Publication of the International Union Against Cancer ?.@-&3 Publication de I Union Internalionale Contre le Cancer Int. J . Cancer: 42,325-328 (1988) 0 1988 Alan R. Liss, Inc.

CIGARETTE SMOKING, ALCOHOL CONSUMPTION AND PRIMARY LIVER CANCER: A CASE-CONTROL STUDY IN THE USA He YLJ, Randall E. HARRIS, Geoffrey C. KABAT and Ernst L. WYNDER Amencan Health Foundation, 320 East 43rd Street, New York, NY 10017, USA.

Cigarette smoking and alcohol consumption were examined as potential risk factors in a case-control study of primary liver cancer (PLC). A total of 165 PLC cases and 465 matched controls from several US hospitals were studied. A weak but statistically significant (p < 0.05) doseresponse relationship was observed between alcohol consumption and PLC in el- derly females independent of other major risk factors (ad- justed O R = 1.87 and 3.48 for 1-2 and > 3 drinks per day, respectively) and a similar trend was evident in elderly males. The risk for PLC was also elevated in elderly females who were current cigarette smokers (adjusted O R = 3.30). Our results suggest that alcohol consumption and cigarette smok- ing may have minor age- and sex-specific effects on the devel- opment of PLC, and underscore the need for further investigations to elucidate major PLC risk factors in US populations.

Trichopoulos el al. (1980) and later Lam et al. (1982) re- ported that cigarette smoking may be a risk factor in primary liver cancer (PLC) in populations with no evidence of hepatitis B virus infection. Since then, 6 casecontrol studies and 3 prospective studies of this association have been conducted, but with inconsistent results. Studies of populations in Greece (Trichopoulos et al., 1980), Hong Kong (Lam et al., 1982), Los Angeles (Yu et al., 1983), Shanghai (Tu et a f . , 1985), and Japan (Oshima et af., 1984) show a positive association be- tween PLC and smoking, whereas study populations from the eastern US (Austin et al., 1986), Italy (Filippazzo et al., 1985), Sweden (Hardell et al., 1984) and Southern Africa (Kew er a f . , 1985) do not. Trichopoulos et al. (1980) and Lam er a f . (1982) found a positive relation only in HBV non- infected individuals, whereas Tu et a f . (1985) and Oshima e? al. (1984) demonstrated the association in HBV carriers.

Chronic alcohol abuse and alcoholic cirrhosis of the liver have long been suspected as major events in the pathogenesis of PLC. This etiologic sequence is supported by case-control studies, primarily in Western countries (Yu et al., 1983; Aus- tin et al., 1986; Filippazzo et af., 1985; Hardell et a f . , 1984), and prospective studies in Japan (Oshima et al., 1984; Inaba et al., 1984; Shibata et al., 1986) in which the odds ratios for PLC were elevated with chronic alcohol abuse. In contrast, case-control studies carried out in parts of Asia with high incidence rates of PLC, such as Hong Kong (Lam er al., 1982) and Shanghai (Tu e? al., 1985), and in Africa (Gelfand et al . , 1972) have failed to demonstrate a relationship between alco- hol and this disease. The disparity between results from differ- ent nations suggests that PLC may be conditioned by different risk factors, depending upon the geographic area.

In the current study we examined alcohol consumption and cigarette smoking as risk factors in PLC utilizing the case- control method. Our study population comprises patients from US hospitals.

SUBJECTS AND METHODS

A total of 165 patients with PLC (ICD-155) and 465 suitable hospital controls were identified from a large computerized registry of medical data from hospital patients compiled by the American Health Foundation. This registry is maintained as an integral part of an ongoing case-control study of tobacco-

related illnesses (Wynder and Stellman, 1977). These patients were identified during 1969-1985, from primary care hospitals in Chicago, New York, Philadelphia, Detroit, Pittsburgh and Los Angeles. At least 2 and in most instances 3 controls were identified for each case, being matched for age at diagnosis, sex, race, hospital, and year of interview. Our choice of hospital controls rests on the assumption that there is no association between the study exposure, i . e . , cigarette smok- ing and alcohol consumption, and the diseases that resulted in hospitalization of the control subjects. The group of control patients excluded individuals with a current diagnosis of to- bacco and alcohol-related cancers (viz., cancers of the respi- ratory system, buccal cavity, esophagus, bladder, and pan- creas), and other diseases ( v i z . , stroke, cirrhosis, chronic bron- chitis and emphysema, and cardiovascular disease).

