Prognostic Impact of Postoperative Skeletal Muscle Decrease in Non-Small Cell Lung Cancer

Journal Pre-proof Prognostic Impact of Postoperative Skeletal Muscle Decrease in Non-Small Cell Lung Cancer Shinkichi Takamori, PhD, Tetsuzo Tagawa, PhD, Gouji Toyokawa, PhD, Mototsugu Shimokawa, PhD, Fumihiko Kinoshita, MD, Yuka Kozuma, MD, Taichi Matsubara, MD, Naoki Haratake, MD, Takaki Akamine, MD, Fumihiko Hirai, PhD, Hiroshi Honda, PhD, Yoshihiko Maehara, PhD PII:

S0003-4975(19)31595-4

DOI:

https://doi.org/10.1016/j.athoracsur.2019.09.035

Reference:

ATS 33168

To appear in:

The Annals of Thoracic Surgery

Received Date: 9 March 2019 Revised Date:

11 August 2019

Accepted Date: 9 September 2019

Please cite this article as: Takamori S, Tagawa T, Toyokawa G, Shimokawa M, Kinoshita F, Kozuma Y, Matsubara T, Haratake N, Akamine T, Hirai F, Honda H, Maehara Y, Prognostic Impact of Postoperative Skeletal Muscle Decrease in Non-Small Cell Lung Cancer, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.09.035. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons

Prognostic Impact of Postoperative Skeletal Muscle Decrease in Non-Small Cell Lung Cancer Running title: Impact of skeletal muscle loss in NSCLC

Shinkichi Takamori, PhD1, Tetsuzo Tagawa, PhD1, Gouji Toyokawa, PhD1, Mototsugu Shimokawa, PhD2, Fumihiko Kinoshita, MD1, Yuka Kozuma, MD1, Taichi Matsubara, MD1, Naoki Haratake, MD1, Takaki Akamine, MD1, Fumihiko Hirai, PhD1, Hiroshi Honda, PhD3, Yoshihiko Maehara, PhD1.

1

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University,

3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan 2

Clinical Research Institute, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku,

Fukuoka, 811-1347, Japan 3

Department of Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1

Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

1

Corresponding author: Tetsuzo Tagawa, PhD Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan e-mail: [email protected]

2

Abstract Background: Preoperative skeletal muscle loss was reported to be associated with a postoperative poor prognosis in non-small cell lung cancer (NSCLC) patients. The aim of this study was to elucidate the relationship between the change in skeletal muscle mass following surgery and the postoperative outcomes in NSCLC patients. Methods: The data analyzed 204 NSCLC patients who had undergone curative lung resection and whose preoperative and postoperative (1 year) computed tomography images were available. The skeletal muscle area (SMA) at the 12th thoracic vertebra level was used. Post/pre ratio was defined as postoperative normalized SMA (cm2/m2) divided by preoperative normalized SMA. The cut-off value was set to post/pre ratio = 0.9. Neutrophil–lymphocyte ratio, platelet– lymphocyte ratio, modified Glasgow prognostic score, and prognostic nutritional index were used to estimate change in the nutritional status. Results: Seventy patients (34.3%) were classified into the SMA-decreased group. Low body mass index was significantly associated with the SMA-decreased patients (p = 0.019). The SMA-decreased status was found to be an independent prognostic factor for overall survival and disease-free survival (p < 0.001 and p = 0.001, respectively). The SMA-decreased status was significantly associated with the postoperative exacerbation of neutrophil–lymphocyte ratio,

3

platelet–lymphocyte ratio, modified Glasgow prognostic score, and prognostic nutritional index (p = 0.009, p = 0.026, p = 0.003, and p = 0.013, respectively). Conclusions: Skeletal muscle loss after surgery is significantly associated with poor postoperative outcomes in NSCLC patients. Further studies are needed for investigating the clinical impact of postoperative nutritional intervention.

