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Background: Human papillomavirus (HPV)+ oropharynx cancer (OPC) has a more favorable prognosis than HPV-negative disease, but the impact of specific HPV genotype and phylogenic clade on patient outcomes is not well understood and has profound implications for treatment de-intensification., Methods: The objective of this single-institution cohort study was to investigate the association of HPV genotype (16 vs high-risk non-16) and clade (A9 vs A7) with OPC outcomes. The primary endpoints were overall survival (OS) and event-free survival (EFS) in patients with M0 disease treated with curative intent., Results: The cohort included 598 patients (87% HPV16, 98% A9). Compared to those with HPV16 OPC, individuals with non-HPV16 OPC had a higher age, comorbidity index, and proportion of non-whites, HIV+ patients, T4 tumors, and stage IV disease (AJCC 7th edition). Non-HPV16 genotype was associated with worse OS in univariate (HR = 2.17, 95% CI, 1.24-3.80, P = .0066), but not in multivariate analysis (HRadj = 0.84, 95% CI, 0.43-1.62, P = .5921). A7 clade was associated with worse OS in univariate (HR = 4.42, 95% CI, 1.60-12.30, P = .0041), but not in multivariate analysis (HRadj = 2.39, 95% CI, 0.57-9.99, P = .2325). Neither HPV genotype (HR = 1.60, 95% CI, 0.99-2.60, P = .0566) nor phylogenic clade (HR = 2.47, 95% CI, 0.91-6.72, P = .0761) was associated with EFS., Conclusion: Non-HPV16 genotype and A7 clade were associated with worse OS and trended toward worse EFS in univariate analyses. The survival differences were more pronounced by phylogenic clade than by HPV16 status, suggesting that the former may be a more useful classification for future studies. However, neither HPV16 status nor phylogenic clade was prognostic when adjusting for patient and tumor covariates, raising the question as to whether possible differences in outcomes are related to distinct clinical profiles rather than inherent viral properties., (Published by Oxford University Press 2024.)

Purpose: The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis., Methods: This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region., Results: The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability., Conclusion: The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis., Competing Interests: Declaration of Competing Interest JPK receiving honoraria from MSD, Merck and BMS; research funding from MSD. No other authors have any conflict of interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: The adoption of transoral robotic surgery and shifting epidemiology in oropharyngeal squamous cell cancer have stimulated debate over upfront and adjuvant treatment. Institutional variation in practice patterns can be obscured in patient-level analyses. We aimed to characterize institutional patterns of care as well as identify potential associations between patterns of care and survival., Methods: This was a retrospective cohort study of patients identified from 2004-2015 in the National Cancer Database. We analyzed 42,803 cases of oropharyngeal squamous cell cancer Stage cT1-2N0-2bM0 (AJCC 7th edition) treated with curative intent surgery and/or radiotherapy. We defined facility-4-year periods to account for changing institutional practice patterns. The 42,803 patients were treated within 2578 facility-4-year periods. We assessed institutional practice patterns, including the ratio of upfront surgery to definitive radiotherapy, case volumes, use of adjuvant therapies (radiotherapy or chemoradiotherapy), and margin positivity rates. Survival associations with institutional practice patterns were estimated with Cox regression., Results: The ratio of upfront surgery to definitive radiotherapy ranged from 80-to-1 to 1-to-23. The institution-level median rate of adjuvant radiotherapy was 69% (IQR 50%-100%), adjuvant chemoradiotherapy was 44% (IQR 0%-67%), and margin-positive resection was 33% (IQR 0%-50%). On patient-level MVA, worse overall survival was not significantly associated with institutional case volume, adjuvant radiotherapy, or adjuvant chemoradiotherapy utilization., Conclusions: High rates of multimodal therapy and positive margins underscore the importance of multidisciplinary care and highlight variable patterns of care across institutions. Further work is warranted to explore indicators of high-quality care and to optimize adjuvant therapy in the HPV era., Competing Interests: J.E.B. served on advisory boards for Galera Therapeutics and Castle Biosciences. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To document the 10-year results of transoral mandibular preservation surgery for patients with T1-2 squamous cell carcinoma (SCC) arising from the lateral oropharynx., Methods: This was a retrospective 30-year review using STROBE guidelines at an academic, tertiary referral center. A total of 294 patients with T1-2 SCC of the lateral oropharynx were reviewed. Only 19% of patients were never-smokers, suggesting a predominantly HPV-negative population. All patients had transoral mandibular preservation surgery. Follow-up therapy included neck dissection (76.5%), induction chemotherapy (57.8%), and postoperative radiation therapy (31.6%) Local control, survival, and functional endpoints, as well as the consequences of local recurrence, were analyzed., Results: The 10-year local disease control was 88.3%. Local recurrence was salvaged in 50% of cases, resulting in an overall 94.5% local control rate. The overall 10-year survival was 50%. Mortality was related to metachronous second primary cancer (MSPC) (29.2%), medical comorbidities (25.7%), uncontrolled local recurrence (10%), and complications following transoral resection (4.2%). In multivariate analysis, the development of an MSPC significantly increased (p < 0.005) the risk of death. Overall, 95.2% of patients achieved mandibular preservation. However, gastrostomy and tracheostomy dependence occurred in 1% and 0.3% of cases, respectively., Conclusions: For a patient population with a significant percentage of tobacco-associated oropharyngeal cancer (OPC), transoral surgery was associated with long-term minimal postoperative complications and a high rate of local control. MSPC was the main cause of death during the first 10 postoperative years. Such long-term figures support transoral surgery as an effective first-line treatment for early-stage predominantly tobacco-related OPC., Level of Evidence: 4 Laryngoscope, 134:4564-4572, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Transoral surgical resectability (TOS) is a prognostic factor for patients with HPV+ T1-2 oropharyngeal squamous cell carcinoma (OPSCC) disease undergoing radiotherapy (RT), but it is unclear whether this holds for HPV-negative (HPV-) patients. We aimed to compare outcomes of potential TOS-candidates vs. non-TOS candidates, among patients who underwent RT/CRT for early T-stage HPV- OPSCC., Methods: For patients treated with RT/CRT for early T-stage HPV-negative OPSCC between 2014 and 2021, pretreatment imaging was reviewed by four head-and-neck surgeons, masked to clinical outcomes, to assess primary-site suitability for TOS. Extracapsular extension (ECE) was assessed by a head-and-neck neuroradiologist. We compared outcomes based on surgical resectability relating to: (1) the primary site tumor alone, and (2) the primary site plus the absence/presence of ECE (overall assessment). Kaplan-Meier curves for overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were compared using the log-rank test., Results: Seventy patients were included in the analysis. The primary site was TOS-favorable in 46/70 (66%). Based on the overall assessment, 41/70 (58.6%) were TOS-favorable. The 3-year OS, DSS and PFS for primary site TOS-favorable versus unfavorable were OS: 76.9% versus 37.4%; DSS: 78.1% versus 46.2%, PFS: 69.9% versus 41.3%, (log-rank test = 0.01, 0.03, 0.04; respectively). Additionally, patients with an overall assessment of TOS favorability demonstrated better survival outcomes compared with TOS-unfavorable patients (OS: 77.3% vs. 46.2%; DSS: 78.2% vs. 56.5%, PFS: 72.3% vs. 42.1%, log-rank test = 0.01, 0.04, 0.01; respectively)., Conclusion: Patients with TOS-favorable HPV-negative early T-stage OPSCC have superior survival outcomes than TOS-unfavorable patients., (© 2024 Wiley Periodicals LLC.)

Human papillomavirus (HPV) infection is a causative factor in the occurrence and progression of oropharyngeal squamous cell carcinoma (OPSCC). In recent years, clinical studies have found that HPV-positive OPSCC patients may present a better prognosis than HPV-negative patients, yet the underlying causes are unclear. This study aimed to investigate the relevance of HPV infection and the prognosis of OPSCC. On this basis, we aimed to establish a prediction model to accurately predict the prognosis and guide clinical practice. We analysed the records of 233 patients with OPSCC. Cox regression was applied to identify factors associated with survival. Moreover, variables with significant discrepancies were integrated into a nomogram model to predict prognosis. The results showed that HPV was an independent prognostic factor for OS and PFS. Immunoglobulin Heavy Constant Mu (IGHM) mRNA was significantly upregulated in patients with HPV-positive OPSCC. Crucially, IGHM expression was associated with better prognosis. The receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis both confirmed that the prognostic model exhibits good performance. In summary, HPV infection were independent prognostic factors for OPSCC. IGHM may be the key contributors to the prognostic differences in HPV-associated OPSCC. This nomogram model was able to accurately predict the prognosis of patients., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Importance: Transoral surgery (TOS) has become the primary surgical treatment for oropharyngeal squamous cell carcinoma (OPSCC). However, despite the increasing incidence of OPSCC in older patients, data regarding the safety and postoperative outcomes of TOS in this subgroup are lacking., Objective: This study aimed to evaluate the safety and postoperative outcomes of TOS in patients with OPSCC aged 70 years or older compared with younger individuals., Design, Setting, and Participants: This retrospective cohort study included patients with microscopic diagnostic confirmation of invasive OPSCC diagnosed between 2010 and 2021. Data were obtained from the US National Cancer Database. Data were analyzed in March 2024., Exposure: Minimally invasive TOS not converted to an open approach., Main Outcomes and Measures: Multivariable logistic and linear regression models were constructed to compare postoperative outcomes, adjusting for baseline patient and tumor characteristics. The results are reported as odds ratios (ORs) or mean differences with corresponding 95% CI, as appropriate., Results: A total of 10 430 patients (mean [SD] age, 60.7 [9.6] years; 8744 [83.8%] male) were included, with 1808 patients (17.3%) aged at least 70 years. No clinically meaningful difference was observed in terms of postoperative mortality at 30 days (adjusted OR, 1.24; 95% CI, 0.65-2.33) or 90 days (adjusted OR, 1.11; 95% CI, 0.65-1.87). Patients aged 70 years or older were less likely to undergo adjuvant radiotherapy (adjusted OR, 0.69; 95% CI, 0.57-0.83) and chemotherapy (adjusted OR, 0.63; 95% CI, 0.51-0.77). In addition, the adjuvant treatment was more frequently not administered in the older population due to patient refusal or comorbidities, despite being clinically indicated (radiotherapy: adjusted OR, 1.36; 95% CI, 1.05-1.77; chemotherapy: adjusted OR, 1.70; 95% CI, 1.17-2.45). No meaningful differences were observed regarding the remaining study outcomes, apart from a slightly longer hospitalization time for older patients, with an adjusted mean difference of 0.39 (95% CI, 0.05-0.74) days., Conclusions and Relevance: Findings from this study suggest that age was not independently associated with postoperative mortality in older patients undergoing TOS for OPSCC. However, older patients less frequently received adjuvant radiotherapy and chemotherapy compared with younger patients, and future studies should be conducted to examine the impact on long-term survival.

