Original Thoracic

The Influence of Serum Sodium Concentration on Prognosis in Resected Non-Small Cell Lung Cancer Naohiro Kobayashi1 Shingo Usui1 Masatoshi Yamaoka2 Yukinobu Goto1 Mitsuaki Sakai1 Yukio Sato1 1 Department of General Thoracic Surgery, Graduate School of

Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki, Japan 2 Department of General Thoracic Surgery, Tsukuba University Hospital, Tsukuba, Ibaraki, Japan

Hisashi Suzuki1

Shinji Kikuchi1

Address for correspondence Naohiro Kobayashi, MD, Department of General Thoracic Surgery, Graduate School of Comprehensive Human Science, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058575, Japan (e-mail: [email protected]).

Thorac Cardiovasc Surg 2014;62:338–343.

Abstract

Keywords

► inflammation ► systemic ► lung cancer treatment ► pathophysiology

Background Hyponatremia is the most common electrolyte disorder and is a negative prognostic factor in several kinds of cancer. However, few reports have referred to hyponatremia in non-small cell lung cancer (NSCLC). In the present study, the authors examined the influence of preoperative serum sodium concentration on survival in completely resected NSCLC. Methods A total of 386 completely resected NSCLC patients were retrospectively analyzed. Results Kaplan-Meier survival curves showed that serum sodium concentration was a significant prognostic factor, and the log-rank statistical value was maximum (9.173, p ¼ 0.002) when the cutoff value of serum sodium concentration was 139 mEq/L. The overall 5-year survival rate of the high-serum sodium concentration group (> 139 mEq/L) was 74.8% and that of the low-serum sodium concentration group ( 139 mEq/L) was 59.7%. Clinicopathological factors showed significant differences between the two groups for leukocyte count, neutrophil count, C-reactive protein, tumor size, and pleural invasion. Conclusions Low-serum sodium concentration, which was associated with tumor status and inflammation, had negative prognostic influence in completely resected NSCLC.

Introduction Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer-related deaths. Several prognostic factors have been proposed in NSCLC, such as age, sex, performance status, tumor size, pleural invasion, lymph node metastasis, and distant metastasis. A significant number of patients have systemic recurrence even in completely resected NSCLC. Hyponatremia is the most common electro-

received June 21, 2013 accepted after revision September 29, 2013 published online December 2, 2013

lyte disorder in hospitalized patients.1 Recently, hyponatremia has been associated with poor outcome in several medical conditions, such as liver cirrhosis, congestive heart failure, infectious diseases, and malignant diseases.2–8 In small cell lung cancer (SCLC), hyponatremia is a common phenomenon as a paraneoplastic syndrome and is reported as one of the negative prognostic factors.2,3 However, few reports have referred to hyponatremia as a prognostic factor in NSCLC.4,5 In this study, the authors examined the influence

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Influence of Serum Sodium Concentration on NSCLC

Table 1 Clinicopathological characteristics of patients Characteristics

Total (n ¼ 386)

Age (mean  SD), y

67.4  10.1

Sex (male/female)

259/127

Materials and Methods

ECOG performance status (0/1/2)

263/28/1

Patients

Smoking index (mean  SD)

791  746

The authors conducted a retrospective analysis of patients diagnosed with NSCLC who underwent surgery at Tsukuba University Hospital between January 2000 and December 2009. Data from 454 patients were obtained from the hospital’s database. Overall 68 patients were excluded due to distant metastasis (n ¼ 25), secondary primary lung cancer (n ¼ 17), preoperative treatment (n ¼ 15), incomplete radical surgery (n ¼ 7), no measurement of serum sodium concentration (n ¼ 3), and receiving dialysis (n ¼ 1). Thus, 386 patients were eligible for this study. Histological classification was performed according to the World Health Organization classification and the tumors were staged according to the TNM classification of malignant tumors. In the department of Tsukuba University Hospital, a peripheral venous blood sample from each patient was routinely examined within a month before surgery.

Resected side (right/left)

221/165

Surgical procedure (Pn/Lob/Seg/PR)

9/306/39/32

Statistical Analysis Overall survival was determined from the date of surgery till the date of death or the last follow-up. Survival curves were constructed using the Kaplan-Meier method, and statistically significant differences between the survival curves were assessed by the log-rank test. In selecting the optimal cutoff value for determining the effect of the serum sodium concentration on survival, a running log-rank test was performed at intervals of 1 mEq/L between the 5th percentile (136 mEq/L) and the 95th percentile (144 mEq/L). The optimal cutoff value was defined when the log-rank statistical value was maximum.9 Then the authors divided the patients into two groups according to the optimal cutoff value to investigate the association with clinicopathological factors. The chi-square test (or Fisher exact test when appropriate) was used for categorical variables, and the t-test was used for continuous variables. To assess the influence on overall survivals, multivariate analysis was performed using the Cox proportional hazards model. The result was considered to be significant when the p-value was less than 0.05. Statistical analyses were performed using IBM Statistics SPSS 19 (IBM Corporation, Armonk, NY).

