Performance at Preoperative Stair-Climbing Test Is Associated With Prognosis After Pulmonary Resection in Stage I Non-Small Cell Lung Cancer

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1 Performance at Preoperative Stair-Climbing Test Is Associated With Prognosis After Pulmonary Resection in Stage I Non-Small Cell Lung Cancer Alessandro Brunelli, MD, Cecilia Pompili, MD, Rossana Berardi, MD, Paola Mazzanti, MD, Azzurra Onofri, MD, Michele Salati, MD, Stefano Cascinu, MD, and Armando Sabbatini, MD Division of Thoracic Surgery and Medical Oncology, Ospedali Riuniti Ancona, Ancona, Italy Background. This investigation evaluated whether the performance at a preoperative symptom-limited stairclimbing test was a prognostic factor in resected pathologic stage I non-small cell lung cancer (NSCLC). Methods. Observational analysis was performed on a prospective database that included 296 patients who underwent pulmonary lobectomy for pathologic stage T1 N0 or T2 N0 NSCLC (2000 to 2008). Patients who received induction chemotherapy were excluded. Survival was calculated by the Kaplan-Meyer method. The log-rank test was used to assess differences in survival between groups. The relationships between survival and baseline and clinical variables were determined by Cox multivariate analyses. Results. Median follow-up was 43 months. The best cutoff associated with prognosis was an 18-meter stair climb. Median (months) survival and 5-year survival of patients who climbed more than 18 meters were significantly longer than those who climbed less than 18 meters (97 vs 74; 77% vs 54%, p 0.001). Cox regression model (hazard ratio) showed that climbing more than 18 meters (0.5; p 0.003), diffusion capacity of the lung for carbon monoxide (0.98; p 0.02), and pt stage (1.8; p 0.02) were independent prognostic factors. Patients who climbed less than 18 meters had increased deaths from cancer (24% vs 15%, p 0.1) or other causes (19% vs 9%, p 0.02). Conclusions. Preoperative cardiopulmonary fitness is a significant prognostic factor in patients after resection for early-stage NSCLC. Interventions aimed at improving exercise tolerance can be useful to improve long-term prognosis after NSCLC operations. (Ann Thorac Surg 2012;93: ) 2012 by The Society of Thoracic Surgeons Lung cancer patients generally have a reduced exercise tolerance compared with the general population [1, 2]. Lung resection may be associated with a varying degree of functional impairment that can further decrease aerobic capacity and predispose the patient to postoperative morbidity and death as well as impaired quality of life [3 5]. To date, however, scant information has been published regarding the association between preoperative fitness and long-term survival of lung cancer patients [6, 7]. The objective of this investigation was to evaluate whether preoperative exercise tolerance measured with a symptom-limited stair-climbing test was a reliable prognosticator associated with long-term survival in stage I non-small cell lung cancer (NSCLC) patients undergoing pulmonary lobectomy. The rationale of this investigation was to find a prognosticator that could be modifiable through the institution of specific rehabilitation programs [8 12]. Accepted for publication Feb 23, Presented at the Poster Session of the Forty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 Feb 1, Address correspondence to Dr Brunelli, Via S. Margherita 23, Ancona 60129, Italy; brunellialex@gmail.com. Patients and Methods This was an observational analysis performed on a prospective database. The study was approved by the local Institutional Review Board. All patients gave their informed consent to participate in the institutional prospective database and for the use of their data for research and clinical purposes. A total of 296 consecutive patients undergoing pulmonary lobectomy and systematic lymph node dissection [13] for pathologic stage I (pt1 or pt2-n0 only) NSCLC and with complete follow-up were analyzed (2000 to 2008). Patients who received induction chemotherapy were excluded. No patients in this series underwent adjuvant chemotherapy or radiotherapy. Exclusion criteria were more advanced pathologic stage, incomplete resections, induction chemotherapy, and inability to perform the preoperative stair-climbing test (40 patients during the same period). Patients were staged according to the American Joint Committee on Cancer, Seventh Edition guidelines [14]. Patients underwent radical resection by board-certified thoracic surgeons generally through a muscle-sparing, nerve-sparing [15] lateral thoracotomy, and as a rule, were extubated in the operating room and managed in a dedicated thoracic surgery unit. Intensive care admission was occasionally planned for patients with compromised 2012 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg BRUNELLI ET AL 2012;93: STAIR-CLIMBING TEST AND NSCLC SURVIVAL preoperative function (ie, peak maximum oxygen consumption 12 ml/kg/min) and otherwise reserved for patients with severe postoperative complications who needed active life support treatment [16]. Postoperative management was standardized and included