Elsevier

Oral Oncology

Volume 50, Issue 6, June 2014, Pages 616-625
Oral Oncology

Oral health, dental care and mouthwash associated with upper aerodigestive tract cancer risk in Europe: The ARCAGE study

https://doi.org/10.1016/j.oraloncology.2014.03.001Get rights and content

Abstract

Objective

We aimed to assess the association of oral health (OH), dental care (DC) and mouthwash with upper-aerodigestive tract (UADT) cancer risk, and to examine the extent that enzymes involved in the metabolism of alcohol modify the effect of mouthwash.

Materials and methods

The study included 1963 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1993 controls. Subjects were interviewed about their oral health and dental care behaviors (which were converted to scores of OH and DC respectively), as well as smoking, alcohol drinking, diet, occupations, medical conditions and socio-economic status. Blood samples were taken for genetic analyses. Mouthwash use was analyzed in relation to the presence of polymorphisms of alcohol-metabolizing genes known to be associated with UADT. Adjusted odds ratios (ORs) and 95%-confidence intervals [CI] were estimated with multiple logistic regression models adjusting for multiple confounders.

Results

Fully adjusted ORs of low versus high scores of DC and OH were 2.36[CI = 1.51–3.67] and 2.22[CI = 1.45–3.41], respectively, for all UADT sites combined. The OR for frequent use of mouthwash use (3 or more times/day) was 3.23[CI = 1.68–6.19]. The OR for the rare variant ADH7 (coding for fast ethanol metabolism) was lower in mouthwash-users (OR = 0.53[CI = 0.35–0.81]) as compared to never-users (OR = 0.97[CI = 0.73–1.29]) indicating effect modification (pheterogeneity = 0.065) while no relevant differences were observed between users and non-users for the variant alleles of ADH1B, ADH1C or ALDH2.

Conclusions

Poor OH and DC seem to be independent risk factors for UADT because corresponding risk estimates remain substantially elevated after detailed adjustment for multiple confounders. Whether mouthwash use may entail some risk through the alcohol content in most formulations on the market remains to be fully clarified.

Introduction

Cancer of the oral cavity, larynx, oropharynx, hypopharynx and esophagus, i.e. upper aerodigestive tract tumors (UADT), account for approximately 129,000 new cancer cases annually in the European Union [1], making them together the 4th and 10th most common cancer site in men and women, respectively.

The most important risk factors are consumption of alcohol and tobacco with a greater than multiplicative joint effect [2]. Among never smokers it is likely that alcohol has little or no effect [1], [3]. There is also increasing evidence that high consumption of fruits and vegetables are protective [4], [5], [6], [7], [8], and emerging evidence for the role of HPV infection in some subsites [9]. Occupational exposures are known risk factors for UADT [10], [11], [12], [13], [14]. Low socioeconomic status (SES) and a downward trajectory of social position over the life-course are also both associated with an increased risk after adjustment for confounding factors [15], [16].

Both a lack of oral hygiene and poor oral health seem to be risk factors for cancers of the UADT, independently from smoking and alcohol consumption [17], [18], [19], [20], [21]. Frequent use of mouthwash may be a risk factor due to the alcohol contained in many formulations [22], [23]. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH) and is further metabolized to acetic acid by aldehyde dehydrogenase (ALDH). Polymorphic variants of the genes ADH1B, ADH1C and ADH7 encoding for rapid metabolism of ethanol have been shown to decrease the risk of UADT [24], [25], [26], [27], [28] indicating that fast metabolism of ethanol reduces its carcinogenic effect. In a genome-wide association study comprising over 8000 cases and 11,000 controls (including our ARCAGE – Alcohol-Related Cancers And Genetic-susceptibility in Europe – study participants), variants in all 4 genes were robustly associated with UADT, with the association for the ADH1B gene variant (rs1229984) being particular prominent among heavy drinkers [25]. Similarly, we hypothesize that an effect of mouthwash may be modified by ADH genes, in particular by the ADH1B variant rs1229984.

The evidence for the risk associated with alcohol-containing mouthwashes is limited. Although a recent meta-analysis showed no statistically significant association between mouthwash-use and oral cancer [29], nevertheless, this issue may still be considered as controversial [30]. While one recent case-control study found a positive association between daily mouthwash use and UADT with, both, alcohol-containing and non-alcoholic mouthwashes [20], another recent study used non-alcoholic mouthwash users as the reference and observed threefold risks among non-users and users of alcohol-containing mouthwashes [21]. The objective of this analysis is to disentangle the effects of mouthwash from major potential confounding factors such as smoking and alcohol and to investigate the role of mouthwash and oral health/dental care more comprehensively [31].

We aim to use a novel approach, developing two composite weighted scores were constructed using indicators of oral health and dental care that were associated with UADT in previous studies. In addition, we investigate the potential risk due to frequent use of mouthwash and its potential effect modification by genetic variants that have been shown to modify the risk of UADT in heavy alcohol drinkers.

