Purpose: On the basis of synergistic effects between green tea polyphenon E (PPE) and EGFR-tyrosine kinase inhibitor in preclinical studies, we conducted a phase Ib study of the PPE and erlotinib combination in patients with advanced premalignant lesions (APL) of the oral cavity and larynx. Patients and Methods: Patients were treated with a fixed dose of PPE (200 mg three times a day) and dose escalation of erlotinib (50, 75, 100 mg daily) for 6 months with tissue biopsy at baseline and 6 months. Primary endpoints were safety and toxicity; secondary endpoints were evaluation of pathologic response, cancer-free survival (CFS), overall survival (OS), and biomarker modulation. Results: Among 21 enrolled patients, 19 began treatment and 17 completed 6 months of treatment with PPE and erlotinib. Main characteristics of treated patients: 15 severe dysplasia or carcinoma in situ and 17 oral cavity. Only skin rash was associated with dose-limiting toxicity and MTD. Recommended doses for phase II studies are PPE 600 mg daily plus erlotinib 100 mg daily for 6 months. Pathologic responses in 17 evaluable patients: pathologic complete response (47%) and pathologic partial response (18%). The 5-year CFS and OS were 66.3% and 93%, respectively. Among tested biomarkers, only phosphorylated ERK was correlated with response to treatment. Conclusions: Treatment with PPE and erlotinib combination was well tolerated in patients with APLs of the head and neck, and showed a high rate of pathologic response with excellent CFS. This combination deserves further investigation for the chemoprevention and/or prevention of second primary tumors in early-stage head and neck cancer.

Background: Data objectively evaluating acute post-transoral robotic surgery (TORS) swallow function are limited. Our goal was to characterize and identify clinical variables that may impact swallow function components 3 weeks post-TORS. Methods: Retrospective cohort study. Pre/postoperative use of the Modified Barium Swallow Impairment Profile (MBSImP) and Penetration-Aspiration Scale (PAS) was completed on 125 of 139 TORS patients (2016–2019) with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma. Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scores were retrospectively calculated. Uni/multivariate analysis was performed. Results: Dysfunctional pre-TORS DIGEST scores were predictive of post-TORS dysphagia (p = 0.015). Pre-TORS MBSImP deficits in pharyngeal stripping wave, swallow initiation, and clearing pharyngeal residue correlated with airway invasion post-TORS based on PAS scores (p = 0.012, 0.027, 0.048, respectively). Multivariate analysis of DIGEST safety scores declined with older age (p = 0.044). Odds ratios (ORs) for objective swallow function components after TORS were better for unknown primary and tonsil primaries compared to base of tongue (BOT) (OR 0.35–0.91). Conclusions: Preoperative impairments in specific MBSImP components, older patients, and BOT primaries may predict more extensive recovery in swallow function after TORS.

OBJECTIVES: The eighth edition American Joint Committee on Cancer (AJCC) Staging incorporates significant changes to the seventh edition in the staging of oropharyngeal squamous cell carcinomas (OPSCC). An important change was the inclusion of OPSCC associated with the human papilloma virus (HPV). Our goal is to compare the performance of both staging systems for patients with HPV-selected and unselected clinical characteristics for OPSCC. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2016, we identified patients with likely HPV-associated OPSCC based on surrogate markers (white males aged <65 years old with squamous cell carcinomas of the tonsil and base of tongue), excluding those who underwent surgery. We re-classified these patients using seventh and eighth edition staging for HPV-selected OPSCC and compared the prediction performance of both staging editions for overall survival (OS) and disease-specific survival (DSS). We performed the same analysis for clinically unselected patients with OPSCC. RESULTS: Our analysis included 9554 patients with a median follow-up of 67 months. Comparing the eighth versus seventh edition for our HPV-selected cohort, clinical staging changed for 92.3% of patients and 10-year OS was 62.2%, 61.2%, 35.3%, and 15.5% for Stage I, II, III, and IV, versus 52.9%, 59.2%, 61.6%, 55.1%, 38.3%, and 15.5% for stage I, II, III, IVA, IVB, and IVC, respectively. A similar pattern was observed for 10-year DSS. The concordance statistics for our HPV-selected cohort were improved for both AJCC 7 (0.6260) and AJCC 8 (0.6846) compared with the unselected cohort, 0.5860 and 0.6457 for AJCC 7 and 8, respectively. CONCLUSION: The overall performance of discrimination improved from AJCC 7 to AJCC 8 for both clinically selected and unselected patients, but more notably for our HPV-selected cohort. Despite the lack of statistically significant differentiation between Stages I and II in AJCC 8 in either groups, markedly improved discrimination was observed between Stages I/II, III, and IV in the HPV-selected cohort.