chest physiotherapy, early mobilization, physical rehabilitation, and adequate paravertebral or systemic analgesic therapy, which was titrated to keep the visual analog pain score below 4 (on a scale from 0 to 10) during the first 48 to 72 hours. Stair-Climbing Test All patients performed a preoperative symptom-limited stair-climbing test as a part of their routine preoperative functional evaluation [17, 18]. The stair-climbing test was usually performed within 1 week of the operation. Our hospital has 16 flights of stairs, each consisting of 11 steps. Each step is meters high. Patients were asked to climb, at a pace of their own choice, the maximum number of steps and to stop only for exhaustion, limiting dyspnea, leg fatigue, or chest pain. All patients were accompanied by a physician, and the patient s pulse rate and capillary oxygen saturation were monitored by means of a portable pulse oximeter with a finger probe. All tests were performed on room air. Follow-up was obtained through routine office visits, by telephone contact, or by data retrieved from the Regional Health Care System database. All patients were monitored through April The cause of death was recorded. Table 1. Characteristics of the 282 Study Patients Variables a Result Age, years 68 (9.8) Male sex, No. (%) 218 (77) FEV 1 % 87.9 (19) Dlco % 78.6 (17.8) FEV 1 /FVC ratio 0.7 (0.1) Pre-op hemoglobin level, g/dl 13.8 (1.7) Coronary artery disease, No. (%) 26 (9) ASA score 2.2 (0.5) ECOG score 0.7 (0.7) Stair-climbing height, meters 20 (4.3) Side of resection, right, No. (%) 147 (52) Site of resection, upper, No. (%) 187 (67) pt1 stage, No. (%) 118 (42) 1797 a Continuous data are expressed as mean (standard deviation) and categoric data as indicated. ASA American Society of Anesthesiologists; Dlco diffusion capacity of the lung for carbon monoxide; ECOG Eastern Cooperative Oncology Group; FEV 1 forced expiratory volume in 1 second; FVC forced vital capacity. test. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated from regression coefficients. A significant level of 0.05 was chosen to assess the statistical significance. A p value of less than 0.05 was regarded as significant. All statistical tests were performed on Stata 9.0 software (Stata Corp, College Station, TX). GENERAL THORACIC Data Analysis The following baseline and tumor variables were tested for a possible association with survival: age, sex, Charlson Comorbidity Index (CCI), body mass index (BMI), American Society of Anesthesiologist (ASA) score, Eastern Cooperative Oncology Group (ECOG) score, preoperative hemoglobin concentration, forced expiratory volume in 1 second (FEV 1 %), diffusion capacity of the lung for carbon monoxide (Dlco %), FEV 1 /forced vital capacity (FVC) ratio, history of coronary artery disease (CAD), preoperative hemoglobin level, pt stage (pt1 vs pt2), histology (adenocarcinoma vs squamous vs others), and altitude reached at stair-climbing test. For the purpose of this study, a threshold effect was searched for the altitude at the stair-climbing test by performing log-rank tests for multiple cutoff values. The value with the highest association with survival was selected. Survival was defined as the interval between the surgical resection and death or last contact. Patients who were not reported as having died at the time of the analysis were censored at the date they were last known to be alive. The Cox multivariate proportional hazard regression model was used to evaluate the effects of the prognostic factors on survival. Predictors with p values of less than 0.2 at univariable analysis were used in a multivariable Cox s proportional hazards model. Survival distribution was estimated by the Kaplan- Meier method. Significant differences in probability of surviving between the strata were evaluated by log-rank Results Patient characteristics are summarized in Table 1. Median follow-up was 43 months. The average altitude reached at preoperative stair climb test was 20 meters. Testing for a threshold effect showed that 18 meters was the best cutoff associated with long-term survival. Compared with patients who climbed less than 18 meters, patients who climbed more than 18 meters had significantly longer median survival of 97 (95% CI, 89 to 105) months vs 74 (95% CI, 63 to 85) months and 5-year survival of 77% vs 54% (p 0.001; Fig 1). Table 2 reports the results of the univariable analysis for overall survival. Along with the altitude reached on the stair-climbing test, the following variables were associated with overall survival (p 0.2) and were used in the multivariable analysis: age, sex, CCI, FEV 1 %, Dlco %, pt stage, preoperative hemoglobin level, and ECOG score. The Cox proportional hazards regression model showed that climbing more than 18 meters (HR, 0.5; p 0.003), Dlco (HR, 0.98; p 0.02), and pt stage (HR, 1.8; p 0.02) were independent prognosticators significantly associated with survival. The pt1 stage patients who climbed more than 18 meters lived significantly longer than those who did not (85% vs 53%, p ; Fig 2). This difference in pt2 stage patients was still present but less evident (71% vs 55%, p 0.15; Fig 3).

