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Smoking and Carcinoma of the Lung Preliminary Report

Date: 19500930/P
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98999449-98999458
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Doll, R.
Hill, A.B.
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R1-037
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Boyd, J.T.
Buckatzsch, M.
Iago, B.
Jones, K.
Kenneway, E.
Newcomb, W.D.
Stocks, P.
Thomson, R.
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98999254/98999663/Selected Lorillard Chronology Materials Volume I of II
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14 Mar 2002
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Medical Research Council
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British Medical Journal
London School of Hygiene + Tropical Medi
Medical Research Council
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98999271/9647

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K_~_ -~1. BRIT'ISH MEDICAL JOURNAL LOIYDOd SATGRDAY SEPTEIIBER 30 1950 SMOKING AlYI) CARCItYOLK-a OF THE LUNG PRELr.NIIVARY REPORT ar RICHARD DOLL, !H.D., M.R.C.P. - Member of the Statistical Research Unit of the ,N<dical Research Councif Ar+o A. BRADFORD HII-L, . Ph.D., DSc- ProJescor of tfedica/ Sransns:, London School o/ Hygiene and Tropical Medirine t Honorary Director oJ the Statiedca! Research Unit of the Medical Researcn Couned disease or are due merely to improved standards of diag- nosis. Some beGeve that the latter factor can be regarded as wholly, or at least maiuly, responsible-for example. Willis (I948), Clemmesea and Busk (1947), and Steiner (1944). On the other haod, Kennaway and Kennaway (1947) and Stocks (1947) have given good reasons for believing that`the rise is at least partly real. The latter. for instance, has pointed out that " the increase of certified respiratory cancer mortality during the past 20 years has been as. rapid in country districts as in the cities with the best diagnostic facilities,.a fact which do<s not support the vtew that such increase merely reflects improved diagnosis f In England and Wales the phenomenal increase in the nttmber of deaths atuibuted to_ cancer off the lung pro- vides one of the most striking_ changes in the pattern of mortality recorded by the Registrar-GeneraL For example, in the quarter of a century between 1922 and 1947 the annual number of deaths recorded increased from 612 to 9,287, or roughly fifteenfold- This remarkable increase is, of course, out of all proportion to the increase of popula- don-both in total and, particularly, in its older age groups. Stocks (1947), using standardized death rates to allow for these population changes, shows the following trend : rate per [00,000 in 1901= 0, males 1.1, females 0.7 ; rate per 100,000 in 1936--9, males 10.6, females 2.5. The rise seems to.have been particularly rapid since the end of the first world war; between 1921-30 and 1941-4 the death rate of men at ages 45 and over increased sixfold and of women of the same ages approXimately threefold. This increase is still continuing. It has occurred, too, in Switzerland. Denmark, the U.S-A., Canada, and AustraGa, and has been reported from Turkey andIapan. Many writers have studied these changes, considering whether they denote a real increase in the incidence of the ~ o cases previously certtfied as bronchttis or other respua- tory affections." He also draws attention to differences in mortality between some of the large cities of England and Wales, differences which it is difficult to eaplain in terms f of diagnostic standards. The large and continued increase in the recorded deaths even within the last five years, both in the national figures Zd in those from teaching hospitals, also makes it hard to lieve that improved diagnosis is entircfy responsible. fn short, there is surHcient reasoo to reject that factor as the . . _`.r= . . . . whole explanation, although no one would deny that it , - may well have been contributory. As a corollary, it ia right and proper to seek for other causes. . Pawesibk Canses of the Inerease - Two main causes have from time to time been put for~_ - ward: (1) a general aunospheric pollution from the exhaust fumes of cars, from the surface dust of tarred roads, and from gas-worh, industrial plants, and coal firer; and (2) the smoking of tobacco. Some characteristics of the . former have certainly become more prevalent in the last 50 years, and there is also no doubt that the smoking of cigarettes has greatly increased. Such associated changes in time can, however, bc no more than suggestive, and until recently there has been singularly little more direct evi- dence. That evidence, based-upon clinical axpfrience and records, relates mainly to the use of tobacco. For instanee, in Germany, Ivtuller (1939) found (hat only 3 out of 86 - male patients with cancer of the lung were non-smokers, while 56 were heavy smokers, and, in contrast, among 86 " healthy men of the same age groups ` there were 14 non- . smokers and only 31 heavy smokers. Similarly, in America, Schrek and his co-workers (1950) reported that 14.6% of 32 male patients with cancer of the lung were non-smokers, against 23.91 of 522 male patients admitted with cancer of sites other than the uoper respiratory and digestive tracts. In this country, 7lxlwall Jones (1949-personal communication) found 8 non-smokers in 82 patients with proved carcinoma of the lung, compared with I I in a corre- sponding group of patients with diseases other than cancer ; this difference is slight, but it i3more.sviking that there were 28 heavy smokers in the cancer group,-against 14 in the comparative group. - Clearly none of these small-scale inquiries can be accepted as conclusive, but they all point in the same direc- \p tion. Their evidence has now been borne out by the results CC) of a large-scale inquiry undertaken-In the U.S.A. by v Wynder and Graham (1950). ~ Wyndcr and Graham found that of 605 men with ~ epldermoid, undifferentiated, or histologically unclassified types of bronchial carcinoma only 1.3% were "noo- "~ smokers'--that is, had averaged less thanone cigar- -b ette a day for the last 20 years-whereas 51.2% of them Ur had smoked more than 20 cigarettes a dav overtte sanx
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r42 SeeT. 36, 195C - SMOKING AND CARCI`iOMA OFZliNG Tana III-Amounr of Tobacco Smoked Daily Before Present l7lness Tnet.e V-d{osr Recent Amouet of T6beeroe Consumed Reeula.ty ae Reeorded at Two fntervtews With rhe Same Patternr at an by Smokers Belore the Onser of Present Illness; (.unYtarclnoma jnterva( bj Six MonthJ or More Par¢nrs and Conrrol Patients with Dueasas Other Than Conccr ` Ftra tntervie. ISecopd Inier~w, tio. N Persma Smokia¢ No. o( hnone . Smakra¢ 0 ! cy.- 5 np. ISep.-~SCp.- SOap.- Total 3 I ~ 9 ~ I ci¢.- _ a 1 ~ 5 5ap- . ISap- .. ~ f 13 5 11 e 9 I 4 0 4 0 , I Tuul .' 8 1 6 18 ~ 13 . 5 0 1 50 to the question "How much did you smoke before the . onset of your present illness 7" The answers to the other questions on smoking habits showed a variability comparable to that shown in Table ifl. It may be concluded, therefore, that, while the detailed amoking histories obtainedd by this investigation are not, as would be expected, strictly accurate, they are reliable-- enough to indicate general trends and to substantiate material differences between groups. Smokers and tion-smokers The simplest comparison that can be made to show whether thne is any association at all between smoking snd carcinoma of the lung is that between the proportion of lung-carclnoma patients who have been smokers and the proportion of smokers in the comparable group or Dubjects without carcinoma of the lung. Such a comparieon is shown in Table IV. TwnE IV-PraooruDn o! Smckerr and .S'an-smokor ,n Lune. corcnnnma Patients and in Controi Patients wirh Di;eates Oth" Thr. i Cancn - ~ Gronc No.af N o or Prob.ev::. Noncndcen Sm.~ken Tea, M.b Laosaarmoma aat=nu f6<9/ 2(PI':J tiax. - P/<xac,i,etnoGi Cmrrol Paeenn ~,m a;ee.><s oaer man onoer i6e91 .: n(a.