First randomized controlled trial comparing stereotactic body radiotherapy and radiofrequency ablation for hepatocellular carcinoma: lessons and key considerations for interpretation of results

Hepatocellular carcinoma (HCC) is a major global health burden, ranking as the sixth most common cancer and the third leading cause of cancer-related death worldwide (1). The therapeutic approach to HCC is determined by several factors, including tumor size, tumor number and liver function. Early-stage HCC is defined as a single lesion of any size or 2–3 lesions each ≤3 cm. Standard recommended treatments for these tumors are surgical resection, radiofrequency ablation (RFA), and liver transplantation (2), but stereotactic body radiotherapy (SBRT) has emerged as a promising alternative treatment modality. The use of high-dose radiation for liver tumors has been limited by concerns about hepatotoxicity, and conventionally fractionated radiotherapy (1.8–2.0 Gy per fraction over several weeks) yielded suboptimal outcomes. However, recent technological advances in radiation delivery have enabled higher doses to be administered while minimizing exposure to surrounding liver tissue. For early-stage HCC, SBRT protocols typically prescribe total doses of 30–60 Gy delivered in 3–6 fractions, which reportedly provides effective tumor control with acceptable toxicity (3).

Although several early-phase clinical studies have yielded promising rates of local control with SBRT for early-stage HCC, concerns remain regarding long-term outcomes. For example, a large-scale retrospective analysis with the National Cancer Database in the United States revealed that the 5-year overall survival (OS) rate was significantly lower in patients treated with SBRT than in those treated with RFA (19.3% vs. 29.8%, P<0.001), even after adjustment for baseline characteristics (4). However, that study had an important limitation: liver function and performance status were not used as confounding variables for creating the propensity score (4). Subsequently, two well-designed, large-scale retrospective studies from Asian countries reported that SBRT provided superior local control and comparable OS to RFA in the treatment of early-stage HCC (5,6). Thus, SBRT is recommended in several international guidelines as an alternative treatment for early-stage HCC in patients who are ineligible for curative surgery or ablative therapies (2,3). However, the absence of a randomized controlled trial (RCT) has limited the widespread use of SBRT.

The recent study by Xi et al. (7) provides valuable insight into this issue. The authors conducted the first RCT comparing SBRT and RFA for the treatment of early-stage HCC. Key eligibility criteria were: (I) age between 18 and 75 years; (II) recurrent small HCC with a maximum diameter of ≤5 cm; (III) Karnofsky performance status ≥90; (IV) Child-Pugh class A liver function; and (V) no contraindications to either SBRT or RFA. A total of 166 patients were randomized in a 1:1 ratio to receive either SBRT or RFA. The primary endpoint, i.e., local progression-free survival, was found significantly longer in the SBRT group than in the RFA group [hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.24–0.87; P=0.01]. However, there was no statistically significant difference in OS between the two groups (HR, 0.91; 95% CI, 0.37–2.22; P=0.83), although the number of deaths was too small to permit detection of a meaningful difference. The study was a single-center study conducted in China, and tumors ≥3 cm, which are generally not considered ideal candidates for RFA, were included. However, we believe that including these patients in the control arm of the trial was justified since complete ablation was achieved in all patients in the RFA group, and the 3-year local progression rate was 24.1%, which is consistent with the results of previous studies (6). We conclude that the findings of the Xi study likely will promote broader use of SBRT as an alternative to RFA and other ablative therapies in the management of recurrent solitary HCC.

To help interpret the Xi results and apply them to our practice, we will discuss three clinical questions: first, are there clinical scenarios in which SBRT should be preferred over RFA? It is not surprising that Xi et al. did not find any difference in OS between SBRT-treated and RFA-treated patients, as patients who were ineligible for either SBRT or RFA were not enrolled (7). A similar situation was present in the SURF trial conducted in Japan, which compared RFA and surgical resection for treatment of early-stage HCC (8). The slow accrual rate in that trial suggests that the investigators selected patients who could be adequately treated with either modality. As a result, not only OS but also recurrence-free survival was similar in the two groups (8). In real-world clinical practice, the local control rate of response to RFA is highly influenced by tumor-related factors such as size, location, and visibility on ultrasound (9). Especially, tumors located adjacent to large vessels are difficult to ablate due to the heat-sink effect. A well-designed retrospective study focusing on perivascular HCC demonstrated that local recurrence occurred more often in patients treated with RFA than in those treated with surgical resection, and OS was also significantly worse in the RFA group (10). Another recent retrospective study suggested that SBRT may improve OS compared to RFA in selected cases, such as relatively large tumors or tumors located near major vessels (11). Although further investigations are needed to draw conclusions, based on the available evidence, we prefer SBRT over RFA in cases with a high risk of local recurrence after RFA, such as large tumors or those located adjacent to large vessels

