The Etiology of Bladder Cancer from the Epidemiological Viewpoint

Anthony B. Miller Cancer Res 1977;37:2939-2942. Published online August 1, 1977.

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[CANCER RESEARCH 37: 2939-2942, August 1977]

The Etiology of Bladder Cancer from the Epidemiological Viewpoint

Anthony B. Miller
Epidemiology Unit, National Cancer Institute of Canada, University of Toronto, 121 St. Joseph Street, Toronto, Ontario, M5S 2R9, Canada

for males than for females, with an excess in the industrial ized areas of North America and Western Europe and low A number of causal environmental factors have been rates in Africa and Asia (6). It is studies such as these that identified for bladder cancer. Quantification of the extent to have pointed to the importance of environmental factors in which known and suspect factors accountfor thecasesthat etiology and promoted the belief that up to 90% of all can occur is one of the current goals of research in bladder cers are preventable because they are due to exogenous cancer epidemiology. factors (9). The 2nd approach is the analytical study in which the Certain occupational groups have been identified for experience of individuals is carefully assessed, either in which a clearly increased risk has been demonstrated; smoking has also been demonstrated as a risk factor. Of the those who have cancer and suitable controls (the case residual, due to presently unknown factors, it has been control study), or in a group of individuals in whom expo pointed out that possibly as much as one-half of the males sure has been documented and who have been subse and maybe two-thirds ofthefemales couldbe accountedfor quently followed (the cohort study). Both types of analytical by coffee drinking. study have been effectively used in occupational studies Preliminary analysis of a case-control study conducted in and have contributed to developing a list of the risk factors Canada has confirmed the importance of cigarette smoking that seem to be relevant for bladder cancer (11). Exposure in both sexes, and has indicated a slightly increased risk to cigarette smoking and carcinogens in the occupational due to consumption of regular coffee in males and due to environment are well established as causal factors, whereas heavy use of instant coffee in both sexes. These risks are a number of factors are still suspect, including artificial only partially accounted for by an association between sweetener use, coffee drinking, excess alcohol consump tion, nitrosamines in the diet, use of certain drugs for the smoking and coffee drinking. Although possibly most of the risk factors have been treatment of infection, consumption of bracken fern, and identified for bladder cancer in males, in females it still the presence of chronic schistosomiasis. seems likely that a number of substances to which the Some time ago it was pointed out that information from population-based case-control studies can enable one to general population is exposed may be found to be carcino genic to the bladder. calculate the extent to which the cases of cancer occurring in the population can be explained, that is by calculating the population-attributable risk percentage (3). Cole (2) showed Introduction that, in Boston, over one-half of the cases of bladder cancer could be explained by cigarette smoking and hazardous Epidemiologists essentially have 2 approaches to investi occupations in men, but only one-third in women, while, of gating etiology. First, they can perform descriptive studies the residual, a substantial proportion would be explained if and evaluate the extent to which incidence or mortality from coffee drinking were causal. Thus, even though we are cancer varies from country to country or from one geo dealing with possibly the one cancer other than cancer of graphic region to another, or within regions by time, and the lung for which a number of environmental factors have can attempt torelate this tofactors operating inthepopula been identified and shown to account for a substantial tion. A prime example of this has been the recent analysis of proportion of the cases that occur, quantification of the cancer mortality by county in the United States, which has extent to which known and suspect factors can account for already served to pinpoint areas in which occupational these cases has to be one of the current goals of research in causes of bladder cancer, some known and some suspect, bladder cancer epidemiology. This is particularly important are operating (10). A similar example is currently being when the incidence of the condition is increasing in both investigated in Canada of a risk in relation to 2 large plants Canada and the United States, at least in males (4), al associated with the aluminum industry. On a larger scale, though at present the life-time risk for bladder cancer, in consideration of international differences has been very the absence of other causes, is only approximately 2% in profitable for leads to the etiology of other cancers. For men and under 0.5% in women (Table 1), while premature bladder cancer, international differences seem to be greater mortality from this cause is also bow (Table 2). One of the great fears for the future is the possibility that increasing environmental exposure to a number of carcino December 1, 1976, Miami Beach, Fla. gens may lead to a substantial increase in cancer incidence Summary
I Presented at the National Bladder Cancer Conference, November 28 to

