Medicare Advantage

Medical Policy

Notification

Drug-Eluting Beads and Bland Embolization for the Treatment of Hepatic Malignancies

Notification Issue Date:

This version of the policy will become effective 12/16/2019.

The published medical literature was updated.

The following ICD-10 Diagnosis Code has been

added

to this policy: C22.7.

Title:

Drug-Eluting Beads and Bland Embolization for the Treatment of Hepatic Malignancies

Policy #:

MA07.041b

Policy

MEDICALLY NECESSARY

BLAND EMBOLIZATION
Bland embolization is considered medically necessary and, therefore, covered for the following indications:

Unresectable hepatocellular carcinoma (HCC)
Liver malignancies caused by neuroendocrine tumors

DRUG-ELUTING BEADS
Drug-eluting beads for the palliative treatment of unresectable cholangiocarcinoma are considered medically necessary and, therefore, covered.

Drug-eluting beads for the treatment of unresectable hepatocellular carcinoma (HCC) are considered medically necessary and, therefore, covered when all of the following criteria are met:

The individual has a patent portal vein on superior mesenteric arterial portovenography.
The individual has adequate liver function as determined by a Child-Pugh score of A or B (see classification table below).
The individual does not have any contraindications to angiography.
The individual does not have any extrahepatic metastases.

CHILD-PUGH CLASSIFICATION TABLE This score employs five clinical measures of chronic liver disease. Each measure is scored 1-3 points, with 3 indicating most severe derangement. Child-Pugh Scoring: A=5-6, B=7-9, C=10-15. It should be noted that different textbooks and publications use different measures. Some older reference works substitute prothrombin time (PT) prolongation for international normalized ratio (INR).
Measure	1 point	2 points	3 points
Hepatic encephalopathy	None	Moderate	Severe
Ascites	None	Moderate	Severe
Serum albumin (g/dL)	Greater than 3.5	2.8-3.5	Less than 2.8
INR	Less than 1.7	1.7-2.20	Greater than 2.20
Serum bilirubin (mg/dL)	Less than 2	2-3	Greater than 3

EXPERIMENTAL/INVESTIGATIONAL

All other uses for bland embolization for the treatment of hepatic malignancies are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

All other uses for drug-eluting beads for the treatment of hepatic malignancies are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

BLAND EMBOLIZATION

Individuals in the studies typically received 1 to 3 treatments performed 6 weeks to 3 months apart in the in-patient setting.

FDA (US Food and Drug Administration)
The following are examples of bland embolization that have received FDA 510(k) marketing clearance (this is not an all-inclusive list):

Bead Block™Compressible Microspheres
Embosphere® Microspheres
Embogold® Microspheres
Embozene® Microspheres
Gelfoam

DRUG-ELUTING BEADS (DEB)

Individuals in the studies typically received 1 to 3 treatments performed 6 weeks to 3 months apart in the in-patient setting.

FDA
The following are examples of DEB that have received FDA 510(k) marketing clearance (this is not an all-inclusive list):

LC Bead™Microspheres
LC Bead™^M1 Microspheres
QuadraSphere™

There is no Medicare coverage determination addressing this service; therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, bland embolization for the treatment of unresectable hepatocellular carcinoma (HCC) and liver malignancies caused by neuroendocrine tumors are covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

Subject to the terms and conditions of the applicable Evidence of Coverage, drug-eluting beads for the treatment of unresectable HCC is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

The FDA has approved several types of beads used for bland embolization and drug-eluting beads under the 510(k) process.

Description

Hepatic tumors can develop as primary liver cancer (most commonly hepatocellular carcinoma [HCC]), which is the fifth most common cancer and the third most common cause of cancer-related deaths worldwide. HCC is also the leading cause of death in patients with cirrhosis. Another primary site of hepatic cancer is cholangiocarcinoma (cancer of the bile ducts), although this is less common than HCC. Cholangiocarcinoma can be divided into intrahepatic and extrahepatic diseases. Hepatic tumors can also develop as liver metastasis from other organs, such as the colorectal region. The overall survival for these individuals is about six months. Hepatic tumors may be difficult to treat because of the advanced stage of the tumors at the time of diagnosis, with an untreated survival rate of approximately three to six months. Individuals may exhibit one or more tumors and may have complications such as liver cirrhosis, chronic hepatitis, extensive liver dysfunction, presence of extrahepatic disease, and macrovascular invasion.

Liver transplantation or resections are the only curative options, but are often not feasible because of the size, number, or location of the tumors. There is no universally accepted treatment for unresectable hepatic tumors. Alternative treatments are available, including radiofrequency thermal ablation (RFA), systemic chemotherapy, external beam radiation, radioembolization, and hepatic embolization with or without localized chemotherapy. Each technique has side effects and varying response rates to treatment.

