Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver

In the medically inoperable patients with solitary hepatocellular carcinoma (HCC), local therapies, such as radiofrequency ablation and transarterial chemoembolization, are used as alternatives. However, several factors, including anatomic and vascular variants, make procedures more challenging. Radiotherapy has historically been used as a palliative option for unresectable HCC. However, recent advances in modern radiotherapy, such as stereotactic body radiation therapy (SBRT), have dramatically increased the use of radiotherapy as a curative modality, particularly in cases ineligible for local ablation therapy or surgical resection. SBRT is a modern approach for delivering ablative high doses of irradiation in small volumes. SBRT in liver tumors, including HCC, provided local control with potential survival benefits in patients with inoperable status. However, the following issues remain to be addressed: the difference between primary and metastatic liver cancers; SBRT-related toxicity and prevention; pathological features of liver cancers; and potential SBRT strategies, including radiobiology-based SBRT and SBRT combined with immunotherapy. We summarized the effectiveness of SBRT and patient tolerance of the therapy. In addition, we present the current status and future perspective of SBRT as a treatment option for HCC.


Introduction
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver [1]. Liver cancers have the seventh highest age-adjusted incidence rate in the world, with 0.8 million cases diagnosed a year [2]. The development of cirrhosis is associated with a high risk for developing HCC with most common risk factors including alcohol, viral hepatitis such as hepatitis C virus (HCV), and nonalcoholic fatty liver disease (NAFLD). Due to the wide prevalence of HCC, it carries a significant economic burden on society at large, especially in the East Asian countries that have hepatitis B virus (HBV). Surveillance programs halve also been implemented to screen for HCC in high-risk individuals, which is more cost-effective than the treatment of HCC. Hepatotropic viruses such as HBV and HCV have a strong association with the development of HCC; thus, the worldwide distribution of HCC mirrors the distributions of such viral infections [3]. Around 80-90% of HCC cases occur in the setting of underlying cirrhosis [4]. In addition, there is an incremental effect of the presence of more than one risk factor responsible for HCC as the presence of HBV/HCV coinfections increases the risk of HCC by two-to sixfolds. Similarly, alcohol abuse further increases this risk [5,6]. Subsequently, we describe the role of radiotherapy in the treatment of HCC, including conventional to modern techniques, possible beneficial cases of radiotherapy, and future direction of liver stereotactic body radiation therapy (SBRT).

General approaches and conventional radiotherapy in the treatment of HCC
The initial approach in the management of HCC is to determine if either surgical resection or liver transplantation is feasible and best survival. The Barcelona Clinic Liver Cancer staging system is the most accepted staging system in clinical settings [7]. Orthotopic liver transplantation is the most efficient option for the treatment of HCC even though the insufficient number of donors makes challenging [8]. Therefore, local therapy is anticipated to be not only a bridging therapy but also a radical therapy in the treatment of HCC. Surgical resection is the standard local therapy for HCC [7]. Since the majority of HCC cases develop in cirrhotic patients, surgical interventions can become challenging, and the treatment has been directed toward liver transplantation. Other local therapies, such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), are used as alternatives in patients with HCC [7][8][9]. However, radical treatment for liver tumors can be challenging due to poor liver function, tumor location, and anatomical barriers. Furthermore, the preservation of residual liver function is required, as liver tumors have a high recurrence potential [9].
Radiotherapy is a local treatment modality and has also been used for palliative care in liver tumors. Conventional radiotherapy has been used approximately 50 Gy in a conventional fractionated schedule which could lead to a response rate as approximately 50-70% [10][11][12][13][14]. High doses of radiation, which are required for HCC, would sometimes exceed the levels tolerated by the background liver [15,16]. However, modern radiotherapies, including stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy (SABR), have recently attracted increasing attention as a therapeutic modality for various malignancies including HCC and have dramatically increased the use of radiation therapy as a curative modality . However, certain issues regarding the current use of SBRT in HCC need to be addressed (e.g., ideal prescription doses, prevention of adverse events, and possible microscopic extension). In this chapter, we document the clinical utility and the present status of SBRT in the management of HCC, including clinical messages and pitfalls in liver cirrhosis and the probable treatment-related toxicities and their prevention, and summarize recent significant updates on biology-based SBRT strategies.