All patients were interviewed at the time of diagnosis and hospitalization by a trained interviewer utilizing a structured questionnaire, which contains information on the following aspects: demographic characteristics including ethnic group, religion, and years of education; occupational status classified into 4 groups (career-oriented professions, skilled labor, un- skilled labor, and others); history of tobacco smoking and alcohol consumption which included type of smoking (ciga- rette, pipe or cigar) and drinking (beer, wine or whiskey), usual number of cigarettes, pipes or cigars smoked per day, usual amount of alcohol consumed per day, and years of duration of smoking and drinking. Reported consumption of 3 alcoholic beverages was converted into whiskey equivalents [whiskey equivalents = beer amount (oz./day)/8 + wine amount (oz./day)/4 + whiskey amount (oz./day)], and cate- gorized into 3 groups: less than 1 oz./day (or drinkslday), 1- 2 oz./day, and more than 3 oz./day. Cigarette smoking was categorized into 3 groups in quality: never smoker, ex-smoker (having given up smoking more than 1 year previously), and current smoker; and 2 groups in quantity: less than 20 ciga- rettes per day (cpd) and more than 20 cpd.

The effects of alcohol consumption and cigarette smoking on PLC risk were measured by odds ratios and 95% confi- dence intervals (Schlesselman et a f . , 1982). Pertinent risk factors and dose-response relationships were examined by subgroup analysis (Rothman and Boice, 1979). Multiple logis- tic regression models were utilized to yield estimates of odds ratios with simultaneous adjustment for age at diagnosis, ethnic group, education, occupation, and religion (Prentice, 1976).

RESULTS

Table I shows the distributions of age at diagnosis, ethnic origin, years of education, religion, and occupation among the 165 PLC cases and 465 matched controls. Of the cases, 92 were male and 73 were female, with a sex ratio of 1.3. Age of onset distributions were similar for males and females, ranging from 21 to 86 years, with most of the cases occurring in the 5th and 6th decades. Frequency distributions by ethnic origin were also similar for males and females. Overall, 85% of the

Received: December 18, 1987 and in revised form February 22, 1988.

326 YU ET AL.

TABLE I - THE DISTRIBUTION OF DEMOGRAPHIC FACTORS BETWEEN PLC CASES AND CONTROLS

Features Females (n=73) Males (n=92)

Cases Controls Cases Controls Number % Number % Number % Number Sb

Age 20-29 30-39 40-49 50-59

70 + Ethnic origin

Caucasian Black Others

< 12 yrs. 12-15 yrs. > 15 yrs.

Protestant Catholic Jewish Others

Occupation Professional Skilled labor Unskilled labor Others

60-69

Years of education

Religion

4 4.4 10 10.9 10 10.9 25 27.2 28 30.4 15 16.2

76 82.6 11 12.0 5 5.4

25 27.2 37 40.2 30 32.6

41 44.6 37 40.2 10 10.9 4 4.3

32 34.8 18 19.6 26 28.3 16 17.3

1 1 28 31 80 71 42

227 28 8

98 86 79

102 95 35 31

79 46 71 67

4.2 5 6.9 13 10.7 9 12.3 16 11.8 9 12.3 35 30.3 21 28.8 56 27.0 19 26.0 60 16.0 10 13.7 22

86.2 65 89.0 184 10.7 7 9.6 15 3.1 1 1.4 3

37.3 21 28.8 58 32.7 39 53.4 113 30.0 13 17.8 31

38.8 31 42.5 75 36. I 28 38.4 84 13.3 8 11.0 31 11.8 6 8.1 12

30.0 9 12.3 30 17.5 20 27.5 55 27.0 9 12.3 23 25.5 35 47.9 94

6.4 7.9

17.3 27.7 29.7 11.0

91.1 7.4 1.5

28.7 55.9 15.4

37.1 41.6 15.4 5.9

14.9 27.2 11.4

TABLE I1 - THE RELATIONSHIP BETWEEN CIGARETTE SMOKING AND PRIMARY LIVER CANCER

Smoking Tofal < 50 yrs. old >50 yrs. old status Cases Controls OR Cases Controls OR Cases Controls OR

