Female Patients with Small Cell Lung Cancer Have Better Survival than Males with Extensive but Not Limited Disease

Although the effect of the patient’s sex on the course of the disease and treatment results in clinical medicine practice is well established in some areas, its value in oncology practice is far from being fully determined [1]. The differential effects of sex on tumor biology, immune system and immune reactions, body composition, and anticancer drug pharmacology may also manifest themselves in the epidemiology, biology, and treatment outcomes of various cancers such as melanoma, gastrointestinal cancers, and lymphoma [1]. Therefore, sex differences in cancer biology and treatment require further research and attention.

The role of sex has not been fully demonstrated in patients with small cell lung cancer (SCLC) that constitutes approximately 15% of lung cancer cases, which is still an important public problem even though its frequency has decreased and favorable outcomes have been obtained with today’s novel treatments. Sex distribution varies according to time, geography, development level, and race, and the studies are far from showing a consensus in terms of survival [2‒14]. In this retrospective study, we aimed to question the clinical significance of sex in patients diagnosed with SCLC.

A total of 378 pathologically confirmed SCLC patients were assessed retrospectively. They were evaluated, treated, and followed up at the oncology clinics from 2013 to 2021.

To stage the disease, patients were divided into two groups by using the VA Lung Study Group’s two-stage classification: limited disease (LD-SCLC) and extended disease (ED-SCLC). Patients were treated with a variety of therapeutic approaches, including surgery, radiotherapy, and platinum-based chemotherapy regimens, and followed up according to standard international guidelines, most notably the European Society of Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) guidelines. Patients were treated with platinum-etoposide-based chemotherapy regimens in the form of cisplatin or carboplatin/etoposide. Patients with LD-SCLC received thoracic radiotherapy, which was started together with the 2nd cycle of chemotherapy. Chemotherapy responsiveness was assessed by radiological examinations of patients who received four cycles of chemotherapy. The patient-related medical records were provided from the cancer registry to investigate the clinical characteristics and survivals of the patients.

χ² tests were performed to determine the effect of clinical parameters on the sex of the patients. Patient survival rates were determined by Kaplan-Meier analysis. Univariate and multivariate analyses were performed using Cox proportional hazards models. Multivariate analysis was evaluated by including prognostic factors that were significant in univariate analysis. A p value ≤0.05 was considered statistically significant. SPSS 21.0 software version was used for general statistical analyses.

The median and age ranges of all men and women at diagnosis were 61 (40–79) and 63 (41–90) years, respectively. While 61 (16.1%) of a total of 378 SCLC patients were women, 26 (19.8%) of a total of 131 LD-SCLC patients, and 35 (14.2%) of 247 ED-SCLC patients were female (Table 1).

In all SCLC patients, regardless of stage, female patients were more likely to be nonsmokers (7.7 vs. 1%, p = 0.04 for LD-SCLC; and 11.4 vs. 1.4%, p = 0.001 for ED-SCLC) and more often to be anemic (26.9 vs. 11.4%, p = 0.04 for LD-SCLC; and 45.7 vs. 28%, p = 0.03 for ED-SCLC) (Table 1). While women with LD-SCLC were diagnosed younger (<60) than men (65.4 vs. 37.1%, p = 0.009), they had larger (>5 cm) tumor diameters (69.2 vs. 42.9%, p = 0.01) (Table 1). In addition, obesity (77.1 vs. 56.4%, p = 0.02) and less weight loss (88.6 vs. 73.6%, p = 0.04) were more common in women with ED-SCLC than in men. However, there were no associations between sex and significant prognostic factors, such as performance status, metastasis site, serum LDH level, response to chemotherapy, and disease recurrence.

Overall survival rates in LD-SCLC patients were found to be similar between sexes; the 1-year, 5-year, and median overall survival rates in women compared to men were 80 versus 68.2%, 5.7% versus 8.8%, and 18 versus 15 months, respectively (p = 0.8) (Fig. 1). On the other hand, female patients diagnosed with ED-SCLC had better survival rates; 1-year overall survivals were 42.8 versus 22.8%, and median overall survivals were 10 versus 7 months, p = 0.008) (Fig. 2).

