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FILE NAME Kent KNT DATE 1950 May 27 DOC KNT116 DOCUMENT DESCRIPTION Journal Article - Tobacco Smoking as a Possible Etiologic Factor in Bronchiogenic Carcinoma - The Journal of the American Medical Association The Journal of the -- --, American Medical Association Published Under the Auspices of the Board of Trustees VOL 143 No. 4 CHICAGO ILLINOIS COPYRIGHT 1950 BY AMERICAN MEDICAL ASSOCIATION MAY 27 1950 TOBACCO SMOKING AS A POSSIBLE ETIOLOGIC FACTOR IN BRONCHIOGENIC CARCINOMA A Study of Six Hundred and Eighty Proved Cases ERNEST L. WYNDER and EVARTS A. GRAHAM St. Louis M.D. General Increase There is rather general agreement that the incidence of bronchiogenic carcinoma has- greatly increased in the last century Statistical studies at the Charity Hospital of New Orleans Ochsner and DeBakey the St. Louis City Hospital Wheele)r and the Veterans Administration Hospital of Hines Ill Avery have revealed that at these hospitals cancer of the lung is now the most frequent visceral cancer in men Autopsy statistics throughout the world show a great increase in the incidence of bronchiogenic carcinoma in relation to cancer in general Kenneway and Kenneway in a careful statistical study of death certificates in England and Wales from 1928 to 1945 have presented undoubted evidence of a great increase in deaths from cancer of the lung In this country statistics compiled by the American Cancer Society show a similar trend during the past two decades Tobacco as a Possible Cause of Increase suggestion that smoking and in particular cigaret smoking may be important in the production of bronchiogenic carcinoma has been made by many writers on the subject even though well controlled and large scale clinical studies are lacking Adler in 1912 was one of the first to think that tobacco might play some role in this regard Tylecote Hoffman McNally Lickint Arkin and Wagner Roffo and 1 Maier were just From the Department of Surgery Washington University School of Medicine and Barnes Hospital This study has been aided by a grant from the American Cancer Society Other phases of it will be presented in subsequent publications 1. Ochsner A. and DeBakey M Surgical Considerations of Primary Carcinoma of the Lung Surgery 8 992-1023 Dec. 1940 2. Wheeler .: Personal communication to the authors 3. Avery E. .; Personnal communication to the authors 4. Kenneway N. M. and Kenneway E. L A Study of the Incidence of Cancer of the Lung and Larynx J. Hyg 86 236-267 June 1936 Kenneway E. L. and Kenneway N. M A Further Study of the Incidence of Cancer of the Lung and Larynx Brit J. Cancer 1 260-298 Sept. 1947 5. Statistics on Cancer New York American Cancer Society Statistical Research Division 1949 p 19 6. Adler .: Primary Malignant Growths of the Lungs and Bronchi New York Longmans Green and Co. 1912 7. Tylecote F. E. Cancer of the Lung Lancet 2 236-257 July 30 1927 8. Hoffman F. .: Cancer of the Lung Am Rev. Tuberc 19 392- 406 April 1929 9. McNally W. .: The Tar in Cigarette Smoke and Its Possible Effects Am J. Cancer 16 1502-1514 Nov. 1932 10. Lickint .: Der Bronchialkrebs der Wehnschr 82 1232-1234 Aug. 2 1935 Rancher M^...nchen med 11. Arkin A. and Wagner D. H Primary Carcinoma of the Lung J. A. M. A. 106 587-591 Feb. 22 1936 12. Roffo A. H Der Tabak als Krebserzeugende Agens Deutsche med Wehnschr 63 1267-1271 Aug. 13 1937 13. Maier H. .: Personal communication to the authors a few of the workers who thought that there was some evidence that tobacco was an important factor in the increase of cancer of the lungs M^...ller in 1939 from a careful but limited clinical statistical study offered good evidence that heavy smoking is an impor- tant etiologic factor In 1941 Ochsner and 15 DeBakey called attention to the similarity of the curve of increased sales of cigarets in this country to the greater prevalence of primary cancer of the lung They emphasized the possible etiologic relationship of cigaret smoking to this condition In a recent paper Schrek ficoncluded that there is strong circumstantial evidence that cigaret smoking is an etiologic factor in cancer of the respira- tory tract and finds that his data are in agreement with the results of a preliminary report presented by Wynder and Graham at the National Cancer Conference in February 1949.3 Purpose of Study purpose of the present study was to attempt to determine so far as possible by clini cal investigations statistical methods and experimental studies the importance of various exogenous factors that might play a role in the induction of bronchiogenic carcinoma In this regard we intended to learn the relative importance of previous diseases of the lungs rural and urban distribution of patients various occu- pations and hereditary background as well as smoking habits By obtaining all this information we hoped to determine whether any of these factors either singly or in combination have had an effect in increasing the increasing incidence of bronchiogenic carcinoma In the present paper the chief emphasis will be placed on our findings in regard to smoking METHOD OF STUDY The results of this study are based on 684 cases of proved bronchiogenic carcinoma It should be empha- sized that the results in this report have not been obtained from hospital records since we learned at the outset of our study that the routine records did not supply satisfactory answers to our questions It was therefore decided to seek the desired information by special interviews Six hundred and thirty patients reported on in this paper have been personally interviewed and in 33 cases we obtained the information by mailing a questionnaire.18 In the remaining 17 cases information for the questionnaire was obtained from a person who had been intimately acquainted with the patient throughout his adult life 14. M^...ller F. .: Tabakmissbrauch und Lungencarzinom Zischr f Krebsforsch 49 57-85 1939 15. Ochsner A. and DeBakey M Carcinoma of the Lung Arch Surg 42 209-258 Feb. 1941 16. Schrek R Baker C. H Ballard G. P. and Dolgoff .: Tobacco Smoking as an Etiological Factor in Disease I. Cancer Cancer Research 10 49-58 Jan. 1950 17. Wynder E. L. and Graham E. A Tobacco and Bronchiogenic Carcinoma Preliminary report to the National Cancer Conference Memphis February 1949 18. The questionnaires cancer of the lungs from were sent Dr. W. L. with to male and female patients with Watson's Thoracic Surgery Service at Memorial Hospital New York 329 san ns 330 TOBACCO SMOKING AND CARCINOMA AND GRAHAM M. A. May May 27 1950 eRem Through the cooperation of many hospitals and phy- of terms ht sicians throughout all parts of the country who per- employed by pathologists in the different hospitals who examined mitted us to interview their patients it is felt that the specimens For example what a adenocarci fairly good cross section of the entire United States some pathologists would designate as an has been obtained The list of noma others would classify as an undifferentiated cooperating institutions and physicians is presented below.19 carcinoma Likewise the term oat cell or round In order to make this survey as uniform as possible carcinoma was at times used a designation whichcelils each interviewer used the questionnaire shown in table 1 Table Etiologic Survey In regard to smoking habits we considered it par- ticularly essential to learn how much a patient had smoked formerly even though he might not smoke at all or smoke little at the time of the interview The reason for this is the well known existence of a time lag between the exposure to a carcinogenic substance and the appearance of cancer Many patients coming into the hospital with chronic discase of the lungs had stopped smoking months or even years previously We therefore asked the patients to estimate the average use of tobacco during the last twenty years of their smoking period The control patients were 1. Have you ever had a lung disease site of disease If so state time duration and Pneumonia Influenza Asthma Lung Abscess Tuberculosis Chest Injuries Bronchiectasis Others 2. Do you or did you ever smoke Yes OF No 3. At what age did you begin to smoke 4. At what age did you stop smoking? 