Prevention and Management of Osteoradionecrosis in Patients With Head and Neck Cancer Treated With Radiation Therapy: ISOO-MASCC-ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for prevention and management of osteoradionecrosis (ORN) of the jaw secondary to head and neck radiation therapy in patients with cancer. METHODS: The International Society of Oral Oncology-Multinational Association for Supportive Care in Cancer (ISOO-MASCC) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library databases were searched for randomized controlled trials and observational studies, published between January 1, 2009, and December 1, 2023. The guideline also incorporated systematic reviews conducted by ISOO-MASCC, which included studies published from January 1, 1990, through December 31, 2008. RESULTS: A total of 1,539 publications were initially identified. There were 487 duplicate publications, resulting in 1,052 studies screened by abstract, 104 screened by full text, and 80 included for systematic review evaluation. RECOMMENDATIONS: Due to limitations of available evidence, the guideline relied on informal consensus for some recommendations. Recommendations that were deemed evidence-based with strong evidence by the Expert Panel were those pertaining to best practices in prevention of ORN and surgical management. No recommendation was possible for the utilization of leukocyte- and platelet-rich fibrin or photobiomodulation for prevention of ORN. The use of hyperbaric oxygen in prevention and management of ORN remains largely unjustified, with limited evidence to support its practice.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Clarification of the margin status by the multidisciplinary tumor board following transoral robotic surgery for p16 positive oropharyngeal squamous cell carcinoma.

Objectives: Margin status interpretation following transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC) is challenging. This study aims to assess the discrepancy between status of margins as reported by the pathologist versus as determined by multi-disciplinary team review (MDTB). Methods: A retrospective study of 57 patients with OPSCC who underwent TORS from January 2010 to December 2016 was conducted. Our primary outcome measure was the discrepancy between the surgical specimen margins as described in the pathology report versus final margin status that was determined after the multi-disciplinary team discussion. Fisher's exact test was used. Results: Based on the pathologist-report, 29 subjects (51%) had positive margins, compared to 2 (4%) after multi-disciplinary team discussion. Receipt of chemotherapy correlated with final margin status as determined by MDTB, not with initial main specimen margins (p = .02 and p = .08, respectively). With a median follow up of 28.4 months, two subjects (4%) had loco-regional recurrence. Conclusion: Following TORS, there was a significant discrepancy between status of margins as reported by the pathologist versus as determined by MDTB review. Chemotherapy was avoided in 93.1% of cases that were originally reported as positive margins by the pathologist with an acceptably low recurrence rate. Level of evidence: 4.

Radiation therapy for low- and high-risk perineural invasion in head and neck cutaneous squamous cell carcinoma: Clinical outcomes and patterns of failure.

BACKGROUND: Perineural invasion (PNI) in head and neck squamous cell carcinoma (HNSCC) portends poor prognosis. Extent of treatment of nerve pathways with varying degrees of PNI and patterns of failure following elective neural radiotherapy (RT) remain unclear. METHODS: Retrospective review of HNSCC patients with high-risk (clinical/gross, large-nerve, extensive) or low-risk (microscopic/focal) PNI who underwent curative-intent treatment from 2010 to 2021. RESULTS: Forty-four patients (mean follow-up 22 months; 59% high-risk, 41% low-risk PNI) were included. Recurrence following definitive treatment occurred in 31% high-risk and 17% low-risk PNI patients. Among high-risk patients, 69% underwent surgery with post-operative RT and 46% underwent elective neural RT. Local control (83% low-risk vs. 75% high-risk), disease-free, and overall survival did not differ between groups. CONCLUSIONS: High local control rates were achieved in high-risk PNI patients treated with adjuvant or primary RT, including treatment of both involved and uninvolved, communicating cranial nerves, with few failures in electively treated regions.

Peripheral lymphocytes and lactate dehydrogenase correlate with response and survival in head and neck cancers treated with immune checkpoint inhibitors.

