Temporal change in liver function after stereotactic body radiation therapy for hepatocellular carcinoma

Introduction

Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed malignancy worldwide. Incidence rates are increasing in many parts of the world, including in Australia where there has been a greater rise over recent decades than for any other cancer type (1). The availability of liver-directed therapies for these patients has also increased over this period. Surgical resection, stereotactic body radiation therapy (SBRT), microwave ablation (MWA) and radiofrequency ablation (RFA) are now prevalent options for definitive treatment. In Australia, data from the Liver Ablative Stereotactic Radiation (LASR) multicentre database demonstrate an increasing utilisation of SBRT in the treatment of HCC over time (2).

Several factors inform the decision-making process when evaluating liver-directed therapies for managing HCC. One of the most significant is the liver function, often compromised in this patient group due to co-existing liver disease including cirrhosis. Patients with HCC have competing risks of disease progression and deteriorating liver function that determine their long-term prognosis and survival (3,4). While there is comparative data of disease control between SBRT and other liver-directed therapies (5,6), there is currently limited data on the evolution of liver function following SBRT (7-10).

Traditionally, the Child-Pugh (CP) score has been used for evaluating liver function, incorporating variables including ascites, encephalopathy, serum albumin, bilirubin, and prothrombin time. Initially developed to estimate operative mortality risk in patients with cirrhosis, the CP score has increasingly been used for estimating liver function to guide management decisions. Recent studies have demonstrated its correlation with survival and toxicity outcomes in patients with HCC treated with SBRT (11-15). Despite its utility, the CP score has notable limitations including subjectivity in the assessment of ascites and encephalopathy, interrelationships between variables, and a lack of granularity given most HCC patients considered for SBRT are CP-A at diagnosis (16).

In this setting, Johnson et al. proposed the albumin-bilirubin (ALBI) score, a simplified model for liver function assessment that provides an alternative to CP score (17). Derived from a large international HCC patient database, the ALBI score offered a simpler, objective and continuous measure of liver function. Additionally, an ALBI grade can also be derived as part of a three-tiered grading system similar to that used to categorise CP scores. The ALBI score has demonstrated predictive value for survival in HCC patients treated with SBRT (7,10,15,18,19). However, there is currently limited data regarding post-treatment evolution of liver function following SBRT as measured by ALBI score. There is also limited data exploring temporal changes in liver function in similar patient cohorts who instead receive liver-directed therapies that are known to have negligible effect on liver function, such as MWA (20,21).

The purpose of this study was therefore to evaluate temporal changes in liver function following SBRT as measured by ALBI score. We also provide comparable data for a control cohort receiving MWA to approximate the non-treatment-related changes in liver function that typically occur over the same timeframe, which are often significant due to co-existing cirrhosis. Finally, we also aim to explore the clinical and radiotherapy dosimetric factors associated with change in ALBI score following SBRT. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-958/rc).

Methods

Patient population

Retrospective data from consecutive patients diagnosed with HCC and treated with SBRT at a single tertiary institution from March 2016 to August 2022 were retrieved. For the control group, patients treated at an affiliated treatment facility within the same timeframe with MWA and without evidence of disease recurrence at 6 months post-procedure were retrieved. Patients who received SBRT were all treated at the Calvary Mater Newcastle. Patients treated with MWA were all treated at the John Hunter Hospital. Both centres are within the Hunter New England local health district which has a common electronic records system from which data was obtained, as described. The decision to use a cohort of MWA patients as a control group was based on existing literature which demonstrates negligible change in liver function post-MWA. All patients were reviewed and discussed at a multidisciplinary team meeting and treatment decisions were made at the discretion of the clinicians. The institutional practice is for small and accessible HCC lesions to preferentially be treated by MWA. Patients with multifocality included both those with previously treated lesions and those receiving SBRT to multiple lesions concurrently. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Hunter New England Human Research Ethics Committee (No. EC00403). Informed consent from participants was not required as this was assessed as negligible risk research due to the de-identified and retrospective nature of the data.

Treatment

Patients who received SBRT were treated in accordance with departmental guidelines. Prior to simulation, fluoroscopy was employed to assess diaphragm motion and reproducibility. Contrast-enhanced planning computed tomography (CT) and magnetic resonance imaging (MRI) images were acquired during deep expiratory breath hold (DEBH). For patients unable to maintain breath hold, a four-dimensional computed tomography (4DCT) scan was obtained. Images were co-registered and contouring was undertaken on the CT dataset. The gross tumour volume (GTV) was delineated based on visible disease across all available imaging modalities, with a variable expansion to the planning target volume (PTV) ranging from 5 to 15 mm, as determined by pre-simulation fluoroscopy. All patients were treated over five fractions, with the prescribed dose determined via a scaling system based on mean liver dose (MLD) that was previously utilised in the Radiation Therapy Oncology Group (RTOG) 1112 trial (22). Radiotherapy details extracted included GTV volume, PTV volume, MLD, radiotherapy dose and liver volume.

