A landmark phase 3 clinical trial has demonstrated that perioperative chemotherapy with the FLOT protocol significantly extends survival compared to neoadjuvant chemoradiation with the CROSS protocol in patients with locally advanced esophageal adenocarcinoma. The ESOPEC trial results, presented at the 2024 American Society of Clinical Oncology Annual Meeting, may reshape treatment standards for this challenging cancer.
Significant Survival Advantage Demonstrated
At a median follow-up of 55 months, patients in the intention-to-treat population who received the FLOT protocol achieved a median overall survival of 66 months compared with 37 months among those treated with the CROSS protocol (HR, 0.70; 95% CI, 0.53-0.92; P = .012). The 3-year overall survival rates were 57.4% versus 50.7%, respectively, while 5-year overall survival rates reached 50.6% versus 38.7%.
"Many patients in the US and Europe are still treated with the CROSS radiochemotherapy protocol. Our study shows that patients with resectable esophageal cancer should have FLOT chemotherapy before and after the operation in order to optimize the chance of curing their tumors in the long term," stated Jens Hoeppner, MD, director of the Department of Surgery at University Medical Center, University of Bielefeld, Germany.
The survival benefit was accompanied by improved progression-free survival, with FLOT patients achieving a median of 38 months compared to 16 months with CROSS (HR, 0.66; 95% CI, 0.51-0.85; P = .001). The 3-year progression-free survival rates were 51.6% versus 35.0%, and 5-year rates were 44.4% versus 30.9%, respectively.
Study Design and Patient Population
ESOPEC was a prospective multicenter study that enrolled patients with esophageal adenocarcinoma across 25 sites in Germany between February 2016 and April 2020. The trial randomly assigned 438 patients 1:1 to receive either the FLOT or CROSS protocol.
Eligible patients were at least 18 years old with pretreatment stage cT1N+, M0 or cT2-4a, N0/+, M0 disease, ECOG performance status of 2 or less, and adequate organ function. Patients with squamous or other non-adenocarcinoma histology, gastric cancer, clinical stage cT1cN0 and cT4b disease, or metastatic disease were excluded.
At baseline, the mean age was 63.1 years in the FLOT arm versus 62.6 years in the CROSS arm. Most patients in both arms were male (89.1% versus 89.4%), had clinical T-stage cT3-4 disease (79.1% versus 81.9%), and had clinical N-stage cN+ disease (77.8% versus 81.6%).
Treatment Protocols and Response Rates
Patients in the FLOT arm received repeated doses of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel every 2 weeks over 4 neoadjuvant cycles prior to surgery and 4 adjuvant cycles after surgery. The CROSS arm patients received neoadjuvant radiation therapy with concurrent carboplatin and paclitaxel for 5 cycles over 5 weeks prior to surgery.
The pathological complete remission rates among patients who underwent surgery favored the FLOT arm at 16.8% compared with 10.0% in the CROSS arm. Complete regression was observed in 18.3% versus 13.3% of patients, while near complete regression occurred in 25.1% versus 39.4%, respectively. Most patients across both arms underwent an R0 resection (94.2% versus 95.0%).
Safety Profile and Mortality
The safety profile showed favorable outcomes for FLOT. In the 90 days post-surgery, 3.2% of patients in the FLOT arm died compared with 5.6% in the CROSS arm. The 30-day postoperative mortality rates were 1.0% versus 1.7%, respectively.
Treatment completion rates varied between arms. A majority of patients in both arms completed neoadjuvant treatment (87.3% versus 67.7%) and received neoadjuvant treatment plus surgery (86.0% versus 82.9%). In the FLOT arm, 63.3% of patients received adjuvant treatment and 52.5% completed adjuvant treatment.
Subgroup Analysis and Clinical Implications
Results from exploratory subgroup analysis demonstrated that the overall survival benefit in favor of FLOT versus CROSS was observed across all examined subgroups. The most pronounced benefit was reported in patients aged less than 60 years (HR, 0.57; 95% CI, 0.34-0.95) and those with clinical T-stage T3-4 disease (HR, 0.68; 95% CI, 0.50-0.92).
"Perioperative chemotherapy with FLOT plus surgery improves OS compared with neoadjuvant chemoradiation with CROSS plus surgery in patients with locally advanced, resectable esophageal adenocarcinoma," Hoeppner concluded.
Evolving Treatment Landscape
While these results may establish FLOT as the new standard of care, experts note that the treatment landscape for esophageal cancer continues to evolve rapidly. Karyn A. Goodman, MD, of the Icahn School of Medicine at Mount Sinai, who discussed the results at ASCO, emphasized that newer treatments, including immunotherapies, are also now options for patients with locally advanced esophageal cancer.
The CheckMate 577 trial showed that giving nivolumab after the CROSS regimen and surgery may be effective for high-risk patients. "The CROSS regimen is very well tolerated by these patients. And I think the CROSS regimen, followed by adjuvant nivolumab, is still a potential option for many of these patients," Dr. Goodman noted.
In the United States, more than 22,000 people are estimated to be diagnosed with esophageal cancer annually, with approximately half diagnosed at a locally advanced stage. The ESOPEC findings provide crucial guidance for treatment selection in this patient population, though ongoing research into immunotherapy combinations and novel treatment approaches continues to advance the field.
