Selective internal radiation therapy with yttrium-90 resin microspheres was better tolerated compared with sorafenib in patients with advanced unresectable hepatocellular carcinoma, However, findings from the phase III SARAH trial did not improve rates of overall survival or progression-free survival. A radiotherapy approach was compared with this targeted therapy in the SARAH trial.
Valerie Vilgrain, MD, PhD
Selective internal radiation therapy (SIRT) with yttrium-90 (Y-90) resin microspheres was better tolerated compared with sorafenib (Nexavar) in patients with advanced unresectable hepatocellular carcinoma (HCC), according to findings from the phase III SARAH trial.1SIRT, however, did not improve rates of overall survival (OS) or progression-free survival (PFS).
Although sorafenib continues to be the recommended treatment for patients with advanced HCC, it is associated with a higher level of adverse events (AEs). In the phase III SHARP trial, 80% of the 299 patients with advanced HCC who were treated with sorafenib had AEs compared with 52% of the 303 patients treated with placebo.2Following positive results with SIRT in previous studies of patients with intermediate-stage and advanced-stage hepatocellular carcinoma, the radiotherapy approach was compared with the targeted therapy in the SARAH trial.
“Patients with advanced or inoperable hepatocellular carcinoma have a poor prognosis, often with underlying cirrhosis, and the treatment option currently available, sorafenib, has a high level of toxicity. As cohort studies have demonstrated the efficacy of SIRT with Y-90 resin microspheres, we set out to compare the efficacy of this treatment versus the current standard of care,” noted lead study author Valérie Vilgrain, MD, PhD, chair of the Department of Radiology at the University Beaujon Hospital in Paris, France, in a statement.
Prior to this study, evidence of the effects of SIRT in HCC was from noncomparative studies. Across 13 open-label single-arm studies involving approximately 400 patients, the estimate of the median OS after SIRT with Y-90 was 15 months (range, 7-27).1
The open-label SARAH trial compared the efficacy and safety of SIRT with Y-90 resin microspheres compared with sorafenib, an oral multikinase inhibitor, in patients with locally advanced and inoperable HCC who did not respond to other treatments or had failed 2 rounds of transarterial chemoembolization.
There were 459 patients from 25 French clinical centers included in the study. Investigators randomized 237 patients to SIRT with Y-90 resin microspheres and 222 to oral sorafenib at 400 mg twice daily, with treatment discontinuation or dose reduction permitted for drug-related AEs according to physician’s choice.
SIRT comprises Y-90 resin microspheres injected directly into the tumors, a method that delivers up to 40 times more radiation than would be possible using standard radiation therapy and spares healthy tissue from radiation exposure.
Of the 184 patients who received SIRT, 115 (63%) received a single administration. Forty-one patients (22%) received contralateral second SIRT treatment and 17 (9%) received ipsilateral second SIRT treatment. An ipsilateral third SIRT treatment was received by 1% of patients and a third contralateral treatment in 5%.
The median dose density was 800 mg/day of sorafenib, with a median cumulative time of intake of 2.8 months. Eighty-two (38%) of 216 patients receiving sorafenib required a dose reduction, and permanent discontinuation occurred in 132 patients (61%).
The patient characteristics were similar between the 2 arms. These included age (median, 66 vs 65 in the SIRT and sorafenib groups, respectively), male majority (89% vs 91%), and unilobar tumor involvement (79% vs 84%). Most patients had an ECOG performance status of 0, BCLC (Barcelona Clinic Liver Cancer) stage C disease, and Child-Pugh liver function class of A5 + A6. In the intention-to-treat population (n = 459), patients experienced a median OS of 8.0 months in the SIRT arm versus 9.9 months in the sorafenib arm (HR, 1.15; 95% CI, 0.94-1.41; P = .18). At 1 year, the OS rates were 39.5% with SIRT and 42.1% with sorafenib. The secondary endpoint of median PFS was similar between both arms: 4.1 and 3.7 month in the SIRT and sorafenib cohorts, respectively (HR, 1.03; 95% CI, 0.85-1.25; P = .76). Five patients in the SIRT arm and 2 in the sorafenib arm experienced a complete response. The disease control rate was 68% with SIRT versus 78% with sorafenib (P = .0346).
In the per-protocol population, the median OS was 9.9 months for patients treated with SIRT compared with 9.9 months for those treated with sorafenib (HR, 0.99; 95% CI, 0.79-1.24). OS rates did not differ significantly between the 2 arms in subgroup analyses.
A secondary endpoint, investigators found that quality of life (QoL) was significantly better in patients who received SIRT versus those who received sorafenib (P = .0048). This continued to increase over time (P = .0447).
Treatment-related AEs were experienced by 77% of patients in the SIRT group and 81% in the sorafenib group; serious AEs were observed in 48% and 52%, respectively. Patients had a median of 5 treatment-related AEs in the SIRT group compared to 10 in the sorafenib group.
The most frequent grade ≥3 AEs were fatigue (9% with SIRT vs 19% with sorafenib), liver dysfunction (11% vs 13%), increased laboratory liver values (9% vs 7%), hematologic abnormalities (10% vs 14%), diarrhea (1% vs 14%), abdominal pain (3% vs 6%), increased creatinine (2% vs 6%), and hand-foot skin reaction (<1% vs 6%). A total of 19 deaths in the SIRT cohort and 12 in the sorafenib cohort were deemed treatment related.
The study findings further demonstrated that the cumulative incidence of radiologic progression in the liver as the first event was significantly lower in the SIRT group compared with the sorafenib arm (P = .014). Additionally, the response rate was 19% versus 11.6% in the SIRT and sorafenib cohorts, respectively.
SARAH represents the first reported randomized controlled trial evaluating SIRT as a standard of care for patients with HCC. Although SIRT was found to be safe, the study did not meet its primary OS endpoint, suggesting that further trials are needed to establish SIRT as a viable option for patients in this setting.
“While SIRT demonstrated significantly reduced side effects, better quality of life, high response rates, and more effectively controlled tumor progression in the liver, the overall survival of patients was not higher than in the sorafenib group,” said Vilgrain. “Nonetheless, this study provides evidence that SIRT may be a better-tolerated alternative for managing this complex and difficult-to-treat disease, deserving further evaluation.”
Additional secondary endpoints, including nontumor liver and tumor dosimetry, cost analysis, and additional QoL analyses, will be reported following further study. The study authors suggested that SIRT will also be investigated in patients with less-advanced HCC.