Commentary International Journal of Cell Cloning 9548-558 (1991)
Lung Cancer: From Triumph to Tragedy David I: Carr Department of Medical Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas, USA
The first article of the first issue of R e Cancer Bulletin in 1949 was the story of one of the triumphs of modem medicine [l].It was a report by the famous thoracic surgeon, Evarts A. Graham,of the first pneumonectomy for lung cancer, which he had performed in 1933. Graham reported that the patient was alive and well 15 years later and that the operation had become accepted throughout the world as the optimal treatment for lung cancer. He further reported that his operative mortality was only 7%, with a 5-year survival rate of 30%for those cases in which lung removal was possible. The second article in that first issue of The Cancer Bulletin, entitled “The Diagnosis of Lung Cancer,” was a review that emphasizedthe importance of early diagnosisand prompt surgical treatment with the implicationthat this would result in vast improvement in the 5-year survival rate, which at that time was only 8% for all cases [2]. Although that article starts with the statement “Cancer of the lung is a common disease,” the annual lung cancer death rates in the United States at that time were only 20/100,000 for males (Fig. 1) and only 5/100,000 for females (Fig. 2). During the first four decades of The Cancer Bulletin, the death rates for lung cancer have increased dramatically for both males and females to the point that lung cancer is now the most common cause of cancer death for both sexes. The American Cancer Society estimates that 93,000 men and 49,000 women will die of this malignancy in the United States in 1989 [3]. This is 35%of all male cancer deaths and 21% of all female cancer deaths-truly an epidemic of tragic proportions. Cause and Prevention
Why was the triumph followed by such a tragedy-a tragedy of such magni*Reprinted with permission from The Cancer Bulktin, Volume 4, Number 6. @l989, Medical Arts Publishing Foundation, Houston, Texas. ~
~~
Correspondence: Dr. David Carr, Department of Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. Received May 31, 1991; accepted for publication May 31, 1991. 0737-1454191/$2.0010 BAlphaMed Press
549
Lung Cancer: From Triumph to Tragedy
1930
1840
1950
1WO
1970
lee0 19m
YUr
Fig. 1. Age-adjusted cancer death rates from 1930 to 1985 for selected sites in males in the United States indicate the tremendous increase in the lung cancer death rate during the last 50 years. Rates are adjusted to the age distributionof the 1970US census. Sources of the data are the National Center for Health Statistics and the US Census Bureau. (Reprinted with permission from Ca-A Cancer Journalfor Clinicians [3]. Copyright 1989 by the American Cancer Society, Inc.)
tude that one is safe in calling it the worst medical disaster in the United States in the last half century? We know now that the major cause of this calamity has been the use of tobacco, especially cigarette smoking, and in retrospect we are forced to conclude that it could have been avoided or at least minimized to a fraction of its present magnitude. In fact, it is amazing that the scientific community, especially the health establishment, recognized the relationship between smoking and lung cancer so slowly and began to take the actions needed to control this epidemic so reluctantly.
oss
Lung Center: From Triumph
5.51
Fig. 3. This painting by Vincent van Gogh is thought to be a self-portrait because he wrote his brother that he was smoking a great deal and had a cough productive of grayish Phlegm.
smoker, and his famous painting of a skull with a cigarette (Fig. 3) is said to be a self-portrait. He once wrote to his brother that he was smoking a great deal and had a cough productive of a grayish phlegm 141. Large-scaleproduction of cigarettes in the United States began in Richmond, Va, in 1876, and the habit slowly increased in popularity during the rest of the 19thcentury and the early part of the 20th century. By the time of World War I,
A LOOK BACK “The relationship between cigarette smoking and lung cancer has been a hotly debated issue of the past decade. ”
“Counterblaste. to ’bbacco.” The Cancer Bulletin. 1964;16(3):53.
so many young men had begun to smoke cigarettes that General John J. Pershing, commander-in-chief of the American Expeditionary Forces in France, cabled to the government: “Tobacco is as indispensable as the daily ration; we must have
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thousands of tons of it without delay,” and tobacco filled the holds of many ships running the gauntlet of German U-boats in the Atlantic Ocean [5]. The medical profession at that time had little if any concern about the harmful effects of smoking, but someone must have been suspicious, as a World War I marching song contained the lines: Ashes to ashes and dust to dust, If the Camels don’t get you, f i e Fatimas must.