BACKGROUND: Little is known regarding associations between peripheral blood biomarkers (PBBMs) and survival, response, and toxicity in recurrent/metastatic head and neck squamous cell carcinomas (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs). METHODS: In this single-institution retrospective cohort study, a dataset of patients with R/M HNSCC treated with ICIs between 08/2012-03/2021 was established, including demographic and clinicopathologic characteristics. Pretreatment PBBMs were collected and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv5, objective response (ORR) by RECIST 1.1, overall survival (OS), and progression-free survival (PFS). Multivariable models for each outcome were created using elastic net variable selection. RESULTS: Our study included 186 patients, with 51 (27%) demonstrating complete or partial response to immunotherapy. Multivariable models adjusted for ECOG performance status (PS), p16, and smoking demonstrated that pretreatment higher LDH and absolute neutrophils, as well as lower percent lymphocytes correlated with worse OS and PFS. Higher LDH and lower % lymphocytes also correlated with worse ORR. CONCLUSIONS: In the largest study to date examining PBBMs in ICI-treated R/M HNSCCs, our variable selection method revealed PBBMs prognostic for survival and response to immunotherapy. These biomarkers warrant further investigation in a prospective study along with validation with CPS biomarker.

Neutrophil to lymphocyte ratio and peripheral blood biomarkers correlate with survival outcomes but not response among head and neck and salivary cancer treated with pembrolizumab and vorinostat.

BACKGROUND: Associations between peripheral blood biomarkers and oncologic outcomes were explored in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HN) and salivary gland cancer (SGC) treated with pembrolizumab and vorinostat on a phase II trial (NCT02538510). EXPERIMENTAL DESIGN: Twenty-five HN and 25 SGCs were treated with pembrolizumab and vorinostat. Baseline peripheral blood was available in 21 HN and 20 SGCs and evaluated for associations with grade ≥3 adverse events (G ≥ 3AE) by CTCAEv4, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS). RESULTS: Higher pretreatment neutrophil-to-lymphocyte ratio (NLR) and neutrophils, as well as lower pretreatment lymphocytes and T helper cells correlated with worse OS and PFS. Higher NLR further predicted increased rates of G ≥ 3AEs. No correlations with ORR were observed. CONCLUSIONS: In a prospectively evaluated cohort of HN and SGCs treated with pembrolizumab and vorinostat, we observed novel associations between peripheral blood biomarkers and oncologic outcomes and toxicities.

Primary thyroid hemangioma, a rare diagnosis in a patient with a painless neck mass.

The aim of this case report is to demonstrate a case of primary thyroid hemangioma in a 62-year-old female who presented with a painless neck mass, treated with right hemithyroidectomy and diagnosed by surgical biopsy. Thyroid hemangiomas are rare, benign lesions which present a diagnostic challenge given the lack of specific imaging findings and clinical manifestations associated with them. However, accurate recognition of these lesions is important and can facilitate conservative, rather than surgical, management strategies. In this report, we discuss a case in a patient whose laboratory assessment raised concern for a thyroid paraganglioma, leading to surgical resection of what was ultimately a benign thyroid hemangioma. We also review the pathophysiology, clinical manifestations, differential diagnostic considerations, and imaging characteristics of thyroid hemangiomas across multiple modalities and discuss strategies for accurately diagnosing these lesions.

Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer.

The tumour-associated microbiota is an intrinsic component of the tumour microenvironment across human cancer types1,2. Intratumoral host-microbiota studies have so far largely relied on bulk tissue analysis1-3, which obscures the spatial distribution and localized effect of the microbiota within tumours. Here, by applying in situ spatial-profiling technologies4 and single-cell RNA sequencing5 to oral squamous cell carcinoma and colorectal cancer, we reveal spatial, cellular and molecular host-microbe interactions. We adapted 10x Visium spatial transcriptomics to determine the identity and in situ location of intratumoral microbial communities within patient tissues. Using GeoMx digital spatial profiling6, we show that bacterial communities populate microniches that are less vascularized, highly immuno­suppressive and associated with malignant cells with lower levels of Ki-67 as compared to bacteria-negative tumour regions. We developed a single-cell RNA-sequencing method that we name INVADEseq (invasion-adhesion-directed expression sequencing) and, by applying this to patient tumours, identify cell-associated bacteria and the host cells with which they interact, as well as uncovering alterations in transcriptional pathways that are involved in inflammation, metastasis, cell dormancy and DNA repair. Through functional studies, we show that cancer cells that are infected with bacteria invade their surrounding environment as single cells and recruit myeloid cells to bacterial regions. Collectively, our data reveal that the distribution of the microbiota within a tumour is not random; instead, it is highly organized in microniches with immune and epithelial cell functions that promote cancer progression.

