Esophageal squamous cell carcinoma (ESCC) is the most common pathological type of esophageal cancer in China. Patients with ESCC have poor long-term survival, especially those with lymphatic metastasis (pN + ESCC). In this retrospective study, we evaluated the correlates of long-term survival time of patients with pN + ESCC. A total of 453 patients with pN + ESCC who underwent surgical R0 resection between Jan 2008 and Sep 2011 were enrolled. The follow-up ended on December 2019. The clinical, pathological, inflammation-related factors and general survival data of these patients were analyzed using SPSS 22.0 software. The 1-, 3-, and 5-year overall survival (OS) rates were 73.7%, 34.6%, and 25.6%, respectively; the 1-, 3-, and 5-year disease-free survival (DFS) rates were 45.0%, 26.3%, and 20.4%, respectively. The median OS and DFS were 23 and 14 months, respectively. On multivariate analyses, gender, site of lesion, number of dissected lymph nodes, stage pTNM, adjuvant therapy, and neutrophil lymphocyte ratio were independent predictors of OS. Site of lesion, stage pTNM, and adjuvant therapy were independent predictors of DFS. Recursive partitioning analysis (RPA) scores of each patient were calculated based on the independent predictors of OS, and the patients were divided into 3 classes: low-risk, medium-risk, and high-risk. The OS, DFS, and local recurrence-free survival were significantly different among these three RPA classes
Esophageal cancer (EC) is the fifth most commonly occurring cancer and the fourth leading cause of cancer-related deaths in China [
A large number of patients experience recurrence after surgery, especially those with pathologic positive lymph node metastasis (pN+) [
The inclusion criteria were (1) patients who had undergone radical esophagectomy with two- or three-field lymphadenectomy between January 2009 and December 2011, (2) esophageal squamous cell carcinoma, (3) pN+ and pT2-4 (pT1N+ was eliminated due to less number of cases) and without distant metastasis, (4) no history of other tumors, (5) Karnofsky performance status ≥70, and (6) survival time at least one month after surgery. The study was approved by the Medical Ethics Committee of The Fourth Hospital of Hebei Medical University. Written informed consent was obtained from all subjects.
In China, the type of R0 resection surgery depends on the tumor location. Left thoracic approach (Sweet surgery) is usually performed in patients with tumor located in the middle and lower esophagus. Right thoracic approach (Ivor-Lewis surgery) is performed in patients with tumor located in the upper esophagus. Radical surgical resection consists of transthoracic subtotal esophagectomy with abdominal and mediastinal lymphadenectomy (two-field) with or without supraclavicular lymphadenectomy (three-field surgery). A gastric tube through the posterior mediastinal route is used as a substitute for the resected esophagus to restore the continuity of the alimentary tract. Pathology and staging were performed according to the AJCC/UICC 7th TNM cancer staging criteria.
Cisplatin combination chemotherapy was used, with either fluorouracil or paclitaxel/docetaxel; the median number of treatment cycles was 3 (range, 1–8). Radiotherapy (three-dimension conformal radiotherapy or intensity modulated radiotherapy) was initiated 4–8 weeks after surgery. The clinical target volume (CTV) was designed as follows: the upper mediastinum, supraclavicular, and lower neck area for upper thoracic ESCC; whole mediastinum with/without supraclavicular area for middle thoracic ESCC; and middle and lower mediastinum and gastric left lymphatic drainage area for lower ESCC. Since the NCCN guidelines do not contain any recommendations for postoperative radiotherapy, the total dosage of radiotherapy was 50–54 Gy administered in 25–28 fractions (1.8–2.0 Gy/fraction, 5 fractions per week) for CTV. Owing to poor tolerance of patients to concomitant postoperative chemoradiotherapy (POCRT), sequential radiotherapy and chemotherapy were administered in this study population. One hundred thirty-one patients were not administered any adjuvant treatment owing to patient’s refusal, intolerance, financial constraints, or other reasons.
All blood samples were collected within one week before surgery; in case of multiple routine blood examinations in the same patient, the last sample obtained before surgery was used in the subsequent analyses. The NLR was calculated by dividing the number of absolute neutrophil count (×109/L) by the number of absolute lymphocyte count (×109/L). The LMR was calculated by dividing the absolute lymphocyte count (×109/L) by the absolute monocyte count (×109/L). The cutoff level for NLR was 3.5 according to the published data [
Follow-up ended on 1, December 2019. The follow-up schedule was every three months for two years, every six months for the next three years, and annually thereafter. Contrast-enhanced computed tomography (CT) of the neck, thorax, and upper abdomen, and routine blood and biochemistry investigations were performed at each follow-up visit. Ultrasonography of neck and upper abdomen, nuclear bone scanning, gastric endoscopy, positron emission tomography, or cytologic puncture was performed, if needed.
