respectively. For those aged 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 of the 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. 1957) 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 198 1a.b,c). Using data from the British Physicians Study, Doll (1971) 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 power of duration. similar to the slope of the regression line when incidence in never smokers is plotted against age (Figure 3). Thus. a first-stage effect was implicated because the excess lung cancer risk among smokers increased with the same power of duration of smoking as the risk with age among never smokers. Moreover, the lung cancer mortality rates among ex-smokers decreased some what initially and then increased slowly in keeping with the increase in risk among never smokers with age (Doll 1971). Armitage (1971) noted that the stabilization 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 (1980) conducted a detailed analysis of the pattern of change in cancer risk after cessation of an exposure. The results supported the Armitage—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 effects on the two stages, Brown 126 * Cigarette smokers by duration of smoking x —-—-— x Cigaretie smokers by age ¢——— * Never smokers by age 1,000 - 100 = oO | ANNUAL INCIDENCE/100,000 MEN 20 30 40 50 60 70 80 YEARS FIGURE 3.—Incidence 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 SOURCE: Doll (1971). with correction of printing error in the original figure. and Chu (1987) reexamined data on ex-smokers from the European case-control study of lung cancer (Lubin et al. 1984a) and concluded that smoking had an almost double relative effect on late-stage events compared with first-stage events. Using data from a case-control study in New Mexico, Whittemore (1988) developed a predictive mode! for lung cancer that showed a twofold stronger effect on late-stage than on early-stage events; the model overpredicted cases among ex-smokers and underpredicted cases among current smokers. Therefore, Whittemore suggested that smoking may have an even stronger effect on late-stage events than was assumed in the model. Alternative models and interpretation of data on former smokers and lung cancer have also been suggested in several recent studies. Freedman and Navidi (1989) tested the 127 fit of the multistage model to data from ACS CPS-I and the U.S. Veterans Study. These researchers observed that crude rates of lung cancer decreased with increasing years of smoking abstinence although the trend was less steep when average amount of smoking and ages when smoking started and stopped were considered in the analysis. Moreover, the observed lung cancer rates among ex-smokers were compared with the expected rates, which were computed in three ways—risk at the ime of quitting, risk at current age with excess risk frozen at the time of quitting, and never smokers of the same age. For each comparison approach, the ratto of observed to expected rates decreased with increasing years of smoking abstinence. Freedman and Navidi (1989) concluded that this pattern was incompatible with the multistage model, which predicts stabilization of excess risk when an individual stops smoking. Gatfney and Altshuler (1988) reexamined data from the British Physicians Study and found that the best-fitting model among current smokers predicted an increase in the excess incidence among ex-smokers. which was inconsistent with the observed decreased rates. These researchers found that a two-stage model fit the incidence of lung cancer in both current smokers and ex-smokers. Gaffney and Altshuler (1988) then proposed a two-stage model with clonal growth in which cigarette smoke induced the initial transition and promoted clonal growth in these cells initiated by cigarette smoke. Moolgavkar, Dewanji, and Luebeck (1989) questioned the biologic plausibility of the proposal by Gaffney and Altshuler (1988) and noted that their model only fit part of the British physicians data set. did not consider each age-smoking level. and discounted the possibility that smoking affected two transition rates in the carcinogenic process. Moolgavkar, Dewanji. and Luebeck (1989) reanalyzed the British Physicians Study within the framework of the two-mutation, recessive oncogenesis model. Based on this mode], the second-mutation rate would be affected by smoking, and a sudden decline in risk after cessation of smoking would be predicted. However, this model implies that smoking affects the last stage ina multistage process. contrary to current considera- tions. In summary, multistage models have been used to describe the interrelationships among number of cigarettes smoked daily. duration, ime since exposure ended, and lung cancer incidence. Several investigators have interpreted the data on risk among former smokers in different ways. The epidemiologic data clearly indicate that the risk among tormer smokers is between that of continuing smokers and never smokers. Various models can be fit to the different data sets. The expected pattern of risk among former smokers is sensitive to the model selected and dependent on the relative magnitude of the effect of smoking on early versus late stages of the process of carcinogenesis. Using multistage models. the data on former smokers are insufficient to allow precise quantification of the relative effects of smoking on the early and late stages of the carcinogenic process. which smoking is assumed to affect. Nevertheless, data indicate that smoking has an effect on the late stages of the carcinogenic process and that cessation reduces Jung cancer occurrence. 