A Meta-analysis of Alcohol Drinking and Oral and Pharyngeal Cancers: Results from Subgroup
F. Turati1,2, W. Garavello1,3, I. Tramacere1, C. Pelucchi1,*, C. Galeone1, V. Bagnardi4,5, G. Corrao4, F. Islami6,7, V. Fedirko8,
P. Boffetta6,9, C. La Vecchia1,2,9and E. Negri1
1Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Giuseppe La Masa 19, 20156 Milan, Italy,2Department of Clinical Sciences and Community Health,
Università degli Studi di Milano, Milan, Italy,3Clinica Otorinolaringoiatrica, DNTB, Università degli Studi di Milano-Bicocca, Milan, Italy,4Department of
Statistics, University of Milano-Bicocca, Milan, Italy,5Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy,6The Tisch
Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA,7Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical
sciences, Tehran, Iran,8International Agency for Research on Cancer, Lyon, France and9International Prevention Research Institute, Lyon, France
*Corresponding author: Tel.: +39-02-39-01-4577; Fax: +39-02-33-200-231; E-mail: firstname.lastname@example.org
(Received 10 May 2012; first review notified 13 July 2012; in revised form 7 August 2012; accepted 8 August 2012)
Abstract — Aims: To quantify the magnitude of the association between alcohol and oral and pharyngeal cancer (OPC) by sex,
smoking habits, type of alcoholic beverage and other factors. Methods: We combined findings from all case–control and cohort
studies published until September 2010 and present in this article the results classified by these factors, using a meta-analytic ap-
proach. Summary relative risks (RRs) were obtained using random-effects models; heterogeneity was assessed using the χ2test.
Results: The association between alcohol and OPC risk was similar in men and women, with similar dose–response relationships.
No notable differences were found with respect to geographic area and other factors, both for drinking overall and heavy (≥4 drinks/
day) drinking. Among never/non-current smokers, the pooled RRs were 1.32 (95% confidence interval, CI, 1.05–1.67) for drinking,
and 2.54 (95% CI, 1.80–3.58) for heavy drinking. The corresponding RRs in smokers were 2.92 (95% CI, 2.31–3.70) and 6.32
(95% CI, 5.05–7.90). The pooled RRs for any drinking irrespective of smoking were 2.12 (95% CI, 1.37–3.29) for wine-, 2.43 (95%
CI, 1.92–3.07) for beer- and 2.30 (95% CI, 1.78–2.98) for spirits-only drinking. The corresponding RRs for heavy drinking were
4.92 (95% CI, 2.80–8.65), 4.20 (95% CI, 1.43–12.38) and 5.20 (95% CI, 2.77–9.78). Conclusion: The alcohol-related RRs are
similar with respect to sex, geographic area and type of alcoholic beverage. The association between alcohol and OPC is stronger in
smokers than in non-smokers.
The association between alcohol consumption and oral and
pharyngeal cancers (OPC) has long been established
(Bagnardi et al., 2001; Brennan et al., 2008; Pelucchi et al.,
2011). It has been estimated that over 30% of all cases of
OPC worldwide are attributable to alcohol drinking (Boffetta
et al., 2006).
In two recent meta-analyses, including >30 studies and
14,000 cases, we found a dose–response relationship
between alcohol and OPC risk (relative risks, RRs, increas-
ing from 1.29 for 10 g ethanol/day to 13.02 for 125 g
ethanol/day) (Tramacere et al., 2010), with higher RRs for
pharyngeal than for oral cancer, particularly at heavy doses
(Turati et al., 2010).
Nevertheless, the magnitude of the association between
alcohol and OPC risk by selected characteristics, such as sex,
smoking habits and type of alcoholic beverage, has yet to be
quantified. Thus, in order to provide estimates of such asso-
ciations, we combined all published data on alcohol and
OPC risk using a meta-analytic approach.
MATERIALS AND METHODS
Identification of studies and collection of data
The methodology of identification of studies and data collec-
tion has been described in a meta-analysis from our research
group, published in 2010 and including 45 publications,
which presented the overall results and the dose–risk relation
between alcohol drinking and OPC risk (Tramacere et al.,
2010). We performed a literature search using PubMed of all
the original articles in English of case–control and cohort
studies, using the MESH terms ‘alcohol’ and combinations of
‘mouth’ or ‘oral’ or ‘pharynx’ or ‘pharyngeal’ and ‘cancer’ or
‘carcinoma’ or ‘neoplasm’, following the Meta-analysis
Of Observational Studies in Epidemiology (MOOSE) guide-
lines (Stroup et al., 2000).
