Aspirin use and head and neck cancer survival and recurrence.

BACKGROUND: Head and neck cancer (HNC) has low 5-year survival, and evidence-based recommendations for tertiary prevention are lacking. Aspirin improves outcomes for cancers at other sites, but its role in HNC tertiary prevention remains understudied. METHODS: HNC patients were recruited in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003 to 2014. Aspirin data were collected through medical record review; outcomes (overall mortality, HNC-specific mortality, and recurrence) were collected through medical record review, Social Security Death Index, or LexisNexis. Cox proportional hazards models were used to evaluate the associations between aspirin use at diagnosis (yes/no) and HNC outcomes. RESULTS: We observed no statistically significant associations between aspirin and cancer outcome in our HNC patient cohort (n = 1161) (HNC-specific mortality: HR = 0.91, 95% CI = 0.68-1.21; recurrence: HR = 0.94, 95% CI = 0.73-1.19). In analyses stratified by anatomic site, HPV status, and disease stage, we observed no association in any strata examined with the possible exception of a lower risk of recurrence in oropharynx patients (HR = 0.60, 95% CI 0.35-1.04). CONCLUSIONS: Our findings do not support a protective association between aspirin use and cancer-specific death or recurrence in HNC patients, with the possible exception of a lower risk of recurrence in oropharynx patients.

TP53 mutations in head and neck cancer.

Head and neck squamous cell carcinomas (HNSCCs) arising in the mucosal linings of the upper aerodigestive tract are highly heterogeneous, aggressive, and multifactorial tumors affecting more than half a million patients worldwide each year. Classical etiological factors for HNSCC include alcohol, tobacco, and human papillomavirus (HPV) infection. Current treatment options for HNSCCs encompass surgery, radiotherapy, chemotherapy, or combinatorial remedies. Comprehensive integrative genomic analysis of HNSCC has identified mutations in TP53 gene as the most frequent of all somatic genomic alterations. TP53 mutations are associated with either loss of wild-type p53 function or gain of functions that promote invasion, metastasis, genomic instability, and cancer cell proliferation. Interestingly, disruptive TP53 mutations in tumor DNA are associated with aggressiveness and reduced survival after surgical treatment of HNSCC. This review summarizes the current evidence and impact of TP53 mutations in HNSCC.

Risk of Disease Recurrence and Mortality Varies by Type of Fat Consumed before Cancer Treatment in a Longitudinal Cohort of Head and Neck Squamous Cell Carcinoma Patients.

BACKGROUND: The associations between specific types of fat and head and neck squamous cell carcinoma (HNSCC) recurrence and mortality rates have not yet been examined. OBJECTIVES: The purpose of this study was to determine how intakes of various fat subtypes before cancer treatment are associated with recurrence and mortality in adults diagnosed with HNSCC. METHODS: This was a secondary analysis longitudinal cohort study of data collected from 476 newly diagnosed patients with HNSCC. Patients completed baseline FFQs and epidemiologic health surveys. Recurrence and mortality events were collected annually. Fat intakes examined included long-chain fatty acids (LCFAs), unsaturated fatty acids (FAs), PUFAs, ω-3 (n-3) PUFAs, ω-6 (n-6) PUFAs, MUFAs, animal fats, vegetable fats, saturated FAs, and trans fats. Associations between fat intake (categorized into tertiles) and time to event were tested using multivariable Cox proportional hazards models, adjusting for age, sex, smoking status, human papillomavirus status, tumor site, cancer stage, and total caloric intake. Intake of fats was compared with the lowest tertile. RESULTS: During the study period, there were 115 recurrent and 211 death events. High LCFA intake was associated with a reduced all-cause mortality risk (HR: 0.55; 95% CI: 0.34, 0.91; P-trend = 0.02). High unsaturated FA intake was associated with a reduced all-cause mortality risk (HR: 0.62; 95% CI: 0.40, 0.97; P-trend = 0.04) and HNSCC-specific mortality risk (HR: 0.51; 95% CI: 0.29, 0.90; P-trend = 0.02). High intakes of ω-3 PUFAs (HR: 0.56; 95% CI: 0.35, 0.91; P-trend = 0.02) and ω-6 PUFAs (HR: 0.57; 95% CI: 0.34, 0.94; P-trend = 0.02) were significantly associated with a reduced all-cause mortality risk. There were no significant associations between other fat types and recurrence or mortality risk. CONCLUSIONS: In this prospective survival cohort of 476 newly diagnosed patients with HNSCC, our data suggest that HNSCC prognosis may vary depending on the fat types consumed before cancer treatment. Clinical intervention trials should test these associations.

