Med Oncol (2014) 31:289 DOI 10.1007/s12032-014-0289-9
ORIGINAL PAPER
Prognostic value of carbohydrate tumor markers and inflammation-based markers in metastatic or recurrent gastric cancer Qing Wang • Yang Yang • Ya-ping Zhang • Zhengyun Zou • Xiaoping Qian • Baorui Liu Jia Wei
•
Received: 23 September 2014 / Accepted: 11 October 2014 / Published online: 26 October 2014 Ó Springer Science+Business Media New York 2014
Abstract We examined the relationship between hematological parameters and clinicopathologic significance in metastatic or recurrent gastric cancer (MRGC) patients, and construct a prognostic index for MRGC patients. We retrospectively reviewed the medical records of 439 patients with MRGC. Tumor markers, inflammation-based markers such as mGPS (which combines CRP and albumin concentrations), NLR, PLR and other hematological parameters were observed in the study. CA125 was more frequently positive with peritoneal recurrence, and CEA was more frequently positive in patients with liver metastases. In the univariate analysis of survival, the following variables were associated with shorter overall survival (OS): male, previous pathology such as nerves invasion and vessel invasion, elevated CEA, CA72-4, CA125 and CA19-9, and inflammation-based variables such as Alb, CRP, mGPS, PLR, NLR, Hb, LDH, AchE and AKP. In the multivariate analysis, mGPS, CEA and CA125 were independent prognostic factors for OS. An exploration of the potential prognostic index model including the three independent factors was carried out, MSTs for the low-, moderate- and high-risk groups were 12, 10.5 and 5 months. Elevated serum CEA, CA125 and mGPS in patients with MRGC are independent negative predictor of prognosis. And the prognostic index was constructed to predict prognosis of MRGC patients more accurately.
Q. Wang Y. Yang Y. Zhang Z. Zou X. Qian B. Liu J. Wei (&) The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China e-mail: [email protected]
Keywords MRGC Prognostic Inflammation-based factors Tumor markers
Introduction Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide despite a significance decline in its incidence and mortality in the past century [1]. In China, most cases are diagnosed as metastatic or recurrent gastric cancer (MRGC) with the 5-year survival rate being less than 5 % [2]. It is important to obtain simple, feasible and cost-less markers to evaluate the prognosis of the MRGC patients. Although serum tumor markers including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), carbohydrate antigen 72-4 (CA72-4) and carbohydrate antigen 24-2 (CA24-2) are not applied for primary diagnosis in gastric cancer, they have been reported to be elevated in patients with gastric cancer and can be used to monitor follow-up [3, 4]. CEA is first identified in 1965 in human colon cancer tissue extracts. Elevated CEA level in peritoneal lavages has been reported to accurately predict peritoneal recurrence after a curative resection of gastric cancer [5]. CA19-9 is one of the antigens of the Lewis family and has been reported with high sensitivity for patients with gastrointestinal adenocarcinomas, especially those of the pancreas [6]. In gastric cancers, the positive rate of CA19-9 is around 16–44 % [7]. CA72-4 is used for detecting gastric, breast, pancreatic, colon and ovarian cancer with the positive rate at nearly 40 % in most gastric cancer studies [7–9]. CA24-2 is a novel tumor marker of potential clinical use in gastrointestinal cancer. Serum CA125 levels are widely used in the diagnosis of ovarian cancer and digestive tract
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malignancies [10]. The relationship between CA125 and gastric cancer with peritoneal recurrence has been reported [7, 11]. Tumor markers are expressed in different biological tissue, indicating the presence of a tumor and reflecting the relative tumor burden. However, the outcome in cancer is not only determined by tumor-related factors, but also by host-related factors. Assessments of inflammation-based factors are easier and more-cost effective. Some inflammation-based prognostic markers such as modified Glasgow Prognostic Scores (mGPS) [12, 13], neutrophil to lymphocytes ratio (NLR) [14, 15] and platelet lymphocytes ratio (PLR) [15] have been detected as prognostic factors in several types of cancer. Although these tumor markers have been studied to reflect aggressive tumor behavior and their expression have been evaluated with follow-up, no tumor markers and inflammation-based scores have been combined to prognostic in MRGC patients. In this study, we aimed to investigate the correlation of tumor markers such as CEA, CA125, CA19-9, CA24-2, CA72-4 and inflammation-based factors such as mGPS, NLR and PLR with prognosis in patients with MRGC, and to construct a prognostic index to predict patients’ survival with MRGC.
Materials and methods Patients Between January 2006 and June 2014, a total of 439 patients with pathology-proven gastric cancer who followed-up at the Comprehensive Cancer Center of Drum Tower Hospital were included in the study. All the patients were diagnosed at stage IV according to tumor-nodemetastasis staging system adopted by American Joint Committee on Cancer (AJCC, 7th, 2010). The diagnosis of MRGC was based on clinical findings, gastroduodenoscopy, computed tomography, magnetic resonance imaging, ultrasonography, pathology and so on. The potential prognostic factors for MRGC were such as clinical characteristic, the platelet count (PLT), hemoglobin level (Hb), albumin, alkaline phosphates (AKP), C-reactive protein (CRP), lactate dehydrogenase (LDH), cholinesterase (AchE), NLR, PLR, mGPS, CEA, CA125, CA19-9, CA24-2 and CA72-4. Patients’ hematological parameters were recorded at the time of metastasis or recurrence. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.
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Inflammation-based prognostic scores Based on previous studies, NLR was calculated as neutrophil count divided by lymphocyte count, PLR was calculated as platelet count divided by lymphocyte count. The cut-off point for NLR and PLR was 3 and 160 [16]. MGPS scores combine CRP and albumin concentrations. Patients with elevated CRP and albumin \35 g/L were assigned a score of 2. Patients with elevated CRP were assigned a score of 1. Patients who have none of these abnormalities were assigned a score of 0 [13].
Cut-off values for tumor markers Serum CEA, CA125, CA19-9, CA24-2, CA72-4 levels were assayed with commercial enzyme immunoassay using Cobas 601 and reagent kits (Roche Diagnostics, Mannheim, Germany). The cut-off values for serum CEA, CA125, CA19-9, CA24-2 and CA72-4 were 5 ng/mL, 30.2 U/mL, 39 U/mL, 15 U/mL and 6.9 U/mL according to the manufacturer’s instructions.
Statistical analysis The Chi-square test was used to evaluate the associations between tumor markers positively and clinicopathological variables. The association between variables was conducted by kappa test. Overall survival (OS) was started from the time of metastasis or recurrence to the date of death or the last follow-up. Univariate analysis, survival analysis and survival curves were estimated according to the Kaplan–Meier method, and the log-rank test was used for the comparison. A multivariate logistic model was built with a Cox regression model using the factors that had potential prognostic on the univariate analysis (p \ 0.1). The prognostic index (PI) of the patients was calculated on the basis of results of multivariate analysis. A result was considered statistically significant when the p value was \0.05. SPSS (version 17, Chicago, USA) statistical software was used for the statistical analysis.
