| Abstract|| |
Liver cancer is the fifth most common cancer in men, the seventh most common in women, and the third most common cause of death from cancer worldwide. Only 30-40% of liver cancer patients present early enough to undergo curative treatments such as surgery or liver transplantation. Local treatment with radiofrequency ablation or ethanol injection is often reserved for non-surgical candidates with early stages of disease. Transarterial embolization has become a widely accepted treatment for asymptomatic patients with unresectable lesions. This review discusses in details the three major forms of transarterial therapies: Bland embolization, chemoembolization, and radioembolization.
Keywords: Chemoembolization, embolization, hepatocellular carcinoma, radioembolization, transarterial treatment
|How to cite this article:|
Jazieh KA, Arabi M, Khankan AA. Transarterial therapy: An evolving treatment modality of hepatocellular carcinoma. Saudi J Gastroenterol 2014;20:333-41
Liver cancer or hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh most common cancer in women. The disease-related mortality was estimated to be 649,000 patients worldwide in the year 2008 (477,000 men and 217,000 women). Additionally, HCC is highly fatal, with an overall ratio of mortality to incidence of 0.93.  HCC is secondary to liver cirrhosis in 80% of patients, and is the primary cause of death in cirrhotic patients in Europe.  Only 30-40% of patients present with early-stage disease open to curative treatments, such as resection or transplantation, while others can only undergo local therapies or palliative care.  As a result, liver cancer is the third most common cause of cancer deaths worldwide. 
Local ablation with radiofrequency or percutaneous ethanol injection is considered the standard of care for patients with early-stage tumors smaller than 5 cm which are not suitable for surgery. Other newly developed ablative therapies, such as microwave or cryoablation, are still under investigation. In tumors <2 cm, radiofrequency ablation (RFA) or ethanol techniques achieve complete responses in more than 90% of cases, with good long-term outcome. 
Transarterial therapies are recommended for asymptomatic patients with multinodular, unresectable disease stage. In this manuscript, we will be discussing the three major transarterial methods of treatment of HCC: Bland embolization [transarterial embolization (TAE)], chemoembolization, and radioembolization. Transarterial bland embolization (TAE) is done using a catheter inserted into the hepatic artery that injects embolizing agents to block blood flow to the tumor without infusion of chemotherapeutic agents.  When chemotherapeutic agents are injected into the artery prior to the infusion of embolizing agents, this is known as transarterial chemoembolization (TACE). Transarterial radioembolization  is done using microspheres containing the radioactive isotope Yttrium-90 selectively injected into the feeding artery.
The purpose of this review is to discuss in further details these three transarterial therapies that have been used to treat cases of HCC.
| Bland embolization|| |
Treatment of liver neoplasms by blocking their arterial blood supply was introduced in the 1950s, and this concept continues to be the foundation of TAE, or bland embolization, in the treatment of unresectable tumors. , Since hepatic tumors derive the majority of their blood supply from the hepatic artery, while the noncancerous liver is supplied primarily by the portal vein, TAE is possible. This allows for selective therapy delivery to cancerous cells and protects the noncancerous liver tissue against ischemic necrosis when the arterial supply is occluded. ,
The goal of bland TAE is to kill tumor cells by blocking tumor vascularity without the administration of chemotherapy. Some commonly used embolizing agents include gelatin sponge particles, polyvinyl alcohol particles, and polyacrylamide microspheres. ,, According to a systematic review, gelatin sponge is the most commonly used embolic agent, but polyvinyl alcohol is possibly more effective.  Even though neither polyvinyl alcohol nor gelfoam has superior survival benefits over the other, considerably less sessions are required if polyvinyl particles are used, as polyvinyl alcohol is more permanent. 
Embolization is recommended for asymptomatic multinodular intermediate-stage disease with no vascular invasion or extrahepatic spread. These patients are considered not eligible for locoregional treatments such as radiofrequency or ethanol ablation. Eligible patients usually have Barcelona Clinic Liver Cancer class B disease.  It is important that patients have conserved hepatic function and a relatively unobstructed portal vein. ,,, Contraindications include decompensated cirrhosis, replacement of both lobes with tumor, extrahepatic metastases, a tumor size larger than 10 cm, severely reduced portal vein flow, untreated varices with risk of bleeding, and bile duct occlusion. ,
Cheng et al. investigated the benefit of pre-liver transplant TAE in treating HCC. Twenty-nine patients were divided into two groups: Group A received bland embolization before the liver transplant and group B only underwent liver transplant. Results of computed tomography (CT) images showed that the bland embolization induced massive tumor necrosis (>85%) in 63.1% of patients in group A. Patients in group A had a better survival of 84% at 5 years than the patients in group B with a survival of 75% at 4 years. The authors concluded that TAE was an effective treatment for HCC before liver transplant.
In a study by Malagari et al. , seventy-one patients (60% men; 11% women) with documented HCC of 3-10 cm in diameter and who were not eligible for surgery were treated with TACE. The results showed 97.05% survival at 12 months, and 88.2% survival at 30 months. Additionally, Alpha Fetroprotein levels decreased significantly at 1 month post each procedure.
