Prevalence of oral and blood oncogenic human papillomavirus biomarkers among an enriched screening population: Baseline results of the MOUTH study.

BACKGROUND: Human papillomavirus (HPV)-related oropharyngeal cancer screening is being explored in research studies, but strategies to identify an appropriate population are not established. The authors evaluated whether a screening population could be enriched for participants with oncogenic HPV biomarkers using risk factors for oral HPV. METHODS: Participants were enrolled at Johns Hopkins Hospitals and Mount Sinai Icahn School of Medicine. Eligible participants were either men aged 30 years or older who had two or more lifetime oral sex partners and a personal history of anogenital dysplasia/cancer or partners of patients who had HPV-related cancer. Oral rinse and serum samples were tested for oncogenic HPV DNA, RNA, and E6 or E7 antibodies, respectively. Participants with any biomarker were considered at-risk. RESULTS: Of 1108 individuals, 7.3% had any oncogenic oral HPV DNA, and 22.9% had serum antibodies for oncogenic HPV E6 or E7. Seventeen participants (1.5%) had both oral and blood biomarkers. HPV type 16 (HPV16) biomarkers were rarer, detected in 3.7% of participants, including 20 with oral HPV16 DNA and 22 with HPV16 E6 serum antibodies (n = 1 had both). In adjusted analysis, living with HIV (adjusted odds ratio, 2.65; 95% CI, 1.60-4.40) and older age (66-86 vs. 24-45 years; adjusted odds ratio, 1.70; 95% CI, 1.07-2.70) were significant predictors of being at risk. Compared with the general population, the prevalence of oral HPV16 (1.8% vs. 0.9%), any oncogenic oral HPV DNA (7.3% vs. 3.5%), and HPV16 E6 antibodies (2.2% vs. 0.3%) was significantly elevated. CONCLUSIONS: Enrichment by the eligibility criteria successfully identified a population with higher biomarker prevalence, including HPV16 biomarkers, that may be considered for screening trials. Most in this group are still expected to have a low risk of oropharyngeal cancer.

Oral Human Papillomavirus Associated With Differences in Oral Microbiota Beta Diversity and Microbiota Abundance.

BACKGROUND: Although cervicovaginal microbiome has been associated with cervical human papillomavirus (HPV) infection, little is known regarding the association of oral microbiome with oral HPV, a cause of oropharyngeal cancer. METHODS: A cross-sectional analysis of 495 participants from the Men and Women Offering Understanding of Throat HPV study was conducted. 16S rRNA gene amplicon sequencing was performed on saliva samples. HPV DNA in oral rinse samples was tested. Associations of oral microbiome diversity, taxon abundance, and predicted functional pathways with oral HPV were assessed, adjusting for age, race/ethnicity, education, human immunodeficiency virus, current smoking, and sequencing batch. RESULTS: Participants with oral HPV (n = 68) compared with those without HPV had similar oral microbiome alpha-diversity yet different beta-diversity (Bray-Curtis distance for bacterial taxa, P = .009; functional pathways, P = .02). Participants with oral HPV had higher abundance of Actinomycetaceae, Prevotellaceae, Veillonellaceae, Campylobacteraceae, Bacteroidetes, and lower abundance of Gemellaceae (false discovery rate <0.10). We also found differential functional potential of oral microbiome by oral HPV status: xenobiotic biodegradation-related pathways were less abundant among participants with oral HPV, suggesting potential xenobiotic-induced toxic effects with implications for HPV susceptibility. CONCLUSIONS: Our findings suggest a shift in oral microbiome community structure, composition, and functional potential between individuals with and without oral HPV.

Validation of NRG Oncology's prognostic nomograms for oropharyngeal cancer in the Veterans Affairs database.

