This work investigates the feasibility of using fast neutrons for intra-operative radiotherapy (nIORT®) in the treatment of aggressive brain cancers, particularly glioblastoma multiforme (GBM). A compact neutron generator produces neutrons of 2.45 MeV energy with high linear energy transfer, elevated relative biological effectiveness (RBE ≅3÷5 times higher than X-rays and electrons) and reduced oxygen enhancement ratio, key factors in overcoming hypoxia-mediated radioresistance. Monte Carlo simulations using the MCNP code demonstrate that the nIORT® device can deliver a diffuse high-flux beam (~108 cm-2 s-1), achieving equivalent dose rates of ~1.2 Gy(RBE)/min and allowing short irradiation times. Unlike standard IORT techniques relying on focused beams of X-rays or electrons, the diffuse neutron beam can treat large and topographically irregular tumor beds, a notable advantage in GBM. The dose gradient in tissues depth induced by fast neutrons exhibits complementary features with respect to the steep behavior of electrons and the more penetrating X-rays, that could be advantageously exploited in balancing the need for an effective local tumor control.

The compactness and limited weight (~120 kg) of the self-shielded nIORT® device remotely operated via a robotic arm, and its ability to administer high dose targets within few minutes, represent fundamental advantages in the view of possible treatments in a hospital OR dedicated to nIORT® without posing safety concerns. Although the nIORT® approach requires specialized equipment, personnel, and careful logistical planning, its enhanced efficacy and broader dose coverage suggest a significant potential in adjuvant therapy. Combining nIORT® with immunotherapy warrants further study, as fast-neutron–induced cell death could intensify immune responses and support synergistic effects of immune checkpoint inhibitors. If clinically validated, nIORT® may offer an important step toward more effective, multimodal treatment strategies - integrating surgery, chemotherapy, and immunotherapy - to improve outcomes for patients with GBM and other high-risk brain malignancies.