[CANCER RESEARCH 50, 6502-6507. October 15, 1990]
Smoking and Drinking in Relation to Cancers of the Oral Cavity, Pharynx, Larynx,
and Esophagus in Northern Italy1
Silvia Franceschi,2 Renato Talamini, Salvatore Barra, Anna E. Barón,Eva Negri, Ettore Bidoli, Diego Serraino, and
Carlo La Vecchia
Epidemiology Unit, Aviano Cancer Center, Via Pedemontana Occ., 33081 Ariano <PN),Italy [S. F., R. T., S. B., A. E. B., E. B., D. S.J; Hormones, Sexual Factors and
Cancer Group—European Organization for Cooperation in Cancer Prevention Studies, Brussels, Belgium fS. F.J; Department of Preventive Medicine and Biometrics,
University of Colorado, Health Science Center, Denver, Colorado 80262 [A. E. B.]; "Mario Negri" Institute for Pharmacological Research, Via Eritrea, 62, 20157 Milan,
Italy ¡E.N., C. L. V.¡;and Institute of Social and Preventive Medicine, University of Lausanne, 1005 Lausanne, Switzerland [C. L. V.]
based case-control study undertaken
Italy.
ABSTRACT
A hospital-based case-control study of upper aerodigestive tract tumors
was conducted between June 1986 and June 1989 in Northern Italy. One
hundred fifty-seven male cases of oral cavity cancer, 134 of pharyngeal
cancer, 162 of laryngeal cancer, and 288 of esophageal cancer, and 1272
male inpatients with acute conditions unrelated to tobacco and alcohol
were interviewed. Odds ratios for current smokers of cigarettes were 11.1
for oral cavity, 12.9 for pharynx, 4.6 for larynx, and 3.8 for esophagus.
For all 4 sites, the risk increased with increasing number of cigarettes
and duration of smoking habits and, with the exception of esophageal
cancer, decreased with increasing age at the start of and years since
quitting smoking. Smokers of pipes and cigars showed a more elevated
risk of cancer of the oral cavity and esophagus than did cigarette smokers.
Significantly increased risks emerged also in heavy drinkers (odds ratio
>60 versus >19 drinks/week = 3.4, 3.6, 2.1, and 6.0 for oral cavity,
pharynx, larynx, and esophagus, respectively), deriving predominantly
from wine consumption.
INTRODUCTION
In Western countries, cancers of the oral cavity, pharynx,
larynx, and esophagus constitute from 2 to 15% of all cancer
incidence (1). A comparison between age-adjusted mortality
rates for males in 27 countries has shown that many European
countries, such as France, Switzerland, Luxemburg, and Italy,
have the highest rates for these tumors (2). In Italy, age-adjusted
mortality (world population) rates among males are 6.2/
100,000 for oral cavity and pharyngeal cancer, 6.6/100,000 for
laryngeal cancer, and 4.8/100,000 for esophageal cancer (2),
with rates being almost double in the northeastern part (3).
Tobacco and alcohol have been well established in several
studies as risk factors for upper aerodigestive tract cancers (412). Several investigations have dealt specifically with the to
bacco and alcohol interaction in the etiology of cancers of the
oral cavity, pharynx, larynx, and esophagus (8, 10-23). Al
though the nature of the biological interaction between these 2
factors has not been definitively established, either multiplica
tive or additive risk models appear to be plausible.
Separating the effects of alcohol and tobacco remains, how
ever, a difficult problem, since heavy drinkers tend to be heavy
smokers and vice versa. Furthermore, very few persons who
neither drink nor smoke have been identified in the etiological
studies of cancers of the upper aerodigestive tract. To further
clarify the role of alcohol and tobacco in the occurrence of
cancers of this type, we here report the data from a hospital-
in the northern part of
MATERIALS AND METHODS
A hospital-based case-control study on tumors of the upper aerodigestive tract has been conducted since June 1986. Cases were males
below age 75 with a histologically confirmed diagnosis of cancer of the
upper aerodigestive tract (i.e., oral cavity, larynx, pharynx, and esoph
agus). Cancers of the nasopharynx and the salivary glands were ex
cluded. All cases had their diagnoses made within 6 months before the
date of interview and were drawn from 2 areas of northern Italy: (a)
the western part of Friuli-Venezia Giulia region (Pordenone province);
and (b) the greater Milan area, in the Lombardy region. The present
data were collected before July 1989.
