The 6-min walk test in the functional evaluation of patients with lung cancer qualified for lobectomy

Abstract

OBJECTIVES

The American College of Chest Physicians guidelines recommend low-technology exercise tests in the functional evaluation of patients with lung cancer considered for resectional surgery. However, the 6-min walk test (6MWT) is not included, because the data on its clinical value are inconsistent. Our goal was to evaluate the 6MWT in assessing the risk of cardiopulmonary complications in candidates for lung resection.

METHODS

We performed a retrospective assessment of clinical data and pulmonary function test results in 947 patients, mean age 65.3 (standard deviation 9.5) years, who underwent a single lobectomy for lung cancer. In 555 patients with predicted postoperative values ≤60%, the 6MWT was performed. The 6-min walking distance (6MWD) and the distance-saturation product (DSP), which is the product of the 6MWD in metres, and the lowest oxygen saturation registered during the test were assessed.

RESULTS

A total of 363 patients with predicted postoperative values <60% and a 6MWT distance (6MWD) ≥400 m or DSP ≥ 350 m% had a lower rate of cardiopulmonary complications than patients with shorter 6MWD or lower DSP values [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.35–0.81] and 0.47 (95% CI 0.30–0.73), respectively. This result was also true for patients with predicted postoperative values <40%, ORs 0.33 (95% CI 0.14–0.79) and 0.25 (95% CI 0.10–0.61), respectively.

CONCLUSIONS

The 6MWT is useful in the assessment of operative risk in patients undergoing a single lobectomy for lung cancer. It helps to stratify the operative risk, which is lower in patients with 6MWD ≥400 m or DSP ≥350 m% than in patients with a shorter 6MWD or lower DSP values.

6-Min walk test, Lung cancer, Lung resection, Preoperative evaluation

INTRODUCTION

Exercise testing plays an important role in the preoperative functional evaluation of candidates for lung resection who have impaired lung function. European guidelines recommend performance of exercise tests in all patients with a forced expiratory volume in the first second (FEV₁) or a transfer factor for carbon monoxide (TLco) below 80% of predicted [1]. A cardiopulmonary exercise test (CPET) with direct measurement of oxygen consumption is preferred. The main problems with this high-technology test are availability and costs, so only a minority of patients have a CPET before lung resection [2]. Probably this was the reason why more recent American College of Chest Physicians (ACCP) guidelines [3] assigned a greater role to low-technology exercise tests (stair climbing or walking tests). However, ACCP and European guidelines do not recommend the 6-min walk test (6MWT), because the few studies evaluating this test in candidates for lung resection reported conflicting results [4]. On the other hand, 6MWT is widely used to evaluate functional capacity, assess prognosis and evaluate response to medical intervention across a wide range of chronic respiratory diseases [5]. Considering these uncertainties, we undertook a comprehensive evaluation of 6MWT in assessing the risk of cardiopulmonary complications in a large group of candidates for lung resection. Since the American Thoracic Society statement on 6MWT was published in 2002, new data on conducting and on the utility of the 6MWT have been published, and a number of novel indices derived from desaturation have been proposed [6–8]. We have included a new index to the analysis, the distance-saturation product (DSP), which integrates both the distance walked and the lowest peripheral capillary oxygen saturation (SpO₂) level and is the product of these 2 measurements [6]. We theorized that the DSP would capture the global functional derangement in candidates for lung resection with impaired ventilatory reserves and thereby could serve as a useful marker of the risk of cardiopulmonary complications.