Oncologic outcomes of salvage surgery and immune checkpoint inhibitor therapy in recurrent head and neck squamous cell carcinoma: A single-institution retrospective study.

BACKGROUND: Survival outcomes in recurrent head and neck squamous cell carcinoma (HNSCC) are poor. This study aimed to compare survival outcomes between salvage surgery and immunotherapy in patients with recurrent advanced HNSCC. METHODS: Patients with advanced stage (stage III or IV) recurrent HNSCC following treatment with platinum-based chemotherapy were included. Survival was estimated using the Kaplan-Meier method, and Cox regression was used for multivariate logistic regression. RESULTS: Two-year overall survival after salvage surgery was 68.6% and after immunotherapy patients was 24.6%. Multivariate logistic regression showed that salvage surgery was associated with improved survival without statistical significance (hazard ratio [HR] 0.12, p = 0.25). Subgroup analysis of patients with oral cavity/oropharyngeal cancer noted improved survival with salvage surgery over immunotherapy (HR 0.006, p = 0.01) and decreased survival with neutrophil-to-lymphocyte ratio (NLR) > 5 (HR 6.4, p = 0.02). CONCLUSION: Our retrospective single-institutional data suggest that resectable advanced stage recurrent HNSCC may have improved survival with salvage surgery in appropriately selected patients, but larger prospective studies are required.

Performance status (PS) as a predictor of poor response to immune checkpoint inhibitors (ICI) in recurrent/metastatic head and neck cancer (RMHNSCC) patients.

BACKGROUND: Anti-PD1 checkpoint inhibitors (ICI) represent an established standard-of-care for patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC). Landmark studies excluded patients with ECOG performance status (PS) ≥2; the benefit of ICI in this population is therefore unknown. METHODS: We retrospectively reviewed RMHNSCC patients who received 1+ dose of ICI at our institution between 2013 and 2019. Demographic and clinical data were obtained; the latter included objective response (ORR), toxicity, and any unplanned hospitalization (UH). Associations were explored using uni- and multivariate analysis. Overall survival (OS) was estimated using a Cox proportional hazards model; ORR, toxicity, and UH were evaluated with logistic regression. RESULTS: Of the 152 patients, 29 (19%) had an ECOG PS ≥2. Sixty-six (44%) experienced toxicity; 54 (36%) had a UH. A multivariate model for OS containing PS, smoking status, and HPV status demonstrated a strong association between ECOG ≥2 and shorter OS (p < 0.001; HR = 3.30, CI = 2.01-5.41). An association between OS and former (vs. never) smoking was also seen (p < 0.001; HR = 2.17, CI = 1.41-3.35); current smoking did not reach statistical significance. On univariate analysis, poor PS was associated with inferior ORR (p = 0.03; OR = 0.25, CI = 0.06-0.77) and increased UH (p = 0.04; OR = 2.43, CI = 1.05-5.71). There was no significant association between toxicity and any patient characteristic. CONCLUSIONS: We observed inferior OS, ORR, and rates of UH among ICI-treated RMHNSCC patients with ECOG 2/3. Our findings help frame discussion of therapeutic options in this poor-risk population.

Trends in Positive Surgical Margins in cT1-T2 Oral Cavity Squamous Cell Carcinoma.