Univariate analysis showing the effects of various clinical variables on survival is shown in Table 2. The significant survival advantage of female ED-SCLC patients in the univariate analysis was maintained also in the multivariate analysis (p = 0.001) (Table 3).

The incidence of SCLC has significantly decreased over the years [2‒5]. A total of 52,527 patients diagnosed with SCLC between 1989 and 2020 that were selected from the population-based Netherlands Cancer Registry showed that the incidence of SCLC has significantly decreased over the last 30 years from 15.1 to 9.93 per 100,000 person-years [2]. Similarly, a retrospective cohort study using data from the National Taiwan Cancer Registry concluded that the percentage of patients with SCLC decreased from 9.3% in 2009 to 6.3% in 2018 [3]. On the other hand, a Chinese study showed that the proportion of population-based new SCLC cases displayed a significantly increasing trend for both sexes from 2010 to 2015, 7.6–10.2% for males and 6.4–8.9% for females [6]. Similarly, the proportion of hospital-based new SCLC cases also simultaneously increased for both sexes from 2008 to 2017, 11.9–17.1% and 10.8–11.6% in males and females, retrospectively [6].

During the last decades, although the incidence of SCLC has been declining, the incidence of SCLC in females has been increasing [4, 5, 7]. In a study of 18,234 SCLC patients from the SEER database, the ratio of female patients (50.2%) was slightly higher than male patients [4]. In another study using the SEER data registry from the NCI, the ratio of men to women decreased from 2.69:1 in 1973 to 1:1 in 2010 [5]. Additionally, a total of 52,527 patients diagnosed with SCLC between 1989 and 2020 were selected from the population-based Netherlands Cancer Registry with an increasing proportion of women from 22% to 50% [2].

Of our patients, 16.1% were women, and limited-stage disease was more frequent in our female patients (19.9 vs. 14.2%). Similarly, Eskandar et al. [5] observed that women presented with the limited-stage disease more often than men (26.28 vs. 20.75%, respectively; p < 0.0001). In the Thoracic Tumor Registry sponsored by the Spanish Lung Cancer Group, women comprised 24.8% of the total 424 patients included in this study [8]. In a Swedish study, women constituted 39.5 percent of a total of 266 SCLC patients [9]. Likewise, in a UK study, 44% were women of 1,707 SCLC patients [10]. On the other hand, a Korean study (n = 591) found a value close to our frequency rates (14.9%) [7].

Because SCLC is correlated with smoking, investigators have assumed that its frequency rates increase progressively with the proportion of female smokers [7]. The most likely reason for this decrease in SCLC cases can be considered as the significant decrease in smoking in men, although there was a slight increase in smoking in women [2]. While cigarette consumption has decreased in men over the years, there is an opposite increase in women. Women, who are more exposed to tobacco, have a higher risk of developing SCLC than men, and the female/male disease ratio gradually increases.

In all our SCLC patients, regardless of stage, female patients were more likely to be nonsmokers and more often to be anemic. While women with LD-SCLC were diagnosed younger (<60) than men, they had larger (>5 cm) tumor diameter. In addition, obesity and less weight loss were more common in women with ED-SCLC than in men. However, there were no associations between sex and significant prognostic factors, such as performance status, metastasis site, serum LDH level, response to chemotherapy, and disease recurrence.

Similar to our findings, Korean women, compared to men, were more frequently never-smokers (48.9 vs. 2.0%, p < 0.001) and had limited diseases (48.9 vs. 37.8%, p = 0.05) [7]. Women had less progressive disease in the M stage than men (52.3 vs. 62.8%, p = 0.031). No significant differences were observed between men and women in treatment, performance status, weight loss, serum levels of albumin, and lactate dehydrogenase. The percentage of Taiwanese never-smokers appeared to vary little in the SCLC population, 15.5% in 2011 and 16.1% in 2018 (p = 0.28) [3]. The study of 18,234 cases from the SEER database between 1973 and 2015 showed that female SCLC patients had smaller tumor sizes (p < 0.001); fewer lung, liver, bone, and brain metastases (p < 0.001); and lower stages (p < 0.001) than male patients [4]. Contrary to our findings, in a UK study, at baseline women had poorer performance status (57 vs. 67%, p = 0.0004); and more female patients were of normal weight or underweight (57 vs. 48%, p = 0.003), but fewer women were anemic (25 vs. 62%, p < 0.0001) [10]. Response rates to chemotherapy between women and men were identical (77 vs. 76%, p = 0.64) similar to our findings, whereas the overall response rate was significantly higher in women in the NCIC CTG series (80 vs. 67%, p < 0.0001) [11].

