The biological treatment planning evolution of clinical fractionated radiotherapy using high LET

Starting from the birth of high linear energy transfer (LET) radiotherapy in USA in the mid-1970s, the field has continuously evolved and to date over 20,000 patients have been treated with ¹²C ions worldwide. The purpose of this contribution is to review the advancements in clinical fractionated radiotherapy using high LET radiation in the last decades, with special focus on biological treatment planning. Along with technological developments for ion acceleration and beam delivery, progress in radiation biology and computational modeling has enabled a remarkable evolution in the planning capabilities of highly conformal, biologically optimized treatment with high LET radiation. In particular, recent efforts have provided the possibility of direct comparison between treatment plans obtained at different facilities with different biological models for the same ion species. This achievement represents an important step forward to gather better understanding of the remaining uncertainties in biological modeling and the impact of fractionation for optimal dose prescriptions, ultimately aiming to promote clinical exploitation of the anticipated, yet not fully demonstrated advantages of high LET-charged particles.