Statin use and head and neck squamous cell carcinoma outcomes.

Head and neck squamous cell carcinoma (HNSCC) is a morbid cancer with poor outcomes. Statins possess anticancer properties such as immunomodulatory and anti-inflammatory effects. The objective of our study is to identify the association between statin use among untreated HNSCC patients and overall death, disease-specific death and recurrence. HNSCC patients were recruited to participate in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003 to 2014. Statin use data were collected through medical record review. Participants were considered a statin user if they used a statin at or after diagnosis. Outcome data were collected through medical record review, Social Security Death Index or LexisNexis. Our analytic cohort included 1638 participants. Cox proportional hazard models were used to estimate the association between ever statin use and HNSCC outcomes. Statin use was seen in 36.0% of participants. We observed a statistically significant inverse association between ever using a statin and overall death (HR = 0.75, 95% CI = 0.63-0.88) and HNSCC-specific death (HR = 0.79, 95% CI = 0.63-0.99) and a nonstatistically significant inverse association for recurrence (HR = 0.85, 95% CI = 0.70-1.04). When investigating the association between statin use and HNSCC outcomes utilizing interaction terms between statin use and human papillomavirus (HPV), statistically significant interactions for HNSCC-specific death and recurrence were identified (HNSCC-specific death: HPV-positive HR = 0.41, 95% CI = 0.21-0.84; HPV-negative HR = 1.04, 95% CI = 0.71-1.51; p-int=0.02; recurrence: HPV-positive HR = 0.49, 95% CI = 0.29-0.84; HPV-negative HR = 1.03, 95% CI = 0.74-1.43; p=int-0.02). Statin use may be protective for adverse outcomes in HNSCC patients, particularly those with HPV-positive disease. If true, these findings could have a meaningful impact on tertiary prevention for this cancer.

Predictors of survival in patients undergoing oropharyngeal surgery for cancer recurrence after radiation therapy.

PURPOSE: The incidence of oropharyngeal squamous cell carcinoma continues to rise with the majority of patients receiving definitive or adjunctive radiation. For patients with locoregional recurrence after radiation, optimal treatment involves salvage surgery. The aim of this study is to identify factors that predict survival to ultimately improve patient selection for salvage surgery. METHODS: Retrospective cohort study at an NCI-designated cancer center. We analyzed patients with a history of head and neck radiation who presented with persistent/recurrent or second primary disease requiring salvage oropharyngeal resection from 1998-2017 (n = 120). Patients were stratified into three classes based on time to recurrence and presence of laryngopharyngeal dysfunction. Primary outcomes were 5-year overall survival (OS) and disease specific survival (DSS). RESULTS: Median OS was 27 months (median follow-up 20 months). Five-year OS was 47% for class I (recurrence > 2 years), 26% for class II (recurrence ≤ 2 years), and 0% for class III (recurrence ≤ 2 years and laryngopharyngeal dysfunction), (p < 0.0001). Five-year DSS showed significant differences between classes (p < 0.0001). On multivariate analysis, class remained predictive of OS (p = 0.04- < 0.001) and DSS (p = 0.04-0.001). Adjuvant radiation after salvage surgery with negative margins showed superior OS (71% vs. 28%, p = 0.01) and DSS (83% vs 37%, p = 0.02) compared to surgery alone and was a significant predictor of improved survival on multivariate analysis (HR 0.1, p = 0.04). CONCLUSION: This study identified a subset of patients with oropharyngeal cancer recurrence within two years of initial treatment and with laryngopharyngeal dysfunction who have poor outcomes for salvage surgery.

Speech and swallowing outcomes after laryngectomy for the dysfunctional irradiated larynx.