BACKGROUND: To test whether nomograms developed by NRG Oncology for oropharyngeal squamous cell carcinoma (OPSCC) patients could be validated in an independent population-based sample. METHODS: The authors tested nomograms for estimating progression-free survival (PFS) and overall survival (OS) in patients from the Veterans Health Administration with previously untreated locoregionally advanced OPSCC, diagnosed between 2008 and 2017, managed with definitive radiotherapy with or without adjuvant systemic therapy. Covariates were age, performance status, p16 status, T/N category, smoking history, education history, weight loss, marital status, and anemia. We used multiple imputation to handle missing data and performed sensitivity analyses on complete cases. Validation was assessed via Cox proportional hazards models, log-rank tests, and c-indexes. RESULTS: A total of 4007 patients met inclusion criteria (658 patients had complete data). Median follow-up time was 3.20 years, with 967 progression events and 471 noncancer deaths. Each risk score was associated with poorer outcomes per unit increase (PFS score, hazard ratio [HR], 1.42 [1.37-1.47]; OS score, HR, 1.40 [1.34-1.45]). By risk score quartile, 2-year PFS estimates were 89.2%, 78.5%, 65.8%, and 48.3%; OS estimates were 92.6%, 83.6%, 73.9%, and 51.3%, respectively (P < .01 for all comparisons). C-indices for models of PFS and OS were 0.65 and 0.67, for all patients, respectively (0.69 and 0.73 for complete cases). The nomograms slightly overestimated PFS and OS in the overall cohort but exhibited high agreement in complete cases. CONCLUSIONS: NRG nomograms were effective for predicting PFS and OS for patients with OPSCC, supporting their broader applicability in the OPSCC population undergoing definitive radiotherapy.

Prevalence of human papillomavirus in head and neck cancers at tertiary care centers in the United States over time.

BACKGROUND: Human papillomavirus (HPV) is responsible for a growing proportion of oropharyngeal squamous cell carcinomas (OPSCCs) among men and White individuals. Whether similar trends apply to women, non-Whites, and non-oropharyngeal squamous cell carcinomas (non-OPSCCs) is unknown. METHODS: This is a cross-sectional analysis combining 2 multi-institutional case series of incident head and neck squamous cell carcinoma (HNSCC) cases. Incident HNSCCs from 1995 to 2012 were enrolled retrospectively using banked tumor samples and medical record abstraction. Incident HNSCCs from 2013 to 2019 were enrolled prospectively. The prevalence of tumor HPV biomarkers was tested over 3 time periods (1995-2003, 2004-2012, and 2013-2019). Centralized testing was done for p16 immunohistochemistry (p16) and oncogenic HPV in situ hybridization (ISH). RESULTS: A total of 1209 incident cases of HNSCC were included. Prevalence of p16- and ISH-positive tumors increased significantly for oropharynx cancers over time. The majority were positive after 2013 for White patients (p16, 92%; P < .001; ISH 94%; P < .001), Black patients (p16, 72%; P = .021; ISH 67%; P = .011), and Hispanic patients (p16, 100%; P = .04; ISH 100%; P = .013). For women with OPSCC, the prevalence of p16- and ISH-positive tumors increased significantly to 82% (P < .001) and 78% (P = .004), respectively. For non-OPSCCs, there was increased p16 and ISH positivity overall with 24% p16 and 16% ISH positivity in the most recent time period (P < .001 for both). CONCLUSIONS: The majority of OPSCCs in US tertiary care centers are now p16 and ISH positive for all sex and race groups. In some populations in the United States, 91% of OPSCCs are now caused by HPV. Few non-OPSCCs are p16 and ISH positive.

Timing, number, and type of sexual partners associated with risk of oropharyngeal cancer.

BACKGROUND: Case-control studies from the early 2000s demonstrated that human papillomavirus-related oropharyngeal cancer (HPV-OPC) is a distinct entity associated with number of oral sex partners. Using contemporary data, we investigated novel risk factors (sexual debut behaviors, exposure intensity, and relationship dynamics) and serological markers on odds of HPV-OPC. METHODS: HPV-OPC patients and frequency-matched controls were enrolled in a multicenter study from 2013 to 2018. Participants completed a behavioral survey. Characteristics were compared using a chi-square test for categorical variables and a t test for continuous variables. Adjusted odds ratios (aOR) were calculated using logistic regression. RESULTS: A total of 163 HPV-OPC patients and 345 controls were included. Lifetime number of oral sex partners was associated with significantly increased odds of HPV-OPC (>10 partners: odds ratio [OR], 4.3 [95% CI, 2.8-6.7]). After adjustment for number of oral sex partners and smoking, younger age at first oral sex (<18 vs >20 years: aOR, 1.8 [95% CI, 1.1-3.2]) and oral sex intensity (>5 sex-years: aOR, 2.8 [95% CI, 1.1-7.5]) remained associated with significantly increased odds of HPV-OPC. Type of sexual partner such as older partners when a case was younger (OR, 1.7 [95% CI, 1.1-2.6]) or having a partner who had extramarital sex (OR, 1.6 [95% CI, 1.1-2.4]) was associated with HPV-OPC. Seropositivity for antibodies to HPV16 E6 (OR, 286 [95% CI, 122-670]) and any HPV16 E protein (E1, E2, E6, E7; OR, 163 [95% CI, 70-378]) was associated with increased odds of HPV-OPC. CONCLUSION: Number of oral sex partners remains a strong risk factor for HPV-OPC; however, timing and intensity of oral sex are novel independent risk factors. These behaviors suggest additional nuances of how and why some individuals develop HPV-OPC.

