Int. J. Cancer: 52,562-565 (1992) 0 1992 Wiley-Liss, Inc.
Publication of the InternationalUnion Against Cancer Publicationde I’Union lnternatlonaleContre le Cancer
RISK FACTORS FOR RENAL-CELL CANCER IN SHANGHAI, CHINA Joseph K. MCLAIJCHLIN’~~, Yu-Tang G A O ~ Ru-Nie , GAO?, Wei ZHENG’,Bu-Tian JI?, William J. BLOT] JR.’ and Joseph F. FRAUMENI, ‘National Cancer Institute, Division of Cancer Etiology, Epidemiology and Biostatistics Program, Bethesda, M D 20852, USA; and ?Shanghai Cancer Institute, Department of Epidemiology, Shanghai, People’s Republic of China. A population-based case-control study of I54 histologically verified renal-cell cancer patients and 157 controls was performed in Shanghai, China, an area with low rates for this tumor. Elevated risks were observed for cigarette smoking (odds ratio (OR) = 2.3; 95% confidence interval (CI): I. I to 4.9), and for increasingcategories of body weight and meat consumption, while reduced risks were seen for increasing categories of fruit and vegetable intake. An increased risk was also observed for regular use of phenacetin-containing analgesics (OR = 2.3; 95% Ck0.7 to 7.0). These findings are consistent with earlier studies in Western countries, and indicate that many of the same etiologic factors for renal-cell cancer operate in low- and high-risk societies.
o 1992 Wiley-Liss,Inc.
Renal-cell cancer is a relatively rare neoplasm in Shanghai, the largest city in China, although its incidence has increased since the mid-1960s (Muir et al., 1987; Shanghai Cancer Registry, 1991). During the period 1978-1982, there were 1.8 cases of renal-cell cancer per 100,000 men and 1.0 per 100,000 women in Shanghai, whereas in the United States the rates were 7.1 per 100,000 men and 3.3 per 100,000 women (adjusted to world standard population) (McLaughlin et al., 1993). Virtually all etiologic studies of renal-cell cancer have been conducted in Western countries, with cigarette smoking and obesity being the most consistently reported risk factors (McLaughlin et al., 1993). Other factors associated with renal-cell cancer include high intake of meat (McLaughlin et al., 1984; Maclure and Willett, 1990) and fat (Talamini et al., 1990), exposure to asbestos (Selikoff et al., 1979; Maclure, 1987), use of prescription diuretics (Yu et al., 1986; McLaughlin et al., 1988), and heavy use of phenacetin-containing analgesics (McLaughlin et al., 1985; Maclure and MacMahon, 1985; McCredie et al., 1988). To investigate risk factors of renal-cell cancer in an area at low risk for this tumor, a population-based case-control study was conducted in Shanghai during the period 1987 to 1989. MATERIAL AND METHODS
All residents of urban Shanghai aged 35 to 74 years who were newly diagnosed with renal-cell cancer (9th Revision ICD 189.0) during the period January 1, 1987, to October 31, 1989, were eligible for study. A total of 223 cases were identified from the population-based cancer registry in Shanghai during this period. The registry, which started operation in 1963 and is a collaborating center of the International Agency for Research on Cancer (Muir et al., 1987), has essentially complete ascertainment of all cancer cases occurring in the urban Shanghai area. Of the cases identified, 195 (87%) were interviewed, while 28 (13%) either refused or could not be located. Microscopic confirmation was collected in 154 (79%) of 195 cases. The analysis was restricted to histologically confirmed cases. Controls were randomly selected from the general population of the Shanghai urban area. The number of controls in each sex- and age (5-year interval)-specific stratum was determined in advance according to the sex and age distribution of the incident cases of renal-cell cancer reported to the Shanghai Cancer Registry from 1982 to 1984. Personal identification cards from the Shanghai Resident Registry were used to select
controls. For all adult residents in urban Shanghai, the cards contain information on name, address, date of birth, sex and other demographic factors. The cards are kept in drawers, with approximately equal numbers of cards in each drawer. Each drawer is numbered by an unique 4-digit code. For each control, a 4-digit random number was generated to define the drawer from which the control was randomly selected. Interviews were obtained for all 157 identified controls. Cases and controls were interviewed in person by trained personnel, usually in the subject’s home. A structured questionnaire was used to elicit detailed information on a number of factors, including demographic variables, tobacco smoking, alcohol consumption, dietary habits, height and body weight, history of previous disease and medications, and occupational history and exposures. Next-of-kin interviews were conducted for 35 cases and 13 controls who had died or were too ill at the time of interview. Since the results from subjects directly interviewed were similar to those from next-of-kin interviews, the results were combined in this paper. The relative risk of renal-cell cancer in this analysis was estimated by the odds ratio ( O R ) (Breslow and Day, 1980). To control for confounding factors, we calculated summary ORs by the maximum-likelihood method, with confidence intervals derived from modification of Cornfield’s method (Cart, 1970), and by logistic-regression modelling (Breslow and Day, 1980). The test for linear trend (one-tailed) was the Mantel extension of the Mantel-Haenszel procedure (Mantel, 1963). Body-mass index (BMI) was used as a measure of obesity, with weight measured in kilograms and height in meters. Diet was assessed using 65 food frequency items for usual adulthood diet prior to 1985. All quartiles used in this analysis were sex-specific and based on the distribution of values among the controls.
RESULTS
The 154 cases (90 men, 64 women) and 157 controls (91 men, 66 women) were similar in age and marital status. The average age at diagnosis was 60 years for men and 61 for women. Cases of both sexes, however, were significantly more educated than controls, with 42% of the cases vs. 20% of the controls having 10 or more years of education. Cigarette smoking was associated with elevated risk of renal-cell cancer among men, with O R of 2.3 (95% CI 1.1 to 4.9) for ever vs. never smoking after adjusting for age and education (Table I). The O R was higher among men who smoked only non-filtered cigarettes ( O R 5.2; 95% CI 1.8 to 15.6). A strong dose-response relationship with pack-years of cigarette smoking was seen among men who smoked only non-filtered cigarettes; but when all smokers were combined the trend was no longer apparent (Table 11). The risk for cigarette smoking was not calculated among women, since few women were regular smokers (6 cases and 11 controls).