SBRT for HCC
The use of SBRT for extracranial tumors was developed by Blomgren et al. [17]. The major feature that distinguishes SBRT from conventional radiation treatment is the delivery of large doses of radiation in a few fractions, which results in a high biologically effective dose (BED). In addition, Zheng et al. have reported that a shortened delivery time could significantly increase the cell killing using in vitro experimentation [41]. The use of a high precision technique is critical to deliver a high dose of radiation to the target and keep rapid fall-off doses away from the target, thereby achieving a maximum treatment efficacy with minimal toxicity to normal tissues [42]. SBRT is now widely accepted as a treatment option for lung and liver tumors characterized by their small size and limited numbers [43].

Advantages
• High possibility of local control • Minimally invasive treatment modality, no requirements for anesthesia or injections • High possibility to overcome anatomical limitations, including poorly defined tumors on ultrasound and tumors which are difficult to puncture • No concern regarding the location close to major vessels, including the portal vein, inferior vein cava, and bile duct

Radiotherapy in the management of HCC with tumor thrombus in vessels
Portal vein tumor thrombosis (PVTT), the most common form of macrovascular invasion of HCC, could propagate further, obstruct the whole vein lumen, and lead to poor prognoses ranging from only 2 to 4 months after supportive care [44,45]. One of the treatment modalities is surgical resection that could lead to median survival time of 8-64 months, 1-, 2-, and 3-year overall survival rates of 31-87, 0-76, and 0-71%, respectively [46]. In addition, there is a potential survival benefit by surgical resection [47]. However, tumor thrombectomy can be associated with high morbidity and mortality rates, up to 23.7% [48]. TACE might be contraindicated for HCC patients with PVTT because of the potential risk of hepatic ischemic damages due to TACE. In addition, PVTT is not an indication for RFA because of the potential cooling effect and challenging status of percutaneous intervention. Although the efficacy of radiotherapy has been reported in patients with tumor thrombus using conventional schedule, the evidence of the survival benefit is insufficiently strong [39][40][41][49][50][51]. In addition, Lin et al. have reported that radiotherapy can recanalize at a rate of 79% in 14 patients with PVTT [51]. However, there are only a few comparison studies among the techniques of radiotherapy [39,51]. Matsuo et al. have reported, in a retrospective study, that the response rate of PVTT or inferior vena cava tumor thrombosis to radiotherapy was 67 and 46% in SBRT and 3D-CRT groups, respectively (P = 0.04) [39]. Moreover, SBRT has an advantage with regard to the shortened treatment term. Radiotherapy including SBRT may have the potential to be the standard technique of radiotherapy in the treatment of PVTT. Figure 3 indicates a case of SBRT for HCC with PVTT.
Radiotherapy can overcome anatomical barriers such as major vessels and achieve a promising local control with minimal invasion. Therefore, a combined multimodal approach including radiotherapy would be needed in the treatment of the HCC with PVTT in order to maximize tumor control and to keep the normal liver damages due to treatment within a safe limit.

Prescription doses of SBRT for HCC
A dose-response relationship has been reported for conventional fractionated and stereotactic radiotherapy, although the best prescription dose of radiotherapy for HCC remains undecided [12,27,52].  [28,29]. Figure 4 shows no dose-response relationship between a 2-year local control and overall survival rates and the total BED of SBRT with the range of prescription doses of ≥72 Gy. Notably, previous reports include various prescription definitions such as the prescription dose for the iso-center (isocentric prescription), a certain percent isodose line of the maximum dose (marginal prescription), and the dose to cover 95% of the PTV (D95 prescription). Based on these data, HCC has been treated with ≥80 Gy of BED 10 and achieved a good local control at our institute as we hypothesized [37].
To distinguish acute and late phases of toxicities is often difficult since liver damage with serum abnormalities can be observed weeks or months later after SBRT [16]. We summarize with focusing on the major toxicities in the liver, gastrointestinal tract, and central bile duct.

