Lung cancer is one of the most frequent cancers in the world. 1.8 million cases were estimated in 2012 (12.9% of total cancers).1 One in five cancer deaths is due to lung cancer, with 1.59 million estimated deaths in 2012. Lung cancer is the leading cause of cancer death among men worldwide.2 Around 10-25% of lung cancer cases occur among individuals who have never smoked.3 In fact, lung cancer in people who have never smoked has been proposed as an independent entity than that occurring in ever smokers.4–6 Lung cancer in persons who have never smoked would be the seventh cause of cancer death worldwide7 if ranked separately.

The epidemiology of lung cancer in people who have never smoked is not well known. Most part of the available literature refers to ever smokers. There are many risk factors for this specific disease, such as environmental tobacco smoke exposure,8 residential radon,9 occupation,10 or previous respiratory diseases.11 Regarding the effect of alcohol consumption and its types on lung cancer appearance, most studies have included mainly ever-smokers and the role of alcohol on the aetiology of lung cancer in patients who have never smoked is not clear. Some studies have observed that alcohol consumption might be a risk factor for lung cancer, with alcohol types (wine, beer, spirits) having a different effect on the onset of the disease.12 Total alcohol consumption has been associated with lung cancer,13,14 but red wine intake seems to be protective while the effect of beer is unclear.15,16

The role of tobacco in the aetiology of lung cancer cannot be disputed,17 but the situation changes when we address the role of alcohol. Analyzing exclusively people who have never smoked would disentangle the specific role of alcohol consumption on lung cancer risk in this subgroup.

Due the lack of information on the association of alcohol consumption and lung cancer risk in people who have never smoked, our main objective is to address whether alcohol consumption, and its different types (beer, wine and spirits) has any effect on the risk of lung cancer through a systematic review of the scientific literature.

A better understanding of the topic reviewed would allow better promotion and health education policies.

We developed a systematic review of the scientific literature following the 2009 PRISMA statement.18

Literature search

We carried out a comprehensive literature search in MEDLINE, EMBASE and CINAHL databases, in order to obtain studies investigating the relationship between lung cancer in persons who have never smoked and alcohol consumption.

To retrieve information we used predefined search strategies. Particularly, to gather information in Pubmed database, we developed the strategy described in Figure 1 employing different combinations of MeSH terms (lung neoplasms, ethanol, wine, beer, alcoholic beverages, alcohol drinking) and free terms (lung neoplasms, lung, neoplasms, lung cancer, ethanol, wine, beer, alcoholic beverages, alcohol drinking, spirits, liquors, hard liquors). We also included additional relevant studies found after manually reviewing the references of the identified publications.

Figure 1.

Search strategy used in PubMed.

(0.51MB).

Our search covered the period comprised from the first of January 1990 to the present, and it was constantly updated until 10/03/2016. We included papers published in English and Spanish and performed in humans. We decided to cover this period trying to get accessible and scientifically current search results.

When several publications were performed on the same study, we included the most recent.

We describe characteristics of the case-control and cohort studies included in Table I of the online Appendix of this article. On Table 2, we show the same information for meta-analysis, and in Table 3 we provide results for lung cancer risk broken down by type of alcoholic beverage.

This systematic review was conducted to clarify the effect of alcohol intake on lung cancer risk in people who have never smoked. There is no clear effect of alcohol consumption on lung cancer risk. While some studies do not show any effect, others show an increased risk with alcohol consumption. Few of them have even obtained a dose-response effect with the increase in alcohol consumption. Very few studies have analyzed the specific effect of different alcoholic beverages on lung cancer risk, nevertheless a low wine consumption is supposed to be protective and spirits are expected to be a risk factor. No hypothesis can be made for beer.

The quality of the included studies was moderate, with an average of 6.14 points. Most of the studies ranged between 5 and 7. Practically all studies adjusted their results by age and sex and very few had sample sizes higher than 500 participants.

The most important limitation to extrapolate results from the included studies is the extremely heterogeneity of the available investigations. Heterogeneity is present in the design, exposure measurement (grams per day, per week, per month, information retrieved or not on specific alcoholic beverages and different locations and populations). The included studies have been conducted throughout the World and represent different consumption patterns and different types of alcoholic beverages. A further limitation is the limited sample size of most available studies. Many of them have been designed to assess the effect of alcohol on lung cancer, and analysis of people who have never smoked is only a secondary result of the research. This situation conducts to obtain imprecise estimations with wide confidence intervals. In fact, there is only one observational study included with more than 1,000 participants. None of the remaining studies has more than 250 never-smoking cases.

For total alcohol consumption, six13,14,27,28,32,33 of the sixteen studies included in the review found a positive association. Four of them13,14,28,32 reported an overall relative risk for drinkers versus non-drinkers from 1.19 in a cohort study14 to 3.47 in a hospital based case-control study.32 One of them33 reported a positive dose response regarding to alcohol consumption, and the last one27 found a statistically significant association in men with alcohol consumption above 5 grams per day. Meta-analysis that we obtained through our search also achieved similar results. The most recent, published in 2011 by Bagnardi et al.,13 and the other, by Korte et al.,14 published in 2002, showed a positive association between alcohol and lung cancer, although the first one not reached statistically significance.

Our review includes three articles with specific results for wine consumption. It seems that low wine consumption acts as a protective factor against lung cancer in people who have never smoked. This protective effect ranges from 0.7 (95%CI: 0.4-1.2) for women who drunk no more than one glass per week in Hu et al.15 to 0.96 (95%CI: 0.47-1.98) for males in the study by Kubik et al.16 By contrast, for those who drunk more than one glass a day, Cui et al.30 found a positive association. However none of the studies reviewed reached statistical significance. Due to the limited evidence no conclusion can be done for wine consumption.

