STE Report: Transarterial Radioembolization for the treatment of Hepatic Neoplasia

Transcription

1 STE Report: Transarterial Radioembolization for the treatment of Hepatic Neoplasia Laura Higgins, MSc Senior Analyst Sarah Rose, PhD Biostatistician Lloyd Sutherland, MD, MSc Project Director Tom Noseworthy, MD, MPH Project Advisor Ken Fyie, MSc Economic Analyst Kelly Burak, MD, FRCPC, MSc Clinical Consultant Diane Lorenzetti, M.L.S Research Librarian Final STE Report November 2010 Partner Organization University of Calgary Center for Health and Policy Studies Alberta Health Technologies Decision Process

2 Copyright HTA Unit, CHAPS, University of Calgary Supported by a financial contribution from Alberta Health and Wellness through the Alberta Health Technologies Decision Process: the Alberta model for health technology assessment and policy analysis. The views expressed herein do not necessarily represent the official policy of Alberta Health and Wellness. The authors declare no conflicts of interest. The authors abide by the conflict of Interest/ non-disclosure agreement with the Alberta Health Technologies Decision Process. Center for Health and Policy Studies, University of Calgary, November 2010 i

3 Executive Summary Introduction The intent of the report was to evaluate the social and demographic (S), safety and effectiveness (T) and fiscal and economic (E) factors related to transarterial radioembolization (TARE) for hepatic neoplasia and their implications for provision of this technology in Alberta. This report focuses on treatment of primary hepatocellular carcinoma (HCC), and secondary metastatic tumour to the liver, most often from colorectal cancer (CRC) or neuroendocrine tumours (NETs) of the gut. Presently demand for TARE is limited to patients whom are not candidates for Methods curative therapies, transarterial chemoembolization (TACE) or who have failed other first-line therapies, and is estimated not to exceed 30 patients per year province wide. Our literature review resulted in four published studies, describing three original randomized controlled trials (RCTs), 33 cohort studies, one meta-analysis, one systematic review and four health technology assessments (HTA) being selected for inclusion. A meta-analysis was performed using published data on the outcomes of interest; data were available for analysis on median survival time, summary survival rates and summary radiological response rate. All data were extracted from the included cohort studies. A cost-effectiveness and budget impact analyses were also completed. Effectiveness measure for the analyses was median survival time. Center for Health and Policy Studies, University of Calgary, November 2010 ii

4 Results TARE appears as safe as TACE and Sorafenib therapies for intermediate and advanced staged patients with HCC, respectively. TARE is as safe as chemotherapy for patients with liver metastases from colorectal cancer (CRCLM). TARE appears safe in patients with metastatic neuroendocrine tumours (mnet). Patients receiving TARE have demonstrated significant survival, radiological response and quality of life benefits as a result of treatment. Significant gaps in the evidence existed as reporting criteria are not standardized. The meta-analysis revealed that survival benefits and radiological responses are seen in patients with portal vein thrombosis (PVT) and in patients whom have failed chemotherapy. Evidence suggests TARE should not be used as a first line therapy in patients with CRCLM or mnet. Economic analysis revealed that TARE is not cost-effective when compared to standard care therapies for intermediate and advanced HCC or CRCLM patients. Conclusions TARE appears safe and effective in HCC patients that have PVT, large tumours, good underlying liver function and less than 20% lung shunting. TARE may also play a role in maintaining or downstaging patients to liver transplant or resection. TARE appears safe and effective in CRCLM and mnet patients who have failed all other first-line therapies. Budget impact considerations appear more appropriate than cost-effectiveness considerations given the relatively small demand for the technology. Center for Health and Policy Studies, University of Calgary, November 2010 iii

5 Table of Contents Executive Summary...ii List of Tables and Figures...viii List of Appendices...ix List of Abbreviations...x Glossary...xii 1. Introduction Purpose of Assessment Report Objectives Research Questions Background Technology Definition Condition Definition Hepatocellular Carcinoma Metastatic Colorectal Carcinoma Metastatic Neuroendocrine Tumours Other Secondary Liver Tumours Methodology Literature Literature Search Selection of Literature Results of Literature Search Data Extraction Social Systems and Demographics (S) Approach to Analysis Technology Effects and Effectiveness (T) Approach to Analysis Economic (E) Approach to Analysis Social Systems and Demographics (S) Patterns of Illness Burden of Illness description of condition(s) Population Dynamics Patterns of Care History Procedures Overview and Trends...30 Center for Health and Policy Studies, University of Calgary, November 2010 iv

6 Access to Technology in Alberta Demand for Technology Health System Capacity Workforce Capacity Infrastructural Capacity Technology Effects and Effectiveness Current Context Technology Technology Comparison Health Canada Approval Condition(s) and Limitations Best Practice Other Jurisdictional Guidelines Diffusion of Technology Effects/Effectiveness Safety Efficacy/Effectiveness Comparative Benefits and Risks Delivery Context Delivery Considerations Related procedures Implementation Considerations Economic Evaluation Literature Review Findings Economic Analysis Approach and Unit Costs Costs of Services Avoided Demand Estimates Results of Economic Evaluation...87 Center for Health and Policy Studies, University of Calgary, November 2010 v

