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March 2003 Health Technology Board for Scotland Positron emission tomography (PET) imaging in cancer management Authors: Bradbury I, Bonell E, Boynton J, Cummins E, Facey K, Iqbal K, Laking G McDonald C, Parpia T, Sharp P, Single A, Walker A. With significant contributions from the Topic Specific Group (see Appendix 1) This report should be referenced as: Bradbury I, Bonell E, Boynton J, Cummins E, Facey K, Iqbal K, Laking G,McDonald C, Parpia T, Sharp P, Single A and Walker A. 2002. Positron emission tomography (PET) imaging in cancer management. Health Technology Assessment Report 2. Glasgow: Health Technology Board for Scotland ISBN 1-903961-31-9 © Copyright Health Technology Board for Scotland, 2002 All rights reserved. This material may be freely reproduced for educational and not for profit puposes. No reproduction by or for commercial organisations is permitted without the express written permission of the Health Technology Board for Scotland. CONTENTS EXECUTIVE SUMMARY ............................................................................................I Background to this assessment ...................................................................................I Aims of this assessment ............................................................................................ II Health Technology Assessment (HTA) evidence ..................................................... II Clinical effectiveness - NSCLC ............................................................................... III Economic evaluation - NSCLC ................................................................................ V Clinical effectiveness – Lymphoma...................................................................... VIII Economic evaluation – Restaging Hodgkin’s disease .............................................IX Patient issues .........................................................................................................XI Organisational issues and budget impact ............................................................... XII Discussion ...................................................................................................... XIII Recommendations to NHSScotland ...................................................................... XIV 1 INTRODUCTION AND OBJECTIVES ...........................................................1-1 1.1 Introduction ....................................................................................1-1 1.1.1 Previous NHS HTA research on PET imaging ..............................1-1 1.1.2 The Scottish HTA on PET imaging ...............................................1-1 1.2 Objectives and scope of this HTA ..................................................1-4 2 BACKGROUND ...............................................................................................2-1 2.1 Description of health problem in Scotland .....................................2-1 2.1.1 Cancer in Scotland ..........................................................................2-1 2.1.2 Lung cancer in Scotland .................................................................2-2 2.1.3 Lymphoma in Scotland ..................................................................2-3 2.2 Perspectives ....................................................................................2-4 2.2.1 Organisation of NHSScotland ........................................................2-4 2.2.2 Organisation of cancer services in Scotland ...................................2-5 2.3 The role of PET in oncology ..........................................................2-5 2.4 Health Technology Assessments of PET imaging .........................2-8 2.4.1 Danish HTA (DACEHTA, 2001) ...................................................2-9 2.4.1.1 Lung cancer ....................................................................................2-9 2.4.1.2 Solitary pulmonary nodules............................................................2-9 2.4.1.3 Colorectal cancer ..........................................................................2-10 2.4.1.4 Head and neck cancer ...................................................................2-10 2.4.1.5 Malignant melanoma ....................................................................2-10 2.4.1.6 Breast cancer ................................................................................2-11 2.4.1.7 Other cancers ................................................................................2-11 2.4.1.8 Alzheimer’s disease ......................................................................2-11 2.4.1.9 Epilepsy ........................................................................................2-11 2.4.1.10 Ischaemic heart disease ................................................................2-11 2.5 Description of the technology ......................................................2-12 2.5.1 Radionuclide imaging...................................................................2-12 2.5.2 PET radiopharmaceuticals ............................................................2-15 2.5.2.1 New tracers ...................................................................................2-16 2.5.3 Instrumentation for PET ...............................................................2-16 2.5.4 Image interpretation .....................................................................2-18 2.5.4.1 Quantitation ..................................................................................2-19 2.5.5 Alternatives to PET ......................................................................2-19 2.5.5.1 Gamma cameras ...........................................................................2-19 2.5.5.2 PET/CT .........................................................................................2-20 3 SOURCES OF EVIDENCE AND DEVELOPMENT OF THE ASSESSMENT QUESTIONS ..........................................................................3-1 3.1 Sources of evidence ........................................................................3-1 3.2 Developing the assessment questions.............................................3-2 4 CLINICAL EFFECTIVENESS – NSCLC ........................................................4-1 4.1 Literature search .............................................................................4-2 4.1.1 Search strategy ...............................................................................4-2 4.1.2 Exclusion criteria ............................................................................4-2 4.2 NSCLC diagnosis in Scotland ........................................................4-3 4.2.1 NSCLC staging...............................................................................4-3 4.2.2 NSCLC diagnostic work-up in Scotland ........................................4-6 4.3 Methodology for clinical effectiveness analyses ..........................4-10 4.3.1 Evaluation of sensitivity and specificity ......................................4-10 4.3.2 Meta-analysis ................................................................................4-11 4.4 Critical appraisal of published literature ......................................4-11 4.4.1 Background ..................................................................................4-11 4.4.2 Systematic reviews .......................................................................4-12 4.4.3 Mediastinal staging.......................................................................4-13 4.4.4 Detection of distant metastases ....................................................4-14 4.4.4.1 Specific sites of metastasis ...........................................................4-15 4.4.5 Changes in patient management ...................................................4-15 4.4.5.1 Surveys of referring physicians ....................................................4-16 4.4.5.2 Prognostic significance of SUR ...................................................4-17 4.4.6 Randomised clinical trials ............................................................4-17 4.4.7 Limitations of the evidence ..........................................................4-19 4.5 Meta-analyses ...............................................................................4-19 4.5.1 Study exclusion criteria ................................................................4-20 4.5.2 FDG-PET sensitivity in CT-negative patients ..............................4-20 4.5.2.1 Sensitivity analysis .......................................................................4-21 4.5.3 PET sensitivity in CT-positive patients ........................................4-22 4.5.3.1 Sensitivity analysis .......................................................................4-23 4.5.4 CT sensitivity and specificity .......................................................4-23 4.5.4.1 Sensitivity analysis .......................................................................4-24 4.5.5 Meta-analysis conclusions ............................................................4-24 4.6 Assessment of safety in clinical practice ......................................4-25 4.7 Conclusions ..................................................................................4-25 5 ECONOMIC EVALUATION - NSCLC ...........................................................5-1 5.1 Literature search .............................................................................5-2 5.1.1 Search strategy ...............................................................................5-2 5.1.2 Criteria for inclusion and exclusion of studies ...............................5-2 5.1.3 Data extraction ...............................................................................5-2 5.2 Economic methods .........................................................................5-2 5.2.1 Background ....................................................................................5-2 5.2.2 Objectives of the economic evaluation ..........................................5-3 5.2.3 The potential for use of FDG-PET in NHSScotland ......................5-3 5.2.4 Model structure...............................................................................5-3 5.2.5 Identification and measurement of the potential benefits and costs of FDG-PET ..........................................................................5-6 5.2.6 Constructing the economic model ..................................................5-8 5.2.7 Methods of analysis ........................................................................5-8 5.2.7.1 Delays in diagnosis and treatment ..................................................5-8 5.2.8 Perspective and horizon..................................................................5-8 5.2.9 Model inputs ...................................................................................5-9 5.2.9.1 Epidemiology ...............................................................................5-10 5.2.9.2 Quality of life ...............................................................................5-11 5.2.9.3 Resource use .................................................................................5-12 5.2.9.3.1 FDG-PET scan ..................................................................5-12 5.2.9.3.2 Mediastinoscopy................................................................5-12 5.2.9.3.3 Surgery ..............................................................................5-13 5.2.9.3.4 Non-surgical treatment (palliative treatment for advanced disease) ..............................................................5-14 5.2.9.3.5 Follow up after surgical treatment and palliative treatment ............................................................................5-15 5.2.10 Assumptions .................................................................................5-15 5.2.10.1 Quality of life (QOL) loss from operations ..................................5-15 5.2.10.2 Strategies for testing and treatment are followed .........................5-15 5.2.11 Discounting costs and benefits occurring in future years .............5-15 5.3 Results ..........................................................................................5-16 5.4 Diagnosis based on PET only .......................................................5-20 5.5 Model testing and savings in surgery ...........................................5-21 5.6 Sensitivity analyses ......................................................................5-22 5.6.1 Accuracy of PET scanning ...........................................................5-23 5.6.2 Increased surgical referral to non-surgical treatment ...................5-24 5.6.3 Reduced surgical morbidity..........................................................5-25 5.6.4 Increased costs of surgery ............................................................5-25 5.6.5 Conclusions of sensitivity analyses ..............................................5-26 5.7 Discussion and conclusions of economic evaluation of NSCLC .5-27 6 CLINICAL EFFECTIVENESS – LYMPHOMA ..............................................6-1 6.1 Introduction ....................................................................................6-2 6.1.1 Literature search strategy ...............................................................6-2 6.1.2 Exclusion criteria ............................................................................6-3 6.2 Lymphoma treatment in Scotland ..................................................6-3 6.3 Possible roles for FDG-PET imaging .............................................6-4 6.3.1 Initial staging ..................................................................................6-4 6.3.2 FDG-PET imaging during therapy .................................................6-4 6.3.3 FDG-PET scanning for detection of recurrence .............................6-4 6.3.4 FDG-PET in the post-treatment assessment of lymphoma ............6-4 6.4 Accuracy of FDG-PET for post-therapy restaging of patients who are CT-positive - studies .........................................................6-5 6.5 Accuracy of FDG-PET for post-therapy restaging in patients who are CT-positive - analysis .......................................................6-7 6.6 Accuracy of FDG-PET in post-therapy restaging (no CT) studies .............................................................................................6-7 6.7 Accuracy of FDG-PET for post-therapy restaging (no CT) analysis ...........................................................................................6-9 6.8 Accuracy of CT scanning for post-therapy re-staging .................6-10 6.9 Conclusions ..................................................................................6-11 7 ECONOMIC EVALUATION – RESTAGING HODGKIN’S DISEASE ........7-1 7.1 Literature search .............................................................................7-2 7.1.1 Search strategy ...............................................................................7-2 7.1.2 Criteria for inclusion and exclusion of studies ...............................7-2 7.1.3 Data extraction ...............................................................................7-2 7.2 Economic methods .........................................................................7-3 7.2.1 Restriction to Hodgkin’s disease (HD) ..........................................7-3 7.2.2 Objectives of the economic evaluation ..........................................7-3 7.2.3 The potential for use of PET in restaging HD in NHSScotland .....7-3 7.2.4 Model structure...............................................................................7-3 7.2.5 Markov treatment model ................................................................7-5 7.2.5.1 Narrative description of the model and assumptions .....................7-5 7.2.6 Identification and measurement of the potential benefits and costs of PET ...................................................................................7-7 7.2.7 Assumptions ...................................................................................7-7 7.2.7.1 Relapse detection ............................................................................7-7 7.2.7.2 Long-term toxicity ..........................................................................7-7 7.2.7.3 No QOL loss for procedures ..........................................................7-7 7.2.7.4 Strategies for testing and treatment are followed ...........................7-7 7.2.8 Methods of analysis ........................................................................7-8 7.2.9 Perspective and horizon..................................................................7-8 7.2.10 Discounting costs and benefits occurring in future years ...............7-8 7.2.11 Model inputs ...................................................................................7-8 7.2.11.1 Epidemiology ...............................................................................7-11 7.2.11.2 Quality of life ...............................................................................7-11 7.2.11.3 Resource use .................................................................................7-12 7.2.11.3.1 CT scan ..............................................................................7-12 7.2.11.3.2 Surveillance .......................................................................7-12 7.2.11.3.3 Radiotherapy (RT) .............................................................7-13 7.2.11.3.4 IVE chemotherapy.............................................................7-14 7.2.11.3.5 Autologous peripheral blood stem cell transplant (PBSCT) ............................................................................7-15 7.2.11.3.6 Long-term toxicities ..........................................................7-16 7.3 Results ..........................................................................................7-16 7.3.1 Uncertainties .................................................................................7-16 7.3.2 Results – Life-years analysis ........................................................7-18 7.3.3 Discussion of results .....................................................................7-20 7.4 Further sensitivity analysis ...........................................................7-20 7.4.1 Lower accuracy from FDG-PET ..................................................7-20 7.4.2 Incorporation of quality weights ..................................................7-20 7.4.3 Variations in discount rate used for clinical benefits ...................7-21 7.4.3.1 Summary ......................................................................................7-23 7.4.4 Discussion ....................................................................................7-23 7.4.4.1 Relationship to previous work ......................................................7-24 7.4.5 Conclusions ..................................................................................7-24 8 PATIENT ISSUES.............................................................................................8-1 8.1 Background ....................................................................................8-2 8.2 The scanning process for the patient ..............................................8-2 8.3 Communication with patients .........................................................8-3 8.3.1 Professional interactions .................................................................8-3 8.3.2 8.4 8.5 8.5.1 8.6 9 Patient information .........................................................................8-4 Consultation questions and responses ............................................8-5 Focus group ....................................................................................8-6 Results ............................................................................................8-6 Conclusions ....................................................................................8-9 ORGANISATIONAL ISSUES ..........................................................................9-1 9.1 Organisation of PET facilities in the UK .......................................9-2 9.1.1 Current facilities .............................................................................9-2 9.1.2 Planning of new facilities ...............................................................9-2 9.2 The PET centre ...............................................................................9-3 9.3 Site planning (layout, regulations) .................................................9-5 9.4 Radiopharmaceutical supply ..........................................................9-6 9.4.1 Radiopharmaceutical licensing and production..............................9-6 9.4.2 Radiopharmaceutical transportation ...............................................9-7 9.4.3 Clinical administration of radiopharmaceuticals ............................9-8 9.5 Staffing ...........................................................................................9-8 9.5.1 Cyclotron support .........................................................................9-10 9.6 Cost per scan and budget impact ..................................................9-12 9.6.1 Costings for options 1, 2 & 3 (fixed facilities) .............................9-12 9.6.1.1 Staffing levels ...............................................................................9-13 9.6.1.2 Patient throughput ........................................................................9-14 9.6.1.3 Operating costs .............................................................................9-14 9.6.1.4 Supply of FDG .............................................................................9-15 9.6.1.5 Training ........................................................................................9-16 9.6.1.6 Laboratory equipment ..................................................................9-16 9.6.1.7 Cost of a PET scanner ..................................................................9-16 9.6.1.8 Building costs ...............................................................................9-16 9.6.1.9 Location of Scottish facility .........................................................9-17 9.6.1.10 Costs not included ........................................................................9-17 9.6.1.11 Summary of annual running costs ................................................9-17 9.6.1.12 Cost per scan ................................................................................9-19 9.6.1.13 Sensitivity analysis .......................................................................9-20 9.6.2 Cost per scan option 4 (Mobile facility) .......................................9-20 9.7 Budget impact ...............................................................................9-23 9.7.1 Annual running cost .....................................................................9-23 9.7.2 Capital costs .................................................................................9-23 9.7.3 Annual cash flow projections .......................................................9-24 9.8 Budget impact discussion .............................................................9-25 9.9 Organisational issues conclusions ................................................9-26 10 DISCUSSION ..................................................................................................10-1 10.1 Scope of the HTA .........................................................................10-1 10.1.1 Clinical effectiveness - NSCLC (section 4) .................................10-1 10.1.2 Economic evaluation NSCLC (Section 5) ....................................10-2 10.1.3 Clinical effectiveness – Lymphoma (Section 6) ..........................10-3 10.1.4 Economic evaluation – Hodgkin’s disease (Section 7) ................10-3 10.1.5 Clinical effectiveness – Other clinical applications (sections 2.3 and 2.4) ...................................................................................10-4 10.1.5.1 Cancer ...........................................................................................10-4 10.1.5.2 Cardiology, neurology and psychiatry .........................................10-5 10.1.6 10.1.7 10.1.8 10.2 10.2.1 10.2.2 10.2.3 10.3 10.4 10.4.1 10.4.2 10.4.3 10.4.4 10.4.4.1 10.4.4.2 10.5 10.6 Safety (Section 4.6) ......................................................................10-5 Patient issues (Section 8) .............................................................10-5 Organisational issues and costings (Section 9) ............................10-5 Assumptions, limitations and uncertainties ..................................10-7 Assumptions .................................................................................10-7 Limitations....................................................................................10-7 Uncertainties .................................................................................10-8 Future developments ....................................................................10-9 Research .......................................................................................10-9 Exploiting the superior accuracy of FDG-PET scanning ...........10-10 Exploiting the imaging of function ............................................10-11 Facilitating research ...................................................................10-11 Approximate scan numbers in Scotland .....................................10-11 Routine clinical use ....................................................................10-11 Health services research .............................................................10-11 Summary and conclusions ..........................................................10-13 Recommendations to NHSScotland ...........................................10-15 11 ACKNOWLEDGEMENTS .............................................................................11-1 12 REFERENCES ..................................................................................................... 1 LIST OF TABLES Table 1-1 Table 2-1 Table 3-1 Table 3-2 Table 4-1 Table 4-2 Table 5-1 Table 5-2 Table 5-3 Table 5-4 Table 5-5 Table 5-6 Table 5-7 Table 5-8 Table 5-9 Table 5-10 Table 5-11 Table 5-12 Table 6-1 Table 6-2 Table 6-3 Table 6-4 Table 6-5 Table 6-6 Table 7-1 Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 Table 7-7 Table 7-8 Table 7-9 Table 7-10 Table 7-11 Table 7-12 Table 7-13 Table 7-14 Table 7-15 Hierarchy of diagnostic efficacy .........................................................1-4 Medicare reimbursement of PET in the US ........................................2-6 Results of clinical effectiveness and economic evaluation scoping literature searches (number of studies by cancer and functionality) ...3-3 Number of economic evaluation papers suitable for this HTA ...........3-4 Guidance on surgical judgement .........................................................4-3 Diagnostic testing ..............................................................................4-10 Comparison of estimates used in NSCLC economic models ..............5-7 Inputs to the HTBS economic model: base case .................................5-9 Distribution of lung cancer ................................................................5-10 Distribution of candidates for PET....................................................5-11 Utilities assigned: base case ..............................................................5-12 Costs and benefits for CT-positive: base case ...................................5-16 Costs and benefits for CT-negative: base case ..................................5-17 Strategies ranked by cost for CT-positive .........................................5-18 Strategies ranked by cost for CT-negative ........................................5-18 Sensitivity analyses: CT-positive ......................................................5-22 Sensitivity analyses results: CT-negative ..........................................5-23 Sensitivity analyses: reduced accuracy of PET .................................5-24 Study characteristics: FDG-PET accuracy in assessment of residual masses ....................................................................................6-6 Results: FDG-PET accuracy in assessment of residual masses ..........6-7 Study characteristics: PET accuracy post therapy...............................6-8 Results: PET accuracy post therapy ....................................................6-9 Study characteristics: CT accuracy post therapy...............................6-10 Results: CT accuracy post therapy ....................................................6-10 Inputs to the HTBS economic model: base case and distributions .....7-9 Cost inputs to the model: base case ...................................................7-10 Post ABVD chemotherapy ................................................................7-13 Post radiotherapy/salvage chemotherapy ..........................................7-13 Post autologous peripheral blood stem cell transplant (PBSCT) ......7-13 Summary costs for consolidation radiotherapy .................................7-13 Model inputs - sensitivity distributions .............................................7-17 Point estimates of life years saved and total costs for female, 20 years old at end of induction therapy ................................................7-18 Point estimates of life years saved and total costs for male, 20 years old at end of induction therapy ................................................7-18 Point estimates of life years saved and total costs for female, 40 years old at end of induction therapy ................................................7-19 Point estimates of life years saved and total costs for male, 40 years old at end of induction therapy ................................................7-19 Point estimates of life years saved and total costs for female, 60 years old at end of induction therapy ................................................7-19 Point estimates of life years saved and total costs for male, 60 years old at end of induction therapy ................................................7-19 Estimated utilities in a 20-year-old woman.......................................7-21 QALY analysis for 20-year-old woman ............................................7-21 Table 7-16 Table 7-17 Table 7-18 Table 7-19 Table 7-20 Table 7-21 Table 9-1 Table 9-2 Table 9-3 Table 9-4 Table 9-5 Table 9-6 Table 9-7 Table 9-8 Table 9-9 Table 9-10 Point estimates of life years saved and total costs for female, 20 years old, 6% discount rates on benefit .............................................7-21 Point estimates of life years saved and total costs for male, 20 years old, 6% discount rates on benefit .............................................7-22 Point estimates of life years saved and total costs for female, 40 years old, 6% discount rates on benefit .............................................7-22 Point estimates of life years saved and total costs for male, 40 years old, 6% discount rates on benefit .............................................7-22 Point estimates of life years saved and total costs for female, 60 years old, 6% discount rates on benefit .............................................7-22 Point estimates of life years saved and total costs for male, 60 years old, 6% discount rates on benefit .............................................7-23 Cost per scan: assumptions ...............................................................9-13 Summary annual running costs .........................................................9-18 Cost per scan .....................................................................................9-19 Mobile PET model: assumptions ......................................................9-21 Mobile PET model: summary costs ..................................................9-22 Mobile PET model: cost per scan .....................................................9-22 Annual running costs (£ million) ......................................................9-23 Capital costs (£ million) ....................................................................9-23 Accumulative cash flow spending: options 1, 2 and 3 (£ million) ....9-24 Accumulative cash flow spending: option 4 (£ million) ...................9-24 LIST OF FIGURES Figure 1-1 Figure 2-1 Figure 2-2 Figure 2-3 Figure 4-1 Figure 4-2 Figure 4-3 Figure 4-4 Figure 4-5 Figure 4-6 Figure 5-1 Figure 7-1 Figure 7-2 Figure 7-3 Figure 7-4 Figure 7-5 Figure 7-6 Figure 7-7 Figure 7-8 Figure 7-9 Figure 7-10 Health Technology Assessment (HTA) process 1-3 Outline of a PET imager 2-14 Whole body image taken using FDG 2-16 A dedicated PET imager 2-17 Lung cancer: T staging 4-4 Lung cancer: N staging 4-5 Diagnostic pathway in Scotland 4-9 False positive versus true positive and fitted SROC curve, for CT-negative patients 4-21 False positive versus true positive and fitted SROC curve, for CT-positive patients 4-22 False positive versus true positive and fitted SROC curve, for all CT data 4-24 NSCLC diagnostic pathways after CT 5-5 Management pathways after induction chemotherapy in HD 7-4 Structure of the Markov treatment model 7-6 Cost effectiveness acceptability curves (CEACs) for female, 20 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-26 Cost effectiveness acceptability curves (CEACs) for male, 20 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-27 Cost effectiveness acceptability curves (CEACs) for female, 40 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-28 Cost effectiveness acceptability curves (CEACs) for male, 40 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-29 Cost effectiveness acceptability curves (CEACs) for female, 60 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-30 Cost effectiveness acceptability curves (CEACs) for male, 60 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-31 Cost effectiveness acceptability curves (CEACs) for female, 20 years. Strategy 5 only (PET only), relative to strategy 3 (CT only), PET specificity distributed as Uniform on (0.6,0.9) 7-32 Cost effectiveness acceptability curves (CEACs) for male, 20 years. Strategy 5 only (PET only), relative to strategy 3 (CT only), PET specificity distributed as Uniform on (0.6,0.9) 7-33 Figure 7-11 Figure 7-12 Figure 7-13 Figure 7-14 Figure 7-15 Figure 7-16 Figure 7-17 Figure 9-1 Figure 9-2 Figure 9-3 Figure 9-4 Cost effectiveness acceptability curves (CEACs) based on QALYs for female, 20 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only) both relative to strategy 3 7-34 Cost effectiveness acceptability curves for female, 20 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-35 Cost effectiveness acceptability curves for male, 20 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-36 Cost effectiveness acceptability curves for female, 40 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-37 Cost effectiveness acceptability curves for male, 40 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-38 Cost effectiveness acceptability curves for female, 60 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-39 Cost effectiveness acceptability Curves for male, 60 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 7-40 A medical cyclotron 9-3 Automated radiochemistry synthesis unit 9-4 Site plan of the John Mallard Scottish Pet Centre, Aberdeen 9-5 St Thomas’ PET facility 9-9 EXECUTIVE SUMMARY Background to this assessment Cancer in Scotland 1. More than 26,000 people in Scotland are diagnosed with cancer every year and cancer is now the leading cause of premature death. 