OBJECTIVES/HYPOTHESIS: To evaluate trends in contemporary positive surgical margin incidence in cT1-T2 oral cavity squamous cell carcinoma and to evaluate factors associated with surgical margin status. STUDY DESIGN: Retrospective analysis of large dataset. METHODS: Retrospective analysis of the National Cancer Database. RESULTS: Between 2004 and 2016, 39,818 patients with cT1 or cT2 oral cavity squamous cell carcinoma received primary curative-intent surgery. Positive surgical margins were present in 7.95% of patients, and univariable adjusted probability of positive surgical margins over the study period declined by 1% per year (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.98-1.0; P = .049). Multivariable regression revealed the annual rate of positive surgical margins declined significantly (OR, 0.95 per year; 95% CI, 0.92-0.97; P < .001). Factors associated with increased odds of positive surgical margins included cT2 disease, subsite, understaged disease, lymphovascular invasion, tumor grade, and positive lymph nodes. Race and socioeconomic status were not associated with surgical margin status. Treatment at an academic center was associated with increased time to definitive surgery (median 35 days IQR 22-50 vs. median 27 days IQR 14-42; P < .001) and a 20% reduction in positive surgical margin rate (OR, 0.80; 95% CI, 0.71-0.90; P < .001). Treatment at high-volume centers was less likely to be associated with positive surgical margins (OR, 0.85; 95% CI, 0.74-0.98; P = .02). CONCLUSION: Surgical subsite, clinical T and N category, presence of lymphovascular invasion, and histologic grade were independent predictors of positive surgical margins. Patients are increasingly being treated at high-volume and academic centers. Overall, the rate of positive surgical margins in cT1-T2 oral cavity squamous cell carcinoma is decreasing. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1962-1970, 2022.

Impact of HPV status on immune responses in head and neck squamous cell carcinoma.

The main objective of our study was to understand the impact of immune cell composition and the tumor-reactivity of tumor infiltrating lymphocytes (TIL) in HPV-positive (HPV+) and HPV-negative (HPV-) head and neck squamous cell carcinoma (HNSCC). TIL cultures were established from primary HNSCC tumors, the T cell subsets were phenotypically characterized using flow cytometry, and Interferon (IFN)-γ ELISA assay was used to determine TIL function. NanoString Immune Profiler was used to determine an immune signature by HPV-status, and multiplex immunohistochemistry (MIHC) was used to quantify immune cell distributions and their spatial relationships. Results showed that HPV+ and HPV- HNSCC had similar capacity to expand IFN-γ reactive TIL populations, and these TIL populations had similar characteristics. NanoString analysis revealed increased differential expression of genes related to B cell functions in HPV+ HNSCC, which were significant at a Benjamini-Yekutieli adjusted p-value of < 0.001. MIHC also displayed increased CD8+ T cell and CD19/CD20+ B cell densities in the tumor region of HPV+ HNSCC as opposed to HPV- HNSCC (p < 0.01). Increases in a combined metric of tumor B cell content and stromal plasma cell content was associated with increased progression-free survival in HPV- HNSCC patients treated with immune checkpoint inhibitor therapy (p = 0.03). In summary, TIL populations expanded from HPV+ and HPV- HNSCC displayed similar IFN-γ reactivity. However, we identified a strong B-cell signature present within HPV+ HNSCC, and higher B and plasma cell content associated with improved PFS in HPV- HNSCC patients treated with immune checkpoint inhibitors.

High End-of-Life Health Care Utilization in a Contemporary Cohort of Head and Neck Cancer Patients Treated with Immune Checkpoint Inhibitors.

Background/Objective: End-of-life health care utilization (EOLHCU) is largely uncharacterized among patients with recurrent/metastatic head and neck squamous cell carcinomas (RMHNSCC), particularly now that immune checkpoint inhibitors (ICI) have been introduced to the treatment landscape. We examined this in a single-institution, retrospective study. Design/Settings: We utilized a database of deceased, ICI-treated RMHNSCC patients to obtain demographic and EOLHCU data, the latter of which included advanced care plan documentation (ACPD) and systemic therapy or emergency room (ER)/hospital/intensive care unit (ICU) admission within 30 days of death (DOD). This was compared with a cohort of deceased thoracic malignancy (TM) patients in an exploratory analysis. Multivariate analysis was performed to examine for association between patient factors (such as age, Eastern Cooperative Oncology Group (ECOG) performance status, or smoking status) and overall survival (OS); associations between the said patient factors and EOLHCU were also evaluated. This study was conducted at an academic, tertiary center in the United States. Results: The RMHNSCC patients (n = 74) were more likely to have ACPD (p < 0.01), an emergency department visit (p < 0.01), and/or hospital admission (p < 0.01) within 30 DOD relative to the TM group. There was no difference in ICU admissions, ICU deaths, or systemic therapy at end of life (EOL). The OS declined in association with ECOG performance status (PS) and smoking. No association was observed between patient factors and any EOLHCU metric. Conclusions: At our center, patients with ICI-treated RMHNSCC have higher rates of both ACPD and EOLHCU, suggesting high symptom burden and representing opportunities for further study into supportive care augmentation.

