NRG-GI003 Phase III Trial Shows No Overall Survival Benefit for Proton Over Photon Radiotherapy in Advanced HCC

The randomized trial enrolled 115 patients with advanced HCC, stratifying by fraction number and vascular thrombosis before assigning proton or photon radiotherapy at doses of 30-67.5 Gy. Primary endpoint overall survival showed no advantage for protons, with 24-month rates of 56.2% versus 69.3% for photons. Secondary endpoints including progression-free survival and local progression were also equivalent, though grade 3+ adverse events trended lower with protons (11% vs 24%, p=0.09). These results indicate local control is achievable in advanced HCC but systemic progression limits survival gains from either modality.

In the context of advanced HCC, where systemic therapies such as atezolizumab-bevacizumab now set the survival benchmark, radiotherapy serves mainly as a local consolidative tool rather than a primary disease-modifying intervention. The absence of survival difference aligns with prior observational series showing equivalent local control between protons and photons once dose and fractionation are matched. The numerically lower toxicity with protons may still matter for patients with borderline liver function, yet the trial was underpowered to confirm this difference. Practical implications favor photon therapy for most patients unless proton centers can demonstrate clear quality-of-life gains in ongoing analyses.

Future studies should prioritize biomarker-selected subgroups, such as those with solitary lesions and preserved liver function, and integrate radiotherapy with modern systemic agents. Quality-of-life endpoints and cost-effectiveness comparisons will determine whether proton therapy retains any role outside research protocols. The trial underscores that HCC is radiosensitive locally, shifting research away from modality comparisons toward optimal sequencing with immunotherapy.