What is the role of the FLOT (docetaxel, oxaliplatin, fluorouracil, and leucovorin) regimen in the treatment of gastric cancer, as demonstrated by the FLOT4 trial?

FLOT Regimen in Gastric Cancer Treatment: The FLOT4 Trial

The FLOT regimen (docetaxel, oxaliplatin, fluorouracil, and leucovorin) is superior to standard ECF/ECX regimens for perioperative treatment of resectable gastric and gastroesophageal junction adenocarcinoma, demonstrating significantly improved overall survival and should be considered the new standard perioperative chemotherapy regimen for these patients. 1

Evidence from the FLOT4 Trial

• The FLOT4 trial was a randomized phase 2/3 study comparing perioperative FLOT with the standard ECF/ECX regimen in patients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma 1
• FLOT significantly reduced the risk of death compared to ECF/ECX with a hazard ratio of 0.77 (95% CI: 0.63-0.94) 1
• Median overall survival was substantially improved with FLOT (50 months vs. 35 months with ECF/ECX), representing a 15-month survival advantage 1, 2
• FLOT also provided better complete resection rates and better complete pathological response rates compared to ECF/ECX 2

FLOT Regimen Components and Administration

• The FLOT regimen consists of:
  • Docetaxel (50 mg/m²)
  • Oxaliplatin (85 mg/m²)
  • Leucovorin (200 mg/m²)
  • 5-Fluorouracil (2600 mg/m² as 24-hour infusion) 1
• Treatment is administered on day 1 of a 2-week cycle 1
• The perioperative protocol includes four preoperative and four postoperative cycles 1

Toxicity Profile

• FLOT is associated with higher rates of:
  • Diarrhea
  • Leuco-neutropenia (51% severe cases)
  • Infections (18% severe cases)
  • Peripheral neuropathy 2
• ECF/ECX regimens are more likely to cause:
  • Severe nausea and vomiting
  • Severe anemia
  • Thromboembolic events 2
• The overall number of serious adverse events was similar between FLOT and ECF/ECX groups 1, 2
• Toxic deaths were rare and comparable between regimens (less than 1% in both groups) 1

Clinical Application

• FLOT is now recommended as the standard perioperative chemotherapy for patients with resectable gastric cancer or adenocarcinoma of the gastroesophageal junction 3
• In the FLOT4 trial, 46% of patients in the FLOT group completed all planned treatment cycles, compared to 37% in the ECF/ECX group 2
• For patients who may not tolerate the full FLOT regimen, dose modifications may be necessary 4
• A Chinese dose-finding study determined a modified FLOT regimen with docetaxel 45 mg/m², oxaliplatin 75 mg/m², leucovorin 200 mg/m², and fluorouracil 2200 mg/m² as the recommended dose for Chinese patients 4

Patient Selection Considerations

• FLOT should be considered for patients with:
  • Locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma 1
  • Good performance status to tolerate the regimen 2
  • Clinical stage T3-4 or node-positive disease 5
• Caution should be exercised in:
  • Elderly patients or those with poor performance status due to increased toxicity 2
  • Patients with significant comorbidities that might increase treatment-related complications 2

Alternative Regimens

• For patients who cannot tolerate FLOT, other evidence-based options include:
  • ECF (epirubicin, cisplatin, 5-FU) 3
  • FOLFOX (5-FU, leucovorin, oxaliplatin) 3
  • XELOX (capecitabine, oxaliplatin) 3
  • SOX (S-1, oxaliplatin) 3
  • FOLFIRI (5-FU, leucovorin, irinotecan) for patients unable to tolerate platinum-based therapy 3

Real-World Effectiveness

• A propensity score-based analysis in Chinese patients showed that FLOT as preoperative chemotherapy improved overall survival compared to initial surgery followed by chemotherapy (HR 0.416; 95% CI 0.218-0.794) 5
• Three-year survival rates were 58.7% with FLOT-first approach versus 30.9% with surgery-first approach 5
• The benefit of FLOT appears to be less pronounced in patients without lymph node metastasis 5

Implementation Challenges

• Despite the proven benefits, there are concerns about implementing FLOT in unselected patients in daily practice due to its toxicity profile 2
• Close monitoring for neutropenia, infections, and diarrhea is essential during FLOT treatment 2
• Prophylactic growth factor support may be considered for patients at high risk of neutropenic complications 2