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

Purpose: Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy in different malignancies. We report the long-term efficacy and safety of pembrolizumab and cabozantinib in patients with RMHNSCC and include a correlative biomarker analysis., Patients and Methods: This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. The primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, and safety of treated patients and describe correlative biomarkers evaluating p-MET expression and tumor immune microenvironment (TIME) using multiplex immunohistochemistry., Results: With median follow-up of 22.4 months, the median PFS was 12.8 months with a 2-year PFS of 32.6% (95% CI, 18.8%-56.3%) and the median OS was 27.7 months with a 2-year OS of 54.7% [95% confidence interval (CI), 38.9%-76.8%]. The median duration of response was 12.6 months with a 2-year rate of 38.5% (95% CI, 30.8%-81.8%). Long-term treatment-related adverse events included manageable hypothyroidism (5.5%) and grade 1 elevated aspartate aminotransferase and alanine aminotransferase (2.8%). Baseline tumor p-MET expression correlated with ORR (P = 0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS [hazard ratio (HR) = 5.27, P = 0.030; HR = 8.79, P = 0.017; HR = 6.87, P = 0.040, respectively]., Conclusions: Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of higher density of CD8+, CD103+, and CSF1-R+ cells in TIME deserve further evaluation in similar clinical settings., (©2024 American Association for Cancer Research.)

Background: Preclinical data suggest antifungal azole derivatives have antitumor efficacy that may modulate response to immune checkpoint inhibitors (ICIs). We aimed to evaluate the association of azole drugs with overall survival (OS) in a population of patients with non-small cell lung cancer (NSCLC) treated with ICI within the Veterans Health Administration (VHA)., Methods: In this retrospective study, the VA Corporate Data Warehouse was queried for patients diagnosed with NSCLC and treated with ICI from 2010 to 2018. Concomitant oral azole use was defined as dispensation by a VA pharmacy within 90 days of the first ICI infusion. Patients who received azole after 30 days were excluded from the analysis to mitigate immortal time bias. OS was measured from the start of ICI. Cox regression and propensity score matching were used to adjust for confounders., Results: We identified 3413 patients with NSCLC receiving ICI; 324 (9.5%) were exposed to concomitant azoles. As a group, azole use was not associated with OS (hazard ratio [HR] = 0.96; 95% CI, 0.84-1.09; P = .51). After stratification by azole type, clotrimazole had an association with better OS on univariable (HR = 0.75; 95% CI, 0.59-0.96; P = .024) and multivariable analysis (HR = 0.71; 95% CI, 0.56-0.91; P = .007). Propensity score matching of patients who received clotrimazole vs no azole yielded 101 patients per matched cohort. Clotrimazole was associated with improved OS, although this did not meet the threshold for statistical significance (HR = 0.74; 0.54-1.01; P = .058)., Conclusion: This observational study demonstrated an association between clotrimazole and OS among patients with advanced NSCLC receiving ICI. These findings build upon preclinical evidence and support further investigation into the potential for clotrimazole as a repurposed FDA drug to improve cancer outcomes., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The purpose of this study was to provide further insights into whether age and/or sex are associated with prognosis in oral tongue squamous cell carcinoma., Methods: This was a retrospective cohort study utilizing hospital registry data from 2006 to 2016 obtained from the National Cancer Database. Identified patients were divided into various cohorts based on age, sex, and staging. A descriptive analysis was performed using chi-square tests and overall survival rates were estimated using Kaplan-Meier method., Results: A total of 17 642 patients were included in the study. The 5-year overall survival rates were 82.0% (95% CI: 79.8%-84.0%) in younger patients versus 67.5% (95% CI: 66.7%-68.3%, p-value <0.0001) older patients. The median overall survival for females was 143.4 months (95% CI: 133.2-NA) versus 129.8 (95% CI: 125.4-138.7, p-value <0.0001) in males., Conclusions: Our analysis suggests that younger age and female sex are both predictors of improved survival in oral tongue squamous cell carcinoma., (© 2024 Wiley Periodicals LLC.)

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS)., Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation., Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023., Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks., Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers., Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed., Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation., Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.

Introduction: Lung cancer survival is improving in the United States. We investigated whether there was a similar trend within the Veterans Health Administration (VHA), the largest integrated healthcare system in the United States., Materials and Methods: Data from the Veterans Affairs Central Cancer Registry were analyzed for temporal survival trends using Kaplan-Meier estimates and linear regression., Results: A total number of 54,922 Veterans were identified with lung cancer diagnosed from 2010 to 2017. Histologies were classified as non-small-cell lung cancer (NSCLC) (64.2%), small cell lung cancer (SCLC) (12.9%), and 'other' (22.9%). The proportion with stage I increased from 18.1% to 30.4%, while stage IV decreased from 38.9% to 34.6% (both P < .001). The 3-year overall survival (OS) improved for stage I (58.6% to 68.4%, P < .001), stage II (35.5% to 48.4%, P < .001), stage III (18.7% to 29.4%, P < .001), and stage IV (3.4% to 7.8%, P < .001). For NSCLC, the median OS increased from 12 to 21 months (P < .001), and the 3-year OS increased from 24.1% to 38.3% (P < .001). For SCLC, the median OS remained unchanged (8 to 9 months, P = .10), while the 3-year OS increased from 9.1% to 12.3% (P = .014). Compared to White Veterans, Black Veterans with NSCLC had similar OS (P = .81), and those with SCLC had higher OS (P = .003)., Conclusion: Lung cancer survival is improving within the VHA. Compared to White Veterans, Black Veterans had similar or higher survival rates. The observed racial equity in outcomes within a geographically and socioeconomically diverse population warrants further investigation to better understand and replicate this achievement in other healthcare systems., Competing Interests: Disclosure DM is a consultant and/or advisor for AstraZeneca, Delfi Diagnostics, Viewray, and Merck; is a scientific advisor for Lungevity Foundation and GO2 Foundation for Lung Cancer; is co-director of the VA Greater Los Angeles Lung Precision Oncology Program; is on the scientific advisory board and owns stock options in Lung Life AI. DG is a founder of SwitchboardMD, is on the advisory board of Histowiz LLC, and owns stock in PortalBurner LLC, Histowiz LLC, and SwitchboardMD. JL is a board member of Rescue Lung Rescue Life and is Co-director of the Tennessee Valley Healthcare System Lung Cancer Screening Program. LS is a member of the Tennessee Valley Healthcare System Lung Cancer Screening Steering Committee and Vice Chair of Health Equity at Vanderbilt University Medical Center Radiology. CS is a Medical Director of the VAPORHCS lung nodule surveillance system, Director for the VISN 20 Centralized Lung Cancer Screening Program, and Chief Consultant for the VA National Center for Lung Cancer Screening. He does not receive additional remuneration for this role. He has a grant from the Oregon Health and Science University Knight Cancer Institute (KCI) to develop a nodule/lung cancer risk prediction model that includes working with a for-profit company, Optellum, Ltd. Neither he nor the KCI receive remuneration for this collaboration. All other authors declare no conflicts of interest., (Published by Elsevier Inc.)

Purpose: Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution., Materials and Methods: Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans., Results: IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99 Gy, P  < .001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60 Gy, P  < .002). Modeled 2-year overall survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P  = .03)., Conclusion: IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC., (© 2024 The Author(s).)