MATERIALS AND METHODS

We retrospectively analysed medical records and 6MWT and pulmonary function test (PFT) results of patients surgically treated at the Department of Thoracic Surgery, National Tuberculosis and Lung Diseases Research Institute in Warsaw between January 2013 and March 2017. Only patients who had undergone a single lobectomy for lung cancer were analysed. Lobectomies were performed by thoracotomy and video-assisted thoracoscopic surgery. Stage I tumours were removed using a minimally invasive technique. The access was not affected by other factors such as patient body mass index, chest deformity or emphysema. The exception to this rule was cases in which the patient had previous empyema. Extended lobectomies (e.g. chest wall resections) were excluded from the analysis. Complications and deaths were those occurring within 30 days postoperatively or later if the patient was still in the hospital. The following cardiopulmonary complications were included: respiratory failure requiring mechanical ventilation for more than 48 h, atelectasis or retention of secretions in the airways requiring bronchoscopy, pneumonia, death of pulmonary causes, myocardial infarction, symptomatic cardiac arrhythmia requiring medical treatment, cardiac failure, pulmonary embolism and cardiac death. The degree of severity of complications was assigned according to the classification system of Dindo et al. [9].

In our hospital, PFTs are performed in all patients prior to elective lobectomy, and predicted postoperative (ppo) lung function is calculated. Patients with ppoFEV₁ and ppoTLco >60% of predicted values proceed to surgery without further functional testing. In patients with ppoFEV₁ or ppoTLco ≤60%, a 6MWT is performed. PFTs included spirometry and TLco measurements using the single breath method. Tests were performed using a MasterScreen system (software version 4.65; Jaeger, Würzburg, Germany). American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 guidelines were followed for all lung function measurements [10, 11]. We used reference values from the 2012 Global Lung Function Initiative for spirometry [12] and from the 1993 ERS/European Community for Coal and Steel for TLco, defining the lower limit of normal at the level of −1.64 z-scores according to the ATS/ERS 2005 guidelines [13]. The 6MWT was conducted on a treadmill by a trained technician, according to ATS guidelines [5]. Patients were instructed to walk at a brisk pace. They were allowed to decrease the pace and rest during the test if needed. Total distance walked and SpO₂ (recorded each min of the test) were measured. The DSP was defined as the product of the final distance walked in metres and the lowest SpO₂. For example, a patient walking a total of 300 m whose SpO₂ fell to 90% would have a DSP of 270 m% (e.g. 300 × 0.90).

Our study was a retrospective analysis of routinely (not experimentally) obtained anonymized data, and informed consent was not collected. The study was accepted by the local ethics committee.

Statistical analyses

Normally distributed data were presented as the mean and standard deviation (SD); categorical data, as n (%). Differences between groups were tested by the Student’s t-test if normally distributed; otherwise they were determined by the Wilcoxon rank sum test. All analyses were 2-tailed. P-values <0.05 were considered statistically significant. Categorical data were tested by the χ² test. The odds ratio (OR), its standard error and the 95% confidence interval (CI) were calculated according to Altman. The confirmatory-type analysis was conducted for 4 tests presented in the column ‘ORs (all complications)’ in Table 1. Here, the Holm method for multiple testing was used with adjusted P-values (in descending order): 0.013, 0.017, 0.025 and 0.050. In this experiment, the difference was statistically significant for all compared pairs. Other tests in our studies can be considered exploratory. Statistical analysis was performed using MedCalc Statistical Software version 19.0.4 (MedCalc Software bvba, Ostend, Belgium, https://www.medcalc.org; 2019).

Table 1:

Odds ratios for having cardiopulmonary complications in patients with impaired lung function according to the 6-min walk test or the DSP

Groups	OR (all complications)	OR (complications ≥ grade 3)
Patients with ppo values ≤60%
6MWD ≥400 m (n = 363; range 400–660 m) vs <400 m (n = 192; range 140–396 m)	0.53 (95% CI 0.35–0.81; P < 0.003)	0.59 (95% CI 0.37–0.93; P < 0.03)
DSP ≥350 m% (n = 424; range 351–667 m%) vs <350 m% (n = 131; range 130–349 m%)	0.47 (95% CI 0.30–0.73; P < 0.001)	0.53 (95% CI 0.32–0.87; P < 0.02)
Patients with ppo values ≤40%
6MWD ≥400 m (n = 45; range 400–580 m) vs <400 m (n = 66; range 130–375 m)	0.33 (95% CI 0.14–0.79; P < 0.02)	0.38 (95% CI 0.15–0.99; P < 0.05)
DSP ≥350 m% (n = 34; range 352–556 m%) vs <350 m% (n = 77; range 130–349 m%)	0.25 (95% CI 0.10–0.61; P < 0.003)	0.31 (95% CI 0.12–0.82; P < 0.02)

CI: confidence interval; DSP: distance-saturation product; 6MWD: 6-min walking distance; OR: odds ratio.

