Standardised definitions and diagnostic criteria for extranodal extension detected on histopathological examination in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis.

Criteria for the diagnosis of extranodal extension detected on radiological imaging in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Extranodal extension of tumour on histopathology is known to be a negative prognostic factor in head and neck cancer. Compelling evidence suggests that extranodal extension detected on radiological imaging is also a negative prognostic factor. Furthermore, if imaging detected extranodal extension could be identified reliably before the start of treatment, it could be used to guide treatment selection, as patients might be better managed with non-surgical approaches to avoid the toxicity and cost of trimodality therapy (surgery, chemotherapy, and radiotherapy together). There are many aspects of imaging detected extranodal extension that remain unresolved or are without consensus, such as the criteria to best diagnose them and the associated terminology. The Head and Neck Cancer International Group conducted a five-round modified Delphi process with a group of 18 international radiology experts, representing 14 national clinical research groups. We generated consensus recommendations on the terminology and diagnostic criteria for imaging detected extranodal extension to harmonise clinical practice and research. These recommendations have been endorsed by 19 national and international organisations, representing 34 countries. We propose a new classification system to aid diagnosis, which was supported by most of the participating experts over existing systems, and which will require validation in the future. Additionally, we have created an online educational resource for grading imaging detected extranodal extensions.

Assessment of endpoint definitions in curative-intent trials for mucosal head and neck squamous cell carcinomas: Head and Neck Cancer International Group consensus recommendations.

Robust time-to-event endpoint definitions are crucial for the assessment of treatment effect and the clinical value of trial interventions. Here, the Head and Neck Cancer International Group investigated endpoint use in phase 3 trials and trials considered potentially practice-changing published between 2008 and 2021 in the curative-intent setting for patients with mucosal head and neck squamous cell carcinoma. Of the 92 trials reviewed, we show that all core components of endpoint reporting were heterogeneous, including definitions of common terms, such as overall survival and progression-free survival. Our report highlights the urgent need for harmonisation of fundamental components of clinical trial endpoints and the engagement of all stakeholders to ensure the transparent reporting of endpoint details.

Assessment of endpoint definitions in recurrent and metastatic mucosal head and neck squamous cell carcinoma trials: Head and Neck Cancer International Group consensus recommendations.

Transparent and precise endpoint definitions are a crucial aspect of clinical trial conduct and reporting, and are used to communicate the benefit of an intervention. Previous studies have identified inconsistencies in endpoint definitions across oncological clinical trials. Here, the Head and Neck Cancer International Group assessed endpoint definitions from phase 3 trials or trials considered practice-changing for patients with recurrent or metastatic mucosal head and neck squamous cell carcinoma, published between 2008 and 2021. We identify considerable and global heterogeneity in endpoint definitions, which undermines the interpretation of results and development of future studies. We show how fundamental components of even incontrovertible endpoints such as overall survival vary widely, highlighting an urgent need for increased rigour in reporting and harmonisation of endpoints.

A Hard Truth to Swallow: Critically Evaluating the MD Anderson Dysphagia Inventory (MDADI) as an Endpoint in Human Papillomavirus-associated Oropharyngeal Cancer Trials.

The MD Anderson Dysphagia Inventory (MDADI), a measure of swallowing-related quality of life, has become the preferred patient-reported outcome measure (PROM) in contemporary clinical trials evaluating the experience of human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPVOPSCC) survivors. With many potentially practice-changing studies using the MDADI composite score as either a primary or coprimary endpoint, or as a key secondary endpoint, it is important to understand its psychometric properties as judged by contemporary PROM standards, with a particular focus on its application to contemporary HPVOPSCC populations. In this critical review, we evaluate contemporary HPVOPSCC studies reporting MDADI outcomes, followed by a detailed evaluation of the psychometric properties of the MDADI. Although the focus of this review was the MDADI, the issues discussed are not unique to the MDADI and have broader applicability to the evaluation and assessment of other PROMs currently in use. First, it may be possible to improve administration of the instrument, as related to missing items, scoring, and the number of items required. Second, although in many instances, the MDADI has been intended as a direct or surrogate measure of swallowing physiology, the MDADI composite score captures a broader health-related quality of life construct affected by both swallowing and eating, the latter of which may be affected by a range of nonswallowing treatment-related toxicities. Finally, a clinically meaningful change of 10 in the MDADI composite score, widely accepted and applied to the clinical trial setting, represents an undoubtably clinically relevant difference in unselected head and neck cancer survivors. However, the smallest difference that might be clinically important to a highly functional HPVOPSCC cohort remains uncertain. Understanding the purpose and properties of the MDADI instrument and furthering the sophistication with which we apply it in this population would improve its interpretation in clinical trials.

