Transcatheter arterial chemoembolization (TACE) and transcatheter arterial embolization (TAE) are catheter-based embolization procedures, with chemotherapeutic agents or without (i.e. bland embolization), respectively. TACE involves the regional injection of some form of chemotherapeutic or antitumor agents immediately followed by an embolizing agent into selected branches of the hepatic arteries supplying a tumor. Both embolization procedures lead to ischemia of the tumor by blockage of the nutrient supply.

This document focuses on 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.

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

• RAD.00033 Selective Internal Radiation Therapy (SIRT) of Primary or Metastatic Liver Tumors (i.e., SIR-Sphere and TheraSpheres)
• RAD.00059 Transcatheter Arterial Chemoembolization (TACE) and Transcatheter Arterial Embolization (TAE) for Malignant Lesions Outside the Liver
• SURG.00025 Cryosurgical Ablation of Solid Tumors Outside the Liver
• SURG.00050 Radiofrequency Ablation to Treat Tumors Outside the Liver
• SURG.00065 Locally Ablative Techniques for Treating Primary and Metastatic Liver Malignancies
• SURG.00068 Implantable Infusion Pumps 
• TRANS.00008 Liver Transplantation

Medically Necessary:

Primary Hepatic Malignancy or Metastatic Tumors to the Liver

Transcatheter arterial chemoembolization (TACE) or transcatheter arterial embolization (TAE) is considered medically necessary as:

• treatment for individuals with liver-only metastasis from uveal (ocular) melanoma; or
• palliative treatment for individuals with neuroendocrine tumors (e.g., carcinoid tumors, pancreatic islet cell tumors, parathyroid, pituitary angiomas) with hepatic metastases when systemic therapy has failed to control symptoms such as carcinoid syndrome (e.g., debilitating flushing, wheezing, and diarrhea); or
• palliative treatment for individuals with symptoms from non-carcinoid neuroendocrine tumors with hepatic metastases (e.g., hypoglycemia, severe diabetes, Zollinger-Ellison Syndrome); or
• palliative treatment for individuals with specific liver-related symptoms due to tumor bulk (e.g., 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 (HCC) or, as a bridge to liver transplantation, when all of the following criteria are met for either indication:

• preserved liver function defined as Childs-Turcotte-Pugh Class A or B; and
• three or fewer encapsulated nodules and the nodules are less than five centimeters in diameter; and
• no evidence of extra-hepatic metastases; and
• no evidence of severe renal function impairment; and
• 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 individuals who:

• may become eligible for liver transplantation except that the hepatic lesion(s) exceed(s) five centimeters in maximal diameter; and
• it can be reasonably expected that treatment with TACE or TAE will result in tumor size reduction to less than five centimeters in maximal diameter.

Investigational and Not Medically Necessary:

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

TACE utilizing chemotherapy-loaded microspheres (i.e. drug-loaded microspheres, drug-eluting beads) is considered investigational and 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.

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

Catheter-based hepatic artery embolization procedures, with or without chemotherapeutic agents, are utilized for the palliative treatment of primary hepatic or metastatic tumors, as a primary treatment for surgically unresectable primary HCC, or, as a bridge to liver transplantation. As early as 1998, Brown and colleagues suggested that transcatheter arterial or bland embolization (TAE) may be as equally effective as TACE for palliative treatment of primary HCC. Despite the current trend toward improved survival with TACE, no clinical evidence to date has demonstrated that TAE is less effective than TACE. Camma and colleagues (2002) confirmed this conclusion in a meta-analysis of randomized controlled trials on TACE for unresectable HCC, citing there was no evidence to demonstrate that TACE is more effective than TAE, as evidenced by no difference in survival between the two techniques. According to the National Comprehensive Cancer Network^® (NCCN^®, 2011) Clinical Practice Guidelines in Oncology ™ for hepatocellular cancer, many of the clinical studies evaluating the effectiveness of TACE, TAE, or both therapies in the treatment of individuals with HCC are confounded by use of a wide range of chemotherapy and type of emulsifying agent (for studies involving TACE), and number of treatment sessions.

Marelli and colleagues (2007) conducted a systematic review and meta-analysis of cohort and randomized controlled trials (n=175) including those involving TACE versus TAE for HCC. The reviewers evaluated whether specific characteristics of the subjects or radiological transarterial techniques resulted in better outcomes. Different anticancer drugs were used as a sole agent; embolizing agents included gelatin sponge particles, polyvinyl alcohol particles, degradable starch microspheres and embospheres. Chemoembolization was found to significantly reduce the overall two-year mortality rate (p=.015) compared with nonactive treatment. Analysis of comparative randomized controlled trials helped to predict that overall mortality was significantly lower in individuals treated with TAE than in those treated with transarterial chemotherapy (p=.039) and that there is no evidence that TACE is more effective than TAE (p=.95), which suggests that the addition of a chemotherapeutic agent did not improve the therapeutic benefit. Post-TACE complications included ascites, 8.3%; acute liver failure, 7.5%; upper gastrointestinal bleeding, 3%; encephalopathy, 1.8%; acute renal failure, 1.8%; and hepatic or splenic abscess, 1.3%. Treatment-related mortality was 2.4%, mainly due to acute liver failure. This meta-analysis confirmed that TACE improved survival (p=.00026); but a meta-analysis of TACE versus TAE alone (three studies, n=412) demonstrated no survival differences (p=0.052). The authors concluded that no chemotherapeutic agent appeared better than any other. In recent years, however, TACE has replaced TAE as the most widely used and studied palliative modality for unresectable HCC (Lau, 2008).

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 (e.g., severe flushing, wheezing, and diarrhea), Zollinger-Ellison Syndrome (multiple bleeding gastrointestinal ulcers), hypoglycemia, severe diabetes, and other neuroendocrine-related manifestations (Christante, 2008, Gupta, 2003; Maluccio, 2006; Roche, 2003). The treatment has been shown to be useful in significantly 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.

Ruutiainen and colleagues (2007) reported on a study of 67 individuals comparing bland embolization to TACE in neuroendocrine tumors with liver metastasis. In this study, 67 individuals underwent 219 embolization procedures: 23 individuals received primarily bland embolization with polyvinyl alcohol (PVA) with or without iodized oil and 44 primarily received chemoembolization with cisplatin, doxorubicin, mitomycin-C, iodized oil, and PVA. Individuals with disease relapse were treated again when feasible. Ten of 67 individuals (15%) were lost to follow-up. Toxicities of grade three or worse in severity occurred after 25% of chemoembolization procedures and 22% of bland embolization procedures. Rates of freedom from progression at one, two, and three years were 49%, 49%, and 35% after chemoembolization and 0%, 0%, and 0% after bland embolization (p=0.16). Individuals treated with chemoembolization and bland embolization experienced symptomatic relief for means of 15 and 7.5 months, respectively (p=0.14). Survival rates at one, three, and five years were 86%, 67%, and 50%, respectively, after chemoembolization, and 68%, 46%, and 33%, respectively, after bland embolization (p=0.18). The authors concluded that chemoembolization demonstrated trends toward improvement in time-to-progression, symptom control, and survival; however, further multicenter prospective randomized controlled trials are warranted. These results are similar to those reported previously by Gupta and colleagues (2003) who noted that in a retrospective series of 81 individuals, hepatic artery embolization or chemoembolization results in symptomatic and radiographic response in most individuals with carcinoid metastases to the liver. Fifty individuals were treated with bland hepatic artery embolization and 31 underwent chemoembolization. Of the 69 individuals in whom radiologic response could be evaluated, partial response was observed in 46 individuals (67%), minimal response in six individuals (8.7%), stable disease in 11 individuals (16%), and progressive disease in six individuals (8.7%). The median duration of response in the 42 individuals with partial response was 17 months (range, 4-51 months). Sixty-three percent of individuals had a reduction in their tumor-related symptoms. The median progression-free survival duration was 19 months (95% confidence interval [CI], 17-21 months); the probability of progression-free survival was 75%, 35%, and 11% at one, two, and three years, respectively. The median overall survival time was 31 months (95% CI, 23-38 months); the survival probability was 93% at one year, 62% at two years, and 24% at five years. The authors commented that cytoreduction should be pursued when possible even if complete resection may not be achievable. Thus, for individuals with metastatic neuroendocrine tumors whose symptoms persist despite systemic therapy and who are not candidates for resection, arterial embolization procedures are an option that can be used for symptomatic treatment.

