Surg Today (2010) 40:923–930 DOI 10.1007/s00595-009-4196-1

Original Article Efficacy of Perioperative Administration of Long-Acting Bronchodilator on Postoperative Pulmonary Function and Quality of Life in Lung Cancer Patients with Chronic Obstructive Pulmonary Disease. Preliminary Results of a Randomized Control Study HIDEMI SUZUKI1,3, YASUO SEKINE1,3, SHIGETOSHI YOSHIDA1, MAKOTO SUZUKI1, KIYOSHI SHIBUYA1, YUICHI TAKIGUCHI2, KOICHIRO TATSUMI2, and ICHIRO YOSHINO1 Departments of 1 Thoracic Surgery and 2 Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan 3 Department of Thoracic Surgery, Tokyo Women’s Medical University, Yachiyo Medical Center, 477-96 Owada Shinden, Yachiyo, Chiba 276-8524, Japan

Abstract Purpose. Long-acting bronchodilators are recommended as a first-line treatment for chronic obstructive pulmonary disease (COPD), although their effects for postoperative lung cancer patients with COPD are still not well known. A prospective randomized trial was used to examine the efficacy of bronchodilators on postoperative pulmonary function and quality of life (QOL). Methods. Twenty lung cancer patients with COPD who had lobectomies were randomized. A control group (n = 10) did not receive bronchodilators. An experimental group (n = 10) received tiotropium and salmeterol. Patients were divided into two COPD grades: stage I COPD and stage II–III COPD. Results for pulmonary function, 6-minute walking test, and the St. George’s Respiratory Questionnaire (SGRQ) were compared. Diaphragmatic motion on dynamic magnetic resonance imaging was also analyzed. Results. The patient demographics were similar in the two groups. Except for pulmonary function results at 2 weeks, no other parameters were significantly different. However, in stage II–III COPD, forced expiratory volume in 1 second, forced vital capacity, inspiratory capacity, the total score of the SGRQ, and diaphragmatic motion in the experimental group (n = 5) were significantly better than those in the control group (n = 4) at various time points (all P < 0.05). Conclusion. The daily inhalation of bronchodilators was effective for maintaining the respiratory function

Reprint requests to: Y. Sekine (address 3) Received: March 31, 2009 / Accepted: November 30, 2009 The first (H.S.) and the second (Y.S.) authors contributed equally to this paper, and both are considered as first co-authors.

and QOL in lung cancer patients with moderate to severe COPD. Key words Chronic obstructive pulmonary disease · Non-small cell lung cancer · Bronchodilator · Quality of life

Introduction Lung cancer remains a significant cause of death for smokers, and smoking is often associated with chronic obstructive pulmonary disease (COPD). A surgical resection offers the best chance for curing lung cancer. However, lung cancer patients with COPD are frequently deemed inoperable due to low cardiopulmonary reserve, and such patients often suffer from pulmonary complications after surgery.1 Chronic obstructive pulmonary disease is one of the leading causes of morbidity and mortality worldwide. At present, it is the fourth most common cause of death among adults.2 Recently, the Global Initiative for Obstructive Lung Disease (GOLD) guidelines and the American Thoracic Society (ATS)/European Respiratory Society (ERS) position paper3 emphasized the role of long-acting bronchodilators, such as tiotropium and salmeterol, and recommended these as first-line treatments for patients with COPD. To date, there have been no studies that evaluated the influence of these drugs on postoperative cancer patients with COPD. We therefore conducted a prospective randomized trial study to examine the efficacy of tiotropium and salmeterol on postoperative pulmonary function and quality of life (QOL) in lung cancer patients with COPD.

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Patients and Methods Study Design This was a 1-year, randomized, parallel-group study to determine the efficacy of tiotropium and salmeterol inhalation in lung cancer patients with COPD. The drugs administered were tiotropium (18 μg/24 h) once daily in the morning and salmeterol (50 μg/12 h) twice daily. Capsules were administered using a dry-powder inhaler device (HandiHaler; Boehringer Ingelheim, Berkshire, UK).