About that time, the author Sinclair Lewis must have had an idea about the relationship between smoking and as he had a character in his classic novel Main Street say that staying in the village of Gopher Prairie was “more dangerous than the cancer that will certainly get me at fifty unless I stop this smoking” [6]. During the 1930s, Pearl, the great biostatistician at Johns Hopkins University, published a short paper entitled “TobaccoSmoking and Longevity” in Science [7]. He reported that smoking had a profound effect on survival so that only 30% of heavy smokers survived to the age of 70 years, whereas 46% of nonsmokers reached that age (Fig. 4). This report should have precipitated intensive research to determinethe cause of the excessivedeath rate for smokers,but instead it seems to have been largely ignored by the health establishment. During these same years, several papers [8-l2] were published which commented on the probable relationship between smoking and lung cancer, but these do not seem to have attracted much attention or to have prompted any intensive study of the problem. The death rate due to lung cancer increased greatly during the 1940s, and finally in 1950the classic retrospective studies of W d e r and Gmham [l31, Lain, Goldrrein, and Gerhardt [14], and Doll and Hill [l5] clearly showed a significant relationshipbetween smoking and lung cancer. However, the first tworeports were cautious: one [l3]concluded only that smoking seemed “to be an important factor in the induction of bronchogenic carcinoma,” and the other [14] noted that the data suggested a causal relation between cigarette smoking and lung cancer. Doll and Hill [l5] were more positive, however, and concluded that lung cancer “may be approximately 50 times as great among those who smoke 25 or more cigarettes a day as among non-smokers.” Many experts doubted that these and other retrospective studies should be accepted as proof of a causal relationship between smoking and lung cancer, but these reports seem to have stimulated the prospective studies that were begun about this time. The classic study by Hammond and Horn [16] and the American Cancer Society enrolled about 200,000 apparently healthy men between the ages of 50 and 69 who were questioned about cigarette smoking, among other things, and who were followed up annually for almost 4 years. Among many other findings, this study showed that all cigarette smokers had > 10 times the risk of death due to lung cancer (other than adenocarcinoma)compared to never-smokers and that
Lung Cancer: From Triumph to Tragedy
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Fig. 4. SuMval curve-s for white males who were heavy smokers (dotted line), moderate smokers (dash line), and nonsmokers (solid line) from data published by Pearl in 1938. He showed that only 30%of heavy smokers survived to age 70, compared with 46% of nonsmokers. (Reprinted with permission from Science 171. Copyright 1938by the AAAS.)
those who smoked more than two packs per day had a lung cancer mortality ratio 64 times that of never-smokers. Nonetheless, many experts continued to doubt the significanceof these data and the results of other prospective studies [lq.Little action was taken, and during the 1950s the sale of cigarettescontinued to increase and the epidemic of lung cancer worsened. In 1959, Surgeon General Leroy E. Burney published a special article [18] inJAMA in which he analyzedthe available data and concluded that smoking was “the principal etiological factor in the increased incidence of lung cancer.” Unfortunately,this had little effect on either the health establishmentor the lay public. In 1962, Luther Terry, who had become Surgeon General, was persuaded by representatives of the American Cancer Society, American Heart Association, National TuberculosisAssociation, and American Public Health Association to appoint an advisory committee to study the problem. The members of the committee were chosen from a list of scientists and physicians who were acceptable to both the health agencies and the tobacco industry as capable and unbiased on
C m
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WHITE MALE
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BLACK MALE
/
125 150
100.
75
m
-
50.
I=35-44 = 45-54
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o + , 75 80 YEAR
,
,
85
,
,
YEAR
Fig. 5. Lung cancer death rates from 1970 through 1983 for white and black males in Texas show the decrease for white males ages 35-44and 45-64 and for black males ages 35-44. (Reprinted with permission from T m Medicine [20].)
the question of the health effects of smoking. This committee made a thorough study of all available data, and a comprehensive report [19] was released to the public in January 1964.Among other findings, it concluded that “cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors.” This report had a profound effect on the health establishment and the lay public, and the cause-and-effectrelationship between cigarette smoking and lung cancer was finally accepted by all but the tobacco industry and a s m a l l minority of physicians and scientists. The sale of cigarettes leveled off and then began to decline. From 1964 to the present, the percentage of adult males smoking has decreased frommore than 50%to about 30%,and the percentage of kmale smokers decreased from 34% to about 25%. Just as the epidemic of lung cancer had followed the increase in smoking with a lag of about 20 years, one might expect a similar intervalbetween the decrease in smoking and any change in the incidence of lung cancer. This decline began in men [20] (Fig. 5) and more recently has been reported for women also [21]. However, about 50 million Americans still smoke, so the epidemicof lung cancer will persist as the worst medical disaster of the last twothirds of the 20th century,accounting for millions ofpreventabledeaths. Our knowledge that tobacco smoke is the major cause of the epidemic of lung cancer should not blind us to the evidence of other aspects of the etiology of this malignancy. The contribution of other carcinogens, such as general urban air pollution, exposure to asbestos, ionizing radiation both in uranium mines and
Lung Cancer: From Triumph to Tragedy
555
due to radon gas trapped in homes, and other occupationalexposures, is well known [22,23]. Furthermore, there is strong evidence of host susceptibility, such as a familial tendency [24] and dietary deficiency [25], to the carcinogens that cause lung cancer. These problems must be considered along with control of tobacco if we are to prevent the epidemic from remaining a major problem into the 21st century.