)To whom correspondence and reprint requests should be addressed, at National Cancer Institute, EPNi415. Bethesda, MD, USA. Received: April 27,1992 and in revised form June 15, 1992.
563
RENAL-CELL CANCER IN SHANGHAI
Table I11 presents the association between renal-cell cancer and relative weight, as measured by the BMI among both men and women for weight at age 40 and age 50. Cases and controls were categorized according to the sex-specific quartile distributions of BMI among controls. Elevated risks were observed with increasing BMI for men and women, although the trend was not consistently monotonic. BMI for other decades of life showed similar dose-response gradients, except at age 20, when there was no relationship to risk. When the BMI results for the top 10% of subjects at age 40 were compared with the lowest BMI quartile, the O R was 4.6 (95% CI 1.1 to 21.3) and 6.9 (95% CI 1.3 to 42.9) for men and women respectively. Some increase in risk was associated with use of oral contraceptives (OR 1.6; 95% CI 0.5 to 5.2) and menopausal hormones (OR 1.9; 95% CI 0.4 to 8.3). Women who used birth-control pills for 2 years or longer had a 2.9-foldincreased risk (95% CI 0.7 to 12.9, but information was too sparse to examine the effect of duration of use. Risks were not associated with number of pregnancies or with histories of hysterectomy (OR 0.9; 95% CI 0.2 to 3.7) or oophorectomy (OR 1.0; 95% CI 0.2 to 4.3). However, risks were lower for those having hysterectomies under age 45 (OR 0.5; 95% CI 0.0 to 3.2) than for women having this operation at age 45 or older (OR 2.5; 95% CI 0.2 to 25.8). The effect of age at oophorectomy could TABLE I - ODDS RATIO (OR) OF RENAL-CELL CANCER FOR CIGARETTE SMOKING AMONG MEN IN SHANGHAI. CHINA statu\
Cases
Controls
OR'
Y55%Cc12
Never smoked cigarettes Ever smoked cigarettes Non-filtered only
23 67 31
34 57 11
1.0 2.3 5.2
1.1-4.9 1.8-15.6
-
'Adjusted for age and education.-TI, confidence interval.
not be evaluated due to missing data on age among the few subjects who underwent this procedure. Age at menarche showed some relation to risk. Compared with women who started menarche over the age of 17, women who began at 13 years of age or younger had an O R of 1.7 (95% CI 0.1 to 24.8). Age at menopause was unrelated to risk. The questionnaire assessed diuretic use, which was limited in Shanghai. The medication most commonly reported as a diuretic had 10 ingredients, including a small amount of diuretic (3.1 mg of hydrochlorothiazide), 2 anti-hypertensive agents (reserpine and dihydralazine sulfate), promethazine, diazepam, vitamins and minerals. The OR for men regularly taking this drug (defined as at least twice per week for 2 weeks or longer) was 1.3 (95% CI 0.2 to 7.1) after adjustment for age, education, BMI, hypertension, and cigarette smoking; and for women the O R was 2.9 (95% CI 0.7 to 13.1) after adjustment for age, education, BMI and hypertension. Since some patients with renal-cell cancer develop hypertension secondary to the tumor, cases and controls who started taking this drug within 5 years of the cancer diagnosis or the interview were excluded, with little effect on the results. Regular consumption of analgesics (defined as at least twice per week for 2 weeks or longer) was uncommon in Shanghai, but regular use of phenacetin-containing analgesics did confer an increased risk ( O R 2.3; 95% CI 0.7 to 7.0) after adjustment for age, sex, education, BMI and cigarette smoking. The O R associated with regular use of non-phenacetin analgesics was 1.6 (95% CI 0.4 to 6.4). Among the drugs inquired about in the questionnaire, few contained aspirin (acetylsalicylic acid), and only one contained acetaminophen, which no subject reported using. Information on history of previous diseases, such as hypertension, diabetes, and diseases of the heart, kidney and
TABLE I1 ODDS RATIO (OR) OF RENAL-CELL CANCER FOR PACK-YEARS OF CIGARETTES BY TYPE ~
OF CIGARETTE AMONG MEN IN SHANGHAI. CHINA ~~
~~
~
All types of cigarettes
Non-filtered cigarettes Pack-vearr
Casea
Controls
None 1-10 11-20 > 20 ( p for trend)
23 8 5 18
34
5 2 4 (p
OR'
1.0 1.9 6.3 9.3 < 0.001)
Y5%C12
Case7
Controls
-
23 20 14 33
34 12 11 34
0.4-9.3 0.8-67.0 2.1-45.2
OR1
9S% CI2
1.0 2.8 2.6 1.9 (p = 0.08)
0.9-8.9 0.8-8.7 0.84.5
-
'Adjusted for age and education.-'CI, confidence interval. TABLE 111 - ODDS RATIO (OR) OF RENAL-CELL CANCER FOR BODY-MASS INDEX (BMI) FOR WEIGHT AT AGES 4DAND SO AMONG MEN AND WOMEN IN SHANGHAI. CHINA Women?