Patients Between July 2005 and April 2007, 276 patients with primary non-small cell lung cancer (NSCLC) underwent surgical resections at Chiba University Hospital. Of these, 20 lung cancer patients with preoperative ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) less than 70% were enrolled and randomized. All of the patients who were enrolled in this study had NSCLC with clinical stages IA or IB, and had lobectomies performed. To eliminate the possible tumor effects on the pulmonary function results,4 any patients with central lung cancer, wider atelectasis, and tumor diameters exceeding 5 cm were excluded. Patients with a known history of asthma, chronic respiratory disease other than COPD, or a recent respiratory tract infection were excluded. Patients receiving regular supplemental oxygen or corticosteroid, or who had a significant concurrent disease other than COPD, were also excluded. Use of all inhaled anticholinergics or longacting β2-agonists was discontinued. All patients were instructed to use inhaled steroids and oral steroids as needed for symptom relief during the baseline period and throughout the entire study, but none of them used steroids during this study. All current smokers were encouraged to cease smoking at the first visit to our hospital, and were confirmed to have stopped smoking at least 2 weeks before surgery. The protocol was approved by the institutional ethics committee, and written informed consent was obtained before any study procedure was undertaken.

Study Protocol Following an initial screening to assess eligibility, patients were randomized into two groups: the experimental group (n = 10) and the control group (n = 10). The control group comprised patients who underwent lobectomy with video-assisted thoracic surgery (VATS) without any bronchodilators. The experimental group consisted of patients who underwent a lobectomy with

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VATS while being administered the daily inhalation of tiotropium and salmeterol. These patients received tiotropium and salmeterol from the preoperative period (approximately 2 weeks before the operation) to 1 year after the operation. No patients used inhaled or oral steroids during the preoperative period or throughout the study period duration. Preoperative pulmonary rehabilitation for COPD patients was done from the time of admission until hospital discharge (approximately 3–4 weeks).5 Spirometry was conducted prior to the start of any therapy using a Fudac-70 spirometer (Fukuda Denshi; Chiba, Japan). Spirometry was repeated at the same time intervals at 2 weeks, 3 and 6 months, and 1 year after surgery. The measurements were made according to the ATS criteria.6 A 6-minute walking test was also conducted at the same time as spirometry. Questionnaires assessing dyspnea and QOL were administered during the preoperative period, and at 3 and 6 months and 1 year postoperatively. Quality of life was determined using the St. George’s Respiratory Questionnaire (SGRQ).7 The most commonly used measures for health status for COPD in the diseasespecific SGRQ have defined thresholds for changes that are regarded as clinically meaningful. The SGRQ contains 50 items in three subscales: symptoms, activity, and impacts. A total score can be calculated from the responses to all 50 items. A low score represents an improvement. A change of 4 U is considered clinically significant. In addition, the patients in each group were divided into two COPD grades: stage I COPD (FEV1 ≥ 80% predicted) and stage II–III COPD (FEV1 < 80% predicted) in accordance with the guidelines of ATS/ERS.3 The trends for the above parameters were analyzed. Adverse events were also tracked throughout the baseline period and for the entire study period. Dynamic magnetic resonance image (MRI) studies were done using a 1.5-Tesla Signa Horizon LX MRI system (GE Yokogawa Medical Systems, Tokyo, Japan). Sixty sequential images of the lung were obtained in 60 s from the lung apex to the base during deep slow breathing. The sequence was a single shot fast-spin echo with a half-Fourier transformation (echo time [TE]: 3.0 ms, field of view [FOV]: 45 × 45 cm, matrices: 256 × 128, slice thickness: 10 mm). Both digital imaging and the communication in medicine (DICOM) viewer software program (Virtual Place Liberty; AZE, Tokyo, Japan) were used to examine the original images. Diaphragm motion was examined by Kondo’s methods with modification.8 First, two images were selected for which the lung area increased to a maximum and decreased to a minimum. The distances from the thoracic apex to the diaphragm at both sides of the mid-clavicular line were

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measured, and the difference between both images was calculated. Statistical Analysis Data were analyzed using the StatView version 5.0 statistical software package (Statistical Analysis Systems, Cary, NC, USA). To compare the experimental and control groups, a Mann–Whitney U-test was used for continuous variables, and a χ2 test or Fisher’s exact test was used for categorical variables. Changes in pulmonary function test parameters and other parameters were statistically analyzed using a one-way factorial analysis of variance (ANOVA) followed by a Bonferroni–Dunn test. Unless otherwise specified, results are given as the mean ± SD. Differences were considered to be significant at P < 0.05.

Results Study Group Demographics All 20 randomized patients completed the study protocol. The surgical morbidity and mortality were both 0% during this study period. The two study groups

were well matched, as there were no significant differences in baseline demographics between the two groups (Table 1). The mean screening FEV1 in the experimental group was 1.96 l (71.9% of predicted), and 1.67 l in the control group (64.2% of predicted). Both groups were divided into two COPD grades: stage I COPD (n = 11) and stage II–III COPD (n = 9). The demographics for each of these groups were also similar (Table 2).

