Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study

• Research
  

Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study

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1. Madlen Schütze, PhD student1,
   
2. Heiner Boeing, professor, department chair1,
   
3. Tobias Pischon, scientist, group head1,
   
4. Jürgen Rehm, professor, director23,
   
5. Tara Kehoe, statistician2,
   
6. Gerrit Gmel, data analyst2,
   
7. Anja Olsen, scientist4,
   
8. Anne M Tjønneland, department head4,
   
9. Christina C Dahm, postdoctoral researcher5,
   
10. Kim Overvad, professor of epidemiology6,
    
11. Françoise Clavel-Chapelon, department head78,
    
12. Marie-Christine Boutron-Ruault, senior scientist78,
    
13. Antonia Trichopoulou, professor of nutrition9,
    
14. Vasiliki Benetou, scientist10,
    
15. Dimosthenis Zylis, scientist10,
    
16. Rudolf Kaaks, professor, division head11,
    
17. Sabine Rohrmann, senior scientist11,
    
18. Domenico Palli, unit chief12,
    
19. Franco Berrino, department chief13,
    
20. Rosario Tumino, director14,
    
21. Paolo Vineis, chair of environmental epidemiology, unit chief1528,
    
22. Laudina Rodríguez, section chief16,
    
23. Antonio Agudo, scientist17,
    
24. María-José Sánchez, lecture director18,
    
25. Miren Dorronsoro, unit chief19,
    
26. Maria-Dolores Chirlaque, scientist2021,
    
27. Aurelio Barricarte, department head21,
    
28. Petra H Peeters, professor of epidemiology22,
    
29. Carla H van Gils, associate professor of epidemiology22,
    
30. Kay-Tee Khaw, professor of clinical gerontology23,
    
31. Nick Wareham, director24,
    
32. Naomi E Allen, scientist25,
    
33. Timothy J Key, deputy director25,
    
34. Paolo Boffetta, professor, deputy director2627,
    
35. Nadia Slimani, scientist, group head26,
    
36. Mazda Jenab, scientist26,
    
37. Dora Romaguera, research associate28,
    
38. Petra A Wark, research fellow28,
    
39. Elio Riboli, director28,
    
40. Manuela M Bergmann, scientist1
    

+ Author Affiliations

1. ¹Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany
   
2. ²Centre for Addiction and Mental Health (CAMH), Toronto, Canada
   
3. ³Institute for Clinical Psychology and Psychotherapy, TU Dresden, Germany
   
4. ⁴Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen
   
5. ⁵Department of Clinical Epidemiology, Aarhus University Hospital, Aalborg, Denmark
   
6. ⁶Department of Epidemiology, School of Public Health, Aarhus University, Aarhus
   
7. ⁷Centre for Research in Epidemiology and Population Health, U1018, Institut Gustave Roussy, F-94805, Villejuif, France
   
8. ⁸Paris South University, UMRS 1018, F-94805, Villejuif
   
9. ⁹WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University
   of Athens Medical School and Hellenic Health Foundation, Greece
   
10. ¹⁰WHO Collaborating Centre for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University
    of Athens Medical School
    
11. ¹¹Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany
    
12. ¹²Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute, Florence, Italy
    
13. ¹³Department of Preventive and Predictive Medicine, Epidemiology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
    
14. ¹⁴Cancer Registry and Histopathology Unit “Civile M.P.Arezzo” Hospital, ASP 7 Ragusa, Italy
    
15. ¹⁵Institute for Scientific Interchange Foundation, Turin, Italy
    
16. ¹⁶Public Health and Participation Directorate, Health and Health Care Services Council, Asturias, Spain
    
17. ¹⁷Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (IDIBELL),
    Barcelona, Spain
    
18. ¹⁸Andalusian School of Public Health, Granada (Spain) and CIBER de Epidemiología y Salud Pública (CIBERESP), Spain
    
19. ¹⁹Public Health Department of Gipuzkoa and CIBERESP, San Sebastian, Spain
    
20. ²⁰Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain
    
21. ²¹CIBER Epidemiología y Salud Pública (CIBERESP), Spain
    
22. ²²Centre for Health Sciences and Primary Care, University Medical Centre, Utrecht, Netherlands
    
23. ²³Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
    
24. ²⁴MRC Epidemiology Unit, Cambridge
    
25. ²⁵Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford
    
26. ²⁶International Agency for Research on Cancer, IARC, Lyon, France
    
27. ²⁷Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA
    
28. ²⁸Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London
    

1. Correspondence to: M Schütze m.schuetze@dife.de
   

• Accepted 4 January 2011
  

Abstract



Objective To compute the burden of cancer attributable to current and former alcohol consumption in eight European countries based
on direct relative risk estimates from a cohort study.


