Clinical trialPhase 2/3Stomach cancerOesophageal cancer
Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial
Lancet · 2019716 patients (356 FLOT and 360 ECF/ECX)
Al-Batran SE, Homann N, Pauligk C, et al. Lancet. 2019. 393:1948-1957
Study type
Clinical trial
Study name
FLOT4
Phase
Phase 2/3
Design
Randomised, controlled, open-label trial at 38 hospitals and oncology practices in Germany
In stomach cancer that has not spread to distant organs but is "locally advanced" because of its size or lymph node involvement, part of the chemotherapy is usually given before surgery and part after. This large German study showed that the four-drug FLOT regimen (once every two weeks) helped patients live significantly longer than the older ECF/ECX regimen (median about 50 months versus 35 months), while the rate of serious side effects was similar in the two groups. That is why FLOT is now one of the standard treatments before and after surgery for patients who are physically fit enough.
Key results
50 months vs 35 months
Median overall survival
FLOT vs ECF/ECX; HR 0.77 (95% CI 0.63 to 0.94)
27% vs 27%
Serious treatment-related adverse events
97 patients in the FLOT group and 96 patients in the ECF/ECX group
2 patients in each group
Toxic deaths
Less than 1% in each group
25% vs 26%
Hospitalisation because of toxicity
89 patients in the FLOT group and 94 patients in the ECF/ECX group
Resectable adenocarcinoma of the stomach or gastroesophageal junction, clinical stage cT2 or higher and/or cN+, without distant metastasesCycle length: Every 14 daysOn the page “Stomach cancer” · Localized resectable disease: perioperative and adjuvant therapy
Resectable adenocarcinoma of the stomach or gastroesophageal junction, clinical stage cT2 or higher and/or cN+, without distant metastases
Resectable gastric or junctional cancer cT2 or higher or cN+ (outside the FDA label)Cycle length: Every 14 daysOn the page “Docetaxel (Taxotere)” · Regimens and dosing
Resectable gastric or junctional cancer cT2 or higher or cN+ (outside the FDA label)
Resectable adenocarcinoma of the stomach or gastroesophageal junction, stage II to IVA (AJCC 8th edition), ECOG 0–1, no active autoimmune diseaseOn the page “Stomach cancer” · Localized resectable disease: perioperative and adjuvant therapy
Resectable adenocarcinoma of the stomach or gastroesophageal junction, stage II to IVA (AJCC 8th edition), ECOG 0–1, no active autoimmune disease
Every 28 days (FLOT every 14 days, i.e., days 1 and 15 of each cycle)
Duration
2 cycles before surgery; after surgery, 2 cycles with FLOT followed by durvalumab monotherapy for up to 10 cycles (a maximum of 12 cycles in total after surgery)
Durvalumab dose and schedule from the FDA label; in the MATTERHORN trial, event-free survival and overall survival were improved. The doses of the individual FLOT components are not stated separately in the label or the abstracts; the standard FLOT4 doses serve as the basis.
Resectable adenocarcinoma of the oesophagus or gastroesophageal junction, clinical stage cT1 cN+ or cT2–cT4a with any N status, no distant metastasesCycle length: Every 14 daysOn the page “Oesophageal cancer” · Locally advanced disease: treatment with curative intent
Resectable adenocarcinoma of the oesophagus or gastroesophageal junction, clinical stage cT1 cN+ or cT2–cT4a with any N status, no distant metastases
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Treatment arms and regimens
1FLOT (experimental group)
Docetaxel 50 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m² and fluorouracil (5-FU) 2600 mg/m² as a 24-hour infusion, all IV on day 1 every two weeks.
Four cycles before surgery (8 weeks) and four cycles after surgery (8 weeks).
2ECF/ECX (control group)
Epirubicin 50 mg/m² and cisplatin 60 mg/m² IV on day 1, with either fluorouracil 200 mg/m² as a continuous IV infusion or capecitabine 1250 mg/m² orally on days 1 to 21; three-week cycles.
Three cycles before surgery and three cycles after surgery.
Source of the regimen details: Abstract of the paper (Lancet 2019) and ClinicalTrials.gov NCT01216644 (dose, route and number of cycles for both groups)
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Patients with histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction (GEJ), clinical stage cT2 or higher and/or with lymph node involvement (cN+), resectable and without evidence of distant metastasis.
Endpoints
Primary endpoint: overall survival (OS; superiority test) in the intention-to-treat population.
Other endpoints: safety, serious treatment-related adverse events (including during the hospital stay for surgery), toxic deaths and hospitalisation because of toxicity.
Safety and side effects
The number of patients with serious treatment-related adverse events (including complications during the hospital stay for surgery) was similar in the two groups (27% in both). There were 2 toxic deaths (less than 1%) in each group, and hospitalisation because of toxicity occurred in 25% of patients in the FLOT group and 26% in the ECF/ECX group. Details of grade 3 and 4 adverse events by type are in the full text.
Clinical significance and place in guidelines
FLOT4 made perioperative FLOT the standard of care for resectable gastric and gastro-oesophageal junction cancer (in patients fit for triplet therapy) in Europe and North America. The 2022 ESMO guideline recommends perioperative chemotherapy for stage IB to III with level of evidence [I, A], and the NCCN guideline (version 2.2025) considers perioperative chemotherapy a category 1 recommendation for resectable T2 or higher tumours with any N. FLOT was also the backbone regimen in the MATTERHORN trial, and the addition of durvalumab to it was FDA-approved in 2025.
Limitations
The trial was open-label (no blinding) and conducted only in Germany; the comparator (ECF/ECX) is a regimen that is used less today. Completion rates of postoperative cycles are reported in the full text, and the triplet regimen is not suitable for older patients or those with poor performance status. Asian populations, in whom upfront surgery and adjuvant therapy are more common, were not studied.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.
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