Men' ~~
BM1 Level
I (low) I1 111 IV (high) (JI for trend)
I (low) I1 111
IV (high) (0for trend)
Cases
Controls
10 20 21 31
20 21 22 23
13 16 19 28
19 21 19 20
OR'
1.0 3.3 2.3 3.6 (p = 0.009)
(D
1.0 1.4 2.1 1.7 = 0.03)
Y5% CI'
Cases
Control5
OR'
Weight at age 40 8 0.8-14.0 15 0.7-8.5 13 1.1-12.6 23
15 14 16 16
0.6-10.9 0.5-7.7 0.9-14.7
Weight at age 50 7 0.4-5.0 17 0.7-10.9 10 0.5-5.7 19
14 15 15 14
0.5-8.2 0.2-4.9 0.7-15.1
1.0 2.6 1.8 3.6 (p = 0.03) 1.0 2.0 1.1 3.3 f D = 0.09)
-
'BMI = wih'; levels for age 40: I, 5 19; 11, 19.1-20.8; 111, 20.9-22.3; IV, > 22.3; for age 50: I, 519.7; 11, 19.8-21.9; 111, 22.0-23.3; IV, >23.3.2BMI = w/h15; levels for age 40: I, 123.7; 11, 23.8-26.7; 111, 26.8-29.2; IV, >29.2; for age 50: I, 524.4; 11, 24.5-27.4; 111, 27.5-30.6; IV, > 30.6.-3Adjusted for age, education and cigarette ~moking.-~CI, confidence interval.-5Adjusted for age and education.
564
McLAUGHLIN E T A L .
thyroid, was also obtained in this study. The diseases were those diagnosed by a physician 2 years prior to the cancer diagnosis for cases or the interview for controls. Only hypertension was associated with a significantly elevated risk. After adjustment for age, education, BMI, blood-pressure medication and smoking, men had an OR of 7.9 (95% CI 2.1 to 29.3) and women an OR of 2.9 (95% CI 0.9 to 9.3). Since renal tumors can cause hypertension, cases and controls who were diagnosed with hypertension within 5 years of the cancer diagnosis or interview were excluded, but there was little change in the risk estimates. Table IV presents OR of renal-cell cancer according to intake of various food groups. Among men, meat consumption was associated with increasing risk, and intake of fruits and vegetables with decreasing risk. Results among women were not as clear-cut, with few food groups showing a strong dose-response gradient, although fruit intake was suggestively related to a reduced risk. Intake of allium (onion, garlic, chives) or cruciferous vegetables (cabbage, cauliflower and Chinese cabbage) did not affect risk. No significant casecontrol differences were seen for consumption of tea, coffee or alcohol. Analysis of usual and most recent occupation revealed little difference between cases and controls in suspected a pn'on' activities such as dry cleaning (no subjects), gasoline-station attendant (0 cases, 1 control), and steel and coke-oven workers (OR 0.3; 95% CI 0.1-2.0). For exposure to a pion' high-risk materials such as asbestos there was no excess risk (OR 0.9; 95% CI 0.1-11.3); for solvents (OR 2.5; 95% CI 0.6-11.2) and gasoline (OR 1.6; 95% CI 0.64.7j, however, there was an increased risk.
obesity may act by promoting hormonal changes, such as increased levels of endogenous estrogens (McLaughlin et a/., 1984). Because little effect was observed for weight at age 20, weight gain during adulthood was chiefly responsible for the association with obesity, an observation seen elsewhere (McLaughlin et al., 1984). Although renal-cell cancer can be induced in certain laboratory animals by estrogens (McLaughlin et al., 1993) and one survey reported an increased risk among women taking menopausal estrogens (Asal et al., 1988), there has been little evidence for hormonal influences in epidemiologic studies (McLaughlin et al., 1993). We observed an increased risk for use of oral contraceptives and menopausal hormones, but the number of exposed cases and controls was limited and the excesses were not significant. A reduced risk for women who had a hysterectomy under the age of 45 and an increased risk for women who started menarche at age 13 years or younger suggest a role for endogenous estrogens, but no relation was seen with number of pregnancies, oophorectomy, or age at menopause. The associations we observed with hormonal factors are not consistent with earlier, larger studies and should be interpreted cautiously. A relation between intake of phenacetin-containing analgesics and renal-cell cancer was first reported in Minnesota (McLaughlin et al., 1984, 1985a) and supported by findings in Massachusetts (Maclure and MacMahon, 1985), Australia (McCredie rt al., 1988), and now in China. Phenacetin was withdrawn from use in the United States and other Western countries in the 1970s, when it was linked to tubulo-interstitial nephropathy and cancers of the renal pelvis and ureter, but it can still be purchased today in Shanghai. Although epidemiologic studies (Yu et a!., 1986; McLaughlin et al., 1988) have found an association between diuretic use and renal-cell cancer, we were unable to evaluate this issue adequately in Shanghai, due to few subjects using drugs that contained only a diuretic. Almost all subjects used one particular product containing many active ingredients, including reserpine, dihydralazine sulfate, diazepam, promethazine, plus a small amount of the diuretic, hydrochlorothiazide (3.1 mg), well below the minimal effective therapeutic dose of 25 mg (Gilman et al., 1985). After adjustment for confounding variables including hypertension, we observed a nearly 3-fold increased risk among female users, although the increase did not reach statistical significance. Excluding subjects who started using this drug within 5 years of the cancer diagnosis or the interview did not change the results. Although we cannot evaluate the risk of diuretics separately from other agents in
DISCUSSION
In Shanghai, an area at low risk for renal-cell cancer, we confirmed the association between cigarette smoking and renal-cell cancer observed in Western countries (McLaughlin et al., 1993). The finding adds to the evidence that cigarette smoking is causally related to this cancer (McLaughlin et al., 1990). The stronger effect for non-filtered cigarettes probably reflects their high tar content. Our results for cigarettes were based on men, since the small number of women smokers precluded a meaningful evaluation of risk. Virtually all studies of renal-cell cancer have found a positive association with obesity, which is more pronounced among women than men (McLaughlin et al., 1993). We also found that risk of renal-cell cancer increased with increasing relative weight as measured by the BMI among both men and women. The mechanism for the association is unclear, but
TABLE IV - ODDS RATIO (OR) OF RENAL-CELL CANCER FOR FOOD GROUPS AMONG MEN AND WOMEN IN SHANGHAI, CHINA Consumption
Meat
levels
OR
I (low) I1 I11 1V (high) ( p for trend)
1.o
3.5 1.3-9.8 3.2 1.1-9.3 4.0 1.4-11.4 (p = 0.005)
I (low) I1
1.o 0.9 1.5
111
IV (high) ( p for (rend)
95WCI'
0.3-2.8 0.6-4.3 0.4-3.6 1.3 ( p = 0.11)
Fruits
Fish
OR
95%C11
1.o 0.5 0.2-1.4 0.9 0.4-2.1 0.4 0.2-1.0 (p = 0.11)
Men'
Vegetables
OR
95%CI'
1.o
-
0.5 0.2-1.1 0.3 0.1-0.8 0.2 0.0-0.5 (p < 0.001) Women3 1.0 1.0 1.0 0.4-2.8 1.3 0.5-3.8 1.1 0.4-2.9 0.9 0.3-2.6 0.7 0.2-2.1 0.7 0.2-2.0 (p = 0.20) (p = 0.07)
OR
9S%CI'
1.o 0.9 0.4-2.1 0.4 0.2-1.0 0.3 0.1-0.7 (p = 0.01)
.o
-
1.7 0.7
0.64.8
1
0.2-2.1 0.6-4.6 (p = 0.33)
1.5
ICI, confidence interval.-'OR adjusted for age, education, cigarette smoking, and body-mass index.-jOR adjusted for age, education, and body-mass index.
