Follow-up for human papillomavirus-related oropharynx cancer concentrated on unequal symptom change (FOCUS): Prospective patient-reported outcome collection.

BACKGROUND: Post-treatment surveillance recommendations for oropharyngeal cancer do not vary with p16 status despite the differences in outcomes. The optimal algorithm personalizing follow-up for these patients remains undefined. Here, we evaluate the feasibility and utility of incorporating electronic patient-reported outcomes (ePROs) and circulating tumor DNA (ctDNA) into routine surveillance for patients treated for p16+ oropharynx cancer. METHODS: A prospective registry was developed in which ePROs and ctDNA were incorporated into routine surveillance among patients with oropharynx cancer. ePROs were emailed monthly for 1 year and blood HPV ctDNA testing was performed every 3-6 months. The primary objective was to assess patient compliance with ePRO-based surveillance with adequate compliance defined as ≥85% of patients completing monthly ePROs. Sensitivity, specificity, and positive/negative predictive values to detect recurrence were calculated for ePROs, HPV ctDNA, or the combination. RESULTS: Of 122 patients who initially expressed interest, 76 completed the electronic consent process and 44/76 (58%) were compliant with monthly surveys over 1 year; thus adequate compliance was not achieved. Technical difficulties associated with ePRO receipt through email largely limited participation. Provider feedback was significantly associated with heightened ePRO compliance. One hundred and six patients had ctDNA testing with a mean number of three tests per patient. Sensitivity to detect recurrence was 75% for the combination of ePROs and ctDNA. CONCLUSION: Despite lower than anticipated compliance with ePROs, our findings show promise for incorporation of HPV ctDNA into surveillance paradigms for HPV-related oropharynx cancer with suggestions of methods to optimize ePRO formats for personalized surveillance.

Clinical, morphologic and molecular heterogeneity of HPV-associated oropharyngeal cancer.

The incidence of human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly and has exceeded cervical cancer to become the most common HPV-induced cancer in developed countries. Since patients with HPV + OPSCC respond very favorably to standard aggressive treatment, the emphasis has changed to reducing treatment intensity. However, recent multi-center clinical trials failed to show non-inferiority of de-escalation strategies on a population basis, highlighting the need to select low-risk patients likely to respond to de-intensified treatments. In contrast, there is a substantial proportion of patients who develop recurrent disease despite aggressive therapy. This supports that HPV + OPSCC is not a homogeneous disease, but comprises distinct subtypes with clinical and biological variations. The overall goal for this review is to identify biomarkers for HPV + OPSCC that may be relevant for patient stratification for personalized treatment. We discuss HPV + OPSCC as a heterogeneous disease from multifaceted perspectives including clinical behavior, tumor morphology, and molecular phenotype. Molecular profiling from bulk tumors as well as single-cell sequencing data are discussed as potential driving factors of heterogeneity between tumor subgroups. Finally, we evaluate key challenges that may impede in-depth investigations of HPV + OPSCC heterogeneity and outline potential future directions, including a section on racial and ethnic differences.

Monitoring Adverse Effects of Radiation Therapy in Patients With Head and Neck Cancer: The FACT-HN-RAD Patient-Reported Outcome Measure.

