SIR-Spheres for the treatment of non-resectable liver tumours: August 2005 MSAC Application 1082 Assessment report

THE PROCEDURE: SIR-Spheres (Selective Internal Radiation Spheres) are yttrium-90 microspheres that are implanted into malignant liver tumours for the purpose of selectively delivering high doses of ionising radiation to the tumour. They are injected into the hepatic artery by means of a trans-femoral catheter or a permanently implanted hepatic artery port with a catheter. Following injection, the SIR-Spheres become concentrated in the microvasculature of the liver cancer, where they have a local radiotherapeutic effect. As tumours within the liver derive their blood supply almost exclusively from the hepatic artery, the SIR-Spheres are preferentially delivered in greater amounts to the tumour rather than to the normal liver parenchyma, which is supplied by both the hepatic artery and the portal vein. Following decay of the yttrium-90, the inert resin microspheres remain implanted in the tissue. SIR-Spheres are used to treat patients with hepatic metastases secondary to colorectal cancer (CRC) in the absence of extrahepatic metastases, when the hepatic metastases are not amenable to surgery or radiofrequency ablation. They may be used in combination with systemic chemotherapy or hepatic arterial chemotherapy (HAC). SIR-Spheres are also used to treat primary non-resectable, non-ablatable hepatocellular carcinoma (HCC); however, this indication is not as common as colorectal liver metastases (CLM) in Australia. MEDICAL SERVICES ADVISORY COMMITTEE - ROLE AND APPROACH: The Medical Services Advisory Committee (MSAC) was established by the Australian Government to strengthen the role of evidence in health financing decisions in Australia. MSAC advises the Minister for Health and Ageing on the evidence relating to the safety, effectiveness and cost-effectiveness of new and existing medical technologies and procedures, and under what circumstances public funding should be supported. A rigorous assessment of evidence is thus the basis of decision making when funding is sought under Medicare. A team from the National Health and Medical Research Council (NHMRC) Clinical Trials Centre was engaged to conduct a systematic review of literature on SIR-Spheres for the treatment of non-resectable liver tumours. An Advisory Panel with expertise in this area then evaluated the evidence and provided advice to MSAC. This review updates MSAC’s assessment of SIR-Spheres published in 2002. MSAC'S ASSESSMENT OF SIR-SPHERES: The evaluation team worked with members of the Advisory Panel to develop specific questions addressing the use of SIR-Spheres for the treatment of non-resectable, nonablatable liver tumours secondary to CRC, and for the treatment of non-resectable, nonablatable HCC. The following two research questions were developed and are assessed in this review: 1st indication: What are the safety, effectiveness and cost-effectiveness of SIR-Spheres used alone or in addition to chemotherapy for treating non-resectable, non-ablatable hepatic metastases secondary to CRC compared with HAC treatment or systemic chemotherapy? 2nd indication: What are the safety, effectiveness and cost-effectiveness of SIR-Spheres for treating nonresectable, non-ablatable HCC compared with transarterial chemoembolisation (TACE) or 131I-lipiodol? A comprehensive search strategy was developed to identify relevant studies and reviews of the safety, effectiveness and cost-effectiveness of SIR-Spheres. In addition to electronic database searches, reference lists of identified publications were hand-searched, and publications were provided by the applicant. A total of eight studies, six (two randomised controlled trials [RCTs], four case series) for the CLM indication and two (case series) for the HCC indication, met criteria for inclusion in the review of effectiveness. An additional eight case series were included for the safety evaluation. CLINICAL NEED: Colorectal metastases of the liver: CRC is the most common cancer after non-melanomatous skin cancer and the third most common cause of cancer death reported to Australian cancer registries. In 2001, CRC accounted for 14.5 per cent of all new cases of cancer and 13.1 per cent of cancer deaths (excluding non-melanocytic skin cancer) (AIHW & AACR 2004). In 2001, premature death from CRC was responsible for an estimated 29 768 person-years of life lost before the age of 75, making it second only to lung cancer for this measure of disease burden (AIHW & AACR 2004). Approximately 50 per cent of patients with CRC will develop liver metastases within 5 