Paul L. Swiecicki

Advanced oropharyngeal squamous cell carcinoma: Pathogenesis, treatment, and novel therapeutic approaches

Oropharyngeal cancer accounts for approximately 2.8% of newly cancer cases. Although classically a tobacco related disease, most cases today are related to infection with human papilloma virus (HPV) and present with locally advanced tumors. HPV related tumors have been recognized as a molecularly distinct entity with higher response rates to therapy, lower rates of relapse, and improved overall survival. Treatment of oropharyngeal cancer entails a multi-disciplinary approach with concomitant chemoradiation. The role of induction chemotherapy in locally advanced tumors continues to be controversial however large studies have demonstrated no difference in survival or time to treatment failure. Surgical approaches may be employed with low volume oropharyngeal cancers and with development new endoscopic tools, more tumors are able to be resected via an endoscopic approach. Given advances in the understanding of HPV related oropharyngeal cancer, ongoing research is looking at ways to minimize toxicities via de-intensification of therapy. Unfortunately, some patients develop recurrent or metastatic disease. Novel therapeutics are currently being investigated for this patient population including immunotherapeutics. This review discusses the current understanding of the pathogenesis of oropharyngeal cancer and treatment. We also discuss emerging areas of research as it pertains to de-intensification as well novel therapeutics for the management of metastatic disease.

Sparing all salivary glands with IMRT for head and neck cancer: Longitudinal study of patient-reported xerostomia and head-and-neck quality of life

BACKGROUND AND PURPOSE While parotid-sparing intensity modulated radiotherapy (IMRT) has demonstrated superiority to conventional RT in terms of observer-rated xerostomia, patient-reported outcome measures (PROMs) have only marginally improved. We investigated how sparing all salivary glands affects PROMs. MATERIALS AND METHODS Patients treated to the bilateral neck with all-gland-sparing IMRT answered xerostomia (XQ) and head-and-neck quality of life (HNQOL) questionnaires. Longitudinal regression was used to assess the relationship between questionnaire scores and mean bilateral parotid gland (bPG), contralateral submandibular gland (cSMG), and oral cavity (OC) doses. Marginal R2 and Akaike information criterion (AIC) were used for model evaluation. RESULTS 252 patients completed approximately 600 questionnaires. On univariate analysis, bPG, cSMG, and OC doses significantly correlated with XQ-summary, XQ-eating, and HNQOL-eating scores. On multivariate analysis, bPG and OC doses significantly correlated with XQ-summary, XQ-eating, and HNQOL-eating scores; and cSMG dose with HNQOL-summary. Combining doses to all three structures yielded the highest R2 for XQ-summary, XQ-rest, XQ-eating, and HNQOL-eating. In the 147 patients who received a mean cSMG dose ≤39Gy, there were no failures in contralateral level IB. CONCLUSIONS Reducing doses to all salivary glands maximizes PROMs. A cSMG dose constraint of ≤39Gy does not increase failure risk.

E6 and E7 antibody levels are potential biomarkers of recurrence in patients with advanced stage human papillomavirus positive oropharyngeal squamous cell carcinoma

Purpose: There is a paucity of biomarkers to predict failure in human papillomavirus–positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) following curative therapy. E6/E7 viral oncoproteins are constitutively expressed in HPV+ tumors and highly immunogenic, resulting in readily detected serum antibodies. The purpose of this study is to determine whether serum E6 and E7 antibody levels can potentially serve as a biomarker of recurrence in patients with HPV+OPSCC. Experimental Design: We evaluated E6/E7 antibody levels in patients with previously untreated, advanced stage (III, IVa-b), HPV+OPSCC receiving definitive chemoradiation under a uniform protocol from 2003 to 2010. Baseline and longitudinal serum samples were obtained from our archived repository. E6/E7 serum levels were measured using a glutathione-S-transferase capture ELISA and quantified by approximating the area under the dilution curve, and were analyzed using ANOVA and linear mixed model for longitudinal analysis. Results: We compared 22 HPV+OPSCC patients who developed recurrence with 30 patients who remained disease-free. There were no differences in T classification, N classification, disease subsite, or smoking status between the groups. In a longitudinal analysis, recurrent patients had significantly higher E6 and E7 serum antibody levels than the nonrecurrent patients over the follow-up period (P = 0.02 and P = 0.002, respectively). Patients who recurred had a lower clearance of E7 antibody than patients who remained disease-free (P = 0.0016). Conclusions: Patients with HPV+OPSCC whose disease recurs have a lower clearance of E6 and E7 antibodies than patients who do not have recurrence. The ratio of E7 antibody at disease recurrence compared with baseline is potentially a clinically significant measurement of disease status in HPV+OPSCC. Clin Cancer Res; 23(11); 2723–9. ©2016 AACR.

Changing the paradigm：the potential for targeted therapy in laryngeal squamous cell carcinoma

Laryngeal squamous cell carcinoma (LSCC) remains a highly morbid and fatal disease. Historically, it has been a model example for organ preservation and treatment stratification paradigms. Unfortunately, survival for LSCC has stagnated over the past few decades. As the era of next-generation sequencing and personalized treatment for cancer approaches, LSCC may be an ideal disease for consideration of further treatment stratification and personalization. Here, we will discuss the important history of LSCC as a model system for organ preservation, unique and potentially targetable genetic signatures of LSCC, and methods for bringing stratified, personalized treatment strategies to the 21st century.

