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I i Arra Ortrologira 28,4989) Easr. 5 FROM THE DEPARTMENT OF CA'JCER' EPIDEMIOLOGY„ RADIUMHEMMETi. THE DEPARTMEI:T OF EPIDEMIOLO- GY, INSTITUTE OF ENVIRONMENTAL MEDICINE. KAROLINSKA IhSTITUTE, ST'OCKHOLkI., AND THE DEPART- MENT OF LUNG MEDICINE. HUDDINGE HOSPITAL. HUDDINGE, SWEDEN.. SMOKING AND PASSIVE SMOKING IN RELATION' TO LUNG CANCER IN WOMEN' C. StiTnsson, G. PERSHAGEN and J. Kt.oMtraEtt Abstract In a population, based case-control study the association be- tween female lung cancer and some possible etiolbgical, agents was investigated; 210 incident cases in Stockholm county. Swe• den. and 209 age-matched population controls were interviewed about their exposure expenences according to a structured ques- tionnaire. A strong association between smoking habits and lung cancer risk was foun& for all histological subgroups. Relative risks for those who had smoked daily, during at least one year ranged between 3.1 for adenocarcinoma to 33.7 for small celll carcinoma in a comparison with never-smokers. All histological types showed strong dose-response relationships for, average daily cigarette consumption, duration of' smoking. and cumula- tive smoking. There was no consistent effect of parental smoking on the lung cancer risk in smokers. Only 38 cases had never been regular smokers and the risk estimates for exposure to environ- mental tobacco smoke were inconclusive. The high relative risks of small cell and squamous cell carcinoma associated with smoking may have implications for risk assessments regardingg passive smoking. Key: unrds: Lung carcinoma, smoking, environmental tobacco smoke, case-control. Carcinoma of the bronchi and lungs (lung cancer) is a common and highly lethal malignant disease. The domi- nating role of smoking as causative factor is established through numerous studies. The incidence is generally much higher among men, but in the USA lung cancer is now replacing breast cancer as the leading cause of cancer mortalit'yamong women (1).Among Swedish womemthe trend for, annual increase of lung cancer is second only to malignant melanoma of the skin (2).. Many studies have shown that adenocarcinoma consti- tutes a greater proportion of the lung cancer incidence in females than in males (3)i The difference can partly be explained by differences in smoking habits between the gend'ers. but there are some indications that a similar pattern can be seenin non•smokers (4, 5). During the last few years several studies have indicated that 'passive smoking' or exposure to environmental to, bacco smoke (ETS) may be of etiological!imponance. The findings have recently been evaluated (6)'. Most of the studies have focussed om the effects of ETS exposure during adulthood, but some data suggest an effect of childhood, exposure both in smokers and non-smoker,s (7, 8). To further investigate the effects on women of smoking and other possible etiological'factors for lung cancer, such as ETS and radon exposure in the home, and possible protective effects of some dietary components, we per- formed a population based case-control study. The first part of the study, addressing the risks associated with smoking and ETS, is presented in this paper.. Material and Methods The study included Swedish,speaking women living in Stockholm county between 1983 and 1986. Persons in the county with suspected or newly detected lung cancer are as a rule referred to one of three clinical departments of lung medicine (Karolinska, Huddinge, and Sodersjukhu- set); or to the Department of Thoracic Surgery (Karo- Accepted for publication 6 September 1988. 2023512837 623

624 C. SSINSSON, G. PERSHAGEF~ AK~D~.1.~. KLOMIh~E~k. Gnska) for further investigation and/or treatmcnt. To be included in the present study, the subjects should be in a physical and mental condition that allowed an inter.ieti. lasting:between one half to one hour. Suspected and confirmed cases were intcr~viewe&in the hospital ward's. For inclusion, in the stvdy the diagnosis should be confirmed microscopically or by unambiguouss chest radiograms in, conjunction with a typical clinical course. The majority of interviews were made before the diagnosis was confirmed. When a case was confirmed and included~ in the study, a population controli born on the same day was chosem at random from the populationi register in Stockholm county. lf~she could not be traced or refused tnpanicipate, she was replaced by another wom- an, who was selected and contacted in the same manner. The controls were interviewed by the same persons that interviewed