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), also known as radioembolization, targets the delivery of small beads or microspheres containing yttrium-90 to the tumor since liver tissue is radiation-sensitive.  This document addresses the use of SIRT. 

Note: For other potential treatments for liver tumors, please see the following documents:

• RAD.00011 Transcatheter Arterial Chemoembolization (TACE) and Transcatheter Arterial Embolization (TAE) for Treating Primary or Metastatic Liver Tumors
• SURG.00065 Locally Ablative Techniques for Treating Primary and Metastatic Liver Malignancies

Medically Necessary:

Selective internal radiation therapy (SIRT) is considered medically necessary as palliative treatment for individuals with:

• Primary hepatocellular carcinoma or metastatic colorectal carcinoma, with symptoms due to hepatic tumor bulk (e.g., pain); or
• Neuroendocrine tumors (e.g., carcinoid tumors, pancreatic islet cell tumors, parathyroid, pituitary angiomas) with hepatic metastases, when systemic therapy has failed to control symptoms such as carcinoid syndrome (e.g., debilitating flushing, wheezing, and diarrhea); or
• Symptoms from non-carcinoid neuroendocrine tumors with hepatic metastases (e.g., hypoglycemia, severe diabetes, Zollinger-Ellison Syndrome).

Investigational and Not Medically Necessary:

Selective internal radiation therapy (SIRT) is considered investigational and not medically necessary when the above criteria are not met.

Selective internal radiation therapy (SIRT) is considered investigational and not medically necessary when used as a bridge to transplantation.

There is extensive published literature regarding technical issues or clinical outcomes of SIRT.  Four of these are reviews of SIRT and other local ablative treatments for liver tumors (Lau, 2003; Ramsey, 2001; Georgiades, 2001; Liu, 2003).  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.

A meta-analysis by Vente and colleagues evaluated the available literature addressing SIRT for unresectable liver metastases (2009).  The authors included all forms of SIRT, including SIR-Spheres and TheraSpheres^®.  This study included 30 articles that included 1,217 subjects.  For individuals with colorectal cancer (CRC) metastases, a total of 19 eligible studies, which included 792 subjects, were included in the analysis.  Of these, 195 had received SIRT as a first-line treatment and 486 received SIRT as salvage therapy.  There was a significant difference in response when used for first-line therapy vs. salvage, with the response rates reported as 91% and 79% respectively (p=0.07).  The median survival, regardless of the microsphere type, chemotherapy protocol, disease stage or salvage vs. first-line, varied between 6.7 to 17 months.  Median survival from time of diagnosis ranged from 10.8 to 29.4 months.  For individuals with hepatocellular carcinoma (HCC), the authors included 14 studies in their analysis.  These studies included 425 subjects who underwent SIRT therapy.  Of these studies, only 12 reported on tumor response, leaving 318 subjects.  The authors noted that treatment with resin microspheres (e.g., SIR-Spheres) was associated with a significantly higher response rate when compared to glass microspheres (e.g., TheraSpheres^®) (89% vs. 78%, p=0.02).  Median survival was reported in only 7 studies.  Median survival from time of SIRT treatment varied between 7.1 to 21 months.  Median survival from time of diagnosis or recurrence was reported to be between 9.4 to 24 months.

SIR-Spheres:  Two reports were found that address the same randomized trial of individuals 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, reports that the study was initially designed to enroll 95 subjects (Gray; 2001). 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 subjects (n=70 eligible for randomization).  Reasons cited for the early closure included:  1) increasing individual 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).  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 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 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 subjects (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 21 subjects 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 individuals with liver metastases of colorectal cancer, but included variable percentages of individuals with clear contraindications to SIRT (16%–50% of subjects had documented extrahepatic disease) and all 3 failed to clearly document other important 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.