In our study, while overall survivals of LD-SCLC patients were found to be similar between sexes (p = 0.8), female ED-SCLC patients had better survival rates (p = 0.008), and the significant survival advantage of female ED-SCLC patients in the univariate analysis was maintained also in the multivariate analysis (p = 0.001). The prognosis of SCLC in female patients is controversial. Various studies are reporting that sex is either non-prognostic [12, 13] or prognostic [2, 4, 5, 7, 9‒11, 14, 15] on survival in SCLC patients. In a large (42,000 males and 38,000 females) US National Cancer Database study from 1992 to 2007, Gaspar et al. [14] reported increased HR for death in males as compared to females in both LD-SCLC (HR 1.19) and ED-SCLC (HR 1.13) patients. Survival analysis showed that women had better cancer-specific survival, which could be explained partially by being presented at an earlier stage compared with men in the SEER registry from NCI between 1973 and 2010 [5]. Moreover, data from six randomized phase II/III chemotherapy trials in Manchester Lung Group and UK Medical Research Council showed that female sex predicted longer survival in both univariate (HR: 0.85, p = 0.006) and multivariate (HR: 0.88, p = 0.04) analyses (10). Similarly, between 1989 and 2008, 266 female patients from southern Sweden with limited SCLC had higher 5-year survival rates than males (28 vs. 5.6%; p = 0.001); females with extensive disease had better 5-year survival compared to males (3.9 vs. 0.7%, 0.023) [9]. Likewise, Hou et al. [4] showed that sex was an independent predictor of survival, and the prognosis of male patients was worse than that of female patients (HR: 1.117, p < 0.001). Similar findings were observed in far eastern SCLC patients [7]. Korean SCLC women had better survival than men (p = 0.034) [7]. Female sex was a prognostic factor predicting better survival, even after stepwise and full adjustment with all prognostic variables (HR: 0.51, p = 0.001 for the entire cohort. They confirmed that sex is an independent prognostic factor in patients with SCLC.

The reasons for the favorable prognosis in female patients with SCLC are still unknown [9]. In addition to findings showing that nonsmoker SCLC patients live longer than smokers [13], the female survival advantage can also be related to generally better female survival in most cancer types as reported in EUROCARE-4 [15]. Otherwise, further investigations of genetic, metabolic, and hormonal variables are needed to explain the difference in survival between sexes [7]. In addition to the association between the female sex and favorable clinicopathological factors, Hou et al. [4] also showed that while the expressions of AMPH, GRIN2C, and WNT4 were higher in men, HOXA5 was more frequently expressed in women; furthermore, RB1 was mutated more often in female patients.

This leads to the conclusion that there are differences between sexes in terms of gene expression levels, mutation frequencies, and types. It remains unclear whether differences in SCLC survival are associated with either environmental habits, such as tobacco exposure, which is also one of the main risk factors accountable for the high mutation burden of SCLC, or sex, which is in relation with genetic predispositions and differences in hormones. Thus, further studies are needed to clear these uncertainties.

Ethical approval and consent are not required for this study in accordance with local or national guidelines.

The authors declare that they have no conflicts of interest.

The authors declare that there is no information about the funding of any research relevant to our study, including sponsor names and explanations of the roles of these sources in the study design, execution, analysis, manuscript conception, planning, writing, and the decision to publish.

Clinical data acquisition and study design: F.T. and A.O. Data analysis: F.T. and K.E. F.T., A.O., and K.E.: prepared, reviewed, revised, and approved the manuscript for submission and interpreted the results.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (F.T.) upon reasonable request.