Quantitative Imaging Biomarker Prospective Validation of Dynamic Contrast-Enhanced MRI as a Metric of Orodental Injury After Radiotherapy (QI-ProVE-MRI)

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PROJECT SUMMARY The rise in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has resulted in a rapidly increasing number of younger and healthier patients being treated with locoregional radiation therapy (RT). Although effective in curing the cancer, deleterious RT effects upon organs-at-risk (OARs) such as the salivary glands, swallowing/masticatory muscles, and mandibular bone can result in lifelong sequelae of RT normal tissue injury such as xerostomia, dysphagia, and osteoradionecrosis (ORN), respectively. These long-term sequelae in a patient population with good clinical outcomes and extended life expectancy are increasingly relevant as latent sources of morbidity and mortality in cancer survivorship. Despite this urgency, a standardized staging and monitoring system to identify patients at risk for developing ORN and other morbidities, and to assess the effectiveness of interventional therapies, is not currently available. At our institution, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is being integrated into a multimodality clinical algorithm aimed at improving diagnosis, staging, and surveillance of disease and toxicity. DCE-MRI can detect altered bone vascularity associated with bone healing, necrosis, and metastatic involvement, with excellent spatial resolution. Based on our previous NIH-funded research, we hypothesize that an increase in DCE-MRI parameters (i.e., Ktrans/Ve) at any timepoint more than 3 months after RT demonstrates increased risk of normal tissue treatment-related toxicity rates. Our objective is to conduct a biomarker analytic and clinical validation study designed to confirm DCE-MRI parameters as quantitative imaging biomarkers, with the formal deliverable of an application for FDA Biomarker Qualification at study completion, via the following specific aims: 1) Prospective qualification and validation of DCE-MRI Ktrans/Ve as an “FDA BEST-defined” quantitative imaging monitoring biomarker of ORN risk; 2) Investigation of DCE-MRI candidate biomarkers for pre-qualification as quantitative imaging biomarkers of soft-tissue structures; 3) Standardization of image acquisition and open source computational/analytic software for orodental DCE-MRI as a potential component of FDA biomarker qualification. Successful completion of this proposal has the potential to revolutionize the diagnosis and management of late RT-induced morbidities and offer clinicians a reliable and FDA Biomarker Qualification Program validated biomarker to stratify patients at risk for OARs injury after RT, monitor bone and soft tissue injury and subsequent oral morbidity, and manage post-RT care appropriately. This work is particularly relevant to NIDCR’s mission of “advancing fundamental knowledge about dental, oral, and craniofacial health and disease and translate these findings into prevention, early detection, and treatment strategies that improve overall health for all individuals and communities across the lifespan”.