Hepatocellular carcinoma (HCC) is one of the most common malignancies and the second leading cause of cancer-related death in the world [1]. Because HCC usually develops in patients with underlying liver cirrhosis, the coexistence of two life-threatening conditions of cancer itself and cirrhosis complicates the prognosis [2]. Child-Pugh classification (CP) is the most widely used system to assess the severity of underlying liver cirrhosis. In HCC patients with well-compensated liver function (CP class A, CP-A), the efficacy and safety of various treatment modalities according to the tumor extent are well documented. However, in cases of a borderline liver function (CP-B), liver cirrhosis further limits the applicability of certain treatment modalities because some standard therapies are a strain on the patients or can cause collateral damage to the non-cancerous liver tissue, thereby potentially further aggravating liver dysfunction [3]. A recent review article suggested that the best approach for treating HCC patients with CP-B would be to assess the prognostic weight of the HCC burden in the individual patient compared with that of cirrhosis severity and to adapt eventual tumor treatment to the liver function for tolerability and potential benefit [4].

Although radiotherapy (RT) was previously limited to HCC treatment owing to the low tolerance dose of the whole liver to RT [5], the developments in imaging and the introduction of 3-dimensional conformal radiotherapy (3DCRT) have enabled the delivery of conformal RT to the partial liver. In addition, further development of RT techniques, including intensity-modulated radiotherapy (IMRT), and stereotactic body radiotherapy (SBRT), have been expanded the role of RT for HCC [6]. Hepatic toxicity after RT is defined as radiation-induced liver disease (RILD), which typically occurs between 2 weeks to 3 months after RT, and the overall incidence has been reported to be 0%-20% [7,8]. Virtually all prospective and retrospective studies have included patients with CP-A and CP-B only, and the most of those with CP-B were classified as CP-B7 [9]. Culleton et al. [10] retrospectively reported that 63% of patients had a decline in CP score of ≥ 2 points after SBRT in HCC patients with CP-B or -C. In contrast, in subgroup analyses of ≤ 20 patients with CP-B in few studies, the incidence of RILD was 27%-63%. This suggest that SBRT should be used with caution or omitted for cases of severely impaired liver function.

Therefore, we performed a retrospective multi-institutional study with a large cohort obtained from 13 institutions of the Korean Radiation Oncology Group (KROG) to evaluate the efficacy and toxicity of fractionated conformal RT for HCC patients with CP-B.

RT is mostly administered to HCC patients with CP-A, and only a few studies have examined the efficacy of RT for CP-B [13,14]. Culleton et al. [10] reported a median OS of 7.9 months in CP-B or -C patients treated with SBRT for HCC: 9.9 months in CP-B7 patients and 2.8 months in CP ≥ 8. In contrast, Nabavizadeh et al. [15] reported a superior survival rate of 11.8 months after SBRT or accelerated hypofractionated RT (AHRT). The authors suggested that favorable patients’ characteristics, such as a unifocal tumor, smaller tumor size, and PVTT in 10% of patients, may have contributed to the improvement in OS. Our fractionated conformal RT showed a comparable survival of 9.4 months, despite the inclusion of patients with unfavorable characteristics, e.g., T3/T4, multiple HCCs, large tumor size, and PVTT. However, local control (LC) was suboptimal compared with SBRT studies with a 1-year LPFS rate of 58.9%. Ohri et al. [16] found that there was no clear evidence for a dose-response relationship with a BED of 60-180 Gy₁₀ for SBRT to primary liver tumors and suggested that SBRT with 60-72 Gy₁₀ was a reasonable fractionation scheme, with a 2-year LPFS of 90%. In addition, Nabavizadeh et al. [15] showed statistically significant superior LC rates for SBRT group compared to AHRT group, with a 2-year LC rate of 94% versus 65%. However, a nationwide survey in Korea reported that SBRT was selectively used for small-sized HCC with CP-A and that RT was mainly considered for advanced HCC and combined treatment using fractionated conformal RT was common clinical practice patterns [17,18]. In addition, HCC occurs in developing countries, especially in Asia where there are limited health resources. Therefore, we suggest that fractionated conformal RT as a practical alternative to SBRT, although further prospective studies to improve its efficacy are required.

