Long-Term Results of a Phase 2 Clinical Trial of Radiation Volume and Dose Deintensification Following Transoral Robotic Surgery and Neck Dissection for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

Extranodal extension (ENE) is an adverse feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and is an indication for adjuvant treatment escalation. Preoperative core needle biopsy (CNB) may cause lymph node capsule disruption related to ENE development; however, evidence regarding this association in OPSCC is lacking. To assess whether preoperative nodal CNB is associated with presence of ENE in final pathology findings among patients with HPV-associated OPSCC targeted for primary surgical resection. This retrospective cohort study was conducted at a single academic tertiary care center from 2012 to 2022. All patients with OPSCC treated with transoral robotic surgery were assessed for eligibility, and primary surgical patients with HPV-associated OPSCC and node-positive disease confirmed on neck dissection were included in analyses. Data were analyzed from November 28, 2022, to May 21, 2023. Preoperative nodal CNB. The primary outcome was presence of ENE in final pathology findings. Secondary outcomes included adjuvant chemotherapy and recurrence rates. Outcomes of interest were investigated against patient demographic, clinical, and pathologic features. Of 106 patients (mean [SD] age, 60.2 [10.9] years; 99 [93.4%] men) included in analyses, 23 patients (21.7%) underwent CNB. Mean (range) preoperative node size was 3.0 (0.9-6.0) cm. Pathologic node class was pN1 in 97 patients (91.5%) and pN2 in 9 patients (8.5%). A total of 49 patients (46.2%) had ENE identified in final pathology analysis. Of 94 patients who received adjuvant therapy, 58 (61.7%) underwent radiation therapy and 36 (38.3%) underwent chemoradiation therapy. There were 9 recurrences (8.5%). In univariate analysis, CNB was associated with ENE (odds ratio [OR], 2.70; 95% CI, 1.03-7.08), but there was no association in a multivariable model including pN class and preoperative node size (OR, 2.56; 95% CI, 0.97-7.27). Compared with pN1 class, pN2 class was associated with ENE (OR, 10.93; 95% CI, 1.32-90.80). There were no associations of ENE with preoperative node size, presence of cystic or necrotic nodes, fine needle aspiration, tobacco or alcohol exposure, pathologic T class, prior radiation, or age. Furthermore, use of CNB was not associated with macroscopic ENE, adjuvant chemotherapy, or recurrence. This cohort study of patients with HPV-associated OPSCC found that preoperative nodal CNB was strongly associated with ENE in final pathology, supporting the possibility of an artifactual ENE component in this population.

Some patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) do not receive guideline-recommended postoperative radiation therapy (PORT) following primary transoral robotic surgery (TORS). Three-hundred and sixty-four patients with treatment-naïve, HPV-associated OPSCC were recommended to receive PORT based on clinicopathological features following TORS. Patients were stratified based on if they received PORT. Oncologic outcomes were compared. The 3-year locoregional failure (LRF) was 32% in patients who did not receive PORT and 4% in patients who received PORT (P < .001). Despite increased LRF, avoiding PORT was not associated with increased 3-year distant metastasis rates (8% vs 4%, P = .56) or worse 3-year survival (95% vs 98%, P = .34). Recurrences in the surgery alone cohort varied between local and regional sites and were often successfully salvaged. Patients with HPV-associated OPSCC who do not receive indicated PORT have an increased risk of LRF but similar survival due to high salvage rates.

Introduction: The aim of this study was to investigate the impact of primary transoral robotic surgery (TORS) versus radiotherapy (RT) on progression-free survival (PFS), overall survival (OS), and 1-year swallowing function for patients with early-stage HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: Patients with stage I-II (AJCC 8th Ed.) HPV-associated OPSCC treated with TORS followed by risk-adapted adjuvant therapy or (chemo)radiotherapy between 2014 and 2019 were identified. PFS, OS, and swallowing outcomes including gastrostomy tube (GT) use/dependence, and Functional Oral Intake Scale (FOIS) change over 1 year were compared. Results: One hundred sixty-seven patients were analyzed: 116 treated with TORS with or without adjuvant RT and 51 treated with RT (50 chemoRT). The RT group had more advanced tumor/nodal stage, higher comorbidity, and higher rates of concurrent chemotherapy. There were no differences in 3-year PFS (88% TORS vs. 75% RT) or OS (90% vs. 81%) between groups, which persisted after adjusting for stage, age, and comorbidity. GT use/dependence rates were higher in the RT group. Mean (SD) FOIS scores in the TORS group were 6.9 (0.4) at baseline and 6.4 (1.0) at 1 year, compared with 6.7 (0.6) and 5.6 (1.7) for the RT group. Only clinical nodal stage was found to be significantly associated with FOIS change from baseline to 1 year. Conclusion: There were no differences in PFS or OS between patients treated with primary TORS or RT for early-stage HPV-associated OPSCC. Clinical N2 status is associated with FOIS change at 1 year and may be the major factor affecting long-term swallowing function, irrespective of primary treatment modality.

