|Year : 2021 | Volume
| Issue : 11 | Page : 1602-1608
Prognostic significance of the metastatic lymph node ratio compared to the TNM classification in stage III gastric cancer
S Gulmez, AS Senger, O Uzun, S Omeroglu, C Ofluoglu, ZO Sert, A Oz, E Polat, M Duman
Department of Gastrointestinal Surgery, University of Health Sciences, Kosuyolu High Specialty Training and Research Hospital, Istanbul, Turkey
|Date of Submission||09-Jun-2020|
|Date of Acceptance||21-Mar-2021|
|Date of Web Publication||15-Nov-2021|
Dr. S Gulmez
Department of Gastrointestinal Surgery, University of Health Sciences, Kosuyolu High Specialty Training and Research Hospital, Istanbul
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: We aimed to evaluate a comparative analysis of the prognostic value of the metastatic lymph node ratio (LNR) and pN (TNM) in stage III gastric cancer. Patients and Methods: A total of 159 stage III gastric cancer patients with curative gastrectomy were retrospectively analyzed. Cutoff values for LNR were designated according to 25%, 50% and 75% percentiles, 0.07, 0.20 and 0.44 respectively. The LNR was divided into four groups as 0 > LNR1 ≤ 0.07; 0.07 > LNR2 ≤0.20; 0.20 > LNR3 ≤0.44; 0.44 > LNR4 ≤1. Results: The mean age of the patients was 61.1 ± 11.3 years. Male predominance was apparent (73.6%). The 1-year overall survival and recurrence rates were 73.6% and 33.6%, respectively. The univariate cox regression analysis demonstrated age and LNR were the main variables that affected overall survival (OS) (p < 0.05). Harvested lymph nodes less than 16 did not affect OS (p = 0.255). The results of the multivariate cox regression analysis revealed that only LNR was an independent prognostic factor (P < 0.001), while pN was not (p > 0.05). Similar results, as with overall survival, could not be revealed clearly for disease free survival (DFS). Conclusions: LNR was an independent significant prognostic factor and superior to pN staging in predicting OS but not for DFS in stage III gastric cancer patients. The high LNR levels in our research were found to be associated with poor survival rates. The percentile system we used to determine cutoff values may be considered as a reliable method. Similarly, LNR also provides a reliable prognostic parameter in future staging systems to help guide treatment algorithm plans.
Keywords: Gastric cancer, LNR, lymph node metastasis, metastatic lymph node ratio, prognosis.
|How to cite this article:|
Gulmez S, Senger A S, Uzun O, Omeroglu S, Ofluoglu C, Sert Z O, Oz A, Polat E, Duman M. Prognostic significance of the metastatic lymph node ratio compared to the TNM classification in stage III gastric cancer. Niger J Clin Pract 2021;24:1602-8
|How to cite this URL:|
Gulmez S, Senger A S, Uzun O, Omeroglu S, Ofluoglu C, Sert Z O, Oz A, Polat E, Duman M. Prognostic significance of the metastatic lymph node ratio compared to the TNM classification in stage III gastric cancer. Niger J Clin Pract [serial online] 2021 [cited 2021 Nov 26];24:1602-8. Available from: https://www.njcponline.com/text.asp?2021/24/11/1602/330459
| Introduction|| |
Gastric cancer is the fifth most common malignancy and ranks third in cancer-related mortality worldwide. Although there has been an increase in survival rates in the last couple of decades, poor prognosis in advanced stages of gastric cancer remains a challenge. There is no known specific symptom of gastric carcinomas. Patients, thus, are generally diagnosed in advanced stages, while the five-year overall survival (OS) of these patients is about 30%.
The addition of first and second-line chemotherapy to surgery in advanced stages improves survival rates. Particularly the pN stage maintains its determinant role in the selection of patients eligible for adjuvant chemotherapy. According to the 8th ed.ition of UICC (International Union Against Cancer) and AJCC's (American Joint Committee on Cancer) tumor-node-metastasis (TNM) staging system, at least 16 lymph nodes (LN) need to be analyzed in order to assess lymph node status in gastric cancers.
