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FILE NAME Kent KNT DATE 1952 Dec 13 DOC KNT125 DOCUMENT DESCRIPTION Journal Article - A Study of the Aetiology of Carcinoma of the Lung - British Medical Journal Do&ll Hill 1952 BRITISH MEDICAL JOURNAL LONDON SATURDAY DECEMBER 13 1952 A STUDY OF THE AETIOLOGY OF CARCINOMA OF THE LUNG BY * RICHARD DOLL M.D. M.R.C.P. . _ Member of the Statistical Research Unit of the Medical Research Council Q AND a A. BRADFORD HILL C.B.E. Ph.D. D.Sc. London School of Hygiene and Tropical Medicine ; Honorary Director of the Professor of Medical Statistics Unit of the Medical Research Council : Statistical Research a previous paper Doll and Hill 1950 we reported e first results of a large iwnivteshticgaarticoinnoumnaderotfaktehne ing determine whether patients either in ing differed materially from other persons smoking habits or in some way which might be heir to the theory that . atmospheric pollution is elated esponsible for the development of the disease We oncluded that smoking is a factor in the production if carcinoma of the lung and this conclusion was in onformity with the results of some other investigations Our first observations were however limited to patients drawn mainly from London and the adjacent counties We have now extended the investigation to other parts of the country and have made more detailed in- quiries into smoking habits Many further patients have been interviewed during January 1950 to Feb- uary 1952 in hospitals in Bristol Cambridge Leeds and Newcastle and also in eight of the wenty London hospitals which operated in the first part of the inquiry Method of the Investigation The method of inquiry was described in detail in the serve previous paper In brief we obtained notifications of becthowieceen patients admitted with cancer of the lung stomach or large bowel to each operating hospital and these patients were interviewed by almoners engaged wholly on our research who recorded the answers to a pre- arranged questionary . The patients with carcinoma of included the stomach or large bowel provided one " control 66 as group but another and more important control was patients other obtained by interviewing with diseases than cancer Each of these latter patients was chosen to match a carcinoma namely of so as within the same year age and group the same sex those patients suspected of having lung cancer who were then in the hospitals At Bristol Cambridge and Leeds they also interviewed a few who were attending the out- at patient departments An important modification was in the choice of the matched control patients It was impossible to obtain the provincial centres a group confined as before to patients with discases other than cancer Our previous analysis however had shown that patients with cancer other than lung carcinoma mainly patients with carcinoma of the stomach or large bowel gave smoking histories indis- include ; tinguishable from those given by cancer patients we therefore widened the matched control group to with certain exceptions other forms of cancer The exceptions which we continued to exclude were cancer of the lip tongue mouth pharynx nose larynx and oesophagus since it has at times been suggested that cancer of these sites may also bear some relationship to tobacco consumption We also excluded all other cancers arising inside the chest Even then it was still difficult in the provincial centres to find an adequately matched control for each lungcarcinoma patient The provincial hospitals had been therfore chosen so that a large number of patien pat tiesnts therefore could be interviewed at each visit They were thoracic or radiotherapeutic centres serving regions is town and country We could not seek control patients in the adjacent general hospitals since these mainly the towns they are situated in and smoking habits vary town countryside On consideration the field of was finally extended to other hospitals or units the same area but only to those serving as regional centres is Thus the like the thoracic or radiotherapeutic centres cases and their controls should be drawn from equally areas of town and country We have also the control series some patients interviewed having lung cancer but in whom the condition was finally xcluded as at the Brompton and Harefield hospitals in the of the investigation It will be shown that this does not influence the results ~ same of each in the same hospital nearly as possible the discharge diagnosis possible '. The classificati n patient was as genera rule based upon the hospital diagnosis time after In the extension of the inquiry this same method has been used but with modifications First notifications were made of patients with lung cancer but no longer of those been with cancer of the stomach or large bowel Secondly contradicting the interviewers could not visit hospitals outside London whenever a suitable patient was admitted they therefore at intervals and interviewed provincial centres I visited the tained from a study of the hospital records patient's discharge death Where that record indefinite information was obtained from the practi- tioner or hospital to whose care the patient had transferred Occasionally evidence the hospital discharge diagnosis became available further 531 patients were interviewed habits in country areas -see the 498 the earlier part of investigation as The reasons why patients were not g~ roup 2 patients initially initialy interviewed having carcinon interviewed were already discharged from hospital 213 ; of the lung stomach bowel later found have diseases 165 dead72 too deaf 33 unable to speak . other and others interviewed as matche clearly . ; while in one case interview was controls not required they were paired when the patients with whor abandoned because the patient's replies appeared were found not to have carcinoma of wholly unreliable No patient refused to be interviewed With the canc groue p alr one the proportion not interviewed was also 15 can see no reason why failure interview all the patients should have biased the results since it was mainly due to the time that had to . In Table II the matched patients in the lung and control groups are compared for sex and age bution places of interview places of residence and for males social status The method of selecting control elapse between the date of notification and the date of the almoner's visit Such losses were of course few in provincial centres since here the almoner was re- Table Comparison Between carcinoma Patients and Matched Control Patients with Other Diseases quired to interview only those in the hospital at the time of her visit The remaining 2,710 patients initially presumed to be suffering from cancer of the lung stomach or large bowel and 1,632 general medical and surgical patients interviewed as matched controls to the carcinoma the patients form the subjects of this analysis Table I gives numbers in each disease group final classifications based hospital discharge diagnosis etc. as described above The 1,488 cases of carcinoma of the Attribute for Com- parison No. of Lung- carcinoma Patients |M F No. of Controi Patients M FP Attribute - for Com- parison No. of Lung- carcinoma Patients M and FM Age 23- 35455565-74 All ages .. 17 116 493 545 186 1,357 Place of inter- : view Greater London Bristol .. Cambridge ..- Leeds i Newcastle All places . . include 23 for which matched controls had not Social class been interviewed when the investigation ended Most RGeegniesrtarla'rs- categories our results therefore relate to the 1,465 cases paired with the 1,465 matched controls other diseases A : 32 II 165 53 172 Place of residence Greater London Other county Cases diagnosed as carcinoma or canceorf the lung or bronchus pleural endothelioma and alveolar carcinoma "the lung have been included in the carcinoma of the group Classification of the diagnoses according to recommendation of the International Symposium on Endemiologoyf Cancer of the Lung Council for the International Organizations of Medical Sciences 1952 gave first order . of of reliability evidence from biopsy tumour primary from operative bronchoscopic or of radiographiccytolgical examination of the primary tumour together examination the sputum or biopsy of be due to second secondary tumour or from necropsy 29 of the examination other hand reliability cytoclytoogliogciaclal examination examination of the sputumexami- operative bronchoscopic or radiographic exami- of withoutbiopsy only % of the third order " LE 750 IV | social All classes .. 172 231 1,357 720 198 214 1,357 boroughs ., Other urban districts .. Rural districts Abroad : * 225 275 ISS 19 All places 1,465 patients leads automatically to an exact correspondence in sex age and places interview Differences in social status show no regular trend and are no greater than - might chance 5.28 = 0.20 the the places of residence reveal con siderable differences : fewer of the carcinoma group were residents of Greater London 17.22 n history and physical examination alone or 70 cases classified in TableI carcinoma of other sites all other cancers arising the chest sarcoma of lung and cancer of the medi/ of the trachea and those other cancers of the passages buccal cavity and oesophagus for possible relationship with smoking has at times postulated . The 36 caseosf * carcinoma of uncer- of 0.01 The meaning of this inequalitiys considered ' later section on place of residence Since our observa- tions show that the consumption tobacco tends to be in if greatest London the inequality will anything have the somewhat reduced contrasts we find between the groups in smoking habits In our previous report however we showed that the inequality was unlikely to be of importance primary include patients with carcinomatosis and some ip nrimwar hy om there was doubt whether the lung growth or secondary " ne 1,278 other diseases B includ)e patients with carcinoma of the stomach or large bowel interviewed in ~ Assessment of Smoking Habits The difficulties of acquiring and assessing accurately them smoking history and the measures taken overcome them were discussed in our previous paper It will be sufficient 4 were asked a if they had patients ages repeat here that of lives b the which .: a at cigarettes their nokehdadat any pearnidodstopped c the amount they were started of the illness which jey habit of smoking before the onset ad ad brought them into hospital ; d the main changes in ever been of the inquiry provide anumber of The jeir smoking history the maximum they smoked in which results habits of the patients can be categorized theanhdabictigaorefttsems o; akinndgfewhtehteheprrotpheoyrtiionnhsaled test by cross- which the smoking and compared : The simplest is the amount smoked the onset of the illness which brought immedi iapses made of the accuracy of the answers after their ately before This however can be very xamining 50 patients again six months or more expected some varia- patient into hospital including heavy smokers some persons irst interview While there as that the data were reliable ing since to smoking periodically and it would wrong to ility of replwye concluded - and to substantiate merely because they were nough to indicate general trends a between groups as smokers substantiate during period of abstention In Table modified form smokers naterial differences Oe the difficulties of inquiry have been . reduced - hrough Fortunately level of taxation remaining almost constant hrough - the National figures show that the total never hroughout the investigation remained fairly namely 213.7 211.5 jome consumptionconsumption ending March 31 1951 213.8 221.2 million lb. in the four years in the standard they Board of Trade 1952 The last major change April 16 1947 when to of duty payable on tobacco was on April 7 1948 it rate it rose from 35s 6d to 54s 10d a lb on ; the comparison is made in a who aredefined as in our previous study persons consistently smoked as much as one cigarette . for long as one year ; the smokers are subdivided according to the amount they were smoking before the onset of atchecirorildlinenssg otrhief amounhatd they up stopped smoking smoking before they last gave This is 58s 2d became women smoking In the latter stages of of the smoking histories were sought sought patients 523 men inquiry somewhat and the last 557 34 women and fuller lungtheir the most recent amount smoked ; Table III shows that in both men and there fewer smokers and considerably more of the carcinoma . iF Smoked Regularly Before the Onset of the Present Illness : carcinoma TABLE Most Recent Amount Amount of Tobacco with Other Diseases . Patients and Matched Control Patients 4 . ik Disease yi Disease Group No. of Non- . smokers 1 Cig.