The Evolution of Clinical Practice Guidelines for the Postoperative Treatment of Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma: Comments and Controversies.

Patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with radiation-based therapy suffer from short- and long-term toxicities that affect quality of life (QOL). Transoral robotic surgery (TORS) has an established role in the management of early OPSCC but adjuvant treatment is often indicated postoperatively due to the high incidence of nodal metastasis associated with advanced human papillomavirus (HPV)-related OPSCC. To overcome the need for adjuvant radiation therapy (RT), neoadjuvant chemotherapy followed by TORS and neck dissection (ND) is proposed. This study aimed to assess if QOL in HPV-associated OPSCC receiving neoadjuvant chemotherapy followed by TORS and ND returns to baseline within 12 months of completing treatment. A 12 month longitudinal study was carried out at McGill University Health Centre in Montreal, Canada, among a convenience sample of patients with American Joint Committee on Cancer Seventh Edition stage III and IVa HPV-related OPSCC who were treated with neoadjuvant chemotherapy followed by TORS and ND. QOL data were obtained pretreatment and at 1, 3, 6, and 12 months following treatment completion using the European Organisation for Research and Treatment of Cancer Core and Head and Neck extension modules. Paired t tests and mixed models for repeated measures analysis were used to assess changes in QOL from baseline to 12 months postoperatively and over time, respectively. Nineteen of 23 patients (median age 58 years) who received the study treatment fulfilled the eligibility criteria. OPSCC subsites were palatine tonsil (n = 12) and base of tongue (n = 7). All 19 patients were treated per protocol and none required adjuvant RT as per pathology review and protocol requirements at a postoperative multidisciplinary team tumor board discussion. No significant differences were found when comparing 12 month QOL follow-up scores to pretreatment scores in measures that would likely be affected by RT [eg, swallowing (P = .7), social eating (P = .8), xerostomia (P = .9)]. In HPV-related OPSCC, neoadjuvant chemotherapy followed by TORS and ND as definitive treatment is associated with excellent QOL outcomes. Postoperative QOL scores returned to baseline by 3 months and were maintained for all measures, indicating a return to normal function.

Clinical evaluation of tumour-infiltrating lymphocytes as a prognostic factor in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma AIMS: The majority of patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OpSCC) have favourable survival outcomes, but a significant minority of individuals will die of their disease. There are currently no definitive criteria with which to identify HPV-associated OpSCC patients with poor outcomes. Recent reports suggest that quantitative evaluation of T-cell subpopulations in OpSCC may be of prognostic value, but the methods used have limited utility in a clinical diagnostic setting. We therefore sought to determine the clinical prognostic utility of tumour-infiltrating lymphocyte (TIL) evaluation in patients with HPV-associated OpSCC within the context of a diagnostic histopathology setting. METHODS AND RESULTS: Representative diagnostic haematoxylin and eosin (H&E)-stained slides from 232 consecutive HPV-associated OpSCC patients were classified as containing a high (TILHi ; diffuse, lymphocytes in>80% of tumour and stroma), moderate (TILMod ; patchy, present in 20-80% of tumour and stroma) or low (TILLo ; sparse or absent, present in <20% of tumour and stroma) TILs. Interobserver reliability was assessed, and TIL category was then correlated with overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses showed statistically significant differences in OS and DFS estimates when TILHi and TILMod patients were compared with TILLo patients (P<0.0001 for TILHi versus TILLo ; P<0.0001 for TILMod versus TILLo ). Statistical significance was retained when TILHi and TILMod patients were grouped into a single category (TILHi ) and compared with TILLo patients (P<0.0001). CONCLUSION: We demonstrate the prognostic utility of TILs in patients with HPV-associated OpSCC in clinical practice. A binary system classifying HPV-associated OpSCC into TILHi and TILLo on the basis of routine H&E staining stratifies patients into those with potentially favourable and unfavourable survival outcomes, respectively.