^,J 6z Famtb: Luny<artmam. pauema (60, - I9 (517•.7 Lt ' 0-01<P<002 Contml p.uu,u ~w Nr.res uLc-rbaacmr(f01 J:fSJJ';J :8 It will be seen that the vast majority of inen have been . emokers at some period of their lives, but also that the verySmall proportion of those with carcinoma of the lung who have been non-smokers (0.3',) is most signific,ntly less than the correspondiog proportion in the control group of other patients (4 "! %). As was to be expected, smoking is shown ro be a much less common habit among women ; but here again the habit wa,t:enificandy more frequent among those with carcinoma of tuc-a,mg. Only 31.'.-a of the lung-carcinoma group were non-,:-':sk.Prs; compared with 53.3°a in the control group. Amomt of Smoking In the simple comparison of Table IV all smokers have been dasslfied together, irrespective of the amount they smoked. In Table V they have been subdivided according to the amount they smoked immediately before the onset of the illness which brought them into hospital. (If they had given up smoking before then, they have been classlfied according to the amou.it smoked immedialelv prior to sivmg it up.i This classification is described subsequently as " the most recent amount smoked." , Mdex: I Luy-cuanome 33 LsU ' 196 ~ 136 ~ 32 r'•-J69S: purnu t6U1 (5-1':) O96Z) O(FJ7J ('-bUy.) 1(S-0$) ~ n-a; Control cenu ?<e-OOl pe I ,W d,xuc: . oNer 141, 55 393 190 71 1 U ' orrd [6II) . LBA;,I ({]1;;) (k}5%)' (11 %) Q'1%) « Famaka: Lune-.'.rcooma r ' 19 ~ 9! 6' o I Ys-5-1Z: GaumralaU (11-170 ta6J}:) QDmiJ,(u6`/Jf (o-viJ la--a1 pUXP<o-lo Coetrol wiKn~ ' (wornen stL aucuea , I - .aok~o(, 11 oe6er E.a 12 10 6 ~ (1 0' mweaK- cuar L'81 (l29k1 (15T/) , t21 i7J i(nff:) I(o-0X) .r~cea a C.r , .. . -. vouoed wenncf/ •Ouncez f wbacco h..e E<ee e.pe+xed u beerp eawraw~ to .o ma¢y aprcne.c. Teert u i>= or ton.cco in :63 nu.aeicze oe.ren.•. .o Nai ibe cnnrervon fans Gu ~em t.ien u: I ac of tobru a~ --a aap,rew a da>: From Table V it wtll be seen that, apart from the general excess oi smokers found (in Table IV) in lungtarcinoma patients, there is in this group a significantly higher pro- portion of hu~ier smokers and a correspondingly lower proportion of Lighter smokers than in the comparative group of other patients. For instance, in tha lung- carcinoma group 26.0% of the male patients fall m the two groups of highcst consumption (25 cigarettes a dagar more), while in the control group of other male patients oaly 13.51 are found there. The same trend is observable fqr women, but the numb<rs involved are small and the difference here between the carcinoma group and their control patients is not quitc technically significant. If, however, the female lung-carcinoma patients are compared with the total r--sco.r.ex r..,rrTr ~~ ~•.oo: u»cea ~..ucrrs .,rti ..ci.,ow. or rwc ~u.c uEH i-• S-a IS-2a 25-a9 50• AVJGdT OF r06ACCO Sl/0KE9 OAiIY (ExaaE55E0 AS CIGAqETTES) Fw. I.-Perecntnge of p+tienv amokm[ d*Rcrenl amounta of - tobacco diily. 98999452
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'46 SflPT 30, 1950 SMOKING AVp C.4RCIXONA OF LUNG did not see ezactly the same proportions of patients in all the groups; the prnportions were very close. -Slorcover, if the patients seen by each of the interviewers are treated tls four separate investigations, htghly significant differences are found between the lung-carcinoma patients and the other patients tnterviewed in three instances. In the fourth the difference is in the same direction• but, owing to the unall number of patients seen, the results are not techn!cally significant tP lies between Q band 0.05 : in this mstance the almoner had to stop work because of illness, having seen only 46 patients with carcinoma of the lungl. - - Discussion To summarize, it is oot reasonable, in our view, to a¢rr bute the results to any special selection of cases or to bias in recording. In other words, it must be concluded that there is a real association between carcinoma of the lung and smoking. Further, the comparison of the smoking habits of patients in dtderent disease groups, shown in Table X, rc,ealed no association berween smoking and other respiratory' diseases or between smoking and cancer of the other snes rmamly stonvach and large bowell. The association th^-retore seems to be spec!fic to carcinoma of the lung. This is not necessarOv to say that smoking caLses carcinoma of the lung. The association would occur if carcinoma of the lung caused people to smoke or if both attributes were end-effacts of a common cause. The habtt of smoking was, howeve-, tnvariably formed before the onset of the disease (as re,ealed by the producteon of symp- tomsl, so that the disease cacaot be heidto have caused Ine habit : nor can we ourselves envisage any common cause likely to IeaG both to the development o[ the habit and to the de,elopment of the diseise '-0 to 50 years later We therefore ;.onclude that smoking is a factor• and ia important factor, in t^e produc_on of carc:noma oi t.^.e lung. Tbe effect of smoking vartes, as would be dcpected, with the amount smoked. Thc extent of the variation couid be estiIDated by comparing the oum'o<rs of pitunts mmr- emwed wne had carcinoma of the lung'x•ith thecorrespond- ing numbers of people m the population. tn the same age groups, who smo4e the sama amounts of tobacco. Our figures, howe,er, are oot reoresentaL1e of the whole country, and this may be of some importance, as country- men smoke, oo the average, less than city dwellers. More- over, as was shown rar!ier, the carcin4ma and the contrcl patients were not comparable with regard :o thr.r piaccs of residence. The dificu)ty can be o,ere.~me by connning ,the comparison to. t:,e i.^Waottants of Greater London. if it be assumed that the pat!ents without caranoma of the lung who h••ed in Greater London at the time of the!r mterview are typical of the mnabitanta of Greater London wnb reeard to their smoking hab!n, then the numb<r oi - people in London smokmg different amounts of tobacco can be estimated. Ratios eao then be obtained betwcen the numbers of patients seen with carcinoma of the lune and the estimated populations at risk who have smoked comparable amounts of tobacco. This has been done for ' each age group, and the results are shown in Table XP, It must be stressed dtat the ratios shown in this tacle arc not measures of the actual risks of developing caranoma of the lung, bvt are put forward tentadacly as pro- portional to these risks. Tnus Table XIV shows cxear!v, and for each see group, '`,;conclusion previously ;eached-that the risk oi develop- ing carcinoma o` the lung increases steadily as tbc amount srnoked increases. If Qte risk amonx non-smokert is taken Tkat? XR'-Ranor ol Pariemu lmerviewed tVrty Carcinor.m ot r ma¢ and vh o Given Dalfy Conrumn~~un ol7abacro ro rhr Ernmcred Poouiatrunr in Grtarer London Smu.krnd the Snme 4~rs11 'r 1 tfae and femole Combrned; Ranor per MJhum •¢c 0 Dmly Coo~n of Tob.ao II cvr. ! 5-te , [5-2< yt~ pt , Tow ctn- ~ cw cip. . c*.~ if- 0• ll 2 1 a i ~ 9 I tl Q 69 Tl ' +y ti_ l: 3< I]9 24 1 139 - 661 1<1 55- ia 131 590 !53 6<4 ' MO 2" as--. a uo wo 310 ; 1,06] 1Lo:, ; 166 • Ruva aauC uo ~ rhen 5 ~ of r.ranoma of Sbe tvc4 ue G~ m luFq as unity and the resulting ratios in the three age groups m. I which a iarge number of patients were interviewed (ages 49 to '»- are averaged, the relative risks become 6, 19. ?b, `~ 49. and 65 when the number of cigarettes smoked a day /: are 3, 10, 20, 35, and, say, 60--that is, the mid-points of I each amokingg group. In other words, on the admittedl fllly specu:a;;,e assumptions we base made, the risk seems to 111 sary in spproxlmatel} sumple proportion with the amount `~ smoked. One anomalous result of our inquiry apotars to ralate~ to Inhahnq, It would be natural to suppose that if smoking.: wer_ harmrul it would be moro tlarmful if the smoke were' inhaled. In fact, whether.the patient inhaled nr-oot did aot secr., to make any dtfference. Lt is possibk that the pauena were not fully aware of the meaning Df.the fenn and answered incorrectly, but the interviewers were not of that opuuon. In the present state of knowledge it s~ more re?sonable to accept the ftnding and wait until the~ size of tL~•e smoke particle which carries the carcinogen r-' de!ermtned. Until this is known nothing can be statzc9 about me effect which any alteration in the rate and depthi of respiration may have on the extent and site of depov[non~ of tae ~a;;,inogen (Davies, 19;9). u.~-^-- - - i L ~OUO (frO:.nJ-s.._[tl .,GO L a ~ __< co~c~~er,o+ or *os.cco ta vi i ~ 2'3"'^ a.....e conwu•.,c. or •oe.cco u ~ ae.eeT*es , . scr 20F ,+r wo .n oun a+ t.e....r..cu .a. .u iDiO i92o iS1YJ iSNO rEAa , Fic :-Drath rar< from e.rtcer of the hm¢ and rve o - consumpuoo of tobecco and a4.unc=. Ho'.v, m conclusion. do these res..lts fit in witu ethe known facts about smoking and carcinoma of the lung Both the consumption of tobacco and the number of dr<' attributed to cancer of rhe lung are knowv to have c: eased• and to have increased largely, in manycountn 98999456
