The phase III ESOPEC trial, conducted in Germany, compared two regimens for locally advanced esophageal cancer and found an overall survival benefit with the perioperative FLOT protocol over the neoadjuvant chemoradiotherapy CROSS regimen. The results were presented during the Plenary Session of the 2024 ASCO Annual Meeting.1
The FLOT protocol includes chemotherapy (fluorouracil, leucovorin, oxaliplatin, docetaxel) before and after surgery. The CROSS protocol includes neoadjuvant chemotherapy (paclitaxel/carboplatin) plus radiation (41.4 Gy) followed by surgery.
“ESOPEC found that perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with the CROSS protocol for improving survival,” said Jens Hoeppner, MD, Professor of Surgery, University Medical Center OWL, University of Bielefeld, Detmold, Germany.
ESOPEC found that perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with the CROSS protocol for improving survival.— Jens Hoeppner, MD
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About ESOPEC
For locally advanced resectable esophageal adenocarcinoma, current guidelines recommend neoadjuvant chemoradiation or perioperative chemotherapy plus surgery. These recommendations were largely based on studies in mixed cohorts of patients. “The ESOPEC trial, therefore, was designed to provide evidence for FLOT or CROSS in a pure adenocarcinoma population,” Dr. Hoeppner said.
ESOPEC randomly assigned 438 patients with resectable esophageal adenocarcinoma (cT1cN+ and cT2–4a, cN–/+) to receive either FLOT for four cycles followed by surgery and then four more FLOT cycles or the CROSS protocol (chemotherapy plus radiation) for four cycles followed by surgery. The primary endpoint was overall survival by intention-to-treat analysis.
Improved Overall Survival With FLOT
At a median follow-up of 55 months, FLOT conveyed a 30% survival benefit over CROSS. Median overall survival was 66 months vs 37 months, respectively (hazard ratio [HR] = 0.70; P = .012). Overall survival rates were 57.4% with FLOT vs 50.7% with CROSS at 3 years and 50.6% vs 38.7%, respectively, at 5 years, Dr. Hoeppner reported.
He noted that in the intention-to-treat population, more than 90% of each arm started neoadjuvant treatment, 87.3% of the FLOT arm vs 67.7% of the CROSS arm completed it with the full scheduled dosage. In the per-protocol population, the benefit held, with median overall survival of 66 months vs 39 months (HR = 0.72; P = .023). Virtually all subgroups derived more benefit from FLOT.
Median progression-free survival was 38 months with FLOT vs 16 months with CROSS (HR = 0.66; P = .001). For FLOT vs CROSS, progression-free survival rates were 51.6% and 35.0% at 3 years and 44.4% and 30.9% at 5 years, respectively.
Pathologic complete remission with postoperative tumor stage ypT0 ypN0 was achieved by 16.8% of the FLOT group and 10.0% of the CROSS group; complete tumor regression was noted in 18.3% vs 13.3%, respectively. Within 90 days after surgery, mortality rates were slightly lower in the FLOT group (3.2% vs 5.6%), but complication rates were generally similar.
Additional Comments
Dr. Hoeppner acknowledged that while ESOPEC was being conducted, new approaches for locally advanced esophageal cancer were developed. The use of adjuvant immunotherapy after neoadjuvant chemoradiation in patients not achieving a complete pathologic response has become an accepted treatment, and organ preservation/active surveillance for clinical complete responders after chemoradiation is an emerging concept. “Despite promising initial studies, the impact of these approaches on overall survival is currently still unclear. Nevertheless, ongoing and future trials will incorporate these concepts and expand our ability to improve cure rates and quality of life,” he said.
Expert Point of View
ASCO discussant Karyn A. Goodman, MD, MS, FASCO, Vice Chair for Research and Quality, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, said ESOPEC showed “an impressive improvement in median overall survival.” However, she noted, there were “some surprising findings” when compared with the performance of the CROSS regimen in previous trials.
Karyn A. Goodman, MD, MS, FASCO
Neo-AEGIS vs ESOPEC
As Dr. Goodman explained, FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) and CROSS (neoadjuvant chemotherapy with paclitaxel or carboplatin plus radiation) have been the two standard-of-care options for locally advanced esophageal adenocarcinoma, with preference largely guided by country of residence. Among several landmark studies of these approaches, most recently the Neo-AEGIS trial2 compared neoadjuvant CROSS with perioperative treatment consisting of either FLOT, epirubicin plus cisplatin, or oxaliplatin plus fluorouracil or capecitabine in 377 patients with esophageal or gastroesophageal junction adenocarcinoma.
Although CROSS improved all markers of local tumor response, this did not translate into an overall survival benefit. In this trial, postoperative complications were similar, and there were no apparent negative effects of preoperative chemoradiation. Dr. Goodman noted that the investigators of the Neo-AEGIS trial said there is “clinical equipoise” between the approaches.
Aiming to further establish the optimal treatment, the ESOPEC study investigators found FLOT to be superior; however, the CROSS protocol seemed to underperform, she suggested. Compared with other studies, the rates of completion of neoadjuvant therapy and achievement of pathologic complete response were both lower, and, of note, median overall survival was 39 months (compared with 43 to 50 months in other trials). Nevertheless, ESOPEC essentially settles the question of which regimen is preferable, but Dr. Goodman does not think “this is the end of the story.”
Introducing Adjuvant Immunotherapy
Newer approaches are proving to be game changers in this type of cancer, such as the use of adjuvant immunotherapy for patients not achieving complete pathologic responses. In CheckMate 577, this approach doubled the disease-free survival rate and reduced metastatic recurrences.3 “In the United States, if you use the CROSS regimen, adjuvant nivolumab is recommended for patients not achieving a complete pathologic response,” Dr. Goodman said. Other studies are evaluating various combinations of checkpoint inhibitors, chemotherapy, and radiotherapy in perioperative and adjuvant settings. Total neoadjuvant approaches are also being assessed.
“Although the results of the ESOPEC trial are impressive,” Dr. Goodman concluded, “the 5-year survival rate of only 50% is still suboptimal. We need to continue to focus on how we can do better for our patients.”
DISCLOSURE: Dr. Hoeppner has received compensation for travel or accommodations from Intuitive Surgical. Dr. Goodman has served as a consultant or advisor to Philips Healthcare and RenovoRx.
REFERENCE
1. Hoeppner J, Brunner T, Lordick F, et al: Prospective randomized multicener phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial). 2024 ASCO Annual Meeting. Abstract LBA1. Presented June 2, 2024.
2. Reynolds JV, Preston SR, O’Neill B, et al: Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): An open-label, randomised, phase 3 trial. Lancet Gastroenterol Hepatol 8:1015-1027, 2023.
3. Kelly RJ, Ajani JA, Kuzdzal J, et al: Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 384:1191-1203, 2021.