RTOG-0129 risk groups are reproducible in a prospective multicenter heterogeneously treated cohort.

BACKGROUND: Recursive partitioning analysis (RPA) from the Radiation Therapy Oncology Group (RTOG)-0129 has identified a low-risk group of patients with oropharynx cancer (OPC) who might benefit from therapeutic de-intensification. These risk groups have not yet been reproduced in an independent cohort treated heterogeneously. Therefore, the objective of this analysis was to validate the RPA risk groups and examine the prognostic impact of novel factors. METHODS: Patients with OPC were enrolled in a prospective study at 3 academic medical centers from 2013 to 2018. Medical record abstraction was used to ascertain clinical variables including staging and survival according to the 7th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. Human papillomavirus-positive tumor status was determined by p16 immunohistochemistry and/or HPV RNA in situ hybridization. Kaplan-Meier and log-rank methods were used to compare survival. Cox proportional hazards were used to generate univariate and multivariable hazard ratios (HRs). RESULTS: Median follow-up time was 3.2 years. The low-, intermediate-, and high-risk groups had significant differences in 2-year overall survival (OS, 99.1%; 95% CI, 94.4%-99.9% vs OS, 93.0%; 95% CI, 74.7%-98.2% vs OS, 80.0%; 95% CI, 40.9%-94.6%; Poverall = .0001) and 2-year progression-free survival (PFS, 97.5%; 95% CI, 92.4%-99.2% vs PFS, 89.3%; 95% CI, 70.3%-96.4% vs PFS, 80.0%; 95% CI, 40.9%-94.6%; Poverall < .002). After adjustment for age, sex, and level of educational attainment, OS and PFS were significantly lower for the intermediate- (OS adjusted hazard ratio [aHR], 5.0; 95% CI, 1.0-23.0; PFS aHR, 3.4; 95% CI, 1.0-11.5), and high- (OS aHR, 7.3; 95% CI, 1.4-39; PFS aHR, 5.0; 95% CI, 1.2-21.6) risk groups compared with the low-risk group. Lower education was also independently significantly associated with worse OS (aHR, 8.9; 95% CI, 1.8-44.3) and PFS (aHR, 3.1; 95% CI, 1.0-9.6). CONCLUSIONS: In patients with OPC, the RTOG-0129 RPA model is associated with OS and PFS in a heterogeneously treated cohort.

Blood-based biomarkers of human papillomavirus-associated cancers: A systematic review and meta-analysis.