years and 20 per cent of patients will already have liver metastases at the time of primary diagnosis (COSA & CAN 1999). If untreated, liver metastases from CRC show a very poor prognosis, with a median survival of 19 to 21 months, and no patients surviving 5 years (Liu et al. 2003). Hepatocellular carcinoma: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. The three major risk factors for development of HCC are alcoholic liver disease, chronic hepatitis B (HBV) infection and chronic hepatitis C (HCV) infection. In 2001, there were 853 new cases of primary liver cancer and 777 deaths (AIHW & AACR 2004), most of which can be attributable to HCC. The incidence rate of HCC in Australia has been steadily increasing in the past two decades, and it is thought that this can be partially explained by the increase in the prevalence of HBV and HCV (Law et al. 2000). Current estimates suggest that there are more than 242 000 Australians who are infected with HCV, and that another 14 499 are infected each year (National Centre in HIV Epidemiology and Clinical Research 2004). Therefore, it can be expected that the incidence rates of HCC will continue to rise in the future. SAFETY: The assessment of the safety of SIR-Spheres is based on information from seven of the eight included studies of SIR-Spheres in CLM and HCC patients, eight additional case series included for the safety assessment (3 evaluating SIR-Spheres and 5 evaluating other Selective Internal Radiation Therapies [SIRTs]), TGA data, and information provided by the applicant. Minor complications and side-effects associated with the use of SIRSpheres include including gastrointestinal (GI) side-effects (abdominal pain, nausea, vomiting and diarrhoea), fever, a transient decrease in haemoglobin and abnormal liver function tests. Major complications which have been reported include death, radiation hepatitis, radiation gastritis, radiation pneumonitis, radiation-induced cirrhosis, hepatic necrosis and GI ulceration. In the included SIR-Spheres safety information seven deaths occurred due to fatal radiation hepatitis, radiation gastritis, acute hepatic necrosis and sepsis associated with neutropaenia. Of these seven deaths, five were reported in the included studies which evaluated a total of 503 patients. In addition, a small number of cases of radiation pneumonitis, radiation-induced cirrhosis, non-fatal radiation gastritis and GI ulceration were found in the included studies. There is limited comparative evidence available to enable an assessment of the safety of SIR-Spheres compared to other therapies used in the treatment of liver tumours. Of the two comparative studies identified, one found no difference in the rate of Grades 3 (severe) and 4 (life-threatening) toxicities between patients treated with SIR-Spheres and HAC and patients treated with HAC alone (Gray et al. 2001), while the other found 13 Grades 3 and 4 toxicities in patients treated with SIR-Spheres and systemic chemotherapy compared to five Grades 3 and 4 toxicities in patients treated with systemic chemotherapy alone (van Hazel et al. 2004). In addition to the safety of patients treated with SIR-Spheres, safety issues arise for personnel involved in implanting SIR-Spheres and handling the device. From the available information it appears that the doses of radiation delivered to personnel are reasonably low and are within ranges recommended by the National Occupational Health and Safety Commission (National Occupational Health and Safety Commission 1995). SIR-Spheres should be implanted in approved centres to ensure that these safety standards are met. EFFECTIVENESS: Effectiveness of SIR-Spheres for treatment of liver metastases of colorectal cancer: Two small RCTs (level II evidence) and four uncontrolled case series reports (level IV evidence) were identified for inclusion in the evaluation of the effectiveness of SIRSpheres in CLM patients. The two RCTs evaluated the use of SIR-Spheres and HAC and of SIR-Spheres and systemic chemotherapy. In the trial comparing SIR-Spheres and HAC to HAC alone, no statistically significant survival benefit was found, however the trial was underpowered to detect a survival difference (Gray et al. 2001). In the trial comparing SIR-Spheres and systemic chemotherapy to chemotherapy alone, a statistically significant increase in survival was seen in patients treated with SIR-Spheres and systemic chemotherapy (29.4 months vs 12.8 months, HR 0.33; 95% CI 0.12–0.91; P = 0.025). This trial, however, used systemic chemotherapy regimens which no longer represent current practice. The survival advantage when SIR-Spheres