Stereotactic body radiotherapy for hepatocellular carcinoma: Five-year prospective registry outcomes from an Australian tertiary transplant centre

Abstract

BACKGROUND

Stereotactic body radiotherapy (SBRT) has emerged as a promising treatment modality for hepatocellular carcinoma (HCC), offering precise high-dose radiation delivery while preserving liver function. However, real-world prospective data from transplant centres, particularly regarding bridging and salvage applications, remain limited. We hypothesised that SBRT would achieve durable local control with acceptable toxicity across diverse clinical indications in a real-world tertiary transplant-centre cohort.

AIM

To evaluate efficacy and safety of SBRT for HCC in a prospective cohort at a tertiary transplant centre.

METHODS

We conducted a prospective, single-centre registry of consecutive HCC patients treated with SBRT between August 2016 and June 2022. The primary endpoint was local control. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and treatment-related toxicity.

RESULTS

With a median follow-up of 23.6 months, 58 patients received 60 SBRT courses for 64 HCC lesions. Most were male (81%), cirrhotic (93.1%) and Child-Pugh A disease (74.1%). Barcelona Clinic Liver Cancer stages were 0/A in 43%, B in 40%, and C in 17%. Most patients (90%) had received prior locoregional treatment. The median prescribed biologically effective dose was 72 Gy, most commonly 40 Gy in 5 fractions. One- and two-year local control rates were 90% and 85%, OS 80% and 60%, and PFS 55% and 40%, respectively. Isolated local failure occurred in 13.3%, while intrahepatic and extrahepatic progression occurred in 35% and 13%. Treatment completion was 98%, with no grade ≥ 3 toxicities.

CONCLUSION

SBRT achieved durable local control with minimal toxicity for HCC, supporting its role as an effective liver-directed treatment option across curative, bridging and salvage clinical settings.

Key Words: Hepatocellular carcinoma; Stereotactic body radiotherapy; Liver-directed therapy; Local control; Treatment toxicity; Prospective registry; Bridging therapy; Salvage treatment

Core Tip: The role of stereotactic body radiotherapy (SBRT) in hepatocellular carcinoma is evolving within contemporary treatment guidelines. In this prospective real-world registry, SBRT achieved durable local control with minimal toxicity across curative, bridging-to-transplant, and salvage indications, including patients with impaired liver function and advanced disease. Despite excellent in-field control, out-of-field intrahepatic progression was the dominant failure pattern, highlighting the importance of integrating SBRT within multidisciplinary, stage-adapted treatment pathways.

INTRODUCTION

Hepatocellular carcinoma (HCC) remains the most common primary liver malignancy and the third leading cause of cancer-related death worldwide, with over 900000 new cases diagnosed annually[1]. The epidemiology of HCC continues to evolve, with rising incidence in Western countries attributable to metabolic dysfunction-associated steatotic liver disease and alcohol-related cirrhosis, while viral hepatitis remains the predominant aetiology in endemic regions of Asia and sub-Saharan Africa[1,2]. This evolving disease burden combined with frequent late-stage presentation, highlights the critical need for effective local therapies across diverse clinical scenarios.

The management of HCC is complex as clinicians must address both the malignancy itself and consider implications of treatment on patients’ liver function. While the Barcelona Clinic Liver Cancer (BCLC) staging system is a widely adopted guide for treatment especially in the West, real-world data suggest that 30%-50% of patients are unsuitable for recommended first-line therapies due to tumour location, vascular proximity, comorbidities, or inadequate hepatic reserve[3]. While surgical resection and liver transplantation remain potentially curative for early-stage HCC, only 20%-30% of patients present with BCLC 0/A disease amenable to these approaches[3,4]. Moreover, HCC patients face waitlist dropout rates of 18%-30% due to tumour progression, highlighting the potential for bridging strategies to maintain transplant eligibility[4,5].

Stereotactic body radiotherapy (SBRT) has emerged as a promising non-invasive local therapy that addresses many limitations of conventional HCC treatments. Unlike conventional radiotherapy, SBRT delivers precisely targeted, ablative radiation doses [typically biologically effective dose (BED₁₀), > 60-100 Gy] in a limited number of fractions, achieving a sharp dose gradient that minimises exposure to functional liver parenchyma.

