The Impact of Second Primary Malignancies on Head and Neck Cancer Survivors: A Nationwide Cohort Study

Background

Head and neck cancer (HNC) is associated with a high rate of developing second primary malignancies(SPMs). But the impact on survival remains poorly understood before. Therefore, we want to estimate the impact of SPMs on HNC survivors.

Methods and Findings

Between 1986 and 2008, a total of 9,996 SPMs were recorded for 93,891 patients with an initial diagnosis of HNC by the Taiwan Cancer Registry. Patients were followed with national death registry database to 2011.Using the Kaplan–Meier method, a time-dependent covariate was employed to compare the survival rates between patients with and without SPMs. A Cox proportional hazards model that treated age and sex as confounders was used to examine the hazard ratios of SPMs. The relative survival rates were calculated using age- and sex-specific life tables for the population. Parametric mixture cure fraction models were then employed to estimate the percentage of cancer survivors who would be cured. Use of the Kaplan–Meier method showed that the crude survival rates differed significantly for patients with and patients without SPMs (log-rank test <0.01). For the results of Cox proportional hazards regression analysis, SPMs had a significant influence on survival rates with univariate (HR 2.59,95% CI 2.53to 2.65) and multivariate analysis (HR 2.34, 2.28 to 2.40). Patients with SPMs of nasopharyngeal carcinoma (NPC) had the highest cure rate at 39%, where as esophageal and lung cancer had the worst prognosis, with a cure rate of 11%.

Conclusions

A worse prognosis was found for second primary cancer such as esophageal or lung cancer. Patients and healthcare providers must strongly consider and have a high clinical suspicion of these SPMs.     

Tea Consumption and Risk of Head and Neck Cancer

Background

The current study evaluated the association between tea consumption and head and neck cancer (HNC) in Taiwan, where tea is a major agricultural product and a popular beverage.

Methods

Interviews regarding tea consumption (frequency, duration, and types) were conducted with 396 HNC cases and 413 controls. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with tea drinking, adjusted for sex, age, education, cigarette smoking, betel quid chewing, and alcohol drinking.

Results

A reduced HNC risk associated with tea drinking (OR for every cup per day = 0.96, 95% CI: 0.93–0.99; OR for ≧5 cups per day = 0.60, 95% CI: 0.39–0.94) was observed. The association was especially significant for pharyngeal cancer (OR for every cup per day = 0.93, 95% CI: 0.88–0.98; OR for ≧5 cups per day = 0.32, 95% CI: 0.16–0.66). A significant inverse association between HNC and tea consumption was observed particularly for green tea.

Conclusions

This study suggests that tea drinking may reduce the risk of HNC. The anticancer property of tea, if proven, may offer a natural chemopreventive measure to reduce the occurrence of HNC.     

Brain-Sparing Methods for IMRT of Head and Neck Cancer

Purpose

Radical radiotherapy for head and neck cancer (HNC) may deliver significant doses to brain structures. There is evidence that this may cause a decline in neurocognitive function (NCF). Radiation dose to the medial temporal lobes, and particularly to the hippocampi, seems to be critical in determining NCF outcomes. We evaluated the feasibility of two alternative intensity-modulated radiotherapy (IMRT) techniques to generate hippocampus- and brain-sparing HNC treatment plans to preserve NCF.

Methods and Materials

A planning study was undertaken for ten patients with HNC whose planning target volume (PTV) included the nasopharynx. Patients had been previously treated using standard (chemo)-IMRT techniques. Bilateral hippocampi were delineated according to the RTOG atlas, on T1w MRI co-registered to the RT planning CT. Hippocampus-sparing plans (HSRT), and whole-brain/hippocampus-sparing fixed-field non-coplanar IMRT (BSRT) plans, were generated. DVHs and dose difference maps were used to compare plans. NTCP calculations for NCF impairment, based on hippocampal dosimetry, were performed for all plans.

