|Subject:||Selective Internal Radiation Therapy (SIRT) of Primary or Metastatic Liver Tumors|
|Policy #:||THER-RAD.00006||Current Effective Date:||01/05/2016|
|Status:||Reviewed||Last Review Date:||11/05/2015|
This document addresses the use of Selective Internal Radiation Therapy (SIRT). At the time of diagnosis, most liver tumors, whether primary or from metastases, are unresectable and chemotherapy is generally only palliative. Various locoregional therapies have been investigated for potential palliation or even cure of unresectable liver tumors. Some examples of such treatments include cryosurgery, radiofrequency ablation (RFA), and transcatheter arterial chemoembolization (TACE). One of these therapies, SIRT, also known as radioembolization, targets the delivery of small beads or microspheres containing yttrium-90 (90Y) to the tumor since liver tissue is radiation-sensitive.
Note: Please see the following related documents for additional information:
Investigational and Not Medically Necessary:
SIRT is considered investigational and not medically necessary when the above criteria are not met.
Two commercial forms of 90Y have received approval by the United States (U.S.) Food and Drug Administration (FDA). TheraSphere® (MDS NordianTM Inc., Ottawa, Ontario) received premarket approval (PMA) in 1997 and SIR-Spheres® (Sirtex Medical Inc., Lake Forest, IL) received approval in 2002 under an FDA Humanitarian Device Exemption (HDE). The uses of both technologies are additionally regulated by the U.S. Nuclear Regulatory Commission (NRC).
There is extensive published literature regarding technical issues and clinical outcomes of SIRT and other locally ablative treatments for liver tumors. Current evidence presents favorable effects of SIRT on locoregional control of liver cancer; yet most lack long-term follow-up data to document the duration of responses or survival after SIRT. At present, no large randomized controlled trial has been published on the safety and efficacy of SIRT, though a growing body of lower level evidence has led to expert consensus support for a limited number of indications. Larger Phase III trials are underway.
Liver-Related Symptoms Due to Tumor Bulk
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 palliative benefit from SIRT for hepatic tumors related to a wide variety of primary cancers. The published data supports the ability of SIRT to provide, at minimum, short-term symptom control by decreasing tumor bulk and reducing the neuroendocrine and endocrine effects of hepatic metastases. SIRT has become widely accepted as a treatment of specific liver-related symptoms due to tumor bulk (for example, pain) from primary or metastatic hepatic tumors.
SIRT for Hepatocellular Carcinoma (HCC)
In 2009, Salem and colleagues published the findings of a large prospective case series. This study included 291 participants with unresectable 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 (PVT) survived a mean of only 5.6 months. Similar findings regarding the impact of PVT on SIRT outcomes were reported by Woodall (2009).
Vente and colleagues (2009) conducted a meta-analysis of the literature addressing SIRT for unresectable liver metastases. The authors included all forms of SIRT, including SIR-Spheres and TheraSpheres, analyzing 30 articles that included 1217 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 versus salvage, with the response rates reported as 91% and 79% respectively (p=0.07). The median survival time varied between 6.7 to 17 months, irrespective of microsphere type, chemotherapy regimen, disease stage, or salvage versus first-line therapy. Median survival from time of diagnosis ranged from 10.8 to 29.4 months. For individuals with 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 seven 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.
In 2011, Sangro and colleagues reported the results of a large case series study of 325 subjects with unresectable HCC who were not considered candidates for other therapeutic approaches and who were treated with SIR-spheres. The median overall survival (OS) was 12.8 months, which varied significantly by disease stage (Barcelona Clinic Liver Cancer staging system [BCLC] A, 24.4 months; BCLC B, 16.9 months; BCLC C, 10.0 months). Survival also varied significantly by ECOG status, hepatic function (Child-Pugh class, ascites, and baseline total bilirubin), tumor burden (number of nodules, alpha-fetoprotein), and presence of extra-hepatic disease. The most significant independent prognostic factors for survival in a multivariate analysis were ECOG status, tumor burden (nodules > 5), international normalized ratio > 1.2, and extra-hepatic disease. Common adverse events included fatigue, nausea/vomiting, and abdominal pain. Grade 3 or higher increases in bilirubin were reported in 5.8% of subjects. All-cause mortality was 0.6% and 6.8% at 30 and 90 days, respectively. The authors concluded that their analysis provided robust evidence of the survival achieved with SIRT, including those with advanced disease and few treatment options. However, the fact that some study centers used retrospectively collected data (n=216) and others prospective data (n=109) introduces potential for bias into this study. Additionally, both the selection criteria and treatment protocols varied between treatment centers and study subjects who had received SIRT as a first-line therapy or for those who had received prior surgical and non-surgical treatments but had progressive disease. Such variations introduce methodological issues which have not been controlled for in the statistical analysis.
In 2011, Salem and colleagues reported the results of a retrospective comparative study of 245 subjects with unresectable HCC treated with TACE (n=122) or SIRT with TheraSpheres(n=123). A total of 75 subjects (30%) did not complete the study (n=44, SIRT arm; n=31, TACE arm) due to transplantation (n=73) or resection (n=2). The authors reported a median time to partial response as measured by WHO criteria was shorter with SIRT than TACE (6.6 vs. 10.3 months, p=0.05). Using the EASL necrosis criteria, the response rates were similar (TACE, 69%; SIRT, 72%; p=0.75), with faster time to EASL response with SIRT (1.2 vs. 2.2 months, p=0.016). Of the remaining 170 subjects, 96 progressed (n=42, SIRT arm; n=54, TACE arm). For median time to progression (TTP), SIRT outperformed TACE (13.3 months vs. 8.4 months, p=0.046). A total of 113 subjects died (n= 59 for TACE, n=54 for SIRT) during the median follow-up time (32.6 months for TACE and 22.7 months for SIRT). In both univariate and multivariate analyses, treatment group was not found to be a significant prognostic factor in survival, but female gender (hazard ratio [HR]=1.69), ECOG status =0 (HR=0.57), Child-Pugh class A (HR=0.58) and United Network for Organ Sharing (UNOS) T1/T2 (HR=0.33) were. Authors concluded that survival times were not significantly different but SIRT demonstrated a longer TTP and reduced toxicity when compared to TACE. Study limitations include a lack of randomization and blinding, a 12-month difference in median follow-up time and a retrospective analysis.
Four additional studies have been published in the past 5 years similarly comparing the safety and efficacy of TACE compared to SIRT in the treatment of unresectable HCC (El Fouly, 2015; Kolligs, 2015; Lance, 2011; Morena-Luna, 2013). These studies include three retrospective comparative studies (combined n=173) and one prospective, open-label multicenter randomized-controlled pilot study (n=28). The studies varied on SIRT's utility as primary versus salvage treatment and outcomes from tumor response versus OS and quality of life outcomes. Some included subjects with PVT or minimal extra-hepatic disease while others excluded for any evidence of PVT or extra-hepatic disease. In aggregate, these studies concluded that outcomes were comparable between SIRT and TACE for unresectable HCC, but SIRT resulted in fewer complications and less hospitalization when compared to TACE.
Several other small studies recently published show a survival or outcome benefit with SIRT in unresectable HCC. A small case-control study by Kwok and colleagues (2014) compared data retrospectively for 30 individuals that received SIRT and 16 that did not; cases were matched on a number of characteristics including liver disease stage, tumor type, size and mean age. SIRT was an independent predictor of survival, but authors also noted that 13% of subjects developed radiation-induced liver disease.
Vouche and colleagues (2014) prospectively assessed the effect of SIRT for radiation segmentectomy on OS and several intermediate outcomes in 102 individuals with treatment naïve, unresectable, solitary HCC ≤ 5 cm, not amenable to RFA. The median TTP was 22.1 months and 33% (33/102) of subjects were transplanted within a median time-frame of 6.3 months. Median OS was 53.4 months. The authors concluded that radiation segmentectomy is effective with a favorable risk prolife for solitary HCC ≤ 5 cm.
