ABSTRACT
Background
The effect of lymph node (LN) dissection on the overall survival of patients with esophageal squamous cell carcinoma (ESCC) treated by neoadjuvant chemoradiation therapy (nCRT) followed by esophagectomy has been controversial. This study investigated the patterns of metastatic LNs after nCRT and the benefits of LN dissection using the efficacy index (EI).
Methods
The EI was calculated by multiplying the frequency (%) of metastases to a zone and the 5‐year overall survival rate (%) of patients with metastases to that zone and then dividing by 100. EIs were compared according to the primary lesion location, response to nCRT, and preoperative radiation coverage.
Results
Among 573 patients, the mean age was 62.66 ± 8.10 years, and 533 (93.02%) were male. The mean number of dissected LNs was 37.62 ± 14.76. In all patients, bilateral recurrent laryngeal LNs and paracardial and left gastric LNs showed high EIs compared with other LN stations, and these patterns were maintained regardless of the primary lesion location. The EIs of bilateral recurrent laryngeal LNs and paracardial and left gastric LNs were still high in complete pathologic responders (ypT0) to nCRT and regardless of preoperative radiation coverage.
Conclusion
In ESCC treated with nCRT followed by esophagectomy, the EI of LNs varied between stations. High EIs of bilateral recurrent laryngeal LNs and paracardial and left gastric LNs after nCRT revealed the importance of adequate and complete dissection of these LN stations regardless of the pathologic response to nCRT and the radiation coverage.
Keywords: efficacy index, esophageal squamous cell carcinoma, lymph node dissection, neoadjuvant chemoradiation therapy
This study showed that the EIs of bilateral recurrent laryngeal LNs and paracardial and left gastric LNs were high after nCRT followed by surgery. The response to nCRT and radiation field did not alter the EI patterns, high EIs of bilateral recurrent laryngeal LNs and paracardial and left gastric LNs after nCRT revealed the importance of adequate and complete dissection of these LN stations regardless of the pathologic response to nCRT and the radiation coverage. It also indicated that the concept of “less‐extensive lymphadenectomy after nCRT” might not be valid.
1. Introduction
Esophageal cancer ranks as the seventh most common cancer and the sixth leading cause of cancer‐related deaths worldwide. It was responsible for 1 in every 18 cancer‐related deaths in 2020 [1, 2]. Patients with locally advanced esophageal cancer (≥ T2 or node‐positive disease) exhibit poor prognosis, with 5‐year survival rates ranging from 15% to 34% [3]. According to the National Comprehensive Cancer Network (NCCN) guidelines, the standard treatment for locally advanced esophageal cancer is multimodality therapy, including neoadjuvant chemoradiation therapy (nCRT) followed by surgery [4]. Although many studies have confirmed the importance of neoadjuvant therapy with preoperative tumor reduction and eradication of micrometastasis [5], esophagectomy and lymph node (LN) dissection remain the mainstay of treatment, and complete resection is one of the most important prognostic factors in surgically treated esophageal cancer.
The completeness of primary lesion resection can be evaluated by the resection margin (R0 or R1, R2 resection). However, controversies persist regarding the definition and criteria for assessing the quality and completeness of LN dissection in esophageal cancer surgery. Despite being a quality indicator for lymphadenectomy, the number of dissected LNs fails to account for the specific locations of the LN stations dissected. To address this limitation, Sasako et al. [6] proposed the efficacy index (EI), a hypothetical figure that represents the potential effect of dissecting a particular LN region on improving the 5‐year survival rate of an entire cohort. Thus, EI is considered a measure of the effectiveness of LN dissection at a specific station, and the LN station with high EI must be dissected. Several studies have reported the EI in esophageal squamous cell carcinoma (ESCC); however, these studies have analyzed patients who underwent esophagectomy regardless of preoperative therapy (upfront and neoadjuvant therapy altogether), and EI data after nCRT alone is lacking [7, 8, 9, 10]. Because preoperative radiation therapy may eradicate tumor cells in both the primary tumor and metastatic LNs, nCRT may significantly affect the EI. Thus, we hypothesized that the EI after nCRT might be different from the EI after upfront esophagectomy or neoadjuvant chemotherapy followed by esophagectomy and might provide insights into the extent of LN dissection after nCRT. Therefore, this study aimed to investigate the EI in ESCC treated by nCRT followed by esophagectomy.
2. Methods
2.1. Patients
The study included patients with intrathoracic ESCC who received nCRT, followed by esophagectomy between 1996 and 2019, and were identified using the Registry for Thoracic Cancer Surgery, which includes all patients who underwent thoracic surgery at the Samsung Medical Center, Korea, since 1994. The exclusion criteria were as follows: (1) salvage or palliative resection, (2) other types of preoperative therapy such as neoadjuvant chemotherapy, (3) incomplete (R1 or R2) resection, and (4) in‐hospital mortality. Finally, 573 patients were analyzed (Figure 1). The study was approved by the Institutional Review Board (2024‐02‐079), and the need for patient consent was waived because of the retrospective design.
FIGURE 1.
CONSORT diagram of patient selection.
