Gender is a non-negligible risk factor affecting the overall survival time of NSCLC patients: a nationwide population-based study

Abstract

Purpose: The aim of this study is to explore the effect of gender on overall survival (OS) in non–small cell lung cancer (NSCLC) patients.

Methods: The Surveillance, Epidemiology, and End Results Database (SEER) was queried for NSCLC cases from 2004 to 2015. A total of 129,864 NSCLC patients were identified to enroll in our study, including 78,460 males and 51,404 females. We compared and analyzed the demographics, socioeconomics, regional differences, tumor characteristics, treatment, and survival time in both groups of patients.

Results: Kaplan-Meier analysis showed improved OS in the female group compared to the male group throughout all stages (P<0.001). Median OS for males were 33.00 (95%CI: 31.88-34.12), 23.00 (95%CI: 21.93-24.07), 11.00 (95%CI: 10.77-11.23), and 4.00 (95%CI: 3.90-4.10) months from stage IB to IV, respectively. Median OS for females were 52.00 (95%CI: 49.53-54.47), 30.00 (95%CI: 27.95-32.05), 13.00 (95%CI: 12.63-13.37), 5.00 (95%CI: 4.85-5.15) months respectively as counterparts. A multivariable Cox regression model was constructed and analyzed on survival for each clinical stage. Being in the female cohort could significantly reduce risks for mortality compared with male cohort at all stages (hazard ratios [HR] of 0.766, 0.797, 0.846, and 0.857 for stages IB through IV respectively, [all P< 0.001]).

Conclusions:  For various stages of patients older than 45 years, the OS of female NSCLC patients with or without chemotherapy is greater than that for male counterparts. Gender is a non-negligible risk factor affecting the overall survival time of NSCLC patients.

Introduction

Lung cancer is one of the most common cancer and is the leading cause of cancer mortality worldwide¹. It is estimated to cause approximately 1.7 million deaths each year ^2,3 and consists mainly of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Of these, NSCLC is more common, accounting for approximately 85% of lung cancers, and its subtypes mainly include squamous cell carcinoma (SCC), adenocarcinoma of the lung (AD), and large cell neuroendocrine carcinoma (LCNC). Currently, the choice of treatment options depends mainly on the stage of lung cancer. For patients with early-stage NSCLC, surgical resection remains the most appropriate treatment. However, the efficacy of surgical treatment for NSCLC patients depends on the patient's physical condition, tumor stage and histological subtype. It has been reported in the literature that the 5-year survival rate of NSCLC patients after surgical treatment is only about 25% ^4–6, and the risk of cancer recurrence still exists even after radical resection surgery. Therefore, combining chemotherapy or radiotherapy with surgery can better eliminate cancer cells and reduce the probability of metastasis. The benefit of chemotherapy in improving overall survival (OS) has been well documented in many clinical trials ^7,8. For advanced NSCLC, combining chemotherapeutic agents with anti-PD-1 or PD-L1 inhibitors played a significant role in improving the OS of patients ^9,10. Chemotherapy in combination with atezolizumab also leads to prolonged progression-free survival (PFS) in patients with EGFR or ALK alterations ¹¹.

Studies have shown that chemotherapy is mostly associated with a clear survival benefit in NSCLC, even in elderly patients over 70, especially for the ages 71–75, taking into consideration their comorbidities ^12–14. For patients aged > 75 years the risk versus benefit has not been studied adequately ¹⁵. Nevertheless, the survival analysis of patients with NSCLC at all stages stratified by gender and the impact of gender on chemotherapy remains unclear. To better answer this question, a population-based cohort study is warranted to determine whether gender has an impact on OS in patients with stage IB to IV NSCLC with or without chemotherapy.