7 7. Discussion Assessment Limitations Evolving Developments Impacts on Alberta Health System Implications for Alberta Conclusions References...98 Tables.108 Table 1. ICD-9 and ICD-10 Diagnostic Codes for Included Cancer Pathologies Table 2. Prevalence and Incidence Rates of Included Cancer Pathologies Table 3. RECIST and WHO Radiological Response Criteria Table 4. TARE Manufacturer and Product Information Table 5. TARE Radiation Exposure Levels for Technician and Treating Physician.116 Table 6. Summary of Study Data Included In Meta Analysis Table 7. Mean Unit Costs and Medical System Utilization from One Course of Treatment Table 8. Aggregated and Incremental Differences in Costs and Life Years Gained Between TARE and Alternative Treatments Table 9. Sensitivity Analysis Based on the Assumption of No Treatment Related Deaths** Table 10. Overall Budget Impact for Varying Levels of Demand for TARE Appendices Appendix I BARCELONA CLINIC LIVER CANCER STAGING CLASSIFICATION130 Appendix II TARE LITERATURE SEARCH TERMS Appendix III - TARE GREY LITERATURE SOURCES Appendix IV- CONSORT STATEMENT 2001 CHECKLIST Appendix V- LITERATURE SEARCH RESULTS Center for Health and Policy Studies, University of Calgary, November 2010 vi

8 Appendix VI INCLUDED RCT AND COHORT STUDIES Appendix VII DATA EXTRACTION FORM Appendix VIII - INCREASING BURDEN OF HCC IN ALBERTA Appendix IX - THERASPHERE ADMINISTRATION SETUP Appendix X- REBOC PANEL RECOMMENDATIONS Figures Figure 5. Median Survival Times for HCC and CRCLM Patients Figure 6. Summary 6 Month Survival Rates for HCC and CRCLM Patients Figure 7. Summary 12 Month Survival Rates for HCC and CRCLM Patients Figure 8. Summary 24 Month Survival Rates for HCC and CRCLM Patients Figure 9. Summary 6 Month Survival Rates by Cancer Pathology Figure 10. Summary 12 Month Survival Rates by Cancer Pathology Figure 11. Summary 24 Month Survival Rates by Cancer Pathology Figure 12. Summary Radiological Response Rates by Cancer Pathology Figure 13. Summary Radiological Response Rate by Cancer Pathology and Response Criteria Center for Health and Policy Studies, University of Calgary, November 2010 vii

9 List of Tables and Figures Tables Table 1. ICD-9 and ICD-10 Diagnostic Codes for Included Cancer Pathologies Table 2. Prevalence and Incidence Rates of Included Cancer Pathologies Table 3. RECIST and WHO Radiological Response Criteria Table 4. TARE Manufacturer and Product Information Table 5. TARE Radiation Exposure Levels for Technician and Treating Physician Table 6. Summary of Study Data Included In Meta Analysis Table 7. Mean Unit Costs and Medical System Utilization from One Course of Treatment Table 8. Aggregated and Incremental Differences in Costs and Life Years Gained Between TARE and Alternative Treatments. Table 9. Sensitivity Analysis Based on the Assumption of No Treatment Related Deaths Table 10. Overall Budget Impact for Varying Levels of Demand for TARE Figures Figure 5. Median Survival Times for HCC and CRCLM Patients Figure 6. Summary 6 Month Survival Rates for HCC and CRCLM Patients Figure 7. Summary 12 Month Survival Rates for HCC and CRCLM Patients Figure 8. Summary 24 Month Survival Rates for HCC and CRCLM Patients Figure 9. Summary 6 Month Survival Rates by Cancer Pathology Figure 10. Summary 12 Month Survival Rates by Cancer Pathology Figure 11. Summary 24 Month Survival Rates by Cancer Pathology Figure 12. Summary Radiological Response Rates by Cancer Pathology Figure 13. Summary Radiological Response Rate by Cancer Pathology and Response Criteria Center for Health and Policy Studies, University of Calgary, November 2010 viii

10 List of Appendices Appendix I BARCELONA CLINIC LIVER CANCER STAGING CLASSIFICATION Appendix II - TARE LITERATURE SEARCH TERMS Appendix III - TARE GREY LITERATURE SOURCES Appendix IV- CONSORT STATEMENT 2001 CHECKLIST Appendix V- LITERATURE SEARCH RESULTS Appendix VI INCLUDED STUDIES Appendix VII - INCREASING BURDEN OF HCC IN ALBERTA Appendix VIII - THERASPHERE ADMINISTRATION SETUP Appendix IX- REBOC PANEL RECOMMENDATIONS Center for Health and Policy Studies, University of Calgary, November 2010 ix

11 List of Abbreviations 5-FU - 99m Tc - AASLD - AFP - ALT - AST - BCLC - BSI - CADTH - CEA - CR - CRC - CRCLM - CT - CTAF - EAG - ECOG - FDA - FUDR - GBq - GI - Gy - HAC - HBV - HCC - HCV - HRQL - HTA - INR - LV - MAA - mcrc - mnet - MRI MUGA - NET - NICE - PD - PEI - PET - PR - PVT - Fluorouracil Technetium Tc99m American Association for the Study of Liver Disease Alpha-fetoprotein Alanine transaminase Aspartate aminotransferase Barcelona Clinic Liver Cancer Classification British Standards Institution Candaian Agency for Drugs and Technologies in Health Carcinoembryonic antigen Complete response Colorectal cancer Colorectal cancer with liver metastases Computerized tomography California Technology Assessment Forums Expert advisory group Eastern Cooperative Oncology Group U.S. Food and Drug Administration Floxuridine Gigabecquerel Gastrointestinal Gray Hepatic arterial chemotherapy Hepatitis B virus Hepatocellular carcinoma Hepatitis C virus Health Related Quality of Life Health Technology Assessment International normalized ratio Leucovorin Macroaggregate albumin Metastatic colorectal cancer Metastatic neuroendocrine tumour Magnetic resonance imaging Multi Gated Acquisition Scan Neuroendocrine tumour National Institute for Health and Clinical Excellence Progressive disease Percutaneous ethanol injection Positron emission tomography Partial response Portal vein thrombosis Center for Health and Policy Studies, University of Calgary, November 2010 x

