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Clinical Policy Title: Radioembolization and chemoembolization for liver cancer

and other indications

Clinical Policy Number: 05.02.08

Effective Date: February 1, 2016

Initial Review Date: November 18, 2015

Most Recent Review Date: February 6, 2018

Next Review Date: February 2019

Related policies:

None.

ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas’ clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of “medically necessary,” and the specific facts of the particular situation are considered by AmeriHealth Caritas when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas’ clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas’ clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas’ clinical policies are not guarantees of payment.

Coverage policy

AmeriHealth Caritas considers the use of radioembolization to be clinically proven and, therefore,

medically necessary to treat cancer in the liver in the following instances (Katsanos, 2017; Rathman,

2015; Memon, 2013; Bester, 2012; Lau, 2012; Coldwell, 2012; Sangro, 2011; Kosmider, 2011; Salem,

2010; Ibrahim, 2008):

Inoperable or unresectable primary hepatic cancer (i.e., hepatocellular carcinoma [HCC]).

Colorectal cancer with exclusively liver metastases.

Neuroendocrine tumors, such as octreotide-resistant carcinoid tumors or refractory

pancreatic neuroendocrine tumors (PNETs), which have spread to the liver.

Ocular melanoma that has spread to the liver when rendered in the context of an

investigational review board (IRB)-approved clinical trial protocol.

Cholangiocarcinoma (i.e., cholangiocellular carcinoma [CCC]) that has spread to the liver

when rendered in the context of an IRB-approved clinical trial protocol.

Liver tumors too large for surgery to shrink them to allow surgical removal.

Policy contains:

Transarterial embolization.

Radioembolization.

Chemoembolization.

Hepatocellular carcinoma.

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Cancers in the liver that cannot be removed surgically and are not responsive to systemic

chemotherapy.

Preoperative treatment of liver cancer prior to orthotopic liver transplant (OLT).

AmeriHealth Caritas considers the use of chemoembolization to be clinically proven and, therefore,

medically necessary to treat cancer in the liver in the following instances (Katsanos, 2017; Spreafico,

2015; Cohen, 2014; Gulec, 2013; Lencioni, 2013; Akahori, 2013; Cannon, 2012; Yang, 2012; Cao, 2012;

Kosmider, 2011; Tokh, 2010):

• Inoperable or unresectable primary hepatic cancer (i.e., HCC).

• Neuroendocrine tumors, such as octreotide-resistant carcinoid tumors or refractory PNETs,

which have spread to the liver.

• Gastrointestinal stromal tumors (GISTs) refractory to tyrosine kinase inhibitor therapy that

have spread to the liver.

• Ocular melanoma that has spread to the liver when rendered in the context of an IRB-

approved clinical trial protocol.

• Cholangiocarcinoma (i.e., CCC) that has spread to the liver when rendered in the context of

an IRB-approved clinical trial protocol.

• Preoperative treatment of liver cancer prior to OLT.

• Postoperative treatment of recurrent liver cancer after OLT.

Limitations:

AmeriHealth Caritas considers the use of radioembolization and chemoembolization to be

investigational and, therefore, not medically necessary in the following instances:

Ocular melanoma metastatic to liver and primary cholangiocarcinoma, except when part of

an IRB-approved clinical trial protocol.

Breast cancer, lung cancer, or other cancers, except as indicated above or when part of an

IRB-approved clinical trial protocol.

Tumors ≤ 3 cm are optimally treated with ablation. Lesions between 3 and 5 cm may be

treated using combination embolization and ablation as long as tumor location is favorable.

Unresectable/inoperable lesions > 5 cm should be treated using arterial embolic

approaches.

In patients with early stage HCC who are not candidates for liver resection or transplant,

radiofrequency ablation (RFA) is considered the best therapeutic choice.

RFA is the recommended procedure for ≥ three unresectable colorectal liver metastases

confined to the liver.

Neuroendocrine tumors have been shown to respond favorably to somatostatin analogs;

however, refractory disease may become apparent in time and require additional therapy

(e.g., RFA).

Note: The criteria of tumor > 5 cm or no more than three lesions in the liver are the indications for

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surgery for HCC and do not pertain to the treatments of radioembolization and chemoembolization

addressed by this policy.

Alternative covered services:

Surgical resection of liver cancer.

Liver transplantation.

Somatostatin-analog treatment of endocrine-active hepatic metastases.

Chemotherapy of liver cancer.

Radiotherapy of liver cancer.

Background

The American Cancer Society estimates there were 35,660 new cases (25,510 in men and 10,150 in

women) of primary liver cancer and intrahepatic bile duct cancer diagnosed in the United States in 2015.

An average man's lifetime risk of getting liver or intrahepatic bile duct cancer is about one in 81, while

an average woman's risk is about one in 196. Most cases occur in people with certain risk factors (male;

Asian or Pacific Island descent; use of anabolic steroids; cigarette smoking; prior hepatitis B or hepatitis

C infection; cirrhosis; obesity; diabetes mellitus; various inherited conditions, such as hereditary

hemochromatosis; and toxins such as aflatoxins, arsenic, and vinyl chloride). The average age at

diagnosis of liver cancer is 63 years.

Angiography of the hepatic circulation can be used to show the arteries that supply blood to a liver

cancer, which can help doctors plan treatment for liver cancer, and can also be used to guide some

types of non-surgical treatment, such as embolization (a procedure that injects substances to try to

block or reduce the blood flow to cancer cells in the liver). Angiography may be done with a

computerized tomography (CT) scanner (CT angiography) or a magnetic resonance imaging (MRI)

scanner (magnetic resonance [MR] angiography), instead of X-ray angiography, because they can give

information about the blood vessels in the liver without the need for a catheter in the artery.

Formal staging systems, such as the 2010 American Joint Committee on Cancer (AJCC) TNM system, are

helpful to get an idea about a patient's prognosis and to help determine the most appropriate

treatment. This staging system is based on the results of the physical exam, imaging, and other tests to

assess the patient for three key pieces of information: 1) T describes the number and size of the primary

tumors, measured in centimeters, and whether the cancer has grown into nearby blood vessels or

organs; 2) N describes the extent of the spread to nearby (regional) lymph nodes; and 3) M indicates

whether the cancer has metastasized to other parts of the body. But for treatment purposes, doctors

often classify liver cancers more simply, based on whether or not they can be entirely cut out (resected).