PURPOSE: To characterize outcomes of total laryngectomy for the dysfunctional larynx after radiation. METHODS: Retrospective case series of all subjects who underwent total laryngectomy for the irradiated dysfunctional larynx between 2000 and 2018 at an NCI-designated comprehensive cancer center at a single tertiary care academic medical center. Main outcomes included enteral tube feeding dependency, functional tracheoesophageal speech, and number and timing of postoperative pharyngeal dilations. RESULTS: Median time from radiation to laryngectomy was 2.8 years (range 0.5-27 years). Functional outcomes were analyzed for the 32 patients with 1-year follow-up. Preoperatively, 81% required at least partial enteral tube feeding, as compared to 34% 1-year postoperatively (p = 0.0003). At 1 year, 81% had achieved functional tracheoesophageal speech, which was associated with cricopharyngeal myotomy (p = 0.04, HR 0.04, 95% CI 0.002-0.949). There were 34% of subjects who required at least one pharyngeal dilation for stricture by 1 year postoperatively. Over half (60%) of the cohort were dilated over the study period. CONCLUSIONS: Laryngectomy for the dysfunctional larynx improves speech and swallowing outcomes in many patients. Cricopharyngeal myotomy is associated with improved postoperative voice. While the need for enteral feeding is decreased, persistent postoperative swallowing dysfunction is common. Careful patient selection and education regarding functional expectations are paramount.

Individualized survival prediction for patients with oropharyngeal cancer in the human papillomavirus era.

BACKGROUND: Accurate, individualized prognostication in patients with oropharyngeal squamous cell carcinoma (OPSCC) is vital for patient counseling and treatment decision making. With the emergence of human papillomavirus (HPV) as an important biomarker in OPSCC, calculators incorporating this variable have been developed. However, it is critical to characterize their accuracy prior to implementation. METHODS: Four OPSCC calculators were identified that integrate HPV into their estimation of 5-year overall survival. Treatment outcomes for 856 patients with OPSCC who were evaluated at a single institution from 2003 through 2016 were analyzed. Predicted survival probabilities were generated for each patient using each calculator. Calculator performance was assessed and compared using Kaplan-Meier plots, receiver operating characteristic curves, concordance statistics, and calibration plots. RESULTS: Correlation between pairs of calculators varied, with coefficients ranging from 0.63 to 0.90. Only 3 of 6 pairs of calculators yielded predictions within 10% of each other for at least 50% of patients. Kaplan-Meier curves of calculator-defined risk groups demonstrated reasonable stratification. Areas under the receiver operating characteristic curve ranged from 0.74 to 0.80, and concordance statistics ranged from 0.71 to 0.78. Each calculator demonstrated superior discriminatory ability compared with clinical staging according to the seventh and eighth editions of the American Joint Committee on Cancer staging manual. Among models, the Denmark calculator was found to be best calibrated to observed outcomes. CONCLUSIONS: Existing calculators exhibited reasonable estimation of survival in patients with OPSCC, but there was considerable variability in predictions for individual patients, which limits the clinical usefulness of these calculators. Given the increasing role of personalized treatment in patients with OPSCC, further work is needed to improve accuracy and precision, possibly through the identification and incorporation of additional biomarkers.

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

BACKGROUND: Recurrent 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. METHODS: Tissue 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. RESULTS: High 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. CONCLUSIONS: An 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.

Elective Paratracheal Lymph Node Dissection in Salvage Laryngectomy.

BACKGROUND: Indications for and efficacy of paratracheal nodal dissection (PTND) in patients undergoing laryngectomy (salvage) for persistent or recurrent laryngeal squamous cell carcinoma are not well-defined. METHODS: A retrospective cohort study was performed for patients undergoing salvage laryngectomy with clinically and radiographically negative neck disease between 1998 and 2015 (n = 210). Univariate and multivariate Cox regression analyses were performed. RESULTS: PTND was performed on 77/210 patients (36%). The PTND cohort had a greater proportion of advanced T classification (rT3/rT4) tumors (78%) than subjects without PTND (55%; p = 0.001). There was a 14% rate of occult nodal metastases in the paratracheal basin; of these, 55% did not have pathologic lateral neck disease. Multivariate analysis controlling for tumor site, tumor stage, and pathologic lateral neck disease demonstrated that PTND was associated with improved overall survival [OS] (p = 0.03; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.38-0.96), disease-free survival [DFS] (p = 0.03; HR 0.55, 95% CI 0.31-0.96), and distant DFS survival (p = 0.01; HR 0.29, 95% CI 0.11-0.77). The rate of hypocalcemia did not differ between subjects who underwent bilateral PTND, unilateral PTND, or no PTND (p = 0.19 at discharge, p = 0.17 at last follow-up). CONCLUSIONS: PTND at the time of salvage laryngectomy was more common in patients with rT3/rT4 tumors and was associated with improved OS and DFS, with no effect on hypocalcemia. In patients undergoing PTND, the finding of occult paratracheal metastases was often independent of lateral neck metastases.

Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.

AIM: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial. METHODS: Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months. RESULTS: LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes. CONCLUSION: This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.

