SBRT,TACE,TARE,or Combined? in the Treatment of Hepatocellular Cancer

The liver is an organ wherein cancer is common. Liver cancer is the fifth most common cancer in the world and second in cancer-related deaths. Hepatocellular carcinoma (HCC) accounts for ∼90% of liver cancers. Most patients are at an advanced stage when diagnosed. Therefore, the chance of treatment is limited. Five-year survival is <10%. ^{1 –3}

Current treatment options in HCC are divided into curative and noncurative treatments. Curative treatments include surgical resection, orthotopic liver transplantation, and ablative techniques. ^3,4 Each of these treatment approaches offers long-term response and a better chance of survival. The purpose of noncurative treatments is to delay or even prevent morbidity and mortality arising from liver involvement. These treatments include transarterial chemoembolization (TACE), transarterial radioembolization (TARE), stereotactic body radiation therapy (SBRT), and systemic chemotherapy. ^{2 –5}

Transarterial treatments for the liver, such as TARE and TACE, have been practiced worldwide for ∼30 years. Although TARE has some advantages, both are implemented with similar technique. But it works with different mechanisms. When TACE is given through peripheral veins, ∼100 times the dose of chemotherapy that can reach the liver tumor can be given directly to the tumor. The hypoxic effect of the accompanying embolization also increases the chance of tumor necrosis. ^2,4,6,7

TARE, with other names in the literature, is referred to as microsphere treatment, Yttrium-90 (⁹⁰Y) treatment, and selective internal radiotherapy (RT). In this process, after the entry into the hepatic artery through a catheter, infusion of charged particles of radioactive ⁹⁰Y microspheres is made. Thus, it ensures the delivery of a high radioactive dose to the tumor. Local tumor doses given by radiomicrocure are 50–150 Gy. The dose can be up to 1000 Gy. Since the portal vein is the main blood source that feeds the liver, the normal liver tissue around the tumor is minimally affected. Thanks to this technique, the systemic effect of radiation is minimized, and tumor nutrition is reduced at the microvascular level and the radiation dose that cannot be applied externally to the entire liver is reached endovascularly. ^7,8

Compared with TARE and TACE, it has less systemic toxicity since it does not contain chemotherapy and has a local effect in the given place. It can also be used as an outpatient treatment method. This makes TARE even more attractive to both patients and doctors. Even if there are abnormal/high liver function tests, if segmental infusion can be performed, TARE treatment can be performed without significant effect on liver functions. ⁹⁰Y used in TARE is a pure particle emitter. It causes necrosis in the applied tissue regardless of the parameters such as tissue difference, tumor type, or cell cycle period. However, since the chemotherapeutic agent is injected with TACE, its effectiveness is proportional to that agent's spectrum of action. Many variables such as tumor type, cell metabolism properties, surface antigens, and tissue blood supply play a role in the effect of the chemotherapeutic agent. It has systemic side-effects. Compared with other TACE, TARE appears to have a more effective potential for regressing patients' stages or making patients suitable for transplantation. ^{4,7 –9} As a result, it can be seen that the combined use of TARE and TACE with correct indication and timing will increase patient benefit.

Primary liver tumors are more resistant to RT than metastatic liver tumors. Intact liver tissue is more sensitive to radiation. RT is applied in the form of internal (brachytherapy and ⁹⁰Y) and external (three-dimensional [3D] conformal RT, intensity-modulated radiotherapy, SBRT, and proton). This treatment can be used alone or in combination with chemotherapy. ² The minimum required dose calculated to treat liver solid tumors is 70 Gy. The maximum dose that the liver can tolerate with external radiotherapy (EBRT) is 35 Gy when given with fractions of 1.8 Gy per day. When median 43 Gy EBRT is given to the entire liver, >50% of patients develop liver dysfunction. ^1,8,9 Although RT is not primarily a preferred method, it has become more frequently used with developments in devices and planning that apply RT.

