Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20 561 cases

E. Radzikowska+, P. Glaz and K. Roszkowski

III Department of Tuberculosis and Lung Diseases, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland

Received 16 July 2001; revised 22 January 2002; accepted 20 February 2002


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background:

The community-based cancer registry was set up and results were analysed to assess differences in clinicopathological parameters between women and men.

Patients and methods:

The Pulmonary Outpatient Departments supplied data on 20 561 lung cancer patients diagnosed in Poland from 1995 to 1998. Data regarding demographics, smoking, histology, treatment and survival were obtained.

Results:

There were 2875 women and 17 686 men with lung cancer. Women were younger than men (60.02 versus 62.18 years; P <0.001). Age <50 years was more frequent in women than in men (23.3% versus 12%; P <0.001). Women with small-cell lung cancer (SCLC) and adenocarcinoma were significantly younger than women with squamous cancer (58.2 and 58.2 versus 61 years; P = 0.05). Also, men with adenocarcinoma and SCLC were younger than men with squamous cancer (60.6 and 60.2 versus 62.3 years; P = 0.05). Squamous cancer was the predominant type of lung cancer both in women (32.5%) and men (55.2%). However, SCLC (26.6% versus 19.9%: P <0.001) and adenocarcinoma (21.6% versus 9.6%; P <0.001) were more frequent in women than in men. Women were more frequently non-smokers than men (18.8% versus 2.4%; P <0.001). Adenocarcinoma patients smoked less intensively than patients with squamous and SCLC both in women (31.4 versus 35.8 and 33.7 packs/year; P <0.02) and in men (38.2 versus 42 and 41.9 packs/year; P <0.002). In multivariate analysis, bad performance status, advanced stage, non-surgical treatment, age >50 years at diagnosis and male gender were significant independent negative prognostic factors.

Conclusions:

Lung cancer was six times more frequent in men than in women. Women with lung cancer were younger than men and smoked less intensively. Over-representation of adenocarcinoma and SCLC was observed in the women. Women with lung cancer had a better prognosis than men.

Key words: histology, lung cancer, prognostic factors, sex, survival


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
At the beginning of this millennium lung cancer is the most frequently diagnosed cancer in Poland and worldwide [1, 2]. During the last few years over 20 000 cases of lung cancer have been recorded in our country every year. Lung cancer incidence has been rising dramatically for several decades. However, since the beginning of the 1990s, stabilisation of the incidence of lung cancer was noted in men, but in women it is still steadily increasing. From 1963 to 1996, the standardised incidence ratio increased from 18.7 to 76.4 for men and 2.7 to 13.4 for women [3].

Many factors may influence the differences in lung cancer incidence between men and women. They may be connected with cigarette smoking, passive smoking, diet, occupation, indoor exposure and also with host factors that can protect against or facilitate the development of the cancer [46]. Several authors have also reported a more favourable prognosis of lung cancer in women than in men; this has been shown in population- and clinical-based studies [714]. However, there are no data in which elements of both forms of studies, i.e. large, un-selected population and clinical information, were included.

This paper focuses on the demographic factors (gender, age, smoking) and factors connected with disease (histology, performance status, stage, treatment and survival) in lung cancer patients.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
From 1995 to 1998, 20 561 lung cancer cases from all parts of Poland were registered with the National Tuberculosis and Lung Diseases Research Institute (NTLDRIR). This represents ~25% of all lung cancer patients diagnosed in Poland during this time and registered in Polish Cancer Register [3].

On the basis of standardised registration card, data regarding demographics, smoking, histological type of cancer, performance status according to Eastern Cooperative Oncology Group (ECOG) scale, clinical stage of the disease, treatment and survival were available. Follow-up information was recorded every 6 months. The diagnosis of lung cancer was based on positive histological or cytological examination (according to WHO criteria), or, in some patients, on clinical and radiological appearances [15]. Patients with mixed tumours, unclassified forms and large-cell lung cancer (2654 cases) were analysed in the group of the other types. Patients without histological confirmation were excluded from analyses of clinical stage, performance status, treatment and multivariate analysis of prognostic factors.