3. oHfowyoumrucshmoktiobnagcc? o did you average per day during the past 20 years Cigarettes Cigars .Pipes 0... cea nee ee cee ee ee, questioned in an identical manner thus any possible error lying in this method of estimating smoking habits was balanced In questioning patients about occupations we attempted to learn all the occupations of a given patient the years during which he had held these jobs and to what type of dusts or fumes he had been exposed Similar details were obtained in regard to other possible exposures such as those a patient might have had in connection with certain hobbies 6. Do you inhale the smok~ Yes No 7. Do you have a chronic cough which you attribute to your smoking especially upon first smoking in the morning Yes If so for how long No Duration . Dec eeee ees 8. Do you smoke before or after breakfast Before O After 9. Name the brand or brands and dates if any given brand has been smoked exclusively for more than five years Change frequently 0 First brand from .... to .... Classification of Smoking order to facilitate a statistical analysis of the results the arbitrary classification of smoking habits given in table 2 was established If a patient smoked for less than twenty years his amount of smoking was adjusted to a twenty year period Thus a patient smoking 20 cigarets for ten years only was classified as smoking 10 cigarets daily class 2 Such adjustments were rarely necessary since only a few patients had smoked for less than Second brand ... to 19 .... exposed 10. What kind of jobs have you held Have you been to dust or fumes while working there Use back of page for detailed tion of possible exposure descrip From /- Position Dust or Fumes twenty years If a man smoked habitually more than one type of tobacco during the last twenty years the various types were added together to make up his classification Thus man who smoked 1 package of cigarets daily as well as 2 cigars was classified as a class IV or an excessive smoker 11. Have you ever been exposed to irritative dusts or fumes outside of your job In particular have you ever sively If so state time and duration used insecticide spray exces- Yes No Type Duration ee... eves .. 12. How much alcohol do you or have you averaged per day and duration in years State time Whiskey . bevaae Beer Wine eee eee cscs ccceasseace Histologic Types insure an undoubted diagnosis microscopic confirmation of the presence of carcinoma was obtained in all cases Some difficulty arose in the histologic classification because of the variation 13. Where were you born and where have you lived most of your life State the approximate time span you have lived in a certain ? locality Up to what grade did you attend school Birthplace . ooee .Home .Educational .Educational Level . 19. California Private patients of Drs L. D. Dugan II Garland E. Holman J. JonesBreWw.er Daniels F. Dolley B. Stephens Hospitals Birmingham General Rogers P. French Good Samson Letterman General Los Angeles County Southern Samaritan Pacific Stanford United California States Marine United States Naval General University of A. Wadsworth General COLORADO Private patients of Brown F. Condon J. Grow F. Harper M. Peck General Denver Drs Hospitals Colorado Rose St. General Fitzsimmons Lukes DISTRICT Fort Logan Veterans General B. Blades E. Davis HospitalsOFGeCoOrLgUetMoBwInA GePorrigveatWeasphaitinegnttson ofWalDtresr Reed JELINOIS Hospitals Cook County Hines Ill MARYLAND Hospitals Johns Veterans Administration MASSACHUSETTS Private patients of Drs Hopkins D. United States Naval pitals Boston City Harken R. Overholt Hos Massachusetts General New England Deaconess MICHIGAN Hospitals Dearborn Veterans of Drs MISSOURI Private patients J. Flance A. Goldman R. Smith Veterans Jewish St. Louis Hospitals Jefferson Barracks pitals Berthold S. City St. Pollack Newark Louis County NewW JERSEY Hos- Drs W. Veterans City NEW YORK Private patients of Cahan H. Maier J. Pool W. Watson Hospitals Bellevue Administration Brooklyn Cancer Memorial Montefiore New York City Cancer Institute Kings County pital Presbyterian Roswell Park Memorial Institute Institute New York Hos Veterans Administration PENNSYLVANIA Private Omo Hospitals 5012 Hospitals Jefferson of Pennsylvania Medical College patients of Dr. J. John- Temple University University LTAH Private patients of Drs W. Rumel Cutler Hospitals Holy Cross St. Marks Salt Lake County General Veterans Administration Dr. W. H. Groves Latter Saints 14. State the cause of death of your parents and of brothers and sisters if any 15. Site of Lesion Etiological Class Microscopic Diagnosis Papanicolaou Class Interviewer .......... terse cone a eee eect gence eeane te cece eees seeees not recognized by some pathologists In some cases pathologists called a lesion from biopsy section merely a carcinoma unclassified It may be said however that in general by far the most prevalent histologic types were the epidermoid or squamous carcinoma and its variant the undifferentiated carcinoma These are the most common types found in males In females the adenocarcinoma has so far been nearly as common as the other types It is unquestionably the epidermoid and undifferentiated carcinomas which have shown the 143 VOLUME NUMBER TOBACCO SMOKING AND CAKLINUMA W NDER AND IVZILI wea greatest increase in recent years For this reason we were particularly interested in studying these types separately from the adenocarcinomas The present report includes 605 male and 25 female patients with epidermoid undifferentiated and unclassified carcinomas and 39 male and 15 female patients with adenocarcinoma In order to determine possible sex variations in the etiology of cancer of the lung results in men and ; women are reported separately Control Study To check all possible bias on the part of the interviewers who saw only patients believed to have bronchiogenic carcinoma it was deemed advisable to conduct a control study in which a nonmedical investigator would interview every patient admitted to the Chest Service of Barnes Hospital without knowing 20 the diagnosis in advance Two interviewers were used for this purpose When the final diagnosis was determined all cases of cancer of the lungs 75 men were separated from the other cases 132 Contro patients under the age of 30 were excluded since there were no cases of cancer in this age group Seventeen male patients for whom no definitive diagnosis could be made were also omitted In addition these interviewers interrogated patients with cancer of the lung at other St. Louis hospitals also without previous knowledge of diagnosis Here the interviewers were given the names of several patients with diseases of the chest in a comparable age group of whom at least 1 was suspected to have bronchiogenic carcinoma The patients with proved cancer of the lung 25 men and the other patients 54 men were added to the Barnes Hospital groups thus collectively making up control study I. To determine the smoking habits as well as the other data contained in the questionnaire of our study of other hospital patients the nonmedical investigators also questioned patients without cancer of the lungs on the general surgical and medical services at Barnes Hospital the Jefferson Barracks Veterans Hospital and the St. Louis City Hospital This group called general hospital population consists of 780 patients Also a total of 552 female patients without cancer of the lungs have been interviewed