Importance: Oral and oropharyngeal cancer have low survival rates, and incidence continues to increase., Objective: To determine whether soluble CD44 and total protein (TP) are useful for monitoring head and neck cancer recurrence, either used in a point-of-care (POC) test or as individual laboratory-based biomarkers., Design, Setting, and Participants: This multi-institutional nonrandomized clinical trial testing a novel diagnostic/screening assay took place across the University of California, San Diego; Johns Hopkins University; the Greater Baltimore Medical Center; New York University; and the San Diego Veterans Affairs Hospital. Patients with newly biopsy-proven, untreated oral cavity and oropharyngeal cancer were enrolled. Patients were enrolled April 2017 to April 2019, and data were analyzed December 2022 to June 2023., Exposure: POC salivary oral rinse test., Main Outcomes and Measures: Oral rinses were collected at pretreatment baseline and 3, 6, 12, and 18 months after completion of therapy; participants were then followed up for 3 years to define disease status. Associations of baseline characteristics with a positive test were evaluated by Fisher exact test. The association of a positive value on the CD44 or TP test with progression-free survival was evaluated in an adjusted multivariable proportional hazards model., Results: Of 172 patients enrolled, the mean (SD) age was 62.5 (10.2) years, and 122 (70.9%) identified as male. Additionally, 92 patients (53.3%) had never smoked, 99 (57.6%) formerly or currently drank alcohol, and 113 (65.7%) presented with oropharyngeal cancers, which were positive for human papillomavirus in 95 (84.1%). Tumor site was associated with test results at baseline; patients with oral cavity cancer had a higher baseline positive POC test rate (47 of 51 [92.2%]) compared to patients with oropharyngeal cancer (85 of 110 [77.3%]). Using Cox regression models with CD44 or TP level as a time-varying covariate, a higher CD44 level showed a statistically significant association with a higher hazard of recurrence (hazard ratio, 1.06; 95% CI, 1.00-1.12), though the TP level was not statistically significant. In multivariate adjusted analysis, higher CD44 and TP levels were associated with increased hazard ratios of recurrence of 1.13 (95% CI, 1.04-1.22) and 3.51 (95% CI, 1.24-9.98), respectively., Conclusion and Relevance: In this multi-institutional nonrandomized clinical trial of an assay, posttreatment longitudinal monitoring for elevated salivary CD44 and TP levels using an enzyme-linked immunosorbent assay-based laboratory test identified patients at increased risk of future cancer recurrence. The CD44 and TP rapid POC test holds some promise, but further development is needed for this indication., Trial Registration: ClinicalTrials.gov Identifier: NCT03148665.

Objective: As the majority of oropharyngeal squamous cell carcinoma (OPSCC) is diagnosed in males, outcomes among females are not well-characterized. We identify sex-specific factors in OPSCC to refine female prognostication., Study Design: Retrospective cohort., Setting: National Cancer Database (NCDB)., Methods: OPSCC cases from the 2004 to 2019 NCDB were identified. Sociodemographic, clinical, and treatment characteristics (including timing between diagnosis and treatment administration) were compared between sexes. Multivariable Cox proportional hazard regression models were constructed to characterize survival in overall and female-only cohorts. Similar multivariable binomial logistic regression and survival models were constructed to assess odds of treatment delays and their effects on survival, respectively., Results: A total of 192,973 OPSCC patients were identified; 36,695 (19%) were female. Females had more human papillomavirus (HPV) negative, lower clinical T and N stage, and higher comorbidity disease. Females experienced lower survival in HPV negative (hazard ratio, HR = 1.11, P < .001) but not HPV-positive disease. Females were more likely to have any treatment initiated over the median of 28 days (odds ratio, OR = 1.04, P = .014) or delays in adjuvant radiotherapy initiation over 6 weeks (OR = 1.11, P = .032). Treatment delay over 60 days (HR = 1.17, P = .016) and delay in adjuvant therapy initiation (HR = 1.24, P = .02) were associated with worse survival among females., Conclusion: In one of the largest analyses of OPSCC, females had poorer survival than males, specifically in HPV-negative disease, despite presentation with less advanced disease. Notably, delays in any treatment initiation and adjuvant radiotherapy initiation were more likely in HPV-negative women and associated with worse survival, highlighting potential systemic weaknesses contributing to poor prognosis among females., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Denmark, alongside other Scandinavian countries, the United States, Canada, and the United Kingdom, has high prevalence of human papillomavirus (HPV). Our oropharyngeal squamous cell carcinoma (OPSCC) database includes all diagnosed cases in Eastern Denmark during a period of more than two decades. We investigated the incidence, survival, and recurrence of patients with OPSCC with combined p16- and HPV testing covering a consecutive 21-year period. Age-adjusted incidence rate (AAIR) per 100,000, survival models, and Cox proportional-hazards model were employed. Two thousand eight hundred thirty-four patients were included (57.5% HPV positive (HPV+)/p16 positive (p16+), 33.7% HPV negative (HPV-)/p16 negative (p16-), 4% HPV+/p16-, and 4.8% HPV-/p16+). The AAIR for all patients increased from 1.8 to 5.1 per 100,000 from 2000 to 2020 linked to an increasing AAIR of HPV+/p16+ OPSCCs from 0.9 to 3.5 per 100,000 from 2000 to 2020. The AAIR for the HPV-/p16- OPSCCs decreased from 1.6 to 1.4 from 2017 to 2020. HPV+/p16+ OPSCCs had a higher 5-year overall survival (OS) of 79.2% compared to the other subgroups (HPV+/p16- OS: 50.4%; HPV-/p16+ OS: 49.4%; HPV-/p16- OS: 35.1%). The AAIR of the total OPSCC group increased from year 2000 to 2020, driven by a rise in the HPV+/p16+ group. A decreasing incidence rate was observed for the HPV-/p16- OPSCCs from 2017 to 2020. The OS for HPV+/p16+ OPSCCs was significantly higher compared to all other HPV/p16 subgroups. Therefore, we recommend testing for combined HPV and p16 status in patients with OPSCC when selecting patients for clinical trials, especially in case of de-escalating/escalating., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Various factors can affect the survival of patients with oropharyngeal cancer. We assessed the expression of protein p16INK4a, Flotillin2, epidermal growth factor receptor, and other clinicopathological features and their prognostic value for this type of cancer. We gathered patient data on demographics, clinicopathological characteristics, treatment patterns, and outcomes. Histologically and by immunochemistry staining we determined expression of prognostic factors and molecular biomarkers. The primary endpoints were overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Survival was assessed using the Kaplan-Meier method and Cox regression model analyses of potential prognostic parameters. After a median follow-up of 78 months, the median OS was 41 months, with an event recorded in 77.8% of patients. Median DFS was 22 months, 37 patients (51.4%) had disease relapse. The DSS survival rate was 58.3% with a median survival of 68 months. In regards to molecular biomarkers previously mentioned, there was no statistical significance for survival categories. After conducting a multivariate analysis of significant variables, we found that only recurrence, vascular invasion, and surgical intervention remained as factors with independent effects on both OS and DFS. Recurrence and the N stage were identified as independent prognostic factors for DSS. Our analysis underscores the complexity of factors that collectively influence survival following the diagnosis of OPSCC. Several factors were found to be statistically significant. These factors included the type of surgical procedure, disease relapse, vascular invasion, lymphatic invasion, perineural invasion, advanced T stage of the disease, N stage of the disease, and smoking status. The significance of these factors may vary across different types of survival. This analysis did not find any significant impact on survival from the growth factors tested, namely epidermal growth factor receptor, Flotillin2, and p16INK4a, in the applied regression models., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

