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Original Research: Lung Cancer |

The Impact of Coexisting COPD on Survival of Patients With Early-Stage Non-small Cell Lung Cancer Undergoing Surgical ResectionEffect of Coexisting COPD on Lung Cancer Survival FREE TO VIEW

Rihong Zhai, MD, PhD; Xiaojin Yu, PhD; Andrea Shafer, MPH; John C. Wain, MD, FCCP; David C. Christiani, MD, FCCP
Author and Funding Information

From the Department of Environmental Health (Drs Zhai, Yu, and Christiani), Harvard School of Public Health; and the Department of Medicine (Dr Christiani and Ms Shafer), and the Department of Surgery (Dr Wain), Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Correspondence to: David C. Christiani, MD, FCCP, Harvard School of Public Health, 665 Huntington Ave, I-1401, Boston, MA 02115; e-mail: dchris@hsph.harvard.edu


Funding/Support: The work was supported by the National Institutes of Health [Grants CA092824, CA074386, CA090578, and ES00002].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(2):346-353. doi:10.1378/chest.13-1176
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Background:  COPD is a recognized risk factor for lung cancer, but studies of coexisting COPD in relation to lung cancer outcomes are limited. We assessed the impact of COPD on overall survival (OS) and progression-free survival (PFS) in patients with early-stage non-small cell lung cancer (NSCLC).

Methods:  Patients (N = 902) with early-stage (stage IA-IIB) NSCLC treated with surgical resection were retrospectively analyzed. The association of self-reported, physician-diagnosed COPD with survivals of NSCLC was assessed using the log-rank and Cox regression models, adjusting for age, sex, BMI, smoking, stages, and performance status.

Results:  Among this cohort of patients with NSCLC, 330 cases had physician-diagnosed COPD, and 572 did not have COPD. The 5-year OS in patients with COPD (54.4%) was significantly lower (P = .0002) than that in patients without COPD (69.0%). The 5-year PFS rates for patients with COPD and without COPD were 50.1% and 60.6%, respectively (P = .007). Compared with patients without COPD, patients with COPD had increased risk of worse OS (adjusted hazard ratio [HRadj] = 1.41, P = .002) and PFS (HRadj = 1.67, P = .003). The associations between COPD and worse survival outcomes were stronger in men and in squamous cell carcinoma (SCC).

Conclusions:  Coexisting COPD is associated with worse survival outcomes in patients with early-stage NSCLC, particularly for men and for SCC.

Figures in this Article

COPD is the fourth leading cause of death, causing > 2.5 million deaths per year worldwide.1 Prevalence surveys suggest that up to almost one-fourth of adults aged ≥ 40 years have mild airway obstructions.2 Moreover, it has been projected that COPD will become the third leading cause of mortality worldwide by 2020.3

In addition to the irreversible airflow obstruction that characterizes the disease,4 COPD has also been found to be an important risk factor for lung cancer, one of the most common cancers worldwide.5,6 The risk of lung cancer in patients with COPD is approximately fivefold greater than that of smokers without COPD,7,8 independent of age and cigarette smoking.7,9 In COPD cohort studies, the incidence ratios for lung cancer ranged from 4.210 to 16.7 per 1,000 person-years.6 Furthermore, studies have suggested that the risk for lung cancer increased in proportion to the degree of airway obstruction.11 Reduction of FEV1 to approximately 90% of predicted value significantly increased the risk for lung cancer by 30% in men and by 2.64-fold in women.12

Although the association of COPD with lung cancer risk is well recognized, relatively less is known about the impact of COPD on lung cancer survival. A few studies have suggested that the prognosis for patients with lung cancer with COPD was worse than that of patients with lung cancer without COPD.13,14 But the effect of COPD on survival after resection of lung cancer is uncertain. Several prospective studies in Japanese patients reported that the overall survival (OS) in patients with lung cancer with COPD was lower than that in patients without COPD,15,16 but these results may not be simply extrapolated to white patients because ethnic differences in survival outcomes in lung cancer have been clearly demonstrated.17,18 Although a study of lung cancer found no difference in overall 5-year survival between patients with COPD and patients without COPD,19 the results of this study are difficult to interpret because the study failed to control for the confounding of other prognostic factors (such as age, sex, stage, performance status, and smoking) on survival.20,21 Furthermore, it remains unclear to what extent the COPD may contribute to lung cancer survival among the different histologic cell types.

