Gastric Cancer

Background:

• Highest incidence: East Asia (Japan, Korea, China)

• Increased in Eastern Europe & South America

• Male predominance (~2:1)

• Major Risk Factors:

  • Chronic H. pylori infection (strongest risk factor)

  • Chronic atrophic gastritis / intestinal metaplasia

  • Smoking

  • High salt/smoked foods, low fruits/vegetables

  • Pernicious anemia

  • Partial gastrectomy (long-term)

  • CDH1 mutation → hereditary diffuse gastric cancer

• Histologic types:

  • Intestinal:

    • Gland-forming

    • Associated with: H. pylori, environmental

  • Diffuse:

    • Poorly cohesive, signet ring cells

    • Associated with: CDH1 mutation

    • may cause linitis plastica (leather bottle stomach)

• Metastatic signs:

  • Virchow node (left supraclavicular)

  • Sister Mary Joseph nodule (umbilical)

  • Krukenberg tumor (ovarian metastasis)

  • Ascites

Diagnosis:

• EGD with biopsy

• Pathology testing:

  • HER2, MSI/MMR status, PD-L1 (CPS score)

• Staging:

  • CAP CT scan

  • Endoscopic ultrasound (EUS) → T & N staging

  • Diagnostic laparoscopy if >T1b to rule out peritoneal disease (can be missed on imaging)

    • T staging:

      • Tis: High grade dysplasia/ intraepithelial tumor without invasion

      • T1: invasion is limited to mucosa (T1a) and submucosa (T1b)

      • T2: invades muscularis propria

      • T3: invades subserosa

      • T4: invades serosa (viceral peritoneum) or adjacent structures

  • >15 lymph nodes should be examined for accurate staging

    • D Dissection Categories:

      • D0 dissection:

        • Incomplete lymphadenectomy (≤15 LNs are resected)

      • D1 dissection:

        • Removal of perigastric nodes (N1) only

      • D2 dissection:

        • Removal of perigastric nodes (N1) and second-tier (N2) nodes (left gastric, common hepatic, celiac, splenic arteries)

Treatment:

Localized Early Stage Gastric Cancer:

• Surgical approach:

  • Tis or T1a: Endoscopic Mucosal Resection (EMR) or Surgery

  • ≥T1b or any N+: Gastrectomy with LN dissection

• Adjuvant therapy depends on:

  • Pathology:

    • pT1:

      • Observation

    • pT2:

      • Observation

      • Adjuvant therapy (if high risk features or D0 dissection)

    • ≥pT3 or any N+:

      • Adjuvant therapy

  • Extend of LN dissection

    • If <D2 dissection:

      • Fluoropyrimidine-based chemoRT

      • Fluoropyrimidine chemo → chemoRT → Fluoropyrimidine chemo (Sandwich approach)

    • If D2 dissection:

      • Adjuvant CAPEOX (preferred)

      • Adjuvant FOLFOX

Locally Advanced Gastric Cancer:

• Stage: ≥T2 or any N+, M0

• Perioperative therapy is preferred:

  • Perioperative chemotherapy 

    • If R0 resection (negative microscopic margin):

      • Preferred:

        • FLOT x4 → Surgery → FLOT x4 (FLOT4-AIO trial)

      • Alternatives:

        • FOLFOX → Surgery → FOLFOX

        • CAPEOX → Surgery → CAPEOX

    • If R1 resection (microscopic positive margin):

      • Re-resection if feasible

      • 5FU based chemoRT if not previously given

    • If R2 resection (macroscopic residual):

      • Often treated as unresectable/metastatic disease

  • Perioperative immunotherapy

    • For MSI-H or dMMR tumors

      • Ipi/Nivo followed by Nivo

      • Pembrolizumab

Metastatic Gastric Cancer:

• Need to test for: HER2, MSI, PDL-1

• First line:

  • HER2 negative, MSS Cancers

    • FOLFOX (or CAPEOX) + Nivolumab: if PDL-1 CPS > 5

      • Checkmate-649

    • FOLFOX (or CAPEOX) + Pembrolizumab: if PDL-1 CPS > 1

    • FOLFOX (or CAPEOX) + Tislelizumab: if PDL-1 CPS >1

    • FOLFOX (or CAPEOX) + Zolbetuximab: if CLDN18.2 positive

    • FOLFOX or XELOX

    • 5 FU + Cisplatin

  • If MSI-H or dMMR (independent of PDL1 status): FOLFOX + IO 

    • Can use Pembrolizumab, Dostarlimab, Ipi/nivo

  • If HER2 positive (more commonly in intestinal subtypes)

    • FOLFOX (or CAPEOX) + trastuzumab +/- pembro (if PDL1 positive)

      • Keynote-811

    • 5FU + Cisplatin + trastuzumab +/- pembro (if PDL1 positive)

• Subsequent Lines:

  • Ramucirumab

  • Ramucirumab + Paclitaxel (RAINBOW)

  • Paclitaxel

  • Docetaxel

  • Irinotecan

  • Enhertu (Fam-trastuzumab deruxtecan) if HER-2 positive (DESTINY-Gastric-01)

  • Pembrolizumab if TMB-high tumors (≥10 mut/Mb)

• Later-Line therapy:

  • Lonsurf (Trifluridine/Tipiracil) for 3rd line or later (TAGS)

    
    

Hereditary syndromes associated with gastric cancer:

• Familial Adenomatous Polyposis (FAP)

  • Caused by germline APC mutation

  • Autosomal dominant

  • Associated with:

    • Gastric polyps and duodenal adenomas/cancer

      • Upper endoscopy surveillance recommended starting age 20–25

    • Colorectal cancer

      • Penetrance approaches 100% if colectomy is not performed

      • Colonoscopy begins in teenage years

    • Papillary thyroid cancer

      • Annual thyroid US is recommended

    • Desmoid tumors

• Hereditary Diffuse Gastric Cancer

  • Associated with CDH1 mutation

  • Autosomal dominant

  • Prophylactic total gastrectomy is recommended in many patients

  • If gastrectomy is deferred:

    • EGD with extensive biopsy protocol q 6-12 months