Comprehending the therapeutic effects of stereotactic body radiation therapy for small hepatocellular carcinomas based on imagings

Surgical resection or radiofrequency ablation (RFA) is considered first-choice treatment for small hepatocellular carcinomas (HCCs). When a patient has a small HCC that is inoperable or unsuitable for RFA, what are alternative treatments? Some oncologists recommend transarterial chemoembolization (TACE), chemotherapy, moleculartargeted therapy, or immunotherapy. However, these treatments have minimally beneficial effects in small HCCs. Stereotactic body radiation therapy (SBRT) is a liver-directed radical therapy for small HCCs, with treatment outcomes similar to those for surgical resection or RFA, but many oncologists do not comprehend its efficacy or accept this therapy. We herein discuss 11 typical patients who received SBRT for various indications: refusal to undergo resection or RFA; surgical resection or RFA considered difficult or unfeasible; residual cancer after surgical resection or RFA or incomplete iodized oil retention after TACE; or tumor recurrence after resection or RFA. We describe each case, including the radiation field, tumor radiation dose, and response to SBRT in both the tumor and liver parenchyma. These clinical data should help readers understand this new therapeutic technique. We also conducted a literature review and found evidence to support survival benefit with SBRT, including good threeand five-year overall survival rates. The purpose of this article is to encourage readers to accept the concept that SBRT is a low-toxicity and effective therapeutic option for patients with small HCCs, which offers substantial local control and improved overall survival, especially for patients with a tumor that is unresectable or unsuitable for RFA, residual tumor after local therapy, or intrahepatic recurrent tumor.


INTRODUCTION
Recent technological advances offer precise and safe radiation delivery to tumors in various areas of the body through imaging guidance. External beam radiation therapy (EBRT) has been recommended as a therapeutic option for HCCs that are considered unresectable according to National Comprehensive Cancer Network guidelines because of the tumor's location, inadequate hepatic reserve, or the presence of comorbidities. SBRT is a type of EBRT technique requiring special equipment for patient positioning and the delivery of high-dose radiation to tumors. There is growing evidence supporting the usefulness of SBRT for patients considered unsuitable for hepatectomy or RFA. However, most oncologists or hepatologists do not understand this treatment technique because of limited use of SBRT in their clinical practice. Herein, we discuss 11 typical patients with HCC to clarify the indications, therapeutic outcomes, treatment-related toxicities, and doses of SBRT, as well as the expected post-SBRT imaging features.

DEFINITIONS
SBRT is an advanced technique of hypofractionated EBRT with photons, which delivers large ablative doses of radiation to tumors. This complex technique relies on the following: (1) stringent control of breathing motion for liver cancer, using four-dimensional computed tomography scans to track respiration-induced hepatic movement; (2) extremely precise patient positioning; and (3) image guidance for radiation delivery.
Early-stage HCC is defined as a solitary tumor with a maximum diameter ≤ 5 cm or multiple nodules (≤ 3 total), each with a maximum diameter ≤ 3 cm, without vascular invasion or extrahepatic metastasis and accompanied by Child-Pugh Class A or B hepatic function (Cases 1-3 and 5). Not all small tumors are classified as early-stage because some have decreased in size after treatment (Case 8). If intrahepatic recurrence (Cases 9 and 10) or Child-Pugh Class C (Case 11) function is present, HCC is considered later stage.

CLINICAL EFFECTIVENESS OF SBRT FOR HCC
There is a growing body of evidence indicating the usefulness of SBRT for the management of patients with HCC. We conducted a literature review and identified several retrospective studies involving the use of SBRT for HCC. These studies have primarily included patients in whom surgical resection or RFA was difficult, unfeasible, or rejected, as well as some patients with intermediate-or advanced-stage HCC. The results of these studies are summarized in Table 1. This table is restricted to studies involving the use of ≤ 10 fractions of SBRT.

Bridging before liver transplantation
SBRT is suitable bridging therapy for patients with HCC awaiting liver transplantation. Sapisochin et al. [14] compared the efficacy of SBRT, TACE, and RFA as a bridge to transplantation in a large cohort of patients with HCC and concluded that SBRT can be a safe alternative to the other, more conventional bridging therapies. However, SBRT has been safer than RFA and TACE when ascites or poor coagulation function are present, as often occurs in patients with underlying liver disease. Wahl et al. [4] 2016 Jang et al. [11] 2013 BCLC A: 53%; B: 29%; C: 18%. Ø < 7 cm 82 33 -60Gy/3Fx 63 39 87 Bibault et al. [12]

RADIATION DOSE
The SBRT dose to HCC has been significantly associated with OS (P = 0.005) in multivariate analysis. Highdose SBRT may increase local control and improve OS in patients with inoperable HCC [11] . In most studies described in the literature, a biologically-equivalent dose (BED) 10 of > 80 Gy has been delivered to the tumors [ Table 1]. Of the 11 typical patients discussed in this manuscript, all received BED10 of ≥ 78 Gy and are alive and well. Although no evidence has emerged to clearly support a minimum or maximum dose of SBRT for HCC, we recommend BED10 of ≥ 80 Gy. Currently, SBRT is most frequently used when surgical resection or RFA would be difficult or unfeasible, as with tumors located at the center of liver, in the hepatic hilar region, or close to large blood vessels (as in Cases 2 and 3, which are shown in Figures 2 and 3). It is also commonly used in patients who are older [Case 4; Figure 4] or have significant comorbidities, such as poor liver function [Case 5; Figure 5].
SBRT may also be used for residual cancer after surgical resection, as in Case 6 [ Figure 6], or after RFA, as in Case 7 [ Figure 7]. In these situations, the tumor is often expected to be difficult to treat with surgery or RFA, but these treatments are tried initially. When residual tumor is found during follow-up, SBRT will generally be the most appropriate treatment.
SBRT may serve as adjuvant treatment for intrahepatic tumors with incomplete iodized oil retention, as in Case 8 [ Figure 8]. TACE can be used to reduce the size of HCCs; however, it is often considered palliative therapy because of incomplete iodized oil retention by intrahepatic tumors. Adjuvant SBRT can function as consolidation treatment, converting palliative therapy to potentially curative therapy.
SBRT has also been used as salvage treatment for intrahepatic tumor recurrence after RFA or surgical resection [Cases 9 and 10; Figures 9 and 10]. Although metachronous intrahepatic recurrence is sometimes

