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Ann Thorac Surg 2007;84:946-950
© 2007 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Association of Chronic Obstructive Pulmonary Disease and Tumor Recurrence in Patients With Stage IA Lung Cancer After Complete Resection

Yasuo Sekine, MD*, Yoshito Yamada, MD, Masako Chiyo, MD, Takekazu Iwata, MD, Takahiro Nakajima, MD, Kazuhiro Yasufuku, MD, Makoto Suzuki, MD, Takehiko Fujisawa, MD

Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

Accepted for publication April 11, 2007.

* Address correspondence to Dr Sekine, Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan (Email: sekine{at}faculty.chiba-u.jp).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Chronic obstructive pulmonary disease (COPD) poses a high risk for postoperative pulmonary complications after lung cancer surgery. We sought to determine the impact of this disease on long-term survival after surgical resection and to identify prognostic factors in pathological stage IA lung cancer.

Methods: A retrospective chart review was completed in 442 patients with pathological stage IA lung cancer, who had a lobectomy with systematic lymph node dissection (30.3%), out of 1,461 patients who underwent lung cancer surgery at our hospital from January 1990 to April 2005. The functional definition of COPD, according to the spirometric guidelines of the Global Initiative for Chronic Obstructive Lung Disease, was forced expiratory volume in 1 second to forced vital capacity less than 70% (FEV1/FVC). The postoperative complications were compared between the non-COPD (362 patients) and COPD (80 patients) groups. Overall survival and disease-free survival were analyzed using the Kaplan-Meier method and log-rank test. Prognostic factors were identified by univariate and multivariate analyses.

Results: The frequencies of all pulmonary complications except for pneumonia and tracheostomy were similar between the two groups. Overall survival and disease-free survival in the COPD group were significantly worse than those in the non-COPD group (p < 0.0001 and p = 0.037, respectively). Significant prognostic factors were larger tumor size (p = 0.0035) and COPD (p = 0.0147). Significant risk factors for cancer recurrence were larger tumor size (p = 0.001) and COPD (p = 0.0105) by multivariate analyses.

Conclusions: Patients with COPD had poorer long-term survival. This may be due to a higher incidence of tumor recurrence.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Lung cancer and chronic obstructive pulmonary disease (COPD) are common fatal diseases. Lung cancer patients with COPD are frequently deemed inoperable due to low cardiopulmonary reserve. However, recent reports suggested the expansion of operative indication in patients with severe COPD [1, 2]. Furthermore, it has been determined that patients with mild to severe COPD preserve pulmonary function after lobectomy better than predicted postoperative function [3–5].

Even though complete resection is functionally possible, pulmonary complications are still major causes of morbidity in patients with COPD [6, 7]. Pulmonary resection decreases the limited respiratory reserve and causes hypoventilation, hypoxia, hypercapnia, and retention of secretions that may lead to respiratory failure. These effects may induce poor short-term survival and quality of life. However, the impact of COPD itself on long-term survival has yet to be investigated [8, 9]. In particular, the risk of lung cancer recurrence in patients with COPD has not been studied.

The purpose of this study was to determine the incidence of various types of postoperative pulmonary complications, and to assess the impact of COPD on long-term overall and disease-free survivals. The subjects of this study were limited to patients in pathological stage IA lung cancer who had undergone complete surgical resection.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
This study was approved by the local Institutional Review Board of the hospital. Informed consent from the patients was waived because of a retrospective study. Out of 1,461 patients who underwent pulmonary resection for lung cancer at Chiba University Hospital from January 1990 to April 2005, 499 patients (34.2%) were pathological stage IA. Because the purpose of this study was to identify whether COPD could be a prognostic factor, 56 cases with incomplete resection and limited resection were excluded. One patient who underwent pneumonectomy was also excluded from the analysis to limit cases to one operative condition. Finally, out of 499 patients with p-stage IA, we selected 442 patients (30.3%) who received complete resection and performed a retrospective chart review. The definition of complete resection was lobectomy with systematic lymph node dissection. No patients received neoadjuvant or adjuvant therapy. Data were collected from our institutional cancer registry database and from patient’s follow-up visits in the physician’s office.

The functional definition of COPD was forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) less than 70% in accordance with the spirometric guidelines of the Global Initiative for Chronic Obstructive Lung Disease [10], and 80 of the 442 patients (18.1%) had COPD. All participants with COPD were involved in a pulmonary rehabilitation program perioperatively according to the severity of COPD [11]. Incentive spirometry and nebulizing by distilled water with or without bronchodilator were routinely encouraged for enhancing lung expansion and airway clearance for one to two weeks before and after surgery. The postoperative morbidities before discharge from the hospital included the following: bacterial pneumonia (confirmed by infiltrative shadows on chest X-ray, positive sputum culture, body temperature ≥37.5°C, and more than 10,000/µL white blood cell count); acute lung injury, such as interstitial pneumonia (aggravation of dyspnea on exertion, deterioration of arterial blood gases, and diffuse interstitial abnormalities); mechanical ventilation for three or more days; bronchial stump dehiscence; empyema (positive bacterial infection of pleural effusion); and tracheostomy and postoperative home oxygen therapy for patients with a partial pressure of oxygen, arterial (PaO 2) less than 55 mm Hg at rest or less than 60 mm Hg on exercise at the time of hospital discharge.