- 5 Cigs.- No. Smoking Daily ' : Cigs.- 15 Cigs.- . 25 Cigs.- : 445 3 299 22.0 38-0 . patients % 49 516 408 162 11.9 2 Men 6-7 30-1 6- * 1,357 carcinoma patients 99.9 -. 61 4.5 91 615 45.3 100 : 1,357 control patients with other diseases | ery a % 12 11.1 11-1 o- 0.9 40 37-0 14 13.0 30 27.8 8 1 0 Women 16.7 7.4 fs 108 ccoantrroclipnatoiemntas pwaittihenottshe1r d0is0eases 11 00 00 . 59 54.6 18 20.4 | f 0.01 ee Men 108 proportions of smokers and smokers 43-99 = 000001 Women 22-6-73 -- 8-99 = 02 amounts 21-69-74 21-69-74 = 000001 Women different the DDiiffffeerreennccee bbeettwweeeenn proportions of smokerssmokers smoking of tobacco in 26-5 normal cigarettes so that a There is.1 oz 4 cigarettes * of tobacco have been expressed expressed as being equivalent to so many cigarettes week cigarettes a day Ounces factor has been taken as oz of tobacco a Conversion TABLE Tobacco Smoked Smoked Regularly Before the Onset of the Present Most Recent Amount of with Other Diseases Subdivided by Place and Date ; Patients and Matched Control Patients with b Percentage Smoking Daily ; y ' Discase Group Place and Date of Interview Percentage | smokers i 1 Cig.-Cig.-Cig.- Cig.- 5 Cigs.- 15 Cigs.- : Illness carcinoma coat of Interview 25 Cigs No. Interviewed Greater London 1948-9 .. & Greater London 1950-1 .. i 2.8 | Carcinoma of lung Bristo 1950-1 .- os Cambridge .. 2.80.0 men 1951 Leeds 1950-1 an Newcastle 1950-1 0.5 0.5 Whole investigation Control other :. pos with patients patients with diseases men oa Greater London 1948-9 .. Greater London 1950 1 . 1950-1 Bristol Cambridge 1951 +2, 0 1950-1 Leeds wee 1950 1 Newcastle 4.24.2 .9 5.3 5.3 . Whole investigation fe" 1 oseTt Greater London 1948-9 0 se TV Greater London 1950-1 . - .. - . Bristol Carcinoma of Jung ROFL | women ~ 1950 1 Cambridge 1951.".. Leeds 1950-1 ee van cee thy ( a baat - Newcastle 1950 1 Whole investigation vee ~~ 0.0 0.03.63.6 8.5 0.8.8 4.9 Greater London 1948-9 .. 2 Greater London 1950-1 .. a Control patients with Bristol 1950-1 1951 . . a ve Cambridge other diseases an Leeds 1950-1 o -} women < | Newcastle 1950-1 - ee . Whole investigation 2.* See footntooTtabele III small numbers and have no reliability J The percentages in parentheses are based upon very - AETIOLOGY OF CARCINOMA LUNG smokers among the lungcarcinoma control patients patients than among the "S carcinoma the lung only 7 Amongst 1,357 men with of or 0.5 were smokers there ; were 61 or 4.5 % among the same number of lifetim diseases At the other end of the men with other with lung carcinoma had scale 25 of the men day or the equivalent in smoked 25 or more cigarettes a pipe tobacco the proportion in the control patients was only 13.4 Similarly 108 women with amongst smokers carcinoma of the lung 37.0 were non- . Among against 54.6 of the women with other diseases more women with cigarettes carcinoma 11.1 had smoked 25 or this proportion waas d0a.y9among tho;se with other diseases These results are essentially ~ in our preliminary report London results for the two periods the same as those recorded In Greater indeed the 1948-9 1948-9 and 1950-1 are remark- OF BRITISH we Ce ee no MEDICAL JOURNAL reasonably time they last gave up Its information is easily obtained aadnvdantage as a criterion is that Its disadvantage is that likely to be accurat sometimes smoking habits vary over vant are considerably and previous habits which a being ignored We have therefore may be rel quantitative estimates of the calculated oth patient's history These are ( amount smoked as reveimmediate aled in t before the patient's illness regularly c the total amount smoked since and d the average amount smoked smoking was begui ceding the patient's illness over daily over the the 10 years pr over the whole of the patient's life penultimate 10 account recorded since the age of 15 taking changes during these periods Qualitatively similar results are estimates is used control The sharpest obtained whichever differentiation carcinoma and control patients for both to be given by the men years average daily amount smoked preceding the patient's illness tion are shown in Table V and differences diferences between the substantially five Newcastle also shows that the contrast between the | the men in the two disease smokingsmoking habits of sistently at the provincial groups was observed quite con- tions of smokers centres In each case the propor- and of men smoking less than ' cigarettes a day were lower and the 25 or more cigarettes a day was proportion smoking the carcinoma patients In higher among obtained during the two women similar results were London while periods of inquiry in Greater at Bristol Cambridge and Leeds the small to warrant num- however the smoking habits of tahtetefnetmiaolne cAat rcinoma patients did not differ matched appreciably from those of their controls fact the proportion of was slightly higher in the smokers carcinoma the number interviewed was group Though from the experience of the small 19 cases the divergence sufficient to be cancer groups elsewhere is statistically significant vincial centres together gives the Adding the pro- : women following figures for particularly those in Table III in the women . ; For men the amount smoked illness is cqually good but the immediately before the patient amount consumed throughout life the estimates of the total goifve15diaffnedretnhceesaverage daily amaovuenrtagoevedraitlhyeapmeonuulnttimsaitnece the age most recent only of the same order as those shown amount smoked the maximum by years ' smoked differentiates the groups less clearly estimates except the amount daily amount ever For women all the patient's illness are smoked inmediately before the amount more discriminating than " the smoked though the maximum daily amount most recenti gives only a slightly increased divergence between ever smoked In view of these the two groups smoking history results with varying we have used in measures of the subsequent tables the average amount smoked daily over the 10 the patient's illness as the years preceding whole life most appropriate criterion " the history should perhaps be a truer exposure to risk but as we pointed measure of ous paper too much out in our previ- the patient to inaccuracy may result from requiring remember habits of many years past Non- | pT Non- Smoking Smoking | Smoking The smokers Smoking 1-14 15+ Total | Cigs Duration Cigs | Comparisons of Smoking Ccoantrroclinoma group |} 16 group 11 28 Comparisons er of the ages at whiwhichch the patipatients ents : : ft 16 : 12 i 28 that they began to smoke the number of reported ! | 6 t smoked and when appropriate the years they had presence The of only one . they last gave up are shown in Tablneumber of years since who had smoked 15 woman with lung carcinoma The carcinoma VI haps or more cigarettes a day is not persurprising average ; it seems that very few women in the to have begun longer and to patients smoking rather are scen on the earlier to have continued provinces smoke so much viewed at Of all the 58 women inter- men these have been rather less inclined to stop In diseases " provincial centres and who suffered from other differences are all statistically significant In other than lung carcinoma carcinoma of women they are not significant but they are in the posibly related to tobacco certain primary site none and carcinoma other of un- direction and no less distinct so that it is same accept them as real reasonable to " cigarettes gave a history of smoking or day In contrast this amount pronounced difference by nearly % of 553 similar women with all was smoked of years since smoking had last beeanppears in the number interviewed interviewed in Greater London other diseases is given up Since the in provinces . the higher proportion of smokers Table II here groups it was thought be due smokers in it seen might smoking fewer than 15 who more to the fact that it is light light smokers cigarettes a 66 readily give up to be true Of In fact the opposite appeared most recent amount smoked will not necessarily give given the 124 male male control patients who had as representation here to include of a smoking history even though defined . the amount smoked by smokers at the 25 or up smoking nearly third 31.5) were smoking who more cigarettes a day when they gave up of those continued to smoke only only 12.2 consumed TABLE V. as much Average Amount of Tobacco Tobacco Smoked Daily Over the 10 Years Preceding the Onset of the Present Illness carcinoma Patients and Matched Control Patients with Other Diseases ; Lung- DiscDiscasae se GroGurpoup No. of Non- No. Smoking Daily Average of ~ smokers Less than 5 - | Men Cigs lung on a | 5 Cigs.- Cigs.- 15 Cigs.- Cigs 25 1,357 carcinoma patients % | Cigs } 50 Cigs | control Women patients diseases % 1.357 patients 99.9 other Lot 100 0.597 61 4.5 55 4.0 489 36 36 ! 1 475 aaj - | 31-8 9.5 Si a 129 570 42 431 293 21.6 21.6 38 2 % % ie 31-8 154 11.3 % Women carcinoma diseases 108 control patients wpiatthieontthse1 r 00 2 40 37.0 16 14.8 ape a 12 0.9 ie . Difference 100 | | , 54-6 25 23-1 24 22.7 18 16.7 14 13.0 6 5.6 13 i ) 0% F between proportions * Ounces of tobacco have been of smokers smoking x p 0 different amounts 93-77 000001 4 Women conversion factor has been taken expressed as as 1 being equivalent to so many cigarettes 17.41 oz of tobacco a week = 4 cigarettes There is 1 oz of tobacco in 26-5 = 001 day a normal cigarettes so that the JEC 13 1952 ~ prraerirs eoraaa nen. - ete Ange AETIOLOGY OF CARCINOMA OF LUNG BRITISH MEDICAL JOURNAL 1275 Up BLE Age at Starting to Smoke Number of Years Smoked and Number of Years Since Smoking was Given carcinoma Patients and Matched Control Patients | ! ex | gen Starting ig. | ] | 1 carcinoma 1. \ Patients No. | % , | Control Patients No. | % | | Under 20 2030- ; 1.077 | 251 | 187 79.8 18.6 1.6 40+ af | 992 264 331 73 {| 76.5 20.4 3.1 All ages 3,350 100.0 | 1,296 100.0 7-95 = < 01 02 Under 20 30-30- | 40+ | 107 || 20 29.4 33.8 36.8 15 12 | | 15 153 | 24.5 30.6 44.9 44.9 All ages 68 | 100-0 | 49 100.0 carcinoma No. of Patients Control Patients Smoking | No. | % | No. | % f 1102040 12 3-3-4 4 345 746 || | 558 55.3 43.3 15 15 725 | 491 | 6.2 55.9 37.9 ] = periods 1,350 100.0 1.296 12.66 = 01 100.0 1] - carcinoma Years of Patients Up Given No. | % 0110201 : 1,280 94.8 | 56 4 4.1 1.0 ay! All period3s,35099.9 25.87 = | | Control Patients | No. 1.172 75 26 233 | % 90.4 | 8 3.8 |1,296 100.0 001 1- 2200-40- | All periods 147 38.2 36 | 5252..9 9 6 | ".8 | 68 99.9 187 53-1 8 20 40.8 40.8 || 3 6'1 0- 1- 10- 20+ | 49 | 100.0 || All periods | | 85.3 13.2 }1.5 1.5 68 | 100.0 41 83.7 + 6 12.2 | 0 : 1 25 49 | 100.0 The Method of Smoking So far the nokers is in only distinction we have drawn between the quantity of tobacco consumed There c however qualitative differences which might be impornamely whether the smoker inhales smokes a pipe ses a cigarette holder smokes tipped cigarettes rolls is own cigarettes or lights his tobacco with matches or On the other hand studying the pure smokers alone we find that 9.4 of those with carcinoma smoked ; the equivalent of less than five cigarettes a day and 13.2 sinoked the equivalent of 25 or more a day in the control the proportions were 15.1 and 4.3 In other group words a higher proportion of the pure smokers with carcinoma of the lung fall into the higher smoking categories -as with the cigarette We conclude as in our earlier report that the method petrol lighter Inhaling the smokers and smokers were asked hether they inhaled with the exception of three lungarcinoma and two control patients in whom the question of smoking is of importance and that smoking a pipe though also related to carcinoma of the lung appears to a smaller risk than smoking cigarettes sec also section carry on estimated risks was inadvertently omitted Of 1,415 carcinoma atients men and women 64.6 said yes and 35.4 said o of the 1,343 control patients with