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748 SEPT. 30, 1950 SMOKING AND CARCINOMA OF LUNG St. Charles's. St lames', St. Mary's. St. Thomas's, University College, Whiuingion. We ue indebted to the staHs of the above-named hospitals fo- havine allowed us to-uuerview their patienu and to have eccess to the hospital noms; also to the individual numbers of the stads, both medical and ley, who notified the cases and collected ihe notes far examination. The work could not have been wrried our wthout their co-operation. Sir Ernest Kennewey and Dr. Pr.y Stocks took part in a conference called by the Medical Research Council, at which this mvesugaiion was initia:c./, and we have been formCm in having their helpful advice throughout its course. Professor W, D. Newcomb has advised us on individual problems of pathology. We are most grateful for this assistance. Finally, we wish to thank Mtss Mama Bucketzsch, Miss Beryl lago, Miss Keena Jones. and Miss Rosemary Thomson, who interviewed the patients and helped xith the analysis of the rceults; and Dr. J. T. Boyd for assistance in the mlculations. . , Reraxcuces Clemmcscn. I.. nnd Busk. T. (1947). Br,t l. Caneer, 1. :5i. DeR. .'d, and Kennnway, E. L. (1950) . Ibid. ln press. Davies. C. N. (1949I 8nr l. indunr Med.. 6. 245. Hill, A. Bradford, and Faoing. E. L. (1948) ibid. 5. I. Kenntway, E. L., and Kennaway, N. M. (1947). BnL !. Cancer, t, 260. MUller, F. H. (19391. Z, Krebr(orsch.. 49- 57 Schrek, R.. Baker, L. A.. Baliard. Q. P.. and DolgerT. S. (1950). C.:aces Res-. 10, 49 Steiner. P. E, (19a:y Arch_ Pmh.. 37, 195. Stoeks. P. (1o4i). Studies on Medical and Population Subjecs, - No. I. Reqional end Locat Ditierences in Cancer Death Rates. Hld.S.O.. Lonaon. Willis, R. A. (19a8). Parholoev of Tumours Buoe-worth, London. Wynder. E. L., and Graham, E. A. (1950). l. Amrr med..-iss.. 143. 329 REGIl4iE FOR TREATMENT OF SEVERE AYD ACUTE LIVER D[SEASE SY A: L LAI^.VER SS-D., 11i-Sc., D.I.C., A-RCS- (From the Section of Chemical Pathology. DeOartmenr of Pathology, Royal Victoria 1nFrmary, Newcastle- . upon-Tyne) - In spite c° increasing biochemical knowledge on the subject of liver necrosis, the hia.h mortality rate of severe liver diseau of acute onset remains a therapeutic challenge, Once coma has occurred a fatal outcome is probable ; a recovery is always an event of note. - It is, however, a remarkable fact that even patients suf- fering from massive necrosis may linger on for a number of days. This is in marked cootrast to the short period of survival of animals after hepatectomy. Moreover, in so-called " acute yellow atrophy " several of the Gvei 5 func- tions mav remain apparently normal until dcath. Even the fasting blood-sugar level may remain within normal liailts. This must surely mean that enough Liver tissue survives to carry out certain highly important metabolic processes. ~ Tnere is also reason to believe that the histological picture of massive necrosis is not unrelated to post-mortem auto- lysis, and that much more liver tissue survives during life thao is apparent aiter death (van Beek and Haex, 1943). Tbesc facts are of great importance. If practically all the liver were necrotic during life, then treatment would obviously be useless. On the other hand, if large oumbers of liver cells were diseased but not dead the possibiliry would remain that the process was reversible, and that a sucrrsful u_=rment might eventually be discovered. In the bope.that the ;at¢er state of affairsaaual49 occurs, I , have bees attempting over a number of ycars to treat thece cases on biochemical principles. - Earlier Worlr Some three years ago treatment was begun in a series of six patients in coma from acute liver disease (Lamer and Mowbrav-paper in preparation). By daily intravenous admtnistratton, each patient received I to 3 g. of cystme ut addition to glucose and plasma. The importance of this amino-acid in the prevention of experimental necrosis had already been demonstrated (Glynn er al., 1945). All these cases presented the clinical picture of " acute yellow atrophy" and all had a fatal outcome. A gross amino-aciduria has been demonstrated in severe liver disease by paper chromatography (Dent, 1949). In view of the known increase in the amino-acid content of the blood, including the thioamino-acids, Dent has suggested that the necrotic Liver cannot utilize them and they could not therefore be of much use in curati~e treatment. There was some possibility that a reflex circulatory upset adecung the I,,er might prevent the cystine reaching the liver cells. With this possibility in view, tetraeth-vl- ammonium bromide was administered to -our sizth case as soon as it became obvious that there was no response to cystine. The downhill progress of the patient was in no way affe0ted. - These discouraging results made it obvious that we were thinking along Incorrect lines. The disea.sed liver cetl required cystine to prevent necrosis but could not utilize it adequately from external sources. The problem, there- fore, was to render the cells less sensitive to cystmdde8- ciency, so that they could utilize their own cystiae until such time as recoverys was complete enough to allpw them to use the amino-acids of surrounding tissue fluid. From this point of view the role assigtied to tocopherol in the production of experimental hepatic necrosis (Schwarz, 1944 ; Gydrgy, 1947 ;-Himswortb and Lindan, 1949) assumes great importance. This' vitamin has therefore been included in the regime of treatment described below. The lntracellular oxidative processes of the liver and other organs also require other vitamins. In their abencc toxic products accumulate wlich could easily-be a`.ictor in the final death of liver cells. The successful applicauon of massive doses of the vitamin-B group in the cholaemia of cirrhosis has already been reported (Patek ef a/., 1948). This form of therapy wts therefore also included in the regime. Recent knowledge of the state of dynamic equilibrium of the body proteins also has a bearing on this problem. It seems Likely that proteins are not only destroyed by wear and tear but are continuously being broken down and resynthesized at a remarkably rapid rate. This protein turnover can be demonstrated with radioactive traccrs. One would not be far wrong in stating that even protein in the body was in a state of dynamic equilibrium with all other proteins (Whipple, 1948). The Liver has been described as the master organ for protein metaboiism. The diminu- tion of the plasma proteins in severe disease of this organ could profoundly upset the normal equilibrium of the tissue proteins and so lead to metabolic upsets. The resulting toxic metabolites could act isnfavourably on already dam- aged Liver cells. It therefore becomes of great importance to administer plasma protein-in severe liver disease, and for this reason it has been included in the regime. Vitamins of the B group have been administered along with a dextrose solution in normal saline- Thc,saline vehicle has been used because of the remarkable tendency for these patients to dcvelop low plasma~chloride levels, probably related to vomiting and possibly to associated renal failure. . 98999458 +
