Adding radiation therapy to sorafenib extends survival in advanced liver cancer
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The addition of stereotactic body radiation therapy to sorafenib extended OS among patients with advanced hepatocellular carcinoma, results of the randomized phase 3 NRG Oncology/RTOG 1112 trial showed.
Data from the study — presented at American Society for Radiation Oncology Annual Meeting — revealed that radiation before sorafenib also delayed tumor progression without compromising a patient’s quality of life.
In addition, researchers observed benefit in patients with microvasculature invasion, who have traditionally been the hardest to treat.
Background
Hepatocellular carcinoma is “perhaps a neglected cancer,” according to Laura A. Dawson, MD, FRCPC, FASTRO, professor of radiation oncology at University of Toronto and practicing radiation oncologist at Princess Margaret Cancer Centre.
“It is one of the leading causes of global cancer death, and its incidence is on the rise in North America,” she said during a news briefing.
Systemic care is the current standard for patients with HCC ineligible for surgical resection or invasive therapies, Dawson noted.
Integration of radiation therapy into management of HCC has been studied for decades but with mixed results that lack data to demonstrate improvements in survival, she added.
The NRG Oncology/RTOG 1112 trial examined the role of SBRT in the treatment of HCC and whether it could improve outcomes when provided in combination with systemic therapy.
Methodology
The multicenter NRG Oncology/RTOG 1112 trial enrolled 193 patients (median age, 66 years; range, 27-84) with newly diagnosed or relapsed advanced HCC who were ineligible for tumor resection or other standard therapies because of certain clinical factors or their cancer returning after standard therapy.
Patient accrual occurred from April 2013 to March 2021, with 177 patients eligible for the final analysis.
Investigators randomly assigned patients in a 1:1 ratio to receive either sorafenib (Nexavar, Bayer) dosed at 400 mg twice daily (n = 92) or SBRT plus sorafenib dosed at 200 mg twice daily and increased to 400 mg twice after 28 days if appropriate (n = 85).
The patients in the SBRT group received 27.5 Gy to 50 Gy in five fractions over 5 to 10 days, with total doses tailored to a patient’s clinical factors.
Forty-one percent of patients had hepatitis C, whereas 19% had hepatitis B or concurrent hepatitis B and hepatitis C.
OS served as the study’s primary endpoint. Secondary endpoints included PFS, time to disease progression (TTP) and safety.
Median follow-up was 13.2 months, with a data cutoff date of July 1.
Key findings
The combination of SBRT plus sorafenib increased median OS to 15.8 months (90% CI, 11.4-19.2) compared with 12.3 months (90% CI, 10.6, 14.3) among those who received sorafenib alone (HR = 0.77; 95% CI, 0.59-1.01).
Investigators found significant improvement in OS for those who received SBRT plus sorafenib after controlling for clinical factors (HR = 0.72; 95% CI, 0.52-0.99). They also reported significant improvement with the combination vs. sorafenib alone in median PFS (9.2 months vs. 5.5 months; HR = 0.55; 95% CI, 0.4-0.75) and median TTP (18.5 months vs. 9.5 months; HR = 0.69; 95% CI, 0.48-0.99).
The two groups had similar rates of adverse events, with 42% in the sorafenib group experiencing grade 3 or higher treatment-related adverse events compared with 47% in the sorafenib-plus-SBRT group. One treatment-related patient death occurred in the sorafenib monotherapy group.
Clinical implications
The results showed that SBRT before sorafenib improves key outcomes among patients with advanced HCC compared with sorafenib alone. This improvement occurred without any increase in serious treatment-related adverse events, Dawson added.
“This study adds to the evolving data on the benefits of radiation in patients with hepatocellular carcinoma,” she told the audience. “SBRT should be added to the toolkit of standard treatment options for patients with hepatocellular carcinoma, with the largest benefit seen among patients with vascular invasion, who are particularly challenging to treat.”
Perspective
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Joshua E. Meyer, MD
HCC is an ever-increasing cause of cancer death but is also complicated by underlying liver function that is often compromised by sharing a root cause of disease with the cancer. In this context, data demonstrate the efficacy of high-dose SBRT, but no randomized phase 3 studies evaluating this technique in this disease had been reported previously.
RTOG/NRG Oncology 1112 is truly a landmark study. It provides randomized, level one evidence that the addition of SBRT to systemic therapy is effective in controlling HCC. This is over and above the best therapy for HCC at the time of the study’s design — sorafenib. We are fortunate to have additional systemic therapies available now that may be more effective or less toxic than sorafenib, but this study demonstrates that the addition of SBRT to what was state-of-the-art chemotherapy provides benefit to patients, even for some with metastatic disease.
A second key finding is that there was no significant increase in toxicity from the radiation, with no statistical difference in the rate of grade 3 or higher adverse effects. These randomized data are extremely important in evaluating these patients, who sometimes struggle to tolerate therapy due to their underlying conditions.
These data have solidified the role of SBRT in treatment of these patients. If surgery is not feasible or appropriate, the combination of SBRT and systemic therapy is an appropriate option — every bit as supported as any other local therapy.
Perspective
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Karyn A. Goodman, MD, MS
This is one of the most important studies that has come out in many years in terms of practice-changing outcomes. The addition of SBRT has demonstrated a significant improvement in overall survival for patients with high-risk HCC, especially those with portal vein or vascular invasion.
Add to this the significant improvement in PFS seen among those who had additional SBRT, and I think we are at a point where we can call this a new standard of care for these difficult-to-treat patients.
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Dawson LA, et al. Abstract LBA 01. Presented at ASTRO Annual Meeting; Oct. 23-26, 2021; San Antonio.
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