Integrating patient-specific clinical and biological factors towards individualizing utilization of proton and photon radiation therapy.

总体--摘要 这是马萨诸塞州综合医院和MD Anderson共同申请的项目项目赠款 癌症中心。我们在最近的计划项目(P01和U19)中取得的进展是关键的- CAL对质子治疗的临床、物理和生物学方面的影响及其作为重要癌症的意义 治疗方式。最近完成的U19(截止日期为8/31/20)的主要成就是：(1)取得了以下成就： 确定的食道、肝脏和胶质瘤的发展和激活质子与光子治疗的随机对照试验 与NRG、NCI和NCTN合作；(2)了解和模拟NOR反应的差异-- MAL组织对高度不同的质子和光子剂量分布模式；(3)了解复杂性 质子相对于光子的生物效应；以及(4)先进强度调制技术的发展。 结合物理不确定性和质子的可变生物有效性的晚期质子治疗。 我们的研究还揭示了在质子生物效应的知识方面的主要空白，显著的限制-- 当前基于群体的正常组织和肿瘤对质子与光子反应的模型，以及 面对患者特征和疾病的异质性，质子治疗的适宜性存在不确定性 未经选择的患者组的治疗技术。从好的方面来看，我们的研究还发现 质子疗法有很强的潜力来减少免疫系统的抑制，这通常与 使用光子疗法，并已被证明会导致不良后果。建议的总体目标 P01是：(A)了解质子疗法与非质子疗法的相对临床、生物学和免疫抑制效应。 光子疗法；(B)根据以下物质的物理、生物和免疫学特性提高疗效 质子和光子；以及(C)采用个体化(而不是基于种群)的方法来研究Se-Se- 为每个患者选择最佳的放射治疗方式，并提高治疗结果的潜力 使用针对个体患者基线和肿瘤特征量身定做的辐射剂量分布。这个 这些目标的实现将在三个项目中进行。项目1：了解正常组织毒素- ICity确定最有可能从质子疗法与光子疗法中受益的患者；项目2：辐射诱导 淋巴细胞减少症(RIL)：理解、预测性建模和发展基于光子和质子的缓解 策略；和项目3：研究肿瘤对质子射线治疗的增敏作用：机制 和生物标记物。这些项目在关于治疗方式选择决定方面是高度整合的， 最大限度地提高治疗率的治疗技术和优化不能通过 任何一个单独的项目。这样的决定必须考虑和平衡正常组织并发症，肿瘤复发 基于基因因子的自体和辐射诱导的免疫抑制。这三个项目将是超级- 由一个管理核心和三个资源核心提供支持：核心1：数据管理和计算 支持；核心2：翻译生物显微镜和成像生物标记物；核心3：生物统计学。

OVERALL - SUMMARY This is a joint application for a program project grant by Massachusetts General Hospital and MD Anderson Cancer Center. The progress we made in our most recent program projects (a P01 and a U19) has been criti- cal to the clinical, physical, and biological aspects of proton therapy and its significance as an important cancer treatment modality. The main achievements of the recently completed U19 (end date 8/31/20) were (1) the de- velopment and activation of definitive esophagus, liver and glioma randomized proton vs. photon therapy trials in cooperation with NRG, NCI and NCTN; (2) understanding and modeling the differences in response of nor- mal tissues to highly disparate proton and photon dose distribution patterns; (3) understanding the complexities of the biological effects of protons relative to photons; and (4) the development of advanced intensity modu- lated proton therapy incorporating physical uncertainties and the variable biological effectiveness of protons. Our research also revealed major gaps in the knowledge of the biological effects of protons, significant limita- tions of the current population-based models of normal tissue and tumor response to protons vs. photons, and uncertainty in the appropriateness of proton therapy in the face of heterogeneities in patient characteristics and treatment techniques in unselected groups of patients. On the bright side, our research also discovered the strong potential of proton therapy to reduce suppression of the immune system, which is commonly associated with photon therapy and has been shown to lead to adverse outcomes. The overall goals of the proposed P01 are (a) understanding relative clinical, biological and immunosuppressive effects of proton therapy vs. photon therapy; (b) enhancing outcomes based on the physical, biological and immunological properties of protons and photons; and (c) applying individualized (as opposed to population-based) approaches for the se- lection of the optimum radiation modality for each patient and to enhance the potential for outcomes with the use of radiation dose distributions tailored to the individual patient’s baseline and tumor characteristics. The achievement of these goals will be carried out in three projects. Project 1: Understanding Normal Tissue Tox- icity to Identify Patients Most Likely to Benefit from Proton vs. Photon Therapy; Project 2: Radiation-Induced Lymphopenia (RIL): Understanding, Predictive Modeling and Developing Photon and Proton-Based Mitigation Strategies; and Project 3: Investigating Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanisms and Biomarkers. The projects are highly integrated in that decisions regarding treatment modality selection, treatment technique and optimization to maximally enhance the therapeutic ratio cannot be accomplished by any one project alone. Such decisions must consider and balance normal tissue complications, tumor re- sponse based on genotypic factors, and radiation-induced immunosuppression. The three projects will be sup- ported by an Administrative Core and three resource cores: Core 1: Data Management and Computational Support; Core 2: Translational Biospecimens and Imaging Biomarkers; and Core 3: Biostatistics.