Epidemiologic approaches to cancer research

Epidemiologic Approaches to Cancer Research Linda Morris Brown and Linda M. Pattern

ANCER is a general term for a group of more than 100 diseases in which abnormal cells grow out of control and can spread throughout the b0dy.l,2 The study of the distribution and determinants of cancer in human populations is called cancer epidemiology.v? Some of the leads concerning cancer etiology have arisen from case-reports and case-series of individuals with cancer which have been reported in the clinical literature. Epidemiologists, unlike medical practitioners, are primarily concerned with cancer in populations rather than in individuals, and with prevention rather than cure.

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EPIDEMIOLOGIC MEASUREMENTS

Although one out of every three individuals will develop cancer at some time during their lives,? the number of persons developing any specific type of cancer is relatively rare. Three measures used by epidemiologists to describe the number of individuals with cancer are incidence, prevalence, and mortality rates. 6-8 For specific types of cancer, these measures are usually presented per 100,000 population. In screening a population for cancer, one is likely to identify both incident and prevalent cases. The incidence rate is the number of new cases of cancer in a defined population diagnosed during a specified period of time divided by the number of people at risk in the same defined population. Knowledge of cancer incidence is important not only for monitoring the occurrence of various types of cancer; but also for evaluating the effectiveness of cancer control programs such as smoking cessation programs aimed at lowering the incidence of respiratory and other smoking-related cancers. The prevalence rate is the number of new and old cases of cancer in a defined population during a specified period of time divided by the number From the Epidemiology and Biostatistics Program, National Cancer Institute, Bethesda, Md. Address reprint requests to Linda Morris Brown, MPH, Epidemiology and Biostatistics Program, National Cancer Institute, Landow Bldg, Room 3C15, Bethesda, MD 20892. This is a US government work. There are no restrictions on its use. 0749-2081/86/0203-0001$00.0010 146

of people at risk of developing cancer in the same defined population. Cancer prevalence is not regularly available in any population, but must be determined by special survey. Knowing the prevalence of cancer may be useful in allocating resources for cancer treatment programs. The mortality rate is the total number of deaths from cancer in a defined population during a specified time period divided by the number of individuals in the same defined population. Since cancer mortality data are more widely available than incidence data, they are most often used to compare the frequency of cancer deaths by geographic region, over time, or in relation to potential etiologic factors: A comparison of cancer incidence and mortality rates over time for a defined population should be useful in evaluating the effectiveness of cancer treatment programs. Since the development of cancer is due to environmental and/or host factors, two different approaches to epidemiology have been employed. Descriptive epidemiology is used to describe patterns of cancer in large populations using demographic data such as age, race, sex, and marital status. Analytic epidemiology is used to group together information collected on specific individuals such as smoking, alcohol, and dietary histories to obtain a more precise understanding of the determinants of cancer. DESCRIPTIVE EPIDEMIOLOGY

Descriptive epidemiology relates the occurrence of cancer in human populations with basic characteristics of the population. These characteristics are referred to as variables of person, place, and time. Persall

The person variables used in descriptive studies include age, sex, race, marital status, socioeconomic status, occupation, nativity, ethnicity, and religion. Since age, sex, and race are the most commonly used of these variables, they will be presented in more detail. Age is a variable that should always be considered in epidemiologic studies of cancer, since the frequency of cancer varies markedly by age. Knowledge of the age distribution of different Seminars in Oncology Nursing, Vol 2. No 3 (August). 1986: pp 146-153

147

EPIDEMIOLOGIC APPROACHES TO CANCER

types of cancers is helpful in developing etiologic hypotheses and in selecting specific age groups for further study. Overall incidence and mortality rates are dependent upon both the age-specific rates and the age structure of the population. Therefore, it is useful to perform either a direct or an indirect statistical procedure to remove the influence of the age distribution when comparing populations with different age ranges. Table I presents the incidence and mortality rates for the years 1973 through 1981 for the eight most common cancers by' race and sex. 9 - 11 For most cancers there is great variation by sex, with females generally having lower rates than males. Knowledge of the sex differential for different tumors is helpful in assessing the relative importance of environmental factors. For example, the incidence of lung cancer is substantially higher for males compared to females reflecting the longer duration and greater intensity of cigarette smoking by men. Racial differences in incidence and mortality are also evident for most types of cancer (Table 1). Some of these differences may be due to genetic factors, while others are more likely due to differences in lifestyle, environmental exposures, medical care, and other factors. Figure 1 presents age-race- and sex-specific incidence rates for stomach cancer in the United States for the years 1977 to 1981. 9 For each racesex group, the rates are low through early adulthood then climb steadily after age 39. Rates are higher for blacks than for whites, and males have higher rates than females.