Timing of postoperative radiation therapy and survival in resected salivary gland cancers: Long-term results from a single institution.

OBJECTIVES: Timely administration of postoperative radiation therapy (PORT) impacts oncologic outcomes in resected squamous cell carcinomas of the head and neck. Salivary gland cancers (SGCs) are uncommon, and timing of PORT has not been extensively explored. We aimed to determine if the interval between surgery and PORT impacts outcomes in SGCs. MATERIALS AND METHODS: This is a retrospective study of patients with SGCs who underwent curative intent surgical resection followed by adjuvant PORT. Locoregional recurrence free survival (LRFS), disease free survival (DFS), and overall survival (OS) were estimated using the Kaplan Meier method. A multivariate analysis explored the association between demographics, tumor characteristics, and PORT timing with oncologic outcomes using a stepwise Cox proportional hazards model. RESULTS: 180 eligible patients were identified. The median time to PORT start was 61 (range 8-121) days. 169 (93.5%) of patients received neutron radiation. With a median follow up of 8.2 years in surviving patients, the 10-year OS and LRFS estimates were 61% and 53%. In a multivariate analysis, nodal involvement, histologic grade, and age at diagnosis were associated with OS, while nodal involvement, tumor size, and age at diagnosis were associated with LRFS and DFS. Time to PORT start or completion was not statistically associated with survival outcomes. CONCLUSION: SGC patients who underwent surgery in our tertiary institution received PORT within a median of 61 days after surgery. With long term follow up, PORT timing in this retrospective series was not associated with worse oncologic outcomes, and support timely administration of PORT.

Consensus of free flap complications: Using a nomenclature paradigm in microvascular head and neck reconstruction.

BACKGROUND: We aim to define a set of terms for common free flap complications with evidence-based descriptions. METHODS: Clinical consensus surveys were conducted among a panel of head and neck/reconstructive surgeons (N = 11). A content validity index for relevancy and clarity for each item was computed and adjusted for chance agreement (modified kappa, K). Items with K < 0.74 for relevancy (i.e., ratings of "good" or "fair") were eliminated. RESULTS: Five out of nineteen terms scored K < 0.74. Eliminated terms included "vascular compromise"; "cellulitis"; "surgical site abscess"; "malocclusion"; and "non- or mal-union." Terms that achieved consensus were "total/partial free flap failure"; "free flap takeback"; "arterial thrombosis"; "venous thrombosis"; "revision of microvascular anastomosis"; "fistula"; "wound dehiscence"; "hematoma"; "seroma"; "partial skin graft failure"; "total skin graft failure"; "exposed hardware or bone"; and "hardware failure." CONCLUSION: Standardized reporting would encourage multi-institutional research collaboration, larger scale quality improvement initiatives, the ability to set risk-adjusted benchmarks, and enhance education and communication.

Neutron Therapy for High-Grade Salivary Carcinomas in the Adjuvant and Primary Treatment Setting.

OBJECTIVES/HYPOTHESIS: Our primary objective was to compare differences in survival of patients with high-grade salivary gland carcinomas (SGCs) receiving adjuvant neutron versus photon radiotherapy using a hospital-based national cohort and restricted mean survival time (RMST) analysis. Our secondary objective was to compare survival of similar patients treated with primary neutron versus photon radiation. STUDY DESIGN: Multicenter, retrospective population-based study of patients within the National Cancer Database from 2004 to 2014. METHODS: One thousand eight hundred forty-four patients were selected on diagnosis of high-grade parotid and submandibular malignancies. One thousand seven hundred seventy-seven patients receiving photon and 67 patients receiving neutron therapy were identified who met inclusion criteria. Patients were then categorized as having primary surgery with adjuvant radiation or primary radiation without prior surgery. Bivariate analysis was performed to assess for differences between groups, and RMST analysis was performed at 1-, 2-, and 5-year timepoints with controlling for available covariate data. RESULTS: There was no significant difference in RMST for patients receiving neutrons over photons at 1, 2, and 5 years in the adjuvant setting. Among patients undergoing primary radiotherapy, there was a difference in RMST of 2.29 months at 1 year and 5.05 months at 2 years for neutrons over photons, though this benefit was not observed at 5 years post-therapy. CONCLUSIONS: For patients with high grade SGCs undergoing adjuvant photon versus neutron radiotherapy, there was no difference in RMST. There was observed to be a significant difference in RMST at 1 and 2 years among patients undergoing primary neutron therapy of up to 5 months. Given the benefit observed with primary neutron therapy, it should be considered in both the primary and adjuvant treatment setting. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:541-547, 2021.

