Clinical UM Guideline

 

Subject: Transcatheter Arterial Chemoembolization (TACE) and Transcatheter Arterial Embolization (TAE) for Treating Primary or Metastatic Liver Tumors
Guideline #: CG-SURG-80 Publish Date:    06/28/2018
Status: New Last Review Date:    05/03/2018

Description

This document addresses the use of TACE or TAE for the treatment of primary liver malignancies and metastatic tumors to the liver in addition to indications for use in specific individuals who are awaiting liver transplantation or who may become eligible for liver transplantation.

TACE and TAE are catheter-based embolization procedures. TACE is combined with a prior injection of a chemotherapeutic agent into the hepatic artery, and TAE is not combined with a chemotherapeutic agent (bland embolization). Both embolization procedures lead to ischemia of the tumor by blockage of the nutrient supply.

Note:  For additional information please refer to the following related documents:

Clinical Indications

Medically Necessary:

Primary Hepatic Malignancy or Metastatic Tumors to the Liver

Transcatheter arterial chemoembolization (TACE) or transcatheter arterial embolization (TAE) is considered medically necessary for any of the following indications:

  1. Treatment for individuals with liver-only metastasis from uveal (ocular) melanoma; or
  2. Palliative treatment for individuals with neuroendocrine tumors (for example, carcinoid tumors, pancreatic islet cell tumors, parathyroid, pituitary angiomas) with hepatic metastases when systemic therapy has failed to control symptoms such as carcinoid syndrome (for example, debilitating flushing, wheezing, and diarrhea); or
  3. Palliative treatment for individuals with symptoms from non-carcinoid neuroendocrine tumors with hepatic metastases (for example, hypoglycemia, severe diabetes, Zollinger-Ellison Syndrome); or
  4. Palliative treatment for individuals with specific liver-related symptoms due to tumor bulk (for example, pain) from any primary or metastatic hepatic tumor.

Hepatocellular Carcinoma or Bridge to Liver Transplantation

TACE or TAE is considered medically necessary as a primary treatment for surgically unresectable primary hepatocellular carcinoma or as a bridge to liver transplantation when all of the following criteria are met for either indication:

  1. Preserved liver function defined as Childs-Turcotte-Pugh Class A or B; and
  2. Three or fewer encapsulated nodules, and each nodule is less than or equal to 5 centimeters in diameter; and
  3. No evidence of extra-hepatic metastases; and
  4. No evidence of severe renal function impairment; and
  5. No evidence of portal vein occlusion.

Hepatocellular Carcinoma in Individuals Who May Become Eligible for Liver Transplantation

TACE or TAE is considered medically necessary for the treatment of an individual when both of the following criteria are met:

  1. May become eligible for liver transplantation except that the hepatic lesion(s) is greater than 5 centimeters in maximal diameter; and
  2. It can be reasonably expected that treatment with TACE or TAE will result in tumor size reduction to less than or equal to 5 centimeters in maximal diameter.

Not Medically Necessary:

TACE or TAE is considered not medically necessary when the above criteria are not met.

TACE utilizing chemotherapy-loaded microspheres (that is, drug-loaded microspheres, drug-eluting beads) is considered not medically necessary for all liver-related indications, including but not limited to, palliative treatment of hepatic metastases from neuroendocrine tumors or unresectable hepatocellular carcinoma, as primary treatment for surgically unresectable primary hepatocellular carcinoma, as a bridge to liver transplantation, or for liver metastasis from other primary tumors.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

CPT

 

37243

Vascular embolization or occlusion, inclusive of all radiological supervision and interpretation, intraprocedural roadmapping, and imaging guidance necessary to complete the intervention; for tumors, organ ischemia, or infarction [when specified as TAE, or TACE not using drug-loaded microspheres or drug-eluting beads]
Note: the procedure using drug-loaded microspheres or drug-eluting beads is considered not medically necessary.

 

 

ICD-10 Procedure

 

04L33ZZ

Occlusion of hepatic artery, percutaneous approach [when specified as TAE, or TACE not using drug-loaded microspheres or drug-eluting beads]
Note: the procedure using drug-loaded microspheres or drug-eluting beads is considered not medically necessary.

 

 

ICD-10 Diagnosis

 

 

For the diagnosis codes listed below or for a metastatic liver tumor from any primary tumor site when criteria are met:

C22.0-C22.9

Malignant neoplasm of liver and intrahepatic bile ducts

C25.4

Malignant neoplasm of endocrine pancreas

C69.30-C69.32

Malignant neoplasm of choroid

C69.40-C69.42

Malignant neoplasm of ciliary body

C73

Malignant neoplasm of thyroid

C74.00-C74.92

Malignant neoplasm of adrenal gland

C75.0-C75.9

Malignant neoplasm of other endocrine glands and related structures

C78.7

Secondary malignant neoplasm of liver and intrahepatic bile duct

C7A.00-C7A.8

Malignant neuroendocrine tumors

C7B.02

Secondary carcinoid tumors of liver

D01.5

Carcinoma in situ of liver, gallbladder and bile ducts

E16.0-E16.2

Drug-induced, other and unspecified hypoglycemia

E16.4

Increased secretion of gastrin (Zollinger-Ellison syndrome)

E34.0

Carcinoid syndrome

Z76.82

Awaiting organ transplant status

Discussion/General Information

Description and Prevalence of the Diseases

According to the National Cancer Institute (NIH), approximately one percent of all men and women will be diagnosed with liver and intrahepatic bile duct cancer at some point during their lifetime (based on 2012-2014 data). Primary hepatobiliary carcinoma pertains to malignancies arising from the liver or the bile ducts, and/or gallbladder known as intrahepatic and extrahepatic cholangiocarcinoma. Hepatic carcinoma can arise either as primary liver cancer or by metastasis to the liver from other tissue origins, such as colorectal carcinoma. Malignancies of the liver are comprised primarily of adenocarcinomas classified by hepatocellular and cholangiocarcinoma cell types. Hepatocellular carcinoma (HCC) is the most common form of hepatic malignancies. The increasing incidence of hepatic carcinoma in the U.S. has been attributed to high incidence of hepatitis C (HCV), nonalcoholic fatty liver disease (NAFLD), and metabolic syndrome (Heimbach, 2017). Cholangiocarcinoma occurs throughout the biliary tree. Surgical excision is the optimal treatment for hepatobiliary primaries, but many tumors are unresectable due to size, location or inadequate liver reserve secondary to a cirrhotic liver. In individuals with unresectable disease, liver transplantation is considered the other curative option. Surgical excision of metastatic liver disease is generally not considered curative, with the exception of individuals with isolated liver metastases without any other evidence of disease.

Neuroendocrine tumors may also involve the liver, where hormone production can cause systemic symptoms. The most common neuroendocrine tumor is the carcinoid tumor where excessive hormone production is associated with carcinoid syndrome, characterized by debilitating flushing, wheezing and diarrhea. Pancreatic endocrine (that is, islet cell) tumors that produce gastrin, insulin or other pancreatic hormones are unusual types of neuroendocrine tumors. Pancreatic endocrine tumors must be distinguished from the more common pancreatic epithelial tumors that arise from the exocrine portion of the pancreas. Surgical resection is typically not possible for neuroendocrine tumors, and treatment may be focused on palliation of specific systemic symptoms. 

Melanoma of the uveal tract (iris, ciliary body, and choroid), also known as ocular melanoma (OM), though rare, is the most common primary intraocular malignancy in adults. Uveal melanomas can arise in the anterior (iris) or the posterior (ciliary body or choroid) uveal tract. Extraocular extension, recurrence, and metastasis are associated with an extremely poor prognosis, and short-term survival (Gragoudas, 1991).

Description of TACE and TAE

Arterial embolization therapy, including TACE and TAE, in the treatment of HCC is based on selective catheter-based infusion of particles targeted to the arterial branch of the hepatic artery feeding the portion of the liver in which the tumor is located. TACE has been investigated to treat resectable, unresectable, and recurrent HCC, as a bridge to liver transplantation, and to treat liver metastases, most commonly from colorectal cancer. TACE of the liver is a proposed alternative to conventional systemic or intra-arterial chemotherapy, and to various nonsurgical ablative techniques, to treat resectable and nonresectable tumors. The rationale for TACE is that infusions of viscous material containing one or more antineoplastic agents may exert synergistic effects: cytotoxicity from the chemotherapy that is potentiated by anoxia in the infarcted region. The liver is especially amenable to such an approach, given its distinct lobular anatomy, the existence of two independent blood supplies, and the ability of healthy hepatic tissue to grow and thus compensate for tissue mass lost during TACE. Another rationale is that TACE delivers effective local doses, while possibly minimizing systemic toxicities associated with oral or intravenous chemotherapy.

TAE is a palliative treatment for individuals with primary hepatic or metastatic tumors including neuroendocrine tumors with hepatic metastases (when systemic therapy has failed to control symptoms such as carcinoid syndrome), for symptoms from non-carcinoid neuroendocrine tumors with hepatic metastases, and for symptoms due to hepatic tumor bulk (that is, pain). TAE is carried out during selective hepatic arterial catheterization through the arteries supplying a tumor and involves the infusion of lipiodol (without a chemotherapeutic agent) followed by embolization using any of the embolic agents (for example, gelatin sponge cubes) as during TACE procedures. Advocates of this catheter-based therapy state that TAE may be equally effective as TACE for palliative treatment of primary liver cancer (Brown, 1998).

