Background
Phase II RCT. 91 patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) not amenable to surgery, ablation, or TACE. Randomized to hypofractionated proton beam therapy (PBT) vs photon 3D-CRT/IMRT. Primary aim: evaluate whether PBT achieves equivalent local control with better liver function preservation due to reduced dose to uninvolved liver. Hong TS et al, JCO 2016. PMID 26668346.
Interventions and follow up
Arm A: Proton beam therapy: 67.5 Gy(RBE) in 15 fractions (HCC) or 58.05 Gy(RBE) in 15 fractions (ICC)
Arm B: Photon 3D-CRT/IMRT: 67.5 Gy in 15 fractions (HCC) or 58.05 Gy in 15 fractions (ICC)
Primary endpoint: Local control; liver function preservation (Child-Pugh progression)
mFollow up: 19.5 month
Arm B: Photon 3D-CRT/IMRT: 67.5 Gy in 15 fractions (HCC) or 58.05 Gy in 15 fractions (ICC)
Primary endpoint: Local control; liver function preservation (Child-Pugh progression)
mFollow up: 19.5 month
Results
2-yr local control (proton): 88.4% vs photon 61.2%, P=.02
Child-Pugh progression (proton): 11.5% vs photon 27.6%, P=.04
2-yr OS: 63.2% (proton) vs 52.3% (photon), P=.26 — trend
Child-Pugh progression (proton): 11.5% vs photon 27.6%, P=.04
2-yr OS: 63.2% (proton) vs 52.3% (photon), P=.26 — trend
Adverse events
Main adverse events: Both arms: grade ≥3 GI toxicity 5% vs 11% (proton vs photon). Grade ≥3 liver toxicity: 8% (proton) vs 16% (photon). No grade ≥5 toxicity. Child-Pugh score deterioration at 3 months was significantly less with proton.
Conclusions
Hypofractionated proton therapy achieves superior 2-year local control and better liver function preservation compared to photon 3D-CRT/IMRT for HCC and ICC. These results support proton therapy as the preferred approach for liver tumors where minimizing uninvolved liver dose is critical.
Key Limitations
Key Limitations: Small sample size (91 patients) — underpowered for OS. Heterogeneous population (HCC + ICC). Photon arm included older techniques (3D-CRT); modern photon SBRT/SABR may perform better. Long-term OS and liver function data needed. Applicability to Child-Pugh B/C cirrhosis is limited.
Clinical Context
This trial is the primary randomized evidence supporting proton therapy for liver tumors. Hypofractionated proton 67.5 Gy/15 fractions is now a standard option for unresectable HCC at proton centers. For good liver function (Child-Pugh A), both proton and photon SBRT are options; proton is preferred when baseline liver function is marginal or Child-Pugh B.
References