Higher carbohydrate intake is associated with increased risk of all-cause and disease-specific mortality in head and neck cancer patients: results from a prospective cohort study.

No studies have evaluated associations between carbohydrate intake and head and neck squamous cell carcinoma (HNSCC) prognosis. We prospectively examined associations between pre- and post-treatment carbohydrate intake and recurrence, all-cause mortality, and HNSCC-specific mortality in a cohort of 414 newly diagnosed HNSCC patients. All participants completed pre- and post-treatment Food Frequency Questionnaires (FFQs) and epidemiologic surveys. Recurrence and mortality events were collected annually. Multivariable Cox Proportional Hazards models tested associations between carbohydrate intake (categorized into low, medium and high intake) and time to recurrence and mortality, adjusting for relevant covariates. During the study period, there were 70 deaths and 72 recurrences. In pretreatment analyses, high intakes of total carbohydrate (HR: 2.29; 95% CI: 1.23-4.25), total sugar (HR: 3.03; 95% CI: 1.12-3.68), glycemic load (HR: 2.10; 95% CI: 1.15-3.83) and simple carbohydrates (HR 2.26; 95% CI 1.19-4.32) were associated with significantly increased risk of all-cause mortality compared to low intake. High intakes of carbohydrate (HR 2.45; 95% CI: 1.23-4.25) and total sugar (HR 3.03; 95% CI 1.12-3.68) were associated with increased risk of HNSCC-specific mortality. In post-treatment analyses, medium fat intake was significantly associated with reduced risk of recurrence (HR 0.08; 95% CI 0.01-0.69) and all-cause mortality (HR 0.27; 95% CI 0.07-0.96). Stratification by tumor site and cancer stage in pretreatment analyses suggested effect modification by these factors. Our data suggest high pretreatment carbohydrate intake may be associated with adverse prognosis in HNSCC patients. Clinical intervention trials to further examine this hypothesis are warranted.

Individualized outcome prognostication for patients with laryngeal cancer.

BACKGROUND: Accurate prognostication is essential to the optimal management of laryngeal cancer. Predictive models have been developed to calculate the risk of oncologic outcomes, but extensive external validation of accuracy and reliability is necessary before implementing them into clinical practice. METHOD: Four published prognostic calculators that predict 5-year overall survival for patients with laryngeal cancer were evaluated using patient information from a prospective epidemiology study cohort (n = 246; median follow-up, 60 months) with previously untreated, stage I through IVb laryngeal squamous cell carcinoma. RESULTS: Different calculators yielded substantially different predictions for individual patients. The observed 5-year overall survival was significantly higher than the averaged predicted 5-year overall survival of the 4 calculators (71.9%; 95% confidence interval [CI], 65%-78%] vs 47.7%). Statistical analyses demonstrated the calculators' limited capacity to discriminate outcomes for risk-stratified patients. The area under the receiver operating characteristic curve ranged from 0.68 to 0.72. C-index values were similar for each of the 4 models (range, 0.66-0.68). There was a lower than expected hazard of death for patients who received induction (bioselective) chemotherapy (hazard ratio, 0.46; 95% CI, 0.24-0.88; P = .024) or primary surgical intervention (hazard ratio, 0.43; 95 % CI, 0.21-0.90; P = .024) compared with those who received concurrent chemoradiation. CONCLUSIONS: Suboptimal reliability and accuracy limit the integration of existing individualized prediction tools into routine clinical decision making. The calculators predicted significantly worse than observed survival among patients who received induction chemotherapy and primary surgery, suggesting a need for updated consideration of modern treatment modalities. Further development of individualized prognostic calculators may improve risk prediction, treatment planning, and counseling for patients with laryngeal cancer. Cancer 2018;124:706-16. © 2017 American Cancer Society.

Hypothyroidism and Wound Healing After Salvage Laryngectomy.

