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