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Adding Radiation to Systemic Therapy Improves Survival in Patients with Advanced Hepatocellular Cancer

January 2023 Vol 16, No 1

According to findings from a phase 3 trial presented at the American Society for Radiation Oncology Annual Meeting 2022, the addition of stereotactic body radiation therapy (SBRT) to sorafenib (Nexavar) can lengthen overall survival (OS) and delay tumor progression in patients with unresectable advanced hepatocellular cancer (HCC) without compromising quality of life.

“Adding SBRT to systemic therapy [with sorafenib] improved overall survival, delayed tumor progression, and lengthened time to progression with no increase in adverse events. SBRT is a new standard treatment option for locally advanced HCC, especially with vascular invasion—a difficult-to-treat disease,” said lead investigator Laura A. Dawson, MD, FRCPC, Professor, Radiation Oncology, and Staff Radiation Oncologist, Princess Margaret Cancer Center, University of Toronto, Ontario, Canada.

Study Details

The randomized phase 3 NRG/RTOG 1112 trial was designed to compare SBRT plus systemic therapy versus systemic therapy alone for advanced inoperable HCC. Of the 193 patients enrolled at 23 sites across the United States and Canada, 177 were evaluable for outcomes. All participants in the study had new or recurrent locally advanced HCC and were ineligible for surgical resection or other local or regional standard therapies due to underlying clinical factors or because their cancer had returned after standard therapy.

At baseline, 74% of patients had macrovascular invasion in the right or left portal vein, which is a poor prognostic sign. “Any degree of macrovascular invasion was permitted, unlike other trials in HCC,” Dr Dawson noted. Median age was 66 years, approximately 40% of patients had hepatitis C, and 85% were male.

Patients were randomized in a 1:1 ratio to sorafenib (the standard of care at the time the trial was initiated) or SBRT escalated as tolerated from 27.5 to 50 Gy in 5 fractions over 10 days (individualized according to clinical factors) followed by sorafenib. Stratification factors included extent of macrovascular involvement, hepatitis B versus hepatitis C, geographical site (North America vs other), and HCC volume (<10%, 10%-40%, and >40%).

“In March 2021, the study closed sooner than expected due to a change in standard of care from sorafenib to atezolizumab [Tecentriq] and bevacizumab [Avastin],” Dr Dawson explained, leaving 177 evaluable patients. “This led to fewer patients than required for overall survival events.”

Median OS (the primary end point) was 15.8 months in the SBRT arm versus 12.3 months in the sorafenib alone arm (P = .055), a 23% improvement favoring SBRT. The difference was statistically significant after controlling for clinical prognostic factors such as performance status and the degree of vascular invasion (P = .042).

Progression-free survival was improved with the addition of SBRT, from 5.5 months with sorafenib alone to 9.2 months with the combination therapy (P <.001). Patients in the combination arm also had longer intervals before their disease progressed (18.5 vs 9.5 months; P = .034).

“There was no concerning increase in adverse events, and treatment-related adverse events were not significantly different between the treatment arms,” Dr Dawson told attendees. Grade ≥3 adverse events were reported in 42% of patients in the sorafenib arm and 47% of those in the SBRT plus sorafenib arm. The rate of grade ≥3 gastrointestinal bleeds was comparable—6% in the sorafenib arm versus 4% in the SBRT plus sorafenib arm. There were 2 deaths in the sorafenib arm and 1 in the SBRT plus sorafenib arm.

Dr Dawson said that future clinical trials will evaluate the role of radiation therapy combined with newer therapies, including immunotherapy. Other remaining questions include the optimal dosing and sequencing of radiation with different therapies, as well as the potential benefit of radiation alone for patients who are ineligible for standard therapies.

Expert Commentary

“This is one of the most important studies to come out for advanced HCC, especially for patients with macrovascular invasion. This is a challenging population to treat. The addition of SBRT improved both progression-free survival and overall survival. We can really at this point call this a new standard of care,” said formal discussant Karyn A. Goodman, MD, MS, Professor and Vice Chair, Research and Quality, Department of Radiation Oncology, Icahn School of Medicine at Mt. Sinai, New York City.

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