Results

Significant reductions in hippocampal doses relative to standard plans were achieved in eight of ten cases for both HSRT and BSRT. EQD2 D40% to bilateral hippocampi was significantly reduced from a mean of 23.5 Gy (range 14.5–35.0) in the standard plans to a mean of 8.6 Gy (4.2–24.7) for HSRT (p = 0.001) and a mean of 9.0 Gy (4.3–17.3) for BSRT (p < 0.001). Both HSRT and BSRT resulted in a significant reduction in doses to the whole brain, brain stem, and cerebellum.

Conclusion

We demonstrate that IMRT plans for HNC involving the nasopharynx can be successfully optimised to significantly reduce dose to the bilateral hippocampi and whole brain. The magnitude of the achievable dose reductions results in significant reductions in the probability of radiation-induced NCF decline. These results could readily be translated into a future clinical trial.     

Different Levels in Alcohol and Tobacco Consumption in Head and Neck Cancer Patients from 1957 to 2013

Objective

To provide a precise quantification of the association between alcohol and tobacco consumption trends in head and neck cancer patients over the past 45 years.

Methods

We combined findings from all studies published until March 2014 and evaluated the association between different levels in alcohol and tobacco consumption and head and neck cancers through a meta-analytic approach.

Results

We included 28 studies involving 13830 patients with head and neck cancer. In patients with alcohol consumption, the pooled odds ratio (OR) and 95% confidence interval (CI) were 1.29(1.06-1.57), 2.67(2.05-3.48) and 6.63(5.02-8.74) for light drinkers, moderate drinkers and heavy drinkers, respectively. In patients with tobacco consumption, the pooled OR and 95% CI were 2.33(1.84-2.95), 4.97(3.67-6.71) and 6.77(4.81-9.53) for light smokers, moderate smokers and heavy smokers, respectively.

Conclusion

The increased alcohol and tobacco consumption trends increased the risk of head and neck cancer over the past 45 years. Tobacco consumption was found to be a stronger risk factor for head and neck cancer than alcohol consumption. Thus, the control should be considered to limit the intake of alcohol and tobacco.     

Exosomes Derived from Squamous Head and Neck Cancer Promote Cell Survival after Ionizing Radiation

Exosomes are nanometer-sized extracellular vesicles that are believed to function as intercellular communicators. Here, we report that exosomes are able to modify the radiation response of the head and neck cancer cell lines BHY and FaDu. Exosomes were isolated from the conditioned medium of irradiated as well as non-irradiated head and neck cancer cells by serial centrifugation. Quantification using NanoSight technology indicated an increased exosome release from irradiated compared to non-irradiated cells 24 hours after treatment. To test whether the released exosomes influence the radiation response of other cells the exosomes were transferred to non-irradiated and irradiated recipient cells. We found an enhanced uptake of exosomes isolated from both irradiated and non-irradiated cells by irradiated recipient cells compared to non-irradiated recipient cells. Functional analyses by exosome transfer indicated that all exosomes (from non-irradiated and irradiated donor cells) increase the proliferation of non-irradiated recipient cells and the survival of irradiated recipient cells. The survival-promoting effects are more pronounced when exosomes isolated from irradiated compared to non-irradiated donor cells are transferred. A possible mechanism for the increased survival after irradiation could be the increase in DNA double-strand break repair monitored at 6, 8 and 10 h after the transfer of exosomes isolated from irradiated cells. This is abrogated by the destabilization of the exosomes. Our results demonstrate that radiation influences both the abundance and action of exosomes on recipient cells. Exosomes transmit prosurvival effects by promoting the proliferation and radioresistance of head and neck cancer cells. Taken together, this study indicates a functional role of exosomes in the response of tumor cells to radiation exposure within a therapeutic dose range and encourages that exosomes are useful objects of study for a better understanding of tumor radiation response.     

