Potential of isotoxic dose escalation with robustly optimized VMAT and IMPT for large hepatocellular carcinoma according to baseline liver function.
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BACKGROUND: Large hepatocellular carcinoma (HCC) adjacent to gastrointestinal (GI) organs presents a constrained radiotherapy problem because dose escalation is limited by both hepatic reserve and serial-organ tolerance. Although intensity-modulated proton therapy (IMPT) can reduce uninvolved liver irradiation, its achievable advantage over volumetric modulated arc therapy (VMAT) may depend on baseline liver function and robustness to treatment uncertainties. PURPOSE: To present and demonstrate a robust isotoxic dose-escalation framework for evaluating IMPT and VMAT in large HCC adjacent to GI organs while accounting for baseline liver function and treatment uncertainty. METHODS: Thirteen patients with HCC (equivalent tumor diameter, 3.0-20.9 cm) underwent comparative IMPT and VMAT treatment planning. Robust optimization incorporated 5-mm setup uncertainty for both modalities and 3% range uncertainty for IMPT. Dose escalation was performed using a fixed dose per fraction of 3.87 Gy while varying the maximum acceptable number of fractions, Nmax, under non-cirrhotic, Child-Pugh A (CP-A), and Child-Pugh B (CP-B) liver-function assumptions. Liver mean dose constraints were evaluated on nominal dose, while serial-organ constraints were assessed using both nominal dose and voxel-wise maximum dose across uncertainty scenarios. Unirradiated liver volume normalized to standard liver volume (ULV/SLV) was used to estimate the relative hazard of radiation-induced liver disease (RILD). RESULTS: In the nominal-dose analysis, IMPT achieved a higher Nmax than VMAT in 5 of 13, 8 of 13, and 8 of 13 patients under non-cirrhotic, CP-A, and CP-B assumptions, respectively, with mean ΔNmax values of 0.38, 1.23, and 1.69 fractions. Similar trends were observed in the voxel-wise maximum-dose analysis, where mean ΔNmax values were 0.00, 1.08, and 1.77 fractions, respectively. VMAT dose escalation was predominantly limited by mean liver dose, whereas IMPT was more frequently constrained by GI maximum-dose limits, indicating a shift from liver reserve to serial-organ tolerance as the primary limiting factor. Among patients with an IMPT dose-escalation advantage, IMPT maintained higher ULV/SLV and correspondingly lower estimated RILD hazard despite treatment escalation. CONCLUSIONS: IMPT provides greater isotoxic dose-escalation potential than VMAT for selected patients with large HCC, particularly when impaired baseline liver function causes photon therapy to be limited by mean liver dose. The proton advantage is ultimately constrained by robust GI organ-at-risk tolerances, emphasizing the importance of integrating baseline liver function, liver reserve, and uncertainty-aware serial-organ evaluation into modality selection and treatment planning.