Pilot study of angiogenic response to yttrium-90 radioembolization with resin microspheres

Abstract

Purpose: To investigate the impact of radioembolization with yttrium-90 resin microspheres on the regulation of angiogenesis through observation of serial changes in a spectrum of angiogenic markers and other cytokines after therapy.

Materials and methods: This prospective pilot study enrolled 22 patients with liver-dominant disease deriving from biopsy-proven hepatocellular carcinoma (HCC) (n = 7) or metastatic colorectal carcinoma (mCRC) (n = 15). Circulating angiogenic markers were measured from serum samples drawn at baseline and at time points after therapy ranging from 6 hours to 120 days. Using multiplex enzyme-linked immunosorbent assay, several classic angiogenesis factors (vascular endothelial growth factor [VEGF], angiopoietin-2 [Ang-2], basic fibroblast growth factor [bFGF], platelet-derived growth factor subunit BB [PDGF-BB], thrombospondin-1 [Tsp-1]) and nonclassic factors (follistatin, leptin, interleukin [IL]-8) were evaluated.

Results: Increases in cytokine levels ≥ 50% over baseline were observed in more than half of all patients studied for many cytokines, including classic angiogenic factors such as VEGF, Ang-2, and Tsp-1 as well as nonclassic factors IL-8 and follistatin (range, 36%-82% for all cytokines). Baseline cytokine levels in patients with overall survival (OS) < 6 months differed significantly from patients with longer survival for Ang-2 (P = .033) and IL-8 (P = .041). Patients with OS ≤ 6 months exhibited transient increases in VEGF and PDGF-BB after therapy compared with patients with OS > 6 months.

Conclusions: Radioembolization is associated with early transient increases in many angiogenic cytokines. In this small sample size, some of these changes were associated with worse OS. This research has important implications for future studies of radioembolization with antiangiogenic therapy performed during and after the procedure.

Keywords: (90)Y; Ang-2; Conc; FGFR; G-CSF; GM-CSF; HCC; HGF; IFN; IL; IP; MCAF; MIP; OS; PDGF; PDGF-BB; PDGFR; PECAM-1; RANTES; TNF; Tsp-1; Tx; VEGF; VEGFR; aFGF; acidic fibroblast growth factor; angiopoietin-2; bFGF; basic fibroblast growth factor; concentration; fibroblast growth factor receptor; granulocyte colony-stimulating factor; granulocyte-macrophage colony-stimulating factor; hepatocellular carcinoma; hepatocyte growth factor; interferon; interferon-inducible protein; interleukin; mCRC; macrophage chemotactic and activating factor; macrophage inflammatory protein; metastatic colorectal carcinoma; overall survival; platelet endothelial cell adhesion molecule; platelet-derived growth factor; platelet-derived growth factor receptor; platelet-derived growth factor subunit BB; regulated on activation, normal T-cell expressed and secreted; thrombospondin 1; treatment; tumor necrosis factor; vascular endothelial growth factor; vascular endothelial growth factor receptor; yttrium-90.

Figure 1

Blood draw schematic for cytokine assessments in single lobar or whole-liver radioembolization treatment plan. Tx = treatment. (Available in color online at www.jvir.org.)

Figure 2

Blood draw schematic for cytokine assessments in sequential bilobar radioembolization treatment plan. Tx = treatment. (Available in color online www.jvir.org.)

Figure 3

Examples of spikes in circulating angiogenic cytokines after radioembolization therapy. First row illustrates representative changes in VEGF from three patients after treatment, second row represents Ang-2, and third row represents PDGF-BB. Points correspond to samples drawn at specific time points after first and second radioembolization treatments. Note the bimodal Ang-2 patterns after therapy for the first and third patients. Also note the strong spike in PDGF-BB after the first treatment for the third patient. Conc = concentration, Tx = treatment. (Available in color online at www.jvir.org.)

Figure 4

Boxplots showing baseline comparisons across survival groups for several angiogenic cytokines. *P < .05. Obs Conc = observed concentration. (Available in color online at www.jvir.org.)

Figure 5

Variations in circulating cytokine levels after radioembolization therapy for classic angiogenesis factors VEGF, Ang-2, PDGF-BB, and Tsp-1 after therapy for two survival groups. Short survival (≤ 6 mo) is shown in green with square symbols; long survival ( > 6 mo) is shown in blue with triangular symbols. Time points marked with an asterisk differed significantly between survival groups on Mann-Whitney U comparisons; time points marked with a plus sign demonstrated significant differences on Cox proportional hazards analysis. Conc = concentration, Tx = treatment. (Available in color online at www.jvir.org.)