Table 2:

Functional characteristics of the patients

	All (n = 947)	Lung function (ppo values)
		ppoFEV1 or ppoTLco values ≤60% (n = 555)	ppoFEV1 and ppoTLco values >60% (n = 392)	P-valuea
Age (years), mean (SD)	65.3 (9.5)	66.1 (8.7)	64.1 (10.4)	0.001
Women/men, n (%)	411/536 (43/57)	247/308 (45/55)	164/228 (42/58)	0.41
FEV1 (% predicted), mean (SD)	84.6 (19.9)	75.5 (17.9)	97.4 (14.7)	<0.001
FVC (% predicted), mean (SD)	97.7 (15.4)	92.7 (14.9)	104.8 (13.0)	<0.001
FEV1/FVC, mean (SD)	0.67 (0.10)	0.63 (0.11)	0.72 (0.07)	<0.001
TLco (% predicted), mean (SD)	74.3 (16.9)	65.0 (12.8)	88.2 (11.5)	<0.001
ppoFEV1 (% predicted), mean (SD)	67.6 (16.6)	59.2 (14.0)	79.5 (12.2)	<0.001
ppoTLco (% predicted), mean (SD)	59.1 (14.4)	50.5 (10.2)	71.7 (9.4)	<0.001

a

ppo values >60% versus ppo values ≤60%.

TLco: transfer factor for carbon monoxide; FEV₁: forced expiratory volume in the first second; FVC: forced vital capacity; ppo: predicted postoperative; SD: standard deviation.

RESULTS

The investigated group comprised 947 patients of whom 411 (43%) were women and 536 (57%) were men. The mean age was 65.3 (SD 9.5) years. Surgical interventions comprised 173 (18%) left lower, 141 (15%) right lower, 228 (24%) left upper, 344 (36%) right upper and 61 (6%) middle lobe lobectomies. In 304 (32%) patients, the calculated ppoFEV₁ was ≤60%, and lung diffusion measurements found ppoTLco ≤60% in 490 (52%) patients. In total, ppoFEV₁ or ppoTLco was below 60% in 555 (59%) patients. Characteristics of the patients are presented in Table 2.

There were no differences in gender distribution between patients with ppo values below and above 60%. Patients with ppo values ≤60% were slightly older and had lower basic lung function compared to patients with ppo values >60%.

The mean distance covered in the 6MWT performed in 555 patients with ppo values ≤60% was 425.8 (SD 75.9) m, and the DSP was 401.6 (SD 73.4) m%. In the entire analysed group of 947 patients, 210 complications were registered, including 8 (0.8%) deaths, which occurred in 171 (18.0%) patients. There were 62 (30%) grade 2, 106 (50%) grade 3, 23 (11%) grade 4a, 11 (5%) grade 4b and 8 (4%) grade 5 complications. The OR for having cardiopulmonary complications was higher in patients with ppo values ≤60% than in patients with ppo values >60% (OR 1.78, 95% CI 1.25–2.54; P < 0.002). In patients with ppo values ≤60%, we looked for 6MWT results, which could determine the risk of cardiopulmonary complications more accurately. The intention was to define a group of patients with good 6MWT results and a potentially low risk of surgery. On the other hand, we checked if patients with a poor performance on the 6MWT had a higher risk of complications compared to patients with good performance during the effort.

