Lung cancer in women compared with men: stage, treatment, and survival

Lung Cancer in Women Compared With Men: Stage, Treatment, and Survival Denise Ouellette, MD, Genevie`ve Desbiens, MD, Claude Emond, MsC, and Gilles Beauchamp, MD Thoracic Surgery, Department of Surgery, Hoˆpital Maisonneuve-Rosemont, University of Montreal, Montreal, Canada

Background. In cardiac disease there appears to be a difference in the treatment of men and women, and thus an advantage in survival in men. This study aimed to determine whether these differences exist in lung cancer. Methods. We undertook a retrospective cohort study in a university hospital. The study population consisted of 104 consecutive women and 104 consecutive men with newly diagnosed lung cancer between March 1988 and June 1990. The following information was collected: sex, age, presenting symptoms, investigations, histology, stage, treatment, and survival. Results. The location of the tumor, presenting symptoms, investigations, and stages were similar in men and

women. There was a difference in the distribution of the various histologic types of lung cancer: Small cell lung cancer was more frequent in women (25% versus 11.5% in men) and squamous cell carcinoma more frequent in men (38% in women versus 51% in men). The overall survival was similar among the two sexes, but there was a survival advantage in women when adjusted for stage. Conclusions. There was a higher incidence of small cell carcinoma in women and squamous cell carcinoma in men. There was evidence of a difference in the survival rate of lung cancer in favor of women according to stage. (Ann Thorac Surg 1998;66:1140 – 4) © 1998 by The Society of Thoracic Surgeons

T

Material and Methods

here has been a drastic increase of lung cancer in women in the past two decades. Currently, death from lung cancer has superseded breast cancer in women. In 1995 in Canada, there were 20,000 new cases of lung cancer, 36.1% among women [1]. Lung cancer appears to be related to the high rate of smoking in women, who lag behind men in smoking cessation. Between 1960 and 1994 there was an almost 50% reduction in smoking among men, but barely 25% of women have done the same [2]. In fact, the smoking-attribute mortality (SAM) has been stable in men since 1985 but continues to increase in women [3]. In the English literature, there are very few articles comparing pathologies between men and women. Recently, however, several articles were published regarding coronary artery disease in men and women. Some authors found a significant sex-related diagnosis and treatment bias [4, 5], while others did not [6 – 8]. This incited us to evaluate whether men benefited from a more extensive investigation and a more aggressive treatment in lung cancer compared with women. We thus postulated the hypothesis of a survival difference among men and women with lung cancer. We also compared the histology and stage among the two sexes.

Accepted for publication April 10, 1998. Address reprint requests to Dr Ouellette, Hoˆpital MaisonneuveRosemont, 5415 boul de l’Assomption, Montre´al, Que´bec H1T2M4, Canada.

© 1998 by The Society of Thoracic Surgeons Published by Elsevier Science Inc

To avoid any bias related to the study goal (comparing lung cancer in men and women), a retrospective study was performed. The study population consisted of 104 consecutive women and 104 men with newly diagnosed lung cancer between the period of March 1988 and June 1990 at a university hospital. The charts were reviewed and the following information was collected by an independent observer: demography (sex, age at diagnosis, site of cancer, histology, stage, presenting symptoms, and investigations), treatment (type of surgical resection, radiotherapy, chemotherapy, or no treatment) and survival. All histology slides were read by a single pathologist who had a special interest in lung pathologies. For the patients who were operated on at our hospital but were followed up at another institution, permission was obtained to review their charts. If the survival status was unclear from the chart, the primary physician or the patient’s family was contacted to verify whether the patient was alive (including date of death to calculate the survival). Statistical analysis was performed with SPSS software for MS Windows 6.1 (Microsoft Corp., Redmond, WA). Comparison between the two groups was obtained by x2 analyses and Pearson’s test and Fisher’s exact two-tailed tests where necessary. To test the hypothesis of survival difference among men and women with lung cancer, survival analysis using BMDP Statistical Software for Cox Proportional Hazards Regression model was performed. A p less than 0.05 was considered statistically significant. 0003-4975/98/$19.00 PII S0003-4975(98)00557-8

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Table 1. Histologic Distributiona Sex

Adenocarcinoma

Squamous Cell Carcinoma

Large Cell Carcinoma

Poorly Differentiated Carcinoma

Non–Small Cell Carcinoma

Small Cell Carcinoma

33 (32%) 32 (31%)

33 (32%) 53 (51%)

3 (2%) 2 (2%)

1 (1%) 2 (2%)

7 (7%) 3 (3%)

27 (25%) 12 (12%)

Women Men a

p 5 0.028.