RENAL-CELL CANCER IN SHANGHAI
our study, the excess risk associated with hypertension is consistent with earlier case-control studies (McLaughlin et a/., 1984; Yu et a/., 1986; Asal et a/., 1988; Maclure and Willett, 1990). The hypertension may be partly due to elevated levels of renin produced by the renal tumor via compression of adjacent tissue (McLaughlin eta/., 1993). The positive association we observed with meat intake is consistent with previous studies, suggesting the possible role of dietary fat or consequent obesity in the etiology of this cancer (McLaughlin et a/., 1984; Maclure and Willett, 1990; Talamini et a/., 1990). Further studies are needed, however, to evaluate whether the association operates through saturated fat or one of its correlates, such as protein or cooking-derived carcinogens, including heterocyclic aromatic amines (Adamson, 1990). In addition, decreased risk was associated with intake of fruit and vegetables, although the effect of vegetables appeared restricted to men. In earlier studies of renal-cell cancer, reduced risks were reported for vegetables (Maclure and Willett, 1990; Talamini et al., 1990), but not fruits. The protective effect of fruit and vegetables thus may apply to renal-cell cancer as well as several other sites of cancer (Steinmetz and Potter, 1992). The reason for the stronger
565
dietary findings among men than among women is not clear. In accordance with previous studies, we found no influence of coffee, tea, or alcohol intake on the risk of renal-cell cancer. Occupational analyses were hampered by the small number of exposed subjects, but we observed no elevated risk among asbestos-exposed workers, in contrast to earlier reports suggesting increased risk (Selikoff et a l , 1979; McLaughlin et al., 1993). Although not statistically significant, there was increased risk for exposure to gasoline (OR 1.6) and solvents (OR 2.5), consistent with some previous studies (McLaughlin et al., 1985b; Partanen et al., 1991). In summary, this population-based case-control study of renal-cell cancer in Shanghai revealed increased risk associated with cigarette smoking, obesity and high consumption of meat, and decreased risk with high consumption of fruits and vegetables, particularly among men. Increased risk was suggested in relation to regular use of phenacetin-containing drugs and to exogenous estrogen use and some hormonerelated variables. The study has identified risk factors in Shanghai similar to those in Western countries, and has provided further evidence for dietary determinants of renalcell cancer.
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ASAL,N.R., GEYER,J.R., RISSER,D.R., LEE, E.T.. KADAMANI, S. and CHEKNG, N., Risk factors in renal-cell carcinoma. 11. Medical history, occupation, multivariate analysis, and conclusions. Cancer Detect. Prev.. 13,263-279 (1988). BRESLOW,N.E. and DAY,N.E., Statistical methods in caticer research: analysis of case-confrolstudies. IARC Scientific Publication 32, IARC, Lyon (1980). GART,J.J., Point and interval estimation of common odds ratio in the combination of 2 x 2 tables with fixed marginals. Biometn'cs. 26, 409-416 (1970).
GILMAN,A.G., GOODMAN.L.S., RALL, T.W. and MURAD,F., The pharmacologic busis of therapeutics, 7th ed., p. 893, Macmillan. New York (1985). MACLURE,M.. Asbestos and renal adenocarcinoma: a case-control study. Emiron. Res., 42, 353-361 (1987). MACLURE,M. and MACMAHON,B., Phenacetin and cancer of the urinary tract. New EngI. J. Med.. 313,1479 (1985). MACLURE, M. and WILLETT, W.C.. A case-control study of diet and risk of renal adenocarcinoma. Cancer Causes and Control, 1, 430-440 (1990).
MANTEL,N., Chi-square tests with one degree of freedom. Extension of the Mantel-Haenszel procedure. J. Amer. Stat. Ass., 58, 690-700 (1963).
M C C R ~ D IM., E , FORD,J.M. and STEWART, J.H., Risk factors for cancer of the renal parenchyma. Int. J. Cancer, 42,13-16 (1988). MCLAUGHLIN, J.K.. BLOT,W.J., DEVESA,S.S. and FRAUMENI, J.F., JR.. Renal cancer. In: D. Schottenfeld and J.F. Fraumeni, Jr. (eds.), Cancer epidemiology and prevention, 2nd ed. Oxford University Press, New York (1YY3).
