Clinical trialPhase 3Oesophageal cancer

Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer

N Engl J Med · 2025438 patients

Hoeppner J, Brunner T, Schmoor C, et al. N Engl J Med. 2025. 392:323-335

Study type: Clinical trial
Study name: ESOPEC
Phase: Phase 3
Design: Randomised, multicentre (Germany), open-label trial, 1:1 ratio
Sample size: 438 patients
Source: N Engl J Med · 2025
Trial registration: NCT02509286

In plain words

This German study compared two common ways of treating the "adenocarcinoma" type of oesophageal cancer before surgery: the four-drug chemotherapy FLOT given before and after surgery, versus chemoradiotherapy before surgery (the CROSS approach). Patients who had FLOT were more likely to be alive: after 3 years, about 57 out of every 100 versus about 51. FLOT had slightly more side effects. This result applies only to adenocarcinoma and not to the squamous type (the type that is more common worldwide, especially in Asia).

Key results

57.4% vs 50.7%

3-year overall survival

HR for death 0.70 (95% CI 0.53 to 0.92); P=0.01; median follow-up 55 months

66 vs 37 months

Median overall survival

As cited in the 2025 ESMO guideline update; 5-year survival 50.6% vs 38.7%

51.6% vs 35.0%

3-year progression-free survival

HR 0.66 (95% CI 0.51 to 0.85)

3.1% vs 5.6%

90-day postoperative mortality

Drugs in this study:Carboplatin (Paraplatin)Docetaxel (Taxotere)Fluorouracil (5-FU)Oxaliplatin (Eloxatin)Paclitaxel (Taxol)

Dose and schedule cards

Perioperative FLOT (ESOPEC trial)

Resectable adenocarcinoma of the oesophagus or gastroesophageal junction, clinical stage cT1 cN+ or cT2–cT4a with any N status, no distant metastasesCycle length: Every 14 daysOn the page “Oesophageal cancer” · Locally advanced disease: treatment with curative intent

Resectable adenocarcinoma of the oesophagus or gastroesophageal junction, clinical stage cT1 cN+ or cT2–cT4a with any N status, no distant metastases

Drug	Dose	Route	Schedule
Docetaxel	50 mg/m²	IV	Day 1
Oxaliplatin	85 mg/m²	IV	Day 1
Leucovorin	200 mg/m²	IV	Day 1
Fluorouracil	2600 mg/m²	IV, 24-hour infusion	Day 1

Cycle length: Every 14 days
Duration: 4 cycles before surgery and 4 cycles after surgery (8 cycles in total)

FLOT doses as in the FLOT4 trial; in ESOPEC, grade 3 or higher adverse events occurred in 58% with FLOT vs 50% with CROSS.

On the page “Oesophageal cancer” · Locally advanced disease: treatment with curative intent

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Perioperative FLOT (221 patients)

Every 2 weeks (day 1): fluorouracil (5-FU) 2600 mg/m² as a 24-hour infusion, leucovorin 200 mg/m², oxaliplatin 85 mg/m² and docetaxel 50 mg/m²; 4 cycles before surgery (8 weeks) and 4 cycles after surgery (8 weeks).

2Preoperative chemoradiotherapy, CROSS regimen (217 patients)

Radiotherapy 41.4 Gy in 23 fractions of 1.8 Gy, concurrent with carboplatin AUC 2 and paclitaxel 50 mg/m² on days 1, 8, 15, 22 and 29 (5 weeks); then surgery.

Source of the regimen details: Doses and schedules for both arms were confirmed from the trial registration on ClinicalTrials.gov (NCT02509286, interventions section).

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with resectable adenocarcinoma of the oesophagus with clinical stage cT1 cN+‎, or cT2 to cT4a with cN+‎ or cN0, without distant metastasis. Enrolment from February 2016 to April 2020.

Endpoints

Primary endpoint: overall survival. Secondary endpoints: progression-free survival, adverse events, postoperative mortality.

Safety and side effects

Among patients who started the assigned treatment, grade 3 or higher adverse events occurred in 58.0% of the FLOT group and 50.0% of the chemoradiotherapy group; serious adverse events were seen in 47.3% and 41.8%, respectively.

Clinical significance and place in guidelines

ESOPEC was the first phase 3 head-to-head comparison of these two strategies with overall survival as the primary endpoint. On this basis, the 2025 ESMO guideline update recommends that patients with locally advanced, resectable adenocarcinoma of the oesophagus or oesophagogastric junction be treated with perioperative FLOT and surgery [I, A], with neoadjuvant chemoradiotherapy considered only if the patient is unsuitable for FLOT [I, C].

Limitations

Only adenocarcinoma was studied; the trial was open-label and grade 3 or higher adverse events were more frequent with FLOT; at the time of design, adjuvant nivolumab after CROSS (CheckMate 577) was not yet available, and this study does not assess its contribution.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.