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Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, 1275 York Avenue, New York, NY 10021===
Presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, May 30-June 3, 2008.
This study was undertaken to characterize the relation between the survival of patients with stage IIIB/IV nonsmall cell lung cancer (NSCLC) and pack-years of cigarette smoking (graded according to the American Joint Committee on Cancer staging system).
Data were analyzed from patients with stage IIIB/IV NSCLC who had completed a prospective smoking questionnaire. The impact of pack-years of cigarette smoking, age, sex, Karnofsky performance status (KPS), and the presence of weight loss >5% was evaluated on overall survival using univariate and multivariate analyses.
Smoking history and clinical data were available for 2010 patients with stage IIIB/IV NSCLC (1004 women and 1006 men). Approximately 70% of patients (1409 patients) had smoked >15 pack-years, 13% (270) were former and current smokers who had smoked ≤15 pack-years, and 16% (331) were never-smokers (<100 lifetime cigarettes). Never-smokers had a longer median survival compared with former or current smokers (17.8 months vs 11.3 months; log‒rank P < .001). Among smokers, patients with a ≤15 pack-year history of smoking had a longer median survival than patients who had smoked >15 pack-years (14.6 months vs 10.8 months; log‒rank P = .03). As the number of pack-years increased, the median overall survival decreased (log‒rank P < .001). Multivariate analysis indicated that a history of smoking was an independent prognostic factor (hazard ratio, 1.36; P < .001).
Although cigarette smoking causes the majority of new cases of lung cancer in the United States, greater than 30,000 patients diagnosed with nonsmall cell lung cancer (NSCLC) each year have never smoked cigarettes. For patients with NSCLC, a history of smoking cigarettes is a negative prognostic factor.1-16 However, among smokers, a history of cigarette smoking can range from patients who smoked a few cigarettes a day for a few years to patients who smoked packs of cigarettes daily for decades.
The importance of amount of cigarette smoking history, as measured by pack-years, is clear from our understanding of the epidemiology of epidermal growth factor receptor (EGFR) gene mutations. Although somatic EGFR mutations are widely known to be more common in patients with NSCLC who never smoked cigarettes, patients with more limited smoking histories are more likely to have EGFR mutations than those with heavy smoking histories.17 In fact, the frequency of EGFR mutations is not significantly different between patients with NSCLC who never smoked and those who smoked cigarettes for up to 15 pack-years.17
Patients with stage IV lung adenocarcinoma whose tumors harbor EGFR mutations in exon 19 or 21 are reported to have response rates >70% and prolonged progression‒free survival after treatment with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib (graded according to the American Joint Committee on Cancer staging system).18-22 The presence of EGFR mutations is reported to predict response to EGFR TKI therapy better than smoking status and may be a positive prognostic factor in patients with advanced lung adenocarcinoma irrespective of therapy.18, 23
The identification and characterization of prognostic factors for patients with NSCLC is important to allow comparison of patient populations in clinical trials and to help guide therapies for some patients. The best prognostic factor for patients with NSCLC is stage of disease.24 Among patients with stage IIIB/IV NSCLC, positive prognostic factors include Karnofsky performance status (KPS) ≥80%, absence of significant weight loss (>5%), and female sex.25, 26 To characterize the relation between survival and pack-years of cigarette smoking, we reviewed prospectively collected smoking data, clinical characteristics, and outcome data for patients with stage IIIB/IV NSCLC.
MATERIALS AND METHODS
Study Design and Patients
All patients evaluated by the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center (MSKCC) complete a prospectively administered smoking questionnaire as part of the standard clinical assessment. Using the smoking questionnaire, the number of pack-years was determined for patients with stage IIIB/IV NSCLC. This cohort includes patients with stage IIIB/IV disease at the time of the initial diagnosis and patients diagnosed with stage IV NSCLC at the time of recurrent disease after previous surgery or radiation. From the medical record, we also obtained data regarding sex, race/ethnicity, age, KPS, and the presence of weight loss >5% within 6 months of the initial visit. This review of records was done under a waiver of authorization approved by the MSKCC Institutional Review Board and Privacy Board.
Patients were categorized as never-smokers if they smoked <100 cigarettes. Former smokers had to have quit at least 1 year before the visit. Current smokers continued to smoke or quit less than 1 year before the visit. Race and ethnicity were reported by the patient.
Differences in clinical characteristics among smoking groups (never, ≤15 pack-years, and >15 pack-years) were tested using the chi-square test for categorical variables and analysis of variance (ANOVA) for continuous variables. Overall survival time was measured from the date of diagnosis of stage IIIB/IV NSCLC until the date of death. Living patients were censored at the date of last evaluation at the institution. Survival data were obtained using the medical record and the Social Security death index. Survival status was updated in March 2008. Survival probabilities were calculated by the Kaplan-Meier method and compared among different groups using the log-rank test. Univariate and multivariate Cox regression analyses were performed to identify variables with independent prognostic significance. Statistical analyses were performed using SAS statistical software (SAS Institute, Inc, Cary, NC).
We evaluated 2010 patients with stage IIIB/IV NSCLC between June 2003 and March 2006. The demographic characteristics of the patients are summarized in Table 1. Never-smokers comprised 16% of the study cohort, with current and former smokers representing 29% and 54% of the patients, respectively. Former and current smokers were subdivided into patients who had smoked ≤15 pack-years and those who had smoked >15 pack-years.17 Never-smokers and former or current smokers with ≤15 pack-years of smoking were younger than patients with a >15 pack-year smoking history (median ages: 59 years, 60 years, and 65 years, respectively; P < .001) and were more likely to be women (66%, 60%, and 44%, respectively; P < .001). The majority of the patients were white. The largest proportion of Asian patients was among never-smokers (15%) compared with those with ≤15 pack-years (6%) and >15 pack-years (1%) groups.