Preoperative evaluation included contrasted chest computed tomography (CT), esophagogastroduodenoscopy, endoscopic ultrasonography, and whole‐body positron emission tomography‐CT (PET‐CT). Two nCRT regimens were used in various periods: Conventional 5‐fluorouracil plus cisplatin (FP) was mainly performed and hypofractionated FP from March 2017 to 2018. Conventional FP consisted of 5‐fluorouracil (5‐FU) 1000 mg/m2/day for 4 consecutive days plus cisplatin 60 mg/m2/day on Day 1 at 3‐week intervals with 44 Gy daily dose of 2 Gy per fraction (BED10 52.8 Gy). Hypofractionated FP consisted of 5‐FU 1000 mg/m2/day for 4 consecutive days plus cisplatin 60 mg/m2/day on Day 1 at 3‐week intervals with 43 Gy daily dose of 2.15 Gy per fraction (BED10 52.3 Gy). Involved‐field RT (IFRT) was used: The gross tumor volume (GTV) consisted of the primary tumor and the involved LNs. The clinical target volume (CTV) was defined as the GTV plus 2–3 cm margins in the longitudinal directions, 0.5–1 cm radially for the primary tumor, and 0.5–1 cm margin in all directions for LNs. The planning target volume was applied 0.5 cm from the CTV in all directions. Esophagectomy and reconstruction were performed 4–6 weeks after neoadjuvant therapy. Three‐field LN dissection was performed on patients with upper thoracic esophageal cancer. Neck dissection was also performed when preoperative CT, PET, or PET‐CT indicated cervical LN metastasis in mid‐ to lower thoracic esophageal cancer.
All patients were regularly followed up at 3–4‐month intervals for the first 2 years after surgery and then every 6 months thereafter. Among those who were lost to follow‐up, telephone interviews were conducted to determine the most recent postoperative outcomes. Chest and upper abdomen CTs were performed at every follow‐up appointment, and annual upper endoscopies were performed to rule out disease recurrence. Overall survival (OS) was calculated from the date of surgery to the end of follow‐up (date of death or last contact).
2.2. Definition of LN Stations
Regional LNs were defined based on the 11th Japanese Classification of Esophageal Cancer [11]. However, esophagectomy and lymphadenectomy were performed en bloc as an institutional policy; paracardial (1 and 2) and left gastric (7) LNs were dissected together along the stomach. In addition, all paraesophageal LNs were dissected with the esophagus attached, even though the Japanese classification divided them into upper (105), mid‐ (108) and lower paraesophageal (110) LNs. Therefore, paraesophageal (105‐108‐110) and paracardial and left gastric (1‐2‐7) LNs were analyzed as one LN station in this study.
2.3. Assessment of the Efficacy of Lymphadenectomy at Each Regional LN Station
The EI was based on the hypothesis that patients with positive nodes in one regional LN who survived 5 years after the resection of positive LNs would not have survived if these LNs were left in situ because dissection of these regional LNs was omitted [6]; therefore, the EI can show the benefit of dissection at a specific LN station. The metastatic rate of each LN station was defined as the frequency of pathologically diagnosed metastases among patients who underwent dissection at each LN station. To assess the efficacy of dissection at each LN station, the EI was calculated by multiplying the metastatic rate (%) at an LN station by the 5‐year OS (%) of the patients who had metastasis at the LN and then dividing by 100 [7, 8]. The 5‐year OS rate of the patients with positive LNs was calculated independently for each LN, irrespective of metastasis to other LNs. The EI was calculated according to the primary lesion location, response to nCRT, and preoperative radiation coverage (in‐field vs. out‐field). Complete pathologic response to nCRT was defined as ypT0 of the primary lesion.
2.4. Statistical Analysis
Continuous variables were described as means ± SDs, and categorical variables were described as frequencies with percentages. The median follow‐up time was estimated using the Kaplan–Meier method. The Cox proportional hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). The two‐proportion z‐test was applied to compare the differences between groups for the positive and 5‐year OS rates. All statistical tests were two‐sided, with the significance level set at 0.05, and were performed using STATA 16 (StataCorp LLC, College Station, TX), and R version 4.2.2 (R Project for Statistical Computing).
3. Results
3.1. Basic Characteristics of the Patients
The basic characteristics of the patients are summarized in Table 1. Of the 573 patients, 167 (29.2%), 234 (40.8%), and 172 (30.0%) had upper, middle, and lower ESCC, respectively. In addition, 279 (48.7%) patients showed complete response to nCRT (ypT0). The mean number of dissected LNs was 37.62 ± 14.76. The median follow‐up period was 56.13 ± 45.90 months.
TABLE 1.
Basic characteristics of the patients.
| Variables | Mean ± SD/frequency (%) |
|---|---|
| Age | 62.66 ± 8.10 |
| Male | 533 (93.02%) |
| Location of lesion | |
| Upper | 167 (29.2%) |
| Middle | 234 (40.8%) |
| Lower | 172 (30.0%) |
| ypT | |
| ypT0 | 279 (48.7%) |
| ypTis | 8 (1.4%) |
| ypT1 | 66 (11.5%) |
| ypT2 | 114 (20.0%) |
| ypT3 | 100 (17.4%) |
| ypT3 | 6 (1.0%) |
| ypN | |
| ypN0 | 310 (54.1%) |
| ypN1 | 178 (31.1%) |
| ypN2 | 65 (11.3%) |
| ypN3 | 20 (3.5%) |
| Mean numbers of dissected LNs | 37.62 ± 14.76 |
Abbreviations: LN, lymph node; SD, standard deviation.
3.2. Comparison of the EI According to the Primary Lesion Location
The EIs in all patients and according to the primary lesion location are summarized in Table 2. In all patients, 106recR and 106recL in the mediastinum showed high EI, and paracardial and left gastric LNs in the abdomen also demonstrated high EI. A high EI was observed in the cervical region; however, it must be interpreted cautiously because the number of patients who underwent neck dissection was relatively small, so the positive rate and EI could be overestimated.
TABLE 2.
