What is the primary treatment recommendation for a patient with HER-2 (human epidermal growth factor receptor 2) neu positive metastatic gastric (stomach) cancer?

Treatment of HER2-Positive Metastatic Gastric Cancer

For HER2-positive metastatic gastric cancer, trastuzumab combined with a fluoropyrimidine (fluorouracil or capecitabine) plus cisplatin is the standard first-line treatment (Category 1 recommendation). 1, 2

First-Line Treatment Regimen

Mandatory Pre-Treatment Assessment

• HER2 testing must be performed using FDA-approved tests specific for gastric cancer (not breast cancer tests), as gastric cancers demonstrate incomplete membrane staining and more frequent heterogeneous HER2 expression compared to breast cancers 1, 2
• Assess left ventricular ejection fraction (LVEF) before initiating therapy, as trastuzumab can cause subclinical and clinical cardiac failure 2
• Verify pregnancy status in females of reproductive potential, as trastuzumab causes oligohydramnios, pulmonary hypoplasia, skeletal abnormalities, and neonatal death 2

Preferred First-Line Regimen

Trastuzumab + Fluoropyrimidine + Cisplatin (Category 1) 1

• Trastuzumab dosing: Initial dose of 8 mg/kg IV over 90 minutes, followed by 6 mg/kg IV over 30-90 minutes every 3 weeks 2
• Fluoropyrimidine options: Either infusional 5-fluorouracil or capecitabine (interchangeable without compromising efficacy) 1
• Platinum agent: Cisplatin is standard; oxaliplatin may be substituted based on toxicity profile 1

Evidence Supporting This Approach

The ToGA trial (n=594) demonstrated that trastuzumab plus chemotherapy improved median overall survival to 13.8 months versus 11.0 months with chemotherapy alone (p=0.046) in HER2-positive metastatic gastric/gastroesophageal junction adenocarcinoma 1, 3. Critically, the survival benefit was limited to patients with IHC 3+ or IHC 2+/FISH-positive tumors (median OS 16.0 vs 11.8 months), with no benefit in IHC 0 or 1+/FISH-positive patients 1.

Treatment Selection Based on Performance Status

For ECOG PS 0-1 (Good Performance Status)

• Two-drug cytotoxic regimens are preferred due to lower toxicity 1
• Three-drug cytotoxic regimens should be reserved for medically fit patients with good PS and access to frequent toxicity evaluation 1
• Add trastuzumab to the chemotherapy backbone 1

For ECOG PS 2 (Moderate Performance Status)

• Two-drug chemotherapy plus trastuzumab with best supportive care is appropriate 4
• Avoid three-drug regimens in this population 4
• Monitor closely for toxicity and deteriorating performance status 4

For ECOG PS ≥3 (Poor Performance Status)

• Best supportive care only is recommended 5, 4
• Do not administer chemotherapy or trastuzumab 5, 4

Second-Line Treatment After Progression

Critical Decision: Do NOT Continue Trastuzumab Beyond Progression

The American Society of Clinical Oncology does not recommend continuing trastuzumab beyond progression, based on the negative Japanese WJOG 7112G trial which failed to improve progression-free survival 5. This is particularly important given evidence of HER2 heterogeneity, where residual tumor cells may be HER2-negative despite initial HER2-positive status 6.

Preferred Second-Line Options (Category 1)

• Ramucirumab plus paclitaxel (superior outcomes in RAINBOW trial) 5, 3
• Single-agent ramucirumab 5
• Docetaxel monotherapy (5.2 months median OS vs 3.6 months with best supportive care alone) 5
• Paclitaxel monotherapy (9.5 months median OS) 5
• Irinotecan monotherapy 5

Critical Toxicity Monitoring

Cardiac Toxicity

• Monitor LVEF at regular intervals during treatment 2
• Discontinue trastuzumab for clinically significant decrease in left ventricular function 2
• Highest risk occurs when trastuzumab is administered concurrently with anthracyclines 2

Infusion Reactions

• Interrupt trastuzumab infusion for dyspnea or clinically significant hypotension 2
• Discontinue for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome 2
• Symptoms usually occur during or within 24 hours of administration 2

Other Toxicities

• Ramucirumab increases risk of bleeding, hypertension, and proteinuria 5
• Taxanes cause myelosuppression and peripheral neuropathy 5
• Monitor for thromboembolic events with cisplatin-based regimens 5

Common Pitfalls to Avoid

1. Do not use breast cancer HER2 testing protocols for gastric cancer – gastric cancers require specific FDA-approved tests due to different histopathology 1, 2

2. Do not continue trastuzumab beyond first progression – no survival benefit demonstrated and tumor heterogeneity may result in HER2-negative resistant clones 5, 6

3. Do not substitute trastuzumab for ado-trastuzumab emtansine or fam-trastuzumab deruxtecan – these are different drugs with different mechanisms 2

4. Do not administer trastuzumab as IV push or bolus – only as IV infusion 2

5. Do not use three-drug regimens in patients with ECOG PS 2 or significant comorbidities – reserve for medically fit patients with frequent toxicity monitoring access 1, 4

6. Do not delay cardiac function assessment – evaluate LVEF before and during treatment to prevent irreversible cardiomyopathy 2