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General Thoracic and Cardiovascular Surgery

, Volume 66, Issue 12, pp 716–722 | Cite as

Positive correlation between sarcopenia and elevation of neutrophil/lymphocyte ration in pathological stage IIIA (N2-positive) non-small cell lung cancer patients

  • Takuma TsukiokaEmail author
  • Nobuhiro Izumi
  • Shinjiro Mizuguchi
  • Chung Kyukwang
  • Hiroaki Komatsu
  • Michihito Toda
  • Kantaro Hara
  • Hikaru Miyamoto
  • Noritoshi Nishiyama
Original Article

Abstract

Objective

Surgical indication in stage IIIA (N2) non-small cell lung cancer is still controversial. Hence, there is a need for the identification of predictors of the postoperative outcome in these patients. Although sarcopenia is expected to be a novel predictor of postoperative outcome in these patients, the underlying clinical features of sarcopenia have not been well investigated. Elevation of neutrophil/lymphocyte ratio indicates cancer-associated inflammation and depression of anticancer immunity. We analyzed the influence of sarcopenia on postoperative prognosis, and investigated the relationship between sarcopenia and neutrophil/lymphocyte ratio in patients with stage IIIA (N2) non-small cell lung cancer.

Methods

We retrospectively investigated 69 patients with stage IIIA (N2) non-small cell lung cancer. We used the L3 muscle index as a clinical measurement of sarcopenia, and divided patients into the sarcopenic (n = 21) and the non-sarcopenic group (n = 48). We then investigated the effect of sarcopenia on postoperative prognosis, and evaluated the correlation between sarcopenia and neutrophil/lymphocyte ratio.

Results

This study included 47 males and 22 females. Univariate analysis revealed that sarcopenia, performance status, and serum cytokeratin-19 fragment level were predictors of poor prognosis; multivariate analysis revealed that performance status and sarcopenia were independent predictors of poor prognosis. The presence of sarcopenia was significantly correlated with neutrophil/lymphocyte ratio elevation.

Conclusions

Sarcopenia is a novel predictor of poor prognosis in patients with stage IIIA (N2) non-small cell lung cancer. Neutrophil/lymphocyte ratio elevation might be the reason for poor prognosis in sarcopenic patients.

Keywords

Sarcopenia Non-small cell lung cancer Lymph node metastasis Neutrophil/lymphocyte ratio 

Introduction

As patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) are heterogeneous, the management of these patients is the most controversial issue in the area of lung cancer [1]. Furthermore, patients with stage IIIA (N2) NSCLC have a poor prognosis, and so the surgical indication in N2 disease remains controversial [2]. Hence, there is a need for novel predictors of the outcome in stage IIIA (N2) NSCLC.

Sarcopenia is the progressive loss of muscle mass and strength, which carries a risk of adverse outcomes such as disability, poor quality of life, and death [3]. Depletion of skeletal muscle mass is the result of an imbalance between the pathways that favor protein synthesis and those that favor breakdown [4]. Sarcopenia is present in more than 50% of patients with advanced cancer [5]. Sarcopenia is reportedly a poor prognostic factor in patients with clinical stage III or IV NSCLC treated with chemotherapy [6], patients with pathological stage I NSCLC treated with pulmonary resection [7, 8], and patients with small cell lung cancer [9]. Hence, sarcopenia is expected to be a novel predictor of postoperative outcomes in patients with stage IIIA (N2) NSCLC.

Elevation of the neutrophil/lymphocyte ratio (NLR) is reportedly a poor prognostic factor in patients with several stages of NSCLC [10, 11]. Inflammatory cells such as neutrophils and lymphocytes play an important role in tumor progression. Elevation of NLR indicates the presence of tumor-associated inflammation, neutrophil-mediated tumor progression, and suppression of the anti-tumor immune response of the lymphocytes [12, 13, 14].

