What is the best approach to manage a patient with gastric cancer?

Management of Gastric Cancer

Surgery with D1+ or modified D2 lymph node dissection combined with perioperative chemotherapy is the preferred approach for resectable localized gastric cancer, while HER2-positive metastatic disease requires trastuzumab plus chemotherapy, and all patients benefit from a multidisciplinary team approach in high-volume centers. 1

Initial Workup and Staging

Perform comprehensive molecular testing on all newly diagnosed patients:

• Universal MSI/MMR testing by PCR, next-generation sequencing, or immunohistochemistry 1
• HER2 testing (immunohistochemistry and FISH) if metastatic disease is documented or suspected 1, 2
• PD-L1 expression testing by CPS score 1

Complete staging evaluation includes:

• Endoscopy of the entire upper gastrointestinal tract with biopsy 3
• Endoscopic ultrasound for potentially resectable cancers 3, 1
• Chest/abdomen/pelvic CT with contrast 3, 1
• FDG-PET/CT if no metastatic disease is evident 1
• CBC, comprehensive metabolic panel 3
• H. pylori testing with treatment when indicated 3

Treatment Algorithm by Stage

Localized Disease (Tis or T1a)

Endoscopic resection is the primary approach for accurate staging and potential cure of early-stage cancers. 1

Locoregional Disease (Stages I-III, M0) - Resectable

The preferred treatment sequence is:

1. Perioperative chemotherapy (Category 1 recommendation): 3, 1

   • FLOT regimen (docetaxel, oxaliplatin, leucovorin, 5-FU) is the current standard with superior outcomes 4
   • Alternative: ECF (epirubicin, cisplatin, 5-FU) or modified ECF regimens 3, 4
   • Administer 3-4 cycles preoperatively

2. Surgical resection with D1+ or modified D2 lymph node dissection: 1, 5

   • Subtotal gastrectomy for distal gastric cancers 3, 1
   • Proximal or total gastrectomy for proximal tumors 3, 1
   • Minimum of 15 lymph nodes must be examined 3
   • Surgery must be performed by experienced surgeons in high-volume centers 1, 5

3. Postoperative treatment based on surgical findings:

   • Complete perioperative chemotherapy (remaining 3-4 cycles) 1
   • Alternative approach: Postoperative chemoradiation plus chemotherapy for T3-T4 tumors and node-positive T1-T2 tumors 3, 1
   • Postoperative chemotherapy is recommended following primary D2 lymph node dissection 3

Preoperative chemoradiation is an alternative option (Category 2B) using cisplatin, paclitaxel, or docetaxel combined with 5-FU or capecitabine. 3

Locoregional Disease - Unresectable

Radiation therapy (45-50.4 Gy) with concurrent 5-FU-based radiosensitization (Category 1) is the standard approach. 3

Metastatic Disease (Stage IV, M1)

First-line systemic therapy selection depends on biomarker status:

For HER2-positive disease (IHC 3+ or IHC 2+ with FISH confirmation):

• Trastuzumab 8 mg/kg loading dose, then 6 mg/kg every 3 weeks plus chemotherapy (Category 1) 3, 1, 2
• Chemotherapy backbone: fluoropyrimidine (5-FU or capecitabine) plus cisplatin 3, 1
• This combination improves median overall survival from 11.1 to 13.5-13.8 months 3, 6, 7

For PD-L1 CPS ≥5 tumors:

• Nivolumab combined with chemotherapy (Category 1) 1
• For PD-L1 CPS <5: nivolumab plus chemotherapy is Category 2B 1

For HER2-negative disease:

• Preferred regimens (two-drug combinations due to lower toxicity): 3, 1
  • Fluoropyrimidine (5-FU or capecitabine) plus cisplatin (Category 1) 3, 1
  • Fluoropyrimidine plus oxaliplatin 3, 1
• Three-drug regimens reserved for medically fit patients with good performance status and access to frequent toxicity monitoring 3

Important chemotherapy interchangeability:

• Infusional 5-FU and capecitabine may be used interchangeably without compromising efficacy 3, 1
• Cisplatin and oxaliplatin may be used interchangeably based on toxicity profile 3, 1
• Infusion is preferred over bolus 5-FU 3

Second-Line Therapy for Metastatic Disease

For patients with ECOG PS ≤2 after first-line progression:

• Ramucirumab 8 mg/kg plus paclitaxel 80 mg/m² every 2 weeks (median OS 9.6 vs 7.4 months with paclitaxel alone) 6, 7
• Alternative: Irinotecan monotherapy (median OS 4.0 vs 2.4 months with best supportive care) 6

For MSI-H/dMMR or TMB-H tumors:

• Pembrolizumab as second-line or subsequent therapy 1
• Alternative: Dostarlimab-gxly 1

Performance Status-Based Treatment Decisions

ECOG PS 0-2 or KPS ≥60%:

• Offer systemic chemotherapy plus best supportive care 6
• Median survival 8 months vs 5 months with best supportive care alone 6

ECOG PS ≥3 or KPS <60%:

• Best supportive care only (absolute contraindication to chemotherapy) 6

Palliative Care and Symptom Management

Best supportive care should be provided concurrently with all treatments, not as an alternative. 3, 6

Acute Bleeding Management

• Prompt endoscopic assessment for hematemesis or melena 3
• Endoscopic interventions: injection therapy, mechanical clips, argon plasma coagulation, or combination methods 3
• Interventional radiology angiographic embolization when endoscopy fails 3
• External beam radiation therapy for acute and chronic bleeding 3

Obstruction Management

Primary goal: reduce nausea/vomiting and allow oral diet resumption 3

Treatment hierarchy:

1. Endoscopic stent placement for outlet obstruction or EGJ/gastric cardia obstruction 3
2. Surgical options: gastrojejunostomy or gastrectomy in select patients 3
3. Radiation therapy or chemotherapy 3
4. Venting gastrostomy when obstruction cannot be alleviated 3

Nutritional Support

• Monitor B12, iron, and calcium levels closely, especially postoperatively 3
• Monthly B12 injections needed due to loss of intrinsic factor 3
• Iron supplementation with acid (orange juice) to maintain adequate levels 3
• Calcium supplementation encouraged 3
• Feeding jejunostomy or nasogastric tubes if caloric intake <1500 kcal/day 3

Critical Monitoring During Treatment

Cardiac monitoring for trastuzumab therapy:

• Assess LVEF prior to initiation and at regular intervals 2
• Withhold dosing for ≥16% absolute LVEF decrease or LVEF below institutional limits with ≥10% decrease 2
• Permanently discontinue for persistent (>8 weeks) LVEF decline 2

Infusion reaction management:

• Decrease infusion rate for mild/moderate reactions 2
• Interrupt for dyspnea or significant hypotension 2
• Discontinue for severe or life-threatening reactions 2

Common Pitfalls to Avoid

Do not proceed directly to surgery for porta hepatis lymph node involvement (Level 3-4 nodes indicate unresectable disease requiring systemic chemotherapy first) 4

Do not use trastuzumab without confirmed HER2 positivity by FDA-approved testing specific for gastric cancer (different from breast cancer testing) 2

Do not administer chemotherapy to patients with ECOG PS ≥3 or imminently dying patients 6

Do not substitute trastuzumab products (do not interchange with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan) 2

Do not extend adjuvant trastuzumab beyond one year (not recommended) 2

Verify pregnancy status before initiating trastuzumab in females of reproductive potential 2