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740 SePT. 30, 1950 SMOKING AND CARCINOMA OF LUNG period. In contrast, they estimated from the experience of 882 other male patients that 14.6% of general hospital patients of the same age composition as the bronchial car- cinoma cases are "non-smokers " and only 19.1 % emoke more than 20 cigarettes a day. They found a similar con- trast between the 25 women with epidermoid and undif- ferentiated bronchial carcinoma and thee other female patients, but no such association with smoking could be found in the small group of patie3ts with adenocarcinoma. or at the Royal Cancer Hospital, but in whom cancer was finally excluded. Because of these differcnces in technique the records obtained from- these hospitals were analysed eeparately. As, however, the relults were in accordance with those found at the other hospitals, all-the records are pre;ented here as a single series. Io view of the method of notification used it could not be expected that the diagnosis then given would invariably be accuratc. The diagnosis of each patient was checked, therefore, after discharge from or death in hospital and , Present Invesffgstion this check was made in all but nine instances (0.4% of The present investigation was planned in 1947, to be the total). In these few cases (three of carcinoma of the carried out on a sufficiently large scale to determine lung, two of carcinoma of the stomach, two of carcinoma whether patients with carcinoma of the lung differed . materially from other persons in respect of their smoking habits or in some-other way which might be related to the atmospheric pollution theory. Patients with carcinoma of the stomach, colon, or rectum were also incorporated in the inquiry, as one of the contrasting groups, and special attention was therefore given at the same time to factors which- might bear upon the aetiology of these forms of malignant disease. A separate report will be made upon these inquirie:. The present smdy is confined to the ques- tion of smoking in relation to carcinoma of the lung. The method of the investigation-was as follows : Twenty London hospitals were asked toco-operate by notifying al1 patients admitted to them with carcinoma of the lung, stomach, colon, or rectum. For the most part these of the rectum, and two noncancer) no records of any sort could be traced,and they have had to be classified accord- ing to the information available at the time of their inter- view. As a general rule the hospital diagnosis on discharge was accepted as the final diagnosis, but occasionally later evidence became available-for example, by h6ro- logical examinanon ar oecropsy-which contradicted that diagnosis. In these instancrs a change was made and the diagnosis based upon the besl evidence. 7Le Data Between ApriJ, 1948, and October, 1949, the notificanoas -- ~ of cancer cases numbered 2,370. It was not, however, pos (- eible to interview all these patienta. To begin with, it had been decided beforehand that no one of 75 years-of age or j hospitals were initially confined to one region of London more should be included m the inquiry, since it wasvnllkely • I (the north-west), to allow ease of travelling, but others were that reliable histories could be obtained from thevery old Illl. subsequently added to increase the scope of the inquiry. A There were 150 such patients. In a further 80-cases the . list of those taking part is given at the end of the paper. diagnosis was tncorrect and bad been changed before the j The method of notification varied : in some it was made by atmoncr paid her visit. Deducting these two groups leaves the admitting clerk on the basis of the admission diagnosis, 2,140 patients who should have been inmr:iewed. 0' -in others by the house-phvsician when a reasonably confi- dent clinical diagnosis had been made- and, in yet others by the cancer registrar or the radiotherapy departmenL None of these methods is likely to have resulted in complete notification, bur there is no reason to suppose that those who escaped notification were a selected group-that is, selected in such a way as to bias the inquiry-as the points of interest in the investigation were either not known ci known on',y in broad outline by those responsible for notifying. . On receipt of the notification an almoner, engaged wholly on research, visited the hospital to interview thepatient, using.a set questionary. During the inquiry four almoners- were employed and all the patients were interviewed by one or other of them. A; well, however, as interviewing the notified patients with cancer of one of the four specified sites, the almoners were required to make similar inquiries of a group of °non-cancer control" patients. Tnese patients were not notified, but for each lung-carcinoma patient visited at a hospital the alrnoners were instructed to interview a patient of the same sex, within the same five- year age group, and in the same hospital at or about the same time. (Where more than- one suitable patient was available the choice fell upon the first one in the ward lists considered by the ward sister to be fit for interview At two specialiTtd hospitals (Brompton Hospital and Harefield Hospital) it was not always possible to secure a control patient by this method, and in such cases a eontrol patient was taken from one of the two neighbouring hospitals, the Royal Cancer and Mount Vernon Hospitals. Even with this relaxation of the rule control cases were deficxnt at the Brompton Hospital and the numbers had to be made up by using the records of patieaa who had been interviewed as csncer patients, cither there these, 408 couid aot be interviewed for the followmg I reasons: already discharged 189, too ill 116, dead 6", too deaf 24, unable to.speak English clearly It, while in one ci the almoner abandoned the mterview as the patients replies appeared wholly unreliable. No patient refused :o kr, interviewed. - The proportion not seen is high, but there is no apparent reason why it should bias the results, I~ was in the main due to the time that inevitably elapsed between the date of notification and the date of the almoner's visit. Tnc remaining [,732 patients, presumed at the inierview to be sufferiog from carcinoma of the lung. ston•,ach. or large bowel, and the '4a general medical and surgical patients originally inteniewed as controls, constitute the subiects ~ of the investigauon. The numbers falling in each disease ; group-that is, after consulting the hospital disc`targe-diag '/II- noses-are shown in Table I. The carcinoma cases are here divided into two groups : Group A consisting of cases in which the diagnoses were confu-med by necrops}', biopsy. - or exploratory operation, and Group B of the remiinder. TentE t.-4rvmber of Pmients Inrerviewed in Each Diseasr G,oup. Su5divided Accordinr to CntcintY o) Dic;nasi,r No of C.ae
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SMO(CiNG AND C~SRC[NOMA OF LUNG .yPy VL-Manmrun Amounr oJ Tobneco E.er Con.rumed ReaulariE p'amo.crrrr uaq-carbnnmu rarmu anc ~ortrrot ranenu Wrrw ;_'?rr piaearer Orker Than Cance . GrWI No. Smotin{ u ailagT M.>mum 'ftay~y~d p; t cit- I 5 cQa - ts c[p-IT ci~-SO Clv. Kqn: I I - D-D 16: Lans-ptduom.' N ~t , 196 ! 1]l 45 Yi I - r/J I(32i7,)'r7uaSp r269•1J n +ynrau (6at) U ;P -lt ! • , <owl Coetrol paienb ( I ' Im Ci,e..n - . - e~rar +h.a I 3l ~ 1.2 . 3)1 ' I1E 1 23 -.o¢e(62]/.. t6-1%J IP&9yJ'a2ryJ (19o.'/J rY ";) Femaa: ' . . Luat-yrcnem. 6 ~ IS i 12 1 1 0 Y-t58: p.rmrs[rt1.. (tb6YJ (SS6'iJ I (~a7J U9-t;0 (p ~9 -2: convd p.nrau! I oo2<P<aos m Guem - ! . twomm . utErr eh.n I 13 I 9 ' 6 ! n I smakini 13 .Y) , (OVIJ 0'6%J >no.r(v) _ {(a2i/J~(J3* 1%JI t2H I i a ~2~r L I vam(3.> Fouo d b- i terLerl T+ea.e ufI-Errimare oJ Tora! Amaunt or Tobacco E, Conrumrd No. wt~ prn 5moked AlroPesher 5 ' Sp.000 'ISO.U00 250.UO0 Spp.Pp , ProbsnEtJicj - I aa- - c~- cw.- + cc., ~ 1~ Is5 . I8J 225 75.., , Y-N1'6p: Cmtrd e.umn I .- ._ ; __ 1 ... -.- . Pc0-001 .irh ans.u ~. onc~r rL.n l6 i190 1 IB] - IA 33 c.ec.r(622)_ ~ (SC/J I(%1(291i,) !s-6};1 P®dn: Lune-ardaam. to I 19 5 7 0 Y-1291; 1M'1YJ I (~J:O (lrr/,) . 01-In . [P07] -z: i 4 00 l< P< coovd Puimu I ' . o-Ul . .icn a+w.a Iwomee orhnr +h.e ; 19 5 3 t 0 socma IS dnrcr (2d7 .. I (6'r9YJ ~ (I1s:;] (lo-rq' (T65;7 rao';1 . rc de- i d.r , yo~pcC +o- germrl number of wome¢ intervmwed-[ha[ ¢, bringingin [heother caocer groups inrerviewed-and making appropria[e allow- aace for age differcaces between them-then [he significanee of the trend in thelr case also is established (y'=13.23 , n-2 ; P appn cimately 0.001 i. 