The role of systemic inflammatory factors in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with peptide receptor radionuclide therapy (PRRT).
Authors: Abou Jokh Casas Estephany , Martinez Lago Nieves , Cabezas Agricola Jose Manuel , Anido Herranz Urbano , Baron Francisco , Fernandez Calvo Ovidio , Quindós Varela Maria , Varela Ferreiro Silvia , Carral Maseda Alberto , De Matias Leralta Jose Maria , Nogareda Seoane Zulema , Cousillas Castiñeira Antia , Rodriguez Martinez de LLano Sofia , Mato Mato Jose Antonio , Fernández Catalina Pablo , Rodriguez Fonseca Omar , Muñiz Garcia Gloria , Bernardez Beatriz , Cameselle Teijeiro Jose Manuel , Pubul Nuñez Virginia 
Published: January 2021

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Background: Inflammation plays a key role in the pathophysiology of many diseases, including cancer. Systemic inflammatory factors have been validated as indicators of ongoing systemic inflammation that could be predictive markers of poor prognosis for oncological outcomes. However, it is unknown the prognostic impact of systemic inflammation markers in patients with GEP-NETs treated with PRRT. Methods: We conducted an observational, retrospective, multicentric study of 40 patients with GEP-NET treated with PRRT belonging to GGNET (Galician Research Group on Neuroendocrine Tumors) network at Nuclear Medicine Department of Santiago de Compostela University Hospital (Spain). The systemic inflammatory markers were calculated as follows: NLR = neutrophil count/lymphocyte count, PLR = platelet count/lymphocyte count, MLR= monocyte count/lymphocyte count, ALB= albumin levels and dNLR = neutrophil count/ (leucocytes count – neutrophils count). For the calculation of the different ratios, baseline analysis and after the second dose were used. The cut-off values were determined as the median of each values, correlating them with progression-free survival (PFS). Results: Data from 40 patients (pts) treated between 2016 and 2020 were recorded. Median age was 63.5 years (range 41-85) and 55% were male. Baseline ECOG PS 0/1/2 was 15 (37.5%)/16 (40%)/9 (22.5%). Tumor location was intestinal 26 pts (65%), pancreas 11 pts (27.5%) and unknown origin 3 pts (7.5%). 15 pts (37.5%) were functioning. Tumor grade G1/G2/G3 were 17 pts (42.5%)/ 20 pts (50%)/ 3 pts (7.5%), and Ki 67 <2/3-20/>20%/unknown were 11 pts (27.5%)/ 21 pts (52.5%)/ 3 pts (7.5%)/ 5 pts (12.5%), respectively. The most frequent site of metastasis was liver 32 pts (80%), lymph nodes 19 pts (47.5%), peritoneum 11 pts (27.5%) and bone 10 pts (25%). Surgery: 22 pts (55%) primary tumor surgery and 8 pts (20%) metastasectomy. Previous systemic treatments included somatostatin analogs (SSA) 40 pts (100%), everolimus 26 pts (65%) and sunitnib 11 pts (27.5%), others 7 pts (17.5%). The baseline cutoff-values for NLR was 2.61, for PLR 110.14, for MLR 0.31, for ALB 4.2. and for dNLR 1.71. The cutoff-values after the 2nd dose for NLR was 2.3, for PLR 2.15, for MLR 0.3, for ALB 4.2 and for dNLR 1.48. With a median follow up of 21 months, 14 pts (35%) had died. Median PFS was 27.2 m (95% CI 16.0-38.4m) and OS was not reached (NR). Pts with baseline higher NLR (>2.61 vs. <2.61) had a significantly lower PFS: 15.8 m vs. NR (HR 0.181; 95% CI 0.051-0.638, p=0.03), which was also true for pts with elevated dNLR (>1.71 vs. <1.71): PFS 15.8 m vs. NR (HR 0.174; 0.049-0.614, p=0.03). Baseline PLR, ALB, MLR and NLR, PLR, ALB, dNLR and MLR values after the 2nd dose was not statistically significant for PFS. Conclusions: We have identified that baseline NLR and dNRL are significant predictive factors in patients with GEP-NETs treated with PRRT.