| Coverage Policy Manual | |
| Policy #: | 2003061 |
| Category: | Radiology |
| Initiated: | December 2003 |
| Last Review: | June 2023 |
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| Radioembolization of Primary & Metastatic Tumors of the Liver | |
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| Description: |
Radioembolization (RE), also referred to as selective internal radiotherapy (SIRT), 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 tumor 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 nonsurgical ablative techniques have been investigated that seek to cure or palliate unresectable hepatic tumors by improving locoregional 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.
RE, referred to as SIRT 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 tumor 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 RE are initially examined by hepatic angiogram to identify and map the hepatic arterial system. At that time, a mixture of 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, 2 commercial forms of yttrium-90 microspheres are available: a glass sphere, TheraSphere® (manufactured by Nordion, Ontario, Canada, under license by BTG International) and a resin sphere, SIR-Spheres® (Sirtex Medical, Lake Forest, IL). 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 Gy), they differ in microsphere size profile, base material (ie, 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. FDA granted premarket approval (PMA) of SIR-Spheres® for use in combination with 5-floxuridine chemotherapy by hepatic arterial infusion (HAI) to treat unresectable hepatic metastases from CRC. In contrast, TheraSphere® was approved by humanitarian device exemption (HDE) for use as monotherapy to treat unresectable HCC. In January 2007, this HDE was expanded to include patients with HCC who have partial or branch portal vein thrombosis. For these reasons, results obtained with 1 product do not necessarily apply to other commercial (or noncommercial) products (see Regulatory Status section).
Unresectable Primary 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 tumoricidal radiation doses. Results of 2 (RCTs have shown a survival benefit for TACE therapy compared with supportive care in patients with unresectable HCC (Llovet, 2002; Lo, 2002). In 1 study, patients were randomly assigned to TACE, transarterial embolization (TAE), or supportive care. One-year survival rates for TACE, TAE, and supportive care were 82%, 75%, and 63%, respectively, and 2-year survival rates were 63%, 50%, and 27%, respectively. Targeted therapies have been investigated for HCC. For example, sorafenib was associated with improved OS in a randomized phase 3 trial with 602 patients (Llovet, 2007).
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% (NCCN, 2015). Patients with unresectable disease may select among fluoropyrimidine-based or gemcitabine-based chemotherapy, fluoropyrimidine chemoradiation or best supportive care.
Unresectable Metastatic CRC
Fifty to sixty percent of patients with CRC 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 in an attempt to downsize the metastases to convert the metastatic lesions to a resectable status (conversion chemotherapy).
In patients with unresectable disease that cannot be converted to resectable disease, the primary treatment goal is palliative, with survival benefit shown with both second- and third-line systemic chemotherapy (Tice, 2010). Recent advances in chemotherapy, including oxaliplatin, irinotecan, and targeted antibodies like cetuximab, have doubled the median survival in this population from less than 1 year to more than 2 years(Tice, 2010). Palliative chemotherapy by combined systemic and HAI may increase disease-free intervals for patients with unresectable hepatic metastases from CRC.
RFA has been shown to be inferior to resection in local recurrence rates and 5-year OS and is generally reserved for patients with potentially resectable disease that cannot be completely resected due to patient comorbidities, location of metastases (ie, 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 (NCCN, 2015). The role of local (liver-directed) therapy (including RE, chemoembolization, and conformal radiotherapy) in debulking unresectable metastatic disease remains controversial (NCCN, 2015).
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, 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), TAE or 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 (King, 2008). Chemoembolization has shown response rates of nearly 80%, but the effect is of short duration and a survival benefit has not been demonstrated (King, 2008).
Miscellaneous Metastatic Tumors
Small 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 (King, 2008).
Regulatory Status
There are currently 2 forms of yttrium-90 microspheres approved by FDA.
In 1999, TheraSphere® (Boston Scientific; previously manufactured by Nordion, under license by BTG International), a glass sphere system, was approved by the FDA through the humanitarian drug exemption process for radiotherapy or as a neoadjuvant treatment to surgery or transplantation in patients with unresectable hepatocellular carcinoma who can have placement of appropriately positioned hepatic arterial catheters (H980006).
On March 17, 2021, TheraSphere received approval through the premarket approval process for use as selective internal radiation therapy (SIRT) for local tumor control of solitary tumors (1-8 cm in diameter), in patients with unresectable hepatocellular carcinoma, Child-Pugh Score A cirrhosis, well-compensated liver function, no macrovascular invasion, and good performance status (P200029).
In 2002, SIR-Spheres® (ex Medical), a resin sphere system, was approved by the FDA through the premarket approval process for the treatment of inoperable colorectal cancer metastatic to the liver (P990065).
FDA product code: NAW.
Coding
Beginning in 2014, the following code is available for the embolization procedure
37243: Vascular embolization or occlusion, inclusive of all radiological supervision and interpretation, intraprocedural roadmapping, and imaging guidance necessary to complete the intervention; for tumors, organ ischemia, or infarction.
In 2004, the following HCPCS code was introduced for radioembolization:
S2095: Transcatheter occlusion or embolization for tumor destruction, percutaneous, any method, using yttrium-90 microspheres.
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Policy/ Coverage: |
Effective November 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres, consistent with their FDA approval, meets primary coverage criteria for effectiveness for the following indications:
Note: An absolute contraindication to Y90 microspheres treatment is a pretreatment 99mTc macro-aggregated albumin (MAA) scan (delivered with flow rates and catheter position that mimic the anticipated Y90 infusion rate and catheter position) that demonstrates the potential of > 30 Gy radiation exposure to the lung or flow to the gastrointestinal tract that cannot be corrected by catheter techniques.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat any indication other than those listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat any indication other than those listed above is considered investigational. Investigational services are an exclusion in the member certificate of coverage
Effective June 2015 through October 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres, consistent with their FDA approval, meets primary coverage criteria for effectiveness for the following patient subsets:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat any indication other than those listed above, including, but not limited to, intrahepatic cholangiocarcinoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat any indication other than those listed above, including, but not limited to, intrahepatic cholangiocarcinoma is considered investigational. Investigational services are an exclusion in the member certificate of coverage
Effective May 2013 – May 2015
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres, consistent with their FDA approval, meets primary coverage criteria for effectiveness for the following patient subsets:
An absolute contraindication to Y90 microspheres treatment is a pretreatment 99mTc macro-aggregated albumin (MAA) scan (delivered with flow rates and catheter position that mimic the anticipated Y90 infusion rate and catheter position) that demonstrates the potential of > 30 Gy radiation exposure to the lung or flow to the gastrointestinal tract that cannot be corrected by catheter techniques.
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat any indication other than those listed above, including, but not limited to, intrahepatic cholangiocarcinoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat any indication other than those listed above, including, but not limited to, intrahepatic cholangiocarcinoma is considered investigational. Investigational services are an exclusion in the member certificate of coverage
Effective, December 2010 – April 2013
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres, consistent with their FDA approval, meets primary coverage criteria for effectiveness for the following patient subsets:
An absolute contraindication to Y90 microspheres treatment is a pretreatment 99mTc macro-aggregated albumin (MAA) scan (delivered with flow rates and catheter position that mimic the anticipated Y90 infusion rate and catheter position) that demonstrates the potential of > 30 Gy radiation exposure to the lung or flow to the gastrointestinal tract that cannot be corrected by catheter techniques.
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat any indication other than those listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat any indication other than those listed above is considered investigational. Investigational services are an exclusion in the member certificate of coverage
Effective, September 2008 through November 2010
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres, consistent with their FDA approval, meets primary coverage criteria for effectiveness for the following patient subsets:
An absolute contraindication to Y90 microspheres treatment is a pretreatment 99mTc macro-aggregated albumin (MAA) scan (delivered with flow rates and catheter position that mimic the anticipated Y90 infusion rate and catheter position) that demonstrates the potential of > 30 Gy radiation exposure to the lung or flow to the gastrointestinal tract that cannot be corrected by catheter techniques.
For contracts without primary coverage criteria selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat any indication other than those listed above is considered investigational. Investigational services are an exclusion in the member certificate of coverage
Effective prior to Sept 2008:
Selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat primary or metastatic liver tumors is not covered based on benefit certificate primary coverage criteria; this technique is the subject of ongoing phase II trials.