the cases. The control interviews were made during a personal visit (58%) or by telephone. A hospital' control group was also included in some of the analyses pertaining to ETS-exposure. This group was selected among those patients with suspected lung cancer who were interviewed, but for whom the subsequent in- vestigation ruled out this diagnosis. The cases and hospital controls were interviewed dur, ing September1983-December 1985. The last population control was interviewed one year later. The time lag between intenieva of cases and population controls was mainly caused by, the interval betwcen admittance of: a patient to a clinic and definite confirmation or rejection of the pretiminary diagnosis. Eighty-six percent of the study subjects were interviewed bytwo physicians (CS and'JK) The remaining subjects were interviewed by two otherr physicians. A structured questionnaire was used for the interviews. It contained questions about frequency of consumption of' food',stuffs rich in vitamin A, carotenoidS, andivitamin,C, exposure to ETS, smoking. and data on all dwellings in whichia subject had lived for more than two years con- tinuously: Exposure to ETS was assessed through ques- tions aboun domestic exposure during childhood as well as domestic and work environment exposure during adult life. The criterion for being classified as a smoker was that the subject should have smoked daily for at least one year. Statistical evaluation was made with the computer pro- gram EPILOG (9). Relative risks (rate ratios) were mainly estimated by stratified analyseswith the extension for trend of the Mantel-Haenszel procedure (10, 11)., In the trend analysis the exposures were scored 1, 2, 3, etc. In the matched analyses the exact method for computing confidence intervals (CI) described by Miettinen was used (12)i In the unmatched analyses Cornfield's method was used (13): For, some of the analyses multiple logistic re- g7essiommodels:were used as well (14). Significance inter- vals presented in the article are two-sided and 95 ~J~ Cl are used throughout., Results The swdy finally included'210 cases and 209 population controls. In addition, 191 inter~ieued patients were shown not to have lung cancer.. For 9 patients primary lung cancer could neither be confirmed nor excluded. Seven subjects refused interview and 5 could not be inter- viewed because of their medical condition. One hundred'and seventy five (84%) of the population controls,were first hand choices. One control did'nos ha\e a corresponding case, since the case had to be excluded during the analysis, when an autopsy revealed primary carcinoma of the colon with, pulmonarymetastases and notprimary, lung cancer. For two cases no controls willing to be interviewed'were found~ Table I shows the microscopical classification of the cases. All but two were histologically or cytologically confirmed. In one of these an autopsy showed chararter- istic macroscopical changes of'~ malignant nature, but un+ fonunately a microscopical investigation was nou made. Adenocarcinoma was most common and constituted ap- proximately one-third of the cases. The age distribution was similar in the different histological groups. Table 2 displays the diagnoses for the non-lung cancer patients along with their smoking status. Malignant dis- ease other than lung cancer was the most common cause and constituted'approximately one-fourth of this group of patients. An additional 17 patients in this group had a malignant disease although not dii•ectly , associated with their respiratory, ailments and consequently not the reason for their hospitalization. Table 2 also shows that the pro- portion of smokers among the population controls was smaller than for the non-lung cancer patients. Smoking. All analyses pertaining to smoking were made using the population controls only. The relative risk for lung cancer for those who had ever smoked vs. never- smokers was calculated bothiin a matched analysis and in an~unmatched~analysis adjusted for agc. The two methods yielded similar results, e.g. the risk estimate for all lung a cancers was 5.8 (Cl: 3.¢1A.3) in the matched analysis and 6.4 (CI: 4.0-1U.5) in the unmatched. The highes risk was seen for small cell cancer (33.7, unmatehed)'an~ the lo1i.'- est for adenocarcinoma (3.1, unmatehed). The mean age for the cases, who were never-smokers, was higher than . for those who had ever smoked (66:3'vs, 61.7, p=0.009) Table 3 shows the dose-response relationships for dif, ferent types of lung cancer with average daily cigarette consumption as exposure variable. Subjectswho had stopped smoking more than two years prior to the inter- view (for population controls two years before the interw view of the corresponding case) were classified as ex- smokers. Small cell and squamous cell earcinomas showed the strongest trend of increasing relative nsk W ith increasing smoking intensity. For some of the estimates the Cl': was very, wide because of the small' number of never-smokers among the cases, especially among those

