Feasibility Study on the nIORT® Adjuvant Treatment of Glioblastoma Multiforme through the Irradiation Field of Fast Neutrons Produced by a Compact Generator

Abstract

The glioblastoma multiforme (GBM) is the most malignant glial brain tumour with average survival time of 6÷18 months. Emerging evidence suggests that GBM cells appears to reprogram their tumour microenvironment, which is a highly heterogeneous and complex system, so that an efficient GBM radiotherapy (RT) should cover both the cells of the GBM and those of its microenvironment. Relying on a 5-year collaborative research study on the intra-operative radiotherapy (IORT) with fast neutrons - the so-called neutron-IORT (nIORT®) technique - the authors think that this objective could be achieved by using an ionizing radiation field of fast neutrons that behave in the biological tissues as a “foam field” hitting both the GBM cancer cells and the neighbouring microenvironment. The nIORT® research activities - conducted by TheranostiCentre Srl, Berkion Technology LLC and ENEA - led to the fabrication of the first prototype of a compact neutron generator (CNG) that, through the deuterium-deuterium fusion reaction, produces neutrons of 2.45 MeV energy having: i) high linear energy transfer; ii) very high relative biological effectiveness (RBE), about 16 times higher than X-rays (and electrons) used in standard RT and IORT treatments; iii) reduced oxygen enhancement ratio, and hence resulting be very effective in cancer cells necrosis and apoptosis. The CNG is self-shielded, limited in size and weight (~120 kg) and manageable remotely by a robotic arm. A new prototype equipped by a cylindrical applicator to be inserted in the surgical cavities is currently under construction, with some technical advancements making possible its installation in an operating room dedicated to nIORT® treatments without posing any safety and environmental concern. In this article the nIORT® potentiality was investigated in the view of the GBM treatment, but the study is however generalisable for the neutron irradiation of other brain cancer pathologies. Accurate Monte Carlo simulations, modelling the CNG equipped with a couple of cylindrical applicators of 4 and 6 cm in diameter inserted in the brain surgical cavity after craniotomy, demonstrated that the nIORT® device operated at 100 kV-10 mA DC supplies a neutron flux ~108 cm-2 s-1 and can deliver equivalent dose rates ~5 Gy (RBE)/min in the centre of the tumour bed. Thus, it could administer the clinical endpoints foreseen by the standard IORT protocols (~10-20 Gy (RBE)) in treatment times of few minutes, by providing a sort of “switching on and off neutron brachytherapy tool” without using needles of radioisotopes (e.g., 252Cf). The near isotropic neutron emission allows to irradiate the tumour bed margins, normally filled by potential quiescent cancer cells, with lower (but still significant) dose levels. This should improve the local control of the tumour through the reduction of local recurrences and metastasis in the tumour microenvironment, and at the same time to avoid adverse effects of the administered neutron radiation field on the surrounding brain central nervous system. Also, the rapid decrease in tissue depth of the dose gradient (within few centimetres) should avoid any adverse effect on normal brain tissues and the neighbouring organs.