3.1. Indications and contraindications

The main role for TACE is reserved for patients with stage B disease based on the Barcelona Clinic Liver Cancer (BCLC) staging system. Stage B disease is defined as patients with large, multinodular disease with good functional status and a Child-Pugh A-B score. Other indications would include downstaging patient's tumor burden to allow for transplantation.

Absolute contraindications would be reserved for patients with poorly compensated advanced liver disease since TACE may exacerbate patient's symptoms and increase risks of progression into liver failure. Other absolute contraindications include refractory bleeding diathesis, large metastatic disease burden outside the liver, active infection, main, right and left portal vein thrombosis as well as refractory encephalopathy.

#### 3.2. Management

decreased recurrence rates with RFA, 9%, compared to MWA, 19% [14]. A review of multiple studies demonstrate overall comparable rates for MWA and RFA in terms of overall survival

A study by Wang compared cryoablation to RFA in patients with HCC lesions less than or equal to 4 cm. Results demonstrated significantly lower local tumor progression rates with cryoablation, 5.6%, compared to RFA, 10% [15]. For lesions larger than 3 cm, the difference became more apparent with progression rates of 7.7% for cryoablation and 18.2% for RFA. The recurrence free survival and overall survival rates were not significantly different between

In patients with metastatic CRC, RFA was shown to have a complete response rate of 91–97% [16]. In patients with five or fewer lesions less than 5 cm, the 5-year survival rate was between 24 and 44% [17]. For patients who had complete tumor ablation, 98% did not require further surgical resection either due to remaining disease free or developing disease progression [18].

Transarterial chemoembolization (TACE) is the most commonly performed procedure by interventional radiologists for treatment of unresectable hepatic malignancies. Nearly half of all HCC patients receive TACE at some point in their disease course [19]. Multiple techniques

The theory behind TACE relies on the liver's dual blood supply as hepatic tumors derive their blood supply mainly from the hepatic artery while normal hepatic parenchyma is predominantly supplied by the portal vein. Percutaneous access to the arterial system is obtained via femoral or radial artery catheterization. Imaging is performed to assess for variant anatomy, portal vein patency, and tumoral blood supply. Angiograms were performed, however in recent years, Cone Beam Computed Tomography (CBCT) has played an important role during locoregional therapies and is recommended as standard of care during chemoembolization [20]. Once the feeding arteries to the tumor are identified, they are selectively catheterized and chemoembolization is performed. Chemoembolization can be achieved by bland embolization, conventional trans-arterial chemoembolization (cTACE) or with drug-eluting embolic trans-

cTACE consists of administering chemotherapeutic agent(s) combined with an ethiodized oil emulsion followed by an embolic agent i.e. Gelfoam, or microspheres. Historically, doxorubicin, cisplatin, and mitomycin C in combination were used for cTACE, however due to shortage of some of the drugs, the regimens changed. Neither drug alone or any combination of these agents have shown to be statistically superior [17, 18]. Currently in the United States and Europe, doxorubicin is used in the majority of cases while miriplatin and cisplatin are used in Japan [21]. Lipiodol is an ethiodized oil that is commonly used for cTACE and has been considered the standard of care. The thick consistency allows it act as an embolic agent, which travels further into the microvascular than microspheres. In addition, lipiodol is radio-opaque and it

and local recurrence.

54 Medical Imaging and Image-Guided Interventions

cryoablation and RFA [15].

3. Transarterial chemoembolization

arterial chemoembolization (DEE-TACE).

have been used for TACE over the past few decades.

TACE is commonly performed under moderate sedation. Pre-procedural hydration may be performed to decrease risk of contrast/chemotherapy-induced nephropathy. Pre-operative antibiotics are only given for patients with high risk for infection such as disrupted biliary drainage pathways.

Patients are usually admitted overnight post-procedure to monitor for potential complications. Most often, patients develop minor symptoms that can be managed medically such as postembolization syndrome. This self-limiting syndrome is comprised of abdominal pain, fever, and nausea and usually occurs within the first 72 h post-procedure. This can be seen in up to 80% of patients. Post-procedural transaminitis is more frequent with cTACE compared to DEE-TACE.