In general, a trend towards transoral resection (as opposed to classic open approaches) + neck dissection + adjuvant radio- (chemo-) therapy has been observed for oropharyngeal carcinoma over the last 20 years. Techniques of transoral surgery (TOS), including transoral laser microsurgery (TLM) and transoral robotic surgery (TORS) have been propagated in retrospective comparisons with conventional surgery or primary radiochemotherapy as gentle, minimally invasive procedures with good late functional results. Meta-analyses of mostly uncontrolled retrospective analyses suggest that TORS may have better disease-free survival (DFS) and a reduced risk of free flap reconstruction compared with open surgery. TORS (TOS) was associated with fewer tumor-positive resection margins (R1), a lower number of recurrences, fewer intraoperative tracheostomies, a shorter inpatient stay and a shorter duration of postoperative nasal tube feeding compared to open surgery. In principle, based on the best evidence currently available from registry studies, stage I-II oropharyngeal carcinomas can be treated either with primary surgery or radiochemotherapy with a comparable chance of survival. With comparable evidence for stage III and IVa, p16neg. oropharyngeal carcinomas, the majority of authors advocate primary surgery followed by adjuvant radiotherapy or radiochemotherapy as the treatment of first choice. For p16pos. patients the results of registry studies are inconsistent, although the largest registry study on 450 HPV-positive stage III patients shows a significant superiority of primary surgery + adjuvant radiochemotherapy. Since all registry studies did not adjust for smoking status, among other factors, the current data situation should be evaluated with the necessary caution., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: nein; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: nein; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Nicht‐Sponsor der Veranstaltung): nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an Firma (Sponsor der Veranstaltung): nein Erklärung zu nichtfinanziellen Interessen Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Aims/introduction: Diabetes has been related to an increased risk of oral cancer. Nevertheless, the impact of diabetes on the outcome of individuals with oral and oropharyngeal cancer is not clear. In this study, a meta-analysis was carried out to assess the link between diabetes and the survival of individuals with oral and oropharyngeal cancer., Materials and Methods: Relevant cohort studies for the meta-analysis objective were obtained through searching electronic databases, such as PubMed, Web of Science and Embase. The data were combined using a random effects model that accounted for differences between studies., Results: A total of 10 cohorts involving 21,871 patients with oral and oropharyngeal cancer were included. Pooled results suggest that compared with those with normoglycemia, oral and oropharyngeal cancer patients with diabetes were associated with a poor overall survival (hazard ratio 1.69, 95% confidence interval 1.29-2.22, P < 0.001; I 2  = 69%). Subgroup analysis suggested a stronger association between diabetes and poor overall survival in patients aged ≥52 years as compared with those aged <52 years (hazard ratio 2.08 vs 1.34, P = 0.03). Other study characteristics, such as study country, tumor stage or follow-up duration, did not seem to significantly affect the association (P for subgroup difference all >0.05). In addition, diabetes was also associated with a poor progression-free survival of patients with oral and oropharyngeal cancer (hazard ratio 1.61, 95% confidence interval 1.30-1.99, P < 0.001; I 2  = 9%)., Conclusions: Patients with oral and oropharyngeal cancer might have a poor survival if they have pre-existing diabetes., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background and Purpose: To optimize our previously proposed TransRP, a model integrating CNN (convolutional neural network) and ViT (Vision Transformer) designed for recurrence-free survival prediction in oropharyngeal cancer and to extend its application to the prediction of multiple clinical outcomes, including locoregional control (LRC), Distant metastasis-free survival (DMFS) and overall survival (OS)., Materials and Methods: Data was collected from 400 patients (300 for training and 100 for testing) diagnosed with oropharyngeal squamous cell carcinoma (OPSCC) who underwent (chemo)radiotherapy at University Medical Center Groningen. Each patient's data comprised pre-treatment PET/CT scans, clinical parameters, and clinical outcome endpoints, namely LRC, DMFS and OS. The prediction performance of TransRP was compared with CNNs when inputting image data only. Additionally, three distinct methods (m1-3) of incorporating clinical predictors into TransRP training and one method (m4) that uses TransRP prediction as one parameter in a clinical Cox model were compared., Results: TransRP achieved higher test C-index values of 0.61, 0.84 and 0.70 than CNNs for LRC, DMFS and OS, respectively. Furthermore, when incorporating TransRP's prediction into a clinical Cox model (m4), a higher C-index of 0.77 for OS was obtained. Compared with a clinical routine risk stratification model of OS, our model, using clinical variables, radiomics and TransRP prediction as predictors, achieved larger separations of survival curves between low, intermediate and high risk groups., Conclusion: TransRP outperformed CNN models for all endpoints. Combining clinical data and TransRP prediction in a Cox model achieved better OS prediction., 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. Published by Elsevier B.V.)

Background: Differences in pretreatment body mass index (BMI) have been associated with survival in squamous cell carcinoma of head and neck (SCCHN). We examined effects of BMI on survival in SCCHN patients after stratifying patients by tumor human papillomavirus (HPV) status and subsite., Methods: Totally 2204 SCCHN patients in a prospective study were included in this secondary analysis. Multivariable Cox models were used to evaluate associations between pretreatment BMI and overall survival, disease-specific survival, and disease-free survival., Results: BMI was significantly higher among patients with HPV-positive tumors than HPV-negative tumors. BMI >25 kg/m 2 was associated with improved survival, while BMI <18.5 kg/m 2 was associated with reduced survival, particularly in patients with HPV-positive oropharyngeal cancer tumors., Conclusions: This exploratory analysis suggests that pretreatment BMI could be an independent prognostic factor of survival outcomes in SCCHN patients, particularly in patients with HPV-positive oropharyngeal cancer tumors. Further prospective investigations are warranted., (© 2024 Wiley Periodicals LLC.)

Background: An estimated 20% of patients with oral and oropharyngeal squamous cell carcinoma (OOSCC) have micrometastases (Mi) or isolated tumor cells (ITC) in the cervical lymph nodes that evade detection by standard histological evaluation of lymph node sections. Lymph node Mi and ITC could be one reason for regional recurrence after neck dissection. The aim of this study was to review the existing data regarding the impact of Mi on the survival of patients with OOSCC., Methods: PubMed and the Cochrane Library were searched for articles reporting the impact of Mi and ITC on patient survival. Two authors independently assessed the methodological quality of retrieved studies using the Downs and Black index. Data were also extracted on study type, number of included patients, mode of histological analysis, statistical analysis, and prognostic impact., Results: Sixteen articles with a total of 2064 patients were included in the review. Among the 16 included studies, eight revealed a statistically significant impact of Mi on at least one endpoint in the Kaplan-Meier and/or multivariate analysis. Three studies regarded Mi as Ma, while five studies found no impact of Mi on survival. Only one study demonstrated an impact of ITC on patient's prognosis in the univariate but not in the multivariate analysis., Conclusion: The majority of cases included in the review were patients with oral cancer. The findings provide low-certainty evidence that Mi negatively impacts survival. Data on ITC were scarcer, so no conclusions can be drawn about their effect on survival. The lower threshold to discriminate between Mi and ITC should be defined for OOSCC since the existing thresholds are based on data from different tumors. The histological, immunohistological, and anatomical characteristics of Mi and ITC in OOSCC as well as the effect of radiotherapy on Mi should be further investigated separately for oral and oropharyngeal carcinomas., 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 Ltd. All rights reserved.)

Importance: Immune checkpoint inhibitors improve survival in recurrent and/or metastatic head and neck cancer, yet their role in curative human papillomavirus-positive oropharyngeal cancer (HPV+ OPC) remains undefined. Neoadjuvant nivolumab and chemotherapy followed by response-adaptive treatment in HPV+ OPC may increase efficacy while reducing toxicity., Objective: To determine the deep response rate and tolerability of the addition of neoadjuvant nivolumab to chemotherapy followed by response-adapted locoregional therapy (LRT) in patients with HPV+ OPC., Design, Setting, and Participants: This phase 2 nonrandomized controlled trial conducted at a single academic center enrolled 77 patients with locoregionally advanced HPV+ OPC from 2017 to 2020. Data analyses were performed from February 10, 2021, to January 9, 2023., Interventions: Addition of nivolumab to neoadjuvant nab-paclitaxel and carboplatin (studied in the first OPTIMA trial) followed by response-adapted LRT in patients with HPV+ OPC stages III to IV., Main Outcomes and Measures: Primary outcome was deep response rate to neoadjuvant nivolumab plus chemotherapy, defined as the proportion of tumors with 50% or greater shrinkage per the Response Evaluation Criteria in Solid Tumors 1.1. Secondary outcomes were progression-free survival (PFS) and overall survival (OS). Swallowing function, quality of life, and tissue- and blood-based biomarkers, including programmed death-ligand 1 (PD-L1) expression and circulating tumor HPV-DNA (ctHPV-DNA), were also evaluated., Results: The 73 eligible patients (median [range] age, 61 [37-82] years; 6 [8.2%] female; 67 [91.8%] male) started neoadjuvant nivolumab and chemotherapy. Deep responses were observed in 51 patients (70.8%; 95% CI, 0.59-0.81). Subsequent risk- and response-adaptive therapy was assigned as follows: group A, single-modality radiotherapy alone or transoral robotic surgery (28 patients); group B, intermediate-dose chemoradiotherapy of 45 to 50 Gray (34 patients); and group C, regular-dose chemoradiotherapy of 70 to 75 Gray (10 patients). Two-year PFS and OS were 90.0% (95% CI, 0.80-0.95) and 91.4% (95% CI, 0.82-0.96), respectively. By response-adapted group, 2-year PFS and OS for group A were 96.4% and 96.4%, and group B, 88.0% and 91.0%, respectively. Lower enteral feeding rates and changes in weight, as well as improved swallowing, were observed among patients who received response-adapted LRT. Pathologic complete response rate among patients who underwent transoral robotic surgery was 67.0%. PD-L1 expression was nonsignificantly higher for deeper responses and improved PFS, and ctHPV-DNA clearance was significantly associated with improved PFS., Conclusions and Relevance: This phase 2 nonrandomized controlled trial found that neoadjuvant nivolumab and chemotherapy followed by response-adapted LRT is feasible and has favorable tolerability, excellent OS, and improved functional outcomes in HPV+ OPC, including among patients with high-risk disease. Moreover, addition of nivolumab may benefit high PD-L1 expressors, and sensitive dynamic biomarkers (eg, ctHPV-DNA) are useful for patient selection., Trial Registration: ClinicalTrials.gov Identifier: NCT03107182.