We analyzed the influence of sarcopenic condition on postoperative prognosis in patients with stage IIIA (N2) NSCLC. The association between sarcopenia and NLR was also investigated to determine the mechanism of the poor prognostic effect of sarcopenia.

Methods

Of 725 patients who underwent definitive pulmonary resection with mediastinal lymph node dissection for primary lung cancer at our hospital from January 2003 to December 2012, we retrospectively investigated 69 patients with stage IIIA (N2) NSCLC. Patients who had preoperative treatments or whose disease was not completely removed were excluded. Patients who underwent pneumonectomy, pulmonary segmentectomy, or partial resection were also excluded. Before surgery, all patients provided informed consent for their examination outcomes and clinical data to be used in clinical studies. The local institutional ethics committee approved this study (approval no. 3754, approval date April 28, 2017).

Clinical and pathological stagings were determined according to the 7th edition of the TMN Classification of Malignant Tumors. Mediastinal lymph nodes with a short axis longer than 10 mm on enhanced computed tomography (CT) were diagnosed as clinically positive for metastasis. Criteria for surgical resection were: histological diagnosis of NSCLC, absence of distant metastasis, no cancer cell-positive pleural or pericardial effusion, no N2 diseases at more than two mediastinal levels, no bulky N2 disease, no N3 disease, and a predicted postoperative forced expiratory volume in 1 s of more than 40%.

After discharge, all patients were examined by chest radiography and estimation of tumor markers every 2–4 months, and by CT every 6 months. The last follow-up review was performed on March 31, 2017.

Platinum doublet chemotherapy was performed as postoperative adjuvant therapy. However, there were no established criteria for the avoidance of adjuvant chemotherapy, and so the instigation of chemotherapy depended on the empirical decision made by the physicians in charge of each case.

The cross-sectional area (cm2) of skeletal muscle at the third lumbar vertebra (L3) level on CT imagery is a recognized measure of systemic muscle mass [15]. The L3 muscle index (L3MI) is defined as the cross-sectional area of muscle at the L3 level, normalized for height (cm2/m2) as with body mass index (BMI), and is a clinical measurement of sarcopenia [16]; i.e., L3MI = cross-sectional area (cm2) of skeletal muscle at the L3 level/height (m2). Yoshizumi et al. [17] found that the measured skeletal muscle area at L3 was significantly correlated with body surface area (BSA), and created a formula to calculate the skeletal muscle area at L3 using the BSA: BSA (m2) = 71.84 × height0.725 × bodyweight0.425 × 10− 4.

Skeletal muscle area at L3 (cm2) for males = 126.9 × BSA − 66.2.

Skeletal muscle area at L3 (cm2) for females = 125.6 × BSA − 81.1.

We used these formulae to calculate the L3MI. Cutoff L3MI values were defined as 52.4 cm2/m2 for males and 38.5 cm2/m2 for females, in accordance with a previous report [16], and patients with a L3MI less than the cutoff value were diagnosed with sarcopenia.

Blood samples were collected within 1 month preoperatively. Body height and weight were measured at the time of hospital admission. A BMI cutoff value was determined in accordance with the guidelines of the World Health Organization [18]. Cutoff values for tumor markers were determined in accordance with institutional cutoff values and previous reports [19, 20, 21]. Prolonged air leakage was defined as air leakage that required pleurodesis or additional thoracic drainage tube placement.

The clinicopathological factors of patients with and without sarcopenia were compared using the Mann–Whitney U test and the χ2 test. Overall survival and disease-free survival were analyzed using the Kaplan–Meier method; differences were assessed using the log-rank test. Independent risk factors associated with survival were calculated using the Cox proportional hazard model. P < 0.05 was considered significant. Statistical analyses were performed using JMP 10 software (SAS Institute, Cary, NC, USA).

Results

Our 69 subjects included 47 males and 22 females, of which 21 patients had sarcopenia and 48 did not. The patient characteristics in accordance with the presence or absence of sarcopenia are shown in Table 1. Sarcopenia was significantly associated with sex, BMI, and percent of vital capacity, but not with performance status (PS).