Design Combination of prospective cohort study with representative population based data on alcohol exposure.


Setting Eight countries (France, Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Denmark) participating in the European
Prospective Investigation into Cancer and Nutrition (EPIC) study.


Participants 109 118 men and 254 870 women, mainly aged 37-70.


Main outcome measures
Hazard rate ratios expressing the relative risk of cancer incidence for
former and current alcohol consumption among EPIC
participants. Hazard rate ratios
combined with representative information on alcohol consumption to
calculate alcohol attributable
fractions of causally related cancers
by country and sex. Partial alcohol attributable fractions for
consumption higher than
the recommended upper limit (two drinks
a day for men with about 24 g alcohol, one for women with about 12 g
alcohol) and
the estimated total annual number of
cases of alcohol attributable cancer.


Results If we
assume causality, among men and women, 10% (95% confidence interval 7
to 13%) and 3% (1 to 5%) of the incidence of total cancer was
attributable to former and current alcohol consumption in the selected
European countries. For selected cancers the figures were 44% (31 to
56%) and 25% (5 to 46%) for upper aerodigestive tract, 33% (11 to 54%)
and 18% (−3 to 38%) for liver, 17% (10 to 25%) and 4% (−1 to 10%) for
colorectal cancer for men and women, respectively, and 5.0% (2 to 8%)
for female breast cancer. A substantial part of the alcohol attributable
fraction in 2008 was associated with alcohol consumption higher than
the recommended upper limit: 33 037 of 178 578 alcohol related cancer
cases in men and 17 470 of 397 043 alcohol related cases in women.


Conclusions
In western Europe, an important proportion of cases of cancer can be
attributable to alcohol consumption, especially consumption
higher than the recommended upper
limits. These data support current political efforts to reduce or to
abstain from alcohol
consumption to reduce the incidence of
cancer.

Introduction


Alcohol consumption is thought to account for a substantial number of deaths worldwide, with Europe and America showing the
highest alcohol attributable fractions of 6.5% and 5.6%, respectively.1
Chronic diseases, especially cancer, contribute markedly to this
burden. In 2007 the International Agency for Research on Cancer (IARC)
added two of the most common cancers—female breast and colorectal
cancer—to the list of cancers causally related to alcohol, which
previously consisted of oral cavity, pharynx, larynx, oesophagus, and
liver cancer.2 Although alcohol consumption is a major risk factor for cancer incidence,3
and Europe is among the regions with the highest per capita alcohol
consumption, detailed information on the fractions of
cancer that are attributable to alcohol
consumption based on direct empirical evidence for the different cancer
sites is sparse,4 5
and systematic and comparable estimations across European countries are
lacking. Moreover, previous estimates of the alcohol
attributable fractions refer to the
burden from current alcohol consumption but do not consider the risk of
former alcohol
consumption. Also, in 2007 the World
Cancer Research Fund/American Institute for Cancer Research published
recommendations
on the maximum recommended daily
alcohol consumption.6 We do not know how much of the burden of incidence of cancer is attributable to alcohol and occurs because of consumption
higher than the recommended upper limit.


We estimated the total
(current and former alcohol consumption) and partial (alcohol
consumption higher than the recommended
upper limit) alcohol attributable
fractions for the incidence of total and specific cancers related to
alcohol in eight European
countries based on hazard rate ratios
from the European Prospective Investigation into Cancer and Nutrition
(EPIC) study and
linked those alcohol attributable
fractions to incidences of cancer to estimate the annual absolute number
of cancer cases
attributable to alcohol in these
countries.

Methods

Study population

The EPIC study is a
multicentre prospective cohort study that, from 1992 to 2000, recruited
about 520 000 randomly selected men and women aged mainly 35-70 from 10
European countries.7 8
Eligible participants were selected from the general population, except
in France, where selection was based on members of the health insurance
system or state school employees, and in Utrecht (the Netherlands),
where selection was based on women attending screening for breast
cancer. Participants gave informed consent and completed questionnaires
on diet and lifestyle. The present analyses included participants free
from cancer at recruitment and who were not in the top or bottom 1% of
the ratio of energy requirement to energy expenditure (n=478 478).
Participants with incomplete information on alcohol consumption at
recruitment or in the past (n=114 481) and missing dietary information
(n=9) were excluded, leaving 363 988 men and women from France, Italy,
Spain, the Netherlands, United Kingdom, Greece, Germany, and Denmark.
France and Utrecht enrolled only women. As we wanted to consider the
risk of cancer incidence associated with former alcohol consumption, we
had to exclude the centres of Norway, Sweden, Bilthoven, and Naples
because they did not have information on past consumption.

