A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC).

BACKGROUND: Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. METHODS: Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. DISCUSSION: The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. TRIAL REGISTRATION: anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

Hepatocellular carcinoma (HCC) is changing its face: analysis of the temporal trends in aetiology and clinical patterns of HCC in South Australia.

BACKGROUND: The epidemiology of chronic liver disease is changing with the introduction of potent antiviral therapies for chronic hepatitis C virus (HCV) and the increasing prevalence of non-alcoholic steatohepatitis (NASH). AIM: To establish the impact of this change on the rates and clinical patterns of hepatocellular carcinoma (HCC) in South Australia (SA). METHODS: Newly diagnosed HCC patients from January 2014 until December 2019 from four tertiary centres in SA were included. The overall age-standardised incidence rates (ASIR) of HCC were calculated using 2016 SA population as the standard. To assess the trends, Join-Point regression models were used to calculate the average annual percentage change (AAPC). Forecasting of overall and aetiology-specific HCC from 2020 to 2024 was performed using linear regression. RESULTS: There were 626 new cases of HCC in SA (males 80%; median age 64 years) during the study period. There was a significant increase in NASH-related HCC (AAPC: +7.0%; P < 0.05) from 2014 to 2019. However, there were no significant differences in the ASIR for overall HCC (AAPC: -4.1%), HCV-related HCC (AAPC: -8.0%) and stage of HCC diagnosis (AAPC: +3.0%; P > 0.05). Forecasting analysis projected the decline and increase in the incidence of HCV and NASH-related HCC, respectively, over the next few years. CONCLUSION: Overall ASIR of HCC has plateaued in SA. However, NASH-related HCC has increased significantly and is expected to continue to increase in the near future. Further research and intervention is required to reduce NASH-related HCC, a major contributor to the current and future burden of HCC.

High rates of treatment stage migration for early hepatocellular carcinoma and association with adverse outcomes: An Australian multicenter study.

Background and Aim: The rate of contraindications to percutaneous ablation (PA) for inoperable early hepatocellular carcinoma (HCC) and subsequent outcomes is not well described. We investigated the prevalence and outcomes of inoperable early HCC patients with contraindications to PA, resulting in treatment stage migration (TSM). Methods: Barcelona Clinic Liver Cancer (BCLC) 0/A patients diagnosed between September 2013 and September 2019 across five hospitals were identified. Primary endpoint was proportion of BCLC 0/A HCCs with contraindications to PA. Secondary endpoints included overall survival (OS), local tumor control (LTC), and recurrence-free survival (RFS). The causal effects of PA versus TSM were assessed using a potential outcome means (POM) framework in which the average treatment effects (ATEs) of PA were estimated after accounting for potential selection bias and confounding. Results: Two hundred twenty patients with inoperable BCLC 0/A HCC were identified. One hundred twenty-two patients (55.5%) had contraindications to PA and received TSM therapy, 98 patients (44.5%) received PA. The main contraindication to PA was difficult tumor location (51%). Patients who received TSM therapy had lower median OS (2.4 vs 5.3 years), LTC (1.0 vs 4.8 years), and RFS (0.8 vs 2.9 years); P < 0.001, respectively, compared with PA. The ATE for PA versus TSM yielded an additional 1.11 years (P = 0.019), 2.45 years (P < 0.001), and 1.64 years (P < 0.001) for OS, LTC, and RFS, respectively. Three-year LTC after PA was suboptimal (65%). Conclusion: Our study highlights high rates of contraindication to PA in early HCCs, resulting in TSM and poorer outcomes. The LTC rate for PA appears suboptimal despite being considered as curative therapy. Both findings support the exploration of improved treatment options for early HCCs.

Stereotactic body radiotherapy in the management of hepatocellular carcinoma: An Australian multi-institutional patterns of practice review.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) is an emerging, therapeutic option in the management of hepatocellular carcinoma (HCC). A multicentre Liver Ablative Stereotactic Radiation (LASR) database was established to provide a collaborative platform for Australian institutions to define the practice of liver SBRT for HCC. This study explores the patterns of SBRT practice amongst Australian institutions. METHODS: This was a multi-institutional retrospective study of patients treated with SBRT for HCC at 10 institutions between January 2013 and December 2019. Patients' demographics, disease characteristics and SBRT details were evaluated. RESULTS: Three hundred and seventeen patients were evaluated with a median age of 67 years (range, 32-90). Liver cirrhosis was present in 88.6%, baseline Child-Pugh score was A5/6 in 85.1% and B7/8 in 13.2%. Median size of HCC treated was 30 mm (range, 10-280). 63.1% had early-stage disease (Barcelona clinic liver cancer (BCLC) stage 0/A) and 36% had intermediate/advanced-stage disease (BCLC B/C). In 2013/2014, six courses of SBRT were delivered, increasing to 108 in 2019. SBRT was prescribed in five fractions for 71.3% of the cohort. The most common dose fractionation schedule was 40 Gy in five fractions (24.3%). Median biologically effective dose (BED10 ) delivered was 85.5 Gy for early-stage and 60 Gy for intermediate/advanced disease, respectively. The most common prescription range was 100-120 Gy BED10 (32.8%). CONCLUSION: SBRT utilisation for HCC is increasing in Australia. There was wide variation in size of tumours and disease stages treated, and prescription patterns. Uniform reporting of clinical and dosimetric details are important in refining the role of liver SBRT.