International Journal of Radiation Biology

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/irab20

Radiofrequency ablation and stereotactic body

radiotherapy for hepatocellular carcinoma: Should
they clash or reconcile?

Chai Hong Rim , Hye Yoon Lee , Jung Sun Kim & Hakyoung Kim

To cite this article: Chai Hong Rim , Hye Yoon Lee , Jung Sun Kim & Hakyoung Kim
(2020): Radiofrequency ablation and stereotactic body radiotherapy for hepatocellular
carcinoma: Should they clash or reconcile?, International Journal of Radiation Biology, DOI:
10.1080/09553002.2021.1857453

To link to this article: https://doi.org/10.1080/09553002.2021.1857453

Accepted author version posted online: 30

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Radiofrequency ablation and stereotactic body radiotherapy for hepatocellular

carcinoma: Should they clash or reconcile?

*Chai Hong Rim, Department of Radiation Oncology, Korea University Ansan Hospital,

Gyeonggido, Korea

*Hye Yoon Lee, Department of General Surgery, Korea University Ansan Hospital,

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Gyeonggido, Korea

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*Jung Sun Kim, Department of Medical Oncology, Korea University Ansan Hospital,

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Gyeonggido, Korea

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Hakyoung Kim, Department of Radiation Oncology, Korea University Guro Hospital, Seoul,

Korea
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*These authors contributed equally to the paper.
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Short title: Clinical selection of RFA and SBRT

Supported by the National Research Fund of Korea (NRF-2019M2D2A1A01031560). The research grant
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supported only methodological aspects including statistical analysis and linguistic correction and did not affect
major contents including the results and conclusions.
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Disclosure of interest: The authors report no conflict of interest.

Author contribution: CH Rim: drafting, conceptualization, supervision, HY Lee: editing, supervision; JS Kim:
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editing and supervision.

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Correspondence to: Prof. Chai Hong Rim. Department of Radiation Oncology, Ansan Hospital, Korea
University, 123 Jeokgeum-ro, Danwon-gu, Ansan, Gyeonggi-do, 15355, Republic of Korea Tel: +82 31 412
6850; Fax: +82 31 412 6851; Email: crusion3@naver.com
ORCID number: CH Rim, 0000-0001-7431-4588; HY Lee, 0000-0001-9077-1412; JS Kim, 0000-0002-7101-
1036
Biography

Chai Hong Rim is a radiation oncologist with 15 years of experience and is also a passionate

researcher. He is the senior author of 40 peer-reviewed articles published in the last three

years; his research specialty includes radiotherapy for liver and lung cancer as well as clinical

decision-making on intractable cancer cases.

Hye Yoon Lee is a professor and chief surgical oncologist at the Korea University Medical

Center. She shared her surgical expertise in drafting the present article.

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Jung Sun Kim is a professor and chief medical oncologist at the Korea University Medical

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Center. She shared her perspective as a medical oncologist for the present article.

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Hakyoung Kim is a radiation oncologist and junior professor at Korea University Medical

Center.

Abstract us
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Until a few decades ago, surgical resection was the only valid option for treating
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hepatocellular carcinoma (HCC). However, various locoregional modalities including

arterial-directed therapy, radiofrequency ablation (RFA), and radiotherapy have been recently
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shown to be effective. RFA is now established as a standard treatment for small localized

HCCs, showing oncological results comparable to those of surgical resection in randomized

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studies. Stereotactic body radiotherapy (SBRT) is a modern radiotherapeutic modality that

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targets tumors with precision and delivers high radiation doses over a short period of time; it

has particularly attracted clinical interest after its therapeutic efficacy was found to be similar
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to that of surgery in early-stage lung cancer. Given its potent disease control capability,

SBRT has also been applied to early HCCs and demonstrated promising results in recent

studies. It has also been noted for its suitability to treat tumors located in anatomical locations

where RFA would be challenging. However, since its effectiveness has not been compared to

that of RFA in randomized studies of patients eligible for RFA, the use of SBRT has been

debated. This review was conducted to guide physicians from all fields involved in the
treatment of early HCC. The therapeutic characteristics and indications of both SBRT and

RFA are described, and recent comparative studies between the two modalities are discussed.