Objective: While tobacco use is understood to negatively impact HPV+ oropharyngeal squamous cell carcinoma (OPSCC) outcomes, debate remains as to how this impact differs between cohorts. Multiple smoking metrics have been identified as having the greatest prognostic significance, and some recent works have found smoking to have no significant impact. Herein, we show through an analysis of four common smoking metrics that while smoking impacts overall survival (OS), it has a limited impact on recurrence-free survival (RFS) in our cohort., Methods: We conducted a retrospective review of patients treated for HPV+ OPSCC in our health system from 2012 to 2019. Patients with metastatic disease or concurrent second primaries were excluded. Four metrics of tobacco use were assessed: current/former/never smokers, ever/never smokers, and smokers with >10 or >20 pack-year (PY) smoking histories. Our main outcomes were 3-year RFS and OS., Results: Three hundred and sixty-seven patients met inclusion criteria. 37.3% of patients (137/367) were never-smokers; 13.8% of patients (51/367) were currently smoking at diagnosis and 48.8% of patients (179/367) were former smokers. No tobacco-use metric significantly impacted 3-year RFS. On univariate analysis, all smoking metrics yielded inferior OS. On multivariate analysis, current and ever smoking status significantly impacted 3-year OS., Conclusion: The impact of tobacco use on HPV+ OPSCC outcomes is not universal, but may instead be modulated by other cohort-specific factors. The impact of smoking may decrease as rates of tobacco use decline., Level of Evidence: 3 (Cohort and case-control studies) Laryngoscope, 134:3158-3164, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Studies have shown lower overall survival for patients with head and neck cancer treated at low-volume or community cancer centers. As the incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma steadily rises in the United States, we hypothesized that a greater proportion of patients with HPV-related oropharyngeal squamous cell carcinoma is being treated at community cancer centers, with a shift toward primary nonsurgical treatment., Methods: This cohort study included patients from the US National Cancer Database who received a diagnosis of HPV-related oropharyngeal squamous cell carcinoma from 2010 to 2019 and underwent treatment at a community cancer center or academic cancer center. The proportion of patients with HPV-related oropharyngeal squamous cell carcinoma treated at community cancer centers and receiving primary nonsurgical treatment was analyzed over time. Four-year overall survival was compared between community cancer centers and academic cancer centers., Results: The majority (67.4%) of 20 298 patients were treated at an academic cancer center, yet the proportion of patients treated at community cancer centers increased by 10% from 2010 to 2019 (P < .01 for trend). The proportion of patients undergoing primary nonsurgical treatment increased from 62.1% to 73.7% from 2010 to 2019 (P < .01 for trend), and patients were statistically significantly more likely to undergo nonsurgical treatment at community cancer centers than at academic cancer centers (adjusted odds ratio = 1.20, 95% confidence interval = 1.18 to 1.22). Treatment at community cancer centers was associated with worse survival overall (adjusted hazard ratio = 1.19, 95% confidence interval = 1.09 to 1.31), specifically for patients receiving primary nonsurgical treatment (adjusted hazard ratio = 1.22, 95% confidence interval = 1.11 to 1.34)., Conclusions: Treatment of HPV-related oropharyngeal squamous cell carcinoma has recently shifted to community cancer centers, with an increase in the proportion of nonsurgical treatment and worse overall survival at these centers compared with academic cancer centers. Concentration of care for HPV-related oropharyngeal squamous cell carcinoma at academic cancer centers and dedicated head and neck cancer centers may increase access to all available treatment modalities and improve survival., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: This study compared treatment and outcomes for patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) based on their travel distance to treatment facility., Materials and Methods: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC in the National Cancer Database from 2010 to 2019 were identified and split into four quartiles based on distance to facility, with quartile 4 representing patients with furthest travel distances. Multivariable-adjusted logistic regression and Cox proportional hazards modeling were used to analyze the primary outcome of treatment received, and secondary outcomes of clinical stage, overall survival, surgical approach (i.e., TORS versus other), and 30-day surgical readmissions., Results: 17,207 patients with HPV-positive OPSCC were evenly distributed into four quartiles. Compared to patients in quartile 1, patients in quartile 4 were 40 % less likely to receive radiation versus surgery (OR = 0.60; 95 % CI = 0.54-0.66). Among the patients who received surgery, quartile 4 had a higher odds of receiving TORS treatment compared to quartile 1 (4v1: OR = 2.38; 95 % CI = 2.05-2.77), quartile 2 (4v2: OR = 2.31, 95 % CI = 2.00-2.66), and quartile 3 (4v3: OR = 1.75; 95 % CI = 1.54-1.99). Quartile 4 had a decreased odds of mortality compared to Quartile 1 (4v1: OR = 0.87; 95 % CI = 0.79-0.97). There were no differences among the quartiles in presenting stage and 30-day readmissions., Conclusions: This study found that patients with furthest travel distance to facility were more often treated surgically over non-surgical management, with TORS over open surgery, and had better overall survival. These findings highlight potential disparities in access to care for patients with HPV-positive OPSCC., Competing Interests: Declaration of competing interest The authors have no financial disclosures or conflicts of interests to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Evaluate the effect of treatment delay on survival in human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) patients undergoing primary surgical resection., Study Design: Retrospective cohort study using the 2010-2017 National Cancer Database., Setting: Multicenter database study., Methods: Patients >18 years old with OPSCC and known HPV status, treated surgically with or without postoperative radiation/chemotherapy were included. Two cohorts based on HPV status were grouped by time to treatment initiation (T D-TI , ≤30, 31-60, ≥61 days) and surgery to radiotherapy (T S-RT , ≤42, 43-66, ≥67 days). Univariate, Kaplan-Meier, and multivariate analyses assessed correlations between demographic and clinical factors with overall survival in treatment delay groups., Results: Included were 1643 HPV-positive OPSCC patients and 391 HPV-negative OPSCC patients. No associations between survival and gender, age, race, insurance, or radiotherapy length were observed. Regardless of HPV status, larger tumor size (>2 cm) and lymphovascular invasion predicted worse survival. HPV negative patients with >4 lymph nodes involved had 2.5× greater mortality risk (P = .039). Robotic surgery was associated with improved survival only in HPV positive patients (hazard ratio [HR]: 0.41, P < .001). In HPV positive patients, higher T D-TI related to lower mean survival, although this was not significant on multivariate analysis. HPV negative patients with >42 days of T S-RT had decreased survival (43-66 days, HR 1.63, P = .049; ≥67 days, HR 2.10, P = .032)., Conclusion: Longer T S-RT was associated with lower overall survival in HPV negative patients. Treatment delay was not associated with survival in HPV positive OPSCC according to multivariate analysis. These findings enhance knowledge about treatment delay effects in OPSCC, aiding providers in decisions and patient communication., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background: Despite the better prognosis associated with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), some patients experience relapse and succumb to the disease; thus, there is a need for biomarkers identifying these patients for intensified treatment. Leucine-rich repeats and immunoglobulin-like domain (LRIG) protein 1 is a negative regulator of receptor tyrosine kinase signaling and a positive prognostic factor in OPSCC. Studies indicate that LRIG1 interacts with the LIM domain 7 protein (LMO7), a stabilizer of adherence junctions. Its role in OPSCC has not been studied before., Methods: A total of 145 patients diagnosed with OPSCC were enrolled. Immunohistochemical LMO7 expression and staining intensity were evaluated in the tumors and correlated with known clinical and pathological prognostic factors, such as HPV status and LRIG1, CD44, Ki67, and p53 expression., Results: Our results show that high LMO7 expression is associated with significantly longer overall survival (OS) (p = 0.044). LMO7 was a positive prognostic factor for OS in univariate analysis (HR 0.515, 95% CI: 0.267-0.994, p = 0.048) but not in multivariate analysis. The LMO7 expression correlated with LRIG1 expression (p = 0.048), consistent with previous findings. Interestingly, strong LRIG1 staining intensity was an independent negative prognostic factor in the HPV-driven group of tumors (HR 2.847, 95% Cl: 1.036-7.825, p = 0.043)., Conclusions: We show for the first time that high LMO7 expression is a positive prognostic factor in OPSCC, and we propose that LMO7 should be further explored as a biomarker. In contrast to previous reports, LRIG1 expression was shown to be an independent negative prognostic factor in HPV-driven OPSCC., (© 2024. The Author(s).)

Purpose: Locoregionally advanced HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has excellent cure rates, although current treatment regimens are accompanied by acute and long-term toxicities. We designed a phase II deescalation trial for patients with HPV+ OPSCC to evaluate the feasibility of an upfront neck dissection to individualize definitive treatment selection to improve the quality of life without compromising survival., Patients and Methods: Patients with T1-3, N0-2 HPV+ OPSCC underwent an upfront neck dissection with primary tumor biopsy. Arm A included patients with a single lymph node less than six centimeters, with no extracapsular spread (ECS) and no primary site adverse features underwent transoral surgery. Arm B included patients who had two or more positive lymph nodes with no ECS, or those with primary site adverse features were treated with radiation alone. Arm C included patients who had ECS in any lymph node and were treated with chemoradiation. The primary endpoint was quality of life at 1 year compared with a matched historical control., Results: Thirty-four patients were enrolled and underwent selective neck dissection. On the basis of pathologic characteristics, 14 patients were assigned to arm A, 10 patients to arm B, and 9 to arm C. A significant improvement was observed in Head and Neck Quality of Life (HNQOL) compared with historical controls (-2.6 vs. -11.9, P = 0.034). With a median follow-up of 37 months, the 3-year overall survival was 100% and estimated 3-year estimated progression-free survival was 96% [95% confidence interval (CI), 76%-99%]., Conclusions: A neck dissection-driven treatment paradigm warrants further research as a deintensification strategy., (©2024 American Association for Cancer Research.)