The NCCN Clinical Practice Guidelines in Oncology for neuroendocrine tumors, carcinoid and islet cell tumors (2011) include a recommendation to consider hepatic regional therapy including arterial embolization and chemoembolization for individuals with locoregional unresectable disease and/or liver metastases (symptomatic, clinically significant tumor burden, or clinically significant disease) (category 2B recommendation).

TACE or TAE as Treatment for Surgically Unresectable Primary HCC 

Randomized controlled trials 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 randomized controlled trials (Llovet, 2002b; Lo, 2002), TACE was shown to prolong survival significantly in select individuals with HCC with preserved liver function and adequate performance status. TACE achieved a median survival of more than two years and converted some individuals into candidates for resection. In a meta-analysis of pooled data of seven randomized controlled trials assessing embolization/chemoembolization as a primary treatment of unresectable HCC in comparison to an untreated control arm, Llovet and Bruix (2003) found a considerable two-year survival benefit associated with TACE treatment compared with control (p=.017). Ideal candidates for chemoembolization 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 three or fewer encapsulated nodules that are less than five centimeters (cm) in diameter, absence of extra-hepatic metastases, no evidence of severe renal function impairment, and no evidence of altered portal blood flow (e.g. portal vein thrombosis) (Bruix, 2005; Lau, 2006; Molinari, 2006). The evidence suggests that individuals who do not meet these criteria do not respond adequately to TACE therapy 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 therapy for HCC were tumor equal to or greater than five centimeters, five or more tumors and extrahepatic disease; portal vein occlusion was not found to be an independent predictor of survival. Overall survival rates observed at one-, two-, and three-years were 66%, 46%, and 33%, respectively. These one-, two-, and three-year survival rates were 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 National Cancer Institute (NCI, 2010) recommends TACE as the most effective option for individuals with localized, unresectable HCC in which nodules are less than five centimeters in diameter. Criteria for suitable candidates include, in general, individuals with unresectable disease occupying less than 50% of hepatic volume, a patent portal vein, near normal liver function studies, bilirubin less than two mg/dl, and no contraindications to angiography as evident by normal coagulation and renal function.

Similarly, the NCCN Clinical Practice Guidelines in Oncology for hepatocellular cancer (2011) include embolization (i.e. chemoembolization, bland embolization, radioembolization) as an option for individuals with unresectable HCC with tumors not amenable to ablation therapy only and in the absence of extrahepatic disease (category 2A recommendation) (Llovet, 2002a; Maluccio, 2008), with the additional recommendation that tumor lesions larger than five centimeters should be treated using arterial embolic approaches. For tumors three to five centimeters, combination therapy can be considered with ablation and arterial embolizations. In addition, in individuals with a bilirubin greater than 3 mg/ml, TACE and TAE are "relatively contraindicated" unless performed as segmental injections (Ramsey, 2002). In the presence of main portal vein thrombosis and liver function characterized as Child-Pugh Class C, TACE is contraindicated as therapy for HCC (absolute contraindication).

Takayasu and colleagues (2006) reported results from an eight-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. Exclusion criteria included extrahepatic metastases, previous treatment, or both, prior to treatment with TACE. The mean follow-up period was 34 months. The overall survival rates by TACE at one, three, five and seven years were 82%, 47%, 26%, and 16%, respectively. The multivariate analyses showed significant differences (p=.0001) in degree of liver damage, alpha-fetoprotein value, maximum tumor size, number of lesions, and portal vein invasion. The 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 five-year survival rate of 26% and a 0.5% mortality rate.

Biselli and colleagues (2005) reported on 56 cirrhotic individuals with unresectable HCC undergoing at least one course of TACE who were matched one to one for sex, age (in five-year periods), parameters of Child-Pugh score, Okuda stage, and tumor type with a control group who only received supportive care. The two groups were comparable for underlying cause of cirrhosis, alpha-fetoprotein serum levels, and Cancer of the Liver Italian Program (CLIP) score. The 56 individuals in the TACE group received a total of 123 treatment courses. Survival rates at 12, 24, and 30 months in individuals receiving TACE were 74.3%. 52.1%, and 38.8%, respectively, with a median survival time of 25 months. Survival rates for individuals receiving supportive care were 39.4%, 25.4%, and 19%, respectively, with a median survival time of seven months (p=.0004). Only TACE and the CLIP score proved to be independent predictors of survival at multivariate analysis. The authors concluded that TACE is an effective therapeutic option for cirrhotic individuals with unresectable HCC and a CLIP score of three or less.

In a prospective, single center study, Molinari and colleagues (2006) reported on the effectiveness of TACE for HCC. Individuals with a Child-Pugh cirrhosis score of "A" or better with unresectable HCC and without radiological evidence of metastatic disease or segmental portal vein thrombosis were assessed between November 2001 and May 2004. There were 54 individuals who satisfied the inclusion criteria, 47 underwent 80 TACE sessions. Chemoembolization was carried out using doxorubicin and lipiodol followed by an injection of embolic particles (when necessary). Repeat treatments were carried out at two to three month intervals for recurrent disease. The survival probabilities at one, two and three years were 76.6%, 55.5%, and 50%, respectively. At six months after the first intervention, 31% of individuals had a partial response and 60% had stable disease. Major adverse events occurred after 20% of sessions, including two treatment-related deaths (4% of individuals). The authors concluded that these survival probabilities at one and two years after TACE were comparable with results in randomized studies from Europe and Asia.

TACE has also 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 six-, 12-, and 18-month recurrence rates for the TACE group compared to the non-TACE group were 22.2% vs 61.6%, 78.0% vs 74.7% and 88.6% vs 80.1%. There were also significant differences between the recurrence rates of the two groups at six months (p<0.0001). The authors concluded that TACE had a good effect in preventing recurrence of HCC at six 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.

Zhou and colleagues (2009) evaluated the effectiveness of preoperative TACE in 108 individuals (hepatitis B carrier, 98.1%) with resectable HCC (equal to or greater than five centimeters), randomly assigned to preoperative TACE treatment (n=52) or no preoperative treatment (control group, n=56). At a median follow-up of 57 months, 41 of 52 (78.8%) individuals in the preoperative TACE group and 51 of 56 (91.1%) individuals in the control group had recurrent disease (p=0.087). The one-, three-, and five-year disease-free survival rates were 48.9%, 25.5%, and 12.8%, respectively, for the preoperative TACE group and 39.2%, 21.4%, and 8.9%, respectively, for the control group (p=0.372). The one-, three-, and five-year overall survival rates were 73.1%, 40.4%, and 30.7% for the preoperative TACE group and 69.6%, 32.1%, and 21.1%, respectively, for the control group (p=0.679). The authors concluded that preoperative TACE did not improve surgical outcome and resulted in individuals dropping out from definitive surgery because of progression of disease and liver failure.

A recent Cochrane review by Oliveri and colleagues (2011) included nine trials with 645 participants comparing treatment with TACE (n=6 trials) or TAE (n=3 trials) versus control for unresectable HCC. Seven trials had low risk of selection bias, but all these trials had other risks of bias. Three trials were stopped early due to interim inspections and one 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 (HR 0.88; 95% CI 0.71 to 1.10). Two trials with low risk of selection bias, no early stopping, and no co-intervention did not establish any significant effect of TACE or TAE on overall survival (Hazard ratio [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 Clinical Practice Guidelines for hepatocellular carcinoma (2011) include a category 2A recommendation and uniform consensus for chemoembolization and bland embolization as standard loco-regional treatment for individuals with unresectable HCC.

TACE or TAE as a Bridge to Liver Transplantation

The role of TACE in the management of individuals with HCC who are waiting liver transplantation is an indication that has been explored in various settings: as a technique to prevent tumor progression while on the wait list, to downstage tumors such that the individual is considered a better candidate for liver transplantation, and to decrease the incidence of post-transplant recurrence in individuals with larger (T3) tumors. These indications are in part related to the current United Network for Organ Sharing (UNOS) liver allocation system referred to as MELD (Model for End-Stage Liver Disease) for adult individuals waiting liver transplantation. The MELD score is a continuous disease severity scale incorporating serum bilirubin, prothrombin time (i.e., international normalized ratio-INR), and serum creatinine into an equation, producing a number that ranges from one to 40. Aside from those in fulminant liver failure, donor livers are prioritized to those with the highest MELD number (UNOS, 2010). This scale predicts the risk of dying from liver disease except for those with HCC, who often have low MELD scores since serum bilirubin, INR, and serum creatinine levels are near normal. Therefore, individuals with HCC are assigned additional allocation points according to the size and number (T stage) of tumor nodules as follows:

• T1: one nodule equal to or less than 1.9 cm
• T2: one nodule between 2.0 - 5.0 cm, or two or three nodules each less than 3.0 cm
• T3: one nodule greater than 5.0 cm, or two or three nodules with at least one greater than 3.0 cm.

