|Subject:||Selective Internal Radiation Therapy (SIRT) of Primary or Metastatic Liver Tumors|
|Policy #:||RAD.00033||Current Effective Date:||07/15/2014|
|Status:||Revised||Last Review Date:||07/08/2014|
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:
Selective internal radiation therapy (SIRT) is considered medically necessary as palliative treatment for individuals with:
Hepatocellular Carcinoma or Bridge to Liver Transplantation
SIRT is considered medically necessary as a primary treatment for surgically unresectable primary hepatocellular carcinoma (HCC) or, as a bridge to liver transplantation, when all of the following criteria are met for either indication:
Hepatocellular Carcinoma in Individuals Who May Become Eligible for Liver Transplantation
SIRT is considered medically necessary for the treatment of individuals with hepatocellular carcinoma who:
Investigational and Not Medically Necessary:
Selective internal radiation therapy (SIRT) is considered investigational and not medically necessary when the above criteria are not met.
SIRT for Primary Hepatocellular Carcinoma, Metastatic Colorectal Carcinoma and Neuroendocrine Tumors
There is extensive published literature regarding technical issues and clinical outcomes of SIRT and other locally ablative treatments for liver tumors. (Georgiades, 2001; Lau, 2003; Liu, 2003; Ramsey, 2001). 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 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.
Two reports were published from a single 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 HAI of 5-FUDR 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 three 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.
A large case series study 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 ). 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."
In 2009, Mulcahy and others reported on a case series study involving 72 subjects with hepatic tumors from metastatic CRC (mCRC). 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 survived a mean of 5.6 months. Similar findings regarding the impact of portal vein thrombosis on SIRT outcomes were reported by Woodall (2009).
A retrospective case series study involving 51 subjects with progressive chemotherapy-refractory mCRC 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. Thirty-one 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%). Thirty-eight subjects (74.5%) died during the 3 year follow-up period. Overall survival 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, lack of a control group and other methodological flaws impair the generalizability of this study.
Sangro and colleagues (2011) reported the results of a large case series study of 325 subjects with HCC who were not considered candidates for other therapeutic approaches and who were treated with SIR-spheres. The median overall survival 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 extrahepatic 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 extrahepatic 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 radioembolization, 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 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 significant methodological issues which have not been controlled for in the statistical analysis.
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 colorectal cancer (mCRC), and the remainder had an assortment of other cancers, including neuroendocrine (n=40), breast, (n=16), unknown primary (n=10), pancreatic (n=8), gastric, (n=8), and others (e.g., melanoma; n=33). No significant differences were noted between the treatment and control groups at baseline, including the presence of extrahepatic 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. Overall survival 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, overall survival was reported as 11.9 months for the mCRC group (p<0.001, vs. control) and 12.7 months in the non mCRC SIRT group (p<0.024, vs. control). SIRT treatment was a significant predictor of overall survival (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 three 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. It should also be noted that the selection of controls was subject to significant selection bias. The findings should be confirmed by a prospective randomized study.
Salem (2012) reported the results of a retrospective comparative study of 245 subjects with HCC treated with chemoembolization (n=122) or SIRT with TheraSpheres (n=123). Seventy five subjects (30%) did not complete the study (n=44 for SIRT, n=31 for chemoembolization) due to transplantation (n=73) or resection (n=2). The authors reported a median time to partial response as measured by World Health Organization (WHO) criteria was shorter with SIRT than chemoembolization (6.6 vs. 10.3 months, p=0.05). Using the European Association for Study of the Liver (EASL) necrosis criteria, the response rates were similar (chemoembolization: 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 for SIRT, n=54 for chemoembolization). For median time to progression (TTP), SIRT outperformed chemoembolization (13.3 months vs. 8.4 months, p=0.046). One hundred thirteen subjects died (n= 59 for chemoembolization, n=54 for SIRT) during the median follow-up time (32.6 months for chemoembolization 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 UNOS T1/T2 (HR=0.33) were. There are many methodological issues with this study, including its retrospective nature, lack of randomization and blinding. The 12-month difference in median follow-up time may have also introduced bias into the results.
In 2013, Benson and colleagues described the results of a case series study of 151 subjects with a variety of liver metastases (colorectal, 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 colorectal, neuroendocrine and other primaries, respectively. Median progression free survival (PFS) was 2.9 and 2.8 months for colorectal and other primaries, respectively. PFS was not achieved in the neuroendocrine group. The median reported survival from SIRT was 8.8 months for colorectal 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 phospatase (8.1%), hyperbilirubinemia (5.3%), lymphopaenia (4.1%), ascites (3.4%) and vomiting (3.4%). The authors concluded that individuals with liver metastases can be safely treated with SIRT. As a case series, conclusions may be subject to bias and further data is warranted.
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; Lau, 2001; Leung, 1995; Tian, 1996). 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 years). 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."
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 that there is a significant palliative benefit derived from SIRT for hepatic tumors from a wide variety of primary cancers. 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. Furthermore, SIRT has become widely accepted as a treatment of specific liver-related symptoms due to tumor bulk (e.g., pain) from any primary or metastatic hepatic tumor.
Other SIRT Applications
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." A study 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 (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 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. They also note the heterogeneous population and open label study methodology makes the findings difficult to generalize to other populations.