Purpose: Salvage surgery is still the best therapeutic option for resectable recurrent oropharyngeal squamous cell carcinoma (rOPSCC). Transoral robotic surgery may potentially reduce the morbidity of standard open approaches. The aim of the study is to present oncological and functional outcomes of a monocentric experience in salvage transoral robotic surgery., Methods: We performed a single-center retrospective analysis of patients submitted to transoral robotic salvage surgery with or without neck dissection for cT1-3 rOPSCC. We investigated complication rate, survival outcomes (Overall Survival, Disease Specific Survival, Loco-Regional Recurrence Free Survival) and functional outcomes (tracheal tube and/or gastrostomy dependence)., Results: Sixty-one patients were included in the analysis. No major complications or perioperative deaths were recorded. The estimated 2-year OS was 76.7%, DSS 81.8% and LRRFS 50.5%. In multivariable analysis rpT, PNI (perineural infiltration) and HPV-positivity were significantly associated with LRRFS (Hazard Ratios: T3 vs T1 6.43, PNI yes vs no 4.19, HPV+ yes vs no 2.63). At last follow up, 97% of patients were tracheal tube-free, while 93% were gastrostomy-free., Conclusion: Transoral robotic salvage surgery is a successful treatment in selected patients affected by rOPSCC because it grants good oncologic and functional outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The purpose of this study was to assess the clinicopathological features of oropharyngeal cancer patients in Jordan based on their HPV status. Sixty-nine biopsies from two hospitals were included. Tissue microarrays were prepared from formalin-fixed paraffin-embedded (FFPE) specimens and stained with antibodies for CDKN2A/P16, EGFR, PI3K, PTEN, AKT, pS473AKT, PS2mTOR, and TIMAP. The cohort was divided according to P16 expression. Chi-square test and survival analyses were employed to evaluate the variations among the study variables and determine the prognostic factors, respectively. P16 expression was found in 55.1% of patients; however, there was no significant association between P16 expression and the patients' clinicopathological features. The Kaplan-Meier test revealed that smoking in P16-positive group and younger age (< 58 years) negatively impacted disease-free survival (DFS) (P = 0.04 and P = 0.003, respectively). Multivariate Cox regression test indicated that smoking, age, PI3K, and AKT were negative predictors of DFS (P = 0.021, P = 0.002, P = 0.021, and P = 0.009, respectively), while TIMAP was a positive predictor (P = 0.045). Elevated P16 expression is found in more than half of the patients' specimens. DFS is negatively affected by younger age and the combined effect of smoking and P16 overexpression. TIMAP is overexpressed in P16-positive oropharyngeal cancer, and it is a favorable predictor of DFS., (© 2024. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Purpose: The optimal treatment strategy for oropharyngeal cancer (OPC) is undetermined. We aim to compare the survival outcomes of OPC patients treated with upfront surgery versus definitive radiotherapy (RT)., Methods: A total of 8057 cases were retrieved from the Surveillance, Epidemiology, and End Results database. Primary endpoints were cancer-specific and noncancer mortalities, which were estimated using cumulative incidence function and compared by Gray's test. Univariate and multivariate Fine-Gray subdistribution hazard models were used to estimate the effects of treatment modality on mortality. Subgroup analyses were performed in propensity-score-matched cohorts. All the analyses were conducted separately in human papillomavirus (HPV)-negative and HPV-positive cohorts., Results: In the HPV-negative cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted subdistribution hazard ratio [SHR], 1.31; 95% confidence interval [CI], 1.05-1.64; P = 0.017) and noncancer mortality (adjusted SHR, 1.59; 95% CI 1.13-2.25; P = 0.008). In the HPV-positive cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted SHR, 1.51; 95% CI 1.23-1.85; P < 0.001) and noncancer mortality (adjusted SHR, 1.53; 95% CI 1.11-2.12; P = 0.009)., Conclusion: Upfront surgery is a superior treatment modality compared with definitive RT in terms of lowering cancer-specific and noncancer mortality in OPC patients, regardless of HPV status. Further prospective clinical trials are needed to confirm our findings., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The prevalence of HPV-negative oropharyngeal cancer (OPC) is higher in Asian countries. Patients with HPV-negative OPC suffer poor outcomes. Multi-omics analysis could provide researchers and clinicians with more treatment targets for this high-risk group. We aimed to explore the prognostic significance of EGFR overexpression and macrophage infiltration in OPC, especially HPV-negative OPC in this study., Methods: EGFR alternation was evaluated with TCGA, PanCancer Atlas through cBioProtal. EGFR mRNA expression in HPV-negative head and neck squamous cell carcinoma was analyzed using the Tumor Immune Estimation Resource (TIMER 2.0). We also examined EGFR/STAT6/MRC1 expression in paraffin-embedded tissues from a p16-negative OPC cohort. The correlation between EGFR expression and macrophage activation was explored using Person's correlation coefficient. The impact of biomarkers or macrophage infiltration on 5-year overall survival and recurrence-free survival were analyzed using Kaplan-Meier survival curves., Results: EGFR alteration rate was 15%, 13%, and 0% for HPV-negative HNSCC (excluding OPC), HPV-negative OPC, and HPV-positive OPC. High EGFR expression was associated with increased tumor infiltration of immune cells, such as macrophages. We observed positive correlations between EGFR, STAT6, and MRC1 expression in p16-negative OPC. Higher MRC1 expression was associated with poorer survival rates., Conclusions: There is strong correlation between EGFR overexpression and M2 polarization in patients with p16-negative OPC. Immunotherapy with or without EGFR inhibitor could be considered in these high-risk patients., (© 2024 Wiley Periodicals LLC.)

Objective: To evaluate the efficacy and safety of cetuximab instead of cisplatin in combination with downstaging radiotherapy for papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV + OPSCC)., Design: Meta-analysis and systematic evaluation., Data Sources: The PubMed, Embase, Web of Science, and Cochrane library databases were searched up to June 8, 2023, as well as Clinicaltrials.gov Clinical Trials Registry, China Knowledge Network, Wanfang Data Knowledge Service Platform, and Wiprojournal.com., Eligibility Criteria for Selecting Studies: Randomized controlled trials reporting results of standard regimens of cetuximab + radiotherapy vs cisplatin + radiotherapy in treating HPV + OPSCC were included. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), local regional failure rate (LRF), distant metastasis rate (DM), and adverse events (AE)., Data Extraction and Synthesis: Two reviewers independently extracted data and assessed the risk of bias of the included studies. The HR and its 95% CI were used as the effect analysis statistic for survival analysis, while the OR and its 95% CI were used as the effect analysis statistic for dichotomous variables. These statistics were extracted by the reviewers and aggregated using a fixed-effects model to synthesise the data., Results: A total of 874 relevant papers were obtained from the initial search, and five papers that met the inclusion criteria were included; a total of 1,617 patients with HPV + OPSCC were enrolled in these studies. Meta-analysis showed that OS and PFS were significantly shorter in the cetuximab + radiotherapy group of patients with HPV + OPSCC compared with those in the conventional cisplatin + radiotherapy group (HR = 2.10, 95% CI [1.39-3.15], P = 0.0004; HR = 1.79, 95% CI [1.40-2.29], P < 0.0001); LRF and DM were significantly increased (HR = 2.22, 95% CI [1.58-3.11], P < 0.0001; HR = 1.66, 95% CI [1.07-2.58], P = 0.02), but there was no significant difference in overall grade 3 to 4, acute and late AE overall (OR = 0.86, 95% CI [0.65-1.13], P = 0.28)., Conclusions: Cisplatin + radiotherapy remains the standard treatment for HPV + OPSCC. According to the 7th edition AJCC/UICC criteria, low-risk HPV + OPSCC patients with a smoking history of ≤ 10 packs/year and non-pharyngeal tumors not involved in lymphatic metastasis had similar survival outcomes with cetuximab/cisplatin + radiotherapy. However, further clinical trials are necessary to determine whether cetuximab + radiotherapy can replace cisplatin + radiotherapy for degraded treatment in individuals who meet the aforementioned characteristics, particularly those with platinum drug allergies., Prospero Registration Number: CRD42023445619., Competing Interests: The authors declare there are no competing interests., (©2024 Hu et al.)

Introduction: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased in recent decades, driven by infection with human papillomavirus (HPV). Transoral robotic surgery (TORS) and neck dissection (ND) has been employed as an alternative to radiotherapy/chemoradiotherapy. The current literature is lacking studies providing an exhaustive overview of recurrence characteristics and long-term outcomes in TORS-treated OPSCC-patients., Methods: All patients treated for OPSCC with primary TORS + ND in Eastern Denmark between 2013 and 2020 were included in the study. The aim was to explore overall survival (OS), recurrence-free survival (RFS), recurrence patterns, and ultimate failure rate (UFR). OS and RFS were examined using the Kaplan-Meier method. Cox proportional regression analyses were employed to examine effect of different variables on risk of death and recurrence., Results: The study included 153 patients of which 88.9 % (n = 136) were treated with TORS alone while 11.1 % (n = 17) received adjuvant therapy. The 1-, 3-, and 5-year OS were 97.4 %, 94.1 %, and 87.6 % while 1-, 3-, and 5-year RFS were 96.6 %, 87.8 %, and 84.9 %. The UFR was 6.5 % in the cohort. Patients with HPV+/p16 + OPSCC had a significantly better 5-year OS of 92.3 % than patients with discordant or double-negative HPV/p16 status (OS = 73.3 %). No differences in outcomes between patients treated with or without adjuvant therapy were found in regression analysis., Conclusion: Excellent survival and disease control was obtained with TORS + ND in this cohort, despite lesser application of adjuvant therapy than other TORS-centers, implying that TORS without adjuvant therapy can be successfully applied in treatment of early-stage OPSCC., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The presence of p16 and neck disease is important predictors of prognosis for oropharyngeal squamous cell carcinoma (OPSCC). Patients who are p16-negative and have clinically node-positive (cN+) disease generally have worse oncologic outcomes. This study aimed to investigate whether upfront neck dissection (UFND) could provide potential benefits for patients with cN+ p16-negative OPSCC., Methods: Through this retrospective study, 76 patients with cN+ p16-negative OPSCC were analyzed, those who received either definite concurrent chemoradiotherapy (CCRT group) or UFND followed by chemoradiotherapy (UFND group). The primary endpoints were regional recurrence-free survival (RRFS), disease-specific survival (DSS), and overall survival (OS). Factors associated with survival were evaluated by univariate and multivariate analysis. Survival between the two groups was compared by propensity score-matched analysis., Results: Matched 23 patients in each group through propensity analysis, the UFND group showed a significantly better 5-year RRFS (94.1% vs 61.0%, p = 0.011) compared to the CCRT group. Univariate analysis revealed that UFND was the sole factor associated with regional control (hazard ratio [HR] = 0.110; 95% CI, 0.014-0.879; p = 0.037). Furthermore, the study found that the CCRT group was associated with a higher dose of radiotherapy and exhibited a significantly higher risk of mortality due to pneumonia., Conclusion: The study indicated that UFND followed by CCRT may be a potential treatment option for patients with cN+ p16-negative OPSCC, as it can reduce the risk of regional recurrence. Additionally, the study highlights that definite CCRT is connected to a larger dose of radiotherapy and a higher risk of fatal pneumonia. These findings could be beneficial in informing clinical decision-making and improving treatment outcomes for patients with OPSCC., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article, (Copyright © 2024, the Chinese Medical Association.)