The concept of embolization is grounded in the fact that liver tumors are highly vascular. If the blood flow to the tumors can be impeded, tumor necrosis will likely occur. In bland embolization (also known as transarterial embolization [TAE] or hepatic arterial embolization [HAE]), the femoral artery is accessed and a catheter containing particulate embolic agents (made of gelatin sponge particles, polyacrylamide microspheres, or polyvinyl alcohol [PVA] particles) is injected into the hepatic tumor's blood supply via the hepatic artery. Bland embolization may or may not use a contrast medium of poppy seed oil (Lipiodol), which has a high rate of accumulation in hepatic tumors.

Another technique, chemoembolization, involves drug-eluting beads (DEB), which are small embolic particles intended to be loaded with a chemotherapeutic agent, mainly doxorubicin or irinotecan. These "loaded beads" are inserted at the point of the tumor's blood supply to block the flow of blood, similar to bland embolization, but with the added benefit of the chemotherapeutic agent slowly dispersing throughout the tumor.

Note: DEB should not be mistaken for a similar procedure called transcatheter arterial chemoembolization (TACE), also referred to as conventional TACE (c-TACE). During the c-TACE procedure, a solution containing a chemotherapeutic agent and Lipiodol is injected into the liver tumor (as in the prior two procedures), followed by the insertion of embolic particles at the tumor's blood supply to promote embolization. The concept of chemoembolization allows the chemotherapeutic agent to be localized for a longer period of time compared to systemic chemotherapy.

Pharmacologic studies show that DEB results in a higher concentration of the drug at the site of the tumor compared to c-TACE. It has been proposed that DEB may cause fewer systemic side effects and less liver toxicity compared to systemic chemotherapy or c-TACE.

BLAND EMBOLIZATION

PEER-REVIEWED LITERATURE
Bland embolization has been studied in individuals with:

Unresectable HCC
Liver metastasis due to primary neuroendocrine tumors
A need for a bridge to liver transplantation.

Some studies note whether the individual had prior therapies (such as chemotherapy, c-TACE, radiation), whereas other studies do not.

Bland Embolization in Unresectable HCC

In 2009, Bonomo G, et al performed a prospective study involving bland embolization in 53 individuals with unresectable HCC who were classified as Child-Pugh Class A & B. (See Policy section for the Child-Pugh Class Table). Only four individuals experienced minor complications, and one individual died due to massive tumor necrosis. The median follow-up time was 6 months; however, the results were reported at the 6-12-- month follow-up as follows: 7 of 74 lesions sustained stable disease (SD), 22 of 74 lesions had partial response (PR), 3 of 74 lesions experienced complete response to therapy (CR), and 11 of 74 lesions had progressive disease (PD). Twenty individuals had a 1-year follow-up with CR sustained in three individuals, PR in five individuals, SD in three individuals, and PD in nine individuals. These 20 individuals represented a 96% overall survival rate. However, the results of this study are limited due to the low number of individuals treated, and a short follow-up time. At each follow-up point, individuals dropped off the study, skewing the tumor response percentages.

Bland Embolization in Neuroendocrine Cancers with Liver Metastasis

Neuroendocrine cancers arise from various endocrine organs throughout the body. Carcinoid tumors (a subset of digestive tumors) and pancreatic islet cancer are both hormone-secreting tumors that are highly vascularized, making them good candidates for treatment via embolization. When there are metastases to the liver, the survival rate has been reported at only 20-40% at 5 years.

A retrospective review of 161 bland embolization treatments in 84 individuals with carcinoid or pancreatic endocrine tumors metastatic to the liver were studied by Strosberg JR et al. Only 23 individuals were evaluated for response rate; 11 of 23 individuals had PR, and 12 of 23 had SD using RECIST criteria. Twenty-eight of 35 individuals evaluated for the presence of tumor markers had a major response (greater than 50% reduction in tumor markers). Sixty-three of 84 individuals experienced clinical symptoms prior to therapy (such as diarrhea, flushing, abdominal pain). After therapy, 55 of 76 individuals reported symptomatic improvement, while 11 had no improvement, and 8 were lost to follow-up.

All individuals experienced post-embolization syndrome, which consists of fever, right abdominal pain, and nausea. Transient increases in liver enzymes were seen, which were decreased to baseline values several weeks later at follow-up. Nine individuals (who all had carcinoid tumors) experienced severe hypertension. Other adverse events reported were one case of myocardial infarction (MI), one case of transient thrombocytopenia, one case of liver hematoma, one case of bilateral pleural effusions, and two deaths two months after embolization due to unknown reasons.

The authors reported that the median overall survival was 44 months in those with carcinoid tumors, 31 months in those with pancreatic endocrine tumors, and 15 months in those with neuroendocrine tumors. Of the 13 individuals who received post-embolization chemotherapy, the overall survival rate was 38 months compared to 44 months in those who did not receive post-embolization chemotherapy. The authors felt that these results were due to the fact that the 10 of 13 individuals studied had pancreatic endocrine tumors, which have a worse prognosis compared to carcinoid tumors. The drawbacks of this study include the small number of individuals evaluated for clinical response, the loss of patients to follow-up, the administration of chemotherapy, and radioactive forms of somatostatin analogs following embolization. Additionally, some results did not note the time-frame of the follow-up.