MCLAUGHLIN, J.K., BLOT,W.J. and FRAUMENI, J.F., JR., Diuretics and renal-cell cancer. J. nut. Cancer Inst., 80,378 (1988). MCLAUGHLIN, J.K., BLOT,W.J.. MEHL,E.S. and FRAUMENI, J.F., JR., Relation of analgesics use to renal cancer: population-based findings. Nut. Cancer Inst. Monogr., 69,213-215 (198.5~). MCLAUGHLIN, J.K.. BLOT,W.J., MEHL,E.S., STEWART, P.A., VENABLE, J.F., JR., Petroleum-related employment and F.S. and FRAUMENI. renal-cell cancer. J. occup. Med., 27,672-674 (19856). MCLAUGHLIN, J.K., HRUBEC,Z., HEINEMAN, E., BLOT, W.J. and FRAUMENI, J.F., JR., Renal cancer and cigarette smoking: 26-year follow-up of US veterans. Public Health Rep., 105,533-537 (1990). MCLAUGHLIN, J.K., MANDEL, J.S., BLOT,W.J., SCHUMAN, L.M., MEHL, J.F., JR., Population-based case-control study of E.S. and FRAUMENI, renal-cell carcin0ma.J. nut. Cancer Inst., 72,275-284 (1984). MUIR,C., WATERHOUSE, J., MACK,T., POWELL,J. and WHELAN,S., Cancer incidence in five continents, Volume V, IARC. Lyon (1987). PARTANEN, T., HEIKKILA, P., HERNBERG, S., KAUPPINEN, T., MONETA, G. and OJAJARVI, A., Renal-cell cancer and occupational ex osure to chemical agents. Scand. J. Work environ. Health, 17,231-239 6991). SELIKOFF, I.J., HAMMOND, E.C. and SEIDMAN, H., Mortality experience of insulation workers in the United States and Canada, 19431976.Ann. N.Y. Acad. Sci., 330,91-116 (1979). SHANGHAI CANCERREGISTRY, Carlcer incidence in Shanghai, China, 1989, Shanghai Cancer Institute (1991). STEINMETZ, K.A. and POTTER,J.D., Vegetables, fruits and cancer. 1. Epidemiology. Cancer Causes and Control, 2,325-357 (1992). TALAMINI, R., BARON,A.R., BARRA,S., BIDOLI,E., LAVECCHIA, C., NEGRI,E., SERRAINO, D. and FRANCESCHI, S., A case-control study of risk factors for renal-cell cancer in northern Italy. Cancer Causes and Control, 1,125-131 (1990). Yu, M.C., MACK,T.M., HANESCH,R., CICIONI,C. and HENDERSON, B.E., Cigarette smoking, obesity, diuretic use and coffee consumption as risk factors for renal-cell carcinoma. J. nut. Cancer Inst., 77,351-356 (1986).
Publication of the InternationalUnion Against Cancer Publicationde I’Union lnternatlonaleContre le Cancer
RISK FACTORS FOR RENAL-CELL CANCER IN SHANGHAI, CHINA Joseph K. MCLAIJCHLIN’~~, Yu-Tang G A O ~ Ru-Nie , GAO?, Wei ZHENG’,Bu-Tian JI?, William J. BLOT] JR.’ and Joseph F. FRAUMENI, ‘National Cancer Institute, Division of Cancer Etiology, Epidemiology and Biostatistics Program, Bethesda, M D 20852, USA; and ?Shanghai Cancer Institute, Department of Epidemiology, Shanghai, People’s Republic of China. A population-based case-control study of I54 histologically verified renal-cell cancer patients and 157 controls was performed in Shanghai, China, an area with low rates for this tumor. Elevated risks were observed for cigarette smoking (odds ratio (OR) = 2.3; 95% confidence interval (CI): I. I to 4.9), and for increasingcategories of body weight and meat consumption, while reduced risks were seen for increasing categories of fruit and vegetable intake. An increased risk was also observed for regular use of phenacetin-containing analgesics (OR = 2.3; 95% Ck0.7 to 7.0). These findings are consistent with earlier studies in Western countries, and indicate that many of the same etiologic factors for renal-cell cancer operate in low- and high-risk societies.
o 1992 Wiley-Liss,Inc.
Renal-cell cancer is a relatively rare neoplasm in Shanghai, the largest city in China, although its incidence has increased since the mid-1960s (Muir et al., 1987; Shanghai Cancer Registry, 1991). During the period 1978-1982, there were 1.8 cases of renal-cell cancer per 100,000 men and 1.0 per 100,000 women in Shanghai, whereas in the United States the rates were 7.1 per 100,000 men and 3.3 per 100,000 women (adjusted to world standard population) (McLaughlin et al., 1993). Virtually all etiologic studies of renal-cell cancer have been conducted in Western countries, with cigarette smoking and obesity being the most consistently reported risk factors (McLaughlin et al., 1993). Other factors associated with renal-cell cancer include high intake of meat (McLaughlin et al., 1984; Maclure and Willett, 1990) and fat (Talamini et al., 1990), exposure to asbestos (Selikoff et al., 1979; Maclure, 1987), use of prescription diuretics (Yu et al., 1986; McLaughlin et al., 1988), and heavy use of phenacetin-containing analgesics (McLaughlin et al., 1985; Maclure and MacMahon, 1985; McCredie et al., 1988). To investigate risk factors of renal-cell cancer in an area at low risk for this tumor, a population-based case-control study was conducted in Shanghai during the period 1987 to 1989. MATERIAL AND METHODS
All residents of urban Shanghai aged 35 to 74 years who were newly diagnosed with renal-cell cancer (9th Revision ICD 189.0) during the period January 1, 1987, to October 31, 1989, were eligible for study. A total of 223 cases were identified from the population-based cancer registry in Shanghai during this period. The registry, which started operation in 1963 and is a collaborating center of the International Agency for Research on Cancer (Muir et al., 1987), has essentially complete ascertainment of all cancer cases occurring in the urban Shanghai area. Of the cases identified, 195 (87%) were interviewed, while 28 (13%) either refused or could not be located. Microscopic confirmation was collected in 154 (79%) of 195 cases. The analysis was restricted to histologically confirmed cases. Controls were randomly selected from the general population of the Shanghai urban area. The number of controls in each sex- and age (5-year interval)-specific stratum was determined in advance according to the sex and age distribution of the incident cases of renal-cell cancer reported to the Shanghai Cancer Registry from 1982 to 1984. Personal identification cards from the Shanghai Resident Registry were used to select
controls. For all adult residents in urban Shanghai, the cards contain information on name, address, date of birth, sex and other demographic factors. The cards are kept in drawers, with approximately equal numbers of cards in each drawer. Each drawer is numbered by an unique 4-digit code. For each control, a 4-digit random number was generated to define the drawer from which the control was randomly selected. Interviews were obtained for all 157 identified controls. Cases and controls were interviewed in person by trained personnel, usually in the subject’s home. A structured questionnaire was used to elicit detailed information on a number of factors, including demographic variables, tobacco smoking, alcohol consumption, dietary habits, height and body weight, history of previous disease and medications, and occupational history and exposures. Next-of-kin interviews were conducted for 35 cases and 13 controls who had died or were too ill at the time of interview. Since the results from subjects directly interviewed were similar to those from next-of-kin interviews, the results were combined in this paper. The relative risk of renal-cell cancer in this analysis was estimated by the odds ratio ( O R ) (Breslow and Day, 1980). To control for confounding factors, we calculated summary ORs by the maximum-likelihood method, with confidence intervals derived from modification of Cornfield’s method (Cart, 1970), and by logistic-regression modelling (Breslow and Day, 1980). The test for linear trend (one-tailed) was the Mantel extension of the Mantel-Haenszel procedure (Mantel, 1963). Body-mass index (BMI) was used as a measure of obesity, with weight measured in kilograms and height in meters. Diet was assessed using 65 food frequency items for usual adulthood diet prior to 1985. All quartiles used in this analysis were sex-specific and based on the distribution of values among the controls.
