Women and Lung Cancer

Women and Lung Cancer* Waiting to Exhale Elizabeth Healey Baldini , AID, IvIPI!; and Gary M. Strau ss, MD , FCCP

Lung cancer is now the leading cause of cancer deaths among women. In the United States, 64,300 women arc expected to d ie of lung cancer in 199 6. Smoking is resp onsib le for about 80% of lung cancer cas es. Unfortunately, the pre val ence of sm oki ng among women remains unacceptably hi gh at about 22 % a n d is expected to su rpass the rate in m en by the ye a r 2000. Sm ok ing rates are hi ghe st among youn g girls a n d the le ss educated . Whether lung cancer represents a different dis ease in women than in men is unclea r. Data are co nflicti ng regarding the magnitude of the relative risk of developing lung cancer due to smo kin g between the genders. There appears to b e a diffe rence in the relative distribution of lung cancer hi stologic feature s betwe en men a n d women that is no t exp lained e n ti rely by differences in smoking patterns. Women who smoke ap pear to b e at h igher ri sk of developing small cell lung cancer than squ am ous cell lung cancer, whereas men who smoke have a sim ila r ri sk for the two hi stol ogic conditions. Furthermore , women sm oke rs are mo r e likely to de velop adenocarcinoma of the lung, and est rogens may pl ay a causative role in this phenomenon. Data a re unclear regard ing whether the outcome of lung cancer treatment differs b etween genders. Solutions to the lung cancer epidemic among US women include (1) prevention of the di sease by reducing smoking rates , (2) improving early detection methods, and (3) exp lori ng new therapeutic str ate gies . (CHEST 1997; 112:2295-2345) SC OPE OF T H E P RO BLEM

L

ung cancer is now the leading cause of cancer deaths in women , having surpassed breast cancer in that role in 1987. Estimates of the leading causes of cancer deaths in women for 1996 are presented in Table I .' At least 79% of lung cancer cases in women are related to smoking.2 Thus , cigarette smoking is the main culprit for this lung cancer epidemic. Women starte d smoking in significant nu mbers during and following World War 11. Although overall smoking rates have declined since reaching a pea k in the 1960s, the current prevalence of smoking among US wome n is still alarmingly high (it was 26% in 1990).3 Furthe rmore, smoking rates among women are expected to surpass those among men by the year 2000.4 Actual and

estimated smoking prevalence among wome n and men in the United States between 1950 and 2000 is shown in Figure 1.4 R The age-adjust ed lung cancer death rates and smoking rates among women have risen in a parallel fashion. Given the 15- to 20-year latency period betwee n smoking and death from lung cancer , these curves are separated in time by about 2 decades . The lung cancer death rate for women rose slowly from about 2.5 cases per 100,000 women in 19,30 to abou t 5 cases per 100,000 in 1960, Since 1960, th e lung cancer death rate has increased rapidly and steadily, and in 1990, it was over 30 per 100,000 women . I Lung cance r death rates among US women from 1930 through 1990 are shown in Figure 2.1.9 As a result of the rapid increase in lung cancer deaths between 1930 and 1990, lung cancer has moved from the sevent h most common to the most common cancer cause of deaths in women . Lung cancer has always been and continues to be more prevalent in men than in women , but the magnitude of this difference is declining. In the 1970s, after severa l decades of a rapidly increasing rate of lung cancer deaths among men, the rate of increase began to slow. Since 1990, this rate has actually decline d, whereas in women it has continued to rise. I As these lung cancer dea th rate pattern s have changed over time, so too has the relative male to female lung cancer mortality ratio. Wherea s historically men have died of lung cancer at a much higher rate than women , in recent years, the relative ratio is

Tabl e 1-1996 Estimated Can cer Deaths for Women *

Disease Site

No. of Deaths

Lung Breast Colon and rectum Leukemia and lymphomas Ovary

64,300 44,300 27,.500 20,960 14,800

*Adapted

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Proportion of Cancer Deaths, %

from Parker et al.'

