Retrospective Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 7, 2018; 24(13): 1429-1439
Published online Apr 7, 2018. doi: 10.3748/wjg.v24.i13.1429
Impact of postoperative TNM stages after neoadjuvant therapy on prognosis of adenocarcinoma of the gastro-oesophageal junction tumours
Michael Thomaschewski, Richard Hummel, Ekaterina Petrova, Juliana Knief, Ulrich Friedrich Wellner, Tobias Keck, Dirk Bausch
Michael Thomaschewski, Richard Hummel, Ekaterina Petrova, Ulrich Friedrich Wellner, Tobias Keck, Dirk Bausch, Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck 23538, Germany
Juliana Knief, Department of Pathology, University Medical Center Schleswig-Holstein, Campus Lübeck, Lübeck 23538, Germany
Author contributions: Thomaschewski M, Hummel R and Bausch D drafted the original manuscript, contributed to design of the study, performance of statistical analyses and interpretation of the results; Petrova E collected the data; Wellner UF performed, reviewed and approved the statistical analyses; Keck T contributed to the design of the study and critically revised the manuscript for important intellectual content; all authors read and approved the final manuscript.
Supported by Land Schleswig-Holstein within the funding programme Open Access Publikationsfonds.
Institutional review board statement: The study was reviewed and approved by the institutional ethics committee (Ethik-Kommission Universität zu Lübeck/Aktenzeichen: 17-379A).
Conflict-of-interest statement: All authors declare no conflict-of-interest related to this article.
Data sharing statement: Consent for data sharing was not obtained and the data are not available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Michael Thomaschewski, MD, Doctor, Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Telephone: +49-451-50040220 Fax: +49-451-5002069
Received: January 22, 2018
Peer-review started: January 22, 2018
First decision: February24, 2018
Revised: March 6, 2018
Accepted: March 10, 2018
Article in press: March 10, 2018
Published online: April 7, 2018
Research background

Adenocarcinoma of the gastro-oesophageal junction (AEG) has a poor prognosis. Neoadjuvant chemotherapy and radiotherapy have significantly improved clinical management and outcome of patients, leading to a major evolution in treatment of oesophageal cancer. Neoadjuvant therapy provides a survival benefit to patients with AEG, through its elimination of micrometastatic disease and potential for down-staging of the primary tumour and/or lymph node metastasis, ultimately leading to higher rates of complete resections (R0). For prediction of prognosis of cancer patients, the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) system has been established. The 8th edition of AJCC staging of cancers of the oesophagus and oesophagogastric junction includes, for the first time, postneoadjuvant tumour/node/metastasis (ypTNM) stage groupings; the previous editions only referred to patients that underwent surgery alone. This raises the question of whether prognosis according to the postoperative pTNM/ypTNM stages is similar between patients that receive neoadjuvant pretreatment (ypTNM) or patients that undergo surgery alone (pTNM). According to the 8th edition AJCC, there are different prognostic implications between postneoadjuvant (ypTNM) and pathologic (pTNM) AEG categories. In detail, prognosis of node-negative (ypN0) and early-stage diseases (ypTNM groups I and II) is worse compared to patients with similar stages who underwent surgery alone. In contrast, for advanced stage AEG, there is no difference of prognosis among patients with identical pTNM/ypTNM stages. Other studies, however, have shown contradictory results. In these studies, the prognostic relevance of postoperative AJCC/UICC TNM staging did not differ between patients with or without neoadjuvant pretreatment.

Research motivation

Due to limited and heterogeneous data, the prognostic relevance of postoperative TNM staging in the era of neoadjuvant therapy of AEG remains unclear. However, due to the generally poor prognosis of AEG and the relevant risk of recurrence, an exact assessment of prognosis according to the TNM staging system is extremely important for the individual patient and for further treatment decision-making.

Research objectives

The main objective of this study was to compare the prognostic relevance of similar postoperative TNM stages between patients with or without neoadjuvant pretreatment. The results were expected to clarify the need of a separate postneoadjuvant stage grouping (ypTNM) for prognostication of AEG patients. Furthermore, in the era of neoadjuvant treatment, other prognostic factors may be relevant for prognostication of survival of patients with AEG.

Research methods

We conducted a retrospective study analysing 254 patients that underwent curative surgical treatment at our University Medical Center Schleswig-Holstein, Campus Lübeck. After excluding patients with preoperative tumour stages that preclude neoadjuvant pretreatment (cT1cN0cM0 and cT2cN0cM0), we performed exact matching to identify patients with or without neoadjuvant pretreatment who would be eligible for the study. Additionally, in-hospital deaths were excluded since we aimed to analyse long-term survival. Study parameters included sex, age, AEG (Siewert) classification, surgical procedure, preoperative staging (including cT, cN and cM categories according to the AJCC Cancer Staging Manual 8th edition), postoperative staging (including T, N and M categories according to the AJCC/UICC Cancer Staging Manual 7th edition, grade of differentiation (G) and resection margin status (R)), long-term survival (defined as time in months as from the day of hospital discharge) and pathologic down-staging/response in tumour (T) and nodal (N) stages after neoadjuvant therapy. Pearson’s chi-square and Fisher´s exact tests were used for statistical analyses of categorical variables (sex, age, AEG (Siewert) classification, surgical procedure and preoperative staging (cTNM)). Long-term survival was analysed using the Kaplan-Meier method. For statistical comparisons, log-rank test was used. A P-value of ≤ 0.05 was considered significant for all statistical analyses.

Research results

After patient selection and exact matching, 174 of the 254 patients were included in the study. Regarding demographics of both groups (no neoadjuvant treatment vs neoadjuvant treatment), patients who received neoadjuvant treatment were significantly younger (58 years vs 64 years, P = 0.043) and presented Siewert type I AEG tumours significantly more often (P < 0.001), resulting in significantly more oesophagectomies than gastrectomies (P < 0.001) for surgical treatment in this group. Patients who received neoadjuvant treatment presented higher preoperative rates of lymph node-positive disease (P = 0.020). Regarding overall survival of the entire study cohort, survival worsened at advanced postoperative AJCC/UICC TNM stages. Comparing long-term survival between patients with or without neoadjuvant pretreatment with identical postoperative TNM stages, no difference could be found. In addition, no difference was found in long-term survival of patients with or without neoadjuvant pretreatment for identical pT, pN or pM stages, G or R. Investigation of other prognostic markers for patients who received neoadjuvant pretreatment involved analysis of the effect of T and N down-staging on long-term survival. Here, we found that T down-staging did not have an impact on long-term survival (P = 0.488), while N down-staging after neoadjuvant treatment provided a significant but borderline improvement in long-term survival (P = 0.053).

Research conclusions

Our retrospective study demonstrated that the prognostic relevance of equivalent postoperative AJCC/UICC TNM stages is similar between patients with or without neoadjuvant pretreatment. Our data provide evidence that the pTNM staging system can be applied for assessment of individual prognosis of patients with AEG, regardless of whether or not they received neoadjuvant treatment. Furthermore, our study showed that N down-staging following neoadjuvant treatment positively affects long-term outcome, emphasizing the need of novel markers for prognostication in the era of neoadjuvant therapy.

Research perspectives

Our data support the idea of modifying the pTNM staging system by incorporating the extent of pathologic response following neoadjuvant treatment, rather than developing separate ypTNM stages. Prognostic factors or markers that reflect tumour biology, rather than the anatomical extent of growth, are promising for the development of new assessments for prognostication of survival of patients with AEG.