Alcohol consumption at
recruitment (in grams per day) was measured with a validated dietary
questionnaire assessing frequency
and portion size of beer/cider,
wine, spirits, and fortified wine covering the 12 months before
recruitment.9 10 11
Consumption in the past was assessed as self reported consumption of
beer, wine, and spirits at the ages of 20, 30, 40, and 50. Based on
consumption in the past and at recruitment we distinguished between
never (no consumption in the past and no consumption at recruitment),
former (consumption in the past but no consumption at recruitment), and
lifetime consumers (consumption in the past and at recruitment). For
lifetime consumers, consumption as applied in this analysis reflects the
past years’ consumption before recruitment.

We obtained information on
incidence of cancer through record linkage with regional cancer
registers in countries with passive
follow-up (Denmark, Italy, the
Netherlands, Spain, UK) or by a combination of methods including
medically verified self reports
of the participant or the next of
kin, cancer or pathology registers, health insurance records, or death
certificates in countries
with active follow-up (France,
Germany, Greece). The follow-up ended between 2002 and 2005,12
and loss to follow-up was relatively low, with <2% in all countries
irrespective of active or passive follow-up. We investigated
cancers with a causal association to
alcohol consumption3
(colorectal (C18-21, ICD-O (international classification of
diseases-oncology, 2nd revision), upper aerodigestive tract (C00-10,
C12-15, C32), liver (C22), female
breast (C50)), as well as total cancer (C00-C80, except C44 skin cancer)
and alcohol related
cancers combined (upper
aerodigestive tract, colorectal, liver, and, for women, female breast
cancer). ICD codes of cancer
end points were in accordance with
the GLOBOCAN-2008 cancer definitions.13

Statistical analysis

We combined hazard rate ratios derived from the EPIC study with representative data on alcohol consumption from the general
population. Cox proportional hazard regressions were applied to compute hazard rate ratios14
during a mean follow-up time of 8.8 years for alcohol consumption among
lifetime consumers per 12 g/day increment (equivalent to one drink of
any alcoholic beverage) and for former compared with never consumers and
incidence of first primary cancer. Age was used as the underlying time
variable with entry and exit time defined as the participant’s age at
recruitment and age at diagnosis of cancer or at censoring,
respectively. Results on some single cancer outcomes have been published
earlier.15 16 17 18 19 20
We used updated information and recomputed hazard rate ratios for these
sites. To control for age and variations in study
procedures across the EPIC centres
we stratified the analyses by age (in 1 year categories) and centre.

All models were run
separately for men and women, and included the following potential
confounders, which were measured at recruitment: smoking (never; past
<10 years ago, ≥10 years ago; current <15, 15-25, or ≥25
cigarettes/day, other (cigars, pipe, cigarettes with missing dose)) and
smoking duration (<10, 10-<20, 20-<30, 30-<40, ≥40 years,
missing (4.1%)); education (higher education/university, technical
school, secondary school, primary school, none or missing (1.2%));
physical activity (inactive, moderately inactive, moderately active,
active)21;
body mass index (BMI; kg/m²); consumption (g/day) of meat and meat
products, fish, fruits and vegetables; fibre, and non-alcohol
energy intake (kJ/day); and, for
women, menopausal status (premenopausal, postmenopausal/surgical,
perimenopausal), age at
menarche (<13, 13/14, >14
years, missing (30.8%)), and whether she had ever breast fed (yes, no,
or missing (32.9%)), ever
used oral contraceptives (yes, no,
or missing (31.6%)), and ever used hormone replacement therapy (yes, no,
or missing (30.6%)).


Restricted cubic spline
regressions (knots: p10, p50, p90 and p25, p50, p75) did not indicate
deviation from linearity of
associations between alcohol and
risk of cancer among lifetime consumers, except for liver cancer in men
(P<0.01 for non-linearity).
We therefore used regression
coefficients (β) as risk functions to express the risk for cancer
incidence per 1 g/day increment
in alcohol consumption among current
lifetime consumers. For simplicity and for comparability we also used
this approach for
liver cancer in men.

We tested effect
modification by smoking for the site specific cancers by including
product terms of smoking status (never,
former, current smoker) with alcohol
(g/day) and performing the likelihood ratio test between nested models.
There was indication
for an effect modification by
smoking for upper aerodigestive tract and liver cancer in men and for
colorectal cancer in women
(P<0.1).