Radiological assessment was performed in all patients, and in 16 657 (81%) patients bronchoscopy was carried out. For diagnosis, transcutaneous needle biopsy of tumour was carried out in 2519 cases (12.25%), lymph nodes biopsy in 1093 patients (5.3%), biopsy of metastases in 351 cases (1.7%) and diagnostic thoracotomy in 1973 cases (9.6%). Extent of the disease was defined according to TNM (tumour–node–metastasis) criteria. Initial treatment was defined as an anticancer therapy received within 6 months of diagnosis. Survival was defined as the time between date of diagnosis and date of death or last visit. Dates of death were confirmed with the Central Address Bureau.

The comparisons of age groups as to frequency of gender, smoking, tumour histology, performance status and type of treatment were tested using the {chi}2 method and Pearson’s test. Smoking (mean values of packs/years) and age (mean values) were analysed by one-way analysis of variance. Kaplan–Meyer survival curves were used to present and analyse the survival data, and statistical differences were assessed by the log-rank test. Univariate and multivariate analysis by Cox’s proportional hazards ratio model were used to test the significance of prognostic factors including gender, age, stage, performance status and histology, and relative risks were estimated [16].


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
During the 4-year period, 20 561 lung cancer cases were registered in NTLDRIR. There were 2875 women and 17 686 men. Women developed the disease at an earlier age than men (60.02 versus 62.18 years; P <0.001). In particular, women with adenocarcinoma and small-cell lung cancer (SCLC) were younger than those with squamous cancer (58.2 and 58.2 versus 61 years; P = 0.05). Also, men with adenocarcinoma were younger than men with squamous cancer (60.6 versus 62.3 years; P = 0.05) (Table 1). Patients without histological diagnosis were older than patients with adenocarcinoma, SCLC and squamous cancer (64.79 versus 59.96, 59.85 and 62.18 years, respectively; P = 0.001). Similarly, women with no histological diagnosis were older than those with adenocarcinoma, SCLC and squamous cancer (58.2, 58.2 and 61 versus 63.05 years, respectively; P <0.05). In addition, men with no histological diagnosis were older than those with adenocarcinoma, SCLC and squamous cancer (59.96, 59.85 and 62.18 versus 65.01 years, respectively; P <0.05) (Table 1).


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Table 1.  Mean age of men and women with lung cancer according to histological type of cancer
 
Pathology
Pathological diagnosis was established for 16 719 (81.3%) patients. Squamous cancer was the predominant type of lung cancer both in men (55.2%) and women (32.5%). A significantly higher percentage of adenocarcinoma (21.6% versus 9.6%; P <0.001) and SCLC cases (26.6% versus 19.9%; P <0.001) was noticed in women than men (Table 2).


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Table 2.  Clinicopathological characteristics of lung cancer patients
 
Smoking
Most of the patients in this review were current or ex-smokers. Only 4.3% of all lung cancer patients were non-smokers. Women were more frequently non-smokers than men (18.8% versus 2.4%; P <0.001), particularly those with adenocarcinoma (26.4%) (Table 2). Men and women with squamous cancer and SCLC were much more likely to have a positive smoking history than men (98.1% and 98.5% versus 94.4%; P <0.001) and women (87.4% and 90.9% versus 73.6%; P <0.001) with adenocarcinoma (Table 3). In addition, these subjects smoked higher numbers of cigarettes and/or for a longer time (Table 4). Women smoked less intensively than men (34 versus 42 packs/years; P <0.001). Women with adenocarcinoma smoked less intensively than women with SCLC and squamous cancer (31.38 versus 33.7 and 35.84 packs/years; P = 0.02). Men with adenocarcinoma consumed fewer cigarettes than men with other histological types of lung cancer (38.2 versus 41.9 and 42 packs/years; P = 0.002) (Table 4).