A retrospective case series study was published by Kennedy and colleagues in 2008.  This study included 148 subjects with hepatic metastases from neuroendocrine tumors including pancreas, lung, colon, ovary, kidney and small intestine. The mean follow-up period was 42 months at the time of publication.  The authors report that there were no acute or delayed toxicity-related adverse events in 67% of the subjects.  Fatigue was reported by 6.5% and nausea and pain reported by 3.2% and 2.7% respectively.  Response to treatment, judged by imaging response was reported to be 90%, with stable disease in 22.7%, partial response in 60.5%, complete response in 2.7%, and progressive disease in 4.9%. The authors indicate there were some participants lost to follow-up, but no details are provided.  The report concludes by noting that compared to data from other studies, SIRT for the treatment of neuroendocrine tumors demonstrates a similar safety profile, improvement in debulking of tumor and survival is similar to other local treatment methods, and that controlled prospective studies are warranted to further investigate these potential benefits.

TheraSpheres:  The largest single series was reported by Salem and colleagues (2002), and described treating approximately 300 subjects 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 subjects and did not specify inclusion or exclusion criteria for treatment.  Investigators only reported outcomes for a cohort of 54 HCC subjects with Okuda stage I and II (median survival: 23 and 11 months, respectively; overall survival at 1 year: 68% and 37%, respectively).  Other early studies were uncontrolled clinical series of 22 subjects with unresectable HCC (Dancey, 2000) or 37 subjects 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 subjects 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 subjects with unresectable HCC (2006). Of the 34 initially staged as UNOS T3, 19 (56%) were downgraded to stage T2 following treatment with yttrium-90 (⁹⁰Y).  Eight 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.

Several case series studies of TheraSpheres were published in 2008.  The largest by Sato and colleagues included 147 subjects with chemo-refractory metastatic hepatic tumors from a variety of primary tumors including colon, breast, neuroendocrine, cholangiocarcinoma and others.  Clinical toxicities reported include fatigue (56%), pain (26%) and nausea (23%).  Imaging response was 42.8% (2.1% complete, 40.7% partial) and biological tumor response 87%.  One year survival was 47%, 2 year survival was 30.9% and overall median survival was 300 days.  Median survival according to primary tumor site was: 457 days for colorectal cancer, 776 days for neuroendocrine tumors, and 207 days for non-colorectal and non-neuroendocrine tumors.  The authors note that the majority of subjects in this study were treated prior to the availability of growth factor inhibitors, which makes the impact of such treatment in conjunction with SIRT impossible to assess on this data.  They also note the heterogeneous population and open label study methodology makes the findings difficult to generalize to other populations.

In 2009, Mulcahy and others reported on a case series study involving 72 subjects with CRC.  The tumor response rate was reported to be 40.3%.  Median time to hepatic progression was 15.4 months and median duration of response was 15 months.  The PET response rate was 77%.  Overall survival from time of first treatment with SIRT was 14.5 months.  The authors noted that survival was significantly impacted by tumor volume, with individuals with less than or equal to 25% tumor replacement volume having a mean survival rate of 18.7 months vs. 5.2 months for those with greater than or equal to 25% tumor replacement volume.  Additionally, the presence of extrahepatic disease had a significant impact on survival. Subjects with extrahepatic disease had an overall survival of 7.9 months vs. 21 months for those without.

Salem and colleagues published the findings of a large prospective case series study in 2009.  This study included 291 participants with HCC.  Using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines, response rates were reported to be 42% and 57% respectively.  Survival times differed significantly between individuals with Child-Pugh A and Child-Pugh B classifications, with the former surviving a mean of 17.2 months and the latter 7.7 months.  Furthermore, individuals with Child-Pugh B class disease with portal vein thrombosis (VT) survived a mean of 5.6 months.  Similar findings regarding the impact of VT on SIRT outcomes were reported by Woodall (2009).