Heterogeneity of hazard rate ratios across centres was examined by the meta-analytic approach22 23
and by including interaction terms of centre and alcohol (g/day) in the
models and applying likelihood ratio tests between
nested models. There was significant
heterogeneity across centres for liver cancer in men and colorectal
cancer in women.
Reasons for heterogeneity are
unknown. Reduction in alcohol consumption could have been the
consequence of pre-diagnostic
diseases (such as liver cirrhosis)
or positive results on screening (such as for liver function markers or
colon polyps) performed
in some but not all EPIC countries.
This could lead to reverse causation2 24 25
and thus to attenuation of the association between alcohol and cancer
in these centres, resulting in heterogeneity of the
association across centres. This
speculation was supported by the fact that the heterogeneity was no
longer present when we
excluded the first four years of
follow-up.

All statistical tests were two sided with significance at the 5% level.

Alcohol attributable fractions

The computation of alcohol
attributable fractions requires not only the information on relative
risks for alcohol consumption
(such as hazard rate ratios) but
also information on the distribution of alcohol consumption within the
general population.
We computed alcohol exposure data
from the general population following an algorithm (triangulation)26 that combined information of alcohol consumption from survey data as reported by the World Health Organization27 and per capita consumption28
for each country and separately for men and women aged ≥15. These sex
and country specific data on alcohol exposure were modelled as gamma
function29 in current consumers of alcohol by applying a formula30 based on the triangulated population mean alcohol intake (combining alcohol survey information with data on per capita alcohol
consumption).26
These gamma functions were shown to fit and best model the right skewed
distribution of alcohol consumption on the population
level. Furthermore, this exhibits
the clear advantage of using alcohol consumption continuously, as the
estimation of alcohol
attributable fractions based on
alcohol categories might lose valuable information. We also obtained
information on the proportions
of never and former consumers of
alcohol from WHO, which used the GENACIS survey as source of
information, except for Greece,
for which data were derived from a
national survey on licit and illicit drug use.31 We then calculated the country and sex specific alcohol attributable fractions reflecting the burden of cancer incidence
associated with total alcohol consumption on the population level (equation A, fig 1)⇓.




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Fig 1 Equations for computation of alcohol attributable fractions

We also computed the part
of the alcohol attributable fraction (partial alcohol attributable
fraction) that reflects the burden
of cancer incidence associated with
alcohol consumption higher than the recommended upper limit6 of two standard drinks a day (>24 g/day) for men and one standard drink a day (>12 g/day) in women (equation B, fig 1)⇑.

For adjusted risk estimates, the prevalence of exposure among cases rather than among the general population should be used,32 33 34 35 36
which is hardly feasible because no exposure information in cases from
the general population is available. We therefore
performed sensitivity analyses by
simulating the distribution of alcohol exposure among cases by using the
alcohol exposure
information in cancer cases in the
EPIC study and shifting this curve towards the alcohol exposure
information of the general
population (by deriving weights by
dividing the gamma distribution of the general population by the gamma
distribution of
the EPIC participants). Doing so, we
simulated the alcohol exposure distribution of cases as if they
originated from the general
population. As expected, the
estimated mean alcohol consumption among cancer cases was higher than
among the general population.
Alcohol attributable fractions were
stratified by sex but not by country because of sparse numbers of cases
in some countries.
This was also why we applied this
approach as a sensitivity analysis and not as our main approach.

As smoking seemed to
modify the association between alcohol and cancers of the upper
aerodigestive tract and liver in men
and colorectal cancer in women, we
also computed hazard rate ratios for alcohol intake (continuous, per 12
g/day and for former
v never consumers) and
cancer incidence among never smokers. For upper aerodigestive tract and
liver cancer the number of cases
became low in men. We therefore
computed the hazard rate ratios in never smokers for men and women
combined with additional
adjustment for sex. Alcohol
attributable fractions were recomputed by replacing the smoking adjusted
hazard rate ratios from
the total EPIC cohort by the hazard
rate ratios in never smokers.

We used 10 000 Monte-Carlo
simulated alcohol attributable fractions, considering the uncertainty
of the hazard rate ratios, to compute the variances, standard errors,
and corresponding 95% confidence intervals of the alcohol attributable
fractions. We estimated the absolute number of alcohol attributable
cancer cases by multiplying the alcohol attributable fractions with the
total number of incidental cancer cases from 2008 derived from the
GLOBOCAN 2008 project.13

The analyses were performed with SAS, version 9.2, and R, version 2.9.1.

Results

Across the countries
investigated, alcohol consumption followed a north south gradient with
Greece and Spain having the highest
proportions of never and former
consumers, and Denmark and Germany having the highest proportion of
lifetime consumers (table
1⇓). This gradient was also seen for the proportions of alcohol consumption higher than the recommended upper limit with Greece
and Spain showing the lowest and Germany and Denmark the highest proportions.