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'From the Joint Center for Radiation Therapy and Division of Medical Oncology, D ana-Farb er Cancer In stitute and Brigham and Women's Ho spital, Harvard Medi cal School, Boston . Reprint requ ests: Elizab eth If. Baldini, MD , MPH, Joint Center for Radiation Therapy, Brigham and Wo me/l's Hospi tal, 75 Francis St, Boston , MA 02115

1950

1960

1970

1980

1990

2000

Year

F IGURE 1. Smoking pr evalen ce for US men and wome n, 1950 to 2000.4 - S CHEST / 112/ 4/ OCTOBER, 1997 SUPPLEMENT

2295

0 0 0 0 0

Ta ble 2-Smo king-Related Cause,~ of Death Among Women in Developed Countries, 1985*

35 30

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a.

l: ClI

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Ot her cancers Ot her respiratory diseases Cancers of esophagus, head, and neck Other causes

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*Adapted from Chollat-Traq uet ,?

Year FIGURE

2. Lu ng cance r death rat es pe r 100,00 0 wo men , 1930 to

1990.'-"

coming closer to unity . Male to female lung cance r mortality ratios fro m 1930 to 1996 are shown in Figure 3.1.\1·1 2 Lun g cance r is not th e only smoking-relat ed killer of women. Th e World Health O rganization cites that at least 2.5% of women smokers will die of a smoking-relate d disease." In absolute terms, about 300,000 wom en in develop ed countries died of smoking-related diseases in 198.5. Th e relative distribution of th ese 300,000 death s is shown in Table 2.:J Th e leading smoking-related causes of death were cardiovascular disease (41%), lung cancer (2 1.1%), and CO PD (18.1%).:J

NATURE OF TH E PnOBLEM :

Is

L UNG CANCER A

DIFFER E NT DISEASE I N WOM E N THAN IN MEN?

Until fairly recently, lun g cancer was a relati vely uncom mon disease among wom en . As a result, available data on wom en and lun g cancer are not plentiful and, in fact, often conflict.

Susceptihiluu

ofWo men to Lung Cancer

Smoking is th e most important risk factor for th e developm ent of lung canc er in both wom en and men .

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Year 3. Male/ fem ale lun g ca nce r mortality ratio, 1930 to HJ96.'-"·12

F IG URE

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Rep ort ed relative risks (Rlls) for th e development of lung cancer in wome n smokers compar ed to wom en non smok ers range from 1.5 to 153.2.1:J.1 9 Th e magnitude of the risk increases with th e duratio n of smoking and tot al exposur e to cigarettes.2.9.1 7.H) Wh ether th e association between smoking and lung cancer is stronger for wom en than for men is uncl ear. Studies add ressing this issue have provided conflicting results. A large case -control study conducted in Ontario for cases diagnos ed between 1981 and 1985 showed an RR of lung cance r for wom en smokers of 27.9 compared with one of 9.6 for men smokers." Th ese result s suggested that women smoke rs were about three times as likelv as men smo kers to develop lung cancer. Another ca;e-control study that included > 8,000 people reported th at women smokers were 1.5 to 2 times more likely to develop lung cancer th an men smokers.>' A pr eviou s study by th e same group!.5 also showed a higher RR of lung cance r for wom en smoke rs, and this was tru e at every level of tar exposure . An even earlier study from 1977 showed an RH oflung cancer for wom en smokers of 16 vs an RR for men smo kers of io.» However, th e Americ an Cancer Society Cancer Preven tion Studi es I and II (CPS-I, C PS-II) both showed a greate r nR oflung canc er deaths for men smokers than for women smokers. " The results of these studies, which assessed smokers aged 35 years and older, are presented in Tab le 3. Th e magni tud e of th e Hfls in these studies changed over tim e , which is most likely related to th e cha nging smoking patterns of men and wom en over th e study periods. Another case-control study, which included nearl y 2,000 women diagnosed as having lung cancer betw een 1982 and 1983 in New Jersey, showed an overall odd s ratio (O H) for lung cancer in women smokers of 8.5.1' A com parable OR of H .6 was found for men smokers in a similar study conducted by the same authors.20 .2 1 Given these conflicting data, it is difficult to discern wheth er the magnitude of the association between cigarette smoking and lung canc er is different for women th an men. Th e intensi ty of smoking was assessed variably in these studies and may be one explanation for th e conflicting result s. In addition, case-co ntrol studi es are pron e to pot enti ally significant biases owing to their retrospective nature and the inhe rent difficulti es of choosing appropriate control subjects. Th ese factors can lead to misclassification and selection biases. Furtherm ore, these studies Multimodality Therapy of Chest Malignancies-Update '96

