The ,Health Benefits of SMOKING CESSATION a report of the Surgeon General 1990 U.S. DEPARTMENT OF HEALTH AND HCIMAN SERVICES Public Health Service Centen for Disease Control Center for Chrome Disease Prevention and Health Promorwn CDC CENTERS FOR DGEASE CONTROL Office on Smoking and Health Rockvllle. Maryland 20857 U.S. Department of Health and Human Ser\ ice\. 7%1> filwlllr Rlvrcytr\ /!f .S/?i,JX- /~,q L`c~c.wfio/~. U.S. Department of Health and Human St'r\~ices. Public Health Service. Center3 for Diwaw Control. Center for Chronic Die;Le Pre\ ention and Health Promotion. Ofke on Smohing and Health. DHHS Publication No. (CDC) YO-K-116. 1990. The Honorable Thomas S. Foley Speaker of the House of -RSpreSSlltSti"eS Washingcon, D.C. 20515 Dear nr. Speaker: It is my pleasure to transmit to the Congress the 1990 Surgeon General's Report on the health consequences of smoking as mandated by Section E(a) of the Public Health Cigarette Smoking Act of 1969 (Pub. L. 91-222). The report YSS prepared by the Centers for Disease Control's Office on Smoking and Health. This report, entitled The Health Benefits of Smoking Cessation, examines hov an individual's risk of smoking-related diseases declines after quittins smoking. The evidence is overvhelming that smoking cessation has major and inmediate health benefits for me" and women of all ages. Smoking cessation increases overall life expectancy and reduces the risk of lung ca"cer, other cancers. heart attack. stroke. and chronic 1"~ disease such as emphysema. The health benefits of smoking cessation far e;ceed any risks from the average S-pound weight gain or any adverse psychological effects that may follov quitting. Cigsrette smoking is the most important preventable cause of death in our sWC.i.Sty. It is responsible for approximately 390,000 deaths each year in the United States, or more than one of every six deaths. We must dl, Sll YP can to prevent young people from taking up this deadly addiction, and ve m"st help smckers quit. Give" the enormous benefits of smoking cessation, and the fact that good smoking cessation programs can achieve abstinence rates of 20 to 40 percent at one-year follovup, these programs are likely to be extremely cost-effective compared with other preventive or curative services. Therefore. I would encourage health insurers to provide psyment for smoking cessation treatments that arc show" to be effective. At a minimum, the treatment of nicotine addiction should be considered as favorably by third-party payers as treatment of alcoholism and ill!clt drug addiction This report should help convince all smokers of the compelling need to quit smoking. Sincerely, Louis W. Sullivan, U.D. SWXetFlLY Enclosure The Honorable Dan Quayle President of the Senate Washington, D.C. 20515 Dear Mr. President: It is my pleasure to transmit co the Congress the 1990 Surgeon General's Report on the health consequences of smoking as mandated by Section g(a) of the Public Health Cigarette Smoking Act of 1969 (Pub. L. 91-222). The report was prepared by the Centers for Disease Control's Office 0" Smoking and Health. This report, entitled The Health Benefits of Smokinn Cessation, examines how a" individual's risk of smoking-related diseases declines after quitting smoking. The evidence is overwhelming that smoking cessation has major and immediate health benefits for me" and wme" of all ages. Smoking cessation increases overall life expectancy and reduces the risk of lung cancer, other cancers, heart attack, stroke, and chronic lung disease such as emphysema. The health benefits of smoking cessation far exceed any risks from the average S-pound weight gain or any adverse psychological effects that may follow quitting. Cigarette smoking is the most important preventable cause of death in our SOCiStY. It is responsible for approximately 390,000 deaths each year in the United Stares, or more than one of every six deaths. We must do all ue can to prevent young people from taking up this deadly addiction, and "e must help smokers quit. Given the enormous benefits of smoking cessation, and the fact that good smoking cessation programs can achieve abstinence rates of 20 to 40 percent at one-year followup. these programs are likely to be extremely &at-effective eonpared withother preventive or curative services. Therefore, I would encourage health insurers to provide payment for smoking cessation treatments that are show" to be effective. At a minimum, the treatment of nicotine addiction should be considered as favorably by third-party psyors as treatment of slcoholism and illicit drug addiction. This report should help convince all smokers of the compelling need to quit smoking. Sincerely, ~&&j,&&& LOUiS w. Sullivan, M.D. secretary Enclosure FOREWORD More than 38 million Americans have quit smoking cigarette\. and nearI> half of all living adults who ever smoked have quit. Unfortunately. \ome SO million American\ continue to smoke cigarettes. despite the many health education programs and anti- smoking campaigns that have been conducted during the past quarter century. despite the declining social acceptability of smoking, and despite the consequences of \mohing to their health. Twenty previous report\ of the Surgeon General have reviewed the health effect\ of smoking. Scientific data are now available on the consequences of smohing ce\\ation for most smoking-related disease\. Previous reports have considered \ome of thece data. but this Report is the first to provide a comprehensive and unified re\,ieu of [hi\ topic. The major conclusions of this volume are: I. Smoking cessation has major and immediate health benefits for men and w-omen of all ages. Benefits apply to persons with and without smoking-related disease. 2. Former smokers live longer than continuing smokers. For example, persons who quit smoking before age 50 have one-half the risk of dying in the next 15 years compared with continuing smokers. 3. Smoking cessation decreases the risk of lung cancer, other cancers, heart attack, stroke, and chronic lung disease. 1. Women who stop smoking before pregnancy or during the first 3 to 4 months of pregnancy reduce their risk of having a low hirthweight baby to that of women who never smoked. 5. The health benefits of smoking cessation far exceed any risks from the average 5pound (2.3-kg) weight gain or any adverse psychological effects that ma! follow quitting. With the long-standing evidence that smoking is extremely harmful to health and the mounting evidence that smoking cessation confers major health benefits. we remain faced with the task of developing effective strategies to curtail the use of tobacco. Two broad categories of intervention are available: prevention of smoking initiation among youth and smoking cessation. Resources for tobacco control are limited. and policymakers must decide how best to allocate those resource\ to smohing prevention and cessation. The goal of public health i\ to intervene a\ earl! a\ pos\iblc to prc`\`ent di\ea\c. disability. and premature death. From that standpoint. prevention of~mokin~ initiation should he a maior priorit!. More than 3.000 tecnafer\ become regular w~oker~ (`UC /I tltr~, in the United State\. Becauw of the strength of nicotine addiction. wme have argued that public health effort\ should focu\ on smohing prevention rather than wioking cessation. Houevcr. thi\ need not be an "either-or" Gtuation. Public health practitioners have categorized interwntion\ into primary. secondnr!. and tertiary prevention. Primary prevention generally refer\ to the elimination of ri\h factors for di\ea\e in asymptomatic persons. Secondary prevention i\ defined a\ the early detection and treatment ofdi\ease. and is practiced using toots wch 3s Pup smear\ and blood pressure \creenin_r. Tertiary prevention con\i\ts of measures to reduce impairment, diaabilit),. and suffering in people I$ ith existing disease. Smoking cessation fall> under the catepor\' of primary prevention a\ does the prevention of smoking initiation. Smoking cessation meets the definition of primq prevention by reducing the rich of morbidity and premature mortality in asymptomatic people. In addition. parent\ who quit smohing reduce or eliminate the rish ofpa~ive- smoking-related disease among their children and reduce the probability that their children will become smoher\. Thu\. there should be no debate about the need for smoking prevention versw cessation-both are important. Public awareness of the health effect\ of smoking ha\ increased substantialI!, through the years. Neverthelcah. important gaps in public hnowledge still exist. Some \moher\ may have failed to quit hecawe of a lath of appreciation of the health hazards of smoking and the benefits of quitting. In the 1987 National Health Intervie% Survey ot Cancer Epidemiology and Control. rehpondentz were asked whether making increases the risk of variou\ disease:, (lung cancer. cancer of the mouth and throat. heart disease. emphysema. and chronic bronchitis) and uhethrr mohing ceaation reduces the rish. Thirty to forty percent of smoker\ either did not believe that \mohiry increases thew risks or did not beliebe that cessation reduces these ri\hs. The\e proportion\ correspond to IS to 20 million smohen in the United State\. Clearly. our efforts to educate the public on the health haLard\ ofmohing and the benefits ofquitting are not yet complete. As we continue and intensit) our efforts to inform the public of thehe finding\. we must make available wwhing cc\sation programs and ser\ ices to those Q ho need them. Although 90 percent of former \moher\ quit without using smoking ce\Mion program\. counseling. or nicotine pm. smoher\ Mho do need this asistancc should ha\e it available. WC endorw the vie\\ rxprewxi in the Preface to the Ic)XX Surgeon General'\ Report that treatment of nicotine addiction should be con\idrred at least ;I\ fa\orabl! by third-part) ptiyor\ ;I\ treatment of atcoholim anti illicit drug addiction. Good smohing cessation trcatmt'nt\ C;III xhie\e :rh\tinencc rate\ of 20 to 40 percent at I -\car followup. Those SLICLYS\ rate\. combined with the enormou\ health benefits ofmokinf cessation. would libel) mahc pa! IIICIII for WIIIC wlohln, (I ce4ation tre3tments cwt- beneficial. For example. research b! the Center\ for Diwazc Control suggests that a smoking cessation program offered to all pregnant \mohers could sa\`e $5 for e\er!, dollar spent b> prz\entin, 0 tow hirthuttiflit-3s~oc~icltt`tl nrc~natul intt`n\i\ e cure and long-term cure. ii This Report should galvanize the health community, to stres\ repeatedly at every opportunity the value of smoking cessation to the 50 million American\ who continue to smoke. James 0. Mason. M.D.. Dr.P.H. William L. Roper. M.D. Assistant Secretaq for Health Director Public Health Service Centers for Disease Control lil PREFACE This Report of the Surgeon General is the 2lst Report of the U.S. Public Health Service on the health consequences of smoking and the first issued during my tenure as Surgeon General. Whereas previous reports have focused on the health effects ot smoking. this Report is devoted to the benefits of smoking cessation. The public health impact of smoking is enormous. As documented in the 1989 Surgeon General's Report. an estimated 390.000 Americans die each year from diseases caused by smoking. This toll includes 1 IS.000 death\ from heart disease: 106.000 from lung cancer: 31.600 from other cancers; 57,000 from chronic obstructive pulmonary disease; 27,500 from stroke: and 52.900 from other conditions related to smoking. More than one of every six deaths in the United States are caused by smoking. For more than a decade the Public Health Service has identified cigarette smoking as the most important preventable cause of death in our society. It is clear, then, that the elimination of smoking would yield substantial benefits for public health. What are the benefits. however, for the individual smoker who quits'? A large body of evidence has accumulated to address that question and derives from cohort and case-control studies, cross-sectional surveys, and clinical trials. In studies of the health effects of smoking cessation. persons classified as former smokers may include some current smokers; this misclassification is likely to cause an underestimation of the health benefits of quitting. Taken together. the evidence clearly indicates that smoking cessation has major and immediate health benefits for men and w'omen of all ages. Overall Benefits of Smoking Cessation People who quit smoking live longer than those who continue to smoke. To what extent is a smoker's risk of premature death reduced after quitting smoking'? The answer depends on several factors, including the number of years of smoking. the number of cigarettes smoked per day, and the presence or absence of disease at the time of quitting. Data from the American Cancer Society's Cancer Prevention Study II (CPS-II) were analyzed in this Report to estimate the risk of premature death in ex-smokers versus current smokers. These data show, for example. that persons who quit smoking before age 50 have one-half the risk of dying in the next IS years compared with continuing smokers. Smoking cessation increases life expectancy because it reduces the risk of dying from specific smoking-related diseases. One such disease is lung cancer, the most common cause of cancer death in both men and women. The risk of dying from lung cancer is 22 times hitcher among male smohers and 12 times higher among female smokers L compared with people u ho have never smoked.The risk of lung cancer declines steadil) in people who quit smoking; after IO years of abstinence, the risk of lung cancer is about 3) to 50 percent of the risk for continuing smokers,. Smoking cessation also reduces the risk of cancers of the larynx. oral cavity. esophagus. pancreas. and urinary bladder. Coronary heart disease (CHD) is the leading cause of death in the United States. Smokers have about twice the risk of dying from CHD compared with lifetime nonsmokers. This excess risk is reduced by about half among ex-smokers after only 1 year of smoking abstinence and declines gradually thereafter. After 15 years ot abstinence the risk of CHD is similar to that of persons who have never smoked. Compared with lifetime nonsmokers. smokers have about twice the risk ofdying from stroke, the third leading cause of death in the United States. After quitting smoking. the risk of stroke returns to the level of people who have never smoked: in some studies this reduction in risk has occurred within 5 years. but in others as long as IS years of abstinence were required. Cigarette smoking is the ma.jor cause of chronic obstructive pulmonary disease (COPD). the fifth leading cause of death in the United States. Smoking increases the risk of COPD by accelerating the ape-related decline in lung function. With sustained abstinence from smoking. the rate of decline in lung function among former smokers returns to that of never smokers. thus reducing the risk of developing COPD. Influenza and pneumonia represent the sixth leading cause of death in the United States. Cigarette smohing increases the risk of respiratory infections such as intluenla. pneumonia. and bronchitis. and smoking cessation reduces the rish. Cigarette smohing is a major cause of peripheral artery occlusive disease. This condition causes substantial mortality and morbidity: complications may include inter- mittent claudication. tissue ischemiu and gangrene. and ultimately. loss of limb. Smoking cessation substantially reduces the risk of peripheral arter) occlusive disease compared with continued smoking. The mortalit> rate from abdominal aortic aneurysm is two to fi\,e times higher in current smokers than in never smohers. Former smohers ha\e half the excess rish of dying from this condition relative to current smohcrs. About 20 million Americans currently ha\,e. or ha\c had. an ulcer of the stomach 01 duodenum. Smohers have an increased rish of developin g gastric or duodenal ulcers. and this increased rish is reduced h> quitting smohing. Benefits at All Ages According to a I YXY Gallup survq. the proportion of smohers 14 ho say they would lihc to give up smohing is loL\er for smokers aged 50 and older (57 percent) than for smokers aged I X-24, (6X percent) and 3019 (67 percent ). Older smokers ma)' be less motivated to quit smohin g because the highly motivated may have quit already at younger ages. leaving a relatively "hard-core" group of older smohers. But man> long-term smohers may Iach motivation to quit for other reasons. Some may believe they are no longer at risk of smohing-related diseases because they have alread) survived smohing for man)' j'ears. Others ma> believe that an) damage that may ha\,e vi been caused by smoking is irreversible after decades of smohing. For similar reasons. many physicians may be less likeI) to counsel their older patients to quit. CPS-II data were used to estimate the effects of quittin, (7 smoking at various ases on the cumulative risk of death during a fixed interval after cessation. The results she\+ that the benefits of cessation extend to quitting at older ages. For example. a health! man aged 60-63 u ho smohes I pack of cigarettes or more per da\ reduces his rish of dying during the next IS learx by IO percent if he quits smoking. These findings support the recommendations of the Surgeon General's I'SXX Workshop on Health Promotion and Aging for the de\~elopmrnt and dissemination of smoking cessation messages and interventions to older persons. I am pleased that a coalition oforganirations and agencies is now worhing toward implementation of those recommendations. including the Centers for Disease Control; the Nut~onal Cancer Institute: the National Heart. Lun g. and Blood Institute: the Administration on Aging: the Department of Veterans Affairs: the Office of Disease Pre\,ention and Health Promotion: the American Association of Retired Persons: ;md the Fox Chase Cancer Center. The major mcssafc of this campaign bill be that it is nc\cr too late to quit smoking. Two facts point to the urgent need for a strong smohing cessation campaign targetin? older Americans: ( I ) 7 million smohers are aged 60 or older: and (2) smoking is :I ma,ior rish FActor for 6 of the I3 leading causes of death among those aged 60 and older. and is a complicating factor for 3 others. Benefits for Smokers with Existing Disease Many smokers who have already developed smoking-related disease or symptoms may be less motivated to quit because of a belief that the damage is already done. For the same reason, physicians may be less motivated to advise these patients to quit. However, the evidence reviewed in this Report shows that smoking cessation yields important health benefits to thoe who already suffer from smoking-related illness. Among persons with diagnosed CHD, smoking cessation markedly reduces the risk of recurrent heart attack and cardiovascular death. In many studies. this reduction in risk has been 50 percent or more. Smoking cessation is the most important intervention in the management of peripheral artery occlusive disease: for patients with this condi- tion, quitting smoking improves exercise tolerance, reduces the risk of amputation after peripheral artery surgery, and increases overall survival. Patients with gastric and duodenal ulcers who stop smoking improve their clinical course relative to smokers who continue to smoke. Although the benefits of smoking cessation among stroke patients have not been studied. it is reasonable to assume that quitting smoking reduces the risk of recurrent stroke just as it reduces the risk of recurrence of othercardiovascular events. Even smokers who have already developed cancer may benefit from smoking cessation. A few studies have shown that persons who stopped smoking after diagnosis of cancer had a reduced risk of acquiring a second primary cancer compared with persons who continued to smoke. Although relevant data are sparse. longer survival might be expected among smokers with cancer or other serious illnesses if they stop smoking. Smoking cessation reduces the rihk of respiratory infection\ such as pneumonia. w,hich are often the immediate causes of death in patient5 with an under- lying chronic disease. The important role of health care providers in counseling patients to quit smoking is well recognized. Health care providers should give smoking cessation advice and assistance to all patients v. ho smohe. including those uith existing illness. Benefits for the Fetus Maternal smoking is associated with several complications of pregnancy including abruptio placentae. placenta previa. bleeding during pregnancy. premature and prolonged rupture of the membranes. and preterm delivery. Maternal smoking retards fetal growth. causes an average reduction in birthweight of 100 g, and doublej the risk of having a low birthueight baby. Studies have shown a 25- to S0-percent higher rate of fetal and infant death\ among women who smoke during pregnancy compared with those wsho do not. Women who stop smohing before becoming pregnant have infants of the \ame birthweight ah those born to women who have never smoked. The same benefit accrue5 to women who quit smoking in the first 3 to 4 month\ of pregnancy and who remain abstinent throughout the remainder of pregnancy. Women who quit smoking at later stages of pregnancy. up to the 30th weeh of gestation. have int'ants with higher birthueight than do women who smoke throughout pregnancy. Smoking is probably the most important modifiable cause of poor pregnanq Cutcome among women in the United State\. Recent estimate\ suggest that the elimination of smoking during pregnancy could prevent about 5 percent of perinatal death\. about 20 percent of low birthweight births. and about 8 percent of preterm deliveries in the United State\. In groups with a high prevalence of smohin, 0 (e.g.. women who have not completed high school I. the elimination of smohing during prepnanq could prevent about IO percent of perinatal death\. about 35 percent of low birth\\eight birth\. and about IS percent of preterm deliverie\. The prevalence of mohing during pregnancy haj declined over time but remain\ unacceptabl!, hi2h. ApproximateI! 30 percent of U.S. women L\ ho are cigarette smokers quit after recognition of pregnancy. and other\ quit later in preganq. However. about 25 percent of pregnant \\omen in the United State\ \mohe throughout preynanc\. A \hoching \tatlstic i\ that half of pregnant uomcn who ha\,e not completed 2 high school smoke throughout prqnanc!. .Van) Momen N ho do not quit mohing during pregnanq reduce their dail? ci garettc consumption: however. reduced con- sumption without quitttng ma> have little or no benetit for hlrthuerfht. Of the ltomen who quit smoking during prepnanc!. 70 percent re\umt' \mohing within t >ear of deliver). Initiatives ha1.e been launched In the public and pri\ate sector\ to reduce smohing during pregxmc!. The\e pqrams should lx expanded. and le\\ educated pregnant women should be a \peciat target of these et'fort\. Strategic\ need to be developed to address the problem of relapse after deli\ er! Benefits for Infants and Children As a pediatrician. 1 am particularly concerned about the effects of parental smohing on infants andchildren. Evidence re\ ieued in the 1986 Surgeon General's Report. 7`1~ HW/I/I Co//.\(,y~rc,/r(.f,.\ c!f'/l/l.~/lllltu~.\, SINI&III~~. indicates that the children of parents who smoke, compared with the children of nonsmohinf parents. have an increased frequency of respiratoq infections 4uch as pneumonia and bronchitis. Man>, studies have found a dose-response relationship between respiratory illness in children and their level of tobacco smoke exposure. Several studies have shown that children exposed to IO~XILXXI smohe in the home are more libel) to develop acute otitis media and persistent middle ear effu\ions. Middle ear disease imposes a substantial burden on the health care system. Otitis media is the most frequent diagnosis made by physicians who care for children. The m> ringotom> and-tube procedure. used to treat otitis media in more than 1 million American children each year. is the most common minor surgical operation performed under general anesthesia. The impact of smoking cessation during or after prepnancq on these associations has not been studied. Hotiever. the dose-response relationship between parental smohing and frequency of childhood respirator), infection{ suggests that smohing cessation during pregnancy and abstinence after delivery would eliminate most ora1 I of the excess risk by eliminating mo\t or all of the exposure. If parents are unwilling to quit smoking for their own sake. I hould urge them to quit for the sake of their children. Passive-smohing-induced infections in infants and )`oung children can cause serious and even fatal illness. .Moreo\,er. children whose parents smoke are much more likely to become smokers themselves. Smoking Cessation and Weight Gain The fear of postcessation weight gain may discourage man) smoher\ from trying to quit. The fear or occurrence of height gain may precipitate relapse among many of those who already have quit. In the I%% Adult Use ofTobacco Survey. current smokers who had tried to quit were asked to judge the importance of several possible reasons for their return to smoking. Twenty-seven percent reported that "actual weight pain" was a "very important" or "somewhat important" reason why they resumed smoking: 22 percent said that "the possibility of gaining weight" was an important reason for their relapse. Forty-seven percent of current smokers and 48 percent of former smohers agreed with the statement that "smoking helps control weight." Fifteen studies involving a total of 20.000 persons were reviewed in this Report to determine the likelihood of gaining weight and the average height gain after quitting. Although four-fifths of smokers who quit gained weight after cessation. the average weight gain was only 5 pounds (2.3 kg). The average weight gain among subjects who continued to smoke was I pound. Thus, smoking cessation produce< a£ greater weight gain than that associated with continued smoking. This weight gain poses a minimal health risk. Moreover. evidence suggests that this small weight pain is accompanied by favorable changes in lipid profiles and in body fat distribution. i\ Smoking cessation programs and messages should emphasize that weight gain after quitting is small on average. Not onI\, is the average postcessation weight gain small. but the risk of large weight gain after quitting is extremely low. Less than -4 percent of those who quit smoking gain more than 20 pounds. Nevertheless. special advice and assistance should be available to the rare person who does gain considerable weight after quitting. For these individuals. the health benefits of cessation still occur. and weight control programs rather than smoking relapse should be implemented. Increases in food intake and decreases in resting energy expenditure are largely responsible for postcessation weight gain. Thus. dietary advice and exercise should be helpful in prevaentinp or reducing postcessation weight pain. Unfortunately. minor weight control modifications to smoking cessation programs do not generally yield beneficial effects in terms of reducing weight gain or increasing cessation rates. A few studies have investigated pharmacologic approaches to postcessation weight control: preliminary results are encouraging but more research is needed. High priority should be given to the development and evaluation of effective weight control programs that can be targeted in a cost-effective manner to those at greatest need of assistance. Psychological and Behavioral Consequences of Smoking Cessation Nicotine withdrawal symptoms include anxiety. irritability. frustration, anger. dif- ficulty concentrating. increased appetite. and urses to smohe. With the possible exception of urges to smohe and increased appetite. these effects soon disappear. Nicotine withdrav~al peaks in the first I to 7 days following cessation and subsides rapidly during the following weeks. With long-term abstinence. former smokers are likely to en.job favorable psychological changes such as enhanced self-esteem and increased iense of self-control. Although most nicotine withdrawal symptoms are short-lived. thej, often exert a strong influence on smokers ability to quit and maintain abstinence. Yicotine withdrawal may discourage many smohers from tr>inF to quit and may precipitate relapse among those who have recently quit. In the I%6 Adult U\e ofTobacco Survey. 39 percent of current smokers reported that irritability was a "very important" or "somew hat important" reason M hy the, resumed smoking after a previous quit attempt. Smokers and ex-smohcrs should be counseled that adverse psychological effects of smohing subside rapid]! over time. Smohing cessation materials and programs. nicotine replacement. exercise. \tre\s management. and dietary counseling can help smohers cope with these symptoms until the!, abate. after LI hich favorable psyhologi- cal changes are likeI> to occur. Support for a Causal Association Between Smoking and Disease Ten> of thousands of studies have documented the associations between cigarette smoking and a Iaye number of serious disease?;. It is safe to say that smoking represents the most extensively documented cause of disease ever investigted in the history of biomedical research. Previous Surgeon General's reports. in particular the landmarh 1964 Report of the Surgeon General's Advisory Committee on Smokin, L 0 ,tnd Health and the I982 Surgeon General's Report on smoking and cancer, examined these associations with respect to the epidemiologic criteria forcausality. These criteria include the consistent>. strength. specificity. coherence. and temporal relationship of the association. Based on these criteria. previous reports have recognired a causal association betueen smohing and cancers of the lung. larynx. esophagus. and oral cavity: heart disease: strobe: peripheral artery occlusive disease: chronic obstructive pulmonary disease: and intrauterine growth retardation. This Surgeon General's Report is the first to conclude that the evidence is now sufficient to identify cigarette smohin, (7 as a cause of cancer of the urinary bladder: the 1983 Report concluded that cigarette smohing is a contributing factor in the development of bladder cancer. The causal nature of most of these associations was v.ell established long before publication of this Report. Nevertheless. it is worth notin, ~7 that the findings of thi\ Report add even more weight to the evidence that these associations are causal. The criterion of coherence requires that deacriptibc epidemiologic findings on disease occurrence correlate with measures of exposure to the suspected agent. Coherence would predict that the increased risk of disease associated with an exposure Lvould diminish or disappear after cessation of exposure. As this Report shows in great detail. the risks of most smoking-related diseases decrease after cessation and with increasing duration of abstinence. Evidence on the risk of disease after smoking cessation is especially important for the understanding of smoking-and-disease associations of unclear causality. For ex- ample, cigarette smoking is associated with cancer of the uterine cervix. but this association is potentially confounded by unidentified factors (in particularby a sexually transmitted etiologic agent). The evidence reviewed in this Report indicates that former smokers experience a lower risk of cervical cancer than current smokers. even after adjusting for the social correlates of smoking and risk of sexually acquired infections. This diminution of risk after smoking cessation supports the hypothesis that smoking is a contributing cause of cervical cancer. Conclusion The Comprehensive Smoking Education Act of 1983 (Public Law 98473) requires the rotation of four health warnings on cigarette packages and advertisements, One of those warnings reads. "SURGEON GENERAL'S WARNING: Quitting Smoking Now Greatly Reduces Serious Risks to Your Health." The evidence reviewed in this Report confirms and expands that advice. The health benefits of quitting smoking are immediate and substantial. They far exceed any risks from the average S-pound weight gain or any adverse psychological effects that may follow quitting. The benefits extend to men and women. to the young and the old. to those who are sick and to those who are well. Smoking cessation represents the single most important \tep that smokers can take to enhance the length and quality of their lives. xi Public opinion poll\ tell u\ that mat smoker\ &ant to quit. This Report provides smokers with new and more pouerf-ul motivation to give up thi\ self-destructive beha\ ior. Antonia C. Novello. M.D.. M.P.H Surgeon General xii ACKNOWLEDGMENTS This Report was prepared by the Department of Health and Human Serv,ices under the general editorship of the Office on Smoking and Health. Ronald M. Davis. M.D.. Director. The Managing Editor wa\ Susan A. Hawk. Ed.M.. MS. Jonathan M. Samet. M.D. (Senior Scientific Editor). Professor of Medicine and Chief. Pulmonary Division. Department of Medicine and the New MexicoTumor Registry. Cancer Center. University of New Mexico, Albuquerque. New Mexico Ronald M. Davis, M.D., Director. Office on Smoking and Health, Center for Chronic Disease Prevention and Health Promotion (CCDPHP), Centers for Disease Control (CDC), Rockville, Maryland Neil E. Grunberg, Ph.D., Professor. Department of Medical Psychology. Uniformed Services University of the Health Sciences. Bethesda, Maryland Judith K. Ockene. Ph.D.. Professor of Medicine, and Director, Division of Preventive and Behavioral Medicine. Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts Diana B. Petitti, M.D., M.P.H., Associate Professor, Department of Family and Com- munity Medicine, University of California at San Francisco, School of Medicine. San Francisco, California Walter C. Willett, M.D.. Dr.P.H.. Professor of Epidemiology and Nutrition. Harvard School of Public Health, and The Channing Laboratory, Department of Medicine. Harvard Medical School and Brigham and Women's Hospital. Boston. Mas- sachusetts Robert Anda. M.D., Epidemiologist. Office of Surveillance and Analysis, CCDPHP. CDC. Atlanta, Georgia John Baron, M.D., Associate Professor of Medicine. Department of Medicine. Dartmouth Medical School, Hanover, New Hampshire Tim Byers. M.D.. M.P.H., Chief, Epidemiology Branch. Division of Nutrition. CCDPHP. CDC, Atlanta. Georgia Arden G. Christen, D.D.S., M.S.D., M.A.. Chairman. Professor, Department of Preven- tive and Community Dentistry, Indiana University School of Dentistry. Indianapolis. Indiana Graham Colditz. Dr.P.H., Assistant Professor of Medicine. Harvard School of Public Health, and the Channing Laboratory, Department of Medicine. Harvard Medical School and Brigham and Women's Hospital. Boston. Massachusetts Carlo C. DiCiemente. Ph.D.. Associate Professor. Department of Psychology. Univer- sity of Houston. Houston, Texas Douglas W. Docket-y, Sc.D.. Associate Professor. Department of Environmental Health. Environmental Epidemiology Program. Harvard School of Public Health. Boston, Massachusetts Gary A. Giovino. Ph.D.. Acting Chief. Epidemiology Branch. Office on Smoking and Health. CCDPHP. CDC. Rockville. Maryland Deborah Grady, M.D., Assistant Professor. Departments of Epidemiology and Medicine, University, of California at San Francisco. School of Medicine. San Francisco. California Neil E. Grunberg. Ph.D.. Professor, Department of Medical Psychology. Uniformed Services University of the Health Sciences. Bethesda, Maryland John R. Hughes. M.D., Associate Professor. Human Behavioral Pharmacology Laboratory, Departments of Psychiatry. Psychology. and Family Practice. University, of Vermont. Burlington. Vermont Robert W. Jeffery. Ph.D., Professor, Division of Epidemiology. School of Public Health. University of Minnesota, Minneapolis, Minnesota LTC James W. Kikendall, M.D.. Assistant Chief. Gastroenterology Section. Walter Reed Army Medical Center, Washington. D.C. Robert Klesges. Ph.D.. Associate Professor. Department of Psychology. Memphis State University, Memphis, Tennessee Lynn Kozlowski. Ph.D.. Head, Behavioral Tobacco Research. Socio-behavioral Re- search Department, Addiction Research Foundation, Toronto. Ontario. Canada Stephen Marcus. Ph.D.. Epidemiologist. Office on Smoking and Health. CCDPHP. CDC. Rockville, Maryland James L. McDonald. Jr.. Ph.D.. Assistant Chairman. Professor. Department of Preven- tive and Community Dentistry. Indiana University School of Dentistry. Indianapolis. Indiana Sherry L. Mills, M.D.. M.P.H.. Medical Officer. Office on Smoking and Health. CCDPHP. CDC. Rockville. Maryland Judith K. Ockene. Ph.D.. Profeswr of Medicine. and Director. Division of Preventive and Behavioral Medtctne. Department of Medicine. Univjersity of Massachusetts Medical School. Worcester. Massachusett\ Carolr Tracy Orleans. Ph.D.. Director. Smohing Cc\sation Srrv,ice\. Fox Chaw Cancer Center. Cheltenham. Pennsylvania Diana B. Pctitti. M.D.. M.P.H.. .Aswciatc Professor. Department of Family and Com- munity, Medtctne. University ofCalifomiaat San Franciwo. School of Medicine, San Franci\co. California John P. Pierce. Ph.D.. Associate Professor. Director. Population Studies and Cancer Prevention. Tobacco Control Pro.icct. University of California. San Diego Cancer Center. San Diego. California Paul R. Pomrehn. Ph.D.. M.S.. Associate Profe\wr. Department of Preventive Medicine and Environmental Health. University of Iowa College of Medicine. Iowa City. Iowa James 0. Procha\ka. Ph.D.. Professor. Director. Cancer Prevention Research Unit. Department of Psychology. Liniversity of Rhode Island. Kirqston. Rhode Island xiv Barbara Rimer. Dr.P.H.. Director, Beha\ ioral Research. Fox Chase Cancer Center. Philadelphia. Pennsylvania Mary Ann Salmon. Ph.D.. Research Specialrst. School of Social Worh. C.A.R.E.S.. University of' North Carolina. Chapel Hill. North Carolina Jonathan M. Samet. M.D. (Senior Scientific Editor). Profehsor of Medicine and Chief. Pulmonary Division. Department of Medicine and the Nea Mexico Tumor Registry. Cancer Center. University of New Mexico. Albuquerque. New Mexico David Savitz. Ph.D.. Associate Professor. Department of Epidemiolog>. School oi Public Health. University of North Carolina. Chapel Hill. North Carolina Charles B. Sherman, M.D.. Director. Pulmonar! Division. Miriam Hospital. Providence. Rhode Island Meir Stampfer. M.D.. Dr.P.H.. Associate Professor of Epidemiolog! Har\ ard School of Public Health. and The Charming Laboratory. Department of Medicine. Harvard Medical School and Brigham and Womm's Hospital. Boston. Massachusetts Wayne F. Velicier. Ph.D.. Professor. Co-Director. Cancer Prclention Research Unit. Department of Psychology. Cnivcrsity of Rhode Island. Kingston. Rhode Island Thomas Vogt. Ph.D., Principle Investigator. Center for Health Research. Portland. Oregon Scott T. Weiss. M.D.. Associate Professor. Harvard School of Public Health. and The Charming Laboratory. Department of Medicine. Harvard Medical School and Brigham and Women's Hospital. Boston. Massachusetts Anna H. Wu-Williams. Ph.D.. Associate Professor. Department of Preventive Medicine. University of Southern California. Los Angeles. California David B. Abrams, Ph.D., Director. Division of Behavioral Medicine. The Miriam Hospital. Associate Professor, Psychiatry and Human Behavior. Brown Universit) Program in Medicine, Providence. Rhode Island Duane Alexander, M.D.. Director. National Institute of Child Health and Human Development. National Institutes of Health. Bethesda. Maryland David Bates. M.D.. FRCP, FRCPC. FACP. FRSC, Professor Emeritus of Medicine. Department of Health Care. University of British Columbia. Vancouver. British Columbia James S. Benson, Acting Commissioner. Food and Drug Administration. Rockville. Maryland Trudy S. Berkowitz, Ph.D.. Associate Professor. Department of Obstetrics. Gynecol- ogy. and Reproductive Science, Mount Sinai School of Medicine. New York. New York Ruth Bonita, M.P.H., Ph.D., Masonic Senior Research Fellow. Geriatric Unit. Univer- sity of Auckland. Auckland 9. New Zealand Lester Breslow, M.D.. M.P.H.. Professorof Public Health and Director. Health Services Research. Division of Cancer Control, Jonsson Comprehensive Cancer Center. University of California. Los Angele\. Los Angeles. California Samuel Broder. M.D.. Director, National Cancer Institute. National Imtitutes of Health. Bethesda, Maryland David Bums. M.D.. Associate Professor. Pulmonary Division. Division of Pulmonary Medicine and Critical Care, University of California at San Diego Medical Center, San Diego, California Benjamin Burrows. M.D.. Director, Division of Respiratory Sciences. University of Arizona Health Sciences Center. University of Arizona School of Medicine, Tucson, Arizona Jane Cauley. Dr.P.H.. Assistant Professor of Epidemiology. Department of Epidemiol- ogy. University of Pittsburgh. Pittsburgh. Pennsylvania Gregory N. Connolly, D.M.D., M.P.H.. Director, Office on Nonsmoking and Health. Massachusetts Department of Public Health. Boston. Massachusetts Thomas M. Cooper, D.D.S.. Professor. University of Kentucky Medical Center. Col- lege of Dentistry. Lexington. Kentucky Stephen Corbin. D.D.S.. M.P.H., Policy Analyst, Disease Prevention. Center for Preventive Services (CPS). CDC. Bethesda, Maryland K. Michael Cummings. Ph.D.. M.P.H.. Cancer Control and Epidemiology. Roswell Park Cancer Institute. Buffalo, New York Joseph W. Cullen. Ph.D.. Director. AMC Cancer Research Center, Denver. Colorado Sir Richard Doll. ICRF Cancer Studies Unit. Oxford. United Kingdom Virginia Ernster. Ph.D.. Professor of Epidemiology. Department of Epidemiology and International Health. University of California. San Francisco. San Francisco. California Jonathan E. Fielding. M.D.. M.P.H.. Vice President and Health Director. Johnson and Johnson Health Management. Inc.. Santa Monica. California Gary D. Friedman. M.D.. M.S.. Division of Research. Kaiser Permanente Medical Care Program. Northern California Region. Oakland. California William Foege. M.D., Executive Director. The Carter Center of Emory University. Atlanta. Georgia Lawrence J. Furman. D.D.S.. M.P.H.. Chief. Dental Disease Prevention Activity. CPS. CDC, Atlanta. Georgia LawrenceGarfinkel. Vice President for Epidemiolog) and Statistic>. DirectorofCanccr Prevention, American Cancer Society. Inc.. New York. New York Barbara A. Gilchrest. M.D.. Professor and Chairman. Department of Dermatolog . Boston University Medical Center. Boston. Mahjachu\ett\ Frederick K. Goodwin. M.D.. Administrator. Alcohol. Drug Abuse. and Mental Health Administration. Rochville. Maryland Robert 0. Greer. Jr.. D.D.S.. Sc.D.. Profes5orand Chairman. Division ofOral Patholog and Oncology. Department of Diagnostic and Biological Sciences. School of Den- tistry. University of Colorado Health Sciences Center. Boulder. Colorado Ellen Gritz. Ph.D.. Director. Division of Cancer Control. Jon\\on Comprehensive Cancer Center. University of California. Lo\ Angele\. Los Angeleh. California xvi Nanq J. Haley. Ph.D.. Associate Chief. Division of Nutrition and Endocrinology. American Health Foundation, Valhalla, New> York Sharon M. Hall. Ph.D.. Professor of Medical Psychology. Department of Psychiatry. University of California. San Francisco. San Francisco Veterans Administration Medical Center. San Francisco. California Robert Harmon. M.D.. Administrator. Health Resources and Services Administration, Rockville. Maryland Jeffrey E. Harris. M.D.. Ph.D.. Associate Professor. Department of Economics. Ma\- sachusetts Institute of Technology. Cambridge. Massachusett\. Clinical Associate. Medical Services. Massachusetts General Hospital. Boston. Massachusetts Norman 0. Harris, D.D.S.. M.S.. University of Texas Health Science Center. San Antonio. Texas Jack Henningfield. Ph.D.. Chief. Clinical Pharmacology Branch. National Institute on Drug Abuse Addiction Research Center, National Institutes of Health. Baltimore. Maryland Robert A. Hiatt. M.D.. Ph.D.. Senior Epidemiologist. Division of Research. Kaiser Permanente Medical Care Program. Oakland California Millicent Higgins. M.D.. Associate Director. Epidemiology and Biometry Program. Division of Epidemiology and Clinical Applications. National Heart. Lung. and Blood Institute. National Institutes of Health. Bethesda. Maryland Carol Hogue. Ph.D., M.P.H.. Director, Division of Reproductive Health. CCDPHP. CDC. Atlanta. Georgia John Holbrook. M.D.. Professorof Internal Medicine. Department of Internal Medicine. University of Utah School of Medicine. Salt Lake City. Utah Richard Hunt. M.D.. Division of Gastroenterology. McMaster University Medical Center. Hamilton, Ontario, Canada Dwight Janerich. D.D.S.. M.P.H.. Professor of Epidemiology. Department of Epidemiology and Public Health. Yale University School of Medicine, New Haven. Connecticut William Kannel. M.D., Professor of Medicine. Department of Preventive Medicine. Boston University School of Medicine, Boston, Massachusetts LTC James W. Kikendall. M.D., Assistant Chief, Gastroenterology Section. Walter Reed Army Medical Center, Washington. D.C. Dushanka V. Kleinman. D.D.S.. M.Sc.D., Section Chief. National Institute on Dental Research. National Institutes of Health. Bethesda, Maryland C. Everett Koop. M.D.. Sc.D., U.S. Surgeon General, I98 i-89. Bethesda. Maryland Jeffrey P. Koplan, M.D.. M.P.H., Director, CCDPHP, CDC. Atlanta. Georgia Lewis H. Kuller, M.D.. Dr.P.H., Professor and Chairperson. Department of Epidemiol- ogy, University of Pittsburgh Graduate School of Public Health. Pittsburgh. Pennsyl- vania Charles L. LeMaistre. M.D., President, The University of Texas M.D. Anderson Cancer Center. Houston. Texas Claude Lenfant, M.D., Director. National Heart, Lung. and Blood Institute. National Institutes of Health, Bethesda, Maryland Richard J. Levine. M.D.. M.S.. M.P.H., Chief Epidemiologist. Chemical Industr! Institute of Toxicology. Research Triangle Park. North Carolina Edward Lichtensrein. Ph.D.. Research Scientist. Oregon Research Institute. Eugene. Oregon Jay H. Luhin. Ph.D.. National Cancer Institute. National Institutes of Health. Rockville. Maryland Alfred C. Marcus, Ph.D., Director. Community Research and Applications. AMC Cancer Research Center. Denver. Colorado Denis M. McCarthy. M.D.. MSc.. Chief. Division of Gastroenterology. University of New Mexico. Department of Medicine. Veterans Administration Medical Center. Albuquerque. New Mexico J. Michael McGinnis. M.D.. Deputy Assistant Secretary for Health. Disease Prevention and Health Promotion. Department of Health Human Services. Washington. D.C. Sonja M. McKinlay. Ph.D.. M.Sc.. M.A.. B.A.. ASA. APHA. AER. SCt. Biometrics Society. Institute of Mathematical Statistics. International Menopause Society. American Association for the Advancement of Science. President. New England Research Institute. Inc.. Watertown. Massachusetts Robert E. Mecklenberg. D.D.S.. M.P.H.. Potomac. Maryland L. Joseph Melton. III. M.D.. Head. Section of Clinical Epidemiology. Department of Health Sciences Research. Mayo Clinic and Foundation. Rochester. Minnesota Anthony Miller. B.A., M.B.B.. M.R.C.P.. M.F.C.M.. F.R.C.P.C.. Professor. Depart- ment of Preventive Medicine and Biostatistics. University of Toronto. Toronto. Ontario, Canada Gregory Morosco. Ph.D.. M.P.H.. Chief. Health Education Branch and Coordinator. Smoking Education Program. National Heart. Lung. and Blood Institute. National Institutes of Health. Bethesda. Maryland Richard L. Naeye. M.D.. Professor and Chairman. Department of Pathology. Pennsyl- vania State University School of Medicine. Hershey. Pennsylvania Thomas A. Pearson. M.D.. M.P.H.. Ph.D.. Director. Mary lmogene Bassett Research Institute,Cooperstown. New York. ProfessorofPuhlic Health in Medicine. Columbia University. New Yorh. New Yorh Terry Pechaceh. Ph.D.. Acting Chief. Smohing. Tobacco, and Cancer Branch. Nation;tI Cancer Institute. National Institutes of Health. Bethesda. Maryland Michael G. Perri. Ph.D.. Professor and Deputy Chairman. Psychology Department. Fairleigh Dichinson University. Teanech. New Jersey Richard Peto. FRS. ICRF Cancer Studies Unit. Oxford. United Kingdom John M. Pinney,. Executive Director. Institute for the Study, of Smohing Brhav ior and Policy. John F. Kennedy School of Government. Harvard University. Cambridge. Massachusetts William F. Raub. Ph.D.. Acting Director. National Institute\ of Health. Bethesda. Maryland Patrick L. Remington. M.D.. Bureau of Community Health Prevention. Wisconsin Division of Health. Madison. Wisconsin Everett R. Rhoades. M.D.. Director. Indian Health Service. Rocbville. Maryland Julius Richmond. M.D.. John D. MacArthur Professor of Health Policy. Emeritus. Division of Health Policy. Research. and Education. Harvard Cniuersity. Boston. Massachusetts XVIII Williatn A. Robinson, M.D.. M.P.H.. Director. Office ot'\linorit! Health. Department of Health and Human Service\. Washington. D.C. William L. Roper. M.D.. M.P.H.. Director. CDC. Atl;rn~~. Georgia Richard B. Rothcnhq. M.D.. A\si\Iant Director for Science. CCDPHP. CDC. Atlanta. Georgia Thomas C. Schelling. Ph.D.. Director. Iwtitute t'or the Stud\ of Smoking Behavior and Policy. Lucius Iv. Littauer Professor of' Political Econotii~, tlar\ard L'ni\,ersit>. Cambridge. Massachusetts Marc B. Schenker. M.D.. M.P.H.. Associate Professor ;md Di\ i\ion Chief. Occupation- al and Environmental Medicine. University of California. Da\ i\. Da\ i\. California Da\,id Schottenfeld. M.D.. Professor and Chairman. Department of Epidetniolog . University of Michigan School of Public Health. Ann Arbor. hlichigan Kathleen L. Schroeder, D.D.S., M.Sc.. Assistant Professor. Section of Oral Biology. The Ohio State University College ot`Dentistr\,. Columbus. Ohto Mary J. Sexton. Ph.D.. M.P.H.. Professor. Department ofEl-7idrmiolo~! and Ptwentive Medicine. University of Maryland School of` Medtcine. Baltimore. Mar! land Saul Shiffman. Ph.D.. Associate Professor. Department of Psychology. L'niwrsit>, ot Pittsburgh. Pittshurgh. Pennsylvania Donald Shopland. Smoking. Tobacco. and Cancer Branch. 2iational Cancer Institute. National Institutes of Health. Bethesda. blur> land Amnon Sonnenberg. M.D.. Associate Professor. Gastroentet.olof! Section. Medical College of Wisconsin. Veterans Administration Medical Center. Milwaukee. Wis- consin Frank E. SpeiLer. M.D.. Professor of Medicine, Harvard Medical School. Professor of Environmental Epidemiology. Harvard School of Public Health. Co-Director. The Channing Laboratory. Department of Medicine. Brigham and Women's Hospital. Boston. Massachusetts Jesse Steinfeld. M.D., San Diego. California Steven D. Stelltnan. Ph.D.. Assistant Commissioner. New Yorh Cit>, Department of Health. New York. Neu York Ira B. Tager, M.D.. M.P.H., Associate Professor of Medicine and Epidemiology and Biostatistics, University ofcalifornia. San Francisco. Veterans Administration Medi- cal Center, San Francisco, San Francisco. California Kenneth Warner. Ph.D.. Senior Fellow. Institute of Gerontology. University, of Michigan. Ann Arbor. Michigan Jonathan S. Weiss. M.D.. Assistant Professorof Dertnatologz. Section of Dertnatology. Emory Clinic, Atlanta. Georgia Noel S. Weiss. M.D., Dr.P.H.. Professor and Chairman. Department of Epidemiology. University of Washington. Seattle, Washington Gail R. Wilensky. Ph.D., Administrator. Health Care Financing .4dministr:ttion. Washington. DC Deborah Winn. Ph.D.. Deputy Director. Division of Health Interview Stati\lics. Na- tional Center for Health Statistics. CDC. Hyattsvillc. Mqland Philip A. Wolf, M.D.. Professor of Neurology. Department of Neurology. Boston University School of Medicine. Boston, Massachusetts Ernst L. Wynder. M.D.. President. American ffcalth Foundation. Neu Yorh. Ur\\ Yorh \i\ Cxnwn Aguirrr. Secretq. Officeon Smohtng and He;~l~h. C'CDPHP. (`DC`. Roc,h\ 111~`. hlar! land Andrea Anderwn. Student Intern. Of`t~ice on Smohln $! ~11111 tic~lltll. C`C`DPI it'. (`I)(`. Rochville. Marylnnd Mxgaret Anglin. Secretq. Oft'icr on Smohin, `7 and Health. CCDPHP. (`DC`. Koch- ville. Maryland Cathy Arney. Graphic Artist. The Circle. Inc.. MCLC;III. Virginia John Arti>. Courier. The Circle. Inc.. McLean. Virgini; Michele Awael. Confrrenctr Coordinator. The C'il-ck. Inc... ZlcLcan. 1'11.21111s John L. Bqrwhy. A\wciate Director for Progr;lm C>pcl-ation\. Ol'l.ic~ on Snlohlns ;111d Health. CCDPHP. CDC. Roch\~ille. Mql;~nd Sonia Bslahirsky. Srcrctary. Office on Snlohin, $1 and Hcal~h. (`(`DPHP. C`D(`. Roc,h- ville. Maryland Barbara Barme\. Admini\tratiw A\\istant. The Circle. Inc.. \lc,l.c;~n. L'Irglnl;l Carol A. Bean. Ph.D.. Acting 2l;ulaging Editor. ..Irtcntl\ Tcc~hnol~~gic~. IIIC... Springfield. Virginia Mari\sa A. Bernctrin. Editor. The Circle. Inc.. IllcLean. L'irslnia Em' Ria Brikcoe. Cont'erencr Coordinator. The Circk. Inc.. \lcl~can. \`irglni.r Karen Broder. Public Information Spwiali\t. Ot't`icc on Smohing a~ld ticalrh. (`CDPtt P. CDC. Rochville. Mar> INKI Barbara M. Broun. Editowl h\\l\t;unt. 00'~ cw Smoking ;untl Health. Rc)ch\ 111~~. h4aryland Catherine E. Burchhardt. Public Int'ormation Speci,llist. Ol't'iw on Srnc\hlns and ticL\l\ll. CCDPHP. CDC. Roth\ ilk. Mar! land Ltx Chapell. Courier. The Circle. Inc.. McLtxn. Virginia Won Choi. Revarch A\\l\tant. Ot't`iw m Smohing and Health. CCDPI IP. C'DC`. Roch\,ilk. Mar> Im~d Trihh Da\.itlwn. Studtxt Intam. Ot't`icc on Smohlng and Health. C`C`DPtiP. C`tX`. Rochville. Maryland Susan E. Da!. Sawtar!. Office OII Snlohln, cr and Health. CCDPHP. C-LX`. Roi,h\ 111~`. hlaryiand Karen M. Dtxs~. .-I\soci;nc Dirt'ctot- I'oI- PoIIc,!. Ott~c~ OH Smohir); and tlcalttj. CCDPHP. CDC'. Roth\ ilk. 3l;rr> land June DOM. Public Health Scr\ 1c.c Congrcs\ionaI Rcpol-t\ (`c)c)rdiii;ltor. Ot`tlce ot'llcattl~ Planning UKI E\~;rluation. Ot`t`icc ot`thc .\\xl\t;tnt Sec~rctar-\ i(v tfcal~ll. M';l\llingtcw. D.C. Joanna Ebling. \+`or-d Proc~c\\lns S~LTI;I~I\~. 7`1~ CirL,Ic. Inc.. \l~~Lean. l'lrglnia Pam Edward\. S!\tem Xdministrator. %lS;\. Inc.. Roth\ 111~. \lar- I;t~~cl Rita Elliott. Technical Editor-. \c\r hlz\ico Tunior Rc:i\tl-! I ni\cl-\lt> rjt' \c\\ Mexico. Albuquerque. NW Xlc\icc) Seth Errwnt. Ph.D.. Epidemic Intelllgcnce Ser\ ice Ot't'lca. 0t'l'lc.c on Smohtll~ ;111d Health. CCDPHP. CDC. Roch\ille. \lar\l;~nd Sharon K. Faupel, Staff Assistant, Office on Smoking and Health. CCDPHP. CDC. Rockville, Maryland Leanna Fernando, Administrative Assistant, New Mexico Tumor Registry, University of New Mexico, Albuquerque, New Mexico David Fry. Editor, The Circle, Inc., McLean, Virginia Lynn Funkhauser, Word Processing Specialist, The Circle, Inc.. McLean, Virginia Amy Carson, Student Intern, Office on Smoking and Health. CCDPHP. CDC. Rock- ville, Maryland Mary Graber. Secretary, University of California at San Francisco, School of Medicine. Department of Family and Community Medicine, San Francisco. California Gwen Harvey, Program Analyst, CCDPHP. CDC. Atlanta. Georgia Patricia Healy, Technical Information Specialist. Office on Smoking and Health. CCDPHP. CDC. Rockville, Maryland Phyllis E. Hechtman. Editorial Assistant. The Circle, Inc.. McLean, Virginia Timothy K. Hensley. Technical Publications Writer-Editor, Office on Smoking and Health, CCDPHP. CDC, Rockville. Maryland Julian Hudson, Courier. The Circle, Inc.. McLean. Virginia Beth Jacobsen, Student Intern, Office on Smoking and Health. CCDPHP. CDC. Rockville. Maryland Renee Kolbe, Program Specialist. Office on Smoking and Health, CCDPHP. CDC. Rockville, Maryland Matt Kreuter, Public Information Specialist, Office on Smoking and Health, CCDPHP. CDC. Rockville, Maryland Peggy Lytton, Editor, The Circle, Inc., McLean, Virginia Diana Lord, Research Psychologist, Department of Medical Psychology. Uniformed Services University of the Health Sciences. Bethesda. Maryland Daniel F. McLaughlin, Editor, The Circle, Inc., McLean. Virginia Jackie L. Meador, Desktop Publishing/Word Processing Specialist. The Circle. Inc.. McLean, Virginia Elaine Medoff-McGovern, Medical Secretary. Division of Preventive and Behavioral Medicine, Department of Medicine. University of Massachusetts Medical School. Worcester, Massachusetts Nancy A. Miltenberger, M.A., Production Editor, The Circle. Inc.. McLean. Virginia Rebecca Mosher, Staff Assistant, New Mexico Tumor Registry. University of New Mexico, Albuquerque, New Mexico Millie R. Naquin, Research Assistant. Office on Smoking and Health, CCDPHP. CDC. Rockville. Maryland Thomas E. Novotny, M.D., Chief, Program Services Activity. Office on Smoking and Health, CCDPHP, CDC, Rockville, Maryland Cathie M. O'Donnell. Project Director, The Circle. Inc., McLean, Virginia Christine Pappas, Editorial Research Assistant, The Channing Laboratory, Harvard School of Public Health. Boston, Massachusetts Stacey M. Parcover, Secretary, Office on Smoking and Health, CCDPHP. CDC, Rockville. Maryland Lida Peterson, Computer Systems Manager. The Circle. Inc., McLean. Virginia Renate J. Phillip\. Graphic .Arti\t. D&top Puhli\hln 2 Desipnrr. The Circle. Iric.. McLean. Vir~~ini~t ` Margaret E. Pickerel. Public Int'ormation and PubIicatlons SpeciaIi\t. ~t`t`icc 011 SIII~~- ing and Health. CCDPHP. CDC. Rochville. Mq land EliAmh Precup. Student Intern. Office on Smohtng and Health. CCDPHP. CDC. Rochville. Maryland Cary R. Prince. Editor. The Circle. Inc.. McLean. Virginia Dick Ray. Director of Computer Sm ice\. The Circle. Inc.. IlcLean. Virginia Nancy J. Rhodes. Editor. The Circle. Inc.. McLean. Virginia Rose Mary Romano. Chiet`. Public Int'orm;Ltion Branch. Oft`icr m Snlohing and Health. CCDPHP. CDC. Rocl\\.ille. Mar! land Lisa Phelph. Computer S>3tern\ Anal! \t. The Circle. Inc.. hlclcan. \`irginia Sel Semler. Sccreta~-1. Oi`ficc on Swrhing and Halth. CCDPHP. CDC. Roth\ 111e. Maryland Jane\ S1in.a. Student Intern. Otl`ice on Smohin 2 imi Health. CCDPHP. CDC. Roch- ville. Marshland Mattie Smith. Srcrrtar!, . CCDPHP. CDC. Roch\,ille. hl;rr> Ixnd Linda R. Spiegrhmn. Administrative Oft`iccr. Office on Smohin: and Health. CCDPHP. CDC. Roth\ ilk. Mar> Imd Traion C. Stallinys. Project Sectmar>. The Circle. Inc.. McLean. C'irsinla Sophia Stewart. Student Intern. Ofl`icr on Smohing and Htxtlth. CCDPHP. CDC. Rock\~illr. Maryland D:tniel R. Tich. Director of Publications. The Circ~lc. II~c~.. LlcLean. \`iyinia Anne Trontell. M.D.. Epidemic Int~lligencr Stm ice Otfiwr. Ot`t`icc on Smohing and Health. CCDPHP. CDC. Roth\ ilk. Mar! land Karen T\,lrr. Cont'erenct` Coordinator. The Circle. Inc.. ZlcLwt. I'tt-ginta Godfrey R. Vw. h1.D.. Student Intern. Ot`ficc on Smohing and Hcal~h. CCDPHP. CDC'. Rock\ ilk. Mar> land Su~n Von Bratmberg. Ini'ormaticm Speci;tli\t. The Circle. lw.. \lcLcarl. Virginl;r Elyse Watwn. Adminiaxtt~c :\\\imnt. Nrn ?,le\ico TUII~~I- RcFi\tr>. L.ni\cr\lt! ot New Mexico. Albuquaque. UC\+ Llcxico Michael F. White. .A \sociate Dirt`ctor for Progr-am De\ ~~lopncn~. C`C`DPHf'. C`DC. Roth\ ilk. Rlx~ land Chxlex WIggin\. Xl.S.P.11.. E~~l~l~~liiologl\t. Xc\\ \lc\~co 1~t11iior RC~I\II-!. I 11i\ C`I.\II\ Of Neu Rle-ilco. .~lhlK~llmp'. Kl?\\ l\tc\tcr, Louiw G. Wist`nxtn. TcchnicA Information Specul~s~. Ott`icc on Snlohlng and tlcalth. CCDPHP. CDC`. Koch\ tllc. \l;rr> I;mcI Rebecca B. b'olt'. Progrm .Inal! st. 0t`t'ic.c ot` Progrant Planning ,~nd I!\ ;rlu,ltioll. C`D(`. Attanta. Gccwgia S. Tannc~- Wra!. Technical Inter-matioll Spcclall\t. Ot't~cc 011 Snlohlng ad llcalth. CCDPHP. CDC. Rtrch\ilk. IlarylmA TABLE OF CONTENTS Foreuord ........................................................... i Preface ............................................................. I Acknowledgments .................................................. xiii ListofTables .................................................... ..xx v ListofFigur& .................................................... xxxi 1. Introduction. Overview, and Conclusions ............................. I 2. Assessing Smoking Cessation and Its Health Consequences .............. 17 3. Smoking Cessation and Overall Mortality and Morbidity ................ 7 1 4. Smoking Cessation and Respiratory Cancer-5 ......................... IO3 5. Smoking Cessation and Nonrespiratory Cancers ...................... I43 6. Smoking Cessation and Cardiovascular Disease ...................... 1 X7 7. Smoking Cessation and Nonmalignant Respiratory Diseases ............ 175 8. Smoking Cessation and Reproduction .............................. 367 9. Smoking, Smoking Cessation, and Other Nonmalignant Diseases ........ 425 10. Smoking Cessation and Body Weight Change ........................ 469 1 I. Psychological and Behavioral Consequences and Correlates of Smoking Cessation ............................................. 5 I7 Volume Appendix. National Trends in Smoking Cessation ................ 579 Glossary ........................................................ ..617 lndex.............................................................61 9 Xklll LIST OF TABLES Chapter 2 Table 1. Measures of false reports of not smoking from studies using nicotine and cotinine as a marker . . 3X Table 2. Measures of false reports from studies using CO as a marker 1 I Table 3. Examples of potential methodologic problems in investigating the health consequences of smoking cessation 17 Chapter 3 Table 1. Summary of longitudinal studies of overall mortality ratios relative to never smokers among male current and former smokers according to duration of abstinence (when reported I 76 Table 2. Overall mortality ratios among current and former smohers. relative to never smokers. by sex and duration of abstinence at date of enrollment. ACS CPS-II . . . . . . . . . . , 7x Table 3. Estimated probability of dying in the next 165year interval for quitting at various ages compared with never smohing and continuing to smoke. by amount smoked and sex . . . x3 Table 4. Summary of overall mortality ratios in intervention studies in which smoking cessation was a component . . . , . 8-t Table 5. Summary of studies of medical care utilization among smokers andformersmokers . . . . .._.................................. Table 6. Relation of smoking cessation to various measures of general health status . . . . . . . . . . . .._.................................. Table 7. Age- and sex-specific mortality rates among never smokers. continuing smokers. and former smokers by amount smoked and duration of abstinence at time of enrollment for subjects in ACS CPS-II study who did not have a history of cancer. heart disease. or stroke and were not sick at enrollment . . . , . . Table 8. Estimated probability of dying in the next 165year interval (95% Cl) for quitting at various apes compared with never smohing and continuing to smoke. by amount smohed and sex . xx 90 . 95 97 \\\ Chapter 4 Table I. Histologic changes (?/ ) in bronchial epithelium by smoking status .___.____.___.,,....._.__,.._._._...,.._.,....,..._._ Table 2. Relative rishs of lung cancer among never, fomter. and current smokers in selected epidemiologic studies . . Table 3. Lung cancer mortality ratios among never. current. and former smokers by number of years since stopped smoking (relative to never smokers). prospective studies . . . . . . . Table 4. Relative risks of lung cancer among former smokers. by number of years since stopped smoking. and current smokers. from selected case ratio\ for COPD among current and former smoher\ hrohen down h) y;Lr\ of ah5tinence . Chapter 8 Table 1, Possible mechanisms for effect of smohing on pregnant!' and pregnancy outcome ,......._........................., . . . Table 2. Summary of studie\ of fertility among smokers and former smoker\ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 3. Summary of studies of perinatal and neonatal mortality in smokers and nonsmoker\ during pregnanq . . Table 3. Estimated relative risk of fetal plu\ infant mortality for maternal smoking in several birthweight groups. adjusting for maternal marital statu\. education. age. and parity . . . Table 5. Summary of studies of perinatal mortality in wloher\ throughout pregnancy. smohers who quit in the early month\ of pregnancy. and nonsmokers during pregnancy Table 6. Summary of studieh of mean birthweight. b>, smoking statuh . Table 7. Summar\, of nonexperimental studie\ of smoking cewttion after conception. mean increase (+) or decrease (6) in birthueight (g) according to timing of cessation Table 8. Summary of nonexperimental studies of relative risk of IOU birthweight for smoking ceaation after conception Table 9. Summary of birthweight outcome in randomized trials ot smohing cessation in pregnancy . . . . Table IO. Smoking and smoking! cehation during pregnancy. summq of results of two wrveys of national probability \ample\ Table I I. Patterns of smoking cessation during pregnarq among selected population4 . . . Table 12. Summary of \tudit`s that estimated relative rish of \ariou~ pregnancy outcome\ for \mohing based on ;t "SJ nthe\ih" of the literature. and attributable risk percent based on several estimate\ of the prevalence of smohing during pregnancy . 3% Table 13. Summary of studies reporting relationship of cigarette smoking and age at natural menopause . . . 3'97 Table II. Summary of studit`\ of age of natural menopause among former smoker5 . . . . . . . . . 399 Table 15. Sexual performance among male former smoher\ 104 Table 16. Sperm quality among smokers and nonsmokers 406 xxviii Table 17. Estimated relative risk of azoospermia or oligospermia among smokers versus nonsmokers or never smokers . . . . . . . . 408 Table 18. Sperm quality among former smokers . . . . . 409 Chapter 9 Table I. Percentage of healed duodenal ulcers among smoking and nonsmokingpatients . . . . . . . . . . . . . . . . . .._..._...._..._........_ 433 Table 2. Results of statistical analysis of pooled data from Table I . 437 Table 3. Recurrences of duodenal ulcer in smokers and nonsmoker\ in clinical trials _ ~. . . . . . . . . . . . . . . . 43X Table 4. Recurrences of gastric ulcer in smokers and nonsmokers in clinical trials . . . . . . . . . . . . . . . . . 442 Table 5. Summary of studies of smoking and bone ma\< . . 445 Table 6. Summary of casernsu\ conference defined relapse as at least one puff per day for 7 da! 4 and recommended that this definition be applied uniformly (Shumaker and Grunbt'rs 19X61: however. thi\ definition is not used in all studies. Any return to \mokin~ that i\ Ic\s than the criterion for relapse is considered a "lapse" or a "slip." n,hich may or may not C;ILI~ a return 10 regular smoking (Brownell et al. 19X6: Marlatt. Curry. Gordon. 19Xx1. Although 75 to X0 percent of relapse occur> at 6 month Y and before (Hunt. Barnett. Branch 1971: Hunt and Bespalec 1973: Hughes ct al. 19X1: Gar\c\. Hcinold. Rohncr 1989). individuals who maintain abstinence for 6 montll\ continue IO rclap~ b\ 12 months and beyond. For example. in a re\,ieu of IO ctudies III u hich minimal or no intervention occurred (i.e.. \elf-change htudieb). relap~c' rate\ at 12 rnontl~~ i'or wmhw who had previously maintained abstinence t'or ;II 1~41 6 mcmth\ ranged t`rom 7 to 35 percent (Cohen et al. 1989). Data from the National lical~h and Nutrition t!\;tmin;111011 Survey I (NHANES-I) Epidemiologic Follouup Stud) demonstrate that even after I year of prolonged abstinence. relapse continues to occur 111 about one-third of former smokers. Relapse continues to occur at a much lovver rate after 2 years (Volume Appendix). In the Multiple Rirh Factor Intervention Trial (MRFIT). a multifact~~t intensive intervention study, Ochene and colleagues (19x2) found that among smokers who had stopped with the aid of intensive intervention. relapse continued to occur throughout the 6 years offollowup. However. relapse has at a much higher rate in the first year than in years two through six. Kirscht and colleagues ( lYX7) reported that Y.5 percent of adults who had been abstinent for 2-l to I I9 monthsreported smohing again in a followup survey. Even after I10 months. 