12 RCT - Randomized controlled trial REBOC - Radioembolization Brachytherapy Oncology Consortium RECIST - Response Evaluation Criteria in Solid Tumours RFA - Radiofrequency Ablation SAE - Serious adverse event SD - Stable disease SIRT - Selective internal radioembolization SPEC - Single photon emission computed tomography TACE - Transarterial chemoembolization TAE - Transarterial embolization TARE - Transarterial radioembolization TBCC HPB - Tom Baker Cancer Center TGA - Therapeutic Goods Administration TTLP - Time to liver progression TTPD - Time to progressive disease ULN - Upper Limit of Normal UNOS - United Network for Organ Sharing WHO - World Health Organization Y 90 - Yttrium- 90 Center for Health and Policy Studies, University of Calgary, November 2010 xi

13 Glossary Alpha-fetoprotein Albumin Alanine Amino-Transferase Aspartate Amino-Transferase Ascites Barcelona Clinic Liver Cancer Bilirubin Catheter Child-Pugh A biomarker often associated with progression of liver cancer as well as some other cancers. A serum protein that is mostly produced by the liver. Decreases in albumin levels can be an indication of advanced liver disease. An enzyme found in high concentrations in the liver. Elevated ALT can be an indication of liver inflammation or hepatitis. The AST/ALT ratio is sometimes used in the differential diagnosis of liver disease (see AST below). An enzyme found in high concentrations in the liver. ALT (see above) elevated along with AST is an indication of viral hepatitis or drug-induced liver damage. AST elevation in the absence of a change in ALT may be an indication of cirrhosis of the liver. Is a term for accumulation of fluid in the peritoneal cavity. It is most commonly associated with cirrhosis and severe liver disease. Classification system that offers a prognostic stratification of patients with hepatocellular carcinoma. The major pigment of bile and is removed from the blood by the liver. Serum bilirubin levels rise when the liver is unable to conjugate and excrete it. Rises in serum bilirubin levels are an indication of liver disease. A flexible tube used to deliver or withdraw fluids from the body. A score used to assess the prognosis of chronic liver disease, mainly cirrhosis. Center for Health and Policy Studies, University of Calgary, November 2010 xii

14 Downstaging Eastern Cooperative Oncology Group Femoral Artery Fluoroscopy FOLFOX FOLFIRI Health-related quality of life Infiltrative Tumour Metastasis Micrometer A situation in which a patient with a previously unresectable tumour or large number of tumours is now eligible for surgery or liver transplant following treatment. Scales and criteria used by doctors and researchers to assess how a patient's cancer is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. Is the chief artery of the thigh supplying blood to the groin and lower extremities. Is an X-ray procedure that takes continuous pictures to evaluate moving structures within the body. Chemotherapy regimen that includes the drugs oxaliplatin, leucovorin and 5-fluorouracil. Depending on the dose of oxaliplatin and method for delivery numbers are used to identify which regimen was followed (i.e. FOLFOX4 and FOLFOX6) Chemotherapy regimen that includes the drugs irinotecan, leucovorin and 5-fluorouracil. An individual's satisfaction or happiness with domains of life insofar as they affect or are affected by health. A type of tumour that has extensively invaded surrounding normal tissue so that it is no longer present in a discrete, encapsulated form. Is a tumour resulting from the migration of tumour cells from the primary tumour. Is a unit of measurement of length. One micrometer is equal to one millionth of a meter (approximately one 25 thousandth of an inch). Center for Health and Policy Studies, University of Calgary, November 2010 xiii

15 Milan Criteria Portal Vein Thrombosis Serum Albumin Upper Limit of Normal United Network for Organ Sharing Are applied as a basis for selecting patients with cirrhosis and hepatocellular carcinoma for liver transplantation. Is a blockage, by a blood clot, of the portal vein, which brings blood to the liver. Is the most abundant plasma protein in mammals and is responsible for maintaining osmotic pressure required for proper distribution of body fluids between intravascular compartments and body tissues. Indicates the maximum value of a test result above which the result is considered elevated. An organization which has established criteria for allocating organs for liver transplant in the USA. ** Parts of the glossary were taken from MDS Nordion s website Center for Health and Policy Studies, University of Calgary, November 2010 xiv

