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w ' ;> v/e (J >^S 99 ,ScrasQncologica 28'lY989),Fasc. S FROM'7FIE DEPARTMENT OF CANCER EPIDEMIOLOGY. RADIUMHEMMET. THE DEPARTMENT OF EPIDE3filOLO- GY;: INSTITUTE OF ENVIRONMENTAL MiEDICINE. KAROLINSK.S 1NSTITUTE, STOCKHIOLM. AND THE DEPART- MENT OF LUIiTG MEDICINE. HUDDINGE HOSPITAL. HUDDItdGE: SWEDEN. SMOKING AND PASSIVE SMOKING IN' RELATION TO LUNG CANCER' IN WOMEN C. SVENSSON, G. PERSHAGEN and I. KLOMINEK , 623 I Abstract c In a population based case-control study the association be- tween female lung,cancer and some possible etiological agents was investigatedl 210 incident cases in Stockholm county, Swe+ den, and 209 age-matched population controls were intetv,icwed', about their exposure experiences according to a structured',qµes- tionnaire:,A strong association between smoking habits and lung cancer risk was found for atl 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 ecUl carcinoma itra 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 ofparental smoking on the lung cancer risk in,smokers, Only 38 cases had never been regular smokers and the risk estimates for exposure to environ- mentali tobacco smoke were inconclusive. The high relative risks of'smallicell and squamous cell carcinoma associated with, smoking may have implications for risk assessments regarding, passive smoking. Key words: 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 mortality among women (l'). Among Swedish women the trend for annual increaseof, lung cancer, is second'only too 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). The difference can partly be explained by differences in smoking habits between the genders, but there are some indications that a similar pattern~can be seen in non-smokers (4. 5): During the last'few years several studies have indicatedl that 'passive smoking' or exposure to environmental to- bacco smoke (ETS) may be of etiological importance. The findings have recently been evaluated (6). ;Nosc of the studies have focussed on the effects of ETS exposure during adulthood„ but some data suggest an effect of childhood exposure both in smokers and non-smokers (7, 8). To further investigate the effects on womeniof smoking andiother possible etiological i factors fior lung cancer, such as ETS andl radon exposure in the home, and possible protective effects of' some dietary camp^r:ent_. ::+e per- formed a populationibased case-control study. The firstt part of the study, addressing the risks associated with smoking and ETS, is presented in this paper:. Matetial and Methods The study includedlSsvedish-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'19g8.

~ ~ . _ . . .. .. !+f"vX` . ., . .. .. . . C. SVENSSON„G. PERSitNGEN AND l; KLOMINEK linska) for further investigation andLor treatment. To bee included in the present study, the subjects should be in a physical and mental l condition that allowed an, interview lasting,between one half to one hour. Suspected and confirmed cases were interviewed in the hospital wardk. For inclusion i in the study the diagnosis should be confirmed microscopically or by unambiguous chest radiograms in, conjunction with a typicall clinical course. The majority of interviews were made before the diagnosis was confirmed. When alcase was confirmed and included in the study, a population control l born on the same day was chosen at random from the population register in Stockholm county: s e cou not, be traced orr refused to participate, she was replaced by another wom- an„who was selected and contacted in the same manner. The controls were interviewed by the same persons thatu interviewed the cases. The control interviews were made during,a personal visit(58!%0) or by telephone. A hospital control group was also included in some of the analyses pertaining, to ETS-exposure. This group wass selbcted'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,September 1!983!-December 1985: The last population control was interviewed one year later. The time lag, between interviews of cases and population cbntrols: was mainly caused by the interval between adtnittance of a patient to a clinic and definite confirmation or rejection of' the preliminary diagnosis. Eighty-six percenrof'thrstudyt subjects were interviewed by two physicians (CS andJK). The remaining, subjects were interviewed by two other physicians. A structured questionnaire was used for the interviews. It contained questions about frequency of consumption of , food-stuffs rich in vitamin A, carotenoids, and vitamin C, exposure to ETS, smoking, and data on all' diwellings_ in wfiicTi a subject had lived for more than two years con- tinuously. Exposure to ETS was assessed through ques- tions about domestic enpasure da; ing childhood as well las 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 onee year. Statistical evaluation was made with the:computer pro- gram EPILOG (9): Relativeri'sks:(rate ratios) werrmainly estimated by stratified analyses with the extension for trend of the Mantel-Haenszel procedure (I11D, 11): Ini the trend analysis the exposures were scored 11, 2, 3, etc. In the matched analyses the exacr method for computing confidence intervals (CI) describediby Mietrtinen was used (12). In the unmatehed, analyses Cornfield's method was used' (13). For some of the analyses multiple logistic re- gression models werrusedlas well,(14). Significance inter- vals presented in the article are two-sided and 95% CI