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What is the best way to manage patients with intermediate-risk prostate cancer? One of the most controversial aspects of treatment is the role of short-term androgen deprivation therapy in combination with definitive radiotherapy. In two randomised trials of patients with mostly intermediate-risk prostate cancer, increased overall survival was reported when short-term androgen deprivation therapy was added to radiotherapy. However, radiation doses in these studies were far below the current standard of care. This limitation, in combination with the heterogeneous nature of the cancers classified as intermediate risk, has complicated the application of these trial results to modern clinical practice. In this Review, we discuss clinical evidence for and against use of short-term androgen deprivation therapy with dose-escalated radiotherapy for patients with intermediate-risk prostate cancer. [ABSTRACT FROM AUTHOR]

NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug-drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug-radiotherapy combinations., Competing Interests: Declaration of interests JMB received grants or contracts from the National Institutes of Health (NIH); royalties or licences from UpToDate; and has a leadership or fiduciary role in other board, society, committee, or advocacy group (paid or unpaid) for the American Society for Radiation Oncology (ASTRO) and is on the Board of Directors as Science Council Chair. SEF reports ongoing research with Novartis and Bayer; received consulting fees from Lantheas, Progenics, Blue Earth, Bayer, Astellas, Pfizer, and Jaansen; payment or honoraria as a speaker for Lantheas, Progenics, Blue Earth, Bayer, Astellas, Pfizer, and Jaansen; participates on an advisory board at Lantheas, Progenics, Blue Earth, Bayer, Astellas, Pfizer, and Jaansen; and has a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid on the board of chancellors at the American College of Radiology. SKJ received grants or contracts from the National Cancer Institute, Merck, Beigene, Guardant, and Adlai made to their institution; consulting fees from Merck, AstraZeneca, Beigene, Radialogica, Syntactx, and IMX; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from ASTRO; is a senior editor at the International Journal of Radiation Biology Physics; received payment for expert testimony from Dechert; support for attending meetings and travel from ASTRO, AstraZeneca, and Merck; and participation on a data safety monitoring board for Advarra. RJK declares ongoing committee role at ASTRO and ongoing senior editor role at International Journal of Radiation Oncology Biology Physics; received grants or contracts from NIH and Bridge Bio to their institution; received consulting fees from HunaTek and Guidepoint Global; has patents planned, issued, or pending with University of Wisconsin; and has leadership or fiduciary role in other board, society, committee, or advocacy group, unpaid with ASTRO. SHL received grants from Beyond Spring, STCube Pharmaceuticals, and Nektar Therapeutics; consulting fees from XRAD Therapeutics; support for attending meetings and travel from AstraZeneca; participated on an advisory board for AstraZeneca and Creatv Microtech; and has stock or stock options from Seek Diagnostics. AMM received consulting fees from AstraZeneca, Merck, Varian Medical Systems, Kortuc, and Siemens; payment for expert testimony from Arizona Legal Group; support for attending meetings and travel from NRG Oncology; and has a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid at American Brachytherapy Society. JM declares in the last 36 months grants or contracts from NIH, Merck, BMS, Genentech, Incyte, Trisalus, Transgene, and EMD Serono; consulting fees from GLG and Guidepoint; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the Association of Northern California Oncologists; participation on a data safety monitoring board or advisory board at Multiplex Thera; and stock or stock options from Multiplex Thera. SPP received grants or contracts from Amgen, AstraZeneca, MedImmune, A2bio, Bristol Myers Squibb, Eli Lilly, Fate Therapeutics, Gilead, Iovance, Merck, Pfizer, and Roche Genentech; and consulting fees from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Certis, Eli Lilly, Jazz, Genentech, Illumina, Merck, Pfizer, Signatera, and Tempus. SS received grants or contracts from Merck, Regeneron, Exelixis, and Innovio; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Exelixis and Medscape; and participated on a data safety monitoring board or advisory board at Luminos, Eisai, and Naveris. MX-W received grants or contracts from NCI; consulting fees from Eli Lilly and Novocure; and participated on a data safety monitoring board or advisory board for Eli Lilly. ZSZ has a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid at the American Board of Radiology. KRP and PAT-S are employed by the NIH. TMW declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Circulating tumor DNA assays have robust potential as molecular surveillance tools. They may also exacerbate patient distress without improving outcomes. We investigate patient acceptability of a validated ctHPVDNA assay (NavDx) during cancer surveillance for HPV(+) oropharyngeal cancer (OPC)., Methods: Consented HPV(+) OPC participants completed the NCCN Distress Thermometer, the Hospital Anxiety Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-General (FACT-G) scale both (1) before NavDx blood draw, and (2) after results were provided. Patients then completed a series of focused questions related to their perceptions of the assay., Results: Overall, 55 patients completed the study, with 98.2 % showing no recurrence. For the NCCN Distress Thermometer, median patient distress decreased (2.0 (IQR 1-5) vs. 1.0 (IQR 0-3)) (p < 0.001) in association with NavDx. Using scores ≥ 4 as a cutoff point to define clinically elevated distress, scores also improved (36.4 % vs. 18.2 %, p = 0.031). For HADS, anxiety significantly improved (5.0 (IQR 2.0-7.0) vs. 3.0 (IQR 1.0-6.5)) (p = 0.037), but not depression (3.0 (IQR 1.0-7.0) vs. 3.0 (IQR 1.0-6.5)) (p = 0.870). FACT-G scores showed no substantial differences. On survey questionnaires, 95.5 % of patients believed the test to be helpful, and 100 % felt "somewhat" or "extremely" confident in the assay as a monitoring tool. While 59.1 % felt that it reduced anxiety, 88.4 % concordantly felt that it did not introduce anxiety., Conclusion: ctHPVDNA as a molecular surveillance tool reduced distress levels in HPV(+) OPC patients, with notably high patient confidence in the approach. Further investigation is warranted to judiciously incorporate this emerging modality in surveillance guidelines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Zumsteg’s spouse does legal work for Johnson & Johnson, Merck, Allergan, and Boehringer Ingelheim through her law firm]., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: As a surrogate of malnutrition, degree of weight loss and recovery from head and neck cancer (HNC) treatment is understudied. The influence of modifiable factors that affect weight, including speech/language pathology (SLP) and nutrition counseling, is also poorly defined. We characterize weight loss trends, baseline weight recovery (BWR), and the impact of interdisciplinary care on oncologic outcomes., Methods: Retrospective cohort study assessing 266 newly diagnosed patients with HNC who completed curative-intent radiation (definitive or adjuvant) between January 2016 to January 2022. Relevant treatment factors were analyzed using multivariable Cox regression models., Results: Altogether, 266 patients completed full-course radiation therapy (RT), encompassing definitive chemoRT (53.0%), surgery with chemoRT (18.4%), surgery with RT (17.7%), and RT alone (10.9%). Patient weight reached a nadir at median 3.0 months (IQR 3.0-11.3) after radiation, with a median weight loss of 12.6% (IQR 7.9-18.7). Notably, only 47.4% exhibited BWR. For those who recovered, median time to BWR was 10.5 months (IQR 3.0-24.0). On multivariable analysis, BWR by 6 months was significantly associated with overall survival (HR 0.28 [95% CI 0.10-0.76], p = 0.013), as was SLP consultation (HR 0.40 [95% CI 0.17-0.92], p = 0.031) and nutrition consultation (HR 0.34 [95% CI 0.13-0.89], p = 0.028)., Conclusion: A high proportion of patients with HNC fail to recover baseline weight after treatment; those that do can take longer than expected to return. Failure to recover baseline weight is associated with a notable decrease in survival. Similarly, SLP and nutrition consultation are independent, modifiable determinants correlated with outcomes, supporting the emphasis on multidisciplinary management. Measures to promote BWR may reduce mortality., (© 2024 Wiley Periodicals LLC.)