1.3 percent of fomrer smokers reported smoking again. Research would be simplified if the probabilrty of remaining a former smoker were 100 percent after a prolonged period of abstinence. If this were the case. then there would be no concern about future misclassification of these confirmed former smokers. However. the continuous nature of the relapse process and the curv'es that represent this process indicate that the probability of maintained cessation u ill never be I00 percent. The available data (Garvey. Heinold. Rosner 19X9: Ochene et al. 19X2: Cohen et al. 1989: Volume Appendix) suggest that for most research purposes. 2-l months of continuous abstinence can be used as a practical criterion for categorizing individuals as confirmed former smokers. However. use of this timeframe is often not feasible or applicable in many research studies, and as a general fuideline for interpreting out- comes-the longer the duration of continuous abstinence. the greater the probability that individuals will remain former smokers. Cessation is a cyclical. not linear. process: smokers cm enter or leave the process at any point (Prochaska and DiClemente 1983: Prochasha et al.. in press) (Figure I). Research on self-change approaches to smoking cessation suggests that the average smoker cycles three to four times through the stages before attaining long-term continuous abstinence and becoming a confirmed former smoher (Prochasha and DiClemente 19X4. 1986: Marlatt. Curry. Gordon I YXX; Schachter 19X2). In a review of self-change studies. Cohen and colleagues ( 19x9) found that onI> -l.3 percent of the participants in the rev iewed studies shifted immedtately, from current smokers to former smokers without experiencing any lapsesor relapses. Most smokers M ho relapse return to a point where they think about stopping again. that is. the contemplation stage. A smaller proportion lose their motivation to change and regress back to the pre- contemplation stage (Prochaska and DiClemente 19X-l). In summary, because of the dynamic nature of change in smohing behavior. an> categorization of smoking status at a single point in time becomes a simplification. A group of former smokers aill include individuals who have stopped recently or who have been abstinent for varyin g lengths of time; some bill maintain abstinence. and some will relapse. Knowledge of the dynamics ofsmohinp cessation and its usual time course can help invtestigators minimize misclassification by choosing the most ap- propriate methods for assessing smoking behavior and the appropriate sampling pro- cedures (e.g. number of measurements made and time betueen repeated measures ot smoking status). Behavioral Measures Self-Report: Questionnaires and Interviews For health research purposes. smoking status is usually assessed by using self- administered questionnaires or interviews. However, other behavioral methods. sur- rogate assessments, and nonbehavioral methods such as biochemical assessments are also used as sources of smoking data. These other sources will be reviewed in subsequent sections. (See also rev,iews by Pechacek. Fox et al. lYX3 and Marsh et al. IYXX.) Questionnaires and interviews may include information concerning smohing at the timeoftheassessmentorconcernin~acompleteorpartial retrospective lifetime history,. Assessment can be made once or serially over time, thus providing more valid data regarding cessation and possible relapse. Infortnation gathered from an intervieu or questionnaire about smoking categorizes respondents as never. current. or former smokers. Two standard items used in the National Health lntetvieu Survey (Volume Appendix) to classify smoking status are "Have you smoked at least 100 cigarettes in your entire life?" and "Do you smoke cigarettes now?" Someone responding "yes" to the first question and "no" to the second would be classified as a former smoker. Such a broad definition for former smokers combines persons who experimented with smoking enough to have smoked lOOcigarettes with individuals who may have smoked during their entire adult life and quit in the week prior to being interviewed. The commonly used item. "Have you smoked at least 100 cigarettes in your entire life?" has an advantage of counting as never smokers those individuals who experi- mented with 1, 2. or quite a few cigarettes. Only those who have smoked at least 5 packs of cigarettes in their lifetime are counted as ever smokers. The arbitrariness of this definition reflects the lack of accepted and standardized definitions for ev'er smokers and never smokers. A definition of never smokers that requires only minimal or no use of tobacco may result in many individuals with extremely low exposure to cigarettes being classified as former smokers. which in general would not be biologi- cally appropriate. Another commonly used type of item. as in the Medical Research Council (MRC) National Survey of Health and Dev,elopment (Britten 19X8). for defining ever smokers is "Have you ever smoked as much as 1 cigarette a day for as long as I year'?" This item is used by the American Thoracic Society. Division of Lung Disease in its Adult Respiratory questionnaire: however. two other choices are added- "or 20 packs of cigarettes" or "12 ounces of tobacco" (Ferris 1978). A comparable questions is "Have you ever smoked at least 5 cigarettes per week. almost every week for at least I year'?" (Petitti. Friedman. Kahn 19X I ). These items that are used to classify ever smokers are based on a combination of the amount of cigarettes smoked (e.g.. 365) and the duration of smoking (e.g.. at least 6 or I3 months). The particular question used to differentiate between ever smokers and never smokers can directly affect categorization of individuals. For example. Petitti. Friedman. and Kahn ( 19X I ) found that with a more specifically defined question such as "Have you ever smoked at least 5 cigarettes per weeh almost every week for at least I year'!" M hich require\ wme period 0f"re~ular" smoking for an individual to be clawificd as an t`ver maker. 12% of?i:! individuals reported being neler smoker\. However. when assessed concurrently ti ith another questionnaire in which regular smoking was not defined and the respondent self-defined waking. 7 percent fewer subjects t II9 of 252) reported being never smokers. Thus, the use of more clearly defined questions. wch as specifying 100 cigarettes in ;1 lifetime. or 1 cigarette per day for I year. or 5 ci_rarettes per week for I year. Mill reduce misclaGtIcatlon. However. some misclassification will still occur for thaw individuals who hmohed for relatively brief periods during their lives but cannot accurately remember hou long they smoked or accurately estimate the number of cigarettes they smoked. Attention also must be paid to defining current or former smokers. Some studies. such as the Cancer Prevention Study I (CPS-1) (Hammond and Garfinkel 1969). define current smokers as those who respond affirmatively to the question "Have you smoked within the past year?" Other studies u$e smoking in the past 6 months as the guideline for current smokers (Coultas et al. 1988). The criteria for questions identifying current smoker\ can range from having smoked in the past year. to the past 6 months. to the past week. or to an unspecified period. A few additional questions will enhance the specificity of the definitions of current smokers and former smokers. These items. or comparable ones. have been used in previous surveys. for example. the 198X Baseline Prevalence Survey for the Community Intervention Trial for Smoking Cessation. funded by the National Cancer Institute: `.At what age did you start smoking on a regular basis?": "On the average. about hou many cigarettes did you smoke per day during the lact I?. months you smohed?": and for former smokers. "When did you quit smoking cigarettes'?" (recorded to exact date if possible). These item\ provide udd- tional information for defining ever smohers. or stratifying by levels of exposure. and for determining the period of abstinence. The dynamic nature of smoking ce\\ation highllghts the importance of being aware that any categorical definition of former smoker in relation to the health effects of smohing cessation will include former woher\ who h:r\,e been abstinent for \,arying period\ of time. Optimally. questions on smohin, ~7 historv should ascertain the duration _ of abstinence for former \moher\. and if possible. abstinence period\ should be treated aj continuous or categorized vuriablc\ in an anal>si\. thus avoidins the problem ot treating former smoher\ ;IS ;1 single group. Howewr. benefit\ of ce\\ation are still clearly observed in spite of the limitation\ of using categorical data. The mo\t common minimum period\ ofabstinencc u$ed for defining former smoking statu\ are 2-l hours. 7 days. and 30 da\\. The National Interagency Council on Smoking and Health ( 1973) recommended using ;I minimum of 7 da> s ofab\tinence for defining cessation. However. becuuw of the nature of mokin g. usin_r ;t short abstinence period to define former smoher\ i\ not optimal in epidemiologic studies. The degree of misclassification of former smoker\ M ill depend on the minimum duration of abstinence u\ed to define former smokers and the criterion wed to consider determine relapse. Many studie\ do not specify a minimum duration of abstinence for indi\,idual\ classified 3s former smohers at ;I particular point in time. Data from such \tudie\ on the aswciation of smohin, 17 ce\\ation L+ ith health and disease outcome\ mu\t bc interpreted cautiously. For example. in the reports of the Whitehall Civil Servants Study (Rose and Hamilton 197X; Rose et al. 1982). the criterion used to define abstinence is not indicated. The only information provided is that the smokers reported that "they were then smoking no cigarettes at all" (Rose and Hamilton 1978). Regardless of the criteria used to define abstinence. the methodology for assessing smoking status, including questionnaire items. needs to be carefully described by investigators. Optimally these items should enhance the process of obtaining informa- tion regarding the duration of abstinence. making it possible to fully determine the relationship of smoking cessation to health and disease outcomes. When reviewing studies of the health effects f smoking, the definition of the former smoker must be carefully assessed, and the effect of the definition on the findings must be carefully examined. Temporal and Frequency Issues Studies vary according to whether smoking is assessed retrospectively or prospec- tively and whether a single assessment or a series of assessments is used. The category of never smokers can be assessed retrospectively. usually relying on a single assess- ment. Requiring subjects to reconstruct more detailed smoking histories can be very demanding. Nevertheless, simply classifying individuals as former smokers or current srnl i reveals very little about the amount of smoking exposure experienced. More pen. .Lnt questions regarding exposure include "How) long have you been abstinent from cigarettes`?`: "At what age did you start smoking`?": "How many cigarettes did you smoke during different periods of your life'?": "How many times did you stop smoking'?"; and "How long did you remain abstinent during each of these occasions'?" A series of repeated assessments can result in inconsistencies such as some in- dividuals reporting smoking at one assessment and later reporting that they never smoked. In a followup study in England. for example, Britten (198X) found 1.296 participants aged 36 who claimed that they had never smoked. Of these. 232 ( IX.7 percent) previously had reported smoking less than I cigarette per day, and 102 (7.9 percent) previously had reported smoking at least I cigarette per day for at least I year. Of the 102 who reported previously that they had been regular smokers, 93 percent reported that the last time they had smoked was at least IO years prior to the survey. If the Britten study had used only one retrospective assessment of the subjects at age 36.323 percent of the 1,296 subjects would have been classified as never smokers and 32.6 percent as former smokers. Assuming that reports at a young age were more accurate because memory bias was less likely to occur, the serial assessment indicates that a more accurate categorization would be 29. I percent for never smokers and 36.5 percent for former smokers. Britten (1988) estimated that misclassification of this magnitude, when applied to a study by Friedman and colleagues ( 1979). would result in only a S-percent increase from 2.41 to 2.53 in relative risks of death for former smokers compared with never smokers. Krall and colleagues ( 1989) found that of 87 middle-aged adults. X7 percent accurate- ly recalled their smoking status of 20 years earlier. but only 71 percent accurately recalled the amount that they had smoked. Furthermore. underestimation of the amount -77 smoked was tu ice as common for 20 years earlier ( I7 vs. 9 percent) and six times more common for 32 years previously (37 vs. 6 percent). Persson and Norell (1989) found that in a random sample of 9.394 individuals in Sweden. retrospective information obtained 6 years later resulted in a strong tendency to overestimate previous cigarette consumption among individuals who had increased their smoking (69 percent over- estimated) and to underestimate among individuals who had decreased their smoking (39 percent underestimated). Subjects with unchanged cigarette consumption showed the highest levels of agreement (X9 percent) between original and retrospective infor- mation. Rather than reconstructing full smoking cessation histories that are subject to biased reporting. many retrospective studies rely on more limited categorization such as never. former, and current smokers. Retrospective studies enable researchers to assess long periods of smoking abstinence without the need to observe the subjects over a long period of time. as would be necessary in prospective studies. Case+zontrol studies. for example. can compare cases with smoking-related diseases with controls with histories of being abstinent for IO to 20 years: in a prospective study. it may be impractical or impossible to study health consequences of cessation with more than IO to 20 years of abstinence (Chapter 2. Part II). Prospective studies have the potential for more reliable and valid measures of smoking status over time. especially when using a series of assessments, than do retrospective studies. In intervention trials, for example. all subjects enter the trial as current smokers. Following intensive intervention. subjects are identified as continuing smokers or former smokers (abstinent). By assessing subjects at specified intervals such as every 1 or 6 month\ over a series of years. especially when paired with biochemical verification (Chapter _. ' see section on Biochemical Markers). researchers can reduce the measurement bias and he more confident in the reliability and validity of measures classifying continuing and former smokers and specifying length of abstinence for former smohers. In MRFIT (Ockene et al. 1990) for example. a series of4month followups over 6 year\ enabled researchers toclassify participants into three categories: persistent quitters (continuous abstainers since the initial intervention). intermittent quitters (abstinent for periods of time since the initial intervention). and continuous smoherx (not abstinent during any of the followup periods). Such precision in measurement is generally not possible or necessary in epidemiologic studies. Prospective stud& may use 3 single assessment to categorize current. former. and never smokers. These studies then prospectively, examine the categories to detect differential rates of morbidity~ and mortality.. As discussed above. the assumption that individuals vvill not change their smoking status maybe a tlavv, with \uch single as\es\ments. Improving Self-Report Measures Ideally. assessments of smoking statu\ need to include standardized questions to determine smoking status. that is never. current. and former smokers. For example. to be categorized as a never smoker. the necessary response bould be "no" to a standard question such as. "Have you ever \mohed at least I cigarette per day for at least I year?" 28 Whenever possible. questions should be used that allow continuous rather than dichotomous scales for rejpon$e. A question such as "Do you smoke regularly?" results in a dichotomous response scale. This scale provides much less information than does a continuous scale. such as the question. "On the average. how many cigarettes do you smoke per day`?" which can range from 0 to 20. 40. 60. or more. Multiple questions such as. `* Have you smoked even a puff of a cigarette in the past 7 days?": "How many cigarette% do you typically smoke each da),`?": and "How many cigarettes do you typically smohc each weeh'l" can be used to refine a category such as current smokers. Inclusion of other indices. such as biochemical markers of smoking (e.g.. sali\,acotinine levels). can also be used to describe smoking statu\. In a followup study. measures of smoking status optimally should be repeated over multiple occasions. especially for dynamic categories lihe current smokers and former smokers. which are open to change over time. Repeated measure\ over a series of occasions provide further reliability and validity for assessments and alw provide greater statistical power for detectin g differences betueen groups. Nevertheless. studies with only a single or a few assessments of smohing behavior have been extremely informative. Alternative BehaGral Measures As a measure of smoking, self-report by questionnaires and interviews is the most common. the least expensive. the easiest to use. and the most feasible in epidemiologic studies (Frederiksen. Martin. Webster lY7Y: Pechacek. Fox et al. 1983). However. other behavioral measures have also been used in clinical studies. Because these measures are generally not used in large-scale epidemiologic studies. they w*ill be presented only briefly m this Chapter. Self-monitoring by the smoker. a measure of smoking commonly used in intervention studies. involves recording by paper. pencil. and mechanical counters each cigarette as it is smoked. The monitoring itself may be a reactive measure and alter the behavior. depending on the nature of the monitored behavior and motivation (Abrams and Wilson 1979: Frederiksen. Martin. Webster 1979; Lipinski et al. 1973: McFall 1978: Orlean\ and Shipley 1982). It is an intrusive measure that is normally restricted to small \tudie\ of high intensity. Other behavioral measures, such as direct observation. collecting and counting cigarette butts (McFall lY78). and measurin f their length (Auger. Wright. Simpson 1979). are even more costly and intrusive and less appropriate for epidemiologic and large intervention studies. Alternative types of behavioral reports for validation of smoking status include verification by an informant (Shipley I981 J. by self-report measure\ tising multiple questions about smoking behavior or status as part of the same interview or question- naire (see above). and by samplin 2 on multiple occasion\. Examples of the latter usually involve long periods of time and often rc\ult in multiple sources of di\- crepancy. (See Lee I9XX for summary.) Surrogate Assessments In some circumstances researchers may need to obtain information from sources other than the index subjects. With some study designs, for example a casen smoking histories vvhile alive. They found that of 77 uiv,es of current smokers, all supplied information about the cases' cigarette smoking status (ever/never) that was in perfect agreement with the information supplied by the cases themselves. Sixty-six (X6 percent) w'ere able to supply complete responses about their husbands' smoking behavior. For those who responded. however. mean values reported by cases and their wives were not significantly different for age at which cases started smoking. years smoked. or average number of cigarettes smoked per day. Wives tended to report 20 cigarettes smoked daily even when their husbands smoked substantially more or fess. Pershagen and Axelson (1982) also reported perfect agreement regarding smoker/nonsmoker status when information was obtained from a close relative (parent. wife. or child) for I4 lung cancer cases compared with information that had previously been obtained from the cases by the physician. Blot. Akiba. and Kato (19X4) also interviewed next of kin in a case, helo\{ IO ng/mL. When nonmohers are aaeshed. the\ rarely have any detectable cotininc' (Benowit~ IYXi: Hale!. Axelrad. Tilton IYX3: Sepkovic and Hale) IYX.5: Zeidenbers et al. 19771. In comparative studieb of different biochemical measures of smoking. cotinine ha3 emerged a$ the measure of choice (Abram\ et al. lYX7: Hale). .4xelrad. Tilton 19X3: Jarvis et al. IYX-I. 19X7: Knight et al. 19X5: Pojer et al. 1YX-l) because of itz superior senGtivity and specificit!. However. it i\ more expensive and more analytically complex than the other biochemical measure\. The value of biochemical meaures is limited to short-term abstinence and cannot be used to document continuous abstinence in long-term \tudie\. CO. with a half-life of 3 to 5 hours. can validate self-reports of not having smoked in the pact 23 to 3X hour> (Benowitz 19x3). Cotinine. with a half-life of I5 to 40 hours. would have limited application for validation beyond a few day\. SCN-. ivith a half-life of 10 to l-1 day\. 36 has been used to validate self-reports of not having smoked in the past 7 days and may be useful to validate up to 3 to 4 weeks. However. specificity of this measure is low compared with cotinine and CO. Bogus Pipeline The bogus pipeline, an assertion to subjects that biochemical assessments will be used to assess smoking status when they will actually only be collected but not evaluated. is used mostly in research with adolescents. One of the reasons given by researchers for continuing to use biochemical verification for at least some proportion of the total subjects is the assertion that if the subjects believ,e biochemical validation will occur. they will be more likely to provide valid responses to self-report measures. This "bogus pipeline effect" was first presented by Evans. Hansen. and Mittelmark ( 1977) from the work of Jones and Sigall ( I97 I ) concerning smoking among adolescents. It is believed that there is great pressure among adolescents to misreport smoking activities, Murray and coworkers ( 1987) provided an estensiv#e review of this aspect. Murray and Perry (1987) attempted to determine the conditions under which a bogus pipeline will be effective by manipulating conditions ofanonymity. They demonstrated that a bogus pipeline for adolescents is more likely to have an effect if there is an expectation that subjects would otherwise perceive large amounts of pressure to report not smoking and there is a credible pipeline message. However, their findings suggest that an effective procedure to ensure anonymity can reduce this pressure and likewise reduce the need for the pipeline. Contextual Issues Affecting Biochemical Assessment The accuracy of self-report measures, the desirability for behavioral or biochemical validation of self-report. and the type of assessment needed are issues that need to be considered in the context of the type of study. the nature and size of the study sample. and possible refusal problems. The nature of the subject sample can affect the likelihood of misreporting and therefore the desirability of validation by biochemical assessment. In Table I. studies demonstrating misreporting rates for individuals who report cessation but who are assessed to be smokers by cotinine or nicotine measurement are classified into three types of subjects: untreated volunteer samples. intervention samples, and high-risk for disease and/or medical patients. Table 2 presents a similar classification of studies demonstrating misreporting with CO validation. The tables are adapted from Lee's work (1988) with the inclusion of additional studies. In cases where multiple cutoff criteria are recorded, the values closest to the optimal cutoff are reported. Several studies should be viewed as outliers and are noted in the tables,. These studies reported unusually high rates of individuals who reported not smoking but were above the cutpoint and also employed cutoff criteria far below optimum cutpoints (Cummings and Richard 198X). For untreated volunteer samples. the mode for individuals classified as smokers by biochemical assessment who reported not smoking is zero, and no sample exceeds 5 37 TABLE I.-Measures of false reports of not smoking from studies using nicotine and cotinine as a marker Wllll;nrl\ 1'1 d I lY7Y 1 H;tlcy. AxclwJ. TlllWl ( IYX3) WaltI c, aI , I YXJ) Nm )l und l.a&ncc ( I'JXX) I'icrce cl ill. ( I YX7 J 0 (O/27) 2 (2/0X) 0 (O/IX) 0.`) (2/Z I ) I .3 ty2.32, 2.1 (S/2.32, 2.2 (33/1,?60) 2.5 (20/X0X, 1.2 (34/X()X) 0 (O/43, 1.0(3/h?.!) TABLE I.--Continued Kwwll et al c I')X7? Stoohq 111 al. ,19X7) Saltvary nIcoIine 7.1 (l/13) Ilrtnary nlcotme II=?. Nnn. Gruder. Chicago Lung Awxxttion Jqxr\hl ( I'MI ce\\i111011 wiy Part 111. titFh-rt\h/mc~lic;tl patient\ Told to Criterion for titlw pivz up reports of not vllohirtg Some group\ 7 ppm co YC\ IO ppm (`0 Ye\ I 2 ppm tconfoundmg exaggerate the apparent benefit\ 01 hia\) ceaatmn Smoking practtce\ and the presence of smoking-related direases affect panicipntton in btudtes (selection hias) .4pperent benefit\ of cr\wtlon ma) hr mcreawd or decrrawd Small number of wbject\ in a stud) A heneficlal effect ofcrsttion may not reach sttisttcal stgntficancr Ecologic Studies Ecologic studies represent a descriptive approach for examining the relation between risk factors and disease. Groups, rather than individuals, are the unit of analysis in ecologic studies. For example, changes in lung cancer mortality rates for selected countries have been examined for correlation with changes in measures of smoking for those countries. such as the percentage of smokers or per capita cigarette consumption (US PHS 1964; Cairns 1975: Cummings 1984; Doll and Peto I98 I ). Ecologic studies often have the advantage of being performed inexpensively and feasibly by using already available data. This design has well-described limitations related to the estimation of exposure and control of confounding, and may yield seriously biased data on exposuredisease relationships (Kleinbaum, Kupper, Morgenstern 1982: Rothman 1986). Cross-Sectional Studies In a cross-sectional or prevalence study, exposure and outcome are assessed at the same point in time among individuals in a population. Because cross-sectional studies measure exposure and outcome variables simultaneously. the true temporal relation between exposure and disease may be obscured (Rothman 1986). However. cross- sectional studies can be readily performed and have supplied much of the evidence on smoking cessation and nonmalignant respiratory diseases (Chapter 7). 47 Cross-sectional studies may be affected by selection hia\. Because cigarette smoking is a strong cause of disease and death. groups studied cross-sectionally may not accurately reflect the natural history of smoking. smoking cessation. and the develop- ment of smoking-related illness. The proportion of heav ier smokers and more suscep- tible smokers may be reduced compared with the original birth cohorts giving rise to the cross-sectional study population (McLaughlin et al. 1987). Former smokers who stopped because ofthe development ofdisease may be underrepresented. whereas those who stopped to reduce the rish of illness may be overrepresented. Information bias is also of potential importance in cross-sectional studies. Pre- existing conditions in survey participants may affect recall of past smoking or may alter the approach used by interviewers to gather smoking information. However. as summarized in Tables I and 7. cross-sectional surveys generally demonstrate low rates of misreporting of smoking status when compared with cotinine and CO levels. As mentioned previously. a single observation on smohing behavior may lead to misclassification of smokers because of the dynamic nature of smoking behavior. Former smokers are typically a heterogeneous group with periods of abstinence ranging from days to years. For example, in the 1986 Adult Use of Tobacco Survey (US DHHS 1989). the subjects' responses were classified in IO categories. -l of which included former smokers. Of the former smokers. 12.5 percent had quit within the past 3 months. 7.X percent had quit in the past 3 to 12 months . 77.3 percent had quit in the past I to 5 years. and 57.4 percent had quit 5 or more y'ears earlier. Cohort Studies In a cohort study. the \ubjrcts are selected on the basis of exposure status (e.g.. smoking behavior) and observed for de\.elopment of disease. Observation may be forward in time (prospective). backward in time (historical or retrospective). or both. Correct conclusions can usually be made about the temporal relation between exposure (smoking cessation) and outcome (reduction of morbidity, or mortality). With the cohort design. multiple health outcomes can be considered simultaneously. For ex- ample, the CPS-I and CPS-II conducted by the American Cancer Society (ACS) examined the effect of smohing bells\ ior on total mortality and specific causes of death. In a study of \mohing cessation. selection bias could affect the findings of cohort studies if subjects lost to observation were more or less lihely to benefit from smoking cessation than subjects remaining under observation (Greenland 1977). For inten,en- tion studies and cohort studies. the rate of sub,ject loss provides an index of the potential selection bias. In a cohort study of smohin, 0 ccs\ation. some Ini\cla\zification of exposure may be introduced if the classification of smoking status is based on a single assessment. Although the categorization of smohing status may' be correct at the time the informa- tion is collected. inevitably some former smoker\ will resume smoking and some current smokers will stop. The extent of the resulting error will increase with the duration of followup. The resulting misclassification will tend to underestimate the effects of quitting because those who relapse to become current smoker\ would not be expected to experience beneficial effects attributable to quitting. 48 For example. in ACS CPS-I involving nearly I million people. Hammond and Garfinkel ( 1969) studied changes in smoking status over a Z-year period. Male former cigarette smokers in 1959-60 who reported that they were smoking in 196142 varied according to duration of prolonged abstinence reported in the lYS9-60 survey. For respondents abstinent le5s than I year in 1959-W. 37.3 percent reported smoking 2 years later; of those reporting abstinence for I to 2 years. 19.1 percent were smohing :! years later; and of those reporting abstinence of more than 2 years. 1.6 percent were smoking 3 years later. For all males who were former smohers in 1959~60. I I .3 percent reported smoking 2 years later. For all female former smoker\ in 195Y-60. 