Potentially resectable or transplantable cancers are cancers that can be completely removed by surgery

or treated with liver transplant with a patient is healthy enough to tolerate the surgery. This would

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include patients who do not have cirrhosis or other serious medical problems. If all of the cancer in the

liver is successfully removed, the overall five-year survival rate is over 50 percent. For people with early-

stage liver cancers who have a liver transplant, the five-year survival rate is in the range of 60 percent –

70 percent. Unfortunately, only a small number of patients with liver cancer present in this group.

Inoperable with only local disease implies that the cancer is small enough and in the right place to be

removed, but the patient is not healthy enough for surgery (e.g., liver cancer in the presence of severe

cirrhosis) and surgery to remove the cancer might not leave enough liver to sustain life. Unresectable

cancers are those cancers that have not spread to the lymph nodes or distant organs, but cannot be

completely removed by surgery. This includes cancers that have grown throughout the liver such that

they cannot be safely removed due to proximity to the great vessels or bile ducts. There is potential for

use of embolization in the treatment of large unresectable cancers to reduce their size sufficiently to

make resection feasible.

Advanced (metastatic) cancers are those that have spread to lymph nodes or other organs. Most

advanced liver cancers cannot be successfully treated with surgery. Embolization is an option for some

patients with tumors that cannot be removed by surgery. It can be used for tumors that are too large

(usually larger than five centimeters across) to be treated with ablation (a treatment that kills tumor

cells without removing them).

Finally, there is the case of a primary tumor elsewhere that has metastasized to the liver (e.g., colorectal

cancer). When these metastases threaten liver function and life, it is possible to treat them with

selective arterial embolization and adjuvant intrahepatic radiotherapy or chemotherapy.

Embolization does reduce some of the blood supply to the normal liver tissue, so it may not be a good

option for those patients whose liver has been damaged by disease (i.e., hepatitis or cirrhosis). This type

of treatment typically does not require a hospital stay.

Searches

AmeriHealth Caritas searched PubMed and the databases of:

• UK National Health Services Center for Reviews and Dissemination.

• Agency for Healthcare Research and Quality’s National Guideline Clearinghouse and other

evidence-based practice centers.

• The Centers for Medicare & Medicaid Services (CMS).

We conducted searches on December 18, 2017. Search terms were: "radioembolization (MeSH),"

"chemoembolization (MeSH)," and "liver cancer."

We included:

• Systematic reviews, which pool results from multiple studies to achieve larger sample sizes

and greater precision of effect estimation than in smaller primary studies. Systematic

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reviews use predetermined transparent methods to minimize bias, effectively treating the

review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies.

• Guidelines based on systematic reviews.

• Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple

cost studies), reporting both costs and outcomes — sometimes referred to as efficiency

studies — which also rank near the top of evidence hierarchies.

Findings

Arterial embolization is also known as transarterial embolization (TAE). In this procedure, a catheter is

introduced into the femoral artery and threaded up into the hepatic artery in the liver. Once the

catheter is in place, small occlusive materials (e.g., Gel-foam® coil) are injected into the artery to plug it

up.

Radioembolization technique combines embolization with radiation therapy and is sometimes known as

transarterial radioembolization (TARE). In the United States, this is done by introducing small beads

called “microspheres” (i.e., TheraSphere® and SIR-Spheres®) that are embedded with a radioactive

isotope (yttrium-90 or Y-90) into the hepatic artery. The radio-infused beads lodge in the blood vessels

near the tumor, where they give off small amounts of radiation to the tumor site for several days. The

radiation travels a very short distance, so its effects are limited mainly to the tumor.

Radioembolization is used predominantly to treat cancer in the liver. The disease may take one of two

forms: 1) primary hepatic cancer (i.e., HCC); and 2) cancer that has metastasized to the liver from a

primary tumor elsewhere (e.g., colorectal cancer). Metastatic colorectal cancer to the liver and primary

HCC are the cancers most often considered for radioembolization treatment.

Lau (2012) reported the results of an expert panel convened to assess radioembolization as therapy for

HCC. The panel noted a number of variables in the outcome of treatment, such as the findings of

imaging of the tumor and its vasculature, tumor and uninvolved liver characteristics, previous therapies,

and localization of the microsphere infusion. There was consensus that radioembolization can improve

the clinical outcomes for selected patients with inoperable liver cancer.

In a systematic review of results from eight European medical centers, Sangro (2011) found that

radioembolization was effective in increasing survival of advanced HCC, demonstrating a median overall

survival of 12.8 months. The authors noted that survival varied significantly by functional status, hepatic

function, tumor burden (number of nodules), and the presence or absence of extrahepatic disease.

Common adverse events were fatigue, nausea, vomiting, and abdominal pain.

In a large randomized controlled trial (RCT) of 291 patients, Salem (2010) administered 526

radioembolization treatments (range one to five) to patients with HCC with response rates of 42 percent

– 57 percent and overall time to progression of 7.9 months. Within this group were a limited number (n

= 56) of patients with portal vein thrombosis whose survival was only 5.6 months.

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Radioembolization has also been used for other forms of cancer affecting the liver, such as 1)

cholangiocarcinoma; 2) breast cancer with solely liver metastasis; 3) neuroendocrine tumors, such as

carcinoid tumors, that have spread to the liver; and 4) gastrointestinal sarcoma, a stromal tumor of the

gut also known as GIST.

A pilot study analyzing the use of Y-90 in 24 patients with biopsy-proven intrahepatic

cholangiocarcinoma (ICC) showed a favorable response to treatment and survival outcomes (Ibrahim,

2008). Imaging follow-up of the study cohort demonstrated partial response in 27 percent, stable

disease in 68 percent, and progression in 5 percent. Most patients (77 percent) showed > 50 percent

tumor necrosis. Median overall survival was 14.9 months. Portal vein thrombosis was noted as a

particularly ominous predictive factor, with patients achieving only 5.7 months of survival.

An ongoing, open clinical trial (Pitton, 2013) comparing selective internal radiotherapy (SIRT) versus

transarterial chemoembolization with drug-eluting beads (DEBs) for the treatment of

cholangiocarcinoma has not yet posted results. A second clinical trial (Leyvraz, 2013), also open to

enrollment, is comparing systemic sorafenib (an anti-angiogenic agent) versus radioembolizatoin with

Sir-Spheres® in the treatment of ocular melanoma.