The number of metastatic lymph nodes is directly dependent on the total number of harvested lymph nodes. This condition requires an adequate lymph node dissection (LND). As a definition of the extension of the LND, rather than the number of resected lymph nodes, an anatomical approach is used, such as D1, where the perigastric region LN is removed, and D2, which includes those outside of this region. The surgeon factor can affect the result here. Also, the number of lymph nodes may vary as per the pathologist, and it may also lead to stage migration, the rate of which can go as high as 10-25. On the other hand, over-harvesting lymph nodes can bring about up-migration. At the same time, the insufficient number of analyzed lymph nodes can also lead to down-migration, both of which may directly affect treatment and survival. Metastases in seven or more regional lymph nodes are defined as pN3 according to TNM staging. Therefore, no patient with less than seven harvested LN can reach the pN3 stage.
Recent studies have reported that the metastatic lymph node ratio (LNR), the ratio of the number of metastatic lymph nodes to the total number of lymph nodes, could alleviate this problem and be an independent prognostic factor.,, In a current study that utilized the Surveillance, Epidemiology, and End Results (SEER) database, the authors have underlined the prognostic significance of LNR-based nomograms.
The purpose of our study was to evaluate a comparative analysis of the prognostic value of LNR and pN in stage III gastric cancer patients.
| Materials and Methods|| |
This study was approved by the Institutional Review Board (IRB) of our institute (IRB No. 2019.7/45-261), following the principles of the Declaration of Helsinki.
The data of a total of 159 stage III gastric cancer patients, who had radical curative resection between December 2006 and December 2018 in our hospital, were retrospectively analyzed [Figure 1]a. All patients had undergone total or subtotal curative gastrectomy with D2 lymph node dissections. The TNM staging of all patients was performed based on UICC and AJCC 8th edition. Accordingly, the lymph node stage is classified as pN1 if there are only 1-2 LN metastases, as pN2 if 3-6 LN is positive, as pN3a if 7-15 LN is metastatic, and as pN3b if there is >15 lymph node involvement according to pathology results. The minimum number of lymph nodes that need to be harvested, therefore, is 16.
|Figure 1: (a) Study design (b) Our percentile system for determination of the LNR-cutoff values|
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Patients with stage I-II and IV cancer, those with less than D2 lymph node dissections, those who received neoadjuvant therapy, those with recurrent tumors, those who underwent emergency surgery, and those with insufficient follow-up data were excluded from the study. In the D2-LND technique, all perigastric (N1) and outside of the perigastric region (N2) nodes were removed. Therefore, at least 16 harvested lymph node conditions were not sought in D2-LND, an anatomical expression compared to the total LN number.
The study variables included age, sex, pT and pN stages, LNR, differentiation grade, tumor location, surgical modality, histological classification, lymphovascular invasion (LVI), and perineural invasion (PNI).
Percentile segments were utilized to identify the cutoff values for LNR. Cutoff values were designated according to 25%, 50%, and 75% percentiles of the LNR, 0.07, 0.20, and 0.44, respectively. The LNR was divided into four groups as 0> LNR1 ≤0.07; 0.07> LNR2 ≤0.20; 0.20> LNR3 ≤0.44; 0.44> LNR4 ≤1 [Figure 1]b.
All the patients covered by the study were referred to the oncology department to receive adjuvant therapy within the first six weeks following resection. Those who accepted treatment were treated with a 5-fluorouracil-based regimen or capecitabine plus oxaliplatin (XELOX) for 6 to 8 cycles. The follow-up period was every three months for the first two years. For those who completed the two-year follow-up period, the next periods were every six months for the following three years and once a year thereafter. For the purposes of this study, the last follow-up was on April 30, 2020.
The SPSS (Statistical Product and Service Solutions) software version 22 for Windows (SPSS Inc. Chicago, IL, USA) was used to analyze the study. The Chi-square test was utilized for the comparison of the distribution of pN groups as per the LNR groups. The Kolmogorov-Smirnov test was used to assess the normality of distribution in numeric data. Within the study's scope, multivariate cox regression analysis was performed to identify categorical variables that might have affected survival. Within the framework of cox regression analysis, the “enter” method was selected to reveal the significance of all variables, while each category was designated as “dummy” in order to demonstrate the impact values of all the groups of categorical variables, and they were also included in the study as independent variables. The Kaplan-Meier method and the log-rank test were used to conduct the survival analyses of the LNR and pN groups. Further, univariate and multivariate cox regression analyses were performed to examine the superiority of LNR and pN levels to each other in predicting survival. A P value of less than 0.05 was defined as statistically significant for all analyses in this study.