6 percent reported smoking 2 vears later. In the U.S. Veterans Study (Roget and Murq IYXO: Kahn 1966). male veterans itt a cohort of 23X.X16 were classified based on responses to questionnaires administered in 1954 or in 1957 (if the 1951 questionnaire was not returned) and then folloued for 16 years to determine the relationship betbeen tobacco use and mortality. Undoubtedly, many of the original current smokers became former smokers as a result of the strong trend of smoking cessation among U.S. males durin_g the followup period (US DHHS lYX9). Repeated assessment of smoking status in a cohort stud) can mitigate misclassifica- tion due tochanges in smoking status over time (Chapter 2. Part I). Repeated measures are often feasibly made in cohort studies to minimiLe the effects of misclassification. Alternatively. validation substudies can be conducted within the cohort to quantify misclassification errors (Greenland I9XX). Case-Control Studies Casexontrol studies involve selection of study suqjects based on the presence (cases) or absence (controls) of a disease. Exposure and other attributes of cases and controls (e.g.. smoking status or lifetime cigarette consumption) are then measured. The groups are compared with respect to the proportion having the attribute of interest to calculate the exposure odds ratio. which estimates the relative risk associated with exposure. Case-control studies can generally be conducted in les\ time than cohort studies or intervention studies and are less expensive to perform. Case+ontrol studies are well suited for evaluation of disease\ with low incidence rates. Case+zontrol analyses may be affected by information bias and selection bias. Case+ontrol studies are prone to information bias if lifetime exposure histories are collected by interview (Schlesselntan 19x21. Retrospective lifetime histories of smoh- ing or other exposures obtained from ill or elderly sub.jecth may introduce misclassifica- tion. SimilarI\.. studies that rel\, on reports from surrogate\ to assess smohing ma). misclassify exposure. If individuals classified as cases recall more accurately or less accurately than those classified as controls, differential misclassification result\ (Gordix 1982). Differential misclassification may also be introduced ifre\pondent~ deliberateI> falsify answers or if interviewers differentialI> gather information from cases and controls (interviewer bias): interviewer\ not blinded to case-control \tatu\ may probe more intensely for a putative causal exposure in cases than in controls (Sachett I Y79). Blinding is often not feasible. and meticulous attention must be directed to training interviewers and to designing questionnaire\ to rcmovc the po\\ibilit!, of intervieuer bias. Although selection bias may affect any case-control study that is not population based. it is unlikely to be of particular importance in most casexontrol studies of smoking cessation. Intervention Trials Intervention trials are designed to test a hypothesized cause-effect relationship or the benefits of a preventive program by modifying the putative causal or preventive factor and measuring the effect on relevant outcome measures. Intervention trials may be directed at individuals or groups. such as communities. Regardless of the unit of observation. the trials may be conducted wsith (e.g.. a clinical trial) or without ran- domization to the intervention. Clinical trials are most commonly used to assess therapeutic interventions. but this design has also been used to evaluate preventive interv,entions. such as smoking cessation. A clinical trial includes one or more comparison groups in which subjects receive the control intervention: subjects are randomly assigned to the treatment and comparison groups to ensure that the groups are comparable with respect to charuc- teristics potentially affecting the outcomes of interest. Individuals or groups such as communities can be the units of randomization. Within the limits of chance. random assignment makes the intervention and control groups similar at the onset of study. Although widely used to test smoking cessation methods. clinical trials have been used infrequently to assess the health benefits of smokin, 0 cessation. In comparison with observation studies. the clinical trial design offers the potential for eliminating or more tightly controlling bias from the selection of subjects and from confounding. However. for many health outcomes, both a large sample size and a lengthy followup period may be needed to have sufficient statistical pow'er. Moreover. in a study of smoking cessation. the power of the trial also depends on the extent of the reduction in smoking in the intervention group. in comparison with the control group. In the reported smoking intervention trials. only ;I minority of participants attained continuous or prolonged abstinence following most cessation interventions (Hunt. Barnett. Branch 1971: Hunt and Bespalec lY73: Ockene et al. 1990). Even with intensiv,e. prolonged inten entions. as in MRFIT. only 42 percent of smokers within the special intervention group were not sntohing at h-scar follow up. and only 76 percent of baseline smobers 2 had been continuously abstinent from cigarettes over this prolonged period (Ockene et al. IYYO). Only a few clinical trials provide information relevant to the health benefits of cessation (Chapter 3). In the Whitehall Civil Servants Study, (Rose et al. 19821. the investigators randomly intervened in smoking with advice from a phy,sician in a group of men at high rish for cardiopulmonary disease. In MRFIT. smoking intervention w'as one component of the rish factor intervention program directed at the special interven- tion group (MRFIT Research Group IYX3). In tnost clinical trials that assess the effect of cessation on disease outcomes. such as the Whitehall Civil Servants Study (Rose et al. 1982). the tn\,estigators did not monitor longitudinally the persistence of quitting or levels of biochemical markers. The only clinical trial that has provided these measures is MRFIT (Ochene et al. lY90). Although SO maintained cessation rates were significantly greater in the special intervention than in the usual care group, to date the difference has not been large enough to provide adequate statistical power to assess the effect of smoking cessation alone on differences in morbidity and mortality between the intervention and control groups (Chapter 3). However, MRFIT was designed as a multifactor trial and did not assess the impact of smoking cessation alone. Because MRFIT results indicated the greatest difference in smoking cessation between special intervention and usual care subjects compared with any other clinical trial and still lacked the power to detect outcome differences from smoking cessation. it is unlikely that smaller trials would have sufficient power to demonstrate an effect of cessation on morbidity and mortality (Chapter 3) (US DHHS 198.3). Compared with observational studies which place few demands directly on subjects. the use of interventions for smoking cessation in clinical trials increases the probability of misreporting smoking status at postintervention followup because of the expectations of the participants and the investigators. Typical periodic followup in clinical trials. however, reduces the chances of misclassification related to relapses or to delayed action to quit smoking-phenomena that are often not adequately recorded in observa- tional studies. Routine followup also allows for more accurate measurements of the duration of prolonged or continuous abstinence and the opportunity to validate with biochemical testing. Intervention trials other than clinical trials also provide information on the health consequences of smoking cessation. A number of studies are in progress involving interventions of varying intensity within a community. The North Karelia project conducted in Finland is such a community trial: a comprehensive, community-based intervention program was conducted to reduce cardiovascular disease (CVD) (Tuomilehto et al. 1986). Mortality rates in North Karelia were compared with those in other areas of Finland. Methodologic Issues Introduction Epidemiologic studies have been the principal source of information on the health benefits of smoking cessation. Although the resulting data have provided strong evidence for the benefits of cessation, the data need to be interpreted with consideration of potential sources of bias and of other methodologic issues. This Section considers the methodologic issues potentially affecting interpretation of studies of the health consequences of smoking ceshation. The criteria for causality have served as a basis for evaluating all of the evidence relevant to a particular association (US PHS 1963: US DHHS 1981. 1989). However. associations found in individual studies must also be assessed carefully. In any epidemiologic or clinical study. association may result by chance, as the result of bias. or through a causal mechanism. Thus. this Section presents an overview of statistical considerations relevant to studies of smoking cessation and the most prominent sources of bias in such studies-information bias and confounding hia\. It also considers the potentially complex problem ofanal!~ing data on the effects of smohing cessation. Statistical Considerations Statistical significance testing addresses the likelihood that an observed association has occurred by chance if. in fact. exposure and disease are unassociated (the null hypothesis). By convention. probability (p) L alues less than 0.05 are generally accepted as "statistically significant"; that is. chance is considered an unlikely explanation for the association. For example. if the p value is less than 0.05. the probability that chance explains the association is less than 5 percent. Confidence intervals describe the range of effects compatible with the data at some specified level of probability. for example 95 percent. Some studies find associations that do not attain statistical significance. "Negative" investigations must be interpreted in the context of an investigation's sample size: a small sample size may not provide sufficient information to test associations in the range of interest. Such small sample sizes often provide inadequate statistical power to test for the anticipated effects of smoking cessation. and such studies are uninforma- tive as a result. In interpreting associations not achieving statistical significance. confidence limits describe the range of effect compatible with the data. Bias In an)' epidemiologic study. associations may be affected h> bias. Biases from misclassification and from confounding need to he considered in interpreting the findings of studies of the consequences of smoking cessation. This Section focuses on the effects of these biases in studies of smohing cessation. Categorizing the dynamic process ofsmohing cessation poses ;I substantial challenge to epidemiologic researchers (Chapter 2. Part I ). hlorrovcr. subject report their o\\ n sniokin, 17 beha\,ior. and reliance on surrogate sources of information on smohing. LIS ma\ bt~ nc:ccssar!. in casc`+control studIt`\. ma\ also introduce error. The c~~scqucnces of misclassi~c~~tion in obser\ ation studies ha\,c recei\ 4 substall- tialcon~ideratic,n in the rpidcmiolog~c litt'rature (Copeland et al. 1977: Greenland 19X0: Fleiss 1% I: Klcinhaum. Kuppcr. I\lor~enstcrn 19X2: Schlc~sclman 19X7: Kothm;r~~ 19X6). Misclassiticatiorl c;m oc`c~ir in classif! in; either e\pc)surc` or outcome. Onl! exposure inisclllssific~ltic~il. that is smohing \t;ltus. will he considered in this Section (Chapter 2, Part I ). Miscl~!s\it`ic~ltiorl nl;~> be cla\sified ;I\ nondifferential (or random) or 215 differential: both types of miscl~rssit'ic~ltion ;!I-e potentialI> relet ant to studies of \mohing cessation. ~0ndit`ferentiA misclasslfic~ition occurs r:uidonil\ In relation to disease or ourcome status. \rhercas diffcrcntial iiiiscl3\sificati(,n al`fects exposure information in a pattern that varies u ith outcome status. For c\;unple, differential ini\classification \roulJ occur in a case+control stud! of lung cancer if cast`s tended to minimize the extent of past smohing in compari\on u ith the information 5 "ii en h\ controls: elderI\ cases and _ controls might introduce nondifferential misclassification from errors in recall of past smoking. The consequences of nondifferential and differential misclassification have been addressed in the epidemiologic literature. Brass ( 1954) is credited with demonstrating that random misclassification in a 2x2 contingency table diminishes an association that exists between two variables: in general for such cross-classified data. nondifferential misclassification of exposure biases toward the null value. indicating no effect of eposure (Rothman 1986). For exposures classified into three or more levels. the consequencs of nondifferential misclassification are not exclusively directed toward reducing the degree of association. Differential misclassification may either strengthen or weaken associations. depending on the direction of the bias in reporting exposure (Kleinbaum, Kupper, Morgenstern 1982: Rothman 1986). The information presented in prior sections of this Chapter describes the directions that bias may take and allows some generalizations. First, some degree of nondifferen- tial misclassification may affect studies of active smoking and of smohing cessation: the extent of misclassification depends on the type of information collected. the choice of respondents (index subject or surrogate). and the health and age of the respondents. Second. because disease is present at the time of interview. nondifferential mis- classification is particularly likely to affect exposure information collected in cross- sectional studies and case/ 2tXS50~: 1376-l 380, December 13. 19X6. COPELAND, K.T.. CHECKOWAY. H.. MCMICHAEL. A.J.. HOLBROOK. R.H. Bias due to misclascification in the estimation of relative ri$h. hro-rc~u/~ Jorrrwl of` ~/`iclc~n~r(~lc~,~~~ 1OS(S):3883YS. May 1977. CORNONI-HUNTLY. J.. BARBANO. H.E.. BRODY. J.A.. COHEN. B.. FELDMAN. J.J.. KLEINMAN. J.C.. MADANS. J. National Health and Nutrition Examtnation 1 Epidemio- ofy Follow~p Survey. P rthlic Hculrlt Rcpm YX:315%25 I. I YX?. COULTAS. D.B.. HOWARD. C.A.. PEAKE. G.T.. 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Con7prd7c~~7- si1.e Ps~c~Aiurr-~ I 8( I ):93- 101, January-February 1977. 69 CHAPTER 3 SMOKING CESSATION AND OVERALL MORTALITY AND MORBIDITY CONTENTS Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...75 Smoking Cessation and Overall Mortality in Cohort Studies . . . . . . . 75 Smoking Cessation and Overall Mortality in Intervention Studies .............. 8-I Smoking Cessation and Medical Care Utilization ........................... X7 Population Projections .............................................. X7 Observational Studies ............................................... X7 Smoking Cessation and Health Status .................................... X7 Conclusions ........................................................ 92 Chapter3 Appendix .................................................. 93 References . . . . . .._................................................. 90 73 INTRODUCTION The overall risk of mortality among smokers has been discussed in several prior reports of the Surgeon General (US PHS 1964. 1969; US DHEW 1979: US DHHS I989 ). The 1989 Report estimated that approximately 390.000 Americans died in I985 from diseases attributable to smoking (US DHHS 1989). Another source (Mattson. Pollack. Cullen 1987) estimated that 36 percent of heavy smokers aged 35 will die before age 85. and 2X percent before age 75. from a disease caused by smoking. Prior reports of the Surgeon General (L'S PHS 196X; US DHEW 1979: US DHHS 19X9) have reviewed the association of smoking with overall morbidity. concluding that ov,erall morbidity is increased among smokers. Quantitative estimates of the amount of morbidity attributable to smoking vary because of differences in the measures of morbidity used. Data from the aggregate of studies of overall mortality and morbidity among \mohers and former smokers show that smoking causes increased risk of morbidity and mor- tality. However. the temporal pattern of the reduced all-cause mortality after quitting and the effects on mortality risk of quitting at variou\ ages have not been fully described. In addition, questions about the benefits of smoking cessation for mortality have arisen because of the results of studies involving interventions to promote smoking cessation. The association of smoking with medical care utilization is a topic that has not been addressed in detail in previous reports of the Surgeon General. This Chapter reviews studies of overall mortality among former smokers, with particular attention to the temporal pattern of decline in mortality after quitting and the association of age at quitting with decline in mortality. Overall mortality in intervention studies that include smoking cessation is discussed with attention to problems of inferring the benefits of smoking cessation for the individual from these studies. Studie\ of medical care utilization by and health status of former smokers are described. SMOKING CESSATION AND OVERALL MORTALITY IN COHORT STUDIES Table I summarizes the results of major cohort studies comparing overall mortality among never, current, and former smokers. The studies consistently showed a substan- tially lower risk of mortality among former smokers in comparison with continuing smokers. Compared with continuing smokers. former smokers had a progressive decline in mortality risk as duration of abstinence increased. although risk in some studies was increased for I to 3 years after cessation, almost certainly because some people quit due to ill health (Chapter 2). The durations of abstinence required for former smokers to reach the mortality risk of never smokers differ among studies. The American Cancer Society (ACS) study of I million American volunteers (Hammond 1966). also known as the 2S-State Study and as the Cancer Prevention Study I (ACS CPS-I). found that after IO years, mortality rates among former smokers of fewer than 20 cigarettes per day reached levels equivalent to those of never smokers. Among former smokers of 30 cigarettes or more per day. 7s TABLE I.--Summary of longitudinal studies of overall mortality ratios relative to never smokers among male current and former smokers according to duration of abstinence (when reported) All I ox Former smoker\ Duration ot ah\tinencc (yr ) s-9 IO-15 >I5 I.5 I.3 I I 1.34 I.01 1.3X I.31 1.x7 I.24 I 47 7.0x 1 .xx I .72 I .hO I.55 I .5x 0.x-l 0.93 0.90 0 91 TABLE I.-Continued Former wwhers All tlurarion\ Study Current smokerc Pcr\i\lent uuIUcr\ California HMO' (Friedman et al. 1981) I .x2 I Sl I.13 mortality risk was still higher than that of never smokers even after IO years of abstinence. The more recent ACS study. ACS CPS-II. is designed similarly to CPS-I. Re- searchers enlisted 77.000 volunteers. who then solicited their friends. neighbors, and relatives to participate in the study. Those enrolled completed a four-page confidential questionnaire on medical history. health behaviors. medication use, and occupational exposures (Stellman and Garfinkel 1986: Garfinkel and Stellman 1988). A total of 52 1,555 men and 658.748 women were enrolled: 4-year followup data ( 1982-86) on the cohort were included in the 1989 Surgeon General's Report (US DHHS 1989). In this Report, mortality rates for all causes of death from the ACS CPS-II were calculated using updated data for the same 4-year followup period (Table 2). Rates were calculated by gender in S-year age groups for current and former smokers according to level of cigarette consumption ( l-20 cig/day, 22 I cig/day for males: I -I 9 cig/day, 220 cig/day for females). Rates for former smokers were further stratified by years since smoking cessation (I! I cig/day Female\ I-IO q/da> 20 Ih Male\ I-20 q/da\ 22 I cig/da> Female\ I-IY cigiday X0 q/da! 2.31 2.Oh 2.M I .x9 I .4x 1.2') I .o I 7.73 I x5 2 IS I .YO 1.77 I fl.5 1.1') I .x7 0.76 I.26 I .J2 I .OI I .09 I .Oo Z.Jh 7.33 2.15 I .-II I 46 I.IX 0 YS In this analysis, subjects who had quit smoking were assigned to the duration of abstinence category appropriate for when they enrolled in the study. This method of assignment tends to blunt the rate of decline of mortality risk according to duration of abstinence when compared with never smokers because former smokers do not change categories as duration of abstinence lengthens. No attempt was made in this study to determine smoking status after enrollment. and persons who had quit at enrollment but had resumed smoking were still considered former smokers. Likewise. persons who smoked at enrollment but subsequently quit remain assigned to the current smoker category. This probably leads to some degree of misclassitication and affects relative risk estimates (Chapter 2). Like AC3 CPS-I and other cohort studies. mortality ratios were substantially lower among former smokers than continuing smokers for all durations of abstinence except that of I to 3 years. With the exclusion of those subjects who had a history of cancer. heart disease, or stroke and those who said they were "sick" at the time of recruitment. mortality ratios were lower among former than continuing smokers for all durations of abstinence, among males at all prior levels of cigarette consumption. and among females who smoked fewer than 20 cigarettes per day before they quit. The difference in the pattern of decline in overall mortality between all subjects and the subset of subjects who were healthy at recruitment provides strong evidence that recent quitters disproportionately include those who have quit because they are ill. In contrast with ACS CPS-I. which was conducted in the early 1960s. mortality ratios among both heavy and light smokers in ACS CPS-II remained substantially elevated in comparison with those of never smokers IO years after quitting. This increase was evident in all subjects and in the subset of subjects who did not have a history of cancer, heart disease, or stroke and who did not state that they were "sick" when recruited. Sixteen years after quitting, the mortality risk among male former smokers of fewer than 2 I cigarettes reached that of never smokers but remained elevated among former smokers of 21 cigarettes or more. Among female former smokers in both categories, mortality was comparable with that of never smokers after 16 years of abstinence. The results of ACS CPS-II are broadly in agreement with those of the British Physicians Study (Doll and Peto 1976; Doll and Hill 1964a,b) and the U.S. Veterans Study (Kahn 1966; Rogot and Murray 1980). In both, the overall mortality risk among former smokers remained elevated in comparison with that of never smokers up to 15 years after quitting, although the risk was substantially less than among continuing smokers. An Australian study of petrochemical workers (Christie et al. 1987) appears to differ from the other cohort studies in finding that overall mortality risk among former smokers reached that of never smokers 5 years after quitting. This study is unique in that subjects classified as former smokers were all persistent abstainers. The differences among other studies in estimates of the duration of abstinence needed for a former smoker to have the same overall mortality risk as a never smoker are likely to be due to other smoking-related factors, such as age at smoking initiation, that differ among study populations and over time (Chapter 2). Irrespective of the duration of abstinence needed to reach the mortality risk of never smokers, former smokers have substantially lower mortality when compared with continuing smokers. For three reprc\entative age groups (NJ--54.60-64, and 70-74 yr). Figure I shows the relative risk of death among current and former smokers compared with never smokers based on recent ACS CPS-II data for the subjects who did not have cancer, heart disease. or stroke and were not "sick" at recruitment. Complete data from ACS CPS-II on mortality in current. former. and never smokers aged 50-74 years are presented in Table 7 of the Chapter Appendix. Data are not presented for those aged less than 45 years and greater than X0 years because there were fewer than IO deaths in almost all of the categories of former smokers. In each of the age subgroups shown in Figure I. among both sexes and among former light and heavy smokers, mortality risk relative to continuing smokers decreased with increasing duration of abstinence. Using a method described by Kleinbaum, Kupper. and Morgenstern (1982). the data from ACS CPS-II were also used to estimate the effects of quitting at various ages on the cumulative risk of total mortality in a fixed interval after cessation. Several assumptions have been made in conjunction with CPS-II age-specific mortality data in order to estimate as many as 16.5 years' risk of death from all causes for individuals who continue to smoke and those who stop smoking. The first assumption is that age-specific mortality mtes measured from 1982-86 CPS-II data remain constant for the next 16.5 years. The first category of smoking cessation is l-2 years: that is. the individual gave up smoking I to 2 years ago. It is assumed that. on average. respondents in the I-2-year category pave up smoking I .5 years ago. Similarly. for the cessation categories 3-S. 6-l 0, and I l-l 5 years, the average durations of abstinence are 1. X. and 13 years, respectively. It is further assumed that respondents are exposed to the age-specific mortality rates of the age interval in which quitting occurs for I .5 years and to each of the next three age intervals for 5 years each, making a total of 16.5 years. For example. a quitter of the -IO-&-year interval would be exposed to the age-specific mortality rates of the 301-t-year-olds for I .S years. to those of 4539-year-old\ for 5 years, to those of SG%-year-old\ for 5 years. and to 5%59.year-olds for 5 years. The results of thi5 analysis. presented in Table 3 and in greater detail in Table X of the Chapter Appendix. \how that the benefits of cessation for total mortality extend to quitting at older age<. For example. a healthy man aged 60-63 years who smokes 21 cigarettes or more per day is estimated to have a chance of dying in the next 16.5 \`ears of 56 percent if he continues to smoke and 5 I percent if he quits. Quitting smoking at younger ages confers even greater proportionate increasej in survival (\ee Figure 7 of the Chapter Appendix ). Framingham investigator\ recentI!, analyred data from their cohort (D'Ago\tino et al. 19X9) and aI\0 found that the benefit\ of quitting apply to those who quit at more advanced age\. These researchers estimated that mean additional life expectancy for those who quit at ages 35 to 39 wah 5. I years for males and 3.2 years for females. For those who quit at ages AS to 69. additional life expectancy was estimated to be I .3 years for males and I .O year for females. As discussed in detail in Chapter _ 7 and other chapters. smokers differ from non- smokers in a variety of social. behavioral. and psychological characteristics. and successful quitters differ from those who continue to smoke (Rode. Ross. Shephard 1972: Blair et al. 19x0: Haines. Imeson. Meade 19X0: McManus and Weeks 1982: Billings and Moos 19X3: Gottlieb 19X3: Brod and Hall 19X-l: Seltzer and Oechsli 19X5: X0 MALES Aged XL54 Current Smokers amount smoked and duration of abstinence x2 TABLE 3.-Estimated probability of dying in the next 16.5year interval for quitting at various ages compared with never smoking and continuing to smoke, by amount smoked and sex Age at quitting or at 51art of interv31 Female\ Age at qutttmg or at \tart of interval Never \moher\ x!o q/da\ Contmumg Former mohrr\ smoker\ 1&`&l 0.03 0.06 0.03 (I ox 0.0-l 4519 0.04 0.0') 0.06 0.1 3 0.0 SO&S-l 0.07 0. l-l 0.07 0.14 (l.OY 55-s') 0.1 I 0.2 I 0. 12 0.27 (I. IS 60-64 0.1 x 0.30 0. I Y (I.38 0.3' 65-6') 0.30 0.46 0.3Y 0.52 (I.32 70-7-1" 0.26 0.4 I 0.77 0.4S (I.3 I Kaprio and Koskenvuo 1988). These differences may exist among adolescents prior to initiation of smoking (Seltzer and Oechsli 1985). For these reasons, interpretations of studies comparing these self-selected groups (never smokers. smokers, and quitters) must consider the problem of confounding (Chapter 2). Misclassification. which is discussed in detail in Chapter A. 7 also must be considered. However, studies of smoking cessation predominantly misclassify persons who are still smoking cigarettes as former smokers, and this would tend to obscure the benefits of cessation in comparison with continued smoking. Further. although the possibility of uncontrolled confounding needs to be considered in epidemiologic studies of smokin, 0 cessation and mortality. the totality of data must be interpreted with consideration of its consistency. To account for the evidence of a benefit of quitting that derives from nonexperimental cohort studies, confounders would need to be distributed quite differently among current and x3 former smokers and would need to be strong predictors of mortality. There is no substantial evidence that thih is the tax. SMOKING CESSATION AND OVERALL MORTALITY IN INTERVENTION STUDIES Five studies. four of which were randombed triak evaluated overall mortality in relation to interventions that included smoking cessation 3s a component. The results of these studies are aummurired in Table 1. TABLE 4.-Summary of overall mortality ratios in intervention studies in which smoking cessation was a component Otil!~ one stud! cxaminccl wlohin g inter\ c'ntion alone t Rwc and Hamilton 197X: Rose et al. 19X2). Of I .145 IIMIC` mwk~~. aged 10 to 59 and at hish ri\h of coronaq heart diNe;Iw (CHDI or chrotttc hronchttis. 7 t-I \+erc randomt~ a\\iyed to a11 interLen- tion group and 73 I to ;I norm;tl cat-c group. hlcn in the inter\ ention group wcrc fi\ en individual ad\ ice to quit \mohing. and if intereaxi III quittins. up to four additional vi5it4 over 12 month\. AI the c)-!car follow up. 55 pcrccnt of responder5 in the intervention reported abbtincnce compared I+ itli 1 I percent in the normal care group. After IO !eat-\ of 1'~~llo~~ up. there \\crc 123 death\ III the inter\,ention group and 1% in the normal care group. The proportionatt' diffcrcnce in total mort;rlit! hewecn the intervention group anti normal cxc group I-2 percent) \\a not \t;iti4icall\ stgnitkxnt. but the confidence inter\;tl \\;I\ u I& 1-12 percent to +23 percent). There \\t're XI X-l smoking-related deaths in the intervention group and Y2 in the normal care group. The proportionate difference in smohing-related deaths has -Y percent. Again the con- fidence interval was wide (-31 percent to +20 percent). Twenty percent of the men in the intervention group who quit smohing cigarettes tooh up pipe or cigar smohing compared with 3 percent of the men in the normal care group. and to the extent that pipe and cigar smoking are mortalit) rish factors. any benefit of cessation of cigarette smohing is obscured. This trial is largely uninformative as to the benefit or lack of benefit of smoking cessation for total mortality because of the small number of subjects. The trial uas further compromised by the relatively poor compliance of the subjects with the intervention: the net reduction in mean cigarette consumption over the IO years of the followup among the intervention group compared ti ith the normal care group was onI\ 7.6 cigarettes per day. Other intervention studies that allow assessment of the relation ofsmohing cessation to overall mortality have involved multiple interventions aimed at reducing several different factors for CHD. The ability to draw conclusions about the effect of smoking cessation on overall mortality from these studies is quite limited for this reason. The North Karelia study targeted a region of Finland that had the world's highest CHD death rate at the time of the study's initiation (Tuomilehto et al. 19X6) and was aimed at modifying smohing. cholesterol levels. and blood pressure. The rest of Finland was used for comparison. In the IO years after initiation of an aggressive risk reduction program. there was a 35percent decrease in smohing in North Karelia compared with a I-percent reduction in the rest of Finland (Salonen et al. IYXY). Blood pressure and cholesterol levels did not change significantly in the intervention area compared u ith the rest of Finland. Total mortality in the intervention area in the IO years after the start of the study declined more rapidly than in the rest of Finland. although the difference in the rate of decline in overall mortality was not statistically significant. For at least two reasons, interpretation of the North Karelis study is problematic with respect to the effect of smoking cessation on overall mortality. First. the study was nonexperimental. with conclusions based on a comparison of total mortalit\, in the stud) area with that of Finland. During the study period. overall mortalit) also declined in the rest of Finland, perhaps because of secular changes in other factors related to mortality and to changes in medical care (Salonen et al. 19X9). Second. the study was not designed to investigate smoking cessation alone. Because of the mixing of inter- ventions for three CHD rish factors, it was difficult to isolate the impact of the smoking cessation component. The Oslo study (Hjermann 19X0: Hjermann et al. 1981; Holme 1982) involved 1.237 normotensive men at high risk for CHD because of their smoking behavior and cholesterol levels. The men were randomly assigned either to recei\,e interventions aimed at reducing both CHD risk factors or to a control group. Tobacco consumption. including pipe and cigar smoking. fell 45 percent more in the intervention group than in the control group. There was also a mean difference of I3 percent in serum cholesterol between the intervention and control groups over 5 years (Hjermann et al. IYX I ). The stud!, was small. and it was not designed toexamine total mortality endpoints; only 42 deaths were X5 observed. Nevertheless. the mortality rate in the intervention group was one-third lower than in the control group (one-sided p value=O. 13). Because there were changes in both smoking and cholesterol levels. the difference in mortality cannot be attributed entirely to smoking cessation. The World Health Organization (WHO) European Collaborative Group conducted an intervention study in factories in four European countries (WHO European Col- laborative Group 1983). The study involved random allocation of 66 factories that employed 49,781 men aged 40 to 59 to an intervention program targeting smoking. cholesterol level. and blood pressure or to a control group. After 4 years. the net reduction in mean cigarettes perday in the intervention factories was X.9 percent (WHO European Collaborative Group 1983). At 6 years. overall mortality in the intervention factories was 3.04 percent: in the control factories. it was 4. IS. The difference was not statistically significant. The Multiple Risk Factor Intervention Trial (MRFIT) was a randomized study of more than 12.000 American men. aged 35 to 57 at entry. who were at high risk for CHD on the basis of their smoking behavior. blood pressure. and cholesterol levels (MRFIT Research Group 1981). Men in the special intervention group received an intensive intervention aimed at reducing hlood pressure and cholesterol and encouraging smok- ing cessation. Men in the usual care group were referred to their physicians and examined annually. The interventions continued over the entire course of the study. At 6 years. q-l.3 percent of special intervention smokers and 3.X percent of the usual care smokers reported cessation. In the 7-year followup data reported in IYXZ. there was no difference in total mortality between the special intervention and usual care groups (MRFIT Research Group lYX3). However. in the 10.5-year follow up data of MRFIT participants. overall mortality for the special intervention participants was 7.7 percent lower than for the usual care group (one-sided p value=O. IO: YO-percent confidence interval (Cl). -16.6 to +7.3) (MRFIT Research Group IYYO). A subgroup of MRFIT special intervention participants. who were hypertensive. had resting electrocurdiograrll abnormalities. and comprised 31 percent of the special intervention group. may have suffered excess mortality as a result of an unanticipated adv,erse effect of one of the antihy~pertcnsive drugs (Cutler. MacMahon. Furberg 19X9). This has recently been sugested as an explanation for the absence of an overall difference in mortality~ between the special intervention and usual care groups at the 7-year follow LIP (MRFIT Research Group. submitted for publication I. Furthermore. Ockene and coworhers ( 1900) recently reported that at IO.5 years. MRFIT participants who quit smohing had significantI\ lower death rates than those who continued to smohe in both special inter\ cntion and usual care groups. Mo5t important. like the other multifactor intervention trials. it is difficult to infer a benefit or a lath of benefit ot smoking cessation for total mortality from this study. In summary. studies in\,ol\ in? smohing cessation interventions include a randomized trial in which smohing cessation was the sole interventton and three intervention studies in M hich it was ;I component. The small six of the former and the mixing of a smohing intervention with other interventions in the latter mahe it impossible to reach con- clusions about the benefits of smohing cessation from these studies alone: however. nonintervention (i.e.. cohort) studies described in the previous Section clearI! indicate a benefit of smoking cessation on overall mortalit!,. SMOKING CESSATION AND MEDICAL CARE L'TILIZATIO\ Population Projections The relationship between smohinf cessation and medical care utilization is acomplcx issue. Data on differential disease and mortalit!, rates comparing smohers and abstainers are abundant. and man\ in\,ectigators have used these data to pro,ject the savings in dollars attributable to smohing cessation (Weinham. Roscnbaum. Sterling IYX7: Leu and Schaub 1'3x3; Lute and Schweit/el- 197X: O\ter. Coldit/. Kelly IYXIJ. Cenerall\~. these projections produce results that depend on the man> assumption\ ot the models that create them. For example. Lute and Schweitzer ( I Y~XJ projected that the total 1976 dollar cost of smohing in the United State\ was about 527.5 billion and that excess medical care costs accounted for about SX.2 billion of tho\r costs. Weinkam. Rosenbaum. and Sterling ( lYX7) and Leu and Schaub ( IYX3). both using population simulation approaches. concluded that mohin, (7 does not. o\er a lifetime. lead to increased medical care utilization. Thi\ is because the short-term higher levels of utilization of smokers are approximateI\, balanced b) shorter longevity and the resulting reduced need for medical care. Oster. Coldity. and Kelly ( 19X-I) used population prcjjcctions to estimate the medical care costs of smoking and the proportion of those costs that are potentialI> recoverable depending on the age at which smokin g is riven up and the level of smohing prior to c quitting. Male light smokers (I yr). and thtw htudiek are highlIghted. XX Data from the National Center for Health Statistics (US DHHS 1980) suggest that former smokers have fewer illness days than continuing smokers, particularly among younger women. Gallop (I 989) found that former smokers have absentee rates between those of current smokers and never smokers. Segovia, Bartlett, and Edwards (1989) conducted a telephone survey of 3.300 adults and found a strong relation between smoking status and the reporting of good health. Persons who had quit smoking for more than 1 year reported good health with about the same frequency as persons who smoked only I to 5 cigarettes per day, whereas those who had quit for less than 1 year reported good health at a frequency comparable with smokers of 16 to 20 cigarettes per day. Balarajan. Yuen, and Bewley ( 1985) examined the associations among various levels of smoking, recent and former cessation, and presence of acute and chronic illness, medical office visits, and doctor consultations. Current smokers had a higher prevalence of acute and chronic illness. and rates varied in relation to the amount smoked. Former smokers who had quit in the year prior to the survey had higher rates of illness compared with continuing smokers. and former smokers who quit more than 1 year prior to the survey had rates between those of never smokers and smokers of 20 cigarettes or more per day. Reed (1983) found no difference in general physical health status between current. former, and never smokers, not otherwise defined. Seidell and colleagues (1986) examined the number of reported health complaints, out of an inventory of 5 1 possible complaints, by smoking status and found that male, but not female, former smokers reported fewer health complaints than smokers. Astrand and Isacsson (1988) found that male employees of a pulp and paper plant who smoked retired at an earlier age than nonsmokers. Data from the 1979 National Health Interview Survey indicate that smokers have more restricted activity days, more bed disability days, more hospital days, more physician visits. and an increased probability of being unable to work or keep house, than nonsmokers (Rice, Hodgson. Sinsheimer 1986). Analyses of data for the 1976-80 Health Interview Surveys showed that smokers have a 55 to 75 percent excess in days with respiratory conditions associated with reduced activity (Ostro 1989). Smokers experience more school absences (Charlton and Blair 1989; Alexander and Klassen 1988) and work absenteeism (Andersson and Malmgren 1986; Coughlin 1987; Hendrix and Taylor 1987: Gallop 1989) than do never smokers. None of these studies reported information on former smokers. These studies are extremely heterogeneous, with some methodologic shortcomings (Chapter 2). Furthermore, smoking is associated with other behaviors that may affect health (Pearson et al. 1987; Stephens 1986). and the studies do not adjust for changes in other risk variables, such as increased exercise, that might be associated with smoking cessation. Taken together, however. the studies are consistent with the hypothesis that smoking cessation produces improvements in health status. This conclusion is evident particularly when considering that smoking-related morbidity is a powerful motivation to quit smoking and that recent quitters are likely to be sicker than continuing smokers. TABLE 6.-Relation of smoking cessation to various measures of general health status Sell-rcpofl ol ~llne\\ and (`hronic ilIne\\ ph!\lcian VI\I~\ Acure illW\\ Outpatient vl\n PhyGcian conwlliition I.0-r' 1.31" 1.76" I .03 I .OY I.29 I .46 I .46 I .43 I.12 I .0x I .OY Gig/day I yr ??I 51 yr >I yr -- Segovia, Bartlett. Edwards (IYXY) Telephone survey of representative sample us adults Self-report of "good health" 4. IX< 1.00" I .a' 3.42' 5.13" 6.13" Gallop (19X9) Workers in the pulp/paper industry Work absence\ I.3' I .OY' I .otf CONCLUSIONS 1. Former smokers live longer than continuing smokers, and the benefits of quitting extend to those who quit at older ages. For example, persons who quit smoking before age 50 have one-half the risk of dying in the next 15 years compared with continuing smokers. 2. Smoking cessation at all ages reduces the risk of premature death. 3. Among former smokers, the decline in risk of death compared with continuing smokers begins shortly after quitting and continues for at least IO to 15 years. After IO to I5 years of abstinence, risk of all-cause mortality returns nearly to that of persons who never smoked. 4. Former smokers have better health status than current smokers as measured in a variety of ways, including days of illness, number of health complaints. and self-reported health status. 92 CHAPTER 3 APPENDIX TABLE 7.-Age- and sex-specific mortality rates among never smokers, continuing smokers, and former smokers by amount smoked and duration of abstinence at time of enrollment for subjects in ACS CPS-II study who did not have a history of cancer, heart disease, or stroke and were not sick at enrollment 4s 1') so s4 55- SY hOM4 hS-hY 70-73 75-74 I Xh.0 42Y.2 25.5.6 702.7 44x.9 1.131.4 733.7 I .YX I. I I.1 IY.4 3,(H)3.0 2.070.5 3.6Yl.S 3.675.3 7.340.6 Current Former wwher\ (22 I cie/d;tv) TABLE 7.-Continued Females Age Never \mokrr\ I5 Current smoker\ Former woher\ IL.4 S-Y lOLl4 15-l') x!o Current waker\ Former smoker\ l-4 S-Y >I0 I .o (7) 15.X(123) lh.O(l5) S.Y(l') 5.3 (Y) 7.0 (7) 11.3(2.6OY) 1x.x (47) 7.7 (X6) 4.7 (I(H)) 4.x (I IS) 2.1 (123) 3.x 4.7 2.5 I .4 IY.Sl-71,Dyr followup: data on former smoker\ In wmmary form 195449, 16-yr followup TABLE 3.-Continued Reference Population Smoking status and yr since stopped wloking Hammond ( 1966) ACS CPS-I male% Never wwkerh Current v~x~k.er~ f%mer \moher\ I0 ACS (unpuhll\hcd tuhulatlww) ACS CPS-II malrb Never w~ohers Current smokers Former smoker\ Ih Mortality ratio5 (N)" Comments I-l') up/day IYSY-67. 7.5.yr followup. men aped SO-69 I .o (32) 1.0(37) 6.5 (X.01 13.7(351) 7.7 (`I) 2Y.I (73) 4.6 (5) 12.0(3X I .o ( I ) 7.2 (22) 0.4 ( I , I.1 ts, I-20 221 cig/dny clg/d;ly I.0 (XI) I .o (XI, 1x.x (60X) X.9(551) 26.7 (32) 50.7 (63) ??.4 (7 I ) 31.2(117) 16.5 (X2) 20.`) (Yh) x.7 (X01 IS.0 ( IOh) h.0 (6Y 1 I?.6 (Y5) 3.1 t I441 5.5 (I 121 TABLE .X-Continued Never \mohcr\ <`urrcnt wiokw I%rmcr \mohcr\ 20 +/day Cl@i) I .o ( IX l ) 7.2 ( 145) 7.Y (3 9.1 (13, 2.0 (7) I .o (4) I.5 (6) I .4 (23) I .o ( IX I ) 16.3 (334) 34.3 (3 I I IY.5 (42) 14.6 (42) Y.I (32) 5.Y (20, 2.6 (IX) TABLE 4.-Relative risks of lung cancer among former smokers, by number of years since stopped smoking, and current smokers, from selected case-control studies Reference Popuhtion Definition of former smoher Smoking status and yr \ince wpprd Graham and Levin (1971) New York At hospital admission Never smoker\ Current vnokers Former smoker5 0-03 >().%I >I-.? >3-IO >I0 Wigle, Mao, Grace (1980) Correa et al. (1984) Alberta. Canada, cancer patient5 At mtervww NR NWCI- \mohcln Current \moher\ Former amohers 3-s 6X >20 Rewlts Aci.juatment" Male\ Crude I .o X.X 42 2 z 3 3 IO.0 3.3 I.3 Mole\ l+males 0. I 0.1 I 0 I .o 3.4 0.9 0.7 0.s 0.7 0.5 0 2 0.4 M;lle\ d f?nlule\ I .o I2 h 77 7.0 3.9 TABLE 4.--Continued Deflnltlon of former maker Smoking status and yr since stopped Results Adjustment'l AItl~r\~~n. Lee. W;rnp (19X.5) (;;I0 c, al , I')XX) NK Never makers Current \mokrr\ Former smoker\ I-2 5-10 >I0 Never smoker\ Current \mokrr\ Former smokers IL4 s-9 2 IO Never smohw Former smokers 5 Mules 0. I I .o I .x 0.4 0.3 Female\ 0.2 I .o 2. I 0.7 0.3 Males Female\ ) .o I .o 3.9 2.9 6.9 7.2 3.1 3.9 LI 3.2 Male\ I .o I I .9 6.1 3.7 I .9 Males Femall3 I .o I .o I.? 2.0 0.6 0.9 Age Age and educatwn At lrab~ I yr at time of lntervleu NK Duration of \mokmg TABLE 4.--Continued Reference Population Defimtion of former \moher ~-.__~ Smoking %13tu\ and yr Gnce stopped -~~~ __. ~~ Lubin et al. (1984a) Pathak et al. (1986) European casexontrol study New Mexico At interview Current smoker\ Former hmokerk 1-4 s-9 l&l4 IS-19 2%?4 x.5 AI least I yr before interview Current smoker\ Former smoker\ S IO 20 Current smokers Former smokers I-S 6-10 >I0 Damber and Larson (19X6) Swedenh NR Males I .u I.1 0.7 0.6 0.4 0.4 0.3 Female\ I .o 0.9 0.7 0.4 0.5 0.5 0.3 Duration of smoking Male\ S6.5 >hS I .o I .o 0.5 0.7 0.2 0.5 0. I 0.3 Male\ 9.S 73 3.0 2.0 Number of q/day Age Graham and Levin I97 I; Pathak et al. 1986). Canada (Wigle. Mao. Grace 1980). Europe (Lubinetal. 1984a;DamberandLarsson 1986).Asia(USDHHS 1982:Gaoetal. 1988). and Latin America (Joly. Lubin. Caraballoso 1983). Although only a few studies had information on female former smokers, the pattern of risk reduction was similar to that observed for males. Decrease in risk after smoking cessation also has been reported for each of the major histologic types of lung cancer (Wynder and Stellman 1977; Lubin and Blot 1984: Benhamou et al. 1985: Higgins and Wynder 1988) (Table 5 and Figure I ). Higgins and Wynder ( 1988) found that the decline in risk after cessation was more consistent for Kreyberg I tumors (primarily squamous cell, small cell. and large cell cancers) than for Kreyberg II tumors (primarily adenocarcinomas and bronchiolo- alveolar carcinomas) (Figure I ). Smokers of filter and nonfilter cigarettes (Wynder and Stellman 1979: Lubin et al. 1984b) and of other tobacco products (Joly. Lubin. Caraballoso 1983: Lubin et al. 1984b; Damber and Larsson 1986; Higgins, Mahan, Wynder 1988) have reduced lung cancer risk following cessation (Table 6). Although the findings of the reviewed studies uniformly indicate lower risk among former smokers. the magnitude and rapidity of the risk reduction with smoking cessation varies among the studies. This variation has several potential explanations. First, years of abstinence among those who stopped smoking for the longest time interval varied from 5 to 25 years or more. Second, although former smokers have a risk of lung cancer between those of continuing smokers and never smokers. the pattern of declining risk as duration of abstinence lengthens has not been fully characterized. The small number of former smokers in some studies limits the precision with which the decline in risk can be described, particularly for the longer durations of abstinence. Third. aspects of the active smoking history. including cumulative smoking exposure up to the time of quitting. age at initiation. years of smoking. number of cigarettes smoked per day. inhalation practices. types of cigarettes and other tobacco products smoked, age at smoking cessation. and the reason for stopping, may modify the risk of lung cancer after cessation (Chapter 4. see section on Effect of Antecedent Smoking History). The varying extent to which these factors havJe been considered in analyzing the effect of cessation may partially explain the differences in risk observed in former smokers among the studies. As discussed below. failure to adjust for previous smoking history may exaggerate the benefit of smoking cessation. but adjustment for cumulative smoking history also may result in overadjustment of the risk estimate (Chapter 2). Fourth, the studies vary in the definition of former or es-smohers and in the analytic treatment of former smohers u ho have recently stopped smoking. In the case ,I? I II I .o I .o 31.3 IO 7 Ft!lll;llt2\ Kreyherg type I II I .o I .o 10.5 4.4 52.X I-t.? 13.6 6.7 74.0 5.0 6.2 3.6 17.1 6.6 5.1 4.1 13.7 5.-J x.x 5.6 5.0 I.7 O.`J Mnh Krc?tm$ t>t>c I II I 0 I .o .I-&.(> 6.1 I'.' 2.1 IO 9 0.J I .o 4.2 M;Itc\ I;CllldC\ ADEN sy ADENO I .o I .o I 0 t 0 0.x 0.6 0.0 0.5 I.1 0.7 0.0 I .o 0 4 0.4 0.4 I .7 0.3 0.3 TABLE &-Relative risks of lung cancer among never, former, and current smokers by types of tobacco products smoked Never smoker\ Former smokers Current smoker\ C`Igarettc~ only I .o 6.Y 16.0 CIg;ir\ only I .o 2.5 3.1 Pipes only I .o 0.7 I .9 Clfars and pipe\ t .(I 2.4 x.5 Mixed woher\ I .o S.1 10,s Y r Gnce stopped I4 2.5 0.6 0.7 4.4 0.0 2.0 0.Y t .2 0.8 I .o t .o I .o I .o C`lgarelte\ only" Plp13 only Y r since \topped t-10 >I0 S.0 1.2 5.0 4.5 9.5 x.0 KREYBERG I (N-330) MEN 30 25 20 15 10 5 0 E L i4 t KREYBERG II (N=204) Y 15 d n r-l r 35 30 25 20 15 10 5 0 15 10 9 10 F: 25 20 5 0 1 - 11 - 21 - 31 - 241 NUMBER OF CIGDAY Yr of abstinence WOMEN KREYBERG I (N-951 KREYBERG II (N=lOO) 01-4 05-9 810-19 sl20-29 * >30 FIGURE l.-Risk of lung cancer by number of cigarettes smoked per day before quitting, number of years of abstinence, sex, and histologic types SOC'RCE: Hlggn\ and W>ndrr (198X) Although this review has emphasized the results of cohort and casexontrol studies. descriptive data on lung cancer mortality in the United States are consistent with a beneficial effect of the declining prevalence of cigarette smoking. Devesa. Blot, and Fraumeni ( IYW) described declining mortality rates for lung cancer at ages belov, 15 years. The decreases were greatest among white men but also occurred among white women and blacks of both sexes. Effect of Antecedent Smoking History The preceding Section reviewed epidemiologic studies describing the pattern of lung cancer rish following smoking cessation. This Section considers factors related to smoking that plausibly could modify the effect of cessation on lung cancer risk: these factors include the duration of smoking. daily cigarette consumption. inhalation prac- tices, types of tobacco products smoked. and age at cessation. Duration of Smohing Duration of smoking prior to cessation is a potentially important modifier of the pattern of risk reduction in ex-smokers. Graham and Levin (1971) examined the rish of lung cancer associated with increasing durations of abstinence and with stratification by duration of smoking (130 or 23 I years and 5-I-10 or 231 years). The decline in risk associated with stopping v~as greater for those who had smoked for shorter periods than for those who had smoked for longer periods. Similar results were reported by Lubin and colleagues ( 19x41). who determined the rish of developing lung cancer by time since stopping hmohing (0. I--1. 5-Y. and 210 years) and total duration of smoking ( I-19. 20-N. 404Y. and 23) Jears). In each category of smoking duration. the rish of developing lung cancer decreased as the number of j'ears since stopping smohing increased. but the rate of decline LI as greater among those who had smohed for a shorter time. Among men who had smoked for I to IY years. the rish ofdeveloping lung cancer after IO ycurs of abstinence dropped to Ie\s than one-third of that among current smohers. On the other hand. t'or men 1% ho had smohed 50 ! ears or more and stopped for at least 10 \`ears. the rish M as still YO percent otthat t`or men LI ho continued to smohe. This analysis. which matched for age and controlled for both duration of smoking and length of abstinence. introduces too man! \anahlcs i'or the temporal dimensions 01` cifarette use (Chapter 7). B! simultaneously considering attained age. duration ot' smohing. and length of abstinence. the anal> tic model incorrect11 forces former smohers to ha\,e ;I ! oungcr age of starting to smohe than current smohers. Ill ;I case--Control stud!, in Sweden. Dambcr and Lars\on ( I YX6) also found higher rt'lati\.e risks among t'onncr smohcrs of pipes and cl,, `o,lrettes u ho had smohrd longer. Brown and Chu ( lYX7) ~ggestcd that t'ailure to ad.iu\t for pre\ ious duration ot smohing ma\ result in rish e\timatc\ i'or former smohers that are too ION and thus exaggerate the henei'ith of smohing cessation. Based on reanalysis of data from the large European cases _ . \ \ \ \ % `4 4 `\\ \ \ \ `A---- --&\ WITHOUT ADJUSTMENT FOR ' \ \ SMOKING DURATION \ \ \ - "' I 0 k lb 1; $0 2k io : YR SINCE QUIT SMOKING FIGURE 2.-Relative risk of lung cancer among ex-smokers compared with continuing smokers as a function of time since stopped smoking, estimated from logistic regression model, pattern adjusted for smoking duration compared with pattern unadjusted for duration SOCiRCE. Hroun and Chu (101171 time than men who had stopped for a shorter time. The relative risk of lung cancer continued to decrease sharply with increasing years of abstinence without adjusting for smoking duration. whereas the decreasing relative risk plateaued when adjusted for duration of smoking (Figure 2). The difference in this pattern was most noticeable for increasing years of smoking abstinence. For those who had stopped smoking for 27 years or more, the relative risk compared with continuing smokers was 0.30 when adjusted for duration, but 0.17 when no adjustment was made. However. control for previous duration of smoking (or cumulative previous smoking history) in determining the risk of lung cancer among former smokers may constitute overadjustment if age and duration of cessation also are included in the model (Chapter 2). In summary, only limited analyses address the effect of duration of previous smoking on the decline in risk following cessation. The data point to less decline of relative risk following cessation, comparing longer term with shorter term studiej. but additional investigation is needed. 123 Daily Cigarette Consumption Previous smohing intensity or number of cigarettes smoked per day also affects the pattern of risk reduction after smoking cessation. In the U.S. Veterans Study. the mortality ratios for lung cancer were 1.3 I, 3.37, 8.31. and IO.05 for ex-smokers who smoked I to 9. IO to 20.2 I to 39. and 40 cigarettes or more per day, respectively (Kahn 1966). The pattern of lung cancer rish reduction by years of smoking abstinence and number of cigarettes smoked has been reported for several studies. In ACS CPS-I and ACS CPS-II (Hammond 1966: Garfinkel and Stellman 1988). the decline in risk with stopping smoking showed a comparable proportional reduction in risk among those who had smoked less (Table 3). In the European case in the trend of ri\h reduction by years of hmohing abstinence (0. 14. 5-Y. and 210) and b>, type of cigarettes moked (filter. mixed. nonfilter) \\erc observed by Lubin and coworher\ ( 19XlhJ in the European case-i'ontrol stud>. Among men. the relative risk for former smokers after stopping smoking for IO lears or more has 0.4 for filter cigarette smokers. 0.3 for nonfiitercigarette smoher5. and 0.5 for mixed filter and nonfilter cigarette smokers. These data were collected in five western European countries from 1976 to IYXO: the tar yields of the products smohed were relatively high in comparison with cigarettes currently smoked in the Ilnited States (Lubin et al. IYX3b). In most studies, cigar and pipe smokers have louver lung cancer risks compared with cigarette smokers (US DHHS IYX2). Former smohers of only pipes or cigars also showed an intermediate risk of lung cancer compared v. ith current smokers and never smohers of these tobacco products (Table 6). In the U.S. Veterans Stud). the lung cancer mortality ratio. compared with never smohers. was I .67 among current smokers who used only pipes or cigars and 1 .SO among former smoker\ (Kahn lY66). In a case-control study ofsmoking-related cancers conducted in the United States. Higgins. Mahan. and Wynder (1988) reported that ex-smokers of cigars only showed a relative risk of 1.5 compared with 3.1 among current smokers of cigars only. The relative rish was 0.7 among ex-smoker\ of pipes only compared with I.Y among current pipe smokers only. Analysis of the pattern of risk among ex-smokers of cigars and pipes only by considering the amount and duration smoked prior to smohing cessation revealed similar patterns of risk reduction among light and heavy smokers. Lubin. Richter. and Blot ( 1984) also examined the pattern of risk reduction by years of smoking abstinence (0. I--1, 25 years) and types of tobacco smoked (cigars onI!,. mixed cigar and cigarette smokers, pipes only. and mixed pipe and cigarette smokers). No apparent differences were observed in the estimated rishs. ivhen analyred by tobacco products. among those who had stopped smoking for at least 5 years. but the numbers of cases who smoked cigars only and pipes only were quite small. On the otherhand. Damber and Larsson ( 1986) reported that the decrease in relative risk among ex-smokers was less pronounced in smokers of pipes compared with cigarette smoker\ only in a case-control study conducted in Sweden. However. in this population. the risk of lung cancer for pipe smokers (RR=6.9) was similar to that of cigarette smokers (RR=7.0). In summary, these analyses. limited by the sample sizes within strata of types of products smoked, do not characterize precisely the changing lung cancer risk following cessation for smokers of various tobacco products. Effect of Age at Cessation Several researchers have suggested that the reduction in rish after smoking cessation may differ by age at cessation. Wynder and Stellman ( 1979) reported that the reduction in risk after cessation was appreciably greater for people aged 50 to 6Y than for those 70 or older. However. only data for those aged SO to 69 were presented in this publication. Pathak and associates (1986) also reported a strong interaction between age and duration of cigarette smohing. Risk of lung cancer among ex-smokers was compared with that of current smokers with adjustment for the amount smohed. For ex-smokers less than 65 years of age. the estimated relative risks compared u ith current smokers declined to 0.39. 0.14, and 0.06 for 5. IO. and 20 years of smoking abstinence. respectively. For those aped 65 or older. the corresponding estimated relative risks were 0.73.0.54. and 0.29. respectively. These two studies suggest that the risk of lung cancer may decline less steeply with increasing abstinence for older ex-smokers. Multistage Modeling Multistage models provide a conceptual framework for facilitating understanding of the relationship of lung cancer incidence with amount smoked, duration of smoking. and time since cessation. These models. proposing theoretical constructs of fundamen- tal biologic mechanisms. have been useful for evaluating epidemiologic data in a biologic framework and thereby furthering the understanding of tobacco carcino- genesis. However, fitting these models to epidemiologic data cannot establish the veracity ofthe underlying biologic theory. Multistage modeling approaches have been used to describe respiratory carcinogenesis and to assess smoking cessation and lung cancer risk. Although a number of different mathematic models of carcinogenesis have been proposed (e.g.. two-stage. multicell, multistage). this discussion primarily ad- dresses the Armitage and Doll (1954. 1957) multistage model, which has been used most extensively in studies of lung cancer. Based on a series of studies examining age-specific mortality rates for various cancers. Armitage and Doll (1954. lYS7) proposed a multistage theory of carcino- genesis. Their model assumes that a single cell can generate a malignant tumor only after undergoing a certain number of genetic changes. Animal studies also support the multistage model. Multistage theories also predict the age pattern of occurrence of many tumors induced in experimental animals by continuous exposure to chemical carcinogens. Experimental regimens involving initiation and promotion provide direct evidence of the effect of early- and late-stage events in the carcinogenic process (Stenback. Peto. Shubik 198la.b.c). Using data from the British Physicians Study,. Doll (197 I ) showed that when the incidence of lung cancer in cigarette smokers was plotted against duration of smoking. incidence increased approximately in proportion to the fourth powerofduration. similar to the slope of the regression line when incidence in never smokers is plotted against age (Figure 3). Thu\. a first-stage effect uas implicated because the excess lung cancer risk among smokers increased with the same power of duration of smoking as the risk with ape among never smokers. Moreover. the lung cancer mortality rates among ex-smoker:, decreased someu hat initially and then increased ,Iowly in beeping with the increase in rish among never smohers vv ith age (Doll I97 I ). Armitage ( 197 I) noted that the stabilir.ation of excess lung cancer risk at the level when smoking stopped suggested that smoking also affected a late stage. namely. the penultimate stage in the carcinogenic process. Day and Brown (IYXO) conducted a detailed analysis of the pattern of change in cancer risk after cessation of an exposure. The results supported the Arnmitage-Doll model. In addition. Day and Brown proposed that the stage affected by the agent and the relative magnitude of the effect of the agent on early and late stages of the carcinogenic process are critical in the determination of risk subsequent to cessation of an exposure. To quantify the magnitude of smoking et'fectj on the two stages. Brown 1,000 100 10 1 X-X Cigarette smokers by duration of smoking x ---a# Cigaretie smokers by age .-. Never smokers by age I I I I I I I 20 30 40 50 60 70 80 YEARS FIGURE 3.4ncidence of bronchial carcinoma among continuing cigarette smokers in relation to age and duration of smoking and among never smokers in relation to age, double logarithmic scale SOCRCE Doll c I')7 I), xlth LO~XC~K~ (11 prIntin; ~`rrw m the w~yn,d figure and Chu ( 1987) reexamined data on ex-smokers from the European case+zontrol stud) of lung cancer (Lubin et al. lOX4a) and concluded that smoking had an almost double relative effect on late-stage events compared with first-stage events. Using data from a case within the framework ofthe two-mutation. recessive oncogenesis model. Ba\ed on this model. the second-mutation rate would be affected by \mohing. and a sudden decline in risk after cessation of smohing v.ould be predicted. HoNever. this model implies that smoking affect\ the last stage in a multi$tape process. contrary to current con\ider:t- tions. In summary. multistage models have been used to describe the interrelationships among number of cigarettes smoked dail>. duration. time \inctz e\posurr ended. and lung cancer incidence. Several In\,c\tigators hale interpreted the data on rish among former smokers in different ~a> \. The epidemiologic data clearI> indicate that the rish among former smohers i\ between that of continuin, (1 smoher\ and nekrr smohers. Various models can be fit to the different data ~1s. The expected pattern ofrith among former sniohers is sensitive lo the model \clectrd and dependent on the relati\ e magnitude of the effect of smohing on earl> \ er\u\ late stage\ of the proces\ ot carcinogenesis. Lsing multistage models. the data on t.ormer smohcr\ are insufficient to allow precise quantification of the relati\ c cffcct\ of \mohin, 0 on the earl\ and late stages of the carcinogenic proce\\. H hich smokin, (7 i4 assumed to affect. Ne~ertticle\\. data indicate that \mohing ha\ an dt'cct on the late \tagt'\ of the carcinogenic proce\c and that cessation reduce\ lung cancer occurrcncc. Cessation After Developing Disease Individuals who stopped smoking are not a randomly selected group in most studies (Chapter 2). Often. smohers quit as a result of developing symptoms of a life- threatening disease or immediately after diagnosis of cancer. This phenomenon is ev id,enced by the increase in risk of lung cancer in the immediate period after cessation. Sotne studies have grouped these former smokers with the continuing smohcrs or have excluded them from the analysis. A few epidemiologic studies have assessed the risk of lung cancer among those who quit for health reasons and for non-health-related reasons. In the U.S. Veterans Study. about 10 percent of the smokers quit because of a doctor's orders: these smokers here presumably ill. The lung cancer mortality ratio relative to never smohers for es- smokers who stopped because of non-health-related reasons MLIS 3.43 compared with 5.83 among ex-smohers who stopped on a doctor's orders and X.98 among continuing smohers (Kahn 1966). In the European case-control study. Brown and Chu ( I YX7) reported that the relative risk of lung cancer for those who stopped smoking because of health reasons compared with those who stopped for reasons other than health uas 1.3 (p?I erg/da\ q/da\ 7.4 i-l.3 Y I 19.5 7 Y 11.6 I .(I Y. I I .5 SY 1-l 26 extent. performance status. and type of protocol treatment. Similarly. statistical sig- nificance was maintained after simultaneous adjustment for both thbmosin and radia- tion therapy. The study b> Bergman and Sorenson ( IYXX) involved 153 small cell lung cancer patients who received combination chemotherap>. Thirty-two had stopped smohing at least 6 months before the initiation of treatment or had ne\`er smoked. 51 patients stopped smoking less than 6 months prior to the start of treatment. and 71 patients continued to smoke during the treatment period: the median survival was 39. 42. and 30 weeks. respectively. Reasons for differences in results betbeen the two studies are not clear. Overall. patients in the study hy Bergman and Sorenson ( 1988) had smoked fewer pack-years. but the median survi\,al and performance status of each of the three 130 smoking status groups were poorer than for the comparable smoking status groups in the study by Johnston-Early and associates ( 1980). LARYNGEALCANCER Pathophysiologic Framework Smoking has been firmly established as a cause of laryngeal cancer (US DHHS 1982. 1989) based on numerous epidemiologic studies. These studie, have employed diverse methodologies and have been performed in different countries and covered various time periods. Tobacco smoke exposure has been measured by number of cigarettes smoked per day. number of years of smoking, age when started to smoke, type of cigarettes smoked. and depth of inhalation (US DHHS 1982). In the larynx, as in the bronchus. a sequence of histologic changes occurs with continued smoking. These changes progress from cells with atypical nuclei. to car- cinoma in situ. to invasive carcinoma. Autopsy studies show that recovery of the laryngeal epithelium can follow smoking cessation. Auerbach, Hammond. and Gar- finkel (1970) studied postmortem specimens of laryngeal epithelium from 942 men (644 current cigarette smokers, 94 cigar and/or pipe smokers, I I6 ex-cigarette smokers. and 88 never smokers). Ex-smokers in this study had stopped smoking for at least 5 years. Compared with current smokers, ex-smokers showed fewer histologic changes: 75 percent of ex-smokers and never smokers showed no cells with atypical nuclei. whereas almost all current smokers showed some cells with atypical nuclei. Similar findings were reported by Muller and Krohn ( 1980). who obtained laryngeal epithelial specimens from autopsy. Of the 148 cases in the study. 24 were never smokers and 24 were ex-smokers who had stopped smoking for at least 5 years. Table 8 shows the relative distribution of selected histologic features by smoking status. Occurrence of all histologic changes was lowest among never smokers, intermediate among ex-smokers, and highest among current smokers. However. the histologic findings of ex-smokers in this study were more similar to those of light current smokers (I0 I IO 3.11 2.x I .o Y.5 7.2 I .o 7.x (1.3 Malt\ I~cnl;tle\ I .o I .o 17.x Y.5 (7.7 6.5 I .o 0.0 3.2 (`lg/d;l) II 70 `I 30 31 40 >40 3.0 J.(I 72 0.Y I.2 I .I) .3 I 3.5 TABLE 9.--Continued `l`U> II\ ct XI (IYXX) Former vnoher\ (yr \incc 4loppetl) I-3 44 7-10 II-15 >Ih Cutrent wider\ Never w~oher\ Relative risk\ Malea 17.9 8.5 3.0 3.4 1.5 I4 3 I .I) Female h.Y 2.6 - X.X I1.h I .o Entlolnry nx I .5 I CONCLUSIONS I. Smohing cessation reduces the risk of lung cancer compared M ith continued \moh- ins. For example. after 10 years of abstinence. the ri\h of lung cancer is about 30 to 50 percent of the rish for continuing smokers: with further abstinence. the ri\h continue\ to decline. 