Patients are typically discharged the next day. The criteria for discharge include appropriate pain control, ambulation, adequate urine production, and tolerating PO intake. TACE may be repeated for tumor control. Multiple treatments are often required until either the MRI shows greater than 90% tumor necrosis, the patient is downstaged, there is a lack of tumor response after at least two treatments, or the development of disease progression or a contraindication to treatment.

#### 3.3. Complications

There are varying criteria in determining patients who are at high risk for post-TACE liver failure. High-risk patients include a total bilirubin greater than 2 mg/dL, INR greater than 1.5, MELD score greater than 15, Child C disease, portal venous thrombosis, thrombocytopenia, or the presence of ascites. While many of these criteria have excluded patients in the past, advancements in technology has led to selective and superselective chemoembolization allowing a number of these patients to be treated. Non-selective chemoembolization can damage surrounding healthy hepatic parenchyma leading patients to decompensated liver failure, especially those with poor hepatic reserve. With selective and superselective techniques, there is increased sparing of viable tissue. Many articles have exhibited TACE being safely performed in high-risk patients. One study demonstrated the rate of selective TACErelated irreversible liver failure to be 3% compared to 20% in nonselective cases [23]. Other studies showed TACE to be safe and effective in patients with portal venous thrombosis, especially in those with hepatic reserve and collateral circulation [24]. Kothary et al. analyzed 65 high-risk TACE procedures which showed a procedure-related morbidity rate of 10.8% and a 30-day mortality rate of 7.7% [25]. Yoon et al. observed a procedure-related morbidity rate of 2% and a 30-day mortality rate of 1% in 96 high-risk patients [26]. Overall, the general consensus seems to be on a case-to-case basis in which baseline hepatic function, hepatic reserve, and overall tumor burden are commonly taken into account.

TACE in patients with unresectable HCC (odds ratio 0.54, 95% CI 0.33–89, P = 0.015 and odds

Liver Directed Therapies

57

http://dx.doi.org/10.5772/intechopen.75163

Several studies have compared DEE-TACE versus cTACE versus bland TACE. The PRECI-SION V study was a prospective randomized study analyzing cTACE versus DEE-TACE. The study did not meet its primary endpoint of superior response rate with DEE-TACE but did show DEE-TACE is better tolerated [32]. One major criticism is that the study used 300–500 μ beads, which are considered large for this application. However other randomized controlled trials also compared cTACE versus DEE-TACE including Golfieri et al. This study on 177 patients did not show any statistical difference in terms of local or overall tumor response with 2 year follow-up but demonstrated reduced post procedural pain with DEE-TACE [33]. Meta-

Interestingly, a randomized trial of 101 patients treated with TAE using microspheres alone versus TACE using doxorubicin-eluting microspheres found no difference in the response to

A recent meta-analysis of randomized controlled trials pertaining to 5700 patients concluded that none of the transcatheter chemoembolization options as stand-alone were superior to transarterial bland embolization. The authors added that the conclusions are based on large information size of moderate quality based on data from 3 randomized controlled trials (RCT) of TAE versus best

The SPACE trial, a randomized, double-blinded, phase II trial, compared Sorafenib with DEB-TACE versus DEB-TACE alone (placebo) in the treatment of intermediate stage HCC. The study did not show improvement in time to progression nor overall survival between the two

Radioembolization, also known as selective internal radiation therapy (SIRT), consists of administering either glass or resin microspheres loaded with radioactive isotope, yttrium-90 (Y-90). Y-90 is a pure better emitter with a half-life of 64.1 h and a mean tissue penetration of 2–3 mm. Radioembolization is currently not part of the standard treatment guidelines. However, promising clinical research has driven its growing use in the management of hepatic malignancies. A multidisciplinary team consisting of surgeons, interventional radiologist, hepatologists, oncologists, and radiation oncologists determines if a patient is a candidate for Y-90 radioembolization. The Barcelona Clinic Liver Cancer (BCLC) and Eastern Cooperative Oncology Group (ECOG) scoring systems are taken into account in the decision process. The microspheres used today are either glass and resin microspheres. Glass microspheres, or TheraSpheres, is FDA approved for the treatment of unresectable HCC. Resin microspheres, or SIR-Spheres, is premarket approved by the FDA for the treatment of hepatic metastases from colorectal cancer in combination with floxuridine. Glass microspheres carry a higher activity load, thus requiring decreased volumes and number of spheres, compared to resin microspheres for the same dose [37]. Since resin

treatment (primary endpoint) and no difference in overall survival [34].

