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Background/aim: Definitive treatment for locally advanced head and neck squamous cell carcinoma (LAHNSCC) is often compromised in older adults due to concerns about potential treatment toxicity intolerance. We reviewed our institutional experience with definitive management of older adults with LAHNSCC., Patients and Methods: From our Institutional Review Board-approved registry, we identified patients aged >60 years with stage III-IV, M0 LAHNSCC (seventh/earlier editions of the American Joint Committee on Cancer classification) treated with definitive radiotherapy from 1993-2019. Indications for concurrent chemotherapy included T3-4 or N2-3 disease. Multivariable analysis using Fine and Gray regression was performed to identify risk factors associated with recurrence. The cumulative incidence method was used to calculate recurrence rates., Results: Overall, 350 patients were identified: 223 aged 60-69, 82 aged 70-74, and 45 aged ≥75 years. Median follow-up was 36.3 months. Two-year recurrence rates were 13.7%, 20.2% and 34.8%, respectively; human papillomavirus-positive disease was present in 190 (85%), 44 (54%), and 25 (56%), respectively; and systemic therapy was given to 194 (87%), 64 (88%), and 23 (56%) patients, respectively. Factors significantly associated with increased risk of recurrence included age ≥75 years, Karnofsky performance status 70-80, clinical N2c-N3, and Charlson score 2-3., Conclusion: Patients aged ≥75 years received less aggressive therapy and experienced increased recurrence compared to younger patients. Outcomes for those aged 70-74 years were similar to younger patients treated with aggressive therapy, despite their inferior performance status/comorbidity, and such patients should not routinely be excluded from standard-of-care therapy. Further study is needed to optimize therapy for a redefined older adult (age ≥75 years) population., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The prognostication of Epstein-Barr virus (EBV) and human papillomavirus (HPV) status in nasopharyngeal cancer (NPC) is unclear., Methods: This retrospective study analyzed NPC from 2000 to 2019., Results: Seventy-eight patients were included: 43 EBV + , 12 HPV + , 23 EBV - /HPV - , and 0 EBV + /HPV + . All p16 + tumors were also positive for HPV-CISH. Baseline characteristics were not different between groups except age, N-classification, and Karnofsky Performance Scale (KPS) (p < 0.05). For EBV + , HPV + , and EBV - /HPV - respectively, 3-year overall survival (OS) was 89.9%, 69.8%, and 52.5% (p = 0.006). EBV - /HPV - status was significantly associated with worse OS but not freedom from progression (FFP) on univariate analysis, and did not remain a significant predictor of OS after adjusting for KPS, age, and group stage., Conclusions: EBV + NPC tumors were seen in younger, healthier patients than HPV + and EBV - tumors, and there were no cases of coinfection. The association of viral status with OS was insignificant after adjusting for KPS and age., (© 2022 Wiley Periodicals LLC.)

