Clinical and Dosimetric Results of Proton or Photon Radiation Therapy for Large (>5 cm) Hepatocellular Carcinoma: A Retrospective Analysis

Abstract

Purpose: To report the clinical and dosimetric attributes of patients with large unresectable hepatocellular carcinoma (HCC) undergoing proton or photon radiotherapy. Methods: We retrospectively analyzed the outcomes and dosimetric indices of 159 patients with >5 cm non-metastatic HCC who underwent definitive radiotherapy using either protons (N=105) or photons (N=54) between 2014 and 2018. Additional photon plans were performed in the 105 proton-treated patients using the same dose prescription criteria for intragroup dosimetric comparison. Results: After a median follow-up of 47 months, patients with biologically effective dose (BED10) ≥75 Gy exhibited significantly better local control (LC, 2-year: 85.6% vs. 20.5%, P<0.001), progression-free survival (PFS, median 7.4 vs. 3.2 months, P<0.001), and overall survival (OS, median 18.1 vs. 7.3 months, P<0.001) compared to those with BED10 <75 Gy. Notably, proton-treated patients had a significantly higher BED10 (96 vs. 67 Gy, P<0.001) and improved LC (2-year: 88.5% vs. 33.8%, P<0.001), PFS (median 7.4 vs. 3.3 months, P=0.001), and OS (median 18.9 vs. 8.3 months, P<0.001) than those undergoing photon radiotherapy. Furthermore, patients treated with protons had significantly lower V1 of the liver (P<0.001), mean upper gastrointestinal (UGI) tract dose (P<0.001), and mean splenic dose (P<0.001), with significantly decreased incidences of radiation-induced liver disease (P=0.007), grade ≥3 UGI bleeding (P=0.001), and grade ≥3 lymphopenia (P=0.003). On multivariate analysis, proton radiotherapy consistently correlated with superior LC (P<0.001), PFS (P<0.001), and OS (P<0.001). In intragroup dosimetric comparison, photon plans demonstrated significantly higher mean liver dose (MLD, P<0.001) compared with actually delivered proton treatments, and 72 (69%) of them had MLD exceeding 28 Gy which necessitated target dose de-escalation. Conclusions: In the context of large HCC radiotherapy, a higher target BED10 was associated with improved outcomes. Notably, proton therapy has demonstrated the capability to deliver ablative doses while also being accompanied by fewer instances of severe toxicity.