A clinical study published in 2007 by Ruutiainen AT, Soulen MC, Tuite CM, et al was a retrospective review of bland embolization compared to c-TACE (using 5-FU, doxorubicin, cisplatin, or others) in 67 individuals with neuroendocrine tumors: 38 (57%) carcinoid, 14 (21%) pancreatic islet-cell, 4 (6%) gastrinomas, 3 (4%) other, and 8 (12%) uncharacterized neuroendocrine tumors. There were a total of 219 embolizations. Forty-four individuals underwent c-TACE, while 23 individuals received bland embolization as the primary treatment. The 30-day mortality rate was 1.4% (two individuals had bland embolization and one individual had c-TACE). Incidence of post-embolization syndrome (characterized by fever, nausea and vomiting, and fatigue) was high, but symptoms were mild. Moderate to severe toxicities occurred in 25% of those who had chemoembolization, and 22% in those with bland embolization. There was a statistically significant increased rate of infections among those treated with c-TACE. Individuals treated with c-TACE and bland embolization for the palliation of carcinoid symptoms experienced relief for a mean of 15 and 7.5 months, respectively, but these results were not statistically significant. Survival rates at 1, 3, and 5 years after therapy were 86%, 67%, and 50%, respectively, after c-TACE, and 68%, 46%, and 33%, respectively, after bland embolization. The mean life expectancy was 44 months with c-TACE, and 39 months with bland embolization, but these results were not statistically significant. The authors also noted that there was a trend for increased overall survival in those with carcinoid tumors, compared to other tumors. Limitations to this study include the small sample size, the loss of ten individuals at follow-up, and the potential selection bias due to the retrospective nature of this study. Also there were cross-over patients who received both treatments, with one treatment being the primary method of therapy.

Complications of Bland Embolization

Complications of bland embolization include post-embolization syndrome, which consists of fever, right abdominal pain, nausea and vomiting, and fatigue. It is reported in up to 81% of individuals. Rarely, complications such as pancreatitis, pulmonary embolism, and respiratory insufficiency occurred.

Professional Organizations Guidelines and Recommendations

Unresectable HCC

The 2010 guidelines of the American Association for the Study of Liver Disease (AASLD) have recommended using c-TACE over bland embolization in individuals with unresectable HCC that is either too large or multifocal for percutaneous ablation techniques such as RFA and who have no extrahepatic tumor spread. Additionally, an expert consensus group of the American Hepato-Pancreato-Biliary Association in 2010 stated that c-TACE is standard for intermediate/advanced unresectable HCC. There were no recommendations in these two guidelines for usage of bland embolization in unresectable HCC. The National Comprehensive Cancer Network (NCCN) states that "All tumors irrespective of location may be amenable to arterially directed therapies provided that the arterial blood supply to the tumor may be isolated without excessive non-target treatment. Arterially directed therapies include bland transarterial embolization (TAE), chemoembolization (transarterial chemoembolization [TACE] and TACE with drug-eluting beads [DEB-TACE]), and radioembolization (RE) with yttrium-90 microspheres." NCCN does not recommend one technique over another.

Neuroendocrine Cancers with Liver Metastasis

NCCN states "for unresectable liver metastases, hepatic regional therapy (arterial embolization, chemoembolization, or radioembolization) are recommended." NCCN does not recommend one technique over another.

DRUG-ELUTING BEADS (DEB)

PEER-REVIEWED LITERATURE
DEB has been studied in individuals with:

Unresectable HCC
Unresectable cholangiocarcinoma
Liver metastasis due to primary colorectal cancer
Liver metastasis due to primary ocular melanoma
Liver metastasis due to primary neuroendocrine tumors
A need for a bridge to liver transplantation
A need to downstage the disease or establish stable disease without extra-hepatic disease progression allowing resection, ablation, or both.

*Some studies note whether the individual had prior therapies (such as chemotherapy, c-TACE, radiation), whereas other studies do not.

DEB in Unresectable HCC

In 2007, Varela M, et al performed a preliminary, prospective study addressing the safety, efficacy, and pharmacokinetics involved with DEB containing doxorubicin for the treatment of unresectable HCC. The study of 27 individuals reported relatively minor complications such as post-embolization syndrome (consisting of fever, right abdominal pain, nausea, and vomiting) in 18-37% of individuals, and mild alterations in liver function parameters. Efficacy was evaluated at 6 months post-procedure, but depending on which assessment tool was used, the tumor response data differs. In another study, the pharmacokinetics of DEB versus c-TACE was studied in 13 individuals and showed a lower peak drug concentration (Cmax) and area under the curve (AUC) with DEB than with c-TACE. According to the authors, this suggests that DEB has less systemic absorption than c-TACE, which could cause fewer side effects and give the individuals a chance at either higher doses or more frequent treatments. Some limitations in this study included the small number of individuals evaluated, the short follow-up time, and the fact that all of the individuals were classified as Child-Pugh A (the least severe class of liver disease). A few other limitations of the study include the lack of a control group and the unavailability of follow-up data for three individuals.