HistologiC Types of Lung Cancer in Women

Table 3-RR of Lung Cancer Deaths Among Women and Men Smokers* HE

CPS -I (1959-65) C PS-II (1982-86)

*Adapt ed

Men

Wom en

11.35 22.36

2.69 11.94

I

from reference 2.

provide infor mation only with respect to RRs. Absolut e risks, which are perhaps more mea ningful from a publi c l~ealth stand~oint , can be assessed only th rough prospec~IV~ population-based studi es. Finally, the back ground incidences of lung cancer among men and women nonsmokers may be significantl y different. For example, men could have a higher background risk of lun g cancer due to environmental exposures. If this were in fact th e case, the ratio of lung cance r deaths for smokers compared to nonsmokers would consequ ently be higher for women , and it would be incorrect to conclude that women smokers are mor e susceptible to lung canc er than men smokers based solely on an RR statistic.w In addition to smoking , oth er establishe d risk factors for th e developm ent of lun g cancer in men have also been confirme d in women. These include a family history of lung cancer , which is both a risk factor on its own and significantly increases risk in smokers .18.2:3 Horwitz et a)23 showed ORs for developing lung cancer were 2.8 in wom~n nonsmokers with a family history of lun g cancer , 11.3 In women smokers, and 30 in women smokers with a f~mily history of lung canc er. A histo ry of prior lung disease, ano th er known risk factor for men , was associate d with an RH of developing lung cancer of 1.2 and 1.56 in two case-control studi es limited to women. 24.25 Lastly, as is the case for men , th e relationship between diet and vitamins and th e developm ent of lun g cance r is unresolved.26-29

Endocrin e Factors and Lun g Cancer In ad?ition to risk factors shared with men , some lung cancer nsk factors may be unique to women, ie, hormones. Taioli and Wynd er'? present ed some suggestive evide nce ~hat exogenous and endogenous estrogens may playa role 1I~ the development of lung canc er , parti cularly adenocarcmoma, among wom en. Using case-control dat a, th ey showed th e following: (1) early age at menopause (40 years or younger) is associated with a reduced risk of adenocarcinoma of the lung (0 1\= 0.3); (2) the use of estrogen rep lacement therapy is associated with a higher risk of adenocarci noma of the lung (OR = 1.7); and (3) th ere is a positive interaction between estrogen replacem ent therapy, smoking , and the developm ent of adenocarcinoma of the lung (0 1\= 32.4). Th e authors postulated that estrogens may be a relevant factor in th e promotion phase of carcinogenesis. Th ese data are intriguing and consistent with the fact that estrogens are known risk factors for th e development of adenocarcinomas of the breast , endome trium, and ovary.:"

. Th e dist~ibution of histologic types of lung cancer differs consistently among men and women. Th e most common histologic types continue to be adenocarcinoma amon g wom en and squamous cell carcinoma among men. T~ble 4. shows th e relative distribution of lung cancer histo logic types among wom en and men whose conditions we re diagnosed between 1984 and 1986 in Orange County, Calif.!? Similar relative distributions have been reported by oth ersY·17,l8.:l2 For both genders, adenocarcinoma is mor e common amon g nonsmokers than smokers . Smoking is a risk factor for all histologic types oflung cancer, but the association is muc.h stronger for squamous cell, small cell, and large cell carcmomas than for adenocarcinomas. Osann !" reported RRs for lun g cance r in women of 35.1 for squamous ce ll, s.mall cell, and large cell carcinoma compared with only 2.5 for adeno carcinoma. Differing distributions oflung cancer histolo gic types among women and men may be associated with differ en ces in smoking patterns , but this does not fully explain the observed differences. Men smokers have a similar OR for th e developm ent of squamous cell and small cell carcinomas, wher eas women smokers app ear to have a much higher OR for the development of small cell vs squamous cell carcinoma. This findin g has been shown in several studies and is demonstrated in Tab le 5.17.19.33 T~1US , t~l e differ ence in the distribution of lun g canc er histologic types between th e genders cannot be explained fully by differen ces in smoking patt erns and potentially suggests basic differen ces in th e etiology of lung cancer between the sexes.

Outcome of Lung Cancer Treatment for lVomen Data are conflicting with regard to the outcome of lung cancer treatment according to gender. Some reports of non-small cell lun g cancer (NSCLC) have shown th at women fare better th an men when treated with sur gery ,34 ra.diation. therapy with or without chemotherap y." and tnmodahty therapy, ie, chemotherapy, radiation therapy, and surgery.:l6 This last study was a Sout hwest Oncology Group trial of 126 pat ients with stage IlIA and IIIB NSC LC .36 Patients wer e treat ed with concur rent chemoth erapy and radiotherapy followed by surgery. Wom en appeared to have a better survival than men by univariate analysis but not by multiva riate analysis. However, surgical

Table 4 -Distri bution of Lung Cancer Cases by Ilistologic Type * Lun g Cancer Histologic Type Aden ocarcinoma Squamous cell carcinoma Small cell carcinoma Large cell carcinoma Other/un specified

Distribution, % I

Men (n = 1,153)

Wom en (n = 833)

28.9 31.2 16.9 9.2 13.8

34.8 20.5 20.3 8.8 1.5.6

I

*Adapte d from Osann et aI.I9 CHEST / 112 / 4/ OCTOBER, 1997 SUPPLEMENT

231 S

Table

for Lung Cancer Among Smokers According to Cell Type

5-0R~

Squamous Cell

Small Cell Carcinom a

Carcino ma

Men Schoen berg et aJl7 Brownson et a\3·1 Osann et al 19

Wom en

Men

Wom en

18.9

10.6

20.1 26.4

22.9 11.4

59.0

11.1 36. 1

37.5

86.0

37.6

series from En gland , Wales, and th e Un ited States have shown that wom en fare wors e than men.37 . :39 Women with NSCLC who underwent sur gery at the Un ivers ity of Mich igan had a 5-year survival rat e of 26% compared with 39% for men .P" The data are similarly incon sistent for patients with small cell lung canc er (SC LC) . A multivariate analysis of 1,521 patients tre ated in five separate Cancer and Leukemia Group B trials between 1972 and 1986 showed that women had significantly better response and survival rates .s" Ho wever, as summarized by Skarin .s! studi es of patients with SCLC perfo rm ed in the Unite d Stat es, Can ada , and Europe have shown fem ale gende r to be a favorable pro gnostic factor for survival .w< ' whereas oth er studies show ed that gende r was not a significant prognostic factor.44 ,45 SOLVING THE PROBLEM

