Methods
Patients
All patients in this study completed a full course of follow-up visits in 2016 and were recruited for this second round of additional study. The inclusion criteria were described as follows: (1) patients underwent radical (R0) esophagectomy with two-field lymphadenectomy in our hospital between January 2008 and December 2012; (2) patients had a pathological diagnosis of ESCC; (3) patients were staged as pT
1–3N
0M
0; (4) patients were not managed with either neoadjuvant or adjuvant therapy; (5) patients were not found to have a history of other malignancies; (6) the postoperative survival time was at least 3 months to minimize the impact of surgical complications on survival; and (7) patients had participated and were followed-up in our previous study [
6]. The exclusion criteria were: (1) patients had non-ESCC at their pathological diagnosis; (2) patients underwent either R
1 or R
2 resection or three-field lymphadenectomy; (3) patients were pathologically staged as either pT
4, pN
+ or M
1; (4) patients were managed with either pre- and/or post-operative adjuvant therapy; and (5) post-operative survival time was less than 3 months.
The study design and related ethical issues were approved by the Medical Ethics Committee of our hospital, and written informed consent was obtained from all patients enrolled in this study. Furthermore, the medical records of all patients were reviewed and information pertinent to the study was extracted from the records, including patient demographics, perioperative work-ups, detailed intraoperative information, and information related to postoperative management as well as long-term follow-ups.
Surgery
The left thoracic approach (Sweet procedure) was routinely chosen to gain access to the primary tumors located in the middle/lower thoracic segment of the esophagus. The right thoracic approach (Ivor Lewis procedure) was used to access the primary tumors located in the upper thoracic segment of the esophagus. Radical surgical resection consisted of transthoracic subtotal esophagectomy with abdominal and mediastinal lymphadenectomy. A gastric tube placed through the posterior mediastinal route was used as a substitute for the resected esophagus to restore the continuity of the alimentary tract. Two-field LN dissection included total mediastinal, perigastric, and celiac lymphadenectomy.
Follow-up
The first postoperative follow-up visits were scheduled for 1 month after the surgery. Thereafter, patients were sequentially followed every 3 months for the first 2 years, every 6 months for the next 3 years, and then every 12 months. The deadline for all follow-ups was December 1st, 2019. During the follow-up visits, patients were re-examined with chest computed tomography (CT) scans, and abdominal and cervical ultrasounds or CTs. When necessary, endoscopy, radionuclide bone imaging, or positron emission tomography (PET)/CT scans were also offered to the patients.
Statistical analysis
In this study, overall survival (OS) was defined as the period from the date of surgery to the date of death or last follow-up. Disease-free survival (DFS) was defined as the time from the date of surgery to the date of the first evidence of recurrence or death of any cause. Recurrence-free survival (RFS) was defined as the period from the date of surgery to the date of the first evidence of tumor recurrence. Locoregional recurrence-free survival (LRFS) was defined as the period from the date of surgery to the date of the first evidence of locoregional recurrence (LRR) of the malignancy. LRR was defined as neoplastic recurrence at the original cancer site or stoma area, or appearance of metastatic lymph nodes in the supraclavicular, mediastinum, or epigastrium regions. Relapses at other sites were defined as distant metastases (DM).
The survival rate was calculated using the Kaplan-Meier method, and comparisons between groups were performed with the log-rank test. A two-tailed p value < 0.05 was considered statistically significant. Multivariate Cox regression analyses were performed to identify prognostic factors for survival. All statistical analyses were conducted using SPSS 22.0 software (IBM Corp, Armonk, NY, USA).
Discussion
The optimal surgical technique for the curative treatment of patients with pN0 esophageal cancer has remained controversial. Currently, the procedures of choice include R0 esophagectomy with two-field lymphadenectomy based on evidence of early submucosal infiltration and early-stage lymphatic dissemination of the cancer, both of which pose challenges for the long-term outcomes of the surgery.
