Accepted Manuscript Prognostic Value of Metastatic Lymph Node Ratio as an Additional Tool to the TNM Stage System in Gastric Cancer Xiao-Jiang Wu, MD, Ru-Lin Miao, MD, Zi-Yu Li, MD, Zhao-De Bu, MD, Lian-Hai Zhang, MD, Ai-Wen Wu, MD, Xiang-Long Zong, MD, Shuang-Xi Li, MD, Fei Shan, MD, Xin Ji, MD, Hui Ren, MD, Jia-Fu Ji, MD PII:
S0748-7983(15)00360-1
DOI:
10.1016/j.ejso.2015.03.225
Reference:
YEJSO 4021
To appear in:
European Journal of Surgical Oncology
Received Date: 1 September 2014 Accepted Date: 13 March 2015
Please cite this article as: Wu X-J, Miao R-L, Li Z-Y, Bu Z-D, Zhang L-H, Wu A-W, Zong X-L, Li S-X, Shan F, Ji X, Ren H, Ji J-F, Prognostic Value of Metastatic Lymph Node Ratio as an Additional Tool to the TNM Stage System in Gastric Cancer, European Journal of Surgical Oncology (2015), doi: 10.1016/ j.ejso.2015.03.225. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Title:
2
Prognostic Value of Metastatic Lymph Node Ratio as an Additional Tool to the
3
TNM Stage System in Gastric Cancer
RI PT
4
Author:
6
Xiao-Jiang Wu, MD1, Ru-Lin Miao, MD1, Zi-Yu Li, MD1, Zhao-De Bu, MD1,
7
Lian-Hai Zhang, MD1, Ai-Wen Wu, MD1, Xiang-Long Zong, MD1, Shuang-Xi Li,
8
MD1, Fei Shan, MD1, Xin Ji, MD1, Hui Ren, MD1, Jia-Fu Ji, MD1
M AN U
SC
5
9 10
1
11
Education, Department of Gastrointestinal Surgery, Peking University Cancer
12
Hospital & Institute, Beijing, China
15
TE D
14
Xiao-Jiang Wu and Ru-Lin Miao contributed equally to this study.
EP
13
Key laboratory of Carcinogenesis and Translational Research, Ministry of
Corresponding to: Jia-Fu Ji, MD, Key Laboratory of Carcinogenesis and
17
Translational Research, Ministry of Education, Department of Gastrointestinal
18
Surgery, Peking University Cancer Hospital, Beijing Cancer Hospital & Institute,
19
Beijing 100142, China.
20
Tel: +86-10-88196048
21
E-mail: [email protected]
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ACCEPTED MANUSCRIPT 23
Running head: Prognostic value of lymph node ratio in gastric cancer
24
Disclosure:
26
Xiao-Jiang Wu and other co-authors have no commercial conflicts of interest in the
27
subject of study.
RI PT
25
28
Synopsis
SC
29
rN stage is a simple and promising prognostic factor of gastric cancer in addition to
31
TNM stage. It correlates with prognosis in stage III patients, but the value in stage I,
32
II and IV patients is yet to be determined.
M AN U
30
AC C
EP
TE D
33
2
ACCEPTED MANUSCRIPT Abstract
35
Background Gastric cancer is one of most common malignancies in the world.
36
Currently the prognostic prediction is entirely based on the TNM staging system. In
37
this study, we evaluated whether metastatic lymph node ratio (rN) at the time of
38
surgery would improve the prognostic prediction in conjunction with the TNM
39
staging system.
40
Methods This retrospective study includes 745 patients, who had been referred for
41
surgery due to gastric cancer between 1995 and 2007 and had at least 15 lymph nodes
42
examined at the time of surgery without preoperative treatment. Clinicopathologic
43
features and overall survival were analyzed using univariate and multivariate modes
44
to identify the risk factors for overall survival.
45
Results Median overall survival of all patients analyzed is 57.8 months and 5-year
46
overall survival is 49.5%. Tumor site, macroscopic type, pTNM stage, and rN stage
47
are identified as independent prognostic factors. Increased positive lymph node ratio
48
correlates with shorter survival in all patients and in each T and N stage. In stage III
49
gastric cancer patients, rN stage shows additional prognostic value on overall survival
50
(p15 lymph nodes tested
84
has not been compared with TNM system9, 11, 13, 15.
SC
In this study, we investigated the prognostic value of the rN stage in patients
M AN U
85
RI PT
78
86
with >15 lymph nodes examined and evaluated the rN stage as an independent
87
prognostic factor for gastric cancer patients with curative resection and the possibility
88
of rN stage as an additional tool to the 7th edition TNM stage system.
