Contrasting clinical outcomes and socio-economic impact of young versus elderly-onset oral squamous cell carcinoma, a novel health economic analysis.

OBJECTIVES: The incidence of young-onset oral squamous cell carcinoma (OSCC) is growing, even among non-smokers/drinkers. The effects of adverse histopathological features on long-term oncologic outcomes between the young and old are controversial and confounded by significant heterogeneity. Few studies have evaluated the socio-economic impact of premature mortality from OSCC. Our study seeks to quantify these differences and their economic impact on society. MATERIALS AND METHODS: Four hundred and seventy-eight young (<45 years) and 1660 old patients (≥45 years) with OSCC were studied. Logistic regression determined predictors of recurrence and death. Survival analysis was calculated via the Kaplan-Meier method. A separate health economic analysis was conducted for India and Singapore. Years of Potential Productive Life Lost (YPPLL) were estimated with the Human Capital Approach, and premature mortality cost was derived using population-level data. RESULTS: Adverse histopathological features were seen more frequently in young OSCC: PNI (42.9% vs. 35%, p = 0.002), LVI (22.4% vs. 17.3%, p = 0.013) and ENE (36% vs. 24.5%, p < 0.001). Although 5-year OS/DSS were similar, the young cohort had received more intensive adjuvant therapy (CCRT 26.9% vs. 16.6%, p < 0.001). Among Singaporean males, the premature mortality cost per death was US $396,528, and per YPPLL was US $45,486. This was US $397,402 and US $38,458 for females. Among Indian males, the premature mortality cost per death was US $30,641, and per YPPLL was US $595. This was US $ 21,038 and US $305 for females. CONCLUSION: Young-onset OSCC is an aggressive disease, mitigated by the ability to receive intensive adjuvant treatment. From our loss of productivity analysis, the socio-economic costs from premature mortality are substantial. Early cancer screening and educational outreach campaigns should be tailored to this cohort. Alongside, more funding should be diverted to genetic research, developing novel biomarkers and improving the efficacy of adjuvant treatment in OSCC.

Improving accuracy in nodal staging of oral cancer: Proposal of a new system.

BACKGROUND: Despite introduction of extranodal extension (ENE) into the AJCC 8th edition of oral cancer staging, previous criticisms persist, such as limited discrimination between sub-stages and doubtful prognostic value of contralateral nodal disease. The purpose of this study was to compare our novel nodal staging system, based on the number of positive nodes and ENE, to the AJCC staging system in surgically treated patients. METHODS: Retrospective analysis of 4710 patients with oral squamous cell carcinoma (OSCC) treated with surgery±adjuvant therapy in 8 institutions in Australia, North America and Asia. With overall survival (OS) and disease specific survival (DSS) as endpoint, the prognostic performance of AJCC 8th and 7th editions were compared using hazard consistency, hazard discrimination, likelihood difference and balance. RESULTS: Our new nodal staging system (PN) a progressive and linear increase in hazard ratio (HR) from pN0 to pN3, with good separation of Kaplan Meier curves. Using the predetermined criteria for evaluation of a staging system, our proposed staging model outperformed AJCC 8th and 7th editions in prediction of OS and DSS. CONCLUSION: PN was the lymph node staging system that provided the most accurate prediction of OS and DSS for patients in our cohort of OSCC. Additionally, it can be easily adopted, addresses the shortcomings of the existing systems and should be considered for future editions of the TNM staging system.

Risk Stratification in Oral Cancer: A Novel Approach.

Background: Oral squamous cell carcinoma (OSCC) is a common head and neck cancer with high morbidity and mortality. Currently, treatment decisions are guided by TNM staging, which omits important negative prognosticators such as lymphovascular invasion, perineural invasion (PNI), and histologic differentiation. We proposed nomogram models based on adverse pathological features to identify candidates suitable for treatment escalation within each risk group according to the National Comprehensive Cancer Network (NCCN) guidelines. Methods: Anonymized clinicopathologic data of OSCC patients from 5 tertiary healthcare institutions in Asia were divided into 3 risk groups according to the NCCN guidelines. Within each risk group, nomograms were built to predict overall survival based on histologic differentiation, histologic margin involvement, depth of invasion (DOI), extranodal extension, PNI, lymphovascular, and bone invasion. Nomograms were internally validated with precision-recall analysis and the Kaplan-Meier survival analysis. Results: Low-risk patients with positive pathological nodal involvement and/or positive PNI should be considered for adjuvant radiotherapy. Intermediate-risk patients with gross bone invasion may benefit from concurrent chemotherapy. High-risk patients with positive margins, high DOI, and a high composite score of histologic differentiation, PNI, and the American Joint Committee on Cancer (AJCC) 8th edition T staging should be considered for treatment escalation to experimental therapies in clinical trials. Conclusion: Nomograms built based on prognostic adverse pathological features can be used within each NCCN risk group to fine-tune treatment decisions for OSCC patients.