In this study, we examine the impact of physician-diagnosed COPD on survival outcomes of early-stage non-small cell lung cancer (NSCLC). We hypothesized that patients with NSCLC with COPD would be associated with worse survival compared with patients without COPD. Since histologic cell type has been suggested as a determinant of the effect of COPD on lung cancer development,6 we also hypothesized that the relationships between COPD and NSCLC outcomes are related to histologic subtype.

Patients

The study was approved by the institutional review boards of Massachusetts General Hospital (MGH) (Partners Human Research Committee, Protocol # 1999P004935/MGH) and the Harvard School of Public Health (Harvard School of Public Health, Office of Regulatory Affairs and Research Compliance, Protocol # 10157 and Protocol # 10178). Details of the study population have been previously reported.21 Briefly, patients (> 18 years old) with pathologically confirmed newly diagnosed NSCLC were consecutively recruited and followed at the MGH between 1992 and 2010. More than 85% of eligible patients were recruited in this cohort, and 96% were white. Demographic information (including age, sex, smoking status and intensity, and BMI) were collected by trained research staff using a standardized questionnaire at the time of recruitment. Informed consent was obtained from each subject or their surrogates to collect follow-up data.

We focused our analysis on patients with stage I (IA, IB) and II (IIA, IIB) NSCLC who had their surgical resection performed at MGH and had follow-up data. We restricted our analyses to whites only because > 95% of patients were white, and ethnicity may influence lung cancer survival.17 We retrospectively extracted clinical information on all patients. The baseline questionnaire listed chronic bronchitis, emphysema, and/or COPD that prompted the participants to indicate those for which he or she had ever been diagnosed by a doctor. Physician-diagnosed COPD was defined as a positive response to chronic bronchitis, emphysema, and/or COPD prior to or on admission to the hospital.9,22,23 We defined COPD via self-report because multiple previous studies have shown that self-reported, physician-diagnosed COPD is highly consistent with spirometry-diagnosed COPD and accurate for epidemiologic studies.2426 In total, 902 patients with early-stage NSCLC were included in this study. Among them, 330 patients were defined as having NSCLC with COPD, and the rest (n = 572) were classified as having NSCLC without COPD.

Outcome Data Collection

The primary outcome of this study was OS, measured from the date of surgery to the date of death (event) or last known to be alive (censored). The secondary outcome was progression-free survival (PFS), defined as the time from the date of surgery to the first date of recurrence of cancer, or death from any cause.21 Data were collected from at least one of the following sources: (1) MGH patient and outpatient records, (2) MGH tumor registry, (3) social security death index, (4) primary physician’s office, and (5) patient or family contact.21 Patients who did not have recurrence who were still alive or lost to follow-up were censored. Date of recurrence was obtained by reviewing the hospital and outpatient records of all patients. For those patients who had their primary follow-up outside of the MGH system, we contacted the primary physician of patients/family to obtain follow-up information.

Statistical Analysis

Data were compared across subgroups using χ2 tests (for categorical variables) and Kruskal-Wallis or t tests (for continuous variables), where appropriate. Associations between COPD and outcomes (OS, PFS) were estimated using the method of Kaplan-Meier to generate survival curves and assessed using the log-rank tests. Cox proportional hazards models were used as our primary analyses, adjusting for age, sex, stage, performance status, smoking status and smoking intensity (pack-years), and BMI. To avoid the influence of collinearity between smoking status and pack-years, we analyzed the effects of smoking status and pack-years on outcomes in separate models in which never smokers and pack-years of 0 were used as references, respectively. To better understand the impact of COPD on NSCLC survival, we conducted analyses in subgroups stratified by sex and histologic subtypes (adenocarcinoma and squamous cell carcinoma [SCC]). All reported P values are from two-sided tests. P value < .05 was considered statistically significant. All statistical analyses used SAS software, version 9.2 (SAS Institute Inc).