TACE procedures require hospitalization for placement of the hepatic artery catheter and workup to establish eligibility for TACE. Prior to the procedure, the patency of the portal vein is demonstrated to ensure an adequate post-treatment hepatic blood supply. With the individual under local anesthesia and mild sedation, a superselective catheter is inserted via the femoral artery and threaded into the hepatic artery. Angiography is then performed to delineate the hepatic vasculature, followed by injection of the embolic chemotherapy mixture. Chemotherapeutic agents delivered with TACE include doxorubicin (the single agent that is most widely used), epirubicin, mitomycin C, or cisplatin, either alone or in combination, mixed with a viscous embolic material (for example, lipiodol). After infusion of this viscous chemotherapeutic agent, embolization of the arterial blood supply to the tumor is completed using embolic agents, including but not limited to, gelatin sponge particles, polyvinyl alcohol particles (PVA), or hydrophilic, polyacrylamide microporous beads, known as microspheres (Embospheres, HepaSphere, QuadraSphere®, BioSphere Medical, Inc., Rockland, MA and DC Bead, LC Bead/Bead Block Compressive Microspheres). Typically, only one lobe of the liver is treated during a single session, with subsequent embolization procedures scheduled from 5 days to 6 weeks later. In addition, since the embolized vessel recanalizes, TACE can be repeated as many times as necessary. Repeat x-rays are taken to confirm that the tumor has been optimally treated. The procedure is usually performed by an interventional radiologist.

The most common adverse event associated with TACE or TAE is post-embolization syndrome which consists of fever, abdominal pain, nausea, vomiting, leukocytosis, and an increase in liver enzymes lasting for a few hours to a few days. This syndrome, which has widely variable manifestations, is usually self-limited and experienced after 80% to 90% of the procedures. The syndrome is treated symptomatically and decreases in severity with subsequent procedures in most individuals. The chemotherapeutic and embolizing agents may also cause acute portal vein thrombosis, acute cholecystitis, biliary tract necrosis, pancreatitis, gastric erosions, or ulcers if they are inadvertently injected into these organs. Infection of the necrotic tumor presenting as liver abscess can also occur. Hepatic insufficiency and liver failure (a major treatment-related complication that may result in morbidity), can develop after TACE in individuals with borderline liver function before treatment (Lau, 2008). Studies have consistently reported that the toxicity of TACE after treatment in individuals with HCC in a standardized oncology protocol setting results in considerably lower toxicity rates than those reported after treatment with currently used systemic chemotherapeutic agents (Buijs, 2008; Llovet, 2002b;). Reported rates of TACE and TAE treatment-associated mortality for both are usually < 5%.

The introduction of preformed, drug-loaded microspheres has emerged as a system proposed to deliver various types of chemotherapy in a precise, controlled and sustained manner to achieve high intratumor concentration over time. Use of these drug-eluting microspheres (DEMs) or (drug-eluting beads) DEBs lengthens the contact time between cancer cells and the chemotherapeutic agents while avoiding damage to the hepatic microcirculation (Kettenbach, 2008). The unique properties of DEMs allow delivery of large amounts of drugs to tumors for a prolonged time, thereby decreasing plasma levels of the chemotherapeutic agent. To date, the FDA has stand-alone approvals for chemotherapeutic and embolic agents used with TACE that are not specifically approved as combination therapy when administered during TACE. According to the manufacturer, DC Bead is not currently available for sale or distribution in the U S. and has not requested FDA approval. Specific chemotherapeutic agents may be approved for a number of oncologic indications and several embolic beads are FDA-approved for “embolization of hypervascular tumors and arteriovenous malformations” (FDA, 2014).

TACE or TAE as Palliative Treatment of Neuroendocrine Tumors and Metastatic Liver Disease

For individuals with hepatic metastasis from neuroendocrine tumors, data in the medical literature confirms that catheter-based arterial embolization procedures, with or without chemotherapy, have a role in the palliative care of individuals with various neuroendocrine tumor symptoms such as carcinoid syndrome (for example, severe flushing, wheezing, and diarrhea), Zollinger-Ellison syndrome, hypoglycemia, severe diabetes, and other neuroendocrine-related manifestations (Christante, 2008, Gupta, 2003; Hur, 2013; Maluccio, 2006; Roche, 2003; Ruutiainen, 2007). The treatment has been shown to be useful in diminishing the effect of these symptoms on the individual, consequently producing significant improvements in the quality of life for individuals with neuroendocrine tumors. TACE or TAE is also known to improve pain and control symptoms attributable to the effect of tumor bulk associated with either primary or metastatic liver disease through shrinkage of tumor size.

The NCCN CPG for neuroendocrine tumors of the gastrointestinal tract and/or distant metastases (V3.2017) includes a recommendation to consider hepatic-directed therapy for hepatic-predominant disease including arterial embolization and TACE for individuals with locoregional unresectable disease and/or distant (liver) metastases (symptomatic, clinically significant tumor burden, or clinically significant progressive disease) (2A recommendation).

TACE or TAE as Treatment for Surgically Unresectable Primary Hepatocellular Carcinoma (HCC)

RCTs in the peer-reviewed literature have focused on the impact of embolization procedures as palliation of noncurable HCC. According to Liapi and Geschwind (2007), TACE is currently considered the mainstay of therapy for unresectable HCC. In two prospective RCTs (Llovet, 2002b; Lo, 2002), TACE was shown to prolong survival significantly in select individuals with HCC with preserved liver function and adequate performance status. In a meta-analysis of pooled data of seven RCTs assessing TAE/TACE as a primary treatment of unresectable HCC in comparison to an untreated control arm, Llovet and Bruix (2003) found a considerable 2-year survival benefit associated with TACE compared with control (p=0.017). Ideal candidates for TACE include individuals with preserved liver function and asymptomatic multinodular tumors without vascular invasion or extrahepatic spread not suitable for radical treatments (Llovet, 2004). Additional criteria include individuals with 3 or fewer encapsulated nodules, each < 5 centimeters (cm) in diameter, absence of extra-hepatic metastases, no evidence of severe renal function impairment, and no evidence of altered portal blood flow (for example, portal vein thrombosis) (Bruix, 2005; Bruix 2011; Lau, 2006; Molinari, 2006). The evidence suggests that individuals who do not meet these criteria do not respond adequately to TACE and receive little or no benefit from the treatment. This is confirmed in a retrospective study by Maluccio and colleagues (2008), where predictors of poor prognosis following TAE for HCC were tumor size ≥ 5 cm, 5 or more tumors, and extrahepatic disease; portal vein occlusion was not found to be an independent predictor of survival. Overall survival (OS) rates observed at 1, 2, and 3 years were 66%, 46%, and 33%, respectively; survival rates increased to 84%, 66%, and 51%, respectively, when only the subgroup of individuals without extrahepatic spread or portal vein involvement by tumor were considered.

The NCCN CPGs in Oncology for hepatobiliary cancer (V1.2018), principles of locoregional therapy state:

Takayasu and colleagues (2006) reported results from an 8-year prospective cohort study of 8510 individuals with unresectable HCC who underwent initial treatment with TACE using emulsion of lipiodol and anticancer agents followed by gelatin sponge particles. The mean follow-up period was 34 months. The OS rates by TACE at 1, 3, 5 and 7 years were 82%, 47%, 26%, and 16%, respectively. Multivariate analyses showed significant differences (p=0.0001) in degree of liver damage, alpha-fetoprotein value, maximum tumor size, number of lesions, and portal vein invasion. TACE-related mortality rate after the initial therapy was 0.5%. The authors concluded that TACE was a safe, therapeutic modality for unresectable HCC, with a 5-year survival rate of 26% and a 0.5% mortality rate.

A Cochrane review (Oliveri, 2011) included 9 trials with 645 participants comparing treatment with TACE (n=6 trials) or TAE (n=3 trials) to control for unresectable HCC. Seven trials had low risk of selection bias, but all had other risks of bias. Three trials were stopped early due to interim inspections and one trial due to slow accrual. Meta-analysis of trials with low risk of selection bias showed that TACE or TAE versus control does not significantly increase survival (Hazard ratio [HR] 0.88; 95% confidence interval [CI], 0.71 to 1.10). Two trials with low risk of selection bias, no early stopping, and no co-intervention did not establish a significant effect of TACE or TAE on OS (HR 1.22; 95% CI, 0.82 to 1.83; p=0.33). Trial sequential analysis confirmed the absence of evidence for a beneficial effect of TACE or TAE on survival, indicating the need for future randomization of up to 383 additional participants in adequately powered and bias-protected clinical trials. Despite the lack of firm evidence to support or refute the use of TACE or TAE for unresectable HCC, the NCCN CPGs for hepatobiliary cancers (V1.2018) include a category 2A recommendation and uniform consensus for TACE and TAE as standard locoregional treatment for individuals with unresectable HCC.

Ongoing phase III RCTs are evaluating combination therapy of sorafenib with TACE or DEB-TACE in individuals with unresectable HCC. The goal of these studies is to clarify the optimal scheduling of sorafenib when used in combination with arterially directed therapies (NCCN, V1.2018).

