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The Prognostic Impact of Minimally Invasive Esophagectomy on Survival after Esophagectomy Following a Delayed Interval after Chemoradiotherapy: A Secondary Analysis of the DICE Study
*Sheraz R. Markar1, *Richard Owen1, *Mark van Berge Henegouwen2, *Suzanne Gisbertz2, *Ewen Griffiths3, *Carlo Castoro4, *Caroline Gronnier5, *Christian Gutschow6, *Guillaume Piessen7, *Peter Grimminger8, Donald Low9, *James Gossage10, *Richard van Hillegersberg11, *Xavier D'Journo12, *Alex Phillips13, *Riccardo Rosati14, *George Hanna15, *Wayne Hofstetter16, Lorenzo Ferri17
1Nuffield Department of Surgery, University of Oxford, Oxford , United Kingdom; 2Amsterdam UMC, Amsterdam, Netherlands; 3Birmingham University Hospitals NHS Foundation Trust, Birmingham, United Kingdom; 4Humanitas Research Hospital, Milan, Italy; 5CHU de Bordeaux, Bordeaux, France; 6University Hospital Zurich, Zurich, Switzerland; 7University Hospital Claude Huriez, Lille, France; 8Johannes Gutenberg University Mainz, Mainz, Germany; 9Virginia Mason Hospital & Seattle Medical Center, Seattle, WA; 10Guy's and St Thomas' Hospitals NHS Foundation Trust, London, United Kingdom; 11UMC Utrecht, Utrecht, Netherlands; 12Chemin des Bourrely, North Hospital, Marseille, Marseille, France; 13Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom; 14San Raffaele Hospital, Milan, Italy; 15Imperial College London, London, United Kingdom; 16MD Anderson Cancer Center, Houston, TX; 17McGill University, Montreal, QC, Canada

Previously, we established that a prolonged interval after chemoradiotherapy prior to esophagectomy was associated with increased 90-day mortality and poorer long-term survival [PMID: 37477039]. The aim of this analysis is to evaluate differences between minimally invasive esophagectomy (MIE) and open esophagectomy (OE) on long-term prognosis in patients with surgery after a prolonged interval (>12 weeks) following chemoradiotherapy (CRT).

This was an international, multi-center, retrospective cohort study involving seventeen tertiary international centers, including patients who received CRT followed by surgery between 2010-2020.

Statistical analysis:
Patients were divided into those who underwent MIE, which was defined as thoracoscopic and laparoscopic approach, vs. OE. For this study, hybrid and robotic esophagectomies were excluded (n=45). Multivariable Cox regression modelling provided hazard ratios (HRs) with 95% confidence intervals (95%CI), and propensity-matched analyses adjusted for relevant patient, oncological and pathological confounding factors.

From DICE, a total of 154 MIE and 356 open esophagectomy received surgery >12weeks after CRT and were included. Significant differences were observed in ASA grade, radiation dose, clinical T and N stage, histological subtype, and tumor location between groups. There were no significant differences between the groups in pathological T or N stage, resection margin status or 90-day mortality. Survival analysis showed MIE was associated with improved survival (log rank test, P=0.0062), which was also shown in multivariate analysis after adjustment for smoking, T and N stage, and histology (HR=1.54; 95% CI 1.1 to 2.2).
Propensity matched analysis, including CRT interval and dose, also showed MIE was associated with a significant improvement in overall survival (log rank test, P=0.016). Further subgroup analysis by radiation dose in all patients with >12week interval showed survival advantage in 40-50Gy dose groups (HR=2.0; 95% CI 1.3 to 3.1), but not in the 50-55Gy dose group (HR=1.3; 95% CI 0.69 to 2.3).

The results of this multi-center international cohort study show MIE associated with an improved overall survival in patients with a prolonged interval from CRT to surgery (>12 weeks), with equivalent pathological outcomes and short-term mortality. The mechanism for this observed improvement in survival remains unknown, with potential hypotheses including a reduction in complications and improved functional recovery observed after MIE.

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