Patient Characteristics

Among the 902 patients with early-stage NSCLC, there were 291 recurrences and 382 deaths. All patients were treated with surgical resection. The median follow-up time among subjects who were still alive was 41 months (range, 0.2-260 months). The 5-year OS and 5-year PFS rates for this cohort were 63.8% and 57.4%, respectively. Detailed demographic, clinical, and treatment information by COPD are presented in Table 1. Mean age, stage, smoking status, pack-years of smoking, and years of quit smoking among former smokers were significantly different between NSCLC with COPD and NSCLC without COPD.

Table Graphic Jump Location
Table 1 —Demographic and Clinical Characteristics for Patients With Early-Stage NSCLC

Data are presented as mean ± SD or No. (%). ECOG = Eastern Cooperative Oncology Group; NSCLC = non-small cell lung cancer; OS = overall survival; PFS = progression-free survival.

a 

Includes adenocarcinoma with bronchioalveolar cell elements.

b 

Log-rank test.

COPD and OS

Kaplan-Meier curves and log-rank test showed that COPD was significantly associated with worse survival (P = .0002) (Fig 1). The 5-year OS rates in patients with COPD (54.4%) was significantly lower than that in patients without COPD (69.0%) (P = .0002).

Figure Jump LinkFigure 1. Kaplan-Meier curve of overall survival (OS) by COPD. COPD was associated with significantly shorter OS in early stage non-small cell lung cancer (P = .0002, log-rank test).Grahic Jump Location

In the univariate analysis of the Cox regression models, COPD was significantly associated with worse OS (hazard ratio [HR] = 1.47; 95% CI, 1.20-1.80; P = .0003). In the multivariate Cox proportional hazard model adjusting for clinicopathologic variables, the adjusted HR (HRadj) for COPD was 1.41 (95% CI, 1.13-1.75; P = .002) when compared with non-COPD (Table 2). In stratified analyses, stronger associations between COPD and worse OS were observed for men (HRadj = 1.50; 95% CI, 1.12-2.01; P = .007), and for patients with SCC (HRadj = 1.50, 95% CI, 1.04-2.15; P = .03) when compared with corresponding HRs in women and patients with adenocarcinoma (Table 3).

Table Graphic Jump Location
Table 2 —HRs for OS According to Clinicopathologic Variables Among Patients With Early-Stage NSCLC

HR = hazard ratio; HRadj = adjusted hazard ratio. See Table 1 legend for expansion of other abbreviations.

a 

Adjusted for all variables shown in table.

Table Graphic Jump Location
Table 3 —Impact of Coexisting COPD on Outcomes of Early-Stage NSCLC Stratified by Sex and Major Histologic Subtype

See Table 1 and 2 legends for expansion of abbreviations.

a 

Adjusted for age, performance status, BMI, smoking (pack-years), and stage.

b 

Adjusted for age, sex, performance status, BMI, smoking (pack-years), and stage.

COPD and PFS

Similar to the results of OS, COPD was associated with a worse PFS in log-rank test (P = .007) (Fig 2). The 5-year PFS rates in patients with NSCLC with COPD (50.1%) were also significantly lower than those in patients with NSCLC without COPD (60.6%) (P = .007). In the univariate analysis, COPD was significantly associated with higher risk of recurrence (HR = 1.39; 95% CI, 1.10-1.76; P = .007). In multivariate analysis, the HRadj for COPD was 1.67 (95% CI, 1.19-2.22; P = .003) for patients with COPD vs patients without COPD (Table 4).

Figure Jump LinkFigure 2. Kaplan-Meier curve of progression-free survival (PFS) by COPD. COPD was associated with significantly shorter PFS in early-stage non-small cell lung cancer (P = .007, log-rank test).Grahic Jump Location
Table Graphic Jump Location
Table 4 —HRs for PFS According to Clinicopathologic Variables Among Patients With Early-Stage NSCLC

See Table 1 and 2 legends for expansion of abbreviations.

a 

Adjusted for all variables shown in table.

