Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide [1]. Surgical resection is the standard treatment for early-stage HCC. However, many cases are unsuitable for resection or ablative treatments because of severe concurrent cirrhosis or advanced HCC [2]. In such cases, radiotherapy (RT) and transarterial chemoembolization are considered as secondary treatments [3,4]. Previously, RT has been infrequently performed due to the relatively low tolerance of the whole liver to RT [5]. Technological advances have made it possible for high doses of radiation to conform to the target volume safely [6,7]. Stereotactic body radiotherapy (SBRT) allows for delivery of a high dose of radiation in a few fractions to HCC by image-guided radiation therapy accompanied by a high degree of accuracy in target delineation. SBRT has been used to treat patients with small HCC who are not eligible for surgery, radiofrequency ablation, or liver transplantation [8].

Radiation-induced liver disease (RILD) is a significant limiting factor in the use of RT because there is no effective treatment for RILD. Predictors of RILD have not been well established yet. Definition and terminology describing RILD or hepatic toxicity resulting from HCC treatment vary among studies [9-12]. Predictive factors for RILD also differ depending on the precise definition used, radiation method, and type of cancer. Some authors have reported that dose-volumetric parameters are important in predicting the development of RILD [6,13,14]. However, others emphasized that clinical factors could predict the development of RILD [7,9,15,16].

Most patients with HCC have preexisting cirrhosis or hepatitis, which may significantly increase the risk of RILD [6]. Information about RILD in chronic liver disease patients remains limited and the predictive factors for RILD have not been validated, particularly for SBRT.

Therefore, the aim of our study is to identify factors that could be used to predict RILD in patients with HCC who were treated with SBRT and to evaluate the clinical significance of RILD.

SBRT has been critical in improving local control or as a potential cure in patients with small HCC as an alternative treatment [8]. Although SBRT has a good local control rate, the risk of RILD still remains uncertain. RILD has long been reported as one of the most serious treatment-related complications for patients who undergo hepatic irradiation [5]. However, predictors of RILD have not been well established yet. The precise definition of RILD in patients with HCC who have underlying liver disease varies somewhat between studies. Recently, RILD has been divided into “classic” and “non-classic” types [17]. Classic RILD is subacute hepatic toxicity that presents with anicteric ascites, hepatomegaly, and elevated alkaline phosphatase levels; it typically occurs between 4 and 8 weeks after the completion of RT. Non-classic RILD is defined as elevated liver transaminases more than five times the upper normal limit or worsening of CP score by 2 or more. In our study, RILD was defined according to the non-classic criteria because non-classic RILD was found in patients with underlying chronic liver disease such as cirrhosis or viral hepatitis [19]. In this study, RILD occurred in 29 of the 117 patients. However, classic RILD did not occur at all. These results were consistent with those of previous studies showing that non-classic RILD was observed in patients with chronic liver disease [13,20].

Our results showed that only pretreatment CP score was significantly associated with the development of RILD. Previous studies have also reported that pretreatment liver function was an important factor in predicting RILD [9,16]. According to Jung et al. [9], the risk of liver toxicity was high in cases of CP class B. Cardenes et al. [16] have reported that CP score is the only factor related to liver toxicity greater than grade 3. The severity of liver cirrhosis is an important clinical predictor of RILD.

Prior published reports have shown that patients with CP class B have a high risk of developing RILD [9,15,21]. However, patients with CP-B7, CP-B8, and CP-B9 would not have the same liver function although all of them are in CP class B. In our study, we analyzed the probability of RILD with an increase in CP score. The probability of RILD was positively correlated with an increase in CP score (p < 0.001) (Fig. 1). Moreover, RILD developed more often in CP-A6 patients than in CP-A5 patients (31.6% vs. 5.7%, p < 0.001) (Table 2). This suggests that it is necessary to distinguish CP-A5 and CP-A6 from the perspective of RILD development. Previous studies have shown that CP-A6 patients have worse liver function due to inflammation and fibrosis [22] and poor overall survival [23] compared to CP-A5 patients. Therefore, patients with CP-A6 have high risk of developing RILD compared to patients with CP-A5.