SMOxING.AND LUNG CANCER IN wOMEK Table I Lung cancercases among ux>men in Srock'holm counn according ro hisroloFicaLr.pe oJ,tumr» and d agnosnr uerifcatian r k Histol. Cytol. No microsc idt Total Mean a e evidence tvidence ev nce n 9~ g (yearsli n % n 9i n 9 All cases 148' 70.5 60 28:6 2 1.0 210 100~0' 62.5 Squamous cell 41 77.4 12 22:6 0 0.0 53' 25:2' 63.7 Small cell 30 66.7 15 33.3 0 0.0 45 21.4 62.6 Adeno 55 76:4 17, 23.6 0 0.0 72 34.3 61.6 Other 22 55.0 16 40.0 2 5.0 40 19.0 62.3 Table 2 Diagnoses and smoking among (emale non.lung cancer parients intertritwed at departments Jor pulmonarr diseases in Stockholm count) as uxll'as proportion of'smod-ers among population con- trots Diagnosis n ~ Smokers ~7r Malignant tumor 47, 24.6 59.6 Breast 13' 6,8 46.2 Gynecological 11 5:& 54.5 Pneumonia or ottier respiratorn infection~ 35 1&1 54.3 Unspecified pulmonary infiltration 23 12'0 65.2 Benign tumoror cyst 22 111.5 40.9 Pleuritis 8 4'.2 50.0 Tuberculosis 5 2.6 60.0' Sarcoidosis 5 2.6 20,Q~ Haemoptysis 5 2.6 100!0: Chronic bronchitis 5 2.6 100i0', Bronchiectasis 4 2.1 75:0. Atelectasis 4 2.1 25:0. Other specified diagnosis 24 12.6 67 0 Unspecsed~dlagnosls 4 2.1 50.0 Total 191 58.11 Population controls 209 42.6 with squamous or small cell cancer. Nevertheless,, the lower limit of the CL was 2.9 and 6.9 respectively' for the lowest smoking categorywithin these groups of cancer. Only one eontrol'F belonged to the highesnt exposure aate- gory; why' the risk estimates for: this category became very imprecise. Average daily consumption of cigarettes was highly correlated to cumulated smoking (r=0!90. C1: 0:88-0.92). and to duration of, the smoking habit (r=0.73. Cl: 0.68--0.77). As a consequence of the high correlations the dose-response relationships were similar for, these expo- sure measures. The influence of the age at debut of daily smoking on relative risk is showmin Table 4. The risks are adjusted for 6?6 duration of, smoking. No statistically significant associ- ation could be found between smoking debut and risk although almost all point estimatesof relative risk were higher for those starting before 25 years of age than aften. Analyses were also:made with simultaneous adjustments for age and intensity of smoking. The results were similar in both types of analysis, although the risk estimates were somewhat higher when,the latter type of standardization was used. This could be expected as persons with an earh debut also had a higher cumulated exposure within each age stratum. Other age stratifications were analysed. but the results were similar, to those presented'. The effect of smoking cessation on relative risk of', lung cancer is shown in Table 5. Few subjects. especially among the cases, with an average d'aily consumptioni of more than 10 cigaretteshad ceased to smoke. The data indicated a considerable decrease in risk already within 10 years of smoking cessation compared to continue&smok- ing. There seemed to be a stronger effect of smoking cessationdor squamous and small cell carcinomas than for the other histological types. Enuironmental robacco smoke. Risk estimatesof 1'ung cancer associated~ withETS were mainly calculated for cases and controls who had never beenidaily smokers. but for exposure to ETS during childhood calculations were al5o made for smokers. To increase power, the risk esti- mates presented for never-smokers were calt:ulated with~ an expanded control group consisting of population con- trols and those norr.lung cancer patients, who did not ha% e any malignancy: The estimates arrived at when using only the population controls were quite similar. The carcinoids and the microscopically unconfirmed cases were excluded from the risk calculations pertaining to ETS. Table 6 shows estimates of relative risk for smokers associated with~exposure to ETS from the parents. Sub- jects with a smoking fatherr only, were classified as ex- posed to low levels while subjects with~a smokingmother were classified as exposed'to high levels regardless of the smoking status of the father. No signifieantl} increased relative risk was seen in any of the exposure groups. 3;~t~tttt;!~'..

