Radioembolization for Primary and Metastatic Tumors of the Liver
Radioembolization (RE), also referred to as selective internal radiotherapy, is the intra-arterial delivery of small beads (microspheres) impregnated with yttrium-90 via the hepatic artery. The microspheres, which become permanently embedded, are delivered to tumors preferentially to normal liver, as the hepatic circulation is uniquely organized, whereby tumors greater than 0.5 cm rely on the hepatic artery for blood supply while normal liver is primarily perfused via the portal vein. RE has been proposed as a therapy for multiple types of primary and metastatic liver tumors.
The use of external-beam radiotherapy and the application of more advanced radiotherapy approaches (eg, intensity-modulated radiotherapy) may be of limited use in patients with diffuse, multiple lesions due to the low tolerance of normal liver to radiation compared with the higher doses of radiation needed to kill the tumor.
Various non-surgical ablative techniques have been investigated that seek to cure or palliate unresectable hepatic tumors by improving loco-regional control. These techniques rely on extreme temperature changes (cryosurgery or radiofrequency ablation [RFA]), particle and wave physics (microwave or laser ablation), or arterial embolization therapy including chemoembolization, bland embolization, or RE.
Radioembolization, referred to as selective internal radiation therapy in older literature, is the intra-arterial delivery of small beads (microspheres) impregnated with yttrium-90 via the hepatic artery. The microspheres, which become permanently embedded, are delivered to tumors preferentially to normal liver, as the hepatic circulation is uniquely organized, whereby tumors greater than 0.5 cm rely on the hepatic artery for blood supply while normal liver is primarily perfused via the portal vein. Yttrium-90 is a pure beta-emitter with a relatively limited effective range and short half-life that helps focus the radiation and minimize its spread. Candidates for radioembolization are initially examined by hepatic angiogram to identify and map the hepatic arterial system. At that time, a mixture of technetium 99-labelled albumin particles is delivered via the hepatic artery to simulate microspheres. Single-photon emission computed tomography imaging is used to detect possible shunting of the albumin particles into gastrointestinal or pulmonary vasculature.
Currently, two commercial forms of yttrium-90 microspheres are available: a glass sphere (TheraSphere) and a resin sphere (SIR-Spheres). Noncommercial forms are mostly used outside the United States. While the commercial products use the same radioisotope (yttrium-90) and have the same target dose (100 Gray), they differ in microsphere size profile, base material (i.e., resin vs glass), and size of commercially available doses. The physical characteristics of the active and inactive ingredients affect the flow of microspheres during injection, their retention at the tumor site, spread outside the therapeutic target region, and dosimetry calculations. The Food and Drug Administration granted premarket approval of SIR-Spheres for use in combination with 5-floxuridine chemotherapy by hepatic arterial infusion (HAI) to treat unresectable hepatic metastases from colorectal cancer. In contrast, TheraSphere was approved by humanitarian device exemption for use as monotherapy to treat unresectable HCC. In January 2007, this HDE was expanded to include patients with hepatocellular carcinoma who have partial or branch portal vein thrombosis. For these reasons, results obtained with one product do not necessarily apply to other commercial (or non-commercial) products.
Unresectable Primary Hepatocellular Carcinoma (HCC)
Most patients with HCC present with unresectable disease, and treatment options are limited secondary to the chemoresistance of HCC and the intolerance of normal liver parenchyma to tumorcidal radiation doses. Results of two randomized controlled trials have shown a survival benefit using transarterial chemoembolization (TACE) therapy compared to supportive care in patients with unresectable HCC. In one study, patients were randomly assigned to TACE, TAE (transarterial embolization), or supportive care. One year survival rates for TACE, TAE and supportive care were 82%, 75% and 63%, respectively; two-year survival rates were 63%, 50% and 27%, respectively. Targeted therapies have been investigated for HCC. For example, sorafenib was associated with improved overall survival in a randomized phase 3 trial with 602 patients.
Unresectable Intrahepatic Cholangiocarcinoma
Cholangiocarcinomas are tumors that arise from the epithelium of the bile duct and are separated into intrahepatic and extrahepatic types. Intrahepatic cholangiocarcinomas appear in the hepatic parenchyma and are also known as peripheral cholangiocarcinomas. Resection is the only treatment with the potential for cure, and 5-year survival rates have been in the range of 20% to 43%. Patients with unresectable disease may select among fluoropyrimidine-based or gemcitabine-based chemotherapy, fluoropyridimine chemoradiation or best supportive care.