The therapeutic efficacy of SBRT in HCC is mediated through several complementary biological mechanisms that distinguish it from conventional fractionated radiotherapy[6]. The delivery of ablative radiation doses (typically BED₁₀ > 60 Gy) causes irreparable DNA double-strand breaks that exceed tumour cell repair capacity, resulting in cell death. Radiation doses exceeding 8 Gy to 10 Gy per fraction also trigger endothelial cell apoptosis, leading to microvascular thrombosis and ischaemic tumour necrosis[7]. This vascular effect is particularly relevant in HCC given its dependence on arterial blood supply. Additionally, SBRT promotes immunogenic cell death, that can stimulate antitumour immune responses[8,9]. This “abscopal” potential is the basis for ongoing trials combining SBRT with immune checkpoint inhibitors. Hepatic regeneration is impaired in the cirrhotic liver so the steep dose gradient of SBRT allows the surrounding liver function to be largely spared despite focal ablative doses within the target volume. This approach is particularly useful for patients with underlying liver dysfunction, including early Child-Pugh B cirrhosis, and those with centrally located tumours where surgical resection or other local therapies may not be feasible[10,11].

SBRT for HCC is supported by a growing body of prospective and retrospective studies, including a meta-analysis, which showed 84%-95% local control rates over 1-3 years[11-14]. Despite increasing adoption, real-world efficacy data from transplant centres remain scarce, particularly regarding bridging strategies and outcomes in patients who failed prior locoregional therapies. Therefore, we evaluated the safety and efficacy of SBRT for HCC at a major Australian liver transplant centre, focusing on local control, survival outcomes, and treatment-related toxicity.

MATERIALS AND METHODS

Study design and patient selection

This study was a prospective registry cohort of consecutive patients with HCC who received SBRT at the Olivia Newton John Cancer Centre, Austin Health, from 1^st of August 2016 to 30^th of June 2022, ensuring a minimum follow-up period of two years. This study received approval from the Austin Health Research Governance Office (HREC/17/QPAH/870, HREC/CD 21/009), with individual patient consent waived due to the low-risk nature of the study. Two patients treated prior to registry establishment in 2016 were included retrospectively, given the strict clinical follow-up protocols in place. As a prospective registry of consecutive patients, no formal sample size calculations were performed. The cohort includes all eligible patients treated during the study period to minimise selection bias.

Eligible patients had HCC diagnosed by histological confirmation or imaging meeting Liver Imaging Reporting and Data System criteria[15]. Prior HCC therapies were permitted. All cases were reviewed at a multidisciplinary liver tumour meeting prior to SBRT. Indications included first-line ablative treatment when other local therapies were unsuitable, bridging to liver transplantation, planned combined therapy, and salvage treatment. Salvage SBRT was defined as treatment for persistent, residual, or recurrent tumour after previous local therapy. Patients with intrahepatic cholangiocarcinoma or secondary liver malignancies were excluded from this analysis.

Data collection

Comprehensive patient data were extracted from electronic medical records, including demographics, tumour characteristics, liver function parameters and treatment details. Key variables comprised tumour size and location, presence of vascular invasion, BCLC stage, Child-Pugh score, albumin-bilirubin (ALBI) grade, Eastern Cooperative Oncology Group performance status, prior liver-directed therapy, SBRT intent and dose fractionation schedules. All data were de-identified and securely stored using a standardised REDCap database (Research Electronic Data Capture, version 13.1)[16].

SBRT treatment protocol

All patients underwent quad-phase contrast-enhanced computed tomography (CT) simulation with immobilisation in a Civco BodyFIX™ vacuum bag for reproducible positioning. Respiratory motion management was achieved through breath-hold and free-breathing techniques. Breath-hold treatments preferentially used exhale breath hold using the Elekta ABC™ device (Elekta, Stockholm). Free-breathing treatments were simulated using 4-dimensional CT (4DCT) for motion assessment. Diagnostic magnetic resonance imaging (MRI) was rigidly registered for target delineation when available.

Gross tumour volume (GTV) was defined as the visible tumour on contrast-enhanced CT and/or MRI. The planning target volume (PTV) for breath-hold patients was a 5 mm isotropic expansion except for 7 mm in the cranio-caudal dimensions to account for setup uncertainties and internal organ motion. Free-breathing PTV expansion was measured from the liver or surrogate volume [e.g., transarterial chemoembolisation (TACE) cavity] motion on 4DCT with a small 3-5 mm additional margin to account for non-respiratory uncertainty.