Communicative Participation and Quality of Life in Pretreatment Oral and Oropharyngeal Head and Neck Cancer.

OBJECTIVE: To determine how communicative participation is affected in patients with oral and oropharyngeal head and neck cancers (HNCs) pretreatment and whether communication function predicts HNC-specific quality of life (QOL) before treatment, beyond known demographic, medical, psychosocial, and swallowing predictors. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care academic medical center. METHODS: Eighty-seven patients with primary oral (40.2%) or oropharyngeal (59.8%) HNC were recruited prior to treatment. T stage, tumor site, and p16 status were extracted from medical records. Demographic and patient-reported measures were obtained. Communicative participation was measured using the Communicative Participation Item Bank (CPIB) General short form. A hierarchical regression analysis included demographic, medical, psychosocial, and functional measures of swallowing and communication as predictors; the University of Washington Quality of Life (UW-QOL v4) composite score was the predicted variable. RESULTS: Median (SD) baseline CPIB scores were 71.0 (11.83); patients with oral cancers reported worse scores. A final sequential hierarchical regression model that included all variables explained 71% of variance in QOL scores. Tumor site, T stage, and p16 status accounted for 28% of variance (P < .001). Perceived depression predicted an additional 28% of the variance (P < .001). Swallowing and communicative participation together predicted an additional 12% of variance (P = .005). Tumor site, perceived depression, swallowing, and communication measures were unique predictors in the final model. Finally, communicative participation uniquely predicted QOL, above and beyond other predictors. CONCLUSION: Pretreatment communication predicted QOL and was negatively affected in some oral and oropharyngeal patients with HNC.

The role of elective neck dissection in high-grade parotid malignancy: A hospital-based cohort study.

OBJECTIVES/HYPOTHESIS: The role of elective neck dissection (END) in patients with clinically N0 (cN0), high-grade parotid carcinoma is unclear. The objective of this study was to assess the association between END and survival in patients with cN0, high-grade parotid carcinoma. STUDY DESIGN: Retrospective, multicenter cohort study. METHODS: A review of hospital-based cases from the National Cancer Data Base was performed. Participants included patients diagnosed with cN0, high-grade parotid cancer between January 1, 2004 and December 31, 2013. The primary exposure was receipt of neck dissection. Secondary exposures included receipt of adjuvant radiation and/or chemotherapy. Univariate and multivariate survival analyses were performed. Unadjusted and adjusted survival estimates were determined. RESULTS: Overall, 1,547 patients were included, with a median follow-up time of 48 months. END did not have a statistically significant effect on 3-year survival (3-year: 69.9%, 95% confidence interval [CI]: 67.2 to 72.6). Survival at 3-years among those not receiving END was 66.1% (95% CI: 62.7 to 69.5). Parotidectomy and adjuvant radiotherapy had the strongest effect on mortality. There was no difference in 3-year survival among patients who underwent parotidectomy and adjuvant radiation stratified by receipt of END nor did END have a statistically significant effect on survival in mucoepidermoid carcinoma, adenocarcinoma, high-risk histology, high T stage, or academic center treatment subgroups. CONCLUSIONS: END did not have a statistically significant effect on survival among cN0 patients with high-grade parotid cancer when taking into account receipt of adjuvant therapy and confounding. The role of END on survival and locoregional control remains to be further elucidated in prospective studies. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1487-1495, 2020.

Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples.

OBJECTIVES: To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer. MATERIALS AND METHODS: Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease. RESULTS: Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent. CONCLUSIONS: If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients.