Prognostic impact of sarcopenia on elderly patients undergoing pulmonary
resection for non-small cell lung cancer
Akihiro Miura1, Hiromasa Yamamoto1,2, Hiroki Sato1, Yasuaki Tomioka1,3, Toshio
Shiotani1,3, Ken Suzawa1,2, Kentaroh Miyoshi1,2, Shinji Otani1,2, Mikio Okazaki1,2,
Seiichiro Sugimoto1,3, Masaomi Yamane1,2 and Shinichi Toyooka1,2
1Department of General Thoracic Surgery and Breast and Endocrinological Surgery,
Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
2Department of Thoracic Surgery, Okayama University Hospital, Okayama 700-8558,
Japan
3Organ Transplant Center, Okayama University Hospital, Okayama 700-8558, Japan
Corresponding author:
Hiromasa Yamamoto, MD, PhD
Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho,
Kita-ku, Okayama 700-8558, Japan
E-mail: [email protected]
Article type: Clinical Original Article
Total number of words: 3602 words
Abstract
＜Purpose＞
The number of elderly patients who undergo surgery is increasing, even though they are at high risk due to decreased physical strength. Further, sarcopenia is generally associated with poor prognosis in patients with non-small cell lung cancer (NSCLC).
＜Methods＞
This study included NSCLC patients over the age of 65 who underwent pulmonary resection in our hospital between 2012 and 2015. Sarcopenia was assessed using psoas muscle mass index based on computed tomography imaging at the level of the third lumbar vertebra. We elucidated the impact of sarcopenia on short- and long-term outcomes after surgery.
＜Results＞
We enrolled 259 patients, including 179 patients with sarcopenia. Patients with sarcopenia before surgery tended to have postoperative complications (p = 0.0521), although they did not show a poor prognosis. In patients with sarcopenia, multivariate analysis revealed that postoperative complications and the progression of sarcopenia one year after surgery were significant risk factors for poor prognosis (p = 0.0169 and
0.00370, respectively).
＜Conclusions＞
The progression of sarcopenia after surgery is associated with poor prognosis in the elderly NSCLC patients with sarcopenia. A strategy to prevent postoperative progressive sarcopenia may be necessary for the improvement of the clinical outcome of this population.
Keywords: Sarcopenia, elderly patient, non-small cell lung cancer, pulmonary
resection
Introduction
Lung cancer is one of the most refractory malignancies and one of the leading causes of cancer deaths worldwide [1, 2]. Despite improvements in treatment, surgical resection is still the best curative treatment for early-stage non-small cell lung cancer (NSCLC) [3]. Clinical outcomes depend not only on tumor-related factors, such as disease spread but also on host factors [4]. The number of elderly patients who undergo surgery for NSCLC is increasing in Japan[5], even though they are at high risk due to decreased physical strength and increased comorbidity. Performing surgery to elderly patients affects not only the overall survival (OS) and recurrence-free survival (RFS) but also the quality of life[6].
Elucidating operative risk factors in elderly patients with NSCLC is crucial for preventing perioperative complications. Sarcopenia is defined as a progressive and generalized skeletal muscle disorder that involves the accelerated loss of muscle mass and function [7]. Recently, several studies have shown that sarcopenia leads to unfavorable clinical outcomes after surgery and chemotherapeutic toxicity in various types of cancers, including lung cancer [8-14]. Sarcopenia is also reported to be a risk factor for postoperative complications in the patients undergoing cardiac surgery [15].
In addition, sarcopenia is known to have a prevalence of 5 to 13% in people aged 60 to 70 years and 11 to 50% in people over 80 years of age [16]. Sarcopenia is one of the indicators used for the evaluation of the physical status of patients. However, the impact of sarcopenia in elderly patients on the incidence of postoperative complications and prognosis have not been sufficiently elucidated. In this study, we investigated the impact of sarcopenia on short- and long-term outcomes of pulmonary resection for NSCLC in elderly patients.
Methods
Patients and surgical procedures.
This retrospective study was approved by the Ethics Committee of the Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and the Okayama University Hospital, Okayama, Japan (approval number: K2010-031), and the requirement of written informed consent was waived. We enrolled elderly patients (≥ 65 years)[17, 18] with NSCLC who had undergone a curative pulmonary resection (lobectomy or segmentectomy) without any induction treatment before surgery between January 2012 and December 2015 at the Okayama University
Hospital, Okayama, Japan. The patients underwent a whole-body computed tomography (CT) within 2 months before the surgery. The surgical procedure was determined according to the patients’ tolerance and tumor characteristics in a clinical conference. The histological classification of the tumors was based on the World Health Organization histological classification of lung cancers, and the pathological stage was determined according to the TNM criteria from the seventh edition of the Union for International Cancer Control Classification [19, 20]. Surgical approach is defined based on skin incision. Skisn incision > 8 cm as Open, 3 < skin incision ≤ 8cm as mini thoracotomy, skin incision ≤ 3cm as thoracoscopic. Postoperative complications, which were observed within 30 days after surgery, were classified according to the Clavien-Dindo classification [21].