Radioembolization for breast cancer metastases to liver (Coldwell, 2012) was evaluated in a narrative

review, citing evidence to support the use of radioembolization in liver metastases from neuroendocrine

and breast cancers. The authors also noted a number of other tumors (e.g., melanoma, lung) with

similar radiobiologic profiles who may respond to this treatment. They noted sufficient liver functional

reserve and good patient performance status in the absence of significant comorbidity was essential for

success. Radioembolization was encouraged in patients showing progression of liver metastases during

treatment hiatus, in tumors that respond poorly to chemotherapy or in treatment-refractory disease.

A systematic review (Yang, 2012) of 37 RCTs inclusive of 1,575 patients examined the use of

radioembolization versus chemoembolization for unresectable neuroendocrine tumor liver metastases

(NETLM). The review examined the efficacy and safety of the use of hepatic arterial chemoembolization,

simple embolization, and radioembolization, and found comparable outcomes for all therapies with

regard to response to treatment, survival, and toxicity. The authors noted that carcinoid had a

particularly high response rate of 67 percent versus 35 percent overall, and concluded these therapies

are safe and effective in the treatment of NETLM.

A small series looked at the impact of radioembolization for GIST metastases to the peritoneum and the

liver in 11 patients failing tyrosine kinase inhibitor (TKI) therapy (Rathman, 2015). Following

radioembolization, three patients showed complete response, five showed partial response, and one

showed stable disease. No patient showed progressive disease after radioembolization. Median survival

was 29.8 months (range, 10 – 72 months). The authors concluded that radioembolization is a safe and

effective therapy for patients with GIST liver metastases, and offered their results as a challenge to the

prevailing notion that GISTs are resistant to radiation therapy.

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Radioembolization is often used in coordination with more well-established cancer treatments, such as

surgery and chemotherapy: 1) radioembolization may be used on liver tumors too large for surgery to

shrink them to allow surgical removal, and 2) chemotherapy and radioembolization may be provided in

combination to maximize the destruction of cancer cells.

In an RCT inclusive of 24 patients with advanced unresectable liver cancer or colorectal cancer

metastases to liver, Cohen (2014) documented the pharmacokinetics of capecitabine in combination

with radioembolization. Radioembolization with Y-90 resin microspheres was administered using a

sequential lobar approach with two cycles of capecitabine. The authors noted a partial response in four

patients (16.7 percent), stable disease in 17 (70.8 percent), and progression in three (12.5 percent).

Median time to progression and overall survival of the metastatic colorectal cancer cohort was 6.4 and

8.1 months, respectively.

Gulec (2013) compared radioembolization with selective arterial chemotherapy versus systemic

chemotherapy for hepatic colorectal cancer metastases. Treatment was administered with Y-90

microspheres and with contemporary standard chemotherapy for colorectal metastases to the liver.

Response to treatment was evaluated by serial fludeoxyglucose positron emission tomography and

computed tomography performed at four weeks, two to four months, and six to eight months. A

decrease in tumor size was seen in 19 of the 20 patients; however, the reduction of tumor size in the

radioembolization with selective arterial chemotherapy group was markedly greater. The authors

concluded that the chemo-radio combination produced superior objective responses compared with

systemic chemo-only treatment in a front-line treatment setting of patients with colorectal cancer liver

metastases.

A narrative review (Memon, 2013) reported on radioembolization employed for treating patients with

unresectable HCC. The authors opined that this technique has proven useful for the majority of patients

with HCC as most of them present in advanced stage, beyond potentially curative options

(resection/liver transplantation). They also noted that radioembolization can be used in downstaging

large tumors to bring them within transplantable criteria, in patients with portal venous thrombosis due

to tumor invasion, and as palliative therapy.

Kosmider (2011) reported a series of 19 patients with unresectable liver metastases from colorectal

cancer treated with radioembolization and chemotherapy. Most (74 percent) had metastatic disease

confined to the liver. Concurrent treatment with 5-fluorourail/leucovorin (n = 7) or 5-

fluorourail/leucovorin/oxaliplatin (FOLFOX; n = 12) was started three to four days before a single

radioembolization treatment. Overall response was 84 percent. Median progression-free survival time

was 10.4 months and median overall survival time was 29.4 months.

Radioembolization can also be a treatment option for cancers in the liver that can’t be removed

surgically and are not responsive to chemotherapy. Bester (2012) retrospectively evaluated the safety

and survival of 339 patients with chemotherapy-refractory liver metastases treated with Y-90. The

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median overall survival after radioembolization was 12.0 months, versus 6.3 months for a standard-care

cohort (n = 51). At three months of follow-up, the incidence of serious adverse events was low. The

authors concluded that radioembolization is an effective and safe treatment for patients with

chemotherapy-refractory hepatic metastases and improves overall survival in a select population of

patients.

Radioembolization is generally only considered as treatment for cancers whose spread is limited to the

liver. Radioembolization is contraindicated in patients with severe liver disease where diminished

hepatic circulation may precipitate hepatic failure, and in patients with abnormal blood flow between

the liver and lungs (i.e., acquired arteriovenous malformation or shunting).

Chemoembolization, also known as transarterial chemoembolization (TACE), combines embolization

with chemotherapy. Specifically, the technique permits dearterialization of the tumor and selective

delivery of chemotherapeutic agents into the tumor's feeding vessels during angiography. Most often,

this is done by using tiny beads that give off a chemotherapy drug for the embolization. TACE can also

be done by giving chemotherapy through the catheter directly into the artery, and then plugging up the

artery. Tumor ischemia raises the drug concentration compared to infusion alone and extends the

retention of the chemotherapeutic drug.

Spreafico (2015) evaluated the short-term safety and effectiveness of the new generation of 70-150 µm

DEBs (M1 DEB) in patients with hepatocellular carcinoma undergoing TACE as a primary therapy or as a

bridge to liver transplantation. A total of 45 consecutive patients underwent TACE with M1 DEB loaded

with doxorubicin (DEBDOX/M1). The mean number of TACE procedures per patient was 1.4. The

objective response rate was 77.7 percent with a median time to best response of three months. In 13

patients, DEBDOX/M1 TACE served as a bridge/down-staging to hepatectomy or liver transplantation.

The authors concluded that DEBDOX/M1 TACE is an effective modality of treatment with promising

results in objective response rate and tumor down-staging.