Background: While both the number (+LN) and density (LND) of metastatic lymph nodes on radical prostatectomy lymphadenectomy predict mortality in prostate cancer, the independent impact of each on overall mortality (OM) is unknown., Methods: We sampled men who underwent radical prostatectomy and lymphadenectomy between 2004 and 2013 from the National Cancer Database. Multivariable Cox proportional hazards analysis with restricted cubic spline was used to assess the non-linear association of +LN count and LND with OM., Results: Of 229,547 men in our sample, 3% (n = 7507) had +LNs, of which 89% had 1-3 +LN and 11% had ≥4 +LN. In multivariable Cox analysis across all patients, OM increased with each additional +LN up to four (HR 1.14, 95%CI 1.06-1.23 per node), with no increase beyond 4 +LN. LND was an independent predictor of OM (HR 1.09, 95%CI 1.06-1.12 per 10% increase). However, after excluding patients with inadequate nodal sampling (<5 LN examined), the variation in OM explained by LND was negligible for patients with ≤3 +LN. In men with 1, 2, and 3 +LN, there was a 0.28%, 0.02%, and 0.50% increase in OM for each 10% increase in LND, compared with 1.9% and 1.6% for men with 4 or 5+ LNs., Conclusions: While +LN count and LND independently predict OM, the impact of LND is negligible in men with ≤3 +LN, who comprise the vast majority of men with +LN. Pathological nodal staging should primarily rely on LN count rather than LND., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The incidence of oral tongue cancers has increased since the 1980s among US men and women for unknown reasons. We investigated associations of inflammatory tongue conditions with risk of cancers of the oral tongue, other oral cavity, and oropharynx among the US elderly individuals (age 65 years or older)., Methods: We conducted a case-control study (2,534 oral tongue cancers, 6,832 other oral cavity cancers, 9,373 oropharyngeal cancers, and 200,000 controls) within the SEER-Medicare data set (1992-2013). Medicare records were used to identify patients with clinically diagnosed inflammatory tongue conditions (glossitis, benign migratory glossitis, median rhomboid glossitis, atrophic glossitis, glossodynia, other specified conditions [eg, atrophy and hypertrophy], and other unspecified conditions) and oral precancer (leukoplakia/erythroplakia). Only conditions preceding cancer/control selection by >12 months were included., Results: The prevalence of inflammatory tongue conditions was significantly higher in patients with tongue cancer than controls (6.0% v 0.6%; odds ratios [ORs], adjusted for age, sex, race, Medicare utilization, and precancer, 5.8 [95% CI, 4.7 to 7.2]). This overall association primarily arose from glossitis, 5.6 (95% CI, 4.4 to 7.2); other specified conditions, 9.1 (95% CI, 5.5 to 15.2); and other unspecified conditions, 13.7 (95% CI, 8.0 to 23.7). These associations remained strongly elevated >5 years preceding tongue cancer (arguing against reverse causation), for conditions diagnosed by a specialist (arguing against misclassification), and among patients who received an oral biopsy (arguing against missed cancer). During 2013, an estimated 1 in 11 patients with oral tongue cancer had a preceding diagnosis of inflammatory tongue conditions. Associations of inflammatory tongue conditions were relatively weak for other oral cavity cancers (ORs, 1.8 [95% CI, 1.5 to 2.3]) and oropharyngeal cancer (OR, 1.3 [95% CI, 1.0 to 1.6]) and were observed only closest to cancer diagnosis., Conclusion: Inflammatory tongue conditions were associated with strongly increased risks of oral tongue cancers and preceded cancer diagnosis by several years, underscoring the need for increased clinical surveillance among patients with such apparently benign diagnoses.

Objective: To characterize malpractice trends related to active surveillance (AS) as a treatment strategy across cancers., Background: Active surveillance is increasingly considered a viable management strategy for low-risk cancers. Since a subset of AS cases will progress, metastasize, or exhibit cancer-related mortality, a significant barrier to implementation is the perceived risk of litigation from missing the window for cure. Data on malpractice trends across cancers are lacking., Methods: Westlaw Edge and LexisNexis Advance databases were searched from 1990 to 2022 for malpractice cases involving active surveillance in conjunction with thyroid cancer, prostate cancer, kidney cancer, breast cancer, or lymphoma. Queries included unpublished cases, trial orders, jury verdicts, and administrative decisions. Data were compiled on legal allegations, procedures performed, and verdicts or settlements rendered., Results: Five prostate cancer cases were identified that pertained to active surveillance. Two cases involved alleged deliberate indifference from AS as a management strategy but were ruled as following the appropriate standard of care. In contrast, 3 cases involved alleged physician negligence for not explicitly recommending AS as a treatment option after complications from surgery occurred. All cases showed documented informed consent for AS, leading to defense verdicts in favor of the physicians. No cases of AS-related malpractice were identified for other cancer types., Conclusions: To date, no evidence of successful malpractice litigation for active surveillance in cancer has been identified. Given the legal precedent detailed in the identified cases and increasing support across national guidelines, active surveillance represents a sound management option in appropriate low-risk cancers, with no increased risk of medicolegal exposure., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Strategies are needed to better identify patients that will benefit from immunotherapy alone or who may require additional therapies like chemotherapy or radiotherapy to overcome resistance. Here we employ single-cell transcriptomics and spatial proteomics to profile triple negative breast cancer biopsies taken at baseline, after one cycle of pembrolizumab, and after a second cycle of pembrolizumab given with radiotherapy. Non-responders lack immune infiltrate before and after therapy and exhibit minimal therapy-induced immune changes. Responding tumors form two groups that are distinguishable by a classifier prior to therapy, with one showing high major histocompatibility complex expression, evidence of tertiary lymphoid structures, and displaying anti-tumor immunity before treatment. The other responder group resembles non-responders at baseline and mounts a maximal immune response, characterized by cytotoxic T cell and antigen presenting myeloid cell interactions, only after combination therapy, which is mirrored in a murine model of triple negative breast cancer., Competing Interests: Declaration of interests H.L.M. has received consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience, and TapImmune. H.L.M. has received research support from Bristol-Myers Squibb; MedImmune, LLC/AstraZeneca; BTG; and Merck. R.B. has received research support (to the institution) from Genentech, AstraZeneca, Merck, Takeda, Eli Lilly, Pfizer, and Seattle Genetics, has received consulting fees from Pfizer, AstraZeneca, Seattle Genetics, and Gilead, and has received compensation to serve as a speaker/panelist for MJH Healthcare, Eli Lilly, and Curio Science. S.L.S. has received project-based research funding from Merck outside of the submitted work. S.R.V.K. is a founder and consultant at Faeth Therapeutics and Transomic Technologies. None of these disclosures are related to this work. No other potential disclosures are reported by any of the authors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The emergence of human papillomavirus (HPV)-positive oropharyngeal cancer and evolving tobacco use patterns have changed the landscape of head and neck cancer epidemiology internationally. We investigated updated trends in oropharyngeal cancer incidence worldwide., Methods: We analyzed cancer incidence data between 1993 and 2012 from 42 countries using the Cancer Incidence in Five Continents database volumes V through XI. Trends in oropharyngeal cancer incidence were compared with oral cavity cancers and lung squamous cell carcinomas using log-linear regression and age period-cohort modeling., Results: In total, 156 567 oropharyngeal cancer, 146 693 oral cavity cancer, and 621 947 lung squamous cell carcinoma patients were included. Oropharyngeal cancer incidence increased (P < .05) in 19 and 23 countries in men and women, respectively. In countries with increasing male oropharyngeal cancer incidence, all but 1 had statistically significant decreases in lung squamous cell carcinoma incidence, and all but 2 had decreasing or nonsignificant net drifts for oral cavity cancer. Increased oropharyngeal cancer incidence was observed both in middle-aged (40-59 years) and older (≥60 years) male cohorts, with strong nonlinear birth cohort effects. In 20 countries where oropharyngeal cancer incidence increased for women and age period-cohort analysis was possible, 13 had negative or nonsignificant lung squamous cell carcinoma net drifts, including 4 countries with higher oropharyngeal cancer net drifts vs both lung squamous cell carcinoma and oral cavity cancer (P < .05 for all comparisons)., Conclusions: Increasing oropharyngeal cancer incidence is seen among an expanding array of countries worldwide. In men, increased oropharyngeal cancer is extending to older age groups, likely driven by human papillomavirus-related birth cohort effects. In women, more diverse patterns were observed, suggesting a complex interplay of risks factors varying by country, including several countries where female oropharyngeal cancer increases may be driven by HPV., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chondrosarcoma is a type of an endochondral bone malignancy that is primarily treated surgically with radiation therapy used in the adjuvant setting or in cases of unresectable disease. Proton therapy has potential advantages compared with traditional photon therapy for the treatment of tumors in close proximity to critical structures due to the theoretic lower exit dose. Studies have shown improved survival in patients with skull base chondrosarcoma who undergo proton therapy. However, there is a lack of randomized data. Further studies are needed to define the role of proton therapy in the treatment of skull base chondrosarcoma., Competing Interests: Conflict of Interest D.M.T. is a consultant for Acclarent, Inc. and 3-D Matrix. A.W.W. is a consultant for 3-D Matrix., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: Elective lymph node dissection (ELND) is performed for many early-stage oral cavity squamous cell carcinomas (OCSCC) with clinically negative necks (cN0), often guided by depth of invasion (DOI). However, DOI is less validated in non-tongue OC sites, and often correlates with other adverse features. We sought to evaluate the utility of DOI versus other factors for independently predicting pathologic lymph node positivity (pN+) in patients with cN0 OCSCC., Methods: Patients with cN0 OCSCC diagnosed from 2010 to 2015 undergoing primary surgery were identified in the National Cancer Data Base., Results: 5060 cN0 OCSCC patients met inclusion criteria. The presence of lymphovascular invasion (LVI) was the strongest independent predictor of pN+ (odds ratio [OR] = 4.27, 95% confidence interval [CI] 3.36-5.42, P < 0.001). High histologic grade also strongly predicted pN+ (OR 3.33, 95% CI 2.20-4.60, P < 0.001). DOI had no association with the likelihood of pN+ among all OCSCC patients, but was predictive among patients within the oral tongue subset (OR 2.01, 95% CI 1.08-3.73, P = 0.03 for DOI > 20 mm vs. DOI: 2.0-3.99 mm)., Conclusion: LVI and grade are the strongest independent predictors of pN+ in cN0 OCSCC. Contrary to prior studies, DOI was not found to be a predictor of pN+ among patients with cN0 OCSCC. However, DOI was a predictor of pN+ or the oral tongue subset, albeit still less strongly than LVI or grade. These findings could potentially be used to better identify a subset of cN0 OCSCC patients who could be considered for omission of ELND in future studies., 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. Dr. Zumsteg's spouse previously performed legal work for Johnson & Johnson, Allergan, Merck, and Boehringer Ingelheim through her law firm., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The comparative impact of histologic variants and grade has not been well described., Methods: Salivary cancer histologies were profiled using hospital and population-based cancer registries. Multivariable models were employed to assess relationships between histology, grade, and survival., Results: On univariate analysis, histologic variants exhibited a wide spectrum of mortality risk (5-year overall survival (OS): 86% (acinic cell carcinoma), 78% (mucoepidermoid carcinoma), 72% (adenoid cystic carcinoma), 64% (carcinoma ex-pleomorphic adenoma), 52% (adenocarcinoma NOS), and 47% (salivary duct carcinoma) (p < 0.001). However, on multivariable analysis these differences largely vanished. Worsening grade corresponded with deteriorating survival (5-year OS: 89% [low-grade], 81% [intermediate-grade], 45% [high-grade]; p < 0.001), which was upheld on multivariable analysis and propensity score matching. Recursive partitioning analysis generated TNM + G schema (c-index 0.75) superior to the existing system (c-index 0.73)., Conclusion: Grade represents a primary determinant of salivary cancer prognosis. Integrating grade into stage strengthens current staging systems., (© 2023 Wiley Periodicals LLC.)