In addition, we examined the factors that should be considered when selecting the appropriate

treatments, and offer our recommendations.

Keywords: radiofrequency ablation; stereotactic body radiotherapy; hepatocellular

carcinoma; liver neoplasm; stereotactic ablative body radiotherapy; comparative studies

Introduction

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Liver cancer is one of the leading causes of cancer death globally, accounting for 8.2% of all

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cancer-related mortalities. Hepatocellular carcinoma (HCC) is the most common type,

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accounting for ~85% of primary liver cancers. Chronic hepatitis B infection is the main cause

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of the high incidence of HCC in East Asia, whereas hepatitis C and alcohol consumption are
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common causes in Western countries (Bray et al. 2018).

Previously, treatment approaches were limited to surgery (including radical resection or

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transplantation), which is the conventional curative method for patients with early-to-

intermediate HCCs. However, accompanying hepatic cirrhosis or decompensation often

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hinders safe surgical attempts; moreover, transplantation is rarely performed because of the
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shortage of donors in Asian countries (KLSCG-NCC 2015; Park et al. 2020). Therefore, in
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recent decades, various locoregional modalities have been applied for cases that are

contraindicated or less suited for surgical approaches (Heimbach et al. 2018; Zhou et al.
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2018).

Among these modalities, radiofrequency ablation (RFA) has been one of the most commonly

used modalities for early-stage HCCs, based on data from randomized studies that showed

survival outcomes comparable to those of surgical resection (Chen et al. 2006; Feng et al.

2012; Ng et al. 2017). RFA has demonstrated very high efficacy (with sustained local

control) against early-stage HCCs, especially those with relatively small sizes. In a large
Korean study of 640 patients with mean tumor diameters of 2.6 cm, local control and survival

rates at 3 years reached 88% and 70%, respectively (D. Choi et al. 2007). In a study of the

long-term outcomes of 1,000 patients, Tateishi et al. (Tateishi et al. 2005) reported that the 3-

year overall survival (OS) rates were 90.8%, 74.3%, and 58.7% for those with tumor sizes of

≤2, 2.1–5, and >5 cm, respectively.

External beam radiotherapy (EBRT) was previously contraindicated owing to unacceptable

hepatotoxicity after whole-liver irradiation. Pioneering applications were initiated in the

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1990s owing to the availability of selective tumor irradiation based on computed tomography

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planning. Early studies have revealed tumor response rates of 45–63% with doses of 45–60

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Gy in conventional fractionations (1.8–2 Gy per fraction) (Ben-Josef et al. 2005; Dawson et

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al. 2000; Rim et al. 2012; Seong et al. 1999). Stereotactic body radiotherapy (SBRT) is an

advanced hypofractionated EBRT technique with photons delivering a large ablative

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radiation dose and is administered together with such methods as cone-beam guidance and
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motion management (including four-dimensional computed tomography-based radiotherapy

planning, gating, or tracking procedures to maximize treatment precision (Guckenberger et al.

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2007; Guckenberger et al. 2008; NCCN 2020). In a recent meta-analysis, the 3-year local

control rate was 86.3% for tumors with diameters up to 5 cm after delivering radiation doses
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of approximately 80–100 Gy in equivalent doses calculated in conventional 2 Gy per fraction

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(EQD2) (Rim et al. 2019).

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RFA is a standard non-surgical modality for early-stage HCC (EASL 2018; Heimbach et al.

2018) given its potent local controllability and feasibility. SBRT is also commonly indicated

for small and localized tumors, and exhibits potent local control for early HCCs; in a previous

study, the 2-year local control rate for tumors <5 cm was of 87% (Rim et al. 2019). Despite

their overlapping indications, randomized trials have not been published; therefore, clinical

decisions should be based on data from observational studies as well as the different
characteristics of the two modalities, which have different biological mechanisms. RFA

involves protein denaturation owing to thermal ablation, while the other results in irreversible

DNA damages caused by reactive oxygen species or direct ionization (Loi et al. 2020).

