The association of pulmonary function, physical activity, cardiorespiratory tness, Borg dyspnea scales and health related quality of life in patients with resected lung cancer

Understanding the determinants of quality of life for the patients after lung resection would be benecial to affect the prevention programs and the treatment strategies. This novel study aims to explore the relationship between pulmonary function, physical activity, cardiorespiratory tness (CRF), dyspnea, and the health-related quality of life (HRQoL) of patients with resected lung cancer. Methods A cross-sectional study design with 38 lung cancer survivors after surgery for one month was conducted. We assessed CRF by measuring maximal oxygen consumption (VO 2max ) and anaerobic threshold (VT).Forced vital capacity (FVC) was measured using a spirometer. Physical activity, dyspnea, and HRQoLwereinvestigated by 6-minute walking distance (6MWD), Borg dyspnea scales, and the SF-36 Health Survey (SF-36), respectively.Data analyses were conducted using SmartPLS to examine path analyses between the measures.


Introduction
Much progress has been made in the diagnosis and treatment for non-small cell lung cancer in recent years, and the prognosis gradually improves corresponding. For a signi cant number of patients, surgical resection is the preferred therapeutic method. Unfortunately, the survival rate following an operation is not satisfactory, more and more patients acquire prolonged postoperative survival [1], and improving quality of life (QoL) for those patients is also important [2]. lung resection has a signi cant short-and long-term impact on pulmonary function and oxygenation [3], and physical activities, measured by 6-minute walking distance (6MWD), were also reported to decline after surgery [4]. And many symptoms including dyspnea, emotional, pain, and side effects of treatment may occur after lung resection. Meanwhile, good quality of life after surgery is one of the main goals of comprehensive treatment. However, lung resection is so invasive that it lowers QoL, especially, in the early period after surgical treatment [5].Unfortunately, a limited number of studies have examined the relationship between pulmonary function, cardiorespiratory tness (CRF), physical activities, dyspnea, and QoL.
Many pieces of evidence showed that the symptoms are involved in the quality of life. For instance, the previous study showed that there was a strong association between the peak oxygen uptakeand 6MWD in adults with achondroplasia [6]. Engberg et al. found that CRT was positively associated with healthrelated QoL in women at risk for gestational diabetes [7]. And Ha D et al. reported that exercise capacity was independently associated with QoL for lung cancer patients after post-curative-intent treatment [8].
Based on those results, we hypothesized that pulmonary function, CRF, physical activities, and dyspnea can in uence QoL in patients with resected lung cancer.
Understanding the determinants of QoL for the patients after lung resection would be bene cial to affect the prevention programs and the treatment strategies. In this study, we investigate the association between pulmonary function, CRF, physical activities, dyspnea, and QoL in patients after lung resection and validate our proposed model.

Study design and population
A cross-sectional study was designed. This study was performed according to the declaration of Helsinki and was approved by the Guangdong provincial people's Hospital.
The patients who underwent a lobectomy or a segmentectomy were recruited following the criteria were non-small-cell lung cancer staged T1, T2, and T3a with or without COPD. The Exclusion factors included: non-small-cell lung cancer staged T3b and T4, associated with other serious chronic diseases; refused to participatein this study.

Protocol
Each patient had a routine full clinical assessment before the inclusion process, and all patients included in the present study provided written informed consent before data collection. The assessments including QoL, CRF, pulmonary function, physical activities, and dyspnea were performed one month after lung resection. Data were collected from February 2015 to November 2018.
Health-related QoL (HRQoL) We assessed HRQoL with a 36-item short-formhealth survey V1 (SF-36) [9]. The survey is a valid and reliable 36-item questionnaire that is widely used to measure QoL. It yields two summary scores of physical (Physical Functioning, Role-Physical, Bodily Pain, and General Health) and mental (Vitality, Social Functioning, Mental Health, and Role-Emotional) health. The scales range from 0 to 100, with 0 indicating the worst situation and 100 indicating the best situation in each domain. CRF A physician examined the patients beforehand to ensure their suitability to perform the test. We assessed CRF by measuring maximal oxygen consumption (VO 2max ) and anaerobic threshold (VT) in incremental (30W/3min) cycle ergometer exercise (Metamax 3B, Cortex, Germany) until patient fatigue. VO 2max was determined as the highest 1-minute average value and was normalized for body mass (mL•kg − 1 •min − 1 ).