Essential data variables for a minimum dataset for head and neck cancer trials and clinical research: HNCIG consensus recommendations and database.

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website.

Carotid Artery Stenosis and Ischemic Stroke in Patients With Head and Neck Cancer Treated With Radiation Therapy: A Critical Review.

The purpose of this review is to summarize the literature on carotid artery stenosis (CAS) and ischemic stroke (IS) in patients with head and neck cancer (HNC) treated with radiation therapy (RT) to guide assessment, screening, and management strategies. Patients treated with RT for HNC are at an elevated risk of developing CAS, with published meta-analyses demonstrating that CAS >50% occurs in approximately 25% of patients. Previous research suggests a 10-year cumulative incidence of stroke between 5.7% and 12.5%. Cardiovascular disease (CVD) risk prediction tools such as Qstroke, QRISK-2, and Framingham risk score perform poorly for predicting IS for patients with HNC who received RT. Duplex ultrasound is the most common imaging modality to assess CAS, but controversy remains as to the utility of screening asymptomatic individuals. Only 3 of the 5 major HNC survivorship guidelines acknowledge RT as a risk factor for CAS or IS, while only 1 makes a specific recommendation on screening for CAS (American Head and Neck Society). Within the general population, only 1 CVD guideline discusses RT as a risk factor for CAS (Society for Vascular Surgery). Clinicians involved in the care of patients with HNC treated with RT should be aware of the increased risk of CAS and IS and the challenges in risk prediction. Although there is a lack of evidence to make firm recommendations, HNC survivorship recommendations should ensure HNC survivors and primary care providers are informed of these risks and the importance of assessment and management of CVD risk factors. Future studies are required to refine risk prediction models in patients with HNC and to determine those most likely to benefit from targeted screening and initiation of early preventative strategies.

Combinatorial Approaches for Chemotherapies and Targeted Therapies With Radiation: United Efforts to Innovate in Patient Care.

Combinatorial therapies consisting of radiation therapy (RT) with systemic therapies, particularly chemotherapy and targeted therapies, have moved the needle to augment disease control across nearly all disease sites for locally advanced disease. Evaluating these important combinations to incorporate more potent therapies with RT will aid our understanding of toxicity and efficacy for patients. This article discusses multiple disease sites and includes a compilation of contributions from expert Red Journal editors from each disease site. Leveraging improved systemic control with novel agents, we must continue efforts to study novel treatment combinations with RT.

A Longitudinal Study Evaluating Sexual Health Outcomes and Prioritization in Patients Undergoing Chemoradiation for Human Papillomavirus-Associated Oropharyngeal Cancer.

PURPOSE: The primary objectives were to describe the longitudinal course of sexual health in people undergoing curative (chemo)radiation therapy ([C)RT) for human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPVOPSCC) and identify factors associated with higher sexual satisfaction 12 months after (C)RT. METHODS AND MATERIALS: Eligible participants from 3 sites were recruited to a prospective observational study between October 2020 and November 2021. Measures of sexual health (22-item European Organization for Research and Treatment of Cancer Sexual Health Questionnaire), treatment outcome priorities (Chicago Priorities Scale), quality of life (30-item European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire), symptom burden (MD Anderson Symptom Inventory-Head and Neck), emotional distress (Patient-Reported Outcomes Measurement Information System - Anxiety and Depression), and facial appearance and appearance distress (FACE-Q) were administered before, at the end, and 3 and 12 months after (C)RT. RESULTS: Of 128 eligible participants, 100 were recruited; sexual health measure data were available for 89 of 98 patients alive at 12 months. Mean sexual satisfaction scores were 51.8 (SD = 26.6) before (C)RT. Mixed model results indicated a clinically significant reduction in sexual satisfaction by the end of (-25.4; 95% CI, -30.7 to -20.2) and 3 months after CRT (-12.2; -17.3 to -7.0) but not 12 months after CRT (-3.8; 95% CI, -9.0 to 1.4). Of 13 treatment outcome priorities, "keeping sexual function" had a median rank of 10 and 9 before and 12 months after (C)RT, respectively; 24% and 26% identified it as a top priority at these times. Cohabiting, having a sexual partner, being sexually active, higher global health status, lower sexual health issues, lower depression, and considering sexual function a top priority were associated with higher sexual satisfaction scores 12 months after (C)RT. CONCLUSIONS: Although affected acutely by (C)RT, average sexual satisfaction returned to near pretreatment levels after 12 months. Sexual function is considered a top survivorship priority by approximately one-quarter of patients with HPVOPSCC.

