Phase 2 trial of neoadjuvant chemotherapy and transoral endoscopic surgery with risk-adapted adjuvant therapy for squamous cell carcinoma of the head and neck.

BACKGROUND: The objective of this study was to demonstrate the feasibility and efficacy of induction chemotherapy, surgery, and pathology-guided adjuvant therapy to treat transorally resectable squamous head and neck cancer. METHODS: Patients had squamous head and neck cancer that was resectable by the transoral route and advanced-stage disease (American Joint Committee on Cancer stage III-IV, T3-T4 tumors, and/or positive lymph nodes). They received treatment with weekly carboplatin at an area under the curve of 2, plus paclitaxel 135 mg/m2 , and daily lapatinib 1000mg for 6 weeks followed by surgical resection. Pathology that revealed margins <5 mm, extracapsular extension, N2a of N2b lymph node status, perineural invasion, or lymphovascular space invasion resulted in adjuvant radiotherapy concurrent with weekly cisplatin. Pathology with N2c/N3 lymph node status or positive margins resulted in radiation with bolus cisplatin. The primary endpoint was the clinical response rate to induction chemotherapy, and a key secondary endpoint was feasibility. RESULTS: Toxicity was modest, and 37 of 40 patients completed study procedures as planned. The clinical response rate was 93%, the pathologic complete response rate was 36%, and the clinical response did not predict for a pathologic complete response. No patient on study follow-up has recurred or died. Twenty-nine of 39 patients who underwent surgery avoided radiation. Speech and swallowing function were well preserved. CONCLUSIONS: The study met both its primary efficacy endpoint and the secondary feasibility endpoint. Neoadjuvant, systemic therapy and surgical resection followed by risk-adapted adjuvant therapy resulted in high response rates and excellent long-term outcomes and should be further studied. Cancer 2018;124:2986-92. © 2018 American Cancer Society.

Elderly patients with squamous cell carcinoma of the head and neck and the benefit of multimodality therapy.

BACKGROUND: Limited data are available regarding outcomes in elderly head and neck cancer patients. This retrospective study was designed to characterize head and neck cancer in geriatric patients. PATIENTS AND METHODS: This study included all patients in a large university-based tumor registry who were diagnosed with head and neck cancer from January 1, 1990, to December 31, 2005. Patients aged ≥70 years at the time of diagnosis were defined as older. Overall survival and progression-free survival were censored at 60 months. Survival differences were compared using the log-rank test. Hazard ratios were estimated using a Cox proportional hazards model, adjusting for potential confounders. RESULTS: Of 1,598 patients identified, 1,166 patients were aged <70 years (i.e., younger) and 281 patients were aged ≥70 years (older). When controlling for possible confounders, older patients were nearly twice as likely to die within 5 years as their younger counterparts (hazard ratio: 1.92). The median life expectancy for older patients was nearly 5 years for stage I-II disease and <2 years for stage III-IV disease. Older patients with stage III-IV disease who received multimodality therapy had 5-year survival similar to that younger patients with stage III-IV disease who were treated similarly (33.2% vs. 44.0%). Older patients with stage III-IV disease who received single-modality therapy had extremely poor survival compared with all other patients (hazard ratio for progression-free survival: 1.5). CONCLUSION: This study highlights the need for better understanding of the factors affecting head and neck cancer outcomes in elderly patients. Information about life expectancy in elderly head and neck cancer patients may help guide treatment decisions.

The addition of chemotherapy to adjuvant radiation is associated with inferior survival outcomes in intermediate-risk HPV-negative HNSCC.

