Benjamin R. Roman

The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers: Insights From a Precision Oncology Sequencing Platform

Importance Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies. Objective To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease. Design, Setting, and Participants After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis. Interventions Next-generation sequencing of tumors and matched normal DNA. Main Outcomes and Measures Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease. Results Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV)-positive tumors, many recurrent and metastatic HPV-positive tumors exhibited a molecular profile more similar to HPV-negative tumors, including enriched frequencies of TP53 mutation (3 of 20 tumors [15%]), whole genome duplication (5 of 20 tumors [25%]), and 3p deletion (11 of 20 tumors [55%]). There were high rates of TERT promoter mutation in recurrent and metastatic HPV-negative HNSCC (13 of 30 tumors [43%]), cutaneous SCC (11 of 21 tumors [52%]), basal cell carcinoma (3 of 4 tumors [75%]), and ACC (5 of 36 tumors [14%]). Activating NOTCH1 mutations were enriched in metastatic ACCs (8 of 36 tumors [22%]). Conclusions and Relevance These findings reveal the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology. To understand the repertoire of targetable alterations in advanced cancers, it is necessary to sequence recurrent and metastatic tumors. These data are important first steps toward implementation of precision head and neck oncology.

Natural History and Tumor Volume Kinetics of Papillary Thyroid Cancers During Active Surveillance

Importance Active surveillance of low-risk papillary thyroid cancer (PTC) is now an accepted alternative to immediate surgery, but experience with this approach outside of Japan is limited. The kinetics (probability, rate, and magnitude) of PTC tumor growth under active surveillance have not been well defined. Objective To describe the kinetics of PTC tumor growth during active surveillance. Design, Setting, and Participants Cohort study of 291 patients undergoing active surveillance for low-risk PTC (intrathyroidal tumors ⩽1.5 cm) with serial tumor measurements via ultrasonography at a tertiary referral center in the United States. Intervention Active surveillance. Main Outcomes and Measures The cumulative incidence, rate, and magnitude of the change in tumor diameter or volume, as well as associations with patient and tumor characteristics. Results Of the 291 patients, 219 (75.3%) were women; mean (SD) age was 52 (15) years. During a median (range) active surveillance of 25 (6-166) months, growth in tumor diameter of 3 mm or more was observed in 11 of 291 (3.8%) patients, with a cumulative incidence of 2.5% (2 years) and 12.1% (5 years). No regional or distant metastases developed during active surveillance. In all cases, 3-dimensional measurements of tumor volume allowed for earlier identification of growth (median, 8.2 months; range, 3-46 months before increase in tumor diameter). In multivariable analysis, both younger age at diagnosis (hazard ratio per year, 0.92; 95% CI, 0.87-0.98; P = .006) and risk category at presentation (hazard ratio for inappropriate, 55.17; 95% CI, 9.4-323.19; P < .001) were independently associated with the likelihood of tumor growth. Of the tumors experiencing volume growth, kinetics demonstrated a classic exponential growth pattern, with a median doubling time of 2.2 years (range, 0.5-4.8 years; median r2 = 0.75; range, 0.42-0.99). Conclusions and Relevance The rates of tumor growth during active surveillance in a US cohort with PTCs measuring 1.5 cm or less were low. Serial measurement of tumor volumes may facilitate early identification of tumors that will continue to grow and thereby inform the timing of surveillance imaging and therapeutic interventions.

Increase in primary surgical treatment of T1 and T2 oropharyngeal squamous cell carcinoma and rates of adverse pathologic features: National Cancer Data Base

There has been increasing interest in the primary surgical treatment of patients with early T classification (T1‐T2) oropharyngeal squamous cell carcinoma (OPSCC), with the stated goal of de‐escalating or avoiding adjuvant treatment. Herein, the authors sought to determine the degree to which this interest has translated into changes in practice patterns, and the rates of adverse postoperative pathologic features.