AUGUST 1977

2939

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A. B. Mil!er
Lifetime Table 1 risk 1972)Cancer (%) of developing cancer by age 75(Canada,

siteMalesFemalesStomach1 .70.7Colon rectum3.83.3Lung5.61.0Breast0.16.8Uterus and

cervix)3.2Ovary1.3Prostate0.3Bladder1 (including

.80.4Brain0.40.3Leukemia0.70.6Total

malignant

disease32.027.0

Potential

Table 2 years of life lost (PYLL) before age cancerPYLL 70 for c sites, based on deaths in Canada, 1973ertain

x10@Cancer MalesFemalesStomach site 8.14.3Colon 14.113.1Lung and rectum 34.28.8Breast

0.131.1Uterus cervix)9.1Ovary8.8Prostate (including 2.2Bladder .80.5Brain 8.65.7Leukemia 12.811.0Total malignant disease

sure that such difficulties will not result in a spurious differ ence being found, as themeshould be similar difficulties of recall of distantly occurring events in both cases and con trols. S The study was conducted in collaboration with epidemiol ogists in the University of British Columbia; in Dalhousie University, Halifax, Nova Scotia; and in Memorial University, St. John's, Newfoundland, who were responsible for the acquisition of cases and controls and the supervision of interviewing using an agreed upon common protocol. The controls were matched to the cases on the basis of age, sex, and geographic residence, the controls being selected on a neighborhood basis by doom-to-door searching. All cases and controls were interviewed in their homes, and the study was introduced to them as one of environment and health. The Epidemiology Unit ofthe National Cancer Insti tute of Canada was responsible for the design, coordina tion, and analysis of the study. The preliminary analysis reported here includes data on 349 case-control pairs from British Columbia, 105 from Nova Scotia, and 64 from Newfoundland, comprising 400 male and 118 female pairs. Some of the conclusions may be subject to modification when the data on the complete study population of approximately 630 case-control pairs are available and the definitive analyses are completed. Results Only a small number of cases worked in industries with known exposure to bladder carcinogens, and very few con trobs, so that although the numbers were small, the relative risks were often substantial (Table 3). Only the relative risk for the chemical industry and for the group of other indus tries in males is statistically significant, although the others are in the expected direction. With regard to tobacco use, risks were first calculated for individuals who gave a history of having ever used any tobacco product, assessing the risk relative to nonusers. The numbers of discordant pairs were 70:18 in males and 34:13 in females, producing highly significant relative risks for tobacco use of 3.9 and 2.6, respectively. Risks have also been calculated for lifetime consumption of both plain and filter cigarettes relative to that of non smokers (Table 4). In both sexes and with both types of cigarettes, a dose-response relationship is seen. The appam ently higher relative risk in females is probably an artifact of relatively small numbers. Although there is an indication in males that the relationship is less clear-cut in smokers of filter cigarettes, this has to be confirmed by a more detailed analysis taking into effect the fact that many of the men who now smoke filter cigarettes used to smoke plain. The study was specifically directed to obtaining detailed estimates of coffee consumption (Table 5). For regular cof fee drinking, although theme is an increase in risk in both sexes, the relative risk, particularly in males, is low, with no indication of a dose-response relationship; for females, the confidence limits include one. However, for instant coffee drinking, in both sexes, the risk for those with a life-time intake of more than 10,000 cups was of the order of 2, this being statistically significant in males and of borderline CANCER RESEARCHVOL. 37

133.2122.7

in both sexes. Some of these agents may exert their carci nogenic potential through the bladder and, therefore, moni toring for changes in incidence and mortality of this site may be particularly critical (11).