Significance of Lymph Node Metastasis in Cancer Dissemination of Head and Neck Cancer

Lymph node metastasis (LNM) in many solid cancers is a well-known prognostic factor; however, it has been debated whether regional LNM simply reflects tumor aggressiveness or is a source for further tumor dissemination. Similarly, the metastatic process in head and neck cancer (HNC) has not been fully evaluated. Thus, we aimed to investigate the relative significance of LNM in metastatic cascade of HNC using functional imaging of HNC patients and molecular imaging in in vivo models. First, we analyzed ¹⁸Fluorodeoxyglucose positron emission tomography (PET) parameters of 117 patients with oral cancer. The primary tumor and nodal PET parameters were measured separately, and survival analyses were conducted on the basis of clinical and PET variables to identify significant prognostic factors. In multivariate analyses, we found that only the metastatic node PET values were significant. Next, we compared the relative frequency of lung metastasis in primary ear tumors versus lymph node (LN) tumors, and we tested the rate of lung metastasis in another animal model, in which each animal had both primary and LN tumors that were expressing different colors. As a result, LN tumors showed higher frequencies of lung metastasis compared to orthotopic primary tumors. In color-matched comparisons, the relative contribution to lung metastasis was higher in LN tumors than in primary tumors, although both primary and LN tumors caused lung metastases. In summary, tumors growing in the LN microenvironment spread to systemic sites more commonly than primary tumors in HNC, suggesting that the adequate management of LNM can reduce further systemic metastasis.     

Dental Management of the Geriatric Head and Neck Cancer Patient1

The geriatric patient presenting with cancer of the head and neck region constitutes slightly less than half of all oral cancers diagnosed. Cancers of this region are generally treated with surgery, radiation, chemotherapy or combinations of these three. These patients not only present with special problems due to their age but also with challenging ones resulting from treatment of their disease. The dentist plays an important role in evaluating the patient's oral health and providing necessary services prior to any curative treatment. The dental diagnosis and treatment protocol practiced at Memorial Hospital are discussed for each therapeutic modality along with the measures taken for follow up care.     

Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas

Background

Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality.

Methods and Findings

Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity’s associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed.

Conclusions

To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.     

Tooth Loss and Risk of Head and Neck Cancer: A Meta-Analysis

Background

Observational studies suggest an association between tooth loss and risk of head and neck cancer. However, whether tooth loss is an independent risk factor for head and neck cancer still remains controversial. The aim of this study is to assess the association between tooth loss and head and neck cancer risk.

Methods

Eligible studies were searched in PubMed and Embase databases from their inception to March 2013. A random-effects model or fixed-effects model was used to calculate the overall combined risk estimates.

Results

Eight case-control studies and one cross-sectional study involving 5,204 patients and 5,518 controls were included in the meta-analysis. The overall combined odds ratio for tooth loss and head and neck cancer was 2.00 (95% confidence interval, 1.28–3.14). Similar results yielded both in the moderate and severe tooth loss group. Sensitivity analysis based on various exclusion criteria maintained this significance with respect to head and neck cancer individually. Little evidence of publication bias was observed.

Conclusion

This meta-analysis suggests that tooth loss is associated with increased risk of head and neck cancer. This increase is probably independent of conventional head and neck cancer risk factors.     

非可控性炎症与头颈恶性肿瘤的关系

"癌症源于慢性炎症"之说越来越被人们关注与认可,已成为近年肿瘤领域研究的热点。与肿瘤密切相关的炎症实质为非可控性炎症,触发并参与肿瘤的发生、发展、浸润转移等各个病理过程;而在肿瘤发生发展过程中,肿瘤细胞同样可通过自分泌或其他方式调控非可控性炎症反应,以利于自身生长。非可控性炎症在头颈恶性肿瘤发生、进展过程中均扮演着十分重要的角色,在此过程中涉及众多分子和信号通路的参与。本文就非可控性炎症与头颈恶性肿瘤(鼻咽癌、喉癌、口腔癌、甲状腺肿瘤及皮肤肿瘤)的相互关系进行简要综述。     

SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients

SPARC up-regulation is a poor prognostic factor in head and neck cancer. It was hypothesized that because of a SPARC-albumin interaction, tumoral SPARC facilitates the accumulation of albumin in the tumor and increases the effectiveness of albumin-bound paclitaxel (nab-paclitaxel). This hypothesis was tested by correlating the response to nab-paclitaxel and SPARC tumor expression in a retrospective analysis of a 60-patient clinical study of nab-paclitaxel as monotherapy against head and neck cancer. Sixteen tumor specimens were available for analysis. There were 11 responders (CR/PR) and 5 nonresponders (SD/PD) among the 16 nab-paclitaxel-treated patients (12/16 SPARC-positive, 75%). Response to nab-paclitaxel was higher for SPARC-positive patients (10/12, 83%) than SPARC-negative patients (1/4, 25%). The SPARC-negative patients exhibited significantly lower response than the overall response rate among all 60 patients (1/4, 25% vs 45/60, 75%). Although preliminary, data are supportive of the hypothesis that SPARC overexpression may correlate with response to nab-paclitaxel. If confirmed in larger studies, treatment with nab-paclitaxel may convert a poor prognosis SPARC-positive patient population into a group with better clinical outcomes.     

Susceptibility of Human Head and Neck Cancer Cells to Combined Inhibition of Glutathione and Thioredoxin Metabolism

Increased glutathione (GSH) and thioredoxin (Trx) metabolism are mechanisms that are widely implicated in resistance of cancer cells to chemotherapy. The current study determined if simultaneous inhibition of GSH and Trx metabolism enhanced cell killing of human head and neck squamous cell carcinoma (HNSCC) cells by a mechanism involving oxidative stress. Inhibition of GSH and Trx metabolism with buthionine sulfoximine (BSO) and auranofin (AUR), respectively, induced significant decreases in clonogenic survival compared to either drug alone in FaDu, Cal-27 and SCC-25 HNSCC cells in vitro and in vivo in Cal-27 xenografts. BSO+AUR significantly increased glutathione and thioredoxin oxidation and suppressed peroxiredoxin activity in vitro. Pre-treatment with N-acetylcysteine completely reversed BSO+AUR-induced cell killing in FaDu and Cal-27 cells, while catalase and selenium supplementation only inhibited BSO+AUR-induced cell killing in FaDu cells. BSO+AUR decreased caspase 3/7 activity in HNSCC cells and significantly reduced the viability of both Bax/Bak double knockout (DKO) and DKO-Bax reconstituted hematopoietic cells suggesting that necrosis was involved. BSO+AUR also significantly sensitized FaDu, Cal-27, SCC-25 and SQ20B cells to cell killing induced by the EGFR inhibitor Erlotinib in vitro. These results support the conclusion that simultaneous inhibition of GSH and Trx metabolism pathways induces oxidative stress and clonogenic killing in HNSCCs and this strategy may be useful in sensitizing HNSCCs to EGFR inhibitors.     

Tumor-suppressor Gene Promoter Hypermethylation in Saliva of Head and Neck Cancer Patients

Head and neck squamous cell carcinoma (HNSCC) accounts for a bulk of the oral and laryngeal cancers, the majority (70%) of which are associated with smoking and excessive drinking, major known risk factors for the development of HNSCC. In contrast to reports that suggest an inverse relationship between smoking and global DNA CpG methylation, hypermethylation of promoters of a number of genes was detected in saliva collected from patients with HNSCC. Using a sensitive methylation-specific polymerase chain reaction (MSP) assay to determine specific methylation events in the promoters of RASSF1A, DAPK1, and p16 genes, we demonstrate that we can detect tumor presence with an overall accuracy of 81% in the DNA isolated from saliva of patients with HNSCC (n = 143) when compared with the DNA isolated from the saliva of healthy nonsmoker controls (n = 31). The specificity for this MSP panel was 87% and the sensitivity was 80% (with a Fisher exact test P < .0001). In addition, the test panel performed extremely well in the detection of the early stages of HNSCCs, with a sensitivity of 94% and a specificity of 87%, and a high κ concordance value of 0.8, indicating an excellent overall agreement between the presence of HNSCC and a positive MSP panel result. In conclusion, we demonstrate that the promoter methylation of RASSF1A, DAPK1, and p16 MSP panel is useful in detecting hypermethylation events in a noninvasive manner in patients with HNSCC.     