Background: Elective neck dissection is a standard of care for pharynx and most larynx cancer patients undergoing surgery, based largely on historical series. It is unclear if this is necessary for all patients in the modern era., Methods: Patients with cN0 oropharynx, larynx, and hypopharynx cancers diagnosed from 2010-2015 undergoing primary surgery were identified in the National Cancer Data Base., Results: Inclusion criteria were met by 4117 cN0 patients. The presence of lymphovascular invasion (LVI) was the strongest independent predictor of pN+ (odds ratio [OR] = 4.19, 95% confidence interval [CI] 3.56-4.93, p < 0.001). Histologic grade strongly predicted pN+ (OR 2.58, 95% CI 1.88-3.59, p < 0.001). A nomogram predicted less than 10% of cN0 patients had pN+ risk <15%., Conclusion: LVI and grade are the strongest predictors of pN+ among patients with cN0 pharynx and larynx cancer. Even in the modern era, pN+ rates warrant neck dissection for cN0 patients., Level of Evidence: 3 Laryngoscope, 133:1660-1666, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer., Materials and Methods: NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; [BF1]) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; [BF2]), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average R 2 between treatment hazard ratios for ICE and OS)., Results: BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated ( R 2 = 0.67), but this was not true for BF1 ( R 2 = 0.09), BF2 ( R 2 = 0.12), or DM ( R 2 = 0.18) and OS., Conclusion: MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.

Importance: Unlike for prostate cancer, active surveillance for thyroid cancer has not achieved wide adoption. The parameters by which this approach is feasible are also not well defined, nor is the effect of patient anxiety., Objective: To determine if expanded size/growth parameters for patients with low-risk thyroid cancer are viable, as well as to assess for cohort differences in anxiety., Design, Setting, and Participants: This prospective nonrandomized controlled trial was conducted at a US academic medical center from 2014 to 2021, with mean [SD] 37.1 [23.3]-month follow-up. Of 257 patients with 20-mm or smaller Bethesda 5 to 6 thyroid nodules, 222 (86.3%) enrolled and selected treatment with either active surveillance or immediate surgery. Delayed surgery was recommended for size growth larger than 5 mm or more than 100% volume growth. Patients completed the 18-item Thyroid Cancer Modified Anxiety Scale over time., Interventions: Active surveillance., Main Outcomes and Measures: Cumulative incidence and rate of size/volume growth., Results: Of the 222 patients enrolled, the median (IQR) age for the study population was 46.8 (36.6-58) years, and 76.1% were female. Overall, 112 patients (50.5%) underwent treatment with active surveillance. Median tumor size was 11.0 mm (IQR, 9-15), and larger tumors (10.1-20.0 mm) comprised 67 cases (59.8%). One hundred one (90.1%) continued to receive treatment with active surveillance, 46 (41.0%) had their tumors shrink, and 0 developed regional/distant metastases. Size growth of more than 5 mm was observed in 3.6% of cases, with cumulative incidence of 1.2% at 2 years and 10.8% at 5 years. Volumetric growth of more than 100% was observed in 7.1% of cases, with cumulative incidence of 2.2% at 2 years and 13.7% at 5 years. Of 110 patients who elected to undergo immediate surgery, 21 (19.1%) had equivocal-risk features discovered on final pathology. Disease severity for all such patients remained classified as stage I. Disease-specific and overall survival rates in both cohorts were 100%. On multivariable analysis, immediate surgery patients exhibited significantly higher baseline anxiety levels compared with active surveillance patients (estimated difference in anxiety scores between groups at baseline, 0.39; 95% CI, 0.22-0.55; P < .001). This difference endured over time, even after intervention (estimated difference at 4-year follow-up, 0.50; 95% CI, 0.21-0.79; P = .001)., Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that a more permissive active surveillance strategy encompassing most diagnosed thyroid cancers appears viable. Equivocal-risk pathologic features exist in a subset of cases that can be safely treated, but suggest the need for more granular risk stratification. Surgery and surveillance cohorts possess oppositional levels of worry, elevating the importance of shared decision-making when patients face treatment equivalence., Trial Registration: ClinicalTrials.gov Identifier: NCT02609685.