2. Although survival rates in many cancers have improved, continued progress requires greater awareness, prevention, earlier diagnosis and better, faster treatment. This will be facilitated by the new organisation of cancer services that has been established in Scotland with expert multidisciplinary involvement in Managed Clinical Networks (MCN), Regional Cancer Advisory Groups and an overarching national advisory group, the Scottish Cancer Group. 3. The most common site of disease is the lung, with approximately 4,600 patients diagnosed each year. These are predominately non-small cell lung cancers (NSCLC) (75%). The treatment of choice in NSCLC is surgical resection, but only 15% of patients will have early disease suitable for potentially curative surgery. The remaining 85% of patients will be potential candidates for chemotherapy and/or radiotherapy. 4. Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) together account for approximately 4% of incident cancers in Scotland, with 130 incident cases of HD and 850 of NHL per year. In Scotland, the five-year survival from HD is approximately 73% and that from NHL is approximately 45%. While NHL most commonly affects older people, HD has a bimodal age distribution with an initial peak at between 15 and 35 years. For HD, many of those affected are young people and a large proportion will die not of lymphoma, but from the toxicity associated with therapy. Therefore, any technology that reduces these effects is likely to have a major positive impact. PET scanning in oncology 1. Positron emission tomography (PET) is a non-invasive imaging procedure used for measuring the concentrations of positron-emitting radioisotopes within tissue in benign and malignant disease. This requires injection of a radiolabelled tracer. In cancer, the most common radiolabelled tracer is FDG, which is glucose labelled with 18Fluorine (2- [18F]-fluoro-2-deoxy-D-glucose). 2. Three-dimensional PET imaging provides information about the level of biological activity in a lesion and can detect tumours due to their high rate of glucose utilisation. This differs from other forms of imaging such as magnetic resonance imaging (MRI), computed tomography (CT) or ultrasound techniques, which mainly show structural (anatomical) information. 3. Malignancies can cause abnormalities of blood flow or metabolism before anatomical changes are apparent. Therefore FDG-PET allows differentiation between malignant and benign abnormalities. This can enable early diagnosis of cancer and improved staging, before metastatic spread occurs. I Aims of this assessment 1. This Health Technology Assessment (HTA) set out with two principal objectives: To determine the role of PET imaging in cancer management: evaluating the clinical and cost effectiveness in terms of impact on patient mortality and morbidity. If PET is found to be clinically and cost effective, to consider the best configuration of PET facilities (and cyclotrons) to serve the Scottish population. Health Technology Assessment (HTA) evidence 1. The HTA used systematic literature searching to identify evidence published in the scientific literature. It also used evidence submitted by professional groups, patient groups, manufacturers, other interested parties and experts. 2. The HTA considers four components: clinical effectiveness, cost effectiveness, patient issues and organisational issues (including budget impact). 3. To determine the value of FDG-PET, diagnostic accuracy is not sufficient and evidence of change in patient outcomes, or a change in patient management, was sought. 4. A review of the literature on the clinical effectiveness and economic evaluation of FDG-PET scanning in oncology was carried out, together with an appraisal of the questions most relevant to Scotland. The largest body of evidence is available for the role of FDG-PET in NSCLC and this is the only indication for which there is data on patient outcomes from randomised, controlled trials. 5. The availability of the evidence and the importance of lung cancer in Scotland, with the largest number of deaths of any cancer, resulted in the decision initially to focus this report on the value of FDG-PET in the staging of patients with potentially operable NSCLC. 6. The value of FDG-PET in improving outcomes is influenced by the potential for successful therapy. Consequently, the use of FDG-PET in lymphoma was also assessed, because it was anticipated that a greater benefit on patient outcomes was possible and a clear patient pathway could be constructed. Analysis Number of studies Specificity (95% CI) Sensitivity (95% CI) FDG-PET in CT-positives 15 0.76 (0.69-0.82) 0.92 (0.87-0.95) FDG-PET in CT-negatives 15 0.90 (0.87-0.93) 0.86 (0.79-0.91) II Clinical effectiveness - NSCLC 1. Clinical effectiveness was evaluated by updating the summary of the literature on the diagnostic accuracy of FDG-PET presented by the Danish Centre for Evaluation and Health Technology Assessment (DACEHTA) in 2001. Databases and websites were searched for literature published between January and October 2001 on FDG-PET and NSCLC. Papers were excluded from the evaluation if they were not about NSCLC staging and did not use PET imaging with FDG as the radiolabelled tracer. 2. The treatment offered to a patient with NSCLC and their prognosis will depend on the stage of their disease. Patients with no lymph node involvement (N0) or disease confined to the ipsilateral peribronchial or hilar nodes (N1) may be candidates for surgery. Spread to the mediastinal nodes (N2, N3) precludes surgical intervention. The current diagnostic pathway in Scotland utilises CT to detect enlarged nodes (greater than 1 cm = CT-positive) and mediastinoscopy is used to confirm the presence or absence of mediastinal lymph node involvement. 3. The accuracy of a diagnostic test is described by the sensitivity (probability that the test is positive when the patient has the disease) and the specificity (probability that the test is negative when the patient does not have the disease). 4. Thirty-three (33) papers on the use of FDG-PET in mediastinal staging were identified. Almost all reported that FDG-PET is more accurate and more sensitive than CT imaging. However, a number of methodological flaws were evident in the studies. These included retrospective rather than prospective series, unclear inclusion criteria and small numbers of patients. 5. Two meta-analyses were performed looking at the accuracy of FDG-PET scanning in NSCLC; one to estimate the sensitivity and specificity for FDG-PET in CT-positive nodes and one to estimate the sensitivity and specificity for PET in CT-negative nodes. The results are shown in the above table. 6. The results demonstrate that PET appears to have substantial value in discriminating diseased from non-diseased nodes, both for CT-positive and CTnegative patients. The estimated sensitivity and specificity are very similar to those reported by Dietlein et al. (2000a), despite differences in the analysis methods and study selection. 7. Nineteen (19) studies provided some data on the usefulness of FDG-PET for the detection of distant (extra-thoracic) metastases. There is evidence that this may be a useful tool in supplementing staging in patients believed to be free of distant metastases. However, these results need to be confirmed in larger randomised trials. 8. Evidence from the literature suggests that the results of FDG-PET may influence patient management, with reports of changes in management in 10% to 40% of patients. However, only two randomised controlled trials (RCT) presented a randomised comparison of FDG-PET and conventional staging techniques, evaluating change in clinical management. III 9. The two RCTs that have been conducted compared the use of FDG-PET in addition to conventional staging with conventional staging alone. These trials yielded contradictory results; one suggests that the addition of FDG-PET imaging produces a cost-effective reduction in the number of ‘futile’ operations whereas the other shows no difference in the number of operations between the two groups. 10. The discrepancy in results appears to be largely due to different approaches to the management of NSCLC taken by surgeons in the two studies, given the results of FDG-PET imaging. Specifically, surgeons in the first study regarded operations on patients with N2 disease as ‘futile’ and avoided it. Although FDG-PET scanning in the second trial detected a similar proportion of N2 disease, surgeons in this study regarded patients with N2 disease as acceptable candidates for resection. 11. In terms of safety, no studies reported any important short-term adverse effects as a result of FDG-PET imaging. There is a risk of secondary cancers developing posed by the radiation dose used in FDG-PET scanning, but the risk is very low (less than 1 in 3000 for a person of normal life expectancy) and the radiation dose is comparable with that associated with CT. IV Economic evaluation - NSCLC 1. Economic evaluation is the comparison of the costs and benefits of two or more courses of action or options. It involves the identification, measurement and valuation of resources used and benefits as seen from a stated perspective and over a stated time horizon. 2. This economic evaluation focused on the role of different tests after a CT scan and the use of FDG-PET in the context of the diagnostic pathway and subsequent clinical management decisions for patients with NSCLC in Scotland. Only costs relating to NSCLC are included. 3. The economic issues surrounding the use of FDG-PET in the investigation of patients with NSCLC relate to the fact that it can detect small but clinically significant metastases in the lymph nodes and in distant sites in the body. 4. The impact of FDG-PET is analysed by a cost-utility analysis. This sets out the change in resource use and the number of quality-adjusted life years (QALY). QALYs estimate the effect on survival and the changes in quality of life stemming from the introduction of FDG-PET. In this model, QALYs are taken from published studies. 5. The model assumes that for a cohort of 100 patients: all patients have had a chest X-ray, bronchoscopy and CT scan; all patients have a definite diagnosis of lung cancer and require staging for decision on management; all patients are fit for surgery if indicated; 30% patients have N2 or N3 disease; 10% patients have occult metastases only detected by PET; for N0/N1 disease, 23% have enlarged lymph nodes; and for N2/N3 disease, 60% have enlarged lymph nodes. The following resources are considered in the analysis: FDG-PET scan; mediastinoscopy; surgery (resection of lung tissue); follow up after potentially curative surgery; treatment of recurrence after potential cure; non-surgical treatment for advanced disease; and follow up after non-surgical treatment. V 6. The cost effectiveness of seven different diagnostic and treatment strategies is evaluated, assuming that all patients are potentially operable and have had a CT scan. The group of seven strategies are considered separately for CT-positive and CT-negative patients. 1 Send all patients for surgery without further testing. 2 Send all patients for non-surgical treatment (chemotherapy and/or radiotherapy) without further testing. 3 Investigate all patients by mediastinoscopy; if negative refer for surgery, if positive refer for non-surgical treatment (reflecting current Scottish practice). 4 Investigate all patients by mediastinoscopy; if negative send them for FDG-PET imaging (negative FDG-PET for surgery, positive FDGPET for non-surgical treatment), if positive refer for non-surgical treatment. 5 Investigate all patients with FDG-PET; if negative refer for surgery, if positive refer for non-surgical treatment. 6 Investigate all patients with FDG-PET; if negative refer for mediastinoscopy (negative for surgery, positive for non-surgical treatment), if positive refer for non-surgical treatment. 7 Investigate all patients with FDG-PET. If this is negative refer for surgery. If this is positive and distant metastases are indicated (N0/1 M1) refer for non-surgical treatment, otherwise refer for mediastinoscopy (negative for surgery, positive for non-surgical treatment). The first two options are unrealistic in the clinical setting and are used for model testing purposes only. 7. The costs and QALYs per patient for CT-positive and CT-negative patients are ranked by least cost shown in the following tables for the base-case analysis. Strategies ranked by cost for CT-positive Total Total cost QALYs Strategy 3 £191,295 71.86 Strategy 1 £197,247 69.81 Strategy 4 £203,720 66.03 Strategy 6 £205,157 66.16 Strategy 7 £206,098 72.11 Strategy 5 £207,690 66.17 Strategy 2 £209,538 44.45 * Incremental Cost Effectiveness Ratio Additional cost £5,952 £12,425 £13,862 £14,803 £1,592 £3,440 Additional QALYs -2.05 -5.83 -5.71 0.25 -5.94 -27.66 ICER* Dominated by 3 Dominated by 3 Dominated by 3 £58,951 Dominated by 7 Dominated by 7 VI Strategies ranked by cost for CT-negative Total cost Total QALYs Strategy 1 £293,127 189.01 Strategy 3 £304,628 189.63 Strategy 7 £318,544 190.96 Strategy 5 £321,492 181.97 Strategy 6 £336,270 181.39 Strategy 4 £337,116 181.28 Strategy 2 £400,614 95.70 * Incremental Cost Effectiveness Ratio Additional cost £11,501 £13,916 £2,949 £17,727 £18,573 £82,071 Additional QALYs ICER* 0.62 1.33 -8.98 -9.57 -9.67 -95.26 £18,589 £10,475 Dominated by 7 Dominated by 7 Dominated by 7 Dominated by 7 8. In the base case, strategies 1, 3 and 7 stand out from the others as potentially cost effective on grounds of cost, patient benefits or both. The base case suggests that in CT-positive patients strategy 7 involving FDG-PET scanning may not be cost effective compared with strategy 3, which is an accurate approximation of the current Scottish practice. In CT-negative patients, the base case suggests that moving from current Scottish practice to strategy 7 is cost effective. Strategy 1 (all for surgery) cannot be ruled out in terms of QALYs. This raises doubts as to whether the model is correctly valuing costs and utilities associated with avoidance of futile surgery, as strategy 1 would not be used in clinical practice. 9. Strategies 1, 3 and 7 do not differ markedly in their total patient impact. Small differences in the total quality of life under alternative strategies magnify their differences in cost when calculating incremental cost effectiveness ratios (ICERs). These differences in cost are also not particularly large in the context of treating cancer. A number of modelling assumptions have been made, and uncertainties surround a number of parameters. Not all can be formally assessed through sensitivity analyses. The sensitivity analyses that have been undertaken show the ICERs to be sensitive to different assumptions, particularly in CT-positive patients. 10. Regardless of the absolute ICER values, the model results show that moving from strategy 3 to strategy 7 is more cost effective in CT-negative patients than in CTpositive patients. It also appears that the closer the accuracy of FDG-PET in detecting distant metastases approaches that of detecting enlarged nodes, the more likely it is that moving from strategy 3 to strategy 7 will be cost effective. This particularly applies to CT-positive patients. 11. From this model, it cannot be unambiguously stated which of strategies 1, 3 and 7 is the most cost effective in CT-positive or CT-negative patients. Health services research in a clinical setting is required to address the data gaps in modelling, particularly for detection of distant metastases and utilities associated with avoidance of futile surgery. VII Clinical effectiveness – Lymphoma 1. Chemotherapy, alone or in combination with radiotherapy (RT), forms the basis of treatment for HD and more aggressive forms of NHL. 2. Since both residual disease, after initial treatment, and recurrent disease may be amenable to curative therapy, the assessment of response to therapy (restaging) and monitoring for recurrence are important aspects of the management of HD and NHL. 3. FDG-PET scanning may be useful in the initial staging of disease, re-staging after therapy, predicting the results of therapy and monitoring for recurrence. Following discussion with experts, the focus of this assessment is the use of FDG-PET in the evaluation of response to treatment and, in particular, on the evaluation of residual masses after induction therapy in patients with HD. 4. Seven published studies using optimal technology were identified and these addressed the accuracy of FDG-PET in determining whether residual masses visible on CT represented active disease. Seven further studies addressed the accuracy of FDG-PET for determining residual masses irrespective of CT results (i.e. including both those who would be negative on CT and those who would be positive). The results of meta-analyses of sensitivity and specificity of these two groups of studies are shown in the following table. Number of studies Specificity (95% CI) Sensitivity (95% CI) FDG-PET in CT-positive residual masses 7 0.89 (0.74 – 0.97) 0.80 (0.59 – 0.94) FDG-PET in post-therapy assessment (CT-positive or CT-negative) 7 0.95 (0.90 – 0.99) 0.81 (0.63 – 0.92) Analysis 5. These results suggest that FDG-PET may be valuable in distinguishing true residual disease post-therapy. s with all imaging techniques, there are difficulties in interpretation because of the absence of a ‘gold standard’ and uncertainty of the appropriate follow-up interval. 6. By way of comparison, a meta-analysis of studies detailing the accuracy of CT scanning in assessing response to therapy was conducted. The estimated sensitivity and specificity were 0.75, 95% CI (0.58-0.88) and 0.45, 95% CI (0.270.64) respectively. 7. The majority of reported studies do not distinguish between results in HD and those in NHL. Therefore, the accuracy data presented for both FDG-PET and CT are relevant for patients with either form of lymphoma. VIII 8. The detection and assessment of possible residual disease following first-line therapy is of considerable importance, because patients with active residual disease may be candidates for further therapy. The evidence clearly shows that FDG-PET is substantially more specific and somewhat more sensitive than CT in the detection of recurrent disease and is effective in discriminating active residual disease from non-viable tumour. Economic evaluation – Restaging Hodgkin’s disease 1. Following discussion with experts, the economic modelling was restricted to HD disease; more HD sufferers are cured by initial therapy and therefore the number of people at risk of inappropriate therapy who may benefit from PET scanning is larger. Furthermore, the clinical markers of residual disease are more effective in NHL. 2. The model has been used to assess the cost effectiveness of FDG-PET as an adjunct to conventional imaging in deciding the further treatment of HD patients who have achieved a partial or complete response to induction therapy. 3. FDG-PET can detect small but clinically significant metastases and is more specific than CT in differentiating active residual disease. It may therefore allow patients to avoid unnecessary RT and the associated mortality and morbidity. 4. Five strategies have been considered, which allocate patients to either immediate consolidation RT or to surveillance (six-monthly follow up by physical examination and CT scanning): Strategy 1: All for surveillance Strategy 2: All for consolidation Strategy 3+: CT-negative for surveillance CT-positive for consolidation Srategy 4: CT-negative for surveillance CT-positive for FDG-PET FDG-PET negative for surveillance FDG-PET positive for consolidation Strategy 5*: FDG-PET negative for surveillance FDG-PET positive for consolidation +Strategy 3 is the current Scottish practice. *A CT scan is performed before FDG-PET but the results are not used in allocating patients to surveillance or consolidation. CT scanning is required in all the strategies to provide a baseline image for comparison with a follow-up CT image. IX 5. The life experience of patients after the post-induction assessment is represented by a Markov treatment model as follows: patients are selected for immediate consolidation RT or surveillance based on the results of CT and FDG-PET imaging; patients under surveillance who relapse are assessed for salvage therapy (either RT or chemotherapy); patients who relapse after RT, or are unsuitable for salvage therapy, are given reinduction chemotherapy; responders to re-induction undergo high-dose chemotherapy (HDCT) and autologous stem cell or bone marrow support; deaths (possibly due to toxicity) may occur during re-induction or HDCT; non-responders to re-induction chemotherapy are treatment failures and receive palliative therapy; and all patients who survive without relapse six or more years after beginning a remission are assumed to exhibit only population all-cause mortality, modified by the late toxicity of RT, salvage therapy or HDCT in those patients who received it (leukaemia, breast cancer, lung cancer and heart disease). 6. The impact of FDG-PET is analysed by a cost-effectiveness analysis that sets out the changes in resource use and life expectancy resulting from the introduction of FDG-PET. QALYs are not used in this analysis because of the paucity of reliable data. Since any advantage offered by FDG-PET is associated with the avoidance of late toxicities that are both potentially fatal and associated with reduced quality of life, any realistic QALY-based comparison would be more favourable to FDGPET, so the analysis presented here is conservative. For both ‘PET-containing’ strategies (strategies 4 and 5), graphs are presented showing the way in which the probability that the strategy is cost effective relative to current standard practice changes as the amount of money NHSScotland is prepared to pay for one additional life year increases. 7. The model was run for six patient types: Male: 20, 40 and 60 years; and Female: 20, 40 and 60 years. 8. Costs were sought for the following resources: CT; FDG-PET; surveillance; radiotherapy; re-induction chemotherapy; non-curative therapy for patients who fail re-induction chemotherapy; autologous peripheral stem cell transplant (PBSCT); and lung cancer, breast cancer, leukaemia – as potential long-term toxicities. 9. The results show that the costs are similar for all strategies and so clinical results (life years gained) play the dominant role in determining cost effectiveness. X 10. Strategy 5 (FDG-PET) uniformly gives the largest expected number of added life years and lowest expected cost across all patient types and appears to be cost effective for essentially all plausible input values, for any value of willingness to pay greater than £5000 per year of life. 11. FDG-PET following CT (strategy 4) is an inherently poorer strategy than strategy 5 because of the lower overall sensitivity of combining the two procedures. However, it is still cost effective relative to the ‘non-PET containing’ strategies, leads to a higher expected value of life years and is a less radical change from current practice than strategy 5. 12. The use of FDG-PET scanning to assign patients with HD to consolidation or surveillance, whether used as the sole imaging tool or as an adjunct to CT in CTpositive patients, is cost effective in the base case provided willingness to pay exceeds £1000, and for almost all input values considered provided willingness to pay exceeds £5000 13. The model also predicts that 36% of patients will receive unnecessary consolidation RT when using CT alone. This would be reduced to 4% for patients assessed using FDG-PET alone, or to 6% for those undergoing FDG-PET after positive CT scan. 14. Although this model has been restricted to HD, the superior accuracy of FDG-PET is likely to translate into significant patient benefits in NHL. Patient issues 1. As the only PET facility in Scotland is used for research purposes, it is not possible to get patients’ views about undergoing a PET investigation in routine clinical practice. However, the professionals believe that PET will prove acceptable to patients as the imager is open and generates very little noise. 2. As a result of this limited experience of PET imaging in Scotland, during the consultation period for this HTA questions were directed to people with cancer, their family members or carers. These people were asked about their experiences of other imaging techniques used in diagnosis and treatment of cancer. Responses provided evidence that some patients would value the additional information provided by PET about their condition. The importance of ensuring that the use of PET does not result in delays in treatment was emphasised. 3. It is important to provide clear information to patients to inform them about all aspects of the imaging process and the injection of a radiopharmaceutical. Patient information leaflets should include diagrams and clear explanations of complicated terms. Other media, such as video and the internet, can also be used. However, it is essential that the consultant fully discusses all aspects of the investigation with the patient, including any associated risks or side effects, and ensures that the information has been understood. 4. The organisation of cancer diagnostic tests will depend on the local situation and should be co-ordinated to reduce the need for patient travel and minimise nonattendance. The funding of patient travel varies regionally. XI 5. PET imaging facilities should be designed to make patients feel comfortable and reduce anxiety by, for example, providing music listening facilities and allowing an adult friend to attend with the patient. 6. Further research into the needs and preferences of patients in relation to PET should be undertaken following its introduction to clinical practice in Scotland. Organisational issues and budget impact 1. The only PET facility currently available in Scotland is based within Aberdeen Royal Infirmary for research purposes. An application is underway for a PET facility in Glasgow. In England, there are five PET facilities in routine clinical use and several others used for research purposes. 2. The optimal location for a PET scanner(s) in Scotland will depend on the size of the patient population, accessibility and clinical expertise. If it were also to be used for research purposes, then it would need to be sited near a suitably staffed research facility. 3. All members of the multidisciplinary team that manage a cancer patient should be educated about the benefits and issues associated with using PET. 4. Radiopharmaceutical production requires a cyclotron for the production of the positron-emitting radionuclide, which is then used to label the chosen pharmaceutical. The facility must comply with all radiopharmaceutical regulations. 5. The half-life of FDG is 110 minutes and it would be feasible for the PET scanning facility to be two to four hours by road from the production facility. However, delivery schedules of the radiopharmaceutical may limit the working hours of the scanner. 6. The staffing requirements for a radiopharmaceutical production facility include radiopharmacists, radiochemists, physicists and cyclotron engineers. There is a shortage of these trained professionals and so training of new staff will be an essential component of the rollout of PET facilities in Scotland. 7. Four possible options for the implementation of a PET facility in Scotland have been considered and the costs per scan and budget impact have been investigated. These options include three different specifications for a fixed PET facility and one mobile PET unit: Option 1 is a fully equipped PET unit (imager, cyclotron, radiochemistry facility) located within a hospital, purchasing support services from the Trust, but with dedicated staff. Option 2 is a fully equipped PET unit (imager, cyclotron, radiochemistry facility) integrated with, and drawing staff skill from, other relevant hospital departments. Option 3 is a PET imager receiving its radiopharmaceuticals from another source. Option 4 is a mobile PET imager receiving its radiopharmaceuticals from another source. XII 8. Mobile PET results in higher long-term costs and a higher overall cost per scan. However, capital costs are substantially lower and the facility could be operational within a few months. 9. Option 2 has the lowest cost per scan (£677) and the lowest running costs. However, a substantial capital outlay would be required to set up this facility (£4.25 million) and there would be a considerable time delay before the service could be initiated. The annual running costs are projected to be £1.02 million. 10. Option 3 would be quicker to set up than option 2 as no cyclotron or radiochemical laboratories are needed. The cost per scan varies according to the source of FDG. This option could be a good way of exploring the viability of PET scanning with a lower capital outlay (£1.83 million). 11. The cost per scan is dependent on the number of patients scanned per annum. This is unlikely to reach full capacity during the first year of service as it will take some time to have a fully trained team of staff, to raise awareness and to promote the service. Discussion 1. his report restricts its conclusions to the use of full-ring FDG-PET in cancer management. 2. Two different approaches to economic modelling have been utilised. In NSCLC, univariate sensitivity analyses have been used. These indicate that the model is not entirely robust and the ordering of cost effective strategies alters according to different cost and benefit assumptions. In particular there is a need to better determine the utilities associated with avoidance of futile surgery. For HD, uncertainties have been formally modelled in a multivariate manner using Bayesian techniques. This has resulted in a model that is robust to all areas of uncertainty. 3. The results for NSCLC show that FDG-PET may be cost effective in CT-negative patients, with PET-negatives sent for surgery and PET-positives sent for mediastinoscopy, but that this result is dependent on model inputs. However, FDG-PET does not appear to be cost effective in CT-positive patients. 4. In HD, FDG-PET is cost effective when used to assign patients to consolidation or surveillance for almost all input values considered, provided the willingness to pay per year of life exceeds £5000. The largest expected value of life years across all patient types is seen when FDG-PET scanning is used instead of CT. 5. It should be emphasised that PET scanning in clinical practice is still largely at the developmental stage, and all patients undergoing FDG-PET should be entered into appropriate clinical and health services research. The collection of data must comply with all regulations on confidentiality, security and consent. It should include outcome data in an agreed format (Appendix 27) to fill in gaps in the evidence base. XIII 6. It is likely that PET will have more of an impact on patient outcomes in cancers that have more effective treatment options available and where the alternative techniques are unsatisfactory. In particular, its use in lung cancer (NSCLC and solitary pulmonary nodule), recurrent head and neck cancer and malignant melanoma looks promising and outcome and economic research should be an early priority in these cancers. Recommendations to NHSScotland As a result of this HTA, HTBS has made recommendations to NHSScotland about the clinical and cost effectiveness of PET imaging for cancer management, these are presented in full in the Health Technology Assessment Advice on positron emission tomography (PET) imaging in cancer management (HTBS, 2002a). Listed below is the summary of recommendations. It is recommended that a PET imaging facility including a cyclotron, dedicated to clinical use and specific health services research applications, should be set up in Scotland to allow Scottish patients and researchers to realise the potential benefits of FDG-PET imaging in cancer management as rapidly as possible. It should be linked to an existing cancer centre, with functional links to the existing PET facility in Aberdeen. It will take approximately two years to build such a facility, so interim solutions for the provision of PET imaging should be considered, particularly for the re-staging of patients with Hodgkin’s disease. Possible options are the use of the John Mallard Scottish PET Centre in Aberdeen, other UK facilities, or the use of a mobile PET facility in a fixed location in Scotland. All patients who require restaging of Hodgkin’s disease should be sent for a FDGPET scan. Extension to the restaging of all patients with lymphoma should be investigated by further research. Appropriate research should be undertaken to inform economic modelling in order to produce a robust assessment of the value of FDG-PET imaging in the staging of patients with NSCLC who are CT-negative in the regional lymph nodes. For other cancers, FDG-PET is likely to add most value where existing diagnostic/monitoring techniques have poor accuracy and information from PET imaging can substantially improve prognosis. This should be evaluated through health services research, taking account of the clinical effectiveness results from other international HTAs. Research priorities should be agreed with multidisciplinary expert groups, Regional Cancer Advisory Groups, the Scottish Cancer Group, the NHS HTA programme and other international research organisations. All research should be coordinated with the Scottish Cancer Clinical Trials Network. All patients undergoing FDG-PET should have outcomes recorded, either through participation in a national or international trial to confirm and extend the current applications of FDG-PET imaging or through health services research designed to allow costs and patient outcomes to be recorded for economic modelling. XIV 1 INTRODUCTION AND OBJECTIVES 1.1 Introduction 1.1.1 Previous NHS HTA research on PET imaging In the late 1990s the UK NHS Research and Development programme recognised that there was still uncertainty regarding the clinical role of positron emission tomography (PET) imaging and so research was undertaken to review the current and potential role of PET, in order to establish research priorities for the future (Robert & Milne, 1999). A literature review to ascertain the level of knowledge regarding the clinical applications of PET was undertaken. Alongside this, a three-round Delphi study involving 41 interested individuals was performed to inform the key Health Technology Assessment (HTA) research questions relating to the use of PET in the UK. Four possible PET modalities were considered: full-ring PET scanners operating in two or three dimensions; partial-ring rotating PET scanners; coincidence imaging with modified gamma camera technology (section 2.5.5.1); and high-energy collimator imaging of 511 keV photons with modified gamma camera technology. The clinical applications advocated for PET were in oncology, cardiology and neurology. However, Robert & Milne (1999) concluded that there was a paucity of evidence relating to the cost effectiveness of the various PET modalities in all of these clinical applications. Although there were many studies of diagnostic accuracy of PET, many were small and subject to bias. They concluded that evidence is needed to show that using PET as a diagnostic technique will alter actual patient management. The Delphi research identified that the key questions of interest related to the evaluation of the cost effectiveness of full-ring PET to determine staging in lung cancer, staging and monitoring treatment response in breast cancer, and assessing myocardial viability when selecting patients for revascularisation surgery. 