Importance: Patients undergoing radiation therapy (RT) for head and neck squamous cell carcinoma (HNSCC) experience a range of debilitating adverse effects (AEs). Patient-reported outcome (PRO) measures to quantify these AEs are a necessary and important component of health care; however, currently available PRO options often measure only disease-related symptoms or AEs of non-RT treatments. Objective: To develop a brief PRO measure of the most common AEs associated with RT for HNSCC. Design, Setting, and Participants: This was a qualitative study that followed the US Food and Drug Administration guidelines to develop a brief measure of patient-reported RT-related AEs (the Functional Assessment of Cancer Therapy-Head and Neck Radiotherapy [FACT-HN-RAD] measure). The study included (1) a literature review of clinical trials; (2) secondary analysis of retrospective concept elicitation interviews (CEIs); (3) electronic surveys of practicing radiation oncologists; (4) mapping of existing items to inform the development of the draft version of the measure; and (5) validation of content and face validity via patient cognitive interviews. Analysis was performed of CEI data and interviews with practicing radiation oncologists. Data analysis was conducted from July 1, 2022, to April 21, 2023. Exposures: Surveys and qualitative interviews. Main Outcomes and Measures: The most common patient-reported RT-related AEs among patients with HNSCC. Results: Of 19 CEI participants, 14 (mean [range] age, 67 [49-86] years; 12 [86%] men and 2 [14%] women) described RT-related AEs and were included in the secondary analysis. Eleven (79%) patients reported difficulty swallowing; 8 (57%), oral pain; 7 (50%), dry mouth; 7 (50%), weight loss; 6 (43%), skin burning; 5 (36%), loss of taste; 5 (36%), voice changes (36%); and 5 (36%), fatigue. Nine radiation oncologists (mean [range] time in practice, 8 [1-42] years; 5 [56%] men and 4 [44%] women) reported the most common AEs: 9 (100%) reported dysgeusia; 7 (78%), xerostomia; 7 (78%), mucositis or oral pain; 8 (89%), dysphagia or odynophagia; 6 (67%), dermatitis; and 3 (33%), fatigue. Together these data informed the development of an 8-item AE-focused measure of pain, dysphagia, xerostomia, dysgeusia, voice changes, dermatitis, fatigue, and weight loss. Cognitive interviews with 10 patients (mean [range] age, 61 [29-84] years; 8 [80%] men and 2 [20%] women) demonstrated strong face validity; all (100%) reported that the measure reflected their experience with RT and stated that the length of the questionnaire was "just right." Conclusions and Relevance: The 8-item FACT-HN-RAD measure captures the most common patient- and physician-reported AEs related to RT for HNSCC. This measure offers a means to serially monitor patient-reported treatment-related AEs and recovery over time in both clinical and research settings. Future work will evaluate the psychometric validity of the measure.

The Current Role of Human Papillomavirus Circulating Tumor DNA in Oropharynx Cancer.

ABSTRACT: Human papillomavirus infection is currently implicated in the majority of oropharyngeal squamous cell carcinoma cases diagnosed in the United States. Circulating tumor DNA (ctDNA) has emerged as a potential biomarker for human papillomavirus-related oropharyngeal squamous cell carcinoma and has the opportunity to improve the diagnosis, treatment, and surveillance of patients with this disease. Changes in ctDNA levels during and after primary therapy may be related to disease response, which can possibly have implications for treatment intensification or de-escalation strategies. Further, ctDNA seems to be sensitive and specific for disease recurrence and may improve upon current methods for assessing both treatment response and failure. In this review, we examine the relevant literature on the use of ctDNA for oropharyngeal cancer treatment and surveillance and discuss current limitations and future directions for this promising biomarker.

The Utility of Interim Positron Emission Tomography Imaging to Inform Adaptive Radiotherapy for Head and Neck Squamous Cell Carcinoma.

ABSTRACT: In this article, as part of this special issue on biomarkers of early response, we review the current evidence to support the use of positron emission tomography (PET) imaging during chemoradiation therapy to inform biologically adaptive radiotherapy for head and neck squamous cell carcinoma. We review literature covering this topic spanning nearly 3 decades, including the use of various radiotracers and discoveries of novel predictive PET biomarkers. Through understanding how observational trials have informed current interventional clinical trials, we hope that this review will encourage researchers and clinicians to incorporate PET response criteria in new trial designs to advance biologically optimized radiotherapy.

Initial Feasibility and Acute Toxicity Outcomes From a Phase 2 Trial of 18F-Fluorodeoxyglucose Positron Emission Tomography Response-Based De-escalated Definitive Chemoradiotherapy for p16+ Oropharynx Cancer: A Planned Interim Analysis.

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

Tumor immune microenvironment alterations using induction cetuximab in a phase II trial of deintensified therapy for p16-positive oropharynx cancer.

BACKGROUND: We sought to characterize early changes in CD8+ tumor-infiltrating lymphocytes and tumor transcriptomes after induction cetuximab in a cohort with p16-positive oropharyngeal cancer on a phase II clinical de-escalation trial. METHODS: Tumor biopsies were obtained before and 1 week after a single cetuximab loading dose in eight patients enrolled in a phase II trial of cetuximab and radiotherapy. Changes in CD8+ tumor-infiltrating lymphocytes and transcriptomes were assessed. RESULTS: One week after cetuximab, five patients (62.5%) had an increase in CD8+ cell infiltration with a median (range) fold change of +5.8 (2.5-15.8). Three (37.5%) had unchanged CD8+ cells (median [range] fold change of -0.85 [0.8-1.1]). In two patients with evaluable RNA, cetuximab induced rapid tumor transcriptome changes in cellular type 1 interferon signaling and keratinization pathways. CONCLUSIONS: Within 1 week, cetuximab induced measurable changes in pro-cytotoxic T-cell signaling and immune content.