Diagnosis of sarcopenia
The psoas muscle mass index (PMI, cm2/m2) was assessed using CT images at the level of the third lumbar vertebra before surgery (pre-PMI). Muscle volume was measured using a manual tracing of the cross-sectional area of the right and left psoas muscles (Fig. 1). The PMI cutoff value for sarcopenia was defined as 6.36 cm2/m2 for
males and 3.92 cm2/m2 for females, as previously described [11, 22]. Further, we assessed the PMI approximately one year after surgery (post-PMI). Based on a previous report, a post/pre ratio of < 0.95 was defined as sarcopenia progression [23].
Statistical analysis.
The Mann-Whitney U test and Fisher’s exact test were used to compare groups and categorical variables. For correlation, we used Spearman’s rank correlation coefficient.
Survival curves were constructed using the Kaplan-Meier method, and the OS and RFS rates were compared using a log-rank test. Cox proportional hazard models were used to identify the prognostic factors of survival. Any factors with p < 0.1 in univariate analysis using the above tests were considered for multivariate analysis. All analyses were performed using JMP ver15 (SAS Institute Inc., Cary, North Carolina, USA). A p- value < 0.05 was considered statistically significant.
Results
Patients.
Between January 2012 and December 2015, 259 patients were enrolled in this study.
The patient characteristics are shown in Table 1. The median age of the study population was 73 years ranging from 65 to 92 years. There were 155 males and 104 females. In total, 211 (81%) patients were diagnosed as cStage I. The histological types included 174 adenocarcinoma (Ad), 56 squamous cell carcinoma (SCC), and 29 other types of carcinoma. Using previously reported cutoff values, we defined 179 patients as sarcopenic and 80 patients as non-sarcopenic. The sarcopenia group had a higher proportion of males (p < 0.001) and an increased presence of a smoking habit (p = 0.0203). The body mass indices (BMIs) in the sarcopenia group were significantly lower than those in the group without sarcopenia (p < 0.001). There was no significant difference between the patients with or without sarcopenia in terms of pre-operative laboratory examinations, clinical/pathological stage, or surgical procedures, including surgical approach and operative procedures.
Although major postoperative complications defined as Clavien-Dindo classification ≥ 2 seemed to be more frequently observed in the group with sarcopenia (p = 0.0521) (Table 1), there were no obvious differences in each postoperative complication between the patients with or without sarcopenia. Detailed postoperative complications are shown in Table 2.
Survival analysis between the patients with or without sarcopenia.
The median follow-up period was 48.7 months (range 3.0–79.6 months). Kaplan-Meier analysis showed that there were no significant differences in the OS or RFS between the patients with or without sarcopenia (Fig. 2). Univariate analyses of several clinical factors on survival after surgery are shown in Table 3. In patients without sarcopenia, lower %VC (p = 0.0188), SCC (p < 0.001), advanced clinical stage (p < 0.001), and blood loss (p = 0.0444) were significant unfavorable factors. Multivariate analysis revealed that advanced clinical stage [hazard ratio (HR), 9.91; 95% confidence interval (CI), 1.39–81.2; p = 0.0211] was the only poor prognostic factor for the survival of patients without sarcopenia. On the contrary, in patients with sarcopenia, male sex (p
= 0.00490), smoking habit (p = 0.0132), lower %VC (p = 0.0371), SCC (p = 0.00593), advanced clinical stage (p < 0.001), blood loss (p = 0.00331), transfusion (p = 0.0122), postoperative complications (p < 0.001), and sarcopenia progression (decrease of PMI) (p = 0.00224) were unfavorable factors for OS. Multivariate analysis showed that postoperative complications and sarcopenia progression (decrease of PMI) [HR, 2.99 and 3.68; 95% CI, 1.22–7.82 and 1.52–9.71; p = 0.0169 and p = 0.00370, respectively]
were poor prognostic factors for the survival of patients with sarcopenia.
Survival analysis between the patients with or without sarcopenia progression in sarcopenic patients.
With regard to the patients with preoperative sarcopenia (n = 179), the data for PMI one year after surgery were available for 160 patients. We were not able to obtain the data for 19 patients because of the patients’ death or insufficient follow-up. Patients with preoperative sarcopenia and postoperative sarcopenia progression exhibited an obvious loss in muscle mass and visceral fat (Supplementary Fig. 1). Most of factors, including surgical procedures, postoperative complications, and recurrence, did not have any significant differences between the patients with or without sarcopenia progression. The patients with sarcopenia progression showed significantly lower %VC compared to the patients without sarcopenia progression (Supplementary Table 1). Recurrence is one of the major reasons for sarcopenia progression and poor prognosis. Thus, we analyzed the impact of sarcopenia progression (decrease of PMI) on prognosis in both sarcopenia group without recurrence (n = 136) and non- sarcopenia group without recurrence (n = 62). Even though excluding the patients with
recurrence, the postoperative sarcopenia progression was the poor prognostic factor in sarcopenic patients (p = 0.0101) (Fig. 3). In addition, multivariate analysis showed that sarcopenia progression was the significant poor prognostic factor for the patients with preoperative sarcopenia excluding the recurrent cases [HR, 4.09; 95% CI, 1.22–
16.6; p = 0.0219] (Supplementary Table 2). Taken together, sarcopenia progression is associated with poor prognosis in patients with sarcopenia.