'ihe results given in Tables IV and V are shown together gzaphically in Fig. I. (T'ae pcrcentages in the figure are not all exactly the same as those in the [ables. In the figure the percentages are b:ued on the totaaf number of patients in each disease group, smokr.s andnon-smokers alike ; in Table V they are percentages of smokers alone.) • eamve~u~'ro,t.+.u 74} ezteot in the previous tables by classifying a patient as a non-smoker only if he has never smoked regularly, by classifying him according to the amount he last smoked regularly if he had given up smoking, and by ignoring changes in smoking habits which had taken place subse- quent to the illness which brought the patient into hoep/taf. Other methods of analysis have ?Lto been adopted. Thus Table VI shows the results in the two main groups when a comparison is made between the maximum amounts ever smoked regularly, and Table VII shows a comparison between the estimated total amounts of tobacco smoked throughout the patients' whold fives. The estimatea of the total amount smoked (expressed as cigarettes) have been made by multiplying the daily amount of tobacco smoked by the number of days that the patient has been in the habit of smoking and making allowance for the major recorded changes in the smoking history. Such estimates may, needless to say, be onty very rough approximations _ ro the truth, but they are, It is thought, accurate enough to reveal broad differences between the groups. The results in Tables V, VI, and VII are, it will be uen• closely similar. Whichever measure of smoking_is taken, :he same result is obt,,;ucd-aamef,v, a signlhcant and clear relationship between smoking and carcinoma of the lung- It might perhaps have been' upected that the more refined concepts-the maximum amount ever smoked and the totaf amount ever smoked-would have shown a Goser relation- ship than the most recent amount smoked before the oaset of the present illness. It must be supposed, however, that any greater efficiency that might be introduced by the use of these measures is counterbalanced by the inaccuracy which results from requiring the patient to remember habits of many years past It seerns, therefore, that we may reasonably adopt "the most recent amount smoked" in subsequent tables as the simplest characteristic to describe a patient's smoking experience. Comparisons of the age at which patients began to smoke, the number of year3 they have smoked, and the numb<r of years they have jlven up smokingare shown in Table VIII. It wdl be see¢ that the lung-carr.noma-patients showed a slight tendency to start smoking earlier in life, to con- tinue longer, and to be less inclined to stop, but the dif- ferentiation is cerrainiy not snarp and the difference is technically significant only with respect to /ength of timc stopped. Cigarettes and Pipes So far no distinction has been made bet,een cigaret[e and pipe smokers, and it is natucal to ask whether both methods of smoking tobacco are equally related to car- cinoma of the lung. Again the di!ytc'alty arises that a man w'ho describes himself as a p:pe smoker may have smoked cigarettes until shortly before interrogation, or, alterna- tively, he may have had his tceth extracted and substituted dgarertes for his pipe. To overcome this, we have excluded ! Smol[tug Flsstory . t`R Going one stage further, it has. been nored earher that the amount. smoked dady at any one period does not, of courx, necessarily give a fair «presentation of the indi- viduafs smoking history. This has beenavercome to same Teat2 VL[I-Age oj Srarting ;o Smoke, Vumber o) Yearr Sm ar+emr an onrro ottenrr wit P d C f P ' h Dtrc Vo.or '-unP P. nu P.ue u P -i T ~ [..~~+rqnoma ICOnterol •Pen n S+.ruot VY - okinq vo. I vr,. vn. ~w ,:es .ce •s5 ~ Ile n .: Icv Ive ~ 11f ~~ II~ 5'I 666 65p akep, and Vumb<r o) Ycprr Sropped Smoking in Lurtgcarannma bSmokert; Lungca.anoma Paienls and Control Patmntt wah r Than Cartcer Y-'.bI a - 2:0'30.~P<05p ares Orher Thort Concer lMale and Female) ~ lns.)ma wcnt Conrrol '~/ ' Lvn¢cerclmm. Cootra Pwmrs I ' ~oer i P.aene Puievn N _ Yran _ I s~opac ~~o. -~ ..1 I- 6a9 w I19 TOJI IR- a\: :6Z ~01 Zo- f3 40. 590 ~ 908 3• S.r ~J d 9 Tou 6d6 yp r+-b65: n-lt 0-p5<P<O10 I e -139; n- 2: d0[<P<0-]2
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Tatt2 XL-Mott Recem Amoonr Smoked by All Petienu Other Than Thore wuh Caru~oma o) Lunq, Dlvided Acrordinq to Whelher They Were Non(ed ar Seieued for /n¢rnrn /aiule ' an& Femair) . ~'o. Smoki.u Duly Mara~d dSek~doa of P.¢cot , _ 0 1 Ct- 3 CIp- (6 Cip.- c~ „ Naf9ed br lwD~WlI,C12) .` 10'• (It }y~ 19 i J01 1 1190 3e5 2 .56d N}0 P4beW br mtwiever frb) .. :'0 -I Xl9 le: B9 .'S1 560 ]I'-1 ISI-9 950 I ¢+-:-la: v_<; trro<P2U9¢ • Sce roomo~c w Tmle %. It can therefore be conduded hat !hereis no evidence of any special bias in favour ^f iight smokers ia the se!ec- tion of the control series of patients. In other words, the Qoup of patients interviewed forms, we believe, a satis- factory control series for the lung~arcinoma patients from the point of view of comparison of smoking habits. Pntient's Smoking History Another possibility to consider is that the lung-carcinoma patlents tended to exaggcrate ~hcir smoking habits. Most of these patients cannot have known that bcy were suffer- rng from cancer, but they would have known that they had respiratory symptoms, and such knowledge might have inAuenced their replies to questions abdut the amount they mtoked. However, Table X has already shown that patients with the other respiratory diseases did not give smoking histories appreciably different from those given by the patients with non-respiratory illnesses. There is no reason, [herefore, to suppose that exaggeration on the part ef the lung-carcinoma patients has been responstble for- the results. - The Interriewers _ When Lhe-investigatlon was planned it was hoped that - interviewers would know only that thev were inter- viewing patients with cancer of one of several sites flung, stomach, or large boweU but not, at the time, the actual SMOKitiG A.'YD CARCINOMA OF LUNG aught into this table all the paticnts with diseases other carcinoma of the lung.) As in other tables where sex and age differences between aups have had to be taken into account, the "ezpected" n bave been obtained by taking the actual numbers patients with each type of disease in each age and sex ~y2bgroup, and calcuiating what proportion of them would jyll in each smoking category if they had had exactly the - y l ~ .:ed in the Tab e. In ,rame habits as all the patients incl ,ether words, we have computed what ought to be the . ®oking habits of each disease group if it behaved in eech sex and at each age like the total population of patienta, and compared them with what, in fact, the) were. tye reiatively large numbers of non-smoken in some of the groups are due to the fact that tflese disease groups ecluded many old womea 'ILcra remains the pdssibility that the interviewers, in eelecting the control patients, took for interview from among the patients available for selection a dispropor- tionare number of light smokers. It is difficult to see huw they could have done so, but the point can be tested indirectly by comparing the smoking habits of the patients vhom they did select for intervlew with the habits off the other patients, other than those with carcinoma of the hmg, whose names were notified by the hospitals. The eomparson is made in Table X.I and reveals no appreciable differersee between the two groups. . s~.,m°l~ 145 sita "I1tis, unfortunately, was impracticable ; the site would be written on the notification form, or the nurse would refer to the diagnoeis in pointing out the patient, or it wouldbaome known that only paurnts with cancer of one of the sites under invesr";at',on would be found in one, particular ward. -Out of I,'J2 patients notified and inter- viewed as cases of can;er, The site of the growth wae known to the interviewer at the tune of-ieterview in all but 61. Serious consideration must therefore be given to the pos- sibifity of interviewers' bias affecting the results (by the interviewers tending to scale up the smoking habits of The lung-carcinoma cases).. Fortunately the material provides a simple method of testing this point. A number of patients were interviewed who, at that time, weree thought to have carcinoma of the iung but in whom the diagnosis was subsequently disproved. The smoking habits of these patients, believed by the inter- viewers to have carcinoma of the lung, can be compared with the habits of the patients who- Infact had carcinoma of the lung and also with the habits of all theother patients: The result of makYng these comparisons is shown in Tables XII and XIII, and it wtfl be seen that the smoting Tim1 7QL-Man Rmem Smnked by Palientt witA Carctnomn of Lnnq and by Pamau 7hooght fncorrertly by the Inrmiewerr-to be Su9tr~c; "omCarcmoma ol Lwg (Male and Femde) Di.cw Groay 40. Smhdnl Du7Y e I CY.