For contracts without primary coverage criteria, selective internal radiation therapy using intra-arterial injection of radiolabeled microspheres to treat primary or metastatic liver tumors is considered investigational. Investigational services are an exclusion in the member certificate of coverage.
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| Rationale: |
“Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com”
A MEDLINE (via PubMed) literature search in August 2003 yielded over 100 citations discussing technical issues or reporting clinical outcomes of SIRT. Four of these were recent reviews of SIRT and other local ablative treatments for hepatic tumors. An additional review focused on outcomes of SIRT reported in studies published through 1994. These reviews summarize the generally favorable preliminary evidence on effects of SIRT, yet also note the lack of long-term follow-up data to document the duration of responses or survival after SIRT.
Clinical studies of SIRT were identified that: included 10 or more patients being treated for primary or metastatic hepatic tumors; reported health outcomes (i.e., survival, response duration); and were published in peer-reviewed journals within the last 10 years. These studies included approximately 1,000 patients and are divided into 3 groups: 1) studies from Australian and New Zealand institutions using SIR-Spheres®; 2) studies from institutions in the United States and Canada using Theraspheres®; and 3) studies from institutions in China and Hong Kong using noncommercial microspheres.
SIR-Spheres®. Two reports were from a randomized trial of patients with unresectable metastases from colorectal cancer treated with hepatic artery infusion (HAI) of 5-fluorodeoxyuridine (5-FUDR) alone (n=34) or with SIRT (n=36).
One paper reported on changes in normal liver and spleen volume following HAI+SIRT, but did not provide data on long-term treatment outcomes (Moroz, 2001). As described in the main report (Gray, 2001), the study was initially designed to enroll 95 patients and detect a 30% increase in median survival for those in the experimental arm compared with controls, with 90% power and 95% confidence. The investigators closed the study after entering 74 patients (n=70 eligible for randomization). Reasons cited for the early closure included: 1) increasing patient and physician reluctance to participate; 2) decision by the FDA to accept intermediate endpoints to support applications for premarket application approval; and 3) lack of funding to complete the study. The smaller studypopulation was adequate to detect increases in response rate (from 20% to 55%) and median time to disease progression (by 32% from 4.5 months) with 80% power and 95% confidence, but lacked sufficient statistical power to detect changes in survival.
To monitor responses to therapy, investigators serially measured serum levels of carcinoembryonic antigen (CEA) and estimated tumor cross-sectional area and volume from repeated computerized tomographic scans read by blinded physicians. They reported increased overall responses (complete plus partial) measured by area (44% versus 18%, p=0.01; HAI+SIRT vs. HAI, respectively) and volume (50% versus 24%, p=0.03), or by serum CEA levels (72% versus 47%, p=0.004). They also reported increased time to disease progression detected by increased area (9.7 versus 15.9 months, p=0.001) or volume (7.6 versus 12.0 months, p=0.04). However, there were no significant differences between treatment arms in actuarial survival rates (p=0.18 by logrank test) or in 11 quality of life measures. Treatment-related complications (grades 3-4) included 23 events in each arm (primarily changes in liver function tests). Nevertheless, investigators concluded that a “single injection of SIR-Spheres® plus HAI is substantially more effective” than the same HAI regimen delivered alone. Despite the investigators’ assertions, these results are inadequate to support their
conclusions for the following reasons: 1) Accrual was halted early, leaving the study underpowered. 2) Although the study involved oversight by an institutional review board, the report suggests early closure was at the sole discretion of the principal investigator without independent review or prospectively designed data monitoring procedures and stopping rules. 3) While in this study, response rate and time to progression after SIRT+HAI appeared superior to the same outcomes after HAI alone, results for the SIRT+HAI group are within the range reported by other randomized trials of HAI in comparable patients. 4) Results of this study may reflect use of a shorter-than-standard duration of HAI therapy, and are confounded by administration of non-protocol chemotherapy before and after SIRT. 5) The reported
increases in response rates and time to progression improved neither duration of survival nor quality of life.
Three additional studies were identified that used SIR-Spheres® with HAI and reported outcome data in some form. These were uncontrolled clinical series (J Natl Cancer Inst, 1996; Stubbs, 2001) or included retrospective control groups treated with HAI alone (Van Hazel, 2004). All 3 studies treated patients with liver metastases of colorectal cancer, but all 3 studies included variable percentages of patients with clear contraindications to SIRT (16%–50% of patients had documented extrahepatic disease) and all 3 failed to clearly document other important patient selection criteria (liver reserve, prior treatment). Median survival after SIRT in these uncontrolled series ranged from 9 to 13.5 months and 1-year survival ranged from 67%–82%. None adequately reported palliative outcomes or effects on disease symptoms.
TheraSpheres®. The largest single series was reported by Salem et al, 2002, who described treating approximately 300 patients with liver carcinomas with SIRT under a humanitarian device exemption at 8 unnamed institutions. The report
provided no additional details on baseline characteristics of the patients and did not specify inclusion or exclusion criteria for treatment. Investigators only reported outcomes for a cohort of 54 HCC patients with Okuda stage I and II (median survival: 23 and 11 months, respectively; overall survival at 1 year: 68% and 37%, respectively). The other studies were uncontrolled clinical series of 22 patients with unresectable HCC or 37 patients with unresectable colorectal liver metastases and reported no, or only limited, survival data (e.g., 54-week median survival in Dancey et al.). None adequately reported palliative outcomes or effects of SIRT on disease symptoms.
Non-commercial Microspheres. Six articles described the use of SIRT with non-commercial forms of 90Y microspheres in 301 patients (n=294 with HCC). These were generally uncontrolled clinical series of heterogeneous patient populations
reporting response rates that ranged from 27% to 72% and 1-year survival rates of 32% to 88% (Lau, 1996; Lau, 1994; Tian, 1996; Leung, 1995; Lau, 2001). None adequately reported palliative outcomes or effects of SIRT on disease symptoms. One study (Cao, 1999)did report a significant difference in median survival after SIRT in 17 patients (19.5 months) compared to HAI treatment of 53 patients (6.5 months). However, the study did not provide data on baseline characteristics of the HAI-treated patients or describe the HAI treatment regimen. In summary, the variability in patient populations, variable or indeterminate nature of microsphere systems administered, lack of long-term outcome data, and uncontrolled nature of the studies limit the applicability of these data.
Van Hazel et al (2004) described a phase 2 study of 21 patients with previously untreated advanced colorectal liver metastases. Time to progression of disease and overall survival was measured in 11 patients who received SIRT and chemotherapy as compared to 10 patients who received only standard chemotherapy. Overall survival was 29.4 months in the SIRT group vs. 12.8 months in the control group. The time to progression of disease was longer in those treated with SIRT and chemotherapy than in those treated with chemotherapy alone. The authors stated, "This small phase 2 randomized trial demonstrated that the addition of a single administration of Sir-Spheres to a regimen of systemic fluorouracil/leucovorin chemotherapy significantly increased both treatment related response, time to progression of disease, and survival with acceptable toxicity. The combination of SIR-Spheres plus systemic chemotherapy is now the subject of ongoing trials to further define patient benefit."
2007 Update
Kennedy and colleagues (2006) reported on results for use of the resin microspheres in 208 patients with liver metastases from colorectal cancer who had failed or were not candidates for standard chemotherapy. There were no complete responses but a 35% partial response by CT (as determined by a 50% decrease in tumor measure at 12 weeks). Median survival was 10.5 months for responders but 4.5 months for non-responders. The authors noted the majority of patients died with persistent liver disease and struggled with uncontrolled systemic metastases. No quality of life or functional status measures were reported. Additionally the authors note their report was a retrospective review with associated problems of a mixture of patients and a lack of a controlled treatment protocol.
While the literature shows anti-tumor activity for SIRT, from published studies it is not yet certain if this treatment results in improved survival or functional status and quality of life. Additional studies are also needed to determine if this should be used as a stand-alone treatment or if should be combined with chemotherapy. Comparisons with other techniques for treatment of primary and metastatic liver cancer are also needed.