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing in the United States and may be underestimated among black individuals. Characterizing the current knowledge level among black individuals is critical to developing interventions to increase awareness. To describe the sociodemographic correlates of knowledge and risk perception of HPV and HPV-associated OPSCC among a predominantly black population. A cross-sectional survey was conducted at a drag racing event on September 12 and 13, 2015, in Madison, Illinois. The setting was a community-based oral head and neck cancer screening and education initiative. Participants were 301 drag race attendees 18 years or older who were conveniently sampled from attendees at an annual drag racing event predominantly patronized by black individuals. The primary outcome was knowledge and risk perception of HPV and HPV-associated OPSCC. An electronic-based questionnaire elicited sociodemographic information and contained oral cancer knowledge and risk perception items, which were combined to form knowledge and risk perception scores. Multivariable linear regression analysis assessed estimates of knowledge and risk perception of HPV and HPV-associated OPSCC. Of the 301 participants (111 female and 190 male) completing the questionnaire, 194 (64.5%) were black. Overall, respondents ranged in age from 18 to 78 years, with a mean (SD) age of 48.0 (13.0) years. The mean (SD) knowledge score was 5.7 (4.6) of 15, and the mean (SD) risk perception score was 2.2 (1.4) of 6. Using multivariable linear regression, we found that, for every 1-year increase in age, knowledge of HPV-associated OPSCC decreased by 5.0% and was worse in men (β = -1.26; 95% CI, -2.33 to -0.18), black vs white individuals (β = -1.29; 95% CI, -2.35 to -0.23), and those with a high school diploma or less vs college graduates (β = -3.23; 95% CI, -4.67 to -1.80). Black individuals also had lower perceived risk of developing HPV-associated OPSCC (β = -0.36; 95% CI, -0.69 to -0.02) compared with white individuals, and participants with a high school diploma or less had lower perceived risk of developing HPV-associated OPSCC compared with those with a college degree or higher (β = -0.59; 95% CI, -1.04 to -0.14). Age and sex were independent correlates of knowledge of HPV-associated OPSCC, while race and education level were correlates of both knowledge and risk perception of HPV-associated OPSCC. These findings should inform future interventions targeted at increasing knowledge of HPV-associated OPSCC in black communities.

To analyse the oncological outcomes following primary Transoral Robotic Surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC). Observational case series. Tertiary centre; first TORS practice to commence in the UK. All consecutive patients undergoing primary TORS with curative intent, with or without adjuvant treatment. Descriptive analysis of patient and tumour pathology variables. Survival outcomes: Overall, Disease-Specific, Progression-Free and Locoregional control. The cohort comprised of 120 patients undergoing TORS with minimum 12-month follow-up data and the following characteristics: mean age 58years, 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 3years (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). 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.

Standard adjuvant therapy for human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) is radiation therapy 60 Gy with or without cisplatin delivered in 30 fractions during 6 weeks. A phase 3 randomized clinical trial demonstrated decreased toxic effects and improved patient-reported outcomes with de-escalated adjuvant radiation therapy (DART) compared with standard therapy; however, outcomes for patients treated in the clinical practice setting following trial adoption remain unknown. To compare characteristics and oncologic outcomes of patients treated with DART during clinical trials (on study) and in clinical practice settings (off study) and report progression-free survival (PFS) by risk category. This retrospective cohort study included patients treated with DART in the MC1273 and MC1675 trials and in clinical practice after study completion at a multisite tertiary care center. Patients with surgically resectable HPV-OPSCC who underwent margin-negative resection between August 20, 2013, and March 21, 2023, and were treated with DART were included in the analysis. Those with prior head and neck cancer, pT0 or pT4 disease, unknown HPV status, metastatic disease at presentation, synchronous primary tumors, induction chemotherapy, or treatment at an outside institution were excluded. Data were analyzed from July 1, 2024, to July 18, 2025. DART consisting of 30 to 36 Gy in 1.5- to 1.8-Gy fractions twice daily with docetaxel 15 mg/m2 on days 1 and 8. Progression-free survival as measured via Kaplan-Meier analysis. A total of 282 patients were included in the analysis: 176 (62.4%) in the on-study group and 106 (37.6%) in the off-study group (252 [89.4%] male; mean [SD] age, 59.1 [9.3] years). Both groups were predominantly male (157 [89.2%] and 95 [89.6%], respectively) and consisted mostly of never smokers (118 [67.0%] and 62 [58.5%], respectively). Pathologic features were similar between groups except for nodal stage (pN1: 155 [88.1%] on study vs 102 [96.2%] off study; pN2: 21 [11.9%] on study vs 4 [3.8%] off study; P = .02). The median follow-up times were 5.2 years (95% CI, 5.2-5.8 years) in the on-study group and 2.2 years (95% CI, 1.9-2.4 years) in the off-study group. Two-year PFS was similar (93% [95% CI, 88%-97%] on study vs 93% [95% CI, 88%-99%] off study). For patients with pN1 and no extranodal extension (ENE), 2- and 5-year PFS were 97% (95% CI, 93%-100%) and 96% (95% CI, 92%-100%), respectively. Patients with pN1 and ENE had a 2- and 5-year PFS of 93% (95% CI, 89%-98%) and 87% (95% CI, 81%-94%), respectively. In this retrospective cohort study of patients receiving DART on and off study, oncologic outcomes were similar between the 2 groups. Fewer patients with pN2 received DART off study, given the interim results of MC1675. Patients with pN1 and no ENE treated with DART had excellent 2- and 5-year PFS, supporting DART as a compelling treatment option in well-selected patients. An additional study that is currently underway will evaluate biomarker risk-stratified treatment of patients with pN1 and ENE receiving DART.

Machine Learning Prediction of Extracapsular Extension in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

Predictors of Recurrence in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

Impact of Smoking and Primary Tumor Subsite on Recurrence in HPV-Associated Oropharyngeal Squamous Cell Carcinoma.

National Comprehensive Cancer Network (NCCN) guidelines recommend routine clinical follow-up as posttreatment surveillance for patients with head and neck cancer (HNC). Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) is a unique subset of HNC, associated with fewer recurrences and improved survival. The utility of this guideline in this patient population is unknown. To determine adherence to the NCCN clinical follow-up guideline, frequency of recurrence detection method, classified as symptom-directed, physician-detected, or imaging-detected, and survival benefit associated with adherence to the NCCN guideline. Retrospective cohort study of patients with HPV-associated OPSCC diagnosed between January 1, 2011, and April 30, 2014, at a large integrated health care system. Multivariable analyses were conducted using the Cox proportional hazards regression model, with patient adherence to NCCN visit guidelines constructed as a time-dependent variable. All data analyses were complete on September 1, 2018. Posttreatment clinical and imaging surveillance. Recurrence and overall survival. Secondary outcome was salvage therapy. Of the 233 study patients with HPV-associated OPSCC, the mean (SD) age at diagnosis was 60.5 (8.7) years; 201 (86.3%) were male, 189 (81.1%) were white, and 109 (46.8%) had a positive smoking history. Median follow-up time through recurrence or all-cause mortality was 4.5 years (interquartile range, 3.8-5.6). Patients demonstrated 83.0% (180 of 217) adherence to NCCN surveillance guidelines in year 1, 52.7% (106 of 201) in year 2, 73.4% (141 of 192) in year 3, 62.3% (96 of 154) in year 4, and 52.9% (45 of 85) in year 5. A total of 3358 clinical surveillance examinations were performed with 22 patients having recurrences. There were 10 symptom-directed, 1 physician-detected, and 11 imaging-detected recurrences. Of the symptom-directed recurrences, salvage therapy was attempted in 5; at the study end date, 1 was alive. Salvage neck dissection was attempted in the physician-detected recurrence; this patient subsequently died. All locoregional recurrences occurred within the first 2 years, and all salvageable recurrences within the first year. Adherence to NCCN guidelines was not protective against all-cause mortality in the multivariable Cox proportional hazards regression model (hazard ratio, 0.76; 95% CI, 0.28-2.05). Among patients with HPV-associated OPSCC, clinical surveillance is of limited utility. Nearly all clinically detected recurrences were elicited by patient symptoms that prompted earlier presentation to the clinician. Adherence to the current schedule does not appear to confer survival advantage, and locoregional recurrences are almost never detected beyond 2 years. These findings support reduction of posttreatment clinical surveillance in this population.

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

Oncologic Outcomes of Transoral Robotic Surgery in HPV-Associated OPSCC: A Systematic Review and Meta-Analysis.