Dosimetry was calculated using Monaco 5™ Elekta Stockholm using isotoxic dose prescription strategy ensuring ≥ 98% PTV coverage while respecting normal organ constraints. This isotoxic approach individualises the prescribed dose for each patient based on tumour size, proximity to organs at risk (OARs), and baseline liver function, aiming to deliver the highest achievable dose while maintaining safety. For liver dose constraints, a minimum of 700 cc of uninvolved liver received less than 15 Gy, while mean liver dose was kept between 13-15 Gy for Child-Pugh A and 6-7 Gy for Child-Pugh B patients, following established protocols[10,17]. Due to various dose fractionation schedules used, BED₁₀ was used for tumour dosimetric reporting.

All patients were treated using volumetric modulated arc therapy with daily image guidance using cone-beam CT (CBCT). For breath hold, stop-and-go CBCT was acquired, with post-correction CBCT. Free-breathing treatments were performed using 4D-CBCT with matching to the exhale phase. Mid-treatment imaging was performed routinely, with 0 mm tolerance for first fractions and 3 mm shift tolerance for subsequent treatments.

Follow-up and assessment

Patients underwent cross-sectional imaging (multiphase MRI or CT) every 3 months for 2 years, then every 6 months until year 5 if in complete response, along with liver function tests and serum alpha-fetoprotein. Changes in tumour burden were assessed using revised Response Evaluation Criteria in Solid Tumours v1.1. Local progression was defined as tumour recurrence within or at the PTV margin. Out-of-PTV disease progression was recorded as distant intrahepatic progression or extrahepatic progression.

Common terminology criteria for adverse events version 4 were used to grade any toxicities. Child-Pugh scores were assessed at each follow-up, with changes at 3 months, 6 months and 12 months analysed to evaluate changes in liver function.

Treatment outcomes are reported per SBRT course (n = 60) unless otherwise specified. For patients who received more than one course of SBRT, each course was analysed separately for local control and progression-free survival (PFS), while overall survival (OS) was calculated from the first SBRT course.

Statistical analysis

The primary endpoint was local control, with secondary endpoints including PFS, OS and toxicity. Time-to-event outcomes were measured from the start of SBRT to progression, death, or last follow-up. Patients who received liver transplantation were censored at the date of transplant, and all survival data were censored at last follow-up with a data cutoff of 20^th January 2025.

Continuous variables are reported as median with interquartile range (IQR) and categorical variables as n (%). Survival outcomes were evaluated using the Kaplan-Meier method, with subgroup analyses by BCLC stage, ALBI class, Child-Pugh score and dose fractionation (BED₁₀). Due to small subgroup size and non-proportional hazards, statistical significance testing was not performed for survival comparisons. Local control was analysed as a first-event endpoint using competing risk analysis, with death and distant progression (intrahepatic or extrahepatic) as competing events. Data analysis was performed using Stata/BE version 18.5.

RESULTS

Patient and tumour characteristics

Between August 2016 and June 2022, 58 patients received a total of 60 SBRT courses treating 64 HCC lesions. Most treatments targeted single lesions (56 courses, 93.3%), while four patients received concurrent treatment for two lesions. Two patients underwent sequential SBRT courses for separate metachronous intrahepatic diseases developing after initial treatment.

The baseline patient characteristics are detailed in Table 1. The median age at treatment was 66.5 years (IQR 60-74), with male predominance (81.0%). Underlying cirrhosis was present in 54 patients (93.1%), with hepatitis C representing the most common aetiology (41.4%), followed by alcohol-related liver disease (32.8%). Most patients had preserved liver function with Child-Pugh A disease (74.1%). Eleven patients (19.0%) had Child-Pugh B cirrhosis, including six patients (10.3%) with Child-Pugh B8 disease. The median model for end-stage liver disease (MELD) score was below 10 in 48.3% of patients, with four patients (6.9%) having scores exceeding 20, primarily driven by elevated serum creatinine. ALBI grade was predominantly grade 2 disease (74.1%), with 22.4% having grade 1 and only 2 patients (3.4%) having grade 3 disease.

Table 1 Patient characteristics at baseline, n (%).