BACKGROUND: Despite the significant societal burden of human papillomavirus (HPV)-associated cancers, clinical screening interventions for HPV-associated noncervical cancers are not available. Blood-based biomarkers may help close this gap in care. METHODS: Five databases were searched, 5687 articles were identified, and 3631 unique candidate titles and abstracts were independently reviewed by 2 authors; 702 articles underwent a full-text review. Eligibility criteria included the assessment of a blood-based biomarker within a cohort or case-control study. RESULTS: One hundred thirty-seven studies were included. Among all biomarkers assessed, HPV-16 E seropositivity and circulating HPV DNA were most significantly correlated with HPV-associated cancers in comparison with cancer-free controls. In most scenarios, HPV-16 E6 seropositivity varied nonsignificantly according to tumor type, specimen collection timing, and anatomic site (crude odds ratio [cOR] for p16+ or HPV+ oropharyngeal cancer [OPC], 133.10; 95% confidence interval [CI], 59.40-298.21; cOR for HPV-unspecified OPC, 25.41; 95% CI, 8.71-74.06; cOR for prediagnostic HPV-unspecified OPC, 59.00; 95% CI, 15.39-226.25; cOR for HPV-unspecified cervical cancer, 12.05; 95% CI, 3.23-44.97; cOR for HPV-unspecified anal cancer, 73.60; 95% CI, 19.68-275.33; cOR for HPV-unspecified penile cancer, 16.25; 95% CI, 2.83-93.48). Circulating HPV-16 DNA was a valid biomarker for cervical cancer (cOR, 15.72; 95% CI, 3.41-72.57). In 3 cervical cancer case-control studies, cases exhibited unique microRNA expression profiles in comparison with controls. Other assessed biomarker candidates were not valid. CONCLUSIONS: HPV-16 E6 antibodies and circulating HPV-16 DNA are the most robustly analyzed and most promising blood-based biomarkers for HPV-associated cancers to date. Comparative validity analyses are warranted. Variations in tumor type-specific, high-risk HPV DNA prevalence according to anatomic site and world region highlight the need for biomarkers targeting more high-risk HPV types. Further investigation of blood-based microRNA expression profiling appears indicated.

Comparison of new magnetic resonance imaging grading system with conventional endoscopy for the early detection of nasopharyngeal carcinoma.

BACKGROUND: Although stratifying individuals with respect to nasopharyngeal carcinoma (NPC) risk with Epstein-Barr virus-based markers is possible, the performance of diagnostic methods for detecting lesions among screen-positive individuals is poorly understood. METHODS: The authors prospectively evaluated 882 participants aged 30 to 70 years who were enrolled between October 2014 and November 2018 in an ongoing, population-based NPC screening program and had an elevated NPC risk. Participants were offered endoscopy and magnetic resonance imaging (MRI), and lesions were identified either by biopsy at a follow-up endoscopy or further contact and linkage to the local cancer registry through December 31, 2019. The diagnostic performance characteristics of endoscopy and MRI for NPC detection were investigated. RESULTS: Eighteen of 28 identified NPC cases were detected by both methods, 1 was detected by endoscopy alone, and 9 were detected by MRI alone. MRI had significantly higher sensitivity than endoscopy for NPC detection overall (96.4% vs 67.9%; Pdifference = .021) and for early-stage NPC (95.2% vs 57.1%; P = .021). The sensitivity of endoscopy was suggestively lower among participants who had previously been screened in comparison with those undergoing an initial screening (50.0% vs 81.2%; P = .11). The authors observed a higher overall referral rate by MRI versus endoscopy (17.3% vs 9.1%; P < .001). Cases missed by endoscopy had early-stage disease and were more commonly observed for tumors originating from the pharyngeal recess. CONCLUSIONS: MRI was more sensitive than endoscopy for NPC detection in the context of population screening but required the referral of a higher proportion of screen-positive individuals. The sensitivity of endoscopy was particularly low for individuals who had previously been screened.

Oncologic outcomes of human papillomavirus-associated oropharynx carcinoma treated with surgery alone: A 12-institution study of 344 patients.

BACKGROUND: The oncologic outcomes of surgery alone for patients with American Joint Committee on Cancer 7th edition (AJCC 7th) pN2a and pN2b human papillomavirus-associated oropharynx squamous cell carcinoma (HPV+OPSCC) are not clear. METHODS: The authors performed a 12-institution retrospective study of 344 consecutive patients with HPV+OPSCC (AJCC 7th pT0-3 N3 M0) treated with surgery alone with 6 months or more of follow-up using univariate and multivariate analyses. RESULTS: The 2-year outcomes for the entire cohort were 91% (182 of 200) disease-free survival (DFS), 100% (200 of 200) disease-specific survival (DSS), and 98% (200 of 204) overall survival (OS). The 18 recurrences within 2 years were 88.9% (16 of 18) local and/or regional recurrences and 11.1% (2 of 18) distant metastases. Recurrences were not significantly associated with smoking, pT stage, or pN stage. The 16 patients with locoregional recurrences within 2 years all underwent successful salvage treatments (median follow-up after salvage: 13.1 months), 43.8% (7 of 16) of whom underwent salvage surgery alone for a 2-year overall salvage radiation need of 4.5% (9 of 200). The 2-year outcomes for the 59 evaluable patients among the 109 AJCC 7th pT0-2 N2a-N2b patients with 1 to 3 pathologic lymph nodes (LNs) were as follows: local recurrence, 3.4% (2 of 59); regional recurrence, 8.4% (5 of 59); distant metastases, 0%; DFS, 88.1% (52 of 59); DSS, 100% (59 of 59); OS, 96.7% (59 of 61); and salvage radiation, 5.1% (3 of 59). CONCLUSIONS: With careful selection, surgery alone for AJCC 7th pT0-T2N0-N2b HPV+OPSCC with zero to 3 pathologic LNs without perineural invasion, extranodal extension, or positive margins results in high DFS, DSS, OS, and salvage treatment success. Because of the short-term follow-up, these data support further investigation of treatment de-escalation in this population.

