Symposium on Malignant Disease

Changing Epidemiology of lung Cancer Increasing Incidence in Women

John F. Beamis, Jr., M.D., Aurum Stein, D.O., and Joseph L. Andrews, Jr., M.D.

Primary lung cancer continues to be a growing health problem in the United States and throughout the world. Incidence and mortality rates are rising yearly for both men and women. Cancer of the lung is now the number one cause of death from cancer in men and the number four cause of death from cancer in women. In 1974 approximately 83,000 new cases of lung cancer occurred in the United States. 19 Table 1 shows mortality rates from lung cancer among men and women in the United States from 1923 to 1969. In 1923 mortality rates for both sexes were relatively low and were approximately equal as reflected by the male to female ratio of 1.03/1. Since the 1930's the increase in mortality from lung cancer among men has been striking. Mortality rates for women have also increased but at a slower rate. The disparity in the rate of increase is seen in the steadily increasing male to female ratio over the period 1923 to 1960. Since 1960, many tumor registries have noted a change in the pattern of the rising incidence of lung cancer. A marked increase has been observed in the rate of rise for women and a leveling off in the rate of rise for men. The male to female ratio decreasing from its peak of 6.6/1 in 1960 reflects this changing pattemP Results of a detailed study of all patients with lung cancer diagnosed at the Lahey Clinic between 1957 and 1972 confirmed our clinical suspicion of an increase of lung cancer in women in recent years. Although the patients seen at the Lahey Clinic are from varied geographic and socioeconomic backgrounds, we believe our experience probably reflects that of others and, by presenting our experience in depth, we wish to call attention to the relatively recent development of another high-risk group for carcinoma of the lung-the smoking woman. Other recent developments in the epidemiology of lung cancer will also be reviewed. MATERIALS AND METHODS The total number and sex distribution of patients with cancer of the lung were obtained from the computerized diagnostic files of the Lahey Medical Clinics of North America- VoL 59, No. 2, March 1975 315

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Table 1. Death Rates from Lung Cancer in the United States':'

YEAR

1923 1930 1934 1940 1944 1950 1954 1960 1966 1969

RATE AMONG

RATE AMONG

WHITE MALES

WHITE FEMALES

PER

100,000

1.55':'-' 3.60 5.30 9.40 12.10 19.50 25.00 36.00 40.20 63.20

PER

100,000

1.50':'* 2.10 2.80 3.20 4.00 4.30 4.40 5.60 6.70 12.40

MALE/FEMALE RATIO

1.03/1 :'* 1.70/1 1.90/1 2.90/1 3.00/1 4.50/1 5.60/1 6.60/1 6.00/1 5.10/1

"Data from National Vital Statistics Division and Bureau of the Census, United States. ':":'Massachusetts data as reported by Lombard.14

Clinic Foundation for the years 1957 to 1972. The clinical records of all women with lung cancer were examined for information pertaining to cell type, age at the time of diagnosis, smoking history, residential and occupational histories, and methods of diagnosis and treatment. One of us (A.S.) independently reexamined available pathologic specimens from these patients without the knowledge of the clinical record. A number of patients, having had tissue diagnoses made at other hospitals, had been referred to the Lahey Clinic for treatment only. Although tissue specimens from these patients were not available for reexamination, most had been reviewed and confirmed at the time of the original referral. Our classification of lung tumors (Table 2) parallels closely that established by the World Health Organization12 in 1967. Alterations were made, in that small cell anaplastic carcinoma (undifferentiated carcinTable 2.