Prevention Since about 80% of lung canc er cases are attributable to smoking, it is clear that the most effective intervention to halt the lung canc er epidemic for both women and men is to reduce smoking rates to zero. It is believed that if everyone wer e to stop smoking, lun g cance r would again be a rare disease . Convincing people to stop smoking is no easy task. Despit e th e overwhelmin g evidence th at smoking causes lung cancer, as well as oth er fatal health problems, smoking rates remain unacceptably high . It is proj ect ed tha t smoking rate s will be higher in women than in men by th e year 2000 .4 Furthermore , the prevalence of smoking is disproportionately high among youn g girls and th e less educated." Currently, more young wome n than young men smoke ; and among women , the rate of smoking initiation is higher and th e rate of smoking cessation lower th an in men: 5 .46 Between 1965 and 1987, smokin g initiation decreased at a rat e of 1.19% per year for men , wher eas for women initiation slowed at a rate of only 0.28% per year." Thus, although antismoking campaigns should be dir ect ed at th e public at large, you ng girls and th e less educated should receive spe cial emphasis. Unfortu nately, th ese very subgro ups are the preferential focus of tobacco advcrtiscm en ts.v' -w Studying ot her methods of lun g cancer p revention , including th e role of diet and vitamins , should also be pursued.

Early Detection For lung cancer cases that cannot be pr event ed , it is important to diagnos e th em at as early a stage as possible. 2325

Survival rates are highest for pati ents who pr esent with early-stage disease .w Th erefore, atte mpts at early det ection of lung cancer should be pursued . Th e role of chest radiograph screening in th e ea rly det ect ion of lun g cancer remains controversial.r" Of note , amon g the 11 prospective studies of lung canc er screening that have been pe rformed to date,51 .62 wom en wer e included in only 2. Therefore, the role of lun g can cer screening with specific referen ce to wom en has not been studied adequately and should be investigated furthe r.

Improvements in Lung Cancer Therapy In addition to lung cance r prevention and early det ection , effor ts should be directed toward improving lung canc er tr eatm ents. Preclinical and clinical trials should be supported, and gender should be addressed as a specific research variab le . Rather than excluding women from lung cancer clinica l trials, as has been don e to a large degree in th e past , wome n should be actively recruited for inclusion.26,63,64 CONCLUSION

In conclusion, lun g canc er has reache d epidemic proportions in wom en . As is th e case for men, lung can cer is now the leading cause of cancer deaths among wom en . It is expe cte d to take the lives of over 64,000 US wom en in 1996 compared to an expe cted 44,000 deaths du e to br east cancer. Th e vast majority of lung cancer cases are attributabl e to smoking, and smokin g prevalence rat es in women are expected to rise slowly into the next century. Wh ether the etiology of lung cancer differs in women and men is unresolved, but th ere app ea r to be some striking differen ces. Th e magnitude of the effect of smoking on lun g cancer risk may not differ acros s the genders , but smoking appears to have a differential impact on the type of lun g cancer that develops. Women who smoke app ear to have a greater risk of developing SCLC than men who smok e . Furthermore, wom en are more likely than men to develop adenocarcinoma of th e lung, and evide nce suggests this may be du e, in part, to the role of exogenous and endogenous estrogens. No definitive statement can be mad e regarding th e outcome of tr eatment for lung cancer amo ng women compared to men . D ata addressing this point conflict and are inconclusive. Solutions to th e lung cancer epide mic that deserv e support include the following: (1) smoking pr evention campaigns with specific emphasis on young children (especially girls) and the less educated ; (2) improvements in the early det ection of lung cance r; and (3) advan ces in lung cancer treatment. REFERENCES 1 Park er SL, Tong T, Bolden S, et al. Can cer statistics, 1996 . CA Cancer J Clin 1996; 46 :5-29 2 Redu cing th e health consequen ces of smoking: 25 yea rs of progress: a rep ort of the Surgeon-Ge neral. Rockville, Md : US D epartment of H ealth and Human Services, Pu blic Health Service , Office of Smoking and Health, 1989; DHHS publication No, (C DC) 89-8411 Multimodality Therapy of Chest Malignancies- Update '96

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27 28

29 30 31 32 33 34 35 36

37 38 39 40 41 42

43 44

45

46 47

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2338

48 49 50

51 .52 ,53

54

55

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Multimodalit y Therapy of Chest Malignancies-Update '96