Long-term survival of esophageal squamous cell carcinoma after surgical treatment in a large-scale retrospective study from a single cancer center

To analyze the long-term overall survival (OS) and influencing factors of patients with esophageal squamous cell cancer (ESCC) under surgical treatment. We collected patients with ESCC who received surgical treatment in Sichuan Cancer Hospital & institute from January 2010 to December 2017, and selected 2,766 patients with thoracic esophageal carcinoma with relatively complete follow-up results as the objects of this study. We analyzed the characteristics, postoperative complications and long-term OS results of those patients. Of the 2766 patients, 81.6% were male, midthoracic esophageal cancer accounted for 53.5%. McKeown was used in 72.0% of patients and Ivor-Lewis was used in 26.4% of patients. About 47.8% of patients received minimally invasive esophagectomy (MIE). The overall complication rate was 25.8%. The 1-year, 3-year and 5-year OS rates were 86.2%, 57.5% and 46.8%, respectively. McKeown had a better long-term OS rate than Ivor-Lewis (49.5% vs 41.2%, P < 0.001), and MIE is superior to open surgery (51.8% vs 42.5%, P < 0.001). McKeown has advantages over Ivor-Lewis. MIE results in better long-term survival outcomes for patients. But more prospective randomized controlled trials with large samples are needed.


Introduction
Esophageal cancer is one of the most common digestive tract tumors.According to GLOBOCAN 2020, the incidence rate of esophageal cancer ranks tenth in the world, and the mortality rate ranks seventh [1].In China, as of 2015, there were 61,732 newly diagnosed cases of esophageal cancer (44,067 in males and 17,667 in females), with a crude incidence of 19.24/10 5 , 6.69% of new cancer cases and 47,373 deaths (34,262 in males and 13,111 in females).The crude mortality rate was 14.76/10 5 , accounting for 8.39% of the total cancer deaths [2].The histological subtypes of esophageal cancer are mainly squamous cell carcinoma and adenocarcinoma.In China, esophageal squamous cell carcinoma (ESCC) is the majority, accounting for about 90% of the incidence of esophageal cancer.The 5-year survival rate of esophageal cancer in China is 20.9% [3,4].In recent years, the multidisciplinary treatment of esophageal cancer has developed rapidly.For resectable ESCC, surgical treatment is still the core.Tumor stage, surgical method, number of lymph nodes dissection and postoperative complications are all factors affecting the long-term survival of postoperative patients.However, at present, there are very few related studies about minimally invasive esophagectomy (MIE) and open surgery, and most of them are retrospective studies with small sample, especially in China.Sichuan Province has a large population and several areas with high incidence of esophageal cancer.In 2015, the incidence rate of esophageal cancer in Sichuan Province was 29.29/10 5 and the mortality rate was 22.20/10 5 , much higher than the average level in China [5].Sichuan Cancer Hospital & Institute carried out MIE earlier in China.Therefore, we analyzed the survival status and operative approaches of patients with ESCC in Sichuan Cancer Hospital & Institute from January 2010 to December 2017, hoping to supplement relevant data on surgical treatment of esophageal cancer in China.

Patients
In this study, Sichuan Cancer Hospital & Institute Esophageal Cancer Case Management Database (SCCH-ECCM Database) was queried, and 3014 patients with esophageal cancer who received surgical treatment in Sichuan Cancer Hospital from 2010.01 to 2017.10 were collected.Among them, 117 patients with non-squamous cell carcinoma and 77 patients with primary multiple carcinomas were excluded.Besides, 35 cases of cervical esophageal cancer and 11 cases of esophageal cancer in the gastroesophageal junction area were excluded, and 2766 cases of thoracic esophageal cancer with complete long-term survival follow-up results were selected as the objects of this study.All patients' pathological stages were adjusted according to the 8th edition of the TNM classification of the AJCC/UICC.We reviewed follow-up data on patients, examining their characteristics, postoperative complications, and long-term overall survival outcomes.

Statistical analyses
SPSS 26.0(IBM, NY, America) was used for statistical processing of patient data, Kaplan-Meier method was used for survival analysis, and Log-rank test was used for comparison between groups.The test level α was set at 0.05.A P value of less than 0.05 was considered statistically significant.

Postoperative complications
The overall incidence of postoperative complications was 25.8%, of which pulmonary infection was the most common (8.6%), anastomotic leakage was 7.5%, pleural effusion needing treatment was 2.5%, and incision infection was 2.2% (Table 3).

