Impact of Metastatic Lymph Nodes on Survival of Patients with pN1-Category Esophageal Squamous Cell Carcinoma: A Long-Term Survival Analysis

Background The morbidity and mortality rates of esophageal squamous cell carcinoma (ESCC) are high in China. The overall survival (OS) of patients with ESCC is related to lymph node (LN) metastasis (LNM). This study aimed to discuss the impact of metastasis in LN stations on the OS of patients with pathologic N1 (pN1) ESCC. Methods Data were obtained from the Esophageal Cancer Case Management database of Sichuan Cancer Hospital and Institute (SCCH-ECCM). Additionally, data of patients with pN1-category ESCC collected between January 2010 and December 2017 were retrospectively analyzed. Results Data from 807 patients were analyzed. The median OS of the patients with one metastatic LN (group 1) was 49.8 months (95 % confidence interval [CI], 30.8–68.9 months), whereas the OS of those with two metastatic LNs (group 2) was only 33.3 months (P = 0.0001). Moreover, group 1 did not show a significantly longer OS than group 2.1 (patients with 2 metastatic LNs in 1 LNM station; P = 0.5736), but did show a significantly longer OS than group 2.2 (patients with 2 metastatic LNs in 2 LNM stations; P < 0.0001). After propensity score-matching, the 5-year survival rate for group 1 was 28 %, whereas that for group 2 was 14 % (P = 0.0027). Conclusions The OS for the patients with one metastatic LN in one LNM was not significantly longer than for the patients with two metastatic LNs in one LNM station. Patients with one LNM station had a significantly longer OS than those with two LNM stations. Thus, the number of LNM stations is a significant determinant of OS in pN1 ESCC. Supplementary Information The online version contains supplementary material available at 10.1245/s10434-024-15019-z.

4][5] The treatment methods for ESCC depend on the tumor stage and location, histologic type, performance status, and comorbidities.
][8][9][10] However, a diagnosis confirmed at an advanced stage of ESCC poses treatment challenges for many patients with ESCC. 1 In addition, due to the delayed diagnosis and poor therapeutic effect of existing treatment methods, the 5-year overall survival (OS) rate is only approximately 30 %. 1,2 Each of the currently available treatment methods works differently.For example, radiotherapy uses high-energy electron beams to shrink the tumor and destroy it. 11In contrast, chemotherapy involves using drugs as infusions or pills to reduce tumor size and inhibit the tumor's growth. 12Immunotherapy activates the immune system to recognize and destroy tumor cells. 13ith advances in technology and research, gene therapy, tumor vaccines, and other new techniques are being developed to treat esophageal cancer. 14,15However, surgery through radical tumor resection continues to be the cornerstone of comprehensive treatment for ESCC. 6,7,9,16][19][20] Currently, the Union for International Cancer Control/ American Joint Committee on Cancer (UICC/AJCC) tumornode-metastasis (TNM) staging and the Japan Esophageal Society (JES) system are the internationally used criteria for cancer staging systems. 9,21According to the UICC/AJCC TNM staging, pathologic N1 (pN1) is defined as one or two metastatic LNs.However, as per the 11th Japanese Classification of Esophageal Cancer, based on tumor location, different LN stations are divided into groups: N1, N2, and N3. 9,21The two systems differ in terms of the LN (N) category.Unlike UICC/AJCC, the JES system focuses more on metastasis of the LN location. 9,21The main purpose of this retrospective study was to discuss the impact of metastasis in different LN stations on the OS of patients with pN1category ESCC.

Study Design and Patients
Data from 2957 patients with ESCC treated at Sichuan Cancer Hospital (SCCH) from January 2010 to December 2017 were retrospectively reviewed.Data and medical records of the patients were obtained from the database of the hospital's Esophageal Cancer Case Management (SCCH-ECCM database).The data extracted included demographics (sex and age), tumor factors such as pathologic disease stage (T and N categories), TNM stage, location and grade, clinical disease stage (lymphovascular invasion, nerve invasion, LNM, metastasis in LN station), and clinical treatment method (radical resection).
At the discretion of individual surgeons and based on patient characteristics, 797 patients underwent right transthoracic esophagectomies with two-or three-field LN dissection.Overall, 579 patients underwent the Mckeown method, 218 patients underwent the Ivor-Lewis method, and 669 patients underwent intraoperative thoracic duct ligation.The clinical staging of each patient was discussed by experts before treatment and surgery.After surgery, the surgeon separated the specimens to obtain the LNs, which were named according to the guidelines.The final pathologic results were interpreted by two pathologists and re-signed by another pathologist.The disease stage was classified according to the UICC/AJCC eighth-edition TNM staging system.
Regarding adjuvant treatment, 127 (15.7 %) patients received postoperative adjuvant chemoradiotherapy (CRT), 308 (38.0 %) patients received postoperative adjuvant chemotherapy (CT), and 17 (2.1 %) patients received postoperative radiotherapy (RT).Hereafter, we refer to this collectively as surgery plus postoperative CT or RT/CRT.The specific types of drugs and their doses were determined based on individual patient characteristics and discussed by experts before treatment.Details of the clinical treatment methods are shown in Table S1.
Patients were followed up once every 3 months for the first 2 years, then once every 6 months thereafter for 3 to 5 years.Overall survival (OS) was defined from the month and year of surgery to death or last follow-up visit in April 2022.
All procedures performed in this study were in accordance with the Declaration of Helsinki as revised in 2013.Due to the retrospective nature of the study, the Ethics Committee waived consent from patients.

Criterion of Adverse Events and Characteristic
The patients were divided into two groups: group 1 (patients with 1 metastatic LN according to pathologic results) and group 2 (patients with 2 metastatic LNs).The patients in group 2 were further divided into two subgroups: group 2.1 (patients with metastasis in 1 LN station) and group 2.2 (patients with metastasis in 2 LN stations).