Male 23 1.00 12 38 1 13 0.66 29 72 I 34 1.10 27 81 1

Never 20 61 1.00 8 Ex 32 85 1.15 3 Current 40 115 1.06 13

Female

.00

.28

.06

28 1.00 21 85 1.00 5 I I 1.27 7 26 1.09

Never 31 113 1.00 10 Ex 12 37 1.18 Current 30 52 2.10'** 8 25 0.90 22 27 3.30'.*

'OR is statistically significant @<0.05).-'Tesr for trend is statistically significant @<0.05).

cases were Caucasian and 11% were Black. No statistically significant differences between cases and controls were found in the frequency distributions of education, religion, and occupation.

Table I1 shows the odds ratios of PLC for ex-smokers and current smokers in relation to never-smokers with stratifica- tion by sex and age. Results show a significant effect of smoking only in females above 50 years of age (OR = 3.30, 95% CI = 1.48-7.93). Categorization of the individuals in this particular subgroup by the number of cigarettes smoked per day (cpd) revealed a significant dose-response, i .e . , the odds ratios corresponding to <20 and >20 cpd were 2.73

respectively. The magnitude and statistical significance of these odds ratios remained unchanged after simultaneous adjustment for age, ethnic origin, religion, year of education, occupation, alcohol consumption, and the interaction of smoking with drinking entered as a cross-product term, in a multiple logistic regression model.

Table III shows the odds ratios of PLC for different levels of alcohol consumption with stratification by sex and age. Results are given to compare 1-2 and > 3 drinks per day with ingestion of lower amounts of alcohol. These data suggest a

(95% CI = 1.08-8.84) and 4.07 (95% CI = 1.32-9.23),

dose-response in both males and females above age 50, but no effect in individuals below age 50. The pattern was strongest in elderly females (ORs = 1.87 and 3.48 for 1-2 and > 3 drinks per day, respectively, p < 0.05 by a Chi-square test for trend). The corresponding trend in males was in the same direction but was not statistically significant (ORs = 1.13 and 1.38, p = 0.20 by a Chi-square test for trend). Considering both sexes, individuals >50 years of age show a trend ap- proaching statistical significance. i .e . , ORs = 1.37 and 1.63 for 1-2 and > 3 drinks per day, respectively, p < O . 10 by a Chi-square test for trend. When the 2 groups (1-2 and > 3 drinks per day) were combined in females aged > 50, the odds ratio for > 1 drink per day vs. < 1 drink per day became statistically significant (OR=2.10, 95% CI= 1.00-4.46). Odds ratios adjusted by multiple logistic regression for age, ethnic origin, religion, years of education, occupation, smoking sta- tus, and the interaction between drinking and smoking, did not differ appreciably from the crude estimates.

DISCUSSION

In our study, the ratio of male to female cases was 1.3 (92:73); 1.2 (76:65) for Whites and 1.6 (11:7) for Blacks,

SMOKING, ALCOHOL A N D PRIMARY LIVER CANCER

TABLE 111 - THE RELATIONSHIP BETWEEN ALCOHOL CONSUMPTION AND PRIMARY LIVER CANCER

321

Drinking Total <50yrs. old >50 yrs. old Status* Cases Controls OR Cases Controls OR Cases Controls OR

Male 0- 33 103 1 .00 9 24 1.00 24 79 1 .00 1 - 31 93 1.04 10 32 0.83 21 61 1.13 3- 23 56 1.28 5 13 1.03 18 43 1.38

0- 42 135 1.00 13 34 1.00 29 101 1 .00 1 - 24 52 1.48 9 24 0.98 15 28 1.87 3- 6 10 1.93 1 5 0.52 5 5 3.48'