In a narrative review, Lencioni (2013) stated that TACE is the current standard of care for patients with

HCC and relatively preserved liver function, absence of cancer-related symptoms, and no evidence of

vascular invasion or extrahepatic spread. TACE may also be offered to patients with early-stage HCC

when surgical options or percutaneous ablation are precluded. The authors noted that in conventional

TACE, the administration of the anticancer-in-oil emulsion is followed by mechanical embolization with

either a spherical or a nonspherical embolic agent, but there is no consensus on the optimal

chemotherapeutic agents to use. Worldwide, the most popular anticancer drug for TACE of HCC is

doxorubicin. On the frequency of therapy, the authors noted that no randomized trials have been

designed to evaluate the optimal frequency of therapy; and that the safety and effectiveness of more

than four TACE procedures are unknown.

Cannon (2012) assessed the safety and effectiveness of chemoembolization with DEBDOX in the

treatment of multi-nodular (greater than or equal to 10 lesions) HCC. At 12 months, a group of 42

patients with multi-nodular disease showed a response rate of 56 percent and median overall survival of

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7.6 months. The authors concluded that DEBDOX treatment is safe and effective when compared to

historical controls and the current best systemic therapy for multi-nodular HCC.

In a narrative review of treatments for HCC, Biolato (2010) wrote “… as locoregional therapy, TACE

allows complete local tumor control of 25 percent – 35 percent and permits an increase of survival in

patients with HCC.” The authors also noted that percutaneous ethanol injection or radio frequency

ablation as neoadjuvant therapy prior to hepatectomy or transplantation was beneficial. The authors

cited DEBs loaded with doxorubicin and sorafenib as a further refinement of interest and recommended

their continued investigation. The authors concluded that TACE is the standard of care for treatment of

unresectable HCC.

Tokh (2010) assessed the safety, efficacy, and survival among 63 patients with unresectable HCC treated

with beads loaded with doxorubicin (DOX). Median tumor size was 4.8 cm (range of 2 – 12 centimeters).

Overall, 81 percent showed tumor regression and alpha-feto protein (AFP) decreased in 79 percent of

patients with elevated levels, with a median fall of 78.5 percent. Actuarial survival was 18.2 months,

leading the authors to conclude that treatment of HCC using DEBDOX is at least equivalent, with milder

toxicity, to conventional TACE.

An RCT of 28 patients with unresectable recurrent HCC following OLT randomized patients to lobaplatin-

based chemoembolization or supportive care to assess response and survival (Zhou, 2010). Eight of the

14 patients in the chemoembolization group (57 percent) showed partial tumor response (> 30 percent

reduction in tumor size), with significantly longer overall survival compared to those who did not. No

severe complications developed during follow-up in patients receiving chemoembolization.

Chemoembolization has been successfully used as a palliative treatment of symptoms associated with

functioning neuroendocrine tumors (i.e., carcinoid tumors) involving the liver. It has also been used in

metastases to liver from GIST, and from PNETs that produce gastrin, insulin, or other pancreatic

hormones.

Gupta (2003) retrospectively studied the outcomes of 81 patients with systemic chemotherapy-resistant

carcinoid metastases to liver when treated with hepatic artery embolization or chemoembolization by

evaluating the clinical and radiologic response rates, duration of response, and progression-free and

overall survival rates of these patients. Fifty patients were treated with bland hepatic artery

embolization, and 31 underwent chemoembolization. Of the 69 patients in whom radiologic response

could be evaluated, partial response was observed in 46 patients (67 percent), minimal response in six

(8.7 percent), stable disease in 11 (16 percent), and progressive disease in six (8.7 percent). The median

duration of response in the 42 patients with partial response was 17 months (range, four – 51 months).

Sixty-three percent of patients had a reduction in their tumor-related symptoms. The median

progression-free survival duration was 19 months (95 percent confidence interval, 17 – 21 months); the

probability of progression-free survival was 75 percent, 35 percent, and 11 percent at one, two, and

three years, respectively. The median overall survival time was 31 months (95 percent confidence

interval, 23 – 38 months); the survival probability was 93 percent at one year, 62 percent at two years,

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and 24 percent at five years.

Cao (2012) evaluated the efficacy and safety of TACE for GIST with liver metastases after the failure of

TKI therapy. Sixty patients who were resistant and/or intolerant to prior imatinib and/or sunitinib were

eligible for the study. The patients were divided into two groups: those in the TACE group (n = 22)

received TACE treatment containing 5 – 20 mL iodized oil and 40 – 80 mg doxorubicin hydrochloride and

TKI reintroduction or best supportive care, and those in control group (n = 38) only received TKI

reintroduction or best supportive care. In the TACE group, 12 patients (54.5 percent) achieved liver

partial response, five patients (22.7 percent) had stable disease, and five patients (22.7 percent) had

progressive disease. Disease control rate of liver metastases was 77.3 percent in the TACE group and

39.5 percent in the control group. The median overall survival in TACE group was also longer than in

control group (68.5 weeks, 95 percent confidence interval [CI]: 57.4 – 79.6 versus 25.7 weeks, 95

percent CI: 23.2 – 28.2) (P = 0.0001). TACE treatment significantly reduced the risk of death (hazard

ratio: 0.109). Patients without extrahepatic metastases treated with TACE had significantly better

prognosis. The authors concluded that TACE is effective and well tolerated in GIST patients with liver

metastases after TKI failure, and it may be an optional treatment for this disease.

Akahori (2013) reported the use of TACE to treat hepatic metastases of PNETs. The authors

administered cisplatin to unresectable PNET metastases with a total of 24 treatments in a small series of

five patients. There was one complete response, three partial responses and one patient whose disease

remained stable over the course of treatment and follow-up. Median survival of 36 months was

achieved without severe toxicity or adverse effect.

A clinical trial of chemoembolization with DEBs versus radioembolization for intrahepatic CCC is

currently recruiting participants at Johannes Gutenberg University Mainz (Pitton, 2013). No results have

been posted.

A systematic review and meta-analysis (Glantzounis, 2016), inclusive of 40 articles and 2,144 patients,

studied portal vein embolization (PVE) in patients with inadequate functional liver reserve (FLR) and

found evidence that the practice before major hepatectomy allows resection of advanced primary

hepato-biliary tumors with good long-term survival.

Policy updates:

A systematic review and meta-analysis (Glantzounis 2016) inclusive of 40 articles and 2144 patients

studied PVE in patients with inadequate functional liver reserve (FLR) and found evidence that the

practice before major hepatectomy allows resection of advanced primary hepato-biliary tumors with

good long term survival.

During the past twelve months there has been further information published regarding radio- and

chewmoembolization for cancer.