Spirometry Baseline respiratory function was similar in the two groups, and no significant differences were observed. As shown in Fig. 1, the trends for changes in FVC, FEV1, and inspiratory capacity (IC) from the baseline period were similar between the two groups, except for FEV1 and FVC at 2 weeks (P < 0.05; Fig. 1A–C). However, stage II–III COPD patients (n = 9) showed significantly better FVC, FEV1, and IC measurements in the experimental group (n = 5) than those for the control group (n = 4) at various time points (Fig. 2A–C; all P < 0.05). In contrast, stage I COPD patients (n = 11) showed similar trends for changes were observed between the two groups.

Table 1. Patients’ characteristics

Age (years) Male patients (%) Smoking index (pack-years) Body mass index Clinical stage: 1A/1B Pathological stage: 1A/1B/2B Preoperative FEV1 (l) Preoperative %FEV1 Preoperative FEV1/FVC (%)

Experimental (n = 10)

Control (n = 10)

P value

50–78 (70.9 ± 7.8) 10/10 (100) 63.6 ± 27.9 21.1 ± 5.6 5/5 6/3/1 1.96 ± 0.72 71.9 ± 23.9 53.4 ± 12.9

54–77 (66.7 ± 6.8) 8/10 (80) 52.2 ± 24.1 22.2 ± 5.5 6/4 5/3/1 1.67 ± 0.67 74.2 ± 22.6 57.7 ± 7.5

0.21 0.15 0.34 0.27 0.67 0.63 0.37 0.47 0.54

The results are the mean ± SD or n (%). FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity

Table 2. Patients’ characteristics by chronic obstructive pulmonary disease (COPD) stage Stage I COPD (n = 11)

Age (years) Male patients (%) Smoking index (pack-years) Body mass index Clinical stage: 1A/1B Pathological stage: 1A/1B/2B Type of lobectomy: upper/lower Preoperative FEV1 (l) Preoperative %FEV1 Preoperative FEV1/FVC (%)

Experimental (n = 5)

Control (n = 6)

69.6 ± 11.3 100.0 55.9 ± 20.2 23.0 ± 2.4 3/2 4/1/0 4/1 2.20 ± 0.48 88.1 ± 7.7 63.3 ± 3.0

65.8 ± 7.7 83.3 46.7 ± 18.6 21.9 ± 2.6 4/2 4/2/0 3/3 2.13 ± 0.21 88.7 ± 7.9 62.4 ± 2.8

Stage II–III COPD (n = 9) P value

Experimental (n = 5)

Control (n = 4)

P value

0.53 0.39 0.58 0.49 0.81 0.80 0.35 0.78 0.52 0.85

72.2 ± 2.3 100.0 63.6 ± 27.9 21.4 ± 2.2 2/3 2/2/1 3/2 1.46 ± 0.22 56.3 ± 8.3 43.3 ± 3.2

68.0 ± 6.2 75.0 52.2 ± 24.1 19.7 ± 1.3 2/2 2/1/1 3/1 1.39 ± 0.39 59.1 ± 7.5 45.0 ± 5.2

0.20 0.29 0.56 0.22 0.80 0.34 0.68 0.31 0.69 0.83

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Fig. 1A–D. Postoperative changes in pulmonary function and St. George’s Respiratory Questionnaire (SGRQ) scores. The mean changes from preoperative baseline for A forced expiratory volume in 1 second (FEV1), B forced vital capacity (FVC), and C inspiratory capacity (IC) were determined at 2 weeks, 3 and 6 months, and 1 year after the operation for the experimental group (solid diamonds; n = 10) and control

group (open diamonds; n = 10). No significant differences were observed, except for FEV1 and FVC at 2 weeks. D The mean changes from preoperative baseline for total SGRQ scores were determined at 3 and 6 months and 1 year postoperatively. The total SGRQ score was significantly improved in the experimental group compared to the control group at 6 months and 1 year after the operation (*P < 0.05)

Six-Minute Walking Test

16.2, respectively). The mean changes at 6 months and 1 year in total score were –3.3 and –2.2 points for the experimental group, and +6.1 and +5.8 points for the control group, respectively (P < 0.05; Fig. 1D). Each of the three SGRQ components (symptom, activity, and impact) was slightly better in the experimental group than in the control group, but was not statistically significant. The stage II–III COPD patients had 6-month and 1-year changes in total scores on the SGRQ of –7.8 and –6.4 points for the experimental group, and +1.2 and +1.3 points for the control group (P < 0.05; Fig. 2D). No significant differences were observed between the experimental and control groups for the stage I COPD patients.