Background: Intensity modulated radiotherapy (IMRT) has become a standard radiotherapy treatment delivery option owing to the advantages it offers in terms of target coverage and organ sparing. Furthermore, the ability to introduce different fractionation for different targets lets us deliver higher doses to the high-risk areas and lower doses to the elective volumes at the same sitting, referred to as simultaneous integrated boost (SIB). In the current study, we intended to retrospectively analyze the clinical outcomes and patterns of the failure of oropharyngeal cancers treated with SIB-IMRT and concurrent chemotherapy at our centre and analyze the factors contributing to poorer outcomes., Material and Methods: Data of oropharyngeal cancer patients treated with SIB-IMRT and concurrent chemotherapy were retrieved from the institutional database. Patient demographic details, histopathological features, staging, treatment details, failure patterns and outcomes were documented. All potential factors were evaluated for outcomes. Radiation was delivered by using the SIB-IMRT technique. High-risk planning target volume (PTV) received 66 Gy in 2.2 Gy/fraction, intermediate and low-risk PTV received 60 Gy and 54 Gy, respectively. Primary endpoint was to assess local control (LC), regional control (RC) and loco-regional control (LRC) rates and secondary end point was to evaluate the survival outcomes - overall survival (OS) and cancer-specific mortality. All survival analyzes were performed using the Kaplan-Meier method., Results: A total of 169 cases were included in the final analysis. The median age was 55 years (range 20-78) with 95.3% males. The base of tongue was the most common primary site. Around 54% cases were node negative with 38% patients having stage IV disease. The local control rates for N0 vs. N+ cases were 74.1 vs. 62.3% (P = 0.046), respectively. Similarly, the 4-year RC rates for N0 vs. N+ cases were 94.4 vs. 83.5% (P = 0.024), respectively. On multivariate analysis, only 4-year RC rates showed significant difference between the two (P = 0.039). No differences were found between T stages in LRC and OS. The 4-year LRC rates for stages 1, 2 vs. 3, 4 were non-significant (69.2 vs. 66.3%; P = 0.178). The 4-year OS rate was 81.3%. The 4-year LC and LRC rates were 67.8 and 89.5%, respectively. There were 54 local and 17 regional failures. The median time to failure was 13 months (range 3.6-82.9)., Conclusion: SIB-IMRT provides comparable outcomes for oropharyngeal cancers. OS and loco-regional recurrences were significantly worse for nodal positive disease.

According to an extensive database, the Objective is to compare surgical versus non-surgical treatment through Propensity Score (PS) for patients with Oropharyngeal Squamous Cell Carcinoma (OPSCC)., Methods: We retrospectively evaluated epidemiological data from 8075 patients with OPSCC diagnosed between 2004 and 2014 and used PS matching to analyze possible prognostic factors for its outcomes with regression analyses., Results: Cox multiple regression analysis to study survival after PS matching shows that type of treatment was associated with death with a hazard ratio of 1.753 (p<0.05) of non-surgical treatment. However, it was not associated with recurrence (p>0.05). In the surgical treatment group, overall survival was 79.9% at one year, 36.4% at five years, and 20.5% at ten years. Disease-free survival was 90.1%, 64.8%, and 56.0% at 1, 5, and 10-years, respectively. In the non-surgical treatment group, overall survival was 60.6% at one year, 21.8% at five years, and 12.7% at ten years. Disease-free survival was 90.8%, 67.2%, and 57.8% at 1, 5, and 10-years, respectively., Conclusion: Patients in the surgical treatment group had better outcomes related to survival. Recurrence is associated with the survival of OPSCC cancer. Recurrence-free survival is similar to both treatments., Level of Evidence: 2C., (Copyright © 2023 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier España S.L.U. All rights reserved.)

Introduction: Cancer is a disease that affects a large number of people worldwide and generates a high mortality rate. Oral and oropharyngeal cancer is considered a public health problem, especially in low- and middle-income countries. By the year 2023, it is estimated that 11,580 people will die in the United States from this cause., Objective: Determine the variation in mortality from oral and oropharyngeal cancer in Chile between 1955 and 2021., Methods: The mortality data was obtained from institutions such as the National Institute of Statistics and the Chile Ministry of Health through the country's death registries, which were classified by gender. Crude mortality rates for each year of the study were calculated from the institutions' mortality data and population data., Results: Crude mortality rates between study years ranged from 0.92 to 1.53. men obtained an average rate of 1.64 per 100,000 inhabitants, and women obtained an average rate of 0.67 per 100,000 inhabitants., Conclusion: The crude mortality rate from oral and oropharyngeal cancer in Chile increased between 1955 and 2021 in both men and women.

We compare outcomes in two large-scale contemporaneously treated HPV-positive (HPV+) oropharynx cancer (OPC) cohorts treated with definitive radiotherapy/chemoradiotherapy (RT/CRT). p16-confirmed HPV+ OPC treated between 2007 and 2015 at PMH and DAHANCA were identified. Locoregional failure (LRF), distant metastasis (DM), and overall survival (OS) were compared. Multivariable analysis (MVA) calculated adjusted-hazard-ratio (aHR) with 95% confidence interval (95% CI), adjusting for cohort, age, gender, performance status, smoking pack-years, T-category and N-category and chemotherapy. Compared to PMH (n = 701), DAHANCA (n = 1174) contained lower TNM-8T-categories (T1-T2: 77% vs 56%), N-categories (N0-N1: 77% vs 67%) and stages (stage I: 63% vs 44% (all P < .001). PMH used standard-fractionation CRT in 69% (481) while 31% (220) received hypofractionated or moderately accelerated RT-alone. All DAHANCA patients were treated with moderately accelerated RT; 96% (1129) received nimorazole (NIM) and 73% (856) concurrent weekly cisplatin. DAHANCA had shorter overall-treatment-time (P < .001), lower gross tumor (66-68 vs 70 Gy) and elective neck (50 vs 56 Gy) doses. Median follow-up was 4.8 years. DAHANCA had higher 5-year LRF (13% vs 7%, aHR = 0.47 [0.34-0.67]), comparable DM (7% vs 12%, aHR = 1.32 [0.95-1.82]), but better OS (85% vs 80%, aHR = 1.30 [1.01-1.68]). CRT patients had a lower risk of LRF (aHR 0.56 [0.39-0.82]), DM (aHR 0.70 [0.50-1.00]) and death (aHR 0.39 [0.29-0.52]) vs RT-alone. We observed exemplary outcomes for two large-scale trans-Atlantic HPV+ OPC cohorts treated in a similar manner. Concurrent chemotherapy was a strong, independent prognostic factor for all endpoints. Our findings underscore the need for a very careful approach to de-intensification of treatment for this disease., (© 2021 UICC.)

The increases observed in incidence and survival of oropharyngeal squamous cell carcinoma (OPSCC) have been attributed to human papillomavirus (HPV) infection, but the survival-impact of specific genotypes is poorly understood. We investigated the potential influence of HPV genotypes on survival in HPV-positive (HPV+) OPSCC. All patients with HPV+/p16+ OPSCC and available genotype data within the period 2011 to 2017 in Eastern Denmark were included. Descriptive statistics on clinical and tumor data, as well as overall survival (OS) and recurrence-free survival (RFS) with Cox hazard models and Kaplan-Meier plots were performed. Overall, 769 HPV+/p16+ OPSCC patients were included of which genotype HPV16 accounted for 86% (n = 662). Compared to high-risk non-HPV16 genotypes (HR non-HPV16), HPV16 patients were younger at diagnosis (median years, 60 vs 64), had a higher male to female ratio (3.7:1 vs 2.1:1), and lower performance scores of ≤1 (90%, n = 559, vs 81%, n = 74). Regarding 5-year OS and RFS, no difference was observed between HPV16 and HR non-HPV16 patients. Subgrouping the HR non-HPV16 group into HPV33 (n = 57), HPV35 (n = 26) and "other genotypes" (n = 24) a significantly worse OS in the "other genotypes" group (hazard rate: 2.33, P = .027) was shown. With similar survival results between HPV16 and non-HPV16 genotypes, genotyping in OPSCC is interesting from an epidemiological point of view as well as in vaccination programs, but not a necessary addition in prognostication of HPV+/p16+ OPSCC., (© 2021 UICC.)

Background: The incidence of human papillomavirus (HPV) positive oropharyngeal cancer (OPC) is rising but HPV negative OPC is decreasing in Western countries. In Taiwan, the incidence of HPV negative OPC is common but the incidence of HPV positive OPC remains unknown. The objective of this study is to estimate the incidence trend and the survival of HPV positive OPC in Taiwan., Methods: Between 1999 and 2014, primary tumor tissues from 425 incident OPCs were obtained from 5 medical centers in Taiwan. 408 OPCs were evaluated by the EasyChip HPV genotyping (King-Car, I-Lan, Taiwan) and 369 OPCs by p16 staining. The clinical data were retrospectively obtained from the medical records., Results: In our study, 29% of OPCs were HPV positive. The percentage of HPV positive OPC was stable from 1999 to 2014 (25% (1999-2002), 30% (2003-2006), 30% (2007-2010), 29% (2011-2014)). The estimated crude incidence rate of HPV positive OPC increased significantly from 0.62 (1999-2002), 1.06 (2003-2006), 1.52 (2007-2010) to 1.74 (2011-2014) per 100,000 person-year. The sensitivity and specificity of p16 staining for positive HPV infection were 92% and 91%, respectively. The 5-year overall survival rates for patients with HPV positive OPC and with HPV negative OPC were 67.8% and 49.0%, respectively (HR = 0.52 (0.35-0.76), p = 0.0005). Patients with HPV positive OPC but no betel nut/cigarette exposure had the best overall survival (5-year: 88.2%, p < 0.0001). Patients with HPV negative OPC and betel nut/cigarette exposure had the worst overall survival (5-year: 46.6%, p < 0.0001). Patients with HPV positive OPC but also with betel nut/cigarette exposure had poorer 5-year overall survival (48.3%, p < 0.01)., Conclusion: The incidence of HPV positive OPC is increasing along with HPV negative OPC, which leads to stably low percentage of HPV positive OPC in Taiwan. HPV positive OPC may become an important head and neck cancer when the incidence of HPV negative OPC declines in the near future. P16 is a useful surrogate marker for HPV infection in OPC and a good prognostic indicator for treatment outcome of OPC. Patients with HPV positive OPC but no betel nut/cigarette exposure has an excellent prognosis. Betel nut/cigarette exposure significantly worsens the prognosis of HPV positive OPC., (© 2022. The Author(s).)

Objective: To analyze the oncologic outcomes and risk factors for recurrence in patients who underwent surgery for oropharyngeal squamous cell carcinoma (OPSCC), and in whom adjuvant therapy was not recommended or was declined., Methods: Retrospective cohort study of patients with OPSCC who were treated with transoral surgery only at a tertiary care academic medical center from April 2010 to March 2019., Results: Seventy-four patients met inclusion criteria. In 16, adjuvant therapy was recommended but declined. There were 8 recurrences, of which 6 had been given recommendations for adjuvant therapy. Of the 8 recurrences, 2 died, 2 are alive with disease, and 4 were successfully salvaged. Five patients died of unrelated causes. Lymphovascular invasion (LVI, P  = .016) had a significant impact on recurrence, while other pathologic features of the primary tumor such as size, location, human papillomavirus (HPV) status, and margin status did not. Margins were classified as "positive" in 4 patients, "close" in 54, and "negative" in 16. There were 3 local recurrences (4.1%), each of whom had declined adjuvant therapy. Lymph node features such as N-stage ( P  = .0004), number of positive nodes ( P  = .0005), and presence of extra-nodal extension (ENE, P  = .0042) had a statistically significant impact on relapse. Smoking history and surgical approach showed no significant impact on recurrence., Conclusion: Patients who undergo surgery for HPV-positive OPSCC with negative margins, no PNI, no LVI, and ≤1 positive lymph node without ENE have low risk for recurrence. These patients can likely be safely treated with surgery alone. Patients with these risk factors who decline adjuvant therapy are at risk for recurrence, and should be monitored.

