Critical reviews in oncology/hematology · 2025
High-grade gastro-entero-pancreatic neuroendocrine neoplasms: An overlooked population in interventional clinical trials. A systematic review.
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Merola Elettra, Dore Maria Pina, Pes Giovanni Mario, Fanciulli Giuseppe
Аннотация
BACKGROUND: High-grade gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of tumors with poor prognosis, including grade 3 neuroendocrine tumors (NETs G3) and neuroendocrine carcinomas (NECs), which represent distinct entities with different clinical outcomes. Our aim was to systematically review the available clinical evidence on therapeutic strategies for sporadic, highly proliferative GEP-NENs.
METHODS: A systematic literature search was conducted using PubMed, Scopus, and Web of Science (last update: August 9, 2025). Endpoints included the evaluation of clinical outcomes from interventional trials and subgroup analysis comparing NET G3 with NEC.
RESULTS: A total of 2135 records were retrieved, with a final inclusion of 28 prospective trials (six randomized trials). Twelve trials exclusively enrolled NECs, one trial focused on NET G3, five provided NET G3/NEC subanalyses, ten included mixed populations without morphological stratification. Owing to the high risk of bias, a meta-analysis was not feasible. In NECs, the highest disease control was achieved with the CAPOXIRI-Bevacizumab regimen (disease control rate, DCR 78.9 %; median progression-free survival, PFS 18 months; overall survival, OS 30.5 months), but the cohort was small (n = 19) and toxicity substantial. Immunotherapy yielded disappointing results, either as monotherapy or in combination with a dual checkpoint blockade (median PFS: ∼2 months). Platinum-based chemotherapy proved poor for NET G3, whereas temozolomide/everolimus and peptide receptor radionuclide therapy offered clear benefits (DCR: 96.1 % and 70 %, respectively).
CONCLUSIONS: High-grade GEP-NENs (particularly NET G3) remain an overlooked population in interventional studies. Progress in precision medicine requires the identification of molecular biomarkers to guide individualized therapy.
METHODS: A systematic literature search was conducted using PubMed, Scopus, and Web of Science (last update: August 9, 2025). Endpoints included the evaluation of clinical outcomes from interventional trials and subgroup analysis comparing NET G3 with NEC.
RESULTS: A total of 2135 records were retrieved, with a final inclusion of 28 prospective trials (six randomized trials). Twelve trials exclusively enrolled NECs, one trial focused on NET G3, five provided NET G3/NEC subanalyses, ten included mixed populations without morphological stratification. Owing to the high risk of bias, a meta-analysis was not feasible. In NECs, the highest disease control was achieved with the CAPOXIRI-Bevacizumab regimen (disease control rate, DCR 78.9 %; median progression-free survival, PFS 18 months; overall survival, OS 30.5 months), but the cohort was small (n = 19) and toxicity substantial. Immunotherapy yielded disappointing results, either as monotherapy or in combination with a dual checkpoint blockade (median PFS: ∼2 months). Platinum-based chemotherapy proved poor for NET G3, whereas temozolomide/everolimus and peptide receptor radionuclide therapy offered clear benefits (DCR: 96.1 % and 70 %, respectively).
CONCLUSIONS: High-grade GEP-NENs (particularly NET G3) remain an overlooked population in interventional studies. Progress in precision medicine requires the identification of molecular biomarkers to guide individualized therapy.