Lung Cancer in Women: The Differences in Epidemiology, Biology and Treatment Outcomes

Maria Patricia Rivera

Disclosures

Expert Rev Resp Med. 2009;3(6):627-634. 

In This Article

Lung Cancer Treatment Outcomes in Women

Women have better responses to therapy for lung cancer, regardless of stage, therapeutic modality or histology. The Surveillance, Epidemiology and End Results (SEER) database (31,226 patients) of lung cancer has been analyzed for prognostic factors and identified low-stage disease, surgical therapy, age younger than 50 years and female sex as favorable prognostic factors for survival.[64] To further characterize the clinical-pathologic differences between male and female lung cancer patients, an analysis of the SEER database from 1975 to 1999 of 228,572 eligible patients revealed that stage-specific relative survival was better for women for all stages of disease (5-year survival rates: 17.3% for women and 13.8% for men; p < 0.0001).[6] A population-based study of 20,561 cases of lung cancer conducted in Poland revealed that female patients had a better prognosis than males regardless of the modality of therapy, with a RR of death of 1 compared with 1.21 in males.[63] Results of a recently published Japanese lung cancer registry study revealed that female gender, adenocarcinoma and age younger than 50 years were significant favorable prognostic factors for survival.[64] As initial treatment, women with early-stage disease undergo surgery more frequently than men,[6] and several studies have shown that in early-stage NSCLC (stage I and II), women will experience superior survival after surgical resection.[12,65–68] In a study by Henschke and the Early Lung cancer Action Program Investigators, women had improved survival compared with men.[12] In this study, the hazard ratio (HR) for fatal outcomes of lung cancer comparing women with men was 0.48. Minami et al. evaluated the results of 1242 surgical resections for lung cancer and noted that women who underwent a complete surgical resection survived longer than their male counterparts.[66] In this study, women younger than 60 years of age did not show a significantly longer survival than men, but women over 60 years of age survived significantly longer. In a study of 451 patients who underwent surgery for early-stage NSCLC, women had a superior median survival when compared with men (41.8 vs 26.9 months respectively).[67] Cerfolio et al. evaluated the risk factors and trends of lung cancer between men and women in a prospective cohort of 1085 patients with NSCLC (671 men and 414 women).[68] In this study, women were younger (p = 0.014) at the time of diagnosis, had a higher incidence of adenocarcinoma (p = 0.01) and presented at an earlier pathologic stage (p = 0.01) than men. The overall 5-year survival rate favored women (60% for women vs 50% for men), and women had better stage-specific 5-year survival rates (stage I: 69% for women vs 64% for men; stage II: 60% for women vs 50% for men; and stage III: 46% for women vs 37% for men).[68] In the Japanese lung cancer registry study, the difference in 5-year survival by sex was almost 20% in NSCLC, in which the 5-year survival rates for men and women were 55.5 and 74.5%, respectively.[64]

With regards to radiotherapy, again female sex has been associated with better survival. In a recent meta-analysis of the Radiation Therapy Oncology Group trials conducted during the 1990s, female sex was the most significant factor driving survival results among nonoperable NSCLC patients. In this meta-analysis, males had a 1.23-times higher mortality rate than females.[69]

A survival advantage has also been reported for women with advanced NSCLC. A study of 378 patients with advanced NSCLC who received chemotherapy on clinical trials noted that female sex was associated with prolonged survival.[70] In a study by Albain et al. of 2531 patients enrolled in 13 Southwest Oncology Group (SWOG) trials, female sex again emerged as a favorable prognostic factor for survival (RR: 0.77).[72] In a recently published study of patients with advanced NSCLC and brain metastases treated with radiation therapy,[72] female sex was the best indicator of improved survival. Results of a recent randomized trial that compared cetuximab (monoclonal antibody) plus chemotherapy versus chemotherapy alone in advanced NSCLC confirmed the prognostic significance of female sex.[73] In this study, the treatment effect following cetuximab plus chemotherapy was 46% in women compared with 27% in men.

In second-line therapy for advanced NSCLC, female sex has also shown to be predictive of improved outcomes. In several studies, the EGF receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, had better efficacy in women. Two large Phase II trials of gefitinib monotherapy, the IRESSA Dose Evaluation in Advanced Lung Cancer (IDEAL) 1 and IDEAL 2 studies, demonstrated that female sex, Asian descent, adenocarcinoma and non-smoking status were predictors of response.[74,75] Similar favorable clinical predictors (female sex, adenocarcinoma, Asian descent and nonsmoking status) were identified in a Phase III randomized trail comparing erlotinib with placebo in previously treated patients with advanced NSCLC.[76] In this study, response to erlotinib was higher among women than among men (p = 0.006).[76] Response rates to the tyrosine kinase inhibitors have been associated with mutations in the EGFR. The improved prognosis observed for women may be secondary to differences in frequency of the underlying activating mutations: 20% in women versus 9% in men.[77,78] In a recent study on 2105 patients with NSCLC, EGFR mutations were found in 350 patients (16.6%), were more frequent in women (69.7%), in never smokers (66.9%) and in patients with adenocarcinomas (80.9%).[76] Median progression-free survival for patients with EGFR mutations treated with erlotinib was 16 months in women and 9 months in men (p = 0.003). Median overall survival was 29 months in women and 18 months in men (p = 0.05).[79]

In contrast to favorable outcomes noted in women with lung cancer who are treated with surgery for early-stage disease, or chemotherapy or radiation for advanced-stage disease, in a recent study of 204 patients (22% female) with unresectable stage III NSCLC who were treated with concurrent chemotherapy and thoracic radiation, no difference in survival or toxicity was seen between female and male patients.[80]

Studies of SCLC have also shown that women have improved outcomes following treatment. A total of 2580 patients enrolled in ten SWOG SCLC trials, including those with both limited- and extensive-stage disease, were analyzed for prognostic indicators.[80] In the trials that enrolled patients with limited-stage disease, female sex predicted the best outcome, with a median survival of 24.4 months among women versus 17.7 months among men. In the trials that enrolled patients with extensive-stage disease, there was a nonsignificant trend toward superior survival in women.[81]

As discussed earlier, HRT has been associated with decreased survival in lung cancer. Ganti et al. reported a retrospective review of 498 women with lung cancer (86% had a smoking history) and noted that women with lung cancer who received HRT were younger than the women who were not on HRT (63 vs 68 years, respectively; p < 0.0001).[82] Overall survival was much better in women who were not on HRT compared with those who were on HRT (79 vs 39 months, respectively).[82] The SWOG Lung Committee analyzed outcomes in six recent lung cancer trials (324 patients, 36% of whom were female) to test the hypothesis that sex-specific toxicity profiles and/or age (as a surrogate for estrogen levels) may explain the differences in treatment outcomes noted between males and females.[83] They found no difference in toxicity profiles between males and females but did find a difference in survival. The median, 1- and 2-year survival rates were better in females than in males (11 months, 46% and 19% vs 8 months, 35% and 11%, respectively). Women had a 14% reduced risk of death from NSCLC. The survival advantage, however, was seen in women 60 years of age or older, suggesting that estrogen levels may interact with the efficacy of chemotherapy. As noted earlier, in a recent post-hoc analysis of a randomized controlled trial, combined HRT was associated with increased risk of death from NSCLC.[46]

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