A Propensity Score-Matched Cohort Study to Evaluate the Association of Lymph Node Retrieval with Long-Term Overall Survival in Patients with Esophageal Cancer

This study investigated whether the quality indicator ‘retrieval of at least 15 LNs’ was associated with better long-term survival and more accurate pathological staging in patients with esophageal cancer treated with neoadjuvant chemoradiotherapy and resection. The results of this study showed that there was no difference in 3-year survival between patients with retrieval of at least 15 LNs versus patients with retrieval of < 15 LNs. In addition, retrieval of at least 10, 20, or 30 LNs was not associated with better 3-year survival compared with patients with fewer LNs (< 10, < 20, and < 30, respectively); however, retrieval of at least 15 LNs was associated with more accurate pathological staging. Positive LNs were found more often in patients with at least 15 retrieved LNs, leading to higher pathological N stages. Furthermore, the 3-year survival in the subgroup of patients with pathological node-negative disease was significantly higher for patients with at least 15 LNs compared with patients with < 15 LNs. These findings support the idea of stage migration; patients with low LN retrieval are likely understaged because positive LNs have been left behind in the resection specimen or may have been left behind in the patient. This may explain the lower 3-year survival for patients with pathological node-negative disease with < 15 LNs compared with patients with at least 15 retrieved LNs.

The therapeutic value of a higher number of retrieved LNs after neoadjuvant therapy is a controversial issue in cancer surgery. For esophageal cancer, many papers have been published on this topic and most studies show an association between the number of nodes retrieved and survival.8,9 The findings of the current study show this relationship only for patients with pathological node-negative disease; in the total group, no relation between LN retrieval and survival was seen. A possible explanation may be patient selection; the patient cohort that is selected covers a more recent period than most other studies. Dutch institutions have started various improvement processes in recent years. The number of LNs resected was implemented as a quality indicator in 2013, which has resulted in an increase in the number of retrieved LNs reported10 The increase in reported LN yield may not only be an effect of more extended LN dissections but may also be due to more detailed pathological examination; therefore, the extra number of examined and counted LNs does not automatically imply an extended lymphadenectomy.

The outcome that there was no survival difference between the two groups may also be due to recent improvements in preoperative and intraoperative imaging, which may lead to better-targeted lymphadenectomy. Better-targeted lymphadenectomy might ensure the quality of LN dissection, but is not necessarily reflected in the high number of LNs. In The Netherlands, the use of preoperative positron emission tomography/computed tomography (PET/CT) and endoscopic ultrasound (EUS) for clinical staging increased. In 2017, a PET/CT was performed in 93% of patients, an EUS was performed in 67% of patients, and an EUS with biopsy was performed in 18% of patients.11 For patients with esophageal squamous cell carcinoma, a recent meta-analysis showed that the pooled sensitivity of PET/CT for detection of regional LN metastasis was 66% (95% CI 66–78%).12 Another recent meta-analysis evaluated the sensitivity of PET/CT and EUS for detecting residual disease after neoadjuvant chemoradiotherapy at the primary tumor site or regional LNs.13 For PET/CT, the sensitivity rates for detection of residual disease in LNs ranged between 0 and 65%. Due to the low number of studies evaluating the sensitivity of PET/CT for detection of residual disease in LNs, the authors could not determine the pooled sensitivity for PET/CT. For EUS, the pooled sensitivity for detection of residual disease in LNs was 68% (95% CI 54–80%).

In future, intraoperative imaging as fluorescence imaging may also help to identify affected LNs.14

A limitation of this study was that with propensity score matching, it was possible to only compare two groups and it was not possible to use the number of LNs as a continuous outcome. Therefore, identifying an optimal number of LNs was not possible. Additionally, not analyzing the number of LNs as a continuous outcome could have been the reason that no survival difference was seen between patients with a low versus high number of retrieved LNs. Another limitation is that this study did not include which LN stations were dissected, therefore it is not known whether these LN stations influenced survival.

A further study with more focus on the extent of LN dissection is needed. It would be desirable to identify an optimal number of LNs that should be removed, or to identify which LN stations should be dissected. For this purpose, the TIGER study is under way;15 the aim of this international observational cohort study is to evaluate the distribution of LN metastases in esophageal carcinoma. In 50 centers, specimens of patients following transthoracic esophagectomy with a two- or three-field lymphadenectomy will be evaluated by a pathologist. The distribution of LN metastases will be evaluated in relation to tumor histology, tumor location, invasion depth, number of LNs and LN metastases, preoperative diagnostics, neoadjuvant therapy, and (disease-free) survival.

Taken together, although the findings of the current study did not show that retrieval of at least 15 LNs was associated with improved 3-year survival, it did show that it was associated with more accurate pathological staging. Since accurate staging is important to determine prognosis, and therefore contributes to better quality of care, it can be concluded that ‘retrieval of at least 15 LNs’ is a relevant quality indicator.