The incidence of RILD after RT is higher in HCC patients with CP-B than with CP-A. An SBRT study for HCC in 29 patients with CP-B or -C reported the highest toxicity rate of 63%, resulting in a worsening of CP score by ≥ 2 points after a median dose of 30 Gy in six fractions [10]. They suggested SBRT for selected CP-B7 patients but did not recommend it for patients with CP ≥ 8 outside of studies. Another study using SBRT (50 Gy in 5 fractions) or AHRT (45 Gy in 18 fractions) presented a worsening of CP score by ≥ 2 points in 27 out of 95 patients (28%) with CP-A or -B7 and in 18 out of 51 patients (35%) with CP-B8, -B9, or -C [15]. As the true tolerability of RT in patients with CP-B or -C is unknown, the authors proposed further prospective trials. In a hypofractionated 3DCRT study using 40-60 Gy with a fraction size of 4-8 Gy, classic or non-classic RILD occurred in 12 out of 20 patients (60%) with CP-B, compared to 7 out of 108 (6%) with CP-A [19]. They stated that CP-B patients did not tolerate the hypofractionated RT. On the other hand, conventional fractionated RT may be more tolerable. A 3DCRT study using 66 Gy in 33 fractions reported that three out of 11 patients (27%) with CP-B experienced grade 4 hepatic toxicity [20]. However, as all of these patients had grade 3 abnormalities before RT, the correlation of toxicity to the RT is not entirely clear. In the current study, non-classic RILD was observed in 19.7% of 132 evaluable patients after fractionated conformal RT with a median fraction size of 2.5 Gy. Considering that normal tissue toxicity is more greatly impacted by fraction size in terms of radiobiology, we suggested the use of fractionated conformal RT for HCC in CP-B patients to minimize toxicity [21]. Because most patients were CP-B7 or -B8, however, the safety of fractionated conformal RT for patients with CP-B9 has still undetermined and we should treat them with considerable caution.

To the best of our knowledge, this is the largest study in published data evaluating predictors for non-classic RILD in HCC patients with CP-B treated with fractionated conformal RT. Although several dosimetric parameters were statistically significant in univariate analysis, we were unable to identify the definite dosimetric constraints because values from the AUC of ROC were suboptimal for the selections of cut-off points. Other recent studies have attempted to obtain the definitive constraints in CP-B patients but did not succeed [15,22]. There are some practical limitations to identify dosimetric predictors. Firstly, our study applied various NLV definitions according to different institutions because plan data which was already approved before RT were retrospectively reviewed. In addition, we defined the α/β ratio of the normal liver as 8 to compare different fractionation schedules among institutions, based on the Korean data reflecting similarities in the underlying disease, applied fraction schemes, and combined modalities [12]. However, the α/β ratio of the normal liver is still unknown, and it ranges between 2, 2.5, 3, 8, and 10 [23-26]. These variances may confound the importance of dosimetric parameters. Secondly, RT for CP-B patients have a higher probability of RILD, especially non-classic RILD: however, the underlying pathology of non-classic RILD remains unclear [7]. Thirdly, CP-B, as a preexisting liver dysfunction, has the intrinsic morbidity. In a randomized trial in advanced HCC patients, the rate of serious adverse events among the placebo group because of progression of cirrhosis or HCC was 52% [27]. However, it is impossible to distinguish between RILD and the natural progression of underlying cirrhosis in a clinical setting. Therefore, further prospective studies are required to minimize confounding factors and obtain practical constraints.

There were some limitations to the current study. Firstly, there was the interinstitutional heterogeneity of HCC management, because the KLCSG and NCC practice guidelinerecommended RT only for HCC patients with well-preserved liver function (CP-A or upper B) and could not encompass all possible clinical situations. However, a certain degree of heterogeneity among institutions mirrors clinical practice in the real world, providing results more representative of what can be achieved in everyday practice than findings from an ideal setting [28]. This is particularly important for HCC as a large gap exists between applied practice and evidence-based treatment, making our multicenter study more representative [29]. Secondly, as we only included patients who received RT ≥ 40 Gy₁₀, patients who could not complete RT or decreased the total dose due to acute toxicities or other possible causes would be excluded. This may overestimate the efficacy of RT for patients with CP-B. Thirdly, this study was a retrospective analysis. Therefore, selection and confounding biases may have occurred, and the rates of hepatic toxicity may have been underestimated. To minimize the effect of these limitations, we only analyzed cases with completed follow-up during the 3 months after RT without disease progression.

In conclusions, fractionated conformal RT showed favorable OS when compared to other published studies in HCC patients with CP-B and a moderate risk of non-classic RILD even if it was lower than that reported in previous SBRT studies. The individual RT for CP-B could be cautiously applied considering that non-classic RILD was the most significant factor affecting OS. In Korea, IMRT and proton beam therapy have been approved by the National Health Insurance Service from 2015. The application of these advanced RT techniques using fractionated RT might provide some answers to improve the efficacy of RT without increasing the incidence of non-classic RILD for HCC patients with CP-B.