What is the recommended management—including full staging, neoadjuvant chemotherapy, extent of lymphadenectomy (D1 versus D2), and adjuvant therapy—for a fit patient under 80 years old with resectable gastric cancer (clinical T2‑T4a, node‑positive or node‑negative, no distant metastases)?

Management of Resectable Gastric Cancer (Clinical Stage T2-T4a, N0 or N+, M0)

Staging Workup

All patients with suspected resectable gastric cancer require a comprehensive staging protocol coordinated through a multidisciplinary team. 1

• CT chest/abdomen/pelvis with multiplanar reconstructions is the initial staging modality to assess for distant metastases 1
• Endoscopic ultrasound (EUS) should be performed for selected gastric cancers to assess depth of invasion and regional lymph nodes 1
• Diagnostic laparoscopy with peritoneal lavage is mandatory before initiating neoadjuvant therapy to exclude occult peritoneal metastases 1, 2
• PET-CT scanning may be added for oesophago-gastric junctional tumors 1
• HER2 testing must be performed on all gastric adenocarcinomas, as HER2-positive metastatic disease requires trastuzumab-based therapy 1, 3

Neoadjuvant (Perioperative) Chemotherapy

For fit patients under 80 years with resectable T2-T4a gastric cancer, perioperative chemotherapy is the preferred treatment approach and should be administered before surgery. 2

• FLOT regimen (fluorouracil, leucovorin, oxaliplatin, docetaxel) is the current standard, delivering 4 preoperative cycles followed by surgery and 4 postoperative cycles, with median survival of 50 months versus 35 months for older ECF-based regimens 3, 2
• ECF/ECX regimen (epirubicin, cisplatin, 5-FU or capecitabine) remains an acceptable alternative when FLOT is unavailable, using 3 preoperative and 3 postoperative cycles, improving 5-year survival from 23% to 36% versus surgery alone 3, 2
• Perioperative chemotherapy provides superior outcomes compared to surgery alone and is a Category 1 recommendation for medically fit patients with stage II-III disease 3, 2

Important Exception

• Signet ring cell carcinoma does not benefit from perioperative chemotherapy and should proceed directly to surgery with D2 lymphadenectomy 2

Surgical Resection

D2 lymphadenectomy is the standard surgical approach for clinical stage II and III gastric cancer in fit patients. 1

Extent of Gastric Resection

• Distal (antral) tumors: subtotal gastrectomy with 3-5 cm proximal margin depending on growth pattern (3 cm for expansive/intestinal type, 5 cm for infiltrative/diffuse type) 1
• Proximal tumors: total gastrectomy 1
• Cardia and type II oesophago-gastric junctional tumors: transhiatal extended total gastrectomy or oesophago-gastrectomy 1
• Frozen section examination of the proximal margin should be performed when adequate margins cannot be achieved 1

Lymph Node Dissection

D2 lymphadenectomy removes perigastric (D1) plus regional lymph nodes along the left gastric, common hepatic, splenic, and coeliac arteries, and is mandatory for stage II-III disease. 1

• Minimum of 15 lymph nodes must be examined for adequate staging, with optimal examination of ≥25 nodes, ideally >30 nodes 1, 4, 2
• D2 dissection provides superior long-term survival compared to D1, with 15-year overall survival of 29% versus 21% (though initial trials showed higher perioperative mortality in Western centers) 1
• Splenectomy and distal pancreatectomy should NOT be performed routinely as part of D2 dissection for distal gastric cancers 1
• Splenectomy is only justified for proximal tumors on the greater curvature/posterior wall near the splenic hilum with high probability of splenic hilar nodal involvement 1
• D2 dissection must be performed in high-volume specialized centers (minimum 15-20 gastric resections per surgeon per year) to achieve acceptable morbidity and mortality 1

Surgical Approach

• Laparoscopic distal gastrectomy is acceptable for clinical stage I disease and may be considered for selected advanced cases in expert hands 1
• Open gastrectomy remains the standard for most stage II-III cancers requiring D2 lymphadenectomy 1

Adjuvant Therapy After Surgery

If D2 Lymphadenectomy Was Performed

Adjuvant chemotherapy alone with CAPOX (capecitabine plus oxaliplatin) for 6-8 cycles is the standard postoperative treatment after adequate D2 resection. 4

• CAPOX provides significant survival benefit with 5-year overall survival of 78% versus 69% for surgery alone (HR for death 0.58) 4
• Adjuvant chemoradiotherapy does NOT improve survival after adequate D2 dissection and should not be added 4
• The CRITICS trial definitively showed no benefit of adding radiotherapy to chemotherapy after D2 lymphadenectomy 4
• S-1 monotherapy for 12 months is an acceptable alternative in Asian patients (5-year survival 71.7% vs 61.1% for surgery alone), but remains investigational in Western populations 4
• Chemotherapy should begin within 4-6 weeks after surgery once adequate recovery is achieved 4

If Inadequate Lymphadenectomy Was Performed (D0/D1 or <14 Nodes)

Postoperative chemoradiotherapy should be considered when lymph node dissection was suboptimal. 4

• The INT-0116 survival benefit (median survival 36 vs 27 months) was established in patients with predominantly D0/D1 dissection (54% D0, 36% D1, only 10% D2) 1, 4
• Chemoradiotherapy is appropriate for: R1 resection (positive margins), examination of <14 lymph nodes, D0/D1 dissection, or absence of neoadjuvant therapy combined with inadequate surgery 4
• Radiation dose: 45 Gy in 25 fractions of 1.8 Gy using IMRT technique 4
• Concurrent chemotherapy: fluoropyrimidine-based regimen (5-FU/leucovorin) during cycles 2 and 3 of a 5-cycle schedule 4

If Perioperative Chemotherapy Was Already Given

Complete the planned postoperative cycles of the same perioperative regimen (4 additional cycles of FLOT or 3 additional cycles of ECF/ECX) 2

Treatment Algorithm Summary

1. Staging: CT chest/abdomen/pelvis + EUS + diagnostic laparoscopy + HER2 testing 1, 3

2. Neoadjuvant therapy (preferred): 4 cycles FLOT or 3 cycles ECF/ECX (except signet ring cell) 3, 2

3. Surgery: D2 lymphadenectomy with appropriate gastric resection (≥15 nodes examined, ideally ≥25) 1, 4

4. Adjuvant therapy:

   • If D2 performed: CAPOX × 6-8 cycles (or complete perioperative regimen if started preoperatively) 4, 2
   • If D0/D1 or <14 nodes: Consider chemoradiotherapy 4
   • If R1 resection: Chemoradiotherapy regardless of lymphadenectomy extent 4

Critical Pitfalls to Avoid

• Do not add radiation after adequate D2 dissection – this increases toxicity without survival benefit 4
• Do not perform routine splenectomy/distal pancreatectomy with D2 dissection for distal gastric cancers 1
• Do not proceed to surgery without diagnostic laparoscopy when neoadjuvant therapy is planned, as occult peritoneal disease will be missed 1, 2
• Do not fail to examine ≥15 lymph nodes – inadequate nodal assessment undermines staging accuracy and treatment decisions 1, 4
• Do not use S-1 in Western populations outside clinical trials, as validation is lacking 4
• Do not delay adjuvant chemotherapy beyond 6 weeks after surgery 4