SBRT in Hepatocellular Carcinoma

Abstract

Stereotactic body radiation therapy (SBRT) is a precision treatment that allows high doses of radiation to be administered to the tumor volume while limiting the dose received by the surrounding healthy organs. This makes it possible to administer ablative doses to the tumor with high local control, making it an alternative in the treatment of hepatocellular carcinoma. This treatment is indicated in patients as a bridge to transplant, inoperable, or complementary treatment to other therapies such as embolization, with local control above 90% according to series. Doses and fractions are variable, and the optimal scheme has not been established. The use of this therapy has increased in recent years, although its evidence is limited. Prospective randomized studies are necessary to make this treatment the first line of action.

1. Introduction

Stereotactic body radiation therapy (SBRT) is derived from the concept of radiosurgery. The American Society of Radiation Oncology (ASTRO) describes it as high-dose, image-guided radiotherapy treatment with tumor ablative intent in a limited number of fractions. Other names used are extracranial stereotactic radiosurgery or stereotactic ablative radiotherapy (SABR) [1].

The success of radiosurgery in intracranial tumors raised interest in its application in the management of extracranial tumors. However, the development of extracranial SBRT has been much later than that of radiosurgery due to the constant internal movement of the organs by respiration and bowel movements. At the cellular level, SBRT produces cellular chromosomal damage, endothelial cell apoptosis, microvascular dysfunction, and increased lymphocyte recruitment.

ASTRO has published recommendations for SBRT treatment, and the American Association of Medical Physics Task Group 101 report has expanded on them [2, 3]. It is necessary to use systems that improve volume delineation and image fusion, including magnetic resonance and/or positron emission tomography, advanced planning algorithms, image-guided radiotherapy systems, intrafraction motion control methods, and patient immobilization systems to achieve stable and reproducible patient positioning, for which various devices that suppress or limit motion have been developed [4].

The process involves a sequence of phases, and the same applies to SBRT treatments. These phases include patient immobilization, motion assessment and management, image acquisition, image set analysis and processing, planning image fusion, volume delineation, radiation planning, quality assurance testing, patient setup in the treatment unit, acquisition of guidance images to allow target relocalization, treatment initiation, real-time monitoring of treatment integrity, and patient stability and tolerance [4].

The main obstacle that must be overcome to perform SBRT treatments involves respiratory-related motion control. Positioning errors during treatment or between treatments must also be taken into account. Image-guided radiation therapy or imaged-guided radiation therapy (IGRT) ensures target relocalization and beam alignment, which is indispensable in SBRT [4].

In SBRT, high-energy photons are used as the source of therapeutic radiation, although charged particles can also be used. There is no standard or absolute consensus solution for achieving a tightly focused high-dose distribution within the planning target volume and rapid dose fall-off outside it, the combination of beam angles or arcs best suited, and each case may present a new planning challenge. These treatments are tailored and personalized to each patient and each tumor [4]. Planning example is shown in Figure 1.

Figure 1.

Hepatocellular carcinoma planning in Cyberknife®.

SBRT treatment sessions are longer than conventional treatments, so patient comfort is another important aspect, controlling patient changes in position between the time of treatment verification by imaging and treatment or even during treatment [4].

2. SBRT in hepatocellular carcinoma

2.1 Indications of SBRT in hepatocellular carcinoma (HCC)

SBRT is indicated in hepatocellular carcinoma that is not a candidate for other therapies, including surgery, radiofrequency, or transarterial chemoembolization (TACE) due to tumor location, proximity to vessels or biliary tract, and/or size. Its use in combination with the aforementioned techniques is also postulated. More evidence is needed for it to become a therapeutic modality of first choice. Data on quality of life can help in this process, making the technique not only effective, but also comfortable and with a low impact on patients’ quality of life.