In a review article, Salem and Thurston, 2006, Part I, comment on patient selection criteria, address differences in the two types of spheres, dosing, the actual treatment procedure, radiation safety, and postprocedural care and follow-up. Their Part 2 article, 2006, addresses radioembolization with yttrium 90 in special situations. In addressing the use of radioembolization after other liver tumor ablative procedures (TACE, radiofrequency) they conclude that 90Y treatment would not be contraindicated given assurance that the hepatic tumor vasculature was not obliterated by the previous treatment. While noting that portal vein thrombosis was a contraindication for the use of yttrium 90 at the time they wrote their article they believed that the administration of yttrium 90 in patients with portal vein thrombosis should be well tolerated. Their one concern in this specific situation was the care that must be taken not to injure, dissect or cause thrombosis in the hepatic artery.
2008 Update
A MEDLINE® search was performed for the period February 2007 through June 2008. Several reports each of SIRT for primary hepatocellular carcinoma and for metastatic liver tumors with multiple primary tumor sites were identified. No studies included a control group or analyses of palliative benefit. Survival comparisons were historical or within subgroups of the cohort reported. Of note, most reports identified (all but 3 single center retrospective cohorts n=44, n=21, n=24) were from the same medical center. Duplicate reporting is possible, although the papers selected for review are the larger case series for each indication (HCC and liver metastases) and likely include many or most of the patients in the smaller reports.
Metastatic Disease
In an open label, nonrandomized phase I clinical trial (n=20), SIR-Spheres were administered on the third or fourth day of the first 14-day cycle of oxaliplatin, fluorouracil, and leucovorin chemotherapy for treatment of inoperable colorectal liver metastases. Two (10%) patients were able to undergo partial hepatic resection after therapy. Also noted were higher than expected (with chemotherapy alone) rates of grade 3 or 4 lymphopenia (44%) and neutropenia (80%) (however, the expected rates with chemotherapy alone were not reported) (Sharma, 2007). This was the only reported down-staging identified for the current update, and the multimodal therapy prevents attribution of the cause of improvement. Hepatic metastases from breast cancer in 44 patients at 3 hospitals were retrospectively reviewed by Coldwell et al , 2007. Patients had failed first-, second, or third-line treatment for their primary tumor and were not candidates for radiofrequency ablation, transcatheter arterial chemoembolization, resection, intensity modulated radiation therapy, or stereotactic radiotherapy. At 12 weeks, a partial response (using World Health Organization [WHO] criteria, at least 50% reduction in the cross-product of the tumor dimensions) to SIR-Spheres was observed by computed tomography (CT) in 47% of patients with recorded follow-up (82% of the total). Symptoms were reported to improve, although no specifics were reported. There were no radiation-related liver failures observed and, at a median follow-up of 14 months, the cohort had not yet reached its expected median survival of 14 months. The largest report of metastatic tumors of the liver was a prospective phase II protocol from two centers, involving 137 patients with mixed primary tumors (colon [n= 51], breast [n= 21], neuroendocrine [n=19], and others [n=46]). All patients had inoperable chemorefractory or progressive liver-dominant metastases that were treated with TheraSphere®. Complete or partial response (WHO criteria at 3 months) was observed in 42.8% of lesions treated, while 10.2% of lesions experienced disease progression in this time. Median survival was 300 days, with 47.8% and 30.9% alive at 1 and 2 years, respectively. Markers of better prognosis, including lower Eastern Cooperative Oncology Group (ECOG) status, lower tumor burden at enrollment, fewer lesions treated, and primary diagnosis of colon cancer (vs. neuroendocrine and noncolon, non-neuroendocrine) were all significantly associated with survival. The authors state that with demonstration of functional response, controlled studies in various subsets of patients, alone or in combination with chemotherapy or biologics, are being initiated. Comparative data are needed to fully assess the effectiveness of therapy (Sato, 2008).
Hepatocellular Carcinoma
A comparison of tumor response and survival among subgroups of patients with and without portal vein thrombosis (PVT) was reported by Kulik et al, 2008. Thirty-four percent of this phase II open-label cohort of 108 unresectable HCC patients treated with TheraSphere® had had either branch or main PVT. At 6 months, WHO criteria partial response was observed in 42.2% of the overall cohort and in 34% and 66% of those with and without PVT, respectively. Kaplan Meier survival was statistically longer in the PVT-free group (467 days) than the branch (304 days) and main PVT (133.5 days) groups. At baseline, the PVT groups had higher tumor burden, Okuda stage, pretreatment bilirubin concentrations, and proportion of patients with portal hypertension than the non-PVT groups. Adverse events for the PVT groups were presented among those with and without baseline cirrhosis. Cirrhotic patients with main PVT were more likely than those without PVT to have worsening of baseline ascites (55% and 15% respectively) with Y90 microsphere treatment; no difference was seen among those without cirrhosis, although the numbers were small. For HCC, expected survival should be in the range of 11 months (sorafenib-treated inoperable HCC patients) (Llovet, 2007). Studies demonstrating improved survival among appropriate comparison groups, versus radiofrequency ablation and/or versus sorafenib, are needed for determining the medical necessity of SIRT.
The Society of Interventional Radiology, using level 2A evidence (panel consensus with low-level evidence), determined that there was sufficient evidence to support the safety and efficacy of Y90 microsphere therapy, with multidisciplinary management, adequate patient selection, and meticulous angiographic technique. They also stated that clinical trials were necessary to define the role of Y90 therapy in relation to other available therapies (Kennedy, 2007). The coverage policy statement was changed.
2009 Update
A MEDLINE® search was performed for the period April 2008 to Dec 2009.
Vente et al, 2009, conducted a meta-analysis on tumor response and survival in patients who received 90Y glass or resin microsphere radioembolization for the treatment of primary liver cancer (HCC) or metastases from colorectal cancer. Included studies were from 1986 onward. Articles written in a language other than English or German were excluded, as were articles that did not present tumor response measured by CT scans or that did not present data on median survival times. Two covariates were included in the meta regression model: 1) whether an older generation of cytostatic agents (5-FU/LV or floxuridine) or a newer generation (5-FU/LV plus oxaliplatin [FOLFOX] or 5-FU/LV plus irinotecan [FOLFIRI]) was used, and 2) whether 90Y-radioembolization was given as salvage therapy or as first-line treatment with adjuvant chemotherapy. To allow comparability of results with regard to tumor response, the category of “any response” was introduced, and included complete response, partial response, and stable disease. Overall tumor response could only be assessed as any response because response categories were not uniformly defined in the analyzed studies.
In a total of 19 eligible studies, 792 patients with metastatic colorectal cancer had undergone 90Y-radioembolization. The specific cytostatic agent(s) that were used did not effect response (p=0.96). Tumor response to 90Y-radioembolization was high, with any response rates of approximately 80% in a salvage setting, and over 90% when used as first-line treatment as neoadjuvant to chemotherapy, regardless of the chemotherapy regimen used. Median survival after 90Y-radioembolization, irrespective of differences in determinants (microspheres type, chemotherapy protocol, and stage: salvage or first-line), varied from 6.7 to 17.0 months. Included were 2 randomized, controlled trials, both on resin microspheres and metastatic colorectal cancer (which were previously addressed in this policy, references 7 and 13). The results showed a survival benefit for the 90Y-radioembolization plus chemotherapy arm, however, since then larger controlled trials have commenced, using more effective chemotherapeutics.
In 14 articles, clinical data were presented on tumor response and survival for 425 patients with HCC who had received 90Y-radioembolization. Treatment with resin microspheres was associated with a significantly higher proportion of any response than glass microsphere treatment (0.89 vs. 0.78; p=0.02). Median survival was reported in 7 studies in which survival time was defined as survival from microsphere treatment or from diagnosis or recurrence of HCC. Median survival from microsphere treatment varied between 7.1 and 21.0 months, and median survival from diagnosis or recurrence was 9.4–24.0 months.
The authors of the meta-analysis concluded that 90Y-radioembolization is associated with high response rates, both in a salvage and first-line setting, but that the true impact on survival will only become known after publication of several ongoing and/or to-be-initiated phase III studies, as well as the results of trials in which 90Y-radioembolization and modern chemotherapy agents are combined with novel biologic agents.
