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

项目总结。头颈癌的标准治疗(即放化疗)的强度 (HNC)在过去20年中有所扩大，导致急性毒性增加了500%。这些 要求苛刻的治疗方案使90%的HNC幸存者产生不良治疗效果。对于一些人来说，辐射诱导的 纤维化(RIF)是进行性的，导致与治疗相关的衰弱效应。最严重的后遗症是 颈部残疾和吞咽困难，这会降低生活质量和存活率。我们的研究团队已经经验地描述了 HNC幸存者颈部残疾和损伤的负担和影响。结果显示，54%的HNC 幸存者报告了颈部残疾，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的特征及其共同发生的不良反应知之甚少 治疗效果轨迹(即随时间变化的模式)，从而阻止了量身定制的发展 减少发病率的干预措施。此外，虽然可靠的生物标记物可以确定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 迟来的RIF。迫切需要了解RIF的临床轨迹和随后的不良反应 并阐明了这些轨迹中潜在的发展和变化的因素，以优化HNC 幸存者的福祉。这项研究的目的是确定RIF和共生的不同轨迹 不良治疗效果(即颈部残疾、吞咽困难)和影响这些轨迹的因素。我们的 中心假设是：1)RIF的显著变异性和共同出现的不良治疗效果存在于 接受放射治疗的HNC患者，2)这种变异将聚集成不同的轨迹，以及3)组 成员资格将由个人因素、癌症/癌症治疗特征和miRNA来解释。 变种。这项前瞻性研究(n=334)采用纵向设计，在辐射前(时间)进行评估 0)，于放疗后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。 目标1是描述RIF的轨迹和共同发生的不良治疗效果(即，颈部残疾， 吞咽困难)和它们的联系。在目标2中，我们将确定个体和癌症/治疗因素 解释RIF的变异性和共同出现的不良治疗效果。《目标3》将探索 放射治疗后24个月出现RIF和共生不良反应。最后，目标4将探索 循环中的miRNAs与RIF的轨迹和共同发生的不良治疗效果相关。团体- 将使用基于和双轨迹建模以及带有模型验证的多项Logistic回归。 这项研究对于开发干预措施以减轻RIF和随后的共生治疗效果至关重要 HNC幸存者经历了降低发病率、提高生活质量和改善生存的经验。此外，miRNAs具有 作为有希望的生物标记物的潜力，以在临床之前更好地确定RIF的风险幸存者 RIF的临床表现，并评估抗RIF治疗的疗效。

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.