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A systematic review and network meta-analysis (Katsanos 2017) of different embolization options for

unresectable hepatocellular carcinoma evaluated bland transarterial embolization , conventional

transarterial chemoembolization, drug-eluting beads -transarterial chemoembolization, and transarterial

radioembolization, either alone or combined with adjuvant chemotherapy, local liver ablation, or

external radiotherapy for unresectable hepatocellular carcinoma (n = 5,763 patients). The primary

endpoint was patient survival expressed as hazard ratios and 95 percent credible intervals. Safety and

objective response were calculated as odds ratios and accompanying 95 percent credible intervals. All

embolization strategies achieved a significant survival gain over control treatment (hazard ratio range,

0.42 – 0.76; very low-to-moderate quality of evidence). However, transarterial chemoembolization,

drug-eluting beads -transarterial chemoembolization, transarterial radioembolization, and adjuvant

systemic agents did not confer any survival benefit over bland transarterial embolization alone

(moderate evidence, except low in the case of transarterial radioembolization). There was moderate

evidence that transarterial chemoembolization combined with external radiation or liver ablation

achieved the best patient survival. Estimated median survival was 13.9 months in control, 18.1 months

in transarterial chemoembolization, 20.6 months with drug-eluting beads-transarterial

chemoembolization, 20.8 months with bland transarterial embolization, 30.1 months in transarterial

chemoembolization plus external radiotherapy, and 33.3 months in transarterial chemoembolization

plus liver ablation. Transarterial radioembolization was the safest treatment; however, all examined

therapies were associated with a significantly higher risk of toxicity over control (odds ratio range, 6.35

to 68.5). Transarterial chemoembolization, drug-eluting beads--transarterial chemoembolization,

transarterial radioembolization, and adjuvant systemic agents did not improve objective response over

bland embolization alone (odds ratio range, 0.85 to 1.65). There was clinical diversity among included

randomized controlled trials, but statistical heterogeneity was low.

Summary of clinical evidence:

Citation Content, Methods, Recommendations

Katsanos (2017)

Comparative effectiveness of

different transarterial

embolization therapies alone or

in combination with local

ablative or adjuvant systemic

treatments for unresectable

hepatocellular carcinoma: a

network meta-analysis of RCTs

Key points:

Systematic review and network meta-analysis of different embolization

options for unresectable hepatocellular carcinoma evaluated bland TAE,

conventional TACE, DEB-TACE, or TARE, either alone or combined with

adjuvant chemotherapy, local liver ablation, or external radiotherapy for

unresectable hepatocellular carcinoma (n = 5,763 patients).

Primary endpoint was patient survival expressed as HR and 95% credible

intervals.

Safety and objective response were calculated as OR and accompanying

95% credible intervals.

All embolization strategies achieved a significant survival gain over control

treatment (HR range, 0.42 – 0.76; very low-to-moderate quality of evidence).

However, TACE, DEB-TACE, TARE, and adjuvant systemic agents did not

confer any survival benefit over bland TAE alone (moderate evidence, except

low in case of TARE).

Estimated median survival was 13.9 months in control, 18.1 months in TACE,

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Citation Content, Methods, Recommendations

20.6 months with DEB-TACE, 20.8 months with bland TAE, 30.1 months in

TACE plus external radiotherapy, and 33.3 months in TACE plus liver

ablation.

TARE was the safest treatment; however, all examined therapies were

associated with a significantly higher risk of toxicity over control (OR range,

6.35 to 68.5). TACE, DEB-TACE, TARE, and adjuvant systemic agents did

not improve objective response over bland embolization alone (OR range,

0.85 to 1.65).

There was clinical diversity among included RCTs, but statistical

heterogeneity was low.

Glantzounis (2016)

Role of PVE in the surgical

management of primary

hepatobiliary cancers

Key points:

Systematic meta-analysis inclusive of 40 articles and 2,144 patients reviewed

indications for PVE in patients with inadequate FLR and analyzed other

parameters such as resection rate, morbidity, mortality, survival after PVE

and hepatectomy for primary hepatobiliary tumors.

Participants’ median age was 61 years.

The median excision rate was 90% for HCCs and 86% for hilar

cholangiocarcinomas.

The main indications for PVE in patients with HCC and presence of liver

fibrosis or cirrhosis was FLR < 40% when liver function was good; FLR < 50%

when liver function was impaired.

The combination of TACE and PVE increased hypertrophy rate and was

associated with better overall survival and disease free survival.

The authors concluded that PVE before major hepatectomy allows resection

in a patient group with advanced primary hepato-biliary tumors and

inadequate FLR, with good long-term survival.

Spreafico (2015)

Transarterial

chemoembolization for

hepatocellular carcinoma with

a new generation of beads:

clinical-radiological outcomes

and safety profile

Key points:

Evaluated the short-term safety and effectiveness of the new generation of 70

– 150 µm M1 DEB.

Objective response rate was 77.7% with a median time to best response of

three months.

In 13 patients, DEBDOX/M1 TACE served as a bridge/down-staging to

hepatectomy or liver transplantation.

Rathman (2015)

Radioembolization in patients

with progressive

gastrointestinal stromal tumor

liver metastases undergoing

treatment with tyrosine kinase

inhibitors

Key points:

Impact of radioembolization for GIST metastases in 11 patients failing TKI

therapy.

No patient showed progressive disease after radioembolization.

Median survival was 29.8 months (range, 10 – 72 months).

Cohen (2014)

Phase I study of capecitabine

combined with

Key points:

RCT inclusive of 24 patients with advanced unresectable liver cancer or

colorectal cancer metastases to liver.

13

Citation Content, Methods, Recommendations

radioembolization using

yttrium-90 resin microspheres

(SIR-Spheres) in patients with

advanced cancer

There was partial response in four patients (16.7%), stable disease in 17

patients (70.8%) and progression in three patients (12.5%).

Median time to progression and overall survival of the metastatic colorectal

cancer cohort was 6.4 and 8.1 months, respectively.

Gulec (2013)

Yttrium-90 microsphere-

selective internal radiation

therapy with chemotherapy

(chemo-SIRT) for colorectal

cancer liver metastases: an in

vivo double-arm-controlled

phase II trial

Key points:

Compared radioembolization with chemotherapy versus systemic

chemotherapy for hepatic colorectal cancer metastases.

Reduction of tumor size in the radioembolization with selective arterial

chemotherapy group was markedly greater.

Memon (2013)

Yttrium 90 microspheres for

the treatment of HCC

Key points:

Narrative review on radioembolization employed for treating patients with

unresectable HCC.