At baseline, 6-min walking distances for the experimental and control groups were similar (428 ± 48 m and 432 ± 78 m, respectively). The distances at 3 and 6 months and at 1 year after surgery showed nearly the same changes for the two groups. No statistically significant differences were observed, even in the stage II–III COPD patients. Health-Related Quality of Life The SGRQ total scores for the experimental and control groups were similar at baseline (28.1 ± 10.1 and 24.8 ±

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Fig. 2. Postoperative changes in pulmonary function and SGRQ scores by chronic obstructive pulmonary disease (COPD) stage. Experimental and control groups were categorized as either stage I or stage II–III COPD (see Patients and Methods). Mean changes from preoperative baseline for A FEV1, B FVC, and C IC were determined at 3 and 6 months and 1 year after the operation. Pulmonary function parameters were significantly better for stage II–III COPD in the

experimental group than in the control group at various points (*P < 0.05). D The mean changes from preoperative baseline for total SGRQ scores were determined at 3 and 6 months and 1 year postoperatively. The total SGRQ score was significantly improved in stage II–III COPD in the experimental group compared to the control group at 6 months and 1 year after the operation (*P < 0.05)

Movement of the Diaphragm on Dynamic MRI

3.4% (experimental group) and –22.1% (control group) at the operative side, and 15.2% (experimental group) and –2.6% (control group) at the opposite side in the II–III COPD patients 1 year after surgery.

Figure 3 shows the changes of the diaphragmatic motion on dynamic MRI at the side of the operation and at the side opposite the operation. Movement of the diaphragm at the preoperation period was nearly the same in the experimental and control groups (Fig. 3A,B). The change of diaphragm motion 1 year after the operation was also similar in the two groups. However, stage II–III COPD patients showed changes of diaphragmatic motion at both sides that were significantly better in the experimental group than in the control group (P < 0.05; Fig 3C,D). The changes of diaphragmatic motion were

Adverse Events The most common adverse event related to tiotropium treatment was dry mouth (10%). During the study, two patients complained of dry mouth after surgery. One patient complained of dry mouth at 1 month after the operation, but this lasted only 3 weeks. Another patient

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Fig. 3A–D. Changes in the diaphragmatic motion on magnetic resonance imaging (MRI). Changes from the preoperative baseline for diaphragmatic motion were determined on MRI for the side of the operation and the side opposite the operation at 1 postoperative year (see Patients and Methods). The changes of distance from the thoracic apex to the diaphragm at the middle clavicular line during deep breathing

are not significantly different between the two groups at the operation-side (A) and the opposite side (B). However, for stage II–III COPD, the change of motion in the experimental group is significantly better on the operation-side (C) and on the opposite side (D) than that of the control group (*P < 0.05)

also complained of dry mouth at 2 weeks after the operation, which continued for 8 months. Their symptoms were mild, and no patients discontinued participation during the study due to dry mouth. There were no deaths or exacerbations related to the medication during the study period.

main treatment for early-stage NSCLC, the frequency of COPD increases the risk of operation because of an impaired postoperative ventilatory function.9 Long-acting bronchodilators, such as tiotropium and salmeterol, are recommended as first-line treatment for COPD according to published guidelines. Several comparative studies have shown that tiotropium was superior to a short-term acting bronchodilator, such as ipratropium, and has some advantages compared to salmeterol.10–12 Another trial showed that the efficacy of combination therapy of tiotropium with salmeterol was superior in comparison to either drug administered separately.13

Discussion Chronic obstructive pulmonary disease may frequently coexist with lung cancer due to common risk factors such as smoking. Although surgery still remains the

