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Research Papers:

Prognostic values of normal preoperative serum cancer markers for gastric cancer

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Oncotarget. 2016; 7:58459-58469. https://doi.org/10.18632/oncotarget.11248

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Fan Feng, Li Sun, Zhen Liu, Shushang Liu, Gaozan Zheng, Guanghui Xu, Man Guo, Xiao Lian, Daiming Fan and Hongwei Zhang _

Abstract

Fan Feng1,*, Li Sun1,*, Zhen Liu1,*, Shushang Liu1, Gaozan Zheng1, Guanghui Xu1, Man Guo1, Xiao Lian1, Daiming Fan1, Hongwei Zhang1

1Department of Digestive Surgery, Xijing Hospital, Fourth Military Medical University, 710032, Xi’an, Shaanxi, China

*These authors have contributed equally to this work

Correspondence to:

Hongwei Zhang, email: [email protected]

Keywords: gastric cancer, CA19-9, AFP, CA125, prognosis

Received: May 29, 2016    Accepted: July 28, 2016    Published: August 12, 2016

ABSTRACT

We examined the prognostic value of normal levels of four serum cancer markers, carcinoembryonic antigen (CEA), carbohydrate associated antigen (CA19-9), alpha-fetoprotein (AFP) and cancer antigen 125 (CA125), in gastric cancer patients. Among 1927 gastric cancer patients enrolled in this study, 1477 were male (76.6%) and 450 were female (23.4%). The median age was 57 years (range 20-86). Clinicopathological features and survival times were recorded, and the association between CEA, CA19-9, AFP, and CA125 levels and patient prognosis was analyzed. The optimal cut-off values were 0.71 for CEA (P=0.317), 9.22 for CA19-9 (P=0.009), 3.76 for AFP (P=0.008) and 15.65 for CA125 (P=0.006). Serum CA19-9 levels correlated with gender, age, and tumor depth (all P<0.05); AFP levels correlated with pathological type (P=0.005); and CA125 levels correlated with gender, tumor size, pathological type, tumor depth and lymph node metastasis (all P<0.05). Relatively high levels of CA19-9, AFP and CA125, still within the normal range, were all associated with poor prognosis (5-year overall survival: 70.6% vs 64.2%, P<0.001. 69.6% vs 54.5%, P=0.011. 70.2% vs 54.9%, P<0.001). However, only CA19-9 and AFP levels were independent prognostic predictors. We conclude that the combined assessment of CA19-9, AFP and CA125 levels could have prognostic value in gastric cancer (P<0.001).


INTRODUCTION

Although the incidence of gastric cancer has decreased worldwide, it is still the fifth most common malignancy and the third leading cause of cancer-related mortality in the world [1]. Surgical resection with extended lymph node clearance remains the only curative therapy for non-metastatic gastric cancer. Even with advances in surgical techniques and adjuvant therapy, the prognosis of advanced gastric cancer is still discouraging due to late diagnosis [2].

A variety of factors are well recognized as prognostic indicators for gastric cancer, including tumor size, tumor depth, lymph node metastasis (LNM), and vessel involvement [3, 4]. In addition, elevated levels of preoperative tumor markers, including CEA [5], CA19-9 [6], AFP [7], and CA125 [8], were demonstrated to be associated with gastric cancer prognosis. However, the prognostic values of these tumor markers within the normal range have not yet been investigated. Therefore, the purpose of this study was to explore the prognostic values of normal, preoperative CEA, CA19-9, AFP, and CA125 levels in gastric cancer.

RESULTS

There were 1477 males (76.6%) and 450 females (23.4%) enrolled in this study. The patient age ranged from 20-86 years (median, 57; mean, 56.6). The follow-up time ranged from 1 to 75 months (median, 26.0; mean, 29.7). The 1-, 3- and 5-year overall survival (OS) rates were 93.7%, 75.6% and 68.0%, respectively (Figure 1). The optimal cut-off values of normal serum CEA, CA19-9, AFP, and CA125 for the prognosis of gastric cancer were calculated using X-tile software and are shown in Figures 2-5. The optimal cut-off values were: 0.71 for CEA (P=0.317), 9.22 for CA19-9 (P=0.009), 3.76 for AFP (P=0.008), and 15.65 for CA125 (P=0.006).

Overall survival of gastric cancer patients with normal serum CEA, CA19-9, AFP, and CA125 levels.

Figure 1: Overall survival of gastric cancer patients with normal serum CEA, CA19-9, AFP, and CA125 levels.