TACE or TAE for Resectable HCC (As Neoadjuvant or Adjuvant Therapy)

TACE has been studied for other indications including large HCC, preoperative shrinkage of resectable HCC, and for tumor types other than HCC and neuroendocrine tumors. Cheng and colleagues (2005a) evaluated the value and limitations of postoperative TACE in preventing recurrence of HCC. In this retrospective study, the authors compared the recurrence rates for a group of 987 individuals with HCC treated with TACE compared to a control group of 643 postoperative individuals with HCC who did not receive TACE. The 6-, 12-, and 18-month recurrence rates for the TACE group compared to the non-TACE group were 22.2% versus 61.6%, 78.0% versus 74.7% and 88.6% versus 80.1%. There were also significant differences between the recurrence rates of the 2 groups at 6 months (p<0.0001). The authors concluded that TACE had a good effect in preventing recurrence of HCC at 6 months, but the rate of recurrence was less satisfactory in a longer period. The data reported in this trial did not demonstrate that TACE resulted in a significant advantage in quality of life or length of survival for these conditions.

Chua and colleagues (2009) conducted a systematic review of neoadjuvant TACE for resectable HCC, evaluating 18 studies including 3 RCTs and 15 observational studies. The review comprised 3927 individuals, of whom 1293 underwent neoadjuvant TACE. The conclusions were that TACE could be used safely and resulted in high rates of pathologic responses but did not appear to improve disease-free survival in the TACE group. No conclusions could be drawn with respect to OS differences between the TACE and non-TACE groups due to the heterogeneity of the results across studies.

Zhou and colleagues (2013) reported on a meta-analysis of 21 studies evaluating preoperative TACE including 4 RCTs and 17 nonrandomized studies with a total of 3210 participants. Preoperative TACE was given to 1431 individuals with the remaining 1779 serving as controls. The 5-year disease-free survival for preoperative TACE in 18 studies ranged from 7% to 57% and 8% to 49% in the controls. In 16 studies, the 5-year OS for preoperative TACE was 15% to 63% and 19% to 63% in the controls. In the pooled analyses, there were no significant improvements with preoperative TACE versus controls in the 5-year disease-free (32% vs. 30%, p=0.17) and OS (40% vs. 45%, p=0.37). Intra-and extra-hepatic recurrence were also not significantly different in the pooled analyses (51% vs. 54% and 13% vs. 10%; p=0.19, respectively).

TACE or TAE as a Bridge to Liver Transplantation

As the incidence of HCC continues to rise and availability of donor organs remains low, the waiting time for potentially curative therapy with orthotopic liver transplantation (OLT) increases. Heckman (2008) noted the incidence of disease progression while listed for transplant was 10% to 23%. Various technologies have been explored to maintain transplant eligibility by controlling disease progression, of which TACE and radiofrequency ablation (RFA) were the most frequently studied. A “bridge” involves the use of locoregional techniques such as TAE and TACE, to promote tumor death and control tumor progression beyond the Milan criteria in order for the individual to remain eligible on the OLT wait list (Heimback, 2017). 

The current Organ Procurement and Transplantation Network (OPTN) and United Network for Organ Sharing (UNOS) allocation policy provides incentives to use locoregional therapies to downsize (downstage) tumors to T2 status and to prevent progression while on the transplant wait list. In addition, the OPTN/UNOS policy appears to implicitly recognize the role of locoregional therapy in the pre-transplant setting. These indications are in part related to the current OPTN/UNOS liver allocation scoring system referred to as the Model for End-stage Liver Disease (MELD) for adults ages 12 and older and the Pediatric End-stage Liver Disease (PELD) scoring system for candidates younger than 12 years of age. The MELD score is a continuous disease severity scale incorporating serum bilirubin, prothrombin time (that is, international normalized ratio-INR), and serum creatinine into an equation, producing a number ranging from 6 (less ill) to 40 (gravely ill). The MELD score estimates how urgently the individual needs a liver transplant within the next 3 months. PELD is similar to MELD but uses additional factors to recognize the specific growth and development needs of children. PELD scores may also range higher or lower than the range of MELD scores. The PELD scoring system includes measures of serum bilirubin, INR, albumin, growth failure, and whether the child is < 1 year old. Candidates must meet the staging and imaging criteria specified in the OPTN/UNOS’s policy, Allocation of Livers and Liver-Intestines Policy: Candidates with Hepatocellular Carcinoma (HCC) (sections 9.3.F.i-ii). Liver candidates can also be assigned a priority status if the candidate meets the requirements for that status. Upon submission of the required information to the OPTN, candidates with HCC that have stage T2 lesions and meet the criteria according to the policies (that is, sections 9.3.F.i-vi.) will be listed at their calculated MELD or PELD score. OPTN/UNOS defines stage T2 lesions as including any of the following:

The largest dimension of each tumor is used to report the size of HCC lesions. Nodules < 1 cm are indeterminate and cannot be considered for additional priority. Past locoregional treatment for HCC (OPTN Class 5 [T2] lesion or biopsy proven prior to ablation) are eligible for automatic priority.

The NCCN CPG for hepatobiliary carcinoma (V1.2018) states:

Bridge therapy is used to decrease tumor progression and the dropout rate from the liver transplant list…It is considered for patients who meet the transplant criteria. A number of studies have investigated the role of locoregional therapies as a bridge to liver transplantation in patients on a waiting list (Llovet, 2008; Majno, 2007).  These studies included…chemoembolization, TACE (Yao, 2003; Graziadel, 2003; Hayashi, 2004), TACE with drug-eluting beads (DEB-TACE) (Nicolini, 2013).

Nicolini and colleagues (2013) reported on a retrospective analysis of individuals with HCC who met the Milan criteria and were treated with TACE or DEB-TACE prior to liver transplant. DEB-TACE was associated with a trend towards higher response rates, that is, ≥ 90% necrosis (44.7% vs. 32.0%; p=0.2834) and higher 3-year relapse-free survival rates after liver transplant (87.4% vs. 61.5%; p=0.0493) compared to TACE.

Limitations of these studies include small sample sizes and heterogeneous study populations; however, the NCCN CPG for hepatobiliary cancer (V1.2018) states, “Nevertheless, the use of bridge therapy in this setting is increasing, and it is administered at some NCCN Member Institutions.”

The Society of Interventional Radiology’s Quality Improvement Guidelines for Transarterial Chemoembolization and Embolization of Hepatic Malignancy (Gaba, 2017) states that TACE may be indicated as a bridge to liver transplantation for individuals with liver-dominant hepatic malignancies.

TACE or TAE as a Technique to Prevent Tumor Progression While on the Liver Transplantation Wait List

Several studies have reported dropout rates of transplant wait-listed candidates treated with locoregional therapy. Early studies consist of small case series lacking controlled data, thus making it difficult to assess contributions of locoregional therapy to time on the transplant wait list.

Yamashiki and colleagues (2005) reported on 288 individuals given various ablative therapies; the dropout rate due to tumor progression at 1 and 3 years was 6.25% and 23%, respectively. Tumors > 3 cm affected the dropout rate due to tumor progression.

Cheng and colleagues (2005b) studied 29 individuals with hepatitis-related cirrhosis and unresectable HCC who received pre-liver transplantation TAE (group A: 19 of 29) or underwent liver transplantation without prior TAE (group B: 10 of 29). The individuals in the pre-liver transplantation TAE group (A) were further subdivided according to the Milan criteria into group A1 (12 of 19) who met the criteria and group A2 (7 of 19) who did not. The primary outcome measure was actuarial survival rate. In the explanted liver, CT images correlated well with pathological specimens, showing that TAE induced massive tumor necrosis (> 85%) in 63% of individuals in group A; all 7 individuals in group A2 exhibited tumor downgrading that met Milan criteria. The overall 5-year actuarial survival rate was 80.6%. The TAE group had a better survival (84% at 5 years) than the non-TAE group, (75% at 4 years). The 3-year survival of group A2 (83%) was also higher than that of group A1 (79%). Tumor necrosis > 85% was associated with survival of 100% at 3 years, which was significantly better than the others who showed < 85% tumor necrosis (57.1% at 3 years) or who did not have TAE (75% at 3 years). The authors concluded that TAE may be considered an effective treatment for HCC before liver transplantation and help in further reducing the dropout rate from transplant wait lists for individuals with HCC.

Obed and colleagues (2007) systematically reviewed the outcome of individuals who underwent TACE for HCC and subsequently OLT, irrespective of tumor size when no tumor progression was observed. Records, imaging studies, and pathology of 84 individuals with HCC were reviewed. Ten individuals were not treated at all, 67 individuals had TACE and 35 were listed for OLT. Tumor progression was monitored by ultrasound and alpha-fetoprotein (AFP) level every 6 weeks. Fifteen individuals showed signs of tumor progression without transplantation. The remaining 20 individuals underwent OLT. Further records of 7 individuals with HCC seen in histological examination after OLT were included. The authors reported that the individuals after TACE without tumor progression underwent transplantation and had a median survival of 92.3 months. Individuals who did not qualify for liver transplantation or had signs of tumor progression had a median survival of 8.4 months. The individuals without treatment had a median survival of 3.8 months. Independent of International Union Against Cancer (UICC) stages, the individuals without tumor progression and subsequent OLT had longer median survival. No significant difference was seen in the OLT treated individuals if they did not fulfill the Milan criteria. The authors concluded that the selection of individuals for OLT based on tumor progression results in good survival, citing the evaluation of individuals with HCC should be based not only on tumor size and number of foci but also on tumor progression and growth behavior under therapy.