other diseases 66.6 aid yes and 33.4 said no The differences are negligible Similar results were obtained for men and women conidered separately Further consideration is paid to nhaling in the section dealing with site of tumour Cigarettes and Pipes persons usually smoke igarettes others usually smoke a pipe Habits however to divide do not remain constant and it has been necessary male smokers into three broad categories a those who the have never smoked a pipe regularly for as long as one year pure cigarette ) ; b those who have smoked cigarettes and a pipe and c those who have never smoked cigarettes regularly for as long as one year pure pipe- smokers Among the 1,350 male carcinoma patients who smoked 3.9 were pure smokers and 74.4 were cigarette among the 1,296 male control pure who smoked the corresponding proportions were patients 6.9 and 69.4 The differences though not striking are Cigarette possible explanation of this lower risk of smoking is that the stem acts as a partial filter of a carcinogenic agent If that were so we might that fewer of the patients with carcinoma of the expect We sought information lung had used cigarette on this point in the latter stages of the inquiry the last 523 pairs of male carcinoma and control patients to be interviewed Judged by the proportions of non- smokers and pure smokers in the two groups these seem to be a representative sample of the last patients total Table VII shows results obtained from them Few TABLE Use of Cigarette Male carcinoma and Matched Control Patients ( Information Obtained During the Last Part of the Investigation Only Disease Disease Group 1 Non- | smokers | Cigarette Never smokers SmokedSmoked -- -- - smokers Cigar- | elles . Holders Used Regu- j Never sionally | larly a a Total cigarette statistically highly significant x for the three groups pure 15.85 = 0.001 It pwiopueld maipxpeedar ptuhraet smoking is less closely associated with the development of lung carcinoma than cigarette- smoking smokers however consume on the aver- less tobacco than cigarette and this must age account for some of the relative deficiency of smokers in the carcinoma group It does not seem that it can of account for the whole difference since the proportion is somewhat lower at each level of ptuorbeaccso mcoonkseumrptsion The relevant figures are as follows : Daily Percentage of Pure smokers among all Smokers at Each Average Consumption Level Measured in Terms of Cigarettes Less than | 5 Cigs 15 Cigs.- 2525 Cigs . Male carcinoma patients Male control patients with | other diseases 1. 9.1 10.9 296 1 10-500 10-500 | 1.3 % } 3.5 \ 2.4 \ - | 523 carcinoma 4 | patients patients . le 523 control patients 26 | | _ + _ 15 479479 15 10 | 504 15 30 413 27 27 467 patients had ever used holders but the proportion of done SO was significantly csmialglear rien tttheegrwouhpo wihtahd carcinoma of the lung % - than in the control patients 12 14.74 = 0.001 This difference might merely be due to an association between using a holder and light smoking but the avail- able evidence suggests not Among the 54 cigarette- smokers in the control group who had used holders five a of fewer than 15 cigarettes % smoked an average ~ of 25 or more the ; day and six 11 smoked an average who Further corresponding figures for the 413 cigarette had not used holders were 32 % and 55 13 Further evidence that an association with light smoking cannot 4 account for the relative deficiency of users of cigarette- negligible put forward Evidently there opposed to the lung Ied to risks associated with en who roll their cigarettes use pipe tobacco view of the presence of arsenic in American tobacco its almost complete absence from Oriental tobacco and Kennaway 1950 it was clearly of interest to determine whether there any difference in the of propor- American and Turkish tobacco smokers in the regularly carcinomaand carcinomaand control groups The results of such inquiry inconclusive because nearly all smokers had habitually smoked Virginian In fact only one smoker found had never regularly smoked it a man of under treatment for an enlarged prostate Of the 504 male carcinoma patients who had smoked cigarettes % said they had at some period regularly tobacco among the 467 control patients The difference is statistically the last part of the investigation inquiries were about the brands of cigarettes smoked and the another tipped cigarettes The results Table VIII show that none of the four main brands recorded was more associated with carcinoma of the lung than proportions are remarkably similar in the two groups On the other hand very few of the men with carcinoma had ever regularly used tipped cigarettes Cigarettes Smoked and Use of Filter- Information Male carcinoma and MatchedMatched Information Obtained During the Last the Investigation Only ee with flavouring agents Questions about chewing tobacco and the were asked of 1,209 male patients with lung use of snut and of the 1,209 corresponding control carcinoma patients show Table IX that fewer patients with lung Tchaercirensoulmtas carcinoma TABLE Use of Tobacco for Chewing and as Snuff Male and Matched Control Patients Information Obtained During Part of the Investigation Only ; Tobacco Chewed Disease Group Tobacco Never Oc asional y Occasionally Less Chewed Less 10 10 Yrs | Yrs Regularly Less 10 10 Yrs | Yrs 1,209 noma carc^<- noma patients .. 1,209 control patients 1,169 1.145 11 17 17 32 Tobacco Never Taken as Snuff Tobacco Taken as Snuff . 1,209 carci- noma patients .. 1,176 8 1,209 control patients oe 1,166 ft Significance patientspatients : tests of differences between carcinoma : : Chewing = Chewing 79 = 01 02 taking 1.36 = 20 30 and . control cigarette ; carcinoma dec. Patients or differences 72 18.2 me 2 21. 36. 9.0 133 33.6 | 396 100.0 were still 3 Control Patients 90 had chewed tobacco 40 or 3.3 against 64 or 5.3 and slightly fewer had ever taken snuff 33 or 2.7 against 43 3.6 ; the are small though statistically significant for chewing : That this latter difference is likely 19.4 real is 14 3.9 - to \ is borne out the fact that it more marked 29.6 . 107 for those who had chewed regularly 28 to 49 than for | 15. 4.2 | 12 39 10.8 those who had done so occasionally to 15 and most 32.1 had for 116 marked for those who chewed regularly more | 361 100.0 than 10 years 17 to 32 The number of patients habit in the of chewing was it small for 106 ps oo ssn ible assess the amount they smoked in comparis with - others It may be there were fewer lung- carcinoma patients who who had chewed tobacco because men chew will smoke less 0 oe ae 501 After the completion of - |<. 504 questions F*or one or more years Nature of the Carcinoma in Relation to Smoking - a Histological Type Te According to WynderWynder and Graham 1950 adenocarci-adenocarci- less ma of the lung is less closely related to _smoking than ma : other histological types of lung carcinoma Primary 4 enocarcinoma of thethe lung is an uncommon condition - of particular interest in relation to smoking in that has invariably been reported reported as being relatively com- in women than in men In the present series all oner with a histologicallyhistologicaly confirmed diagnosis approxi- ients ately 70 in each sex have been divided according to : pe with the following results conclude thanto difference relativelyrelatively smokers and average consumption consumption less than five cigarettes the patients with adenocarcinoma in both possible that larger numbers wouldwould have supported and findings Graham's possible histologically Table X also shows that it is not to detect ence amount smokedsmoked between the cases diagnosed histologically and those in whom the diagnoses were histologicallyhistologically This result suggests that the " clinical diagnoses is accurate not surprising in ings at thoracotomythoracotomy or at necropsy of the tumour bronchoscopically in 20.4 while in many of the remainderremainder bronchoscopic tumour tion suggestedsugested the presence of a carcinomacarcinoma though tumour ; | of a | ! | 2 < Anaplastic Confirmation S 11335577 women | 48 || % 441 In present pweerriephceornaslildeyred i ~ Histological Histological Histological Type |. Epidermoid Epidermoid Epidermoid Oat Adeno- Adeno- carcinoma Anaplastic Anaplastic Unclassi Unclassi | fied No Histological Histological | men .. 475% 18 23 303 33% | 33% 38 10 13 105 11 % 16 . 29 seen Co, Site Tumour within The site of origin interest since it interest interest since it is of a tumour possible possible that aetiological aetiological aetiological the bronchioles reach 90.4 the main bronchi but not the series series 1,154 considered considered arisen centrally and 122 9.6 fe not possible to decide ' ee patients 1 habits _ smoking Analysis of the smoking of the patientspatients X the numbers of men and women reveals no difference between them dIifnferTenatblaemounts of tobacco are shown separately for each two groups smoked but a slight difference in the histological type of growth and are compared with the amounts of inhaling See TableTable XI The comparison : numbers expectedexpected from the experienceexperience of all male and allow for differences in age distribution of the patients whom the diagnosisdiagnosis was confirmed not central and peripheralperipheral growths . but - these differences There is no statisticalystatistically significant differ- with and do not materially materially affect the results ) It with between the amountsamounts smoked by patients in the are small that a slightly higher higher proportion of the males ednicffeerent histological groups in either sex The number small be seen peripheral growths inhaledinhaled regularly 62.6 compared of proved cases of adenocarcinoma adenocarcinoma is however too the 10 Years Preceding the Onset of the : Present Illness TABLE Average Amount AmDounit voifdeTdobAaccccoordiSnmgokteo dHiDsatiolloygiOcvaelrTthye pe carcinoma Patients : Amount Average om Smoked DailyDaily over 10Years Smoking | Clgs : Clgs No. No. of Cigs + Non | | | HistolHoigisctaol loHigstologicial calTypeTypeType Less than 5 Cigs 5 Cigs.- smokers ie ; A 106-7 Epidermoid carcinoma 475 a 8-2 anaplastic Oat or carcinoma 303 Adenocarcinomia 33 .. . Type unclassified 105 .. Histological evidence obtained 916 .. .. histological evidence 441 1 2-4 2 1.8 2 0.2 0 0.6 5 4.9 2 2.1 14 19.3 12 11.2 2 0.9 8 4-7 36 34.5 19 20.5 Men 169 110 106-7 7 370 36 370 322 328-5 167 160.5 175 172.4 105 111.4 16 12 38 38-0 334 322-4 141 152.6 116 114 74 72.0 | 6 23 24 ~ 219 225-8 112 105.2 5 . Women 1.6 No C Epidermoid carcinoma 18 a 2 ) Oat or anaplastic carcinoma 38 .. + Adenocarcinoma 10 . . : Type unclassified 13 pType anctassificd 11 8.6 12 11.2 5 3.8 1 5.5 13 0 6 Histological evidence obtainedobtained 79 each ~ No histological evidence 29 29 28-7 11 11 patients table all That * in are the numbers thathatt woulwouldd havehave group female The figures in parentheses with which the group is smoking habits as all the the patients in part C all female female same same of the growth in part B allall male patients * 1 1.9 6 : 2 2 2 8 Se 10 11-1 5 3.9 4 4.3 9 10.0 1 2.7 5 3.0 20 18.4 5 6-6 compared occurred if the patients in the histological group occurred is in part A of the being with histologicalhistological evidence of the growth patients in in the PeripherallyPeripheral y Arising Centrally PatientsPatients with Carcinoma of Lung Centrally * I 11..66 7 7 Oo 1.4 4 1-6 1 1.6 ~ 4 4.3 - 2 1.0 1 12 10.9 2 3.2 8 10-1 question had had at age exactly male patients with histological evidence partpart D all patients and and Corre- Prevalence of Inhaling TABLE Control Patients | sponding Matched es: Group Disease Group Looe a cs be oneet esi - Regularly Smokers Inhaling No. of ~ = Occasionally - Occasionally tn _: Occasionally - Bees _ Never peripheral ? Male carcinoma patients with 52.4 9 558 52.4 1.070 central growths ees oe ae | 62 | 116 growths corresponding : wees 26.1 35-7 380 35-7 30 ee Male control corresponding to carcinoma patients with cafe 1,070 central growths 116 peripheral growths Mt 2 583 57.1 - 63 53.3 99.9 ( ee 1,064 : 99.%9 115 coe carpatients carpatients Female with |. control patients corresponding 84 central growths 6 peripheral growths my corresponding corresponding Fematloecarcinoma patients with ' 84 . central growths ++ ~ 6 peripheral growths .