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Comparison of the 8 th union for international cancer control lymph node staging system for gastric cancer with two other lymph node staging systems

The log odds of positive lymph nodes (LODDS) and the metastatic lymph node ratio (MLR) staging systems have previously been demonstrated to exhibit advantages compared with the tumor-node-metastasis (TNM) staging system in predicting the prognosis of gastric cancer. The current study compared the prognostic significance of the newest Union for International Cancer Control Node classification with the LODDS and MLR staging systems. From September 2010 to December 2012, all medical records for patients with gastric cancer at the Third Affiliated Hospital of Soochow University were retrospectively analyzed and the clinicopathologic characteristics were reviewed. Cut-off points were selected to divide the patients with gastric cancer into different groups. Univariate and multivariate analyses were performed to identify the prognostic risk factors for gastric cancer. The Harrell's concordance index (C-index) was adopted to compare the prognostic value of the three staging systems. A total of 877 patients with gastric cancer who met the inclusion criteria were analyzed in the current study. The patients were classified according to the three MLR subgroups as follows: MLR0 (MLR=0), MLR1 (00.5). Based on multivariate analysis, LODDS, MLR and pathological node (pN) stage could significantly predict survival rates of patients with gastric cancer. According to the C-index, the LODDS staging system more accurately predicted the 5-year overall survival for patients with gastric cancer compared with the other two staging systems. In summary, the current study has identified that LODDS may be superior to the MLR and pN staging systems in predicting the prognosis of patients with gastric cancer. However MLR may exhibit advantages compared with LODDS for patients who have undergone adequate lymphadenectomies.


Introduction
Gastric cancer is the fourth most common cancer type worldwide, with >93,000 new cases diagnosed every year, and is the second leading cause of cancer-associated cases of mortality, following lung cancer with 700,000 deaths each year (1,2). Gastric cancer is considered to be prevalent in east Asia, particularly in China (3). Currently, primary tumor resection with lymphadenectomy is the main surgical treatment for resectable gastric cancer; however, most cases of gastric cancer are diagnosed in the advanced stage as the symptoms of early stage disease are often atypical (4).
The 8th edition of the tumor-node-metastasis (TNM) staging system (5), established by the American Joint Committee on Cancer and the Union for International Cancer Control (UICC), is the most commonly used system for predicting the prognosis of gastric cancer (6). The 8th edition TNM staging system is considered to be an objective and reliable method for predicting the prognosis of patients with gastric cancer (7), however, the requirement of at least 15 retrieved lymph nodes (LNs) limits the use of this system in clinical practice (8). Furthermore, stage migration may occur if a low number of LNs are retrieved, which may underestimate the severity of the disease (9).
Previously, a number of new methods for predicting the prognosis of gastric cancer have been proposed. The metastatic lymph node ratio (MLR) is used as a supplement to the TNM staging system and is defined as the ratio of metastatic LNs to the total number of retrieved LNs (10). Several previous studies have demonstrated that MLR has advantages compared with the UICC pathological node (pN) staging system in predicting the prognosis of gastric cancer (11)(12)(13)(14). Another prognostic parameter, the log odds of positive LNs (LODDS), is defined as the log of the ratio of positive LNs to negative LNs (15). A number of studies have indicated that the prognostic value of LODDS is superior to the MLR and pN systems (15)(16)(17). The current study evaluated the prognostic significance of the LODDS and MLR staging systems compared with the 8th UICC pN staging system.

Materials and methods
Patients. Between September 2010 and December 2012, all medical records for patients with gastric cancer treated at the Third Affiliated Hospital of Soochow University (Changzhou, China) were retrospectively analyzed. The inclusion criterion was adenocarcinoma R0 resection with D2 LN dissection. Patients with M0 and M1 statuses were excluded from the study. Patients who had received neoadjuvant chemotherapy or radiotherapy were also excluded due to the possibility of incorrect staging. Specific data are presented in Fig. 1. Clinicopathologic characteristics, including age, sex, tumor size, tumor location, tumor differentiation, tumor depth (pT stage), pN stage and TNM stage, were reviewed. Follow-up was conducted by telephone calls, e-mails and on-site visits. Informed written consent was received from all patients and the current study was approved by the Ethics Committee of The Third Affiliated Hospital of Soochow University.
Statistical analysis. All analyses were performed using SPSS (version 16.0; SPSS, Inc., Chicago, IL, USA) and R software (version 3.0.0; www.r-project.org). Kaplan-Meier analysis followed by a log-rank test was used to compare the survival between subgroups. Univariate and multivariate analyses were performed using a Cox proportional hazards model. The Harrell's concordance index (C-index) was used to compare the accuracy of the prognostic predictions of different staging systems. A higher C-index indicates a better predictive accuracy. P<0.05 was considered to indicate a statistically significant difference.

Results
Patient characteristics. A total of 877 patients with gastric cancer met the aforementioned criteria and were analyzed in the current study. The clinicopathological characteristics are presented in Table II. The number of patients ≤60 and >60 years of age was 459 and 418, respectively. There were 605 male patients and 272 female patients. A total of 275 (31.4%) patients received postoperative chemotherapy. The majority of patients were in an advanced stage, with T3 and T4 patients accounting for 48.2 and 25.3%, respectively, and T1 and T2 patients accounting for 10.4 and 16.1%, respectively. Table III, risk factors were evaluated using univariate and multivariate analyses. Prognostic factors included age, sex, tumor location, tumor size, tumor differentiation, pT stage, pN stage, TNM stage, MLR and LODDS. Overall survival rates were shown for patients in different T subgroups (Fig. 2), N subgroups ( Fig. 3), TNM subgroups ( Fig. 4), MLR subgroups ( Fig. 5) and LODDS subgroups (Fig. 6). Based on univariate analysis, pT stage, pN stage, tumor size, tumor differentiation, MLR, LODDS and TNM were identified as significant prognostic risk factors for gastric cancer. However, based on multivariate analysis, tumor size and pT stage were not identified as significant prognostic factors.