Results The study population consisted of 208 patients (104 women and 104 men). There was no difference in mean age for female and male patients: 60.97 6 10.89 and 61.49 6 10.29 years, respectively. There was a difference in the distribution of the different histologic types of lung cancer between men and women which was statistically different (p 5 0.028) (Table 1). Small cell carcinoma of the lung was found more frequently in women (25% in women versus 11.5% in men). Among the non–small cell lung cancer cases, squamous cell carcinoma occurred more frequently in men (38% in women versus 51% in men). The distribution of the lesions among the five lobes of the lung was similar (p 5 0.475) (Table 2). There was also one tumor in the left main bronchus in one woman and one not specified in another. Men and women were distributed between the various stages in a similar manner when patients with SCC were excluded (p 5 0.256) (Table 3). The three most frequent presenting symptoms in women, in decreasing order, were pain, cough, and dyspnea, while in men they were pain, hemoptysis, and cough. In 12 women and 18 men the lesion was an incidental finding on a routine chest roentogenogram. There was no significant difference in the overall presentation. There were no differences in the type of investigation that men and women underwent. These included chest roentogenograms, chest computed tomographic scan, bone scan, pulmonary function test, abdominal ultrasound, liver function test, bronchoscopy, mediastinoscopy, and percutaneous lung biopsy. One exception was noted— computed tomographic scan of the brain was more frequent in women (37 women versus 22 men). A total of 29 women and 34 men underwent some form of pulmonary resection, for a ratio of 1.0:1.17. The type of surgery was similar with the exception that more pneumonectomies and wedge resections were performed in men (Table 4). A total of 60 and 70 men received radiotherapy as either single treatment or adjuvant treatment. However, 24 women received chemotherapy compared

with 14 men, although this was not statistically significant. Seven women and two men refused treatment. At the time of analysis, there were 17 women and 16 men alive; 87 women and 88 men were dead. There was no statistical difference between the two sexes. The overall survival for both men and women who were dead at time of analysis was a mean of 12 months (median, 8 months), whereas the survival for those still alive was a mean of 74 months (median, 72 months). The overall mean survival for women was 24 months, and for men, 18 months, showing no statistical difference (p 5 0.41) (Table 5; Figure 1). To assess whether the stage of the disease influenced survival among these two groups, survival was reanalyzed adjusting for stage with the Cox proportional hazards regression model (stages I, II, IIIa, IIIb, and IV). A significant survival advantage in women was found (p 5 0.02). Women appeared to live 12 months longer than men at any stage (Table 6).

Comment In the keynote address at the National conference on Gynecologic Cancers in Orlando in spring 1992, Ho [9] stated that lung cancer had replaced uterine cancer among the cancers causing the highest mortality in women. Indeed there was a 500% increase mortality caused by lung cancer in women between 1950 and 1985 [10]. Ho also noted that breast cancer remains the leading cause of death. This was no longer true by 1997, as lung cancer had superseded breast cancer as the leading cause of death in women in the United States [10]. The correlation between smoking and lung cancer has held since the initial epidemiologic study by Doll and Hill in 1951 [11]. Several other researchers have obtained similar results [12, 13]. Zang and Wynder [14] developed a new index estimating lung cancer risk, cumulative tar exposure (formula 5 No. of cigarettes 3 Tar concentration 3 Duration of exposure) [14]. There was a steep, near-linear dose response. The odds ratios for lung cancer in women were consistently higher than those in men with the same exposure to tar, particularly among long-term smokers who smoked heavily. Zang and

Table 2. Site of Tumor Distributiona Gender

Right Upper Lobe

Right Middle Lobe

Right Lower Lobe

Left Upper Lope

Left Lower Lobe

Women Men

44 44

8 5

15 12

24 35

11 8

a

Overall p 5 0.475.

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Ann Thorac Surg 1998;66:1140 – 4

Table 3. Staging Distributiona

Table 5. Survival of Men and Women (%)a

Gender

I

II

IIIa

IIIb

IV

Year

Women Men

25 26

2 6

20 34

6 7

25 19

1 2 3 5

a

Overall p 5 0.256.

a

Wynder considered that potential explanations for this sex-related difference may include hormonal, reproductive, and dietary differences. Few articles in the English-language literature compare various aspects of lung cancer between men and women. Andrews and colleagues [15] at the Lahey Clinic noted that the ratio of women to men treated for lung cancer increased dramatically from 1:6.8 between 1957 and 1960 to 1:1.8 between 1977 and 1980. Andrews and associates [15] also found that adenocarcinoma comprised the largest group of lung tumors (38%) in women, followed by squamous cell (20%), large cell carcinoma (15%), and small cell carcinoma (13%). In our review, we found similar incidences of adenocarcinoma (31.7%) and squamous cell carcinoma (31.7%) in women, but small cell carcinoma was more frequent and represented 25% of lung tumors in women. In 1990, El-Torky and el-Zeky [16] noticed a significant proportion of small cell carcinoma in women (30%), comparable to our results and thus representing the second most frequent histologic type after adenocarcinoma (40%), whereas squamous cell carcinoma accounted for 23% of cases. Their study demonstrated that in men, squamous cell carcinoma remains the most frequent lung cancer (37%) (51% in our study), despite its declining incidence over the years, followed by adenocarcinoma (27%). The changes in incidence in the histologic types may reflect advances in methods of tumor diagnosis with immunohistochemistry since the 1980s. In our study the mode of presentation varied slightly between men and women. Men sought medical attention more frequently for chest pain, hemoptysis, and cough. As shown in studies of coronary artery disease, men are more often taken seriously when complaining of chest pain, whether of cardiac or pulmonary cause. This may influence the type of investigation and treatment offered to both sexes. We did not find disparity in the extent of investigations of men and women, with one exception. Women had cerebral computed tomographic scans more frequently than did men. This may reflect the fact that women have a higher incidence of adenocarcinoma than men, and that histologic type has a higher propensity to metastasize to the brain.