are used in combination with current chemotherapy regimens is unknown. All six included studies demonstrated anti-tumour activity of SIR-Spheres, but only the small van Hazel et al. (2004) trial used standardised criteria to measure tumour response. This study found a statistically significant increase in tumour response rates in patients treated with SIR-Spheres and systemic chemotherapy compared to those treated with systemic chemotherapy alone (van Hazel et al. 2004). Effectiveness of SIR-Spheres for the treatment of hepatocellular carcinoma Two case series of fair quality were identified for inclusion in the evaluation of the effectiveness of SIR-Spheres in HCC. Both case series reported partial or complete tumour response in up to 50 per cent of patients, demonstrating that SIR-Spheres have antitumour activity. This provides weak evidence for the effectiveness of SIR-Spheres in patients with non-resectable, non-ablatable HCC. Without comparative studies, however, it is not possible to draw any conclusions about the effectiveness of SIR-Spheres compared to other existing treatments in patients with HCC. COST-EFFECTIVENESS: Cost-effectiveness of SIR-Spheres for treatment of liver metastases of colorectal cancer: A trial-based economic model supplied by the applicant and an exploratory economic evaluation were used to evaluate the cost-effectiveness of SIR-Spheres and systemic chemotherapy in patients with CLM. The trial-based economic model is based on the van Hazel et al. (2004) trial, which compared SIR-Spheres and 5-fluorouracil plus leucovorin systemic chemotherapy (5-FU/LV) to 5-FU/LV systemic chemotherapy alone. This economic model showed that the addition of SIR-Spheres to 5-FU/LV results in an incremental cost per life-year gained of $21 524 compared to 5-FU/LV alone. Sensitivity analyses show that this cost per life-year gained may range from $12 270 to $88 119; the wide range indicates that the incremental cost-effectiveness ratio is particularly sensitive to changes in survival estimates. As the van Hazel et al. (2004) trial used a systemic chemotherapy regimen that is no longer considered current practice, an economic model comparing SIR-Spheres and current systemic regimens (FOLFOX6 and FOLFIRI; see Glossary) to current chemotherapy regimens alone was developed. Assuming 3 different scenarios for the magnitude of survival benefits, two alternative follow-up regimens associated with adding SIR-Spheres to current chemotherapy regimens and two different schedules of chemotherapy cycles (10 and 20 cycles), the cost per life-year gained ranged from $8009 for the ‘best-case scenario’ (incremental survival benefit of 1.65 years with less intensive follow-up and 10 cycles of FOLFOX/FOLFIRI) to $133 653 for the ‘worst-case scenario’ (incremental survival benefit of 0.3 years with more intensive follow-up and 20 cycles of FOLFOX/FOLFIRI) when compared to the current chemotherapy regimens alone. These estimates are based on the assumption that SIR-Spheres will be used in the same manner with current chemotherapy regimens as they were used with 5-FU/LV in the van Hazel et al. (2004) trial. Due to the lack of trial data about the effectiveness of SIRSpheres in combination with current chemotherapy regimens, the results of the exploratory economic evaluation should be viewed as an exploration of the possible costs and benefits associated with the use of SIR-Spheres alongside current chemotherapy regimens. COST-EFFECTIVENESS OF SIR-SPHERES FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA: As the effectiveness of SIR-Spheres as a treatment for patients with HCC has not been established, cost-effectiveness could not be established, and an economic evaluation was not conducted. RECOMMENDATIONS: 1st indication: MSAC recommends that on the strength of evidence pertaining to the treatment of patients with hepatic metastases secondary to colorectal cancer which are not suitable for resection or ablation, interim public funding should be supported for first line treatment by administration of SIR-Spheres in combination with systemic chemotherapy using 5FU and leucovorin, with the collection of survival data. This data should be reported to MSAC within three years. - The Minister for Health and Ageing endorsed this recommendation on 28 November 2005 2nd indication: As there is currently insufficient evidence pertaining to the treatment of non-resectable, non-ablatable hepatocellular carcinoma with SIR-Spheres, MSAC recommends that public funding should not be supported at this time. - The Minister for Health and Ageing endorsed this recommendation on 28 November 2005