Results Patient characteristics For all 439 patients, the median survival time was 9 months. The majority of patients were male (72.7 %) and elderly than 50 (77.9 %). More than half of patients (56.7 %) underwent curative operation, while 43.3 % had
Med Oncol (2014) 31:289
palliative surgery. Pathologically, 168 patients (64.4 %) had tumor larger than 5 cm, 251 patients (79.9 %) had poorly differentiated tumor, and 108 patients (47.8 %) had diffuse adenocarcinoma according to Lauren’s classification. A total of 147 patients (38.2 %) had tumor at lower area of stomach, and 106 patients (27.5 %) had tumor at middle area of stomach. A total of 269 patients (64 %) had peritoneal recurrences, and the same number of patients had (61.9 %) distance recurrences at the diagnosis of MRGC cancer. From laboratory test, 139 (41.1 %) had increased CEA, 106 (45.9 %) had increased CA125, 122 (40 %) had increased CA19-9, 87 (38.2 %) had increased CA24-2 and 140 (51.3 %) had increased CA72-4. A total of 263 (70.7 %) patients were allocated to mGPS 0 and 29.3 % to mGPS C 1. Nearly half of the patients (46.2 %) had PLR C 160, and 53.8 % had PLR \ 160. A total of 192 (52.7 %) were allocated to NLR C 3 and 47.3 % to NLR \ 3. There were 43.3 % patients with elevated level of Hb and 13.2 % with elevated PLT. A few patients (20.9 %) allocated to high level of LDH, 1.1 % to low level. 0.8 % patients had high level of AchE, while 10.4 % had low level. Ten percent patients allocated to high AKP and 5.5 % to low. Details are listed in Table 1.
Association between clinical features and tumor markers or inflammation-based factors A comparison of the baseline characteristics according to tumor markers such as CEA, CA125, CA19-9, CA24-2 and CA72-4 and inflammation-based factors such as NLR, PLR and mGPS is listed in Table 2. The following factors differ significantly between the two groups in CA125: age (p = 0.004), differentiation (p = 0.042), vessel invasion (p = 0.017) and peritoneal involvement (p = 0.039), and the following factors differ greatly in CEA: gender (p = 0.02) and liver involvement (p = 0.044). CA19-9, CA72-4 and CA24-2 levels are associated with peritoneal involvement (p = 0.01; p = 0.00; p = 0.00, respectively), and CA24-2 level is associated with tumor size (p = 0.05) (Table 2). This analysis demonstrated that high levels of CA125, CA19-9, CA72-4 and CA24-2 in MRGC patients are likely to have peritoneal recurrence, while high level of CEA is likely to have liver metastasis. A correlation among the five tumor markers (CEA, CA125, CA19-9, CA24-2 and CA72-4) was observed of the patients by kappa test. NLR is associated with age, and mGPS and PLR did not differ in gender, age, tumor size, location, differentiation, nerve invasion, vessel invasion, peritoneal involvement and liver involvement. However, mGPS was associated with PLR and NLR (p \ 0.001; p \ 0.001, respectively). PLR was associated with NLR (p \ 0.001).
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Association of inflammation-based variables and tumor marker with survival Univariate survival analysis of survival rate with tumor markers Male patients had shorter OS compared with female (8.5 vs. 9 months, p = 0.05), and previous pathology such as nerves invasion (p = 0.014) and vessel invasion (p = 0.024) was associated with OS. The OS for patients with nerves invasion was 8 and 10.5 months for patients without nerves invasion. OS value of the patients with vessel invasion was 4 months, shorter than vessel negative one. The OS was lower in patients with elevated CEA, CA72-4, CA125 and CA19-9 compared to those with normal level of tumor marker (p = 0.03; p = 0.002; p = 0.02; p = 0.019, respectively). The OS for patients with elevated CEA was 7.5 and 10 months for patients with normal CEA. The OS for patients with elevated CA72-4 was 8 and 10.5 months for patients with normal CA72-4. The OS for patients with elevated CA125 was 8 and 10 months for patients with normal CA125. Patients with elevated CA19-9 were estimated 6.5 months, and patients with normal CA19-9 were estimated 9.5 months (Table 1). According to the tumor markers with prognostic value, we divided these patients into 5 groups, 19.87 % of patients had 0 positive tumor markers, 27.15 % patients had 1 elevated tumor marker, 23.18 % had 2 elevated tumor markers, 20.53 % patients had 3 elevated tumor markers and 9.27 % patients had 4 elevated tumor markers. The relationship between the outcome of the patients with MRGC and the number of elevated tumor marker is listed in the Fig. 1. An increase in OS was associated with less elevated tumor marker. Patients with four elevated tumor marker had a significantly poorer median survival when compared with patients with none elevated tumor marker at the time of metastasis or recurrence (4.5 vs. 14 months, p = 0.012). The more the positive tumor markers are, the poorer the survival would be. Univariate survival analysis of survival rate with inflammation-based factors The univariate survival analysis demonstrated that inflammation-based variables such as Alb (p = 0.000), CRP (p = 0.000), mGPS (p = 0.000), PLR (p = 0.015), NLR (p = 0.006), Hb (p = 0.009), LDH (p = 0.002), AchE (p = 0.005) and AKP (p = 0.002) were significantly associated with OS (Table 1). The OS for patients with low-level Alb was 6 and 10 months for patients with normal level of Alb. Patient with elevated CRP had shorter OS compared with patients with normal CRP (6 vs. 10 months, p = 0.000). The OS for patients with mGPS 0 was 10 and
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Table 1 Patient characteristics and univariate analysis of prognostic factors for overall survival in MRGC patients No. of patients
Percent
MST (months)
p value \0.05
Gender
No. of patients
Percent
MST (months)
\0.05
CEA
Male
319
72.70
8.5
\10
199
58.90
Female
120
27.30
9
C10
139
41.10
7.5
Age
NS
10 \0.01
CA72-4
C50
342
77.90
9
\6.9
133
48.70
10.5
\50
97
22.10
9
C6.9
140
51.30
8
242
56.70
9
CA125 \30.2
125
54.10
10
185
43.30
8
C30.2
106
45.90
8
\39
183
60.00
9.5
C39
122
40.00
6.5
\15
141
61.80
6.5
C15
87
38.20
3.5
C35
255
78.00
10
\35
72
22.00
6
\8
229
69.80
10
C8
99
30.20
6
Surgery Curative Palliative
NS
Tumor size
NS
C5 cm
168
64.40
7.5
\5 cm
93
35.60
9
Differentiation Moderately Poorly
NS 63
20.10
9
251
79.90
8
Serosa invasion
NS
Positive
199
60.70
8
Negative
129
39.30
9.5 \0.05
Nerves invasion Positive
242
84.00
8
Negative
46
16.00
10.5
Vessel invasion Positive Negative
\0.05 257
85.70
4
43
14.30
6
Lauren’s differentiation Intestinal
\0.05
CA24-2
0.265
\0.01
Alb
\0.01
CRP
C1 NS
\0.05
CA19-9
mGPS 0
\0.01 263
70.70
10
109
29.30
6 \0.05
PLR
93
41.20
9
C160
168
46.20
8
Diffuse
108
47.80
8
\160
196
53.80
9.5
Mixed
25
11.10
6
C3
192
52.70
8
172
47.30
10
Tumor location
\0.01
NLR NS
Upper
96
25.10
4.5
\3
Middle
106
27.50
4.5
HB
Lower
147
38.20
4
C120
161
43.30
10
Whole
36
9.40
5
\120
211
56.70
7
58
19.80
C300
49
13.20
6
323
86.80
9.5
284 76
78.00 20.90
