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 tumor-confined increase of radiobiologically effective doses by irradiation with a primary beam is the Boron Neutron Capture Therapy (BNCT) which exploits the 10B(n,a)7Li reaction. The BNCT is defined as a binary approach since an external neutron beam serves no therapeutic purpose by itself but is needed to trigger the secondary particles which bring about the radiobiologically effective action on the tumor A boron-10 (10B)-labeled carrier must deliver higher concentrations of 10B to target tumor cells compared to the concentrations uptaken by surrounding normal tissues. The administration of borated formulation is followed by irradiation with low-energy neutrons. When a neutron collides with 10B, high-LET particles, i.e., a-particles and recoiling 7Li particles, are released within one cell’s diameter by the 10B(n, a)7Li neutron capture reaction, which occurs with a high cross section (3738 b) at thermal energy. These high-LET particles can destroy the 10B-containing cells without exerting hazardous effects on the adjacent normal cells. Therefore, if sufficient quantities of boron compounds can be made to accumulate selectively in tumor cells with enough contrast to surrounding normal cells, the BNCT becomes an ideal radiotherapy modality. The selective properties of BNCT make it a radiotherapy option potentially useful also for disseminated or infiltrated malignancies. BNCT requires: a) low-energy neutron beams, whose availability is not trivial; b) selectivity in boron uptake by tumor cells only; c) a complex dosimetry of the mixed-field arising from neutron interaction with the tissue elements. Recently another binary approach has been proposed that exploits the 11B(p, a)8Be reaction, whose cross section resonates at 675 keV, hence being termed Proton-Boron Capture Therapy (PBCT). In protontherapy such energies are those of protons as they slow down across the tumor region. The latter eliminates the requirement for selective boron uptake by cancer cell as alpha particles will be not generated, in principle, in healthy tissues at the beam entrance channel where incident proton energy is too high from that of the cross section maximum; thus if proven viable, PBCT would elegantly bypass one of the most critical requirements of BNCT.