RESULTS
The 154 cases (90 men, 64 women) and 157 controls (91 men, 66 women) were similar in age and marital status. The average age at diagnosis was 60 years for men and 61 for women. Cases of both sexes, however, were significantly more educated than controls, with 42% of the cases vs. 20% of the controls having 10 or more years of education. Cigarette smoking was associated with elevated risk of renal-cell cancer among men, with O R of 2.3 (95% CI 1.1 to 4.9) for ever vs. never smoking after adjusting for age and education (Table I). The O R was higher among men who smoked only non-filtered cigarettes ( O R 5.2; 95% CI 1.8 to 15.6). A strong dose-response relationship with pack-years of cigarette smoking was seen among men who smoked only non-filtered cigarettes; but when all smokers were combined the trend was no longer apparent (Table 11). The risk for cigarette smoking was not calculated among women, since few women were regular smokers (6 cases and 11 controls).
)To whom correspondence and reprint requests should be addressed, at National Cancer Institute, EPNi415. Bethesda, MD, USA. Received: April 27,1992 and in revised form June 15, 1992.
563
RENAL-CELL CANCER IN SHANGHAI
Table I11 presents the association between renal-cell cancer and relative weight, as measured by the BMI among both men and women for weight at age 40 and age 50. Cases and controls were categorized according to the sex-specific quartile distributions of BMI among controls. Elevated risks were observed with increasing BMI for men and women, although the trend was not consistently monotonic. BMI for other decades of life showed similar dose-response gradients, except at age 20, when there was no relationship to risk. When the BMI results for the top 10% of subjects at age 40 were compared with the lowest BMI quartile, the O R was 4.6 (95% CI 1.1 to 21.3) and 6.9 (95% CI 1.3 to 42.9) for men and women respectively. Some increase in risk was associated with use of oral contraceptives (OR 1.6; 95% CI 0.5 to 5.2) and menopausal hormones (OR 1.9; 95% CI 0.4 to 8.3). Women who used birth-control pills for 2 years or longer had a 2.9-foldincreased risk (95% CI 0.7 to 12.9, but information was too sparse to examine the effect of duration of use. Risks were not associated with number of pregnancies or with histories of hysterectomy (OR 0.9; 95% CI 0.2 to 3.7) or oophorectomy (OR 1.0; 95% CI 0.2 to 4.3). However, risks were lower for those having hysterectomies under age 45 (OR 0.5; 95% CI 0.0 to 3.2) than for women having this operation at age 45 or older (OR 2.5; 95% CI 0.2 to 25.8). The effect of age at oophorectomy could TABLE I - ODDS RATIO (OR) OF RENAL-CELL CANCER FOR CIGARETTE SMOKING AMONG MEN IN SHANGHAI. CHINA statu\
Cases
Controls
OR'
Y55%Cc12
Never smoked cigarettes Ever smoked cigarettes Non-filtered only
23 67 31
34 57 11
1.0 2.3 5.2
1.1-4.9 1.8-15.6
-
'Adjusted for age and education.-TI, confidence interval.
