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      Does the lymph node yield affect survival in patients with esophageal cancer receiving neoadjuvant therapy plus esophagectomy? A systematic review and updated meta-analysis

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          Abstract

          Background

          Conflicting data have been reported on the prognostic impact of the extent of lymphadenectomy during esophagectomy for esophageal cancer (EC) after neoadjuvant therapy, especially after neoadjuvant chemoradiotherapy (nCRT).

          Methods

          A comprehensive online search was performed to explore the association between increased lymph node yield (LNY) and survival of patients with EC, in which the overall survival (OS) was set as the primary outcome. In addition to analysis of the entire cohort, subgroup analyses of different induction therapy and different populations were also performed.

          Findings

          A total of 19528 patients from twelve studies were included in our study. The pooled data revealed that more lymph node harvested was associated with better OS (HR = 0·87; 95% CI: 0·79–0·95, p < 0·001). Notably, a higher LNY was associated with better OS if the threshold was less than 18. However, more thorough lymphadenectomy might not bring additional survival benefits when it came to a cutoff value more than 18. The subgroup analysis further revealed that a higher LNY after nCRT was associated favorable survival. In terms of subset analysis of different populations, increased LNY was associated with longer OS in Western populations but not in Eastern.

          Interpretation

          Increased LNY during esophagectomy after neoadjuvant therapy, especially after nCRT, might be associated with improved OS. More studies are warranted to assess the survival benefits of a higher LNY receiving neoadjuvant therapy plus esophagectomy, especially in Eastern populations.

          Funding

          Supported by the projects from Suzhou Key Laboratory of Thoracic Oncology (SZS201907), Suzhou Key Discipline for Medicine (SZXK201803), the Science and Technology Research Foundation of Suzhou Municipality (SYS2018063, SYS2018064), Municipal Program of People's Livelihood Science and Technology in Suzhou (SS2019061) and Major Project for Social Development, Jiangsu Provincial Department of Science and Technology (SBE2020750085).

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          Most cited references24

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          Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901.

          Although often investigated in locally advanced esophageal cancer (EC), the impact of neoadjuvant chemoradiotherapy (NCRT) in early stages is unknown. The aim of this multicenter randomized phase III trial was to assess whether NCRT improves outcomes for patients with stage I or II EC. The primary end point was overall survival. Secondary end points were disease-free survival, postoperative morbidity, in-hospital mortality, R0 resection rate, and prognostic factor identification. From June 2000 to June 2009, 195 patients in 30 centers were randomly assigned to surgery alone (group S; n = 97) or NCRT followed by surgery (group CRT; n = 98). CRT protocol was 45 Gy in 25 fractions over 5 weeks with two courses of concomitant chemotherapy composed of fluorouracil 800 mg/m(2) and cisplatin 75 mg/m(2). We report the long-term results of the final analysis, after a median follow-up of 93.6 months. Pretreatment disease was stage I in 19.0%, IIA in 53.3%, and IIB in 27.7% of patients. For group CRT compared with group S, R0 resection rate was 93.8% versus 92.1% (P = .749), with 3-year overall survival rate of 47.5% versus 53.0% (hazard ratio [HR], 0.99; 95% CI, 0.69 to 1.40; P = .94) and postoperative mortality rate of 11.1% versus 3.4% (P = .049), respectively. Because interim analysis of the primary end point revealed an improbability of demonstrating the superiority of either treatment arm (HR, 1.09; 95% CI, 0.75 to 1.59; P = .66), the trial was stopped for anticipated futility. Compared with surgery alone, NCRT with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II EC. © 2014 by American Society of Clinical Oncology.
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            Prognostic role of pretreatment blood neutrophil-to-lymphocyte ratio in advanced cancer survivors: A systematic review and meta-analysis of 66 cohort studies.

            Neutrophil-to-lymphocyte ratio (NLR) is crucial for the incidence and mortality of various tumors. However, little is known on NLR and its association with prognosis in advanced tumors. Here we performed a meta-analysis to establish the prognostic significance of pretreatment blood NLR for advanced tumors.
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              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.

              To investigate whether the number of lymph nodes metastasis (LNMs) and the ratio between metastatic and examined lymph nodes (LNs) are better prognostic factors when compared with traditional staging systems in patients with esophageal carcinoma. The accuracy of the 6th UICC/TNM classification is suboptimal, especially when not taking into account neoadjuvant therapy and lymphadenectomy extent. For 536 patients who underwent curative en bloc esophagectomy, in whom 51.5% (n = 276) received neoadjuvant chemoradiation, LNMs were classified according to the 6th UICC/TNM classification and systems based on the number ( 4) or the ratio ( 0.2) of LNMs. Survival of the respective stages, predictors of survival, and influence of both chemoradiation and number of examined LNs were studied. After a median follow-up of 50 months, the 5-year survival rates were 47% for the entire population, significantly poorer for patients with >4 LNMs (8% vs. 53%, P 0.2 (22% vs. 54%, P 4 and a ratio of LNMs >0.2 were the only predictors of poor prognosis. The prognostic role of both the number and the ratio of LNMs was maintained whether patients received neoadjuvant chemoradiation or not. Moreover, LN ratio is shown to be more accurate for inadequately staged patients ( or =15 examined LNs). Staging systems for esophageal cancer that use the number ( 4) and the ratio ( 0.2) of LNMs have greater prognostic importance than the current staging systems because of the good stratification of the groups and their clinical utility, taking into account neoadjuvant therapy and lymphadenectomy extent.
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                Author and article information

                Contributors
                Journal
                EClinicalMedicine
                EClinicalMedicine
                EClinicalMedicine
                Elsevier
                2589-5370
                31 July 2020
                August 2020
                31 July 2020
                : 25
                : 100431
                Affiliations
                [a ]Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
                [b ]Department of Thoracic Surgery, Suzhou Kowloon Hospital Shanghai Jiaotong University School of Medicine, Suzhou, China
                [c ]Department of Thoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
                Author notes
                [* ]Corresponding author. chentongt@ 123456sina.com
                [** ]Corresponding authors.
                [1]

                Drs. Chen D, Mao Y and Xue Y equally contributed to the work.

                [2]

                These authors contributed equally as co-senior authors.

                Article
                S2589-5370(20)30175-9 100431
                10.1016/j.eclinm.2020.100431
                7397690
                32775970
                8e0c2851-3135-490a-a110-a721fdfa33b3
                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 April 2020
                : 4 June 2020
                : 4 June 2020
                Categories
                Research paper

                esophageal cancer,lymph nodes,neoadjuvant therapy,surgery,prognosis

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