'Test for trend is statistically significant @<0.05).-'Drinking status is classified according to ounces of whiskey equivalents

Female

consumed per day.

which is slightly lower than expected. Examination of US incidence data (SEER) (National Institutes of Health, 1981) reveals a sex ratio of 2.5 for all ethnic origins (2.2 for Whites and 2.5 for Blacks). The relatively low sex ratio of cases in our study could be due to different referral patterns or differ- ences in exposure to risk factors between the 2 sexes in the metropolitan area sampled. However, in view of the variation in the sex ratio (from 1.1 to 5.1) among SEER reporting centers, it is also possible that the low sex ratio was produced by chance.

Chronic infection with hepatitis B virus (HBV) is known to be a major risk factor in the development of PLC (Beasley et al . , 1981). Since we did not have data on HBV infection, the derived odds ratios relating cigarette smoking and alcohol consumption to the development of PLC could not be adjusted for HBV seropositivity. Cautious interpretation of the findings is therefore warranted.

Table IV summarizes the current literature on the relation- ship between cigarette smoking and PLC. Of the 11 published studies, 5 showed an elevated risk for PLC in cigarette smok- ers, but the relative risk is not particularly high, ranging from 2.6 to 5.8. Our results demonstrate a modest effect of only current cigarette smoking on PLC, specific for females over 50 years of age (OR = 3.3, ~ ~ 0 . 0 5 ) . There was no associa- tion between cigarette smoking and PLC in males, irrespective of age, or in females under 50 years of age. Lam et al. (1982) also found an association between cigarette smoking and PLC in HBsAg-negative patients over age 50, and Trichopoulos et al. (1980) reported a stronger association among persons over 60 years of age. However, sex-specific estimates were not presented in either of these reports.

A weak association between cigarette smoking and PLC in older age groups has been observed in several studies, includ- ing our own (Trichopoulos et al., 1980; Lam et al . , 1982). One possible explanation for this age-specific effect may be that PLC in young patients may result from exposure to strong risk factors, such as HBV andlor aflatoxins, which in turn shorten the course of pathogenesis, whereas PLC development in older patients may be the result of weaker etiologic factors which lead to a slower progression of antecedent events in the development of PLC. It may also be important to consider the starting age at exposure to different risk factors in an individ- ual's life-time, which, consequently, may shift the course of pathogenesis forward or backward. For example, people may be exposed to HBV and/or aflatoxins early in life, but typically are not exposed to tobacco and alcohol until adulthood.

The positive association between PLC and cigarette smoking in elderly females and the complete absence of any association in younger patients or in males of any age in our study suggests that the effect of cigarette smoking on PLC is influenced by sex as well as age. The only other study in which a sufficient number of patients was examined to allow stratification by sex was that of Stemhagen et al. (1983) in which no effect of

T.4BLE 1V - SUMMARY OF STUDIES ON CIGARETTE SMOKING AND PRIMARY LIVER CANCER

Type of Number of RR and study cases 95% CI Author and place

Trichopoulos ef al. , 1980

Lam et al., 1982 Greece

Hong Kong Yu et al . , 1983

USA Oshima ef al., 1984

Japan Tu et al., 1985

China

Japan

USA

Shibata et nl., 1986

Stemhagen ec al., 1983

Filippazzo el al. , 1985

Austin ef al., 1986

Kew et al., 1985 South Africa

Hardell et al., 1984

Italy

USA

Sweden

Case- 79

Case- 107

Case- 78

Cohort 20

Cohort 70

Cohort 22

Case- 265

Case- 120

Case- 86

Case- 240

Case- 102

control

control

control

control

control

control

control

control

5.5(2.0-15.6)

3.3(1.0-13.4)

2.6( 1 .O-6.7)

5.8( 1 .O-34.2)

4.6@<0.05)

4.8'

0.7(0.5-l.l)M l.O(O.6-1.7)F O.S(O.4-1.5)

1.6(0.7-3.7)

No association

No association

'Relative risk was reduced after controlling for alcohol consumption

cigarette smoking was observed in either sex. The female- specific effect of cigarette smoking on PLC observed in our study is a novel finding and will require further investigation to confirm.

