The Prognostic Importance of the Number of Dissected Lymph Nodes After Induction Chemoradiotherapy for Esophageal Cancer

doi:10.1016/j.athoracsur.2014.08.073

The Annals of Thoracic Surgery

Volume 99, Issue 1, January 2015, Pages 265-269

Presented at the Sixtieth Annual Meeting of the Southern Thoracic Surgical Association, Scottsdale, AZ, Oct 30–Nov 2, 2013.

https://doi.org/10.1016/j.athoracsur.2014.08.073 Get rights and content

Background

Analyses of adequacy of lymph node dissection during resection of esophageal cancer are based on patients who have not undergone induction chemoradiotherapy. We sought to determine the minimum number of dissected lymph nodes necessary to ensure adequate staging after induction chemoradiotherapy.

Methods

A prospectively maintained thoracic surgery database was queried to identify consecutive patients undergoing postinduction esophagectomy from 1996 to 2010. Cox proportional hazard and recursive partitioning survival analyses were performed.

Results

Complete lymph node data were available for 395 patients. Mean age was 59.5 years, and 64 patients (16%) were female. The median number of dissected lymph nodes was 8 (range, 0 to 63). When pathologic (p)T stage, pN stage, and the number of dissected lymph nodes were used as predictors, only pN stage (odds ratio, 1.3; 95% confidence interval, 1.2 to 1.7) and age (odds ratio, 1.03; 95% confidence interval, 1.01 to 1.04) independently predicted survival. Recursive partitioning was performed on 262 pN0 patients using T stage and the number of dissected lymph nodes as predictors. No pN0 patient with 28 lymph nodes dissected died during follow-up. For patients with fewer than 28 lymph nodes dissected, the next prognostic factor was T stage. For pT1-2 N0 patients, the number of lymph nodes dissected did not affect survival. For pT3-4 N0 patients, a significant survival decrement was noted for patients with fewer than 7 lymph nodes dissected compared with those with more than 7 lymph nodes dissected.

Conclusions

T stage determines prognosis in postinduction pN0 patients with fewer than 28 lymph nodes evaluated. Postinduction pT3N0 patients with fewer than 7 lymph nodes evaluated are understaged.

Section snippets

Acquisition of Clinical Data

After Institutional Review Board approval, a prospectively maintained thoracic surgery database was queried to identify consecutive patients undergoing esophagectomy after induction chemoradiotherapy at Duke University Medical Center from January 1996 to December 2010. Patients received various chemotherapy regimens during the study course and daily radiation dosing over 6 weeks for a total of 45 to 50 Gy. The analysis excluded patients who did not have survival information or complete lymph

Results

Complete lymph node data were available for 395 patients. Of these, 262 were node-negative on pathologic analysis of the resected specimen after induction chemoradiotherapy. Demographic information is presented in Table 1. Patients were a mean age of 59.5 years (range, 34 to 83 years), and 64 (16.2%) were female. Operations performed included Ivor Lewis in 148 (37.5%), transhiatal in 115 (29.1%), and McKeown in 101 (25.6%). Pretreatment staging was determined by endoscopic ultrasound (EUS)

Comment

The American Joint Committee on Cancer Staging Manual states that an adequate lymphadenectomy requires resecting 12 to 22 nodes [14]. However, this range was derived from analyses of patients who received esophagectomy alone [6]. The extent of lymphadenectomy and its effect on staging in patients receiving induction chemoradiotherapy has not been adequately addressed. Because induction chemoradiotherapy is widely used, supported by randomized trials and recommended in guidelines for many

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Cited by (29)