Materials and Methods

A case-control study of bladder cancer has been per formed in 2 geographically distinct areas of Canada, British Columbia, and the Atlantic provinces of Nova Scotia and Newfoundland, in an attempt to elucidate further the factors that are relevant in populations in which known hazardous occupations were not particularly prevalent. Thus, the study areas were chosen partly because the provinces concerned did not have concentrations of chemical factories such as are found in Quebec and Ontario. Neither were thememany occupations relevant to rubber working, electric cable man ufacturing, etc. Nevertheless, population movement occurs from central and western Canada to British Columbia, while people who have worked in Ontario or Quebec may return to their home provinces in the east on retirement. Thus, a questionnaire was designed to obtain information from cases and controls on lifetime occupation as well as lifetime exposure to cigarette smoking, coffee drinking, and other suspected causal factors. The interviewers were trained to administer the questionnaire with equal facility to both cases and controls. Although problems of recall may affect estimates of exposure, the case-control design should en 2940

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The Epidemiologica! Table 3

inCanadaMalesFemalesDiscordantDiscordantIndustrypairs Occupational oxposure in case-control study of biadder cancer

Viewpoint

riskChemical12/1 12.0@0/0Rubber5/1 5.00/0Photography6/2

Relative

riskpairsRelative

3.00/0Spray 2.00/0Petroleum8/2 painting16/8 4.00/0Medicine13/4 3.312/91.3Other110/53 2.1@5/41.3

ap <0.01.

Table 4 (riskMalesFemalesDiscordantDiscordantNo. Lifetime cigarette consumption in case-control study of

relative to nonsmokers)ladder

cancer in Canada

riskPlain of packs smokedpairs cigarettes1-5,00020/10 1.35,001-20,000 10.5aFilter 31/9 More than 20,00071/20
cigarettes1-5,000

Relativeriskpairs 2.014/11 3.6a@ 3,4)21/2 1.7@1

Relative

5,001-20,000
p < 0.05.

5.0@a More than 20,00054/32

45/24

1.9a@

2.3

6/3

2.014/6 Table 5

15/3

Lifetime

intake of coffees

estimated

in case-control

study of bladder

cancer in Canada

less)Lifetime

(risk relative to 500 cups or

FemaleDiscordant Discordant
riskRegular intake (cups)Males coftee pairs Relative risk pairs Relative

500-40,000 More than 40,000 Instant coffee

500-10,000 Morethanl0,00029/20 2.6ap
<0.01.

26/19
39/32 59/29

1.4 1.4
1.2 2.1

9/11 7/3
10/10 13.5

0.8 2.3
1.0

significance in females. The measure used in this prelimi nary analysis may not be the best measure and, for both coffee consumption and cigarette smoking, other measures of consumption, particularly in relation to various time pe nods, will be examined. Other variables examined so far include (a) tea drinking, which showed no association; (b) various factors associ ated with bladder symptoms, which showed significantly increased risk; and (c) residence in a property that was not on a public water supply, which showed significantly in creased risk in males. The latter variable was included in an attempt to get a handle on nitrate consumption, which seems to be higher in those who drink well water. It has been suggested that urinary tract infection in people living in areas with high concentrations of nitrate in the drinking water may beadto increased risk of bladder cancer because of the ability of bacteria to catalyze the nitrosation of secondary amines (8). However, our finding of a signifi
AUGUST 1977

cantly increased risk in males but not in females does not seem to fit this hypothesis, since urinary tract infections would be expected to be more prevalent in females than in males. The effect of drinking spirits has also been exam ined, with no clear association emerging, in contradistinc tion to another recent study, which, incidentally, showed no effect of coffee drinking (12). One of the difficulties over assessing the etiobogical rele vance of coffee drinking is the fact that it is associated with cigarette smoking. Control for this in the preliminary analy sis resulted in the disappearance of the effect of regular coffee in females and of instant coffee in males (Table 6). However, as before, these observations need confirmation in a more detailed analysis, particularly taking note of the interaction between different types of cigarette smoking and coffee consumption. Nevertheless, as a first attempt, it is perhaps permissible to calculate the proportion of cases that can be accounted for by these various factors in terms 2941

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A. B. Miller Table 6
Effect of controlling for cigarette smoking on risk associated with lifetime intake of coffee
(risk of drinking more than 5000less)Males cups relative to drinking 500 cups or