Background Pathologic extranodal extension (ENE) has traditionally guided the management of head and neck cancers. The prognostic value of radiographic ENE (rENE) in HPV-associated oropharyngeal squamous cell carcinoma (HPV+OPX) is uncertain. Methods HPV+OPX patient with adequate pre-treatment radiographic nodal evaluation, from a single institution were analyzed. rENE status was determined by neuroradiologists’ at time of diagnosis. Distant metastasis-free survival (DMFS), overall survival (OS), locoregional recurrence-free survival (LRFS) and were estimated using Kaplan-Meier methods. Cox proportional hazards models were fit to assess the impact of rENE on survival endpoints. Results 168 patients with OPX+SCC diagnosed between April 2008 and December 2014 were included for analysis with median follow-up of 3.3 years. Eighty-eight percent of patients received concurrent chemoradiotherapy. rENE was not prognostic; its presence in HPV+OPX patients did not significantly impact OS, LRFS, or DMFS. Conclusions In patients with HPV+OPX, rENE was not significantly associated with OS, LRFS, or DMFS.

OBJECTIVES: The late effects of RT are not well reported in patients with oral tongue cancer (OTC). This study reports the incidence of late effects and factors associated with the development of late effects in OTC patients. METHODS: Patients with OTC treated in our institution from 2003 to 2013 were evaluated. The association between RT doses, including mandible maximum and minimum doses and total 3D maximum dose, and late toxicity, defined as development of osteoradionecrosis (ORN), percutaneous endoscopic gastrostomy (PEG) tube dependence for >6 months after treatment, and narcotic dependency >6 months posttreatment were assessed using both univariate and multivariable (MV) analysis. RESULTS: Seventy-six patients with OTC (45% males and 55% females) were treated with definitive surgical resection followed by adjuvant RT. The median follow-up was 4.3 years. Combined late toxicities were reported in 38% of patients. Thirty-four percent of the patients had narcotic dependency and, 3.9% of the patients had ORN of the mandible. Thirteen percent of patients developed PEG tube dependency that was significantly associated with a higher 3D maximum radiation dose on univariate analysis (p < 0.01). On MV analysis, 3D maximum dose remained significantly associated with long-term PEG tube dependency (p = 0.05). CONCLUSION: Patients with OTC treated with adjuvant RT are at significant risk for development of late toxicities. Increasing maximum dose is associated with long-term PEG tube dependence, and care should be taken to reduce the "hot spot" within radiation treatment plans as much as possible.

Purpose: Our previous work suggested that HER3 inhibition sensitizes head and neck squamous cell carcinoma (HNSCC) to EGFR inhibition with cetuximab. This study aimed to define the role of HER3 in cetuximab resistance and the antitumor mechanisms of EGFR/HER3 dual targeting in HNSCC. Experimental Design: We treated cetuximab-resistant HNSCC UMSCC1-C and parental UMSCC1-P cell lines with anti-EGFR antibody cetuximab, anti-HER3 antibody MM-121, and their combination. We assessed activities of HER2, HER3, and downstream signaling pathways by Western blotting and cell growth by sulforhodamine B (SRB) and colony formation assays. HER3-specific shRNA was used to confirm the role of HER3 in cetuximab response. The combined efficacy and alterations in biomarkers were evaluated in UMSCC1-C xenograft and patient-derived xenograft (PDX) models. Results: Cetuximab treatment induced HER3 activation and HER2/HER3 dimerization in HNSCC cell lines. Combined treatment with cetuximab and MM-121 blocked EGFR and HER3 activities and inhibited the PI3K/AKT and ERK signaling pathways and HNSCC cell growth more effectively than each antibody alone. HER3 knockdown reduced HER2 activation and resensitized cells to cetuximab. Cetuximab-resistant xenografts and PDX models revealed greater efficacy of dual EGFR and HER3 inhibition compared with single antibodies. In PDX tissue samples, cetuximab induced HER3 expression and MM-121 reduced AKT activity. Conclusions: Clinically relevant PDX models demonstrate that dual targeting of EGFR and HER3 is superior to EGFR targeting alone in HNSCC. Our study illustrates the upregulation of HER3 by cetuximab as one mechanism underlying resistance to EGFR inhibition in HNSCC, supporting further clinical investigations using multiple targeting strategies in patients who have failed cetuximab-based therapy.

