Novel Functional Anatomic and Biomarker Indices of Radiation-Induced Female Sexual Toxicities in a Multi-Center Cohort

项目摘要 到2020年，美国约有100万女性患者将患有盆腔癌，其中约一半将 在治疗过程中接受了放射治疗。优化癌症导向和 支持疗法，以尽量减少辐射的副作用，提高生活质量越来越多， 认可.在癌症治疗对生活质量产生不利影响的许多方面中， 继续从事愉快的性行为，这是人类一生中必不可少的功能， 女性癌症幸存者长期被忽视的临床问题。毒性和正常组织的当前分类 在放射肿瘤学中，对女性勃起组织的解剖学和关键功能（唤醒）的解释很差 和性高潮）的能力。此外还 尚未测试放射治疗后观察到的阴道和粪便微生物组生态的变化是否 有助于增加对辐射引起的阴道毒性和性功能障碍的易感性， 最近在辐射引起的胃肠道毒性的背景下进行了探索。因为大约70%的女性 盆腔恶性肿瘤现在存活至少5年，必须确定预测因子和机制， 长期女性性功能障碍，以改善生活质量的显着作用，给予性活动的整体 well-being.加速减轻或预防盆腔放疗相关女性性功能障碍的进展 功能障碍，我提出的研究目的是1）建立一个功能解剖域（皮肤，阴道， 勃起）分类的长期辐射相关性功能障碍的多中心，纵向队列， 接受盆腔放射治疗的女性患者; 2）定义和/或验证性放射治疗的新剂量学预测因子 每个解剖结构域中的功能障碍;以及，3）确定每个解剖结构域的定量成像和微生物组生物标志物指数。 对特定性器官的辐射损伤。我提出的研究将是第一个分析 放射治疗对女性勃起解剖器官的影响，从而阐明了 不良的性功能结果，特别是与性唤起和性高潮有关的结果， 了解辐射对所有女性性解剖领域的影响。这些进步将使重新设计 放射治疗方案，以改善这种结果和识别成像生物标志物，以评估剂量- 数量反应和这些干预措施的有效性。此外，我们将率先测试 假设观察到的阴道和粪便微生物组生态学的改变有助于增加 对辐射引起的阴道毒性和性功能障碍的敏感性。我的目标是开创 这些代表性不足的科学领域提供了一个创新的，量身定制的方法，以预防，缓解， 和治疗放射治疗相关的女性性毒性。

Project Summary Abstract In 2020, about 1 million female patients in the US will be living with pelvic cancers, and roughly half of them will have received radiation during their course of treatment. The importance of optimizing cancer-directed and supportive therapies to minimize the adverse effects of radiation and improve quality of life is increasingly recognized. Among the many aspects of quality of life adversely impacted by cancer treatment is the ability to continue engaging in pleasurable sexual behaviors, an essential human function throughout the lifespan, and a clinical problem long overlooked in female cancer survivors. Current classifications of toxicity and normal tissues in radiation oncology account only poorly for the anatomy and critical function of female erectile tissues (arousal and orgasm) with respect to such patients' capacities to engage in pleasurable sexual behaviors. In addition, it has yet to be tested whether observed alterations of vaginal and stool microbiome ecology after radiotherapy contribute to increased susceptibility to radiation-induced vaginal toxicity and sexual dysfunction, as has been explored recently in the context of radiation-induced gastrointestinal toxicity. Because roughly 70% of women with pelvic malignancies now survive at least 5 years, it is imperative to identify predictors and mechanisms of long-term female sexual dysfunction to improve quality of life given the significant role of sexual activity in overall well-being. To accelerate advances in mitigating or preventing pelvic radiotherapy-associated female sexual dysfunction, my proposed research aims to 1) establish a functional anatomic-domain (dermatologic, vaginal, erectile) classification of long-term radiation-related sexual dysfunction in a multi-center, longitudinal cohort of female patients undergoing pelvic radiotherapy; 2) define and/or validate novel dosimetric predictors of sexual dysfunction in each anatomic domain; and, 3) identify quantitative imaging and microbiome biomarker indices of radiation damage to specific sexual organs. My proposed study will be the first to analyze the effects of radiotherapy on the erectile anatomic organs in females, and will thereby both elucidate the anatomic bases of adverse sexual function outcomes, especially those related to arousal and orgasm, and advance overall understanding of radiation effects for all female sexual anatomic domains. These advances will enable redesign of radiotherapy protocols to improve such outcomes and identification of imaging biomarkers to assess dose- volume response and the effectiveness of such interventions. In addition, we will be the first to test the hypothesis that observed alterations of vaginal and stool microbiome ecology contribute to increased susceptibility to radiation-induced vaginal toxicity and sexual dysfunction. I aim to pioneer key discoveries in these underrepresented scientific areas to provide an innovative, tailored approaches to prevention, mitigation, and treatment of radiotherapy-associated female sexual toxicities.