16 1. Introduction 1.1. Purpose of Assessment The present report reviews the use of transarterial radioembolization (TARE) for the treatment of primary and secondary hepatic neoplasia for the purpose of considering its potential as a publically funded health service in Alberta Report Objectives 1. To review the effectiveness/efficacy and safety of TARE compared to standard care for the treatment of patients with primary and secondary hepatic neoplasia. 2. To review the social, ethical and legal considerations for the provision of TARE for the treatment of patients with primary and secondary hepatic neoplasia. 3. To review the fiscal and economic considerations for the provision of radioembolization for the treatment of patients with primary and secondary hepatic neoplasia Research Questions Is the survival of patients with intermediate stage hepatocellular carcinoma (HCC) receiving transarterial radioembolization (TARE) similar to patients who receive transarterial chemoembolization (TACE)? Is the survival of patients with advanced stage HCC receiving TARE similar to patients who receive sorafenib chemotherapy? Is the safety of TARE similar to the safety of TACE and sorafenib therapy for patients with intermediate and advanced staged HCC? Center for Health and Policy Studies, University of Calgary, October

17 Is TARE cost effective in intermediate and advanced stage HCC when compared to TACE and sorafenib therapy? Is the survival of patients with liver metastases from colorectal cancer (CRCLM) receiving TARE similar to patients who receive systemic or regional chemotherapy? Can TARE safely be added to systemic or regional chemotherapy regimens, and if so are there survival benefits of the concomitant therapy compared to standard of care for CRCLM patients? Is TARE cost effective in CRCLM patients when compared to systemic and regional chemotherapy? Is TARE safe, effective and cost effective for use in patients with neuroendocrine tumours of the liver (mnet)? 2. Background 2.1. Technology Definition TARE in the present context is used to describe a new technology specifically designed for the treatment of liver tumours (i.e. hepatic neoplasia), and can also be referred to as selective internal radiation therapy (SIRT) or radioembolization. TARE for liver tumours involves the selective delivery of radiation via intrahepatic arteries. TARE is emerging as a new and promising treatment modality for managing patients with nonresectable primary and secondary hepatic neoplasia 1. The specific delivery agent considered in the present report is yttrium-90 (Y 90 ) microspheres. Y 90 is a high energy beta emitting radioisotope that can be incorporated into glass or resin microspheres 2. In TARE, Center for Health and Policy Studies, University of Calgary, October

18 these microspheres are injected into the hepatic artery, usually via a transfemoral approach, and end up in the liver where they emit their beta energy. The selectivity of these microspheres for targeting tumour tissue, as opposed to normal liver parenchyma, is in large part due to the vascular supply of the tumour. The overwhelming majority of tumour tissue in the liver derives its blood supply from the hepatic artery, while normal liver tissue is supplied mainly by the portal vein. This vascular selectivity allows for high doses of radiation to be absorbed by tumour tissue, while keeping the absorbed dose of radiation by normal liver tissue at a low level 1, 3. The ability of TARE to selectively destroy cancerous tissues while sparing normal tissues circumvents one of the main limitations of external beam radiation Condition Definition TARE has been used to treat both primary and secondary hepatic neoplasia. Although there is preliminary evidence for the widespread use of this technology in a variety of liver metastases, the present report is focused on three of the most commonly reported and emerging indications for use. Specifically, primary hepatic neoplasia (hepatocellular carcinoma) and two cases of secondary hepatic neoplasia (colorectal cancer with liver metastases and metastatic neuroendocrine tumours) will be discussed Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is a primary malignancy of the liver that is typically associated with chronic liver inflammation or cirrhosis. Worldwide, the vast majority of cases are related to chronic hepatitis B virus (HBV) infection 4. In North America, the majority of Center for Health and Policy Studies, University of Calgary, October

19 cases occur in a cirrhotic liver, with hepatitis C virus (HCV) being the leading cause 5, 6. HCC is the most common form of primary liver cancer and is a major health concern, accounting for more than 600,000 new cases worldwide per year 4. HCC is one of the few cancers that has an increasing incidence in Canada. A Canadian report detailing the age-standardized incidences of HCC between 1969 and 1997 found a 3.4% increase per year in men and 1.2% per year in women. The authors of the report also included a fitted non-linear multiplicative model used to estimate the projected incidence and mortality of HCC in Canada for the year 2010, with the estimated number of new cases being 1,565 and the number of deaths being Additional studies on the incidence rates for HCC predict that the incidence rates per 100,000 could be as high as 18.5 (with 7,672 new cases each year) for males and 4.1 (with 1,709 new cases each year) for females amongst Canadians aged years 8. The incidence of HCC is highest among the elderly, with incidence rates per 100,000 of almost 25 in persons 75 or older in the year This is thought to be largely due to the fact that a latency period of approximately 20 years exists between contraction of viral hepatitis and the onset of HCC. Practices of intravenous drug use, needle sharing, unsafe sex and unscreened blood transfusions during the 1960s, 1970s and early 80s are all thought to have contributed to the transmission of the HCV. Increased immigration from eastern Asian countries and other areas of high endemicity for HBV and HCV have contributed to the increased rates 7. The treatment options for HCC vary by the extent of disease, underlying liver function and the performance status of the patient. In Alberta, patients are staged and Center for Health and Policy Studies, University of Calgary, October