aree used throughout. Results The study finally included 21i0 cases and 209 population.' controls. In addition, 191 interviewed patients were shown not to have lung cancer. For 91patients primary lung, eancer could neither be con6rmed' nor excludedi Seven subjects refused interview and 5' could not be inter- viewed because of their medical condition. One hundred and seventy-five (84'%6) of' the population controls were firschand choices. One controlldid nou have a corresponding case, since the case had'to be excluded during the analysis, when an autopsy revealed' primary carcinoma of the colon with pultnonary metastases and not primary lung,cancer. For two cases no controls willing to be interviewed were found . Table I shows the microscopical classification of thee cases. All but two were histologically or cytologically confirmedi In one of these an autopsy showed character- istic macroscopicalichanges of malignant nature, but un- fortunately a microscopical investigation was nou made. Adenocarcinoma was most, common i and constituted i ap- proximately one-thir8' 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'thisgroup of patients. An additional 17 patients in this group had' a malignant disease although not directly associatedl with their respiratory ailments andleonsequently 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. - Svnoking: 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 both in a matched analysis and in an unmatched analysis adjusted forage: The two methods yielded similar results, e:g. the risk estimate for all lung, cancers was 5.8'(CI: 3.4-10.3) in the,matched analvsis:and 6.4 (Cli 4.0-10.5) in the unmatched. 71he:highest risk was seen for small cell, cancer (33.7, unmatched) andlthe low- est for adenocarcinoma (3.1, unmatched). The mean agee for the cases, who were never smpkers, was higher than, for those who hadlever 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. Subjects who had stopped smoking more than two ly;ears prrior to the inter- view (for population, controls two years before the inter- view of the corresponding, case) were classified as ex- smokers. Small cell and squamous cell carcinomas showed the strongest trend of increasing relative risk with increasing smoking intensity. For some of the estimates the CI was very wide because of the small number of never-smokers among the cases, especially among those

i' SMOKING AND LUNG CANCER IN WoMEN '- Table I Lung cancer cases among taomen in Stockholm county according to histological t9•pr, of tumor and'diagnostic verification Histol. Cy,toU id No microsc. id Total I Mean e a evidence ev ence ence ev n % g tyearst n 9o n % n `7c A41 cases 148 70:5 60 28:6 2 1.0 210 I00;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 A'deno 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 sntokirtg among female non-lung cancer patients interviewed ar'departmenrs jorp, ulmonar9• diseases in Stockholm county as uxll'as proportion of'smokers among population con- trols Diagnosis n 9i Smokers Malignant tumor 47 24.6 59:6' Breast 13 6.8 46:2' Gynecological 111 5.8 54.5' Pneumonia or other, respiratory, infection 35 18.3 54.3' Unspecified pulmonary infiltration 23 1? 0 65.2 Benign tumor or cyst 22 11.5 5 40.9 Pleuritis 8 4.2 50.0 Tuberculosis 5 2.6 60.0 Sarcoidosis 5 2.6 20.0 Haemoptysis 5 2.6 100.0 Chronic bronchitis 5 2.6 100.0 Bronchiectasis 4 2.1 75.0 Atelectasis 4 2.1 25.0 Other specified diagnosis, 24 12.6 67.0 Unspecified' diagnosis 4 2.1 50.0 Total! 191 58.1 Population controls 209' 42.6 with, squamous or, small cell cancer. Nevertheless, the lower limit,of the CI was 2.9 and 6.9 respectively for the lowest smoking category within these groups of cancer. Only one control belonged to the highest exposure cate- 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, CC 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 shown in Table 4l The risks are adjusted for 625 duration of smoking; No statistically signifcant, associ- ation could be foundl between smoking debut and risk although almost all' point estimates of relative risk were higher for those starting before 25 years of age than after. 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 early' debut also had a higher cumulated exposure within each i 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 daily consumption ofi more than 10 cigarettes had ceased to smoke. The data, indicated,aleonsiderable decreasrin risk alreadywithin 100 years of smoking,cessation compared to continued smok- ing. There seemed to be a stronger effect of smoking cessation for squamous and small cell carcinomas than ftirr the other histological types. Environmrntal'to6acco smoke. Risk estimates of lune cancef associated with ETS were mainly calculatedi for cases andieontrols who had never been daily smokers. but for exposure to ETS during childhood calculations were also made for smokers. To increase power, the risk esti- mates presented for never-smokers were calculated with an expanded, controllgroup consisting of populationicon- trols and those non-lung,cancer patients, who did nochave anymalignancy. The estimates arrivedlat 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 father only, were classified as ex- posed to low levels while subjects with a smoking mother were classified as exposed to high levels regardless of the smoking status of the father. No significantly increased relative risk was seen in any of the exposure groups.