Diagnosis and Treatment The epidemic of lung cancer resulted in tremendous interest in the diagnosis and treatment of the disease and the publication of thousands of articles [26]. Great improvementshave been made in the diagnosis of the malignancy and in evaluation of the patient prior to initiation of treatment. It is now possible to make an accurate histologic or cytologic diagnosis in almost all cases of lung cancer and to estimate the stage or the anatomic extent of the cancer in most. Both of these are essential in the optimal treatment of the patient. Surgical resection, when possible, remains the optimal treatment of lung cancer, and the innumerable improvements in preoperative care, surgical technique, and postoperative care have made such curative treatment possible for thousands of patients each year. This has led to many studies of screening of asymptomatic individuals at high risk for development of lung cancer, i.e., cigarette smokers over the age of 45 years. It was assumed that routine roentgenograms of the thorax and examinations of the sputum for cancer cells would detect a large percentage of lung cancer cases while the disease was still confined to the lung and could be curatively resected. Unfortunately, the basic biologic nature of lung cancer results in its invasion of the blood vessels or the lymphatics or both while the primary tumor is still in the undetectable phase of its growth. The primary lesion must be about 1 cm in diameter to be detected on a roentgenogram. Such a lesion contains about 1 billion cancer cells. Thirty doublings are required for a mass of cells to grow from one cell to 1 billion cells, and the average doubling time for a mass of lung cancer cells is at least 3 months. Therefore, it is obvious that the slowly developing lung cancer usually has years to invade the vessels and metastasize to the regional lymph nodes or distant organs or both before it can be detected on a routine roentgenogram of the thorax. As a result, the screening studies have shown only a modest increase in the detection of resectable lung cancers and have not reduced the death rate of the disease. Most experts now agree that mass screening is not cost-effective as a public health measure. On the other hand, some argue that it is a reasonable part of the routine examination of selected persons who request a thorough search for asymptomatic cancer and other diseases. For many patients with unresectable cancers or with recurrence after surgical treatment, radiotherapy, using modem equipment such as the linear accelerator, is of great help, curing some patients and relieving symptoms for many more. Assessing the role of chemotherapy for lung cancer is more difficult. Many
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combinations of drugs have been proved to be of modest value in the small cell type of lung cancer, producing a decrease in the size of the tumor in almost all cases, complete disappearancein some, and a long-term cure in a few cases. The optimal combination of drugs, the best regimen of therapy, and the proper duration of treatment remain unknown. Equally uncertain is the way to combine radiotherapy and surgery with chemotherapy to achieve the best results. The other common cell types of lung cancer-squamous cell carcinoma, adenocarcinoma, and large cell carcinoma-are frequently grouped together and called nonsmall cell lung cancer. Of the many studies of single drugs and numerous combinations of two or more drugs in the treatment of this group of lung cancers, few have demonstrated any significant benefit and all have been toxic and even occasionally fatal. Similar results have been obtained when such chemotherapy has been combined with radiotherapy or surgery. However, be-
A LOOK BACK “lkepropositions advanced in reaction to the Public Health Service report [lW] are, roughly, of two kinds-plans to discourage the use of tobacco, particularly cigarette smoking, and research intended ultimutely to make the habit harmless. Thefirst group includes recommendationsthat cigarette advertising campaigns no longer include athletes, pretty girls, handsome, sophisticated looking men, anything that would glamorize the habit. Labeling of cigarettes as harmful has also been suggested. Educationul campaignsfor school-age children and establishment of cigarette withdrawal clinics in cities have been proposed. It has even been suggested that the sale of cigarettes to persons under 18 be prohibited by law.” “Counterblaste to Tobacco.” The Canrer Bulletin. W64;16(3):54.
cause the only alternative for many patients is supportive care and the treatment of their symptoms, such chemotherapy is in widespread use worldwide. Whenever possible, such treatment should be a part of an organized clinical research project to increase our knowledge of the results of the chemotherapy of lung cancer and to guide us into more productive experiments. Despite all these efforts, the prediction in the first issue of Zhe Cancer Bulletin that the survival rate could “be vastly improved” has not been achieved. It is true that the 5-year survival rate of 8% reported at that time for all cases has been increased to ll% for blacks and l3% for whites. In other words, the mortality rate has been decreased from 92% to 88% [3]. Obviously, there is great need for improvement in our management of this disease.