Diagnostic challenges and prognostic implications of extranodal extension in head and neck cancer: a state of the art review and gap analysis.

Extranodal extension (ENE) is a pattern of cancer growth from within the lymph node (LN) outward into perinodal tissues, critically defined by disruption and penetration of the tumor through the entire thickness of the LN capsule. The presence of ENE is often associated with an aggressive cancer phenotype in various malignancies including head and neck squamous cell carcinoma (HNSCC). In HNSCC, ENE is associated with increased risk of distant metastasis and lower rates of locoregional control. ENE detected on histopathology (pathologic ENE; pENE) is now incorporated as a risk-stratification factor in human papillomavirus (HPV)-negative HNSCC in the eighth edition of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) TNM classification. Although ENE was first described almost a century ago, several issues remain unresolved, including lack of consensus on definitions, terminology, and widely accepted assessment criteria and grading systems for both pENE and ENE detected on radiological imaging (imaging-detected ENE; iENE). Moreover, there is conflicting data on the prognostic significance of iENE and pENE, particularly in the context of HPV-associated HNSCC. Herein, we review the existing literature on ENE in HNSCC, highlighting areas of controversy and identifying critical gaps requiring concerted research efforts.

Comprehensive profiling identifies tumour and immune microenvironmental differences in clinical subsets of cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinomas (cSCCs) are the second most diagnosed skin cancer worldwide; however, little is known about the pathobiological factors that contribute to the diverse clinical outcomes seen. OBJECTIVES: To profile cSCCs comprehensively and identify the pathological processes that contribute to the disparities seen in their clinical behaviour. METHODS: We characterized the genomic, transcriptomic and immunohistochemical profiles of 211 cSCC tumours, including 37 cSCCs from immunocompromised patients. RESULTS: cSCCs from immunocompromised patients were characterized by a lack of B cells in the peritumoral stroma compared with immunocompetent patients. Further, an abundance of a memory B-cell-like population in the peritumoral stroma was associated with a better prognosis in all patients (immunocompetent and immunocompromised), as well as only immunocompetent patients. No differences in genetic -variants, tumour mutational burden or mutational signatures were observed between cSCCs from immunocompetent and immunocompromised patients. Thus, differences in survival between cSCCs from immunocompromised patients and immunocompetent patients are not likely to be driven by tumour genomic factors, but may be associated with differential host immune response. cSCC not from a primary head and neck site had lower tumour mutational burden and exhibited upregulation of the epithelial-mesenchymal transition programme compared with head and neck cSCC. Both factors were implicated with poorer responses to immune checkpoint inhibition, and the latter with poorer survival. CONCLUSIONS: We identified tumour and host immune factors that contribute to the disparate clinical behaviour of cSCC, with broad translational application, including prognostication, treatment prediction to current therapies and the identification of novel anticancer therapy approaches in cSCC.

Evaluation of the validity and screening performance of a revised single-item fear of cancer recurrence screening measure (FCR-1r).

OBJECTIVE: Fear of cancer recurrence (FCR) is highly prevalent among cancer survivors, but irregularly identified in practice. Single-item FCR measures suitable for integration into broader psychosocial screening are needed. This study evaluated the validity of a revised version of the original FCR-1 (FCR-1r) and screening performance alongside the Edmonton Symptom Assessment System - Revised (ESAS-r) anxiety item. METHODS: The FCR-1r was adapted from the FCR-1 and modelled on the ESAS-r. Associations between FCR-1r and FCR Inventory-Short Form (FCRI-SF) scores determined concurrent validity. Relationships of FCR-1r scores with variables related (e.g., anxiety, intrusive thoughts) and unrelated (e.g., employment/marital status) to FCR determined convergent and divergent validity respectively. A Receiver-Operating Characteristic analysis examined screening performance and cut-offs for the FCR-1r and ESAS-r anxiety item. RESULTS: 107 participants were recruited in two studies (Study 1, July-October 2021, n = 54; Study 2: November 2021-May 2022, n = 53). The FCR-1r demonstrated concurrent validity against the FCRI-SF (r = 0.83, p < 0.0001) and convergent validity versus the Generalised Anxiety Disorder-7 (r = 0.63, p < 0.0001) and Impact of Event Scale-Revised Intrusion subscale (r = 0.55, p < 0.0001). It did not correlate with unrelated variables (e.g., employment/marital status), indicating divergent validity. An FCR-1r cut-off ≥5/10 had 95% sensitivity and 77% specificity for detecting clinical FCR (area under the curve (AUC) = 0.91, 95% CI 0.85-0.97, p < 0.0001); ESAS-r anxiety cut-off ≥4 had 91% sensitivity and 82% specificity (AUC = 0.87, 95% CI 0.77-0.98, p < 0.0001). CONCLUSIONS: The FCR-1r is a valid and accurate tool for FCR screening. Further evaluation of the screening performance of the FCR-1r versus the ESAS-r anxiety item in routine care is needed.

