American Journal of Epidemiology Copyright © 1991 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved

Vol. 134, No 12 Panted in U S.A.

LETTERS TO THE EDITOR RE: "WHEN GENIUS ERRS: R. A. FISHER AND THE LUNG CANCER CONTROVERSY" The commentary by Paul D. Stolley on R. A. Fisher's role in the cigarette smoking and lung cancer controversy of the late 1950s and early 1960s (1) evoked many memories of those who were active participants in the discussions of this issue in those days. By then, corroborative support for the initial case-control studies of 1950 (2-4) was at hand, the first prospective studies on British physicians had been published by Doll and Hill (5, 6), skin cancer had been produced with cigarette tars in mice and in rabbits (7, 8), and established tumorigenic compounds had been identified in cigarette smoke (9). Nevertheless, the views of Fisher as well as Berkson were attentively pursued by commercial interests and by smokers who sought a reprieve from guilt feelings regarding the possible consequences of tobacco use. Moreover, professionals in medicine and in the sciences were relatively apathetic to the smoking and health issue at that time. Initially, we were hesitant in using the word "cause" when describing the association of cigarette smoking and lung cancer. In 1950, Dr. Evarts Graham and I referred to tobacco smoke as "playing an important role in the etiology of bronchiogenic carcinoma" (2). It was not until 1954 that I delineated this causal relation in a paper entitled "Tobacco as a Cause of Lung Cancer" (10). In a 1959 review article in the Journal ofthe National Cancer Institute, Cornfield, Haenszel, Hammond, Lilienfeld, Shimkin, and I addressed all of the issues that had then been raised about the causal association of cigarette smoking and lung cancer (11). Yet, the debate persisted. In 1961, the New England Journal of Medicine published a discourse between myself and Clarence Cook Little, Scientific Director of the Tobacco Industry's Research Committee, and took an equivocal stand in an accompanying editorial entitled "The Great Debate" (12-14). While leaning toward the conclusion of my presentation, the editorial nevertheless stated: "It is enough to say that most of the evidence is statistical and demonstrates a close association between heavy cigarette smoking and lung cancer. However, it is generally believed that statistics in the hands of a master can be made to prove almost anything." The editorial concluded: "Each individual must choose his own course, whether to woo the lady nicotine or abjure the filthy weed, while the search for truth continues." Clearly, in the 1950s great caution was exer-

cised in respect to establishing the causative association of cigarette smoking and lung cancer, and the validity of the reports on a causal relation that had been published in this decade, was generally not acknowledged until the mid-1960s through the impact of the Report on "Smoking and Health" of the Royal College of Physicians in England in 1962 (15), and the first US Surgeon General's Report on Smoking and Health in 1964 (16). One issue that received much attention from Fisher (17) and others (3) was the fact that the initial study by Doll and Hill (4) appeared to show a negative correlation between inhalation of tobacco smoke and lung cancer. There was then, as there is now, reluctance to recognize one of the key problems of retrospective studies, the bias of cancer patients in responding to questions about life-style habits that have possibly contributed to their illness. It is likely that the individual with an established lung disease will respond very differently to a question on smoking habits, and specifically on inhalation of the smoke, than will a healthy person in the control group. This same bias is likely to occur when questions on sexual behavior are asked of a patient with cervical cancer, or questions on exposure to sunlight are to be answered by a patient with melanoma, or when the matter of caloric intake is raised with an obese person. As epidemiologists, we need to be aware of a "wish bias" that can influence patient responses and thus compromise the validity of our conclusions (18). Quite apart from the issue of bias, it has been confirmed time and time again that there is a dose-response relation between smoking and lung cancer and that the degree of inhalation does significantly increase the relative risk for lung cancer mortality of a smoker (19). Hospital-based, case-control studies were criticized then, as they are still today, but it should be recognized that such studies are at the very core of epidemiologic knowledge and that their findings can be conclusive if such issues as case/ control selection, biases, subgroup analyses, and confounders are carefully considered. Whenever this was the case, conclusions of case-control studies have withstood the scrutiny of peer review and have, in due time, been confirmed by other epidemiologic techniques. In the early 1950s, the interviews were usually conducted by the investigators themselves. I for one travelled from coast to coast in 1949 to