Metastastatic Breast Cancer
At this time, the evidence addressing the use of SIRT to treat hepatic metastases from breast cancer is limited. Several of the studies previously mentioned included subjects with breast cancer as part of their study population, including Bester (n=16/390), Cianni (n=32/110), and Sato (n=2/147). However, these studies did not provide breast cancer-specific outcomes data.
Two small studies have investigated the impact of SIRT on this population. Bangash and colleagues reported a prospective case series study of 27 subjects who underwent salvage SIRT treatment for hepatic breast cancer metastases (2007). At 90-days after treatment, complete or partial tumor response on CT was noted in 9 subjects (39.1%). Stable disease was reported in 12 subjects (52.1%), and progressive disease was noted in 2 subjects (8.8%). Positive tumor response on PET was noted in 17 (63%) subjects. Median survival for subjects ECOG 0 vs. ECOG 1, 2, or 3 was 6.8 months (n=15) and 2.6 months (n=12), respectively (p=0.24). Survival by tumor burden <25% vs. >25% was 9.4 months (n=21) and 2.0 months (n=6), respectively (p<0.0001).
Another small prospective case series study involving 23 subjects with hepatic breast cancer metastases was reported by Jakobs and others (2008). At a median follow-up of 4.2 months complete response was seen in none of the subjects, but partial response was reported in 61%, of subjects. Stable disease and progressive disease were reported in 35% and 4% of subjects, respectively. The authors reported that the median overall survival was 11.7 months with median survival of responders being 23.6 months and non-responders 5.7 months. Comparing subjects with and without extrahepatic disease, median survival was 9.6 and 16 months, respectively (p=0.077). Median survival time for subjects with response was 23.6 months vs. those without response at 5.7 months (p=0.005). Treatment-related hepatic toxicity was noted in one subject.
Small size significantly limits the utility of these findings. Further study of the use of SIRT for hepatic metastases from breast cancer is warranted.
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. This use has been the subject of a limited number of studies.
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.
In 2009 Lewandowski and colleagues published the results of a non-randomized controlled study that compared transcatheter arterial chemoembolization (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). One 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, time to progression was 18.2 months for the TACE group and 33.3 months in the SIRT group. For TACE, overall survival without censoring to radical therapies (e.g., transplantation/resection) at 1, 2 and 3 years were 75%, 42% and 19% , respectively, and 81%, 69% and 59% for SIRT (p=0.008). When censored to radical therapies, overall survival at 1, 2 and 3 years were 73%, 28% and 19% for the TACE group and 77%, 59% and 45% for the SIRT group (p=0.18). Two out of 11 of the TACE subjects have recurred following transplantation with a 1-year recurrence free survival of 73%. Two out of the 9 SIRT subjects have recurred following transplantation with a 1-year recurrence free survival of 89%. This difference was not found to be statistically significant.
At this time, the data addressing the use of SIRT as a bridge to transplantation method is limited but promising. There is building consensus among experts in favor of the use of SIRT as reasonable and effective as a bridge to transplantation. This is partially based upon the evidence from the Kulik and Lewandowski studies described above, but also on the available data from studies of SIRT for other conditions that demonstrate significant tissue destruction and shrinking of liver lesions resulting in improved health outcomes.
As the incidence of HCC continues to rise and availability of donor organs remains low, the waiting time for potentially curative therapy with orthotopic liver transplantation (OLT) increases. 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 transcatheter arterial chemoembolization (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 (2014) provides incentives to use loco-regional therapies to downsize 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 three 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 one 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:
The largest dimension of each tumor is used to report the size of HCC lesions. Nodules less than 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.
The NCCN guideline in Oncology for hepatocellular carcinoma (2014) states:
Bridge therapy is used to decrease tumor progression and the dropout rate from the liver transplant list. It is considered for patients who meet the transplant criteria. Unresectable/inoperable lesions >5cm should be considered for treatment using arterially directed or systemic therapy.
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) which are glass beads bound to 90Y, and SIR-Sphere® (Sirtex Medical Limited; Lake Forest, IL) where 90Y is bound to resin beads. 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:
|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]|
|S2095||Transcatheter occlusion or embolization for tumor destruction, percutaneous, any method, using yttrium-90 microspheres|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2015]|
|For the diagnosis codes listed below for primary liver tumors:|
|155.0||Malignant neoplasm of liver, primary|
|155.1||Malignant neoplasm of intrahepatic bile ducts|
|155.2||Malignant neoplasm of liver, not specified as primary or secondary|
|230.8||Carcinoma in situ of liver and biliary system|
|V49.83||Awaiting organ transplant status|
|For the following diagnosis code ranges for palliation of liver metastases:|
|209.00-209.36||Malignant carcinoid tumors|
|209.70-209.79||Secondary neuroendocrine tumors|
|251.4-251.9||Abnormality of secretion of glucagon, gastrin (Zollinger-Ellison syndrome), other disorders of pancreatic internal secretion|
|ICD-10 Procedure||[For dates of service on or after 10/01/2015]|
|3E053HZ||Introduction of radioactive substance into peripheral artery, percutaneous approach [when specified as SIRT using yttrium-90 microspheres]|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2015]|
|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. Clarified bridge to transplant criteria.
Medical Policy & Technology Assessment Committee (MPTAC) review.
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. No change to position statement.
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 |
|Anthem, Inc.||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|