Introduction: Neck mass is the most common presentation of human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinoma (OPSCC). Recently, circulating tumor HPV-DNA (ctHPVDNA) assays have been developed to detect active OPSCC. This pilot study investigates the diagnostic accuracy of ctHPVDNA in establishing HPV status for known vs. unknown OPSCC presenting as a neck mass., Methods: A single-institution pilot study was conducted on all patients with OPSCC presenting as a neck mass between 2021 and 2022. The diagnostic accuracy of ctHPVDNA was compared to that of standard diagnostic procedures used to obtain HPV status according to the American Society of Clinical Oncology (ASCO) guideline for squamous cell carcinoma of unknown primary (SCCUP). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ctHPVDNA were calculated., Results: A total of 27 patients were included; 70.4% were current or former smokers, 48.1% (N = 13) had identifiable primaries, and 51.9% (N = 14) had SCCUP. Four patients with known primaries required operative direct laryngoscopy with biopsy (DLB) to establish HPV status. Two patients with SCCUP underwent diagnostic transoral robotic surgery (TORS) to establish HPV status and localize the primary. Twelve patients underwent therapeutic TORS and neck dissection. The gold standard for HPV status was based on final histopathologic p16 or HPV in situ hybridization (ISH) staining during workup/treatment. ctHPVDNA had 95.8% sensitivity, 100% specificity, 100% PPV, and 75% NPV in predicting HPV-positive OPSCC in the whole sample. Binary logistic regression model using ctHPVDNA results to predict HPV-positive OPSCC was significant (-2 log likelihood = 5.55, χ 2  = 8.70, p <.01, Nagelkerke's R squared = .67). Among patients with identifiable primaries, all patients had HPV-positive tumors on final pathology, and ctHPVDNA was positive in 100%. In the unknown primary patients, ctHPVDNA had 90.9% sensitivity, 100% specificity, 100% PPV, and 75% NPV., Discussion: ctHPVDNA demonstrated good diagnostic accuracy for both known and unknown primaries. Incorporation of ctHPVDNA into the diagnostic algorithm for SCCUP may reduce the need for multiple procedures to establish HPV status., Competing Interests: MT has received research grant support and honoraria for speaking/teaching from Intuitive Surgical, Inc. Palo Alto, CA, USA and for speaking from Naveris, Inc. Waltham, MA, USA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kais, Santiago, Han, Clump, Stokes, Fancy, Cui, Martin and Turner.)

Background: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy., Methods: We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r 2 greater than 0·7 was used as criteria for clinically relevant surrogacy., Findings: We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r 2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r 2 0·83), and progression-free survival (Kendall's τ 0·88 and r 2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r 2 0·88), distant metastasis-free survival (r 2 0·96), and progression-free survival (r 2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival., Interpretation: We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints., Funding: NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan., Competing Interests: Declaration of interests LAG reports grant funding from the PROTEUS Consortium. JAB reports royalties or licenses from Bristol Myers Squibb, Eli Lilly, and Merck Serono; consulting fees from Cel-Sci, Merck Serano, and ICON; payment for lectures or presentations from Bristol Myers Squibb, Eli Lilly, Merck Serano, and Cel-Sci; and support for attending meetings or travel from Bristol Myers Squibb, Eli Lilly, and Merck Serono. MLG reports research funding from Genocea Biosciences, Bristol Myers Squibb, Genentech, Kura, Cullinan Labs, Agenus, LaRoche, NRG Oncology, and the University of Cincinnati; consulting fees from iTeos Therapeutics, Istari Oncology, LLX Solutions, OncLive Intellisphere, Seagen, Sensei Biotherapeutics, Kura Oncology, Coherus Biosciences, Mirati Therapeutics, BioNtech AG, Sensei Biotherapeutics, Caladrius Biosciences, Bristol Myers Squibb, Bicara Therapeutics, Bayer Healthcare Pharmaceutics, Genocea Biosciences, Shattuck Labs, EMD Serono, Debiopharm, Merck & Co, Ipsen Biopharmaceuticals, Gilead Sciences, Nektar Therapeutics, Eisai Medical Research, Roche, Roche Diagnostics, NewLink Genetics, Aspyrian Therapeutics, Amgen, TRM Oncology, AstraZeneca Pharmaceuticals, Celgene, and Exelixis; payment from OncLive and Roche; and support for meetings or travel for presentations from the American Association for Cancer Research, the American Society of Clinical Oncology, and the Society for Immunotherapy of Cancer. SK reports research funding from Merck, Bristol Myers Squibb, Castle Biosciences, and Regeneron; consulting fees from Merck, Bristol Myers Squibb, Regeneron, and Galera Therapeutics; and honorarium from Varian Medical Systems. Q-TL reports a leadership role as RTOG Group Chair for NRG Oncology and support from RTOG Foundation for attending meetings and travel. MM reports clinical trial drug support from Bristol Myers Squbb, and grant funding from the PROTEUS Consortium and Livestrong Foundation, advistory board of Adaptimmune. DLM reports a grant from the National Cancer Institute (3R01CA262388-02S1 NCI Diversity Supplement Award). EM reports a University of Michigan M-Cubed Grant (P30CA046592). JAR reports non-financial interests National Comprehensive Cancer Network Thyroid Cancer Panel and American Thyroid Association Guidelines Task Force. DIR reports payments from Merck to the Scientific Advisory Board for presentations. MJS reports consulting fees from Innovative Analytics. WAS reports a research grant from Georgia Research Alliance. PT-S reports NRG Oncology SDMC Grant from the National Cancer Institute (NCI). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Importance: Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence., Objective: To evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins., Design, Setting, and Participants: The American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023., Main Outcomes and Measures: Main outcomes were risk factors for local recurrence., Results: A total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group., Conclusions and Relevance: In this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Purpose: To review our initial experience with proton-based SBRT to evaluate the planning outcomes and initial patient tolerance of treatment., Patients and Methods: From Sep. 2019 to Dec. 2020, 52 patients were treated with proton SBRT to 62 lesions. Fractionation varied by indication and site with a median of 5 fractions and median fractional dose of 8 Gy. Planning outcomes, including plan heterogeneity, conformity, and PTV volume receiving 100% of the prescription dose (PTV V100%) were evaluated. Acute toxicities were prospectively recorded, and patient reported outcomes were assessed prior to and at completion of treatment using the MD Anderson Symptom Inventory (MDASI) and EQ-5D5L visual analogue score (VAS)., Results: All treated patients completed their course of proton-based SBRT. The mean conformity index was 1.05 (range 0.51-1.48). R50% values were comparable to ideal photon parameters. PTV V100% was 89.9% on average (40.44% - 99.76%). 5 patients (10%) required plan modification due to setup or tumor changes. No patients developed a new grade 3 or greater toxicity during treatment. Comparing pretreatment to end of treatment timepoints, there was a significant improvement in the mean VAS (65 to 75, p = 0.014), with no significant change in the mean MDASI symptom (1.7, 1.8; p = 0.79) or interference (2.3, 2.4; p = 0.452) scores., Conclusion: Proton-based SBRT can achieve dosimetric goals required by major clinical photon trials. It was well-tolerated with no decrement in patient reported outcomes and a mean 10-point improvement in VAS at the conclusion of SBRT. Further follow-up is necessary for tumor control and late effects analysis., Competing Interests: Additional Information and Declarations The authors would like to thank the Winship Cancer Institute at Emory University and the Emory Proton Therapy Center. Research reported in this publication was supported in part by the Biostatistics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Authors’ disclosure of potential conflicts of interest Jeffrey Bradley reports Varian, Inc research grant and participation on Genentech, Inc, AstraZeneca, Inc, and Mevion Medical Systems Scientific Advisory Board. Other authors have nothing to disclose., (© 2024 Old City Publishing, Inc.)