TACE to Downstage HCC Prior to Liver Transplantation

In select individuals with more advanced HCC without distant metastasis, downstaging therapy is used to reduce the tumor burden for those individuals who are beyond the accepted transplant criteria.

Yao and colleagues (2005a) reported on a case series of 30 individuals with HCC who underwent a variety of locoregional therapies including TACE, specifically to downstage tumors to meet the University of California at San Francisco (UCSF) transplant criteria. Eligibility for locoregional therapy seeking to downstage individuals included either 1 nodule between 5 cm and 8 cm in diameter; 2 or 3 nodules with at least 1 between 3 cm and 5 cm in diameter, with the sum of diameters no > 8 cm; or 4 or 5 nodules all ≤ 3 cm, with sum of diameters < 8 cm. Among the 30 individuals, 21 (70%) met the criteria for locoregional therapy and 16 of these were successfully downstaged and underwent transplantation. No tumors recurred at a median follow-up of 16 months. The authors concluded that downstaging can be successfully achieved in most individuals, but that data regarding tumor recurrence requires longer follow-up.

Chapman and colleagues (2008) evaluated outcomes of downstaging individuals with TACE to allow eligibility for OLT. A total of 76 individuals with stage 3/4 HCC were potential transplant candidates if downstaging was achieved by TACE. OLT was considered based on follow-up imaging findings. Individuals were tracked who were successfully downstaged within the Milan criteria, tumor response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, findings at explant, and outcomes after transplant. A total of 18 of 76 (23.7%) individuals had adequate downstaging to qualify for OLT under the Milan criteria. By RECIST, 27 of 76 (35.5%) individuals had a partial response (PR), 22 of 76 (29%) had stable disease, and 27 of 76 (35.5%) had progressive disease. A total of 17 of 76 (22.4%) individuals who met other qualifications underwent OLT after successful downstaging (13 of 38 stage 3; 4 of 38 stage 4). Explant review demonstrated 28 identifiable tumors in which post-TACE necrosis was > 90% in 21 (75%). At a median of 19.6 months (range 3.6-104.7), 16 of 17 (94.1%) individuals who underwent OLT were still alive. One individual expired 11 months after OLT secondary to medical comorbidities and 1 individual with recurrent HCC subsequently underwent resection of a pulmonary metastasis and was still alive at 63.6 months from OLT. The authors proposed that select individuals with stage 3/4 HCC can be successfully downstaged to Milan criteria with TACE and those transplanted had midterm disease-free and OS, similar to stage 2 HCC. The treatment strategy proposed in this study is limited in drawing conclusions as the data was evaluated retrospectively from a case series of individuals. In addition, only 22% of the stage 3/4 HCC individuals who received TACE went on to OLT, eliminating many individuals with progressive disease. 

Heckman and colleagues (2008) studied the effect of locoregional therapy on survival utilizing TACE, yttrium-90Y, RFA, or resection prior to OLT for HCC. A retrospective review of a prospectively collected database included groups consisting of 50 individuals that received therapy (20 TACE; 16: yttrium-90Y; 13 RFA, 3 resections) in Group I and 73 individuals in the transplanted without therapy (Group II). Median wait list time was 28 days (range 2-260 days) in Group I, and 24 days (range 1-380 days) in Group II. Median time from therapy to OLT was 3.8 months (range 9 days to 68 months). A total of 12 individuals (24%) were successfully downstaged with 8 of these 12 receiving TACE. Survival was not statistically significantly different between the 2 groups (p=0.53). The 12 individuals who were downstaged did not have a significant difference in survival as compared with those who received therapy but did not respond or the individuals who were transplanted without therapy (p=0.76). This review suggests that locoregional therapy, particularly TACE, is a safe tool for individuals on the transplant list, does not impact survival, and can downstage selected individuals to allow for OLT.

The NCCN CPG for hepatobiliary cancers (V1.2018), principles of surgery, includes the following recommendation:

Patients meeting the UNOS criteria [(single lesion ≤5 cm, or 2 or 3 lesions ≤3cm]…) [should] be considered for transplantation using either cadaveric or living donation. Patients with tumor characteristics that are marginally outside of the UNOS guidelines may be considered for transplantation at select institutions. For patients with initial tumor characteristics beyond the Milan criteria who have undergone successful downstaging therapy (ie, tumor currently meeting Milan criteria), transplantation can also be considered.

The Society of Interventional Radiology’s Quality Improvement Guidelines for Transarterial Chemoembolization and Embolization of Hepatic Malignancy (Gaba, 2017) states that TACE may be indicated as a downstage to liver transplantation for individuals with liver-dominant hepatic malignancies.

TACE as an Ablative Technique to Reduce Recurrence Rates in Those with T3 Lesions

Some individuals with T3 lesions apparently are cured with liver transplantation, although most experience recurrent tumor. In a decisive 1996 study, the 4-year recurrence-free survival was 92% in those who met the “Milan criteria” compared to 59% in those who did not; additional studies confirm this difference in recurrence-free survival rate (Sauer, 2005). However, other institutions have reported similar outcomes with expanded criteria defining T3 lesions as a single nodule 6.5 cm or less, or 3 nodules or less with none > 4.5 cm, and total tumor diameters 8 cm or less. These expanded criteria are known as the UCSF criteria (Merli, 2005).

The question is whether TACE may decrease recurrence rate in individuals meeting these UCSF criteria. Yao and colleagues (2005b) published a detailed analysis of 121 individuals with HCC who underwent transplantation. A total of 78 individuals (64%) had T2 lesions, while an additional 27 individuals (22.3%) met the expanded UCSF criteria, termed T3A lesions. The remaining individuals had T1, T3B, or T4 lesions. Select individuals received a variety of preoperative locoregional therapies, including TACE or ablative therapies, such as percutaneous ethanol injection (PEI), RFA, or combined therapies. TACE was used most commonly in 43.5% of individuals. However, more than half these individuals received TACE within 24 hours of transplant to decrease the risk of tumor dissemination at the time of hepatectomy. A total of 38.7% of individuals did not receive preoperative locoregional therapy. The 1- and 5-year recurrence-free survival was similar in those with T2 and T3A lesions, while the corresponding recurrence rates were significantly lower for those with T3B and T4 lesions.

The authors also compared recurrence-free survival of those who did and did not receive locoregional therapy. For those with T2 lesions, the recurrence rates were similar whether or not the individual received locoregional therapy. However, for T3 lesions (including both T3A and T3B), the 5-year recurrence-free survival was 85.9% for those who received locoregional therapy compared to 51.4% in those who did not. When the data for T2 and T3 lesions were grouped together, the 5-year recurrence-free survival was 93.8% for those who received locoregional therapy compared to 80.6% in those who did not. The authors concluded that preoperative locoregional therapy may confer a survival benefit in those with T2 or T3 lesions. The authors note several limitations to the study, including the retrospective nature of the data, and the marginal statistical significance of the improved survival given the small numbers of individuals in each subgroup; only 19 individuals were in the T3A (UCSF expanded criteria) subgroup. In addition, no protocol specified which type of locoregional therapy to offer different individuals. These therapies are only offered to those individuals with adequate liver reserve; such individuals may have an improved outcome regardless of the preoperative management.

TACE or TAE as a Treatment for Intrahepatic Cholangiocarcinoma

According to the NCI, malignant tumors of the liver are primarily adenocarcinomas, with two major cell types: hepatocellular and cholangiocarcinoma. Cholangiocarcinoma is classified as either extrahepatic or intrahepatic, with the latter composed of epithelial cells that arise from the epithelium of the intrahepatic bile ducts. Cholangiocarcinomas are rare compared with HCC, comprising < 10% of primary malignancies of the liver. Complete surgical resection of intrahepatic cholangiocarcinoma (ICC) offers the only potentially curative therapy. Recurrence of ICC is frequent after surgical resection, with survival rates reported as low as 20% to 43% at 5 years. Therefore, most individuals are candidates for palliative therapy, including biliary drainage, systemic chemotherapy, radiation therapy, and photodynamic therapy; however, these options have limited benefit in symptom control and prolongation of survival.

Kim and colleagues (2008) retrospectively evaluated TACE or transcatheter arterial chemoinfusion (TACI) for unresectable ICC in measurements of clinical efficacy and prognostic factors associated with clinical success. Data was reviewed on 49 individuals who were treated with TACE (n=124 sessions) or TACI (n=96 sessions). Tumor response was evaluated based on computed tomography scans obtained 1 to 3 months after TACE or TACI. After treatment, 27 (55%) of the participants showed radiographic response, with multivariate analysis confirming that tumor vascularity (odds ratio [OR], 31.2; p=0.002) was the only independent factor associated with radiographic response. The median and mean survival periods among the participants were 12 and 24 months. Multivariate Cox regression analyses showed that tumor size (OR, 2.64; p =0.048), tumor vascularity (OR, 13.5; p<0.001), and the Child-Pugh class (OR, 3.65; p=0.014) were the independent factors associated with the length of the survival period. Large tumor size, tumor hypovascularity, and Child-Pugh class B were poor prognostic factors for determining the OS period. Despite several imitations in the study, including the nonrandomized and retrospective study design, the authors concluded that TACE is well tolerated and may be effective in prolonging survival in individuals with unresectable ICC.