Place Studies of the frequency of cancer by geographic area have led to the formulation of many interesting etiologic hypotheses. Such studies of place usually entail either international comparisons or comparisons within subunits of one country. For example, a correlational study'? found high rates of respiratory cancer mortality to be consistently high in US counties where shipyards were engaged in the construction and repair of large naval and cargo vessels during World War II. This finding suggested that shipyard exposures to asbestos may have contributed to the excesses of respiratory cancer mortality seen in coastal areas of the United States. International comparisons are most commonly

Table 1. Age·Adjusted* Incidence (SEERIU and Mortality Rates

White males lung Prostate Colon-rectum Bladder lymphomas leukemia Stomach Pancreas Black males Prostate lung Colon-rectum Stomach Esophagus Pancreas Bladder larynx White females Breast Colon-rectum Cervix (uterine) Corpus (uterine) lung Ovary lymphomas Pancreas Black females Cervix (uterine) Breast Colon-rectum lung Corpus (uterine) Pancreas Ovary Stomach

Incidence Rate!100,OOO

Monality Rate!100,OOO

78.4 71.5 59.5 28.8 15.0 13.5 12.4 11.4

66.6 20.7 25.8 7.1 7.4 9.0

114.5 111.4 54.5 21.1 16.6 14.0 12.6

41.9 85.5 19.1 15.8 15.4 13.5 5.6 4.6

90.8 44.5 41.2 30.2 24.8 14.1 11.2 7.4

26.8 24.4 3.6 1.9 17.6 8.4 5.0 6.7

77.3

10.1 26.1 20.2 17.4 2.8 8.8 6.6 6.9

17.9

74.6 44.5 26.9 14.4 11.4 9.6 8.5

8.3

10.7

Rates are given for the eight most common cancers for each race-sex group (1973-1981). * Values are age-adjusted to the 1970 US standard population. t Data include both malignant and in situ tumors. ; 1985 submission.

based on data from population-based registries of cancer incidence in the United States and selected foreign countries. Such comparisons are particularly useful for cancer research since residents of foreign countries have very different lifestyles, which may' have an' impact on the incidence of a particular type of cancer. Within the United States, mortality statistics provide the most complete data for regional com-

BROWN AND POITERN

148

parisons. Comparisons can be made by regions of the country, urban v rural areas, state economic areas, counties, and local areas. The creation of cancer maps to examine geographic variations in cancer mortality'P-'! has led to the development and testing of hypotheses comparing known characteristics of the regions . Figure 2 illustrates the striking regional variation in colorectal cancer mortality between 1970 and 1980 for US white males.P Rates were strikingly elevated in the northeast, while the rates in the south and west were notably lower than the US average. Two reasons suggested to explain these findings are more extensive urbanization and higher socioeconomic status of the northeast compared to the other areas and regional differences in dietary patterns. 13

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Age Rg . 1. Age-sex-race-specific incidence rates of stomach cancer-Surveillance, Epidemiology, and End Results (SEER) program, 1977-1981. e-e, black male; 0 - 0, white male; e·· ·e, black female; 0 - • ·0 , wh ite female.

Study of the patterns of cancer by time is a basic component of cancer epidemiology. Changes in cancer incidence and mortality generally occur over years or decades . The se types of changes are referred to as secular changes or secular trends. Figure 3 presents the age- specific incidence rates

Rg. 2. US age-adjusted (1960 US standardl mortality rates of colorectal cancer for white males, 1970-1980. • • significantly > US rate (in highest decile). III!, significantly> US rate lnot in highest decile). 13,significantly < US rate. 0, not significantly different from US rate. (Reprinted with permission.'3)

EPIDEMIOLOGIC APPROACHES TO CANCER

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Ii Fig. 3. Age-specific Incidence rates of testicular cancer for white males. • •• the Sec· and National Cancer Survey (SNCS). 1947-1948; 0---0. the Third National Cancer Survey ITNCS). 1969-1971; and •• • •• • the Surveillance. Epldemlology. and End Results (SEER) program. 1979-1981.

