Neoadjuvant Therapy and Lymphadenectomy in Esophageal Cancer: Both Are Essential to Maximize Survival Benefit

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To the Editor:
We read with great interest the article by Talsma et al.1 The authors addressed the role of extended lymphadenectomy after neoadjuvant chemoradiotherapy (CRT) for esophageal cancer. The study population in this article consisted of the patients who participated in the CROSS trial.2 The CROSS trial, published in 2012, proved convincingly the survival benefit of neoadjuvant CRT, followed by surgery over surgery alone for esophageal cancer [median overall survival of 49.4 months in the CRT surgery group vs 24.0 months in the surgery group; hazard ratio (HR) = 0.657; 95% confidence interval, 0.495–0.871; P = 0.003]. This significant survival benefit in CRT surgery groups has been attributed to sterilization of surgical margins (reflected by a higher frequency of R0 resection in the CRT surgery group than in the surgery-alone group, 92% vs 69%; P < 0.001) and sterilization of positive lymph nodes. On the basis of this premise, Talsma et al1 questioned the applicability of lymphadenectomy in the CRT surgery group.
The authors evaluated the role of lymphadenectomy in both groups—CRT surgery and surgery alone. The authors opined, based on statistical analysis, the number of resected nodes was significantly associated with survival (HR = 0.76 per every 10 additionally resected nodes; P < 0.01) in the surgery-alone group; moreover, a positive association exists between the number of resected nodes and the number of resected positive nodes. This conclusion sheds light on the role of adequate lymphadenectomy in esophageal cancer and strengthens its therapeutic potential in addition to its role in better final disease staging. The authors further clarified that the adequate lymphadenectomy failed to provide therapeutic benefit in the CRT surgery group, as the number of resected positive nodes were independent of total resected nodes and so questioned the role of lymphadenectomy in esophageal cancer. They were of the opinion that this discrepancy can be attributed to sterilization of many initial positive nodes carried out by neoadjuvant CRT.
We believe that this is oversimplification of a complex issue. Although the number of lymph nodes might be more reliable and robust than surgical approach alone for the purpose of statistical analysis, the concept of systematic lymphadenectomy is based on the careful dissection of anatomically well-defined nodal stations.2 It also needs to be highlighted that the number of resected lymph nodes is a surrogate marker for the quality of lymphadenectomy for the purpose of statistical analysis in view of wide variations in surgical philosophy and practice between institutions and individual surgeons; however, the effect of the surrogate factor (the number of resected lymph nodes) cannot be placed above that of the real factor, that is, surgical diligence in lymph node dissection.
We believe that the issue of stage migration is overstated in the context of extended lymphadenectomy for several cancers. Stage migration (Will-Rogers phenomenon) can possibly explain the stage for stage survival benefit owing to a better staging by a more thorough lymphadenectomy, but it cannot explain the survival benefit of the entire cohort of patients including all stages. An impeccable trial design to address the question of survival benefit (therapeutic potential) of lymphadenectomy in esophageal cancer would be to compare systematic lymphadenectomy versus no lymphadenectomy, head to head, irrespective of the stage (to avoid the confounding effect of stage migration). As we do not have such a randomized trial, the studies focusing on the results of extended lymphadenectomy for esophageal cancer become important sources of data to understand the value of such procedure. Most of the surgical series in esophageal cancer that do not focus on lymph node dissection show 5-year overall survival rates between 20% and 25%.

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