Additionally, each has different anatomical considerations in terms of preferred clinical

indications. Although they share the clinical goal of curative ablation of early HCCs, each is

selected for a different reason in clinical practice. Several researchers have recently

performed comparative studies of both modalities (Hara et al. 2019; N. Kim et al. 2020; Lee

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et al. 2020; Rajyaguru et al. 2018; Wahl et al. 2016), although some of their data have

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subsequently been rebutted.

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This review discusses the differences and similarities between the two modalities in terms of

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technical characteristics and practical implications for treating HCC. The literature on

comparative clinical studies is comprehensively discussed based on a selective review as well

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as a meta-analysis previously performed by our team. Selection strategies are suggested
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based on the discussion of clinical, technical, and other practical aspects.

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Technical characteristics and practical implications

RFA is a thermal ablation method in which transcutaneous electrodes are implanted into the
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tumor bulk, following which an oscillating electrical current (450–500 kHz) is conveyed to
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produce ionic agitation and friction-based heat. For most tumors, irreversible protein
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denaturation occurs upon exposure to 45–50°C for 3 min, and immediate coagulation

necrosis occurs at temperatures >60 °C (Gazelle et al. 2000; Loi et al. 2020). Tumors near

organs such as the diaphragm, gastrointestinal tract, major vessels, or the biliary tract are

contraindicated owing to possible thermal damage to these organs. Blood flow from major

vessels might yield heat dissipation, referred to as the “heat-sink effect,” resulting in

incomplete responses in tumors near these vessels. Efficient heat transfer from the electrode
throughout the tumor bulk is inversely related to the tumor size; hence, local failure rates can

reach 30–50% in tumors with diameters >3 cm (Crocetti et al. 2010; Y.-s. Kim et al. 2013;

KLCA 2019). Although rare in modern practice, serious complications related to invasive

approaches such as neoplastic seeding and hemorrhagic complications are still of concern

(Bertot et al. 2011; Goto et al. 2010).

EBRT eradicates tumors via irreversible DNA damage caused by reactive oxygen species or

direct ionization. Although DNA damage also occurs in normal surrounding tissues,

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radiotherapy achieves its therapeutic efficacy owing to the difference in radiosensitivity

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between tumor and normal tissues (Brady et al. 2013). Skeletal muscles and major vessels

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have relatively high tolerances for radiation, and minor fibrosis or contracture due to SBRT

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bystander irradiation usually does not cause serious toxicities (Gillette et al. 1995; Xue et al.

2016). The major hindrances to performing SBRT are hepatotoxicity and damage to the small
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bowel. In a recent multi-institutional study, a Child-Pugh score elevation of ≥2 was higher in
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the SBRT arm than in the RFA arm (11.2% vs. 4.7%, p<0.001), although the overall

frequencies of serious complications were comparable (N. Kim et al. 2020). In practice,
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SBRT usually causes liver changes a few centimeters outside of the target (near the

contouring line) with 40–60% of the prescribed dose (Figure 1) (Jung et al. 2018; N. Sanuki
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et al. 2014b). Such reactions in the liver usually increase and peak approximately six months
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after SBRT, with approximately three-quarters of them diminishing or resolving by the time
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of the 12-month follow-up (Sanuki-Fujimoto et al. 2010).

