What is the recommended adjuvant chemoradiotherapy regimen—including timing, radiation dose, concurrent chemotherapy, and subsequent systemic chemotherapy—for a patient with stage III gastric cancer after curative D2 gastrectomy?

Adjuvant Chemotherapy After D2 Resection for Stage III Gastric Cancer

For stage III gastric cancer after curative D2 gastrectomy, adjuvant chemotherapy with CAPOX (capecitabine plus oxaliplatin) for 6-8 cycles is the standard treatment; adjuvant chemoradiotherapy is NOT recommended after adequate D2 lymphadenectomy. 1

Standard Adjuvant Chemotherapy Regimen

The NCCN recommends adjuvant CAPOX as the preferred regimen for stage III gastric adenocarcinoma following D2 lymphadenectomy. 1 This recommendation is based on the CLASSIC trial, which demonstrated:

• 3-year disease-free survival: 74% vs 59% (surgery alone) 1
• 5-year overall survival: 78% vs 69% (surgery alone) 1
• Hazard ratio for death: 0.58 1

CAPOX Administration Details

• Duration: 6-8 cycles total 1
• Timing: Initiate within 4-6 weeks after surgery once adequate recovery is achieved 1
• Components: Capecitabine plus oxaliplatin doublet 2

Alternative Regimen for Asian Patients

• S-1 monotherapy for 12 months is an acceptable alternative in Asian populations 1, based on the ACTS-GC trial showing 5-year overall survival of 71.7% vs 61.1% with surgery alone (HR 0.669) 2, 1
• S-1 is administered at 80 mg/m² daily for 4 weeks followed by 2 weeks rest, repeated for 1 year 2
• S-1 remains investigational in North America and has not been validated in Western populations 1

Role of Adjuvant Chemoradiotherapy After D2 Resection

Adjuvant chemoradiotherapy is NOT recommended after adequate D2 lymphadenectomy (≥25 lymph nodes examined, ideally >30). 1 This is a critical distinction based on multiple lines of evidence:

Why Chemoradiotherapy Is Not Indicated After D2 Resection

• The CRITICS trial demonstrated no survival benefit: patients receiving chemotherapy alone had similar overall survival and progression-free survival compared to those receiving chemoradiotherapy after D2 gastrectomy 2
• The Korean ARTIST and ARTIST II studies confirmed no survival benefit from adding radiotherapy to adjuvant chemotherapy in patients with D2 lymphadenectomy 2
• The INT-0116 trial that established chemoradiotherapy included 54% of patients with inadequate D0 dissection and only 10% with D2 dissection 1, meaning the benefit applied primarily to suboptimal surgery 2

When Chemoradiotherapy May Be Considered

Chemoradiotherapy should be reserved for specific situations:

• Suboptimal surgery (D0/D1 dissection) 1
• Examination of fewer than 14 lymph nodes 1
• R1 resection (positive margins) when re-resection is not feasible 2, 1
• No neoadjuvant therapy was given AND inadequate lymphadenectomy was performed 2, 1

Chemoradiotherapy Technical Details (If Indicated)

If chemoradiotherapy is deemed necessary in the above scenarios:

• Radiation dose: 45 Gy in 25 fractions of 1.8 Gy (five fractions per week) 2
• Technique: Intensity-modulated radiotherapy (IMRT) 2
• Concurrent chemotherapy: Fluoropyrimidine-based regimen 2
• Regimen example: 5-FU/leucovorin with concurrent radiotherapy during cycles 2 and 3 of a 5-cycle regimen 2

Critical Surgical and Pathologic Requirements

Adequate pathologic staging requires examination of at least 14 lymph nodes (optimal ≥25) to confirm stage III disease and justify adjuvant chemotherapy toxicity. 1 This is essential because:

• Inadequate lymph node sampling may understage the disease 1
• The benefit of adjuvant therapy is predicated on accurate staging 1

Common Pitfalls to Avoid

1. Do not add radiation after adequate D2 dissection – this adds toxicity without survival benefit 2, 1
2. Do not confuse perioperative chemotherapy (pre- and post-surgery) with adjuvant-only chemotherapy – if surgery has already been performed, only post-operative chemotherapy is given 3
3. Do not delay chemotherapy initiation beyond 6 weeks – optimal timing is 4-6 weeks post-surgery 2, 1
4. Do not use S-1 in Western populations without understanding it remains investigational 1

Summary Algorithm

For stage III gastric cancer after curative D2 gastrectomy:

1. Verify adequate surgery: ≥14 lymph nodes examined (ideally ≥25), R0 resection 1
2. Standard treatment: CAPOX for 6-8 cycles, starting within 4-6 weeks 1
3. Alternative (Asian patients): S-1 monotherapy for 12 months 2, 1
4. Do NOT add radiation if D2 dissection was adequate 2, 1
5. Consider chemoradiotherapy ONLY if: D0/D1 dissection, <14 nodes examined, or R1 resection 2, 1