The long-term outcomes were determined from medical records and follow-up information. Overall survival (OS) was defined as the time from operation to death (or the last follow-up visit). Disease-free survival (DFS) was defined as the time from operation to first disease failure, including locoregional recurrence (LR), distant metastasis, and combined recurrence or death from any cause. Locoregional recurrence-free survival (LRFS) rate was measured from the date of surgery to the date of first evidence of local or regional recurrence. LR included recurrence in the primary esophageal tumor bed, anastomotic sites, and regional lymph nodes (LNs) including supraclavicular, mediastinal, and celiac axis LNs. Recurrence beyond those sites was considered distant metastasis (DM). Recurrences or metastases were documented from clinical investigation reports including CT, esophagoscopy plus biopsy, or positron emission tomography (PET)/CT.
All statistical analyses were conducted using SPSS 22.0 software (IBM Corp, Armonk, NY, USA). OS and DFS were calculated via Kaplan–Meier analysis, and between-group differences assessed using the log-rank test. Multivariate analyses were performed using a Cox proportional hazard regression model.
A total of 453 patients were enrolled in this study. The clinical characteristics of the study population are summarized in Table
Clinical characteristics.
Factors | No. |
---|---|
Male | 338 |
Female | 115 |
60 (37–83) | |
Upper | 40 |
Middle | 312 |
Lower | 101 |
6 (1–16) | |
10 (1–34) | |
2.77 (0.76–50.67) | |
3.50 (0.50–22.36) | |
Two-field | 430 |
Three-field | 23 |
Factors | No. |
pT2 | 57 |
pT3 | 367 |
pT4 | 29 |
pN1 | 294 |
pN2 | 131 |
pN3 | 28 |
IIb | 42 |
IIIa | 250 |
IIIb | 108 |
IIIc | 53 |
Well-middle | 331 |
Poor | 122 |
No | 131 |
POCT | 222 |
PORT | 57 |
POCRT | 43 |
At the end of the follow-up, 363 patients had died, including 310 deaths due to the relapse of tumor and 53 deaths due to non-neoplastic causes. The 1-, 3-, 5-, 8-year OS and median survival time were 73.7%, 34.6%, 25.6%, 18.9%, and 23 months (20.8–25.2), respectively (Figure
The curves of overall survival (OS) and disease-free survival (DFS) for all patients.
Results of univariate analysis showing factors associated with survival of patients with pN + ESCC.
Factors | N. | OS | DFS | LRFS | ||||||
---|---|---|---|---|---|---|---|---|---|---|
3-year | 5-year | 3-year | 5-year | 3-year | 5-year | |||||
Gender | ||||||||||
Male | 338 | 34.0 | 23.9 | 0.040 | 25.2 | 18.8 | 0.115 | 40.1 | 34.0 | 0.199 |
Female | 115 | 36.5 | 30.3 | 29.6 | 25.1 | 48.1 | 44.7 | |||
≤60 years | 247 | 37.6 | 28.0 | 0.084 | 26.0 | 21.9 | 0.349 | 40.0 | 35.9 | 0.510 |
>60 years | 206 | 31.1 | 22.7 | 26.7 | 18.8 | 54.2 | 38.2 | |||
Upper | 40 | 47.5 | 30.0 | 0.047 | 38.6 | 25.8 | 0.011 | 48.9 | 45.6 | 0.070 |
Middle | 312 | 30.0 | 22.3 | 22.4 | 17.3 | 39.8 | 33.1 | |||