4

Surgery is one of the most effective therapeutic modalities for achieving favorable prognosis in patients with non-small cell lung cancer (NSCLC) [1]. Among the host-related prognostic factors, skeletal muscle loss has recently been reported to predict poor postoperative outcomes for survival in patients with various types of cancer [2-5]. Decreased skeletal muscle status has been expressed as sarcopenia [2]. Sarcopenia is caused by various mechanisms, such as age-related change, insufficient nutrition, neurodegenerative diseases, low physical activity, insulin resistance and cancer cachexia [6]. Recent studies have shown that preoperative sarcopenia is significantly associated with the postoperative poor outcomes in patients with malignant tumors including NSCLC [2-4]. However, the postoperative change in skeletal muscle mass in cancer patients has not been well investigated. There is some evidence that the decrease in skeletal muscle area (SMA) is significantly related to a postoperative poor prognosis in patients with malignant disease, including cancers of the esophagus, kidney, bladder, and ovary [7-10].

Our previous study has

shown that skeletal muscle decrease following surgery was an independent prognostic factor of overall survival (OS) and disease-free survival (DFS) (hazard ratio for death, 3.82; 95% confidence interval, 1.44 to 10.55) [11]. However, the previous study analyzed only patients with early NSCLC who had undergone lobectomy to avoid the effect of disease stage and limited resection on outcome. Therefore, in this retrospective study, we investigated patients

5

with early and advanced NSCLC who had undergone lobectomy, pneumonectomy, and limited resection, and analyzed whether the postoperative change in SMA had prognostic impact. In order to explain the potential association between postoperative skeletal muscle loss and poor prognosis, we investigated whether decreased SMA reflects the deterioration of the inflammatory/nutritional statuses.

6

Patients and Methods Patients

The data of 204 patients who underwent complete lung resection and were pathologically diagnosed as primary NSCLC whose computed tomography (CT) images were taken within 1 month preoperatively and around 1 year (ranging from 10 to 14 months) postoperatively at the Department of Surgery and Science, Kyushu University Hospital (Fukuoka, Japan) were enrolled in the current study. The paravertebral muscle at the 12th thoracic (Th12) level was measured for assessing skeletal muscle loss in the present study. Pathological staging (pStage) was determined using the 7th edition of the TNM Classification of Malignant Tumors. In addition, sex, age, smoking history (pack year index [PY]: multiplying the number of packs of cigarettes smoked per day by the number of years), histological type, body mass index (BMI) within one month before surgery, PS, adjuvant therapy, and surgical procedure were also analyzed. The cut-off values of age, PY, and BMI were decided based on the previous studies [12-14]. Hemoglobin, neutrophil count, lymphocyte count, platelet count, albumin, AST, ALT, creatinine, cholesterol, C-reactive protein, carcinoembryonic antigen, and cytokeratin fragments were investigated in blood examinations within 1 month before operation and at approximately 1 year (ranging from 10 to 14 months) after operation. Each cut-off value of the blood collection items was set to a standard value at Kyushu University Hospital

7

(Fukuoka, Japan). Forced expiratory volume in 1 s (FEV1.0%) was also analyzed. The institutional review board of Kyushu University (Fukuoka, Japan) approved this study (IRB No.28-309).

Imaging and assessment of SMA As shown in Fig. 1a, the paravertebral muscle area (cm2) at the Th12 level was used for the analysis of SMA in this retrospective study [11]. The SMA was measured with OsiriX® software (32 bit, version 5.8, Geneva, Switzerland) using Hounsfield Units with a threshold from −29 to +150 Hounsfield Units [7]. The Th12 muscle index was defined as follows: paravertebral muscle area (cm2) at the Th12 level was divided by height (m) squared. The post/pre ratio (PPR) was calculated as follows: postoperative Th12 muscle index divided by preoperative Th12 muscle index [11]. In the statistical analyses, all patients were divided into a ‘SMA-decreased’ group (PPR < 0.9) or a ‘SMA-stable/increased’ group (PPR ≥ 0.9). The cut-off value was set to 0.9 according to the results of previous studies that indicated 10% loss in SMA was an independent postoperative prognostic factor in patients with cancer [15]. In the detailed analyses of the survival probabilities (Supplementary Fig. 1), all patients were classified into three categories: ‘PPR > 0.95,’ ‘0.95 ≥ PPR ≥ 0.9,’ and ‘PPR < 0.9.’