as control patients on our surgical and medical services Two objects were to be realized by this control study One was to learn of possible exposures to exogenous irritants of a large group of patients without cancer of the lung and the other to test the validity of the interviews made by those who knew the suspected diagnosis in a given case in advance Age Distribution in Control Cases For proper statistical evaluation of a study of this kind it is obvious that the age distribution should be the same in the con- trol cases as in the cases of cancer of the Jungs Since no patients with cancer of the lungs below 30 or above 80 years of age were seen no controls beyond these ages have been included The controls comprised the unselected patients as they entered the Barnes Hospital and other St. Louis hospitals For that reason their age distribution is not identical with that of the patients with cancer In order to be able to evaluate the cases without cancer on the basis of the same age distribution as that found in the cases of cancer the following adjust- ments were made The combined results include data on 780 cases with- distribution 30 to 39 18.7 per cent 40 to 49 21 per cent 50 to 59 26.9 per cent 60 to 69 20.5 per cent and 70 to 79 12.8 per cent For the age distribution in the 605 cases of cancer see table 5. The smoking classifications of the control cases have been made proportional to the age distribution among the cases of cancer by multiplying the percentage value of each smoking classification for each age group of the controls by the proportion of cases of cancer in that age group For example in the age group 30 to 39 of the controls there were 146 18.7 per cent patients of whom 20 13.6 per cent were nonsmokers However since of the patients with cancer only 2.3 per cent fell into this age group the value of 13.6 per cent was made proportional to the age distribution in the cases of cancer 2.3 per cent In a similar manner the smoking values for the control group aged 40 to 49 were made proportional to 17.4 per cent Finally the quotients of the smoking classifications in each age group were added to make the percentage values shown in figure 3. The detailed data which compare the smoking classifications of the two groups according to age are shown in table 6 It was from those data that the proportional values were obtained TABLE Classification of Smoking Habits Group eee 2 3 5 ee Nonsmokers Less than 1 * more than 20 years cigaret per day for Light smokers From 1 to 9 cigarets per day * for more than 20 years Moderately heavy smokers From 10 to 15 * eigarets per day for more than 20 years Heavy smokers From 16 to 20 cigarets * day for more than 20 years per Excessive smokers From 21 to 34 cigarets per * day for more than 20 years Chain smokers 35 cigarets or more per day * for at least 20 years * Pipe and cigar smokers have been included by arbitrarily counting and 1 cigar as cigarets and 1 pipeful as 2cigarets Includes minimal smokers from 1 to 4 cigarets a day or the equivalent in pipes or cigars for more than 20 years The 100 cases of cancer and the 186 cases of control study I were made proportional in the same manner Control just cited physicians tionnaire Study II In addition to the control it was thought to be valuable to have carry out similar interviews using our It was thought that the results would study other ques- serve as an effective control for the cases collected under our own supervision At this time we are reporting preliminary results based on 83 patients interviewed at the Bellevue Hospital Columbia University Division New York by Dr. H. G. Turner ; at the Boston City Hospital by Dr. G. W. Ware at the Crile Veterans Hospital Cleveland Ohio by Dr. C. T. Surington and at the Veterans Administration Hospital Hines 111. by Dr. E. J. Shabart RESULTS The first data to be presented are based on 605 proved cases of bronchiogenic carcinoma in men other than adenocarcinoma Five hundred and ninety of these cases have been diagnosed on the basis of tissue biopsy out cancer Among these there is the following age 20. 21. pital Betty G. Proctor A.B. and Adele B. Croninger M.A. City Hospital Jewish Hospital and Veterans Administration Hos- 2222.. X 2.3 13.6 13.6 2.3 = 100 0.312 0.312 shown in figure 3 23. Of the service of 24. Of the service of This is the determined Dr. James B. Dr. John W. quotient which added to the others in the same manner makes the data Amberson Strieder 332 TOBACCO SMOKING AND CARCINOMA AND GRAHAM J. May 27 1950 9 on the basis of examination of sputum and 1 on the basis of study of the pleural fluid Comparison of Independent Studies the smoking habits of the 605 patients with cancer of the lungs are compared with those of the general hospital population it might be well to compare the results in the two control study III studies and the interviewed and group of 422 patients collected by one of us ~\ NONE LIGHT MODERATELY HEAVY HEAVY EXCESSIVE CHAIN Fig Control study I. Amount of smoking in percentage 100 male patients with cancer of the lungs solid bars patients with other chest diseases lined bars having the among and 186 male same and economic distribution age E. L. W. to determine any possible bias in cases in which the suspected diagnosis was known in advance and whether the data are sufficiently similar to warrant their discussion as a group mountain state series includes 13 patients of Mormon faith Mormons in general were found to smoke much less than our general hospital population Among the Mormon patients with cancer of the lung however there was only 1 nonsmoker 72 years old The others were time users of tobacco Comparing the three studies we note little difference For example nonsmokers account for 0.0 per cent in control study I 2.4 per cent in control study II and 1.4 per cent in study III The percentage of heavy to chain smokers in these three groups is 88 86.7 and 85.2 respectively while the percentage of excessive and respectively chain smokers totals 53 59 and 49 Since we thus have essential difference in three studies we shall not been able to determine any the amount of smoking in the from here on refer to the total results of 605 cases Age Distribution The age distribution of cancer of the lungs in the present series shows 2.3 per cent of the patients to be under 40 years of age while 79.3 per cent were 50 years or older table 5 This distribution readily shows that it would be of little value to study the smoking habits of the younger age groups for the Control Study I This group consists of 100 patients with cancer of the lungs and 186 with diseases of the chest other than cancer interviewed by two nonmedical investigators who had no previous knowledge of the diagnosis in a given case The data show no non- smokers fig 1 among the cancer group while there are 14.1 per cent nonsmokers among the patients with other thoracic diseases Ninety per cent of the patients with cancer are in the classification of moder- ately heavy to chain smokers and 53 per cent are excessive and chain smokers while among the patients without cancer 75.3 and 23 per cent respectively fell among these smoking groups Control Study 11 The data in table 3 cover 83 male patients with cancer of the lungs interviewed inde- Table Control Study II Amount of Smoking in 83 Cases of Proved Cancer of the Lung as Determined by Investigators Using the Same Questionnaire as that Used in the Cases of this Study : Cases . cce era aes Amount of Smoking None be ceeeeees Light Moderately heavy Heavy . Excessive cece ae Chain .. Bellevue Hospital Turner 22 1 2 2 & 8 8 Boston City Hospital Ware 18 , 0 # 2 5 6 - Crlle Veterans Hospital Suring ton 15 Hines Veterans Hospital Shabart 30 1 0 1 6 7 0 0 1 { i 6 H by pendently physicians in other cities Among each small group of cases