Statistical Analysis
Categorical variables are presented as percentages.Results were calculated using the chi-square test or Fisher's exact test.The OS rate was calculated based on the time from the month and year of surgery to the date of death or last follow-up evaluation.Hazard ratios (HRs) and 95 % confidence intervals (CIs) were calculated.Independent OS risk factors were identified using univariate Cox regression analyses.Cox proportional hazards regression models were used to assess the impact of all baseline covariates on outcomes.Kaplan-Meier curves were created using Graph-Pad Prism 9 (GraphPad Software, San Diego, CA, USA) to evaluate the observation system.Log-rank tests were used to describe the median at specific time points in 95 % CI.
Furthermore, two comparable groups of patients (groups 1 and 2; groups 1 and 2.1; or groups 1 and 2.2) were created using propensity score-matching (PSM) and adjusting unbalanced covariates.For PSM, the caliper was set to a width of 0.02, and the 1:1 closest-match method was used.The PSM procedure analyzed all the variables in the baseline profile (sex, age, pathologic differentiation grade, lymphovascular invasion, nerve invasion, tumor location, pathologic T category, eighth-edition TNM stage, thoracic surgery, abdominal surgery, and clinical treatment method).
A P value lower than 0.05 was considered statistically significant.Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) software version 23.0 (SPSS, Chicago, IL, USA).
In terms of age, 765 (94.8 %) of the patients were younger than 75 years, and 42 (5.2%) were 75 years of age or older.Furthermore, 662 (82.0 %) of the patients were males, and 145 (18.0 %) were females.Stage III or IV disease was recorded for 754 (93.4 %) of the patients (Table 1).Statistical differences were observed between groups 1 and 2 in terms of lymphovascular invasion (P = 0.028) and eight TNM stages (P = 0.02).After PSM, the two groups were comparable.

DISCUSSION
Medical records in the SCCH-ECCM database of the patients who underwent esophagectomy for ESCC were retrospectively analyzed.Based on the grouping of the patients and the pathologic status, our results indicated that the patients with one metastatic LN had significantly longer OS than those with two sites (P = 0.0001).However, the OS for the patients with one metastatic LN station was not significantly longer than for the patients with two metastatic LNs in one metastatic LN station (P = 0.5736).Moreover, the patients with one metastatic LN had a significantly longer OS than the patients with two metastatic LNs in two LN stations (P < 0.0001).These findings remained after PSM, showing no significant difference in the OS between the patients in groups 1 and 2 (P = 0.0027) and no significant difference between the patients in groups 1 and 2.1 (P = 0.2258).However, a significant difference was observed in the OS between the patients in groups 1 and 2.2 (P = 0.0037).In addition, the number of metastatic LNs and the stations of metastatic LNs exhibited significant effects (P = 0.003 vs. P < 0.001) after multivariate analyses.We believe that metastasis in LN stations is one of the crucial predictors affecting OS after esophagectomy.Thus, we can infer that for patients with pN1 ESCC, the number of metastatic LN stations can lower the OS compared with metastatic LNs.
The current standard treatment method for ESCC includes primarily comprehensive treatment through surgery. 7,9,16,21atients may receive chemotherapy, chemoradiotherapy, or immunotherapy combined with chemoradiotherapy before esophagectomy. 7,16,22,23After esophagectomy, additional immunotherapy is considered. 2425,26 Considering the pattern of metastasis in ESCC, LN stations have certain clinical value and are gaining increased importance. 8,27he TNM staging criteria of the JES system are being progressively developed and enhanced, and the transition from the 11th to the 12th Japanese Classification of Esophageal Cancer highlights the shift from the location-based classification to the number-based classification akin to UICC/AJCC TNM staging. 9However, TNM staging using the AJCC/UICC system emphasizes the number of resected metastatic LNs and LN stations. 21The data in this study focused not only on the LNM number but also on the LNM stations.It was based on the pN1 status identified using FIG. 3  Several studies have confirmed that different LN stations have distinct clinical values. 8,27,28Ma et al. 28 showed that the resection of subcarinal and left tracheobronchial LNs has a high clinical value. 28,29Furthermore, subcarinal LNM has been shown to decrease the OS of patients.According to the JES system, subcarinal LNM was classified as the pN2 category for upper, middle, and lower thoracic ESCC. 9Another example is the left tracheobronchial LN station.Although LN resection of this station can improve OS, because of the high difficulty level associated with the procedure and the potential risk of serious complications, even life-threatening effects resulting from improper management, the necessity of lymphadenectomy in all stations is debatable. 29Thus, the factors of LNs that affect OS are complex and multi-sourced.Nevertheless, relevant studies and our research currently confirm that systematic LN dissection is necessary to accurately diagnose the pathological stage of LNs and improve the prognosis of survival in patients.
Our study had limitations.First, although numerous studies on the pattern of LN metastasis have been conducted, the precise pattern of LN metastasis remains uncertain.The importance of each LN station in OS still is controversial and heterogeneous.Second, although the size of the samples from high-volume thoracic surgery centers was relatively large, this was a single-center retrospective analysis.Third, due to heterogeneity, after PSM, the sample size for statistical analysis decreased by hundreds of cases.Future studies using data from multicenter prospective clinical trials are warranted for further assessment of the LN stations, clinical value, and TNM staging.

CONCLUSIONS
The OS for the patients with one LNM was not significantly longer than for the patients with two LNs in one metastatic LN station.Moreover, patients with one metastatic LN station had a significantly longer OS than those with two LN stations.Thus, the number of metastatic LN stations is a significant determinant of OS for patients with pN1category ESCC.

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