Chemotherapy Before and After Surgery May Be New Standard Treatment for Some Patients with Esophageal Cancer

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ASCO Perspective Quote

“There is considerable disagreement as to whether giving all adjuvant therapy upfront versus ‘sandwich’ adjuvant therapy before and after surgery is the better standard of care for locally advanced resectable esophageal cancer. This randomized clinical trial from Europe answers that question for patients similar to those in enrolled in the trial: preoperative plus postoperative chemotherapy provides better outcomes.” – Jennifer Tseng, MD, MPH, Boston Medical Center, Boston, Massachusetts

Study at-a-Glance


Locally advanced esophageal adenocarcinoma


438 patients with locally advanced esophageal adenocarcinoma that can be treated with surgery from 25 centers across Germany

Main Takeaway

Treatment with chemotherapy before and after surgery through the FLOT protocol improves survival for people with locally advanced, resectable esophageal adenocarcinoma and helps them live longer when compared to chemoradiotherapy before surgery through the CROSS protocol.  


  • Currently, both treatments are considered standard of care for resectable, locally advanced esophageal cancer with similar outcomes for long-term survival. Which protocol patients receive often depends on where they receive treatment.
  • The findings could have an impact on national and international treatment guidelines for esophageal cancer. Currently both studied protocols are recommended by the guidelines.

ALEXANDRIA, Va. — For patients with locally advanced esophageal adenocarcinoma that can be treated with surgery, chemotherapy treatment before and after surgery improved survival when compared to chemoradiotherapy before surgery. The research will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 31-June 4 in Chicago, Illinois.

About the Study

The phase 3 ESOPEC clinical trial compared two treatment strategies for locally advanced esophageal adenocarcinoma that could be treated with surgery. The CROSS protocol is treatment with chemoradiotherapy before surgery. The FLOT protocol is treatment with chemotherapy before and after surgery. A total of 221 participants were randomized to the FLOT protocol arm and 217 participants were randomized to the CROSS protocol arm. The median age of the study participants was 63 years, and 89% of the participants were men. About 70% of esophageal cancer diagnoses are in men.

Key Findings

  • For all study participants, 403 started some form of treatment and 371 went on to receive surgery (191 in the FLOT arm and 180 in the CROSS arm). 
  • In the 90 days after surgery, 4.3% of the participants had died (3.2% in the FLOT arm and 5.6% in the CROSS arm), and after a median follow-up of 55 months, 218 participants had died (97 in the FLOT arm and 121 in the CROSS arm). 
  • Median overall survival was 66 months (5 years, 6 months) in the FLOT arm and 37 months (3 years, 1 month) in the CROSS arm.
  • At 3 years, participants who received FLOT had a 30% lower risk of dying than those who received CROSS. The 3-year overall survival rates were 57% for the FLOT arm and 51% in the CROSS arm.
  • Of the 359 participants whose tumor regression status was known, a pathological complete response was achieved in 35 patients in the FLOT arm and 24 in the CROSS arm. 

“Many patients in the U.S. and Europe are still treated with the CROSS radiochemotherapy protocol. Our study shows that patients with resectable esophageal cancer should have FLOT chemotherapy before and after the operation in order to optimize the chance of curing their tumors in the long term,” said lead study author Jens Hoeppner, MD, FACS, FEBS, University Medical Center OWL, University of Bielefeld, Detmold, Germany

Next Steps

Researchers will study whether surgery can be avoided in patients with cancers that have a complete pathological response to treatment with the FLOT or CROSS protocols and show no growth during active surveillance. Active surveillance is when regular tests, such as blood tests and radiologic imaging, are done to monitor if a cancer has come back. When surgery is avoided, the esophagus is preserved, giving patients a better quality of life. 

This study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation).

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