Long-Term Results of a Multi-Institutional Phase II Study of Hypofractionated Proton Beam Irradiation of Unresectable Primary Liver Tumors

Purpose/Objective(s)To report the long-term outcomes of a prospective, multi-institutional phase II trial of hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).Materials/MethodsThis single-arm, phase II, multi-institutional study enrolled 92 patients with localized, unresectable, biopsy-confirmed HCC or ICC with a Child-Turcotte-Pugh score (CTP) of A or B, and ECOG performance status of 0 to 2, to receive proton radiotherapy to a maximum dose of 67.5 GyRBE in 15 fractions. Overall survival (OS) and progression-free survival (PFS) rates were estimated using the Kaplan-Meier method.ResultsThe patient characteristics, treatment techniques, and two-year outcomes have been previously reported on the 83 evaluable patients in this trial, including 44 with HCC and 39 with ICC who at that time had a median follow-up of 19.5 months. This updated analysis includes a median follow-up of 60.8 months (range 10.3–121.5) and 45.9 months (range 31.1–49.5) among the survivors with HCC and ICC, respectively. For those with HCC, the 5-year OS rate was 25.9% (95% CI 0.13-0.40), with a median OS of 29.2 months. For those with ICC, the 5-year OS rate was 12.3% (95% CI 0.03–0.27), with a median OS of 20.8 months. The 5-year PFS rate was 23.4% (95% CI 0.092-0.41) in HCC and 11.0% (95% CI 0.030-0.25) in ICC. As previously reported, two patients (6.8%) with HCC recurred locally, both within 2 years of treatment, and there were no further local failures. Among the patients with ICC, only one additional local failure occurred, for a total of 7/39 patients (17.9%), with a median time to recurrence of 26.1 months (range 5.5–42.3 months). All patients with local failure had CTP A scores, with a median tumor size of 5.8 cm (range 3.5–7.6 cm). The median radiation dose received by those who had a local recurrence was 58.0 GyRBE (range 45.0–67.5). Local failures occurred in 12.3% (7/57) of patients who received a BED less than 80.5 Gy and in 7.7% (2/26) of those who received a BED greater than 80.5 Gy. Distant failures, including intrahepatic non-local failures, occurred in 56.8% (25/44) of patients with HCC with a median time to progression of 10.2 months (range 2.7–63.6). In those with ICC, distant failures occurred in 61.5% of patients (24/39), with a median time to progression of 5.8 months (range 0.4–68.4). There were no grade 3 or greater late toxicities, including no late biliary toxicity.ConclusionHypofractionated proton beam therapy is associated with durable, high rates of local control for both HCC and ICC, however, distant failures are common and remain a challenge. There were no significant late adverse effects, including no late biliary obstruction. Future strategies to incorporate radiation and systemic therapies, including immunotherapy, should be explored to further improve the long-term outcomes of HCC and ICC.