Unresectable Metastatic Colorectal Cancer
Fifty to sixty percent of patients with colorectal cancer will develop metastases, either synchronously or metachronously. Select patients with liver-only metastases that are surgically resectable can be cured, with some reports showing 5-year survival rates exceeding 50%. Emphasis on treating these patients with potentially curable disease is on complete removal of all tumor with negative surgical margins. Most patients diagnosed with metastatic colorectal disease are initially classified as having unresectable disease. In patients with metastatic disease limited to the liver, preoperative chemotherapy is sometimes used to downsize the metastases to convert the metastatic lesions to a resectable status (conversion chemotherapy).
In patients with unresectable disease, the primary treatment goal is palliative, with survival benefit shown with both second- and third-line systemic chemotherapy. Recent advances in chemotherapy, including oxaliplatin, irinotecan, and targeted antibodies like cetuximab, have doubled the median survival in this population from less than one year to more than two years. Palliative chemotherapy using combined systemic and hepatic arterial infusion may increase disease-free intervals for patients with unresectable hepatic metastases from CRC.
Radiofrequency ablation has been found inferior to resection in local recurrence rates and 5-year overall survival, and is generally reserved for patients with potentially resectable disease that cannot be completely resected due to patient comorbidities, location of metastases (i.e., adjacent to a major vessel) or an estimate of inadequate liver reserve following resection. RFA is generally recommended to be used with the goal of complete resection with curative intent. The role of local (liver-directed) therapy (including radioembolization, chemoembolization and conformal radiotherapy) in debulking unresectable metastatic disease remains controversial.
Unresectable Metastatic Neuroendocrine Tumors
Neuroendocrine tumors are an uncommon, heterogeneous group of mostly slow-growing, hormone-secreting malignancies, with an average patient age of 60 years. Primary neuroendocrine tumors vary in location, but most are either carcinoids (which most commonly arise in the midgut) or pancreatic islet cells. Carcinoid tumors, particularly if they metastasize to the liver, can result in excessive vasoactive amine secretion including serotonin and are commonly associated with the carcinoid syndrome (diarrhea, flush, bronchoconstriction and right valvular heart failure).
Although they are considered to be indolent tumors, at the time of diagnosis, up to 75% of patients have liver metastases, and with metastases to the liver, 5-year survival rates are less than 20%. Surgical resection of the metastases is considered the only curative option; however, less than 10% of patients are eligible for resection, as most patients have diffuse, multiple lesions.
Conventional therapy is largely considered to be palliative supportive care, to control, eradicate or debulk hepatic metastases, often to palliate carcinoid syndrome or local pain from liver capsular stretching. Therapies for unresectable metastatic neuroendocrine tumors include medical (somatostatin analogs like octreotide), systemic chemotherapy, ablation (radiofrequency or cryotherapy), transcatheter arterial embolization (TAE) or chemoembolization (TACE), or radiation. Although patients often achieve symptom relief with octreotide, the disease eventually becomes refractory, with a median duration of symptom relief of approximately 13 months, with no known effect on survival. Systemic chemotherapy for these tumors has shown modest response rates of limited duration, is better for pancreatic neuroendocrine tumors compared with carcinoids, and is frequently associated with significant toxicity. Chemoembolization has shown response rates of nearly 80%, but the effect is of short duration and a survival benefit has not been demonstrated.
Miscellaneous Metastatic Tumors
Case reports have been published on the use of RE in many other types of cancer with hepatic metastases, including breast, melanoma, head, and neck (including parotid gland), pancreaticobiliary, anal, thymic, thyroid, endometrial, lung, kidney, gastric, small bowel, esophageal, ovarian, cervical, prostatic, bladder, and for sarcoma and lymphoma.
There are currently two forms of yttrium-90 microspheres approved by FDA.
A glass sphere system, TheraSphere® (manufactured by Nordion, Ontario, Canada, under license by BTG International) was approved through the HDE process in 1999 for radiation treatment or as a neoadjuvant to surgery or transplantation in patients with unresectable HCC who can have placement of appropriately positioned hepatic arterial catheters (H980006).