10 5.5
4
1.10
11
326
88.80
9
3
0.80
20
Surgery Proximal
NS 8.5
Distal
118
40.30
9.5
\300
117
39.90
8
LDH
Lung metastasis Yes No
NS 45
10.60
7.5
381
89.40
9
Liver metastasis
109–245 C245 \109
NS
NS
\0.01
\0.01
AchE
Yes
155
36.80
9
3.7–13.2
No
266
63.20
8.5
C13.2
123
\0.01
PLT
Whole
p value
Med Oncol (2014) 31:289
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289
Table 1 continued No. of patients
Percent
MST (months)
PR
p value NS
Yes
269
64.00
8
No
151
36.00
10
Yes
269
61.90
9
No
151
36.00
8
LR Yes
41
0.097
7
No
381
0.903
9
DR
No. of patients \3.7
Percent
MST (months)
38
10.40
5.5
308
84.60
9
C185
36
9.90
\47
20
0.055
\0.01
AKP 47–185 NS
p value
4.5 10
NS
PR peritoneal recurrence, DR distance recurrence, LR local recurrence, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9, CA125 carbohydrate antigen 125, CA72-4 carbohydrate antigen 72-4, CA24-2 carbohydrate antigen 24-2, PLT the platelet count, Hb hemoglobin level, Alb albumin, AKP alkaline phosphates, CRP C-reactive protein, LDH lactate dehydrogenase, AchE cholinesterase, mGPS modified Glasgow Prognostic Scores, NLR neutrophil to lymphocytes ratio, PLR platelet lymphocytes ratio, NS not significance
6 months for patients with mGPS 1 or 2. Patients with PLR larger than 160 had shorter OS compared to patients with a smaller PLR (8 vs. 9.5 months, p = 0.015). The OS for patients with NLR larger than 3 was 8 and 10 months for patients with NLR smaller than 3. Low level of Hb was correlated with shorter OS than normal level of Hb (7 vs. 10 months, respectively). Patients with low-level LDH seem to have better prognosis than high level (11 vs. 5.5 months). OS for patients with high level of AchE was 5.5 months, shorter than low level of AchE. Similarly, patients with low AKP level seem to have better outcome compared to high level (10 vs. 4.5 months, respectively) (Fig. 2). Multivariate survival analysis of survival rate in MRGC patients COX proportional hazard analysis was performed in order to assess the independent prognostic factors with OS. In multivariate analysis, vessel invasion (p = 0.02), elevated serum CEA (p = 0.046), elevated serum CA125 (p = 0.029) and mGPS (p = 0.004) were independently associated with OS (Table 3). Only the mGPS [hazard ratio (HR) 1.323; 95 % confidence interval (CI) 1.096–1.597; p = 0.004], CEA (HR 0.72; 95 % CI 0.522–0.994; p = 0.046) and CA125 (HR 0.647; 95 % CI 0.438–0.957; p = 0.029) were associated independently with overall survival (Table 3). Construct a prognostic index An exploration of the potential PI model including the three independent factors was carried out. PI = CEA (0 or 1) ?CA125 (0 or 1) ?mGPS (0, 1 or 2). Patients with a zero prognostic index were categorized as low-risk group (N = 95), those with a prognostic index of 1 or 2 were categorized as moderate risk group (N = 89), and those with a prognostic
index of 3 were categorized as high-risk group (N = 45). MSTs for the low-, moderate- and high-risk groups were 12, 10.5 and 5 months, respectively (p = 0.000) (Fig. 3).
Discussion The aim of our study was to identify a significantly prognostic predictor including tumor-related factors such as tumor marker and host-related factors such as inflammation-based factors in MRGC patients and construct a prognostic index to predict survival in MGGC patients. Due to the low sensitivity and specificity of tumor markers, NCCN Clinical Practice Guideline did not recommend any tumor marker to predict outcome of patient. CA72-4 is reported to be the best marker for diagnosis in gastric cancer as it is the one of the most specific and sensitive markers to monitor gastric cancer [17, 18]. There is a rare study reported the association between CA24-2 and outcome of gastric cancer. Victorzon et al. [19] showed a worse outcome, even only a bit elevated CA19-9 compared to normal level of CA19-9. In the present study, the positive rate of CEA, CA19-9, CA24-2, CA72-4 and CA125 was 41.1, 40.0, 38.2, 51.3 and 45.9 %, respectively, and each of these tumor markers has predict value for prognosis. In multivariate analysis, CEA and CA125 were independent predictors in MRGC patients. CEA has been used as a tumor predictor for nearly 20 years, and 15.9–57.6 % gastric cancer patients had elevated CEA [7, 20]. It has been reported that CEA level was related to liver metastasis of gastric cancer and the correlations between preoperative CEA and CA19-9 [18]. In the current study, 41.1 % of the MRGC patients had elevated CEA. There is correlation between CEA and liver metastasis, gender and age. CA125 is rarely studied in gastric cancer, especially in
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Med Oncol (2014) 31:289
Table 2 The association between tumor markers or inflammation-based factors and clinicopathological features with MRGC patients CA125 \30.2
CEA
CA199
CA724
C30.2
p
\5
C5
p
\39
C39
p
\0.01
146
114
\0.05
142
92
NS
54
25
42
31
137
111
134
93
63
28
50
30
80
41
73
35
38
31
34
26
19 76
NS
22 114
13 69
NS
NS
106
56
NS
22
11
116
62
18
6
108
74
91
31
70
47
105
76
\6.9
C6.9
p
99
108
NS
32
32
100
105
31
36
41
46
29
27
23 78
11 78
NS
NS
Age C50
96
78
\50
29
29
Gender Male
88
77
Female
37
30
NS
C5 cm
41
30
\5 cm
32
20
20 7
73 65
\0.05
21 119
Yes
70
52
NS
112
66
No
17
9
22
15
Yes
73
59
119
76
No
16
3
19
9
Yes
70
78
126
71
No
47
29
98
40
\0.05
NS
NS
Tumor size NS
NS
NS
NS
Differentiation Poorly differentiated Moderately differentiated Nerve invasion 70
66
15
14
78
72
13
9
Vessel invasion \0.05
NS
NS
NS
Peritoneal involvement \0.05
NS
\0.01
74
55
103
36
55
50
71
90
\0.01
Liver involvement Yes
50
33
No
69
74
NS
CA242
62
59
129
77
\0.05
PLR
NS
NLR
NS
mGPS
\15
C15
p
\160
C160
p
\3
C3
p
0
1
C50
106
136
NS
120
160
\0.05
141
138
NS
220
61
1
\50
61
86
48
37
51
35
78
10
0
105 65
31 21
NS
124 44
146 51
NS
141 51
126 47
NS
216 82
57 14
1 0
NS
C5 cm
54
19
\0.05
57
77
NS
63
70
NS
104
33
0
NS
\5 cm
26
20
31
39
34
39
54
16
1
164
45
0
39
8
0
150
47
1
31
7
0
165
46
0
26
6
0
2
p
Age NS
Gender Male Female Tumor size
Differentiation Poorly differentiated
18
7
Moderately differentiated
82
45
Yes
68
43
No
19
5
Yes
77
47
No
15
4
NS
21
25
93
115
79
115
16
24
86
121
12
21
NS
22
22
107
101
NS
NS
Nerve invasion NS
NS
85
109
15
25
90
117
14
19
NS
NS
Vessel invasion
123
NS
NS
NS
NS
Med Oncol (2014) 31:289
Page 7 of 10
289
1
p
Table 2 continued CA242
PLR
\15
C15
Yes
78
54
No
65
17
Yes
56
77
No
26
57
NLR
mGPS
p
\160
C160
p
\3
C3
p
\0.01
112
123
NS
133
103
NS
54
65
54
61
0
2
Peritoneal involvement 21
10
0
268
60
1
1
19
112
1
17
211
NS
Liver involvement NS
63
66
104
123
a
NS
74
52
114
113
NS
NS
b
c
Fig. 1 Relationship between independent prognostic factors and overall survival in patients with MRGC. a CEA, b CA125, c GPS
MRGC. 51.3 % patients had elevated CA125, and elevated CA125 was associated with age [50 years, poorly differentiation and peritoneal involvement. It seemed that elevated CEA may predict liver metastasis and elevated CA125 may predict peritoneal recurrence [11, 21].