Sociodemographic and lifestyle factors may play a role in determining whether patients with clinically localized prostate cancer (PC) are managed with active surveillance (AS), radical prostatectomy (RP), or radiation therapy (RT); however, these relationships have not been well examined. In a cross-sectional study conducted within an equal access healthcare system, multivariable adjusted regression analysis revealed that living with a spouse or partner was associated with a 65% lower chance of being managed by RT (P = 0.001) and 57% lower risk of being managed by AS (P = 0.042) compared with RP. No other sociodemographic or lifestyle factors were independently associated with treatment modality., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: A better understanding of the relationship between the spread of head and neck squamous cell carcinoma (HNSCC) to regional lymph nodes (LNs) and the frequency and manner of treatment failure should help design better treatment intensification strategies. In this study, we evaluated the relationship between recurrence patterns, mortality, and number of pathologically positive (+) LNs in HNSCC in 3 prospective randomized controlled trials., Methods and Materials: We performed a secondary analysis of 947 patients with HNSCC enrolled in RTOG 9501 (n = 410), RTOG 0234 (n = 203), and EORTC 22931 (n = 334) undergoing surgery and postoperative radiation ± systemic therapy. Multivariable models were constructed for overall survival (OS), disease-free survival (DFS), locoregional relapse (LRR), and distant metastases (DM). Restricted cubic splines were used to model the nonlinear relationship between +LN number and outcomes., Results: In multivariable analysis, OS and DFS decreased with each +LN without plateau, most pronounced up to 5 +LNs (OS: hazard ratio [HR], 1.21 per +LN; 95% confidence interval [CI], 1.10-1.34; P < .001; DFS: HR per +LN, 1.19; 95% CI, 1.08-1.30; P < .001) and more gradually beyond this (OS: HR per +LN, 1.02; 95% CI, 1.01-1.06; P < .001; DFS: HR per +LN, 1.04; 95% CI, 1.02-1.06; P < .001). In contrast to LRR risk, which increased sharply up to 5 +LNs (HR per +LN, 1.28; 95% CI, 1.10-1.50; P < .001) but plateaued beyond this (HR per +LN, 1.00; 95% CI, 0.96-1.04; P = .98), DM risk increased continuously with increasing +LNs (≤5 +LNs: HR per +LN, 1.10; 95% CI, 1.01-1.20; P = .04; >5 +LNs: HR per +LN, 1.05; 95% CI, 1.02-1.08; P = .003)., Conclusions: In high-risk resected HNSCC, increased mortality was associated with increased +LN count. LRR and DM risk both increased in parallel up to 5 +LNs, but only DM continued to increase for further +LN increases. These differing recurrence patterns can help inform design of future treatments., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Nodal staging systems vary substantially across solid tumors, implying heterogeneity in the behavior of nodal variables in various contexts. We hypothesized, in contradiction to this, that metastatic lymph node (LN) number is a universal and dominant predictor of outcome across solid tumors., Methods: We performed a retrospective cohort analysis of 1 304 498 patients in the National Cancer Database undergoing surgery between 2004 and 2015 across 16 solid cancer sites. Multivariable Cox regression analyses were constructed using restricted cubic splines to model the association between nodal number and mortality. Recursive partitioning analysis (RPA) was used to derive nodal classification systems for each solid cancer based on metastatic LN count. The reproducibility of these findings was assessed in 1 969 727 patients from the Surveillance, Epidemiology, and End Results registry. Two-sided tests were used for all statistical analyses., Results: Consistently across disease sites, mortality risk increased continuously with increasing number of metastatic LNs (P < .001 for all spline segments). Each RPA-derived nodal classification system produced multiple prognostic groups spanning a wide spectrum of mortality risk (P < .001). Multivariable models using these RPA-derived nodal classifications demonstrated improved concordance with mortality compared with models using American Joint Committee on Cancer staging in sites where nodal classification is not based on metastatic LN count. Each RPA-derived nodal classification system was reproducible in a large validation cohort for all-cause and cause-specific mortality (P < .001). High quantitative nodal burden was the single strongest tumor-intrinsic variable associated with mortality in 12 of 16 disease sites., Conclusions: Quantitative metastatic LN burden is a fundamental driver of mortality across solid cancers and should serve as a foundation for pathologic nodal staging across solid tumors., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Financial hardship is a growing concern for patients with cancer. Patients with head and neck cancer (HNC) are particularly vulnerable, given that a third leave the workforce following treatment. The goal of our study was to characterize financial hardship in the psychologic response (response to increased expenses) and coping behaviors (behaviors patients adopt to manage their care in the setting of increased expenses) domains in patients with HNC compared with patients with other cancers., Methods: This was a retrospective cohort study of nationally representative public survey data from 2013 to 2018 in the National Health Interviews Survey, an annual cross-sectional household survey. We included respondents age ≥ 18 years who reported a diagnosis of cancer and identified a subset of patients with HNC. Our main outcomes were financial hardship in the psychologic response and coping behaviors domains., Results: Our sample included a weighted population of 357,052 patients with HNC and 21.4 million patients with other cancers. Compared with patients with other cancers, patients with HNC reported greater levels of coping behaviors hardship (31% v 23%, P = .015), but similar levels of psychologic financial hardship (73% v 72%, P = .787). Medicaid or uninsured patients more often reported coping behaviors hardship. On multivariable analysis, HNC (odds ratio, 1.51; 95% CI, 1.01 to 2.24) was independently associated with coping behaviors hardship., Conclusion: To our knowledge, this is the first study to evaluate financial hardship in patients with HNC compared with patients with other cancers that includes Medicaid and uninsured patients, who are more often to have financial hardship. Patients with HNC have greater levels of hardship in the coping behaviors domain compared with patients with other cancers, but similar levels in the psychologic response domain., Competing Interests: Michelle L. MierzwaResearch Funding: Debiopharm Group Zachary S. ZumstegConsulting or Advisory Role: EMD Serono, Scripps Proton Therapy CenterOther Relationship: King and Spalding LLP Mark E.P. PrincePatents, Royalties, Other Intellectual Property: Receive royalties for several head and neck cancer cell lines managed by EMD Millipore Corp, US Patent US 7,723,112 B2. Compositions and Methods for Diagnosing and Treating Cancer Patents licensed to OncoMed. This is a method for sorting cancer cells to isolate cancer stem cells Lesly A. DossettResearch Funding: AHRQ Michelle M. ChenResearch Funding: NIHNo other potential conflicts of interest were reported.

Purpose: Prostate cancer pathological nodal staging uses a single category for all node-positive patients. We sought to improve risk stratification by creating and validating a novel pathological nodal staging system incorporating number of metastatic lymph nodes (+LNs)., Materials and Methods: A total of 118,450 men who underwent radical prostatectomy for nonmetastatic prostate cancer in the National Cancer Database comprised our development cohort. Multivariable Cox proportional hazards analysis with restricted cubic splines was used to assess the nonlinear association between number of +LNs and overall mortality (OM). A novel staging system based on number of +LNs was derived by recursive partitioning analysis. The staging system was validated for prediction of OM and prostate-specific mortality in 105,568 men with nonmetastatic prostate cancer undergoing radical prostatectomy from the Surveillance, Epidemiology, and End Results database. Discrimination was assessed via Harrell's c-index., Results: In multivariable Cox analysis, OM risk increased with higher number of +LNs up to 4 (HR 1.30 per each LN+, 95% CI 1.23-1.38), with a nonstatistically significant increase in risk (HR 1.05, 95% CI 0.99-1.11) beyond 4 +LN. In the development cohort, recursive partitioning analysis identified optimal cutoffs at 0 (N0: referent), 1 (N1: HR 1.40, 95% CI 1.25-1.58), 2 (N2: HR 1.67, 95% CI 1.40-1.99), 3-5 (N3a: HR 2.18, 95% CI 0.84-2.60) and ≥6 (N3b: HR 3.00, 95% CI 2.37-3.79) +LNs. In the validation cohort, these groups had markedly different 10-year OM (0+ LNs, N0: 15%; 1+ LN, N1: 35%; 2+ LNs, N2: 43%; 3-5 +LNs, N3a: 52%; and ≥6 +LNs, N3b: 59%; p <0.05) and prostate-specific mortality. The novel staging system improved survival classification over current staging for node-positive patients (optimism-corrected c-index 0.669 [95% CI 0.668-0.671] vs 0.649 [95% CI 0.648-0.651])., Conclusions: Pathological nodal staging in prostate cancer is improved with stratification by number of +LNs.