2. The reduced risk of lung cancer among former w~ohers i\ oh3erved in male\ and females. in smokers of filter and nonfilter cigarette>. and for all histologic types of luns cancer. 3. Smohing cessation lower\ the risk of larynyxl cancer compared with continued smoking. 1. Smohing ce\\ation reduce\ the severity and extent of premalignant histologic changes in the epithelium of the larynx and lung. References ALDERSON, M.R.. LEE. P.N.. WANG. R. Risks of lung cancer. chronic bronchitis. ischaemic heart disease. and stroke in relation to type of cigarette smoked. .lou/.rwl of E/?/d'nriolo,~~ trrrtl Con7/777//7i7~ Hcr~ltlr 3Y(4):2Xh-293. December 1 YXS. AMERICAN CANCER SOCIETY. Unpublished tabulations. ARMITAGE. P. Discussion on paper hy R. Doll. .lorrr-/rt/l of 7hc R(JJU/ S~c17i.s//c~c/I Soc.ret?. A134:155-156. 1971. ARMITAGE. P.. DOLL. R. The age distribution of cancer and a multi-stage theory of carcinogenesis. British ./07//77~1/ c$Cu/7wr 8: l-l I . 195-t. ARMITAGE. P.. DOLL. R. A two-stage theory of carcinogenew in relation to the age distribution of human cancer. B/-iris/7 .lor/r/7ct/ ofC~w7wr I I : I6 I-164,. 19.57. AUERBACH. 0.. GARFINKEL. L.. HAMMOND. E.C. Relation of smoking and age to findings in lung parenchyma: A microscopic study. Cl7cw 6% I t:2Y-35. January 1974. AUERBACH. 0.. GERE. J.B.. FORMAN. J.B.. PETRICK. T.G.. SMOLIN. H.J.. MLIEHSAM. G.E.. KASSOUNY. D.Y.. STOUT. A.P. Changes in the bronchial rptthelium in relation to smoking and cancer of the lung. .4 report of progress. i%`crc, h~ltrr7rl .lortr~7t/l of Merlic~i/rr' 256(3):97-104. January 17, 1957. AUERBACH. 0.. HAMMOND. E.C.. GARFINKEL. L. Histologtc changes m the larynx in relation to smoking habits. c`crww 2S( I ):92-10-l. January 1970. AUERBACH. 0.. HAMMOND. EC.. GARFINKEL. L.. BENANTE. C. Relation of smoking and age to emphysema. Whole-lung section stud!,. Nc,i\, E/7,g/tr/7cl .lor/r/7trl c!f Medic 717~ 2X6( 16):853-X57. April 70. 1972. AUERBACH. 0.. STOUT. A.P.. HAMMOND. EC.. GARFINKEL. L. Changes in bronchial epithelium in relation to sex. age. residence. smoking and pneumonia. R;rzic, E/7,~/o/7cl./o7//./7ol of`Mcdic~i/7r 267(j): I I l-l 25. July 19. I Yh'a. AUERBACH. 0.. STOUT. A.P.. HAMMOND. E.C.. GARFINKEL. L. Bronchial epithelium in former smokers. Nw E/7q/c//7d ./oI//~/~LI/ ~!f'MedicY/~e 267t3 ): I I Y- 125. July I Y. 1962h. AUERBACH. 0.. STOUT. A.P.. HAMMOND. E.C.. GARFINKEL. L. Smoking habits and age in relation to pulmonary changes. Rupture of alveolar septums. fibrosis and thickening of walls of small arteries and arterioles. hicu E/7,~/o/d Jorr7~/7c// of'M~dki/7c 269(X)): 103% 1054. November 14. 1963. AUERBACH. 0.. STOUT. A.P.. HAMMOND, E.C.. GARFINKEL. L. Interrelationships among various histologic changes in bronchial tubes and in lung parenchyma. An7er~ic~tu7 Ke\~ie~. r!fRes/)i~u/or.~ Discuw 90(6):867-X76. December 1964. BENHAMOU. S.. BENHAMOU, E., TIRMARCHE, M.. FLAMANT. R. Lung cancer and use of cigarettes: A French case-control study. Jorrr-/7u/ of the NuI~o/~u/ Cufrt CI lux7i717t~ 74(6):1169-l 17.5. June 19x5. BERGMAN. S.. SORENSON. S. Smoking andeffect ofchemotherapy in small cell lung cancer. 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The c;~u\es of lung cancer in Louisiana. In: Il~/ell. M.. Correa. P. (ed\.) Ll//+! ctnrc~c~r' C~/rc.\l~.\ ~111d Pi-c,1 l'/rfi/vr. P,-rlc~cc~/l~r~~.c ~lf`llrr~ Ilrrc~r~lrtrri~ltl~,/ LWI' C`rllrc-c,r L'/,clt/rc~ C~/tfi'w~~c.c, Ncu Orleans: Verlq Chcmic International. Inc.. 19X-l. p. 73. DAUBER. L.A.. LARSSON. L.G. Smohing and lung cancer utth special refxd to t!Je of smoking and type ofcancer. A c;tv--controI study in north Sv.eden. B,-iri\/,./or,r-,tcl/ofCo,rc (`I 535 ,:673-6X I. May 10X6. DAY. N.E. Epidemiological data and multistage carcinopenc\i\. In: Btirrsonyi. M.. Lapi\. K.. Day. N.E.. Yama\ahi. H. (edz.) Mc~t/c/.\. Mc,c~/rc/~~i.\/r/v t/lx/ Erio/o,p\. of' 7ltnlcw Proruo/io/r. Lyon: IARC. lYX5. pp. MY-357. DAY. N.E.. BROWN. C.C. Multt\tage model\ and primary pro cntton of cancer. ./ow~rtr/ ot t/w R;tr/io/rtr/ Ctrrtc w //t\/iro/c f&1):977-YXY. April I YXO. DEVESA. S.S.. BLOT. W.J., FRAUMENI. J.F. JR. Decltning lunp cancer totes among )outy men and \%omen tn the United State\: .4 cohort analysk ./c~rrrw/ off/w ,Vr///orw/ Cr/,rc.c,v /usrirt/fc~ X I : 156X- I 5 7 1 . I YXY. DOLL. R. The age distribution of cancer: Implication\ for model\ ofcarctnogenest~. ./rjr,r/~r// of'rtw Roy// .Srtr/r.\rrc~r// .Soc~icv,v A 131: 133-l 66. I97 I DOLL. R.. GRAk'. R., HAFNER. B.. PETO. R. Mortalit> in relatton to \mohtnf: 22 bear\` obwvation\ on kmale Britt\h doctor\. HI-I/;\/I .Wc,c//c c//./c~r//./rc// 2X0(62 lY):Y67-Y7l. April 5. IYXO. DOLL. R.. HILL. A.B. Mortality tn rclatwn to wtohing: Ten years' ohvrvation\ of British doctor\. Bvrrrsl~ Mcv//w/ .torowl I : I iYY-I-I IO. Ma) 30. I YhJ. DOLL, R.. PETO. R. blortality in relation to wiohin2: 20 yearh` oknations on male Britirh doctor\. &rri.sh Mrclic,ol .I~~rrm// 2: 1525% 1536. Dwemtw 25. I Y76. DOLL. R.. PETO. R. Cigarette \tnoking and bronchial carcinom;t: Do\e and time rrlattonhhlp\ atnonp regular wloher\ and lifelong non-moherz. ./owrttr/ c,f'E/,iclc,t,rr~j/,~~~, oml C~~w~~~~~~r\ Hctrlflr 31(1):303~3 13. December lY7X. ELWOOD. J.M.. PEARSON. J.C.G.. SKIPPEN. D.H.. JACKSON. S.M. Alcohol. smoking. wcial and occupational factor\ in the ac`tiology ot`cancerofthe oral ca\ It!. phar! nx and lar> nx. /,ttc~,.trt/tio/f[// .toromr/ ~~t'(`rr/lc~cv~ 31:6034 12. I YX1. FALK. R.T.. PICKLE. L.W.. BROWN. L.M.. !vlASON. T.J.. BUFFLER. P.A.. FRAUMENI. J.F. JR. Eftrct ofmohtn? and alcohol conwmption on lar). nseal cancer rt\h m co;t\tal Tc`u\. Ccr,rc,c>/. Rcsc,trr.c /I -!Y( I-l 1:-10211O'Y. Jtil! 15. I YXY. FARBER. E. The multtxtep nature of caner de\elopmwt. Cw( (`I' Kcccwj-c II 11:12 171223. October 19X-1. FLAbDERS. W.D.. ROTHMAN. K.J. Interaction of ;Ilcohol and tobacco in larl,n~~al c;Lnct'r. Anwit UII ./mmtr/ ,!l'E/~iclc,,trro/c,~?. I I& 3 ):37 I-i7Y. March I YX2. FREEDMAN. D.A.. NAVIDI. W.C. `vlulti\tuge model\ for carcinogencsi\. E/lr,f,-o,crlrc,rlro/ Hcwlrlr Prr-.\/w/i\ c\ XI : 169-l XX. May IYXY. GAFFNEY. M.. ALTSHULER. B. Exammatton of the role of cigarette mohc tn lung carcinogenesk u\tng multi\tage model\. .tltro-llc/t lff r/w rVr/rioll1/l COIli ('I' /ll.\rl/lrrc~ X0( 12):Y25-Y3 I, Augu\t 17. I YXX. GAO. Y.T.. BLOT. W.J.. ZHENG. W.. FRALMENI. J.F.. HSI'. C.W. Lung cancer and smohtnp tn Shanghai. //~rc~~~tftrr/o~rc//./or~~~~~o/ of E/Gc/c'r)lro/oq\. 17(21:277-2X0. June I YXX. 13X GARFINKEL. L.. STELLMAN. S.D. Smoking and lung cancer in women: Findings in a prospective study. Cuticer Rescc~rc~/t 48(23):695 I-6955. December I. 1988. GRAHAM, S.. LEVIN, M.L. Smoking withdrawal in the reduction of rish of lung cancer. Cancer 27(4):865-87 1. April I97 1. HAENSZEL. W.. LOVELAND. D.B.. SIRKEN. M.G. Lung-cancer mortality as related to residence and smoking historic\. I. White males. ./orrrxu/ of'rhc, Nutir~tinl Ca,rc~o- //rsrrf(((c~ 28:947-1001. April 1962. HAMMOND, E.C. Smoking in relation to the death rates of one million men and women. In: Haenszel. W. (ed.) El'idf,nlio/o~~;t,u/ Approtrc~tre.r I,J r/w Strtr!\ c!f'Cur~t~er (I/U/ Other Chrrvrrc~ Diseuws. NC1 Monograph 19. U.S. Department of Health. Education. and Welfare. Public Health Service. National Cancer Institute. January 1966. pp. 127-203. HIGGINS, 1.T.. WYNDER. E.L. Reduction in risk of lung cancer among ex-smokers with particular reference to histologic type. C'ar~c~rr 62( I I ):2397-2401. December I. 19x8. HIGGINS, I.T.T.. MAHAN. C.M.. WYNDER. E.L. Lung cancer among cigar and pipe smokers. P wI.eufi\,e Meclrr i/w 17( I ): 1 I61 28. January 198X. JOHNSTON-EARLY. A.. COHEN, M.H.. MINNA. J.D., PAXTON. L.M.. FOSSIECK. B.E. JR.. IHDE. D.C.. BUNN. P.A. JR.. MATTHEWS, M.J.. MAKUCH. R. Smoking abstinence and small cell lung cancer survival. ./or(/./rol c!t r/tc ilntc~r-rc~tr~~ M~~tl/c~u/ 4.\.xo( i&w 244( I9):2 175-2 179. November 14. 19X0. JOLY. O.G., LUBIN. J.H., CARABALLOSO. M. Dark tobacco and lung cancer in Cuba. ./arc/xc// c![rltc Nu/iomd Crrrrc,er Instit~r~e 70(6): 1033- IO.39. June 1983. KAHN. H.A. The Dom study of smoking and mortality among U.S. veterans: Report on etsht and one-half years of observation. In: Haenszel. W. (ed.) Et~iclet?~ir~/o,~ic~cr/At~t~,~ouc~hes 10 /kc Slur/~ of Cum er uful C)flw~- Chronir Di.wuse.c. NC1 Monograph 19. U.S. Department of Health, Education. and Welfare. Public Health Service. National Cancer Institute. January 1966. pp. I-12.5. LUBIN. J.H.. BLOT. W.J. Assessment of lung cancer risk factors by histologic category. ./ofrrrrc~/ r!j'fhe Nutinfiol Currt,t,,. //l.stitlctr 73(2):383-389, August I%-?. LUBIN. J.H., BLOT, W.J., BERRINO. F.. FLAMANT. R.. GILLIS. C.R.. KUNZE. M.. SCHMAHL. D., VISCO. G. Modifying risk of developing lung cancer by changing habits of cigarette smoking. Brifixh Medicd .lmrr7o/ 28816435 ): 1953-l Y.56. June 30. 1984a. LUBIN. J.H.. BLOT, W.J.. BERRINO. F.. FLAMANT. R.. GILLIS. C.R.. KUNZE. M.. SCHMAHL, D.. VISCO. G. Patterns of lung cancer rish according to type of cigarette smoked. Irtterrintiorrcrl ./oitrxal c!fCur~( (`I- 3:569-576. I984b. LUBIN. J.H.. RICHTER, B.S.. BLOT. W.J. Lung cancer risk with cigar and pipe use. Jor~mrrl ofthe Nurior~ul Corrcx~r. lnsrirrtre 73(2):377-38 I. August 19X-t. MCDOWELL. E.M.. HARRIS. C.C.. TRUMP, B.F. Histogenesis and morphogenesis of bronchial neoplasm. In: Shimosato, Y., Melamed. M., Nettesheim. P. (eds.) Mo,l7/1~?gc'"psi.(;.~ of'Lttrt,q Cartc,o.. Volume I. Boca Raton. Florida: CRC Press. 19X2. pp. I-36. MOOLGAVKAR. S.H.. DEWANJI. A.. LUEBECK. G. Cigarette smoking and lun,g cancer: Reanalysis of the British doctors' data. .Ioi(/xul r$(/tc, No/io,~c// Ctrjrc e/' //r.srinrrc 8 I (6):-l I5- 420. March IS, 198'). MULLER. K.M.. KROHN. B.R. Smoking habits and their relationship to precancerous lesions of the larynx. JOI(J-iitrl of Cuii(,ei. Rcvror.c,h trntl Cliiric UI Oiic~o/o,q~ 96(2):2 I l-217. IYXO. OLSEN. J.. SABROE. S.. FASTING, U. Interaction of alcohol and tobacco as risk factors in cancer of the laryngeal region. ./otoxc~l c!f`El'ic/c,nfir,/o,~~ tr& Conrnr(oiiry Hdtl~ 39(2 ): I65- 168. June 1985. PATHAK. D.R.. SAMET. J.M.. HUMBLE. C.G.. SKIPPER. B.J. Determmants of lung cancer risk in cigarette smokers in New: Mexico. .Ir~icrxc~/ of'tlu~ Ntrriorrnl C`trrrcx~r Iiistitrirc 76(3):5Y7- 604. April 19X6. PETO. J. Early- and late-stage carcmogene\is in mouse \kin and In man. In: BGrzs(inyi. M.. Lapis, K.. Day. N.E.. Yamasaki. H. (rds.) .Mr&/.\. Mc~c./l~/~~/\nl.c t/)1(/ &tirj/o,yx of' 7rrn,olr,. Pwnrorio~~. Lyon: IARC. 1 YXI. pp. 33%370. PHILLIPS. D.H.. HEWER, A., MARTIN. C.N.. GARNER. R.C.. KING. M..M. Correlation of DNA adduct levels in human lung with cigarette smoking. !%`c/ntr.e 336(6101 ):790-792. December 2?-2Y. IYXX. RANDERATH. E.. MILLER. R.H.. MITTAL. D.. AVITTS. T.A.. DUNSFORD. H.A.. RANDERATH. K. Covalent DNA damqe in tissues of cigarette smohers as determined hq "`P-postlabeling assay. ./o/r,-,ro/ c!f rhc, ,v"lc!tioflcl/ CUII(.LJI. //~.srj!ll/c 8 I (5):3-l I-337. March l 19X9. ROGOT. E., MURRAY. J.L. Smoking and causes of death among U.S. veterans: I6 years of observation. P~rhlic, Hculth /?q~~~/`~.s Y5(3):2 13-227. May-June 1980. SACCOMANNO. G.. ARCHER. V.E.. AUERBACH. 0.. SAUNDERS. R.P.. BRENNAN. L.M. Development of carcinoma of the lun, 17 as reflected tn exfoliated cells. Ctr,rcc/. 3 I ( I ):256-270. January 1971. STENBACK. F.. PETO. R.. SHUBIK. P. Initiation and promotion at different ages and doses in 7200 mice. I. Methods. and the apparent persistence of initiated cells. &.itr.slr Jolrj./lu/ of Co/1~~c/~44(1):1-13.July 198la. STENBACK. F.. PETO. R.. SHUBIK. P. Initiation and promotion at different ages and doses in 2100 mice. Il. Decrease in promotion bv TPA with age&g. B/.irich ./o~rr!,o/ (!/`Co!rc,~r. 44(l):]%`3.July IYXlb. STENBACK, F.. PETO. R.. SHUBIK. P. Initiation and promotion at different ages and doses in 2200 mice. III. Linear extrapolation from high doses may underestimate low-dose tumour risks. R/?risll Jorrr./itil of'Cojlc,cj,- W( I ):21-31. July I9X Ic. TUYNS, A.J.. ESTEVE. J.. RAYMOND. L.. BERRINO, F.. BENHAMOU. E.. BLANCHET. F.. BOFFETTA. P.. CROSIGNANI. P.. DEL MORAL. A.. LEHMAKK. W.. ET AL. Cancer of the larynx/hypopharynx. tobacco and alcohol: IARC International Case-Control Stud) in Turin and Varese (Italy). Zaragoza and Navarra (Spain). Geneva (Swnzerland) and Calvados (France). /,~rc'i.,~atio,lrr/ Jr)ro.,ltr/ of Ctr,,c,cl~- 4 I1J):4X3--20 I . April 15. 10x8. U.S. DEPARTMENT OF HEALTH AND HUM?rN SERVICES. Tllr Hcwlth Co,t.~eyrre/l(.r.s oj Snlokiq: CU~~C~O~. ,4 Kcy~,.t ,~t rlrc, .SII~C~O/~ &,~c/-~r/. L1.S. Department of Health and Human Services. Public Heath Service.Officeon Smohlng and Health. DHHS Publication No. (PHS, x2-50179. 19x2. U.S. DEPARTMENT OF HEALTH .4ND HCM.4N SERVICES. 7-/r<, Heulth C~,rr.\cc/ltolc,c,s of SnloXlrl,~.~ cIiwflic~ oh.\rrlct Ill`l' LlfU~ ni.\tYrw .A Rq""/ 1!/' /AC Sfrrywi Gcvlcv~tr/. U.S. Department of Health and Human Sen ice\. Public Health Serb ice. Office on Smokmg and Health. DHHS Publication No. (PHS) XJ-50205. IYXI. U.S. DEPARTMENT OF HEALTH r\ND HL'M.4N SERVICES. 7-11~~ Hctrlrl7 Co/l.\c,c/lrc,/lc,c,.\ of ImYdrorrrri~~ .stm~Aiu~. .4 Rt~/`fw/ cq r/w Sfri-,~l~~Jll GcrIc~rtrl. 1'3. Department of Health and Human Services. Public Health Sen ice. Centers for Disease Control. DHHS Publication No. ,CDC j X733YX. 19X6. U.S. DEPARTMENT OF HEALTH AND HC`XIAN SERVICES. Reclrrt ir,y //,c H~lrh Come- ~pm C.S 0f` .Snd~t~~ 2.5 ~~cw-.s of' PuJ:`I-CV. .4 Rrp/-t of //fly Sfrrqcwrl Grw,u/. U.S. Department of Health and Human Senlces. Public Health Senice. Centers for Disease Control, Center for Chronic Di\es\e Prevention and Health Promotion. Office on Smohins and Health. DHHS Publication No. (CD0 X9-X-II I. 19x9. U.S. DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE. Sn,oX~rq (11r~/ Hrc~lrh il Report c!frlrp S~lqco/l &,r~c?rz~/. U.S. Department of Health, Education. and Welfare. Public Health Service. Office of the Assistant Secretary for Health. Office on Smoking and Health. DHEW Publication No. (PHS) 79-50066. 1979. 140 U.S. PUBLIC HEALTH SERVICE. S,voX/,i,q tr/rt/ H~wlrh. Rc/~~wI of I/W AC/I isor:\. Cor~rnrirrc~c~ lo /Iw S~rr.qvcw <;c,wrx/ cd r/w P~rh//c, Hctrlrlr .Sc/-r~/c~c. U.S. Department of Health. Education. and Welfare. Public Health Scn~ce. Center for Disease Control. PHS Publication No. I 103. 196-I. WHITTEMORE. X.S. Effect of cigarette smohing in epidemiolofical \tudle\ of lung cancer. Sttrfrstic .< 111 Mcvlic~//rt~ 7( I-2 ):223-23X, January-February I OXX. WIGLE. D.T.. M.40. Y.. GRACE. M. Relative importance of \mohing ;I\ a ri\k factor for selected cancers. C`o,rtrmohing cehhation. and thu\ comparison\ olri\h berireen current and former smoker\ map' he conf'ounded b>, alcohol consumption (Chapter I I 1. In three investigation\. the effect of smoking ce\hation w;t\ examined and past alcohol coti- \umption was controlled by multiple logistic regression (Blot et al. IYXX: Kabat and Wjnder IYXY: Kabat. Hebert. Wynder IYXY ). In the three htudics. estimate\ ol`relatt\e ri\h\ t'or both current and t'onner hmoherh were similar to those observed in studies in which alcohol was not included ;I> an adjustment factor. The stability of the relative rich estimate\ for stnohing with adjustment for alcohol intahe suggests that alcohol doe\ not substantially confound the relationship befueen oral cancer ri\h and cigarette smohing status and that the lower risk of former smohet-\ cannot be explained b> lower levels ofalcohol consumption (Chapter I I ). One stud) was sufficiently large to permit detailed stratified analysis of the modification of the smohing effect by alcohol consumption (Blot et al. 198X). In thi:, study. former smoher\ were observed to have a lower risk than current smohers for both men and women at each of five levels ofalcohol consumption. The U.S. Veterans Study (Kahn lY66) demonstrated that at each of three levels of past cigarette smoking exposure. former smokers had lower rich of oral cancer than did current smokers. Kabat. Hebert. and Wynder (IYXY) controlled for past cigarette exposure by tnultiple logistic regression and found that relative rihk estimates. which were adjusted for past alcohol and cigarette consumption. did not difftr from the crude estimates for fortner smohers ( 1 .O vs. 1 .O relative to never smohers). Second primary cancers of the mouth and pharynx occur commonly in person\ v. ith an initial primary cancer in the mouth. pharynx. or larynx. Several studie\ ha\,e addressed the incidence ofhecond primaries ofthe mouth. pharynx. or larynx in relurion to smoking status after diagnosis and treatment of the first prima-\. The finding\ ot these studie\ are inconclusive. w)ith some indicating reduced rihk of a second primq af'ier cessation (Moore lY65; Moore 1971: Wynder et al. 196Y: SiI~erman. Gorshb. Greenspan 19X3) and others showins no clear benefit of cessation (Castigliano IYhX: Schottenfeld, Gantt. Wynder IY71: Chapter 5. 5ee section on blultiple Pi-imaE. Cancers). The result\ of t&o studies indicated that continued \mohinp after diagnosic of oral cancer may reduce survival. particularly in combination with alcohol consumption (Johnston aid B;tll;tntyne I Y77: Stevens et al. 1983 ). These analyses. however. did not aci.iu\t for the tnore advanced stage of cancer among u$cr\ of alcohol and tobacco at presentation (Johnston and Ballantynr 1977). The rehulth of studA of oral cancer and cigarette smoking cessation indicate that former smohers experience ;I lower ri\h of oral cancer than current hmohers and that this lower rish does not appear to be ;I result of confounding by alcohol or level of cigarette consumption prior to ces4on. The rish of oral cancer has been shoun to drop substantially within 3 to 5 years ofce\sation. Esophageal Cancer Smoking i4 a major cause of esophageal cancer (US DHHS 1981. 19X9). In the United States. the proportion of esophageal cancer deaths attributable to tobacco has been estimated to be 7X percent for men and 75 percent for women (US DHHS 19X9). .A5 for cancer of the oral cu\,ity. cigarette smoking is an independent risk factor for esophageal cancer but can also act in conjunction with alcohol to increase cancer risk. Table 7 summarixe~ the studie\ that have esatnined the relationship between smoking cexttion and esophageal cancer rish. In these studies. the risk of esophageal cancer for current stnoher\ range\ from I .7 to 6.4 titnes the risk among never makers (median of approximateI> 5). These tindinfs are Gmilur to those for oral cancer as shown in Table I. The risks for \mohinf and esophageal cancer uere similar among male\ and females. Three year\ after cessation. former smohers sho\sed lower ri\h\ than current smoher\ in each study summarized in Table 2. \sith the exception of the Swedish prospective \tud\; (Cederlofet al. 1 Y75) in M hich mohin, -associated risk\ were considerabl\ IOU er than in any other stud). tio\\ever. in follo~up of this cohort. more dramatic elevarionx in tnale mortalit> from s\ophageal cancer uere ohser\txi in current \moker5 relative 10 never mohcrx standardized mortalit! ratio\ were I I for I to 7 2 tobacco per ci;t~. 4.5 for X to I5 g tobacco per &I> . arid 5.4 for more than I5 g of tobacco per da (Car\ren\en. Pershqen. Ehlund 10X7). For fomxr moherh. the st;tndardi/ed mortality ratio ~34 I .i. Approximalel> 3 to 5 bear\ after ces\;ttion. rish ol'e~phngeal cancer ua\ reduced hq approximatcI> 50 percent in the t\\o \tudie\ ptxxtdin, (7 information b> duration of ahtincnce (Table 2 I. Data are \ er! \cmt about the effect\ of cesation on the ri\h ot esophafc~il cancer o\er long period\ of abstinence. The L'.S. Veteran\ Stud) shoued that the ri\h among former \mohrr\ \<;I\ lo\+c'r at each of four le\,els of pat number\ of cigarette\ 3mohcd per da>. A multivariate anal> \i\ in whtch Itfetime alcohol consumption M ;I\ irxluded ;I\ an adjustment factor (La Vecchia. Liati el al. IYX6) produced relati\ e ri\h\ for current and former \tnoher\ that \bcre similar IO those oh\er\ed in other \tudie\. In thi\ \tud!. the crude relative ri\h f'or ex-smohcrs LIH\ nexl! identical to one that ~34 xiju\ted for alcohol con\utnption (2.7 \\. 3.01. u,, \ ocTe\tiiig that ~rlcohol u:ih not 3 confounder in the estimates of the benefits of cc\\ation. X \tud\ that ~a'r limited to nondrinher~ (La Vecchia and Negri I YXY) ;tIw produced rish estimate\ for \mohiq that aerc \er! 152 TABLE 2.-Studies of esophageal ranter that have examined the effect of smoking cessation TABLE 2.--C'ontinued similar to those derived from other studies. supporting an earlier observation of elevated risk for esophageal cancer in nondrinking smokers (Tuyns 1983 ). This review of past research on esophageal cancer and cigarette smoking cessation indicates that former smokers experience a lower risk of esopha_peal cancer than do current smokers. and that this lower risk is not because ofconfounding by lower alcohol intake among former smokers. Pancreatic Cancer The association. noted for many years. between smoking and cancer of the pancreas is considerably weaker than that between smoking and oral or esophageal cancer (US DHHS 1982). Although the causal mechanisms underlying this association are unclear. smoking has nonetheless been regarded as a contributing factor in cancer ofthe pancreas (US DHHS 1982. 1989). In the United States in 19X5. the proportion of pancreatic cancer deaths attributable to smoking has been estimated to be 29 percent in men and 33 percent in women (US DHHS 1989). Table 3 summarizes studies of the relationship between pancreatic cancer and smoking cessation. In these studies, current smokers had risks ranging from I .O to 5.3 times (median of approximately 2) the risk among never smokers. Risks for pancreatic cancer associated with smoking were similar for males and females. Former smokers generally had lower risk than current smokers for pancreatic cancer. but the available data do not characterize adequately the change in risk with duration of abstinence. The large caseZ!O 70 NP risk of pancreatic cancer than current smokers. This diminution of risk with abstinence serves to strengthen the hypothesis that smoking is a contributing cause of pancreatic cancer. Although alcohol does not appear to be a confounder in the assessment of the benefits of smoking cessation. the possibility of confounding by other factors. \uch as diet or amount of prior cigarette consumption. has not been adequately studied. Bladder Cancer As with pancreatic cancer. the relationship between bladder cancer ri\h and smoking has been noted for many years. However. because relative rish\ have not been great]) elevated and because of uncertainty about the effects of unidentified confounding factors in this disease. the causality of this association haj been considered less certain compared with other diseases in earlier reports of the Surgeon General (US DHHS 19X2). Smoking has nonethelec\ been regarded a\ a contributing factor in bladder cancer: in 1985, it was estimated that in the United State\ 17 percent of bladder cancer deaths in males and 37 percent in females are attributable to smohinp (US DHHS lYX9). A particular problem with causal inference in smokin, CT and bladder cancer arise\ because of the inconsistent finding of clear exposure-response relationship\ in all studies. as has been observed between cigarette smoking and respiratory cancers. However. the usual measures of exposure to tobacco smoke may not accurately index the bladder's dose of tobacco-related carcinogens. The International Agency for Research on Cancer (IARC) concluded. based on evidence available through 19x5, that smoking of different forms of tobacco is causally related to cancers of the bladder and renal pelvis (IARC 1986). In addition to the studies reviewed in the 1982 Surgeon General'\ Report (US DHHS 19X2) and in the 19X6 report of IARC ( 19X6). more recent data document a consistent association between cigarette smoking and bladder cancer. In an extended followup of a cohort of 25,000 Swedish males, mortality rates for bladder cancer were increased fourfold among ever smokers compared with never smokers (Carstensen, Pershagen, Eklund 19X7). In current smokers, the risk of death from bladder cancer was approximately three times greater at all levels of consumption. The excess mortality from bladder cancer among current smokers was comparable in the American Cancer Society (ACS) Cancer Prevention Study II (CPS-II) (Table 4). An extension of a large hospital-based case-control study, originally reported in 1977 (Wynderand Goldsmith I977), showed similar increases in risk among male and female smokers (Augustine et al. 1988). The study included 1.3 16 male and 505 female cases and 3.940 male and I.504 female controls interviewed in 9 U.S. cities between I969 and 1984. For current smokers, odds ratios increased to approximately 3.5 for male and female smokers of 21 to 30 cigarettes per day. Odds ratios were lower among former smokers, although the risk did not decline as the duration of abstinence lengthened (Table 4). The findings of a recent population-based case-control study documented similar levels of bladder cancer risk associated with cigarette smoking (Slattery et al. 19XX). Slattery and coworkers (19XX) assessed cigarette smoking and bladder cancer in 3.72 white male cases and 6X6 controls in Utah. The overall crude odds ratio for current IL3 4-h 7.-IO II-15 216 IL.1 341 7-10 I I-I.5 zth TABLE 4.-Continued Reference Population (yr of DeGgn data collection) (number ofwhjecr\) (knder Rl\h ret;ltwc to nwer wwher\ Currcm Former smohcr\ rmohen Wynder and Gotdamith ( 1977) h US cities ( IYh%74) Cavz:control (574:56X) (ls5:154) Male 2.6 2.Y I .s I .h I .2 I.1 2.5 I 2 Vineih et at (IYX3) Cartwrlght et al. (IYX3) Mornwn et al (IYX4) Italy (lY7X-XI) Erlgld (lY7X-XI) Ca\e:controt (755:276) Case:control (Y.v:l.Jo') (3'757Y,, Bowm. MA (107677) Manchuter. UK (1976-7X) Nagoyii. Japan (lY7~7X~ Caw:controt t3'7:3', I ) (lfd:ll?l t3vX:4Yo) (lss:c!41) (`x:44?) (hh: 146) MLlltT 6.0 Male I .h (`awxontrol (5l?:s')h) (SOS: 13(W) Malt Female Mule Fwl;ltc 3.4 3.0 t .CJ I.2 7.v 2' t .h 1.7 I ..v 7.2 4.5 I.8 I .h I.1 2.2 .I 2.3' 22' ?.I' 0.Y' 1.7' I.? 1.2' NP NP TABLE 4.-Continued Slattery et al (IYXX) Claude. Frcn~el- Brymr. Kuwe ( IYXX) ACS CPS-II (unpuhl~~hed tshulathl\) Hurch et al. (IYXY) Utah (lY77-x.31 C;mxia (IY7Y-X2) Case:control (332:6x6) Caaexonrrol (531521) Prwpective (421.663) (h0.5.75X) Cohe:control (627flO2) (IYY:IYo) Male 3.7 3.7 2.7 I .Y 1.X MLlk 3.5 I .x M;k! 2.`) 2.0 Fl!malc 2.X 2.0 Mde 27 I .7 km;de 2.6 I.1 0.557 X-IS I6 29 ?70 NI' NP Y P smohing. compared M ith never smohing. was 3.69 (95-percent confidence interval (CI ). 2.5X-5.26). Ho&ever. an expoatre-response relationship u'a\ not evident with reported average number of cigarettes smoked daily. The odds ratios for former smokers declined only after X years or more of ab>,tinence. Table 3 summuri~e\ finding\ from studies that have examined the relationship between cigarette smoking cessation and risk of bladder cancer. Of all the non- respiratory cancer \iteh. the relationship betwteen bladder cancer risk and cigarette smoking cessation has been most extensively studied. In these studies. the risk among current smokers ranges from I .O to 7.2 times the risk among never smokers (median of approximately 3): rishs are similar among male5 and females. More recent studies conducted since the mid-1970s tend to show> higher ri$kh for current smokers than do the earlier studies. The higher ri5ks in more recent studies may reflect the earlier age of starting to smoke of more recent cohorts of smokers (US DHHS 1989) or the presence of a long latency period for the smoking effect to become fully manifest after initiation in susceptible personh. Beyond the first few years of abstinence. former smokers generally have lower risks than current smokers. The study conducted in six U.S. cities (Wynder and Stellman 1977; Wynder and Goldsmith 1977) indicated an approximate SO-percent reduction in risk after 6 years of abstinence. with risk returning to that of nonsmokers among men after IS years. A similar return to nonsmoker ribh was also observed after 6 year\ of abstinence in an English study (Cartwright et al. 19X3) and in an Argentine study after 20 years (Iscovich et al. 19X7). However. results from other studies (Howe et al. IYXO: Vineis. Esteve. Terracini 19X-t: Hartge et al. 19X7: Burch et al. 19X9) indicated that the reduction in rish in the first few years after ces;sation is followed by little subsequent additional reduction. even beyond IOor I5 years ofabhtinence. These observations are in contra\t to those for the other cancer site\ review,ed in this Chapter. In some studiej. the analyse\ controlled for the possible confounding effect3 of lower cigarette consumption among former smoker5 prior to cec\ation. The U.S. Veteran\ Study (Kahn 1966) showed no reduction in ri\h for former smokers. compared M ith current smoher\. at level\ of past cigarette consumption of I pack or less per dab. There wa\ an approximate SO-percent reduction in risk. however. for those former smokers who had previousI) \mohed more than I pack per dab. Mo\t studies that included past cigarette smoking exposure as a co\ ariatc in multiple logistic regression anal) se\ (Wigle, Mao. Grace IYXO: Howe et al. 19X0: Vinei\. Estete. Terracini 19X-l: Claude. Frent;rel-Beyme. Kun,v IYXX: Slatter; t'l ;I]. IYXX: Burch et al. IYX9) show,cd relative risks that were similar to those observed in studies in which no such adjustment M;I\ made. A large multicenter study conducted b!, NC1 (Hartfe et al. lYX7) contained sufficient numbers of subject\ for detailed subgroup analykrs. Table 5 displays the findings of thi\ study when both average cigarette do\e per da> and duration of smokiq are cross-classified for current and former \mohers. In each of these nine categories. bladder cancer ri\k was lob,er among former smokers than among current smokers. .A\ reviewed above. the amount of e\,idence supporting cigarette smohing as a cause of bladder cancer has become increasingly compelling \ince the 19X2 Report of the Surgeon General (US DHHS 19X3). which focused on cancer. Multiple studies of I63 TABLE 5.-Bladder cancer risk according to smoking dose, duration of smoking, and smoking status varying design conducted throughout the world have shown statistically significant increases in risk of bladder cancer among smokers. Cigarette smoking. determined to be a contributory factor in bladder cancer in past reports of the Surgeon General (L'S DHHS 1983. 1989). can now be identified as causally associated with bladder cancer. The evidence adequately meets the criteria for causality established in the 1964 Report (US PHS 1964). The decline in risk of bladder cancer with cessation further supports the conclusion that cigarette smoking causes bladder cancer. This diminution in risk cannot be explained by confounding from lower cumulative consumption among former smokers compared with continuing smokers. Cervical Cancer Recently, an association has been noted between cancer of the uterine cervix and cigarette smoking (Williams and Horm 1977; Stellman. Austin, Wynder 1980: Lyon et al. 1983; Hellberg. Valentin, Nilsson 1983: Berggren and Sjostedt 1983; Peters et al. 1986; Brock et al. 1988: Nischan. Ebeling. Schindler 1988). However, because of the possibility of confounding by unidentified factors (in particular, a sexually transmitted etiologic agent), this association has not been identified as causal (US DHHS 1981, 1989; IARC 1986). Components of tobacco smoke can be identified in the cervical mucus of smokers (Sasson et al. 1985; Schiffman et al. 1987). These compounds have been found not only to display mutagenic activity in this environment (Holly et al. 1986). but also to have the ability to impair local immunity by reducing the populations of Langerhans' cells within the cervical epithelium (Barton et al. 198X). The reduction in circulating levels of P-carotene caused by cigarette smoking is yet another mechanism whereby cigarettes may increase the risk of cervical cancer (Harris et al. 1986: Brock et al. 198X; Stryker et al. 1988). Thus. the association of cigarette smohing with cervical cancer is biologically plausible. Table 6 summarizes findings from studies that have examined the relationship between cervical cancer risk and cigarette smoking cessation. In these studies, the risk among current smokers ranges from 1.0 to 5.0 times the risk among never smokers (median of approximately 2). Smoking-associated risks for invasive cancer and for carcinoma in situ are generally similar. After the first year of abstinence, former smokers have lower cervical cancer risk than current smokers in most studies. Exceptions include the study conducted in Milan (La Vecchia, Franceschi et al. 1986). which showed risk reduction for invasive cancer but not for carcinoma in situ among former smokers. and the study conducted in Central America (Herrero et al. 19X9) in which no association with smoking was observed at all, even for current smokers. The effect of time since stopping has not yet been well studied for cervical cancer, but observations from a large multicenter study conducted by NC1 (Brinton. Schairer. Haenszel et al. 19X6) suggested that risk reduction may occur fairly rapidly after cessation. One study found that smokers tended to have a poorer prognosis for survival after radiation treatment for invasive cervical cancer, but no data were presented regarding smoking cessation (Kucera et al. 1987). A major concern in studies of smoking and cervical cancer has been the potential for confounding by factors that would predispose a woman to become infected with a sexually transmitted agent that might be causally related to the disease, such as human papilloma virus (Stellman. Austin. Wynder 1980; Winkelstein et al. 1984: IARC 1986). Therefore, it is important to note that those studies that controlled for risk factors for sexually transmitted disease (Trevathan et al. 1983: Greenberg et al. 1985: Herrero et al. 1989: Slattery et al. 1989) produced relative risk estimates for current and fomler smokers that were quite similar to those from studies that made no such adjustments. The association of smoking and cervical cancer has been considered by some to be a result of residual confounding by inadequately measured indicators of exposure to a sexually transmitted agent. Although factors such as the number of past sexual partners are only surrogates for a hypothetical etiolngic infectious agent, they are the very same social correlates of tobacco smoking that would suggest this type of confounding. Therefore. even though such factors as age at first intercourse and the number of sexual partners are imperfect indicators of infection by a possible etiologic agent. their inclusion as covariates in multivariate analyses may be sufficient to control confound- ing to some extent in the analysis of the effects of smoking on cervical cancer ri&. This review of the evidence on cervical cancer and cigarette smoking cessation indicates that there is a consistently observed association between cervical cancer rish and cigarette smoking and that former smokers experience a lower risk of cervical cancer than current smohers. even after adjusting for the social correlates of smoking and risk of sexually acquired infections. Thi, observed diminution of risk after cessation lends support to the hypothesis that smoking is a contributing cause of cervical cancer. Based on a recent c0mprehensiv.e review of epidemiologic studies providing data on smoking and cervical cancer. Winkelstein (1990) concluded that smoking is causally associated vvith cervical cancer. 