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Introduction: The established association between thyroid disorders (TD) and its two main subtypes-hyperthyroidism and hypothyroidism-and the incidence of oral and oropharyngeal cancer (OCPC) has been substantiated. However, the direct causal relationship and potential intermediary mechanisms linking these conditions have not been clearly defined in prior studies., Material & Methods: This study employed univariate Mendelian randomization (MR) analysis to explore those relationship. Instrumental variables from genome-wide association study (GWAS) datasets for TD (n = 218,792), hyperthyroidism (n = 460,499), hypothyroidism (n = 213,990), and OCPC (n = 12,619), along with 41 intermediary inflammatory cytokines (n = 8293), were analyzed. Inverse variance weighting (IVW) method assessed the causal relationships, while summary MR analysis with pQTL datasets from decode and 91 inflammatory cytokines explored the cytokines' roles as biomarkers and therapeutic targets for OCPC. Multivariable MR (MVMR) analysis quantified the mediation effect of these cytokines in the TD-OCPC relationship., Results: UVMR analysis provided strong evidence for a causal relationship between TD (OR = 1.376, 95 % CI = 1.142-1.656, p = 0.001), hyperthyroidism (OR = 1.319, 95 % CI=1.129-1.541, p = 0.001), hypothyroidism (OR = 1.224, 95 % CI = 1.071-1.400, p = 0.003), and the risk of OCPC. CXCL9 was identified as a significant intermediary in mediating the risk of OCPC from TD and its two subtypes (OR = 1.218, 95 % CI = 1.016-1.461, P = 0.033), suggesting its potential as a predictive biomarker for OCPC. MVMR analysis further revealed that CXCL9 mediated 7.94 %, 14.4 %, and 18 % of the effects of TD, hyperthyroidism, and hypothyroidism on OCPC risk, respectively., Discussion: This study not only elucidated the potential causal relationships between TD including its two subtypes and OCPC risk, but also highlighted CXCL9 as a pivotal mediator in this association., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Objective: Studies have demonstrated that tonsillectomy may alter the risk of oropharyngeal cancer (OPC). We systematically reviewed the evidence and pooled data to examine such an association., Methods: PubMed, Embase, and Scopus were searched up to 25 th April 2023. Studies reporting an association between tonsillectomy and oropharyngeal cancer risk at any site were included., Results: Five studies were eligible. All examined the risk of tonsillar and base of the tongue (BOT) cancer with prior history of tonsillectomy. On meta-analysis of the data, prior history of tonsillectomy was associated with a significantly decreased risk of tonsillar cancer. The second meta-analysis showed that history of tonsillectomy did not significantly alter the risk of BOT cancer. However, after exclusion of one study, the results showed an increased risk of BOT cancer with a history of tonsillectomy., Conclusions: The scarce data available in the literature suggests that tonsillectomy may reduce the risk of tonsillar cancer but does not alter the risk of BOT cancer. Further studies are needed to explore the association between tonsillectomy and the risk of OPC., (Copyright © 2024 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

Background: Effective screening for oropharyngeal cancer is lacking. Four oncogenic HPV clearance definitions were explored to understand long-term natural history for persistent oncogenic oral HPV (oncHPV), the precursor of oropharyngeal cancer., Methods: Prospective multicenter cohort of participants living with/at-risk for HIV, with oral rinse and gargle samples collected every 6 to 12 months for up to 10 years and tested for oncHPV. HPV clearance definitions included 1 (clear1), 2 (clear2), 3 (clear3) consecutive negatives, or being negative at last two visits (clearlast)., Results: Median time to clearance of oncHPV exceeded 2 years for conservative definitions (clear3: 2.38, clearlast: 2.43), but not lenient (clear1: 0.68, clear2: 1.15). By clear3, most incident infections cleared at 2, 5, 8 years (55.1%, 75.6%, 79.1%), contrary to prevalent infections (37.1%, 52.5%, 59.5%, respectively). In adjusted analysis, prevalent oncHPV, older age, male sex, and living with HIV were associated with reduced clearance. Of 1,833 subjects screened, 13.8% had prevalent oncHPV and 47.5% of those infections persisted ≥5 years, representing 6.5% of persons screened. Two men with prevalent oral HPV16 developed incident oropharyngeal cancer [IR = 1.62 per 100 person-years; 95% confidence interval (CI), 0.41-6.4]. Many with oral HPV16 persisted ≥5 years (and/or developed HPV-oropharyngeal cancer) among those with 2 (72.2%), ≥2 of first 3 (65.7%), or 3 (80.0%) consecutive positive oHPV16 tests, but not after 1 (39.4%)., Conclusions: In our 10-year study, most incident infections cleared quickly. However, half of prevalent oncHPV persisted ≥5 years, suggesting increased risk with persistent oncHPV at >2 visits., Impact: We identified groups with persistent oncHPV at increased risk of oropharyngeal cancer and contextualized risk levels for those with oral HPV16 infection., (©2024 American Association for Cancer Research.)

The use of conventional chemotherapy in conjunction with targeted and immunotherapy drugs has emerged as an option to limit the severity of side effects in patients diagnosed with head and neck cancer (HNC), particularly oropharyngeal cancer (OPC). OPC prevalence has increased exponentially in the past 30 years due to the prevalence of human papillomavirus (HPV) infection. This study reports a comprehensive review of clinical trials registered in public databases and reported in the literature (PubMed/Medline, Scopus, and ISI web of science databases). Of the 55 clinical trials identified, the majority (83.3%) were conducted after 2015, of which 77.7% were performed in the United States alone. Eight drugs have been approved by the FDA for HNC, including both generic and commercial forms: bleomycin sulfate, cetuximab (Erbitux), docetaxel (Taxotere), hydroxyurea (Hydrea), pembrolizumab (Keytruda), loqtorzi (Toripalimab-tpzi), methotrexate sodium (Trexall), and nivolumab (Opdivo). The most common drugs to treat HPV-associated OPC under these clinical trials and implemented as well for HPV-negative HNC include cisplatin, nivolumab, cetuximab, paclitaxel, pembrolizumab, 5-fluorouracil, and docetaxel. Few studies have highlighted the necessity for new drugs specifically tailored to patients with HPV-associated OPC, where molecular mechanisms and clinical prognosis are distinct from HPV-negative tumors. In this context, we identified most mutated genes found in HPV-associated OPC that can represent potential targets for drug development. These include TP53 , PIK3CA , PTEN , NOTCH1 , RB1 , FAT1 , FBXW7 , HRAS , KRAS, and CDKN2A .