Cut-off value of serum CEA for the prognosis of gastric cancer as calculated using X-tile.

Figure 2: Cut-off value of serum CEA for the prognosis of gastric cancer as calculated using X-tile.

Cut-off value of serum CA19-9 for the prognosis of gastric cancer as calculated using X-tile.

Figure 3: Cut-off value of serum CA19-9 for the prognosis of gastric cancer as calculated using X-tile.

Cut-off value of serum AFP for the prognosis of gastric cancer as calculated using X-tile.

Figure 4: Cut-off value of serum AFP for the prognosis of gastric cancer as calculated using X-tile.

Cut-off value of serum CA125 for the prognosis of gastric cancer as calculated using X-tile.

Figure 5: Cut-off value of serum CA125 for the prognosis of gastric cancer as calculated using X-tile.

Thus, CA19-9, AFP, and CA125 were tested in univariate and multivariate analyses as prognostic predictors of gastric cancer. The univariate analysis showed that age, tumor size, pathological type, tumor depth, LNM, CA19-9, AFP, and CA125 were risk factors for gastric cancer (Table 1). However, only age, tumor size, pathological type, tumor depth, LNM, CA19-9, and AFP were independent prognostic factors according to multivariate analysis (Table 2). Moreover, relatively high levels of CA19-9, AFP, and CA125 were associated with poor prognosis (5-year OS: 70.6% vs 64.2%, P<0.001. 69.6% vs 54.5%, P=0.011. 70.2% vs 54.9%, P<0.001; Figures 6-8). Clinicopathological features between the high- and low-level groups of CA19-9, AFP, and CA125 were analyzed and are summarized in Tables 3-5, respectively. Serum CA19-9 levels were correlated with gender, age, and tumor depth (all P<0.05), serum AFP levels were correlated with pathological type (P=0.005), and serum CA125 levels were correlated with gender, tumor size, pathological type, tumor depth, and LNM (all P<0.05).

Table 1: Univariate analysis of risk factors for prognosis of gastric cancer

Prognostic factors

β

Hazard ratio (95% CI)

P value

Gender

0.226

1.253(0.999-1.572)

0.051

Age

0.234

1.264(1.035-1.542)

0.021

Tumor location

-0.037

0.964(0.868-1.070)

0.488

Tumor size

1.291

3.636(2.977-4.441)

0.000

Pathological type

0.554

1.740(1.509-2.007)

0.000

Tumor depth

0.872

2.393(2.124-2.696)

0.000

Lymph node metastasis

0.777

2.174(1.986-2.380)

0.000

CEA

-0.213

0.808(0.606-1.077)

0.808

CA19-9

0.376

1.456(1.194-1.777)

0.000

AFP

0.348

1.417(1.083-1.852)

0.011

CA125

0.493

1.637(1.286-2.085)

0.000

Table 2: Multivariate analysis of risk factors for prognosis of gastric cancer

Prognostic factors

β

Hazard ratio (95% CI)

P value

Age

0.247

1.280(1.005-1.630)

0.046

Tumor size

0.623

1.865(1.447-2.405)

0.000

Pathological type

0.262

1.300(1.030-1.640)

0.027

Tumor depth

0.436

1.547(1.293-1.850)

0.000

Lymph node metastasis

0.520

1.683(1.472-1.923)

0.000

CA19-9

0.331

1.393(1.096-1.770)

0.007

AFP

0.459

1.583(1.166-2.149)

0.003

Table 3: Comparison of clinicopathological characteristics between two groups

Characteristics

Low CA19-9
(n=1134)

High CA19-9
(n=793)

P
value

Gender

 

 

0.013

 Male

892

585

 

 Female

242

208

 

Age

 

 

0.000

 ≤60

744

425

 

 >60

390

368

 

Tumor location

 

 

0.360

 Upper third

290

218

 

 Middle third

218

131

 

 Lower third

538

389

 

 Entire

88

55

 

Tumor size (cm)

 

 

0.369

 ≤5

858

614

 

 >5

276

179

 

Pathological type

 

 

0.890

 Well differentiated

145

100

 

 Moderately differentiated

276

187

 

 Poorly differentiated

670

480

 

 Signet ring cell or Mucinous

43

26

 

Tumor depth

 

 

0.004

 T1

307

201

 

 T2

192

134

 

 T3

384

228

 

 T4

251

230

 

Lymph node metastasis

 

 

0.052

 N0

527

319

 

 N1

199

148

 

 N2

170

134

 

 N3

238

192

 

Table 4: Comparison of clinicopathological characteristics between two groups

Characteristics

Low AFP
(n=1687)