In 2009, Lammer J, Malagari K, Vogl T, et al performed a prospective, single-blind, phase II, randomized study (PRECISION V) comparing doxorubicin administration by DEB or c-TACE in the treatment of unresectable HCC in 212 individuals. DEB had a slightly better tumor response rate than c-TACE, but it was not statistically significant. According to the authors, DEB is not superior to c-TACE because the difference in objective response (OR) rate (defined as CR plus PR) and disease control rates (defined as OR plus SD) was not significant. They stratified the data to show that individuals with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease had a statistically significant increase in OR and disease control rates with DEB compared to c-TACE. As far as safety, there was no difference in statistical significance between DEB and c-TACE, although there was a trend for a lower overall frequency of adverse effects with DEB, as well as a statistically significant reduction in serious liver toxicity and a lower rate of doxorubicin-related side effects (such as alopecia, mucositis, bone marrow suppression, skin discoloration). The shortcomings of this study included an overall follow-up of only 6 months, and the mean dose of doxorubicin in the DEB group was higher than in the c-TACE group (295 vs. 223 mg).

In 2010, Malagari K, Pomoni M, Spyridopoulos TN, et al performed a cohort study with doxorubicin in DEB for 237 individuals with unresectable HCC. Information for the study was obtained mostly prospectively, and the remainder of the information was retrieved retrospectively from the individual's clinical records. Over a period of 6 months, 86.5% of individuals reported post-embolization syndrome, a mild transient syndrome involving nausea, vomiting, right abdominal pain, and fatigue. Other mild to moderate adverse events that occurred included cholecystitis 5.48%, ascites/encephalopathy 4.2%, pleural effusion 3.37%, and the moderate to severe adverse events of liver failure (1.68%), and abscess (1.26%). Of note, there were no incidences of abscesses in individuals treated with the smallest bead diameter. Doxorubicin-related side effects (alopecia, skin discoloration, mucositis, and bone marrow suppression) were not seen in any individuals, showing that doxorubicin was localized. The 30-day mortality rate was 1.26% (3 of 237 individuals). The authors reported that only 10% of the individuals had progressive disease at the 6-month follow-up period, but the authors did not note the actual numbers of individuals present at that follow-up. Another drawback to this study is the short overall follow-up time of 6 months.

DEB in Unresectable Cholangiocarcinoma

The only curative approaches for the treatment of cholangiocarcinoma are surgery or transplantation and individuals with cholangiocarcinoma may have poor prognosis even after surgery. Additionally, by the time the diagnosis for this disease is made, the majority of patients have unresectable cholangiocarcinoma. There is a lack of standardized treatment regimens for unresectable cholangiocarcinoma. The choices of treatment in those with unresectable cholangiocarcinoma involve systemic chemotherapy that may have partial efficacy, palliative biliary drainage and stenting (in extrahepatic cholangiocarcinoma), or locoregional therapies. Participation in a clinical trial is also another option that is available to explore an unproven therapy. Evidence regarding safety and efficacy of DEB, when this therapy is employed for unresectable cholangiocarcinoma, is very limited. Preliminary data for DEB for the treatment of cholangiocarcinoma consist of small case series or case reports. Unresectable intrahepatic cholangiocarcinoma may have slightly better outcomes than unresectable extrahepatic disease when locoregional therapies are administered; however, experience in clinical practice suggest that DEB may be offered only as a palliative option for unresectable cholangiocarcinoma.

DEB in Colorectal Cancer with Liver Metastasis

In 2009, Martin RC, et al published interim results on an open-label, multi-center, single-arm study of DEB containing irinotecan in 55 individuals with unresectable colorectal liver metastases who were refractory to systemic chemotherapy. Their interim report discussed findings on safety and efficacy at a median follow-up of 18 months. Adverse events (including nausea, vomiting, and liver dysfunction) were relatively mild, and there was an increase in the incidence of these events as the dose increased. The authors reported that one individual died of a serious adverse event (due to liver dysfunction), while 12 of 46 individuals died due to disease progression. Of note, 6 individuals (10%) were downstaged and were able to have surgery or radiofrequency ablation. The median disease-free and overall survival from the time of the first treatment was 247 days and 343 days, respectively. The authors reported that the predictors of overall survival were the presence of extrahepatic disease and the extent of prior chemotherapy (failing first- and second-line vs. failing greater than second-line therapy). They also reported that the number or size of lesions and extent of liver replacement were not predictors of overall survival. One major drawback to this study included the large number of patients not reached at follow-up or lost to follow-up (9 individuals at the 12-month point and 29 individuals at the 18-month point).

In 2010, Martin RC, et al published the final results of this trial. Again, safety data was relatively mild in severity except for three accounts of severe liver dysfunction. The overall response rates of DEB (calculated as CR plus PR) were 65% at 3 months, 50% at 6 months, and 40% at 12 months. The authors reported overall and progression-free survival rates of 19 months and 11 months, respectively, but the drawback of these results was that the author was only using data from seven patients who had a complete response. Another limitation to this study included the receiving of concomitant chemotherapeutic agents; 30% of individuals were also taking Xeloda or infusional 5-fluorouracil (5-FU) along with DEB.