p16 immunohistochemistry for primary tumor detection in HPV-positive squamous cell carcinoma of unknown primary.

PURPOSE: To examine the potential benefit of reevaluation of original slides and p16 immunohistochemistry (IHC) of tonsillectomy specimens for primary tumor identification in cases of human papillomavirus (HPV) positive squamous cell carcinoma (SCC) of the head and neck of unknown primary. MATERIALS AND METHODS: Through a retrospective review, we identified all patients 18 or older who presented at our institution from 2003 to 2015 with histologically confirmed HPV-positive SCC in a cervical lymph node with unidentified primary tumor after initial workup. For patients for whom specimens were available, an expert head and neck pathologist re-reviewed original hematoxylin and eosin (H&E) slides to confirm absence of tumor and performed p16 IHC and deep sectioning of tissue blocks to identify potential tumor foci. RESULTS: Among 735 patient records assessed, 80 were HPV-positive SCC with unknown primary, 28 of which did not have a primary tumor identified, and 20 with original specimens available. Upon re-review of 103 original H&E slides, invasive SCC was identified for 2 patients. Deep sectioning and p16 IHC did not identify additional primary tumors. CONCLUSION: Re-review of original slides by an expert head and neck pathologist, but not p16 staining or deeper H&E sections, was able to identify additional tumors.

Burden of comorbidities is higher among elderly survivors of oropharyngeal cancer compared with controls.

BACKGROUND: The prevalence of survivors of oropharyngeal cancer (OPC) is increasing due to improved survival for individuals with human papillomavirus (HPV)-related disease. Although elderly survivors of OPC are known to have a high burden of comorbidities, to the authors' knowledge it is unknown how this compares with a similar cohort without a history of cancer. METHODS: The current retrospective, cross-sectional study included individuals with a first incident primary diagnosis of OPC from 2004 through 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked databases and matched controls. The baseline prevalence and subsequent incidence of comorbid conditions were identified. The association between comorbidity and overall survival was evaluated. RESULTS: A total of 2497 eligible patients with OPC were matched to 4994 noncancer controls. Baseline comorbidity was higher in cases (Charlson Comorbidity Index >0 for 48.5% of cases vs 35.8% of controls). At 5 years, cases were more likely than controls to develop comorbidities. Survivors of OPC were at high risk (≥20% cumulative prevalence by 5 years) of developing several comorbidities, including cardiovascular diseases, cerebrovascular disease, chronic obstructive pulmonary disease, and tobacco abuse, and were at moderately high risk (10%-19% cumulative prevalence) of developing other conditions including carotid artery occlusive stroke, alcohol abuse, depression, and anxiety. In both cases and controls, the presence of the majority of comorbidities either at the time of diagnosis or during the follow-up period was associated with worse survival. CONCLUSIONS: Patients with OPC have a higher comorbidity burden compared with matched controls, both at baseline and during survivorship, the majority of which are associated with decreased survival. Oncologic surveillance of survivors of OPC should include screening for highly prevalent conditions.

Transcervical sonography and human papillomavirus 16 E6 antibodies are sensitive for the detection of oropharyngeal cancer.

