Document 70E72K80N5erbyq9GpNzNOYQV

FILE NAME Kent KNT DATE 1950 Sept 30 DOC KNT117 DOCUMENT DESCRIPTION Journal Article - Smoking Carcinoma of the Lung - British Medical Journal Dell Hill 1950 BRITISH MEDICAL JOURNAL LONDON SATURDAY SEPTEMBER 30 1950 SMOKING AND CARCINOMA OF PRELIMINARY REPORT THE LUNG BY RICHARD DOLL M.D. M.R.C.P. .. Member of the Statistical Research Unit of the Medical Research Council ; AND \ A. BRADFORD HILL Ph.D. D.Sc. Professor of Medical Statistics London School of Hygiene and Tropical Medicine Honorary Director of the Statistical Research Unit of the Medical Research Council in England and Wales the phenomenal increase in the number of deaths attributed to cancer of the lung pro- whole explanation although no one would deny that it may well have been contributory As a corollary it is vides one of the most striking changes in the pattern of right and proper to seek for other causes nortality recorded by the Registrar For example In the quarter of a century between 1922 and 1947 the Possible Causes of the Increase innual number of deaths recorded increased from 612 to Two main causes have from time to time been put for- 1,287 or roughly fifteenfold This remarkable increase is of course out of all proportion to the increase of popula- ward : ) a general atmospheric pollution from the exhaust fumes of cars from the surface dust of tarred roads and both in total and particularly in its older age groups Stocks 1947 using standardized death rates to allow for from works industrial plants and coal fires and 2 the smoking of tobacco Some characteristics of the hese population changes shows the following trend : rate ^ er 100,000 in 1901-20 males 1.1 females 0.7 rate per former have certainly become more prevalent in the last 50 years and there is also no doubt that the smoking of 00,000 in 1936 m9ales 10.6 females 2.5 The rise seems cigarettes has greatly increased Such associated changes o have been particularly rapid since the end of the first in time can however be no more than suggestive and until world ; war between 1921-30 and 1940-4 the death rate of nen at ages 45 and over increased sixfold and of women of recently there has been singularly little more direct evidence That evidence based upon clinical experience and he same ages approximately threefold This increase is still records relates mainly to the use of tobacco For instance ontinuing It has occurred too in Switzerland Denmark in Germany M^...ller 1939 found that only 3 out of 86 he U.S.A. Canada and Australia and has been reported male patients with cancer of the lung were smokers rom Turkey and Japan Many writers have studied these changes considering whether they denote a real increase in the incidence of the lisease or are due merely to improved standards of diag- tosis Some believe that the latter factor can be regarded s wholly or at least mainly responsible example Villis 1948 Clemmesen and Busk 1947 and Steiner 1944 On the other hand Kennaway and Kennaway 1947 and Stocks 1947 have given good reasons for partly elieving that the rise is at least real The latter " or instance has pointed out that the increase of certified espiratory cancer mortality during the past 20 years has jeen as rapid in country districts as in the cities with the est diagnostic facilities a fact which does not support the iew that such increase merely reflects improved diagnosis if cases previously ory affections certified as bronchitis or other respira- He also draws attention to differences in nortality between some of the large cities of England and 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 workers 1950 reported that of 82 male patients with cancer of the lung were smokers against 23.9 of 522 male patients admitted with cancer of sites other than the upper respiratory and digestive - tracts In this country Thelwall Jones personal communication found 8 smokers 82 patients with .- proved carcinoma of the lung compared with 11 in a corre- than - spondinggroup of patients with diseases other ; cancer there - this difference is slight but it is more striking that oo oe in were 28 heavy smokers in the cancer group against14 oe be the comparative group Clearly none of these small inquiries can accepted as conclusive but they all point in the same direc- tion Their evidence has now been borne out by the results by of a scale inquiry undertaken in the U.S.A. : Vales differences which it is difficult to explain in terms of diagnostic standards Wynder Graham 1950 Wynder and Grahamundiferntiaed found that of 605 men with unclassified ven " The large and continued increase in the recorded deaths epidermoid undifferentiatedor histologically within the last five years both in the national figures _ types of bronchial carcinoma only 1.3 were non, in ind in those from teaching hospitals also makes it hard smokers --that is had averaged less than one cigar- to believe that improved diagnosis is entirely responsible short sufficient the cigarettes day the there is reason to reject that factor as ette a day for the last 20 whereas 51.2 of . them had smoked more than 20 a over same 4 ee 41 S> MOKING 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 68 smokers and only 19.1 smoke than 20 cigarettes day They found a similar con- trast between the 25 women with epidermoid and undif- ferentiated bronchial carcinoma and the other female patients but no such association with smoking could be found in the small group of patients with adenocarcinoma or at the Royal Cancer Hospital but in whom cancer finally excluded Because of these differences in technique the records obtained from these hospitals were analysed separately As however the results were in accordance are with those found at the other hospitals all the records 7 presented here as a single series not In view of the method of notification used it could - be expected that the diagnosis then given would invariably be accurate The diagnosis of each patient was checked checked therefore after discharge from or death in hospital and Present Investigation The present investigation was planned in 1947 to be carried carried out on a sufficiently large scale to determine 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 actiology of these forms of malignant disease A separate report will be made upon this check was made in all but nine instances 0.4 of the total In these few cases three of carcinoma of the lung two of carcinoma of the stomach two of carcinoma of the rectum and two cancer 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 general rule the hospital diagnosis on discharge was accepted as the final diagnosis but occasionally later evidence became available example by histo logical examination at necropsy contradicted that diagnosis In these instances a change was made and the diagnosis based upon the best evidence | these inquiries The present study is confined to the ques- The Data 2 tion of smoking in relation to carcinoma of the lung - The method of the investigation was as follows : Twenty London hospitals were asked to operate by notifying all _ patients admitted to them with carcinoma of the lung .. stomach colon or rectum For the most part these hospitals were initially confined to one region of London the north to allow ease of travelling but others were - subsequently added to increase the scope of the inquiry A list of those taking