A single arm, open-label study was reported by Mulcahy et al, 2009, and involved 72 patients with unresectable hepatic colorectal metastases treated with 90Y microspheres (TheraSphere®). To determine response, 128 lesions were used. A partial response rate using WHO criteria was noted in 29 of 72 patients (40.3%), and at the lesional level the response rate was 40.6% (partial response rate 37.5%; complete response rate 3.1%). Stable disease was observed in 44.5% of patients, and disease progression was found in 14.8% of patients. Median follow-up was 26.2 months. Median overall survival was 40.3 months (95% CI: 29.0–51.6 months) for all patients from the time of cancer diagnosis, 34.6 months (95% CI: 24.4–41.8 months) from the time liver metastases were diagnosed, and 14.5 months (95% CI: 9.6–21.9) from the time of 90Y therapy. A substratification analysis was performed, and favorable prognostic factors that indicated a benefit from 90Y therapy included an Eastern Cooperative Oncology Group (ECOG) performance status of 0, a liver tumor burden of 25% or less, and the absence of extrahepatic disease. For the patients with an ECOG performance status of 0 at the time of 90Y treatment, the overall median survival from the onset of liver metastases was 42.8 months, or a 5-year survival rate of 25.9%, which are comparable outcomes to survival data for patients treated with primary resection, chemotherapy followed by resection, or radiofrequency ablation.
Hong et al, 2009, described a similar survival benefit for patients with progressive liver-dominant colorectal metastatic adenocarcinoma. Twenty-one patients had transarterial chemoembolization (CE)(37 procedures) and 15 had radioembolization with (90)Y (RE) (19 procedures). Median survival time was 7.7 and 6.9 months for the CE and RE groups respectively. The 1-, 2-, & 5-year survival time was 43%, 10% and 0% for the CE group, and 34%, 18% and 0% for the RE group.
Salem and colleagues, 2009, reported outcomes in 291 patients with HCC, treated with Y90 as part of a single-center prospective longitudinal cohort study; 561 treatments were administered (mean: 1.8, range: 1-5. Response rates were 42% and 57% based on WHO and EASL criteria respectively. Overall time to progression (TTP) was 7.9 months. Survival times differed between Child-Pugh A and B patients (A: 17.2 mo, B: 7.7 mo). Child-Pugh B patients with portal vein thrombosis (PVT), survived 5.6 months.
National Cancer Institute (NCI) Clinical Trials
Two phase III trials are currently recruiting patients (NCT00724503 and NCT00199173) and 1 trial is ongoing (NCT00109954).
NCT00724503 is a randomized, multicenter phase III trial to assess the effect of adding SIRT, using SIR-Spheres microspheres, to a standard chemotherapy regimen of FOLFOX as first-line therapy in patients with non-resectable liver metastases from primary colorectal adenocarcinoma.
NCT00199173 is a phase III trial comparing hepatic intra-arterial injection of 90Y microspheres (SIR spheres) versus infusional intravenous 5-FU in colorectal cancer metastatic to the liver only and refractory to standard chemotherapy.
NCT00109954 is a prospectively randomized controlled phase III trial comparing TheraSphere® with cisplatin-based TACE (transarterial chemoembolization) in the management of advanced stage, unresectable hepatocellular carcinoma.
2010 Update
Unresectable primary hepatocellular carcinoma (HCC)
Salem and colleagues (2010) reported the results of a single-center, prospective, longitudinal cohort study of 291 patients with hepatocellular carcinoma treated between January 2004 and December 2008 (Salem, 2010). The patient population was heterogeneous, and included patients with portal vein thromboses (43%), advanced disease and extrahepatic metastases (16%), which are usually exclusionary criteria for studies using locoregional therapy. Data were collected prospectively and included toxicity, imaging, and survival outcomes. Patients were staged by Child Pugh scores. Eighty seven percent of patients had received no prior therapy. A total of 526 treatments were administered. Scans were performed 4-6 weeks after each treatment and then at 2-3 month intervals once all disease was treated. Median follow-up time was 30.9 months. Imaging follow-up was available in 273 patients, with an average of 4.3 scans per patient. By World Health Organization (WHO) criteria, response rates were 42%; by European Association for the Study of the Liver (EASL) criteria, 57%, with 23% complete response (CR) and 34% partial response (PR). Response rates were better in patients with Child Pugh A disease (WHO, 49%; EASL 66%) than those with Child Pugh B disease (WHO, 36%; EASL 51%), and WHO response rates varied by baseline largest tumor size: smaller than 5 cm, 44%; 5-10 cm, 42%; and larger than 10 cm, 33%. Survival for patients with Child Pugh disease A and B was 17.2 months and 7.7 months, respectively (p=0.002). The authors concluded that patients with Child Pugh A disease, with or without portal vein thrombosis, benefitted most from the treatment but that the role of yttrium-90 in certain patients with HCC requires further exploration, including controlled studies comparing yttrium-90 with alternative locoregional therapies (RFA and TACE) and yttrium-90 in various combinations with systemic targeted therapies in advanced disease.
Carr and colleagues (2010) reported on a consecutive series of patients with HCC who were seen at a single medical center and who were not candidates for surgical resection (Carr, 2010). Patients either received conventional cisplatin-TACE between the years 1992 and 2000 (n=691), yttrium-90 microspheres between 2000 and 2005 (n=99), or no treatment (n=142). Median overall survival for the yttrium-90 group versus the TACE group was 11.5 months [95% CI, 8-16 months] versus 8.5 months [95% CI: 8-10 months], respectively (p<0.05). Untreated patients had a median survival of 2 months. Although the authors felt there was a slight selection bias toward milder disease in the yttrium-90 group, they concluded that yttrium-90 and TACE appear to be equivalent regional therapies for patients with unresectable, nonmetastatic HCC.
Unresectable metastatic neuroendocrine tumors
In 2010, Cao and colleagues reported the outcomes of 58 patients with unresectable neuroendocrine liver metastases from 2 different hospitals treated with yttrium-90 microspheres (SIR-Spheres) from 2003 to 2008. Data were examined retrospectively from a database (Cao, 2010). Response was assessed with radiographic evidence before and after radioembolization and measured by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Patients typically had a CT scan within 3 months of treatment and every 3 to 6 months until disease progression or death. Systemic chemotherapy was routinely given at 1 institution but not the other. Mean patient age at the time of radioembolization was 61 (range: 29-84 years), and 67% of patients were men. Primary tumor site was variable and included small bowel, pancreas, colon, thyroid, lung, and unknown. Thirty-one patients underwent surgical resection of their primary tumor, which was classified as low-grade in 15, intermediate-grade in 7, and high-grade in 7. Forty-three percent of patients had extrahepatic metastatic disease at study entry. Prior therapies before radioembolization included liver resection in 19 patients, TAE or TACE in 6, ablation or percutaneous ethanol injection in 10, previous chemotherapy in 20, concurrent chemotherapy in 34, and post-radioembolization chemotherapy in 5 patients. Median follow-up was 21 months (range 1-61 months). Fifty-one patients were evaluable, and 6 achieved a complete response, 14 a partial response, 14 had stable disease, and 17 had disease progression. Overall survival (OS) rates at 1, 2, and 3 years were 86, 58, and 47%, respectively. Median survival was 36 months (range: 1-61 months). Prognostic factors for survival included extent of tumor involvement of the liver, radiographic response to treatment, presence of extrahepatic disease at the time of radioembolization, histological grade of tumor, and whether patients were responders (versus nonresponders) to radioembolization. Factors that were not significant prognostic features included age, sex, ECOG status, and previous therapy.
King and colleagues reported outcomes in patients treated in a single-institution prospective study (King, 2008). Thirty-four patients with unresectable neuroendocrine liver metastases were given radioactive microspheres [SIR-Spheres] and concomitant 7-day systemic infusion of 5-FU, between 2003 and 2005. Mean patient age was 61 years (range: 32-79 years), and 65% were men. Mean follow-up was 35.2 +/- 3.2 months. The mean interval from diagnosis of hepatic metastases and treatment with SIR therapy was 36.6 +/- 6.7 months. Primary tumor sites were variable and included bronchus (n=1), thyroid (n=2), gastrointestinal (n=15), pancreas (n=8), and unknown (n=8). Subjective changes from baseline hormone symptoms were reported every 3 months. Twenty-four patients (71%) had, at baseline assessment, symptoms of carcinoid syndrome, including diarrhea, flushing, or rash. At 3 months, 18 of 33 patients (55%) reported improvement of symptoms, as did 16 of 32 (50%) at 6 months. Radiologic tumor response was observed in 50% of patients and included 6 CR (18%), and 11 PR (32%). Mean OS was 29.4 +/- 3.4 months.
Kennedy and colleagues conducted a retrospective review of 148 patients from 10 institutions with unresectable hepatic metastases from neuroendocrine tumors who received resin microspheres (Kennedy, 2008). All patients had completed treatment of the primary tumor and metastatic disease and were not excluded based on prior therapy. Total number of resin microsphere treatments was 185, with retreatment in 22.3 % of patients (19.6% received two treatments, and 2.7%, 3 treatments). All patients were followed with imaging studies at regular intervals to assess tumor response (using either WHO or RECIST criteria) until death, or they were censured if a different type of therapy was given after the microspheres. The male to female ratio was 49% to 51%, respectively, and median age was 58 years (range: 26-95 years). Median follow-up was 42 months. By imaging, response rates were stable disease 22.7%, partial response 60.5%, complete response 2.7%, and progressive disease 4.9%. Hepatic and extrahepatic metastases contributed to death in the majority of patients, with 7% lost to follow-up. Median survival was 70 months. The authors conclude that radioembolization can deliver high doses of radiation preferentially to hepatic metastases from neuroendocrine tumors with encouraging response rates by imaging and symptomatic improvement (although there were no data presented in the study regarding symptoms).
Rhee and colleagues reported the results of a multicenter, open label Phase II study to assess the safety and efficacy of radioembolization, using glass or resin microspheres, in 42 patients with metastatic neuroendocrine liver disease who had failed prior treatment(s), including medical (e.g., octreotide), surgical resection, bland or chemoembolization, and radiofrequency or cryoablation (Rhee, 2008). Mean patient age was 58 +/- 12 years for glass and 61 +/- 11 years for resin microspheres. RECIST criteria were used to assess tumor response, which showed 92% of glass patients and 94% of resin patients were partial responders or had stable disease at 6 months after treatment. Median survival was 22 and 28 months for glass and resin, respectively.
Recommendations from the current NCCN guidelines for metastatic neuroendocrine tumors (carcinoid or islet cell) include regional therapy which includes radioembolization as category 2A. (V.2.2010).
2012 Update
A review of the MEDLINE database was conducted for this policy review through April 2012. There were no randomized controlled trials identified that have not been previously discussed and no new information that would prompt a change in the coverage statement.
2013 Update
This update primarily addresses the treatment of intrahepatic cholangiocarcinoma. The literature relating to the treatment of this indication is summarized below as well as new literature on miscellaneous tumors.
Intrahepatic Cholangiocarcinoma (ICC)
Cholangiocarcinomas originate in the epithelium of the bile duct. Four case series on use of RE in ICC are summarized here.
A study by Hoffman et al. of RE with yttrium-90 resin microspheres included 24 patients with nonresectable chemorefractory intrahepatic ICC and no extrahepatic disease (Hoffman, 2012). The mean age of the sample was 65.2 years and the sample was 45.5% female. ECOG performance status was 0 in 51.5%, 1 in 21.2% and 2 in 27.3%. Previous therapy included chemotherapy in 78.8%, surgery in 36.4%, TACE in 9.1%, RFA in 5.1% and EBRT in 3.0%. Tumor response was assessed by RECIST criteria. A CR was seen in 0%, PR in 36.4%, stable disease (SD) in 51.5% and progressive disease in 15.2%. Follow-up ranged between 3.1 and 44 months (median: 10 months). Median overall survival was 22 months and median time to progression was 9.8 months. Favorable subgroups with respect to survival included those with ECOG performance status of 0, tumor burden as percentage of liver volume of 25% or less, response by CA-19-9 criterion and RECIST PR. The same subgroups except those with a CA-19-9 response had favorable time to progression results. Data were collected retrospectively and no toxicity results were reported.
A 2011 study by Haug et al. addressed 26 consecutive patients with unresectable ICC who underwent RE with yttrium-90 glass microspheres (Haug, 2011). All patients had a Karnofsky performance status of 60% or more. Mean age was 64.3 years, 31% had extrahepatic disease and 42% were female. Treatment given previously included chemotherapy in 65%, surgery in 28%, local therapy in 20% and none in 24%. Tumor response results according to RECIST criteria were: CR in 0%, PR in 22%, SD in 65% and PD in 13%. Median overall survival was 51 weeks and multivariate analysis of found that a partial response from quantitative interpretation of positron emission tomography was a significant independent predictor of survival. Authors found no cases of grade 3 toxicity in transaminases or bilirubin.
In 2010, Saxena et al. published results for 25 patients with unresectable ICC who received RE with yttrium-90 resin microspheres (Saxena, 2010). Extrahepatic disease was present in 48%, mean age was 57 years and 48% of patients were female. Prior treatment included surgery in 40%, chemotherapy in 72%, RFA in 6.1% and EBRT in 3.0%. By RECIST tumor response criteria, CR was seen in 0%, PR in 24%, SD in 48% and PD in 20%. Follow-up was collected between 0.4 and 55 months (median: 8.1 months). In the entire group, median overall survival was 9.3 months. Among subgroups, longer survival duration was seen in patients with peripheral tumors and those with ECOG performance status of 0. The proportion of patients with both grade 3 albumin toxicity and grade 3 bilirubin toxicity was 8%. Grade 3 alkaline phosphatase toxicity was observed in 4%. One patient (4%) experienced duodenal ulcer due to malperfusion of yttrium-90 microspheres.
A study by Ibrahim and colleagues from 2008 reported results on RE with yttrium-90 glass microspheres among 24 patients with unresectable ICC (Ibrahim, 2008). The group was 33% female and had a median age of 68 years. Extrahepatic disease was present in 33%. ECOG performance status was 0 in 42%, 1 in 50% and 2 in 8%. Prior chemotherapy had been used in 29%. Using the WHO tumor response criteria, CR was observed in 0%, CR in 27%, SD in 68% and PD in 5%. Follow-up was collected over a median of 17.7 months and median overall survival was 14.9 months. Subgroups that had favorable survival results included those with ECOG performance status of 0, no previous chemotherapy and peripheral tumor. Grade 3 albumin toxicity was found in 17%, grade 3 bilirubin toxicity in 4% and 1 patient (4%) developed a duodenal ulcer.
In summary, intrahepatic cholangiocarcinoma (ICC): To date, studies on use of radioembolization in patients with intrahepatic cholangiocarcinoma consist of small case series. No studies have been published comparing radioembolization to other treatments such as chemotherapy or chemoradiation. Available studies varied with respect to patient characteristics, particularly presence of extrahepatic disease, previous therapy and performance status.
Miscellaneous Tumors
A 2013 study by Cianni and colleagues included 52 women with chemotherapy-refractory breast cancer and inoperable liver metastases (Cianni, 2013). RE treatment entailed yttrium-90 resin microspheres. The median age was reported as 57.5 years. ECOG performance status was 0 in 55.7%, 1 in 26.9% and 2 in 17.3%. Extrahepatic disease was present in 46.1%. Chemotherapy had been administered previously in all patients, surgery in 17.3%, TACE in 3.8% and RFA in 3.8%. Tumor response results by RECIST criteria were: CR in 0%, PR in 56%, SD in 35% and PD in 10%. Median overall survival was 11.5 months. Patients were retrospectively divided into two risk groups based on ECOG performance status, degree of liver tumor burden and whether extrahepatic disease was present. Median survival in the low risk group was 14.3 months, significantly better than in the high risk group (8.2 months). Grade 3 gastritis was seen in two patients (4%).
Haug et al. published a case series of 58 women with chemotherapy-refractory breast cancer and unresectable hepatic metastases (Haug, 2012). They received RE with yttrium-90 resin microspheres. The mean age was 58 years and all patients had a Karnofsky performance status of 60% or higher. Extrahepatic disease was present in 66%. Prior treatments were not mentioned. By RECIST criteria, a CR was seen in 0%, PR in 25.6%, SD in 62.8% and PD in 11.6%. Mean follow-up covered 27.5 weeks. The median overall survival for the sample was 47 weeks. Two indices derived from quantitative interpretation of positron emission tomography were significant predictors of survival. Bilirubin toxicity was at grade 3 in 3% and grade 4 in 2%. Transaminase toxicity was grade 3 in 5% and grade 4 in 2%.