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for testicular cancer among white males for three time periods based on data from three sources.!" These data illustrate the dramatic increases in testicular cancer that have occurred in young adults aged 15 to 44 years over the past several decades and highlight this age-group as an important one to observe and study. Some of the more common cancers that have shown changes in incidence over the decade from 1973 to 19829.15.16 are presented in Table 2. During this time period, the incidence of lung cancer in women and melanoma in both men and women almost doubled. Increases were also seen for bladder and breast cancers in females and lung and prostate cancers in males. Cancers that decreased significantly during this time period were cancer of the stomach in men and cancers of the uterine cervix, uterine corpus, and stomach in women. Birth cohort analysis is another way to examine time trends. A birth cohort is a group of individuals born during a specific time period (eg, a decade). Analysis of such cohorts provides information on how the incidence of a cancer is changing over time. It may also give clues to the etiology of a cancer since members of a birth cohort are likely to share common exposures that may have changed over time. ANALYTIC EPIDEMIOLOGY

Although descriptive epidemiology is useful in providing clues to the etiology of cancer, the more

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specialized methods of analytic' epidemiology are necessary to test specific hypotheses of causality. The two major types of analytic studies are the cohort (prospective) study and the case-control (retrospective) study.

Table 2. Age-Adjusted· Incidence Rates (SEER)U: Cancer Site

Sex

1973

1977

1982

M

25.4 6.3

26.3 7.0

27.8 7.6

F

1.0 85.4

0.9 86.9

0.9 91.8

Cervix (uterine)

F

47.3

47.0

39.4

Colon-rectum

M

F

55.0 42.6

60.4 44.8

61.4 44.4

Corpus (uterine)

F

30.3

29.8

24.1

Lung

M

73.1 18.3

80.5 24.8

84.4 32.4

Melanoma

M

F

6.1 5.5

8.6 7.5

10.7 8.9

Prostate

M

64.1

75.5

80.9

Stomach

M F

15.1 6.7

13.1 6.0

13.1 5.5

Bladder

F Breast

M

F

Values are given per 100,000. * Age-adjusted to the 1970 US standard population. t Data include both malignant and in situ tumors. ; 1985 submission.

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Cohort Studies In a cohort study of cancer, a group of subjects who are exposed or not exposed to a suspected etiologic factor is selected and then followed over time to determine their incidence of cancer. There are basically two types of cohort studies. One is the prospective study in which the cohort is identified and classified by exposure status in the present and then followed forward in time to determine if cancer develops. Such a design is impractical to investigate the relationship between exposures and the development of cancer for several reasons. Because the development of a specific type of cancer is relatively rare and the latency period is generally long, a large number of individuals would need to be followed over a long period of time; this would be an extremely expensive and time-consuming endeavor. Alternatively, a historical prospective study identifies a cohort and ascertains occurrences of cancer at the present time, but exposure status is determined from past records. When the development of cancer is the outcome, the historical prospective study is the more feasible type of cohort study to conduct. Selection of cohort. For studies of cancer, preexisting records on specific populations are primarily used to select the cohort to be studied and to classify the extent of exposure to a potential carcinogen. Employment records of industrial workers and medical records of individuals who were treated with specific modalities are often used to identify cohorts exposed to suspected carcinogens. In addition to information obtained from such records, exposure history and other relevant data such as demographics and smoking history should be obtained directly from the individuals in the study cohort when feasible. In occupational cohort studies the standardized mortality ratio (SMR) is a commonly used evaluajive measure of mortality.!? It is an age-adjusted measurement of risk which compares observed mortality in an occupational cohort with a nonexposed group, usually based on the general population, to evaluate whether there is excess mortality within an industry.P Another commonly used measure is the proportionate mortality ratio (PMR). It is a method used to compare the proportion of deaths from specific causes that occurred among persons employed in the occupational cohort of interest with the proportion of specific causes of death that occurred among men

BROWN AND POTIERN

in the US general population. 18 The PMR is most often used when there is reason to believe that overall morbidity and mortality from specific causes in the occupational group of interest are lower than in the general population due to the selection of healthy individuals into an occupation.l? An elevated SMR or PMR for specific cancers may suggest that some exposure occurring within the occupation/industry of interest has an etiologic role in the development of cancer. A potential problem in cohort studies is the introduction of bias due to subjects self-selecting their exposures (eg, men who select painting as an occupation are consequently exposed to paint and solvents). The randomized clinical trial, which eliminates such bias, is a specialized type of prospective study in which subjects are randomly assigned to either a study group or a control group. The study group generally receives the experimental therapy, whereas the control group receives a standard form of therapy. Analysis of cohort studies. The purpose of analytic studies of cancer is to determine whether there is an association between a certain exposure and the development of a specific cancer. A comparison of the incidence rates of cancer among exposed and nonexposed subjects provides insight into whether an exposure affects the risk or probability of developing cancer and if so, the magnitude of the effect. Several measures of risk are used to describe the effect. The relationship between an exposure and cancer occurrence is measured by the relative risk (RR), which is the ratio of the incidence rate of cancer in the exposed group to the incidence rate in the nonexposed group. An RR of 1.0 indicates that there is no excess risk in the exposed group whereas an RR greater than one indicates that exposed individuals are at a greater risk of developing cancer than the nonexposed individuals. The size of the RR indicates the strength of the association between the particular exposure and the cancer. For example, an RR of 1.5 signifies a "weak" association, whereas an RR of 10.0 indicates a very "strong" association. Person-years of observation are often used for calculating incidence rates in a cohort study in which subjects are observed for varying lengths of time. This approach takes into account the exact length of time each subject contributes to the study.