8

Analysis of the association between inflammatory/nutritional indices and SMA To investigate the association between inflammatory/nutritional status and change in SMA, the neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), modified Glasgow prognostic score (mGPS), controlling nutritional status (CONUT), and prognostic nutritional index (PNI) were calculated as described previously [16-19]. In brief, NLR and PLR were calculated as neutrophil and platelet count divided by lymphocyte count [16]. The mGPS score was defined as shown in Supplementary Table 1 [17]. The CONUT score was calculated as shown in Supplementary Table 2 [20, 21]. The PNI was defined as follows: 10 × albumin + 0.005 × lymphocyte count [18]. The postoperative change in the inflammatory/nutritional status was analyzed by calculating the difference between preoperative and postoperative indices at approximately 1 year (10–14 months) after surgery. The change in each index was expressed as ∆NLR/y, ∆PLR/y, ∆mGPS/y, ∆CONUT/y, and ∆PNI/y.

Statistical analysis The survival probabilities were estimated using the Kaplan–Meier method. The difference of the survival probabilities was analyzed with the log-rank test. OS was defined as the months from the operation until death regardless of the reason. DFS was defined as the

9

months from the operation until recurrence. Univariate and multivariable analyses were performed with the log-rank test and a proportional hazard model. Cox proportional hazard regression models were used to calculate hazard ratios for positive risk factors with the backward elimination method. The association between skeletal muscle loss and the clinicopathological factors was analyzed using Student’s t test, the Mann–Whitney U test, or Pearson’s χ2 test where appropriate. The differences were considered statistically significant when the p-value was less than 0.05. All analyses were performed with JMP® 13.0 (SAS Institute Inc., Cary, NC, USA).

10

Results

Patient characteristics

The patient characteristics are shown in Supplementary Table 3. Median age was 68 ranging between 29 and 93. One hundred and twenty-two (59.8%) were men, and mean BMI was 22.2 (standard deviation [SD]: 3.4). One hundred and twenty-eight (62.7%) were current or former smokers, and median PY was 24 ranging between 0 and 125. One hundred and fifty-three (75.0%) were pStage I, and 30 (14.7%) were pStage II; 159 (78.0%) and 37 (18.1%) were diagnosed as adenocarcinoma and squamous cell carcinoma, respectively; almost all patients (98.0%) were PS 0 or 1. Adjuvant chemotherapy was administered for 50 patients (24.5%). One hundred and fifty-six (76.5%), 20 (9.8%), 24 (11.8%), and 4 (1.9%) patients underwent lobectomy, segmentectomy, wedge resection, and pneumonectomy, respectively.

Change in SMA after complete resection of NSCLC To analyze the loss of SMA, PPR was defined as the value of the postoperative Th12 muscle index (cm2/m2) divided by the preoperative Th12 muscle index. An example of CT images before and after curative lung resection is shown in Fig. 1a, and the histogram of PPR in the all cases is shown in Fig. 1b. The average of PPR in the all cases was 0.93 ranging from 0.51 to 1.20 (SD: 0.10). The average of the preoperative Th12 muscle index in men and women

11

was 11.91 (cm2/m2) and 11.04 (cm2/m2), which decreased to 10.99 (cm2/m2) and 10.45 (cm2/m2), respectively (Supplementary Fig. 2). The Th12 muscle index decreased significantly in men following complete resection of NSCLC (p = 0.009), but the change in the Th12 muscle index did not reach statistical significance in women (p = 0.115).

The clinical factors associated with SMA-decreased status Of the 204 patients, 70 (34.3%) were classified as the SMA-decreased group with the cut-off value of PPR being 0.9 (Fig. 1b). The SMA-decreased group was significantly associated with low BMI (p = 0.019). However, no significant difference in other clinical factors such as age, pStage, and preoperative SMA was observed between the SMA-decreased and SMA-stable/increased groups. The data are summarized in Table 1.