Liver toxicity
Liver toxicity, such as classic and non-classic radiation-induced liver disease (RILD), is one of the most common dose-limiting toxicities in liver radiotherapy [15,16,56,57]. Clinical RILD occurs between 2 weeks and 7 months, typically within 4-8 weeks following hepatic radiotherapy. The patient presents with fatigue, weight gain, increased abdominal girth, hepatomegaly, anicteric ascites, and an elevation in alkaline phosphatase (over twice the upper limit of the normal values). Treatment options for RILD are limited, and the condition can become fatal due to liver failure [56,[58][59][60][61]. Non-classic RILD occurs in patients with underlying chronic hepatic disease, such as cirrhosis and viral hepatitis, and is characterized by jaundice and/or markedly elevated serum transaminases (over five times the upper limit of the normal values), developing between 1 week and 3 months after the completion of hepatic radiotherapy [19,61]. The mean dose of less than 30 Gy has been considered as safe but radiation tolerance of the liver in a conventional radiotherapy [19]. However, the actual mean doses appropriate for liver irradiation in SBRT have not been adequately investigated. Furthermore, radiotherapy has the potential to reactivate hepatitis B virus and differentiating patients may be necessary [62,63]. There are differences in radiosensitivity between patients with normal and cirrhotic livers; cirrhotic liver may yield a higher radiosensitivity than normal liver [16,57]. In addition, Child-Pugh B, particularly scores of ≥8, was considered a significant risk factor for severe hepatic toxicity and poor prognosis [21,31,64]. Culleton et al. reported that 63% of 29 HCC patients with Child-Pugh B or C, receiving SBRT, declined Child-Pugh score by two points after 3 months [31].
As the liver is widely accepted as a parallel organ, a part of it can receive a high dose of irradiation as long as the functions as a whole organ are preserved [65][66][67]. Indeed, Schefter et al., Olsen et al., and Kang et al. used dose constraint, as the liver volume was >700 mL when the dose administered was less than 15 and 17 Gy in three fractions [22,68,69]. However, intrahepatic recurrence often occurs after a radical treatment for liver tumors because of chronic liver diseases, and such tumors have a chance to receive second radical treatment [9,70]. Thus, the prediction of the volume of liver dysfunction is essential in order to spare the residual liver volume. After SBRT, focal dysfunction was noted in the irradiated background liver. Sanuki et al. have shown that the threshold dose of focal liver dysfunction was 30 and 25 Gy in five fractions in patients with Child-Pugh A and B, respectively, using magnetic resonance imaging (MRI) [71]. Similarly, Doi et al. have reported that focal liver dysfunction can occur at 40 and 70 Gy of BED 2 in the cirrhotic and normal liver, respectively, at a minimum dose [57]. Figure 5 indicates a focal liver damage 3 months after SBRT. We have presented SBRT strategy with checkpoints to ensure safe treatment modality in SBRT for liver tumor [72]. To prevent RILD-related mortality, we evaluate the mean doses for the liver first and then analyze the potential loss of hepatic function in terms of BED (Figure 6).

Gastrointestinal injury
Ionizing radiation exerts an anticancer effect by reacting with molecular oxygen and water to generate reactive oxygen species that can attack deoxyribose in deoxyribonucleic acid (DNA). Sublethal doses of radiation can cause non-repairable DNA damage [73]. Intestine is a radiosensitive tissue because of the rapid turnover rate, and this can be a dose-limiting factor in SBRT. Gastrointestinal injuries including bleeding, ulcers, and perforations have been described, and the incidence of symptomatic gastrointestinal toxicities was less than 10% in majority of the previous reports ( Table 2). However, severe toxicities, which can be lethal, have also been described in SBRT in the upper abdomen including liver [22,30,[74][75][76]. Kang et al. have highlighted the possible association between severe gastrointestinal toxicity and the existence of mucosal ulceration prior to radiotherapy [22]. Barney et al. reported that the combination of SBRT and vascular endothelial growth factor inhibitor increased the risk of grade 3 or greater gastrointestinal toxicities [77]. Careful assessment is therefore required prior to the implementation of combined treatments, such as targeted therapy. Kavanagh et al. recommended that the volume of stomach receiving >22.5 Gy should be ideally minimized to <5 cc, with Dmax of <30 Gy in three fractions [80]. Sanuki et al. suggested that SBRT could be performed with the avoidance of severe toxicities when the target had a distance of >2 cm from the bowel [81]. An increased number of fractions may reduce BED for normal tissues in SBRT for liver tumors close to the gastrointestinal tract [57]. Since there are no established strategies for the prevention and treatment of radiation-induced gastrointestinal injury, efforts should be required to minimize radiation doses for gastrointestinal tracts [82].