Combination of tumor markers predicts the prognosis more precisely. Marrelli et al. [22] reported that CEA, CA19-9 and CA72-4 should be used in combination to obtain significant prognostic information. In the study of Chio et al. [21], they combined two or more tumor markers
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289 Page 8 of 10
Med Oncol (2014) 31:289 Table 3 Multivariate analysis of overall survival OS (months) Gender Male
8.5
Female
9
Nerve invasion Positive
8
Negative
10.5
Vessel invasion Positive
4
Negative
6
CEA \10 C10
and increased sensitivity to 68 % in predicting recurrence. Marrelli et al. reported 87 % sensitivity when combining preoperative tumor markers. Kochi showed poorer prognosis when both CEA and CA19-9 were positive compared to when they both negative. In the present study, there was a correlation between the tumor markers, and as the number of elevated tumor markers increase, the prognosis would be worse. Montovani et al. [23] demonstrated the role of host inflammatory response in the development and progression of cancer. Inflammatory response triggered by tumor cells plays a major role in the development and progress in cancer. Therefore, inflammation-based factors such as NLR, PLR and mGPS are used as prognostic factors in various cancers. Previous studies have shown that elevated NLR is a poor indicator in ovarian cancer [24], hepatocellular carcinoma [25], colorectal cancers [26], lung cancer, malignant lymphoma [27] and advanced gastric cancer. Hirashima et al. [28] demonstrated that elevated NLR accompanies low survival rate in early gastric cancer. Yamanaka et al. [14] reported similar results in advanced gastric cancer. In the present study, 52.7 % patients had a high level of NLR (NLR C 3) with a median survival time of 8 months, which was shorter than patients with NLR \3 (median survival time: 10 months). Elevated NLR was a predictor for outcome in the MRGC patients but was not the independent factor according to the multivariate analysis. PLR is another index of systemic inflammation elicited by tumor. Preoperative PLR is regarded as an independent significant prognostic marker in resected pancreatic ducal adenocarcinoma and colorectal cancer [29, 30]. In the present study, the median survival time in
123
\6.9
10.5
C6.9
8
CA125 \30.2
10
C30.2
8
CA19-9 \39
9.5
C39
6.5
mGPS 0 C1 C160
8
LDH
9 20
1.92
1.107–3.330
\0.05
0.72
0.522–0.994
\0.05
1.321
0.929–1.878
NS
0.647
0.438–0.957
\0.05
0.798
0.569–1.119
NS
1.323
1.096–1.597
\0.01
0.828
0.624–0.1.097
NS
0.895
0.671–1.195
NS
1.214
0.94–1.569
NS
1.057
0.854–1.308
NS
1.031
0.809–1.315
NS
5.5
AKP
\47
NS
5.5
C13.2
C185
0.923–2.236
11
3.7–13.2
47–185
1.437
10
AchE
\3.7
\0.05
9.5
\3
C245
0.956–2.030
8
10
\109
1.393
6
C3
109–245
p
10
PLR \160 NLR
95 % CI
10 7.5
CA72-4
Fig. 2 Relationship between the number of positive tumor markers and overall survival in patients with MRGC
HR
9 4.5 10
patients with PLR of 160 or larger (n = 168) is 8.5 and 10 months in those with PLR smaller than 160 (n = 196). It was a prognostic factor but not the independent one. mGPS, a combined assessment of CRP level and serum albumin, was regarded as one of the most useful scoring
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Conclusion In summary, the study results show that mGPS, CA19-9 and CEA are independent markers of poor survival in patients with MRGC. Our finding may be useful for evaluating the outcome more precisely and predict recurrence by combining tumor markers, inflammation-based factors, other hematological markers and patients’ clinic pathology. We emphasis the importance of CA125, which was ignored in gastric cancer previously. In the present study, we propose a new prognostic index for patients with MRGC. However, larger-scaled prospective studies are needed to confirm these results.
Fig. 3 Relationship between PI and overall survival in patients with MRGC
systems in determining long-time survival in patients with advanced malignancies, including gastric cancer [12, 13, 31]. It might reflect both systemic inflammatory response and physical nutritional decline [32]. Superior prognostic value of mGPS with regard to other biochemical parameters and independent of tumor site in patients with cancer is reported [33, 34]. Similarly, in the present study, only mGPS associated independently with overall survival of all the inflammatory relative factors. The presence of a mGPS 1 or 2 predicts poor survival compared to a mGPS of 0, which was consistent with other studies. MGPS was superior to NLR and PLR in predicting prognosis in the MRGC patients. MGPS was associated with NLR and PLR significantly (p \ 0.001; p \ 0.001, respectively), and NLR was correlated with PLR in our study. CRP is a nonspecific but sensitive marker of inflammatory response, and previous studies have demonstrated that elevated CRP is a poor predictor for malignant tumors including gastric cancer [29, 35]. Hiroyuki et al. reported CRP as an independent prognostic factor in stage IV gastric cancer [36]. Further studies are needed to clarify the mechanism of systemic inflammatory response in gastric cancer patients. Other hematological parameters such as LDH, AKP, AchE and Hb were also powerful prognostic factors in MRGC patients. We adopt three risk factors for survival (CEA, CA125 and mGPS) to develop the index. The prognostic model on the basis of these three parameters separated patients into three groups with distinct prognosis. We believe that this PI can be used to predict patients’ outcome more accurately and help clinicians and patients make clinical decisions and tailor treatment based on the estimated prognosis.
Acknowledgments This work was funded by grants from the National Natural Science Foundation of China (Grant No. 81000980, 81220108023, 81370064), Jiangsu Provincial Program of Medical Science (BL2012001) and the distinguished young investigator project of Nanjing (JQX12002). Conflict of interest of interest.