C SYENSSON+ oXlF>R57lF1iff11TJD'7: kL.t) Table 3 Rtlaritx risk (RR) for lung cancer among, unmen in Stockholm counm in relarion1 ro aturage daily cigarette consumption' Never- rs k Ex-smokers Current smokers p for d' smo e n n R'R' >0-10 cig/day >J0-20 cig/day >20 cig/day tren (9595 CI) n RR (95:'%'o CID n RR, (95% CI), n RR (95% CI)" All cases 38' 30 2.6 42' 4.6 81 12.6 • 1,9; 59.0 <1.4x 10-' (1.4-5.1) (2.5-9.3) (6.5-25.2) (7.6-) Squamous cell 5' 6' 4.0 10 9.7 28', 36.2 4' 96.0 <3;8x 10'" (1.0-16.9) (2.9-45.9) (II210-168.9) (6.9-) Small cell 2' 5I 9.1 13 33.7 20' 72:1i 5' 215.8 <1.8x10"'a (114-69.7) (6.9-265.3) (11.9-452.6) (18.3-) Adeno 22' 12' 1.8 12 2.2 22' 5.4 4 19.7 <1.7x10"' (0.8-413) (1.0-5.8) (2:4'-13:2) (J.7-) Other 9` 7' 2.5 7 3.6 11 7.5 6 82.5 <8:0x 10'"' (0.84!1) (1'.1-13!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 interview (for controls 2 years before the interview of the matched case) are classified as ex-smokers. Ex-smokers not included in calculations of linear, trend. The exposures were scored 1, 2. 3 andl4l ' Upper, confidence intervals not given because of'imprecision of estimates due to the small number of individuals in the high exposure stratum. Table 4 Relatiut risk (RR) for lung cancer among, women in Stockholm county associated with agr at debute of daily smoking" >25 years 19-25 years -18'years p for trend=' n n RR (95% Cl) n R'R' (959o CI)' All cases 32' 58 2.0 52' 1.2 0:9 (0:8-53) (0.5-2.8) Squamous cell 9 18 2.0 15' 1.1 0;9' (0:6-7:3) (0.3-3.8) Small celll 7' 18 2:2' 13 1.3 0!9' (0.6-8.4) (0.4-4.9) Adeno 10 11 1.6' 17' 1.3 0i6 (0:4-6A)', (0.4-4.4) Other 6 ll 2?' 7 1L0 0!7 (0:5-9.9), (0.2-4:2) Controls 18 14 21 ' Stratified analysis adjusted for duration of smoking. Subjects who had stopped smoking,more than 2 years before the,interview (for controls 2 years before,the interview ofthe matched case) are excluded. = The exposures were scored 1„2'and 3. although all risk estimates exceeded 1.0' in i women i withh smoking mothers. In never-smokers, adenocareinoma constituted the dominating,histological group with 22 (57:9%) of the total of 38 carcinomas. There were only 5 squamous cell and12 small cell carcinomas, making specific analyses of these histological groups unfeasible. Table 7 shows risk estimates fiordifferent'ETS exposure variables among' never-smokers. Most of the point esti- mates of the relative risk were greater than unity but' the CI were wide due to the small number of'cases. There were no significant trends. Multiple regression analysis yielded risk estimates very similar to those presented in the table. There was a significantly increased!'ri'sk' of being ex- posed to ETS in the home,, if the subject' herself'was a

Table 3 Refatitx risk (RR) for lung cancer among women in Stockholm counrn associated with smoking cessation (sc) compared to current smok'ing, (t?-2'years after cessation)' Current, smoking 3-10 years since cessation >10 years since cessation p for trend=' n n RR (95i% CI) n RR (95% CI) 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) Small cell, 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;08I (0.2-3.2) (0:1-1.6). Controls 52 13 24 t' Stratifiedlanalysis adjusted for age and,average daily cigarette consumption. _' The exposures were scored lL 2 and 3. Table 6 Relatiue risk (RR) for lung cancer among, ecYer smoking women in Stockholm counrv in relation to parental smoking during the first decade of life, ' Unex- di Father smoker Mother smoker p for trend3 pose n n RR (959ro C1): n RR (95% CI4 1 It , 7J All cases 94 57 0:8' 19 IL8 0.9 (0:3-1.4) (0.5-7.0) Squamous cell 27 17' 0.7 4 IL3 0.6 (0:3-1.7): (0_2-8.8) Small cell 25 13 0.7 52.1 1.0 (0:3-1_8): (0.3-14.0) Adeno 23 19 1.1 8' 3.0 0.3 (0.5-2.5) (0.6-2'1L61 Other 19 8'. 0:4 2' 1.1 0.08 (0.1-1.3) (0.0-20.0) , -4:.: Controlk 45 39 5 ~ ' Stratified analy,sis adjusted for age and average daily cigarette consumption. ~ Regardless of smoking habits of,the father. '' The exposures were scored I, 2 and I3, smoker. The point'estimate for cases was 4.0 (CIt 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 (iRR 1.9„ Cl: 1.0-3.7). For cases the corresponding point, estimate was 1.1 (CI: 0.5-2.6). Discussion Alll subgroups of' lung cancer were strongly associated! with smoking. Due to the small number of never-smokers 42 -8981Q5 among, the cases, especially among squamous and smalll cell' caneers, and of heavy smokers among the eontrols., the confidence intervals were wide. The magnitudes of the risk estimates were greater than, but nou incompatible with, results from previously, published studies on female lung cancer (15-18). Contrary to previous studies (15, 17, 19) no clear associ- ation between early smoking debut and risk was seen. although, mosr 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- 1M