In 2007, Osuga et al. investigated the clinical outcomes of TAE using superabsorbent polymer microspheres (SAP-TAE) as an initial therapy for previously untreated HCC unamenable to surgery or ablation.  The study's cohort consisted of 59 patients who underwent bland embolization using 100- to 200-μm reconstituted SAP particles (SAP-TAE) as the primary treatment. The patients underwent a total of 121 sessions of SAP-TAE, with one to five sessions per patient. Postembolization syndrome (PES) was minimal after SAP-TAE in all patients, and no major complications were observed. Thirteen patients underwent SAP-TAE only, while the other 46 patients underwent subsequent chemoembolization. The median survival period was 30 months. Overall survival rates at 1- and 2-year intervals were 100% and 83%, respectively. The authors concluded that SAP-TAE was a safe and repeatable therapy for HCC unamenable for surgery or ablation.
In 2008, Maluccio et al.  reported their findings from a sample of 322 patients with unresectable HCC who were treated with embolization. Selective embolization of arterial vessels feeding the hepatic tumors was performed with spherical embolic particles (40-120 μm) or small (50 μm) polyvinyl alcohol intended to block the terminal vessels. The survival rates of the patients were 66% at 1 year, 46% at 2 years, and 33% at 3 years, while the median survival for the entire sample was 21 months. The authors concluded that bland embolization with small particles to cause terminal vessel blockade of the hepatic artery was an effective treatment method for patients with inoperable HCC.
In a recent study, 53 patients underwent bland embolization for a total of 74 lesions.  Results at 1-month, 3- to 6-month, and 6- to 12-month follow-up were 62%, 37%, and 16%, respectively, for patients with stable disease and 35%, 56%, and 51%, respectively, for patients with partial response. Also, 7% of the patients had a complete response, i.e. no evidence of lesions. Twenty of the 53 patients had at least a 1 year of follow-up, with an overall survival rate of 96%.
Bland embolization has been used for recurrent HCC as well. Covey et al. reported their results on the use of bland embolization in 45 patients with postoperative HCC tumor recurrence. In their study, 97% of the 45 patients had Okuda stage I disease. The 1-, 2-, and 5-year survival rates were 86%, 74%, and 47%, respectively, while the median overall survival was 46 months. By their last follow-up, 6.6% of the patients were alive with no evidence of viable disease. The authors concluded that bland arterial embolization following HCC recurrence was an effective method of salvage therapy for those patients with good liver function.
The most common toxicity from bland embolization therapy and chemoembolization is a PES consisting of fever, nausea, abdominal pain, and vomiting. ,, Rare but extreme complications include ischemic hepatitis, pancreatitis, bacteremia, renal failure, and hepatic failure, all of which can lead to death. ,,, Results of several researches using multiple microsphere sizes have shown that though microspheres smaller than 40 mm tend to collect in tumor arterioles, they may pass through arteriovenous shunts and sinusoids into the systemic circulation and, as a result, can cause grave embolic complications. ,
| Chemoembolization|| |
According to the Society of Interventional Radiology,  chemoembolization is a minimally invasive treatment for liver cancer that delivers a high dose of cancer-killing drug (chemotherapy) directly to the liver while depriving the tumor of its blood supply by blocking, or embolizing, the arteries feeding the tumor. A Japanese radiologist Dr. Yamada first introduced this technique in the late 1970s for patients with unresectable HCC. 
No standard protocol of TACE has been universally adopted, so there are variations in the procedure done and the drugs used. Anticancer drugs used include doxorubicin,  cisplatin,  and epirubicin.  According to the evidence so far, none of these drugs has been proven to be superior to the others. ,
Regardless of the chemotherapeutic drug used, it is usually emulsified in lipiodol, or iodized poppy seed oil, that is used as a carrier for local cytotoxic chemotherapy. When lipiodol is injected into the hepatic artery, it remains in the tumor tissue even after it is cleared from normal hepatic tissue, seemingly due to the absence of Kupffer cells in the tumor.  Although previously having been thought to increase the effectiveness of TACE, recent evidence shows that there is no benefit with lipiodol.  The embolizing agents used are usually gelatin sponge particles and polyvinyl alcohol. 
There is no uniform agreement on the criteria for selecting patients appropriate for TACE. The indications are quite similar to those of bland embolization. Patients with tumor unamenable to surgical resection or ablation, as well as patients with Barcelona Clinic Liver Cancer class B or intermediate-stage disease are usually considered eligible for chemoembolization.  The contraindications for TACE are also similar to those of bland embolization, and include decompensated cirrhosis, replacement of both lobes with tumor, extrahepatic metastases, a tumor size larger than 10 cm, severely reduced portal vein flow, untreated varices with risk of bleeding, and bile duct occlusion. , High albumin level is associated with a better survival, whereas a high alpha-fetoprotein (AFP) level and large tumor size indicate high risk of morbidity. ,
Lo et al. conducted a randomized controlled trial (RCT) with 80 patients and reported their findings on a group of patients with unresectable HCC who underwent either supportive care or chemoembolization (given variable doses of an emulsion of cisplatin in lipiodol and gelatin sponge particles). Each patient in the chemoembolization group received 1-15 sessions, with a median of 4.5 sessions per patient. Chemoembolization resulted in a marked tumor response, and the survival rates were considerably improved in the chemoembolization group with 1-, 2-, and 3- year survival rates of 57%, 31%, and 26%, respectively. Survival in the control group was 32% at 1 year, 11% at 2 years, and 3% at 3 years. Another trial by Llovet et al. reported the findings on 112 HCC patients treated with embolization or chemoembolization or supportive care alone. Twenty-five of 37 patients who were treated with embolization, 21 of 40 patients treated with chemoembolization, and 25 of 35 given supportive care died. The 1- and 2-year survival rates were 82% and 63% for the chemoembolization group, 75% and 50% for the bland embolization group, and 63% and 27% for the supportive care group, respectively. The authors of both studies concluded that chemoembolization greatly improves survival of selected patients with unresectable HCC.