As specified in UNOS's Allocation of Livers document (UNOS, 2010), a candidate with Stage II HCC, in accordance with the American Liver Tumor Study Group Modified Tumor-Node-Metastasis (TNM) Staging Classification, that meets all of the medical criteria specified in Section 3.6.4.4 (i) and (ii) of the UNOS policy, may receive extra priority on the wait list. A candidate with an HCC tumor that is greater than or equal to two centimeters and less than five centimeters, or, no more than three lesions, the largest being less than three centimeters in size (Stage T2 tumors) may be registered as a MELD/PELD (Pediatric End-stage Liver Disease) score equivalent to a 15% probability of candidate death within three months. 

The UNOS allocation system provides incentives to use loco-regional therapies to downsize tumors to T2 status and to prevent progression while on the transplant wait list. In addition, the UNOS policy appears to implicitly recognize the role of loco-regional therapy in the pretransplant setting. For example, section 3.6.4.4 (i) of the UNOS policy regarding the workup of candidates with HCC states as follows, "In addition, the candidate must have at least one of the following: vascular blush corresponding to the area of suspicion seen on the above imaging studies, an alpha-fetoprotein level of >200 ng/ml, an arteriogram confirming a tumor, a biopsy confirming HCC, chemoembolization of lesion, radiofrequency, cryo, or chemical ablation of lesion" (UNOS, 2010).

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 loco-regional therapy. These early studies lacked controlled data making it difficult to assess contributions of loco-regional therapy to time on the wait list.

Given these limitations the following case series have been reported. Graziadei and colleagues (2003) reported on 48 individuals with HCC waiting transplantation; all underwent TACE every six to eight weeks until a complete response or a donor organ became available. No individuals were removed from the list due to tumor progression, and the mean wait time was 178 plus or minus 105 days. Maddala and colleagues (2004) studied the dropout rates of 54 individuals receiving TACE while waiting transplantation. During a median wait time of 211 days (range 28-1,099 days), the dropout rate was 15%. Fisher and colleagues (2004) reported on 33 individuals who received multimodality ablation therapy, consisting primarily of radiofrequency ablation or TACE. Five individuals (12%) were removed from the wait list after waits of five to 14 months. In this protocol, individuals with tumors greater than five centimeters were not considered transplant candidates until the tumor was completely ablated using TACE, radiofrequency ablation (RFA), or another technique. Yamashiki and colleagues (2005) reported on 288 individuals given various ablative therapies; the dropout rate due to tumor progression at one and three years was 6.25 and 23%, respectively. Tumors greater than three centimeters 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 (greater than 85%) in 63% of individuals in group A; all seven individuals in group A2 exhibited tumor downgrading that met Milan criteria. The overall five-year actuarial survival rate was 80.6%. The TAE group had a better survival (84% at five years) than the non-TAE group, (75% at four years). The three-year survival of group A2 (83%) was also higher than that of group A1 (79%). Tumor necrosis greater than 85% was associated with survival of 100% at three years, which was significantly better than the others who showed less than 85% tumor necrosis (57.1% at three years) or who did not have TAE (75% at three 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.

A systematic review by Obed and colleagues (2007) assessed the outcome of individuals who underwent TACE for HCC and subsequently orthotopic liver transplantation (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 six weeks. Fifteen individuals showed signs of tumor progression without transplantation. The remaining 20 individuals underwent OLT. Further records of seven 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.

The Society of Interventional Radiology's Position Statement on Chemoembolization of Hepatic Malignancies (Brown, 2006) cites the critical role chemoembolization plays in the prevention of progression of HCC until a donor liver becomes available. The position taken is that, based on the available literature (Fischer, 2004), chemoembolization as a bridge to transplantation is an option in permitting eventual cure by inhibiting tumor growth in this subset of individuals so they can remain on the transplant wait list. 

TACE to Downgrade HCC Prior to Liver Transplantation

Yao and colleagues (2005a) reported on a case series of 30 individuals with HCC who underwent a variety of loco-regional therapies including TACE, specifically to downstage tumors to meet the University of California at San Francisco (UCSF) transplant criteria. Eligibility for loco-regional therapy seeking to downstage individuals included either one nodule between five centimeters and eight centimeters in diameter; two or three nodules with at least one between three centimeters and five centimeters in diameter, with sum of diameters no greater than eight centimeters; or four or five nodules all less than or equal to three centimeters, with sum of diameters less than eight centimeters. Among the 30 individuals, 21 (70%) met the criteria for loco-regional 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. Seventy-six individuals with stage III/IV 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. Eighteen 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, 22 of 76 (29%) had stable disease, and 27 of 76 (35.5%) had progressive disease. Seventeen of 76 (22.4%) individuals who met other qualifications underwent OLT after successful downstaging (13 of 38 stage III; 4 of 38 stage IV). Explant review demonstrated 28 identifiable tumors in which post-TACE necrosis was greater than 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 one 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 III/IV HCC can be successfully downstaged to Milan criteria with TACE and those transplanted had midterm disease-free and overall survival, similar to stage II 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 III/IV HCC individuals who received TACE went on to OLT, eliminating many individuals with progressive disease. 

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

Published literature reflects ongoing discussion as to whether the UNOS allocation criteria should expand to include individuals with larger tumors (Fernandez, 2003; Sauer, 2005; Yao, 2001; Yao, 2002). Some individuals with T3 lesions apparently are cured with liver transplant, although most experience recurrent tumor. For example, 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. For example, Yao and colleagues (2002) at UCSF reported similar recurrence-free survival after transplant in individuals with T2 and a subset of those with T3 tumors. This T3 subset was defined as a single nodule 6.5 centimeters or less, or three nodules or less with none greater than 4.5 centimeters, and total tumor diameters eight centimeters 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. Seventy-eight 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 pre-operative loco-regional 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 loco-regional therapy. The one- and five-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 loco-regional therapy. For those with T2 lesions, the recurrence rates were similar whether or not the individual received loco-regional therapy. However, for T3 lesions (including both T3A and T3B), the 5-year recurrence-free survival was 85.9% for those who received loco-regional 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 loco-regional therapy compared to 80.6% in those who did not. The authors concluded that preoperative loco-regional 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. For example, only 19 individuals were in the T3A (i.e., UCSF expanded criteria) subgroup. In addition, no protocol specified which type of loco-regional 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 (2010), 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 less than 10% of primary malignancies of the liver. Complete surgical resection of intrahepatic cholangiocarcinoma (ICC) offers the only potentially curative therapy; however, only 30% of individuals are surgical candidates due to the presence of advanced disease at the time of diagnosis (Burger, 2005). Recurrence of ICC is frequent after surgical resection, with survival rates reported as low as 20% to 43% at five 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.

Until recently, there have been few studies reporting the safety and efficacy of TACE or TAE as palliative treatment of ICC. The results of two small retrospective studies reported that TACE as palliative treatment may be able to prolong survival in selected individuals with ICC who would otherwise succumb to disease progression under other palliative treatment modalities (Burger, 2005; Herber, 2007). In another retrospective study, Kim and colleagues (2008) 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 transcatheter arterial chemoinfusion (TACI) (n = 96 sessions) between 1997 to 2007. Tumor response was evaluated based on computed tomography scans obtained one to three 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=.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 =.048), tumor vascularity (OR, 13.5; p<.001), and the Child-Pugh class (OR, 3.65; p=.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 overall survival 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.

Additional studies have been published in the peer-reviewed medical literature, including a retrospective review by Park and colleagues (2011) that compares 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 (equal to or greater than grade 3) hematological and non-hematological toxicities was 13% and 24%, respectively, with no deaths within 30 days following TACE. The objective tumor regression (equal to or greater than partial response) 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. Thirty-seven 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%. Forty-five of 62 participants were evaluable for morphologic response after completion of their initial cycle: 11% (n=5) partial responses, 64% (n=29) stable, and 24% (n=11) progressed. Median time to progression from first chemoembolization was eight 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 chemoembolization 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 (partial response and stable disease) of ICC and adenocarcinoma of unknown primary in 76% of evaluable participants. Overall survival after TACE showed the best outcomes for those receiving multidisciplinary integrated liver-directed and systemic therapies.