The authors opined that this technique has proven useful for the majority of

patients with HCC.

Noted that radioembolization can be used in downstaging large tumors to

bring them within transplantable criteria.

Lencioni (2013)

Chemoembolization of HCC

Key points:

Narrative review stated TACE is the current standard of care for patients with

HCC and relatively preserved liver function, absence of cancer-related

symptoms, and no evidence of vascular invasion or extrahepatic spread.

There is no consensus on the optimal chemotherapeutic agent(s) to use, but

worldwide the most popular is DOX.

No randomized trials have been designed to evaluate the optimal frequency

of therapy.

Akahori (2013)

Significant efficacy of new

transcatheter arterial

chemoembolization technique

for hepatic metastases of

pancreatic neuroendocrine

tumors

Key points:

Reported the use of TACE to treat hepatic metastases of PNETs.

Administered cisplatin to unresectable PNET metastases with a total of 24

treatments in a small series of five patients.

There was one complete response, three partial responses, and one patient

with stable disease.

Median survival of 36 months was achieved.

Pitton (2013)

SIRT versus TACE for the

treatment of CCC

Key points:

Open study comparing SIRT versus TACE with DEBs for the treatment of

intrahepatic CCC.

No study results posted.

Leyvraz (2013)

Sorafenib and

radioembolization with Sir-

Key points:

Open study evaluating chemotherapeutic agent sorafenib and

14

Citation Content, Methods, Recommendations

Spheres® for the treatment of

metastatic ocular melanoma

radioembolization with Sir-Spheres® for the treatment of metastatic ocular

melanoma.

No study results posted.

Cannon (2012)

Management of diffuse

hepatocellular carcinoma (≧

10 lesions) with DOX-loaded

DC beads is a safe and

effective treatment option

Key points:

Assessed safety and effectiveness of DEBDOX in the treatment of multi-

nodular HCC.

42 patients with multi-nodular disease showed a response rate of 56% and

median overall survival of 7.6 months.

Bester (2012)

Radioembolization versus

standard care of hepatic

metastases: comparative

retrospective cohort study of

survival outcomes and adverse

events in salvage patients

Key points:

Evaluated the safety and survival of chemotherapy-refractory liver metastases

treated with Y-90.

The median overall survival after radioembolization was 12.0 months, versus

6.3 months for a standard-care cohort (n = 51).

Lau (2012)

Patient selection and activity

planning guide for SIRT with

yttrium-90 resin microspheres

Key points:

Expert panel convened to assess radioembolization as therapy for HCC.

Consensus that radioembolization can improve the clinical outcomes for

selected patients with inoperable liver cancer.

Yang (2012)

Radioembolization and

chemoembolization for

unresectable neuroendocrine

liver metastases — a

systematic review

Key points:

Systematic review of 37 RCTs inclusive of 1,575 patients examined

radioembolization versus chemoembolization for unresectable NETLM.

Carcinoid had a particularly high response rate of 67% versus 35% overall.

Cao (2012)

Transcatheter arterial

chemoembolization for

gastrointestinal stromal tumors

with liver metastases

Key points:

Evaluated TACE for GIST with liver metastases after the failure of TKIs in 60

patients, who were resistant and/or intolerant to prior imatinib and/or sunitinib.

Twelve (54.5%) patients achieved liver partial response, five patients (22.7%)

had stable disease, and five patients (22.7%) had progressive disease.

Median overall survival of 12.8 months.

Coldwell (2012)

Radioembolization in the

treatment of unresectable liver

tumors: experience across a

range of primary cancers

Key points:

Presented evidence to support the use of radioembolizatoin in liver

metastases from neuroendocrine and breast cancers.

The narrative review noted a number of other tumors (e.g., melanoma, lung)

with similar radiobiologic profiles who may respond to this treatment.

Radioembolization was advocated in patients showing progression of liver

metastases during treatment hiatus, in tumors that respond poorly to

chemotherapy, or in treatment-refractory disease.

15

Citation Content, Methods, Recommendations

Sangro (2011)

European Network on

Radioembolization with yttrium-

90 resin microspheres (ENRY)

(2011), survival after yttrium-90

resin microsphere

radioembolization of HCC

across Barcelona clinic liver

cancer stages: a European

evaluation

Key points:

Systematic review of radioembolization from eight European medical centers.

Survival varied significantly by functional status, hepatic function, tumor

burden (number of nodules), and presence or absence of extrahepatic

disease.

Kosmider (2011)

Radioembolization in

combination with systemic

chemotherapy as first-line

therapy for liver metastases

from colorectal cancer

Key points:

Series of 19 patients with unresectable liver metastases from colorectal

cancer were treated with radioembolization and chemotherapy.

Overall response was 84%.

Median progression-free survival time was 10.4 months and median overall

survival time was 29.4 months.

Biolato (2010)

TACE for unresectable HCC: a

new life begins?

Key points:

Wrote “…as locoregional therapy, TACE allows complete local tumor control

of 25% – 35% and permits an increase of survival in patients with HCC.”

The authors concluded that TACE is the standard of care for treatment of

unresectable HCC.

Tokh (2010)

TACE with DEB in HCC: a

large single-institution

experience

Key points:

Series of 63 patients with unresectable HCC treated with beads loaded with

DOX.

81% showed tumor regression, and AFP decreased in 79% of patients.

Actuarial survival was 18.2 months.

Zhou (2010)

Chemoembolization with

lobaplatin mixed with iodized

oil for unresectable recurrent

hepatocellular carcinoma after

orthotopic liver transplantation

Key points:

RCT of 28 patients with unresectable recurrent HCC following OLT

randomized to lobaplatin-based chemoembolization or supportive care.

57% showed partial tumor response (> 30 percent reduction in tumor size)

with significantly longer overall survival.

Salem (2010)

Radioembolization for HCC

using yttrium-90 microspheres:

a comprehensive report of

long-term outcomes

Key points:

RCT of 291 patients administered HCC radioembolization treatment.

Response rates of 42% – 57% and overall time to progression of 7.9 months.

Ibrahim (2008)

Treatment of unresectable

cholangiocarcinoma using

Key points:

Pilot study of yttrium-90 in 24 patients with ICC.

Partial response in 27%, stable disease in 68%, and progression in 5%.

16

Citation Content, Methods, Recommendations

yttrium-90 microspheres:

results from a pilot study

Median overall survival was 14.9 months.