Impact of increasing lymph node yield on staging, morbidity and survival after esophagectomy for esophageal adenocarcinoma
2023, European Journal of Surgical Oncology
Citation Excerpt :
Although there are guidelines from the East on the extent of lymphadenectomy for squamous cell esophageal carcinoma, the exact extent to which lymph nodes should be dissected for esophageal adenocarcinoma (EAC) remains controversial. Several studies have established a minimum lymph node yield, varying from 15 to 30 [10–16]. Besides, the consequences of extended lymphadenectomy on staging, morbidity and survival are reported contradictory in literature [12,17–23].
Extended lymphadenectomy during esophagectomy for esophageal cancer may increase survival, but also increase morbidity. This study analyses the influence of lymph node yield after transthoracic esophagectomy for esophageal adenocarcinoma on the number of positive lymph nodes, pathological N-stage, complications and survival.
Consecutive patients undergoing transthoracic esophagectomy for esophageal adenocarcinoma between 2010 and 2020 were prospectively recorded (follow-up until January 2022). Lymph node yield was analyzed as continuous and dichotomous variable (≤30 vs. ≥31 nodes). The effect of lymph node yield on number of positive lymph nodes, complications, disease-free (DFS) and overall survival (OS) was assessed in multivariable regression analyses.
585 patients were included. Median lymph node yield increased from 25 (IQR 20–34) in 2010 to 39 (IQR 32–50) in 2020. Higher lymph node yield was associated with more positive lymph nodes (≥31 vs. ≤30 IRR 1.39, 95%CI 1.11–1.75). In 258 (y)pN + patients, the percentage of (y)pN3-stage increased with 14% between patients with ≤30 and ≥ 31 lymph nodes examined (p 0.014). Higher lymph node yield was not associated with more complications. Superior survival was seen in patients with ≥31 vs. ≤30 lymph nodes examined [DFS: HR 0.73, 95%CI 0.58–0.93, OS: HR 0.71, 95%CI 0.55–0.93)].
A lymph node yield of 31 or higher was associated with upstaging and superior survival after esophagectomy for esophageal adenocarcinoma, without increasing morbidity. Extended lymphadenectomy may therefore be regarded as an important part of the multimodal treatment of esophageal cancer.
Extent of Lymphadenectomy Is Associated With Improved Overall Survival After Esophagectomy With or Without Induction Therapy
2017, Annals of Thoracic Surgery
Citation Excerpt :
Even for patients with persistent nodal disease, those who received lymphadenectomy consistent with the WECC cut points still had significant improvement in 3-year OS [14]. An institutional analysis at Duke University found that there was no threshold number of examined lymph nodes for patients receiving induction therapy with pathologic T1/T2 tumors, whereas for pathologic T3/T4 tumors, significant improvements in survival were detected with 7 or more lymph nodes examined [15]. However, given the low correlation between clinical and pathologic staging, it could be challenging to replicate these survival benefits prospectively.
National Comprehensive Cancer Network (NCCN) guidelines recommend sampling 15 or more lymph nodes during esophagectomy. The proportion of patients meeting this guideline is unknown, as is its influence on overall survival (OS).
Univariate analysis and logistic regression were performed to identify variables associated with sampling 15 or more lymph nodes among patients undergoing esophagectomy in the National Cancer Data Base (NCDB). The NCCN guideline was evaluated in Cox proportional hazards modeling, along with alternative lymph node thresholds. Positive to examined node (PEN) ratios were calculated, and OS was compared using Kaplan-Meier analysis.
From 2006 to 2012, only 6,961 of 18,777 (37.1%) patients undergoing esophagectomy had sampling of 15 or more lymph nodes. Variables associated with sampling 15 or more lymph nodes included income greater than or equal to $38,000, procedure performed in an academic facility, and increasing clinical T and N stages. Induction therapy was associated with a decreased likelihood of 15 or more lymph nodes being sampled. The largest decrease in mortality hazard in patients undergoing upfront esophagectomy was detected when 25 lymph nodes or more were sampled (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.67–0.89; p < 0.001), whereas for patients undergoing induction therapy, sampling of 10 or 15 or more lymph nodes was associated with optimal survival benefit (HR, 0.81; 95% CI, 0.74–0.90; p < 0.001). PEN ratios of 0 to 0.10 were associated with maximum survival benefit among all patients undergoing esophagectomy. For patients with a PEN ratio of 0, increases in OS were detected with higher lymph node sampling (85.3 months for sampling of 20 or more lymph nodes versus 52.0 months for sampling 1–9 lymph nodes; p < 0.001).
For patients undergoing upfront esophagectomy, there may be an increased survival benefit for examining 20 to 25 lymph nodes, which is higher than current recommendations. However, only a minority of patients are meeting current guidelines.
Total Lymphadenectomy and Nodes-Based Prognostic Factors in Surgical Intervention for Esophageal Adenocarcinoma
2016, Annals of Thoracic Surgery
Citation Excerpt :
The TNM system is the guide for the therapy of solid cancers. Prognostic factors based on topography and the number of metastatic lymph nodes removed during surgical resection will probably remain valuable if they are supported by new data obtained from prospective multicenter studies based on rigorous modalities of lymphadenectomy (tailored or total) and dedicated methods of study of the surgical specimen aimed to extend the number of nodes examined [25] and if they consider micrometastases [26]. Biological characteristics based on new diagnostic techniques—such as sampling of whole-exome sequencing, next-generation sequencing, and circulating tumor cells—are increasingly being used, propelled by the request for personalized therapy for cancer.
