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* From the Divisions of Cardiothoracic Surgery (Drs. Cerfolio and Bryant), Hematology and Oncology (Dr. Robert), and Pulmonary/Allergy/Critical Care (Dr. Garver), the Department of Radiation Oncology (Dr. Spencer), and the School of Medicine (Drs. Scott and Sharma), University of Alabama at Birmingham, Birmingham, AL.
Correspondence to: Robert J. Cerfolio, MD, FCCP, Professor of Surgery, Chief of Thoracic Surgery, Division of Cardiothoracic Surgery, University of Alabama at Birmingham, 1900 University Blvd, THT 712, Birmingham, AL 35294; e-mail: Robert.cerfolio{at}ccc.uab.edu
Abstract
Objective: Bronchogenic malignancy is the number one cause of cancer deaths in both men and women worldwide. National registry-based studies have shown gender disparity in clinicopathologic characteristics and in survival. This study evaluates the risk factors and trends of lung cancer between genders.
Methods: A prospective cohort of consecutive patients with non-small cell lung cancer (NSCLC) who were carefully clinically (all underwent dedicated positron emission tomography scans) and pathologically staged with stage I, II, or III disease underwent homogenous treatment algorithms and were followed up over a period of 7 years. Primary outcomes were 5-year survival and response to neoadjuvant therapy.
Results: There were 1,085 patients (671 men and 414 women). Groups were similar for race, pulmonary function, smoking history, comorbidities, neoadjuvant therapy, histology, and resection rates. Women were younger (p = 0.014), had a higher incidence of adenocarcinoma (p = 0.01), and presented at an earlier pathologic stage (p = 0.01) than men. The overall age-adjusted and stage-adjusted 5-year survival rate favored women (60% vs 50%, respectively; p < 0.001). Women had better stage-specific 5-year survival rates (stage I disease, 69% vs 64%, respectively [p = 0.034]; stage II disease, 60% vs 50%, respectively [p = 0.042]; and stage III disease, 46% vs 37%, respectively [p = 0.024]). Women who received neoadjuvant chemotherapy alone (n = 76) were more likely to be a complete or partial responder than men (n = 142; p = 0.025).
Conclusions: Despite uniform staging and treatment, the 5-year survival rate of women with stage I to III NSCLC was better than men overall and at each stage. Women are more likely to have adenocarcinoma, to present with earlier stage disease, and to be younger. Interestingly, women respond better to neoadjuvant chemotherapy.
Key Words: lung cancer • staging • surgery
Although smoking rates have declined in the United States, lung cancer continues to be a pandemic.1 It is the number one cause of cancer-related deaths worldwide. In 2003, there were 171,900 patients in whom lung cancer was diagnosed, and 157,200 deaths due to lung cancer in the United States alone.1 Lung cancer takes the lives of more female Americans than the next three most common female cancers (ie, breast, colorectal, and ovarian cancer) combined. In addition, it kills more American men than the next three most common male cancers (ie, prostate, colorectal, and pancreatic cancer) combined. Lung cancer alone is responsible for an estimated 27% of all cancer deaths.2 It has claimed the lives of American icons such as Walt Disney, John Wayne, Yul Brunner, Nat "King" Cole, Ed Sullivan, Lucille Ball, Roger Maris, and most recently Peter Jennings. Eighty percent of patients afflicted with lung cancer have non-small cell lung cancer (NSCLC), which is potentially curable if diagnosed early.
Although the incidence of lung cancer in men has declined, it had sharply risen in women until 2004. If these current trends continue, the incidence of lung cancer is projected to be identical for women and men over the next decade.3 Furthermore, lung cancer may be avoidable since 9 in 10 patients are smokers.
Given these statistics, aggressive approaches to identify epidemiologic and biological trends of lung cancer as well as to better target prevention, screening, and treatment efforts are needed at both the national and individual institution level. Gender-associated differences in the clinicopathologic characteristics and survival of patients with lung cancer appear to exist, but the findings are conflicting. Previous studies4567 have reported that women receive a diagnosis at a younger age (< 50 years of age) have an increased susceptibility to the development of lung cancer and better survival. Gender-related differences in the incidence of histologic subtypes, stage at presentation, and survival rates have also been reported.46 However, these reports are plagued by the inherent limitations of studies that use large registry-based databases, feature inconsistent staging, use clinical instead of pathologic staging,8 are retrospective, have many patients with advanced disease, apply different treatment algorithms for different stages of disease, and use a multitude of physicians. Additionally, survival analysis from data obtained over long time periods may be subject to lead-time bias, is confounded by multiple treatment strategies, has exposure to evolving chemotherapeutic agents, and uses surrogate end points for the assessment of treatment success. Thus, we decided in January of 1998 to prospectively study gender-associated clinicopathologic and survival differences for patients with NSCLC who presented to our surgical clinic. This study eliminates many of these aforementioned confounders because a large number of patients presented to one institution from several geographic regions, all underwent careful pathologic staging as opposed to clinical staging, and patients were treated with homogenous protocols. In addition, we focused on those with early-stage disease (ie, not stage IV disease) in an attempt to examine survival differences between men and women.
Materials and Methods
Study Design and Patients
This is a consecutive cohort of patients with biopsy-proven NSCLC who were pathologically staged by one surgeon at University Hospital at the University of Alabama at Birmingham. All data were prospectively entered in an electronic database by the attending surgeon. Patients were seen and followed up between January 1998 and March 2005. Patients were excluded if they were 
19 years of age, had histology that was not NSCLC, or had biopsy-proven stage IV cancer. Figure 1
outlines the algorithm used. In general, patients with stage I disease underwent resection, those with stage II disease received neoadjuvant platinum-based chemotherapy, and those with biopsy-proven stage IIIa disease received neoadjuvant chemoradiotherapy. Patients with Pancoast tumors were excluded from this study (because they had stage II disease but received radiation and chemotherapy). Selected patients with stage IV disease who underwent complete resection (some with a single brain metastasis and others with unsuspected M1 nodules in the same lung) were also excluded from this study. All patients were clinically staged using 5-mm collimated CT scans of the chest and upper abdomen, and in addition all patients underwent dedicated positron emission tomography (PET) using 2-deoxy-2–18F-fluoro-D-glucose F-18 (FDG). Pathologic staging was required for inclusion in this study. The institutional review board at the University of Alabama at Birmingham approved this study as well as the prospective database used to collect the data.
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2.5 on FDG-PET scan or 1 cm on the greatest axis on CT scan) were biopsied prior to pulmonary resection. Mediastinoscopy and/or endoscopic ultrasound fine-needle aspiration were used to biopsy different nodal stations as previously described.9 All suspicious metastatic (M1) sites determined by FDG-PET scan or CT scan were also investigated and/or biopsied. Patients with suspected M1 disease in the liver, adrenal gland, or contralateral lung underwent definitive biopsy to prove or disprove the presence of M1 cancer. If the bone or brain was suspected to harbor metastases, MRI was considered to be the standard reference. The TNM pathologic stage was assessed using the international staging system.10
Treatment Strategy
If a patient had biopsy-proven N2 disease, they underwent platinum-based chemoradiotherapy (using 4,500 to 6,600 cGy) and were restaged with dedicated PET and CT scans. If patients were negative for N2 disease after the completion of their neoadjuvant therapy, they underwent resection. If a patient had biopsy-proven or suspected N1 disease, they underwent neoadjuvant platinum-based chemotherapy and then resection. If patients had biopsy-proven N3 or M1 disease, they were treated with chemoradiotherapy and did not undergo resection. Patients who were negative for N1 and N2 disease underwent thoracotomy with pulmonary resection. At thoracotomy, complete thoracic lymphadenectomy (not nodal sampling) was used exclusively. Pathologic review was performed via standard techniques, and immunohistochemical staining was employed when appropriate.