A review of drugs in development for the personalized treatment of head and neck squamous cell carcinoma

ABSTRACT Introduction: Head and neck squamous cell carcinoma remains a highly morbid and fatal disease, with poor survival rates among patients with advanced and recurrent disease. Recent advances in next generation sequencing, targeted therapeutics, and precision medicine trials are expanding treatment options for head and neck cancers; thus greater awareness of this rapidly evolving field is important. Areas covered: Recent next-generation sequencing studies in head and neck squamous cell carcinoma, targeted therapy clinical trials involving head and neck squamous cell carcinoma. Expert commentary: This review discusses the current state of head and neck cancer treatment, and considerations and implications for the incorporation of personalized medicine and targeted therapy for head and neck cancers in a dynamic clinical landscape.

Palliative Head and Neck Cancer Treatment for Asymptomatic Disease

Palliative Head and Neck Cancer Treatment for Asymptomatic Disease Otolaryngology– Head and Neck Surgery 2018, Vol. 159(1) 25–28 American Academy of Otolaryngology–Head and Neck Surgery Foundation 2018 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599818761861 http://otojournal.org Divya Yerramilli, MD, MBE*, Kevin J. Kovatch, MD*, Annie W. Chan, MD, Paul Swiecicki, MD, Danielle N. Margalit, MD, MPH, and Andrew G. Shuman, MD

From VA Larynx to the future of chemoselection: Defining the role of induction chemotherapy in larynx cancer

Organ preservation protocols utilizing induction chemotherapy as a selection agent have played a critical role in the treatment of advanced laryngeal squamous cell carcinoma (LSCC). The selection of patients who will have a good response to chemoradiation allows for organ preservation in a significant group of patients and minimizes the rate of surgical salvage. While there remains debate regarding its utility when compared to surgery or other organ preservation regimens, the data does suggest an important role for induction chemotherapy in LSCC. In addition, there are continued opportunities to identify pretreatment biomarkers for induction chemotherapy, whether genetic, epigenetic or cellular, that could predict response to treatment and select patients to therapy (whether organ preservation or surgery). As our understanding of the biology of larynx cancer advances, induction paradigms have utility for the development and adoption of novel agents and therapeutics. The background of induction chemotherapy as a selection agent and future directions of this approach are discussed.

Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma

BackgroundRecurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4+, CD8+ and/or CD103+ TIL status in patients with advanced LSCC.MethodsTissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4+, CD8+, and CD103+ TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4+, CD8+, and CD103+ TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC.ResultsHigh tumor CD103+ TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8+ or CD4+ TIL content. On multivariate analysis, an “immune-rich” phenotype, in which tumors were enriched for both CD103+ and CD4+ TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC.ConclusionsAn immune profile driven by CD103+ TIL content, alone and in combination with CD4+ TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.

Alternative Imaging Response Criteria with the Use of Axitinib in Head and Neck Cancer: An Exploratory Analysis Utilizing the Choi Criteria

Objective: The purpose of this study was to explore the utility of the Choi Criteria in judging response to axitinib therapy in unresectable recurrent or distant metastatic head and neck squamous cell carcinoma. Methods: Radiologic and clinical data was evaluated in a retrospective fashion from a single-arm phase II clinical trial of axitinib for the treatment of unresectable recurrent or metastatic head and neck squamous cell carcinoma. Twenty-nine patients had imaging to which the Choi Criteria were applied in an exploratory fashion. Responses rates by Choi Criteria were compared to those identified by RECIST v1.0 and statistical analyses were performed to evaluate significance. Association of best response to survival was also examined for each criteria (RECIST v1.0 and Choi). Results: Application of the Choi Criteria demonstrated that 65.5% of patients achieved a partial response versus 6.9% by RECIST v1.0. Disease control rate was identical by Choi Criteria and RECIST v1.0 at 72.4%. Response to therapy based on Choi Criteria correlated to significantly improved estimated overall survival at 12 months (63% vs. 20%, p=0.03), whereas response to therapy based on RECIST was not a significant predictor of survival. Conclusion: The Choi Criteria appear to better identify patients responding to therapy with the anti-angiogenic tyrosine kinase inhibitor axitinib versus RECIST v1.0 in this exploratory analysis. Use of the Choi Criteria to guide treatment decisions in further studies utilizing axitinib in this population may better identify patients benefiting from therapy.

Capecitabine after Surgical Salvage in Recurrent Squamous Cell Carcinoma of Head and Neck

Due to the high incidence of recurrent squamous cell carcinoma of the head and neck and the toxicity profile of current salvage regimens, there is a need for tolerable and effective treatment options. We performed a retrospective matched case series to report our experience with recurrent high-risk patients who received capecitabine (CAP) therapy in the adjuvant setting after salvage therapy. The 5-year recurrence-free survival rates for the CAP and control cohorts were 54% (95% CI, 0.27%-0.75%) and 27% (95% CI, 0.09%-0.50%), respectively. Multivariable Cox modeling showed a significant improvement in recurrence-free survival in the CAP cohort (hazard ratio, 0.19; 95% CI, 0.04-0.92; P = .0392). While this was a respective analysis that could not control for all variables, these exploratory findings offer insights that may inform a prospective study to determine CAP efficacy.