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Ann Thorac Surg 2000;69:245-249
© 2000 The Society of Thoracic Surgeons

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Original Articles

Sex-associated differences in survival of patients undergoing resection for lung cancer

^a Department of Surgery, The University of Chicago, Chicago, Illinois, USA
^b Department of Medicine, The University of Chicago, Chicago, Illinois, USA
^c Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois, USA

Address reprint requests to Dr Ferguson, Department of Surgery, The University of Chicago, 5841 S Maryland Ave, MC 5035, Chicago, IL 60637
e-mail: mferguso{at}surgery.bsd.uchicago.edu

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. The increasing incidence of lung cancer among women prompted us to assess whether sex-associated differences exist in the presentation and survival of patients who undergo major lung resection for lung cancer.

Methods. We performed a retrospective review of patients who had major lung resection for lung cancer from January 1980 to June 1998.

Results. There were 265 men and 186 women. Women were younger (60.7 ± 0.8 versus 63.6 ± 0.6 years; p = 0.005). Adenocarcinoma was more common among women (48% versus 40%; p = 0.001). Pathologic stages for men were: I = 43%, II = 26%, IIIA = 25%, IIIB or IV = 6%, and for women: I = 52%, II = 20%, IIIA = 22%, IIIB or IV = 6% (p = 0.146). Median survival was better for women (41.8 versus 26.9 months; p = 0.006). This was due both to a difference in stage at presentation and to a better median survival rate for adenocarcinoma compared with squamous cell cancer. The data suggest an association between sex and survival, although this failed to reach statistical significance. Sex influenced survival with a relative risk for women of 0.67 (95% confidence interval 0.35 to 1.29; p = 0.231 adjusted for stage, cell type, age, and spirometry).

Conclusions. There are sex-associated differences in the presentation and possibly in the survival of patients with lung cancer. This finding has possible implications regarding the selection of patients for therapy and for the design of randomized therapeutic trials.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
The incidence of lung cancer in women has increased more than threefold during the past 3 decades, surpassing breast cancer as the leading cause of cancer mortality in women in the United States [1]. In recent years, much attention has been focused on this sharply rising incidence of lung cancer among women [2–5]. Most investigations have concentrated on survival data comparing men and women in the total lung cancer population, on differing incidences of cigarette smoking in women compared to men, on gender differences in cell type distribution, and on sex-associated differences in age at diagnosis. Patients with surgically treatable lung cancer are an important subgroup of lung cancer patients because they constitute the most favorable class with respect to long-term survival. Randomized therapeutic trials involving such patients are common, and trials aimed at preventing the development of new cancers recently have opened. However, information on sex-associated differences in surgically treatable patients is scant. This study describes a retrospective analysis of sex-associated differences in the presentation and survival of patients who have undergone major lung resection for lung cancer.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
We retrospectively reviewed patients with an initial primary lung cancer who underwent major lung resection (lobectomy, bilobectomy, or pneumonectomy) at The University of Chicago Hospitals from January 1980 to June 1998. All patients were evaluated with a history and physical examination, posteroanterior and lateral chest radiographs, and blood tests including a complete blood count and serum chemistries. Computed tomographic (CT) scans of the chest and upper abdomen (including the liver and adrenal glands) were performed routinely since 1983. Bone scintigrams and brain CT scans were performed in cases of bone pain, neurologic symptoms or signs, and in all patients with T3 primary tumors or with stage IIIA or more advanced cancers. Pulmonary function tests were performed routinely. Quantitative pulmonary ventilation and perfusion scans and measurements of maximum oxygen consumption during exercise were carried out in patients with marginal pulmonary function. All patients had a preoperative or intraoperative bronchoscopic examination. Cervical mediastinoscopy or parasternal mediastinotomy were routinely performed in patients with abnormal mediastinal lymph nodes on CT scan and in patients with suspected T3 disease, and were used in other selected patients.

All patients were treated according to the prevailing protocols at the time of presentation. Patients with clinical stage I and stage II non-small cell lung cancers underwent thoracotomy and lung resection directly, the latter group sometimes receiving postoperative radiotherapy and chemotherapy. Some patients with stage IIIA or IIIB lung cancer, so classified on the basis of T3/T4 or N2 disease, were treated with preoperative radiation therapy and chemotherapy in conjunction with lung resection. Other patients with stage IIB lung cancer, based on the presence of a T3 primary lung cancer without apparent lymph node enlargement, were initially treated by surgical resection. Patients with N2 disease discovered at operation had postoperative adjuvant chemotherapy and radiotherapy. All patients were staged at a weekly multidisciplinary chest oncology conference, based on the final pathologic diagnosis, and all have subsequently been staged using the current American Joint Committee on Cancer (AJCC) staging system [6].

Follow-up was performed in the majority of patients through periodic clinic visits until the present time or patient’s death. In other patients, annual contact with the treating physician or the patient was performed through our institutional cancer registry. Follow-up was complete until death or within 1 year of analysis in survivors in 419 of 451 patients (92.9%). Operative mortality was defined as death from any cause during hospitalization for lung resection or within 30 days of operation.