Tooth Loss and Head and Neck Cancer: A Meta-Analysis of Observational Studies

Backgroud

Epidemiological studies have shown that tooth loss is associated with risk of head and neck cancer (HNC); however, the results were inconsistent. Therefore, we conducted a meta-analysis to ascertain the relationship between tooth loss and HNC.

Methods

We searched for relevant observational studies that tested the association between tooth loss and risk of HNC from PubMed and were conducted up to January 30, 2013. Data from the eligible studies were independently extracted by two authors. The meta-analysis was performed using the Comprehensive Meta-Analysis 2.2 software. Sensitivity and subgroup analyses were conducted to evaluate the influence of various inclusions. Publication bias was also detected.

Results

Ten articles involving one cohort and ten case-control studies were yielded. Based on random-effects meta-analysis, an association between tooth loss and HNC risk was identified [increased risk of 29% for 1 to 6 teeth loss (OR = 1.29, 95% CI = 0.52–3.20, p = 0.59), 58% for 6 to 15 teeth loss (OR = 1.58, 95% CI = 1.08–2.32, p = 0.02), 63% for 11+ teeth loss (OR = 1.63, 95% CI = 1.23–2.14, p<0.001), 72% for 15+ teeth loss (OR = 1.72, 95% CI = 1.26–2.36, p<0.001), and 89% for 20+ teeth loss (OR = 1.89, 95% CI = 1.27–2.80, p<0.001)]. The sensitivity analysis shows that the result was robust, and publication bias was not detected.

Conclusions

Based on the current evidence, tooth loss is probably a significant and dependent risk factor of HNC, which may have a dose-response effect. People who lost six or more teeth should pay attention to symptoms of HNC, and losing 11 teeth or 15 teeth may be the threshold.     

Socioeconomic and Other Demographic Disparities Predicting Survival among Head and Neck Cancer Patients

Background

The Institute of Medicine (IOM) report, “Unequal Treatment,” which defines disparities as racially based, indicates that disparities in cancer diagnosis and treatment are less clear. While a number of studies have acknowledged cancer disparities, they have limitations of retrospective nature, small sample sizes, inability to control for covariates, and measurement errors.

Objective

The purpose of this study was to examine disparities as predictors of survival among newly diagnosed head and neck cancer patients recruited from 3 hospitals in Michigan, USA, while controlling for a number of covariates (health behaviors, medical comorbidities, and treatment modality).

Methods

Longitudinal data were collected from newly diagnosed head and neck cancer patients (N = 634). The independent variables were median household income, education, race, age, sex, and marital status. The outcome variables were overall, cancer-specific, and disease-free survival censored at 5 years. Kaplan-Meier curves and univariate and multivariate Cox proportional hazards models were performed to examine demographic disparities in relation to survival.

Results

Five-year overall, cancer-specific, and disease-free survival were 65.4% (407/622), 76.4% (487/622), and 67.0% (427/622), respectively. Lower income (HR, 1.5; 95% CI, 1.1–2.0 for overall survival; HR, 1.4; 95% CI, 1.0–1.9 for cancer-specific survival), high school education or less (HR, 1.4; 95% CI, 1.1–1.9 for overall survival; HR, 1.4; 95% CI, 1.1–1.9 for cancer-specific survival), and older age in decades (HR, 1.4; 95% CI, 1.2–1.7 for overall survival; HR, 1.2; 95% CI, 1.1–1.4 for cancer-specific survival) decreased both overall and disease-free survival rates. A high school education or less (HR, 1.4; 95% CI, 1.0–2.1) and advanced age (HR, 1.3; 95% CI, 1.1–1.6) were significant independent predictors of poor cancer-specific survival.

Conclusion

Low income, low education, and advanced age predicted poor survival while controlling for a number of covariates (health behaviors, medical comorbidities, and treatment modality). Recommendations from the Institute of Medicine’s Report to reduce disparities need to be implemented in treating head and neck cancer patients.