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

ABSTRACT: 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.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.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.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.

SUBMITTER: Carpizo DR

PROVIDER: S-EPMC5496007 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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

Carpizo Darren R DR Gensure Rebekah H RH Yu Xin X Gendel Vyacheslav M VM Greene Samuel J SJ Moore Dirk F DF Jabbour Salma K SK Nosher John L JL

Journal of vascular and interventional radiology : JVIR 20131220 2

<h4>Purpose</h4>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.<h4>Materials and methods</h4>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 we ...[more]

PMID: 24360887

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Project description:BackgroundCoincidence imaging of low-abundance yttrium-90 (90Y) internal pair production by positron emission tomography with integrated computed tomography (PET/CT) achieves high-resolution imaging of post-radioembolization microsphere biodistribution. Part 2 analyzes tumor and non-target tissue dose-response by 90Y PET quantification and evaluates the accuracy of tumor 99mTc macroaggregated albumin (MAA) single-photon emission computed tomography with integrated CT (SPECT/CT) predictive dosimetry.MethodsRetrospective dose quantification of 90Y resin microspheres was performed on the same 23-patient data set in part 1. Phantom studies were performed to assure quantitative accuracy of our time-of-flight lutetium-yttrium-oxyorthosilicate system. Dose-responses were analyzed using 90Y dose-volume histograms (DVHs) by PET voxel dosimetry or mean absorbed doses by Medical Internal Radiation Dose macrodosimetry, correlated to follow-up imaging or clinical findings. Intended tumor mean doses by predictive dosimetry were compared to doses by 90Y PET.ResultsPhantom studies demonstrated near-perfect detector linearity and high tumor quantitative accuracy. For hepatocellular carcinomas, complete responses were generally achieved at D70 > 100 Gy (D70, minimum dose to 70% tumor volume), whereas incomplete responses were generally at D70 < 100 Gy; smaller tumors (<80 cm3) achieved D70 > 100 Gy more easily than larger tumors. There was complete response in a cholangiocarcinoma at D70 90 Gy and partial response in an adrenal gastrointestinal stromal tumor metastasis at D70 53 Gy. In two patients, a mean dose of 18 Gy to the stomach was asymptomatic, 49 Gy caused gastritis, 65 Gy caused ulceration, and 53 Gy caused duodenitis. In one patient, a bilateral kidney mean dose of 9 Gy (V20 8%) did not cause clinically relevant nephrotoxicity. Under near-ideal dosimetric conditions, there was excellent correlation between intended tumor mean doses by predictive dosimetry and those by 90Y PET, with a low median relative error of +3.8% (95% confidence interval, -1.2% to +13.2%).ConclusionsTumor and non-target tissue absorbed dose quantification by 90Y PET is accurate and yields radiobiologically meaningful dose-response information to guide adjuvant or mitigative action. Tumor 99mTc MAA SPECT/CT predictive dosimetry is feasible. 90Y DVHs may guide future techniques in predictive dosimetry.

Project description:Transarterial radioembolization (TARE) is a form of brachytherapy in which intra-arterially injected yttrium-90-loaded microspheres serve as a source for internal radiation purposes. On the average, it produces disease control rates exceeding 80% and it is a consolidated therapy for hepatocellular carcinoma (HCC); however, current data are all based on retrospective series or non-controlled prospective studies since randomized controlled trials comparing it with the other liver-directed therapies for intermediate and locally advanced stage HCC are still underway. The data available show that TARE provides similar or even better survival rates when compared to transarterial chemoembolization (TACE). First-line TARE is best indicated for both intermediate-stage patients (staged according to the barcelona clinic liver cancer staging classification) who have lesions which respond poorly to TACE due to multiple tumors or a large tumor burden, and for locally advanced-stage patients with solitary tumors, and segmental or lobar portal vein tumor thrombosis. In addition, emerging data have suggested the use of TARE in patients who are classified slightly beyond the Milan criteria regarding radical treatment for downstaging purposes. As a second-line treatment, TARE can also be applied in patients progressing to TACE or sorafenib; a large number of phase II/III trials are ongoing with the purpose of evaluating the best association with systemic therapies. Transarterial radioembolization is very well tolerated and has a low rate of complications which are mainly related to unintended non-target tissue irradiation, including the surrounding liver parenchyma. The complications can be additionally reduced by accurate patient selection and a strict pre-treatment evaluation including dosimetry and assessment of the vascular anatomy. Since a correct treatment algorithm for potential TARE candidates is not clear and standardized, this comprehensive review analyzes the best selection criteria for patients who really benefit from TARE and also the new advances of this therapy, which can be a very important weapon against HCC.

Project description:A selective intra-arterial liver injection using yttrium-90-loaded microspheres as sources for internal radiation therapy is a form of transarterial radioembolization (TARE). Current data from the literature suggest that TARE is effective in hepatocellular carcinoma (HCC) and is associated with a low rate of adverse events; however, they are all based on retrospective series or non-controlled prospective studies, since randomized controlled trials comparing the other liver-directed therapies for intermediate and locally advanced stages HCC are still ongoing. The available data show that TARE provides similar or even better survival rates. TARE is very well tolerated and has a low rate of complications; these complications do not result from the embolic effects but mainly from the unintended irradiation to non-target tissue, including the liver parenchyma. The complications can be further reduced by accurate patient selection and a strict pre-treatment evaluation, including dosimetry and assessment of the vascular anatomy. First-line TARE is best indicated for intermediate-stage patients (according to the Barcelona Clinic Liver Cancer [BCLC] staging classification) who are poor candidates for transarterial chemoembolization or patients having locally advanced disease with segmental or lobar branch portal vein thrombosis. Moreover, data are emerging regarding the use of TARE in patients classified slightly above the criteria for liver transplantation with the purpose of downstaging them. TARE can also be applied as a second-line treatment in patients progressing to transarterial chemoembolization or sorafenib; a large number of Phase II/III trials are in progress in order to evaluate the best association with systemic therapies. Given the complexity of a correct treatment algorithm for potential TARE candidates and the need for clinical guidance, a comprehensive review was carried out analyzing both the best selection criteria of patients who really benefit from TARE and the new advances of this therapy which add significant value to the therapeutic weaponry against HCC.

Project description:Background and aimsLocoregional therapies, including yttrium-90 radioembolization, play an important role in the treatment of unresectable HCC. The aim of the LEGACY (Local radioEmbolization using Glass Microspheres for the Assessment of Tumor Control with Y-90) study was to evaluate objective response rate (ORR) and duration of response (DoR) in patients with solitary unresectable HCC treated with yttrium-90 glass microspheres.Approach and resultsLEGACY is a multicenter, single-arm, retrospective study conducted at three sites that included all eligible, consecutive patients with HCC treated with radioembolization between 2014 and 2017. Eligibility criteria included solitary HCC ≤ 8 cm, Child-Pugh A cirrhosis, and Eastern Cooperative Oncology Group performance status 0-1. Primary endpoints were ORR and DoR based on modified Response Evaluation Criteria in Solid Tumors in the treated area (localized), as evaluated by blinded, independent, central review. Radioembolization was performed with intent of ablative-level dosimetry in a selective fashion when possible. Overall survival was evaluated using Kaplan-Meier and multivariate Cox proportional hazards. Among the 162 patients included, 60.5% were Eastern Cooperative Oncology Group 0, and the median tumor size was 2.7 cm (range: 1-8) according to blinded, independent, central review. Radioembolization served as neoadjuvant therapy for transplantation or resection in 21.0% (34 of 162) and 6.8% (11 of 162) of patients, respectively, and as primary treatment for all others. Median follow-up time was 29.9 months by reverse Kaplan-Meier. ORR (best response) was 88.3% (CI: 82.4-92.4), with 62.2% (CI: 54.1-69.8) exhibiting a DoR ≥ 6 months. Three-year overall survival was 86.6% for all patients and 92.8% for those neoadjuvant patients with resected or transplanted liver.ConclusionsIn this multicenter study of radioembolization, clinical meaningful response rates and prolonged DoR were observed in the treatment of unresectable, solitary HCC ≤ 8 cm.

Dataset Information

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

Publications

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

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