Gramenzie and colleagues (2015) retrospectively assessed the efficacy and safety of SIRT (n=63) compared to sorafenib (n=74) for unresectable HCC in 137 subjects. Cases included had a Child-Pugh class A or B, performance status ≤ 1, no metastases and no previous systemic therapy. Median OS of the two groups were comparable, being 14.4 months in sorafenib and 13.2 months in SIRT participants, with 1-, 2- and 3-year survival rates of 52.1%, 29.3% and 14.7% vs 51.8%, 27.8% and 21.6% respectively. A total of 2 SIRT participants underwent liver transplantation after successful downstaging; no sorafenib participants were downstaged to transplant. Authors conclude that "Further studies are needed to define the precise role of [SIRT] in the composite scenario of HCC treatments, in a perspective that considers not only prognosis, but also quality of life."
The National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology® for HCC (2015) states the following with Category 2A recommendations in the Principles of Locoregional Therapy section:
Bridge to Transplantation
SIRT has also been proposed as a treatment for subjects who have exhausted other treatment options, but continue to be viable candidates for orthotopic liver transplantation (OLT).
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 90Y. A total of 8 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.
In 2009, Lewandowski and colleagues published the results of a nonrandomized controlled study that compared TACE (n=43) to SIRT with Theraspheres (n=43) as a method of downstaging subjects with T3 HCC as a bridge to transplantation. The authors reported that successful downstaging to T2 was observed in 31% (11/35) of TACE subjects and 58% (25/42) of SIRT subjects (p=0.023). This trend was noted in all lesion sizes. The median time to UNOS downstaging was not reached in the TACE group, but was reported as 3.1 months in the SIRT group (p=0.027). There was no significant difference in the number of subjects downstaged to resection, but 8 TACE and 18 SIRT subjects were downstaged to RFA treatment. The median WHO time to progressive disease was 19.6 months in the TACE group vs. 48.6 months in the SIRT group (p=0.008). The 1-year progression rates according to EASL criteria were 4% in the TACE group and 8% in the SIRT group (p=0.01). Using the UNOS criteria, TTP was 18.2 months for the TACE group and 33.3 months in the SIRT group. For TACE, OS without censoring to radical therapies (for example, transplantation/resection) at 1, 2 and 3 years were 75%, 42% and 19% , and 81%, 69% and 59%, respectively, for the SIRT group (p=0.008). When censored to radical therapies, OS at 1, 2 and 3 years were 73%, 28% and 19% for the TACE group and 77%, 59% and 45% , respectively, for the SIRT group (p=0.18). A total of 2 out of 11 of the TACE subjects had relapsed following transplantation with a 1-year relapse free-survival of 73%, 2 out of the 9 SIRT subjects relapsed following transplantation with a 1-year relapse-free survival of 89%. This difference was not found to be statistically significant.
SIRT for Treatment of Metastatic Tumors to the Liver
Two reports were published from a single randomized trial of individuals with unresectable metastases from CRC treated with hepatic artery infusion (HAI) of 5-fluorodeoxyuridine (5-FUDR) alone (n=34) or HAI of 5-FUDR with SIRT (n=36). The first published report 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 report, the main report of this study, describes how it was initially designed to enroll 95 subjects (Gray; 2001). However, when investigators detected 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 only 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 TTP (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 (CT) 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 TTP 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. Limitations to this study include: (1) accrual was halted early, leaving the study underpowered; (2) early closure was at the sole discretion of the principal investigator without independent review or prospectively designed data monitoring procedures and stopping rules; (3) 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; and (5) they did not report on survival.
In 2005, Lim and colleagues reported on a study of 32 subjects to prospectively evaluate the efficacy and safety of SIRT in individuals with inoperable liver metastases from CRC who have failed 5-FU based chemotherapy. A total of 30 subjects were treated between January 2002 and March 2004. In July 2004, the median follow-up was 18.3 months. Median participant age was 61.7 years (range 36-77 years). The authors concluded that: "In patients with metastatic CRC 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."