Lower | 101 | 42.5 | 34.2 | 33.6 | 28.1 | 47.1 | 44.0 | |||
<6 cm | 219 | 37.0 | 26.5 | 0.415 | 28.3 | 22.6 | 0.140 | 42.1 | 35.7 | 0.965 |
≥6 cm | 234 | 32.4 | 24.7 | 24.5 | 18.4 | 42.4 | 38.4 | |||
<12 | 264 | 31.8 | 23.6 | 0.045 | 23.9 | 18.8 | 0.169 | 41.8 | 37.5 | 0.656 |
≥12 | 189 | 38.6 | 28.2 | 29.8 | 22.7 | 42.5 | 35.7 | |||
Two-field | 430 | 33.5 | 24.4 | 0.071 | 25.3 | 19.3 | 0.202 | 41.8 | 38.9 | 0.322 |
Three-field | 23 | 56.5 | 47.8 | 45.9 | 41.3 | 50.5 | 50.5 | |||
Well-middle | 331 | 34.4 | 25.0 | 0.603 | 25.2 | 19.4 | 0.196 | 42.6 | 37.8 | 0.935 |
Poor | 122 | 35.2 | 27.3 | 29.5 | 23.1 | 41.4 | 34.8 | |||
pT2 | 57 | 45.6 | 34.4 | 0.007 | 31.6 | 24.9 | 0.003 | 38.6 | 35.4 | 0.121 |
pT3 | 367 | 34.6 | 25.3 | 27.1 | 20.8 | 44.9 | 38.8 | |||
pT4 | 29 | 13.8 | 13.8 | 6.9 | 6.9 | 16.3 | 16.3 | |||
pN1 | 294 | 42.2 | 32.4 | <0.001 | 32.4 | 25.1 | <0.001 | 47.6 | 40.6 | <0.001 |
pN2 | 131 | 23.7 | 15.1 | 17.6 | 13.6 | 34.0 | 32.3 | |||
pN3 | 28 | 7.1 | 3.6 | 3.6 | 3.6 | 10.3 | 10.3 | |||
IIb | 42 | 50.0 | 42.7 | <0.001 | 35.7 | 29.2 | <0.001 | 38.3 | 34.8 | <0.001 |
IIIa | 250 | 41.2 | 30.2 | 32.5 | 24.4 | 51.1 | 43.0 | |||
IIIb | 108 | 25.0 | 17.6 | 18.5 | 14.8 | 35.5 | 33.6 | |||
IIIc | 53 | 11.3 | 9.1 | 5.7 | 5.7 | 13.2 | 13.2 | |||
No | 131 | 20.6 | 15.2 | <0.001 | 15.4 | 13.1 | <0.001 | 31.4 | 28.4 | <0.001 |
POCT | 222 | 36.5 | 28.0 | 27.5 | 20.8 | 39.6 | 33.5 | |||
PORT | 57 | 43.9 | 27.4 | 29.8 | 24.2 | 53.1 | 53.1 | |||
POCRT | 43 | 55.7 | 42.8 | 48.8 | 35.5 | 69.2 | 57.0 | |||
<3.5 | 314 | 38.5 | 28.7 | 0.002 | 27.8 | 22.2 | 0.070 | 42.3 | 37.5 | 0.473 |
≥3.5 | 139 | 259 | 18.5 | 23.0 | 16.5 | 42.0 | 35.3 | |||
≤3.5 | 233 | 30.4 | 21.9 | 0.033 | 22.9 | 18.3 | 0.043 | 40.4 | 34.9 | 0.154 |
>3.5 | 220 | 39.1 | 29.5 | 30.0 | 22.6 | 44.1 | 38.9 |
LN: lymph node; POCRT: postoperative chemoradiotherapy; POCT: postoperative chemotherapy; PORT: postoperative radiotherapy; NLR: neutrophil lymphocyte ratio; LMR: lymphocyte monocyte rate.
On multivariate analyses, gender, site of lesion, dissected LN, pTNM, adjuvant therapy, and NLR were independent predictors of OS (Table
Results of multivariate analysis showing factors associated with OS of patients with pN + ESCC.
Factors | Hr (95% CI) | |
---|---|---|
Male | 1.346 (1.053–1.722) | 0.018 |
Female | 1 | |
Upper | 1.056 (0.688–1.621) | 0.804 |
Middle | 1.350 (1.037–1.758) | 0.026 |
Lower | 1 | |
<12 | 1.258 (1.010–1.567) | 0.041 |
≥12 | 1 | |
IIb | 1 | |
IIIa | 1.328 (0.883–1.996) | 0.173 |
IIIb | 2.055 (1.329–3.179) | 0.001 |
IIIc | 2.766 (1.719–4.450) | <0.001 |
No | 1 | |
POCT | 0.603 (0.471–0.773) | <0.001 |
PORT | 0.539 (0.379–0.765) | 0.001 |
POCRT | 0.400 (0.264–0.606) | <0.001 |
<3.5 | 0.737 (0.590–0.920) | 0.007 |
≥3.5 | 1 |
The 1-, 3-, 5-, 8-year DFS and median survival time were 54.0%, 26.3%, 20.4%, 16.6%, and 14 months, respectively (Figure
Factors associated with DFS and LRFS on multivariate COX analysis.