not be evaluated due to missing data on age among the few subjects who underwent this procedure. Age at menarche showed some relation to risk. Compared with women who started menarche over the age of 17, women who began at 13 years of age or younger had an O R of 1.7 (95% CI 0.1 to 24.8). Age at menopause was unrelated to risk. The questionnaire assessed diuretic use, which was limited in Shanghai. The medication most commonly reported as a diuretic had 10 ingredients, including a small amount of diuretic (3.1 mg of hydrochlorothiazide), 2 anti-hypertensive agents (reserpine and dihydralazine sulfate), promethazine, diazepam, vitamins and minerals. The OR for men regularly taking this drug (defined as at least twice per week for 2 weeks or longer) was 1.3 (95% CI 0.2 to 7.1) after adjustment for age, education, BMI, hypertension, and cigarette smoking; and for women the O R was 2.9 (95% CI 0.7 to 13.1) after adjustment for age, education, BMI and hypertension. Since some patients with renal-cell cancer develop hypertension secondary to the tumor, cases and controls who started taking this drug within 5 years of the cancer diagnosis or the interview were excluded, with little effect on the results. Regular consumption of analgesics (defined as at least twice per week for 2 weeks or longer) was uncommon in Shanghai, but regular use of phenacetin-containing analgesics did confer an increased risk ( O R 2.3; 95% CI 0.7 to 7.0) after adjustment for age, sex, education, BMI and cigarette smoking. The O R associated with regular use of non-phenacetin analgesics was 1.6 (95% CI 0.4 to 6.4). Among the drugs inquired about in the questionnaire, few contained aspirin (acetylsalicylic acid), and only one contained acetaminophen, which no subject reported using. Information on history of previous diseases, such as hypertension, diabetes, and diseases of the heart, kidney and
TABLE I1 ODDS RATIO (OR) OF RENAL-CELL CANCER FOR PACK-YEARS OF CIGARETTES BY TYPE ~
OF CIGARETTE AMONG MEN IN SHANGHAI. CHINA ~~
~~
~
All types of cigarettes
Non-filtered cigarettes Pack-vearr
Casea
Controls
None 1-10 11-20 > 20 ( p for trend)
23 8 5 18
34
5 2 4 (p
OR'
1.0 1.9 6.3 9.3 < 0.001)
Y5%C12
Case7
Controls
-
23 20 14 33
34 12 11 34
0.4-9.3 0.8-67.0 2.1-45.2
OR1
9S% CI2
1.0 2.8 2.6 1.9 (p = 0.08)
0.9-8.9 0.8-8.7 0.84.5
-
'Adjusted for age and education.-'CI, confidence interval. TABLE 111 - ODDS RATIO (OR) OF RENAL-CELL CANCER FOR BODY-MASS INDEX (BMI) FOR WEIGHT AT AGES 4DAND SO AMONG MEN AND WOMEN IN SHANGHAI. CHINA Women?
Men' ~~
BM1 Level
I (low) I1 111 IV (high) (JI for trend)
I (low) I1 111
IV (high) (0for trend)
Cases
Controls
10 20 21 31
20 21 22 23
13 16 19 28
19 21 19 20
OR'
1.0 3.3 2.3 3.6 (p = 0.009)
(D
1.0 1.4 2.1 1.7 = 0.03)
Y5% CI'
Cases
Control5
OR'
Weight at age 40 8 0.8-14.0 15 0.7-8.5 13 1.1-12.6 23
15 14 16 16
0.6-10.9 0.5-7.7 0.9-14.7
Weight at age 50 7 0.4-5.0 17 0.7-10.9 10 0.5-5.7 19
14 15 15 14
0.5-8.2 0.2-4.9 0.7-15.1
1.0 2.6 1.8 3.6 (p = 0.03) 1.0 2.0 1.1 3.3 f D = 0.09)
-
'BMI = wih'; levels for age 40: I, 5 19; 11, 19.1-20.8; 111, 20.9-22.3; IV, > 22.3; for age 50: I, 519.7; 11, 19.8-21.9; 111, 22.0-23.3; IV, >23.3.2BMI = w/h15; levels for age 40: I, 123.7; 11, 23.8-26.7; 111, 26.8-29.2; IV, >29.2; for age 50: I, 524.4; 11, 24.5-27.4; 111, 27.5-30.6; IV, > 30.6.-3Adjusted for age, education and cigarette ~moking.-~CI, confidence interval.-5Adjusted for age and education.
564
McLAUGHLIN E T A L .
thyroid, was also obtained in this study. The diseases were those diagnosed by a physician 2 years prior to the cancer diagnosis for cases or the interview for controls. Only hypertension was associated with a significantly elevated risk. After adjustment for age, education, BMI, blood-pressure medication and smoking, men had an OR of 7.9 (95% CI 2.1 to 29.3) and women an OR of 2.9 (95% CI 0.9 to 9.3). Since renal tumors can cause hypertension, cases and controls who were diagnosed with hypertension within 5 years of the cancer diagnosis or interview were excluded, but there was little change in the risk estimates. Table IV presents OR of renal-cell cancer according to intake of various food groups. Among men, meat consumption was associated with increasing risk, and intake of fruits and vegetables with decreasing risk. Results among women were not as clear-cut, with few food groups showing a strong dose-response gradient, although fruit intake was suggestively related to a reduced risk. Intake of allium (onion, garlic, chives) or cruciferous vegetables (cabbage, cauliflower and Chinese cabbage) did not affect risk. No significant casecontrol differences were seen for consumption of tea, coffee or alcohol. Analysis of usual and most recent occupation revealed little difference between cases and controls in suspected a pn'on' activities such as dry cleaning (no subjects), gasoline-station attendant (0 cases, 1 control), and steel and coke-oven workers (OR 0.3; 95% CI 0.1-2.0). For exposure to a pion' high-risk materials such as asbestos there was no excess risk (OR 0.9; 95% CI 0.1-11.3); for solvents (OR 2.5; 95% CI 0.6-11.2) and gasoline (OR 1.6; 95% CI 0.64.7j, however, there was an increased risk.