Case–control and cohort studies considering at least three
levels of alcohol consumption and reporting the odds ratio
(OR) or RR or hazard ratio (HR) for oral and/or pharyngeal
cancer and the corresponding confidence interval (CI)—or
sufficient information to calculate them—for each exposure
level were included in the present analysis.
(Tramacere et al., 2010), four other publications were identi-
fied through a careful review of the reference lists in the pub-
lications retrieved (Sankaranarayanan et al., 1989; Boffetta
et al., 1992; Wang et al., 2005; Allen et al., 2009), while
another one (Applebaum et al., 2007) was excluded, since
the results were based on the same data reported by Peters
et al. (2006). Moreover, the update of the literature search to
(Shanmugham et al., 2010). Thus, we collected information
on 49 publications (Wynder and Bross, 1957; Vincent and
Marchetta, 1963; Keller and Terris, 1965; Martinez, 1969;
Bross and Coombs, 1976; Graham et al., 1977; Elwood
et al., 1984; Brugere et al., 1986; Blot et al., 1988; Tuyns
et al., 1988; Merletti et al., 1989; Rossing et al., 1989;
Sankaranarayanan et al., 1989; Boffetta and Garfinkel, 1990;
Franceschi et al., 1990; Zheng et al., 1990; Choi and Kahyo,
Alcohol and Alcoholism Vol. 48, No. 1, pp. 107–118, 2013
Advance Access Publication 4 September 2012
© The Author 2012. Medical Council on Alcohol and Oxford University Press. All rights reserved
by guest on September 8, 2015
1991; Oreggia et al., 1991; Boffetta et al., 1992; Kabat et al.,
1994; Maier et al., 1994; Andre et al., 1995; Bundgaard
et al., 1995; Takezaki et al., 1996, 2000; Hayes et al., 1999;
Bouchardy et al., 2000; Moreno-Lopez et al., 2000; Garrote
et al., 2001; Schwartz et al., 2001; Zavras et al., 2001;
Balaram et al., 2002; Lissowska et al., 2003; Znaor et al.,
2003; Altieri et al., 2004; Castellsague et al., 2004;
Menvielle et al., 2004; Lee et al., 2005; Rosenquist et al.,
2005; Wang et al., 2005; Peters et al., 2006; Suzuki et al.,
2006; Vlajinac et al., 2006; De Stefani et al., 2007;
Subapriya et al., 2007; Ide et al., 2008; Sapkota et al., 2008;
Allen et al., 2009; Shanmugham et al., 2010).
In order to perform stratified analyses by sex, type of alco-
holic beverage and smoking habits, 11 additional publica-
tions were considered (Wynder et al., 1957; Winn et al.,
1984; Kabat and Wynder, 1989; Barra et al., 1990; Mashberg
et al., 1993; Franceschi et al., 1994, 1999; De Stefani et al.,
1998; Talamini et al., 1998; Fioretti et al., 1999; Bosetti
et al., 2000). These provided the subgroup analyses of inter-
est from some of the 49 studies previously identified.