| Results|| |
As a result of the analysis of 159 stage III gastric cancer patients with curative surgery, the mean age of the patients was 61.1 ± 11.3 years. The rate of patients who were younger than 65 years of age was 59.7%. Male predominance was apparent (73.6%). The median overall survival was 26.56 ± 3.65 months (95% CI, 19.441-33.692), the median disease-free survival was 20.99 ± 2.58 months (95% CI, 15.916-26.064), and the median follow-up period was 19.9 (1.1-155.7) months. The 1-year overall survival and recurrence rates were 73.6% and 33.6%, respectively. The frequency distribution of the pT stage was 2.5%, 8.8%, 45.9%, and 42.8% for pT1, pT2, pT3, and pT4, respectively. The dominant distribution of patients in pN and LNR groups was in the pN3 group with 46.2% and the LNR2 group with 28.3%. 69.8% of the patients had poorly differentiated tumors. The number of patients with less than 16 harvested lymph nodes in this study was 21 (13.2%). Patients with tumors larger than 5 cm and less than or equal to 5 cm were 51.6% and 48.4%, respectively. [Table 1] presents the distribution of demographic, clinical, and histopathological characteristics of the patients.
|Table 1: Demographic, Clinical and Histopathological Data of All 159 Patients, and the Effect of their Variables on Overall and Disease-Free Survival|
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According to the results of the multivariate cox regression analysis [Table 1], age and LNR were the main variables that affected OS (P < 0.05). However, in the pT stage, only those with the pT1 had 1.7 times more OS rate than those with the pT4 (p = 0.043). Other variables were not statistically significant in terms of OS (P > 0.05). The mortality risk was 1.6 times higher in the age group ≥65 years of age than in the group <65. It was also seen in the LNR subgroups that as the group's level went up, so did the mortality risk. The comparison of the subgroups revealed that each subgroup had a significant effect on OS (P < 0.05). The OS rate of the LNR1 group was 2.6 times higher than the LNR2 group, 5.2 times higher than the LNR3 group, and 5.4 times higher than the LNR4 group. When the variables that significantly affect DFS were analyzed, it was only observed that the recurrence rate was 2.5 times lower in pN2 compared to pN1 (p = 0.032) and 4.4 times higher in LNR4 than LNR1 (p = 0.029).
There was a statistically significant relationship in the comparison of pN stages according to the LNR groups (p < 0.001). The LNR1 group was entirely made up of the pN1 stage patients except for 8.1% of the pN2 patients. The highest number of patients in the LNR2 group was the pN2 stage patients with 73.0%. Most of the LNR3 and LNR4 patients consisted of those in the pN3 stage [Table 2].
The results of the Kaplan-Meier analysis performed for both the pN and LNR groups taking into account median OS and DFS revealed a statistically significant difference (P < 0.001) [Figure 2]. Interestingly, this present study showed that the OS and DFS rates of pN2 and LNR2 patients were more elevated than those in pN1 and LNR1. The Chi-square test, performed according to the adjuvant treatment distribution, showed a significant relationship between the pN and LNR groups. (p = 0.001 vs. 0.003, respectively). In contrast to 57.1% of patients in the pN1 group, 29.7% of pN2 did not complete adjuvant treatments. Six patients in the pN1 group and two patients in the pN2 group died during the chemotherapy-period, severe chemotherapy intolerance was observed in nine patients in the pN1 group and four patients in the pN2 group, nine patients in the pN1 group and two patients in the pN2 group refused chemotherapy from the start, four patients in the PN1 group and three patients in the pN2 group could not receive chemotherapy due to severe comorbidity. Similarly, this rate was higher in the LNR1 group than in LNR2 (55.3% vs. 37.8%, respectively) [Table 3]. This observation may be an explanation of the unexpected survival differences.
|Figure 2: Kaplan-Meier analysis (a) OS for pN (b) OS for LNR (c) DFS for pN (d) DFS for LNR|
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In order to answer the question as to whether pN or LNR was superior in their impact on survival, the data of the patients were studied by univariate and multivariate cox regression analysis. While this probability for OS was 0.001 for pN, the same test showed that this rate was more robust for LNR (P < 0.001). The univariate analysis results demonstrated that the effect of LNR on OS was superior to the pN stage. The results of the multivariate analysis, moreover, revealed that only LNR was effective (P < 0.001) while the pN stage was not (P > 0.05), when the pN stage and LNR were analyzed together as independent variables. Therefore, the effect of LNR on OS was higher than at the pN stage. Similar results, as with overall survival, could not be revealed cleanly for DFS [Table 4].