20 managed according to the Barcelona Clinic Liver Cancer (BCLC) staging system (see Appendix I). Patients with early stage disease can be managed using resection, liver transplantation or radiofrequency ablation (RFA). Unfortunately, only approximately 30% of patients are candidates for these curative intent therapies. Patients with intermediate stage HCC may benefit from TACE and patients with advanced stage HCC may benefit from sorafenib if they have preserved liver function. Unfortunately, approximately 30% of patients present with advanced liver failure (Child Pugh class C cirrhosis). If these patients are not liver transplant candidates they typically survive only between 3-6 months, regardless of the tumour characteristics, and as such are offered only palliative care 4. Based on the increasing incidence of HCC worldwide and in Canada, the poor prognosis of patients with intermediate and advanced stage HCC and the limited treatment options that exist, new technologies such as TARE are receiving the attention of medical and health care providers Metastatic Colorectal Carcinoma Every year 850,000 people are diagnosed with colorectal cancer (CRC) and 500,000 die from the disease worldwide. CRC is the fourth most common cancer in Canada, with incidence rates only falling behind prostate, lung and breast cancer. In Canada, CRC is the second leading cause of cancer related deaths. It is estimated that in the year 2009, 22,000 Canadians were diagnosed with CRC and 9,100 deaths were attributable to the cancer. Alberta has the second lowest age standardized incidence and mortality rates of CRC in Canada, for both men and women; British Columbia has the lowest 10. Although the Center for Health and Policy Studies, University of Calgary, October

21 incidence and mortality rates of CRC have declined in recent years, the number of new cases is predicted to rise in coming years due to the increasing population of seniors 11. Colorectal cancer starts as benign polyps and, if left undiagnosed, progresses to cancerous tumours within any part of the large intestine. Screening techniques for detection of polyps include: examining stool for occult blood, sigmoidoscopy and colonoscopy. The Forzani/MacPhail colon cancer screening center in Calgary has offered screening for average and high risk individuals since Alberta Health Services recommends screening for everyone over the age of 50. Cancer of the gastrointestinal tract commonly metastasizes to the liver as a result of portal vein drainage of the gut 12. In fact, approximately 50-60% of CRC patients will develop liver metastases at some point 13. Secondary hepatic neoplasia resulting from CRC is commonly referred to as colorectal cancer with liver metastases (CRCLM). CRCLM patients, similar to HCC patients, usually present at tumour stages that are too advanced for surgical resection. It has been estimated that only 15% of cases will be candidates for surgical resection. As such, CRCLM is the primary cause of death in patients initially diagnosed with CRC. For the remaining patients, treatment options are usually palliative with regional or systemic chemotherapy being the standard of care. Management of patients with metastatic CRC (mcrc) in Alberta is according to the Alberta Health Services Metastatic Colorectal Cancer Clinical Practice Guidelines 14. Generally the guidelines acknowledge that mcrc usually represents an incurable situation, where best supportive care should be offered to patients in the hopes of maintaining or improving quality of life or prolonging life, if possible. Patients with low (i.e. good) Eastern Cooperative Oncology Group (ECOG) scores Center for Health and Policy Studies, University of Calgary, October

22 - assess how the disease affects the daily living abilities of the patient - (i.e. 0, 1 or 2) are offered palliative chemotherapy. A variety of different chemotherapy regimens are available with the regimen selected dependent on an assessment of the individual patient s goals, physical status and other life circumstances Metastatic Neuroendocrine Tumours Neuroendocrine tumours (NETs) are rare neoplasms that present a complex challenge to diagnosis and treatment. NETs are slow growing tumours of the neuroendocrine system and are commonly found in the gastrointestinal (GI) tract. Metastases to the liver, from NETs (mnet) in the forgut, midgut and hindgut may occur and, as with mcrc, the liver may be the only additional site involved. Care for patients with liver metastasis from spread of GI NETs, is similar to that of patients with either HCC or CRCLM, with resection, ablation, TACE, systemic or regional chemotherapy all being possible treatment options. Again, most patients with liver metastases from NETs are not candidates for curative therapies and as such are offered palliative care. For this reason, there is some evidence to suggest that TARE may be a treatment option for these types of tumour metastases as well Other Secondary Liver Tumours The liver is the second most common site for metastatic spread, after the lymph nodes. Primary sites most commonly metastasizing to the liver are the eye (77.8%), pancreas (75.1%), breast (60.6%), gallbladder and extrahepatic bile ducts (60.5%), colon or rectum (56.8%), and stomach (48.9%) 16. Although there is the potential for any primary cancer to Center for Health and Policy Studies, University of Calgary, October

23 metastasize to the liver, the extent to which the primary site metastasizes to other locations is one of the main determinants for treatment with TARE. Specifically, while some primary tumours seem to selectively metastasize to the liver (i.e. CRC) others spread without this specificity (i.e. lung). TARE is typically not considered a treatment option for liver metastases with extensive extra-hepatic spread as these patients are at an extremely advanced stage of disease. 3. Methodology 3.1. Literature Literature Search We searched the following electronic databases: MEDLINE (OVID), PubMED, Cochrane Database of Systematic Reviews (OVID), Cochrane CENTRAL Register of Controlled Trials (OVID), EMBASE (OVID), NHS Economic Evaluations Database (OVID), Health Technology Assessment Database - University of York (OVID), Database of Reviews of Effects (OVID), and EconLit (EBSCO). These databases were searched for clinical trials, cohort studies systematic reviews/meta-analyses, health technology assessments (HTAs) and economic reports published between 1950 and February Observational studies, case reports, animal and in vitro studies, duplicate publications, preliminary reports of data later presented in full, dose-finding studies, and studies that did not follow patients for more than three months and with greater than 20% loss to follow-up were excluded. The Search Strategy is presented in Appendix II. We also searched both manufacturers websites, the reference lists of studies included in our review, the national registry of current and ongoing clinical trials as well as any unpublished material that the Center for Health and Policy Studies, University of Calgary, October

