One of the major treatment modalities for several types of cancers is RT, and ROS and clustered DNA damage are thought to be critical to mediate the effect of IR. Many decades of experimental research in cellular and molecular radiation biology provide evidence suggesting that nuclear DNA is the critical target of IR, and both the initial and residual levels of DSBs are linked to the biological effects of radiation, and that DNA damage and repair is relevant to carcinogenesis . Precise delivery of radiation beams to site of solid tumors has improved with advances in medical physics and engineering. Among these, the use of proton beams as an alternative to traditional high energy electrons has at least in theory, improved accuracy of targeting and reduction in surrounding tissue toxicity. Long term follow-up data for significant patient cohort sizes will enable us to compare the potential benefits of proton beam therapy. OCDLs are a hallmark of IR although their endogenous levels are relatively low . Radiation dose and quality dictates the complexity of DNA damage induced by the particle. Increasing dosage and LET (linear energy transfer) correlates with higher accumulation of clustered lesions in cancer cells . The recruitment kinetics of DNA repair proteins is dependent on the level of LET . The fact that DNA repair capability is compromised with increasing complexity of damage underscores the importance of these lesions in therapy . One of the significant and therapeutic advantages of high LET IR is that there are extensive amounts of clustered damage leading to increased relative biological effectiveness (RBE) vs. both photon-based and even proton-based modalities . As recently reviewed by Mohamad et al. , comparison of conventional photon-based external beam radiation to carbon ion radiotherapy reveals that carbon ions result in a better and more targeted-to-the-tumor dose distribution, higher LET and RBE. This improved RBE relates to the unique high-LET radiation-induced complex DNA damage that overpowers the DNA repair system of tumor cells as also showed for example by earlier studies using human monocytes exposed to 56Fe ions (LET=148 keV/µm) . The use of carbon or other high-LET particles maybe a solution in the case of difficult to treat tumors, including those that are hypoxic, radio-resistant, or located deeper in the body . On the history of carbon-ion based RT, one of the pioneers was the National Institute of Radiological Sciences (NIRS) which started treating patients with beams in the Heavy Ion Medical Accelerator (HIMAC) in Chiba, Japan in 1994. Following Japan, Germany in 1997 in the Gesellschaftfür Schwerionenforschung (GSI) in Darmstadt, treated their first patient and later in the Heidelberg Ion Therapy Center (HIT) in 2009. Therefore based on clinical evidence, mostly originating from Japan and Germany, high-LET radiations maybe a promising RT modality with limited radiation toxicity .