Development and Clinical Implementation of an Automated Virtual Integrative Planner for Radiation Therapy of Head and Neck Cancer.

Purpose: Head and neck (HN) radiation (RT) treatment planning is complex and resource intensive. Deviations and inconsistent plan quality significantly affect clinical outcomes. We sought to develop a novel automated virtual integrative (AVI) knowledge-based planning application to reduce planning time, increase consistency, and improve baseline quality. Methods and Materials: An in-house write-enabled script was developed from a library of 668 previously treated HN RT plans. Prospective hazard analysis was performed, and mitigation strategies were implemented before clinical release. The AVI-planner software was retrospectively validated in a cohort of 52 recent HN cases. A physician panel evaluated planning limitations during initial deployment, and feedback was enacted via software refinements. A final second set of plans was generated and evaluated. Kolmogorov-Smirnov test in addition to generalized evaluation metric and weighted experience score were used to compare normal tissue sparing between final AVI planner versus respective clinically treated and historically accepted plans. A t test was used to compare the interactive time, complexity, and monitor units for AVI planner versus manual optimization. Results: Initially, 86% of plans were acceptable to treat, with 10% minor and 4% major revisions or rejection recommended. Variability was noted in plan quality among HN subsites, with high initial quality for oropharynx and oral cavity plans. Plans needing revisions were comprised of sinonasal, nasopharynx, P-16 negative squamous cell carcinoma unknown primary, or cutaneous primary sites. Normal tissue sparing varied within subsites, but AVI planner significantly lowered mean larynx dose (median, 18.5 vs 19.7 Gy; P < .01) compared with clinical plans. AVI planner significantly reduced interactive optimization time (mean, 2 vs 85 minutes; P < .01). Conclusions: AVI planner reliably generated clinically acceptable RT plans for oral cavity, salivary, oropharynx, larynx, and hypopharynx cancers. Physician-driven iterative learning processes resulted in favorable evolution in HN RT plan quality with significant time savings and improved consistency using AVI planner.

Immunogenetic Determinants of Susceptibility to Head and Neck Cancer in the Million Veteran Program Cohort.

Increasing rates of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and 16,048 matched controls. Significant polymorphisms were further examined in a non-Hispanic white (NHW) validation cohort (OPC = 1,206; non-OPC = 955; controls = 4,507). For overall HNSCC susceptibility in NHWs, we discovered and validated a novel 9q31.1 SMC2 association and replicated the known 6p21.32 HLA-DQ-DR association. Six loci/genes for overall HNSCC susceptibility were selectively enriched in African-Americans (6p21.32 HLA-G, 9q21.33 GAS1, 11q12.2 CD6, 11q23.2 NCAM1/CD56, 17p13.1 CD68, 18q22.2 SOCS6); all 6 genes function in antigen-presenting regulation and T-cell activation. Two additional loci (10q26 DMBT1, 15q22.2 TPM1) were uncovered for non-OPC susceptibility, and three loci (11q24 CRTAM, 16q21 CDH5, 18q12.1 CDH2) were identified for HPV-positive OPC susceptibility. This study underscores the role of immune gene variants in modulating susceptibility for both HPV-driven and non-HPV-driven HNSCC. Additional large studies, particularly in racially diverse populations, are needed to further validate the associations and to help elucidate other potential immune factors and mechanisms that may underlie HNSCC risk. SIGNIFICANCE: Several inherited variations in immune system genes are significantly associated with susceptibility to head and neck cancer, which could help improve personalized cancer risk estimates.

Prognostic value of CD103+ tumor-infiltrating lymphocytes and programmed death ligand-1 (PD-L1) combined positive score in recurrent laryngeal squamous cell carcinoma.