BACKGROUND: Only high-risk tumors with extranodal extension (ENE) and/or positive surgical margins (PSM) benefit from adjuvant therapy (AT) with concurrent chemoradiation (CRT) compared to radiation therapy (RT) in locally advanced head and neck squamous cell carcinoma (HNSCC). Optimal treatment for intermediate-risk tumors remains controversial. We categorized patients based on their surgical pathologic risk factors and described AT treatment patterns and associated survival outcomes. METHODS: Patients were identified from CHANCE, a population-based study, and risk was classified based on surgical pathology review. High-risk patients (n = 204) required ENE and/or PSM. Intermediate-risk (n = 186) patients had pathological T3/T4 disease, perineural invasion (PNI), lymphovascular invasion (LVI), or positive lymph nodes without ENE. Low-risk patients (n = 226) had none of these features. RESULTS: We identified 616 HPV-negative HNSCC patients who received primary surgical resection with neck dissection. High-risk patients receiving AT had favorable OS (HR 0.50, p = 0.013) which was significantly improved with the addition of chemotherapy compared to RT alone (HR 0.47, p = 0.021). When stratified by node status, the survival benefit of AT in high-risk patients persisted only among those who were node-positive (HR: 0.17, p < 0.0005). On the contrary, intermediate-risk patients did not benefit from AT (HR: 1.26, p = 0.380) and the addition of chemotherapy was associated with significantly worse OS compared to RT (HR: 1.76, p = 0.046). CONCLUSION: In high-risk patients, adjuvant chemoradiotherapy improved OS compared to RT alone. The greatest benefit was in node-positive cases. In intermediate-risk patients, the addition of chemotherapy to RT increased mortality risk and therefore should only be used cautiously in these patients.

CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition.

Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by a transcriptional coactivator fusion composed of cyclic AMP-regulated transcriptional coactivator 1 (CRTC1) and mastermind-like 2 (MAML2). The mechanisms by which the chimeric CRTC1/MAML2 (C1/M2) oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that C1/M2 induces transcriptional activation of the non-canonical peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant PGC-1α4, which regulates peroxisome proliferator-activated receptor gamma (PPARγ)-mediated insulin-like growth factor 1 (IGF-1) expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. C1/M2-positive tumors exhibit IGF-1 pathway activation, and small-molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1 receptor (IGF-1R) inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγ inhibition with inverse agonists. These results yield insights into the aberrant coregulatory functions of C1/M2 and identify a specific vulnerability that can be exploited for precision therapy.

Long-term Survival in Head and Neck Cancer: Impact of Site, Stage, Smoking, and Human Papillomavirus Status.

OBJECTIVES/HYPOTHESIS: Literature examining long-term survival in head and neck squamous cell carcinoma (HNSCC) with human papillomavirus (HPV) status is lacking. We compare 10-year overall survival (OS) rates for cases to population-based controls. STUDY DESIGN: Prospective cohort study. METHODS: Cases surviving 5 years postdiagnosis were identified from the Carolina Head and Neck Cancer Study. We examined 10-year survival by site, stage, p16, and treatment using Kaplan-Meier and Cox proportional hazard models. Cases were compared to age-matched, noncancer controls with stratification by p16 and smoking status. RESULTS: Ten-year OS for HNSCC is less than controls. In 581 cases, OS differed between sites with p16+ oropharynx having the most favorable prognosis (87%), followed by oral cavity (69%), larynx (67%), p16- oropharynx (56%), and hypopharynx (51%). Initial stage, but not treatment, also impacted OS. When compared to controls matched on smoking status, the hazard ratio (HR) for death in p16+ oropharynx cases was 1.5 (95% confidence interval [CI]: 0.7-3.1) for smokers and 2.4 (95% CI: 0.7-8.8) for nonsmokers. Similarly, HR for death in non-HPV-associated HNSCC was 2.2 (95% CI: 1.7-3.0) for smokers and 2.4 (95% CI: 1.4-4.9) for nonsmokers. CONCLUSIONS: OS for HNSCC cases continues to decrease 5 years posttreatment, even after stratification by p16 and smoking status. Site, stage, smoking, and p16 status are significant factors. These data provide important prognostic information for HNSCC. LEVEL OF EVIDENCE: 2 Laryngoscope, 129:2506-2513, 2019.

An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma.

The incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing and implicated in more than 60% of all oropharyngeal carcinomas (OPSCCs). Although whole-genome, transcriptome, and proteome analyses have identified altered signaling pathways in HPV-induced HNSCCs, additional tools are needed to investigate the unique pathobiology of OPSCC. Herein, bioinformatics analyses of human HPV(+) HNSCCs revealed that all tumors express full-length E6 and identified molecular subtypes based on relative E6 and E7 expression levels. To recapitulate the levels, stoichiometric ratios, and anatomic location of E6/E7 expression, we generated a genetically engineered mouse model whereby balanced expression of E6/E7 is directed to the oropharyngeal epithelium. The addition of a mutant PIK3CAE545K allele leads to the rapid development of pre-malignant lesions marked by immune cell accumulation, and a subset of these lesions progress to OPSCC. This mouse provides a faithful immunocompetent model for testing treatments and investigating mechanisms of immunosuppression.

Genomic representations using concatenates of Type IIB restriction endonuclease digestion fragments.

We have developed a method for genomic representation using Type IIB restriction endonucleases. Representation by concatenation of restriction digests, or RECORD, is an approach to sample the fragments generated by cleavage with these enzymes. Here, we show that the RECORD libraries may be used for digital karyotyping and for pathogen identification by computational subtraction.

Comparison of Patient- and Practitioner-Reported Toxic Effects Associated With Chemoradiotherapy for Head and Neck Cancer.

IMPORTANCE: Agreement between patient- and practitioner-reported toxic effects during chemoradiotherapy for head and neck cancer is unknown. OBJECTIVE: To compare patient-reported symptom severity and practitioner-reported toxic effects among patients receiving chemoradiotherapy for head and neck cancer. DESIGN, SETTING, AND PARTICIPANTS: Forty-four patients participating in a phase 2 trial of deintensified chemoradiotherapy for oropharyngeal carcinoma were included in the present study (conducted from February 8, 2012, to March 2, 2015). Most treatment (radiotherapy, 60 Gy, with concurrent weekly administration of cisplatin, 30 mg/m2) was administered at academic medical centers. Included patients had no prior head and neck cancers, were 18 years or older, and had a smoking history of 10 pack-years or less or more than 10 pack-years but 30 pack-years or less and abstinent for the past 5 years. Cancer status was untreated human papillomavirus or p16-positive squamous cell carcinoma of the oropharynx or unknown head and neck primary site; and cancer staging was category T0 to T3, category N0 to N2c, M0, and Eastern Cooperative Oncology Group performance status 0 to 1. Baseline, weekly, and posttreatment toxic effects were assessed by physicians or nurse practitioners using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Patient-reported symptom severity was measured using the Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE). Descriptive statistics were used to characterize raw agreement between CTCAE grades and PRO-CTCAE severity ratings. INTERVENTIONS: Baseline, weekly, and posttreatment toxic effects assessed using CTCAE, version 4.0, and PRO-CTCAE. MAIN OUTCOMES AND MEASURES: Raw agreement indices between patient-reported toxic effects, including symptom frequency, severity, and interference with daily activities (score range, 0 [none] to 4 [very severe]), and practitioner-measured toxic effects, including swallowing, oral pain, and hoarseness (score range, 1 [mild] to 5 [death]). RESULTS: Of the 44 patients included in the analysis (39 men, 5 women; mean [SD] age, 61 [8.4] years), there were 327 analyzable pairs of CTCAE and PRO-CTCAE symptom surveys and no treatment delays due to toxic effects. Patient-reported and practitioner-reported symptom severity agreement was high at baseline when most symptoms were absent but declined throughout treatment as toxic effects increased. Most disagreement was due to lower severity of toxic effects reported by practitioners (eg, from 45% agreement at baseline to 27% at the final week of treatment for pain). This was particularly noted for domains that are not easily evaluated by physical examination, such as anxiety and fatigue (eg, severity of fatigue decreased from 43% at baseline to 12% in the final week of treatment). CONCLUSIONS AND RELEVANCE: Practitioner-reported toxic effects are lower than patient self-reports during head and neck chemoradiotherapy. The inclusion of patient-reported symptomatic toxic effects provides information that can potentially enhance clinical management and improve data quality in clinical trials.

Use of mobile device technology to continuously collect patient-reported symptoms during radiation therapy for head and neck cancer: A prospective feasibility study.