C. SVENSSON, G. PERSHAGEN AND l. tQt.'ONRNEK' Table 7 Rrltrtiur risk (RR) for lung cancer among neuer smok'ing, women in Stockholm counn^ in relation to different measures oj'exposure to ETS' Cases Controls RR 95'% CI Exposure ftom the parents: ' Unexposed 19 98'. 1.0 Father smoker 1 2 71 0.9 0.4-2.3 Mother smoker 3' 5' 3.3 0.5'-18!8' (p for trend': 0.6) Exposure as adult, Unexposed 10 1.0 At home or at,work --TT 90' 1.2 0.4-2.9 At home and i at work 7' 24 2.1 0.f.-8.1. (p for trend': 0.4) Lifetime exposure, Unexposed 7 35 1.0 As,childs or adult 15; ' 88 1.4 0.2-2.5 As chiltl? and adult 12' 51 1L9 0:2-3,7 (p fortrend°: 0:5) " Stratified analysis adjusted for age: Age 0-9 years. ' The,exposures were scored Il 2 and 3. tionships inithe other studies as well as irnstudies on men, the present findings were unexpected~ A possible explana- tionicould be that those who started to smoke at a younger age inhaled less deeply or that they to a greater extent, smokedlcigarettes with flter tips': The observed decrease in the relative risk of lung,cancer after smoking,cessation is in agreement:with previous observations (16, 18. 20). Approximately one-third' ofl all cases were classified ass adenocarcinoma. Among, the never-smokers adtnocarci- noma constituted almost 60% of the, cases. Among the, current smokers the corresponding figure was 27%. The proportion iof adenocarcinuma among the never-smokers is in good agreement with several' previous studies on, female liing cancer (5, 16. _"1~-23): The results pertaining to ETS: inithe present study weree not conclusive. The small number of', never-smokers, among the cases could' be one important reason. It should be noted; however, than most of the point estimates of relative risk were greater than unity which agree withi results from previous studies on ETS exposure and' with risk estimates concerning,active smoking (6, 24). To reliably estimate the risk associated with ETS, it is essential to identify a sufficient number of never-smok- ers. In the present study, only 38 of the 210 eases had never been daily smokers. Four of these were excluded from the calculations of risks associated with ETS, since they, had' carcinoids or tumors which were not, conf tmed microscopically. A post hoc calculation of power for dt- tecting a 50% excess risk associated with exposure to ETS in the home, showed that it was in fact only about 10'%I. For deteeting, small nsks, it is essential to minimize misclassification of exposure. The variables characteriz- ing exposure to ETS'used in this study, may not be optimal in this respect. Both intensity and temporal aspects of the exposure are probably of importance for the outcome. It is very difdicult; however, to retrospectively quantify ETS exposure. The tolerance for tobacco smoke differs be- taveen individuals, and it is not improbable that this can influence their exposure estimates. If such individual in- formation bias exists, it, is uncertain 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 thee work environment. The high risks found for, smokers with a low consump- tion in this study, and particularly for squamous and small' cell carcinomas, have implications for the assessment of lung cancer risks associated witlt ETS. On one hand, theyy suggesn that, relative risks of 3 or, even higher for squa- mous and small cell carcinomas in heavily exposed 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 wouldi be expected to primarily gi ve rise to increased risks of these histological types. A,CKNIOWLEDGEMENTS This study has been supported by the Jubilee Fund of the Swedish, National Bank. Wt also want- to thank Dri ytar_gareta Lingner for valuble help in, the collection of data. Request fpr reprints:, Dr Christer Svensson. Department of Epidtmiology; Institute of, Environmental Medicine. Karolinska Institute: P:O: Box 60208.,S-10401 Stockholm, Sweden. ItEFER;EIdCES I. US'Departmeni'of Health and'Human Services. The health consequences of, smoking: A report of the surgeon generall Office on smoking and health: Rockville. Md 1982. 2. National Board of Health and Welfare. Cancer incidence in Sweden 1983; Stockholm: Allmanna Foriaget. 1986: 17. . 3. IARC. Tobacco smoking. IARC'monographs on the evalua• tion of th'e carcinogenic risk of chemicals to humans. 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