Search

Objective: Stage 3 patients with clinically positive nodal metastasis are treated with therapeutic neck dissection and adjuvant systemic therapy. The aim of our study was to examined the predictability of pre-operative CT as a nodal drainage assessment tool., Methods: Retrospective review of all patients with clinically positive head and neck cutaneous melanoma between 2010 and 2019. Clinical disease was diagnosed as radiological suspicious, biopsy-proven node. A pre-operative CT evaluation for nodal metastasis was compared to pathology report., Results: A total of 53 patients were included. Forty patients (75.5%) were males with a mean age of 59 (SD 15.52). The majority of patients (26.4%) had an unknown primary site. The most common sites for primary were the cheek in eight patients (15.1%) followed by forehead (9.4%) and lateral neck (9.4%). Preoperative CT predicted nodal disease in 84.6% of cases. The primary region that mainly failed from the previously described clinical prediction was the upper anterior neck with 83.3% parotid involvement. A total of 10 patients (18.9%) were diagnosis with non-clinical nodes on pathology with a median non-clinical node of 1 (range 1-2). Of them, 9 (90%) were in the same clinical levels detected by CT. Pre-operative CT was associated with a neck level accuracy of 98.1%., Conclusion: Stage 3 head and neck melanoma with clinically positive nodal metastasis that are eligible for an adjuvant systemic treatment, may benefit from a highly selective neck dissection according to their pre-operative imaging studies. This should be further evaluated in a large-scale clinical trial., Level of Evidence: 3 Laryngoscope, 134:4292-4297, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes., (© 2024. The Author(s).)

Background: The causes for delays during the COVID19 pandemic and their impact on head and neck cancer (HNC) diagnosis and staging are not well described., Methods: Two cohorts were defined a priori for review and analysis-a Pre-Pandemic cohort (June 1 to December 31, 2019) and a Pandemic cohort (June 1 to December 31, 2020). Delays were categorized as COVID-19 related or not, and as clinician, patient, or policy related., Results: A total of 638 HNC patients were identified including 327 in the Pre-Pandemic Cohort and 311 in the Pandemic Cohort. Patients in the Pandemic cohort had more N2-N3 category (41% vs. 33%, p = 0.03), T3-T4 category (63% vs. 50%, p = 0.002), and stage III-IV (71% vs. 58%, p < 0.001) disease. Several intervals in the diagnosis to treatment pathway were significantly longer in the pandemic cohort as compared to the Pre-Pandemic cohort. Among the pandemic cohort, 146 (47%) experienced a delay, with 112 related to the COVID-19 pandemic; 80 (71%) were clinician related, 15 (13%) were patient related, and 17 (15%) were policy related., Conclusions: Patients in the Pandemic cohort had higher stage disease at diagnosis and longer intervals along the diagnostic pathway, with COVID-19 related clinician factors being the most common cause of delay., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Purpose: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN., Methods: Consecutive patients with head and neck cancer (HNC) treated with curative-intent intensity-modulated radiation therapy (IMRT) (≥45 Gy) from 2011 to 2017 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared with 15 existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection)., Results: ORN was identified in 219 of 2,732 (8%) consecutive patients with HNC. Factors associated with high risk of ORN were oral cavity or oropharyngeal primaries, received IMRT dose ≥60 Gy, current/ex-smokers, and/or stage III to IV periodontal condition. The ORN rate for high-risk versus low-risk patients was 12.7% versus 3.1% ( P < .001) with an AUC of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, ClinRad, was proposed on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems., Conclusion: We identified risk factors for ORN and proposed a novel ORN classification system on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN and may facilitate clinical care and clinical trials.

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4-6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection., (© 2024. The Author(s).)

Background: For oral cavity squamous cell carcinoma (OSCC), extent of extranodal extension (ENE) (minor, ≤2 mm; major, >2 mm) is differentially prognostic, whereas limitations exist with the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N-classification (TNM-8-N)., Methods: Resected OSCC patients at four centers were included and extent of ENE was recorded. Thresholds for optimal overall survival (OS) discrimination of lymph node (LN) features were established. After dividing into training and validation sets, two new N-classifications were created using 1) recursive partitioning analysis (RPA), and 2) adjusted hazard ratios (aHRs) and were ranked against TNM-8-N and two published proposals., Results: A total of 1460 patients were included (pN0: 696; pN+: 764). Of the pN+ cases, 135 (18%) had bilateral/contralateral LNs; 126 (17%) and 244 (32%) had minor and major ENE, and two (0.3%) had LN(s) >6 cm without ENE (N3a). LN number (1 and >1 vs. 0: aHRs, 1.92 [95% confidence interval (CI), 1.44-2.55] and 3.21 [95% CI, 2.44-4.22]), size (>3 vs. ≤3 cm: aHR, 1.88 [95% CI, 1.44-2.45]), and ENE extent (major vs. minor: aHR, 1.40 [95% CI, 1.05-1.87]) were associated with OS, whereas presence of contralateral LNs was not (aHR, 1.05 [95% CI, 0.81-1.36]). The aHR proposal provided optimal performance with these changes to TNM-8-N: 1) stratification of ENE extent, 2) elimination of N2c and 6-cm threshold, and 3) stratification of N2b by 3 cm threshold., Conclusion: A new N-classification improved staging performance compared to TNM-8-N, by stratifying by ENE extent, eliminating the old N2c category and the 6 cm threshold, and by stratifying multiple nodes by size., (© 2023 American Cancer Society.)

Oral toxicities such as osteoradionecrosis can be minimized by dental screening and prophylactic dental care prior to head and neck (HN) radiation therapy (RT). However, limited information is available about how dental insurance interacts with prophylactic dental care and osteoradionecrosis. To address this gap in knowledge, we conducted a cohort study of 2743 consecutive adult patients treated with curative radiation for HN malignancy who underwent pre-radiation dental assessment and where required, prophylactic dental treatment. Charts were reviewed to determine patient demographics, dental findings, dental treatment and development of osteoradionecrosis following radiation. Three insurance cohorts were identified: private-insured (50.4 %), public-insured (7.3 %), being patients with coverage through government-funded disability and welfare programs, and self-pay (42.4 %). More than half the public-insured patients underwent prophylactic pre-radiation dental extractions, followed by self-pay patients (44 %) and private-insured patients (26.6 %). After a median follow-up time of 4.23 years, 6.5 % of patients developed osteoradionecrosis. The actuarial rate of osteoradionecrosis in the public-insured patients was 14.7 % at 5-years post-RT, compared to 7.5 % in private-insured patients and 6.7 % in self-pay patients. On multivariable analysis, dental insurance status, DMFS160, age at diagnosis, sex, tumor site, nodal involvement, years smoked and gross income were all significant risk factors for tooth removal prior to HN radiation. However, only public-insured status, tumor site and years smoked were significant risk factors for development of osteoradionecrosis. Our findings demonstrate that lack of comprehensive dental coverage (patients who self-pay or who have limited coverage under public-insured programs) associates strongly with having teeth removed prior to HN RT. Nearly 1 in 6 patients covered under public-insurance developed osteoradionecrosis within 5 years of completing their treatment. Well-funded dental insurance programs for HN cancer patients might reduce the number of pre-RT extractions performed in these patients, improving quality of life post-RT., 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 © 2023 Elsevier Ltd. All rights reserved.)

Objective: We recently described the development of the Neck Fibrosis Scale (NFS). In this submission, we confirm domain structure and validate a scoring system for the NFS., Study Design: Prospective cross-sectional study., Methods: Between January 2020 and December 2021, 127 head and neck cancer patients with varying degrees of cutaneous neck fibrosis completed the original 15 item NFS. Exploratory factor analysis was used to identify optimal groupings with similar underlying factors. The association between the domains of the NFS and various measures of neck morbidity (i.e., construct validity) were assessed using gamma regression., Results: Exploratory factor analysis confirmed 13 of the 15 items from the NFS mapped onto two factors, which were labelled 'physical' and 'emotional' domains. Of the remaining two items, 'energy' did not load uniquely onto one factor and was removed. 'Neck-swelling' did not load on either factor (loadings <0.3) but was retained within the physical domain based on clinical importance. This resulted in a revised 14-item questionnaire. Internal consistency for these two domains was high (>0.8, p < 0.01). Both the physical and emotional domains of the revised NFS show strong correlation with the neck dissection impairment index and neck range of motion. The physical domain strongly correlated with neck elasticity (0.902 [95%CI 0.839-0.972], p < 0.01). Patients receiving multimodal therapy had physical domain scores that were 31.6% [95% 13.9-51.8] higher (worse) than unimodal therapy patients., Conclusions: A domain structure and scoring strategy have been developed for the NFS. Future efforts should be directed toward an evaluation of responsiveness., Level of Evidence: NA Laryngoscope, 133:2198-2202, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Postoperative head and neck cancer patients are at increased risk for alcohol withdrawal syndrome. Literature has shown that in this patient population, alcohol withdrawal is associated with an increase in postoperative medical and surgical complications, length of hospitalization, and hospital-related costs. Harm reduction and addiction medicine philosophies can reduce morbidity and mortality, but have not been fully validated in perioperative surgical management for head and neck cancer. This commentary synthesizes key principles of addiction medicine and current strategies that Otolaryngology-Head and Neck Surgery surgeons can consider in their perioperative assessment and management of alcohol withdrawal syndrome in their patients., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Background: Tobacco use is a major risk factor for developing head and neck squamous cell carcinoma (HNSCC). However, the prognostic associations with smoking cessation are limited. The authors assessed whether smoking cessation and increased duration of abstinence were associated with improved overall (OS) and HNSCC-specific survival., Methods: Clinicodemographic and smoking data from patients with HNSCC at Princess Margaret Cancer Center (2006-2019) were prospectively collected. Multivariable Cox and Fine and Gray competing-risk models were used to assess the impact of smoking cessation and duration of abstinence on overall mortality and HNSCC-specific/noncancer mortality, respectively., Results: Among 2482 patients who had HNSCC, former smokers (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.58-0.87; p = .001; N = 841) had a reduced risk of overall mortality compared with current smokers (N = 931). Compared with current smokers, former smokers who quit >10 years before diagnosis (long-term abstinence; n = 615) had the most improved OS (aHR, 0.72; 95% CI, 0.56-0.93; p = .001). The 5-year actuarial rates of HNSCC-specific and noncancer deaths were 16.8% and 9.4%, respectively. Former smokers (aHR, 0.71; 95% CI, 0.54-0.95; p = .019) had reduced HNSCC-specific mortality compared with current smokers, but there was no difference in noncancer mortality. Abstinence for >10 years was associated with decreased HNSCC-specific death compared with current smoking (aHR, 0.64; 95% CI, 0.46-0.91; p = .012). Smoking cessation with a longer duration of quitting was significantly associated with reduced overall and HNSCC-specific mortality in patients who received primary radiation., Conclusions: Smoking cessation before the time of diagnosis reduced overall mortality and cancer-specific mortality among patients with HNSCC, but no difference was observed in noncancer mortality. Long-term abstinence (>10 pack-years) had a significant OS and HNSCC-specific survival benefit., (© 2023 American Cancer Society.)