Efficacy index in all patients and according to the location of the primary lesion.
| Lymph node station | Total 573 patients | Upper ESCC (n = 167) | Middle ESCC (n = 234) | Lower ESCC (n = 172) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dissected patients | Positive rate | 5‐year OS | EI | Dissected patients | Positive rate | 5‐year OS | EI | Dissected patients | Positive rate | 5‐year OS | EI | Dissected patients | Positive rate | 5‐year OS | EI | |
| 104R (+102R) | 193 | 13.47 | 40.26% | 5.42 | 108 | 12.96 | 54.78% | 7.10 | 65 | 10.77 | 42.86% | 4.62 | 20 | 25.00 | 0% | 0.00 |
| 104L (+102L) | 199 | 8.04 | 35.16% | 2.83 | 113 | 9.73 | 42.42% | 4.13 | 66 | 4.55 | 33.33% | 1.52 | 20 | 10.00 | 0% | 0.00 |
| 101R | 138 | 11.59 | 47.54% | 5.51 | 75 | 12.00 | 46.30% | 5.56 | 46 | 8.70 | 44.34% | 3.86 | 17 | 17.65 | 50.88% | 8.98 |
| 101L | 121 | 17.36 | 48.20% | 8.37 | 66 | 21.21 | 46.43% | 9.85 | 37 | 18.92 | 45.01% | 8.52 | 37 | 0.00 | 52.61% | 0.00 |
| Total cervical region | 258 | 29.46 | 32.25% | 9.50 | 148 | 27.70 | 37.97% | 10.52 | 87 | 29.89 | 30.77% | 9.20 | 23 | 39.13 | 11.11% | 4.35 |
| Paraesophageal | 427 | 6.79 | 41.18% | 2.80 | 111 | 7.21 | 48.84% | 3.52 | 180 | 7.78 | 35.29% | 2.74 | 136 | 5.15 | 36.00% | 1.85 |
| Subcarina (7) | 557 | 6.10 | 31.91% | 1.95 | 163 | 4.29 | 50.00% | 2.15 | 226 | 7.52 | 29.17% | 2.19 | 168 | 5.95 | 23.08% | 1.37 |
| 106recR | 496 | 13.91 | 23.00% | 3.20 | 144 | 18.75 | 25.93% | 4.86 | 198 | 14.14 | 28.13% | 3.98 | 154 | 9.09 | 7.14% | 0.65 |
| 106recL | 497 | 11.67 | 21% | 2.41 | 148 | 11.49 | 17.65% | 2.03 | 207 | 13.53 | 25.00% | 3.38 | 142 | 9.15 | 15.38% | 1.41 |
| 9R | 234 | 1.28 | 49.40% | 0.63 | 74 | 1.35 | 54.17% | 0.73 | 90 | 2.22 | 47.87% | 1.06 | 70 | 0.00 | 46.55% | 0.00 |
| 9L | 212 | 4.72 | 46.97% | 2.22 | 61 | 3.28 | 51.55% | 1.69 | 82 | 2.44 | 44.44% | 1.08 | 69 | 8.70 | 45.31% | 3.94 |
| 10R | 48 | 0.00 | 48.07% | 0.00 | 17 | 0.00 | 54.47% | 0.00 | 21 | 0.00 | 43.06% | 0.00 | 10 | 0.00 | 47.90% | 0.00 |
| 10L | 163 | 2.45 | 46.78% | 1.15 | 42 | 0.00 | 51.29% | 0.00 | 68 | 2.94 | 43.52% | 1.28 | 53 | 3.77 | 46.07% | 1.74 |
| Total mediastinal | 572 | 26.40 | 26.38% | 6.96 | 167 | 26.35 | 29.55% | 7.79 | 234 | 29.06 | 29.27% | 8.51 | 171 | 22.81 | 17.95% | 4.09 |
| Paracardial + left gastric | 527 | 24.86 | 35.30% | 8.77 | 152 | 14.47 | 34.64% | 5.01 | 220 | 25.91 | 38.47% | 9.97 | 155 | 33.55 | 32.55% | 10.92 |
| Common hepatic | 495 | 2.02 | 29.75% | 0.60 | 149 | 1.34 | 45.59% | 0.61 | 195 | 2.56 | 43.48% | 1.11 | 151 | 1.99 | 43.75% | 0.87 |
| Celiac | 379 | 4.75 | 34.55% | 1.64 | 108 | 2.78 | 40.00% | 1.11 | 161 | 4.35 | 36.10% | 1.57 | 110 | 7.27 | 48.65% | 3.54 |
| Total abdominal region | 564 | 25.71 | 34.47% | 8.86 | 165 | 15.15 | 33.94% | 5.14 | 230 | 26.52 | 36.35% | 9.64 | 169 | 34.91 | 33.67% | 11.75 |
Abbreviations: EI, efficacy index; ESCC, esophageal squamous cell carcinoma; OS, overall survival.
In upper and middle ESCC, bilateral recurrent laryngeal LNs (106recR and 106recL) in the mediastinum and the paracardial and left gastric LNs in the abdomen showed high EIs. The EIs of paracardial and left gastric LNs increased when the primary lesion is located in the lower esophagus. In lower ESCC, the EIs for 104R and 104L were 0% because the 5‐year OS rate in patients with metastasis at 104R and 104L was 0%.
3.3. Comparison of the EI According to the Response to nCRT
The EIs according to the response to nCRT are summarized in Table 3. In 279 patients with ypT0, 106recR and 106recL showed high EI (3.83 and 2.45, respectively). The EIs of 106recR and 106recL were still high in the ypT+ group (2.63 and 2.35, respectively). The positive rates of each LN station were high in the ypT+ group, whereas the 5‐year OS was higher in the ypT0 group.