Patient-Reported Symptom Severity, Health-Related Quality of Life, and Emotional Distress Trajectories During and After Radiation Therapy for Human Papillomavirus-Associated Oropharyngeal Cancer: A TROG 12.01 Secondary Analysis.

PURPOSE: This secondary analysis of clinical trial TROG 12.01, involving patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma, aimed to identify patient-reported outcome (PRO) trajectories before, during, and after chemoradiotherapy. METHODS AND MATERIALS: Head and neck cancer symptom severity (HNSS) and interference (HNSI), generic health-related quality of life (HRQL), and emotional distress were assessed with the MD Anderson Symptom Inventory-Head and Neck, Functional Assessment of Cancer Therapy-General, and Hospital Anxiety and Depression Scale questionnaires, respectively. Latent class growth mixture modeling (LCGMM) was used to identify distinct underlying trajectories. Baseline and treatment variables were compared between trajectory groups. RESULTS: The LCGMM identified latent trajectories for all PROs: HNSS, HNSI, HRQL, anxiety, and depression. Four HNSS trajectories (HNSS1-4) were identified, distinguished by differences in HNSS at baseline, during the peak of treatment symptoms, and during early and intermediate recovery. All trajectories were stable beyond 12 months. The reference trajectory (HNSS4, n = 74) score was 0.1 (95% confidence interval [CI], 0.1-0.2) at baseline, peaking at 4.6 (95% CI, 4.2-5.0), with rapid early recovery (1.1; 95% CI, 0.8-2.2) and gradual improvement to 12 months (0.6; 95% CI, 0.5-0.8). Patients in HNSS2 (high baseline, n = 30) reported higher baseline scores (1.4; 95% CI, 0.8-2.0) but were otherwise similar to HNSS4. Patients in HNSS3 (low acute, n = 53) reported reduced acute symptoms (2.5; 95% CI, 2.2-2.9) with stable scores beyond 9 weeks after chemoradiotherapy (1.1; 95% CI, 0.9-1.4). Patients in HNSS1 (slow recovery, n = 25) had slower recovery from an acute peak of 4.9 (95% CI, 4.3-5.6) to 0.9 (95% CI, 0.6-1.3) at 12 months. Age, performance status, education, receipt of cetuximab, and baseline anxiety varied between trajectories. The other PRO models demonstrated clinically relevant trajectories, with distinct associations with baseline factors. CONCLUSIONS: LCGMM identified distinct PRO trajectories during and after chemoradiotherapy. These and their associations with variations in the characteristics and treatment factors of patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma provide clinically relevant insights into identifying patients who may require increased support before, during, or after chemoradiotherapy.

Treatment outcomes of standard (high dose) cisplatin and non-standard chemotherapy for locally advanced head and neck cancer.

INTRODUCTION: Concurrent chemoradiotherapy with high-dose (HD) cisplatin is the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Due to the higher treatment-related adverse effects with standard therapy, alternative regimens (non-standard therapy), namely, lower dose weekly cisplatin, carboplatin/paclitaxel, or cetuximab are considered. There is, however, no consensus on non-standard regimens. We aimed to investigate the efficacy and safety profile of these regimens. METHODS: This single centre retrospective cohort study included all consecutive adult patients with newly diagnosed LA-HNSCC treated with either standard or non-standard regimens between January 2016 and April 2021. The primary outcome was 2-year failure-free survival (FFS). The secondary outcomes included acute toxicities, hospitalisation rates, dose modifications, treatment failure rates (TFR), and overall survival. RESULTS: About 235 patients were included in the final analysis; median age was 61 years (IQR 55-67), and 87% were male. Most had oropharyngeal tumours (85.5%) and p16-positivity was frequent (80%). About 56% received non-standard regimens: weekly cisplatin = 79 and non-cisplatin = 48. These patients had higher Charlson Comorbidity Index (CCI; p < .001) and lower European Cooperative Oncology Group (ECOG)-0 (p = .003). There was no difference in 2-year FFS (hazard ratio [HR] = 1.16; 95% confidence interval - [CI] 0.65-2.05), hospitalisation and grade-3 toxicity rates between the two regimens. Nausea and vomiting were lower in the non-standard regimen (3.0% vs. 16%, p < .001). Dose reductions, adjusted for age, sex, and CCI, were less likely in the non-standard regimen (OR = 2.36; 95%-CI: 1.01-5.49, p = .007). CONCLUSIONS: We demonstrated similar efficacy of lower dose weekly cisplatin and carboplatin/paclitaxel regimens and better safety profile of weekly cisplatin compared to standard HD cisplatin regimens for LA-HNSCC. Multicenter randomised control trials are required in HD cisplatin-ineligible patients.