Importance: While several studies have documented a link between socioeconomic status and survival in head and neck cancer, nearly all have used ecologic, community-based measures. Studies using more granular patient-level data are lacking., Objective: To determine the association of baseline annual household income with financial toxicity, health utility, and survival., Design, Setting, and Participants: This was a prospective cohort of adult patients with head and neck cancer treated at a tertiary cancer center in Toronto, Ontario, between September 17, 2015, and December 19, 2019. Data analysis was performed from April to December 2021., Exposures: Annual household income at time of diagnosis., Main Outcome and Measures: The primary outcome of interest was disease-free survival. Secondary outcomes included subjective financial toxicity, measured using the Financial Index of Toxicity (FIT) tool, and health utility, measured using the Health Utilities Index Mark 3. Cox proportional hazards models were used to estimate the association between household income and survival. Income was regressed onto log-transformed FIT scores using linear models. The association between income and health utility was explored using generalized linear models. Generalized estimating equations were used to account for patient-level clustering., Results: There were 555 patients (mean [SD] age, 62.7 [10.7] years; 109 [20%] women and 446 [80%] men) included in this cohort. Two-year disease-free survival was worse for patients in the bottom income quartile (<$30 000: 67%; 95% CI, 58%-78%) compared with the top quartile (≥$90 000: 88%; 95% CI, 83%-93%). In risk-adjusted models, patients in the bottom income quartile had inferior disease-free survival (adjusted hazard ratio, 2.13; 95% CI, 1.22-3.71) and overall survival (adjusted hazard ratio, 2.01; 95% CI, 0.94-4.29), when compared with patients in the highest quartile. The average FIT score was 22.6 in the lowest income quartile vs 11.7 in the highest quartile. In adjusted analysis, low-income patients had 12-month FIT scores that were, on average, 134% higher (worse) (95% CI, 16%-253%) than high-income patients. Similarly, health utility scores were, on average, 0.104 points lower (95% CI, 0.026-0.182) for low-income patients in adjusted analysis., Conclusions and Relevance: In this cohort study, patients with head and neck cancer with a household income less than CAD$30 000 experienced worse financial toxicity, health status, and disease-free survival. Significant disparities exist for Ontario's patients with head and neck cancer.

Background: Risk of contralateral nodal metastases in oropharyngeal squamous cell carcinoma (OPSCC) is relatively low, however, many OPSCC patients receive bilateral neck treatment. This study evaluates the oncological outcomes with management of the contralateral cN0 neck based on lymphatic mapping with single photon emission computed tomography (SPECT-CT)., Methods: Retrospective evaluation of patients with lateralized cT1-2 and contralateral cN0 OPSCC treated with primary surgery between December 2017 and October 2019. All patients underwent pre-operative lymphatic mapping using SPECT-CT. Clinical parameters including demographics, tumor characteristics and oncological outcomes were recorded., Results: Thirteen patients underwent primary site resection with transoral robotic surgery (TORS) and ipsilateral neck dissection with or without adjuvant therapy. Twelve patients (92.3%) had ipsilateral drainage on SPECT-CT, whereas 1 (7.7%) patient had bilateral neck lymphatic drainage. Four patients (30.8%) underwent post-operative radiation therapy (PORT). Three patients with unilateral drainage on SPECT-CT underwent PORT with unilateral neck irradiation, and 1 patient with bilateral drainage underwent PORT with bilateral neck irradiation. Seven (53.8%) patients were staged as pT1, 6 (46.2%) patients as pT2, 6 (46.2%) patients were pN0, 3 (23.1%) patients were pN1, 1 (7.7%) patient was pN2a for and 3 (23.1%) patients were N2b. The median distance of the tumor from midline was 1.05 cm (0.0-1.58). Primary sites included tonsil (n = 10, 76.9%) and tongue base (n = 3, 23.1%). The median follow-up time was 15.4 months. All patients were disease free at the latest follow-up with no contralateral neck failures., Conclusions: Pre-operative mapping of lymphatic drainage in early stage OPSCC with SPECT-CT is a promising tool which can reduce treatment to the contralateral neck potentially without compromising oncological outcomes., (© 2022. The Author(s).)

Purpose: Intensity-modulated radiation therapy (IMRT) has enabled risk-tailored approach to elective mucosal and nodal clinical target volumes (CTVs) in treatment of head and neck carcinoma of unknown primary (HNCUP). This study report outcomes following such approach., Methods: HNCUP patients treated with definitive IMRT between 2005 and 2018 were reviewed. Local failure (LF), regional failure (RF), distant metastasis (DM), overall survival (OS) and grade ≥3 late toxicity (LT) were analyzed. Multivariable analysis (MVA) was used to identify OS predictors for entire cohort and cN2-3 subgroup., Results: A total of 203 patients were eligible: cN1 (7%), cN2a (14%), cN2b (46%), cN2c (14%) and cN3 (19%). Among 118 patients with known HPV status (by p16 staining), 81 (68%) were positive. IMRT target volume spared contralateral tonsil (55%), bilateral or contralateral sides of hypopharynx (72%), nasopharynx (72%), larynx (87%) and contralateral uninvolved neck (21%). Median follow-up was 5 years. Five-year LF, RF, DM, OS, and LT were 3%, 14%, 10%, 79%, and 7% respectively. Four patients developed mucosal recurrence: 3 within and 1 at the margin of the elective mucosal CTV. None of ipsilateral neck irradiation patients failed in the contralateral uninvolved neck. MVA identified cN2c-N3, HPV-negative status and older age as predictors for inferior OS. Within cN2-3 subgroup (n = 189): cN2c-N3, HPV-negative status and older age predicted lower OS, while concurrent chemotherapy was associated with better OS., Conclusion: Definitive IMRT with risk-adaptive radiation volume de-escalation for HNCUP resulted in high probability of tumor control with acceptable rate of late toxicity., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: Percutaneous endoscopic gastrostomy (PEG) placement is essential for the provision of enteral nutrition in select head and neck cancer (HNC) patients. Minimally invasive tube placement is facilitated through one of two techniques, push or pull, but there have been conflicting results regarding safety profiles of these procedures. The objectives of this study were to determine the association of PEG insertion technique with gastrostomy tube complications, including stomal metastases., Methods: A multi-institutional retrospective cohort study of patients with HNC undergoing PEG insertion by either the pull (gastroscope assisted) or push (fluoroscopy assisted) technique was performed. Tube-related complications included infection, dislodgement, deterioration, leak, and other. Adjusted analysis was performed via a multivariable logistic regression model., Results: 1,575 patients were included across three institutions. Tube-related complications occurred in 36% of patients, the most common being peristomal leak (13%) and infection (16%). The push technique (OR 2.66, 95% CI: 1.42-4.97), and the presence of T4 disease (OR 4.62, 95% CI: 1.58-13.51), were associated with a greater risk of developing any tube-related complication. Infection rates were similar between pull and push cohorts. All detected stoma metastases occurred with the pull technique, with an overall prevalence of 0.32% amongst the cohort., Conclusions: The push technique is associated with a greater risk of developing any tube-related complication, but the rate of stomal metastases may be higher with the pull technique. There is potential for quality improvement measures to improve tube-related complications associated with either technique., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Out-of-pocket costs (OOPC) associated with treatment have significant implications on quality of life and survival in cancer patients. Head and neck cancer patients face unique treatment-related challenges, but to date OOPC have been understudied in this population., Aims: This study aims to identify and measure OOPC for patients with head and neck cancer (HNC) in Ontario., Methods: HNC patients between 2015 and 2018 at Princess Margaret Cancer Centre in Toronto were recruited. Participants completed OOPC questionnaires and lost income questions during radiation, post-surgery, and 3, 6, 12, and 24 months after completion of treatment. Associations between OOPC and treatment modality and disease site were tested with multivariable hurdle regression., Results: A total of 1545 questionnaires were completed by 657 patients. Median estimated OOPC for the total duration of treatment for participants undergoing chemoradiation was $1452 [$0-14 616], for surgery with adjuvant radiation or chemoradiation (C/RT) was $1626, for radiation therapy alone was $635, and for surgery alone was $360. The major expenses for participants at the mid-treatment time-point was travel (mean $424, standard error of the mean [SEM] $34) and meals, parking, and accommodations (mean $617, SEM $67). In multivariable analysis, chemoradiation, surgery with C/RT, and radiation were associated with significantly higher OOPC than surgery alone during treatment (791% higher, p < .001; 539% higher, p < .001; 370% higher, p < .001 respectively) among patients with non-zero OOPC. Participants with non-zero OOPC in the laryngeal cancer group paid 49% lower OOPC than those with oropharyngeal cancers in adjusted analysis (p = .025)., Conclusions: Patients undergoing treatment for HNC pay significant OOPC. These costs are highest during treatment and gradually decrease over time. OOPC vary by patient demographics, clinical factors, and, in particular, treatment modality., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: To evaluate the diagnostic performance of radiologic extranodal extension (rENE) in predicting major (>2 mm) and minor (≤2 mm) pathologic ENE (pENE)., Methods: All oral cavity squamous cell carcinoma patients who underwent neck dissection with pathological nodal disease (pN+) between 2010 and 2015 were reviewed. Preoperative computed tomography and/or magnetic resonance imaging were reviewed by two head and neck neuroradiologists., Results: Three hundred and thirty-four patients were included. The sensitivity and specificity of rENE were 37% [95% CI 29-44] and 98% [95% CI 96-100], respectively. Sensitivity for pENE improved in the subset of patients with major ENE (48% [95% CI 38-57]). The presence of rENE was associated with inferior 3-year overall survival: 26% [95% CI 17-41] versus 60% [95% CI 54-67]., Conclusions: This large cohort study demonstrates high specificity, but low sensitivity for preoperative imaging in the detection of pENE in OCSCC. Patients with rENE demonstrated poor OS. pENE in the absence of rENE is still an adverse risk factor., (© 2022 Wiley Periodicals LLC.)