EPIDEMIOLOGIC APPROACHES TO CANCER

Case-Control Studies In a case-control study of cancer a group of individuals with the cancer (the cases) and a group of individuals without the cancer (the controls) are identified and histories of exposure to suspected etiologic factors are obtained.F? Information on past exposures may be collected from a variety of sources including questionnaires (either interviewer or self-administered), medical records, and physician records. Selection of cases. Cases of a particular type of cancer are generally chosen from one of the following sources: (1) all persons newly diagnosed with the cancer in one or more hospitals or medical institutions during a specified time period, (2) all persons newly diagnosed with the cancer in a defined population such as a city, county, or state (usually obtained through local or state tumor registries), or (3) all deaths from a particular cancer in a defined population during a specified time period. Ascertainment of cases who are deceased is usually accomplished using data from state vital statistics departments and death certificates. It is important to have complete ascertainment of all cases to ensure that the cases included in the study are representative of all individuals from the same population with that type of cancer. Selection bias would occur if there were systematic differences in the etiologic factors being studied between those cancer patients included in a study and those excluded. For example, if nonparticipating cases in a case-control study of lung cancer were heavier smokers than participating cases, the risk estimate for smoking would be artificially low. Selection of controls, Selection bias can also be due to the improper selection of controls, resulting in misleading information. Controls should be chosen to represent the population from which the cases were chosen. Because of referral patterns, hospital-based series of cancer cases are usually not representative of the population near the hospitals. To overcome this problem, patients with other types of cancer or other kinds of referrable diseases are often used as controls. Other sources of controls for hospital-based cases are relatives of the cases (usually siblings), friends, or neighbors. When cancer cases are selected from a tumor registry that covers a defined population, the controls should be a sample of persons without the

151

cancer from the same population. Some of the methods used for choosing such population-based controls are random digit telephone dialing procedures or random selection from available listings such as city or town lists, motor vehicle registration lists, and telephone directories. Often, controls are chosen so that they are similar to cases on specific characteristics such as age, sex, or race in order to simplify the analysis by limiting the number of factors that may vary between cases and controls. This may involve either individual matching of controls to cases or group matching within five or ten year age groups. Analysis of case-control studies. The measure of association in a case-control study is the odds ratio (OR), which is an estimate of the true relative risk (RR). It is also referred to as the crossproduct ratio ad/be, where a, b, c, and d refer to exposure and disease status as indicated by the letters in parentheses in Table 3. This table also presents the numbers of testicular cancer cases and controls who reported a history of cryptorchidism (undescended testis) in a case-control study of testicular cancer by Pottern et aU 1 The risk (or odds ratio) of testicular cancer associated with a history of cryptorchidism can be calculated as follows: OR

= (25 x 252)/(7 x 246) = 3.7.

The OR of 3.7 actually means that a man with a history of cryptorchidism has 3.7 times the risk of developing testicular cancer compared to a man without such a history. The term relative risk has also been used in the case-control literature to refer to the cross-product ratio, but odds ratio is the preferred term. Two major methodologic concerns of case-control studies, the potential for interviewer bias and recall bias by the subject, are illustrated by this case-control study of testicular cancer.U Interviewers were not "blind" to the case-control status of the subjects and may have subconsciously gathered information differentially for the cases and controls. However, since the interviewers Table 3. Testicular Cancer Cases and Controls by History of Cryptorchidism Cryptorchidism (Exposure)

No. of Cases (Disease)

No. of Controls (No Disease)

Yes

25 (a)

7 (b)

No

246 (e)

252 (d)

