# Investigating the Secondary Thermal Neutron Intensity of Neutron Capture-Enhanced Proton Therapy
## 4 Discussion
This is attributed to thermal neutrons produced during proton irradiation becoming isotropic as they result from evaporation processes and undergo scattering, leading to a characteristic 1/En energy distribution. [PERSON] et al. reported that proton irradiation generated thermal neutrons in the order of 10\({}^{8}\) per Gy, which could significantly enhance therapeutic efficacy with a realistic neutron capture agent concentration [6]. In contrast, in our study, we found a thermal neutron fluence in the order of 10\({}^{7}\) per Gy, which was approximately lower than that reported by [PERSON] et al. This result may be attributed to differences in the energy range of the neutrons generated or factors related to the spot size and energy of the proton beam. However, since alpha particles produced from neutron capture have high radiation weighting factors (approximately 20-fold) and LET characteristics, an increase in the biological dose remains promising. Figure 5 shows that target depth influences thermal neutron fluence, with deeper targets producing more thermal neutrons. However, this displacement increased with the proton energy as the neutron peak shifted away from the proton Bragg peak, and a difference of 15.9 cm was observed at the maximum energy of 228.7 MeV. SOBP and thermal neutron peak alignment are crucial for an optimal NCEPT. In our study, when the proton energy was 90.8 MeV, the depths of the Bragg and thermal neutron fluence peaks were most closely aligned, with a depth of 6.5 cm. To deliver the same dose to targets deeper than this region, a higher proton energy and a larger number of protons are required. However, in such cases, the peak of the thermal neutron fluence could occur outside the target region. This issue can be addressed by adjusting the direction of the proton beam and modifying the proton-beam path length using a bolus material. Specifically, the bolus extends the path length, which in turn increases the proton energy used, leading to a separation between the SOBP and the secondary thermal neutron peak. This minimizes unexpected BNCRs in at-risk organs and creates the dose distribution to incorporate the thermal neutron intensity required for sensitization at the target position. Our findings are critical in developing a treatment plan that achieves the desired thermal neutron distribution and maximizes the dose enhancement effects in NCEPT. These findings underscore the need for caution in clinical applications, particularly regarding areas outside the target volume. This study has several limitations. First, this study is a phantom study, and the results may differ from actual patient treatment. Second, in current boron neutron capture therapy applications, boron-containing compounds such as boronophenylalanine are used to selectively deliver boron to tumor cells [25]. Although boronophenylalanine demonstrates relatively high uptake efficiency in tumor cells, the development of more effective and selective agents for boron delivery is crucial for improving treatment outcomes [26]. This challenge is equally relevant in NCEPT; however, it was not addressed in this study as the focus was solely on thermal neutrons. Research focused on drug development, and achieving a high thermal neutron field will likely be crucial for the successful implementation of NCEPT. Finally, conventional proton therapy typically involves approximately 20 fractionated sessions, necessitating technologies and drugs to maintain high intracellular boron levels throughout these treatments. With proton FLASH therapy exploring the application of significantly fewer fractions [27,28], the possibility of integrating NCEPT into such protocols is anticipated. These techniques and further research could enable the selective killing of cancer cells while protecting tumor stromal cells and the microenvironment to some extent; however, additional studies are required.