TY - JOUR T1 - Investigation of systemic treatment responses and prognostic factors in metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) TT - Metastatik gastroenteropankreatik nöroendokrin karsinomlarda (GEP-NEC) sistemik tedavi yanıtlarının ve prognostik faktörlerin araştırılması AU - Türkel, Alper AU - Ercan Uzundal, Duygu AU - Gürler, Fatih AU - Deliktaş Onur, İlknur AU - Gülcü, Serkan AU - Yalçıntaş Arslan, Ülkü PY - 2025 DA - October Y2 - 2025 DO - 10.32322/jhsm.1744286 JF - Journal of Health Sciences and Medicine JO - J Health Sci Med /JHSM /jhsm PB - MediHealth Academy Yayıncılık WT - DergiPark SN - 2636-8579 SP - 959 EP - 965 VL - 8 IS - 6 LA - en AB - Aims: This study aimed to evaluate responses to first- and second-line treatments, survival outcomes, and potential factors affecting survival in patients with metastatic gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC).Methods: This retrospective study included 42 patients with metastatic GEP-NEC from three centers. First and second-line chemotherapy regimenswere examined. The median progression-free survival (mPFS1 and mPFS2) for firstand second-line treatments and overall survival (mOS) were evaluated. The effects of CRP levels, LDH levels, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) on survival were investigated as potential prognostic factors.Results: Median follow-up was 15 months (3-113). mPFS1 was 5 months (95% CI: 2.88-7.11) and mPFS2 was 2 months (95% CI: 1.67-2.32). The mOS was 15 months (95% CI: 10.90-19.09). Curative surgery patients had a 28-month mOS, and patients who could not undergo surgery had a mOS of 14 months (p=0.010). Patients with NLR KW - Extrapulmonary KW - neuroendocrine carcinoma KW - GEP-NEC KW - NLR N2 - Giriş: Bu çalışmada, metastatik gastroenteropankreatik nöroendokrin karsinom (GEP-NEC) tanılı hastalarda, birinci ve ikinci basamak tedavilere yanıtlar, sağkalım sonuçları ve sağkalımı etkileyen potansiyel faktörlerin değerlendirilmesi amaçlanmıştır.Yöntem: Bu retrospektif çalışmaya üç merkezden metastatik GEP-NEC'li 42 hasta dahil edilmiştir. Birinci ve ikinci basamak kemoterapi rejimleri incelenmiştir. Birinci ve ikinci basamak tedaviler için ortanca progresyonsuz sağkalım (mPFS1 ve mPFS2) ve genel sağkalım (mOS) değerlendirilmiştir. CRP düzeyleri, LDH düzeyleri, nötrofil-lenfosit oranı (NLR) ve trombosit-lenfosit oranının (PLR) sağkalım üzerindeki etkileri olası prognostik faktörler olarak araştırılmıştır.Bulgular: Ortanca takip süresi 15 ay (3-113) olarak saptandı. mPFS1 5 ay (95% CI: 2,88-7,11) ve mPFS2 2 ay (95% CI: 1,67-2,32) idi. mOS 15 ay idi (95% CI: 10,90-19,09). Küratif amaçlı cerrahi yapılan hastaların mOS'si 28 ay iken, opere edilemeyen hastaların mOS'si 14 ay idi (p = 0,010). NLR < 2,56 olan hastaların mOS'si, NLR ≥ 2,56 olanlara göre daha uzundu (22 ay - 14 ay, p = 0,019). Çok değişkenli analiz, daha düşük NLR skorları ve Ki67 değerlerinin daha uzun mOS ile ilişkili olduğunu göstermiştir [HR: 0,38 (95% CI: 0,18-0,79), p = 0,010 ve HR: 0,41 (95% CI: 0,20-0,84), p = 0,015].Sonuç: Çalışmamız, daha yüksek NLR skorları ve Ki67 değerlerinin mOS'yi önemli ölçüde kötüleştirdiğini göstermiştir. Sağkalım sonuçları (OS, PFS1 ve PFS2) mevcut literatürle uyumluydu. Kötü prognozları, kısa sağkalım süreleri ve standart tedavi önerilerinin eksikliği nedeniyle nöroendokrin karsinomlarda yeni tedavi seçenekleri ve prognostik belirteçlere ihtiyaç vardır. CR - Korse CM, Taal BG, van Velthuysen ML, Visser O. Incidence and survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry. Eur J Cancer. 