AHNS Series—Do you know your guidelines? Guideline recommended follow-up and surveillance of head and neck cancer survivors

In this first article of the “Do You Know Your Guidelines” series, we review National Comprehensive Cancer Network (NCCN) recommendations and underlying evidence for the follow‐up and surveillance of head and neck cancer survivors. The goals of follow‐up and surveillance care are (1) to maximize long‐term oncologic outcomes of therapy with appropriate evaluation for recurrence, (2) to maximize functional and quality of life outcomes, and (3) minimizing unnecessary and harmful low‐value care. Finding the right balance of testing and surveillance is a challenge for providers and patients. Herein, we review all NCCN recommendations for head and neck cancer survivors. We pay particular attention to an area of controversy: the use of ongoing surveillance imaging, in particular, PET/CT scans.

Guideline recommended follow‐up and surveillance of head and neck cancer survivors

In this first article of the “Do You Know Your Guidelines” series, we review National Comprehensive Cancer Network (NCCN) recommendations and underlying evidence for the follow‐up and surveillance of head and neck cancer survivors. The goals of follow‐up and surveillance care are (1) to maximize long‐term oncologic outcomes of therapy with appropriate evaluation for recurrence, (2) to maximize functional and quality of life outcomes, and (3) minimizing unnecessary and harmful low‐value care. Finding the right balance of testing and surveillance is a challenge for providers and patients. Herein, we review all NCCN recommendations for head and neck cancer survivors. We pay particular attention to an area of controversy: the use of ongoing surveillance imaging, in particular, PET/CT scans.

Cost-Effectiveness Analysis of Papillary Thyroid Cancer Surveillance

The recent overdiagnosis of subclinical, low‐risk papillary thyroid cancer (PTC) coincides with a growing national interest in cost‐effective health care practices. The aim of this study was to measure the relative cost‐effectiveness of disease surveillance of low‐risk PTC patients versus intermediate‐ and high‐risk patients in accordance with American Thyroid Association risk categories.

Patterns of Treatment Failure and Postrecurrence Outcomes Among Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma After Chemoradiotherapy Using Modern Radiation Techniques

Importance Even though 15% to 50% of patients with head and neck squamous cell carcinoma (HNSCC) experience recurrence, relatively little is known regarding patterns of treatment failure and postrecurrence outcomes after chemoradiotherapy using modern radiation techniques (intensity-modulated radiotherapy [IMRT]). Recurrence patterns are significantly affected by variations in the quality of radiotherapy, which may confound findings from multicenter trials. Objective To assess patterns of treatment failure and postrecurrence outcomes for patients with HNSCC treated with contemporary radiotherapy techniques. Design, Setting, and Participants This large single-institution cohort study reviewed the outcomes of 1000 consecutive patients with stage III to IVB oropharyngeal carcinoma (n = 703), laryngeal carcinoma (n = 126), or hypopharyngeal carcinoma (n = 46) treated with definitive IMRT with or without concurrent chemotherapy, as well as patients with oral cavity carcinoma (n = 125) treated with postoperative IMRT with or without concurrent systemic therapy, from December 1, 2001, to December 31, 2013, with a median follow-up of 65.1 months among surviving patients. Data analysis was performed from January 31, 2016, to February 17, 2017. Main Outcomes and Measures Patterns of treatment failure and overall survival following locoregional failure or distant metastasis. Results Among the 1000 patients (186 women and 814 men; mean [SD] age, 59.3 [10.8] years), there were no marginal or isolated out-of-radiation-field failures. Among subsites, the cumulative incidence of local failure was highest among patients with oral cavity carcinoma vs those with oropharyngeal carcinoma (hazard ratio, 5.2; 95% CI, 3.1-8.6; P < .001). Furthermore, patients with oral cavity carcinoma experienced significantly shorter survival following distant metastasis (hazard ratio, 3.66; 95% CI, 1.98-6.80; P < .001). Patients with oropharyngeal carcinoma positive for human papillomavirus or p16 lived longer after locoregional failure compared with patents with oropharyngeal carcinoma negative for human papillomavirus or p16 (median survival, 36.5 vs 13.6 months; P = .007) but not after distant metastasis. Salvage surgery was associated with improved overall survival following locoregional failure (hazard ratio, 0.51; 95% CI, 0.34-0.77; P = .001); oligometastatic disease (1 vs ≥2 lesions: hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001) was associated with improved overall survival following distant metastasis. Conclusions and Relevance Overall survival after recurrence of HNSCC is influenced by the HNSCC subsite and human papillomavirus or p16 status, as well surgical and systemic interventions. An oligometastatic phenotype characterizes patients with solitary metastasis after chemoradiotherapy. These findings have important implications for clinical trial designs for HNSCC in the recurrent and oligometastatic setting.

