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

• 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
• 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

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.

项目摘要 放射治疗(RT)用于软组织肉瘤(STS)的治疗，通常与 外科手术切除肉眼疾病。对于术前放疗，通常使用50Gy等量的2Gy分次(EQD2)， 术后放疗60~66GyEQD2。对于最终的(仅用RT治疗)时间表，剂量从75- 需要100GyEQD2。随着RT领域的变化，STS正在得到越来越多的治疗 低分割计划，但大剂量和/或高剂量/分次高剂量联合放射治疗较大的肿瘤 体积会增加正常组织的毒性。的确，接受RT治疗的STS患者有较大的骨质和软组织风险 组织问题，包括皮肤毒性、无法愈合的溃疡、坏死、淋巴水肿、骨折和第二 恶性肿瘤(SMN)。该项目将检验闪光质子放射治疗(F- 与标准PRT(S-PRT)相比，PrT)可使正常软组织和骨骼免于早期/晚期毒性， 而这两种方法在控制肉瘤生长方面将是同样有效的。我们的初步数据显示 F-PRT与S-PRT相比，皮肤损伤、正常组织炎症、淋巴水肿和血管损伤。此外 为了模拟放疗的典型副作用，将其作为一种需要高剂量放疗以实现局部控制的恶性肿瘤， 肉瘤是评估F-PRT是否充分调节RT治疗的一个很好的试验场 该指标可用于其他癌症的临床应用。在目标1中，F-PRT消除组织效应的能力 在活体小鼠中，将使用以下假设来检验RT治疗肉瘤的障碍 模型：(1)与S-PRT相比，F-PRT的正常组织毒性中的炎性成分将减弱， 与S-PRT相比，F-PRT术后纤维化和淋巴水肿不那么严重，原因是减少了 关键驱动因子，如TFG-b和VEGF-C(II)F-PRT将对组织血管系统产生较小的损伤和保存 它的相关基质，提供了比S更快、更完全的皮肤和骨骼恢复- PRT。在目标2中，我们将评估F-PRT治疗小鼠肉瘤的临床结果。在长期的 在接受全身照射的小鼠的幸存者中，我们发现F-PRT治疗组的肿瘤比 治疗组采用S-普鲁特治疗。在Aim 2.1中，我们将使用具有瞬时p53基因敲除的小鼠模型 与野生型对照相结合，测试F-PRT降低SMN发生率的能力 S-PRT。在目标2.2中，我们将在荷肉瘤的小鼠身上进行剂量递增研究，以确定治疗 将F-PRT的窗口作为一个或三个分数添加到操作前设置中。在目标3中，我们将进行 第1阶段剂量递增研究，使用术前(截肢)剂量从21-30Gy4个剂量水平的一部分到 确定F-PRT的安全性和耐受性，并提供疗效的病理证据。对于第二阶段的最终结果 试验中，我们将在床位匹配的条件下确定低分馏(3组分)F-PRT的可行性、毒性和有效性 由第一阶段研究告知的最大剂量水平，为未来F-PRT试验的设计提供参数 在患有STS和其他恶性肿瘤的人类身上。