Two studies have already shown that the five-year OS rates were 51.2% for pT
1–3N
0M
0 [
3] and 52.9% for stage pN
0 [
4] ESCC patients who underwent two-field surgery without neoadjuvant or adjuvant chemoradiation therapies. Moreover, another study based on 2588 patients with pT
1–3N
0M
0 EC [
18] further reported that the postoperative five- and 10-year OS rates were 67.1 and 57.6%, respectively, and the cause-specific survival (CSS) rates were 80.8 and 77.7%, respectively. In this retrospective study, 488 pT
1–3N
0M
0 ESCC patients underwent R0 esophagectomy with two-field lymphadenectomy in the absence of either preoperative neoadjuvant or postoperative adjuvant therapy. At 3, 5 and 8 years following the surgery, the OS rates were 73.0, 62.1 and 56.5%, and the DFS rates were 63.7, 53.1 and 46.3%, respectively.
Taken together, even with the slight variation in five-year OS rates among the different studies, the OS remains at approximately 50% for radical esophagectomy coupled with two-field lymphadenectomy without significant improvement for different patient populations or different surgical teams. Chen et al. [
19] reported that three-field lymphadenectomy results in five and 10-year OS rates of 71.3 and 57%, respectively, for pT
1-4aN
0M
0 ESCC patients, which were significantly improved compared to the two-field procedure, indicating early lymphatic dissemination might not be confined to regional LN surrounding the lesion. However, Shao et al. [
20] showed that the OS was not different between two-field and three-field LN dissection for pN
0 ESCC patients. Taken together, the use of three-field LN dissection to potentially improve OS should be further investigated.
To better understand the risk factors associated with the OS of ESCC patients after two-field lymphadenectomy, survival analyses with univariate as well as multivariate Cox regression models were used in the current study. The results indicated that pT
1–3N
0M
0 ESCC patients who presented with neoplasms in the upper-thoracic segment had the worst OS and DFS in comparison to patients with tumors in the middle or lower thoracic segments. Although this was similar to previous studies of EC patients who were mainly operated on through the left thoracic approach [
5,
21], it was also contrary to several studies that have demonstrated that the site of the lesion is not associated with prognosis for ESCC patients who are operated on using the right thoracic approach [
3,
4,
19,
22]. Therefore, additional studies are required to investigate and validate the true influence that the site of the lesion has on the OS of patients.
Prospectively, preoperative CT assessments may allow for the visualization of potential LN metastases, which can help to determine the surgical approach and procedure that will result in the best long-term prognosis for the patient. Because the surgical method used in this study was the Sweet procedure, this might have led to insufficient mediastinal LN dissection and subsequent potentiation of metastasis of SLNs. As such, the present study identified SLNs in CT prior to surgery as an independent risk factor associated with OS and DFS.
Several studies have suggested that OS was not significantly impacted in patients with middle or lower thoracic EC who underwent a Sweet or Ivor Lewis esophagectomy [
23‐
27], while the study from Ma Q et al. [
26] showed that the three- and five-year rates of CSS and OS were better for the pN
0 ESCC patients with left transthoracic approaches (eg. Sweet) compared to those with right transthoracic approaches (eg. Ivor Lewis), indicating that the location of cancer impacts the long-term survival of patients.
The pT stage was another important independent factor for OS and DFS in our study as well as other studies. The studies by either Xie et al. [
22] and Gao et al. [
18] reported that the five-year OS rates were 75.1 and 77.8% for pT
1, 50.4 and 54.2% for pT
2, and 37.0 and 34% for pT
3 ESCC patients with pN
0 after two-field surgery, respectively. Chen et al. [
19] reported that the five- and 10-year OS rates were 83.8 and 71.9% for pT
1N
0M
0, 78.8 and 67.4% for pT
2N
0M
0, 67.8 and 51.1% for pT
3N
0M
0 ESCC patients after three-field surgery, respectively. Our results also showed that the pT stage was associated with RFS and LRFS, suggesting that early diagnosis and surgical interventions are important for the long-term prognosis of EC patients.