Non-commercial microspheres:  Several articles described the use of SIRT with non-commercial forms of ⁹⁰Y microspheres in 301 subjects (n=294 with HCC).  These were generally uncontrolled clinical series of heterogeneous subject 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 subjects (19.5 months) compared to HAI treatment of 53 subjects (6.5 months).  However, the study did not provide data on baseline characteristics of the HAI-treated subjects or describe the HAI treatment regimen.  In summary, the variability in 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 subjects to prospectively evaluate the efficacy and safety of Selective Internal Radiation (SIR) spheres in individuals with inoperable liver metastases from colorectal cancer who have failed 5FU based chemotherapy.  Thirty subjects were treated between January 2002 and March 2004.  As of July 2004 the median follow-up is 18.3 months. Median participant 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."

Cianni and colleagues reported the use of an unspecified ⁹⁰Y microsphere product on 110 subjects with liver metastases from a wide variety of primary cancers, including: colorectal, breast, gastric, pancreatic, pulmonary, esophageal, pharyngeal, cholangiocarcinoma and melanoma (2010).  The authors reported complete or partial response in 45 subjects, stable disease in 42 subjects and progressive disease in 23 subjects.  While the results in this study are promising for cancers beyond the previously discussed and well studied indications (HCC, colorectal, etc.), the data presented for others such as esophageal, breast etc. are hampered by small sample sizes.  Further studies with larger sample sizes are needed.  The authors themselves state that "Further phase III clinical trials should clearly determine the real and effective impact of radioembolization with Y-90 on survival rates, experimenting with the combination of SIRT, chemotherapy and modern biological agents as a first-line treatment."

In summary, most studies addressing the use of SIRT for hepatic tumors are uncontrolled and have relatively short-term follow-up.  However, there is sufficient data to demonstrate that there is a significant palliative benefit derived from SIRT.  The published data to date supports the ability of SIRT to provide short-term symptom control for individuals suffering from hepatic tumors by decreasing tumor bulk and reducing neuroendocrine and endocrine effects of hepatic metastases.

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 individuals with primary cancers other than 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 individuals with unresectable hepatic metastases from CRC.  However, durable responses to chemotherapy are less likely for those 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., glass versus resin, respectively) 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.

Palliative care: Medical treatments that are intended to alleviate pain and suffering.

The following codes for treatments and procedures applicable to this document 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 may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