Deintensification therapy for human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV(+) OPSCC) is under active investigation. An adaptive treatment approach based on molecular stratification could identify high-risk patients predisposed to recurrence and better select for appropriate treatment regimens. Collectively, 40 HPV(+) OPSCC FFPE samples (20 disease-free, 20 recurrent) were surveyed using mass spectrometry-based proteomic analysis via data-independent acquisition to obtain fold change and false discovery differences. Ten-year overall survival was 100.0 and 27.7% for HPV(+) disease-free and recurrent cohorts, respectively. Of 1414 quantified proteins, 77 demonstrated significant differential expression. Top enriched functional pathways included those involved in programmed cell death (73 proteins, p = 7.43 × 10 -30 ), apoptosis (73 proteins, p = 5.56 × 10 -9 ), β-catenin independent WNT signaling (47 proteins, p = 1.45 × 10 -15 ), and Rho GTPase signaling (69 proteins, p = 1.09 × 10 -5 ). PFN1 ( p = 1.0 × 10 -3 ), RAD23B ( p = 2.9 × 10 -4 ), LDHB ( p = 1.0 × 10 -3 ), and HINT1 ( p = 3.8 × 10 -3 ) pathways were significantly downregulated in the recurrent cohort. On functional validation via immunohistochemistry (IHC) staining, 46.9% (PFN1), 71.9% (RAD23B), 59.4% (LDHB), and 84.4% (HINT1) of cases were corroborated with mass spectrometry findings. Development of a multilateral molecular signature incorporating these targets may characterize high-risk disease, predict treatment response, and augment current management paradigms in head and neck cancer.

Introduction: The addition of brachytherapy (BT) in high risk prostate cancer is supported by Level 1 evidence. Whether all high risk patients benefit from BT to the same extent is unknown. The National Cancer Database (NCDB) was used to investigate overall survival (OS) differences between GS 8 and 9-10 treated with external beam radiation (EBRT) only or BT +/- EBRT., Materials and Methods: We included localized prostate adenocarcinoma definitively treated with radiation between 2004-2014. Patients were stratified into various radiation treatment groups: EBRT 7560 - 8640 cGy, EBRT 5940 - 7540 cGy, and BT +/- EBRT. All EBRT only and BT +/- EBRT patients received ADT. A multivariable Cox proportional hazard model was used to assess OS. Propensity score matching was used to account for differences between groups. Median survival was determined based on Kaplan-Meier survival curves., Results: 30,698 patients were included. On multivariable analysis among GS 8 patients, BT was associated with improved OS compared to 7560 - 8640 cGy (HR-0.80 (95% CI 0.70-0.92, P = 0.002). In Gleason 9-10 BT did not result in improved OS compared to 7560 - 8640 cGy (HR- 0.91 (95% CI 0.79 - 1.05, P = 0.212). Results remained significant with propensity score matching and removing patients with medical comorbidities., Conclusion: BT was associated with improved OS when compared to 7560 - 8640 cGy in GS 8, but not in Gleason 9-10 disease. This hypothesis generating study suggests there may be variable benefit with BT in high risk prostate cancer patients on OS. Future prospective studies are needed to investigate whether the benefit of BT is similar across all high risk prostate cancer patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: Given the evolving patterns of lymph node evaluation for cutaneous melanoma, it is unclear whether the current nodal classification system will continue to accurately reflect prognosis in the modern era. Existing nodal staging for cutaneous melanoma was developed primarily for patients undergoing completion lymph node dissection (CLND) for node-positive disease and does not produce groups with continuously increasing mortality., Objective: To develop and validate a modified nodal classification system for cutaneous melanoma., Design, Setting, and Participants: This retrospective cohort analysis included 105 785 patients with cutaneous melanoma undergoing surgery and nodal evaluation from January 1, 2004, to December 31, 2015, in the National Cancer Database. Extent of lymph node dissection was available for patients diagnosed in 2012 and onward. Multivariable models were generated with number of positive lymph nodes modeled using restricted cubic splines. A modified nodal classification system was derived using recursive partitioning analysis (RPA). The proposed lymph node classification system was validated in 85 499 patients from the Surveillance, Epidemiology, and End Results (SEER-18) database. Data were analyzed from April 9, 2020, to May 28, 2021., Main Outcomes and Measures: Overall survival., Results: Among the 105 785 patients included in the analysis (62 496 men [59.1%]; mean [SD] age, 59.9 [15.5] years), number of positive lymph nodes (hazard ratio [HR] per lymph node for 0 to 2 positive lymph nodes, 2.48 [95% CI, 2.37-2-61; P < .001]; HR per lymph node for ≥3 positive lymph nodes, 1.10 [95% CI 1.07-1.13; P < .001]), clinically detected metastases (HR, 1.35; 95% CI, 1.27-1.42; P < .001), and in-transit metastases (HR, 1.48; 95% CI, 1.34-1.65; P < .001) were independently associated with mortality. An RPA-derived system using these variables demonstrated continuously increasing mortality for each proposed lymph node classification group, with HRs of 1.83 (95% CI, 1.76-1.91) for N1a, 2.72 (95% CI, 2.58-2.86) for N1b, 3.79 (95% CI, 3.51-4.08) for N2a, 4.56 (95% CI, 4.22-4.92) for N2b, 6.15 (95% CI, 5.59-6.76) for N3a, and 8.25 (95% CI, 7.64-8.91) for N3b in the proposed system (P < .001). By contrast, the current American Joint Committee on Cancer (AJCC) nodal classification system produced a more haphazard mortality profile, with HRs of 1.83 (95% CI, 1.76-1.91) for N1a, 3.81 (95% CI, 3.53-4.12) for N1b, 2.59 (95% CI, 2.30-2.93) for N1c, 2.71 (95% CI, 2.56-2.87) for N2a, 4.51 (95% CI, 4.17-4.87) for N2b, 3.44 (95% CI, 2.60-4.55) for N2c, 6.06 (95% CI, 5.51-6.67) for N3a, 8.15 (95% CI, 7.54-8.81) for N3b, and 6.90 (95% CI, 5.60-8.49) for N3c. As a sensitivity analysis, the proposed system continued to accurately stratify patients when excluding those undergoing CLND for microscopic lymph node metastases. This system was validated for overall survival and cause-specific mortality in SEER-18. Last, a new overall staging system for node-positive patients was developed by RPA and demonstrated improved concordance vs the AJCC, 8th edition system (C statistic, 0.690 [95% CI, 0.689-0.691] vs 0.666 [95% CI, 0.666-0.668])., Conclusions and Relevance: The findings of this cohort study suggest that a modified nodal classification system can accurately stratify mortality risk in cutaneous melanoma in an era of increasing use of sentinel lymph node biopsy without CLND and should be considered for future staging systems.

Background: While numerous factors determine prognosis in papillary thyroid carcinoma (PTC), distant metastasis (M1) represents one of the most dire. Escalating nodal burden and aggressive histology may contribute to higher metastatic risk, but this relationship is poorly defined and challenging to anticipate. We evaluate the predictive impact of these histological features on predicting distant metastases at initial presentation. Methods: Univariate and multivariable logistic regression models of conventional and aggressive thyroid cancer variants (well-differentiated papillary thyroid carcinoma [WDPTC], diffuse sclerosing variant [DSV], tall cell variant [TCV], poorly differentiated thyroid cancer [PDTC], and anaplastic thyroid carcinoma [ATC]) identified via U.S. cancer registry data were constructed to determine associations between M1 status and quantitative nodal burden. Associations between metastatic lymph node (LN) number and M1 disease were modeled using univariate and multivariable logistic regression with interaction terms, as well as a linear continuous probability model. Results: Overall, M1 prevalence at disease presentation was 3.6% ( n  = 1717). When stratified by subtype, M1 prevalence varied significantly by histology (WDPTC [1.0%], DSV [2.3%], TCV [4.1%], PDTC [17.4%], ATC [38.4%] [ p  < 0.001]). For WDPTC, M1 prevalence escalated with metastatic LN number (0 LN+ [0.5%], 1-5 LN+ [2.0%], 6-10 LN+ [3.4%], >10 LN+ [5.5%] [ p  < 0.001]) and LN ratio ( p  < 0.001). A statistically significant interaction was observed between histology and increasing nodal burden for M1 risk. On multivariable analysis, each successive metastatic LN conferred increased M1 risk for WDPTC (odds ratio [OR] 1.06 [1.05-1.08], p  < 0.001) and TCVs (OR 1.04 [1.02-1.07], p  < 0.001). In contrast, other aggressive variants had a higher baseline M1 risk, but this did not vary based on the number of positive LN (DSV, OR 1.02 [0.95-1.10], p  = 0.52; PDTC, OR 1.00 [0.98-1.02], p  = 0.66; ATC, 1.00 [0.98-1.02], p  = 0.97). Conclusions: Progressive nodal burden independently escalates the risk of distant metastasis in WDPTC and TCVs of PTC. Conversely, aggressive variants such as PDTC and ATC have substantial M1 risk at baseline and appear to be minimally affected by metastatic nodal burden. Consideration of these factors after surgery may help tailor clinical decision-making for treatment and surveillance. Further studies are warranted to calibrate the ideal management approach for these higher risk patient groups.

Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses. Antibiotic-mediated depletion or gnotobiotic exclusion of fungi enhances responsiveness to radiation, whereas antibiotic-mediated depletion of bacteria reduces responsiveness and is associated with overgrowth of commensal fungi. Further, elevated intratumoral expression of Dectin-1, a primary innate sensor of fungi, is negatively associated with survival in patients with breast cancer and is required for the effects of commensal fungi in mouse models of radiation therapy., Competing Interests: Declaration of interests S.L.S. and D.M.U. hold a patent for Targeting Fungi in Combination with Cancer Therapy (US Patent No. 62/393,546)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Squamous cell carcinomas (SCCs) comprise one of the most common histologic types of human cancer. Transcriptional dysregulation of SCC cells is orchestrated by tumor protein p63 (TP63), a master transcription factor (TF) and a well-researched SCC-specific oncogene. In the present study, both Gene Set Enrichment Analysis (GSEA) of SCC patient samples and in vitro loss-of-function assays establish fatty-acid metabolism as a key pathway downstream of TP63. Further studies identify sterol regulatory element binding transcription factor 1 (SREBF1) as a central mediator linking TP63 with fatty-acid metabolism, which regulates the biosynthesis of fatty-acids, sphingolipids (SL), and glycerophospholipids (GPL), as revealed by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based lipidomics. Moreover, a feedback co-regulatory loop consisting of SREBF1/TP63/Kruppel like factor 5 (KLF5) is identified, which promotes overexpression of all three TFs in SCCs. Downstream of SREBF1, a non-canonical, SCC-specific function is elucidated: SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCC epigenome, which converge on activating cancer-promoting pathways. Indeed, SREBF1 is essential for SCC viability and migration, and its overexpression is associated with poor survival in SCC patients. Taken together, these data shed light on mechanisms of transcriptional dysregulation in cancer, identify specific epigenetic regulators of lipid metabolism, and uncover SREBF1 as a potential therapeutic target and prognostic marker in SCC., (© 2021. The Author(s).)

Background: Modern disease staging systems have restructured human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) oropharyngeal carcinoma (OPC) into distinct pathologic nodal systems. Given that quantitative lymph node (LN) burden is the dominant prognostic factor in most head and neck cancers, we investigated whether HPV- and HPV+ OPC warrant divergent pathologic nodal classification., Methods: Multivariable Cox regression models of OPC surgical patients identified via U.S. cancer registry data were constructed to determine associations between survival and nodal characteristics. Nonlinear associations between metastatic LN number and survival were modeled with restricted cubic splines. Recursive partitioning analysis (RPA) was used to derive unbiased nodal schema., Results: Mortality risk escalated continuously with each successive positive LN in both OPC subtypes, with analogous slope. Survival hazard increased by 18.5% (hazard ratio [HR], 1.19 [95% CI, 1.16-1.21]; P < .001) and 19.1% (HR, 1.19 [95% CI, 1.17-1.21]; P < .001), with each added positive LN for HPV- and HPV+ OPC, respectively, up to identical change points of 5 positive LNs. Extranodal extension (ENE) was an independent predictor of HPV- OPC (HR, 1.55 [95% CI, 1.20-1.99]; P < .001) and HPV+ OPC (HR 1.73 [95% CI, 1.36-2.20]; P < .001) mortality. In RPA for both diseases, metastatic LN was the principal nodal covariate driving survival, with ENE as a secondary determinant. Given the similarities across analyses, we propose a concise, unifying HPV-/HPV+ OPC pathologic nodal classification schema: N1, 1-5 LN+/ENE-; N2, 1-5 LN+/ENE+; N3, >5 LN+., Conclusion: HPV- and HPV+ OPC exhibit parallel relationships between nodal characteristics and relative mortality. In both diseases, metastatic LN number represents the principal nodal covariate governing survival, with ENE being an influential secondary element. A consolidated OPC pathologic nodal staging system that is based on these covariates may best convey prognosis., Lay Summary: The current nodal staging system for oropharyngeal carcinoma (OPC) has divided human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) OPC into distinct systems that rely upon criteria that establish them as separate entities, a complexity that may undermine the core objective of staging schema to clearly communicate prognosis. Our large-scale analysis revealed that HPV- and HPV+ pathologic nodal staging systems in fact mirror each other. Multiple analyses produced conspicuously similar nodal staging systems, with metastatic lymph node number and extranodal extension delineating the highest risk groups that shape prognosis. We propose unifying HPV- and HPV+ nodal systems to best streamline prognostication and maximize staging accuracy., (© 2021 American Cancer Society.)

Background: Although higher thyroidectomy volume has been linked with lower complication rates, its association with incidental parathyroidectomy remains less studied. The volume relationship is even less clear for central neck dissection, where individual parathyroid glands are at greater risk., Methods: Patients undergoing thyroidectomy with or without central neck dissection were evaluated for incidental parathyroidectomy, hypoparathyroidism, and hypocalcemia. Univariate and multivariable analyses were performed using binary logistic regression., Results: Overall, 1,114 thyroidectomies and 396 concurrent central neck dissections were performed across 7 surgeons. Incidental parathyroidectomy occurred in 22.4% of surgeries (range, 16.9%-43.6%), affecting 7.1% of parathyroids at risk (range, 5.8%-14.5%). When stratified by surgeon, lower incidental parathyroidectomy rates were associated with higher thyroidectomy volumes (R 2  = 0.77, P = .008) and higher central neck dissection volumes (R 2  = 0.93, P < .001). On multivariable analysis, low-volume surgeon (odds ratio 2.94, 95% confidence interval 2.06-4.19, P < .001), extrathyroidal extension (odds ratio 3.13, 95% confidence interval 1.24-7.87, P = .016), prophylactic central neck dissection (odds ratio 2.68, 95% confidence interval 1.65-4.35, P <.001), and therapeutic central neck dissection (odds ratio 4.44, 95% confidence interval 1.98-9.96, P < .001) were the most significant factors associated with incidental parathyroidectomy. In addition, incidental parathyroidectomy was associated with a higher likelihood of temporary hypoparathyroidism (odds ratio 2.79, 95% confidence interval 1.45-5.38, P = .002) and permanent hypoparathyroidism (odds ratio 4.62, 95% confidence interval 1.41-5.96, P = .025), but not permanent hypocalcemia (odds ratio 1.27, 95% confidence interval 0.48-3.35, P = .63). Higher lymph node yield in central neck dissection was not associated with higher incidental parathyroidectomy rates (odds ratio 1.13, 95% confidence interval 0.85-8.81, P = .82)., Conclusion: Higher surgical volume conferred a lower rate of incidental parathyroidectomy. Nonetheless, greater lymph node yield in central neck dissections did not result in greater parathyroid-related morbidity. Such findings support the value of leveraging surgical volume to both optimize oncologic resection and minimize complication rates., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Although pathologic tumor grade is a well-established prognostic risk factor that impacts staging and treatment decisions across multiple cancer types, its role in head and neck squamous cell carcinoma (HNSCC) is less certain., Methods: HNSCC patients diagnosed from 2010 to 2015 and undergoing primary surgery in the National Cancer Data Base were identified. Propensity score matching and multivariable Cox regression were performed., Results: Among 27 041 HNSCC patients, 13 941 had oral cavity cancers (OCC). Intermediate-grade (hazard ratio [HR] 1.16, 95% CI 1.07-1.26, P < .001) and high-grade (HR 1.38, 95% CI 1.26-1.52, P < .001) tumors had worse survival than low-grade tumors. This magnitude was comparable to other well-established prognostic factors, including margin positivity, extranodal extension, and lymphovascular invasion. By contrast, there was no association between grade and survival in larynx/hypopharynx or HPV(-) oropharynx cancer., Conclusions: The prognostic impact of pathologic grade is highly variable across head and neck subsites and is the strongest among OCC patients., (© 2020 Wiley Periodicals LLC.)

