🧬 Chemotherapy Options for Locally Advanced Gastric Cancer in 2025: A Complete Guide
From Systemic Therapy to Intraperitoneal Chemotherapy: What Oncologists Need to Know
📈 Introduction: The Urgent Need for Better Gastric Cancer Strategies
Gastric cancer remains a significant global health challenge, with over 1 million new cases and 769,000 deaths annually, according to the WHO. Most patients are diagnosed at a locally advanced stage (LAGC)—when tumors have invaded the muscular layer or adjacent structures but have not yet metastasized.
While surgical resection is the only curative approach, outcomes are poor without systemic intervention. The latest review published in Cancers (MDPI, 2025) systematically evaluates modern chemotherapy strategies, from standard perioperative approaches to emerging targeted and locoregional innovations.
🧪 What Is Locally Advanced Gastric Cancer (LAGC)?
LAGC refers to non-metastatic but deeply invasive tumors—often classified as T3 or T4, possibly involving regional lymph nodes (N+), but without distant metastasis (M0). These cases require multimodal treatment for the best outcomes.
💉 Standard of Care: Perioperative Chemotherapy + Surgery
🧾 Historical Context
- Before 2006, surgery alone was common but showed high recurrence rates (especially peritoneal relapse).
- Trials like MAGIC (UK) and FLOT4 (Germany) proved that perioperative chemotherapy improves survival and reduces micrometastasis.
⚙️ Common Regimens Today (2025)
| Regimen | Drugs | Notes |
|---|---|---|
| FLOT | 5-FU, Leucovorin, Oxaliplatin, Docetaxel | High efficacy, good downstaging, standard in EU |
| FOLFOX | 5-FU, Leucovorin, Oxaliplatin | Preferred in fragile patients |
| XELOX | Capecitabine, Oxaliplatin | Oral option (capecitabine) |
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Advantages of Neoadjuvant (Preoperative) Chemotherapy:
✅ Tumor downsizing
✅ Early systemic control
✅ Assessment of chemo-sensitivity
✅ Improved R0 resection rates
🧬 Molecular and Targeted Therapies
Personalized medicine is advancing gastric cancer care by targeting specific molecular markers.
🎯 HER2-Positive Gastric Cancer
- Trastuzumab (anti-HER2) + chemotherapy is standard in metastatic HER2+ disease.
- Trials are ongoing for neoadjuvant HER2-targeted therapy in localized LAGC.
🔄 Ongoing Targets in 2025
| Target | Agents | Status |
|---|---|---|
| HER2 | Trastuzumab, T-DXd | In clinical trials for perioperative use |
| VEGF | Ramucirumab, Bevacizumab | Studied in advanced/metastatic setting |
| PD-1/PD-L1 | Nivolumab, Pembrolizumab | Promising in MSI-high or EBV+ tumors |
🌊 Intraperitoneal Chemotherapy (IPC): A Promising Frontier
Peritoneal recurrence is the most frequent relapse site in LAGC. IPC strategies aim to deliver high drug concentrations locally, minimizing systemic toxicity.
🔥 HIPEC (Hyperthermic Intraperitoneal Chemotherapy)
- Performed immediately after surgery with heated chemo circulated in the abdomen.
- May benefit patients with serosal invasion or minimal peritoneal disease.
- Still experimental in LAGC, but used routinely in pseudomyxoma and ovarian cancers.
💨 PIPAC (Pressurized Intraperitoneal Aerosol Chemotherapy)
- Minimally invasive; chemo aerosolized into the peritoneum via laparoscopy.
- Suitable for patients with peritoneal carcinomatosis in non-resectable disease.
🧪 Limitations:
- Lack of large RCTs
- Complex logistics and costs
- Need for biomarker selection
🧩 Key Challenges and Future Directions
| Challenge | Implication |
|---|---|
| No consensus on IPC use | More RCTs are needed to define role in standard care |
| Biomarker selection lacking | Treatment is still empirical in many cases |
| Poor response prediction | Chemo-resistance remains a major issue |
🔬 Future strategies include:
- Liquid biopsy to monitor response
- AI-guided therapy planning
- Neoantigen vaccines in immunogenic tumors
📊 Clinical Trials to Watch (2025–2027)
| Trial | Focus | Region |
|---|---|---|
| FIGHT-GC | Trastuzumab + FLOT in neoadjuvant setting | Europe |
| GASTRIPEC | HIPEC vs. no HIPEC after D2 resection | Germany |
| KEYNOTE-811 | Pembrolizumab + Trastuzumab | Global |
📝 Final Thoughts: Toward Tailored Multimodal Oncology
Chemotherapy for locally advanced gastric cancer has evolved beyond a one-size-fits-all approach. In 2025, successful treatment hinges on multidisciplinary coordination, molecular profiling, and clinical trial enrollment.
As IPC and targeted therapies mature, and with AI and biomarkers guiding personalized regimens, the next decade could significantly improve survival for patients with this historically fatal disease.