Objective: The objective of this study was to evaluate the construct validity of 2 health utility instruments-the EuroQoL-5 Dimension (EQ-5D) and the Health Utilities Index-Mark 3 (HUI-3)-and to compare them with disease-specific measures in patients with head and neck cancer., Study Design: Prospective cross-sectional analysis., Setting: Princess Margaret Cancer Centre., Methods: Patients were administered the EQ-5D, HUI-3, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its head and neck cancer module (EORTC QLQ-H&N35), and the University of Washington Quality of Life Questionnaire (UWQoL). Several a priori expected relations were examined. The correlative and discriminative properties of the various instruments were examined., Results: A total of 209 patients completed the 4 questionnaires. A significant ceiling effect was observed among EQ-5D responses (23% reported a maximum score of 1). The EQ-5D (rho = 0.79) and HUI-3 (rho = 0.60) had a strong correlation with the social-emotional domain of the UWQoL. The EQ-5D had a moderate correlation with the physical domain of the UWQoL (rho = 0.42), whereas the HUI-3 had a weak correlation (rho = 0.29). The EQ-5D and HUI-3 were able to distinguish among levels of health severity measured on the EORTC QLQ-C30 though not the QLQ-H&N35. Comparatively, the UWQoL was able to distinguish levels of disease severity on the EORTC QLQ-C30 and QLQ-H&N35., Conclusion: The results of this study demonstrate that disease-specific domains from head and neck quality-of-life instruments are not strongly correlated with the EQ-5D and HUI-3. Consideration should be put toward development of a disease-specific preference-based measure for health economic evaluation., Level of Evidence: 4.

Importance: Patient-derived xenografts (PDXs) offer the opportunity to identify patients with oral cavity squamous cell carcinoma (OSCC) who are at risk for recurrence and optimize clinical decision-making., Objective: To develop and validate a prediction score for locoregional failure (LRF) and distant metastases (DM) in OSCC that incorporates PDX engraftment in addition to known clinicopathological risk factors., Design, Setting, and Participants: In this retrospective cohort study, PDX models were generated from patients with OSCC treated with curative intent at Princess Margaret Cancer Centre (Toronto, Canada) between 2006 and 2018. The cohort included 288 patients (aged ≥18 years) with a new diagnosis of nonmetastatic (M0) OSCC whose tumor samples were available for engraftment under the skin of xenograft mice. Patients were scored as a nonengrafter if PDX formation did not occur within 6 months. Data analysis was performed between August 2006 and May 2018., Interventions: All patients received up-front curative-intent surgery followed by either observation or postoperative radiation with or without concurrent chemotherapy based on institutional guidelines., Main Outcomes and Measures: Main outcomes were LRF, DM, and overall survival (OS). Multivariable analysis (MVA) was used to identify predictors of LRF and DM. Factors retained in the final MVA were used to construct a prediction score and classify patients into risk groups., Results: Overall, 288 patients (mean [SD] age at diagnosis, 63.3 [12.3] years; 112 [39%] women and 176 [61%] men) with OSCC were analyzed. The MVA identified pT3-4, pathologic extranodal extension, and engraftment as predictors of LRF and DM. Patients whose tumors engrafted (n = 198) were more likely to develop LRF (hazard ratio [HR], 1.98; 95% CI, 1.24-3.18) and DM (HR, 2.64; 95% CI, 1.21-5.75) compared with nonengrafters. A prediction score based on the aforementioned variables identified patients at high risk and low risk for LRF (43.5% vs 26.5%), DM (38.2% vs 8.4%), and inferior OS (34% vs 66%) at 5 years. Additionally, rapid engraftment was shown to be similarly prognostic, with rapid engrafters demonstrating higher rates of relapse and poor OS., Conclusions: In this cohort study, a prediction score using OSCC PDX engraftment, in conjunction with pT3-4 and pathologic extranodal extension, was associated with improved prognostic utility of existing clinical models and predicted patients at risk for LRF, DM, and poor survival.

Purpose: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has risen rapidly, because of an epidemic of human papillomavirus infection. The optimal management of early-stage OPSCC with surgery or radiation continues to be a clinical controversy. Long-term randomized data comparing these paradigms are lacking., Methods: We randomly assigned patients with T1-T2, N0-2 (≤ 4 cm) OPSCC to radiotherapy (RT) (with chemotherapy if N1-2) versus transoral robotic surgery plus neck dissection (TORS + ND) (with or without adjuvant therapy). The primary end point was swallowing quality of life (QOL) at 1-year using the MD Anderson Dysphagia Inventory. Secondary end points included adverse events, other QOL outcomes, overall survival, and progression-free survival. All analyses were intention-to-treat. Herein, we present long-term outcomes from the trial., Results: Sixty-eight patients were randomly assigned (n = 34 per arm) between August 10, 2012, and June 9, 2017. Median follow-up was 45 months. Longitudinal MD Anderson Dysphagia Inventory analyses demonstrated statistical superiority of RT arm over time ( P = .049), although the differences beyond 1 year were of smaller magnitude than at the 1-year timepoint (year 2: 86.0 ± 13.5 in the RT arm v 84.8 ± 12.5 in the TORS + ND arm, P = .74; year 3: 88.9 ± 11.3 v 83.3 ± 13.9, P = .12). These differences did not meet the threshold to qualify as a clinically meaningful change at any timepoint. Certain differences in QOL concerns including more pain and dental concerns in the TORS + ND arm seen at 1 year resolved at 2 and 3 years; however, TORS patients started to use more nutritional supplements at 3 years ( P = .015). Dry mouth scores were higher in RT patients over time ( P = .041)., Conclusion: On longitudinal analysis, the swallowing QOL difference between primary RT and TORS + ND approaches persists but decreases over time. Patients with OPSCC should be informed about the pros and cons of both treatment options (ClinicalTrials.gov identifier: NCT01590355)., Competing Interests: Anthony C. NicholsResearch Funding: Novartis Canada Pharmaceuticals Inc (Inst) Eric BertheletResearch Funding: Eisai Eric WinquistConsulting or Advisory Role: Merck, Bayer, Eisai, Amgen, Roche, IpsenResearch Funding: Roche/Genentech (Inst), Merck (Inst), Pfizer (Inst), Eisai (Inst), Ayala Pharmaceuticals (Inst) David A. PalmaThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Employment: London Health Sciences Centre (LHSC)Patents, Royalties, Other Intellectual Property: US patent: a method for analyzing a three-dimensional computed tomography image, US patent application no. 61/896349 (not licensed, no commercial or financial impact)No other potential conflicts of interest were reported.

Background: This study examined long-term health utility and symptom-toxicity trajectories among patients with head and neck cancer (HNC)., Methods: For patients diagnosed with HNC (2014-2019), Health Utility Index 3 (HUI-3), Edmonton Symptom Assessment Scale (ESAS), and MD Anderson Symptom Inventory (MDASI) surveys (including both the core and head and neck cancer modules) were prospectively collected at multiple time points (at the baseline, after surgery, during radiotherapy, and 3, 6, 12, and 24 months after treatment). Locally estimated scatterplot smoothing plots were generated to describe HUI-3, ESAS, and MDASI trajectories over time by clinicodemographic factors, treatment modality, and tumor subsite. Contributions of clinical factors were assessed with univariable and multivariable analyses., Results: In 800 patients, the treatment modality and the tumor subsite produced unique HUI-3, ESAS, and MDASI trajectories. Patients treated with surgery alone experienced rapid improvements in HUI-3, ESAS, and MDASI scores postoperatively. Among patients treated with chemoradiotherapy, patients with nasopharyngeal carcinoma had greater declines in HUI-3 during treatment in comparison with patients with oropharyngeal carcinoma, but they had similar ESAS/MDASI scores. Among patients treated with radiotherapy, patients with laryngeal carcinoma had better HUI-3/ESAS/MDASI scores than those with oropharyngeal carcinoma during treatment, but they slowly converged after treatment. Female sex, an age > 75 years, a household income < $40,000, a Charlson comorbidity score > 1, an Eastern Cooperative Oncology Group performance status > 0 (at the baseline), and current smoking were independently associated with worse HUI-3 trajectories. HUI-3 had mild to moderate correlations (ρ = 0.2-0.5) with individual symptom-toxicity trajectories., Conclusions: Long-term HUI-3 trajectories are associated with tumor subsite, clinicodemographic, and treatment factors, and this may be partly explained by relationships with symptoms/toxicities. Separate evaluations by subsite and treatment should occur in health utility and symptom-toxicity studies of HNC., Lay Summary: This study indicates that the long-term health utility and symptoms/toxicities of patients with the most common head and neck cancers (ie, squamous cell carcinomas and nasopharyngeal carcinomas) differ over time with a variety of factors, including the tumor anatomic site, treatment volume, clinicodemographic characteristics (eg, age, human papillomavirus status, tumor stage, gender, smoking status, alcohol status, education, and comorbidities), and treatment modalities. Generalizations across all head and neck cancers should be strongly discouraged. Future studies should evaluate health utility, symptoms and toxicities, and patient need assessments separately for each anatomic site and treatment modality., (© 2021 American Cancer Society.)

