What chemotherapy regimens (peri‑operative FLOT [docetaxel, oxaliplatin, leucovorin, 5‑fluorouracil]; first‑line CAPOX [capecitabine plus oxaliplatin] or FOLFOX [oxaliplatin, leucovorin, 5‑fluorouracil]; HER2 [human epidermal growth factor receptor 2]‑positive with trastuzumab) are recommended for gastric adenocarcinoma, including second‑line options?

Chemotherapy for Gastric Adenocarcinoma

For perioperative treatment of resectable gastric adenocarcinoma, FLOT (docetaxel, oxaliplatin, leucovorin, 5-fluorouracil) is the preferred regimen, delivering superior overall survival compared to older regimens like ECF/ECX. For advanced/metastatic disease, first-line treatment depends critically on HER2 and PD-L1 status: HER2-positive tumors require trastuzumab plus fluoropyrimidine/platinum doublet, while HER2-negative tumors with PD-L1 CPS ≥5 should receive checkpoint inhibitor (nivolumab or pembrolizumab) combined with fluoropyrimidine/oxaliplatin chemotherapy 1.

Perioperative Chemotherapy (Resectable Disease)

FLOT is the category 1 recommendation for perioperative treatment of localized gastric adenocarcinoma 1. The landmark FLOT4 trial demonstrated that perioperative FLOT (4 preoperative + 4 postoperative cycles) achieved:

• Median overall survival of 50 months vs 35 months with ECF/ECX (HR 0.77,95% CI 0.63-0.94)
• Pathological complete response rate of 16% vs 6%
• Similar toxicity profile to ECF/ECX 2

The FLOT regimen consists of: docetaxel 50 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², and 5-fluorouracil 2600 mg/m² as 24-hour infusion, given every 2 weeks 1, 2.

For HER2-positive resectable disease, adding trastuzumab to perioperative FLOT achieved a 21.4% pathological complete response rate in a phase II trial, with promising 3-year overall survival of 82.1% 3. This represents an emerging option, though not yet standard of care.

First-Line Therapy for Advanced/Metastatic Disease

HER2-Positive Disease

Trastuzumab combined with fluoropyrimidine plus cisplatin is the category 1 recommendation 1, 4. The combination with oxaliplatin is category 2A. Trastuzumab should be added to first-line chemotherapy for tumors with IHC 3+ or IHC 2+ with FISH confirmation (HER2:CEP17 ratio ≥2) 1.

Critical caveat: Trastuzumab should NOT be combined with anthracyclines due to cardiotoxicity risk 5.

HER2-Negative Disease

The treatment algorithm depends on PD-L1 status:

For PD-L1 CPS ≥5 (Category 1):

• Nivolumab + fluoropyrimidine (fluorouracil or capecitabine) + oxaliplatin 1, 6
• The CheckMate-649 trial showed median OS of 14.4 vs 11.1 months (HR 0.71, P<0.0001) with nivolumab addition 7

For PD-L1 CPS 1-5:

• Nivolumab + chemotherapy may be considered case-by-case (Category 2B) 1, 6

For PD-L1 CPS <1:

• Fluoropyrimidine + platinum doublet WITHOUT checkpoint inhibitor 1, 6

Preferred cytotoxic doublets include:

• FOLFOX (fluorouracil, leucovorin, oxaliplatin) - preferred due to lower toxicity than cisplatin 7, 1
• CAPOX (capecitabine plus oxaliplatin) 7
• Fluoropyrimidine plus cisplatin 4

Oxaliplatin is explicitly preferred over cisplatin due to superior tolerability, particularly in patients >65 years where FOLFOX showed significantly better outcomes (OS 13.9 vs 7.2 months) 1, 7.

For elderly/frail patients, low-dose CAPOX (60% of standard dose) demonstrated non-inferior PFS with significantly lower toxicity 7, 1.

Three-drug regimens (DCF or modified DCF) should be reserved ONLY for medically fit patients with excellent performance status, large tumor burden, and access to frequent toxicity monitoring 1, 4. The standard DCF regimen carries excessive toxicity; dose-modified versions are preferred if triplet therapy is chosen 7.

Second-Line Therapy

Ramucirumab plus paclitaxel is the preferred category 1 recommendation 1, 7, 8. The RAINBOW trial demonstrated median OS of 9.63 vs 7.36 months (P<0.0001) compared to paclitaxel alone 7.

Alternative second-line options:

• Ramucirumab monotherapy (category 1) 7, 8
• Single-agent taxanes (paclitaxel or docetaxel) - category 1 7, 8
• Single-agent irinotecan - category 1 7
• FOLFIRI (if not used first-line) 7
• Ramucirumab + FOLFIRI or irinotecan 7

For HER2-positive disease progressing after trastuzumab, fam-trastuzumab deruxtecan-nxki achieved 51% objective response rate and median OS of 12.5 months in the DESTINY-Gastric01 trial, though with risk of interstitial lung disease requiring careful monitoring 7, 8.

Performance Status Considerations

Patients with KPS <60% or ECOG PS ≥3 should receive palliative/best supportive care ONLY - no systemic therapy 1, 5.

Patients with KPS ≥60% or ECOG PS ≤2 can receive systemic therapy with palliative/best supportive care 1, 5.

Two-drug regimens are strongly preferred over three-drug regimens for advanced disease due to lower toxicity without compromising efficacy 1, 5.

Critical Pitfalls to Avoid

1. Do not use ramucirumab in first-line therapy - the RAINFALL trial showed no benefit, and it is only indicated second-line or later 7

2. Do not continue trastuzumab beyond first-line in HER2-positive disease (except with fam-trastuzumab deruxtecan-nxki as a distinct agent) 8

3. Do not add checkpoint inhibitors to HER2-positive first-line therapy unless specifically indicated by trial data 1

4. Verify PD-L1 testing methodology - CPS (combined positive score) is the validated metric, not TPS alone, for gastric adenocarcinoma 1, 6

5. Ensure adequate premedication with corticosteroids for docetaxel-containing regimens to prevent hypersensitivity reactions 9