Individual patient data meta-analysis of neoadjuvant chemotherapy followed by surgery versus upfront surgery in esophageal or gastro-esophageal carcinoma.
Authors: Faron Matthieu , Cheugoua-Zanetsie Armel Maurice , Nankivell Matthew Guy , Winter Kathryn A. , Law Simon , van der Gaast Ate Van Der , Ychou Marc , Mauer Murielle , Valmasoni Michele , Roth Jack A. , Blanchard Pierre , Thirion Pierre Guillame , Tierney Jayne F. , Gebski Val , Burmeister Bryan H. , Paoletti Xavier , Yang Hong , van Sandick Johanna W. , Ducreux Michel , Michiels Stefan 
Published: June 2021

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Background: Defining the optimal neoadjuvant treatment for resectable locally advanced esophageal carcinoma remains an open question. The debate is fuelled by the fact that most of the available randomized clinical trials (RCT) accrued two histological subtypes (adenocarcinoma (AC) and squamous cell carcinoma (SCC)) and two anatomical locations (TE and GEJ). The aim of this individual patient data (IPD) meta-analysis was to investigate the effect of preoperative chemotherapy on survival with a specific focus on histological subtypes and anatomical locations. Methods: Were eligible published or unpublished RCT closed to accrual before December 2015 and comparing neoadjuvant chemotherapy (CS) to primary surgery (S), identified by electronic database, conference proceedings and clinical trial register. All analyses were conducted on IPD obtained from trial Investigators. The Primary endpoint was overall survival (OS), Secondary endpoints were disease-free survival (DFS) with a 6-months landmark time, local/distant relapse/death without relapse as competing events. Two subgroup analyses were pre-planned one on the histological subtype and another on the anatomical location. A stratified logrank test was used for OS and DFS, and a stratified fine and gray model for competing events. HR, and risk ratios (RR) were combined using a random effect model. Results: IPD were obtained from 12 RCT (2601 patients) out of 16 identified (2863 patients) When compared to S, CS was associated with a significantly increased OS, (HR = 0.85[0.78-0.92], p < 0.0001), with a 5-year absolute OS benefit of 5.7%. However, the subgroup analysis by histological subtype showed an OS benefit from CS higher for AC (HR = 0.80[0.72-0.91], p < 0.01), when compared to SCC (HR = 0.90[0.80-1.01], p = 0.06), but with p for interaction = 0.2. In the subgroup analysis by anatomical location CS benefit was seen across both anatomical location with a trend in favor of GEJ (TE: HR = 0.89[0.81-0.98], p = 0.02 GEJ: HR = 0.71[0.57-0.88]), p < 0.01, p for interaction = 0.057). CS also improved DFS (HR = 0.81[0.74-0.88], p < 0.0001), with the same trend for the subgroup analyses, with apparent significant benefit for AC HR = 0.80[0.72-0.91] when compared to SCC HR = 0.90[0.80-1.01], (p for interaction 0.045) and a similar benefit for both location (TE: HR = 0.89[0.81-0.98] p < 0.01, GEJ: HR = 0.71[0.57-0.88], p = 0.095, P for interaction 0.11). Local (HR = 0.76[0.63-0.92], p = 0.0045) and distant (HR = 0.87[0.76-0.99], p = 0.04) relapses were also significantly lower in the CS arm, with no significant variation according to histological subtypes or tumor location. Conclusions: Neoadjuvant chemotherapy significantly improves OS when added to upfront surgery and was equally effective in AC and SCC. A slightly more pronounced effect was observed for overall survival in the GEJ location vs. the TE.