DEB in Ocular Melanoma with Liver Metastasis

Ocular melanoma (OM) is the most common primary cancer of the eye in adults and represents about 5% of all melanoma diagnoses. In up to 95% of individuals with OM, the metastases first appear in the liver. A study in 2009 by Fiorentini G, et al was a prospective, phase II study using DEB with irinotecan for the treatment of liver malignancy due to OM. All 10 individuals in the trial had a metastasis reduction of 60-90% with only mild to moderate side effects seen. Two patients died at 4 and 6 months post-treatment. Eight individuals reported an increase in their quality of life. The drawbacks of this study included the small number of individuals evaluated and the short follow-up time (median follow-up 6.5 months).

DEB in Neuroendocrine Cancers with Liver Metastasis

A trial published in 2008 by de Baere T, Deschamps F, Teriitheau C, et al studied the use of doxorubicin containing DEB in gastroenteropancreatic endocrine tumors (GEP). Twenty individuals underwent a total of 34 treatments with DEB. One month after the first treatment cycle, 9 of 11 individuals symptomatic for carcinoid crisis (mainly characterized by diarrhea and flushing) had a 50% reduction in these symptoms, which was maintained at month 3 in all individuals. At the 3-month follow-up, 16 individuals had PR, while three individuals had SD, and one individual had PD. In one individual with PR, the disease became resectable after 6 months; although because of postoperative septic complications, the individual died. At the median follow-up time point of 15 months, 9 of 20 individuals had no tumor progression, and 10 of 20 had disease progression. A critical safety endpoint discovered at the 1-month follow-up time period was that 5 individuals experienced DEB-induced peripheral liver necrosis. The authors also reported post-embolization syndrome (consisting of fever, right abdominal pain, nausea, and vomiting) lasting less than 7 days in 23 treatments (67%), compared to post-embolization syndrome lasting more than 7 days in 7 treatments (22%); four treatments (11%) did not have this adverse event. Also 2-3 days after treatment, the mean values of certain liver enzymes were above normal range. The limitations of this study included a small population size and short follow-up. There is also a lack of evidence as to which dose of doxorubicin should be used for treatment.

DEB in Colorectal Cancer with Liver Metastasis for the Purpose of Surgical Downstaging

Bower M, Metzger T, Robbins K, et al looked at the technique of surgical downstaging with irinotecan DEB in metastatic colorectal carcinoma. Because surgery is the first-line treatment for liver malignancies, this open-label, single-arm trial looked at 55 individuals who initially presented with unresectable liver malignancies to demonstrate DEB's effects on downstaging their disease in order to allow for resection or RFA. There were a total of 90 treatments of DEB performed. The results reported that 11 individuals (20%) demonstrated either a significant response and downstaging of their disease or stable disease without extra-hepatic disease progression, allowing resection, ablation, or both. The results of this study are limited by the fact that 15 individuals had prior liver lobectomies or RFA; additionally, concomitant systemic chemotherapy was being performed in 30% of individuals. Although DEB is still being researched for safety and efficacy in individuals with hepatic malignancies, the data for this subset of individuals studied for the purpose of surgical downstaging are too limited.

STUDIES COMPARING DEB AND BLAND EMBOLIZATION
Bland Embolization and DEB in Unresectable HCC

In 2009, Malagari K, et al performed a prospective, randomized comparison of doxorubicin-eluting beads and bland embolization for HCC in 87 individuals. The trend of a better response rate was seen in complete and stable disease in DEB compared to bland embolization at 6 and 12 months; stable disease at 12 months was statistically significantly higher in DEB compared to bland embolization. There was a higher recurrence rate for bland embolization at 12 months compared to DEB (bland=78%, DEB=45%), although there was no difference in survival rates within 1 year between both groups. As far as safety, there were no differences in complications between either group. A weakness of this study was the loss of patients to follow-up at the 12-month point.

DEB and Bland Embolization: Usage Prior to Liver Transplantation

Nicolini A, et al performed a retrospective study of 8 individuals undergoing DEB with epirubicin versus 8 individuals undergoing bland embolization before liver transplantation for HCC. Individuals on the transplant waiting list depend on locoregional therapies to maintain their current disease state (prevent progression) or to downstage their disease; some of the therapies have proposed an improved disease-free survival after the transplantation. The majority of individuals were Child-Pugh Class A. The authors originally looked at 49 individuals, but excluded 33 due to various criteria such as Child-Pugh Class C. In the DEB population, CR=63% (statistically significant), PR=12%, SD=0%, PD=25%. In the bland embolization population, CR=0, PR=63%, SD=0%, PD=37%. There were no differences in treatment-related complications. Major limitations to this study are the small sample size, and, because it is a retrospective study, potential selection bias. Although DEB is still being researched for safety and efficacy in individuals with hepatic malignancies, the data for this subset of individuals studied regarding stable disease or tumor regression prior to liver transplantation are too limited.