After discharge from the hospital, patients visited our outpatient clinic regularly every one to six months. Tumor recurrence or metastasis was routinely checked every 6 to 12 months by chest computed tomography (CT), brain magnetic resonance imaging (MRI), positron emission tomography with 18F-fluoro-2-d-glucose (FDG-PET), bone scintigraphy, and several serum tumor markers. The overall survival and the disease-free survival were analyzed for each group of patients.

Statistical Analysis
Data were analyzed using Stat View version 5.0 (SAS Inc, Cary, NC). To compare the differences between non-COPD and COPD groups, the Mann-Whitney U test was used to analyze for continuous variables, and the Fisher exact test was used to analyze for categoric variables. The survival curves were estimated with the Kaplan-Meier method, and the difference in survival times between the two groups was calculated by the log-rank test. Overall survival was defined as the time elapsed from the date of surgery to death from any cause or to last follow-up. The disease-free survival was calculated as the time elapsed from the date of surgery to clinical or radiographic demonstration of the first recurrence. The mean follow-up period was 74.0 ± 46.2 months (median 62.3 months). The Cox proportional hazard model was applied for identifying prognostic factors. Gender, age, body mass index (BMI), smoking index, tumor size, histology, percent of predicted FEV1, FEV1/FVC, and COPD were selected as possible prognostic factors. Significant risk factors in the univariate analysis (p < 0.05) were analyzed by multivariate analysis.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Perioperative Patient Characteristics
Perioperative patient characteristics are summarized in Table 1. Patients with COPD were significantly older and thinner than patients without COPD. Male patients, squamous cell carcinoma, positive smoking history, and higher smoking index were more frequent in the COPD group than in the non-COPD group. Pulmonary function tests revealed significantly poorer FEV1, percent predicted FEV1, and FEV1/FVC in the COPD group compared with the non-COPD group.


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  		Table 1 Perioperative Patient Characteristics
 
Postoperative Morbidity and Mortality
Postoperative pulmonary complications and mortality are summarized in Table 2. Pneumonia and tracheostomy were more frequent in the COPD group than in the non-COPD group (p < 0.0001 and p = 0.0047, respectively). The frequencies of all other pulmonary complications were similar between the two groups. No patients died postoperatively during the hospital stay.


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  		Table 2 Postoperative Complications and Mortality
 
Survival Analysis
Forty-seven patients (13.0%) in the non-COPD group and 27 patients (33.8%) in the COPD group died during the study period. Forty-nine (13.5%) patients in the non-COPD group and 17 patients (21.3%) in the COPD group had recurrence of the primary lung cancer. The cumulative overall survivals of the non-COPD and COPD groups at five years were 91.6% and 77.0% (p < 0.0001; Fig 1), and the disease-free survival of these two groups at five years were 88.1% and 76.6%, respectively (p = 0.037; Fig 2).


Figure 1
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  		Fig 1. Overall survival in patients with p-stage IA lung cancer after pulmonary resection. The cumulative survivals at five years are 91.6% in the non-COPD group and 77.0% in the COPD group (p < 0.0001). (--- = non-COPD; — = COPD; COPD = chronic obstructive pulmonary disease.)

 

Figure 2
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  		Fig 2. Disease-free survival in patients with p-stage IA lung cancer after pulmonary resection. The disease-free survival at five years are 88.1% in the non-COPD group and 76.6% in the COPD group (p = 0.037). (--- = non-COPD; — = COPD; COPD = chronic obstructive pulmonary disease.)

 
Univariate and Multivariate Analyses of Risk Factors for Long-Term Overall Mortality
We attempted to clarify risk factors for long-term overall mortality by univariate (Table 3) and multivariate (Table 4) analyses. Male, higher age, lower BMI, bigger tumor size, squamous cell carcinoma and COPD in the univariate analysis, and bigger tumor size and COPD in the multivariate analysis were identified as significant prognostic factors. Tables 5 and 6 Go show risk factors for cancer recurrence. Only bigger tumor size and COPD were identified as risk factors determined by univariate and multivariate analyses.