In 2006, Takayasu et al. conducted a study on a large cohort of 8510 HCC patients to elucidate the survival of these patients and to analyze the factors affecting the survival. The patients were treated with TACE consisting of lipiodol, chemotherapy, and gelatin sponge particles. Exclusion criteria were any previous treatment taken prior to the TACE and/or extrahepatic metastases. The overall median survival of the patients was 34 months. The survival rates were 82% at 1 year, 47% at 3 years, 26% at 5 years, and 16% at 7 years. According to the authors, the degrees of liver damage, tumor node metastases stage (proposed by the Liver Cancer Study Group of Japan), and the AFP levels were independent risk factors for patient survival. The procedure-related mortality rate after the initial therapy was 0 .5%.
An RCT was conducted on 108 patients with resectable HCC to evaluate the effects of preoperative TACE on resectable HCC.  The patients were randomly divided into two groups. One group underwent preoperative chemoembolization and the other did not. Five patients in the preoperative chemoembolization group did not undergo surgery because of liver failure or extrahepatic metastasis. The preoperative chemoembolization group had a longer operation time and a lower resection rate. According to the results, there was no considerable difference between the two groups in operative blood loss, surgical morbidity, and hospital mortality. At a median follow-up of 57 months, 78.8% of the patients in the preoperative chemoembolization group and 91.1% of the patients in the control group had recurrent disease. The overall survival rates for the preoperative chemoembolization group were 73.1% at 1 year, 40.4% at 3 years, and 30.7% at 5 years, while the overall survival rates of the control group were 69.6% at 1 year, 32.1% at 3 years, and 21.1% at 5 years. The authors concluded that preoperative chemoembolization did not improve the surgical outcome because it resulted in drop-out from definitive surgery due to progression of disease and liver failure.
A more recent RCT has shown the effects of a novel chemoembolization procedure on HCC using iodized oil and degradable starch microspheres (DSM).  The researchers randomly divided 45 patients with HCC into three equal groups: One group received lipiodol, second group received DSM, and the third one received both lipiodol and DSM. All patients received cisplatin as the chemotherapeutic drug. The response rates were 40% in the lipiodol group, 53.4% in the DSM group, and 80% in the lipiodol + DSM group. The median progression-free survival time for the lipiodol group, DSM group, and the lipiodol + DSM group was 177 days, 287 days, and 377 days, respectively. There were no severe adverse effects amongst the three groups. The authors concluded that transarterial infusion using lipiodol and DSM was superior to transarterial infusion using lipiodol only or DSM only.
Chemoembolization has been compared to other procedures as well. Liem et al. reported their findings of TACE applied to 114 patients who were also eligible for RFA.  The treatment-related mortality and morbidity were 1% and 19%, respectively, while the overall survival rates at 1, 3, and 5 years were 80%, 43%, and 23%, respectively. The authors concluded that the morbidity, mortality, and survival data after TACE for small HCCs eligible for RFA were comparable to those reported after RFA in the literature, and suggested the need for a randomized comparison of the two treatment modalities for small HCCs. Another study was done to determine the effect of combining chemoembolization with RFA in patients with large hepatic tumors.  Patients treated with TACE-RFA had better overall survival rates than those treated with TACE alone or RFA alone. The authors ended by stating that TACE-RFA was superior to TACE alone or RFA alone in improving the survival for patients with HCC larger than 3 cm.
The conclusion of a meta-analysis of seven RCTs evaluating arterial embolization in 545 patients with intermediate unresectable disease gave stronger evidence and showed improved 2-year survival after chemoembolization with cisplatin and doxorubicin compared to controls, with no survival benefit from bland embolization only. 
A more recent meta-analysis of nine RCTs has confirmed that TACE does improve survival, and a meta-analysis of three RCTs including 412 patients comparing chemoembolization versus bland embolization alone demonstrated no survival difference. 
Based on the aforementioned evidence, TACE has become the standard treatment for unresectable asymptomatic HCC and bland embolization is currently not recommended as a standard first-line treatment for asymptomatic unresectable HCC according to the guidelines of the European Association for the Study of Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), as well as the Saudi Association for the Study of Liver Diseases and Transplantation (SASLT). ,,
Although transarterial administration of chemotherapeutic agents helps escaping the first-pass metabolism in the liver and results in delivery of higher concentrations into the tumor, a significant proportion of the dose passes into the systemic circulation contributing to the PES. , PES occurs in approximately 60-80% of patients due to embolization of the non-involved liver tissue as well as the systemic effect of the infused chemotherapy,  and ranges between mild symptoms such as abdominal pain, fever, nausea, and vomiting to life-threatening conditions such as liver failure and abscess formation. In addition to PES, systemic toxicity induced by doxorubicin, such as bone marrow suppression, myocardial dysfunction, mucositis, and alopecia, are commonly encountered in as high as 60% of patients and may limit the total dose administered to a given patient.  According to a systematic review, treatment-related mortality was 2.4% (range 0-9.5%) in 37 trials involving 2858 patients. 