some variation is of course to be expected In each of the individual groups nearly half or more of the patients are excessive or chain smokers Grouping the data of the four independent investigators together we find 2.4 per cent nonsmokers and 93.9 per cent moderately heavy to chain smokers ( fig 2 while | * Minimal smoker For definition Nee previous classification of smokers purpose of control studies since still unknown to us cancer of phenomenon in thein for the lungs is reasons a rare Combined Data on Amount of Smoking data on the amount of smoking among 605 patients with cancer of the lungs and 780 male patients with other diseases reflect the results of the individual studies reported It may also be noted that there is no essen- 2.4 37 tial difference in the amount of smoking between the NONE LIGHT MODERATELY -HEAVY EXCESSIVE CHAIN general hospital population and patients with diseases of the chest who do not have cancer The total results HEAVY : show that whereas there are 14.6 per cent nonsmokers Fig 2.Control cases of cancer of Chicago Dr. C. York and Dr. G. study II Percentages for amount the lungs collected independently by T. Surington Cleveland Dr. H. W. Ware Boston of smoking in 83 Dr. E. J. Shabart G. Turner New 59 per cent are excessive and chain smokers The results of the two control studies correspond closely to one another as well as to the results of study III table 4 The results in relation to the areas or hospitals where the cases were observed show uniformity Small differences between the groups may well be explained on the basis of the small size of each series The 25. Eight of these cases were diagnosed in Dr. Papanicolaou's laboratory on conclusive evidence of carcinoma One sputum and one pleural fluid examination were made at the Boston City Hospital among the male general population there are 1.3 per cent nonsmokers among the male patients with cancer of the ; lungs and while there are 54.7 per cent heavy to chain smokers and 19.1 per cent excessive and chain smokers among the general hospital group there are 86.4 and 51.2 per cent respectively among the patients with cancer All these differences seem highly significant The results on the amount of smoking according to age groups table 6 show that in general the patients with cancer of the lungs in their forties and early fifties have smoked more heavily than the older patients with this disease This observation does not seem to apply to the few patients in their thirties The age group 70 to 79 has greatest percentage of light and moderately heavy smokers Uwe NUMBER cere 4 AMPA Y wWatd Wrakaat at fae ae wae The frequency of nonsmokers in the age groups shown for the patients without cancer is significantly different from that among patients with cancer in the same age groups However in the 30 to 39 age group the smoking habits of the patient with cancer are difficult to evaluate since too few patients of this age have been seen TABLE Study III Amount of Smoking Among Male Patients With Cancer of the Lung in Relation to Area or Hospital Where Cases Were Observed Wynder Hospitals Areas or Hospitals Barnes 76 eee eens Los Angeles 50 San Francisco 50 Mountain states 50 St. Louis 25 eeenees Eastern and northern states 500 New York City 66 Memorial Hospital .... V 18.4 12.0 20.0 14.0 20.0 10.3 20.0 23.6 Total soe 18.2 Smoking Classification % IV 31.5 32.0 28.0 26.0 36.0 [ 43.4 12,0 30.0 38.0 32.0 11 5.3 12.0 14.0 18.0 12.0 I 0.0 0.0 2.0 4.01 0.0 Average Age 1.8 54.8 4.0 59.5 0.0 54.9 2.0 00.1 8 58.2 23.0 40.0 27.3 40.0 32.3 28.1 20.0 7.7 10.9 30.8 36.7 11.4 0.0 71886 0.0 71886 5.51 71886 1 71886 56.1 55.8 57.0 56.7 This * I and tuble does not include any cases represented in control studies , Includes 1 minimal smoker TABLE Age Distribution in 605 Cases of Cancer of the Lung in Men Control Study 1 Class O p is 0.0002 class plus class I p is 0.0002 classes 3 to 5 inclusive p is 0.0226 class 4 plus class 5 p is 0.0002 class 4 p is 0.0046 and class 5 p is 0.0016 Combined Results The values for the combined results of 605 patients with cancer of the lung as compared with 780 men in the general hospital population are as follows class O class O plus class 1 classes 3 to 5 inclusive class 4 plus class 5 class 4 and class 5 have p values which are in all cases less than 0.0001 Their conclusion is as follows On the basis of the statistical data for both the control study I and the combined results when the nonsmokers and the total of the high smoking classes of patients with lung cancer are compared with patients who have other diseases we can reject the null hypothesis that smoking has no effect on the induction of cancer of the lungs If smoking does not have anything to do with the induction of cancer of the lungs then the observed deviation could occur only with the probability p as shown above Miscellaneous Nearly all 98.7 per cent the cigaret smokers of the cancer group but fewer pipe 62.5 per cent and cigar 18 per cent smokers stated that they inhaled consciously Seventy and a half per cent of cancer patients interviewed stated that they usually began to smoke before breakfast Type of Tobacco Among the general hospital population pipes and cigars were smoked most prominently Age Groups Percentage of Cases 2.3 17,4 42.0 30.9 6.8 NONE LIGHT MODERATELY HEAVY HEAVY EXCESSIVE CHAIN TABLE Percentage Distribution of Amount of Smoking in Respect to Age Groups Among 780 Men in the General Hospital Population and 605 Men with Cancer of the Lungs* Age Groups An. 30-39 40-49 poy ty No. of Cases 146 14 164 105 50-59 00-69 70-79 petty ihe phn 210 259 160 187 100 41 Amount of smoking class ... ae 13.0 1 nan 2 wee 5.5 17.1 3 . 41.0 7.1 7.1 14.8 42.9 9.7 9.7 1.9 18.0 3.8 37.1 29.5 14.8 1.0 7.1 17.6 7.4 43.3 36.0 14.3 18.7 20.0 28.7 1.1 1.1 13.0 38.0 25.0 13.0 21.0 16.0 2.4 12.2 24.4 29.3 4 eens 14.8 5 8.2 28.6 0.0 14.0 10.3 28.6 36.2 10.5 6.7 31.1 19.4 10.6 6.8 30.5 15.5 15.0 10.0 17.1 14.0 * The percentages for the general male hospital population are given in the left hand columns In comparing the amount of smoking among the various age groups one must also consider the type of tobacco used which has undergone a marked shift particularly when the youngest and oldest age groups are considered Statistical Analysis of Data statistical analysis of these data has been carried out by Dr. Paul R. Rider professor of mathematics at Washington University and H. David Hartstein M.A. instructor of statistics ; at Washington University On the assumption that smoking has no effect on the induction of cancer of the lungs the probability p of a deviation from expectation as great or greater than that observed is as follows Fig 3.Percentages for amount of stoking among 605 male patients with cancer of the lungs solid bars and 780 men in the general hospital population without cancer lined bars with the same age and economic distribution in the older age groups For example only 4.3 per cent of the smokers in the age group 30 to 39 used chiefly pipes or cigars 11.0 per cent in the age group 40 to 49 12.9 per cent in the age group 50 to 59 30 per cent in the age group 60 to 69 and 38 per cent in the age group 70 to 79. Only those patients were tabulated as cither pipe or cigar smokers who smoked a given type of tobacco predominantly over the last twenty years of their smoking period Among the adjusted general hospital population we find 12.4 per cent pipe smokers and 7.8 per cent cigar smokers and among the patients with cancer 4.0 per cent and 3.5 per cent respectively fig 4 of pipe The average age of the pipe smokers with cancer of the hung was 60.5 with a range of 52 to 78 and the average age of the cigar smokers with cancer of the lung was 63.1 the range being from 53 to 76. The average number of pipes smoked by the cancer patients was 15.6 and the