Material And Methods

Data Source and Study Population

The population-based study was traced from the Surveillance, Epidemiology, and End Results Database (SEER), a joint project composed of 18 cancer registries in the United States ¹⁶. The database provides clinical statistics information on approximately 28% of all cancer patients enrolled in the US Medical Record System ¹⁷. The coverage includes socio-economic elements such as geographical environment, education level and family income, as well as pathological characteristics such as the nature, size and stage of tumors. The SEER captures detailed clinical and demographic data to facilitate the analysis of association between treatment and survival time. We queried and downloaded the clinical data in SEER database of patients diagnosed with NSCLC from 2004 through 2015. The criteria for excluding patients were set as follows: if they were lost to follow-up or had missing information on survival or tumor staging throughout the treatment process, if lung cancer was not the first diagnosis or the primary cancer. We finally analyzed a total of 129,864 pathologically confirmed NSCLC patients registered in this database, including 78,460 males and 51,404 females. They were categorized as receiving chemotherapy or not. The screening flow chart is shown in Figure 1.

Variables 

From the SEER database we extracted the detailed clinical information of NSCLC patients, the main ingredients are composed of race, sex, region, primary site, grade, laterality, histological type, lymph nodes removed, tumor stage, chemotherapy, bone/ brain/liver/lung metastasis, first malignant indicator, age at diagnosis, insurance status, marital status, high school education, and median family income. A total of 20 variables were included in the univariate and multivariate statistical analysis.

Statistical Analysis

All statistical analysis was performed by using IBM SPSS, version 20.0 (IBM Corp, Armonk, NY, USA). We compared the baseline clinical statistics between male and female cohorts by using χ2 tests for categorical variables. Kaplan–Meier survival curves were applied to estimate the survival time of patients and the method of log-rank test was adopted. To reduce the influence of confounding factors, a multivariable Cox regression analysis was further performed to predict the independent risk factors affecting OS for each clinical stage. A p-value < 0.05 was considered a statistically significant difference.

Results

Patient Population

A total of 129,864 NSCLC cases were identified based on demographics, tumor and treatment characteristics in our study, including 78,460 male and 51,404 female patients stratified by sex. Most patients in men or women were white race (81.8% versus 83.3%), regions of the population were distributed in the east (49.5% versus 46.6%). Their tumors were mainly located in the upper lung lobe (52.1% versus 50.7%), had a laterality to right (55.2% versus 56.0%), more likely to be poorly-differentiated grade (Grade III/IV: 34.0% versus 32.4%). Majority of the patients had 0-3 lymph nodes removed (73.5% versus 70.9%) and the most histological types was squamous cell carcinoma (78.7% versus 66.9%), followed by adenocarcinoma (13.3% versus 24.5%), and large cell carcinoma (8.0% versus 8.6%). More patients, both men and women, were stuck in the advanced stage (stage III/IV: 73.9% versus 71.0%), and nearly half of them receipt of chemotherapy (47.5% versus 44.7%). However, there was a lower proportion of patients with bone (7.3% versus 6.0%), brain (3.6% versus 3.8%), liver (3.9% versus 3.2%) and lung (6.8% versus 6.7%) metastasis. The majority of patients in the entire cohort were elderly (age ≥65 years: 68.5% versus 71.3%) and more often accompanied by a positive first malignant indicator (77.0% versus 77.2%). Socioeconomic factors for this population were divided into having a good insurance status (73.0% vs. 74.1%), a high level of schooling (80.2% vs. 79.0%), and a generally high level of household income (85.7% vs. 88.7%). Female patients were more likely to be divorced or separated compared to their male marital status (35.9% vs. 57.4%). The baseline characteristics of patients are presented in Table 1.

Kaplan-Meier OS and Median Survival for NSCLC Patients Stratified by Sex and Age at Stages IB through IV

Kaplan-Meier OS for the entire cohort was 21.8%, when further calculated in accordance with stage, was 42.6%, 34.2%, 20.8%, and 10.0% for stages IB, II, III, and IV respectively (Figure 2). Stage-specific OS was significantly better for female patients at each stage (log-rank test, P < 0.001 for all stages) (Figure 3). Kaplan-Meier analysis showed improved OS in the female group compared to the male group throughout all stages (P <0 .001). Further using age as a stratification factor, the survival curves were almost extremely similar at stages IB through IV(P<0.005), except for younger patients in stage IB and II (P=0.055, P=0.096), presenting a higher survival rate in female (Figure S1-S4).