Hepatotoxicity is correlated with the dose of irradiation and irradiated volume. Regarding

hypofractionated radiotherapy or SBRT (3–6 fractions in total), at least 700 cc of normal liver

tissue should be irradiated at less than 15 Gy, and the mean normal liver volume dose should

be below 13–15 Gy (Hanna et al. 2018; KLCA 2019; NCCN 2020; Pan et al. 2010). SBRT

for patients with Child–Pugh scores ≥8 is generally not recommended in the clinic except for
select Child-Pugh B7 patients (Bae et al. 2019; Culleton et al. 2014). The small bowel has a

relatively low radiation tolerance, and even minor radiation damage can lead to serious

toxicities, including perforation. Notably, modern SBRT regimens are usually prescribed at

≥80 Gy in EQD2 (Rim et al. 2019); therefore, a distance of at least 2 cm from the small

bowel is generally recommended for safe conduction of SBRT (Naoko Sanuki et al. 2014a).

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Figure 1. Dynamic computed tomography images acquired at the time of patients’ 10-month follow-
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up showing three different types of radiation damage after stereotactic body radiotherapy (SBRT). (A)
Type 1: hyperdensity in all the enhanced phases, which is the most common type (76.9%); (B) Type
2: hypodense in the arterial and portal phases but isodense in the venous phase (10.3%); (C) Type 3:
isodense in all enhanced-phase dose distributions of SBRT (12.8%; more commonly observed in
Child-Pugh class B cases). Adapted from (Kimura et al. 2015).
When comparing the two modalities, SBRT appears to be less subject to anatomical

considerations than RFA, although patients with decompensated liver function and those with

tumors near the small bowel are still contraindicated. Modern computed tomography-based

planning can cover the entire tumor with the prescribed dose, regardless of its size, as long as

toxicity does not exceed acceptable levels. However, the effectiveness of RFA can be

enhanced by stringent complementary methods such as artificial pleural effusions or ascites

(Figure 2). Teratani et al. (Teratani et al. 2006) performed RFA using artificial ascites in 207

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patients with HCCs in high-risk regions (i.e., <5 mm from a large vessel or extrahepatic

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organ). Early complication rates were 5.8% and 3.5% for patients with and without tumors in

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non-high-risk locations, respectively (p=0.18), and the two-year local recurrence rates were

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3.1% and 1.7%, respectively (p=0.27). In a recent Chinese series involving 382 patients with

tumors in high-risk locations (Yang et al. 2015), the complication rate (while acceptable) was
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higher in the high-risk group than in the control group (4.9% vs. 0.8%, p=0.04), and the local
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progression rate was also moderately higher (12.7% vs. 7.1%, p=0.046). However, the OS

was not significantly different between the groups (p=0.371). As such, it is expected that the
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efficacy and feasibility of RFA are significantly correlated with the learning curves of

interventionists (Poon et al. 2004).

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 Figure 2. Radiofrequency
ablation (RFA) using the
artificial ascites method. (A)
Hypoechoic hepatocellular
carcinoma (arrows) in segment 3
near the stomach (S); (B)
Artificial ascites inserted
through an angiosheath (arrow);
(C) Artificial ascites (arrow) is
observed between the liver
(asterisk) and stomach (S); (D)
RFA zone (asterisk) and
adjacent stomach (arrow) after

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the procedure. Adapted from (J.
W. Kim et al. 2015).

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For tumors larger than 3 cm, combined treatment with TACE could be an option to enhance
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the effectiveness of RFA. In a recent meta-analysis comparing RFA plus TACE to RFA

alone, both OS (hazard ratio [HR]: 0.62, p<0.001) and recurrence-free survival (HR: 0.55, p
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<0.001) were significantly longer with combined treatment (X. Wang et al. 2016). In another
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meta-analysis, Lu et al. (Lu et al. 2013) reported that the OS was significantly higher with

combined treatment (odds ratio: 2.27, p<0.0001), although the benefit was not significant in
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the subgroup of patients with tumors smaller than 3 cm (odds ratio: 1.30, p=0.49). Major
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complication rates were not significantly different between the two arms in either of the

meta-analyses.
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To summarize, RFA is contraindicated for tumors anatomically located near major vessels or

the biliary tract, diaphragm, or gastrointestinal tract as well as for lesions measuring >3 cm,

as they are difficult to treat using this method. However, stringent complementary approaches