Park and colleagues (2011) retrospectively compared clinical outcomes and survival benefits of TACE for unresectable ICC with supportive care. A total of 155 subjects with similar baseline tumor characteristics met the entry criteria and underwent TACE (72 subjects) or supportive treatment (83 subjects). After TACE, the incidence of significant (≥ grade 3) hematological and non-hematological toxicities was 13% and 24%, respectively, with no deaths within 30 days following TACE. The objective tumor regression (≥ PR) was achieved in 23% of the subjects in the TACE group. The Kaplan-Meier survival analysis showed that the survival period was significantly longer in the TACE group (median 12.2 months) than in the supportive treatment group (median 3.3 months, p<0.001). The authors concluded that TACE is safe and offers greater survival benefits than supportive treatment for the palliative treatment of unresectable ICC.

Kiefer and colleagues (2011) evaluated response and survival rates in 61 individuals after TACE for unresectable ICC. A total of 37 participants had pathologically proven cholangiocarcinoma, and 25 had poorly differentiated adenocarcinoma of unknown primary (likely cholangiocarcinoma). A mean of two treatments per participant were performed during the initial cycle; 20 participants received a second cycle of TACE. The 30-day disease-specific mortality was 0%. A total of 45 of 62 participants were evaluable for morphologic response after completion of their initial cycle: 11% (n=5) PRs, 64% (n=29) stable and 24% (n=11) progressed. Median time to progression from first TACE was 8 months, with 28% free of progression at 12 months. Median survival from time of diagnosis was 20 months, with 1-, 2-, and 3-year survival of 75%, 39%, and 17%, respectively. Median survival from time of first TACE was 15 months, with 1-, 2-, and 3-year survival of 61%, 27%, and 8%, respectively. There was no statistically significant difference in survival between participants with cholangiocarcinoma and those with poorly differentiated adenocarcinoma. The authors concluded that TACE provided local disease control (PR and stable disease) of ICC and adenocarcinoma of unknown primary in 76% of evaluable participants. The OS after TACE showed the best outcomes for those receiving multidisciplinary integrated liver-directed and systemic therapies.

Knüppel and colleagues (2012) reported a retrospective review of 195 individuals with intrahepatic (57%) or extrahepatic (43%) cholangiocarcinoma who received either chemotherapy or a combination of photodynamic therapy or TACE with chemotherapy. Some of the individuals underwent surgical resection. Individuals who only received palliative care (no surgery) survived 9.8 months longer with combination chemotherapy and TACE (n=14) versus chemotherapy alone (n=81) (median survival for chemotherapy plus TACE: 22.0 months versus for chemotherapy alone 12.2 months; p=0.039). Survival was not reported for extrahepatic versus intrahepatic cholangiocarcinoma.

Boehm and colleagues (2015) reported on a meta-analysis of 20 studies (n=657) on the hepatic artery therapies of TACE, hepatic artery infusion and yttrium-90 microspheres for ICC. The median OS was lowest for TACE and drug-eluting bead TACE (12.4 and 12.3 months, respectively) when compared with hepatic artery infusion (22.8 months) and yttrium-90 microspheres (13.9 months). Complete and PR to therapy was also lowest with TACE (17.3%) compared with yttrium-90 microspheres (27.4%) and hepatic artery infusion (56.9%); however, TACE had less grade 3/4 toxicity than hepatic artery infusion (0.26 vs. 0.35 events per person, respectively).

In summary, most of the data for the use of TACE to treat unresectable ICC is from retrospective reviews without randomization or a control group. Despite these limitations, the data suggests a survival benefit with TACE versus supportive care or systemic chemotherapy alone in the management of unresectable ICC; in addition, specialty consensus opinion suggests that TACE or TAE may be a treatment option for unresectable ICC.

TACE or TAE as a Treatment for Uveal (Ocular) Melanoma Metastatic to the Liver

Uveal melanoma, also known as ocular melanoma (OM), although rare, is considered the most common primary ocular malignancy occurring in adults. Metastatic disease is frequently confined to the liver, and once diagnosed, the prognosis is extremely poor. The median survival rate for those individuals with liver metastases has been reported at 5 to 7 months. TACE for the management of hepatic metastases of melanoma was first reported in a small, retrospective study (n=30) by Mavligit and colleagues (1988) and a retrospective, comparative review of case reports (n=201) from the M.D. Anderson Cancer Center registry for the years 1968-1991 (Bedikian, 1995).

The Bedikian study (1995) and subsequent studies (Huppert, 2011; Patel, 2005) report a consistent finding that response rates to treatment of metastatic uveal melanoma with TACE are < 50%; therefore, the primary goal of treatment is directed at arresting the progression of metastatic liver disease and improving survival rates in those individuals with liver-only metastasis.

The NCCN CPG for uveal melanoma (V1.2018) includes the following recommendation:

In general, uveal melanomas may have lower response rates to drug-based therapies than cutaneous melanoma, but efficacy has in general been more limited; however, individual patients on occasion may derive substantial benefit. Regionally directed therapies such as hepatic chemoembolization or radioembolization should be considered.

TACE or TAE for Hepatic Metastasis from Other Primary Tumors

The Society of Interventional Radiology (Gaba, 2017) quality improvement guidelines for TACE and TAE for hepatic malignancy state that other tumors that may present with liver-dominant metastases, including breast carcinoma and soft-tissue sarcomas (including gastrointestinal stromal tumors) have been successfully treated with TACE or embolization. Compared with historical controls, survival appears to be improved, “although randomized prospective data are not available.”

TACE for Hepatic Metastases from Colorectal Cancer

For individuals with liver metastases from colorectal cancer who do not qualify for surgical resection, systemic chemotherapy is considered the first-line treatment. However, more than 60% of individuals experience treatment failures and disease progression. For the large proportion of those in whom second- and third-line medical treatment has failed, other palliative therapies to control disease progression and symptoms have been studied, including TACE. The early studies of TACE for metastatic colorectal cancer consist of small numbers of participants with variable results across studies due to variation in participant selection criteria and treatment regimens (Salman, 2002; Sanz-Altamira, 1997; Tellez, 1998).

Vogl and colleagues (2009) evaluated tumor control and survival in individuals with unresectable liver metastases of colorectal origin that did not respond to systemic chemotherapy and were treated with TACE. Participants were treated at 4-week intervals, with a total of 2441 TACE procedures performed (mean, 5.3 sessions per participant), using 1 of 3 local chemotherapy protocols. Local tumor control was PR in 68 participants (14.7%), stable disease in 223 participants (48.2%), and progressive disease in 172 participants (37.1%). Median survival from the start of TACE treatments was 14 months. The 1- and 2-year survival rates after TACE were 62% and 28%, respectively. No difference in survival was observed between the 3 different local chemotherapy protocols.

The Agency for Healthcare Research and Quality (AHRQ) (Belinson, 2012) issued an evidence report on the comparative effectiveness and harms of the various local hepatic therapies (including hepatic arterial infusion, radioembolization, RFA, stereotactic body radiotherapy, TACE, and TACE-DEBs) for metastases to the liver from unresectable colorectal cancer. No studies reporting the use of TAE met the inclusion criteria for this review. The report states the strength of the evidence (all studies were case series) is insufficient to draw conclusions about OS, quality of life, or adverse events. Due to the absence of comparative data, the report is limited in drawing conclusions regarding the efficacy and effectiveness of local hepatic therapies, including TACE or TACE with DEBs, for individuals with unresectable colorectal cancer metastases to the liver who had no or only minimal evidence of extrahepatic disease, and whose disease was refractory to systemic therapy (Albert, 2011; Aliberti, 2011; Fiorentini, 2007; Hong, 2009; Martin, 2011). For the studies reporting outcomes on OS, published data on clinical outcomes is limited by the “poor characterization of the patient populations (e.g., number and size of metastases, performance status)” and variations in the delivery of TACE (for example, dose and drugs delivered). The report concludes that in the absence of comparative data, “conducting RCTs (ideally head-to-head comparisons) to answer many important questions is desirable, but challenging.”

A Cochrane review (Riemsma, 2013) concluded that in individuals with colorectal liver metastases, no significant survival benefit or benefit on extrahepatic recurrence was found when comparing TACE to palliative care. “At present, transarterial (chemo) embolisation cannot be recommended outside randomised clinical trials.”

The NCCN CPGs for colon cancer (V2.2018) and rectal cancer (V1.2018) address a number of non-surgical liver-directed therapies for the treatment of unresectable metastatic disease. The NCCN states that arterially directed catheter therapy is an option for a highly selective group of individuals with chemotherapy-resistant/-refractory disease and with predominant hepatic metastases.

Additional study is needed in the form of RCTs of homogeneous populations to demonstrate the efficacy of TACE for treatment of liver metastasis from colorectal cancer.

TACE for Hepatic Metastases from Breast Cancer

Vogl and colleagues (2010) reported the efficacy of repeated treatments with TACE in individuals with unresectable hepatic metastases from breast cancer. A total of 1068 TACE were performed (mean 5.1 sessions per participant, range: 3-25). Participants received either 1 of 2 chemotherapeutic agents alone (mitomycin-C or gemcitabine) or in combination. Tumor response was evaluated by MRI according to RECIST criteria. For all chemotherapy protocols, local tumor control in participants was PR 13% (27 of 208), stable disease 50.5% (105 of 208), and progressive disease 36.5% (76 of 208). The 1-, 2-, and 3-year survival rates after TACE were 69%, 40%, and 33%. Median and mean survival times from the beginning of the TACE sessions were 18.5 and 30.7 months. Treatment with mitomycin-C only showed median and mean survival times of 13.3 and 24 months, and with gemcitabine only 11 and 22.3 months. With a combination of mitomycin-C and gemcitabine, median and mean survivals were 24.8 and 35.5 months, respectively.