626 C. SVENSSON,G. PERSHAGE6 AND li. RLOMINEK Table 3 Relariue risk IRR) for lung cancer among women in Stockholm counn in reltrtion to awrrage dailti cigaretre consumpt on' Never Ex-smokcrs Current smokers p for k trend ers smo n n RR (959 CI) >0-10 cig/day >10-20 cigldag >20 ctg%day n RR (959r CIl n RR (9t9 Cl) n RR (959r Cll' All cases 38 30 2.6 42 4.6 811 12.6 19 59.0 <1.4'x 10" (1.4-5.1) (2.5-9:3) (6.5-25.2) (7:6-), Squamous cell 5 6 4.0 l0' 9.7 28 36.2 4 96A <3:8 x l01° (1.0-16.9) (2.9-45.9)' (12.0-168.9)1 (6:9-)', Small cell 2 5 9.1 13 33.7 20 72.1 1 5 215.8 <1.8 x 10- (1."9.7) (6.9-265.3) (11.9--452.6), (1813-)'. Adeno 22 12 1.8 12 2.2 22 5.4 4 1917, <1.7x10- (0:8-4.3) (1.0-5:8) (2.4-13.2) (1.7-) Other 9 7 2.5 7 3.6 11 7.5 6 82.5 <8.Ox 10'' (0:8-8.1) (1t1~13.4), (2.2-24.3) (7:6-) Controls 120 36 30 22 1 ' The estimates are adjusted'for age. Subjects who had stopped smoking more than 2 years before the interniew (for controls 2 years before the inter-view of the matched case) are classifiel ex-smokcrs. t Ex-smokers not,included in calculations of linear trend. The exposures were scored 1. 2. 3 and 4. t Upper confidence intervals not given because of imprecision of estimates due to the small number of individuals in the high exposure stratum. Table 4 Relative risklJtR1 Jor lung cancer among tuomrn in Srockholm counn associated with age at debute of dl smoking' >25 years 19-25 years -18 years p for trend' n, n RR (959o CIIi n RR (95 c CI) All cases 32 58 2:0 52 1.2 0!9' (0.8-5.3) (05-'-.8) Squamous cell 9 18 2:0 15 ].1 0,9 (0:6-7_3)l (03-3.8) Smallcell 7 18 2:2' 13 1.3 0;9 Adeno 10 1'1 (0:6-5.4) 1.6 17 (0:+1--4.9) 1.3 0.6 Other 6 IQ (0.4-6.0): 2:2 (0:4-4.4) 1.0 M (0.5-9.9) (0:2-4.2), Controls 18 14 21 ' Stratifiedanalysis adjusted for duration of smokinQ. Subjects who had stopped smoking more than 2 yoars before the interview (for controls 2 years before the intervim of the matched case) are exciuded., " The exposures were scored 1,2 and 3. although all risk estimates exceeded 1.0 in women with smoking mothers. In never-smokers, adenocarcinoma constituted the dominating histological group with 22 (57.9r/c) of the total of 38 carcinomas. There were only S squamous ee1l and 2 sml cell: careinomas, making specific analyses of these histologicali groups unfeasiblc. Table 7 shows risk estimates for different ETS exposure variables among never-smokcrs.Most of the point esti- mates of the relative risk were greater than unity but the Cl were wide due to the small number of cases. There were no significant trends. Multiplt regression analysis yielded risk estimates very similar to those presented in the table. There was a significantly inereasr& 'risk' of being ex- posed to ETS in the home, if the sutiject herself was a

