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

IMPORTANCE: Oral cavity cancer often requires multidisciplinary management, subjecting patients to complex therapeutic trajectories. Prolonged treatment intervals in oral cavity cancer have been associated with poor oncological outcomes, but there has yet to be a study investigating treatment times in Canada. OBJECTIVE: To report treatment delays for patients with oral cavity cancer in Canada and evaluate the outcomes of treatment delays on overall survival. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study was performed at 8 Canadian academic centers from 2005 to 2019. Participants were patients with oral cavity cancer who underwent surgery and adjuvant radiation therapy. Analysis was performed in January 2023. MAIN OUTCOMES AND MEASURES: Treatment intervals evaluated were surgery to initiation of postoperative radiation therapy interval (S-PORT) and radiation therapy interval (RTI). The exposure variables were prolonged intervals, respectively defined as index S-PORT greater than 42 days and RTI greater than 46 days. Patient demographics, Charlson Comorbidity Index, smoking status, alcohol status, and cancer staging were also considered. Univariate (log rank and Kaplan-Meier) and multivariate (Cox regression) analyses were performed to determine associations with overall survival (OS). RESULTS: Overall, 1368 patients were included; median (IQR) age at diagnosis was 61 (54-70) years, and 896 (65%) were men. Median (IQR) S-PORT was 56 (46-68) days, with 1093 (80%) patients waiting greater than 42 days, and median (IQR) RTI was 43 (41-47) days, with 353 (26%) patients having treatment time interval greater than 46 days. There were variations in treatment time intervals between institutions for S-PORT (institution with longest vs shortest median S-PORT, 64 days vs 48 days; η2 = 0.023) and RTI (institution with longest vs shortest median RTI, 44 days vs 40 days; η2 = 0.022). Median follow-up was 34 months. The 3-year OS was 68%. In univariate analysis, patients with prolonged S-PORT had worse survival at 3 years (66% vs 77%; odds ratio 1.75; 95% CI, 1.27-2.42), whereas prolonged RTI (67% vs 69%; odds ratio 1.06; 95% CI, 0.81-1.38) was not associated with OS. Other factors associated with OS were age, Charlson Comorbidity Index, alcohol status, T category, N category, and institution. In the multivariate model, prolonged S-PORT remained independently associated with OS (hazard ratio, 1.39; 95% CI, 1.07-1.80). CONCLUSIONS AND RELEVANCE: In this multicenter cohort study of patients with oral cavity cancer requiring multimodal therapy, initiation of radiation therapy within 42 days from surgery was associated with improved survival. However, in Canada, only a minority completed S-PORT within the recommended time, whereas most had an appropriate RTI. An interinstitution variation existed in terms of treatment time intervals. Institutions should aim to identify reasons for delays in their respective centers, and efforts and resources should be directed toward achieving timely completion of S-PORT.

IMPORTANCE: Despite the sizeable global burden of hearing loss, cochlear implants have poor penetrance among eligible hearing-impaired individuals. Identifying populations who may benefit from a cochlear implant but among whom penetrance is poor is an important aim in reducing the health-related and economic effects of hearing loss on both individuals and society. OBJECTIVES: To explore the association of socioeconomic status (SES) with cochlear implant candidacy and the decision to undergo cochlear implantation. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was performed in a tertiary academic center. All adult patients evaluated for cochlear implant candidacy from January 1, 1999, through December 31, 2022, were included in the analysis. EXPOSURES: Household income quintile and rural or urban residence were used as proxies for SES based on zip code linkage to US Census and US Department of Agriculture data. MAIN OUTCOMES AND MEASURES: Odds of cochlear implant candidacy and surgery. RESULTS: A total of 754 individuals underwent candidacy evaluations and were included in the analysis (386 [51.2%] women; mean [SD] age, 64.0 [15.7] years). Of these, 693 (91.9%) were cochlear implant candidates, and 623 candidates (89.9%) underwent cochlear implantation. Multivariable analyses demonstrated that individuals in the highest income quintile had lower odds of cochlear implant candidacy compared with those in the lowest income quintile (odds ratio [OR], 0.26 [95% CI, 0.08-0.91]), and candidates in the highest income quintile had greater odds of undergoing cochlear implant surgery compared with those in the lowest quintile (OR, 2.59 [95% CI, 1.14-5.86]). Living in a small town or a micropolitan or rural area was associated with lower odds of undergoing cochlear implant surgery compared with living in a metropolitan core (OR, 0.18 [95% CI, 0.04-0.83]) after controlling for distance to the primary implant center. CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that individuals with higher SES are less likely to qualify for a cochlear implant; however, those who qualify are more likely to undergo surgery compared with those with lower SES. These findings highlight a hearing health care disparity that should be addressed through further studies to guide population-based initiatives.