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152

were unaware of the hypotheses under investigation, knowledge of the study subjects' status would not seriously affect the risk estimates. The potential for recall bias or misleading results due to selective memory on the part of the testicular cancer cases is greater in this type of study. Because of the location of the tumor, it was possible that testicular cancer cases may have been more aware of a history of cryptorchidism than controls. To circumvent this problem, the analysis was focused on subjects whose undescended testis was either surgically corrected or whose condition remained uncorrected at the time of cancer diagnosis. Thus, multiple approaches can be used to prevent or minimize the effects of interviewer and recall biases, yielding a more accurate risk estimate. Another measure of risk, the attributable risk (AR), is the proportion of cancer incidence that can be attributed to a specific exposure. It is calculated as the incidence of cancer in the exposed subjects minus the incidence of cancer in the nonexposed . An attributable risk of 0.80 for cigarette smoking and -lung cancer would mean that 80% of the lung cancers can be attributed to cigarette smoking. CRITERIA FOR JUDGING CAUSALITY

Most epidemiologic studies are conducted with groups of people who have variou s characteristics in addition to the one under investigation. These other characteristics are called confounding variables when they are related to both the cancer and the exposure factor being studied. Confounding variables often make it difficult to determine whether a factor and a cancer are actually causally related. A false association can also be due to chance or can result from biases in the study design or methods. There are four criteria that arc important to consider when determining whether an association is likely to be causal. The first is the strength of the association. The greater the RR or OR, the more likely it is that a true association exists. Confidence intervals or P values are often calculated to

assess the statistical significance of the RR or OR estimate and help to evaluate the role of chance. Additionally , the association is considered stronger if the factor being studied exhibits a dose-response relationship (ie , lung cancer risk increases with increasing number of cigarettes smoked). A second important criterion is the consistency of the association. Similar associations reported for different population groups, in different location s, by different researchers , using different study methodologies, strengthen the case for causality. The third criterion is a temporal relationship. The exposure factor must precede the disease. The time relationshhip is especially important to consider when evaluating studies of cancer, since a long latency period (20 or more years) may exist between time of exposure and development of disease. Finally, the biologic plausibility of the association should be evident. In other words, the association should make sense in terms of the current scientific and medical information known about the factor and the cancer. For example, the development of most mesotheliomas of the lung is clearly due to the presence of inhaled asbestos fibers in the pleural or periton eal cavity . 22 CONCLUSION

The primary role of the cancer epidemiologist is to discover the causes of cancer. Nurses and other medical practitioners can assist the epidemiologist by taking complete medical histories, since patients' records are a valuable source of epidemiologic data. Descriptive and analytic epidemiologic studies provide medical personnel with knowledge about precursor conditions and etiologic factors that could influence an individual 's risk for developing cancer. Nurses can use this knowledge directly by answering patients' questions about the causes of cancer, detecting early signs of cancer, and promoting cancer prevention through patient education.

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EPIDEMIOLOGIC APPROACHES TO CANCER

6. Last JM: A Dictionary of Epidemiology. New York, Oxford, 1983 7. Newell GR: Epidemiolo gy of cancer, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer Principles & Practice of Oncology, Vol I. Philadelphia, Lippincott, 1985, pp 151-182 8. Hutchinson GB: The epidemiologic method, in Schottenfeld D, Fraumeni JF Jr (eds): Cancer Epidemiology and Prevention. Philadelphia, W.B . Saunders , 1982, pp 3-14 9. Horm JW, Asire AJ, Young JL Jr, ct al: SEER Program Cancer Incidence and Mortality in the United Stales 1973-81. DHHS Publicat ion No. (NIH) 85-1837, Washington , DC,

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14. Brown LM, Pottern LM, Hoover RN, et al: Testicular cancer in the United States: Trends in incidence and mortality. Int J Epidemiol (in press) 15. Ernster VL, Sacks ST, Holly EA, et al: U.S. Cancer Rates by Sex, Race, and Age: Graphics of SEER Program Data, 1973-1977. New York, American Cancer Society Inc, 1985 16. Page HS, Asire AJ: Cancer Rates and Risks. DHHS Publication No. (NIH) 85-691, 1985 17. McMichael AJ: Standardized mortality ratios and the "healthy worker effect": Scratching beneath the surface. J Occup Med 18:165-168, 1976 18. Goldsmith JR: What do we expect from an occupational cohort? J Occup Med 17:126-127, 1975 19. Zeighami EA, Morris MD: The measurement and interpretation of proportionate mortality. Am J EpidemioI1l7:9097, 1983 20. Cole P: The evolving case-control study. J Chronic Dis 32:15-27, 1979 21. Pottern LM, Brown LM, Hoover RN, ct al: Testicular cancer risk among young men: Role of cryptorchidism and inguinal hernia. JNCI 74:377-381, 1985 22. Hirsch A, Brochard P, DeCremoux II, et al: Features of asbestos-exposed and unexposed mesothelioma. Am J 1nd Med 3:413-422, 1982