TABLE 3.
Efficacy index according to the response to neoadjuvant chemoradiation therapy.
| Lymph node station | ypT0 patients (n = 279) | ypT+ patients (n = 294) | p | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dissected group | Positive group | Positive rate | 5‐year OS | EI | Dissected group | Positive group | Positive rate | 5‐year OS | EI | Positive rate | 5‐year OS | |
| 104R (+102R) | 91 | 11 | 12.09% | 45.45% | 5.49 | 102 | 15 | 14.71% | 37.28% | 5.48 | 0.595 | 0.680 |
| 104L (+102L) | 90 | 3 | 3.33% | 33.30% | 1.11 | 109 | 13 | 11.93% | 35.90% | 4.28 | 0.026 | 0.932 |
| 101R | 71 | 4 | 5.63% | 62.85% | 3.54 | 67 | 12 | 17.91% | 34.43% | 6.17 | 0.024 | < 0.001 |
| 101L | 58 | 4 | 6.90% | 63.71% | 4.39 | 63 | 17 | 26.98% | 35.34% | 9.54 | 0.004 | < 0.001 |
| Total cervical region | 119 | 21 | 17.65% | 57.14% | 10.08 | 139 | 55 | 39.57% | 22.67% | 8.97 | < 0.001 | 0.005 |
| Paraesophageal | 207 | 5 | 2.42% | 69.05% | 1.67 | 220 | 24 | 10.91% | 21.67% | 2.36 | < 0.001 | < 0.001 |
| Subcarina (7) | 272 | 7 | 2.57% | 66.67% | 1.72 | 285 | 27 | 9.47% | 20.00% | 1.89 | 0.001 | 0.002 |
| 106recR | 235 | 20 | 8.51% | 45.00% | 3.83 | 261 | 49 | 18.77% | 13.99% | 2.63 | 0.001 | 0.011 |
| 106recL | 242 | 14 | 5.79% | 42.31% | 2.45 | 255 | 44 | 17.25% | 13.64% | 2.35 | < 0.001 | 0.045 |
| 9R | 108 | 1 | 0.93% | 69.44% | 0.64 | 126 | 2 | 1.59% | 29.57% | 0.47 | 0.654 | < 0.001 |
| 9L | 102 | 4 | 3.92% | 68.14% | 2.67 | 110 | 6 | 5.45% | 28.29% | 1.54 | 0.599 | < 0.001 |
| 10R | 22 | 0 | 0.00% | 65.05% | 0.00 | 26 | 0 | 0.00% | 32.76% | 0.00 | < 0.001 | |
| 10L | 77 | 0 | 0.00% | 63.64% | 0.00 | 86 | 4 | 4.65% | 30.96% | 1.44 | 0.055 | < 0.001 |
| Total mediastinal | 279 | 44 | 15.77% | 52.22% | 8.24 | 293 | 107 | 36.52% | 15.78% | 5.76 | < 0.001 | < 0.001 |
| Paracardial + left gastric | 255 | 50 | 19.61% | 62.56% | 12.27 | 272 | 81 | 29.78% | 18.35% | 5.46 | 0.007 | < 0.001 |
| Common hepatic | 240 | 2 | 0.83% | 68.18% | 0.57 | 255 | 8 | 3.14% | 22.17% | 0.70 | 0.069 | < 0.001 |
| Celiac | 188 | 0 | 0.00% | 62.15% | 0.00 | 191 | 0 | 0.00% | 28.25% | 0.00 | < 0.001 | |
| Total abdominal region | 273 | 56 | 20.51% | 58.55% | 12.01 | 291 | 89 | 30.58% | 20.43% | 6.25 | 0.006 | < 0.001 |
Abbreviations: EI, efficacy index; OS, overall survival.
3.4. Comparison of the EI According to the Radiation Field
The EIs according to the preoperative radiation coverage were also investigated (Table 4). In addition, 214 (37.3%), 394 (68.7%), and 189 (33.0%) patients received radiation therapy at the neck, upper mediastinum, and abdominal region, respectively. In the neck region, the EIs of patients who received radiation therapy (in‐field) showed high EI in bilateral 101 and 104. Patients with metastasis at bilateral 104 without preoperative radiation showed a 5‐year OS rate of 0%; therefore, EIs were also 0. In the upper mediastinal and abdominal regions, the EIs of bilateral 106rec and paracardial and left gastric LNs were high regardless of the radiation coverage.
TABLE 4.
Efficacy index according to the radiation field.
| Lymph node station | In‐field | Out‐field | p | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dissected group | Positive group | Positive rate | 5‐year OS | EI | Dissected group | Positive group | Positive rate | 5‐year OS | EI | Positive rate | 5‐year OS | |
| Neck region | ||||||||||||
| 104R (+102R) | 124 | 22 | 17.74% | 47.91% | 8.50 | 55 | 2 | 3.64% | 0.00% | 0.00 | 0.011 | |
| 104L (+102L) | 126 | 12 | 9.52% | 38.89% | 3.70 | 57 | 1 | 1.75% | 0.00% | 0.00 | 0.058 | |
| 101R | 87 | 8 | 9.20% | 46.45% | 4.27 | 38 | 4 | 10.53% | 50.54% | 5.32 | 0.816 | 0.497 |
| 101L | 70 | 12 | 17.14% | 47.06% | 8.07 | 39 | 4 | 10.26% | 51.15% | 5.25 | 0.330 | 0.500 |
| Upper mediastinum | ||||||||||||
| 106recR | 178 | 32 | 17.98% | 26.63% | 4.79 | 280 | 32 | 11.43% | 16.67% | 1.91 | 0.049 | 0.422 |
| 106recL | 186 | 22 | 11.83% | 20.00% | 2.37 | 268 | 29 | 10.82% | 36.36% | 3.93 | 0.738 | 0.301 |
| Abdominal region | ||||||||||||
| Paracardial + left gastric | 197 | 42 | 21.32% | 41.96% | 8.95 | 283 | 73 | 25.80% | 34.46% | 8.89 | 0.258 | 0.359 |
Abbreviations: EI, efficacy index; OS, overall survival.