Table 1

Characteristics of patients according to the presence of Sarcopenia

Characteristics

All (n = 69)

Sarcopenia (n = 21)

No sarcopenia (n = 48)

P value

Mean age, years (± SD)

65.9 ± 9.8

67.9 ± 10.8

65.1 ± 9.3

0.282

Gender

 Male

47

19

28

0.005

 Female

22

2

20

 

Performance status

 0

55

15

40

0.301

 1

13

6

7

 

 2

1

0

1

 

Smoking index

 

800 (0, 2850)

800 (0, 2800)

0.984

BMI (kg/m2)

 < 18.5

9

7

2

< 0.001

 18.5 ≦ to < 25.0

43

14

29

 

 25.0 ≦

17

0

17

 

Blood findings

 Albumin (g/dl)

 

3.9 (2.5, 4.4)

4.1 (3.1, 4.7)

0.062

 Hemoglobin (g/dl)

 

13.8 (8.9, 17.1)

14.0 (9.2, 16.1)

0.430

Respiratory function

 %VC (%)

 

101 (70, 127)

109 (70, 142)

0.035

 %FVC (%)

 

100 (70, 127)

107 (67, 142)

0.090

 FEV1.0% (%)

 

76 (57, 96)

76 (55, 87)

0.201

Clinical stage

 IA

22

6

16

0.857

 IB

28

8

20

 

 IIA

2

1

1

 

 IIB

8

3

5

 

 IIIA

7

3

4

 

Tumor size (mm)

34 (14, 83)

39 (20, 83)

32 (14, 61)

0.083

Histological subtypes

 Adenocarcinoma

59

18

41

0.974

 Non-adenocarcinoma

10

3

7

 

Status of N2 nodal extension

 Skip/sequential

24/45

9/11

15/34

0.284

 Single/multiple

44/25

14/7

30/18

0.552

Values are median (range); BMI body mass index, %VC percent of vital capacity, %FEV1.0 percent of forced expiratory volume in 1 s, FEV1.0% forced expiratory volume in 1 s as a percent of forced vital capacity, CEA carcinoembryonic antigen, CYFRA cytokeratin 19 fragment

The median follow-up duration was 56 months, during which 54 patients had recurrent disease, and 42 patients died. The sarcopenic group had a significantly poorer prognosis compared with the non-sarcopenic group, with 5-year survival rates of 23 and 60%, respectively (P < 0.01; Fig. 1). Patients with sarcopenia also had a significantly shorter disease-free survival period compared with the non-sarcopenic group (P < 0.01; Fig. 2).

Fig. 1

Overall survival curves according to the presence or absence of sarcopenia

Fig. 2

Disease-free survival curves according to the presence or absence of sarcopenia

In univariate analysis, PS, sarcopenia, and serum cytokeratin-19 fragment level > 3.5 ng/ml were significantly associated with poor prognosis. Multivariate analysis showed that PS and sarcopenia were independent factors associated with poor prognosis (Table 2).

Table 2

Results of univariate and multivariate analyses of overall survival

 

Univariate analysis

Multivariate analysis

HR

95% CI

P value

HR

95% CI

P value

Age

 ≧ 65 vs < 65

1.7

0.31–1.07

0.080

   

Gender

 Male vs Female

1.4

0.75–2.91

0.286

   

Performance status

 0 vs 1–2

3.1

1.48–6.12

0.004

3.4

1.58–6.88

0.001

BMI (kg/m2)

 ≧ 18.5 vs < 18.5

1.9

0.72–4.31

0.179

   

Sarcopenia

 Yes vs No

3.1

1.78–6.34

< 0.001

3.1

1.58–6.06

0.001

CEA (ng/ml)

 > 5.0 vs ≦ 5.0

1.5

0.82–3.09

0.183

   

CYFRA (ng/ml)

