What are the recommended neoadjuvant regimens for gastric adenocarcinoma?

Neoadjuvant Therapy for Gastric Adenocarcinoma

For locally advanced gastric adenocarcinoma (cT3-4aN+M0, stage cIII), FLOT (5-fluorouracil, leucovorin, oxaliplatin, docetaxel) is the preferred neoadjuvant regimen, demonstrating superior overall survival, disease-free survival, and pathological response rates compared to older regimens. 1, 2

Treatment Algorithm by Clinical Stage and Tumor Location

For Stage cIII Gastric Adenocarcinoma (cT3-4aN+M0)

Grade I (First-Line) Recommendations:

• FLOT regimen (Evidence 2A): This has emerged as the new standard based on the FLOT4-AIO study, showing prolonged median disease-free survival and overall survival, higher pathological response rates, and better R0 resection rates with tolerable toxicity profiles compared to ECF/ECX regimens 1, 2
• FOLFOX (leucovorin + fluorouracil + oxaliplatin) (Evidence 2A) 1
• SOX (S-1 + oxaliplatin) (Evidence 2A) 1

Grade II (Alternative) Recommendations:

• PF (cisplatin + 5-fluorouracil) (Evidence 2A) 1
• XELOX (oxaliplatin + capecitabine) (Evidence 2A) 1

For Esophagogastric Junction (EGJ) Carcinoma, Stage cIII

Preferred approach:

• Neoadjuvant chemoradiotherapy: 45-50.4 Gy with concurrent fluoropyrimidine, platinum, or taxanes (Evidence 1B) 1
  • This is based on studies showing reduced local recurrence and improved survival trends for EGJ tumors specifically 1

Alternative approach:

• Neoadjuvant chemotherapy using the same regimens as above (Evidence 2A) 1

For cT4bNanyM0, Stage cIVA (Without Unresectable Factors)

• Multidisciplinary team (MDT) discussion is mandatory to determine optimal treatment 1
• Clinical trial participation is strongly encouraged 1

Specific Dosing Regimens

FLOT Protocol:

• Docetaxel 50 mg/m² IV day 1
• Oxaliplatin 85 mg/m² IV day 1
• Leucovorin 200 mg/m² IV day 1
• 5-FU 2600 mg/m² as 24-hour continuous infusion day 1
• Repeat every 2 weeks for 4 preoperative cycles 3, 4

For Gastric Adenocarcinoma (FDA-approved):

• Docetaxel 75 mg/m² IV over 1 hour on day 1
• Cisplatin 75 mg/m² IV over 1-3 hours on day 1
• 5-FU 750 mg/m²/day as continuous IV infusion for 5 days
• Repeat every 3 weeks 3

Critical Timing and Sequencing

Preoperative Phase:

• Administer 4 cycles of chosen regimen preoperatively 1, 2
• Laparoscopic exploration with cytological examination of peritoneal washings should be performed before initiating neoadjuvant therapy to detect occult metastases 1, 2

Response Assessment:

• Evaluate efficacy using EUS, CT, or PET/CT after neoadjuvant therapy 1
• Proceed to surgery 2-4 weeks after completion of chemotherapy 5

Postoperative Phase:

• For patients achieving R0 resection with positive radiological/pathological response, continue the same preoperative chemotherapy regimen for 4 additional cycles 1, 2
• For patients failing to achieve R0 resection, postoperative chemoradiotherapy is recommended 1, 2

Evidence Hierarchy and Nuances

Why FLOT is Superior: The FLOT4-AIO study demonstrated that FLOT extends median overall survival by approximately 13 months (50 months vs 37 months, HR 0.77) compared to ECF/ECX, with higher pathological complete response rates 1. This represents a clinically meaningful survival benefit that justifies the three-drug regimen despite increased toxicity 1.

Regional Considerations:

• Perioperative chemotherapy has proven superior to surgery alone in Western populations 1
• Asian studies demonstrate improved tumor remission rates and R0 resection rates with neoadjuvant approaches 1
• S-1-containing regimens show modest survival improvement versus 5-FU regimens (HR 0.91), but dosing differs between Asian and non-Asian populations, limiting generalizability 6

Oxaliplatin vs Cisplatin: Oxaliplatin-containing regimens may extend OS by less than one month compared to cisplatin-containing regimens (HR 0.81), with potentially better tolerability, particularly in elderly patients 6. This makes oxaliplatin-based regimens (FLOT, FOLFOX) attractive alternatives 1.

Common Pitfalls and How to Avoid Them

Inadequate Staging:

• Pitfall: Proceeding to neoadjuvant therapy without laparoscopic staging may miss occult peritoneal or liver metastases present in up to one-third of cases 1, 2
• Solution: Perform diagnostic laparoscopy with peritoneal washings before initiating treatment 1, 2

Inappropriate Regimen Selection:

• Pitfall: Using older ECF regimens when FLOT is available and tolerable 1
• Solution: Reserve ECF/modified ECF for patients unable to tolerate docetaxel-containing regimens 1

Failure to Complete Postoperative Chemotherapy:

• Pitfall: Only 50-60% of patients complete postoperative chemotherapy due to surgical complications and delayed recovery 1
• Solution: Optimize nutritional status preoperatively, ensure adequate performance status, and closely monitor for early intervention of complications 1

Misapplication of Chemoradiotherapy:

• Pitfall: Using neoadjuvant chemoradiotherapy for non-EGJ gastric cancers outside clinical trials 1
• Solution: Reserve chemoradiotherapy for EGJ carcinomas (stage cIII); use chemotherapy alone for other gastric locations 1

Toxicity Management:

• Pitfall: Inadequate premedication leading to severe hypersensitivity reactions or fluid retention with docetaxel 3
• Solution: Premedicate with dexamethasone 16 mg/day (8 mg twice daily) for 3 days starting 1 day before docetaxel administration 3

Special Populations

Disease Progression During Neoadjuvant Therapy:

• MDT discussion is mandatory 1
• Consider switching to alternative chemotherapy regimens or proceeding directly to surgery if technically feasible 1

R1/R2 Resection After Neoadjuvant Therapy:

• MDT discussion required to determine optimal postoperative management 1
• Postoperative chemoradiotherapy should be strongly considered 1, 2