Chemotherapy or Chemoradiotherapy for Resectable Esophageal Cancer?

• More than 510 thousand people each year are diagnosed with esophageal cancer , which is the 9th most common cancer worldwide.
• The most effective treatment approach has long been debated, particularly for patients with resectable esophageal adenocarcinoma.
• The ESOPEC trial, whose results were published on 22 January 2025 in NEJM , was conducted in Germany and compared chemotherapy given before and after surgery with chemoradiotherapy given only before surgery.
• The aim was to determine which of these approaches had better effects on patients’ survival and disease progression.

Better Local Control or Better Systemic Control?

Chemotherapy before and after surgery and chemoradiotherapy before surgery alone are both important approaches for treating resectable esophageal adenocarcinoma. Each, however, has limitations.

Preoperative chemoradiotherapy alone is known to be less effective at controlling the spread of cancer to other parts of the body and can cause severe adverse effects during treatment. By contrast, FLOT chemotherapy (fluorouracil, leucovorin, oxaliplatin, and docetaxel) may provide more effective systemic control but also carries risks. This study compared the effects of the two approaches on survival.

Details of the ESOPEC Trial

Patients were randomly assigned to two groups. The first received perioperative FLOT, meaning chemotherapy before and after surgery, while the second received preoperative chemoradiotherapy: 41.4 Gy of radiotherapy with carboplatin and paclitaxel.

• Participant Characteristics: 438 patients, median age 63 (89% men, 11% women)

• Disease Status: Clinical stage cT1 cN+, cT2–4a cN+, or cT2–4a cN0

• Design: A phase 3, randomized, controlled, open-label (unblinded) study conducted at 25 centers in Germany

Patients underwent surgery within 4-8 weeks after completing preoperative treatment.

The primary endpoints were overall survival (the proportion alive at three years) and progression-free survival.

Results

• Overall Survival:

  • The three-year overall survival rate in the FLOT group was 57.4% (confidence interval [CI]: 50.1% - 64.0%)

  • In the preoperative chemoradiotherapy group, it was 50.7% (CI: 43.5% - 57.5%)

  • FLOT reduced the risk of death by 30% (HR: 0.70; P=0.01)

• Freedom From Disease Progression:

  • Progression-free survival in the FLOT group was 51.6% (CI: 44.3% - 58.4%)

  • In the chemoradiotherapy group, it was 35.0% (CI: 28.4% - 41.7%)

• Adverse Effects:

  • Severe adverse effects (e.g., grade 3+) occurred in 58% of the FLOT group

  • The rate of severe adverse effects in the chemoradiotherapy group was 50%

  • The most common serious adverse event was pneumonia (FLOT: 5.3%; chemoradiotherapy: 8.7%)

• Mortality Within 90 Days After Surgery:

  • 3.1% in the FLOT group

  • 5.6% in the chemoradiotherapy group

Commentary

Mortality during the first 90 days after surgery was higher in the chemoradiotherapy group. This suggests that chemoradiotherapy may increase early risks. Based on these results, FLOT chemotherapy may become a new standard treatment option for resectable esophageal adenocarcinoma .

However, conducting the trial only in Germany raises questions about whether its findings can be generalized to other patient groups. Furthermore, given the adverse-effect profile of FLOT, alternative regimens with fewer adverse effects need to be developed.

In addition, tailoring treatment choices to individual patient needs requires more data, particularly on treatment response and adverse effects.

In conclusion, perioperative chemotherapy with FLOT provided better survival outcomes than preoperative chemoradiotherapy alone. This trial offers important guidance for clinical practice in esophageal cancer.