We read with great interest the systematic review and meta-analysis of Lv et al (1) about the impact of remnant lymph node metastases after neoadjuvant therapy and surgery in patients with pathologic T0 esophageal carcinoma. The authors conclude that pT0 patients with remnant lymph node metastases have a poor survival.
We congratulate the author with this important work, but a couple of points in their manuscript merit discussion:
First, the definition of ypT0N1 in the manuscript is "complete response in the primary tumor with residual tumor in lymph nodes". Complete response in the primary tumor means that not a single viable tumor cell is present anymore or tumor regression grade 1 according to Mandard (TRG1) (2). From the manuscript of Reynolds et al (3) the authors included survival of TRG1 and TRG2 which is information of 61 patients in the ypT0N0 group instead of the correct number of 36 and 14 patients in the ypT0N+ group instead of the correct number of only 1 patient. On the other hand, TRG1N1 and TRG2N1 might follow a similar survival curve, as both are categorized as "major responders" (4).
Second, building on the same ypT0N1 definition, this means that the number of invaded lymph nodes is not defined, although the authors refer to American Joint Committee on Cancer (AJCC) esophageal staging 7th edition, were N1 is defined as 1 or 2 invaded lymph nodes. However, most included papers in the analysis - but not all (5) - made use of the AJCC esophageal staging 6th edition, were N1 was defined as one or more invaded locoregional lymph nodes. Further analysis of the included studies showed that at least 8 patients are N2 or N3 according to the 7th edition. Furthermore there is a significant difference in overall survival between ypT0N1 and ypT0N2/3 according to AJCC 7th edition (6).
Third, the authors did not include the largest study performed on this topic by Chao et al (6) in 1102 patients of which 319 ypT0N0, 50 ypT0N1 according to the 6th edition or 41 ypT0N1 according to the 7th edition, but they might have had a good reason for that.
Altogether this means that in the very small group of 131 ypT0N1 patients in the analysis, at least 13 patients should be removed and potentially 50 patients should be added depending on the definitions used. This is worth a recalculation of overall survival curves for ypT0N1 according to the 6th edition, for ypT0N according to the 7th edition and even for TRG1+TRG2N1.
Therefore we suggest correct definitions for ypT0N1 in esophageal carcinoma to be able to compare all results in future trials. Nevertheless, the main message that complete response in the primary tumor with residual tumor in lymph nodes portens poor survival, will probably stand even after recalculation. Indeed the final remark that ypT0N1 should be included in a modified staging was heard and ypT0N1 was suggested to become Stage IIIA while ypT0N2 became stage IIIB in current AJCC esophageal staging 8th edition (7).
The authors have no potential conflicts of interest to declare.
Department of thoracic surgery, University hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
1 Lv HW, Li Y, Zhou MH, Cheng JW, Xing WQ. Remnant lymph node metastases after neoadjuvant therapy and surgery in patients with pathologic T0 esophageal carcinoma impact on prognosis: A systematic review and meta-analysis. Medicine. 2017 Jun;96(26):e7342.
2 Mandard AM, Dalibard F, Mandard JC, et al.. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73:2680–2686.
3 Reynolds JV, Muldoon C, Hollywood D, Ravi N, Rowley S, O'Byrne K, Kennedy J, Murphy TJ. Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer. Ann Surg 2007;245:707-716.
4 Depypere L, Moons J, Lerut T, et al. Neoadjuvant chemoradiation treatment followed by surgery for esophageal cancer: there is much more than the mandard tumor regression score. Acta Chir Belg. 2016 Jul 29:1-7.
5 Blackham AU, Yue B, Almhanna K, Saeed N, Fontaine JP, Hoffe S, Shridhar R, Frakes J, Coppola D, Pimiento JM. The prognostic value of residual nodal disease following neoadjuvant chemoradiation for esophageal cancer patients with complete primary tumor response. J Surg Oncol. 2015 Nov;112(6):597-602.
6 Chao YK, Chen HS, Wang BY, Hsu PK, Liu CC, Wu SC. Prognosis of patients with pathologic T0 N+ esophageal squamous cell carcinoma after chemoradiotherapy and surgical resection: results from a nationwide study. Ann Thorac Surg. 2016 May;101(5):1897–902.
7 Rice TW, Ishwaran H, Kelsen DP, Hofstetter WL, Apperson-Hansen C, Blackstone EH, et al. Recommandations for neoadjuvant pathologic staging (ypTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals. Dis Esophagus. 2016 Nov;29(8):906-912.