Variable	n = 58
Median age (IQR)	66.5 (60-74)
Gender
Male	47 (81.03)
Female	11 (18.97)
ECOG
0	52 (89.66)
1	3 (5.17)
2+	3 (5.17)
Liver cirrhosis
No	4 (6.90)
Yes	54 (93.10)
Pre-existing liver disease
HBV	9 (15.52)
HCV	24 (41.38)
EtOH	19 (32.76)
MASLD	14 (24.14)
Other	2 (3.45)
Unsure/unknown	2 (3.45)
Nil	2 (3.45)
Child-Pugh status
5	20 (34.48)
6	23 (39.66)
7	5 (8.62)
8	6 (10.34)
ALBI
Grade 1	13 (22.41)
Grade 2	43 (74.14)
Grade 3	2 (3.45)
MELD
< 10	28 (48.28)
10-19	26 (44.83)
> 20	4 (6.90)

ECOG: Eastern Cooperative Oncology Group; HBV: Hepatitis B virus; HCV: Hepatitis C virus; EtOH: Alcohol-related liver disease; MASLD: Metabolic dysfunction-associated steatotic liver disease; ALBI: Albumin-bilirubin; MELD: Model for end-stage liver disease; IQR: Interquartile range.

Most patients had prior locoregional treatments (90%), most commonly TACE in 85%. Tumour stages according to BCLC system were 0/A in 43.3%, B in 40.0%, and C in 16.7%. The median maximum diameter of the largest lesion was 24.5 mm (IQR 17.5-35.0 mm), with portal vein tumour thrombus present in 10% of cases. Baseline serum alpha-fetoprotein levels had a median of 7.5 ng/mL (IQR 3.2-20.1), ranging from 1 ng/mL to 758 ng/mL, with 26 patients (43.3%) having above 10 ng/mL (Table 2).

Table 2 Tumour characteristics and stereotactic body radiotherapy parameters (n = 60 treatment courses), n (%)/interquartile range.

Variable	n = 60
BCLC stage
Stage 0	10 (16.67)
Stage A	16 (26.67)
Stage B	24 (40.00)
Stage C	10 (16.67)
Vascular invasion	6 (10.00)
Reason for SBRT
First-line curative ablation	2 (3.33)
Salvage curative ablation	13 (21.67)
Bridge to liver transplant	13 (21.67)
Alternative to TACE/SIRT/sorafenib	7 (11.67)
In combination with TACE	15 (25.00)
Non-ablative treatment of recurrence after prior locoregional therapies	10 (16.67)
Prior HCC treatment
TACE	51 (85.00)
RFA/microwave	18 (30.00)
Resection	2 (3.33)
SIRT	2 (3.33)
Percutaneous ethanol injection	2 (3.33)
No prior treatment	6 (10.00)
Motion management
Exhale breath-hold	32 (53.33)
Inhale breath-hold	18 (30)
Free breathing	10 (16.67)
Dose fractionation
40 Gy in 5 fractions	27 (45.00)
30 Gy in 5 fractions	10 (16.70)
50 Gy in 5 fractions	5 (8.30)
40 Gy in 6 fractions	4 (6.45)
35 Gy in 5 fractions	4 (6.45)
Other schedules	10 (16.70)
Median BED10 prescription dose (Gy)	72 (53.25-72.00)
Maximum tumour diameter (mm)	24.5 (18-35)
GTV volume (cc)	4.83 (2.87-14.73)
PTV volume (cc)	21.82 (14.66-48.91)
PTV D95 (Gy)
First lesion	66.3 (49.00-73.40)
Second lesion (n = 4)	67.60 (58.96-72.82)
PTV Dmin
First lesion	61.42 (45.93-71.33)
Second lesion (n = 4)	68.47 (57.97-73.07)
PTV Dmax
First lesion	106.19 (76.21-112.58)
Second lesion (n = 4)	113.72 (109.67-130.09)
Liver-GTV (cc)	1560.9 (1156.80-2015.20)
Mean dose to liver-GTV (Gy)	4.56 (3.06-6.33)
Liver-GTV volume (cc) < 15 Gy	1146 (944-1431)
OAR limiting dose
Liver	9 (15.00)
Stomach/oesophagus	3 (5.00)
Small bowel	1(1.67)
Large bowel	1 (1.67)
Central bile ducts	9 (15.00)
Heart	7 (11.67)
Other (chest wall, IVC and duodenum)	10 (16.67)
Patient completed prescribed course	59 (98.33)

BCLC: Barcelona Clinic Liver Cancer; SBRT: Stereotactic body radiotherapy; TACE: Transarterial chemoembolisation; SIRT: Selective internal radiation therapy; RFA: Radiofrequency ablation; BED₁₀: Biologically effective dose; GTV: Gross tumour volume; PTV: Planning target volume; OAR: Organ at risk; IVC: Inferior vena cava.