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Table 3.  The number and percentage of smoking men and women according to histological type of lung cancer
 

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Table 4. Tobacco smoking of lung cancer patients according to histological type of lung cancer
 
Performance status
The majority of patients had a good performance status (0/1 on the ECOG scale; 57.4%). About 11.8% of patients had poor performance status (3/4 on the ECOG scale). There were no differences in performance status between men and women (Table 2).

Clinical stage of the disease
Data regarding clinical stage of cancer were available for 15 212 patients (91%) with histological diagnosis. Stage I cancer was recorded in a similar proportion in men as in women (27.1%). Distant metastases were observed in 1893 cases (14.8%). A significantly higher percentage of women than men with disseminated diseases was observed (20.3% versus 13.9%; P <0.001). However, the opposite situation was noticed for men and women with stage II (12.2% versus 15.2%; P = 0.03) and III (40.5% versus 43.9%; P = 0.03) disease, where a higher percentage of men than women was observed (Table 2).

Initial therapy
The NTLDRI registry includes information on treatment received within 6 months after the initial diagnosis. However, these data were not comprehensive for all therapy that patients received during the course of the disease. Sufficient data considering therapy was obtained for 12 378 patients (74%) with histological diagnosis. Significantly more women than men were treated with surgery (23.2% versus 18.8%; P <0.0001); also, a higher percentage of women were treated by surgery in combination with chemotherapy and radiotherapy (7.3% versus 5.5%; P <0.003).

Chemotherapy was administered to 29.9% of women and 28.2% of men, and radiotherapy to 14.5% of women and 14.6% of men. Over-representation of men in the groups treated symptomatically (27.9% versus 22%; P <0.0001) and refusing therapy (5% versus 3.1%; P = 0.0005) was observed (Table 5).


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Table 5. Treatment of lung cancer patients
 
Prognostic factors
Univariate analysis of absolute survival revealed that gender [relative risk of death (RR) 1.21], age (RR = 1.19), histology (squamous RR = 1.09, SCLC RR = 1.36, other RR = 1.2), performance status (ECOG 2 RR = 1.63, ECOG 3/4 RR = 2.67), clinical stage (II RR = 1.45, III RR = 1.86, IV RR = 2.73) and type of treatment (non-surgical treatment RR = 3.03) were significant prognostic factors (Table 6).


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Table 6.  Univariate analysis of relative risk of death
 
Results of a multivariate analysis of absolute survival using these variables are presented in Table 7. The RR was significantly higher for men (RR = 1.15), patients >50 years of age (RR = 1.18) and those treated non-surgically (RR = 2.96). SCLC histology (RR = 1.42), poor performance status (ECOG 3/4) (RR = 2.58), and clinical stage II (RR = 1.4), III (RR = 1.86) and IV (RR = 2.71) were independent negative predictors of survival.


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Table 7.  Multivariate analysis of relative risk of death adjusted to age, gender, histological type of lung cancer, performance status and stage of the disease (n = 11 479 patients)
 
When curves of absolute survival were analysed, females had better prognosis than males (Figure 1).



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Figure 1. Overall survival of lung cancer patients with relation to gender.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The occurrence of lung cancer varies between countries [1, 2]. Lung cancer incidence in Poland is one of the highest in the world. Although the proportion of females to males is increasing in our cancer population, it is still lower than in other countries [3].

Age is the major determinant of cancer risk. The peak of incidence was noted in the cohort of patients aged 60–69 years. In our population, the highest percentage of patients was in this group. Nevertheless, the median age of Polish patients is lower than that reported in other countries [13, 17]. Women were younger than men. This was observed for women and men when histological type was taken into account. In particular, adenocarcinoma was diagnosed in younger age both in women and in men. This relationship has been reported previously [10, 14, 17, 18].