Histologic Classification of Lung Tumors':' Epidermoid carcinoma (grades 1 to 3) Adenocarcinoma Undifferentiated carcinoma Large cell Giant cell Clear cell Small cell Combined epidermoid and adenocarcinoma Bronchiolar carcinoma Bronchial carcinoid Bronchial cylindromatous adenocarcinoma Bronchial muco-epidermoid carcinoma Carcinosarcoma Pulmonary blastoma Pulmonary teratoma Unclassified

':'Classification used by the Laboratory of Pathology, New England Deaconess Hospital, Boston, is a modification of the World Health Organization Classification, 1967.1'

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EPIDEMIOLOGY OF LUNG CANCER

oma, small cell type) is not broken down into its several cell types, that is, fusiform cell type, polygonal cell type, and so forth; bronchiolar (bronchiolar-alveolar) carcinoma is separated from other adenocarcinomas; and papillary tumors are included under the appropriate cell type rather than classified separately. To reevaluate the relationship between cigarette smoking and cell type, the Kreyberg system of grouping lung tumors was used. Kreyberg's group 1 tumors have been related to smoking and include epidermoid, undifferentiated, small cell and undifferentiated, and large cell tumors; group 2 tumors include adenocarcinomas and bronchiolar-alveolar cell tumors and were not associated with smoking by Kreyberg.ll

RESULTS Table 3 shows the distribution by sex of the total 1145 patients with lung cancer seen at the Lahey Clinic Foundation between 1957 and 1972. Because yearly fluctuations were sometimes large, yearly totals were grouped into four 4-year periods from 1957 to 1972. The per cent of women among the total number of patients seen at the Lahey Clinic for any reason was essentially unchanged (55 per cent) during this period. This table demonstrates a marked rise in the total number of women seen with carcinoma of the lung over the study period. The 71 women seen in the period from 1969 to 1972 is nearly double the number seen in the period from 1957 to 1960. A steady increase is evident in the per cent of women among the total patients with lung cancer from 13 per cent in the 1957 to 1960 period to 30 per cent during 1969 to 1972 and a steady decline in the male to female ratio from 6.8/1 in the period 1957 to 1960 to 2.4/1 in the 1969 to 1972 period. This change is statistically significant (P=O.OI). The clinical records of 231 women with lung cancer were examined. Of these, 182 had surgical or autopsy specimens adequate for a specific diagnosis. Malignancy was diagnosed by cytology in 19, and bronchogenic carcinoma was diagnosed clinically in 30 patients. Pathology slides of tissue from 149 of the patients were available for reexamination. Pathologic diagnosis made at this time agreed with the original diagnosis in all but 8 per cent of the cases; these 8 per cent were regrouped according to the present classification of lung tumors outlined in Table 2. The distribution by cell types of those women with known tumor Table 3. Primary Lung Cancer, 1957-1972 1145 Cases; Distribution by Sex 1957-1960

1961-1964

1965-1968

1969-1972

Men Women Total

258 (87%) 38(13%) 296

214 (82%) 46 (18%) 260

266(78%) 75(22%) 341

177 (71 %) 71 (29%) 248

Male/female ratio

6.8/1

3.5/1

2.4/1

4.6/1

TOTAL

915 (80%) 230(20%) 1,145 4.0/1

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Table 4. Lung Cancer in Women, 1957-1972; 201 Cases with Known Histology CELL TYPE

1957-1960

1961-1964

Epidermoid Adenocarcinoma Undifferentiated Large cell Small cell Other Totals

8 (24%) 12(35%)

2(6%) 9 (25%)

5 (15%) 2 (6%) 7 (20%) 34

10(28%) 7(19%) 8 (22%) 36

1965-1968

1969-1972

TOTAL

12 (18.5%) 19(29%)

10(15%) 22 (33%)

32(16%) 62(31%)