The authors declare that they have no conflict
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ORIGINAL PAPER
Prognostic value of carbohydrate tumor markers and inflammation-based markers in metastatic or recurrent gastric cancer Qing Wang • Yang Yang • Ya-ping Zhang • Zhengyun Zou • Xiaoping Qian • Baorui Liu Jia Wei
•
Received: 23 September 2014 / Accepted: 11 October 2014 / Published online: 26 October 2014 Ó Springer Science+Business Media New York 2014
Abstract We examined the relationship between hematological parameters and clinicopathologic significance in metastatic or recurrent gastric cancer (MRGC) patients, and construct a prognostic index for MRGC patients. We retrospectively reviewed the medical records of 439 patients with MRGC. Tumor markers, inflammation-based markers such as mGPS (which combines CRP and albumin concentrations), NLR, PLR and other hematological parameters were observed in the study. CA125 was more frequently positive with peritoneal recurrence, and CEA was more frequently positive in patients with liver metastases. In the univariate analysis of survival, the following variables were associated with shorter overall survival (OS): male, previous pathology such as nerves invasion and vessel invasion, elevated CEA, CA72-4, CA125 and CA19-9, and inflammation-based variables such as Alb, CRP, mGPS, PLR, NLR, Hb, LDH, AchE and AKP. In the multivariate analysis, mGPS, CEA and CA125 were independent prognostic factors for OS. An exploration of the potential prognostic index model including the three independent factors was carried out, MSTs for the low-, moderate- and high-risk groups were 12, 10.5 and 5 months. Elevated serum CEA, CA125 and mGPS in patients with MRGC are independent negative predictor of prognosis. And the prognostic index was constructed to predict prognosis of MRGC patients more accurately.
Q. Wang Y. Yang Y. Zhang Z. Zou X. Qian B. Liu J. Wei (&) The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China e-mail: [email protected]
Keywords MRGC Prognostic Inflammation-based factors Tumor markers
Introduction Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide despite a significance decline in its incidence and mortality in the past century [1]. In China, most cases are diagnosed as metastatic or recurrent gastric cancer (MRGC) with the 5-year survival rate being less than 5 % [2]. It is important to obtain simple, feasible and cost-less markers to evaluate the prognosis of the MRGC patients. Although serum tumor markers including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), carbohydrate antigen 72-4 (CA72-4) and carbohydrate antigen 24-2 (CA24-2) are not applied for primary diagnosis in gastric cancer, they have been reported to be elevated in patients with gastric cancer and can be used to monitor follow-up [3, 4]. CEA is first identified in 1965 in human colon cancer tissue extracts. Elevated CEA level in peritoneal lavages has been reported to accurately predict peritoneal recurrence after a curative resection of gastric cancer [5]. CA19-9 is one of the antigens of the Lewis family and has been reported with high sensitivity for patients with gastrointestinal adenocarcinomas, especially those of the pancreas [6]. In gastric cancers, the positive rate of CA19-9 is around 16–44 % [7]. CA72-4 is used for detecting gastric, breast, pancreatic, colon and ovarian cancer with the positive rate at nearly 40 % in most gastric cancer studies [7–9]. CA24-2 is a novel tumor marker of potential clinical use in gastrointestinal cancer. Serum CA125 levels are widely used in the diagnosis of ovarian cancer and digestive tract
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malignancies [10]. The relationship between CA125 and gastric cancer with peritoneal recurrence has been reported [7, 11]. Tumor markers are expressed in different biological tissue, indicating the presence of a tumor and reflecting the relative tumor burden. However, the outcome in cancer is not only determined by tumor-related factors, but also by host-related factors. Assessments of inflammation-based factors are easier and more-cost effective. Some inflammation-based prognostic markers such as modified Glasgow Prognostic Scores (mGPS) [12, 13], neutrophil to lymphocytes ratio (NLR) [14, 15] and platelet lymphocytes ratio (PLR) [15] have been detected as prognostic factors in several types of cancer. Although these tumor markers have been studied to reflect aggressive tumor behavior and their expression have been evaluated with follow-up, no tumor markers and inflammation-based scores have been combined to prognostic in MRGC patients. In this study, we aimed to investigate the correlation of tumor markers such as CEA, CA125, CA19-9, CA24-2, CA72-4 and inflammation-based factors such as mGPS, NLR and PLR with prognosis in patients with MRGC, and to construct a prognostic index to predict patients’ survival with MRGC.
Materials and methods Patients Between January 2006 and June 2014, a total of 439 patients with pathology-proven gastric cancer who followed-up at the Comprehensive Cancer Center of Drum Tower Hospital were included in the study. All the patients were diagnosed at stage IV according to tumor-nodemetastasis staging system adopted by American Joint Committee on Cancer (AJCC, 7th, 2010). The diagnosis of MRGC was based on clinical findings, gastroduodenoscopy, computed tomography, magnetic resonance imaging, ultrasonography, pathology and so on. The potential prognostic factors for MRGC were such as clinical characteristic, the platelet count (PLT), hemoglobin level (Hb), albumin, alkaline phosphates (AKP), C-reactive protein (CRP), lactate dehydrogenase (LDH), cholinesterase (AchE), NLR, PLR, mGPS, CEA, CA125, CA19-9, CA24-2 and CA72-4. Patients’ hematological parameters were recorded at the time of metastasis or recurrence. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.
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Inflammation-based prognostic scores Based on previous studies, NLR was calculated as neutrophil count divided by lymphocyte count, PLR was calculated as platelet count divided by lymphocyte count. The cut-off point for NLR and PLR was 3 and 160 [16]. MGPS scores combine CRP and albumin concentrations. Patients with elevated CRP and albumin \35 g/L were assigned a score of 2. Patients with elevated CRP were assigned a score of 1. Patients who have none of these abnormalities were assigned a score of 0 [13].
Cut-off values for tumor markers Serum CEA, CA125, CA19-9, CA24-2, CA72-4 levels were assayed with commercial enzyme immunoassay using Cobas 601 and reagent kits (Roche Diagnostics, Mannheim, Germany). The cut-off values for serum CEA, CA125, CA19-9, CA24-2 and CA72-4 were 5 ng/mL, 30.2 U/mL, 39 U/mL, 15 U/mL and 6.9 U/mL according to the manufacturer’s instructions.
Statistical analysis The Chi-square test was used to evaluate the associations between tumor markers positively and clinicopathological variables. The association between variables was conducted by kappa test. Overall survival (OS) was started from the time of metastasis or recurrence to the date of death or the last follow-up. Univariate analysis, survival analysis and survival curves were estimated according to the Kaplan–Meier method, and the log-rank test was used for the comparison. A multivariate logistic model was built with a Cox regression model using the factors that had potential prognostic on the univariate analysis (p \ 0.1). The prognostic index (PI) of the patients was calculated on the basis of results of multivariate analysis. A result was considered statistically significant when the p value was \0.05. SPSS (version 17, Chicago, USA) statistical software was used for the statistical analysis.