Impact of postoperative decrease in SMA on survival and recurrence The SMA-decreased group (PPR < 0.9) had a significantly poorer OS than the SMA-stable/increased group as shown in Fig. 2a (p < 0.001). Regarding DFS, the SMA-decreased

group

(PPR

<

0.9)

had

a

significantly

poorer

DFS

than

the

SMA-stable/increased group (p < 0.001). The Kaplan–Meier curve is shown in Fig. 2b. The univariate analyses of OS and DFS are shown in Supplementary Table 4. In multivariable

12

analyses, SMA were significant prognostic factors of OS and DFS (p < 0.001 and p = 0.001, respectively) (Table 2). In the detailed analyses of the survival probabilities, the degree of poor OS and DFS depended on the extent of the decrease in SMA (Supplementary Fig. 1a and Fig. 1b). We also performed an additional analysis in which all patients who recurred before CT scans are excluded. The SMA-decrease remained an independent prognostic factor for OS and DFS (Supplementary Table 5).

Association

between

postoperative

decrease

in

SMA

and

change

in

each

inflammatory/nutritional index As shown in Table 3, the SMA-decreased status was significantly associated with the postoperative exacerbation of NLR, PLR, mGPS and PNI (p = 0.009, p = 0.026, p = 0.003, and p = 0.013, respectively). The correlations between change in SMA and that in inflammatory/nutritional statuses are shown in Fig. 3 and Table 4. Patients with NLR decrease, PLR decrease, mGPS stable/decrease, and CONUT stable/decrease showed significantly shorter OS in comparison to those with NLR increase, PLR increase, mGPS increase, and CONUT increase groups, respectively (Supplementary Fig. 3; p = 0.001, p = 0.007, p < 0.001, and p < 0.001, respectively).

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Comment In the current study, we demonstrated that SMA-decreased status (PPR < 0.9) after operation was significantly associated with the postoperative poor prognosis in patients with NSCLC (Fig. 2). Skeletal muscle loss was an independent predictive factor for OS and DFS (Table 2). In addition, postoperative skeletal muscle loss was significantly associated with the exacerbation of a postoperative inflammatory/nutritional condition (Table 3). Only a few reports have shown the relationship between surgery and postoperative impact on sarcopenia in cancer patients [10, 15]. Miyake et al. reported that the median change in the psoas major muscle area at the level of the 3rd lumbar vertebra (L3) was –10.0% (–44.6 to –0.1) during 1–3 months after cystectomy in patients with carcinoma of the bladder [15]. However, Fukushima et al. revealed that the median change in the psoas major muscle area at L3 level was +0.2% (–35.1 to +28.3) during 5–6 months after cytoreductive nephrectomy in patients with metastatic renal cell carcinoma [10]. Our study has shown that lung resection mostly resulted in skeletal muscle loss following operation, with the median PPR being 0.93 (0.51 to 1.20) after 1 year postoperatively (Fig. 1b). These controversial findings may result from the differences in the postoperative period from operation to the analyses of SMA and whether the operation was of curative or palliative intent.

As shown in Table 1, the

patients’ characteristics of the SMA-decreased group (PPR < 0.9) was significantly associated

14

with low BMI. BMI is one of the most useful markers of nutritional status and obesity [22]. However, BMI is calculated by only body weight and height, and does not always reflect nutritional status, PS, or physical activity. The patients whose pleural effusion is increasing or body edema is exacerbating would gain weight and may be overestimated in the BMI analysis. Furthermore, our multivariable analysis for the relationship between DFS and clinical factors showed that BMI was not an independent prognostic factor (Table 2). Thus, a postoperative change in SMA may be a better indicator of the nutritional status and predictor of the postoperative prognosis. Recently, the relationship between an exacerbation of sarcopenia and OS and/or cancer-specific outcomes has been reported in various diseases such as ovarian and esophageal cancer [8-10, 15, 23, 24]. Our findings that a SMA-decreased status after curative lung resection was an independent prognostic factor of postoperative poor OS/DFS may confirm the results of these previous reports (Fig. 2 and Table 2). The extent of the decrease in SMA depended on the degree of poor OS/DFS (Supplementary Fig. 1). As shown in Table 3, skeletal muscle loss was significantly related to the exacerbation of NLR, PLR, mGPS, and PNI. Possible explanation for the association between the postoperative skeletal muscle loss and poor prognosis is that decreased SMA reflects the deterioration of the inflammatory/nutritional statuses, which are associated with patients’ immune status [25, 26].

