In the NRG Oncology clinical trial NRG-RTOG 1112, which sought to better determine the role of stereotactic body radiation therapy (SBRT) in the treatment of patients with advanced hepatocellular carcinoma (HCC), it was demonstrated that adding SBRT to Sorafenib improved overall survival (OS). These results were presented during the Plenary Session of the American Society for Radiation Oncology's (ASTRO) Annual Meeting in October 2022. NRG Oncology designed and led this trial which was conducted in the National Clinical Trials Network with funding from the National Cancer Institute, part of the National Institutes of Health.
"Historically, radiation therapy has not been an accepted treatment option for patients with liver cancer. This trial demonstrated that SBRT is an effective treatment for patients with unresectable liver cancer. The majority of patients studied had invasion of their cancer to the hepatic vessels, a poor prognostic factor. SBRT improved survival in these patients and delayed the time to cancer progression, with no increase in toxicity, compared to patients treated with Sorafenib alone. This study should help to change practice, bringing SBRT to the armamentarium of standard treatment options for patients with liver cancer." stated Laura A. Dawson, MD, of the Princess Margaret Cancer Centre /University Health Network in Toronto and lead author of the NRG-RTOG 1112 abstract.
From April 2013 to March 2021, the Phase III NRG/RTOG 1112 trial accrued 193 patients from 23 sites, and 177 eligible patients were randomized to Sorafenib (n=92) vs. SBRT followed by Sorafenib (n=85). The median age was 66 years (27-84). Forty-one percent had Hepatitis C, and 19% had Hepatitis B or both Hepatitis B and C. All patients had preserved liver function (Child Pugh A5 – 75% and A6 – 25%). Eight-two percent of patients had advanced HCC (as defined as Barcelona Clinical Liver Cancer (BCLC) Stage C); 74% of patients had macrovascular invasion of their HCC, and 4% had extra-hepatic metastases. .
The planned sample size was 292 patients (238 OS events, hazard ratio [HR]=0.72, 80% power, 1-sided alpha=0.05), but accrual closed early, primarily due to a change in HCC standard of care systemic therapy. Statistics were amended to report data as of 7/1/2022, projecting 155 OS events providing 65% power for the original hypothesis, with the same alpha. OS and progression-free survival (PFS) were estimated by Kaplan-Meier and arms compared using the log-rank test. Cox proportional hazards models were used to analyze treatment effect. The time to tumor progression (TTP) was estimated with cumulative incidence and arms compared using Gray's test. Secondary endpoints were tested with 2-sided alpha=0.05.
The trial results demonstrated that adding SBRT to Sorafenib improved OS, PFS, and time to progression (TTP) in patients with advanced hepatocellular carcinoma, with no significant increase in adverse events (AEs). Dr. Dawson commented that, "the early closure of the study meant that study power was reduced. Despite this, clinically and statistically significant improvements in outcomes with the addition of SBRT were observed. An important question for future clinical trials will be to determine what the benefits are and what the best sequencing is for SBRT when used in patients treated with immunotherapy."
At a median follow-up for all and alive patients of 13.2 and 33.7 months, respectively, with a total of 153 OS events, the median OS was improved from 12.3 months (90% CI 10.6, 14.3) with Sorafenib to 15.8 months (90% CI 11.4-19.2) with SBRT followed by Sorafenib (HR=0.77 [90% CI 0.59, 1.01], 1-sided p=0.0554). After adjusting for performance status, presence of extra-hepatic metastases, liver function (Child Pugh A5 vs. A6), and degree of tumor macrovascular invasion, OS was statistically significantly improved for patients receiving SBRT (HR=0.72, 95% CI 0.52-0.99, 2-sided Cox p=0.042). Median PFS was improved from 5.5 months (95% CI 3.4-6.3) with Sorafenib to 9.2 months (95% CI 7.5-11.9) with SBRT followed by Sorafenib (HR=0.55, 95% CI 0.40-0.75, 2-sided p=0.0001). TTP was also improved with SBRT followed by Sorafenib (HR=0.69, 95% CI 0.48-0.998, 2-sided Gray's p=0.034). Treatment-related grade 3+ AEs were not significantly different (Sorafenib – 42%, SBRT followed by Sorafenib – 47%; p=0.52).
This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), UG1CA189867 (NCORP), and U24CA180803 (IROC) from the National Cancer Institute (NCI).
Citation
Dawson LA, Winter KA, Knox J, Zhu A, Krishnan S, Guha C, Kachnic LA, Gillin MT, Hong TS, Craig TD, Hosni A, Chen E, Noonan A, Koay EJ, Sinha R, Lock MI, Ohri N, Dorth JA, Moughan J, Crane CH. (2022, October). Randomized Phase III Study of Sorafenib vs. Stereotactic Body Radiation Therapy (SBRT) Followed by Sorafenib in Hepatocellular Carcinoma (HCC). Paper presented at the annual meeting of the American Society for Radiation Oncology. San Antonio, TX.
About NRG Oncology
NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of patients with cancer. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit corporation that integrates the research of the legacy National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG) programs. The research network seeks to carry out clinical trials with emphases on gender-specific malignancies, including gynecologic, breast, and prostate cancers, and on localized or locally advanced cancers of all types. NRG Oncology's extensive research organization comprises multidisciplinary investigators, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists, and statisticians, and encompasses more than 1,300 research sites located world-wide with predominance in the United States and Canada. NRG Oncology is supported primarily through grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI's National Clinical Trials Network.
