Project 1: OPC-ORN

ABSTRACT: PROJECT 1 (OPC-ORN) Current standard-of-care external beam radiotherapy (EBRT) for human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) offers high cure at the cost of severe delayed adverse sequelae. Osteoradionecrosis (ORN) is a highly morbid, delayed bone-related complication that at early stages causes pain and multiple dental procedures, and later stages progresses to jaw fracture, possible oral fistula, and requires major oral surgery for removal of de-vascularized mandibular bone, thus with substantial implications on healthcare costs, function, and quality of life. Given the excellent outcomes for HPV-associated OPC and long-term survival of these typically younger patients, early detection, surveillance, and mitigation of delayed adverse sequelae such as ORN to improve survivorship represents a major healthcare challenge. Through our studies we have established elevated DCE-MRI Ktrans as a candidate diagnostic biomarker of mandibular injury under FDA-NIH BEST (Biomarkers, EndpointS, and other Tools) definitions, as well as a reasonably likely surrogate endpoint of ORN. A significant knowledge gap exists relative to the actual incidence, symptom trajectory and potential biomarkers of ORN development after post-radiation latency this growing OPC survivor population and innovative strategies are necessary to identify and monitor this chronic/delayed ORN-associated therapeutic sequela. The challenge of managing therapy-related normal tissue injury represents a significant unmet public health need. Our work promotes the overarching hypothesis that subclinical mandibular injury is prevalent before symptomatic manifestation, can be risk-stratified by dosimetric and clinical criteria before observable ORN, is presaged by both image biomarker and symptomatic progression, and can be potentially altered by hemorheologic drug candidates. We will develop our approach through the following Specific Aims (SAs). First, we will prospectively characterize the natural history, temporal symptom, and candidate imaging biomarker trajectories in OPC survivors at elevated risk of ORN. We aim to prospectively characterize time-to-ORN disease states and related toxicity events via objective measures, and validate clinico- dosimetric time-to-event models, including modifying treatments (e.g., proton therapy, pentoxifylline) and imaging biomarkers. Second, we will define potential toxicity profiles as phenotypic biomarker for ORN-related toxicity clusters and marker for patient-centered tracking of ORN outcomes. Third, we will evaluate in vivo revascularization profiles of hemorheologic drug candidates (pentoxifylline vs cilostazol) within a pragmatic “window of opportunity” trial for patients with advanced ORN planned for image-guided segmental mandibulectomy/reconstruction. We expect to provide critical knowledge regarding clinical markers, trajectories, and mitigation of ORN to enhance our efforts to monitor and treat this devastating delayed sequela of curative treatment.