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 demonstrated a similar safety profile, improvement in debulking of tumor and survival similar to other local treatment methods, and that controlled prospective studies are warranted to further investigate these potential benefits.
In 2009, Mulcahy and others reported on a case series study involving 72 subjects with hepatic tumors from metastatic 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 positron emission tomography (PET) response rate was 77%. OS 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 extra-hepatic disease had a significantly adverse impact on survival. Subjects with extra-hepatic disease had an OS of 7.9 months vs. 21 months for those without.
A retrospective case series study involving 51 subjects with progressive chemotherapy-refractory metastatic CRC treated with SIRT was published in 2011 by Nace and colleagues. CEA response was available in 41 subjects (80.4%), 17 (41%) showed a response to therapy. A total of 31 subjects (60.8%) had imaging available for review, and none demonstrated a complete response. Partial response was noted in 4 subjects (13%), stable disease in 20 (64%), and progressive disease in 7 (23%). A total of 38 subjects (74.5%) died during the 3 year follow-up period. OS was 10.2 months. Notably, subjects who had previously received cetuximab therapy had a significantly decreased median survival (5.1 months, p=0.001). The significant loss to follow-up (n=20; 39%), lack of a control group and other methodological concerns impact the generalizability of this study.
A retrospective, nonrandomized controlled study evaluating the use of SIRT as a salvage treatment for individuals with hepatic metastases was described by Bester and colleagues in 2012. The study involved 390 subjects, 339 who were treated with SIRT and 51 who either declined SIRT or were ineligible due to variant hepatic arterial anatomy or extensive hepatopulmonary shunting and who were subsequently used as controls. Of the SIRT treated subjects, 224 had metastatic CRC, and the remainder had an assortment of other metastatic cancers, including neuroendocrine (n=40), breast (n=16), unknown primary (n=10), pancreatic (n=8), gastric (n=8), and others (for example, melanoma; n=33). No significant differences were noted between the treatment and control groups at baseline, including the presence of extra-hepatic disease and hepatic tumor burden. At the time of final follow-up, 59% (201/390) of the SIRT subjects had died, while 76% (39/51) of the control group had died. OS was reported to be 12 months for the SIRT group and 6.3 months for the control group (p<0.001). In a subgroup analysis, OS was reported as 11.9 months for the CRC group (p<0.001 vs. control) and 12.7 months in the non CRC SIRT group (p<0.024 vs. control). SIRT treatment was a significant predictor of OS (p<0.002), with a 43% reduction in the hazard of death vs. control subjects. An important finding is that the site of primary tumor was not a significant predictor of outcomes. No SIRT-related deaths were reported within the 3 month follow-up period. However, several significant complications were noted, including Grade 1 abdominal pain in the immediate postoperative period as well as within 1 month of treatment. The authors comment that this study was limited due to lack of randomization, and its retrospective nature.
In 2013, Benson and colleagues described the results of a case series study of 151 subjects with a variety of liver metastases (CRC, n=61; neuroendocrine, n=43; and other tumor types, n=47) that were refractory to other therapies subsequently treated with TheraSpheres. Disease control rates were 59%, 93% and 63% for CRC, neuroendocrine and other primaries, respectively. Median progression-free survival (PFS) was 2.9 and 2.8 months for CRC and other primaries, respectively. PFS was not achieved in the neuroendocrine group. The median reported survival from SIRT was 8.8 months for CRC and 10.4 months for other primaries. The authors stated that the median survival for subjects with neuroendocrine tumors has not been reached. Grade 3/4 adverse events included pain (12.8%), elevated alkaline phosphatase (8.1%), hyperbilirubinemia (5.3%), lymphopenia (4.1%), ascites (3.4%) and vomiting (3.4%). The authors concluded that individuals with liver metastases can be safely treated with SIRT.