such as using artificial ascites can help circumvent these contraindications, especially if the

interventionists are skilled. Combined treatment with TACE could be an option aimed at
reducing local failure, especially for tumors measuring >3 cm, which is the technical

limitation threshold. SBRT is less affected by these anatomical considerations; however,

adequate liver function and a safe distance from the small bowel should be preserved. From a

practical perspective, the advantage of RFA is that it can be completed in one or a few

sessions, while SBRT commonly necessitates 3–5 visits over 1–2 weeks. In addition, the

costs of radiotherapy commonly burden the budgets of individuals or their insurance

providers because the purchase and operation of a linear accelerator are inevitably expensive;

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its estimated mean cost is approximately 4 million US dollars (Brady et al. 2013). Therefore,

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clinical characteristics, available medical resources, and financial perspectives should be

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considered when making clinical decisions.

Clinical comparison between the two modalities us

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RFA has been consistently used as a non-surgical standard ablative method for small HCCs.
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In contrast, SBRT, which has fewer anatomical limitations and is less invasive than RFA, has

recently received attention and is increasingly applied in clinical practice (Rim et al. 2020;
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Rim et al. 2019). Although these two modalities have different characteristics and

advantages, they also have indications that overlap considerably. While randomized trials are
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yet to be completed, several researchers have performed clinical comparative studies.

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Among such studies, a study by Wahl et al. (Wahl et al. 2016) is the most well-known, as it
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ignited the notion of comparing the two modalities. In their retrospective study, they used

inverse probability of treatment weighting to adjust for imbalances in the SBRT and RFA

treatment groups while investigating factors including liver function, cirrhosis, alpha

fetoprotein level, and the number of previous treatments. After balancing, the OS was found

to be similar in both groups, although local control was significantly worse in the RFA group

than in the SBRT group (hazard ratio [HR]: 2.63; p=0.016). The difference was not
significant in patients with tumors measuring <2 cm (p=0.15), but it was significant in those

with tumors measuring ≥2 cm (HR: 3.35, p=0.025). Of note, a greater tumor size predicted

local failure after RFA (HR: 1.54 per cm, p=0.006), but not after SBRT (p=0.617). In a

similar vein, a relatively large Japanese case series also yielded results that favored SBRT, as

the 3-year local recurrence rate was significantly lower in the SBRT arm than in the RFA arm

(5.3% vs. 12.9%, p<0.01) even though the former had a significantly higher proportion of

patients with tumors that were higher stage, closer to adjacent organs, and larger. Again, the

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OS was similar between the groups after propensity score matching (70.4% vs. 69.1% in the

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SBRT and RFA arms, respectively) (Hara et al. 2019).

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In contrast to these results, a study by Rajyaguru et al. (Rajyaguru et al. 2018), published in

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the same journal in which Wahl et al. reported their aforementioned data (Wahl et al. 2016),

produced results that favored RFA. According to propensity-matched analysis using a

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national cancer database, the five-year OS rate was significantly higher in their RFA arm than
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in their SBRT arm (29.8% vs. 19.3%, p<0.001). Data on local tumor control were not

provided. The main drawback of their study was that data for liver fibrosis/cirrhosis were
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missing for >70% of patients. In another study using a United States patient database, liver

cirrhosis was the most common factor leading to mortality in patients with liver cancer
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(Golabi et al. 2017). Given that it lacked information on tumor controls, the study has been
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criticized for possible patient selection issues. Before propensity matching, ~3,700 patients
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underwent RFA according to the database, which is 12 times more than the ~300 patients

who underwent SBRT. This reflects the fact that, since RFA is accepted as a standard

treatment for early HCC, patients who underwent SBRT tended to belong to a population that

exhibited intractable factors, such as the tumor being in a difficult location or the

development of liver decompensation (N. Sanuki and Takeda 2018).