Factors | ||||
---|---|---|---|---|
HR (95% CI) | HR (95% CI) | |||
Upper | 1.045 (0.685–1.596) | 0.838 | 1.074 (0.628–1.836) | 0.795 |
Middle | 1.373 (1.062–1.776) | 0.016 | 1.406 (1.020–1.938) | 0.038 |
Lower | 1 | 1 | ||
IIb | 1 | 1 | ||
IIIa | 1.311 (0.884–1.944) | 0.178 | 0.876 (0.571–1.343) | 0.543 |
IIIb | 1.873 (1.224–2.866) | 0.004 | 1.300 (0.814–2.078) | 0.272 |
IIIc | 2.600 (1.637–4.129) | <0.001 | 1.870 (1.115–3.135) | 0.018 |
No | 1 | 1 | ||
POCT | 0.656 (0.517–0.833) | <0.001 | 0.840 (0.627–1.126) | 0.244 |
PORT | 0.604 (0.426–0.857) | 0.005 | 0.490 (0.301–0.797) | 0.004 |
POCRT | 0.388 (0.258–0.583) | <0.001 | 0.333 (0.190–0.584) | <0.001 |
At the end of the follow-up, 245 (54.1%) patients developed LR. The 1-, 3-, 5-, 8-year LRFS, and median LRSF time were 67.7%, 49.0%, 42.2%, 36.9%, and 24 (18.7–29.3) months, respectively. On univariate analyses, pN, pTNM, and adjuvant therapy showed a significant association with LRFS
In a recent study, a recursive partitioning analysis (RPA) model was used to predict the OS of patients with ESCC [
According to our RPA score system, the patients were allocated into six groups. The number of patients with RPA scores of 0, 1, 2, 3, 4, 5, and 6 was 1, 44, 106, 168, 95, 29, and 10, respectively. We stratified the patients into 3 classes based on the RPA scores: class 1 (low-risk group: RPA score = 0–2, 151 cases); class 2 (medium-risk group: RPA score = 3, 168 cases); class 3 (high-risk group: RPA score = 4–6, 134 cases). The OS, DFS, and LRFS were significantly different among the three classes (see Figure
The curves of overall survival (OS), disease-free survival (DFS), and locoregional-free survival with different recursive partitioning analysis (RPA) scores (class 1 : 0–2, class 2 : 3, class 3 : 4–6).
In this study, the 3-year and 5-year OS rates of patients with pN + ESCC were 34.6% and 25.6%, respectively. The 3-year and 5-year DFS rates were 26.3% and 20.4%, respectively. The median OS time was 23 months, while the median DFS time was 14 months. Lu et al. reported 22% 5-year OS rate of patients with pN + EC [
In our study, postoperative chemotherapy (POCT), PORT, and POCRT were found to significantly improve the OS and DFS in comparison with surgery alone (SA) for pN + ESCC patients after R0 resection, which has been summarized in our previous report [
UICC stage was another independent prognostic factor for OS and DFS in our study. In several studies, clinical stage was an independent prognostic factor for OS and DFS in patients with II-III ESCC [
In our study, primary tumor location was an independent predictor of OS and DFS. The OS and DFS were significantly lower in middle-segment than in lower-segment EC. Yu et al. [
The number of dissected LNs was an independent predictor of OS and DFS in this study. The OS and DFS were significantly decreased in patients with <12 dissected LNs. In a study by Dutkowski et al., the maximum increase in the sensitivity of pN classification was observed when the number of examined lymph nodes increased from 0 to 6 [
In this study, female patients showed significantly higher OS than male patients; gender was an independent factor for OS, but not for DFS. Several other studies [
Tumor recurrence was the most frequent reason of failure for ESCC patients after surgery. In our study, adjuvant therapy was associated with LRFS. PORT and POCRT significantly increased the LRFS; however, POCT was not associated with prolonged LRFS in comparison with SA. In the study by Ni et al. [
In our study, we used the cutoff value of NLR based on the published data. Preoperative NLR was an independent predictor of OS, but not of DFS or LRFS. In the study by Feng et al. [
In our study, LMR was associated with OS and DFS in univariate analysis; however, LMR was not an independent predictor of OS or DFS. In the study by Gao et al. [
Recently, nomogram and recursive partitioning analysis (RPA) scores have been used to predict the postoperative survival of patients with ESCC. Zheng et al. [
Some limitations of our study should be considered while interpreting the results. First, this was a retrospective single-center study. Therefore, the possibility of selection bias cannot be excluded despite the use of multivariate analysis. Second, the left thoracic approach was used for most of the patients in our study; therefore, the impact of different surgical approaches was not considered in the analysis. The number of dissected LNs was found to influence OS and DFS in our study; this was partly associated with the surgical approach. Third, the target dosages of PORT and the scheme and cycles of POCT were slightly different and were not analyzed in detail. However, our results demonstrated the survival benefit of postoperative adjuvant therapy in these patients; we intend to evaluate this issue in detail in our future study. Finally, our PRA scores were summarized from the training cohorts but not verified in the validation cohorts; this will be performed in our future study.
In our study, several factors were found to influence the postoperative OS, DFS, and LRFS of patients with pN + ESCC who underwent radical resection; stratification of all patients into three classes based on RPA scores significantly predicted the risk of survival, including OS, DFS, and LRFS.
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
The authors gratefully acknowledge the financial supports from Hebei Clinical Research Center for Radiation Oncology and Oncology Department of Hebei Medical University.