Complications of DEB

Complications of DEB include post-embolization syndrome, which was reported in up to 85% of individuals. To a lesser degree, some individuals may exhibit signs of liver failure, liver abscess, pleural effusion, cholecystitis, ascites, hypertension, gastritis, dehydration, anorexia, anemia, gastrointestinal bleed, pancreatitis, and skin erythema.

PROFESSIONAL ORGANIZATIONS GUIDELINES AND RECOMMENDATIONS
Unresectable HCC

Although professional organizations such as the American Association for the Study of Liver Disease (AASLD), the National Comprehensive Cancer Network (NCCN), and the National Cancer Institute (NCI) have recommendations concerning the usage of c-TACE in liver malignancies, no organization is specifically recommending DEB for the treatment of liver malignancies. AASLD states that c-TACE "is likely to be phased out and replaced by DEB." NCCN made a statement regarding the Lammer, et al (2010) study, which showed comparable effectiveness for c-TACE and DEB and less toxicity with DEB, as follows: "However, in other prospective randomized studies, DEB was associated with survival advantage, better local response, fewer recurrences and longer time-to-progression. These results need to be confirmed in large prospective randomized studies."

Unresectable Cholangiocarcinoma

NCCN states that "intra-arterial chemotherapy (with or without systemic chemotherapy) may be used in a clinical trial or at experienced centers" for the treatment of unresectable cholangiocarcinoma, yet there are no references or recommendations about using DEB specifically.

Neuroendocrine Cancers with Liver Metastasis

NCCN states that "for unresectable liver metastases, hepatic regional therapy (arterial embolization, chemoembolization, or radioembolization) are recommended." NCCN does not recommend one treatment over another. Their references for the technique of chemoembolization do not include DEB studies.

Usage Prior to Liver Transplantation

NCCN states that "All patients with HCC should be evaluated for potential curative therapies (resection, transplantation, and for small lesions, ablative strategies). Locoregional therapy should be considered in patients who are not candidates for surgical curative treatments, or as a part of a strategy to bridge patients for other curative therapies. These are broadly categorized into ablation, arterially directed therapies, and radiotherapy."

PEER-REVIEWED DATA AND COMMUNICATIONS

Lencioni et al (2013) stated that TACE is the current standard of care for patients with intermediate-stage HCC and relatively preserved liver function. In a meta-analysis of RCTs comparing conventional TACE regimens including the administration of an anticancer-in-oil emulsion followed by embolic agents versus best supportive care, TACE was shown to improve median survival from 16 to 20 months. Various strategies to improve outcomes for this patient group have become the subject of much ongoing clinical research. The introduction of an embolic DEB has been shown to substantially improve the pharmacokinetic profile of TACE, providing levels of consistency and repeatability not available with conventional regimens while concomitantly significantly diminishing systemic drug exposure. In randomized trials, DEB-TACE significantly reduced liver toxicity and drug-related adverse events compared with conventional TACE. These investigators reviewed technique, indications and contraindications, and clinical outcomes of conventional and DEB-TACE in the management of HCC. In addition, scientific background and early clinical experience with the use of combination regimens including TACE and systemically active molecular-targeted agents with anti-angiogenic properties were discussed. The authors concluded that the combination of DEB-TACE and anti-angiogenic therapy represents a potentially powerful approach that is currently undergoing clinical investigation in a phase III setting.

In a meta-analysis, Gao and associates (2013) evaluated the effectiveness of DEB-TACE compared with conventional TACE (cTACE). These researchers included 7 studies (a total of 693 patients) to compare DEB-TACE with cTACE. The pooled (OR were calculated using a random or fixed effects model. MEDLINE, EMBASE and the Cochrane Database were searched for articles published from dates of inceptions up to February 20, 2012. Sensitivity analysis and publication bias estimate were also performed to evaluate the potential risk bias in the overall results of pooled analysis. The pooled estimates for tumor response of DEB-TACE were not significantly different from those of cTACE, with CR (OR: 1.18; 95 % CI: 0.81 to 1.71; p = 0.394), PR (OR: 1.37; 95 % CI: 0.94 to 1.99; p = 0.101), stable disease (SD) (OR: 0.88; 95 % CI: 0.51 to 1.51; p = 0.637), PD (OR: 0.85; 95 % CI: 0.52 to 1.38; p = 0.512), DC (OR: 1.37, 95 % CI: 0.95 to 1.98; p = 0.089) and OR (OR: 1.40; 95 % CI: 0.97 to 2.000; p = 0.070). The authors concluded that the current evidence suggests that DEB-TACE is able to accomplish the same tumor response as cTACE. Moreover, they stated that although this analysis provided a comprehensive look at published data involving the clinical effectiveness of DEB-TACE compared with conventional TACE, additional large scale of RCTs are still needed.

