The 459-patient randomised controlled SARAH study shows that local treatments of advanced or inoperable hepatocellular carcinoma with selective internal radiation therapy (SIRT) did not lead to a planned superiority difference in overall survival compared to standard-of-care systemic therapy with sorafenib. However, SIRT had far fewer side-effects and patients who received this treatment had a significantly better quality of life.
The investigator-initiated SARAH (Sorafenib vs. radioembolization in advanced hepatocellular carcinoma) study directly compared the efficacy of SIRT using yttrium-90 [Y-90] resin microspheres (Sir-spheres, Sirtex) vs. sorafenib (Nexavar; Bayer). The trial was launched in December 2011 and concluded enrolment in February 2015, with 237 patients receiving SIRT. The primary endpoint of the study was overall survival and secondary endpoints included progression-free survival, time to radiological progression at any site and in the liver as the first event, tumour response, quality of life, and safety and toxicity.
Valérie Vilgrain, Department of Radiology, Beaujon Hospital, Assistance Publique – Hôpitaux de Paris (AP-HP) and Université Paris Diderot, Sorbonne Paris Cité, France, principal investigator of the SARAH study, said: “Neither sorafenib nor SIR-Spheres Y-90 resin microspheres produced a statistically significant difference in overall survival of the patients we studied. Despite 26.6% of patients in the SIRT arm not receiving Sir-spheres per protocol, the primary endpoint of overall survival by intention-to-treat [ITT] was not significantly different (median 8 vs. 9.9 months; p=0.18).Moreover, if we look at the patients who received Sir-spheres or sorafenib according to the SARAH protocol, median overall survival was identical (9.9 vs. 9.9 months; p=0.92).”
Patients with advanced or inoperable hepatocellular carcinoma who usually received one or two treatments of SIRT had similar survival compared to patients who received standard twice-daily systemic treatment with sorafenib, but with less than half the number and significantly fewer severe treatment-related adverse effects and significantly better quality of life. Almost 70% of the patients in the SARAH study had advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage C), with portal vein thrombosis and no extrahepatic spread. Most of the other patients had failed two cycles of transarterial chemoembolization.
Vilgrain presented the data at The International Liver Congress 2017, Amsterdam, The Netherlands, and also at the European Conference on Interventional Oncology (ECIO) in Bilbao, Spain.
The trial further demonstrated that the cumulative incidence of radiologic progression in the liver as the first event was significantly lower in the SIRT group compared to the sorafenib group (p=0.014), and the response rate was significantly higher in the SIRT group compared to the sorafenib group (19% vs. 11.6%, p=0.042). Median progression free survival was 4.1 months and 3.7 months in the SIRT and sorafenib groups, respectively (p=0.765). Overall, there were 1,297 and 2,837 treatment-related adverse events including 230 and 411 grade 3, in the SIRT and sorafenib groups, respectively. Both the side-effect profile and quality of life scores were significantly better over time in the SIRT group compared to the sorafenib group (p=0.005).
“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 vs. the current standard of care,” said Vilgrain.
The difference in the frequency and severity of side effects of patients treated with SIRT vs. sorafenib is clear. Significantly fewer patients treated with SIRT had any treatment-related side effects at all (76.5% vs. 94.0% for sorafenib; p<0.001), and these were also less severe (≥ grade 3; 40.7% vs. 63.0%, respectively; p<0.001). Moreover, those patients treated with SIRT who reported treatment-related side-effects experienced a median of only five such events over the course of the SARAH study, compared to a median of 10 events in those who received sorafenib (p<0.001).
General treatment-related symptoms such as fatigue (42% vs. 65%; p<0.001), abdominal pain (20% vs. 29%; p=0.032), nausea or vomiting (12% vs. 23%; p=0.001) and infection (4% vs. 11%; p=0.007) were also significantly less frequently reported and less severe for patients receiving Sir-spheres microspheres, compared to sorafenib.
Fewer patients receiving SIRT experienced treatment-related diarrhoea (13% vs. 68% for sorafenib; p<0.001), hand-foot skin reaction (0.4% vs. 21%; p<0.001), anorexia (13% vs. 32%; p<0.001), weight loss (6% vs. 21%; p<0.001) and alopecia (0% vs. 16%; p<0.001), as well as infections (4% vs. 11%; p=0.007), hypertension (3% vs. 13%; p<0.001) and non-gastrointestinal haemorrhage (3% vs. 10%; p=0.002).
The results of quality of life surveys filled out by SARAH participants at three month intervals after their initial treatment showed that patients treated with Sir-spheres maintained their health status over the duration of the SARAH study, whereas patients receiving sorafenib reported a significant and sustained decline in quality of life (group effect: p=0.005; time effect: p<0.001; between group difference increase over time: p=0.045).
There were few potential SIRT-associated treatment-related complications and, importantly, no radioembolization-induced liver disease (radiation hepatitis) experienced.
“In terms of what matters for patients, the findings from this first large head-to-head comparison of liver-directed SIRT and systemic chemotherapy with sorafenib also show clearly that liver-directed procedures with Sir-spheres result in a significantly better tolerance of treatment and quality of life,” Vilgrain stated. “I believe this consideration should be a critical factor in selecting first-line treatment for this patient population in the future.”