BACKGROUND: Human papillomavirus 16 (HPV-16) E6 seropositivity is a promising early marker of human papillomavirus-driven oropharyngeal cancer (HPV-OPC), yet more sensitive imaging modalities are needed before screening is considered. The objective of this study was to determine the sensitivity of transcervical sonography (TCS) for detecting clinically apparent HPV-OPC in comparison with computed tomography (CT) and positron emission tomography (PET)/CT. METHODS: Fifty-one patients with known or suspected HPV-OPC without prior treatment underwent oropharyngeal TCS and blood collection (for HPV multiplex serology testing). Eight standard sonographic images were collected; primary-site tumors were measured in 3 dimensions if identified. Each patient underwent a full diagnostic workup as part of standard clinical care. The pathologic details, HPV status, final staging, and imaging findings were abstracted from the medical record. The sensitivity of each imaging modality was compared with the final clinical diagnosis (the gold standard). RESULTS: Twenty-four base of tongue cancers (47%), 22 tonsillar cancers (43%), and 2 unknown primary cancers (4%) were diagnosed; 3 patients (6%) had no tumors. All p16-tested patients were positive (n = 47). Primary-site tumors were correctly identified in 90.2% (95% confidence interval [CI], 78.6%-96.7%) with TCS, in 69.4% (95% CI, 54.6%-81.7%) with CT, and in 83.3% (95% CI, 68.6%-93.0%) with PET/CT. TCS identified tumors in 10 of 14 cases missed by CT and recognized the absence of tumors in 3 cases for which CT or PET/CT was falsely positive. The smallest sonographically identified primary-site tumor was 0.5 cm in its greatest dimension; the average size was 2.3 cm. Among p16-positive patients, 76.1% (95% CI, 61.2%-87.4%) were seropositive for HPV-16 E6. CONCLUSIONS: TCS and HPV-16 E6 antibodies are sensitive for the diagnosis of HPV-OPC.

Prevalence of comorbidities and effect on survival in survivors of human papillomavirus-related and human papillomavirus-unrelated head and neck cancer in the United States.

BACKGROUND: The increasing incidence of human papillomavirus (HPV)-related head and neck cancer (HNC) has led to the increasing prevalence of survivors, yet to the best of the authors' knowledge the prevalence of comorbidities during the survivorship period and their effects on survival are relatively unknown. METHODS: In this retrospective cross-sectional study, individuals with a first incident primary diagnosis of HNC from 2004 through 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked databases were included in the analysis and classified as patients with HPV-related or HPV-unrelated HNC. The presence of 30 comorbid conditions of interest was identified. Associations between comorbidity and treatment group as well as overall survival were evaluated. RESULTS: The study population consisted of 8025 patients with HPV-unrelated HNC and 2499 patients with HPV-related HNC. Hypertension, congestive heart failure, cerebrovascular disease, and chronic obstructive pulmonary disease all were found to be highly prevalent at the time of the cancer diagnosis and increased over time for both groups. These comorbidities were found at significantly lower rates in the HPV-related HNC population, yet were associated with an increased risk of death in both groups. The probabilities of developing cancer-related comorbidities such as pneumonia, dysphagia, weight loss, malnutrition, and dental issues rose significantly in both groups after treatment but were more likely in patients with HPV-related HNC. In both groups of patients, the presence of each comorbidity either at the time of diagnosis or during survivorship was associated with a significantly increased risk of death. CONCLUSIONS: There is a large burden of comorbidities in both patients with HPV-related and HPV-unrelated HNC, both of which are associated with decreased survival. Oncologic surveillance should not be limited to the evaluation of disease status, but also should include screening for the highly prevalent conditions associated with the risk of death.

The prevalence of human papillomavirus in oropharyngeal cancer is increasing regardless of sex or race, and the influence of sex and race on survival is modified by human papillomavirus tumor status.