Four studies have reported on use of RE in patients with hepatic metastases from melanoma (Gonsalves, 2011; Kennedy, 2009; Klingenstein, 2013; Piduru, 2012). Three studies included only patients with ocular melanoma (Gonsalves, 2011; Kennedy, 2009; Klingenstein, 2013) and the fourth included patients with either ocular or cutaneous melanoma (Piduru, 2012). Sample sizes ranged between 11 and 32 patients. Three studies excluded those with poor performance status. Median age was in the 50s for three studies and 61 in the fourth. One article did not describe any previous treatment and one described it incompletely. Three studies reported tumor response data, by RECIST criteria. Among 32 patients in the study by Gonsalves et al. (2011) one patient had a CR (3%), one had a PR, 18 patients had SD (56%) and 12 patients had PD (38%) (37). In the study of 13 patients published by Klingenstein et al. (2013), none had a CR, 8 had a PR (62%), 2 had SD (15%) and three had PD (23%) (39). Nine of 11 patients in the article by Kennedy et al. (2009) provided response data: one had CR, 6 had PR, 1 had SD and 1 had PD (Kennedy, 2009). Median survival in Gonsalves, Klingenstein, and Kennedy were 10.0 months, 19 months and not yet reached, respectively. Gonsalves reported 4 patients (12.5%) with grade 3-4 liver toxicity. Klingenstein observed one patient with marked hepatomegaly. Kennedy described one grade 3 gastric ulcer. The fourth study (Piduru et al., 2012, n=12) did not include any toxicity data.
National Cancer Institute (NCI) Clinical Trial Database (PDQ®) and ClinicalTrials.gov Registry
The following is a list of ongoing or unpublished comparative studies using radioembolization for primary or metastatic liver tumors.
Unresectable HCC
Four RCTs comparing yttrium-90 RE with TACE have either not been published or have not yet been completed.
NCT00109954 enrolled a target of 120 patients with advanced unresectable HCC. The study start date was February 2005 and the current trial status is unknown. NCT00867750 began in March 2006, enrolling 28 patients with unresectable HCC and was completed in June 2011. The start date of NCT00956930 was August 2009 with an expected completion date of August 2016. NCT01381211 began in September 2011, enrolling a target of 140 patients with intermediate HCC.
Two RCTs compare sorafenib with yttrium-90 RE. NCT01135056 had a start date of July 2010. It aims to enroll 360 patients with locally advanced HCC and close in July 2015. NCT01482442 started in December 2011 and is scheduled to finish March 2015. The target sample size of 400 will include patients with advanced HCC not eligible for resection, transplantation and RFA.
In two RCTs, sorafenib is included in both treatment arms. NCT01556490 began in March 2012, comparing sorafenib alone with sorafenib plus RE in patients with unresectable HCC. It aims to enroll 400 patients and mark completion by October 2016. NCT01126645 compares RFA plus sorafenib with RE plus sorafenib among patients with inoperable HCC. It began in December 2010 and is expected to finish in February 2014.
NCT00846131 uses RE in both arms and one arm combines it with sorafenib. Included patients have pre-transplant HCC with the intention of downstaging/bridging. With a target enrollment of 40, the trial started in February 2009 and is scheduled for completion in February 2014.
Metastatic colorectal cancer
Four RCTs that have not been published or completed compare anticancer agents to those same agents plus RE.
NCT00724503 assesses the effect of adding SIRT, using SIR-Spheres microspheres, to a standard chemotherapy regimen of FOLFOX as first-line therapy in patients with nonresectable liver metastases from primary colorectal adenocarcinoma (SIRFLOX). The primary outcome measure is progression-free survival. Trial status is active, with estimated enrollment of 450 and estimated study completion date of December 2012.
NCT01483027 began in January 2012 as a comparison between standard of care second-line chemotherapy versus that chemotherapy plus TheraSphere RE. Target enrollment is 360 patients with liver metastases from CRC that progressed after first-line therapy. Completion is expected in September 2016.
NCT01721954 is a comparison of the FOLFOX6m chemotherapy regimen +/- bevacizumab versus FOLFOX6m chemotherapy regimen +/- bevacizumab plus SirSphere RE. A target sample of 200 patients have liver metastases from CRC not treatable by surgery or local ablation. The start date is February 2013 and completion is expected in January 2014.
ISRCTN83867919 is an open-label randomized Phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver only or liver-predominant metastatic colorectal cancer (FOXFIRE). The primary outcome measure is overall survival. Target number of participants is 490 with an anticipated end date of January 2014.
One RCT completed in 2010 but not yet published compared 5FU chemotherapy with SIR-Sphere RE. The patient population consists of patients who had liver metastases and were refractory to standard chemotherapy.
2014 Update
A literature search conducted through February 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
In a 2013 systematic review, Saxena et al evaluated 20 studies on RE for chemoresistant, unresectable CRC liver metastasis totaling 979 patients (Saxena, 2013). After RE, the average reported CRs and PRs from 16 studies was 0% (range, 0%-6%) and 31% (range, 0%-73%), respectively. Nine months was the median time to intrahepatic progression (range, 6-16 months). Eleven studies reported OS rates and 12 months was the median survival time (range, 8.3-3.6).
In another 2013 systematic review, Rosenbaum et al evaluated 13 relevant articles on RE as monotherapy and 13 studies on RE combined with chemotherapy for chemoresistant, unresectable CRC liver metastasis (Rosenbaum, 2013). CR, PR, and SD rates ranged from 29% to 90% with only RE and from 59% to 100% for RE with chemotherapy At 12 months, survival ranged from 37% to 59% with only RE and from 43% to 74% for RE combined with chemotherapy.
Michl et al reported on RE for pancreatic cancer in 2014 (Michl, 2014). Response was seen in 47% with median local progression-free survival (PFS) in the liver of 3.4 months (range, 0.9-45.0). Median OS was 9.0 months (range, 0.9-53.0), and 1-year survival was 24%.
Data on the use of RE in other tumors metastatic to the liver are limited and are composed of patient numbers too small to draw meaningful conclusions.
2015 Update
This policy is being updated with a literature search through May 2015. This update focuses on the indication for unresectable hepatic metastases from uveal melanoma.
Melanoma
The evidence related to the use of RE for uveal melanoma consists of relatively small observational studies.
In 2014, Xing et al conducted a retrospective observational study to compare outcomes for patients with unresectable melanoma (both uveal and cutaneous) liver metastases refractory to standard chemotherapy treated with either yttrium-90 RE (n=28) or best supportive care (n=30) (Xing, 2014). The groups were similar at baseline in terms of Child-Pugh class, ECOG Performance Status scores, age, sex, and race. Patients treated with RE had larger tumor size at baseline than those treated with best supportive care (mean, 7.28 cm vs 4.19 cm; p=0.02). Median OS from diagnosis of melanoma liver metastases was longer in RE-treated subjects (19.9 mo vs 4.8 mo; p<0.000), as was the median OS from diagnosis of the primary melanoma (119.9 months vs 26.1 months; p<0.001). Pre- and posttreatment imaging studies were available for 24 of 28 (85.7%) of those treated with RE. Of those, no patients had a CR; 5 patients (17.9%) had PR, 9 patients (32.1%) had SD, and 10 patients (35.7%) had PD. Two patients receiving RE had major (grade 5) clinical toxicities (ascites and hepatic encephalopathy and eventual mortality).
Also in 2014, Eldredge-Hindy et al retrospectively evaluated outcomes for the use of yttrium-90 RE in 71 patients with biopsy-confirmed uveal melanoma liver metastases (Eldredge-Hindy, 2014). The median time from the diagnosis of liver metastases to RE was 9.8 months (95% CI, 7.4 to 12.2 months), and 82% of patients had received prior liver-directed therapies. Sixty-one patients (86%) had CT or magnetic resonance imaging evaluation of treatment response at 3 months post-RE. Of those, 5 patients (8%) had a PR, 32 patients (52%) had SD, and 24 patients (39%) had DP. Median OS RE was 12.3 months (range, 1.9-49.3 months).