1.1.2 The Scottish HTA on PET imaging This HTA from the Health Technology Board for Scotland (HTBS) focuses on the use of full-ring PET scanners in cancer management in Scotland, with the radiopharmaceutical 2-[18F]-fluoro-2-deoxy-D-glucose, also known as FDG. Scotland has one PET scanner, which is used for research purposes, but not for routine clinical use. Cancer in Scotland: Action for change (Scottish Executive Health Department, 2001a) highlighted the fact that new imaging techniques such as PET imaging appear to be making a significant contribution to cancer clinical care in the United States but future investment decisions need to take account of the HTBS Advice arising from this HTA. The full objectives of this HTA are presented in section 1.2. HTBS uses the internationally recognised definition of HTA (INAHTA, 2000), which describes it as a multidisciplinary field of policy analysis that studies the medical, 1-1 social, ethical and economic implications of the development, diffusion and use of health technology. The HTA considers four components as identified in Figure 1-1: clinical effectiveness, economic evaluation, patient issues and organisational considerations. This assessment report presents the evidence relating to each of these sections and a final discussion, and recommendations that bring together the key aspects from each section. This HTA follows the process published by HTBS (HTBS, 2001a). This involves the submission of evidence from a wide variety of sources, expert staff to undertake the analyses, a multidisciplinary expert Topic Specific Group (TSG) to collect and critique evidence and analyses, quality assurance (QA) by the HTBS Governance Board and wide-ranging open consultation and expert review. In this HTA, national and international evidence is critically appraised, taking account of Scottish circumstances, so that clear, practical recommendations can be made to the National Health Service in Scotland (NHSScotland). This HTA report is accompanied by two other summary documents. The Health Technology Assessment Advice is aimed at policy makers, NHS Board decision makers and healthcare professionals. An Understanding HTBS Advice document is published explaining to patients, carers and the public how the evidence was reviewed and the reasons for the HTBS recommendations. All products are available on the HTBS website www.htbs.co.uk. 1-2 Figure 1-1 Health Technology Assessment (HTA) process Topic proposal & filtration Selection by HTBS Board: Definition of the policy question(s) & objective Determination of background information Planning: scoping & protocol development Definition of evidence question(s) Assessment Report Working with Evidence Clinical Effectiveness Epidemiology Economic Evaluation Organisational Issues Patient Issues Scottish Interpretation with Topic Specific Group Board & external review including Open Consultation Conclusions & Recommendations Final Assessment Report Dissemination of Report, Advice, Understanding Implementation of HTA by NHS Boards Review of the HTA by HTBS 1-3 1.2 Objectives and scope of this HTA This HTA set out with two principal objectives: 1. To determine the role of PET imaging in cancer management by evaluating the clinical and cost effectiveness in terms of impact on patient outcome (morbidity/mortality). 2. If PET is found to be clinically and cost effective, to consider the best configuration of PET facilities and cyclotrons to serve the Scottish population. The detailed assessment questions outlined at the start of the HTA are presented in Appendix 2. Fryback & Thornbury (1991) explained that the utility of a diagnostic test might be described on one or more levels in a hierarchy, with higher levels of the hierarchy relating more closely to the social impacts of the technology. Table 1-1 Hierarchy of diagnostic efficacy 1 Technical 2 Diagnostic accuracy 3 4 5 6 Diagnostic thinking Therapeutic Patient outcome Societal Technical imaging quality Sensitivity, specificity, positive predictive value, negative predictive value Likelihood ratio Changes in therapeutic choices (patient management) Improvement in morbidity/mortality Cost-benefit analysis The aim of this HTA was to focus on levels 5 and 6, that is evaluating outcomes of importance to patients and undertaking an economic evaluation that was relevant to Scotland. In an economic evaluation it is necessary to consult with experts to determine the precise patient pathway for a cancer in Scotland, to estimate all the benefits and resources used on that pathway (to the end of the patient’s life) and to determine strategies in which PET might be used. This model will be different for every individual cancer and for each stage of cancer and is extremely complex to construct. Therefore it is necessary to choose a particular cancer and question to study. For this HTA, the initial approach was to identify the cancer that was thought to have the strongest evidence base. Initial literature searches identified that the strongest evidence for the effect of PET on patient outcomes was available for the staging of non-small cell lung cancer (NSCLC) (section 3.2). Furthermore, NSCLC is common in Scotland (section 2.1.2). Therefore, this HTA was initially focused on staging in NSCLC. The value of PET in improving outcomes is influenced by the potential for successful therapy. Patient outcomes in NSCLC are poor and it was recognised that an evaluation of the use of PET in another cancer, in which the benefits may be more apparent and which had not been extensively studied, would be of value in the assessment of this technology. Following discussion with Scottish Experts (Scottish Cancer Group, Personal communication, 2002), an evaluation of the clinical and cost 1-4 effectiveness of PET scanning in lymphoma (restaging Hodgkin’s disease) was undertaken for this HTA. Further detail of the rationale for choosing these two cancers for assessment is presented in section 3.2. Although this HTA has only considered two cancers in detail in terms of clinical and cost effectiveness, the patient issues and organisational issues apply to all uses of PET. Furthermore, other recent HTAs are reported (section 2.4), which summarise the clinical effectiveness of PET for other cancers and in certain cardiology and neurology indications. Unfortunately these focus mainly on diagnostic accuracy and few cost effectiveness studies are available. 1-5 2 BACKGROUND 2.1 Description of health problem in Scotland 2.1.1 Cancer in Scotland Our National Health: A plan for action, a plan for change (Scottish Executive Health Department, 2000) states that more than 26,000 people in Scotland are diagnosed with cancer every year. In Scotland, there have been improvements in cancer survival rates, but further progress requires continued effort on a number of fronts. Better awareness and prevention, earlier diagnosis and better, faster treatment all have a part to play in reducing both the incidence of cancer and the number of deaths. In 2002, a major service re-design initiative was initiated to improve the patient journey from referral to treatment establishing Managed Clinical Networks (MCN) for all cancer services (section 2.2.2). Cancer in Scotland: Action for change (Scottish Executive Health Department, 2001a) the ‘Cancer Strategy’ indicates that cancer is now the leading cause of premature death amongst the Scottish population, with 14,740 dying of cancer in 1999. Since the national cancer registration system began in 1959, records show that there has been a year-on-year increase in the total number of new cases of cancer diagnosed in Scotland. This is largely due to the ageing of the population. Compared with the rest of western Europe, the age-standardised incidence of and mortality from cancer in Scotland are high. Examination of outcomes for particular types of cancer almost always shows low case-survival in Scotland (and the rest of the UK) compared with other western European countries. The outcome for an individual patient is also determined by where the cancer develops and how it is treated. In contrast to the increasing incidence of many cancers, deaths from cancer are falling. More Scots are being diagnosed with cancer but fewer under the age of 75 are dying from it. This is due to improved secondary prevention and treatment. Factors influencing the outcome of cancer care include the extent of disease at the time of diagnosis and co-existing illness. Both of these factors are probably influenced by deprivation. The Cancer Scenarios: An aid to planning cancer services in Scotland (Scottish Executive Health Department, 2001b) presents models of cancer incidence and mortality trends from 1960-1996, with projections of numbers of incident cancer cases and deaths expected up to the period 2010-2014. Different projections are provided for various scenarios of developments in cancer management strategies. The most important factors that could reduce the incidence of, and mortality from, cancer are a reduction in smoking prevalence and changes in diet. However, prompt investigation and appropriate patient management are also noted as essential to improve outcomes. This was also identified in the Cancer Strategy (Scottish Executive Health Department, 2001a), in which it was proposed that, by 2005, the maximum wait from urgent referral to treatment will be two months for all cancers. 2-1 2.1.2 Lung cancer in Scotland Approximately 4,600 patients were diagnosed with lung cancer in Scotland in 1998 and 75% of these (3,450 patients) had NSCLC (Scottish Executive Health Department, 2001b). The treatment of choice in NSCLC is surgical resection. However, only approximately 15-20% of patients will have local disease that is suitable for this potentially curative surgery. The remaining 85% of patients will be possible candidates for chemotherapy or radiotherapy (RT), although many will be unfit to receive chemotherapy or will decline it when offered. Scottish Cancer Registry statistics suggest that only around 10% of patients with NSCLC receive chemotherapy (Clinical Resource and Audit Group, 2002). Scotland leads the international tables in both incidence and mortality of lung cancer. This has been due, historically, to a high prevalence of smoking, perhaps coupled with poor diet and some industrial exposures (Scottish Executive Health Department, 2001b). Survival from lung cancer is poor in Scotland when compared internationally, and factors that may account for this include: late presentation; more co-morbidity; different tumour biology/behaviour; delays in investigation; delays in treatment; lack of access to specialist advice and treatment; under-treatment/therapeutic nihilism; more complete follow up in cancer registration data. It seems unlikely that more accurate cancer registration data can explain the significant survival differences, especially in comparison to the Nordic countries, which also have high-quality registration data. It is not inconceivable that patients in Scotland may have tumours of different biology and/or behaviour since, even within Scotland, evidence is emerging of biological differences between breast cancers in women from deprived areas compared with those from affluent areas (Thomson et al., 2001). Higher levels of co-morbidity may also be a consideration, along with late presentation and delays in investigation and treatment. Exposure to known occupational carcinogens, including asbestos, radon, chromium, nickel and inorganic arsenic compounds, increase the risk of lung cancer. The most common occupational cause of lung cancer in Scotland relates to asbestos exposure (particularly the crocidolite or blue type). In the west of Scotland, where there has been a large amount of industrial exposure to asbestos, about 6% of all lung cancers in men may be related directly to asbestos (De Vos Irvine et al., 1993). In 1998, there were 3,948 deaths registered due to lung cancer (General Register Office for Scotland, 2000). The survival from lung cancer remains very poor and has not changed during the last 25 years. Fifty per cent (50%) of patients are dead within four months of the diagnosis with more than 80% of patients dead at one year. Only 6% of lung cancer patients are alive at five years (Scottish Cancer Intelligence Unit, 2000). Almost all of the surviving patients have been treated with curative surgery. 2-2 The Scottish Executive Health Department (2001c) has highlighted that for the lung cancer (and colorectal cancer) pathway there needs to be a re-design of the service to improve the patient journey through diagnosis, treatment and follow up (section2.2.2). 2.1.3 Lymphoma in Scotland Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL), both now recognised as lymphomata, jointly account for approximately 4% of cancer incidence in Scotland. Although NHL is predominantly a disease of older people (median age of onset is 65 years), both NHL and HD can also affect younger people. Indeed the age distribution of HD is bimodal, with a peak incidence between 15 and 35 years but 25% of people affected being over 60 years (Scottish Executive Health Department, 2001b). The incidence of NHL in Scotland and other parts of the UK, Europe and the USA, has increased by approximately 4% per annum over the last two decades. There is no obvious aetiology in the majority of cases seen, although there are some known associations, including HIV infection and immunosuppression after transplantation (Scottish Executive Health Department, 2001b). Since both HD and some subtypes of NHL are highly sensitive to chemotherapy, a large proportion of patients survive beyond five years. In Scotland, the five-year relative survival for HD is 73% (Scottish Executive Health Department, 2001b) and data from the Scotland and Newcastle Lymphoma Group (SNLG) database indicate a five-year survival of 80% in patients under 60 years (compared with 86% in USA). For NHL, the Scottish Cancer Registry data show a five-year relative survival of 45% (55-60% in patients under 60 years) (Scottish Executive Health Department, 2001b). New multidrug chemotherapy regimens are being developed for lymphoma and treatment initiatives focus on ensuring that patients receive optimal treatment with the highest efficacy-to-toxicity ratio. A particular issue in this context is the appropriate treatment of patients with apparent residual disease after induction therapy (Dr M Mackie, Consultant Haematologist, Western General Hospital, Edinburgh, Personal communication, 2002). Patients in remission following induction chemotherapy may be offered consolidation RT for the treatment of residual masses. However, radiation treatment is itself associated with toxicity, including the development of other malignancies and cardiotoxicity. Some residual masses detected after treatment are due to dead tissue and scarring and do not represent active disease (Segall, 2001). Furthermore some patients may have active disease outside the radiation fields and will not benefit from RT. In order to minimise unnecessary exposure to potentially toxic radiation treatment, further investigations are needed to identify those patients who will receive no benefit from RT at this point. Magnetic resonance imaging (MRI) and Gallium scanning have been used to discriminate residual active disease but neither modality is universally successful in achieving this goal (Front et al., 1997). There is evidence that PET may have a useful role to play (Cremerius et al., 2001) and this is investigated in detail in the new economic modelling presented in section 7 of this report. 2-3 2.2 Perspectives 2.2.1 Organisation of NHSScotland NHSScotland, like the NHS in other parts of the UK, provides comprehensive health care for its citizens, and is free at the point of use. It is funded mainly by direct taxation in the form of income tax and National Insurance Contributions, with a small proportion of funding coming from patient charges, such as for dental care and prescriptions. A key advantage of the UK’s funding system is its fairness, providing maximum separation between an individual’s financial contributions and their use of health care. After social security payments, health is the biggest single component of public expenditure (Wanless, 2001). Mortality and morbidity rates are higher in Scotland than in England, reflecting differences in their populations and environmental and socio-economic factors. However, alongside these greater health needs, Scotland has more health care resources. Funding per head, the number of hospital beds and professional health care staff are all above the levels in England (Wanless, 2001). NHSScotland has core aims of improving the health of the population and reducing inequalities in health. There are currently five priority topics: coronary heart disease/stroke, cancer, mental health, children and young people, and older people (Scottish Executive Health Department, 2000). In 1998 the UK health expenditure per capita was £1,510 or 6.8% of the gross domestic product (GDP) (5.7% publicly funded and 1.1% privately funded). The European Union (EU) weighted average figures were £1,824 and 8.4% of GDP (6.4% publicly funded and 2.1% privately funded) (Wanless, 2001). Scotland has higher public health service expenditure per capita than the UK average (Wanless, 2001). NHSScotland has around 132,000 staff, including more than 63,000 nurses, midwives and health visitors and over 8,500 doctors. There are also more than 7,000 general practitioners, including doctors, dentists, opticians and community pharmacists, who are independent contractors providing a range of services within the NHS in return for various fees and allowances (www.show.scot.nhs.uk/public/publicindex.htm). The Scottish Executive Health Department (SEHD) leads the central management of NHSScotland. It oversees the work of 15 NHS Boards responsible for planning health services for people in their area and, through the boards, the activities of the 28 acute and primary care NHS Trusts responsible for providing services to patients and the community (www.show.scot.nhs.uk/public/publicindex.htm). Primary Care Trusts have been developing Local Health Care Co-operatives (LHCCs), which initially involved only general practitioners but are now evolving into multiprofessional organisations. The aim of LHCCs is to allow local decision making (with involvement of local communities) to improve health and health care (Hopton & Hill, 2001). A number of special Health Boards also exist which have Scotland-wide remits for specific functions. For example, NHS Education for Scotland commissions education and training for some NHS staff and HTBS provides advice on the clinical and cost effectiveness of new and existing health technologies. 2-4 More information about the health service in Scotland can be obtained from www.show.scot.nhs.uk and http://www.show.scot.nhs.uk/publicationsindex.htm. 2.2.2 Organisation of cancer services in Scotland The Cancer Strategy (Scottish Executive Health Department, 2001a) heralded a more organised approach to cancer care across Scotland, recognising the value of a multidisciplinary approach to patient care. To better coordinate cancer care, MCNs covering the three regions of Scotland were put in place during 2002. These multidisciplinary groups agree care protocols and audit the outcome of treatment. Three Regional Cancer Advisory Groups (RCAG) (Scottish Executive Health Department, 2001c) were established in Scotland (North, South East and West) during 2001 to work with NHS Boards to plan investment in equipment, chemotherapy and staff on the basis of regional clinical need. They are intended to focus, stimulate and facilitate change and implementation of the Cancer Strategy. RCAGs provide reports to local NHS Boards on the MCN audit data in their area and work closely with the Boards to agree investment plans based on priorities that are agreed across the region. The Scottish Cancer Group is an advisory group of the Scottish Executive whose remit includes oversight of the implementation of the Cancer Strategy; they work closely with the RCAGs. Overall responsibility for monitoring and steering implementation centrally lies with the SEHD Implementation Steering Group. 2.3 The role of PET in oncology Diagnostic strategy and quality is vitally important in the treatment of cancer and necessitates close collaboration between radiologists, nuclear medical staff and clinicians. Accurate staging is important for determining treatment, since local treatment of curative intent, such as surgery or RT, is only realistic when no distant metastases are present. Accurate diagnostic methods are necessary for evaluating the effects of treatment and following treatment any recurrence needs to be detected as soon as possible to achieve the best results. PET is an innovative technology that has been in use since the 1970s. In contrast to computed tomography (CT) or MRI which both provide images based upon anatomy, PET creates images that reflect biochemical processes and blood flow. Most radioisotopes used in clinical PET are combined with organic compounds. The most commonly used isotope is 2-[18F]-fluoro-2-deoxy-D-glucose (FDG), which competes with glucose for absorption and metabolism in a wide variety of cells. Because cancer cells often use glucose at higher rates than normal or benign tissue, FDG can potentially identify a primary or metastatic cancer before structural evidence of disease is present, and can differentiate malignant from benign structural abnormalities (Phelps, 2000). Similarly, metabolic activity within the brain, heart and other organs can be reflected by uptake of FDG. A detailed description of PET and associated technology is given in section 2.5. 2-5 Many cancer patients have metastases at the time of initial diagnosis and this includes some who are diagnosed with only primary cancer. Detection of disease at a late stage, when metastases are present, leads to complicated therapies, poor prognosis and increased medical care costs. If PET, or any other diagnostic test, could identify cancer before the gene that enables malignant metastatic spread is expressed, more patients would be shifted from the group with metastases to the group with only primary cancer. Improved patient outcomes should then result as many primary cancers are curable whereas patients with metastases have a poor prognosis. A number of roles for the use of PET scanning in patients with cancer, or a suspected diagnosis of cancer, have been proposed (O’Doherty & Marsden, 2000): diagnosis; staging; provision of quantitative or qualitative information on whether chemotherapy actually arrives at a tumour site; evaluation of treatment response; whether there are features about the tumour that may make treatment less effective (e.g. hypoxia, poor blood flow); identification of disease recurrence during follow up. Table 2-1 Medicare reimbursement of PET in the US Lung cancer (Non-small cell) Solitary pulmonary nodules (SPNs) Lymphoma Lymphoma Colorectal cancer Colorectal cancer Head and neck cancers (excluding central nervous system and thyroid) Initial staging, diagnosis, staging and restaging Characterisation Staging and restaging only when used as an alternative to Gallium scan Diagnosis, staging and restaging Determining location of tumours if rising carcinoembryonic antigen level suggests recurrence Diagnosis, staging and restaging Diagnosis, staging and restaging Evaluating recurrence prior to surgery as an alternative to a Gallium scan Diagnosis, staging and restaging (but not Melanoma reimbursed for evaluating regional nodes) Oesophageal cancer Diagnosis, staging and restaging Staging, restaging and monitoring tumour response Breast cancer to treatment Medicare Coverage Issues Manual, http://www.cms.hhs.gov/manuals/06_cim/ci50.asp#_50_36; Centers for Medicare and Medicaid Services, 2002 Melanoma As shown in Table 2-1, in the US, Medicare permits use of PET in several cancers. However, for each cancer, Medicare is quite specific about when PET should be used. Taking NSCLC as an example, Medicare reimburses the following: 2-6 Initial staging: PET performed with a concurrent CT scan on a primary cancerous lung tumour that is pathologically confirmed. Diagnosis: In clinical situations where PET may assist in avoiding an invasive diagnostic procedure, or in where PET may assist in determining the optimal anatomical location to perform an invasive diagnostic procedure. Staging: Where the staging is in doubt after a standard diagnostic work-up PET may be used or if PET could potentially replace a standard imaging test when it is expected that conventional tests will be insufficient for patient management. European countries also use PET extensively in oncology, with the greatest number of scanners and the greatest use in Germany (Confidential evidence submission, 2001). Germany regularly hosts consensus conferences on PET, which establish ‘indications’ for PET. At the 2000 conference, a systematic literature review was presented identifying 533 papers relevant to oncology (Reske & Kotzerke, 2001). This led to the following recommendations for uses of PET imaging in cancer management. The following indications were considered as ‘established clinical use’: nodal (N)-staging NSCLC (Section 4.2.1); extrathoracic metastatic (M)-staging (Section 4.2.1) (except brain metastases) in lung cancer; recurrence in lung cancer; differential diagnosis (benign/malignant) of pulmonary lesions in patients with increased surgical risk in lung cancer; therapy control in high-grade (aggressive) NHL; diagnosis of recurrence or follow up in malignant melanoma in pT3 and pT4 tumours or following metastases; restaging in radioiodine-negative lesions in endocrine/neuro-endocrine tumours; staging of lymph nodes and distant metastases in oesophageal cancer; differential diagnosis (inflammation versus malignancy) in pancreatic cancer; restaging in suspected relapse in colorectal cancer; N-staging in head and neck cancer; diagnosis of recurrence in head and neck cancer; carcinoma of unknown primary origin; differentiation of recurrence and scar in high-grade gliomas; detection of tumour dedifferentiation in brain tumour relapse; and localisation of brain tumour site for biopsy. 2-7 The following indications were considered as ‘probable clinical use’: differential diagnosis (benign/malignant) of pulmonary lesions in patients without increased surgical risk in lung cancer; staging in HD; therapy control in HD; staging in high-grade (aggressive) NHL; M- and N-staging in malignant melanoma (Breslow >1.5 mm or known lymph node involvement); diagnosis of relapse in pancreatic cancer; therapy control in colorectal cancer; N-staging in breast cancer (without value in small tumours); radioiodine-positive lesions in differentiated thyroid carcinoma; differential diagnosis (benign/malignant) in bone and soft tissue tumours of the primary or biological aggressiveness for planning the surgical procedure; brain tumour grading; estimation of residual brain tumour mass following surgery; and differentiation of cerebral lymphoma and toxoplasmosis. The following indications were considered as ‘useful in individual cases’: therapy control in lung cancer tumours; differential diagnosis (benign/malignant) in breast cancer; M-staging in breast cancer; recurrence in ovarian cancer; and in case of second tumour in head and neck cancer. For other indications there was considered to be a paucity of data. As will be discussed in section 4, it is likely that these indications have been considered on the basis of the diagnostic accuracy of PET and not considering the effects on patient management or patient outcomes, or cost effectiveness, which are the objectives of this report. 2.4 Health Technology Assessments of PET imaging PET scanning has been the subject of HTAs by many international HTA Agencies. All HTAs focused on literature reviews of clinical effectiveness and in a few cases, cost effectiveness analyses were also reviewed. DIMDI (2000), another German government agency, did a comprehensive literature review to find cost-effectiveness studies of FDG-PET. They found 14 oncological studies (six studies alongside clinical trials, eight modelling studies), seven cardiology studies (all modelling studies) and one in neurology. No other Government HTA Agencies have undertaken full economic evaluations to model the value of FDG-PET imaging in terms of patient outcomes. 2-8 Overall, the HTAs concluded that FDG-PET was more accurate than conventional technologies in diagnosis and that this had the potential to translate into improvements in therapeutic benefit, particularly in pinpointing areas for RT and identifying distant metastases. All HTA reports agreed that the quality of evidence available supporting routine clinical application of FDG-PET is generally very poor. Indeed, the ICES group in Canada found no Grade A evidence articles for the use FDG-PET in any cancer, with studies often based on case series of highly selected patients (ICES, 2001). All agree that further well-designed, prospective studies are essential. In particular, Australia (MSAC, 2000, 2001) has recommended limited reimbursement of FDG-PET in some indications, on the proviso that data are collected in studies specifically to inform future decisions about the use of PET. As an example of the conclusions from one of these reports, HTBS has translated the Danish HTA (DACEHTA, 2001) and conclusions from the report are presented in section 2.4.1. HTBS has built upon the work of DACEHTA in NSCLC augmenting their literature review to update the evidence on clinical effectiveness (section 4) and undertaking an economic model in this cancer (section 5). We have also taken another of the cancers for which DACEHTA identified that more work was needed, lymphoma, and undertaken definitive analyses of clinical and cost effectiveness (sections 6 and 7). 2.4.1 Danish HTA (DACEHTA, 2001) The following text is taken verbatim from the HTBS translation of the Danish HTA and reproduced with the kind permission of DACEHTA. 2.4.1.1 Lung cancer Gradually considerable data become available which indicates that PET is superior to other investigations in diagnosing NSCLC, pinpointing primary tumours, mediastinal staging and identifying distant metastases. However, it is difficult to compare the results of the various investigations, since all are patient series with internal controls. Methods of evaluating PET results vary greatly and there is a need for these to be standard. Investigations using both qualitative assessment (visual analyses) and semiquantitative assessment have found no significant differences. Most investigations use an internal histological control, but CT evaluation varies, as does the degree of lymph node sampling. One Dutch randomised investigation however shows that at the highest evidence level, PET is superior to CT in mediastinal staging and appears to be cost effective. In the USA and Australia, attempts are currently being made to reproduce these results in the form of randomised investigations. 2.4.1.2 Solitary pulmonary nodules The published data all agree that PET provides very high diagnostic accuracy and can improve diagnosis of solitary pulmonary nodules (SPNs). However, no prospective or retrospective investigations have been published containing data on survival. Investigations cannot be directly compared on account of their differing inclusion criteria, and the high prevalence of malignancy suggests a serious election bias, which might encourage too much being read into diagnostic accuracy. All the investigations were patient series with internal controls. 2-9 2.4.1.3 Colorectal cancer The overall evidence for use of FDG-PET in colorectal cancer is still sparse, and there is a need for large well-conducted investigations, with bigger control groups to minimise selection bias. Unblinded image analysis is also required. It is possible that PET can provide important information in certain cases where recurrence remains suspected after negative initial investigations. As long as diagnostic accuracy from existing data can be confirmed in larger future investigations, PET will probably be the most precise method for assessing recurrence in colorectal cancer. It is not known whether the diagnostic benefits will have therapeutic implications, since recurrent colorectal cancer can only be cured in rare instances. Nevertheless, it is expected that operations for solitary metastases will be performed on a better selection basis, since surgery can be spared on patients in whom PET indicates a wider spread of the disease. 2.4.1.4 Head and neck cancer The existing data suggests that PET may be particularly useful in diagnosing suspected recurrence after radiation treatment, where clinical investigation and CT/MR are uncertain because of cicatricial tissue. The method is simple to use, but expensive in resources. It is not known whether diagnostic benefits will have therapeutic implications, but a prospective Danish investigation is now underway. PET’s potential to identify unknown primary tumours and lymph node metastases seems clear. This group of patients can be cured by radiation treatment alone, but this is often given over a large area. Identification of the primary lesion can have the therapeutic consequence that either the area radiated is reduced, or radical treatment cannot be offered. However, there is still too little data available and larger prospective investigations are awaited. Conditions are roughly similar for staging of head and neck cancer with FDG-PET. More precise demarcation of tumours and lymph node regions may involve more optimal radiation treatment, besides assisting surgeons in the possible dissection of lymph nodes. At the moment too little data is available, and no investigations have yet been published containing a systematic analysis of the therapeutic implications. Larger prospective investigations into survival time, lymph node recurrence and the side effects of radiation treatment are awaited. Much is expected of combined PET/CT, which will utilise the increased sensitivity of PET and the high structural resolution of CT. However, this data has not yet been published. 2.4.1.5 Malignant melanoma The included published results show that PET has greatest diagnostic value when evaluating localised melanoma for major surgical intervention. PET is best used for diagnosing lymph node metastases and visceral metastases. The value of the method appears to be definite, as the finding of metastatic disease makes major surgical intervention obsolete, which saves the patient from unnecessary operations and is thought to reduce the overall expense. 2-10 2.4.1.6 Breast cancer PET appears to be a promising method for detection or exclusion of axillary lymph node metastases, but the existing data is however encumbered with a certain amount of uncertainty because of several serious sources of error and methodological points of uncertainty. The provisional results indicate a high negative predictive value, but before we can draw any conclusions from this, larger prospective investigations should be conducted with higher levels of evidence. Future investigations might show if the method is superior to other methods, but this should be evaluated using harder outcome measures, such as survival, costs and patient stress. 