Additional studies in the peer-reviewed literature consist of small case series and a retrospective review (Giroux, 2004; Li, 2005). Further studies are needed in the form of RCTs to determine the treatment benefit and long term survival rates of TACE in the treatment of liver metastasis from breast cancer. The NCCN CPGs for breast cancer (V4.2017) do not address TACE or TAE as a treatment option for hepatic metastases from primary breast cancer.

TACE or TAE for Hepatic Metastases from Other Primary Tumors

The evidence in the peer-reviewed medical literature in the form of small case series, comparative trials, and retrospective studies is insufficient to demonstrate the efficacy of TACE or TAE for the treatment of liver metastases from other primary tumors including, but not limited to, non-small cell lung cancer (NSCLC), ovarian cancer (Vogl, 2012), and other tumors of unknown (occult) primary sites. Metastatic disease to the liver from tumors other than primary neuroendocrine tumors is generally treated with surgery, chemotherapy, or both (Artinyan, 2008). Additional study in the form of RCTs is needed to demonstrate the efficacy of TACE or TAE for the treatment of liver metastases from other primary (non-neuroendocrine and -uveal melanoma) tumor sites.

TACE with Drug-Loaded Microspheres or Drug-Eluting Beads (DEBs)

The development of DEBs or injectable microspheres loaded with chemotherapy is currently being studied as a drug delivery system for intraarterial treatment of hepatic lesions during TACE. In the setting of locoregional hepatic intraarterial infusion, TACE-administered DEBs are precisely delivered with a controlled and sustained release, as well as high intratumoral concentration for a sufficient time without damaging the surrounding hepatic tissue. Randomized studies are currently underway to determine the additional value of this technique over other established methods of TACE. To date, the U.S. Food and Drug Administration (FDA) has not cleared TACE-administered DEBs or microspheres loaded with chemotherapeutic agents for sale or distribution in the United States. Several brands of DEBs include, but are not limited to, DC Bead® (Biocompatibles UK Ltd., Farnham, Surrey, UK): 1) DEB (DEBDOX®) loaded with doxorubicin for the purpose of embolization of vessels supplying malignant hypervascular tumor(s) or the delivery of a local, controlled, sustained dose of doxorubicin to hepatic lesions, and 2) DEB (DEBIRI®) loaded with irinotecan, also indicated for embolization of vessels supplying malignant colorectal cancer metastases to the liver; and, HepaSphere™ Microspheres (Biosphere Medical, Inc., Rockland, MA, USA) loaded with doxorubicin for embolization of HCC and metastases to the liver. A search of the Clinical Trials.gov database identified ongoing, interventional, phase I-IV trials evaluating the safety and efficacy of TACE utilizing DEBs in the treatment of ICC, refractory colorectal cancer with liver metastasis, primary or refractory HCC, and unresectable liver metastasis from neuroendocrine tumors (Bhagat, 2013) (NIH, 2016).

TACE with DEBs for Liver Metastases from Colorectal Cancer

A search of the literature has identified a number of studies (Fiorentini, 2012; Martin, 2009; Martin, 2015; Pawlik, 2011; Poggi, 2008) and results of a multi-institutional registry (Martin, 2010) evaluating the use of drug-loaded beads (microspheres), including doxorubicin-, irinotecan-, and oxaliplatin-eluting beads, administered during TACE for hepatic metastases from colorectal cancer.

Poggi and colleagues (2008) evaluated the feasibility and safety of treatment with oxaliplatin-eluting microspheres (OEM-TACE) in individuals with unresectable liver metastasis of colorectal cancer and unresectable intrahepatic cholangiocarcinoma. A total of 15 individuals (8 with colorectal carcinoma liver metastases, 7 with intrahepatic cholangiocarcinoma) were treated with 27 sessions of OEM-TACE. According to RECIST criteria, stable disease was observed in 8 out of the 15 individuals (53.3%), a PR in 2 individuals (13.3%) and intrahepatic or extrahepatic tumor progression in 5 of 15 individuals (33.3%). The investigators concluded that OEM-TACE is a safe and feasible treatment without major adverse events and with a favorable pharmacokinetic profile.

Martin and colleagues (2009) conducted an open-label, prospective, multicenter observational trial of individuals with unresectable metastases to the liver from colorectal cancer. Following failure of standard systemic chemotherapy, 55 individuals underwent 99 treatments, most individuals receiving 1 or 2 treatments based on the extent and location of the liver disease, utilizing TACE with irinotecan-loaded DEBs. Individuals were followed for any treatment-related adverse experiences for 30 days after each treatment and monitored for survival. There were 30 (30%) sessions associated with adverse reactions during or after the treatment. The most common adverse events were periprocedural pain, nausea, and hypertension. The median disease-free and OS from the time of first treatment was 247 days and 343 days. A total of 6 individuals (10%) were downstaged from their original disease status. Of these, 4 individuals were treated with surgery and 2 with RFA. Neither number of liver lesions, size of liver lesions or extent of liver replacement (≤ 25% vs. > 25%) were predictors of OS. In multivariate analysis, only the presence of extrahepatic disease (p=0.001), extent of prior chemotherapy (failed first- and second-line vs. > second-line failure; p=0.007) were predictors of OS. A major limitation of this study was that all individuals did not receive the same adjunct medication or the same type of treatments with the irinotecan-loaded DEBs.

Richardson and colleagues (2013) systematically reviewed an RCT and five observational studies (n=235) on the use of TACE with irinotecan-DEBs for the treatment of unresectable colorectal liver metastasis. Survival times ranged from a median of 15.2 months to 25 months. The most common adverse event was postembolization syndrome (abdominal pain, nausea, and vomiting) followed by hypertension. In the RCT in this review (Fiorentini, 2012), 74 participants were randomly allocated to TACE with irinotecan-DEBs (n=36) or systemic irinotecan, fluorouracil and leucovorin (FOLFIRI) (n=38). The OS in the irinotecan-DEBs group was significantly longer with a median OS of 22 months (95% CI, 21-23 months) compared to 15 months (95% CI, 12-18 months) for the FOLFIRI chemotherapy group (p=0.031). Progression-free survival was 7 months in the irinotecan-DEBs group compared to 4 months in the FOLFIRI group; and, the difference between groups was statistically significant (p=0.006, long-rank). Extrahepatic progression occurred in all participants by the end of the study, at a median time of 13 months in the irinotecan-DEBs group compared to 9 months in the FOLFIRI group; however, a statistically significant difference between groups was not observed (p=0.064, log-rank). Additional large RCTs comparing TACE with irinotecan-DEBs to alternative management strategies are needed to confirm these findings.

Martin and colleagues (2015) assessed the response and adverse event rates for DEBIRI with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab as a first-line treatment for unresectable colorectal liver metastasis. Participants were randomly assigned to modified FOLFOX (mFOLFOX) and bevacizumab or mFOLFOX, bevacizumab, and DEBIRI (FOLFOX-DEBIRI). The primary endpoint was the response rate; secondary endpoints were adverse events, the rate of conversion to resection, and progression-free survival (PFS). The intention-to-treat (ITT) analysis included 70 participants. The first 10 enrolled participants were required by the FDA to be treated only in the treatment arm (FOLFOX-DEBIRI) for safety and pharmacokinetic studies; the remaining 60 participants were randomly assigned to either the treatment arm (FOLFOX-DEBIRI, n=30 participants) or the control arm (FOLFOX, n=30 participants). Randomized participants were similar with respect to the extent of liver involvement (30% vs. 30%), but a greater percentage of participants in the FOLFOX-DEBIRI arm had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 2 (57% vs. 31%) and extrahepatic disease (56% vs. 32%, p=0.02). The median numbers of chemotherapy cycles were similar (10 vs. 9). Grade 3/4 adverse events occurred in 32 participants in the DEBIRI arm (144 events) and 19 participants (36 events) in the control arm. The overall response rate (ORR) was significantly greater in the FOLFOX-DEBIRI arm compared to the FOLFOX/bevacizumab arm at 2 months (78% vs. 54%; p=0.02), 4 months (95% vs. 70%; p=0.03), and 6 months (76% vs. 60%; p=0.05). There was significantly more downsizing to resection in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm (35% vs. 16%; p=0.05), and improved median PFS (15.3 vs 7.6 months). Additional study is needed to confirm these results in a larger prospective RCT comparing this DEBIRI technique with conventional TACE for unresectable colorectal liver metastasis.

TACE with DEBs for Unresectable HCC

A search of the literature has identified a number of studies using drug-loaded beads (microspheres) using doxorubicin- or epirubicin-eluting beads administered during TACE (Varela, 2007; Poon, 2007; Grosso, 2008; Reyes, 2009; van Malenstein, 2011) for unresectable HCC.