As the prognosis for squamous cell carcinoma of the head and neck remains unsatisfactory when compared to other malignancies, novel therapies targeting specific biomarkers are a critical emerging area of great promise. One particular class of drugs that has been developed to impede tumor angiogenesis is vascular endothelial growth factor-tyrosine kinase inhibitors. As current data is primarily limited to preclinical and phase I/II trials, this review summarizes the current and future prospects of these agents in squamous cell carcinoma of the head and neck. In particular, the combination of these agents with immunotherapy is an exciting area that may be a promising option for patients with recurrent or metastatic disease, evidenced in recent trials such as the combination immune checkpoint inhibitors with lenvatinib and cabozantinib. In addition, the use of such combination therapy preoperatively in locally advanced disease is another area of interest., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Puttagunta, Pamulapati, Bates, Gross, Stokes, Schmitt, Steuer, Teng and Saba.)

Background: The PACIFIC trial established consolidative durvalumab after concurrent chemoradiation as standard-of-care in patients with stage III or unresectable non-small cell lung cancer (NSCLC). Black patients, however, comprised just 2% (n = 14) of randomized patients in this trial, warranting real-world evaluation of the PACIFIC regimen in these patients., Methods: This single-institution, multi-site study included 105 patients with unresectable stage II/III NSCLC treated with concurrent chemoradiation followed by durvalumab between 2017 and 2021. Overall survival (OS), progression-free survival (PFS), and grade ≥3 pneumonitis-free survival (PNFS) were compared between Black and non-Black patients using Kaplan-Meier and Cox regression analyses., Results: A total of 105 patients with a median follow-up of 22.8 months (interquartile range, 11.3-37.3 months) were identified for analysis, including 57 Black (54.3%) and 48 (45.7%) non-Black patients. The mean radiation prescription dose was higher among Black patients (61.5 ± 2.9 Gy vs. 60.5 ± 1.9 Gy; p = .031), but other treatment characteristics were balanced between groups. The median OS (not-reached vs. 39.7 months; p = .379) and PFS (31.6 months vs. 19.3 months; p = .332) were not statistically different between groups. Eight (14.0%) Black patients discontinued durvalumab due to toxicity compared to 13 (27.1%) non-Black patients (p = .096). The grade ≥3 pneumonitis rate was similar between Black and non-Black patients (12.3% vs. 12.5%; p = .973), and there was no significant difference in time to grade ≥3 PNFS (p = .904). Three (5.3%) Black patients and one (2.1%) non-Black patient developed grade 5 pneumonitis., Conclusions: The efficacy and tolerability of consolidative durvalumab after chemoradiation appears to be comparable between Black and non-Black patients., (© 2023 American Cancer Society.)

Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC., Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS)., Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020., Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo)., Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS., Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84)., Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis., Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.

Inhibitors of apoptosis proteins (IAPs) inhibit the intrinsic and extrinsic cell death pathways, promoting cell survival. Antagonists of these pathways are under study as anti-cancer therapeutics. A high proportion of head and neck squamous cell carcinomas (HNSCCs) have genomic alterations in IAP pathways, resulting in the dysregulation of cell death pathways and rendering them susceptible to IAP antagonist therapy. Preclinical studies suggest IAP antagonists, also known as second mitochondria-derived activator of caspases mimetics, may be effective treatments for HNSCC, especially when combined with radiation. Mechanistic studies have shown both molecular mechanisms (i.e., enhanced cell death) and immune mechanisms (e.g., immunogenic cell death and T-cell activation), underlying the efficacy of these drugs in preclinical models. Phase I/II clinical trials have shown promising results, portending a future where this class of targeted therapies becomes incorporated into the treatment paradigm for head and neck cancers. IAP antagonists have shown great promise for head and neck cancer, especially in combination with radiation therapy. Here, we review recent preclinical and clinical studies on the use of these novel targeted agents for head and neck cancer., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: We evaluated our institutional experience to assess potential racial inequities in insurance coverage for proton therapy in patients with head and neck (HN) cancer., Methods and Materials: We examined the demographics of 1519 patients with HN cancer seen in consultation at our HN multidisciplinary clinic (HN MDC) and 805 patients for whom a proton insurance authorization was sought (PAS) from January 2020 to June 2022. The prospects for proton therapy insurance authorization were prospectively noted based on each patient's ICD-10 (International Classification of Diseases, 10th Revision) diagnosis code and their specific insurance plan. Proton-unfavorable (PU) insurance were those plans whose policy describes proton beam therapy as "experimental" or "not medically necessary" for the given diagnosis., Results: For patients seen in our HN MDC, Black, Indigenous, and people of color (BIPOC) were significantly more likely to have PU insurance than non-Hispanic White (NHW) patients (24.9% vs 18.4%, P = .005). In multivariable analysis including race, average income of residence ZIP code, and Medicare eligibility age, BIPOC patients had an odds ratio of 1.25 for PU insurance (P = .041). In the PAS cohort, while there was no difference in the percentage of patients receiving insurance approval for proton therapy between NHW and BIPOC populations (88% vs 88.2%, P = .80), for patients with PU insurance, the median time to determination was significantly longer (median, 15.5 days), and the median time to start any radiation of any modality was longer (46 vs 35 days, P = .08). Compared with NHW patients, the median time from consultation to start of radiation therapy was longer for BIPOC patients (37 vs 43 days, P = .01)., Conclusions: BIPOC patients were significantly more likely to have insurance plans unfavorable to proton therapy coverage. These PU insurance plans were associated with a longer median time to determination, a lower approval rate for proton therapy, and a longer time to start radiation of any modality., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICI) are commonly used in the management of patients with advanced non-small cell lung cancer (NSCLC), but response is suboptimal. Preclinical data suggest ICI efficacy may be enhanced with concomitant nonsteroidal anti-inflammatory (NSAID) medications., Patients and Methods: In this retrospective study, the Veterans Health Administration Corporate Data Warehouse was queried for patients diagnosed with NSCLC and treated with ICI from 2010 to 2018. Concomitant NSAID use was defined as NSAID dispensation by a VA pharmacy within 90 days of the any ICI infusion. To mitigate immortal time bias, patients who started NSAIDs 60 or more days after ICI initiation were excluded from analysis. Survival was measured from start of ICI., Results: We identified 3634 patients with NSCLC receiving ICI; 2336 (64.3%) were exposed to concomitant NSAIDs. On multivariable analysis, NSAIDs were associated with better overall survival (HR = 0.90; 95% CI, 0.83-0.98; P = .010). When stratifying by NSAID type, diclofenac was the only NSAID with significant association with overall survival (HR = 0.75; 95% CI, 0.68-0.83; P < .001). Propensity score matching of the original cohort yielded 1251 patients per cohort balanced in characteristics. NSAIDs remained associated with improved overall survival (HR = 0.85; 95% CI, 0.78-0.92; P < .001)., Conclusion: This study of Veterans with NSCLC treated with ICI demonstrated that concomitant NSAIDs are associated with longer OS. This may indicate that NSAIDs can enhance ICI-induced antitumor immunity and should prospectively validated., Competing Interests: Disclosure NTS has no disclosures. WAS has no disclosures. MB has no disclosures. RJ has no disclosures. DAG has no disclosures. ZH has no disclosures. AB has no disclosures. VS has no disclosures. MCL has no disclosures. SSR has received grant funding and/or other support (for consultancy) from Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Takeda, Tesaro, Advaxis, AbbVie, and Genentech/Roche. VPS is on the SAB of BERG and HiFiBio Therapeutics, and an equity holder in Aggamin Pharmaceuticals and Victa Biotherapeutics. DM has received travel support and speaking honoraria from Varian Medical Systems., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Established prognostic factors for head and neck squamous cell carcinoma (HNSCC) mostly consist of clinical and tumor features assessed before treatment. We report a novel application of DNA methylation in peripheral blood before and after radiation therapy to further improve outcomes stratification., Methods and Materials: Peripheral blood samples from patients with nonmetastatic HNSCC were obtained for methylation analysis 1 week before and 1 month after radiation therapy. Patients were randomized 1:1 to a Discovery Cohort or a Validation Cohort. In the Discovery Cohort, associations between genome-wide methylation change (posttreatment minus pretreatment) and recurrence-free survival (RFS) as well as overall survival (OS) were evaluated using Cox regression. A methylation risk score (MRS) was then constructed from methylation levels at the top associated sites, filtered for residing within the regulatory regions of genes expressed in cells of hematopoietic lineage. The prognostic value of MRS was separately assessed in the Discovery and Validation Cohorts., Results: Between December 2013 and September 2018, 115 patients participated in this study. Human papilloma virus negative status, oral cavity cancer, gastrostomy tube insertion, and higher neutrophil count before radiation therapy were associated with shorter RFS and OS (P < .05). Genes downstream of the methylation sites comprising MRS are HIF1A, SF1, LGALS9, and FUT5, involved in hypoxia response, blood cell maturation, and immune modulation. High MRS (in the top third) was significantly associated with worse RFS (hazard ratio [HR], 7.1; 95% confidence interval [CI], 1.4-35.5; P = .016) and OS (HR, 15.9; 95% CI, 1.6-153.6; P = .017) in the Discovery Cohort, independent of the aforementioned risk factors. These findings were replicated in the Validation Cohort, for which high MRS also independently predicted worse RFS (HR, 10.2; 95%, CI 2.4-43.4; P = .002) and OS (HR, 3.7; 95% CI, 1.3-10.4; P = .015)., Conclusions: We successfully trained and validated a signature of DNA methylation in peripheral blood before and after radiation therapy that stratified outcomes among patients with HNSCC, implicating the potential for genomics-tailored surveillance and consolidation treatment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Anterior cervical discectomy and fusion is a common procedure performed by spine surgeons with rare complications and high treatment success. Late presentation of retropharyngeal abscess in patients with a history of anterior cervical discectomy and fusion is rare but can have devastating consequences. There is a paucity of data to guide medical and surgical management of retropharyngeal abscess in these patients., Methods: We discuss 7 patients who presented to our institution with a late retropharyngeal abscess after having a history of anterior cervical discectomy and fusion. A review and description of the current literature regarding treatment and outcomes is described., Results: Seven patients presented to our institution with a retropharyngeal abscess ranging from 10 months to 7 years after undergoing anterior cervical discectomy and fusion. All patients received at least a 6-week course of appropriate intravenous antibiotics. Only one patient had their initial ACDF instrumentation removed at the time of presentation for the abscess. Four out of the 7 patients were treated with irrigation and debridement in addition to intravenous antibiotics, whereas 3 patients were treated with no surgery and intravenous antibiotics alone. All patients were asymptomatic at final follow up., Conclusions: Late retropharyngeal abscess after anterior cervical discectomy and fusion is a rare complication. Surgical management should be considered along with long term antibiotics. Removal of implants may not be necessary for infection resolution. Antibiotic treatment alone may be indicated for patients who are not septic, do not have airway compromise, or and can be considered for poor surgical candidates.