Results Patient characteristics For all 439 patients, the median survival time was 9 months. The majority of patients were male (72.7 %) and elderly than 50 (77.9 %). More than half of patients (56.7 %) underwent curative operation, while 43.3 % had
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palliative surgery. Pathologically, 168 patients (64.4 %) had tumor larger than 5 cm, 251 patients (79.9 %) had poorly differentiated tumor, and 108 patients (47.8 %) had diffuse adenocarcinoma according to Lauren’s classification. A total of 147 patients (38.2 %) had tumor at lower area of stomach, and 106 patients (27.5 %) had tumor at middle area of stomach. A total of 269 patients (64 %) had peritoneal recurrences, and the same number of patients had (61.9 %) distance recurrences at the diagnosis of MRGC cancer. From laboratory test, 139 (41.1 %) had increased CEA, 106 (45.9 %) had increased CA125, 122 (40 %) had increased CA19-9, 87 (38.2 %) had increased CA24-2 and 140 (51.3 %) had increased CA72-4. A total of 263 (70.7 %) patients were allocated to mGPS 0 and 29.3 % to mGPS C 1. Nearly half of the patients (46.2 %) had PLR C 160, and 53.8 % had PLR \ 160. A total of 192 (52.7 %) were allocated to NLR C 3 and 47.3 % to NLR \ 3. There were 43.3 % patients with elevated level of Hb and 13.2 % with elevated PLT. A few patients (20.9 %) allocated to high level of LDH, 1.1 % to low level. 0.8 % patients had high level of AchE, while 10.4 % had low level. Ten percent patients allocated to high AKP and 5.5 % to low. Details are listed in Table 1.
Association between clinical features and tumor markers or inflammation-based factors A comparison of the baseline characteristics according to tumor markers such as CEA, CA125, CA19-9, CA24-2 and CA72-4 and inflammation-based factors such as NLR, PLR and mGPS is listed in Table 2. The following factors differ significantly between the two groups in CA125: age (p = 0.004), differentiation (p = 0.042), vessel invasion (p = 0.017) and peritoneal involvement (p = 0.039), and the following factors differ greatly in CEA: gender (p = 0.02) and liver involvement (p = 0.044). CA19-9, CA72-4 and CA24-2 levels are associated with peritoneal involvement (p = 0.01; p = 0.00; p = 0.00, respectively), and CA24-2 level is associated with tumor size (p = 0.05) (Table 2). This analysis demonstrated that high levels of CA125, CA19-9, CA72-4 and CA24-2 in MRGC patients are likely to have peritoneal recurrence, while high level of CEA is likely to have liver metastasis. A correlation among the five tumor markers (CEA, CA125, CA19-9, CA24-2 and CA72-4) was observed of the patients by kappa test. NLR is associated with age, and mGPS and PLR did not differ in gender, age, tumor size, location, differentiation, nerve invasion, vessel invasion, peritoneal involvement and liver involvement. However, mGPS was associated with PLR and NLR (p \ 0.001; p \ 0.001, respectively). PLR was associated with NLR (p \ 0.001).
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Association of inflammation-based variables and tumor marker with survival Univariate survival analysis of survival rate with tumor markers Male patients had shorter OS compared with female (8.5 vs. 9 months, p = 0.05), and previous pathology such as nerves invasion (p = 0.014) and vessel invasion (p = 0.024) was associated with OS. The OS for patients with nerves invasion was 8 and 10.5 months for patients without nerves invasion. OS value of the patients with vessel invasion was 4 months, shorter than vessel negative one. The OS was lower in patients with elevated CEA, CA72-4, CA125 and CA19-9 compared to those with normal level of tumor marker (p = 0.03; p = 0.002; p = 0.02; p = 0.019, respectively). The OS for patients with elevated CEA was 7.5 and 10 months for patients with normal CEA. The OS for patients with elevated CA72-4 was 8 and 10.5 months for patients with normal CA72-4. The OS for patients with elevated CA125 was 8 and 10 months for patients with normal CA125. Patients with elevated CA19-9 were estimated 6.5 months, and patients with normal CA19-9 were estimated 9.5 months (Table 1). According to the tumor markers with prognostic value, we divided these patients into 5 groups, 19.87 % of patients had 0 positive tumor markers, 27.15 % patients had 1 elevated tumor marker, 23.18 % had 2 elevated tumor markers, 20.53 % patients had 3 elevated tumor markers and 9.27 % patients had 4 elevated tumor markers. The relationship between the outcome of the patients with MRGC and the number of elevated tumor marker is listed in the Fig. 1. An increase in OS was associated with less elevated tumor marker. Patients with four elevated tumor marker had a significantly poorer median survival when compared with patients with none elevated tumor marker at the time of metastasis or recurrence (4.5 vs. 14 months, p = 0.012). The more the positive tumor markers are, the poorer the survival would be. Univariate survival analysis of survival rate with inflammation-based factors The univariate survival analysis demonstrated that inflammation-based variables such as Alb (p = 0.000), CRP (p = 0.000), mGPS (p = 0.000), PLR (p = 0.015), NLR (p = 0.006), Hb (p = 0.009), LDH (p = 0.002), AchE (p = 0.005) and AKP (p = 0.002) were significantly associated with OS (Table 1). The OS for patients with low-level Alb was 6 and 10 months for patients with normal level of Alb. Patient with elevated CRP had shorter OS compared with patients with normal CRP (6 vs. 10 months, p = 0.000). The OS for patients with mGPS 0 was 10 and
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Table 1 Patient characteristics and univariate analysis of prognostic factors for overall survival in MRGC patients No. of patients
Percent
MST (months)
p value \0.05
Gender
No. of patients
Percent
MST (months)
\0.05
CEA
Male
319
72.70
8.5
\10
199
58.90
Female
120
27.30
9
C10
139
41.10
7.5
Age
NS
10 \0.01
CA72-4
C50
342
77.90
9
\6.9
133
48.70
10.5
\50
97
22.10
9
C6.9
140
51.30
8
242
56.70
9
CA125 \30.2
125
54.10
10
185
43.30
8
C30.2
106
45.90
8
\39
183
60.00
9.5
C39
122
40.00
6.5
\15
141
61.80
6.5
C15
87
38.20
3.5
C35
255
78.00
10
\35
72
22.00
6
\8
229
69.80
10
C8
99
30.20
6
Surgery Curative Palliative
NS
Tumor size
NS
C5 cm
168
64.40
7.5
\5 cm
93
35.60
9
Differentiation Moderately Poorly
NS 63
20.10
9
251
79.90
8
Serosa invasion
NS
Positive
199
60.70
8
Negative
129
39.30
9.5 \0.05
Nerves invasion Positive
242
84.00
8
Negative
46
16.00
10.5
Vessel invasion Positive Negative
\0.05 257
85.70
4
43
14.30
6
Lauren’s differentiation Intestinal
\0.05
CA24-2
0.265
\0.01
Alb
\0.01
CRP
C1 NS
\0.05
CA19-9
mGPS 0
\0.01 263
70.70
10
109
29.30
6 \0.05
PLR
93
41.20
9
C160
168
46.20
8
Diffuse
108
47.80
8
\160
196
53.80
9.5
Mixed
25
11.10
6
C3
192
52.70
8
172
47.30
10
Tumor location
\0.01
NLR NS
Upper
96
25.10
4.5
\3
Middle
106
27.50
4.5
HB
Lower
147
38.20
4
C120
161
43.30
10
Whole
36
9.40
5
\120
211
56.70
7
58
19.80
C300