Objectives: Patients with human papillomavirus (HPV) associated squamous cell carcinoma of the oropharynx (SCC-OP) have improved overall survival (OS) after distant metastasis (DM) compared to HPV negative patients. These patients may be appropriate candidates for enrollment on clinical trials evaluating the efficacy of metastasis-directed therapy (MDT). This study seeks to identify prognostic factors associated with OS after DM, which could serve as enrollment criteria for such trials., Materials and Methods: From an IRB approved multi-institutional database, we retrospectively identified patients with HPV/p16 positive SCC-OP diagnosed between 2001 and 2018. Patterns of distant failure were assessed, including number of lesions at diagnosis and sites of involvement. The primary outcome was OS after DM. Prognostic factors for OS after DM were identified with Cox proportional hazards. Stepwise approach was used for multivariable analysis., Results: We identified 621 patients with HPV-associated SCC-OP, of whom 82 (13.2%) were diagnosed with DM. Median OS after DM was 14.6 months. On multivariable analysis, smoking history and number of lesions were significantly associated with prolonged OS. Median OS after DM by smoking (never vs ever) was 37.6 vs 11.2 months (p = 0.006), and by lesion number (1 vs 2-4 vs 5 or more) was 41.2 vs 17.2 vs 10.8 months (p = 0.007)., Conclusion: Among patients with newly diagnosed metastatic HPV-associated SCC-OP, lesion number and smoking status were associated with significantly prolonged overall survival. These factors should be incorporated into the design of clinical trials investigating the utility of MDT, with or without systemic therapy, in this population., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: De-intensified treatment strategies for early human papillomavirus-positive (HPV+) oropharynx cancer (OPC) rely on selecting patients with an excellent prognosis. The criterion for enrollment in current de-intensification trials is ≤10 pack-years. More nuance to the pack-year criteria may expand enrollment, improve patient outcomes, and prevent overtreatment. It was hypothesized that patients with more than 10 pack-years may experience favorable outcomes if smoking cessation has been achieved., Methods: From an institutional review board-approved database, patients with HPV+ oropharyngeal squamous carcinoma treated definitively with radiation with or without chemotherapy were retrospectively identified. Patients with a history of smoking who were eligible for national de-intensification trials were included (cT1-2N1-2b or T3N0-2b [American Joint Committee on Cancer, seventh edition]). Cox regression with penalized smoothing splines was used to evaluate nonlinear effects of cessation. Recursive partitioning analysis (RPA) was used to objectively search for relationships between the 2 colinear variables (pack-years and time since cessation)., Results: Among 330 patients meeting the inclusion criteria, 130 (40%) were never smokers, 139 (42%) were former smokers, and 61 (18%) were current smokers. With standard therapy, all former smokers achieved a progression-free survival (PFS) rate higher than 91%, regardless of pack-year exposure. Nonlinear Cox regression demonstrated that more recent cessation was associated with significantly worse PFS even among those with ≤20 pack-years. RPA demonstrated that only current smokers experienced a 2-year PFS rate lower than 91%; former smokers, regardless of pack-years, experienced a 2-year PFS rate higher than 91%., Conclusions: The 10-pack-year rule may not apply to all early HPV+ OPCs, particularly for former smokers. Future randomized de-intensification trials should consider a broader and more nuanced approach until the predictive role of smoking status is established., (© 2020 American Cancer Society.)

Objectives: This study examines the utility of surveillance imaging in detecting locoregional failures (LRF), distant failures (DF) and second primary tumors (SPT) in patients with human papillomavirus (HPV) associated oropharyngeal cancer (OPC) after definitive chemoradiotherapy (CRT)., Methods and Materials: An institutional database identified 225 patients with biopsy proven, non- metastatic HPV+ OPC treated with definitive CRT between 2004 and 2015, whose initial post-treatment imaging was negative for disease recurrence (DR). Two groups were defined: patients with <2 scans/year Group 1 and patients with ≥2 scans/year Group 2. The Mann-Whitney test or Chi-square was used to determine differences in baseline characteristics between groups. Fine & Gray regression was used to detect an association between imaging frequency, DR and diagnosis of SPT., Results: Median follow up was 40.8 months. 30% of patients had ≥T3 disease and 90% had ≥ N2 disease (AJCC 7th edition). Twenty one failures (9.3%) were observed, 7 LRF and 15 DF. Six LRF occurred within 24 months and 14 DF occurred within 36 months of treatment completion. Regression analysis showed Group 2 had increased risk of DR compared to Group1 (HR 10.3; p = 0.002) albeit with more advanced disease at baseline. Five SPT were found (2 lung, 2 esophagus, and 1 oropharynx) between 4.5 and 159 months post-CRT., Conclusion: Surveillance imaging seems most useful in the first 2-3 years post treatment, and is particularly important in detecting DF. Surveillance scans for SPT has a low yield, but should be considered for those meeting lung cancer screening guidelines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The role of smoking among patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is unclear., Methods: A retrospective cohort study of patients with HPV(+) OPSCC from 2001 to 2015 at a tertiary-care institution was conducted. The primary outcome was overall survival (OS)., Results: Among 484 included patients, 94 (19.4%) were active smokers, 226 (46.7%) were former smokers, and 164 (33.9%) never smoked. Among active smokers, 82 patients (87.2%) had a ≥10 pack-year and 69 (73.4%) had a ≥20 pack-year smoking history. After adjusting for covariates, active smoking was a significant predictor of inferior OS (HR 2.28, P < .001) and PFS (HR 2.26, P < .001). When including pack-years as the covariate, ≥20 pack-years predicted a decreased effect-size for inferior OS and PFS., Conclusions: For patients with HPV(+) OPSCC, active smoking at diagnosis is the most powerful covariate capturing smoking history to predict OS and PFS., (© 2019 Wiley Periodicals, Inc.)