Objective: Oral cavity and oropharyngeal cancer (OOPC) is a devastating disease often caught in late stages. People who use tobacco are at higher risk of OOPC. Tobacco cessation discussions and OOPC screenings are important factors in decreasing the risk of OOPC or its late stage diagnosis. As research on sex differences has been increasing-from research on biomedical to psychological and sociological determinants-there is a potential difference, by sex, as to whom is more likely to have a tobacco cessation discussion and OOPC screening. The objective of this study is to determine if there is an association of sex with tobacco cessation discussions and OOPC screenings conducted by dental healthcare professionals among participants who currently use tobacco., Method: Data from 8 years of the National Health and Nutrition Examination Survey (2011-2018) were merged. Data from participants, ages 30 years and above, who self-reported current use of tobacco, a dental visit within the previous year and responsed to questions about oral cancer screening were analysed for frequency determination and logistic regression analysis. Having the combination of neither OOPC screening nor discussion about the benefits of not using tobacco was the outcome in the analysis., Results: There were 22.1% who had an OOPC screening by a dental professional within the previous year. Of the 41% who reported having had a conversation with a dental professional within the previous year about the benefits of tobacco cessation, 9.8% reported having both the conversation and OOPC screening. Males were less likely than females to have the combination of neither OOPC screening nor advice about tobacco cessation than females (adjusted odds ratio: 0.74; 95%CI: 0.57, 0.96)., Conclusion: There is an increased need for OOPC screening and the discussion of tobacco use by dental professionals among their patients who use tobacco, particularly for female patients., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Transoral robotic surgery (TORS) opens new perspectives. We evaluated the outcomes for patients having undergone TORS after previous radiotherapy., Methods: A retrospective multicenter study (n = 138) in a previously irradiated area between 2009 and 2020. Survival was assessed with the Kaplan-Meier method. Prognostic factors were evaluated using a chi-squared test, Fisher's test, or Wilcoxon's test., Results: The median length of hospital stay was 12.5 days. Bleeding was the most frequent postoperative complication (15.2%, n = 22). Prophylactic vessel ligation did not significantly decrease bleeding. Complications were significantly lower for Tis, T1, and N0 tumors. 91.6% (n = 120) of the patients with a perioperative tracheotomy could be decannulated. Larynx was functional for 65.94% of the patients. The median length of follow-up was 26 months. The 5-year overall and relapse-free survival rates were respectively 59.9% and 43.4%., Conclusion: Oncological and functional results confirmed the value of TORS as a treatment in previously irradiated area., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Chronic Human Papilloma Virus (HPV) infection is supplanting alcohol and tobacco intoxications as the leading cause of oropharyngeal cancer in developed countries. HPV-related squamous cell carcinomas of the oropharynx (HPV + OSC) present better survival and respond better to radiotherapy and chemotherapy. Regulatory T cells (T REG ) are mainly described as immunosuppressive and protumoral in most solid cancers. However, T REG are paradoxically associated with a better prognosis in HPV + OSCs. The transcription factor FoxP3 is the basis for the identification of T REG . Among CD4 + FoxP3 + T cells, some have effector functions. A medical hypothesis is formulated here: the existence of a CD137 (4.1BB)-Eomesodermin (Eomes) activated pathway downstream of TCR-specific activation in a subpopulation of CD4 + FoxP3 + T cells may explain this effector function. Evidence suggest that this axis may exist either in CD4 + FoxP3 + T cells or CD8 + T cells. This pathway could lead T cells to strong antitumor cytotoxic activity in a tumor-specific manner. Furthermore, CD137 is one of the most expected targets for the development of agonist immunotherapies. The identification of CD137 + Eomes + FoxP3+/- T cells could be a key element in the selective activation of the most anti-tumor cells in the HPV + OSC microenvironment., (© 2024. The Author(s).)

Introduction: The incidence of human papillomavirus (HPV)-related oropharyngeal cancer is rising, thus the understanding of HPV infection and vaccination among oral healthcare professionals is becoming increasingly important. This study aimed to investigate the knowledge of Dutch dental hygiene students on HPV infection and vaccination and assessed various aspects of HPV-related oropharyngeal cancer., Methods: This descriptive cross-sectional study invited the entire Dutch dental hygiene student population registered in September 2016 to complete an online questionnaire concerning the knowledge of HPV infection and vaccination, including the aspects of HPV-related Oro-Pharyngeal Squamous Cell Carcinoma (OPSCC). Data were analysed using t-tests, Mann-Whitney U tests and Chi-square tests., Results: Invited were all 1248 Dutch dental hygiene students and 232 (18.6%) students completed the questionnaire. More than 95% of the students indicated HPV infection as a risk factor for OPSCC and 48.7% was aware of the availability of HPV vaccination. Additionally, students considered it important to discuss HPV as a risk factor for oropharyngeal cancer with their patients. In general, the students scored highest on the questions about risk factors for OPSCC and poorest on the questions about general HPV knowledge and HPV vaccination. Although the mean overall knowledge score was significantly higher in senior compared with junior students, knowledge scores of senior students remained insufficient., Conclusion: This study identified deficits in knowledge of HPV and HPV vaccination among Dutch dental hygiene students. Future research should focus on improving the content of dental hygiene curricula and development of ongoing educational tools for dental hygienists., (© 2023 The Authors. International Journal of Dental Hygiene published by John Wiley & Sons Ltd.)

While abundant evidence exists linking alcohol, tobacco, and HPV infection to a carcinogenic impact on the oropharynx, the contribution of inhalational workplace hazards remains ill-defined. We aim to determine whether the literature reveals occupational environments at a higher-than-average risk of developing oropharyngeal cancer (OPC) and summarize the available data. To identify studies assessing the relationship between occupational exposure and risk of OPC, a search of the literature through the PubMed-NCBI database was carried out and, ultimately, 15 original articles meeting eligibility criteria were selected. Only original articles in English focusing on the association between occupational exposure and risk or death of specifically OPC were included. The available data are supportive of a potentially increased risk of OPC in waiters, cooks and stewards, artistic workers, poultry and meat workers, mechanics, and World Trade Center responders exposed to dust. However, the available literature on occupation-related OPC is limited. To identify occupational categories at risk, large cohorts with long follow-ups are needed. Identification of causal associations with occupation-related factors would require dose-response analyses adequately adjusted for confounders.

Abstract: Circulating tumor DNA (ctDNA) has become an area of intense study in many solid malignancies including head and neck cancer. This is of particular interest for human papillomavirus-mediated oropharyngeal squamous cell carcinoma as this cohort of patients has excellent survival and is undergoing current clinical trials aimed at treatment de-escalation. Recent studies have demonstrated the prognostic implications of pretreatment ctDNA and the utility of monitoring ctDNA during and posttreatment; however, there is a need for a more critical understanding of ctDNA as it is beginning to be incorporated into clinical trials. This review discusses the current state of ctDNA in oropharynx cancer focusing on ctDNA kinetics and minimal residual disease detection and ends with a discussion of future applications., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Human papillomavirus infection is currently implicated in the majority of oropharyngeal squamous cell carcinoma cases diagnosed in the United States. Circulating tumor DNA (ctDNA) has emerged as a potential biomarker for human papillomavirus-related oropharyngeal squamous cell carcinoma and has the opportunity to improve the diagnosis, treatment, and surveillance of patients with this disease. Changes in ctDNA levels during and after primary therapy may be related to disease response, which can possibly have implications for treatment intensification or de-escalation strategies. Further, ctDNA seems to be sensitive and specific for disease recurrence and may improve upon current methods for assessing both treatment response and failure. In this review, we examine the relevant literature on the use of ctDNA for oropharyngeal cancer treatment and surveillance and discuss current limitations and future directions for this promising biomarker., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Smoking, alcohol consumption, and human papillomavirus (HPV) infection are known risk factors for oral squamous cell carcinoma (OSCC) including SCC of oropharynx (SCCOP) and SCC of oral cavity (SCCOC). Researchers have examined each of these risk factors independently, but few have observed the potential risk of their interaction. This study investigated the interactions among these risk factors and risk of OSCC., Methods: Totally 377 patients with newly diagnosed SCCOP and SCCOC and 433 frequency-matched cancer-free controls by age and sex were included. Multivariable logistic regression was performed to calculate ORs and 95% CIs., Results: We found that overall OSCC risk was independently associated with smoking (adjusted OR(aOR), 1.4; 95%CI, 1.0-2.0), alcohol consumption (aOR, 1.6; 95%CI, 1.1-2.2), and HPV16 seropositivity (aOR, 3.3; 95%CI, 2.2-4.9), respectively. Additionally, we found that HPV16 seropositivity increased the risk of overall OSCC in ever-smokers (aOR, 6.8; 95%CI, 3.4-13.4) and ever-drinkers (aOR, 4.8; 95%CI, 2.9-8.0), while HPV16-seronegative ever-smokers and ever-drinkers had less than a twofold increase in risk of overall OSCC (aORs, 1.2; 95%CI, 0.8-1.7 and 1.8; 95%CI, 1.2-2.7, respectively). Furthermore, the increased risk was particularly high for SCCOP in HPV16-seropositive ever-smokers (aOR, 13.0; 95%CI, 6.0-27.7) and in HPV16-seropositive ever-drinkers (aOR, 10.8; 95%CI, 5.8-20.1), while the similar increased risk was not found in SCCOC., Conclusion: These results suggest a strong combined effect of HPV16 exposure, smoking, and alcohol on overall OSCC, which may indicate a strong interaction between HPV16 infection and smoking and alcohol consumption, particularly for SCCOP., (© 2023. The Author(s).)