2.4.1.7 Other cancers Clinical development is also being pursued in the following oncological areas: lymphoma oesophageal cancer primary brain tumours occult primary tumours testicular cancer. 2.4.1.8 Alzheimer’s disease (This text has been edited slightly to make it more understandable in translation.) There is selection bias with the investigations of PET in Alzheimer’s disease (AD). There is little evidence from prospective investigations in patients with possible AD, but some evidence in probable AD. However, there is no evidence that PET increases diagnostic certainty compared with perfusion investigations using single photon emission computed tomography (SPECT), which is a more readily available imaging technique. Perfusion investigations with dedicated PET and for example, O15-H2O, may possibly be a supplement, but this tracer is very short-lived and therefore cannot be distributed outside departments with their own cyclotron. 2.4.1.9 Epilepsy The results are still too preliminary and too few to give an overall picture of the diagnostic value of PET for epilepsy. There appears to be no evidence that PET can replace perfusion investigations with SPECT, which is much more easily accessible. As the affected patient group in Denmark is relatively small, there appears to be no need [for] clinical use of PET in assessing the operation indication with uncontrolled complex, partial epilepsy. PET may possibly be a supplement to SPECT after MR scanning and electroencephalogram, if the location of the trigger zone is still unresolved. 2.4.1.10 Ischaemic heart disease Many of the included studies were unblended and without control groups. All of the studies were case series with indirect diagnostic tests and a low evidence level, corresponding to category III for clinical evidence. The larger scale investigations 2-11 were unable to retrieve the high sensitivity and specificity of studies published earlier. On the basis of the smaller investigations with 20-40 patients, concordance appears to exist between PET and other studies such as SPECT and low-dose dobutamine echocardiography regarding sensitivity. The positive predictive values of 46-95% and negative predictive values of 66-96% are very unreliable, since KAG control is lacking. The fluctuating results with FDG uptake can be due to fluctuating inclusion criteria and varying evaluation methods. It is possible that the contractile reserve cannot be described on the basis of single metabolic investigations. Intensive research is being conducted within this area, and increased knowledge of pathophysiological mechanisms may possibly lead to the development of new, better diagnostic methods. Large scale, multi centre investigations with a higher evidence level are necessary before the ultimate role of PET for ischaemic heart disease can be determined. However, it is doubtful whether these studies will be carried out since very ill patients are involved, who in many instances are in urgent need of revascularization. 2.5 Description of the technology (from text provided by Professor P Sharp) 2.5.1 Radionuclide imaging PET imaging is a form of radionuclide imaging, which uses radioactively-labelled pharmaceuticals (radiopharmaceuticals) for diagnostic purposes. This is a well established technique in modern health care and a detailed description of the technique, known as nuclear medicine, can be found in many textbooks (see for example, Sharp et al., 1998). For cancer, increased metabolic activity at a cancer tumour site results in increased uptake of a radiopharmaceutical and so there are many potential uses of PET imaging in oncology While the spatial resolution and image noise achieved with PET is worse than with other diagnostic techniques, such as X-ray imaging or MRI, its strength is in producing images of the biochemistry of the tissue or organ as opposed to anatomy. PET provides functional information about activity and processes, unlike conventional X-rays, MRI, CT and ultrasound, which provide predominantly anatomical information. Images of the distribution of the pharmaceutical are formed by detecting the gamma rays emitted by the decay of the radioactive label, while the diagnostic information depends upon the pharmaceutical employed. Conventional nuclear medicine uses radioactive elements that emit gamma ray photons, this being the only radiation sufficiently energetic to penetrate through tissue and so be detected externally. Imaging is carried out with a gamma camera and can be either planar or tomographic, the latter being known as SPECT. PET also employs radiopharmaceuticals, but in this case the label is a positronemitting radionuclide. Positron-emitting radionuclides were first discovered in the 1940s. The positron is a positively-charged electron emitted from nuclei that are unstable due to an excess of protons. The emitted positron carries with it energy, which it loses in interacting with conventional negatively-charged electrons in the 2-12 material through which it passes. When it has lost almost all of its energy it is captured by an electron and the resulting pair of positive and negative electrons is known as positronium. These two particles rapidly annihilate, reappearing as two gamma rays. In order to conserve energy the two gamma rays will each carry an energy of 511 keV, the total energy being equal to the mass of the two electrons. If the positron carried no energy at the time it was captured, then the gamma rays would travel in diametrically opposed directions, otherwise the angle between them will be slightly less than 180 degrees. Thus compared with normal decay, the positron decay produces a pair of gamma rays rather than a single one.To produce an image of the distribution of the radiopharmaceutical, the gamma camera not only has to detect the presence of gamma rays but also locate from where in the body they were emitted. Gamma rays cannot be focused by a lens, and instead a collimator is used. This is a lead plate through which several thousand holes run from the front to the back face. Gamma rays can only pass through the collimator if they travel parallel to the axes of the holes; radiation travelling in any other direction will be absorbed by the lead. While the lens forms an image by focusing light, the collimator does so by excluding all radiation except that travelling in a particular direction. Thus, one of the major drawbacks of radionuclide imaging is its low sensitivity, with only about one in a thousand of the emitted gamma rays actually being used to form the image. PET imaging does not need such collimation. By detecting the simultaneous arrival of a pair of gamma rays, the position of emission can be computed as lying on the line connecting the two rays. By looking at points of intersection of thousands of such lines, an image can be formed and the source accurately located. A typical PET imager is shown in Figure 2-1. It consists of a ring detector, which surrounds the patient and collects a high proportion of the pairs of gamma rays emitted, connected to electronics that record the coincident arrival of pairs of gammas. 2-13 Figure 2-1 Outline of a PET imager Imaging ring Detector Point of Positron Emission Gamma ray 1 Image produced Gamma ray 2 Coincidence Detector Circuit Detector geometries other than the full-ring system (such as gamma cameras) are in use (section 2.5.5). The spatial resolution of a PET imager is better than that of a gamma camera; typically 3 to 6 mm in clinical applications, or down to 1.5 mm in ideal conditions. It is ultimately determined by the energy of the positron emission. However, the strength of the technique does not lie primarily in its better resolution, which is still not competitive with that of other techniques. Conventional, single photon nuclear medicine is limited by the fact that no biologically important element has a radioisotope suitable for imaging and that the ability to quantify the amount of radiopharmaceutical in an organ is restricted by the effects of attenuation of the radiation. However, biologically important elements such as 11Carbon, 13Nitrogen, 15Oxygen and 18Fluorine, do have positron-emitting isotopes and so can be used to label a wide variety of pharmaceuticals for PET imaging. By combining emission with transmission imaging, PET also permits the accurate measurement of the amount of radiopharmaceutical at a point in the body. Since PET uses very small amounts of positron-labelled molecules, it can measure the function of biological processes, such as blood flow, with minimal disturbance. To do so requires a compartmental model that describes the process and the way the labelled molecules mimic or trace it. The PET imager measures the changing tissue concentration of the labelled molecule over time, or the accumulated concentration at a given time, which is determined by the rate of transport and chemical reactions in which the radiopharmaceutical participates. For this reason PET has been called molecular imaging (Phelps, 2000). 2-14 However, there are disadvantages. The biologically interesting positron emitters all have a short lifetime. The longest one in routine imaging is 18Fluorine with a half-life of 110 minutes. The other tracers have half-lives as short as two minutes for 15Oxygen. Thus it is necessary to have a production facility, a cyclotron, for positron-emitting radionuclides located close to the imaging facility and a radiochemistry laboratory for rapid labelling of the pharmaceutical. For 18Fluorine, transportation from a cyclotron within two hours journey time is possible (section 9.4.2), but for other isotopes, on-site production is necessary. 2.5.2 PET radiopharmaceuticals Currently the main PET tracer in oncology is glucose labelled with 18Fluorine (FDG). Neoplastic degeneration is associated with increases in glycolysis because of a progressive loss of the tricarboxylic acid cycle (TCA) (Weber, 1977). Glucose is also used to provide the carbon backbone to meet the high cell replication rates of tumours (Weber, 1977). A complete loss of the TCA cycle can amplify glucose consumption 19-fold per adenosine triphosphate molecule (ATP). This is because only two ATP molecules are generated when a molecule of glucose is metabolised to lactate, whereas 38 ATP molecules are generated when a molecule of glucose is completely metabolised to carbon dioxide and water in the TCA cycle. Glucose consumption is further increased by the activation of the hexose monophosphate shunt. These two factors increase glucose consumption as neoplastic degeneration progresses (Phelps, 2000). Thus neoplasms are differentiated from surrounding tissue by their high uptake of FDG. These properties appear to be common for all malignancies. FDG was first synthesized by Ido et al. (1978). FDG undergoes glycolysis in tumours but the dephosphorylation of FDG-6-phosphate is relatively slow, so FDG gradually accumulates within the cells (Figure 2-2). The concentration of FDG reaches a plateau when the rate of dephosphorylation equals the rate of uptake into the cell. In experimental studies, this occurs about 45-60 minutes after injection, so clinical imaging is normally carried out after this interval. The kidney does not recognise FDG as glucose, so it is largely excreted by glomerular filtration, although there is some reabsorption in the proximal tubule. In a normal subject about half of the injected dose is excreted in the urine 2 to 2.5 hours after injection. 2-15 Figure 2-2 Whole body image taken using FDG (Metastatic deposits can be seen in the area of the lungs and spine.) In clinical practice it is found that absolute measurement of glucose uptake into lesions or specific organs is difficult because of differences in the size and body composition of patients, and individual variations in glucose metabolism. When required, approximate quantitation is achieved by using the standardised uptake value (SUV), which is an estimate of the uptake of FDG into the lesion or organ of interest, compared with the mean uptake in the rest of the body. However, some concerns have been expressed about the robustness of SUV as a measure of FDG uptake (Keyes, 1995). 2.5.2.1 New tracers Currently, most PET oncology studies use FDG. This is likely to continue for some time but some interesting new tracers are under assessment. These include 11Carbon Thymidine (Strauss, 1997) and a 18Fluorine Fluorothymidine (FLT) for cell proliferation, a 18Fluorine Metronidazole derivative for tumour hypoxia and 18Fluorine fluoro-estradiol as an oestrogen receptor (ER) tracer. This allows depiction of ER heterogeneity within breast cancers and also detection of loss of ER expression with treatment or disease progression. 11Carbon and 18Fluorine choline tracers are being used to look at membrane synthesis and these show considerable promise in prostate cancer, where FDG is less effective. 2.5.3 Instrumentation for PET Positron decay gives rise to two 511 keV photons travelling in diametrically opposed directions. It is the recognition of such coincident pairs of photons by detectors placed on opposite sides of the body that allows the position of the source of the radiation to be determined. Since collimators are not needed, the efficiency of detection is considerably improved compared with the conventional gamma camera approach. However, as the imaging process depends on detecting both of each pair of photons, effective imaging involves surrounding the patient with the radiation detector (Figure 2-3) and consequently such dedicated PET systems are expensive. 2-16 Figure 2-3 A dedicated PET imager The high-energy photons are stopped in a scintillation crystal. Such crystals need to have good ‘stopping power’, and bismuth germanate oxide (BGO) has been the standard for the last few years. The recent introduction of lutetium based detectors, together with faster electronics, offers an increase in sensitivity so that examination times can be considerably reduced. A typical block detector consists of a single crystal of BGO, which has been sawn into an array of 8x8 distinct crystal elements. The depth of the saw-cuts determines the amount of light directed to each of four photomultiplier tubes. These blocks then form the ring around the patient. The axial field of view, i.e. along the length of the patient, depends upon the number of detector rings employed. A two-ring system (16 detectors deep) would give 31 slices and a three ring system, 47 slices. Typically each slice would be 3.4 mm thick, giving a field of view of 11 cm for a two ring and 16.2 cm for a three ring system. By moving the patient through the detector ring, larger fields of view can be achieved. In addition to a true coincidence, the image may be degraded by artefactual coincidences, which will result in incorrect spatial information. Thus the coincidence system must be designed to keep processing time to a minimum and to reduce the effect of false coincidences. This is done both electronically and by using lead or tungsten discs, known as septa, inserted between detector planes to reduce scatter. 2-17 With the septa in place, data are acquired as a series of two dimensional (2D) slices. With the inter-plane septa retracted all possible coincidences are acquired creating a three dimensional (3D) volume of data from which slices may be extracted (Bendriem & Townsend, 1998). It increases the sensitivity by a factor of about 10, allowing lower doses and/or shorter acquisition times to be used. There are, however, a number of problems with the 3D technique and, in general it does not lend itself to imaging of extended sources, such as the trunk, although it is advantageous for the brain. One of the strengths of PET is its ability to accurately quantify the amount of radioactivity in an organ or region of interest. This requires that a correction be made for attenuation of radiation in the patient. This is done by the acquisition of a ‘Transmission Image’ when the patient is in position, using an external positron source, usually 68Germanium (68Ge) with a half-life of 275 days. The process takes about 20 minutes, and is in addition to the time required for the emission image. One of the major limitations of PET is the lack of anatomical landmarks, particularly in the thorax, abdomen and pelvis. Therefore for applications in oncology, PET images need to be interpreted in conjunction with CT or MRI anatomy. Although coregistration of images obtained from separate examinations can be carried out on an image processing workstation, the advantages of simultaneous acquisition of anatomical and functional data are self-evident. Mounting both a spiral CT and a partial ring PET device on a single imaging gantry offers the possibility of combining functional and anatomical data in the same examination (section 2.5.5.2). Typically, the CT acquisition is performed first followed by PET acquisition. The anatomical CT data can then be used to apply attenuation correction for the PET data and the resulting images can be displayed separately or fused together, obviating the need for the 68Ge system. 2.5.4 Image interpretation Although PET scanners can have a very high sensitivity, this can often be accompanied by a large amount of unwanted background data arising from two sources. The first of these is scatter where one or both of the 511 keV photons has scattered in the patient; this is significant for large patients and when imaging the torso. Scatter is particularly troublesome in PET because many current detectors have poor energy resolution. Also, many photons interact via a Compton scatter and deposit only a fraction of their energy in the detector. As a result, energy thresholds are usually set at approximately 300 keV and scatter fractions are high. The second form of noise is not encountered in single photon systems. Random coincidences arise when two single photons from different annihilations are detected within the very short (approximately 10 nanoseconds) window that is used to define a coincidence event. The scanner has no way of discriminating between these random coincidences and true coincidences. There are various schemes to correct for the systematic effects of scatter and random events; however, the noise that is introduced into the image cannot be removed and depends on the basic design of the scanner. 2-18 The noise due to scatter and random events is a particular problem for scanners that operate in 3D mode. To keep random and scatter coincidences to a minimum, many scanners restrict coincidences to pairs of photons that lie within transaxial planes of the scanner, and thin lead or tungsten septa are placed between these planes. In 3D mode, the inter-slice septa are removed and coincidences are permitted between all detector rings with the result that the sensitivity is much increased but so are the scatter and randoms. Image reconstruction of PET data is usually performed using the standard filtered back projection algorithm and modified versions of this that are applicable to data acquired in 3D mode. Increasingly, iterative reconstruction techniques are being used. These can take account of the statistical properties of the data and result in higher quality reconstructions. 2.5.4.1 Quantitation In the majority of clinical cases, PET scanning is just used to detect lesions (tumours). For this purpose Bleckmann et al. (1999) and Lonneux et al. (1999) have shown that images not corrected for attenuation show better contrast between the lesion and the background. However, there are other factors, besides plain contrast, that influence the ability to perform an accurate diagnosis. These factors include consistency of lesion detection across a number of scans, differences between clinical examiner, and size and shape of the lesion. It has been suggested that these factors may outweigh contrast as cues for visual detection of lesions (Lonneux et al., 1999). Furthermore Bai et al. (2000) have shown that the attenuation artefact is non-linear and may produce both locally enhanced and decreased contrast depending on the position of the lesion (i.e. it may not be detected in some cases). They suggest that both corrected and uncorrected images should be used for diagnosis. While questions remain about the need for attenuation correction for lesion detection, there is little doubt that it is required for absolute (or even relative) quantification of lesion uptake (Bailey, 1998), which may be required when assessing response to therapy, for example. 2.5.5 Alternatives to PET 2.5.5.1 Gamma cameras As an alternative to full PET imaging, two or more planar detector, multi-headed gamma cameras could be used. Using a dual- or multi-headed gamma camera for PET has the obvious advantage that the same instrument can also be used for single photon imaging as well. However, there are relatively few studies available that can be used to evaluate the specificity and predictive value of gamma cameras and most are small case series, which are subject to bias. Initial comparisons have shown that dedicated PET and gamma cameras perform equally well in detecting lesions larger than about 2 cm, but dedicated PET systems are more accurate for the detection of small lesions (Yutani et al., 1999; Tatsumi et al., 2001). Consequently it was decided to focus this HTA on dedicated PET systems. 2-19 A study is currently underway at the Royal Hallamshire Hospital, Sheffield looking at the diagnostic accuracy of a combined gamma camera/CT system in the diagnosis of positive lymph nodes in NSCLC. It will be interesting to evaluate the results of this trial once it is completed. 2.5.5.2 PET/CT PET images lack anatomical detail and a transmission image is required to calculate the attenuation correction of the radiation in the patient. This takes approximately 20 minutes in addition to the imaging scan. The use of a CT scanner allows the attenuation data to be acquired in a shorter time while also providing diagnostically useful CT images. There have been recent advances in the development of combined PET/CT scanners, which may help to address these issues by producing combined images. Costs of PET/CT scanners are greater than PET imagers alone (of the order of 50% higher) and maintenance costs are also higher. However, it is hoped that diagnostically superior images may be produced and that scan time will be reduced, thus allowing higher patient throughput. However, there is no published evidence of this to date, and no such evidence was submitted to HTBS. Images from individual PET/CT scans are provided in Appendix 3. Phelps (2000) proposes that PET/CT scanners could be used for the following: improve the PET image through fast and accurate attenuation correction; improve localisation of abnormalities detected using PET; radiotherapy and surgery planning; evaluation of therapy outcome by localising regions of oedema and scarring; and produce the highest possible quality PET and CT information with the least inconvenience. Comments have been received from a number of interested parties claiming that, as well as reducing the time required for a transmission scan, PET/CT systems may be more accurate than PET alone in the staging and diagnosis of cancer. To assess the evidence currently available for this claim, a literature search was conducted for peerreviewed papers addressing the use of PET/CT fusion images in mediastinal staging of NSCLC. The search identified three papers reporting the use of PET/CT fusion images in mediastinal staging of NSCLC, and two additional papers reporting the use of PET and CT images that were ‘visually coordinated’. The results given in these papers are described in Appendix 4. From the small number of published studies, it would seem that some sort of correlation between PET and CT is useful, but that fusion images actually add little or nothing in this application in NSCLC. 2-20 Some of the questions that would need to be answered before deciding whether PET/CT will be effective in practice are: 1. What percentage of PET scans require quantitation? In some cases the aim is to detect the spread of a cancer. While correcting for attenuation may improve the accuracy of the image, there is conflicting evidence (from the few studies that have been done) on whether it improves the ability to detect the spread. If quantitation is not required then a combined PET/CT scanner does not offer any improvement in throughput, thus negating one of its advantages. 2. What percentage of scans require anatomical registration? In some cases the fact that a tumour has spread is enough to change the management of the patient (i.e. make them unsuitable for surgery). In these cases there is no need for any anatomical registration. 3. Is the registration that can be obtained on the combined scanner significantly better than that using two separate scans? Clearly it is easier to co-register a PET and a CT image if they are taken with the patient in the same position. However, even in this case, co-registration may not be perfect. For example in order to get good diagnostic CT images patients are often asked to hold their breath during the CT scan. This is not possible for the PET scan since it takes too long. Therefore breathing motion will introduce some error. Also in some cases the CT scan may be taken with the arms above the head (to improve quality) and this position may be too uncomfortable for the longer PET scan so the arms may be placed by the patients side, thereby changing the position of internal organs. The results of the literature review show that there is much less evidence available for assessment of PET/CT than there is for PET alone. This is not surprising as PET/CT scanners are a relatively new technology, but it means that there is insufficient evidence to attempt a robust economic evaluation. Hence this report has focused on dedicated PET imagers. 2-21 3 SOURCES OF EVIDENCE AND DEVELOPMENT OF THE ASSESSMENT QUESTIONS 3.1 Sources of evidence The HTAs undertaken by HTBS use international evidence from a range of sources: published literature, grey literature (e.g. academic and government reports, conference abstracts) and information submitted from a variety of interested parties. The following interested parties were invited to submit evidence for this assessment (those marked * did not reply and those marked + did not have anything additional to contribute): Professional/Specialist Groups British Institute of Radiology* College of Radiographers* Royal College of Radiologists Scottish Council of the Society of Radiographers+ Institute of Physics and Engineering in Medicine Medical Research Council+ British Nuclear Medicine Society Society of Radiographers Royal College of Physicians (London) European Association of Nuclear Medicine Intercollegiate Standing Committee on Nuclear Medicine Patient Groups British Lung Foundation (Scotland)* Scottish Breast Cancer Campaign* Imperial Cancer Research Fund* McMillan Cancer Relief* Sargent Cancer Care of Children (Scotland)* Scottish and Newcastle Lymphoma Group Scottish Association of Prostate Cancer Support Groups* Breast Cancer Care* Colon Cancer Care+ Manufacturers ADAC Laboratories Alliance Medical CTI PET systems GEM Systems USA Marconi* Marken Time Critical Express Amersham Health Siemens Medical Solutions Strand Transport Service Limited+ Synektix Trionix* 3-1 Manufacturers were asked to respond to the following questions: 1. Summarise the evidence for clinical and cost effectiveness of gamma cameras versus dedicated PET scanners in the provision of PET as part of cancer management. 2. In your view would it be necessary for the effective use of PET in cancer management to have an on-site cyclotron? 3. Summarise developments in the field of PET imaging technology that may, in the next two years, have an important impact on the effectiveness of PET imagers in cancer management. The TSG submitted a range of technical and operational materials about existing PET facilities in the UK, general technical information and patient information leaflets. For clinical effectiveness and the economic evaluation a systematic literature review was undertaken. As explained in sections 1.2 and 3.2, this focused on the staging of NSCLC and lymphoma. For NSCLC, the literature review built on a recently published high quality HTA from Denmark (DACEHTA, 2001). For organisational and patient issues the focus was placed on submitted evidence, selected literature references and grey literature from a variety of sources. 3.2 Developing the assessment questions At the outset it was realised that there is substantial literature on the diagnostic accuracy of FDG-PET. However, it was agreed that, in order to determine the value of FDG-PET, evidence of change in patient outcomes should be obtained (section 1.2). If this was not available, change in patient management may be considered a sufficient surrogate. Diagnostic accuracy would not be sufficient. So the first step in the HTA was to determine which cancer might have sufficient patient outcome or management data for evaluation. The HTBS TSG highlighted seven cancers (lung, head and neck, prostate, colorectal, breast, lymphoma and melanoma) where FDG-PET imaging may be of potential use and summarised five main areas of FDG-PET application by functionality (diagnosis, staging, functional information for prognosis, evaluation of early response to treatment and evaluation of sub-clinical response). This formed the basis of literature searches undertaken in MEDLINE (July 2001) to assist in scoping the assessment questions. The scoping searches resulted in a total of 1811 clinical articles and 190 economic articles for all cancers. A summary of the number of papers identified is presented in Table 3-1. 3-2 Table 3-1 Results of clinical effectiveness and economic evaluation scoping literature searches (number of studies by cancer and functionality) Lung Diagnosis Staging Prognosis Early response Sub-clinical response Total* Head and neck Prostate Colorectal Clinical papers 88 88 90 64 50 37 189 205 93 210 188 156 14 14 9 3 23 0 2 0 3 0 0 580 37 490 Breast Lymphoma Melanom a 58 77 38 38 49 14 7 4 0 0 0 0 230 196 Economic papers Total 67 49 1 31 18 * Note: Papers may be duplicated within functionality criteria. 177 101 10 14 The results of the searches were reviewed and the following broad exclusion criteria were applied: 4. 1. Duplicate references within the list 5. 2. Articles not specifically on the individual cancer 6. 3. Studies not using FDG as the radiolabelled tracer 7. 4. Review articles or letters describing general use of PET 8. 5. Studies not specifically using PET 9. 6. Articles not written in English 10. 7. Animal studies. This reduced the number of relevant papers and the studies included for consideration were corroborated by the reviews done by other HTA organisations; in particular a recent report produced by the Danish Centre for Evaluation and Health Technology Assessment (DACEHTA, 2001) which summarises the literature on the use of FDGPET in oncology, cardiology and neurology and a report prepared by the Medical Services Advisory Committee (MSAC) for the Commonwealth Minister for Health and Aged Care in Australia (MSAC, 2000). 3-3 The HTBS appraisals team subsequently held discussions with a subgroup of the TSG members to define specific questions for assessment, based on the results of this literature search. The following HTBS questions were proposed in order of importance to Scotland: 1. What is the role of FDG-PET in the evaluation of the SPN? 2. What is the role of FDG-PET in selecting patients presenting with NSCLC for surgical resection? 3. What is the role of FDG-PET in recurrent lymphoma? 4. What is the role of FDG-PET in squamous cell head and neck cancer recurrence after major surgery (excluding thyroid)? 5. What is the role of FDG-PET in assessing patients for recurrent colorectal cancer: (a) when there is a single site of known recurrence, does it help the decision on surgical resectability? (b) when tumour markers are rising but no recurrent site is evident, does it aid in localising the recurrence? The HTBS appraisals team considered the feasibility of assessing these five cancers against the evidence questions that were to be applied to all cancers (Appendix 2 – questions 4.1, 4.2, 4.3, 4.5), relating to the: quality of clinical effectiveness evidence; availability of economic modelling information; and importance of the cancer in Scotland. On the first factor, the HTBS appraisals team considered the reports produced by the DACEHTA (2001) and the MSAC (2000) to provide a good summary of the evidence available on the role of FDG-PET in oncology to May 2001. It was clear that the largest body of evidence is available for the role of FDG-PET in lung cancer. It was also determined that the only randomised trials that evaluated patient outcomes were in NSCLC and were to be published in 2001/2002. Information from randomised trials did not appear to be available for any other cancers. Table 3-2 Number of economic evaluation papers suitable for this HTA Lung: SPN Lung: NSCLC Lymphoma Head and neck Colorectal 3 3 2 0 0 Table 3-2 shows that, of the eight relevant published economic evaluations, six related to lung cancer, three to the role of FDG-PET in evaluating SPNs (HTBS question 1), and three to the role of FDG-PET in surgical resection of NSCLC (HTBS question 2). 3-4 The lack of studies that could act as a basis for the economic evaluation of HTBS questions 3-5, together with the poor quality of clinical data on the role of FDG-PET in patient management within lymphoma, head and neck and colorectal cancers, resulted in the initial decision to concentrate on the staging of NSCLC for this HTA. The importance of NSCLC, which is the most common cause of cancer death in Scotland, was an additional factor in this decision. However, it was subsequently recognised that the value of PET is influenced by the potential for successful therapy and patient outcomes in NSCLC are poor (section 2.1.2). Consequently FDG-PET was assessed for another cancer, in which greater treatment benefit was possible, for which a clear patient pathway could be determined and which had not been extensively studied by other organisations, namely Hodgkin’s disease. Consequently, this HTA presents analyses of clinical effectiveness and cost effectiveness that compare the addition of FDG-PET with current standard diagnostic work-ups for the staging of NSCLC (section 4 and 5) and restaging of Hodgkin’s disease after induction therapy (sections 6 and 7). Clinical effectiveness evidence from other HTAs is used in the discussion to consider the value of FDG-PET in other cancers (section 10). Patient and organisational issues relate to all patients who may undergo a PET scan and these are presented in sections 8 and 9. 