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 an option for the treatment of 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 five to seven 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). Following this study, Bedikian and colleagues (1995) reported on treatment outcomes for individuals with uveal melanoma involving the liver in a retrospective, comparative review of case reports (n=201) from the M.D. Anderson Cancer Center registry for the years 1968-1991. These case reports were analyzed to determine the prognostic factors that significantly influenced survival after diagnosis of a first metastatic tumor in the liver. Individuals were treated with systemic therapies, hepatic intra-arterial chemotherapies, and chemoembolization of liver metastases. Individuals treated with a cisplatin-based regimen as first-line chemoembolization had a 36% response rate (16 of 44 individuals) and 25% (five of 20 individuals) for subsequent treatments, compared to a one percent response rate for individuals treated with systemic chemotherapy or hepatic arterial chemotherapeutic infusions. Responders to treatment survived a median of 14.5 months; individuals who underwent systemic therapy survived five months. The subset of individuals that did not respond to chemoembolization survived a median of five months.

The Bedikian study (1995) and subsequent studies report a consistent finding that response rates to treatment of metastatic uveal melanoma with TACE are less than 50%, therefore, the primary goal of treatment is directed at arresting the progression of metastatic liver disease. Between January 1993 and December 1995, Agarwala and colleagues (2004) enrolled 19 individuals with uveal melanoma with liver metastasis in a small phase I/II randomized controlled trial to evaluate escalating doses of intrahepatic chemotherapy with cisplatin, with or without polyvinyl sponge (PVS). Seven individuals were treated with intrahepatic cisplatin, four with PVS, and three without. The dose was escalated to 125 mg/m² with or without PVS in the remaining 12 individuals. The overall response rate was 16%. Dose-limiting toxicities included renal, hepatic and hematological effects. The investigators concluded this therapy produced a "modest response rate" in individuals with ocular melanoma and liver metastases. In another non-randomized, phase II clinical trial by Patel and colleagues (2005), individuals with hepatic metastases from uveal melanoma were treated with a BCNU chemoembolization protocol. Of the 30 individuals enrolled, 24 completed at least one treatment to all targeted liver metastases, with 18 of 24 individuals experiencing regression or stabilization of hepatic metastases for at least six weeks. The overall response rates (complete and partial responses) for intention-to-treat individuals and for individuals who were evaluable for response were 16.7% and 20.4% respectively. The median overall survival of the entire intention-to-treat group of individuals was 5.2 months, for individuals with complete or partial response in hepatic metastasis 21.9 months, for individuals with stable disease 8.7 months, and for those with progressive disease 3.3 months. The investigators noted, however, that 13 of 18 individuals who achieved complete response, partial response or stable disease subsequently developed progression of extrahepatic metastases with control of hepatic metastases.

Vogl and colleagues (2006) evaluated the palliative treatment of individuals with liver metastases from uveal melanoma in a small, prospective pilot study (n=12) from July 2000 to July 2004. Six of the individuals presented with solitary live metastases (6-12 centimeters in size) and six individuals with oligonodular metastases (less than or equal to 6). Individuals were treated with mitomycin, lipiodol, and an injection of resorbable microspheres for vascular occlusion. The TACE procedure was reported as well tolerated in all individuals without any relevant side effects. Three individuals responded to TACE with a size reduction of more than 50% (partial response), five individuals with stable disease, and four individuals with progressive disease with an increase in volume of more than 25%. Mean survival following primary tumor treatment was 32.9 months, and after first embolization, 19.5 months. Lower survival rates were reported for the progressive group (16.5 months). The authors concluded that repeated TACE offers a palliative treatment option in individuals with oligonodular liver metastases of malignant uveal melanoma.

Sharma and colleagues (2008) described the use of TACE in a small, uncontrolled case series of 20 individuals with Stage IV, liver-dominant metastases of ocular (n=17) or cutaneous melanoma (n=3). The 20 individuals underwent 46 TACE sessions (mean, 2.4 sessions; range, 1-5). The mean and median overall survival times were 334 and 271 days, respectively. There were no deaths within 30 days of treatment. Thirteen of the 20 individuals had progression of disease; the mean and median progression-free survival times for these individuals were 321 and 185 days, respectively. The investigators concluded that TACE is a safe treatment that results in longer survival than has been noted among historical controls (cited as four months). Thus, for individuals with metastatic uveal melanoma who have disease confined to the liver, the metastatic disease may respond to TACE treatment and may improve survival rates.

Huppert and colleagues (2011) reported the results of a pilot trial of 14 individuals with hepatic metastases from uveal melanoma who underwent TACE. Participants received a mean of 2.4 treatments (34 total treatments among the 14 participants) with cisplatin (n=31) or carboplatin (n=3) followed by embolization with polyvinyl alcohol particles. All participants received additional systemic immunochemotherapy or best supportive care. Tumor response was evaluated using RECIST criteria. Eight participants (57%) achieved partial response, four (29%) had stable disease and tumor progression occurred in two participants (14%). Median time to progression was 8.5 months (range: 5-35 months). Median survival after the first TACE was 14.5 months in responders compared to 10 months in non-responders (p=0.18, not significant) and 11.5 months (3-69 months) in all participants. Survival advantage was most pronounced for participants with tumor occupying less than 25% of the liver volume (n=7) with a median of 17 months, versus 11 months in the seven participants with more than 25% involvement of the liver (p=0.02). The authors state that, for comparison with no treatment, survival after detection of liver metastases is two to seven months with a median one-year survival rate less than 30%. Response rates for systemic chemotherapy are less than 10%, and 20 to 50% with immunochemotherapy, but with only a median survival of five to nine months and serious toxicity.

TACE or TAE for Liver Metastasis from Other Primary Tumors

The Society of Interventional Radiology (SIR, 2009) states that chemoembolization has shown promising early results with some types of metastatic 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 breast cancer (Giroux, 2004; Li, 2005; Vogl, 2010), colorectal cancer (Albert, 2011; Lang, 1993; Salman, 2002; Sanz-Altamira, 1997; Tellez, 1998), non-small cell lung cancer (NSCLC), 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 randomized, prospective trials 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.

The NCCN Clinical Practice Guidelines in Oncology for colorectal cancer (2011) address a number of non-surgical liver-directed therapies for the treatment of unresectable metastatic disease, including arterial radioembolization with yttrium-90 microspheres, arterial chemoembolization, and conformal (stereotactic) radiation therapy. The NCCN states these therapies should be considered in a highly selective group of individuals, as their role in the treatment of colorectal metastases is controversial. Arterial-directed embolic therapy is considered a category 3 recommendation for selected individuals with predominant hepatic metastases (Hong, 2009). For occult cancers (cancers of unknown primary [CUP]), the NCCN (2011) includes chemoembolization as a locoregional therapeutic option for unresectable localized liver lesions (either localized adenocarcinoma or neuroendocrine) (category 2 recommendation). The NCCN (2011) currently does not address TACE or TAE as a treatment option for breast cancer metastatic to the liver.

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

The development of drug-eluting beads (DEBs) or injectable microspheres loaded with chemotherapy is currently being tested 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. A search of the clinical trials database identified seven ongoing, interventional, Phase I/II  trials evaluating the safety and efficacy of TACE utilizing DEBs in the treatment of refractory colorectal cancer with liver metastasis (irinotecan beads with and without intravenous cetuximab) and in the treatment of primary or refractory HCC (doxorubicin or sorafenib beads) (NIH, 2011).

TACE with DEBs for Unresectable Liver Metastasis 

A search of the literature has identified a number of studies using drug-loaded microspheres, in particular, doxorubicin-eluting beads administered during TACE. 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. Fifteen individuals (eight with colorectal carcinoma liver metastases, seven with intrahepatic cholangiocarcinoma) were treated with 27 sessions of OEM-TACE. The data suggested that the microspheres can bind oxaliplatin entirely, providing a mean concentration within the tumor that was twenty-times higher than the extratumoral liver concentration in the OEM-TACE individuals. According to RECIST criteria, stable disease was observed in eight out of the 15 individuals (53.3%), a partial response in two individuals (13.3%) and intrahepatic or extrahepatic tumor progression in five out of the 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.