Several smaller studies published from 2009 to 2012 reported on the use of RE in patients with hepatic metastases from melanoma (Gonsalves, 2011; Kennedy, 2009; Klingenestein, 2013; Piduru, 2012). Three studies included only patients with ocular melanoma (Gonsalves, 2011; Kennedy, 2009; Klingenestein, 2013), and the fourth included patients with either ocular or cutaneous melanoma (Piduru, 2012). Sample sizes ranged between 11 and 32 patients. Three studies excluded those with poor performance status. Median age was in the 50s for 3 studies and 61 in the fourth. One article did not describe any previous treatment, and one described it incompletely. Three studies reported tumor response data, by RECIST criteria. Among 32 patients in the study by Gonsalves et al (2011), 1 patient had a CR (3%), 1 had a PR; 18, SD (56%); and 12, PD (38%) (Consalves, 2011). In the study of 13 patients published by Klingenstein et al (2013), none had a CR; 8, PR (62%); 2, SD (15%); and 3, PD (23%) (Klingenstein, 2013). Nine of 11 patients in the article by Kennedy et al (2009) provided response data: 1 had CR; 6, PR; 1, SD; and 1, PD.64 Median survival in Gonsalves, Klingenstein, and Kennedy were 10.0 months, 19 months and not yet reached, respectively. Gonsalves reported 4 patients(12.5%) with grade 3-4 liver toxicity. Klingenstein observed 1 patient with marked hepatomegaly. Kennedy described 1 grade 3 gastric ulcer. The fourth study (Piduru et al [2012], N=12) did not include any toxicity data.
2018 Update
A literature search conducted using the MEDLINE database through May 2018 did not reveal any new information that would prompt a change in the coverage statement.
Unresectable Hepatocellular Carcinoma
Tao et al (2017) reported on a network meta-analysis comparing nine minimally invasive surgeries for treatment of unresectable hepatocellular carcinoma (HCC) (Tao, 2017). The interventions included were transarterial hemoembolization (TACE), TACE plus sorafenib, sorafenib, TACE plus high-intensity focused ultrasound, TACE plus percutaneous ethanol injection, drug-eluting bead (DEB) plus TACE (DEB-TACE), yttrium-90 radioembolization (90Y RE), TACE plus external-beam radiation therapy (EBRT), and ethanol ablation. The network included 17 studies with 2669 patients and 4 studies with 230 patients including 90Y RE. In a pairwise meta-analysis, patients treated with 90Y RE were more likely to achieve complete remission than those who received TACE (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.3 to 15.1). However, in the network meta-analysis, there was no significant difference between the corresponding 8 treatments and TACE with respect to complete remission, partial response, stable disease, and objective response rate. The treatments were ranked for several outcomes using surface under the cumulative ranking curves (SUCRA). TACE plus EBRT had the highest SUCRA ranking in complete remission (77%), partial response (89%), progressive disease (95%), and objective response rate (81%). Ludwig et al (2017) conducted a meta-analysis of studies that indirectly compared DEB-TACE with 90Y RE for HCC (Ludwig, 2017). Fourteen studies (total N=2065 patients) comparing DEB-TACE or 90Y RE with conventional TACE for primary HCC treatment were included. The pooled estimate of median survival was 23 months for DEB-TACE and 15 months for RE. The estimated 1-year survival was significantly higher for DEB-TACE (79%) than for RE (55%; OR=0.57; 95% CI, 0.36 to 0.92; p=0.02). Survival did not differ statistically significantly at 2 or 3 years but did favor DEB-TACE. At 2 years, survival was 61% for DEB-TACE and 34% or RE (OR=0.65; 95% CI, 0.29 to 1.44; p=0.29) and at 3 years survival was 56% and 21% (OR=0.71; 95% CI, 0.21 to 2.55; p=0.62), respectively.
Two systematic reviews published in 2016 compared RE with TACE for the treatment of unresectable HCC. Lobo et al (2016) selected 5 retrospective observational studies (total N=533 patients) (Lobo, 2016). Survival at 1 year did not differ statistically between RE (42%) and TACE (46%; relative risk [RR], 0.93; 95% CI, 0.81 to 1.08; p=0.33). At 2 years, the survival rate was higher for RE (27% vs 18%; RR=1.36; 95% CI, 1.05 to 1.76; p=0.02), but there was no statistically significant difference in survival rates at 3, 4, or 5 years. Postprocedural complications were also similar in the 2 groups. Facciorusso et al (2016) included 10 studies (total N=1557 patients), two of which were randomized controlled trials (RCTs).11 The OR for survival was not statistically significant at 1 year (OR=1.0; 95% CI, 0.8 to 1.3; p=0.93) but favored RE in years 2 (OR=1.4; 95% CI, 1.1 to 1.90; p=0.01) and 3 (OR=1.5; 1.0 to 2.1; p=0.04).
Vente et al conducted a meta-analysis evaluating tumor response and survival in patients who received 90Y glass or resin microsphere RE for the treatment of primary HCC or metastases from colorectal cancer (CRC) (Vente, 2009). (Refer to the Unresectable Metastatic CRC section for the data from the metaanalysis as pertains to that disease.) Selected studies were from 1986 onward and presented tumor response (measured by computed tomography) and data on median survival times. To allow comparability of results regarding tumor response, the category of “any response” was introduced and included complete remission, partial response, and stable disease. Overall tumor response could only be assessed as any response because response categories were not uniformly defined in the analyzed studies. In 14 articles, clinical data were presented on tumor response and survival for 425 patients with HCC who had received 90Y RE. Treatment with resin microspheres (0.89) was associated with a significantly higher proportion of any response than glass microsphere treatment (0.78; p=0.02). Median survival was reported in 7 studies, in which survival time was defined as survival from microsphere treatment or diagnosis or recurrence of HCC. Median survival from microsphere treatment varied between 7.1 months and 21.0 months, and median survival from diagnosis or recurrence ranged from 9.4 to 24.0 months.
Radioembolization as a Bridge to Liver Transplantation for Unresectable HCC
Salem reported on results of a phase 2 RCT comparing conventional TACE and TheraSphere radioembolization (Y90) for treatment of unresectable, unablatable HCC (Salem, 2016). Twenty-four patients were assigned to Y90 and 21 patients to conventional TACE; the ultimate goal of treatment for these patients was liver transplantation. The primary outcome was time to progression using intention-to-treat analysis. Median follow-up was 17 months. In the conventional TACE group, there were 7 transplants at a median of 9 months (range, 3-17 months). In the Y90 group, there were 13 transplants at a median of 9 months (range, 4-15 months). Median time to progression exceeded 26 months in the Y90 group and 6.8 months in the conventional TACE group (hazard ratio, 0.12; 95% CI, 0.03 to 0.56; p=0.007). Median survival was 19 months in Y90 and 18 months in conventional TACE (p=0.99). Adverse events were similar between groups, with the exception of more diarrhea (21% vs 0%) and hypoalbuminemia (58% vs 4%) in the conventional TACE group. A limitation of the OS analysis was the censoring of the survival outcome at liver transplantation given that transplantation is related to the treatment effect.
Intrahepatic Cholangiocarcinoma
Jia et al (2017) retrospectively reviewed all 24 patients who underwent Y90 RE for unresectable and failed first-line chemotherapy for ICC at a single institution.31 Mean follow-up was 11 months (range, 3-36 months). Median OS from time of diagnosis was 24 months (range, 18-30 months) and from the RE procedure was 9 months (range, 6-12 months). Survival rates at 6, 12, and 30 months was 70%, 33%, and 20%, respectively.
Mosconi et al (2016) retrospectively analyzed 23 consecutive patients with unresectable or recurrent ICC at a single institution (Mosconi, 2016). Overall median survival was 18 months (95% CI, 14 to 21 months). Survival was significantly longer in treatment-naive patients (52 months) than in those who received other treatments before RE (16 months; p=0.009).
2019 Update
A literature search was conducted through May 2019. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Systematic Reviews
Kulik et al published a systematic review of 18 comparative studies and 31 noncomparative studies that included patients with unresectable HCC who needed a liver transplant and received transplant alone or some type of bridging therapy as well (Kulik, 2018). Of the 18 comparative studies, 2 studies (n=257 patients) reported on the incidence of dropout from transplantation wait-lists, and patients receiving bridging therapy. This group had reduced risk of dropout due to disease progression, compared with those receiving transplantation alone (RR=0.32). Between-group differences were not statistically significant for mortality (5 comparative studies; n=531 patients) or recurrence rate (10 comparative studies; n=889 patients). Subgroup analysis was conducted for types of bridging therapy: for all-cause mortality after transplantation, the RR was 1.124 with TAE compared with transplantation alone (1 cohort). For disease recurrence, the RR for this bridging therapy type was 2.374 compared with transplantation alone. No RCTs were identified, and most of the selected studies had a high risk of bias on patient selection, adequate follow-up, and funding source when reported.