Liver function analysis

Biochemical data were extracted from the electronic medical records of each patient at specified intervals, including pre-treatment and at 3, 6, and 12 months post-treatment. Parameters measured included serum levels of albumin, bilirubin, creatinine, sodium, and international normalized ratio (INR). An assessment of the presence and severity of ascites and encephalopathy at these time points was made from patient notes and follow-up imaging. These variables were utilised to calculate hepatic function scores, such as ALBI and CP, at the pre-specified time points. ALBI grade was calculated as described in the original paper by Johnson et al. (17). Change in liver function was measured as the absolute difference in value from the time of measurement to that recorded at baseline. Incidence of significant drop in liver function, defined as change in CP ≥2 at 6 months, was also noted.

For exploring factors predictive of change in hepatic function following SBRT, the primary endpoint was absolute change in ALBI score at 6 months. The 6-month time point has been utilised in other studies exploring change in liver function in this setting (7,23-25). It allows sufficient time for the effects of SBRT on liver function to manifest, while reducing the influence of potential long-term confounding variables.

Statistical analysis

Demographic and clinical characteristics of patients were summarised using means, ranges and proportions, as appropriate. Differences in patients’ characteristics between the SBRT and control groups were compared using Fisher’s exact test for categorical variables and Mann-Whitney U test for continuous variables. In each group, changes in hepatic function at various time points was compared to baseline hepatic function using the Wilcoxon signed-rank test. Comparison of hepatic function as measured by ALBI and CP was done via Chi-squared test. In the SBRT cohort, association between clinical and radiotherapy dosimetric factors and the absolute change in ALBI score at 6 months were evaluated using linear regression analysis. Variables showing significant associations on univariate analysis were included in a multivariate linear regression analysis using stepwise selection. The relationship between clinically utilised MLD and change in liver function were further quantified using linear regression analysis. Missing data was handled by pairwise deletion.

Results

Patient characteristics

A total of 126 patients were included in the analysis, 72 in the SBRT and 54 in the control group. Mean tumour diameter for all patients was 29.5 mm, however this was significantly higher in the SBRT group than the control group (36.6 vs. 20.0 mm, P<0.01), see Table 1. Demographic characteristics for patients who received SBRT are shown in Table 2. The median age was 68.3 years, with 62 (86%) patients being male. The majority (86%) were of Eastern Cooperative Oncology Group (ECOG) performance status 0–1. In the SBRT cohort, 37 patients (51%) received 50 Gy in five fractions, whereas the remainder received lower biological doses [median dose 50 Gy, interquartile range (IQR), 40–50 Gy]. The median follow-up duration was 20.9 months (IQR, 12.3–33.0 months).

Temporal change in liver function

Baseline liver function and tumour size for both the SBRT and control groups is shown in Table 1. Baseline liver function was similar in both groups, with most patients recording scores indicating good functional reserve. A CP score of A5 was recorded for 37 patients in the SBRT group (51%) and 31 patients in the MWA group (57%), with no difference seen in the distribution of scores between these groups (P=0.27). The mean ALBI grade score for all patients the entire cohort at baseline was −2.28, with no significant difference between SBRT and MWA groups (−2.26 vs. −2.30, P=0.68). A total of 47 patients in the SBRT group (65%) and 33 patients in the control group (61%) were ALBI Grade 2 at diagnosis, with no difference in the distribution of scores between groups (P=0.86). Figure 1 demonstrates the temporal change in hepatic function in each group as measured by using ALBI score. Following SBRT, a gradual decline in hepatic function (as seen by an increase in ALBI score) was observed over each of the time-points, reaching significance at 3 months post-treatment (−2.27 vs. −2.14, P<0.01) and continuing to 12 months’ post-treatment (−2.27 vs. −1.99, P<0.01), see Tables 3,4. No such change was seen in the control group at any time point, with mean ALBI grade score not significantly different from baseline to 12 months’ post-treatment (−2.30 vs. −2.10, P<0.12), see Tables 3,4. The incidence of significant changes in liver function, defined in previous studies as an increase in CP score of ≥2 or ALBI score ≥1 (25-28), was low in both groups. An increase in ALBI grade by ≥1 was seen in 12 (20.8%) SBRT patients and nine (16.7%) control patients (P=0.43). Similarly, an increase in CP score of ≥2 at 6 months was seen in ten (13.9%) SBRT patients and five (9.3%) MWA patients (P=0.35). There was strong correlation between ALBI and CP scoring systems in SBRT patients at both baseline (rs=0.715, P<0.01) and at 6 months (rs=0.757, P<0.01) post-treatment time-points. There were no cases of recurrent disease in either of the control or SBRT cohorts at 6 months’ post-treatment.

