Neoadjuvant Chemotherapy for Gastric Adenocarcinoma
FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) is the recommended neoadjuvant chemotherapy regimen for resectable locally advanced gastric adenocarcinoma, demonstrating superior pathological complete response rates, disease-free survival, and overall survival compared to older regimens. 1, 2, 3
Primary Indication for Neoadjuvant Therapy
- Neoadjuvant chemotherapy is indicated for patients with cT3-4aN+M0, stage cIII gastric adenocarcinoma according to the 8th AJCC/UICC clinical staging system 1
- Laparoscopic exploration with cytological examination of intraperitoneal washings should be performed before initiating neoadjuvant therapy to detect occult metastases that would change management 1, 2
Standard FLOT Regimen
The FLOT regimen consists of: 1, 4, 5
- Docetaxel 50 mg/m² IV on day 1
- Oxaliplatin 85 mg/m² IV on day 1
- Leucovorin 200 mg/m² IV on day 1
- 5-Fluorouracil 2600 mg/m² as 24-hour continuous infusion on day 1
- Repeated every 2 weeks for 4 preoperative cycles, followed by surgery, then 4 postoperative cycles 1, 6
Evidence supporting FLOT superiority: The FLOT4-AIO study demonstrated that FLOT achieved a 16% pathological complete response rate compared to 6% with ECF/ECX regimens (p=0.02), along with prolonged median disease-free survival, overall survival, and higher R0 resection rates with tolerable toxicity 1, 6
Alternative Regimens (When FLOT Cannot Be Tolerated)
Grade I alternatives (Evidence 2A): 1, 3
- FOLFOX: Leucovorin + fluorouracil + oxaliplatin
- SOX: Oxaliplatin + S-1
- PF: Cisplatin + 5-fluorouracil
Grade II alternatives (Evidence 2A): 1, 3
- XELOX: Oxaliplatin + capecitabine
- ECF: Epirubicin + cisplatin + 5-FU
- Modified ECF
These alternatives are appropriate for patients who cannot tolerate the three-drug FLOT regimen due to performance status, comorbidities, or toxicity concerns 3
Special Consideration: Gastroesophageal Junction (GEJ) Adenocarcinoma
For stage cIII EGJ carcinoma specifically, neoadjuvant chemoradiotherapy is the Grade I recommendation: 1
- Radiation dose: 45-50.4 Gy with concurrent chemotherapy
- Concurrent regimens include fluoropyrimidine + platinum or taxanes
- This approach reduces local recurrence rates more effectively than chemotherapy alone for EGJ tumors 1
However, neoadjuvant chemotherapy with FLOT remains an acceptable Grade II alternative for EGJ tumors 1
Critical Toxicity Management
Common grade 3-4 adverse events with FLOT: 6
- Neutropenia (52% of patients) - most frequent toxicity
- Leucopenia (28%)
- Nausea (9%)
- Infection (12%)
- Fatigue (9%)
Prophylactic G-CSF should be considered to mitigate hematological toxicities, particularly in patients at higher risk 4
Postoperative Management Algorithm
After neoadjuvant therapy and surgery: 1, 2
If R0 resection achieved with positive response: Continue the same preoperative chemotherapy regimen for 4 additional postoperative cycles 1
If R1/R2 resection or disease progression during neoadjuvant therapy: Multidisciplinary team discussion required to determine optimal treatment, with strong encouragement for clinical trial participation 1
If pathological complete response (pCR) achieved: The guidelines support completing the planned postoperative chemotherapy cycles even with pCR 1
Common Pitfalls to Avoid
Do not use carboplatin as a substitute for cisplatin or oxaliplatin in curative-intent perioperative regimens, as it has inferior efficacy 7
Do not delay surgery beyond 2-4 weeks after completing neoadjuvant chemotherapy, as this may compromise surgical outcomes 7
Do not omit laparoscopic staging before neoadjuvant therapy - it detects occult peritoneal or liver metastases in up to 30% of patients deemed resectable by imaging alone, preventing futile neoadjuvant therapy 1, 2
Ensure adequate D2 lymphadenectomy at surgery - the survival benefits of perioperative chemotherapy are optimized when combined with high-quality surgical technique 1
Regional Variation Note
While FLOT is the Western standard, adoption varies in Asian countries where it has not been widely developed, and alternative regimens like SOX may be preferred based on regional experience and S-1 availability 3