average number of cigars 6.8 per day for the last twenty years of their smoking history This amount of smoking is decidedly higher than that found among the general cigar and pipe smokers Duration of Smoking The duration of smoking in years dates to the first time the patient began smoking habitually to any degree Of 605 patients with cancer in our series 96.1 per cent had smoked for twenty years or more 85.4 per cent for thirty years or more 68.2 per cent for thirty years or more and 50.2 per 334 TOBACCO SMOKING AND CARCINOMA AND GRAHAM J. M. May 27 1950 cent for forty years or more One patient with epidermoid cancer began to smoke at 45 20 cigarets a day and clinical symptoms of cancer of the lungs developed at 50 class I smoker He had no other exposure to irritants Only three of the patients with bronchiogenic cancer began to smoke after the age of 25 fig 5 many years and that most of the heavy smokers are young women On the basis of our arbitrary smoking classification we found 79.6 per cent of the women to be nonsmokers while 11.3 per cent were moderately heavy to chain smokers and only 1.2 per cent of the controls in the cancer age 28 were excessive or chain smokers for at least twenty years fig 6 91.2 65.2 COMMENT COMMENT Universal Increase one feels that the greatly increased incidence of cancer of the lungs is real and that this increase is most marked in men one may theorize that the change has been due to an external factor or group of factors nationally prevalent but applicable to men more and over a longer period than to women 14.6 1.3 L 7.8 3.5 1LI2 4.0 NON SMOKERS CIGARS PIDES CIGARETS Fig 4. Smoking habits and type of tobacco smoked in percentages in 605 cases of cancer of the lungs solid bars and 780 men in the general hospital population lined bars with a similar age and economic distribution Adenocarcinoma in Men Among 39 20 men with adenocarcinoma there were 4 nonsmokers 10.3 per cent a percentage higher than that found for the other types of bronchiogenic carcinoma There were 7 chain smokers 18 per cent significantly more than in the general male hospital population Ten and tenths per cent were excessive 38.5 per cent heavy 15.4 per cent moderately heavy and 7.7 per cent light smokers Among the latter there were 2 minimal smokers Influence of Tobacco in a small percentage of cases cancer of the lungs occurs in nonsmokers and minimal smokers and since it obviously does not develop in every person who has been a heavy smoker for a long time it is apparent that smoking cannot be the only etiologic factor in the induction of the disease From the evidence presented however the temptation is strong to incriminate excessive smoking and in particular cigaret smoking over a long period as at least one important factor in the striking increase of bron- chiogenic carcinoma for the following reasons ( ) it Data on Women 27 27 27 Among 13 women with adeno- carcinoma and 2 designated as having terminal bron- chiolar carcinoma there was not 1 heavy smoker Thirteen were nonsmokers and 2 light smokers Among 25 patients with epidermoid and undifferentiated carci noma however there were 15 smokers of many years duration as well as 10 nonsmokers Among those who smoked there were 1 light 4 moderately heavy 6 heavy 2 excessive and 2 chain smokers ts 0.0 02 0.5 0 1.4 5.9 10 14 15 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 Fig 5. Percentages for duration of smoking in years starting with the time when the patient first began to smoke habitually in 605 cases of cancer of the lungs . To determine the smoking habits among women in the general hospital population 552 patients without cancer of the lung have been interviewed at this hospital The data resulting from this study show that but few women in the cancer age have been heavy smokers for LIGHT MODERATELY HEAVY HEAVY EXCESSIVE CHAIN Fig 6.Amount of smoking in percentage among 780 male patients vertically lined bars and 552 female patients horizontally lined bars of the general hospital population with the same age and economic distribution as found among cases of cancer of the lungs is rare to find a case of epidermoid or undifferentiated carcinoma in a male patient who has not been at least a moderately heavy smoker for many years 2 the use of cigarets is much greater among patients with cancer of the lungs than among other patients of the same age and economic groups 3 the sex distribution of cancer of the lungs roughly corresponds to the ratio of term smoking habits of the two sexes see section on Duration of Smoking 4 the enormous increase in the sale of cigarets in this country approximately parallels the increase of bronchiogenic carci- noma." Amount of Smoking data have clearly shown that the average patient with cancer of the lungs smokes much more heavily than the average patient of the same age and economic group with some other disease This contrast becomes even greater if our observation of Mormons is considered who as a group smoke far less than the general hospital population Mormons with cancer of the lung were with one exception con- siderable smokers 26. Includes Turner 27. Includes Ware 3 cases : 4 cases of Dr. of Dr. C. T. Surington and 1 case of Dr. H. G. H. G. Turner and 3 cases of Dr. G. W. 28. See table 5 29. It is taken would mean little commodities for granted of course that by itself since similar curves could be drawn such parallelism for many other VOLUME 143 NUMBER 4 TOBACCO SMOKING AND CARLINOMA AND UKANAM , The fact that patients with bronchiogenic cancer in their forties and fifties had smoked more heavily than Lag Period If smoking is to be regarded as an important etiologic factor in the development of cancer those in whom the cancer developed at a later age may of the lungs apparently a time lag exists for this dis- indicate that the greater the irritation the sooner will ease as well as for carcinoma of the bladder known to cancer develop in a susceptible person Such an obser- occur years after cessation of exposure to aniline We vation obviously does not apply to the individual case have now seen 3 cases in which clinical signs of cancer but rather to the age groups taken collectively Too of the lung appeared ten years or more after the patient few patients below the age of 40 have been seen in order to evaluate this age group stopped smoking The 3 patients had smoked for thirty years or more and none gave a history of occupational In general it appears that the less a person smokes the less are the chances of cancer of the lung developing or other irritative exposures Two of them had stopped smoking because of a bothersome chronic cough and and conversely the more heavily a person smokes the greater are his chances of becoming affected with this clisease 1 because of concomitant heart disease In 1 of the patients a 67 year old warehouse clerk clinical symptoms of cancer developed thirteen years after the cessa- Type of Tobacco majority of patients with cancer of the lungs are cigaret sinokers rather than pipe or cigar smokers ratio being over and above that found in the general population This fact may be due to one of the following reasons tion of smoking The phenomenon of the lag period is of course well known in cancer research Adenocarcinoma in Since the great increase in cancer of the lungs has mostly involved the epidermoid and undifferentiated carcinomas it would 1. Cigaret smokies more frequently inhaled than is that of either pipes or cigars Obviously the lungs of an inhaler are exposed to a greater concentration of smoke than those of a person who does not consciously inhale appear that the exogenous factors possibly affecting these types of cancer play a lesser role if any in the induction of adenocarcinomas of the lung in men As yet we have not seen a sufficient number of cases of