24 EAG thought should be included. A complete list of grey literature sources is presented in Appendix III. The Expert Advisory Group (EAG) provided expert opinion on the search strategy for this review Selection of Literature The titles and abstracts yielded by our search of the literature were reviewed by two independent reviewers (LS, LH). Decisions regarding full text papers to review were based on the explicit inclusion/exclusion criteria detailed below. Disagreements were resolved through discussion and consensus. Papers were selected for full text review if they were identified as an RCT, cohort study, HTA, systematic review, meta-analysis or economic report. Additionally, they had to focus on patients who received TARE for the treatment of primary or secondary hepatic neoplasia, were followed for at least three months after the start of the intervention and reported on at least one of the following: survival, radiological response, toxicities, tumour markers, adverse events or quality of life measurements. It was decided that cancer types included in the review should be limited to HCC, CRCLM and mnet of the liver. Because such a small number of non HCC, CRCLM and mnet patients have received TARE, addressing the appropriateness of use in these patient populations was not feasible. The EAG was consulted and agreed. After the full text review, it was decided that cohort studies published before 1990 and that did not present data separately for each included cancer type (i.e. HCC, CRCLM or mnet) would be excluded. Also, only retrospective cohort studies with a significant number of patients were included. These additional exclusion criteria (i.e. studies published prior to 1990 and retrospective cohort studies) were added to narrow the included studies to Center for Health and Policy Studies, University of Calgary, October

25 a feasible number, to focus on the most current and relevant information on the therapy and to focus on the cancer types included in the report. All RCTs included patients with CRCLM and were judged to be of high quality according to CONSORT statement checklist - (See Appendix IV). Quality assessments were not performed for cohort studies Results of Literature Search A total of 373 titles and abstracts of potential RCTs, cohort studies, meta-analyses, systematic reviews, HTAs and economic reports were retrieved. 116 articles were selected for full text review. In addition, we found four HTA reports. The full Canadian Agency for Drugs and Technologies in Health (CADTH) 17, Medical Services Advisory Committee (MSAC) 18, National Institute for Health and Clinical Excellence (NICE) 19 and California Technology Assessment Forums (CTAF) 20 reports are available on the internet. The completeness of the RCT search was confirmed by comparison with the RCTs identified from the most recent HTA. Another phase III RCT was submitted by a member of the EAG who thought it should be included, as it was published in August of 2010 it was not originally included in the report. The final results of the literature review, and included in this report, are 43 studies. Four published studies describing three original RCTs, 33 cohort studies, one meta-analysis, two systematic reviews and four HTA reports comprised the 43 included studies. For HCC, no RCTs were identified, 18 cohort studies, one HTA and one meta-analysis were included. For mcrc, 3 RCTs, 13 cohort studies, 3 HTAs, one systematic review and one meta-analysis were included. Lastly, for mnet one systematic review and two cohort studies were included. For a Quorum diagram of the full literature search results see Appendix V and for details of the included studies see Appendix VI. Center for Health and Policy Studies, University of Calgary, October

26 For the three RCTs identified, the usual care comparator (i.e. control arm) was either systemic chemotherapy or regional chemotherapy (hepatic arterial chemotherapy (HAC)). The intervention for the RCTs was systemic chemotherapy + TARE or HAC + TARE. Thus, the RCTs evaluated the addition of TARE to a standard chemotherapy regimen. In total, papers included for HCC reported on 1103 patients, with mean ages between approximately 52 and 65 years, published between 1994 and 2010 and reported on outcomes such as survival, radiological response, time to disease progression (TTDP), alfa-fetoprotein (AFP), serious adverse events (SAE), toxicities and health related quality-of-life (HRQL). In most, TARE was the only treatment, although in some treatment with TARE or TACE occurred. For CRCLM papers, a total of 840 patients were reported on, with mean ages between 55 and 65 years, published between 1992 and Outcomes addressed are the same as with HCC patients, with the exception that HQRL and AFP were not reported and carcinoembryonic antigen (CEA) was. Comparators for CRCLM patients included systemic or regional chemotherapy. The two included mnet studies, reported on a total of 76 patients, mean ages reported were 58 and 61 years and both were published in Outcomes reported included survival, radiological response and hormone levels. No comparators were examined Data Extraction Data extraction was performed by two independent reviewers (LS, LH). Data extraction was performed using a form developed by our team (see Appendix VII). Information was extracted in three different categories: Study Design, Treatment Details and Outcome Measures. The following information was extracted: Study Design type (i.e. Center for Health and Policy Studies, University of Calgary, October

27 RCT, cohort study, meta-analysis/systematic review, HTA), sample selection (i.e. random, consecutive, other), type of microsphere (i.e. TheraSpheres or SIR-Sphere), type of cancer (i.e. HCC, CRCLM, mnet), cancer staging (i.e. BCLC, Child-Pugh, Okuda etc.), sample size (n), median age, mean age, gender of sample, loss to sample (i.e number of participants not available for follow-up) and quality of life; Treatment Details any relevant treatment details such as, number of treatments, concomitant therapy, dosage, treatment/patient accrual dates etc.; Outcome Measures radiological response data (i.e. CT, MRI, PET), tumour size, tumour volume, tumour marker (i.e. CEA, AFP etc., TTDP, mortality, median survival, toxicities and SAEs) Social Systems and Demographics (S) Approach to Analysis This section included information intended to address the profiles of illness and patterns of care, as well as to identify potential inequities in health status or care across population groups. Also included in this section were data used to estimate the need for TARE in Alberta. Information from published articles retrieved through our literature search, medical specialty books and clinical experts that were consulted for this report was included in this section. To estimate the potential demand for TARE in Alberta, we used both published incidence and prevalence rates, for both Canada and Alberta, along with Alberta specific diagnosis data for the conditions indicated for TARE. This data, along with the ICD-9 and ICD-10 diagnostic codes, are presented in Tables 1 and 2. Center for Health and Policy Studies, University of Calgary, October