14(22%) 8(12%) 12 (18.5%) 65

15 (23%) 8(12%) 11 (17%) 66

44 (22%) 25(12%) 38(19%) 201

histology is shown in Table 4. No statistically significant change is evident in the distribution of cell type over the years studied. In accordance with previous studies,22,25 adenocarcinoma comprised the largest group categorized by cell type in all periods and accounted for 31 per cent of all tumors. The undifferentiated large cell tumors made up the next largest group followed by epidermoid and undifferentiated small cell tumors. When cell types are combined for grouping by the Kreyberg classification (Table 5), the total number in each group increased, but no significant change can be seen in the proportion of group 1 (smokingrelated) and group 2 (nonsmoking-related) tumors. When known smokers and nonsmokers are differentiated within the Kreyberg classification (Table 6), the group largely responsible for the current increase in the total number of women with lung cancer, smoking women with group 1 tumors, becomes apparent. The numbers of nonsmokers with group 1 tumors and smokers and nonsmokers with group 2 tumors changed little over the study period. Table 7 further characterizes the total group of women with lung cancer. There has been a steady decrease in the proportion of nonsmokers from 55 per cent in the period 1957 to 1960 to 26 per cent in the period 1969 to 1972 and a corresponding increase in smokers from 40 to 49 per cent. The urban-rural residence distribution, based on residence at the time of diagnosis, changed little and probably reflects that of Lahey Clinic patients in general. Although occupational histories were frequently neglected in the clinical records, a slight decrease in the per cent of women who were housewives at the time of diagnosis and an increase in the number of women employed outside the home were evident. No specific high-risk occupations were identified. The average age Table 5. Lung Cancer in Women, 1957-1972; Breakdown by Kreyberg Classification GROUP

1957-1960

1961-1964

1965-1968

1969-1972

TOTAL

2 Total

15(44%) 14(41%) 29

19 (55%) 10 (28%) 29

34(52%) 23(35%) 57

35(53%) 24 (36%) 59

103(59%) 71(41%) 174

Per cents are based on all cases with known histology.

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EPIDEMIOLOGY OF LUNG CANCER

Table 6.

Smokers and Nonsmokers among Women with Lung Cancer Grouped by Kreyberg Classification

GROUP

1957-1960 1961-1964 1965-1968 1969-1972

TOTAL

Group 1 Smokers Nonsmokers

5 10

8 4

27 6

21 5

61 (43%) 25 (18%)

Group 2 Smokers Nonsmokers Period totals

5 7 27

0 7 19

8 12 53

8 9 43

21 (15%) 35 (24%) 142

at the time of diagnosis was 57 years in the periods from 1957 to 1960 and 1969 to 1972 and 60 years in the periods from 1961 to 1964 and 1965 to 1968.

DISCUSSION Cancer of the lung, relatively uncommon during the first decades of this century, has increased in incidence at an astonishing rate in the last 40 years. Survival rates are discouraging and have made the disease a major cause of death in the United States and in most industrialized countries. Mortality rates have increased more rapidly in men than in women (Table 1), which may partially be attributed to the greater occupational exposure of men to possible carcinogens. A number of specific industrial agents, including asbestos, uranium, chromium, nickel, chloromethyl methyl ether, and arsenic, have been associated with an increased risk of the development of lung cancer. 7 • 8,15.18.23 However, of the entire group of Table 7. Women with Lung Cancer, 1957-1972; Smoking, Residential, and Occupational Histories 1957-1960

1961-1964

1965-1968

1969-1972

Smoking history Never smoked, per cent Smokers, per cent Unknown, per cent

55 40 5

49 23 28

37 58 5

26 49 25

Residence history Urban, per cent Rural, per cent Unknown, per cent

60 40 0

64 36 0

58 40 2

65 33 2

Occupational history At home, per cent Outside, per cent Unknown, per cent

58 21 21

75 14

62 25 13

49 36 15

11

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Table 8. Estimate of Per Cent of Smokers in the United States 18 Years and Older" PER CENT OF

PER CENT OF

YEAR

MALES

FEMALES

1920 1925 1930 1935 1940 1945 1950 1955 1960 1965 1970

46 52 57 63 65 65 65 65 60 51 42

2 2 2 8 14 20 26 32 38 34 30

':'Data from national surveys as reported in References 3 and 9.

