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in 1943, were impressed not only with the clinical observations of a high proportion of tobacco smokers among lung cancer patients but also with the rise in the percentage of lung cancers in autopsy series in Cologne and Jena. Among the early observations in the United States were those of Ochsner and DeBakey (258) who were impressed by the probable relationship be- tween cigarette smoking, and luna cancer. The initial observations prior to Muller's work were not, however, corroborated by surveys including controls without lung cancer. As early as 1928, Lombard and Doering (221) in a studyof'~ cancer patients' habits in Massachusetts, wrote that "any study of the habits of individuals with cancer is of little value without a similar study of individ- uals without cancer." Their analysis of 217 cases of cancer and 217 controls identified, among other things, an association between heavy smok- ing (all types combined ) and cancer in~ general, and between pipe smoking, and oral cancer in~ particular. The pipe smokers then~ constituted the bulk (73.1 percent)i of the heavy smokers. This is of historical interest in rela- tion to the present-day percentage of heavy cigarette smokers. Further- more, since there were but five lung cancers in Lombard°s test group in an era before much of the rise in hing cancer incidence had occurred, the data were not adequate to demonstrate an, association between lung cancer and cigarette smoking. Probably the first study designed to explore this association system- aticallk- was by Miiller in 1939 (250) who had noted the increase in~ per- centage of primary carcinomas of the lung, being diagnosed at autopsy be- tween the years 1918 and 1937 in Cologne, an~ increase almost entirely in males. Although consid'ering other variables as possibly, related to the rise in lung, cancer mortality, such as increases in street dusts, automobilee exhaust! gases, war gas exposure in World War I, increased use of X-rays, influenza, trauma, tubercul'bsis, and industrial growth (air pollution?), he took special cognizance of the preponderant increase: of~ lung, cancer among, males and the parallel rise in tobacco consumption f'rom~ shortly before and since World War I and selec.tedl this variable for study. In what appears to be a caref'ully conducted inquiry of smoking habits in a series of 86 lung cancer patients and 86 apparently~~ healthy controls; matched by age,, a significant excess of heavy smokers was observed among the lung cancer patients. In the next ten years, three more case-control studies or comparisons withh cancers of other sites reached the literature (280, 309, 363) and from 1950 to the present time 25 additional retrospective (38, 82, 138, 147, 150, 152, 192, 199, 207, 211, 222, 236, 238, 277, 283, 301, 311, 314, 316, 335, 337, 365, 375, 379, 381) and 7 prospective studies (25, 83i 84, 87, 88; 96, 97, 157, 162, 163) were undertaken. Retrospective Studies The 29 retrospective studies of the association between~ tobacco smoking and lung cancer are sumarized in Tables 2 and 3. As these tables suggest, the studies varied considerablly in design and method. Methodologic varia- tions have occurred in the omission, inclusion, or;treatment of the f'ollowing: 150

METHODOLOGIC VARIABLES Subject SelectionL 1. Males and/or females. 2. Occupational groups 3. Hospitalized cases 4. Autopsy series 5. Total lung cancer deaths in an area 6. Samplings of nationwide lung cancer deaths Control Selection- 1. Age matching vs. age groups 2. Healthy individhals 3. Patients hospitalized for other cancers 4. Patients hospitalized! for causes other than cancer S. Deaths fromicancers of other sites 6. Deaths fromiother causes than cancer 7. Samplings of the general population Method' of Interviewing- 1. Mailed questionnaires 2. Personall interviewing of subjects (or relatives) and controls a): By professional personnel b) By non-professional personnel Tobacco-use Histories- 1. By type of smoking (separately and combined ). 