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Table 1

 Proportions of never, former, and lifetime consumers of alcohol and mean alcohol consumption in lifetime consumers in general
adult population aged 15 years or older

Among male and female lifetime consumers, the risk for all the cancers we included increased with each additional drink a
day (table 2)⇓.
Former consumption compared with never was associated with a
considerably higher risk for total and alcohol related cancer
in men. We could not compute the risk
for former consumers of alcohol and upper aerodigestive tract and liver
cancer in men
because of low number of cases in those
who had never consumed alcohol. Hence, we computed alcohol attributable
fractions
for upper aerodigestive tract and liver
cancer in men based on the hazard rate ratio for former alcohol
consumption and total
cancer.

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Table 2

 Adjusted hazard rate ratios (HRRs)* (95% confidence intervals) per 12 g/day increment for lifetime consumers and for former
versus never consumers (reference category) of alcohol

If we assume causality, these estimates would translate into 10% (95% confidence interval 7% to 13%) of total cancer in men
(table 3)⇓ and 3.0% (1% to 5%) of total cancer in women (table 4)⇓
being attributable to alcohol consumption in these selected European
countries. In both sexes the alcohol attributable fraction was highest
for cancer of the upper aerodigestive tract (44% (31% to 56%) in men;
25% (5% to 46%) in women), followed by liver cancer (33% (11% to 54%)
and 18% (−3% to 38%), respectively). Alcohol consumption was associated
with 17% (10% to 25%) of cases of colorectal cancer in men and 4% (−1%
to 10%) in women. Also, 5% (2% to 8%) of cases of breast cancer in women
could be associated with total alcohol consumption. The alcohol
attributable fractions varied across countries because of the
differences in alcohol exposure, with relatively high alcohol
attributable fractions for Spanish men compared with men in other
countries. Confidence intervals of the alcohol attributable fractions,
however, overlapped for all countries in both men and women.

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Table 3

Proportion of cancer cases attributable to alcohol use in men aged ≥15 years. Figures are percentages (95% confidence interval)

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Table 4

Proportion of cancer cases attributable to alcohol use in women aged ≥15
years. Figures are percentages (95% confidence interval)

Partial attributable fractions for alcohol consumption higher than two drinks a day in men accounted for 10% of colorectal
cancer, 27% of liver cancer, and 38% of upper aerodigestive tract cancer (fig 2⇓),
which accounted for 57% to 87% of the total alcohol attributable
fractions. The proportion of cancer associated with alcohol
consumption higher than the recommended
upper limit did not vary much by country in men, except for Greece and
Spain, where
partial alcohol attributable fractions
were somewhat lower because of the lower proportions of men consuming
more than two
drinks a day. In women, partial alcohol
attributable fractions accounted for 3% of colorectal cancer, 4% of
breast cancer,
7% of liver cancer, and 25% of upper
aerodigestive tract cancer (fig 3⇓),
which accounted for 40% to 98% of the total alcohol attributable
fractions. For all cancers investigated in women, the partial alcohol
attributable fraction was lowest in Spain, Greece, and Italy and highest
in Germany, Denmark, and the UK. When we compared total with partial
alcohol attributable fractions, a substantial part (40-98%) of the
incidence of alcohol attributable cancer occurred because of alcohol
consumption higher than the recommended upper limit in both men and
women. The remaining part of the total alcohol attributable fraction
(2-60%) was associated with consumption of less than the recommended
upper limit and former consumption. In men, about three in 100 alcohol
related cancer cases were associated with alcohol consumption of ≤24
g/day and more than 18 in 100 were associated with alcohol consumption
>24 g/day. In women one in 100 alcohol attributable cancer cases was
associated with alcohol consumption of ≤12 g/day and about four in 100
associated with alcohol consumption >12 g/day.




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Fig 2
Total and partial alcohol attributable fractions with 95% confidence
intervals and corresponding number of cases of cancer
with 95% confidence intervals in
men in selected EPIC countries (Italy, Spain, UK, Greece, Germany,
Denmark) in 2008. UADT=upper
aerodigestive tract




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Fig 3
Total and partial alcohol attributable fractions with 95% confidence
intervals and corresponding number of cases of cancer
with 95% confidence intervals in
women in selected EPIC countries (France, Italy, Spain, UK, Netherlands,
Greece, Germany,
Denmark) in 2008. UADT=upper
aerodigestive tract

In terms of total numbers of
cases of alcohol related cancer, and if we accept that there is a causal
association between alcohol consumption and occurrence of cancer, in
2008, 33 037 of 178 578 alcohol related cancer cases in men and 17 470
of 397 043 alcohol related cancer cases in women were associated with
alcohol consumption of more than two (one for women) drinks a day.
Cancer of the upper aerodigestive tract accounted for the highest number
of alcohol attributable cases in men (22 022 cases), with Germany
showing most cases (table 5⇓). In women, breast cancer contributed most to the number of alcohol attributable cancer cases with 12 589 cases (fig 2, table 5⇑ ⇓).
The numbers of total alcohol attributable cancer cases varied
considerably by country, mainly because of different population
sizes in the investigated countries but
also because of varying alcohol attributable fractions across the
countries.

