At the time of diagnosis, most liver tumors, whether primary or from metastases, are unresectable and chemotherapy is generally only palliative. Consequently, various alternative therapies have been investigated for potential palliation or even cure of unresectable liver tumors.  Some examples of such treatments include cryosurgery, radiofrequency ablation, and chemoembolization.  One of these therapies, Selective Internal Radiation Therapy (SIRT), targets the delivery of small beads or microspheres containing yttrium-90 to the tumor since liver tissue is radiation-sensitive.  This policy addresses the use of SIRT.

Investigational/Not Medically Necessary:

Selective internal radiation therapy (SIRT) is considered investigational/not medically necessary for all indications including, but not limited to, the treatment of primary or metastatic tumors of the liver.
 

There is extensive published literature regarding technical issues or clinical outcomes of SIRT.  Four of these are recent reviews of SIRT and other local ablative treatments for liver tumors (Lau, 2003; Ramsey, 2001; Georgiades, 2001; Liu, 2003).   An additional review focuses on outcomes of SIRT reported in studies published through 1994 Ho (1998). 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 for detailed review that: 1) included 10 or more patients being treated for primary or metastatic hepatic tumors; 2) reported health outcomes (i.e., survival, response duration); and 3) 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 non-commercial microspheres.

SIR-Spheres:  Two reports were found that address the same 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).  The first paper by Moroz and colleagues (2001) reported on changes in normal liver and spleen volume following HAI+SIRT, but did not provide data on long-term treatment outcomes.  The second paper, which is the main report of this study, Gray (2001) reports that the study was initially designed to enroll 95 patients. The study detected a 30% increase in median survival for those in the experimental arm compared with controls, with 90% power and 95% confidence.  However, 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 study population 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). Theyalsoreportedincreasedtimetodisease 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 differencesbetween treatment arms in actuarial survival rates (p= 0.18 by log rank 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 aninstitutional 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 (Kemeny, 2002; Meta-Analysis Group, 1996).   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.

Several additional studies were identified that used SIR-Spheres® with HAI and reported outcome data in some form.  One small randomized controlled trial was reported by Van Hazel and colleagues (2006). This study included only 21 patients with untreated advanced colorectal metastases within the liver.  Longer time to progressive disease was reported in the group treated with SIRT combined with HAI when compared to the group treated with HAI-alone (18.6 months vs. 3.6 months).  Median survival time was also significantly better in the combination treatment group, 29.4 months vs. 12.8 months in the HAI-alone group.  The authors reported no difference in quality of life measurements between groups at 3 months.  The authors’ note that only limited conclusions can be drawn from the results due to the small number of study subjects.   The other studies were uncontrolled clinical series (Gray, 2000; Stubbs, 2001) or included retrospective control groups treated with HAI alone Stubbs (2001). 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 and colleagues (2002) 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 hepatocellular carcinoma (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 (Dancey, 2000) or 37 patients with unresectable colorectal liver metastases (Herba, 2002) and reported no, or only limited, survival data (e.g., 54-week median survival in Dancey and colleagues (2000).  None adequately reported palliative outcomes or effects of SIRT on disease symptoms.

In 2004, Steel and colleagues reported on a non randomized parallel cohort study of health related quality of life in 28 patients with primary HCC treated with SIRT (TheraSpheres) compared to HAI alone.  The authors concluded that further research “that includes a larger sample size and longer follow-up is necessary to make definitive conclusions regarding the efficacy and effect on health related quality of life.”

A case series study by Kulik and colleagues details the use of TheraSpheres in 150 patients with unresectable HCC (2006). Of the 34 patients initially staged as UNOS T3, 19 (56%) were downgraded to stage T2 following treatment with ⁹⁰Y.  Eight patients were successfully downgraded and received orthotopic liver transplants following treatment.  The authors report survival to be 84%, 54% and 27% at 1, 2, and 3 years respectively.

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, 1998; 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.

In 2005, Lim and colleagues reported on a study of 32 patients to prospectively evaluate the efficacy and safety of Selective Internal Radiation (SIR) spheres in patients with inoperable liver metastases from colorectal cancer who have failed 5FU based chemotherapy.  Thirty patients were treated between January 2002 and March 2004. As of July 2004 the median follow-up is 18.3 months. Median patient age was 61.7 years (range 36-77). The authors concluded that: “In patients with metastatic colorectal cancer that have previously received treatment with 5-FU based chemotherapy, treatment with SIR-spheres has demonstrated encouraging activity. Further studies are required to better define the subsets of patients most likely to respond.”