Central hepatobiliary tract toxicity
Eriguchi et al. documented asymptomatic bile duct stenosis in 2/50 patients, receiving >20 Gy in five fractions to the central liver [83]. One of these patients received SBRT on two occasions to the central liver tumors and developed abnormalities in liver enzymes. The abnormal region visible on a computed tomography scan corresponded to the site irradiated up to a cumulative maximum dose of 88 Gy in two sessions of SBRT. The authors concluded that SBRT for liver tumors in the hepatic hilum was feasible with minimal biliary toxicity. Osmundson et al. analyzed 96 patients with liver tumors, including 20 CCCs, who received different schedules of SBRT, and reported that the incidence of hepatobiliary toxicity ≥Grade 2 and 3 was 24.0 and 18.8%, respectively [84]. Furthermore, CCC, biliary stent, V BED10 72 ≥ 21 cc, V BED10 66 ≥ 24 cc, and DmeanBED 10 ≥ 14 Gy to central hepatobiliary tract were associated with hepatobiliary toxicity [81]. The same groups reported radiation-induced pathological changes of the bile duct in resected surgical specimens 25 months after SBRT and concluded that liver toxicity should be considered while treating central liver lesions [85]. The same group has also reported a dose-volume association between ≥Grade 3 hepatobiliary toxicity and doses for central biliary tract and suggested V BED10 40 < 37 cc and V BED10 30 < 45 cc as dose-volume constraints in SBRT for primary liver tumors [86].
The anatomical structures in the hepatic hilum make radical treatment for liver tumors, such as surgery and RFA, more challenging. In such a scenario, SBRT can be a better option in comparison to other modalities, and to the best of our knowledge, there is no apparent consensus on the use of SBRT with few reports addressing this point. Further studies are required to determine the dose constraints for the bile duct, as there can be potential dose constraints due to the central hepatobiliary tract toxicity.

Current issues and future perspective of liver SBRT
Liver SBRT is a well-established and promising treatment for a limited number of small tumors. We have set out the difference between primary and metastatic liver cancers, considering the occurrence and prevention of toxicities. However, further questions regarding the pathological features of liver cancers, and potential SBRT strategies, including radiobiologybased SBRT and SBRT combined with immunotherapy, have not yet been fully addressed. Figure 6. The current recommended treatment protocol to provide a safe SBRT for HCC in cirrhotic liver. To minimize the risk of radiation-induced liver disease and liver damage, two different checkpoints were included. Herein, we propose a safe treatment protocol for SBRT of liver tumors. First, liver function is evaluated according to the Child-Pugh classification (Step 1). Next, the liver doses are evaluated to prevent RILD. A mean BED 2 of less than 73 and 16 Gy for the whole liver should be maintained to prevent RILD in patients with Child-Pugh A and B liver function, respectively (Step 2). Finally, the volume of hepatic dysfunction is assessed to estimate the residual liver volume (Step 3). Abbreviations: SBRT, stereotactic body radiation therapy; HCC, hepatocellular carcinoma; BED, biologically effective dose.

Potent strategies of SBRT based on radiation biology
Brown et al. reported that a greater endothelial cell damage and vascular damage, leading cancer cell apoptosis, can be caused by SBRT, and reoxygenation can increase antitumor effect in fractionated radiotherapy [87]. Shibamoto et al. concluded that reoxygenation could be promoted by a 72-h break period in SBRT [88]. No prospective clinical trials exist in terms of evaluation of the benefit of a break in SBRT. However, a longer overall treatment time (e.g., 1-2 fractions per week: 2-week schedule) may yield better local control outcomes in SBRT [89,90]. SBRT for larger tumors has still unclear roles and is challenging because they are usually in exclusion criterion.
In addition, large tumor size (≥2-4 cm) has been reported to be a predictive factor for poor outcomes after SBRT for HCC [23,30,32]. Further biological assessment might yield potential factors that improve treatment outcomes such as escalated doses, treatment schedule with a break, combined therapy with ideal chemotherapy, individualized treatment, and particle therapies.