Objectives/hypothesis: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct clinical entity with good prognosis, unique demographics, and a trend toward treatment deintensification. Patients with this disease may opt out of recommended postoperative radiation therapy (PORT) for a variety of reasons. The aim of this paper was to examine factors that predict patient refusal of recommended PORT in HPV-associated OPSCC, and the association of refusal with overall survival., Study Design: Retrospective population-based cohort study of patients in the National Cancer Database., Methods: We conducted a retrospective cohort study of patients in the National Cancer Database diagnosed with OPSCC between January 2010 and December 2015. We primarily assessed overall survival and the odds of refusing PORT based on demographic, socioeconomic, and clinical factors. Analysis was conducted using multivariable logistic regression and multivariable Cox proportional hazards model., Results: A total of 4229 patients were included in the final analysis, with 156 (3.7%) patients opting out of recommended PORT. On multivariable analysis, patient refusal of PORT was independently associated with a variety of socioeconomic factors such as race, insurance status, comorbidity, treatment at a single facility, and margin status. Lastly, PORT refusal was associated with significantly lower overall survival compared to receipt of recommended PORT (hazard ratio 1.69, confidence interval 1.02-2.82)., Conclusions: Patient refusal of recommended PORT in HPV-associated OPSCC is rare and associated with variety of disease and socioeconomic factors. PORT refusal may decrease overall survival in this population. Our findings may help clinicians when counseling patients and identifying those who may be more likely to opt out of recommended adjuvant therapy., Level of Evidence: 3 Laryngoscope, 132:339-348, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Increasing evidence has elucidated the clinicopathological significance of tumor microenvironment (TME) cells. However, TME differences associated with human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) have not been well characterized. In our study, we comprehensively determined the TME infiltration patterns in 315 OPSCC patients, and systematically correlated the TME phenotypes with genomic characteristics and clinical features of OPSCCs. In this way, we observed the enrichment of high endothelial cells and adaptive immune cells in HPV-positive (HPV+) OPSCCs, in contrast to the enrichment of fibroblasts and capillary endothelial cells in HPV- negative (HPV-) OPSCCs. By focusing on immune checkpoint genes, we constructed a coexpression network using genes that were differentially expressed between HPV+ and HPV- OPSCCs. Functional analysis of the network indicated that HPV+ OPSCCs had elevated immune activities by promoting adaptive immune response and suppressing activities related to extracellular matrix organization. Subsequently, clinical analysis showed that identified TME-relevant genes were closely associated with the prognosis and therapy response in OPSCC. Importantly, results from the TME analysis were further validated using an independent OPSCC cohort., (© 2021 UICC.)

Objective: Trans Oral Robotic Surgery (TORS) is a modality in the management of oropharyngeal squamous cell carcinoma(OPSCC). This study was planned to determine whether Selective Neck Dissection (SND) is oncological safe procedure even in patients with lymph node metastases., Methods: OPSCC patients were divided into Modified Radical Neck Dissection (MRND) and SND groups. The outcome measures were overall survival (OS), disease-free survival (DFS) and regional recurrence free survival (RRFS)., Results: Thirty-seven SNDs and 18 MRNDs were performed. Regional relapse rate was 6.1% in SND group whilst 18.8% in MRND group(p=0.19). The 5-year OS, DFS and RRFS rates' differences were not statistically significant between SND and MRND groups (p=0.40, p=0.42 and p=0.18, respectively). At multivariate analysis, advanced stage impacted the 5-year OS and DFS(HR=9.39, p<0.01 and HR=11.03, p=0.04)., Conclusions: The SND seems to be effective in a TORS framework. The indication should be accurately discussed by the multidisciplinary tumor board., (Copyright © 2021. Published by Elsevier B.V.)

Importance: Oropharyngeal cancer (OPC) incidence is rising among men in the US. Comprehensive assessments of nationwide trends in OPC incidence and mortality by demographics, tumor characteristics at diagnosis, and geography are lacking., Objective: We examined secular trends in OPC incidence and mortality rates in all 50 US states and the District of Columbia (DC)., Design, Setting, and Participants: In this cross-sectional study, we used the US Cancer Statistics data set to examine OPC incidence trends from 2001 through 2017. Observed and incidence-based mortality trends were evaluated using data from the National Center for Health Statistics and Surveillance Epidemiology and End Results program, respectively. Data analysis was conducted from January to April 2021., Results: Nationwide, 260 182 OPC cases were identified; 209 297 (80%) occurred in men, 168 674 (65%) with regional stage, and 142 068 (55%) in the Southeast and Midwest regions, during 2001 to 2017. Incidence of OPC increased nationally 2.7% per year among men, with a notable (over 3% per year) rise among non-Hispanic White men and in men aged 65 years and older. Overall, among women, the annual percentage change was 0.5% (95% CI, -0.28% to 1.22%). Among men, with a 3.1% per year rise (95% CI, 2.4% to 3.8%), regional-stage OPC incidence increased nearly 2-fold. Among women, regional-stage OPC incidence increased 1.0% per year (95% CI, 0.3% to 1.7%). Among men, OPC incidence increased in all states and regions except Alaska, DC, and Wyoming. Among men, the most pronounced increases (more than 3.5% per year) were clustered in the Southeast and Midwest regions. Among women, a rise of more than 2% per year was also concentrated in the Southeast and Midwest regions. Among men, OPC incidence-based mortality increased 2.1% per year (95% CI, 1.0% to 3.2%) overall in recent years (from 2006 to 2017). In contrast, among women, the annual percentage change in OPC incidence-based mortality was -1.2% (95% CI, -2.5% to 0.1%)., Conclusions and Relevance: The findings of this cross-sectional study suggest that the incidence of OPC has continued to increase nationally among men in the US, with rapid increases among the elderly population. The notable rise in regional-stage OPC and the concurrent recent rise in mortality among men is troubling and calls for urgent improvements in prevention. Distinct geographic patterns with notable rises in the Midwest and Southeast regions imply the need for improved and targeted prevention as well as future studies to understand etiological reasons for geographic disparities.

Background: Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed "epigenetic age acceleration", has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration (IEAAHorvath and IEAAHannum), one marker of extrinsic epigenetic age acceleration (EEAA), one optimised to predict physiological dysregulation (AgeAccelPheno), one optimised to predict lifespan (AgeAccelGrim) and a DNA methylation-based predictor of mortality (ZhangScore). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer (n = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated., Results: IEAAHannum and AgeAccelGrim were associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57; p = 0.007] and 1.40 [95% CI 1.06, 1.83; p = 0.016], respectively). There was weak evidence that the addition of AgeAccelGrim to the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p value for difference = 0.069)., Conclusion: In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification., (© 2022. The Author(s).)

Purpose: The purpose of this study was to assess the efficacy in terms of neck failure of an initial neck dissection before definitive chemoradiotherapy in N2-3 oropharyngeal squamous cell carcinomas, as well as the dosimetric impact and the acute and delayed morbidity of this approach., Materials and Methods: All patients consecutively treated between 2009 and 2018 with definitive chemoradiotherapy using intensity-modulated conformal radiotherapy (IMRT) for a histologically proven N2-3 oropharyngeal squamous cell carcinomas were retrospectively included. The therapeutic approach consisted of induction chemotherapy, followed by cisplatine-based chemoradiotherapy preceded or not by neck dissection. Neck dissection was discussed on a case-by-case basis in a dedicated multidisciplinary tumour board for patients with a dissociated response to induction chemotherapy, defined as a better response on the primary than on the node. Chemoradiotherapy without neck dissection was systematically performed in case of a major lymph node response to induction chemotherapy (decrease in size of 90% or more). Intensity-modulated radiotherapy using a simultaneous-integrated boost delivered 70Gy in 35 fractions on macroscopic tumour volumes, 63Gy on intermediate-risk levels or extra-nodal extension and 54Gy on prophylactic lymph node areas., Results: Two groups were constituted: 47 patients without an initial neck dissection (62.7%), and 28 patients with a neck dissection prior to definitive chemoradiotherapy (37.3%). Initial patient characteristics were not statistically different between the two groups. The median follow-up was 60.1months (range: 3.2-119months). Incidence of neck failure was higher in patients without neck dissection (P=0.015). The neck failure rate at 5years was 19.8% (95% confidence interval: 7.4-30.6%; P=0.015) without neck dissection versus 0% following neck dissection. All lymph node failures occurred in the planned target volume at 70Gy. Upfront neck dissection suggested a decrease in the mean dose received by the homolateral parotid gland (P=0.01), mandible (P=0.02), and thyroid gland (P=0.02). Acute toxicity of chemoradiotherapy after neck dissection suggested a reduction in grade≥3 adverse events (P=0.04), early discontinuation of concomitant chemotherapy (P=0.009) and feeding tube-dependence (P=0.008) in univariate analysis. During follow-up, there was no difference between the two groups in terms of xerostomia, dysgeusia, dysphagia or gastrostomy dependence in univariate analysis., Conclusion: Neck dissection prior to definitive chemoradiotherapy in N2-3 oropharyngeal squamous cell carcinoma was associated with high neck control without additional mid and long-term morbidity., (Copyright © 2021 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Objective: Diagnostic delay in human papillomavirus-associated oropharynx squamous cell carcinoma (HPV(+)OPSCC) is common due to nonspecific symptoms. We aim to describe the disease burden and oncologic outcomes of patients with HPV(+)OPSCC diagnosed >12 months after symptom onset., Study Design: This is a retrospective cohort study of HPV(+)OPSCC patients receiving intent-to-cure treatment (including surgery ± adjuvant therapy or primary chemoradiation)., Setting: 2006-2016, tertiary care center., Methods: Tumor stage was compared between patients with and without delayed diagnosis using χ 2 tests. Kaplan-Meier survival analysis with univariate and multivariable Cox regressions were used to determine the effect of diagnostic delay on oncologic outcomes., Results: In total, 664 patients were included. Compared to patients diagnosed <12 months from symptom onset (n = 601), those diagnosed at >12 months (n = 63) were more likely to have T4 disease and higher overall American Joint Committee on Cancer (AJCC) clinical stage at presentation ( P < .01 for both). At 5 years, rates of overall survival, cancer-specific survival, progression-free survival, and distant metastases-free survival in the delayed diagnosis cohort were 80%, 90%, 80%, and 89%, respectively. A >12-month delay in diagnosis did not significantly impact overall survival (adjusted hazard ratio [aHR], 1.16; 95% CI, 0.58-2.31), cancer-specific survival (aHR, 0.83; 95% CI, 0.29-2.39), progression-free survival (aHR, 1.15; 95% CI, 0.56-2.37), or distant metastases-free survival (aHR, 1.00; 95% CI, 0.42-2.40) after adjusting for age, sex, and clinical AJCC stage ( P > .05 for all)., Conclusions: Delayed diagnosis of HPV(+)OPSCC is associated with greater burden of disease at presentation, but oncologic outcomes remain favorable across treatment modalities. When appropriate, intent-to-cure therapy should be pursued despite diagnostic delay., Level of Evidence: Level III.