part is given at the end of the paper The method of notification varied ; in some it was made by the admitting clerk on the basis of the admission diagnosis _ in others by the physician when a reasonably confi. dent clinical diagnosis had been made and in yet others by the cancer registrar or the radiotherapy department None of these methods is likely to have resulted in complete notification but there is no reason to suppose that those - who escaped notification were a selected group is - selected in such a way as to bias the inquiry the points of interest in the investigation were either not known or - known only in broad outline by those responsible for notifying . On receipt of the notification an almoner engaged wholly _ on research visited the hospital to interview the patient . using a set questionary During the inquiry four almoners were employed and all the patients were interviewed by one or other of them As 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 cancer control patients These patients were not notified but for each carcinoma patient visited at a hospital the almoners were instructed to interview a patient of the same sex within the same fiveyear age group and in the same hospital at or about the same time Where more than one suitable patient was Between April 1948 and October 1949 the notifications 3 of cancer cases numbered 2,370 It was not however pos- sible to interview all these patients To begin with had 4 been decided beforehand that no one of 75 years of age or 4 more should be included in the inquiry since it was unlikely that reliable histories could be obtained from the very old 4 : There were 150 such patients In a further 80 cases the diagnosis was incorrect and had been changed before the almoner paid her visit Deducting these two groups leaves 2,140 patients who should have been interviewed Of these 408 could not be interviewed for the following : reasons already discharged 189 too ill 116 dead 67 too deaf 24 unable to speak English clearly 11 while in one case the almoner abandoned the interview as the patient's replies appeared wholly unreliable No patient refused to be interviewed The proportion not seen is high but there is no apparent reason why it should bias the results It was in the main suffering due to the time that inevitably elapsed between the date of notification and the date of the almoner's visit The remaining 1,732 patients presumed at the interview to be from carcinoma of the lung stomach or large bowel and the 743 general medical and surgical patients originally interviewed as controls constitute the subjects of the investigation The numbers falling in each disease group is after consulting the hospital discharge diag- noses shown in Table I. The carcinoma cases are here divided into two groups Group A consisting of cases in which the diagnoses were confirmed by necropsy biopsy or exploratory operation and Group B of the remainder ; Table Number of Patients Interviewed in Each Disease Group Subdivided According to Certainty of Diagnosis No. of Cases available the choice fell upon the first one in the ward lists considered by the ward sister to be fit for interview - At two specialized hospitals Brompton Hospital and - Harefield Hospital it was not always possible to secure a control patient by this method and in such cases a control '. 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 deficient at the Brompton Hospital and the numbers had to be made up by using the records of patients Disease Group Group A. Diagnosis Confirmed at Necropsy etc. Group B. Other Criteria Diagnosis Diagnosis Carcinoma of lung stomach we " " colon and rectum " " Other malignant diseases . i Diseases other than cancer controls Other cases an .. Excluded All cases ve 489 178 | 220 28 412 ' 19 _ | _ _- ; _ _- - - 1 => _ who had been interviewed as cancer patients either there _ no car no in BEX gro ret we Stc to as ca Wi atat at pS i i" f SEPT 1950 * MEDICAL JOURNAL The 81 patients classified in Table I as having " other malignant diseases were interviewed as cases of carci- noma of the lung stomach or large bowel or as non- checking cancer controls On the subsequent of the diag- nosis either they were found to have primary carcinoma in some site other than one of those under special histological investigation or examination showed that the growth was not in fact carcinoma example sarcoma endothelioma etc. The 335 other cases either were interviewed as cases of carcinoma of the lung stomach or large bowel and were subsequently found not to be cases of malignant disease or having been interviewed as cancer controls they became redundant when the cases of carcinoma of the lung with which they were paired were found not to be carcinoma of the lung The four excluded 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 carcinomoaf the breast and to carcinoma of the cervix uteri respectively ; the other two showed evidence of primary carcinoma in two of the sites under special investigation is lung and 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 radiotherapeutic centres difference disappears : Of these 98 patients with carcinoma of the lung 56 lived in the County of London 42 in outer London and none else- where of their cancer numbers were 60 38 and insignificant difference controls the corresponding 0 clearly an Itis evident therefore that the control group of patients strictly with diseases other than cancer is comparable with | the group of carcinoma patients in important respects but differs slightly with regard to the parts of England from which the patients were drawn It is unlikely that difference will invalidate comparisons but it must be kept in mind;fortunately it can be eliminated if necessary confining patients the group comparisons to the smaller of in district hospitals of seen . seen ; . Assessment of Smoking Habits smoking The assessment of the relation between tobacco and diseaseis complicated by the fact that smoking habits change A man who has been a light smoker for years may . become a heavy smoker; a heavy smoker may cut down his consumption or give up smoking indeed may do repeatedly An acute respiratory disease may force the sufferer to stop smoking or he may be advised to stop for one of many pathological conditions In 1947 a further the complication was introduced by the Chancellor of Exchequer the duty on tobacco being raised to such an extent that many people made large cuts in the amount of tobacco they smoked to restore them partially or TABLE Comparison Between carcinoma Patients und Non- : cancer Patients Selected as Controls With Regard to Sex and Age Social Class Place of Residence No. of Lung- carcinoma Patients M F No. of cancer Control . Patients M F Social Class Registrar General's Categories Men Only No. of Lungcarcinoma Patients | No. of Non- cancer Patients NOPASOWAN NOPASOWAN NOPASOWAN NOPASOWAN NOPASOWAN NOPASOWAN NOPASOWAN NOPASOWAN NOPASOWAN NOPASOWAN Omtoma ar | Omtoma ar 2} 6: 18 Omtoma ar 36 Omtomaaar 87 Omtomaaar 130 |j Omtoma ar 145 Omtoma ar 109 Omtoma ar 89 Omtoma ar 27 ff 4 and . of III V . 