-iSClp--l]Cfp..,~ Civgy+ huenn nW araooma ollwa II' ~0 ~ 26i j m5 I)a (ttA) . JI r.rdL ~ I/6d - VFO i 15T1 al • m P ' 1f 25 81 acurs .v®n r u r 'o ha.ewc e.Ylwvg'A9» , 50 16 I 2s1 Ir0 : r6-0 5a0 ~.rlJ 1+-S-VS; n-e:P<0-NI. • ?.c ruomou iu Tabk X. • Ttm i. a IuZn aumber d cas. io ihh QouV ~'au one Ifapiul eoulfed W®a .GataM rpr Crpnchw'.npY: /l] ou1 nf It,c aN ,IYnRactlY tLauBbt tD Sare •dtnaluay.annravie.eCa:Ntmpr4l. ' Tate XRL-Matt Recrv! .~mounr Smukrd by Patlente Incor+ectly Thougk! by tn< hrrr'v~ewrn so be Su?eriu; Jrom Carcin,ma o,r - Lun; and A!I Othn Ponenu No! SuJermt jrom Carnnoma of Lung (.Nale and Pemale) D4e.r amap Mo. Sipdru.g Da85- C t cix- ~ 5 Cip.-'t 5 CIrA.- u P.omu hvar.ec6y IEOU~i uo 15` 33 50 is 6..ecetvnomavflunpR09)t b-0 - ?T! ,11-0 I4Ld I VA All otL<r peocnu ao~ tudrnrs 142 lfU 980 - 121 ' 1!0 &nmarvmm.oflua,iL5511fA2 • 146 5814 ; 1221 16+2 e'_,.Sx: n-4:osa<P<o,o. • aw roomn< b T.nte X. • See rx¢oie m Teb1e rII. habits of the patients who were incorrectly thought to have carcinoma of the lung at the time of interview are sharply distinguished from the habits of those patients who did in facYhave carcinoma e[ the lung (Table XIq, but they do not differ signtficantly from the habits of the other patients interviewed (Table XIII). - It is therefore clearly not possible to attribute the results of this inquiry to bias on the part of The interviewers, as, had there been any appreclablc-bias, the smoking habits of the patients thought incorrectly to have carcinoma of the lung would have bean recorded as being Gke those of the true lung-carnnoma subjccts aod tiot the same as those without carcmoma of the lung. We may add that the results cannot be due to different workeqs {nterv/ewing different numbers of patients in the cancer and control groups, for, while the four interviewers .c. -s ~.
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C 744 Serr. 30, 1950 SMOKING AND CARCINOMA OF LUNG a[1 the men who gave a history of having ever consistently smoked both pipes and cigarettes and have compared the proportions of " pure pipe " and " pure cigarette " smokers among the lung-carclffbma and noncahcer control petientc. The results are as follows : of the 525 lung-carcinoma patients who had smoked,either pipes or cigarettes but not both 5.7% were pipe smokers and 94-.3 % were ngarette smokers; of 507 control patients with other diseases 9.7%. were pipe smokers and 90.3 "a were cigarette smokers. The lower proportion of pipe smokers, and the corresponding excess of cigarette smokers, in the lung-carcinoma group is unlikely to be due to chance (x'=5.70 ; n=1 ; 0.01< P <0.02 ). It therefore seems that pipe smoking is less closely related to carcinoma of the lung than cigarette smoking- -On the other hand, it has been shown in Table V that light smoking is less closely related to carcinoma of the lung than heavy smoking, so that tha resuft might be explained merely an the grounds that pipe smokers tend to smoke less tobacco. tobacco than clgarctce smokers, but thts ts unltkely to be the whole explanation of the relative deficiency of pipe smokers observed in the carcinoma group. We find a higher proportion of cigarette smokers and a lower pro- portion of pipe smokers among the lung-carc4noma patients than among the control group of non-caneer patients at each level of consumption of tobacco-that i6, at 1-4, 5-14, 15-7a, and 25- cigarettes or their equivalent a day. On the other hand, if we consider the " pure pipe " smokers by themselves and subdivide them according to the amount smoked, then we nnd a higher proportion of the csrcinoma patients than of the control group in the higher smoking categories-that is, smoking more than 6 ozL of tobacco a week. In short, the results of this subdivisien are similar to those shown in Table V for all smokers. It seenre that the method by which the tobacco is smoked is of impor- tance and that smoking a pipe, though also related to carcinoma of the lung, carries a smaller risk than smoking cigarettes: With the data at our disposal we are unabld to determine bow great the difference in risk may be. Inhaling Another differeoce between smokers is that some inhale and others do not. All patients who smoked were asked ' whether or not they inhaled, and the answers er5 given by the lung{arcinoma and noo-cancer control patients were as follows : of the 688 lung-carcinoma patients who smoked (men and women) 61.6 % said they inhaled and 38.4 % said they did not; tbc corresponding figures for the 650 patients with other diseases were 67.21 inhalers and 32.8% non- inhalers. It would appear that lung-carcinoma patients inhale slightly less often than other patients (X'=4.58 ; a-l; 0.02<P<0.051 However, the difference q not large. and if the lung-carcinoma patients are compared with all the other patients interviewed, and the nxessarv allowance is made for sex and age, the difference becomes insignificant (ti'=0.19 ; n=l ; 0.50<P<0.70). . Irltefpretation of ResUlti Though from the previous tables there seems to be no doubt that there is a direct association between smoking and carcinoma of the lung it is nec-essary to consider alter- native explanations of the results. Could they be due to an unrepm&entative sample of patients with carcinoma of - the lung or to a choice of acontrol series which was not truly comparable? Could they have been prcdt5ced by an exaggeration of their smoking habits- by patients who thought they had an illness which could be attributed to smolung? Could they be produced by bias on the part of the intrrvlewe:s in taking and interpreting the histories' Selection of Patients for Interview The method b}which the patient.s with carcinoma of " the lung were obtaioed has been discussed earlier; there is no reason to suppose thaLthey were anything other rhan a represe.n.tauve sample of the lung-carctnoma patients - I attending the-selected London hospitals. The control ' patients, as was shown in Table 11, were exactly compar. ' ~ able so far as sex and age were concerned and they were ~ sufficiently comparable with regard to social class for the difference between the two series to be ignored. They were not who8y comparable from the point of view of place of residence. The difference in this respect, however, was that more of the lung-carcinoma patients came from small towns and re;z; districts, and the hgures in this inquiry show that consumption of tobacco per head in these areas is-less thanin London. Clearly this feature cannot hace In-fact, pipe smokers do consume, on the average, Icss - accounted for the observation that the lung-carcinorna patients smokcd more. Further, if the comparison is con- -~-~ fined to patie::" seen in district hospitals-and all of these resided in Gr^_ater London-the results are the same !Table IX). a { T~e IX.-.NoY Re-_rnf Amoum Smoked 6y Luagcaermonw and ,{~F _. . ._ ___ ._____...-. ..,,.,..._.- ........ ...... ~,..,._.., L'. D4eue Grar' Vo SmdunyDulr -` - 0 I Cig.-ISCip.-aSCiog- ~,+ ~; L-.~E[eo/ w~enlt '.~- CuCi1C1 ctha:Lanrauar,58I .. 