- ae, nar 24, I: woe ey 14 Q- inhaling occasional 24 lt inhaling tests Prevalence of regular plus with Significance carcinoma patients centralcentral compared with compared < carcinoma growths = , 0.05 peripheral peripheral growths with correspondingcorrespondingcorresponding corespondicng ontrols 2-4-07 2-4-07 = , 02 2-1-79 1,0 10 Male lung patients with central growthsgrowths Male patients patients with peripheral peripheral growths growths compared with cor esponding corresponding controls Male patients patients 13 1278 DEC 1952 AETIOLOGY OF CARCINOMA OF LUNG the men with central growths 52.4 % BRITISH MEDICAL JOURNAL ., cant difference 0.05 level The patients sitnatistically signifi- TABLE XII.EstimatedXI.Estimated Annual also be compared compared with their each group can per 1,000 Men and Death Rates from Lung Cance Lung -- then found that the males their own matched controls It is London by Age per 1,000 Group and Women Living Cance Greate rather fewer regular with central growths include Smoked DailyDaily in Preceding 10 Average Years 57.1 while while the inhalers than their controls 52.4 to Years Years rather more group 62.6 to with peripheral growths contain 53.3 The difference Annual Death Rate per 1,000 Persons Rate significant in the former case in Sex Sex Average Amount ~ and Age Non- Smoked Preceding DailyDaily in Lung- Men 2545- smokers than 5 Cigs 1 Ten Years carcinoma Preceding Years | . carcinoma S 15 25 | [ Cigs 50 Cigs | Cigs.- i Cigs + Inter- viewed { OT re ar aCe igs ett 65-74 Women | 0.006 25- 0.04 j | 65.- 45-74 | 0.09 0.32 The 0.06 0.70 | 0.34 | 0.59 | 0.13 1.19 2.37 i | 9 | { 39 13 * The reasons for the 4 expJunglRaaitneeds in the text see saecdtoipotnioonn oafmotuhnist smemaoskureed of smoking habits based Jung are given inointaolibcsservation of fewer than five cases of carcinoma of the Registrar The present investigation cannot . these figures for the cannot provide estimates of interviewed were drawn whole country country since the patients drawn mainly from GreaterGreater smoking habits and the lung cancer death London and between countryside and town For rate both vary report of the example in 1949 the death rates from shows lung cancer in that the the recorded and 292 per million in men were 597 521 398 county boroughs boroughs outside respectively Greater London Greater London other urban districts and rural districts the preceding 10 years The jects were aged 45-64 and and greatest the number of our sub- therefore be the rates for this graphically againmsotstthreeliable reliable In the Chart these are shown the amounts smoked assumptions made that the death It : appears on rate proportion approximately simple proportionproportion with the smoked Among women the death rate amount but the numbers are seems to rise more slowly , smaller smaller and considerably less reliable 5.0- 5.0- 1,000 1,000 ; For the Greater London proceed on three area alone we may however habits assumptions a that the of reported by the control patients without smoking the lung who who lived in Greater carcinoma their interview are at each London at the time of the inhabitants of age and in each sex typical of _ Greater London smoking habits reported by the generally b that the the lung also living in Greater patients with carcinoma of _ interview are typical of the London at the time of their _ disease during the period of inhabitants who died of the the survey and c that the deaths attributed by the both in men Registrar to lung cancer and in women provide a of the actual numbers of deaths duc reasonable estimate lung On these to carcinoma assumptions not wholly 1,000 ob PER RATE #0 RATE DEATH DEATH DEATH 20 ESTIMATED ESTIMATED ESTIMATED ESTIMATED 1.0 ESTIMATED Xk MEN O--=90 WOMEN region death rates for eacheach level of tobacco consumption 5 20 40 30 40 given by AVERAGE 50 60 been taken as NUMBER OF CIGARETTES CIGARETTES SMOKED DAILY persons Estimated for annual death death rates from lung cancer in smoking different within men and for women aged 45-64 in Greater London been estimated from the data amounts for of tobacco have amount of tobacco smoked daily measuredreilnattieornmstoofthe average the _ of age groups 25-44 45-64 anedac6h5-s7e4x and for each in the preceding 10 years cigarettes : Thus at ages 45-64 Greater London with we had 932 male patients resident in Cigarettes or Pipe . diseases were lung On the same smokers ing 10 9.3 % had smoked an averageaveragecaovrecrinthoema 4.1 tive of Greater assumptions that our data data are representa- day years of 42.6 an fewer than five cigarettes cigarettes or their preced- equivalent mortality rates forLoenacdhon it is also possible to estimate average of 5-14 5-14 a day 29.9 a a day 12.8 an % an average of 15-24 only cigarettes and type of smoker is cigarettes pipe 50 or average of 25-49 a day and 1.3 % an more a day The male population of average of Greater London the pure smokers pipe only As previously shown late are few and we can therefore calcu- ages 45-64 was 937,000 and this this at above proportions of population has been given the ~ smokers and rates only for the oneone broad results are age group 45-74 The amounts making these smokers of different estimates - we ignore the lung- is too small to make any material , but their proportion Estimated Annual Mortality Rates from the numbers of difference ) In the same per 1,000 Men Aged 45 74 Lung Cancer cancers in Greaterpersons of each sex and ageage dying from way Daily for Preceding 10 YearsAvienrTaegremAsmount Smoked of . of the London in 1950 have beenbeen divided lung Cigarettes basis Less than | were intervieswmeodking habits of the lungcarcinoma patuiepntosnwthhoe 5 $ Cigs 15 Cigs Cigs 25 Cigs 50 Cigs 4- Pure ij. smokers The death rates thus obtained cigurcite- |} 1-71 | both age and amount smoked Table XII increase with cig- Smokers of cig- 1.11 2.16 H 3.50 7.37 7.37 figure for male TheyThey pass from a arettes pipe 0.87 1.67 negligible | | order of 1 in non smokers aged 25-44 to a level of the 100 per year among men aged 65-74 Pute smokers All smokers 0.951 ' 1-04 1.35 1.98 0.79+ | 3.35 | 2.08+ 2.241 2.241 - | have smoked an average average of 25 cigarettes or who | 1-66 2.05 3.42 5.42 more a day for * See footnote to Table III Based on fewer than 5 cases DEC 13 1952 AETIOLOGY OF CARCINOMA OF LUNG BRITISH MEDICAL Journal 1279 at each smoking level the estimated death rate of pipeokers is less than that of cigarette and the differe increases with heavier smoking In three of the four ups the death rate of those smoking cigarettes and pipe intermediate With the amount of data at our disposal 1 the assumptions made in calculating these rates we uld be reluctant to draw any precise conclusion on the ative level of the risks But it certainly appears that the ks are less in smokers than in cigarette d perhaps to the greatest extent in the smoking egories Town and Country There seem to be differences in smoking habits between wnsmen and countrymen briefly referred to above and ir data may be used to see whether they can wholly or rtially account for the reported different mortality rat^s m carcinoma of the though they are insufficient give more than an approximate answer The patients terviewed in this inquiry lived in different parts of the untry Grouping them according to place of residence 2 can roughly estimate the smoking habits of persons ving in Greater London county boroughs urban districts sons occupationally exposed to motor fumes or road dust do not appear more frequently in the carcinoma group The results will be published in full later Social class has already been considered Table II it showed no significant difference between the male patients with lung carcinoma and their controls This observation is in keeping with the Registrar 1930-2 decennial supplement on occupational mortality though in the pre- sent inquiry the lack of association may be overemphasized from the fact that our control patients were usually and deliberately taken from the same hospitals as the patients with carcinoma of the lung This designed equality in some respects may give an overestimated equalitiyn social : class Place of Residence ~ The General's evidence that cancer of the lung is more frequent in the large towns than in the smaller' towns and countryside suggests that a higher proportion of our carcinoma patients would be expected to have been living in Greater London and the county boroughs In fact as shown in Table II this was not the case If . however the patients places of residence are analysed : Able Smoking Habits of Male Patients Living in Different Parts of the Country ; Divided According to Density of Population Standardized to age distribution of population of England and Wales aged 25-74 Area of Residence o, Greater London borough County district Other urban district tural district , i Percentage of . smokers ) 5.1 6.8 8.4 10.4 Percentage Smoking Daily Average of Less than 5 Cigs 5 Cigs.- 15 Cigs.- - 25 Cigs 8.3 6.6 13.3 13-7 38.3 42-7 37.1 40.8 33.7 34.0 32.3 27.6 14.6 9.9 8.9 7.7 Percentage of Pure Cigarette and Pure -smokers smokers . . No. of Patients Interviewed 74-2 66-3 59.9 58.4 16.0 22.8 23.9 21.5 4.8 1,393 4.1 240 7.8 439 9.8 327 nd rural districts There were however relatively few atients living in the country and a special survey was herefore made in February 1950 of the smoking habits of 531 other patients aged 25-74 admitted to hospitals in ural areas of Dorset and Wiltshire To facilitate comparisons the male inhabitants of England and Wales between the ages of 25 and 74 have been taken is standard population and the smoking habits in this population have been estimated from the incidence rates of smoking actually observed in the age groups in cach of he four areas Table XIII It appears that as the place > residence becomes more highly urbanized the proporion of smokers and of pure smokers decreases and the proportion of heavier smokers and pure cigarettemokers increases Thus the changes are in the direction which would lead to a higher death rate from carcinoma of the lung in the towns Whether they can account for he observed differences in mortality is difficult to say On the assumption that the estimated death rates of Table XII should prevail equally in all areas it would seem that he recorded differences in mortality between town and country are greater than could be attributed wholly to the differences in smoking habits In other words the differinces in smoking habits shown in Table XIII are not ufficient to lead to a rural mortality rate which is only about half that of the large towns Other Aetiological Factors : The inquiry here reported was designed to throw light n any aetiological agent in carcinoma of the lung ^xampleon substances which pollute the atmosphere The questions on smoking were merely one facet of the investigation We now turn to other aspects separately for those interviewed in Greater London and those interviewed in the provinces a different picture is obtained Table XIV Of patients interviewed in Greater London fewer with - lung carcinoma lived there 76 compared with the controls 87 ; more lived in each of the other types of area Of patients interviewed in the provinces more with lung carcinoma lived in the county boroughs 45 against 38 and fewer lived in rural districts 22 against 28 The differences in Greater London can reasonably be explained on the grounds that patients with cancer living outside London tend more than patients with other diseases to come to London for treatment In the provinces how-| ever the control patients with other diseases were interviewed in hospitals which were deliberately chosen because like the thoracic units they also served as regional centres ~ Consequently there should not be on demographic grounds _ any deficiency among them of patients living in the smaller towns or in the countryside It would be reasonable to suspect that any difference between the places of residence Matched TABLE Place of Residence carcinoma and ey Control Patients Subdivided by Place of Interview Place of Residence Greater London Other county boroughs Other urban districts Rural districts Abroad : Place of Interview | Greater London . - Provinces Lung- Lung- carcinoma Patients Control Patients | Control Lung-Lung- carcinoma |- Patients Patients | Patients Patients oe .. |. 