In recent years, the place of SBRT, which has higher doses, has been started to be investigated. In EBRT, SBRT treatment planning is very important. It covers complex and critical processes such as determining the areas to irradiate the target in SBRT, the accessories to be used in the positioning and beam area, the treatment doses and the irradiation technique. In this context, to plan the treatment, the patient is displayed on the CT simulator at a desired fixed position, the location of the tumor is determined, and the target volume to be irradiated is defined. In this context, in the planning of the treatment, the patient is imaged in a fixed position on the CT-simulator, the location of the tumor is determined and the target volume to be irradiated is defined. ^1,4 In the study conducted by Su et al., it was reported that SBRT dose was BED10 ≥ 100 and ≥74 Gy in an equivalent dose 2 Gy fraction in HCC treatment. ¹

In the studies performed, the tumor response rate in TACE ranged from 17% to 61.9%, and the complete tumor response rate was <5%. Five-year survival (1%–8%) was found to be quite low in TACE due to tumor recurrence and extracapsular spread. ⁴ Therefore, combined therapies have been tried in the literature. Combined with TACE, RT has been reported to be more effective than RT alone or TACE treatment alone in many retrospective studies. ^1,3,10 In one study, disease-free survival was found to be 18 months in patients who underwent SBRT after TACE. Although 1-year overall survival and local control ranks were 92.6 and 96.3, respectively, no acute toxicity was reported in any patient. ⁸ In the study conducted by Su et al., the effectiveness of the treatment they applied SBRT alone or as a treatment in addition to TAE/TACE in patients with non-resectable (tumor diameter over 5 cm) and HCC cancer classified as Child-Turcotte-Pugh Class A or B, and they looked at its reliability. The dose of SBRT was 30–50 Gy (3–5 fractions). The mean overall survival was 42.0 months in the TAE/TACE + SBRT group, whereas it was 21.0 months in the SBRT group. The overall survival of 1.3 and 5 years was 75.5%, 50.8, and 46.9% in the TAE/TACE + SBRT arm, whereas it was 62.4, 32.9, and 32.9 lower in the SBRT arm (p = 0.047). Progression-free, local recurrence, and distant metastasis-free survival were found in the TAE/TACE + SBRT group and SBRT dose was stated to be important in prognosis. In the meta-analysis performed by Hu et al. on 25 studies involving 2577 patients, patients who underwent RT (3D conformal radiotherapy, SBRT) after TACE were found to be better in terms of both full response to treatment and a 1-year survival compared with patients who received TACE alone. In addition, in the combined arm, gastroduedenal ulcer, transaminase of the area, and total bilirubin increased. Hardy-Abeloos et al. compared patients who underwent SBRT after TARE and those who underwent SBRT after TACE. They did not see a significant increase in the rate of local control, overall survival, and toxicity. However, the objective response rate was found worse after TARE. As a result, it was reported that SBRT application after TARE was more effective than SBRT application without increased risk of complications that can be seen with increased radiation use. ⁷ Oladeru et al. examined the efficacy and safety of external (SBRT) and internal RT (⁹⁰Y) in local tumor control in the treatment of nonresectable HCC. Survival was 14 months in SBRT and 12 months in ⁹⁰Y. However, this difference was not significant. ⁹

As a result, the contribution of reducing tumor burden to survival is accepted for patients with nonsurgical HCC, and aggressive minimally invasive methods, as well as systemic treatments, local–regional treatments, come to the fore. TACE, TARE, and SBRT are reliable, effective, and promising methods of treatment for patients with liver tumors that cannot be operated on. Since HCC has a heterogeneous tumor structure, the optimal dose and fractionation scheme in SBRT are not clearly known. Dose adjustment and radiation-induced liver disease are seen as major problems in TARE. The true place of TACE therapy in the treatment algorithm is not clear. There is a need for prospective randomized controlled multicenter studies that will compare the efficacy and safety of treatment schemes.