Two-field lymphadenectomy was chosen as the routine procedure for the surgical management of ESCC, and numerous studies have already shown that the number of dissected LNs can influence the long-term mortality of ECSS patients. Xie et al. [
22] reported that the five-year OS rates for dissected LN numbers of 0–14, 15–19, 20–24, and ≥ 25 in pT
1–3N
0M
0 ESCC patients were 28.5, 47.7, 56.4 and 60.4% after surgery, respectively. Yang et al. had demonstrated the five-year OS rates for pN
0 ESCC patients with dissected LN numbers of < 6, 6–9, 10–17, and ≥ 18 were 40.8, 50.6, 55.9 and 71.4%, respectively [
28]. However, Altorki et al. reported that only over 40 LNs dissected could produce significantly better OS rates, compared with less than 16 LNs dissected [
13]. A single study [
29] has aggressively claimed that the number of dissected LNs is not associated with the OS of pN
0 EC patients. Our study found that the five-year OS rates for patients with dissected LNs < 12 and ≥ 12 were 58.5 and 70.2%, respectively. While these data are similar to some of the previous studies, it also suggests that the optimal number of dissected LNs to improve long-term outcomes should be further investigated.
In our study, patient age was associated with OS but not with DFS for pT
1–3N
0M
0 ESCC patients. Chen et al. [
19] also showed that the five-year OS rate for pN
0 ESCC patients was 76.5% for those younger than 60 years of age and 63.3% for those 60 years of age or older. Other studies [
4,
25,
29] have also shown age as an independent factor for OS in ESCC patients.
Recently, nomogram and RPA scores have been used to predict the survival of ESCC patients following surgery and to stratify postoperative patients into varying risk groups. Many studies from various clinic groups have reported their methods to establish nomograms to classify the risk level of the ESCC patient. Zheng et al. [
15] selected five independent predictors of OS (gender, age, dissected LNs, pT, and pN status) to evaluate clinical nomograms in ESCC patients after surgery. Yu et al. [
16] used the LN metastatic ratio and adjuvant therapy to construct their nomogram and RPA to classify patients with IIB-III ESCC. Ni et al. [
17] attempted to include patient age, pTMN stage, and management modalities to classify ESCC. Duan et al. [
30] used five independent prognostic variables to build the nomograms to predict DFS and OS of ESCC patients undergoing postoperative chemo and radiation therapy. This prognostic nomogram provided an individualized risk estimate of survival in patients after esophagectomy followed by postoperative chemoradiation therapy. Deng et al. [
24] used eight independent risk factors to build the nomogram to predict the OS of patients with pT
1N
+/T
2-4aN
0–3, M
0 ESCC after surgery. The prognostic efficacy of the nomogram in the training and validation cohorts was significantly greater than that of the American Joint Committee on Cancer (AJCC) staging system.
We classified pT
1–3N
0M
0 ESCC patients into three classes (low, middle, and high risk) according to the RPA scores; the OS, DFS, RFS and LRFS were significantly different among the three classes. For the low-risk group, the five-year OS was > 90% and the recurrence rate was very low. Therefore, postoperative adjuvant therapy is not needed. For the middle-risk group, the five-year OS was approximately 65% and postoperative adjuvant therapy should be considered. For the high-risk group, the five-year OS was approximately 50% and postoperative adjuvant therapy should be strongly recommended. Several studies have shown the value of postoperative adjuvant therapy in pN
0 EC patients [
18,
19,
31,
32]; however, the adverse effects related to postoperative adjuvant therapy are a considerable hurdle for patients to undertake therapy. Therefore, it may be more reasonable to select postoperative adjuvant therapy based on the likelihood of postoperative survival and/or recurrence in ESCC patients.
Several pitfalls can be found in our study. Firstly, this retrospective case-matched study was conducted with patients from a single-center. Therefore, the possibility of selection bias could not be entirely excluded despite the use of the multivariate analysis. Secondly, most of the patients in our study underwent the left thoracic approach for R0 esophagectomy and two-field lymphadenectomy with a median number of 10 dissected LNs. As such, the data and subsequent conclusions might only be suitable for similar patients. Thirdly, the details of recurrence and salvage therapy were not shown in this study. Salvage therapy might impact the OS of our patients.
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