791 31 133 62 18 _ 900 16 71 42 6 0 194 142 93 I 0 rs 122 ns Occupation and Social Class Occupational histories were taken from all patients but these reveal no gross association between any type of occupation and lung carcinoma which might indicate an actiological agent of general significance example per- 1" places | 1,035 | 1,035 430 430 | . ; Difference between places of residence Patients interviewed in Greater London 40-50 = 0.001 abroad Patients interviewed in provinces excluding patients residing abroad 6.25 interviewed 02 05 of patientisn the carcinomanad control groups would reflect in differences in the relative incidence of the conditions the different The observation in the provinces a smaller proportion of the carcinoma than of the patients lived in the country supports therefore the contention that lung carcinoma is less common in rura urban areas . Evidence can also be obtained by comparing for patients living in a given type of area at the time of interview the proportion who had previlioveud a sn ly long time in the countryside Table Among the carcinoma patients living in Greater London the time of interview had previously lived for 10 or more years in a rural district among control patients living in Greater London pyrene in the soot of domestic fires might be conducive the development of carcinoma Analysis was made of patie kinds of heating used in the rooms of all the hou in which the patients had resided for three or more yea and the numbers of years were calculated that each had been exposed his living to a coal fire a fire an electric fire an anthracite stove a radiator or ot form of heating The results Table XVI reveal very lit difference in the histories given by the two : groups patients : Previous Respiratory Illnesses A large number of the control patients had some respij tory disease and we clearly cannot assume that the histo nit: Residence for 10 or More Years in the Country- side divided carcinoma and Matched Control Patients Subdivided by Place of Residence at the Time of Interview Residence at =: of Time ; Interview na 2 Greater London . Other county +: boroughs Other urban tricts .. 7 dis . Rural districts .. - carcinoma Patienta Lived for 10 or | No. Inter- More Years in a Rural District viewed No. % 791 34 4.3 225 13 5.8 275 155 19 37 136 I 13.5 87-7 _ Control Patients No. Inter- viewed 900 : Lived for 10 or More Years in Rural District | __-- No. % 62 6.9 181 2 6.6 213 164 7 200 149 200 15-0 90.9 coed patie of previous respiratory illnesses given by these would be characteristic of other patients generally would not therefore be proper to compare the lun carcinoma patients with the general control - groups patients to determine whether previous respiratory illness play any part in the aetiology of carcinoma of the lun We have accordingly compared carcinoma patien with patients with other forms of cancer mainly stomac and lar- ge bowel and excluding those in whom the site . origin of the growth was in no doubt and also those wi growths elsewhere in the chest upper respiratory passage and mouth The general cancer group was not selected to be of the san sex and age distribution as the carcinoma group and it therefore necessary to allow for sex and age differences betwe All places | 1,465 221 15-1 1,465 255 17.4 them For this purpose we have first calculated for all the canc patients put together stomach large bowel .- reported incidence of previous respiratory illness in each sex ar > the proportion was 6.9 For each type of area this proportion is lower among the carcinoma patients The differences though slight are consistent and in con- year age subgroup These rates we have then applied to t numbers of patients of corresponding sex and age with a care noma of the lung and b other forms of cancer to calculate ho many cases of previous respiratory illness would have occurre formity with the previous conclusion They are not however statistically significant 6.45 = 0.20 : Residence Near a Gasworks Gasworkers have been reported as specially liable to carcinoma of the lung Kennaway and Kennaway 1947 Doll 1952 and it was therefore thought possible that residence near a gasworks with inhalation of its fumes might conduce to the disease All the patients were asked whether they had ever lived near a gasworks and if so for how long The results revealed no difference 23.0 in each subgroup if both types of patients had had these san rates of attack The total number expected for each illness wi then readily obtained by summing the numbers in each subgrou The numbers expected on the basis of equality can he con pared with the histories actually recorded To avoid bias due t any confusion between an earlier independent respiratory illne in which our interest lay and an illness induced by the presenc of the tumour we included in the analysis only such illnesses a had occurred at least five years before the interview Occasionall illnesses occurring more than five years previously may have bee due to a growing tumour but the number is unlikely w think to be important 1,465 of the carcinoma patients and 21.5 315 1,465 of the control patients had lived near a gasworks for a year or more 0.95 = 0.30 This result agrees with that obtained by McConnell Gordon Jones 1952 Questions were asked about the past occurrence of pneu monia pulmonary tuberculosis pleural effusion chroni bronchitis asthma and chronic nasal catarrh The result Table XVII show that the carcinoma patients mor frequently had a history of preceding pneumonia or chroni Further Exposure to Different Forms of Heating Further Further information on the possible effects of exposure to coal was sought by asking the form of heating used the houses in which the patients had lived This question also related to the possibility that exposure to benz- bronchitis while other respiratory illnesses were referre to with approximately equal frequency by the two groups The differences in the incidence of pneumonia and chroni bronchitis are statistically significant particularly the latter though the actual proportion of carcinoma patient with positive histories is not large with each disease 17 Exposure to Different Forms of Heating carcinoma and Matched Control Patients obtained during part of the investigation only Information Disease Group Lung carcinoma Other diseases Lung carcinoma Other diseases | Lung carcinoma Other diseases Lung carcinoma Other diseases Lung carcinoma Other diseases Lung carcinoma Lung diseases No. of Patients Exposed for Different Durations of Time Never 9 11 1,261 1,258 - 1,192 1,169 1,184 1,172 1,191 1,169 1,192 1,189 1 Yr.- 23 105 22 12 27 74 62 71 66 on no 59 30 Yrs.- 434 429 3 1 02 02 14 21 g 12 14 16 50 Yrs + - 735 726 TO TO AN AN IT IT on on 10 or Total No. of Patients 1,271 1,271 1,271 1,271 1,271 1,271 1,271 1,271 1,271 1,271 1,271 1,271 Significance Test of Significance of Difference . 01 = 70 : Combining all over 1 yr 0-39 = 1,0 0T Combining all over 30 yrs : x25 n P 10 21 Combining all over 30 yrs 84 = 2 50 < 7 Combining all over 30 yrs + = 2.89 n 20 < - Combining all over 30 yrs 17 2,0 95 bre DEC 1952 AETIOLOGY CARCINOFOLMUNAG MEDICAL JOURNAL ABLE Frequency of Occurrence of Respiratory illnesses in the Past History ; carcinoma and Other Cancer : : Patients ns Fi i carcinom~ Patients Other Cancer Patients Type of Respiratory Illness | History of Illness 5 or More ; Years Previously i No. of - No. of ; Patients Observed Expected { Patients History of Illness 5 or More Years Previously Observed Expected Test of Significance of Difference . ; | sthma te ironic bronchitis .. oe 1,465 1,465 ronic nasal catarrh o. 1,465 eural effusion a 1,465 jeumonia tuberculosis tuberculosis 1,465 lmonary tuberculosis 1,465 No. 19 254 198 25 250 11 % 1-3 17.3 13.5 1.7 17.1 0.8 No. 19 222.9 189.2 25.7 224-8 13.1 853 853 853 853 853 853 No. 13 94 90 14 83 8 % 1.5 11.3 11.0 1.7 10.1 11 No. 12-5 125.1 98.8 13.3 108.2 5.9 ; 0.033 14-13 14-13 1,0 = 00 0.90 0.90 1.35 = 30 | 057 1.0 0.<900 .90 10.03 = 101 . . 1.09 = 0.20 0.30 * Excluding cancer patients notified incorrectly as having lung carcinoma see Table XIX ABLE Frequency of Occurrence of Previous monia and Chronic Bronchitis carcinoma and Other - ; Cancer Patients Subdivided by Age and Sex - Men : Women 5 Age : ' i carcinoma Patients History of Illness 5 or More Years Previously No. of Patients | Poeumonia Chronic Bronchitis No. % | No. % Other Cancer Patients | carcinoma Patients History of Illness 5 or More Years Previously History of Illness or More Years Previously No. of Patients PneumoniaPneumonia ; Chronic No. Bronchitis | Patients PneumoniaPneumonia | Chronic Chronic Bronchitis No. % | No. % | i No. % No. % Other Cancer Patients , or HMisotorry e of Illness Years Previously 5 Previously No. of Patients PneumoniaPneumonia Bronchitis No. % | No. % 19 18 | 15 | 44443 0 | 22459 oF 3 07 5- en 17 S 18 7 q 16 07 3 443 0 7 22459 4 22 17 12 0533 116 46 15 26 d i | | | 1} 5- 1. 493 83 17 72 15 109 15 14 5 ] 10 www 44443 11 10 26 81 22459 5 s 0533 | | | | 5- | 545 103 19 107 20 213 20 9 | 27 13 34 44443 9 7 21 101 22459 S| 13 0533 j | | | | 5-74 : 186 26 14 30 16 151 18 12 ; 22 15 www 44443 17 4 22 112 22459 8 14 13 | | | | | | | el Total .. 1,357 236 ~- 230 526 61 C 62 ~ 108 14 24 327 1 22 32 = H * See footnote to Table XVII ct t ; = Pneumonia Detailed figures for the previous occurrence of these two TABLE Frequency of Occurrence of Previous liseases are given in Table XVIII The carcinoma and Chronic Bronchitis Patients Incorrectly Thought to atients show a uniformly higher incidence of each disease have carcinoma Subdivided by Age and Sex ; nee In both sexes and in all age groups though in men many i of the differences are quite small In neither group how- Patients Incorrectly Thought to have Lung Carcinoma o-o 4 F ever does the frequency of past history of pneumonia Men ] Women : Ms naturally expected ncrease with age as would patients be their earlier It is not - History of History IllnessIllness ; History of Ilnes Illness ry unlikely older forgot their More patients unlikely that some earlier attacksattacks forgot Age or More Years 5 or Years Previously : some pneumonia This being so the differences found : j i Previously No. of i Pneumonia etween the carcinoma and the other cancer patients PNaoti.enotfs Chronic : Patients Pneumonia Chronic ' F Pneumonia Pneumonia other Pneumonia with respira- arisen i Pneumonia nay merely have arisen because patients with a respira- PneumoniaPneumonia Bronchitis Bronchitis No. No. % % | % ory disease recall more completely their previous respira- % No. % % } No. No. No. % NNo o..% % | ory No. infections which which is for infections for the led % reason us is very : ory | 35- 17 11 | } 14 4} } o exclude other respiratory illnesses from the control . 25 14 22 30 ! group This possibility can however be tested by com- 45- | 79 1 14 10 13 25 4 16 5 20 i | | paring the histories given by patients thought to have 5565-74 98 25 26 25 26 25 3 12 9 36 15 S 34 a0 1 3% 20 i | | interviewed interviewed arcinoma arcinoma of the lung when they were interviewed but In whom the diagnosis turned out to be erroneous Table XIX with the histories given by the carcinoma patients and by the other cancer patients Table XVIII notified patients in incorrectly every - notified nearly The incorrectly patients gave in every sex and age group a history of previous pneumonia and chronic patients given bronchitis similar bronchitis of similar frequency to that given by the patients with lung carcinoma and of greater frequency than that of the patients with other forms of cancer For all sex and age groups taken together the proportions with a positive ages | 267 55 - 53 - 68 13 | 16 Comparison with patients proved to have lung carcinoma Patients incorrectly thought to have lung carcinoma No. giving a history of previous pneumonia - No. expected to give s1 uch . 1.64 hi6 stor4 y -1 2 0 0 oe . . 68 59-9: ee No. giving a history of previous chronic bronchitis =. No. expected to give histho isr toy ry 30 a = 1-20 0.20 < bee . Comparison with other cancer patients 69 69D vet history -pneumonia patients carcinoma incorrectly notified patients patients 20 carcinoma patients 17 other cancer patients 10 ; chronic bronchitis incorrectly notified patients 21 patients patients { carcinoma patients % carcinoma 17 other cancer patients When age and differences are allowed for Table XIX PatientsNo. giivingncorrectly thoughtprevioushavepneumoniacarcinoo mea we oe 68, No. expectetdo give such history 48.22 No.No. giving a history of 1384 n~ m1 chronic 0-001 bronchitis No. expected to give hisathiostroryy. 