Background: Masticator space involvement in oral cavity squamous cell carcinoma (OCSCC) is considered an unresectable disease. Nevertheless, achieving negative resection margins is feasible in limited masticatory space involvement., Materials and Methods: A multi-institutional study on OCSCC patients with masticator space invasion who underwent surgical resection. Margin status was assessed according to anatomic tumor involvement of the inframandibular and supra-mandibular notch., Results: One-hundred and thirty-two patients met the inclusion criteria. Then, 67 patients (50.8%) were diagnosed with a supra-notch tumor and 65 (49.2%) with an infra-notch disease. Negative margins were more common in the infra-notch group (43.3 vs. 23.1%, p = 0.014), and positive margins were more common in the supra-notch group (41.5 vs. 23.9%, p = 0.041). Multivariable analysis demonstrated that supra-notch tumors had an increased likelihood for involved resection margins (odds ratio = 2.46, p = 0.036)., Conclusion: OCSCC patients with masticator space involvement are prone for positive surgical margins in tumors extending above the supra-mandibular notch., (© 2021 Wiley Periodicals LLC.)

Objectives/hypothesis: Sarcopenia is a hallmark of aging and its identification may help predict adverse postoperative events in patients undergoing head and neck surgery. The study objective was to assess the relationship between sarcopenia and postoperative complications and length of stay in patients undergoing major head and neck cancer surgery., Study Design: Prospective cohort study., Methods: A prospective cohort study was performed of patients 50 years and older undergoing major head and neck surgery. Sarcopenia was defined as low muscle mass (determined by neck muscle cross-sectional imaging) with either low muscle strength (grip strength) or low muscle performance (timed walk test). Logistic regression was applied on binary outcomes, and linear regression was used for log-transformed length of hospital stay (LOS). Univariate and multivariate analyses were performed., Results: Of the 251 patients enrolled, pre-sarcopenia was present in 34.9% (n = 87) and sarcopenia in 15.6% (n = 39) of patients. Patients with sarcopenia were more likely to be older (P = .001), female (P = .001), have a lower body mass index (P = .001), and lower preoperative hemoglobin (P < .001). On univariate analysis, the presence and severity of sarcopenia was associated with the development of medical complications (P = .029), higher grade of complications (P = .032), LOS (P = .015), and overall survival (P = .001). On multivariate analysis, sarcopenia was associated with a longer LOS (β = 0.32 [95% CI: 0.19-0.45], P < .001) and worse overall survival (HR = 2.21 [95% CI: 1.01-4.23], P = .017)., Conclusions: Sarcopenia may aid in the prediction of prolonged hospital stay and death in patients who are candidates for major head and neck surgery., Level of Evidence: 3 Laryngoscope, 132:356-363, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: The ideal strategy in the treatment of mucosal melanoma of the head and neck (MMHN) remains unclear. Our objective was to evaluate the importance of surgical margins, radiotherapy, and systemic therapy in MMHN., Study Design: Retrospective Single Institutional Review., Methods: Retrospective review of patients with MMHN treated at a tertiary care oncology center between 1999 and 2016., Results: Seventy-six patients were included, 60 of whom were treated with curative intent. Negative or close margins compared with positive margins were associated with higher 3-year overall survival (OS) (62% vs. 29% vs. 13% P = .012), disease-free survival (33% vs. 29% vs. 4% P = .003), and distant control (48% vs. 29% vs. 22% P = .039). Cases with pre-/postoperative radiotherapy had a marginally higher locoregional control versus without (69% vs. 59%, P = .117). Immunotherapy for recurrent and/or metastatic disease was associated with an increase in 3-year OS (15% vs. 3% P = .01)., Conclusion: Achieving negative surgical margins is relevant in disease control. Despite small sample size, our data suggest that radiotherapy may enhance surgical outcomes. Immunotherapy has therapeutic benefit., Level of Evidence: 3 Laryngoscope, 131:2269-2276, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The cost utility of image-guided surveillance using computed tomography (CT) and positron emission tomography (PET)-CT to planned postradiation neck dissection (PRND) was compared for the management of advanced nodal human papillomavirus-positive oropharyngeal cancer following chemoradiation., Methods: A universal payer perspective was adopted. A Markov model was designed to simulate four treatment approaches with 3-month cycles over a lifetime horizon: 1) CT surveillance, 2) standard PET-CT surveillance, 3) a novel PET-CT approach with repeat PET at 6 months postchemoradiation for equivocal responders, and 4) PRND. Parameters including probabilities of CT nodal progression/resolution, PET avidity, recurrence, and survival were obtained from the literature. Costs were reported in 2019 Canadian dollars and utilities were expressed in quality-adjusted life years (QALYs). Deterministic and probabilistic sensitivity analyses were performed to evaluate model uncertainty., Results: PET-CT surveillance dominated CT surveillance and PRND in the base case scenario, and the novel PET-CT approach was the most cost-effective strategy across a wide range of variables tested in one-way sensitivity analysis. On probabilistic sensitivity analysis, novel PET-CT surveillance was the most cost-effective strategy in 78.1% of model iterations at a willingness-to-pay of $50,000/QALYs. Novel PET-CT surveillance resulted in a 49% lower rate of neck dissection compared with traditional PET-CT, and yielded an incremental benefit of 0.14 QALYs with average cost savings of $1309., Conclusions: Image-guided surveillance including PET-CT and CT are more cost effective than PRND. The novel PET-CT approach with repeat PET for equivocal responders was the dominant strategy and yielded both higher benefit and lower costs compared with standard PET-CT surveillance., (© 2021 American Cancer Society.)

Purpose: Circulating tumor DNA (ctDNA) enables personalized treatment strategies in oncology by providing a noninvasive source of clinical biomarkers. In patients with low ctDNA abundance, tumor-naïve methods are needed to facilitate clinical implementation. Here, using locoregionally confined head and neck squamous cell carcinoma (HNSCC) as an example, we demonstrate tumor-naïve detection of ctDNA by simultaneous profiling of mutations and methylation., Experimental Design: We conducted CAncer Personalized Profiling by deep Sequencing (CAPP-seq) and cell-free Methylated DNA ImmunoPrecipitation and high-throughput sequencing (cfMeDIP-seq) for detection of ctDNA-derived somatic mutations and aberrant methylation, respectively. We analyzed 77 plasma samples from 30 patients with stage I-IVA human papillomavirus-negative HNSCC as well as plasma samples from 20 risk-matched healthy controls. In addition, we analyzed leukocytes from patients and controls., Results: CAPP-seq identified mutations in 20 of 30 patients at frequencies similar to that of The Tumor Genome Atlas (TCGA). Differential methylation analysis of cfMeDIP-seq profiles identified 941 ctDNA-derived hypermethylated regions enriched for CpG islands and HNSCC-specific methylation patterns. Both methods demonstrated an association between ctDNA abundance and shorter fragment lengths. In addition, mutation- and methylation-based ctDNA abundance was highly correlated ( r > 0.85). Patients with detectable pretreatment ctDNA by both methods demonstrated significantly worse overall survival (HR = 7.5; P = 0.025) independent of clinical stage, with lack of ctDNA clearance post-treatment strongly correlating with recurrence. We further leveraged cfMeDIP-seq profiles to validate a prognostic signature identified from TCGA samples., Conclusions: Tumor-naïve detection of ctDNA by multimodal profiling may facilitate biomarker discovery and clinical use in low ctDNA abundance applications., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objective: To understand changes in frailty and quality of life (QOL) in frail versus non-frail patients undergoing surgery for head and neck cancer (HNC)., Methods: Prospective cohort study of patients (median age 67 (50, 88)) with HNC undergoing surgery from December 2011 to April 2014. Fried's Frailty Index, Vulnerable Elders Survey (VES-13), and comprehensive QOL assessments (EORTC QLQ-C30 and HN35) were completed at baseline and 3, 6, and 12-month post-operative visits. Change in frailty and QOL over time was compared between frailty groups (non-frail (score 0), pre-frail (score 1-2), and frail (score 3-5)) using a mixed effects model. Predictors of long-term elevated frailty (12 months > baseline) were analyzed using logistic regression., Results: The study had 108 patients classified as non-frail (47%), 104 pre-frail (mean (SD) 1.3 (0.4), 45%), and 17 frail (3.4 (0.6); 7%). Frailty score decreased significantly for frail patients 3 months post-operatively (2.1 (1.0); P = .002) and remained significantly lower than baseline at 6 and 12 months (2.1 (1.4); P = .0008 and 2.2 (1.5); P = .005, respectively) while frailty score increased for non-frail patients at 3 months (1.1 (1.0); P < .001) and then decreased. Forty-eight patients (21%) had long-term elevated frailty, with baseline frailty and marital status identified as predictors on univariate analysis. The frail population had significantly worse QOL scores at baseline, which persisted 12 months post-operatively., Conclusions: Frail patients demonstrate a decrease in frailty score following surgical treatment of HNC. Frail patients have significantly worse QOL scores on longitudinal assessment and would benefit from supportive services throughout their care., Level of Evidence: 3 Laryngoscope, 131:E2232-E2242, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: In early oral cavity cancer, elective neck dissection (END) for the clinically node-negative (cN0) neck improves survival compared with observation. This paradigm has been challenged recently by the use of positron emission tomography-computed tomography (PET-CT) imaging in the cN0 neck. To inform this debate, we performed an economic evaluation comparing PET-CT-guided therapy with routine END in the cN0 neck., Methods: Patients with T1-2N0 lateralized oral tongue cancer were analyzed. A Markov model over a 40-year time horizon simulated treatment, disease recurrence, and survival from a US health care payer perspective. Model parameters were derived from a review of the literature., Results: The END strategy was dominant, with a cost savings of $1576.30 USD, an increase of 0.055 quality-adjusted life years (QALYs), a net monetary benefit of $4303 USD, and a 0.22 life-year advantage. END was sensitive to variation in cost and utilities in deterministic and probabilistic sensitivity analyses. PET-CT became the preferred strategy when decreasing occult nodal disease to 18% and increasing the negative predictive value (NPV) of PET-CT to 89% in 1-way sensitivity analyses. In probabilistic sensitivity analysis, assuming a cost effectiveness threshold of $50,000 USD/QALY, END was dominant in 64% of simulations and cost effective in 69.8%., Conclusion: END is a cost-effective strategy compared with PET-CT in patients who have node-negative oral cancer. Although lower PET standardized uptake value thresholds would result in fewer false negatives and improved NPV, it is still uncertain that PET-CT would be cost effective, as this would likely result in more false positive tests., (© 2021 American Cancer Society.)