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  		Table 3 Univariate Analysis of Risk Factors for Overall Mortality with Proportional Hazard Model
 

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  		Table 4 Multivariate Analysis of Risk Factors for Overall Mortality with Proportional Hazard Model
 

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  		Table 5 Univariate Analysis of Risk Factors for Disease-Free Survival with Proportional Hazard Model
 

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  		Table 6 Multivariate Analysis of Risk Factors for Disease Free-Survival with Proportional Hazard Model
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Patients with a very low preoperative FEV1 and FEV1/FVC ratio are less likely to lose respiratory function after lobectomy and sometimes may see improvement [5]. Based on such experience, the indication for surgery in lung cancer patients with COPD has been extended, and the traditional standards of functional limitation for curative resection have been reevaluated. We previously reported that FEV1 had deteriorated less than expected after lobectomy, even in patients with mild to moderate COPD compared with patients without COPD [4]. However, long-term effects of volume loss by surgical resection in lung cancer patients with COPD have not been investigated. We clarified in this study that patients with COPD and pathological stage IA lung cancer had acceptable postoperative morbidities after curative complete resection. Falcoz and colleagues [12] reported risk factors for in-hospital death after general thoracic surgery, and COPD was not an independent risk factor. In our study, however, patients with COPD had a poorer long-term survival due to higher recurrence of lung cancer than patients without COPD. This result was similar to the report by Lopez-Encuentra and colleagues [9]. They reported that COPD comorbidity could have a prognostic value in pathological stage I non-small cell lung cancer when it was analyzed using conditional survival. This effect was observed two years after resection surgery and it was related directly with the degree of functional loss (FEV1%).

Lung cancer is closely related to COPD. Skillrud and colleagues [13] reported that the occurrence of lung cancer in patients with COPD was five times higher than in patients without COPD. The Multiple Risk Factor Intervention Trial (MRFIT) [14] reported that the risk of lung cancer death was related not to the smoking index but to the flow limitation (the severity of COPD). The trial also reported that patients with flow limitation had a sevenfold greater risk of lung cancer death than did those without flow limitation for patients in the same smoking index group. These results suggest that COPD is a strong promoting factor of lung cancer. Therefore, we speculate that COPD may accelerate recurrence and metastasis of lung cancer after surgery.

Chronic obstructive pulmonary disease is characterized by alveolar destruction and inflammation of the airway induced mainly by cigarette smoke. The mechanism of lung cancer occurrence in patients with COPD has not been clarified. Several hypotheses, such as chronic inflammation of bronchial and alveolar mucosa by carcinogenic substances [15], direct injury of DNA and inhibition of DNA restoration by oxidative stress [16, 17], and genetic mutation and variation [18, 19] are proposed. It has been reported [20] that interleukin (IL)-13 and its associated receptors, IL-1, IL-1beta promoter single nucleotide polymorphisms, and many genetic factors, are associated with COPD and development of lung cancer. We hypothesize that some genetic mutation and abnormal expression or suppression may accelerate cancer recurrence and metastasis in patients with COPD. We are now conducting studies to find the critical role of some genetic mutations in this mechanism.

Previous studies have shown that postoperative pulmonary complications were closely linked to COPD [8, 21, 22]. They suggested that the cause of poor prognosis and poor quality of life in patients with COPD was respiratory deterioration. In this study, only pneumonia and tracheostomy were observed more frequently in COPD patients than in non-COPD patients. However, there was no postoperative in-hospital mortality in the two groups. Satambrogio and colleagues [23] also reported the same mortality and morbidity in patients with FEV1 greater than 80% and FEV1 less than 80%.

Univariate analysis revealed that higher age, lower BMI, bigger tumor size, squamous cell carcinoma, low percent predicted FEV1, low FEV1/FVC, and COPD were significant prognostic factors by univariate analysis. However, multivariate analysis revealed that only bigger tumor size and COPD were significant prognostic factors. For stage IA, adenocarcinoma was predominant in cases with COPD even though the fraction with squamous cell carcinoma was higher than that in non-COPD cases. In stages II and III, squamous cell carcinoma was clearly predominant in cases with COPD in our database, and survival was similar in patients with and without COPD (data not shown). The impact of COPD on survival was clear only in stage IA. This may be because the impact of cancer behavior on survival was much stronger than the influence of COPD in advanced stages.

This retrospective study has certain limitations and biases. After tumor recurrence and metastasis, additional therapy for recurrence was done according to the patient’s condition. Some patients who had low cardiopulmonary function could not tolerate aggressive chemotherapy and radiotherapy. This might have influenced the survival results. Second, COPD should not be defined only by the functional limitation. Other criteria, such as diffusion capacity, radiologic evaluation, and clinical criteria should have been taken into consideration [24]. It is possible that the use of other criteria for COPD could produce results that differ from ours. Third, this is a small dataset of a single center study. Therefore, there may be several confounding variables. It should be verified in a large prospective study.

In conclusion, although the incidences of postoperative complications were acceptable in patients with COPD, they had poorer long-term survivals because they may have a higher incidence of tumor recurrence. We should be watchful not only for postoperative functional deterioration but also for higher recurrence of lung cancer in patients with COPD.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

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