Background
Sequential phase I and II trials (Princess Margaret Hospital). 102 evaluable patients with active HCC unsuitable for standard locoregional therapies (TACE, RFA, surgery). Child-Turcotte-Pugh class A disease required, with ≥700 mL non-HCC liver. SBRT dose range 24–54 Gy in 6 fractions. Two sequential trials (Trial 1: 2004–2007, n=50; Trial 2: 2007–2010, n=52). TVT (tumor vascular thrombosis) present in 55%; extrahepatic disease in 12%.
Interventions and follow up
Arm A: 6-fraction SBRT (24–54 Gy) based on liver tolerance model; dose escalated in Trial 1 and standardized in Trial 2
Arm B: N/A — single-arm prospective trial
Primary endpoint: Toxicity and local control at 1 year (LC1y by RECIST)
mFollow up: Median 17 month
Arm B: N/A — single-arm prospective trial
Primary endpoint: Toxicity and local control at 1 year (LC1y by RECIST)
mFollow up: Median 17 month
Results
LC1y: 87% (95% CI 78%–93%)
Grade ≥3 toxicity: 30%
Median OS: 17.0 months (95% CI 10.4–21.3 months)
Treatment-related deaths: 7 (6.9%) possibly treatment-related
Grade ≥3 toxicity: 30%
Median OS: 17.0 months (95% CI 10.4–21.3 months)
Treatment-related deaths: 7 (6.9%) possibly treatment-related
Adverse events
Main adverse events: Grade ≥3 toxicity in 30%; 7 possibly treatment-related deaths (1.1–7.7 months post-SBRT), mainly in patients with TVT. Dose and Trial 2 (refined selection) were associated with improved LC on univariate analysis. TVT was the only independent prognostic factor for OS (HR 2.47).
Conclusions
Six-fraction SBRT achieved 87% 1-year local control in locally advanced HCC with TVT and prior treatment failure, with a median OS of 17 months. These results provided strong rationale for studying SBRT for HCC in a randomized trial (RTOG 1112 vs sorafenib).
Key Limitations
Key Limitations: Single-arm prospective study without a control arm. 30% grade ≥3 toxicity is substantial and possibly dose-dependent. High-risk population (55% TVT, 12% extrahepatic disease) limits applicability to typical HCC SBRT candidates. 7 possibly treatment-related deaths in a hepatically compromised population highlights careful patient selection needs. No OS comparison to sorafenib available in this study.
Clinical Context
This sequential phase I/II experience is the largest prospective SBRT dataset for advanced HCC and served as the primary feasibility basis for the NRG/RTOG 1112 randomized trial (SBRT followed by sorafenib vs sorafenib alone). LC1y of 87% with 6-fraction SBRT is consistent across multiple single-institution series and supports SBRT as a viable local therapy for HCC unsuitable for standard treatments.
References