What is the role of neoadjuvant chemotherapy and immunotherapy in the treatment of gastric cancer, particularly in patients with locally advanced disease?

Role of Neoadjuvant Chemotherapy and Immunotherapy in Gastric Cancer

Direct Recommendation

For patients with locally advanced resectable gastric cancer, perioperative chemotherapy with the FLOT regimen (docetaxel, oxaliplatin, 5-FU/leucovorin) is the current standard of care, demonstrating superior survival, pathological response rates, and R0 resection rates compared to older regimens. 1, 2 Neoadjuvant immunotherapy combined with chemotherapy shows promising early results with significantly higher pathological complete response rates, but remains investigational and should be considered only in clinical trial settings. 3

Neoadjuvant Chemotherapy: Evidence-Based Approach

Established Benefits

Perioperative chemotherapy has proven superior to surgery alone in Western populations, with demonstrated improvements in overall survival and disease-free survival. 1 The evidence shows:

• FLOT regimen is the preferred choice, showing prolonged median disease-free survival, overall survival, higher pathological response rates, and improved R0 resection rates with tolerable toxicity compared to ECF/ECX regimens. 1, 2
• Neoadjuvant chemotherapy significantly increases tumor resectability rates (86.4% vs 55-60% with surgery alone). 4
• Meta-analyses demonstrate improved overall survival (P = 0.001) and progression-free survival (P < 0.001) with neoadjuvant chemotherapy. 5

Alternative Regimens

When FLOT is not feasible, acceptable alternatives include: 1, 2

• ECF (epirubicin + cisplatin + 5-FU)
• Modified ECF
• XELOX (oxaliplatin + capecitabine)
• FOLFOX (oxaliplatin + 5-FU)
• SOX (oxaliplatin + S-1)

Critical Staging Requirements

Laparoscopic exploration with cytological examination of intraperitoneal washings must be performed before initiating neoadjuvant therapy to detect occult peritoneal metastases that imaging frequently misses. 1, 2 This prevents inappropriate treatment of patients with undetected metastatic disease.

Neoadjuvant Immunotherapy: Emerging Evidence

Current Status

Neoadjuvant immunotherapy combined with chemotherapy is investigational and not yet standard of care, though early real-world data are encouraging. 3 A recent single-center study demonstrated:

• Significantly higher pathological complete response (pCR) rates with immunochemotherapy (22.4% vs 4.8%, P = 0.011) compared to chemotherapy alone. 3
• Superior T downstaging (65.3% of patients) and N downstaging (55.1% of patients). 3
• Overall TNM downstaging in 85.7% of patients receiving immunochemotherapy. 3
• Comparable safety profile with no significant difference in grade ≥3 adverse events (11.7% vs 9.8%, P = 0.240). 3

Important Limitations

The immunotherapy data comes from a single-center retrospective study with short follow-up, showing no significant difference in 1-year overall survival (100% vs 93.5%, P = 0.195) or disease-free survival (81.6% vs 75.8%, P = 0.144). 3 Multicenter randomized trials are urgently needed before this can be recommended as standard practice. 3

Neoadjuvant Chemoradiation: Limited Role

Neoadjuvant chemoradiation remains experimental and has not demonstrated confirmed survival advantages in comparative randomized studies. 1 The evidence shows:

• Theoretical advantages (limited radiation fields, higher chance of radical surgery) have not translated to proven clinical benefit. 1
• For gastroesophageal junction (GEJ) adenocarcinoma specifically, neoadjuvant chemoradiotherapy may reduce local recurrence, but survival benefit remains unproven. 1
• Neoadjuvant chemoradiation should only be considered for stage III GEJ carcinoma or within clinical trials. 1

Treatment Algorithm for Locally Advanced Disease

For Resectable Disease:

1. Perform laparoscopic staging with peritoneal washings 1, 2
2. Administer FLOT regimen (4 cycles preoperatively) 1, 2
3. Proceed to D2 gastrectomy with adequate lymphadenectomy (minimum 14 nodes, optimally ≥25) 2, 6
4. Continue FLOT postoperatively (4 additional cycles) 2
5. If R0 resection not achieved, add postoperative chemoradiotherapy 1, 2

For Unresectable Disease:

1. Initiate concurrent chemoradiotherapy for patients with good performance status 2
2. Re-evaluate for surgical resection after treatment response 1, 2
3. Recommended chemoradiotherapy regimens include capecitabine + paclitaxel, cisplatin + 5-FU/capecitabine, or oxaliplatin + 5-FU/capecitabine 2

Common Pitfalls and Caveats

Do not proceed with neoadjuvant therapy without laparoscopic staging, as imaging misses peritoneal metastases in a significant proportion of patients, leading to inappropriate treatment. 1, 2, 6

Do not use neoadjuvant chemotherapy in early-stage disease (stage I), as it may be detrimental to survival without providing benefit. 7 There is insufficient evidence to support adjuvant chemotherapy for stage I patients except those with lymph node metastasis. 1

Do not assume Asian trial results apply to Western populations, particularly regarding oral fluoropyrimidines like S-1, which showed benefit in Japanese D2 dissection trials but require validation in Western populations. 1

Manage toxicity proactively with FLOT, as three-drug regimens carry higher toxicity risk requiring careful monitoring and dose adjustments. 2

Do not offer neoadjuvant immunotherapy outside clinical trials, as long-term survival data are lacking despite promising pCR rates. 3

Ensure adequate lymph node evaluation (minimum 14 nodes, optimally ≥25) during surgery, as inadequate sampling leads to understaging and suboptimal treatment planning. 2, 6