De Baere and colleagues (2008) studied the use of doxorubicin-DEBs in twenty individuals with liver metastases from well differentiated gastroenteropancreatic (GEP) endocrine tumors. Three months after TACE, 16 of 20 individuals (80%) exhibited a partial response, three (15%) had stable disease, and one (5%) had progressive disease. The investigators suggested that TACE with DEBs was well tolerated and appeared effective,  however, a comparative study with a standard TACE or transarterial embolization regimen was warranted to define the best protocol for transarterial treatment of GEP liver metastases.

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 one or two 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 overall survival from the time of first treatment was 247 days and 343 days. Six individuals (10%) were downstaged from their original disease status. Of these, four were treated with surgery and two with radiofrequency ablation. Neither number of liver lesions, size of liver lesions or extent of liver replacement (equal to or less than 25% vs greater than 25%) were predictors of overall survival. In multivariate analysis, only the presence of extrahepatic disease (p=0.001), extent of prior chemotherapy (failed first-and second-line vs greater than second-line failure; p=0.007) were predictors of overall survival. 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.

TACE with DEBs for Unresectable HCC

In a phase I/II clinical trial, Varela and colleagues (2007) assessed the safety, pharmacokinetics and efficacy of TACE using doxorubicin-DEBs in 27 Child-Pugh A cirrhotic individuals (76% male, 59% HCV) with untreated large, multifocal HCC. The mean diameter of lesions treated was 4.6 centimeters, the majority classified as stage Okuda I (n=26). Individuals received chemoembolization 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 six months. DEB-TACE was reported as well tolerated with an acceptable safety profile. Two cases developed liver abscess, one leading to death. The overall response rate was 75% (n=24) (66.6% on intention-to-treat). After a median follow-up of 27.6 months, one- and two-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 phase I of the trial (dose-escalating phase, starting from 25 mg to 150 mg doxorubicin in cohorts of three individuals, n=15), two courses of TACE using doxorubicin-DEBs were given at two month intervals. The 150-mg doxorubicin dose was used for the phase II study (n=20). Primary end points were treatment-related complications and deaths. Secondary end points included tumor response (assessed by CT scan) and pharmacokinetics of doxorubicin. In the phase I, no dose-limiting systemic toxicity was observed. The treatment-related complication rate was 11.4%, with four of the serious events occurring within 30 days of treatment. There were no treatment-related deaths. The pharmacokinetic endpoint of the study showed a low peak plasma doxorubicin concentration (49.4 plus or minus 23.7 ng/mL) with no systemic toxicity observed. Among 30 individuals who completed two courses of TACE, the partial response rate and the complete response rates were 50% and 0%, respectively, by RECIST criteria at CT scan one month after the second TACE. The investigators of this trial suggested that TACE using doxorubicin-DEBs is a safe and effective treatment for HCC; however, a phase III randomized trial was 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 early results of a multicenter trial using HepaSphere™ microspheres (BioSphere Medical, Inc., Rockland, MA) 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 1-month follow-up, complete tumor response was observed in 24 of 50 (48%), partial response in 18 of 50 (36%), and stable disease in eight of 50 (16%) individuals. There were no cases of disease progression. At six-month follow-up (31 of 50 individuals), complete tumor response was obtained in 16 of 31 (51.6%), partial response in eight of 31 (25.8%), and progressive disease in seven of 31 (22.6%) individuals. Within the initial nine-month follow-up, TACE with HepaSphere was successfully repeated twice in three individuals, whereas three individuals underwent the procedure three 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.

In an open-label, single-center, single-arm study, Malagari and colleagues (2008) studied the safety and efficacy of doxorubicin-DEBs delivered by TACE in 62 cirrhotic individuals with documented single unresectable HCC. Mean tumor diameter was 5.6 centimeters (range, three to nine centimeters) classified as Okuda stages I (n = 53) and II (n = nine). Individuals received repeat embolizations with DEBs every three months (maximum of three) with a maximum doxorubicin dose of 150 mg per embolization. Overall, efficacy was reported as an objective response according to the European Association for the Study of the Liver (EASL) criteria, observed in 59.6%, 81.8%, and 70.8% across three treatments. A complete response was observed in 4.8% after the first procedure and 3.6% and 8.3% after the second and third procedures, respectively. At nine months a complete response was seen in 12.2%, an objective response in 80.7%, progressive disease in 6.8%, and 12.2% showed stable disease. Severe procedure-related complications were seen in 3.2% (cholecystitis and liver abscess). Postembolization syndrome was observed in all individuals. The investigators concluded that TACE using doxorubicin-DEBs is a safe and effective treatment of HCC as demonstrated by the low complication rate, increased tumor response, and sustained reduction of alpha-fetoprotein levels.

Reyes and colleagues (2009) conducted a small, prospective, single-center phase II pilot study evaluating the safety and efficacy of TACE with doxorubicin-DEBS for individuals with unresectable HCC. Twenty individuals (75% Child-Pugh A, 95% Eastern Cooperative Oncology Group performance status zero to one, 60% Barcelona Clinic Liver Cancer [BCLC] stage C, tumor size 6.9 centimeters) underwent 34 DEB-TACE sessions. Postembolization syndrome was observed in only one individual; no individuals had progression of a treated lesion while undergoing treatment. At six months, the disease control rate was 95% using RECIST. Overall survival rates at one and two years were 65% and 55%, respectively; median overall survival 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."

TACE with DEBs Compared to Conventional TACE for Unresectable HCC

Lammer and colleagues (2009) 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™, Biocompatibles UK Ltd., Farnham, Surrey UK) for the treatment of primary unresectable HCC. The primary efficacy endpoint at six 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 one TACE. The DEB-TACE group showed higher rates of complete response, objective response (primary endpoint), and disease control compared to the conventional TACE group, (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The differences in rates, including the primary endpoint rate was not statistically significant (p=0.11). However, 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 (treatment-related adverse events [SAEs] within 30 days of a procedure): 19 (20%) DC Bead™ individuals experienced 28 events and 21 (19%) of conventional TACE individuals experienced 24 events. Supplementary post hoc analysis indicated that the incidence of SAEs within 30 days of a procedure was consistently lower in the DC Bead™ group for the less advanced and for the more advanced individual based on the four stratification factors. 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."

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. In Okuda stage I, survival in groups A and B were 501 (421-528) and 354 days (148-560, p=0.02). In Child-Pugh classes A and B, survival in groups A and B were 641 (471-810) and 323 days (161-485, p= 0.002). Median survival in individuals with CLIP score equal to or less than three in groups A and B were 469 (358-581) and 373 days (195-551, p=0.03). Grade five 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 NCI-Common Terminology Criteria for Adverse Events (CTCAE) grade three or four 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."

TACE with DEBs in the Evaluation of Tumor Response after OLT 

Nicolini and colleagues (2010) retrospectively compared radiologic tumor response and degree of necrosis in explanted livers after TACE with epirubicin-loaded DC Beads™ compared to bland embolization in individuals on a transplant wait list. Sixteen individuals were treated with bland embolization (n=8) with 100-300-μm Embosphere^® particles (BioSphere Medical, Inc., Rockland, MA, USA) or TACE with epirubicin-loaded 100-300-μm DC Bead™ particles (n=8) every other month until complete tumor devascularization. Computed tomography was performed every three months until recurrence; explanted livers (n=49) were analyzed to evaluate the degree of necrosis in the nodules. After OLT, individuals were followed for evaluation of survival and disease status. The groups were comparable for baseline characteristics. Most individuals had Child-Pugh class A disease. Solitary HCC was found in 75% of individuals. Mean target lesion size was 32 mm plus or minus 15.4. TACE with DEBs achieved complete necrosis in 77% of lesions whereas bland embolization achieved complete necrosis in 27.2% of lesions. There was a significant difference between bland embolization and TACE with DC Bead™ with regard to histologic necrosis (p=.043). No significant treatment-related complications were observed for either group. Fifteen individuals are alive with no tumor recurrence. The authors suggested that TACE with DEBs before OLT achieved higher rates of complete histologic response than bland embolization, with no serious adverse events observed. A limitation cited by the authors was the small sample size, enabling them "to draw only preliminary conclusions regarding the potential value of chemoembolization with drug-eluting beads. Further studies in a larger subject cohort are undoubtedly necessary to confirm these preliminary findings." A second limitation was reported as the "retrospective nature of the study; in fact that there was no predefined study protocol at the time of evaluation" making it difficult to reach definitive conclusions.