The 2 areas under study were not covered by cancer registries and,
thus, it was not possible to estimate the proportion of upper aerodiges
tive tract cancers in relation to the total incidence rate. The study
hospitals, however, included the majority of diagnostic and therapeu
tical facilities available in the areas under surveillance and, therefore,
the largest proportion of upper aerodigestive tract cancers will have
been referred there. Furthermore, interviews were generally (90%)
conducted within 2 months from cancer diagnosis, thus minimizing
losses caused by patient death and disability.
One hundred fifty-seven males with histologically confirmed cancer
of the tongue and oral cavity (ICD-IX1 = 140, 141, 143, 144, and 145);
Received3/28/90;accepted6/29/90.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1This study was supported by the Italian Association for Cancer Research,
and the Italian League Against Tumors, Milan. Italy, and conducted within the
framework of the Italian National Research Council Applied Project "Oncology"
134 with cancer of the pharynx, junction between hypopharynx and
larynx included (ICD-IX = 146, 148, and 161.1): 162 with laryngeal
cancer (remaining ICD-IX = 161), and 288 with cancer of the esophagus
(ICD-IX = 150) were interviewed. Males admitted for acute illnesses
in the same hospitals were eligible as controls. None of these patients
had malignant tumors or any condition known to be related to alcohol
and tobacco consumption. A total of 1272 male controls chosen on the
basis of area of residence and age within quinquennia were interviewed.
Of these, 26% were admitted for nontraumatic orthopedic conditions
(mainly low back pain and disc disorders), 25% for traumatic orthopedic
conditions (mainly fractures and sprains), 19% for acute surgical con
ditions (included plastic surgery), 17% for eye disorders, and 13% for
other illnesses (e.g., skin disorders). All study patients had their inter
views during the course of their hospitalization. No next-of-kin re
spondents were used. Incidence of refusal to interview was about 2%
for cases and 3% for controls.
Interviewers were trained to reduce variability between study areas,
using the same precoded questionnaire to obtain information on sociodemographic factors; occupation; lifestyle, including tobacco and
alcohol consumption habits; dietary habits; and past history of ear,
nose, and throat diseases. All information referred to patient behavior,
before the onset of symptoms of the disease that led to hospital
admission. Information on smoking habits included smoking status
(never, ex-, or current smoker), number of cigarettes smoked per day
before the onset of symptoms, years of cigarette smoking, the age at
starting to smoke, and, for the exsmokers, years since quitting smoking.
The part of the questionnaire relating to alcohol habits included the
number of days per week that each alcohol-containing beverage (wine,
ì
The abbreviations used are: ICD-IX, International Classification of Diseases
Number: OR, odds ratio.
(Contract 87.01544.44).
1 To whom requests for reprints should be addressed.
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TOBACCO. ALCOHOL. AND UPPER AERODIGESTIVE
TRACT CANCERS
Table 1 Distribution of oral cavity, pharynx, larynx, and esophagus cancer cases and controls according to age and sociodemographic characteristics":
Northern Italy, 1986-89
Site of cancer
157)CharacteristicAge
Oral cavity
<n=
(n=134)No.27405611257237*121223475A24*%2030428195428991265618Larynx
162)No.126177122510037*12150529116*%738487156223793335710Esophagus
(n =
1272)No.3544363471351745315671141158
(n=
288)No.4199111375915574"262628016822*%14343913205426991306
(n =
(yr)<4950-5960-6970+Education
(yr)S45-78+Marital
statusNever
marriedEver
marriedOccupationClerical/professionalManual
workerFarmerNo.37495318398731'23134*347740*%243134112555201585235126Pharynx
flTotal sample size varies with the number of cases and controls with incomplete information.
* As compared with control group, difference was significant (P i 0.05).
beer, hard liquor) was consumed, the number of drinks per day before
the onset of symptoms, and the duration of habit in years. Taking into
account the different alcohol concentrations, one drink corresponded
to 150 ml of wine, 330 ml of beer, and 30 ml of hard liquor.
