By Will Boggs MD
NEW YORK (Reuters Health) - 27/5/2019
"FLOT is the first regimen to show a survival improvement of a new regimen over another effective regimen in the multimodal therapy of gastric and gastroesophageal junction cancer," said Dr. Salah-Eddin Al-Batran from UCT-University Cancer Center, in Frankfurt, Germany.
"Definitely, FLOT should be the standard of care in the routine therapy of our patients. It should also represent the control arm for future randomized trials," he told Reuters Health by email.
The combination of epirubicin, cisplatin, and fluorouracil (ECF) has been shown to improve survival when administered before or after surgery in patients with gastric adenocarcinoma, but five-year survival rates remained low at 36%.
Dr. Al-Batran and colleagues from 38 German sites evaluated perioperative FLOT versus ECF or the combination of epirubicin, cisplatin and capecitabine (ECX) in their randomized phase 2/3 trial of 716 patients with locally advanced gastric or gastroesophageal junction adenocarcinoma.
The primary outcome, median overall survival, was significantly longer in the FLOT group (50 months) than in the ECF/ECX group (35 months), the team reports in The Lancet, online April 11.
Estimated overall survival in the FLOT group was 68% at two years, 57% at three years and 45% at five years, compared with 59%, 48% and 36%, respectively, in the ECF/ECX group.
Median disease-free survival was also significantly longer in the FLOT group (30 months) than in the ECF/CCX group (18 months).
There were significantly more grade 3 or 4 nausea, vomiting, anemia and thromboembolic events in the ECF/ECX group and significantly more grade 3 or 4 infections, neutropenia, diarrhea and neuropathy events in the FLOT group.
At least 95% of each group proceeded to surgery, although significantly more patients in the FLOT group (94%) than in the ECF/ECX group (87%) received tumor surgery.
More patients in the FLOT group (85%) than in the ECF/ECX group (78%) achieved margin-free (R0) resection.
The groups did not differ in the incidence of postoperative complications, median duration of hospital stay, or number of reoperations and deaths within 30 days of surgery.
The relative treatment effect of FLOT was consistent across age, anatomical site, histology and clinical stage subgroups.
"The (older) 2-drug regimens such as cisplatin/5-FU or FOLFOX are no longer standard of care," Dr. Al-Batran said. "They can be used in patients with reduced ECOG performance status who do not qualify for FLOT."
Physicians should "treat their patients with resectable gastric or gastroesophageal junction cancer of a stage T2 or higher with perioperative FLOT," he said. "It is important that physicians also use FLOT as the control arm in future trials to further improve survival."
"Although Al-Batran and colleagues' findings reaffirm FLOT to be associated with significant improvement in overall survival with a median of 50 months, the 5-year survival rate remains less than 50%, implying that more efforts are needed to improve the efficacy of the treatment," write Dr. Yoon-Koo Kang and Dr. Hyungwoo Cho from Asan Medical Center at the University of Ulsan College of Medicine, in Seoul, in a linked editorial.
As examples, they describe ongoing trials of preoperative radiotherapy and anti-HER2 antibodies (for HER2-positive tumors) and suggest considering immune checkpoint inhibitor-based regimens in either preoperative or postoperative settings.
Dr. Erling Audun Bringeland from Trondheim University Hospital and the Norwegian University of Science and Technology, in Norway, who recently reviewed perioperative chemotherapy for resectable gastric cancer, told Reuters Health by email, "It should be noted that the FLOT regimen is a toxic one, not very different from the MAGIC regimen. Less than 50% of all patients embarking on this regimen of perioperative chemotherapy will be able to complete all four preoperative and all four postoperative scheduled chemocycles."
"Moreover, in spite of some patients enduring such toxic regimens, 5-year survival rate is no more than 45%, probably somewhat lower as a non-negligible proportion of the patients have a somewhat short follow-up, as commented by the authors," he said. "This all attests that further research is needed. The results of this trial are nowhere close to being any breakthrough - but merely an increment of a step forward along a long way to go."
Dr. Joseph Chao from City of Hope's Gastrointestinal Cancer Program, in Duarte, California, who has researched various aspects of gastric cancer and its treatment, told Reuters Health by email, "FLOT has already entered professional guideline recommendations and treatment pathways, though should be reserved for select, fit patients, given this regimen still carries some significant side effects. ECF should no longer be prescribed, given the clear survival benefit demonstrated with the FLOT regimen."
"The FLOT4 trial does not address the question of whether it should replace the current other major standard of care of neoadjuvant chemoradiation," he said. "Ongoing phase 3 trials comparing these two approaches should hopefully shed more light on optimizing outcomes for these patients."
Sanofi-Aventis and Chugai funded the study and had various relationships with many of the authors, including Dr. Al-Batran.