Anthony C. Nichols

HPV-16 infection predicts treatment outcome in oropharyngeal squamous cell carcinoma:

Objective: To determine if patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) treated with chemoradiation have improved outcomes. Study Design: A retrospective search was used to identify patients with OPSCC treated with concurrent chemoradiation. Pretreatment biopsy specimens were tested for HPV-16 infection and p16 expression. Methods: Forty-four patients with OPSCC treated with concurrent chemotherapy and intensity-modulated radiation therapy were identified. Eligibility criteria included a minimum two years of follow-up, or biopsy-proven recurrence. In situ hybridization was applied to archival tumor specimens, with HPV-16-positive status defined as positive staining of tumor cell nuclei. p16 expression was assessed by immunohistochemistry. Results: Twenty-seven tumors (61%) were positive for HPV-16 and 29 tumors (66%) expressed p16. HPV-16 infection was highly correlated with p16 expression (P < 10−7). Three-year disease-free and overall survival for all patients was 66 percent and 79 percent respectively. Patients with tumors infected with HPV-16 had improved overall (OS) and disease-free survival (DFS) after chemoradiation (OS: hazard ratio [HR] = 0.21, P = 0.01; DFS: HR = 0.30, P = 0.02). Conclusion: Patients with OPSCC tumors that are infected with HPV-16 have improved survival after treatment with concurrent chemoradiation.

Early-stage squamous cell carcinoma of the oropharynx: Radiotherapy vs. Trans-Oral Robotic Surgery (ORATOR) – study protocol for a randomized phase II trial

BackgroundThe incidence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased over the last three decades due to newly found associations with human papillomavirus (HPV) infection. Primary radiotherapy (RT) is the treatment of choice for OPSCC at most centers, and over the last decade, the addition of concurrent chemotherapy has led to a significant improvement in survival, but at the cost of increased acute and late toxicity. Transoral robotic surgery (TORS) has emerged as a promising alternative treatment, with preliminary case series demonstrating encouraging oncologic, functional, and quality of life (QOL) outcomes. However, comparisons of TORS and RT in a non-randomized fashion are susceptible to bias. The goal of this randomized phase II study is to compare QOL, functional outcomes, toxicity profiles, and survival following primary RT (± chemotherapy) vs. TORS (± adjuvant [chemo] RT) in patients with OPSCC.Methods/DesignThe target patient population comprises OPSCC patients who would be unlikely to require chemotherapy post-resection: Tumor stage T1-T2 with likely negative margins at surgery; Nodal stage N0-2, ≤3 cm in size, with no evidence of extranodal extension on imaging. Participants will be randomized in a 1:1 ratio between Arm 1 (RT ± chemotherapy) and Arm 2 (TORS ± adjuvant [chemo] RT). In Arm 1, patients with N0 disease will receive RT alone, whereas N1-2 patients will receive concurrent chemoradiation. In Arm 2, patients will undergo TORS along with selective neck dissections, which may be staged. Pathologic high-risk features will be used to determine the requirement for adjuvant radiotherapy +/- chemotherapy. The primary endpoint is QOL score using the M.D. Anderson Dysphagia Inventory (MDADI), with secondary endpoints including survival, toxicity, other QOL outcomes, and swallowing function. A sample of 68 patients is required.DiscussionThis study, if successful, will provide a much-needed randomized comparison of the conventional strategy of primary RT vs. the novel strategy of primary TORS. The trial is designed to provide a definitive QOL comparison between the two arms, and to inform the design of an eventual phase III trial for survival outcomes.Trial registrationNCT01590355

Detection of circulating tumor cells in advanced head and neck cancer using the cellsearch system

Early detection of circulating tumor cells (CTCs) offers the possibility of improved outcome for patients with head and neck squamous cell cancer (HNSCC).

The Role of Transoral Robotic Surgery in the Management of Oropharyngeal Cancer: A Review of the Literature

Background. Transoral robotic surgery (TORS) is an emerging treatment option for the treatment of head and neck malignancies, particularly for oropharyngeal squamous cell carcinoma (OPSCC). Preliminary studies have demonstrated excellent oncologic and functional outcomes that have led to a resurgence of interest in the primary surgical management of OPSCC. The aim of the present study was to review the evidence base supporting the use of TORS in OPSCC. Methods. Studies evaluating the application of TORS in the treatment of head and neck squamous cell carcinoma (HNSCC), and more specifically OPSCC, were identified for review. Further searches were made of reference lists for complete evaluation of minimally invasive surgery (MIS) in treating OPSCC. Results. Seventeen results relating to the application of TORS in treatment of OPSCC were identified. Further results relating to the role of transoral laser microsurgery (TLM) in OPSCC were included for review. Feasibility, oncologic, and functional data is summarized and discussed. Discussion. Management strategies for patients with OPSCC continue to evolve. Minimally invasive surgical techniques including TORS and TLM offer impressive functional and oncologic outcomes particularly for patients with early T-classification and low-volume regional metastatic disease. Potential exists for treatment deintensification, particularly in patients who are HPV positive.