FemalesDiscordant Discordant
riskRegular pairs Relative risk pairs Relative

coffee Uncontrolled ControlledInstant coffee Uncontrolled Controlled

a Summary

45/31 13/9

1.4 1.4

15/12 6/10

1.3 0.6

77/50 21/25
categories

1.5 0.8
of plain cigarettes

17/11 10/6
(0 to 1000 packs,

1.5 1.7
1001 to

risk over 3 smoking

10,000packs, and more than 10,000packs). Table 7 Case-controlstudy of bladder cancer in Canada(estimated percentage)%MalesFemalesKnown population-attributable risk although they need not be the same in all countries, or that there is some common low level of risk which might not be due to the environment in all countries. My preference is for the environmental explantation, but this review underlines that we still have a long way to go to identify the responsible agents, especially with regard to bladder cancer in females, and that further endeavors, both analytical and experimen tal, are needed in this area. In the meantime, in terms of prevention, the message is clear in relation to occupational exposure and cigarette smoking.

100Suspect occupations 251Cigarette occupations

5629Coffeedrinking smoking 2713Total

accounted for

11843

of the population-attributable risk percentage. Paradoxi cabby,more than 100% of the cases in males seem to be accounted for on the basis of occupational exposure, ciga mettesmoking, and coffee drinking, but under one-half in females (Table 7). Discussion This preliminary analysis seems to indicate that the inter action between environmental factors in the etiology of bladder cancer is complex and requires more than just individual factor consideration. There have already been a number of contrasting observations that suggest that the relationship between coffee drinking and bladder cancer, for example, is by no means clear-cut, and prolonged study may be needed in order to unravel all its complexities (1, 7, 12). Doll (5) has pointed out that the range of international variation of lifetime cumulative incidence up to 75 years of age for bladder cancer is only 4-, compared with 7-fold for breast cancer, 20-fold for cancer of the cervix, 100-fold for bronchus cancer, and as much as 300-fold for cancer of the esophagus. This suggests either that environmental factors causing induction of this cancer are very widespread,

References
1. Cole,P.Coffee-drinking andCancer of theLowerUrinary Tract.Lancet, 2. Cole,P.A Population Based Studyof Bladder Cancer. In: R.DollandI. 3. Cole,P.,andMacMahon, B. Attributable RiskPercent in Case-Control Studies. Brit.J. Preventative SocialMed.,25:242-244, 1971. 4. Cutler, S.J., andDevesa, S.S.Trends inCancer Incidence andMortality 5. Doll,R. Epidemiology of Cancer: CurrentPerspectives. Am.J. Epide
miol. 104: 396404, 1976. in the U. S. A. In: R. Doll and I. vodopija (eds.), Host Environment Interactions in the Etiology of Cancer in Man, pp. 15-34. Lyon, France: International Agency for Research on Cancer, 1973. Vodopija (eds.), Host Environment Interactions in the Etiology of Cancer in Man, pp. 8387. Lyon. France: International Agency for Research on Cancer, 1973. 1: 1335-1337, 1971.

6. Doll,R.,Muir,C.,andWaterhouse, J. A. H. (eds).Cancer Incidence in 7. Fraumeni, J. F., Scotto,J., and Dunham, L. J. Coffee-drinking and 8. Hawksworth, G. M., and Hill, M. J. Bacteria andthen-Nitrosation of 9. Higginson, J. Present Trends inCancer Epidemiology. Can.Cancer Rca. 10. Mason, T.J., MacKay, F.W., Hoover, R., Blot,W.J., andFraumeni, J. F. 11. Miller,A. B. TheEpidemiological Basisof PublicPolicy.Can.Cancer Res.Conf.11:2-12,1976.
12. Morgan, R. W., and Jam, M. G. Bladder Cancer: Smoking, Beverages and Artificial Sweeteners. Can. Med. Assoc. J., 111: 1067-1070, 1974. Atlas of Cancer Mortality for U.S. Counties, 1950-1969. DHEW Publica tion No. (NIH), pp. 75-780, 1975. Conf. 8: 40-75. New York: Pergamon Press, 1969. Secondary Amines. Brit. J. Cancer, 25: 520-526, 1971. BladderCancer. Lancet,2: 1204,1971. Five Continents, Vol. 2. New York: Springer-verlag, 1970.

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