BIOHOT (BIOphysical characterization of Helium and Oxygen ion beams for hadronTherapy

Hadrontherapy (HT) presently uses protons and 12C ions to treat deep-seated and radioresistant tumors due to their favorable inverse dose-depth profile and, in the case of 12C ions, their higher relative biological effectiveness (RBE). However, particles of intermediate and higher charge, 4He and 16O ions, may improve dose localization and tumor control. A knowledge gap exists between predictions and available data. BIOHOT will study the biophysical properties of these ions through an integrated approach by in vitro measurements of clinically useful endpoints, cellular radioresponse predictive models, and microdosimetry. 4He ions at clinically relevant energies (≅ 250 MeV/n) present reduced lateral scattering and range straggling, with a higher linear energy transfer (LET) compared to protons, hence better spatial selectivity and increased RBE, with still negligible fragmentation beyond the Spread-Out Bragg Peak (SOBP). This is attractive for pediatric patients, where lowering the risk of radiotherapy-induced secondary cancers is mandatory. Heavier ions such as 16O, on the other hand, offer an even smaller later-scattering-generated penumbra and greater LET than 12C ions across the entire target volume, making them in principle more effective at counteracting hypoxia-induced radioresistance. In addition, at the entrance (plateau), the physical dose to normal tissue could be further decreased thanks to the higher RBE, partly offsetting the bigger fragmentation tail. As the choice of the “optimal” ion depends on several factors, e.g. type of tumor and healthy tissue, target position and depth, and beam ballistics, biologically and LET-optimized SOBPs require a thorough biophysical characterization.Therefore, we shall measure normoxic and hypoxic cancer cell death and migration, DNA damage induction and repair proficiency in cells of tumors prospectively benefitting from 4He and 16O ions, i.e., osteosarcoma and pancreatic cancer. The former is most common among children, hence a candidate for 4He-based HT; the latter is already treated with 12C ions due to its radioresistance. Normal-tissue toxicity, a limiting factor for curative dose, will be evaluated using endpoints related to late sequelae, e.g. senescence and inflammation. An innovative 3D model will be also used for a better mimicry of the in vivo environment. Monte Carlo simulations coupled with microdosimetric measurements will complete the biophysical characterization of 4He and 16O beams in terms of LET profile, secondary productions and model-verified biological and physical parameters. Activities will be carried out at Heidelberg Ion- Therapy center (HIT), where 4He-based HT is starting, and at CNAO, where a new source is planned for 2023 as use of both ions is considered. Clinical SOBPs will be thus available at both facilities during the project. Obtained data will help evidence-based, disease-specific ion type selection and serve as facility intercomparison between HIT and CNAO.