References

Professional society guidelines/other:

American Cancer Society. Cancer Facts & Figures 2015. Atlanta, Ga: American Cancer Society; 2015.

American Joint Committee on Cancer. Liver. In: AJCC Cancer Staging Manual. 7th ed. New York, NY:

Springer; 2010:191 – 195.

Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2013. National Cancer

Institute. Bethesda, MD, 2016.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary

Cancers. V.2.2014. Web site. www.nccn.org. Accessed December 22, 2017.

Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients

(SRTR). OPTN / SRTR 2012 Annual Data Report: liver. Rockville, MD: Department of Health and Human

Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of

Transplantation; 2012. Website.

http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/03_liver_13.pdf. Accessed December 22, 2017.

United States Department of Health and Human Services. The Health Consequences of Smoking — 50

Years of Progress. A Report of the Surgeon General. Website.

http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf Accessed

December 22, 2017.

Peer-reviewed references:

Akahori T, Sho M, Tanaka T, et al. Significant efficacy of new transcatheter arterial chemoembolization

technique for hepatic metastases of pancreatic neuroendocrine tumors. Anticancer Res. 2013

Aug;33(8):3355 – 8.

Asnacios A, Fartoux L, Romano O, et al. Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab

in patients with progressive advanced stage hepatocellular carcinoma: Results of a multicenter phase 2

study. Cancer. 2008;112:2733 – 2739.

Bartlett DL, DiBisceglie AM, Dawson LA. Cancer of the liver. In: DeVita VT, Lawrence TS, Rosenberg SA,

eds. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia,

17

Pa: Lippincott Williams & Wilkins; 2011:997 – 1018.

Bester L, Meteling B, Pocock N, Pavlakis N, Chua TC, Saxena A, et al. Radioembolization versus standard

care of hepatic metastases: comparative retrospective cohort study of survival outcomes and adverse

events in salvage patients. J Vasc Interv Radiol 2012;23:96 – 105.

Biolato M, Marrone G, Racco S, et al. Transarterial chemoembolization (TACE) for unresectable HCC: A

new life begins? Eur Rev Med Pharmacol Sci. 2010;14(4):356 – 362.

Brandi G, de Rosa F, Agostini V, et al. Metronomic capecitabine in advanced hepatocellular carcinoma

patients: a phase II study. Oncologist. 2013;18(12):1256 – 7.

Bruix J, Tak WY, Gasbarrini A, et al. Regorafenib as second-line therapy for intermediate or advanced

hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer. 2013;49(16):3412

– 9.

Cannon RM, Urbano J, Kralj I, et al. Management of diffuse hepatocellular carcinoma (≧ 10 Lesions) with

doxorubicin-loaded DC beads is a safe and effective treatment option. Onkologie. 2012;35(4):184 – 188.

Cao G, Li J, Shen L, Zhu X. Transcatheter arterial chemoembolization for gastrointestinal stromal tumors

with liver metastases. World J Gastroenterol. 2012 Nov 14;18(42):6134 – 40.

Cohen SJ, Konski AA, Putnam S, et al. Phase I study of capecitabine combined with radioembolization

using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer. Br J Cancer.

2014;111(2):265 – 271.

Coldwell D Sangro B, Salem R, Wasan H, Kennedy A. Radioembolization in the treatment of unresectable

liver tumors: experience across a range of primary cancers. Am J Clin Oncol. 2012;35(2):167 – 77.

El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118 – 1127.

Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245 – 1255.

Glantzounis GK, Tokidis E, Basourakos SP, Ntzani EE, Lianos GD, Pentheroudakis G. The role of portal

vein embolization in the surgical management of primary hepatobiliary cancers. A systematic review.

Eur J Surg Oncol. 2016;0748-7983(16):30177-9.

Graf H, Jüngst C, Straub G, et al. Chemoembolization combined with pravastatin improves survival in

patients with hepatocellular carcinoma. Digestion. 2008;78:34 – 38.

Gulec SA , Pennington K, Wheeler J, et al. Yttrium-90 microsphere-selective internal radiation therapy

with chemotherapy (chemo-SIRT) for colorectal cancer liver metastases: an in vivo double-arm-

18

controlled phase II trial. Am J Clin Oncol. 2013 Oct;36(5):455 – 60.

Hassan MM, Spitz MR, Thomas MB, et al. Effect of different types of smoking and synergism with

hepatitis C virus on risk of hepatocellular carcinoma in American men and women: Case-control study.

Int J Cancer. 2008;123:1883 – 1891.

Heo J, Reid T, Ruo L, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic

vaccinia JX-594 in liver cancer. Nat Med. 2013 Mar;19(3):329 – 336.

Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in

hepatocellular carcinoma. N Engl J Med. 2008;359:1995 – 2004.

Ibrahim S, Mulcahy M, Lewndowski R, et al. Treatment of unresectable cholangiocarcinoma using

yttrium-90 microspheres: results from a pilot study. Cancer 2008:113:2119 – 28.

Ishizuka M, Kubota K, Shimoda M, Kita J, Kato M, Park KH, Shiraki T. Effect of menatetrenone, a vitamin

k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized

controlled trial. Anticancer Res. 2012;32(12):5415 – 5420.

Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Canc J Clin. 2011;61:69 – 90.

Katsanos K, Kitrou P, Spiliopoulos S, Maroulis I, Petsas T, Karnabatidis D. Comparative effectiveness of

different transarterial embolization therapies alone or in combination with local ablative or adjuvant

systemic treatments for unresectable hepatocellular carcinoma: A network meta-analysis of randomized

controlled trials. PLoS One. 2017 Sep 21;12(9):e0184597. doi: 10.1371/journal.pone.0184597. Collection

2017. Review. PubMed PMID: 28934265; PubMed Central PMCID: PMC5608206.

Kosmider S, Tan TH, Yip D, Dowling R, Lichtenstein M, Gibbs P.Radioembolization in combination with

systemic chemotherapy as first-line therapy for liver metastases from colorectal cancer. J Vasc Interv

Radiol. 2011;22(6):780 – 6.

Lau W, Kennedy A, Kim Y, et al. Patient Selection and Activity Planning Guide for Selective Internal

Radiotherapy With Yttrium-90 Resin Microspheres. Int J Rad Onc Biol Phys 2012;82(1):401 – 407

Lencioni R, Chen XP, Dagher L, Venook AP. Treatment of intermediate/advanced hepatocellular

carcinoma in the clinic: How can outcomes be improved? Oncologist. 2010;15(suppl 4):42 – 52.