3. IV and . A00028 All classes .. A00028 Il A00028 Place ofresidence A00028 County of Lon- A00028 don .. |] A00028 Outer London Other county borough Urban district Rural district . Abroad or in Services 77 388 184 649 DE 203 AUN AUN AUN 15 87 396 166 649 22 22 16 54 27 4 completely in the succeeding months Fortunately the ~~ interviewing of patients was not begun till a year after the last major change was made in the tobacco duty in any case the effect was minimized by interviewing the control patients pari passu with the carcinoma patients so that the change in price is likely to have affected all groups similarly The difficulties of a varying consumption can be largely overcome if a more detailed smoking history is taken than is customary in the course of an ordinary medical examination example one man who was described in the hospital notes as being a smoker admitted to the almoner that he had been a very heavy smoker until a few years previously In this investigation therefore the patients were closely questioned and asked a if they had smoked at any period of their ; lives b the ages at which ; they had started and stopped c the amount they were in the the habit of smoking before onset of the illness which | | Total M All ages 649 60 | 649 60 | F | 709 709 ' * One from control patient was selected in error the wrong age group It will be seen that the lungcarcinoma patients and the compar- me control group of cancer patients are exactly able with regard to sex and age but that there are some differences with regard to social class and place of resi- dence The difference in social class distribution is small and is no more than might easily be due tochance 1.61 = 0.30 The difference place of residence is however large 31.49; =; 0.001 and Table II shows that a higher proportion of the lung patients were resident outside London at the time of their had brought them into hospital d the main changes in history and the maximum they had ever been their smoking ; in the habit of smoking e the varying proportions smoked in pipes inhaled and _ cigarettes ; and f whether or not they To record and subsequently to tabulate these details was necessary todefine what meant bya smokerdetails man the term for example include the woman who tookone cigarette annually after her Christmas dinner or the of 50 who youth smoked a couple of cigarettesto see whether he liked it and decided did not If so it doubtful smoker wwhetherhether anyone at therefore could defineddescribedasinquiry inquiry admissiotno hospital This difference can be explained on the grounds that people with cancer came to London from other parts of the country for treatment at special centres When a comparison is made between the 98 lung- carcinoma patients and the 98 controls who were seen at district hospitalsin Londonis those regional board hospitals which do not have special surgical thoracic or functionof the patient's memory andveracity To assess their reliability 50 unselected control patients withdiseases 742 SEPT 30 1950 SMOKING AND CARCINOMA OF LUNG TABLE Amount of Tobacco Smoked Daily Before Present Illness as Recorded at Two Interviews With the Same Patients at an Interval of Six Months or More mo TABLE Most Recent Amount of Tobacco Consumed Regularl by Smokers Before the Onset of Present Illness carcinom Patients and Control Patients with Diseases Other Than Cance First No. Interview of .Persons Smoking cigs.- 15 cigs .. 2505cciiggss Total Second Interview ; No. of Persons Smoking : 0 mo cy : cig.- nee | 5 cigs cigs - 25 cicgigss.-.- 4 133 1 133 361 133 361 131 361 131 131 50 ci+ gs 00 00 Total g 17 14 4 t 8 6 18 13 5050 5050 5050 the question How much did to onset of your your present present illness ? illness you smoke before the questions habits - The answers to the other questions on smoking habits showed a variability comparable to that shown in Table III - It may be concluded therefore that while the detailed smoking histories obtained 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 smokers The simplest comparison that can be made to show whether there is any association at all between smoking and carcinoma of the lung is that between the proportion of carcinoma patients who have been smokers and the proportion of smokerisn the comparable group of subjects without carcinoma of the lung Such a compari- son is shown in Table IV TABLE Proportion of Smokers and smokers in Lung- carcinoma Patients and in Control Patients with Diseases Other Than Cancer Disease Group Disease Group No. of No. of smokers | Smokers Probability Test Males carcinoma carcinoma patients 649 % Control patients with diseases other than cancer 649 : 27 4.2 Females | carcinoma patients 60 | 19 31.7 | H Control patients with diseases H other than cancer 60 . 32 53.3 647 622 41 28 P exact method - 0.00000064 = 5-76 = 1 0.01 < 02 a | It will be seen that the vast majority of men have been smokers at some period of their lives but also that the very small proportion of those with carcinoma of the lung who have been smokers 0.3 is most significantly less than the corresponding proportion in the control group of other patients 4.2 As was to be expected smoking is shown to be a much less common habit among ; women but here again the habit was significantly more frequent among those with carcinoma of the lung Only 31.7 of the carcinoma group were smokers compared with 53.3 in the control group Amount of Smoking In the simple comparison of Table IV all smokers have - been classified 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 classified according to the amount smoked immediately prior to giving it up This classification is described subsequently as the most recent amount smoked No. Smoking Daily Group Disease : Cigs Cigs Ciga | 1 Cig.- 5 Cigs 15 Cigs Cigs Ciga Males | | | | | carcinoma patients 647 33 % 250 38.6 196 30 136 % 32 % Control patients with diseases i other than 55 293 190 71 13 cancer 622 | 8.8 | 4|7 30 | 11-4 | % Females carcinoma 17-1 46-3 % 14-6 % : patients 41 . ( 17-1 | 46-3 | 22-0 | 14-6 | ) 0.05 Control patients other than | | cancer 28 -. 42.9 10 42.9 35-7 . 21 | ; | | arettedsd % 0.0 0.0 smoking or more te ggreotuhpeerd man Ounces of tobacco have been expressed as being equivalent to so cigarettes There is i oz of tobacco in 26-3 normal cigarettes so that th conversion factor has been taken as 1 oz of tobacco a week = 4 cigarettes a day From Table V it will be seen that apart from the genera excess of smokers found in Table IV in carcinoma patients there is in this group a significantly higher pro portion of heavier smokers and a correspondingly lowe proportion of lighter smokers than in the comparativi group of other patients For instance in the lung carcinoma group 26.0 of the male patients fall in the two groups of highest consumption 25 cigarettes a day or more while in the control group of other male patients only 13.5 are found there The same trend is observable for women but the numbers involved are small and the difference her between the carcinoma group and their control patients ~fl not quite technically significant If however the femal carcinoma patients are compared with the tota ; CONTROL (| WITHOUT PATIENTS CANCER PATIENTS WITH CARCINOMA OF THE LUNG 907 PATIENTS PATIENTS PATIENTS Ff PATIENTS : PATIENTS PATIENTS 40+ MEN 45 PERCENTAGE PERCENTAGE PERCENTAGE 20 PERCENTAGE PERCENTAGE PERCENTAGE | PERCENTAGE PERCENTAGE O 9 4 10.3 10.3 fe) 3 -4-4 5-14 AMOUNT OF TOBACCO " EXPRESSED AS 15-24 SMOKED DAILY CIGARETTES 60 53 PATIENTS i PATIENTS PATIENTS PATIENTS WOMEN OF OF L PERCENTAGE PERCENTAGE 297 PERCENTAGE PERCENTAGE PERCENTAGE PERCENTAGE L. PERCENTAGE PERCENTAGE PERCENTAGE FIG 1-4 5-14 15-24 25+ AMOUNT OF TOBACCO SMOKED DAILY EXPRESSED AS CIGARETTES Percentage of patients smoking different amounts of tobacco daily . \ 2 SEPT 30 1950 SMOKING AND CARCINOMA OF LUNG . BRITISH 743 MEDICAL JOURNAL . TABLE Maximum Amount of Tobacco Ever Consumed Regularly by Smokers carcinoma Patients and Control Patients with Diseases Other Than Cancer extent in the previous tables by classifying a patient as a smoker only if he has never smoked regularly by classifying him according to the amount he last smoked Disease Group No. Smoking as a Daily Maximum Probability 1 Cig | 5 Cigs.