Hepatic (liver) tumors can arise either as primary liver cancer or by metastasis to the liver from other tissues or organs.  Local therapy for hepatic metastasis is indicated only when there is no extrahepatic disease, which rarely occurs for patients with primary cancers other than colorectal carcinoma (CRC) or certain neuroendocrine malignancies.  At present, surgical resection with tumor-free margins and liver transplantation are the only potentially curative treatments.  For liver metastases from CRC, randomized trials have reported that post-surgical adjuvant chemotherapy (administered systemically or via the hepatic artery) decreases recurrence rates and increases time to recurrence.  Important prognostic factors for survival include site and extent of primary tumor, hepatic tumor burden, and performance status.

Unfortunately, most hepatic tumors are unresectable at diagnosis, due either to their anatomic location, size, number of lesions, concurrent nonmalignant liver disease, or insufficient hepatic reserve.  Palliative chemotherapy by combined systemic and hepatic artery infusion (HAI) may increase disease-free intervals for patients with unresectable hepatic metastases from CRC.  However, durable responses to chemotherapy are less likely for patients with unresectable primary hepatocellular cancer (HCC).

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, particle and wave physics (microwave or laser ablation), or pharmacologic/biochemical interventions.  Another of these, selective internal radiation therapy (SIRT), relies on targeted delivery of small beads (microspheres) impregnated with radioactive yttrium-90 (⁹⁰Y).  The rationale for SIRT is based on the following:  1) the liver parenchyma is sensitive to radiation; 2) 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; and 3) ⁹⁰Y 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 SIRT are initially examined by liver angiography and technetium (^99mTm) lung scan to rule out aberrant hepatic vasculature or significant lung shunting that would permit diffusion of injected microspheres.

Currently two commercial forms of ⁹⁰Y microspheres are available: TheraSpheres® (MDS Nordion, Ottowa, Canada) and SIR-Sphere® (Sirtex Medical Limited; Lake Forest, IL).  Non-commercial forms are used mostly outside the United States.  While the commercial products use the same radioisotope (⁹⁰Y) and have the same target dose (100 Gy), they differ in microsphere size profile, base material (i.e., resin versus glass) and size of commercially available doses.  These 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.  Note also that the U.S. Food and Drug Administration (FDA) granted premarket approval of SIR-Sphere®, for use in combination with 5-floxuridine (5-FUDR) chemotherapy by HAI, to treat unresectable hepatic metastases from colorectal cancer.  In contrast, TheraSpheres® is approved by humanitarian device exemption (HDE) for use as monotherapy to treat unresectable HCC.  For these reasons, results obtained with one product do not necessarily apply to other commercial (or non-commercial) products.

Metastatic tumor:  a cancerous tumor that has spread beyond the boundaries of the primary organ to other organs and/or lymph nodes

The following codes for treatments and procedures applicable to this policy are included below for informational purposes.   Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.   Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational/Not Medically Necessary:

HCPCS

ICD-9 Diagnosis

Peer Reviewed Publications:

1. Cao X, He N, Sun J, et al. Hepatic radioembolization with Yttrium-90 glass microspheres for treatment of primary liver cancer.  Chin Med J. (Engl) 1999; 112(5):430-432. 
2. Dancey JE, Shepherd FA, Paul K, et al.  Treatment of nonresectable hepatocellular carcinoma with intrahepatic ⁹⁰Y-microspheres.  J Nucl Med. 2000; 41(10):1673-1681. 
3. Georgiades CS, Ramsey DE, Solomon S, et al. New non-surgical therapies in the treatment of hepatocellular carcinomas.  Tech Vasc Intervent Radiol. 2001; 4(3):193-199. 
4. Gray B, Van Hazel G, Buck M, et al.  Treatment of colorectal liver metastases with SIR-Spheres plus chemotherapy.  GI Cancer. 2000; 3(4):249-257. 
5. Gray B, Van Hazel G, Hope M, et al. Randomized trial of SIR-Spheres® plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer.  Ann  Oncol.. 2001; 12(12):1711-1720. 
6. Herba MJ, Thirlwell MP.  Radioembolization for hepatic metastases.  Semin Oncol. 2002; 29(2):152-9. 
7. Ho S, Lau WY, Leung TW, et al.  Internal radiation therapy for patients with primary or metastatic hepatic cancer.  Cancer. 1998; 83(9):1894-1907. Kemeny MM, Adak S, Gray B, et al.  Combined-modality treatment for respectable colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy – an intergroup study.  J Clin Oncol. 2002; 20(6):1499-1505.
8. Kennedy AS, Coldwell D, Nutting C, et al.  Resin ⁹⁰Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience. Int J Radiat Oncol Biol Phys. 2006; 65(2):412-425. 
9. Kulik LM, Atassi B, van Holsbeeck L, et al. Yttrium-90 microspheres (TheraSphere(R)) treatment of unresectable hepatocellular carcinoma: Downstaging to resection, RFA and bridge to transplantation. J Surg Oncol. J Surg Oncol. 2006; 94(7):572-586.
10. Lau WY, Ho S, Leung TW, et al.  Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intra-arterial infusion of ⁹⁰Yttrium microspheres.  Int J Radiat Oncol Biol Phys. 1998; 40(3):583-592. 
11. Lau WY, Ho S, Leung WT, et al.  What determines survival duration in hepatocellular carcinoma treated with intra-arterial yttrium-90 microspheres?  Hepatogastroenterology. 2001; 48(38):338-340.  
12. Lau WY, Leung TW, Yu SC, et al. Percutaneous local ablative therapy for hepatocellular carcinoma.  A review and look into the future.  Ann Surg 2003; 237(2):171: 171-9. 
13. Lau WY, Leung WT, Ho S, et al.  Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study.  Br J Cancer. 1994; 70(5):994-999. 
14. Leung TW, Lau WY, Ho SK, et al.  Radiation pneumonitis after selective internal radiation treatment with intra-arterial ⁹⁰yttrium-microspheres for inoperable hepatic tumors.  Int J Radiat Oncol Biol Phys. 1995; 33(4):919-924. 
15. Lim L, Gibbs P, Yip D, et al. Prospective study of treatment with selective internal radiation therapy spheres in patients with unresectable primary or secondary hepatic malignancies. Intern Med J. 2005; 35(4):222-227.
16. Liu LX, Zhang WH, Jiang HC. Current treatment for liver metastases from colorectal cancer.  World J Gastroenterol 2003; 9(2):193-200. 
17. Meta-Analysis Group in Cancer.  Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer.  J Natl Cancer Inst. 1996; 88(5):252-258. 
18. Moroz P, Anderson JE, Van Hazel G, et al.  Effect of selective internal radiation therapy and hepatic arterial chemotherapy on normal liver volume and spleen volume.  J Surg Oncol. 2001; 78(4):248-252. 
19. Ramsey DE, Geschwind JF. New interventions for liver tumors.  Semin Roentgenol. 2002; 37(4):303-311. 
20. Salem R, Thurston KG, Carr BI. et al.  Yttrium-90 microspheres: radiation therapy for unresectable liver cancer.  J Vasc Interv Radiol. 2002; 13(9 Pt 2):S223-S229. 
21. Salem R, Lewandowski RJ, Atassi B, et al.  Treatment of unresectable hepatocellular carcinoma with use of 90Y microspheres (TheraSphere): safety, tumor response, and survival. J Vasc Interv Radiol. 2005; 16(12):1627-1639. 
22. Steel J, Baum A, Carr B.  Quality of life in patients diagnosed with primary hepatoccellular carcinoma:   hepatic: hepatic arterial infusion of cisplatin versus 90-yttrium microspheres (Therasphere)  Psycho-oncology. 2004;13:73-79. 
23. Stubbs RS, Cannan RJ, Mitchell AW.  Selective internal radiation therapy with ⁹⁰Yttrium microspheres for extensive colorectal liver metastases.  J Gastrointest Surg. 2001; 5(3):294-302. 
24. Stubbs RS, Cannan RJ, Mitchell AW.  Selective internal radiation therapy (SIRT) with ⁹⁰Yttrium microspheres for extensive colorectal liver metastases.  Hepatogastroenterology.. 2001; 48(38):333-337. 
25. Tian JH, Xu BX, Zhang JM, et al.  Ultrasound-guided internal radiotherapy using yttrium-90-glass microspheres for liver malignancy.  J Nucl Med. 1996; 37(6):958-963. 
26. Trinchet JC, Ganne-Carrie N, Beaugrand M.  Review article:  intra-arterial treatments in patients with hepatocellular carcinoma.  Aliment Pharmacol Ther. 2003; 17(suppl. 2):111-118. 
27. Van Hazel G, Blackwell A, Anderson J, et al.  Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol. 2004; 88(2):78-85.

Colorectal Cancer
Hepatocellular Carcinoma
Hepatic Metastases
Liver Tumors
Metastatic Liver Tumors
Selective Internal Radiation Treatment
Selective Internal Radiation Therapy
SIR®-Spheres®
SIRT
TheraSphere®
yttrium-90 Microspheres

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member's contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

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