**2.4 Treatment schedules with SBRT in hepatocellular carcinoma: Dose and fractionation**

A wide variety of doses and fractions have been described for the treatment of hepatocellular carcinoma with SBRT. These doses vary according to different studies from 30 to 50 Gy in 3–6 fractions. Liver function and the dose received by healthy organs influence the choice of the prescription dose. Some studies have shown that the administration of higher doses is decisive for local control and overall survival, but others have not. In fact, hepatocellular carcinoma is considered a radiosensitive tumor, such that, above a threshold dose, there may be little benefit in additional

doses with increased toxicity. For small tumors far from healthy tissues (especially gastrointestinal organs), 40 Gy in five fractions can be used. For larger tumors, where doses must be limited due to hepatic tolerance, individualized schedules can be used in each prescription [11, 30]. In addition, this may vary according to the treatment planning technique.

Prescribing doses have not yet been fully defined; there are many different treatment schedules in the literature. It is important to emphasize that patients with Child Pugh stages B 8–9 and C are underrepresented in SBRT studies [29, 31]. When they are included, radiotherapy doses are reduced. Given the underrepresentation of these patients in studies, Culleton et al published prospective (14 patients) and retrospective (15 patients) data with Child Pugh B and C, 76% with portal vein tumor invasion and 24% with extrahepatic disease. The median dose prescribed was 30 Gy in six fractions. Overall survival was 32% at 1 year and better in patients with Child Pugh B7 compared to higher Child Pugh. Progression at 1 year was 45%, and worsening of functional class 2 was observed in 63% at 3 months. The most common side effect was Grade 1–2 asthenia. There were no toxicities greater than or equal to grade 3. There was no tumor progression despite lowering the dose. Sixty percent of patients died in the first year due to liver disease with or without active hepatocellular carcinoma. Elevated AFP was associated with worse survival [7]. Dose recommendations have recently been published by the ASTRO [26].

#### **2.5 Side effects with SBRT in hepatocellular carcinoma**

In addition to the doses in the treatment volume, the assessment of doses in healthy organs, in the unaffected liver, and in gastrointestinal organs is very important.

Radio-induced liver toxicity, radio-induced hepatitis, or radio-induced liver disease (RILD) is a form of subacute liver damage due to radiotherapeutic treatment. However, it has been described in other treatments such as chemotherapy administration and in conditioning for marrow transplantation. It is one of the most feared complications in radiotherapeutic treatment and hinders dose escalation and re-irradiation of hepatobiliary or lower gastrointestinal tract tumors [32, 33].

Biliary toxicity includes the risk of biliary stricture, duodenal, gastric or intestinal toxicity, ulceration, and perforation. ASTRO has recently published tolerance recommendations for these organs at risk [28]; see **Table 2**.

Other studies include dose limits in large vessels and esophagus. Tolerance limits in large vessels include doses of 50Gy/5 fractions (40–60Gy, 3–5 fractions) and maximum dose on large vessels of 52.5Gy in five fractions with a grade 3 toxicity of 0.2%, grade 4 of 0%, and grade 5 of 0.3%26. Esophageal dose limits include maximum doses of 32.3–43.4 Gy in five fractions or 35Gy in four fractions [34].

### **2.6 Factors of response in SBRT of hepatocellular carcinoma**

#### *2.6.1 Local control*

In the literature, there is great heterogeneity of doses, and the optimal dose has not been established. The aim is to develop models of the dose-control relationship in order to optimize treatment. Lausch et al used their data to develop a model, including 36 patients with hepatocellular carcinoma treated with a median of 4 Gy in each session (2–10 Gy), with a total median dose of 52 Gy (29–83 Gy). The investigators demonstrated radiosensitivity of hepatocellular carcinoma with respect to liver


#### **Table 2.**

*Dose-limiting organ risk dose recommendations for liver and luminal structures according to ASTRO guideline [26].*

metastases, including colorectal metastases, and suggested that increasing the dose increases local control [35]. Jang et al developed a model based on tumor size, demonstrating that high doses are necessary to achieve tumor control in large lesions [12]. In addition, a Tumor Control Probability (TCP) model has recently been published with multi-institutional data, including a total of 431 patients with hepatocellular carcinoma, concluding that there does not appear to be a dose-response relationship in SBRT in hepatocellular carcinoma. The authors recommend conservative schedules in hepatocellular carcinoma, such as 8–10 Gy per fraction in five fractions; doses >50 Gy in five fractions increase the risk of toxicity without improving local control [36]. In the study by Cardenes et al, dose escalation from 36 Gy, with increments of 2 Gy in 2 Gy, was studied, finding that the dose of 48 Gy in three fractions (Biological Effective Dose (BED) = 125 Gy, EQD2 EQD2 =104 Gy) presented a local control at 2 years of 90% and minimal toxicity [37]. Jang et al found that an increase in EQD2 from 104Gy to 126Gy resulted in an increase in local control from 90 to 100% [30]. Yamashita et al analyzed the treatment of 79 patients with hepatocellular carcinoma, finding no difference in local control with doses above and below 100 Gy of biologic equivalent dose. Their local control at 2 years was statistically different when comparing lesions above and below 3 cm in maximum diameter (local control 64% vs. 85%) [13]. The dose response may simply reflect the variation in lesion size in different trials and the ability to give a high dose in small lesions.

## *2.6.2 Overall survival*

Another major topic of discussion is whether dose is related to survival. In 2013, a prospective study with 102 patients with Child Pugh A hepatocellular carcinoma, Bujold et al demonstrated that patients receiving <30 Gy in six fractions (BED=45 Gy, EQD2=38 Gy) vs. 30 Gy had local control at 2 years 66% vs. 85% [12]. This difference did not translate into improved overall survival, being, however, the major cause of

progression. These data suggest that dose escalation does not increase overall survival. A Korean study by Seong et al included 398 patients (Child Pugh A 73.9%) from 10 different centers. This study demonstrated an overall survival benefit for patients who received BED>=53Gy [38]. Dose escalation is limited by the tolerance of the organs at risk. There are nomograms and multivariate models that demonstrate that liver function, especially in Child Pugh B and C, and tumor size are more determinant in survival compared to dose escalation. Although dose correlates with local control, and local control with overall survival, only in a minority of patients does it result in a survival benefit. Doses in hepatocellular carcinoma higher than 84 Gy do not seem to be justified by the minimal increase in local control and significant increase in toxicity. In the study by Myungsoo et al, a tumor volume greater or less than 214 cm3 and a total dose greater or less than 105 Gy of effective biological dose were established as prognostic factors for progression-free survival. Based on these factors, patients were divided into a favorable and unfavorable prognostic group. Local progression-free survival and overall survival were better in the favorable group than in the unfavorable group (2-year local progression-free survival rate: 51.3% vs. 30.0%, 2-year OS rate: 72.8% vs. 30.0%) [39].
