Carbon-ion radiotherapy for hepatocellular carcinoma with major vascular invasion: a retrospective cohort study

Primary liver cancer, mostly hepatocellular carcinoma (HCC), is the sixth most frequently diagnosed cancer and the fourth leading cause of death worldwide [1]. The American Association for the Study of the Liver Disease/Barcelona Clinic for Liver Cancer (AASLD/BCLC) staging system and treatment guidelines recommend various treatment modalities and combination therapies according to cancer stage and liver function [2]. Macroscopic vascular invasion (MVI) has a huge impact on the treatment outcomes and survival of patients with HCC, in addition to tumor size, number of tumors, and liver function [3‐7]. The AASLD/BCLC staging system and treatment guidelines classify HCC with MVI as advanced-stage disease and recommends systemic therapy [2]. Although atezolizumab + bevacizumab combination immunotherapy has achieved better survival than sorafenib alone, the prognosis remains poor, with a median survival of only 20 months [8]. The reasons for this are a low complete response rate to systemic therapy and rapid disease progression.

Given that tumor thrombi are often the leading cause of death in these patients, local therapy could play an important role, especially with the improved overall survival (OS) benefits of new systemic treatment options. Surgical resection has been explored in patients with MVI, showing longer survival than nonsurgical treatment in cases with vascular invasion limited to the first-order branch of the portal vein or the major hepatic vein [9, 10]. However, its suitability depends on disease progression and general condition of the patient, and may not be indicated for all HCC with MVI.

Different treatment modalities, such as radiotherapy, are used in unresectable cases. Several studies have reported treatment outcomes of photon radiotherapy for unresectable HCC with MVI [11‐13]. Although photon radiotherapy demonstrates a better prognostic benefit than sorafenib in patients with HCC and MVI, the OS remains unsatisfactory, with a median of 10.9 months (versus 4.8 months for sorafenib) [14]. Local recurrence (LR) poses a challenge due to the physical limitations of X-rays [14]. Meanwhile, particle therapy, including carbon-ion radiotherapy (C-ion RT), offers better dose distribution properties owing to the Bragg peak and reduced lateral scattering. This enables a higher prescribed dose for HCC compared to photon radiotherapy [15]. Previous studies have reported that the irradiation volume of the liver is lower with C-ion RT compared to that of stereotactic body radiotherapy (SBRT) or intensity-modulated radiotherapy [16, 17]. Several articles, including prospective studies, have reported promising clinical outcomes of C-ion RT for HCC, and its potential effectiveness in HCC with MVI [18‐21].

This study aimed to evaluate the safety and efficacy of C-ion RT for the treatment of HCC with MVI.

In this retrospective cohort study, the 2-year LR and OS rates were 8.9% and 70.0%, respectively, without grade 4 or 5 adverse events, in patients with HCC with MVI treated with C-ion RT. In univariate analysis, naïve tumor, single lesion, and two-fraction protocol were significant factors, and in multivariate analysis, ALBI grade 1 and single lesion were identified as independent significant factors for OS. Although there was no difference in the LC depending on the fraction protocols, the two-fraction protocol was a significant factor. We acknowledge that selection bias may have been influenced by the clinical trials of the two-fraction protocols.

To the best of our knowledge, only one small-scale study has reported C-ion RT for HCC with MVI, and our outcomes are similar to those of this study; the 2-year LR and OS rates were 22% and 64%, respectively, without grade 4 or 5 adverse events [32]. A multicenter prospective registry study on proton beam radiotherapy reported a 3-year OS rate of 21.7% for patients with HCC with portal vein tumor thrombus [33]. Regarding LR in unresectable HCC with MVI, studies of patients treated with conventional photon radiotherapy alone or combination therapy with transcatheter arterial chemoembolization (TACE) have demonstrated that the overall response rate (defined as complete remission + partial remission) is only 40–50%, and unfavorable LR remains a challenge for photon radiotherapy [11‐13]. SBRT was performed to reduce the LR rate following conventional radiotherapy techniques. Matsuo et al. reported an overall response rate of 67% and a 1-year LR rate of 20.4% for SBRT for MVI, and both rates were significantly superior to those of conventional photon radiotherapy [34].