TACE with drug-eluting beads
Drug-eluting beads (DEB) are soft, deformable, spherical particles composed of a polyvinyl alcohol hydrogel designed to bind with anthracycline drugs such as doxorubicin.  More than 98% of the doxorubicin dose is absorbed by the beads after 20-120 min (from 100-300 to 700-900 μm, respectively) of mixing with 25 mg/ml of doxorubicin. Upon loading with doxorubicin, the beads undergo a slight decrease in size, up to 20% when loading at 25 mg/ml, which is more pronounced with larger beads.  When beads are infused intra-arterially, elution occurs in a controlled and sustained fashion due to ion exchange with the surrounding environment, unlike the rapid release of the drug from lipiodol in conventional TACE. , The C max plasma concentration following intra-arterial infusion of DEB loaded with doxorubicin is reached in 5 minutes and is similar for both low and high loading doses.  Studies comparing DEB-TACE to conventional TACE pharmacokinetics show that peak plasma concentration of doxorubicin following intra-arterial administration is markedly lower in DEB groups, ,, with much slower release of drug into the tumor for a period of more than 14 days. 
The clinical introduction of chemoembolization with DEB allowed maximum and prolonged intratumoral release of the chemotherapeutic agent with minimal systemic effects, in addition to tumor ischemia induced by blocking the tumor vascularity. ,,,
Initial phase I/II evaluation of this method conducted by Poon et al. revealed no dose-limiting toxicity for up to 150 mg of doxorubicin, which was used for 20 patients in the phase II study.  This study prompted other investigators to further evaluate the safety and effectiveness of this treatment. Several RCTs and cohort studies compared the safety and efficacy of c-TACE to DEB-TACE. ,,,,,,,, In the PRECISION V study, 212 patients were randomized to TACE with DCB loaded with doxorubicin or c-TACE with doxorubicin, and the primary endpoint was tumor response based on the EASL at 6 months. Although DEB-TACE group showed higher rates of complete response, objective response, and disease control compared with the c-TACE group, the hypothesis of superiority was not met. However, patients with a more advanced disease showed a significant increase in objective response with DEB compared to c-TACE. DC bead was associated with improved tolerability, with a significant reduction in serious liver toxicity.  Ferrer Puchol et al. evaluated 72 patients with unresectable HCC (c-TACE n = 25; DEB-TACE n = 47) and found that the latter method is safe and better tolerated, and may lead to better tumor necrosis. However, there was no statistically significant survival benefit or response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST).  A phase II trial comparing 35 patients treated with DEB-TACE to 70 historical controls treated with c-TACE confirmed the previous findings of decreased systemic toxicity and hospital stay.  Similarly, a phase II trial randomized 30 patients to either c-TACE or DEB-TACE with superabsorbent polymer (SAP).  This study reached the same conclusion of decreased systemic levels of doxorubicin leading to lower incidence of drug-induced toxicity. In a retrospective study of 71 patients, survival in Child-Pugh A and B classes from the first transcatheter therapy was better in patients treated with DEB compared to c-TACE (641 vs. 323 days, respectively). However, there were no significant differences in the median survival of patients in Child-Pugh class C when treated with either therapy. 
The administered beads and doxorubicin dose may vary according to the disease volume and distribution. Majority of previous studies used beads with size range between 100-300 and 300-500 μm. Martin et al. evaluated  118 patients who received a total of 186 treatments with a median total treatment dose of 75 mg and median overall total hepatic exposure of 150 mg. Most patients were treated with bead sizes of 100-300 μm or 300-500 μm. They reported even distribution of adverse events across bead sizes as well as multiple patients receiving two different bead sizes in one treatment.
The data from a prospective, non-controlled, repeat treatment registry of 206 patients undergoing 343 treatments for HCC indicated that smaller beads offer the opportunity for repeated treatments, a larger cumulative dose delivery, a lesser degree of complete stasis, and fewer adverse events.  The recommended treatment dose range reported by the PRECISION study  is 100-150 mg per patient, which was shown to be safe and effective even at the highest dose.  Dose adjustments for bilirubin levels may also be used, as in Varela et al.'s study (<25.6 mol/l, 75 mg/m 2 ; 25.6-51.3 mol/l, 50 mg/m 2 ; and 51.3-85.5 mol/l, 25 mg/m 2 ).  The majority of previous studies reported no dose-limiting systemic toxicity effects such as marrow suppression or cardiac failure. In a study comparing DEB-TACE to c-TACE, analysis of the systemic side effects of doxorubicin (alopecia, skin discoloration, mucositis, and marrow suppression) established a significant benefit in favor of DC bead (11.8%) over cTACE (25.9%). Alopecia, the most commonly occurring event, was mild (grade 1) and seen in only one case (1.1%) of DEB-TACE, while in the c-TACE arm, almost half of the alopecia events (11 events) were of pronounced/total hair loss (grade 2). Marrow suppression and mucositis were more common and of greater severity in c-TACE compared to DEB-TACE patients.  Reyes et al. prospectively evaluated the safety of DEB-TACE in 20 patients with unresectable HCC and found a lower rate of grade 3 and 4 toxicity. Only one patient suffered grade III leukocytopenia 30 days post procedure and six more patients had grade I/II leukocytopenia. Mild alopecia was seen in only one case.  The lower incidence of systemic toxicity allows the use of higher doxorubicin dosage, which seems not to be associated with a higher incidence of major chemotherapy-related adverse events.  The feasibility of higher dose administration may also enhance the therapeutic response by overriding the capacity of the multidrug resistance pump that characterizes HCC cells. 
| Radioembolization|| |
The principle of radioembolization is similar to that of chemoembolization, but it is performed using radioactive microspheres to kill tumor cells instead of cytotoxic drugs. This treatment integrates the radioactive isotope Yttrium-90 into the embolic molecules that are injected through a catheter into the hepatic arteries supplying the neoplasm. The particles block the small tumor blood vessels where they locally irradiate the surrounding cells resulting in cell death.  This technique allows for a higher dose of radiation to be administered to a local area, without subjecting a large volume of healthy tissue in the body to the radiation. Two radioembolic agents are commercially available: TheraSpheres ® (Nordion, Ottawa, Canada)  and SIR-Spheres ® (Sirtex Med ical Inc., Woburn, MA, USA). 