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Table 5

 Total number* of alcohol attributable cancer cases for general population in 2008 in selected countries

The sensitivity analysis
using the alcohol consumption data in the cancer cases only had similar
results to those in tables
3 and 4 (data not shown). The maximum
deviation was 3 percentage points in men for alcohol related cancers
(29% v 32%) and 2 percentage points in women for upper aerodigestive tract cancer (23% v 25%).

Given there is a causal
association between alcohol consumption and risk of cancer in people who
have never smoked, sensitivity
analyses with the hazard rate ratios of
never smokers indicated noticeable differences compared with alcohol
attributable
fractions that were based on hazard
rate ratios adjusted for smoking from the total cohort, particularly for
liver cancer,
for which the alcohol attributable
fraction in men who had never smoked (AAF_Sens) was 78% compared with 33% in the total population, and for upper aerodigestive tract cancer, for which the AAF_Sens was 14% compared with 44%. The alcohol attributable fractions for colorectal cancer in women differed by 3 percentage points
with AAF_Sens 1% v 4%, which was, however, within the confidence interval computed for the alcohol attributable fraction based on estimates
of the total cohort.

Discussion

If we assume causality, our
analysis shows that about 10% of total cancer in men and 3% in women
could be attributed to current
and former alcohol consumption in the
European countries included in this study. In relative terms, the
alcohol attributable
fraction of cancer incidence was
highest for cancer of the upper aerodigestive tract, followed by liver
cancer. The highest
absolute number of alcohol attributable
cancer cases in men was found for upper aerodigestive tract and in
women for breast
cancer. Furthermore, a substantial part
of the alcohol attributable cancer cases were associated with
consumption of more
than two or one standard drinks per day
for men and women, respectively.

Comparison with other studies

Few previous studies have reported on alcohol attributable mortality37 38 39 40 41 42 43 or incidence4 5 44 45 of cancer. Published estimates for alcohol attributable incidence of cancer in Europe38 and France44 were of similar magnitude to our estimates. For women both higher5 45 and lower44
alcohol attributable fractions for single cancer sites were reported.
Differences could emerge because we considered also
the risk of cancer associated with
former consumption of alcohol, or because of the risk functions used by
one study,44 which were not derived for men and women separately,46
or because of the different application of alcohol exposure data. One
British study used population means of alcohol consumption,5
while we applied gamma distributions, which better represent the right
skewness of the data on alcohol consumption. Because
of the various methods used to
compute the alcohol attributable fractions in previous studies and
because of limited data,
no comparable estimates across the
European countries on the alcohol attributable burden of cancer have
been available until
now.

Besides the total burden,
we also quantified the burden of cancer incidence associated with
exceeding the recommended maximal daily limit of alcohol. We found that a
substantial part of this incidence was associated with consumption
above the recommended upper limit, indicating the potential for cancer
prevention merely by adhering to the current recommendations. For cancer
sites with markedly higher risks for former compared with never
consumers—such as liver cancer —a noticeable part of the total alcohol
attributable fractions was associated with former consumption. That also
explains why for those cancers the partial alcohol attributable
fractions associated with consumption above the recommended upper limit
were lower than for cancers with less strong risk estimates in former
consumers, such as breast cancer. Alcohol consumption below the
recommended upper limit accounted for a modest part of the total alcohol
attributable fraction of alcohol related cancers, with at least three
in 100 cases of cancer in men and one in 100 cases in women. This shows
that following the current recommendation would not eliminate alcohol
attributable cancer incidence completely. In contrast, for all cause
mortality alcohol consumption is often shown to be associated with a
lower risk for up to four drinks a day in men and two drinks a day in
women.47 This lower risk is probably because of the lower risk of death from cardiovascular disease, especially coronary heart disease
and ischaemic stroke.48 49 50 Heavy alcohol consumption above the recommended upper limit, however, was shown to be not related to48 or detrimental for46 cardiovascular diseases, whereas for cancer, as shown by many studies46 51
including ours, there is no sensible limit below which the risk of
cancer is decreased. Therefore, even though light to moderate
alcohol consumption might decrease
the risk for cardiovascular disease and mortality, the net effect of
alcohol is harmful.1 Thus, alcohol consumption should not be recommended to prevent cardiovascular disease or all cause mortality.