3.5. Risk Factors for the OS
Multivariable analysis was performed to find the risk factors for OS (Table 5). In all patients and subset analysis of the primary lesion location, pathologic states such as ypT and ypN were associated with OS, whereas metastasis to a specific region was not related to OS.
TABLE 5.
Multivariable analysis for overall survival in all patients and according to the primary lesion location.
| All patients | Upper‐ESCC group | Mid‐ESCC group | Lower‐ESCC group | |||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | p | HR (95% CI) | p | HR (95% CI) | p | HR (95% CI) | p | |
| Age | 1.011 (0.997–1.025) | 0.136 | 1.002 (0.974–1.030) | 0.915 | 1.021 (0.998–1.045) | 0.079 | 1.009 (0.981–1.037) | 0.547 |
| Sex (male vs. female) | 1.403 (0.851–2.312) | 0.184 | 1.964 (0.696–5.542) | 0.202 | 1.700 (0.717–4.029) | 0.228 | 0.872 (0.389–1.953) | 0.739 |
| ypT (vs. ypT0) | ||||||||
| ypTis | 2.886 (1.335–6.238) | 0.007 | 8.117 (1.898–34.711) | 0.005 | 4.433 (1.342–14.640) | 0.015 | 1.358 (0.311–5.924) | 0.684 |
| ypT1 | 1.583 (1.116–2.246) | 0.010 | 1.830 (0.995–3.369) | 0.052 | 1.589 (0.935–2.699) | 0.087 | 1.064 (0.481–2.351) | 0.879 |
| ypT2 | 1.526 (1.141–2.041) | 0.004 | 1.531 (0.867–2.704) | 0.142 | 1.071 (0.672–1.707) | 0.772 | 2.318 (1.353–3.970) | 0.002 |
| ypT3 | 2.063 (1.526–2.788) | < 0.001 | 2.036 (1.177–3.522) | 0.011 | 1.874 (1.147–3.061) | 0.012 | 2.199 (1.207–4.006) | 0.010 |
| ypT4 | 6.337 (2.752–14.592) | < 0.001 | 8.849 (1.828–42.844) | 0.007 | 14.059 (1.681–117.568) | 0.015 | 5.907 (1.723–20.246) | 0.005 |
| ypN (vs. ypN0) | ||||||||
| ypN1 | 1.401 (0.885–2.218) | 0.150 | 1.006 (0.417–2.429) | 0.989 | 1.162 (0.585–2.308) | 0.669 | 1.955 (0.769–4.973) | 0.159 |
| ypN2 | 2.542 (1.251–5.168) | 0.010 | 0.906 (0.224–3.664) | 0.890 | 2.311 (0.791–6.753) | 0.126 | 7.256 (1.807–29.126) | 0.005 |
| ypN3 | 2.505 (1.119–5.606) | 0.025 | 0.889 (0.198–3.988) | 0.878 | 3.217 (0.866–11.949) | 0.081 | 5.658 (1.171–27.336) | 0.031 |
| Metastasis to cervical region | 0.802 (0.540–1.192) | 0.275 | 1.050 (0.527–2.092) | 0.889 | 0.942 (0.521–1.702) | 0.843 | 0.878 (0.316–2.441) | 0.803 |
| Metastasis to mediastinal region | 1.331 (0.888–1.995) | 0.166 | 1.952 (0.865–4.405) | 0.107 | 1.333 (0.734–2.422) | 0.345 | 1.255 (0.534–2.949) | 0.603 |
| Metastasis to abdominal region | 1.046 (0.712–1.537) | 0.819 | 1.362 (0.622–2.983) | 0.440 | 1.054 (0.578–1.922) | 0.864 | 0.854 (0.389–1.877) | 0.695 |
Abbreviations: CI, confidence interval; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio.
4. Discussion
This study showed that the EIs of bilateral recurrent laryngeal nerve LNs and paracardial and left gastric LNs were still high after nCRT followed by surgery. The response to nCRT and radiation therapy coverage appeared not to alter the EI patterns. In addition, the metastasis to specific regions was not related to poor survival after adjusting for the ypT and ypN.
The optimum extent of lymphadenectomy for esophageal cancer has been debated, and no consensus has been established on the definition of optimal lymphadenectomy in esophagectomy. The current NCCN guideline suggests that a minimum of 15 LNs must be dissected during esophagectomy for accurate staging and optimal survival [4]. Several studies have reported that the number of dissected LNs is related to survival after neoadjuvant therapy followed by esophagectomy [12]. Although many studies have reported the number of dissected LNs as a quality parameter for LN dissection [13], this number cannot reflect the location of the dissected LN station. If LN dissection focuses exclusively on regions where metastasis is less common, neglecting the sites where it frequently occurs, the total number of LNs removed may still meet the criteria that are based on the number of LNs.