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interview hundreds of lung cancer patients and controls, an exercise that caused Lester Breslow first to think of irreconcilable biases (L. Breslow, personal communication, 1950). However, one advantage of this experience is that the investigator gets an intimate understanding of the way patients reply to the questions. Today, many epidemiologists deal with outcome data presented on a computer print-out; they do not conduct their own interviews, and therefore, do not develop a sensitivity to identifiable biased responses. In reaching conclusions on causality then and now, an epidemiologist must sort out the various pieces of evidence and determine what does and does not fit, and why. We then need to consider the criteria of judgement so succinctly stated in the US Surgeon General's report on "Smoking and Health" in 1964 (16). Unfortunately, these requirements are often overlooked today, even when investigators are dealing with weak associations. Clinical alertness can often provide unusual leads. Evarts Graham used to tell us that, in the early 1930s, when a lung cancer case was admitted to Barnes Hospital in St. Louis, the surgical residents would be called in to see this unusual case, a practice we may do today for lung cancer cases among nonsmokers. What ultimately made the association between smoking and lung cancer so abundantly clear was its sheer magnitude, and the fact that all of the epidemiologic, biologic, and biochemical information fit the criteria for causality. Epidemiology, as medicine itself, is an art as well as a science. The better our training, the better the scientific base on which we act, and the more likely will we accurately interpret scientific data whether they relate to the diagnosis, or the etiology of disease. Sound judgement is particularly necessary as we evaluate the large number of weak associations that are now being observed in epidemiology, and we need to weigh the issues carefully before drawing any conclusions as to causality. Reflecting on the past, on memories so vividly brought back by Dr. Stolley's article (1), I am reminded of the many obstacles that existed in the early years of the tobacco and lung cancer issue. Some of Fisher's views on host factors that contribute to lung cancer may well be addressed in future studies in molecular biology because they are scientifically intriguing and likely to contain a clue in regard to the mechanism of cancer induction. However, with respect to the relation between cigarette smoking and lung cancer, we now state with certainty that Fisher erred; more importantly, we know that scientific truth prevailed, and this has given us the opportunity for intervention. Clearly, in the absence of cigarette smoking, lung cancer mortality will be significantly reduced.

As more and more adults have stopped smoking, lung cancer rates have begun to decline in the younger age groups, as we predicted according to Koch's postulates (20). The chain of evidence for causality has thus been closed. REFERENCES

1. Stolley PD. When genius errs: R. A. Fisher and the lung cancer controversy. Am J Epidemiol 1991; 133:416-25. 2. Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma. JAMA 1950; 143:329-36. Republished as a "Landmark Article." JAMA 1985,253:2986-94. 3. Levin ML, Goldstein H, Gerhardt PR. Cancer and tobacco smoking. A preliminary report. JAMA 1950; 143:336-8. 4. Doll R, Hill AB. Smoking and carcinoma of the lung. Preliminary report. BMJ 1950;2:739-48. 5. Doll R, Hill AB. The mortality of doctors in relation to their smoking habits. A preliminary report. BMJ 1954;l:1451-5. 6. Doll R, Hill AB. Lung cancer and other causes of death in relation to smoking. A second report on the mortality of British doctors. BMJ 1956;2:1071 81. 7. Wynder EL, Graham EA, Croninger AB. Experimental production of carcinoma with cigarette tar. Cancer Res 1953; 13:855-64. 8. Graham EA, Croninger AB, Wynder EL. Experimental production of carcinoma with cigarette tar. IV. Successful experiments with rabbits. Cancer Res 1957;17:1058-66. 9. Wynder EL, Hoffmann D. A study of tobacco hydrocarbons. Cancer 1959; 12:1079-86. 10. Wynder EL. Tobacco as a cause of lung cancer. Pennsylvania Med J 1954;57:1073-83. 11. Cornfield J, Haenszel W, Hammond EC, et al. Smoking and lung cancer: recent evidence and a discussion of some questions. J Natl Cancer Inst 1959;22:173-203. 12. Little CC. Some phases of the problem of smoking and lung cancer. N Engl J Med 1961 ;264:1241-5. 13. Wynder EL. An appraisal of the smoking-lung cancer issue. N Engl J Med 1961;264:1235-40. 14. New England Journal of Medicine. Editorial "The Great Debate." N Engl J Med 1961;264:1234. 15. Royal College of Physicians. Smoking and health. London: Pitman Medical, 1962. 16. US Dept. of Health, Education and Welfare. Smoking and health. A report of the Advisory Committee to the Surgeon General of the US Public Health Service. Washington, DC: USGPO, 1964. (PHS publication no. 1103). 17. Fisher RA. Smoking—the cancer controversy: some attempts to assess the evidence. Edinburgh: Oliver and Boyd, 1959. 18. Wynder EL, Higgins IT, Harris RE. The wish bias. J Clin Epidemiol 1990;43:619-21. 19. National Cancer Institute. Changes in knowledge of the health consequences of smoking. 25th anniversary report on the health consequences of smoking. US Public Health Service, CDC Office on Smoking and Health. Washington, DC: USGPO, 1989. (DHHS publication no. (CDC) 89-8411). 20. Brock TD. Robert Koch: a life in medicine

Letters to the Editor and bacteriology. New York: Springer-Verlag, 1988:180.