The Future Predicting the future is hazardous to one’s professional health, but a study
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of the past may help in suggestingfuture developments. The use of tobacco, especially cigarette smoking, soared from 1900 to 1964, when it leveled off and then began to decline slowly. Smoking is no longer socially acceptable, so public pressure is motivating many people to quit smoking, including some of those who accepted the evidence that smoking was hazardous to some people’s health but who had a personal “illusionof immortality.’’ It seems safe to predict that the percentage of people smoking will continue to decrease and that this will be followed by a decrease in the incidence of lung cancer. Nonetheless, the annual incidence will remain a great burden, as so many millions of people are still smolung. Therefore, lung cancer will continue to be the most common cause of cancer death throughout the rest of the 20th century and into the 2lst century. The prevention of lung cancer by persuading people not to smoke is of primary importance and is working, but too slowly. An exciting new development is the experimentalstudy of the chemoprevention of lung cancer, e.g., examining cigarette smokersto discover which ones have precancerous lesions of the bronchial mucosa, and administering l3-cis-retinoic acid or beta-carotene to determine if this will reverse the abnormality in the bronchial mucosa as it has done for precancerous lesions in the mouth. If successful, this might be of benefit but should never lead to the conclusionthat it would make cigarettes harmless because of the many other harmful effects of smoking. The diagnosis and treatmentof the disease will remain a frustrating problem. In most cases, the biology of the malignancy results in its disseminationfrom the primary site in the lung to regional lymph nodes or more distant sites or both before it becomes detectableby presently available techniquesof dqnosis of asymptomatic disease, i.e., roentgenograms of the thorax and cytologic examination of the sputum. Surgicalresection will remain the best available treatment but will be applicable to and successful for only that minority of cases which are slow-growing and are detected by a routine x-ray of the thorax before symptomsdevelop. Radiotherapy will remain of great value to many, curing a fkw who are lucky enough to have radiation-sensitivedisease limited to the field of therapy and palliating many more. Experimentalchemotherapy has been of some value, especially for those with small cell lung cancer, but none of the available drugs either singly or in the innumerable combinations tested have been adequate. New drugs may be discovered that will be a great leap forward, but so many have been studied and have Wed that it is difficult to be optimistic about the future of chemotherapy as a cure for these many thousands of patients. Immunotherapy has been promising for many years, but the promises have been much greaterthan the results to date. Such research will and should continue, but it seems doubtful that it will significantly reduce the lung cancer death rate. In conclusion, it seems sak to predict that thoracic oncology will remain a challenge to all physicians throughout the remaining professional lives of those who are dedicated to the care of these patients today. And we shall continue to
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be guided by the Uth-century French folk saying:
To cure sometimes, to relieve often, to comfort always.
References 1 2 3 4 5
6 7 8 9 10
Graham AG. The first total pneumonectomy. Cancer Bull. l949;1:2-4. The diagnosis of lung cancer. Cancer Bull. 1949;1:5-7. Silverberg E, Lubera JA. Cancer statistics. Ca. 1989;39:3-20. van Gogh V. The Complete Letters of Vincent van Gogh. Greenwich, COM: New York Graphics Society; 1959;2:482,485. 'bylor P.The Smoke Ring: Tobacco, Money and Multinational politics. New York, NY Pantheon Books; 1984. Lewis S. Main Street. New York, I W Harcourt, Brace and World Inc; 1920. Pearl R. Tobacco smoking and longevity. Science. 1938;87.216-217. Qlecote FE. Cancer of the lung. Lancet. 1927;2:256-257. Hoffman FL. Cancer and smoking habits. Cancer Res. 1950:10:50-67. McNally WD. The par in cigarette smoke and its possible effects. Am J Cancer.
1932;16:lSO2-1514. 1 1 Arkin A, Wagner DH. Primary carcinoma of the lung. JAMA. l936;106:587-591. 12 Ochsner A, DeBakey M. Carcinoma of the lung. Arch Surg. 1941;42:209-258. 13 Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma-a study of six hundred and eighty-four proved cases. JAMA. l950143:329-336. 14 Levin ML, Goldstein H. Gerhardt PR. Cancer and tobacco smoking. JAMA. 1950; 143:336-338. 15 Doll R, Hill AB. Smoking and carcinoma of the lung. Br Med J. 1950;2:739-748. 16 Hammond EC, Horn D. Smoking and death rates-report on forty-four months of follow-up of 187,783men. JAMA 1958;166:1294-1308. 17 Doll R, Hill AB. Lung cancer and other causes of death in relation to smoking. Br Med J. 1956;2:1071-1082. 18 Burney LE. Smoking and lung cancer. JAMA. 1959;171:135-143. 19 Smoking and Health. Washington, DC: Government Printing Office; 1964. 20 Newell GR, Lynch HK, Carr M:Decreasing lung cancer deaths among young men in Texas. T ~ xMed. l985;81:29-31. 21 Garfinkel L,Stellman SD. Smoking and lung cancer in women: findings in a prospective study. Cancer Res. l988;48:6951-6955. 22 Newell GR. Comments on epidemiology, etiology, and prevention of lung cancer. Cancer Bull. l980;32:76-77. 23 Samet JM. Radon and lung cancer. JNCI. l!389;81:745-757. 24 lbkuhata GK. Familial factorsin human lung cancer and smoking. Am J Public Health. l964;54:24-32. 25 Shekelle RB, Liu S, Raynor WJ,et al. Dietary vitamin A and risk of cancer in the Western Electric study. Lancet. 1981;2:ll85-ll90. 26 Can DT,Holaye PY. Bronchiogenic carcinoma. In: Murray JF, Nadel JA. Textbook of Respiratory Medicine. Philadelphia, PA: WB Saunders Co.; 1988:ll74-1250.
