Adjuvant Chemotherapy for Stage III Gastric Adenocarcinoma After D2 Dissection
For stage III gastric adenocarcinoma after D2 lymphadenectomy, adjuvant chemotherapy with capecitabine plus oxaliplatin (CAPOX/XELOX) is the recommended standard of care, based on the CLASSIC trial demonstrating improved 3-year disease-free survival from 59% to 74% and 5-year overall survival from 69% to 78%. 1
Primary Treatment Recommendation
Capecitabine plus oxaliplatin (CAPOX) should be administered for 6-8 cycles following D2 resection, as this regimen has demonstrated significant survival benefits specifically in the post-D2 dissection setting. 1 The CLASSIC trial enrolled 1,035 patients with stage II-IIIB gastric cancer after D2 dissection and showed a hazard ratio for death of 0.58 for disease-free survival. 1
Alternative Regimens for Asian Populations
If the patient is of Asian descent and S-1 is available, S-1 monotherapy for 12 months is an equally valid option, based on the ACTS-GC trial showing 5-year overall survival improvement from 61.1% to 71.7% (HR 0.669) after D2 gastrectomy. 1, 2 However, S-1 remains investigational in North America and has not been validated in Western populations. 1
For stage III disease specifically, S-1 plus docetaxel demonstrates superior outcomes compared to S-1 alone, with 3-year overall survival of 77.7% versus 71.2% (HR 0.742) and should be considered the preferred regimen when treating Asian patients with stage III disease. 3, 4
Critical Context: D2 Dissection Changes the Treatment Algorithm
Postoperative chemoradiotherapy is NOT recommended after adequate D2 lymphadenectomy (≥25 lymph nodes examined, ideally >30). 1 The benefit of chemoradiotherapy was established in the INT-0116 trial where 54% of patients underwent inadequate D0 dissection and only 10% had D2 dissection. 1
Chemoradiotherapy should only be used when:
- D0 or D1 dissection was performed (suboptimal surgery) 1, 5
- Fewer than 14 lymph nodes were examined 1
- The patient did not receive any neoadjuvant therapy 1, 5
A meta-analysis of Asian patients after D2 dissection showed that chemoradiotherapy improved locoregional control (HR 0.53) and disease-free survival (HR 0.72) but did not significantly improve overall survival (HR 0.79, p=0.08) compared to chemotherapy alone. 6
Perioperative Chemotherapy Alternative
If the patient had NOT yet undergone surgery, perioperative chemotherapy would be the preferred approach, with 3 cycles of ECF (epirubicin, cisplatin, 5-FU) or FLOT (5-FU, leucovorin, oxaliplatin, docetaxel) before and after surgery. 1, 7 The MAGIC trial demonstrated 5-year survival improvement from 23% to 36.3% with perioperative ECF. 1, 7 FLOT has shown superiority with median survival of 50 months versus 35 months for ECF/ECX. 7
However, since this patient has already undergone D2 dissection, postoperative chemotherapy alone is the appropriate strategy. 1
Common Pitfalls to Avoid
Do not reflexively add radiation therapy after D2 dissection - this is a common error based on extrapolating the INT-0116 trial results, which primarily benefited patients with inadequate surgery. 1 The NCCN explicitly states that "postoperative chemoradiation remains an effective and preferred treatment after D0 or D1 dissection but not after D2 dissection." 1
Ensure adequate pathologic staging - at least 14 lymph nodes must be examined, with 25 or more being optimal, to confirm true stage III disease and justify the toxicity of adjuvant chemotherapy. 1, 7
Verify R0 resection status - patients with R1 resection (positive margins) may benefit from chemoradiotherapy regardless of lymphadenectomy extent. 1
Treatment Monitoring
Chemotherapy should be initiated within 4-6 weeks after surgery once the patient has adequately recovered. 1 Treatment completion rates for CAPOX are approximately 74%, with dose reductions commonly required for oxaliplatin (62% of patients) and S-1 (42% of patients). 8
The main grade 3-4 toxicity is neutropenia (32%), with peripheral neuropathy being manageable through dose adjustments. 8 Treatment should continue for the planned duration unless disease progression or unacceptable toxicity occurs.