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However, the perioperative treatment for COPD patients is not well known. We previously reported that COPD was a significant risk factor for developing respiratory-related complications, which may explain the poor long-term survival in lung cancer patients with COPD.14 A decreased FEV1 significantly correlated with postoperative complications. Achieving a significant improvement in FEV1 was therefore thought to be a reasonable therapeutic objective. The present study demonstrated that significant FEV1 improvement was observed by use of salmeterol and tiotropium in lung cancer patients with moderate to severe COPD. O’Donnell et al. reported that improvement in exercise tolerance was significantly correlated with an increase in IC, but not FEV1.15 O’Donnell et al. also showed that changes in IC, as an index of resting hyperinflation, were better correlated with changes in dyspnea and exercise tolerance than FEV1.16 Tiotropium leads to a reduction in hyperinflation, which is accompanied by improvements in exertional dyspnea and exercise endurance. COPD has been previously characterized by irreversible airflow disease. However, recent GOLD guidelines defined COPD as airflow limitation that is not fully reversible. Reversibility depends, primarily, on acetylcholine released by the vagus nerve. Tiotropium inhibits the effects of acetylcholine by binding to the muscarinic receptors on bronchial smooth muscles. The greatest effect on bronchoconstriction arises from muscarinic receptors, especially the M3 receptor, which is selectively inhibited by tiotropium. Tiotropium leads to reduced hyperinflation, which is accompanied by improvements in symptoms and lung function. Moreover, combined therapy might be more beneficial than therapy with one agent alone.13 Therefore, in cases with a more severe airflow limitation or hyperinflation, greater improvements of lung function might be shown with the use of bronchodilators. Our results showed a significant improvement in both FEV1 and IC, including FVC in stage II–III COPD patients. O’Donnell et al. reported that an improvement in exercise tolerance was significantly correlated with an increase in respiratory function.15 However, the results of 6-min walking tests were not comparable with the changes of lung function in the present study. The reason is unclear, although it might be due to the small scale of this study and factors other than respiratory function, such as those related to leg dysfunctions or general health conditions. Dynamic MRI was examined to analyze the diaphragmatic motion to support these results for the respiratory function. The changes in the movement of the diaphragm in the stage II–III COPD patients in the experimental group were significantly better than in the control group. One of the main mechanisms for tiotropium is improving air trapping.16 When air trapping is

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improved, the movement of the diaphragm becomes more dynamic. Interestingly, an improvement in the diaphragmatic motion was more apparent on the side opposite to the operative side. That volume reduction of the lung might have made the mediastinum shift to the operative side, with an increase in the motion space for the contralateral lung, may thus have led to a wider diaphragmatic motion.17,18 Chronic obstructive pulmonary disease still poses considerable therapeutic challenges. This study focused on improvements in the pulmonary function and QOL in order to evaluate the efficacy of medication for COPD. Quality of life is not directly proportional to lung function variables, especially FEV1. But in general, patients with significant airway obstruction have a poor score on QOL questionnaires. The reversibility of an airway obstruction has implications in the prognosis.19 The SGRQ is one of the most widely used instruments for assessing health-related QOL in pulmonary disease, and shows a good correlation with FEV1.20 This study provides support that the use of tiotropium and salmeterol leads not only to functional improvement but also to maintenance of health-related QOL after surgery in moderate to severe COPD patients. This preliminary trial has some limitations. First, the number of patients studied was not sufficient. Even with a small number, however, significant differences for pulmonary function, QOL, and diaphragmatic motion were observed in stage II–III COPD. Second, the effects of the operation on lung function and QOL might be variable in each patient. Tumor size, surgical procedures, or the grade of emphysema may affect postoperative lung function due to lung volume reduction effects.21 To minimize these problems, we limited the patients who underwent a lobectomy for lung cancer to clinical stage I, and added a comparison for the same stages of COPD. Preoperative lung function results after administration of bronchodilators should have been included in this study. If these data had been gathered, more precise evaluation of drug effects might have been possible. However, the same surgical procedures were selected in both groups, and volume reduction effects are thought to have been the same. Furthermore, the effects of the short-term inhalation of bronchodilators before surgery still remain unclear. Therefore, we did not perform preoperative pulmonary function tests immediately before surgery. Third, pulmonary rehabilitation maintains the lung function and exercise tolerance for COPD patients. Casaburi et al. reported that tiotropium in combination with pulmonary rehabilitation improves exercise tolerance of COPD patients compared to pulmonary rehabilitation alone.22 In this study, all participants with COPD were involved in the same pulmonary rehabilitation program perioperatively. Therefore, the effect of rehabilitation was not considered in this analysis.22

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This study measured the relatively short-term results for the lung function and QOL. We therefore plan to focus on the long-term impact of this combination therapy on the respiratory function QOL, exacerbation, and survival.23 In conclusion, this study demonstrated combined treatment with salmeterol and tiotropium to thus be safe and effective for the perioperative treatment of lung cancer patients with moderate to severe COPD. This treatment modality may therefore provide benefits for lung cancer patients with COPD who require a surgical resection.

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