Potential needs of clinical tumor volume margin in liver SBRT
Definition of clinical tumor volume (CTV) is the volume that includes both gross and microscopic disease and is created by adding several mm to 1.5 cm to gross tumor volume (GTV), in order to allow for microscopic extension. However, CTV is frequently equal to GTV in SBRT [91]. It is still poorly understood whether CTV margins are necessary, as there are limited reports of microscopic extension of liver tumors as premises for radiotherapy. HCC is characterized by direct invasion and a potential high presence of daughter nodules around the tumor that may lead to locoregional recurrence [92]. Wang  have first reported that a larger margin to GTV inclined to improve local control and survival outcomes in clinical data, suggesting the benefit of CTV margins [37]. Further clinical translational studies should be conducted in order to assess the optimal CTV margins.

Current knowledge of Immuno-SBRT
Regression of tumors outside the radiation field after local radiotherapy, due to systemic induction of antitumor immunity, is called the abscopal effect [95]. SBRT combined with immune checkpoint inhibitor has recently resulted in unexpected clinical complete responses from distant sites from the irradiated areas, in various malignancies [96][97][98]. Recently, synergistic effects of radiotherapy combined with immunotherapy have been reported in both preclinical and clinical studies, with the high possibility of the abscopal effect, which may significantly change the treatment strategies for metastatic diseases [96][97][98][99][100][101][102][103][104][105]. However, the optimal treatment schedule and doses in the combined setting of radiotherapy and immunotherapy are poorly understood at present. Young et al. reported an enhanced efficacy of immune-radiotherapy administered concurrently with radiotherapy [101]. In a meta-analysis of preclinical data, Marconi et al. reported that the probability of abscopal effects is 50% when a BED of 60 Gy is generated [102]. Moreover, SBRT may provide smaller target volumes, and in a clinical trial involving patients with pancreatic cancer, Wild et al. found that hypofractionation could minimize the toxic effects on circulating lymphocytes [106]. By expanding its application range from small tumors to metastases, SBRT might have good potential to achieve newer objectives in systematic disease, although further investigations are required.

Advantages of particle therapy in treatment for HCC in cirrhotic liver
The use of particle therapy, such as proton and carbon ion therapy for liver tumors, is a promising strategy to increase the dose of radiation without a concurrent increase in toxicity.
Particle therapy exhibits a narrow Bragg peak at a defined depth for a defined energy [73].
Particle therapy can provide high concentrations of radiation doses to the target by positioning individual Bragg peaks to coincide with the areas of the target. In photon radiotherapy, the doses that the liver receives have a strong positive relationship with the irradiated target volume, and unacceptable higher doses might be irradiating to the background liver in the treatment of large live tumors [72]. Particle therapy can reduce the liver volume that receives low to intermediate doses, resulting in the reduction of mean liver doses with an advantage of target conformity [107,108]. In addition, carbon ion therapy offers the added potential benefit of an increased relative biological effectiveness and a lower oxygen enhancement ratio due to the high linear energy transfer that may improve responses in hypoxic areas of tumors, which are more resistant to photon radiotherapy [73]. A relevant clinical consideration is that particle therapy can benefit relatively large tumors, such as >3 cm (particularly >5 cm) and patients with poor liver function, which are limiting for SBRT [109].

Conclusions
For HCC, SBRT is safe and effective, with excellent local control achieved. Tumors that are relatively small and distant from gastrointestinal tissues are strong candidate for SBRT in curative intent. Therefore, novel strategies should be developed based on new knowledge of biological responses to radiation therapy. State-of-the-art liver SBRT remains a pioneering strategy in multimodal therapy.