Treatment characteristics

Active motion management was employed in 83.3% of treatments, with exhale breath-hold being the predominant technique (53.3%), followed by inhale breath-hold (30.0%). Free-breathing treatment with 4DCT-based internal target volume was used for 10 patients (16.7%) unable to maintain adequate breath-hold. Fiducial markers for image guidance were used in seven patients (12.1%) with lesions poorly visualised on CBCT.

SBRT served as a first-line curative treatment in two patients (3.3%) and as an alternative to TACE or sorafenib in seven patients (11.7%). Upfront combination therapy was used in 25% of cases, where TACE and SBRT were planned together for tumours not suitable for thermal ablation but still considered for curative local treatment. Thirteen patients (21.7%) received SBRT as bridging therapy to liver transplant, of whom ten (76.9%) successfully proceeded to surgery. The three remaining patients dropped out due to myocardial infarction, new diagnosis of cholangiocarcinoma > 2 cm, and patient decision to delist, respectively. Salvage SBRT was delivered to 13 patients (21.7%), most commonly after prior TACE (85%) or radiofrequency ablation (RFA).

The predominant dose-fractionation schedule was 40 Gy in 5 fractions (45.0% of patients), followed by 30 Gy in 5 fractions (16.7%) and 50 Gy in 5 fractions (8.3%). The median BED₁₀ was 72 Gy (IQR 53.25-72 Gy). High-dose coverage was achieved across all treated lesions (Table 2 for PTV D95, D_max and D_min), including multifocal cases. OAR sparing was prioritised given the underlying liver dysfunction in this cohort. The median liver-GTV (total liver excluding the GTV) volume was 1560.9 cm³ (IQR 1156.8-2015.2 cm³), with a mean dose to the liver-GTV of 4.6 Gy (IQR 3.1-6.3 Gy). The dose-limiting OAR varied by tumour location, where liver parenchyma (15.0%), central bile ducts (15.0%), and heart (11.7%) frequently influenced dose prescription.

Treatment outcomes

Local control: With a median follow-up of 23.6 months (IQR 13.5-36.8), the 1-year and 2-year local control rates were 90% and 85%, respectively (Figure 1A). Isolated local failure was relatively low, only occurring in 8 patients (13.3%) during the study period. Among the 5 patients receiving BED₁₀ ≥ 100 Gy, local failure occurred in 1 patient (20%), compared with 7 of 55 patients (12.7%) receiving BED₁₀ < 100 Gy; however, this comparison is limited by the small number of high-dose patients. Table 3 summarises the treatment outcomes.

Figure 1 Treatment outcomes. A: Local control rates, with death and distant progression as competing events; B: Progression-free survival, with failure defined as death, distant relapse, extrahepatic failure, or local failure; C: Cumulative incidence of local failure, with death, distant intrahepatic relapse, and extrahepatic failure as competing events.

Table 3 Treatment outcomes including local control, progression patterns, and survival, n (%).

Variable	n = 60
Median follow up (months)	23.6 (13.50-36.80)
Site of first relapse
Local failure	8 (13.33)
Distant intrahepatic disease	21 (35.00)
Extrahepatic disease	8 (13.33)
Subsequent treatment for intrahepatic relapse
TACE	6
SBRT	2
OLT	2
Other	6
Systemic therapy	12
Death	34 (56.67)
Cause of death
Cancer-related death	26
Non-cancer related	5
Liver failure	2
Unknown	1

TACE: Transarterial chemoembolisation; SBRT: Stereotactic body radiotherapy; OLT: Orthotopic liver transplantation.

PFS and patterns of failure: PFS at 1 year and 2 years were 55% and 40%, respectively (Figure 1B). Out-of-field intrahepatic progression was the most common pattern of failure, occurring in 21 patients (35%). Extrahepatic progression occurred as the first site of failure in 8 patients (13.3%).

Competing risk analysis (Figure 1C) showed that the cumulative incidence of local failure plateaued at 15% by 2 years. However, distant intrahepatic relapse emerged as the dominant failure pattern (30% at 3 years), substantially exceeding both local failure and extrahepatic progression.

Following intrahepatic progression, various treatment approaches included TACE (six patients), liver transplantation (two patients), and additional local therapies such as repeat SBRT (two patients), microwave ablation (three patients), selective internal radiation therapy (SIRT; two patients), and percutaneous ethanol injection (one patient). A total of 12 patients eventually received systemic therapy, with the combination of atezolizumab and bevacizumab being the most common therapy.