AC C
EP
TE D
89
5
ACCEPTED MANUSCRIPT 90
Patients and Methods
91
Study Design and Patients
92
All patients with gastric cancer surgically treated at Peking University Cancer Hospital from November 1995 to March 2007 were enrolled in this retrospective
94
study. The inclusion criteria include: (1) pathologically-proved adenocarcinoma; (2)
95
tumors arising in the distal stomach or arising in the proximal 5cm but not crossing
96
the esophagogastric junction as required by the 7th edition of the AJCC cancer staging
97
manual;16 (3) patients received radical gastrectomy with at least 15 lymph nodes
98
examined. Patients without postoperative follow-up or who received preoperative
99
treatment were excluded. A total of 188 patients were excluded from the analyses due
100
to inadequate follow up records (n=87) or preoperative treatment (n=101). A total of
101
745 cases were included to final analysis in this study. All patients included received
102
D2 surgery according to the Japanese gastric cancer treatment guidelines by a single
103
surgical team and the lymph nodes were harvested from the specimen by designated
104
surgeons after surgery. The pathological examinations were performed by the same
105
pathologist team. Patients with pathological advanced stage tumors were advised to
106
receive postoperative chemotherapy according to the treatment guidelines. This study
107
was approved by the Ethics Committee of Peking University Cancer Hospital.
SC
M AN U
TE D
EP
AC C
108
RI PT
93
Demographic, clinical, and pathologic features were analyzed and listed in
109
Table 1. The mean age of the patients was 57.81 years. The male to female ratio was
110
2.2. Among all the patients whose BMI were available, 11.4% were underweight
111
(BMI25). 6
ACCEPTED MANUSCRIPT 112 113 114
Evaluation Criteria Lymph node ratio is defined as the number of metastatic lymph nodes divided by the total number of lymph nodes examined.17 The rN stage was further stratified into
116
4 grades (rN0-3) according to previous studies that are corresponding to
117
0, >0-0.2, >0.2-0.5, and >0.518, 19. The TNM stage was determined according to the 7th
118
edition of the AJCC Cancer Staging Manual.7
120
SC
M AN U
119
RI PT
115
Statistical Methods
The overall survival (OS) was defined as the time from operation to the date of
122
death or last known contact when data of death was not known. Patients alive were
123
censored at the date of last follow-up contact. Overall survival was plotted and
124
calculated using the Kaplan-Meier method, and differences between groups were
125
compared by the Log-rand test. Cox proportional hazard modeling was performed for
126
the univariate and multivariate adjusted factor analyses. The forward stepwise method
127
was applied in the multivariate analysis. Statistical analyses were performed using
128
SPSS Version 18.0. P values less than 0.05 (two-tailed) were considered statistically
129
significant.
EP
AC C
130
TE D
121
7
ACCEPTED MANUSCRIPT 131
Results
132
Patients Characteristics The demographic features and the tumor characteristics of the 745 patients
134
included in this study are listed in Table 1. Among all the tumors, 44.4% were located
135
in the lower third of the stomach and 19.7% were in the upper third. Early gastric
136
cancer accounts for
S0748-7983(15)00360-1
DOI:
10.1016/j.ejso.2015.03.225
Reference:
YEJSO 4021
To appear in:
European Journal of Surgical Oncology
Received Date: 1 September 2014 Accepted Date: 13 March 2015
Please cite this article as: Wu X-J, Miao R-L, Li Z-Y, Bu Z-D, Zhang L-H, Wu A-W, Zong X-L, Li S-X, Shan F, Ji X, Ren H, Ji J-F, Prognostic Value of Metastatic Lymph Node Ratio as an Additional Tool to the TNM Stage System in Gastric Cancer, European Journal of Surgical Oncology (2015), doi: 10.1016/ j.ejso.2015.03.225. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Title:
2
Prognostic Value of Metastatic Lymph Node Ratio as an Additional Tool to the
3
TNM Stage System in Gastric Cancer
RI PT
4
Author:
6
Xiao-Jiang Wu, MD1, Ru-Lin Miao, MD1, Zi-Yu Li, MD1, Zhao-De Bu, MD1,
7
Lian-Hai Zhang, MD1, Ai-Wen Wu, MD1, Xiang-Long Zong, MD1, Shuang-Xi Li,
8
MD1, Fei Shan, MD1, Xin Ji, MD1, Hui Ren, MD1, Jia-Fu Ji, MD1
M AN U
SC
5
9 10
1
11
Education, Department of Gastrointestinal Surgery, Peking University Cancer
12
Hospital & Institute, Beijing, China
15
TE D
14
Xiao-Jiang Wu and Ru-Lin Miao contributed equally to this study.
EP
13
Key laboratory of Carcinogenesis and Translational Research, Ministry of
Corresponding to: Jia-Fu Ji, MD, Key Laboratory of Carcinogenesis and
17
Translational Research, Ministry of Education, Department of Gastrointestinal
18
Surgery, Peking University Cancer Hospital, Beijing Cancer Hospital & Institute,
19
Beijing 100142, China.
20
Tel: +86-10-88196048
21
E-mail: [email protected]
AC C
16
22 1
ACCEPTED MANUSCRIPT 23
Running head: Prognostic value of lymph node ratio in gastric cancer
24
Disclosure:
26
Xiao-Jiang Wu and other co-authors have no commercial conflicts of interest in the
27
subject of study.