men in whom lung cancer developed, only small numbers have been exposed to these industrial carcinogens. By far the most important factor in the development of lung cancer is a history of cigarette smoking. The Surgeon General's report of 1964 states, "in comparison with nonsmokers, average male smokers of cigarettes have approximately a 9- to 10-fold risk of developing lung cancer and heavy smokers at least a 20fold risk."20 A large number of men in the United States began smoking cigarettes during the years immediately preceding and following World War I (Table 8), and by 1920 46 per cent of American men were smoking cigarettes.3 Mortality rates for men with lung cancer began to rise sharply in the 1930's, approximately 20 years after significant numbers of men began smoking cigarettes (Fig. 1). Given a 20 to 30 year lag period, lung cancer mortality rates for men, although slightly decreased in recent years, have continued to rise, paralleling the increase in cigarette consumption. The recent observations that mortality rates for men are leveling off may be reflecting the slight decrease in the number of male smokers since the Surgeon General's report in the 1960's. Significant numbers of women did not begin smoking cigarettes until the years before World War 11 (Table 8). However, by 1960 nearly 40 per cent of the women in the United States were smoking. From the experience in men, a rise could be predicted in the incidence of lung cancer in women some 20 to 30 years after large numbers of women began smoking. Figure 1 bears this out, showing an increase in lung cancer death rates among women since 1960. The mortality curve for women is now similar to that of men in 1930. We believe our study, although retrospective and not confined to a specific geographic population, reflects national statistics because we have seen significantly more women with carcinoma of the lung in recent years than in the earlier years of our study period (Table 3). The proportion of these women who were cigarette smokers has also increased. Although mortality rates for women are now approaching those for men, the lung cancer mortality rate for men is still five times higher. Bur-

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EPIDEMIOLOGY OF LUNG CANCER

bank3 has calculated a dose-response curve between cigarette consumption and lung cancer and suggests the difference in rates between men and women is due to the difference in past cigarette smoking, men having had a longer and more concentrated exposure to cigarette carcinogens. Wynder et al. 24 point out that smoking intensity factors, such as the number of cigarettes smoked a day, age at the time of starting smoking, duration of smoking, use of low tar cigarettes, and the habit of inhaling, are less among women smokers and may be protecting them somewhat from the development of lung cancer. Theories suggesting that steroid factors or the presence of two X chromosomes may be acting as defense mechanisms against lung cancer in women have not been substantiated. l The epidermoid, undifferentiated large cell, and undifferentiated small cell tumors, combined into group 1 by Kreyberg, have been associated closely with cigarette smoking in men and women.ll If the current increase in lung cancer in women is entirely due to smoking, a disproportionate rise would be expected in group 1 cell types rather than in group 2 tumors, adenocarcinoma and bronchiolar-alveolar cell tumors, which have not been as closely related to smoking. 5 , 6,14,24 Wynder et al. 25 have recently shown an increase in epidermoid tumors among American women with lung cancer from 32 per cent of all tumors in 1956 to 51 per cent in his 1970 to 1972 study period. Our data demonstrate no significant change in cell type distribution or in distribution by the Kreyberg classification in the total group of patients during the years studied (Tables 4 and 5). However, when only those patients with known smoking histories and known cell types are analyzed, it is evident that the group largely responsible for the recent increase in the total number of cases is smoking women with group 1 tumors (Table 6).

"0SMOKING OF U.S. POPULATION CIGARETTES

LUNG CANCER MORTALITY RATE per 100,000 POPULATION

100

,50 I

I

-,..-

..

80 d'smoker~s_ _ _ _ _....

,:

60

0

l'l··

"

: ~20

!

• •-

.~

I

~

~

.........

-140 I

130 :

....

//

I I

I I I I

d'Ca Mortality ....• ~

//

I

I

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40

20

l'

~IO I ~ Ca Mortality

....0

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:

L-____,-____~~··~·~··~·~.:•.~o.:.:•.~.o~.:..~~:.:.•:..~o:..:.o:.:.•:•.:.o~·_··_··_~__··-r____J:o 1910

1920

1930

1940

1950

1960

1970

Figure 1. Increasing lung cancer mortality rates for United States men and women from 1920 to 1972 shown with the incidence of smokers (per cent) for men and women. Increasing curves for lung cancer mortality follow increased smoking incidence rates in both men and women by 20 to 30 years, but the rise in female smoking incidence and lung cancer mortality is 30 to 40 years after that for men.