Because the number of dissected LNs could not be a sufficient indicator for optimal lymphadenectomy, the EI has been applied in gastric and esophageal cancer. As mentioned in the methods section, therefore, the EI can show the benefit of dissection at a specific LN station, under the hypothesis that patients with positive nodes in one regional LN who survived 5 years after the resection of positive LNs would not have survived if these LNs were left in situ because dissection of these regional LNs was omitted [6]. A handful of studies have reported the EI in ESCC and the higher EI in bilateral recurrent laryngeal LNs (106recR and 106recL) and paracardial LNs (1 and 2) than in other LN stations [7, 8, 9, 10]. Because the EI can be altered by dissection patterns, treatment modalities, the definition of LN station, and patients' characteristics [8], the direct comparison of the absolute EI within the published studies may be inappropriate, so it must be interpreted within each study. However, previous studies have reported similar patterns that bilateral recurrent laryngeal nerve LNs and paracardial LNs showed high EI, and these results have been used as evidence to support the importance of complete dissection of these LN stations.
Theoretically, the EI can be changed according to the preoperative therapy. Neoadjuvant therapy has been reported to not only decrease the frequency of LN metastases but also change the distribution of LN metastases [14, 15, 16], and these effects could change the EI compared with the EI of patients who received upfront surgery. However, previous studies have analyzed upfront esophagectomy and neoadjuvant therapy followed by esophagectomy [7, 8, 9, 10]; therefore, these studies could not verify the potential changes of the EI according to the effect of preoperative therapy. The relationship between preoperative therapy and the EI could be an important issue because it is related to the extent of lymphadenectomy. Some investigators have proposed that the extent of lymphadenectomy can be minimized after neoadjuvant therapy for esophageal cancer [14, 17, 18]. Talsma et al. [14] reported that the number of resected LNs correlated with survival after surgery alone but not after nCRT and concluded that the benefit of maximal LN dissection after preoperative CRT is questionable by analyzing the results of the CROSS study. Conversely, other studies have emphasized the clinical importance of extensive lymphadenectomy on patient survival even after neoadjuvant therapy [19, 20, 21, 22]. Therefore, understanding EI changes according to neoadjuvant therapy is important to address controversies on whether less‐extensive lymphadenectomy can be appropriate after neoadjuvant therapy.
Miyata et al. [23] examined the EI of LN dissection for each LN station in patients with ESCC who received neoadjuvant chemotherapy. Even after neoadjuvant chemotherapy, bilateral recurrent laryngeal LNs and paracardial LNs still showed high EI, irrespective of the tumor location, similar to patients without neoadjuvant therapy. In addition, the EI for each LN station did not vary according to the response to neoadjuvant therapy. They concluded that the EI of each LN was not affected by neoadjuvant chemotherapy; therefore, complete LN dissection is important after neoadjuvant chemotherapy. In addition, they suggested that the EI patterns after nCRT might be different to the neoadjuvant chemotherapy or upfront esophagectomy because nCRT shows better locoregional controls than neoadjuvant chemotherapy in general [23]. In this study that analyzed patients who received nCRT only, bilateral recurrent laryngeal nerve nodes (106recR and 106recL) and paracardial LNs (1 and 2) still showed high EI, and the EI was not changed according to the pathologic response or radiation coverage. This finding showed that even after nCRT, the EI patterns are similar to upfront surgery or neoadjuvant chemotherapy followed by surgery, and the concept of “less‐extensive lymphadenectomy after nCRT” is not still valid.
Interestingly, in this study, we calculated the EI according to the coverage of preoperative radiation therapy. When evaluating the locoregional control of nCRT, considering the field of radiation is critical. Radiation may include elective LN irradiation (ENI) depending on the location of the primary tumor or may be guided by delineating appropriate margins from the primary tumor and involved LNs, a practice referred to as IFRT, by the references and policies of the radiation oncologist. Hanami et al. analyzed 184 patients with ESCC who were treated with nCRT followed by surgery, and ENI was used [24]. In this analysis, although approximately 50% of patients who were clinically diagnosed with LN metastasis before treatment were downstaged by nCRT, LN metastases were extensive in cervical, mediastinal, and abdominal areas, even within the radiation field. They concluded that systematic and adequate lymphadenectomy is essential after nCRT with ENI and esophagectomy, but they did not calculate EI. In our institution, we applied IFRT, and extensive lymphadenectomy was performed as an institutional policy. Our results showed that the EI patterns were not different according to the preoperative radiation coverage. In upper esophageal cancer, although the upper mediastinum was routinely covered by preoperative radiation therapy, the EIs of 106recR and 106recL were still high. These findings showed that even in the LN station that received preoperative radiation with IFRT, extensive and adequate lymphadenectomy is mandatory.
The definition of the N factor in ESCC, between the number of LN metastases and the location of metastatic LNs, is still controversial. If the survival rate varies depending on the presence of metastases at specific regions or in specific LN stations, even if these are defined as the same regional LNs, these LNs could be defined as a high N stage or distant metastasis (M1) rather than regional LNs. Regarding this problem, Kanemura et al. [9] analyzed both the EI and recurrence patterns of each LN station and suggested that the LN station with low EI and high recurrence rate must be classified as M1 instead of regional LNs. Miyata et al. [25] reported that metastasis to a specific LN station such as the middle mediastinal region and celiac LNs is related to the OS in patients with neoadjuvant chemotherapy followed by surgery, whereas our results showed that metastasis to specific regions was not related to survival. The definition of the N stage and regional LNs must be studied with large data in the future.
This study had some limitations. First, not all LN stations were dissected in all patients. Specifically, because neck dissection was performed in cases in which clinically metastatic LNs are suspicious, the positivity rate can be overestimated; therefore, the EI of the neck nodes can also be overestimated. Second, the definition of the LN station in this study is slightly different from the Japanese classification [11], particularly regarding paraesophageal and left gastric, and paracardial LNs. Third, the response to nCRT was classified only by the pathologic response in the primary tumors; accurate assessment of the response in metastatic LNs appears challenging. Finally, changes in EIs after nCRT must be compared with EIs after upfront surgery; however, it is not possible because neoadjuvant therapy followed by surgery is the standard therapy in locally advanced ESCC. Despite these limitations, this is the first study that analyzed patients who received nCRT followed by esophagectomy only and compared the EIs according to the response to nCRT and radiation field.
