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Randomized Controlled Trial
. 2021 Jun 20;39(18):1995-2004.
doi: 10.1200/JCO.20.03614. Epub 2021 Apr 23.

Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial

Ben M Eyck  1 , J Jan B van Lanschot  1   2 , Maarten C C M Hulshof  3 , Berend J van der Wilk  1 , Joel Shapiro  1 , Pieter van Hagen  1 , Mark I van Berge Henegouwen  4 , Bas P L Wijnhoven  1 , Hanneke W M van Laarhoven  5 , Grard A P Nieuwenhuijzen  6 , Geke A P Hospers  7 , Johannes J Bonenkamp  8 , Miguel A Cuesta  9 , Reinoud J B Blaisse  10 , Olivier R Busch  4 , Geert-Jan M Creemers  11 , Cornelis J A Punt  12   13 , John Th M Plukker  14 , Henk M W Verheul  15   16 , Ernst J Spillenaar Bilgen  17 , Maurice J C van der Sangen  18 , Tom Rozema  19   20 , Fiebo J W Ten Kate  21 , Jannet C Beukema  22 , Anna H M Piet  23 , Caroline M van Rij  24 , Janny G Reinders  25 , Hugo W Tilanus  26 , Ewout W Steyerberg  27   28 , Ate van der Gaast  29 ; CROSS Study Group
Affiliations
Randomized Controlled Trial

Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial

Ben M Eyck et al. J Clin Oncol. .

Abstract

Purpose: Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen.

Methods: From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses.

Results: The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent (P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13).

Conclusion: The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.

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Conflict of interest statement

Mark I. Van Berge HenegouwenConsulting or Advisory Role: Medtronic, Johnson & Johnson, Mylan, Alesi SurgicalResearch Funding: Olympus, StrykerTravel, Accommodations, Expenses: Johnson & Johnson Hanneke W. M. Van LaarhovenConsulting or Advisory Role: Lilly/ImClone, Nordic Group, Bristol Myers Squibb, ServierResearch Funding: Bristol Myers Squibb, Bayer Schering Pharma, Celgene, Janssen-Cilag, Lilly, Nordic Group, Philips Healthcare, Roche, Merck Sharp & Dohme, Servier, Merck KGaATravel, Accommodations, Expenses: AstraZeneca Grard A. P. NieuwenhuijzenHonoraria: Medtronic, LillyConsulting or Advisory Role: MedtronicResearch Funding: Medtronic Geke A. P. HospersConsulting or Advisory Role: Roche, MSD, Amgen, Bristol Myers Squibb, NovartisResearch Funding: Bristol Myers Squibb, Seerave Foundation Cornelis J. A. PuntConsulting or Advisory Role: Nordic Bioscience Henk M. W. VerheulConsulting or Advisory Role: Glycostem Ewout W. SteyerbergPatents, Royalties, Other Intellectual Property: Royalties from Springer for a book “Clinical Prediction Models”No other potential conflicts of interest were reported.

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