Perioperative Chemotherapy in Esophageal Cancer
A PLAIN LANGUAGE SUMMARY
Based on the NEJM publication: Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer
by J. Hoeppner et al. (published January 23, 2025)
In this trial, researchers evaluated whether periopera-
Esophageal cancer is diagnosed in more than
tive chemotherapy improves overall survival as
510,000 persons worldwide each year, making it the
compared with preoperative chemoradiotherapy in
ninth most common form of cancer.
patients with resectable esophageal adenocarcinoma.
WHY WAS THE TRIAL DONE? PATIENTS
Resectable esophageal adenocarcinoma
For patients with resectable esopha
WHO 438 adults
geal adenocarcinoma, two multimodal
approaches — perioperative chemo Median age, 63 years
therapy with FLOT (fluorouracil, Men: 89%; Women: 11%
leucovorin, oxaliplatin, and docetaxel)
plus surgery or preoperative chemo CLINICAL Clinical stage cT1 cN+,
STATUS
radiotherapy (radiotherapy at a dose of cT2–4a cN+, or cT2–4a
41.4 Gy and carboplatin and paclitaxel) cN0 resectable esophageal
plus surgery — have been shown to adenocarcinoma without
improve survival outcomes. However, metastatic spread
concerns about both regimens re Tumors in the esophagus
mained, including inadequate control or near it and extending
of systemic disease with preoperative chemoradiotherapy and toxic into the esophagus
effects and a somewhat low percentage of patients with R0 status ECOG performance-
(margins of resected tissue free of tumor cells) with FLOT. status score of 0, 1, or 2
(range, 0 [full activity] to
5 [death])
HOW WAS THE TRIAL CONDUCTED? Adequate hematologic,
renal, hepatic, cardiac,
Patients were randomly assigned to receive FLOT (four cycles before surgery
and pulmonary function
and four cycles after surgery) or preoperative chemoradiotherapy. Surgery
was performed 4 to 8 weeks after the first four cycles of FLOT or the last No previous radiotherapy
dose of preoperative chemoradiotherapy. The primary end point was overall or chemotherapy
survival.
Preoperative
FLOT Chemoradiotherapy
TRIAL DESIGN
• PHASE 3
• UNBLINDED
• RANDOMIZED
• CONTROLLED
• LOCATION: 25 CENTERS IN GERMANY
221 Patients 217 Patients
1 Copyright
Copyright
©©2025
2023
Massachusetts
Massachusetts
Medical
Medical
Society.
Society.
The n e w e ng l a nd j o u r na l of m e dic i n e
RESULTS Overall Survival
Hazard ratio for death, 0.70 (95% CI, 0.53–0.92); P=0.01
FLOT was superior to preoperative chemoradiotherapy 100
with regard to overall survival at 3 years. The median
Percentage of Patients
80
follow-up was 55 months. 57.4
60 (95% CI, 50.1–64.0)
Progression-free survival, a secondary end point, was FLOT
50.7
51.6% in the FLOT group and 35.0% in the preopera 40 (95% CI, 43.5–57.5)
tive-chemoradiotherapy group. Preoperative
20
Chemoradiotherapy
0
0 12 24 36 48 60 72 84
Months since Randomization
Adverse events of grade 3 or higher and serious adverse events were somewhat MORTALITY AT 90 DAYS
more common with FLOT than with preoperative chemoradiotherapy overall.
The only serious adverse event with an incidence of 5% or more was pneumonia
(incidence, 5.3% with FLOT and 8.7% with preoperative chemoradiotherapy).
Adverse Events of
Serious Adverse Events
Grade 3 or Higher
100
Percentage of Patients
80
58.0
60 50.0 47.3 41.8 The Kaplan–Meier estimate of
40
mortality at 90 days after surgery
20 was 3.1% in the FLOT group and
0 5.6% in the preoperative-chemo
FLOT Preoperative FLOT Preoperative
Chemoradiotherapy Chemoradiotherapy radiotherapy group.
LIMITATIONS AND REMAINING QUESTIONS
• The trial was conducted entirely in Germany, CONCLUSIONS
which may limit the generalizability of the In patients with resectable esophageal
findings.
adenocarcinoma, FLOT perioperative
• Whether de-escalation to a chemotherapy dou
chemotherapy led to improved survival
blet or a switch to preoperative chemoradiothera
py is preferable in patients with FLOT-related outcomes as compared with preoperative
adverse events remains unanswered. chemoradiotherapy.
Links: Full Article | NEJM Quick Take | Editorial
FURTHER INFORMATION
Trial registration: ClinicalTrials.gov number, NCT02509286
Trial funding: German Research Foundation
Full citation: Hoeppner J, Brunner T, Schmoor C, et al. Perioperative chemotherapy or preoperative chemoradiotherapy in esophageal cancer.
N Engl J Med 2025;392:323-35. DOI: 10.1056/NEJMoa2409408.
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