 > 3.5 vs ≦ 3.5

2.1

1.02–4.15

0.045

1.8

0.82–3.57

0.097

Tumor size (mm)

 > 30 vs ≦ 30

1.6

0.85–3.13

0.151

   

Clinical stage

 I vs II-III

1.3

0.65–2.61

0.409

   

Histological subtypes

 Adenocarcinoma vs Others

1.4

0.55–2.89

0.477

   

Status of N2 nodal extension

 Skip vs Sequential

1.0

0.56–2.15

0.842

   

 Single vs Multiple

1.0

0.54–1.93

0.980

   

HR hazard ratio, CI confidence interval, BMI body mass index, CEA carcinoenbryonic antigen, CYFRA cytokeratin 19 fragment

Platinum doublet postoperative chemotherapy was received by 38 patients (55%). Three patients (3%) were treated with other drugs in a clinical trial. There were no significant differences between the sarcopenic and the non-sarcopenic group in the frequency of postoperative complications, duration of postoperative hospitalization, duration of thoracic drainage, administration of adjuvant chemotherapy, or cause of death (Table 3).

Table 3

Postoperative clinical courses according to the presence of Sarcopenia

 

All (n = 69)

Sarcopenia (n = 21)

No Sarcopenia (n = 48)

P value

Operative complications

19 (29%)

8 (32%)

13 (27%)

0.899

 Prolonged air leakage

9

3

6

 

 Pneumonia

3

2

1

 

 Arrhythmia

3

1

2

 

 Chylothorax

2

0

2

 

 Recurrent nerve palsy

2

0

2

 

 Surgical site infection

0

1

0

 

Postoperative hospitalization (days)

13 (4, 73)

12 (7, 73)

13 (4, 48)

0.886

Duration of thoracic drainage (days)

5 (2, 44)

5 (3, 13)

5 (2, 44)

0.800

Postoperative chemotherapy

 Platinum doublet

38 (55%)

10 (48%)

28 (58%)

0.189

 Other

3 (4%)

0 (0%)

3 (7%)

 

Causes of death

 Primary lung cancer

37 (54%)

16 (72%)

21 (44%)

0.890

 Other causes

5 (7%)

2 (10%)

3 (6%)

 

Values are median (range)

The two groups did not significantly differ in C-reactive protein level and preoperative leucocyte count in the blood (Fig. 3a, b). However, the NLR was significantly higher in the sarcopenic group than in the non-sarcopenic group (P = 0.013; Fig. 3c).

Fig. 3

The preoperative leucocyte level (a) and the C-reactive protein level (b) in the blood according to the presence or absence of sarcopenia. The preoperative neutrophil/lymphocyte ratio in the blood according to the presence or absence of sarcopenia (c)

Discussion

The present findings showed that sarcopenia was an independent predictor of poor prognosis in patients with stage IIIA (N2) NSCLC. The sarcopenic group also had a significantly lower disease-free survival rate than the non-sarcopenic group. Furthermore, the present study was the first to demonstrate the correlation between the sarcopenic condition and elevation of NLR. Muscle cells generate antiproliferative mediators, and depression of these mediators is reportedly associated with poor prognosis in sarcopenic patients [22]. We demonstrated that the presence of cancer-associated inflammation and depression of anticancer immunity is a possible novel mechanism of tumor progression in patients with sarcopenia.

Interleukin (IL)-6 and tumor necrosis factor (TNF)-α are implicated in the pathogenesis of tumor-associated inflammation, and induce a high NLR [23]. This tumor-associated systemic inflammation induces tumor-related wasting of skeletal muscle tissue. Furthermore, the ubiquitin proteasome system plays a key role in skeletal muscle proteolysis [24]. Systemic inflammatory signals including IL-1, IL-6, and TNF-α activate muscular nuclear factor-kappa β (NF-κβ) signaling and subsequent ubiquitin proteasome system-mediated proteolysis [3]. In the present study, the sarcopenic group had a significantly lower percentage of females than the non-sarcopenic group. An experimental animal model revealed that females were less affected by tumor-related IL-6-mediated wasting of skeletal muscle tissue than males because of the anti-inflammatory effect of sex hormones, such as estrogen [25]. This suggests that patients with sarcopenia may have tumor-associated inflammation.