2. By amount and type 3. By amount, type, and duration 4. By inhalation~ practices Other Variables Concurrently Studied- 1. Geographic distribution a) Regional bY Urban-rural 2. Occupation 3. Marital status 4. Coffee and alcohol consumption 5 Other nutritional factors 6. Parity 7. War gas exposures 8. Other pathologic conditions 9. Hereditary factors 10. Air pollution 11. Previous respiratory conditions This listing of methodologic variations is by no means complete, nor does it imply that't'he individual retrospective studies should be criticized for their choice of study methods and factors for observation. The individual points of criticism have usually applied to one or two studies but not t'oall. It is indeed striking that every one of the retrospective studies ofl male lung cancer cases showed an association betweem smoking and lung, cancer. All1 have shown that proportionately more heavy smokers, are found among the lung cancer patients than in the control populations and proportionately fewer non-smokers among the cases than among the con- trols. Furthermore, the disparities in proportions of heavy smokers between "test" groups and controls are statistically significant in all the studies. The differences in proportions of non•smokers among the two groups are also~statisticallly significant in all studies but one (236)I; in the latter study, although there were fewer non-smokers among lung cancer patients, the difference was very small. In the studies which dealt wi'th female cases of lung cancer~, similar find- ings are noted in all of them with one exception (238). In this latter study, although significantly more heavy smokers were found among, the lung cancer cases than among the controls, the proportion of non-smokers among the cases was distinctly higher than among the controls. This is the only inconsistent finding among, all the retrospective studies. Its meaning is not clear but the aut'hors have indicated that non-response among their female cases was 50 percent. The weight to be attached to the consistency of the findings in the retro- spective studies is enhanced when one considers that these studies exhibit considerable diversity in method'olbgic approach. 151

N ;.r:rAfia'Ls's TABLE 2.-Outline of methods used in retrospective studies of smoking in relation to lung cancer Number of persons and method of selection Investigator year and Country Sex of Collection of data , , reference cases Cases - - Controls MUller 1930 (250) Germany M 86 Lung cancer decedents, BOrger 86 Healthy men of the sanre age Cases: Questionnaire sent to relatives of Ilospital, Cologne. deceased. Controls: Not stated. Sehaircr and Schoenfger Germany M 93 Cancer decede.nts autopsied at Jena --- 270 Men of the, city of Jena aged 53 and Cases: Questionnaire sent to next of kin 1943 (309). Pathological Institute, 1930-1941: - 54(average age of lung cancer victuns= (195 for hmg canrer). Controls: Ques- - a3.9). - tionnaire sent to 700. Potter and'fully 1945 (280) U.S.A. M 43 Male patients aged over 40 in Mas- 1,847 Patients of same group with - Cases and controls interviewed in clinlc9 ---- - sachusetts cancer clinics with cancer diagnoses he rt ha n ncer. o t cx - ---- of respiratory tract. _ _ _ _ _ _ _ _ - - -- Wessink 1948 (363) Netherlands M 134 Male clinic patients with lung can- 100 Normal men of same age groups as Cases: Interviewed In cllnic. Controls: cer. cases. Not stated. Schrek et al., 19,50 (311) U.B.A. M 82 Male lung cancer niLses among 5,003 - 522 Miscellaneous tumors other than Smoking habits recorded during routine - -- - -- -- - - - - patients recorded, 1941-4!}. - Iung, larynx and pliarynz. - hospital interview. - . Mills and I'orter 1950 (237) U.$.A. M 444 Respiratory cancer decedents in 4;30 Samplo of residents matched by age Ca.ses: Relatives queried by mail ques- - in Detroit, Cincinnati, 1940-45 and in Cobunbus, Ohio, from census tracts tionnaire or personalvisit. Controls: _ 1942--16. " stratificd by degrec of air pollution. House-to-house interviews. Levin et al., 19.50 (207) U.8.A. M 236 Cancer hospital patients diagnosed 481 Patients in same hospital with non- Cases and controls: Routine clinical lung caneer. cancer diagnoses, history taken before diagnosis. " VJ der & Graham 1950 U.S.A. M-F 605 Hospital and private lung cancer --- 780 Patients of several hospitals with Nearly all data by personal interview; a - 381). patients in many cities. diagnoses other than lung cancer. few cases by questionnaire; a fow from intimate acquaintane,es. Some Inter- views with knowledge or presumption -- of diagnosis, some with none. - McConnellet a1.,1952 (236) England M-F 