Background: To evaluate treatment modalities of T4 larynx cancer in older adults using SEER-Medicare., Methods: The database was queried for patients aged 66 and older with nonmetastatic T4 laryngeal squamous cell cancer from 2006 to 2015. Treatment modalities compared were surgery plus chemoradiation (SCR), surgery plus radiation (SR), chemoradiation (CR), surgery (S), and radiation (R). Multivariate analysis and Kaplan-Meier methods were used to explore the relationship of treatment modality and survival. Total cancer-related costs were calculated., Results: A total of 438 patients met inclusion criteria. Patients receiving CR or SR had similar CSS to SCR (HR 1.36 and HR 1.24, respectively). Those receiving S (HR 2.00) or R (HR 2.41) had significantly worse CSS. Similar findings were observed for OS. Cancer care-related costs were not significantly different but highest in SCR ($162215) and lowest in R ($121421)., Conclusion: Older patients with T4 larynx cancer had similar survival rates when treated with CR, SR, and SCR. Average total health care costs were not significantly different between modalities. Patients not eligible for triple-modality could consider these other treatment options., (© 2022 Wiley Periodicals LLC.)

Background: The safety of presurgical thromboprophylaxis using low molecular weight heparin (LMWH) has not been well described in head and neck oncologic surgery with free tissue transfer (HNS-FTT)., Methods: Retrospective chart review of HNS-FTT patients receiving versus not receiving presurgical subcutaneous enoxaparin (Px-LMWH) was performed. Outcomes included estimated blood loss (EBL), hematoma, flap compromise, DVT or pulmonary embolus (PE). Fisher's exact test and Wilcoxon Rank Sum test were performed to compare groups. Odds ratios and associated 95 % confidence intervals were provided as appropriate., Results: 43 of 128 patients (34 %) received Px-LMWH. There was no significant difference in EBL, hematoma, or flap complications between groups. Patients without Px-LMWH had higher rates of DVT and PE, although the difference did not reach statistical significance (p = 1.00, 0.095, respectively)., Conclusion: Presurgical Px-LMWH can be used in major head and neck reconstructive surgery without increased intraoperative blood loss or postoperative complications. Larger studies will need to be done to determine the impact of Px-LMWH on DVT and PE in this patient population., Competing Interests: Conflicts of interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The implementation of knowledge-based planning (KBP) continues to grow in radiotherapy clinics. KBP guides radiation treatment design by generating clinically acceptable plans in a timely and resource-efficient manner. The role of multiple KBP models tailored for variations within a disease site remains undefined in part because of the substantial effort and number of training cases required to create a high-quality KBP model. In this study, our aim was to explore whether site-specific KBP models lead to clinically meaningful differences in plan quality for head-and-neck (HN) patients when compared to a general model. One KBP model was created from prior volumetric-modulated arc therapy (VMAT) cases that treated unilateral HN lymph nodes while another model was created from VMAT cases that treated bilateral HN nodes. Thirty cases from each model (60 cases total) were randomly selected to create a third, general model. These models were applied to 60 HN test cases - 30 unilateral and 30 bilateral - to generate 180 VMAT plans in Eclipse. Clinically relevant dose metrics were compared between models. Paired-sample t-tests were used for statistical analysis, with the threshold for statistical significance set a priori at 0.007, taking into consideration multiple hypothesis testing to avoid type I error. For unilateral test cases, the unilateral model-generated plans had significantly lower spinal cord maximum doses (12.1 Gy vs 19.3 Gy, p < 0.001) and oral cavity mean doses (20.8 Gy vs 23.0 Gy, p < 0.001), compared with the bilateral model-generated plans. The unilateral and general models generated comparable plans for unilateral HN test cases. For bilateral test cases, the bilateral model created plans had significantly lower brainstem maximum doses (10.8 Gy vs 12.2 Gy, p < 0.001) and parotid mean doses (24.0 Gy vs 25.5 Gy, p < 0.001) when compared to the unilateral model. Right parotid mean doses were lower for bilateral model plans compared to general model plans (23.8 Gy vs 24.4 Gy). The general model created plans with significantly lower brainstem maximum doses (10.3 Gy vs 10.8 Gy) and oral cavity mean doses (35.3 Gy vs 36.7 Gy) when compared with bilateral model-generated plans. The general model outperformed the bilateral model in several dose metrics but they were not deemed clinically significant. For both case sets, the unilateral and general model created plans had higher monitor units when compared to the bilateral model, likely due to more stringent constraint settings. All other dose metrics were comparable. This study demonstrates that a balanced general HN model created using carefully curated treatment plans can produce high quality plans comparable to dedicated unilateral and bilateral models., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative mortality for oropharynx squamous cell carcinoma (OPSCC) with transoral robotic surgery (TORS) varies from 0.2% to 6.5% on trials; the real-world rate is unknown., Methods: NCDB study from 2010 to 2017 for patients with cT1-2N0-2M0 OPSCC with Charleson-Deyo score 0-1. Ninety-day mortality assessed from start and end of treatment at Commission on Cancer-accredited facilities., Results: 3639 patients were treated with TORS and 1937 with radiotherapy. TORS cohort had more women and higher income, was younger, more often treated at academic centers, and more likely to have private insurance (all p < 0.05). Ninety-day mortality was 1.3% with TORS and 0.7% or 1.4% from start or end of radiotherapy, respectively. From end of therapy, there was no significant difference on MVA between treatment modality., Conclusions: There is minimal difference between 90-day mortality in patients treated with TORS or radiotherapy for early-stage OPSCC. While overall rates are low, for patients with expectation of cure, work is needed to identify optimal treatment., (© 2022 Wiley Periodicals LLC.)