322

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In a retrospective study of lung cancer in British women, KennedylO demonstrated an increase in the total number of cases in recent years, but no change in the cell type distribution from 1955 to 1971 was noted. He concluded that factors other than cigarette smoking must be responsible for the majority of lung cancers in British women. As an alternative to Kennedy's conclusion, our data suggest that all cell types are related to cigarette smoking. The difference in cell type distribution between our study and Wynder's is difficult to explain. Since Kreyberg's review in 1962, the association between cigarette smoking and adenocarcinoma has been documented in men26 and also appears to be true for women. 3 Our data possibly underestimate the number of smokers because smoking histories were obtained from the clinical records at the time of diagnosis. A number of nonsmokers could have been exsmokers, and, in two of the 4year periods, 25 per cent of the patients had unknown smoking histories. More accurate data on smoking might have more closely demonstrated the relationship between smoking and all lung tumor cell types. In reviewing our study, Wynder's study, and the national smoking and lung cancer mortality rates, we believe the increase in the number of women smokers since 1930 has been reflected in the recent rise. in both group 1 tumors and adenocarcinomas. Wynder's data indiCate that epidermoid carcinomas may be increasing in frequency at a greater rate than other cell types. In all studies of lung cancer epidemiology as well as in our study, there are significant numbers of patients who have never smoked and yet lung cancer, both epidermoid carcinoma (group 1) and adenocarcinoma (group 2), developed. Some of these patients may have been exposed to industrial carcinogens. Occasional small high-risk groups of nonsmoking women have been identified, such as the Latin women living in El Paso County, Texas, who are exposed to high levels of polynuclear aromatic hydrocarbons and DDT from living in poorly ventilated adobe houses heated by open wood, coal, and oil fires. 1O ,16 However, these specific groups can only account for a small per cent of lung cancers in nonsmokers. The one factor to which smokers and nonsmokers alike are exposed is the air they breathe. Numerous studies, showing a higher incidence of lung cancer among urban dwellers than among those living in rural communities,4, 17 implicate air pollution as a causative factor in the development of lung tumors. Currently, urban dwellers are estimated to have approximately twice the incidence of pulmonary cancer as their rural counterparts.4 Although no specific air pollutant has been proved to cause lung cancer in humans, polycyclic organic matter has been implicated because similar compounds are found in cigarette smoke. 4 The atmospheric level of benzo[a]pyrene (C2o H 12 ), a compound of polycyclic organic matter, has been used as an index of urban air pollution because it can be measured easily and because it has been shown to be oncogenic in some laboratory animals. 4 Carnow and Meier,4 in a study of the relationship between air pollution and lung cancer, have hypothesized that there exists "a causal relation between air pollution and pulmonary cancer death rate at the rate of a 5 per cent increase for each increment of