100 Lung cancer patients, unselected, 200 Inpatients of same hospitals, Personal interviews by the authors of - in 3 hospitals in Liverpool area, matcheil by age and sei, without c[m• both cases and controls, with few ex- 1940-19. - --- ---- cer, 1944-50. ceptions:__ Doll and Hill 1952 (82) Great M-F ,465 Patients with lung cancer in hos- 1 1,465 Patients in same hospitals, Personal interviews of cases and controls Britain. _ _ pitals of several cities. matched by sex and age group; some by almoners. with cancer of other sites, sofne with- out cancer. Sadowsky et al., 1953 (301) U.B.A. M 477 Patients with lung cancer I_n_ hos- 615 Patients in same hospitals with il1- Personal questioning by trained intsr- pitals in 4 states. nesses other than cancer. viewers. ~ 6z~`.4S94f:0 ,, _

wynuer and Cornneld U.d.A. M 63 Physicians reported in A.M.A. 133 Physicians of same group dying of Mailquestionnairetoestatesofdeoedonts 1953 (379). Journal as dying of cancer of t3ie cancer of certain other sites. lung Koulumies 1953 (192) Finland M-F 812 Lung cancer patients diagnosed at 300 Outpatients of same hospital aged Cases and controls questioned about one hospital in 16 years. over 40, living in similar circum- - smoking ha bits -wh en- taking case stances, and without cancer, February _ _ _ histories. and March-1952: Lick_in_ t_ 1953 (211) Germany M-F 246 Lung cancer patients in a number 2.002 Sample of persons without cancer Personal interviews by staff members of of hospitals and clinics. living in the same area and of same sex cooperating hospitals and clinics, and age range as cases. . . corresponding in time to Interviews of . . . . ... ..... . ... . . ea5es. Breslow et al., 1954 (38) U.S.A. __- M-F - 818 Lung cancer patients in il Califor- 518 Patients admitted to same hospitals Cases and controls questioned by trained n_ ia hospitals, ospitals, 1949-52 about the same time, for conditions interviewers, each matched pair by the other than cancer or chest disease, same person. matched for race, sex, and age group. Watson and Conte 1954 U.S.A. M-F 301 All patients of Thoracic Clinic at 468 All patients of same clinic during The 769 consecutive patients of case and (365). Memorial Hospital who were diag- same period with diagnoses other than control Qroupswere questioned by the nosed lung cancer, 1950-52. lung cancer, same trained interviewer. Osell 19.M (138) -- - -- Switzerland -- M 135 Men with diagnosis of bronchial 135 Similar hospital patients with diag- Personal interviews, all by the same carcimmma. noses other than lung cancer, and of person. - the same age. Randig 1954 (283) Germany M-F 448 Lung cancer patients in a number 512 Patients with other diagnoses, Controls were interviewed at about the of West Berlin hospitals, 1952-.1951. - matched for a¢e: same time as the cases, each case- pair by the same physician. 8tocks and Campbell 1955 - (Preliminary; see 19.57 report below.) - (337). Wynder et al., 1959 (375) U.S.A. F 105 Patients with lunq cancer in sev- 1,304 Patients at Memorial Center with Cases: Personal Interview or question- eral New York City hospitals, 1953- tumors of sites other than respiratory nairemailedtocloserelatlves or friends - 5. or upper alimentary, 1953-1955. Controls: Personal lutervlew. Segi et al., 1957 (316) Japan M-F 207 Patients with lung cancer in 33 5,636 Patients free of cancer In 420 local Cases and controls by personal interview hospitals in all parts of the country, health centers, selected to approxi- using long questionnaire on occupa- 1053-55. mate the sex and age distributions of tional and medical history and living cas~s. habits. Mills and Porter 1957 (238) U.S. A. M-F 578 Residents of defined areas dying of 3,310 Population sample approximately Cases: From death certiflcates, hospital respiratory cancer; I947-55. proportional to oases as regards areas records, and close relatives or friends. of residence, and 10 years or more in Controls: Personal home visits or tele- the area. phone calls, usually interviewing housewife: -- Stocks 1957 (335) England M-F - 2,356 Patients suffering from or dying - 9,362 Unselected patients of the same Cases: Histories taken at the hospital or with lung cancer within certain area admitted for conditions other from relativesby health visitors. areas. than cancer. Controls: Personai lnterview in hospital.

