Full Exchange Pharmacokinetic Model Analysis of Dynamic Contrast-Enhanced MRI Data for Identification of Vascular Habitats and Evaluation of Treatment Response in Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinomas

The current standard of care treatment for inoperable human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) patients includes concurrent cisplatin and radiation therapy with a total dose of 70Gy over a period of 7 weeks. As reported by our group and others, the full dose of CRT regimen is associated with a considerable acute and chronic toxicity profile, negatively impacting the quality of life of OPSCC patients. Moreover, treatment related morbidities result in adverse social and economic consequences. Given that HPV-positive OPSCCs are more chemo-radiosensitive in patients who are typically younger and have a high likelihood of surviving their disease, there is great interest across the world in the development of de-escalated therapeutic strategies. The de-escalation approaches include omitting, replacing, or reducing cytotoxic chemotherapy; reducing dose or field of radiation therapy; and incorporation of less-invasive surgical procedures. The goal of these treatment de-intensification strategies is to maintain good cure rates while preserving normal functional outcomes and minimizing long-term morbidity.

Despite promising outcome measures with de-escalated radiation therapy in HPV-positive OPSCC patients, clinical trials have also reported considerable variability in response among individual patients receiving low-dose radiation therapy. Between 5-25% of these patients develop disease recurrence (at loco-regional or distant sites) within 2 years post-treatment. Recently, two large phase-III trials, RTOG 1016 and De-ESCALaTE, demonstrated inferior outcomes [hazard of locoregional failure in de-escalated treatment arm was more than twice that of standard of care treatment arm (HR=2.05, 95%CI=1.35-3.10; p=0.0005)] in HPV-positive OPSCC patients. Taken together, these findings advocate for applying a cautious approach while selecting HPV-positive OPSCC patients for de-escalation therapies. In clinical practice, less advanced tumor (T0-T3) or nodal (N0-N2) stage, and non-significant smoking history (less than or equal to 10 pack years as threshold) are generally used for selecting patients for de-escalation therapies. However, there is a lack of consensus on the utility of these highly subjective factors which are not sufficiently appropriate to identify suitable candidates for participating in de-escalation trials. Additionally, response to induction therapy, determined by greater than or equal to 50% reduction in tumor size, relative to baseline, has been used to select patients. However, measurement of tumor volume using anatomical images alone is not a good predictor of treatment response. Assessment of pre- and early post-treatment hypoxia from the primary tumor and metastatic nodes using F-FMISO (fluoromisonidazole)-positron emission tomography (PET) has also been used to select patients for receiving de-escalated radiation therapy. However, nonspecific and overlapping findings have been reported with F-FMISO-PET in HNSCCs, raising concerns about its utility as a reliable imaging biomarker. Moreover, F-FMISO radiotracer is not readily available for clinical applications around the world.

Therefore, there is a pressing need for the development of reliable, objective, and quantifiable MRI biomarkers for risk stratification and individualized decision making for HPV-positive OPSCC patients.