RI PT
25
28
Synopsis
SC
29
rN stage is a simple and promising prognostic factor of gastric cancer in addition to
31
TNM stage. It correlates with prognosis in stage III patients, but the value in stage I,
32
II and IV patients is yet to be determined.
M AN U
30
AC C
EP
TE D
33
2
ACCEPTED MANUSCRIPT Abstract
35
Background Gastric cancer is one of most common malignancies in the world.
36
Currently the prognostic prediction is entirely based on the TNM staging system. In
37
this study, we evaluated whether metastatic lymph node ratio (rN) at the time of
38
surgery would improve the prognostic prediction in conjunction with the TNM
39
staging system.
40
Methods This retrospective study includes 745 patients, who had been referred for
41
surgery due to gastric cancer between 1995 and 2007 and had at least 15 lymph nodes
42
examined at the time of surgery without preoperative treatment. Clinicopathologic
43
features and overall survival were analyzed using univariate and multivariate modes
44
to identify the risk factors for overall survival.
45
Results Median overall survival of all patients analyzed is 57.8 months and 5-year
46
overall survival is 49.5%. Tumor site, macroscopic type, pTNM stage, and rN stage
47
are identified as independent prognostic factors. Increased positive lymph node ratio
48
correlates with shorter survival in all patients and in each T and N stage. In stage III
49
gastric cancer patients, rN stage shows additional prognostic value on overall survival
50
(p15 lymph nodes tested
84
has not been compared with TNM system9, 11, 13, 15.
SC
In this study, we investigated the prognostic value of the rN stage in patients
M AN U
85
RI PT
78
86
with >15 lymph nodes examined and evaluated the rN stage as an independent
87
prognostic factor for gastric cancer patients with curative resection and the possibility
88
of rN stage as an additional tool to the 7th edition TNM stage system.
AC C
EP
TE D
89
5
ACCEPTED MANUSCRIPT 90
Patients and Methods
91
Study Design and Patients
92
All patients with gastric cancer surgically treated at Peking University Cancer Hospital from November 1995 to March 2007 were enrolled in this retrospective
94
study. The inclusion criteria include: (1) pathologically-proved adenocarcinoma; (2)
95
tumors arising in the distal stomach or arising in the proximal 5cm but not crossing
96
the esophagogastric junction as required by the 7th edition of the AJCC cancer staging
97
manual;16 (3) patients received radical gastrectomy with at least 15 lymph nodes
98
examined. Patients without postoperative follow-up or who received preoperative
99
treatment were excluded. A total of 188 patients were excluded from the analyses due
100
to inadequate follow up records (n=87) or preoperative treatment (n=101). A total of
101
745 cases were included to final analysis in this study. All patients included received
102
D2 surgery according to the Japanese gastric cancer treatment guidelines by a single
103
surgical team and the lymph nodes were harvested from the specimen by designated
104
surgeons after surgery. The pathological examinations were performed by the same
105
pathologist team. Patients with pathological advanced stage tumors were advised to
106
receive postoperative chemotherapy according to the treatment guidelines. This study
107
was approved by the Ethics Committee of Peking University Cancer Hospital.
SC
M AN U
TE D
EP
AC C
108
RI PT
93
Demographic, clinical, and pathologic features were analyzed and listed in
109
Table 1. The mean age of the patients was 57.81 years. The male to female ratio was
110
2.2. Among all the patients whose BMI were available, 11.4% were underweight
111
(BMI25). 6
ACCEPTED MANUSCRIPT 112 113 114
Evaluation Criteria Lymph node ratio is defined as the number of metastatic lymph nodes divided by the total number of lymph nodes examined.17 The rN stage was further stratified into
116
4 grades (rN0-3) according to previous studies that are corresponding to
117
0, >0-0.2, >0.2-0.5, and >0.518, 19. The TNM stage was determined according to the 7th
118
edition of the AJCC Cancer Staging Manual.7
120
SC
M AN U
119
RI PT
115
Statistical Methods
The overall survival (OS) was defined as the time from operation to the date of
122
death or last known contact when data of death was not known. Patients alive were
123
censored at the date of last follow-up contact. Overall survival was plotted and
124
calculated using the Kaplan-Meier method, and differences between groups were
125
compared by the Log-rand test. Cox proportional hazard modeling was performed for
126
the univariate and multivariate adjusted factor analyses. The forward stepwise method
127
was applied in the multivariate analysis. Statistical analyses were performed using
128
SPSS Version 18.0. P values less than 0.05 (two-tailed) were considered statistically
129
significant.
EP
AC C
130
TE D
121
7
ACCEPTED MANUSCRIPT 131
Results
132
Patients Characteristics The demographic features and the tumor characteristics of the 745 patients
134
included in this study are listed in Table 1. Among all the tumors, 44.4% were located
135
in the lower third of the stomach and 19.7% were in the upper third. Early gastric
136
cancer accounts for