An UpToDate review on “Nonsurgical therapies for localized hepatocellular carcinoma: Transarterial embolization, radiotherapy, and radioembolization” (Curley et al, 2013) states that “A newer approach to TACE uses drug-eluting beads (DEBs) that slowly release chemotherapy, thus diminishing systemic toxicity. Early results from retrospective reports and several small prospective randomized trials suggest similar rates of tumor control as with conventional TACE, with lower rates of serious hepatobiliary toxicity, although follow-up is short in most series:

A meta-analysis of seven studies comparing conventional TACE versus DEB-TACE (five prospective randomized trials and two retrospective comparative reports, totaling 693 patients) concluded that the pooled estimates for tumor response with DEB-TACE were not significantly different from those of conventional TACE (odds ratio [OR] for disease control 1.37, 95 % CI 0.95-1.98).
Comparative toxicity was addressed in the largest randomized trial, the PRECISION V trial, in which conventional TACE using doxorubicin (50 to 75 mg/m2) was directly compared to DEB-TACE (150 mg doxorubicin per procedure) in 212 patients with Child-Pugh A/B cirrhosis and unresectable HCC. The DEB group had lower rates of treatment-emergent adverse events in the hepatobiliary system (16 versus 25 percent). The mean maximum postchemoembolization alanine transaminase increase with DEB-TACE was 50 percent less than in the conventional TACE group (p < 0.001), and the mean maximum aspartate transaminase increase was 41 percent lower. Furthermore, despite a higher mean total dose of doxorubicin in the DEB-TACE group (295 versus 233 mg), there was a small but statistically significant difference in mean change from baseline in left ventricular ejection fraction (LVEF) of 4 percentage points that favored DEB-TACE group. The incidence of postembolization syndrome was similar between both groups (25 versus 26 percent for DEB-TACE and conventional TACE). On the other hand, treatment-emergent gastrointestinal adverse events occurred more often in patients treated with DEB-TACE (61 versus 45 percent).

The authors of the above UpToDate review noted that “Where available, TACE using drug-eluting beads may be preferred, although long-term experience with this modality is limited”.

Idilman et al (2013) determined the effect of trans-arterial chemo-embolization (TACE) treatment on survival in patients with HCC and examined the efficacy and tolerability of 2 different TACE procedures: (i) conventional TACE and (ii) drug-eluting beads (DEB), in these patients. A total of 40 patients with HCC treated with TACE between January 2007 and March 2011 were included. Thirty-seven patients had Child-Pugh class A and the remaining 3 had class B. Intra-arterial administration of doxorubicin with lipiodol-based conventional TACE or DEB-TACE was performed. Eighty sessions were performed with a median of 2 sessions. Sixteen patients were treated with conventional TACE and 11 with DEB-TACE, and 13 were treated with both treatment procedures in separate sessions. Primary outcome was defined as patient survival after treatment. The median follow-up was 19 months. The median overall survival of patients was 23.2 months. The survival of patients with Child-Pugh class A was significantly better than that of patients with class B (24 versus 6 months, p = 0.004). No statistically significant difference in survival was observed between conventional TACE and DEB-TACE treatments (p > 0.05). Baseline low serum albumin level (p = 0.003) and the presence of portal vein thrombosis (p = 0.011) negatively affected patient survival. Side effects of conventional TACE and DEB-TACE were similar. The authors concluded that based on the results of this study and in comparison with the findings in the literature, TACE treatment was seen to improve overall survival and provide better outcome in selected patients with HCC. They stated that no differences in survival or side effects were observed between the 2 TACE treatment modalities (conventional TACE and DEB-TACE).

Spreafico et al (2015) evaluated the short-term safety and effectiveness of the new generation of 70-150 µm drug-eluting beads (M1 DEB) in patients with hepatocellular carcinoma undergoing TACE as a primary therapy or as a bridge to liver transplantation (LT). A total of 45 consecutive patients underwent TACE with M1 DEB loaded with doxorubicin (DEBDOX/M1). Clinical data were recorded at 12, 24, and 48 hours, 7 and 30 days after treatment. Response was assessed by computed tomographic scan according to the modified response evaluation criteria in solid tumors criteria, and a second DEBDOX/M1 TACE was scheduled within 6 weeks in case of a non-complete response. All patients had well-compensated cirrhosis (97.7 % Child A, 44.4 % hepatitis C virus, median age of 61 years). Twenty patients (44.4 %) had Barcelona Clinic for Liver Cancer class B disease; the median number of nodules and their sum of diameters were 2 (range of 1 to 6) and 43 mm (range of 10 to 190), respectively. The mean number of TACE procedures per patient was 1.4. Objective response rate (complete + partial response) was 77.7 % with a median time to best response of 3 months (95 % confidence interval [CI]: 2 to 4). In 13 patients, DEBDOX/M1 TACE served as a bridge/down-staging to LT/surgery. Pathology showed that more than 90 % necrosis was achieved in 10 of 28 nodules. DEBDOX/M1 TACE was well-tolerated, and the grade 3/4 adverse event rate was low (1 of 65 procedures). The authors concluded that DEBDOX/M1 TACE is an effective procedure with a favorable safety profile and promising results in terms of objective response rate, tumor down-staging, and necrosis.

