Prognostic Biomarkers for Patients With Human Papillomavirus (HPV) Positive Oropharyngeal Squamous Cell Carcinoma

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.