CONTRAINDICATIONS FOR SBRT IN SMALL HCC
If tumors and luminal structures (esophagus, stomach, duodenum, or intestine) are closely situated at < 1 cm, SBRT is relatively contraindicated for this patient. However, hypofraction imaging-guided radiation therapy could be recommended when HCC is inoperable or unsuitable for RFA.
At least 700 mL of normal liver (Child-Pugh Class A) must receive < 15 Gy. If this condition is not met, we must be careful in choosing such patients.
The safety of liver radiation for HCC in patients with Child-Pugh Class C cirrhosis has not been established, but SBRT could be used as bridging therapy for patients with HCC awaiting liver transplantation.

HCC
Tumor response rates increase over time after SBRT. Sanuki et al. [15] reported that HCC complete response increased from 24% at three months after SBRT to 67%, 71%, and 93% at 6, 12, and 24 months, respectively, after SBRT [15] . Using modified Response Evaluation Criteria In Solid Tumor (mRECIST) criteria, complete response occurred within three months after completing SBRT in Cases 9 and 11 and > 9 months after SBRT in Cases 1, 5, and 7. Of note, we prefer to evaluate tumor response to SBRT using European Association for the Study of the Liver (EASL) or mRECIST criteria rather than RECIST criteria [16] . Case 7, for example, exhibited a complete response according to EASL or mRECIST criteria in the fourth year after completion of SBRT, but only a stable disease and partial response using RECIST criteria, at six months and one year after completing SBRT, respectively. Similarly, Case 5 had a partial response using EASL or mRECIST criteria, but stable disease using RECIST criteria, at six months after completing SBRT.

Liver parenchymal reactions
Early focal liver reaction refers to a surrounding low-intensity area observed on both computed tomography (CT) and magnetic resonance imaging (MRI) scans within six months after completing SBRT. This focal reaction is more visible in patients who undergo initial therapy with SBRT, as shown in Cases 1, 2, and 5.
The incidence of hyperdensity reactions in irradiated hepatic parenchyma may gradually increase after 6 months post-SBRT completion, potentially interfering with accurate assessment of treatment response and being misinterpreted as recurrent tumor. Lack of washout in the delayed phase in hypervascular areas helps distinguish SBRT-related changes from residual or recurrent HCC [19] . Hyperdensity will typically disappear 2-3 years after treatment, as shown in Case 6 [ Figure 6H]. Hypodensity represents the presence of regional liver atrophy within 1-2 years, as shown in Cases 1 [ Figure 1F], and 5 [ Figure 5H].
The types of focal reaction did not appear to be related to liver function in our cases. The focal liver reaction threshold dose following SBRT for HCC is 30 Gy for livers with Child-Pugh Class A function and 25 Gy for livers with Child-Pugh Class B function, when delivered in five fractions [20,21] . The doses used in our cases [ Figures 1C, 2C, and 5D] were consistent with these thresholds.

Hepatic damage
A consensus article summarizing the results of 15 previously published studies, including 1063 patients with HCC undergoing SBRT, reported that only eight patients (0.8%) developed Grade 5 liver failure, and most fatalities from liver failure occurred in patients with Child-Pugh Class B liver function [22] . However, we have observed no fatal radiation-induced liver disease in our clinical practice.
The safety of SBRT for HCC in patients with Child-Pugh Class C liver function has not been established. Class C function is generally considered a contraindication to all HCC treatment except liver transplantation.
No deterioration in liver function occurred after SBRT in Cases 5 and 11, who had Child-Pugh Class C liver function. Furthermore, some patients undergo > 1 course of SBRT, as exemplified by Case 10, who received a total of three courses because of the development of de novo HCCs. Together, these observations suggest that SBRT produces little liver parenchymal damage.

Other toxicities
Gastrointestinal toxicity is another potential concern with SBRT, especially when luminal structures, such as the esophagus, stomach, duodenum, or intestines, are close to the tumors being treated. Grade 3 or higher gastrointestinal toxicities were reported in 1.4% of patients from previously published studies, but fatal gastrointestinal bleeding did not occur [22] . Other complications, such as rib fractures, chest or abdominal wall pain, biliary stricture, and musculoskeletal discomfort, have been noted occasionally. Overall, most toxicities from SBRT are generally infrequent and mild.

THE LIMITATION OF SBRT
Firstly, there is a lack of randomized clinical trials to compare the treatment outcome among SBRT, resection, and RFA. Thus, SBRT can only be used as an alternative treatment when operation and RFA are impossible. Secondly, vaguely defined SBRT has led to inconsistent radiation doses and fractions globally, with ≤ 5 fractions in the United States and ≤ 10 fractions in the rest of the world. A dose of 55.5 Gy in 15 fractions was delivered to Case 8, and complete response was achieved. This is not strictly part of SBRT; at this point, we are not interested in the definition of SBRT, as we care more about the local control and long-term survival.

CONCLUSION
SBRT is an effective therapeutic option based on proven studies for patients with small HCCs; is complementary to the existing treatment options, as illustrated by the typical cases; and is safe with minimal toxicities.