2013;49(8):1975-1983. doi:10.1016/j.ejca.2012.12.022 CR - Boyar Cetinkaya R, Aagnes B, Thiis-Evensen E, Tretli S, Bergestuen DS, Hansen S. Trends in incidence of neuroendocrine neoplasms in norway: a report of 16,075 cases from 1993 through 2010. Neuroendocrinology. 2017;104(1):1-10. doi:10.1159/000442207 CR - Cho MY, Kim JM, Sohn JH, et al. Current trends of the incidence and pathological diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Korea 2000-2009: multicenter study. Cancer Res Treat. 2012;44(3):157-165. doi:10.4143/crt.2012.44.3.157 CR - Dasari A, Mehta K, Byers LA, Sorbye H, Yao JC. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: a SEER database analysis of 162,983 cases. Cancer. 2018; 124(4):807-815. doi:10.1002/cncr.31124 CR - Mitry E, Baudin E, Ducreux M, et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer. 1999;81(8):1351-1355. doi:10.1038/sj.bjc.6690325 CR - Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer. 1991;68(2):227-232. doi:10.1002/1097-0142 (19910715)68:2 <227::aid-cncr2820680202>3.0.co;2-i CR - Andreatos N, McGarrah PW, Sonbol MB, et al. Managing metastatic extrapulmonary neuroendocrine carcinoma after first-line treatment. Curr Oncol Rep. 2023;25(10):1127-1139. doi:10.1007/s11912-023-01438-w CR - Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24(1):152-160. doi:10.1093/annonc/mds276 CR - Panzuto F, Merola E, Pavel ME, et al. Stage IV gastro-entero-pancreatic neuroendocrine neoplasms: a risk score to predict clinical outcome. Oncologist. 2017;22(4):409-415. doi:10.1634/theoncologist.2016-0351 CR - Nießen A, Schimmack S, Sandini M, et al. C-reactive protein independently predicts survival in pancreatic neuroendocrine neoplasms. Scientific Reports. 2021;11(1):23768. doi:10.1038/s41598-021-03187-x CR - Zou J, Li Q, Kou F, et al. Prognostic value of inflammation-based markers in advanced or metastatic neuroendocrine tumours. Curr Oncol. 2019;26(1):e30-e38. doi:10.3747/co.26.4135 CR - Grenader T, Pavel ME, Ruszniewski PB, et al. Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors. Anticancer Drugs. 2020;31(3):216-222. doi:10.1097/cad.0000000 000000909 CR - Shirasawa M, Yoshida T, Horinouchi H, et al. Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment. Br J Cancer. 2021;124(5):925-932. doi:10.1038/s41416-020-01188-7 CR - Kim HJ, Lee KH, Shim HJ, et al. Prognostic significance of the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in neuroendocrine carcinoma. Chonnam Med J. 2022;58(1):29-36. doi:10. 4068/cmj.2022.58.1.29 CR - Shi M, Zhao W, Zhou F, et al. Neutrophil or platelet-to-lymphocyte ratios in blood are associated with poor prognosis of pulmonary large cell neuroendocrine carcinoma. Translat Lung Cancer Res. 2020;9(1):45-54. CR - Yamaguchi T, Machida N, Morizane C, et al. Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system. Cancer Sci. 2014;105(9):1176-1181. doi:10.1111/cas.12473 CR - Yoon SE, Kim JH, Lee SJ, et al. The impact of primary tumor site on outcomes of treatment with etoposide and cisplatin in grade 3 gastroenteropancreatic neuroendocrine carcinoma. J Cancer. 