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.

PROJECT NARRATIVE. Radiation-induced fibrosis (RIF) is a common treatment-related sequela experienced by head and neck cancer survivors and is associated with co-occurring adverse treatment effects. However, an understanding of the phenotypes and predictors of RIF and subsequent adverse effects (i.e., neck disability, dysphagia) is lacking, prohibiting the development of tailored interventions to improve patient survivorship.