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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.)

Background: Development of evidence-based post-treatment surveillance guidelines in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is limited by comprehensive documentation of patterns of recurrence and metastatic spread., Methods: A retrospective analysis of patients diagnosed with R/M HNSCC at a National Cancer Institute-designated cancer center between 1998- 2019 was performed (n = 447). Univariate and multivariate analysis identified patterns of recurrence and predictors of survival., Results: Median overall survival (mOS) improved over time (6.7 months in 1998-2007 to 11.8 months in 2008-2019, p = .006). Predictors of worse mOS included human papillomavirus (HPV) negativity (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.2-2.6), high neutrophil/lymphocyte ratio (HR, 2.1 [1.4-3.0], disease-free interval (DFI) ≤6 months (HR, 1.4 [1.02-2.0]), and poor performance status (Eastern Cooperative Oncology Group, ≥2; HR, 1.91.1-3.4). In this cohort, 50.6% of recurrences occurred within 6 months of treatment completion, 72.5% occurred within 1 year, and 88.6% occurred within 2 years. Metachronous distant metastases were more likely to occur in patients with HPV-positive disease (odds ratio [OR], 2.3 [1.4-4.0]), DFI >6 months (OR, 2.4 [1.5-4.0]), and body mass index ≥30 (OR, 2.3 [1.1-4.8]). Oligometastatic disease treated with local ablative therapy was associated with improved survival over polymetastatic disease (HR, 0.36; 95% CI, 0.24-0.55)., Conclusion: These data regarding patterns of distant metastasis in HNSCC support the clinical utility of early detection of recurrence. Patterns of recurrence in this population can be used to inform individualized surveillance programs as well as to risk-stratify eligible patients for clinical trials., Plain Language Summary: After treatment for head and neck cancer (HNC), patients are at risk of recurrence at prior sites of disease or at distant sites in the body. This study includes a large group of patients with recurrent or metastatic HNC and examines factors associated with survival outcomes and recurrence patterns. Patients with human papillomavirus (HPV)-positive HNC have good survival outcomes, but if they recur, this may be in distant regions of the body and may occur later than HPV-negative patients. These data argue for personalized follow-up schedules for patients with HNC, perhaps incorporating imaging studies or novel blood tests., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: 18 F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation., Methods and Materials: This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months., Results: There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P = .018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P = .037) compared with patients receiving standard CRT., Conclusions: Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Recent insights into the biologic characteristics and treatment of oropharyngeal cancer may help inform improvements in prognostic modeling. A bayesian multistate model incorporates sophisticated statistical techniques to provide individualized predictions of survival and recurrence outcomes for patients with newly diagnosed oropharyngeal cancer., Objective: To develop a model for individualized survival, locoregional recurrence, and distant metastasis prognostication for patients with newly diagnosed oropharyngeal cancer, incorporating clinical, oncologic, and imaging data., Design, Setting, and Participants: In this prognostic study, a data set was used comprising 840 patients with newly diagnosed oropharyngeal cancer treated at a National Cancer Institute-designated center between January 2003 and August 2016; analysis was performed between January 2019 and June 2020. Using these data, a bayesian multistate model was developed that can be used to obtain individualized predictions. The prognostic performance of the model was validated using data from 447 patients treated for oropharyngeal cancer at Erasmus Medical Center in the Netherlands., Exposures: Clinical/oncologic factors and imaging biomarkers collected at or before initiation of first-line therapy., Main Outcomes and Measures: Overall survival, locoregional recurrence, and distant metastasis after first-line cancer treatment., Results: Of the 840 patients included in the National Cancer Institute-designated center, 715 (85.1%) were men and 268 (31.9%) were current smokers. The Erasmus Medical Center cohort comprised 300 (67.1%) men, with 350 (78.3%) current smokers. Model predictions for 5-year overall survival demonstrated good discrimination, with area under the curve values of 0.81 for the model with and 0.78 for the model without imaging variables. Application of the model without imaging data in the independent Dutch validation cohort resulted in an area under the curve of 0.75. This model possesses good calibration and stratifies patients well in terms of likely outcomes among many competing events., Conclusions and Relevance: In this prognostic study, a multistate model of oropharyngeal cancer incorporating imaging biomarkers appeared to estimate and discriminate locoregional recurrence from distant metastases. Providing personalized predictions of multiple outcomes increases the information available for patients and clinicians. The web-based application designed in this study may serve as a useful tool for generating predictions and visualizing likely outcomes for a specific patient.