BACKGROUND: The purpose of this study was to evaluate the influence of sex and race/ethnicity upon prevalence trends of human papillomavirus (HPV) in oropharyngeal cancer (OPC) and survival after OPC. METHOD: This was a cohort study of patients included in the United States National Cancer Database who had been diagnosed with OPC between 2010 and 2015. Outcomes were HPV status of tumor specimens and overall survival. Sex- and race-stratified trends in HPV prevalence were estimated using generalized linear modeling. The influence of sex, race, and HPV tumor status on overall survival was compared by Kaplan-Meier method and Cox Proportional Hazards models. RESULTS: This analysis included 20,886 HPV-positive and 10,364 HPV-negative OPC patients. The prevalence of HPV-positive tumors was higher among men (70.6%) than women (56.3%) and increased significantly over time at a rate of 3.5% and 3.2% per year among men and women, respectively. The prevalence of HPV-positive tumors was highest among whites (70.2%), followed by Hispanics (61.3%), Asians (55.8%), and blacks (46.3%). Blacks and Hispanics experienced significantly more rapid increases in prevalence of HPV-positive tumors over time compared with whites (6.5% vs 5.6% vs 3.2% per year, respectively). In HPV-positive OPC, neither sex nor race/ethnicity was associated with survival among patients with HPV-positive OPC. In contrast, for HPV-negative OPC, risk of death was significantly higher for women versus men (adjusted hazard ratio [aHR], 1.17; 95% confidence interval [CI], 1.08-1.26) and blacks versus whites (aHR, 1.21; 95% CI, 1.10-1.33). CONCLUSION: The prevalence of HPV-positive tumors is increasing for all sex and race/ethnicity groups in the United States. Sex and race are independently associated with survival for HPV-negative but not HPV-positive OPC.

Priorities, concerns, and regret among patients with head and neck cancer.

BACKGROUND: In the era of deintensification, little data are available regarding patients' treatment preferences. The current study evaluated treatment-related priorities, concerns, and regret among patients with head and neck squamous cell cancer (HNSCC). METHODS: A total of 150 patients with HNSCC ranked the importance of 10 nononcologic treatment goals relative to the oncologic goals of cure and survival. The level of concern regarding 11 issues and decision regret was recorded. Median rank was reported overall, and factors associated with odds of rank as a top 3 priority were modeled using logistic regression. RESULTS: Among the treatment effects analyzed, the odds of being a top 3 priority was especially high for cure (odds, 9.17; 95% confidence interval [95% CI], 5.05-16.63), followed by survival and swallow (odds, 1.26 [95% CI, 0.88-1.80] and odds, 0.85 [95% CI, 0.59-1.21], respectively). Prioritization of cure, survival, and swallow was similar based on human papillomavirus (HPV) tumor status. By increasing decade of age, older participants were found to be significantly less likely than younger individuals to prioritize survival (odds ratio, 0.72; 95% CI, 0.52-1.00). Concerns regarding mortality (P = .04) and transmission of HPV to the patient's spouse (P = .03) were more frequent among participants with HPV-associated HNSCC. Regret increased with additional treatment modalities (P = .02). CONCLUSIONS: Patients with HNSCC overwhelming prioritize cure, followed by survival and swallow. The decreased prioritization of survival by older age supports further examination of treatment preference by age. The precedence of oncologic over nononcologic priorities among patients regardless of HPV tumor status supports the conservative adoption of deintensification regimens until the interplay between competing oncologic and nononcologic treatment goals is better understood.

Validation of NRG oncology/RTOG-0129 risk groups for HPV-positive and HPV-negative oropharyngeal squamous cell cancer: Implications for risk-based therapeutic intensity trials.

BACKGROUND: Radiation Therapy Oncology Group (RTOG)-0129 recursive partitioning analysis was the basis for risk-based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors' knowledge, the question of whether RTOG-0129 overall survival (OS) estimates for low-risk, intermediate-risk, and high-risk groups are similar in other data sets or applicable to progression-free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG-0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups. METHODS: Prospective randomized clinical trials were analyzed retrospectively. RTOG-0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG-0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible. RESULTS: There was a total of 260 patients and 287 patients, respectively, from RTOG-0129 and RTOG-0522, with median follow-ups for surviving patients of 7.9 years (range, 1.7-9.9 years) and 4.7 years (range, 0.1-7.0 years), respectively. Previous OS differences in RTOG-0129 persisted at 5 years. In RTOG-0522, the 5-year OS rates for the low-risk, intermediate-risk, and high-risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5-year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG-0522 among a subgroup of patients considered to be at very good risk (p16-positive disease, smoking history of ≤10 pack-years, and classified with T1-T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5-year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group. CONCLUSIONS: RTOG-0129 risk groups persisted at 5 years and were reproducible in RTOG-0522. However, there was variability in the estimates. These data underscore the importance of long-term follow-up and appropriate patient selection in therapeutic deintensification trials.