Lung Cancer: From Triumph to Tragedy David I: Carr Department of Medical Oncology, The University of Texas M.D.Anderson Cancer Center, Houston, Texas, USA
The first article of the first issue of R e Cancer Bulletin in 1949 was the story of one of the triumphs of modem medicine [l].It was a report by the famous thoracic surgeon, Evarts A. Graham,of the first pneumonectomy for lung cancer, which he had performed in 1933. Graham reported that the patient was alive and well 15 years later and that the operation had become accepted throughout the world as the optimal treatment for lung cancer. He further reported that his operative mortality was only 7%, with a 5-year survival rate of 30%for those cases in which lung removal was possible. The second article in that first issue of The Cancer Bulletin, entitled “The Diagnosis of Lung Cancer,” was a review that emphasizedthe importance of early diagnosisand prompt surgical treatment with the implicationthat this would result in vast improvement in the 5-year survival rate, which at that time was only 8% for all cases [2]. Although that article starts with the statement “Cancer of the lung is a common disease,” the annual lung cancer death rates in the United States at that time were only 20/100,000 for males (Fig. 1) and only 5/100,000 for females (Fig. 2). During the first four decades of The Cancer Bulletin, the death rates for lung cancer have increased dramatically for both males and females to the point that lung cancer is now the most common cause of cancer death for both sexes. The American Cancer Society estimates that 93,000 men and 49,000 women will die of this malignancy in the United States in 1989 [3]. This is 35%of all male cancer deaths and 21% of all female cancer deaths-truly an epidemic of tragic proportions. Cause and Prevention
Why was the triumph followed by such a tragedy-a tragedy of such magni*Reprinted with permission from The Cancer Bulktin, Volume 4, Number 6. @l989, Medical Arts Publishing Foundation, Houston, Texas. ~
~~
Correspondence: Dr. David Carr, Department of Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. Received May 31, 1991; accepted for publication May 31, 1991. 0737-1454191/$2.0010 BAlphaMed Press
549
Lung Cancer: From Triumph to Tragedy
1930
1840
1950
1WO
1970
lee0 19m
YUr
Fig. 1. Age-adjusted cancer death rates from 1930 to 1985 for selected sites in males in the United States indicate the tremendous increase in the lung cancer death rate during the last 50 years. Rates are adjusted to the age distributionof the 1970US census. Sources of the data are the National Center for Health Statistics and the US Census Bureau. (Reprinted with permission from Ca-A Cancer Journalfor Clinicians [3]. Copyright 1989 by the American Cancer Society, Inc.)
tude that one is safe in calling it the worst medical disaster in the United States in the last half century? We know now that the major cause of this calamity has been the use of tobacco, especially cigarette smoking, and in retrospect we are forced to conclude that it could have been avoided or at least minimized to a fraction of its present magnitude. In fact, it is amazing that the scientific community, especially the health establishment, recognized the relationship between smoking and lung cancer so slowly and began to take the actions needed to control this epidemic so reluctantly.
oss
Lung Center: From Triumph
5.51
Fig. 3. This painting by Vincent van Gogh is thought to be a self-portrait because he wrote his brother that he was smoking a great deal and had a cough productive of grayish Phlegm.
smoker, and his famous painting of a skull with a cigarette (Fig. 3) is said to be a self-portrait. He once wrote to his brother that he was smoking a great deal and had a cough productive of a grayish phlegm 141. Large-scaleproduction of cigarettes in the United States began in Richmond, Va, in 1876, and the habit slowly increased in popularity during the rest of the 19thcentury and the early part of the 20th century. By the time of World War I,
A LOOK BACK “The relationship between cigarette smoking and lung cancer has been a hotly debated issue of the past decade. ”
“Counterblaste. to ’bbacco.” The Cancer Bulletin. 1964;16(3):53.
so many young men had begun to smoke cigarettes that General John J. Pershing, commander-in-chief of the American Expeditionary Forces in France, cabled to the government: “Tobacco is as indispensable as the daily ration; we must have
552
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thousands of tons of it without delay,” and tobacco filled the holds of many ships running the gauntlet of German U-boats in the Atlantic Ocean [5]. The medical profession at that time had little if any concern about the harmful effects of smoking, but someone must have been suspicious, as a World War I marching song contained the lines: Ashes to ashes and dust to dust, If the Camels don’t get you, f i e Fatimas must.
About that time, the author Sinclair Lewis must have had an idea about the relationship between smoking and as he had a character in his classic novel Main Street say that staying in the village of Gopher Prairie was “more dangerous than the cancer that will certainly get me at fifty unless I stop this smoking” [6]. During the 1930s, Pearl, the great biostatistician at Johns Hopkins University, published a short paper entitled “TobaccoSmoking and Longevity” in Science [7]. He reported that smoking had a profound effect on survival so that only 30% of heavy smokers survived to the age of 70 years, whereas 46% of nonsmokers reached that age (Fig. 4). This report should have precipitated intensive research to determinethe cause of the excessivedeath rate for smokers,but instead it seems to have been largely ignored by the health establishment. During these same years, several papers [8-l2] were published which commented on the probable relationship between smoking and lung cancer, but these do not seem to have attracted much attention or to have prompted any intensive study of the problem. The death rate due to lung cancer increased greatly during the 1940s, and finally in 1950the classic retrospective studies of W d e r and Gmham [l31, Lain, Goldrrein, and Gerhardt [14], and Doll and Hill [l5] clearly showed a significant relationshipbetween smoking and lung cancer. However, the first tworeports were cautious: one [l3]concluded only that smoking seemed “to be an important factor in the induction of bronchogenic carcinoma,” and the other [14] noted that the data suggested a causal relation between cigarette smoking and lung cancer. Doll and Hill [l5] were more positive, however, and concluded that lung cancer “may be approximately 50 times as great among those who smoke 25 or more cigarettes a day as among non-smokers.” Many experts doubted that these and other retrospective studies should be accepted as proof of a causal relationship between smoking and lung cancer, but these reports seem to have stimulated the prospective studies that were begun about this time. The classic study by Hammond and Horn [16] and the American Cancer Society enrolled about 200,000 apparently healthy men between the ages of 50 and 69 who were questioned about cigarette smoking, among other things, and who were followed up annually for almost 4 years. Among many other findings, this study showed that all cigarette smokers had > 10 times the risk of death due to lung cancer (other than adenocarcinoma)compared to never-smokers and that
Lung Cancer: From Triumph to Tragedy
553
Fig. 4. SuMval curve-s for white males who were heavy smokers (dotted line), moderate smokers (dash line), and nonsmokers (solid line) from data published by Pearl in 1938. He showed that only 30%of heavy smokers survived to age 70, compared with 46% of nonsmokers. (Reprinted with permission from Science 171. Copyright 1938by the AAAS.)
those who smoked more than two packs per day had a lung cancer mortality ratio 64 times that of never-smokers. Nonetheless, many experts continued to doubt the significanceof these data and the results of other prospective studies [lq.Little action was taken, and during the 1950s the sale of cigarettescontinued to increase and the epidemic of lung cancer worsened. In 1959, Surgeon General Leroy E. Burney published a special article [18] inJAMA in which he analyzedthe available data and concluded that smoking was “the principal etiological factor in the increased incidence of lung cancer.” Unfortunately,this had little effect on either the health establishmentor the lay public. In 1962, Luther Terry, who had become Surgeon General, was persuaded by representatives of the American Cancer Society, American Heart Association, National TuberculosisAssociation, and American Public Health Association to appoint an advisory committee to study the problem. The members of the committee were chosen from a list of scientists and physicians who were acceptable to both the health agencies and the tobacco industry as capable and unbiased on
C m
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WHITE MALE
175
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-
BLACK MALE
/
125 150
100.
75
m
-
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I=35-44 = 45-54
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,
,
85
,
,
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Fig. 5. Lung cancer death rates from 1970 through 1983 for white and black males in Texas show the decrease for white males ages 35-44and 45-64 and for black males ages 35-44. (Reprinted with permission from T m Medicine [20].)
the question of the health effects of smoking. This committee made a thorough study of all available data, and a comprehensive report [19] was released to the public in January 1964.Among other findings, it concluded that “cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors.” This report had a profound effect on the health establishment and the lay public, and the cause-and-effectrelationship between cigarette smoking and lung cancer was finally accepted by all but the tobacco industry and a s m a l l minority of physicians and scientists. The sale of cigarettes leveled off and then began to decline. From 1964 to the present, the percentage of adult males smoking has decreased frommore than 50%to about 30%,and the percentage of kmale smokers decreased from 34% to about 25%. Just as the epidemic of lung cancer had followed the increase in smoking with a lag of about 20 years, one might expect a similar intervalbetween the decrease in smoking and any change in the incidence of lung cancer. This decline began in men [20] (Fig. 5) and more recently has been reported for women also [21]. However, about 50 million Americans still smoke, so the epidemicof lung cancer will persist as the worst medical disaster of the last twothirds of the 20th century,accounting for millions ofpreventabledeaths. Our knowledge that tobacco smoke is the major cause of the epidemic of lung cancer should not blind us to the evidence of other aspects of the etiology of this malignancy. The contribution of other carcinogens, such as general urban air pollution, exposure to asbestos, ionizing radiation both in uranium mines and
Lung Cancer: From Triumph to Tragedy
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due to radon gas trapped in homes, and other occupationalexposures, is well known [22,23]. Furthermore, there is strong evidence of host susceptibility, such as a familial tendency [24] and dietary deficiency [25], to the carcinogens that cause lung cancer. These problems must be considered along with control of tobacco if we are to prevent the epidemic from remaining a major problem into the 21st century.
Diagnosis and Treatment The epidemic of lung cancer resulted in tremendous interest in the diagnosis and treatment of the disease and the publication of thousands of articles [26]. Great improvementshave been made in the diagnosis of the malignancy and in evaluation of the patient prior to initiation of treatment. It is now possible to make an accurate histologic or cytologic diagnosis in almost all cases of lung cancer and to estimate the stage or the anatomic extent of the cancer in most. Both of these are essential in the optimal treatment of the patient. Surgical resection, when possible, remains the optimal treatment of lung cancer, and the innumerable improvements in preoperative care, surgical technique, and postoperative care have made such curative treatment possible for thousands of patients each year. This has led to many studies of screening of asymptomatic individuals at high risk for development of lung cancer, i.e., cigarette smokers over the age of 45 years. It was assumed that routine roentgenograms of the thorax and examinations of the sputum for cancer cells would detect a large percentage of lung cancer cases while the disease was still confined to the lung and could be curatively resected. Unfortunately, the basic biologic nature of lung cancer results in its invasion of the blood vessels or the lymphatics or both while the primary tumor is still in the undetectable phase of its growth. The primary lesion must be about 1 cm in diameter to be detected on a roentgenogram. Such a lesion contains about 1 billion cancer cells. Thirty doublings are required for a mass of cells to grow from one cell to 1 billion cells, and the average doubling time for a mass of lung cancer cells is at least 3 months. Therefore, it is obvious that the slowly developing lung cancer usually has years to invade the vessels and metastasize to the regional lymph nodes or distant organs or both before it can be detected on a routine roentgenogram of the thorax. As a result, the screening studies have shown only a modest increase in the detection of resectable lung cancers and have not reduced the death rate of the disease. Most experts now agree that mass screening is not cost-effective as a public health measure. On the other hand, some argue that it is a reasonable part of the routine examination of selected persons who request a thorough search for asymptomatic cancer and other diseases. For many patients with unresectable cancers or with recurrence after surgical treatment, radiotherapy, using modem equipment such as the linear accelerator, is of great help, curing some patients and relieving symptoms for many more. Assessing the role of chemotherapy for lung cancer is more difficult. Many
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combinations of drugs have been proved to be of modest value in the small cell type of lung cancer, producing a decrease in the size of the tumor in almost all cases, complete disappearancein some, and a long-term cure in a few cases. The optimal combination of drugs, the best regimen of therapy, and the proper duration of treatment remain unknown. Equally uncertain is the way to combine radiotherapy and surgery with chemotherapy to achieve the best results. The other common cell types of lung cancer-squamous cell carcinoma, adenocarcinoma, and large cell carcinoma-are frequently grouped together and called nonsmall cell lung cancer. Of the many studies of single drugs and numerous combinations of two or more drugs in the treatment of this group of lung cancers, few have demonstrated any significant benefit and all have been toxic and even occasionally fatal. Similar results have been obtained when such chemotherapy has been combined with radiotherapy or surgery. However, be-
A LOOK BACK “lkepropositions advanced in reaction to the Public Health Service report [lW] are, roughly, of two kinds-plans to discourage the use of tobacco, particularly cigarette smoking, and research intended ultimutely to make the habit harmless. Thefirst group includes recommendationsthat cigarette advertising campaigns no longer include athletes, pretty girls, handsome, sophisticated looking men, anything that would glamorize the habit. Labeling of cigarettes as harmful has also been suggested. Educationul campaignsfor school-age children and establishment of cigarette withdrawal clinics in cities have been proposed. It has even been suggested that the sale of cigarettes to persons under 18 be prohibited by law.” “Counterblaste to Tobacco.” The Canrer Bulletin. W64;16(3):54.
cause the only alternative for many patients is supportive care and the treatment of their symptoms, such chemotherapy is in widespread use worldwide. Whenever possible, such treatment should be a part of an organized clinical research project to increase our knowledge of the results of the chemotherapy of lung cancer and to guide us into more productive experiments. Despite all these efforts, the prediction in the first issue of Zhe Cancer Bulletin that the survival rate could “be vastly improved” has not been achieved. It is true that the 5-year survival rate of 8% reported at that time for all cases has been increased to ll% for blacks and l3% for whites. In other words, the mortality rate has been decreased from 92% to 88% [3]. Obviously, there is great need for improvement in our management of this disease.