Background: To determine if the extent of high-dose gross tumor volume (GTV) to clinical target volume (CTV) expansion is associated with local control in patients with p16-positive oropharynx cancer (p16+ OPC) treated with definitive intensity modulated proton therapy (IMPT)., Methods: We performed a retrospective analysis of patients with p16+ OPC treated with IMPT at a single institution between 2016 and 2021. Patients with a pre-treatment PET-CT and restaging PET-CT within 4 months following completion of IMPT were analyzed., Results: Sixty patients were included for analysis with a median follow-up of 17 months. The median GTV to CTV expansion was 5 mm (IQR: 2 mm). Thirty-three percent of patients (20 of 60) did not have a GTV to CTV expansion. There was one local failure within the expansion group (3%)., Conclusion: Excellent local control was achieved using IMPT for p16+ OPC independent of GTV expansion. IMPT with minimal target expansions represent a potential harm-minimization technique for p16-positive oropharynx cancer., (© 2023 Wiley Periodicals LLC.)

The recent increase in high-risk human papillomavirus (HR-HPV)-associated oral and oropharyngeal cancers has gained considerable importance due to their distinct clinical and molecular characteristics. However, the natural history of oral HPV from acquisition to persistence and malignant transformation is still unclear. The global prevalence of oral HPV infection in healthy individuals ranges from 0.67% to 35%, while 31%-38.5% in head and neck cancer (HNC). The persistence rate of oral HR-HPV infection is 5.5% -12.8% globally. India has the highest HNC burden due to apparent differences in predisposing factors compared with the West. The prevalence of oral HPV in healthy individuals and its contribution to HNC is less evident in Indian studies. HR-HPV-associated HNC in this region accounts for 26%, with an active infection in 8%-15% of these tumors. There is a lack of concordance in the expression of p16 as a surrogate marker for HPV detection in HNC because of differences in behavioral risk factors. Due to a lack of evidence, treatment de-escalation cannot be implemented despite the improved outcome of HPV-associated oropharyngeal cancers. This review critically analyzes the existing literature on the dynamics of oral HPV infection and HPV-associated HNC, identifying potential avenues for future research. A better understanding of the oncogenic role of HR-HPV in HNC will help to formulate novel therapeutic approaches and is expected to have a significant public health impact as preventive strategies can be implemented., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: To develop machine learning (ML) models for predicting positive margins in patients undergoing transoral robotic surgery (TORS)., Methods: Data from 453 patients with laryngeal, hypopharyngeal, and oropharyngeal squamous cell carcinoma were retrospectively collected at a tertiary referral center to train (n = 316) and validate (n = 137) six two-class supervised ML models employing 14 variables available pre-operatively., Results: The accuracy of the six ML models ranged between 0.67 and 0.75, while the measured AUC between 0.68 and 0.75. The ML algorithms showed high specificity (range: 0.75-0.89) and low sensitivity (range: 0.26-0.64) in detecting patients with positive margins after TORS. NPV was higher (range: 0.73-0.83) compared to PPV (range: 0.45-0.63). T classification and tumor site were the most important predictors of positive surgical margins., Conclusions: ML algorithms can identify patients with low risk of positive margins and therefore amenable to TORS., (© 2022 Wiley Periodicals LLC.)

Opinion Statement: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) incidence has been increasing in recent decades. Treatment of the locally advanced HPV-related OPSCC includes a multidisciplinary approach. Immunotherapy with immune checkpoint inhibitors is used in the treatment of patients with recurrent/metastatic head and neck squamous cell carcinomas (HNSCC), including HPV-related OPSCC patients. There is increasing knowledge of the role of HPV in the tumor immune microenvironment. Therefore, HPV status of OPSCC plays an essential role in the design of immunotherapy clinical trials in both curative intent and metastatic settings. Moreover, HPV has become a potential therapeutic target, with vaccines and adoptive T-cell therapies being developed against HPV for the treatment of OPSCC. Several novel studies are designed to target HPV in combination with immune checkpoint inhibitors. Thus, HPV-related OPSCC remains a unique subgroup in the immunotherapy era., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: A primary goal in transoral robotic surgery (TORS) for oropharyngeal squamous cell cancer (OPSCC) survivors is to optimize swallowing function. However, the uncertainty in the outcomes of TORS including postoperative residual positive margin (PM) and extranodal extension (ENE), may necessitate adjuvant therapy, which may cause significant swallowing toxicity to survivors., Methods: A secondary analysis was performed on a prospective registry data with low- to intermediate-risk human papillomavirus-related OPSCC possibly resectable by TORS. Decision trees were developed to model the uncertainties in TORS compared with definitive radiation therapy (RT) and chemoradiation therapy (CRT). Swallowing toxicities were measured by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST), MD Anderson Dysphagia Inventory (MDADI), and the MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) instruments. The likelihoods of PM/ENE were varied to determine the thresholds within which each therapy remains optimal., Results: Compared with RT, TORS resulted in inferior swallowing function for moderate likelihoods of PM/ENE (>60% in short term for all instruments, >75% in long term for DIGEST and MDASI) leaving RT as the optimal treatment. Compared with CRT, TORS remained the optimal therapy based on MDADI and MDASI but showed inferior swallowing outcomes based on DIGEST for moderate-to-high likelihoods of PM/ENE (>75% for short-term and >40% for long-term outcomes)., Conclusion: In the absence of reliable estimation of postoperative PM/ENE concurrent with significant postoperative PM, the overall toxicity level in OPSCC patients undergoing TORS with adjuvant therapy may become more severe compared with patients receiving nonsurgical treatments thus advocating definitive (C)RT protocols., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Social habits such as smoking and drinking alcohol are well-known causative agents for oral and oropharyngeal squamous cell carcinoma (OSCC/OPSCC). Human papillomavirus (HPV) is a known causative agent for OPSCC. However, we often encounter patients with no identifiable risk factors. There is growing evidence of the role of occupational carcinogens in the pathogenesis of oral cancer. The aim of this study therefore was to identify any occupational carcinogens linked to oral cancer. We carried out a systematic review of the literature using PubMed, EMBASE, and Medline, along with a retrospective review of patients treated in a regional unit over 25 years. Occupations were classified based on the UK Standard of Classification 2020. Data analysis was completed using the chi-squared test. A total of 17 papers met the inclusion criteria for review. In our retrospective study a total of 874 patients were identified of whom 31% were blue-collar workers, 32.8% were white-collar workers, 20.2% were unemployed/housewives, and 16% workers in other occupations. The majority of blue-collar workers were in the construction industry and had maximum exposure to hydrocarbons and exhaust fumes. The aetiology of oral and oropharyngeal SCC is multifactorial and there is no consensus on the role of occupational carcinogens. We showcase our patient cohort and discuss the occupational exposures that appear to make them susceptible to OSCC and OPSCC. Further multicentre studies are required to enable us to understand fully the pathogenesis of oral cancer and help us to inform relevant organisations, the aim being to reduce the incidence of occupation-related cancer., (Copyright © 2022 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background/purpose: Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients' quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC., Material and Methods: We performed a retrospective cohort study ( N  = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) ( N  = 180), or 24 Gy IMRT (2 Gy fractions) ( N  = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT., Results: All cases of PRMU ( N  = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% ( N  = 46) vs. 12% ( N  = 18) for conventional fractionation ( p  = 0.003). Most PRMU developed within nine months ( N  = 48). PRMU occurring > nine months ( N  = 16) were mainly observed in the SBRT boost group ( N  = 15). Sex ( p  = 0.048), acute tube feeding ( p = < 0.001), tumor subsite tonsil ( p  = 0.001), and N stage ( p  = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions., Conclusion: The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.