Our team performed a meta-analysis of comparative controlled studies; the pooled result

showed that the two-year local control rate for patients with HCC who underwent SBRT and

RFA were comparable (84.5% vs. 79.5%, p=0.431), although the former was more effective

in controlling liver metastases than in the latter (83.6% vs. 60%, p<0.001). Regarding HCC,

the OS was significantly longer in the RFA arm than in the SBRT arm (odds ratio: 1.43,

p=0.023), although one of the included studies (Rajyaguru et al. (Rajyaguru et al. 2018))

heavily influenced the result because of the large number of patients. We concluded that the

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OS rates were different despite comparable local efficacies for both modalities, suggesting

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that possible selection bias was present (e.g., SBRT has been commonly attempted for lesions

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that are not amenable to other local modalities) and that further investigation is necessary.

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Shortly thereafter, an international multicenter study from seven Asian institutions (N. Kim et

al. 2020) found a significantly lower cumulative local recurrence rate after SBRT than after
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RFA (16.4% vs. 31.1%, p<0.001, after balancing). Although the OS rate was higher in the
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RFA arm before propensity matching, the difference in survival became insignificant after

balancing the arms (two-year mortality rates after balancing: 22.4% and 28.9% for the SBRT
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and RFA arms, respectively). Once again, tumor size was related to local control after RFA

but not after SBRT, and local control of SBRT was superior in patients with subphrenic
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tumors, even on pre-balancing analysis.

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The selected comparative studies are summarized in Table 1. When observing the clinical
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results of recent comparative studies, the following common trends were observed: 1) SBRT

showed comparable or more efficacious local control than RFA, especially for tumors with

large sizes or difficult locations; and 2) RFA produced better survival, although that outcome

might have been diminished after balancing, reflecting potential patient selection biases.

Although serious complications were not common with either modality, those due to direct
 physical damage were frequent following RFA (e.g., bleeding, perforation, or fistula).

Hepatic dysfunction or radiation damage to the gastrointestinal tract was common after SBRT.

Table 1. Summary of selected comparative studies

†
No. Factors
Recruit Patient SBRT
of related to Concluding
Source -ment populatio schem Patient outcomes following RFA vs. SBRT
Author patien local remark
date n e
(pub. ts control
year) Toxici Common type
LC, 2 OS, 2
ty, ≥ of serious
years years toxicities
G3
Tumors of Bleeding
≥2 cm:

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Acute and/or Tumor size

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Inoperabl 72% vs. toxicit perforation vs. for RFA
“SBRT appears to
e, non- 60 Gy 82% 53% y: Liver (HR 1.54
Wahl et Univ. of be a reasonable
2004– metastatic in 3–5 (p=0.025) vs. 11% decompensati per cm,
al. Michigan, 224 first-line treatment

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2012 . <5 cm in fractio Tumors of 46% vs. on (e.g. RILD p=0.006)
(2016) US of inoperable,
size ns. <2 cm: (p=NS) 5% or worsening not for
larger HCC.”
(97%) 86% vs. (p=0. ascites) SBRT
86% 31) (p=0.617)
(p=0.15)

us “RFA
superior
yields

survival… in the
an
absence of RCT,
65%
National our findings
Rajyagu vs.
United 2004– T1–T2 should be
ru et al. 796 NA NA 47% NA NA
States 2013 N0 considered when
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(2018) (p<0.0
database recommending
01)
ablative therapy
for localized
unresectable
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HCCs”
Hepatic Tumor size
failure, biliary (>3 cm) for
fistula, plural RFA (HR “SBRT provides
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effusion vs. GI 1.27, better LC than

