Findings from the phase 3 ESOPEC trial demonstrate an overall survival advantage with a perioperative chemotherapy regimen known as FLOT compared with a neoadjuvant chemoradiation approach, called CROSS, in patients with resectable, locally advanced esophageal adenocarcinoma.
The study results, presented as a late-breaking abstract at the American Society of Clinical Oncology (ASCO) annual conference, help settle a long-standing debate about whether chemotherapy with FLOT — 5-florouracil, leucovorin, oxaliplatin, and docetaxel — before and after surgery, or neoadjuvant radiation plus CROSS — carboplatin and paclitaxel — followed by surgery is the best approach.
There has been "considerable disagreement as to whether giving all adjuvant therapy upfront versus 'sandwich' adjuvant therapy before and after surgery is the better standard of care for locally advanced resectable esophageal cancer," Jennifer Tseng, MD, of Boston Medical Center, Boston, said in an ASCO press release. This randomized clinical trial shows the sandwich approach "provides better outcomes."
The practice-changing ESOPEC findings will have an important effect on the management of patients with resectable esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, but local and distant failures remain a challenge in this population, explained invited discussant Karyn A. Goodman, MD.
Advances since the initiation of ESOPEC — such as immunotherapy options and personalized strategies — suggest the esophageal adenocarcinoma story is still evolving, said Goodman, professor and vice-chair of research and quality in the Department of Radiation Oncology at Icahn School of Medicine at Mount Sinai, New York City.
The ESOPEC trial
Both the FLOT and CROSS regimens are established standards of care in resectable esophageal adenocarcinoma, and the choice of treatment has largely varied based on geographical location.
The current randomized, prospective, open-label ESOPEC trial, however, demonstrated that FLOT can prolong overall survival, first author Jens Hoeppner, MD, from the University of Bielefeld in Detmold, Germany, reported.
Overall, 438 patients with locally advanced, resectable esophageal adenocarcinoma recruited between February 2016 and April 2020 from 25 sites in Germany and randomized to either FLOT (n = 221) or CROSS (n = 217). The median age was 63 years, and most (89.3%) were men. Patients were followed until November 2023, and median follow-up was 55 months.
Patients in the FLOT arm received four cycles — one every 2 weeks for 8 weeks —followed by surgery 4-6 weeks later. FLOT cycles were reinitiated 4-6 weeks after surgery and given every 2 weeks for 8 weeks.
Those in the CROSS arm received one cycle per week of radiation therapy for 5 weeks plus carboplatin and paclitaxel followed by surgery 4-6 weeks after the last cycle.
Overall, 86% received both neoadjuvant therapy and surgery in the FLOT arm vs 82.9% in the CROSS group. Among these patients, 16.8% in the FLOT group achieved a pathological complete remission vs 10.0% in the CROSS arm.
In the intention-to-treat population, median overall survival was almost twice as long in the FLOT group — 66 months vs 37 months. At 3 years, those who received FLOT had a 30% lower risk of dying (hazard ratio [HR], 0.70), with 57.4% patients alive at that point compared with 50.7% patients in the CROSS arm.
The 5-year overall survival was 50.6% in the FLOT group vs 38.7% in the CROSS group.
Patients receiving FLOT also demonstrated improved progression-free survival (PFS), with a median PFS of 38 months vs 16 months. The 3-year PFS was 51.6% with FLOT vs 35.0% with CROSS (HR, 0.66). The exploratory subgroup analyses for sex, age, ECOG status, and clinical T and N stages also favored FLOT.
The 30-day postoperative mortality was 1.0% in the FLOT group and 1.7% in the CROSS group, and the 90-day postoperative mortality rate was 3.2% and 5.6%, respectively.
Based on these findings, perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with CROSS, Hoeppner concluded.
Goodman agreed, noting that, in the wake of ESOPEC, FLOT will likely be adopted as a more standard approach in the United States for patients who are fit. And, for patients who are not candidates for FLOT, CROSS is a reasonable option, she said.
But, she asked, does it really have to be an either/or situation?
Multiple studies, including Goodman's 2021 Alliance/CALGB 80803 study, have demonstrated promising outcomes with combined modalities and adapting therapy based on treatment response. Several trials, for instance, are evaluating combining FLOT and CROSS, with some showing the approach is feasible and comes with manageable toxicity.
It's also important to look outside of FLOT and CROSS. During ESOPEC, new approaches entered the treatment landscape, including the use of adjuvant immunotherapy following neoadjuvant chemoradiation and surgery for noncomplete response.
Take the CheckMate 577 study, which found that adjuvant nivolumab immunotherapy after preoperative CROSS and surgery significantly reduced metastatic recurrence and doubled disease-free survival in patients who did not achieve a complete response. This approach is now a standard of care for those patients.
FLOT plus neoadjuvant nivolumab may also be a viable option, Goodman noted, but we haven't yet seen "any benefit in survival with the combo of chemotherapy and immunotherapy for resectable esophago-gastric cancer."
Further studies are needed to evaluate the synergy of immunotherapy and radiotherapy. The next chapter of the esophageal adenocarcinoma story may feature a "best-of-both-worlds" approach that combines induction chemotherapy, followed by personalized chemoradiation, surgery, and potentially adjuvant immunotherapy, Goodman explained.
While the ESOPEC findings are impressive, the 5-year overall survival of only 50% is still suboptimal, she noted. "Given the poor prognosis with this disease, we need to continue to develop clinical trials to identify better targets, novel treatment combinations, and select patients that will respond best to specific treatment."
ESOPEC was funded by the Deutsche Forschungsgemeinschaft (German Research Foundation). Hoeppner reported receiving travel, accommodations, and expenses from Intuitive Surgical. Goodman reported a relationship with the national Cancer Institute and consulting or advisory roles for Novartis, Philips healthcare, RenovoRX, and Roche/Genentech.
Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X @SW_MedReporter.