21-43 69 oe . : oe . OD 44.5 the incorrectly notified patients and the carcinoma patients do not differ significantly while the differences between the incorrectly notified patients and the group of other cancers are highly significant It would seem there- fore that the more frequent history of a preceding attack of pneumonia or of frequent attacks of chronic bronchitis in the carcinoma group may well result from patients with respiratory symptoms recalling their previous attacks os of certain common respiratory illnesses more readily than other patients though it is possible that the cancer suffered and the incorrectly diagnosed groups both have a ' greater frequency of such attacks in the past On the present evidence we feel unable deduce any aetiological relationship between lung carcinoma and previous respirawe tory illness _ AETIOLOGY OF CARCINOMA OF LUNG . BRITISH MEDICAL JOURNAL the Validity of Results preliminary several The larger and more detailed detailed data sented here confirm those in our that we have pre- support suport our conclusion that there is an associatiroenpobrettwaenedn smoking and carcinoma E of the lung of the Other explanations fuly figures might howeverhowever be possible and we care- namely considered alternatives in our earlier a that our group group with carcinomacarcinoma of the paper- lung was ; patients with that disease b that the group were not truly comparable a distribution by the of smoking habits very similar to that other groups but very different from show carcinoma patients that of th sugges These observations make it a to attribute the results to unreasonable we exaggeration by by the lung bias on the part we believed by the of the interviewers since results them to have lung patients carcinoma wh carcinoma but wh ; c that the method of had led to the choice of carcinoma patients tended becausebecause of their exaggerate their smoking habits habits e that the disease to tended to scale interviewers up the smoking habits of the carcinoma ; individual patients and f that the individual interviewers might have obtained different results and have interviewed different -and in proportions of the patients the various disease groups patients who were selected as controls viewers the by the inter The main points of the on basis laid down that is the group against these alternativealternative arguments arguments that we put forward explanations explanations are illustrated in disease group and the great majority of the " otherredsipsieraasteosryi Table XX which , utilizing utilizing the various patients shows the groups of control The further extensive data amounts of proportions proportions who smoked different tion of our first report have collected since the publicas tobacco standardized according to the age to the earlier proved to be essentially similar -:* dbiesttwreiebuntion of the population of England and Wales data and we have obtained no information to throw subsequent the ages of 45 and 74 doubt on the validity of the In this standardization the incidenceincidence rate of smoking smoking in a given sion that there is a real association between conclu- carcinoma of the lung smoking and aogfe group in a given sample of patientspatients was applied to the number Some men to women - in that age group in England and Wales figures for the smoking habits of the general give the numbers of smokers in in the general population The Jation of Great Britain in 1951 have been popu- summation of the figures thus derived derived from eacheach other purposes by the Social obtained for group gave the total total distribution in the separate age smokers of different standard standard population of amounts were then of Information and it is of intSeurresvteytoofseethehoCwenttrheasle Office pare with the habits com percentage distribution distribution as shown in Table converted into a XX of the recorded by our hospital patients The groups under 45 The two age years were omitted from the calculations because there were few such patientspatients in some disease survey general population was made in and was based upon interviews made by trainedMay 1951 unreliable figures would would have process of standardizationstandardization been given groups and these undue weight in the tors with a representative random investiga- - population of Great Britain sample of the civilian _ names of aged 21 years and over The | Table XX shows a) that the carcinoma from localpersons to be interviewed were selected at random - tains a smaller proportion of smokers group con- urban records in a representative sample of about 100 and a higher proportion of and light smokers and rural local authority areas of different other disease heavy smokers than any of the throughout Great Britain The sample thus types adequately ' groups and b that the proportions in the represented the population in group of patients incorrectly thought to have carcinoma of other relevant factors respect of sex age and all % the lung and in the groups with other with cancer in other sites and with roetshpeirratory diseases part of The questions about smoking were other an extensive investigation concerned mainly with 2 similar We would as diseases before lay special stress are way assutbojects they were however drawn up in such a group of patients believed by the upon the interviewers of our permit the replies to be; compared with those carcinoma of the lung at the time of interview to have inquiry disease proved finally not to have that interview but who This group revcals To avoid difficulties of geographical variations in ; smoking * Table The Smoking Habits of Patients in Different Disease Groups Standardized According to the Age the Population Age Distribution of of EnglandEngland and Wales Aged 45 7a4t June 30 Disease Disease Group j Percentage Smoking Daily Peargceeonft- Average of Less smokers Non- smokers than is Cigs.- 5 Cigs Cigs.- Cigs.- Carcinoma of lung .. { incorrectly thought to have car- cinoma of lung Other respiratory cases . dis- a -., Other cancers Other diseases 0.3 5.3 1.9 4.6 5.6 Women | Carcinoma of lung .. Patients - incorrectly thought to have car- 4 of lung cinoma Other respiratory cases dis- | - Other cancers didsi-s- Other diseases 40.6 66.9 66.5 68.4 55.9 4.6 9.9 9.9 2.4 9.0 13.7 16.4 | 22.4 14.3 22.1 35.0 37.8 38.7 26.0 26.9 9.5 4.2 11.1 5.0 3.6 No. of PaItniteenr-ts viewed Agvieedwed 45-74 1,224 202 301 473 875 90 45 25 294 157 ; Social Survey sample as a standard and adjusted the patients | to that age distribution before distribution of the different calculating the percentage |. grades of smokers by as usual ~~ applying the incidence rates of smoking in the patients at each given age to the Social Survey population of at. that age and summing for the age groups Persons of 75 and over were excluded Table XXI shows that the of smokers and light smokers percentages closely but it appears on the whole tahamtonsgomewwohmaetnheaavgireere smoking habits have been recorded amongst the patients ; i than in the sample of the general public Differences in the dates of the interviews to February 1952 in the one April 1949 are case May 1951 in the other unlikely to have influenced the results the national consumption of tobacco varied appreciably as very little over that period It may be argued that the differences indicate an association between smoking and many separate diseases they may on the other hand result from the different methods of interviewing and from the of interviewers different groups employed The comparison cer- tainly provides no evidence that the association we have ' a sea 1283 OF CARCINOMA LUNG 13 1952 - AETIOLOGY DECLE Comparison Between Smoking Habitisn othfe PIantvieesnttis- Without Carcinoma of the Lung Interviewed and of the General Public Interviewed by the Social gation Greater London Only Survey Investigators; Residents in BRITISH | 1283 OF JOURNAL MEDICAL diagnosed and histologically proved These 5 men and 29 . women said that they had never smoked at all or had smoked so little as never to have consumed as much as one cigarette a day for as long as one year Such patients in the ordinary course of their lives must have inspired air Subjects Men ients with diseases Percent- age of Non- smokers Most Recent Amount Smoked | Percentage Smoking : | i 5 15 25 Cig.- | Cigs.- | Cigs.- | Cigs = . | No. Inter- viewed containing tobacco smoke and it is not possible to say whether the discase would occur in its complete absence The reasonable presumption is that it would Experience | of cancer in other sites for example cancer of the skin indicates that it is unlikely for one environmental agent to be the effective cause in all cases other than lung car- inoma general pub- 7.0 nple of general pub- ic Social Survey | 12.0 Women ! tients tients with diseases : other than lung car- 1 cinoma .. .. | 54-7 4.2 | , 43-3 32.1 7.0 | | 44.2 | 28.1 | 13.0 21.6 8.2 13.4 | 1,390 8.5 199 - ' 2.5 456 Whether smoking is the sole cause of the increase in the disease in recent years is another matter There is no evjdence to show whether there has been an increased inci- , dence among smokers It is certain we think that some if not much of the increase is spurious and merely the result of improved diagnosis Rigdon and Kirchoff | micplSeocoifaglenSeurravlepyub. - 52.9 16.9 24.3 4.7 1.2 255 1952 have pointed out that in the U.S.A. the death rate in the different States is positively \ attributed to lung cancer * is three less than that shown in Table XIII because the correlated with the number of physicians per 1,000 inhabi- This number interviewed in the special investigation in rural hospitals hospitals are not and it can be shown from their figures that this is Atiuednetsd tants true independently of the correlation with cigarette con- between smoking and carcinoma of the lung can sumption is also related to the number of physicians oserved selective choice for comparison with the per 1,000 inhabitants The extent to which the increase is attributed to a other patients who tended to real does not however affect the present evidence from of carcinoma patients which the association between smoking and lung carci- e light smokers noma is deduced It would be material if it were proved | Discussion that there had in fact been no true increase of the discase ; following a great increase in the consumption of tobacco In discussing the data of our preliminary report we con- but that in our opinion is as far from having been proved luded that there is a real association between carcinoma that the recorded increase is all real The position then of the lung and smoking but pointed out that this is not as see it is a that an association has been demon- ecessarily to say that smoking causes carcinoma of the as we and elsewhere smoking and The association would occur if carcinoma of the strated of the lung h that independently of this evi- uunngg caused people to smoke or if both attributes were habit of smoking was carcinoma there has been a recorded increase over the years in dence the discase and an effects of a common cause The before the onset of the disease the number of deaths attributed to of tobacco lowever invariably formed ; the production of symptoms so that the increase has also occurred in the consumption and particularly of cigarettes c that the increase in the as revealed by disease cannot be held to have caused the habit nor can of deaths recorded is relatively greater than the common cause likely to lead number but the actual rela- we ourselves envisage any both to the development of the habit and to the develop- We therefore increase in the consumption of tobacco tion between the real increase in the number of deaths and ment of the discase 20 to 50 years later the increase in the consumption of tobacco is entirely a conclude that smoking is a factor and an important factor matter of conjecture in the production of carcinoma of the lung environmental factors other than tobacco Schairer Investigations in Germany M^...ller 1939 and Needless to say be responsible