Clinical trial NCT01482442: SorAfenib Versus RADIOEMBOLIZATION in Advanced Hepatocellular Carcinoma
Official title: A Prospective Randomized Open-labeled Trial Comparing RADIOEMBOLIZATION With Yttrium 90 Microspheres and Sorafenib in Patients With Advanced Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Liver Carcinoma
Keywords: Liver, HCC
Liver, interventional procedures
Liver, randomized studies
Liver, targeted therapy
Liver, RADIOEMBOLIZATION
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2011-11-30
Enrollment: 496
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether RADIOEMBOLIZATION with 90 Yttrium microspheres is more effective on overall survival in advanced Hepatocellular carcinoma (HCC) with or without portal venous obstruction and no extrahepatic extension than sorafenib which is now the standard treatment of advanced HCC.

Detailed description: Background: In patients with advanced hepatocellular carcinoma, sorafenib is now the standard treatment with an increased median overall survival but an overall incidence of treatment-related adverse events of 80%. There is growing interest for RADIOEMBOLIZAION with 90 Yttrium microspheres. It involves infusion of embolic microparticles of glass or resin impregnated with the isotope yttrium-90 through a catheter directly into the hepatic arteries. A substantial number of open-label single-group studies showed supporting evidence for a potential efficacy on overall survival and acceptable or low toxicity. Trial design: multicenter, prospective, controlled, open label randomized trial of Y90 RADIOEMBOLIZATION versus sorafenib. Participants: Adult patients with 1) advanced HCC according to BCLC staging system (stage C) with or without portal vein thrombosis 2) ECOG performance status of 2 or less 3) adequate haematological, renal and hepatic functions 4) liver cirrhosis Child Pugh A - B7 and 5) no extrahepatic metastasis. Interventions: In the sorafenib group, patients will receive continuous oral treatment with 400 mg of sorafenib twice daily. In the Y90 RADIOEMBOLIZATION group, patients will first undergo angiography and scintigraphy for eligibility assessment (absence of or acceptable lung shunting) and preconditioning (embolization). RADIOEMBOLIZATION therapy with infusion of Y90 microspheres will be performed secondly. Objectives: The primary objective is to compare the efficacy of Y90 RADIOEMBOLIZATION to sorafenib in the treatment of advanced hepatocellular carcinoma. Secondary objectives include the comparison of safety profiles, quality of life and health care costs between the two therapeutic groups. Outcomes: The primary endpoint is the median overall survival time. Secondary endpoints include adverse events reported according to the NCI CTC, progression-free survival at 6 months, response rates, general and hepatic-specific quality of life scores, health care costs which comprise the MICROCOSTING of Y90 RADIOEMBOLIZATION from the viewpoint of the hospital and the full cost of each strategy. Sample size: 400 participants (200 par arm). The trial have 80% power to detect a clinically meaningful increase in median survival time of 4 months between sorafenib (expected median survival time 10.7 months) and Y90 RADIOEMBOLIZATION (expected median survival time 15 months) with a two-tailed type I error risk of 5%. Randomization: 1 to 1 randomization will be stratified according to recruiting center, ECOG performance status (a score of 0 vs. a score of 1 or 2), presence or absence of macroscopic vascular invasion (obstruction of portal vein or any branch vs none) and previous chemoembolisation failure . Randomly permuted blocks of random sizes will be used. Study duration and Setting: Accrual period 24 months. Additional follow-up period: 12 months. 14 centres involving both clinicians (hepatologists, hepatobiliary surgeons, and oncologists) and radiologists and Nuclear medicine physicians on each site.

Eligibility criteria: Inclusion Criteria:

* Histological or cytological diagnosis or meet the AASLD criteria for diagnosis of HCC and at least one uni-dimensional lesion measurable according to RECIST criteria by CT-scan or MRI
* Adult over 18 years old and estimated life expectancy over 3 months
* Patient with advanced HCC according to BCLC staging system (stage C) with or without portal vein thrombosis, not eligible for surgical resection, liver transplantation nor radiofrequency ablation OR patient with progression or recurrence of HCC after surgical or locoregional treatment not eligible for surgical resection, liver transplantation nor radiofrequency ablation OR patients in whom chemoembolisation has failed after two courses (patients who have received only one course of chemoembolisation are eligible if the failure of the first round shows that a second round will have no more impact; patients who have received more than two courses of chemoembolisation are still eligible if the arterial network is perfectly normal on a CT scan in the arterial phase). Failure is defined as the absence of an objective response after two courses of treatment in the treated nodule (objective response according to modified RECIST criteria and/or EASL criteria).
* ECOG performance status under or equals 1
* Adequate haematological function: Hb over or equals 9g/100mL, absolute neutrophil count over or equals 1 500/mm3, platelet count over or equals 50 000/mm3
* Adequate renal function; serum creatinine under 150μmol/L
* Bilirubin under or equals 50 µmol/L, AST or ALT uner or equals 5 x ULN, INR under or equals 1.5
* Liver cirrhosis Child Pugh A - B7
* written informed consent

