Summarize gastric cancer, including its pathology, staging, and current treatment recommendations, for a medical student preparing for a general surgery exam.

Gastric Cancer: General Surgery Exam Summary

Epidemiology & Risk Factors

Gastric cancer is the fifth most common cancer globally and the third leading cause of cancer death, with marked geographic variation—highest incidence in Northeast Asia (Japan, Korea, China) and lowest in North America and Western Europe 1, 2. Peak incidence occurs in the seventh decade with a male:female ratio exceeding 1.5 3.

Key risk factors include:

• Helicobacter pylori infection (most important modifiable risk)
• Male gender
• Cigarette smoking
• High salt intake, diets low in fruits/vegetables
• Atrophic gastritis, Menetrier's disease
• Genetic syndromes: hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome 3, 2

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Pathology & Classification

Over 95% are adenocarcinomas, classified by:

Anatomic Location

• Proximal/cardia vs. distal/non-cardia
• Assess Siewert category for gastroesophageal junction (GEJ) tumors 1

Histologic Type (Lauren Classification)

• Intestinal type: Well-differentiated, glandular pattern, associated with H. pylori, environmental factors, forms mass lesions
• Diffuse type: Poorly differentiated, signet-ring cells, infiltrative growth (linitis plastica), associated with hereditary factors 1, 2

Staging Classification

• Early gastric cancer: Confined to mucosa/submucosa (T1), regardless of lymph node status 4
• Advanced gastric cancer: Invades muscularis propria or deeper (≥T2) 4
• Use TNM 8th edition AJCC/UICC staging system 3, 4

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Diagnosis & Staging Workup

Diagnosis requires gastroscopic or surgical biopsy with histology reported per WHO criteria 3.

Complete Staging Includes:

• Physical examination, CBC, liver/renal function tests
• Upper GI endoscopy with biopsy (gold standard for diagnosis)
• CT chest/abdomen/pelvis with oral and IV contrast
• Endoscopic ultrasound (EUS): Determines T and N stage, tumor extent (less useful for antral tumors) 3, 5
• Laparoscopy with peritoneal washings: Mandatory for all potentially resectable cases to exclude occult peritoneal metastases 3, 5
• PET/CT: Consider if no M1 disease evident, may detect occult metastases (often negative in diffuse-type) 1, 5

Biomarker Testing (Essential for Advanced Disease)

Universal testing recommended 1, 6:

• MSI/MMR status (by PCR/NGS or IHC)—all newly diagnosed patients
• HER2 status (IHC/ISH)—if advanced/metastatic disease
• PD-L1 expression—if advanced/metastatic disease
• CLDN18.2 testing—if advanced/metastatic disease 6
• NGS should be considered for comprehensive molecular profiling 1, 6

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Treatment: Localized/Locoregional Disease

Endoscopic Resection (Early Gastric Cancer)

Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is indicated for T1a tumors meeting ALL criteria 5:

1. Confined to mucosa
2. Well-differentiated (G1-2)
3. <2 cm diameter
4. Non-ulcerated
5. No lymphovascular invasion

Expanded criteria may be considered if ≤2 criteria are not met 5.

Surgical Resection

Surgery is the only potentially curative modality for stages I–IV M0 3.

Key surgical principles:

• D2 lymphadenectomy is standard of care: Minimum 14 lymph nodes, optimally ≥25 nodes recovered 3, 5
• Extended D2-3 dissection shows no survival superiority over D1 in Western trials, but D2 is preferred 3
• Subtotal gastrectomy for distal tumors with ≥3 cm proximal margin (5 cm for diffuse-type)
• Total gastrectomy for proximal tumors 5
• Splenectomy only if splenic hilum involvement; avoid routine distal pancreatectomy 7

Perioperative/Adjuvant Therapy

For stage IB or higher with microsatellite stability, perioperative chemotherapy is the preferred approach 3, 5:

Perioperative Chemotherapy (European Standard)

• FLOT regimen (5-FU, leucovorin, oxaliplatin, docetaxel): 3 cycles pre-op + 3 cycles post-op 4, 5
• Alternative: ECF/ECX/EOX (epirubicin, cisplatin/oxaliplatin, 5-FU/capecitabine): 3 cycles pre-op + 3 cycles post-op 3
• UK MRC trial showed perioperative ECF improved 5-year survival from 23% to 36.3% 3