Purpose: To describe the utilization pattern of head and neck (HN) surveillance imaging and explore the optimal strategy for radiologic "residual" lymph node (LN) surveillance following definitive (chemo)radiotherapy (RT/CRT) in human papillomavirus (HPV)+ oropharyngeal carcinoma (OPC)., Methods: All HPV+ OPC patients who completed RT/CRT from 2012 to 2015 were included. Schedule and rationale for post-treatment HN-CT/MRI were recorded. Imaging findings and oncologic outcomes were evaluated., Results: A total of 1036 scans in 412 patients were reviewed: 414 scans for first post-treatment response assessment and 622 scans for the following reasons: follow-up of radiologic "residual" LN(s) (293 scans/175 patients); local symptoms (227/146); other (17/16); unknown (85/66). Rate of scans with "unstated" reason varied significantly among clinicians (3-28%, p < 0.001) and none of them yielded any positive imaging findings. First post-treatment scans identified 192 (47%) patients with radiologic "residual" LNs. Neck dissection (ND) was performed in 28 patients: 16 immediately (6/16 positive), 10 after one follow-up scan (2/10 positive), and 2 after 2nd follow-up scan (1/2 positive). Thirty patients had >2 consecutive follow-up scans at 2-3-month intervals, and none showed subsequent imaging progression or regional failure., Conclusions: Pattern of HN imaging utilization for surveillance varied significantly among clinicians. Imaging surveillance reduces the need for ND. However, routine HN-CT/MR surveillance without clinical symptoms/signs does not demonstrate proven value in identifying locoregional failure or toxicity. Radiologic "residual" LNs without adverse features are common. If two subsequent follow-up scans demonstrate stable/regressing radiologic "residual" LNs, clinical surveillance without further imaging appears to be safe in this population., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: We aimed to compare unstimulated saliva flow using 3-minute modified Schirmer test (MST) following bilateral vs unilateral radiotherapy (RT) in oropharyngeal carcinoma (OPC)., Methods: We reviewed OPC patients treated with definitive intensity-modulated radiation therapy (IMRT) between 2011 and 2017. MST was measured at baseline, 1-/6-/12-/24-month post-RT. MST values were compared between bilateral-RT vs unilateral-RT groups. Multivariable logistic regression analysis (MVA) identified predictors of hyposalivation (MST < 25 mm)., Results: Total 498 bilateral-RT and 36 unilateral-RT patients were eligible. The MST values at 1-/6-/12-/24-month post-RT were all significantly reduced from baseline for the entire cohort. Baseline unilateral-RT and bilateral-RT MST values (in mm) were similar (P = .2), but much higher for unilateral-RT 1-month (mean: 19.1 vs 13.0, P = .03), 6-month (20.5 vs 9.3, P < .001), 12-month (20.1 vs 11.9, P < .01), and 24-month post-RT (22.2 vs 13.9, P = .04). MVA confirmed that unilateral RT reduced the likelihood of hyposalivation vs bilateral RT (OR 2.36, P = .006)., Conclusion: Unilateral RT reduces unstimulated salivary flow in OPC patients., (© 2020 Wiley Periodicals LLC.)

Purpose: To determine the outcomes of oral cavity squamous cell cancer (OSCC) patients treated with non-surgical approach i.e. definitive intensity-modulated radiation therapy (IMRT)., Methods: All OSCC patients treated radically with IMRT (without primary surgery) between 2005-2014 were reviewed in a prospectively collected database. OSCC patients treated with definitive RT received concurrent chemotherapy except for early stage patients or those who declined or were unfit for chemotherapy. The 5-year local, and regional, distant control rates, disease-free, overall, and cancer-specific survival, and late toxicity were analyzed., Results: Among 1316 OSCC patients treated with curative-intent; 108 patients (8%) received non-operative management due to: medical inoperability (n = 14, 13%), surgical unresectability (n = 8, 7%), patient declined surgery (n = 15, 14%), attempted preservation of oral structure/function in view of required extensive surgery (n = 53, 49%) or extensive oropharyngeal involvement (n = 18, 17%). Sixty-eight (63%) were cT3-4, 38 (35%) were cN2-3, and 38 (35%) received concurrent chemotherapy. With a median follow-up of 52 months, the 5-year local, regional, distant control rate, disease-free, overall, and cancer-specific survival were 78%, 92%, 90%, 42%, 50%, and 76% respectively. Patients with cN2-3 had higher rate of 5-year distant metastasis (24% vs 3%, p = 0.001), with detrimental impact on DFS (p = 0.03) and OS (p < 0.02) on multivariable analysis. Grade ≥ 3 late toxicity was reported in 9% of patients (most common: grade 3 osteoradionecrosis in 6%)., Conclusions: Non-operative management of OSCC resulted in a meaningful rate of locoregional control, and could be an alternative curative approach when primary surgery would be declined, unsuitable or unacceptably delayed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: In the wake of the coronavirus disease 2019 (COVID-19) pandemic, access to surgical care for patients with head and neck cancer (HNC) is limited and unpredictable. Determining which patients should be prioritized is inherently subjective and difficult to assess. The authors have proposed an algorithm to fairly and consistently triage patients and mitigate the risk of adverse outcomes., Methods: Two separate expert panels, a consensus panel (11 participants) and a validation panel (15 participants), were constructed among international HNC surgeons. Using a modified Delphi process and RAND Corporation/University of California at Los Angeles methodology with 4 consensus rounds and 2 meetings, groupings of high-priority, intermediate-priority, and low-priority indications for surgery were established and subdivided. A point-based scoring algorithm was developed, the Surgical Prioritization and Ranking Tool and Navigation Aid for Head and Neck Cancer (SPARTAN-HN). Agreement was measured during consensus and for algorithm scoring using the Krippendorff alpha. Rankings from the algorithm were compared with expert rankings of 12 case vignettes using the Spearman rank correlation coefficient., Results: A total of 62 indications for surgical priority were rated. Weights for each indication ranged from -4 to +4 (scale range; -17 to 20). The response rate for the validation exercise was 100%. The SPARTAN-HN demonstrated excellent agreement and correlation with expert rankings (Krippendorff alpha, .91 [95% CI, 0.88-0.93]; and rho, 0.81 [95% CI, 0.45-0.95])., Conclusions: The SPARTAN-HN surgical prioritization algorithm consistently stratifies patients requiring HNC surgical care in the COVID-19 era. Formal evaluation and implementation are required., Lay Summary: Many countries have enacted strict rules regarding the use of hospital resources during the coronavirus disease 2019 (COVID-19) pandemic. Facing delays in surgery, patients may experience worse functional outcomes, stage migration, and eventual inoperability. Treatment prioritization tools have shown benefit in helping to triage patients equitably with minimal provider cognitive burden. The current study sought to develop what to the authors' knowledge is the first cancer-specific surgical prioritization tool for use in the COVID-19 era, the Surgical Prioritization and Ranking Tool and Navigation Aid for Head and Neck Cancer (SPARTAN-HN). This algorithm consistently stratifies patients requiring head and neck cancer surgery in the COVID-19 era and provides evidence for the initial uptake of the SPARTAN-HN., (© 2020 American Cancer Society.)