External beam irradiation is not effective in the treatment of HCC because of the radiosensitive nature of normal liver tissue.  The external radiation doses in excess of 35 Gy will result in liver failure with subsequent ascites, hepatomegaly, and elevated liver enzymes, which will occur weeks to months after therapy. ,, With radioembolization, radiation doses of up to 150 Gy can be administered without causing the clinical complications seen with external beam radiation. ,,,
The criteria for selecting patients suitable for radioembolization have been laid out by a consensus panel consisting of professionals from interventional radiology, nuclear medicine, radiation oncology, medical and surgical fields.  Patients who are not amenable to resection or conventional TACE and have a life expectancy longer than3 months are considered for radioembolization. Contraindications include irreversible total serum bilirubin greater than 2 mg/dl, excessive tumor size with poor hepatic function, and a compromised portal vein.
Salem et al. carried out a study to determine the safety, tumor response, and survival of 43 patients with inoperable HCC who were treated with Yttrium-90 during a 4-year period. Patients were divided into three groups based on treatment method and risk stratification (group 0, segmental; group 1, lobar low risk; group 2, lobar high risk). Forty-seven percent of the patients had an objective tumor response and 79% had a tumor response when percent reduction and/or tumor necrosis were used as a measure of tumor response. The median survival for group 0 was 46.5 months, for group 1 was 16.9 months, and for group 2 was 11.1 months. The authors reported no life-threatening adverse events related to treatment.
Sangro et al. reported their findings on 24 Child-Pugh class A patients with HCC who underwent Yttrium-90 radioembolization. Reduction in the size of target lesions was observed in all but one patient. When taking only target lesions into consideration, disease control rate and response rate were 100% and 23.8%, respectively. The authors concluded that radioembolization using resin microspheres had a significant antitumor effect against HCC.
In 2006, Kulik et al. reported their results on 35 patients who were not eligible for transplantation, resection, or ablation, and underwent radioembolization. Sixty-six percent of the cohort was effectively downstaged to resection, transplantation, or RFA. The 1-, 2-, and 3-year survival rates were 84%, 54%, and 27%, respectively, and the median survival by Kaplan-Meier analysis for the entire cohort was 800 days. According to the authors, the data suggested that intra-arterial Yttrium-90 microspheres can be used as a bridge to transplantation, surgical resection, or RFA.
In 2011, Salem et al. compared the effectiveness of radioembolization to chemoembolization. Patients with HCC treated by chemoembolization or radioembolization with Yttrium-90 microspheres had similar survival times, but radioembolization resulted in longer time to progression and produced less toxicity than chemoembolization.
In a retrospective study comparing the outcomes between radioembolization and chemoembolization, there was no significant difference in survival. However, PES was significantly more severe in patients who underwent chemoembolization. 
A systemic review by Sangro et al. concluded that radioembolization has a significant antitumor effect against HCC and can prevent local tumor growth. The authors also said that by implementing strict selection criteria and conservative models for calculating radiation activity that should be delivered, radioembolization can be performed safely even in cirrhotic patients, and without significant PES or radiation-induced liver disease. This is comparable with another recent systemic review by Yang et al.,  according to which radioembolization with Yttrium-90 microspheres is an effective and safe treatment for patients with unresectable HCC.
As with bland embolization and chemoembolization, the most common side effect of radioembolization is PES consisting of nausea, vomiting, fever, and abdominal pain. , Other complications include portal vein thrombosis, jaundice, radiation gastritis, increasing bilirubin level, cirrhosis, and ascites.  [Table 1] compares the results of different transarterial therapies for HCC.
| Conclusion|| |
Overall, the evidence today suggests that transarterial therapies of bland embolization, chemoembolization, and radioembolization are effective in the treatment of inoperable HCC, especially if the patients are carefully selected. These treatments have some complications, but have rarely caused any severe adverse effects and, thus, are safe if done correctly. However, there is a need for more evidence to compare these methods head to head, as well as with other treatments of HCC. One of the problems with the current evidences which should be addressed is that the methods of applying the treatments are not standardized among the studies, particularly concerning chemoembolization. More studies should also be done to observe the effects of combining these treatments with others.