Discussion
Through the data analysis of 2766 patients with thoracic ESCC, the 5-year OS was 46.8%, higher than the average level.Sichuan Cancer Hospital & Institute, the largest tertiary cancer hospital in southwest China, started total MIE as early as April 2010.From 2010 to 2017, surgery is   still the main treatment for ESCC in China, and the proportion of neoadjuvant therapy is low.The results of this study represent the current status of surgical treatment for esophageal cancer in that period to a certain extent.
The results of survival analysis indicated that women had better long-term survival outcomes than men in patients with ESCC (62.0%vs 43.3%, P < 0.001).Similar results can be found in most cancer-related studies.Haupt et al. also demonstrated a higher incidence and mortality in males compared with females in non-reproductive system tumors, this may be related to the fidelity of the genetic code [6].
In China, the choice of esophageal cancer surgery has long been controversial, especially between Sweet and Ivor-Lewis.To date, few studies have investigated the overall survival outcome of esophagectomy in China, and most of them are retrospective low volum studies.Sweet procedure is generally considered to be easier to perform with shorter operation time and better tolerance from patients.Ivor-Lewis can offer better visualization of the thoracic esophagus, and has advantages in lymph node dissection, but it will cause more postoperative complications [7,8].But a randomized clinical trial demonstrated that, patients in the Ivor-Lewis group experienced a lower incidence of in-hospital morbidity and shorter hospital stay compared with those in the Sweet group [8].Therefore, we need more prospective clinical trials.Our study, a retrospective study with large sample sizes shows that McKeown is by far the most commonly performed esophagectomy and in terms of long-term survival, there was an advantage over Ivor-Lewis (49.5% vs. 41.2%,P < 0.001).In this period, the proportion of neoadjuvant therapy and comprehensive treatment is low, and surgery is still the main treatment, so the number of lymph node dissection is closely related to the survival and prognosis of patients.In this study, (22.4 ± 12.3) lymph nodes had advantage in our patients (52.1% VS 51.1%, P = 0.94), which may be due to the small number of minimally invasive Ivor-Lewis cases in our patients (82 cases).In addition, previous relevant studies have shown that the prognosis of patients with minimally invasive Ivor-Lewis is even better than that of minimally invasive McKeown, because the former has shorter operation time and hospital stay and a lower incidence of postoperative complications [9][10][11][12].But there are still doctors preferring the minimally invasive McKeown because they believe that a neck anastomotic leakage is easier to cure than a chest anastomotic leakage [13].
MIE has become the mainstay treatment for esophageal cancer, and MIE showed an advantage over open surgery in our study (51.8% vs. 42.5%,P < 0.001).A multicenter randomized controlled trial in Japan showed that MIE surgery had advantages in terms of intraoperative blood loss, length of stay, and complication rate.This conclusion was also confirmed in our patients, who had a significantly lower incidence of postoperative complications with MIE(22.7 vs 28.7, P < 0.001).Japanese surgeons even argued that MIE's greatest advantage was not its low invasiveness, but its more thorough and meticulouslymphadenectomy lymphadenectomy.However, none of these studies showed significant benefits of MIE in long-term survival [14][15][16].The JCOG1409 currently being carried out in Japan is a multi-center clinical study on open surgery versus MIE.This study is still in progress, while there is no similar prospective clinical study in China.Therefore, it remains to be concluded whether minimally invasive surgery or open surgery can bring  better long-term benefits to patients with ESCC.Therefore, the results of this study have significant instruction for clinical practice.There are still many shortcomings in this study, including: 1.The database is retrospective.From 2010 to 2017, the economy of Sichuan region was still underdeveloped, and the process of follow-up and data input were still flawed.A large number of esophagectomies were performed each year, but there were only 2766 patients with complete follow-up data, so that the data related to DFS, clinical stage and recurrence and metastasis are lacking.

Fig. 1 Fig. 2
Fig. 1 Kaplan-Meier curve of overall survival for patients

Fig. 5
Fig. 5 Kaplan-Meier curves of overall survival stratified by surgical method

2 .
The proportion of neoadjuvant therapy is too low.Chinese Society of Clinical Oncology (CSCO) and Chinese Anti-cancer Association (CACA) published their esophageal cancer diagnosis and treatment guidelines in 2019 and 2022, respectively, and the first prospective multicenter clinical trial of neoadjuvant chemoradiotherapy in China was only published in 2018, these factors account for the low percentage of patients who received neoadjuvant therapy in our data.In summary, based on this large-sample single-center retrospective study, it is well confirmed that MIE can bring more radical lymph node dissection and better long-term survival compared with open surgery in the real world.McKeown also shows its advantage in OS.The results have important significance for the selection of ESCC esophagectomy, and also add clinical evidence to the data of ESCC surgery in China.With the continuous development of minimally invasive techniques and treatment concepts, we believe, minimally invasive McKeown and robot-assisted minimally invasive McKeown can bring more surgical benefits to patients.

Table 1
Baseline characteristics of patients

Table 2
Surgical procedure and outcomes

Table 3
postoperative complications