7 complication p=0.03) but RFA, with
multinatio (e.g. duodenal not for comparable
<6 cm in
nal centers Media 71.1% ulcer, SBRT toxicities. SBRT
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size, ≤3 in
Kim et (Korea, n 68.9% vs. vs. 2.6% abdominal (p=0.96); appears to be an
number, ‡
al. Taiwan, 626 EQD 83.6% 77.6% vs. pain) in non- effective
w/o
(2020) China, 2 of (p<0.001) (p=0.3 1.6% balanced alternative to
vascular
Japan, 72 Gy 08) cohorts, RFA... particularly
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invasion
Hong SBRT for larger tumors
Kong) showed (>3 cm) in a
better LC subphrenic
for location.”
subphrenic
tumors
Maximum In non- “OS, LC, and liver
≤3 cm in 35–40 3 Two grade 5 cases balanced failure are similar
size, ≤3 in Gy in years: (peritonitis, cohorts, LC between RFA and
3 year:
Hara et Yokohama number, 5 F or 69.1% hemorrhagic gastric was higher SBRT-HFRT.
2012– 79.8% vs.
al. Univ., no 212 36– vs. ulcer) in the RFA in the Radiotherapy has
2016 93.6%
(2019) Japan extrahepat 45 Gy 70.4% group, no serious SBRT arm several
(p<0.01)
ic in 12– (p=0.8 toxicity in the SBRT despite a advantages (e.g.
metastase 15 F 6) group higher rate better efficacy for
s of tumors tumors near
 attached to vessels). SBRT-
vessels HFRT can be an
(26% vs. acceptable
5.2%) alternative to
RFA…”

Complications “RFA was

None due to direct associated with
OR: of the physical better OS for
1.43 includ damage (e.g. HCC, but the
(95% ed bleeding, discrepancy
CI: studie pneumothorax between LC and
Lee et Meta-analysis of 7 controlled studies 79.5% vs.
1.05– s ) vs. hepatic OS requires
al. studies published for HCC involving 84.5% NA
1.95) report dysfunction or further
(2020) after 2014 1755 patients (p=0431)
favorin ed GI investigation, as
g RFA signifi complication they are both local
(p=0.0 cant modalities
23) differ showing

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ence equivalent

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efficacy.”
Abbreviations: SBRT, stereotactic body radiotherapy; HFRT, hypofractionated radiotherapy; RFA, radiofrequency ablation; LC, local control; OS,
overall survival; G3, grade 3; RCT, randomized controlled trial; RILD, radiation-induced liver disease; GI, gastrointestinal; HR, hazard ratio; OR, odds

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ratio; CI, confidence interval; NA, not applicable; NS, not significant.
†
Number after balancing methods
‡
Equivalent dose in 2 Gy per fraction scheme

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SELECTION STRATEGIES AND FUTURE PERSPECTIVE

Currently, none of the clinical treatment guidelines for HCC specifically and clearly outline a
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strategy for choosing between RFA and SBRT. Nonetheless, some international guidelines
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suggest broad recommendations. The National Comprehensive Cancer Network guidelines

(NCCN 2020) stated in its version 3 (2020) edition that “There is growing evidence for the
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usefulness of SBRT in the management of HCC. SBRT can be considered as an alternative to

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the ablation/embolization techniques…or when these therapies have failed or are

contraindicated.” The European Society of Medical Oncology guidelines also stated that

“SBRT may be considered as alternative for RFA, for cases with high risk of local failure or

having difficult location.” The Asia-Pacific Association for the Study of the Liver suggested

in a similar vein that “SBRT and proton beam … are reasonable options for patients who

have not responded to other local modalities and have no extrahepatic disease, limited tumor
burden, and relatively good liver function” (Omata et al. 2017). In light of the above,

evidence for the efficacy and feasibility of SBRT for early HCCs is emerging; however, it is

not yet considered a standard option but is regarded as an alternative or surrogate choice for

intractable cases not eligible for RFA.

When choosing between the two modalities in the clinic, multiple factors should be

considered simultaneously. The higher evidence level of RFA and the advantage of SBRT in

being less affected by tumor location and size may be the most important considerations for

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each. Practical aspects, such as the fact that RFA is usually completed in fewer sessions and

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that SBRT requires costly equipment, should also be considered. In addition, RFA has a

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steeper learning curve for interventionists (Poon et al. 2004); skillful and rigorous approaches

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might enable the treatment of tumors in difficult locations, while its feasibility and efficacy

might be less certain in newly established units. Rare but serious complications such as
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neoplastic seeding and hemorrhage could still occur owing to the disease’s invariably
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invasive nature (Bertot et al. 2011; Goto et al. 2010). SBRT is less subject to learning curves

because many steps of the treatment process are computer-based and internationally
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standardized, especially regarding dose constraints of organs for safety (Hanna et al. 2018).