SBRT is an effective treatment for hepatocellular carcinoma with acceptable toxicity rates in selected patients. Despite being a procedure intended for patients who are not candidates for other treatments, it has demonstrated excellent local control in prospective and retrospective studies (studies are summarized in Table 1). It can be used as an exclusive treatment or in combination with other treatments. Based on the available data, it appears to complement local techniques.

Study	Child Pugh (CP)	n	Lesions	PVT (%)	Size	Doses (fr)	Follow-up	OS (2 a)	Toxicity
Lasley et al Phase-I-II (2015) [5]	A; B7/8+: 81/19	59	39; 26	20	33.6 cc (2.0–107.3)	48Gy (36–48)/3) CPB: 40/5; Median 30Gy (6)	33.3 m CP A; 46.3 m CP B	2-y: 72% CPA; 33% CPB; 3-y: 61% CPA; 26% CPB	Liver: 4 p CPA; 8p CPB Grade 3/4
Kang et al Phase-II (2012) [6]	A; B/AC	41; 6; 5	56	11	2.9cc (1.3–7.8)	42–60Gy (3)	17 m	68.7%	Gastrointestial:3p Grade 3; 2p Grade 4
Culleton et al (2014) [7]	B7/8/9: 69/24/3; C10:3	29		76		30Gy (6)		1-y 32%	63% had decline in CP score by 2 or more at 3 months
Méndez Romero et al phase II (2006) [8]			45; 11 HCC	25	3.5cc (0.5–7.2)	25Gy (5); 30Gy (3)	12.9 m	1-y 75%	4p =>Grade 3; 1p CP B liver failure
Sanuki et al (2014) [9]	A; B/A	137; 48	185	—	<5cm	40Gy; 35Gy	24 m	3-y: 70%	24p >Grade 3; 19 p worse 2 points CP; 2p G5 liver failure
Su et al (2016) [10]	A; B/AC	114; 18	175	—	3cm (1.1–5.0)	42–46 Gy (3–5) 28–30Gy (1)	21 m	1-y: 94.1%; 3-y: 73.5%; 5-y: 64.3%	11p => Grade 3
Scorsetti et al (2015) [11]	A; B	43	63	20	4.8cc (1–12.5)	48–75Gy (3); 36–60Gy (6)	8 m	1-y: 77.9+/−8.2; 2-y: 43.5+/−14	7p =>Grade 3; No RILD
Bujold et al Phase-I-II (2013) [12]	A/; AC	102; 55		55	7.2cc (1.4–23.1)	36 (24–54)/6	31.4 m	1 a: 55%	=> Grade 3 30%
Yamashita et al (2015) [13]	A; B	67; 9		—		48 Gy (4); (40Gy/4–60Gy/10)	21 m	2-y: 53%	No Grade 3
Andolino et al (2011) [14]	A; B /AC	36; 24	60		3.2 cm	44Gy (3); 40Gy (8)	27 m	67%	No =>Grade 3; 13% liver >Grade 1; 20% worse CP
Bibault et al (2013) [15]	A; B/AC	67; 8	96	—	3.7cm (3.0–4.4)	40–45 (3)	10 m	1-y: 78.5%; 2-y: 50.4%	No => Grade 3
Park et al (2013) [16]		26	28		<6cm	40–50Gy (10)		1-y: 88.5%; 2-y: 67.2%	>Grade 3 1 p
Takeda et al (2014) [17]		73		—		35–40Gy (5)	31.3 m	1-y: 100%; 2-y: 87%; 3-y: 73%	Liver Grade 3 = 32 p
Wahl et al (2016) [18]	A; B; C	57; 24; 2	83	—	2.2 cm	30–50Gy		1-y: 70%; 2-y: 53%	Grade >3 3p

Table 1.

Retrospective and prospective studies of hepatocellular carcinoma SBRT.

HCC: hepatocellular carcinoma, PVT: portal vein thrombosis, OS: overall survival, and RILD: radio-induced liver disease.

The combination of SBRT and TACE offers theoretical advantages by decreasing tumor size facilitating SBRT with smaller tumors, and chemotherapy can be radiosensitizing. In addition, lipiodol is radiopaque and may aid IGRT [19].