High AFP
(n=240)

P
value

Gender

 

 

0.105

 Male

1303

174

 

 Female

384

66

 

Age

 

 

0.235

 ≤60

1015

154

 

 >60

672

86

 

Tumor location

 

 

0.746

 Upper third

444

64

 

 Middle third

300

49

 

 Lower third

818

109

 

 Entire

125

18

 

Tumor size (cm)

 

 

0.304

 ≤5

1295

177

 

 >5

392

63

 

Pathological type

 

 

0.005

 Well differentiated

209

36

 

 Moderately differentiated

426

37

 

 Poorly differentiated

989

161

 

 Signet ring cell or Mucinous

63

6

 

Tumor depth

 

 

0.185

 T1

439

69

 

 T2

294

32

 

 T3

542

70

 

 T4

412

69

 

Lymph node metastasis

 

 

0.949

 N0

744

102

 

 N1

302

45

 

 N2

267

37

 

 N3

374

56

 

Table 5: Comparison of clinicopathological characteristics between two groups

Characteristics

Low CA125
(n=1608)

High CA125
(n=319)

P
value

Gender

 

 

0.000

 Male

1268

209

 

 Female

340

110

 

Age

 

 

0.345

 ≤60

983

186

 

 >60

625

133

 

Tumor location

 

 

0.334

 Upper third

429

79

 

 Middle third

295

54

 

 Lower third

772

155

 

 Entire

112

31

 

Tumor size (cm)

 

 

0.000

 ≤5

1255

217

 

 >5

353

102

 

Pathological type

 

 

0.038

 Well differentiated

217

28

 

 Moderately differentiated

392

71

 

 Poorly differentiated

939

211

 

 Signet ring cell or Mucinous

60

9

 

Tumor depth

 

 

0.003

 T1

436

72

 

 T2

287

39

 

 T3

504

108

 

 T4

381

100

 

Lymph node metastasis

 

 

0.000

 N0

739

107

 

 N1

286

61

 

 N2

252

52

 

 N3

331

99

 

Overall survival of gastric cancer patients according to CA19-9 levels.

Figure 6: Overall survival of gastric cancer patients according to CA19-9 levels.

Overall survival of gastric cancer patients according to AFP levels.

Figure 7: Overall survival of gastric cancer patients according to AFP levels.

Overall survival of gastric cancer patients according to CA125 levels.

Figure 8: Overall survival of gastric cancer patients according to CA125 levels.

The prognostic value of the combination of CA19-9, AFP, and CA125 for gastric cancer was also evaluated. Gastric cancer patients were divided into four groups: Group 1) low CA19-9, low AFP and low CA125; Group 2) high CA19-9, low AFP, and low CA125; or low CA19-9, high AFP, and low CA125, or low CA19-9, low AFP, and high CA125; Group 3) high CA19-9, high AFP, and low CA125, or high CA19-9, low AFP, and high CA125; or low CA19-9, high AFP, and high CA125; and Group 4) high CA19-9, high AFP, and high CA125. As shown in Figure 9, OS rates were gradually reduced along with increasing levels of CA19-9, AFP, and CA125 (P<0.001).

Overall survival of gastric cancer patients according to the combination of CA19-9, AFP, and CA125 levels.

Figure 9: Overall survival of gastric cancer patients according to the combination of CA19-9, AFP, and CA125 levels.

DISCUSSION

A large number of studies have investigated the predictive value of elevated preoperative serum CEA, CA19-9, AFP, and CA125 levels for the prognosis of gastric cancer. However, no studies have investigated the prognostic value of normal CEA, CA19-9, AFP, and CA125 levels in gastric cancer patients. The present study found that relatively high levels of CA19-9, AFP, and CA125 within the normal limits were associated with a poor prognosis in gastric cancer.

Elevated preoperative serum CEA, CA19-9, AFP, and CA125 have been previously associated with a poor prognosis in gastric cancer. A meta-analysis of 14,651 gastric cancer patients found that elevated serum CEA was an independent prognostic risk factor [5]. Similarly, another meta-analysis of 11,408 gastric cancer patients showed that elevated serum CA19-9 was associated with a poor prognosis [9]. Elevated serum AFP has also been associated with a poor prognosis in gastric cancer, and it can predict liver metastasis after radical resection [7, 10, 11]. Elevated serum CA125 levels have been associated with peritoneal metastasis of gastric cancer [12, 13], and elevated CA125 in peritoneal lavage was associated with peritoneal dissemination and a poor prognosis [14].