To evaluate prognostic factors based on the number of resected lymph nodes, we considered 202 patients who underwent radical resection and “total lymphadenectomy” for esophageal adenocarcinoma according to a prospective protocol.
Fifty-eight tumors surrounded by Barrett’s epithelium underwent esophagectomy and esophagogastrostomy, and 144 tumors without Barrett’s epithelium underwent esophageal resection at the azygos vein level, total gastrectomy, and Roux-en-Y esophagojejunostomy. All nodes and fat tissue were resected at the following stations: chest 4L and R3, R4, R7, R8, and R9 (TNM seventh edition) and abdomen 1–12 according to the Japanese Classification of Gastric Carcinoma (1998). The nodes were counted, excluding fragments. The correlations between the number of nodes yielded and the ratio of the metastatic lymph nodes/lymph nodes yielded with pT stage, grading measurements, and cancer-specific survival (CSS) were calculated.
A total of 6,270 nodes were yielded (interquartile range per patient, 22–38; minimum, 4 nodes; maximum, 61 nodes). In 3 of 21 (14%) stage pT1 cases, less than 10 nodes were counted, in 2 of 27 (8%) stage pT2 cases, less than 20 were counted, and in 73 of 154 (47%) stage pT3-4 cases, less than 30 nodes were counted. The lymph node yield (LNY) and T stage were not correlated (r = 0 .048; p = 0.5). The metastatic lymph nodes to lymph nodes yielded ratio was correlated with pT stage (r = 0.272; p = 0.0001), and G (r = 0.385; p = 0.0001). CSS positively correlated with pT stage (p = 0.02), G (p = 0.001), and metastatic lymph nodes/lymph nodes yielded ratio (p = 0.01) (multivariate analysis).
The total number of lymph nodes to be removed in total and within each T stage indicated as thresholds could not be reached in up to 38.6% of patients. The metastatic lymph nodes/lymph nodes yield ratio not the total LNY, did correlate with cancer-specific survival.
Esophageal Cancer: Improvements in Treatment, Staging, and Now Prognostic Indicators?
2016, Seminars in Thoracic and Cardiovascular Surgery
Prognostic Relevance of Lymph Node Regression After Neoadjuvant Chemoradiation for Esophageal Cancer
2016, Seminars in Thoracic and Cardiovascular Surgery
Citation Excerpt :
Regression of the primary tumor has been widely studied and confirmed to be a relevant prognostic factor after neoadjuvant chemotherapy as well as chemoradiation for esophageal cancer.5,19 There are few studies examining the influence of chemoradiation on LN metastasis.19-23 Robb et al analyzed the effect of the number of LNs reported as resected and the number of LNs invaded on the prognosis of esophageal cancer after neoadjuvant chemoradiation.
Prognostic factors after preoperative chemoradiation for patients with advanced esophageal cancer are under discussion. Treatment response measured in the primary tumor is a well-defined prognostic marker. The prognostic relevance of tumor regression in lymph nodes (LNs), eg, histomorphologic characteristics must be evaluated in a larger series of patients. From 1997-2010, 403 patients with cT3N×M0 esophageal cancer underwent preoperative chemoradiation followed by transthoracic esophagectomy. Histopathologic response of the primary tumor was graded in resected specimens as “minor” (≥10% vital residual tumor cells) or “major.” The LNs of all patients without LN metastases (ypN0 n = 222, adenocarcinoma n = 129, squamous cell carcinoma n = 93) were reevaluated for central fibrosis. Univariate and multivariate analyses were performed on histomorphologic criteria of examined LNs and used to correlate these with tumor response and prognosis. The 5-year survival rate (5YSR) for all patients was 30%. Overall, 5480 LNs were reevaluated for the existence of central fibrosis in ypN0 cases. The prognostic relevance of the LN regression (LNR) grading system was confirmed for all patients with univariate (P < 0.001) and multivariate (P = 0.02) analyses. In results, the 5YSR for ypN0 patients overall was 37%, for patients with major response by the primary tumor was 42%, and for minor responders was 19% (P < 0.001). Analyzing LNR in major responders, the group with less than 3 LNs with central fibrosis (n = 52) showed significantly better prognosis (5YSR = 63%) compared to those with more (5YSR = 34%), (P = 0.016). Conclusion includes morphologic signs of metastatic LNR after chemoradiation, such as central fibrosis, are of prognostic relevance for patients with advanced esophageal cancer, especially for those with major response of the primary tumor.
Optimal lymph node yield in oesophagectomy for oesophageal cancer: a nationwide population-based study
2024, European Journal of Cardio-thoracic Surgery

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Original articleGeneral thoracicThe Prognostic Importance of the Number of Dissected Lymph Nodes After Induction Chemoradiotherapy for Esophageal Cancer

Background

Methods

Results

Conclusions

Section snippets

Acquisition of Clinical Data

Results

Comment

Ann Thorac Surg

J Gastrointest Surg

J Gastrointest Surg

Worldwide esophageal cancer collaboration

Dis Esophagus

7th edition of the AJCC cancer staging manual: esophagus and esophagogastric junction

Ann Surg Oncol

The prognostic importance of the number of involved lymph nodes in esophageal cancer: implications for revisions of the American Joint Committee on Cancer staging system

J Thorac Cardiovasc Surg

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

Ann Surg

Optimum lymphadenectomy for esophageal cancer

Ann Surg

Lymphadenectomy extent is closely related to long-term survival in esophageal cancer

Eur J Cardiothorac Surg

Original article
General thoracic
The Prognostic Importance of the Number of Dissected Lymph Nodes After Induction Chemoradiotherapy for Esophageal Cancer