3 1798 BRUNELLI ET AL Ann Thorac Surg STAIR-CLIMBING TEST AND NSCLC SURVIVAL 2012;93: Fig 1. Kaplan-Meier overall survival estimates are shown for stage I non-small cell lung cancer patients who underwent surgical resection according to their performance on the preoperative stair-climbing test. High: 18 meters (solid line). Low: 18 meters (dashed line). Log-rank test p Fig 2. Kaplan-Meier overall survival estimates are shown for pathologic pt1 N0 stage non-small cell lung cancer patients who underwent stair-climbing test. High: 18 meters (solid line). Low: 18 meters (dashed line). Log-rank test p Patients who climbed less than 18 meters had higher cancer-specific (24% vs 15%, p 0.1) and other-cause mortality rates (19% vs 9%, p 0.02). Figure 4 shows the cancer-specific survival for patients who climbed more than 18 meters compared with those who climbed less than 18 meters. The log-rank test showed a significant difference between the two groups (p 0.04). Comment The association between exercise tolerance and prognosis in cancer survivors has been rarely reported. Regular moderate-intensity exercise is known to be associated with a 30% to 50% reduction in the risk of cancer-specific mortality and all-cause mortality after a diagnosis of early breast or colorectal cancer [19 22]. Two studies have evaluated the prognostic importance of exercise tolerance in lung cancer. Kasymjanova and colleagues [6] assessed the prognostic value of the 6-minute walk test in patients with inoperable NSCLC and found that a walk distance of 400 meters or more was the only variable significantly associated with survival. Jones and colleagues [7] investigated the prognostic value of aerobic capacity before lung cancer operations and found that low peak maximum oxygen consumption was associated with poorer survival. The objective of the present study was to verify whether preoperative fitness in patients with radical Table 2. Results of the Univariable Analysis to Test Association of Several Variables With Overall Survival Variables p Value Sex 0.14 a Age b Charlson Comorbidity Index 0.18 b FEV 1 % 0.1 b Dlco % b Stair climb height b Coronary artery disease 0.7 a Hemoglobin level 0.18 b ASA 0.8 b ECOG 0.04 b Histology 0.6 a pt stage 0.02 a a By log-rank test. b By univariable Cox proportional hazard regression. ASA American Society of Anesthesiologists; Dlco diffusion capacity of the lung for carbon monoxide; ECOG Eastern Cooperative Oncology Group; FEV 1 forced expiratory volume in 1 second. Fig 3. Kaplan Meier overall survival estimates are shown for pathologic pt2 N0 stage non-small cell lung cancer patients who underwent stair-climbing test. High: 18 meters (solid line). Low: 18 meters (dashed line). Log-rank test p 0.2.

