Carbon Ion Radiotherapy: A Review of Clinical Experiences and Preclinical Research, with an Emphasis on DNA Damage/Repair

Abstract

Compared to conventional photon-based external beam radiation (PhXRT), carbon ion radiotherapy (CIRT) has superior dose distribution, higher linear energy transfer (LET), and a higher relative biological effectiveness (RBE). This enhanced RBE is driven by a unique DNA damage signature characterized by clustered lesions that overwhelm the DNA repair capacity of malignant cells. These physical and radiobiological characteristics imbue heavy ions with potent tumoricidal capacity, while having the potential for simultaneously maximally sparing normal tissues. Thus, CIRT could potentially be used to treat some of the most difficult to treat tumors, including those that are hypoxic, radio-resistant, or deep-seated. Clinical data, mostly from Japan and Germany, are promising, with favorable oncologic outcomes and acceptable toxicity. In this manuscript, we review the physical and biological rationales for CIRT, with an emphasis on DNA damage and repair, as well as providing a comprehensive overview of the translational and clinical data using CIRT.

Keywords: DNA repair; carbon therapy; complex DNA damage; hadron therapy; proton therapy; radiation oncology.

Figure 1

(A) Percentage depth dose (PDD) curves comparing carbon ion beams to high (18 MV) and low (120 kVp) energy photon beams. (B) Percentage depth dose curves comparing carbon ion to proton beams.

Figure 2

(A) High- linear energy transfer (LET) radiation-induced DNA damage consists of clustered lesions which eventually promote genomic instability and, if DNA repair is not successful, cell death. (B and C) Simulated particle track projections of oxygen (B, upper panel) and silicon (C, upper panel) beams. Immunofluorescence staining for the DNA damage protein γ-H2AX showing track structures in human fibroblasts after oxygen (B, lower panel) and silicon (C, lower panel) beams. (Permission was granted to adapt and re-publish these images from Sridharan et al. “Understanding Cancer Development Processes after HZE-Particle Exposure: Roles of ROS, DNA Damage Repair and Inflammation” Radiat Res 2015; 183:1–26 and from Saha et al. “Biological Characterization of the Low-Energy Ions with High-Energy Deposition on Human Cells” Radiat Res 2014; 182:282–291). ROS: reactive oxygen species.

Figure 3

Repair of high- and low-LET radiation-induced DNA damage. Low-LET radiation-induced DNA double-strand breaks (DSBs) are typically repaired by non-homologous end joining (NHEJ) or both NHEJ and homologous recombination (HR) if cells are in S or G2 phases of the cell cycle. The repair of complex DSBs generated by high LET radiation including carbon ions is poorly understood. The less efficient repair response after high-LET radiation leads to DNA damage remaining unrepaired for long periods of time and eventually may promote genome instability and cell death.