Background: While numerous factors affect prognosis in papillary thyroid carcinoma (PTC), the comparative impact of histologic grade has not been well described. Moreover, indications for external beam radiation therapy (EBRT) remain imprecise. We evaluate clinicopathologic characteristics and outcomes for PTC stratified by grade., Methods: We profiled histologic grade for PTC (well differentiated, moderately differentiated, poorly differentiated) via hospital (National Cancer Database) and population-based (Surveillance, Epidemiology, and End Results) registries. Cox regression was used to adjust for clinicopathologic covariates. Statistical interactions between subtypes and the effect of EBRT on survival were assessed., Results: Collectively, worsening clinicopathologic factors (age, tumor size, extrathyroidal extension, nodal spread, M1 disease) and outcomes (disease-free survival, overall survival) correlated with less differentiated state, across all histologic grades (p < 0.001). Multivariable analysis showed escalating hazard with loss of differentiation relative to well-differentiated PTC (moderately differentiated hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.04-1.41, p = 0.02; poorly differentiated HR 2.62, 95% CI 2.23-3.08, p < 0.001). Correspondingly, greater survival benefit was associated with EBRT for poorly differentiated cases (HR 0.36, 95% CI 0.18-0.72, p = 0.004). This finding was upheld after landmark analysis to address potential immortal time bias (HR 0.37, 95% CI 0.17-0.80, p = 0.01)., Conclusions: Worsening histologic grade in PTC is independently associated with parallel escalation in mortality risk, on a scale approximating or surpassing established thyroid cancer risk factors. On preliminary analysis, EBRT was associated with improved survival in the most aggressive or least differentiated subvariants. Further investigation is warranted to examine the efficacy of EBRT for select poorly differentiated thyroid carcinomas.

Background: Studies have observed that women have better outcomes than men in melanoma, but less is known about the influence of sex differences on outcomes for other aggressive cutaneous malignancies., Objective: To investigate whether women and men have disparate outcomes in Merkel cell carcinoma (MCC)., Methods: Patients with nonmetastatic MCC undergoing surgery and lymph node evaluation were identified from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analysis and Cox proportional hazards regression models were used for overall survival, and competing-risks analysis and Fine-Gray models were used for cause-specific and other-cause mortality., Results: The NCDB cohort (n = 4178) included 1516 (36%) women. Women had a consistent survival advantage compared with men in propensity score-matched analysis (66.0% vs 56.8% at 5 years, P < .001) and multivariable Cox regression (hazard ratio, 0.68; 95% confidence interval, 0.61-0.75; P < .001). Similarly, women had a survival advantage in the SEER validation cohort (n = 1202) with 457 (38.0%) women, which was entirely due to differences in MCC-specific mortality (5-year cumulative incidence: 16.4% vs 26.7%, P = .002), with no difference in other-cause mortality (16.8% vs 17.8%, P = .43) observed in propensity score-matched patients., Limitations: Potential selection bias from a retrospective data set., Conclusion: In MCC, women have improved survival compared with men, driven by MCC-related mortality., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Current lymph node (LN) staging for Merkel cell carcinoma (MCC) does not account for the number of metastatic LNs, which is a primary driver of survival in multiple cancers., Objective: To determine the impact of the number of metastatic LNs on survival in MCC., Methods: Patients with MCC undergoing surgery were identified from the National Cancer Database (NCDB). The association between metastatic LN number and survival was modeled with restricted cubic splines. A novel nodal classification system was derived by using recursive partitioning analysis. MCC patients undergoing surgery in the Surveillance, Epidemiology, and End Results (SEER) Program were used as validation cohort., Results: Among 3670 patients in the NCDB, increasing metastatic LN number was associated with decreased survival (P < .001). Mortality risk increased continuously with each additional positive LN when using multivariable, nonlinear modeling. According to a novel staging system derived via recursive partitioning analysis, the hazard ratio for death in multivariable regression compared with patients without LN involvement was 1.24 (P = .049), 2.08 (P < .001), 3.24 (P < .001), and 6.13 (P < .001) for the proposed N1a (1-3 metastatic LNs with microscopic detection), N1b (1-3 metastatic LNs with macroscopic detection), N2 (4-8 metastatic LNs), and N3 (≥9 metastatic LNs), respectively. This system was validated in the SEER cohort and showed improved concordance compared with the American Joint Committee on Cancer, Eighth Edition., Limitations: Retrospective design., Conclusions: Number of metastatic LNs is the dominant nodal factor driving survival in patients with MCC., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Patients who are older and sicker are ideal candidates for bladder sparing therapy for muscle invasive bladder cancer given risks of treatment related morbidity with radical cystectomy and cancer mortality with observation. However, little is known about the independent impact of age, comorbidity and life expectancy on utilization of bladder sparing therapy., Methods: We sampled 19,228 patients with muscle invasive bladder cancer diagnosed between 2004 and 2013 from the National Cancer Database. We used multivariable multinomial logistic regression to determine relative risk ratios and predicted probabilities of receipt of bladder sparing therapy by estimates of life expectancy, and by age and comorbidity at diagnosis., Results: On multivariable analysis decreasing life expectancy was significantly associated with higher use of bladder sparing compared with cystectomy (relative RR 1.08, 95% CI 1.07-1.08). However, absolute changes were modest with predicted probability of bladder sparing increasing from 8%, 10%, 12%, 14% and 17% among patients with 25-year, 20-year, 15-year, 10-year and 5-year life expectancies, respectively. By comparison, rates of cystectomy decreased from 54%, 47%, 39%, 32% and 26% and rates of observation increased from 22%, 26%, 31%, 36% and 40% across the same life expectancy subgroups, respectively. Age had a stronger effect on relative risk of bladder sparing than comorbidity. Predicted probabilities of bladder sparing therapy increased from 8%, 12%, 16% and 19% among 60-year-old, 70-year-old, 80-year-old and 90-year-old patients, respectively, while the probability was 13%, 13% and 15% among patients with Charlson scores of 0, 1, and 2+, respectively., Conclusions: Bladder sparing therapy is underused in patients who are older and sicker with limited life expectancy who currently primarily receive observation or, less often, radical cystectomy.

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

Importance: Transoral robotic surgery has been widely adopted since approval by the US Food and Drug Administration in December 2009, despite limited comparative data., Objective: To compare the long-term outcomes of transoral robotic surgery with those of nonrobotic surgery for patients with early-stage oropharyngeal cancer., Design, Setting, and Participants: A retrospective cohort comparative effectiveness analysis was performed of patients in the National Cancer Database with clinical T1 and T2 oropharyngeal squamous cell carcinoma diagnosed between January 1, 2010, and December 31, 2015, who underwent definitive robotic and nonrobotic surgery. Multivariable Cox proportional hazards regression analysis and propensity score matching were performed in patients with known human papillomavirus status to adjust for patient- and disease-related covariates. Survival after robotic and nonrobotic surgery was also compared in 3 unrelated cancers: prostate, endometrial, and cervical cancer. Statistical analysis was performed from April 10, 2019, to May 21, 2020., Main Outcomes and Measures: Overall survival., Results: Of 9745 patients (7652 men [78.5%]; mean [SD] age, 58.8 [9.6] years) who met inclusion criteria, 2694 (27.6%) underwent transoral robotic surgery. There was a significant increase in the use of robotic surgery from 18.3% (240 of 1309) to 35.5% (654 of 1841) of all surgical procedures for T1 and T2 oropharyngeal cancers from 2010 to 2015 (P = .003). Robotic surgery was associated with lower rates of positive surgical margins (12.5% [218 of 1746] vs 20.3% [471 of 2325]; P < .001) and lower use of adjuvant chemoradiotherapy (28.6% [500 of 1746] vs 35.7% [831 of 2325]; P < .001). Among 4071 patients with known human papillomavirus status, robotic surgery was associated with improved overall survival compared with nonrobotic surgery in multivariable Cox proportional hazards regression (hazard ratio [HR], 0.74; 95 CI, 0.61-0.90; P = .002). Similar results were seen when analyzing only the subset of facilities offering both robotic and nonrobotic surgery. The 5-year overall survival was 84.8% vs 80.3% among patients undergoing robotic vs nonrobotic surgery in propensity score-matched cohorts (P = .001). By contrast, there was no evidence that robotic surgery was associated with improved survival in other cancers, such as prostate cancer (HR, 0.92; 95% CI, 0.79-1.07; P = .26), endometrial cancer (HR, 0.97; 95% CI, 0.90-1.04; P = .36), and cervical cancer (HR, 1.27; 95% CI, 0.96-1.69; P = .10)., Conclusions and Relevance: This study suggests that transoral robotic surgery was associated with improved surgical outcomes and survival compared with nonrobotic surgery in patients with early-stage oropharyngeal cancer. Evaluation in comparative randomized trials is warranted.