Oropharyngeal cancer is increasingly caused by human papillomavirus (HPV), and this increase is believed to be caused by changing sexual behaviour. It has been hypothesised that an immune response to HPV through sexual intercourse is much stronger than an immune response elicited from oral sex. Therefore, people who have their debut of oral sex before or at the same time as sexual intercourse would have a weaker immune response to HPV and hence be more likely to develop a persistent oral HPV infection and oropharyngeal cancer. Drake et al (Cancer. 2021;127[7]:1029-1038) found some evidence that supported this hypothesis. We have reanalysed two of our Australian cohorts with similar data in order to provide a perspective of Drake and colleagues' publication, as sexual behaviour varies depending on culture and geographical location. We found that engaging in oral sex (OR 4.46, 95% CI [1.88-10.62]) and being younger than 20 years at oral sex debut (OR 9.46, 95% CI [3.53-25.31]) were both very strong risk factors for oropharyngeal cancer. Participants in the general population cohort who had their sexual intercourse debut before the age of 18 were more likely to be oral HPV positive (OR 2.69, 95% CI [1.50-4.83]). Oral sex debut before sexual intercourse debut was quite uncommon in our two Australian cohorts. However, timing of or sexual debuts may further add to risks of oropharyngeal cancer, and future studies should be designed to investigate timing and order of sexual debuts to help clarify the roles of these potential causal factors., (© 2022 UICC.)

Abstract: Despite the availability of prophylactic human papillomavirus (HPV) vaccines, there is a growing incidence of HPV-associated head and neck squamous cell carcinomas (HPV-HNSCC) worldwide. The viral etiology of HPV-HNSCC provides an opportunity to develop personalized immune-based therapies, which target the unique viral- or tumor-specific proteins. Novel HPV-targeted immunotherapeutic approaches in clinical development are reviewed. Early results from these trials highlight new opportunities and potential challenges ahead. Immunotherapies for HPV-associated HNSCCs will require a tailored combinatorial approach based on preexisting mechanisms of host immune resistance. As the field continues to identify the relevant HPV types 16 and 18 immunogenic epitopes that are presented by diverse HLA class I alleles, improved HPV-targeted biologics and clinical monitoring tools can be developed and applied to a broader cancer patient population., Competing Interests: Conflicts of Interest and Source of Funding: S.I.P. has received consultancy payments from Abbvie, Astrazeneca/MedImmune, Cue Biopharma, Fusion Pharmaceuticals, MSD/Merck, Newlink Genetics, Oncolys Biopharma, Replimmune, Scopus Biopharma, and Sensei Bio. She has received grants/research support from Abbvie, Astrazeneca/MedImmune, Cue Biopharma, Merck, and Tesaro. J.S.C. owns stocks in Sensei Biotherapeutics. This study was supported through NIH/NCI 5 R01 CA257623, NIH/NCI P01 CA 240239, and FDA R01 FD006341., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

In 1988, Blot and colleagues reported results from a U.S. case-control study of oral cavity or pharyngeal (oropharyngeal and hypopharyngeal) cancers, with results showing independent associations of smoking and alcohol with increased risk, multiplicative interaction effects between smoking and alcohol, and that nearly three-quarters of these cancers are attributable to smoking and alcohol. The report by Blot and colleagues represents a landmark in oropharyngeal cancer epidemiology. This study, the largest at the time, introduced several novel concepts in oropharyngeal cancer epidemiology that remain relevant today-etiologic heterogeneity, statistical interaction effects, adjusted attributable fractions, and disparities by sex and race/ethnicity. Perhaps the most significant recognition in the field since 1988 is the etiologic association of human papillomavirus (HPV, primarily HPV16) with cancers arising in the oropharynx. Today, more than 80% of oropharyngeal cancers in the United States are caused by HPV while only approximately 3% of oral cavity cancers are caused by HPV. This etiologic heterogeneity across head and cancer subsites revealed by HPV is manifest at the genetic/genomic, epidemiologic, and clinical levels. Tobacco and alcohol remain the major etiologic factors for oral cavity cancers while HPV is the major cause of oropharyngeal cancers. Thus, tobacco and alcohol control and prophylactic HPV vaccination remain the most promising prevention tools for oral cavity and oropharyngeal cancers at this time. Importantly, the ever-emerging alternative tobacco products, such as smokeless tobacco/snus, hookah and water pipes, e-cigarettes, flavored cigars and cigarillos, and oral dissolvable products, represent a key public health concern and the carcinogenic effects of these products remains an active area of investigation. See related article by Blot and colleagues, Cancer Res 1988;48:3282-7., (©2022 American Association for Cancer Research.)

Background: Cancers of the oral cavity and pharynx encompass a heterogeneous group of cancers for which known risk factors include smoking, alcohol consumption and human papilloma virus (HPV) infection but their influence is site-specific with HPV mainly influencing oropharyngeal cancer. Their incidence and survival rates are not well known over extended periods of time., Patients/methods: Data were obtained for Finnish (FI) and Swedish (SE) patients from the Nordcan database recently updated through 2019. Age-adjusted incidence trends (FI from 1953, SE from 1960) and relative survival rates for years 1970 through 2019 were calculated., Results: We observed a prominent increase in oral and oropharyngeal cancers in FI and SE men and women but the trend for oral cancer was interrupted for SE men in 1985 and possibly also for FI and SE women in 2015. The trend changes in male and female oral cancer was confirmed in data for Denmark and Norway. Relative survival for these cancers has improved overall but they differed for one cluster of oral, oropharyngeal and nasopharyngeal cancers with 60-70% 5-year survival in the last period and hypopharyngeal cancer with 25% male survival. In all these cancers, survival for old patients was unfavorable., Discussion/conclusion: We hypothesize that reduction in smoking prevalence helped to stop the increase in oral cancer especially in men. As the prevalence of smoking is decreasing, HPV is becoming a dominant risk factor, particularly for the increasing oropharyngeal cancer. Prevention needs to emphasize sexual hygiene and HPV vaccination., (© 2022. The Author(s).)