Ernst L. Wynder American Health Foundation New York, NY 10017

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Editor's note: In accordance with Journal policy, Dr. Stolley was asked if he wished to respond to the above letter but chose not to do so.

RE: "A PROSPECTIVE POPULATION-BASED STUDY OF ALCOHOL USE AND NONINSULIN-DEPENDENT DIABETES MELLITUS" We would like to comment on the recent article by Holbrook et al. (1). Their principal result was that alcohol appeared to be associated with the risk of non-insulin-dependent diabetes mellitus in men, but not in women. Further confirmation of the relation in men comes from the Paris Prospective Study, where a positive relation was demonstrated between the results from a clinical examination of the liver (a surrogate for alcohol consumption which was not available) and the incidence of diabetes (2). In comparison to subjects with a normal liver, the relative risk of diabetes in subjects with an abnormal liver was 1.3, and for a very abnormal liver, 2.5. A second study showed that the relative risk of diabetic men dying from cirrhosis was 14 (95 percent confidence interval (CI) 5.7-33), in comparison with subjects who had normal glucose tolerance (3). Diabetes was defined in these studies on the basis of either a prior clinical diagnosis of diabetes or elevated fasting or 2-hour glucose levels following an oral glucose tolerance test; known diabetics were not separated from those screened diabetic. In the Paris Prospective Study, a more detailed analysis (4) revealed that the increased risk of death from cirrhosis was mainly associated with subjects who had been screened as diabetic on the basis of elevated fasting or 2-hour glucose levels, with relative risks found of 21 (95 percent CI 9.1-49) in screened subjects and 3.1 (95 percent CI 0.41-? 4) in subjects known, clinically, to be diabetic. Yhe consumption of alcohol was included in a dietary study of a sample of 500 men in the Paris Prospective Study. For the 446 men who were not known to be diabetic, the average daily consumption was high in comparison with other studies, 49 g/day (range, 0-210 g/ day); there were 20 teetotallers. While the median glucose concentrations of these men remained fairly stable with increasing alcohol concentrations, the percentage who would be screened as diabetic using the World Health Organization criteria (5) was 3 percent for the 364 men with an alcohol consumption greater than 20 g/day; for the 82 subjects with a lower consumption, none were classified as diabetic. These results

agree with those of Holbrook et al. (1), who in their figure 1 showed that the rate of incidence of diabetes increased when the alcohol consumption was in the upper tertile, a consumption of more than 25 g/day. It is well known that hyperglycemia is associated with cirrhosis and this could be considered as a part of the insulin resistance syndrome. However, this insulin resistance has different characteristics to that in non-insulin-dependent diabetic subjects (6). Insulin resistance may also exist in subjects who drink, because of impaired liver function and/or portal hypertension with extrahepatic shunting, as demonstrated in a recent study (7). In those who have a chronic alcohol consumption, diabetes, as diagnosed by the oral glucose tolerance test, has yet to be documented as overt diabetes with the associated diabetic complications. REFERENCES

1. Holbrook TL, Barrett-Connor E, Wingard DL. A prospective population-based study of alcohol use and non-insulin-dependent diabetes mellitus. Am J Epidemiol 1990; 132:902-9. 2. Papoz L, Eschwege E, Warnet J-M, et al. Incidence and risk factors of diabetes in the Paris Prospective Study (GREA). In: Eschwege E, ed. Advances in diabetes epidemiology. Amsterdam: Elsevier Biomedical Press, 1982:113-22. 3. Balkau B, Eschwege E, Ducimetiere P, et al. The high risk of death by alcohol related diseases in subjects diagnosed as diabetic and impaired glucose tolerant: the Paris Prospective Study after 15 years of follow-up. J Clin Epidemiol l991;44:465-74. 4. Balkau B, Eschwege E, Fontbonne A, et al. Cardiovascular and alcohol-related deaths in abnormal glucose tolerant and diabetic subjects. Diabetologia 1992;35 (in press). 5. WHO Study Group. Diabetes mellitus. WHO Tech Rep Ser 1985;727. 6. Petrides AS, DeFronzo RA. Glucose metabolism in cirrhosis: a review with some perspectives for the future. Diabetes Metab Rev 1989;8:691-709. 7. Petrides AS, Riely CA, DeFronzo RA. Insulin resistance in noncirrhotic idiopathic portal hypertension. Gastroenterology 1991; 100:245-51.

Re: "When genius errs: R. A. Fisher and the lung cancer controversy".

American Journal of Epidemiology Copyright © 1991 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 134, N...
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