The mean survival times for male patients at stages IB through IV were 52.82 (95%CI: 51.85-53.80), 44.19 (95%CI: 42.88-45.50), 25.09 (95%CI: 24.60-25.59), and 10.78 (95%CI: 10.51-11.04) months compared with 66.29 (95%CI: 65.06-67.52), 52.87 (95%CI: 51.09-54.66), 31.35 (95%CI: 30.62-32.09), and 15.14 (95%CI: 14.71-15.57) months respectively for female patients. Median OS for males were 33.00 (95%CI: 31.88-34.12), 23.00 (95%CI: 21.93-24.07), 11.00 (95%CI: 10.77-11.23), and 4.00 (95%CI: 3.90-4.10) months from stage IB to IV, respectively. For the female patients, the median OS were 52.00 (95%CI: 49.53-54.47), 30.00 (95%CI: 27.95-32.05), 13.00 (95%CI: 12.63-13.37), 5.00 (95%CI: 4.85-5.15) months respectively as counterparts. The survival difference values for the male and female cohorts were greater in stage IB/II (13.47 and 8.68 months) than in stage III/IV (6.26 and 4.36 months) (Summarized in Table2).

Chemotherapy for NSCLC Patients Stratified by Sex at Stages IB through IV

Kaplan-Meier OS for patients not receiving chemotherapy at stages IB through IV were 42.1%, 25.6%, 14.2%, and 6.8% respectively. In comparison, we calculated the improved OS were 44.4%, 42.7% 25.8%, and 13.4% (all P<0.001) in the corresponding stages when chemotherapy was administered (Figure 4). Similar Kaplan-Meier survival trends were observed in the gender subgroup analysis of all stages (P<0.05), indicating that chemotherapy could be a positive treatment for men or women at stages IB through IV (Figure 5-6).

Following the sequence of stages, the median OS for male cohorts who received chemotherapy compared to those without chemotherapy were listed as 35.00 (95%CI: 32.51-37.49) versus 32.00 (95%CI: 30.74-33.26), 30.00 (95%CI: 27.95-32.05) versus 16.00 (95%CI: 14.87-17.13), 15.00 (95%CI: 14.66-15.34) versus 5.00 (95%CI: 4.78-5.22), and 8.00 (95%CI: 7.84-8.16) versus 2.00 (95%CI: 1.96-2.05) months, respectively. A similar contrast in the female cohort was performed, the median OS for patients receiving chemotherapy compared to those without chemotherapy were enumerated as 52.00 (95%CI: 45.62-58.38) versus 52.00 (95%CI: 49.30-54.70), 46.00 (95%CI: 42.01-49.99) versus 19.00 (95%CI: 17.34-20.66), 19.00 (95%CI: 18.38-19.62) versus 7.00 (95%CI: 6.61-7.39), and 10.00 (95%CI: 9.73-10.28) versus 2.00 (95%CI: 1.90-2.10) months, respectively (summarized in Table 3). We get a conclusion from the data analysis described above that female patient who received chemotherapy or without seem to have a longer median OS in comparison with male patients at the same stage.

Establishment of A Multivariate Regression Model

A separate multivariable Cox proportional hazards model for mortality was constructed and the effect of all relevant variables on survival for each clinical stage are summarized in Table 4. Being in the male sex group was a statistically significant predictor for mortality at all stages, while a better survival effect was presented in the female groups (hazard ratios [HR] of 0.766, 0.797, 0.846, and 0.857 for stages I through IV, respectively [all P < 0.0001]). Another significant predictor for mortality that could not be ignored at all stages was the impact of increasing age on OS. An increasing HR for mortality was observed for the subgroup of patients with increasing age, such as for age≥75 were 2.812, 2.331, 1.474, and 1.303 at stages I through IV, respectively (all P < 0.001). We also predicted other clinically significant risk factors for mortality across all stages, including grade, histological type, lymph nodes removed, chemotherapy, first malignant indicator, and social impactors of insurance status, marital status, and median family income. Multivariable regression analysis also showed other statistically significant predictors for mortality only at specific stages. For example, among the subset of patients with bone/brain/lung metastasis for stage III/IV more often associated with worse OS.

Discussion

In the entire cohort, the majority of NSCLC patients were elderly, more likely to be of poorly differentiated grade, with 0–3 lymph nodes resected, and more patients had SCC pathology, staying in advanced stages, with nearly half being advised to choose a chemotherapy regimen. Also, the percentage of cases with distant metastases was very low. To our knowledge, the current study clearly elaborated the efficacy of chemotherapy for male or female patients with NSCLC at stages IB though IV^18–20. The primary contribution of this study was the prolonged OS in female patients compared to male cohort across all stages. This survival advantage for females persisted even after stratification by different age groups, in both younger and older patients. When male/female patients receive chemotherapy at their respective stages, they can live longer compared to patients who do not receive chemotherapy. In other words, chemotherapy has similar positive treatment effects for both men and women with NSCLC disease.

Although some studies have shown differences across the cohort, more detailed stage-specific survival differences between male and female patients have not been further detected to date ^21–24. The main aim of our study was to break this limitation. In our analysis, differences in gender played an independent role in the survival impact of patients with NSCLC at all stages. When stratified by age and chemotherapy variables, female patients had improved overall and median survival rates compared to males for stages IB to IV. Surprisingly, younger patients (age < 45 years) did not have a very significant survival advantage in the early stage (stage IB/II) subgroup. An increased lethality was occurred as patients reached more advanced stages, resulting in a sharp decline of the survival rate in either the male or female groups. For example, median OS was 36.5% higher for female patients in stage I than for male patients, with an absolute numerical difference of up to 19.0 months of additional life compared to only 1.0 months for stage IV patients.

Age was also used as an independent impact factor for all stages of OS. A significant survival difference was observed between youth and older patients in the respective multivariate regression model. The trend toward increased HR for mortality with increasing age implied that older patients were more likely to suffer from other comorbidities for an increased incidence of fatal events ^25,26. Typically, worse performance status has been proved to be a significant predictor for mortality in older patients ^27–29. A major finding in John Michael Valotto's analysis was that blacks were more likely to have NSCLC at a younger age and had lower OS than whites³⁰. Their findings also demonstrate significantly longer survival in married patients or those with domestic partners, even with metastatic disease. The study conducted by Theresa A Hastert³¹ in which 54,737 participants were collected provides ample evidence that cancer mortality is higher among residents from low socioeconomic areas than those from high socioeconomic areas. However, blacks in our study did not show significantly worse survival compare to whites. On the other hand, we have demonstrated that insured patients, those who are married or have domestic partner and those with higher household income have a lower risk of cancer mortality, consistent with the above findings.

A well-sourced SEER database has been excavated in our study, patients at stages IB through IV may benefit from chemotherapy, especially in the advanced stages of the disease. Our findings suggested that the survival time has increased nearly two-fold for patients receipt of chemotherapy with stage III/IV NSCLC compared with those without chemotherapy. The effectiveness of chemotherapy for patients with NSCLC has been well documented by a large body of published literature ^32–34. Timothy Winton ³⁵ retrieved 482 patients at stage IB or II NSCLC from the Canadian National Cancer Institute and reported a significantly prolonged OS when patients treated with surgery plus chemotherapy compared with those treated with surgical resection alone (P = 0.04).

Shun Lu et al ³⁶ noted tecilizumab combination chemotherapy as a first-line treatment for locally advanced or metastatic non-squamous NSCLC (rationale 304). Shengxiang Ren et al ³⁷ have verified camrelizumab plus carboplatin and paclitaxel as the first-line treatment for advanced squamous non-small cell carcinoma in phase 3 clinical trials.

This survival trend noted in the current analysis differs from previous studies of poorly prognostic NSCLC subtypes, such as large cell neuroendocrine carcinoma ³⁸, for which chemotherapy is effective only at early stages. Despite statistical biases in the treated patients, multivariable Cox proportional hazards analysis and Kaplan-Meier estimation curves in NSCLC cohort showed a similar phenomenon across all stages: female patients acquired more survival benefits than male before and after chemotherapy. There are also studies that support our view. Antonio L Visbal ³⁹ analyzed a cohort of 2,724 men (59%) and 1,894 women (41%) with NSCLC and found that male gender was an unfavorable prognostic factor for NSCLC survival. Similarly, Damien J⁴⁰ analyzed the National Inpatient Sample (NIS) dataset from 2002 to 2007, considering more than 50 different variables in terms of gender, race, and socioeconomic status, and concluded that female gender was a significant independent correlate of postoperative morbidity and mortality, and was associated with lower odds of death and postoperative complications compared to men. Cox regression model for each stage showed that sex, increasing age, grade, histological type, lymph nodes removed, chemotherapy, first malignant indicator, and social impactors such as insurance status, marital status, and median family income were all significant predictors of mortality. Theoretically, although there are specific treatment guidelines for different stages of NSCLC ^41,42 in reality for each stage the confounding factors such as tumor types, size, differentiation, and age of patients must be considered to measure an appropriate treatment strategy rather than a single treatment paradigm.

The size of our research on the efficacy of chemotherapy for patients with NSCLC belongs to a large-scale, multi-institutional study, which has some certain advantages over single-institutional studies often limited to smaller sample size and biased data. Due to tobacco use being closely associated with the incidence and mortality of lung cancer ^43–47, it is a pity that details of tobacco inhalation history are omitted from the SEER database. Other limitations of our retrospective analysis study refer to the failure to record some interesting variables such as lung imaging, pulmonary function tests, nodal status, and comorbidity scores.

In recent years, personalized treatment regimens for advanced NSCLC have focused on targeted therapies (mainly tyrosine kinase inhibitors (TKI) ^48–50. This modality has now achieved remarkable success because of molecular specificity and biomarkers. The scope of application of targeted therapies include TKI for EGFR-mutants, ALK-rearrangements (ALK), ROS1-rearrangements or BRAF^+ V600E mutants advanced-stage NSCLC ^51,52. Immunotherapy as another new therapeutic direction has also greatly boosted the treatment prospects for NSCLC, especially with breakthroughs in immune checkpoint inhibitors such as anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies.

Conclusions

In our study, the OS of female NSCLC patients with or without chemotherapy is greater than that for male counterparts at stages IB through IV, except for patients who were less than 45 years old. In conclusion, we infer that gender is a non-negligible risk factor affecting the overall survival time of NSCLC patients. Our study provides the idea that more specific and personalized treatments can be developed for different gender groups in the future.

Abbreviations

SEER, the Surveillance, Epidemiology, and End Results; OS, Overall Survival; NSCLC, Non-Small Cell Lung Cancer; SCLC, Small Cell Lung Cancer; SCC, Squamous Cell Carcinoma; AD, Adenocarcinoma; LCNC, Large Cell Neuroendocrine Carcinoma; HR, Hazard Ratio.

Declarations

Acknowledgements

Not applicable.

Authors' contributions

Conception and design: L.L., B.B.W., C.H.W., and S.S.X. Acquisition, statistical analysis, or interpretation of the data: all authors. Drafting of the manuscript: L.L., B.B.W., C.H.W., and S.S.X. All authors reviewed and approved the final version of the manuscript.

Funding 

None.

Availability of data and materials

Data analyzed in this manuscript are publicly available from the Surveillance, Epidemiology, and End Results Program (https://seer.cancer.gov).

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing financial interests.

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Tables

Table 1: Basic Cohorts Characteristics

SCC, squamous cell carcinoma; AD, adenocarcinoma; LCC, large cell lung carcinoma. 

Table 2 Kaplan-Meier OS and Median Survival for NSCLC Patients Stratified by Sex at Stages IB through IV

NSCLC, non-small cell lung cancer; OS, overall survival; CI, confidence interval. 

Table 3 Chemotherapy for NSCLC Patients Stratified by Sex at Stages IB through IV

NSCLC, non-small cell lung cancer; OS, overall survival; CI, confidence interval. 

Table 4 Multivariable Cox Regression Model for Mortality at Each Clinical Stage

SCC, squamous cell carcinoma; AD, adenocarcinoma; LCC, large cell lung carcinoma; HR, hazard ratio; A p-value of less than 0.05 represents a significant statistical difference.