SAN FRANCISCO — Adding stereotactic body radiation therapy (SBRT) to sorafenib produced better outcomes among patients with hepatocellular carcinoma (HCC) than sorafenib used alone, according to new findings.
The use of SBRT in this setting improved both overall survival and progression-free survival (PFS). There was no increase in adverse events with the addition of SBRT, and results trended toward a quality-of-life benefit at 6 months.
“This adds to the body of evidence for the role of external-beam radiation, bringing SBRT to the armamentarium of treatment options for patients — particularly those with locally advanced HCC and macrovascular invasion, especially if they are treated with tyrosine kinase inhibitors [TKIs],” said lead study author Laura A. Dawson, MD, a clinician scientist at the Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Canada.
Dawson presented the findings here at the Gastrointestinal Cancers Symposium (GICS) 2023.
Approached for an outside comment, Mary Feng, MD, professor of radiation oncology at the University of California, San Francisco, said, “This study is really groundbreaking.”
She added that the investigators should be congratulated for executing this ambitious study with worldwide enrollment for a serious disease.
“There are very few studies demonstrating an overall survival benefit from radiation or any local control modality,” she told Medscape Medical News. She suggested that the survival benefit seen in this trial was “likely due to the high percentage of patients (74%) with macrovascular invasion, who stand to benefit the most from treatment.
“This study has established the standard of adding SBRT to patients who are treated with TKIs and raises the question of whether adding SBRT to immunotherapy would also result in a survival benefit. This next question must also be tested in a prospective clinical trial,” she said.
At the study’s inception, sorafenib was the standard of care for patients who were unable to undergo surgery, ablation, and/or transarterial chemoembolization (TACE). Dawson explained that sorafenib had been shown to improve median overall survival, although there was less benefit if macrovascular invasion was present.
“Integrating radiation strategies in HCC management has been a key question over the past few decades,” she said.
In the current study, Dawson and colleagues added SBRT to sorafenib. The cohort included 177 patients with new or recurrent HCC who were not candidates for surgery, ablation, or TACE. They were randomly assigned to receive either sorafenib 400 mg twice daily or to SBRT (27.5 – 50 Gy in five fractions) followed by sorafenib 200 mg twice daily; the dosage was then increased to 400 mg twice daily after 28 days.
SBRT Improves Outcomes
The original plan was to enroll 292 participants, but accrual closed early when the standard of care for systemic treatment of HCC changed following the results of the phase 3 IMbrave150 trial, which showed the superiority of atezolizumab plus bevacizumab as frontline therapy for locally advanced or metastatic HCC. The closure of accrual was agreed upon by the investigators and the data safety monitoring committee, and their statistical analysis plan was revised accordingly. The study became time driven rather than event driven, she noted. This resulted in a decrease from 80% power to 65% power.
The median age of participants was 66 years (range, 27 – 84 years); 41% had hepatitis C, and 19% had hepatitis B or B/C. Additionally, 82% had Barcelona Clinic Liver Cancer stage C disease, and 74% had macrovascular invasion.
The median follow-up was 13.2 months overall and 33.7 months for living patients.
Median overall survival improved from 12.3 months with sorafenib alone to 15.8 months with the addition of SBRT to the regimen (hazard ratio [HR] = 0.77; one-sided P = .0554). A prespecified multivariable analysis showed that the combination therapy resulted in a statistically significant improvement in overall survival after adjustment for confounders (HR, 0.72; P = .042).
Similarly, median PFS also improved from 5.5 months with sorafenib alone to 9.2 months with SBRT and sorafenib (HR = 0.55; two-sided P = .0001).
With regard to safety, gastrointestinal bleeds occurred in 4% of patients in the combination arm, vs 6% of those in the monotherapy arm. Overall, rates of treatment-related grade 3+ adverse events did not significantly differ between study arms (42% vs 47%; P = .52). There were three grade 5 events; two in the sorafenib-only group and one in the SBRT/sorafenib group.
The researchers also evaluated quality of life (QoL). “Our hypothesis was that patients treated with SBRT and sorafenib would have improved quality of life 6 months after the start of treatment compared to sorafenib alone,” said Dawson.
About half (47%) of participants agreed to fill out QoL assessments, but baseline and 6-month data were available for only about 21% of participants. Although the numbers were considered too small to analyze statistically, substantial improvement was seen in the group that received combination therapy. A total of 10% of patients who received sorafenib reported improvement on the FACT-Hep score, vs 35% of patients who received SBRT/sorafenib.
“As compared to sorafenib, SBRT improved overall survival and progression-free survival, with no observed increase in adverse events in patients with advanced HCC,” concluded Dawson.
Where Does Radiation Fit?
Invited discussant Laura Goff, MD, associate professor of medicine, Vanderbilt Ingram Cancer Center, Nashville, Tennessee, reiterated that SBRT given prior to sorafenib improved outcomes compared to sorafenib alone, and while not definitive, QoF scores appeared to improve at 6 months for the combination arm. “This reassures our concerns about toxicity,” she said.
Goff pointed out that since the study closed early, owing to changes in standard of care for HCC, the question arises — where does radiation fit in the array of options now available for HCC?
“For one, sorafenib plus SBRT represents an intriguing first-line option for patients who cannot be treated with immunotherapy, such as those who experience a posttransplant recurrence,” Goff said. “There is also renewed interest in radiation therapy in liver-dominant HCC, and there is active investigation ongoing for a variety of combinations.”
Dawson reported relationships with Merck and Raysearch. Goff reported relationships with Agios, ASLAN, AstraZeneca, Basilea, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Exelixis, Genentech, Merck, and QED Therapeutics.
Gastrointestinal Cancers Symposium (GICS) 2023: Abstract 489. Presented January 20, 2023
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