supportive care, 4 RCT of TAE versus TACE and 2 TAE versus DEB-TACE [35].

ratio 0.53, 95% CI 0.32–0.89, P = 0.017) [31].

analysis on the topic has had equivocal results.

groups [36].

4. Radioembolization

Non-target embolization can occur due to reflux of chemoembolic agents or failure to recognize the arterial anatomy supplying non-hepatic structures. This can lead to gastrointestinal ulceration/perforation, pancreatitis, cholecystitis, pneumonitis, or skin burns.

Hepatic abscess formation is rare in patients with unaltered anatomy. However, patients with post-surgical or disrupted anatomy of the biliary tree are at increased risk due to colonization of the biliary tree from enteric flora. One study showed 6 out of 7 patients with a prior bilioenteric anastomosis formed hepatic abscesses even after receiving standard broad spectrum prophylactic antibiotics [27]. Another study showed no formation of hepatic abscess in four patients with prior bilioenteric anastomosis when adding an aggressive bowel preparation [28]. In addition, gas formation within embolized hepatic tumors may occur postprocedurally which may lead to the misdiagnosis of a hepatic abscess.

Vascular complications are uncommon but include access site hematomas, pseudoaneurysms, or arteriovenous fistulas.

Other rare complications include sepsis, biliary strictures, variceal bleeding, renal failure, or chemotherapy-related toxicities such as alopecia, anemia, or myelosuppression.

#### 3.4. Results

Multiple studies have shown TACE to increase overall survival when compared to conservative management. A randomized control trial by Llovet et al. was terminated early as it demonstrated the one-year and two-year survival rates for chemoembolization to be 82 and 63% compared to 63 and 27% for supportive care [29]. Another randomized trial by Lo et al. showed the one-year and two-year survival rates for chemoembolization to be 57 and 31% compared to 32 and 11% for supportive care [30]. Two meta-analyses of randomized controlled trials by Camma et al. and Llovet et al. showed a significant decrease in 2 year mortality with TACE in patients with unresectable HCC (odds ratio 0.54, 95% CI 0.33–89, P = 0.015 and odds ratio 0.53, 95% CI 0.32–0.89, P = 0.017) [31].

Several studies have compared DEE-TACE versus cTACE versus bland TACE. The PRECI-SION V study was a prospective randomized study analyzing cTACE versus DEE-TACE. The study did not meet its primary endpoint of superior response rate with DEE-TACE but did show DEE-TACE is better tolerated [32]. One major criticism is that the study used 300–500 μ beads, which are considered large for this application. However other randomized controlled trials also compared cTACE versus DEE-TACE including Golfieri et al. This study on 177 patients did not show any statistical difference in terms of local or overall tumor response with 2 year follow-up but demonstrated reduced post procedural pain with DEE-TACE [33]. Metaanalysis on the topic has had equivocal results.

Interestingly, a randomized trial of 101 patients treated with TAE using microspheres alone versus TACE using doxorubicin-eluting microspheres found no difference in the response to treatment (primary endpoint) and no difference in overall survival [34].

A recent meta-analysis of randomized controlled trials pertaining to 5700 patients concluded that none of the transcatheter chemoembolization options as stand-alone were superior to transarterial bland embolization. The authors added that the conclusions are based on large information size of moderate quality based on data from 3 randomized controlled trials (RCT) of TAE versus best supportive care, 4 RCT of TAE versus TACE and 2 TAE versus DEB-TACE [35].

The SPACE trial, a randomized, double-blinded, phase II trial, compared Sorafenib with DEB-TACE versus DEB-TACE alone (placebo) in the treatment of intermediate stage HCC. The study did not show improvement in time to progression nor overall survival between the two groups [36].
