For high‑grade gastric neuroendocrine carcinoma, should neoadjuvant platinum‑based chemotherapy followed by surgery and adjuvant chemotherapy be used instead of adjuvant chemotherapy alone?

Neoadjuvant Chemotherapy Should Be Used for High-Grade Gastric Neuroendocrine Carcinoma

For high-grade gastric neuroendocrine carcinoma (NEC), neoadjuvant platinum-based chemotherapy followed by surgery and adjuvant chemotherapy should be used instead of adjuvant chemotherapy alone, as this approach significantly improves overall survival. 1

Evidence Supporting Neoadjuvant Approach

Survival Benefit Demonstrated

• Neoadjuvant chemotherapy significantly improved overall survival compared to surgery-first approaches in patients with locally advanced gastric NEC and mixed adenoneuroendocrine carcinoma (MANEC). 1
• In the largest retrospective study specifically examining this question, patients receiving neoadjuvant chemotherapy demonstrated superior OS compared to those undergoing surgery first (P = 0.032). 1
• Multivariate analysis confirmed neoadjuvant chemotherapy as an independent favorable prognostic factor for overall survival. 1

Response Rates and Pathological Effects

• Among patients receiving neoadjuvant chemotherapy, 65% achieved objective responses (complete or partial remission) according to RECIST 1.1 criteria. 1
• Pathological complete response was achieved in 5% of patients, with 30% showing significant tumor regression (grades 1-2). 1
• The treatment was well-tolerated with postoperative complication rates similar between neoadjuvant and surgery-first groups. 1

Contrast with Adjuvant-Only Approach

Limited Benefit of Adjuvant Chemotherapy Alone

• A large multi-center Chinese study of 804 patients with resectable gastric NEC or MANEC found no survival benefit from adjuvant chemotherapy alone after surgery. 2
• After propensity score matching, overall survival in the adjuvant chemotherapy group was similar to the no-chemotherapy group. 2
• Neither 5-FU-based regimens nor platinum-based combinations (etoposide plus cisplatin or irinotecan plus cisplatin) demonstrated survival advantages when used solely in the adjuvant setting. 2

Treatment Algorithm

Recommended Platinum-Based Regimens

• First-line platinum-based chemotherapy with etoposide is the standard neoadjuvant approach, following the paradigm established for small cell lung cancer. 3, 4
• Alternative platinum doublets with irinotecan have shown comparable efficacy in recent randomized trials. 4
• For patients unable to tolerate platinum-based therapy, FOLFOX (5-fluorouracil with oxaliplatin) has demonstrated antitumor activity in relapsed disease. 5

Surgical Timing and Approach

• Surgery should be performed after neoadjuvant chemotherapy if R0 resection remains achievable. 1
• Radical gastrectomy with D2 lymphadenectomy is recommended following neoadjuvant treatment. 6
• Response evaluation using CT imaging should be performed after neoadjuvant therapy to assess resectability. 6

Adjuvant Component

• Continue the same platinum-based regimen postoperatively as adjuvant therapy, particularly in patients who achieved pathological complete response or significant tumor regression. 6, 1
• The perioperative approach (neoadjuvant + adjuvant) mirrors successful strategies used in gastric adenocarcinoma, where perioperative chemotherapy improved 5-year survival from 23% to 36-38%. 6

Critical Distinctions from Gastric Adenocarcinoma

Different Biology Requires Different Approach

• While gastric adenocarcinoma guidelines support either perioperative or adjuvant-only chemotherapy as equivalent options 6, gastric NEC specifically benefits from the neoadjuvant component. 1, 2
• The aggressive nature of poorly differentiated NECs, with high proliferation rates (Ki-67 index), necessitates early systemic therapy to address micrometastatic disease. 3
• Adjuvant chemotherapy alone failed to demonstrate benefit in gastric NEC, unlike in adenocarcinoma where adjuvant chemoradiotherapy showed survival advantages. 2, 6

Common Pitfalls to Avoid

Do Not Delay Systemic Therapy

• Avoid surgery-first approaches in locally advanced gastric NEC, as this eliminates the proven survival benefit of neoadjuvant treatment. 1
• Early-stage gastric cancers (T1) may actually have worse outcomes with neoadjuvant chemotherapy 7, but this data pertains to adenocarcinoma, not high-grade NEC which behaves more aggressively.

Do Not Use Adenocarcinoma Regimens

• Standard gastric adenocarcinoma regimens (ECF, FLOT) are not appropriate for NEC. 6
• Platinum-etoposide combinations remain the backbone of therapy for gastric NEC, not fluoropyrimidine-based triplets. 3, 4

Distinguish from Well-Differentiated NETs

• The 2019 WHO classification separates well-differentiated grade 3 NETs (NET G-3) from poorly differentiated NECs, with NET G-3 having better prognosis and different management. 3
• Type 1 and Type 2 gastric NETs associated with hypergastrinemia are managed differently, often with endoscopic resection for lesions ≤2 cm. 6, 8
• High-grade gastric NEC requires aggressive multimodality therapy, not the observation or endoscopic approaches used for low-grade NETs. 6