Lencioni R, Crocetti L. Local-regional treatment of hepatocellular carcinoma. Radiology. 2012;262:43 –

58.

Lencioni R, Petruzzi P, Crocetti L. Chemoembolization of hepatocellular carcinoma. Semin Intervent

Radiol. 2013;30(1):3 – 11.

19

Lewandowski RJ, Geschwind JF, Liapi E, Salem R. Transcatheter intraarterial therapies: Rationale and

overview. Radiology. 2011;259:641 – 657.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.

2008;359:378 –390.

Memon K, Lewandowski RJ, Riaz A, Salem R. Yttrium 90 microspheres for the treatment of

hepatocellular carcinoma. Recent Results Cancer Res. 2013;190:207 – 24.

Miyake Y, Kobashi H, Yamamoto K. Meta-analysis: The effect of interferon on development of

hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Gastroenterol.

2009;44:470 – 475.

Onaca N, Davis GL, Jennings LW, Goldstein RM, Klintmalm GB. Improved results of transplantation for

hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver

Transplantation. Liver Transpl. 2009;15(6):574 – 80.

Rathmann N, Diehl SJ, Dinter D, et al. Radioembolization in patients with progressive gastrointestinal

stromal tumor liver metastases undergoing treatment with tyrosine kinase inhibitors. J Vasc Interv

Radiol. 2015;26(2):231 – 8.

Salem R, Lewandowski R, Mulcahy M, et al. Radioembolization for Hepatocellular Carcinoma Using

Yttrium-90 Microspheres: A Comprehensive Report of Long-term Outcomes. Imaging and Advanced

Technology. 2010;138(1), 52 – 64.

Samuel M, Chow PK, Chan Shih-Yen E, Machin D, Soo KC. Neoadjuvant and adjuvant therapy for surgical

resection of hepatocellular carcinoma. Cochrane Database Syst Rev. 2009;(1):CD001199.

Sangro B, Carpanese L, Cianni R, et al. European Network on Radioembolization with Yttrium-90 Resin

Microspheres (ENRY) (2011), Survival after yttrium-90 resin microsphere radioembolization of

hepatocellular carcinoma across Barcelona clinic liver cancer stages: A European evaluation. Hepatology,

54: 868 – 878.

Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular

carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14(1):55 – 63.

Shen Q, Fan J, Yang XR, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular

carcinoma: a large-scale, multicentre study. Lancet Oncol. 2012;13(8):817 – 826.

Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of

bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26:2992 – 2998.

20

Spreafico C, Cascella T, Facciorusso A, et al. Transarterial chemoembolization for hepatocellular

carcinoma with a new generation of beads: Clinical-radiological outcomes and safety profile. Cardiovasc

Intervent Radiol. 2015;38(1):129 – 134.

Thomas MB, Morris JS, Chadha R, et al. Phase II trial of the combination of bevacizumab and erlotinib in

patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009;27:843 – 850.

Toh HC, Chen PJ, Carr BI, et al. Phase 2 trial of linifanib (ABT-869) in patients with unresectable or

metastatic hepatocellular carcinoma. Cancer. 2013;119(2):380 – 387.

Uhm JE, Park JO, Lee J, et al. A phase II study of oxaliplatin in combination with doxorubicin as first-line

systemic chemotherapy in patients with inoperable hepatocellular carcinoma. Cancer Chemother

Pharmacol. 2009;63:929 – 935.

Weber S, Jarnagin W, Duffy A, et al. Liver and bile duct cancer. In: Abeloff MD, Armitage JO, Lichter AS,

Niederhuber JE. Kastan MB, McKenna WG, eds. Clinical Oncology. 4th ed. Philadelphia, Pa: Elsevier;

2008:1569 – 1579.

Yamakado K, Nakatsuka A, Takaki H, et al. Early-stage hepatocellular carcinoma: radiofrequency ablation

combined with chemoembolization versus hepatectomy. Radiology 2008;247:260-266.

Yang TX, Chua TC, Morris DL. Radioembolization and chemoembolization for unresectable

neuroendocrine liver metastases - a systematic review. Surg Oncol. 2012;21(4):299 – 308.

Ye SL, Takayama T, Geschwind J, et al. Current approaches to the treatment of early hepatocellular

carcinoma. Oncologist. 2010;15(suppl 4):34 – 41.

Yeo W, Chung HC, Chan SL, et al. Epigenetic therapy using belinostat for patients with unresectable

hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of

tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J

Clin Oncol. 2012;30(27):3361 – 3367.

Zhang CH, Xu GL, Jia WD, Ge YS. Effects of interferon alpha treatment on recurrence and survival after

complete resection or ablation of hepatocellular carcinoma: A meta-analysis of randomized controlled

trials. Int J Cancer. 2009;124:2982 – 2988.

Zhong C, Guo RP, Li JQ, et al. A randomized controlled trial of hepatectomy with adjuvant transcatheter

arterial chemoembolization versus hepatectomy alone for Stage IIIA hepatocellular carcinoma. J Cancer

Res Clin Oncol. 2009;135:1437 – 1445.

Zhou B, Shan H, Zhu KS, et al. Chemoembolization with lobaplatin mixed with iodized oil for

21

unresectable recurrent hepatocellular carcinoma after orthotopic liver transplantation. J Vasc Interv

Radiol. 2010;21(3):333 – 8.

CMS National Coverage Determination (NCDs):

No NCDs identified as of the writing of this policy.

Local Coverage Determinations (LCDs):

No LCDs identified as of the writing of this policy.

Commonly submitted codes

Below are the most commonly submitted codes for the services and items subject to this policy. This is

not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and

bill in accordance with those manuals.

CPT Code Description Comment

37243 Vascular embolization for tumors

75894 Transcatheter therapy, embolization, any method, radiologic supervision and interpretation

ICD-10 Code Description Comment

C22.0 Liver cell carcinoma

C22.1 Intrahepatic bile duct carcinoma

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

C25.4 Malignant neoplasm of the endocrine pancreas

C69.90 Malignant neoplasm of unspecified site, unspecified eye

C69.91 Malignant neoplasm of unspecified site, right eye

C69.92 Malignant neoplasm of unspecified site, left eye

C78.7 Metastatic neoplasm, liver

Z09 Encounter for f/u exam after completed treatment for conditions other than malignant neoplasm

HCPCS Level II Code

Description Comment

N/A