Analysis of prognostic factors and survival. As presented in
Comparison of prognostic value among the three systems. The C-index was used to compare the prognostic discrimination of the three staging systems. As demonstrated in Table IV, when all patients were included (LN ≥0), the C-index of the LODDS staging system was significantly higher compared with the C-indexes of the MLR and pN staging systems (C-index=0.795, 0.790 and 0.779, respectively; P<0.001). The patients were divided into two groups according to the number of LNs retrieved. When the number of retrieved LNs was <15, the C-index of the LODDS staging system was significantly higher compared with that of the MLR and pN staging systems (C-index=0.792, 0.781 and 0.790, respectively; P<0.001). However, when the number of retrieved LNs was ≥15, the C-index of the MLR was significantly higher compared with the LODDS and pN staging systems (C-index=0.772, 0.780 and 0.698, respectively; P=0.001).

Discussion
The TNM system is widely used to offer guidance for the treatment of gastric cancer (7). The 8th edition of the TNM staging system for gastric cancer was released in 2016, replacing the 2009 7th edition (8). Compared with the previous edition, the 8th edition has no changes in the definition of T and N classifications. A noteworthy difference in the 8th edition system involves separate consideration of N3a and N3b in the TNM staging system, which has been demonstrated to achieve improved prognosis prediction in patients with stage III gastric cancer (5,6). A number of previous studies have indicated that the MLR is an improved method for evaluating the prognosis of patients with  gastric cancer compared with the previous TNM staging system (18,19). In addition, the LODDS staging system has been demonstrated to be superior in terms of accuracy compared with the MLR and TNM systems with regard to
In the current study, the LODDS, MLR and the 8th UICC pN staging systems were evaluated to compare prognostic prediction. A number of factors were responsible for making the current study novel. Firstly, the 8th UICC pN staging system was considered in the current study, which, to the best our knowledge, has not been considered in previous studies. Secondly, the 8th pN, MLR and LODDS staging systems were all compared together while the majority of previous studies have only compared the UICC pN staging system with one other system. Finally, the current study divided the patients into two groups based on the number of retrieved LNs (<15 or ≥15), which may increase the accuracy of determining the best system. The current study concluded that the LODDS staging system is superior to the MLR and TNM staging systems, particularly in patients with <15 retrieved LNs.
Based on univariate and multivariate analysis, the MLR, LODDS and pN staging systems were all significantly associated with prognosis. Similar outcomes were identified in a number of previous studies. Jian-Hui et al (16) analyzed 935 patients undergoing radical surgery treatment and demonstrated that the three systems were all independent factors for overall survival based on multivariate analysis. Furthermore, this study concluded that LODDS was the superior staging system. Tóth et al (19) revealed that the LODDS staging system was the best predictor of prognosis when <16 LNs were retrieved and the MLR should be applied in patients who underwent extended lymphadenectomies. Aurello et al (23) analyzed 177 patients and identified that the LODDS staging system, nodal ratio and pN are all prognostic factors based on multivariate analysis, and the LODDS staging system was capable of predicting survival     even when <15 LNs were harvested. These studies, in addition to the current study, all supported the hypothesis that LODDS can better minimize stage migration compared with the pN system, particularly when an insufficient number of LNs are retrieved (20).
There is no agreement regarding a cut-off value for MLR in patients with gastric cancer. Zeng et al (24) divided patients into four subgroups and used X-tile to determine the optimal cut-off value. Cut-off values can also be adopted based on commonly used values in previous studies. Tóth et al (19) categorized MLR with four subgroups according to previously published cut-off values. In addition, the median MLR may be used as the cut-off value (1,2). The current study selected the median MLR as the cut-off value and divided the patients into three subgroups. It was identified that patients with high MLRs had low 5-year overall survival rates, as reported by Ke et al (25) in an analysis of 370 patients who underwent R0 surgery. This method of LODDS classification is relatively consistent. The current study stratified LODDS at an interval of 0.5 and compared the overall survival between adjacent subgroups. This method has been adopted by a number of previous studies (15,19,26,27).
The current study compared the C-index of the LODDS, MLR and 8th UICC pN staging systems. The LODDS staging system demonstrated the largest C-index when all patients were included. The same result appeared in the group with <15 LNs retrieved. In the group with ≥15 LNs retrieved, the MLR demonstrated the largest C-index. The results were generally consistent with a study conducted in 2016, in which the LODDS staging system was revealed to be an independent prognostic factor and superior to the MLR and 7th UICC pN staging systems (15). Aurello et al (23) concluded that the success of the LODDS staging system was not associated with the number of LNs examined and revealed that LODDS could predict survival when <15 LNs were retrieved, which was verified by the current study.
In conclusion, the LODDS and MLR staging systems may be adopted as alternative pN staging systems to predict the prognosis of patients with gastric cancer. Both systems were identified to be superior compared with the 8th edition of the UICC pN staging system. The LODDS staging system exhibits a higher prognostic accuracy compared with MLR when an inadequate number of LNs are retrieved, while MLR is applicable to predict prognosis in cases with adequate lymphadenectomies. MLR, metastatic lymph node ratio; LODDS, log odds of positive nodes; LN, lymph nodes; C-index, Harrell's concordance index; CI, confidence interval; TNM, tumor-node-metastasis. a Compared with the system with the highest C-index.