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EPIDEMIOLOGY OF LUNG CANCER

pollution as indexed by 1 benzo[a]pyrene unit." Some researchers believe atmospheric carcinogens to be the primary factors causing lung cancer noting that migrants from countries with high to countries with low cancer rates, such as from Great Britain to New Zealand, appear to have a lower incidence of lung cancer than would be expected in their native country. The lower incidence of lung cancer in women has been attributed to differences in the atmosphere inside and outside the home. Air within the home tends to be freer of contaminants because the particles tend to settle out; in contrast, air outside the home is constantly stirred up by air currents which keep dust particles within the atmosphere. 21 Langston13 has indicated that the mortality rate from lung cancer is highest for persons born during 1890 to 1900 and apparently is decreasing for those born after that time. Sterling and Pollack21 note that the mortality rate for lung cancer currently is increasing only in the older age groups, has stabilized in the middle age groups, and is decreasing in the younger age groups. They suggest that older generations were exposed to high levels of atmospheric benzpyrene and other polycyclic organic matter liberated from the combustion of coal, which was used extensively as a home heating agent prior to World War II, and that the marked decrease in the use of coal since that time has lowered the exposure to atmospheric carcinogens for the younger generations. Multiple factors are involved in the etiology of lung cancer. Cigarette smoking, atmospheric pollution, and industrial exposures are the three areas that have been implicated thus far in numerous epidemiologic studies. Primary lung cancer 20 years ago was mainly a disease of white males. Our study reflects recent national trends and demonstrates a considerable increase in the numbers of women in whom lung cancer developed. Other investigators have demonstrated a marked increase in lung cancer among blacks over the past three decades. 2 Neither sex nor color appears to afford protection from lung cancer. If current trends persist, lung cancer will continue to rise rapidly in women. Male to female mortality ratios should continue to decrease but will probably never reach the 1923 ratio of 1.03/1, owing to the greater smoking and environmental exposures of men. On a more optimistic note is the fact that since the Surgeon General's report in 1964, both sexes have demonstrated a decline in cigarette smoking9 (Fig. 1). Hopefully, this decline in personal air pollution, combined with improvements in non personal air pollution in industry and in cities, will be reflected in lowered mortality from lung cancer in the future.

SUMMARY Recent worldwide reports show a large increase in the incidence of lung cancer in both men and women. To detail changes in the epidemiology of lung cancer relating to the incidence in men and women, we reviewed the patterns of diagnosis of 1145 patients with lung cancer seen at the Lahey Clinic between 1956 and 1972, during which time the proportion of all men and women seen was unchanged. The total number

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of women with lung cancer increased greatly and has almost doubled during this period. Lung cancer in women is now increasing at a faster rate than in men so that the male to female incidence has decreased from 6.8/1 (1957 to 1960) to 2.4/1 (1969 to 1972). We reviewed in detail the case histories and pathology of 231 women with lung cancer. No significant change was evident in cell type distribution during the study years. The most frequently seen tumors in women were adenocarcinoma (31 per cent), undifferentiated large cell cancer (22 per cent), epidermoid carcinoma (16 per cent), and undifferentiated small cell carcinoma (12 per cent). Among those women with known smoking histories, the group most responsible for the recent increase in women with lung cancer was comprised of smoking women in whom Kreyberg group 1 (smoking-related) tumors developed. ACKNOWLEDGMENTS

We wish to thank Merle A. Legg, M.D., and William A. Meissner, M.D., of the Laboratory of Pathology of the New England Deaconess Hospital for their advice and assistance in the review of the pathologic material; Jules Schwaber, M.D., Jeffery Parker, M.D., Edwin Kroeker, M.D., and Richard Johnson, M.D., of the Lahey Clinic for suggestions and review of the paper; and Fred Li, M.D., and Raymond Murphy, M.D., of the Harvard Medical School for their guidance at the beginning of this project; and Dr. Yvonne Bishop for her statistical help.