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There are some limitations to this study. First, we decided to set a cut-off value to PPR = 0.9 to match a previous report [15]. We think it is important to validate this cut-off value in other populations with NSCLC. Second, we used SMA for the analysis of skeletal muscle amount at the level of Th12 in this study. Prado et al. reported that the skeletal muscle area at the L3 level was more suitable for predicting the prognosis in cancer patients [2]. However, it should be emphasized that the L3 level is not routinely included in follow-up CT scans of the thoracic area. Thus, some researchers have suggested that the skeletal muscle area at the 1st lumbar level may be a surrogate for that at the L3 level in small-cell lung cancer [27]. Our previous study also showed a correlation between the skeletal muscle area at the Th12 level and that at the L3 level (R2 = 0.360, p < 0.001; unpublished data); thus, we believe that it was reasonable to use the values at the Th12 level to assess the SMA in patients with NSCLC [11, 28]. In conclusion, postoperative skeletal muscle loss was significantly associated with postoperative poor prognosis. Future prospective studies are needed to clarify whether nutritional support improves OS and/or PFS.

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status

and creatine

2019;11(3):927-35.

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kinase. Journal

of Thoracic

Disease

1 2

Table 1. The characteristics of the SMA-stable/increased patients and SMA-decreased patients. SMA-stable/increased (Post/pre ratio≥0.9; n=134)

Factors

66.7 (10.4)

SMA-decreased (Post/pre ratio<0.9; n=70)

0.668a

Age (years)

mean (SD)

Sex (n)

man (n=122) woman (n=82)

BMI (kg/m2)

mean (SD)

Smoking status (n)

non-smoker (n=76) smoker (n=128)

53 (39.5%) 81 (60.5%)

23 (32.9%) 47 (67.1%)

0.348b

Pack year

median (range)

20 (0-120)

35 (0-125)

0.212c

Pathological stage (n)

I (n=152) II/III (n=52)

95 (70.9%) 39 (29.1%)

57 (81.4%) 13 (18.6%)

0.101b

Performance status (n)

0 (n=151) ≥1 (n=53)

105 (78.4%) 29 (21.6%)

46 (65.7%) 24 (34.3%)

0.051b

Surgical procedure (n)

≥lobectomy (n=160) sublobar resection (n=44)

106 (79.1%) 28 (20.9%)

54 (77.1%) 16 (22.9%)

0.746b

FEV1.0% < 70% (n)

absent (171)

114 (85.1%)

57 (81.4%)

0.506b

79 (59.0%) 55 (41.0%) 22.6 (3.4)

22

67.4 (10.3)

P value

43 (61.4%) 27 (38.6%) 21.4 (3.3)

0.732b

0.019a

present (33)

3 4 5 6

20 (14.9%)

13 (18.6%)

Preoperative SMA (cm2/m2) mean (SD) 11.5 (2.3) 11.6 (2.5) SMA, skeletal muscle area; SD, standard deviation; BMI, body mass index; FEV1.0, Forced expiratory volume in 1 s a Student’s t test b χ2 test c Mann-Whitney U test

23

0.765a

7 8 9

Table 2. Results of multivariable analyses of disease-free and overall survival in patients who had undergone surgical resection of non-small cell lung cancer (n = 204). Factors

Age (years)

Sex

BMI (kg/m2)

Pathological stage

pl

CEA (mg/mL)

N

Disease-free survival Multivariable analysis HR（ （95% CI） ） P value

≥75

42

Overall survival Multivariable analysis HR（ （95% CI） ） P value 2.02 (1.05-3.75)

<75

162

0.035

man

122

2.02 (1.06-4.11)

woman

82

0.031

<20

52

1.98 (1.07-3.57)

≥20

152

0.030

II, III

52

2.20 (1.25-3.82)

2.00 (1.05-3.74)

I

152

0.006

0.036

present

51

2.38 (1.39-4.04)

3.28 (1.80-6.00)

absent

153

0.002

<0.001

>3.2

94

2.08 (1.22-3.66)

1.97 (1.08-3.72)

≤3.2

110

0.007

0.026

24

Skeletal muscle area

10

decreased stable/increased

70 134

2.92 (1.79-5.01) 0.001

4.60 (2.47-8.81) <0.001

HR, hazard ratio; CI, confidence interval; BMI, body mass index; pl, pleural invasion; CEA, carcinoembryonic antigen.