An UpToDate review on “Nonsurgical therapies for localized hepatocellular carcinoma: Transarterial embolization, radiotherapy, and radioembolization” (Curley et al, 2019) states that “Drug-eluting beads -- A newer approach to TACE, which is being used at most centers, uses DEBs that slowly release chemotherapy, theoretically reducing treatment-related toxicity. Results from several small prospective randomized trials and a meta-analysis of seven randomized trials of TACE versus DEB-TACE suggest similar rates of tumor control as with conventional TACE but lower rates of postprocedure pain and serious hepatobiliary toxicity, although follow-up is short in most series. On the other hand, a 2017 network analysis comparing various methods of hepatic arterial embolization concluded that TACE and DEB-TACE were associated with a similar risk of serious adverse effects.

Furthermore, the NCCN’s clinical practice guideline on “Hepatobiliary cancers” (Version 3.2019) notes that “DEB-TACE has also been evaluated in patients with unresectable HCC …. Malagari et al also showed that DEB-TACE resulted in higher response rates, lower recurrences, and longer TTP compared to TAE in patients with intermediate-state HHC; however, this study also did not show any OS benefit for DEB-TACE .... Golfieri et al compared DEB-TACE to conventional TACE in a randomized study of 177 patients with intermediate stage, unresectable, persistent, or recurrent HCC, and reported no significant efficacy or safety differences between the two approaches; however, DEB-TACE was associated with less post-procedural abdominal pain …. Dhanasekaran et al reported a survival advantage for DEB-TACE over conventional TACE in a prospective randomized study of 71 patients with unresectable HCC. However, these results need to be confirmed in large propsective studies.”

LIMITATIONS OF ALL STUDIES

The evidence supporting the techniques of bland embolization and DEB is limited for a number of reasons. First, there is only one example of a large randomized controlled study, and there are very few comparative studies with enough power to demonstrate the safety and efficacy of these techniques. Most of the studies addressing these technologies had short durations (6 months or less) and only included individuals with a Child-Pugh Class A or B, and excluded Class C, which is the most severe class of individuals. An important drawback that was found in many studies was the loss of individuals at each follow-up period, where data may have been skewed in order to show favorable outcomes. The literature for these studies does not establish the best candidates for either procedure per the various stratification factors (such as Child-Pugh Class, ECOG Performance Status, etc.). Furthermore, the superiority of these treatments compared to other locoregional options are still being investigated. As far as the devices themselves, there is a lack of evidence in designating the optimal diameter of the beads that should be used and the number of treatments each individual needs. For DEB specifically, there is also limited experience as to which chemotherapeutic agents should be used and what dose should be used. The need is present for long-term studies with outcomes that include rates of survival.

Bland embolization displays promising results in slowing the progression of liver tumors in the small population of individuals that was studied that had unresectable HCC or neuroendocrine tumors that metastasized to the liver. To date, the literature seems to demonstrate that the technique has been relatively safe in this group of individuals. Bland embolization may be an option for locoregional therapy in those individuals with unresectable HCC or neuroendocrine tumors that have metastasized to the liver.

The technique of c-TACE has been well-studied over the years and has long-term data on its safety and efficacy for use in unresectable liver metastasis. While the safety and efficacy of DEB are still being investigated, the short-term evidence displayed in these trials shows promising outcomes in safety and efficacy in those individuals with unresectable HCC. Comparative studies do not show a statistically significant difference between the survival outcomes of DEB and c-TACE, although some of the outcomes trended more favorably to DEB than c-TACE when post-hoc analysis and/or stratification were performed. However, these studies lacked uniformity because they included individuals who had no prior therapies, and, conversely, also included individuals who had prior therapies such as RFA, c-TACE, systemic chemotherapy, or immunotherapy. Therefore, for those individuals with unresectable HCC who have depleted their options of treatment, DEB may be an alternative to established therapies to achieve desired survival outcomes.

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Coding

CPT Procedure Code Number(s)

37243, 75894

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

C22.0 Liver cell carcinoma

C22.7 Other specified carcinomas of liver

C22.8 Malignant neoplasm of liver, primary, unspecified as to type

C22.1 Intrahepatic bile duct carcinoma

C22.9 Malignant neoplasm of liver, not specified as primary or secondary

C24.0 Malignant neoplasm of extrahepatic bile duct

C24.8 Malignant neoplasm of overlapping sites of biliary tract

C24.9 Malignant neoplasm of biliary tract, unspecified

C78.7 Secondary malignant neoplasm of liver and intrahepatic bile duct

C78.80 Secondary malignant neoplasm of unspecified digestive organ

C78.89 Secondary malignant neoplasm of other digestive organs

C7B.02 Secondary carcinoid tumors of liver

D01.5 Carcinoma in situ of liver, gallbladder and bile ducts

E34.0 Carcinoid syndrome

HCPCS Level II Code Number(s)

N/A

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Version Effective Date:

12/16/2019

Version Issued Date:

12/16/2019

Version Reissued Date:

10/19/2022