Introduction: As immunotherapy has improved distant metastasis-free survival (DMFS) in Non-Small Cell Lung Cancer (NSCLC), isolated locoregional recurrences have increased. However, management of locoregional recurrences can be challenging. We report our institutional experience with definitive intent re-irradiation using Intensity Modulated Proton Therapy (IMPT)., Method: Retrospective cohort study of recurrent or second primary NSCLC or LS-SCLC treated with IMPT. Kaplan-Meier method and log-rank test were used for time-to-event analyses., Results: 22 patients were treated from 2019 to 2021. After first course of radiation (median 60 Gy, range 45-70 Gy), 45% received adjuvant immunotherapy. IMPT re-irradiation began a median of 28.2 months (8.8-172.9 months) after initial radiotherapy. The median IMPT dose was 60 GyE (44-60 GyE). 36% received concurrent chemotherapy with IMPT and 18% received immunotherapy after IMPT. The median patient's IMPT lung mean dose was 5.3 GyE (0.9-13.9 GyE) and 5 patients had cumulative esophagus max dose >100 GyE with 1-year overall survival (OS) 68%, 1-year local control 80%, 1-year progression free survival 45%, and 1-year DMFS 60%. Higher IMPT (HR 1.4; 95% CI 1.1-1.7, p=0.01) and initial radiotherapy mean lung doses (HR 1.3; 95% CI 1.0-1.6, p=0.04) were associated with worse OS. Two patients developed Grade 3 pneumonitis or dermatitis, one patient developed Grade 2 pneumonitis, and seven patients developed Grade 1 toxicity. There were no Grade 4 or 5 toxicities., Discussion: Definitive IMPT re-irradiation for lung cancer can prolong disease control with limited toxicity, particularly in the immunotherapy era., Competing Interests: KH and JB report as potential commercial or financial conflicts of interest the following relationships: AstraZeneca consultant/advisory board RefleXion Medical funded research, advisory board, Jazz pharmaceuticals funded research, Ultimate Opinions in medicine honorarium. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Janopaul-Naylor, Cao, McCall, Switchenko, Tian, Chen, Stokes, Kesarwala, McDonald, Shelton, Bradley and Higgins.)

Introduction: Patients receiving stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) are typically inoperable, in concordance with guidelines that advocate surgical resection as preferred treatment for operable patients. This differential treatment allocation complicates retrospective comparisons of surgery with SBRT by introducing the potential for confounding by operability., Methods: PubMed was queried for manuscripts reporting primary data from retrospective comparisons of overall survival (OS) between patients undergoing surgery versus SBRT for early-stage NSCLC. Each manuscript was categorized for two outcomes: (1) whether treatment allocation was based on a determination of patient operability, and (2) whether a direct OS comparison between operable SBRT patients and surgically treated patients was included. Associations with variables of interest were measured with statistical significance prespecified at p < 0.10., Results: From 3,072 manuscripts identified in our query, sixty-one analyses met screening criteria. Twenty-one (34 %) reported operability status influencing treatment allocation. These were more likely to be published in journals with a surgical focus (52 vs 20 %) and impact factor < 5 (81 vs 58 %), and to contain cohorts from institutional datasets (81 vs 55 %), and to have a radiation oncologist as first (43 vs 25 %) or senior (43 vs 28 %) author. Seven (11 %) manuscripts featured a direct OS comparison between SBRT and surgery., Conclusion: Nearly-two-thirds of peer-reviewed retrospective studies that have compared OS between surgery and SBRT for early-stage NSCLC lack information on patient operability status, and nearly 90% lack a direct comparison between operable SBRT patients and those receiving surgery., 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 © 2022. Published by Elsevier B.V.)

Background: Peroxisome proliferator-activated receptor agonists such as fibrates restore oxidative metabolism in cytotoxic T-lymphocytes, thereby enhancing response to immune checkpoint inhibitors (ICI) in preclinical models. However, there is no evidence in humans on the clinical impact of fibrates as an adjunct to ICI., Methods: In this cohort study of Veterans with non-small cell lung cancer (NSCLC) receiving ICI, fibrate exposure was defined as a prescription filled within 90 days of an ICI infusion. Overall survival (OS), measured from the start of ICI, was compared between exposed and unexposed Veterans. Cox multivariable analysis (MVA) was used to identify factors associated with OS. A sensitivity analysis of Veterans with stage IV NSCLC who received docetaxel without ICI was similarly performed., Results: The ICI cohort included 3593 Veterans, of whom 301 (8.5%) coincidentally received a fibrate. Veterans receiving fibrates were more likely to be older, white, male, and married, and to have greater comorbidity burden, but less likely to receive chemotherapy. Coincidental fibrates were associated with improved OS both on MVA (HR 0.86, 95%CI 0.75-0.99) and in a matched subset (HR 0.75, 95%CI 0.63-0.90). In contrast, among the cohort of 968 Veterans treated with chemotherapy, fibrates did not have a significant impact on OS by MVA (HR 0.99, 95%CI 0.79-1.25) or in a matched subset (HR 1.02, 95%CI CI 0.75-1.39)., Conclusions: Concomitant fibrates are associated with improved OS among NSCLC patients receiving ICI but not among those receiving chemotherapy. This hypothesis-generating observation supports a potential role for fibrates as an adjunct to immunotherapy., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Large analyses of T4 larynx cancer (LC) have raised concerns that larynx preservation (LP) contributes to reduced survival compared with laryngectomy (LGX). The role of operability has not been previously considered as a confounder., Methods: We queried the National Cancer Database for T4M0 LC diagnosed 2004-2015. Patients were categorized as undergoing LGX, chemoradiotherapy but operable (LP-operable), and chemoradiotherapy inoperable (LP-inoperable). Overall survival (OS) was estimated by Kaplan-Meier. Cox multivariate analysis (MVA) identified variables associated with OS., Results: We identified 1405 LGX, 164 LP-operable and 1969 LP-inoperable patients. Compared with LGX, MVA demonstrated worse OS among LP-inoperable (HR 1.28 95%CI 1.17-1.40, p < 0.01) but not LP-operable patients (HR 1.12 95%CI 0.91-1.39, p = 0.28)., Conclusions: LP-operable patients did not have significantly worse OS than those undergoing LGX., (© 2022 Wiley Periodicals LLC.)

