Proton Beam Therapy for HCC Exceeding up-to-Seven Criteria

Abstract

Whilst standard treatment for intermediate-stage hepatocellular carcinoma (HCC) is transcatheter arterial chemoembolization (TACE), those exceeding "up-to-seven" criteria don't respond as such as those within, and systemic therapy is suggested to be more beneficial. This is sought to be both because of the limited efficacy of TACE and its hepatic toxicity. Proton beam therapy (PBT) offers high local control and low toxicity rates, and we hypothesize that the same can be said in this patient group also. We here present the outcome of PBT for primary HCC exceeding "up-to-seven" criteria. Primary HCC treated with PBT between 2010 and 2018 were extracted from an all-in treatment database and retrospectively reviewed. (Maximum diameter of the largest tumor in centimeters) + (tumor count) > 7 was considered as exceeding "up-to-seven" criteria. Local recurrence was defined as tumor re-enlargement or the appearance of arterial phase hyperenhancement. Adverse events were evaluated by CTCAE v5.0. Overall survival and recurrence-free survival were determined by the Kaplan-Meier method, and local recurrence was analyzed as cumulative incidence with death as a competing risk. All statistical analyses were done using R. Out of 202 primary cases, 79 exceeded the "up-to-seven" criteria. The median tumor diameter was 8.0 cm (range 3.1 - 20 cm) and macroscopic vascular invasion (MVI) was observed in 26 cases. For tumor count, 36 were solitary, 28 were between 2 - 3, and 15 had 4 or more. According to the modified ALBI grade, 38 were grade 1, 18 were grade 2a and 23 were 2b. The prescribed dose was 66 Gy / 10 Fr for 6, 72.6 Gy / 22 Fr for 60, 74 Gy / 37 Fr for 12 and 60 Gy / 15 Fr for one case after relative biological effect weighting of 1.1. With a median follow-up period of 33 months (IQR 15 - 57 months), 2-year overall survival was 62% (95% C.I. 50 - 72%) and median survival time was 37 months (95% C.I. 30 - 52 months). 2-year recurrence-free survival and local recurrence rate were 42% (95% C.I. 30 - 53%) and 8% (95% C.I. 3 - 15%) respectively. Cox regression analysis revealed modified ALBI grade as the only significant risk factor for survival (hazard ratio 1.80, 95% C.I. 1.27 - 2.55, p = 0.0010) among age, sex, alpha-fetoprotein level, MVI, tumor count, and size. Other than one case of early death (2 weeks after treatment) with an unknown causal relationship, there were no adverse events of grade 4 or higher observed. PBT for primary HCC exceeding "up-to-seven" criteria appears to be safe and effective. Local control of intrahepatic lesions may be beneficial even in intermediate-stage cases, while results of this study suggests that suppression of out-of-field recurrence is required for further survival prolongment.