Sensitivity Analysis

We examined the correlations between smoking intensity and COPD in the entire cohort (N = 902). The Pearson correlation coefficient between smoking and COPD was moderate (0.20), suggesting that the relationship between COPD and NSCLC outcome was likely independent of smoking intensity. Consistent with this, in multivariate Cox regression analysis adjusting for smoking variables, COPD remained significantly associated with NSCLC outcomes, suggesting that COPD was an independent risk factor for NSCLC prognosis. When the analysis was confined to patients who were never smokers (n = 93; defined as having smoked < 100 cigarettes over his or her lifetime), COPD was significantly associated with worse PFS (HRadj = 6.04; 95% CI, 1.37-26.57; P = .02) and a trend of worse OS (HRadj = 2.734; 95% CI, 0.652-11.47; P = .17) (Table 5).

Table Graphic Jump Location
Table 5 —HRs for Outcomes of Early-Stage NSCLC in Never Smokers (n = 93)

See Table 1 and 2 legends for expansion of abbreviations.

a 

Adjusted for all variables shown in table.

In the present study, we found that coexisting COPD was associated with worse OS and PFS in patients with early-stage NSCLC. The associations between COPD and worse NSCLC outcomes were stronger in those who had SCC and in men.

Although the biologic mechanisms through which COPD may influence NSCLC prognosis are unclear, several lines of evidence suggest that our results are biologically plausible. First, COPD is characterized with local (pulmonary) and systemic chronic inflammation, which may result in repeated injury and repair, stimulating cell turnover and potential genetic errors, and ultimately lung cancer growth.27,28 Second, DNA repair capacity is associated with poorer survival in patients with NSCLC.29 Increased oxidative stress in COPD may cause DNA damage and carcinogenesis.30 In support of this, our previous report in this cohort has suggested that functional genetic variations in DNA repair genes are associated with NSCLC prognosis.31 Third, studies have suggested that COPD is associated with abnormal apoptosis and cell cycle regulation,32 which is a critical mechanism implicated in the prognosis of NSCLC.33 Fourth, epigenetic alterations, such as aberrant DNA methylation and microRNA profiles, are important mechanisms in the modification of NSCLC prognosis,34 and studies have shown that COPD is associated with aberrant DNA methylation.35 Additionally, COPD has been associated with several clinical comorbidities,36 which may adversely affect the outcomes of coexisting NSCLC.

Stratification analyses showed that the association of COPD with NSCLC survival was stronger for SCC and weaker for adenocarcinoma. Given that cigarette smoking dosage (pack-years) is directly related to the prognosis of NSCLC,37 and that smoking is a stronger risk factor for SCC than for adenocarcinoma of the lung,38 our results raise the question whether smoking exposure level is an independent risk factor for NSCLC outcomes. In our previous studies in this cohort, we have shown that smoking exposure levels were associated with worse survival in patients with early-stage NSCLC.21 In the present study, smoking level in SCC was significantly higher than that observed in adenocarcinoma. In multivariate analyses, smoking (pack-years) was independently associated with worse OR and PFS in a dose-response manner. These findings are in line with other reports in which smoking level was associated with poorer lung cancer prognosis.39 The observation that smoking exerted a higher impact on SCC than adenocarcinoma may reflect different response pathways of the lung depending on the exposure to pulmonary carcinogens and the extent of tissue damage.40

We found that male patients with NSCLC with COPD tended to experience an elevated risk of poorer prognosis than that of women. Although the reasons for this observation are not clear, a meta-analysis including 32,701 women and 54,099 men from 39 cohorts has confirmed that female sex was significantly associated with better survival in patients with NSCLC.41 Moreover, it is possible that there may be sex differences in physician diagnosis of COPD.24,42 Further examinations of the potential underlying biologic mechanisms may be warranted to better understand sex differences in the association between COPD and NSCLC outcomes.

The strengths of this study include a large sample size, which allows us to examine the association between COPD and survival by histologic subtypes and sex. A second strength is that we have complete demographic, clinical, and follow-up information, allowing us to control for the impacts of multiple confounding factors and minimize bias of results due to incomplete information. Third, our study population is homogeneous regarding histopathology and surgical therapy, with exclusion of patients receiving adjuvant therapy. Last, the robustness of our findings is supported by the consistent association across all end points (OS and PFS).