In 2014, Saxena and colleagues conducted a systematic review assessing the safety and efficacy of SIRT in chemorefractory CRC metastases to the liver. A total of 20 studies comprising 979 subjects were chosen for inclusion. Following treatment, the percentage of participants with a radiological response, partial response and stable disease was 0%, 31% and 40.5%, respectively. The median TTP and OS were 9 and 12 months, respectively, and the overall acute toxicity rate ranged from 11 to 100%. Zero percent of 979 participants achieved a complete response; only 2 studies enrolled more than 100 participants. Some of the studies used resin-based microspheres while others used glass-based microspheres and negative prognostic indicators were variable as was the use of concomitant chemotherapy. This may account, in part, for the range of outcomes reported across the studies. Authors conclude that, "There exists a need, however, to conduct prospective, adequately powered studies to further evaluate this treatment modality."
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: CRC, 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, CRC, 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."
A study by Sato and colleagues (2008) included 147 subjects with chemorefractory metastatic hepatic tumors from a variety of primary tumors including colon, breast, neuroendocrine, cholangiocarcinoma and others (2008). 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 was 87%. The 1-year survival was 47%, 2-year survival was 30.9% and median OS was 300 days. Median survival according to primary tumor site was: 457 days for CRC, 776 days for neuroendocrine tumors, and 207 days for non-CRC 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. They also note the heterogeneous population and open-label study methodology makes the findings difficult to generalize to other populations.
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 extra-hepatic 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 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 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, SIRT, relies on targeted delivery of small beads (microspheres) impregnated with radioactive 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.
Heckman (2008) noted the incidence of disease progression while listed for transplant was 10-23%. Various technologies have been explored to maintain transplant eligibility by controlling disease progression, of which TACE and RFA were the most frequently studied. A "bridge" to liver transplant involves ablative techniques to minimize and control disease progression to allow individuals with limited HCC to remain eligible on the OLT waitlist. The goal of bridging is to prevent drop-off from the waiting list and to improve post-transplant survival (DuBay, 2011).
The current Organ Procurement and Transplantation Network (OPTN) and United Network for Organ Sharing (UNOS) allocation policy (2015) encourages the use of loco-regional therapies to downsize (downstage) tumors to T2 status and to prevent progression while on the transplant wait list. In addition, the OPTN/UNOS policy appears to implicitly recognize the role of loco-regional therapy in the pre-transplant setting. These indications are in part related to the current OPTN/UNOS liver allocation scoring system referred to as the Model for End-stage Liver Disease (MELD), for adults ages 12 and older, and the Pediatric End-stage Liver Disease (PELD) scoring system for candidates younger than 12 years of age. The MELD score is a continuous disease severity scale incorporating serum bilirubin, prothrombin time (i.e., international normalized ratio-INR), and serum creatinine into an equation, producing a number ranging from 6 (less ill) to 40 (gravely ill). The MELD score estimates how urgently the individual needs a liver transplant within the next 3 months. PELD is similar to MELD but uses additional factors to recognize the specific growth and development needs of children. PELD scores may also range higher or lower than the range of MELD scores. The PELD scoring system includes measures of serum bilirubin, INR, albumin, growth failure, and whether the child is less than 1 year old. Candidates that meet the staging and imaging criteria specified in the OPTN/UNOS Allocation of Livers and Liver-Intestines Policy: Candidates with Hepatocellular Carcinoma (HCC) sections 9.3.G.iv-v may receive extra priority on the "Waiting List." A candidate with an HCC tumor that is stage T2 may be registered at a MELD/PELD score equivalent to a 15% risk of candidate death within 3 months if additional criteria are also met. OPTN/UNOS defines stage T2 lesions as including any of the following:
The largest dimension of each tumor is used to report the size of HCC lesions. Nodules <1 cm are indeterminate and cannot be considered for additional priority. Past loco-regional treatment for HCC (OPTN Class 5 [T2] lesion or biopsy proven prior to ablation) are eligible for automatic priority.