28 3.3. Technology Effects and Effectiveness (T) Approach to Analysis The RCTs evaluating the safety and effectiveness of TARE were analyzed qualitatively. There were not sufficient RCTs or data to perform any quantitative analyses. The clinical outcomes of interest identified throughout the literature were median survival, survival rates, radiological response, tumour marker response, SAE and quality of life measures. Unfortunately, collection of data varied from study to study. Specifically, standardized criteria are seldom reported and the type of data reported between studies varied. The majority of cohort studies were uncontrolled. Cohort studies were analyzed qualitatively and quantitatively. A meta-analysis was performed using published data on the outcomes of interest. Data was available for analysis on median survival time, summary survival rates and summary radiological response rate. There were insufficient data for metaanalyses of the other outcome measures; however we addressed them qualitatively where appropriate. With respect to the meta-analyses performed for survival and radiological response, we developed a list of factors that could account for heterogeneity if it were observed. These factors included: cancer type (i.e. HCC, CRCLM or mnet), sphere type (i.e. TheraSpheres or SIR-Spheres), presence of extrahepatic disease or portal vein thrombosis and response criteria used (i.e. WHO or RECIST). Only the variables of cancer type and response criteria could be tested in a meta-regression analysis due to inconsistencies in reporting of the other factors. There were not enough data for an analysis on mnet patients for any of the outcome measures, but a qualitative summary of the use of TARE in Center for Health and Policy Studies, University of Calgary, October

29 these patients is included at the end of the section. The meta-analysis and meta-regression were performed using the meta and metareg packages, respectively, in STATA version 9.0. For the median survival analysis, the median survival times were retrieved from studies which reported them and estimated from the Kaplan-Meier curves for those that did not report the median but presented the Kaplan-Meier curve. The median times were plotted for each author and by type of cancer, but it was not possible to calculate summary estimates of the median survival time as patient specific data were not reported. The median of the median survival times (i.e the median survival time of all the included survival times) was calculated both overall (both HCC and CRCLM) and by cancer type. In total, 15 studies had data available for analysis , 23, 24, 27-29, 32, 33,. Of the included studies, nine were HCC papers 35 and six were CRCLM papers 22, 25, 26, 30, 31, 34. The summary survival rates (i.e. the mean survival rate of all patients included in each study) at six, 12 and 24 months were estimated from the Kaplan-Meier curves where available. In each case the 95% confidence intervals for the survival rate were estimated using binomial confidence intervals which do not take into account censored observations (i.e. an incomplete observation; in this case mainly due to patients surviving past the study completion date). This will result in an underestimation of the length of the confidence interval when censoring was present. The number of censored observations was very small in most studies, but increased as time increased. Therefore the confidence intervals for 24 months are those which will be underestimated the most. The summary survival rates were estimated using the inverse variance method and the heterogeneity across studies examined. Summary estimates were presented by cancer type. A total of 15 studies were included in the Center for Health and Policy Studies, University of Calgary, October

30 survival rate analysis 21-29, ; ten including patients with HCC 21, 23, 24, 27-29, 32, 33, 35, 36 and five including patients with CRCLM 22, 25, 26, 31, 34. A meta-analysis of summary radiological response rates was also conducted. This was done by combining the proportions of complete and partial responses and the 95% confidence intervals using the inverse variance method and the heterogeneity examined. The summary estimates were also calculated for each cancer type and each response criteria (i.e. WHO or RECIST) separately and the heterogeneity within each was examined. WHO and RECIST criteria were selected as the two most commonly reported response criteria (see 22, 23, 26, 27, 31, 33, Table 3 for response criteria). In total ten studies were included in the analysis 34, ; three including HCC patients 23, 27, 33 22, 26, 31, 34, 37- and seven including CRCLM patients Economic (E) Approach to Analysis This report undertakes a cost-effectiveness analysis. Effectiveness is measured in terms of life-years gained, while costs are broken into pre-treatment, treatment, and posttreatment, and then aggregated, for each of the comparators. For HCC, these comparators were obtained from the HCC provincial clinical guidelines 41 and include: 1) TACE, using regular chemotherapy and using DC beads; 2) TARE; 3) Sorafenib. TACE is typically used in intermediate HCC patients (i.e. BCLC stage B), while sorafenib is used in advanced HCC patients (i.e. BCLC stage C). The analysis will look at Center for Health and Policy Studies, University of Calgary, October