The role of human papillomavirus on the prognosis and treatment of oropharyngeal carcinoma.

Human papillomavirus positive oropharyngeal cancer (HPV-positive OPC) is a distinct subtype of head and neck carcinoma (HNC) distinguished from HPV-negative HNC by its risk factor profile, clinical behavior, and molecular biology. Compared to HPV-negative HNC, HPV-positive OPC exhibits significantly better prognosis and an enhanced response to treatment. Recognition of the survival benefit of HPV-positive tumors has led to therapeutic de-intensification strategies aiming to mitigate treatment-related toxicities while maintaining high response rates. In this review, we summarize key aspects of oral HPV infection and the molecular mechanisms of HPV-related carcinogenesis. We review the clinical and molecular characteristics of HPV-positive OPC that contribute to its improved prognosis compared to HPV-negative HNC. We also discuss current and emerging treatment strategies, emphasizing potential mechanisms of treatment sensitivity and the role of therapeutic de-intensification in HPV-positive OPC. Lastly, we examine literature on the management and prognosis of recurrent/metastatic HPV-positive OPC with a focus on the role of salvage surgery in its management.

Head and neck squamous cell cancers in the United States are rare and the risk now is higher among white individuals compared with black individuals.

BACKGROUND: The increasing incidence of oropharyngeal squamous cell cancer (OPSCC) is well established. However, up-to-date incidence estimates and trends for head and neck squamous cell cancers (HNSCCs) overall, including major anatomic sites, and nonoropharyngeal (non-OP) HNSCCs by sex, race, and age in the United States are not well described. METHODS: A retrospective analysis of incident HNSCCs during 1992 through 2014 using the Surveillance, Epidemiology, and End Results database was performed to evaluate the incidence of HNSCCs overall, OPSCC, and non-OP HNSCC (those of the larynx, oral cavity, hypopharynx, nasopharynx, and nasal cavity). Incidence rates were calculated overall and by subgroups of interest, and incidence rate ratios were used to compare rates between groups. The incidence rates presented were per 100,000 population and were age adjusted to the 2000 US standard population (19 age groups; Census P25-1130). The annual percent change (APC) was modeled with and without joinpoints. RESULTS: The incidence of HNSCC overall declined (average APC [aAPC], -0.8; P<.001) despite significant increases in the incidence of OPSCCs, most notably between 2000 and 2014 (APC, 2.1; P<.001). Significant declines in incidence were observed for all non-OP HNSCC sites for both women and men (P<.001 each). Among women, the risk of OPSCC also significantly decreased (aAPC, -0.8; P = .002), whereas the risk among men was stable during 1992 through 2001 (APC, 0.4; P = .42) and then significantly increased from 2001 to 2014 (APC, 2.7; P<.001). Decreases in the risk of non-OP HNSCC were especially large for black women (aAPC, -2.6; P<.001) and men (aAPC, -3.0; P<.001). Although the incidence of HNSCC previously was highest among black individuals, since 2009 its incidence has been higher among white compared with black individuals. CONCLUSIONS: The incidence of HNSCC is declining, especially for non-OP HNSCC and among black individuals. Cancer 2018;124:2125-33. © 2018 American Cancer Society.

Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients. METHODS: In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (Ptrend = .01) but not among p16-negative patients (Ptrend = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001-2013, 53-64 years). Among patients ≥ 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (Ptrend = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16-negative status. CONCLUSIONS: The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. © 2018 American Cancer Society.

Treatment preferences in human papillomavirus-associated oropharyngeal cancer.

The population of survivors with human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) is rising. The improved prognosis of this etiologic subset is reflected in new staging guidelines as well as ongoing deintensification trials aiming to preserve excellent survival while decreasing treatment-related toxicities. However, as staging criteria and treatment standards evolve in the era of transoral surgery and deintensification, little is known regarding the needs and treatment preferences of patients with HPV-OPSCC. Herein, the current knowledge regarding treatment preferences and priorities, quality of life and concerns among patients with HPV-OPSCC is reviewed.