25

11 12

Table 3. The inflammatory/nutritional indices of the SMA-stable/increased patients and SMA-decreased patients. SMA-stable/increased (Post/Pre ratio≥0.9; n=134)

Factors Preoperative inflammatory/nutritional indices NLR mean (SD) PLR

mean (SD)

mGPS

mean (SD)

CONUT

mean (SD)

PNI

mean (SD)

Postoperative change in inflammatory/nutritional indices ∆NLR/y mean (SD)

2.6 (2.1) 144.2 (64.6) 0.1 (0.3)

SMA-decreased (Post/Pre ratio<0.9; n=70)

P valuea

2.5 (2.2)

0.819

143.8 (77.0)

0.966

0 (0.2)

0.360

1.0 (1.1)

1.2 (1.3)

0.326

50.5 (4.8)

50.5 (4.9)

0.958

0.4 (2.8)

0.009

-0.5 (2.0)

∆PLR/y

mean (SD)

-18.3 (55.7)

6.0 (98.6)

0.026

∆mGPS/y

mean (SD)

-0.1 (0.4)

0.1 (0.5)

0.003

∆CONUT/y

mean (SD)

0.01 (1.1)

0.36 (1.7)

0.082

∆PNI/y

mean (SD)

-8.2 (4.6)

-10.0 (5.6)

0.013

26

13 14 15 16 17 18

SMA, skeletal muscle area; NLR, neutrophil-lymphocyte ratio; SD, standard deviation; PLR, platelet-lymphocyte ratio; mGPS, modified Glasgow prognostic score; CONUT, controlling nutritional status; PNI, prognostic nutritional index; ∆, difference between preoperative and postoperative inflammatory/nutritional indices (1 year after operation). a Student’s t test

27

19 20

Table 4. The correlations between postoperative changes in mGPS or CONUT and those in skeletal muscle area

Factors ∆mGPS/y Post/pre ratio (mean [SD])

21 22

Value 0 0.94 (0.10)

≤–1 0.99 (0.08)

≥1 0.84 (0.17)

∆CONUT/y ≤–1 0 1-3 ≥4 Post/pre ratio (mean [SD]) 0.95 (0.09) 0.93 (0.10) 0.91 (0.10) 0.86 (0.18) mGPS, modified Glasgow prognostic score; CONUT, controlling nutritional status; ∆, difference between preoperative and postoperative inflammatory/nutritional indices (1 year after operation); SD, standard deviation.

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Figure legends

Fig. 1 (a) One example of the paravertebral muscle area at the 12th thoracic vertebrae (Th12) level before and after curative lung resection. (b) The histogram of post/pre ratio (PPR) is shown.

Fig. 2 Kaplan–Meier curves for (a) overall survival and (b) disease-free survival according to the postoperative change in skeletal muscle area.

Fig. 3. The plots for the correlations between postoperative changes in the (a) neutrophil– lymphocyte ratio, (b) platelet–lymphocyte ratio, and (c) prognostic nutritional index and those in skeletal muscle area are shown.

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List of abbreviations

NSCLC: non-small cell lung cancer PS: performance status SMA: skeletal muscle area OS: overall survival DFS: disease-free survival CT: computed tomography Th12: 12th thoracic pStage: pathological stage PY: pack year index BMI: body mass index FEV1.0%: forced expiratory volume in 1 s PPR: post/pre ratio NLR: neutrophil–lymphocyte ratio PLR: platelet–lymphocyte ratio mGPS: modified Glasgow prognostic score CONUT: controlling nutritional status PNI: prognostic nutritional index SD: standard deviation L3: 3rd lumbar vertebra

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