Abstract
Tumor microenvironment inflammation contributes to the proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, and reduced treatment response. We aimed to evaluate the early predictive and prognostic significance of markers of systemic inflammation in patients receiving somatostatin-receptor targeted peptide receptor radionuclide therapy (PRRT). This retrospective observational cohort study included 33 patients with advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) treated with PRRT. Pretreatment blood-based inflammatory biomarkers, e.g., C-reactive protein levels (CRP), white blood cell count (WBC), and absolute neutrophil count (ANC), were documented and inflammation indexes, e.g., neutrophil-lymphocyte ratio (NLR) and Platelet × CRP multiplier (PCM), were calculated. Tumor burden was determined using [68Ga]Ga-DOTA-TATE PET/CT before enrollment and every 2 cycles thereafter until progression. Therapy response was assessed using RECIST 1.1, including its volumetric modification. Inflammatory biomarkers and inflammatory indexes demonstrated marked heterogeneity among patients, and were significantly higher in non-responders (e.g., CRP (p < 0.001), ANC (p = 0.002), and PCM (p < 0.001)). Change in whole-body tumor burden after two cycles of PRRT was significantly associated with CRP (p = 0.0157) and NLR (p = 0.0040) in multivariate regression analysis. A cut-off of 2.5 mg/L for CRP (AUC = 0.84, p = 0.001) revealed a significant outcome difference between patients with adversely high vs. low CRP (median PFS 508 days vs. not yet reached (HR = 4.52; 95% CI, 1.27 to 16.18; p = 0.02)). Tumor-driven systemic inflammatory networks may be associated with treatment response, change in tumor burden, and prognosis in patients with GEP-NETs receiving PRRT.
Highlights
peptide receptor radionuclide therapy (PRRT) was performed according to the joint International Atomic Energy Agency (IAEA; Vienna, Austria), European Association of Nuclear Medicine (EANM; Vienna, Austria), and Society of Nuclear Medicine and Molecular Imaging (SNMMI; Reston, VA, USA) practical guidance in accordance with the Rotterdam protocol as published [20]
A total of 33 patients (Table 1) with GEP-NETs who underwent a total of 181 PRRT cycles (5.5 ± 2.3 per patient and with a mean administered activity of 7.4 GBq per cycle) were analyzed
During the follow-up period of 30 ± 20 months, 16/33 (48.5%) patients progressed, while 17/33 (51.5%) patients showed a response to PRRT
Summary
Zou et al have investigated the role of systemic inflammation-based markers in patients with inoperable advanced or metastatic NETs, and suggested that the high-sensitivity inflammation-based prognostic index (HSPI) was an independent predictor of shorter overall survival [15], underlining the potential prognostic significance of cancer-related inflammation in NETs. In the setting of external beam radiation therapy, tumor-related pretreatment leukocytosis and neutrophilia have been associated with resistance to radiotherapy, immune suppression, and promotion of metastasis [16,17,18]. Based on previous data about cancer-related inflammation and experience with external radiation therapy, we speculated that blood-based inflammatory biomarkers may have both predictive and prognostic significance in the context of internal theranostic radionuclide therapy We tested this hypothesis in a cohort of patients with gastroenteropancreatic NETs undergoing PRRT, and analyzed the relationship between systemic inflammatory biomarkers and outcome
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