Women

Men

Both

44.6 27.1 23.3 17.4

39.2 21.5 14.7 11.7

42.4 24.8 19.5 13.6

There are no statistical differences.

Men and women received similar treatments for their disease in our study. A total of 29 women and 34 men had some form of surgical resection. This differs from studies on coronary artery disease in which it was thought that physicians may pursue less aggressive management in women [5]. It is interesting that more women than men refused treatment (7 women versus 2 men). Does this finding suggest that the women are older and tend to accept their ill fate? It does not appear so: The 2 men who refused treatment were 61 and 60 years old, whereas the mean age of the 7 women who refused treatment was 65 years (median, 71 years; range 45 to 74 years). All patients refusing treatment had advanced disease either stage IV non–small cell carcinoma or extended small cell carcinoma for which treatment has little to offer. Aitakov and coworkers [17] noted that more men in Russia underwent surgery with a ratio of men to women 7.4:1.0. We did not find such a disparity; our ratio was 1.17:1.0 men to women, and probably reflects the tendency to offer similar treatments to both sexes in the Western world. Many studies analyze the survival rate of lung cancer according to stage or treatment modality in both sexes combined. However, few articles compare survival between men and women. Johnson and associates [18] found a survival advantage in women over men with small cell carcinoma lung cancer treated with chemotherapy (median survival, 13 months for women versus 10 months for men). Our overall (all stages considered) 5-year survival for men and women combined was 13.6%. When analyzed separately, the 5-year survival for women was 17.4%, and for men, 11.7%, which was not statistically significant (Table 5). When adjusted for stage, however, we found a statistically significant difference in survival in favor of women (Table 6). In conclusion, in this study we intended to verify the hypothesis that there is a difference in survival among men and women. If this were true, could it be related to early diagnosis and more aggressive treatment favoring men, as in coronary artery disease? Although they may have slightly different presenting symptoms, men and

Table 4. Type of Surgical Resectiona Sex

Exploration Alone

Wedge Resection

Lobectomy

Bilobectomy

Lobectomy With Chest Wall Resection

Pneumonectomy

7 7

1 6

14 11

3 3

3 0

1 7

Women Men a

Overall p 5 0.071.

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When adjusting these two groups with a coefficient according to stage, there is a survival advantage in women, and they seem to live 12 months longer than men. This may be related to an intrinsic factor such as hormones.

References

Fig 1. Survival curve comparing men and women.

women are investigated in a similar manner and have same treatment according to the stage of their disease. There was no overall survival difference between men and women from a statistical standpoint, but there appears to be a clinical advantage in women, as they survive a mean of 24 months versus 18 months in men. Table 6. Survival Estimate (%) According to Gender and Stage Year Sex Women

Men

Stage

1

2

3

4

5

I II IIIa IIIb IV Small cell carcinoma I II IIIa IIIb IV Small cell carcinoma

81.6 84.3 48.9 40 9.7 51.6 66.1 78.2 35.5 26.5 3.4 38.3

75.2 72.5 26 17.7 1.2 28.6 45.8 62.9 14.2 8.2 0.17 16.4

58.4 68.8 20.8 13.4 0.6 23.3 40.3 58.3 10.3 5.4 0.06 12.2

53.4 63.9 15.3 9 0.22 17.5 33.7 52.4 6.6 3 0.01 8

47.2 63.1 14.5 8.4 0.18 16.7 32.7 51.5 6.1 2.8 0.01 7.5

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INVITED COMMENTARY This analysis of 208 patients contributes to a large literature of prognostic factors and the role of female sex in lung cancer outcome. These previous reports emphasized the importance of a sufficient sample size, the © 1998 by The Society of Thoracic Surgeons Published by Elsevier Science Inc

number of predictive factors studied, and use of multivariate models. The most important predictors of favorable survival were stage of disease (separately within small cell and non–small cell), performance status, serum 0003-4975/98/$19.00 PII S0003-4975(98)00932-1