相对生物效应（RBE）是质子重离子放疗中最为重要的生物参数。面对国内外精准放疗的发展，当前主流的RBE计算方法存在各自的局限，限制了质子重离子放疗的精细化水平。同时，RBE值的精细计算对临床效应评估的影响也受到关注。因此，本文主要研究两个问题：一是如何尽可能精细地计算RBE值，二是精细RBE值对定量评估临床效应会产生哪些影响。具体工作如下：（1）建立了精细化的生物RBE计算模型MKM_1和MKM_2。在当前日本国立放射医学研究所（NIRS）使用的微剂量动力学模型（MKM）的基础上，考虑初级辐射损伤产额随射线品质的变化，改进了MKM固定的剂量二次项系数β值存在的局限，建立了更为精细的MKM_1和MKM_2。相比MKM和NIRS最新建立的SMK模型，MKM_1和MKM_2能够更好地反映物理剂量、射线品质、细胞辐射敏感性等因素对生物RBE值的影响，在应用于辐射抗性细胞和高剂量水平时更具优势，而且还进一步考虑了乏氧条件对细胞存活效应的影响。（2）探索了组织类型精细化的临床RBE计算方法。结合当前日本NIRS和德国亥姆霍兹重离子研究中心（GSI）的重离子临床RBE计算方法优势，以及本文精细生物RBE模型MKM_2，考虑组织器官的辐射敏感性差异，分别建立了更为精细的肿瘤靶区和正常组织临床RBE计算方法。以食管癌为例，对本文临床RBE计算方法和其他两种方法的计算结果进行对比分析。该方法初步探索了临床RBE的组织类型精细化，从而能够更好地借鉴光子放疗经验指导重离子治疗实践。（3）开展了精细质子重离子RBE的临床应用研究。根据精细化临床RBE计算方法，本文建立了一套碳离子放疗的临床RBE基础数据库，包含4种不同细胞辐射敏感性和26种正常组织临床效应。同时，基于真实肝癌病例，分析使用精细的变化质子RBE对正常肝组织NTCP和肝肿瘤TCP评估结果的影响，并考虑了剂量分割方案、αX/βX值不确定度等影响因素。结果显示，当前临床使用质子RBE=1.1的近似可能高估了质子治疗增益比，而且病人辐射敏感性差异的临床影响相比光子放疗可能会更为显著。本文的工作一方面系统建立了更为精细化的RBE计算方法，另一方面也为精细RBE的临床效应影响研究提供了有益参考。

Relative biological effectiveness (RBE) is the most important biological parameter in proton and heavy ion therapy. Currently, with the development of precise radiotherapy around the world, main methods of RBE calculation have their own limitations, which lower the precision level of proton and heavy ion therapy. Besides, more attention is paid to the impact of precise RBE calculation on the estimation of clinical effect. Therefore, two problems were researched in this thesis: one was how to calculated RBE as precisely as possible, and the other was how to evaluate the impact of precise RBE on the quantitive estimation of clinical effect. Main work of this thesis is shown as follows:(1) Development of MKM_1 and MKM_2 models for precise biological RBE calculation. Based on the microdosimetric kinetic model (MKM) which is now used by National Institute of Radiological Science (NIRS), two precise models MKM_1 and MKM_2 were built considering the variation of the yield of the primary radiation lesion with the radiation quality, and the limitation of the constant coefficient β for dose square term of MKM was improved. In comparison with MKM and newly SMK model developed by NIRS, MKM_1 and MKM_2 could better reflect the impact of factors such as physical dose, radiation quality and cell radiosensitivity on the biological RBE, and have an advantage in application for the radioresistant cell and high dose level. The impact of hypoxia on the cell survival was also studied. (2) Exploratory of a tissue-specific calculation method of clinical RBE. More precise calculation methods of clinical RBE for tumor and normal tissue were established respectively with tissue-specific radiosensitivity considered, combining the advantage of the method of NIRS in Japan and Gesellschaft für Schwerionenforschung (GSI) in Germany and using the precise biological RBE model MKM_2 developed in this thesis. Take the esophageal cancer as an example, the results of the calculation method of clinical RBE in this thesis and the other two methods were compared and analyzed. This method preliminarily explored the calculation of tissue-specific clinical RBE, so that the experience from photon therepay could be better utilized to guide the clinical practice of heavy ion therapy. (3) Research of the appilication of precise clinical RBE of proton and heavy ions. According to the precise calculation method of clinical RBE, a basic database for clinical RBE calculation in carbon ion therapy was built, which includes 4 kinds of cell radiosensitivities and 26 kinds of normal tissue complications. Besides, the impact of precise variable proton RBE on the estimation result of the NTCP of normal liver and TCP of liver tumor was analyzed based on the clinical liver cancer case, with the influence factors such as dose fractionation scheme and αX/βX uncertainty considered. The results show currently clinical application of proton RBE=1.1 possibly overestimates the therapeutic ratio of proton therapy, and the impact of the interpatient variability in radiosensitivity on the clinical effect could be more significant in proton therapy than in photon therapy.The research in this thesis has systematically established a more precise RBE calculation method, and could also provide a helpful reference for the study of impact of precise RBE on the estimation of clinical effect.