To address the effect of liquor and spirits, we have independent results in three investigations included in the review.15,16,32 It seems also reasonable to hypothesize that lung cancer risk in people who have never smoked increases with this type of alcohol consumption. Except Kúbik et al.,16 the other authors reported a positive association.

Results obtained for beer consumption are heterogeneous, although a review by Bandera et al.12 concluded that there may be an association between beer consumption and lung cancer (though it also included ever-smokers), in our review only two papers have available data but with opposite results. Raising a hypothesis would require more data.

Two of the studies in this review included results for total lung cancer risk and for its different histological subtypes. Troche et al.22 developed an independent analysis for adenocarcinoma, squamous cell carcinoma, small cell carcinoma and undifferentiated carcinoma, but due to the limited number of cases among people who had never smoked, they lost statistical power for testing an association. Freudenheim et al.,27 Rohrmann et al.,25 Shimazu et al.,24 Rachtan,32 Zang et al.31 and Bagnardi et al.29 considered the first three subtypes, but they did not performed the analysis exclusively in never smoking individuals. Kubik et al.16 use never smokers as referent. Ethanol in alcoholic beverages is classified by the International Agency for Research on Cancer as a group 1 carcinogenic to humans.34

There are several possible physiological explanations by which alcohol acts as carcinogenic. Acetaldehyde, it's primary metabolite, forms adducts with DNA in cultured human epithelial cells35 and, coupled with the induction of cytochrome P-4502E1, increases production of reactive oxygen species and nitrogen species.36 Another explanation suggests that the penetration of carcinogens through the mucosa of upper aerodigestive organs is enhanced by the role of alcohol, which could act as a solubilising agent of these carcinogens.37 Other possible mechanism could be the change in methylation and gene control resulting from the interaction produced in the intake, absorption and metabolism of vitamin B12 and B6.38

On the other hand, some studies associate the consumption of alcohol to protective effect on lung cancer risk, due to lower concentrations of various systemic biomarkers of inflammation39 on moderate alcohol drinkers, and to reduced oxidative damage.40 It is worthwhile to highlight the particular effect of wine polyphenols, especially resveratrol, whose results from in vitro and laboratory animals experiments demonstrate that it might induce neoplasic cell apoptosis in several cancer types.41

There exists a risk of bias in the included studies. Most of them have only adjusted their results by age and sex and do not consider environmental tobacco smoke. Furthermore, no study has considered residential radon exposure. In any case, radon seems not to be associated with alcohol consumption and therefore could act only as an effect modifier but not as a confounding variable. The case is different for ETS exposure that might be associated with alcohol consumption, especially in hospitality environments (previous to tobacco laws enforcement). Finally, the possibility of publication bias exists. We should not disregard that studies finding no effect for alcohol consumption or its different types could have been rejected due to the possible lack of statistical significance.

The present systematic review has some advantages. We have designed a comprehensive search strategy to minimize the risk of losing relevant information, and a proof of this is that the initial screening obtained more than 800 items. All included articles were reviewed independently by two reviewers. We obtained the same information from all of them, as the result of a thoroughly extraction. Finally, all included items were rated on the quality scale developed specifically.

Regarding limitations, besides the aforementioned high heterogeneity, we might have missed some studies published in languages different than English or Spanish though we are not aware of missing any study due to language limitations in our search. It is possible that some of these papers have been published in journals not indexed in Medline, EMBASE or CINAHL. This heterogeneity has impeded to obtain a quantitative result through a meta-analysis. Some potential biases might be present in the assessed studies. It is known that between 5 and 10% of ex-smokers are usually classified as never smokers. Some people could underestimate alcohol consumption, especially in the highest intake group. This information bias can lead to make misclassification of the exposure and finally to underestimate the effect. A last limitation resides in the different measurement of alcohol consumption used in the included publications. The alcohol content of a glass of wine can be different in distinct locations and the same can happen with the conclusion regarding consumption.

Only one study considered when analyzing the effect of alcohol type total alcohol consumption as a control variable.30 It would have been very interesting to consider which percentage of total alcohol consumption comes from a specific beverage type, but this information was not available in the studies reviewed.

Regarding the study question, the relevance of the present findings for drinkers is uncertain. In any case, we have to highlight that given the lack of studies; the effect of alcohol drinking on lung cancer in individuals with the highest alcohol intake should not be disregarded. This affirmation is reinforced by the fact that ethanol has been classified as a human carcinogen.

The main conclusion might be that there is an impressive lack of knowledge on the effect of alcohol consumption on lung cancer risk in people who have never smoked. There is also hardly any information on different alcoholic beverages. With the available studies, it seems that alcohol consumption, especially in high amounts, seems to increase the risk of lung cancer in people who have never smoked. It is extremely important to make an effort to increase research available exclusively in never smokers individuals to better assess the role of tobacco consumption in this subpopulation.

Carlos Álvarez-Dardet.

J.A. García-Lavandeira and A. Ruano-Ravina performed the literature search and selected the papers to be included. A. Ruano-Ravina had the idea of performing the systematic review. J.M. Barros-Dios and J.A. García-Lavandeira decided the search strategy. All authors have provided critical input to the manuscript content and approve its final version. All authors are responsible of the manuscript content. This paper is part of the work conducting to the PhD degree of J.A. García-Lavandeira.

This paper has been funded by a competitive research grant of the Xunta de Galicia: 10CSA208057PR “Risk factors of lung cancer in never smokers: a multicentre case-control study in the Northwest of Spain.”

None.