| References|| |
|1.||Liver Cancer Incidence and Mortality Worldwide in 2008 Summary. GLOBOCAN 2008 Cancer Fact Sheet.; 2008; Available from: http://globocan.iarc.fr/factsheets/cancers/liver.asp. [Last cited in 2013]. |
|2.||Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-17. |
|3.||EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56:908-43. |
|4.||Bland Embolization. Interventional Oncology 2013; Available from: http://io.nmff.org/patients/bland-embolization/. [Last accessed date March, 2014]. |
|5.||Interventional Radiology Treatments for Liver Cancer. Society of Interventional Radiology; 2013; Available from: |
|6.||Doyon D, Mouzon A, Jourde AM, Regensberg C, Frileux C. Hepatic, arterial embolization in patients with malignant liver tumours (author′s transl). Ann Radiol 1974;17:593-603. |
|7.||Markowitz J. The hepatic artery. Surg Gynecol Obstet 1952;95:644-6. |
|8.||Gyves JW, Ziessman HA, Ensminger WD, Thrall JH, Niederhuber JE, Keyes JW Jr, et al. Definition of hepatic tumor microcirculation by single photon emission computerized tomography (SPECT). J Nucl Med 1984;25:972-7. |
|9.||Bierman HR, Byron RL Jr, Kelley KH, Grady A. Studies on the blood supply of tumors in man. III. Vascular patterns of the liver by hepatic arteriography in vivo. J Natl Cancer Inst 1951;12:107-31. |
|10.||Maluccio MA, Covey AM, Porat LB, Schubert J, Brody LA, Sofocleous CT, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2008;19:862-9. |
|11.||O′Neil BH, Venook AP. Hepatocellular carcinoma: The role of the North American GI Steering Committee Hepatobiliary Task Force and the advent of effective drug therapy. Oncologist 2007;12:1425-32. |
|12.||Ramsey DE, Kernagis LY, Soulen MC, Geschwind JF. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol 2002;13:S211-21. |
|13.||Marelli L, Stigliano R, Triantos C, Senzolo M, Cholongitas E, Davies N, et al. Transarterial therapy for hepatocellular carcinoma: Which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Interv Radiol 2007;30:6-25. |
|14.||Brown DB, Pilgram TK, Darcy MD, Fundakowski CE, Lisker-Melman M, Chapman WC, et al. Hepatic arterial chemoembolization for hepatocellular carcinoma: Comparison of survival rates with different embolic agents. J Vasc Interv Radiol 2005;16:1661-6. |
|15.||Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis 1999;19:329-38. |
|16.||Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: Diagnosis and treatment. Gastroenterology 2002;122:1609-19. |
|17.||Bonomo G, Pedicini V, Monfardini L, Della Vigna P, Poretti D, Orgera G, et al. Bland embolization in patients with unresectable hepatocellular carcinoma using precise, tightly size-calibrated, anti-inflammatory microparticles: First clinical experience and one-year follow-up. Cardiovasc Interv Radiol 2010;33:552-9. |
|18.||Osuga K, Hori S, Hiraishi K, Sugiura T, Hata Y, Higashihara H, et al. Bland embolization of hepatocellular carcinoma using superabsorbent polymer microspheres. Cardiovasc Interv Radiol 2008;31:1108-16. |
|19.||Raoul JL, Sangro B, Forner A, Mazzaferro V, Piscaglia F, Bolondi L, et al. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: Available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev 2011;37:212-20. |
|20.||Cheng BQ, Jia CQ, Liu CT, Fan W, Wang QL, Zhang ZL, et al. Chemoembolization combined with radiofrequency ablation for patients with hepatocellular carcinoma larger than 3 cm: A randomized controlled trial. JAMA 2008;299:1669-77. |
|21.||Malagari K, Alexopoulou E, Chatzimichail K, Hall B, Koskinas J, Ryan S, et al. Transcatheter chemoembolization in the treatment of HCC in patients not eligible for curative treatments: Midterm results of doxorubicin-loaded DC bead. Abdom Imaging 2008;33:512-9. |
|22.||Covey AM, Maluccio MA, Schubert J, BenPorat L, Brody LA, Sofocleous CT, et al. Particle embolization of recurrent hepatocellular carcinoma after hepatectomy. Cancer 2006;106:2181-9. |
|23.||Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology (Baltimore, Md) 2002;35:1164-71. |
|24.||Pelletier G, Ducreux M, Gay F, Luboinski M, Hagege H, Dao T, et al. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: A multicenter randomized trial. Groupe CHC. J Hepatol 1998;29:129-34. |
|25.||Huo TI, Wu JC, Huang YH, Chiang JH, Lee PC, Chang FY, et al. Acute renal failure after transarterial chemoembolization for hepatocellular carcinoma: A retrospective study of the incidence, risk factors, clinical course and long-term outcome. Aliment Pharmacol Ther 2004;19:999-1007. |
|26.||Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet 2002;359:1734-9. |
|27.||Bastian P, Bartkowski R, Kohler H, Kissel T. Chemo-embolization of experimental liver metastases. Part I: Distribution of biodegradable microspheres of different sizes in an animal model for the locoregional therapy. Eur J Pharm Biopharm 1998;46:243-54. |
|28.||Brown KT. Fatal pulmonary complications after arterial embolization with 40-120- micro m tris-acryl gelatin microspheres. J Vasc Interv Radiol 2004;15:197-200. |