49
13.20
6
323
86.80
9.5
284 76
78.00 20.90
10 5.5
4
1.10
11
326
88.80
9
3
0.80
20
Surgery Proximal
NS 8.5
Distal
118
40.30
9.5
\300
117
39.90
8
LDH
Lung metastasis Yes No
NS 45
10.60
7.5
381
89.40
9
Liver metastasis
109–245 C245 \109
NS
NS
\0.01
\0.01
AchE
Yes
155
36.80
9
3.7–13.2
No
266
63.20
8.5
C13.2
123
\0.01
PLT
Whole
p value
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Table 1 continued No. of patients
Percent
MST (months)
PR
p value NS
Yes
269
64.00
8
No
151
36.00
10
Yes
269
61.90
9
No
151
36.00
8
LR Yes
41
0.097
7
No
381
0.903
9
DR
No. of patients \3.7
Percent
MST (months)
38
10.40
5.5
308
84.60
9
C185
36
9.90
\47
20
0.055
\0.01
AKP 47–185 NS
p value
4.5 10
NS
PR peritoneal recurrence, DR distance recurrence, LR local recurrence, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9, CA125 carbohydrate antigen 125, CA72-4 carbohydrate antigen 72-4, CA24-2 carbohydrate antigen 24-2, PLT the platelet count, Hb hemoglobin level, Alb albumin, AKP alkaline phosphates, CRP C-reactive protein, LDH lactate dehydrogenase, AchE cholinesterase, mGPS modified Glasgow Prognostic Scores, NLR neutrophil to lymphocytes ratio, PLR platelet lymphocytes ratio, NS not significance
6 months for patients with mGPS 1 or 2. Patients with PLR larger than 160 had shorter OS compared to patients with a smaller PLR (8 vs. 9.5 months, p = 0.015). The OS for patients with NLR larger than 3 was 8 and 10 months for patients with NLR smaller than 3. Low level of Hb was correlated with shorter OS than normal level of Hb (7 vs. 10 months, respectively). Patients with low-level LDH seem to have better prognosis than high level (11 vs. 5.5 months). OS for patients with high level of AchE was 5.5 months, shorter than low level of AchE. Similarly, patients with low AKP level seem to have better outcome compared to high level (10 vs. 4.5 months, respectively) (Fig. 2). Multivariate survival analysis of survival rate in MRGC patients COX proportional hazard analysis was performed in order to assess the independent prognostic factors with OS. In multivariate analysis, vessel invasion (p = 0.02), elevated serum CEA (p = 0.046), elevated serum CA125 (p = 0.029) and mGPS (p = 0.004) were independently associated with OS (Table 3). Only the mGPS [hazard ratio (HR) 1.323; 95 % confidence interval (CI) 1.096–1.597; p = 0.004], CEA (HR 0.72; 95 % CI 0.522–0.994; p = 0.046) and CA125 (HR 0.647; 95 % CI 0.438–0.957; p = 0.029) were associated independently with overall survival (Table 3). Construct a prognostic index An exploration of the potential PI model including the three independent factors was carried out. PI = CEA (0 or 1) ?CA125 (0 or 1) ?mGPS (0, 1 or 2). Patients with a zero prognostic index were categorized as low-risk group (N = 95), those with a prognostic index of 1 or 2 were categorized as moderate risk group (N = 89), and those with a prognostic
index of 3 were categorized as high-risk group (N = 45). MSTs for the low-, moderate- and high-risk groups were 12, 10.5 and 5 months, respectively (p = 0.000) (Fig. 3).
Discussion The aim of our study was to identify a significantly prognostic predictor including tumor-related factors such as tumor marker and host-related factors such as inflammation-based factors in MRGC patients and construct a prognostic index to predict survival in MGGC patients. Due to the low sensitivity and specificity of tumor markers, NCCN Clinical Practice Guideline did not recommend any tumor marker to predict outcome of patient. CA72-4 is reported to be the best marker for diagnosis in gastric cancer as it is the one of the most specific and sensitive markers to monitor gastric cancer [17, 18]. There is a rare study reported the association between CA24-2 and outcome of gastric cancer. Victorzon et al. [19] showed a worse outcome, even only a bit elevated CA19-9 compared to normal level of CA19-9. In the present study, the positive rate of CEA, CA19-9, CA24-2, CA72-4 and CA125 was 41.1, 40.0, 38.2, 51.3 and 45.9 %, respectively, and each of these tumor markers has predict value for prognosis. In multivariate analysis, CEA and CA125 were independent predictors in MRGC patients. CEA has been used as a tumor predictor for nearly 20 years, and 15.9–57.6 % gastric cancer patients had elevated CEA [7, 20]. It has been reported that CEA level was related to liver metastasis of gastric cancer and the correlations between preoperative CEA and CA19-9 [18]. In the current study, 41.1 % of the MRGC patients had elevated CEA. There is correlation between CEA and liver metastasis, gender and age. CA125 is rarely studied in gastric cancer, especially in
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Table 2 The association between tumor markers or inflammation-based factors and clinicopathological features with MRGC patients CA125 \30.2
CEA
CA199
CA724
C30.2
p
\5
C5
p
\39
C39
p
\0.01
146
114
\0.05
142
92
NS
54
25
42
31
137
111
134
93
63
28
50
30
80
41
73
35
38
31
34
26
19 76
NS
22 114
13 69
NS
NS
106
56
NS
22
11
116
62
18
6
108
74
91
31
70
47
105
76
\6.9
C6.9
p
99
108
NS
32
32
100
105
31
36
41
46
29
27
23 78
11 78
NS
NS
Age C50
96
78
\50
29
29
Gender Male
88
77
Female
37
30
NS
C5 cm
41
30
\5 cm
32
20
20 7
73 65
\0.05
21 119
Yes
70
52
NS
112
66
No
17
9
22
15
Yes
73
59
119
76
No
16
3
19
9
Yes
70
78
126
71
No
47
29
98
40
\0.05
NS
NS
Tumor size NS
NS
NS
NS
Differentiation Poorly differentiated Moderately differentiated Nerve invasion 70
66
15
14
78
72
13
9
Vessel invasion \0.05
NS
NS
NS
Peritoneal involvement \0.05
NS
\0.01
74
55
103
36
55
50
71
90
\0.01
Liver involvement Yes
50
33
No
69
74
NS
CA242
62
59
129
77
\0.05
PLR
NS
NLR
NS
mGPS
\15
C15
p
\160
C160
p
\3
C3
p
0
1
C50
106
136
NS
120
160
\0.05
141
138
NS
220
61
1
\50
61
86
48
37
51
35
78
10
0
105 65
31 21
NS
124 44
146 51
NS
141 51
126 47
NS
216 82
57 14
1 0
NS
C5 cm
54
19
\0.05
57
77
NS
63
70
NS
104
33
0
NS
\5 cm
26
20
31
39
34
39
54
16
1
164
45
0
39
8
0
150
47
1
31
7
0
165
46
0
26
6
0
2
p
Age NS
Gender Male Female Tumor size
Differentiation Poorly differentiated
18
7
Moderately differentiated
82
45
Yes
68
43
No
19
5
Yes
77
47
No
15
4
NS
21
25
93
115
79
115
16
24
86
121
12
21
NS
22
22
107
101
NS
NS
Nerve invasion NS
NS
85
109
15
25
90
117
14
19
NS
NS
Vessel invasion
123
NS
NS
NS
NS
Med Oncol (2014) 31:289
Page 7 of 10
289
1
p
Table 2 continued CA242
PLR
\15
C15
Yes
78
54
No
65
17
Yes
56
77
No
26
57
NLR
mGPS
p
\160
C160
p
\3
C3
p
\0.01
112
123
NS
133
103
NS
54
65
54
61
0
2
Peritoneal involvement 21
10
0
268
60
1
1
19
112
1
17
211
NS
Liver involvement NS
63
66
104
123
a
NS
74
52
114
113
NS
NS
b
c
Fig. 1 Relationship between independent prognostic factors and overall survival in patients with MRGC. a CEA, b CA125, c GPS
MRGC. 51.3 % patients had elevated CA125, and elevated CA125 was associated with age [50 years, poorly differentiation and peritoneal involvement. It seemed that elevated CEA may predict liver metastasis and elevated CA125 may predict peritoneal recurrence [11, 21].