Figure 1 Change in ALBI score over time for SBRT and MWA (control) groups. ALBI, albumin-bilirubin; MWA, microwave ablation; SBRT, stereotactic body radiation therapy.

Factors associated with change in liver function following SBRT

In the SBRT cohort, the mean decline in liver function at 6 months measured using the ALBI score was 0.25±0.59. Tumour lesion size (P<0.01), GTV size (P<0.01), PTV size (P<0.01), MLD (P=0.05) and multifocality (P=0.02) were significantly correlated to change in ALBI at 6 months, see Figures 2,3. On multivariate analysis only multifocality (P=0.01) and PTV size (P<0.01) remained statistically significant. The linear relationship of MLD and change in ALBI score was defined by: change in ALBI score = 0.048 + (0.032 * MLD). There was no significant correlation between gender (P=0.73), ECOG status (P=0.11), previous treatment (P=0.50) and baseline CP score (P=0.23) to change in ALBI score at 6 months.

Figure 2 Relationship between multifocality and change in ALBI score at 6 months post-SBRT. ALBI, albumin-bilirubin; SBRT, stereotactic body radiation therapy.

Figure 3 Relationship between mean liver dose (Gy) and change in ALBI score at 6 months post-SBRT. ALBI, albumin-bilirubin; SBRT, stereotactic body radiation therapy.

Discussion

The assessment of liver function is of central importance in patients with HCC who are being evaluated for liver-directed therapy. While CP score has traditionally been used for this purpose, the recent development of tools such as the ALBI score have offered a simpler and more objective measure of liver function. The ALBI score has been shown to correlate with overall survival and toxicity in patients receiving SBRT for HCC, however there is limited data relating to its ability to measure temporal changes in liver function following SBRT.

To our knowledge, this is the largest study to date quantifying temporal changes in liver function, as assessed by the ALBI score, in patients with HCC treated with SBRT. We found liver function as measured by ALBI score demonstrated a progressive decline over the 12-month period post-SBRT, however this was only significant in a minority of patients. Additionally, our control group also demonstrated a trend towards reduced liver function, indicating the decline seen in SBRT patients is partially contributed to by non-treatment-related factors. There was strong correlation between ALBI and CP scores, supporting ALBI as an appropriate alternative for assessment of liver function in this setting. We also identified factors associated with greater decline in liver function as measured by ALBI score, including larger radiotherapy target volumes and higher MLD. Collectively, this data helps inform the use of ALBI alongside other tools in estimating the risk of liver dysfunction and guiding treatment-related decisions.

In terms of temporal changes in liver function seen in our study, the SBRT group demonstrated a significant and progressive decline as measured by ALBI score at 3, 6 and 12 months post-treatment. This is a well-established effect of SBRT, perhaps best described in a recent meta-analysis by Bae et al. (29). Their study analysed outcomes for HCC patients treated with SBRT across 17 observational studies, reporting ≥ grade 3 acute hepatic toxicity rates of 0–30% and ≥ grade 3 late hepatic toxicity rates of 0–9%, with incidence rates varying by the criteria used. Studies included were retrospective in nature and utilised CP score rather than ALBI, limiting their applicability to our study. There are a very limited number of studies which have recorded ALBI scores post-SBRT in this cohort. To our knowledge, the largest was published by Toesca et al., who followed 40 HCC patients and noted a mean decline in ALBI score of 0.35 at 12 months, similar to the mean decline of 0.28 seen in our study (7).

