Stereotactic body radiation therapy (SBRT) given prior to sorafenib improved overall survival, progression-free survival, and time to disease progression in patients with unresectable advanced hepatocellular cancer vs sorafenib alone, including those with macrovascular invasion, according to the results of the randomized, phase III NRG/RTOG 1112 trial. These findings were presented at the 2022 American Society for Radiation Oncology (ASTRO) Annual Meeting.1
Ann Dawson, MD, FASTRO
“Adding SBRT to systemic therapy [with sorafenib] improved overall survival, delayed tumor progression, and lengthened the time to disease progression, with no concerning increase in adverse events, in locally advanced hepatocellular carcinoma, most with vascular invasion—a difficult-to-treat disease,” stated lead author Laura Ann Dawson, MD, FASTRO, of Princess Margaret Cancer Centre, University of Toronto, Canada. “These results are consistent with prior studies suggesting a benefit to SBRT,adding SBRT to the tool kit of standard treatment options for patients with locally advanced hepatocellular carcinoma, especially with vascular invasion.”
“Hepatocellular carcinoma is perhaps a neglected cancer. It is a leading cause of global cancer death, and it is on the rise. At the time of study inception, the standard of care for patients who were not suitable for surgery or ablation was sorafenib,” she explained. “More recently, immunotherapy—particularly atezolizumab plus bevacizumab—has become a new standard of care.”
In previous studies, sorafenib improved median overall survival in this patient population by about 3 months vs placebo. However, a lesser magnitude of benefit was observed with sorafenib in patients with macrovascular invasion. “Integrating radiation strategies in hepatocellular carcinoma management has been a key question over the past decade, with promising outcomes observed in patients with macrovascular invasion,” explained Dr. Dawson.
Study Details
NRG/RTOG 1112 was designed to evaluate the role of SBRT plus systemic therapy for hepatocellular carcinoma in a phase III randomized controlled trial. A total of 193 patients (177 eligible for analysis) were enrolled at 23 sites primarly in the United States or Canada, with one patient accrued from Hong Kong and one from Australia. All patients enrolled in the trial had new or recurrent locally advanced hepatocellular carcinoma and were ineligible for surgical or other locoregional standard therapies.
Patients were randomly assigned 1:1 to receive sorafenib as the standard of care vs SBRT from 27.5 to 50 Gy in 5 fractions over 10 days (individualized according to clinical factors such as position of the tumor relative to normal tissues) followed by sorafenib.
“In March 2021, the study closed sooner than expected due to a change in the standard of care from sorafenib to atezolizumab and bevacizumab,” Dr. Dawson explained, leaving 177 evaluable patients. “This led to fewer patients than required for the number of overall survival events, and thus the power of the study was reduced from 80% to 65%.”
At baseline, 74% had macrovascular invasion, involving the main portal vein or the main right or left portal vein—a poor prognostic sign. “Any degree of macrovascular invasion was permitted, unlike other trials in hepatocellular carcinoma,” Dr. Dawson noted.
The primary endpoint was overall survival. Median follow-up was 13.2 months. Median overall survival was 15.8 months for the SBRT arm vs 12.3 months for the sorafenib-alone arm (P = .055)—a 23% improvement favoring SBRT. The difference was statistically significant after the investigators controlled for clinical prognostic factors on a planned multivariate analysis, including performance status and degree of vascular invasion (P = .042). “Median overall survival was longer than expected in a preimmunotherapy era,” Dr. Dawson said.
SBRT significantly improved median progression-free survival (P = .0001) from 5.5 months with sorafenib alone to 9.2 months, for a 45% improvement favoring the addition of SBRT. Median time to disease progression was also significantly improved with SBRT, from 9.5 months with sorafenib alone to 18.5 months with SBRT (P = .034).
“There was no concerning increase in adverse events, and treatment-related adverse events did not significantly differ between treatment arms,” Dr. Dawson told listeners. Grade 3 or higher adverse events were reported in 42% of patients on the sorafenib-alone arm and 47% on the SBRT/sorafenib arm. The rate of grade 3 or higher gastrointestinal bleeds was comparable: 6% in the sorafenib-alone arm and 4% in the SBRT/sorafenib arm. There were two deaths in the sorafenib-alone arm and one in the SBRT/sorafenib arm.
Dr. Dawson said she looks forward to future clinical trials to evaluate the role of radiation therapy combined with newer drug therapies. “There is a growing number of preclinical and early clinical studies suggesting that SBRT may be synergistic with immunotherapy, with more than an additive benefit for patients,” she said.
Additional Commentary
Karyn A. Goodman, MD, MS, of Icahn School of Medicine at Mount Sinai, New York, commented: “This is one of the most important studies to come out for advanced hepatocellular carcinoma, especially for patients with macrovascular invasion. This is a challenging population to treat. The addition of SBRT improved both progression-free and overall survival. At this point, we can call this a new standard of care in patients receiving sorafenib, and it sets the stage for future studies incorporating SBRT with newer agents in advanced hepatocellular carcinoma.”
Karyn A. Goodman, MD, MS
Mary Feng, MD
Mary Feng, MD, Vice Chair for Clinical Research and Professor, Department of Radiation Oncology, University of California, San Francisco, and formal discussant of Dr. Dawson’s presentation, agreed that hepatocellular carcinoma is a global problem. In fact, she pointed out, this trial enrolled patients from three continents.
“RTOG 1112 remains a landmark study, as treatments for hepatocellular carcinoma have historically been so limited. This is a new standard of care for patients who are on sorafenib and similar drugs,” Dr. Feng noted. “[Dr. Dawson] and her colleagues must be congratulated for initiating and completing this global study to combat a global problem.”
DISCLOSURE: Dr. Dawson has received honoraria and research funding from Merck. Dr. Goodman has served as an advisor or consultant to Novartis, Philips Healthcare, RenovoRx, Roche/Genentech, and Syntactx. Dr. Feng has received research grants from AstraZeneca and Varian.
REFERENCE
1. Dawson LA, Winter K, Knox J, et al: NRG/RTOG 1112: Randomized phase III study of sorafenib vs. stereotactic body radiation therapy followed by sorafenib in hepatocellular carcinoma. 2022 ASTRO Annual Meeting. Abstract LBA 01. Presented October 24, 2022.