The incidence of cardiopulmonary complications in 363 patients with ppo values ≤60% who covered a distance of at least 400 m was significantly lower than in patients who covered shorter distances. Because grade 2 complications were mild (cardiac arrhythmias requiring pharmacological treatment), we assessed the OR for more severe complications (grade 3 or higher). Again, patients with a 6-min walking distance (6MWD) of at least 400 m had fewer cardiopulmonary complications than patients with a shorter 6MWD. There were no differences in the distribution of the types of lobectomies between groups with 6MWD ≥400 m and <400 m (χ² test).

A total of 111 patients with ppo values ≤40% were considered a subgroup with a potentially high risk of complications. An analysis of these patients showed that 45 patients with a 6MWD ≥400 m had fewer complications than patients with a 6MWD below 400 m and fewer severe complications (grade 3 or higher). A similar analysis of complications was performed for DSP. The incidence of cardiopulmonary complications in 424 patients (76% of patients with ppo values ≤60%) with DSP ≥ 350 m% was significantly lower than in patients with DSP <350 m%. The OR for more severe complications (grade 3 or higher) in patients with a DSP ≥350 m% was lower compared to that in patients with a DSP <350 m%. There were no differences in the distribution of the types of lobectomies between groups with a DSP ≥350 and <350 m% (χ² test). A total of 77 patients with ppo values ≤40% and a DSP ≥350 m% had lower rates of any grade of complication than patients with lower DSP values and a lower rate of grade ≥3 complications.

Table 1 and Fig. 1 present the results of an analysis of cardiopulmonary complications in these subgroups.

Figure 1:

Odds ratios for having cardiopulmonary complications according to the 6MWD or the distance-saturation product. (A) Patients with ppo values ≤60%. (B) Patients with ppo values ≤40%. DSP: distance-saturation product; ppo: predicted postoperative; 6MWD: 6-min walking distance.

DISCUSSION

Surgical resection remains the treatment of choice for early-stage non-small-cell lung cancer, offering the best prospect of long-term survival. However, many lung resection candidates present impaired cardiopulmonary function and limited exercise capacity, mainly due to coexisting chronic obstructive lung disease or ischaemic heart disease, which are associated with increased risk from surgery [14]. Major thoracic surgery and the immediate postoperative period represent severe stresses to both the circulatory and respiratory systems, so preoperative exercise capacity should be a more sensitive predictor of post-thoracotomy morbidity and death than resting PFTs. ERS/ESTS clinical guidelines recommend performance of an exercise test in all patients with FEV₁ or TLco below 80% of predicted [1]. Newer ACCP guidelines from 2013 recommend performing an exercise test in patients with ppoFEV₁ or ppoTLco below 60% of predicted [3]. The gold standard is the CPET with direct measurement of oxygen consumption (VO₂ peak) during incremental exercise on a cycle or treadmill. Because CPET is not easily accessible, ACCP recommendations advise performing low-technology exercise tests before CPET. Several studies have investigated the role of low-technology exercise tests, stair climbing, the shuttle walking test (SWT) and 6MWT in predicting complications in patients having a thoracotomy. Olsen et al. [15] found that patients who were able to climb 3 flights of stairs had a reduced number of complications. Holden et al. [16] reported that a 6MWD of >1000 feet and a stair climb of >44 stairs were predictive of low mortality within 90 days after an operation. In a group of 54 patients, Pierce et al. [17] found the 6MWD indicative of respiratory failure but not of other complications after lung resection. In a study by Nakagawa et al. [18], desaturation during the 6MWT was found to be a good substitute for CPET in risk assessment for lung cancer surgery. Another surrogate test for CPET is the SWT, which appears to be closely associated with the peak oxygen consumption (VO₂ peak) estimated by formal exercise testing [19]. Win et al. [20] reported that all patients who achieved 400 m on the SWT had a peak oxygen consumption of at least 15 ml/kg/min, which is considered the safe value for thoracic surgery. In another study by Lewis et al. [21], a VO₂ peak of >15 ml/kg/min corresponded to an SWT distance of 450 m. However, Win et al. [20] did not find any statistically significant difference in the SWT distance between 70 patients with and 69 patients without complications after the operation. On the other hand, there were also studies on the 6MWT in which the authors [4, 22, 23] were not able to find any differences in the walking distance between complicated and non-complicated patients evaluated for lung resection. However, all these series were small, ranging from 22 to 73 patients. Based on these data, only stair climbing and shuttle walk tests, not the 6MWT, are recommended by the international guidelines on functional qualification for resectional surgery [1, 3, 24]. Because the results of studies investigating the value of the 6MWT in predicting outcome after surgery thus far are inconsistent, we have undertaken a comprehensive analysis of the 6MWT in lung resection candidates. Measurement properties of the 6MWT have been the most extensively researched and established. The 6MWT was introduced by Guyatt et al. [25] as a modification of the 12-min walk test of McGavin. It shows good reliability and validity as a measure of functional capacity. In patients with chronic obstructive lung disease or heart failure, the distance walked strongly correlated with the maximal oxygen uptake measured during CPET [26–27]. Due to its self-paced protocol, it is well tolerated in patients with impaired lung function [28]. Researchers who compared the 6MWT to the shuttle walk test found that the former is easier to administer, requires less equipment and is more reflective of the activities of daily living [29, 30].