Patients were evaluated for age, tobacco use, tumor stage, operation, year of operation, and histology. The distributions of these variables were compared between men and women and between cell types (comparing squamous cell and adenocarcinoma only) using the ² test for discrete variables and Student’s t-test for continuous variables (Minitab 12.0; Minitab, Inc, State College, PA). Survival was measured from the date of operation, and median survival rates were calculated according to the Kaplan-Meier method [7]. Differences in survival rates between groups were tested for significance using the log-rank test [8]. A Cox proportional hazards analysis of survival was performed using selected covariates with stratification by stage [9]. All survival comparisons and analyses were performed using Systat 8.0 (SPSS, Inc, Chicago, IL). Data are expressed as mean ± standard error of the mean and differences were considered statistically significant when the p value was less than 0.05.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Major lung resections were performed in 451 patients with lung cancer. There were 265 men and 186 women with a mean age of 62.4 ± 0.5 years (range 35 to 87 years). Women were younger than men (Table 1). Ninety-five percent of the patients had a current or prior smoking history, and men were more likely than women to be current or prior tobacco smokers. The forced expiratory volume in 1 second expressed as a percent of predicted (FEV₁%) was higher in women than in men, but there was no significant difference between men and women in the diffusing capacity for carbon monoxide expressed as a percent of predicted (DLCO%). The distribution of operations performed on men and women was similar. The operative mortality rate was 8.6% overall (7% for lobectomy and bilobectomy, 15% for pneumonectomy). There was no significant difference between men and women, and operative mortality was not affected by pathologic stage or year of operation. The postoperative length of stay was similar between the two groups.

View larger version (22K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curves according to stage for patients who underwent major lung resection for lung cancer. Vertical hatch marks represent censored data points. Error bars represent 95% confidence intervals.

View larger version (21K): [in this window] [in a new window]   Fig 2. Kaplan-Meier survival curves for all stages combined for men and women who underwent major lung resection for lung cancer. Vertical hatch marks represent censored data points. Error bars represent 95% confidence intervals. Numbers at bottom indicate patients available for evaluation at each time point. (M = men; W = women.)

View larger version (18K): [in this window] [in a new window]   Fig 3. Kaplan-Meier survival curves according to stage (A, Stage I; B, Stage II; and C, Stage III) for men and women who underwent major lung resection for lung cancer. Vertical hatch marks represent censored data points. Error bars represent 95% confidence intervals. Numbers at bottom indicate patients available for evaluation at each time point. (M = men; W = women.)

	Comment

Top Abstract Introduction Patients and methods Results Comment References

The differences in clinical characteristics between men and women in this review, including age, cell type distribution, and tumor stage, are similar to our previously reported findings and those of others [2, 4]. The incidence of cigarette smoking among women in the current study, 90%, is somewhat higher than in our previous publication of 84% and is higher than that in the series reported by Mitsudomi and colleagues, 75% [10]. This reflects a possible increase in tobacco usage among women over time. The spirometric measurements of women in this group were significantly better than those of men, which is likely due in part to the fact that the mean age and percentage of smoking for women were significantly less than for men. Interestingly, however, there was no apparent difference between men and women in DLCO%, which has been shown to be an important independent predictor of morbidity and mortality after major lung resection for lung cancer [11]. The reasons for this discrepancy are unclear. There were no significant differences in types of operations or mortality rates between men and women in this study, which makes the survival analyses comparing men and women valid. The overall operative mortality rate of 8.6% in this series is similar to rates reported by others [12, 13].

Our finding that patients with adenocarcinoma had a better overall survival than did patients with squamous cell cancer is supported by some authors [10, 14]. In contrast, other reports about the influence of cell type on long-term survival suggest that squamous cell histology provides a relative survival advantage compared to other cell types. The reasons for this discrepancy are uncertain. In some reports all nonsquamous histologies are grouped together for purposes of statistical comparison, which may select out poorly differentiated squamous cell cancers that are lumped with the nonsquamous cell cancer group [15, 16]. It is known that a high degree of differentiation provides a relative survival advantage [13, 17]. However, in other reports direct comparisons between squamous cell cancers and adenocarcinomas suggest either no difference in survival between the groups [17–19] or a survival advantage for squamous cell histology [20, 21]. Additional data are required before these discrepancies can be clarified.

An overall survival advantage for females compared to males with non-small cell lung cancer has been observed previously [2, 4]. In patients with unresectable non-small cell lung cancer who were treated with chemotherapy, the survival rate of women is greater than that of men [22, 23]. A survival advantage for women has also been reported for patients who have undergone resection for lung cancer, which our current study corroborates [13, 14, 21, 24, 25]. The reasons for the possible superior survival of women with lung cancer are not completely understood. Some reports indicate that non-small cell lung cancers have an abundance of estrogen receptors, suggesting that they may be under hormonal control [26]. In addition, the presence of an allele loss that occurs more frequently in men and is associated with decreased survival has recently been reported [27]. These and other factors, including physiologic variables and the cause of long-term mortality, require further investigation as possible explanations for the better long-term survival we observed among women with lung cancer.

This retrospective review has potential weaknesses due to the length of time over which data were collected for analysis. The natural evolution of patient presentation, selection, and treatment, both surgical and nonsurgical, may have had some influence on our results. Nevertheless, our findings have possible implications regarding the selection of patients for operation and postoperative adjuvant therapy, and for the design of randomized therapeutic trials. Extrapolation of results based primarily on data from men with lung cancer may underestimate the long-term survival of women and the impact of therapy recommended for them. Further investigation into sex-associated differences in the presentation and survival of lung cancer patients is warranted.

	Acknowledgments

 
The authors gratefully acknowledge the help of Theodore Karrison, PhD, for reviewing the statistical analyses.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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