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Intra-Arterial TheraSphere Yttrium-90 Glass Microspheres in the Treatment of Patients With Unresectable Hepatocellular Carcinoma: Protocol for the STOP-HCC Phase 3 Randomized Controlled Trial.

ABSTRACT: BACKGROUND:Globally, hepatocellular carcinoma is the second most common cause of cancer deaths. It remains challenging to intensify cancer treatment without impairing liver function. OBJECTIVE:The objective of the TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) study is to examine the hypothesis that transarterial radioembolization (TheraSphere yttrium-90 glass microspheres) combined with standard first-line treatment with sorafenib will improve outcomes over treatment with sorafenib alone in unresectable hepatocellular carcinoma. The STOP-HCC study is the largest international, multicenter, prospective study of intra-arterial treatment in combination with sorafenib in unresectable hepatocellular carcinoma. Here we report the study design. METHODS:STOP-HCC is a prospective, phase 3, open-label, randomized controlled study conducted across up to 105 sites in North America, Europe, and Asia. Eligible adults have unresectable hepatocellular carcinoma and a life expectancy of at least 12 weeks, 1 or more unidimensional measurable lesions, Child-Pugh score 7 points or less, and Eastern Cooperative Oncology Group Performance Status score 1 or lower, and are candidates for treatment with sorafenib. Presence of branch portal vein tumor thrombosis is permitted. Patients were randomly assigned in a 1:1 ratio to receive either sorafenib alone or transarterial radioembolization followed by sorafenib within 2 to 6 weeks. The primary outcome is overall survival. Secondary outcomes are time to progression, time to untreatable progression, time to symptomatic progression, tumor response, quality of life, and adverse event occurrence. The study is an adaptive trial, comprising a group-sequential design with 2 interim analyses with 520 patients, and an option to increase the sample size to 700 patients at the second interim analysis. The sample size of 520 patients allows for 417 deaths to give 80% power to detect an increase in median overall survival from 10.7 months for the sorafenib group (based on the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol [SHARP] trial) to 14.2 months for the transarterial radioembolization+sorafenib group (hazard ratio 0.754) with 2-sided alpha of .05. The increased sample size of 700 patients allows for 564 deaths to give 80% power to detect a smaller difference in median overall survival from 10.7 months for the sorafenib group to 13.7 months for the transarterial radioembolization+sorafenib group (hazard ratio 0.781). RESULTS:Enrollment for the study completed in September 2017. Results of the first and second interim analyses were reviewed by the Independent Data Monitoring Committee. The recommendation of the committee, at both interim analyses, was to continue the study without any changes. CONCLUSIONS:The STOP-HCC study will contribute toward the establishment of the role of combination therapy with transarterial radioembolization and sorafenib in the treatment of unresectable hepatocellular carcinoma with and without branch portal vein tumor thrombosis. TRIAL REGISTRATION:ClinicalTrials.gov NCT01556490; https://clinicaltrials.gov/ct2/show/NCT01556490 (Archived by WebCite at http://www.webcitation.org/7188iygKs). REGISTERED REPORT IDENTIFIER:RR1-10.2196/11234.

SUBMITTER: Chauhan N

PROVIDER: S-EPMC6115595 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Intra-Arterial TheraSphere Yttrium-90 Glass Microspheres in the Treatment of Patients With Unresectable Hepatocellular Carcinoma: Protocol for the STOP-HCC Phase 3 Randomized Controlled Trial.

Chauhan Nikhil N Bukovcan Janet J Boucher Eveline E Cosgrove David D Edeline Julien J Hamilton Bonnie B Kulik Laura L Master Fayaz F Salem Riad R

JMIR research protocols 20180815 8

<h4>Background</h4>Globally, hepatocellular carcinoma is the second most common cause of cancer deaths. It remains challenging to intensify cancer treatment without impairing liver function.<h4>Objective</h4>The objective of the TheraSphere in the Treatment of Patients with Unresectable Hepatocellular Carcinoma (STOP-HCC) study is to examine the hypothesis that transarterial radioembolization (TheraSphere yttrium-90 glass microspheres) combined with standard first-line treatment with sorafenib w ...[more]

PMID: 30111528

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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.

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:To quantify differences that exist between dosimetry models used for 90Y selective internal radiation therapy (SIRT).Retrospectively, 37 tumors were delineated on 19 post-therapy quantitative 90Y single photon emission computed tomography/computed tomography scans. Using matched volumes of interest (VOIs), absorbed doses were reported using 3 dosimetry models: glass microsphere package insert standard model (SM), partition model (PM), and Monte Carlo (MC). Univariate linear regressions were performed to predict mean MC from SM and PM. Analysis was performed for 2 subsets: cases with a single tumor delineated (best case for PM), and cases with multiple tumors delineated (typical clinical scenario). Variability in PM from the ad hoc placement of a single spherical VOI to estimate the entire normal liver activity concentration for tumor (T) to nontumoral liver (NL) ratios (TNR) was investigated. We interpreted the slope of the resulting regression as bias and the 95% prediction interval (95%PI) as uncertainty. MCNLsingle represents MC absorbed doses to the NL for the single tumor patient subset; other combinations of calculations follow a similar naming convention.SM was unable to predict MCTsingle or MCTmultiple (p>.12, 95%PI >±177 Gy). However, SMsingle was able to predict (p<.012) MCNLsingle, albeit with large uncertainties; SMsingle and SMmultiple yielded biases of 0.62 and 0.71, and 95%PI of ±40 and ± 32 Gy, respectively. PMTsingle and PMTmultiple predicted (p<2E-6) MCTsingle and MCTmultiple with biases of 0.52 and 0.54, and 95%PI of ±38 and ± 111 Gy, respectively. The TNR variability in PMTsingle increased the 95%PI for predicting MCTsingle (bias = 0.46 and 95%PI = ±103 Gy). The TNR variability in PMTmultiple modified the bias when predicting MCTmultiple (bias = 0.32 and 95%PI = ±110 Gy).The SM is unable to predict mean MC tumor absorbed dose. The PM is statistically correlated with mean MC, but the resulting uncertainties in predicted MC are large. Large differences observed between dosimetry models for 90Y SIRT warrant caution when interpreting published SIRT absorbed doses. To reduce uncertainty, we suggest the entire NL VOI be used for TNR estimates when using PM.

Dataset Information

Intra-Arterial TheraSphere Yttrium-90 Glass Microspheres in the Treatment of Patients With Unresectable Hepatocellular Carcinoma: Protocol for the STOP-HCC Phase 3 Randomized Controlled Trial.

Publications

Intra-Arterial TheraSphere Yttrium-90 Glass Microspheres in the Treatment of Patients With Unresectable Hepatocellular Carcinoma: Protocol for the STOP-HCC Phase 3 Randomized Controlled Trial.

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