The beneficial outcomes of physical training to improve sarcopenia in non-cancer patients have been reported, with a duration of rehabilitation programs of 8–12 weeks [26, 27]. Because of the long program duration, a preoperative physical training regimen intended to promote recovery from sarcopenia may be impossible in patients with lung cancer. If tumor-associated inflammation is the cause of both sarcopenia and elevation of the NLR, anti-inflammatory treatments should be planned to improve the prognosis in patients with NSCLC who have sarcopenia. An anti-IL-6 antibody has been shown to have potential benefits in treating various cancers, either as a single agent or in combination with other chemotherapy drugs [28]. Cancer therapy targeting NF-κβ signaling is expected to be beneficial in controlling tumor progression [29]. Circulating neutrophils form neutrophil extracellular traps (NET) contribute to tumor progression and metastasis in the tumor microenvironment. Kanamaru reported that disruption of the NET by DNase might be useful to prevent peritoneal recurrence after abdominal surgery. Controlling the NET may become a practical treatment for patients with a high NLR [30].

This study had some limitations. First, it was a retrospective study that included only a small number of patients. As most of the included patients did not have clinical N2 NSCLC, the present results may not be applicable to a general population of patients with stage IIIA (N2) disease. The accumulation of more data is warranted. Second, the L3MI cutoff value for sarcopenia used in the present study was 52.4 cm2/m2 for males, and 38.5 cm2/m2 for females, as these values were widely used in several articles [16, 31, 32]. However, Kimura et al. reported that the L3MI cutoff values for sarcopenia in Japanese patients with inoperable stage III–IV NSCLC are 41.0 and 38.0 cm2/m2 [6]. Most of the patients in the present study had a PS of 0 or 1, while the study by Kimura et al. included some patients with a PS of 2 or 3 [6]; hence, there was a difference between studies in the general condition of the patients. In the present study, the lowest L3MI value in the male patients was 44.7 cm2/m2. If we had used 41 cm2/m2 as the L3MI cutoff value, none of the present patients would have been categorized as sarcopenic. It may be important to calculate separate cutoff values for sarcopenia based on ethnicity, cancer type, and disease stage. Third, the survival of these patients depends on the intensity of chemotherapy. However, criteria for adjuvant chemotherapy were not established; establishment of such criteria is desired in the future. Fourth, the formula used in the present study was calculated using physical findings in healthy adults. We used this formula because almost all patients in the present study were classified as have a PS of 0 or 1. Using the formula could delete the measurement error of L3MI, and patients could avoid unnecessary CT at the lumbar vertebra level.

Conclusion

Sarcopenia was an independent predictor of poor prognosis in patients with stage IIIA (N2) NSCLC, and elevation of NLR might be a crucial reason for this poor prognosis in patients with sarcopenia. Sarcopenia may become a criterion to determine the treatment strategy for patients with N2 NSCLC.

Notes

Compliance with ethical standards

Conflict of interest

All the authors have no conflicts of interest.

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Copyright information

© The Japanese Association for Thoracic Surgery 2018

Authors and Affiliations

  • Takuma Tsukioka
    • 1
    Email author
  • Nobuhiro Izumi
    • 1
  • Shinjiro Mizuguchi
    • 1
  • Chung Kyukwang
    • 1
  • Hiroaki Komatsu
    • 1
  • Michihito Toda
    • 1
  • Kantaro Hara
    • 1
  • Hikaru Miyamoto
    • 1
  • Noritoshi Nishiyama
    • 1
  1. 1.Department of Thoracic SurgeryOsaka City University HospitalOsakaJapan

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