The incidence of esophageal adenocarcinoma (EAC) is increasing, particularly in high-income countries, with almost 86,000 new cases globally in 2020.¹ While surgery is the mainstay for cure in non-metastatic disease, multimodality treatment can improve survival in these patients.¹ For early-stage tumors with no node involvement, endoscopic resection or surgery alone is the current standard of care, whereas for locally advanced tumors, neoadjuvant chemoradiation or perioperative chemotherapy in addition to surgery is recommended.¹ During the 2024 ASCO Annual Meeting, Dr. Jens Hoeppner from the University of Bielefeld, Germany, presented the results from the ESOPEC trial, which involved a head-to-head comparison of perioperative chemotherapy (5-fluorouracil, leucovorin, oxaliplatin, docetaxel [FLOT]) versus neoadjuvant chemoradiation (41.4 Gy paclitaxel/carboplatin [CROSS]) in EAC in terms of their efficacy, safety, and postoperative morbidity and mortality.¹

In this trial, 438 EAC patients with clinical stage cT1N+ or cT2-4a, cN0/+, cM0 from 25 sites in Germany were enrolled and randomly assigned 1:1 to receive perioperative chemotherapy (n=221) or neoadjuvant chemoradiation (n=217).¹ In the perioperative FLOT group, patients received a chemotherapy regimen consisting of 4 cycles in 8 weeks of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel 4-6 weeks before and after surgery.¹ In the neoadjuvant CROSS group, patients received a radiation dose of 41.4 Gy and 5 cycles in 5 weeks of paclitaxel/carboplatin 4-6 weeks before surgery.¹ The primary endpoint of the study was overall survival (OS) while the secondary endpoints included progression-free survival (PFS), postoperative pathological stage, and postoperative complications.¹ Other secondary endpoints such as adverse events, recurrence-free survival, site of tumor recurrence, and quality of life were not presented at the meeting.¹

After a median follow-up of 55 months in the intention-to-treat population, there were 97 and 121 deaths in the FLOT group and the CROSS group respectively, with a median OS time of 66 months (95% CI: 36-not estimable [NE]) for the FLOT group and 37 months (95% CI: 28-43) in the CROSS group.¹ This translates to 3-year and 5-year OS rates of 57.4% and 50.6% in the FLOT group compared with 50.7% and 38.7% in the CROSS group (HR=0.70; 95% CI: 0.53-0.92; p=0.012).¹ Similar results were obtained in the per-protocol population, consisting of 221 patients in the FLOT group and 217 patients in the CROSS group who started neoadjuvant, with a median OS time of 66 months (95% CI: 38-NE) for the FLOT group and 39 months (95% CI: 29-45) in the CROSS group.¹ The 3-year and 5-year OS rates for the per-protocol population were 58.1% and 51.8% in the FLOT group compared with 52.6% and 40.5% in the CROSS group (HR=0.72; 95% CI: 0.54-0.96; p=0.023).¹ When OS was explored in several subgroups including sex, age, Eastern Cooperative Oncology Group (ECOG) status, and clinical T and N stages, FLOT was favored in all subgroup analyses.¹

For the secondary endpoints, the median PFS was 38 months (95% CI: 21-NE) for the FLOT group and 16 (95% CI: 12-22) in the CROSS group.¹ The 3- and 5-year PFS rates were 51.6% and 44.4% in the FLOT group compared with 35.0% and 30.9% in the CROSS group (HR=0.66; 95% CI: 0.52-0.85; p=0.001).¹ Pathological complete remission (defined as ypT0 ypN0) was achieved in 16.8% of patients in the FLOT group and 10.0% in the CROSS group.¹ Postoperative complications were similar in both groups, with a 30- and 90-day postoperative mortality of 1.0% and 3.2% in the FLOT group compared to 1.7% and 5.6% in the CROSS group.¹

In conclusion, the ESOPEC trial results indicate that perioperative FLOT + surgery may be a more effective treatment approach than neoadjuvant CROSS + surgery, and should be considered the preferred approach for improving OS in patients with locally advanced, resectable EAD.