166 TABLE &--Studies of cervical cancer and smoking cessation Reference Location (yr of Design data collection) (number of subjects) Risk relative to never smokers Current Former smokers smokers Yr since qwttmg Comment\ Cederlof et al. (lY7.5) Clarke. Morgan. Newman (1982) Marshall ct al. (1983) Trevathan et al. (IYX3) Greenberg et al (IYXS) Brinton. Schairer, Haenwel et al. ( IYXh) La Vecchin. Franccschi et al. I IYXh) Sweden ( 1963-72) Toronto, Ontario (1973-763 Buffalo. NY (1957-65) Atlanta, GA (19X0-81) England ( 1968-83) 5 US citieh (19X?-X4, Milan. Italy (IYXI-X4) Prospective (27,700) Case:control ( I785G.5) Case:control (5 13:4YO) Caw:control lYY:2KX) Prospective (17.032) Caae:control t4)30:7')73 Caaexontrol (1X3:1X3) (230:220) s.0 2.3 I.6 4.2 3.0" I.5 I.4h 1.7 3.0 I.7 0.x 2.1 0.7 2.2 I.1 I .o I.1 2.5 0.x NR NR NK NR NR 74 5-Y >I0 NK NR Cancer incidence Invawe cancer (`arcinomu in \itu Ad~uwxl for wxual partner\. birth control pill\. SE.5 Inva\iw anccr incidence Ad~uwd for age at marriage. birth control pItI\, SES Adjusted for sexual partner\. age at first mttxcourw. SES TABLE 6.--Continued Breast Cancer In general. prior research has shown little relation betvveen cigarette smoking and the risk of breast cancer (Baron 1984: Rosenberg et al. 1984: Baron et al. 1986): however. in recent years, several reports have raised the possibility that there might be a weak positive association (Table 7). Because there has been considerable discussion about the possible role of smoking in breast cancer in recent literature. the relationships among cigarette smoking, smoking cessation. and breast cancer risk are reviewed. Cigarette smoking creates a set of physiologic conditions that result in various antiestrogenic effects (Baron 1984: Jensen, Christiansen. Rodbro 1985: Michnovicz et al. 1986). as well as affecting body mass (Camey and Goldberg 1984: Hofstetter et al. 1986: Chapters 9. IO, I I ). The relationship betvveen cigarette smoking and body mass is a particularly important consideration in studies of breast cancer, because body mass has a complex age-dependent association with breast cancer risk. with obesity being protective in premenopausal ages but slightly risk-enhancing later in life (Willett et al. 1985). Table 7 summarizes findings from studies that have examined the relationship between breast cancer risk and the cessation of cigarette smoking. The risk of breast cancer among current smokers ranges from less than I .O to 4.6 times greater than among never smokers (median approximately I ). The relative risks of smoking do not consistently differ in premenopausal and postmenopausal age groups. In addition, there is little consistency regarding the change in risk observed after smoking cessation. Former smokers have lower risks in some studies, but higher risks in others. Adjustment for other breast cancer risk factors does not appear to completely remove the weak association observed in some studies (Schechter. Miller, Howe 1985; Rohan and Baron 1989). In one study it was found that smokers tended to have a greater prevalence of tumor-positive axillary lymph nodes at the time of diagnosis than did never smokers and former smokers, a finding that could not be explained by patient delay (Daniel1 1988). This association was not confirmed, however, in a recent report based on I O-year followup of the Nurses Health Study cohort that included 1,373 cases with information on extent of disease at diagnosis (London et al. 1989). This review of breast cancer and cigarette smoking suggests that cigarette smoking is not associated with breast cancer. Consistent changes in risk are not observed with smoking cessation. Endometrial Cancer The relationship between cigarette smoking and cancer of the endometrium is unique among the associations of smoking with cancers at various sites; of the sites for which smoking has been associated with a change in risk, endometrial cancer is the only cancer for which there is fairly consistent evidence of an inverse (protective) relationship (Baron 1984; Lesko et al. 1985; Stockwell and Lyman 1987), an effect that may be limited to postmenopausal women (Smith, Sowers, Bums 1984: Koumantaki et al. 1989). The reasons for the lower risk among women who smoke are not well under-. 169 TABLE 7.-Studies of breast cancer and smoking cessation LocatIon (yr ot DestJy data collection) tnumber of suhjcct\) Menopau\al XtatUS Kisk relative to never smokers Current Former smoker\ smoker\ Yr since ywtting Commenrs Cederlof et 31. (lV75) Schcchter, Mtllrr. Howe (IYX.5) Hiatt and Fireman ( I YXh) Brinton. Schurer, Stanford et al. (10x6) stochw~ll and Lyman ( I YH7) Brownson et 01. (IYXX) Adami et al. (IWX) Rohan and Baron (19X')) Sweden (lYh3-72) Canada (IYXO~X2) Northern Calil'omta (IY6`~XO) Untted State\ t 1973-75) Flortda (IYXI) Missourt ( IY7Yw%) Sweden and Norway ( Iox4-~x5 ) Awtralia (IYK~X4) Prospective (27.700) C~w:control (4`): 134) (7 I:?IY) Proqxtnw (X4.172) Caae:wntrol (447503) thl4:XIX) Caw:control (4.01 1:2.`)52) Ca~rxontrol (1 14:20X) (206:x72) Cnbexontrol (427,517) Ca\e:control (146: 132) (2X0:2xX) Pre and pot Pre po\t Prr po\t Pre Po\t Pre Pwt Pre Pwt Pre and pwt Pre Pwt 0.6 4.6 I.1 I.2 I.1 I.1 I.1 1.3" 1.2" 2.3 1.2 I .o I.3 I.5 0.4 1.x 0.x I.2 I.3 I .4 NR I .o NR 0.9 NR 0.`) NR I.2 0.7 0.x 2.4 0.9 NR Cancer incidence >I >_I NR NR Adjusted for xveral breast cancer risk factory Cancer incidence NK NR Relative risk calculated from crude data >I tl Adjusted fbr szveral breast cancer ri& fnaor5 TABLE 7.--Continued Reference Location (yr of Design data collection) (number ofsuh,jects) Menopausal \tatus Kid relative lo never mohers ~`urrent Former smokers smoherh Yr since quitting Comment\ London et al. (19x0) United State\ ( IY7h-X0) Prohpective ( I 17.557) Pre Post I .O" I.1 NR 1.1" I.1 NR stood. but may be due to smoking effects on estrogen production and metabolism. including increased 2-hydroxylation ofestradiol in smokers (Michnovicz et al. 1986). an earlier age at menopause in smokers (Baron 1981). and indirect effects of the body weight differences between smokers and nonsmokers. such as the production ot estrogens from precursors within adipose tissue (MacDonald et al. 197X: Chapters 8 and IO). Table 8 includes a summary of findings from studies ofendometrial cancer that have examined cigarette smoking cessation. Although the risk ofendometrial cancer among current smokers in these studies is approximately 30 percent lower than that among never xmohers. the risk among ex-smokers is similar to. or slightly greater than. that among current smohers. This review of past research on endometrial cancer risk and cigarette smoking cessation sugests that current smokers are at lower risk of endometrial cancer than never smokers. but it is not clear whether this protective effect of smoking on endo- metrial cancer risk might be reversed soon after cessation of cigarette smoking. Although further investigation of the mechanisms for the protective effect of smoking on endometrial cancer is of scientific interest to better understand the effects of smoking on hormones and of hormones on endometrial cancer risk, this inverse association with smoking has no public health relevance, as the well-substantiated risks to other organ systems from continued smoking far outweigh any potential benefits to the endo- metrium. Other Cancer Sites The metabolic products of tobacco smohe can be found in ovarian follicular fluid (Hellberg and Nilsson 198X). However. there i\ little evidence that smohing ih as- sociated with cancer of the ovary (Byers et al. 1983: Baron 1983: Baron et al. 1986: Stockwell and Lyman 1987; Whittemore et al. 198X: Mori et al. 1988). The rish of ovarian cancer differs little for either current or former mohers. a\ indicated in the only two studies that have examined the effect of cigarette smoking cessation on ovarian cancer rish (Table 8). Tobacco has been regarded as a contributing f;ictor for cancer of the kidne? (US DHHS 1982. 1989). The U.S. Veterans Study (Kahn 1966: Repot and Murray 19X0) and ACS CPS-II (ACS. unpublished tabulation\) qgest onI1 \msll difference\ in mortality from renal cancer between current and former amohers (Table XI. A study of renal pelvis and ureteral cancers in Copenhagen (Jensen et al. 198X). hob,ever. showed a pattern of risk diminution with abstinence Gmilar to that observed in bladder cancer. a site with the same histologic type of transitional-cell tumors. Cancers of the anu1r and peni\ are considered possibly to result from infection by a sexually transmitted agent in a v.aj analogous to cancer of the uterine cervix (Daniel1 1985; Daling et al. 1987: Hellberg et al. 1987). Smokers hake been found to be at increased risk both for cancerofthe penis (Hellberg et al. 19X7) and anus (Daling et al. 1987: Holmes et al. 198X) in recent ctudie\. Only one study has examined the effect of cessation on the risk of these cancers (Hellberg et al. 1987). This study found that 172 TABLE I.--Studies of cancer at selected sites that have examined the effect of smoking cessation Cederlof et al. (197% Lrsko et al. (1985) Stockwell and Lyman ( 19X7) Cederlof et al. (lY75) Stockwell and Lyman (19X7) Franks et al. (IYX7) Kahn ( 1966) Roget and Murray I IYXOJ Jensen et al. (IYXX) Sweden ( 1963-72) X North American citte\ (1976-X3) Florida (IYXI) Sweden (1963-72) Florida (IYXI) United Stab (IWO-X2) US veterans (19.54&62) [IS veteran\ (1954-6Y) Copenhagen ( 1979~X2) Proqxctive (27.700) Casexontrol (50X:706) Ca5e:control (9Yo:?.Ys2) Prospective (27.700) Case:control (hwx2,YS2) Cawxontrol Prospective (24X.lY.5) Prospective (293.YSXJ (`nxexontrol (Y6:`XX) Endomctrtum Endomctrnm Ovary Ovary Kidney Kldncy 0.5 l).x'l 0.x" 0.5 1.1" I.1 I .4 I .`I 3.7 I .h O,kJ 0.0 I .6 II.0 0.`) I.5 I.2 I .4 N P NI' NI' NI' >I NF' NI' NI' TABLE X.--Continued Kisk relative 1o never Keterencc Population (yr o! data collectwn 1 Design (number of\uhject~ Cancer site smoker\ Current Former smokers \mokcr\ Yr since quitting Comment\ Hcllhcrg et al. SWd~ll (I`JX7) (NPI Cederlof'ct 31. (1')7S) S\*cdcn (lY63-77) Rogol and Murray ( I YXO) IIS veternn\ (lYS4dY) Yu e1 al. (14X3) Lo\ Angclr\. CA ( l'J7Sm 70) Kahn ( IYtx) (`rdcrlof et a. (l'J7.5) Roger and Murray (IYXO) Nomura er aI. (IYYO) Kahn ( IYhh) US veteran\ ( l'JSJ~h2) Prwpectivr t17.300) <`ahe:comrol (76:76) Prospeclive (23X.195) Prwpect ivc (?7.3001 Pro\pective (2YJ.YSX) Prwpectwe l7.YYO) Plnqeclive (74X.l'JS) Pt!Ill\ Liver Liver Liver Stomach Stomach Stomach I .h 2.4 2.3 1.X" I .4 I.3 I.5 2.7 I .J I .7 I .o I .X I.1 I.1 0.7 I.1 I .o I .s NP NP NP NP NP NP NP NP N P Cancer incidence in males Cancer mortality Abtnincr\ for 210 yr were considered never hmokers Excludes "doctor`s order\" quilter\ Cancer mortality Cancer mcldence in males Extension of US Verrran\ Stud) Cohort identified 1065-6X and followed through October 19x6 Exclude\ "dnctor`x order\" qulttw Cancer mortality TABLE &--Continued Reference Population (yr of data collection) Design (number of wbjects) Cancer Gte Rihk relative to never \molLer\ Current Former wloherh smokers Yl \ince quitting Comments Cederlof et al. (1975) Roger and Murray ( I980) Trichopoulos et al. (1987) ACS CPS-II (unpublished tabulations) Sweden (I 963-72) US veterans ( 195449) Greece ( 1976-84) United States ( 1982-86) Prospective (27.300) (27.700) Proqxctive (24X.ooO) Case:control ( 104:454) (X9:454) Prospective (42 I .623) (605.758) Leukemia (Males) (Females) I.1 0.4 0.X I .o NP NP Cancer incidence Leukemia I .h I.5 NP Extcmion of US Veterans Study Liver HB,Ag HR,Ag+ 3.3" I .6'( 2.x I.3 NP NP Kidney (Mules) (Females) NP NP Cancer mortality current smokers had a penile cancer risk I .6 times that of never smokers. but the risk among former smokers was similar to that among current smokers (Table 8). Primary hepatocellular cancer has been associated with smoking in a number of recent studies (Trichopoulous et al. 1980: Lam et al. 1981: Yu et al. 1983: Oshima et al. 1984: Trichopoulos et al. 1987; Hirayama 1989). This association is of potentially great public health importance because of the high incidence of primary liver cancer and the epidemic of cigarette smoking worldwide, which is increasingly involving countries in which liver cancer is the leading cause of cancer mortality. The mechanism whereby smoking might affect liver cancer risk is unknown. Although potential confounding by alcohol consumption is of concern in interpreting this association. the association of smoking with hepatocellular cancer has remained significant in several studies after controlling for alcohol intake (Trichopoulos et al. 1980: Yu et al. 1983; Oshimaet al. 1984; Trichopoulos et al. 1987). One case. /r,lc,,.rfrrtiorfu/ .lor,,.,kr/ <$Crrrrc.rr. 3 I (3):557-S6 I. April 15. 19xX. JENSEN, O.M.. WAHRENDORF. J.. BLEITNER. M.. KNUDSEN. J.B.. SORENSEN, B.L. The Copenhagen case,nw~/c Ilt>.c lo r/w Slrtrl~ of CU/iW/~ 1111d Orlrar CIlI~olllr~ Di\cw\c~.\. NC1 Monograph 19. U.S. Department ot Health. Education. and Welfare. L1.S. Public Health Service. National Cancer Institute. January 1966. pp. I-125. KINLEN. L.J.. ROGOT. E. Leukemia and \mohmp habIt\ among Cnited States wtcran\. B~.rti.cll M&rr (I/ ./orcwtrl 207(66-l9):657-65Y. Scptcmber IO. I YXX. KOUMANTAKI. Y.. TZONOL. A., KOUMANTAKIS, E.. KAKLAMANI, E.. ARXV,4N- TINOS. D.. TRICHOPOULOS. D. A ca\e irradl:rtmn in the treatment ofcarcmoma of the cervix. Ctrr~c,r,. hO( I ): 11, July I. 10x7. LAVECCH1A.C.. FRANCESCHI. S.. DECARLI. A.. F.4SOLI. M..GENTILE. A..TOGNONI. G. Cigarette smoklnf and the risk of cervical neoplu\ia. .-\rwrlc.o,~ ./orf,.~rtr/ of E/)/k,~rc~>/~~,q> 113 I ):27-2Y. January IYXh. LA VECCHIA. C.. LIATI. P.. DECARLI. A.. NEGRELLO. I.. FR.4NCESCHI. S. Tar ) leld\ ofcigarette\ and the ri\h ofwqhagral cancer. /~~rc,~.,rtr/io,rr//.I,~rc/.,r~~/ofC~r,~~ c~r'iX:.3X I -3X5. 1086. LA VECCHIA. C.. LIATI. P.. DEC.4RLI. A.. NEGRI. E.. FRANCESCHI. S. Coffee conwmp- tion and rish of pancrcatlc cancer. /r,lr,.,ftrt,~jrrt,l ./r~l/,-,w/ o/`Ctl/lc (`I' 10:3OY%.3 13. September IS. 19x7. LA VECCHIA. C.. NEGRI. E. The role of alcohol in ocwphafca1 cancer in non-mohcrr. and the role of tobacco in non-drinhcr\. //lrc~,-,/~///rj/r~// .I<),,, w/ /$Ct///c (`I' 1315 ):7X-&7X.5. Md! IS. IYXY. LAM. K.C.. YC. M.C.. LEUNG. J.W.C.. HENDERSON. B.E. Hepatltij B virus and cigarcttc wiokmg: Ri\h factor\ for hcp~ttocellular c;Lrcinomil in Hong Ken:. C`tr/rwf. Ro.wtr/-c Ir -13 12):5116-52-1X. Deccmhrr IYX2. IX? LESKO. SM.. ROSENBERG. L.. KAUFMAN. D.W.. HELMRICH. S.P.. MILLER. D.R.. STROM. B.. SCHOTTENFELD. D.. ROSEh3HElY. N.B.. KNAPP. R.C.. LEWIS. J.. SHAPIRO. S. C&arette smoking and the rixh of endometrial cancer. !Vtr\t. E,!q/c/,I 77~~ o/r~,g> 130:43x355. 197x. MACK. T.M.. YU. M.C.. HANISCH. R.. HENDERSON. B.E. Pancrea\ cancer and amolin?. beverage consumption. and pa\t medical history. .I~~r~/~rl~// of thc~ Norio/~cl/ (`0/1(.cr /nstif,r/c 76( I ):49%60. January I YX6. MACMAHON. B.. YEN. S., TRICHOPOULOS. D.. WARREN. K.. NARDI. G. Coffee and cancer of the pancreas. N~M, E77,~/~77~l./orr7-71~7/ c$MrdicY7rc 303i 1 I ):630-633. March I?. 1 YX I MARSHALL, J.R.. GRAHAM. S.. BYERS. T.. SW.4NSON. M.. BRASURE. J. Diet and smokmp in the epidemiology of cancer of the cen!ix. .Icwurrrl off/w Ntrfio77rrl Ctr77c cr /n.srrt~c~r 70(5):X37-851. May 1983. MICHNOVICZ. J.J.. HERSHCOPF. R.J.. NAGANLMA. H.. BRADLOW. H.L.. FISHMAK. J. Increased 7-hydroxylation of estradiol as a possible mechanism for the anti-estrocpenic effect of cigarette smoking. N~TM. O7gla77rl.lor77.77r~l cfMeclrc~i77c 3 I S(2 I ): INS- 1309. Novem- ber 19X6. MILLS. P.K.. BEESON. W.L.. ABBEY. D.E.. FRASER. G.E.. PHILLIPS. R.L. Dietap habit\ and past medical history as related to fatal pancreas cancer risk among Adventists. Co77w7- 61(12):257X-2585. June IS. 19Xx. MOORE. C. Smoking and cancer of the mouth. pharynx. and larynx. ./o~r~~rcd of`tlrc Anwr% m Medicul Assoc~ic~tior7 19 l(4): I07- I 10. January 25. I Y6S. MOORE. C. Cigarette smoking and cancer of the mouth. pharynx. and larynx. A continuing study. Jo1tr77ul of t/w Ar77rrko77 Mcdic~ul Assoc~irrtiot7 2 I X(3):553-558, October 2.5. lY7 I. MORI, M.. HARABUCHI. 1.. MIYAKE. H., CASAGRANDE. J.T.. HENDERSON. B.E.. ROSS. R.K. Reproductive. genetic. and dietary risk factors for ovarian cancer. An7c7~ic~trrr .lort777u/ ofEpidemio/o,qy 12X(4):77 l-777. October IYXX. MORRISON, A.S.. BURING. J.E.. VERHOEK, W.G.. AOKI. K.. LECK. I.. OHNO. Y.. OBATA. K. An international study of smoking and bladder cancer. Jo7tr~7trl c!f` b'~-o/o,p~~ 13 I (4):6SC-654. April 19X4. NISCHAN. P., EBELING, K.. SCHINDLER, C. Smoking and invasive cervical cancer rish. Results from a case-control study. An7rr.ir,cu7 .Jo~rmu/ of Epidcn7io/o,q~ 12X( I ):74-77. July 198X. NOMURA, A., GROVE. J.S.. STEMMERMANN. G.N.. SEVERSON. R.K. A prospective study of stomach cancer and its relation to diet, cigarettes, and alcohol consumption. Cru7wr- Re.seu7~l7 SO:67743 I. February 1. 1990. NORELL. S.E.. AHLBOM. A.. ERWALD. R.. JACOBSON. G.. LINDBERG-KAVIER. 1.. OLIN, R., TORNBERG. B., WIECHEL. K.L. Diet and pancreatic cancer: A case-control study. Am~ricu~7 ./07rr77c1/ of Epidcn7iology 124(6):X94-901. December I9 X6. OLSEN. G.W.. MANDEL. J.S.. GIBSON. R.W.. WATTENBERG. L.W.. SCHLMAN. L.M. A casexontrol study of pancreatic cancer and cigarettes. alcohol. coffee. and diet. ,A777c1-ic U/I .lo7rr77ul ofPuhk Hculrh 79(X ): IO1 6-l 019. 19X'). IX3 OSHIMA. A.. TSLIKUMA. H.. HIYAMA. T.. FI~JJMOTO. 1.. YAMANO. H.. TANAKA. M. Follovv-up study of HBs AX-postttve blood donors u ith special reference toeffect ofdrinhing and amohing on development of Itver cancer. //rrcwtrr~~wtrI ./w/./w/ of Ctwwr. 31:775-779. IYX4. PETERS. R.K..THOMAS. D.. HACAN. D.G.. MACK. T.M.. HENDERSON. B.E. Risk factors for invasive cetvical cancer among Latinas and nonLatinus in Los Angeles County. ./~~f~17t(1/ o/'t/re Norior7/// C///r/ ('I' I/rv//r//!t* 7715): 1063-1077. November 19X6. ROGOT. E.. MURRAY. J.L. Smoking and causes of death among U.S. veterans: I6 years' of obsewation. P///dir Hcolrh Rqxj/~\ 9.5( 3 ):2 13-2-92. May/June 19X0. ROHAN. T.E.. BARON. J.A. Ctgarette smohtng and breast cancer. AnM~r~/t~url Jolo-IlUl of Epitkt77io/r~,q~ l29( I ):3632. January IYXY. ROSENBERG. L..SCHWIKGL. P.J.. KAUFMAN. D.W.. MILLER. D.R.. HELMRICH. S.P.. STOLLEY. P.D.. SCHOTTENFELD. D.. SHAPIRO. S. Breastcsncerandciparette smoktng. .NcM. &/7,~/t~r7t/./orr/~/7c// of'Mct/ic~//rc 3 lOt2):92-93. January 12. 19X-t. SASSON. I.M.. HALEY. N.J.. HOFFMANN. D.. WYNDER. E.L.. HELLBERG. D.. NJLSSON. S. Cigarette stnohing and neoplasra of the uterine cervix: Smohe constituents in cervical mucus. Nc\t~ E/rglr//rcl ./o~rrxcr/ /fMctlit i/7c 3 I2tS ):3 15-3 16. January 3 I. 19x5. SCHECHTER. M.T.. MILLER. A.B.. HOWE. G.R. Cigarette smohing and breast cancer: A case-control study of screening participants. Anro-ic.trrr .lo~r~xcr/ of`E/,ir/c~n7iolr,,y~ I Z I t4):379- 4X7, April I YXS. SCHIFFMAN. M.H.. HALEY. N.J.. FELTON. J.S.. ANDREWS. A.W.. KASLOW. R..4.. LANCASTER. W.D.. KURMAN. R.J.. BRINTON. L.A.. LANNOM. L.B.. HOFFMANN. D. Biochemtcal epidemiology ofcetvical neoplasia: Measuring cigarette smoke constttuents in the cervix. C'r/ww Rc\co7-c.h J7( 14):3Xx6-3X88. July IS. lYX7. SCHOTTENFELD. D. Multiple primary cancers. In: Schottenfeld. D.. Fraumeni. J.F. Jr. (eda.! Ctr/7w/. Epit/cr77/o/o,~~ /1/7/l Pre~~c~/rr/o/r. Philadelphia: W.B. Saunders. Co.. I YX?. p. 1025. SCHOTTENFELD. D.. GANTT. R.C.. WYNDER. E.L. The role of alcohol and tobacco tn multiple prima? cancers ofthe upperdigestive sy stem. larynx and lung: A prospectiw stud!. P/~c~~c/~c~I`~ Mctlic i77c' 3(1):277-2Y3. June 1971. SEVERSON. R.K. Cigarette smohtnp and leukemta. Cur7r c~-60(2t:111-111. July IS. 19X7. SILVERM,4N. S. JR.. GORSKY. M.. GREENSPAN. D. Tobacco uwpe in patients ~tth head and nech carcinomas: A followup study on habit changes and second prnt~ary oral/oropharyngeal cancers. ./,w/Y7cl/ of //7/Z Ar77c~/-/c~~l/7 ne/rrtr/ .A.\srJc~/~rrro~7 lO6( I t:33-35. January 19x3. SLATTERY. M.L.. ROBISON. L.M.. SCHCMAN. K.L.. FRENCH. T.K.. ABBOTT. T.M.. OVERALL, J.C. JR.. GARDNER. J.W. CtXarctte smokmg and exposure to passive smohe are risk factors for cervical cancer. Jofr~~~rul of r/7/3 r\r71~/-1c~trt7 Mctlic trl AMOC rtrf7017 26l( I I ):lSu)-ISYX, March 17. IYXY. SLATTERY. M.L.. SCHUMACHER. h1.C.. U'EST. D.W.. ROBISON. L.M. Smokmp and bladder cancer. The modifytng effect ofcifarettes on other factors. CC//~< (`I. 61(_7):402-t(lX. January IS. 19xX. SMITH. E.M.. SOWERS. M.F.. BURNS. T.L. Effects ofsmohing on the development of female reproducttve cancers. ./or(/.rrc// wl ................................ 211 Studies of Smohing Cessation and Rish of Aortic Aneurysm ............... 211 Smohing Cessation and Peripheral Arterial Occlusive Di\ea\e ............... 211 Smohing Cessation and Development of Peripheral c\rtery Di\ea\e Z-l.3 Smohinf Cessation and Prognosi\ of Peripheral Artery Disease Z-l.1 Surnmar~ ........................................................ 11-J Smohing Cehation and Cerebrovascular Disease .............. ........... 215 Studies of Smohing Cessation and Ri+ of Cerebrovawular Disease ......... 2-W Cro\s-Sectional Studic\ .......................................... 7-K Case-Control Studieh ........... ................................ 7-K Prospective Cohort Studies ....................................... 2IY Summary of Observational Studies ........ ........................ 75 I Intervention Studie\ ............................................. 251 Influence of Prior Levels of` Smohing ............................... 25 I Effect of Duration of Abstinence ................................... 32 Oral Contraceptives and Stnohing Cessation ......................... 25X Effect of Smoking Cessation After Strohe .... ...................... 260 Summary ........................................................ 2hO Conclusions ..................................................... ..~60 References ...................................................... ..26 I IIVTRODLCTION Cigarette smoking is firmly established as an important cause of coronary heart disease (CHD). arteriosclerotic peripheral vascular disease. and stroke (US DHHS 1983. 1989). Eliminating smohing presents an opportunit) for bringing about a major reduction in the occurrence of CHD. the leading cause of death in the United States. Before examining the epidemiologic evidence relating zmohin, ~7 cessation and rish of CHD and other forms of cardiovascular disease (CVD). the mechanisms by uhich smohing leads to these diseases are briefly reviewed. The objectives in considering these mechanisms are to address the plausibility that smoking cessation reduces rish of CVD. to estimate the expected magnitude in rish reduction. and to assess the rapidit) with which any risk reduction might occur. Whether these mechanisms are immedi- ately reversible. irreversible. or slowly reversible i\ of particular rele\,ance to the rapidity with which smoking cessation will reduce rich. The role of smohins in the pathogenesis of CHD is discussed at length. Th e etiologies of peripheral \ ascular disease and stroke share several common features M ith CHD: thus. discussion focuses on distinguishing features. PATHOPHYSIOLOGIC FRAMEWORK Smoking and Development of CHD Pathogenesis of CHD. which includes the clinical manifestations of myocardial infarction (MI). angina pectoris. and sudden death. is extremely complex and mediated by multiple mechanisms and etiologic factors (Munro and Cotran 198X). At least five interrelated processes are likely to contribute to the clinical manifestations of MI- atherosclerosis. thrombosis, coronary artery spasm. cardiac arrhythmia, and reduced capacity of the blood to deliver oxygen. Smoking appears to influence many steps in the development of CHD. Although not all of these effects are proven fully. the evidence for an influence on several mechanisms is convincing. The exact components of cigarette smoke that are responsible are not known in each instance. but experimental data have implicated nicotine and carbon monoxide (CO) in several processes. Other products of cigarette smoking, such as cadmium. nitric oxide. hydrogen cyanide. and carbon disulfide. have been hypothesized to play a rote. but their quantitative contribu- tions remain unknown (US DHHS 1983). Atherosclerosis Atherosclerosis is the mechanical narrowing of medium-sized arteries by the proliferation of smooth muscle cells. lipid accumulation. and ultimately. plaque forma- tion and calcification (Munro and Cotran 1988). These lesions develop over decades and are not immediately reversible; whether they are substantially reversible at all in humans is a matter of current interest. Reversibility has been demonstrated in non- human primates (Clarkson et al. 1984: Malinow and Blaton 1983) and huggested in studies of humans using repeated arteriography (Blanhenhorn et al. 1987). Smohing is I91 clear]) associated with the presence of atherosclerosis of the coronary arterie>, small arteries of the myocardium. the aorta. and other vessels ;I\ demonrtrated in man! autops) and angiographic studies (US DHHS lYX3). The development of athero- sclerosis is complex. and several processes are likely to be important. Endothelial damage is thought to play ;I primary role in the development of atherosclerosis by exposing the arterial intima to blood lipids and white cells and bj stimulating platelet adhesion. The endothelial damage can be an actual physical denudation. but toxic functional damage may have similar consequences. In animal studies. serum nicotine at levels similar to those of human smokers caused endothelial damage (Krupshi et al. 19X7: Zimmerman and McGeachie 19X7). Evidence that smoking has a direct toxic effect on human endothelium is provided by the observation that smoking 9 tobacco cigarettes approximately doubled the number of nuclear- damaged endothelial cells in circulating blood (Davis et al. 198.5. 1986): smoking non-tobacco cigarettes had little effect. In addition. Asmussen and Kjeldsen (1975) found pronounced degenerative changes of the umbilical artery endothelium at the time of delivery among mothers who smoked: these changes were not present in the arteries of nonsmoking mothers. Smooth muscle cell proliferation is a primary feature of atherosclerotic lesions and may result from several stimuli: the mo5t clearly demonstrated is platelet-derived growth factor from adherent platelets. Smoking appears to increase the adherence of platelets to arterial endothelium: blood draun from persons after smoking 3 cigarettes results in a more-than-hundredfold adhesion of platelets to rabbit endothelium than does blood drawn from persons before smoking or from ne\`er smohers (Pittilo et al. 19X1). Platelets from chronic smohers have a greater tendenc) to aggregate on an artificial surface than do those from nonsmokers (Rival. Riddle. Stein lY87). In minipig>. both cigarette smoke and CO increase the adhesion of platelets to arterial endothelium (Marshall I YX6). The intluence of smohing on platelet activity is discussed further in the following section. Lipid infiltration of the arterial intima. largely cholesterol, is another primaq feature of atherosclerosis and is directly related to higher blood levels of low-densit! lipoprotein cholesterol (LDL-C) and reduced blood levels of high-density lipoprotein cholesterol (HDLC'). Smoking reduces the level of HDL-C. A strong inverse associa- tion betv,eren daily cigarette consumption and HDL-C has been observed in man) cross-sectional studies in the United States (Freedman et al. 19X7; Gordon and Doyle 19X6: Reichle!, Mueller. Hanis et al. lYX7: Willett et al. IYX3) and in other countries (Assmann. Schultc. Schrleuer IYXI; Goldhourt et al. I9Xh: Gomo lY86; Jacobsen and Thelle IYX7: Pellctier and Baher IYX7: Robinson et al. 19X7: Tuomilehto et al. 19X6). In a longitudinal. community-based study. HDL-C decreased among persons starting to smoke and increased among those &ho stopped smoking (Fortmann. Haskell. Williams 19X6). In other prospectike studies. smoking abstinence ha\ been associated M,ith substantial increases in HDL-C levels in both men and women (Hulley. Cohen. Widdouson IY77: Hubert et al. 19X7: Rabhin 19X-t). In a stud) among young adults in Louisiana. those \vho began smohing experienced substantial reductions in HDL-C compared with those u ho did not start (Freedman et al. I%%). HDL-C increased among I3 adult women who \uccessfully stopped smohing for 18 days. but decreased to its previous levels among those vvho returned to smohing (Stamford et al. IYXh). Thus. data indicate that smoking reduces the level of HDL-C. a potent protective factor against CHD. In a number of studies. smokers ha\,e been found to hav,e higher levels of triglycerides (Freedman et al. 19X6: Jacobsen and Thelle 19X7; Gomo 19X6: Willett et al. lYX3): however. the independent relation of triglyceride level with rish of CHD is not clear. Smoking appears to have little. if any. relation with LDL-C level. Howsever. smokers have approximately twice the level of serum malondialdehydt of nonsmohers (Nadiger. Mathew. Sadasivudu lYX7): malondialdehyde can alter LDL-C and may promote its incorporation into arterial wall macrophages (Steinberg et al. IYXY). In a metabolic study among young men. smokers had a decreased cholesterol net transport from cell membranes into plasma. which could partially explain the accumulation of cholesterol in arterial walls (de Parscau and Fielding 19X6). Thrombosis Coronary artery thrombosis, resulting from platelet-fibrin thrombi, is a key element in most cases of MI. Thrombi are visualized in a high percentage of coronary arteries studied angiographically within hours of the onset of infarction (DeWood et al. I YXO). and agents that lyse thrombi are effective treatments for MI (Stampfer et al. 19x7; Loscalzo and Braunwald IYXX). The efficacy of aspirin. an antiplatelet agent. in preventing MI further supports the role of thrombus formation (Steering Committee of the Physicians' Health Study Research Group lYX9). The finding that smoking is associated with history of MI even after controlling for atherosclerosis (Hartz et al. 19X I ) emphasizes the importance of mechanisms in addition to those that promote atherosclerosis. Platelets play a central role in thrombus formation in addition to releasing growth factors that stimulate the proliferation of smooth muscle cells in arterial intima (Pack- ham and Mustard 19X6). Platelets can form microthrombi that become incorporated into the arterial wall, thus contributing to plaque formation and participating in generation of larger platelet-fibrin thrombi that may acutely occlude a coronary artery. Smoking cigarettes acutely increases spontaneous platelet aggregation in humans (Davis et al. 1985) and in dogs with coronary artery stenosis (Folts and Bonebrake 19X2). Madsen and Dyerberg ( 19X4) observed that smoking 2 high-nicotine cigarettes substantially reduced bleeding time among healthy young men, although ex vivo tests of platelet aggregability vvere only minimally inhibited. In this study. smoking low nicotine cigarettes and inhalation of CO had little effect on bleeding time. Shortened platelet survival, an indirect indicator of activation. was observed in smokers and reverted to normal after 4 weeks of smoking abstinence (Fuster et al. 19X I ). Studies of smoking and platelet aggregation ex vivo in response to the typical stimuli used in the laboratory. such as adenosine diphosphate (ADP) or thrombin. are incon- sistent. Increased aggregation has been seen with platelets from chronic smokers (Belch et al. 1984) and in blood drawn IO minutes after smoking I cigarette (Renaud et al. 19x5; Renaud et al. 1984); in the latter study. aggregation was associated with blood nicotine levels but not with carboxyhemoglobin (COHb) levels. However. in other studie\. ex viva platelet aggregation was not related to cigarette smoking (Pittilo et al. 19x3; Dotevall et al. 19X7: de Loyeril et al. IYXS: Madsen and Dyerberg 19X3). In one large study. aggregation in response to ADP stimulation was actually somewhat greater in nonsmoker\ (Meade et al. 19X5). Studies of the effect of smoking on platelet production of thromboxane. which mediates the aggregatorv effect. have also been inconsistent. In some studie\. smohing was found to acutely increase thromboxane blood levels. which reflect the capacity to produce thromboxane in response to stimula- tion. and urinary metabolitea. which reflect the normal steady-state production (Toivanen. Ylikorhala. Viinihka 19X6: Marasini et al. 19X6: Fischer et al. 1986). However. serum thromboxane B? level\ were found to be similar among chronic smokers compared with nonsmokers in another study (DotevaIl et al. 19X7). The serious limitation\ of cx vivo aggregability measurements in the evaluation of in vivo platelet activity have been noted (Fitqerald. Oates. Nowak 19Xx). These researchers meawred urinary excretion of a thromboxane metabolite and found elevated levels in chronic smohers that were reduced to the level ofnon~mokers after aspirin administra- tion. suggesting ;I platelet origin of the excess excretion (Nowak et al. 1987). The luch of a consistent relation between making and ex viva te\ts of platelet aggregability despite the demowtration that platelets of smoker\ adhere more readily to endothelium has led to the suggestion that wioking inhibits the production in arterial walls ofprostacyclin. an inhibitor of platelet aggregation (Mad\en and Dyerberp 1984). Reinders and coworkers ( 19X6) demnnwated that the production of prostacyclin b) cultured human endothelial cells is impaired by incubation with cigarette \mokc condensate. Pittilo and colleague3 ( 1982) also found that smoking reduce\ endothelial cell synthesis of pro\tacyclin in rats. Thu\. in \.i\o making-related effects on platelet function may be mediated in part b>, an interaction with endothelium. Fibrinogen levels have been found to be elevated among smoker\ in numerow cross-sectional studies (Meade et al. 19X6: Kennel. D'Agostino. Belanger 19X7: Wil- helm\en et at. 19x3: DotevaIl et al. 19X7: Belch et al. IYX3: Ballei\en et al. IYX5). Fibrinogen levels. in turn. are \trongl!. related to ri\h ofCHD and stroke (Meade et at. lYX6: Kannel. D'Ago\tino. Bel;inycr 19X7: Wilhelmwn et al. t9X4). Smohing ce\w tion rewlted in ;I decrease in fibrinogen levels after 1 w,eeh\ among Y female moher\ (Harenberg et aI. t YX5) and after X LI eeh\ among I1 mule maker\ (Ernst and Matrai 1987). In the latter stud\. the level\ after X v,eeh\ \+eere similar to those among nc\`er maker\. When fibrinogen M;I\ remeasured after 5 bears. \ alues had decreased to the level\ofnever smoker\ among men u ho had stopped wiohin, L ~7 ,tnd had incren\ed amonp thaw M,ho started or rrsumcd wiohing (Made. Imcson. Stirling 19X7). In multivariate analk\e\ ofdata from the Fram~ngham Stud! (Kanncl. D'.Qo\tino. Belrmger 19X7) and Northu ich Parh Stud! (Me& et al. 19X6) that both included cigarette smoking as uell ;I\ fibrinogen le\ttl\, fibrinogen retained a clear independent a\socistion \\ ith ri\h ot CHD. whereas the effect of smohing \~a\ sub~tantiatt! reduced after the inclusion of fibrinogen in the model. Thi\ anatysi\ wggest\ that elevated fibrinogen le\,els ma> mediate a quantitativeI! important part of the effect ot` smoking on CHD rish. Other clotting abnormrrlitie\. such as increuwd plasma viscosity and reduced red cclt deformabilit>. that tend to promote thrombw formation ha\,e alw been obwrwd in smohers (Belch et al. IYX-!). In addition. Iewls of plawiinogen. which promote\ I\\i\ of thrombi. are lower in smokers (Wilhelmsen et a). 