TABLE 2.-Outline of methods used in retrospective stu dies o f smoking in relation to lung cancer-Continued Number of persons and method of selection Investigator, year, and Country Sex of Collection of data reference cws_e_s_ Cases Controls Schwartz and Denoix 1957 France M 602 Patients with bronchopulmonary 1,204; 3 groups: patients ]n same hospi- Personal interviews in the hospital; cases (313). cancer in hospitals in Paris and a tals with -other cancer, with non- and controls at about the same time by few other cities. cancer illness, and accident cases, the same interviewer. matched by age group. - - ------ Haenszel et al., 1958 (150) U.S.A. F 158 Lung cancer patients available for 339 Patients in same hospital a nd service Personal interviews by resident, medical interview in 29 hospitals, 1955-57. _ at same time, next older and next social worker, or clinic secretary. younger than-each-case.--- Lombard and Snegireff U.S.A. M 500 Men dying or lung cancer, micro- 4,238 Controls in 7 groups including Personal interviews by trained workers. _ 1959 (222). scopically confirmed, 1952-5.9. volunteers, hospital and clinic pa- tients, random population sample, and house-to-house survey samples. Pernu 1960 (277) Finland M-F 1,606 Respiratory cancer patients in 4 1,773 Cancer-free persons recruited by Cases: From ease histories or mailed hospitals and from cancer registry Parish Sisters of 2 institutes in all questionnaires. between 1944 and 1958. parts of the country. Controls: Questionnaires distributed by Parish Sisters. - Haenszel et al., 1962 (147) U.S.A. M 2,19( Sample of 10 percent of white 31,516 Random sample from Current Cases: By mail from certifying physi- male lung cancer deaths in the U.S. Population Survey used to estimato cians and family informants. in 1959. population base. - Populatlon: Personal interview by Census enumerators. Lancaster 1962 (199) Australia M 238 Hospital patients with lung cancer 476 Twogr oups, one with other cancer, Personal interviews of both cases and one with some other disease, matched - eontrois in hospitals. by sex and age. Haenszel and Taeuber U.S.A. F 749 Sample of 10 percent of white 34,339 Random sample from Current Cases: By mail from certifying physi- 1963 1 (152). female lung cancer deaths in the Population Survey used to estimate cians and family informants. U.S. in 1858and 1959. - population base. Population: Personal interview by Census enumerators. I To be published. I-4 S911f;0 -a.