Opinion Statement: Human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing in incidence, and has now become the most common head and neck cancer (HNC). Studies have demonstrated that HPV associated OPSCC is associated with a favorable prognosis compared with its HPV-negative counterparts, yet standard multimodality therapy is often associated with substantial acute and late treatment-related toxicity. While locoregional control is improved in HPV+ OPSCC, distant metastasis rate has gained recognition as a major cause of death in this population, with some studies suggesting similar rates as non-HPV-related cancers. Induction chemotherapy has been of long-standing interest in locoregionally advanced HNC, yet its use in combination with concomitant chemoradiation remains an area of controversy as a survival benefit remains unproven following randomized trials. Nevertheless, response to induction chemotherapy remains an important dynamic and prognostic biomarker, with response-adaptive de-intensified therapy in HPV+ OPSCC gaining traction in single-arm phase II studies demonstrating promising results. The emergence of immunotherapy in the recurrent/metastatic setting for HNC has led to enthusiasm to incorporate in the curative setting, yet its role remains undefined. Our institutional paradigm for HPV+ OPSCC incorporates induction therapy followed by risk and response adaptive locoregional treatment. Ultimately, the role of induction therapy in HPV+ OPSCC will need to be investigated in a randomized setting to be incorporated routinely into clinical practice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This study aimed to assess the utility of deep learning analysis using pretreatment FDG-PET images to predict local treatment outcome in oropharyngeal squamous cell carcinoma (OPSCC) patients., Methods: One hundred fifty-four OPSCC patients who received pretreatment FDG-PET were included and divided into training (n = 102) and test (n = 52) sets. The diagnosis of local failure and local progression-free survival (PFS) rates were obtained from patient medical records. In deep learning analyses, axial and coronal images were assessed by three different architectures (AlexNet, GoogLeNET, and ResNet). In the training set, FDG-PET images were analyzed after the data augmentation process for the diagnostic model creation. A multivariate clinical model was also created using a binomial logistic regression model from a patient's clinical characteristics. The test data set was subsequently analyzed for confirmation of diagnostic accuracy. Assessment of local PFS rates was also performed., Results: Training sessions were successfully performed with an accuracy of 74-89%. ROC curve analyses revealed an AUC of 0.61-0.85 by the deep learning model in the test set, whereas it was 0.62 by T-stage, 0.59 by clinical stage, and 0.74 by a multivariate clinical model. The highest AUC (0.85) was obtained with deep learning analysis of ResNet architecture. Cox proportional hazards regression analysis revealed deep learning-based classification by a multivariate clinical model (P < .05), and ResNet (P < .001) was a significant predictor of the treatment outcome. In the Kaplan-Meier analysis, the deep learning-based classification divided the patient's local PFS rate better than the T-stage, clinical stage, and a multivariate clinical model., Conclusions: Deep learning-based diagnostic model with FDG-PET images indicated its possibility to predict local treatment outcomes in OPSCCs., (© 2021. The Author(s).)

Background: The goal of this study was to comprehensively investigate the association of chemotherapy with trajectories of acute symptom development and late symptom recovery in patients with oropharyngeal cancer (OPC) by comparing symptom burden between induction chemotherapy followed by concurrent chemoradiotherapy (ICRT), concurrent chemo-radiotherapy (CRT), or radiotherapy (RT) alone., Methods: Among a registry of 717 patients with OPC, the 28-item patient-reported MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN) symptoms were collected prospectively at baseline, weekly during RT, and 1.5, 3 to 6, 12, and 18 to 24 months after RT. The effect of the treatment regimen (ICRT, CRT, and RT alone) was examined with mixed-model analyses for the acute and late period. In the CRT cohort, the chemotherapy agent relationship with symptoms was investigated., Results: Chemoradiation (ICRT/CRT) compared with RT alone resulted in significantly higher acute symptom scores in the majority of MDASI-HN symptoms (ie, 21 out of 28). No late symptom differences between treatment with or without chemotherapy were observed that were not attributable to ICRT. Nausea was lower for CRT with carboplatin than for CRT with cisplatin; cetuximab was associated with particularly higher scores for acute and late skin, mucositis, and 6 other symptoms. The addition of ICRT compared with CRT or RT alone was associated with a significant increase in numbness and shortness of breath., Conclusion: The addition of chemotherapy to definitive RT for OPC patients was associated with significantly worse acute symptom outcomes compared with RT alone, which seems to attenuate in the late posttreatment period. Moreover, induction chemotherapy was specifically associated with worse numbness and shortness of breath during and after treatment., Lay Summary: Chemotherapy is frequently used in addition to radiotherapy cancer treatment, yet the (added) effect on treatment-induced over time is not comprehensively investigated This study shows that chemotherapy adds to the symptom severity reported by patients, especially during treatment., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Sexual behavior is associated with human papillomavirus (HPV)-positive head and neck cancer, whereas tobacco and alcohol use are associated with HPV-negative cancer. A case-control study was designed to investigate additional demographic and behavioral factors independently associated with these distinct oral cancers., Methods: From 2011 to 2014, 249 newly diagnosed oral cavity and oropharyngeal squamous cell carcinoma (OSCC) cases were matched (1:2) on age, gender, and self-identified race to 498 controls without a cancer history attending the outpatient otolaryngology clinic at The Ohio State University in Columbus. Cases were stratified by detection of high-risk HPV DNA and RNA in tumors. Demographic and behavioral data were collected using an audio computer-assisted self-interview, and associations with HPV-positive versus HPV-negative OSCCs were investigated by use of univariable and multivariable conditional logistic regression models., Results: After adjustment for oral sexual behavior, the odds of HPV-positive cancer decreased with the patient's years of education. Annual income, tobacco smoking, alcohol drinking, marijuana smoking, and poor oral hygiene were not associated with HPV-positive OSCC. In contrast, the odds of HPV-negative OSCC increased independently with decreased annual income, decreased with a high number of marijuana hit-years, and increased with fewer than annual dental visits after adjustment for lifetime tobacco and alcohol use. Sexual behavior and education were not associated with HPV-negative OSCC., Conclusions: The distinct risk-factor profiles for HPV-positive and HPV-negative OSCC are confirmed and extended in this case-control study, thus supporting 2 principal etiological pathways for OSCC development., Lay Summary: Sexually acquired human papillomavirus (HPV) infection is an established cause of tonsil and base of tongue cancers. This study compared and contrasted risk factors for HPV-positive and HPV-negative oral cancers. Low number of years of education and sexual behavior are associated with HPV-positive cancer. In contrast, low annual income, infrequent dental visits, and tobacco and alcohol use are associated with HPV-negative cancers. Long-term marijuana use appears protective for HPV-negative cancer. Public health efforts to address these modifiable risk factors may prevent oral cancer., (© 2021 American Cancer Society.)

Objectives: While smoking is associated with worse outcomes in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), the magnitude of this association is unclear given the heterogenous smoking definitions and outcomes. Our objective was to investigate the association between smoking, survival, and recurrence in HPV-related OPSCC using multiple smoking metrics reported in the literature., Materials and Methods: This was a retrospective cohort study of 375 adults with p16+ OPSCC undergoing surgical resection (n = 272) or definitive chemoradiation (n = 103) at a tertiary academic institution from 2006 to 2017. The primary outcome was overall survival (OS). Secondary outcomes included disease-free survival (DFS), disease-specific survival (DSS), and recurrence. We used multiple smoking metrics commonly cited in previous studies, including ever versus never smokers, current versus former/never smokers, ≤10 versus >10 pack-year, ≤20 versus >20 pack-year, and continuous pack-year., Results: There were 375 patients, median age 58 years, with 326 (87%) males, and median follow-up of 52 months. Of all smoking metrics, >20 pack-year history was the strongest predictor of both OS (HR 2.24, 95% CI: 1.19-4.20) and DFS (HR 1.67, 95% CI: 1.04-2.66) on univariable and multivariable analysis after adjusting for age, overall stage, and comorbidities. Patients with >20 pack-year smoking history were also more likely to have recurrence (HR 1.59, 95% CI: 0.95-2.67) after adjusting for overall stage., Conclusion: Heavier smoking >20 pack-years was the strongest smoking metric associated with 2-times worse survival and recurrence. Our findings suggest that >20 pack-year smoking history may be a more useful cutoff for risk stratification models but requires further validation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background/aim: While in many Western countries the number of tonsillectomies decreases significantly, there is an increasing incidence of oropharyngeal carcinomas. For, obviously, removal of the tonsils will reduce individual risk for tonsil cancer, the question of tonsillectomy as a prevention strategy is suggested. This study focused on this question by carrying out a literature research., Materials and Methods: A literature research was performed (www.pubmed.gov; Search words: tonsillectomy, oropharyngeal cancer, tonsil cancer, prevention) without applying additional filters., Results: Out of the 16 identified studies, three population-based studies were evaluated. Individual incidence of tonsil cancer is significantly lower after removal of tonsils; however, risk elimination by tonsillectomy has not been proven. One of the studies revealed increasing numbers of base of the tongue cancer after previous tonsillectomy., Conclusion: The increase in oropharynx carcinomas can currently be attributed not to the decreasing tonsillectomy rates, but to the increase in HPV infections. A previous tonsillectomy reduces the individual risk of developing tonsil carcer. Tonsillectomy as prevention for oropharyngeal cancer cannot be recommended and may even be a disadvantage concerning base of the tongue cancers., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: TNM8 introduced a new staging system for HPV positive oropharyngeal squamous cell carcinoma (OPSCC). This study aimed to investigate whether the changes made in TNM8 offer the perceived benefit in prognostication when compared to TNM7 in a specific patient population in the North East of England., Methods: A retrospective cohort comparison study of all patients with HPV positive OPSCC (n = 106) through the Newcastle Head and Neck MDT between January 2012 to December 2014. Overall survival (OS) and Disease specific survival (DSS) data at 3 years was gathered for both TNM7 and TNM8. Log rank test was used to compare survival curves. Harrell's C-index adjusted for age and smoking status was used to assess prognostic ability of the two staging methods., Results: TNM8 downstages disease (TNM7 stage IV patients n = 74, TNM8 stage IV patients n = 2) but gives a more even distribution of patients across disease stages. Survival for TNM8 stage II and III is similar. In our small cohort, the log-rank test detected differences in OS between stages for both scoring methods (TNM7 p = 0.006, TNM8 p < 0.001) and similarly for DSS (TNM7 p = 0.001, TNM8 p < 0.001). Harrell's C-index was similar for both models for OS (TNM7 0.71, TNM8 0.71) and DSS (TNM7 0.74, TNM8 0.70)., Conclusion: TNM8 downstages disease and prognosticates well for stage I disease but does not differentiate between stage II and III disease when compared to TNM7. Further adaptation is required to address this to make TNM8 a more accurate prognostic tool.

Purpose: Human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) treatment outcomes are re-defining management. Traditional margins, the role of extranodal extension (ENE) and adjuvant treatment intensity continue to be debated. This study aimed to determine the impact of margins, ENE and adjuvant therapy on survival following transoral robotic surgery (TORS)., Methods: Patients treated with TORS at an academic center were retrospectively identified (2013-2019). Survival outcomes were evaluated using Kaplan-Meier curves., Results: 48 patients were included. 40 (83%) were male. Mean age was 61.2 years. 43 (90%) were stage I. 22 (45.8%) had ENE. 31 (65%) had margins >1 mm. 38 (79%) had indications for radiation therapy; 9 (24%) refused. Chemotherapy was recommended in 36 (75%) patients; 24 (67%) refused. Locoregional control was 98%, metastasis-free survival was 96%, and disease-specific survival was 100% at 5-years. Overall survival was 95%., Conclusions: Given the high survival rate seen after TORS, it is likely that margins, ENE and adjuvant treatment may not significantly contribute to outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Racial disparities for overall survival (OS) in head and neck cancer have been well described. However, the extent to which these disparities exist for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), and the contribution of demographic, clinical, and socioeconomic status (SES) variables, is unknown., Materials and Methods: Patients were identified from the Carolina Head and Neck Cancer Epidemiology Study (CHANCE), a population-based study in North Carolina. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for OS in black versus white patients with sequential adjustment sets., Results: A total of 157 HPV-associated OPSCC patients were identified. Of these, 93% were white and 7% were black. Black patients with HPV-associated OPSCC were more likely to be younger, have an income <$20,000, live farther away from clinic where biopsy was performed, and have advanced T stage at diagnosis. Black patients had worse OS in the unadjusted analysis (HR 4.9, 95% CI 2.2-11.1, p < 0.0001). The racial disparity in OS slightly decreased when sequentially adjusting for demographic, clinical, and SES variables. However, HR for black race remained statistically elevated in the final adjustment set which controlled for age, sex, stage, smoking, alcohol use, and individual-level household income, insurance, and education level (HR 3.4, 95% CI 1.1-10.1, p = 0.028)., Conclusion: This is the first population-based study that confirms persistence of racial disparities in HPV-associated OPSCC after controlling for demographic, clinical, and individual-level socioeconomic factors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Trans Oral Robotic Surgery (TORS) is a fascinating new technique that has proved to be a safe and feasible treatment of oropharyngeal squamous cell carcinoma (OPSCC). The aim of this study is to compare oncological outcomes of OPSCC-patients treated with either TORS (with or without adjuvant therapy) or definitive chemoradiation therapy (CRT)., Materials and Methods: This study involved 129 patients with OPSCC, treated with TORS or definitive CRT at our Department between 2008 and 2018. Clinicopathological characteristics, treatment specifications and oncological outcomes were evaluated retrospectively., Results: Definitive CRT was administered in 69 patients (53,5%), while 60 (46,5%) were surgically treated with TORS alone or in combination with adjuvant therapy. Patients who underwent adjuvant therapy after TORS received a lower dosages of cisplatin and radiation than the CRT group (p < 0.01). There was no statistical difference in 5-year survival rate and in disease free interval between TORS and CRT groups. Albeit 5-year overall survival in the HPV-related tumours was better, the HPV status did not affect the rate of local and regional recurrence. Treatment groups (TORS vs. CRT) were not found affecting survivals on multivariate analysis. Tube feeding dependency rate was low between both groups (1.7% in TORS vs. 4.8% in CRT groups)., Conclusion: The modern management of OPSCC must be tailored to each patient. Although the definitive CRT remains a milestone, TORS is proving to be a valid and safe treatment option. The choice of single therapeutic strategy requires an evaluation by a multidisciplinary team., Competing Interests: Declaration of Competing Interest Claudio Vicini and Filippo Montevecchi are consultants and proctors for Intuitive Surgical Inc. All other authors have nothing to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Accurate determination of human papilloma virus (HPV) status is critical when identifying patients with oropharyngeal squamous cell carcinoma (OPSCC) who may be candidates for de-escalation trials. In this study we investigated whether local p16 screening, by immunohistochemistry (IHC), has high positive predictive value (PPV) for HPV status in a good prognosis HPV positive OPSCC (HPVOPSCC) population treated on a clinical trial., Methods and Materials: Patients enrolled on the TROG 12.01 randomised trial for good prognosis HPVOPSCC were randomised based on local p16 IHC testing but subsequently had central p16 IHC and HPV RNA in situ hybridisation (HPV RNA ISH) testing. Correlations between the local and central p16 and central HPV RNA ISH were studied. The main outcome was the positive predictive value (PPV) of local pathology laboratory testing of p16., Results: 176/182 patients had samples available for central testing. 172/176 were evaluable for central testing of p16, and all were confirmed to be p16 positive (172/172, 100%, 95% CI = [97.9%, 100%]). Similarly, 100% of those evaluable for HPV RNA ISH (155/155, 100%, 95% CI = [97.6%, 100%]) were confirmed HPV positive, indicating p16 overexpression driven by transcriptionally active HPV and a PPV of 100% for local p16 testing., Conclusions: Our results validate the suitability of local pathology laboratory p16 testing alone, in populations with a high attributable fraction of OPSCC due to HPV, to screen and enrol low risk HPVOPSCC patients onto de-intensification trials. This obviates the need for upfront more complex and expensive HPV assays and/or central laboratory testing., Competing Interests: Declaration of Competing Interests Richard Young - institutional grant from Roche; Ben Solomon - personal fees from Merck Sharp & Dohme, personal fees from Bristol-Myers Squibb, grants and personal fees from Roche, grants from Regeneron, personal fees from AstraZeneca, grants and personal fees from Pfizer, personal fees from Genentech, personal fees from Loxo Oncology; Christopher Angel - institutional grant from Roche; Sandro Porceddu - personal fees from Merck Sharp & Dohme, personal fees from Merck, personal fees from Celgene; Danny Rischin - grants from Merck Sharp & Dohme, grants from Merck, grants from Bristol-Myers Squibb, grants from GSK, grants from Roche, grants from Regeneron, grants from Amgen, grants and personal fees from MSD, Trial Steering Committees and/or Advisory Boards (all uncompensated) - MSD, Merck, Bristol-Myers Squibb, GSK, Regeneron; June Corry, Christopher Wratten, Andrew Macann, James Jackson, and Alan Herschtal - no disclosures., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Radiotherapy (RT) without chemotherapy is considered a standard of care for the management of American Joint Committee on Cancer (AJCC) 7th edition (7E) T1-2N1 oropharyngeal squamous cell carcinoma (OPSCC). Recent data suggests concurrent chemoradiation (CCRT) may benefit these patients but did not include human papillomavirus (HPV) status. Given the radiosensitivity differences between HPV-positive versus HPV-negative OPSCC, the effect of chemotherapy may differ in these patients., Methods: We analyzed patients in the National Cancer Database diagnosed between 2010 and 2015 with AJCC 7E stage cT1-2N1M0 OPSCC and known HPV status undergoing definitive RT or CCRT., Results: Overall, 1964 patients were included, including 1297 (66%) HPV-positive and 667 (34%) HPV-negative patients. 66% received CCRT and 34% received RT alone. In multivariate analysis, CCRT was associated with improved survival compared with RT alone (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.57-0.87; P = 0.001). In propensity score-matched cohorts, 4-year overall survival was 87.4% vs 78.4% in HPV-positive patients receiving CCRT and RT alone, respectively (P = 0.002), and 65.5% vs 58.9% in HPV-negative patients, respectively (P = 0.2). There was no evidence that HPV-positivity diminished the association between CCRT and longer survival (HR, 0.57; 95% CI, 0.42-0.81) versus what was observed in HPV-negative patients (HR, 0.86; 95% CI, 0.64-1.16) (interaction P = 0.06)., Conclusions: CCRT is associated with improved survival in AJCC 7E T1-2N1 OPSCC. Despite the radiosensitivity of HPV-positive OPSCC, the association of CCRT with improved survival for T1-2N1 HPV-positive OPSCC was at least as strong, if not stronger, than what was observed in HPV-negative patients., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest related to this work. ZSZ was on the external advisory board for the Scripps Proton Therapy Center and has consulted for EMD Serono. All other authors have no disclosures., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Alcohol is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk., Methods: Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking., Results: For all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx)., Conclusions: Present results further encourage the reduction of alcohol intensity to mitigate HNC risk.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients., Methods: We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002-2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival (p < 0.05)., Results: Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p = 0.002, p = 0.003 respectively). RPA identified 30 pack-years (PY) as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ > 30 PY patients didn't differ significantly from HPV- patients (p = 0.72, p = 0.27, respectively). HPV+ > 30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p = 0.03, 76% vs 88.3%; p = 0.07, and 52.3% vs 74%; p = 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively., Conclusions: Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV + OPSCC smokers should be avoided.

Purpose: While smoking is linked to worse outcomes for human papillomavirus (HPV)-related oropharyngeal squamous cell cancer (OPSCC), the magnitude of this association and the amount of smoking exposure necessary to confer clinically significant differences in outcomes is unclear. Recent studies suggested that greater tobacco exposure results in higher risk of cancer progression and death. Our study objective was to perform a systematic review of the association between smoking and HPV-related OPSCC outcomes., Materials and Methods: A literature search was conducted in April 2019 to identify relevant articles using Embase, Medline, Scopus, CENTRAL, and Cochrane databases. All studies were independently screened by two investigators to identify studies that assessed HPV-positive patients as an independent cohort, specified smoking measures, and reported locoregional recurrence (LRR), overall survival (OS), disease-specific survival (DSS), or disease-free survival (DFS) in association with smoking., Results: Of 1130 studies identified, 10 met final inclusion criteria with 2321 total patients, mean age 57.5 years. Smoking measures included ever vs never, current vs never/former smokers, ≤10 vs >10 pack-year, and continuous pack-years. Of these studies, 8 (80%) showed a significant effect of smoking on increasing recurrence and mortality. Adjusted HRs for LRR ranged from 0.6 to 5.2, OS from 1.3 to 4.0, DSS from 2.3 to 7.2, and DFS from 1.02 to 4.2 among heavier smokers compared to lighter/non-smokers., Conclusions: While there was significant variability in smoking metrics and reported outcomes, all studies reporting statistically significant HRs showed that smoking was associated with worse outcomes. Further studies using uniform smoking measures are necessary to better understand this association., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Prognostic factors specific to surgically managed human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) are not fully understood. Medical co-morbidities may have an impact on survival after surgical treatment. We aimed to identify co-morbidities associated with distant metastases-free survival (DMFS) and cancer-specific survival (CSS) in HPV(+)OPSCCs., Methods: This is a retrospective case series of HPV(+)OPSCC patients at a tertiary referral center from 2007 to 2016. All patients in the study underwent primary intent-to-cure transoral resection with concomitant neck dissection ± adjuvant radiation ± chemotherapy. Exclusion criteria included a history of previous head and neck cancer or distant metastases at diagnosis. Associations with DMFS and CSS were evaluated using univariable and multivariable Cox regression and summarized with hazard ratios (HRs)., Results: 406 patients were included in the cohort (100% HPV(+), 90% Male). All had tumors of the tonsil (62%) or base of tongue (38%). Median follow-up for the cohort was 4.0 years (IQR: 2.6-6.2). Higher tumor stage and a higher Adult Comorbidity Evaluation-27 score were significantly associated with worse DMFS and CSS (p < 0.02 for all). A history of diabetes mellitus (N = 36, 9%) was significantly associated with DMFS (HR 3.05 [95%CI 1.26-7.37], p = 0.014) and CSS (HR 4.82 [95%CI 1.84-12.61], p = 0.001). On multivariable analysis, after adjusting for tumor stage, diabetes remained significantly associated with worse DMFS (HR 2.58 [95%CI 1.06-6.26], p = 0.037)., Conclusion: Diabetes mellitus may be associated with worse DMFS and CSS in surgically managed HPV(+)OPSCC., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Delayed diagnosis of oral cavity and oropharyngeal cancer is associated with a poor prognosis. Despite progress in systemic therapy and radiotherapy, there has only been a slight improvement in the five-year survival rate. A non-invasive diagnostic method that consists of an assessment of specific proteins in saliva samples may significantly facilitate assessment of treatment results in patients diagnosed with oral and oropharyngeal cancer. The aim of this study was to assess the levels of IL-17 and TNF- α in the saliva of patients with oral and oropharyngeal cancer. The study was conducted prior to treatment in patients hospitalized in the Frederic Chopin Provincial Specialist Hospital No. 1 in Rzeszów, Poland. Saliva samples were collected from subjects on an empty stomach. Cytokine concentrations in the saliva were measured with ELISA and Luminex Multiplex Assays. The higher salivary concentrations of IL-17A, IL-17F, and TNF- α were significantly associated with disease advancement. Lower levels of IL-17A were associated with colonization of the oral cavity with aerobic bacteria. On the other hand, higher concentration of TNF- α was observed in patients with positive aerobic culture of oral swabs. Our results suggest that IL-17A, IL-17F, and TNF- α measured in the saliva may be a potential biomarker for cancer of the oral cavity and oropharynx., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Kinga Zielińska et al.)

Objectives: To compare risk factors and survival in people with oropharyngeal cancer (OPC) and cancer unknown primary (CUP)., Materials and Methods: We recruited 5511 people with head and neck cancer between 2011 and 2014. We collected data on age, gender, smoking, sexual behaviour, treatment intent, stage, co-morbidity, p16 protein overexpression and biological samples. We assessed human papillomavirus (HPV) status using serological response and p16 immunohistochemistry. We followed up participants to identify those who had died. We used Cox proportional hazards regression models to estimate survival and adjust for confounders., Results: Of the 4843 people with squamous cell cancer 196 had CUP - a prevalence of 4.0% (95% CI 3.5% to 4.6%). Of those people with OPC and CUP 69% (1150/1668) and 60% (106/178) respectively had HPV driven tumours. People with HPV driven tumours were likely to be younger, male, non-smokers, with higher stage disease, a history of oral sex and less co-morbidity. People with HPV negative CUP and HPV driven CUP had the survival of people with a stage II/III HPV negative OPC and a stage I/II HPV driven OPC respectively. The adjusted hazard ratio for HPV driven OPC and CUP compared with HPV negative OPC and CUP was 0.46 (95% CI 0.35 to 0.59) and 0.34 (95% CI 0.14 to 0.82) respectively., Conclusion: HPV driven CUP is likely to be HPV driven OPC. Identifying effective methods of detecting occult OPC could improve CUP management and allow the detection of early lesions in high risk groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Human immunodeficiency virus-infected (HIV + ) individuals are disproportionately at risk for human papillomavirus (HPV)-associated cancers, but the magnitude of risk estimates varies widely. We conducted a retrospective study using a large U.S.-based cohort to describe the relationship between HIV infection and incident cervical, oropharyngeal, and anal cancers., Methods: Using 2001-2012 U.S. Medicaid data from 14 states, we matched one HIV + to three HIV-uninfected (HIV - ) enrollees on sex, race, state, age, and year, and followed persons for up to 10 years. We developed Cox proportional hazards models comparing HIV + to HIV - for time to cancer diagnosis adjusted for demographic and comorbidity attributes., Results: Our cohorts included 443,592 women for the cervical cancer analysis, and 907,348 and 906,616 persons for the oropharyngeal and anal cancer analyses. The cervical cancer cohort had a mean age of 39 years and was 55% Black. The oropharyngeal and anal cancer cohorts were 50% male, had a mean age of 41 years, and were 51% Black. We estimated the following HRs: cervical cancer, 3.27 [95% confidence interval (CI), 2.82-3.80]; oropharyngeal cancer, 1.90 (95% CI, 1.62-2.23; both sexes), 1.69 (95% CI, 1.39-2.04; males), and 2.55 (95% CI, 1.86-3.50; females); and anal cancer, 18.42 (95% CI, 14.65-23.16; both sexes), 20.73 (95% CI, 15.60-27.56; males), and 12.88 (95% CI, 8.69-19.07; females)., Conclusions: HIV + persons were at an elevated risk for HPV-associated cancers, especially anal cancer., Impact: Medicaid claims data corroborate previous estimates based on registries and clinical cohorts., (©2020 American Association for Cancer Research.)

Background: Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival., Results: Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (P Bonferroni < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10 -05 )., Conclusions: Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.

Background: Incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly in many western countries due to Human papillomavirus (HPV) and tobacco smoking, with a considerable overlap. Immunotherapy directed at the PD1/PD-L1 axis have shown promise in head and neck cancer and other cancer types. PD-L1 expression may indicate a poorer prognosis, and at the same time indicate a possible benefit of anti-PD-L1 immunotherapeutic agents. The primary aim of this study was to establish the prognostic effect of PD-L1 expression after primary curative radiotherapy alone. Material and methods: A cohort of 303 OPSCC patients treated with primary, curative intended radiotherapy was established. PD-L1 expression was evaluated by immunohistochemistry on formalin fixed, paraffin embedded tissue sections. PD-L1 positivity was defined as a Combined Positive Score (CPS) ≥1, indicating staining of either tumor cells, lymphocytes or macrophages. Results: Median follow-up was 5.3 years. With 199 deaths, there was no difference in overall survival between patients with PD-L1+ and PD-L1- tumors (adjusted hazard ratio [aHR] and 95% confidence interval [CI]: 1.0 [0.71-1.4]). Also, locoregional failure was similar between the two groups (aHR 1.1 [CI: 0.68 - 1.7]). Tumors were PD-L1+ in 76% of cases, significantly more among HPV p16+ tumors (82% vs. 70%, p  = .01). Interestingly, higher prevalence of PD-L1+ expression was seen in HPV p16+ patients with <10 pack-years of tobacco-smoking (93%) compared to HPV p16+ smokers (76%) or HPV p16-negative patients (70%) ( p  = .003). Conclusion: PD-L1 expression had no prognostic significance in OPSCC patients treated with primary radiotherapy alone. A substantial proportion of OPSCC tumors show PD-L1 overexpression, especially in HPV p16+ tumors in patients with little or no smoking history.

Background: The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing. Patients with HPV-associated and HPV-unassociated OPSCC differ in many aspects, which may also impact their diagnostic and management timelines. This study aims at studying the patient, primary health care (PHC) and specialist-care (SC) delays and possible differences between these two patient groups in seeking medical care., Methods: We reviewed all new patients with OPSCC treated between 2016 and 2018 at our institute, which covers a referral area of 1.6 million people. We collected data on patients' symptoms and factors influencing why they sought medical care using a patient-reported questionnaire and hospital records. We compared delays based on patient and tumor characteristics., Results: In our study population of 83 patients, the median patient delay was 30 days (range, 0-366), with a median PHC delay of 15 days (range, 0 days-2.5 years), and a median SC delay of 54 days (range, 12-231). The SC delay was further divided into diagnostic hospital delay and treatment delay, each with a median length of 16 days (range, 0-237) and 29 days (range, 0-73), respectively. Furthermore, we found that p16 status did not associate with delays. A longer patient delay associated with specific tumor factors, such as a larger primary tumor and a lower UICC 7th edition stage. Patients that had multiple visits or did not have a follow-up visit scheduled at the initial appointment had longer PHC delays. Treatment delay was significantly longer for patients scheduled for (chemo-)radiotherapy than for those undergoing surgery with or without (chemo-)radiotherapy., Conclusions: Although delays remained short for the majority of OPSCC patients, long delays require further evaluation and improvement of management. Awareness of presenting symptoms among cancer risk patients and prompt referral practice or a follow-up visit at PHC represent key factors to shortening these delays. Ultimately, the causes for delays in SC appear multifactorial and require institutional quality control.