Background: The prognostic relevance of human papillomavirus (HPV) status in non-oropharyngeal (OPX) squamous cell cancer (SCC) of the head and neck is controversial. We evaluated the impact of high-risk HPV status on overall survival (OS) in patients with non-OPX SCC using a large database approach. Methods: The National Cancer Data Base was queried to identify patients diagnosed from 2004–2014 with SCC of the OPX, hypopharynx (HPX), larynx, and oral cavity (OC) with known HPV status. Survival was estimated using Kaplan-Meier methods; distributions were compared with log-rank tests. Propensity score matching (PSM) and inverse probability of treatment weighing (IPTW) methods were utilized; cohorts were matched on age, sex, Charlson-Deyo score, clinical group stage, treatments received, and anatomic subsite. Propensity analyses were stratified by group stage. Results: 24,740 patients diagnosed from 2010–2013 were analyzed; 1,085 patients with HPX, 4804 with larynx, 4,018 with OC, and 14,833 with OPX SCC. The proportions of HPV positive cases by site were: 17.7% in HPX, 11% in larynx, 10.6% in OC, and 62.9% in OPX. HPV status was prognostic in multiple un-adjusted and propensity-adjusted non-OPX populations. HPV positivity was associated with superior OS in HPX SCC with hazard ratio (HR) of 0.61 (p<0.001, IPTW), in stage III-IVB laryngeal SCC (HR 0.79, p=0.019, IPTW), and in stage III-IVB OC SCC (HR 0.78, p=0.03, IPTW). Conclusions: Positive high-risk HPV status is associated with longer OS in multiple non-oropharynx head and neck populations – hypopharynx, locally-advanced larynx and oral cavity. If prospectively validated, these findings have implications for risk-stratification.

Human papilloma virus (HPV) causes a subset of head and neck squamous cell carcinomas (HNSCC) of the oropharynx. We combined targeted DNA- and genome-wide RNA-sequencing to identify genetic variants and gene expression signatures respectively from patients with HNSCC including oropharyngeal squamous cell carcinomas (OPSCC). DNA and RNA were purified from 35- formalin fixed and paraffin embedded (FFPE) HNSCC tumor samples. Immuno-histochemical evaluation of tumors was performed to determine the expression levels of p16INK4A and classified tumor samples either p16+ or p16-. Using ClearSeq Comprehensive Cancer panel, we examined the distribution of somatic mutations. Somatic single-nucleotide variants (SNV) were called using GATK-Mutect2 (“tumor-only” mode) approach. Using RNA-seq, we identified a catalog of 1,044 and 8 genes as significantly expressed between p16+ and p16-, respectively at FDR 0.05 (5%) and 0.1 (10%). The clinicopathological characteristics of the patients including anatomical site, smoking and survival were analyzed when comparing p16+ and p16- tumors. The majority of tumors (65%) were p16+. Population sequence variant databases, including gnomAD, ExAC, COSMIC and dbSNP, were used to identify the mutational landscape of somatic sequence variants within sequenced genes. Hierarchical clustering of The Cancer Genome Atlas (TCGA) samples based on HPV-status was observed using differentially expressed genes. Using RNA-seq in parallel with targeted DNA-seq, we identified mutational and gene expression signatures characteristic of p16+ and p16- HNSCC. Our gene signatures are consistent with previously published data including TCGA and support the need to further explore the biologic relevance of these alterations in HNSCC.

One of the largest factors affecting disease recurrence after surgical cancer resection is negative surgical margins. Hyperspectral imaging (HSI) is an optical imaging technique with potential to serve as a computer aided diagnostic tool for identifying cancer in gross ex-vivo specimens. We developed a tissue classifier using three distinct convolutional neural network (CNN) architectures on HSI data to investigate the ability to classify the cancer margins from ex-vivo human surgical specimens, collected from 20 patients undergoing surgical cancer resection as a preliminary validation group. A new approach for generating the HSI ground truth using a registered histological cancer margin is applied in order to create a validation dataset. The CNN-based method classifies the tumor-normal margin of squamous cell carcinoma (SCCa) versus normal oral tissue with an area under the curve (AUC) of 0.86 for inter-patient validation, performing with 81% accuracy, 84% sensitivity, and 77% specificity. Thyroid carcinoma cancer-normal margins are classified with an AUC of 0.94 for inter-patient validation, performing with 90% accuracy, 91% sensitivity, and 88% specificity. Our preliminary results on a limited patient dataset demonstrate the predictive ability of HSI-based cancer margin detection, which warrants further investigation with more patient data and additional processing techniques to optimize the proposed deep learning method.

The speed and scale of the global COVID-19 pandemic has resulted in unprecedented pressures on health services worldwide, requiring new methods of service delivery during the health crisis. In the setting of severe resource constraint and high risk of infection to patients and clinicians, there is an urgent need to identify consensus statements on head and neck surgical oncology practice. We completed a modified Delphi consensus process of three rounds with 40 international experts in head and neck cancer surgical, radiation, and medical oncology, representing 35 international professional societies and national clinical trial groups. Endorsed by 39 societies and professional bodies, these consensus practice recommendations aim to decrease inconsistency of practice, reduce uncertainty in care, and provide reassurance for clinicians worldwide for head and neck surgical oncology in the context of the COVID-19 pandemic and in the setting of acute severe resource constraint and high risk of infection to patients and staff.