A large-scale clinical trial has found that proton therapy does not improve survival for patients with locally advanced liver cancer compared to traditional photon radiation, contrary to earlier expectations.
The NRG-GI003 trial, a multicenter randomized study, enrolled patients with measurable liver cancer. Researchers compared outcomes for those treated with proton therapy versus photon therapy. More than 90% of patients had a Child-Turcotte-Pugh (CTP) score of A, and 79% had a single tumor.
Results showed that patients receiving photon therapy lived more than twice as long as those given proton therapy: 54.9 months versus 26.6 months. This difference was most pronounced in patients with larger tumors (5 cm or greater), where photon therapy delivered a greater than twofold survival advantage. For smaller tumors, neither treatment modality showed a clear benefit.
Progression-free survival (PFS) did not differ significantly between groups, with medians of 16.9 months for proton therapy and 13.7 months for photons. Local progression rates were also similar, at about 20% for both treatments. The trial’s design aimed to deliver high radiation doses safely, but only 58% of proton therapy patients received the highest planned dose.
Proton therapy did reduce exposure to uninvolved liver tissue, which translated into fewer severe side effects. Grade 3 or higher treatment-related adverse events occurred in 24% of photon patients versus 11% in the proton group. The most common side effect was decreased lymphocyte counts, reported in 10 in the photon group and 3 in the proton arm.
Investigators had hypothesized that proton therapy would improve survival by limiting damage to healthy liver tissue. However, photon therapy outperformed expectations, likely due to advances in systemic therapies, particularly immune checkpoint inhibitors. The trial’s lead author, Theodore Hong of Dana-Farber Cancer Institute, noted that photon therapy’s success challenged assumptions about proton therapy’s advantages.
Subgroup analysis identified three key factors influencing survival: CTP grade (A5 vs. B7), presence of tumor vascular thrombus, and treatment/tumor size interaction. The latter suggested that proton therapy may not benefit all patients equally.
One unexpected finding was photon therapy’s superiority for larger tumors, where protons had been expected to perform better. The trial’s design required balancing tumor dose, liver dose, and tumor volume, which may have limited proton therapy’s ability to deliver higher doses.
The study included patients with up to three tumors and allowed prior treatments like chemotherapy, surgery, or ablation. Treatment was delivered in either five or 15 fractions, with most patients (59%) receiving the longer schedule. The trial’s interim analysis led to early termination due to a hazard ratio of 1.3, which met futility criteria.