31 using TARE versus TACE for intermediate patients and TARE versus sorafenib for advanced patients. An analysis for CRCLM was also performed. The selected comparators include: 1) TARE; 2) Palliative treatment (in which pain-relieving medication is the only treatment given) These comparators were selected after the Technology and Effectiveness component revealed that other standards of care for CRCLM were superior to TARE in the outcome measures addressed therefore not an appropriate comparison for this patient population (i.e. TARE would not be administered as a first-line therapy). For mnet, an economic analysis could not be completed due to a number of factors. These factors included, but were not limited to, the level and quantity of evidence available for this population, the lack of appropriate comparators for this population and the lack of Alberta specific clinical guidelines for this population. The analysis includes costs from the healthcare perspective societal costs, such as lost caregiver salaries or drugs paid out-of-pocket or via private insurance plans, are not included because data for these measures could not be obtained. Healthcare system costs include treatment costs paid by Alberta Health and Wellness, as well as associated physician and inpatient costs. Due to imprecision in estimating costs, variation will be accounted for in all calculations. This is further detailed in section 6.2 and Table 7a and 7b. The specific model used to simulate the costs based on this uncertainty is a Markov model, in which there are specific chances of adverse events occurring. The timeframe for Center for Health and Policy Studies, University of Calgary, October

32 cost estimates assumed that the time between treatments (for those who receive more than one) is an identical three months for both TARE and TACE and that all patients receiving sorafenib would do so for 5.5 months while palliative therapy for CRCLM would be provided for six months. Resource requirements are given in Table 7a. Effectiveness measures are detailed in Table 7a. Cost measures are detailed in Table 7b. The effectiveness measures do not consider (directly) patient quality-of-life, which is one intended benefit of the TARE treatment. All measures, included in the analysis were taken from previous literature, the meta-analyses performed in this report, experts consulted for this report and EAG members. Effectiveness measures included median survival times, serious adverse events and minor adverse events. Clinical pathways were identified through the literature and through consultation with experts in the field and the EAG. In the model, a cohort of 100 patients was drawn, with the chance of death or other adverse events occurring during each treatment. These are mentioned further in section Costs were then aggregated and averaged for the 100 patients. This was done 100 times in a Monte Carlo-style analysis, with a grand average reported as the overall cost in Table 8. This allowed for the results to be relatively uninfluenced by any extreme cost values. Incremental costs and effectiveness the differences in costs and life years gained between TARE and a comparator treatment -- were then calculated with the differences in cost divided by the differences in effectiveness, this ratio yields a cost per life year gained value that informed the final results. Sensitivity analyses, including life expectancy differences and the elimination of treatment related deaths (i.e. all patients fully complete Center for Health and Policy Studies, University of Calgary, October

33 their treatment) were also completed, and are noted in section and Table 9. An overall budget impact is given in section and Table Social Systems and Demographics (S) 4.1. Patterns of Illness Burden of Illness description of condition(s) Cancers of the liver may be conveniently divided into two major groups, primary cancer of the liver, also known as hepatocellular carcinoma (HCC), and metastatic tumour to the liver, most often from colorectal cancer (CRC). The major risk factor for HCC is viral hepatitis, particularly HBV and HCV 4. It is estimated that 1 in 12 persons worldwide is chronically infected with HBV or HCV. In endemic countries, HBV spread is vertical from mother to child with the tumour presenting decades later. HCV infection is most commonly diagnosed in the 3 rd and 4 th decades of life, with parenteral transmission from past blood products or intravenous drug use being the most common mode of infection. The acute infection with HCV is often asymptomatic and only after years will patients typically present with signs and symptoms of chronic hepatitis that has progressed to cirrhosis and HCC. Alcohol induced cirrhosis remains an important cause of cirrhosis and HCC in North America, however Canadian data suggests that increases in incidence of HCC is mainly attributable to hepatitis B and C infection, as alcoholic cirrhosis has declined in recent years 40. Based on Alberta Health and Wellness data, the incidence of HBC and HBV infection more than doubled from , from a rate of 7.1 to 15.7 per 100,000 Albertans. Alcoholic cirrhosis has also increased in this time period, although not as significantly, from a rate of 11.7 to 14.8 per 100,000 Albertans. Insulin resistance has also Center for Health and Policy Studies, University of Calgary, October

34 been linked to HCC, and with rates of obesity and diabetes increasing rapidly in North America, we may expect further increases in HCC due to non-alcoholic fatty liver disease. Lang and associates estimated the annual cost of HCC in the United States to be $454.9 million dollars with per patient costs of $33,000 (1999 dollars) 41. Healthcare costs and lost productivity accounted for 89.2% and 10.8% total costs respectively. Costs associated with localized HCC accounted for the highest proportion (44.5%) of the total cost of illness, or million. Regional, distant, and unstaged HCC accounted for 31.0%, 13.9% and 10.6% of total costs, respectively 41. Colorectal cancer starts as benign polyps which, if not removed, can progress to cancerous tumours within any part of the large intestine. Due to venous drainage of the gut into the portal vein, spread of the cancer to the liver is a likely occurrence. CRC is common and there is a large economic toll on society from health care costs associated with care; in fact, costs of treatment continue to rise. Rises in health care costs are primarily driven by newer regimens of chemotherapy and biologics that have been accepted as standard of care. These new regimens, while expensive, have proven to be significantly more effective, with survival benefits of 8 10 months, over the older less expensive regimens 42. Individuals also have to bear the burden of this cancer through years of life lost, disability, pain, emotional impact on family members, and loss of family income. Neuroendocrine tumours typically are the result of either a carcinoid tumour or an islet cell neoplasm. Most commonly NETs are found in the GI tract. The GI tract contains as many as 15 endocrine cell types, all of which may be a potential source for the development of endocrine tumours. It is estimated that approximately 10-20% of NETs Center for Health and Policy Studies, University of Calgary, October