Histological type (Ad/Sq/Large/others)

241/96/23/26

Pathological staging (I/II/III)

240/90/56

Cause of death (NSCLC/others/unknown)

58/32/2

Abbreviations: Ad, adenocarcinoma; ECOG, Eastern Cooperative Oncology Group; Large, large cell carcinoma; Lob, lobectomy or bilobectomy; NSCLC, non-small cell lung cancer; Pn, pneumonectomy; PR, partial resection; Sq, squamous cell carcinoma; SD, standard deviation; Seg, segmentectomy; y, year.

136 mEq/L), and they had no neurological dysfunctions due to hyponatremia, such as fatigue, nausea, anorexia, and headache. A total of 240 patients were classified as stage I, 90 patients were classified as stage II, 56 patients were classified as stage III. Overall 39 patients had postoperative adjuvant treatment and 89 patients had recurrences of lung cancer. The overall 5-year survival rate of all 386 patients was 70.0%.

Optimal Cutoff Value for the Effect of Serum Sodium Concentration on Survival Kaplan-Meier survivals described that the prognosis of lower serum sodium concentration groups were poorer than that of higher serum sodium concentration group (►Table 2). The log-rank statistical values were significant when the cutoff values of serum sodium concentration were 137, 139, and 140 mEq/L. The maximum log-rank statistical value was 9.173 (p ¼ 0.002) when the cutoff value was 139 mEq/L. KaplanMeier survival curves of the high-serum sodium concentration group (high-Na, serum sodium concentration > 139 mEq/L, n ¼ 263) and the low-serum sodium concentration group (low-Na, serum sodium concentration  139 mEq/L,

Results Patients’ Characteristics The clinicopathological characteristics of patients (259 men and 127 women) are shown in ►Table 1. The patients’ ages at the time of operation ranged from 29 to 89 years (mean, 67.4 y). The mean follow-up was 41.2 months (range, 1–118 mo). The serum sodium concentration ranged between 130 and 149 mEq/L (mean, 140.4 mEq/L, ►Fig. 1). Nine patients (2.3%) had sodium concentration below the normal range (less than

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Fig. 1 Graph showing distribution of serum sodium concentration in 386 patients. Thoracic and Cardiovascular Surgeon

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of preoperative serum sodium concentration on survival and investigated the relationships of the serum sodium concentration to clinicopathological factors in completely resected NSCLC.

Kobayashi et al.

Influence of Serum Sodium Concentration on NSCLC

Kobayashi et al.

Table 2 Running log-rank statistical value and 5-year survival rate in each cutoff value of serum sodium concentration Cutoff value of serum sodium concentration (mEq/L)

136

137

138

139

140

141

142

143

144

Log-rank statistical value

1.689

7.746

3.612

9.173

5.173

1.197

0.468

1.25

0.353

5-y survival rate of lower Na group (%)

31.8

45.5

58.1

59.7

64.8

67.7

69.5

69.4

69.8

5-y survival rate of higher Na group (%)

71.8

73.1

73.3

74.8

75

74.6

72.2

74.9

77.1

Abbreviations: Na, serum sodium concentration; y, year.

n ¼ 123) according to the optimal cutoff value are shown in ►Fig. 2. The overall 5-year survival rate of the high-Na group (74.8%) was significantly higher than that of the low-Na group (59.7%, p ¼ 0.002).

Relationships between Serum Sodium Concentration and Clinicopathological Factors The relationships between the serum sodium concentration and clinical factors are shown in ►Table 3. Low-Na was significantly related to sex (p < 0.001), Eastern Cooperative Oncology Group performance status (p ¼ 0.013), and smoking index (p ¼ 0.02). As to comorbidity and history, patients with liver disease were more frequent in low-Na group than in high-Na group (p ¼ 0.006). The liver diseases were hepatitis C or B (n ¼ 11), liver cirrhosis (n ¼ 4), autoimmune hepatitis (n ¼ 1), and alcoholic liver injury (n ¼ 1). In chronic obstructive pulmonary disease, interstitial pneumonia, diabetes mellitus, renal disease, and cardiac disease including arrhythmia and ischemic heart disease, there were no significant differences between the groups. As for blood laboratory data, high leukocyte count (p ¼ 0.002), high neutrophil count (p ¼ 0.012), low albumin (p ¼ 0.037), high alkaline phosphatase (ALP, p < 0.001), high gamma-guanosine triphosphatase (γ-GTP, p ¼ 0.005), low cholinesterase (p < 0.001), and high C-reactive protein (CRP, p ¼ 0.001) were significantly corre-