OBJECTIVES: In an evolving era of immunotherapeutic options for persistent or recurrent laryngeal squamous cell carcinoma (LSCC), there is a need for improved biomarkers of treatment response and survival to inform optimal treatment selection and prognostication. Herein, our primary objective was to explore correlations between tumor infiltrating lymphocytes (TILs) and PD-L1 Combined Positive Score (CPS). Secondarily, we sought to explore their combined association with survival outcomes in patients with persistent or recurrent LSCC treated with salvage surgery. MATERIALS AND METHODS: This was a retrospective cohort study at a single academic medical center. Immunohistochemistry staining for TILs and PD-L1 was performed on a tissue microarray of persistent or recurrent LSCC pathologic specimens. Correlations between TIL subsets and PD-L1 CPS were examined using Pearson's correlation coefficient and survival outcomes were analyzed with the Kaplan-Meier method and log-rank tests. RESULTS: Only CD103+ TILs showed a statistically significant, weakly-positive correlation with PD-L1 CPS (r2 = 0.264, p < 0.015). No other TIL subsets correlated with PD-L1 CPS in our cohort. The most favorable survival outcomes were seen in patients with pathologic N0 tumors showing high CD103+ TILs and/or high PD-L1 CPS staining. CONCLUSION: Among patients with persistent or recurrent LSCC, CD103+ TILs only modestly correlated with PD-L1 CPS. A combined biomarker score incorporating CD103+ TILs and PD-L1 CPS greatly enhanced survival discrimination. This model may have additional utility in predicting the clinical benefit of immunotherapies in persistent or recurrent LSCC in the future.

Randomized Phase II Study of Physiologic MRI-Directed Adaptive Radiation Boost in Poor Prognosis Head and Neck Cancer.

PURPOSE: We conducted a randomized phase II multicenter clinical trial to test the hypothesis that physiologic MRI-based radiotherapy (RT) dose escalation would improve the outcome of patients with poor prognosis head and neck cancer. PATIENTS AND METHODS: MRI was acquired at baseline and at RT fraction 10 to create low blood volume/apparent diffusion coefficient maps for RT boost subvolume definition in gross tumor volume. Patients were randomized to receive 70 Gy (standard RT) or 80 Gy to the boost subvolume (RT boost) with concurrent weekly platinum. The primary endpoint was disease-free survival (DFS) with significance defined at a one-sided 0.1 level, and secondary endpoints included locoregional failure (LRF), overall survival (OS), comparison of adverse events and patient reported outcomes (PRO). RESULTS: Among 81 randomized patients, neither the primary endpoint of DFS (HR = 0.849, P = 0.31) nor OS (HR = 1.19, P = 0.66) was significantly improved in the RT boost arm. However, the incidence of LRF was significantly improved with the addition of the RT boost (HR = 0.43, P = 0.047). Two-year estimates [90% confidence interval (CI)] of the cumulative incidence of LRF were 40% (27%-53%) in the standard RT arm and 18% (10%-31%) in the RT boost arm. Two-year estimates (90% CI) for DFS were 48% (34%-60%) in the standard RT arm and 57% (43%-69%) in the RT boost arm. There were no significant differences in toxicity or longitudinal differences seen in EORTC QLQ30/HN35 subscales between treatment arms in linear mixed-effects models. CONCLUSIONS: Physiologic MRI-based RT boost decreased LRF without a significant increase in grade 3+ toxicity or longitudinal PRO differences, but did not significantly improve DFS or OS. Additional improvements in systemic therapy are likely necessary to realize improvements in DFS and OS.

Magnetic Resonance Guided Radiotherapy for Head and Neck Cancers.

Radiotherapy is an integral component of head/neck squamous cell carcinomas (HNSCCs) treatment, and technological developments including advances in image-guided radiotherapy over the past decades have offered improvements in the technical treatment of these cancers. Integration of magnetic resonance imaging (MRI) into image guidance through the development of MR-guided radiotherapy (MRgRT) offers further potential for refinement of the techniques by which HNSCCs are treated. This article provides an overview of the literature supporting the current use of MRgRT for HNSCC, challenges with its use, and developing research areas.

Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: Patients with resected, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%-69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear. PATIENTS AND METHODS: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1-3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60-66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0. RESULTS: From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27-80), 30% were female, 86% had stage T3-T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%-90%) in the intermediate-risk group and 66% (95% CI, 55%-84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%-77%). No new safety signals were identified. CONCLUSIONS: Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.