SMOKJNG AIN~D~ LUNG CANCEP'~ IN~ wOMEN~. Table 5 Relariur risk (RR),for lung eancer among utomen in Srockholm.eounrx assoeioted u;nh smok'rng cessation ts() compared ro currenr smoking f4-2 vears aJrrr cessarroni' Current3-10 years since >10 years since p for smoking Cessation cessation trend' n n RR (95C7 Ci) n RR (9517, C1) All cases 142 16 0.6 14 0.3 0.0004 (0.2-1.4) (0.1-0.6) Squamous cell 42 5 0.5 . 1 0.0 0.0006 (0.1-1.6) (0:0-0.4) Smallicell 38 2 0.3' 3 0;2 0.001 (0.0-1.3) (0:0-0.7 ) Adeno 38 5 0.5 7 0.5 0.06' (0.1-1.7) (0:2-1.5) Other 24 4 0.7 3 0.4 0.08 (0.2-3,2) (0.1-1.6), Controls 52 13 24. Stratified analysis adjusted1or age and average daily cigarette consumption. ' The exposures were scored 1. 2 and 3. Table 6 Relatiue risk lRRI for lung cancer among euer smoking women in Stockholm ea.n» in relation toparenrQl smoking during the first decade of life' Unex- osed Father smoker Mother smoker pSor trend' p n n RR (95 % CI1, n RR (95 y'r CI ) All cases 94 57 0:8' 19 1.8' 0:9' (0:3-1.4), (0.5-7.0) Squamous cell 27, 17 0.7 4 1.3 0.6 (0.3'-1.7) (0.2-8 .8): Small ce]l 25 13' 0.71 5 2.1 1.0 (0.3-1.8) (0.3-14.0), Adeno 23 19 ltli 8 3.0 0.3 (0.5-2.5) (0.6-21.6) Othen 19 8 0.4 2 1.1 0.08 (0.1-1.3) 10:0-20L0Y Controls 45 39 5 Stratified analysis adjusted'for age and average daily cigarette consumption. t Regardless oflsmoking habits of the father. ' The exposures were scored 1, 2 and 3. smoker. The point estimate for cases was 4.0 (CI: 1.7-9.3) and for controls 3,0 (CI: 1.5-6.2). For controls there was also a significantly increased 'risk' of being exposed to ETS on the job if the subject had ever smoked (RR 1.9, CI: 1.0-3.7). For cases the corresponding point estimate was 1.1 (CI': 0.5-2.6). ~ 1 Discussion All subgroups of lung cancer were strongly associated with smoking. Due to the smallinumber of'never-smokers 6_7 among the cases, especially among squamous and small cell cancers, andl of heavy smokers among the controls. the confidence intervals were wide. The magnitudes of'the risk estimates were greater than, but not incompatible with, results from previously published studies on female lung cancer Contrary to previous studies (15. 17. 19) no clear associ- ation between; early smoking debut and risk was seen, although most of the point estimates were greater than unity when smoking debut after age 25 was used as refer- ence category: In light of the clear dose-response rela. 42-B9gl0i

628 C. S4'ENSSON..G. P£RSHAGENAND 1. KIOMINEK Table 7, Refatiur risk' (RR) Jar lung cancer among never smoking tuomen in Stockholm counn in relalion to different measures o(erposure lo ETS" Cases Controls RR 95% C Exposure from the parents" Uttexposed 19 98 1.0 Father smoker 12 71 0.9 0.4-2.3 Mother smoker~ 3 5 3.3 0.5-18.8 d l (p for trend': 0.6) u t. Exposure as a Unexposed 10 60 1.0 At home or at work 17 90 1.2 0.4-2.9 At home and at work 7 24 2.1 .• 0.6-8.1 (pSor trend': 0.4)! Lifetime exposure Unexposed 7 35 1.0 As childi or adult 15 88 1.4 0.2-2.5 As child' and adult 12 51 1.9 0.2-3.7 (p for trend'-: 0:5). Stratified analysis adjusted'for age. Age 0-9 years. The exposures were scored 1. 2 and 3. tionships in the other studies as well as imstudies on men. the present findings were unexpectedl A, possible explana- tion could be that,those who started to smoke at a younger age inhaled less deeply, or that~ they to a greater extent, smoked cigarettes with filter tips. The observed decrease in the relative risk of lung cancer after, smoking cessation is in agreement with previous observations (116. 18. 