3-5 CLINICAL EFFECTIVENESS – NSCLC 4 Summary A systematic review and critical appraisal of the literature was undertaken to determine the effectiveness of FDG-PET in NSCLC with regard to mediastinal staging, the detection of distant metastases, changes in patient management and clinical outcomes. A meta-analysis of diagnostic accuracy was performed, using a summary receiver operating characteristic curve (SROC) to estimate the sensitivity and specificity in CT negative patients, CT-positive patients and both groups combined. Meta-analysis shows that, for NSCLC patients who are CT negative, the estimated specificity of FDG-PET scanning is 0.9, 95% confidence interval (CI) (0.87, 0.93), with sensitivity at this specificity of 0.86, CI (0.79, 0.91). Meta-analysis shows that, in NSCLC patients who are CT positive, the estimated specificity of FDG-PET scanning is 0.76, CI (0.69, 0.82), with sensitivity at this specificity of 0.92, CI (0.87, 0.95). Published studies conclude that FDG-PET is superior to CT and other conventional tools in the mediastinal staging of NSCLC, in the investigation of possible distant metastases in NSCLC and in other selected areas of oncology. Two randomised controlled trials comparing diagnostic strategies in NSCLC, with and without FDG-PET, have been reported. The two trials produced contradictory results. One trial (van Tinteren et al., 2002) demonstrated that the addition of FDG-PET produces a cost-effective reduction in the number of futile thoracotomies, whereas the other (Boyer et al., 2001) found no difference between the strategies. This appears largely due to different approaches to the management of NSCLC, given the results of FDG-PET scanning. No randomised trials report evidence on quality-of-life outcomes following use of FDG-PET for staging NSCLC. The published studies suffer from a number of deficiencies and further welldesigned research is needed. Potential risks associated with PET imaging relate mainly to the administration of the radiopharmaceutical. However, in all published literature no adverse events have been reported as a result of PET scanning. There is a risk of second cancers posed by the radiation dose in PET scanning, but this is very low. 4-1 4.1 Literature search 4.1.1 Search strategy Scoping searches were undertaken in July 2001, as part of the process to help define the assessment question. This included a search for HTAs, systematic reviews and other evidence-based reports on the application of PET in cancer management. In addition, exploratory searches of MEDLINE were undertaken to try and establish the quantity and the quality of the evidence on the impact of PET on patient management, vis-à-vis diagnostic accuracy. Section 3.2 presents the results of these literature searches and describes how the decision was reached that HTBS would focus on NSCLC and update the systematic literature search on the diagnostic accuracy of FDG-PET presented by the DAHCETA (DACEHTA, 2001). To update the Danish HTA the following approaches were adopted: The databases MEDLINE (Ovid), PreMEDLINE (Ovid) and Embase (Ovid) were searched. The search was split into two concepts: positron emission tomography and non-small-cell lung cancer (NSCLC) with all relevant subject headings and free text terms identified for each concept. The search was limited to records added to the databases from January 2001 onwards. No language restrictions were applied. Attempts were made to identify additional randomised controlled trials and ongoing research, not indexed in MEDLINE or Embase, by searching sources such as the Cochrane Controlled Trials Register, Current Controlled Trials (mRCT) and the websites of professional organisations. Members of the TSG and Experts were consulted to check for completeness of the included studies and, in particular, to help identify unpublished (grey) literature and ongoing research. The bibliographies of relevant studies were scanned for further studies. Further information about the search and a flow chart detailing the systematic literature selection process are presented in Appendix 5. 4.1.2 Exclusion criteria Clinical effectiveness papers were excluded from review according to the following criteria: duplicate references within the list; articles not about NSCLC staging; studies not using PET; studies not using FDG as the radiolabelled tracer; review articles or letters describing general use of PET, with no formal metaanalysis; and animal studies. For the meta-analysis, further exclusion criteria were used. These are described in section 4.5.1. 4-2 4.2 NSCLC diagnosis in Scotland 4.2.1 NSCLC staging The treatment offered to patients with NSCLC (and their outcome) will depend on the stage of their disease. To lay the foundations for the clinical effectiveness and economic evaluation, detailed information is needed about the current diagnostic pathway used to stage NSCLC in Scotland. On this basis, the potential value of FDGPET in the Scottish clinical setting can be evaluated. The TNM classification of lung cancer (Sobin and Wittekind, 1997) considers the extent of the primary tumour (T status), condition of regional nodes (N status) and presence (1) or absence (0) of distant metastases (M status). Diagrammatic representation of T and N status is presented in Figures 4-1 and 4-2. The Scottish Intercollegiate Guidelines Network guideline on lung cancer (SIGN, 1998a) recommends staging patients (Stage 0 to Stage IV) according to the TNM classification, as follows: Stage 1A Stage 1B Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IV T1 T2 T1 T2 T3 T1 T2 T3 Any T T4 Any T N0 N0 N1 N1 N0 N2 N2 N1, N2 N3 Any N Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1. As shown in Table 4-1, other professional organisations recommend similar staging categories. There is agreement that those with M1 (distant metastases) or N3 (involving contralateral mediastinal or hilar, scalene or supraclavicular nodes) disease rule out surgery, but N2 (involving ipsilateral mediastinal, subcranial nodes) are a matter for clinical judgement (see section 4.2.2). Table 4-1 Guidance on surgical judgement BTS Operable Stage I (T1 N0, T2 N0) Stage II (T1 N1, T2 N1, T3 N0) Surgical judgement or only in trial Stage IIIA (T3 N1, T1-3 N2) English cancer guideline* Stage I Stage IIA Stage IIB Stage IIIA SIGN Stage I, II Stage IIIA Stage IIIB (anyT N3, T4 N2) or Stage IIIB, IV Stage IIIB, IV IV (anyT anyN M1) *NHS Executive document: Guidance on Commissioning Cancer Services – Improving Outcomes in Lung Cancer Not operable 4-3 Figure 4-1 Lung cancer: T staging Reproduced with permission from Hanson J, Armstrong P, Lung cancer. In: Imaging in Oncology (eds JES Husband, RH Reznek). London: Isis Medical Media, 1998: 4566. 4-4 Figure 4-2 Lung cancer: N staging Reproduced with permission from Hanson J, Armstrong P, Lung cancer. In: Imaging in Oncology (eds JES Husband, RH Reznek). London: Isis Medical Media, 1998: 45-66. 4-5 4.2.2 NSCLC diagnostic work-up in Scotland Consultation with lung cancer experts in Scotland indicates that to accurately stage patients with NSCLC, the following diagnostic procedures are involved: history and physical examination (including assessment of performance status, weight and weight loss); chest X-ray, if this is normal, but clinical suspicion is high, further investigations should be undertaken; haematology and biochemistry, including serum calcium, alkaline phosphatase and liver function tests to determine metastatic status; fibre-optic bronchoscopy (day case under topical anaesthesia) in those who are sufficiently fit (this will yield a positive histological diagnosis in up to 80% of cases; those who are unfit may receive sputum cytology); CT of the thorax with contrast medium; biopsy of mediastinal lymph nodes more than 1 cm in the short axis, by superior mediastinoscopy or anterior mediastinotomy; pathological diagnosis by bronchoscopic biopsy, brush or bronchoalveolar lavage cytology, percutaneous fine needle aspirate or image-guided needle biopsy; ultrasound or other organ specific scans if there is clinical or biochemical evidence to suggest metastatic disease (if tests are normal, incidence of occult metastatic disease outside the chest is less than 5%); and pulmonary function tests. Following this, appropriate treatment of the patient is decided. Surgery, chemotherapy, RT and palliative care are possible, with surgery (lobectomy or pneumonectomy) being the treatment that offers the best chance of cure in patients with NSCLC. The diagnostic/staging work-up outlined above is in line with the recommendations in the SIGN guideline (SIGN, 1998a), the Scottish standards on management of lung cancer (CSBS, 2001) and the BTS guideline on selection of patients with lung cancer for surgery (BTS, 2001). However, in practice there are regional differences in the way staging is performed, the order of tests and the resulting treatment decisions. CT is used for T and N staging, but false-positive and false negative results can occur. Other conditions may cause one or more lymph nodes to be enlarged and thus be interpreted as cancerous when in fact they are not, and metastases in a node may be so small that the CT image is interpreted as benign when it is cancerous. To determine where FDG-PET might be used, HTBS has had detailed conversations with lung cancer experts in Scotland to determine the flow of diagnostic work-up and clinical decision-making process. 4-6 Patients with suspected NSCLC can be referred to a chest physician by their general practitioner (GP) and may already have a suspicious chest X-ray (especially if an open access service is available locally). Relatively few patients who do not have lung cancer are referred; an important consideration in view of the fact that the early signs and symptoms are not so specific. A small number of cases are referred as incidental findings during other health care e.g. on a routine chest X-ray prior to elective surgery for another condition. Other referral patterns are also possible and still probably not uniform across Scotland. The pattern of referral and subsequent management of patients on the cancer register in Yorkshire, England during 1993 has been evaluated and also identifies self-referral through Accident and Emergency departments. The conclusion is that patients without a suspicious chest X-ray are less likely to have specialist care and lower rates of chemotherapy, RT or surgery (Melling et al., 2002). From the surgical viewpoint, the strategy is to establish the tissue diagnosis, then to establish resectability (T and N status), the presence of distant metastases (M status) and fitness for surgery. For non-clinicians, thinking in terms of these four tasks can be helpful. In practice, however, the process is not divided up into a neat sequence. The literature talks of an index of suspicion (usually for diagnosis of cancer) but a more accurate understanding of the clinician's thought-process might be one index for each of the four problems, with new information becoming available at each contact with the patient. For example, when the patient attends for a test on their lymph nodes they might be complaining of new pain suggestive of distant site metastases. Following referral, the next investigation would ideally be a CT scan but, given waiting times, bronchoscopy may be undertaken first. This has the advantage of allowing biopsy samples to be taken for histology and random washings and brushings for cytology. By this stage, about 60% of cases can be diagnosed as NSCLC. Image-guided needle biopsy can give a definite diagnosis in a further 20 to 30%. Of the remaining 10 to 20% a small number might be referred for surgery on the basis of a suspicious chest X-ray showing a solitary tumour strongly suggestive of cancer. However, most patients who do not have obvious advanced disease will go on for further investigation. Resectability depends on size, extension to ribs and pleura, and the extent of nodal disease. CT of the lungs and abdomen (notably the liver and adrenal glands) is a reliable guide to tumour size and will also show obvious metastases beyond the lymph nodes in the area scanned. It also shows the size of lymph nodes, a factor that has some prognostic value. It is common practice to regard lymph nodes that are more than 1 cm in diameter as ‘enlarged’ or CT-positive and lymph nodes of less than 1 cm as ‘normal’ or CT-negative. Enlarged nodes have a much higher probability of tumour spread to that node. 4-7 Patients with lymph nodes that are not enlarged are candidates for surgery (subject to fitness). For those with enlarged lymph nodes, mediastinoscopy is the next line of investigation. This investigation is (close to) definitive for lymph nodes that can be reached but, in about a quarter of cases with affected lymph nodes, mediastinoscopy cannot detect disease. Where there is no suggestion of lymph node involvement, patients are candidates for surgery. Where lymph node disease is detected, however, clinical judgement is required. Small primary cancers with lymph node involvement on the same side of the body (T1N2 disease) might be candidates for surgery but ideally this would be in the context of a trial. Those with more extensive disease (especially N3 disease) are very unlikely to be surgical candidates. There appears to be one major alternative to this general work-up in Scotland, with one centre that undertakes percutaneous image-guided biopsy of lymph nodes or of adrenal gland/liver for metastatic disease instead of mediastinoscopy and which reserves mediastinoscopy for cases where such a biopsy is not possible or cannot be performed. It is important to screen for metastases in distant parts of the body, typically by CT scan or MRI of the brain and radionuclide bone scans. SIGN (1998a) guidance suggests only investigating patients with symptoms that are indicative of secondary disease in the brain and skeleton. However, it should be noted that patients with obvious advanced disease would be identified and referred on throughout the diagnostic process and not only at the final stage. Similar comments apply to the assessment of patient fitness to undergo surgery. The doctor responsible for the diagnostic investigation strategy may be able to identify patients who are obviously unfit, even before they see an anaesthetist. For patients with no other obvious contraindications, the anaesthetist makes a final assessment when the patient is admitted before surgery. In practice, treatment decisions will be complex and are now facilitated by the multidisciplinary MCNs (section 2.2.2) being established in Scotland. For example, a meeting of surgeons, physicians, radiologists, oncologists and palliative care specialists might review evidence from chest X-ray, bronchoscopy, CT of lungs and abdomen, and mediastinoscopy. In some cases decisions must be made on the balance of probabilities. For example, CT might show enlarged lymph nodes that cannot be reached by mediastinoscopy. Surgery can reveal the extent of lymph node involvement. Either more accurate staging will be made at the start of the operation or sampling of lymph nodes following resection of the primary tumour will show the 'true' extent of spread. A typical diagnostic and treatment pathway for NSCLC in Scotland is shown in Figure 4-3. Despite initiatives to achieve standardisation across Scotland, as highlighted in section 5.2.3, there is still variability in the diagnostic approaches. These will be investigated in further detail in the economic evaluation. 4-8 Figure 4-3 Diagnostic pathway in Scotland CT (sometimes with fine needle aspiration) NONSURGICAL TREATMENT ENLARGED NODES NORMAL NODES (CT-positive) (CT-negative) MEDIASTINOSCOPY POSITIVE LYMPH NODE NONSURGICAL TREATMENT SURGERY MEDIASTINOSCOPY NEGATIVE LYMPH NODE POSITIVE LYMPH NODE SURGERY NON-SURGICAL TREATMENT NEGATIVE LYMPH NODE SURGERY To determine how FDG-PET might help in this diagnostic process, consultation with Scottish experts suggested that it has four possible roles in the pre-operative staging of NSCLC: 1. to investigate lymph nodes inaccessible after mediastinoscopy; 2. to replace mediastinoscopy in the investigation of normal or enlarged lymph nodes; 3. to investigate the 10% of patients in whom bronchoscopy/fine needle biopsy does not give a definite diagnosis; and 4-9 Ultrasound/CT/isotope scans for bone and brain occult metastases on the basis of haematology/biochemistry or signs and symptoms Patient considered fit for surgery undergoes chest X-ray, haematology, biochemistry, bronchoscopy (fine needle aspiration) 4. as an additional procedure in the investigation of distant metastases where sensitivity for occult metastases is around 90%. This list is not definitive. For example, patients could be referred for FDG-PET after bronchoscopy without having CT. However, a number of experts have indicated that in these circumstances they would still wish to see CT results even if they had PET for the anatomical detail. These are not the only ways in which FDG-PET might contribute to NSCLC management. For example, it might be used as an additional procedure to stage patients for radical RT, helping to plan therapy by defining site of tumour, especially in the mediastinum, as well as allowing assessment of response to this therapy. In addition, FDG-PET may have a role in solving difficult palliative problems e.g. causes of pain. 4.3 Methodology for clinical effectiveness analyses 4.3.1 Evaluation of sensitivity and specificity The particular diagnostic decision of interest is the decision about whether a patient presenting with primary NSCLC and no evidence of distant metastases has metastatic spread to N2 or N3 lymph nodes. This is assumed to take the form of a simple yes/no decision, which may of course be correct or not (relative to the patient’s ‘true state’), as shown in Table 4-2. Table 4-2 Diagnostic testing True disease state Imaging result Yes (N2/N3) No (N0/N1) Yes (N2/N3) TP True Positive FN False Negative No (N0/N1) FP False Positive TN True Negative The ‘accuracy’ of a diagnostic test is normally described by two quantities, the sensitivity and specificity (or equivalently the true positive rate (= sensitivity) and the false positive rate (=1 – specificity)). Sensitivity is the probability that a test result is positive given the subject has the disease. In a suitable experiment the sensitivity can be estimated by: TP/(TP+FN). Specificity is the probability that a test result is negative given the subject does not have the disease. In a suitable experiment the specificity can be estimated by: TN/(TN+FP). In this HTA, because of the structure of the economic model used, the sensitivity and specificity of FDG-PET was estimated for CT-negative and CT-positive patients separately. 4-10 4.3.2 Meta-analysis Data allowing the estimation of sensitivity and specificity are available from a number of studies (section 4.5) and have been combined using a meta-analysis approach (DerSimonian & Laird, 1986). The specificity and sensitivity for a particular study are not independent, but ‘traded off’ depending on specific local rules for the interpretation of PET images. Consequently the relationship between sensitivity and specificity has been estimated by construction of a summary receiver operating characteristic (SROC) curve using the unweighted regression method described in Moses et al. (1993), and in Appendix 6. This technique allows display of the ‘estimated relationship’ in the form of a graph plotting the FP rate against the TP rate, see for example, Figure 4-4. The pooled specificity has then been calculated by standard meta-analysis techniques (DerSimonian & Laird, 1986). Although, in principle, a SROC curve could be summarised by ‘reading off’ the specificity at any desired sensitivity (or vice versa) it is not obvious that the reading of PET scans can, in fact be ‘tuned’ in such a fashion (see also Samson et al., 2001). In this report, therefore, the results are summarised by presenting the pooled specificity from a random-effects meta-analysis (DerSimonian & Laird, 1986) or a fixed-effects meta-analysis if this was not calculable. The sensitivity was estimated from the ROC curve at this specificity. A pooled specificity estimate was calculated by combining the logit transformed FP rates, using inverse variance weighting and confidence intervals calculated assuming normality (DerSimonian & Laird, 1986). Confidence intervals for the sensitivity estimate were calculated as in Moses et al. (1993). See Appendix 6 for further details. As part of the meta-analysis, a test was done to determine whether the SROC curve was symmetric (this is referred to below as the test for constant odds ratios, since the equivalent condition is that the ratio [odds (TP)/odds (FP)] be constant between studies). Figures 4-4 to 4-6 display plots of the TP rate against the FP rate for each of the studies, in each of the three meta-analyses, together with the fitted ROC curves. If the model (as shown in Appendix 6) is a completely accurate description of the data, the points will all fall close to the fitted line (as in Figure 4-6). A poor fit, with points falling well away from the line (as in Figure 4-5) suggests that patient populations or machine performance may differ between studies (which is, indeed, quite likely). 4.4 Critical appraisal of published literature 4.4.1 Background This section reviews the wide variety of published material reporting on various aspects of the use of FDG-PET in NSCLC. In addition to reports of studies of accuracy in mediastinal staging (section 4.4.3), a number of other reports have been published under the following headings: systematic reviews (section 4.4.2); detection of extra-thoracic metastases (section 4.4.4); changes in patient management resulting from the use of FDG-PET (section 4.4.5); and randomised clinical trials (RCTs) (section 4.4.6). 4-11 There is considerable overlap between the groups of studies dealing with mediastinal staging, detection of extra-thoracic metastases and changes in patient management. However, it appears worthwhile to describe separately the three types of outcome. 4.4.2 Systematic reviews Three systematic reviews which included meta-analyses of the diagnostic performance of FDG-PET for NSCLC were found in the literature search (Dwamena et al., 1999; Fischer et al., 2001 and Hellwig et al., 2001). These reviews all conclude that FDG-PET has higher sensitivity and specificity than CT for the staging of mediastinal lymph nodes. The reviews are discussed in detail in Appendix 8. Their conclusions were that: FDG-PET was both more sensitive and more specific than CT in lymph node staging; the quality of evidence available was generally low; and no evidence was available on patient outcomes. Two further review articles (Haberkorn, 2001; Vansteenkiste & Stroobants, 2001) containing narrative summaries of the available evidence were also identified. Haberkorn (2001) claims that FDG-PET scanning is likely to be of great value in the initial staging of NSCLC, in the planning of therapy and in monitoring response to that therapy. In the area of staging, he suggests that a chest X-ray should be followed immediately by a PET scan, with CT scanning used only if the FDG-PET scan is positive. Haberkorn (2001) also claims that FDG-PET scanning is valuable in the staging of breast and colorectal cancers, and in detecting recurrent disease in these tumours. He concludes that the most important task for the future is to develop diagnostic algorithms to allow optimal therapy on the basis of FDG-PET and other imaging tools. The review of Vansteenskiste & Stroobants (2001) concentrates on NSCLC, and covers a wide variety of topics within this area. Specifically, they argue that: since FDG-PET has a high sensitivity for N2/N3 disease, a negative scan will exclude the need for mediastinoscopy. However, they also argue that mediastinoscopy is appropriate following a positive FDG-PET scan. They state that in their experience this strategy reduces the number of mediastinoscopies by 50%; there is as yet insufficient data to be sure of the value of FDG-PET in detecting distant metastatic disease; FDG-PET may have a useful role in combination with CT in planning radiotherapy; in a pilot study (Vansteenkiste et al., 1998a) PET appeared valuable in selecting patients whose mediastinal (N2) disease had been successfully treated by induction chemotherapy. They state that a larger study is in progress to confirm these results, and that if successful this may allow appropriate selection of candidates for radical surgery after induction chemotherapy; and they conclude by stating that the value of FDG-PET in NSCLC requires validation by large-scale randomised studies, focusing on outcome parameters (survival, quality of life and cost effectiveness). 4-12 4.4.3 Mediastinal staging The HTBS literature search identified a total of 33 papers reporting studies of mediastinal staging. Brief details of the study designs are shown in Appendix 9. The results of these studies are summarised in a series of meta-analyses which are presented in section 4.5. A number of methodological flaws and problems affect the majority of these studies, and make it difficult to draw conclusions about the accuracy of FDG-PET from any meta-analysis or overview. Specific problems identified include: many of the studies are retrospective case series; the ‘gold standard’ for mediastinal disease is (except for one paper) nodal dissection or sampling, but the dissection/sampling protocols vary between papers and are not clearly described in some of them; some of the studies considered ‘all patients referred for PET scanning’. It is unclear whether such patients are representative of the general population of (early stage) NSCLC patients; many of the studies are based on quite small groups (12 of the 33 studies contain fewer than 50 ‘evaluable’ patients); and methods of interpreting PET images differ between studies, with the majority using some form of visual assessment and a small number using SURs, either alone or as an aid to interpretation. Studies relying on visual interpretation varied in the number of readers (between one and three). In general, no assessment of inter-observer variation was presented. Three further points relate to the utility of these studies in informing the economic model. First, only studies reporting results for differentiation of N2/N3 disease from N0/N1 disease are useful in determining accuracy in pre-surgical staging; secondly only studies which allow the three-way cross-tabulation of PET results, CT results and ‘surgical truth’ are useful here because of the structure of the economic model used (section 5.2.4). Finally and more generally, although the study authors have generally been careful to report that PET scans were read independently of clinical data, they are generally less clear in reporting whether PET scans were read independently of the CT images. In fact, since in clinical use these tools would likely be used together, it would be appropriate, if possible, to confine analysis to studies in which they were read together. Unfortunately it is not, generally, possible to decide whether specific studies meet this condition. The authors of some papers acknowledge these problems, but regard these issues as simply part of the problems of clinical studies. From another perspective, of course, they are simply part of the strong argument for basing decisions on RCTs whenever possible. When evaluating papers for clinical effectiveness, it was clear that two distinct approaches are taken to interpretation of the PET scan results; the majority involve ‘visual interpretation’ by one or more experienced people (in some studies this involved the grading of regions of increased uptake on a (subjective) 5 point scale 4-13 (1 = minimal uptake, 2 = lower than mediastinal blood pool, 3 = same intensity as mediastinal blood pool, 4 = greater intensity than mediastinal blood pool, 5 = much greater intensity than mediastinal blood pool) with 4 or 5 read as malignant, in others a simple binary decision was taken). The others calculate standardised uptake values (SUV) and assign as malignant any region with an SUV exceeding some cut-off value. Vansteenkiste et al. (1998b) report that for an appropriate choice of cut-off they obtain very similar results with visual and SUV- based approaches. For further discussion of standardised uptake ratios (SURs), see section 4.4.5.2. Additionally, all the reported prospective series excluded patients with ‘obvious bulky mediastinal disease’. The papers reporting retrospective series do not state whether such exclusions were performed, but it seems unlikely that such patients would have been referred for PET scanning. In summary, the majority of these studies report that FDG-PET is both more specific and more sensitive than CT imaging, but a number of methodological flaws were evident in the studies. None of them report any form of randomised comparison between the methods. 4.4.4 Detection of distant metastases Nineteen studies provide some data on the usefulness of FDG-PET scanning in detecting distant (extra-thoracic) metastases. Details of these studies are given in Appendix 10 and Appendix 11. Appendix 12 presents numerical data on the incidence of ‘unexpected’ (i.e. not conventionally detected) metastases found by FDG-PET. Some studies used nonoptimal sodium iodide (NaI) detectors (those shown in normal font in Appendices 10, 11 and 12). Despite this, these studies generally show good agreement to studies with the optimal detectors, concluding that between 10 and 20% more distant metastases are detected by FDG-PET imaging than by other techniques. In general, these studies have similar limitations to those noted in section 4.4.3. Additionally: inclusion criteria differed between studies (Appendix 10). For example some studies (e.g. Changlai et al., 2001; Bury et al., 1997 and Valk et al., 1995) included all patients referred for FDG-PET scanning with suspected or proven NSCLC, whereas other studies (e.g. MacManus et al., 2001a; Weder et al., 1998 and Lewis et al., 1994) explicitly included only patients thought suitable for radical therapy on the basis of clinical investigation; and FDG-PET results are generally compared with those obtained using ‘standard’ methods, but the standard varies between studies and is not tightly defined. In summary, although there is evidence that FDG-PET may be useful in supplementing conventional staging in patients without clinical evidence of distant metastases, there is again a need for well-controlled trials to demonstrate conclusively the value of the tool in this setting. 4-14 4.4.4.1 Specific sites of metastasis Three papers deal in more detail with the application of FDG-PET scanning to detect metastases at specific sites. Erasmus et al. (1997) and Gupta et al. (2001a) examined the accuracy of FDG-PET scanning relative to CT scanning in assessing adrenal masses. Erasmus et al. (1997) examined the results of FDG-PET scanning 33 adrenal masses found on CT scan. On biopsy, 23/33 (70%) were found to be cancerous, hence 10 were falsely positive on CT scan. FDG-PET scans were positive for all 23 of the cancerous lesions, and negative for 8/10 (80%) non-cancerous lesions. Gupta et al. (2001a) examined 30 patients with adrenal abnormalities seen on either FDG-PET or CT scan. In 7/30 patients the adrenal mass was biopsied, the rest were followed over a minimum of one year using repeat CT scan, and assigned to be cancerous or otherwise on the basis of changes in lesion size and appearance over this period. Eighteen patients were found to have a cancerous lesion by these criteria. Five false-negative findings and four false-positive results occurred with CT, compared with one false positive and one false negative for FDG-PET. Bury et al. (1998) report a comparison of bone scintigraphy and FDG-PET scanning in 110 NSCLC patients. Areas that appeared positive on either scan were investigated by further radiography or biopsy. The diagnostic standard used was ‘considered by the clinician in charge to be positive’. Twenty-one areas of patients were found to have metastatic disease (note that to be ‘discovered’, an area had to be positive on at least one of bone scintigraphy or FDG-PET, therefore the true sensitivity of both methods cannot be determined from these data). Both FDG-PET and scintigraphy had true-positive rates of 19/21 (90%), however the false- positive rate for scintigraphy was 45/89 (51%), as against 2/89 (2%) for FDG-PET. Since this work was performed using a non-optimal NaI detector, it is possible that these results may understate the value of FDG-PET in detecting bony metastases. In summary, it appears that FDG-PET may have value in detecting or ruling out metastatic spread to the adrenals or bone, but that as Gupta et al. (2001a) conclude ‘these results require confirmation in larger prospective studies’. 4.4.5 Changes in patient management Many of the papers reviewed claims that PET scanning resulted in changes in patient management. majority of patients, the changes described involve moving from curative to palliative treatment, because PET detected previously unsuspected distant or regional metastatic spread. This result is somewhat exaggerated because many of the studies were specifically confined to patients believed to be candidates for curative surgery or RT (e.g. MacManus et al., 2001a; Kalff et al., 2001 and Lewis et al., 1994). Conversely, reports of changes in management from non-resectable to resectable tend to be sporadic notes in papers whose major focus is mediastinal staging, e.g. Changlai et al. (2001) report that 39/156 (25%) patients were moved from resectable to nonresectable as a result of PET scanning, whereas 22/156 (14%) became resectable after PET scanning. Similarly, Gupta et al. (1999) report that in 5/63 (8%) patients PET showed that distant metastases apparent on conventional images were negative for cancer. 4-15 Although interesting, these reports do not provide sufficient evidence of the value of PET for patient management, for the following reasons: in none of the studies was a randomised comparison performed between PET and conventional staging techniques, which would provide the clearest evidence of benefit; since the studies focused on patients referred for PET scanning, the referring physicians presumably anticipated that some changes would occur, and may have been using PET to confirm their ‘clinical suspicions’, thus overstating the likely effect of PET in unselected patients; and changes in management following PET scanning may be very dependent on local preferences, reimbursement policies, and experience with the technique. Again, the effect of such issues on the apparent difference between PET results and ‘conventional’ results may best be controlled in a randomised trial. MacManus et al. (2001a, 2001b) have undertaken a prospective study in patients with nonresectable NSCLC who were potential candidates for radical chemoradiation. This shows that PET may have the potential to improve the selection of patients for radical chemoradiation, but that there is no evidence to show that this improves patient survival or quality of life. A full appraisal of this study is presented in Appendix 13. 