Purpose: The risk of developing head and neck squamous cell carcinoma (HNSCC) in patients with graft versus host disease (GVHD) after bone marrow transplant (BMT) is well established but large series reporting outcomes are sparse., Methods: Retrospective, single institution, study of patients with GVHD and HNSCC after BMT, between January 1, 1968, and June 30, 2016., Results: In total, 25 patients were studied, of which 21 (84%) were male and 4 (16%) were female. Mean age for BMT was 41 (18-65) years. All patients developed GVHD, most common site was oral cavity (19 patients, 76%). Mean age for diagnosis of HNSCC was 52 (28-76) years. Mean time between BMT and diagnosis of HNSCC was 12 (2-13) years. The 2-year progression-free survival (PFS) was 61.4%, 5-year PFS was 56.7%. The 2-year overall survival (OS) was 82.8%, 5-year OS was 68.7%., Conclusion: HNSCC can develop many years after BMT in patients without the classic risk factors for head and neck cancer. The majority were seen with oral cancer and with early-stage disease likely due to active surveillance and early detection in this patient population., (© 2020 Wiley Periodicals LLC.)

Background: We sought to develop mapping functions that use EORTC responses to approximate health utility (HU) scores for patients with head and neck cancer (HNC)., Methods: In total, 209 outpatients with HNC completed the EORTC QLQ-C30 & QLQ-H&N35 (EORTC), EQ-5D-5L and the HUI-3. Results of the EORTC were mapped onto both EQ-5D-5L and HUI-3 scores using ordinary least squares regression and two-part models., Results: The OLS model mapping EORTC onto the EQ-5D-5L performed best (adjusted R 2 = .75, 10-fold cross-validation RMSE = 0.064, MAE 0.050). The HUI-3 model mapping onto EORTC through OLS was more limited (adjusted R 2 = .5746, 10-fold cross cross-validation RMSE = 0.168, MAE 0.080). The EQ-5D-5L model was able to discriminate between certain clinical indices of disease severity on subgroup analysis., Conclusion: The EORTC to EQ-5D-5L mapping algorithm has good predictive validity and may enable researchers to translate EORTC scores into HU scores for head and neck patients with cancer., (© 2020 Wiley Periodicals, Inc.)

Background: The treatment of head and neck cancer (HNC) may cause significant financial toxicity to patients. Herein, the authors have presented the development and validation of the Financial Index of Toxicity (FIT) instrument., Methods: Items were generated using literature review and were based on expert opinion. In item reduction, items with factor loadings of a magnitude <0.3 in exploratory factor analysis and inverse correlations (r < 0) in test-retest analysis were eliminated. Retained items constituted the FIT. Reliability tests included internal consistency (Cronbach α) and test-retest reliability (intraclass correlation). Validity was tested using the Spearman rho by comparing FIT scores with baseline income, posttreatment lost income, and the Financial Concerns subscale of the Social Difficulties Inventory. Responsiveness analysis compared change in income and change in FIT between 12 and 24 months., Results: A total of 14 items were generated and subsequently reduced to 9 items comprising 3 domains identified on exploratory factor analysis: financial stress, financial strain, and lost productivity. The FIT was administered to 430 patients with HNC at 12 to 24 months after treatment. Internal consistency was good (α = .77). Test-retest reliability was satisfactory (intraclass correlation, 0.70). Concurrent validation demonstrated mild to strong correlations between the FIT and Social Difficulties Inventory Money Matters subscale (Spearman rho, 0.26-0.61; P < .05). FIT scores were found to be inversely correlated with baseline household income (Spearman rho, -0.34; P < .001) and positively correlated with lost income (Spearman rho, 0.24; P < .001). Change in income was negatively correlated with change in FIT over time (Spearman rho, -0.25; P = .04)., Conclusions: The 9-item FIT demonstrated internal and test-retest reliability as well as concurrent and construct validity. Prospective testing in patients with HNC who were treated at other facilities is needed to further establish its responsiveness and generalizability., (© 2020 American Cancer Society.)

Purpose: This study investigated nicotine dependence as an independent risk factor for upper aerodigestive tract (UADT) cancers, including lung and head and neck cancers (HNC). The study aimed to isolate the direct effect of nicotine dependence, independent of tobacco smoking., Methods: A case-control study with a total of 4957 participants was conducted in Ontario, Canada, of which 2964 categorized as either current or former smokers were used in the analysis. Nicotine dependence of ever-smokers (2360 UADT cases and 604 controls) was measured using the Fagerström Test for Nicotine Dependence. Using mediation analyses and adjusted logistic regression models, we decomposed the direct effect of nicotine dependence and the mediated effect of smoking duration to quantify the risks of lung and HNC. The role of human papillomavirus (HPV) and cancer subtypes were assessed., Results: Most individual nicotine dependence behaviours showed positive associations with lung cancer with approximately 1.8 to 3.5-fold risk increase, and to lesser extent with 1.4 to 2.3-fold risk for HNC. Nicotine dependence is partially accountable for increased risks of lung cancer (OR = 1.20, 95%CI = 1.13-1.28) and HNC (1.12, 95%CI = 1.04-1.19). Nicotine dependence had a greater effect on the risk of HPV-negative oropharyngeal cancer (OR = 3.06, 95%CI = 1.65-5.66) in comparison to HPV-positive oropharyngeal cancer (OR = 1.05, 95%CI = 0.67-1.65). The direct effects of nicotine dependence remained significant after accounting for cumulative tobacco exposures., Conclusion: Nicotine dependence increases the risks of lung and HNC cancers after accounting for tobacco smoking, suggesting potential toxic effects of nicotine. These results are informative for the safety consideration of nicotine exposures., Competing Interests: The authors have declared that no competing interests exist.

Background: The objective of this study was to identify a subgroup of patients with head and neck squamous cell carcinoma (HNSCC) who might be suitable for hypofractionated radiotherapy (RT-hypo) during the COVID-19 pandemic., Methods: HNSCC cases (oropharynx/larynx/hypopharynx) treated with definitive RT-hypo (60 Gy in 25 fractions over 5 weeks), moderately accelerated radiotherapy (RT-acc) alone (70 Gy in 35 fractions over 6 weeks), or concurrent chemoradiotherapy (CCRT) during 2005-2017 were included. Locoregional control (LRC) and distant control (DC) after RT-hypo, RT-acc, and CCRT were compared for various subgroups., Results: The study identified 994 human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma cases (with 61, 254, and 679 receiving RT-hypo, RT-acc, and CCRT, respectively) and 1045 HPV- HNSCC cases (with 263, 451, and 331 receiving RT-hypo, RT-acc, and CCRT, respectively). The CCRT cohort had higher T/N categories, whereas the radiotherapy-alone patients were older. The median follow-up was 4.6 years. RT-hypo, RT-acc, and CCRT produced comparable 3-year LRC and DC for HPV+ T1-2N0-N2a disease (seventh edition of the TNM system [TNM-7]; LRC, 94%, 100%, and 94%; P = .769; DC, 94%, 100%, and 94%; P = .272), T1-T2N2b disease (LRC, 90%, 94%, and 97%; P = .445; DC, 100%, 96%, and 95%; P = .697), and T1-2N2c/T3N0-N2c disease (LRC, 89%, 93%, and 95%; P = .494; DC, 89%, 90%, and 87%; P = .838). Although LRC was also similar for T4/N3 disease (78%, 84%, and 88%; P = .677), DC was significantly lower with RT-hypo or RT-acc versus CCRT (67%, 65%, and 87%; P = .005). For HPV- HNSCC, 3-year LRC and DC were similar with RT-hypo, RT-acc, and CCRT in stages I and II (LRC, 85%, 89%, and 100%; P = .320; DC, 99%, 98%, and 100%; P = .446); however, RT-hypo and RT-acc had significantly lower LRC in stage III (76%, 69%, and 91%; P = .006), whereas DC rates were similar (92%, 85%, and 90%; P = .410). Lower LRC in stage III predominated in patients with laryngeal squamous cell carcinoma receiving RT-acc (62%) but not RT-hypo (80%) or CCRT (92%; RT-hypo vs CCRT: P = .270; RT-acc vs CCRT: P = .004). CCRT had numerically higher LRC in comparison with RT-hypo or RT-acc in stage IV (73%, 65%, and 66%; P = .336)., Conclusions: It is proposed that RT-hypo be considered in place of CCRT for HPV+ T1-T3N0-N2c (TNM-7) HNSCCs, HPV- T1-T2N0 HNSCCs, and select stage III HNSCCs during the COVID-19 outbreak., (© 2020 American Cancer Society.)

Introduction: The SARS-CoV-2 virus (COVID19) pandemic has placed extreme pressures on the Canadian Healthcare system. Many health care regions in Canada have cancelled or limited surgical and non-surgical interventions on patients to preserve healthcare resources for a predicted increase in COVID19 related hospital admissions. Also reduced health interventions may limit the risk of possible transmission of COVID19 to other patients and health care workers during this pandemic. The majority of institutions in Canada have developed their own operational mandates regarding access to surgical resources for patients suffering from Head and Neck Cancers during this pandemic. There is a large degree of individual practitioner judgement in deciding access to care as well as resource allocation during these challenging times. The Canadian Association of Head and Neck Surgical Oncology (CAHNSO) convened a task force to develop a set of guidelines based on the best current available evidence to help Head and Neck Surgical Oncologists and all practitioners involved in the care of these patients to help guide individual practice decisions., Main Body: The majority of head and neck surgical oncology from initial diagnosis and work up to surgical treatment and then follow-up involves aerosol generating medical procedures (AGMPs) which inherently put head and neck surgeons and practitioners at high risk for transmission of COVID19. The aggressive nature of the majority of head and neck cancer negates the ability for deferring surgical treatment for a prolonged period of time. The included guidelines provide recommendations for resource allocation for patients, use of personal protective equipment for practitioners as well as recommendations for modification of practice during the current pandemic., Conclusion: 1. Enhanced triaging should be used to identify patients with aggressive malignancies. These patients should be prioritized to reduce risk of significant disease progression in the reduced resource environment of COVID19 era. 2. Enhanced triaging including aggressive pre-treatment COVID19 testing should be used to identify patients with high risk of COVID19 transmission. 3. Enhanced personal protective equipment (PPE) including N95 masks and full eye protection should be used for any AGMPs performed even in asymptomatic patients. 4. Enhanced PPE including full eye protection, N95 masks and/or powered air purifying respirators (PAPRs) should be used for any AGMPs in symptomatic or presumptive positive COVID 19 patients.