BACKGROUND: Patients undergoing salvage laryngectomy are predisposed to radiation-induced hypothyroidism and impaired wound healing secondary to the tissue effects of prior treatment. The impact of hypothyroidism on postoperative wound healing is not established. METHODS: A single-institution retrospective case series was performed. The inclusion criteria specified preoperatively euthyroid adults who underwent salvage laryngectomy with concurrent neck dissection between 1997 and 2015 for persistent or recurrent laryngeal squamous cell carcinoma after radiation or chemoradiation therapy (n = 182). The principal explanatory variable was postoperative hypothyroidism, defined as thyroid-stimulating hormone (TSH) higher than 5.5 mIU/L. The primary end points of the study were pharyngocutaneous fistulas and wounds requiring reoperation. Multivariate analysis was performed. RESULTS: The fistula rate was 47% among hypothyroid patients versus 23% among euthyroid patients. In the multivariate analysis, the patients who experienced hypothyroidism in the postoperative period had a 3.6-fold greater risk of fistula [95% confidence interval (CI) 1.8-7.1; p = 0.0002]. The hypothyroid patients had an 11.4-fold greater risk for a required reoperation (24.4 vs 5.4%) than the euthyroid patients (95% CI 2.6-49.9; p = 0.001). The risk for fistula (p = 0.003) and reoperation (p = 0.001) increased with increasing TSH. This corresponds to an approximate 12.5% incremental increase in the absolute risk for fistula and a 10% increase in the absolute risk for reoperation with each doubling of the TSH. CONCLUSION: Postoperative hypothyroidism independently predicts postoperative wound-healing complications. The association of hypothyroidism with fistula formation may yield opportunities to modulate wound healing with thyroid supplementation or to provide a biomarker of wound progression.

A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer.

BACKGROUND: AT-101 is a BCL-2 Homolog domain 3 mimetic previously demonstrated to have tumoricidal effects in advanced solid organ malignancies. Given the evidence of activity in xenograft models, treatment with AT-101 in combination with docetaxel is a therapeutic doublet of interest in metastatic head and neck squamous cell carcinoma. PATIENTS AND METHODS: Patients included in this trial had unresectable, recurrent, or distantly metastatic head and neck squamous cell carcinoma (R/M HNSCC) not amenable to curative radiation or surgery. This was an open label randomized, phase II trial in which patients were administered AT-101 in addition to docetaxel. The three treatment arms were docetaxel, docetaxel plus pulse dose AT-101, and docetaxel plus metronomic dose AT-101. The primary endpoint of this trial was overall response rate. RESULTS: Thirty-five patients were registered and 32 were evaluable for treatment response. Doublet therapy with AT-101 and docetaxel was well tolerated with only 2 patients discontinuing therapy due to treatment related toxicities. The overall response rate was 11 % (4 partial responses) with a clinical benefit rate of 74 %. Median progression free survival was 4.3 months (range: 0.7-13.7) and overall survival was 5.5 months (range: 0.4-24). No significant differences were noted between dosing strategies. CONCLUSION: Although met with a favorable toxicity profile, the addition of AT-101 to docetaxel in R/M HNSCC does not appear to demonstrate evidence of efficacy.

Multiple imputation of missing covariates for the Cox proportional hazards cure model.

We explore several approaches for imputing partially observed covariates when the outcome of interest is a censored event time and when there is an underlying subset of the population that will never experience the event of interest. We call these subjects 'cured', and we consider the case where the data are modeled using a Cox proportional hazards (CPH) mixture cure model. We study covariate imputation approaches using fully conditional specification. We derive the exact conditional distribution and suggest a sampling scheme for imputing partially observed covariates in the CPH cure model setting. We also propose several approximations to the exact distribution that are simpler and more convenient to use for imputation. A simulation study demonstrates that the proposed imputation approaches outperform existing imputation approaches for survival data without a cure fraction in terms of bias in estimating CPH cure model parameters. We apply our multiple imputation techniques to a study of patients with head and neck cancer. Copyright © 2016 John Wiley & Sons, Ltd.

Does Quitting Smoking Make a Difference Among Newly Diagnosed Head and Neck Cancer Patients?