this type of cancer to warrant definitive conclusions It 2. Because of the greater physical and economic con- appears however that on the basis of present data one venience more persons are heavy smokers of cigarets is more likely to find nonsmokers or minimal smokers than of either pipes or cigars Among the latter one with this type of cancer than with the other types finds more minimal and light smokers than among the At the same time however the percentage of chain ig former smokers among men with adenocarcinomas of the lung 3. Certain irritative substances may be present in cigarets in greater amounts than in pipes or cigars The role of paper the use of insecticides during the growth of the tobacco and other ingredients warrant further research in this regard Duration of Smoking of the chief reasons many investigators have thought that tobacco has no effect on the development of cancer of the lungs has been their belief that women today smoke as much as men and that if tobacco plays a role the sex ratio of the disease should be about equal The data presented demonstrate that it makes little difference how many women smoke today or have smoked for the past ten years since results have shown that over 96 per cent of patients with cancer of the lungs have smoked for more than twenty years and that over 80 per cent have smoked for more than thirty years It is of course difficult to tell whether the impor- tant point in this regard is the fact that these persons have smoked for many years or that they have been heavy smokers for a brief period because we have noted that also among the general male hospital population nearly all smokers have been smoking since their youth For this reason it is difficult to evaluate the one case in our study in which the patient smoked only from his forty to his fiftieth year at which time clinical signs of cancer developed If one may judge from control data on women it would appear that a long duration of smoking is at least one important factor in the induction of cancer of the lungs The relatively low incidence of the condition in women might be explained by the fact that few women in the cancer age have smoked for an extensive period On the basis of a twenty year period of smoking it may be of interest to note that while only 1.2 per cent of the women were excessive or chain smokers by is greater than among the general hospital population It seems therefore that tobacco smoke has also some influence on the induction of adenocarcinoma in men even though as judged from the incidence the influence on this type is much less marked than on the other types of bronchiogenic carcinoma Cancer of the Lungs in Women observers have commented on the fact that bronchiogenic carci- noma while on the increase among both men and women is increasing more rapidly among men In 100 consecutive cases collected by 30 Lindskog in 1938 to 1943 the ratio was 4.5 to 1 and in another series collected in 1947 and 1948 the ratio had reached 24 to 1. At Barnes Hospital the ratio in our last 150 cases has been 18.5 to 1. This shift in ratio has been noted in varying proportions throughout the country a radical change warrants a careful analysis Such The insufficient number of cases of cancer of the lungs in women in our survey does not allow definite conclusions at this time So far however smoking seems to have had no apparent effect on the incidence of adenocarcinoma in women It is of great interest that we have observed 10 cases of epidermoid and undifferentiated carcinoma of the lungs of women who were nonsmokers with no history of occupational or other irritative exposure This percentage of non- smokers in women with cancer of the lung is much higher than that found among men Proper explanations for this finding remains to be advanced At the same time it appears strongly suggestive that heavy smoking plays a significant role in the induction of epidermoid and undifferentiated carcinoma of the lungs in women since the percentage of heavy smokers is considerably higher in the cancer group than in the general hospital control group contrast 19.1 per cent of the male controls were in those _ smoking groups a ratio which points in the same direction as the sex ratio of lung cancer 30. Lindskog G. .: Bronchiogenic 674 Oct. 1946 31. Lindskog G. F. and Bloomer Cancer 1 234-237 July 1948 Carcinoma Ann Surg W. .: Bronchiogenic 124 667Carcinoma 336 CANCER AND TOBACCO CONCLUSION AND SUMMARY 1. Excessive and prolonged use of tobacco cigarets seems to be an important factor in especially the tion of bronchiogenic carcinoma induc- SMOKING ET AL CANCER AND TOBACCO A Preliminary Report May M. 1950 SMOKING 2. Among 605 men with other than bronchiogenic carcinoma adenocarcinoma 96.5 per cent were moder- ately heavy to chain smokers for with 73.7 many years compared per cent population without among the general male hospital 51.2 cancer Among the cancer group per pared to cent 19.1 were excessive or per cent in the chain smokers com- without cancer general hospital group 3. The occurrence of carcinoma of the lung in a male nonsmoker or minimal smoker is a 2.0 per cent rare phenomenon 4. Tobacco seems at this time to play a similar but somewhat less evident role in the induction of dermoid and epi- undifferentiated carcinoma in women Among this group a greater percentage of nonsmokers will be found than among the men with 10 of 25 being nonsmokers 5. Ninety and tenth cancer of the lungs who had a pheirstcoernyt ooff psamtoikenitnsg whiatdh smoked for over twenty years Few women have smoked for such a length of time and this is to be one of the reasons for the believed the disease greater incidence of among men today MORTON L. LEVIN HYMAN GOLDSTEIN . and PAUL R. GERHARDT Albany Y. M.D. M.D. M.D. The published literature on use of tobacco and possible association with human its clearcut consistent cancer fails to show ture for the observations Reviews of the litera- past twenty years reveals that it is often conflicting and that it consists for the most studies which are inconclusive because of part lack of quate samples lack of random of ade- controls or failure to selection lack of proper and standardize the data Potter Tully have reported a higher proportion of smokers in patients with cancer of the buccal and respiratory tract among males over cavity the 40 who were seen at Massachusetts age of Since 1938 a cancer clinics history of tobacco usage has been obtained routinely from all patients admitted to Roswell Park Memorial Institute Buffalo the These his- 915 os 43.D Abs Abs Abs 6. There may be a lag period of ten between the cessation of years or more smoking tobacco and the occur- rence of clinical symptoms of cancer me f PERCENTAGE PERCENTAGE PERCENTAGE PERCENTAGE 0.0 PERCENTAGE PERCENTAGE 7. Ninety and tenth per cent of male patients with cancer of the lungs were found to be cigaret smokers 4.0 per cent pipe smokers and 3.5 33.9 fl SHOKERS SHOKERS 11.0 SHOKERS SHOKERS *, . . i Lt . cent cigar smokers is greater than per This prevalence of cigaret smok- ing lation of the among the general hospital popu- inhalation same age group The greater practice of among cigaret smokers is believed to be factor in the increased incidence of the disease a 8. The influence of tobacco on the development of adenocarcinoma seems much less than on the other types of bronchiogenic carcinoma 20 . PIPES ree.. ce 4. PARTS ae * ane @ ae i \ L 1! os 25-21 35-49 534 55-64 73-81 AGE IN YEARS i 4 83-76 - ON ADMISSION Percentage of patients who had ever smoked by type of smoking 9. Three independent studies have resulted in so uniform that one may deduce the data from each of them same conclusions ADDENDUM on Since the data presented in this 45 additional interviews of male paper were tabulated moid or undifferentiated