for part of the presumed increase The Sch^niger 1943 and in the U.S.A. Schrck Baker Ballard may played by any such factors cannot however be and Dolgoff 1950 Wynder and Graham 1950 Levin pdaerdtuced merely from a contemporaneous increase in their Goldstein and Gerhardt 1950 Mills and conclusions Porter 1950 In Britain incidence and in the death rate from lung cancer is of correlation in time a direct association have led to very similar McConnell Gordon and Jones 1952 found no difference in 100 lung- on the basis a the disease and exposure to them must be demon- between additional but between the proportions of smokers strated In the present investigation some carcinoma patients and in 200 control patients collected hand they showed a con- evidence was obtained that lung carcinoma not very strong rural areas but otherwise in urban than in at a later date On the other between the siderable difference among cigarette is commoner found major or clear association apart from that : smoking the larger quantities 44.1 of the proportions smoked more than 20 cigarettes we no a with the consumption of tobacco that we made no inquiries carcinoma group had We should perhaps point out . a day against 23.2 of the controls . which would throw light upon a relationship between the The present analysis of nearly 1,500 cases or more than development of lung carcinoma and an attack of influenza - double the number dealt with in our preliminary report during the pandemic of 1918-19 relationship from time the conclusion then reached and has revealed no in the literature see Lancet 1951 2 737 supports alternative explanation example in the use of petrol to time suggested It would be difficult to gather sufficiently accurate informa- lighters tion on such a disease after the passage of so many years It has been suggested that subjects with a particular We note a that no appreciable increase in lung cancer+ constitution may be prone to develop a the may occurred in Iceland Dungal 1950 though the influenza phhaybsiitcaolf smoking and b carcinoma of the lunrgathaenrd tthhaant has there and b that in Britain influenza pandemic was severe both sexes almost equally as judged by the association might therefore be indirect in 1918-19 affected causal Parnell 1951 We know of no evidence of such mortality while deaths from lung cancer occur predomi- constitution characteristic of patients with lung in men ae a physical carcinoma If it does exist we should still have to find nantly environmental factor to account for the increased Lung CancerMillioni Millioni some of the disease in recent years Influenza Million Death Rate per | || | incidence is factor in the production of Year Death Rate per Year F To say that smoking a that it contri- _F M M 4 carcinoma of the lung is not of course to say 1948 422 83 butes to the development of all cases of the disease All 1918 3,360 2,967 1949 453 86 that the disease occurs in smokers and 1919 1,350 1,101 observers agree in the present series there were 34 such cases confidently 1284 DEC methods of appreciable difference our results carry equal risks As in our There is also an in sho smoking previous report pipe appeartso be less closely associated with between men living in town and smoking haf country which to than smoking cigarettes In the present observa- lead to a higher death rate in the towns but not found we have that contrasted with extent that is actually observed ~ of rather fewer the patients with carcinomaotohefrtphaetileunntgs ; It may be that other factors also operate used a - cigarette or smoked these different death rates in men and in to prodi tipped These observations are of interest though it and in the countryside women in toy On the other hand the to draw any conclusions from them ship between smoking and lung carcinoma is relati few people have limited themselves throughout . example common lives to one method of smoking It must also be to be more complex than that depicted in TablequXitIeI liIk observation would smoking which remembered that any technique is differenti- especially the light smokers suggest that si associated with a tendency to light smoking will to hold their cigarettes in their mouthsamloesnsg them neces- sarily according to our figures appear to be less than men and not to smoke them to the continuou lung related to carcinoma Nevertheless it seems closely number of cigarettes a day may not therefoerne d An eqi these results pipes may that possible cigarette and filter thing from the point of view of cancer risk be the sar may to some unknown extent each partly by men and by women when smok Again differences in separate consumpti active agent before it reaches the respir^tory tract of cigarettes in town and country may have been the other hand the observation that patients nounced 10 or 20 years ago than they are day moWree pr ~ recognize that they inhale are found who - no information to guide us ha no more frequently in carcinoma group than in the control somewhat paradoxical We group appears : beSttwoecekns t1he95s2ize hoafs ahowever shown a distinct relatio pointed out however in our assessed by the number preliminary report that until the size of the particles carry- Iotccupied dwellings the mortality from lung cance ,, that is the carcinogen determined nothing can be stated would seem likely that some agent other than about the effect which differences in depth of respiration present perhaps in domestic chimney smoke tobacc have on the extent and site of deposition of the exhaust fumes of cars is at least partly responosribline th carcinogen From the present extended observations it the excess mortality in towns fo seems that patients with growths of central origin inhale Comparisons between the recorded death less frequently than normal though the difference is epochs and in different countries rates at differen small while patients with peripheral growths very inhale rather more frequently may Such a finding could be interpretation present many difficulties in Varying standards of of death differences in methods diagnosis of the caus if smoke when not inhaled expected sumption of of preparation and con the large bronchi while were to penetrate mainly to 50 tobacco changes in consumption over the las inhaling spread the deposition of years may all introduce gross errors smoke particles more evenly throughout the bronchial tree .From the evidence collected about each patient's some correlation between national Nevertheless figures for cigarette con- sumption and the death rate from lung cancer habits it has been possible to smoking expected though in view of the would be the risks of dying from carcinocmoampouftethesolmue ng esintimdaiftfeesreontf the correlation is uncertainties of the data unlikely to be high Studying the inci- dence of lung cancer in some age groups at different levels of tobacco consumption we would Doll and Kennaway 1951 Europea6n countries Daff consumption validity emphasize are speculative and of tobacco conclude The dependent per head has been for the last 10 first that the smoking habits of the namely higher in Switzerland than in the years rather interviewed in this inquiry and residcenatricn iGnreoatmear Lpaotnidenotns are representative of the habits in United Kingdom and Norway has been about half that in the other two countries while the crude death disease of all persons dying of the end of the rates at the beginning and ; secondly that the period were roughly in the proportion of 10 other diseases inter- ECinggalreatntde and Wales to 5 Switzerland and 2 Norway and residents of Greater London tion of 4 consumption was approximately in the propor- are representative of the habits of the general population England and Wales to 2 Switzerland and 1 Greater 1950 and thirdly that the actual Norway and was more in accord with the relative death numbers of deaths from carcinoma of the lung in each rates The increase in the number of deaths has been about sex in Greater London were close to the numbers recorded the Registrar The only one of these the same twofold in all three countries but the in consumption of tobacco and increase cigarettes has been tions upon which we have a check is the second assump- The differences in the incidence of cancer of the less tions smoking habits made by the Social Observa- therefore quite differcnt in extent from those in the lung are | - section of inhabitants of Greater Survey upon of tobacco consumed they are more like quantity London do not radically from the observations based upon our different from those in the though still - quantity of cigarettes consumed The study of the relation between the national patients though they reveal rather fewer heavy smokers we have found Keeping these tion of tobacco and the national incidence of consump- assumptions in mind estimates indicate that the risk of dying of lung carci- lung has scarcely begun cancer of the increases with age as is of course known and in No responsible agent in tobacco smoke has been detected approximately simple arithmetical proportion with the The suggestion that arsenic introduced by insecticides sprayed on the growing crop might be a factor would test the truth of this conclusion is to see whether seem to be discountenanced by the absence of arsenic . with the observed incidences of lung carcinoma from Turkish tobacco and the high proportion of lung of tobacco consumption in different sections of the community and in different parts of the world In this carcinoma found at necropsy in Istanbul Daff Doll and Kennaway 1951 ; Saglam 1944 Benzpyrene has not is country there a pronounced difference in the smoking been detected in cigarette smoke Waller 1952 Long- of men and women it appears inadequate to account continued exposure of mice to tobacco atmospheres containing for the whole excess of cases which occur in men as is smoke has failed to produce lung cancer Camp- shown by the different death rates estimated for each bell 1936 Lorenz Stewart Daniel and Nelson 1943 but level of tobacco sex it may be of significance in view of our 2 consumption Figure based upon it Table XII and the On the other hand the sex ratio smoke was brought to the mice through filnodnigngtsubtheast tIhne the relatively few cases observed in smokers is not of incompatible with a similar incidence in men and women the absence smoking could not be identical because associated with certain industrial occupations contrast the tumours of the skin of mice can be produced by application of tars obtained from tobacco burnt at temperatures which occur in normal smoking Lamb and Sanders 1932 Flory 1941 Goulden Kennaway and Urquhart 1952 have pointed out that carcinogenic agents BRITISH * MEDICAL JOURNAL tobacco } i tobacco smoke and in town dust might supplement one a day or the equivalent in pipe The corre- mother and have summarized the available data about the ~ dditive effects of two carcinogens An tobinatc obc aco co jmoke might be by itself only weakly if at all carcinogenic but might act as a carcinogen in the presence of for Example the benzpyrene in urban atmospheres Summary oei, sponding figure for the male control patients was only 13.4 For women these proportions were 11.1 for the carcinoma group and 0.9 for the controls For men these differences are present consistently in - each of the five areas of inquiry For women they are present in London but not in the 28 patients observed in the provincial towns where only one woman with aetiolgyot In an investigation designed to throw light on the aetiology of carcinoma of the lung nearly 5,000 hospital patients have been interviewed by four specially appoin- fed almoners The interviews took place in the years the heavier smoking habits was found - Estimated death rates for Greater London on assump- tions stated in the text indicate that the mortality from carcinoma of the lung may increase in approximately to 1952 in hospitals in London Bristol Cambridge 1948 Newcastle and for a limited purpose Leeds in the rural areas of Dorset and Wiltshire The questions asked covered a very wide range including the occupa- tional histories of the patients where they had lived and the forms of domestic heating in their homes their previous attacks of respiratory illnesses their habits with regard to smoking and for other purposes some particulars of