9 9, . SU 19 ; 11 t'-n68-. n-4. o-ol<P<fhol It might posslbiy be argued uhat the choice of a controi group of pauents with various medical and surgica, con- ditions has, of itself, resulted in the selection of subjects with a smoking hlstory less than the average. Tbis would seem very unlikely, as we know of no evidence to seggest that less than average smdring is a character:stic of per- sons wid) any one group of diseases, and it certainly could not be held that it is equaJv a cbaracterisuc of prsons suffering from aii diseases other than carcinoma of the Iung. Yet in Tabie X the smoking hablts of the paueots T.atE X-Mort Reccal ,4movn) Smoked by e!1 Pet,entr O:her Than Ti,aa< with Car:momc.o) Lunq, Dfmd<d Accordin¢ ro T'pe of Doeare r.Nc;e ond Femulel - ~ ~a Carcr, «scr :n.n o.~ x)6• dhue('I81 .- 1YJC G.eaae, aner thav - ~' Rem,~ u~ (SJ5/ e'IL e.rma..,cw.r u,o..e ( I s6t . cs Gutxammuivl Ei.eeae U91.. la 7 S5 1 ONertlir..a(215) . )B SG6 No. SmdciaQ oulr J t C,y- 5 cip.- 15 cip.- c~~ 78 :n uo r 83.3 D6 9 ' 1118 530 33 128. 38 34 W4 1361 Rb' 3d1 19 ba ]9 213 16-1 . 13-8 3P5 lb-3 )1 e Il) 91 15 S:J I 13P2 73 8 J/5 24 : 91 µ 18 Zlf i 16-0 ' Id9 22 1 . t-mu; o-ts: o-m<PCtrxi. •~ r. fiyuru ,hu- rhe arnul oumben oMer.ea. tbou m iWV .rz me numce,. ,au s«,Id Sa.e ocvuree Ir [be a,es a~o m a'>dr. h.d h.d ia ..ch .et aC . cac8 ye wcLLr :LC uur, moksy hsn,u .a .tl lLC I wmut ,rctvdd ~ tha table . in five main groups of diseases are compared, allowing for their sex and age composition, and no significant differ- ence can be demopstrated between them. (We have 98999454
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L SMOKING AD1p CARCINOMA OF.LUNG this century. The trends in this country are given in Fig. 2, -:'and show that over the last 25 years the Increasrin deaths %attributed to cancer of the lung has been much greater ,' than the increase in tobaccat:onsumption. This might well 4 be because the increased number of deaths in the latter years is partly an apparent increase, due to improved diag- nosie t in other words, it is not wholly a reflection of increased prevalence of cancer oCthe lung. On the other hand, it is possible that the carcinogeniCagent is introduced during the cultivation or preparation of tobacco for con- sumption and that chanees in the methods of cultivation i- and preparation have occurred as well as changes in coh- ~ in e2 !6 Iy of 1y to nt te tg re id te n smokers in the population from whtch the patients were drawn. For reasons given earlier this cannot be done, but an estimate can be obtained of the expected sex ratio of cases occurring among pon-smokers in the Greater London area. From the experience of the patients without car- cinoma of the lung who lived in Greater London at the time of their interview it can be calculated that there were, (4 in 1918, 175,000 men and 1,582.000 women in London ~ _ between the-ages"of 25 and 75 who had never been . smokers accerding to our definition of the term. Taking these figures, subdivided by age, in association with the age distribution of the 16 cases of carcinoma of the lung ~. observed among non-smokers living in Greater London, it can be calculated that, if the incidence of the disease were -equal among qon-smokers of both sexes, one case should have occurred tn a man and IS in women. In fact, the observed ratio was 0 to 16, . ' - " This finding is consistent with the theory that the risk G of developing carcinoma of the lung is the same in both men and women, apart from the influence of smoking. It is not, however, possible to demonstrate with the data at our disposal that different amounts of smoking are sufHcient to account for the overall sex ratio, - As to the nature of the carcinogen we have no evidence. The only carcinogenic substance which has been found in tobacco smoke is arsenic (Daff and Kennaway 1950), but , - !!l111[j[["` the evidence that arsenic can produce carcinoma of the lung is suggestive rather than conclusive (Hill and Fantng, 1948). Should arsenic prove to be the carcinogen, the possibility arises thatt it is not the tobacco itself which is dangerous. lnsecticides containing arsenic have been used - for the protection of the growing crop since the end of the last century and might conceivably be the source of the responsible factor. This, too, might account for the obser- vation that deaths from cancer of -the lung have increased more rapidly than the consumption of tobacco. sumphon. However that may be, it u clearly not posstble ~' to deduce a simple time relationship in this country between e the consumption of tobacco and the number of deaths attri- ; buted to cancer of the lung. The greater prevalence of carcinoma of the lung in men- comparedwith womenn leads naturally to the suggestion that smoking may be a cause, since smoking is predomi- '• nantly a male habit. Although increasing numbers of women are beginning to smoke, the greatt majority of women now of the cancer age have either never smoked or have only recently.started eo do so. It is therefore • tempting to ascribe the high sex ratio to the greater con- sumption of tobacco by men. If this were true it would be expected that the incidence of carcinonn of the lung would be the same among non-smokers in both sexes. In this series, 2 out of 649 men and 19 out of 60 women with ~ carcinoma of the lung were non-smokers. 1 4 Th calculate the incidence rates among nor.-smokers of either sex tt is necessary to estimate the number of non- teTIe°"'ta,t«,.a.u. 747 Sammary The great increase in the number of deaths attributed to cancer of the lung in the last 25 years justiCxs the search for a cause in the environment. An investigation was therefore carried out into the possible association of, carcinoma of the lung with smoking, exposure to car and fuel fumes, occupation, etc. The preliminary findiogs with regard to smoking are reported. 7he material for the investigation was obtained from twenty hospitals in the London region which notifind patients with cancer of the lung, stomach, and large bowel. Almoners then visited and interviewed each patient. The patients with carcinoma of the stomach and large bowel served for compari- son and, in addition, the almoners interviewed a non-cancer control group of general hospital patients, chosen so as to be of the same sex and age as the lung-carcinoma ptients. Altogether (49 men and 60 women with carcinoma of the lung were interviewed. OF the men 0.}Wo and of the women 31.71 were non-smokers tas denned in the text). The corre- sponding figures for thee non-caocer control groups were: men 4.21., women 53.3 0. --- Amongthe smokers a relatively high proponion of the patients with carcinoma of Ihe lung fell in the heavicr srhoking categones. For example. ~of the male and 14.6"%, of the female lung-carcinoma patients who cmoked gave as their most recent smoking habiu prior to their ill„ns the equivalent of 25 or more cigarclta a day, while only 13.5% OF the male and none of the female non-carcer control patients-smoked as much. Similar differences were found when comparisons were madq-betwecn the maximum amounts ever smoked and the ntimated-• total amounts ever smoked. Cigarette smoking was more closely related to carcinoma OF the lung than pipe smoking. No distinct association was foundwith inhaling. - Taken as a whole, the lungtarcinoma patients had begun to smoke earlier and had continued for longer than Ihe controls. but the differences were very small and not statistically signin- cane Rather fewer lung-carcinoma patients had given up smoking. Consideration has been given to the possibility that the results could have been produced by the selection of an unsuitable group of control patients, by patients with respiratory disease exaggerating their smoking habiC, or by bias on the part of the interviewers. Reasons are given for excluding all these possibilhies, and it is -orcludeQ that smoking is an important factor in the cause of carcinoma of the lung. From consideration of the smoking histories given by the patients without cancer of the lung a tentative estimate was made of the number of p<opie who smoked different amounts of tobacco in Greater London. and hence the reFauve risks of developing Ihe disease amnng different grades of smokers were calculated. Tht figures obtained are admittedly speculative, but suggest that- above the age of 45, the risk of developing the disease increases in simple proportion with the amount smoked and that it may be approaimatety 50 times as great among those who smoke 25 or more cigarettes a day as among oon-smoken. The observed sex ratio among non-smokers (based, it must be stressed, on very few cases) can be readily accounted for if the true incidence amon; noo-smokers is equal in both sexes. ft is not possible to deduce a simple time relationship between the increased consumption of tobacco and the increased number of deaths attributed to cancer of the lung. This may be because part of the incrcas% is apparent-that is, due to improved diagnosis-but it may also be because the carcinogen in tobacco smoke is introduced into the tobacco during its cultivation or preparation. Greater changes may have taken place in the methods involved in these proce,s<s than in the actual amount of tobacco consumed. Co-operaring Hospirei.r.-Bromrton, Certral Middlesex, " Fulham. Hackney, Hammersmi:h, Harefield, Lambeth. Lewisham, Middlesex, Mnunt Vernon-and the Radium Institute, New End, Royal Cancer, Royal Free, St. Bartholomcw's,