The ORs for the smoking and alcohol variables, together with their
approximate 95% confidence intervals, were calculated accounting for;
the study design variables—age and area of residence; potential confounders—years of education, and occupation in 3 strata (i.e., profes
sional and clerical, manual workers, and farmers); and the reciprocal
confounding effect of either alcohol or tobacco (24). These estimates
were obtained by unconditional multiple logistic regression (25). As a
final step, a multiple logistic regression model was fitted with interac
tion terms between alcohol and smoking, in addition to the terms listed
above. Attributable risks were computed by means of the method
described by Bruzzi et al. (26).
RESULTS
Table 1 shows the distribution of cases and controls according
to cancer site for age and sociodemographic characteristics.
Years of education are inversely related to the diseases studied.
A difference between cases and controls in marital status was
observed only for oral cavity. With reference to occupation,
controls tended to be more in the professional and clerical
category, whereas cases tended to be more often farmers.
Tobacco Smoking. Table 2 gives the distribution of cases and
controls. Very few patients described themselves as nonsmokers. The adjusted ORs for current smokers of cigarettes
were 11.1 for oral cavity, 12.9 for pharynx, 4.6 for larynx, and
3.8 for esophagus. These risks increased significantly with
increasing number of cigarettes smoked per day and duration
of smoking habits for all cancer sites. Also, age at starting to
smoke showed a similar pattern of strong inverse relation to
risk for all sites considered, except esophagus (Table 2). Among
exsmokers, those who had quit smoking for more than 10 years
showed ORs close to unity for oral cavity (1.1) and larynx (1.2),
and somewhat above unity for pharynx and esophagus. For
smokers of only pipe or cigars, risks more elevated than in
cigarette smokers were found for cancer of the oral cavity (20.7)
and esophagus (6.7), whereas for the other tumors, the lack of
individuals who smoked only pipe or cigars prevented us from
addressing this issue.
Alcohol Drinking. The alcohol-related risks, adjusted for to
bacco, are shown in Table 3. A highly significant direct trend
in risk with an increasing number of drinks of wine consumed
per week emerged for each cancer site. Significantly elevated
risks, however, became apparent only in those who drank 56 or
more glasses of wine per week (about 1 liter/day), with the
weakest associations emerging for laryngeal cancer (OR = 2.8
versus 5.3, 4.0, and 4.9 for oral cavity, pharynx, and esophagus,
respectively). ORs of 8.5, 10.9, 4.2, and 14.0, respectively, were
seen among those persons who reported drinking 84 or more
glasses of wine per week.
Beer and hard liquor were consumed much less frequently
than wine, and significant risks for these beverages emerged
only for cancer of the eosphagus [OR = 1.8 for beer and for
hard liquor (Table 3)]. Due to the positive correlation of wine
with other alcoholic beverage consumption, all ORs for beer
and hard liquor were somewhat reduced by allowance for wine
consumption. Total alcohol intake mostly reflected wine con
sumption and, in a similar way, showed for heavy drinkers (60
or more drinks per week) the most elevated OR for esophageal
cancer (OR = 6.0), and the lowest for laryngeal cancer (OR =
2.1). The duration of an alcohol-drinking habit did not appear
to be related to risks for any of the upper aerodigestive tract
tumors considered here.
Smoking and Alcohol Interrelationship. The joint effect of
tobacco and alcohol intake is examined in Table 4 in terms of
distribution of cases and controls and in Table 5 ¡nterms of
corresponding ORs. Cases of oral cavity and pharyngeal cancer
are considered together; further, abstainers and light alcohol
drinkers (<35 drinks/week) are combined since the associated
ORs (Table 2) appeared to be very similar. As concerns smoking
status, it was defined in 4 categories: (a) nonsmokers; (b) light—
exsmokers who quit >10 years ago, or smokers of 1-14 ciga
rettes/day for <30 years; (c) intermediate—15-24 cigarettes/
day regardless of duration, 30-39 years duration regardless of
amount, 1-24 cigarettes/day for >40 years, or >15 cigarettes/
day for <30 years; (d) heavy—smokers of >25 cigarettes/day
for >40 years.