Sensitivity analysis

Smoking, known to be
closely related to alcohol consumption, could be a potential synergistic
risk factor, particularly for
cancer of the upper aerodigestive
tract. A possible synergistic effect modification of smoking on the risk
of alcohol and
cancer could lead to an
overestimation of the alcohol attributable fraction.52
We observed a substantially higher alcohol attributable fraction for
liver cancer and a considerably lower alcohol attributable
fraction for upper aerodigestive
tract cancer in men when we applied the hazard rate ratios for alcohol
consumption among
never smokers. Potential effect
modification by smoking was also indicated for colorectal cancer in
women, for which the alcohol
attributable fraction computed by
using hazard rate ratios among never smokers was lower than the overall
alcohol attributable
fraction, but within the 95%
confidence interval. In the groups of never smokers the number of cases
of cancer was limited
in the EPIC study, which led to a
limited power to assess the association between the consumption of
alcohol and risk of cancer
in this subgroup. This could be one
explanation why the alcohol attributable fractions differed from the
originally computed
overall alcohol attributable
fractions. We could also have overestimated the alcohol attributable
fraction for upper aerodigestive
tract cancer in men because of the
effect of smoking. However, a recent pooled analysis of 17 European and
American case-control
studies investigating people who had
ever consumed alcohol compared with those who had never consumed
alcohol in relation
to head and neck cancer in people
who had never smoked,4 53
estimated a population attributable fraction of 29.5% in men and 31.5%
women. These estimates are of similar magnitude to
our estimates based on results from
the total EPIC study population, suggesting the estimates of our overall
alcohol attributable
fractions to be valid. Regarding
liver cancer, smoking is a recognised causal risk factor.3
Thus, there is no plausible explanation for the substantial higher
alcohol attributable fraction for liver cancer based on
risk estimates computed in those who
had never smoked. Therefore, the limited power because of low numbers
of cases and the
resulting imprecise point estimates
of the hazard rate ratios in never smokers is the most plausible
explanation for the considerably
higher alcohol attributable fraction
of liver cancer.

Advantages and limitations

Our results are limited by
the underlying data quality to generate the relative risk functions and
by the data on alcohol exposure. The risk estimates were adjusted for
several confounders—for example, dietary factors or extensive adjustment
for smoking, the main confounder for the association between alcohol
and risk of cancer. Different confounding in the various countries we
investigated is unlikely to play a major role because the relative risk
estimates were observed to be relatively homogenous across the
countries. Also, the relative risk estimates are in line with results
from meta-analyses24 46 54 and with the evaluation of the carcinogenicity of alcohol,26
which supports the validity of our effect estimates for alcohol
consumption and risk of cancer. Loss to follow-up, though
low, could have led to
underestimation of the risk of cancer, as high risk or exposed people
are more likely to be lost to
follow-up. Recall bias is unlikely
to have had an impact on the relative risk estimates as the exposure
information was assessed
before the cancer occurred. Also,
under-reporting of alcohol consumption because of social desirability
should not have affected
our risk estimates, assuming that
under-reporting was independent of later case and non-case status and
that this did not
change the ranking of the study
participants. As the EPIC study population is a convenience sample, the
transferability of
study results to the general
population could be questioned. Selective participation, however, should
not impair aetiological
conclusions expressed as relative
risk estimates because these effect measures are both internally and
externally valid.8 55

The data on alcohol consumption were representative for the countries investigated, and they were quantified comparably across
all countries.27
Thus, the exposure information is highly comprehensive and comparable,
resulting in directly comparable alcohol attributable
fractions across the selected
countries. Comparison of previous country specific alcohol attributable
fraction estimates was
impeded as the studies used
different methods and strategies to compute the alcohol attributable
burden of cancer incidence.4 5 44 45
As the prevalence of alcohol exposure differs across the European
countries, however, we would also expect the burden of
alcohol attributable cancer
incidence to differ across the countries, which is of potential interest
for public health policy
makers.

We have provided a
systematic and comparable overview of the alcohol attributable cancer
incidence for several European countries,
and presented alcohol attributable
fractions for causally related cancer sites based on empirical original
data for both the
total (current and former) alcohol
consumption as well as for alcohol consumption higher than the
recommended upper limit.
We considered the risk from former
alcohol consumption and could thus capture, in contrast with previous
studies, the full
burden of cancer incidence
associated with alcohol consumption. The gamma distributions we used for
current alcohol consumption
overcome the limitation of using
categorical risk estimates and categories of proportions of alcohol
consumption. This is
of particular value because the risk
of cancer increases linearly and alcohol consumption follows a strongly
right skewed
distribution. The attributable
burden of cancer incidence associated with consuming above the
recommended upper limit illustrates
the potential of avoidable cancer
incidence, if the recommendations of the WCRF/AICR6
are followed. Until now, it was only speculated that reducing alcohol
consumption to two drinks a day in men and one drink
a day in women would be beneficial
in terms of incidence of cancer. We have now computed quantitative
measures, both relative
(alcohol attributable fraction) and
absolute (total number of cancer cases), for the burden associated with
alcohol consumption
above the recommended upper limit.