20). Approximately one-third of all cases were classifie&as adenocarcinoma. Among the never-smokers adenocarci- noma constituted almost 60%r of the cases. Among the current smokers the corresponding figure was 27 r/ . The proportion of adenocarcinoma among the never-smokers is in good agreement with several previous studies on female lung cancer (5, 16, 21-23). The results pertaining to,ETS in the present study were not; conclusive. The small number of never-smokers among the cases could be one important reason. lt should be noted, however, that most of the point estimates of relative risk were greater than unity which agree with ~ results from previous studies on ETS exposure and with risk estimates conceming active smoking (6,,24)a To reliably estimate the risk associated with ETS, it is essential I to identify a sufficient number of never-smok- ers. Tn the present study, only 38 of the 210 cases ha& never been daily smokers. Four of these were exclilded from the calculations of risks associated with ETS, since they had carcinoids or tumors which were not confirmed microscopically. A post hoc calculation of power for de- tecting a 50% excess risk associated with exposure to~ ETS in the home, showed that it was in fact only about, 10%. For detecting small nsks, it is essential to minimize misclassification of exposure. The variables charactenz- ing exposvre to ETS usedlin this stud~ mayy not be optimal in this respect. Both intensity and temporal aspects of.the exposure are probably of importance for the outcome. It, is very difficult, however„to retrospectiwely quantifN ETS exposure. The tolerance for tobacco smoke differs be- tween individuals, and it is not improbable that this can influence their exposure estimates. lf such individuali in- formation bias exists, it is uncertaim whether it leads to non-differential or systematic misclassification. There are also difficulties involved'! in assessing the relative impor- tance of domestic exposure compared to exposure in the work environment. The high risks found for smokers with~a Ibµ consump- tion in this study, and panicularly for squamous and'ismall cell carcinomas, have implications for the assessment of lung cancer risks associated withETS. On one hand, theyy suggest that relative risks of 3 or even higher for squa- mous and~small cell carcinomas in heavily ezposed indi- viduals may not be unreasonable.,On the other hand, they make control of confounding by smoking a critical issue. A, poor control of confounding would be expected~ too primarily give rise to increased risks of these histological', types. ACKNOWLEDGEMENTS This study has been supported by the Jubilee Fund' of' the Swedish, National Bank We also want to thank Dr Margareta Lingnerifor valilble help in the collection of data. Request for reprinrs Dr Chtister Svensson. Depanment' of Epidemiology. Institute of Environmental Medicine. Karo4inska . Institute. P:O: Box 60206. S:10401 Stockho6m. Swnd'en, REFERENCES 1. US Department of Health and Human,Services. The health consequences of smoking: A report of the surgeon general. Office on smoking and health. Rockville. Md 1982. 2. National Bbard of Health and Welfare. Cancer incidence in Sweden 1983. 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