their dietary habits and use of purgatives lished Preliminary figures on smoking were published in a previous paper Doil and Hill 1950 The present paper gives corresponding data for the whole of the material collected as well as the analysis of other simple proportion with the amount smoked . Amongst - in men of ages 45-64 the death rate smokers negligible while in the smoking categories it estimated to reach 3 to 5 deaths per annum per 1,000 livin.g.. - wo Regular users of petrol lighters were found with equal 7 frequenciyn patients with lung carcinoma and in the control patients with other diseases 42.9 and 41.3 : the proportions who said they inhaled were similar 64.6 and 66.6 and so were the proportions cigarette who had smoked mainly rolled * cigarettes 20.7 and 19.1 On the other hand rather fewer of the cigarette patients with lung carci questions included in the inquiry The main comparisons are between 1,465 patients with carcinoma of the lung and an equal number of matched control patients with other diseases each of these being carefully chosen so as to be of the same age the same sex and so far as possible in the same hospital at the same time as a carcinoma patient There is no appreciable difference between the two groups in the number of persons belonging to the Registrar five social classes and no association has been found between any type of occupation and lung carcinoma which would suggest the presence of an aetiological agent likely to be of general significance With regard to the possible effects of fumes in the atmosphere both within and without the home there is no significant difference between the groups Of the carcinoma patients 23.0 and of the control patients 21.5 had lived near a gasworks for a year or more Their use of coal gas electric fires or other forms of heating in the rooms of their homes did not differ appreciably In conformity with the national death rates rather fewer of the carcinoma patients lived or had lived in the countryside and more correspondingly in the noma had ever used a cigarette regularly % - against 12 of the controls and only 3 out of 504 had smoked tipped cigarettes compared with 15 out of 467 controls The observations in these respects are too few for a definite conclusion but conceivably they maymay have a bearing on the appreciably lower risks reported here for smokers compared with cigarette Each of these methods of smoking might partly separate - out an active agent before it reached the respiratoryrespiratory tract The validity of these various results is studied and it ~ is concluded that the association between smoking and carcinoma of the lung is real It is not argued . that tobacco smoke contributes to the development of all cases of the disease most unlikely event It is not argued that it is the sole cause of the increased death rate of recent years nor that it can wholly explain the different mortality rates between town and country ACKNOWLEDGMENTS The following hospitals operated in the investigation . - surgery Frenchay departments of plastic and jaw Me neurological surgery and thoracic surgery Cambridge Addenbrooke's radiotherapeutic : centre . and . Papworth Hall towns The carcinoma group in comparison with patients with other forms of cancer more often gave a history of suggests a previous attack of pneumonia and of chronic bronch- itis Detailed analysis of the data however that this difference may be due merely to the lung- carcinoma patients with their respiratory symptoms recalling more readily than other persons their previous attacks of respiratory illness . data are not accurate enough for an aetiological relationship to be postulated Of the 1,357 men with carcinoma of the lung 7 or 0.5 were smokers as defineidn the text of the 108 women there were 40 or 37.0 The corresponding figures for their paired controls were 61 m",,4n .5 and 59 women 54.6 Of the men with lung carcinoma 25.0 reported that they had been smoking before the onset of their illness an average of 25 or more cigarettes Leeds General Infirmary thoracic department we Brompton Central Middlesex : Fulham Hackney Hammersmith Harefield Lambeth Lewisham Middlesex Mount Vernon and the Radium Institute New End Royal Cancer Royal Free St. Bartholomew's St. Charles's St. James's St. Thomas's University College and Whittington Newcastle - Infirmary -. department neurological surgery and Shotley Bridge General departments plastic surgery radiotherapy and thoracic surgery Wiltshire and Dorset in the survey of habits of rural only Blandford Bridport General Dorset County Odstock Poole General Portwey Weymouth Salisbury General Wey- Westminster Memorial Victoria Wimborne Shaftesbury mouth and District and Yeatman Memorial Sherborne medical of We are indebted to the staffs these hospitals for allowing us to interview their patients and to have access the hospital notes also to the individual members of the staffs medical and lay who notified the cases and collected notes for examination The work could not have been out without their operation no 1286 DEC 13 1952 _ _. AETIOLOGOFY CARCINOMA OF LUNG Faulkner We most grateful for advice on the interpretation of patho- . logical specimens to Professor W. G. Barnard Drs A. B. and W. Clegg Professor W. D. Bratton R. J. Sandry A. C. Thackray K. Newcomb Drs D. M. Pryce and for assistance in Weavers and R. R. Wilson determining the final diagnoses in the patients interviewed to Dr. A. Adelstein Mr. G. P. Alexander Mr. P. R. Allison Mr. R. C. Bell Mr. R. Belsey Dr. J. R. Bignall Dr. D. M. J. Burns Mr. R. Dobson Dr. J. Mr. G. M. FitzGibbon Mr. G. K. Harrison Mr. G. A. Hendry Mr. F. I. . Herbert Mr. E. Hoffman Mr. G. A. Mason Professor J. S. Mitchell Mr. K. Price Dr. G. O. Richardson Mr. C. A. Ross : Mr. M. Ross Mr. G. F. Rowbotham Dr. K. R. Stokes and _ Dr. G.Strang , _ * Sir Ernest Kennaway and Dr. Percy Stocks took part in a conference called by the Medical Research Council at which the . ~ investigation was initiated and we have been fortunate in having their helpful advice throughout its course Dr. John and Dr. Ian Sutherland kindly read our draft reporKtnoawnedldween have benefited by their criticisms ; . statisticiaanlosfo tghreatGeefunleratol DRre.gisWt.er P.OffDi.ceLotogatnhe chGioevf emrendmiecnatl . Social Survey and to the Statistics Division of the Board of Trade for the provision of data and to the Statistical Department of the Ministry of Labour for preparing the punched cards used - in the mechanical analysis of the results Finally we wish Iago Miss Keena to thank Miss Marna Buckatzsch Miss Beryl Jones and Miss Rosemary Thomson who inter- viewed the patients and together with Mrs. Joan analysed the results Bodington They worked untiringly and at all and the main burden of the work fell on their shoulders hours REFERENCES Board of Trade 1952 Accounts relating to Trade and United Kingdom January 1951 and Navigation of the January 1952. H.M.S.O. London Campbell J. A. 1936 Brit J. exp Path 17 146 Council ' for the International Organizations of Medical Sciences be published 1952 To Daff M. E. Doll R. and Kennaway E. L. 1951 ~ a~ nd Kennaway E. L. 1950 Ibid 173 - Brit J. Cancer 5. 1 LIFE BY R. S. ALLISON M.D. F.R.C.P. D.P.M. Physician in Charge of Neurological Department Victoria Hospital Belfast Royal Royal Grow old along with me ! The best is yet to be ; The last of life for which the first was made " As Robert Browning's words imply it is psychogenic factors probable that cal reactions causing simple anxiety and hysteri play less part in later life than earlier ages But as Sir Humphry they Rolleston do at quoting another authority " Whatever remarked favour of it old age is a losing may game be said in chriagnhiailnctiudmeonucresof cerebral vascular disease and intra- occur with some frequency Affective disturbances are common But I should like chiefly to the two principal organic to refer later life the syndromes seen in syndrome of acute clouding of conscious- | ness delirium or confusion and that of dementia There is presenile former to particularly the relation of the to intracranbiiaolchdeimsiecaasle and toxic factors and of the latter 1. Biochemical and Toxic Causes of Psychiatric Symptoms in Later Life Doll R. 1952 Brit J. industr Med 9 180 and Hill A. B. 1950 British Medical Journal 2. 739 Dangal N. 1950 Lancet 2 245 Flory C. M. 1941 Cancer Res 1. 262 . Goulden F. Kennaway E. L. and Urquhart M. E. 1952 Cancer 6. 1 Brit J. Gerhardt Kennaway E. L. and Kennaway N. M. 1947 Ibid 1 260 - Lamb W. M. and Sanders E. 1932 1. Hyg Lond 32 298 Levin M. L. Goldstein H. and R. 1950 3. Amer med Ass 143 336 Daniel Lorenz E. Stewart H. L. Cancer Res 3 123 abstract J. H. and Nelson C. V. 1943 651 McConnell R. B. Gordon K. C. T. and Jones T. 1952 Lancet Mills A. and Porter M. M. 1950 Cancer Res 10 539 2. Miller H. 1939 Z. Krebsforsch 49 57 Parnell R. W. 1951 Lancet 1 963 Rigdon R. H and Kirchoff H. 1952 Medicine 10 76 Texas Reports on Biology and Saglam T. 1944 Bull Fac Med Istanbul 7. pt 2 3793 Schairer E. and Sch^niger E. ( 1943 Z. Krebsforsch 54 261 Schrek R. Baker L. A. Ballard G. P. and Dolgoff S. 1950 Res 10 49 Cancer - Stocks P. 1952 Brit J. Cancer 6. 99 Waller E. 1952 Ibid 6 8 registration Great as are the differences between the growth and decline both the age periods of show an undue very young and the very old in mental instability in response to disturbances their body chemistry Thus an elderly exhibits at the most only slight mental signs of person who through the fortuitous introduction of ageing may toxic factor develop acute mental a biochemical or clouding of consciousness symptoms indicative of In increasing order of severity these are 1 Simple impairment of attention and recall often associated with a facile and push of talk or euphoric affect 2 Perseveration showing itself in the spontaneous behaviour in the speech and in the response to simple requests for 3 Disorientation in time place and persons usually at some stage with confabulation In many instances concrete orientation may be correct or the time sense only lost but further testing will reveal evidence of abstract disorientation 4 In more severe cases there are grossly defective grasp and delirium with irrational behaviour noisy and ; Wynder E. L. and Graham E. A. 1950 J. Amer med Ass 143 329 phosphorescence _ The centenary of the birth of Antoine Henri Becquerel the French physicist falls on December 15. Like his father . and grandfather before him he occupied the chair of at the Mus^'ed'Histoire Naturelle Paris to which hpheyswiacss appointed in 1892. Three years later he became of physics at the Ecole Polytechnique the discovery that uranium professor In 1896 he made ores at ordinary temperatures emit an invisible radiation similar in several respects to rays and capable of fogging a photographic plate after passing through metal plates Pierre and Marie Curie investigated this radiation and showed it to be an atomic phenomenon They named it radioactivity The discovery of radium by the Curies followed in 1898 and they shared the Nobel Prize for Physics with Becquerel in Becquerel also made important contributions 1903 to the know- ledge of magnetism polarization of light .. and absorption of light in crystals He died at Croisic Brittany on August 25 1908 Recognized causes of such usually reversible effects are toxaemia from fever or urinary infection ; the incautious use of bromides morphine barbiturates or other drugs and vitamin deficiency Other causes which although known are less generally appreciated include dehydration alkalosis anoxia and hypoglycaemia Dehydration If sufficient fluid intake is not secured dehydration will arise in any feverish condition or after a surgical operation such as prostatectomy requiring general anaesthesia The statement that the patient has 66 passed urine has little weight in this respect unless it is known that the output is adequate and the specific gravity satisfactory The after- care of old people undergoing operation for cataract also deserves note Hallucinations and disorientation or acute delirium may occur as the result of a combination of un- favourable circumstances such as recumbency bandaging Read in opening a discussion in the Section of Psychiatry au the Joint Annual Meeting of the British Medical Association and Irish Medical Association Dublin 1952