Perioperative FLOT outdoes ECF/ECX for gastric, gastro-oesophageal junction adenocarcinoma
Use of docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as perioperative therapy in patients with locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma confers superior overall survival benefit compared with the standard of care epirubicin and cisplatin plus fluorouracil or capecitabine (ECF/ECX), according to the results of the open-label phase II/III FLOT4 trial.
“To our knowledge, this is the first trial to show significant improvement over the available standard of care ECF,” expanding the available options for the treatment of locally advanced, resectable gastric and gastro-oesophageal adenocarcinoma, the investigators said.
FLOT4 randomized 716 patients (median age 62 years; 74.45 percent male) from Germany with histologically confirmed advanced (≥cT2 and/or cN+) disease to undergo surgical resection with either three preoperative and three postoperative 3-week ECF/EFX cycles (control; n=360) or four preoperative and four postoperative 2-week FLOT cycles (experimental; n=356).
Compared with ECF/ECX, FLOT yielded a significant increase in the primary endpoint of overall survival (median, 50 vs 35 months), cutting the risk of death by 23 percent (hazard ratio [HR], 0.77, 95 percent CI, 0.63–0.94; p=0.012). This survival advantage was consistent across subgroups defined by age, anatomical site, histology and clinical stage.
The respective estimated overall survival at 2, 3 and 5 years were 68 percent, 57 percent and 45 percent in the experimental arm vs 59 percent, 48 percent and 36 percent in the control arm. [Lancet 2019;393:1948-1957]
FLOT also produced substantial improvements in the margin-free resection rate (85 percent vs 78 percent; p=0.016) and disease-free survival (median, 30 vs 18 months; HR, 0.75, 0.62–0.91; p=0.0036).
There were no significant between-group differences observed in the rates of serious adverse events (27 percent in both arms), toxic deaths (<1 percent in both arms) and hospitalization for toxicity (25 percent with FLOT vs 26 percent with ECF/ECX).
Doses administered were 50 mg/m2 for docetaxel, 85 mg/m2 for oxaliplatin, 200 mg/m2 for leucovorin and 2,600 mg/m2 for fluorouracil as 24-h infusion on day 1 in the experimental arm; and 50 mg/m2 for epirubicin and 60 mg/m2 for cisplatin on day 1 plus either 200 mg/m2 for fluorouracil as continuous intravenous infusion or 1,250 mg/m2 for capecitabine orally on days 1 to 21 in the control arm.
In light of the present data and despite some limitations, the investigators proposed that FLOT be regarded as the recommended perioperative chemotherapy for patients with gastric cancer or adenocarcinoma of the gastro-oesophageal junction including Siewert type I tumours, as well as those with or without Barret mucosa, and hence the new standard of care for patients who would have been candidates for perioperative ECF or CF.
Feasible, with caveats
In a linked commentary piece, Drs Yoon-Koo Kang and Hyungwoo Cho from the University of Ulsan College of Medicine in Seoul, South Korea, echoed the investigators’ sentiment but qualified that FLOT should be recommended as perioperative chemotherapy in Europe only, as there are issues that need to be addressed before the regimen can be considered as a globally accepted standard of care. [Lancet 2019;393:1914-1916]
For the most part, the dose intensity of docetaxel in FLOT4 was high relative to that of Asian triplet regimens evaluated in the phase III JCOG0501 and PRODIGY trials, with grade 3 or 4 neutropaenia observed in approximately 50 percent of the patients treated with FLOT, according to Kang and Chan. [J Clin Oncol 2018;36:4046; J Clin Oncol 2015;33:TPS4136]
“This raises the concern of the feasibility of this regimen … in the Asian population, who are known to be more vulnerable to bone marrow suppression,” they said.
The experts also underscored the possibility of having to increase the tolerability of the postoperative treatment by decreasing the dose intensity or the number of cycles of FLOT or by using a more tolerable regimen, given that only 60 percent of patients in the experimental arm started the allocated postoperative chemotherapy and 46 percent completed all the allocated cycles.
“[T]he postoperative treatment strategy might need to be more individualized according to the parameters that reflect the response to preoperative treatment, such as tumour regression grade,” Kang and Chan wrote.
Finally, although the findings “reaffirm FLOT to be associated with significant improvement in overall survival with a median of 50 months, the 5-year survival rate remains <50 percent, implying that more efforts are needed to improve the efficacy of the treatment,” they added.