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The Role of Adjuvant Chemotherapy in Surgically Managed, p16-Positive Oropharyngeal Squamous Cell Carcinoma

Educational Objective
To understand the changing role of adjuvant chemotherapy in p16-positive oropharyngeal squamous cell carcinoma (OPSCC).
1 Credit CME
Key Points

Question  Is there a survival difference between patients with surgically managed, p16-positive oropharyngeal squamous cell carcinoma who receive adjuvant radiotherapy and patients who receive adjuvant chemoradiotherapy?

Findings  In this cohort study of 195 surgically managed, p16-positive patients, an inverse probability-weighted, multivariate analysis indicated that the receipt of adjuvant chemotherapy is not significantly associated with disease-free survival but is associated with a statistically insignificant yet clinically meaningful increase in all-cause mortality.

Meaning  Among patients with p16-positive oropharyngeal squamous cell carcinoma managed surgically with adjuvant radiotherapy, the addition of adjuvant chemotherapy may be unnecessary.


Importance  Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has a favorable prognosis, and p16 immunohistochemistry is a surrogate marker of high-risk HPV infection and strong prognosticator. Given this favorable prognosis, treatment de-escalation for p16-positive OPSCC is now being considered with the goal of decreasing treatment-associated morbidity without compromising tumor control. The role of adjuvant chemotherapy in this setting is becoming increasingly unclear.

Objective  To compare survival between surgically managed patients with p16-positive OPSCC who received adjuvant chemoradiotherapy and patients who received adjuvant radiotherapy alone.

Design, Setting, and Participants  This was a cohort study of patients with OPSCC diagnosed from June 1996 to June 2010, with follow-up through December 2014, at a single tertiary referral center. One hundred ninety-five surgically managed, p16-positive patients without a history of head and neck cancer or distant metastasis at time of diagnosis were included.

Exposures  Patients were dichotomized into adjuvant radiotherapy and adjuvant chemoradiotherapy groups.

Main Outcomes and Measures  Overall survival was the primary outcome, and disease-free survival was the secondary outcome. Propensity-weighted multivariate Cox proportional hazards analysis was conducted to quantify the effect of adjuvant chemotherapy on survival.

Results  The study included 195 patients with p16-positive, surgically managed OPSCC. Median duration of follow-up was 87 months (interquartile range, 68-116 months). Ninety patients received adjunct chemoradiotherapy (mean age, 54.3 years), 88 patients received adjuvant radiotherapy (mean age, 56.4 years), and 17 patients received surgery alone. The 5-year overall survival rate for patients who received adjuvant chemoradiotherapy was 82% (95% CI, 73%-90%) and 84% (95% CI, 76%-91%) for patients who received adjuvant radiotherapy alone. The 5-year disease-free survival rate for patients who received adjuvant chemoradiotherapy was 79% (95% CI, 71%-88%) and 79% (95% CI, 70%-88%) for patients who received radiotherapy alone. After weighting cases by the inverse probability of receiving adjuvant chemotherapy and controlling for age, comorbidity, smoking, pathological T stage, and pathological N stage, the receipt of adjuvant chemotherapy was not significantly associated with disease-free survival (adjusted hazard ratio, 0.91; 95% CI, 0.59-1.42) but was associated with a statistically insignificant yet clinically meaningful increase in all-cause mortality (adjusted hazard ratio, 1.46; 95% CI, 0.91-2.33).

Conclusions and Relevance  Among patients with p16-positive OPSCC managed surgically with adjuvant radiotherapy, the addition of adjuvant chemotherapy provided no additional disease-free survival benefit and was associated with worse overall survival. These results should help inform future clinical trials aiming to deescalate treatment for p16-positive patients.

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Article Information

Corresponding Author: Jay F. Piccirillo, MD, Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine in St Louis, 660 S Euclid Ave, PO Box 8115, St Louis, MO 63110 (piccirilloj@ent.wustl.edu).

Accepted for Publication: September 1, 2016.

Published Online: December 1, 2016. doi:10.1001/jamaoto.2016.3353

Author Contributions: Dr Piccirillo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Skillington, Kallogjeri, Piccirillo.

Acquisition, analysis, or interpretation of data: All Authors.

Drafting of the manuscript: Skillington, Piccirillo.

Critical revision of the manuscript for important intellectual content: Skillington, Kallogjeri, Lewis.

Statistical analysis: Skillington, Kallogjeri.

Administrative, technical, or material support: Kallogjeri.

Study supervision: Piccirillo.

Other—pathology support for diagnosis and patient outcome data collection and organization: Lewis.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and none were reported. Drs Kallogjeri and Piccirillo own stock and serve as consultants for potentiaMED, but the work is not related to the submitted manuscript. No other disclosures are reported.

Funding/Support: This publication was supported by the Washington University Institute of Clinical and Translational Sciences grants UL1 TR000448 and TL1 TR000449 from the National Center for Advancing Translational Sciences.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr Piccirillo is the Editor of JAMA Otolaryngology–Head & Neck Surgery, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Additional Contributions: We thank the members of the Head and Neck Division of the Department of Otolaryngology–Head and Neck Surgery at Washington University for their role in the surgical management of the patients described herein.

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