- 15 Cigs Cigs Cigs + ProbaTbestility Males : carcinoma 24 208 196 174 | | | | patients 647 % 32-1 30 26-9 : Control patients with diseases 45 % : j 23-16 | = 0.001 regularly if he had given up smoking and by ignoring changes in smoking habits which had taken place subsequent to the illness which brought the patient into hospital Other methods of analysis have also been adopted Thus Table VI shows the results in the two main groups when a comparison is made between the maximum amounts 242 other than 38 201 118 23 ! | | | | cancer 622 6.1 38-9 32-3 % % ex Females carcinoma patients 41 | Control patients with diseases 6 15 12 19.5 14-6 | 36-6 . | 29-3 | 19-5 other than cancer 28 : | | | | 12 32-1 4 42.9 32-1 % % 0.0 0 | % 3.6 3.6 : + = 7.58 | = 0-02 0.05 Women smoking 15 | or more cig arettes a day grouped to- | gether i I TABLE Estimate of Total Amount of Tobacco Ever Consumed by Smokers carcinoma Patients and Control Patients with Diseases Other Than Cancer No. Who have Smoked Altogether Probability | 365 | || || || | Cigs.- 50,000 Cigs.- 150,000 250,000 Cigs.- Cigs.- | Probability 500,000 ; Test Cigs I ever smoked regularly and Table VII shows a comparison between the estimated total amounts of tobacco smoked throughout the patients whole lives The estimates of the total amount smoked expressed as cigarettes have beenbe n made by multiplying the daily amount of tobacco smoked by the number of days that the patient 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 only very rough approximations to 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 seen closely similar Whichever measure of smoking is taken the same result is obtained a significant and clear relationship between smoking and carcinoma of the lung It might perhaps have been expected that the more refined carcinoma 19 145 patients 647 | 2.9 | 22.4 Control patients 183 225 75 28-3 | 34 | % with diseases other than 36 190 182 179 35 cancer 622 % 30-5 | | | | | Females ; | * 10 19 carcinoma | patients 41 24 | 46.3 j 29-3 28-9 5-6 : i 5 7 0.0 12 1 % | 0.0 x30-60 7 = i 0.001 j 1 x12.97 | = concepts maximum amount ever smoked and the total amount ever smoked have shown a closer relation- ship than the most recent amount smoked before the onset 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 Control patients | ' with diseases : : other than | | | | | cancer 28 . 19 67 % 10-7 | j % 17.9 10-7 3-6 : 0.0 0.0 . H ! | | : 0.001 < 0.01 Women smoking 15 1 or more cig- j arettes a day grouped together number of women interviewed is bringiinnthge other cancer groups interviewed and making appropriate allowance for age differences between them the significance of the trend in their case also is established x= 13.23 ; = P approximately 0.001 The results given in Tables IV and V are shown together graphically in Fig 1. The percentages in the figure are not all exactly the same as those in the tables In the figure the percentages are based on the total number of patients in each disease group smokers and smokers which results from requiring the patient to remember habits | of many years past It seems 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 years they have smoked and the number of years they have given up smoking are shown in Table VIII It will be seen that the carcinoma patients showed a slight tendency to start smoking earlier in life to continue longer and to be less inclined to stop but the differentiation is certainly not sharp and the difference is technically significant only with respect to length of time stopped Cigarettes and Pipes alike ; in Table V they are percentages of smokers alone Smoking History Going one stage further it has been noted earlier that the amount smoked daily at any one period does not of course necessarily give a fair representation of the individual's smoking history This has been overcome to some So far no distinction has been made between cigarette - j.. and pipe smokers and it is natural to ask whether both methods of smoking tobacco are equally related to car- | . cinoma of the lung Again the difficulty arises that a man who describes himself as a pipe smoker may have smoked | cigarettes until shortly before interrogation or alterna- tively he may have had his teeth extracted and substituted - cigarettes for his pipe To overcome this we have excluded carcinoma TABLE VIII Age , of Starting to Smoke Number of Years Smoked and Number of Years Stopped Smoking in Patients and Control Patients with Diseases Other Than Cancer Male Smoking and Female 7 os Age at Starting carcinoma Patients No. % Control Patients No. % No. Years of | Smoking Under | 20 ole nt a 541 118 17 12 78-6 | 17.2 ft | 4.2 488 129 22 11 75.1 |] 19.8 5.1 1102040+ carcinoma : ' Patients No. % 14 21 351 302 5-1 5-1 51.0 | 43-9 | . Control Patients No. % |} 18 32 338 262 + 7 52-0 | 40-3 . _ Years of Stopped 0 11020+ | carcinoma Patients | No. | % 649 30 4 5 | 94.3 | 4.4 1.3 ages .. | 688 650 Total 688 | 650 Tota 688 | 4 x2 2.40 n = 2 0.30 < 0.50 ; 4-65 = 2 05 10 i - Control | Patients No. 590 37 141 95 650 | MEDICAL JOURNAL men who gave history of having ever consistently the smoked both pipes cigarettes pin and have comparethde of and" pure cigarette and cancer control patients thought they had an illness which could be attributed to smoking Could they be produced by bias on the parti of the interviewers in taking and interpreting the histories Selection of Patients for Interview The method by which the patients with carcinoma of were pipe smokers and 90.3 % were cigarette smokers The lower proportion of pipe smokers and the corresponding of cigarette smokers in the carcinoma group carcinoma the lung were obtained has been discussed earlier there is reason to suppose that they were anything other than a representative sample of the carcinoma patients attending the selected London hospitals The control patients as was shown in Table II were exactly compar unlikely to be due to chance 5.70 = 0.01 able so far as sex and age were concerned and they were sufficiently comparable with regard to social class for the therefore seems that pipe smoking is less closely related carcinoma carcinoma lung than cigarette smoking On the hand it has been shown in TableV that light smoking smoking is less closely related to carcinoma of the lung heavy smoking so that the result might be explained than on merely the grounds that pipe smokers tend to smoke , less tobacco ; difference between the two series to be ignored They were not wholly comparable from the point of view of place of residence The difference in this respect however was that more of the carcinoma patients came from small towns and rural districts and the figures in this inquiry show that consumption of tobacco per head in these areas is less than in London Clearly this feature cannot have In fact pipe smokers do consume on the average less tobacco smokers tobacco than cigarette smokers but this is unlikely to be the whole explanation of the relative deficiency of pipe observed in the carcinoma group We find a - higher proportion of cigarette smokers and a lower proportion of pipe smokers among the carcinoma patients than among the control group of cancer patients at - each level of consumption of tobacco is at 1-4 accounted for the observation that the carcinoma patients smoked more Further if the comparison is confined to patients seen in district hospitals all of these resided in Greater London results are the same Table IX TABLE Most Recent Amount Smoked by carcinoma and Control Patients Seen in District Hospitals Male and Femalej . 