Patients with portal vein invasion by hepatocellular carcinoma have a very poor prognosis. However, they have been included in treatment with SBRT [5, 6, 7] with encouraging results. Recanalization after SBRT facilitates treatment with TACE, which is less effective in vascular invasion. Partial and complete responses have been described with SBRT 37–75% with recanalization in 44–76% and low rates of severe toxicities [20, 21]. The maximum response time can be a few months.

Around 25–44% of patients on the transplant waiting list progress to transplantation. SBRT can help reduce this. Between 63% and 100% of patients reach transplantation with low toxicity rates and partial or complete response in 14–27% and 23–64% of lesions [22, 23]. Mohamed et al compared SBRT, TACE, radiofrequency, and Yttrium-90 microspheres as bridging therapy to transplantation in a retrospective series with 60 patients [24]. Mean necrosis was not statistically significant between treatment modalities, and toxicities were lower with SBRT and Yttrium-90. Despite being retrospective studies with few patients, it appears that SBRT is an effective and well-tolerated treatment as a bridge to transplantation and is competitive with other treatments.

Another scenario being explored is the combination with immunotherapy; the antigenic exposure produced by SBRT and the possible potentiating effect of immunotherapy, already demonstrated in other tumors, have been described. Studies are currently underway to explore the usefulness of the combined treatment of SBRT and immunotherapy due to the excellent results of immunotherapy in hepatocellular carcinoma [25].

The comparative studies available in retrospective series suggest that SBRT is a competitive treatment with other more established treatments. Given its potential, prospective comparative studies are needed [26].

2.2 Technical characteristics of SBRT in hepatocellular carcinoma

After correct immobilization of the patient, a planning CT scan is performed. The patient will be placed in supine decubitus position with the arms behind the head, avoiding that they remain in the entrance of the treatment beams. For the correct acquisition of the image, it is essential to know the contrast uptake times of each of the lesions and the need or not to use oral contrast when the stomach is close to the treatment field.

The CT image for hepatic SBRT will be acquired with intravenous contrast. The way of acquiring the contrast varies according to the location and type of tumor. The most commonly used contrast in MRI is gadolinium; however, there are organ-specific contrasts in MRI, and these are mainly used in the diagnosis of focal hepatic lesions in which previous imaging tests have been inconclusive. The three agents that have been developed for this purpose are mangafodipir trisodium (Mn-DPDP), gadobenate dimeglumine (Gd-BOPTA), and gadoxetic acid (Gd-EOB-DTPA). Poorly differentiated HCC does not pick up these contrasts, but it has been described that some well-differentiated hepatocellular carcinoma may do so.

2.2.1 Image acquisition in hepatocellular carcinoma

Because of its special behavior, CT contrast acquisition for hepatocellular carcinoma is somewhat different from other tumors. In the normal liver, hepatic irrigation is mainly by the portal vein and to a lesser extent by the hepatic artery. In the process of hepatocarcinogenesis, arterial vascularization predominates over portal vascularization. For this reason, the diagnosis of hepatocellular carcinoma is based on its vascular behavior and radiological studies are performed with contrast in arterial, portal, and late phases, in addition to alpha-fetoprotein levels and histological analysis.

The typical radiological characteristics of hepatocellular carcinoma in both CT and MRI in the dynamic study are contrast hyperenhancement in the arterial phase with early washout in the late phase, the latter phase being decisive for the diagnosis as it becomes hypodense/hypointense with respect to the normal liver parenchyma, presenting in some cases a pseudocapsule image. Another important characteristic of hepatocellular carcinoma is its internal mosaic appearance due to the presence of areas with different density in CT or heterogeneous signal in MRI that mainly appear in the postcontrast study.

Sometimes hepatocellular carcinoma can be hypovascular and show no arterial hypervascularization, in which case the portal and late phases are very important, where they remain hypodense/hypointense or even have atypical behavior with hyperenhancement in the arterial phase and absence of late washout [27].