Incorporation of adverse features in advanced oral cancer improves precision in staging and patient prognostication.

BACKGROUND: Despite revised staging criteria, stratification of patients with advanced oral squamous cell carcinoma (OSCC) remains difficult. Well-established features like perineural invasion (PNI), differentiation, and lymphovascular-invasion (LVI) are controversial, and hence omitted from staging. We endeavor to better stratify this cohort by identifying predictors of survival in advanced OSCC (T3-4). METHODS: Seven hundred and forty-two patients with T3-4 OSCC underwent surgery from 2006 to 2013. Cox regression was performed to determine predictors of overall survival (OS). RESULTS: OS was adversely impacted by PNI (p = 0.046), LVI (p = 0.038), moderate/poor differentiation (p = 0.001), close/involved surgical margins (p = 0.002), pT (p = 0.034), and pN (p < 0.001). The cumulative number of adverse histopathological features predicted poorer OS; HR 2.64 (CI 1.42-4.90) for one adverse feature and HR 4.23 (CI 2.34-7.67) for ≥2. CONCLUSION: In advanced OSCC, stratification with histopathologic risk factors can predict survival even in maximally treated patients; adjuvant therapies are unable to entirely mitigate this risk. Incorporation of adverse features into future editions of TNM can improve precision in staging and identify candidates for treatment escalation.

Geographical heterogeneity in the American Joint committee on Cancer oral cancer staging and prognostic implications.

OBJECTIVES: The AJCC 8th edition (AJCC 8) has introduced depth of invasion (DOI) and extranodal extension (ENE) into staging for oral squamous cell carcinoma (OSCC). Although validations have been performed on institutional datasets have shown a good performance, particularly in early OSCC, there have been no studies on diverse patient populations that determine the impact on prognostic heterogeneity. MATERIALS AND METHODS: Retrospective analysis of 4710 patients with oral squamous cell carcinoma (OSCC) treated with surgery +/- adjuvant therapy in 8 institutions in Australia, North America and Asia. With overall survival (OS) as endpoint, the prognostic performance of AJCC 7th and 8th editions were compared using Akaike Information Criterion (AIC), Bayesian Information Criteria (BIC), Harrell's concordance index (C-index). RESULTS: When comparing AJCC 8 to AJCC 7, the heterogeneity in prediction of OS increased for T-category and N-category while remaining unchanged for TNM staging, suggesting AJCC 8 increased complexity with no improvement in predictive value. There were significant differences in median DOI and incidence of ENE between geographical regions, resulting in dissimilar rates of stage-migration when adopting AJCC 8. CONCLUSION: In an attempt to improve prognostic performance, AJCC 8 introduced more variables; however heterogeneity in these results in significant geographical differences in model discrimination and performance. Caution should be applied as this may result in inaccurate and unreliable prognostic predictions that may impact treatment recommendations.

Prognostic determinants of locally advanced buccal mucosa cancer: Do we need to relook the current staging criteria?

OBJECTIVES: Current guidelines advocate non-surgical treatment for T4b buccal mucosa carcinoma with surgery preferred in other stages. We investigated oncologic outcomes of this cohort in comparison with T4a cohort, treated by similar multi-modality approach of primary surgery followed by adjuvant treatment and identified prognostic determinants of survival. MATERIALS AND METHODS: Oncologic outcome of prospectively accrued 282 patients with cT4a and cT4b buccal mucosa squamous cell carcinoma were evaluated for overall survival (OS) and disease free survival (DFS) at 2 years of the whole cohort and for the subgroups of T4a and T4b patients. Multivariate Cox proportional hazards regression analysis was performed to identify prognostic determinants. RESULTS: Of 277 eligible patients treated and followed for a median period of 21 months, the OS was comparable between T4a and T4b as 64% vs 58%, (p = 0.354). The DFS between the two subgroups was 64% vs 61%, (p = 0.316). Although there was 47% pathologic down staging from the clinical stage, there was no significant difference in oncologic outcome between pT4a and pT4b (OS, 57% vs 58% for T4a and T4b, p = 0.687; DFS, 58% vs 60% for T4a and T4b, p = 0.776). On multivariate analysis, extra capsular spread (p = 0.042), lateral pterygoid muscle involvement (p = 0.035) and defaulting adjuvant treatment (p < 0.001) were independent predictors of outcome for the T4b cohort when other factors were controlled. CONCLUSIONS: Primary surgery followed by adjuvant chemo-radiotherapy offers comparable results in selected T4b gingiva and buccal mucosal cancer, suggesting the need to relook the staging criteria for oral cavity cancer.