Combination of tumor markers predicts the prognosis more precisely. Marrelli et al. [22] reported that CEA, CA19-9 and CA72-4 should be used in combination to obtain significant prognostic information. In the study of Chio et al. [21], they combined two or more tumor markers
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289 Page 8 of 10
Med Oncol (2014) 31:289 Table 3 Multivariate analysis of overall survival OS (months) Gender Male
8.5
Female
9
Nerve invasion Positive
8
Negative
10.5
Vessel invasion Positive
4
Negative
6
CEA \10 C10
and increased sensitivity to 68 % in predicting recurrence. Marrelli et al. reported 87 % sensitivity when combining preoperative tumor markers. Kochi showed poorer prognosis when both CEA and CA19-9 were positive compared to when they both negative. In the present study, there was a correlation between the tumor markers, and as the number of elevated tumor markers increase, the prognosis would be worse. Montovani et al. [23] demonstrated the role of host inflammatory response in the development and progression of cancer. Inflammatory response triggered by tumor cells plays a major role in the development and progress in cancer. Therefore, inflammation-based factors such as NLR, PLR and mGPS are used as prognostic factors in various cancers. Previous studies have shown that elevated NLR is a poor indicator in ovarian cancer [24], hepatocellular carcinoma [25], colorectal cancers [26], lung cancer, malignant lymphoma [27] and advanced gastric cancer. Hirashima et al. [28] demonstrated that elevated NLR accompanies low survival rate in early gastric cancer. Yamanaka et al. [14] reported similar results in advanced gastric cancer. In the present study, 52.7 % patients had a high level of NLR (NLR C 3) with a median survival time of 8 months, which was shorter than patients with NLR \3 (median survival time: 10 months). Elevated NLR was a predictor for outcome in the MRGC patients but was not the independent factor according to the multivariate analysis. PLR is another index of systemic inflammation elicited by tumor. Preoperative PLR is regarded as an independent significant prognostic marker in resected pancreatic ducal adenocarcinoma and colorectal cancer [29, 30]. In the present study, the median survival time in
123
\6.9
10.5
C6.9
8
CA125 \30.2
10
C30.2
8
CA19-9 \39
9.5
C39
6.5
mGPS 0 C1 C160
8
LDH
9 20
1.92
1.107–3.330
\0.05
0.72
0.522–0.994
\0.05
1.321
0.929–1.878
NS
0.647
0.438–0.957
\0.05
0.798
0.569–1.119
NS
1.323
1.096–1.597
\0.01
0.828
0.624–0.1.097
NS
0.895
0.671–1.195
NS
1.214
0.94–1.569
NS
1.057
0.854–1.308
NS
1.031
0.809–1.315
NS
5.5
AKP
\47
NS
5.5
C13.2
C185
0.923–2.236
11
3.7–13.2
47–185
1.437
10
AchE
\3.7
\0.05
9.5
\3
C245
0.956–2.030
8
10
\109
1.393
6
C3
109–245
p
10
PLR \160 NLR
95 % CI
10 7.5
CA72-4
Fig. 2 Relationship between the number of positive tumor markers and overall survival in patients with MRGC
HR
9 4.5 10
patients with PLR of 160 or larger (n = 168) is 8.5 and 10 months in those with PLR smaller than 160 (n = 196). It was a prognostic factor but not the independent one. mGPS, a combined assessment of CRP level and serum albumin, was regarded as one of the most useful scoring
Med Oncol (2014) 31:289
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Conclusion In summary, the study results show that mGPS, CA19-9 and CEA are independent markers of poor survival in patients with MRGC. Our finding may be useful for evaluating the outcome more precisely and predict recurrence by combining tumor markers, inflammation-based factors, other hematological markers and patients’ clinic pathology. We emphasis the importance of CA125, which was ignored in gastric cancer previously. In the present study, we propose a new prognostic index for patients with MRGC. However, larger-scaled prospective studies are needed to confirm these results.
Fig. 3 Relationship between PI and overall survival in patients with MRGC
systems in determining long-time survival in patients with advanced malignancies, including gastric cancer [12, 13, 31]. It might reflect both systemic inflammatory response and physical nutritional decline [32]. Superior prognostic value of mGPS with regard to other biochemical parameters and independent of tumor site in patients with cancer is reported [33, 34]. Similarly, in the present study, only mGPS associated independently with overall survival of all the inflammatory relative factors. The presence of a mGPS 1 or 2 predicts poor survival compared to a mGPS of 0, which was consistent with other studies. MGPS was superior to NLR and PLR in predicting prognosis in the MRGC patients. MGPS was associated with NLR and PLR significantly (p \ 0.001; p \ 0.001, respectively), and NLR was correlated with PLR in our study. CRP is a nonspecific but sensitive marker of inflammatory response, and previous studies have demonstrated that elevated CRP is a poor predictor for malignant tumors including gastric cancer [29, 35]. Hiroyuki et al. reported CRP as an independent prognostic factor in stage IV gastric cancer [36]. Further studies are needed to clarify the mechanism of systemic inflammatory response in gastric cancer patients. Other hematological parameters such as LDH, AKP, AchE and Hb were also powerful prognostic factors in MRGC patients. We adopt three risk factors for survival (CEA, CA125 and mGPS) to develop the index. The prognostic model on the basis of these three parameters separated patients into three groups with distinct prognosis. We believe that this PI can be used to predict patients’ outcome more accurately and help clinicians and patients make clinical decisions and tailor treatment based on the estimated prognosis.
Acknowledgments This work was funded by grants from the National Natural Science Foundation of China (Grant No. 81000980, 81220108023, 81370064), Jiangsu Provincial Program of Medical Science (BL2012001) and the distinguished young investigator project of Nanjing (JQX12002). Conflict of interest of interest.
The authors declare that they have no conflict
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