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.

Abstract

BACKGROUND:

Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma. We aimed to compare the efficacy and safety of sorafenib to that of selective internal radiotherapy (SIRT) with yttrium-90 (90Y) resin microspheres in patients with hepatocellular carcinoma.

METHODS:

SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done at 25 centres specialising in liver diseases in France. Patients were eligible if they were aged at least 18 years with a life expectancy greater than 3 months, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Child-Pugh liver function class A or B score of 7 or lower, and locally advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer [BCLC] stage C), or new hepatocellular carcinoma not eligible for surgical resection, liver transplantation, or thermal ablation after a previously cured hepatocellular carcinoma (cured by surgery or thermoablative therapy), or hepatocellular carcinoma with two unsuccessful rounds of transarterial chemoembolisation. Patients were randomly assigned (1:1) by a permutated block method with block sizes two and four to receive continuous oral sorafenib (400 mg twice daily) or SIRT with 90Y-loaded resin microspheres 2-5 weeks after randomisation. Patients were stratified according to randomising centre, ECOG performance status, previous transarterial chemoembolisation, and presence of macroscopic vascular invasion. The primary endpoint was overall survival. Analyses were done on the intention-to-treat population; safety was assessed in all patients who received at least one dose of sorafenib or underwent at least one of the SIRT work-up exams. This study has been completed and the final results are reported here. The trial is registered with ClinicalTrials.gov, number NCT01482442.

FINDINGS:

Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent, 237 were assigned to SIRT and 222 to sorafenib. In the SIRT group, 53 (22%) of 237 patients did not receive SIRT; 26 (49%) of these 53 patients were treated with sorafenib. Median follow-up was 27·9 months (IQR 21·9-33·6) in the SIRT group and 28·1 months (20·0-35·3) in the sorafenib group. Median overall survival was 8·0 months (95% CI 6·7-9·9) in the SIRT group versus 9·9 months (8·7-11·4) in the sorafenib group (hazard ratio 1·15 [95% CI 0·94-1·41] for SIRT vs sorafenib; p=0·18). In the safety population, at least one serious adverse event was reported in 174 (77%) of 226 patients in the SIRT group and in 176 (82%) of 216 in the sorafenib group. The most frequent grade 3 or worse treatment-related adverse events were fatigue (20 [9%] vs 41 [19%]), liver dysfunction (25 [11%] vs 27 [13%]), increased laboratory liver values (20 [9%] vs 16 [7%]), haematological abnormalities (23 [10%] vs 30 [14%]), diarrhoea (three [1%] vs 30 [14%]), abdominal pain (six [3%] vs 14 [6%]), increased creatinine (four [2%] vs 12 [6%]), and hand-foot skin reaction (one [<1%] vs 12 [6%]). 19 deaths in the SIRT group and 12 in the sorafenib group were deemed to be treatment related.

INTERPRETATION:

In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, overall survival did not significantly differ between the two groups. Quality of life and tolerance might help when choosing between the two treatments.

FUNDING:

Sirtex Medical Inc.

• Authors: Valérie Vilgrain, Helena Pereira, Eric Assenat, Boris Guiu, Alina Diana Ilonca, Georges-Philippe Pageaux, Annie Sibert, Mohamed Bouattour, Rachida Lebtahi, Wassim Allaham, Hélène Barraud, Valérie Laurent, Elodie Mathias, Jean-Pierre Bronowicki, Jean-Pierre Tasu, Rémy Perdrisot, Christine Silvain, René Gerolami, Olivier Mundler, Jean-Francois Seitz, Vincent Vidal, Christophe Aubé, Frédéric Oberti, Olivier Couturier, Isabelle Brenot-Rossi, Jean-Luc Raoul, Anthony Sarran, Charlotte Costentin, Emmanuel Itti, Alain Luciani, René Adam, Maïté Lewin, Didier Samuel, Maxime Ronot, Aurelia Dinut, Laurent Castera, Gilles Chatellier, SARAH Trial Group
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 18 Issue 12 Pg. 1624-1636 (12 2017) ISSN: 1474-5488 [Electronic] England
• PMID: 29107679 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Phenylurea Compounds
• Yttrium Radioisotopes
• Yttrium-90
• Niacinamide
• Sorafenib

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects)
• Brachytherapy (methods)
• Carcinoma, Hepatocellular (drug therapy, mortality, pathology, radiotherapy)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Follow-Up Studies
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms (drug therapy, mortality, pathology, radiotherapy)
• Male
• Microspheres
• Middle Aged
• Neoplasm Invasiveness (pathology)
• Neoplasm Staging
• Niacinamide (administration & dosage, adverse effects, analogs & derivatives)
• Phenylurea Compounds (administration & dosage, adverse effects)
• Radiotherapy Dosage
• Sorafenib
• Survival Analysis
• Treatment Outcome
• Yttrium Radioisotopes (therapeutic use)