Financial Hardship in Patients With Head and Neck Cancer.

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.

Imaging response assessment for predicting outcomes after bioselection chemotherapy in larynx cancer: A secondary analysis of two prospective trials.

BACKGROUND AND PURPOSE: Bioselection with induction chemotherapy in larynx cancer is associated with excellent larynx preservation and disease-specific survival but requires visual inspection of the primary tumor. We retrospectively compare clinical and imaging response in bioselected patients to develop predictive models of surgeon-assessed response (SR), laryngectomy-free survival (LFS), and overall survival (OS) in bioselected patients. MATERIALS AND METHODS: In a secondary analysis of patients on two single-institution bioselection trials, model building used a regularized regression model (elastic-net) and applied nested cross-validation. Logistic regression-based model was used to predict SR and Cox proportional hazard-based models were used to predict LFS and OS. RESULTS: In 115 patients with a median age of 57 years, most patients had supraglottic tumors (73.0%) and T3/T4 disease (94.8%). Definitive treatment was chemoradiation in 76.5% and laryngectomy in 23.5%. Change in primary tumor (OR = 5.78, p < 0.001) and N-classification (OR = 1.64, p = 0.003) predicted SR (AUC 0.847). Change in tumor volume (HR = 0.58, p < 0.001) predicted LFS (c-index 0.724). N-classification (HR = 1.48, p = 0.04) and pre-chemotherapy tumor volume (HR = 1.30, p = 0.174) predicted OS (c-index 0.552). CONCLUSIONS: Imaging offers a non-invasive opportunity to evaluate response to induction chemotherapy, complementary to surgeon assessment. Further evaluation of approaches to bioselection that optimize generalizability of this paradigm are needed, and clinical trials utilizing imaging to predict outcomes including LFS are warranted.

A Consideration for Surgical Management in Select T4b Oral Cavity Squamous Cell Carcinoma.

OBJECTIVES: The role of surgery for conventionally "unresectable" (cT4b) oral cavity squamous cell carcinoma is unclear. We analyzed factors associated with overall survival in cT4b relative to cT4a oral cavity squamous cell carcinoma. METHODS: We identified 6830 cT4a and 522 cT4b oral cavity squamous cell carcinoma chemoradiation or surgery + adjuvant therapy patients in the National Cancer Data Base from 2004 to 2016. The main outcome was overall survival. Statistical analysis was performed using chi-squared tests, univariable and multivariable regression analysis. RESULTS: The cT4b group had a higher rate of positive margins (30.4% vs 21.3%, P = .009) and downstaging (41.2% vs 13.1%; P < .001) compared to cT4a, while only 1.7% were upstaged. cT4b surgery + chemoradiation patients had similar survival to cT4a surgery + radiation (HR 0.93; 95% CI, 0.70-1.25) and cT4a surgery + chemoradiation patients (HR, 0.92; 95% CI, 0.69-1.23), while cT4b surgery + radiation patients had worse OS (HR, 1.55; 95% CI, 1.05-1.47). CONCLUSIONS: Clinical T4b staging is a poor predictor of pathologic staging given a high rate of downstaging on final pathology. Surgical resection with adjuvant chemoradiation is an option in select cT4b oral cavity squamous cell carcinoma patients.

Tumor-Infiltrating Lymphocytes in Patients With Advanced Laryngeal Cancer Undergoing Bioselection.

OBJECTIVE: Bioselection to assess tumor response after induction chemotherapy has been introduced as an alternative treatment strategy to total laryngectomy for patients with advanced larynx squamous cell carcinoma (LSCC). Tumor-infiltrating lymphocytes (TILs) have proven to serve as prognostic biomarkers in head and neck cancer but have not been evaluated as a way to select patients for treatment paradigms. The aim of this study is to evaluate the role of pretreatment TILs in patients with advanced LSCC undergoing the bioselection paradigm. STUDY DESIGN: Retrospective study. SETTING: Tertiary care hospital. METHODS: Patients with advanced LSCC treated with bioselection and available tissue were included (N = 76). Patients were stratified into CD8-low and CD8-high cohorts by using the median TIL count. Kaplan-Meier survival analysis and multivariate cox regression were performed with SPSS version 26 (IBM). RESULTS: After controlling for tobacco use, tumor site, and stage, a high CD8 TIL count was an independent predictor of improved 5-year disease-specific survival (hazard ratio, 0.17 [95% CI, 0.03-0.84]; P = .03). CD8 TIL counts did not predict response to induction chemotherapy; however, subgroup analysis of patients treated with chemoradiation therapy revealed that CD8 TIL count was significantly associated with degree of response (P = .012). CONCLUSION: These findings support prior data published by our group showing that TILs are predictive of disease-specific survival in patients with head and neck cancer. CD8 TIL counts were significantly associated with degree of clinical response after induction chemotherapy. These results suggest that pretreatment assessment of tumor-infiltrating CD8 cells could be useful in selecting patients.

