Proton boron capture therapy and neutron capture enhanced proton therapy: a critical review of investigational approaches in proton therapy.

Proton Boron Capture Therapy (PBCT) and Neutron Capture Enhanced Proton Therapy (NCEPT) have been proposed as investigational approaches to improve the therapeutic effectiveness of proton therapy through additional nuclear reactions within the tumor region. Both techniques aim to enhance localized energy deposition and biological damage by introducing boron or other neutron capture agents prior to proton irradiation. Following their introduction, numerous theoretical, simulation-based, experimental and microdosimetric studies have been conducted to evaluate their potential. However, the reported outcomes remain highly inconsistent, ranging from significant dose enhancement to negligible effects, making the actual therapeutic benefit of these approaches controversial. This review provides a comprehensive and critical analysis of proton therapy-based PBCT and NCEPT studies reported in the literature. Theoretical models, Monte Carlo simulations, experimental investigations, and microdosimetric evaluations are systematically examined and compared in order to provide a concise overview of the current understanding of these techniques. Particular emphasis is placed on the underlying physical mechanisms, reported dose enhancement and biological implications. Analysis of the available literature indicates that, under clinically relevant boron concentrations, both PBCT and proton therapy-based NCEPT generally produce negligible or only marginal enhancement. Even at elevated boron concentrations, most studies have reported limited enhancement, although some investigations have observed significant physical or biological effects. The primary limitations are the relatively low proton-boron reaction cross section in PBCT and the insufficient production of thermal neutrons in proton-based NCEPT. However, limited physical dose enhancement does not necessarily exclude biological effects reported experimentally, which require further microdosimetric and radiobiological investigation. Overall, the clinical applicability of these approaches remains uncertain and requires further investigation.