REFERENCES 1. Ashley, D. J., and Davies, H. D.: Lung cancer in women. Thorax, 24:446-450 (July) 1969. 2. Blake, W. 0., Todd, D., Allen, M., et al.: The changing picture of primary carcinoma of the lung. J. Natl. Med. Assoc., 64:99-101 (March) 1972. 3. Burbank, F.: V.S. lung cancer death rates begin to rise proportionately more rapidly for females than for males: a dose-response effect? J. Chronic Dis., 25:473-479 (Aug.) 1972. 4. Carnow, B. W., and Meier, P.: Air pollution and pulmonary cancer. Arch. Environ. Health, 27:207-218 (Sept.) 1973. 5. Deaner, R M., and Trummer, M. J.: Carcinoma of the lung in women. J. Thorac. Cardiovasc. Surg., 59:551-554 (April) 1970. 6. Doll, R, Hill, A. B., and Kreyberg, L.: The significance of cell type in relation to the aetiology of lung cancer. Br. J. Cancer, 11 :43-48 (March) 1957. 7. Figueroa, W. G., Raskowski, R, and Weiss, W.: Lung cancer in chloromethyl methyl ether workers. N. Engl. J. Med., 288:1096-1097 (May 24) 1973. 8. Fraser, R G., and Pare, J. A. P.:Diagnosis of Diseases of the Chest. An Integrated Study Based on the Abnormal Roentgenogram. Vol. 11. Philadelphia, W. B. Saunders Co., 1970, p.738. 9. Green, D. E., and Nemzer, D. E.: Changes in cigarette smoking by women-an analysis, 1966 and 1970. Health Serv. Rep., 88:631-636 (Aug.-Sept.) 1973. 10. Kennedy, A.: Relationship between cigarette smoking and histological type of lung cancer in women. Thorax, 28:204-208 (March) 1973. 11. Kreyberg, L.: Histological lung cancer types. A morphological and biological correlation. Acta Path. Microbiol. Scand. Suppl.157:1-92, 1962. 12. Kreyberg, L.: Histological Typing of Lung Tumours. Vol. 1. International Histological Classification of Tumours. Geneva, World Health Organization, 1967, 28 pp. 13. Langston, H. T.: Lung cancer-future projection. J. Thorac. Cardiovasc. Surg., 63:412415 (March) 1972. 14. Lombard, H. L., and Huyck, E. P.: An epidemiological study of lung cancer among females. Growth, 32:41-56 (March) 1968. 15. Louria, D. B., Joselow, M. M., and Browder, A. A.: The human toxicity of certain trace elements. Ann. Intern. Med., 76:307-319 (Feb.) 1972.

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16. Macdonald, E. J., Lichtenstein, H., Nooner, D., et al.: Epidemiological factors in lung cancer among women in El Paso County, Texas 1944-1969. J. Am. Med. Worn. Assoc., 28:459-464 passim (Sept.) 1973. 17. Schneiderman, M. A., and Levin, D. L.: Trends in lung cancer. Mortality, incidence, diagnosis, treatment, smoking, and urbanization. Cancer, 30:1320-1325 (Nov.) 1972. 18. Selikoff, I. J., Churg, J., and Hammond, E. C.: Asbestos exposure and neoplasia. J.A.M.A., 188:22-26 (April 6) 1964. 19. Silverberg, E., and Holleb, A. I.: Cancer Statistics, 1974-world wide epidemiology. Ca, 24:2-6 (Jan.-Feb.) 1974. 20. Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. P.H.S. Publication No. 1103. Washlngton, D.C., V.S. Government Printing Office, 1964, 387 pp. 21. Sterling, T. D., and Pollack, S. V.: The incidence of lung cancer in the V.S. since 1955 in relation to the etiology of the disease. Am. J. Public Health, 62:152-158 (Feb.) 1972. 22. Vincent, T. N., Satterfield, J. V., and Ackerman, L. V.: Carcinoma of the lung in women. Cancer, 18:559-570 (May) 1965. 23. Wagoner, J. K., Archer, V. E., Lundin, F. E., Jr., et al.: Radiation as the cause oflung cancer among uranium miners. N. Engl. J. Med., 273:181-188 (July 22) 1965. 24. Wynder, E. L., Covey, L. S., and Mabuchi, K.: Lung cancer in women: Present and future trends. J. Natl. Cancer Inst., 51 :391-401 (Aug.) 1973. 25. Wynder, E. L., Bross, I. J., Cornfield, J., et ai: Lung cancer in women; a study of environmental factors. N. Engl. J. Med., 255:1111-1121 (Dec. 13) 1956. 26. Weiss, W., Boucot, K. R., Seidman, H., et al.: Risk of lung cancer according to histologic type and cigarette dosage. J.A.M.A., 222:799-801 (Nov.) 1972. Lahey Clinic Foundation 605 Commonwealth Avenue Boston, Massachusetts 02215