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The 81 patieats classified in Table I as having •• other ~~,~ tralignant diseases" were intervi,ewed as cases of carci- oma of the lung, stomach, or large bowel, or as non- cancer cancer controls- On the subsequent checking of the diag- :, nosis- either they were found to have primary carcinoma ' in snme site other than one of those under special investigation or histological examination showed that the growm was not, in fact, carcinoma-for example, sarcoma,, reticulotndothelioma, etc. The 335 "other cases ' either were interviewed as cases of carcinoma of the lung,- stomacb, or large bowel and were subsequendy fouad oot to be cases of malignant disease or, having beeninterviewed as noa-cancer controls, they became redundant when the cases of carcinoma of the lung with wbich they were paired were found not to be carcinoma of the tung. The four " exciuded " cases were excluded on grounds of doubt about their true category. Two were diagnosed at hos- pital as primary carcinoma of the lung, but there was reason to suppose that the growths might have been secon- dary to carcinoma of the breast and to carcinoma of the tervia uteri : especttvely ; the other two showed evtdeoce of - primary carcinoma in two of the sites under special investigauon-:hat is, lung a-nd colon, and stomach and colon. The 709 control patients with diseases other than cancer form a group which was, as previously stated, deliberately selected to be closely comparable in age and sex with the carcinoma of the lung patients- Comparisons between these two groups are shown in Table II. 'C..u-n R.-Comearuan @erweerr Lunqtarcinamc Potrrnti and San- umrcer Patmnrr SclrCed er Ce+voU, With Rcqmd to Sa, Aqe, Soeial C'an, ~nd P'.aer nf R<::drnte I No. of ~ No. of Sma Csu ' ' L rn~ ~ Noe.car¢r (R mrnr ~ vs of Yo. of A~ ~tvnom.a i Ccnrtoi ~cnrru•s i L:my- ~om P.wau I P._cnrs C.~arLV nom.' cmccr ~ (--I - Nm Owr) t P.arnu P.omu M r F~ M F 2 1 i - I 1 t.n1 [t . "T 31 5 01 6 0. 111 :89 3S6 15- Id i' 3 Is ` 3 1 Iv.ad v . 191 166 .5- I Fr ' IO i 99 10 i:I:.u.nJ SQ .. ! IIU : II l0 t I ' 11 t.s ,. 50- .. ~ IrA ' 9109 9~ Co,m,r of Lm- 6~9 QL - ' 9 J d9• 3j dnn . . sl6 u7l: I 3a ;a : G:.Yr cqUnf/ I ' I ~omu¢h a ' ,uva 95 -Rcr.Itli~uR . Q i ~er~.c ar m - tM9 m >t 16 fa ~ ' : Seryrea 11 4 Ulapz 6+9 LU ot9 W ~,Tou1tM-Fn.. '04 709 • ooa covvoi m c+ror. fr® ~e .~ .e. ~C It will be seen that the lung-carcmoma padeots and the control group -of non-cancer patients are exactly compar- able with regard to sex and age, but that there are some dider<nces with regard to soaal class and place of resi- dence. The difference in social c', ,s distribution is small and is no more than might easily be due to chance (y'=1.61 ', n=2 t 0,30<P¢0.50), The difference in place of residence is, however, Iarge lr'=)L49 ; r.-5 ; P<0!70I\ and Table It shows that a higher propornon of the lung patients were resident outside London at the time of their admission to hospital- This difference can be explained °the grounds that people with cancer came to London ttparts of the counny, for treatment at special =~~,,~--uirec. -wneu a cnmparison is made betwcen tife 98 {ung- 'dreinoma patients a:id~irs 98 controls who were scen at district hospitals in Londco-c:~1, is, those regiooai ooard hospitals which do not have special surgical thoracic or ,M.t xaraw..,_ 741 radiotherapeutic centres--the difference diseppears. Of these 98 patients with carcmoma of the ltmg, 56 lived in the Counry of. Loodon, 42 in outer London, and none else- where ; of their non<anccr control.s the corraponding numbers were 60, 38, and 0, clearly an insignifica.nt difference. It is evident, therefore, that the control group of patients with diseases other than cancer is strictly comparable with the group of luog-carcioorna patients in important rupects but differs slightly with regard to the parts of Englaod from which the patients were drawn. It is unlikely that this difference will invalidate comparisons, but it must be kept in mind ; fortunately, it can be eliminated, if necessary, by conlining comparisons to the smaller group of patients seen in the district hospitals, . Assessment of Smoking Kabiti The assessment of the relation between tobacco-smoking and disease is complicated by the fact that smoking habits change. A man who bas been a light smoker for years may become a heavy smoker ; a hcasy smoker may cut down his consumption or gi.e up srr.zking-and, indeed, may do so repeatedly, An acute respiratory disease may force the sufferer to stop smoking, or he maj be advised to stop for one of many pathological conditions. In 1947 a further complication was introduced by the Chancellor of the Exchequer, the duty on tobacco being raised to such an extent that many people made large cuts in the amount of tobacco they smoked-often to restore them par4ally or completely in the succeeding months- Fortunately the interviewing of patients was not begun till a year after the last major change 'was made inn the tobacco duty; in any case the effect was minimized by interviewing the con- trol patients pari pmisu w'tth the lung<arrinoma patients, so that the change in price is likely 'o have affected all groupe similarly. The difficulties-of a varying ronswnption can be largeiy overcome if a more detailedd smoking history ia..taken than is customary 'a the course of an ordinary medical examr natioo--for example, one man who was describul in !he hospital notes as being a non-smoker admitted to the almoner that he bad been a very heavy smoker until a few years previously. In this in•.astigation, therefore, the patients were cioselv questioned and asked (a) if they had smoked att any period of C~ur lives ; (b) the ages at w-hica they had-started and stopped ;(d the amount they were in the habit of smoking be:or_ the onset of the illness which had brought them into hospital ; io) the main changes in their smoking history and the maximum they had ever b<en in rbe habit of smoking ; le) the varying proportions smokcd in pipes aod cigarettes ; and Qi whether or not they inhaled To record and subsequently to tabulate these details it was necessary to define what was meant by a smoker. Did the term, for example, include the woman who took one cigarette annually after her Christmas dinner, or the man of 50 who as a youth smoked a couple of cigarettes to see whether he liked it aod decided he did not? If so, it is doubL`ul whether anyone at all couid be described as a non- smoker. A smoker was therefore defined in this inquiry as a person who had smok=d as much as one cigarette a day for as long as one year, and any fess consistent amount was ignored. The histories obtained were,- of course, a function of the patien['s memory and veracity. To assess their reliability 50 unselected control patients with diseases other than cancer were interviewed- a sxnnd time six months or more after their initial interview. Table III shows the comparison between the two answers obta!acd

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