TACE with DEBs Compared to TAE for Unresectable HCC

In a prospective, randomized study, Malagari and colleagues (2010) studied 84 individuals with intermediate-stage HCC), comparing doxorubicin-loaded DC Beads™ versus bland embolization with Bead Block™ (Biocompatibles UK Ltd., Farnham, Surrey, UK) particles larger than 100 µm. The primary endpoints of the study were local response, time to progression, and recurrence-free rate. The hypothesis of the study was since DEB-TACE is standardized and reproducible, a comparison with bland TACE can readily reveal the potential value of the chemotherapeutic agent. Group A (n = 41) was treated with doxorubicin DEB-TACE, and group B (n = 43) with bland embolization at set time intervals (two months), with a maximum of three embolizations. Tumor response was evaluated using the EASL criteria and alpha-fetoprotein levels. At six months a complete response was seen in 11 individuals (26.8%) in the DEB-TACE group and in six individuals (14%) in the bland embolization group; a partial response was achieved in 19 individuals (46.3%) and 18 (41.9%) individuals in the DEB-TACE and bland embolization groups, respectively. Recurrences at nine and 12 months were higher for bland embolization (78.3% vs. 45.7%) at 12 months. Time to progression (TTP) was longer for the DEB-TACE group (42.4 or minus 9.5 and 36.2 plus or minus 9.0 weeks), at a statistically significant level (p=0.008). The authors concluded that DEB-TACE presents a better local response, fewer recurrences, and a longer TTP than bland embolization with Bead Block™ particles larger than 100 µm. However, the authors stated that survival benefit and bland embolization with smaller particles (less than 100 µm) must be addressed in future studies to better assess the clinical value. Another limitation of the study 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."

TACE with or without DEBs in Combination with other Treatments for HCC

Scartozzi and colleagues (2011) retrospectively analyzed the role of traditional TACE with either lipiodol or drug-eluting microspheres in terms of response rate, TTP, overall survival (OS) and toxicity in individuals with HCC. Participants in the first group were undergoing traditional TACE (selective TACE with infusion of chemotherapeutic agents associated with lipiodol, without the use of microspheres) or pTACE (superselective TACE with drug-eluting microspheres). The second group included participants who received TACE or pTACE in addition to other treatments, such as liver resection, liver transplantation, alcoholic or laser ablation, radiofrequency thermal ablation, or systemic therapies. One hundred and fifty participants were analyzed. In the global participant population the median OS was 46 months for lipiodol TACE and 19 months for pTACE (p<0.0001), TTP was 30 months versus 16 months for participants receiving TACE or pTACE respectively (p=0.003). These results were confirmed among the group of participants who exclusively received TACE or pTACE. Neither response rate nor toxicity was different between TACE or pTACE. At multivariate analysis, age, the Okuda stage, type of TACE and number of TACE proved to be independent prognostic factors influencing OS. The authors concluded that in their experience, lipiodol TACE showed a better OS and TTP over pTACE, without difference in toxicity profile and response rate. Among the staging systems analyzed, only the Okuda stage seemed able to reliably predict treatment outcomes.

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. Finally, the NCCN's current practice guidelines for hepatobiliary cancers (2011) suggest there is a need for large randomized prospective studies to confirm if TACE with DEBs is associated with better local control, fewer recurrences, a longer time-to-progression, and an overall survival advantage.

According to the NCI (2011), it is estimated that 24,120 men and women (17,430 men and 6,690 women) will be diagnosed with and 18,910 men and women will die of cancer of the liver and intrahepatic bile duct in 2010. Malignant hepatic tumors may be primary, such as hepatocellular carcinoma or arise from metastases from other cancers such as colorectal carcinoma. Surgical excision is the optimal treatment for hepatocellular 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 the carcinoid syndrome, characterized by debilitating flushing, wheezing and diarrhea. Pancreatic endocrine (i.e., 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. The mean age-adjusted incidence of uveal melanoma in the United States is approximately 4.3 new cases per million population. Uveal melanoma is diagnosed mostly at older ages, with a progressively rising age-specific incidence rate that peaks near the age of 70. Host susceptibility factors associated with the development of this cancer include Caucasian race, light eye color, fair skin color, and the ability to tan (Singh, 2005). Uveal melanomas can arise in the anterior (iris) or the posterior (ciliary body or choroid) uveal tract. Iris melanomas have the best prognosis, whereas melanomas of the ciliary body have the worst prognosis. Most uveal tract melanomas originate in the choroid. The ciliary body is less commonly a site of origin, and the iris is the least common. Melanomas of the posterior uveal tract are cytologically more malignant, detected later, and metastasize more frequently than iris melanoma. Extraocular extension, recurrence, and metastasis are associated with an extremely poor prognosis, and short-term survival (Gragoudas, 1991). Systemic metastases are generally hematogenous in origin, and the first site identified is usually the liver, although lung, bone, and subcutaneous sites are also common (Diener-West, 2005). In the Collaborative Ocular Melanoma Study trials, the liver was the only site of detectable metastasis in 46% of individuals with metastases reported during follow-up or at the time of death; 43% had metastases diagnosed in the liver and other sites. In individuals with a history of ocular melanoma who present with hepatic metastases of unknown origin, metastatic melanoma is usually considered in the differential diagnosis (NCI, 2007).

Arterial embolization therapy, including chemoembolization (TACE) and bland embolization (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. The NCCN practice guidelines for hepatobiliary cancers (2011) recommend that individuals with unresectable/inoperable disease who are eligible to undergo embolization therapy and have tumor lesions greater than five centimeters should be treated using arterial embolic approaches, whereas those individuals with lesions three to five centimeters can be considered for combination therapy with ablation and arterial embolization. TACE has been investigated to treat resectable, unresectable, and recurrent hepatocellular carcinoma, 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, 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 chemoembolization. Another rationale is that TACE delivers effective local doses, while possibly minimizing systemic toxicities associated with oral or intravenous chemotherapy.

The most common complication of TACE and 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 thombosis, 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 (Llovet, 2002b; Buijs, 2008). Reported rates of TACE and TAE treatment-associated mortality for both are usually less than five percent.

The TACE procedure requires hospitalization for placement of the hepatic artery catheter and workup to establish eligibility for chemoembolization. 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 (e.g. 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™, GelSpheres™, LC Bead™/Bead Block™ Compressive Microspheres, Biocompatibles UK, Ltd., Farnham, Surrey, UK). Typically, only one lobe of the liver is treated during a single session, with subsequent embolization procedures scheduled from five days to six weeks later. In addition, since the embolized vessel recanalizes, chemoembolization 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 preformed by an interventional radiologist.

The recent 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 U.S. Food and Drug Administration (FDA) has stand-alone approvals for chemotherapeutic and embolic agents used with TACE that are not specifically approved as combination therapy when administered during chemoembolization. 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, 2008).

Transcatheter arterial embolization (TAE), known as bland embolization, 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 (i.e., pain). TAE is carried out during selective hepatic arterial catheterization through the arteries supplying a tumor, involving the infusion of lipiodol (without a chemotherapeutic agent) followed by embolization using any of the embolic agents (e.g. gelatin sponge cubes) as during TACE procedures. Advocates of this catheter-based therapy state that bland embolization may be equally effective as TACE for palliative treatment of primary liver cancer (Brown, 1998).

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 one of three categories:

• Childs A (5-6 points): 10 year survival 80-90%
• Childs B (7-9 points): 5 year survival 60-80%
• Childs C (10-15 points): 2 year survival less than 50%

Cancer of the Liver Italian Program (CLIP): A tumor classification system from Italy that includes scoring for eight 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 three-stage tumor classification system for HCC which combines assessment of liver function and tumor load; staging is dependent on tumor size (more or less than 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: A cancer that originates within liver cells, as opposed to having spread to the liver from other organs.

The following codes for treatments and procedures applicable to this document 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. 