obesity may act by promoting hormonal changes, such as increased levels of endogenous estrogens (McLaughlin et a/., 1984). Because little effect was observed for weight at age 20, weight gain during adulthood was chiefly responsible for the association with obesity, an observation seen elsewhere (McLaughlin et al., 1984). Although renal-cell cancer can be induced in certain laboratory animals by estrogens (McLaughlin et al., 1993) and one survey reported an increased risk among women taking menopausal estrogens (Asal et al., 1988), there has been little evidence for hormonal influences in epidemiologic studies (McLaughlin et al., 1993). We observed an increased risk for use of oral contraceptives and menopausal hormones, but the number of exposed cases and controls was limited and the excesses were not significant. A reduced risk for women who had a hysterectomy under the age of 45 and an increased risk for women who started menarche at age 13 years or younger suggest a role for endogenous estrogens, but no relation was seen with number of pregnancies, oophorectomy, or age at menopause. The associations we observed with hormonal factors are not consistent with earlier, larger studies and should be interpreted cautiously. A relation between intake of phenacetin-containing analgesics and renal-cell cancer was first reported in Minnesota (McLaughlin et al., 1984, 1985a) and supported by findings in Massachusetts (Maclure and MacMahon, 1985), Australia (McCredie rt al., 1988), and now in China. Phenacetin was withdrawn from use in the United States and other Western countries in the 1970s, when it was linked to tubulo-interstitial nephropathy and cancers of the renal pelvis and ureter, but it can still be purchased today in Shanghai. Although epidemiologic studies (Yu et a!., 1986; McLaughlin et al., 1988) have found an association between diuretic use and renal-cell cancer, we were unable to evaluate this issue adequately in Shanghai, due to few subjects using drugs that contained only a diuretic. Almost all subjects used one particular product containing many active ingredients, including reserpine, dihydralazine sulfate, diazepam, promethazine, plus a small amount of the diuretic, hydrochlorothiazide (3.1 mg), well below the minimal effective therapeutic dose of 25 mg (Gilman et al., 1985). After adjustment for confounding variables including hypertension, we observed a nearly 3-fold increased risk among female users, although the increase did not reach statistical significance. Excluding subjects who started using this drug within 5 years of the cancer diagnosis or the interview did not change the results. Although we cannot evaluate the risk of diuretics separately from other agents in
DISCUSSION
In Shanghai, an area at low risk for renal-cell cancer, we confirmed the association between cigarette smoking and renal-cell cancer observed in Western countries (McLaughlin et al., 1993). The finding adds to the evidence that cigarette smoking is causally related to this cancer (McLaughlin et al., 1990). The stronger effect for non-filtered cigarettes probably reflects their high tar content. Our results for cigarettes were based on men, since the small number of women smokers precluded a meaningful evaluation of risk. Virtually all studies of renal-cell cancer have found a positive association with obesity, which is more pronounced among women than men (McLaughlin et al., 1993). We also found that risk of renal-cell cancer increased with increasing relative weight as measured by the BMI among both men and women. The mechanism for the association is unclear, but
TABLE IV - ODDS RATIO (OR) OF RENAL-CELL CANCER FOR FOOD GROUPS AMONG MEN AND WOMEN IN SHANGHAI, CHINA Consumption
Meat
levels
OR
I (low) I1 I11 1V (high) ( p for trend)
1.o
3.5 1.3-9.8 3.2 1.1-9.3 4.0 1.4-11.4 (p = 0.005)
I (low) I1
1.o 0.9 1.5
111
IV (high) ( p for (rend)
95WCI'
0.3-2.8 0.6-4.3 0.4-3.6 1.3 ( p = 0.11)
Fruits
Fish
OR
95%C11
1.o 0.5 0.2-1.4 0.9 0.4-2.1 0.4 0.2-1.0 (p = 0.11)
Men'
Vegetables
OR
95%CI'
1.o
-
0.5 0.2-1.1 0.3 0.1-0.8 0.2 0.0-0.5 (p < 0.001) Women3 1.0 1.0 1.0 0.4-2.8 1.3 0.5-3.8 1.1 0.4-2.9 0.9 0.3-2.6 0.7 0.2-2.1 0.7 0.2-2.0 (p = 0.20) (p = 0.07)
OR
9S%CI'
1.o 0.9 0.4-2.1 0.4 0.2-1.0 0.3 0.1-0.7 (p = 0.01)
.o
-
1.7 0.7
0.64.8
1
0.2-2.1 0.6-4.6 (p = 0.33)
1.5
ICI, confidence interval.-'OR adjusted for age, education, cigarette smoking, and body-mass index.-jOR adjusted for age, education, and body-mass index.
RENAL-CELL CANCER IN SHANGHAI
our study, the excess risk associated with hypertension is consistent with earlier case-control studies (McLaughlin et a/., 1984; Yu et a/., 1986; Asal et a/., 1988; Maclure and Willett, 1990). The hypertension may be partly due to elevated levels of renin produced by the renal tumor via compression of adjacent tissue (McLaughlin eta/., 1993). The positive association we observed with meat intake is consistent with previous studies, suggesting the possible role of dietary fat or consequent obesity in the etiology of this cancer (McLaughlin et a/., 1984; Maclure and Willett, 1990; Talamini et a/., 1990). Further studies are needed, however, to evaluate whether the association operates through saturated fat or one of its correlates, such as protein or cooking-derived carcinogens, including heterocyclic aromatic amines (Adamson, 1990). In addition, decreased risk was associated with intake of fruit and vegetables, although the effect of vegetables appeared restricted to men. In earlier studies of renal-cell cancer, reduced risks were reported for vegetables (Maclure and Willett, 1990; Talamini et al., 1990), but not fruits. The protective effect of fruit and vegetables thus may apply to renal-cell cancer as well as several other sites of cancer (Steinmetz and Potter, 1992). The reason for the stronger
565
dietary findings among men than among women is not clear. In accordance with previous studies, we found no influence of coffee, tea, or alcohol intake on the risk of renal-cell cancer. Occupational analyses were hampered by the small number of exposed subjects, but we observed no elevated risk among asbestos-exposed workers, in contrast to earlier reports suggesting increased risk (Selikoff et a l , 1979; McLaughlin et al., 1993). Although not statistically significant, there was increased risk for exposure to gasoline (OR 1.6) and solvents (OR 2.5), consistent with some previous studies (McLaughlin et al., 1985b; Partanen et al., 1991). In summary, this population-based case-control study of renal-cell cancer in Shanghai revealed increased risk associated with cigarette smoking, obesity and high consumption of meat, and decreased risk with high consumption of fruits and vegetables, particularly among men. Increased risk was suggested in relation to regular use of phenacetin-containing drugs and to exogenous estrogen use and some hormonerelated variables. The study has identified risk factors in Shanghai similar to those in Western countries, and has provided further evidence for dietary determinants of renalcell cancer.
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