Purpose: In men with localized prostate cancer, the addition of androgen-deprivation therapy (ADT) or a brachytherapy boost (BT) to external beam radiotherapy (EBRT) have been shown to improve various oncologic end points. Practice patterns indicate that those who receive BT are significantly less likely to receive ADT, and thus we sought to perform a network meta-analysis to compare the predicted outcomes of a randomized trial of EBRT plus ADT versus EBRT plus BT., Materials and Methods: A systematic review identified published randomized trials comparing EBRT with or without ADT, or EBRT (with or without ADT) with or without BT, that reported on overall survival (OS). Standard fixed-effects meta-analyses were performed for each comparison, and a meta-regression was conducted to adjust for use and duration of ADT. Network meta-analyses were performed to compare EBRT plus ADT versus EBRT plus BT. Bayesian analyses were also performed, and a rank was assigned to each treatment after Markov Chain Monte Carlo analyses to create a surface under the cumulative ranking curve., Results: Six trials compared EBRT with or without ADT (n = 4,663), and 3 compared EBRT with or without BT (n = 718). The addition of ADT to EBRT improved OS (hazard ratio [HR], 0.71 [95% CI, 0.62 to 0.81]), whereas the addition of BT did not significantly improve OS (HR, 1.03 [95% CI, 0.78 to 1.36]). In a network meta-analysis, EBRT plus ADT had improved OS compared with EBRT plus BT (HR, 0.68 [95% CI, 0.52 to 0.89]). Bayesian modeling demonstrated an 88% probability that EBRT plus ADT resulted in superior OS compared with EBRT plus BT., Conclusion: Our findings suggest that current practice patterns of omitting ADT with EBRT plus BT may result in inferior OS compared with EBRT plus ADT in men with intermediate- and high-risk prostate cancer. ADT for these men should remain a critical component of treatment regardless of radiotherapy delivery method until randomized evidence demonstrates otherwise.

Background: Merkel cell carcinoma is an uncommon malignancy often requiring multidisciplinary management. The purpose of this study was to determine whether high-volume facilities have improved outcomes in patients with Merkel cell carcinoma relative to lower-volume facilities., Methods: A total of 5304 patients from the National Cancer Database with stage I-III Merkel cell carcinoma undergoing surgery were analyzed. High-volume facilities were the top 1% by case volume. Multivariable Cox regression and propensity score-matching were performed to account for imbalances between groups., Results: Treatment at high-volume facilities (hazard ratio: 0.74; 95% confidence interval: 0.65-0.84, P < .001) was independently associated with improved overall survival (OS) in multivariable analyses. In propensity score-matched cohorts, 5-year OS was 62.3% at high-volume facilities vs 56.8% at lower-volume facilities (P < .001). Median OS was 111 months at high-volume facilities vs 79 months at lower-volume facilities., Conclusion: Treatment at high-volume facilities is associated with improved OS in Merkel cell carcinoma. Given the impracticality of referring all elderly patients with Merkel cell carcinoma to a small number of facilities, methods to mitigate this disparity should be explored., (© 2020 Wiley Periodicals, Inc.)

Importance: While well-differentiated papillary thyroid carcinoma (WDPTC) outcomes have been well characterized, the prognostic implications of more aggressive variants are far less defined. The rarity of these subtypes has led to their consolidation as intermediate risk for what are in fact likely heterogeneous diseases., Objective: To analyze incidence, clinicopathologic characteristics, and outcomes for aggressive variants of papillary thyroid carcinoma (PTC)., Design, Setting, and Participants: This cohort study used data from 2000 to 2016 from hospital-based and population-based US cancer registries to analyze aggressive PTC variants, including diffuse sclerosing (DSV), tall-cell (TCV), insular, and poorly differentiated (PDTC) subtypes. These variants were compared against WDPTC and anaplastic cases. Data analysis was conducted from January 2019 to October 2019., Main Outcomes and Measures: Age-adjusted incidence was calculated via annual percentage change (APC) using the weighted least-squares method. Overall survival and disease-specific survival were analyzed via Cox regression. Propensity-score matching was used to adjust survival analyses for clinical and demographic covariates., Results: Collectively, 5447 aggressive PTC variants were identified (including 415 DSV, 3339 TCV, 362 insular, and 1331 PDTC cases), as well as 35 812 WDPTC and 2249 anaplastic cases. Over the study period, a substantial increase in aggressive variant incidence was observed (APC, 9.1 [95% CI, 7.33-10.89]; P < .001), surpassing the relative increases observed in WDPTC (APC, 5.1 [95% CI, 3.98-6.12]; P < .001) and anaplastic cases (APC, 1.9 [95% CI, 0.75-3.05]; P = .003; parallelism P < .007). Survival varied markedly based on histologic subtype, with a wide spectrum of mortality risk noted; 10-year overall survival was 85.4% (95% CI, 84.6%-86.3%) in WDPTC, 79.2% (95% CI, 73.6%-85.3%) in DSV, 71.9% (95% CI, 68.4%-75.6%) in TCV, 45.1% (95% CI, 40.2%-50.6%) in PDTC, 27.9% (95% CI, 20.0%-38.9%) in the insular variant, and 8.9% (95% CI, 7.5%-10.6%) in anaplastic cases (P < .001). These differences largely persisted even after adjusting for inherent differences in baseline characteristics by multivariable Cox regression and propensity-score matching., Conclusions and Relevance: An upsurge in aggressive PTC incidence was observed at a rate beyond that seen in WDPTC or anaplastic thyroid carcinoma. Moreover, long-term survival outcomes for aggressive PTC subgroups exhibit heterogeneous clinical behavior and a wide range of mortality risk, suggesting that treatment should be tailored to specific histologic subtypes. Given increasing prevalence and disparate outcomes, further investigation to identify optimal therapeutic strategies is needed in these diverse, understudied populations.

Importance: In men with recurrent prostate cancer, addition of long-term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment., Objective: To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT., Interventions: Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years., Design, Setting, and Participants: In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019., Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM)., Results: Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20; P = .01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97; P = .05)., Conclusions and Relevance: These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population., Trial Registration: ClinicalTrials.gov Identifier: NCT00002874.

Objectives: The United States has a heterogenous health insurance landscape for patients <65 years. We sought to characterise the impact of primary payer on overall survival (OS) in insured patients younger than 65 with head and neck squamous cell carcinoma (HNSCC) treated with definitive radiotherapy., Design/study/participants: The National Cancer Database was queried for patients <65 years old diagnosed from 2004 to 2014 undergoing definitive radiotherapy ± chemotherapy for cancers of the nasopharynx, oropharynx, hypopharynx and larynx. Uninsured patients and oropharyngeal cancers without known HPV status were excluded., Main Outcome: Overall survival., Results: Overall, 27 292 insured patients were identified, including 17 060 (62.5%) with private insurance. Median follow-up was 52.1 months. In multivariable models, patients receiving Medicaid (HR = 1.66, 95% CI 1.57-1.75, P < .001), Medicare (HR = 1.64, 95% CI 1.55-1.73, P < .001) and other government insurance (HR = 1.44, 95% CI 1.29-1., P < .001) had independently increased mortality in comparison to those with private insurance. In propensity score-matched cohorts, 5-year OS was 65.5% vs 50.6% for privately vs government-insured patients, respectively (P < .001). In multivariable subgroup analysis, private insurance was associated with improved survival in all subgroups. However, the magnitude of this effect was most pronounced in patients with HPV-positive oropharyngeal cancer vs non-HPV-related cancer (interaction P < .001), younger patients (interaction P = .001), and those without comorbidity (interaction P < .001)., Conclusions: Patients <65 with HNSCC undergoing definitive radiation with private health insurance have markedly longer survival relative to patients with government-sponsored insurance. This illustrates that increasing access to care may be necessary, but is not sufficient, to mitigate the significant disparities in the US healthcare system., (© 2019 John Wiley & Sons Ltd.)