While P16 immunohistochemistry (IHC) is a well-established surrogate marker of Human Papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC), Retinoblastoma 1 (RB1) loss may lead to p16 overexpression in the absence of HPV. We determined the proportion of p16-positive/HPV-negative OSCC with RB1 loss and other alterations in RB1/p16 pathway, and tested RB1 IHC as a prognostic biomarker for OSCC, along with the 8th edition of AJCC staging manual. P16 and RB1 IHC and HPV DNA in situ hybridization (ISH) were performed on 257 OSCC. High risk HPV RNA ISH, RB1 fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) were done on p16-positive/HPV DNA ISH-negative OSCC. Disease free survival (DFS) was used as an endpoint. In the entire cohort and in p16-positive (n = 184) and p16-negative (n = 73) subgroups, AJCC 8th edition staging correlated with DFS (p < 0.01). RB1 IHC showed RB1 loss in p16-positive OSCC only (79/184, 43%). RB1 loss by IHC is associated with a better DFS, without providing additional prognostic information for patients with p16-positive OSCC. HPV RNA ISH was positive in 12 of 14 HPV DNA ISH-negative cases. RB1 IHC showed loss in 10 of 15 HPV DNA ISH-negative cases and in 1 of 2 HPV RNA ISH-negative cases. Overall, only one case of p16-positive/HPV RNA ISH-negative OSCC showed RB1 loss by IHC (1/184, 0.5%). Of the 10 p16-positive and HPV DNA ISH-negative cases with RB1 loss by IHC, 2 had RB1 hemizygous deletion and 3 showed Chromosome 13 monosomy by FISH. No RB1 mutations were detected by NGS. Other molecular alterations in p16-positive/HPV DNA ISH-negative cases included TP53 and TERT mutations and DDX3X loss. HPV-independent RB1 inactivation rarely results in false positive p16 IHC. RB1 inactivation by high risk HPV E7 oncoprotein may co-exist with RB1 deletion. RB1 loss is a favorable prognosticator and occurs exclusively in p16-positive OSCC. The 8th edition of the AJCC staging manual satisfactorily predicts DFS of OSCC patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To analyze the patterns, risk factors, and salvage outcomes for locoregional recurrences (LRR) after treatment with transoral robotic surgery (TORS) for HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC)., Study Design: Retrospective analysis of HPV+ OPSCC patients completing primary TORS, neck dissection, and NCCN-guideline-compliant adjuvant therapy at a single institution from 2007 to 2017., Methods: Features associated with LRR, detailed patterns of LRR, and outcomes of salvage therapy were analyzed. Disease-free survival (DFS) and overall survival (OS) were calculated for subgroups of patients receiving distinct adjuvant treatments., Results: Of 541 patients who completed guideline-indicated therapy, the estimated 5-year LRR rate was 4.5%. There were no identifiable clinical or pathologic features associated with LRR. Compared to patients not receiving adjuvant therapy, those who received indicated adjuvant radiation alone had a lower risk of LRR (HR 0.28, 95% CI [0.09-0.83], P = .023), but there was no difference in DFS (P = .21) and OS (P = .86) between adjuvant therapy groups. The 5-year OS for patients who developed LRR was 67.1% vs. 93.9% for those without LRR (P < .001). Patients who initially received adjuvant chemoradiation and those suffering local, in-field, and/or retropharyngeal node recurrences had decreased disease control after salvage therapy., Conclusion: LRR rates are low for HPV+ OPSCCs completing TORS and guideline-compliant adjuvant therapy. Patients without indication for adjuvant therapy more often suffer LRR, but these recurrences are generally controllable by salvage therapy. Improved understanding of the patterns of recurrence most amenable to salvage therapy may guide treatment decisions, counseling, and adjuvant therapy de-escalation trials., Level of Evidence: 3 Laryngoscope, 131:E2865-E2873, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Human papillomavirus (HPV) infection in patients with oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant for better prognosis. However, there remain HPV-positive patients who have poor outcomes. The stratification strategy for detecting high-risk patients among those with HPV-positive OPSCC has not been well delineated, especially for Asian patients. We undertook a retrospective cohort study on the survival rate of 89 Japanese patients diagnosed with primary OPSCC. The tumors were concurrently analyzed for the presence of HPV E6 DNA/mRNA, viral DNA load, p16 expression, viral physical status, and viral variant lineage. Human papillomavirus 16 viral DNA was found in 45 (51%) OPSCCs. Human papillomavirus 16 DNA-positive OPSCCs with higher viral load (classified as HPV16 DNA-medium/high OPSCCs) showed significantly favorable overall survival and progression-free survival compared with HPV16 DNA-positive OPSCCs with lower viral load (<10 copies/cell; HPV16 DNA-low OPSCCs) and HPV16 DNA-negative OPSCCs. E6 mRNA expression was observed in all HPV16 DNA-medium/high OPSCCs but not in HPV16 DNA-low OPSCCs. Notably, p16-positive and HPV16 DNA-negative/low OPSCCs showed significantly worse survival than p16-positive and HPV16 DNA-medium/high OPSCCs and resembled HPV-unrelated OPSCCs with regard to survival and risk factor profile. Although not significant, a trend toward shorter survival was observed for HPV16-integrated OPSCCs. Phylogenetic analysis revealed two major types of HPV16 variants termed Asian (A4) and European (A1/A2/A3) variants, but no difference in survival between these variants was observed. Altogether, these findings suggest that HPV viral load is a potentially informative factor for more accurate risk stratification of patients with OPSCC., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objectives: To analyse the oncological outcomes following primary Transoral Robotic Surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC)., Design: Observational case series., Setting: Tertiary centre; first TORS practice to commence in the UK., Participants: All consecutive patients undergoing primary TORS with curative intent, with or without adjuvant treatment., Main Outcome Measures: Descriptive analysis of patient and tumour pathology variables. Survival outcomes: Overall, Disease-Specific, Progression-Free and Locoregional control., Results: The cohort comprised of 120 patients undergoing TORS with minimum 12-month follow-up data and the following characteristics: mean age 58 years, 91 males (76%), 78 tonsil (65%) and 34 base of tongue primaries (28%), 89% HPV-related OPSCC. The surgical pathology revealed 14 (12%) with positive margins, 19 (16%) had close margins <2mm and 31% with extranodal extension. The treatment was as follows: 39 (33%) treated with TORS alone, 50 (42%) received adjuvant radiotherapy and 31 (26%) received adjuvant radiotherapy with chemotherapy. There were 15 recurrences. Estimated survival for all patients at 3 years (95% CI): overall 85% (78-92), disease-specific 90% (85-96), progression-free 86% (79-92) and locoregional control 90% (84-96). The equivalent survival figures for the HPV-related cases alone were as follows: overall 88% (82-94), disease-specific 93% (87-98), progression-free 88% (81-95) and locoregional control 92% (87-98)., Conclusions: Whilst TORS has become a common practice in the management of OPSCC in the UK, these are the first reported oncological outcomes. For selected patients, TORS with or without adjuvant therapy is an appropriate treatment modality., (© 2021 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Background: Image guidance in radiation oncology has resulted in significant improvements in the accuracy and precision of radiation therapy (RT). Recently, the resolution and quality of cone beam computed tomography (CBCT) for image guidance has increased so that tumor masses and lymph nodes are readily detectable and measurable. During treatment of head and neck squamous cell carcinoma (HNSCC), on-board CBCT setup imaging is routinely obtained; however, this CBCT imaging data is not utilized to predict patient outcomes. Here, we analyzed whether changes in CBCT measurements obtained during a course of radiation therapy correlate with responses on routine 3-month follow-up diagnostic imaging and overall survival (OS)., Materials/methods: Patients with oropharyngeal primary tumors who received radiation therapy between 2015 and 2018 were included. Anatomical measurements were collected of largest nodal conglomerate (LNC) at CT simulation, end of radiation treatment (EOT CBCT), and routine 3-month post-RT imaging. At each timepoint anteroposterior (AP), mediolateral (ML) and craniocaudal (CC) measurements were obtained and used to create a 2-dimensional (2D) maximum., Results: CBCT data from 64 node positive patients were analyzed. The largest nodal 2D maximum and CC measurements on EOT CBCT showed a statistically significant correlation with complete response on 3-month post-RT imaging (r = 0.313, p = 0.02 and r = 0.318, p = 0.02, respectively). Furthermore, patients who experienced a 30% or greater reduction in the CC dimension had improved OS (Binary Chi-Square HR 4.85, p = 0.028)., Conclusion: Decreased size of pathologic lymph nodes measured using CBCT setup imaging during a radiation course correlates with long term therapeutic response and overall survival of HNSCC patients. These results indicate that CBCT setup imaging may have utility as an early predictor of treatment response in oropharyngeal HNSCC., (© 2021. The Author(s).)