Exclusion Criteria:

* Another primary tumour, with the exception of conventional basal cell carcinoma or superficial bladder neoplasia
* Extrahepatic metastasis
* Advanced HCC previously treated
* Advanced liver disease with Child-Pugh score over 7 or active gastrointestinal bleeding or encephalopathy or ascites refractory to diuretic therapy Women who are pregnant or breast feeding
* Allergy to contrast media
* Contraindication to hepatic artery catheterisation, such as severe peripheral vascular disease precluding catheterisation
* Psychiatric or other disorder likely to impact on informed consent
* Patient unable and/or unwilling to comply with treatment and study instructions
* Patient unable to swallow oral medications

Primary outcomes:
measure: Median overall survival time
timeFrame: 36 months
Secondary outcomes:
measure: Common Terminology Criteria for Adverse Events
timeFrame: 36 months
measure: Progression-free survival
timeFrame: month 6
measure: Response rate
timeFrame: 36 months
measure: General and hepatic specific quality of life scores
timeFrame: 36 months
measure: Health care costs
timeFrame: 36 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens #2
city: Angers
country: France
facility: CHU Angers #3
city: Besançon
country: France
facility: CHRU Besançon Hôpital Jean Minjoz #21
city: Bondy
country: France
facility: Hôpital Jean Verdier #25
city: Caen
country: France
facility: Hôpital Côte de Nacre #4
city: Clamart
country: France
facility: Hôpital Antoine Béclère #29
city: Clichy
country: France
facility: Hopital beaujon #1
city: Créteil
country: France
facility: Henri Mondor #24
city: Dijon
country: France
facility: CHU Dijon Hôpital Bocage #22
city: Grenoble
country: France
facility: CHU Grenoble #5
city: Lyon
country: France
facility: Hôpital Edouard Herriot #6
city: Lyon
country: France
facility: Lyon La croix Rousse #27
city: Marseille
country: France
facility: Institut Paoli Calmettes #7
city: Marseille
country: France
facility: CHU Marseille Hôpital La Timone #23
city: Montpellier
country: France
facility: Hôpital Saint Eloi #8
city: Nancy
country: France
facility: Hôpital de Brabois #9
city: Nantes
country: France
facility: Hotel Dieu #10
city: Nice
country: France
facility: Hôpital de L'Archet #11
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou #13
city: Pessac
country: France
facility: Hôpital Haut Leveque #14
city: Poitiers
country: France
facility: CHU Poitiers La Milétrie
city: Reims
country: France
facility: CHU Robert Debré #28
city: Saint-Priest en Jarez
country: France
facility: CHU Saint Etienne Hôpital Nord #17
city: Strasbourg
country: France
facility: Hôpital de Hautepierre #18
city: Villejuif
country: France
facility: Paul Brousse #19
city: Villejuif
country: France
facility: Institut Gustave Roussy #20
Study officials:
affiliation: Department of radiology
name: Valerie Vilgrain, PD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zarca K, Mimouni M, Pereira H, Chatellier G, Vilgrain V, Durand-Zaleski I; SARAH Trial Group. Cost-Utility Analysis of Transarterial Radioembolization With Yttrium-90 Resin Microspheres Compared With Sorafenib in Locally Advanced and Inoperable Hepatocellular Carcinoma. Clin Ther. 2021 Jul;43(7):1201-1212. doi: 10.1016/j.clinthera.2021.04.018. Epub 2021 May 28.
citation: Hermann AL, Dieudonne A, Ronot M, Sanchez M, Pereira H, Chatellier G, Garin E, Castera L, Lebtahi R, Vilgrain V; SARAH Trial Group. Relationship of Tumor Radiation-absorbed Dose to Survival and Response in Hepatocellular Carcinoma Treated with Transarterial Radioembolization with 90Y in the SARAH Study. Radiology. 2020 Sep;296(3):673-684. doi: 10.1148/radiol.2020191606. Epub 2020 Jun 30.
citation: Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, Sibert A, Bouattour M, Lebtahi R, Allaham W, Barraud H, Laurent V, Mathias E, Bronowicki JP, Tasu JP, Perdrisot R, Silvain C, Gerolami R, Mundler O, Seitz JF, Vidal V, Aube C, Oberti F, Couturier O, Brenot-Rossi I, Raoul JL, Sarran A, Costentin C, Itti E, Luciani A, Adam R, Lewin M, Samuel D, Ronot M, Dinut A, Castera L, Chatellier G; SARAH Trial Group. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1624-1636. doi: 10.1016/S1470-2045(17)30683-6. Epub 2017 Oct 26.
citation: Vilgrain V, Abdel-Rehim M, Sibert A, Ronot M, Lebtahi R, Castera L, Chatellier G; SARAH Trial Group. Radioembolisation with yttrium-90 microspheres versus sorafenib for treatment of advanced hepatocellular carcinoma (SARAH): study protocol for a randomised controlled trial. Trials. 2014 Dec 3;15:474. doi: 10.1186/1745-6215-15-474.