We included only the single lobectomy for analysis because it is the most frequently performed type of resection. Moreover, the extent of the operation is a strong risk factor for complications. By analysing only the single lobectomy, we wanted to obtain a homogeneous group of patients and limit the impact of this factor on the results of the analysis. We have shown, in a large group of patients with limited lung function, that the 6MWT helps to stratify the risk of cardiopulmonary complications after lung resection. The rate of cardiopulmonary complications in patients with a 6MWT distance of ≥400 m was lower than that in patients with shorter distances. This result was true for any grade, for more severe (grade ≥ 3) complications and in the increased risk subgroup, that is, patients with ppo values ≤40%. We used the desaturation–distance product; it is a new simple measure used to predict outcomes in idiopathic fibrosis [6], which, to our knowledge, has never been used in functional evaluation before lung resection. Because patients with DSP ≥350 m% had a lower risk of complications than patients with lower DSP values, it also seemed to be useful when assessing complications of any grade, grade ≥3 complications and the subgroup of patients with more severely reduced lung function (ppo values ≤ 40%).

Limitations

This was a retrospective analysis of clinical and functional data, and it would be desirable to confirm our results in a prospective study. The 6MWT was performed on a treadmill rather than in a corridor, which is preferred by ATS guidelines [5]. We chose a treadmill because it was easier and more precisely registered the heart rate and the saturation level while the patient was exercising.

CONCLUSION

The 6MWT is of value for the assessment of operative risk in patients undergoing a single lobectomy for lung cancer. The distance walked or the DSP helps to stratify the risk of complications, which may be particularly useful in centres without access to CPET. The majority of patients with ppo values <60% achieved the 6MWD ≥400 m or DSP value ≥350 m%, thereby constituting the group with reduced risk of complications despite impaired lung function.

Conflict of interest: none declared.

Author contributions

Stefan Wesolowski: Conceptualization; Data curation; Formal analysis; Validation; Writing—original draft; Writing—review & editing. Tadeusz M. Orlowski: Conceptualization; Formal analysis; Writing—review & editing. Marek Kram: Conceptualization; Investigation; Writing—review & editing.

Abbreviations

Abbreviations
 
• ACCP

  American College of Chest Physicians

 
• ATS

  American Thoracic Society

 
• CI

  Confidence interval

 
• CPET

  Cardiopulmonary exercise test

 
• DSP

  Distance-saturation product

 
• ERS

  European Respiratory Society

 
• FEV₁

  Forced expiratory volume in the first second

 
• OR

  Odds ratio

 
• PFT

  Pulmonary function test

 
• ppo

  Predicted postoperative

 
• SD

  Standard deviation

 
• SpO₂

  Oxygen saturation

 
• SWT

  Shuttle walking test

 
• TLco

  Transfer factor for carbon monoxide

 
• 6MWT

  6-min walk test