For a patient with stage III gastric cancer (clinical T3, clinical N1), PD‑L1 CPS 35, HER2‑negative, and microsatellite stable disease, what is the recommended next step in management?

Perioperative FLOT Chemotherapy Followed by Surgery with D2 Lymphadenectomy

For your stage III gastric cancer (cT3N1, HER2-negative, MSS, PD-L1 CPS 35), proceed with perioperative FLOT chemotherapy (4 cycles preoperatively, then surgery, then 4 cycles postoperatively) as the standard of care. 1, 2

Treatment Algorithm

1. Immediate Next Step: Perioperative FLOT

• FLOT regimen: 5-FU, leucovorin, oxaliplatin, and docetaxel
• Timing: 4 cycles preoperatively → surgery → 4 cycles postoperatively
• Rationale: FLOT is the established standard for resectable stage IB-III gastric cancer, demonstrating superior overall survival (50 months vs 35 months with ECF/ECX; HR 0.77, P=0.012) 2

2. Surgery: D2 Gastrectomy

• Perform at a high-volume surgical center
• D2 lymphadenectomy is mandatory
• Timing: After 4 preoperative FLOT cycles, assuming adequate response and resectability 2

3. Postoperative Completion

• Complete remaining 4 cycles of FLOT postoperatively
• No radiation therapy: Post-operative RT provides no added benefit after R0 resection with perioperative chemotherapy 2

Why NOT Immunotherapy in Your Case (Despite High PD-L1)

While your PD-L1 CPS of 35 is exceptionally high, immunotherapy is NOT currently standard for resectable/perioperative stage III gastric cancer with MSS status:

• KEYNOTE-859 established pembrolizumab + chemotherapy for advanced/metastatic HER2-negative disease with PD-L1 CPS ≥1, showing improved OS (15.7 vs 11.8 months for CPS ≥10) 1
• However, this applies to unresectable, locally advanced, or metastatic disease—not your resectable stage III presentation
• The ESMO 2022 guidelines explicitly state that for resectable stage IB-III disease, perioperative FLOT remains standard 2

Emerging Context (Not Yet Standard)

• Case reports suggest chemoimmunotherapy may benefit MSI-H locally advanced gastric cancer 3
• One case report showed response in MSS disease with very high PD-L1 (CPS ≥70) 4
• However: These are case reports, not level I evidence. Clinical trials are ongoing for immunotherapy in the perioperative setting, but results are not yet practice-changing 2, 5

MSS Status Considerations

Your MSS (microsatellite stable) status is critical:

• MSI-H tumors show better prognosis and may not benefit from adjuvant chemotherapy after R0 resection 2
• Your MSS tumor requires full perioperative chemotherapy as planned
• MSS tumors have historically shown less dramatic responses to immunotherapy compared to MSI-H, though high PD-L1 may modify this 4, 6

Clinical Pitfalls to Avoid

1. Don't skip preoperative chemotherapy: Neoadjuvant therapy allows tumor downsizing, increases R0 resection rates, and ensures more patients receive systemic therapy (postoperative completion rates are lower) 2

2. Don't add radiation: Multiple trials (CRITICS, ARTIST, ARTIST II) show no benefit of adding RT to perioperative chemotherapy with D2 surgery 2

3. Don't pursue immunotherapy outside clinical trials: Despite your high PD-L1, there is no level I evidence supporting immunotherapy in resectable stage III gastric cancer. FLOT remains superior and proven 1, 2

4. Don't perform inadequate lymphadenectomy: D2 dissection is mandatory; D1 dissection is associated with worse outcomes 2

If Disease Progresses or Becomes Unresectable

Should your tumor prove unresectable after staging or progress during neoadjuvant therapy:

• Then consider pembrolizumab + fluoropyrimidine + platinum chemotherapy for HER2-negative, PD-L1 CPS ≥1 disease (your CPS 35 qualifies) 1
• This would reclassify you as having locally advanced unresectable disease, where immunotherapy becomes standard first-line therapy 1, 2

Bottom line: Your high PD-L1 is noted and may become relevant if curative resection is not achieved, but for now, proceed with proven perioperative FLOT and surgery. 1, 2