We also examined the recovery rate from RILD after SBRT with increased the CP score. Only CP-A5 patients recovered completely from RILD. The recovery rate from RILD was moderate in patients with CP-A6 (50%) and CP-B7 (42.9%). However, the recovery rate from RILD was significantly lower in CP ≥ B8 patients: 0% in CP-B8 patients and in CP-B9 patients (Fig. 1). We concluded that RILD was not tolerable in CP ≥ B8 patients because the risk of RILD was high and the recovery rate from RILD was low. Several studies have reported that liver toxicity is not tolerable in CP ≥ B8 patients. Huertas et al. [24] have suggested that liver toxicity is moderate in CP score ≤ 7 (CP ≤ B7) patients and that only these patients should be deemed eligible for SBRT. A prospective study has suggested that the only factor associated with more than grade 3 or greater liver toxicity or death within 6 months was CP score 8 or greater (p = 0.030) [16]. Andolino et al. [25] also have suggested that previous liver function (CP ≥ B8) is a limiting factor for toxicity.

We could predict that SBRT would influence the liver function. However, there are few studies on how liver function changes after SBRT. Tse et al. [26] have suggested that the most clinically significant change after SBRT is a downward change in CP classification from A to B in patients with HCC. In this study, we evaluated the change in liver function at 3 and 6 months after SBRT and found that the decline in liver function was significant in CP ≥ B7 patients. Changes in liver function in patients with CP-A5 and CP-A6 were very minimal. Their liver function was improved at 6 months after SBRT. In patients with CP-B7, change in the CP score was more than 1 point. However, CP class remained CP class B without downward change. Especially, deterioration of liver function was severe in patients with CP ≥ B8. Their CP class was progressed from CP class B to class C (Fig. 2). These results suggest that patients with CP-A5 and CP-A6 could tolerate the damage caused by SBRT. In patients with CP-B7, there is a need to monitor liver function carefully and adjust dose per fraction and total dose. According to Fig. 1 and 2, it would be appropriate to consider that hepatic reserve function significantly varies from CP-A5 to CP-B9.

In several previously reported studies, RILD has been associated with dose-volumetric factors. Son et al. [13] have reported that TLV receiving a dose < 18 Gy is a predictive factor for RILD, which was defined as CP progression or grade 2 or higher hepatic toxicity. The study of Liang et al. [14] has found that the percentage of TLV exceeding 20 Gy irradiation (V₂₀) is an independent dose-volume histogram predictor for RILD after SBRT. Another study also has reported that V₃₀ is correlated with the occurrence of radiation-induced hepatic toxicity after three-dimensional conformal RT [27]. However, our study showed that dose-volumetric parameters, such as V₂₀ and V₃₀, could not predict RILD after SBRT. The mean NLV was smaller in the patients who had RILD than in those who did not have RILD (971.23 ± 297.90 cm³ vs. 1,236.01 ± 332.93 cm³, p = 0.002). In multivariate analysis, NLV did not predict RILD. Results of study indicated that clinical factors were more influential than dose-volumetric factors in the development of RILD because most patients had chronic liver disease such as viral hepatitis and liver cirrhosis with relatively small irradiated target volume (mean PTV, 38.76 ± 19.08 cm³).

The relationship between RILD and survival has not been validated. A previous study has reported that RILD after SBRT could influence survival. Liang et al. [14] and Son et al. [28] have reported that the presence of RILD can shorten the median survival time. However, in our study, the presence of RILD was not relevant to overall survival. Only CP score was significantly related to overall survival. Although the presence of RILD was not relevant to overall survival, the development of RILD in patients with poor liver function (CP ≥ B8) appeared to be a clinically significant factor that could affect overall survival because most CP ≥ B8 patients did not recover from deteriorated liver function caused by RILD. There have been reports that patients with poor liver function could affect survival. Cardenes et al. [16] have reported that patients with CP-B with scores of 8 or greater are at high risk of severe toxicity and even death. In other study, patients with CP-B7 had improved survival and less toxicity than CP ≥ B8 patients [29]. According to these results, RILD in CP ≥ B8 patients could lead to irreversible deterioration of liver function, thereby affecting survival.

Our study has some limitations. First, it was a retrospective study. Second, the study population was relatively small. However, we included only HCC patients treated by SBRT. Third, we included a small number of patients with CP class B. Further investigation is needed to clarify the relationship between RILD and survival.

In conclusion, CP score is closely associated with development of RILD in patients with chronic liver disease. SBRT is a tolerable treatment for patients with CP ≤ B7, but not in those with CP ≥ B8. Caution should be used when SBRT is performed for patients with advanced liver cirrhosis.