FLOT Chemotherapy Demonstrates Superior Survival and Distant Recurrence Control Over CROSS in Esophageal Adenocarcinoma
Key Insights
Perioperative FLOT (search) chemotherapy achieved a 3-year overall survival rate of 61.1% compared to 55.9% with CROSS chemoradiotherapy in patients with nonmetastatic esophageal adenocarcinoma (search).
FLOT (search) treatment significantly reduced distant recurrence rates to 31.5% versus 47.2% with CROSS, demonstrating superior systemic tumor control.
The phase 3 ESOPEC trial results show FLOT (search)'s improved recurrence-free survival with a median of 47 months compared to 19 months for CROSS.
Perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT (search)) has demonstrated superior survival outcomes and systemic tumor control compared to carboplatin and paclitaxel (CROSS) chemoradiotherapy in patients with nonmetastatic esophageal adenocarcinoma (search), according to results from the phase 3 ESOPEC trial published in the Journal of Clinical Oncology.
Survival Benefits Favor FLOT Regimen
With a median follow-up of 56 months, the FLOT (search) group achieved a 3-year overall survival rate of 61.1% compared to 55.9% in the CROSS group (HR, 0.71; 95% CI, 0.53-0.97; P = .030). Among the 435 patients who underwent tumor resection, 80 patients in the FLOT group and 98 patients in the CROSS group died during the follow-up period.
The survival advantage was primarily driven by reduced tumor-related mortality. The 3-year cumulative incidence rates of death with recurrence were 32.3% in the FLOT (search) group versus 34.9% in the CROSS group (HR, 0.70; 95% CI, 0.50-0.98; P = .040). Deaths without evidence of recurrence occurred in 6.6% and 9.2% of patients, respectively (HR, 0.79; 95% CI, 0.38-1.65; P = .53).
Recurrence-Free Survival Shows Marked Improvement
FLOT (search) treatment resulted in significantly improved recurrence-free survival, with a 3-year rate of 54.5% compared to 39.0% with CROSS (HR, 0.67; 95% CI, 0.51-0.89; P = .005). The median recurrence-free survival was 47 months for FLOT versus 19 months for CROSS, representing a substantial clinical benefit.
Distant Recurrence Control Drives Treatment Advantage
The most striking difference between treatments was observed in distant recurrence patterns. FLOT (search) achieved a 3-year cumulative incidence of distant recurrence of 31.5% compared to 47.2% with CROSS (HR, 0.59; 95% CI, 0.43-0.82; P = .002). This reduction was particularly evident in distant recurrences occurring without simultaneous local or regional recurrences, with rates of 20.4% versus 34.4%, respectively (HR, 0.53; 95% CI, 0.36-0.79; P = .002).
Common metastatic sites showed reduced incidence with FLOT (search) treatment. Hematogenous metastases occurred less frequently with FLOT (HR, 0.59; 95% CI, 0.37 to 0.92; P = .021), while distant lymphatic metastases (HR, 0.60; 95% CI, 0.34 to 1.05; P = .074) and pleural and peritoneal metastases (HR, 0.63; 95% CI, 0.36-1.09; P = .098) also showed numerical reductions.
Comparable Locoregional Control
Both treatment approaches demonstrated similar efficacy for locoregional disease control. The 3-year cumulative incidence of locoregional recurrence was 20.2% in the FLOT (search) group and 17.4% in the CROSS group (HR, 1.00; 95% CI, 0.62-1.61; P = .99). Local recurrence occurred in 19 versus 15 patients, respectively (HR, 1.03; 95% CI, 0.51-2.06; P = .94), while regional recurrence was evident in 29 versus 27 patients (HR, 0.89; 95% CI, 0.52-1.52; P = .68).
Study Design and Patient Population
The ESOPEC trial randomized 435 patients with resectable esophageal adenocarcinoma (search) to receive either FLOT (search) and surgery (n = 221) or CROSS and surgery (n = 217). Eligible patients had cT1 cN+ cM0 or cT2 to cT4a cNany cM0 esophageal adenocarcinoma and underwent tumor resection.
Inclusion criteria required histologically verified adenocarcinoma of the esophagus, age 18 years or older, no prior abdominal or thoracic radiotherapy, ECOG performance status 0-2, and adequate organ function. The study excluded patients with squamous cell or other non-adenocarcinoma histology, advanced inoperable or metastatic disease, and prior chemotherapy.
Clinical Implications
"These results indicate that CROSS had insufficient effects on distant recurrence compared with FLOT (search) and that the increased mortality is a consequence of lower systemic antitumor efficacy," wrote lead study author Florian Lordick, MD, of the University Cancer Center Leipzig (search). The findings suggest that perioperative chemotherapy with FLOT provides superior systemic disease control while maintaining comparable locoregional efficacy.
The investigators acknowledged that undetected distant metastases represented a study limitation, as PET/CT and staging laparoscopy were not mandatory for all patients before study inclusion. Despite this limitation, the results highlight the potential of perioperative chemotherapy to reduce systemic relapse and improve long-term disease control in patients with esophageal adenocarcinoma (search).