Currently, two commercial forms of 90Y microspheres are available: TheraSpheres, which are glass beads bound to 90Y, and SIR-Sphere, in which 90Y is bound to resin beads. Non-commercial forms are used mostly outside the U.S. 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. FDA granted PMA of SIR-Sphere, for use in combination with 5-floxuridine (5-FUDR) chemotherapy by HAI, to treat unresectable hepatic metastases from CRC cancer. In contrast, TheraSpheres is approved by 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:
|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|
|79445||Radiopharmaceutical therapy, by intra-arterial particulate administration [when specified as transcatheter tumor destruction procedure using yttrium-90 microspheres]|
|C2616||Brachytherapy source, nonstranded, yttrium-90, per source [when specified as yttrium-90 microspheres]|
|S2095||Transcatheter occlusion or embolization for tumor destruction, percutaneous, any method, using yttrium-90 microspheres|
|3E053HZ||Introduction of radioactive substance into peripheral artery, percutaneous approach [when specified as SIRT using yttrium-90 microspheres]|
|For the diagnosis codes listed below for treatment of primary liver tumors:|
|C22.0-C22.9||Malignant neoplasm of liver and intrahepatic bile ducts|
|D01.5||Carcinoma in situ of liver, gallbladder and bile ducts|
|Z76.82||Awaiting organ transplant status|
|For the following diagnosis code ranges for palliation of liver metastases:|
|E16.0-E16.2||Drug-induced, other and unspecified hypoglycemia|
|E16.4||Increased secretion of gastrin (Zollinger-Ellison syndrome)|
When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
Metastatic Liver Tumors
Selective Internal Radiation Therapy
Selective Internal Radiation Treatment
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.
Medical Policy & Technology Assessment Committee (MPTAC) review.
Hematology/Oncology Subcommittee review. Updated Rationale and Reference sections. Changed document number from RAD.00033 to THER-RAD.00006. Removed ICD-9 codes from Coding section.
Hematology/Oncology Subcommittee review. Clarified criteria, and updated Scope, Rationale, Background/Overview, Coding and Reference sections.
Hematology/Oncology Subcommittee review. Clarified bridge to transplant criteria.
Hematology/Oncology Subcommittee review. Clarified medically necessary criteria regarding bridge to transplantation tumor size and number. Updated Rationale and Reference sections.
Updated Coding section with 01/01/2014 CPT changes; removed 37204 deleted 12/31/2013, and 75894.
Hematology/Oncology Subcommittee review. Updated title by removing specific product names. Revised medically necessary position statement to include treatment of liver-related symptoms due to any primary or metastatic tumors. Added medically necessary position statements for SIRT as a bridge to transplantation for individuals with HCC when criteria are met, or for those who may meet transplant criteria with SIRT as a result of decreased tumor size. Updated Rationale, Coding and Reference sections.
Hematology/Oncology Subcommittee review. Wording clarification made to medically necessary criterion for neuroendocrine tumors. Updated Websites.
Hematology/Oncology Subcommittee review.
Hematology/Oncology Subcommittee review. Updated Coding and Reference sections.
Hematology/Oncology Subcommittee review. Updated position statement to consider SIRT medically necessary for the treatment of hepatocellular carcinoma, primary or metastatic hepatic carcinoid tumors, hepatic metastases of colorectal cancer or islet cell tumors. Updated Rationale, Coding and Reference sections
Hematology/Oncology Subcommittee review. No change to position statement. Updated Rationale and Reference sections
MPTAC review. No change to position statement.
Hematology/Oncology Subcommittee review. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." Updated references.
Hematology/Oncology Subcommittee review. No change to position statement. Updated Rationale and Reference sections.
|Reviewed||06/08/2006||MPTAC review. References updated, 2005 small study added to the rationale section. No change to position statement.|
|Revised||07/14/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
|Pre-Merger Organizations||Last Review Date||Document Number||Title|
|01/29/2004||RAD.00033||Selective Internal Radiation Therapy (SIRT, i.e. SIR-Spheres and TheraSpheres) Brachytherapy|
|WellPoint Health Networks, Inc.||12/02/2004||4.11.11||Selective Internal Radiation Therapy of Primary or Metastatic Liver Tumors|