4 Ann Thorac Surg BRUNELLI ET AL 2012;93: STAIR-CLIMBING TEST AND NSCLC SURVIVAL Fig 4. Kaplan Meier cancer-specific survival estimates are shown for pathologic stage I stage non-small cell lung cancer patients who underwent stair-climbing test. High: 18 meters (solid line). Low: 18 meters (dashed line). Log-rank test p resection for stage I NSCLC was associated with longterm survival after pulmonary lobectomy. We evaluated exercise tolerance by a symptom-limited stair-climbing test, a form of constant work rate maximal exercise that is routinely used in our unit for risk-stratification and operability selection [17]. The stair-climbing test is a reliable test to predict postoperative early morbidity and death [23], and in this study we used it to investigate long-term survival. We found that median overall survival was 23 months longer in patients who climbed higher than 18 meters compared with those who climbed to a lower altitude. The effect of exercise tolerance was independent of other confounders when adjusted in a multivariable analysis and can be partly explained by increased deaths from cancer recurrence and other causes (such as cardiopulmonary complications). In fact, cancer-specific survival was also longer in patients who climbed more than 18 meters. These findings may have important clinical implications because exercise tolerance is a modifiable prognosticator. Structured rehabilitation programs may improve aerobic capacity in the preoperative setting [2, 8 12, 24, 25] with the potential to influence residual quality of life and long-term survival. Patients who are in better clinical condition before the operation can have a lower risk of early and late cardiopulmonary complications after the operation. This would explain the reduction in deaths from causes other than cancer recurrence. However, a better performance at the stair-climbing test was also associated with a longer cancer-specific survival and with the reduction in cancerrelated deaths. The beneficial effects of physical activity and physical function on cancer recurrence has been the focus of recent investigations and may be related to a reduction in body weight and composition, beneficial 1799 changes in metabolic and sex hormones, growth factors, adipokines, immune function, or inflammation [25 27]. Although this study includes a homogeneous sizeable sample of patients undergoing pulmonary lobectomy in a single center with standardized procedures and pathways of care and with a long follow-up, it may have some limitations: We included pathologic stage I NSCLC (T1 2N0) only. Further studies are warranted to confirm our findings in other stages of disease. The study included patients undergoing radical pulmonary lobectomy performed through a muscle-sparing lateral thoracotomy. The interaction between exercise and prognosis for other type of resections or surgical accesses (including videoassisted thoracoscopic procedures) needs to be confirmed. Exercise tolerance was evaluated through stairclimbing test. We found a cutoff of 18 meters in our setting was the best prognosticator. Structural differences across different hospital makes this cutoff value difficult to standardize and warrants future confirmation by independent investigators. We only assessed preoperative exercise tolerance. Although preoperative and postoperative fitness levels may be correlated [28], their relationship across time may not be linear, and the influence of this interaction on prognosis may deserve further investigations. Owing to the retrospective nature of the study, we cannot completely rule out the possibility that lower levels of exercise tolerance may reflect other occult predictors for poor prognosis. For instance, the occurrence of postoperative cardiopulmonary complications, which may be associated with poor fitness, was associated in this series with poorer long-term 5-year survival of 61% for complications vs 75% for no complications (log-rank test p 0.01). However, our findings remained unchanged after adjusting for other potential prognosticators. There is a cumulating body of data showing a potential association between physical fitness after cancer diagnosis and treatment and survival. All of these data, such as the present findings, are observational; therefore, causeand-effect cannot be assumed. These preliminary findings look promising, but the only way to answer whether increased physical activity can reduce recurrence or deaths due to cancer is to design randomized controlled clinical trials [29]. In conclusion, we found that preoperative cardiopulmonary fitness was a significant prognosticator in patients operated on for early-stage lung cancer. Exercise tolerance may influence physiologic outcomes associated with cancer, such as immune function, body weight and composition, insulin regulation, and the metabolic syndrome, that can potentially affect survival. Interventions aimed at improving exercise tolerance can possibly improve long-term prognosis after lung cancer operations. GENERAL THORACIC

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A simple test (stair-climbing) accompanied by the surgeon s intuition, experience, and a few objective tests has been a valuable tool for surgeons. The simple stair-climb is usually not standardized, lacks objective assessment, and is not scientific. Despite these limitations, few deny its usefulness in patient assessment. Some authors, including the present authors, have tried to address these limitations and improve our understanding of this test relative to tolerating surgery. The authors [1] have now taken another step and have used this simple test to predict prognosis after surgery for early stage lung cancer. It would be too easy to dismiss this finding as oversimplified. The observation of a correlation between stair-climbing and prognosis begs further questions. Is it reproducible? What is stair-climbing measuring, or is it just a surrogate for something else? Larger numbers of patients are required to confirm these findings. Can this test predict outcome in advanced 2012 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur