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

Abstract

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.

Long‐term analysis of transorally resected p16 + Oropharynx cancer: Outcomes and prognostic factors

“…The extent of ECS was not graded for this study; however, in a previous publication that included nearly all patients from the current study cohort, application of ECS grading showed the highest grade of ECS (graded STM) to associate with reduced DFS. Administration of adjuvant therapy associated with improved DFS, and reduced number of recurrences correlative with our recently published matched study by Jackson et al However, addition of chemotherapy to postoperative radiation did not associate with additional benefit corroborating findings from the thesis and other reports on HPV‐related OPSCC, some of which include national cancer database analyses . The median (range) adjuvant radiation dose at the primary, ipsilateral, and contralateral neck in our study cohort was 66 (48–70), 66 (36–70), and 56 (45–66) grays (Gy).…”

Smokers or non-smokers: who benefits more from immune checkpoint inhibitors in treatment of malignancies? An up-to-date meta-analysis

“…Among patients receiving adjuvant chemotherapy, smoking reduced progression-free survival and overall survival in ovarian cancer [52]. The similar poor prognosis has also been confirmed in HNSCC [53]. Mechanically, Ye et al [54] recently found that smoking increased the expression of the TM4SF1 gene, which promotes NSCLC proliferation, invasion, and chemo-resistance through regulation of the DDR1/Akt/ERK-mTOR axis.…”

Impact of Smoking on Survival Outcomes in HPV‐Related Oropharyngeal Carcinoma: A Meta‐analysis

“…12 Sinha and Skillington both found that smoking negatively affected DFS in ever versus never smokers (HR, 2.3; 95% CI, 1.12-4.76; P = .023; HR, 3.42; 95% CI, 1.61-7.26; P \ .05). 9,12 Haughey also reported that current versus never smoking negatively affected DFS (HR, 5.25; 95% CI, 1.39-19.85; P = .014) but did not find a significantly increased risk for DSS. 13 Kaczmar et al did not find a significantly increased risk of disease recurrence using the 10-pack year smoking threshold.…”