In conclusion, this study showed that the EIs of bilateral recurrent laryngeal LNs and paracardial and left gastric LNs were high after nCRT followed by surgery. The response to nCRT and radiation field did not alter the EI patterns, high EIs of bilateral recurrent laryngeal LNs and paracardial and left gastric LNs after nCRT revealed the importance of adequate and complete dissection of these LN stations regardless of the pathologic response to nCRT and the radiation coverage. It also indicated that the concept of “less‐extensive lymphadenectomy after nCRT” might not be valid.
Author Contributions
Seong Yong Park: concept and design. Boram Park, Seong Yong Park, Dongryul Oh: acquisition, analysis, or interpretation of data. Jiyoun Park, Seong Yong Park, Boram Park, Dongryul Oh: drafting of the manuscript. Jiyoun Park, Boram Park, Seong Yong Park, Dongryul Oh, Yeong Jeong Jeon, Junghee Lee, Jong Ho Cho, Hong Kwan Kim, Yong Soo Choi, Jae Il Zo, Young Mog Shim: critical revision of the manuscript for important intellectual content. Boram Park: statistical analysis. Seong Yong Park, Hong Kwan Kim: obtained funding. Seong Yong Park: administrative, technical, or material support.
Conflicts of Interest
The authors declare no conflicts of interest.
Funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (No. 2022R1A2C209310611) and by a grant of the Korean Cancer Survivors Healthcare R&D Project through the National Cancer Center, funded by the Ministry of Health & Welfare, Republic of Korea (RS‐2023‐CC139856).
Jiyoun Park and Boram Park contributed equally as co‐first authors.
Seong Yong Park and Dongryul Oh contributed equally as co‐corresponding authors.
Contributor Information
Seong Yong Park, Email: syparkcs@gmail.com.
Dongryul Oh, Email: dongryul.oh@samsung.com.
Data Availability Statement
The data used in this study are available upon reasonable request from the corresponding author. However, access to the data is subject to the completion of the data transfer agreement process required by the affiliated institution.
References
- 1. Kim H. W. and Park S. Y., “Current Trends in the Epidemiology and Treatment of Esophageal Cancer in South Korea,” Journal of Chest Surgery 58, no. 1 (2025): 15–20, 10.5090/jcs.24.078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Sung H., Ferlay J., Siegel R. L., et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 71, no. 3 (2021): 209–249, 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
- 3. Enzinger P. C. and Mayer R. J., “Esophageal Cancer,” New England Journal of Medicine 349, no. 23 (2003): 2241–2252, 10.1056/NEJMra035010. [DOI] [PubMed] [Google Scholar]
- 4. Strong V. E., D'Amico T. A., Kleinberg L., and Ajani J., “Impact of the 7th Edition AJCC Staging Classification on the NCCN Clinical Practice Guidelines in Oncology for Gastric and Esophageal Cancers,” Journal of the National Comprehensive Cancer Network 11, no. 1 (2013): 60–66, 10.6004/jnccn.2013.0009. [DOI] [PubMed] [Google Scholar]
- 5. Li J. and Ma S., “History and Current Situation of Neoadjuvant Treatment for Locally Advanced Esophageal Cancer,” Thorac Cancer 12, no. 17 (2021): 2293–2299, 10.1111/1759-7714.14069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Sasako M., McCulloch P., Kinoshita T., and Maruyama K., “New Method to Evaluate the Therapeutic Value of Lymph Node Dissection for Gastric Cancer,” British Journal of Surgery 82, no. 3 (1995): 346–351, 10.1002/bjs.1800820321. [DOI] [PubMed] [Google Scholar]
- 7. Tachimori Y., Ozawa S., Numasaki H., et al., “Efficacy of Lymph Node Dissection by Node Zones According to Tumor Location for Esophageal Squamous Cell Carcinoma,” Esophagus 13 (2016): 1–7, 10.1007/s10388-015-0515-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Udagawa H., Ueno M., Shinohara H., et al., “The Importance of Grouping of Lymph Node Stations and Rationale of Three‐Field Lymphoadenectomy for Thoracic Esophageal Cancer,” Journal of Surgical Oncology 106, no. 6 (2012): 742–747, 10.1002/jso.23122. [DOI] [PubMed] [Google Scholar]
- 9. Kanemura T., Miyata H., Takeoka T., et al., “Significance of Dissection in Each Regional Lymph‐Node Station of Esophageal Cancer Based on Efficacy Index and Recurrence Patterns After Curative Esophagectomy,” Esophagus 20, no. 3 (2023): 402–409, 10.1007/s10388-022-00977-8. [DOI] [PubMed] [Google Scholar]
- 10. Li K., Nie X., Li C., et al., “Mapping of Lymph Node Metastasis and Efficacy Index in Thoracic Esophageal Squamous Cell Carcinoma: A Large‐Scale Retrospective Analysis,” Annals of Surgical Oncology 30, no. 9 (2023): 5856–5865, 10.1245/s10434-023-13655-5. [DOI] [PubMed] [Google Scholar]