4.4.5.1 Surveys of referring physicians Two further papers, McCain et al. (2000) and Tucker et al. (2001) report the results of surveys of referring physicians’ views on the usefulness of PET in patient management. McCain et al. (2000) carried out two surveys, one covering all physicians who referred patients with known or suspected thoracic malignancies to the Wake Forest University Baptist Medical Center Comprehensive Cancer Center for PET scanning between April 1998 and February 1999, asking them to indicate whether the scan results had influenced treatment decisions, and to rate the usefulness of PET scans in management on a five-point scale (with 1 being not at all useful and 5 being extremely useful). Of 126 questionnaires, 98 were returned. The respondents rated PET’s usefulness in management of 4.28 (s.d. 0.74), and in 64 cases PET was said to have influenced treatment. The authors also sent questionnaires to 488 chest clinicians across the US, asking whether PET was available to them, if so to rate its usefulness, and if not whether they would like to have it available. Only 129 responses were received, of which 51 were from physicians with access to PET. The average rating from this group was 2.77. The authors conclude that it is important for future uses of PET to define more closely the subgroups of patients in whom it is genuinely valuable (they believe this to explain the discrepancy between Wake Forest and national findings). Tucker et al. (2001) attempted to assess the value of PET in clinical care in the first year of use at a centre in Honolulu. They also undertook two surveys, the first covering all referring physicians, the second restricted to two physicians (a pneumonologist and a surgical oncologist) who referred most frequently. In the first survey they received 464 responses from 517 mailed questionnaires (they mailed one questionnaire per patient, so it is not clear how many physicians replied). Forty percent of the cases covered were of lung cancer, 18% head and neck and 11% 4-16 colorectal. Two hundred and eight responses (45%) stated that the PET scan had changed patient management, 204 (44%) that it had ‘decision making value’ and 51 (11%) that it had no value. The second survey covered a total of 53 cases, 43 of them lung cancer. In 70% of cases ‘therapy was affected’ (in 20 cases surgery was cancelled, in 11 cases surgery was undertaken despite having been thought futile before the PET scan). No data were available on the outcomes of these patients. Although these two surveys provide an interesting picture of the use of PET in two US centres, they clearly do not provide convincing evidence that the advantages perceived by the respondents are real, nor that they would be realised in other clinical settings. 4.4.5.2 Prognostic significance of SUR Ahuja et al. (1998) reported on the prognostic significance of SUR in NSCLC. They considered a series of 149 patients who had both a PET scan and pathologically confirmed diagnosis of NSCLC, with the scan and diagnosis no more than eight weeks apart. Sixty-nine patients were stage I/II, 55 stage III and 31 stage IV. The patients were followed up using institutional tumour registry data (median follow up 21 months). The authors assessed the association of SUR for the primary lesions by choosing a cut-off value (they state that the log rank test was used to determine a statistically significant cut-off) of 10. Presumably this was found as the value yielding the most significant difference between the two groups. They state that, in this database, an SUR value greater than 10 remained a significant predictor of survival in a proportional hazards model even after adjustment for lesion size and stage. They go on to suggest that SUR could be used as a prognostic tool, for example to select patients for post-operative chemotherapy. However, the authors make no attempt to replicate their results on independent data, and since it is well known that the test procedure they appear to have used is likely to inflate the apparent significance of an effect, such replication should precede any clinical application of the approach. One further study (Vansteenkiste et al., 1999) relates prognosis to SUR value, unfortunately using a different cut-off value (7). However, the results of these two studies do indeed suggest that the SUR value may be of prognostic significance. 4.4.6 Randomised clinical trials There are two randomised trials of the use of FDG-PET imaging in NSCLC. The first of these (van Tinteren et al., 2000) has recently been reported in The Lancet (van Tinteren et al., 2002). One hundred and eighty-eight NSCLC patients who were medically fit for operation and apparently clinically resectable were randomised between a conventional work-up (CWU), based on current guidelines (e.g. National Comprehensive Cancer Network (Ettinger et al., 1996)) and to conventional work-up plus FDG-PET to detect locoregional or distant metastasis. Ninety-six patients were 4-17 randomised to CWU alone and 92 to CWU + PET, of whom 90 actually underwent a scan. Pre-treatment characteristics and work-up procedures were similar between the two groups; 70% of patients in each group had clinical stage I/II disease. Work-up for all patients included a chest CT scan, and 58% of patients (very similar between groups) had at least one test to identify distant metastatic disease. The primary outcome was the number of ‘futile’ thoracotomies performed, i.e. the number of thoracotomies found to be definitely non-curative at operation. The difference in futile thoracotomy rates between the CWU group (39/96) and CWU + PET group (19/92) was significant, with p=0.003 (Chi-squared test). Additionally, the reduction in futile surgery was relatively independent of clinical stage (31/68 versus 16/64 in stage I/II and 8/28 versus 3/27 in stage III). The authors commented that positive FDG-PET results, which were not confirmed by biopsy or other imaging techniques, were not definitive for tumour and were ignored when the decision to operate was made. They also note that the need for such confirmation may impose additional costs and delays on the patient. Finally, they note that the design of their study allows the effect of FDG-PET scanning on final outcomes to be evaluated in a way that reflects the importance of the complete diagnostic profile. For example, one patient underwent surgery despite a negative scan result for the primary lesion, an action that was justified by the diagnosis of NSCLC. Such interactions between FDG-PET and other diagnostic tools are difficult to model (Kosuda et al., 2000). Boyer et al. (2001), currently reported only in abstract and American Society of Clinical Oncology (ASCO) conference slides, performed a similar study in Australia, in which 179 clinical stage I/II patients were randomised to conventional staging with or without FDG-PET. This study was designed to assess the ability of FDG-PET to reduce the rate of ‘futile’ thoracotomies by detecting distant metastatic disease in these apparently early stage patients. At the time of reporting 164 patients were evaluable, 80 in the conventional arm and 84 in the FDG-PET arm. The thoracotomy rate in the conventional arm was 98%, compared with that in the FDG-PET arm of 96% (no significant difference). The futile surgery rates are not quoted. The death rates in the two groups after 10- months median follow up were also extremely similar (16% versus 15%). As in van Tinteren et al. (2002), patient management was only affected by FDG-PET finding distant metastatic disease confirmed by other imaging or biopsy. However, in Boyer et al. (2001), the proportion of patients with distant metastases detected by FDG-PET was very small compared with other studies. There were three major differences between the two studies. First, Boyer et al. enrolled only patients who were at clinical stage I or II, whereas van Tinteren et al. enrolled stage I, II and III. Secondly, the surgical policy used in Boyer et al. indicated that patients with N2 disease should undergo thoracotomy, whereas operations on patients with N2 were viewed as ‘futile’ in van Tinteren et al. Finally, in van Tinteren et al. FDG-PET scanning was used to exclude benign lesions, whereas this was not done in Boyer et al. 4-18 It is likely that the apparent differences in results between the studies are explained, at least in part, by these three differences in design. First, five of the 20 ‘prevented’ thoracotomies in van Tinteren et al. (2002) were due to the detection of a benign primary lesion and secondly Boyer et al. (2001) note that FDG-PET scanning did detect N2 disease in 13 patients. Finally, in Boyer et al. (2001), the occurrence rate of (FDG-PET detectable) distant metastases was very low in the early stage group. Unfortunately neither randomised controlled trial collected quality-of-life data, arguing that the short-term psychological advantage of surgery, which the patient believed might be curative would ‘bias’ this comparison. However, such data would have been invaluable to inform the economic evaluation. 4.4.7 Limitations of the evidence As noted by DACEHTA (2001), although there is accumulating evidence that FDGPET scanning appears to be more sensitive and specific than CT scanning in mediastinal staging, and to be of value in detecting or investigating possible distant metastases, there are methodological weaknesses and problems with much of the published research. Most crucially, the majority of published work does not involve randomised trials, and is focused on diagnostic accuracy rather than patient outcomes such as surgery rates, survival and quality of life. The ‘unexpected’ results of Boyer et al. (2001) help illustrate why outcome-based RCTs are preferable tools for the evaluation of diagnostic techniques such as PET. First, by allowing the effect of PET scanning to be compared with genuinely standardised alternatives and by ensuring comparability of patient groups, they remove many potential sources of bias. Secondly, they allow the actual behaviour of patients and clinicians when confronted with the information provided by PET scanning to be studied, rather than relying on the assumptions underpinning model based approaches. 4.5 Meta-analyses Three meta-analyses have been performed, to estimate sensitivity and specificity for CT scanning overall, to estimate sensitivity and specificity of FDG-PET in CTnegatives and CT-positives. These analyses were undertaken to inform the economic evaluation (section 5). 4-19 4.5.1 Study exclusion criteria The following exclusion criteria were used to exclude trials from the meta-analysis: studies reporting only nodal-based results were excluded. Although the papers of Wahl et al. (1994); Patz et al. (1995) and Valk et al. (1995) were included in the Dietlein et al. (2000a) economic model and other systematic reviews, they have been excluded from this analysis because they are based on nodal results, rather than patient results; studies reporting results only for N0 versus N positive were excluded; studies which did not allow FDG-PET results to be determined for CT-negative and CT-positive patients separately were excluded from the analyses in sections 4.5.2 and 4.5.3; and four of the papers included (Chin et al., 1995; Vansteenkiste et al., 1998a; Vansteenkiste et al., 1998b and Vansteenkiste et al., 1997) used a different definition of enlarged lymph nodes from those in the remaining papers (1.5 cm versus 1 cm). The data from these papers have been retained in the main analyses, but are excluded in a sensitivity analysis. The studies selected are a subset of those displayed in Appendix 9 and are shown in Appendix 14. This latter table contains additional data extraction columns needed for the meta-analyses presented in sections 4.5.2 and 4.5.3. Professor P. Sharp, Chair of the TSG, reviewed all the selected studies for technical adequacy and concluded that all the studies, with the possible exception of Bury et al. (1996a) were technically adequate. Details are presented in Appendix 15. Since the results of the Bury et al. (1996a) study were similar to the remaining studies, it has been retained in the meta-analyses. 4.5.2 FDG-PET sensitivity in CT-negative patients The 15 papers included in the analysis of CT-negative patients are shown in Appendix 13. The paper of Liewald et al. (2000) is excluded from this analysis because it only reports data on CT-positive patients. The analysis was conducted as described in Appendix 6. The results of this analysis are as follow: Total number of patients = 547 Total number of studies = 15 Pooled specificity estimate 0.9, 95% Confidence Interval (0.87, 0.93). Estimated sensitivity at specificity 0.9 is 0.86, 95% Confidence Interval (0.79, 0.91). The estimated SROC is plotted in Figure 4-4. This is a fixed effects estimate because the between- study variance estimate was negative. There was no evidence of non-constant odds ratios (Appendix 7). 4-20 False positive versus true positive and fitted SROC curve, for CT-negative patients 0.0 0.2 0.4 True 0.6 0.8 1.0 Figure 4-4 0.0 0.2 0.4 0.6 0.8 1.0 False Corrected, with SROC 4.5.2.1 Sensitivity analysis The results obtained after removing the four papers that used a different threshold for defining enlarged lymph nodes (Chin et al., 1995; Vansteenkiste et al., 1998a; Vansteenkiste et al., 1998b and Vansteenkiste et al., 1997) were extremely similar Pooled specificity estimate 0.9, 95% Confidence Interval (0.86, 0.93). Estimated sensitivity at specificity 0.9 is 0.85, 95% Confidence Interval (0.77, 0.91). This is a fixed effects estimate because the between study variance estimate was negative. There was no evidence of non-constant odds ratios (Appendix 7). 4-21 4.5.3 PET sensitivity in CT-positive patients The data from 15 studies were available for the analysis of CT-positive patients. The details were essentially as in section 4.5.2, except that the paper of Liewald et al. (2000) could be included, and that of Farrell et al. (2000) was excluded, because these authors only considered CT-negative patients. Results from all studies: Total number of patients = 357 Total number of studies = 15 Pooled specificity estimate 0.76, 95% Confidence Interval (0.69, 0.82). Estimated sensitivity at specificity 0.76 is 0.92, 95% Confidence Interval (0.87, 0.95). The estimated SROC is plotted in Figure 4-5. This is a fixed effects estimate because the between- study variance estimate was negative. There was no evidence of non-constant odds ratios (Appendix 7). False positive versus true positive and fitted SROC curve, for CT-positive patients 0.0 0.2 0.4 True 0.6 0.8 1.0 Figure 4-5 0.0 0.2 0.4 0.6 0.8 1.0 False Corrected, with SROC 4-22 4.5.3.1 Sensitivity analysis Again, similar results were obtained when the four papers that used a different threshold for defining large lymph nodes were excluded. Pooled specificity estimate 0.75, 95% Confidence Interval (0.67, 0.82). Estimated sensitivity at specificity 0.75 is 0.92, 95% Confidence Interval (0.86, 0.96). This is a fixed effects estimate because the between- study variance estimate was negative. There was no evidence of non-constant odds ratios (Appendix 7). 4.5.4 CT sensitivity and specificity The data from 17 studies were available for the analysis of all patients (CT-positive and negative). All the studies shown in Appendix 14 were included, except the studies of Liewald et al. (2000) and Farrell et al. (2000). Additionally, data from the studies of Dunagan et al. (2001), Hagberg et al. (1997) and Steinert et al. (1997) were included, as they supplied patient-based data sufficient to calculate specificity and sensitivity for CT screening of mediastinal lymph nodes. The results of this analysis are as follow: Total number of patients = 863 Total number of studies = 17 Pooled specificity estimate 0.76, 95% Confidence Interval (0.70, 0.81). Estimated sensitivity at specificity 0.76 is 0.65, 95% Confidence Interval (0.61, 0.69). The estimated SROC is plotted in Figure 4-6. This is a random effects estimate. There was no evidence of non-constant odds ratios (Appendix 7). 4-23 False positive versus true positive and fitted SROC curve, for all CT data 0.0 0.2 0.4 True 0.6 0.8 1.0 Figure 4-6 0.0 0.2 0.4 0.6 0.8 1.0 False Corrected, with SROC 4.5.4.1 Sensitivity analysis A sensitivity analysis performed by removing the four studies reporting results with a different threshold for defining enlarged lymph nodes gave very similar results: Pooled specificity estimate 0.78, 95% Confidence Interval (0.71, 0.83). Estimated sensitivity at specificity 0.76 is 0.63, 95% Confidence Interval (0.59, 0.68). This is a random effects estimate. There was no evidence of non-constant odds ratios (Appendix 7). 4.5.5 Meta-analysis conclusions Although the plots suggest some inadequacy in the fit, there is no evidence that any available study level covariates are able to explain the observed heterogeneity, and the summaries appear to adequately reflect the observed sensitivity and specificity. Note that in the analysis of CT-negative patients (section 4.5.2), the range of false-positive rates is restricted, which may exaggerate the apparent lack of fit seen in Figure 4-4. Additionally, the two most outlying studies in this group Magnani et al. (1999) and Weng et al. (2000) both contribute very small numbers of patients (three and four, respectively) to this analysis. The results are essentially unaltered if they are removed. 4-24 Consequently, the meta-analyses of sensitivity and specificity demonstrate that FDGPET appears to discriminate diseased from non-diseased nodes, both for normal sized (section 4.5.2) and enlarged (section 4.5.3) mediastinal lymph nodes. Interestingly, the estimated sensitivity and specificity for FDG-PET in both CTnegative and CT-positive patients are very similar to those found by Dietlein et al. (2000a), despite the differences in both analysis methods (no account taken of the joint distribution of sensitivity and specificity) and study selection. 4.6 Assessment of safety in clinical practice Potential risks associated with PET imaging relate to the administration of the radiopharmaceutical and the dose of radiation delivered by the PET tracer, but this is relatively small. There is a very small risk of secondary cancers posed by the radiation dose used in PET scanning. One FDG-PET scan delivers a radiation dose of 7 mSv, which is similar to that associated with CT and according to the National Radiological Protection Board (1998a) corresponds to a lifetime cancer risk of less than 1 in 3000 for a person of normal life expectancy. Silberstein (1998) states that there were no reported adverse events from 80 000 PET scans undertaken in 22 US PET centres. No adverse events related to FDG-PET scanning were reported in any of the studies reviewed for this HTA. Also, a systematic review of PET in all cancers (Reske & Kotzerke, 2001), evaluating 533 papers in detail, did not identify any radiopharmaceutical-related complications or adverse events. Therefore, it is reasonable to conclude that PET scanning is essentially free from short-term adverse effects, as the data are incompatible with anything except an extremely low rate of adverse effects. 4.7 Conclusions FDG-PET imaging appears to produce superior specificity and sensitivity compared with CT scanning in staging mediastinal lymph node involvement in potentially operable NSCLC patients. However, it is notable that in CT-positive patients (with enlarged nodes), the pooled estimate of specificity of FDG-PET is only 0.76, CI (0.69, 0.82), so for one in four of these patients the test result will be a false positive, e.g. indicating that they have distant metastases, when they do not. For CT-negative patients the specificity of FDG-PET is much higher 0.9, CI (0.87, 0.93) and in fact the confidence intervals for CT-negative and CT-positive patients do not overlap. It also appears to be more accurate for the assessment of some distant sites of metastatic disease (specifically, evidence exists for adrenal glands and bone metastases). In both cases the available evidence consists of data from generally rather small, nonrandomised studies, many of which focus on selected patient groups. However, the studies present a reasonably consistent picture and suggest an advantage for FDGPET over CT in these applications. 4-25 There is some evidence that the results of FDG-PET scanning can cause changes in patient management. In two studies patient management was changed in over 60% of patients (Kalff et al., 2001 and Kutlu et al., 2001), but both of these studies used sub– optimal PET technology. Other studies report such changes in between approximately 10% and 40% of patients. Only two studies employed a randomised, simultaneous comparison between patient management with and without FDG-PET (van Tinteren et al., 2000; Boyer et al., 2001). These two studies provide contradictory results, suggesting that the value of FDG-PET scanning, as measured by final patient outcomes, is dependent on the treatment decision-making protocol. In this case, the type of patients scanned, whether PET is used to detect benign primary lesions and what is considered a futile thoracotomy all have an important part to play. There remains a need for large well-controlled trials to demonstrate conclusively the benefits of FDG-PET in staging potentially operable NSCLC patients. Other possible applications of FDG-PET, such as determination of prognosis and assessment of treatment response lack a conclusive evidence base. The available evidence (Section 4.6) suggests that FDG-PET is essentially safe, i.e. essentially without clinically observable adverse events. 4-26 5 ECONOMIC EVALUATION - NSCLC Summary A number of possible strategies for the utilisation of FDG-PET based on diagnostic pathways used in Scotland for NSCLC have been explored. All but one focus on the use of FDG-PET following CT scanning. Economic evaluation of the introduction of FDG-PET involves estimating the change in resource use, impact on survival and changes in quality of life for the whole patient journey through each of the strategies to end of life or sustained cure. It has not proved possible to obtain reliable data for all parts of the model, particularly for utilities. However, model testing indicates that the model’s prediction of the number of operations avoided by the use of FDG-PET is similar to estimates from the van Tinteren et al. (2002). This gives some confidence in the model. The results from the model suggest that three strategies are not strongly differentiated by their average patient benefits and costs: strategy 1 of sending all patients to surgery, strategy 3 of mediastinoscopy with surgery for negatives and non-surgical treatment for positives, and strategy 7 of FDG-PET with surgery for negatives and mediastinoscopy for positives. In CT-positive patients, strategy 1 shows a worse patient outcome and slightly higher cost than strategy 3. In CT-negative patients, strategy 3 is more costly but slightly more effective than strategy 1, to give an incremental cost effectiveness ratio (ICER) of £18,589. This raises doubts as to whether the model is correctly valuing costs and utilities associated with surgery. Strategy 7 is the most costly of the three, with slightly higher patient benefits. The base case suggests that the additional benefits of strategy 7 are small relative to their higher costs in CT-positive patients (ICER £58,951). However, it appears more likely that strategy 7 is cost effective in CTnegative patients (ICER £10,475). Sensitivity analysis shows a lower accuracy of FDG-PET increases the ICER of moving from strategy 3 to strategy 7 in CT-positive patients, but has less impact in CT-negative patients. The ability of FDG-PET to detect distant metastases is uncertain. If this is similar to its accuracy in detecting enlarged nodes, the ICER of moving to strategy 7 in CT-positive patients is considerably improved. Strategies have been differentiated by cost. It has not been possible to differentiate patient life expectancies or utilities to the same degree. Modelling shows limited differences in aggregate patient benefits between strategies 1, 3 and 7. Small absolute changes to these aggregates would significantly affect the reported ICERs. Accurately addressing this requires clinical data as to FDG-PET accuracy in detecting metastases as well as enlarged nodes, and greater differentiation of life expectancies after treatment. Better patient utility data during and after treatment is also needed. Modelling conclusions should be confirmed through the collection of health services research data. 5-1 5.1 Literature search 5.1.1 Search strategy Searches were undertaken, in July 2001, as part of the scoping to help define the assessment question (see section 3.2). The NHS Economic Evaluation Database (NHS EED), the Health Economic Evaluations Database (HEED) and the websites of major health economics research centres were searched for economi c evaluations. In addition: the databases MEDLINE (Ovid), PreMEDLINE (Ovid) and Embase (Ovid) were searched. The search was split into three concepts: positron emission tomography, non-small cell lung cancer (NSCLC) and terms to identify economic evaluations. All relevant subject headings and free text terms were identified for each concept. The search was restricted to studies published from 1990 onwards. No language restrictions were applied; members of the TSG and experts were consulted to check for further economic evaluations; and the bibliographies of relevant studies were scanned for further evaluations. Further information about the search is presented in Appendix 5. 5.1.2 Criteria for inclusion and exclusion of studies The following exclusion criteria were applied when reviewing the economic literature search results: 1. review articles not containing data in the form of a model or study; 2. studies not carried out in a population that might be broadly relevant to Scotland (i.e. American or European); and 3. articles not written in English. 5.1.3 Data extraction The studies used in the economic modelling are described in Appendix 16. Critique of these studies appears in the development of the HTBS economics model in section 5.2.10. 5.2 Economic methods 5.2.1 Background Economic evaluation is the comparison of the costs and benefits of two or more courses of action or options. It involves the identification, measurement and valuation of resources used and benefits as seen from a stated perspective and over a stated time horizon. The results quantify the costs and benefits to allow comparisons with other uses of the resources. The most efficient option is the one that gives the greatest benefit from the resources. Economic evaluation has been applied extensively in health care and 'good practice' guidance is available, including guidance from HTBS (HTBS, 2002b). This economic evaluation was carried out with this guidance in mind and sought to create a model that clearly reflects the diagnosis and treatment of patients in NHSScotland. 5-2 For diagnostic technologies, Sassi et al. (1997) note that one of the main deficiencies of economic evaluations is a failure to consider how diagnostic information impacts on patient management and final outcomes. Commonly, evaluations implicitly assume that more accurate tests lead to health gain. Instead, they advocate a threestage process that includes: (i) assessing how the sensitivity and specificity of a technology varies across types of disease and patient; (ii) taking explicit account of the response of clinical decision-makers to further diagnostic information either by modelling the decision-making process or by observing the use of the technology in practice (studying the empirical relationship between information inputs and treatment outputs from the 'black box' of decision-making); and (iii) explicitly modelling the impact of change in management on final outcomes. In Section 4 of this report, the evidence available for these three components has been critically appraised and will be used as a basis for the economic modelling. 5.2.2 Objectives of the economic evaluation 1. To review the existing English-language literature on the economics of FDG-PET in staging NSCLC in order to assess the quality and relevance to the issue facing NHSScotland. 2. To use the selected literature as the basis for constructing a simple spreadsheet that models the flow of patients through different diagnostic and treatment strategies for NSCLC. 3. To use this model to estimate the costs and benefits of each strategy, and hence to estimate the net costs and benefits of introducing FDG-PET for this specific indication. 4. To assess whether the key economic results arrived at above would still hold under alternative plausible scenarios. 5.2.3 The potential for use of FDG-PET in NHSScotland The use of FDG-PET must be considered in the context of the diagnostic pathway and subsequent treatment management decisions used for patients with NSCLC in Scotland. A ‘standard pathway’ was identified following initial discussion with lung cancer experts in Scotland. This is outlined in section 4.2.2. However, further questioning of the detail of the pathway showed that there is variation across Scotland in the diagnostic procedures that are undertaken and subsequent management of patients (Appendix 17). This has led to the identification of five possible diagnostic strategies that are plausible for NSCLC in Scotland, four of which involve FDG-PET. 5.2.4 Model structure Most experts believe that CT would always be needed in the diagnostic pathway given the lack of anatomical detail provided by PET. Hence the economic modelling concentrates on strategies in which CT has been performed and patients are classified 5-3 as CT-positive (enlarged nodes) or CT-negative (normal nodes) then further investigations and treatment are undertaken. The five possible diagnostic strategies are compared with two options that will test the economic model at its limits, but which would not be used in clinical practice (strategies 1 and 2). Strategies after CT: 1. Send all patients for surgery without further testing. 2. Send all patients for non-surgical treatment (chemotherapy and/or RT) without further testing. 3. Investigate all patients by mediastinoscopy – if this is negative refer for surgery and if positive refer for non-surgical treatment. 4. Investigate all patients by mediastinoscopy – if this is negative send them for a FDG-PET scan (negative FDG-PET for surgery, positive FDG-PET for nonsurgical treatment) and if positive refer for non-surgical treatment. 5. Investigate all patients by FDG-PET scan – if this is negative refer for surgery, if this is positive refer for non-surgical treatment. 6. Investigate all patients by FDG-PET scan – if FDG-PET is negative refer for mediastinoscopy (and if this is negative then for surgery, if positive then for non-surgical treatment), if FDG-PET is positive refer for non-surgical treatment. 7. Investigate all patients by FDG-PET scan - if FDG-PET is negative refer for surgery. If FDG-PET is positive and distant metastases are indicated (N0/1 M1) refer for non-surgical treatment, otherwise refer for mediastinoscopy (negative for surgery, positive for non-surgical treatment). These options are presented schematically in Figure 5-1. Note that in Figure 5-1, ‘non-surgical treatment’, refers to chemotherapy and/or RT. In addition, a strategy of using FDG-PET before CT is considered in the sensitivity analysis (section 5.4). One expert noted that PET could be useful in decision- making for radical RT treatment (CHART). However, as discussed in section 4.4.5 there is insufficient evidence to determine long-term resource use and patient outcomes (Appendix 13) for this use of FDG-PET in this situation. Hence it has not been considered in this report, but this will clearly be an important area for consideration when more data accumulate. CT scanning is not a perfect test for regional disease but the division of patients into those with normal and enlarged lymph nodes does create ‘low-risk’ and ‘high-risk’ groups. Since these differ, each of the seven strategies was run for each group separately. 5-4 Figure 5-1 NSCLC diagnostic pathways after CT 1. All for surgery 2. All for non-surgical treatment –ve Surgery +ve Non-surgical treatment 3. Mediastinoscopy –ve –ve Surgery +ve Non-surgical treatment –ve Surgery +ve Non-surgical treatment PET 4. Mediastinoscopy +ve Non-surgical treatment –ve Surgery +ve Non-surgical treatment –ve Mediastinoscopy 5. FDG-PET 6 FDG-PET +ve Non-surgical treatment –ve Surgery 7. FDG-PET +ve (N0/1 M1) +ve (other) Non-surgical treatment –ve Surgery +ve Non-surgical treatment Mediastinoscopy +ve : positive –ve : negative ‘Non-surgical treatment’ – chemotherapy and/or radiotherapy. 5-5 On the basis of the seven strategies following CT, the economic model has been constructed as follows: an estimate made of the underlying (‘true’) staging distribution in the population who may be eligible for PET; sensitivity, specificity, mortality and cost estimated for each type of test; assumptions made about clinicians decision-making following staging results; conversion of these changes in management into health outcomes; and diagnostic strategies compared in terms of resource use and health gain. 5.2.5 Identification and measurement of the potential benefits and costs of FDGPET The economic issues surrounding the use of FDG-PET in the investigation of patients with NSCLC relate to the fact that FDG-PET can detect small but clinically significant metastases in the lymph nodes and in distant sites in the body. As a result it may: (i) increase the number of correct operations in those for whom it offers a potential cure (N0/1 M0) and reduce the number of missed operations within this group; (ii) avoid the resource cost of futile operations in patients for whom it does not offer a potential cure (N2/3 and M1 patients); (iii) avoid the mortality and morbidity associated with futile operations; (iv) by altering the number of futile operations, alter the number of ‘open and shut operations’ where N2/3 or M1 patients are operated upon, the futility of the operation realised during operation and patients referred on to appropriate palliation; (v) allow palliative treatment to be offered at an earlier stage of the disease when symptom control may be more effective in N2/3 and M1 patients who are not operated upon; (vi) allow more appropriate palliative care to be offered to N2/3 M1 patients who are not operated upon; and (vii) reduce the numbers of other diagnostic investigations. Offsetting these potential advantages might be factors such as: (i) the costs of setting up and running the PET scanner; (ii) changes to the number of correct operations among N0/1 M0 patients due to the specificity of PET and false positive results; (iii) additional costs of palliative treatment if patients are being referred at an earlier stage; (iv) additional side effects from a longer period of palliative treatment; and (v) loss of the hope which potentially curative surgery offers (even if this subsequently proves to have been false hope because the patient had advanced disease and the operation was futile). 