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. Cao CQ, Yan TD, Bester L, et al. Radioembolization with yttrium microspheres for neuroendocrine tumour liver metastases. Br J Surg. 2010; 97(4):537-543.   
3. Cianni R, Urigo C, Notarianni E, et al. Radioembolisation using yttrium 90 (Y-90) in patients affected by unresectable hepatic metastases. Radiol Med. 2010; 115(4):619-633.
4. 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.
5. Dunfee BL, Riaz A, Lewandowski RJ, et al. Yttrium-90 radioembolization for liver malignancies: prognostic factors associated with survival. J Vasc Interv Radiol. 2010; 21(1):90-95.
6. 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.
7. 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.
8. 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. 
9. Gulec SA, Fong Y.  Yttrium 90 microsphere selective internal radiation treatment of hepatic colorectal metastases. Arch Surg. 2007; 142(7):675-682.
10. Herba MJ, Thirlwell MP.  Radioembolization for hepatic metastases. Semin Oncol. 2002; 29(2):152-159.
11. 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.
12. 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.
13. Kennedy A, Nag S, Salem R, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: a consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys. 2007; 68(1):13-23.
14. 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.
15. Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol. 2008; 31(3):271-279. 
16. King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer. 2008; 113(5):921-929. 
17. 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.
18. Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology. 2008; 47(1):71-81. 
19. 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.
20. 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. 
21. 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: 171-179.
22. 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.
23. 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.
24. 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.
25. Liu LX, Zhang WH, Jiang HC. Current treatment for liver metastases from colorectal cancer.  World J Gastroenterol 2003; 9(2):193-200.
26. Liu MD, Uaje MB, Al-Ghazi MS, et al. Use of Yttrium-90 TheraSphere for the treatment of unresectable hepatocellular carcinoma. Am Surg. 2004; 70(11):947-953.
27. 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.
28. 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.
29. Mulcahy MF, Lewandowski RJ, Ibrahim SM, et al. Radioembolization of colorectal hepatic metastases using yttrium-90 microspheres. Cancer. 2009; 115(9):1849-1858.
30. Ramsey DE, Geschwind JF. New interventions for liver tumors.  Semin Roentgenol. 2002; 37(4):303-311.
31. Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg. 2008; 247(6):1029-1035.
32. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2009; 138(1):52-64.
33. 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.
34. Salem R, Lewandowski R, Roberts C, et al. Use of Yttrium-90 glass microspheres (TheraSphere) for the treatment of unresectable hepatocellular carcinoma in patients with portal vein thrombosis. J Vasc Interv Radiol. 2004; 15(4):335-345.
35. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2010; 138(1):52-64. 
36. 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.
37. Sato KT, Lewandowski RJ, Mulcahy MF, et al., Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres--safety, efficacy, and survival. Radiology, 2008; 247(2):507-515.
38. Sato K, Lewandowski RJ, Bui JT, et al. Treatment of unresectable primary and metastatic liver cancer with yttrium-90 microspheres (TheraSphere): assessment of hepatic arterial embolization. Cardiovasc Intervent Radiol. 2006; 29(4):522-529.
39. Sato KT, Omary RA, Takehana C, et al. The role of tumor vascularity in predicting survival after yttrium-90 radioembolization for liver metastases. J Vasc Interv Radiol. 2009; 20(12):1564-1569. 
40. Saxena A, Chua TC, Bester L, et al. Factors predicting response and survival after yttrium-90 radioembolization of unresectable neuroendocrine tumor liver metastases: a critical appraisal of 48 cases. Ann Surg. 2010; 251(5):910-916.
41. Steel J, Baum A, Carr B.  Quality of life in patients diagnosed with primary hepatocellular carcinoma: hepatic arterial infusion of cisplatin versus 90-yttrium microspheres (Therasphere) Psycho-oncology. 2004; 13(2):73-79.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. Van Hazel G, Pavlakis N, Goldstein D, et al. Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using Yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy. J Clin Oncol. 2009; 27(25):4089-4095.
48. Vente MA, Wondergem M, van der Tweel I, et al. Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis. Eur Radiol. 2009; 19(4):951-959.
49. Woodall EC, Scoggins CR, Ellis SF, et al. Is selective internal radioembolization safe and effective for patients with inoperable hepatocellular carcinoma and venous thrombosis? J Am Coll Surg. 2009; 208(3):375-382.
50. Young JY, Rhee TK, Atassi B, et al. Radiation dose limits and liver toxicities resulting from multiple yttrium-90 radioembolization treatments for hepatocellular carcinoma. J Vasc Interv Radiol. 2007; 18(11):1375-1382.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American College of Radiology (ACR) Practice Guideline for Radioembolization with Microsphere Brachytherapy Device (RMBD) for Treatment of Liver Malignancies. 2008. Available at: http://www.acr.org/SecondaryMainMenuCategories/quality_safety/guidelines/ro.aspx. Accessed on August 26, 2011.
2. NCCN: Practice Guideline in Oncology. Available at: http://www.nccn.org/index.asp. Accessed on August 26, 2011.
   • Colon Cancer. v3.2011. February 25, 2011. 
   • Neuroendocrine Tumors. v2.2011. April 14, 2011.
   • Hepatobiliary Cancers. v2.2011. May 29, 2011.
3. Townsend A, Price T, Karapetis C. Selective internal radiation therapy for liver metastases from colorectal cancer. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD007045.

Colorectal Cancer
Hepatic Metastases
Hepatocellular Carcinoma
Liver Tumors
Metastatic Liver Tumors
Radioembolization
Selective Internal Radiation Therapy
Selective Internal Radiation Treatment
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.