Radiotherapy is the primary treatment modality for nasopharyngeal carcinoma (NPC). Successful curative treatment requires optimal radiotherapy planning and precise beam delivery that maximizes locoregional control while minimizing treatment-related side effects. In this article, we highlight considerations in target delineation, radiation dose, and the adoption of technological advances with the aim of optimizing the benefits of radiotherapy in NPC patients.

Background/purpose: Higher estimated radiation doses to immune cells (EDIC) have correlated with worse overall survival (OS) in patients with locally-advanced non-small cell lung cancer (NSCLC) prior to the PACIFIC trial, which established consolidative durvalumab as standard-of-care. Here, we examine the prognostic impact of EDIC in the durvalumab era., Materials/methods: This single-institution, multi-center study included patients with unresectable stage II/III NSCLC treated with chemoradiation followed by durvalumab. Associations between EDIC [analyzed continuously and categorically (≤6 Gy vs > 6 Gy)] and OS, progression-free survival (PFS), and locoregional control (LRC) were evaluated by Kaplan-Meier and Cox proportional methods., Results: 100 patients were included with median follow-up of 23.7 months. The EDIC > 6 Gy group had a significantly greater percentage of stage IIIB/IIIC disease (76.0 % vs 32.6 %; p < 0.001) and larger tumor volumes (170 cc vs 42 cc; p < 0.001). There were no differences in early durvalumab discontinuation from toxicity (24.1 % vs 15.2 %; p = 0.27). Median OS was shorter among the EDIC > 6 Gy group (29.6 months vs not reached; p < 0.001). On multivariate analysis, EDIC > 6 Gy correlated with worse OS (HR: 4.15, 95 %CI: 1.52-11.33; p = 0.006), PFS (HR: 3.79; 95 %CI: 1.80-8.0; p < 0.001), and LRC (HR: 2.66, 95 %CI: 1.15-6.18; p = 0.023). Analyzed as a continuous variable, higher EDIC was associated with worse OS (HR: 1.34; 95 %CI: 1.16-1.57; p < 0.001), PFS (HR: 1.52; 95 %CI: 1.29-1.79; p < 0.001), and LRC (HR: 1.34, 95 %CI: 1.13-1.60; p = 0.007)., Conclusions: In the immunotherapy era, EDIC is an independent predictor of OS and disease control in locally advanced NSCLC, warranting investigation into techniques to reduce dose to the immune compartment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Evaluate factors associated with treatment delays and their effect on survival in laryngeal squamous cell carcinoma., Study Design: Retrospective cohort study., Setting: National Cancer Database., Methods: Patients receiving primary radiation or surgery for laryngeal squamous cell carcinoma were included from 2004 to 2017. The primary outcomes were the diagnosis-to-treatment interval (DTI) and 5-year survival. Variables of prolonged DTI (>30 days) were assessed via logistic regression models. Survival was then assessed through Cox proportional hazards models. Candidate variables for both outcomes included age, sex, race, ethnicity, distance to treatment facility, insurance coverage, treatment facility type, TNM T stage, nodal status, and DTI (in models estimating survival)., Results: An overall 136,203 patients with laryngeal cancer were identified, from which 51,747 remained after exclusions were applied: 18,499 received primary surgery and 33,248 received primary radiation. Being a member of a racial or ethnic minority, advanced age, female sex, ≥30 miles from treatment facility, lack of insurance, treatment at an academic cancer center, and primary radiation were associated with a prolonged DTI. However, in spite of a faster DTI, treatment at a community cancer center was independently associated with higher mortality (hazard ratio, 1.2; P < .0001)., Conclusions: Despite being associated with prolonged DTI, receiving treatment at a high-volume academic facility was associated with significantly improved survival. Our results indicate that improved referral pathways or outreach may help improve survival in laryngeal cancer, especially in high-risk populations.

Background: Operability is both a crucial determinant in treatment selection and a potential confounder in analyses comparing surgery with non-surgical approaches such as stereotactic body radiotherapy (SBRT). We aimed to assess the association between operability status and intervention with post-treatment mortality in early-stage non-small cell lung cancer (NSCLC)., Patients and Methods: We defined four groups of patients with cT1-T2N0M0 NSCLC diagnosed 2010 to 2014 from the National Cancer Database: SBRT patients deemed operable vs. inoperable and surgery patients receiving open vs. minimally-invasive approaches. Mortality rates at 30, 60, and 90 days post-treatment were calculated and compared., Results: We abstracted 80,108 patients, 0.8% undergoing SBRT and operable, 13.2% undergoing SBRT and inoperable, 52.4% undergoing open surgery, and 33.7% undergoing minimally-invasive surgery. Mortality rates were highest among open surgery patients and lowest among operable SBRT patients (2.0% vs. 0.2% at 30 days and 3.7% vs. 0.7% at 90 days), with intermediate results in the other two groups. These findings persisted on multivariate Cox regression: compared to patients undergoing minimally-invasive surgery, mortality risk was highest among open surgery patients (30 days HR 1.32, 95%CI 1.16-1.51; 90 days HR 1.36, 95%CI 1.24-1.50; both P < .001) and lowest among operable SBRT patients (30 days HR 0.09, 95%CI 0.01-0.64; 90 days HR 0.15, 95%CI 0.05-0.46; both P ≤ .016). These associations were maintained in a propensity score-matched subset., Conclusion: Operable patients undergoing SBRT experience minimal post-treatment mortality compared to their inoperable counterparts. These findings illustrate the potential for confounding by operability to bias results in cohort studies that compare surgical vs. non-surgical approaches in early-stage NSCLC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Locoregional recurrence remains common after treatment of head and neck cancer, warranting careful surveillance in follow-up. Although randomized data support an initial positron emission tomography/computed tomography several months after treatment, evidence supporting subsequent imaging is limited, and most recurrences ultimately manifest clinically. Cooperative group studies and consensus guidelines vary widely in their recommendations regarding surveillance imaging. Patients with indeterminate findings, new symptoms, or areas difficult to examine in clinic may avoid invasive and potentially morbid interventions with judicious use of subsequent imaging. For any patient undergoing posttreatment imaging, standardized reporting criteria provide a framework for risk-stratification that can enhance communication and potentially guide management., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: We assessed locoregional control with omission of intentional primary site radiation after transoral robotic surgery (TORS) and quantified nontargeted primary site dose., Methods: Following Institutional Review Board (IRB) approval, patients treated with primary TORS resection for squamous cell carcinomas of the oropharynx were reviewed. Patients with cT1-2 tumors, >2 mm margins, in whom the surgeon resected the primary without revising specimen-driven margins, qualified for omission of primary site radiation., Results: From 2014 to 2019, 112 patients met criteria. Fifty-nine (52%) patients did not receive radiation targeting the primary site; of whom, 22 received no radiation. In this group, there were no local failures; mean age was 58 years and median follow-up was 25 months. Thirty-seven patients received adjuvant radiation targeting the neck, mean bystander dose to the primary site was 28.8 Gy (range, 13.3-50.6 Gy)., Conclusion: In a 59 patient population, omission of radiation to the primary site after TORS resulted in no locoregional failures., (© 2021 Wiley Periodicals LLC.)

