Increasing particle therapy biological effectiveness by nuclear reaction-driven binary strategies

Charged particle inverted dose-depth profile represents the physical pillar of protontherapy. On the other hand, there is no obvious radiobiological advantage in the use of protons since their LET in the clinical energy range (a few keV/µm, at mid-Spread-Out Bragg Peak, SOBP) is too low to achieve a cell-killing effect significantly greater than in conventional radiotherapy. This currently prevents protontherapy from being useful against intrinsically radioresistant cancers. Radioresistance of cancer cells implies dose-escalation regimes to achieve tumor local control. .In theory, every tumor can be controlled if a sufficiently high dose can be delivered that is able to suppress the proliferative potential of all cancer cells. However, in clinical practice, the maximum radiation dose is unfortunately limited by the tolerance of the surrounding normal tissue. A well-known relationship links physical radiation quality (LET) and its biological effectiveness (RBE), based on the notion that cellular lethality increases with the degree of DNA damage clustering, i.e. complexity, which reflects the nano-scale model of radiation action. Therapeutic 12C ion beams show a LET at mid-SOBP of about 50 keV/µm, conferring these particles a greater RBE for tumor cell killing, which is the radiobiological justification for their use against radioresistant cancers. However, the non-negligible dose deposition beyond the SOBP due to nuclear fragmentation and economical issues encumber this form of hadrontherapy. Additionally, limited radiobiological data exist on long-term normal tissue radiotoxicity. It is already known from previous studies that many different factors are associated with radioresistance of cancer cells and multiple reviews have already described some of the possible mechanisms underlying radioresistance during conventional radiotherapy. Examples are cancer stem cells and hypoxia, as well as perturbations in survival pathways, DNA damage repair pathways, developmental pathways. Many molecular inhibitors have been tested in combination with conventional radiotherapy, while only very few have been tested in combination with protons or carbon ions. Since particle therapy is on the rise, this calls for further exploration of these combined therapies in a preclinical setting. Previously, particle radiation facilities provided limited access for biological experiments, which limited the time to perform such experiments. However, international consortia on particle therapy research are growing and now recognize the potential of radiobiological experimental work. Therefore, the European Particle Therapy Network is producing a considerable effort to form a network of research and therapy facilities in order to coordinate and standardize radiobiological experiments. For carbon ions specifically, limited data on combination therapies are available. This is mainly due to the high RBE of carbon ions by which the additional benefit of molecular inhibitors might be difficult to demonstrate. Furthermore, the use of carbon ions worldwide is limited, which could also explain why fewer studies have been published regarding combination treatment with carbon ions. In the next paragraph, combined molecular approaches targeting specific repair pathways will be briefly illustrated, together with an outlook of recently proposed systemic approaches where radiation may upregulate the fundamental anti-cancer response by the immune system. In the context of achieving greater RBE at cell tumor inactivation while maintaining reasonably low-dose levels in healthy tissues, the role of physics and, specifically of certain nuclear reactions, has recently re-gained center stage in the form of so-called binary strategies. Historically, the first approach to predict a