2019; 10(14):3140-3144. doi:10.7150/jca.30355 CR - Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22(4):657-664. doi:10.1530/erc-15-0119 CR - Freis P, Graillot E, Rousset P, et al. Prognostic factors in neuroendocrine carcinoma: biological markers are more useful than histomorphological markers. Scientific Reports. 2017;7(1):40609. doi:10.1038/srep40609 CR - Matsas S, Junior PNA, Giglio AD. Prognostic role of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in advanced gastric cancer treated with immunotherapy: a systematic review and meta-analysis. J Clin Oncol. 2024;42(3_suppl):397-397. doi: 10.1200/JCO.2024.42.3_suppl.397 CR - Liu T, Chen X, Mo S, et al. Molecular subtypes and prognostic factors of lung large cell neuroendocrine carcinoma. Transl Lung Cancer Res. 2024;13(9):2222-2235. doi:10.21037/tlcr-24-292 CR - Panni RZ, Lopez-Aguiar AG, Liu J, et al. Association of preoperative monocyte-to-lymphocyte and neutrophil-to-lymphocyte ratio with recurrence-free and overall survival after resection of pancreatic neuroendocrine tumors (US-NETSG). J Surg Oncol. 2019;120(4):632-638. doi:https://doi.org/10.1002/jso.25629 CR - Abdelmalak R, Lythgoe MP, Evans J, et al. Exploration of novel prognostic markers in grade 3 neuroendocrine neoplasia. Cancers. 2021; 13(16):4232. CR - Zhou X, Du Y, Huang Z, et al. Prognostic value of PLR in various cancers: a meta-analysis. PLoS One. 2014;9(6):e101119. doi:10.1371/journal.pone.0101119 CR - Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1-10. doi:10.1200/JCO.19.02105 CR - Andre T, Berton D, Curigliano G, et al. Antitumor activity and safety of dostarlimab monotherapy in patients with mismatch repair deficient solid tumors: a nonrandomized controlled trial. JAMA Netw Open. 2023;6(11):e2341165. doi:10.1001/jamanetworkopen.2023.41165 CR - Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-1365. doi:10.1016/S1470-2045(20)30445-9 CR - Mohamed A, Vijayvergia N, Kurian M, Liu L, Fu P, Das S. Exploring real world outcomes with nivolumab plus ipilimumab in patients with metastatic extra-pulmonary neuroendocrine carcinoma (EP-NEC). Cancers (Basel). 2022;14(11):2695. doi:10.3390/cancers14112695 CR - Salama AKS, Li S, Macrae ER, et al. Dabrafenib and trametinib in patients with tumors with BRAF(V600E) mutations: results of the NCI-MATCH trial subprotocol H. J Clin Oncol. 2020;38(33):3895-3904. doi:10.1200/JCO.20.00762 CR - Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 2022;23(10):1261-1273. doi:10.1016/s1470-2045(22)00541-1 CR - Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540. doi:10.1016/s1470-2045(19)30856-3 CR - Demetri GD, De Braud F, Drilon A, et al. Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors. Clin Cancer Res. 2022;28(7):1302-1312. doi:10. 1158/1078-0432.Ccr-21-3597 CR - Yamamoto S, Sakakibara N, Hirano H, et al. The real-world selection of first-line systemic therapy regimen for metastatic gastroenteropancreatic neuroendocrine neoplasm in Japan. Sci Rep. 2022;12(1):17601. doi:10. 1038/s41598-022-22718-8 CR - Hospital NTU. Tarlatamab for advanced extrapulmonary small cell carcinoma and neuroendocrine carcinoma (TAURUS). 2025. CR - Inkeun Park AMCRP. Efficacy and safety evaluation of tarlatamab in advanced extrapulmonary neuroendocrine carcinoma patients (DeLLight). 2025. UR - https://doi.org/10.32322/jhsm.1744286 L1 - https://dergipark.org.tr/tr/download/article-file/5062660 ER -