Women were found to be more likely to have adenocarcinoma and SCLC than men. Squamous cancer was the predominant type of lung cancer among men, and <10% of them had adenocarcinoma. Different patterns of histological types of lung cancer were observed in Poland in comparison with the USA, China or Denmark, where over-representation of adenocarcinoma has been noted [17, 19, 20]. The distribution of main histological types of lung cancer in Poland was similar to that described in Finland and Scotland [2, 21, 22].

Smoking is associated with all types of lung cancer, with a dose–response relationship. The majority of men and women in our review had a history of smoking, but significantly more women than men were non-smokers (24.5% versus 3.6%), particularly those with adenocarcinoma. The connection between smoking and lung cancer was most evident among patients with squamous and SCLC, and weaker for adenocarcinoma. There are some studies indicating that duration of smoking is more important influence on histological type of cancer than number of cigarettes smoked [5, 23]. Both men and women with squamous cancer in our study smoked more intensively than patients with other histological types of cancer. Ferguson et al. [10] and McDuffie et al. [18] obtained similar results.

Women developed lung cancer at a younger age, were more likely to be lifetime non-smokers, consumed fewer cigarettes per day and smoked for a short period of time. All those factors suggested that women are more susceptible to carcinogenic compounds of cigarette smoke and environmental noxious conditions due to genetic background [4, 2426]. Recently, it was shown that gene for gastrin-releasing peptide receptor (GRPR) was located on chromosome X [27]. The activation of this receptor has been associated with proliferative response of bronchial cells. It has been suggested that GRPR gene was expressed more frequently in women than in men in the absence of smoking, and that expression of this gene was activated earlier in women in response to tobacco smoke. Another explanation of this phenomenon may be connected with hormonal status. Estrogen replacement therapy, as well as short menstrual cycle and late menopause, have been reported to increase the risk for adenocarcinoma in women [28]. The majority of women diagnosed with lung cancer are postmenopausal; however, in this study adenocarcinoma patients were younger than patients with other histological types of lung cancer. The role of estrogen receptors in development and proliferation of lung cancer cells is not known, and conflicting results have been presented. Sex hormones influence the development of fetal lung, but lung is not a target organ for sex hormones during adulthood [28, 29]. The potential role of sex hormones in the development of lung cancer is obscure, and more data are needed to establish it.

The most important prognostic factors for lung cancer patients were performance status, clinical stage of the disease and surgical treatment. The significant role of these factors has been underlined in many clinical- and population-based studies, and also in the data presented here [14, 30].

In our material, females with lung cancer had a survival benefit compared with males, taking into account age, histology, performance status, extension of the disease and treatment. This overall survival advantage of women was described first in data based on Danish Register information, and recently by Ramalingam et al. [14] from a population-based study, and also by others [17, 3134]. Ederer and Merheimer [8], Minami et al. [31], Mark et al. [35], and Inoue et al. [36] found female gender to be a good prognostic factor for patients treated by surgery. However, Bingal and Martin [37], and Kirsh et al. [38] reported opposite results. Also, in our previous data on a smaller population of patients, female gender was found to be an independent significant positive prognostic factor [13].

Further studies are needed to elucidate all problems connected with sex-associated differences in clinico-pathological characteristics and survival of lung cancer patients.


    Acknowledgements
 
We are grateful to Professor Ewa Rowiáska-Zakrzewska for helpful discussion and Dr Mariusz Chabowski for editorial assistance. The authors acknowledge the enormous work of the chest physicians from all parts of Poland. This work was supported by the National Tuberculosis and Chest Diseases Research Institute (grant no. 3).


    Footnotes
 
+ Correspondence to: Dr E. Radzikowksa, III Department of Tuberculosis and Lung Diseases, National Tuberculosis and Lung Diseases Research Institute, Warsaw 01-138, Pßocka 26 St., Poland. Tel: +48-22-6912229; Fax: +48-22-6912408; E-mail: e.radzikowska@igichp.edu.pl Back


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