Discussion
In this study, the postoperative OS and RFS were not significantly different between the elderly patients with or without sarcopenia. Although we used a previously reported method to diagnose sarcopenia [11, 22], there was no obvious difference in the patients’ characteristics between the patients with sarcopenia or without sarcopenia.
A recent retrospective cohort study showed that the prevalence of sarcopenia was associated with poor prognosis [8, 10, 11, 14, 24, 25]. In contrast, some studies showed no obvious relationship between preoperative sarcopenia and poor prognosis [8, 25-28]. Thus, the relationship between the prevalence of sarcopenia and prognosis is controversial. The muscle mass volume and PMI value decrease depends on aging,
and our study included higher frequency of sarcopenic patients compared to the studies previously reported [11, 22], because we focused on only elderly patients. The impact of sarcopenia on postoperative prognosis in elderly patients might be different to the patients in younger groups. To date, no study of sarcopenia focusing on only the elderly patients has been reported.
We focused on elderly patients who had undergone pulmonary resection. Elderly patients tend to have many comorbidities and, thus, are at an increased risk of developing postoperative complications after standard resection, resulting in a poor prognosis [29, 30]. Additional perioperative management for these patients is crucial for improving the clinical outcomes of surgery, including not only OS but other post- operative complications. Multivariate analysis revealed that postoperative complications were an unfavorable prognostic factor in patients with sarcopenia, indicating that the patients with sarcopenia require intensive intervention to avoid complications. Limited resection is one of the options to minimize operation-related complications. Shinohara et al. reported that performing limited surgery might contribute to a better OS in patients with sarcopenia [22]. The other option is to improve muscle mass by adequate preoperative rehabilitation or nutrition. The
importance of preoperative nutritional management and rehabilitation has been clarified in previous reports, which showed that muscle mass could recover through the administration of nutrients and rehabilitation before surgery[31, 32].
In addition, we assessed the progression of postoperative sarcopenia and demonstrated that the progression of sarcopenia is strongly associated with poor prognosis among the patients with sarcopenia. We occasionally encounter the patients with no obvious complications in their perioperative course, who weaken gradually after surgery. Pulmonary resection may be invasive for elderly patients[33], which results in a reduction in respiratory function, muscle mass, and physical activity.
Lower pulmonary function is reported as one of the factors for sarcopenia [34]. Even though there was no significant relationship between pulmonary dysfunction and sarcopenia existence, our result shows that preoperative lower %VC was related to the progression of sarcopenia in patients with sarcopenia. Therefore, postoperative changes in the pre-operative general conditions of elderly patients should be monitored on a long-term basis after discharge. From this perspective, the progression of sarcopenia could be an indicator of the long-term condition of elderly patients. Some academic societies also recommend that sarcopenia should be defined not only
according to the loss of muscle mass at a certain point but also the decline in muscle strength and physical performance during long-term follow-up. [35-38]. Thus, prospective studies to explore the association between sarcopenia and treatment- related functional impairments are required, and they should include physical abilities in the definition of sarcopenia.
There are some limitations to our study. First, our study is a retrospective study, and thus, the time points of measuring PMI is varied among the cases. Second, this study was conducted in a single institution over a long period, and the sample size was not large.
In conclusion, we determined that the sarcopenic elderly NSCLC patients with postoperative complications or the progression of sarcopenia had a worse OS than non-sarcopenic patients. For improving the postoperative prognosis of elderly NSCLC patients, intensive perioperative management, as well as systematic postoperative long-term management, should be considered in the future.
Acknowledgments
We thank that Drs. Naomichi Murata and Yukio Kobayashi, The Center for Special
Needs Dentistry, Okayama University Hospital, for their providing advice and encouragement. This work is supported by Management Expensive Grants in National University Corporations in Japan.
Conflict of Interest
The authors have no conflict of interest to declare.
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Figure legends
Fig. 1. Bilateral psoas muscle areas at the level of the third lumber vertebrae on preoperative computed tomography were measured. (a)(b) Representative image of patients (a) with sarcopenia and (b) without sarcopenia.
Fig. 2. (a) The overall survival curves in patients with or without sarcopenia. (b) The recurrence-free survival curves in patients with or without sarcopenia.
Fig. 3. (a) The overall survival curves in patients with or without sarcopenia
progression in the preoperative sarcopenic group without recurrence (n = 136). (b)
The overall survival curves in patients with or without more than 5% decrease of PMI in the preoperative non-sarcopenic group without recurrence (n = 62).
Supplementary Figure legends
Supplementary Fig. 1. (a)(b) Representative images of the patients with sarcopenia progression. (a) the preoperative image and (b) the image one year after surgery.