1983: Belch et al. 1984). but the levels increase after smoking cessation (Harenberg et al. 1985). Spasm Coronary artery spasm can cause acute ischemia manifested as angina pectoris and may promote thrombus formation at the site of repeated arterial constriction (Felts and Bonebrake 19X2). Both chronic and acute cigarette smoking have a demonstrable vasoconstrictor effect on the coronary vasculature (Klein 1 YX3). Compared V. ith never smokers. current smokers have an approximately twentyfold risk ofvasospastic angina pectoris (Scholl et al. 1986). Coronary artery spasm has also been identified bl angiography after smoking a single cigarette (Maouad et al. 1983). Smohing-induced vasoconstriction has been demonstrated in patients with atherosclerotic coronary artq disease (Martin et al. 19X3) that is mediated by an cx-adrenergic increase in coronary artery tone (Winniford et al. 19X6). In addition. smokin, L 0 3cutely increases platelet and plasma vasopressin (Nussey et al. 19X6) as well as the carrier protein of vasopressin and oxytocin (de Lorgeril et al. 1985). In addition to causing acute arterial spasm. cigarette smoking appears to be associated with a reduction in long-term coronary arter) diameter independent of atherosclerotic plaque (Fried. Moore. Pearson 19X6). although the mechanism for this relationship is unclear. Arrhythmias In some instances, arrhythmias can precipitate Ml by reducing cardiac output or increasing myocardial demand. More importantly. arrhythmias are a major complica- tion of infarction. Thus. reducing the threshold for serious arrhythmias tends to increase the case-fatality rate of MI. Cigarette smoking was found to lower the threshold for ventricular fibrillation in a study of animals (Downey et al. 1977) and was found to be associated with a 2 I -percent increased prevalence of ventricular premature beats on two-minute electrocardiographic rhythm strips obtained from IO. I I9 men (Hennekens et al. 19X0). Smoking-related ventriculararrhythmias may contribute to the occurrence of cudden death and to increased case-fatality ratios during the courre of MI. Reduced Blood Oxygen Delivery Cigarette smoking acutely increases myocardial oxygen demand b\, raising peripheral resistance, blood pressure, and heart rate (Martin et al. 1983: Klein 1984). Concurrently, the capacity of the blood to deliver oxygen is reduced by increased COHb, greater viscosity (Galea and Davidson 19X.S). and higher coronaq vascular resistance. Imbalance between oxygen requirement and delivery as a result of these factors is not likely to be a cause of MI but may contribute to infarction in the presence of significant atherosclerotic narrowing of vessels. Consistent with these mechanisms. low levels of COHb exacerbate myocardial ischemia during graded exercise (Allred et al. 19X9). and smoking is associated with more frequent and longer ischemic episodes detected by ambulatory electrocardiographic monitoring among patients M ith chronic stable CHD (Barr\ et al. 19X9). Blood and plasma 1 iscwities among former smokers are lower than thaw among current smoker\ and Gmilar to thaw amon never smoker\ (Ernst and Matrai 19X7 ). In the wit stud>,. both blood and pluma viscosity decreased after wioking ce\\ation and were similar to levels of never makers after X weeks. Reduced oxygen delivery to the myocardium ma) play a role in lowering the threshold for ventricular arrhythmias. In addition to influencing the development ofCHD. smoking ha\ been hypotheGzed to have direct toxic effect\ on the myocardium. Hartz and coworkers ( I9X-I) found ;i nearly threefold increavzd prevalence of diffuse ventricular hypoLine\is among heavy smoker5 compared with never makers within 3 population of patients undergoing diagnostic coronary ungiography and ventriculogrsphy. Smoking and Development of Peripheral Arterial Disease The extremely strong aswcistion between smoking and peripheral artery disease is likely to be mediated largely through the mechanisms that promote atherosclerosis (Criqui et al. 1989). The peripheral \awcon\trictive effect\ of smoking. mediated bj nicotine-stimulated release of catecholamines (US DHHS 19X3). are likely to play a further important role (Lusty et al. 19X I ). Smoking and Development of Cerebrovascular Disease Cerebrovawulur diwae reprewnt\ a heterogeneous group of pathologic processes that include infarction due to jteno\is and thrombo\i\ (referred to here a\ ischemic stroke). embolism from the heart. and hemorrhage from medium-hized vessels in the wbarachnoid space (wbarachnoid hemorrhage) and from microaneutyms of smaII penetrating vessel\ (intracerebral hemorrhage). The association of \mokinp with ischemic strobe i\ likely to be mediated largely through the mechanisms that promote atherosclerwis and thrombus formation. Associations between smoking and extent of cerebral artery athcrowlero\i\ ha\ e been obher\ ed at Irutop\) among persons u ho haw died of cauw\ unrelated to CVD (Reed et al. I9XX) and among volunteer\ in 3 crowaectlonal stud> evaluated b! ;I nonin\as~\.t` method (Rogers et al. 19X.3). Smoking was a1w ;I strong predictor of the extent and w~erity of cerebral ve\\el atherowlcro\i\ in an Italian multicenter \tud> of rever\ible cerebral ischemic attack> fPas\ero et A. 19X7) and in an in\c\tiyation of 2X pair\ of Finnish tn in\ (Haapanen et al. 19x9). The mechanistic ba\i\ i\ unhnoun for the strong relation hettieen smoking and \ubarachnoid hemorrhage (US DHHS 19X9: Shinton and Beever\ 19X9). which is thought to result mo\t commonl! from the rupture of a baccuI;Lr aneurysm. .Although hypertension i\ a\sociatcd uith thij occurrence. chronic \mohing is unrelated to w\tained elwation in blood prehwre. A ueah and clinically unimportant inverse relation with hypertension ha\ been \een in several studie\ ISchoenenbeqer 19X2; US DHHS 1983). although the association betw,ecn cigarette smoking and risk of hyper- tension was obser\,ed in 3 large pro\pecti\e ime5tigation (Witteman et al. 1990). .Anticipated Effects of Smoking Cessation on Risk of Cardiovascular Diseases Based on Know ledge of Mechanisms The possible effects ofsmohing cessation on the rish of CHD are illustrated in Figure 1. The incidence of CHD increases sharpI!, with age mm~, `7 both smohers and net CI smokers: similar patterns are seen V. ith other smohing-related cardio\,ascular diseases. At each age. the rates are higher for smohers. and the increase with age is more rapid among smokers (US DHHS 19X3: ACS. unpublished tabulations). probabl\ because ot the ongoing. cumulati\,e damage caused bj smoking. Thus. the absolute excess incidence or mortalit>. (attributable rish) of CHD due to smohing. represented b> the vertical difference bet&eeen the lines for- smokers and never smokers in Figure I. increases u ith age. However. the relative rish. represented b!, the ratio of incidence or mortality rates, tends to decrease with age. Theoretically possible outcomes ofsmokinfcessation are depicted by lines A. B. and C (Figure I ). Line A represents an immediate and complete reversal of the effect ot smoking. so that the quitter ahnost instantly assumes the rate of the never smoher. Line B represents the worst-case scenario: although the stimulus for progressive damage is removed. no reversibility exists so that the former smoker assumes a constant absolute excess risk above that of the never smoker. In this case. it is apparent that quitting would still provide a substantial benefit compared with not quitting and that the relatiic risk for a former smoker compared with a never smoker w,ould decline over time. An intermediate effect of smoking cessation is depicted by line C: the effects of smohinp are slow~ly reversed. and the rate for the quitter gradually approaches that of the never smoker. The effects of smoking on CHD are probably mediated by multiple mechanisms. several of which are well established. Some of the effects of smoking appear to be reversible within days or weeks, including the increase in platelet activation. clotting factors. COHb, coronary artery spasm. and increased susceptibility to ventricular arrhythmias. Other effects may be irreversible or only slowly reversible. such as the development of atherosclerosis as a result of smooth muscle proliferation and lipid deposition in the arterial intima resulting from lower HDL-C levels. Thus. persons who stop smoking are likely to experience a component of rapid decline in risk compared with those who continue to cmoke and another component that more slowly approaches the risk of never smokers. Because the effects of smoking are multiple and complex. the rapidity and magnitude of risk reduction achieved by smoking cessation can best be estimated by empirical data based on epidemiologic studies in humans. Available data are examined in detail in the remaining sections of this Chapter. SMOKING CESSATION AND CHD Epidemiologic evidence on smoking and CHD has been reviewed in detail in previous reportsofthe U.S. Surgeon General (US PHS 1964: US DHEW 1971. 1979; US DHHS 1983, 1989). After an exhaustive review of the data, the 1983 Report of the Surgeon General concluded that "cigarette smoking is a major cause of CHD in the United States for both men and women" and "should be considered the most important of the knon n CHD Mortality (par 100,000 porron - yrrrd 700 800 600 400 300 200 100 0 1 I 40 46 I I 60 66 Age L L 60 06 FIGURE I.-Hypothetical effects of smoking cessation on risk of CHD if mechanisms are predominantly rapidly reversible (A), irreversible (I!), or slowly re\ ersible (C ). (CHD mortalit! rates shown in solid lines are for men in ACS CPS-II, 198246.3 modifiable riA t`actors t'or CHD" I C'S DHHS 1983. p.6). O\erull. the Report noted that smoher\ ha\e about a 70-percent e\c`c`\\ death rate t`rom CHD. and hea\ ier vwLer\ have an even greater eaces\ risk. IYX Since IYX3. additional e\,idence has accumulated to further support these con- clusions. Some of these data were presented or summarized in the I YXY Report of the Surgeon General (US DHHS IYXY). For IYX5. cigarette smoking was estimated to be responsible for 71 percent of all CHD deaths in the United States among men aged 65 years or older and for 15 percent of CHD deaths among younger men. Tv.elve percent of the CHD deaths among women aged 65 or older and -1 I percent of those in bounger &omen were attributed to cigarette smoking. In 19X5. I I5.0()0 deaths from CHD were attributed to cigarette smoking. A large amount of data supports the vie\+ that active cigarette smohing substantialI! increase5 risk of CHD. Data also indicate that former smokers have a lower risk ot CHD than do current smokers. Despite methodolofic and geographic differences. the studies are remarkably consistent in demonstrating a reduced risk of CHD among former smokers. Much of this literature has been reviewed in earlier reports of the Surgeon General (US DHEW lY7Y: US DHHS lYX.3) as dell as h> Kuller and colleagues ( 1987). This Section reviews the epidemiologic e\,idence of the effects of cigarette smohing cessation on CHD rish. specifically MI and CHD death. The relevant studies ma\' be divided into those that examine the effect among apparently healthy individuals (primary prevention) and the effect among individuals already diagnosed uith CHD for risk of recurrence or CHD death (secondary prevention). Cross-sectional studies of the extent of coronary atherosclerosis also provide relevant information. Cross-Sectional Studies In a detailed study of coronary atherosclerosis. Auerbach and couorhers (lY76) examined I .O% autopsied hearts from patients at the East Orange Veterans Administra- tion Hospital and found that smokers had more severe disease than never smohers. with past smokers having intermediate levels. Those who died from CHD or diabetes or those who had hearts weighing more than 500 g were excluded. After aci,iustment for age. current cigarette smokers had a prevalence of advanced CHD that ranged from 11.7 to 33.4 percent. depending on the number of cigarettes smohed per day. The prevalence among never smokers was 5.3 percent compared with I I .O percent among former smokers. The prevalence odds ratio of advanced versus no disease or minimal disease was 2.4. when former smokers were compared with never smokers. In contrast. among current smokers of I to 2 packs per day. the ratio was 6.7. A similar pattern was observed for different pathologic manifestations of CHD. The effect of duration ot abstinence among former smokers was not analyzed. Ramsdale and coworkers ( 1985) used arteriography to assess the extent of coronar) atherosclerosis before surgery for valve replacement among 3X7 patients. All patients provided a smoking history, including age at initiation of smoking and cessation of smoking and average number of cigarettes cmoked per weeh. Among never smohers. X7 percent had no stenosis greater than SO percent: only 60 percent of past smohers and 60 percent of current smokers were without this degree of stenosis. Of never smohers. only 2.6 percent had three or more arteries affected compared with 10.6 percent of former smokers and 13.2 percent of current smohers. Both current and past smoher-\ had more were coronary artery diseaw. The median xx~re among ne\er smokers and current smokers was 0.2 and 7.X. respectively. For pa\t smokers. the data were prehented by duration since quitting. There was no evidence for a trend of decreased effect by increasing time since cesation. The median score for those quitting within the previou\ 5 year\ wa\ 5.0; for 5 to 10 year\. 5.0: and for IO year\ or more. 7.5. Coronary atherosclerosi\ was positi\,ely correlated with lifetime number of cigarette\ smoked among both current or past smokers. In this study. past smokers had a slightly worse coronary ri~ not repre~entati\e of the general popula- tion. Nonethelchs. the\e studies wpport the view that hmohing cause\ an increase in atherosclerosi\ and that very recent quitting has little impact on coronar!~ \teno\i\. Fried. Moore. and Pearson ( IYXh) studied the effects of \mohing h> a\he\Gng the coronary diameter in 3 I men \\ho had normal coronar\' arteringrams. Men M ith an! detectable \tenoGs in the main coronary arterie\ or more than 75 percent in an! coronq branch were excluded to assess the effect\ of mohing on the caliber of coronary arterie\ in the absence of atherosclerosi\. These researcher\ found that after udjuhtment for alcohol intahe (which i\ ;l\\ociated M ith u ider arteries ). current and former \moher\ had 10 to SO percent nxro~~er urterie\ than did neker smoher\. The pa$t \moher\ had someuhat narrower arterie\ than current smokers although thi\ uas not stati\ticall!. Ggniticant. Of the I I cx+mohcr\. 6 had quit in the previous year. This \tudg sugge\th the po\\ihility of another per\i\ting effect of mohing. apart from promoting atheroxlero\i\. not rapidI! raerwd b) cc\\stlon. Studies of Smoking Cessation and Risk of MI Among Healthy Persons Case-Control Studies Table I wmmarizes data from ca\e+wntrol \tudie\ (Wlllett et al. 198 I : Rosenberg. Kaufman. Helmrich. Miller et al. 1985: LaVecchia et al. IYX7: Rosenberg. Palmer. Shapiro 1990). of men and Momen from the LInited State\ and abroad. Prospective \tudie\ of CHD are generally considered lea prone to bias than ca\exontrol htudie\. although casexontrol \tudie\ are probuhly 1~54 susceptible to mi\cla~sificntion rewlt- in? from resumption of smohing mnong former smoker\. For example. an individual diagnosed u ith a recent MI can probably recall his or her \mohing \tatu\ .just before the infarction with cowiderable accuracy (Chapter 7). Thu\. c:l\exontroI \tudiek ma> TABLE I.-Case-control studies of CHD risk among former smokers Reference Population Number of CBIC\ Willett et al. (19X1) Nurses Health Study: women aged JO-55 263 5.260 Nested m cohort 2Y Overall I .o 10.7-1.h) 2.0 (7.34.0) Quit I-4 yr I .s (0.7-3. I ) Rosenberg. Eastern US men aged 45 1.x73 2.775 Hwpitnl-bawd Kaufman. Helmrich. Shaptro (19x5) Rosenberg. &tern US women aped 40 5.55 1364 Ho\pitnl-bawd Kaufman. Helmrtch, Miller et al. ( 1985) LaVecchia et al. (10x7) Italian women aged 45 IhX 2.51 34x 3s @It S-4 yr I.3 to.x-3.0) Quit 210 yr O.h(O.l-1.3) I.1 (O.`J-1.4) I 0(0.7-1.0) I .A-7.0 depending 011 cig/da, TABLE I.--Continued @IIt oungcr age group. and the excess risk declined with increasing duration of abstinence. In men aged 31 to 53 year\. the relative rish among former smohers of I to 4 \ ears' duration M ;I\ I .Y compared u ith ne\ er smohers: relative ri$k further declined to 1 .4 to 1 .3 with a maximum of 20 years' duration ot abstinence. In contrast. persistent smohers had a relative rish of3.S. In this study. those who quit had smoked about IO percent fewer cigarettes per day before quitting than did persistent smokers. The British Physicians Study also included 6. IY4 women. for whom the data \h'ere reported sepsrately (Doll et al. 19X0). These women completedquestionnaires in IYS I. I Y61. and 1973. In contrast to most studies among adults. a substantial minority of nonsmoking women in this cohort initiated cigarette smohing between 195 I and 1961. Thus. the rates of smoking-related diseases among thoe classified as never smokers are likely to be overestimated because never smokers. defined according to the 195 I data. included a proportion of subsequent current smokers. Overall. the relative risk of CHD mortality among former smokers was 0.Y compared with I .O to 2.2 among current smokers. depending on the amount smoked. Because there were only 26 cases among former smokers. a detailed analysis was not performed. The first large-scale American Cancer Society (ACS) cohort was assembled in 1952 when 1X7.783 men aged SO to 6Y. living in 9 States, completed a questionnaire related primarily to smoking (Hammond and Horn 19SXa.b). The men were enrolled by over 22.000 ACS volunteers each of whom was asked to enroll IO individuals, excluding those who were seriously ill. There was no further update of cigarette uce. These men were studied for fatal outcomes for an average of 44 months. for a total of 667.753 person-years. Cause of death for 1 1,870 individuals was determined by death certifi- cate. Compared with never smokers. the relative risk of death due to CHD among current smokers of less than I pack per day was 1.75. Among former smokers of less than I pack per day, those quitting within the previous year had a relative risk of 2.09. those quitting 1 to 10 years earlier had a risk of 1 .S4, and those quitting for more than 10 years had a relative risk of I .09. A similar pattern was observed among smohers of 1 pack or more per day: among current smokers, the relative risk was 2.3: among quitters within the past year. 3.00: among quitters of I to 10 years. 2.06; and among quitters of more than IO years, I .60 (Figure 3). The authors speculated that the elevated 20s TABLE 2.--Cohort studies of CHD risk among former smokers Aged 55~64 Quit I 3 yr I .9 5 0 yr I.4 lO~bl4yr 1.7 ?I5 yr I.3 I.7 Awl 26.5 < Quit I ~4 yr I .O 5 Vyr I.3 IO l4yr 1.2 >lSyr I.1 I .3 TABLE 2.--Continued Reference Populallon Followup Numtwr of caes cinlollg former smohers Rcl:n~vc rd.\ compn~wtt \* irh nwcr w~,her\" Ftrrmer Currrm \mohrrs winher\ (`ommenl\ L)oll cl al. (10X0) Brni\h phyxicinns: 6. IYl women Hammond and Horn (1YSt-h.h) I X7.7X3 men aged SW50 44 mu for CUD denth\ 2.3 x0 40 IX fl4 40 Hammond and ACS CPS-I: 35X.533 men free of (iarflnhrl ( 1069) diagnosed CHD 6 yr for CIID mortatlty 7') 57 SS S2 70 0.01 Quit< I )r 2.OY I 10>1- I.54 >I0 y,- I.OY Prevlou\ly >I ppd Quit i I yr 3 (H) I-IOyr 7.06 >I0 yr I .hO Prevwu\ly I-t') clg/d:q Qull cl yr I.hl I--l\r I.21 5 Yir I.26 IO 141, ().%I >20 \r I .IlX TABLE 2.--Continued Reldive ri\ks compnred with never smoker\" Kelerrncc tlalnmond ;md (Llrllnhcl I IYW) ~C(IIltIIlUcd) anlonp former wlokerr 62 IS4 13s I33 x0 Former Current wlnher\ wwkrrs Comment\ 2.5s Prevlou\ly 220 clg/dsy Quit lhjr 1.17 I 76 Women 220 L?r/d;l) QW Nyr 1.10 0.Y I. I (W-2.7) 0.7 Aged 3Y40 I .Y Aged SOL5Y I. I 2.3 Only baseline kmohing data wed 2.0 3.0 depending on amount mokrd No data on duratwn I.3 Smohing intirrm;ttion upduted biennially 2.5 TABLE 2.-Continued Number of case\ Rclativr ri\h\ compared wuh never vnohcr\" Reference Population Followup among former \moher\ Former smoher\ Current 5moher~ Comments Cederlofet al. (lY75) Sample ofSl. 91 I Swedish IOyr 07 Quit I-Y yr I .s lOLlI 1.7 men aged I X49 Only hawlme Smoked . SOURCE. Hammond and Horn ( lY5Xhl. risk among recent quitters reflected the inclusion of men who stopped smoking because of early symptoms of heart disease. A second cohort study. the ACS Cancer Prevention Study 1 (CPS-I) (formerly called the ACS Z-State Study). was undertaken between 19% and 1972. Recruitment was by family, and eligible families had at least one person aged 35 or older. All family members aged 3.5 or older wtere asked to participate in the study: more than I million persons were enrolled. In a 6-year followup of 358.513 men free of diagnosed serious illness. clear reductions in risk ofCHD mortality were observed among former smokers compared with current smokers (Hammond and Garfinkel 1969). Among those smok- ing less than I pack per day. the relative risk among current smokers was I .90. Among those who stopped in the previous year. the relative risk v.as 1.61. and amon_e those with 10 years or more of abstinence. the risk was nearly the same a\ that for never smoher5. A similar pattern was observed among those smoking 1 pack or more per day. Current smokers at that level had a relative risk of 2.55. Quitters of less than 1 year had a relative risk of I .6 1. and those with between IO and 20 years of abstinence had only a slightly elevated relative risk of I .2S. Because of the very large number of deaths and the careful followup. the estimates of effect are relatively precise. In this period. cigarette smoking declined substantially. especially in the predominantly white, mid- dle- to upperclass groups represented by the study population. Hence. some misclas- sification of the current smoking group may have occurred. but the relative risks among former smokers. apart from the most recent quitters (some of whom inevitably resumed smoking). are likely to be accurate. In 19X2. a third ACS cohort. CPS-II. was initiated in SO States. The methods for recruitment and the population enrolled were similar to CPS-I. but the cohort was larger, vvith more than I .2 million participants (Chapter 3). Preliminary data based on 4 years of followup were published in the 19X9 Surgeon General`s Report (US DHHS 1989). Among men. former smokers aged 35 or younger had relative risks of CHD of 1.31. those aged 36 to 63 had I .7S. and those 65 or older had 1.29; the relative rijhs among current smokers were 1.94 . 3.X I. and I .62. respectively. A generally similar pattern wa\ jeen among women. When the data are examined by amount of previous smoking and time since quitting. the pattern of changing risk is influenced by the presence of disease at enrollment. When those who reported themselves a\ sick or as having previously diagnosed cancer. heart disease. or stroke at baseline were not excluded from the analysis, men who previou4y smoked fewer than 2 I cigarettes per day and who had quit smoking within the previous 3 years experienced a CHD mortality rate that was about 6 percent higher than that among current smokers. However, vvith increasing duration of abstinence, the risk among former smokers came very close to that of never smokers: after I6 years or more. the relative risk was 1.01 (US DHHS 1989). It is likely that the early peak in mortality among recent quitters partly reflects the effect of having included those vvho quit because of smoking-related illness. After excluding those with cancer. heart disease, and stroke at baseline, this early excess mortality is less apparent (Table 2). In all categories. those who quit 1 to 2 years earlier had relative risks substantially lower than those of current smokers. Findings are less consistent for those who quit within the past year. presumably because of a high incidence of smoking resumption in that group and the possible inclusion of persons who stopped smoking as a result of symptoms due to undiagnosed illness. A very similar pattern was observed among men who smoked 21 cigarettes or more per day, except that the relative risks were higher for all but those with the shorter period of abstinence. The absolute rates were lower for women, as expected, and the relative risks are thus statistically unstable. Neverthe- less, the overall patterns among female smokers were generally similar to those among male smokers. To examine the effects of smoking cessation at different ages. CPS-II data on cumulative mortality rates due to CHD were tabulated for 5-year categories of age at cessation. (See Table 3 and Chapter 3 for a description of the methods used to calculate these rates.) The mortality rates used for these calculations were based on subjects not TABLE 3.- Estimated probability of dying from ischemic heart disease in the next l&5-year interval (95% CI) for quitting at various ages compared with never smoking and continuing to smoke, by amount smoked and sex Age at quitting or at start of mterval Never smoker\ Continuing \moken Former smoker\ ,sician's orders were excluded from the analysis. Mortalit!, in this cohort uas monitored. and death certificates were obtained to assess cause of death. Smohing status after the baseline questionnaire was not ascertained. After 16 years offollo~up. quitters at enrollment when compared with never smohcrs had relative risks of I. IS for all cardio\,ascular mortality and I. 16 for CHD death specifically (Roget and Murray IYXO). In contrast. men who uere current smokers at baseline had relative risks of 1.5X for these two categories. Among past smokers. risk of death due to CVD increased with higher pre\,ious usual daily cigarette consumption. The relative risks among past smohers. compared Gth never smohers. ranged from I .02 for less than IO cigarettes per day to I .33 for 40 ciparettes or more per day. This gradient M as more pronounced among current smokers I Figure 1). A gradient was also apparent for decreasing rish with increasing duration of cmohing abstinence. For both cardiovascular and coronary mortality. there was a moderate decrease in risk with short duration of abstinence and a smaller. but consistent decline in rish uith longer periods of abstinence (Figure 5). After 20 years or more of abstinence. the relative risk of CVD was I .04. and for coronary death. the risk M as I .05. The major strength of the U.S. Veterans Study is the large numbers. M ith 2 I.1 Ii deaths from CVD among smohers and 9.077 among former smokers. The long followup period without reclassification of smokin, (7 status is a limitation. \\ hich M ill tend to lead to an underestimate of the effect of sustained smohing and an underestimate of the benefit5 of quitting (Chapter 2). This source of potential bias ma! not ha\e marhcdl~ distorted the estimates in this stud!: in the follo~up of this cohort (Roget and Murray 19X0). the relative risk for cardiovascular mortalit\ associated M ith current smoking at enrollment \\a\ I .h? at X.5 years and I .5X at I6 !ears: for coronar\ disease. the relative rish U;I\ I .6l at X.5 years and 1.5X at I6 vex\. Thus. the impact of misclassification of current smohers M ho quit (and therefore lowered their rish) as persistent smohcrs appears to be slight. A similar comparison of the relati\.e rishs among former smohers is less int'ormati\e in assessing the impact ofmisclassificati~,n. hfost quitters u ho resume smohins do 40 ~~ithin 2 years after cessation. Thcret'tore. IniscI~Issit`ication of e\-smoher5 betuecn X.5 and I6 fears of cessation is likeI> to he small. For both cardio\us~ular mortalit! and coronar! mortalit>. the relati\ e ri&\ among ex-smohers declined slightI> from I .2 I at X.5 hears of follo\vup to I. I5 and I. I6 at I6 yxrs of` follow up. This is consistent u ith the in\ crst` relation bet~reen duration of smohing cessation ;und mortalit\' ratio. Among current mohers In the l:.S. Veterans Stud!. the relati\.e rishs of coronar> disease \\ere slightI> hisher after X.5 years of follow up (relati\ e rish (RR )= I .Y5 for >20 cig/da\ ) than after 2.5 \cai-s of follo~up (RR=1 .75 I tDom 10.54). As expected. tho\e M ho stopped smohing on ;I ph\ slcian's orders v,ere at higher rish of death regardless of their smohinf statu\. An earl!, report of combined data from the Framinyham and Albany Heart Studies (Do! Ie et al. I Yh2) included 4. I20 men free from coronq di\easc at entr) into the stud!.. The Framingham Stud) data were bard on 6 lrars oft`ollouup and the Albany &art Stud! data on X bears of follo\~up. .4mong the 4 I I former smohers in the combined cohort. the rcIati\t' rish of Ml (age-adiusted) U;I~ 0.Y compared u ith nt'\`cr 71X . Gordon, Kennel. and McGee (1471) assessed the effects of \mol\ing cessation. In thi\ analysis. anyone who smoked for I lear or more during the mo\t recent ?-year interval between examinations was considered ~1 current moher. Ap- proximately 20 percent of men who reported that they had quit smoking a~ entr! into the studs resumed \mohing: about halfofthose smoked very little oronly intermittentI> after resumption. Compared with current smoker>. former smokers had B 30.percent reduction in fatal and nonfatal CHD (escluding angina): the relati\,e ri\h ;imong current smokers compared w>ith that among never \moken was 1.3. Other coronary ri4 factor\ were examined in detail: there uere no \ipnificant difference\ between per\i\tent smohers and those who quit. but those who quit Mere more likely to be ill. Hence. it would be expected that acl.justment for confoundin, ~7 would have revealed even greater benefit from cea\ation. The benefit of quitting seemed more marked in younger men. However. there w'ere only 73 cases ofCHD amon? the quitter\ \o that a detailed analysi\ could not be performed. The Western Collaborative Group Study monitored a cohort of 3.514 men for an average of X.5 years for CHD incidence (Rosenman et al. lY75). Information collected at baseline among men aged 3Y to 39 indicated that former maker\ had a relative rirh of 1.9 compared with that of never smokers . 30 percent lower than among current makers. For men aged SO to SY. former smokers had a relative ri\k of I. I compared with never smokers. 40 percent less than among current makers. Thih effect of cessation wa\ slightly greater than that observed after 4.5 years of followup (Jenkin\. Ro\enman. ZyLanski 196X). The difference between the age groups could be a true effect or may reflect different levels of misclassification: it is possible that a greater proportion of the quitters in the younger group than in the older group resumed smoking. In 1963. a prospective