The risk of oral cavity and pharyngeal cancer for the highest
levels of alcohol and smoking was increased 80-fold relative to
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TOBACCO, ALCOHOL. AND UPPER AERODIGESTIVE
Table 2 OR for oral cavity, pharynx,
cancerNo.
157)Never
smoked'Cigar
smokeronlyCigarette
or pipe
larynx, and esophagus
TRACT CANCERS
cancers in males according
to smoking habits": Northern
Italy, 1986-89
interval)Pharynx112.98.014.217.629.38'6.415.525.546.16'7.912.816.025.53'3.1-52.9
(95% confidence
Site of
in
in
in
in
oral cavity pharnvx
esophagus
larynx
(n =
162)81152256859204985208351No.
(n =
288)177264631109166731277015145Controls
(n =cavity28914967313396258414255300224498247120.711.15.314.314.339.32'5.914.318.043.61'9.210.013625.14'5
1272)
Oral
(n=
(n =134)20132306141283668147048No.
smokerNo.
cigarettes/day£1415-2425+XÎ
of
24J7.142.50'1.95.27.246.91'2.45.16.533.59'0.3-26.1"2.2-9.61.0
trendYears
smoking1-2930-3940+XÃŽ
of cigarette
trendAge
smoking25+17-24<|7xf
started
4-4 8
trend46147267942344969237454No.
Years since quit smoking
cigarettes
0.8-18.0
29
197
1.1 0.3-5.1
3.7
1.2 0.4-3.3
2.2
10+
10
9
5
1.6-20.8 11.3
2.6-49.4
2.0-10.4
5.7
4.6
2.5
<10
26
32
41
203
20
13.22'
20.09'
18.78'
7.60'
XÃŽ
trend
°Total sample size varies with the number of cases and controls with incomplete information.
* Estimates from logistic regression adjusted for age, area of residence, years of education, occupation, and number of alcoholic drinks per week.
c Reference category.
" Mantel-Haenszel estimates adjusted only for age and area of residence because of the small number of cases.
Table 3 OR for oral cavity, pharynx,
cancerNo.
(n=157)Glasses
in
oral cavitv
larynx, and esophagus
cancers in males according
to alcohol drinking
habits':
Northern
1.1-4.3
1.3-4.8
Italy, ¡986-89
interval)Pharynx10.71.93.110.946.44''10.50.90.4710.41.20.2410.91.53.621.66
confidence
Site of
in
in
in
pharynx
larvnx
esophagus
(n =1272)
Oral1472653962501862894617115178921926436033236621438536743311.11
(n=134)961628453094112873105113143473314054No.
(n=162)321032275|101211625115123539275145225168No.
(n =
288)322557609420219264316735864541115876093116Controls
of wine/wk
0-6'7-2021-3435-5556-8384+xi
72.6-9.53.6-20.20.6-1.80.5-1.40.4-1.30.6-1.30.5-2.51.6-6.21.7-7.10.7-2.00.4-1.3OR*(95%
9-3.71.6-6.14.7-25.30.3-1.00.5-1.50.2-0.90.8-1.80.4-2.00.8-3.11.8-7.
71.6-4.41.6-10.60.6-2.10.8-2.50.2-0.80.5-1.30.52-301
9498.547.68"11
8-6.96.4-30.606-1.61.2-2.80
trendGlasses
beer/wkOf1-1314+XJ
of
00.80.3010.70.90.6611.13.23.418.74''11.20.71.28cavity0.5-2.309-3
trendGlasses
liquor/wkOc1-67+XÃŽ
of hard
trendTotal
drinks/wk£19'20-3435-5960+XÎ
no. of
trendYears
use<30'30-3940+XÕ
of alcohol
trend12620276824111202691194715146365395360No.
°Total sample size varies with the number of cases and controls with incomplete information.
* Estimates from logistic regression adjusted for age. area of residence, years of education, occupation, and smoking habits.
' Reference category.
the lowest levels of both factors. For laryngeal cancer, the
combined effects of alcohol and smoking at the highest level
for each variable increased the risk 12 times over that for the
lowest levels. The effects of alcohol in nonsmokers were ex
tremely difficult to assess since no cases of laryngeal cancer
were seen among nonsmokers at the highest level of alcohol
consumption.