Adjuvant Chemotherapy (Asian Standard)

• S-1 monotherapy for 12 months after D2 resection (Japanese data): 3-year OS 81.1% vs. 70.1% surgery alone 3
• Capecitabine + oxaliplatin (XELOX) or capecitabine + cisplatin for 6 months 4, 5

Postoperative Chemoradiotherapy (US Standard)

• 5-FU/leucovorin + concurrent RT (45 Gy): 15% improvement in 5-year OS 3
• Indicated if suboptimal surgery (<D2 dissection) or R1/R2 resection 4, 5
• Not widely accepted in Europe due to toxicity concerns and surgical quality issues in trials 3

Preoperative Chemoradiotherapy

• Consider for GEJ tumors or if concern for R1/R2 resection 4, 5
• DT 45-50.4 Gy with concurrent fluoropyrimidine, platinum, or taxanes 4

Critical caveat: Postoperative chemotherapy alone (without pre-op component) has NOT consistently shown survival benefit and should not be offered outside clinical trials 3.

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Treatment: Unresectable/Metastatic Disease

First-Line Therapy

Combination chemotherapy is standard for good performance status (ECOG 0-1) 3:

Chemotherapy Regimens

• Platinum + fluoropyrimidine + anthracycline: ECF, ECX, EOX (non-inferior to ECF with easier administration) 3
• Docetaxel + 5-FU/cisplatin: Increased activity but more toxic 3
• Irinotecan + 5-FU/leucovorin: Similar activity to 5-FU/cisplatin 3

Targeted Therapy (Biomarker-Driven)

• HER2-positive: Trastuzumab + chemotherapy (first-line standard) 8, 6, 2
• PD-L1 positive/MSI-H: Nivolumab or pembrolizumab + chemotherapy 6, 9
  • High TMB (≥10 mut/Mb) + PD-L1 positive: Best outcomes with nivolumab + chemotherapy (HR 0.33) 10
• CLDN18.2 high expression: Zolbetuximab + chemotherapy (median OS 16.4 vs. 13.4 months, HR 0.77) 9

Second-Line Therapy

• Ramucirumab (anti-VEGFR2) ± paclitaxel 2
• Trastuzumab deruxtecan (HER2-positive) 9
• Pembrolizumab (MSI-H/TMB-H) 9
• Taxanes or irinotecan-based regimens 3

Third-Line Therapy

• Nivolumab or pembrolizab (anti-PD-1) 2
• Trifluridine/tipiracil 9

No standard second-line regimen exists; consider clinical trial enrollment 3.

Unresectable Locoregional Disease

• Concurrent chemoradiotherapy (Grade I recommendation) for ECOG 0-1 4
• Reassess for surgery after treatment if R0 resection achievable 4

Palliative Care

• ECOG ≥2: Best supportive care, nutritional support, symptom management 4, 8
• Obstruction: Self-expanding metal stents (short life expectancy) vs. gastrojejunostomy (longer prognosis) 8
• Bleeding/pain: RT, endoscopic therapy, pain medications per NCCN guidelines 8

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Follow-Up

No evidence that intensive surveillance improves outcomes 3. Symptom-driven visits are recommended for most cases 3. Perform directed imaging only if patient is candidate for palliative chemo/radiotherapy upon relapse 3.

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Key Exam Pearls

1. Surgery alone is insufficient for most gastric cancers in Western populations—multimodality therapy is standard
2. D2 lymphadenectomy with ≥15 nodes (optimally ≥25) is the surgical standard
3. Perioperative chemotherapy (FLOT or ECF) is preferred over adjuvant-only approaches for resectable disease ≥stage IB
4. Laparoscopy is mandatory before neoadjuvant therapy to exclude occult peritoneal disease
5. Biomarker testing (HER2, MSI/MMR, PD-L1, CLDN18.2) is essential for advanced disease to guide targeted therapy
6. Endoscopic resection is curative only for T1a tumors meeting strict criteria
7. Postoperative chemo alone (without pre-op component) should NOT be standard practice
8. Median survival for metastatic disease is <1 year with chemotherapy alone; targeted therapies improve outcomes in biomarker-selected patients