The main limitation of this study, and of other studies of this type, is that we are unable to distinguish whether COPD is in the causal pathway for NSCLC prognosis or whether both COPD and NSCLC are related to an underlying exposure or molecular mechanism. Nonetheless, the findings suggest even COPD in never smokers is still an important prognostic factor for NSCLC. In the present study, physician-diagnosed COPD at admission was ascertained by self-report and may be associated with a certain degree of misclassification. However, studies have shown that a questionnaire-based approach to defining COPD was strongly associated with spirometry-based COPD and was quite accurate for epidemiologic studies.25,26 For example, a validation study indicated that about 90% of subjects with self-reported physician-diagnosed COPD had airflow obstruction.24 It is also possible that a proportion of undiagnosed COPD cases may exist in the current cohort. If present, however, this misclassification of self-reported COPD would probably underestimate true COPD effect on NSCLC outcomes.

In conclusion, patients with early-stage NSCLC with COPD had worse survival outcomes than patients without COPD. Given that clinical guidelines for NSCLC treatment provide clinicians with little guidance in caring for patients with coexisting COPD,43 results of this study have clinical implications for the early identification of those at greater risk of NSCLC prognosis and those who will benefit from more optimal targeted treatment.

Author contributions: Dr Christiani had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Zhai: contributed to the planning of the study, study design, data analysis and interpretation; drafted the initial manuscript; and approved the final manuscript as submitted.

Dr Yu: contributed to study design, data analysis and interpretation, and manuscript preparation and review.

Ms Shafer: contributed to recruitment of study subjects, clinical data collection, and manuscript preparation and review.

Dr Wain: contributed to the planning of the study, assembly of the study subjects, phenotyping of the patients, and manuscript preparation and review.

Dr Christiani: contributed to the planning of the study, study design, assembly of the study subjects, obtaining the project funding, and approved the final manuscript as submitted.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: We thank patients for their participation in this study. We also thank Nancy Diao, MS, for data management and staff at Massachusetts General Hospital for their assistance with this project.

HR

hazard ratio

HRadj

adjusted hazard ratio

MGH

Massachusetts General Hospital

NSCLC

non-small cell lung cancer

OS

overall survival

PFS

progression-free survival

SCC

squamous cell carcinoma

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Figures

Figure Jump LinkFigure 1. Kaplan-Meier curve of overall survival (OS) by COPD. COPD was associated with significantly shorter OS in early stage non-small cell lung cancer (P = .0002, log-rank test).Grahic Jump Location
Figure Jump LinkFigure 2. Kaplan-Meier curve of progression-free survival (PFS) by COPD. COPD was associated with significantly shorter PFS in early-stage non-small cell lung cancer (P = .007, log-rank test).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Demographic and Clinical Characteristics for Patients With Early-Stage NSCLC

Data are presented as mean ± SD or No. (%). ECOG = Eastern Cooperative Oncology Group; NSCLC = non-small cell lung cancer; OS = overall survival; PFS = progression-free survival.

a 

Includes adenocarcinoma with bronchioalveolar cell elements.

b 

Log-rank test.

Table Graphic Jump Location
Table 2 —HRs for OS According to Clinicopathologic Variables Among Patients With Early-Stage NSCLC

HR = hazard ratio; HRadj = adjusted hazard ratio. See Table 1 legend for expansion of other abbreviations.

a 

Adjusted for all variables shown in table.

Table Graphic Jump Location
Table 3 —Impact of Coexisting COPD on Outcomes of Early-Stage NSCLC Stratified by Sex and Major Histologic Subtype

See Table 1 and 2 legends for expansion of abbreviations.

a 

Adjusted for age, performance status, BMI, smoking (pack-years), and stage.

b 

Adjusted for age, sex, performance status, BMI, smoking (pack-years), and stage.

Table Graphic Jump Location
Table 4 —HRs for PFS According to Clinicopathologic Variables Among Patients With Early-Stage NSCLC

See Table 1 and 2 legends for expansion of abbreviations.

a 

Adjusted for all variables shown in table.

Table Graphic Jump Location
Table 5 —HRs for Outcomes of Early-Stage NSCLC in Never Smokers (n = 93)

See Table 1 and 2 legends for expansion of abbreviations.

a 

Adjusted for all variables shown in table.

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