Varela and colleagues (2007) assessed the safety, pharmacokinetics and efficacy of TACE using doxorubicin-DEBs in a phase I/II clinical trial of 27 Child-Pugh A cirrhotic individuals (76% male, 59% HCV) with untreated large, multifocal HCC. The mean diameter of lesions treated was 4.6 cm, the majority classified as stage Okuda I (n=26). Individuals received TACE with DEBs at doses adjusted for bilirubin and body surface. Clinical and analytical data were recorded at 24 and 48 hours, 7, 14 and 30 days after first and second TACE. Response rate was assessed by CT at 6 months. DEB-TACE was reported as well tolerated with an acceptable safety profile. Two cases developed liver abscess, 1 case leading to death. The ORR was 75% (n=24) (66.6% on ITT). After a median follow-up of 27.6 months, 1- and 2-year survival was reported as 92.5% and 88.9%, respectively. The investigators concluded that TACE using doxorubicin-DEBs is an effective procedure and appears to be able to significantly exceed the antitumoral efficacy of conventional TACE. Limitations of this trial include the small sample size and a 15% drop-out rate.

Poon and colleagues (2007) conducted a small phase I/II trial (n=35) to assess the safety and efficacy of TACE using DEB for individuals with unresectable HCC and Child-Pugh class A cirrhosis. In the phase I, no dose-limiting systemic toxicity was observed. The treatment-related complication rate was 11.4%, with 4 of the serious events occurring within 30 days of treatment. There were no treatment-related deaths. Among 30 individuals who completed 2 courses of TACE, the PR rate and the complete response (CR) rate were 50% and 0%, respectively, by RECIST criteria at CT scan 1 month after the second TACE. The investigators suggested that TACE using doxorubicin-DEBs is a safe and effective treatment for HCC; however, a phase III RCT is necessary to compare this treatment with conventional TACE using doxorubicin-lipiodol emulsion. This trial was limited in drawing conclusions due to its small sample size, lack of a control group, and the high withdrawal rate (7 of 35, 20%) before completion of the study.

Grosso and colleagues (2008) presented the results of a multicenter trial using HepaSphere microspheres loaded with doxorubicin or epirubicin for TACE in individuals with unresectable HCC. All of the procedures were reported as technically successful without major complications. At 6-month follow-up (31 of 50 individuals), complete tumor response was obtained in 16 of 31 (51.6%), PR in 8 of 31 (25.8%), and progressive disease in 7 of 31 (22.6%) individuals. Within the initial 9-month follow-up, TACE with HepaSphere was successfully repeated twice in 3 individuals, whereas 3 individuals underwent the procedure 3 times. The investigators suggest these early results demonstrate that TACE using HepaSphere was well tolerated, has a low complication rate, and is associated with promising tumor response; however, longer follow-up on larger series of individuals is necessary to confirm these preliminary results.

Reyes and colleagues (2009) conducted a prospective, single-center phase II pilot study evaluating the safety and efficacy of TACE with doxorubicin-DEBS for individuals with unresectable HCC. A total of 20 individuals (60% Barcelona Clinic Liver Cancer [BCLC] stage C; tumor size 6.9 cm) underwent 34 DEB-TACE sessions. The 6-month disease control rate using RECIST was 95%. The OS rates at 1 and 2 years were 65% and 55%, respectively; median OS was 26 months. The authors suggested the slightly lower survival rates in this study with DEB-TACE might be related to subject sampling that included advanced stage HCC (60% BCLC stage C), when compared with prior studies that included subjects with early HCC. In addition, the authors cited “a limitation of the study was that it does not offer a sample size calculation designed to test a hypothesis.”

In an industry-supported, multicenter prospective registry study, Lee and colleagues (2017) assessed the efficacy and safety of DEB-TACE for nodular hepatocellular carcinoma. A total of 152 subjects received DC Bead particles loaded with doxorubicin. The primary outcome was the 6-month tumor response, and the secondary outcomes were safety and survival. At 6 months post-treatment, 121 subjects were available for analysis. The complete response was 43% and the objective response was 55.4%. The cumulative progression-free survival (PFS) rate was 65% and the overall survival rate was 97.4%. Common side effects included abdominal pain, nausea, vomiting, and fever. Serious adverse events occurred in 7.2%, including persistent deterioration of liver function (3.9%) and prominent biliary injury (19.7%). The study was limited by a small sample size and a loss to follow-up of 30.3% at 6 months. The authors concluded that DEB-TACE had an “acceptable safety profile and 6-month tumor and survival rate.”

For HCC, the Society of Interventional Radiology’s Quality Improvement Guidelines for Transarterial Chemoembolization and Embolization of Hepatic Malignancy (Gaba, 2017) states that drug-eluting transarterial chemoembolization is “associated with favorable pharmacokinetics and reduced systemic drug and may improve drug delivery compared with conventional trasarterial chemoembolization.”

TACE with DEBs Compared to TACE or TAE for Unresectable HCC

Lammer and colleagues (2010) conducted a prospective, multicenter, randomized trial (PRECISION V), comparing doxorubicin delivered by conventional TACE (n=108) with TACE utilizing doxorubicin-DEB (n=93) (DC Bead) for the treatment of primary unresectable HCC. The primary efficacy endpoint at 6 months (tumor response rates measured by review of MRI studies) based on the Modified Intention-to-Treat (MITT) population was defined as all randomized individuals who received at least 1 TACE. The DEB-TACE group showed higher rates of CR, objective response (primary endpoint), and disease control compared to the conventional TACE group; however, the differences in rates, including the primary endpoint rate was not statistically significant (p=0.11). Individuals with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (p=0.038) compared to conventional TACE. In addition, there was no statistically significant (p=0.86) difference between treatments for the primary safety endpoint, that is treatment-related adverse events (SAEs) within 30 days of a procedure. The investigators concluded that TACE with DC Bead and doxorubicin showed improved tolerability with a significant reduction in serious liver toxicity and doxorubicin-related side effects versus conventional TACE. A limitation of the study was the number of individuals required to show statistically significant superiority was underestimated due to the higher response rate of conventional TACE (44%) compared with the original assumption (35%). Therefore, “statistical superiority in objective response rates (of DEB-TACE) compared to conventional TACE could not be demonstrated.”

Malagari and colleagues (2010) studied 84 individuals with intermediate-stage HCC in a prospective, randomized study comparing doxorubicin-loaded DC Beads versus TAE with Bead Block® (Biocompatibles UK Ltd., Farnham, Surrey, UK) particles larger than 100 µm. The primary endpoints were local response, time to progression, and recurrence-free rate. Group A (n=41) was treated with doxorubicin DEB-TACE, and group B (n=43) with TAE at set time intervals (2 months). At 6 months a CR was seen in 11 individuals (26.8%) in the DEB-TACE group and in 6 individuals (14%) in the TAE group; a PR was achieved in 19 individuals (46.3%) and 18 (41.9%) individuals in the DEB-TACE and TAE groups, respectively. Recurrences at 9 and 12 months were higher for TAE (78.3% vs. 45.7%) at 12 months. Time to progression (TTP) was longer for the DEB-TACE group (p=0.008). The authors concluded, however, that survival benefit and TAE with smaller particles (< 100 µm) must be addressed in future studies to better assess the clinical value. Another limitation cited by the authors “is that it focuses on local response - a questionable surrogate for survival, which is the ultimate and validated measure of disease response.”

Dhanasekaran and colleagues (2010) explored the long-term survival benefits comparing conventional TACE with TACE utilizing doxorubicin-DEBs (LC Bead®, Biocompatibles UK Ltd., Farnham, Surrey, UK) for individuals (n=71) with unresectable HCC. Between 1998 and 2008, 45 (63.4%) individuals received therapy with DEB (group A) and 26 (36.6%) individuals underwent conventional TACE (group B). Median survival from diagnosis of HCC in groups A and B were 610 (351-868) and 284 days (4-563; p=0.03), respectively. Grade 5 clinical toxicity- and procedure-related death (30 days) due to liver failure was experienced by 6.6% (3 of 45) of individuals treated with DEB and 7.8% (2 of 26) of the individuals treated with conventional TACE. No grade 3 or 4 clinical toxicities were experienced in either group. The authors suggested that TACE with DEB offers a survival advantage over conventional TACE for individuals with unresectable HCC; however, several limitations of the study include the small number of subjects and its retrospective design (case-controlled comparison). In addition, “the survival benefit demonstrated on our study must be considered preliminary and need further exploration in prospective randomized controlled studies.”

A number of meta-analysis and systematic reviews compare the safety and efficacy of conventional TACE to DEB-TACE in the treatment of unresectable HCC. Hui and colleagues (2015) evaluated the efficacy and safety of DEB-TACE (with doxorubicin) and conventional TACE in the treatment of unresectable HCC. A total of 527 participants were evaluated from four randomized trials (Lammer, 2010; Malagari, 2010; van Malenstein, 2011; Vogl, 2011). Relative risk (RR) outcomes were calculated by two independent investigators using a Revman 5.0 software system. The DEB-TACE participants experienced fewer side effects including alopecia (RR 0.05, 95% CI: 0.01-0.24; p=0.0002) and myelosuppression (RR 0.32, 95% CI: 0.14-0.75; p=0.009). There was no significant difference reported between the therapies in the efficacy analysis of CR (RR 1.36, 95% CI: 0.89-2.08; p=0.16), PR (RR 1.14, 95% CI: 0.80-1.62; p=0.48), stable disease (RR 0.93, 95% CI: 0.60-1.40; p=0.73), progressive disease (RR 0.80, 95% CI: 0.56-1.12; p=0.19), OR (RR 0.91, 95% CI: 0.48-1.72; p=0.26) and disease control (RR 1.18, 95% CI: 1.00-1.39; p=0.05). Limitations of this meta-analysis include evaluation of trials that were heterogeneous in study purpose, design and research methods, the relatively small number of participants, and use of other curative therapies.