For esophageal cancer, high levels of combined alcohol and
cigarette consumption increased the risk 18 times over the risk
for the lowest levels of consumption. At variance with other
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TOBACCO, ALCOHOL, AND UPPER AERODIGEST1VE TRACT CANCERS
Table 4 Distribution of oral cavity, pharynx, larynx, and esophagus cancer cases
and controls according to smoking and alcohol drinking habits': Northern Italy,
¡986-89
intake<35
drinks/wkSmoking
Table 5 ORs" for oral cavity/'pharynx, larynx, and esophagus cancers in males
according to smoking and alcohol drinking habits: Northern Italy, 1986-89
intakeSmoking
Alcohol
Alcohol
status*Oral
drinks/wk1.65.426.640.22.31.65.07.110.41.40.87.98.811.03.1
drinks/wk2.310.936.479.63.4-5.49.511.72.87.9
drinks/wkIe3.714.125.0Ie1.05.4
drinks/
drinks/
cavity/pharynxNonsmokersLightIntermediateHeavyTotalLarynxNonsmokersLightIntermediateHeavyT
drinks/wkNo.411120171522151001713481210931160174318536281289281614691253%37791121175125868196156613232
wkNo.24524620327434333212SO3197814114817019219362%1334341022032522208311728540661512960+
wkNo.044710611855973043474551360684234912613211%03316401641755022142825212302410117Total
status*Oral
cavityNonsmokersLightIntermediateHeavvTotalPharynxNonsmokersLightIntermediateHeavyTotalLarynxNonsmokersLightIntermediateHeavyTotalEsophagusNonsmokersLightIntermediateHea
" Estimates from logistic regression equation including age, area of residence,
years of education, occupation, drinks per week, and smoking habits, as appro
priate.
* See Table 4, Footnote b.
c Reference category.
and suggests that cancer risk among exsmokers substantially
declines after 10 years or more after cessation of smoking.
As regards the risks associated with different types of alco
holic beverages, wine seems to exert the strongest effect when
compared with beer and hard liquor. This result was not at
variance with studies from other countries (8, 10, 14, 27, 33,
34) when levels of exposure to various alcoholic beverages are
taken into account, since wine is by far the predominant bev
°Total sample size varies with the number of cases and controls with incom
erage consumed in Italy (10, 14, 27). Only esophageal cancer
plete information.
risk seemed to be enhanced significantly by moderate consump
Smoking status defined in 4 categories: (a) nonsmokers; (h) light, exsmokers
who quit >10 years ago, or smokers of 1-14 cigarettes/day for <30 years: (c)
tion of alcoholic beverages other than wine. Due to the positive
intermediate, 15-24 cigarettes/day regardless of duration, 30-39 years' duration
correlation with wine consumption, however, when the associ
regardless of amount. 1-24 cigarettes/day for >40 years, or >15 cigarettes/day
ations of esophageal cancer with beer and hard liquor were
for <30 years; (d) heavy, smokers of 225 cigarettes/day for 240 years.
adjusted for wine, they became weaker.
Some potential limitations in the methodology of this casecancer sites, in cancer of the esophagus, the effect of drinking
60 or more alcoholic drinks per week in nonsmokers was control study should be noted. First, the use of hospital-based
slightly stronger than the effect of heavy smoking in light controls in studying the etiology of cancers that are clearly
related to smoking habits, such as cancers of the upper aerodrinkers (OR = 7.9 versus 6.4).
digestive tract, has been widely criticized based on the fact that
hospital controls tend to smoke more than does the general
DISCUSSION
population (35). In the present study, however, the distribution
Role of Tobacco and Alcohol. The associations of tobacco and of smoking and drinking habits in hospital controls (from which
patients with tobacco- and alcohol-related diseases were ex
alcohol with cancers of the upper aerodigestive tract have been
cluded)
turned out to be very similar to that of the general
reported since the early part of the century (4, 5, 7). Not until
population
of the same area (36). Furthermore, no inconsist
more recently, however, have good estimates of risk associated
encies in alcohol-related ORs emerged when the 4 major diag
with alcohol and tobacco been obtained (8-12). Some studies
have shown a strong dose-response relationship for each of nostic groups (i.e., trauma, orthopedic, surgical, and miscella
these 2 substances after controlling for the exposure to the neous conditions) were used separately.
