April 09, 2021
Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) was recognized in the mid-2000s as a distinct clinical entity — seen in younger patients, with smaller primary site tumors and fewer second primary tumors, and in progressively larger numbers of patients compared with HPV-negative head and neck cancer.
"Evidence quickly arose that patients with HPV(+)OPSCC had a better prognosis than patients with HPV-negative head and neck tumors," says Eric J. Moore, M.D., chair of Otolaryngology at Mayo Clinic in Rochester, Minnesota. "Because more patients with treated HPV(+)OPSCC are living longer with excellent oncologic outcomes, many head and neck oncology teams are investigating de‐escalation treatments in an attempt to mitigate the morbidity of treatment while maintaining high disease control rates."
In 2013, Mayo Clinic instituted a prospective phase 2 trial of aggressive dose de‐escalation of adjuvant chemoradiotherapy after complete resection of HPV(+)OPSCC. The therapy consisted of two weeks of twice-daily radiation therapy (RT) totaling 30‐36 Gy with weekly doses of docetaxel 15 mg/m2. Study results were published in the Journal of Clinical Oncology in 2019.
"The trial demonstrated two‐year locoregional control, progression‐free survival, and overall survival of 96%, 91% and 99%, with improved swallowing and quality of life compared with historical controls. Some patients, however, did experience recurrence, and critiques of this study point to a favorable patient cohort and lack of comparative data," notes Dr. Moore.
To address these concerns, Dr. Moore and fellow researchers sought to compare prior de‐escalation outcomes to a contemporary cohort of patients who would have otherwise met inclusion criteria for the referenced de‐escalated RT but received standard adjuvant treatment after surgery. The researchers also aimed to identify clinical and pathological risk factors associated with progression to inform considerations around patient selection for de‐escalated therapy. Their retrospective study was published in Head and Neck in 2021.
Cohort comparison
Patients with HPV(+)OPSCC from the prior phase 2 clinical trial of primary surgery and neck dissection followed by dose de‐escalated RT (N = 79) were compared with a cohort of patients who received standard adjuvant therapy (N = 115) to assess local recurrence‐free, regional recurrence‐free, distant metastases‐free survival and progression‐free survival.
The standard therapy cohort included a subset of 115 consecutively treated patients with HPV(+)OPSCC, 10 or less pack years of smoking, and negative final margins following transoral robotic surgery and neck dissection between May 25, 2007, and April 24, 2015, followed by standard adjuvant RT (60 Gy intensity‐modulated RT) or chemoradiotherapy (cisplatin with 60 Gy intensity-modulated RT).
Progression outcomes
"All patients completed margin clearing surgery and simultaneous neck dissection in one operation. Patients had their specimens examined by frozen section pathology, and margins were taken until clear during the primary surgery. All patients completed their prescribed adjuvant RT therapy," says Dr. Moore. "Patients in the de‐escalation cohort were older: median 61 years vs. 55 years. Tonsil tumors were more common in the standard therapy group. Otherwise, no differences between groups were noted." The researchers report the following outcomes:
- Of the total 194 patients, 23 experienced progression at a median of 1.1 years following surgery (10 patients in the de‐escalated cohort and 13 patients in the standard cohort).
- The median duration of follow‐up for those who did not experience progression was 4.1 years.
- The three‐year progression-free survival rate was not significantly different between cohorts: 87% for the de‐escalated cohort and 90% for the standard cohort.
- The majority of failures were isolated distant metastases (65%).
Of the 23 patients with progression, reported patterns of failure include the following:
- Four had local recurrence
- Three had regional recurrence
- One had regional recurrence and subsequently developed distant metastases
- Fifteen developed distant metastases
There were no notable differences between the de‐escalation and standard cohorts. The three‐year local recurrence‐free, regional recurrence‐free, and distant metastases‐free survival rates were 99% vs. 96%, 98% vs. 99%, and 91% vs. 91%, for standard and de‐escalation, respectively.
Due to the low number of events, especially local and regional recurrence, associations of clinical and pathological factors with outcomes were limited to progression. "The most important risk factors for progression were higher T stage, pN2 disease, and the presence of extranodal extension, or ENE," says Dr. Moore. "Patients with both pN2 and ENE were at particularly high risk of disease progression, most notably at distant sites."
Further strategies are needed
Dr. Moore concludes: "Our findings support that patients with HPV(+)OPSCC who undergo surgical resection and neck dissection and meet criteria for adjuvant therapy can undergo aggressive dose de‐escalation of RT without increasing risk of progression locally, regionally or at distant sites. They also suggest that further strategies are needed to control for distant disease failure in patients with high‐risk disease such as pN2 disease and ENE, regardless of adjuvant RT dose — and that local de‐escalation may offer comparable locoregional control with a significant improvement in functional outcomes. Local de‐escalation in the setting of high-risk distant failure is a worthwhile strategy and may allow for intensification of systemic therapies."
For more information
Ma DJ, et al. Phase II evaluation of aggressive dose de‐escalation for adjuvant chemoradiotherapy in human papillomavirus‐associated oropharynx squamous cell carcinoma. Journal of Clinical Oncology. 2019;37:1909.
Moore EJ, et al. Human papillomavirus oropharynx carcinoma: Aggressive de‐escalation of adjuvant therapy. Head and Neck. 2021;43:229.