IMPORTANCE: The association of primary tumor volume with outcomes in T3 glottic cancers treated with radiotherapy with concurrent chemotherapy remains unclear, with some evidence suggesting worse locoregional control in larger tumors. OBJECTIVE: To evaluate the association of primary tumor volume with oncologic outcomes in patients with T3 N0-N3 M0 glottic cancer treated with primary (chemo)radiotherapy in a large multi-institutional study. DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional retrospective cohort study involved 7 Canadian cancer centers from 2002 to 2018. Tumor volume was measured by expert neuroradiologists on diagnostic imaging. Clinical and outcome data were extracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) outcomes were assessed with marginal Cox regression. Laryngectomy-free survival (LFS) was modeled as a secondary analysis. Patients diagnosed with cT3 N0-N3 M0 glottic cancers from 2002 to 2018 and treated with curative intent intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Overall, 319 patients met study inclusion criteria. EXPOSURES: Tumor volume as measured on diagnostic imaging by expert neuroradiologists. MAIN OUTCOMES AND MEASURES: Primary outcomes were OS and DFS; LFS was assessed as a secondary analysis, and late toxic effects as an exploratory analysis determined before start of the study. RESULTS: The mean (SD) age of participants was 66 (12) years and 279 (88%) were men. Overall, 268 patients (84%) had N0 disease, and 150 (47%) received concurrent systemic therapy. The mean (SD) tumor volume was 4.04 (3.92) cm3. With a mean (SD) follow-up of 3.85 (3.04) years, there were 91 (29%) local, 35 (11%) regional, and 38 (12%) distant failures. Increasing tumor volume (per 1-cm3 increase) was associated with significantly worse adjusted OS (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11) and DFS (HR, 1.04; 95% CI, 1.01-1.07). A total of 62 patients (19%) underwent laryngectomies with 54 (87%) of these within 800 days after treatment. Concurrent systemic therapy was associated with improved LFS (subdistribution HR, 0.63; 95% CI, 0.53-0.76). CONCLUSIONS AND RELEVANCE: Increasing tumor volumes in cT3 glottic cancers was associated with worse OS and DFS, and systemic therapy was associated with improved LFS. In absence of randomized clinical trial evidence, patients with poor pretreatment laryngeal function or those ineligible for systemic therapy may be considered for primary surgical resection with postoperative radiotherapy.

Objective: To determine the persistence of human papillomavirus (HPV) infection following treatment of HPV-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC).Methods: A cross-sectional study was undertaken at The Ottawa Hospital (Ottawa, ON, Canada), a tertiary academic hospital and regional cancer center. Adult patients who were diagnosed with HPV + OPSCC between the years of 2014 and 2016 and treated with curative intent, and who were alive and willing to consent were eligible for inclusion. A saliva assay was used to test for the presence of HPV DNA in a random sample of patients. qPCR was used to amplify DNA from saliva samples.Results: Saliva samples were obtained from 69 patients previously treated with HPV + OPSCC. All patients had a minimum of 2 years of follow-up. 5 patients tested positive for HPV: 2 were positive for HPV-16, 2 for HPV-18, and 1 “other” HPV type. No patient in our study cohort had suffered recurrence post-treatment.Conclusions: This study is the first to demonstrate the prevalence of persistent oncogenic HPV DNA in saliva following treatment for HPV + OPSCC. This prevalence appears to be low, despite the fact that persistent HPV infection is a precursor for the development of HPV + OPSCC. This finding raises questions about what factors influence the clearance or persistence of HPV DNA in saliva after treatment for HPV + OPSCC, and may add to our understanding about the longitudinal effects of HPV infection in these cancers.