|29.||Yamada R, Nakatsuka H, Nakamura K, Sato M, Itami M, Kobayashi N, et al. Hepatic artery embolization in 32 patients with unresectable hepatoma. Osaka City Med J 1980;26:81-96. |
|30.||Kawai S, Tani M, Okamura J, Ogawa M, Ohashi Y, Monden M, et al. Prospective and randomized trial of lipiodol-transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: A comparison of epirubicin and doxorubicin (second cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan. Semin Oncol 1997;24 (2 Suppl 6):S6-38-S6-45. |
|31.||Ueno K, Miyazono N, Inoue H, Nishida H, Kanetsuki I, Nakajo M. Transcatheter arterial chemoembolization therapy using iodized oil for patients with unresectable hepatocellular carcinoma: Evaluation of three kinds of regimens and analysis of prognostic factors. Cancer 2000;88:1574-81. |
|32.||Bhattacharya S, Novell JR, Winslet MC, Hobbs KE. Iodized oil in the treatment of hepatocellular carcinoma. Br J Surg 1994;81:1563-71. |
|33.||Liem MS, Poon RT, Lo CM, Tso WK, Fan ST. Outcome of transarterial chemoembolization in patients with inoperable hepatocellular carcinoma eligible for radiofrequency ablation. World J Gastroenterol 2005;11:4465-71. |
|34.||Takayasu K, Arii S, Ikai I, Omata M, Okita K, Ichida T, et al. Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients. Gastroenterology 2006;131:461-9. |
|35.||Zhou WP, Lai EC, Li AJ, Fu SY, Zhou JP, Pan ZY, et al. A prospective, randomized, controlled trial of preoperative transarterial chemoembolization for resectable large hepatocellular carcinoma. Ann Surg 2009;249:195-202. |
|36.||Yamasaki T, Hamabe S, Saeki I, Harima Y, Yamaguchi Y, Uchida K, et al. A novel transcatheter arterial infusion chemotherapy using iodized oil and degradable starch microspheres for hepatocellular carcinoma: A prospective randomized trial. J Gastroenterol 2011;46:359-66. |
|37.||Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology (Baltimore, Md) 2003;37:429-42. |
|38.||Abdo AA, Hassanain M, AlJumah A, Al Olayan A, Sanai FM, Alsuhaibani HA, et al. Saudi guidelines for the diagnosis and management of hepatocellular carcinoma: Technical review and practice guidelines. Ann Saudi Med 2012;32:174-99. |
|39.||Bruix J, Sherman M. Management of hepatocellular carcinoma: An update. Hepatology (Baltimore, Md) 2011;53:1020-2. |
|40.||Kalayci C, Johnson PJ, Raby N, Metivier EM, Williams R. Intraarterial adriamycin and lipiodol for inoperable hepatocellular carcinoma: A comparison with intravenous adriamycin. J Hepatol 1990;11:349-53. |
|41.||Kalva SP, Iqbal SI, Yeddula K, Blaszkowsky LS, Akbar A, Wicky S, et al. Transarterial chemoembolization with Doxorubicin-eluting microspheres for inoperable hepatocellular carcinoma. Gastrointest Cancer Res 2011;4:2-8. |
|42.||Hong K, Khwaja A, Liapi E, Torbenson MS, Georgiades CS, Geschwind JF. New intra-arterial drug delivery system for the treatment of liver cancer: Preclinical assessment in a rabbit model of liver cancer. Clin Cancer Res 2006;12:2563-7. |
|43.||Lewis AL, Gonzalez MV, Lloyd AW, Hall B, Tang Y, Willis SL, et al. DC bead: In vitro characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol 2006;17:335-42. |
|44.||Poon RT, Tso WK, Pang RW, Ng KK, Woo R, Tai KS, et al. A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. Clin Gastroenterol Hepatol 2007;5:1100-8. |
|45.||van Malenstein H, Maleux G, Vandecaveye V, Heye S, Laleman W, van Pelt J, et al. A randomized phase II study of drug-eluting beads versus transarterial chemoembolization for unresectable hepatocellular carcinoma. Onkologie 2011;34:368-76. |
|46.||Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: Efficacy and doxorubicin pharmacokinetics. J Hepatol 2007;46:474-81. |
|47.||Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: Results of the PRECISION V study. Cardiovasc Interv Radiol 2010;33:41-52. |
|48.||Malagari K, Pomoni M, Kelekis A, Pomoni A, Dourakis S, Spyridopoulos T, et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Interv Radiol 2010;33:541-51. |
|49.||Malagari K, Pomoni M, Spyridopoulos TN, Moschouris H, Kelekis A, Dourakis S, et al. Safety profile of sequential transcatheter chemoembolization with DC Bead: Results of 237 hepatocellular carcinoma (HCC) patients. Cardiovasc Interv Radiol 2011;34:774-85. |
|50.||Dhanasekaran R, Kooby DA, Staley CA, Kauh JS, Khanna V, Kim HS. Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC). J Surg Oncol 2010;101:476-80. |
|51.||Ferrer Puchol MD, la Parra C, Esteban E, Vano M, Forment M, Vera A, et al. Comparison of doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) with conventional transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma. Radiologia 2011;53:246-53. |
|52.||Petruzzi NJ, Frangos AJ, Fenkel JM, Herrine SK, Hann HW, Rossi S, et al. Single-center comparison of three chemoembolization regimens for hepatocellular carcinoma. J Vasc Interv Radiol 2013;24:266-73. |
|53.||Recchia F, Passalacqua G, Filauri P, Doddi M, Boscarato P, Candeloro G, et al. Chemoembolization of unresectable hepatocellular carcinoma: Decreased toxicity with slow-release doxorubicineluting beads compared with lipiodol. Oncol Rep 2012;27:1377-83. |
