Dysphagia is a dose-limiting toxicity of radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC), and is the primary functional endpoint of contemporary oropharyngeal cancer trials (e.g., RTOG-1221, ECOG-3311). Conformal methods of radiation delivery hold promise to lessen the burden of dysphagia by minimizing dose to dysphagia-aspiration related structures (DARS). Recent work has focused on dose to the pharyngeal constrictors and larynx as a driver of dysphagia, but emerging data suggest the importance of oral cavity dose to swallowing outcomes. Lingual strength correlates with aspiration and swallowing endpoints in healthy subjects and patients with dysphagia, and our published data show that radiation dose to the anterior oral cavity predicts for long-term dysphagia after oropharyngeal intensity modulated photon therapy (commonly referred to as IMRT). Dose trade-offs required in IMRT plans using photon beams have been shown by our collaborators to result in elevated doses to the anterior oral cavity. This is thought to contribut to a greater degree of acute mucositis and predispose to chronic dysphagia despite other dose advantages of IMRT. Proton radiation (IMPT) is proposed as a novel method to de-escalate oropharyngeal RT by reducing collateral radiation dose to uninvolved normal structures adjacent to target volumes that are largely unavoidable with traditional IMRT using photon beams. Our preliminary data support a specific dose advantage with proton therapy (IMPT) to the region of the anterior oral cavity. We hypothesize that the oral cavity dose advantage with proton therapy (IMPT) translates to functional advantages over photon therapy (IMRT) in lingual strength, and ultimately in swallowing outcome. Thus, the primary objective of this application is to establish the relationship between RT technique (IMPT versus IMRT), anterior oral cavity dose, and lingual strength as they contribute to radiation-associated dysphagia after OPSCC. In this application, we propose to conduct correlative studies in a subgroup of patients enrolled on a parent randomized radiotherapy clinical trial. The investigative team has developed an IRB-approved, activated randomized phase II/III trial of IMPT versus IMRT for oropharyngeal cancer that will examine primary toxicity and survival endpoints. In this R03 application, we propose to prospectively examine three correlative questions in a subgroup of patients enrolled in the phase II portion of this trial: 1) is lingual strength better after IMPT vs. IMRT, 2) does anterior oral cavity dose correlate with lingual strength after highly conformal oropharyngeal RT, and 3) does lingual strength correlate with dysphagia after highly conformal oropharyngeal RT?
The annual number of incident oropharyngeal cancer cases is projected to double by 2030. Oropharyngeal cancer survivors are often diagnosed young, in the 5th decade of life, and have the potential to live decades with the effects of head and neck radiotherapy required for cure of their cancer. This application seeks understand novel mechanisms that may be targeted to lessen difficulty swallowing (dysphagia) after highly-conformal curative radiotherapy for oropharynx cancer, as swallowing is a driver of post-treatment quality of life and a top functional priority among survivors.
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