Germane to this concordance is a recent study (386) of Seventh Day Adventists, a religious group in which smoking, and alcohol consumption are uncommon. On the basis of expectancy ofi male lung, cancer incidence derived from the control population~ only 101percent of the cases expected were actually found among Seventh Day Adventists. FORM OF TOBACCO USE In considering the details of the individual retrospective studies listed in Tables 2 and 3, 13' of'~ the studies, combining, all forms of tobacco consump- tion, found a significant association between smoking of any type and lung cancer (138, 1199, 211, 250, 277, 280, 283, 309, 316, 363, 365, 379, 381) ; 16 studies yielded an even stronger association with cigarettes albne as com- pared! to pipe and/or cigar smoking (38, 82, 147, 192, 207, 222, 236;, 237, 238, 277, 283, 301, 311, 314, 335, 379) when these forms -)f smoking were considered separately and in combinations for males. The females, in the studies investigating the relationship of smoking and lung cancer among them, were almost invariably cigarette smokers so that comparisons with other forms of tobacco use were not indicated. AMOUNT SMOKED Twenty-six of the studies quantitated the amount of smoking, per day either by combining weights of tobacco consumed in any form, or, more often, by quantities of the specific forms of tobacco. In each of the studies investigating male lung cancer, the degree of association increased as the amount of smoking, increased (38, 82, 138, 147, 150, 192, 199, 211, 222, 236, 250, 277, 280, 283, 301, 309, 311, 314, 316, 335, 363, 365, 379, 381). One retrospective study (82) by Doll and Hill found a sharper difference in amount smoked between cases and controls among recent smokers (10 years preceding onset of the disease) than in a: comparison of the maximum amount ever smoked. The authors cautione& against accepting this finding as being against their hypothesis of a gradient of risk (which would more properly be tested by the whole life history of! "exposure to risk") by citing the inaccuracies resulting from "requiring the patient to remember habits of many years past." Of the 11 retrospective studies with data on females and tobacco use by amount smoked daily, six (211, 236, 277, 283, 365, 381) showed trends of increasing, association with amount smoked daily, but had too few cases for reliability of the trend. However, five studies (82, 150, 152, 335, 375) did have large numbers of female lung cancer cases for analysis by smoking class; three of these (150; 152, 375) were directed towards female cases only. In each of these latter five studies, the degree of association increased with the amount of cigarettes smoked daily. Four of the retrospective studies dealt~ with ex-srnokers as well (147, 152, 211, 314)~; in one of these (31i4.), where relative risks were derived indirectly by the Cornfield method (61), and in another by conventional use of' stand- ardized mortality ratios (147), male ex-smokers showed a lower risk than 155 -A

TABLE 3.--Croup characteristics in retrospective studies on lung cancer and tobacco use Authors $efer-. enCe Year MOller _____ (250) 1939 Schairer & Schoeniger=== (309) 1943 Potter &'Fully -_ _ (280) 1945 Wassink____ ____ (363) 1918 Schrek et al_____________ '311) 1950 Mills & Porter__________ (237) 1950 Levin et al______________ (207) 1950 Wynder & Flraham_____ (381) 1950 McConnell et al_-.______ (236) 1952 Doll & II111_____________ (82) 1952 Sadowsky et al.._____-__. (301) 1953 Wynder & CornOeld___. (379) 1953 #oulumles__________ ____ _ (192) 1953 Lickint_________________ (211) 1953 Breslow et al____________ (38) 1954 Watson & Conte________ (365) 1954 Osell-------------------- (138) 1954 RandlB--------------•--- (283) 1954 Stocks & Campbell__.__ (337) 1955 Wynder et al_=_____-____ (375) 1956 Segtet al________________ (316) 1957 Mills & Porter__________ (238) 1957 Stocks------------------ (335) 1957 Schwartz & DenolY._ (313) 1957 Haenszelet al_:______(150) 1958 Males Females Cases Controls Cases Controls Remarks Num- Percent Percent Num- Percent Percent Num- Percent Percent Num- Percent Percent ber non- heavy ber non- heavy her non- heavy her non= heavy smokers smokers ~ smokers smokers I smokers smokers r smokers smokers I 88 3.5 85.1 80 18.3 36.0 93 3.2 31.2 270 15.9 9.3 (•) (•) 181emale cases not 43 7. 0 30.2 1,847 26.0 23 0 ? S ( (q 134 4.8 54.8 100 19.2 19.2 (') extlm Percentages chart. 