The signal characteristics of hepatocellular carcinoma on MRI is variable. In T1-weighted sequences, about one-third are seen as hypointense lesions, one-third are isointense, and another third are hyperintense (due to hemorrhage or fatty degeneration). In T2-weighted sequences, the signal intensity is closely related to the degree of malignancy, and the higher the degree of malignancy the more hyperintense in T2. Sometimes, there may be hypointense areas in T2 sequences, related to the presence of a scar, old bleeding (hemosiderin), or necrosis. In cases in which the capsule is present, it is hypointense in T1 and hyperintense in the postcontrast study. Fat deposition is easy to demonstrate on MRI (up to 14%) using T1 sequences. Peritumoral edema corresponding to compressed liver parenchyma can be seen in approximately 20% of cases. In diffusion sequences, hepatocellular carcinoma shows signal hyperintensity, with low ADC values, which translates a diffusion restriction due to high cellularity.

2.2.2 Volume delineation

The imaging test used in the calculation algorithms for radiotherapy is CT; however, the definition of the gross tumor volume (GTV) in planning CT in liver tumors sometimes requires the use of supporting imaging tests that allow a correct visualization of the tumor, including different phases, sequences, or contrast acquisition times.

The efficacy of SBRT is totally dependent on the delimitation of the GTV, and an erroneous delimitation would mean on the one hand leaving tumor volume out of the irradiation field and on the other hand irradiating more healthy tissue than necessary, increasing the possibility of side effects.

The definition of the GTV in hepatocellular carcinoma requires the identification of abnormal areas in all phases of a multiphase CT and/or MRI. The definition of GTV typically represents a union of these findings. When vascular thrombosis is present, the definition of the lesion is more complex and is best visualized in the venous or late phases, requiring multiple images [28]. In liver metastases and pancreatic adenocarcinoma, PET/CT could be of added value in tumor delimitation to CT and/or MRI, although it is difficult to define the borderline uptake area (SUV).

2.3 Local control with SBRT in hepatocellular carcinoma

In the literature, there are multiple prospective studies, phase I and II, of SBRT in hepatocellular carcinoma with local control at 2 years ranging from 64 to 95% (Table 1).

Méndez Romero et al published the first prospective study in 2006. Eight patients had hepatocellular carcinoma with 11 lesions larger than 7 cm. Dose prescription was based on lesion size and the presence of cirrhosis. Local control at 1 year was 75%. Local failure was only observed at low doses (25 Gy in 5 fractions) [8]. Kang et al published a phase II study including patients with incomplete response to TACE and Child Pugh A. Local control at 2 years after SBRT (42–60Gy in three fractions) was 95% [6].

Two of the retrospective studies with the largest number of patients are the study by Sanuki et al, in 2013, and Su et al [9, 10]. The former included 185 patients with 185 lesions, <=5cm. The prescription doses were 40 and 35 Gy for Child Pugh A and B, respectively, in five fractions. Local control at 3 years was 91%19. In the study by Su et al, the authors who published the result of 114 Child Pugh A and 18 B non-candidates for other treatments, with 175 lesions, all less than or equal to 5 cm treated with 42–46 Gy in 3–5 fractions, local control at 1 year was 91% [10].

Recently, Rim et al performed a systematic review and meta-analysis analyzing 32 studies with 1950 patients, including local control and overall survival (OS) as the primary objective, and toxicity as a secondary objective. Local control at 3 years was 83.9%. The median tumor size was 3.3 cm (1.6–8.6 cm). The median dose, calculated in EQD2 (equivalent dose in 2 Gy fractions), was 48–114.8Gy (median 83.3 Gy). Concluding that SBRT in hepatocellular carcinoma provides excellent local control at 3 years [29]. Most of these studies include patients with hepatocellular carcinoma in Child Pugh A and B cirrhotic livers. In all of them, there is great heterogeneity in dosimetric parameters with doses ranging from 12 Gy in three fractions to 55 Gy in five fractions.