Objective: The rising incidence of head and neck squamous cell carcinoma (HNSCC) calls for the assessment and improvement of currently available therapies that may enhance the therapeutic ratio in these patients. Statin drugs are one of the most widely used drug classes in the world for their lipid-lowering properties. As such, statins have been widely studied and found to possess pleiotropic effects that may make them effective in cancer treatment and toxicity mitigation. The aim of this review is to examine the potential use of statin drugs as adjunctive therapy in patients with HNSCC., Data Sources: PubMed., Review Methods: Any preclinical or clinical articles pertaining to the effects of statin drugs on treatment-related toxicity or survival outcomes in patients with head and neck cancer were included in this narrative review., Conclusions: Emerging data suggest that statins may improve survival and reduce toxicities associated with chemotherapy and radiotherapy in patients with head and neck cancer, by mechanisms that are poorly understood at present., Implications for Practice: Given their affordability and safety, statins deserve further study as a tool to improve oncologic outcomes and enhance survivorship in patients with HNSCC., Competing Interests: Disclosures: Competing interests: Nicole C. Schmitt: advisory board—Checkpoint Surgical, Sensorion; book royalties—Plural Publishing; research funding—Astex Pharmaceuticals. Sponsorships: None. Funding source: Supported in part by Winship Cancer Institute., (© The Author(s) 2021.)

Background: Preclinical evidence suggests a link between the renin-angiotensin system and oncogenesis. We aimed to explore the impact of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in head and neck cancer (HNC)., Methods: Over 5000 patients were identified from the Surveillance, Epidemiology, and End Results-Medicare linked dataset and categorized according to ACEi and ARB and diagnoses of chronic kidney disease (CKD) or hypertension (HTN). Overall survival (OS) and cancer-specific survival (CSS) were compared using Cox multivariable regression (MVA), expressed as hazard ratios (HR) with 95% confidence intervals (95%CI)., Results: No significant MVA associations for OS or CSS were found for ACEi. Compared to patients with CKD/HTN taking ARB, those with CKD/HTN not taking ARB experienced worse OS (HR 1.28, 95%CI 1.09-1.51, p = 0.003) and CSS (HR 1.23, 95%CI 1.00-1.50, p = 0.050)., Conclusions: ARB usage is associated with improved OS and CSS among HNC patients with CKD or HTN., (© 2021 Wiley Periodicals LLC.)

Purpose: Phase 1 clinical trials have established low-dose, whole-lung radiation therapy (LD-RT) as safe for patients with coronavirus disease 2019 (COVID-19)-related pneumonia. By focally dampening cytokine hyperactivation, LD-RT may improve disease outcomes through immunomodulation., Methods and Materials: Patients with COVID-19-related pneumonia were treated with 1.5 Gy whole-lung LD-RT, followed for 28 days or until hospital discharge, and compared with age- and comorbidity-matched controls meeting identical disease severity criteria. Eligible patients were hospitalized, severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) positive, had radiographic consolidations, and required supplemental oxygen but had not rapidly declined on admission or before drug therapy or LD-RT. Efficacy endpoints were time to clinical recovery, radiographic improvement, and biomarker response., Results: Ten patients received whole-lung LD-RT between April 24 and May 24, 2020 and were compared with 10 control patients blindly matched by age and comorbidity. Six controls received COVID-19 drug therapies. Median time to clinical recovery was 12 days in the control cohort compared with 3 days in the LD-RT cohort (hazard ratio 2.9, P = .05). Median time to hospital discharge (20 vs 12 days, P = .19) and intubation rates (40% vs 10%, P = .12) in the control and LD-RT cohorts were compared. Median time from admission to recovery was 10 versus 13 days (P = .13). Hospital duration average was 19 versus 22.6 days (P = .53). Average hospital days on supplemental oxygen of any duration was 13.1 versus 14.7 days (P = .69). Average days with a documented fever was 1 versus 4.3 days (P = .12). Twenty-eight-day overall survival was 90% for both cohorts. The LD-RT cohort trended toward superior rates of improved radiographs (P = .12) and delirium (P < .01). Statistically significant reductions were observed in numerous hematologic, cardiac, hepatic, and inflammatory markers., Conclusions: A prospective cohort of predominantly elderly hospitalized patients with COVID-19-related pneumonia were recovered to room air quicker than age- and comorbidity-matched controls, with trending or significant improvements in delirium, radiographs, and biomarkers, and no significant acute toxicity. Low-dose, whole-lung radiation for patients with COVID-19-related pneumonia appears safe and may be an effective immunomodulatory treatment. Larger prospective randomized trials are needed to define the efficacy of LD-RT for COVID-19., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives/hypothesis: For locally advanced oral squamous cell carcinoma (OSCC) treated by surgery and adjuvant therapy, consensus has yet to be reached on whether the optimal time to initiate surveillance positron emission tomography/computed tomography (PET/CT) scan is before or after adjuvant therapy. In this study, we characterize the utility of PET/CT scans obtained 3 months after adjuvant therapy., Study Design: PET/CT scans were obtained for 220 patients with stage III, IVA, or IVB OSCC who underwent resection followed by adjuvant radiotherapy or chemoradiotherapy., Methods: Using the Neck Imaging Reporting and Data System, PET/CT scans were dichotomized as suspicious (primary or neck category ≥3, or distant lesion present) versus nonsuspicious. We then computed differences in locoregional progression, distant progression, and overall survival; positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity; and success rate of salvage., Results: Sixty-seven patients (30%) had suspicious PET/CT scans, which were significantly associated with local failure (hazard ratio [HR] 14.0, 95% confidence interval [CI] 7.3-26.6), distant failure (HR 18.4, 95% CI 9.6-35.3), and poorer overall survival (HR 9.5, 95% CI 5.0-17.9). Overall PPV, locoregional PPV, NPV, sensitivity, and specificity were 85%, 79%, 73%, 58%, and 92%, respectively. Among those with biopsy-confirmed progression, 37 patients (65%) underwent salvage therapy; four (11%) were without evidence of disease at last follow-up., Conclusions: For locally advanced OSCC, PET/CT scan 3 months after adjuvant therapy is strongly predictive of disease recurrence and survival, demonstrating improved performance over postoperative imaging in previous studies. Following a suspicious post-adjuvant therapy PET/CT scan, cure of locoregional recurrence is possible but unlikely., Level of Evidence: 4 Laryngoscope, 2020., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Management of tracheal squamous cell carcinoma (TSCC) has been complicated by the lack of prognostic data and staging. We describe the epidemiology of TSCC and current treatment approaches., Methods: Five hundred thirty-two adult patients with primary TSCC from 2004 to 2012 in the National Cancer Database were identified. Demographic, clinical factors, and 5-year overall survival were analyzed. Staging was classified as localized, regional extension, and distant spread. Treatment modality was defined as "no treatment (NT)," "limited surgery (LS)," "curative surgery (CS)," "LS with any adjuvant therapy (AT) (LS+AT)," "CS with AT (CS+AT)," "radiation therapy (RT)," or "chemoradiation (CRT).", Results: Overall survival was 25%. Majority of cases were males, white, and occurred in sixth/seventh decades. Twenty-six percent of cases received CRT, 20% underwent LS+AT or CS+AT, 20% underwent LS or CS only, and 17% underwent RT alone. On multivariate analysis, CS (HR 0.42, 95% CI: 0.26-0.69), CS+AT (HR 0.44, 95% CI: 0.36-0.77), CRT (HR 0.48, 95% CI: 0.35-0.67), and RT (HR, 0.66 95% CI: 0.46-0.94) were associated with decreased likelihood of death compared to NT. Elderly patients and those with poor performance status had worse outcomes even on multivariate analysis., Conclusions: TSCC is increasingly treated with surgery and systemic therapy in addition to RT, with improved survival outcomes. CS, CS+AT, CRT, or RT provided improved survival advantage in patients with variable levels of improvement based on the extent of the disease. Prospective trials would help differentiate survival advantages between treatment modalities. Patients' goals of care, comorbidities, and age should be considered when deciding appropriate treatment recommendations., Level of Evidence: NA Laryngoscope, 130:405-412, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Background : Early mortality is a major deterrent to oncologic management, often preventing delivery of therapy or leading to administration of treatment that offers limited benefit from aggressive interventions. Due to more recent progress in therapeutic options for stage IV non-small cell lung cancer (NSCLC) patients, identifying those at high risk of early mortality (within 30 days) could have implications for treatment selection. Because early mortality following diagnosis of metastatic non-small cell lung cancer (NSCLC) is not well-characterized, this investigation evaluated national trends and predictors thereof. Material and methods: The National Cancer Database was queried for cases of pathologically confirmed metastatic NSCLC with complete vital status and clinical information, diagnosed between 2006 and 2014. Multivariable logistic regression ascertained factors associated with 30-day mortality. Results: Of 346,681 patients, 45,861 (13%) experienced early mortality over the past decade, which remained relatively constant over time. Predictors of early mortality included advancing age (>65 years), male gender, Caucasian race, non-private insurance, lower income, greater comorbidities, residence in metropolitan and/or lesser-educated areas, treatment at community centers, patients with no prior history of cancer and regional differences ( p  < .01 for all). Early mortality was highest in patients older than 80 years with multiple comorbidities (29%). The majority of patients (71%) who died within 30 days did not receive any therapy. Conclusions: A fair proportion of NSCLC patients experience early mortality, which has not decreased over time. The majority of patients with early mortality do not receive treatment. Prognostic factors for early mortality should be considered during initial evaluation and subsequent follow-up of these patients. Doing so may impact systemic treatment selection by medical oncologists, management of (oligo)metastatic disease by radiation and surgical oncologists and cost-effective administration of these therapies in the stage IV NSCLC population.

