophenylalanine (BPA); brain tumors; head and neck cancer; sodium borocaptate (BSH).

FIGURE 1

Chemical Structure of boronophenylalanine (BPA) and sodium borocaptate (BSH).

FIGURE 2

Dot plot of total boron concentrations (µg/g) in tumor and normal brain samples for individual patients with either astrocytomas (A) or glioblastomas (G). Patients received sodium borocaptate at a dose of 15, 25, or 50 mg/kg body weight, and tissues were sampled 3‐7 h following termination of the infusion except for 3 patients with astrocytomas, from whom tissue samples were taken after 12 h (A50,12). Normal brain boron concentrations are indicated by •, and tumor boron concentrations by ∘. Larger circles (○/●) indicate 2 identical concentrations, and the largest circles (◯/⬤) indicates 3 identical concentrations.

FIGURE 3

Blood boron concentrations from a phase II clinical trial of accelerator‐based BNCT for malignant gliomas [64] (solid line) and from a previous study by Elowitz et al. [20] (dotted line). BPA (SPM‐011) was administered intravenously at a dose of 400 mg/kg body weight over 2 h, followed by a continuous infusion of BPA at a dose of 100 mg/kg body weight until the completion of neutron irradiation. Neutron irradiation with ABNS was started 2 h post the initiation of BPA infusion (200 mg·kg⁻¹·h⁻¹ for 2 h + 100 mg·kg⁻¹·h⁻¹ for 1 h). The duration of irradiation was carefully managed to ensure the scalp irradiation dose did not exceed 8.5 Gy‐Eq. Abbreviations: ABNS, accelerator‐based neutron source; BNCT, boron neutron capture therapy; BPA, boronophenylalanine.