For the analysis restricted to never/non-current smokers,
we selected studies reporting risk estimates in subjects who
never smoked in their life (Blot et al., 1988; Merletti et al.,
1989; Kabat et al., 1994; Talamini et al., 1998; Fioretti et al.,
1999; Hayes et al., 1999; Garrote et al., 2001; Schwartz
et al., 2001; Lissowska et al., 2003; Znaor et al., 2003;
Castellsague et al., 2004; Lee et al., 2005; Wang et al.,
2005) and also studies considering non-current smokers
(never plus ex-smokers) (Wynder et al., 1957; Bross and
Coombs, 1976; Winn et al., 1984; Bundgaard et al., 1995;
Subapriya et al., 2007). Some studies analyzing the associ-
ation between alcohol consumption and OPC risk in light-
smokers were excluded (Graham et al., 1977; Oreggia et al.,
1991; Mashberg et al., 1993; Peters et al., 2006; De Stefani
et al., 2007) [for the study by Merletti et al. (1989), we
excluded RR estimates for men, since smokers of up to 7 g
of tobacco per day]. Other seven studies, which did not
publish results for alcohol drinking in never/non-current
smokers in separate reports but were included in the
INHANCE Consortium publication by Hashibe et al. (2007),
were also considered in this subgroup analysis for the heavy
drinking analysis (see Supplementary data, Appendix 1, for
details). For the analysis in smokers, whenever possible, we
selected RR estimates for ever smokers. When results in the
original studies were presented in more than one smoking
category, these categories were combined. Three publications
that included in the stratified analysis by smoking habits
some subjects with laryngeal cancer among the case series
(Elwood et al., 1984; Tuyns et al., 1988; Peters et al., 2006),
and one publication analyzing cumulative lifetime alcohol
consumption across smoking strata (Zheng et al., 1990) were
For the analysis by type of alcoholic beverage, we
included exclusively the studies reporting findings on con-
sumption of wine-, beer- and/or spirits-only (detailed in-
formation on the definition of spirits consumption in the
original articles is reported in the footnote of Fig. 3). For
example, we included the paper published by De Stefani
et al. (1998), which considered consumption of wine- and
liquor-only, rather than a more updated one of the same
group (De Stefani et al., 2007), reporting results from a
larger dataset without distinguishing the subjects who
consumed only wine or only liquor from those consuming
more than one type of alcoholic beverage.
Two review team members (F.T. and I.T.) reviewed all the
studies and abstracted the following information in a stand-
ard format: study design, country, number of subjects (cases,
controls or cohort size), duration of follow-up (for cohort
studies), years of study conduction (for case-control studies),
sex of the study population, variables adjusted for in the ana-
lysis, RR estimates for categories of alcohol drinking and the
corresponding 95% CI and, when available, the number of
cases and non-cases for each level of alcohol consumption.
(Tramacere et al., 2010). Briefly, our measure of interest was
the RR or the HR for cohort and the OR for case–control
studies. Whenever available, we considered multivariate risk
estimates; otherwise, we utilized or computed the crude RRs
(and the corresponding 95% CIs) from the distribution of
cases and non-cases. When a study reported multivariate
RRs but not the corresponding CIs, the SE of the adjusted
estimate was obtained by penalizing the SE of the crude RR
by a factor of 1.5. In the Million Women study (Allen et al.,
2009), we derived the floated variances, from the 95%
floated CIs provided by the authors, to obtain RRs and 95%
CIs for different categories of alcohol consumption compared
with non-drinkers (Easton et al., 1991).
We used gram as the measurement unit for ethanol, as-
suming that one drink=12.5 g, 1 ml of ethanol =0.8 g and
1 ounce =28.35 g of ethanol. We assigned to each consump-
tion category the dose corresponding to the midpoint of the
range, and, for the open-ended upper category, the dose was
assumed to be 1.2 times the lower bound (Berlin et al.,
When possible, we chose non-drinking as the reference
category. In several studies, however, occasional drinking
was included in the reference category. Therefore, we
defined the reference category of our analyses as ‘non- or oc-
casional drinking’. We defined ‘moderate drinking’ as
consumption of 1–2 drinks/day, and ‘heavy drinking’ as
≥4 drinks/day. When more than one study category fell in
the range of alcohol consumption considered (i.e. heavy,
moderate and drinking in general), we calculated the study-
specific pooled estimates using, whenever possible, the
method proposed by Hamling et al. (2008), taking into
account the correlation between risk estimates; otherwise, we
used fixed-effects models.
We derived meta-analytic summary estimates using random-
effects models, which consider both within- and between-study
variations (Greenland, 1987). We assessed the heterogeneity
among studies using the χ² test (Greenland, 1987) (results were
defined heterogeneous for P<0.10) and the I² statistic. We per-
meta-regression model in a non-linear dose–response relation-
ship framework, providing the best fitting two-term fractional-
polynomial model (Rota et al., 2010).
For the analyses by smoking habits and type of alcoholic
beverage, in addition to combining results from studies iden-
tified through the literature search, we carried out sensitivity
analyses including results from the INHANCE Consortium
108Turati et al.
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