Alcohol has been convincingly shown to be an important risk factor in the development of PLC, with risk estimates ranging from 3.2 to 8.0 (Table V). In our study, a significant dose-response was found in elderly females and a weaker dose-response pattern was evident among elderly males. Spe- cifically, females over age 50 who ingested more than one drink per day had an approximately 2-fold increase in risk in relation to individuals who consumed lesser amounts. Of the studies listed in Table V, that of Stemhagen et al. (1983) is the only one in which the results are given by sex. These authors found that the highest odds ratios occurred in female alcoholics (OR=8.4). The results of our study are therefore similar to theirs but less dramatic, viz., a dose-response relationship was evident between alcohol and PLC only in females, and the strongest effect of alcohol was present in females who were heavy drinkers ( > 3 drinks per day, OR=3.5).

Effects of cigarette smoking on PLC may be correlated with effects of alcohol consumption, and vice versa; i .e . , there may be an effect modification between these 2 risk factors. Shibata et al. (1986) showed that the association between PLC and cigarette smoking disappeared after controlling for alcohol consumption; likewise, Austin et al. (1986) found that the

328 YU ET AL

TABLE V - SUMMARY OF THE STUDIES ON ALCOHOL CONSUMPTION AND PRIMARY LIVER CANCER

Type of Number of Relative study cases risk Author and place

Sternhagen et nl., 1983

Yu et al., 1983

Austin e t a / . , 1986

Bulatao-Jayme et a/. , 1982

Oshima et al., 1984

Inaba et a]. , 1984

Filippazzo er al., 1985

Shibata et a / . , 1986

USA

USA

USA

Philippines

Japan

Japan

Italy

Case- 265 2.O(M) control 5.6(F)

Case- 78 4.2 control

Case- 86 3.3' control

Case- 90 4.1' control

Cohort 20 8.0'

Case- 62 3.2 '

Case- 120 3.2' control

control Cohort 22 5.1'

Japan

Sweden control Hardell et d., 1984 Case- 102 4.3'

'Statistical significance of relative risk estimate at p <0.05.

association of cigarette smoking and PLC was weakened by adjustment for alcohol consumption. In contrast, Yu et al. (1983) found that the association between PLC and cigarette smoking was independent of alcohol. In these 3 studies, the positive effect of alcohol on PLC retained statistical signifi- cance after adjustment for cigarette smoking. In our investi- gation, odds ratios due to alcohol or cigarette smoking were only slightly reduced by adjustment for the other factor, which suggests that each of these risk factors has an effect on PLC risk which is independent of the other.

Differences in study design, sample size, composition of the

population sampled, selection of controls, and type and accu- racy of data collected may all contribute to inconsistencies among the studies of PLC and risk factors. An important limitation in our study and some others is the absence of data on HBV; i . e . , our estimates of odds ratios due to cigarette smoking and alcohol consumption are not controlled for HBV seropositivity. An example of the potential effect of HBV is given by Inaba et al. (1984), who reported that alcohol inter- acts synergistically with HBV seropositivity in the develop- ment of PLC.

In conclusion, our results support the role of alcohol con- sumption as a probable minor risk factor in the development of primary liver cancer in elderly patients, and principally in females. Our findings also support a weak positive association between PLC and cigarette smoking, but this effect was spe- cific for elderly females only. Since PLC risk factors may be sex- and age-specific, we suggest the need for further investi- gations with a sufficient number of cases to stratify results by age and sex, in addition to serologic data in order to test for the effects of alcohol, smoking, HBV, and interactions among these primary risk factors. In view of these findings, we emphasize that factors other than cigarette smoking and alco- hol consumption need to be elucidated to account for the pathogenesis of PLC in US populations.

ACKNOWLEDGEMENTS

This work was supported by the National Cancer Institute and the American Cancer Society. Dr. He Yu is supported by a fellowship from the US Summit Corporation. The authors also thank Dr. J.R. Hebert and Dr. C. La Vecchia for review- ing an early draft of the paper, as well as Ms. V. Liang and Ms. E. Chung for assistance with computer programming.

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