Section snippets

Materials and methods

Briefly, the ARCAGE multicenter case-control study for 13 centers (cf. Table 1) in 9 European countries collected extensive lifestyle data including oral health (OH) and dental care (DC) [32]. The study was approved by the ethical review board of the coordinating center, IARC, and the respective local boards in all centers. All subjects signed an informed consent form. With a common protocol, cases were defined as those patients newly diagnosed with primary squamous cell tumors of the UADT

Results

The overall response proportion was 80% in cases and 66% in controls. The study group comprised 1963 cases and 1993 controls after exclusion of prevalent cases, subjects with tumors of the salivary glands, carcinoma in situ and non-UADT as well as controls with non-eligible diseases (Table 1).

The majority of the cases (48%) had tumors of the mouth and oropharynx, followed by hypopharynx and larynx (36%) and esophagus (12%). The site of origin was not assigned in 5% because the tumor had

Discussion

Our study showed that both poor oral health and poor dental care were associated with increased risk of UADT cancer independently of other known risk factors. Semi-quantitative scores of OH and DC revealed a dose–effect relationship with the risk of UADT tumors. Frequent use of mouthwashes (3+ times/day) was associated with an elevated risk of developing UADT cancer.

The strengths of our study include: (i) statistical power – this is one of the largest case-control studies to-date which has

Funding

This work was supported by the European Community (5th Framework Programme) [grant number QLK1-CT-2001-00182], University of Athens Medical School and Bureau of Epidemiologic Research Academy of Athens, for the Athens center; Padova University (Contract No. CPDA057222) for the Padova center; Compagnia San Paolo, AIRC, and Piedmont Region for the Turin center. The Estonian study was supported by Targeted Financing from Estonian Government: SF0180142, European Union through the European Regional

Conflict of interest statement

None declared.

Acknowledgements

The authors thank the patients and their families for their participation and gratefully acknowledge the study interviewers and our clinical colleagues in hospitals and primary care who supported this study.

GJM and TVM partly worked on this study while at the University of Manchester. We acknowledge the help of Dr. Ann-Marie Biggs, Professor Martin Tickle and Professor Phil Sloan in study conduct in the Manchester center.

We are grateful for the editorial support by Ina Alvarez in revising

References (52)

  • P. Lagiou et al.

    Diet and upper-aerodigestive tract cancer in Europe: the ARCAGE study

    Int J Cancer

    (2009)
  • G. D’Souza et al.

    Case-control study of human papillomavirus and oropharyngeal cancer

    New Engl J Med

    (2007)
  • M.P. Purdue et al.

    Occupational exposures and head and neck cancers among Swedish construction workers

    Scand J Work Environ Health

    (2006)
  • L. Tarvainen et al.

    Cancer of the mouth and pharynx, occupation and exposure to chemical agents in Finland [in 1971–1995]

    Int J Cancer

    (2008)
  • A. Dietz et al.

    Exposure to cement dust, related occupational groups and laryngeal cancer risk: results of a population based case-control study

    Int J Cancer

    (2004)
  • H. Ramroth et al.

    Occupational wood dust exposure and the risk of laryngeal cancer: a population based case-control study in Germany

    Am J Indust Med

    (2008)
  • L. Richiardi et al.

    Occupation and risk of upper aerodigestive tract cancer: The ARCAGE study

    Int J Cancer

    (2011)
  • D.I. Conway et al.

    Socioeconomic inequalities and oral cancer risk: a systematic review and meta-analysis of case-control studies

    Int J Cancer

    (2008)
  • N. Schmeisser et al.

    Life course social mobility and risk of upper aerodigestive tract cancer in men

    Eur J Epidemiol

    (2010)
  • T. Bundgaard et al.

    Case-control study of squamous cell cancer of the oral cavity in Denmark

    Cancer Causes Control

    (1995)
  • K. Rosenquist et al.

    Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma. A population-based case-control study in southern Sweden

    Acta Otolaryngol

    (2005)
  • N. Guha et al.

    Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case-control studies

    Am J Epidemiol

    (2007)
  • M.N. Eliot et al.

    Periodontal disease and mouthwash use are risk factors for head and neck squamous cell carcinoma

    Cancer Causes Control

    (2013)
  • J.S. Chang et al.

    Investigating the association between oral hygiene and head and neck cancer

    Oral Oncol

    (2013)
  • M.J. McCullough et al.

    The role of alcohol in oral carcinogenesis with particular reference to alcohol-containing mouthwashes

    Aust Dent J

    (2008)
  • D.W. Lachenmeier et al.

    Salivary acetaldehyde increase due to alcohol-containing mouthwash use: a risk factor for oral cancer

    Int J Cancer

    (2009)
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