Purpose: To assess associations between imaging biomarkers from standard of care pre-treatment CT and FDG-PET scans and locoregional (LR) and distant metastatic (DM) recurrences in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiotherapy (CRT)., Methods: An institutional database from a single NCI-designated cancer center identified 266 patients with p16+ OPSCC treated with definitive CRT in our department from 2005 to 2016 with evaluable pre-treatment FDG-PET scans. Quantitative SUV metrics and qualitative imaging metrics were determined from FDG-PET and CT scans, while clinical characteristics were abstracted from the medical record. Associations between clinical/imaging features and time to LR (TTLRF) or DM (TTDMF) failure and overall survival (OS) were assessed using univariable Cox regression and penalized stepwise regression for multivariable analyses (MVA)., Results: There were 27 LR and 32 DM recurrences as incident failures. Imaging biomarkers were significantly associated with TTLRF, TTDMF and OS. FDG-PET metrics outperformed CT and clinical metrics for TTLRF, with metabolic tumor volume being the only significant feature selected on MVA: C-index = 0.68 (p = 0.01). Radiographic extranodal extension (rENE), positive retropharyngeal nodes (RPN+), and clinical stage were significant on MVA for TTDMF: C-index = 0.84 (p < 0.001). rENE, group stage, and RPN+ were significant on MVA for OS: C-index = 0.77 (p < 0.001)., Conclusions: In the largest study to date of uniformly treated patients with CRT to evaluate both pretreatment CT and FDG-PET, radiographic biomarkers were significantly associated with TTLRF, TTDMF and OS among patients with p16+ OPSCC treated with CRT. CT metrics performed best to predict TTDMF, while FDG-PET metrics showed improved prediction for LRRFS. These metrics may help identify candidates for treatment intensification or de-escalation of therapy., Statement of Translational Relevance: Pre-treatment imaging features from standard-of-care PET/CT imaging show promise for predicting long-term outcomes following HPV-associated oropharynx cancer (HPV-OPC) therapy. This study comprehensively characterizes qualitative and quantitative pre-treatment imaging metrics associated with time to pattern-specific failure in a cohort of 266 patients treated uniformly with definitive chemoradiation. Multivariate analysis (MVA) for time to locoregional failure (TTLRF), time to distant metastatic failure (TTDMF), and overall survival (OS) was performed. FDG-PET metrics outperformed CT and clinical metrics for TTLRF. CT radiographic extranodal extension, positive retropharyngeal nodes, and stage strongly predicted TTDMF (combined C-index = 0.84, log rank p < 0.001). Number of smoking pack-years complemented clinical and imaging features only in patients without radiographic extranodal extension or positive retropharyngeal nodes. Time to pattern-specific failure is important for guiding treatment de-escalation strategies, which intend to reduce treatment-related toxicity in patients with relatively long expected survival times. This study suggests that PET/CT features should play a crucial role in future de-escalation trials and management of HPV-OPC patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The incidence of oropharyngeal squamous cell carcinoma continues to rise with the majority of patients receiving definitive or adjunctive radiation. For patients with locoregional recurrence after radiation, optimal treatment involves salvage surgery. The aim of this study is to identify factors that predict survival to ultimately improve patient selection for salvage surgery., Methods: Retrospective cohort study at an NCI-designated cancer center. We analyzed patients with a history of head and neck radiation who presented with persistent/recurrent or second primary disease requiring salvage oropharyngeal resection from 1998-2017 (n = 120). Patients were stratified into three classes based on time to recurrence and presence of laryngopharyngeal dysfunction. Primary outcomes were 5-year overall survival (OS) and disease specific survival (DSS)., Results: Median OS was 27 months (median follow-up 20 months). Five-year OS was 47% for class I (recurrence > 2 years), 26% for class II (recurrence ≤ 2 years), and 0% for class III (recurrence ≤ 2 years and laryngopharyngeal dysfunction), (p < 0.0001). Five-year DSS showed significant differences between classes (p < 0.0001). On multivariate analysis, class remained predictive of OS (p = 0.04- < 0.001) and DSS (p = 0.04-0.001). Adjuvant radiation after salvage surgery with negative margins showed superior OS (71% vs. 28%, p = 0.01) and DSS (83% vs 37%, p = 0.02) compared to surgery alone and was a significant predictor of improved survival on multivariate analysis (HR 0.1, p = 0.04)., Conclusion: This study identified a subset of patients with oropharyngeal cancer recurrence within two years of initial treatment and with laryngopharyngeal dysfunction who have poor outcomes for salvage surgery.

Background: Patients with recurrent oropharyngeal cancer often require extensive salvage surgery. For patients with clinically N0 necks, the indication for concurrent neck dissection remains unclear. This study aimed to determine predictors, prevalence, and distribution of nodal disease in patients treated with salvage oropharyngectomy., Methods: In a case series with data collection at a single tertiary academic National Cancer Institute (NCI)-designated comprehensive cancer center, this study analyzed patients treated with prior radiation or chemoradiation who had persistent, recurrent, or second primary squamous cell carcinoma of the oropharynx requiring oropharyngeal resection between 1998 and 2017 (n = 95). Clinical and oncologic characteristics and treatment outcomes were collected, and statistical analyses were performed., Results: The overall rate of nodal positivity was 21% (24/95), and the rate of occult nodal disease was 6% (4/65). Ipsilateral and contralateral level 2 were the most common areas harboring positive nodes. Bivariate analysis showed female sex (p = 0.01), initial overall stage (p = 0.02), and N status (p = 0.03), as well as recurrent overall and T stage (p = 0.05) to be predictors of nodal disease. In the multivariate analysis, recurrent T stage continued to be significantly predictive of pathologic nodal disease. Both computed tomography (CT) and positron emission tomography-CT were moderately accurate in predicting nodal disease in the salvage setting (area under the curve, 0.79 and 0.80, respectively)., Conclusion: Occult nodal disease is observed in few patients undergoing salvage oropharyngeal resection. This study identified factors predictive of nodal disease in patients undergoing salvage oropharyngectomy and appropriate diagnostic tests in this setting.

