乌鸦传媒

SAN ANTONIO -- Adding radiation therapy to systemic treatment significantly improved overall survival (OS) in advanced liver cancer, according to a randomized trial reported here.

Median OS improved from 12.3 months with the targeted drug sorafenib (Nexavar) to 15.8 months with stereotactic body radiation therapy (SBRT) followed by sorafenib. Landmark survival analyses from 6 to 24 months all favored the SBRT arm, and the magnitude of the benefit increased over time.

"In patients with advanced hepatocellular carcinoma, compared to sorafenib alone, SBRT prior to sorafenib improved overall survival, progression-free survival (PFS), and time to progression (TTP), without a concerning increase in adverse events," reported Laura Dawson, MD, of Princess Margaret Cancer Center in Toronto, at the American Society for Radiation Oncology (ASTRO) annual meeting.

"Considering the univariate analysis and the multivariable analysis, this study adds to the evolving data on the benefits of radiation in the treatment of hepatocellular carcinoma patients, adding SBRT to the toolkit of standard treatment options for patients with metastatic carcinoma, with perhaps the largest benefits in those patients who have vascular invasion, a particularly challenging patient population to treat," she noted. "I hope this does help raise awareness of the importance of hepatocellular carcinoma, and also the huge added benefit that SBRT can add in the treatment of these patients."

The results will bring a new standard of care to patients with a difficult-to-treat condition, said Karyn Goodman, MD, of the Icahn School of Medicine at Mount Sinai in New York City, at an ASTRO press briefing.

"This is really one of the most important studies that's come out in many years in terms of practice-changing outcomes," said Goodman "We've see that with patients who have very high-risk HCC, especially patients who have portal vein or macrovascular invasion, that there's been a significant improvement in overall survival. This is a very difficult patient population, and adding SBRT to this group improved both the progression-free survival and overall survival. I think we're really at a point where we can call this a standard of care for patients."

Global Disease Burden

Globally, HCC remains a leading cause of cancer death, and the incidence has been rising in North America, Dawson noted during the introduction to primary findings from the NRG/RTOG1112 trial. Systemic therapy is the standard of care for HCC that is unresectable or not suitable for thermal ablation or regional therapies. When NRG/RTOG1112 began, the multikinase inhibitor sorafenib represented standard systemic therapy, having demonstrated from 7.9 to 10.7 months in a placebo-controlled trial.

Patients with macrovascular invasion derive less benefit from systemic therapy and have worse outcomes, Dawson continued.

"Integrating radiation strategies into the treatment of patients with HCC has been studied for decades, mostly in single-arm studies," she said. "There have been some improved response rates, recanalization of vessels, in fact longer survival than expected. There have been a few randomized trials, mostly conducted with hepatic arterial radioembolization with yttrium-90, but those trials have not shown improvement in survival."

NRG/RTOG1112 tested the hypothesis that SBRT followed by sorafenib would improve OS versus single-agent sorafenib in advanced HCC. PFS and TTP were key secondary endpoints. Eligible patients had locally advanced HCC that was unsuitable for, refractory to, or had recurred following surgery, radiofrequency ablation, or transarterial chemoembolization. Patients had a maximum tumor burden ≤20 cm, and any degree of vascular invasion was allowed.

Patients were randomized to daily standard-dose sorafenib or SBRT followed by a modified dosing schedule of sorafenib. Median follow-up was 13.2 months, including 33.7 months for patients who remained alive at the end of the study.

Key Findings, Implications

The primary analysis showed that beginning treatment with SBRT reduced the survival hazard by 23% versus single-agent sorafenib (95% CI 0.59-1.01, P=0.055). A survival benefit in favor of the SBRT arm emerged within 6 months (88% vs 71%) and remained evident to 24 months (33% vs 23%).

A multivariable analysis confirmed that preceding sorafenib with SBRT significantly reduced the survival hazard (HR 0.72, 95% CI 0.52-0.99, P=0.042). Confirming a large volume of existing data, macrovascular involvement was a significant negative predictor of survival (HR 2.34, 95% CI 1.63-3.34, P<0.0001).

Analysis of secondary endpoints showed that the addition of SBRT significantly improved median PFS from 5.5 months with sorafenib alone to 9.2 months (HR 0.55, 95% CI 0.40-0.75, P=0.0001). Median TTP was 9.5 months with sorafenib monotherapy, increasing to 18.5 months with SBRT followed by sorafenib (HR 0.69, 95% CI 0.48-0.99, P=0.034).

The frequency of grade ≥3 adverse events (AEs) did not increase with the addition of SBRT (75%) versus single-agent sorafenib (74%). Gastrointestinal bleeding occurred in 6% of the sorafenib group and 4% of the SBRT arm.

Though single-agent sorafenib is no longer standard of care for advanced HCC, the findings remain relevant to the current clinical practice environment, Dawson and Goodman told 乌鸦传媒 by email.

"I believe these results are applicable to any patient who receives approved TKIs [tyrosine kinase inhibitors] for HCC (and also meeting eligibility criteria)," said Dawson. "I hypothesize that there will be improved outcomes with SBRT when the systemic therapy is immunotherapy based, especially in patients with macrovascular invasion [MVI], who have less benefits with immunotherapy than patients without MVI. However, the exact benefits and optimal sequencing of radiation therapy and immunotherapy are unknown, and hopefully this will be the focus of future clinical trials."

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