In HCC cases with macrovascular invasion, all six patients progressed within 3 years, despite having received prior therapies including resection, ablation, TACE and/or SIRT. The pattern of failure following SBRT in this subgroup was predominantly systemic, with four patients developing metastatic disease (two within the first year) and two patients experiencing local recurrence.

OS: The 1-year and 2-year OS rates were 80% and 60%, respectively (Figure 2A). 34 patients (56.6%) died during the observation period, with cancer-related mortality in 26 patients (76.5%), non-cancer-related death in 5 patients (14.7%), liver failure in 2 patients (5.9%), unknown cause in 1 patient (2.9%). Both patients who died from liver failure developed widespread distant intrahepatic disease progression at 11 months and 3 years post-SBRT respectively. As these patients did not exhibit sequelae associated with radiation-induced liver disease, we concluded that deaths were likely disease-related.

Figure 2 Kaplan-Meier survival outcomes. A: Overall survival; B: Overall survival stratified by Barcelona Clinic Liver Cancer stage. BCLC: Barcelona Clinic Liver Cancer stage.

Two-year OS rates were 73% for BCLC 0/A, 62% for BCLC B, and 45% for BCLC C, though formal statistical comparison was not performed due to limited sample size (Figure 2B).

OS at 2 years was 67% for patients with baseline Child-Pugh A and 47% for those with Child-Pugh B (Figure 3A). Patients whose Child-Pugh score increased by ≥ 2 points at 3 months had a 2-year OS of 41%, compared with 66% for those with stable or minimally changed score (Figure 3B). The same pattern persisted at 6 and 12 months (Figure 3C and D).

Figure 3 Kaplan-Meier overall survival curves stratified by Child-Pugh score. A: Baseline Child-Pugh score: Child-Pugh 5-6 (Child-Pugh A) vs Child-Pugh 7-8 (Child-Pugh B); B: Child-Pugh change at 3 months (< 2 vs ≥ 2 points increase); C: Child-Pugh change at 6 months (< 2 vs ≥ 2 points increase); D: Child-Pugh change at 12 months (< 2 vs ≥ 2 points increase).

Of the six Child-Pugh B8 patients, two patients had durable local control with survival exceeding 2 years post-SBRT (including one who underwent successful liver transplantation), whereas four experienced distant progression with three cancer-related deaths and one death from unknown causes.

Toxicity: Treatment was well-tolerated, with 59 of 60 SBRT courses (98.2%) completed as prescribed. One patient voluntarily declined further treatment after receiving two of five planned fractions (16 Gy of planned 40 Gy). This patient showed stable disease in the target lesion but had developed progression elsewhere in the liver at 6-month follow-up. No grade ≥ 3 acute or late toxicities were observed.

Acute grade 2 toxicities (≤ 3 months) included fatigue in four patients (6.7%), abdominal pain in two (3.3%), and nausea in one (1.7%), all managed conservatively without treatment modification or hospitalisation. No vomiting, skin ulceration, or dermatitis was observed. Grade 2 fatigue persisted beyond 3 months in 3 patients but resolved by 12 months.

No patients experienced classic radiation-induced liver disease. Five patients (8.3%) experienced a clinically significant decline in liver function (Child-Pugh score increase ≥ 2) at 6 months. These patients had baseline Child-Pugh scores of 5 to 6, ALBI grade 2, and MELD scores between 8 and 17. The liver mean doses received ranged from 3.9 Gy to 6.8 Gy and there were no treatment-related deaths. Among these patients, four had disease progression (three with distant intrahepatic progression and one with isolated local progression). The fifth patient had a baseline MELD score of 17 and died from extrahepatic disease more than three years after SBRT. No long-term radiation-related complications, including gastrointestinal ulceration, biliary stricture, or chest wall toxicity, were observed during the follow-up period.

Exploratory prognostic analysis

Univariable Cox regression results are presented in Supplementary Table 1. For OS, BCLC stage showed a stepwise increase in mortality risk relative to stage 0 [hazard ratio (HR) 3.87, 95% confidence interval (CI): 1.27-11.80, P = 0.017]. Tumour size (HR 1.34 per 10 mm, 95%CI: 1.06-1.70, P = 0.016) and vascular invasion (HR 2.68, 95%CI: 1.00-7.14, P = 0.049) were also predictors of OS. Neither ALBI grade, Child-Pugh score, nor BED₁₀ were significantly associated with OS. For PFS, vascular invasion (HR 2.96, 95%CI: 1.23-7.11, P = 0.015) and BCLC stage C (HR 3.51, 95%CI: 1.26-9.78, P = 0.016) were significant predictors. Multivariable Cox regression was not performed due to insufficient number of outcome events relative to predictors.

