Radiation-Induced Fibrosis and Co-occurring Adverse Treatment-Related Effects in Head and Neck Cancer Survivors

项目摘要。标准治疗的强度（即，头颈部癌症的治疗 (HNC)在过去的二十年里，这种情况已经扩大，导致急性毒性增加了500%。这些 苛刻的治疗方案使90%的HNC幸存者具有不良的治疗效果。对一些人来说，辐射引起的 纤维化（RIF）是进行性的，导致使人衰弱的治疗相关效应。最严重的后遗症是 颈部残疾和吞咽困难，这降低了生活质量和生存率。我们的研究团队根据经验描述了 HNC幸存者颈部残疾和损伤的负担和影响。结果显示，54%的HNC 幸存者报告颈部残疾，颈部残疾的增加与吞咽困难的恶化有关 症状然而，我们对RIF的特征及其并发的不良反应知之甚少， 治疗效果轨迹（即，随着时间的推移而变化的模式），从而禁止定制的开发 减少发病率的干预措施。此外，虽然可靠的生物标志物，以确定那些在RIF的最大风险， 不存在，我们的初步工作表明，特定的循环microRNAs（miRNAs）可能与 晚期RIF。有一个关键的需要，以了解临床轨迹的RIF和随后的不良反应 并阐明这些轨迹发展和变化的潜在因素，以优化HNC 幸存者的幸福本研究的目的是确定RIF和共发的不同轨迹， 不利的治疗效果（即，颈部残疾、吞咽困难）以及影响这些轨迹的因素。我们 中心假设是：1）RIF的显著变异性和同时发生的不良治疗作用存在于 接受放射治疗的HNC患者，2）这种变异性将聚集成不同的轨迹，3）分组 成员资格将通过个体因素、癌症/癌症治疗特征和miRNA来解释。 变化.这项前瞻性研究（n=334）采用纵向设计，在放疗前（时间）进行评估。 0)并在放疗后1（时间1）、6（时间2）、12（时间3）和24个月（时间4，探索性）进行随访。 目的1是描述RIF的轨迹和同时发生的不良治疗反应（即，颈部残疾， 吞咽困难）及其关联。在目标2中，我们将确定个体和癌症/治疗因素， 解释RIF的变异性和同时发生的不良治疗作用。Aim 3将探索 放疗后24个月内的RIF和同时发生的不良治疗反应。最后，Aim 4将探索 与RIF的轨迹和共同发生的不良治疗作用相关的循环miRNA。组- 将采用双轨迹模型和多项式逻辑回归模型验证。 这项研究对于制定干预措施以减轻RIF和随后的并发治疗效应至关重要 HNC幸存者的经验，以降低发病率，提高生活质量和改善生存。此外，miRNAs具有 作为有前景的生物标志物，在临床治疗前更好地确定存在RIF风险的幸存者的潜力 RIF的临床表现，并评估对抗RIF治疗的治疗反应。

PROJECT SUMMARY. The intensity of standard treatments (i.e., chemoradiation) for head and neck cancer (HNC) has amplified over the last two decades, resulting in a 500% increase in acute toxicities. These demanding regimens leave 90% of HNC survivors with adverse treatment effects. For some, radiation-induced fibrosis (RIF) is progressive, leading to debilitating treatment-related effects. The most serious sequelae are neck disability and dysphagia, which reduces QOL and survival. Our research team has empirically described the burden and impact of neck disability and impairment in HNC survivors. Results showed that 54% of HNC survivors reported neck disability and that increasing neck disability was associated with worsening dysphagia symptoms. However, we know very little about the characterization of RIF and its co-occurring adverse treatment effects trajectories (i.e., patterns of change over time), thus prohibiting the development of tailored interventions to mitigate morbidity. Also, while reliable biomarkers to determine those at greatest risk for RIF do not exist, our preliminary work indicates that specific circulating microRNAs (miRNAs) may be associated with late RIF. There is a critical need to appreciate the clinical trajectories of RIF and subsequent adverse effects and elucidate the factors underlying the development and variability in these trajectories to optimize HNC survivors’ well-being. The purpose of this study is to determine the distinct trajectories of RIF and co-occurring adverse treatment effects (i.e., neck disability, dysphagia) and the factors that impact those trajectories. Our central hypothesis is that 1) substantial variability in RIF and co-occurring adverse treatment effects exist in HNC patients receiving radiation, 2) this variability will cluster into distinct trajectories, and 3) group membership will be explained by individual factors, cancer/cancer treatment characteristics, and miRNA variations. This prospective study (n=334) uses a longitudinal design with assessments at pre-radiation (Time 0) and follow-up at 1 (Time 1), 6 (Time 2), 12 (Time 3), and 24 months (Time 4, exploratory) post-radiation. Aim 1 is to characterize the trajectories of RIF and co-occurring adverse treatment effects (i.e., neck disability, dysphagia) and their associations. In Aim 2, we will determine the individual and cancer/treatment factors that explain variability in RIF and the co-occurring adverse treatment effects. Aim 3 will explore the trajectories of RIF and co-occurring adverse treatment effects through 24 months post-radiation. Finally, Aim 4 will explore circulating miRNAs associated with trajectories of RIF and co-occurring adverse treatment effects. Group- based and dual trajectory modeling and multinomial logistic regression with model validation will be employed. This study is essential to develop interventions to mitigate RIF and subsequent co-occurring treatment effects HNC survivors experience to reduce morbidity, increase QOL and improve survival. Moreover, miRNAs have the potential to serve as promising biomarkers to better determine survivors at risk for RIF before the clinical manifestations of RIF occur and to assess therapeutic response to anti-RIF treatments.