Definitions
Downstaging was defined as pathologic proof of reduction in the nodal status and/or decrease in the T status of the tumor. A pathologic complete responder or a complete pathologic response was defined as having no residual viable tumor in the resected pathologic specimen in a patient with biopsy-proven NSCLC who had undergone neoadjuvant therapy. Partial response was defined as pathologic confirmation of some but not complete cellular death of viable cancer cells.
Statistical Analysis
Continuous data are presented as medians, and categoric data are presented as percentages. Characteristics of the patients and treatments were compared by Fisher exact test or Pearson 
2 test for categoric data, and by the Wilcoxon test for continuous data. Survival estimates were derived by Kaplan-Meier analysis, and log-rank tests were used to assess differences in survival among the groups. Stratified log rank analyses and Cox proportional-hazards modeling were used to investigate and adjust for major prognostic and stratification factors. A two-sided p value of < 0.05 was considered to be statistically significant. Patients who were alive at the end of the study period were censored for purposes of data analysis. Analysis was performed using a statistical software package (SAS, version 9.0; SAS Institute; Cary, NC).
Data Collection and Follow-up
Patients were actively followed up after pathologic staging and treatment until the end of this study. For patients who underwent complete resection, follow-up consisted of chest and abdominal CT scan every 6 months for the first 2 years and yearly afterward. Patients who did not undergo complete resection underwent more frequent follow-ups. Data were obtained from multiple sources, such as clinic letters, follow-up scans, hospital computer information systems, tumor registry, social security death index, and telephone calls and letters from oncologists and other physicians. The time to disease recurrence (defined as biopsy-proven recurrent NSCLC), disease progression, or death due to lung cancer was recorded. All information was entered into our prospective database. Data acquisition for new patients was stopped on March 1, 2005, for this study, but the collection of follow-up data continued.
Results
Patient Characteristics
Between January 1998 and March 2005, 1,085 patients (671 men and 414 women) were entered into this study. Patient characteristics are shown in Table 1
. Race, comorbidities, smoking rates, pulmonary function test results, neoadjuvant therapy rates, and resection rates were similar between men and women. However, women were younger than men (p = 0.014), presented with an earlier disease stage (p = 0.01), and had a higher incidence of adenocarcinoma (p = 0.01). Survival analysis was performed on the 93.4% of patients who were followed up (6.6% were lost to follow-up).
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Previous reports have suggested that women with NSCLC fare better men. However, many of these studies have been registry-based or metaanalyses57111213 and thus may have been flawed by their retrospective nature and inaccurate data. In contrast, this study was prospective. It included > 1,000 consecutive patients and features the best clinical staging available followed by careful pathologic staging. In addition, if patients underwent resection, complete thoracic lymphadenectomy was performed as opposed to nodal sampling. Furthermore, after pathologic staging all patients had treatment strategies determined by one physician at one university that serves a large geographic are in the southeastern region of the United States. Limitations of this study include the loss to follow-up of 6.6% of patients, the fact that the patient population studied was composed of those who presented to a surgical clinic, the minor variations in the doses and types of chemotherapy, and variations in the amount of radiotherapy used. The fact that this is a surgical series obviously biases the data toward earlier stage disease. This may further accentuate the role that gender plays, which may not be clinically significant in patients with stage IV disease.
Certain clinicopathologic differences among men and women were found in this study. Visbal et al3 in 2004, Alexiou et al14 in 2001, and Minami et al15 in 2000 found that women are more likely than men to have adenocarcinoma. We report a similar finding. This may be attributed to the effects of estrogen, which is a known risk factor for the development of adenocarcinoma.161718 It has also been shown that patients with adenocarcinoma may have improved survival.1920 We have shown that squamous cell carcinoma has a higher maximum standard uptake value on FDG-PET scans than adenocarcinoma, and a higher maximum standardized uptake value has been correlated with more virulent and biologically aggressive tumors and worse patient survival rates.21 In addition, we have shown that patients with squamous cell cancer may respond better to cisplatin-based neoadjuvant chemotherapy than those with adenocarcinoma.22 However, even though we did not find a statistically significant impact on survival based on tumor histology, we performed a separate analysis that controlled for tumor type, and even then women had superior survival rate than men.
The median age of patients in our series (67 years of age) was higher than that reported by Radzikowska et al6 in 2002, which was a study of 20,561 patients with NSCLC from Poland. Our report, which has a wider age range (23 to 84 years of age) and a higher median age is more representative of patients with NSCLC in the United States. This may be due to the fact that our series used a consecutive group of patients. Our study, like most other reports,4567 found that women presented at a younger age than men. This age difference may be linked to genetic abnormalities between the sexes such as oncogenes, tumor suppressor genes, viral infections specific to women such as human papilloma virus, growth factors, or a reflection of the changing gender-based trends in smoking over the past few decades. Further studies are needed.
Like previous studies, we found that women have a better age-adjusted 5-year survival rate than men overall23 as well as within each stage.24 These findings held true even on multivariate analysis, which controlled for the several univariate factors that affected survival (ie, age, histology, and stage). Possible causes include biological, hormonal, and molecular factors that differ between genders. For example, women are known to have a different nicotine metabolism than men,25 have a higher incidence of p53 and K-ras mutations,2627 and have a greater susceptibility to tobacco. Additionally, human papilloma virus infection has been shown to be associated with NSCLC.2829 Yet, despite these risk factors for women, women have a better 5-year survival rate even when adjusted for age. Obviously, there is a complex array of other unknown factors at work, and further research is needed to better understand the pathophysiologic mechanisms. A careful inspection of Figure 3 suggests that the survival advantage for women occurs predominantly within the first few months after diagnosis. However, we could not demonstrated any treatment-related mortality to explain this finding, and a further separation of the curves is also noted between 20 and 24 months as well.
One of the most provocative findings in this study is that women in whom stage II NSCLC was diagnosed had a statistically higher response rate to neoadjuvant chemotherapy than men. This is a unique finding and is made possible only because of the strict treatment algorithm we employed for these patients, since many studies do not offer neoadjuvant therapy for patients with clinical N1 disease. Interestingly, when neoadjuvant radiotherapy was added to the chemotherapy employed for those patients with stage IIIa-from-N2 disease, the survival advantage was lost. A trial by the Southwest Oncology Group showed that female gender was a positive independent prognostic factor for survival in patients who received neoadjuvant radiochemotherapy for stage III NSCLC.30 The mechanism for this remains unclear.
In conclusion, we found in this large prospective study, which features strict entry criteria, staging, and similar treatment algorithms, that women with pathologic stage I, II, and III NSCLC have a better overall survival rate, as well as a better stage-for-stage 5-year survival rate than men. Women are more likely to be younger and to have adenocarcinoma. Interestingly, women are more likely to respond to neoadjuvant chemotherapy. Further studies are needed to prove or disprove these findings as well as to elucidate the pathophysiology. These data may help us to improve the dismal 13% overall 5-year survival rate for patients with NSCLC by helping to target new therapeutic options.
Footnotes
Abbreviations: FDG = 2-deoxy-2–18F-fluoro-D-glucose F-18; NSCLC = non-small cell lung cancer; PET = positron emission tomography
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication April 9, 2006. Accepted for publication June 16, 2006.
References
and ß and show biological responses to estrogen. Cancer Res 2002;62,2141-2150This article has been cited by other articles:
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  A. Bryant and R. J. Cerfolio Differences in Epidemiology, Histology, and Survival Between Cigarette Smokers and Never-Smokers Who Develop Non-small Cell Lung Cancer Chest, July 1, 2007; 132(1): 185 - 192. [Abstract] [Full Text] [PDF]
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