When truth is unwelcome: the first reports on smoking and lung cancer

1950 should have been a very bad year for the tobacco companies. Five case-control studies published within a nine-month period reported that cigarette smoking was associated with lung cancer in men (1-5). In retrospect, the strength of the association in the two largest and most influential of these studies--by Ernest Wynder & Evarts Graham in the Journal of the American Medical Association (JAMA) (1), reproduced below, and by Richard Doll & Austin Bradford Hill (both of whom were later knighted for their work) in the British Medical Journal (2)--should have been sufficient to evoke a much stronger and more immediate response than the one that actually occurred (6). Had the methods for calculating and interpreting odds ratios been available at the time, the British study would have reported a relative risk of 14 in cigarette smokers compared with never-smokers, and the American study a relative risk of nearly 7, too high to be dismissed as bias. The medical and scientific communities were notably resistant to the idea that smoking caused lung cancer (7, 8), despite these publications. Doctors and scientists were as unreceptive as the general public, because most of them smoked (6). Doll has observed that "the ubiquity of the habit ... had dulled the collective sense that tobacco might be a major threat to health" (8). Thus, an intriguing dimension of the impact of these early studies is the manner in which persistence and the accumulation of scientific evidence ultimately prevailed, despite the formidable resistance against it. Remarkably, Ernest Wynder was still a medical student when he began interviewing lung cancer patients at Belleview Hospital in 1948, while a summer student at New York University. At the time he had never heard of the field of epidemiology and had no training in statistics (7). His motivation for beginning the study was anecdotal: he had witnessed the autopsy of a man who proved to have lung cancer, and whose widow later reported that her husband smoked two packs of cigarettes a day. When Wynder returned to medical school at Washington University, St Louis, he recruited an unlikely but influential ally in Evarts Graham. Dr Graham was a distinguished thoracic surgeon, chair of the Department of Surgery, and a heavy smoker. He was initially unconvinced of the need for a study of smoking and lung cancer. His senior associate, Thomas Burford, echoed this scepticism, pronouncing that "smoking was not a cause of lung cancer" while puffing on his cigarette. Nevertheless, Evarts allowed Wynder to interview patients with lung cancer and other diseases on the surgical wards, and later provided him with letters of introduction to other surgeons and contacts at the American Cancer Society (ACS) so that the study could be extended to other areas of the United States (7). Wynder employed what was at the time a novel epidemiological study design, the case-control study. Wynder was not alone in experiencing resistance to the new methodology, as well as to the disturbing hypothesis that smoking might cause lung cancer. Levin et al. completed a smaller study of smoking and cancer and submitted the manuscript to JAMA shortly before Wynder & Graham submitted theirs. The journal was hesitant to publish the paper by Levin and his co-workers because of the unfamiliar study design and preliminary nature of the data (9, 10). On receipt of the much larger study with similar design and findings, and with the internationally respected Graham as co-author, JAMA decided to publish both papers in the same issue (1, 3). In the United Kingdom, Doll & Hill--who were also smokers--were doubtful that cigarette smoking was an important cause of lung cancer when they began their case-control study in 1948 (8). They noted that the combustion products from coal were more potent as carcinogens than was tobacco condensate when painted on the skin of mice (8). They initially expected that the large increase in lung cancer mortality in the United Kingdom and the United States was more likely to have resulted from the widespread tarring of roads and exhaust from motor vehicles than from cigarette smoking. …