Background
Phase II single-arm trial (NRG Oncology/RTOG 1112 precursor experience, Massachusetts General Hospital). 83 patients with HCC (n=44, 3 tx cohorts) or intrahepatic cholangiocarcinoma (iCCA, n=37, 2 tx cohorts) treated with hypofractionated proton beam therapy (PBT). Child-Pugh A/B liver function. Dose escalation across cohorts targeting PBT delivery in 15 fractions using dose painting to account for liver function and volumes.
Interventions and follow up
Arm A: HCC cohorts — PBT 67.5 GyE/15 fx (large vessel invasion excluded) or escalated
Arm B: iCCA cohorts — PBT 58.05 GyE/15 fx or escalated
Primary endpoint: Local control (LC) at 2 years and toxicity
mFollow up: 19.5 month
Arm B: iCCA cohorts — PBT 58.05 GyE/15 fx or escalated
Primary endpoint: Local control (LC) at 2 years and toxicity
mFollow up: 19.5 month
Results
N/A: Single-arm phase II
2-year LC (HCC): 95%
2-year LC (iCCA): 94%
Median OS (HCC): 30 months
Median OS (iCCA): 19 months
2-year OS: 63% (HCC), 46% (iCCA)
2-year LC (HCC): 95%
2-year LC (iCCA): 94%
Median OS (HCC): 30 months
Median OS (iCCA): 19 months
2-year OS: 63% (HCC), 46% (iCCA)
Adverse events
Main adverse events: Grade 3+ toxicity: 10% (HCC), 22% (iCCA). No grade 5 treatment-related events. Higher toxicity in iCCA patients, possibly related to biliary anatomy. No unexpected proton-specific toxicities observed.
Conclusions
Hypofractionated proton beam therapy achieved excellent 2-year local control rates (95% HCC, 94% iCCA) with acceptable toxicity, demonstrating the feasibility and efficacy of high-dose hypofractionated PBT for both primary liver cancers. Long median OS (30 months for HCC, 19 months for iCCA) compared favorably with historical systemic therapy outcomes.
Key Limitations
Key Limitations: Non-randomized phase II trial — no comparison to photon SBRT or systemic therapy. Mixed tumor histologies and fractionation schemas limit uniform interpretation. Limited sample size per cohort. 19.5-month median follow-up may underestimate late toxicities. Proton-specific advantages over photon SBRT not directly established; randomized comparison ongoing.
Clinical Context
This trial established the safety and preliminary efficacy of hypofractionated proton therapy for HCC and iCCA, contributing to the evidence base supporting both SBRT and PBT as ablative liver radiation approaches. The ~95% 2-year LC rates are consistent across proton and photon liver SBRT series. Results support further investigation comparing proton vs photon approaches, particularly in Child-Pugh B patients or those with large tumor volumes where normal liver sparing is critical.
References