5-14 15-24 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 find a higher proportion of the carcinoma patients than of the control group in the higher smoking categories is smoking more than 6 oz of tobacco a week In short the results of this subdivision are similar Disease Group | diseases carcinoma patients Control patients with diseases other than cancer 98 . No. Smoking Daily : Cigs.- Cigs.- 25 + 0 1 Cig 5 Cigs.- 15 Cigs.- Cigs | 2 12 36 27 21 : a 9 . | | | 9 50 19 : 3 ** - 11.68 11 4 < 0.002 .02 to those shown in Table V for all smokers It seems that by is of metth obo acc d o is smoked impor- tance and smoking pipe related to carcinoma the lung carries a smaller risk than smoking cigarettes With the data at our disposal we are unable to determine how great the difference in risk may be It might possibly be argued that the choice of a control group of patients with various medical and surgical con- ditions has of itself resulted in the selection of subjects with a smoking history less than the average This would seem very unlikely as we know of no evidence to suggest that less than average smoking is a characteristic of per- Inhaling Another difference between smokers is that some inhale _ and others do not All patients who smoked were asked whether or not they inhaled and the answers given by with sons any one group of diseases and it certainly could not be held that it is equally a characteristic of persons suffering from all diseases other than carcinoma of the lung Yet in Table X the smoking habits of the patients the carcinoma and cancer control patients were as follows ; of the 688 carcinoma patients who smoked men and women 61.6 said they inhaled and 38.4 said they did not ; the corresponding figures for the 650 patients with other diseases were 67.2 inhalers and 32.8 non- inhalers It would appear that carcinoma patients TABLE Most Recent Amount Smoked by all Patients Other Than Those with Carcinoma of Lung Divided According to Type of Disease Male and Female ^' Disease Group a 0 No. Smoking Daily | 1 5 Cigs Cig 5 Cigs | Cigs 25 (3 15 Cigs Cigs 4 slightly % inhale less often than other patients 4.58 = 0.02 However the difference is not large and if the carcinoma patients are compared with all the other patients interviewed and the necessary allowance is made for sex and age the difference becomes insignificant 0.19 = 0.70 | | | | Cancer other than carcinoma 236 ; 78 1237 of lung 718 .. ve 2 220-0 | 85-3 236.9 Respiratory disease other than 42 | 33 | 128 cancer 335 disease 166 47-0 | 29.7 | 136.1 Cardiovascular disease 166 22 19 , 64 177 16.7 73-8 110 322.8 98 84.1 38 39.5 . intestinal disease 32B 39 55.7 31 32.3 143 130.2 81 75-8 Other diseases 215 38 36.6 . 24 211 91 86.0 44 48.9 57 53.0 34 38 23 18.3 34 34-5 18 22.1 Interpretation of Results smokin~ Though from the previous tables there seems to be no doubt doubt that there is a direct association between and carcinoma of the lung it is necessary to consider alter- an native explanations of the results Could they be due to an unrepresentative sample of patients with carcinoma of the lung or to a choice of a control series which was not truly comparable Could they have been produced by exaggeration of their smoking habits by patients who x = 20 n '16 20 < 30 The roman figures show the actual numbers observed those in italics are the numbers that would have occurred if the disease group in question had hot in each sex and at each age exactly the same smoking habits as all the patieou included in the table in five main groups of diseases are compared allowing for differ their sex and age composition and no significant ence can be demonstrated between them We have * SEPT 30 1950 SMOKING AND CARCINOMA OF LUNG BRITISH MEDICAL JOURNAL brought into this table all the patients with diseases other than carcinoma of the lung As in other tables where sex and age differences between groups have had to be taken into account the " " expected numbers have been obtained by taking the actual numbers of patients with each type of disease in each age and sex subgroup subgroup and calculating what proportion of them would fall in each smoking category if they had had exactly the game habits as all the patients included in the Table In other words we have computed what ought to be the moking habits of each disease group if it behaved in each sex and at each age like the total population of patients and compared them with what in fact they were The relatively large numbers of smokers in some of the groups are due to the fact that these disease groups Included many old women : There remains the possibility that the interviewers in electing the control patients took for interview from mong the patients available for selection a disproporionate number of light smokers It is difficult to see how they could have done so but the point can be tested Indirectly by comparing the smoking habits of the patients whom they did select for interview with the habits of the other patients other than those with carcinoma of the ing whose names were notified by the hospitals The comparison is made in Table XI and reveals no appreciable Bifference between the two groups site This unfortunately was impracticable the site would be written on the notification form or the nurse would refer to the diagnosis in pointing out the patient or it would become known that only patients with cancer of one of the sites under investigation would be found in one particular ward Out of 1,732 patients notified and interviewed as cases of cancer the site of the growth was known to the interviewer at the time of interview in all but 61 \~ Serious consideration must therefore be given to the pos- . sibility of interviewers bias affecting the results by the ~~: interviewers tending to scale up the smoking habits of the carcinoma cases Fortunately the material provides a simple method of testing this point A number of patients were interviewed who at that time were thought to have carcinoma of the lung but whom the diagnosis was subsequently disproved The smoking habits of these patients believed by the interviewers to have carcinoma of the lung can be compared with the babies of the patients who in fact had carcinoma of the lung and also with the habits of all the other patients The result of making these comparisons is shown in Tables XII and XIII and it will be seen that the smoking TABLE Most Recent Amount Smoked by Patients with Carcinoma of Lung and by Patients Thought Incorrectly by the Interviewers to be Suffering from Carcinoma of Lung Male and Female ABLE Most Recent Amount Smoked by All Patients Other Than Those with Carcinoma of Lung Divided According to Whether They Were Notified or Selected for Interview Male and Female . Method of Selection of Patient Notified Notified byby hohossppitail tal 11,,003322 felected by interviewer 730 . 