Our second question is: can the results of the Xi study be applied to practice in other countries? Clinical features of the enrolled patients reflected the local features in China: most had hepatitis B, and more than 90% had a Child-Pugh score of 5. In contrast, in many other countries, patients with hepatitis C, alcohol-related liver disease, or metabolic dysfunction-associated steatotic liver disease are more common and are often associated with more severely impaired liver function. According to a recent meta-analysis (12) (in which we participated), OS after SBRT for HCC was poorer in Western countries than in Asian countries, despite similar control rates of local disease. This observation suggests that while the underlying cause of liver disease may not affect local control, it can significantly influence post-treatment outcome. Furthermore, we have reported that liver function deteriorated more after SBRT in patients with impaired baseline liver function than in those with preserved function (13). We also found that an increase in albumin-bilirubin (ALBI) score after SBRT or RFA was associated with poor prognosis (13). Although current guidelines recommend SBRT for patients with a Child-Pugh score of 5–7 (12), the potential negative impact of SBRT on liver function in these patients (not assessed in this study) should not be overlooked. Also, several aspects of SBRT may vary across institutions, including the use of fiducial markers, image-guided radiotherapy protocols, management of respiratory motion, and dose fractionation schemes. Therefore, while the Xi study provides valuable data, caution is warranted when extrapolating the findings to different patient populations. Especially, the post-treatment course and longitudinal changes in liver function may differ across regions due to variations in the underlying causes of liver disease and baseline hepatic functional reserve. Moreover, the ALBI score and modified ALBI grade may better reflect baseline liver function and post-treatment changes over time than does the Child-Pugh score (13).

Our third question is: what is the optimal method for assessing local control of HCC after SBRT? A recent consensus statement from multiple international societies recommends radiological follow-up every 3 months after SBRT, preferably using magnetic resonance imaging (MRI) (14). The follow-up protocol in the Xi study aligned with this recommendation. However, no high-quality studies have yet determined the optimal imaging modality or interval for assessing local tumor control after SBRT. Often, treated tumors retain arterial hypervascularity for several months or even years after SBRT, despite local control being achieved (15). Furthermore, irradiation of the surrounding liver parenchyma can induce changes such as arterial-phase hyperintensity and/or low signal intensity in the hepatobiliary phase, which may obscure the tumor margins and complicate the interpretation of imaging studies (15). Therefore, it is recommended that radiological assessments be conducted by radiologists or hepatologists who have expertise in interpreting post-SBRT images. In our experience, there are cases in which tumor size cannot be accurately measured on contrast-enhanced computed tomography (CT) or MRI but can be clearly visualized with ultrasonography. Thus, ultrasonography may be helpful when CT or MRI alone provides insufficient information to evaluate local control.

In summary, SBRT is an important treatment option for early-stage HCC and offers better local control than RFA. To optimize the application of SBRT, it is essential to understand: (I) its efficacy, unlike RFA, is not influenced by tumor size or location; (II) liver disease etiology and baseline liver function can affect longitudinal liver function and post-treatment survival; and (III) there are pitfalls in interpreting radiological images following SBRT. Careful consideration given to these factors will facilitate the appropriate and effective use of SBRT in the management of early-stage HCC. To better explain why the improvement in local control did not translate into an OS benefit, we encourage the authors to clarify the recurrence patterns, liver function at recurrence, and post-recurrence treatments in more detail.

Acknowledgments

The authors thank William R. Brown, MD, director of the International Medical Editing Service, LLC, USA, for the English language review.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-603/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-603/coif). The authors have no conflicts of interest to declare.

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