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Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib.

ABSTRACT: Background:Although lenvatinib was recently approved for treatment of advanced unresectable hepatocellular carcinoma (HCC) based on the phase III REFLECT trial, no biomarkers for management of lenvatinib treatment have been established. The aim of this study is to identify predictive biomarkers for the management of lenvatinib treatment in advanced HCC patients. Methods:A total of 41 patients with advanced HCC were enrolled in this retrospective study. Serum levels of 22 circulating cytokines and angiogenic factors (CAFs) were measured by multiplex Luminex assay. Profiles of CAFs, clinical chemistry/hematology parameters, and clinical background were evaluated to explore biomarkers associated with clinical outcomes. Results:Relative dose intensity (RDI) decreased significantly between weeks 1-2 and 3-4 (p?

SUBMITTER: Ono A

PROVIDER: S-EPMC7249573 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib.

Ono Atsushi A Aikata Hiroshi H Yamauchi Masami M Kodama Kenichiro K Ohishi Waka W Kishi Takeshi T Ohya Kazuki K Teraoka Yuji Y Osawa Mitsutaka M Fujino Hatsue H Nakahara Takashi T Murakami Eisuke E Miki Daiki D Kawaoka Tomokazu T Abe-Chayama Hiromi H Zhang Peiyi P Liu Songyao S Makokha Grace Naswa GN Tsuge Masataka M Imamura Michio M Hayes C Nelson CN Chayama Kazuaki K

Therapeutic advances in medical oncology 20200520

<h4>Background</h4>Although lenvatinib was recently approved for treatment of advanced unresectable hepatocellular carcinoma (HCC) based on the phase III REFLECT trial, no biomarkers for management of lenvatinib treatment have been established. The aim of this study is to identify predictive biomarkers for the management of lenvatinib treatment in advanced HCC patients.<h4>Methods</h4>A total of 41 patients with advanced HCC were enrolled in this retrospective study. Serum levels of 22 circulati ...[more]

PMID: 32547646

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Project description:Recently, it has been reported that the relative dose intensity (RDI) of adjuvant chemotherapy (AC) influences survival in various cancers, but there are very few reports about RDI in pancreatic ductal adenocarcinoma (PDAC). The optimal timing for initiation of AC for PDAC also remains unknown. The aim of this study was to identify the significance of RDI and the time interval between surgery and initiation of AC on survival of patients with PDAC. Clinicopathological factors that affect RDI were also investigated.A total of 311 consecutive PDAC patients who underwent curative resection between May 2005 and January 2015 were enrolled. Patients who underwent neoadjuvant chemoradiation, had UICC stage IV disease, or had early recurrences within 6 months were excluded, and the remaining 168 cases were analyzed.Patients with RDIs ≥80% (n = 79) showed significantly better overall survival (OS) compared to patients with RDIs <80% (n = 55) (median survival time (MST): 45.6 months, 26.0 months, P < 0.001). Patients with no AC (n = 34) showed the worst OS (MST: 20.8 months). Whether the AC was initiated earlier or later than 8 weeks after surgery did not influence survival, either in patients with RDIs ≥80% (P = 0.79) or in those with <80% (P = 0.73). Patients in the S-1 monotherapy group (n = 49) showed significantly better OS than patients in the gemcitabine monotherapy group (n = 51) (MST: 95.0 months, 26.0 months, respectively; P = 0.001). Univariate analysis conducted after adjusting for the chemotherapeutic drug used identified several prognostic factors; male gender (P = 0.01), intraoperative blood transfusion (P = 0.005), lymph node metastasis (P = 0.03), and postoperative WBC count (P = 0.03). Multivariate analysis identified intra-plus postoperative blood transfusion (P = 0.002) and high postoperative platelet-to-lymphocyte ratios (PLR) (P = 0.04) as independent predictors of poor RDI.Efforts to maintain RDI had a greater impact on survival than the struggle to start AC early after surgery. Intra-plus postoperative blood transfusion and a high postoperative PLR could be predictive markers of reduced RDI in AC of PDAC patients. Avoidance of perioperative blood transfusions where possible and nutritional support during the perioperative period could maintain adequate RDI and may lead to improved long-term outcome.