Of, perhaps, greater concern is the potential misclassification
other (10, 11,27-30).
In the present study, elevated risks were found in all sites for of exposure and confounding variables used in this study. Selfreports of smoking habits and alcohol consumption, in partic
number of cigarettes smoked per day, the length of smoking
habit, and early age at starting to smoke, which have also been ular, may suffer from less-than-perfect reliability, and if such
reliability is differential between cases and controls, the direc
previously reported (10, 11, 27). In agreement with previous
findings (10, 27, 29, 31, 32), the risk associated with pipe and tion and magnitude of residual confounding is not predictable
cigars is suggestive of a strong effect on the oral cavity and (37). We believe that the standardization of the questionnaire
and its administration across the study areas minimized the
esophagus, and a more moderate effect on the larynx. A de
potential for eliciting smoking and drinking habits differentially
creased risk for longer duration of quitting smoking observed
here is also compatible with the findings in another study (10), from cases and controls. Furthermore, there is no reason to
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TOBACCO, ALCOHOL, AND UPPER AERODIGESTIVE
believe that preferential recall among cases could account for
the elevated ORs.
Smoking and Alcohol Interaction. In an effort to understand
the ways in which alcohol and tobacco act, several investigators
have modeled the risk of disease using multiplicative risk
models, additive risk models, and models that allow for an
intermediate effect between additive and multiplicative (38, 39).
Several studies of oral cavity and pharyngeal cancer (7, 8, 10,
11, 20, 21, 40) have empirically examined the interaction be
tween alcohol consumption and smoking. For the highest levels
of consumption for both factors, estimates of risk compared
with the lowest levels of consumption range from 8.0 to 141.6.
The present study estimate fell at the high end of this range
and was compatible with a greatly elevated risk for heavy
smokers who also drank heavily.
As concerns the combined effects of smoking and alcohol on
laryngeal cancer (7, 11, 12, 15, 31, 40-42), estimates of risk at
the highest levels of exposure for both factors ranged from 8.0
to 22.1. Again, the results of our study were not inconsistent
with this set of values representing elevated risk, but with a
magnitude lower than that for oral cavity and pharyngeal can
cer.
As concerns esophageal cancer, fewer studies have examined
the joint effects of tobacco and alcohol intake (6, 7, 14, 22),
generally showing multiplicative effects. Using 10 g of alcohol
per drink and 2 g of tobacco per cigarette, the risk reported in
this study was 17.5 based on approximately 90 g or more per
day of alcohol and 25 g or more of tobacco per day. Such risk
estimates fell in the range provided by previous work on the
subject (6, 14), although they were at the lowest end.
Attributable Risks and Conclusions. The interest of this work
is to add further quantitative evidence toward the association
between alcohol and tobacco and 4 different neoplasms of the
upper aerodigestive tract. From a public health viewpoint, the
present study shows attributable risks (26) of over 75% for
every site for smoking and alcohol together. Smoking, however,
showed a higher attributable risk than alcohol for cancers of
the oral cavity (76% versus 55%), pharynx (69% versus 45%),
and larynx (70% versus 26%). For cancer of the esophagus,
alcohol showed a slightly higher attributable risk than smoking
(52% versus 40%).
As noted by a number of investigators (10, 15, 25), the
implication of an interaction between smoking and alcohol,
which appears to be, on the whole, greater than additive, is a
reduction in the occurrence of cancers of the upper aerodigestive
tract by eliminating or moderating one or the other of these
high-risk behaviors. In northern Italy, where both smoking and
heavy alcohol consumption are widespread (36, 43, 44), public
health interventions to discourage smoking and heavy drinking
have a great potential to result in gains to society in terms of
reductions in cancer morbidity and mortality.
).
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
ACKNOWLEDGMENTS
The authors wish to thank Tiziana Angelin and Derna Gerdol for
interviewing patients and Anna Redivo for editorial assistance.
27.
28.
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Smoking and Drinking in Relation to Cancers of the Oral Cavity,
Pharynx, Larynx, and Esophagus in Northern Italy
Silvia Franceschi, Renato Talamini, Salvatore Barra, et al.
Cancer Res 1990;50:6502-6507.
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