Xie and colleagues (2015) performed a systematic review and meta-analysis comparing the safety and efficacy of conventional TACE to DEB-TACE for inoperable HCC. A total of 652 participants from four RCTs (Golfieri, 2014; Lammer, 2010; Sacco, 2011; van Malenstein, 2011), one prospective uncontrolled study, and one prospective case-control study were included in this analysis. Use of DEB-TACE was associated with a significantly higher objective tumor response rate compared with conventional TACE (RR: 1.14, 95% CI 1.01-1.29; p=0.03) and a slightly lower incidence of adverse events. The OS benefit was similar between conventional TACE and DEB-TACE participants (p=0.875). The authors repeated the analysis after excluding the case-control study and reported similar results for objective tumor response rates and OS benefit. Limitations of this review include analysis of trials with small sample sizes, inclusion of non-randomized trials, heterogeneity of study participants at baseline, use of different criteria for evaluating tumor response, and use of different types of DEBs (in pharmacokinetics, mechanical properties, and embolic actions). The authors concluded “...we do not have efficient survival evidence to recommend DEB-TACE over conventional TACE considering the similar OS between them.”

Facciorusso and colleagues (2016a) performed a meta-analysis to evaluate if the efficacy and safety of DEB-TACE was superior to conventional TACE in the treatment of unresectable HCC. The analysis evaluated four RCTs and eight observational studies of 1449 participants, including results from a recently published large retrospective, single-center, non-randomized trial (Kloeckner, 2015) and a large single-center observational comparative case series (Facciorusso, 2016b). The authors evaluated 1-, 2-, and 3-year survival rates between the 2 treatments by obtaining HRs from Kaplan-Meier curves in order to perform an unbiased comparison of survival estimates; in addition, rates of objective response and severe adverse events were evaluated. The pooled ORs of survival rate at 1, 2, and 3 years did not differ significantly but showed a decreasing trend in favor of DEB-TACE as time elapsed since treatment (OR: 0.76, 0.68, and 0.57, respectively). According to the authors, this finding was due to the difference in follow-up time length between the 2 treatment arms in the majority of included studies, and consistent with the conclusions reported in the systematic review by Xie and colleagues (2015). This trend was also confirmed by meta-analysis of plotted HRs (HR: 0.86, 0.71-1.03; p=0.10). Pooled data of objective response showed no significant difference between DEB-TACE and conventional TACE for unresectable HCC (OR: 1.21, 0.69-2.12; p=0.51). A total of nine studies with 1026 participants reported data on severe adverse event rates with no statistically significant difference between the 2 treatment groups (OR: 0.85, 0.60-1.20; p=0.36). The authors concluded that based on the inclusion of the three large case series, their findings showed “...only a non-significant trend of superiority of DEB-TACE in terms of ORR (OR: 1.21, 0.69-2.12, p=0.51). Such a trend was confirmed by additional subgroup and sensitivity analysis performed after removing two outlier studies.” Limitations of this analysis include the high heterogeneity between study designs and use of different criteria for evaluating tumor response. Additional randomized controlled trials of homogenous populations and similar study methodology that report long-term results and survival data are needed to reduce the selection bias and heterogeneity reported in the current studies that compare DEB-TACE to conventional TACE for the treatment of unresectable HCC.

Katsanos and colleagues (2017) performed a network meta-analysis of RCTs to compare the effectiveness of different transarterial embolization therapies. They analyzed 55 RCTs (n=5763) published between 1988 and 2017 on TAE, TACE, DEB-TACE, transarterial radioembolization (TARE), and adjuvant therapies for individuals with preserved liver function and unresectable HCC. The primary endpoint was survival. There was a similar survival between TAE and TACE (HR 0.87; 95% CI, 0.71 to 1.07). TACE plus radiotherapy or plus ablation was more effective than TACE alone. TACE, DEB-TACE, TARE, and adjunctive systemic agents (combined with TACE or DEB-TACE) did not show a better survival over bland TAE. Median survival period was 18.1 months for TACE, 20.6 months for DEB-TACE, 20.8 months for bland TAE, 24.3 months for TARE, and over 30 months with TACE combined with external radiotherapy or percutenous liver tumor ablation. Low to moderate evidence showed that the most effective treatment was TACE combined with external radiation therapy (surface under the cumulative ranking curve [SUCRA] 86%) or percutaneous tumor ablation (SUCRA 96%). The authors concluded that the tumor objective response or survival benefit of TACE, DEB-TACE, TARE and adjuvant systemic agents was not superior to TAE for unresectable HCC. However, low to moderate evidence suggested that TACE combined with external radiotherapy or local liver ablation may improve tumor response and survival rates over TAE.

In summary, the overall limitations of these studies include small sample size, lack of a randomized control group, and high drop-out rates that affect the measurement of long-term outcomes. Randomized trials comparing DEB-TACE with other TACE techniques are currently underway in the United States. Additional trials comparing DEB-TACE with TAE are required in order to draw conclusions concerning the efficacy of one treatment over another. The development of these studies will further identify individuals that will best respond to targeted locoregional anticancer treatment of neuroendocrine tumors with hepatic metastases and HCC with DEBs. There is a need for large randomized prospective studies to confirm if DEB-TACE is associated with better local control, fewer recurrences, a longer time-to-progression compared to conventional TACE or TAE in individuals with intermediate-state HCC, and an OS advantage.

Definitions

Childs-Turcotte-Pugh (CTP): A scoring system for severity of liver disease and likelihood of survival based on the presence of: degenerative disease of the brain (encephalopathy), the escape or accumulation of fluid in the abdominal cavity (ascites), laboratory measures of various substances in the blood (see table below), and the presence of other co-existing diseases; after calculating the CTP score using a table similar to the one below, candidates can be classified into 1 of 3 categories:

Variable

1 Point

2 Points

3 Points

Encephalopathy

None

Moderate

Severe

Ascites

None

Mild

Moderate

Albumin (mg/dL)

Greater than 3/5

2.8-3.5

Less than 2.8

Prothombin time (International Normalized ratio) prolonged

Less than 4

4-6

Greater than 6

Bilirubin (mg/dL)
Primary biliary cirrhosis
Cirrhosis/primary
Primary sclerosing cholangitis

1-4

4-10

Greater than 10

All other diseases

Less than 2

1-3

Greater than 3

Cancer of the Liver Italian Program (CLIP): A tumor classification system from Italy that includes scoring for 8 clinical parameters for HCC, combining the Child-Turcotte-Pugh scoring system with tumor criteria including tumor morphology, portal invasion, and alpha fetoprotein levels.

Encapsulated nodules: Any group of abnormal cells confined to a specific area, surrounded by a covering of specialized cells called a capsule.

Extra-hepatic metastases: Tumors that have spread outside the liver that originate from HCC or other primary liver tumors.

Hepatic metastases: Cancer that has spread from its original location in the body to the liver.

Okuda classification: A 3-stage tumor classification system for HCC which combines assessment of liver function and tumor load; staging is dependent on tumor size (more or < 50% of the liver area affected) and the functional capacity of the liver, as assessed by albumin and bilirubin levels and the presence of ascites.

Palliative treatment: Treatment given for relief of symptoms and pain rather than effecting a cure.

Primary hepatocellular cancer (HCC): A cancer that originates within liver cells, as opposed to having spread to the liver from other organs.

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Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Radiology (ACR). ACR Appropriateness Criteria Radiologic Management of Hepatic Malignancy. Review 2015. Available at https://acsearch.acr.org/docs/69379/Narrative/. Accessed on March 19, 2018.
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    • Breast Cancer (V4.2017). Revised February 7, 2018.
    • Colon Cancer (V2.2018). Revised March 14, 2018.
    • Hepatobiliary Cancers (V1.2018). Revised February 14, 2018.
    • Neuroendocrine Tumors (V3.2017). Revised June 13, 2017.
    • Occult Primary (Cancer of Unknown Primary [CUP]. (V1.2018). Revised November 9, 2017.
    • Rectal Cancer (V1.2018). Revised March 14, 2018.
    • Uveal Melanoma (V1.2018). Revised March 15, 2018
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Websites for Additional Information
  1. National Cancer Institute (NCI). Cancer Topics. Available at: http://www.cancer.gov/cancertopics. Accessed on March 16, 2018.
    • Adult Primary Liver Cancer Treatment (PDQ®). Last modified February 6, 2018.
    • Childhood Liver Cancer Treatment (PDQ). Last modified September 26, 2017.
    • Intraocular (Eye) Melanoma Treatment (PDQ). Last modified February 8, 2018.
    • Islet Cell Tumors (Endocrine Pancreas) Treatment (PDQ). Last updated February 8, 2018.
  2. U.S. National Institutes of Health (NIH). Clinical trials: drug-eluting beads. Available at: https://clinicaltrials.gov/ct2/search . Accessed on March 19, 2018.
Index

Transcatheter Arterial Chemoembolization (TACE)
Transcatheter Arterial Embolization (TAE)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

New

05/03/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

New

05/02/2018

Hematology/Oncology Subcommittee review. Initial document development. Moved content of RAD.00011 Transcatheter Arterial Chemoembolization (TACE) and Transcatheter Arterial Embolization (TAE) for Treating Primary or Metastatic Liver Tumors to new clinical utilization management guideline document with the same name.