ABSTRACT: PROJECT 3 (OPC-RAD) Modern-day X-ray–based radiation therapy (IMRT), given with chemotherapy, has improved survival outcomes for patients with oropharyngeal squamous cell carcinoma (OPSCC). However, various radiation-related late side effects are known to cause progressive, irreversible long-term and delayed treatment sequelae, such as late radiation-associated dysphagia (L-RAD). L-RAD, occurring in about 15% of long-term survivors of OPSCC, can lead to chronic impairments in eating, weight loss, gastrostomy-tube dependence, and worse quality of life long after cure of the OPSCC. L-RAD–related aspiration can result in pneumonia, hospitalization, death, and financial toxicity for patients and the health care system. Strategies to prevent or mitigate L-RAD are urgently needed. Intensity-modulated proton therapy (IMPT) is less toxic than IMRT because it exposes less surrounding normal tissues to damaging radiation than IMRT. The ability to identify patients most likely to benefit from IMPT to mitigate the risk of developing L-RAD after IMRT would help to ensure the best use of limited resources. To date, no such means of doing so have been identified. Pentoxifylline+Tocopherol (PENTOCO) are being investigated for radiation-induced fibrosis; however, whether these drugs can prevent and mitigate L-RAD is unknown. We are running the largest multi-site (21 institutions) phase II/III randomized trial comparing IMPT vs IMRT for the treatment of OPSCC (NCT01893307); we recently completed the enrollment and treatment of all 440 patients. Among the goals of this ongoing trial is to robustly characterize outcomes through 5 years after treatment. We are also initiating a new prospective, longitudinal trial “STOP4LATE-FIBROSE”, which will have 250 patients enrolled and is seeking the therapeutic potential of PENTOCO as antifibrotic agents in the early post-RT phase to prevent and mitigate cutaneous and subcutaneous radiation-induced fibrosis. Here, to define the trajectories and mechanisms underlying L-RAD after IMPT or IMRT, we aim to (i) extend data collection for trial NCT01893307 to 10 years (outcomes are survival, toxicity, trismus measurement, test of masticating solids and swallowing, taste impairment, salivary function, and oral intake score); (ii) analyze the collected data to identify relevant markers of L-RAD (e.g., dosimetric, biological, imaging, functional, and patient-reported outcomes [PROs]); (iii) evaluate whether IMPT (vs. IMRT) can prevent or mitigate L-RAD, and whether pentoxifylline+ vitamin E can prevent or mitigate L-RAD. Our long-term objectives are to identify means of preventing and mitigating L-RAD. Our immediate goals are reflected in our specific aims: (1) Characterize L-RAD after IMPT vs. IMRT, and identify phenotypes of L-RAD. (2) Determine mechanisms underlying L-RAD after IMRT vs. IMPT; model the risk of developing L-RAD after IMPT vs. IMRT. (3) Determine the relative efficacy of PENTOCO for preventing and reducing of...