Objective: Frailty has emerged as an important determinant of many health outcomes across various surgical specialties. We examined the published literature reporting on frailty as a predictor of perioperative outcomes in head and neck cancer (HNC) surgery., Study Design: Narrative review with limited electronic database search and cross-referencing of included studies., Methods: PubMed was searched from inception until June 2019 to capture studies evaluating an association between frailty and perioperative outcomes among patients undergoing HNC surgery. Primary outcomes included mortality and morbidity, whereas secondary outcomes included in-hospital cost, length of stay, readmission, and discharge disposition., Results: We identified nine series examining frailty as a predictor of outcomes in HNC. The majority of studies (77%) identified patients using a large population-based database such as the National Surgical Quality Improvement Project or National Inpatient Sample. Frailty measures applied in the HNC surgery literature include the modified frailty index, Groningen Frailty Indicator, and John Hopkins Adjusted Clinical Groups frailty-defining diagnosis indicator. Most studies demonstrated a significant association between frailty and perioperative outcomes, including mortality, perioperative complications, and Clavien-Dindo grade IV complications. Furthermore, frailty was associated with greater length of hospital stay, readmission rate, and likelihood of discharge to short-term or skilled nursing facilities., Conclusion: The current literature demonstrates the utility of frailty as a predictor of perioperative mortality and morbidity. Further research is needed to develop frailty screening measures in order to risk-stratify patients and optimize modifiable factors preoperatively. Laryngoscope, 130:1436-1442, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To evaluate whether frailty and functional measures are predictors of perioperative complications and length of hospital stay (LOS) in patients undergoing head and neck cancer surgery., Study Design: Prospective study., Methods: Patients 50 years and older undergoing major head and neck cancer surgery between 2011 and 2015 preoperatively completed Fried's Frailty Index, Barthel Index, Lawton-Brody questionnaire and Vulnerable Elders Survey-13. Primary outcome measures were postoperative complications and LOS, which were analyzed using multivariable logistic and linear regression models., Results: There were 274 patients recruited (105 aged 50-64 and 169 aged 65 and older). Of these, 119, 132, and 23 were defined as non-frail, pre-frail, and frail, respectively. Frailty score and functional measures were not predictors of overall complications. In multivariable models, frailty score (odds ratio [OR] = 1.36; 95% confidence interval [CI], 1.04-1.78, P = .025) was a predictor of medical complications and Clavien-Dindo Grade III and higher complications independent of age and comorbidity. Higher frailty score (β = 1.07; 95% CI, 1.02-1.12, P = .0025) and less independence on the Lawton Brody (β = -0.08; 95% CI, -0.11 to -0.05, P < .001) and Barthel Index (β = -0.12; 95% CI, -0.19 to -0.06, P < .001) were predictors of increased LOS., Conclusions: Frailty was a predictor of type and severity of complications. Both frailty and measures of independence in activities of daily living were independent predictors of LOS. Frailty and functional assessment can help surgeons identify patients at risk of adverse postoperative outcomes and thus aid in counselling patients as well as identifying patients that may benefit from comprehensive geriatric assessment and targeted interventions., Level of Evidence: Prognosis study 2b Laryngoscope, 130:E340-E345, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: There is no mechanism to predict health utility (HU) values from the University of Washington Quality of Life Questionnaire (UWQoL) scores. We sought to develop a mapping algorithm capable of using UWQoL data to approximate HU scores., Methods: Outpatients with head and neck cancer completed the UWQoL, EQ-5D, and the Health Utilities Index-Mark 3 (HUI-3). Results of the UWQoL were mapped onto both EQ-5D and HUI-3 scores using ordinary least-squares regression models. Two-part models were explored. The predictive power of the model was assessed using 10-fold cross-validation., Results: A total of 209 patients were recruited. The reduced model converting UWQoL data into EQ-5D scores performed best (adjusted R 2 = 0.628, root mean square error = 0.076). Both models demonstrated construct validity by discriminating between clinical indices of disease severity., Conclusions: The abovementioned algorithms enable researchers to perform health economic evaluations with existing UWQoL data in cases where prospectively collected HU values are not available., (© 2019 Wiley Periodicals, Inc.)

Background: Risk of contralateral nodal metastases in oropharyngeal squamous cell carcinoma (OPSCC) is currently based on clinical risk factors. We propose lymphatic mapping with single photon emission computed tomography (SPECT-CT) for tumor-specific delineation of lymphatic drainage to guide treatment., Methods: Retrospective review of lymphatic drainage patterns in cT1-2 OPSCC and contralateral cN0 neck with a nonoperative, awake injection of 99 m-Tc sulfur colloid and SPECT-CT., Results: Ten patients were reviewed. Primary sites included tonsil (n = 8, 80%) and tongue base (n = 2, 20%). All patients tolerated awake injections with no complications. Nine patients (90%) demonstrated satisfactory migration of radiotracer to neck node(s) with seven (78%) to the ipsilateral lateral neck, one (11%) to the ipsilateral lateral neck and retropharynx, and one (11%) to bilateral lateral neck nodes., Conclusions: Characterization of lymphatic drainage in OPSCC is feasible using a nonoperative injection technique and SPECT-CT. Drainage to the contralateral neck is rare, warranting further study to tailor treatment appropriately., (© 2019 Wiley Periodicals, Inc.)

Importance: Clinicians should understand the prevalence of depression and decision regret in patients with head and neck cancer and whether these factors differ with age or frailty., Objectives: To assess whether age and frailty are associated with preoperative and/or worsening postoperative depression and postoperative decision regret in patients undergoing major head and neck surgery and to identify additional factors associated with depression and decision regret., Design, Setting, and Participants: This prospective cohort study was conducted at a single institution, with patients aged 50 years or older undergoing major head and neck surgery recruited from December 1, 2011, to April 30, 2014. Statistical analysis was performed from July 1, 2018, to June 30, 2019., Main Outcomes and Measures: Frailty, functional, and geriatric depression assessments were completed before surgery and 3, 6, and 12 months after surgery. Decision regret assessment was completed 6 months after surgery. The prevalence of depression and decision regret was determined by age group. Change in depression over time was compared between age groups using a linear-effects model. Variables potentially associated with moderate to severe depression and decision regret were analyzed using a logistic regression model., Results: The study included 274 patients (68 women and 206 men; mean [SD] age, 67.8 [9.5] years). Of these, 105 (38.3%) were 50 to 64 years of age and 169 (61.7%) were 65 years or older. The rate of preoperative moderate to severe depression was 9.6% (21 of 219), with no difference between younger and older adult cohorts. For both age groups, depression scores increased in the postoperative period from baseline to 6 months. At 12 months, there was a difference in depression scores between the younger and older adult cohort (4.8 [4.6] vs 3.1 [3.6]). A higher preoperative Fried Frailty Index score (odds ratio, 2.58 [95% CI, 1.63-4.06]) was associated with preoperative moderate to severe depression. For all patients, the mean Decision Regret Scale score was 18.2 (range, 0-95), and 26.7% of patients (48 of 180) had moderate to severe regret. There was no difference in Decision Regret Scale scores between younger and older patients. Preoperative depression but not frailty is associated with postoperative moderate to severe decision regret (odds ratio, 1.17 [95% CI, 1.06-1.28])., Conclusions and Relevance: In this cohort study, there was no difference based on age in the prevalence of moderate to severe depression or decision regret. A higher preoperative frailty score was associated with depression but not decision regret. Preoperative depression was the only factor associated with moderate to severe decision regret on multivariate analysis. Understanding the prevalence of and factors associated with moderate to severe depression and decision regret may aid in identifying patients who would benefit from more extensive preoperative counseling and preoperative and postoperative multispecialty assessment and treatment.

The objective of this article was to review the indications for transoral robotic surgery (TORS) in head and neck malignancies. The role of imaging in patient selection will be specifically reviewed. TORS is a recently developed technique that allows minimally invasive surgeries to be performed in the head and neck. TORS has a role in the de-escalation of oropharyngeal cancers, which allows for lower doses of chemoradiation therapy (this is a technique currently in clinical trials). Additionally, this technique allows for less invasive surgery and decreases associated complications. TORS can also be performed at other subsites. Cross-sectional imaging has a prominent role to help identify suitable candidates for this type of surgery. This article will review important anatomy and staging related to TORS. Additionally, the key imaging features for patient selection (indications and contraindications) will be presented along with case illustrations., (© 2019 Wiley Periodicals, Inc.)