5 0 307 301.8 | 70 75.2 No. Smoking Daily | Cigs.- Cig.- 1 Cig.- 5 | Cigs.- 15 Cigs.- Cigs.- 25 Cigs | | 114 354 179 78 | | | | 119.0 71 345.2 309 186.1 192 80.0 88 | 66.0 | 317 | 184.9 | 86.0 Disease Disease Group O Patients with carcinoma of lung | 709 we os o Patients incorrectly thought to || have carcinoma of lung 209 21 31 35 24.3 No. Smoking Daily | 1 Cig 40 48-0 | 25 i 170 5 Cigs Cigs Cigs + 269 276.0 83 76.0 205 201.0 50 54.0 174 152-7 16 37.3 x2 = 29.76 = 4 < 0.001 . * See footnote to Table X. in hospital There is a large number of cases in this group because one hospital notified all cases admitted for bronchoscopy 147 out of the 209 incorrectly thought to have carcinoma of the lung were interviewed at this : yt 2-14 = 4 0-<800 -80 i * See footnote to Table X. gh Lg It can therefore be concluded that there is no evidence f any special bias in favour of light smokers in the selec- ion of the control series of patients In other words the roup of patients interviewed forms we believe a satis- actory control series for the carcinoma patients from be point of view of comparison of smoking habits Patient's Smoking History Another possibility to consider is that the carcinoma atients tended to exaggerate their smoking habits Most f these patients cannot have known that they were suffer- ig from cancer but they would have known that they ^drespiratory symptoms and such knowledge might have fluenced their replies to questions about the amount they atients moked However Table X has already shown that with the other respiratory diseases did not give moking histories appreciably different from those given y. the patients with respiratory illnesses There is no ason therefore to suppose that exaggeration on the part ason the carcinoma patients has been responsible for ie results : . . The Interviewers When the investigation was planned it was hoped that ic interviewers would know only that they were inter- ewing patients with cancer of one of several sites lung tomach or large bowel but not at the time the actual TABLE Most Recent Amount Smoked by Patients Incorrectly Thought by the Interviewers to be Suffering from Carcinoma of Lung and All Other Patients Not Suffering from Carcinoma of Lung Male and Female Disease Group No. Smoking Daily | 0 1 Cig 5 Cigs.- 15 Cigs 25 Cigs + | Patients incorrectly thought to have carcinoma of lung 209 35 36-8 ||| All other patients not suffering carcinoma || from of lung 1,553 342 340-2 25 20-4 160 | 164-6 83 82.0 580 | 5810 50 48-8 321 | 322-2 16 20.8 ! 150 { 145-2 = 2.58 = 4 50 0-70 * See footnote to Table X. See footnote to Table XII 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 fact have carcinoma of the lung Table XII but they do not differ significantly 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 appreciable bias the smoking habits of the patients thought incorrectly to have carcinoma of the lung would have been recorded as being like those of the true carcinoma subjects and not the same as those without carcinoma of the lung oo We may add that the results cannot be due to different workers interviewing different numbers of patients in the cancer and control groups for while the four interviewers .746 SEPT 30 1950 SMOKING AND CARCINOMA CARCINOMA OF LUNG - BRINSK MEDICAL JOURN did not see exactly the same proportions of patients in all the groups proportions were very close Moreover if the patients seen by each of the interviewers are treated as four separate investigations highly significant differences are found between the carcinoma patients and the other patients interviewed in three instances In the fourth the difference is in the same direction but owing to the small number of patients seen the results are not technically significant P lies between 0.10 and 0.05 in this instance the almoner had to stop work because of illness having seen only 46 patients with carcinoma of the lung _ TABLE Ratios of Patients Interviewed With Carcinom Lung and with a Given Daily Consumption of Tobacco to Estimated Populations in Greater London Smoking the : Amounts Male and Female Combined Ratios per Millic Age 25- |) 35- an 4.5- e 55- . 65-74 . Daily Consumption of Tobacco | | | 50- | | Cigs | 5-14 15-24 | 28-49 50- T 01-4 01-4 Cigs 15-24 28-49 50- . | | 0 Il 2 9 f2 34 | 14 | 133 21 | 110 2 43 178 6 | 41 | 241 28 67 429 380 463 844 300 510 | 1,063 _ 77 667 600 2,000 |! 5] ] * Ratios based on less than 5 cases of carcinoma of the tung are given in Discussion To summarize it is not reasonable in our view to attri- 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 Table X patients in different disease groups shown in revealed no association between smoking and other respiratory diseases or between smoking and cancer of the other sites mainly stomach and large bowel The association therefore seems to be specific to carcinoma of the lung This is not necessarily to say that smoking causes carcinoma of the lung The association would occur if carcinoma of the lung caused people to smoke or if both attributes were effects of a common cause The habit of smoking was however invariably formed before the onset of the disease as revealed by the production of symp- toms so that the disease cannot be held to have caused the habit nor can we ourselves envisage any common cause likely to lead both to the development of the habit and to the development of the disease 20 to 50 years later We therefore conclude that smoking is a factor and an important factor in the production of carcinoma of the as unity and the resulting ratios in the three age grou which a large number of patients were interviewed i 45 to 74 are averaged the relative risks become 6 19 49 and 65 when the number of cigarettes smoked a are 3 10 20 35 and say that is the poin each smoking group In other words on the admit speculative assumptions we have made the risk seen vary in approximately simple proportion with the am smoked One anomalous result of our inquiry appears to 1 to inhaling It would be natural to suppose that if sm were harmful it would be more harmful if the smoke inhaled In fact whether the patient inhaled or no not seem to make any difference It is possible tha patients were not fully aware of the meaning of the and answered incorrectly but the interviewers were of that opinion In the present state of knowledge more reasonable to accept the finding and wait unti size of the smoke particle which carries the carcinog determined Until this is known nothing can be s about effect which any alteration in the rate and ( of respiration may have on the extent and site of depo of the carcinogen Davies 1949 lung i. The effect of smoking varies as would be expected with the amount smoked The extent of the variation could be estimated by comparing the numbers of patients inter- viewed who had carcinoma of the lung with the correspond- ing numbers of people in the population in the same age who smoke the same amounts of tobacco Our groups figures however are not representative of the whole country and this may be of some importance as countrymen smoke on the average less than city dwellers More- . over as was