Background: The purpose of this analysis is to evaluate whether postoperative radiotherapy (PORT) at the same facility as surgery portends to better survival outcomes compared to PORT given at a different facility., Methods: Patients underwent upfront surgery at the National Cancer Database reporting facility followed by PORT. PORT was coded as performed at either the same facility or at a different facility as surgery., Results: A total of 10 832 patients were selected. Five-year overall survival (OS) was higher in patients undergoing PORT at the same facility: 52.5% vs 48.4% (P < 0.001). PORT performed at the same facility was associated with improved OS under multivariate (HR, 0.92; P = 0.01) and propensity score matched (hazard ratio, 0.90; P = 0.004) analyses., Conclusions: OS was better among patients with head and neck cancer who received PORT at the same facility as surgery., (© 2019 Wiley Periodicals, Inc.)

Objective: Opioid use and abuse is a national health care crisis, yet opioids remain the cornerstone of pain management in cancer. We sought to determine the risk of acute and chronic opioid use with head and neck squamous cell cancer (HNSCC) treatment., Study Design: Retrospective population-based study., Setting: Surveillance, Epidemiology and End Results (SEER)-Medicare database from 2008 to 2011., Subjects and Methods: In total, 976 nondistant metastatic oral cavity and oropharynx patients undergoing cancer-directed treatment enrolled in Medicare were included. Opiate use was the primary end point. Univariate and multivariable logistic analyses were completed to determine risk factors., Results: Of the patients, 811 (83.1%) received an opioid prescription during the treatment period, and 150 patients (15.4%) had continued opioid prescriptions at 3 months and 68 (7.0%) at 6 months. Opioid use during treatment was associated with prescriptions prior to treatment (odds ratio [OR], 3.28; 95% confidence interval [CI], 2.11-5.12) and was least likely to be associated with radiation treatment alone (OR, 0.35; 95% CI, 0.18-0.68). Risk factors for continued opioid use at both 3 and 6 months included tobacco use (OR, 2.23; 95% CI, 1.05-4.71 and OR, 3.84; 95% CI, 1.44-10.24) and opioids prescribed prior to treatment (OR, 3.84; 95% CI, 2.45-5.91 and OR, 3.56; 95% CI, 1.95-6.50). Oxycodone prescribed as the first opioid was the least likely to lead to ongoing use at 3 and 6 months (OR, 0.33; 95% CI, 0.17-0.62 and OR, 0.26; 95% CI, 0.10-0.67)., Conclusion: Patients with oral/oropharyngeal cancer are at a very high risk for receiving opioids as part of symptom management during treatment, and a significant portion continues use at 3 and 6 months after treatment completion.

Objective: Gynecologic oncology group protocol 249 (GOG 249) is the contemporary US study that aimed to define the standard of care adjuvant therapy for patients with high-intermediate risk (HIR) endometrial cancer; patients were randomized to pelvic radiation therapy (RT) or vaginal brachytherapy (VBT) with chemotherapy (VBT-C). The preliminary results of GOG 249 were recently presented, yet the management of patients represented in this trial remains controversial. We set out to review US patterns of care for patients meeting eligibility criteria for GOG 249., Methods: The National Cancer Database (NCDB) was used to identify patients meeting GOG 249 eligibility criteria between 2010 and 2015. The Man-Kendall trend test was used to assess for significant trends over time., Results: We identified 23,015 patients that met study inclusion criteria. Between 2010 and 2015, there was a decline in the use of pelvic RT from 9.8% to 7.5%, although not meeting statistical significance (p = 0.136), and an increase in the use of VBT-C from 4.6% to 7.7% (p = 0.017). Most patients did not receive treatment per either arm of GOG 249, with observation being the most common approach throughout this era, although the percentage of patients observed decreased from 58.1% to 45.8% between 2010 and 2015 (p = 0.003). Further, 21.5% of patients received VBT alone in 2010, increasing to 30.3% by 2015 (p = 0.003)., Conclusions: National practice trends in HIR endometrial cancer reveal that a large number of patients are observed in lieu of receiving adjuvant therapy. Further, the utilization of pelvic RT has declined below utilization of VBT-C, despite a lack of data supporting either improved disease outcomes or toxicity with this experimental regimen on GOG 249., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The comparative efficacy of cisplatin (CDDP), carboplatin, and cetuximab (CTX) delivered concurrently with radiation for locally advanced oropharyngeal squamous cell carcinoma continues to be evaluated., Methods: The linked Surveillance, Epidemiology, and End Results-Medicare database was used to identify and compare patient and disease profiles, mortality, toxicity, and overall cost for patients with oropharynx cancer undergoing definitive concurrent chemoradiation with CDDP, carboplatin, or CTX between 2006 and 2011. The human papillomavirus status was unknown. The primary outcome was 2-year overall survival (OS)., Results: Four hundred nine patients receiving concurrent CDDP (n = 167), carboplatin (n = 69), or CTX (n = 173) were included. Those who were older, those who were nonwhite, and those with a Charlson Comorbidity Index ≥ 2 were less likely to receive CDDP. Two-year OS was inferior with CTX (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.08-2.60; P = .020) and no different with carboplatin (HR, 1.31; 95% CI, 0.73-2.35; P = .362) in a Cox proportional hazards model (reference CDDP). There was no statistically significant difference between carboplatin and CTX (HR, 1.28; 95% CI, 0.77-2.14; P = .891). Rates of antiemetic use and hospital visits for nausea/emesis/diarrhea or dehydration were statistically higher with CDDP. Pneumonia rates were higher with carboplatin. In the multivariate model, the corrected mean per-patient spending was significantly higher for CTX and carboplatin than CDDP ($61,133 and $65,721 vs $48,709)., Conclusions: Patients who received CDDP had improved OS. CDDP was also associated with slightly lower overall costs and higher antiemetic usage and hospital visit rates, although a strong selection bias was observed because those receiving CTX and carboplatin were older and had higher comorbidity scores., (© 2018 American Cancer Society.)