Chemotherapy regimen improves survival in advanced esophageal cancer
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Key takeaways:
- FLOT protocol conferred longer OS at multiple endpoints compared with CROSS in patients with advanced esophageal adenocarcinoma.
- FLOT had median OS more than 2 years longer in randomized, phase 3 trial.
CHIGAGO — Perioperative chemotherapy improved OS in patients with locally advanced esophageal adenocarcinoma compared with chemoradiation prior to surgery, results form a randomized phase 3 trial presented at ASCO Annual Meeting showed.
Study participants who received the FLOT protocol (fluorouracil, leucovorin, oxaliplatin and docetaxel) before and after surgery had a median OS almost 2.5 years longer than those treated with the CROSS regimen (41.4Gy plus carboplatin and paclitaxel), both considered standard of care for the patient population.
“This was our hypothesis,” Jens Hoeppner, MD, FACS, FEBS, professor of general and visceral surgery at University Medical Center OWL, University of Bielefeld in Detmold, Germany, told Healio. “I saw it in my patients. Usually when they [experience] recurrence, it’s not a local recurrence — it’s a systemic recurrence,” he added. “They develop metastases in the liver or a distant compartment, and we knew that FLOT is more effective in the distant compartment. The more pronounced effect on the distant compartment will make a difference in the survival rate and in progression-free survival.”
Background and methodology
The FLOT and CROSS protocols have long been debated for individuals with esophageal adenocarcinoma based on results from previous studies, Hoeppner said.
However, those trials did not evaluate the same patient populations, he explained.
“We were the first to go for a head-to-head comparison,” Hoeppner said.
The ESOPEC trial, conducted across 25 sites in Germany, included 438 adults (median age, 63 years; 89% men) with various stages of resectable esophageal adenocarcinoma.
Researchers randomly assigned study participants in a 1:1 ratio to receive treatment with FLOT (n = 221) or CROSS (n = 217).
The impact of each treatment regimen on OS served as the study’s primary endpoint.
Results and next steps
Participants in the FLOT arm had lower mortality rates at multiple checkpoints following surgery.
Overall, 4.3% of patients died within 90 days of surgery (3.2% in FLOT; 5.6% in CROSS), and 218 died at a median follow-up of 55 months (97 in FLOT; 121 in CROSS).
The FLOT arm had a 30% lower mortality risk at 3 years and a higher OS rate (57% vs. 51%).
The FLOT cohort had a median OS of 66 months, whereas the CROSS group had a median OS of 37 months.
The FLOT group also had more complete responses (35 vs. 24).
Researchers plan to investigate whether patients with esophageal adenocarcinoma need surgery if they have a complete response to either FLOT or CROSS and do not have tumor growth during active surveillance.
“We’re used to seeing a significant proportion of patients who achieve complete response after neoadjuvant treatment,” Hoeppner said. “We operate on these patients, and get from pathology the result that there were no vital tumor cells in this subgroup — so we as surgeons and [our] patients must ask was it right to operate if there was no vital tumor in the specimen we took out,” he added. “The next [step] is to define these patients, identify them and not to operate on this subgroup, which is around 15% to 20%.”
Hoeppner noted the CROSS protocol still has benefits for patients with squamous-cell carcinoma, but not for patients with adenocarcinoma.
“If you ask a radiation oncologist, [they might say] do some immunotherapy and adjuvant and we can get better results,” Hoeppner said. “But the classic CROSS protocol, with neoadjuvant chemoradiation, surgery and no adjuvant treatment, will be out.”
“There is 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, MPH, surgical oncologist and gastrointestinal surgeon at Boston Medical Center, said in an ASCO-issued press release. “This randomized clinical trial from Europe answers that question for patients similar to those enrolled in the trial: preoperative plus postoperative chemotherapy provides better outcomes.”
Perspective
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Dani Castillo, MD
The data appears to favor the FLOT regimen over CROSS. However, in real practice, the choice between the two depends on patient preference or tolerability, functional status, and goals of care. Some early esophageal adenocarcinomas may be overtreated with FLOT, potentially missing the opportunity for adjuvant immunotherapy for patients who have a nonpathologic complete response. For those with high nodal burden disease, FLOT may be more beneficial.
ESOPEC is a well-designed phase 3 study with many patients and a very homogeneous patient population, which raises important clinical questions regarding tailored practice. Ongoing studies are needed that incorporate stratification factors such as Siewert type, nodal burdens, and symptoms at the time of diagnosis. Global studies should encompass patients from diverse backgrounds to ensure comprehensive data analysis.
Perspective
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Patrick Boland, MD
The Phase III ESOPEC study is a practice changing study comparing standard of care chemotherapy, FLOT, to chemoradiation with carboplatin and paclitaxel. Though completion rates of neoadjuvant therapy were low in the CROSS arm (67.7%), this was almost exclusively due to an omitted dose of chemotherapy, presumably owing to transient cytopenias, as commonly seen in practice. Full radiation treatment was completed in 98% of patients. A persistent absolute PFS improvement of near 15% was achieved by 3 years in the patient group receiving FLOT. Importantly Survival was significantly improved, with a median overall survival (OS) increase from 37 to 66 months and absolute overall survival (OS) improvements of 6.7% at 3 years and 11.9% at 5 years. The subset of patients with younger age, T3/T4 vs T1/T2 and N+ disease appeared to derive greatest benefit from FLOT, while there was no subgroup that hinted at a better outcome with chemoradiation. FLOT is the new standard.
It is a fair criticism that the chemoradiation arm did not utilize adjuvant nivolumab. However, we still don’t actually know whether this strategy from Checkmate-577 improves survival. And we don’t know whether any potential survival benefit makes up for the OS sacrifice with use of initially inferior systemic treatment. Long term follow-up from this Checkmate-577 will be extremely important as we navigate patients with this disease, as will the results of TOPGEAR, a study that compares the strategy of neoadjuvant chemotherapy to that of adding chemoradiation after a course of neoadjuvant chemotherapy: FLOT or EC(O)F(X).
Given that the median age of patients diagnosed with esophageal cancer is 68, there remain many patients who will not be eligible for treatment with FLOT. In these cases, a chemoradiation approach makes most sense at present, with adjuvant nivolumab as indicated. In addition, patients with earlier stage and clinically node negative tumors, with a lesser risk of systemic spread, likely derive less absolute benefit from FLOT. This is another scenario where a chemoradiation based approach may remain preferred. As suggested in the excellent plenary discussion, risk adapted strategies, combinatorial strategies, and the focused development of approaches that may allow selective organ preservation should remain priorities moving forward. Long term quality of life is so important in this disease.
RWJBarnabas Health
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Hoeppner J, et al. Abstract LBA1. Presented at: ASCO Annual Meeting; May 31-June 4, 2024: Chicago.
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