5-6 Table 5-1 Comparison of estimates used in NSCLC economic models Variable Base case patient Prevalence of N2/N3 CT sensitivity for N2/N3 CT specificity for N2/N3 FDG-PET sensitivity FDG-PET specificity Mediastinoscopy: Specificity Sensitivity CT mortality PET mortality Biopsy mortality Mediastinoscopy mortality Surgery mortality Surgery morbidity Biopsy morbidity Mediastinoscopy morbidity (years) Gambhir et al. (1996) Otherwise healthy 64-year-old white man 31% Dietlein et al. (2000a) 62-year-old, ASA okay, bronchoscopy and thoracic CT already 30% 67% 60% 73% 77% 90% 91% CT-negative 76% CT-positive 89% CT-negative 97% CT-positive 81% CT-negative 74% CT-positive 95% CT-negative 96% CT-positive 76% 0.0025% 0% 0.3% 100% 78% 0 0 - - 0.5% 3% 1 month 2.5 days 3.7% 0.1 year - - 0.02 Life expectancy after surgery 7 years if ‘cure’ Life expectancy after palliation 1 year ‘unresectable’ Cost of thoracic CT Cost of thoracic FDG-PET Cost of biopsy Cost of mediastinoscopy Cost of surgery Non-surgical treatment Discount rate Scott et al. (1998) Otherwise healthy 64-year-old white man $700 (£467) $378 (£252) $1,200 (£800) $2,000 (£1,333) $3,000 (£2,000) $4,360 (£2,907) $30,000 (£20,000) $0 N/A $18,500 (£12,333) N0/1, M0 4.5 years N2/3, M0 1.8 years M1 0.5 years N0/1, M0 2.6 years (resectable) N2/3, M0 1.8 years M1 0.5 years 585 EURO (£364) 1,227 EURO (whole body) (£763) 1,138 EURO (£708) 11,656 EURO (£7,249) 11,378 EURO (£7,077) 5% 5-7 5.2.6 Constructing the economic model The Scottish economic model started with an assessment of the economic models of Gambhir et al. (1996), Scott et al. (1998) and Dietlein et al. (2000a). The key inputs to these economic models are presented in Table 5-1. The estimates used in the three models are broadly similar, apart from the cost of procedures, with FDG-PET ranging from £763-£1,333 and surgery ranging from £7,429-£20,000. As may be anticipated, the cheaper costs occur in the German study (Dietlein) and more expensive costs occur in the US study (Gambhir). These models all used cost-utility analysis with QALYs. QALYs are appropriate for this disease given the different morbidities associated with the different stages of the disease and with the associated treatments. However, caveats associated with the QALY calculations are discussed in section 5.2.9.2. Dietlein et al. (2000a) have constructed the most detailed model, with clear explanations of the source of the inputs to the model and the estimates of benefit that seem plausible for the Scottish situation. However, this study has some limitations: it does not consider all plausible options for the use of FDG-PET (as outlined in section 5.2.4); the simple approach taken of combining original data from the literature on the sensitivity and specificity of tests independently is inappropriate; and costs are taken from German national reimbursement rates and charges, and hence cannot be assumed to be representative of Scotland. Despite the limitations, the Dietlein model is still useful to confirm the main costs and benefits associated with NSCLC, to give an outline for an economic model structure that is appropriate Scotland, and to provide a basis for some of the data inputs. 5.2.7 Methods of analysis The impact of FDG-PET is analysed by a cost-utility analyses, which sets out the resource use and calculates the number of QALYs from the effect on survival and the changes in quality of life for each strategy. Sensitivity analyses were performed to make allowance for the uncertainty in inputs to the model. This involves varying the data inputs in the base case to assess the impact on the results, indicating which of the data inputs contribute most to the main findings of the economic evaluation. 5.2.7.1 Delays in diagnosis and treatment The number of investigations was assumed not to delay treatment or to alter the patient’s prognosis (except through changes to staging). 5.2.8 Perspective and horizon HTBS guidance (HTBS, 2002b) indicates that a HTA is undertaken from a full societal perspective considering social and ethical issues alongside the issues of the clinical and cost effectiveness of the health technology. However, it is recognised that 5-8 in the economic evaluation it may not be possible to quantify all the consequences and resources associated with such a wide perspective. Consequently, for the base case, the economic evaluation should assess changes from the stance of NHSScotland, patients, families and carers, with quantification of other costs and consequences as far as possible. It also states that the time horizon should be sufficient for the main health outcomes and resource uses to be explored, with any use of extrapolation fully explained. In this analysis, only NHS costs relating to NSCLC management were included, as this would cover the key costs given the short life expectancy and intensity of treatment received by these patients. Similarly, the time horizon is assumed to be the lifetime of the patient. 5.2.9 Model inputs The inputs for the HTBS economic model for Scotland are summarised in Table 5-2, with a more detailed explanation of their source in the following sections. Table 5-2 Inputs to the HTBS economic model: base case Variable Base case patient Prevalence of N2/N3 True staging distribution FDG-PET sensitivity FDG-PET specificity Mediastinoscopy: Specificity Sensitivity CT and PET mortality Mediastinoscopy mortality Surgery mortality Life expectancy (LE) after surgery LE after palliation Utilities to reflect health-related quality of life Cost of thoracic FDG-PET Cost of mediastinoscopy Cost of surgery Non-surgical treatment: Radical radiotherapy Chemotherapy Best supportive care Input / assumption 62-year-old fit for either surgery or non-surgical treatment (Dietlein et al., 2000a) 30% (Dietlein) See section 5.2.9.1 on ‘Epidemiology’ CT-negative 86% CT-positive 92% (Section 4.5) CT-negative 90% CT-positive 76% (Section 4.5) 100% (Dietlein) 72% (Dietlein) 0% (Dietlein) 0.5% (Dietlein) 3.7% (Dietlein) N0/1, M0 4.5 years N2/3, M0 1.8 years M1 0.5 years (Dietlein) N0/1, M0 2.6 years N2/3, M0 1.8 years M1 0.5 years (Dietlein) See section 5.2.9.2 on ‘Health-related quality of life’ £677 (HTBS calculation, see chapter 9) £375 (based on Scottish data on stay and cost) £3,419 (based on Scottish data on resource use and cost) £2,102 £4,003 £3,371 (HTBS Comment, 2001b and HTBS radiotherapy costs) 5-9 It is interesting to note that the Scottish costs for procedures are even cheaper than the German costs. This is discussed further in section 5.2.9.3.3. 5.2.9.1 Epidemiology It is necessary to determine which patient group is likely to be affected if FDG-PET were to be introduced. The base-case analysis assumes the patient is a 62-year- old man with no co-morbidities of relevance to operative risk or prognosis. Ideally, the economic evaluation would be carried out with knowledge of the true staging distribution of the patients. Data from three Scottish audits of patients with a diagnosis of lung cancer were identified (Gregor et al., 2001; Kesson et al., 1998 and Fergusson et al., 1996) and help determine the epidemiological inputs to the model. Data from Gregor et al. (2001) suggest the distribution shown in Table 5-3. Table 5-3 Distribution of lung cancer All lung cancers1 Definite NSCLC2 Localised 33% 41% Regional spread 25% 28% Distant metastases 31% 25% Unknown 11% 6% 1 Excludes 9% of the original sample for which records could not be traced. 2 Excludes small cell lung cancer and 29% of patients who had no histology. It should be emphasised that this is not definitive because the data reflect imaging/staging practices in the mid-1990s. The study also showed that many patients were not fully investigated. If PET had been available and it had detected small foci of secondary disease, then the proportions would be more evenly allocated across the three stages listed. The other problem is that the audit applies to the whole cohort of lung cancer patients; it is not specific to the group who might be eligible for PET. For example, many patients with clear metastatic disease will have been excluded as will those obviously unfit for major surgery. To overcome this, the model assumptions have been based on the model of Dietlein et al. (2000a). These are as follows: patients have a definite diagnosis of lung cancer and require staging; assume that patients have already had chest X-ray, bronchoscopy and CT; patients would be fit for surgery if this were indicated; 30% of patients have N2 or N3 disease; 10% have occult metastases that are only detected by PET; for N0/N1 disease, 23% have enlarged lymph nodes; and for N2/N3 disease, 60% have enlarged lymph nodes. The underlying staging distribution for the patients who might be candidates for PET can be determined from Table 5-4. This table shows the estimated proportion of patients at each stage of disease compared with CT scan results – either normal lymph nodes (CT-negative) or enlarged lymph nodes (CT-positive). 5-10 Table 5-4 Distribution of candidates for PET Normal lymph nodes Enlarged lymph nodes N0/1, M0 48.4 14.6 N0/1, M1 5.4 1.6 N2/3, M0 10.7 16.3 N2/3, M1 1.2 1.8 The assumptions from Dietlein et al. (2000a) are consistent with a rate of metastases at distant sites of 5% (M1 disease). Advice received during consultation was that the figure in UK clinical practice is likely to be nearer to 10%. To reflect this, the figures in the Table 5-4 were doubled for M1 disease in the base case and the figures for other stages were reduced on a pro rata basis. 5.2.9.2 Quality of life The data to reflect quality of life are effectively weights attached to the survival figures in Table 5-2. Taking one as being equivalent to full health and zero as a state that is as bad as being dead, other health states can be ranked and valued (including potential negative values) according to their inherent unpleasantness. There are no Scottish utility values for this disease, so literature estimates have been used. Three relevant studies were identified from the literature that calculated utilities. Berthelot et al. (2000) considered metastatic NSCLC and took values from 24 oncologists using a visual analogue scale. The following utilities were derived: best supportive care: utility 0.53 (survival 0.49 years); and chemotherapy: utility 0.52 to 0.65 depending on which regimen used (survival 0.76 – 1.06 years). Values in a paper by Marshall et al. (2001) were derived from Earle et al. (2000), but this source does not clearly identify who made the utility judgements, but it appears to be the authors themselves. These values are: local disease: utility 0.88; regional disease: utility 0.8; and distant metastases: utility 0.69. Table 5-5 sets out the utilities used in the base case. Major assumptions have had to be made in this step of the model. Firstly, utility values have had to be drawn from different and questionable sources for the current context. Secondly, while it has been possible to differentiate costs for different stages of treatment, it has not been possible similarly to differentiate utility values for different stages of treatment beyond that stated in Table 5-5. Little is known about the utilities in those sent for correct or for futile operations, or about the effect upon utility of RT, chemotherapy and other supportive care packages for the three distinct stages of disease. 5-11 Table 5-5 Stage of disease N0/N1, M0 Utilities assigned: base case Treatment Surgery Utility* 0.88 N2/N3, M0 Surgery 0.65 N0-3, M1 Surgery 0.65 N0/N1, M0 N2/N3, M0 N0-3, M1 Non-surgical treatment Non-surgical treatment Non-surgical treatment 0.65 0.65 0.65 Based on Earle’s figure for local disease Berthelot’s figure for advanced disease which responds to treatment Berthelot’s figure for advanced disease which responds to treatment Berthelot’s figure for advanced disease which responds to treatment Berthelot’s figure for advanced disease which responds to treatment Berthelot’s figure for advanced disease which responds to treatment *An additional adjustment was made to assume that the last month of survival before a lung cancer death would be 0.52 based on Berthelot’s figure for advanced disease that does not respond well to treatment. 5.2.9.3 Resource use The resource use of relevance for each strategy is as follows: FDG-PET scan; mediastinoscopy; surgery (resection of lung); follow up after potentially curative surgery; treatment of recurrence after potential cure; palliative treatment for advanced disease; and follow up after palliative treatment. All the costs stated here are at 2002/03 prices. 5.2.9.3.1 FDG-PET scan HTBS has calculated the cost of a FDG-PET scan in section 9.6 using a bottom-up approach. A complex PET scan (high resolution with attenuation correction) would cost around £677. The FDG-PET Centre at St. Thomas's Hospital, London also indicated their PET scan charges to other NHS trusts. This was £784 for a body scan (scan with no attenuation correction) and £873 for a complex scan. Although there is a difference in costs here, it is important to note that the cost per scan calculated by HTBS is modelled on a PET facility operating in Scotland. However, the difference between the estimated costs per scan will have little impact on the results presented here. 5.2.9.3.2 Mediastinoscopy The cost of mediastinoscopy was estimated on the basis that 50% were day cases and 50% required one night stay in hospital. The time in theatre is assumed to be 15 minutes (Professor J McKillop, Muirhead Professor of Medicine, University of Glasgow, Personal communication, 2001). It is feasible to carry out more procedures as a day case but patients often receive other investigations at the same time. However, this also means that not all of the costs are attributable to mediastinoscopy and the cost used is thus a slight overestimate. 5-12 From Scottish Health Service Costs (Common Services Agency, Information and Statistics Division, 2001), and indexing at 5% for 2002/03 prices, a surgical day case costs £393 and a night in hospital costs £357 (this includes £78 for theatre). It is thus assumed that the cost of a mediastinoscopy is £375. 5.2.9.3.3 Surgery The cost of surgery reflects several potential operations. The type of surgery depends on the site of the primary tumour. In some cases lobectomy is adequate but in the remainder a pneumonectomy is required. The cost of surgery was based on a median stay of eight days (Mr A Kirk, Consultant Cardiothoracic Surgeon, Western Infirmary, Glasgow, Personal communication, 2002). It is assumed that 5% of patients require Intensive Therapy Unit (ITU) admission and the remainder go to the High Dependence Unit (HDU) for one night. The Scottish Health Service Costs (Common Services Agency, Information and Statistics Division, 2001) show the average cost per case in a general surgical ward in a Scottish acute hospital to be £1697 with an average stay of five days. Indexing this at 5% for 2002/03 prices, this is £1782. This implies an average cost per day of £357. This includes allowances for medical staff time, nursing staff time, pharmacy, other health care workers (Allied Health Professions: AHPs), theatre time and laboratory costs as well as overheads. Thus a seven-day stay would cost as follows: Medical staff Nursing staff Pharmacy AHPs Other direct care Theatre Laboratory “Overheads” TOTAL £318 £669 £180 £124 £22 £623 £155 £765 £2,856 A stay of eight days involves seven days on the ward at £357 per day as above, plus one day in HDU at £835 for 95%, plus one night in ITU at £1312 for 5%. Note that the HDU cost is calculated as the average of general surgical ward and intensive care costs. In addition, it is assumed that after discharge the patient consults their GP (or practice nurse) four times at a cost of £15.30 per consultation. The cost including follow-up is thus £3,419. This estimated cost is much lower than that used by Dietlein et al. (2000a). The Dietlein et al. (2000a) figure for surgery includes an allowance for 12 days on a surgical ward, three days in intensive care, plus a special payment for the surgery carried out. By contrast, the Scottish figures would be seven days on a surgical ward, one day in intensive care and no special allowance for surgery (although it could be argued that theatre costs might be underestimated by this method). The German cost per day for general surgery is 321 euros and for intensive care 1218 euros. At an exchange rate of one euro equals 63.3 pence; this converts to £203 and £772 respectively. The Scottish figures are £357 and £1312. Therefore, the Dietlein et al. (2000a) figure is higher because of: 5-13 assumed longer hospital stay, especially in (i) (ii) (iii) intensive care; use of ITUs rather than HDUs as in Scotland; and a special remuneration allowance of 4350 euros (£2,754) for carrying out the procedure. This is partly offset by lower costs per day for ward and intensive care. Those correctly undergoing surgery (N0/1 M0) are assumed to incur only the cost of surgery of £3,419. While this figure does make an allowance for theatre time, this may be low for lung resection. Similarly, some correctly operated upon will relapse. Arriving at accurate average costs for these events has not proved possible, but they are addressed in the sensitivity analysis with the cost of surgery being increased by 50%, coupled with 50% of those correctly operated upon receiving Best Supportive Care (BSC) as described below. ‘Open and shut’ operations where enlarged lymph nodes (N2/3) or metastatic disease (M1) are revealed are assumed to be referred for non-surgical treatment as described below. Surgery is assumed to identify 10% of those with N2/3 disease, and an additional 1% with M1 disease. Those with N2/3 disease or M1 disease who are operated upon but not identified as such, i.e. futile operations that are not ‘open and shut’, are assumed to present again with advanced disease and be treated with chemotherapy as described below. 5.2.9.3.4 Non-surgical treatment (palliative treatment for advanced disease) The costs of non-surgical treatment are based on costs estimated in the recent HTBS comment on NICE guidance regarding the role of chemotherapy in advanced (stage III and IV) NSCLC (HTBS, 2001b). The lowest chemotherapy cost was £4,003 (£3,812 indexed at 5%) for cisplatin plus vinorelbine (VNB). The guidance also calculates BSC without chemotherapy to cost £3,371 (£3,210 indexed at 5%). In addition, radical RT costs for a course of 20 fractions have been calculated by HTBS at £2,102, through a bottom-up approach. Included is a provision for patient travel time, assuming that 63% of patients use public/own transport and 32% use the hospital transport service. Those identified as having N2/3 disease, including those identified as such during ‘open and shut’ operations, are assumed to be offered radical RT. The base case assumes that all accept radical RT, but that they subsequently also present for VNB. It is recognised that this is likely to overestimate the number that will receive radical RT. However, changing this to only 50% of those identified with N2/3 disease with the remainder only incurring VNB does not markedly affect average costs per patient. Those identified as having M1 disease, including those identified as such during ‘open and shut’ operations, are assumed to be offered VNB. The base case assumes that all accept. It is recognised that this is likely to overestimate the number that will accept chemotherapy. However, reducing this to only 50% of those identified as having M1 disease with the remainder only incurring BSC again does not markedly affect average costs per patient. 5-14 For modelling purposes, further assumptions have to be made about the ability of PET to differentiate between N2/3 and M1 disease in N2/3 M1 patients. Sensitivities and specificities for PET have been calculated on the basis of detecting N2/3 disease. Consequently, the base case assumes that a positive PET scan for N2/3 M1 patients results in them being seen as and treated as N2/3 patients. The sensitivity analysis alters this assumption; a PET positive result for N2/3 M1 patients being seen and treated as having M1 disease. 5.2.9.3.5 Follow up after surgical treatment and palliative treatment Subsequent costs of follow up are assumed to be the same whatever the initial treatment, the NICE (2001a) guidance indicating a figure for terminal care of £1,408 (£1,341 indexed at 5%). These are assumed to be common to all treatment options, and have been omitted from the analysis. This may not be appropriate for major surgery as downstream support costs following discharge from hospital might not be insignificant. However, it has not been possible to quantify what the resource use for this might be. 5.2.10 Assumptions 5.2.10.1 Quality of life (QOL) loss from operations Some authors (e.g. Dietlein et al., 2000a; Gambhir et al., 1996) have hypothesised that patients suffer reduced QOL when they are undergoing tests or surgery, for example in terms of discomfort or anxiety. They make arbitrary reductions from life expectancy to reflect a QALY ‘penalty’ for the inherent unpleasantness of consuming health care. It was assumed that undergoing and surviving surgery involved a loss of 0.15 QALYs, but major uncertainty surrounds the appropriate value for this. Given the uncertainty surrounding the appropriate value for the QOL loss from operations, this is explored in the sensitivity analyses by setting the QOL loss for correct operations to zero and reducing it for futile operations to 0.1 QALYs. 5.2.10.2 Strategies for testing and treatment are followed As discussed in section 4, much of the empirical evidence on PET relates to its accuracy, with limited uncontrolled evidence on change in patient management. The model assumes that all involved in the management of the patient follow the strategy, without ordering any other tests. In fact, the RCTs were designed so that clinicians could not act on PET results without confirmation (van Tinteren et al., 2002; Boyer et al., 2001). 5.2.11 Discounting costs and benefits occurring in future years It is common practice in economic evaluations to allow for the timing of effects by assuming a positive rate of time preference. Thus, events occurring in the future have a lower weight when viewed from the present perspective. The HTBS economic guidance (HTBS, 2002b) recommends that costs should be discounted according to the UK Treasury discount rate (currently 6.0%) and health effects should be discounted using the time preference part of the Treasury discount rate (currently 1.5%). 5-15 Dietlein et al. (2000a) report undiscounted average life expectancies in summary form. These have been used as the basis for calculating patient benefits. It has not been possible to disaggregate these figures, with Dietlein’s reported averages being used as the basis for calculating patient benefits. Given the immediacy of progression through to death in those not successfully operated upon and the limited life expectancy of those correctly operated upon, it is felt that the effect of applying a 1.5% discount rate to benefits would be minor. The majority of treatment costs are incurred immediately or soon after diagnosis. Only ongoing and terminal care costs among those N0/1 M0 patients successfully operated upon are likely to be materially affected by discounting. Given the uncertainty surrounding post-operative follow up costs and the terminal care costs among N0/1 M0 patients who have successful operations, costs have not been discounted because this would have only a minor effect upon aggregated costs. 5.3 Results The model was constructed and run in an EXCEL spreadsheet for a representative cohort of 100 patients, 34.3% being CT-positive and 65.6% being CT-negative. To illustrate how the data inputs are used to derive costs and QALYs, an example of the calculation for one diagnostic strategy is shown in Appendix 18. The results of the base case evaluation are presented for CT-positive patients in Table 5-6. Within the cohort of 100, about a third of patients (34.3) were CT-positive, with 14.5 suitable for surgery (N0/1 M0) and the remaining 19.8 suitable for non surgical treatment, as described in Section 5.2.9.3.4. Table 5-6 Costs and benefits for CT-positive: base case 34.3 patients of which 14.5 are suitable for operation Strategy 1 Strategy 2 Strategy 3 Strategy 4 Strategy 5 Strategy 6 Strategy 7 Correct operations 14.55 0.00 14.48 11.00 11.06 11.00 14.53 Missed operations 0.00 14.55 0.07 3.55 3.49 3.55 0.02 Futile operations 19.77 0.00 6.67 0.53 1.58 0.53 6.24 Mean cost £5,747 £6,105 £5,573 £5,935 £6,051 £5,977 £6,004 Mean QALY 2.03 1.30 2.09 1.92 1.93 1.93 2.10 Mean life years 93.04 68.96 93.38 87.67 88.04 87.86 93.59 Strategy 1 sends all patients to surgery, while strategy 2 sends all to non-surgical treatment on an initial assumption of all being N2/3 M0. All other strategies involve further diagnostics, with only those not being indicated as having enlarged nodes or metastasis going to surgery. Strategy 3 uses mediastinoscopy, strategy 4 augmenting this with FDG-PET for those indicated as being suitable for surgery. The other strategies initially test patients with PET, with strategy 5 relying solely upon FDGPET. Strategy 6 sends those indicated as suitable for surgery for a confirmatory mediastinoscopy, while strategy 7 sends those indicated as unsuitable for operating upon for a confirmatory mediastinoscopy. 5-16 The simple strategies of sending all to surgery (strategy 1) or all to palliative care (strategy 2) have the obvious implications for the numbers of correct and incorrect operations undertaken. Strategies 4, 5 and 6 have the attraction of incurring around five fewer futile operations in CT-positive patients relative to strategies 3 and 7. However, this is at the expense of missing more than three patients who should have been operated upon. Strategies 3 and 7 are similar in terms of the number of correct operations and missed operations, though the number of futile operations avoided is slightly better for strategy 7. For CT-positive patients strategies 1, 3 and 7 have a higher mean QALY per patient and a higher mean life expectancy, but the mean cost per patient is similar among strategies. Consequently, the base case analysis suggests that strategies 1, 3 and 7 offer the greatest patient benefits, coupling these with a lower cost per patient. The results of the base-case evaluation are presented for CT-negative patients in Table 5-7. The remaining two-thirds of the cohort (65.6 patients) were CT-negative, with 48.4 suitable for surgery and the remaining 17.2 suitable for non-surgical treatment. Table 5-7 Costs and benefits for CT-negative: base case 65.6 patients of which 48.4 are suitable for operation Strategy 1 Strategy 2 Strategy 3 Strategy 4 Strategy 5 Strategy 6 Strategy 7 Correct operations 48.41 0.00 48.17 43.35 43.57 43.35 48.35 Missed operations 0.00 48.41 0.24 5.06 4.84 5.06 0.06 Futile operations 17.21 0.00 8.64 1.21 2.41 1.21 4.41 Mean cost £4,467 £6,105 £4,642 £5,137 £4,899 £5,124 £4,854 Mean QALY 2.88 1.46 2.89 2.76 2.77 2.76 2.91 Mean life years 3.53 2.26 3.52 3.39 3.41 3.40 3.53 As for CT-positive patients, the simple strategies of 1 and 2 have the obvious implications for the number of correct and incorrect operations. Similarly, strategies 4, 5 and 6 have the attraction of incurring fewer incorrect operations, avoiding between six and seven futile operations relative to strategy 3 but only between two and three operations relative to strategy 7. However, again, this is at the expense of missing around five patients who should have been operated upon. Strategies 3 and 7 remain similar in terms of the number of correct operations and missed operations, but for CT-negative patients the high specificity of PET (0.90) causes strategy 7 to avoid four futile operations relative to strategy 3. The above suggests that strategy 3 of sending patients for a mediastinoscopy and strategy 7 of sending patients for a PET scan with those apparently unsuitable for surgery being sent for a confirmatory mediastinoscopy are likely to offer the greatest patient benefits, though these are not strongly distinguished from strategy 1 in CTnegative patients. The principal distinction between strategies 3 and 7 and strategy 1 is the additional number of futile operations avoided. Strategies 2, 4, 5 and 6 appear to offer poorer patient outcomes than strategies 1, 3 or 7, and have higher average costs per patient, though strategy 4 is marginal less costly 5-17 than strategy 7 for CT-positive patients. However, the differences in terms of patient outcomes and costs are not especially large between patients, apart from strategy 2 of sending all to palliation which performs poorly. Table 5-8 and Table 5-9 give the incremental cost effectiveness ratios (ICERs). An ICER examines the additional cost that one strategy incurs compared with another, evaluating this against the additional patient benefits. The formal calculation of an ICER divides the difference in costs by the difference in patient benefits, to give the incremental cost per incremental QALY. Where a number of strategies are being compared, the ICERs are calculated using the following process: strategies are ranked in terms of cost from the least expensive to the most expensive; the least expensive strategy is compared with the next least expensive strategy. If the next least expensive strategy results in lower patient benefits this strategy is said to be ‘dominated’ as it requires additional expense but results in lower patient benefits. The dominated strategy is excluded from subsequent calculation of ICERs; the ICERs are calculated for each successive alternative, from the cheapest to the most expensive. If the ICER for a given strategy is higher than that of the next most effective strategy then this strategy is ruled out on the basis of ‘extended dominance’; and finally the ICERs are recalculated excluding all the strategies that are ruled out using the notions of dominance and extended dominance. Applying these principles strategies 1-7 are ranked in Table 5-8 and Table 5-9. Table 5-8 Strategy 3 Strategy 1 Strategy 4 Strategy 6 Strategy 7 Strategy 5 Strategy 2 Table 5-9 Strategy 1 Strategy 3 Strategy 7 Strategy 5 Strategy 6 Strategy 4 Strategy 2 Strategies ranked by cost for CT-positive Total cost Total QALYs £191,295 £197,247 £203,720 £205,157 £206,098 £207,690 £209,538 71.86 69.81 66.03 66.16 72.11 66.17 44.45 Additional cost £5,952 £12,425 £13,862 £14,803 £1,592 £3,440 Additional QALYs -2.05 -5.83 -5.71 0.25 -5.94 -27.66 ICER Dominated by 3 Dominated by 3 Dominated by 3 £58,951 Dominated by 7 Dominated by 7 Strategies ranked by cost for CT-negative Total cost Total QALYs £293,127 £304,628 £318,544 £321,492 £336,270 £337,116 £400,614 189.01 189.63 190.96 181.97 181.39 181.28 95.70 Additional cost £11,501 £13,916 £2,949 £17,727 £18,573 £82,071 Additional QALYs 0.62 1.33 -8.98 -9.57 -9.67 -95.26 ICER £18,589 £10,475 Dominated by 7 Dominated by 7 Dominated by 7 Dominated by 7 5-18 The results suggest that in CT-positive patients the current Scottish practice of mediastinoscopy prior to surgery (strategy 3) is superior to sending all for surgery, as would be anticipated given the relatively low proportion of CT-positive patients who should get surgery. Strategy 7 of sending all patients for a FDG-PET scan and sending FDG-PET positive patients for a confirmatory mediastinoscopy1 requires approximately £60,000 per additional QALY and thus is unlikely to be considered cost effective. The economic model indicates that among CT-negative patients the option of sending all for surgery cannot be ruled out on grounds of patient impact alone. It results in all who are suitable for surgery receiving a correct operation, but this is at the expense of roughly double the number of futile operations (17.21 or 26% of CT-negative patients) compared with strategy 3. However, Strategy 1 will not be used in clinical practice and is used here as a test of the economic model. This raises doubt as to whether the model is correctly valuing the costs and utilities associated with surgery. However, for CT-negative patients the results suggest that the current Scottish practice of mediastinoscopy is likely to be cost effective compared with sending all patients for surgery. Furthermore, it is even more cost effective to use FDG-PET as outlined in strategy 7, compared with strategy 3. This result appears to differ from that in CT-positive patients because a greater proportion of CT-negative patients are suitable for surgery and the specificity of FDG-PET is greater in CT-negative patients. The base case of the model strongly suggests that strategy 2 is dominated by other strategies. It also indicates that strategies 4, 5 and 6 are dominated, though this should be interpreted with some caution given the difficulties in assigning life expectancies and utility values, together with the other uncertainties surrounding the model. The differences between strategies in average QALY values are not large, though greater differentiation is reported between strategies in CT-positive patients than between strategies in CT-negative patients. However, relative to strategies 1, 3 and 7, strategies 4 to 6 perform poorly. They miss around 3 and 5 patients suitable for surgery in CTpositive and CT-negative patients respectively, which is only marginally less than their reduction in futile operations relative to strategies 3 and 7. Concentrating upon strategies 1, 3 and 7 the base case modelling suggests that: the principal potential benefit of FDG-PET scanning is to limit the number of futile operations carried out. Within CT-positive patients the specificity of FDGPET is relatively low at 0.76, compared with the specificity of mediastinoscopy of 1.00 for N2/3 disease. As a consequence, only around 1% of CT-positive patients would avoid futile operations if strategy 7 is employed instead of strategy 3. There is virtually no effect upon the number of missed operations among those suitable for surgery; within CT-negative patients, the specificity of FDG-PET is much better at 0.90. As a consequence around 6% of CT-negative patients would avoid futile operations if strategy 7 is employed instead of strategy 3. There may also be a small increase in the number of correct operations undertaken; the base case of surgery suggests that strategy 3 of sending all for mediastinoscopy is cost effective relative to strategy 1 of surgery for all patients; and FDG-PET only appears to be potentially cost effective in strategy 7. This is not clear cut in CT-positive patients. Given the higher proportion of these patients 5-19 who are not suitable for surgery, the current Scottish practice of sending all for mediastinoscopy cannot be ruled out given its 100% specificity for N2/3 disease. The findings of the ECRI report (ECRI, 1998) conclude that FDG-PET is cost effective when used to replace mediastinal biopsy (by mediastinoscopy or mediastinotomy) after a negative CT scan in patients with confirmed NSCLC who are candidates for resection. The set of strategies considered by ECRI involved using FDG-PET to replace direct mediastinal examination, rather than as an adjunct to mediastinoscopy, and so is not directly comparable with the results obtained here. ECRI took careful account of the post-surgery costs of treating lung cancer, the financial and morbidity costs of operative complications and of the costs of rebiopsy for technical failures. They also conducted a number of sensitivity analyses, taking account of the wide cost ranges presented for all the diagnostic tools, and including in the set of strategies one in which FDG-PET replaces CT completely. They conclude that their analysis is superior to previous work, because of the broader range of issues accounted for, and that the results are robust to plausible changes in input values. However, direct comparison of the ECRI findings with those of the model presented here would only be possible by rerunning their model with a strategy including the use of both mediastinoscopy and FDG-PET. The base-case results of the HTBS model suggest that FDG-PET is cost effective as a diagnostic test subsequent to patients being found to be CT negative, but that FDGPET should only replace mediastinoscopy if the FDG-PET scan result is negative. The model suggests those CT-negative patients who receive a positive result from a FDGPET scan should still be sent for a confirmatory mediastinoscopy given its 100% specificity for N2/3 disease. Among those patients found to be CT positive, the evidence that PET is cost effective is more muted than in the base case. 5.4 Diagnosis based on PET only The seven strategies considered so far in this chapter have all assumed that PET scanning would be performed following CT scanning. An alternative would be to use FDG-PET as soon as the diagnosis of NSCLC has been confirmed and the patient has been assessed for suitability for surgery. Therefore a further, potential patient pathway has PET coming first followed by CT to provide the additional anatomical detail necessary for treatment. This requires further modelling assumptions as to what happens to true FDG-PET negatives which are subsequently seen by CT to be positive, and false FDG-PET positives which are subsequently seen by CT to be negative. In the absence of evidence about the combined sensitivity and specificity of this combination of diagnostic tools, it has been assumed that the combined sensitivity and specificity is that of FDG-PET alone. As a consequence, the patient impact of the ‘all for FDG-PET’ strategy is the summation of the patient impact of strategy 5 in CT-enlarged and CT-normal patients. Similarly, the cost of strategy 5 is the same summation, minus the number of CT scans avoided. One CT scan would be avoided in each patient not undergoing surgery and undergoing palliation, as all palliation costs include an allowance for any CT scans necessary to them. (In this model, the cost of a CT is £97, calculated from the 5-20 Scottish Health Services Costs (Common Services Agency, Information and Statistics Division, 2001) with indexing at 5%.) This yields a total patient impact from the all for PET strategy of 248 QALYs (in 100 patients), coupled with a total cost of £525,183. The parallel figures for strategy 7 are 263 QALYs and £524,642. As a consequence, it appears that the all for PET strategy is dominated by strategy 7. 