INTRODUCTION: To determine if smoking after a cancer diagnosis makes a difference in mortality among newly diagnosed head and neck cancer patients. METHODS: Longitudinal data were collected from newly diagnosed head and neck cancer patients with a median follow-up time of 1627 days (N = 590). Mortality was censored at 8 years or September 1, 2011, whichever came first. Based on smoking status, all patients were categorized into four groups: continuing smokers, quitters, former smokers, or never-smokers. A broad range of covariates were included in the analyses. Kaplan-Meier curves, bivariate and multivariate Cox proportional hazards models were constructed. RESULTS: Eight-year overall mortality and cancer-specific mortality were 40.5% (239/590) and 25.4% (150/590), respectively. Smoking status after a cancer diagnosis predicted overall mortality and cancer-specific mortality. Compared to never-smokers, continuing smokers had the highest hazard ratio (HR) of dying from all causes (HR = 2.71, 95% confidence interval [CI] = 1.48-4.98). Those who smoked at diagnosis, but quit and did not relapse-quitters-had an improved hazard ratio of dying (HR = 2.38, 95% CI = 1.29-4.36) and former smokers at diagnosis with no relapse after diagnosis-former smokers-had the lowest hazard ratio of dying from all causes (HR = 1.68, 95% CI = 1.12-2.56). Similarly, quitters had a slightly higher hazard ratio of dying from cancer-specific reasons (HR = 2.38, 95% CI = 1.13-5.01) than never-smokers, which was similar to current smokers (HR = 2.07, 95% CI = 0.96-4.47), followed by former smokers (HR = 1.70, 95% CI = 1.00-2.89). CONCLUSIONS: Compared to never-smokers, continuing smokers have the highest HR of overall mortality followed by quitters and former smokers, which indicates that smoking cessation, even after a cancer diagnosis, may improve overall mortality among newly diagnosed head and neck cancer patients. Health care providers should consider incorporating smoking cessation interventions into standard cancer treatment to improve survival among this population. IMPLICATIONS: Using prospective observational longitudinal data from 590 head and neck cancer patients, this study showed that continuing smokers have the highest overall mortality relative to never-smokers, which indicates that smoking cessation, even after a cancer diagnosis, may have beneficial effects on long-term overall mortality. Health care providers should consider incorporating smoking cessation interventions into standard cancer treatment to improve survival among this population.

The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis.

The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis.

A phase II study evaluating axitinib in patients with unresectable, recurrent or metastatic head and neck cancer.

BACKGROUND: Axitinib is an oral, potent, small molecule tyrosine kinase inhibitor with selective inhibition of VEGFR 1,2, 3, as well as inhibition of potential downstream effectors of the EGFR pathway. Given the upregulation of EGFR and VEGFR in head and neck squamous cell carcinoma, treatment with axitinib holds promise as a rational targeted therapy. PATIENTS AND METHODS: Patients with unresectable, recurrent or metastatic head and neck squamous cell carcinoma were included in this open label, single arm, phase II trial. Primary endpoint was 6 month progression free survival. All patients received single agent axitinib with planned dose escalation based on tolerability. A planned interim efficacy analysis was performed after enrollment of 30 patients. RESULTS: Forty-two patients were registered, 30 were evaluable. While treatment was well-tolerated with no severe bleeding events, only 19 patients were able to achieve full planned dose. The best overall response rate was 6.7% (two partial responses) with a disease control rate of 76.7%. Median progression free survival was 3.7 months (95% Confidence Interval (CI): 3.5-5.7) and overall survival was 10.9 months (95% CI: 6.4-17.8). Exploratory analysis demonstrated that patients with a smaller sum of diameter of target lesions experienced improved response rates, and better progression-free and overall survival. CONCLUSION: Treatment with single agent axitinib should be considered due to acceptable toxicity profile and favorable median overall survival compared to standard therapies.

Head and Neck Cancers, Version 1.2015.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

Diet and proinflammatory cytokine levels in head and neck squamous cell carcinoma.

BACKGROUND: Proinflammatory cytokine levels may be associated with cancer stage, recurrence, and survival. The objective of this study was to determine whether cytokine levels were associated with dietary patterns and fat-soluble micronutrients in patients with previously untreated head and neck squamous cell carcinoma (HNSCC). METHODS: This was a cross-sectional study of 160 patients with newly diagnosed HNSCC who completed pretreatment food frequency questionnaires (FFQs) and health surveys. Dietary patterns were derived from FFQs using principal component analysis. Pretreatment serum levels of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) were measured using an enzyme-linked immunosorbent assay, and serum carotenoid and tocopherol levels were measured by high-performance liquid chromatography. Multivariable ordinal logistic regression models examined associations between cytokines and quartiles of reported and serum dietary variables. RESULTS: Three dietary patterns emerged: whole foods, Western, and convenience foods. In multivariable analyses, higher whole foods pattern scores were significantly associated with lower levels of IL-6, TNF-α, and IFN-γ (P ≤ .001, P = .008, and P = .03, respectively). Significant inverse associations were reported between IL-6, TNF-α, and IFN-γ levels and quartiles of total reported carotenoid intake (P = .006, P = .04, and P = .04, respectively). There was an inverse association between IFN-γ levels and serum α-tocopherol levels (P = .03). CONCLUSIONS: Consuming a pretreatment diet rich in vegetables, fruit, fish, poultry, and whole grains may be associated with lower proinflammatory cytokine levels in patients with HNSCC.