The factors that potentially influence both modalities are summarized in Figure 3.
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 Figure 3. Factors related to each of

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radiofrequency ablation (RFA) and

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stereotactic body radiotherapy (SBRT)

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when considering clinical treatment.

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Two trials are currently underway to directly compare each of RFA and SBRT with proton
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therapy (NCT02640924 and NCT03898921, respectively). In addition to head-to-head
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comparisons, studies that combine RFA and radiotherapy are also being conducted (RFA

alone vs. RFA and radiotherapy: NCT03988998, NCT00557024, and NCT04202523). Even
ed

if the results of randomized trials comparing RFA and SBRT are published soon, there are

several clinical and socioeconomic factors that should be considered as part of clinical
pt

decision-making, as mentioned above. Therefore, the clinical selection of either of the two
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modalities should be based on sufficient discussion between departments and must be

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determined conscientiously rather than being driven by interdepartmental competition, given

that all departments share the ultimate goal of curing the patient.

In a recent randomized study, the combined application of a vascular endothelial growth

factor-targeting agent and immune checkpoint inhibitor demonstrated superior oncologic

outcomes to that of the previous standard sorafenib (Finn et al. 2020). Although both RFA

and SBRT affect tumors locally, preclinical studies have revealed that local tumor responses
can lead to changes in the tumor microenvironment and systemic immune activation (C. Choi

et al. 2019; Tang et al. 2017; van den Bijgaart et al. 2017). TACE has also been shown to

induce tumor-associated antigen responses (Ayaru et al. 2007), and enhance the level of

anticancer immunotherapy targets (L. Wang et al. 2015). Enhanced immune activation was

observed in the tumor microenvironment of resected HCCs that underwent radioembolization

(Chew et al. 2019). Therefore, the combination of these local modalities with immunotherapy

can potentially produce clinically promising results (Greten et al. 2019). Such a combination

t
might reduce intrahepatic recurrence, which is an intractable problem even after successful

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local control of the primary tumors, and can provide a new perspective in terms of the clinical

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selection of local modalities.

Concluding remarks and our two cents us

an
In the past, treatment options for liver cancer were very limited. However, in recent decades,
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various treatment methods such as thermal ablation, arterial directed therapy, systemic

treatment, and radiotherapy have successfully demonstrated their efficacy and feasibility. The
ed

indications of these modalities might be complementary, but they can also overlap. Some

researchers have described the selection or comparison between HCC treatment modalities as
pt

a fierce battle (Sanduzzi-Zamparelli and Bruix 2018). However, the enemy of every
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physician should be the disease itself, not another doctor with a different specialty. Although
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the results of randomized studies have not yet been published, the efficacy of tumor control

using SBRT is expected to be at least comparable to that using RFA, considering data from

the various balanced studies and clinical experiences. Although survival was more favorable

after RFA than it was after SBRT in several studies, possible selection bias (e.g., if SBRT is

preferred for difficult-to-treat or recurrent lesions compared to other local modalities) should

be considered. SBRT has played an important complementary role, especially for patients
with tumors that are large or intractable. Furthermore, HCC has heterogeneous biological and

epidemiological characteristics. The amount of socioeconomic resources that can be utilized

also varies among societies. Competition among treatment modalities might advance the

efficacy of treatment itself and enable treatments that are optimized for various indications.

Overall, our opinion is that the clinical decisions regarding which modality to use should be

made after considering various factors related to treatment application, based on an individual

assessment of patients as well as on conscientiousness and not the fervor of competition.

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ed
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