Development and Assessment of a Model for Predicting Individualized Outcomes in Patients With Oropharyngeal Cancer.

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

Adjuvant radiation and cetuximab improves local control in head and neck cutaneous squamous cell carcinoma: Phase II study.

BACKGROUND: Cutaneous squamous cell carcinoma of the head/neck (CSCCHN) is common due to chronic sun exposure. As CSCCHN highly expresses EGFR, we prospectively studied postoperative concurrent cetuximab with radiotherapy for locally advanced CSCCHN (LA-CSCCHN). MATERIALS AND METHODS: Single-institutional phase II trial of LA-CSCCHN (NCT XXXX). Adjuvant radiation was given with concurrent cetuximab. Primary endpoint of 2-year LRC and secondary objectives of 2-year disease-free survival (DFS) and 2-year OS were assessed by Kaplan-Meier analysis. RESULTS: Twenty-four patients ages 47-88 (median 71 years) were treated from 2014 to 2017. Fourteen patients had T3/4 disease, 5 had N1 disease, and 7 were N2/3. At median follow-up of 42 months, median OS and DFS was not reached and 64 months. Two-year OS was 75%, 2-year DFS was 70.8%. LRC was 91.1% at 2 years. All grade 3 adverse events were related to skin toxicity (12.5% radiation-related dermatitis, 16.7% cetuximab-related rash). CONCLUSIONS: LRC compares favorably to historical data examining postoperative radiation alone but requires further investigation.

Patient Burden with Current Surveillance Paradigm and Factors Associated with Interest in Altered Surveillance for Early Stage HPV-Related Oropharyngeal Cancer.

INTRODUCTION: Optimal surveillance paradigms for survivors of early stage human papillomavirus (HPV)-related oropharyngeal cancer are not well defined. This study aimed to characterize patient interest in and factors associated with an altered surveillance paradigm. MATERIALS AND METHODS: We surveyed patients with Stage I or II HPV-related oropharyngeal cancer treated at a tertiary care institution from 2016 to 2019. Primary outcomes were descriptive assessment of patient knowledge, interest in altered surveillance, burdens of in-person appointments, and priorities for surveillance visits. Ordinal regression was used to identify correlates of interest in altered surveillance. RESULTS: Sixty-seven patients completed surveys from February to April 2020 at a median of 21 months since completing definitive treatment. A majority (61%) of patients were interested in a surveillance approach that decreased in-person clinic visits. Patients who self-identified as medical maximizers, had higher worry of cancer recurrence, or were in long-term relationships were less likely to be interested. Patients reported significant burdens associated with surveillance visits, including driving distance, time off work, and nonmedical costs. Patients were most concerned with discussing cancer recurrence (76%), physical quality of life (70%), mortality (61%), and mental quality of life (52%) with their providers at follow-up visits. CONCLUSION: Patients with early stage HPV-related oropharyngeal cancers are interested in altered surveillance approaches, experience significant burdens related to surveillance visits, and have concerns that are not well addressed with current surveillance approaches, including physical and mental quality of life. Optimized surveillance approaches should incorporate patient priorities and minimize associated burdens. IMPLICATIONS FOR PRACTICE: The number of patients with HPV-related oropharyngeal cancers is increasing, and numerous clinical trials are investigating novel approaches to treating these good-prognosis patients. There has been limited work assessing optimal surveillance paradigms in these patients. Patients experience significant appointment-related burdens and have concerns such as physical and mental quality of life. Additionally, patients with early stage HPV-related oropharyngeal cancers express interest in altered surveillance approaches that decrease in-person clinic visits. Optimization of surveillance paradigms to promote broader survivorship care in clinical practice is needed.