lated with low-Na. The associations with pathological factors are shown in ►Table 4. Low-Na was significantly associated with larger tumor size (p < 0.001) and positive pleural invasion (p ¼ 0.033), which influenced advanced tumor status (p ¼ 0.004) and advanced staging (p ¼ 0.034). In histology, low-Na was significantly less frequent in adenocarcinoma (p < 0.001) and more frequent in squamous cell carcinoma (p ¼ 0.025) and large cell carcinoma (p ¼ 0.009). No significant differences were detected between the groups in age, surgical procedure, diuretics use, postoperative adjuvant treatment, nodal status, vascular invasion, and lymphatic invasion. As for the causes of death, 58 out of 82 patients (63%) died from NSCLC and there was no significant difference between the groups. Other principal causes of death were infectious diseases (n ¼ 10), other malignancies (n ¼ 9), and brain infarction (n ¼ 4).

Multivariate Analysis The results of multivariate analysis are shown in ►Table 5. The hazard ratio of low-Na was 1.527 (95% confidence interval: 1.005–2.322, p ¼ 0.047). Other significant factors were tumor size (hazard ratio: 2.524, 95% confidence interval: 1.527–4.052, p < 0.001), pleural invasion (hazard ratio: 1.610, 95% confidence interval: 1.038–2.496, p ¼ 0.033), and nodal status (hazard ratio: 2.032, 95% confidence interval: 1.317–3.135, p ¼ 0.001).

Discussion

Fig. 2 Kaplan-Meier survival curves of the serum sodium concentration at the optimal cutoff value (139 mEq/L) are shown (p ¼ 0.002). The overall 5-year survival rates were 74.8% for the high-serum sodium concentration group (serum sodium concentration > 139 mEq/L, n ¼ 263) and 59.7% for the low-serum sodium concentration group (serum sodium concentration  139 mEq/L, n ¼ 123). Na, serum sodium concentration. Thoracic and Cardiovascular Surgeon

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The present study showed that low-serum sodium concentration had poor prognostic influence in completely resected NSCLC. Previously hyponatremia was reported as a poor prognostic factor in hepatocellular cancer,6 gastric cancer,7 renal cell cancer,8 and SCLC.2,3 As for NSCLC, Muers et al proposed hyponatremia as a negative predictive factor in NSCLC patients who did not receive curative treatment for their condition,4 and Jacot et al showed that hyponatremia was one of the independent poor prognostic factors in untreated NSCLC patients of all stages.5 Hyponatremia is important as a marker of underlying disease and for recognizing potential morbidity.10,11 The causes of hyponatremia are various, such as syndrome of inappropriate secretion of antidiuretic hormone (SIADH), excessive water intake, hypotonic infusion, gastrointestinal sodium losses, diuretic use, renal failure, congestive heart failure, liver cirrhosis, nephrotic syndrome, hypothyroidism, adrenal insufficiency, diabetic decompensation, and so on.1 The

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Table 3 Relationship between preoperative serum sodium concentration and clinical factors p-Value

Serum sodium concentration 139 mEq/L

>139 mEq/L

(n ¼ 123)

(n ¼ 263)

67.5  10.0

67.3  10.3

0.869

Sex (male/female)

101/22

158/105

< 0.001

ECOG performance status (0/1/2)

80/14/1

183/14/0

0.013

Smoking index (mean  SD)

912  648

734  782

0.02

COPD

7

11

0.512

Interstitial pneumonia

5

3

0.072

Diabetes mellitus

19

25

0.087

Ischemic heart disease

11

17

0.382

Arrhythmia

4

17

0.195

Liver disease

11

7

0.006

Renal disease

1

5

0.379

5/96/13/9

4/210/26/23

0.457

7,500  4,100

6,300  1,800

0.002

Age (mean  SD), y

Surgical procedure (Pn/Lob/Seg/PR) Blood laboratory data Leukocyte counts (mean  SD), mm-3 -3

4,700  3,800

3,700  1,400

0.012

Lymphocyte counts (mean  SD), mm-3

1,900  730

1,900  700

0.542

Albumin (mean  SD), g/dL

3.9  0.5

4.0  0.4

0.037

ALP (mean  SD), U/L

261  87

229  68

< 0.001

γ-GTP (mean  SD), U/L

46  49

32  35

0.005

Cholinesterase (mean  SD), U/L

283  83

313  72

< 0.001

Neutrophil counts (mean  SD), mm

Creatinin (mean  SD), mg/dL

0.77  0.24

0.76  021

0.192

CRP (mean  SD), mg/dL

1.36  3.32

0.36  0.71

0.001

Diuretics use

9

12

0.266

Postoperative adjuvant chemotherapy

16

23

0.195

Recurrences of NSCLC

33

56

0.213

Cause of death (NSCLC/others/unknown)

