SorAfenib Versus RADIOEMBOLIZATION in Advanced Hepatocellular Carcinoma (SARAH)

A Prospective Randomized Open-labeled Trial Comparing RADIOEMBOLIZATION With Yttrium 90 Microspheres and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

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.

Study Overview

• Status: Completed
• Conditions: Liver Carcinoma
• Intervention / Treatment: Drug: sorafenib; Drug: SIR-Sphere

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.

• Study Type: Interventional
• Enrollment (Actual): 496
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHU Amiens #2
  • Angers, France, 49933
    • CHU Angers #3
  • Besançon, France, 25030
    • CHRU Besançon Hôpital Jean Minjoz #21
  • Bondy, France, 93140
    • Hôpital Jean Verdier #25
  • Caen, France, 14033
    • Hôpital Côte de Nacre #4
  • Clamart, France, 92140
    • Hôpital Antoine Béclère #29
  • Clichy, France, 92110
    • Hopital beaujon #1
  • Créteil, France, 94000
    • Henri Mondor #24
  • Dijon, France, 21000
    • CHU Dijon Hôpital Bocage #22
  • Grenoble, France, 38043
    • CHU Grenoble #5
  • Lyon, France, 69003
    • Hôpital Edouard Herriot #6
  • Lyon, France, 69004
    • Lyon La croix Rousse #27
  • Marseille, France, 13009
    • Institut Paoli Calmettes #7
  • Marseille, France, 13385
    • CHU Marseille Hôpital La Timone #23
  • Montpellier, France, 34295
    • Hôpital Saint Eloi #8
  • Nancy, France, 54511
    • Hôpital de Brabois #9
  • Nantes, France, 44093
    • Hotel Dieu #10
  • Nice, France, 06002
    • Hôpital de L'Archet #11
  • Paris, France, 75908
    • Hôpital Européen Georges Pompidou #13
  • Pessac, France, 33604
    • Hôpital Haut Leveque #14
  • Poitiers, France, 86021
    • CHU Poitiers La Milétrie
  • Reims, France, 51100
    • CHU Robert Debré #28
  • Saint-Priest en Jarez, France, 42270
    • CHU Saint Etienne Hôpital Nord #17
  • Strasbourg, France, 67098
    • Hôpital de Hautepierre #18
  • Villejuif, France, 94275
    • Paul Brousse #19
  • Villejuif, France, 94805
    • Institut Gustave Roussy #20

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: sorafenib group; Patients will receive continuous oral treatment with 800 mg of sorafenib daily (Nexavar, Bayer HealthCare Pharmaceuticals-Onyx Pharmaceuticals). Treatment interruptions and dose reductions (to 400 mg once daily) will be permitted for drug-related adverse effects. At the discretion of the investigator, the dose may be re-escalated to after the resolution of the adverse event.	Drug: sorafenib; Patients will receive continuous oral treatment with 800 mg of sorafenib daily (Nexavar, Bayer HealthCare Pharmaceuticals-Onyx Pharmaceuticals). Treatment interruptions and dose reductions (to 400 mg once daily) will be permitted for drug-related adverse effects. At the discretion of the investigator, the dose may be re-escalated to after the resolution of the adverse event.
Active Comparator: radioembolization group; The first step will check patient eligibility and prepare conditioning by performing selective mesenteric and hepatic angiography (to document the arterial tumor supply and to occlude extrahepatic vessels) and 99mTc-macroaggregated albumin scintigraphy. The second step is RADIOEMBOLIZATION therapy. One to two weeks after patient eligibility and conditioning, treatment is performed with SIR-Sphere (SIRTEX Medical Ltd.,Lane Cove,Australia).	Drug: SIR-Sphere; The first step will check patient eligibility and prepare conditioning by performing selective mesenteric and hepatic angiography (to document the arterial tumor supply and to occlude extrahepatic vessels) and 99mTc-macroaggregated albumin scintigraphy. The second step is RADIOEMBOLIZATION therapy. One to two weeks after patient eligibility and conditioning, treatment is performed with SIR-Sphere (SIRTEX Medical Ltd.,Lane Cove,Australia).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median overall survival time	Median overall survival time since randomisation	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Common Terminology Criteria for Adverse Events	Adverse events reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0	36 months
Progression-free survival	Progression-free survival at 6 months	month 6
Response rate	Response rate (complete response, partial response, stable disease)	36 months
General and hepatic specific quality of life scores	General and hepatic specific quality of life scores	36 months
Health care costs	Health care costs which comprise 2 parts: 1) the microcosting of Y90 radioembolization from the viewpoint of the hospital and 2) the full cost of each strategy	36 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Ministry of Health, France
• Investigators: Principal Investigator: Valerie Vilgrain, PD, PhD, Department of Radiology

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: November 28, 2011
• First Submitted That Met QC Criteria: November 29, 2011
• First Posted (Estimate): November 30, 2011

Study Record Updates

• Last Update Posted (Estimate): January 16, 2017
• Last Update Submitted That Met QC Criteria: January 13, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Liver, HCC; Liver, interventional procedures; Liver, randomized studies; Liver, targeted therapy; Liver, RADIOEMBOLIZATION
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: P101103