128 Cessation After Developing Disease Individuals who stopped smoking are not a randomly selected group in most studies (Chapter 2). Often, smokers quit as a result of developing symptoms of a life- threatening disease or immediately after diagnosis of cancer. This phenomenon is evidenced by the increase in risk of lung cancer in the immediate period after cessation. Some studies have grouped these former smokers with the continuing smokers or have excluded them trom 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 !0 percent of the smokers quit because of a doctor’s orders: these smokers were presumably ill. The lung cancer mortality ratio relative to never smokers for ex- smokers who stopped because of non-health-related reasons was 4.43 compared with 5.83 among ex-smokers who stopped on a doctor’s orders and 8.98 among continuing smokers (Kahn 1966). In the European case-control study. Brown and Chu (1987) 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 was 1.3 (p<0.001). Moreover, the percentage who stopped for health reasons decreased with increasing years of abstinence. Among those who had stopped for | year or less, 95.8 percent stopped because of health reasons compared with 65.7 percent of longer term ex-smokers. In ACS CPS-I], men and women who did not have a history of heart disease. stroke, or cancer at the time of interview showed a decreased risk of lung cancer in the first 2 years after smoking cessation when compared with continuing smokers. In contrast, the risks for all subjects combined (i-e.. those with and without a history of previous chronic disease) were increased during the first 2 years after smoking cessation when compared with continuing smokers. The lower risks among the group with no history of previous disease compared with the total group persisted for subsequent periods of smoking abstinence (Table 7). ° Cessation After Diagnosis of Lung Cancer Two studies examined the relationship between smoking status and treatment out- come of patients with small cell lung cancer. In the study by Johnston-Early and associates (1980), survival was prolonged in patients who were ex-smokers or who had stopped smoking at diagnosis, whereas no difference in survival by smoking status was detected in the study by Bergman and Sorenson (1988). The study by Johnston-Early and colleagues (1980) involved 112 patients with small cell lung cancer; 20 had stopped smoking before diagnosis: 35 had stopped at diagnosis: and 57 continued smoking. Therapies included chemotherapy with radiation therapy. with or without thymosin fraction V. The three patient groups were similar in disease extent, pretreatment performance status, pack-years smoked, and age and sex distribu- tion. The patients who had stopped smoking prior to diagnosis had the best survival, followed by those who had stopped at diagnosis, and finally by those who continued smoking; the median survival for the three groups was 70. 52, and 47 weeks, respec- tively. Overall survival differences remained after individually adjusting for disease 129 TABLE 7.—Standard mortality ratios of lung cancer among former smokers in ACS-CPS II (relative to never smokers) by years of smoking abstinence, daily cigarette consumption at time of cessation, and history of chronic disease No history of chronic disease" All respondents 1-20 221 1-20 22) cig/day cig/day cig/day cig/day Males Current smokers 23.5 31S 18.8 26.9 Former smokers (vr since stopped) d0 3.6 4.0 7.2 0.9 1.2 LO 34 3.5 tel TABLE 9.—Continued Reference Population Wynder and 6US cities Stellman (1977) Tuyns etal. (1988) European countries Smoking status Former smokers (yr since stopped) 1-3 4H 7-10 1-15 216 Current smokers Never smokers Former smokers (yr since stopped) i! 4-9 210 Current smokers Relative risks Males Females (7.9 6.9 8.5 2.6 4.0 —_ 3.4 BX 2.5 — 14.3 11.6 1.0 1.0 Males Endolarynx Hypopharynx L.St 1.09 0.52 0.28 0.28 0.32 1.0 1.0 NOTE: ACS CPS HeAmercan Cancer Society Cancer Prevention Study "Reference category by never smokers. CONCLUSIONS Smoking cessation reduces the risk of lung cancer compared with continued smok- ing. For example. after 10 years of abstinence. the risk of lung cancer is ubout 30 to 50 percent of the risk for continuing smokers: with further abstinence. the risk continues to decline. . The reduced risk of lung cancer among former smokers is observed in males and females. in smokers of filter and nonfilter cigarettes. and for all histologic types of lung cancer. Smoking cessation lowers the risk of laryngeal cancer compared with continued smoking. 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Journal of the National Cancer lnstitic 62(3):471- 477, March 1979, {44 CHAPTER 5 SMOKING CESSATION AND NONRESPIRATORY CANCERS 143 CONTENTS Introduction 0.0... ccc cece cece cece cece eves eveetvtveeeeevevenevevs. 147 Review of Specific Sites. 00.00. c ec cece cece cece e eevee eeeeess .. 147 Oral Cancer... ce eee eee nee ene 147 Esophageal Cancer .. 2.0.00. cette eens 152 Pancreatic Cancer... ce eee ee beeen nee 155 Bladder Cancer... 2.000 co cece eee e eee eens 159 Cervical Cancer oo. ee nee eee nnn 165 Breast Cancer 0. ce eee tee eee ee 169 Endometrial Cancer 20.0000. cee ee eee eee 169 Other Cancer Sites 0.000 cc ee cece ene 172 Multiple Primary Cancers... 0.0.0... ccc ccc cceeececveeeeeueeuvevreees 176 SUMMAFY oo eee cee eee eve esc e eee teeetveeeveteveveseveesy 177 Conclusions v.sssssssssssvsvvvveeel Wa References ...........5. a D) INTRODUCTION Lung cancer, the first neoplasm causally linked to cigarette smoking, has been the cancer most thoroughly studied with respect to exposure—response relationships and benefits of cessation (US DHHS 1982). Subsequently, cigarette smoking has been established as a cause of cancer at diverse other sites. For some sites (e.g., oral cavity). the target cells are exposed directly to the various constituents of tobacco smoke. For other sites (e.g.. urinary bladder), absorption, transport. and metabolic activation of carcinogens in tobacco smoke result in exposure of target tissues. This Chapter reviews the evidence on smoking cessation and cancer risk at various nonrespiratory sites. The sites selected for review are those for which cigarette smoking has been determined to be a cause of cancer, or contributing cause. or those for which evidence indicates a possible association. Methodologic issues encountered in inferring causality on the effects of smoking cessation have been discussed in Chapter 2 and will not be reviewed in detail in this Chapter. Potential confounding by differences in prior tobacco exposure at the time of quitting. and by differences between former smokers and continuing smokers in other cancer-related risk factors may pose a greater obstacle to causal inference for the nonrespiratory cancers than for cancers of the lung or larynx: the smoking effects are generally smaller for nonrespiratory cancers, and the potential confounding factors are more numerous. REVIEW OF SPECIFIC SITES Oral Cancer Tobacco use is a major cause of oral cancer (US PHS 1964: US DHHS 1982, 1989). An exposure-response relationship has been identified between the amount of tobacco consumed and the risk of cancer of the oral cavity after considering the effects of alcohol consumption. The proportion of 1985 oral cancer deaths attributable to cigarette smoking in the United States has been estimated to be 92 percent for men and 61 percent for women (US DHHS 1989). The oral cavity, like the lung. receives direct exposure to cigarette smoke. Presumably. the causal association of cigarette smoking with cancer of the oral cavity reflects this contact and the same initiating and promoting agents that are considered to determine the development of lung cancer. Table 1 summarizes studies that have examined the relationship between smoking cessation and oral cancer risk. In these studies, the risk of oral cancer among current smokers ranges from 2,0 to 18.1 times (median of approximately 4) the risk among never smokers. Oral cancer risks for women who are currently smoking seem lower than those for men in studies conducted prior to the mid-1970s, but little difference by gender has been noted in more recent research. This gender pattern may be because of the initiation of smoking at an older age among earlier birth cohorts of women (US DHHS 1989) born during this century and the resultant low cumulative lifetime exposure of such women. 147 stl TABLE 1|.—Studies of oral cancer and smoking cessation Risk relative to never smokers Yr Population (yr of Design Current Former since Referenee data collection) (number of subjects) Gender smokers smokers quitting Comments Kahn US veteruas Prospective Male 3.8 1.9 NP Excludes “doctor's orders” (1966) (1954 62) (248,195) quitters Cancer mortality Cederlot etal Sweden Prospective (L975) (1963-72) (27.300) Male 2.7 OR NP Cancer incidence (27.700) Female 2.0 0 NP Wonder and Steliotan 6 US cithes Case:control Male RY 9.0 1-3 (1977) (1969 75) (4976.5 34) 3.5 4 3.2 7-10 3.4 tl-15 1.6 216 (27026522) Female 44 3.8 }-3 2.2 4-4 LA 7-10 0.6 Hl-t5 0.8 216 Rogotand Murray US veterans Prospective Male 4.2 1.7 NP Excludes “doctor's orders” (1980) (195-4 69) (293,958) quitters Cancer mortality Extension of US Veterans Study 6Fl TABLE 1.—Continued Risk relative to never smokers Yr Population (yr of Design Current Former since Reference data collection) (number of subjects) Gender smokers smokers quitting Comments Wigle. Mao, Grace Alberta, Canada Case:control (1980) (1971-73) (84:1,002) Male 8.7 3.5 NP (41:674) Female 4.3 OLS NP Spitz et al. Houston, TX Case:control Male 4.5" 6.1 <5 (1988) (1985-87) (121:127) 2.2 S-14 1.0 BIS (S049) Female 5.5" 98 <5 45 S-14 1S 215 Blot etal. 4 areas in United States Case:control Male 3.4 11 1-9 Adjusted for alcohol (1988) (1984-85) (762:837) ht 10.19 consumption 0.7 220 (352:431) Female 47 1.8 19 O.8 lOo19 0.4 220 Franco et al. Brazil Case contro] Male 93 29 ] 4° 1.5 >] 2.0 10 NP 18.1 6.4 NP 5.8 2.5 Adjusted tor alcohol Adjusted for alcohol and previous number of cig/day Cancer mortality NOTES NP=not provided: ACS CPS He American Cancer Society Cancer Prevention Study HH. “Computed ay a wetghted average from cigaretic dose specitic relative risks presented in the paper, Weights are the number of controls within each stratum of smoking