DISCUSSION

Our experience at a high-volume Australian liver transplant centre showed that SBRT achieved very good local control with minimal toxicity across a clinically heterogenous HCC population, including patients treated with curative intent, as bridging to liver transplantation, and in salvage settings following prior locoregional therapy. These findings reflect contemporary clinical practice, where SBRT is increasingly utilised when guideline-recommended options are infeasible, contraindicated, or have failed. Despite excellent local tumour control, distant intrahepatic progression remained the dominant pattern of failure, highlighting that SBRT is an effective liver-directed treatment but must be integrated within multidisciplinary, stage-adapted management pathways to optimise long-term outcomes.

Local control and dose considerations

We observed 90% at 1 year and 85% at 2 years with conservative dosing strategy (median BED₁₀ of 72 Gy), comparable to published series reporting 80%-100% local control over 1-3 years[18-20]. Our institutional approach favoured conservative prescription strategy (median BED₁₀ 72 Gy), informed by early experience and the high prevalence of cirrhosis. Meta-analyses consistently demonstrated improved control for smaller tumours and with dose escalation, though the optimal ablative dose remains undefined[11,21]. While retrospective studies suggest BED₁₀ ≥ 100 Gy may improve outcomes, dose escalation is constrained by risk of gastrointestinal toxicity, particularly for perivascular or central lesions[22,23]. A formal dose-response analysis was not performed in our cohort as only 5 patients (8.3%) received BED₁₀ ≥ 100 Gy and dose selection was determined by tumour location and liver function rather than randomisation, with patients receiving lower dose typically having more adverse tumour or liver function. Nevertheless, the high local control achieved with moderate doses supports that durable control is attainable at moderate doses with meticulous motion management and isotoxic planning. BED₁₀ was not significantly associated with OS or PFS on univariate analysis, likely reflecting the narrow dose range and confounding isotoxic prescription in this cohort.

Toxicity profile

SBRT was well tolerated, with 98.3% of patients completing their prescribed course and no grade ≥ 3 acute toxicities observed. None of the eleven Child-Pugh B7/8 patients experienced significant liver function deterioration, likely due to our conservative liver dose constraints (mean liver dose 6-7 Gy vs 13-15 Gy for Child-Pugh A).

The small subset (8.3%) of patients experienced a ≥ 2-point Child-Pugh score increase within 6 months. These cases occurred primarily in the setting of intrahepatic progression, suggesting that liver decompensation was more likely attributable to tumour progression rather than radiation-induced hepatotoxicity.

Rates of subacute or chronic liver toxicity from SBRT remain low in modern practice, typically < 10% in prospective and large retrospective series, which aligns with our findings[10-13]. As we did not observe classic radiation-induced liver disease, our results suggest that carefully selected Child-Pugh B7/8 patients may still benefit from definitive radiation with appropriate dose constraints.

Baseline Child-Pugh score showed numerical differences in survival outcomes in our cohort, consistent with literature demonstrating impaired liver function correlates with inferior survival regardless of local tumour control[23,24].

Clinical applications: Salvage therapy, bridging and combination therapy

In our cohort, SBRT was utilised in several clinical scenarios. Salvage SBRT was delivered to 13 patients (21.7%), after prior TACE (n = 9) or RFA/resection (n = 4), with all patients achieving local control. In non-ablative salvage for recurrences where the goals shift towards disease stabilisation and deferral of systemic therapy, isolated local failure occurred in only one patient. Among intermediate-stage BCLC B patients treated after TACE failure or when repeat TACE was infeasible, no in-field recurrences occurred, and failures were limited to distant intrahepatic progression. A recent meta-analysis by Komiyama et al[25] similarly found that SBRT offered comparable OS and superior local control relative to TACE. Our findings suggest that SBRT may help maintain disease control when TACE is no longer feasible or has failed.

Seventy-seven percent of our patients who received bridging SBRT proceeded to transplantation, with dropout occurring mainly due to non-cancer comorbidities rather than disease progression. Wong et al’s prospective study demonstrated that SBRT lowered waitlist dropout rates compared to TACE (23.3% vs 45.8%, P = 0.034)[26]. Similarly, Sapisochin et al[27] demonstrated that SBRT had comparable waitlist dropout and 5-year post-listing survival rates relative to TACE and RFA. The biological efficacy of SBRT as a bridging therapy is further supported by pathological studies showing complete tumour necrosis in 28%-48% of excised tumours, indicating possible cytoreduction[26-28]. In our experience, SBRT effectively maintained disease control during the transplant waitlist period, with no bridging patients dropping out due to tumour progression.