82 14.6 18.3 522 23.9 9.2 (t) 444 7.2 S •? 430 30.5 (•') (•) 236 15.3 (") 481 21.7 (") (') Quantity smoked sldered . 605 1.3 51.2 780 14.8 19.1 40 57.5 25. 0 552 79.6 1.2 93 5.4 38.5 186 6.5 23.2 7 67.1 (") 14 78.6 (") 1.357 0.5 25.1 1.357 4.5 13.4 108 37.0 11.1 108 54.6 0.9 Percentage "heavy understated. 477 3.8 (") 615 13.2 ('•) (') (7redient with smoked. 63 4.1 87.8 133 20.8 29.3 f') (') (') ( ) (~) (') 812 0.8 58.9 300 18:0 25:0 f••) (•') ('•) (•) (') (') 224 1: 8 35.8 1.000 16. 0 4.8 22 64.0 4.5 1, 002 90.4 0. 1 b18 3.7 74.1 518 10.8 42.7 (•') O (•') (") (") ('•) Data include 493 females. 265 1.9 71.7 287 9.7 51.8 36 58.3 2.8 181 82.0 1.1 135 0.7 68.1 135 16.0 14.0 (•) (') (') (•) (*) (') 415 1.2 34.2 381 5.4 17:9 33 51.5 3.0 131 70.3 0 (See reference ( 335) helow ) ('3 (') (') 105 56.2 16.2 1,304 66.0 3. 4 166 (••) (•') 2,124 (") Quantities smoked averages only. D are statistically s 484 8.4 26.0 1,588 27.6 5.3 94 83.0 4.3 1,722 73.3 0.8 Percent "heasy" understated. O survey respons female cases. 2,101 1.0 28. 2 5,960 8.7 22.3 255 67.6 17.2 3,402 88_ 8 10.7 602 1 58. 2 1,204 9.6 36.2 (') (') (') (') (') (') (*) (0) (') (') (•) (') 158 51. 9 14.6 A.~9 6n 6 A 2 analyzed. ated from not oon- " smokers amount males, 25 stated as iffereneee ignificant. smokers nly 50% e among C`'LS94f:U

} ombard & L Snegirott____ (222) 1959 500 1.6 ('•) 4,238 11.0 (••) Authors' calculations fo heavy smoking o based lifetime number of pack of cigarettes. emu___________________ (277) 1960 1,477 6.6 34.5 713 37.2 20.8 129 85.3 26.4 1,060 91.6 0.7 Quantitl es given only I Haenazel et al___________ (147) 1962 2.191 3.4 41.9 f') 16.2 12.0 - grams per day. Population sample of 31,61 used as base. Not a case controi study. . ancaster--------------- (199) 1962 238 2.5 86.1 476 20.1 71.2 Haenszel & Taeuber_••_ (152) r19fi3 (•) (•) 749 60.9 11.5 (1) 67.3 2.5 Population sample of 34,33 used as base. Not a cese control study. I For this table heavy smokers are deflned as those smoking 20 or more cigarettes per day. I To be published. - •Does not apply. '•Data not given. r n a n 6 = 9 •

current smokers but greater than non-smokers. In a third study (152) of lung cancer in women, the ex-smoker risk was lower than the current-smoker risk but approximately equal to that for the non-smoker. i 0 DURATION OF SMOKING Duration of smoking was considered im 12 of the retrospective studies (82, 150, 207; 222, 236, 283, 301, 311, 316, 335, 375, 381). In only six of them, however, were : the data treated im such a way as to permit evaltiation of the relationship between duratiom of smoking and lung cancer-two studies in males (207,, 301) ; two in males and! females (82, 236)~; and two in females only (150, 375). Among the studies of male lung cancer, Levin (207), correcting his data for age, found a relationship between the number of years of cigarette smoking and lung cancer. McConnell (236) found a significant difference in duration of smoking, between cases and controls, but was reluctant to draw any definite conclusions. On the other hand, Dolli and Hill (82), in their age: and sex-matched study, showed a distinct and statistically significant association between the duration of smoking among males. In a well-conceived analytic study, Sadowsky et al. (301), recognizing that' duration of smoking is a function of age„ controlled the age variable, and found an increasing prevalence rate of lung cancer with an increase in duration of smoking among all age groups (age at diagnosis). Among the studies including data on female lung cancer, McConnell had too few female cases to resolve the question ofl dbration of smoking (236) and Doll and Hill, though finding differences between cases and controls, could not establish statisticall significance (82). In the two investigations in which only female lung cancer cases were studied (150, 375), neither showed an independent association between, duration of smoking and lung cancer. Haenszel states, however, that "among women, the association of' starting age and duration of tobacco use with current rate is so strong that it may be unrealistic to expect' to find a separate duration effect in retro- spective studies of limited size" (150). AGE STARTED SMOKING Closely related' to duration of smoking, and thus pertinent to the length of time that subjects have been, exposed to tobacco smoke is the variable of age