Stereotactic ablative radiotherapy as a novel strategy in patients with oligometastatic hepatocellular carcinoma

Introduction

According to the latest Barcelona Clinic Liver Cancer staging system, patients with extrahepatic oligometastatic disease (OMD) are categorized into advanced stage C, and the standard treatment is systemic therapy consisting of atezolizumab combined with bevacizumab (1,2). In this state, radiation therapy is usually administered as a palliative treatment. However, the concept of OMD, which is an intermediate state between localized and systemically metastasized disease, was recently expanded. Under this situation, there have been promising reports that local therapies, including stereotactic ablative radiotherapy (SABR), improve the prognosis of OMD in various types of cancer (3-6). Research is particularly advanced in the field of lung cancer. Theelen et al. reported a pooled analysis of two randomized trials in which patients with metastatic non-small-cell lung cancer were randomly allocated to receive immunotherapy (pembrolizumab) with or without radiotherapy (6). Median progression-free survival (PFS) was 4.4 months for pembrolizumab alone, vs. 9.0 months for pembrolizumab plus radiotherapy [hazard ratio (HR) =0.67; 95% confidence interval (CI): 0.45–0.99; P=0.045], and median overall survival (OS) was 8.7 months for pembrolizumab alone, vs. 19.2 months for pembrolizumab plus radiotherapy (HR =0.67; 95% CI: 0.54–0.84; P=0.004). Meanwhile, the recently published NRG-BR002 trial in breast cancer (7) and the NRG-LU002 trial in lung cancer (8), both of which used PFS as a primary endpoint, did not demonstrate the efficacy of local therapy for OMD. According to the mechanism of the abscopal effect, SABR for OMD can theoretically be considered effective (9). However, clinical trials have produced mixed results regarding its efficacy, and clear evidence has not yet been established. In this way, it remains challenging to demonstrate the clinical utility of SBRT for OMD in various types of cancer.

In hepatocellular carcinoma (HCC), several studies demonstrating the efficacy of combining SABR and immune checkpoint inhibitors (ICIs) in patients with locally advanced HCC have been conducted (10-12). Juloori et al. reported a phase I randomized trial of SABR followed by nivolumab plus ipilimumab or nivolumab alone in patients with advanced or unresectable HCC. The authors concluded that SABR with nivolumab plus ipilimumab produced favorable outcomes compared with immunotherapy alone (10). Wang et al. reported a retrospective study of SABR combined with lenvatinib with or without PD-1 inhibitors as an initial treatment for unresectable HCC (12). They concluded that the combined use of both lenvatinib and programmed cell death protein 1 (PD-1) inhibitors with SBRT was associated with improved OS compared with lenvatinib and SBRT alone with a manageable safety profile. However, prospective clinical trials focused on OMD in HCC have been limited. The present study, termed “Efficacy of stereotactic ablative radiotherapy in patients with oligometastatic hepatocellular carcinoma: A phase II study”, provides a valuable contribution, as it demonstrated the efficacy of SABR for OMD (13).

Interpretation of the trial “Efficacy of stereotactic ablative radiotherapy in patients with oligometastatic hepatocellular carcinoma: A phase II study”

This study prospectively investigated the efficacy and safety of SABR in patients with oligometastatic HCC. The eligibility criteria were controlled primary HCC and one to five metastatic lesions amenable to SABR, and 40 patients with 62 lesions were enrolled. After a median follow-up of 15.5 months, the 2-year OS rate was 80%, and median PFS was 5.3 months, including 1- and 2-year PFS rates of 21.2% and 0%, respectively. The 2-year time to local progression, objective response rate, and disease control rate were 91.1%, 75.8%, and 98.4%, respectively. The most noteworthy point is the discrepancy between OS and PFS. Generally, a decline in PFS could be considered to be associated with a decline in OS; however, this study recorded a different outcome. The reason for this is that unlike the SABR-COMET trial (3), which included other types of cancers, the high local control of HCC by SABR, including metastatic lesions, is believed to support the results. HCC tends to recur within the liver because of the presence of multifocal tumors arising from viral infection. However, the local control rate of SABR for primary HCC exceeded 90% in various prospective trials (14-17). Similarly, SABR for OMD achieved a high local control rate in this study. We agree with their opinion that aggressive SABR effectively improves OS in patients with oligometastatic HCC. However, improvements in PFS are also important. This research mentioned the factors associated with PFS that a shorter time to OMD from the controlled primary lesion was independently (P=0.039; HR =2.127) alongside age (P=0.002; HR =3.316), Child-Pugh class (P=0.004; HR =0.150), and alpha-fetoprotein levels (P=0.019; HR =0.266). In this study, because patient enrollment occurred from 2021 to 2022, only 3 patients (7.5%) received atezolizumab and bevacizumab, which comprise the current standard regimen, as systemic treatment. If the standard regimen had been used, the time to OMD from the controlled primary lesion might have been improved. In addition, only 4 patients (10%) received ICIs as a systemic treatment in this study. Active combinations including ICIs could potentially lead to better PFS considering that Kim et al. revealed that the level of soluble programmed cell death-ligand 1 was significantly increased in patients with HCC who received SABR (18).

Regarding toxicities, the incidence of severe toxicities was extremely low (overall 10% of patients experienced acute toxicity, 7.5% experienced late toxicity, and no patients experienced grade ≥3 toxicity). This result was also reflected in the quality of life (QOL) assessment. All QOL scores remained stable, whereas patients who did not receive systemic treatments had improved insomnia and social functioning scores using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) before and 0, 1, and 3 months after SABR. In this study, approximately half of the patients had lung metastases. According to the systematic review of QOL surveys for early-stage non-small-cell lung cancer following SABR and surgery, QOL outcomes were favorable after SABR. Nevertheless, QOL initially declined and then returned to baseline in 6–12 months for most patients after surgery (19). In this manner, SABR can be considered a minimally invasive treatment, even when targeting various organs.

Finally, the authors identified four limitations, including the low rate of ICI combination therapy, and all of their points were convincing. Additionally, it cannot be denied that the good OS might have been influenced by the fact that the study mostly targeted solitary metastases and it had a relatively short follow-up period. As the authors explained, a phase III trial with an increased number of patients is desirable.

Conclusions

This was a single-arm trial with several limitations, but considering the scarcity of studies targeting only OMD from HCC, it is a significant study providing basic data for future comparative trials. Additionally, the fact that the QOL survey highlighted the minimally invasive nature of SABR suggests that SABR could become a first-line treatment for OMD, which requires the treatment of multiple sites or repeated interventions.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-131/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-131/coif). T.K. has received lecture fees from AstraZeneca. 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.

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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