24/16/1

34/16/1

0.724

Abbreviations: ALP, alkaline phosphatase; CRP, C-reactive protein; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; Lob, lobectomy or bilobectomy; NSCLC, non-small cell lung cancer; Pn, pneumonectomy; PR, partial resection; γGTP, gamma-guanosine triphosphatase; Seg, segmentectomy; SD, standard deviation; y, year.

most common cause of hyponatremia in cancer patients is SIADH.11 SIADH is associated with malignant diseases, infection, disorders of the central nervous system, drugs, and other causes.10 In SCLC, 25% of patients have hyponatremia and it has been estimated that 10% of patients have SIADH.2,12,13 Ectopic production of arginine-vasopressin or atrial natriuretic peptide is recognized as a cause of SIADH.13,14 In NSCLC, the incidence of hyponatremia is 1 to 8%, and SIADH occurs in only 0.7% of patients.5,12 In this study, the incidence rate of hyponatremia was low (2.3%). Although, arginine-vasopressin and atrial natriuretic peptide were not measured in each patient, the cases with SIADH are considered to be very few. Therefore, the authors consider that the influence of SIADH could be negligible in their study.

The data showed that low-Na group was associated with higher leukocyte count, higher neutrophil count, and higher level of CRPs. The low-Na group was also associated with larger tumor size and pleural invasion which resulted in advanced staging. Previously, the authors reported that the neutrophil count was associated with tumor size and pleural invasion.15 As the neutrophil count is a fundamental marker of inflammation, the authors consider that low-Na could be reflected by cancerrelated inflammation, which indicates the severity or nature of inflammation occurring within or around the tumor. Hyponatremia is recently recognized as a complication of several inflammatory diseases and as being related to inflammatory cytokines.16–18 There is mounting evidence for the relationship between hyponatremia and interleukin-6 (IL-6).16,18,19 IL-6 is one of the important proinflammatory cytokines and can Thoracic and Cardiovascular Surgeon

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Comorbidity and history

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Table 4 Relationship between preoperative serum sodium concentration and pathological factors Serum sodium concentration

p-Value

139 mEq/L

>139 mEq/L

(n ¼ 123)

(n ¼ 263)

Pathological staging (I/II/III)

65/35/23

175/55/33

0.034

Tumor status (T1/T2/T3/T4)

39/58/25/1

132/98/30/3

0.004

Nodal status (N0/N1/N2)

88/16/20

195/40/28

0.281

Tumor size (mean  SD), cm

3.7  2.4

2.8  1.7

< 0.001

Pleural invasion (pl1–3/pl0)

54/69

86/177

0.033

Pulmonary metastasis (pm1/pm0)

11/112

20/243

0.652

Vascular invasion (positive/negative)

59/63

115/147

0.413

Lymphatic invasion (positive/negative)

53/69

96/166

0.203

Adenocarcinoma

61

180

< 0.001

Squamous cell carcinoma

39

57

0.025

Large cell carcinoma

13

10

0.009

Others

10

16

0.455

Histological type

Abbreviation: SD, standard deviation.

Table 5 Multivariate analysis using cox hazard proportional model Variable

Adjusted hazard ratio (95% CI)

Serum sodium concentration Tumor size Pleural invasion Nodal status

 139 mEq/L

1.527

> 139 mEq/L

1

> 3.0 cm

2.524

 3.0 cm

1

Positive

1.610

Negative

1

1–2

2.032

0

1

p-Value

(1.005–2.322)

0.047

(1.572–4.052)

< 0.001

(1.038–2.496)

0.033

(1.317–3.135)

0.001

Abbreviation: CI, confidence interval.

regulate vasopressin secretion under physiological conditions.16 IL-6 is also recognized as a central cytokine of the cancer immune response and induces a systemic inflammatory response.20 Therefore, it is speculated that the inflammatory response, probably via inflammatory cytokines represented by IL-6, could explain why lower sodium concentration causes poor prognosis in this study. Low-Na was associated with liver disease in comorbidity and history, and also correlated with high ALP, high γ-GTP, and low cholinesterase. Low-Na might be associated with poor hepatic functions, although liver diseases were not a significant prognostic factor. As for diuretics use, significant difference between the groups was not recognized. A limitation of this study was the number of cases, as this study was a completely retrospective study in a single institute. Additionally, a serum sodium concentration could vary with conditions of the patients. Further investigations are needed to verify these results. Thoracic and Cardiovascular Surgeon

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In conclusion, patients with low-serum sodium concentration had a tendency of poor prognosis in completely resected NSCLC, probably because serum sodium concentration was associated with tumor status and inflammation. To the authors’ best knowledge, this is the first report that focused on serum sodium concentration in resected NSCLC and investigated the correlation between serum sodium concentration and clinicopathological factors.

Conflict of Interest The authors report no conflict of interest.

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Influence of Serum Sodium Concentration on NSCLC