when smoking was startedl Relatively few of the retrospective studies have dealt with this variable. Koulumies (192) found that males with lung, cancer had started smoking significantly earlier in life. In fact, 143 of his 845 cases or 17 percent began to smoke below 10 years of age as compared to 6.5 percent among his matched controls. The study of male cases and controls by Breslow et al. (38) found a definite trend in the same direction. Pernu (277) found a statistically significant difference in age at start of smoking, with a higher proportion of the male lung cancer group starting at under 15 years of age. Lancaster (199) indicated that the male lung cancer patients began to smoke at a significantly younger age. One other study (283) showed no difference. Of the three investigations of female lung cancer which explored this variable, there were too few smokers in one study for a test of significance (277), and in the remaining two (150, 283), no differences were found. 158

INHALATION If the association between smoking, particularly cigarette smoking, and lung cancer is a causal' relationship, then inhalation, should provide more exposure than non-inhalation and should thus contribute significantly to the lung cancer loadl Four retrospective investigations were addressed to this question. In the earlier Doll and Hill study (82), no difference in the proportioni of smokers inhaling was found among male and female cases and controls. However, four subsequent studies of men (38, 211, 222, 313')) found' inhalation of cigarettes significantly associated with lung cancer. Although in Breslow's study (38) of age-, sex- and race-matched case and control patients, the variable ` quantity-smoked" was not held' constant in the comparison when type of smoking though not quantity was controlled, an association was found! between inhalation and lung cancer. In the studyy by Schwartz and Denoix ('3'13) who held constant both type of smoking and' amount of cigarettes smoked, the relationship of inhalation was significant for those smoking cigarettes alone but not for the smokers of both cigarettes and pipes. Furthermore, although inhalers among lung cancer patients averaged a significantly higher number of cigarettes per day than dld the controls, the relative risk differences between inhalers and non-inhalers, calculated' by the Cornfield method (61), become smaller and almost equal each other at the highest cigarette consumption levels. Lombard and Snegireff (222) demonstrated similar relative risk ratios. HISTOLOGIC TYPE The earliest retrospective study which considered histologic type of lung cancer was by Wynder and Graham (381) in 1950: These authors presented data on smoking habits of male and female adenocarcinomatous patients and for female patients with epidermoid cancers which were but 25 in number. With this partial analysis only a hint of' a higher proportion of smokers among female epidermoid cases could be derived. Of the 1,465 lung cancers in the Dolll and Hiill retrospective study(;82) , 995 werehistologically, con- firmed (916 males and 79 females). Of the confirmed cases, 85 percent of thee males and 71 percent of the females were of the epidermoid or anaplastic types. Although no statistically significant difference in smoking habits was elicited for the several types, a relatively higher proportion of non-smokers and light smokers were found among patients of both sexes wit'h ad'enocarcinoma. Following the presentation by Kreyberg, of a Typing Classification of the epid'ermoid and oat cell or anaplastic types as Group I and the adenocar- cinoma and bronchiolar or alveolar cell types as Group II', and the suggestion of' a relationship between Group I and smoking (196), several ensuing retrospective studies dealt with this question. Breslow's study revealed a higher percentage of non-smokers among the patients with: adenocarcinoma than among those with epidermoid types (38). In rapid succession six additional retrospective studies analyzed the rela- tionship between histologic type of lung cancer and smoking. The 1956 study of female lung cancers by Wynder et al. (375) indicated that adeno- carcinomata apparently had little or no relationship to smoking but that a relationship did exist between smoking and the epidermoid and anaplastic: types. Schwartz et al. (313), similarly, in 1957, found a highly significant 714-422 0-64-12 159