What is the ideal first-line therapy for nonresectable, non–transplantable eligible, liver-only hepatocellular carcinoma? In a debate at the 2019 Gastrointestinal Oncology Conference, Mark Yarchoan, MD, had the unenviable task of convincing the audience that systemic therapy was the way to go.
Mark Yarchoan, MD
What is the ideal first-line therapy for nonresectable, nontransplantable eligible, liver-only hepatocellular carcinoma (HCC)? In a debate at the 2019 Gastrointestinal Oncology Conference, Mark Yarchoan, MD, had the unenviable task of convincing the audience that systemic therapy was the way to go.
“Sorafenib [Nexavar] beats supportive care, so there is very clear evidence that we have systemic therapies that work,” said Yarchoan, assistant professor of oncology at Johns Hopkins Medicine. “For patients with either intrahepatic and extrahepatic [disease], there really is a role for thinking about systemic therapy first.”
Many treatment guidelines, including those from the American Association for the Study of Liver Diseases, recommend transarterial chemoembolization (TACE) as first-line treatment for patients with intermediate stage HCC. Yarchoan, an assistant professor of oncology at Johns Hopkins School of Medicine, argued that systemic therapy like sorafenib improves survival while TACE does not.
He cited a multicenter, phase III, double-blind, placebo-controlled trial of 602 patients with advanced HCC who had not received prior systemic therapy, the median overall survival (OS) was 10.7 months in the sorafenib group and 7.9 months in the placebo group (HR, 0.69; 95% CI, 0.55-0.87;P<.001).1
“If the patients had extrahepatic or intrahepatic disease, it didn't matter,” he said. “There was better survival with sorafenib than placebo. That's been shown with virtually every study.”
Furthermore, Yarchoan added, data published in 1995 showed that lipiodol chemoembolization did not improve survival while often causing acute liver failure in patients with unresectable HCC but who did not have severe liver disease.2
He went on to say that TACE would be rejected if it were submitted for FDA approval today. He pointed to results from the phase III SARAH and the SIRveNIB trials comparing sorafenib versus selective internal radiotherapy (SIRT) with yttrium-90 (Y90) resin microspheres.3,4
In SARAH, the median OS favored the sorafenib arm (9.9 vs 8.0 months; HR, 1.15; 95% CI, 0.94-1.4;P= .18).3The median OS similarly favored sorafenib in SIRveNIB (10.0 vs 8.8 months; HR 1.1; 95% CI, 0.9-1.4;P= .36).4
“If Y90 came in front of the FDA for a nonequivalency study with these data, the FDA would shoot it down,” Yarchoan said. “There are very strict criteria for noninferiority; in both cases, Y90 failed to meet our bar for noninferiority. Based on these studies, sorafenib is the gold standard for first-line therapy.”
Michael C. Soulen, MD, director of interventional oncology at the University of Pennsylvania’s Abramson Cancer Center, argued in favor of liver-directed therapy. He said that data from 6 studies show that conventional TACE improves survival compared with best supportive care.
Findings from a study conducted in Barcelona showed that chemoembolization was superior for survival (HR, 0.47; 95% CI 0.25-0.91;P= .025), with a 2-year survival probability of 50% compared with 27%, favoring embolization.5
However, there are more up-to-date studies showing a survival advantage for TACE, the largest of which was published inHepatologyin 2014. Results from that trial of 502 patients showed that the addition of adjuvant brivanib (BMS-582664) to TACE did not improve median OS.6
“While [the study] was negative for brivanib, it does show the effect of chemoembolization, which in both arms had a median survival of about 26 months and a 2-year survival [rate] better than 50%,” Soulen said.
Data published in October 2019 inCardioVascular and Interventional Radiologyshowed a single-arm trial of 142 patients with HCC who was not eligible for curative treatment, these patients were assigned to doxorubicin-loaded HepaSphere 30-60 μm. The median OS was 31 months with an overall response rate (ORR) >80% and a 2-year OS rate >70%.7
“Here we have a handful of large, prospective, controlled modern trials all done within the past 10 years showing that, in fact, the median survival for chemoembolization in these large populations is somewhere between 2 years and 3 years, and 2-year survival you expect to be better than 50%,” Soulen said.
He added that real-world data support TACE in this population. Findings from a systemic review of 101 articles involving 10,108 patients treated with lipiodol TACE were selected for the efficacy analysis. The collective ORR was 52.5% (95% CI, 43.6%-61.5%) with a 2-year OS rate of 51.8% and a 5-year OS rate of 32.4%. The median OS was 19.4 months (95% CI, 16.2-22.6).8
“Liver-directed therapy is the treatment of choice for eligible patients with intermediate to advanced unresectable HCC,” Soulen said. He added that median OS and 2-year survival rates for TACE are double what is seen with first-line tyrosine kinase inhibitors and immune modulation agents, although that is in part because populations in drug trials are almost exclusively advanced patients or those who've already undergone unsuccessful liver-directed therapy.
Systemic therapies, he concluded, should be reserved for those who are ineligible for TACE, those who've already undergone 2 unsuccessful cycles of TACE, and for those who are sequenced with liver-directed therapy for selected advanced disease cases.