What is the recommended palliative chemotherapy regimen for a patient with advanced or metastatic gastric (stomach) cancer?

Palliative Chemotherapy for Gastric Carcinoma

For patients with advanced/metastatic gastric cancer and good performance status (ECOG PS ≤2), the preferred first-line regimen is a fluoropyrimidine plus oxaliplatin doublet (FOLFOX or CAPOX), with trastuzumab added for HER2-positive tumors and nivolumab added for PD-L1 CPS ≥5 tumors. 1

Patient Selection for Chemotherapy

Systemic chemotherapy should be offered to patients with:

• ECOG performance status ≤2 or Karnofsky Performance Status ≥60% 1
• Adequate organ function (bilirubin ≤1.5× ULN) 2
• No uncontrolled hypertension or recent major surgery 2

Chemotherapy provides superior survival compared to best supportive care alone (median OS 8 months vs 5 months), along with improved quality of life and symptom palliation. 1

Essential Molecular Testing Before Treatment

All patients must undergo HER2 testing (IHC and/or FISH) before initiating chemotherapy, as HER2-positive patients benefit from trastuzumab addition. 1, 3

Additional recommended testing includes:

• PD-L1 expression by CPS 1, 3
• MSI/MMR status 3
• CLDN18.2 status 3

First-Line Chemotherapy Regimens

Preferred Two-Drug Regimens (Lower Toxicity)

Two-drug combinations are preferred over three-drug regimens due to lower toxicity while maintaining efficacy. 1

For HER2-Negative Disease:

FOLFOX (Category 1): 1, 3

• Oxaliplatin 85 mg/m² IV day 1
• Leucovorin 400 mg/m² IV day 1
• 5-FU 400 mg/m² IV bolus day 1, then 2400 mg/m² continuous infusion over 46 hours
• Every 2 weeks

CAPOX/XELOX (Preferred): 3

• Capecitabine 1000 mg/m² PO twice daily days 1-14
• Oxaliplatin 130 mg/m² IV day 1
• Every 3 weeks

EOX: 1, 3

• Epirubicin 50 mg/m² IV day 1
• Oxaliplatin 130 mg/m² IV day 1
• Capecitabine 625 mg/m² PO twice daily continuously
• Median OS 11.2 months (superior to ECF with HR 0.80, P=0.02) 1

For HER2-Positive Disease (IHC 3+ or IHC 2+/FISH+):

Trastuzumab + Cisplatin + Fluoropyrimidine (Category 1): 1

• Trastuzumab 8 mg/kg IV loading dose, then 6 mg/kg every 3 weeks
• Cisplatin 80 mg/m² IV day 1 every 3 weeks
• 5-FU or capecitabine
• Median OS improves from 11.1 to 13.8 months (HR 0.74, P=0.0048) 1

For PD-L1 CPS ≥5:

Nivolumab + Fluoropyrimidine + Oxaliplatin (Category 1): 1

• Provides additional survival benefit in this biomarker-selected population

Three-Drug Regimens (Reserve for Medically Fit Patients Only)

Modified DCF (only for excellent PS with frequent toxicity monitoring access): 1, 3

• Docetaxel 40 mg/m² (NOT 75 mg/m² due to excessive toxicity)
• Cisplatin 75 mg/m²
• 5-FU 750 mg/m²
• Standard-dose DCF (docetaxel 75 mg/m²) should be avoided due to 69% grade 3-4 toxicity rate 3

Key Substitutions Supported by Evidence

Oxaliplatin is preferred over cisplatin due to lower toxicity (thromboembolism 7.6% vs 15.1%, P=0.0003) with equivalent efficacy (HR 0.92). 1

Capecitabine is superior to infused 5-FU for overall survival within doublet and triplet regimens, eliminating need for indwelling venous access. 1

Second-Line Chemotherapy

For patients with disease progression after first-line therapy and maintained ECOG PS ≤2:

Ramucirumab + Paclitaxel (Category 1): 1, 2

• Ramucirumab 8 mg/kg IV every 2 weeks
• Paclitaxel 80 mg/m² IV on days 1,8,15 of 28-day cycle
• Median OS 9.6 months vs 7.4 months with paclitaxel alone 2

Ramucirumab monotherapy: 1, 2

• For patients unable to tolerate combination therapy
• Median OS 5.2 months vs 3.8 months with placebo (HR 0.78, P=0.047) 2

Irinotecan: 1

• Improves survival vs best supportive care (median 4.0 vs 2.4 months, HR 0.48, P=0.023)

Critical Toxicity Management

Dose Modifications Required For:

Proteinuria: 2

• Withhold for urine protein ≥2 g/24 hours
• Permanently discontinue for >3 g/24 hours or nephrotic syndrome

Hypertension: 2

• Monitor blood pressure regularly
• Manage with antihypertensives; withhold for severe uncontrolled hypertension

Neutropenia: 2

• Monitor CBC before each cycle
• Reduce paclitaxel dose by 10 mg/m² increments for grade 4 hematologic toxicity

Special Populations

Elderly Patients (≥70 years):

Age alone is not a contraindication to palliative chemotherapy. 1

• Pooled analysis shows no significant differences in efficacy or tolerability
• Consider comorbidities, organ function, and performance status
• 60% dose reduction of capecitabine/oxaliplatin is noninferior with better tolerability 3

Patients with Poor Performance Status (ECOG PS 3-4):

Best supportive care only—do not offer chemotherapy. 1

Common Pitfalls to Avoid

1. Do not use standard-dose DCF (docetaxel 75 mg/m²) without dose modification due to unacceptable toxicity 3

2. Do not start chemotherapy without HER2 testing in patients with metastatic disease, as this identifies candidates for trastuzumab 1, 3

3. Do not use cisplatin when oxaliplatin is available, as oxaliplatin has superior toxicity profile with equivalent efficacy 1, 3

4. Do not offer three-drug regimens to patients with ECOG PS 2 or those without easy access to frequent toxicity monitoring 1

5. Do not continue chemotherapy if performance status deteriorates to ECOG PS ≥3—transition to best supportive care only 1

6. Do not delay palliative interventions (stenting for obstruction, radiotherapy for bleeding) while pursuing chemotherapy 1

Monitoring During Treatment

• Performance status assessment at each visit to identify deterioration 1
• CBC, renal function, liver function before each cycle 2
• Urine protein monitoring (dipstick or protein/creatinine ratio) 2
• Blood pressure monitoring 2
• Thyroid function periodically 2