Project 2: Mitigation of radiation toxicity in treatment of sarcoma with FLASH vs. Standard dose rates

项目 2：使用 FLASH 与标准剂量率治疗肉瘤时减轻放射毒性

基本信息

批准号：
10573285
负责人：
Theresa M Busch
金额：
$ 47.81万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573285
关键词：
Abdomen Acute Adjuvant Therapy Amputation Anatomy Attenuated Blood Vessels Bone Tissue Canis familiaris Cells Clinic Clinical Clinical Trials Design Data Development Disease Dose Dose Rate Electron Beam Excision Fibrosis Fracture Future Goals Growth Human Implant Incidence Inflammation Inflammatory Injury Intestines Investigation Leg Limb structure Long-Term Survivors Lymphedema Malignant Neoplasms Marrow Modality Modeling Morbidity - disease rate Mus Necrosis Neoadjuvant Therapy Normal tissue morphology Operative Surgical Procedures Pathologic Patients Phase Process Production Protocols documentation Protons Radiation Toxicity Radiation therapy Recovery Regimen Reporting Risk Safety Schedule Second Primary Cancers Second Primary Neoplasms Severities Skin Soft tissue sarcoma TP53 gene Testing Therapeutic Therapeutic Index Therapy trial Time Tissues Toxic effect Transgenic Mice Translating Tumor Volume VEGFC gene Vascular Endothelial Growth Factor C Whole-Body Irradiation Work barrier to care bone chronic ulcer clinical outcome assessment clinically relevant design efficacy study in vivo irradiation knock-down mouse model novel osteosarcoma particle phase 1 study preservation proton beam proton therapy radiation mitigation safety and feasibility sarcoma side effect skin damage soft tissue standard of care stem tissue injury translational study tumor

项目摘要

Project Summary Radiotherapy (RT) is used in the treatment of soft tissue sarcomas (STS), frequently in conjunction with surgical removal of gross disease. For pre-op RT, 50 Gy equivalent in 2 Gy fractions (EQD2) is commonly used, while post-op RT requires 60–66 Gy (EQD2). For definitive (curative with RT alone) schedules, doses from 75– 100 Gy (EQD2) are needed. Paralleling changes in the RT field, STS are being treated with increasingly hypofractionated schedules, but the combination of high dose and/or high dose per fraction RT to larger tumor volumes can increase normal tissue toxicity. Indeed, patients with STS who receive RT risk major bone and soft tissue problems including skin toxicity, non-healing ulcers, necrosis, lymphedema, bone fractures and second malignant neoplasms (SMNs). This project will test the overall hypothesis that FLASH proton radiotherapy (F- PRT) spares normal soft tissues and bone from early/late toxicities compared with standard PRT (S-PRT), whereas the two modalities will be isoeffective in controlling sarcoma growth. Our preliminary data show reduced skin damage, normal tissue inflammation, lymphedema, and vascular damage with F-PRT vs S-PRT. In addition to modeling typical side effects of RT, as a malignancy that requires high dose RT to achieve local control, sarcoma represents a good proving ground to evaluate whether F-PRT sufficiently modulates RT therapeutic index to be clinically useful in other cancers. In Aim 1, the ability of F-PRT to abrogate tissue effects that pose barriers to the treatment of sarcomas with RT will be tested using the following hypotheses in in vivo mouse models: (i) the inflammatory component of normal tissue toxicity to F-PRT will be attenuated relative to S-PRT, leading to less severe fibrosis and lymphedema after F-PRT compared to S-PRT by reducing the production of pivotal drivers, such as TFG-b and VEGF-C (ii) F-PRT will produce less injury to tissue vasculature and preserve its associated matrix, providing for faster and more complete recovery of skin and bone than is feasible with S- PRT. In Aim 2, we will assess clinical outcome in murine sarcomas treated with F-PRT. Among the long-term survivors of mice treated with whole body irradiation, we find fewer tumors in the F-PRT-treated group than in the group treated with S-PRT. In Aim 2.1, we will employ a mouse model with transient p53 knockdown in conjunction with wildtype controls, to test the ability of F-PRT to reduce the incidence of SMNs compared with S-PRT. In Aim 2.2 we will perform dose escalation studies in mice bearing sarcomas to define the therapeutic window of F-PRT when added in the pre-op setting as either one or three fractions. In Aim 3, we will conduct a phase 1 dose escalation study using pre-op (amputation) doses from 21-30 Gy (4 dose levels) in one fraction to determine safety and tolerability of F-PRT and provide pathologic evidence of efficacy. For a phase 2 definitive trial, we will determine feasibility, toxicity and efficacy of hypofractionated (3 fraction) F-PRT at a BED-matched maximum dose level informed by the Phase I study to provide parameters for the design of future F-PRT trials in humans with STS and other malignancies.