The use of planned multimodality therapy in selected patients reflect a pragmatic curative approach for lesions in challenging anatomical locations and advanced disease[17,29,30]. Several studies suggest improved survival when radiotherapy is integrated with locoregional or systemic therapies, including better outcomes than sorafenib alone in patients with macrovascular invasion[29-32]. In our cohort, all patients with macrovascular invasion eventually progressed systemically, yet SBRT provided meaningful local control and systemic therapy initiation was reasonably delayed.

Patterns of failure and integration with systemic therapy

Despite very good local control with SBRT, distant intrahepatic progression (35%) was the dominant failure pattern in our cohort. This pattern likely reflects at least two non-mutually exclusive biological processes. Some patients may harbour occult intrahepatic micrometastases at the time of SBRT that are below radiologic detection and therefore not eradicated by focal treatment[33]. In parallel, the cirrhotic liver itself represents a carcinogenic field, where prolonged exposure to hepatitis viruses, alcohol or metabolic injury drives widespread molecular alterations that predispose to de novo tumorigenesis[34]. HCC also develops within a chronically inflamed yet immunosuppressive microenvironment characterised by impaired natural killer cell cytotoxicity, dysfunctional antigen presentation, enrichment of regulatory T cells and programmed death-ligand 1 dysregulation, which may compromise immunosurveillance against residual or nascent disease[35].

These findings suggest that for patients with higher risk biology, repeated local therapy alone may be insufficient and earlier integration of systemic therapy deserve consideration. This is particularly relevant given that atezolizumab-bevacizumab improves survival over sorafenib in unresectable HCC[36], and combined-modality data suggest radiotherapy integrated with systemic therapy may improve outcomes in selected patients[30-32]. Preclinical research suggests radiation may promote immunogenic cell death, tumour antigen presentation and cytokine release, supporting the rationale for combining SBRT with immune checkpoint inhibitors[8,9]. Future prospective studies should evaluate risk-adapted sequencing of SBRT with immunotherapy or anti-angiogenic therapy, particularly in patients with vascular invasion or repeated intrahepatic relapse.

Study limitations and future directions

Our study benefits from a consistent institutional SBRT protocol and a prospective database, but the relatively small sample size, lack of a control group, and potential selection bias from referral patterns may limit generalisability of our findings. Where possible, we have contextualised our outcomes against published comparative data. Patients referred for SBRT often have impaired liver function, prior locoregional failure, bridging or salvage intent, making randomisation frequently impractical and challenging. This challenge is reflected in the broader literature, as both the TRENDY trial (target 100, enrolled 30) and phase III trial by Comito et al[37] (target 80, enrolled 40) comparing SBRT with TACE were closed prematurely due to slow accrual[38]. Notably, a recently published randomised study Ma et al[39] comparing SBRT with RFA for recurrent HCC ≤ 5 cm demonstrated significantly better local control with SBRT. In this setting, prospective observational data provide important real-world evidence on treatment effectiveness, safety, and patterns of failure in patient populations commonly under-represented in randomised trials.

Future research should address these limitations through larger prospective comparative trials to better define SBRT’s role within first-line treatment pathways. The 2026 BCLC guidelines now recognise SBRT as an ablative option for very early-stage (BCLC-0) HCC in treatment-naive patients with good liver function, while the 2025 ESMO guidelines recommend SBRT as an alternative to thermal ablation for early-stage disease ineligible for or recurrent after standard therapies[40,41]. Further studies should also explore the combination of SBRT and systemic agents, particularly immunotherapy, to reduce distant progression. Ongoing evaluation of hepatic and immune-mediated toxicities will be important to ensure safety and preserve liver function as the clinical use of SBRT continues to expand[42].

CONCLUSION

SBRT achieved durable local control with minimal toxicity in a real-world transplant-centre cohort, including patients with advanced stage disease and impaired liver function who are frequently excluded from clinical trials. Our findings support SBRT as a versatile treatment across curative, bridging, and salvage settings, particularly when guideline-recommended options are not feasible.

ACKNOWLEDGEMENTS

Institutional support for data collection and analysis was provided by the Department of Radiation Oncology, Austin Health, in collaboration with the University of Melbourne.