The Future Predicting the future is hazardous to one’s professional health, but a study
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of the past may help in suggestingfuture developments. The use of tobacco, especially cigarette smoking, soared from 1900 to 1964, when it leveled off and then began to decline slowly. Smoking is no longer socially acceptable, so public pressure is motivating many people to quit smoking, including some of those who accepted the evidence that smoking was hazardous to some people’s health but who had a personal “illusionof immortality.’’ It seems safe to predict that the percentage of people smoking will continue to decrease and that this will be followed by a decrease in the incidence of lung cancer. Nonetheless, the annual incidence will remain a great burden, as so many millions of people are still smolung. Therefore, lung cancer will continue to be the most common cause of cancer death throughout the rest of the 20th century and into the 2lst century. The prevention of lung cancer by persuading people not to smoke is of primary importance and is working, but too slowly. An exciting new development is the experimentalstudy of the chemoprevention of lung cancer, e.g., examining cigarette smokersto discover which ones have precancerous lesions of the bronchial mucosa, and administering l3-cis-retinoic acid or beta-carotene to determine if this will reverse the abnormality in the bronchial mucosa as it has done for precancerous lesions in the mouth. If successful, this might be of benefit but should never lead to the conclusionthat it would make cigarettes harmless because of the many other harmful effects of smoking. The diagnosis and treatmentof the disease will remain a frustrating problem. In most cases, the biology of the malignancy results in its disseminationfrom the primary site in the lung to regional lymph nodes or more distant sites or both before it becomes detectableby presently available techniquesof dqnosis of asymptomatic disease, i.e., roentgenograms of the thorax and cytologic examination of the sputum. Surgicalresection will remain the best available treatment but will be applicable to and successful for only that minority of cases which are slow-growing and are detected by a routine x-ray of the thorax before symptomsdevelop. Radiotherapy will remain of great value to many, curing a fkw who are lucky enough to have radiation-sensitivedisease limited to the field of therapy and palliating many more. Experimentalchemotherapy has been of some value, especially for those with small cell lung cancer, but none of the available drugs either singly or in the innumerable combinations tested have been adequate. New drugs may be discovered that will be a great leap forward, but so many have been studied and have Wed that it is difficult to be optimistic about the future of chemotherapy as a cure for these many thousands of patients. Immunotherapy has been promising for many years, but the promises have been much greaterthan the results to date. Such research will and should continue, but it seems doubtful that it will significantly reduce the lung cancer death rate. In conclusion, it seems sak to predict that thoracic oncology will remain a challenge to all physicians throughout the remaining professional lives of those who are dedicated to the care of these patients today. And we shall continue to
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be guided by the Uth-century French folk saying:
To cure sometimes, to relieve often, to comfort always.
References 1 2 3 4 5
6 7 8 9 10
Graham AG. The first total pneumonectomy. Cancer Bull. l949;1:2-4. The diagnosis of lung cancer. Cancer Bull. 1949;1:5-7. Silverberg E, Lubera JA. Cancer statistics. Ca. 1989;39:3-20. van Gogh V. The Complete Letters of Vincent van Gogh. Greenwich, COM: New York Graphics Society; 1959;2:482,485. 'bylor P.The Smoke Ring: Tobacco, Money and Multinational politics. New York, NY Pantheon Books; 1984. Lewis S. Main Street. New York, I W Harcourt, Brace and World Inc; 1920. Pearl R. Tobacco smoking and longevity. Science. 1938;87.216-217. Qlecote FE. Cancer of the lung. Lancet. 1927;2:256-257. Hoffman FL. Cancer and smoking habits. Cancer Res. 1950:10:50-67. McNally WD. The par in cigarette smoke and its possible effects. Am J Cancer.
1932;16:lSO2-1514. 1 1 Arkin A, Wagner DH. Primary carcinoma of the lung. JAMA. l936;106:587-591. 12 Ochsner A, DeBakey M. Carcinoma of the lung. Arch Surg. 1941;42:209-258. 13 Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma-a study of six hundred and eighty-four proved cases. JAMA. l950143:329-336. 14 Levin ML, Goldstein H. Gerhardt PR. Cancer and tobacco smoking. JAMA. 1950; 143:336-338. 15 Doll R, Hill AB. Smoking and carcinoma of the lung. Br Med J. 1950;2:739-748. 16 Hammond EC, Horn D. Smoking and death rates-report on forty-four months of follow-up of 187,783men. JAMA 1958;166:1294-1308. 17 Doll R, Hill AB. Lung cancer and other causes of death in relation to smoking. Br Med J. 1956;2:1071-1082. 18 Burney LE. Smoking and lung cancer. JAMA. 1959;171:135-143. 19 Smoking and Health. Washington, DC: Government Printing Office; 1964. 20 Newell GR, Lynch HK, Carr M:Decreasing lung cancer deaths among young men in Texas. T ~ xMed. l985;81:29-31. 21 Garfinkel L,Stellman SD. Smoking and lung cancer in women: findings in a prospective study. Cancer Res. l988;48:6951-6955. 22 Newell GR. Comments on epidemiology, etiology, and prevention of lung cancer. Cancer Bull. l980;32:76-77. 23 Samet JM. Radon and lung cancer. JNCI. l!389;81:745-757. 24 lbkuhata GK. Familial factorsin human lung cancer and smoking. Am J Public Health. l964;54:24-32. 25 Shekelle RB, Liu S, Raynor WJ,et al. Dietary vitamin A and risk of cancer in the Western Electric study. Lancet. 1981;2:ll85-ll90. 26 Can DT,Holaye PY. Bronchiogenic carcinoma. In: Murray JF, Nadel JA. Textbook of Respiratory Medicine. Philadelphia, PA: WB Saunders Co.; 1988:ll74-1250.