The epidemic of human papillomavirus and oropharyngeal cancer in a Canadian population

BACKGROUND Sexually transmitted infection with the human papillomavirus (hpv) is responsible for a significant burden of human cancers involving the cervix, anogenital tract, and oropharynx. Studies in the United States and Europe have demonstrated an alarming increase in the frequency of hpv-positive oropharyngeal cancer, but the same direct evidence does not exist in Canada. METHODS Using the London Health Sciences Centre pathology database, we identified tonsillar cancers diagnosed between 1993 and 2011. Real-time polymerase chain reaction was then used on pre-treatment primary-site biopsy samples to test for dna from the high-risk hpv types 16 and 18. The study cohort was divided into three time periods: 1993-1999, 2000-2005, and 2006-2011. RESULTS Of 160 tumour samples identified, 91 (57%) were positive for hpv 16. The total number of tonsillar cancers significantly increased from 1993-1999 to 2006-2011 (32 vs. 68), and the proportion of cases that were hpv-positive substantially increased (25% vs. 62%, p < 0.002). Those changes were associated with a marked improvement in 5-year overall survival (39% in 1993-1999 vs. 84% in 2006-2011, p < 0.001). When all factors were included in a multivariable model, only hpv status predicted treatment outcome. INTERPRETATION The present study is the first to provide direct evidence that hpv-related oropharyngeal cancer is increasing in incidence in a Canadian population. Given the long lag time between hpv infection and clinically apparent malignancy, oropharyngeal cancer will be a significant clinical problem for the foreseeable future despite vaccination efforts.

Esthesioneuroblastoma: The Massachusetts Eye and Ear Infirmary and Massachusetts General Hospital Experience with Craniofacial Resection, Proton Beam Radiation, and Chemotherapy

OBJECTIVES To determine the efficacy of craniofacial resection and proton radiation for the management of esthesioneuroblastoma (ENB). DESIGN A retrospective chart review was performed of all patients presenting with ENB and completely managed at the Massachusetts General Hospital (MGH) and the Massachusetts Eye and Ear Infirmary (MEEI) from 1997 to 2006. SETTING A tertiary referral center. MAIN OUTCOME MEASURES Disease-free and overall survival. PARTICIPANTS All patients presenting with ENB and completely managed at the MGH and the MEEI from 1997 to 2006. RESULTS Ten patients were identified with a median follow-up time of 52.8 months. Average age at presentation was 45 years. Nasal obstruction was the most common presenting symptom. Three patients presented with Kadish stage B disease and seven with stage C. No patient had evidence of cervical or metastatic disease at presentation. Seven patients were treated with craniofacial resections (CFR) followed by proton beam radiation with or without chemotherapy. Three patients were treated with initial chemotherapy with no response. They subsequently underwent CFR followed by proton beam radiation. The 5-year disease-free and overall survival rates were 90% and 85.7%, respectively, by Kaplan-Meier analysis. No patient suffered any severe radiation toxicity. CONCLUSION ENB can be safely and effectively treated with CFR followed by proton beam irradiation. Proton irradiation may be associated with less toxicity than photon irradiation. The role of chemotherapy remains unclear.

Bcl2 and Human Papilloma Virus 16 as Predictors of Outcome following Concurrent Chemoradiation for Advanced Oropharyngeal Cancer

Purpose: Oropharyngeal squamous cell carcinoma (OPSCC) associated with human papilloma virus (HPV) is rapidly growing in incidence. Despite better prognosis than OPSCC associated with traditional risk factors, treatment failure still occurs in a significant proportion of patients. We had identified the antiapoptotic protein Bcl2 as a marker for poor outcome in advanced OPSCC treated with concurrent chemoradiation. To determine whether Bcl2 and HPV together might further characterize treatment response, we examined whether the prognostic value of Bcl2 was independent of HPV status. Experimental Design: Pretreatment tumor biopsies from 68 OPSCC patients were tested for HPV by in situ hybridization and were immunostained for Bcl2 to evaluate relations with disease-free (DFS) and overall survival following platin-based concurrent chemoradiation. Median follow-up among surviving patients was 47 months (range, 10-131 months). Results: Bcl2 and HPV independently predicted DFS and overall survival. Hazard ratios (with 95% confidence interval) for positive versus negative status in bivariate Cox proportional hazard analysis of DFS were 6.1 (1.8-21) for Bcl2 and 0.11 (0.035-0.37) for HPV. Only 1 of 32 HPV-positive/Bcl2-negative tumors recurred. Pretreatment Bcl2 expression was specifically associated with distant metastasis; five of six distant metastases occurred in the <40% of patients whose primary tumors were Bcl2 positive. Conclusions: Independent of HPV status, pretreatment Bcl2 expression identifies a subset of OPSCC patients having increased risk of treatment failure, particularly through distant metastasis, after concurrent chemoradiation. Considering HPV and Bcl2 together should help in devising better personalized treatments for OPSCC. Clin Cancer Res; 16(7); 2138–46. ©2010 AACR.

Racial differences in stage and survival in head and neck squamous cell carcinoma.

Objectives: The goal of this study was to characterize differences in survival between black patients and white patients with squamous cell carcinoma of the head and neck (HNSCCA).

Surgical salvage of the oropharynx after failure of organ-sparing therapy

The purpose of this study was to evaluate the efficacy of salvage surgery for local recurrences of oropharyngeal squamous cell carcinoma (OPSCC) and identify predictors of survival.

Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas

Human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs) are deadly and common cancers. Recent genomic studies implicate multiple genetic pathways, including cell signaling, cell cycle and immune evasion, in their development. Here we analyze public data sets and uncover a previously unappreciated role of epigenome deregulation in the genesis of 13% of HPV-negative HNSCCs. Specifically, we identify novel recurrent mutations encoding p.Lys36Met (K36M) alterations in multiple H3 histone genes. histones. We further validate the presence of these alterations in multiple independent HNSCC data sets and show that, along with previously described NSD1 mutations, they correspond to a specific DNA methylation cluster. The K36M substitution and NSD1 defects converge on altering methylation of histone H3 at K36 (H3K36), subsequently blocking cellular differentiation and promoting oncogenesis. Our data further indicate limited redundancy for NSD family members in HPV-negative HNSCCs and suggest a potential role for impaired H3K36 methylation in their development. Further investigation of drugs targeting chromatin regulators is warranted in HPV-negative HNSCCs driven by aberrant H3K36 methylation.