A resin sphere system, SIR-Spheres® (Sirtex Medical, Lake Forest, IL), was approved through the PMA process in 2002 for the treatment of inoperable CRC metastatic to the liver.
Radioembolization may be considered medically necessary to treat primary hepatocellular carcinoma that is unresectable and limited to the liver (See Policy Guidelines).
Radioembolization may be considered medically necessary in primary hepatocellular carcinoma as a bridge to liver transplantation.
Radioembolization may be considered medically necessary to treat hepatic metastases from neuroendocrine tumors (carcinoid and noncarcinoid) with diffuse and symptomatic disease when systemic therapy has failed to control symptoms.
Radioembolization may be considered medically necessary to treat unresectable hepatic metastases from colorectal carcinoma, melanoma (ocular or cutaneous), or breast cancer that are both progressive and diffuse, in patients with liver-dominant disease who are refractory to chemotherapy or are not candidates for chemotherapy or other systemic therapies.
Radioembolization is considered investigational for all other hepatic metastases except as noted above.
Radioembolization may be considered medically necessary to treat primary intrahepatic cholangiocarcinoma in patients with unresectable tumors.
Radioembolization is considered investigational for all other indications not described above.
Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
In general, radioembolization is used for unresectable HCC that is greater than 3 cm.
There is little information about the safety or efficacy of repeated RE treatments or about the number of treatments that should be administered.
Radioembolization should be reserved for patients with adequate functional status (Eastern Cooperative Oncology Group [ECOG] Performance Status 0-2), adequate liver function and reserve, Child-Pugh score A or B, and liver-dominant metastases.
Symptomatic disease from metastatic neuroendocrine tumors refers to symptoms related to excess hormone production.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
3/25/2004: Approved by Medical Policy Advisory Committee (MPAC)
4/29/2004: Code Reference section completed
7/10/2009: Policy reviewed, no changes
09/03/2010: Changed "Selective Internal Radiation Therapy" to "Radioembolization" in the title and throughout policy. Policy statement re-written to indicate that selective cases of hepatocellular carcinoma and metastatic neuroendocrine tumors may be considered medically necessary. Code Reference section changed from non-covered to covered. Added ICD-9 codes 155.0-155.2, 197.7, and 209.72 as covered diagnoses.
06/21/2011: Deleted the following policy statement: Radioembolization is considered investigational to treat unresectable hepatic metastases from colorectal carcinoma. Added a policy statement to indicate that radioembolization may be considered medically necessary to treat unresectable hepatic metastases from colorectal carcinoma that are both progressive and diffuse in patients with liver-dominant disease who are refractory to chemotherapy or are not candidates for chemotherapy.
04/26/2012: Policy reviewed; no changes.
08/09/2013: Added policy statement to indicate that radioembolization is considered investigational to treat primary intrahepatic cholangiocarcinoma.
04/29/2014: Policy reviewed; description updated. Added information regarding unresectable intrahepatic cholangiocarcinoma to the policy description. Added a policy statement to indicate that radioembolization is considered investigational for all other indications not described.
09/01/2015: Code Reference section updated for ICD-10. Added ICD-9 procedure codes 38.86 and 99.29. Removed deleted CPT codes 37204 and 75894 and replaced with 37243.
11/13/2015: Policy description updated regarding yttrium-90 microspheres. Medically necessary policy statement updated to state that radioembolization may be considered medically necessary to treat unresectable hepatic metastases from colorectal carcinoma, melanoma (ocular or cutaneous), or breast cancer that are both progressive and diffuse, in patients with liver-dominant disease who are refractory to chemotherapy or are not candidates for chemotherapy or other systemic therapies. Investigational policy statement revised to state that radioembolization may be considered medically necessary to treat primary intrahepatic cholangiocarcinoma in patients with unresectable tumors. It previously stated: Radioembolization is considered investigational to treat primary intrahepatic cholangiocarcinoma. Policy guidelines updated regarding radioembolization and to add medically necessary and investigative definitions.
12/08/2015: Code Reference section updated to add ICD-10 diagnosis code C22.1.
05/26/2016: Policy number A.8.01.43 added.
09/22/2016: Policy description updated. Policy statements unchanged.
Blue Cross Blue Shield Association policy # 8.01.43
This may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.