项目概要放射治疗 (RT) 用于治疗软组织肉瘤 (STS)，通常与对于术前放疗，通常使用 2 Gy 剂量中的 50 Gy 当量 (EQD2)，而术后放疗需要 60-66 Gy (EQD2)，对于最终的（单独放疗即可治愈）方案，剂量为 75- 需要 100 Gy (EQD2) 来并行改变 RT 场，STS 的治疗也越来越多。大分割方案，但针对较大肿瘤采用高剂量和/或每次分割高剂量放疗的组合事实上，接受放疗的 STS 患者会增加主要骨骼和软组织的毒性。组织问题，包括皮肤毒性、不愈合的溃疡、坏死、淋巴水肿、骨折和第二该项目将检验 FLASH 质子放射治疗 (F-) 的总体假设。与标准 PRT (S-PRT) 相比，PRT）可以使正常软组织和骨骼免受早期/晚期毒性，而我们的初步数据显示，这两种方法在控制肉瘤生长方面效果相同。此外，F-PRT 与 S-PRT 相比还可以减少皮肤损伤、正常组织炎症、淋巴水肿和血管损伤。模拟放疗的典型副作用，作为一种需要高剂量放疗才能实现局部控制的恶性肿瘤，肉瘤是评估 F-PRT 是否足以调节 RT 治疗的良好试验场目标 1 是 F-PRT 消除组织效应的能力。将使用以下假设在小鼠体内测试放疗治疗肉瘤的障碍模型：(i) F-PRT 正常组织毒性的炎症成分相对于 S-PRT 会减弱，与 S-PRT 相比，F-PRT 后通过减少关键驱动因素，如 TFG-b 和 VEGF-C (ii) F-PRT 将对组织脉管系统产生较小的损伤并保护组织血管系统其相关基质，比 S- 能够更快、更完全地恢复皮肤和骨骼 PRT。在目标 2 中，我们将评估 F-PRT 治疗的小鼠肉瘤的长期临床结果。在接受全身放射治疗的小鼠的幸存者中，我们发现 F-PRT 治疗组的肿瘤比对照组少在目标 2.1 中，我们将采用短暂性 p53 敲低的小鼠模型。与野生型对照相结合，测试 F-PRT 与对照组相比降低 SMN 发生率的能力在目标 2.2 中，我们将在患有肉瘤的小鼠中进行剂量递增研究，以确定治疗方法当作为一个或三个分数添加到预操作设置中时，F-PRT 的窗口在目标 3 中，我们将进行一次。第一阶段剂量递增研究，使用术前（截肢）剂量从 21-30 Gy（4 个剂量水平）分次到确定 F-PRT 的安全性和耐受性，并为 2 期疗效提供病理学证据。试验中，我们将确定大分割（3 分割）F-PRT 在 BED 匹配的可行性、毒性和疗效 I 期研究提供的最大剂量水平为未来 F-PRT 试验的设计提供参数患有 STS 和其他恶性肿瘤的人类。