shown earlier the carcinoma and the contro patients were not comparable with regard to their places of residence The difficulty can be overcome by confining the comparison to the inhabitants of Greater London If it be assumed that the patients without carcinoma of the lung who lived in Greater London at the time of their interview are typical of the inhabitants of Greater London with regard to their smoking habits then the number of people in London smoking different amounts of tobacco can be estimated Ratios can then be obtained between the numbers of patients seen with carcinoma of the lung and the estimated populations at risk who have smoked amounts of tobacco This has been done for comparable and the results are shown in Table XIV each age group It must be stressed that the ratios shown in this table are not measures of the actual risks of developing carcinoma of the lung but are put forward very tentatively as pro- portional to these risks Thus Table XIV shows clearly and for each age group the conclusion previously reached the risk of developing carcinoma of the lung increases steadily as the amount smoked increases If the risk among smokers is taken es DEATH FROM CANCER OF THE 250 LUNG ENGLAND & WALES de MIL ION MIL ION -- CONSUMPTION OF TOBACCO U KA ; MIL ION CONSUMPTION OF TOBACCO AS de PER 200 | Q CIGARETTES U.K PER LUNG 4, B LUNG THE 150- THE OF = OF CANCER CANCER rere) CANCER * CANCER CANCER x 4 ee FROM x- FROM FROM RATE sob RATE ae 8 4 DEATH p . DEATH 20 DEATH eaewiws| aware aw 1900 1910 1920 esPaeeewews vaweuwe 1930 1940 19 YEAR THE RATES ARE BASED ON 3 YEAR AVERAGES YEARS EXCEPT 1947 FOR ALL FIG Death rate from cancer of the lung and consumption of tobacco and cigareties rate How in conclusion do these results fit in with | known facts about smoking and carcinoma of the Both the consumption of tobacco and the number of attributed to cancer of the lung are known to ha creased and to have increased largely in many coi i , _ SEPT 30 1950 SMOKINGSMOKING AND CARCINOMA OF LUNG BRITISH MEDICAL JOURNAL 747 his century The trends in this co given in Fig 2 ben and show that over the last 25 years the crease in deaths ttributed to cancer of the lung has been much greater han the increase in tobacco consumption This might well e because the increased number of deaths in the latter ears is partly an apparent increase due to improved diagtosis in other words it is not wholly a reflection of ncreased prevalence of cancer of the lung On the other and it is possible that the carcinogenic agent is introduced luring the cultivation or preparation of tobacco for conumption and that changes in the methods cultivation nd preparation have occurred as well as changes in conumption However that may be it is clearly not possible o deduce a simple time relationship in this country between he consumption of tobacco and the number of deaths attri- uted to cancer of the lung The greater prevalence of carcinoma of the lung in men ompared with women leads naturally to the suggestion hat smoking may be a cause since smoking is predomiantly a male habit Although increasing numbers of vomen are beginning to smoke the great majority of vomen now of the cancer age have either never smoked have only recently started to do so It is therefore empting to ascribe the high sex ratio to the greater conumption of tobacco by men If this were true it would expected that the incidence of carcinoma of the lung would be the same among smokers in both sexes In his series 2 out of 649 men and 19 out of 60 women with The great increase in the number of deaths attributed to cancer of the Jung in the last 25 years justifies the search for a cause in the environment An investigation was - therefore carried out into the possible association of carcinoma ofthe lung with smoking exposure to car and fuel fumes occupation etc. The preliminary findings with regard to smoking are . reported a The material for the investigation was obtained from twenty hospitals in the London region which notified 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 cancer control group of general hospital patients chosen so as to be , of the same sex and age as the carcinoma patients Altogether 649 men and 60 women with carcinoma of the lung were interviewed Of the men 0.3 and of the women 31.7 were smokers as defined in the text The corresponding figures for the cancer control groups were men 4.2 women 53.3 ; Among the smokers a relatively high proportion of the patients with carcinoma of the lung fell in the heavier smoking categories For example 26.0 of the male and 14.6 of the female carcinoma patients who smoked gave as their most recent smoking habits prior to their illness the equivalent of 25 or more cigarettes a day while only 13.5 of the male and none of the female cancer control patients smoked as much Similar differences were found when comparisons were made between the maximum amounts ever smoked and the estimated arcinoma of the lung were smokers total amounts ever smoked To calculate the incidence rates among smokers of ither sex it is necessary to estimate the number of nonmokers in the population from which the patients were rawn For reasons given earlier this cannot be done but n estimate can be obtained of the expected sex ratio of ases occurring among smokers in the Greater London rea From the experience of the patients without carinoma of the lung who lived in Greater London at the me of their interview it can be calculated that there were 1948 175,000 men and 1,582,000 women in London etween the ages of 25 and 75 who had never been nokers according to our definition of the term Taking hese figures subdivided by age in association with the ge distribution of the 16 cases of carcinoma of the lung bserved among smokers living in Greater London it an be calculated that if the incidence of the disease were qual among smokers of both sexes one case should ave occurred in a man and 15 in women In fact the bserved ratio was 0 to 16 This finding is consistent with the theory that the risk f developing carcinoma of the lung is the same in both en and women apart from the influence of smoking It not however possible to demonstrate with the data at ur disposal that different amounts of smoking are sufficient > account for the overall sex ratio As to the nature of the carcinogen we have no evidence Cigarette smoking was more closely related to carcinoma of the lung than pipe smoking No distinct association was found with inhaling Taken as a whole the carcinoma patients had begun to smoke earlier and had continued for longer than the controls but the differences were very small and not statistically significant Rather fewer carcinoma patients had given up smoking Consideration 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 habits or by bias on the part of the interviewers Reasons are given for excluding all these possibilities and it is concluded 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 people who smoked different amounts of tobacco in Greater London and hence the relative risks of developing the disease among different grades of smokers were calculated The 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 approximately 50 times as great ' among those who smoke 25 or more cigarettes a day as among smokers : . The observed sex ratio among smokers based it must be stressed on very few cases can be readily accounted for if the true incidence among smokers is equal in both sexes he only carcinogenic substance which has been found in bacco smoke is arsenic Daff and Kennaway 1950 but e evidence that arsenic can produce carcinoma of the ung is suggestive rather than conclusive Hill and Faning 948 Should arsenic prove to be the carcinogen the ossibility arises that it is not the tobacco itself which is angerous Insecticides containing arsenic have been used or the protection of the growing crop since the end of the ast century and might conceivably be the source of the esponsible factor This too might account for the obseration that deaths from cancer of the lung have increased nore rapidly than the consumption of tobacco It is not possible to deduce a simple time relationship between ~ the increased consumption of tobacco and the increased numbe - of deaths attributed to cancer of the lung This may = because part of the increase is apparent is due* improved diagnosis it may also be because the carcin * in tobacco smoke is introduced into the tobacco duriritly cultivation or preparation Greater changes may have ases place in the methods involved in these processes than ings actual amount of tobacco consumed .eKnetnnser operating Hospitals Certral Kenner Fulham Hackney Hammersmith Harefield al al but Lewisham Middlesex Mount Vernon and the Radium aan New End Royal Cancer Royal Free St. Bart eee - St. Charles's St. James St. Mary's St. Thomas's University College Whittington staffs We are indebted to the of the named hospitals for having having allowed | us to interview their patients and to have access to the hospital notes also to the individual members of the staffs both medical and lay who notified the cases and collected the notes examination The work could not have been carried out without operation Sir Ernest Kennaway and Dr. Percy Stocks their took part in a conference called by the Medical Research Council at which this investigation was initiated and we have been fortunate in having their helpful advice throughout its course Professor W. Newcomb has advised us on individual problems of pathology We are most grateful for this assistance Finally we wish to thank Miss Marna Buckatzsch Miss Beryl lago Miss Keena Jones and Miss Rosemary Thomson who interviewed the patients and helped with the analysis of the results and Dr. J. T. Boyd for assistance in the calculations . REFERENCES Clemmesen J. and Busk T. 1947 Brit J. Cancer 1 253 Daff M. and Kennaway E. L. 1950 Ibid In press Davies C. N. 1949 Brit J. industr Med 6 245 Hill A. Bradford and Faning E. L. 1948 Ibid 5 1 . Kennaway E. L. and Kennaway N. M. 1947 Brit J. . Cancer . 1 260 M^...llerF. H. 1939 Z. Krebsforsch 49 57 Schrek R. Baker L. A. Ballard G. P. and Dolgoff S. 1950 Cancer Res 10 49 Steiner Steiner P. E. 1944 Arch Path 37 185 Stocks P. 1947 Studies on Medical and Population Subjects No. 1. Regional and Local Differences in Cancer Death Rates Wynder H.M.S.O. London Willis R. A. 1948 Pathology of Tumours Butterworth London E. L. and Graham E. A. 1950 J. Amer med Ass 143 [a REGIME FOR TREATMENT OF SEVERE AND ACUTE LIVER DISEASE BY A. L. LATNER M.D. M.Sc. D.I.C. A.R.C.S. _ From the Section of Chemical Pathology Department of Pathology Royal Victoria Infirmary Newcastle- Tyne In spite of increasing biochemical knowledge on the subject of liver necrosis the high mortality rate of severe liver disease 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 contrast to the short period of survival of animals after hepatectomy Moreover in called acute yellow atrophy several of the liver's functions may remain apparently normal until death Even the _ fasting blood level may remain within normal limits This must surely mean that enough liver tissue survives to carry out certain highly important metabolic processes that There is also reason to believe the histological picture of massive necrosis is not unrelated to mortem autolysis and that much more liver tissue survives during life han apparent after death van Beek and Haex 1943 These facts are of great importance If practically all liver were necrotic during life then treatment would ously be useless On the other hand if large numbers yer cells were diseased but not dead the possibility pd remain that the process was reversible and that a sful treatment might eventually be discovered In ; pe that the latter state of affairs actually occurs I the en attempting over a number of years to treat principles ing smokes c smokes on biochemical biochemical principles principrincipples les smokes Ratios Sarlier Work Some three y ago treatment was begun in a series six patients coma from acute liver disease Latner and Mowbray in preparation By daily intravenous administration each patient received 1 to 3 g of cystine in addition to glucose and plasma The importance of this amino in the prevention of experimental necrosis already been demonstrated Glynn et al 1945 All these cases presented the clinical picture of acute yellow atrophy and all had a fatal outcome A gross aciduria has been demonstrated in severe liver disease by paper chromatography Dent 1949 In view of the known increase in the amino contenotf the blood including the thioamino Dent has suggested that the necrotic liver cannot utilize them and they could y not therefore be of much use in curative treatment There was some possibility that a reflex circulatory upset affecting the liver might prevent the cystine reaching the liver cells With this possibility in view tetraethylammonium bromide was administered to our sixth case as soon as it became obvious that there was no response to cystine The downhill progress of the patient was in no way affected ; These discouraging results made it obvious that we were thinking along incorrect lines The diseased liver cell required cystine to prevent necrosis but could not utilize it adequately from external sources The problem theres fore was to render the cells less sensitive to cystine defi ciency so that they could utilize their own cystine until such time recovery was complete enough to allow them to use the amino of surrounding tissue fluid From this point of view the role assigned to tocopherol in the production of experimental hepatic necrosis Schwarz 1944 Gy^rgy 1947 Himsworth and Lindan 1949 assumes great importance This vitamin has therefore been included in the regime of treatment described below The intracellular oxidative processes of the liver and other organs also require other vitamins In their absence toxic products accumulate which could easilbye a factor in the final death of liver cells The successful application of massive doses of the vitamin group in the cholaemia of cirrhosis has already been reported Patek et al 1948 This form of therapy was 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 tracers One would not be far wrong in stating that every 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 metabolism 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 unfavourably on already dam for aged liver cells It therefore becomes of great importance to administer plasma protein in severe liver disease and 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 The saline vehicle has been used because of the remarkable tendency for these patients to develop low chloride levels probably related to vomiting and possibly to associated renal failure