|54.||Sacco R, Bargellini I, Bertini M, Bozzi E, Romano A, Petruzzi P, et al. Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011;22:1545-52. |
|55.||Song MJ, Chun HJ, Song do S, Kim HY, Yoo SH, Park CH, et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol 2012;57:1244-50. |
|56.||Song MJ, Park CH, Kim JD, Kim HY, Bae SH, Choi JY, et al. Drug-eluting bead loaded with doxorubicin versus conventional Lipiodol-based transarterial chemoembolization in the treatment of hepatocellular carcinoma: A case-control study of Asian patients. Eur J Gastroenterol Hepatol 2011;23:521-7. |
|57.||Martin RC 2 nd , Rustein L, Perez Enguix D, Palmero J, Carvalheiro V, Urbano J, et al. Hepatic arterial infusion of doxorubicin-loaded microsphere for treatment of hepatocellular cancer: A multi-institutional registry. J Am Coll Surg 2011;213:493-500. |
|58.||Martin R, Irurzun J, Munchart J, Trofimov I, Scupchenko A, Tatum C, et al. Optimal technique and response of doxorubicin beads in hepatocellular cancer: Bead size and dose. Korean J Hepatol 2011;17:51-60. |
|59.||Reyes DK, Vossen JA, Kamel IR, Azad NS, Wahlin TA, Torbenson MS, et al. Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: Initial experience in the United States. Cancer J (Sudbury, Mass) 2009;15:526-32. |
|60.||Burrel M, Reig M, Forner A, Barrufet M, de Lope CR, Tremosini S, et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design. J Hepatol 2012;56:1330-5. |
|61.||TheraSphere® Liver Cancer Therapy. Nordion; 2013; Available from: http://www.nordion.com/therasphere/home_us/index.asp [Last accessed date: March, 2014] |
|62.||About SIR-Spheres microspheres. Sirtex; [cited 2013]; Available from: http://www.sirtex.com/us/clinicians/about-sir-spheres-microspheres/ [Last accessed date 2014 Mar]. |
|63.||Ingold JA, Reed GB, Kaplan HS, Bagshaw MA. Radiation Hepatitis. Am J Roentgenol Radium Ther Nucl Med 1965;93:200-8. |
|64.||Geschwind JF, Salem R, Carr BI, Soulen MC, Thurston KG, Goin KA, et al. Yttrium-90 microspheres for the treatment of hepatocellular carcinoma. Gastroenterology 2004;127 (5 Suppl 1):S194-205. |
|65.||Lawrence TS, Robertson JM, Anscher MS, Jirtle RL, Ensminger WD, Fajardo LF. Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys 1995;31:1237-48. |
|66.||Dawson LA, McGinn CJ, Lawrence TS. Conformal chemoradiation for primary and metastatic liver malignancies. Semin Surg Oncol 2003;21:249-55. |
|67.||Dawson LA, McGinn CJ, Normolle D, Ten Haken RK, Walker S, Ensminger W, et al. Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol 2000;18:2210-8. |
|68.||Kennedy AS, Nutting C, Coldwell D, Gaiser J, Drachenberg C. Pathologic response and microdosimetry of (90) Y microspheres in man: Review of four explanted whole livers. Int J Radiat Oncol Biol Phys 2004;60:1552-63. |
|69.||Yorke ED, Jackson A, Fox RA, Wessels BW, Gray BN. Can current models explain the lack of liver complications in Y-90 microsphere therapy? Clin Cancer Res 1999;5 (10 Suppl):3024-30s. |
|70.||Kennedy A, Nag S, Salem R, Murthy R, McEwan AJ, Nutting C, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: A consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys 2007;68:13-23. |
|71.||Salem R, Lewandowski RJ, Atassi B, Gordon SC, Gates VL, Barakat O, et al. Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): Safety, tumor response, and survival. J Vasc Interv Radiol 2005;16:1627-39. |
|72.||Sangro B, Bilbao JI, Boan J, Martinez-Cuesta A, Benito A, Rodriguez J, et al. Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma. Int J Radiat Oncol, Biol Phys 2006;66:792-800. |
|73.||Kulik LM, Atassi B, van Holsbeeck L, Souman T, Lewandowski RJ, Mulcahy MF, et al. Yttrium-90 microspheres (TheraSphere) treatment of unresectable hepatocellular carcinoma: Downstaging to resection, RFA and bridge to transplantation. J Surg Oncol 2006;94:572-86. |
|74.||Salem R, Lewandowski RJ, Kulik L, Wang E, Riaz A, Ryu RK, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 2011;140:497-507.e2. |
|75.||Lance C, McLennan G, Obuchowski N, Cheah G, Levitin A, Sands M, et al. Comparative analysis of the safety and efficacy of transcatheter arterial chemoembolization and yttrium-90 radioembolization in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol 2011;22:1697-705. |
|76.||Sangro B, Salem R, Kennedy A, Coldwell D, Wasan H. Radioembolization for hepatocellular carcinoma: A review of the evidence and treatment recommendations. Am J Clin Oncol 2011;34:422-31. |
|77.||Yang TX, Chua TC, Morris DL. Radioembolization and chemoembolization for unresectable neuroendocrine liver metastases-A systematic review. Surg Oncol 2012;21:299-308. |
|78.||Kennedy AS, Coldwell D, Nutting C, Murthy R, Wertman DE Jr., Loehr SP, et al. Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: Modern USA experience. Int J Radiat Oncol Biol Phys 2006;65:412-25. |
Khalid A Jazieh
Alfaisal University, P.O. Box 50927, Riyadh 11533
Source of Support: None, Conflict of Interest: None