patients with epider- cancer of the lung have been obtained Eight of these patients have been interviewed by Dr. J. L. Ehrenhaft from the University of Iowa Hospital 9 were given our questionnaire by Lt. Col. J. M. Salyer from Fitzsimons General Hospital and 7 were reported on by Dr. E. J. Shabart from the Vet- erans Administration Hospital Hines Ill these 24 cases there Among smokers 7 heavy were no nonsmokers or light smokers 13 excessive smokers and 4 chain smokers TwentyTwenty additional been interviewed by Miss patients have Croninger the Barnes Hospital Chest Service Among these there were 1 nonsmoker a 72 year old blacksmith 10 heavy sThmeoskeer4s5 6caesxecsesswihviechsmionkcelrudse and 4 chain smokers made at two additional reports independently centers University of Iowa and Fitzsimons General Hospital show the noted in the larger series same trend tories are part of the regular clinical history and taken before the final diagnosis has been are This procedure is considered established the especially important from standpoint of excluding bias Approximately half the patients admitted to the institute found not to have cancer Special attenatrieon swuibtshequently to the history of smoking has not been respect group of conditions so that these paid to any single sumed to be free from bias whichremciorgdhst mraesyulbte fprroem- preconceived ideas as to relation between a particular form of cancer smoking and The histories record the date smoking began dura- tion type of smoking and amount per day The relia- bility of the quantitative aspects aspects of by a history is of course highly variablesmoIkt iinsgproebstauimneedd however that such errors are not selective with to presence or absence of respect patients suspected by cancer especially their physicians of since only are admitted to the Institute having cancer With technical assistance of Elizabeth From the Bureau of Cancer Control Brezee and Division of David Robbins York State Department of IIealth Medical Services New New Dr. Louis C. Kress Dr. Joseph G. Hoffman Ralston of the staff of the Roswell Park and Miss Olive C. by making available the records of the Memorial Institute assisted gestions as to the planning of the study institute and by making sug 1. Potter Cancer E. A. and Tully M. R The Statistical Problem in Massachusetts Am J. Pub Health Approach 35 to the 485-490 1945 NUMBER 143 CANCER AND TOBACCO SM"NINGAAN dad nee This report is based on a study of 1,045 male cancer patients and male noncancer patients The cancer sites selected were lung lip pharynx esophagus colon rectum and a scattered number of other sites The noncancer patients were those with symptoms referable to the same sites but which proved not to be due to cancer Only the users of cigarets pipes and cigars are considered here since the number of patients who used snuff or chewing tobacco was negligible Smokers engaging in more than one form of smoking entered into separate analysis for each such form so that the sum of smokers is less than the sum of smokers of each The factor studied was whether or not the type patient had ever smoked regardless of whether he was a simoker at the time of admission + Over 80 per cent of all patients were smokers table ) Prevalence of smokers regardless of type did not vary strikingly with age past the age of 25 see the accompanying figure Prevalence of cigaret smokers however decreased with age and that of pipe smokers and cigar smokers increased with age Obviously comparison of groups with differing age composi- tion would show different proportions of cigaret pipe of and cigar smokers because this factor alone Accord- ingly comparisons should be made of specific prevalence rates or of prevalence rates standardized for age TABLE Prevalence of Smokers Among Male Cancer and Noncancer Patients by Type of Smoking No. Cases Percentage of - All Types Clgarets Smokers Pipes ... Cigars Cigars In tables 4 and 5 the data are presented to show the among relative prevalence of lung and lip cancer non- smokers and among cigar^'t pipe and cigar smokers in the patient population There were more than twice as many cases of lung cancer among cigaret smokers as among any other group Pipe smokers and cigar Table Prevalence of Smokers Among Male Patients by Type of Smoking and Diagnostic Group * Percentage of Smokers A : Any Type f No. of pe Diagnosis Lung cancer compared Cases 236 % F 84.7 with- Other cancer except lip 065 Lung nontumors 124 Other noncancer 481 82.9 21.1 78.3 0.58 0.30 0,06 Cigaret 2 ee % P 66.1 P 48.0 58.1 44.1 0.01 0.02 0.01 Pipes 3 oe % P 13.5 1... Cigars 4 ee % P 11.2 a. 0.01 0.09 0.01 = 20.3 13.1 0.01 0.64 22.7 Lip cancer compared with Other cancer except lung ees br eeeeneeace Lip nontumors ee Other noncancer 148 466 $ 554 84.5 2... 82.9 74.0 78.1 0.58 0.09 0.23 45.5 48.0 48.0 46.4 0.48 0.78 0.81 23.8 30.7 28.8 0.01 0.0 0.0 26.5 20.3 34,9 19.6 0.11 0.22 0.08 * Age standardized smokers had no more cancer of the lung than did non- smokers Lip cancer was significantly increased among pipe smokers but not among cigaret smokers Cases of lip cancer were increased also among cigar smokers In table 4 persons who smoked more than one type of tobacco are counted in each category In table 5 only those who smoked but one type of tobacco are con- sidered The observations in table 4 with respect to Cancer . ance eeee Noncancer oe reece eee P cccceeerecene feeaee 1,045 005 saeet 84.8 77.8 0.01 56.0 46.0 0.01 80.9 24.9 0.01 22.4 20.8 0.17 cancer are the same as in table 5 i e only cigaret smokers show any significant increase of lung cancer over nonsmokers For lip cancer only pipe smokers * Age standardized P denotes probability here and in tables 2 and 3 show a significant increase over nonsmokers No other site of cancer that was included in this by applying the specific rates to a standard population The latter device was adopted using the entire study was found to be associated with any particular type of smoking However not all sites of cancer were series of 1,650 patients as the standard population The significant observations are summarized in tables 1 2 3 4 and 5. There were more smokers among cancer patients than noncancer patients because of an excess of cigaret and pipe smokers among the former table ) This excess was due entirely to the increased percentage of cigaret smokers among patients with cancer of the lung and the increased percentage of pipe smokers among patients with cancer of the lip table 2 These differences in turn were confined to those who had smoked cigarets or pipes for iwenty years or longer table ) It should be noted that the prevalence rates of smok- ers in columns 2 and 4 of table 3 are standardized rates obtained by applying the specific rates for each subgroup to the age distribution of the total group of 1,650 male patients Since length of smoking is related to age this statistical procedure was necessary to exclude the possibility that the greater percentage of 25 years or more smokers in the cancer groups was due solely to the greater proportion of older persons in these groups The failure to find comparable differences in smokers of less than twenty years duration may be due to the relatively small percentage of such smokers which may be expected in an older population Further study of large numbers of younger patients may alter this observation TABLE Prevalence of Cigaret and Pipe Smokers Male Patients by Duration of Smoking and Diagnostic Group Among Duration of Smoking Under 25 Yr Diagnosis ee _, No. 1 2 Cases No. %% P Cigaret Smokers Lung cancer compared withOther cancer except lung and and lip Lung nontumors , eer ec eee eee Other noneanc^r 6. eee ee eee eee 236 124 481 11.7 74 13.0 0.62 19 10.3 0.23 82 0.31 Pipe Smokers Lip cancer compared with Other cancer except lung and lip Lip nontumors ... ee. e ree Other noncancer es 6... peereenees 143 066 $ 554 8 7.8 oe 26 3.9 0.02 5 10.6 0.35 35 5.8 0.24 = #fiYr and K. = Over ~ 8 4 No. * PF 148 233 54.1 0 24.9 36,9 128 29.8 ..