Although our study demonstrated a decline in liver function post-SBRT, only 13.9% of patients recorded a clinically relevant decline in liver function, previously defined in literature as a change in CP score ≥2 at 6 months post-treatment (25-28). Interestingly, 9.3% of patients in the control group also recorded this change, indicating that a subset of clinically significant liver function decline observed in the SBRT cohort reflects non–treatment-related factors, such as the natural history of co-existing cirrhosis. This finding was supported by a recent publication by Bryant et al., who developed mixed effects models to estimate the extent to which decline in liver function in HCC patients receiving SBRT was attributable to radiation toxicity versus progression of cirrhosis (30). The estimated proportion attributable to progressive cirrhosis was 14.2% at 6 months and 24.9% at 12 months, with the remainder attributable to SBRT. Compared with Bryant et al., our control cohort demonstrated a greater mean ALBI change at 12 months, likely contributing to our finding that a larger proportion of post-SBRT liver function decline was attributable to cirrhosis rather than SBRT. This may reflect differences in control cohort selection, as our use of MWA patients was intended to provide a closely matched comparator to the SBRT cohort, with broadly similar patient and tumour characteristics. Irrespective of the precise contribution of each factor, Bryant et al. also reported an increasing relative contribution of cirrhosis to liver function decline over time, with a corresponding reduction in the relative impact of SBRT. Similar findings were reported by Toesca et al., who observed a significant early decline in liver function within 3 months post-treatment, followed by a more gradual decline (7).

In predicting the patients more likely to experience a significant decline in liver function post-SBRT, our study identified tumour size, GTV volume, PTV volume, MLD and multifocality as factors significantly correlated to change in ALBI at 6 months post-SBRT. In an exploratory analysis, we found a linear relationship between MLD and change in ALBI score. This supports dose-volume parameters of normal liver tissue as the most important determinant in post-treatment changes to liver function. These findings highlight the importance of motion management and image guidance techniques in minimising the irradiated volume and MLD. The majority of our patients were treated in DEBH, with use of a 4DCT with free-breathing for those who could not achieve reproducible breath hold. Other available approaches include abdominal compression, dynamic tracking and gating, with the optimal approach dependent on the available technology, expertise of staff and individual patient factors (31). Other factors including gender, ECOG status and previous treatment were not predictive of such changes.

Our study also found excellent correlation between ALBI and CP score both at baseline (P<0.001) and 6 months post-treatment (P<0.001). This is consistent with existing literature which has consistently demonstrated strong correlation both at baseline and post-treatment with SBRT (7,32,33). This provides further support for use of ALBI as an alternative to CP for assessment of liver function in this setting, particularly given its aforementioned advantages of greater objectivity, granularity and independency. Alternatively, CP and ALBI could potentially be used in a complimentary manner to more accurately predict risk of liver dysfunction post-treatment. This approach was suggested in the study by Lo et al., which found the cut-off point between ALBI grade 1–2 as highly sensitive but not specific for this endpoint, whereas the opposite was true for the CP A-B cut-off point (19).

In evaluating this data, it is important to note the differences in the clinical utilisation of SBRT and MWA in the control group. Although both approaches are classified as ablative treatments appropriate for very early and early stage disease as per the Barcelona Clinic Liver Cancer system (34), in our practice smaller lesions are managed with MWA whereas SBRT is reserved for larger lesions or those which are inaccessible or respond poorly to MWA. These differences are reflected in the patient and tumour characteristics for each group in this study. Liver function is therefore only one of multiple factors that should be considered in determining optimal management. Our decision to include the MWA cohort was done to approximate a control group to allow for better assessment of the extent to which SBRT directly impacts on liver function. However, given differences in these patient cohorts, this only serves as an approximation. Further limitations of this study include its retrospective design and reliance on data obtained from only two treatment centres within a single health district.

The availability of prospective data, such as that being collected in the ongoing SOCRATES trial (35), offers an opportunity to validate our findings in an independent cohort. Additionally, our department has initiated prospective data collection for this patient cohort to help inform future studies.

Conclusions

Our study demonstrates a temporal decline in liver function post-SBRT for HCC which is measurable by ALBI score. This decline is only significant in a minority of patients and appears partly attributable to non-treatment-related factors. SBRT remains an effective treatment modality for patients with HCC not amenable or responsive to ablative techniques such as MWA, particularly given the competing risk of disease progression. Future studies in this area should consider incorporating ALBI score to further assess its utility in clinical management decisions.

Acknowledgments

Previous presentation: data included in oral presentation at RANZCR ASM Melbourne, October 23 2025.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-958/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-958/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-958/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-aw-958/coif). J.M. has grants/contracts from Varian, board participation for Varian and Astellas, and stocks in GenesisCare, SeeTreat and Margin Clear. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Hunter New England Human Research Ethics Committee (No. EC00403). Informed consent from participants was not required as this was assessed as negligible risk research due to the de-identified and retrospective nature of the data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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