The prevalence of human papillomavirus (HPV) in squamous cell carcinoma of unknown primary in the head and neck (SCCUPHN), and prognosis by HPV status of SCCUPHN patients has been difficult to estimate because of the rarity of this subtype. In MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, EMBASE, Cochrane library and Web of Science searches, observational studies and clinical trials that reported survival rates of patients with SCCUPHN by HPV status were identified. Meta-analysis estimated the prevalence and prognosis (overall survival, OS; progression-free survival, PFS) of SCCUPHN by HPV status, and compared them to studies of oropharyngeal squamous cell carcinoma (OPSCC) from the same institutions and across continents. In 17 SCCUPHN studies (n = 1,149) and 17 institution-matched OPSCC studies (n = 6,522), the pooled HPV prevalence of SCCUPHN was 49%, which was only 10% (95%CI: 1-19%) lower than OPSCC prevalence in the underlying population. Estimated 5-year OS for HPV-negative SCCUPHN was 44% (95%CI: 36-51%) vs. HPV-positive SCCUPHN of 91% (95%CI: 86-96%); hazard ratio (HR) for OS was 3.25 (95%CI: 2.45-4.31) and PFS was 4.49 (95%CI: 2.88-7.02). HRs by HPV status for OPSCC were similar to that in SCCUPHN. While North American SCCUPHNs had higher HPV prevalence than European SCCUPHNs (OR = 2.68 (95%CI: 1.3-5.6)), HR of OS for HPV-negative vs. HPV-positive patients were similar in both continents (HRs of 3.78-4.09). Prevalence of HPV among SCCUPHN patients were lower than in OPSCC. The survival benefit conferred by being HPV-positive was similar in SCCUPHN as in OPSCCs, independent of continent., (© 2019 UICC.)

Background: The image-guided operating room (OR) is an emerging standard for dealing with complex cases in many surgical disciplines including neurosurgery, thoracic surgery, maxillofacial trauma, and orthopedic surgery. Its use in head and neck oncological surgery is not well established. The primary aim of this study was to assess the image quality of cone-beam CT (CBCT) under real clinical conditions. The secondary aim was to assess the effect on surgical performance and decision making., Methods: Intraoperative 3D imaging was performed using a CBCT capable C-Arm mounted on a multi-axis robot (Siemens Zeego) in the image-guided OR. All patients had immediate preoperative imaging taken with further intraoperative imaging performed as required. Ten initial patients, comprising 28 intraoperative scans, were used for questionnaire-based image reviews conducted with experienced head and neck clinicians. Scans were assessed for aspects of both image quality and clinical utility, on separate 5-point Likert scales (1-5)., Results: The median rating for bony detail was 4 out of 5. Vascular detail was increased (P < 10 -8 ) from 1 to 3 with the use of IV contrast (region of interest CT# was 284 HU [SD, 47 HU]). Images were rated as 4 for freedom from artifact. Soft tissue definition was 2, with no significant improvement (P = .2) with the addition of IV iodinated contrast. Surgeons rated the greatest clinical utility (4) for the CBCT when assessing postreconstruction imaging of a complex case., Conclusions: The image quality of CBCT in the image-guided OR is good for bony detail and complex oncological reconstructions in the head and neck setting but probably has limited benefit for intraoperative soft tissue delineation. Future studies must also focus on clinical outcomes to help demonstrate the value of the image-guided OR., (© 2019 Wiley Periodicals, Inc.)

Objective: A number of in vitro and clinical studies have suggested potential antineoplastic effects of metformin. The impact of this medication on outcomes in head and neck cancer is less clear. Our aim was to determine the effect of metformin on outcomes within our large cohort of head and neck cancer patients with Type II Diabetes (T2DM)., Study Design: Retrospective cohort study., Setting: Tertiary Cancer Centre., Subjects and Methods: A retrospective review of individuals with head and neck squamous carcinoma (HNSCC) and T2DM between January 2005 and December 2011 at Princess Margaret Cancer Centre was conducted. Medication history was obtained from surveys at initial presentation and electronic medical record review. Using Cox regression analyses, the association between metformin use and local, regional and distant failures was explored. Subgroup analyses were conducted for oral cavity, oropharynx and larynx., Results: A total of 329 HNSCC patients with T2DM were identified, including 195 metformin users and 134 non-metformin users. Patients were well-matched in terms of clinical, pathologic, and treatment factors. No difference in local, regional, or distant failure was observed between diabetic metformin users and diabetic non-metformin users for the entire cohort or within subgroup analysis for subsite. No difference between the two groups was observed for overall survival, recurrence-free survival, and disease-specific survival at 5 years., Conclusion: No association between metformin use and oncologic outcomes were observed in this large cohort of HNSCC patients. Multicenter, prospective studies may be needed to verify previous studies identifying a potential anti-neoplastic effect of this medication.

Objectives: The Fragility Index (FI) is a novel tool for evaluating the robustness of statistically significant findings in a randomized control trial (RCT). It measures the number of events upon which statistical significance depends. We sought to calculate the FI scores for RCTs in the head and neck cancer literature where surgery was a primary intervention., Data Sources: Potential articles were identified in PubMed (MEDLINE), Embase, and Cochrane without publication date restrictions., Review Methods: Two reviewers independently screened eligible RCTs reporting at least one dichotomous and statistically significant outcome. The data from each trial were extracted and the FI scores were calculated. Associations between trial characteristics and FI were determined., Results: In total, 27 articles were identified. The median sample size was 67.5 (interquartile range [IQR] = 42-143) and the median number of events per trial was 8 (IQR = 2.25-18.25). The median FI score was 1 (IQR = 0-2.5), meaning that changing one patient from a nonevent to an event in the treatment arm would change the result to a statistically nonsignificant result, or P > .05. The FI score was less than the number of patients lost to follow-up in 71% of cases. The FI score was found to be moderately correlated with P value (ρ = -0.52, P = .007) and with journal impact factor (ρ = 0.49, P = .009) on univariable analysis. On multivariable analysis, only the P value was found to be a predictor of FI score (P = .001)., Conclusions: Randomized trials in the head and neck cancer literature where surgery is a primary modality are relatively nonrobust statistically with low FI scores. Laryngoscope, 128:2094-2100, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Lentigo maligna is an in situ form of cutaneous melanoma that commonly arises on the head and neck. Various surgical and nonsurgical treatment options are available but no randomized trials exist to guide practice., Objective: To determine the current treatment practices for lentigo maligna of the head and neck in Ontario, Canada., Materials and Methods: Cross-sectional survey of dermatologists, plastic surgeons, and head and neck surgeons., Results: The response rate was 35% (190/542). Wide excision with immediate reconstruction was the most commonly recommended treatment for tumors on the cheek (69%), whereas staged excision with margin control was recommended most often for tumors on the nasal ala (60%). Overall, 5 mm was the most frequently recommended initial surgical margin (69%); 26.5% of respondents recommended margins wider than 5 mm. For tumors on the nasal ala, eyelid, and ear helix, more than 30% of respondents recommended an initial margin narrower than 5 mm., Conclusion: Although surgical excision is the predominant treatment modality for lentigo maligna on the head and neck, practices vary considerably in terms of the type of excision and the initial margin used. Potential response bias and the geographic restriction of our sample may limit the generalizability of our results.

Objective: (1) To estimate the prevalence of radiographically positive Retro-Pharyngeal Lymph Nodes (RPLN) in unknown primary carcinoma of the head and neck and (2) to determine the prognostic implications of radiographically positive RPLN and other radiographic features (3) to identify patients at low risk for retropharyngeal metastasis., Materials and Methods: The medical records of all 68 eligible patients treated at the Princess Margaret Cancer Centre between 2000 and 2014 were retrospectively reviewed for demographic, clinical, pathologic, and radiologic data. Radiologic data included: RPLN, extra capsular spread (ECS), neck staging and cystic/necrotic or matted neck nodes. LRR, DR, DFS and OS were estimated using the competing risk methods and the Kaplan-Meier method., Results: Seven patients had concerning RPLN (10.3%). Forty-four patients were p16 positive (65%). RPLN status did not have any effect on LRR, DFS, DR and OS. Radiological ECS and p16 (neg.) status were found to be significant predictors of LRR (p = 0.023; p = 0.014). Matted nodes, radiological ECS and p16 (neg.) status were found to be significant predictors of DFS (p = 0.012; p < 0.001; p = 0.014). Matted nodes and radiological ECS were found to be significant predictors of OS (p = 0.017; p = 0.0036). Only radiological ECS was found to be a significant predictor of distant recurrence (p = 0.0066)., Conclusions: 10% of CUP patients will harbor radiological positive RPLN. A large proportion of CUP patients are positive for p16. Radiologic features such as ECS and matted nodes can predict worse outcomes., (Copyright © 2018. Published by Elsevier Ltd.)

Bidirectional communication between cells and their microenvironment is crucial for both normal tissue homeostasis and tumor growth. During the development of oral tongue squamous cell carcinoma (OTSCC), cancer-associated fibroblasts (CAFs) create a supporting niche by maintaining a bidirectional crosstalk with cancer cells, mediated by classically secreted factors and various nanometer-sized vesicles, termed as extracellular vesicles (EVs). To better understand the role of CAFs within the tumor stroma and elucidate the mechanism by which secreted proteins contribute to OTSCC progression, we isolated and characterized patient-derived CAFs from resected tumors with matched adjacent tissue fibroblasts (AFs). Our strategy employed shotgun proteomics to comprehensively characterize the proteomes of these matched fibroblast populations. Our goals were to identify CAF-secreted factors (EVs and soluble) that can functionally modulate OTSCC cells in vitro and to identify novel CAF-associated biomarkers. Comprehensive proteomic analysis identified 4247 proteins, the most detailed description of a pro-tumorigenic stroma to date. We demonstrated functional effects of CAF secretomes (EVs and conditioned media) on OTSCC cell growth and migration. Comparative proteomics identified novel proteins associated with a CAF-like state. Specifically, MFAP5, a protein component of extracellular microfibrils, was enriched in CAF secretomes. Using in vitro assays, we demonstrated that MFAP5 activated OTSCC cell growth and migration via activation of MAPK and AKT pathways. Using a tissue microarray of richly annotated primary human OTSCCs, we demonstrated an association of MFAP5 expression with patient survival. In summary, our proteomics data of patient-derived stromal fibroblasts provide a useful resource for future mechanistic and biomarker studies.