Clinical impact of prolonged diagnosis to treatment interval (DTI) among patients with oropharyngeal squamous cell carcinoma

PURPOSE/OBJECTIVE(S) We examined practice patterns using the National Cancer Data Base (NCDB) to determine risk factors for prolonged diagnosis to treatment interval (DTI) and survival outcomes in patients receiving chemoradiation for oropharyngeal squamous cell carcinoma (OPSCC). METHODS AND MATERIALS We identified 6606 NCDB patients with Stage III-IV OPSCC receiving chemoradiation from 2003 to 2006. We determined risk factors for prolonged DTI (>30days) using univariate and multivariable logistic regression models. We examined overall survival (OS) using Kaplan Meier and multivariable Cox proportional hazards models. RESULTS 3586 (54.3%) patients had prolonged DTI. Race, IMRT, insurance status, and high volume facilities were significant risk factors for prolonged DTI. Patients with prolonged DTI had inferior OS compared to DTI⩽30days (Hazard Ratio (HR)=1.12, 95% CI 1.04-1.20, p=0.005). For every week increase in DTI there was a 2.2% (95% CI 1.1-3.3%, p<0.001) increase in risk of death. Patients receiving IMRT, treatment at academic, or high-volume facilities were more likely to experience prolonged DTI (High vs. Low volume: 61.5% vs. 51.8%, adjusted OR 1.38, 95% CI 1.21-1.58; Academic vs. Community: 59.5% vs. 50.6%, adjusted OR 1.26, 95% CI 1.13-1.42; non-IMRT vs. IMRT: 53.4% vs. 56.5%; adjusted OR 1.17, 95% CI 1.04-1.31). CONCLUSIONS Our results suggest that prolonged DTI has a significant impact on survival outcomes. We observed disparities in DTI by socioeconomic factors. However, facility level factors such as academic affiliation, high volume, and IMRT also increased risk of DTI. These findings should be considered in developing efficient pathways to mitigate adverse effects of prolonged DTI.

Adoption of transoral robotic surgery compared with other surgical modalities for treatment of oropharyngeal squamous cell carcinoma.

Transoral robotic surgery (TORS) has increased for treatment of oropharyngeal squamous cell carcinoma (OPSCC). To define the adoption of TORS, we analyzed patterns of surgical treatment for OPSCC in the US.

Defining Value-Driven Care in Head and Neck Oncology

In the USA, increasing attention is being paid to adopting a value-based framework for measuring and ultimately improving health care delivery. Value is defined as the benefit achieved relative to costs. The numerator of the value equation includes quality of care and outcomes achieved. The denominator includes costs, both financial costs and harms of treatment. Herein, we describe these elements of value as they pertain to head and neck cancer. A particular focus is to identify areas of the value equation where physicians have some control. We examine quality in each of three dimensions: structure, process, and outcomes. We also adopt Porter’s three-tiered hierarchy of outcomes model, with specific outcomes relevant to patients with head and neck and thyroid cancer. Finally, we review issues related to costs and harms. We believe these findings can serve as a framework for further efforts to drive value-based delivery of head and neck cancer care.