Conclusions and policy implications

In conclusion, if we
assume causality between alcohol consumption and overall and specific
cancer incidence, a considerable
proportion of the most common and
most lethal cancers is attributable to former and current alcohol
consumption in the selected
European countries, especially to
consumption above the recommended upper limit. This strongly underlines
the necessity to
continue and to increase efforts to
reduce alcohol consumption in Europe,56 both on the individual and the population level.

What is already known on this topic

• Alcohol consumption has been causally related to cancers of the oral cavity, pharynx, larynx, oesophagus, liver, colorectum,
  and female breast
  
• 
  
  Current
  estimates of the alcohol attributable burden of these cancers refer
  mostly to current alcohol consumption and to Europe
  as a whole, and do not
  include the risk associated with previous alcohol consumption
  

What this study adds

• 
  
  If we assume
  causality between alcohol consumption and cancer, about 10% of all
  cancer cases in men and 3% of all cancer cases
  in women are
  attributable to current and former alcohol consumption in the
  investigated European countries
  
• 
  
  For cancers
  that are causally related to alcohol consumption, the proportions were
  32% in men and 5% in women, with a substantial
  part (40-98%) being
  attributable to current alcohol consumption above the recommended upper
  limit of two drinks a day in men
  and one drink a day in
  women
  

Notes

Cite this as: BMJ 2011;342:d1584

Footnotes

• 
  
  Contributors: All
  authors had full access to all of the data (including statistical
  reports and tables) and take responsibility
  for the integrity of the data and
  the accuracy of the data analysis. All authors MS, MMB, TP, HB, JR, TK,
  and ER were responsible
  for study concept and design. HB,
  TJK, K-TK, PP, AB, MD, M-DC, MJS, LR, AA, PV, RT, FB, DP, AT, RK, FC-C,
  KO, AMT, AO, CD,
  M-CB-R, VB, DZ, SR, CvG, NW, MJ,
  NS, DR, PAW, and ER acquired the data. MS, MMB, HB, TP, JR, TK, GG, PB,
  NEA, and PP analysed
  and interpreted the data. MS, MB,
  TP, HB, JR, TK, NEA, KO, PP, and PB drafted the manuscript, which was
  critically revised
  for important intellectual
  content by all the authors. MS, JR, TK, GG, TP, and MMB were responsible
  for the statistical analysis.
  MMB, JR, and HB supervised the
  study. MS is guarantor.
  
• 
  
  Funding: The work was
  performed (partly) within the coordinated action EPIC
  (SP23-CT-2005-006438), which has received research funding from the
  Community’s Sixth Framework Programme, as well as by the “Europe Against
  Cancer” Programme of the European Commission (SANCO); Deutsche
  Krebshilfe; German Cancer Research Center; German Federal Ministry of
  Education and Research; Danish Cancer Society; Health Research Fund
  (FIS) of the Spanish Ministry of Health (grant No: Network RCESP
  C03/09); Spanish Regional Governments of Andalucia, Asturias, Basque
  Country, Murcia and Navarra; ISCIII, Red de Centros RETIC(RD06/0020)
  (grant No: C03/09); Cancer Research UK; Medical Research Council, UK;
  Stroke Association, UK; British Heart Foundation; Department of Health,
  UK; Food Standards Agency, UK; Wellcome Trust, UK; Italian Association
  for Research on Cancer (AIRC); Compagnia di San Paolo; Progetto
  Integrato Oncologia-PIO, Regione Toscana; Dutch Ministry of Public
  Health, Welfare and Sports; National Cancer Registry of the Netherlands;
  Greek Ministry of Health and Social Solidarity; Hellenic Health
  Foundation and Stavros Niarchos Foundation. The funders were independent
  of the research of the presented study.
  
• 
  
  Role of sponsors: The sponsors had no input in the design, the conduct, the analysis, or the interpretation of the study,
  and did not influence the manuscript preparation.
  
• 
  
  Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf
  (available on request from the corresponding author) and declare: no
  support from any organisation for the submitted work;
  no financial relationships with
  any organisations that might have an interest in the submitted work in
  the previous three
  years; no other relationships or
  activities that could appear to have influenced the submitted work.
  
• 
  
  Ethical approval: The EPIC study was approved by the IARC ethical committee and by the local ethics committees relevant for
  each study centre. All participants gave informed consent.
  
• 
  
  Data sharing: No additional data available.
  

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