A meta-analysis also reported a favorable local response rate to SBRT [35]. SBRT is expected to achieve a lower LR rate than conventional techniques. However, owing to the physical characteristics of photons, SBRT has limited tissue-sparing benefits, particularly for the surrounding normal tissues. SBRT also increases the irradiation dose to the normal liver tissue and the risk of radiation-induced liver disease, especially in large lesions [36]. Thus, SBRT is recommended only for small tumors (generally < 3–5 cm), because of the normal liver constraints. As the median tumor diameter in this study was 4.6 cm, cases with MVI were often large lesions, and it was challenging to adapt SBRT to all cases. This limitation does not apply to particle therapy because of its physical characteristics, including the Bragg peak. Various studies have consistently reported similar or equivalent dose to peripheral lesions with particle therapy, resulting in reduced LR [32, 37‐39].

However, reports on C-ion RT for HCC without MVI have shown only a few cases of late grade 3 or severe adverse events [20]. Late grade 3 adverse events were observed in 5% of the patients in our study. The details of these events are as follows: for liver dysfunction after C-ion RT, grade 3 increases in liver-derived enzymes were observed in two patients, but there was no serious hepatic damage deteriorating the Child–Pugh grade. There were no cases of suspected radiation-induced liver disease in contrast to the 5–10% risk associated with photons [26]. Grade 3 dermatitis as a late adverse event is observed in patients treated using passive scattering methods. In contrast, no cases of grade 3 or higher dermatitis as a late adverse event were observed in patients treated with energy scanning. In cases of MVI treated with photon radiotherapy with or without TACE adverse events of grade ≥ 3 accounted for at least 10%, encompassing all adverse events [12, 13]. The incidence of C-ion RT-related late grade 3 adverse events in the current study may be slightly higher than that previously reported [32]. However, this rate is clearly lower than that of photon radiotherapy; thus, we considered it to be acceptable.

For over a decade, sorafenib has been recommended by the AASLD/BCLC staging system and treatment guidelines as the primary treatment modality for HCC with MVI; however, the median survival benefit is only 10 months [2]. This study found no difference in OS before and after 2008, when sorafenib was introduced, partly because the therapeutic effects of sorafenib were limited. In recent years, atezolizumab + bevacizumab combination immunotherapy has prolonged survival to 20 months; however, this is still far from satisfactory compared to the outcomes of early-to intermediate-stage HCC [8]. In our study, the 2-year OS rate was 70%, consistent with favorable results reported by other studies on particle therapy as a radical treatment, with 2-year OS rates ranging from 48 to 88% [32, 37, 38]. Considering that these reports preceded combination immunotherapy, the reduced LR of particle therapy may have contributed to the prolonged OS. This finding is consistent with the successful results of surgical resection in resectable cases of HCC with MVI [9, 10]. However, unlike surgical resection, which requires extensive anatomical resection for advanced disease, particle therapy affects only the tumor and a small surrounding volume; thus, it is more feasible in a wider patient population. Unsurprisingly, the liver function-related adverse events following particle therapy have been minimal [32, 37‐39].

However, although the C-ion RT resulted in favorable LR rates, it was still far from satisfactory. The 2-year PFS was only > 33%, which was not surprising considering the systemic nature of HCC with MVI. Thus, despite C-ion RT achieving better results as a local therapy, it should be considered for further improvement. Although radiotherapy has long been known for its immunogenicity, the benefits of combining it with immune checkpoint inhibitors (ICIs) have yet to be proven clinically [40]. Given that C-ion RT is expected to have stronger local immunogenic and immunosuppressive characteristics than photons and protons, combination therapy with ICIs would be interesting [41, 42].

This study has some limitations. First, it had a single-center retrospective design and was thus subject to numerous biases. Although investigator-derived bias was minimized to the fullest extent possible, it was still prone to other biases such as selection. Second, the number of enrolled patients was small, limiting our ability to thoroughly investigate the risk factors affecting the outcome. Although to the best of our knowledge, this is the largest study to date, a prospective study aimed at advanced HCC is required. Third, the patient inclusion spanned more than 20 years, since 1995, and the treatment strategies for HCC and viral hepatitis have changed drastically during this period. Consequently, the outcomes reported in this study may not reflect the current clinical outcomes. Nevertheless, considering the results of this study, any potential bias would likely only push the outcomes downward and, does not affect the value of C-ion RT for these patients. A randomized study with larger patient cohort is warranted to assess the true clinical impact of C-ion RT.

In conclusion, C-ion RT for HCC with MVI resulted in more favorable LR rates and longer survival than those reported in previous studies.