PURPOSE: Accurate assessment of toxicity allows for timely delivery of supportive measures during radiation therapy for head and neck cancer. The current paradigm requires weekly evaluation of patients by a provider. The purpose of this study is to evaluate the feasibility of monitoring patient reported symptoms via mobile devices. METHODS AND MATERIALS: We developed a mobile application for patients to report symptoms in 5 domains using validated questions. Patients were asked to report symptoms using a mobile device once daily during treatment or more often as needed. Clinicians reviewed patient-reported symptoms during weekly symptom management visits and patients completed surveys regarding perceptions of the utility of the mobile application. The primary outcome measure was patient compliance with mobile device reporting. Compliance is defined as number of days with a symptom report divided by number of days on study. RESULTS: There were 921 symptom reports collected from 22 patients during treatment. Median reporting compliance was 71% (interquartile range, 45%-80%). Median number of reports submitted per patient was 34 (interquartile range, 21-53). Median number of reports submitted by patients per week was similar throughout radiation therapy and there was significant reporting during nonclinic hours. Patients reported high satisfaction with the use of mobile devices to report symptoms. CONCLUSIONS: A substantial percentage of patients used mobile devices to continuously report symptoms throughout a course of radiation therapy for head and neck cancer. Future studies should evaluate the impact of mobile device symptom reporting on improving patient outcomes.

Effectiveness of chemoradiation for head and neck cancer in an older patient population.

PURPOSE: The purpose of this study was to compare chemoradiation therapy (CRT) with radiation therapy (RT) only in an older patient population with head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (1992-2007), we identified a retrospective cohort of nonmetastatic HNSCC patients and divided them into treatment groups. Comparisons were made between CRT and RT cohorts. Propensity scores for CRT were estimated from covariates associated with receipt of treatment using multivariable logistic regression. Standardized mortality ratio weights (SMRW) were created from the propensity scores and used to balance groups on measured confounders. Multivariable and SMR-weighted Cox proportional hazard models were used to estimate the hazard ratio (HR) of death for receipt of CRT versus RT among the whole group and for separate patient and tumor categories. RESULTS: The final cohort of 10,599 patients was 68% male and 89% white. Median age was 74 years. Seventy-four percent were treated with RT, 26% were treated with CRT. Median follow-up points for CRT and RT survivors were 4.6 and 6.3 years, respectively. On multivariable analysis, HR for death with CRT was 1.13 (95% confidence interval [CI]: 1.07-1.20; P<.01). Using the SMRW model, the HR for death with CRT was 1.08 (95% CI: 1.02-1.15; P=.01). CONCLUSIONS: Although the addition of chemotherapy to radiation has proven efficacious in many randomized controlled trials, it may be less effective in an older patient population treated outside of a controlled trial setting.

Patterns of care in older patients with squamous cell carcinoma of the head and neck: a surveillance, epidemiology, and end results-medicare analysis.

BACKGROUND: There is growing evidence in the literature that older patients may not benefit from more intensive therapy for head and neck squamous cell carcinoma (HNSCC). A growing number of patients with HNSCC are age 65 years or older; however, much of the evidence base informing treatment decisions is based on substantially younger and healthier clinical trial populations. The purpose of this study was to assess the patterns of care of older HNSCC patients to better understand how age is associated with treatment decisions. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (1992­2007), we identified patients with non-metastatic HNSCC (n = 10,867) and categorized them by treatment: surgery vs. non-surgery and chemoradiotherapy (CRT) vs. radiotherapy (RT). Multivariate logistic regression models were used to identify variables associated with the receipt of surgery and CRT. RESULTS: Increasing age was associated with decreased odds of receiving CRT (OR = 0.94; 95% CI 0.93­0.94) but not surgery (OR 1.00; 95% CI 0.99­1.00). Co-morbidity and race were not associated with receipt of either surgery or CRT. Utilization of CRT increased while surgery decreased between 1992 and 2007. CONCLUSION: Age may influence the receipt of CRT for older HNSCC patients. There has been an increasing trend in the receipt of CRT and a decrease in primary surgery.