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.

Organ at risk	Three fractions	five fractions	Toxicity
Liver, non-cirrhosis	Median < 12–15Gy; > 700cc>19Gy	Median < 15–18Gy > 700cc <21Gy	RILD
Liver, CP A	Media < 10–12Gy	Median < 13–15Gy; >700cc<15Gy	Increase in CP > 2 at 3 months
Liver, CP B7	—	Median < 8–10 Gy; >500cc < 10Gy	Increase in CP > 2 at 3 months; RILD
Biliary tract	D0.03cc < 37.7Gy	D0.03cc > 40.5Gy	Stenosis
Gastric	D0.03cc < 22Gy; D10cc < 16.5Gy	D0.03cc < 32Gy; D10cc < 18Gy	Ulcer
Duodenum	D0.03cc < 22Gy; D5cc < 16.5Gy	D0.03cc < 32Gy; D5cc < 18Gy	Ulcer
Small bowel	D0.03cc < 25Gy; D5cc < 18Gy	D0.03cc < 32Gy; D5cc < 19.5Gy	Ulcer
Large bowel	D0.03cc < 28Gy; D5cc < 24Gy	D0.03cc < 34Gy; D5cc < 25Gy	Ulcer

Table 2.

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

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 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].

3. Overall survival

Overall survival is around 66.7% at 3 years [40]. In the study by Méndez Romero et al, overall survival at 1 year was 75%18 and in the study by Bujold et al, 55% (24–54 Gy in six fractions) [12]. And in the study by Su et al, overall survival at 1 year was 94%20. Kang et al reported an OS at 2 years after SBRT (42–60 Gy in three fractions) of 69% [6]. In the study by Sanuki et al, overall survival at 3 years was 70%, with no difference between doses of 35 and 40 Gy [9]. Overall survival at 1, 2, and 3 years in the study by Rim et al. was 72.6, 57.8, and 48.3%, respectively [29].

When the intention of the treatment is neoadjuvant, the aim is to prevent progression of patients on the waiting list for liver transplantation and to prevent them from leaving the waiting list. SBRT is an effective treatment as a bridge to transplantation. One study retrospectively included 10 patients with hepatocellular carcinoma on the transplant list treated with SBRT. Two patients had Child Pugh B and one had Child Pugh C, the median tumor size was 3.4 cm (2.5–5.5 cm), and the median dose was 51 Gy in 3 fractions. Four patients had received previous treatment with TACE. All patients were successfully transplanted. On anatomic-pathologic review, three patients had complete response and three patients had minimal remainder. The 5-year overall survival and progression-free survival were 100%, and there were no toxicities greater than or equal to grade 3 [41]. Mannina et al analyzed their experience using SBRT in 38 patients with hepatocellular carcinoma, and all patients were transplanted [40]. Complete response was observed in 45% of lesions and partial response in 23%, with poor concordance between radiological and pathological evaluation. Overall survival at 1, 2, 3, and 5 years was 92, 86, 77, and 73%, respectively [42].

4. Evaluation of response

The Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 criteria take into account changes in tumor size, underestimating the detection of complete response and overestimating partial responses. Disappearance of arterial hyperenhancement is considered a complete response, while a 30% reduction is a partial response and a 20% increase is progression [43, 44]. If none of these changes is present, it is considered stable disease. Different criteria may be useful for ablation, embolization, or systemic treatment, but their application in SBRT is unclear. Most clinical trials of SBRT in hepatocellular carcinoma use these criteria for response assessment, and there is a need to standardize the response by unifying the imaging changes observed after SBRT in hepatocellular carcinoma. Facciuto et al showed correlation of RECIST v1.1 with complete response in 14% of patients at 3 months [23]. Mannina et al retrospectively evaluated 38 patients with hepatocellular carcinoma (Child Pugh A 45%) treated with SBRT prior to transplantation and demonstrated low concordance of complete responses or partial response with RECIST (sensitivity 90% and specificity 17%), mRECIST (sensitivity 54% and specificity 50%), and European Association for the Study of the Liver (EASL) (sensitivity 83% and specificity 18%); however, no patient was incorrectly categorized to progression [42].