IMPORTANCE: The optimal approach for treatment deescalation in human papillomavirus (HPV)–related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown. OBJECTIVE: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16–positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up. INTERVENTIONS: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings). MAIN OUTCOMES AND MEASURES: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects. RESULTS: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03210103

Central giant cell granulomas are benign tumours of the mandible, presenting in children and young adults. Divided into non- and aggressive subtypes, the aggressive subtype is relatively rare and can occasionally progress rapidly, resulting in significant morbidity. We present a case of an aggressive central giant cell granuloma (CGCG) in a six year-old female. The lesion originated in the right mandibular ramus and progressed rapidly to involve the condyle. Diagnosis was made using a combination of imaging and pathology. A timely en bloc resection of the hemi-mandible was performed with placement of a reconstructive titanium plate and condylar prosthesis. Our case demonstrates the importance of considering CGCG in the differential diagnosis of rapidly progressive mandibular lesions in the pediatric population. Prompt diagnosis and management can greatly improve long-term outcomes.

We sought to expand upon preliminary data suggesting that metformin confers a survival benefit to patients with head and neck squamous cell carcinoma (HNSCC). A large-scale retrospective cohort study of all patients in Ontario diagnosed with squamous cancer of the larynx, hypopharynx, and nasopharynx between Dec 1st 2007 to Dec 1st 2012 was undertaken. The Institute for Clinical and Evaluative Sciences was accessed to obtain patient demographic, treatment and outcome information. We included patients on metformin at the time of diagnosis. Kaplan Meier methods and Cox Regression models were used. Patients taking metformin at the time of diagnosis had a higher comorbid status but were otherwise similar to patients without metformin usage. Using multivariate analysis, neither overall survival nor disease specific survival was improved in patients on metformin (OS: HR 1.123, p= .338; DSS: HR 1.048, p= .792). No survival advantage was observed in patients with HNSCC taking metformin at the time of diagnosis.

Human papillomavirus (HPV) is an important cause of head and neck squamous cell carcinoma (HNSCC), especially in young people. These tumours overexpress p16 and respond well to treatment. The rapid detection of HPV in patients with HNSCC may expedite treatment when p16 status is not immediately available. Saliva-based DNA collection kits and nested polymerase chain reaction (PCR) were used to determine the HPV status of 62 individuals with biopsy-proven HNSCC. Immunohistochemistry was used to determine tumour p16 status. A total of 62 patients were included in the study. Twenty-nine samples (47%) were positive for HPV DNA, the majority of which were high risk (HR) subtypes (79%). Patients who tested positive for HR HPV were more likely to have a tumour arising in the oropharynx compared to a non-oropharyngeal site (74 vs 26%; p= 0.003). A positive HR HPV saliva assay was 100% specific (95% CI 59–100%) and had a 100% positive predictive value (95% CI 75–100%) for a p16 positive tumour arising in the oropharynx. In contrast, a negative HR HPV assay had a 96% negative predictive value (95% CI 80–100%) for tumours arising in a non-oropharyngeal site. Independent of site, the saliva assay had a sensitivity of 77% (95% CI 54–91%) and a specificity of 94% (95% CI 77–99%), respectively, for a p16 positive tumour. We show that a saliva based assay is an effective method for detecting HPV in patients with HNSCC and that a positive HR HPV test is highly specific for p16 positive tumours arising in the oropharynx. This simple and rapid test could be used in cases where a biopsy of the primary tumour is not readily available.