Pulmonary function
Pulmonary volumes including forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV 1 ) were measured using a spirometer (Electgraph HI-101, CHEST, Tokyo, Japan), and corrected for temperature and barometric pressure, according to the American Thoracic Society recommendations [10].
Each patient performed at least three trials and the best performance was used for analysis. Because QoL had a poor correlation with FEV 1 [11], we choose FVC for the statistical analysis.

Physical activities
Physical activity was determined by 6-MWD [12]. 6-MWD was carried out under the same conditions. Patients were instructed to walk at their fastest pace to cover the longest possible distance over 6 min. The longest walk was taken to represent the value.

Borg dyspnea scale
Prior to pulmonary function testing, the patients were requested to quantify their sensation of dyspnea by pointing to a score on the Borg scale category ratio 10 (CR10).

Statistical analysis
Data were expressed as the mean values ± SD for ordinal or continuous variables, and as numbers and percentages for categorical variables. Statistical analysis was performed using GraphPad Prism software version 8.0 for Windows (GraphPad Software, San Diego, California, USA), and SMARTPLS 3.0 was used to run con rmatory factor analysis (CFA) and to verify the internal consistency, reliability, and validity of the theoretical model. We examined whether the variables were normally distributed with the Andersondarling test, then we used Spearman's correlation coe cients (Rs) for non-normally distributed variables. For normally distributed variables, we used Pearson's correlation coe cients (Rp). Finally, the structural model was estimated and used SmartPLS to examine path analyses between the measures., and the proposed hypotheses were con rmed.

Results
Clinical characteristics Table 1 summarizes the characteristics, CRF, HRQoL, FVC, 6MWD, and Borg dyspnea scales of the patients. 31 patients underwent a lobectomy, and 7 patients had a segmentectomy. All of the patients did not perform the preoperative treatment, and the TNM classi cation of the lung cancers were as following: 24 stages 1, 10 stages 2, and 4 stages 3a. The types of lung cancer cells were as follows: 22 adenocarcinomas, 13 squamous carcinomas, and 3 others. The correlation matrix of CRF, FVC, 6MWD, Borg dyspnea scales and HRQoL were shown in Table 2.
VO 2max and VT were positively associated with 6 out of 8 domain scales of the SF-36. FVC was positively associated with the role-Emotional, vitality, and general health scales of the SF-36. Borg dyspnea scales were negatively associated with the physical functioning, physical functioning, and mental health scales of the SF-36. And 6MWD was positively associated with the physical functioning, mental health, and social functioning scales of the SF-36.  Evaluation of the structural model Table 3 and Fig. 1 showed that the hypothesis model was supported and indicated an acceptable model t. The R 2 value for QoL construct is 0.385 which means 38.5% of the changes in QoLwere due to pulmonary function, cardiorespiratory tness, physical activities, and dyspnea in the model (Fig. 1). The path linking CRF to the perceived QoL was positive and statistically signi cant, and the path linking FVC, 6MWD, and Borg scales to QoL was not positive and statistically insigni cant (Fig. 1). We foundthatFVC (f 2 = 0.265) and 6MWD (f 2 = 0.389) have a medium to large effect size on the perceived CRF while CRF was found to have large effect sizes on perceived QoL (Table 4).  According to the views from Preacher and Hayes [13],the path model for the relationships between physical activities (β = 0.441, P < 0.05), pulmonary function (β = 0.462, P < 0.05), dyspnea (β = 0.491, P < 0.05), and QoLwere statistically signi cant. However, after adjusting the indirect effects of the mediator, the direct effect of physical activities(β = 0.045, P > 0.05), pulmonary function (β = 0.190, P > 0.05) or dyspnea (β = 0.19, P > 0.05) on HRQoL was no longer signi cant, as shown in Fig. 2-4. The indirect effects indicate that there is a mediation. Figure 4 depicts that pulmonary function or physical activities was positively related to engagement in CRF, which in turn was signi cantly related to QoL (Fig. 2,4). And Borg scales need to be positively related to physical activities, then signi cantly related to CRF and QoL (Fig. 3).