- 0.01 0.01 0.01 00 162 11 87 35.7 22.0 21,6 17.9 wee 0.01 0.04 0.01 * Age standardized studied It is planned to continue analysis of the records of the Roswell Park Memorial Institute to pro- vide data regarding all types of malignant tumors These data indicate that in a hospital population cancer of the lung occurs more than twice as frequently those who have smoked cigarets for twenty ayemaornsg than among other smokers or nonsmokers of comparable age Pipe smokers apparently experience 338 RHEUMATOID ARTHRITIS ET AL an almost equal increase in the incidence of lip cancer compared with other smokers or nonsmokers It is somewhat surprising to find that the type of smoking i e cigarets for lung cancer pipe for lip cancer is the associated factor rather than the actual use of tobacco The data suggest although they do not establish a causal relation between cigaret and pipe smoking and cancer of the lung and lip respectively The statistical association may of course be due to some other unidentified common factor between these types of smoking and lung and lip cancer Cancer is now erally considered a disease attributable to multgiepnl-e causative factors Among these are irritants The _ generalization has been advanced 2 that although not all irritants are carcinogenic all carcinogens are irri- TABLE Comparison of the Proportion of Cases of Lung Lip Cancer Among Among Male Nonsmokers and Smokers of 25 Years Duration or More at Roswell Park Memorial Institute Institute 1938-1948 and No. of Persons Nonsmokers compared with Cigaret Smokers Pipe smokers .... sea 203 600 353 Cigar smokery ........ 263 Lung Cancer a A. Cases Rates 23 8.6 1 48 20.7 8.0 22 8,5 Pt Pt 0.01 1.00 0.97 Lip Cancer a Cases Rate Pt 20 6.9 37 0.55 60 0.01 39 0.03 * Standardized for age against age distribution of Probability of the observed difference between smokers occurring by chance alone T Multiple smokers e g persons smoking robaceo plus those smoking only one type more total males sunokers and non- than one type of . Table Comparison of the Proportion * of Cases of Lung Lip Cancer Among Male Nonsmokers and Smokers of 25 Years Duration or More at Roswell Park Memorial Institute 1938-1948 and Lung Cancer No. of -~ T - r Pt Persons Cases Rate Pt Nonsmokers compared with All smokers .... 293 761 23 148 8.6 17.1 OL, 0.01 Cigaret smokers 1 479 105 20.9 0.01 Pipe smokers .. cere 160 19 10.6 0.48 Cigar smokers 110 04 12.8 0.18 Lip Cancer _ ey Cases Rate Pt 20 6.9 73 8.9 0.29 22 5.1 0.29 84 15,7 0.01 17 11.6 0.13 * Standardized for age against age distribution of total males Probability of the observed difference between smokers and smokers occurring by chance alone non- EPINEPHRINE PREGNENOLONE AND TESTOS- TERONE IN THE TREATMENT OF RHEUMATOID ARTHRITIS C. MAYNARD GUEST M.D. Albany N. Y. WILLIAM H. KAMMERER M.D. RUSSELL L. CECIL M.D. and SOLOMON A. BERSON New York M.D. Reports of the effectiveness of cortisone Kendall's compound E or dehydrocorticoste- rone and of pituitary adrenocorticotropic hormone ACTH in the treatment of rheumatoid arthritis and spondylitis ' have given rise to the hope that substances known to stimulate endogenous production or libera- tion of pituitary adrenocorticotropic hormone might also that be effective in these conditions Vogt demonstrated in several different species of animals that the amount of active cortical material released into the vein in one minute is many times that suprarenal which can be extracted from both adrenal cortices by present meth- of ods The administration epinephrine was found increase the amount of cortical material which to could be recovered from suprarenal venous blood by several hundred per cent. Her results suggested that nephrine administered in doses epi- that might be liberated approaching the amounts normally within the body stimu- lates the adrenal cortex directly 4 Long concluded that the action of epinephrine on the adrenal cortex is indirect and is dependent on the presence of the 5 anterior pituitary gland Thorhn as emphasized the fact that epinephrine is effective in stimulating the pituitary system in man He and his collabo- rators showed that epinephrine increases oxy- steroid and ketosteroid excretion and lowers the total circulating eosinophil count by 50 per cent or more in normal subjects but not in those with pituitary 7 or adrenocortical insufficiency Almy and Laragh con- firmed the observation that epinephrine consistently produces eosinopenia in normal persons Thorn gested using 0.5 mg of epinephrine sug- subcutaneously every six hours in patients with rheumatoid arthritis and referred to improvement which he had obtained in Persons smoking only one type of tobacco tants that is capable of inducing chronic reparative hyperplasia Berenblum za has shown also that an irri- tant croton resin basic tar fraction which is noncarcinogenic alone may nevertheless increase the percentage of tumors produced when its action is combined with that of a carcinogen Thus some experimental basis exists for explaining the apparent effect of cigaret and pipe smoking although the true nature of the association with lung and lip cancer remains to be determined 2. a Berenblum .: Irritation and 233-244 Oct. 1944. Carcinogenesis Arch Path 38 b Pullinger B. .: First of Some Polycyclic Hydrocarbons J. Path & Effect on Mouse Skin Bact 50 463.471 1940 Medical Service From the of the Veterans the Arthritis Clinic New York Hospital and Administration the Hospital cine of Cornell University Medical College New Department of York and Bronx Medi N. Y. Reviewed in the Veterans Administration and published with approval of the Chief Medical Director published the The statements and conclusions by the authors are a result of their own studies and do necessarily reflect 1. Hench P. the opinion or policy of the Veterans not Administration The Effect of .; Kendall E. .; Slocumb C. H. and Polley H. .: Hydroxy Dehydrocorticosterone Adrenal Cortex Compound E and of tropic Hormone on Rheumatoid Arthritis Pituitary Adrenocortico Staff Meet Mayo Clin 24 181 1949 Preliminary Report Proc 2. Vogt M The Output of Cortical Hormone by the Mammalian Suprarenal J. Physiol of the Secretion of 102 341 1943 Some Aspects of the Physiology Medicine Exper Medth&e SAudrregna5 l 2C7or9te1x94w7ith a Bearing on Clinical 3. Vogt M Observations on Some : Conditions Affecting of Hormone Output by the Suprarenal Cortex J. Physiol 103 the Rate 4. Long G. N. H Recent Studies on the Function of 317 1944 Cortex Bull New York Acad Med 23 260 1947 the Adrenal 5. Thorn G. W . The Diagnosis and Treatment of Adrenal Insufici- ency Springfield Ill Chas C Thomas Publisher 1949 Insufici- 6. Thorn G. W Hill S. .; Smith Bayles T. B Massell B. .; Forsham P. .; S. and Warren J. .: Studies on the Relation of P2i4t1u5i29ta1r94y9 Function to Rheumatic Disease New England J. Med Chapter Safeguarding the Profession physician should aid in safeguarding the profession against admission to it of those who are deficient in moral character or education 3 III of the PRINCIPLES OF MEDICAL ETHICS of the American Medical Association 7. Almy T. P. and Laragh J. .: phils Reduction in Circulating Circulating Eosino Eosino Following Epinephrin Insulin and Surgical Operations Am J. Med 507 1949 Dehydrocorticosterone 8. Thorn G. W. In discussion Slocumb C. H. and Polley H. F Dehydrocrticosterone Cortex 17 on Hench P. .; Kendall E. C C Effect of a Hormone of the Adrenal Pituitary Adrenocorticotropic Hormonoen Compound Rheumatoid E and of the before the Second Annual Meeting of the Arthritis read Asociation Association of American Physicians Atlantic City N. J. May 3 1949 :