Objectives/hypothesis: Patients with human papillomavirus (HPV)-induced cancer of unknown primary (CUP) are generally excluded from clinical trials, despite surgical series reporting detection rates of occult oropharynx primaries of >80%. We performed a matched-pair analysis to compare outcomes between T0N1-3M0 HPV+ CUP and T1-2N1-3M0 HPV+ oropharynx known primary (OPX)., Study Design: Retrospective cohort study at a single institution., Methods: Patients with early T stage, node positive HPV+ OPX or CUP treated with curative intent between 1998 and 2016 were identified. For a subgroup of CUP patients with an unknown HPV status, we imputed HPV status and included patients with a >80% probability of being HPV+. Cohorts were matched based on patient demographics using a nearest neighbor propensity technique. After matching, patients were grouped according to either a favorable or unfavorable risk stratification designations per current NRG Oncology clinical trial enrollment criteria. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan-Meier analysis., Results: Of 298 patients with T1-2N1-3 OPX, 48 were matched to 48 HPV+ CUP patients (32 with confirmed and 16 imputed HPV status). Median follow-up for CUP (34.1 months) and OPX (27.8 months) patients were similar (P = .23).There were no significant differences between the CUP and OPX groups for 3-year DFS (89% vs. 85%, P = .44), and 3-year OS (91% vs. 91%, P = .11), respectively., Conclusions: Patients with T0N+M0 HPV-induced CUP have similar survival outcomes to matched patients with T1-2N+M0 HPV+ OPX. These patients can reasonably be included in clinical trials investigating the role of treatment deintensification and risk stratified similar to patients with early-stage known primary OPX cancer., Level of Evidence: 4. Laryngoscope, 128:1379-1385, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To analyze a cohort of patients with HPV positive, oropharyngeal squamous cell carcinoma (OPSCC) treated with lower radiation dose to clinically involved lymph nodes., Materials and Methods: We retrospectively identified patients with HPV positive, OPSCC treated with definitive chemoradiotherapy (70-74.4Gy) to the primary site and, since a post-radiation neck dissection was planned, 54Gy to the involved nodal areas. Neck dissection was ultimately omitted in all cases due to complete response. All patients were treated with a 3 field approach with sequential boost plans. Composite plans were generated retrospectively and primary tumor and lymph node GTVs were contoured and nodes were expanded by 5mm to form a CTV. Mean dose, dose to 95% (D95) and dose to 99% (D99) were determined., Results: Fifty patients treated from 2008 to 2010 with 113 involved nodes were identified. The median age was 57years, and 6%, 46%, and 48% were current, former, and never smokers. Ninety percent of patients received concurrent cisplatin based chemotherapy. Median D95 and D99 to involved nodes were 59.8Gy and 55.9Gy respectively. At a median follow up of 54.1months, two patients developed nodal failure and four developed metastatic disease. Five year loco-regional control, disease free survival and overall survival were 96%, 81% and 86% respectively., Conclusion: In this exploratory analysis, regional lymph node control in HPV positive oropharyngeal cancer was not compromised by dose de-escalated radiotherapy to involved nodes in the setting of concurrent cisplatin based chemotherapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)