Background: The purpose of this study was to evaluate the AJCC eighth edition clinical staging system for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma and to further understand how clinical stage and smoking history affect oncologic outcomes. The purpose of this study was to present the understanding of how clinical stage and smoking history affect oncologic outcomes in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) is critical for selecting patients for treatment deintensification., Methods: Kaplan-Meier and Cox regression were used to evaluate overall survival (OS), locoregional recurrence-free survival (LRFS), and distant recurrence-free survival (DRFS). Concordance statistics (C-indices) were used to compare discriminating ability., Results: The OS and DRFS but not LRFS were significantly distributed using the American Joint Committee on Cancer (AJCC) seventh and eighth editions criteria. The C-indices for OS, LRFS, and DRFS were 0.57, 0.54, and 0.60, respectively, using the AJCC seventh edition, and 0.63, 0.53, and 0.65, respectively, using the AJCC eighth edition. On multivariate analysis, 1 + pack-year smoking history correlated with OS (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.2-3.1; P < .01) but not LRFS or DRFS., Conclusion: These results support implementation of the AJCC eighth edition for HPV-associated oropharyngeal SCC. Clinical stage may be more important than smoking history in selection for deintensification., (© 2018 Wiley Periodicals, Inc.)

Background: Accurate, individualized prognostication in patients with oropharyngeal squamous cell carcinoma (OPSCC) is vital for patient counseling and treatment decision making. With the emergence of human papillomavirus (HPV) as an important biomarker in OPSCC, calculators incorporating this variable have been developed. However, it is critical to characterize their accuracy prior to implementation., Methods: Four OPSCC calculators were identified that integrate HPV into their estimation of 5-year overall survival. Treatment outcomes for 856 patients with OPSCC who were evaluated at a single institution from 2003 through 2016 were analyzed. Predicted survival probabilities were generated for each patient using each calculator. Calculator performance was assessed and compared using Kaplan-Meier plots, receiver operating characteristic curves, concordance statistics, and calibration plots., Results: Correlation between pairs of calculators varied, with coefficients ranging from 0.63 to 0.90. Only 3 of 6 pairs of calculators yielded predictions within 10% of each other for at least 50% of patients. Kaplan-Meier curves of calculator-defined risk groups demonstrated reasonable stratification. Areas under the receiver operating characteristic curve ranged from 0.74 to 0.80, and concordance statistics ranged from 0.71 to 0.78. Each calculator demonstrated superior discriminatory ability compared with clinical staging according to the seventh and eighth editions of the American Joint Committee on Cancer staging manual. Among models, the Denmark calculator was found to be best calibrated to observed outcomes., Conclusions: Existing calculators exhibited reasonable estimation of survival in patients with OPSCC, but there was considerable variability in predictions for individual patients, which limits the clinical usefulness of these calculators. Given the increasing role of personalized treatment in patients with OPSCC, further work is needed to improve accuracy and precision, possibly through the identification and incorporation of additional biomarkers., (© 2018 American Cancer Society.)

Distinguishing between distantly metastatic and metachronous lung primary carcinoma is challenging for patients with a history of head and neck cancer. There are implications for registry data, prognosis and related counseling, and management options, including eligibility for precision oncology trials. Patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma who were treated under a uniform clinical protocol and achieved a complete response were identified in a single-institution prospective head and neck cancer epidemiology database (n = 205). Fifteen patients presented with pulmonary nodule(s) after completion of therapy. We describe our algorithm for the evaluation of these patients, including histopathology, p16 immunohistochemistry, and HPV in situ hybridization.

Background: Oropharyngeal cancers are increasingly associated with human papillomavirus (HPV). Little is known about the experience of patients receiving this diagnosis., Methods: Semistructured interviews were conducted with ten survivors of HPV-related oropharyngeal cancer. The interviews were transcribed, and recurring themes were identified., Results: Physicians were a trusted source of information regarding HPV. Framing the diagnosis in terms of prognosis resonated with patients. The uncertainty about transmission, latency, and communicability colored the dialogue about HPV. Despite some understanding of prevalence and transmission, patients worried about their partner's risk. Patients sought information about HPV on the Internet, but it was not easily navigable. Emotional reactions to the diagnosis remained mostly cancer-centric rather than HPV-centric. A patient-education handout was developed in response to patient questions., Conclusions: Additional educational resources explaining the facts about HPV in HNSCC in a consistent way including content of highest priority to patients may improve understanding of HPV., (Copyright © 2012 Wiley Periodicals, Inc.)