Pharyngocutaneous fistula (PCF) is a problematic complication following total laryngectomy. Disagreement remains regarding predisposing factors. This study examines perioperative factors predicting PCF following total laryngectomy using a large multicenter data registry. Retrospective cohort analysis was performed using patients undergoing total laryngectomy in the ACS-NSQIP database for 2006–2014. Sub-analysis was performed based on reconstruction type. Outcome of interest was PCF development within 30 days. Multivariate analysis of 971 patients was performed. Three variables showed statistical significance in predicting PCF: wound classification of 3 and 4 vs. 1–2 (OR 6.42 P< 0.0004 and OR 8.87, P< 0.0042), pre-operative transfusion of > 4 units of packed red blood cells (OR 6.28, P= 0.043), and free flap versus no flap reconstruction (OR 2.81, P= 0.008). This study identifies important risk factors for development of PCF following total laryngectomy in a large, multi-institutional cohort of patients, thereby identifying a subset of patients at increased risk.

There are no nationwide studies documenting changes in cutaneous malignant melanoma incidence or association of incidence with socioeconomic status (SES) in Canada. We sought to determine whether melanoma incidence increased from 1992 to 2006 and if there was an association between SES and melanoma incidence. Additionally, we studied whether there was a correlation between province of residence and melanoma incidence. Cases from the Canadian Cancer Registry were reviewed. Demographic and socioeconomic information were extracted from the Canadian Census of Population data. Cases were linked to income quintiles by postal code. A negative binomial regression was performed to identify relationships among these variables. Overall incidence of melanoma in Canada increased by 67 % from 1992 to 2006 (p< 0.0001). The increase in incidence was greater for melanoma in situ compared with invasive melanoma (136 % versus 52 % [p< 0.0001]). Incidence was positively correlated with higher income quintiles; the incidence rates among patients in the lowest income quintiles were 67 % of that for the highest income quintiles (p< 0.0001). A wide variety of explanations have been postulated for an increased incidence in melanoma among persons of higher SES, including access to and awareness of screening, more access to vacations in sunny climates, and increased leisure time. Variations in incidence of melanoma by urban vs. rural location and province may indicate differences in access to dermatologists across Canada. Melanoma incidence is increasing in Canada and is higher among people in high SES groups. This rise is likely due to a combination of factors including a true rise in incidence due to increases in sun exposure, and also an increased detection rate, particularly in those who are more aware of the disease and have access to resources for detection.

Thyroid cancer incidence in Canada is increased in high socioeconomic groups, and in urban compared with rural areas. The objective of this study was to analyze patterns in thyroid cancer incidence across Canada, particularly with respect to the major urban areas across the country, to identify whether there are any discrepancies in thyroid cancer incidence between Canadian cities. Cases were drawn from the Canadian Cancer Registry. Demographic and socioeconomic information were extracted from the Canadian Census of Population data. We linked cases to income quintiles (InQs) by patients’ postal codes, and categorized residence by census metropolitan area ((CMA), population >100,000). Within the Toronto CMA we further classified by census subdivision (CSD). There were a total of 33 CMAs across the country. After controlling for demographic and socio-economic factors, we found that the Toronto CMA had an IRR of thyroid cancer that was significantly higher than all other CMAs across the country. For 70 % of CMAs and CAs across Canada, the IRR for thyroid cancer was less than half of the IRR for thyroid cancer in the Toronto CMA. As Toronto is one of the largest CMAs, we then subdivided the Toronto area into CSDs to examine how incidence of thyroid cancer varies within this large area. The Toronto City core was used as the reference category and all other areas were compared directly to it. In doing so, we found that a contiguous area of three CSDs North of Toronto had higher IRRs compared with the Toronto city core: Markham, Vaughan and Richmond Hill. After controlling for demographic and socioeconomic factors, we found that the Toronto CMA has the highest incidence of thyroid cancer nationwide. Several explanations could account for this discrepancy including increased detection due to increased access to imaging, differences in ethnicity or environmental exposures.

Following publication of the original article [1], the authors reported an error in one of the author names. In this Correction the incorrect and correct author names are listed.

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Human papilloma virus (HPV) is emerging as the primary cause for some head and neck cancers. The objective of this study was to investigate the association between head and neck cancer (HNC) survival and socioeconomic status (SES) in Canada, and to investigate changes in the relationship between HNC survival and SES from 1992 to 2005.