Discussion
This study used the path-analyses method to examine the relationship between CRF, FVC, 6MWD, Borg scale, and health-related QoL in patients with lung resection. Our results showed that FVC was poor correlated with QoL. And Bog scales were a strong correlation with physical activities only. Though 6MWD and FVC were positively associated with QoL, an insigni cant direct effect between QoL with FVC or 6MWD was observed. Our ndings also showed that CRT was a strong correlation with QoL, and took charge of 38.4% of the changes in the perceived quality of life in the model. CRF as a mediator between Pulmonary function, physical activities, Borg scale, and QOL is novel.
Many pieces of evidence showed that lung resection had a signi cant impact on respiratory function, and the de cits may reduce the patients' QoL [3,5]. However, Brunelliet al. found that QoL had a poor correlation with FEV1 and CO lung diffusion capacity [3]. In the present study, we also showed that FVC was not related to QoL. Noting that FVC was positively associated with the general health, vitality, and role-emotional scales of the SF-36, those results indicated that FVC only affected a few functioning scales and could not be taken as surrogates for QOL evaluation [11]. Because the indirect effects from FVC to QoLwere observed in our study, pulmonary function-enhancing intervention may be useful in improving quality of life in patients with resected lung cancer.
Wolkoveet al. reported that dyspnea is poorly correlated with pulmonary function in patients with obstructive lung disease [14]. In the present study, we found that Borg scales were positively associated with physical activities from our mediation model. Furthermore, the main negative relationship between Borg scales and the domains of the SF-36 was physical functioning and role-physical in this study. And the worsening dyspnea caused patients to reduce their physical activities [15]. Those results indicated that Borg dyspnea scaleswere preferred to describe the physical status.
Lung cancer survivors always experience QoL impairments, and engagement in physical activity is associated with better QoL. Also, physical activity was independently associated with QoL in lung cancer patients withpost-curative-intent treatment [8]. We also found that 6MWD was associated with QoL but the signi cance level was P = 0.044. However, 6MWD recovery in elderly patients after lung cancer surgery was not related to their health-related QOL recoveries [4]. One of the possible reasons for the inconsistent results is that the effect of physical activity on QoL is indirect. Our results con rmed the possibility and an indirect effect between QoL with physical activities were observed.
Cardiorespiratory tness is determined mainly by aerobic physical activity, and CRF is strong associated with the physical dimensions of health-related QoL [16]. In our study, CRF (VT and VO 2max ) was positively associated with the physical dimensions except for the pain of QoL, and CRF had a direct effect on QoL.
In fact, muchevidence showed that there was a strong correlation between 6MWT [6], pulmonary function [4], and CRF. Our results clearly showed that the relationship between physical activity, pulmonary function, and QoL was signi cantly mediated by CRF in patients with lung cancer resection. This result was similar to the previous works that CRF mediated the effects of 12-week aerobic exercise on general fatigue in a woman with systemic lupus erythematosus [17]. As a mediator, CRF also affected the effects of a Mediterranean diet on the mental component summary of QoL. In our study, CRF (VT and VO 2max ) was positively associated with 3 out of 4 mental domains of QoL.
In the clinic, QoL in patients with resected lung cancer was poor. Poor QoL means di culty for these kinds of patients to deal with a range of de cits or limitations related to cognitive, psychosocial, physical, sensory functioning, and other aspects of performance [18]. The results in the present study showed that only 38.5% of the changes in QoLwere due to CRF. Thus, the improving QoL program for the patients with lung resection not only focuses on how to improve CRT, but also pays more attention to other impact factors.
With regard to the limitations of this study, the small number of patients (n = 38) means that the study lacked statistical strength. Second, some other factors that could affect QoL in patients with resected lung cancer were not included in our structural equation modelings such as family supportand economic level. Third, this was a single-center study.
In conclusion, CRF has a direct effect on the quality of life in patients with resected lung cancer. Furthermore, CRT, as mediated variably, can mediate the relationship between pulmonary function, physical activity, Borg dyspnea, and quality of life. In the future, more attention to improving CRT is needed for improving the quality of life of patients with resected lung cancer.

Declarations
Con icts of interest: The authors have no con icts of interest to declare. Acknowledgments: None A data availability statement: All data generated and/or analyzed during the present study are included in this article.
Contributions: XP Li drafted the rst version of the manuscript. All authors were involved in all stages of the study design and data collecting, and submission to ethical committee was done by MS Zhang. XP Li and MS Zhang were involved in statistical analysis. All authors read and approved the nal version of the manuscript.
Ethics approval: This study was performed according to the declaration of Helsinki and was approved by the Guangdong provincial people's Hospital (No. 2012124H(R2)).
Patient consent for publication: All patients provided written patient consent for publication. Mediating effect of pulmonary function on quality of life, via CRF.