A total of 1568 deaths (78%) had occurred at the time of analysis. Never-smokers had a longer median survival than former and current smokers (17.8 months vs 11.3 months; log‒rank P < .001) (Fig. 1). Never-smokers had a 2-year survival rate of 39% compared with 21% for former and current smokers (log-rank P < .001) (Fig. 1). The effect on survival of the amount of cigarette smoking was apparent when we subdivided the former and current smokers into ≤15 pack-years and >15 pack-years groups. Never-smokers had a 3-month longer median survival compared with smokers who smoked ≤15 pack-years, and a 7‒month longer survival compared with those who smoked >15 pack-years (17.8 months vs 14.6 months vs 10.8 months; log‒rank P = .03) (Fig. 2). Similarly, the 2-year survival rate was greatest for never-smokers compared with ≤15 pack-year and >15 pack-year smokers (39% vs 29% vs 20%; log-rank P = .03). We further subdivided former and current smokers into groups by smaller increments of pack-years smoked. Due to the large number of subgroups, the survival data are presented as median survivals (Fig. 3). As the number of pack-years increased, the median survival decreased. In univariate analysis, which included weight loss, sex, age, KPS, and smoking history, smoking history was found to predict overall survival, with a hazard ratio similar to that of other known prognostic factors (Table 2). In a multivariate analysis (Table 3), which included sex, age, KPS, and weight loss, cigarette smoking history was an independent prognostic factor.
HR was adjusted for age, sex, Karnofsky performance status, and weight loss >5%. An HR >1.00 indicates worse survival.
Current + former vs never
≤15 pack-y vs never
>15 pack-y vs ≤15 pack-y
>15 pack-y vs never
NSCLC in never-smokers has a distinct biology, natural history, and responsiveness to EGFR TKI therapy.27 Although multiple previous studies have demonstrated the negative effects of smoking on patients with NSCLC, these results are confounded by several factors.1-16 In some reports, never-smokers accounted for a small proportion of patients.6, 10 Although the majority of reports defined never-smokers as individuals who smoked <100 cigarettes, some previous studies have used inconsistent definitions of never-smokers.5-8, 15 In other studies, retrospective chart reviews did not include a detailed dose quantification by pack-years of cigarettes smoked.3, 6-8, 11, 13, 15, 16 Most studies included a heterogeneous population comprised of patients with all stages and types of lung cancer.1, 3, 5, 6, 8, 10, 11, 15 Small cell lung cancer, a disease with a different natural history from NSCLC, has even been included in some analyses.6, 10
In contrast, the current study cohort consisted exclusively of patients with stage IIIB/IV NSCLC. We obtained detailed smoking history data by using a prospectively administered questionnaire. With this large cohort of North American patients with advanced NSCLC, we demonstrated an inverse relation between the amount of cigarette smoking and survival. Our analysis is unique because it demonstrates that the amount of cigarette smoking is important.
Although the large number of patients with a clearly documented cigarette smoking history and a uniform stage of disease make these data powerful, there are limitations to our analysis. Current and former smokers were grouped together in this analysis. Although several other studies have shown that lung cancer patients who continue to smoke have a poorer outcome,6, 8-10, 14 to the best of our knowledge, the current study is the first to highlight a significant dose-response relation between smoking and survival. Patients in this cohort received a wide variety of therapies, raising the possibility that the outcomes could have been affected by the particular therapies administered. Scagliotti et al noted that never-smokers with NSCLC who received 1 of 2 cisplatin-based doublet chemotherapies had a 5-month better median survival compared with former or current smokers, supporting a survival difference based on smoking status and independent of treatment type.28 Because patients with a minimal smoking history are more likely to carry sensitizing EGFR mutations and therefore respond to erlotinib or gefitinib, there is a possibility that the effect on overall survival is a result of EGFR TKIs. However, earlier patient cohorts studied by Nordquist et al and Marks et al that demonstrated survival differences based on cigarette use were not treated with EGFR TKIs.8, 29 Finally, we have not performed a systematic evaluation of the medical comorbidities for these patients. We have accounted for these issues by adjusting for KPS, age, and weight loss through the multivariate analysis. The uniformly short overall survival reported for patients with advanced NSCLC makes it unlikely that medical comorbidities alone could account for the findings observed here. Toh et al demonstrated that there was no significant association between the presence of comorbidities and survival on univariate and multivariate analyses.11 Finally, in the study by Nordquist et al, the improvements in overall survival noted with never-smokers were the same as the improvements observed with regard to cancer-specific survival.8
These results, together with published studies, emphasize the negative prognostic effects of cigarette smoking in patients with NSCLC.1-16 We believe we have demonstrated for the first time that an inverse relation exists between the extent of cigarette smoking and survival. These data suggest that NSCLC in never-smokers is at 1 end of a spectrum, demonstrating the negative prognostic impact of cigarette smoking. Based on these findings, we recommend that, in clinical trials, when an imbalance could exist in the amount of cigarettes smoked by patients in the comparison arms, investigators should stratify patients by smoking status. All clinical trials assessing survival in patients with stage IIIB/IV NSCLC should report the cigarette smoking history for all patients.
CONFLICT OF INTEREST DISCLOSURES
Supported in part by National Institutes of Health Grant 5T32CA009207.