|Table 4: The Impact of pN and LNR on Overall and Disease-Free Survival by Univariate and Multivariate Cox Regression Analyses|
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| Discussion|| |
Lymph node metastasis is one of the most significant factors that determine prognosis in gastric cancer. The number of metastatic lymph nodes also determines the pN stage in the UICC/AJCC TNM classification. Accurate and reliable results incorporated in this will have a direct impact on both the treatment scheme and the prognosis. This classification is widely used today. However, it has been reported that pN may be affected by the total number of harvested lymph nodes and cause stage migration. This condition is known as “the Will Rogers-phenomenon”. Moreover, when D1 lymph node dissection is performed as the surgical modality or insufficient D2 dissection is performed, stage migration remains a problem., Another critical factor is that, although an accurate D2-LND was performed with the appropriate surgical anatomical approach, the specimen contained a small number of LNs due to inexperienced pathologist assessment. LNR, an alternative lymph node staging, has gained currency based on this fact. Within the last couple of years, studies in the literature have underlined the superiority of LNR to the pN stage in predicting prognosis in pancreatic, colorectal,, lung, and breast cancers.
The first LNR-based study in gastric cancer was published by Kwon et al. in 1996. The predictive reliability of pN has been questioned since then. However, there has yet to be a consensus on the cutoff values of LNR. Based on these facts, we aimed to investigate the prognostic value of LNR in comparison to pN in our study, covering 159 patients who had undergone surgery because of stage III gastric cancer.
It is understood that in a meta-analysis by Zhu et al. covering gastric cancer patients, the authors preferred to categorize LNR rather than using a single one cutoff value. Although the number of categories ranged from 2 to 6, it was seen that the most common ones were 3 or 4. Other than these, although Attaallah et al. worked on a single cutoff value (37%), they concluded that this value was not significant. Similarly, Espín et al. used a single cutoff value (20%). The difference between these two last studies was that Espín et al. stated that the LNR-based staging system had no prognostic significance. When one takes into account the best cutoff values presented in previous studies, it was seen that these figures varied between 1% and 89%. Further, it was seen that 1%, 10%, and 25% stood out as the most frequently used triple cutting values in four-category LNR studies.,,,,, The initial cutoff value in such studies was 1%. Yet Liu et al., who adopted the 80% extreme value, used 0.40 (40% and 80%) as the initial value while Zeng et al. utilized 0.50 (50% and 80%). More examples can be offered within this scope with different cutoff values. It was seen that the best cutoff values for LNR vary from one study to another. Many of these studies, however, agree that LNR is an independent prognostic factor for gastric cancer. We preferred the percentile system, which is a simple, practical, and well-accepted method, in our study, to designate the cutoff value of LNR. We divided LNR into four groups as 0> LNR1 ≤0.07, 0.07> LNR2 ≤0.20, 0.20> LNR3 ≤0.44, 0.44 >LNR4 ≤1. The multivariate cox regression analysis results revealed that all 4 LNR groups had an impact on survival. Therefore, we concluded that LNR was an independent significant prognostic factor. The same analysis did not confirm the prognostic effect of pN in this study.
Another critical question was whether the LNR could predict the patient's survival in the case of resected LN less than 16. Hou et al., in response to this question, in their study of 221 gastric cancer patients, could not show a significant predictive value, as well as Ke et al. However, Zhang et al. reported that LNR was an independent prognostic factor under the same conditions, while pN did not have the same effect. As a result of our findings, when less than 16 lymph nodes were sampled, LNR was not an independent prognostic factor.
Whether the impact of pN and LNR on overall survival had superiority over each other was tested by univariate and multivariate cox regression analysis. Although both variables were significant within the scope of the univariate analysis, the fact that multivariate analysis showed that only LNR had statistical significance led us to the main inference of our study. The same results were not clearly valid for DFS. Thus, LNR had no advantage over pN for recurrence-free survival.
Our study had a couple of limitations. Firstly, the design of this study was retrospective. An additional limitation was details of specific chemotherapy combination and specific duration.
In conclusion, the results of our study revealed that LNR was an independent significant prognostic factor and superior to pN staging in predicting OS but not for DFS in stage III gastric cancer patients. The high LNR levels in our research were found to be associated with poor survival rates. The percentile system we used to determine cutoff values may be considered as a reliable method. Similarly, LNR also provides a reliable prognostic parameter in future staging systems to help guide treatment algorithm plans.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]