Although gastric cancer patients with normal, preoperative serum CEA, CA19-9, AFP, and CA125 had favorable prognoses, the prognostic value of relatively high levels of the four tumor markers within the normal limits was important to test. We found that relatively high levels of CA19-9, AFP, and CA125 were associated with poor prognosis of gastric cancer. However, serum CEA did not have prognostic value. Further, the combination of relatively high levels of CA19-9, AFP, and CA125 increased the prognostic value for gastric cancer, even though the levels were all within the normal limits. These results provide new insights into the prognosis of gastric cancer patients with normal, preoperative tumor markers.

Levels of CEA, CA19-9, AFP, and CA125 are also widely used to monitor recurrence or metastasis of gastric cancer after radical gastrectomy. Patients with normal postoperative CEA levels have a better prognosis [15]. Similarly, Kwon et al. reported that postoperative normalization of CA19-9 can be a surrogate for potentially curative surgical treatment and can be used as a prognostic factor for gastric cancer [16]. However, the predictive value of these tumor markers within normal limits after radical gastrectomy still needs further investigation.

A strong correlation between tumor marker levels and clinicopathological characteristics has been reported previously. Serum CEA levels were associated with tumor depth, LNM, TNM stage, and liver metastasis [17, 18]. Serum CA19-9 levels were also associated with tumor depth and LNM, as well as lymphatic-vascular invasion [19, 20]. Serum AFP levels were associated with LNM, vascular invasion, and liver metastasis [21], and serum CA125 was correlated with vascular invasion, LNM, and tumor stage [22]. We found that serum CA19-9 levels were correlated with gender, age, and tumor depth, serum AFP levels were correlated with pathological type, and serum CA125 levels were correlated with gender, tumor size, pathological type, tumor depth, and LNM.

There are several limitations to our study. First, it was a retrospective study of a single center’s experience. Multi-center studies are needed to verify these findings. Second, the sample size was not large, especially for the patients with high levels of CA19-9, AFP, and CA125, which may result in bias during analysis. Third, the prognostic value of normal, CEA, CA19-9, AFP, and CA125 levels for gastric cancer patients after radical gastrectomy during follow-up were not investigated. Nonetheless, we conclude that relatively high levels of preoperative serum CA19-9, AFP, and CA125 within the normal limits are associated with poor prognosis of gastric cancer. Thus, the combination of CA19-9, AFP and CA125 levels could further increase the predictive value for the prognosis of gastric cancer.

MATERIALS AND METHODS

This study was performed in the Xijing Hospital of Digestive Diseases affiliated with the Fourth Military Medical University. From September 2008 to March 2015, a total of 1927 gastric cancer patients were enrolled. The inclusion criteria were as follows: 1) no neoadjuvant chemotherapy, 2) radical D2 gastrectomy, 3) normal, preoperative serum CEA, CA19-9, AFP, and CA125 levels, and 4) with follow-up data. This study was approved by the Ethics Committee of Xijing Hospital, and written informed consent was obtained from all patients before surgery.

The four serum tumor markers were detected within 7 days before surgery. The cut-off values for serum CEA, CA19-9, AFP, and CA125 were 5 ng/ml, 27 U/ml, 8.1 ng/ml, 35 U/ml. Preoperative data including gender, age, tumor location, serum CEA, serum CA19-9, serum AFP and serum CA125 were recorded. All patients were treated with proximal, distal, or total gastrectomy with D2 lymphadenectomy. The surgical procedure was based on the recommendations of the Japanese Gastric Cancer Treatment Guidelines [23]. The depth of primary tumor and degree of lymph node involvement were defined according to the TNM classification. Tumor size, differentiation status, tumor depth, and LNM data were also collected during the pathological examination. The patients remained in follow-up until November, 2015 with enhanced chest and abdominal CT and gastroscopy every 3 months.

Data were processed using SPSS 22.0 for Windows (SPSS Inc., Chicago, IL, USA). The optimal cut-off values of serum CEA, CA19-9, AFP, and CA125 for prognosis of gastric cancer were calculated using X-tile software [24]. Discrete variables were analyzed using Chi-square or Fisher’s exact tests. Significant risk factors identified by univariate analysis were further assessed by multivariate analysis using logistic regression. OS was analyzed by Kaplan-Meier method. A P value of 0.05 was considered statistically significant.

ACKNOWLEDGMENTS

This study was supported in part by grants from the National Natural Scientific Foundation of China [NO. 31100643, 31570907, 81572306, 81502403, XJZT12Z03].

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

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