Elsevier

The Lancet Oncology

Volume 18, Issue 12, December 2017, Pages 1624-1636
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(17)30683-6Get rights and content

Summary

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.

Introduction

Primary liver cancer is the second most common cause of cancer-related deaths worldwide, caused by hepatocellular carcinoma in 70–90% of patients.1, 2 Surveillance is recommended in at-risk patients to detect hepatocellular carcinoma that is amenable to curative treatment. Despite this surveillance, however, many patients are diagnosed when they are already at an intermediate or advanced stage of the disease.

Research in context

Evidence before this study

We searched PubMed for articles published between Jan 1, 2000, and Jan 1, 2017, focusing solely on publications of large-scale randomised clinical trials for advanced hepatocellular carcinoma with the search terms “sorafenib” and “selective internal radiation therapy (SIRT)”. We identified three trials confirming the survival gain obtained with sorafenib in hepatocellular carcinoma compared with placebo. No previous large-scale randomised trials with SIRT were identified. Sorafenib is the reference treatment for advanced hepatocellular carcinoma, having increased median overall survival compared with placebo from 8 months to 11 months in the SHARP trial. However, sorafenib has a high level of toxicity (80% of patients had adverse events in the SHARP trial). Overall, the evidence of the effects of SIRT in unresectable hepatocellular carcinoma is from retrospective, non-comparative studies. Across 13 open-label, single-arm studies involving approximately 400 patients with advanced hepatocellular carcinoma, the combined estimate of the median overall survival after SIRT with yttrium-90 microspheres was 15 months (range 7–27). The present study was therefore designed to ascertain whether SIRT could increase median overall survival with fewer side-effects or a better quality of life (QOL), or both, compared with sorafenib.

Added value of this study

In patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation, when compared with sorafenib, SIRT did not improve overall or progression-free survival but it significantly increased tumour response, reduced the incidence of adverse events, and improved QOL.

Implications of all the available evidence

These results suggest that SIRT might be better tolerated than sorafenib in patients with locally advanced or intermediate-stage hepatocellular carcinoma, and these results might lead to changes in the recommended treatment algorithm for these patients.

Sorafenib, an oral multikinase inhibitor, has become the reference treatment in advanced hepatocellular carcinoma, since it has been shown to significantly increase overall survival compared with placebo (10·7 months vs 7·9 months in the SHARP trial).3, 4, 5 However, discontinuation and dose reduction of sorafenib are frequently necessary because of adverse events such as diarrhoea, fatigue, and hand-foot skin reaction.4, 5, 6 Transarterial chemoembolisation is the reference treatment in intermediate-stage hepatocellular carcinoma. Two randomised clinical trials7, 8 and two meta-analyses9, 10 have shown its superiority compared with placebo in improving overall survival. However, even with optimal technique, many patients do not respond after transarterial chemoembolisation.11

Selective internal radiotherapy (SIRT) with yttrium-90 (90Y) is a therapeutic procedure applied via the hepatic artery, allowing targeted delivery of high-dose radiation to liver tumours. The small size of the microspheres loaded with 90Y together with the short penetration of radiation into tissues increases tumour targeting while sparing the liver parenchyma. Growing evidence supports the efficacy of SIRT in intermediate-stage and advanced-stage hepatocellular carcinoma. In a retrospective study, patients with unresectable hepatocellular carcinoma treated with SIRT had better survival than a matched control group,12 even after adjusting for disease severity. Two cohort studies13, 14 of patients with intermediate-stage and advanced-stage hepatocellular carcinoma (325 and 291 patients) have shown a promising antitumour effect of SIRT, with a median overall survival of 16·9–17·2 months for intermediate-stage disease and 10–12 months for advanced-stage disease. However, a Cochrane review15 of SIRT for unresectable hepatocellular carcinoma concluded that there was insufficient evidence to assess the beneficial and harmful effects of this therapeutic procedure with 90Y microspheres in unresectable hepatocellular carcinoma.

The SorAfenib versus Radioembolization in Advanced Hepatocellular carcinoma (SARAH) trial was therefore designed with the aim of comparing the efficacy and safety profile of SIRT and sorafenib in patients with locally advanced or intermediate-stage hepatocellular carcinoma not eligible for curative treatment.

Section snippets

Study design and patients

SARAH was a multicentre, open-label, randomised, controlled, investigator-initiated, phase 3 trial done in France, at 25 centres specialised in liver diseases (appendix p 3). An independent data safety and monitoring board monitored safety for the duration of the study. The study was done in accordance with the Declaration of Helsinki, approved by an ethics committee, and complied with the provisions of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals

Results

Between Dec 5, 2011, and March 12, 2015, 467 patients were randomly assigned; after eight patients withdrew consent (two in the SIRT group and six in the sorafenib group), 459 patients were included in the intention-to-treat population (237 [52%] in the SIRT group and 222 [48%] in the sorafenib group; figure 1). The two groups were well balanced at baseline; no clinically relevant differences between the groups were observed in either the intention-to-treat population or the per-protocol

Discussion

The multicentre, open-label, randomised, controlled, phase 3 SARAH trial did not show a difference in overall survival between SIRT and sorafenib among patients with locally advanced or intermediate-stage hepatocellular carcinoma after unsuccessful transarterial chemoembolisation. However, tumour response and QOL were significantly better in the SIRT group than in the sorafenib group and safety was better in the SIRT group than in the sorafenib group.

Overall survival in the SIRT group was

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    A complete list of SARAH trial investigators is provided in the appendix

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