Case Series
Chan et al retrospectively analyzed data from 10 patients from a prospectively collected database who were treated with resin- (n=6) or glass-based (n=4) RE for unresectable combined hepatocellular cholangiocarcinoma (Chan, 2017). No toxicities of grade 3 or greater were reported. Seven patients had elevated a-fetoprotein and/or cancer antigen 19-9 levels before treatment: of these, 4 had one or more of the biomarkers decrease by 50% or more, and 2 patients had a decrease of 25% to 49%. According to RECIST version 1.1 criteria, all patients had stable disease; however, under the modified RECIST criteria, 6 patients had a partial response to RE. Median OS from the first RE was 10.2 months, and median PFS from the same time point was 5.2 months. The macrovascular invasion was reported to be a significant prognostic factor of OS (p=0.005).
Hepatic Sarcoma
Miller et al retrospectively reviewed 39 patients with metastatic (n=37) or primary (n=2) liver sarcoma in a multicenter study (Miller, 2018). All patients had received at least 1 course of chemotherapy before receiving resin-based (n=17) or glass-based (n=22) 90Y RE. Most toxicities observed (93%) were grade 1 or 2, and objective response rate (complete and partial responses) was 36%. Six months after treatment, 30 patients showed stable disease or response, and overall median OS was 30 months (95% CI, 12 to 43 months). The study was limited by its retrospective nature and by differences in patient selection and therapy techniques among the 4 centers represented. Also, the study might have been statistically underpowered.
2020 Update
A literature search was conducted through May 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Abdel-Rahman et al conducted a meta-analysis of RCTs comparing RE alone or combined with other systemic or locoregional treatments to placebo, no treatment, or other similar interventions in patients with unresectable HCC (Abdel-Rahman, 2020). Six RCTs (total n=1340) were identified, all of which were assessed by authors as being at high risk of bias. The authors reported the certainty of evidence as low to very low. Meta-analysis was able to be performed using data from more than 1 RCT for few comparisons. Based on meta-analysis of 2 RCTS, disease control rate was not significantly different between RE and sorafenib (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84 to 1.05), though RE was associated with less hand-foot skin reactions (RR, 0.02; 95% CI, 0.00 to 0.06), skin rash (RR, 0.11; 95% CI, 0.04 to 0.34), diarrhea (RR, 0.11, 95% CI, 0.04 to 0.34), and hypertension (RR, 0.10; 95% CI, 0.01 to 0.88). Based on meta-analysis of 3 RCTs, the risk of serious adverse events did not differ between RE and TACE (RR, 1.47; 95% CI, 0.66 to 3.25).
Venerito et al performed a meta-analysis to assess the noninferiority of SIRT as monotherapy or followed by sorafenib versus sorafenib monotherapy on OS (Venerito, 2020). A noninferiority margin of 1.08 in terms of hazard ratio (HR) was prespecified. Three RCTs were included (total n=1,243), and meta-analysis demonstrated SIRT with or without sorafenib was noninferior to sorafenib monotherapy in OS (median, 10.2 and 9.2 months; HR, 0.91; 95% CI, 0.78 to 1.05). Treatment-related severe adverse events were reported in 28.9% vs 43.3% of patients treated with SIRT and sorafenib monotherapy, respectively (p<0.01).
Yang et al conducted a meta-analysis of RCTs to compare effects of DEB-TACE, TACE, and RE on the primary outcome of overall survival (Yang, 2020). Compared with TACE, RE was associated with similar 1-year OS (RR, 0.91; 95% CI 0.79 to 1.05), but a better OS than TACE at 2 years (RR, 0.87; 95% CI, 0.80 to 0.95) and 3 years (RR, 0.90; 95% CI 0.85 to 0.96). Overall survival was not significantly different between RE and DEB-TACE at 1 year (RR, 0.83, 95% CI, 0.68 to 1.02), but DEB-TACE was associated with better OS at 2 years than RE (RR, 0.40; 95% CI, 0.19 to 0.84). However, pooled HRs indicated that RE was superior to TACE in overall survival (HR, 0.84; 95% CI, 0.70 to 1.00) and that DEB-TACE was superior to RE in overall survival (HR, 0.59; 95% CI, 0.38 to 0.91).
Facciorusso et al performed a retrospective analysis that compared patients with HCC treated with RE plus sorafenib (n=45) with propensity score-matched patients treated with sorafenib alone (n=90) (Facciorusso, 2020). No significant differences were identified in median OS (10 vs. 10 months; p=0.711), median PFS (6 versus 7 months; p=0.992), and objective response rate (45.5% versus 42.8%; p=1).
Gabr et al performed a retrospective review that reported on long-term outcomes of liver transplantation for patients with HCC who were bridged or down staged with RE (Gabr, 2020). From 2004 to 2018, 207 patients underwent transplant after RE. Median OS from transplant was 12.5 years, with median time to liver transplantation of 7.5 months (interquartile range, 4.4 to 10.3). Overall, 169 patients were bridged and 38 were down staged to liver transplant. Overall survival rates at 3, 5, and 10 years were 84%, 77%, and 60%, respectively.
Zori et al performed a retrospective cohort analysis that compared patients with HCC undergoing bridging locoregional therapy with RE (n=28) to TACE (n=37) prior to liver transplant (Zori, 2020). Three-year survival was not significantly different with RE vs TACE (92.9% vs. 75.7%; p=0.052). However, microvascular invasion occurred in 3.6% versus 27% of patients treated with RE versus TACE (p=0.013).
Frilling et al reported results from a case series of 24 patients that were then included in a meta-analysis of patients treated with SIRT for neuroendocrine liver metastases (Frilling, 2019). Overall, 26 additional studies were included in the meta-analyses, which reported a fixed-effects weighted averages for objective response rate of 51% (95% CI, 47% to 54%) and disease control rate (complete response, partial response, or stable disease) of 88% (95% CI, 85% to 90%).
Egger et al performed a retrospective cohort analysis comparing patients with neuroendocrine liver metastases treated with RE (n=51) or TACE (n=197) (Egger, 2020). Between RE and TACE, there were no differences in overall morbidity (13.7% vs. 22.6%, respectively; p=0.17), grade 3/4 complication (5.9% vs. 9.2%; p=0.58), 90-day mortality (9.8% vs 5.2%; p=0.21), median OS (35.9 months vs. 50.1 months; p=0.3), or progression-free survival (15.9 vs. 19.9 months; p=0.37). However, disease control rate was greater for TACE compared with RE (96% vs. 83%, p<0.01).
Wasan et al analyzed OS from 3 studies of chemotherapy with and without RE (Wasan, 2017). Overall, 549 patients were randomly assigned to FOLFOX alone and 554 patients were assigned FOLFOX plus SIRT. Overall survival was not significantly different between groups (HR, 1.04; 95% CI, 0.90 to 1.19).
Mokkarala et al performed a propensity score-matched retrospective analysis of patients with colorectal metastases treated with DEB-TACE (n=47) or RE (n=155) (Mokkarala, 2019). Extra-hepatic metastasis was more frequent with DEB-TACE (68.1% vs. 47.7%; p=0.014), as was occurrence of ≥10 liver lesions (42.2% vs. 68.8%; p=0.001). Toxicity was not significantly different between DEB-TACE and RE (27% vs. 9.1%, respectively; p=0.057). Treatment with DEB-TACE was not a prognostic factor for survival (HR, 0.94; 95% CI, 0.54 to 1.65).
Feretis et al performed a systematic review of RE for treatment of metastatic intrahepatic breast cancer (Feretis, 2020). Twelve case series were included (total n=452; range, 7 to 81), with a duration of follow-up ranging from 6 to 15.7 months in studies reporting follow-up duration. Overall, 52.2% of patients had breast metastases not confined to the liver. Radioembolization provided disease control in 81% of patients, and OS ranged from 3.6 to 20.9 months, with an estimated mean survival of 11.3 months.
Rowcroft et al planned to perform a meta-analysis of studies of patients with liver-only metastases of uveal melanoma treated with systemic therapy, isolated hepatic perfusion, hepatic artery infusion, TACE, SIRT, and immunoembolization (Rowcroft, 2020). However, due to heterogeneity in available data, meta-analysis was not performed. The authors descriptively reported that 6 non-comparative retrospective cohort studies (n=150; range, 8 to 71) evaluated the use of SIRT, which reported median OS ranged from 9 to 24 months…
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