Return to work in head and neck cancer survivors: a systematic review.

PURPOSE: Cancer survivors face higher rates of unemployment compared with individuals without a history of cancer. Compared to other cancer types, head and neck cancer (HNC) survivors face unique disease and treatment-specific issues that may limit return to work (RTW). This review aimed to determine employment outcomes of HNC survivors post-treatment and identify factors associated with RTW. METHODS: A systematic search was conducted in MEDLINE, CINAHL and PsycINFO in December 2021. Inclusion criteria included adults (≥ 18 years); completed treatment for HNC; data available on RTW post-treatment. Both quantitative and qualitative studies were considered. Studies were critically appraised and data synthesised narratively. RESULTS: Twenty-nine publications were included: 22 quantitative, four qualitative and three mixed methods. The proportion of HNC survivors who RTW ranged from 32 to 90%, with participants taking 3.6-11 months to RTW. Working in a professional role and having a supportive work environment were positively associated with RTW. CONCLUSIONS: The proportion of HNC survivors who RTW varies significantly which may be due to the heterogeneity between the studies including difference in clinical characteristics of the participants and/or sample size. Future studies that are longitudinal, adequately powered and measure a range of clinical and demographic variables are needed to better understand the RTW experience and assist development of effective RTW strategies. IMPLICATIONS FOR CANCER SURVIVORS: This review suggests potential areas for intervention, including enhanced symptom management and engaging with employers to foster supportive work environments to support RTW of HNC survivors.

Patient- and Clinician-Reported Outcomes in Human Papillomavirus-Associated Tonsillar Carcinoma Treated With Unilateral and Bilateral Intensity Modulated Radiation Therapy-A Substudy From TROG 12.01.

PURPOSE: The aim of this TROG 12.01 substudy was to report longitudinal variations in patient- (PRO) and clinician-reported outcomes based on receipt of unilateral (URT) or bilateral radiation therapy (BRT). METHODS AND MATERIALS: Patients with lateralized T1-2 N1-2b human papillomavirus-associated tonsillar carcinoma (AJCC7) enrolled on TROG 12.01 were eligible. The primary endpoint was patient-reported radiation symptom severity score (MDASI-RSS) at 2 years, a composite of 9 MDASI-Head and Neck (HN) symptom items. Secondary endpoints included patient-reported symptom burden and interference (MDASI-HN), quality of life (FACT-HN), emotional distress (HADS), return to work (RTW), clinician-reported performance status scale (PSS-HN), and late adverse events (CTCAE). Mean MDASI-RSS, symptom severity (MDASI-SS), symptom interference (MDASI-SI) and selected single items were compared 1 week, 3 months, and 2 years post-RT. RESULTS: Seventy-four patients were eligible for analysis (26 URT, 48 BRT). Median follow-up was 3.7 years (1.8-5.2 years). Sociodemographic, staging, and treatment variables were mostly balanced, with larger primaries observed in the BRT group. Four regional failures were reported (3 URT, 1 BRT), including one isolated contralateral regional failure in the URT cohort. Mean MDASI-RSS scores did not differ at 2 years (URT vs BRT, 1.1 vs 1.3; difference 0.1 [95% CI: -0.7 to 0.9], P = .75) or at any other time points for the MDASI-RSS, MDASI-SS, and MDASI-SI scores, except for worse MDASI-SI 1 week after treatment in the BRT group (4.7 vs 5.6). Fatigue (6.6 vs 5.4) at 1 week and dry mouth (3.5 vs 2.0) at 2 years were also worse in the BRT group. FACT-HN, HADS, RTW, PSS-HN, and CTCAE results were similar across the follow-up period. CONCLUSIONS: In this favorable-risk cohort, treatment laterality resulted in fewer differences than anticipated in patient-reported or clinician-reported outcomes. Two years after treatment patients treated with BRT reported significantly worse dry mouth. Longer follow-up is needed to determine the impact of treatment laterality on late effects.