Project description:BackgroundCirculating angiogenic cytokines (CACs) have been confirmed as prognostic biomarkers and therapeutic targets in several solid tumors. However, their role as prognostic biomarkers in resected pancreatic ductal adenocarcinoma (PDAC) is unknown.ResultsThe expression of CACs in patients with PDAC differs from those with CP both pre- and postoperatively. Correlation analyses show significant correlations between circulating levels of CACs: VEGF was correlated with IL-6 (r = 0.457), FGF (r = 0.44), G-CSF (r = 0.543), HGF (r = 0.586) and SDF-1α (r = 0.784) before the surgery. The circulating levels of TNF-α correlated with the serum concentration of IL-4 before (r= 0.656) and after the resection (r = 0.776 on POD 3, r = 0.865 on POD 7). Gender did not show any correlation with serum levels of CAC, except for significantly higher levels of EGF in males (P = 0.002). Other clinicopathological variables such as age (< 65 vs. > 65 years), T, N, or UICC stage did not have an association with the cytokine levels. The multivariate model including the entire angiogenic panel revealed that postoperative increasing levels of EGF (P = 0.023), PDGFA-A (P = 0.024), TNF-α (P = 0.001) and IL-8 (P = 0.049) were associated with a favorable prognosis, whereas elevating levels of VEGF (P = 0.005) correlated with a poor cancer-specific survival.Materials and methodsPreoperative and postoperative blood samples were collected in patients undergoing surgery for PDAC (n = 40) or chronic pancreatitis (CP; n = 9). Serum levels of 13 angiogenic cytokines (IL-4, IL-6, FGF-b, G-CSF, TNF-α, VEGF, HGF, SDF-1α, IL-8, EGF, Ang-1, PDGF-AA and PlGF) were analyzed using ELISA and Multiplex. Prognostic factors were identified by a Cox proportional hazards model.ConclusionsPostoperative changes of serum levels of certain angiogenic cytokines correlate with patients' prognosis after resection for pancreatic cancer. CACs should thus be considered as biomarkers in patients with resected pancreatic cancer.

Project description:Lenvatinib (E7080), an oral multi-kinase inhibitor, has inhibitory action on tumor cell proliferation and tumor angiogenesis in preclinical models. We evaluated correlations between pharmacodynamic (PD) biomarkers with patient clinical outcomes in a lenvatinib phase 1 dose-escalation study.Plasma angiogenic proteins were evaluated as potential PD biomarkers of response to lenvatinib in a dose-escalation phase 1 study. Lenvatinib was administered to 27 patients by twice-daily dosing in 3-week cycles; 2 weeks of treatment followed by 1 week of rest until discontinuation. Blood samples for plasma proteins were collected on days 1 (baseline), 8, and 15 of cycle 1, and days 1, 8, and 15 of cycle 2. Selected clinical outcomes, including tumor shrinkage and adverse events (AEs), were used for correlative analyses of pharmacokinetic parameters and PD biomarkers.Tumor shrinkage and changes in PD biomarkers (increased vascular endothelial growth factor [VEGF] and stromal cell-derived factor 1 alpha [SDF1?] levels and decreased soluble VEGF receptor 2 [sVEGFR2] levels) significantly correlated with increasing lenvatinib exposure. Observed changes in levels of VEGF, SDF1?, and sVEGFR2 were maintained on day 15 of cycle 1, but returned to baseline during the 1-week rest period, and similar changes were induced by reinstitution of treatment in cycle 2. The worst grades of hypertension, proteinuria, and fatigue were associated with changes in VEGF and HGF at day 8 of cycle 1. Maximum tumor shrinkage was correlated with increased SDF1? levels. Decreased sVEGFR2 level was also correlated with tumor shrinkage and frequency of hypertension, proteinuria, and fatigue. Tumor shrinkage significantly correlated with the worst grade of proteinuria, but not with hypertension or fatigue.PD biomarker changes observed in plasma angiogenic proteins are correlated with lenvatinib-induced tumor shrinkage and AEs. Our findings warrant further assessment of plasma proteins associated with angiogenesis as potential biomarkers of lenvatinib activity.ClinicalTrial.gov: NCT00280397 (January 20, 2006).

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Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib.

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Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib.

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