- 11. Japan Esophageal Society , “Japanese Classification of Esophageal Cancer, 11th Edition: Part I,” Esophagus 14, no. 1 (2017): 1–36, 10.1007/s10388-016-0551-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Chen D., Mao Y., Xue Y., Sang Y., Liu D., and Chen Y., “Does the Lymph Node Yield Affect Survival in Patients With Esophageal Cancer Receiving Neoadjuvant Therapy Plus Esophagectomy? A Systematic Review and Updated Meta‐Analysis,” EClinicalMedicine 25 (2020): 100431, 10.1016/j.eclinm.2020.100431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Groth S. S., Virnig B. A., Whitson B. A., et al., “Determination of the Minimum Number of Lymph Nodes to Examine to Maximize Survival in Patients With Esophageal Carcinoma: Data From the Surveillance Epidemiology and End Results Database,” Journal of Thoracic and Cardiovascular Surgery 139, no. 3 (2010): 612–620, 10.1016/j.jtcvs.2009.07.017. [DOI] [PubMed] [Google Scholar]
- 14. Koen Talsma A., Shapiro J., Looman C. W., et al., “Lymph Node Retrieval During Esophagectomy With and Without Neoadjuvant Chemoradiotherapy: Prognostic and Therapeutic Impact on Survival,” Annals of Surgery 260, no. 5 (2014): 786–792, 10.1097/SLA.0000000000000965. [DOI] [PubMed] [Google Scholar]
- 15. Robb W. B., Dahan L., Mornex F., et al., “Impact of Neoadjuvant Chemoradiation on Lymph Node Status in Esophageal Cancer: Post Hoc Analysis of a Randomized Controlled Trial,” Annals of Surgery 261, no. 5 (2015): 902–908, 10.1097/SLA.0000000000000991. [DOI] [PubMed] [Google Scholar]
- 16. Castoro C., Scarpa M., Cagol M., et al., “Nodal Metastasis From Locally Advanced Esophageal Cancer: How Neoadjuvant Therapy Modifies Their Frequency and Distribution,” Annals of Surgical Oncology 18, no. 13 (2011): 3743–3754, 10.1245/s10434-011-1753-9. [DOI] [PubMed] [Google Scholar]
- 17. Vallbohmer D., Holscher A. H., DeMeester S., et al., “A Multicenter Study of Survival After Neoadjuvant Radiotherapy/Chemotherapy and Esophagectomy for ypT0N0M0R0 Esophageal Cancer,” Annals of Surgery 252, no. 5 (2010): 744–749, 10.1097/SLA.0b013e3181fb8dde. [DOI] [PubMed] [Google Scholar]
- 18. Shridhar R., Hoffe S. E., Almhanna K., et al., “Lymph Node Harvest in Esophageal Cancer After Neoadjuvant Chemoradiotherapy,” Annals of Surgical Oncology 20, no. 9 (2013): 3038–3043, 10.1245/s10434-013-2988-4. [DOI] [PubMed] [Google Scholar]
- 19. Mariette C., Piessen G., Briez N., and Triboulet J. P., “The Number of Metastatic Lymph Nodes and the Ratio Between Metastatic and Examined Lymph Nodes Are Independent Prognostic Factors in Esophageal Cancer Regardless of Neoadjuvant Chemoradiation or Lymphadenectomy Extent,” Annals of Surgery 247, no. 2 (2008): 365–371, 10.1097/SLA.0b013e31815aaadf. [DOI] [PubMed] [Google Scholar]
- 20. Visser E., Markar S. R., Ruurda J. P., Hanna G. B., and van Hillegersberg R., “Prognostic Value of Lymph Node Yield on Overall Survival in Esophageal Cancer Patients: A Systematic Review and Meta‐Analysis,” Annals of Surgery 269, no. 2 (2019): 261–268, 10.1097/SLA.0000000000002824. [DOI] [PubMed] [Google Scholar]
- 21. Solomon N., Zhuge Y., Cheung M., Franceschi D., and Koniaris L. G., “The Roles of Neoadjuvant Radiotherapy and Lymphadenectomy in the Treatment of Esophageal Adenocarcinoma,” Annals of Surgical Oncology 17, no. 3 (2010): 791–803, 10.1245/s10434-009-0819-4. [DOI] [PubMed] [Google Scholar]
- 22. Torgersen Z., Sundaram A., Hoshino M., et al., “Prognostic Implications of Lymphadenectomy in Esophageal Cancer After Neo‐Adjuvant Therapy: A Single Center Experience,” Journal of Gastrointestinal Surgery 15, no. 10 (2011): 1769–1776, 10.1007/s11605-011-1635-2. [DOI] [PubMed] [Google Scholar]
- 23. Miyata H., Yamasaki M., Makino T., et al., “Therapeutic Value of Lymph Node Dissection for Esophageal Squamous Cell Carcinoma After Neoadjuvant Chemotherapy,” Journal of Surgical Oncology 112, no. 1 (2015): 60–65, 10.1002/jso.23965. [DOI] [PubMed] [Google Scholar]
- 24. Hamai Y., Emi M., Ibuki Y., et al., “Distribution of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma After Trimodal Therapy,” Annals of Surgical Oncology 28, no. 3 (2021): 1798–1807, 10.1245/s10434-020-09106-0. [DOI] [PubMed] [Google Scholar]
- 25. Miyata H., Sugimura K., Yamasaki M., et al., “Clinical Impact of the Location of Lymph Node Metastases After Neoadjuvant Chemotherapy for Middle and Lower Thoracic Esophageal Cancer,” Annals of Surgical Oncology 26, no. 1 (2019): 200–208, 10.1245/s10434-018-6946-z. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used in this study are available upon reasonable request from the corresponding author. However, access to the data is subject to the completion of the data transfer agreement process required by the affiliated institution.