When services may be Medically Necessary when criteria are met: 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met; for TACE utilizing chemotherapy-loaded microspheres for the diagnosis codes listed above; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Agarwala SS, Panikkar R, Kirkwood JM. Phase I/II randomized trial of intrahepatic arterial infusion chemotherapy with cisplatin and chemoembolization with cisplatin and polyvinyl sponge in patients with ocular melanoma metastatic to the liver. Melanoma Res. 2004; 14(3):217-222.
2. Artinyan A, Nelson R, Soriano P, et al. Treatment response to transcatheter arterial embolization and chemoembolization in primary and metastatic tumors of the liver. HPB (Oxford). 2008; 10(6):396-404.
3. Bedikian AY, Legha SS, Mavligit G, et al. Treatment of uveal melanoma metastatic to the liver: a review of the M. D. Anderson Cancer Center experience and prognostic factors. Cancer. 1995; 76(9):1665-1670.
4. Biselli M, Andreone P, Gramenzi A, et al. Transcatheter arterial chemoembolization therapy for patients with hepatocellular carcinoma: a case-controlled study. Clin Gastroenterol Hepatol. 2005; 3(9):918-925.
5. Brown DB, Chapman WC, Cook RD, et al. Chemoembolization of HCC: patient status at presentation and outcome over 15 years at a single center. AJR Am J Roentgenol. 2008; 190(3):608-615.
6. Brown KT, Nevins AB, Getrajdman GI, et al. Particle embolization for hepatocellular carcinoma. J Vasc Interv Radiol. 1998; 9(5):822-828.
7. Buijs M, Vossen JA, Frangakis C, et al. Nonresectable hepatocellular carcinoma: long-term toxicity in patients treated with transarterial chemoembolization--single-center experience. Radiology. 2008; 249(1):346-354.
8. Burger I, Hong K, Schulick R, Georgiades C, et al. Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution. J Vasc Interv Radiol. 2005; 16(3):353-361.
9. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology. 2002; 224(1):47-54.
10. Chapman WC, Majella Doyle MB, Stuart JE, et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg. 2008; 248(4):617-625.
11. Cheng BQ, Jia CQ, Liu CT, et al. Chemoembolization combined with radiofrequency ablation for patients with hepatocellular carcinoma larger than 3 cm: a randomized controlled trial. JAMA. 2008; 299(14):1669-1677.
12. Cheng HY, Wang X, Chen D, et al. The value and limitation of transcatheter arterial chemoembolization in preventing recurrence of resected hepatocellular carcinoma. World J Gastroenterol. 2005a; 11(23):3644-3646.
13. Cheng YF, Huang TL, Chen TY, et al. Impact of pre-operative transarterial embolization on the treatment of hepatocellular carcinoma with liver transplantation. World J Gastroenterol. 2005b; 11(10):1433-1438.
14. Christante D, Pommier S, Givi B, Pommier R. Hepatic artery chemoinfusion with chemoembolization for neuroendocrine cancer with progressive hepatic metastases despite octreotide therapy. Surgery. 2008; 144(6):885-893; discussion 893-894.
15. de Baere T, Deschamps F, Teriitheau C, et al. Transarterial chemoembolization of liver metastases from well differentiated gastroenteropancreatic endocrine tumors with doxorubicin-eluting beads: preliminary results. J Vasc Interv Radiol. 2008; 19(6):855-861.
16. Dhanasekaran R, Kooby DA, Staley CA, et al. Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC). J Surg Oncol. 2010; 101(6):476-480.
17. Diener-West M, Reynolds SM, Agugliaro DJ, et al. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol. 2005; 123(12):1639-1643. 
18. Fernandez GA, Robles R, Marin C, et al. Can we expand the indications for liver transplantation among hepatocellular carcinoma patients with increased tumor size? Transplant Proc. 2003; 35(5):1818-1829.
19. Fisher RA, Maluf D, Cotterell AH, et al. Non-resective ablative therapy for hepatocellular carcinoma: effectiveness measured by intention-to-treat and dropout from liver transplant waiting list. Clin Transplant. 2004; 18(5):502-512.
20. Giroux MF, Baum RA, Soulen MC. Chemoembolization of liver metastasis from breast carcinoma. J Vasc Interv Radiol. 2004; 15(3):289-291.
21. Gragoudas ES, Egan KM, Seddon JM, et al. Survival of patients with metastases from uveal melanoma. Ophthalmology. 1991; 98(3):383-389, discussion 390.
22. Graziadei IW, Sandmueller H, Waldenberger P, et al. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl. 2003; 9(6):557-563.
23. Grosso M, Vignali C, Quaretti P, et al. Transarterial chemoembolization for hepatocellular carcinoma with drug-eluting microspheres: preliminary results from an Italian multicentre study. Cardiovasc Intervent Radiol. 2008; 31(6):1141-1149.
24. Gupta S, Yao JC, Ahrar K, et al. Hepatic artery embolization and chemoembolization for treatment of patients with metastatic carcinoid tumors: the M.D. Anderson experience. Cancer J. 2003; 9(4):261-267.
25. Herber S, Otto G, Schneider J, Manzl N, et al. Transarterial chemoembolization (TACE) for inoperable intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol. 2007; 30(6):1156-1165.
26. Hong K, McBride JD, Georgiades CS, et al. Salvage therapy for liver-dominant colorectal metastatic adenocarcinoma: comparison between transcatheter arterial chemoembolization versus yttrium-90 radioembolization. J Vasc Interv Radiol. 2009; 20(3):360-367.
27. Huppert PE, Fierlbeck G, Pereira P et al. Transarterial chemoembolization of liver metastases in patients with uveal melanoma. Eur J Radiol. 2010; 74(3):e38-44.
28. Kettenbach J, Stadler A, Katzler IV, et al. Drug-loaded microspheres for the treatment of liver cancer: review of current results. Cardiovasc Intervent Radiol. 2008; 31(3):468-476.
29. Kiefer MV, Albert M, McNally M, et al. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study. Cancer. 2011; 117(7):1498-1505.
30. Kim JH, Yoon HK, Sung KB, et al. Transcatheter arterial chemoembolization or chemoinfusion for unresectable intrahepatic cholangiocarcinoma: clinical efficacy and factors influencing outcomes. Cancer. 2008; 113(7):1614-1622.
31. Kivelä T, Eskelin S, Kujala E. Metastatic uveal melanoma. Int Ophthalmol Clin. 2006; 46(1):133-149.
32. Lammer J, Malagari K, Vogl T, et al.  Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of HCC: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010; 33(1):41-52.
33. Lang EK, Brown CL Jr. Colorectal metastases to the liver: selective chemoembolization. Radiology. 1993; 189(2):417-422.
34. Lau WY, Lai EC. Hepatocellular carcinoma: current management and recent advances. Hepatobiliary Pancreat Dis Int. 2008; 7(3):237-257.
35. Lau WY, Yu SC, Lai EC, Leung TW. Transarterial chemoembolization for hepatocellular carcinoma. J Am Coll Surg. 2006; 202(1):155-168.
36. Li XP, Meng ZQ, Guo WJ, Li J. Treatment for liver metastases from breast cancer: results and prognostic factors. World J Gastroenterol. 2005; 11(24):3782-3787.
37. Liapi E, Geschwind JF. Transcatheter and ablative therapeutic approaches for solid malignancies. J Clin Oncol. 2007; 25(8):978-986.
38. Llovet JM. Evidence-based medicine in the treatment of hepatocellular cancer. J Gastroenterol Hepatol. 2002a; 17 Suppl 3:S428-433.
39. Llovet JM, Bruix J. Systemic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003; 37(2):429-442.
40. Llovet JM, Fuster J, Bruix J. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004; 10(2 Suppl 1):S115-120.  
41. Llovet JM, Real ML, Montaña X, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. Lancet. 2002b; 359(9319):1734-1739.
42. Lo C, Ngan H, Tso W, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002; 35(5):1164-1171.
43. Maddala YK, Stadheim L, Andrews JC, et al. Drop-out rates of patients with hepatocellular cancer listed for liver transplantation: outcome with chemoembolization. Liver Transpl. 2004; 10(3):449-455.
44. Malagari K, Chatzimichael K, Alexopoulou E, et al. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients. Cardiovasc Intervent Radiol. 2008; 31(2):269-280.
45. Malagari K, Pomoni M, Kelekis A, et al. Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with Bead Block for hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2010; 33(3):541-551.
46. Maluccio MA, Covey AM, Porat LB, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2008; 19(6):862-869.
47. Maluccio MA, Covey AM, Schubert J, et al. Treatment of metastatic sarcoma to the liver with bland embolization. Cancer. 2006; 107(7):1617-1623.
48. Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol. 2007; 30(1):6-25. 
49. Martin RC, Robbins K, Tomalty D, et al. Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: an interim report. World J Surg Oncol. 2009; 7:80.
50. Mavligit GM, Charnsangavej C, Carrasco CH, et al. Regression of ocular melanoma metastatic to the liver after hepatic arterial chemoembolization with cisplatin and polyvinyl sponge. JAMA. 1988; 260(7):974-976.
51. Merli M, Nicolini G, Gentilli F, et al. Predictive factors of outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma. Transplant Proc. 2005; 37(6):2535-2540.
52. Molinari M, Kachura JR, Dixon E, et al. Transarterial chemoembolisation for advanced hepatocellular carcinoma: results from a North American Cancer Centre. Clin Oncol (R Coll Radiol). 2006; 18(9):684-692.
53. Nicolini A, Martinetti L, Crespi S, et al. Transarterial chemoembolization with epirubicin-eluting beads versus transarterial embolization before liver transplantation for hepatocellular carcinoma. J Vasc Interv Radiol. 2010; 21(3):327-332.
54. Obed A, Behan A, Pullmann K, et al. Patients without hepatocellular carcinoma progression after transarterial chemoembolization benefit from liver transplantation. World J Gastroenterol. 2007; 13(5):761-767.
55. Park SY, Kim JH, Yoon HJ, et al. Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma. Clin Radiol. 2011; 66(4):322-328.
56. Patel K, Sullivan K, Berd D, et al. Chemoembolization of the hepatic artery with BCNU for metastatic uveal melanoma: results of a phase II study. Melanoma Res. 2005; (4):297-304.
57. Poggi G, Quaretti P, Minoia C, et al. Transhepatic arterial chemoembolization with oxaliplatin-eluting microspheres (OEM-TACE) for unresectable hepatic tumors. Anticancer Res. 2008; 28(6B):3835-3842.
58. Poon RT, Tso WK, Pang RW, et al. A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. Clin Gastroenterol Hepatol. 2007; 5(9):1100-1108.
59. Ramsey DE, Kernagis LY, Soulen MC, Geschwind JF. Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol. 2002; 13(Pt 2):S211-221.
60. Reyes DK, Vossen JA, Kamel IR, et al. Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: initial experience in the United States. Cancer J. 2009; 15(6):526-532. 
61. Roayaie S, Frischer J, Emre SH, et al.  Long-term results with multimodal adjuvant therapy and liver transplantation for the treatment of hepatocellular carcinomas larger than 5 centimeters. Ann Surg. 2002; 235(4):533-539.
62. Roche A, Girish BV, de Baere T, et al. Trans-catheter arterial chemoembolization as first-line treatment for hepatic metastases from endocrine tumors. Eur Radiol. 2003; 13(1):136-140.
63. Ruutiainen AT, Soulen MC, Tuite CM, et al. Chemoembolization and bland embolization of neuroendocrine tumor metastases to the liver. J Vasc Interv Radiol. 2007; 18(7):847-855.
64. Sadick M, Haas S, Loehr M, et al. Application of DC beads in hepatocellular carcinoma: clinical and radiological results of a drug delivery device for transcatheter superselective arterial embolization. Onkologie. 2010; 33(1-2):31-37.
65. Salman HS, Cynamon J, Jagust M, et al. Randomized phase II trial of embolization therapy versus chemoembolization therapy in previously treated patients with colorectal carcinoma metastatic to the liver. Clin Colorectal Cancer. 2002; 2(3):173-179.
66. Sanz-Altamira PM, Spence LD, Huberman MS, et al. Selective chemoembolization in the management of hepatic metastases in refractory colorectal carcinoma: a phase II trial. Dis Colon Rectum. 1997; 40(7):770-775.
67. Sauer P, Kraus TW, Schemmer P, et al. Liver transplantation for hepatocellular carcinoma. Is there evidence for expanding the selection criteria? Transplantation. 2005; 80(1 suppl):S105-108.
68. Scartozzi M, Baroni GS, Faloppi L, et al. Trans-arterial chemo-embolization (TACE) with either lipiodol (traditional TACE) or drug-eluting microspheres (precision TACE, pTACE) in the treatment of hepatocellular carcinoma: efficacy and safety results from a large mono-institutional analysis. J Exp Clin Cancer Res. 2010; 29:164.
69. Sharma KV, Gould JE, Harbour JW, et al. Hepatic arterial chemoembolization for management of metastatic melanoma. AJR Am J Roentgenol. 2008; 190(1):99-104.
70. Singh AD, Bergman L, Seregard. Uveal melanoma: epidemiologic aspects. Ophthalmol Clin North Am. 2005; 18(1viii):75-84.
71. Takayasu K, Arii S, Ikai I, et al. Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients. Gastroenterology. 2006; 131(2):461-469.
72. Tellez C, Benson AB III, Lyster MT, et al. Phase II trial of chemoembolization for the treatment of metastatic colorectal carcinoma to the liver and review of the literature. Cancer. 1998; 82(7):1250-1259.
73. Varela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007; 46(3):474-481.
74. Vogl T, Eichler K, Zangos S, et al. Preliminary experience with transarterial chemoembolization (TACE) in liver metastases of uveal malignant melanoma: local tumor control and survival. J Cancer Res Clin Oncol. 2007; 133(3):177-184.
75. Vogl TJ, Naguib NN, Nour-Eldin NE et al. Transarterial chemoembolization (TACE) with mitomycin C and gemcitabine for liver metastases in breast cancer. Eur Radiol. 2010; 20(1):173-180.
76. Yamashiki N, Tateishi R, Yoshida H, et al. Ablation therapy in containing extension of hepatocellular carcinoma: a simulative analysis of dropout from the waiting list for liver transplantation. Liver Transpl. 2005; 11(5):508-514.
77. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: comparison of the proposed USCF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl. 2002; 8(9):765-774.
78. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001; 33(6):1394-1403.
79. Yao FY, Hirose R, LaBerge JM, et al. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl. 2005a; 11(12):1505-1514.
80. Yao FY, Kinkhabwala M, LaBerge JM, et al. The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma. Am J Transplant. 2005b; 5(4 pt 1):795-804.
81. Zhou WP, Lai EC, Li AJ, et al. A prospective, randomized, controlled trial of preoperative transarterial chemoembolization for resectable large hepatocellular carcinoma. Ann Surg. 2009; 249(2):195-202.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Brown DB, Geschwind JF, Soulen M, et al. Society of Interventional Radiology (SIR) position statement on chemoembolization of hepatic malignancies. J Vasc Interv Radiol. 2006; 17(2):217-223.
2. Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005; 42(5):1208-1236. 
3. NCCN Clinical Practice Guidelines in Oncology™ (NCCN). © 2010 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 30, 2011.
   • Breast Cancer (V2.2011). Revised March 25, 2011.
   • Colon Cancer (V2.2012). Revised August 30, 2011.
   • Hepatobiliary Cancers (V2.2011). Revised June 29, 2011.
   • Melanoma (V2.2012). Revised September 21, 2011.
   • Neuroendocrine Tumors (V1.2011). Revised April 12, 2011.
   • Occult Primary (Cancer of Unknown Primary [CUP]. (V1.2011) Revised April 12, 2011.
   • Rectal Cancer (V2.2012). Revised August 30, 2011.
4. Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev. 2011; (3):CD004787.
5. Organ Procurement and Transplantation Network. United Network for Organ Sharing (UNOS). Policies: 3.6 Organ Distribution: Allocation of Livers. Revised November 9, 2010. Available at: http://optn.transplant.hrsa.gov/policiesAndBylaws/policies.asp. Accessed on September 30, 2011.
6. Society of Interventional Radiology (SIR). Interventional radiology treatments for liver cancer. 2011. Available at: http://www.sirweb.org/patients/liver-cancer/. Accessed on September 30, 2011.
7. U.S. Food and Drug Administration 510(k) Premarket Notification Database. LC Bead and Bead Block™ Compressible Microspheres. No. K094018. Rockville, MD: FDA. April 16, 2010. Available at: http://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm. Accessed on September 30, 2011.

1. National Cancer Institute (NCI). Available at: http://www.cancer.gov/cancertopics/alphalist. Accessed on September 30, 2011.
   • Intraocular (Eye) Melanoma Treatment (PDQ^®). Last modified December 5, 2007.
   • Liver Cancer Treatment, Adult Primary (PDQ^®). Last modified July 8, 2010.
2. U.S. National Institutes of Health (NIH). Clinical trials: drug-eluting beads. Available at: http://www.clinicaltrials.gov/ct2/results?term=drug-eluting+beads. Accessed on September 30, 2011.