The timing of imaging response assessment is crucial. Sanuki et al demonstrated median time to complete response of 5.9 months (1.2–34.2 months) [45]. Complete response increased from 24% at 3 months to 67% at 6 months and 71% at 12 months. Kimura et al demonstrated that 25.3% had residual arterial hyperenhancement at 3 months, which decreased significantly to 2% at 6 months [46]. Price et al demonstrated discordance between response assessment by EASL and RECIST [47]. Evaluating the mean decrease in tumor size (RECIST), they found 35, 37, 48, and 55% reduction at 3, 6, 9, and 12 months, respectively. However, a decrease in arterial enhancement of 50% (partial response by EASL) was more predictive of response in the first 6 to 12 months.

After SBRT, there are changes in the surrounding liver tissue. According to these changes, some authors have described temporal changes in hyperenhancement, corresponding to areas of high dose, finding an increase in hyperenhancement from 12% at 1 month to 54% at 6 months. The delay in image acquisition shows isoattenuation in most patients, being rare in the late phase, which may help to distinguish the response to treatment. In addition, the degree of cirrhosis may predict different behavior [45]. Kimura et al found that the majority of tumors in Child Pugh A patients went from hypo- or isoattenuation to hyperattenuation within 6 months of treatment; however, no such changes were seen in Child Pugh B patients. It should be noted that the optimal response time is at least 6 to 12 months after SBRT, lesion stability, or shrinkage is associated with local treatment success, arterial phase hyperenhancement may persist despite complete pathologic response, and late washout may persist after SBRT [48]. Some of these lesions may be incorrectly categorized as treatment failures by administering unnecessary additional treatments.

5. Quality of life with SBRT in hepatocellular carcinoma

The available evidence is limited, and the assessment tools vary from study to study. There are no studies limited to the evaluation of quality of life in patients with primary and secondary liver tumors. Moreover, there are differences in these pathologies that make it difficult to group them together. However, the change in quality of life in oncology patients after treatment can be substantial.

A systematic review published by Mutsaers et al [49] evaluated the quality of life of patients after treatment with SBRT in primaries or liver metastases. A total of 392 patients from four prospective studies and one abstract were analyzed. The review concludes that quality of life is preserved after SBRT treatment.

The prospective longitudinal study by Klein et al [50] using the FACT-Hep and QLQ-C30 quality of life questionnaires included 99 patients with hepatocellular carcinoma. Loss of appetite and asthenia worsened at 1 month, but recovered by 3 months, with no significant changes in quality of life in the series. Shun et al [51] found factors, including depression, functional status, and symptom severity associated with changes in quality of life. Nutritional status and mental health during treatment could affect quality of life. The most common changes were asthenia and nutritional status.

There is little evidence to compare quality of life data from SBRT with other treatments such as radiofrequency, TACE, or surgery. If we review quality of life after other local treatments, the studies by Rees et al [52] (liver resection) and Toro et al [53] (liver resection, TACE, radiofrequency, or no treatment) suggest a stable score; however, the studies by Eid et al [54] (liver resection or ablation) and Huang et al [55] (resection vs. radiofrequency) suggest a worsening. Similar variations are seen post-chemo/Yttrium-90 [56]. Based on this limited data analysis, SBRT is a comparable or favorable alternative to other techniques.

6. Conclusion

SBRT treatment of hepatocellular carcinoma is an effective treatment with limited complications. More studies are needed to establish definitive indications, response and survival factors, and evaluation of response to treatment.

Acknowledgments

I would like to thank Hospital Ramón y Cajal and the research foundation of Hospital Ramón y Cajal for their support.

Conflict of interest

The authors declare no conflict of interest.