In each study summarized in Table 1. the ri4 oforal cancer U;I\ lower atnong former smokers after the first few years of abstinence than for current \moLer\. After 3 to 5 years of \mohing abstinence. oral cancer ri4 decreased b!, SO percent. In ;I study in Argentina (Isco\,ich et al. IYX7) and in the large multicenter stud) conducted b! the C.S. National Cancer Institute (NCI) (Blot et al. IYXXJ. the ri\h of oral cancer among tormer mohers after IO year\ of abstinence WLII comparable u ith that among ne\ t`r mokerh. Thi\ observation has been interpreted as an indication tha[ the greatr\t effect ot` smohing on oral cancer rich ma)' be in the later (postinitiation) stage\ of carcino- genesi\ (Blot et al. IYXX). Although it is isell hnonn that stnoheless tobacco (ST) increaec the rish of oral cancer (Winn et al. IYXI: US Dl1HS 10X6) and that stopping the u\e of' ST reduce\ the prevalcncc of premalignsnt tissue change\ in the mouth (Gupta et aI. IYX(1). there i\ little information on the ri\h of oral cancer in former u\er\ of' ST. Compared wjith current smoher\. t'ormer makers ma\' ha\ c different alcohol drinhing habit\ het'ore and after >mohing 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