5.5 Model testing and savings in surgery The HTBS model was tested to see if it would predict the results of the van Tinteren et al. (2002) trial. In the control group of the Dutch trial, 78 of 96 patients (81%) had surgery compared with 60 of 92 in the PET group (65%). Sixty-six per cent of the control group had a mediastinoscopy whereas 25 patients went straight to surgery. In the PET group 73% had a mediastinoscopy. This suggests there was a mixture of the seven strategies of the HTBS model being used. To try to approximate this, the following was assumed: Control group: 66% of patients are following strategy 3 and 34% are following the ‘straight to surgery’ path. FDG-PET group: 73% are following strategy 6 (PET with mediastinoscopy for negatives and non-surgical treatment for positives) and 27% are sent for surgery after FDG-PET. The HTBS model predicts equivalent to 85 operations in the control group and 68 in the FDG-PET group. The difference is 17 operations per 100, whereas the Dutch trial showed a difference of 16 per 100. The conclusion drawn from this is that the HTBS model can adequately predict the number of operations avoided in a real clinical trial. While the exact impact upon patient quality of life of avoiding these futile operations is difficult to quantify, there is little controversy that such an effect exists. Patients would welcome the increased likelihood that if offered surgery this is likely to be the correct course of action for them as opposed to a false hope. At a time when skilled surgical time is in very short supply, freeing up resources by reducing the numbers of futile operations is also especially valuable. 5-21 5.6 Sensitivity analyses Published models for the use of FDG-PET scanning in NSCLC have been used and modified following extensive input from Scottish lung cancer experts. Despite this, there are major gaps in our knowledge about resource use and benefits at different stages in the disease process. These gaps have been filled by assumptions, some of which have been tested by one-way sensitivity analyses. Sensitivity analyses can be used to evaluate how conclusions arising from the economic model vary depending on assumptions. The results of some of the sensitivity analyses undertaken by HTBS are presented in Table 5-10 and Table 5-11, for the three most favourable strategies: 1, 3 and 7. These report the change in the absolute values, together with the percentage change in relation to the base case values. Table 5-10 Sensitivity analyses: CT-positive Mean cost Mean QALYs Base case Strategy 3 £5,573 2.09 Strategy 1 £5,747 2.03 Strategy 7 £6,004 2.10 FDG-PET accuracy: Lower CI bounds for sensitivity and specificity Strategy 3 £5,573 0.0% 2.09 0.0% Strategy 1 £5,747 0.0% 2.03 0.0% Strategy 7 £6,040 0.6% 2.10 -0.2% FDG-PET accuracy: Upper CI bounds for sensitivity and specificity Strategy 3 £5,573 0.0% 2.09 0.0% Strategy 1 £5,747 0.0% 2.03 0.0% Strategy 7 £5,980 -0.4% 2.10 0.1% FDG-PET accuracy: +ve in N2/3 M1 treated as M1 Strategy 3 £5,573 0.0% 2.09 0.0% Strategy 1 £5,747 0.0% 2.03 0.0% Strategy 7 £5,867 -2.3% 2.10 0.1% Open and shut: 50% of N2/3 surgery and 5% of M1 surgery Strategy 3 £5,692 2.1% 2.09 0.0% Strategy 7 £6,148 2.4% 2.10 0.0% Strategy 1 £6,175 7.5% 2.03 0.0% Surgery morbidity: Nil for N0/1 M0 surgery, others -0.1 QALY Strategy 3 £5,573 0.0% 2.16 3.4% Strategy 1 £5,747 0.0% 2.12 4.4% Strategy 7 £6,004 0.0% 2.17 3.3% Surgery costs: +50% and 50% of N0/1 M0 surgery require BSC Strategy 3 £7,311 31.2% 2.09 0.0% Strategy 7 £7,726 28.7% 2.10 0.0% Strategy 1 £8,144 41.7% 2.03 0.0% ICER Dominated by 3 £58,951 Dominated by 3 £153,948 Dominated by 3 £40,623 Dominated by 3 £30,881 £62,329 Dominated by 7 Dominated by 3 £62,116 £56,746 Dominated 5-22 Table 5-11 Sensitivity analyses results: CT-negative Mean cost Mean QALYs Base case Strategy 1 £4,467 2.88 Strategy 3 £4,642 2.89 Strategy 7 £4,854 2.91 FDG-PET accuracy: Lower CI bounds for sensitivity and specificity Strategy 1 £4,467 0.0% 2.88 0.0% Strategy 3 £4,642 0.0% 2.89 0.0% Strategy 7 £4,892 0.8% 2.91 -0.1% FDG-PET accuracy: Upper CI bounds for sensitivity and specificity Strategy 1 £4,467 0.0% 2.88 0.0% Strategy 3 £4,642 0.0% 2.89 0.0% Strategy 7 £4,827 -0.6% 2.91 0.1% FDG-PET accuracy: +ve PET scan in N2/3 M1 treated as M1 Strategy 1 £4,467 0.0% 2.88 0.0% Strategy 3 £4,642 0.0% 2.89 0.0% Strategy 7 £4,806 -1.0% 2.91 0.0% Open and shut: 50% of N2/3 surgery and 5% of M1 surgery Strategy 1 £4,613 3.3% 2.88 0.0% Strategy 3 £4,683 0.9% 2.89 0.0% Strategy 7 £4,903 1.0% 2.91 0.0% Surgery morbidity: Nil for N0/1 M0 surgery, others -0.1 QALY Strategy 1 £4,467 0.0% 3.00 4.1% Strategy 3 £4,642 0.0% 3.00 3.9% Strategy 7 £4,854 0.0% 3.02 3.8% Surgery costs: +50% and 50% of N0/1 M0 surgery require BSC Strategy 3 £7,313 57.5% 2.89 0.0% Strategy 1 £7,373 65.1% 2.88 0.0% Strategy 7 £7,424 53.0% 2.91 0.0% 5.6.1 ICER £18,589 £10,475 £18,589 £14,264 £18,589 £8,347 £18,589 £7,836 £7,400 £10,892 £67,353 £12,083 Dominated £5,502 Accuracy of PET scanning To explore the effects of the accuracy of FDG-PET scanning being lower than the central estimates for sensitivity and specificity as used in the base case, these can be replaced by the relevant lower bounds of the 95% confidence intervals as reported in the clinical effectiveness section. In addition to affecting the mean patient cost and QALYs of strategy 7 as shown in Table 5-10 and Table 5-11, this also impacts upon the numbers of operations, as shown below in Table 5-12. Table 5-12 also shows the impact if a positive PET scan result leads to N2/3 M1 patients avoiding mediastinoscopy and being referred to the appropriate palliative regimen. The main patient impact of the lower accuracy of FDG-PET in strategy 7 falls principally upon the increase in false negatives who are incorrectly sent for surgery. This is greatest among CT-positive patients with a little under one futile operation, or slightly over 2% of the CT-positive patient population. While the absolute increase in futile operations is around the same in CT-negative patients, this is only slightly over 1% of the CT-negative patient population. 5-23 Table 5-12 Sensitivity analyses: reduced accuracy of PET CT-positive Correct operations Base case Strategy 7 14.53 Lower CI bounds for sensitivity and specificity Strategy 7 14.53 -0.04% Upper CI bounds for sensitivity and specificity Strategy 7 14.54 0.03% Positive FDG-PET scan in N2/3 M1 treated as M1 Strategy 7 14.53 0.00% CT-negative Correct operations Base case Strategy 7 48.35 Lower CI bounds for sensitivity and specificity Strategy 7 48.34 -0.04% Upper CI bounds for sensitivity and specificity Strategy 7 48.37 0.03% Positive FDG-PET scan in N2/3 M1 treated as M1 Strategy 7 48.35 0.00% Incorrect operations 6.24 6.97 11.80% 5.79 -7.08% 5.77 -7.46% Incorrect operations 4.41 5.11 15.76% 4.00 -9.45% 4.11 -6.95% Note that there is also an impact from the increase in false positives, with more patients being sent for unnecessary mediastinoscopy. This increases costs slightly, with the attendant risk of a slight increase in deaths from mediastinoscopy. Given the limited differences in average patient QALYs between the strategies, these changes have a major effect upon the likely cost effectiveness of strategy 7. For CTpositive patients the ICER of moving from strategy 3 to strategy 7 roughly trebles to £153,948. The effect is more muted among CT-negative patients, but the ICER of moving from strategy 3 to strategy 7 still increases by around 40% to £14,264. Note that the effect of using the upper bounds of the confidence intervals for the accuracy of FDG-PET is not symmetric to using the lower bounds. The costeffectiveness ratios of moving from strategy 3 to strategy 7 are affected less, falling to £40,623 and £8,347 for CT-positive and CT-negative patients respectively. If the accuracy of PET in detecting metastases is similar to that for detecting N2/3 disease, this would greatly affect the number of patients in the N2/3 M1 group being treated appropriately under strategy 7. In the CT-positive group the prevalence of patients with N2/3 M1 disease is roughly treble that in the CT-negative group. As a consequence, greater differentiation of N2/3 disease into M0 and M1 disease by PET would have the greatest impact in the CT-positive group. The ICER would fall from £58,951 to £30,881 in the CT-positive group, and from £10,475 to 7,836 in the CTnegative group. 5.6.2 Increased surgical referral to non-surgical treatment The base-case analysis assumes that 10% of operations on N2/3 patients and 1% of operations in N0/1 M1 patients are ‘open and shut’ operations, these patients being referred to the relevant non-surgical intervention. If these percentages are increased to 50% and 5% respectively the average cost of treatment for CT-positive patients increases by around 2% for strategies 3 and 7, while the increase for strategy 1 is 5-24 greater at 7.5% as would be expected. Proportionately fewer CT-negative patients are affected by this, and the increases in costs are correspondingly lower, at around 1% for strategies 3 and 7, and 3.3% for strategy 1. Given the model structure, patient benefits are unaffected by this. As a consequence, the cost effectiveness of moving from strategy 3 to strategy 7 is reduced slightly among CT-positive patients, with strategy 1 remaining dominated. Among CTnegative patients strategy 1 remains the least costly, but the cost effectiveness of moving from strategy 1 to strategy 3 is markedly increased. 5.6.3 Reduced surgical morbidity The base case analysis assumes that all patients undergoing surgery incur a 0.15 QALY detriment. This detriment may be related to whether surgery is correct or futile. Removing this detriment from those correctly operated upon (N0/1 M0) and reducing it to 0.1 QALY for the remainder being operated upon increases the average QALY value for patients under all strategies. This affects patient morbidity in correct operations as no additional operative morbidity is applied, and reduces the morbidity associated with incorrect operations by 33%. Among CT-positive patients, these effects increase the patient benefits of strategy 1 more than for strategy 3, but this remains insufficient for strategy 1 not to be dominated by strategy 3. Strategy 3 is also less penalised for its greater number of incorrect operations, and the cost effectiveness of moving to strategy 7 reduced. Strategy 7 remains apparently cost effective among CT-negative patients assuming a reduced utility penalty of sending all for surgery. 5.6.4 Increased costs of surgery Surgical costs may be underestimates, as outlined in section 5.2.9.3.3. For those correctly operated upon the base case analysis also assumes a cure. Increasing the costs of surgery by 50% and allowing for 50% of those correctly operated upon requiring BSC naturally impact more upon the cost of strategy 1 than strategies 3 or 7, making strategy 1 increasingly less attractive. Given the proportionately greater numbers undergoing surgery in the CT-negative group under strategies 3 and 7 than in the CT-positive group, the cost effectiveness of moving from strategy 3 to strategy 7 is more affected for them, improving to £5,502 per incremental QALY. Since the strategies 1, 3 and 7 involve greater surgery their costs increase more than the costs of strategies involving more direct referrals to palliation, even though this palliation is often incorrect. However, this does not affect the cost effectiveness conclusions. For CT-positive patients, strategy 4 is the most attractive of the other strategies, but the cost-effectiveness of moving from it to strategy 3 is £1,655 cost per QALY. For CT-negative patients, strategy 5 is the most attractive of the other strategies, but the cost effectiveness of moving from it to strategy 3 is £1,190 cost per QALY. Note that this is the only sensitivity analysis under which strategies other the 1, 3 and 7 are not dominated. 5-25 5.6.5 Conclusions of sensitivity analyses The sensitivity analyses have focused upon the three strategies: the hypothetical strategy 1 of sending all to surgery; current Scottish practice being strategy 3 of sending all for mediastinoscopy, with mediastinoscopy negatives receiving surgery; and strategy 7 of sending all for FDG-PET, FDG-PET positives receiving a confirmatory mediastinoscopy with all negative results receiving surgery. For CT-positive patients, the base-case analysis suggested that strategy 7 was unlikely to be cost effective relative to strategy 3 (£58,951 per additional QALY). The cost effectiveness of strategy 7 reduces if the lower confidence intervals for the accuracy of FDG-PET are applied, though applying the upper confidence intervals causes the ICER to reduce to £40,623 per QALY. Assuming improved accuracy of FDG-PET in detecting M1 disease has the greatest effect upon this ICER. If FDG-PET is as accurate at detecting M1 disease as it is at detecting N2/3 disease the ICER of moving from strategy 3 to strategy 7 in CT-positive patients is £30,881 per QALY. For CT-negative patients, the costs of strategy 1 are affected if there are increased referrals from incorrect operations to radical RT. The effects of this are more muted for strategies 3 and 7, and strategy 1 appears less attractive. The opposite effect is observed from lower surgical morbidity. This increases the average patient quality of life for strategy 1 more than that of strategies 3 and 7. As a consequence, the cost effectiveness of strategy 3 is called into question. However, it should be noted that the impact of a reduced surgical morbidity upon the average patient quality of life of strategy 1 relative to strategy 3 is extremely small, and it is difficult to have confidence in this result. Within all the sensitivity analyses, it still appears likely that strategy 7 is cost effective compared with strategy 3 for CT-negative patients. 5-26 5.7 Discussion and conclusions of economic evaluation of NSCLC Seven different diagnostic and treatment strategies for the use of FDG-PET after CT in staging NSCLC have been compared in an economic evaluation, using estimates of benefits and resource use from Scotland wherever these were available. Three strategies appear to stand out in terms of either better patient impact, lower cost, or both: the hypothetical strategy 1 of sending all to surgery; used as a test of the model; strategy 3 of sending all for a mediastinoscopy, negatives being sent for surgery and positives to non-surgical interventions; and strategy 7 of sending all for FDG-PET, negatives being sent to surgery and positives for a confirmatory mediastinoscopy2, mediastinoscopy negatives being sent to surgery and positives to non-surgical interventions. The most reliable reported outcomes from the model relate to the number of correct operations, the number of missed operations and the number of futile operations under each strategy. On these grounds, among CT-positive patients in the base case, strategy 1 is unattractive as it incurs treble the number of futile operations (57% of CTpositive patients) compared with strategies 3 and 7, which have a very small increase in the number of correct operations. For patients who are CT-negative the number of futile operations in the base case for strategy 1 is still roughly double (26% of CT-negative patients) that of strategy 3, and this is coupled with only a slight increase in the number of correct operations. Strategy 3 is also differentiated from strategy 7 in CT-negative patients, due to the specificity of FDG-PET being much better than in CT-positive patients. In the base case, strategy 3 produces roughly double the number of futile operations and slightly fewer correct operations than strategy 7. None of the formal sensitivity analyses cause the number of correct, missed and futile operations to alter much in any of the strategies. As a consequence, it appears robust that the cost effectiveness of FDG-PET in CT-negative patients will be better than the cost effectiveness of PET in CT-positive patients. Similarly, it appears robust that the greater the accuracy of FDG-PET in differentiating N2/3 patients into those with M1 disease and those without, the more likely it is that FDG-PET will be cost effective. However, formal calculation of cost effectiveness and ICERs requires that costs be attached to treatments, with treatments conferring patient benefits in terms of both life expectancies and patient utilities. It has been possible to differentiate the costs of treatment into broad categories, though the follow-up costs of those correctly operated upon have not been modelled beyond a sensitivity analysis. The greater these followup costs are the less attractive is strategy 1, and the less attractive is strategy 7 relative to strategy 3 though this latter effect would be minor. It has not been possible to differentiate the life expectancies and the patient utilities that result from treatments to the same degree as treatment costs. The principal differentiation of patient impacts that have been modelled is the increased life expectancy from a correct operation, the higher patient utility after a correct operation and the patient utility detriment associated with undergoing an operation. When these are aggregated and compared across the different strategies, 5-27 differences in the lifetime utility accruing to those correctly undergoing surgery largely cancel out the differences in any utility detriment not being applied to those avoiding futile surgery. As a consequence, the differences in the total patient utilities under strategies 1, 3 and 7 are small. Items that would affect these totals would have a major impact upon ICERs. Such items clearly include the life expectancies from the different treatments and the patient utilities associated with these treatments. Some of the uncertainties associated with these inputs have been studied in the sensitivity analyses presented in Section 5.6, in particular, the utility penalty for surgery, the proportion of patients undergoing ‘open and shut’ surgery, the proportion of patients undergoing chemotherapy/RT after surgery and the cost of surgery. However, some important inputs cannot be addressed in this analysis. The model structure has been driven by the available data, and it has not been possible to differentiate life expectancies from the various treatments and patient utilities to the same degree as it has been for costs. The model would be improved: by better activity-based accounting; with better data on clinical outcomes, such as survival rates, by stage of disease and treatment; and using utilities elicited from patients or the general public. This could be achieved by targeted health services research in Scotland (or the UK). As these uncertainties remain largely unquantified it is unknown whether changes to the model inputs would make FDG-PET more or less cost effective. Concentrating upon the numbers of correct operations and futile operations in the correct model still suggests that ICER of FDG-PET in CT-negative patients is likely to be better than that in CT-positive patients. However, further research is needed to obtain the required evidence from pragmatic clinical settings. 5-28 6 CLINICAL EFFECTIVENESS – LYMPHOMA Summary A systematic review and critical appraisal of the literature was undertaken to determine the accuracy of FDG-PET in detecting possible residual disease following induction chemotherapy in patients with lymphoma (restaging lymphoma). Bayesian meta-analysis indicated that for post-induction chemotherapy in patients who showed residual masses on CT, the sensitivity of FDG-PET was 0.80, CI (0.59, 0.94), with a specificity of 0.89, CI (0.74, 0.97). Bayesian meta-analysis indicated that the sensitivity of FDG-PET to detect residual masses following induction chemotherapy (with no CT results) was 0.81, CI (0.63, 0.92), with a specificity of 0.95, CI (0.90, 0.99). Bayesian meta-analysis of CT scanning to detect residual masses following inducation therapy found a sensitivity of 0.75, CI (0.58, 0.88) and specificity of 0.45, CI (0.27, 0.64). Although the studies of accuracy in restaging lymphoma after induction therapy are generally retrospective and involve heterogeneous patient groups and variable followup times, FDG-PET is substantially more specific and somewhat more sensitive than CT for the detection of recurrent disease and is effective in discriminating active residual disease from non-viable tumour. 6-1 6.1 Introduction It has been proposed that FDG-PET may be useful in the initial staging of disease, the assessment of response to therapy (restaging), predicting the results of therapy early during treatment and monitoring for possible recurrence (Kostakoglu & Goldsmith, 2000). Following discussion with Scottish haematologists, it was decided that the assessment of FDG-PET in lymphoma should focus on its use in the assessment of response to therapy and, in particular, on the assessment of residual masses. A brief overview of the literature relating to other possible applications of FDG-PET scanning in lymphoma is presented in sections 6.3.1 to 6.3.4. Following critical appraisal of published literature meta-analyses of combined sensitivity and specificity have been undertaken. To allow direct input into the economic model in section 7, this has used the Bayesian methods of Rutter & Gatsonis (1995) implemented in WinBUGS 1.3 (http://www.mrcbsu.cam.ac.uk/bugs/welcome.shtml). Further details of the modelling methodology are presented in Appendix 19. 6.1.1 Literature search strategy A systematic literature search on the role of PET, and comparators, in the assessment of post-treatment residual mass was undertaken in March/April 2002. The following approaches were adopted: health technology assessments, systematic reviews and other evidence-based reports were identified, to establish the current evidence base; the databases MEDLINE (Ovid), PreMEDLINE (Ovid) and Embase (Ovid) were searched to identify primary studies. The search was split into three concepts: positron emission tomography, lymphoma and detection of residual mass with all relevant subject headings and free text terms identified for each concept. The databases were searched from their start date. No language restrictions were applied; attempts were made to identify additional RCTs and ongoing research, not indexed in MEDLINE or Embase, by searching sources such as the Cochrane Controlled Trials Register, Current Controlled Trials (mRCT) and the websites of professional organisations; members of the TSG and experts were consulted to check for completeness of the included studies and,in particular, to help identify unpublished (grey) literature and ongoing research; and the bibliographies of relevant studies were scanned for further studies. Further information about the search and a flow chart detailing the systematic literature selection process are presented in Appendix 5. 6-2 6.1.2 Exclusion criteria The following exclusion criteria were applied: studies using obsolete (NaI) detector technology, gamma camera PET or nonstandard technology; studies concerned solely with the accuracy of Gallium 67 scanning; and multiple studies found dealing with the same patients (only the most recent was included). 6.2 Lymphoma treatment in Scotland Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) together account for approximately 4% of incident cancers in the UK (Scottish Executive Health Department, 2001b). NHL is most common in older people, with a median age of onset of 65 years, while HD has a bimodal age distribution, which peaks at between 15 and 35 years and again at 65 years. The incidence of NHL has increased at approximately 4% per annum over the past two decades; the reason for this is unclear (Scottish Executive Health Department, 2001b). In Scotland, the five-year survival from HD is approximately 73% (compared with 86% in the US) and that from NHL is approximately 45%, which is slightly lower than the corresponding US figure (Scottish Executive Health Department , 2001b). Chemotherapy, alone or in combination with RT, forms the basis of treatment for HD and more aggressive forms of NHL. A wide variety of treatment regimens have been employed (Eghbali et al., 2000) with the joint objectives of maximising the cure rate and minimising the acute and longterm toxicity experienced by patients. Since both residual disease, after initial treatment, and recurrent disease may still be amenable to curative therapy, restaging of disease after initial treatment and monitoring for recurrence are important aspects of the management of HD and NHL. This part of the assessment focuses specifically on the role of FDG-PET scanning in lymphoma management and only treatment options considered in the economic evaluation will be described in detail. 6-3 6.3 Possible roles for FDG-PET imaging 6.3.1 Initial staging The results available from the use of FDG-PET (and other imaging tools) pose two substantial problems of interpretation. First, since biopsy confirmation of lesions is frequently impossible, the diagnostic accuracy can usually only be confirmed by follow up. It is not clear, however, what duration of follow up is appropriate, or how the confounding effects of treatment should be allowed for. Secondly, since systemic chemotherapy is the treatment of choice for many patients, it is unclear how valuable increased accuracy of staging is likely to be. However, Segall (2001) notes that FDGPET may be valuable in confirming or ruling out the possibility of administering radiation to patients whose disease appears confined to a small region. The reviews by Talbot et al. (2001) and Kostakoglu & Goldsmith (2000) suggest that FDG-PET has similar accuracy to CT in staging nodal involvement of lymphoma and may have superior sensitivity in detecting abdominal and central nervous system disease (e.g. Rodriguez, 1998; Hoffman et al., 1999). However, the majority of studies reported are retrospective and contain relatively small numbers of patients (all studies contained fewer than 100 patients). Coiffier (2001) comments that the small changes in staging seen in the studies are unlikely to cause significant changes in management, whereas Willkomm et al. (1998) concluded that FDG-PET resulted in the upstaging of a large number of patients and may thus have a significant impact on management. 6.3.2 FDG-PET imaging during therapy Jerusalem et al. (2000) and Romer et al. (1998) both show that the change in FDG uptake six weeks after the start of therapy is strongly correlated with the relapse- free interval after completion of therapy. In principle, this result could be used to allow the selection of patients to receive intensified therapy, or treatment with different drugs. However, such a trial has not yet been performed. 6.3.3 FDG-PET scanning for detection of recurrence According to Talbot et al. (2001), Bar-Shalom et al. (2001) and Kostakoglu & Goldsmith (2000), FDG-PET is more accurate than CT for detecting recurrent disease, especially in differentiating recurrent disease from residual scarring. However, the original studies on which this conclusion is based are rather small and, in common with the other imaging studies, are handicapped by the absence of a ‘gold standard’. Kostakoglu & Goldsmith (2000) argue however that, because of the sensitivity of FDG-PET demonstrated in primary staging, it should also be included in long-term follow-up strategies to detect recurrence. 6.3.4 FDG-PET in the post-treatment assessment of lymphoma The peer-reviewed reports of original work in this area are described in section 6.4. This section outlines the important issues and the qualitative conclusions proposed by previous reviews. 6-4 The detection and assessment of possible residual disease following first-line therapy is of considerable importance, because patients with active residual disease may be candidates for further therapy. A particular problem is posed by patients with residual masses evident on CT, which may occur in 60% of patients with mediastinal involvement at presentation (Israel et al., 1990). Bar-Shalom et al. (2001) and Talbot et al. (2001) both conclude that FDG-PET has significant value in discriminating between active disease and residual scarring/fibrosis in such patients. According to Bar-Shalom et al. (2001) PET appears to have similar accuracy to Gallium SPECT for these applications, and is, therefore, likely to be preferred on the grounds of convenience, both by patients and health care providers. The use of Gallium SPECT as a comparator has not been considered further in this report for the following reasons (Professor J McKillop, Muirhead Professor of Medicine, University of Glasgow and Professor PF Sharp, Chair of the TSG (Professor of Medical Physics, University of Aberdeen & Grampian Hospitals NHS Trust), Personal communication, 2002): SPECT with high dose Gallium 67 citrate (Ga-67) has been used in evaluation of lymphoma (King et al., 1994). It has proven to be successful in assessment of recurrence or residual disease after primary therapy in the mediastinum in patients whose pretreatment scan shows uptake. Gallium 67 SPECT does, however, suffer from shortcomings, which preclude its widespread use in lymphoma patients: the high-energy emissions of Ga-67 require a high-energy collimator. Many departments in Scotland do not have such a collimator and, more importantly, some SPECT cameras are unable to perform satisfactorily with such a heavy collimator; following injection of the tracer, the patient must be imaged 48 and/or 72 hours later. This necessitates multiple outpatient visits by the patient or admission for the duration of the study; a significant proportion of untreated lymphomas do not show Ga-67 uptake and thus a post-treatment study is of no value; and the large bowel excretes a substantial fraction of the injected Ga-67. This makes the evaluation of abdominal and pelvic lymph nodes very difficult. 6.4 Accuracy of FDG-PET for post-therapy restaging of patients who are CT-positive - studies Eight published studies were identified that addressed the accuracy of FDG-PET for restaging HD post induction therapy in patients who showed residual masses on CT scan. The paper by Maisey et al. (2000) was excluded because the scanner used was recognised to have substandard performance. The remaining studies are summarised here. The study characteristics are shown in Table 6-1 and accuracy data are displayed in Table 6-2. 6-5 Table 6-1 Study Dittmann et al. (2001) Mikhaeel et al. (2000a) Naumann et al. (2001) Study characteristics: FDG-PET accuracy in assessment of residual masses Number of patients 40 HD 24 evaluable, 16 had scans for recurrence 32 (15 HD, 17 NHL) 58 (43 HD, 15 NHL) Patient source Design Dose (MBq) Equipment Diagnostic standard 26 evaluations of residual masses I: 2 II: 12 III: 6 IV: 6 Retrospective 400 GE Advance Follow up (no median reported, minimum 6 months) 32 with residual masses 62 evaluations of residual masses I-II: 13 III–IV: 19 Retrospective 350 ECAT 951R I: II: III: IV: 1 23 12 22 Prospective 300-370 ECAT EXACT HR+ Follow up (median 38 months) Follow up (median 30 months) I: 1 II: 9 III: 7 IV: 2 Relapse: 11 I: 3 II: 15 III: 9 IV: 9 I: 7 II: 13 III: 5 IV: 9 Prospective 370 ECAT EXACT HR+ Follow up (median 28 months) Prospective 270 ECAT EXACT Follow up (median 28 months) Weihrauch et al. (2001) 28 HD patients 29 evaluations of residual masses Bangerter et al. (1999) 36 (14 HD, 22 NHL) 36 with residual masses de Wit et al. (1997) 34 (17 HD, 17 NHL) 31 evaluable, 3 received chemothr’ py post PET 37 HD 34 with residual masses de Wit et al. (2001) Patient characteristics 50 evaluations of residual masses Retrospective 250-400 ECAT EXACT 47 Follow up (median 62 weeks) Retrospective 250-400 ECAT EXACT 47 Follow up (median 25 months) 6-6 6.5 Accuracy of FDG-PET for post-therapy restaging in patients who are CT-positive - analysis Table 6-2 Study Dittmann et al. (2001) Mikhaeel et al. (2000a) Naumann et al. (2001) Weihrauch et al. (2001) Bangerter et al. (1999) de Wit et al. (1997) de Wit et al. (2001) Results: FDG-PET accuracy in assessment of residual masses PET evaluation Visual Visual (2 readers) Visual + SUV Visual Visual, read with clinical history Visual ‘part of daily routine’ Visual ‘part of daily routine’ PET independent of CT True positive – PET, residual mass True negative – PET, residual mass +ve -ve +ve -ve No 7 1 1 17 No 8 2 1 21 No 5 2 3 48 No 6 3 4 16 No 5 2 4 25 No 9 0 5 17 No 10 1 12 27 As with all imaging techniques, there are difficulties in interpretation because of the absence of a ‘gold standard’ and uncertainty as to the appropriate follow-up interval. Furthermore, it has been suggested (Bar-Shalom et al., 2001) that the accuracy of FDG-PET may vary with the pretreatment stage. However, there is no evidence for this from a between-study comparison but, with only five studies, such a test will be very weak. The meta-analysis indicates that for patients who have residual masses on CT, FDGPET has a sensitivity of 0.80, CI (0.59, 0.94) and specificity of 0.89, CI (0.74, 0.97), which suggests that FDG-PET may be valuable in distinguishing true residual disease post-therapy. 6.6 Accuracy of FDG-PET in post-therapy restaging (no CT) - studies FDG-PET may also be used to assess post-induction therapy response without using the results of a CT scan, this may be done by ignoring CT scan results that have been taken or in patients for whom no CT results are available. The review identified 10 published papers on this topic, three of which were excluded; two because a non-optimal scanner using NaI detection was used (Jerusalem et al., 2001 and Jerusalem et al., 1999b), and one because it recapitulated two other studies (Spaepen & Mortelmans, 2001). The remaining papers are combined using meta-analysis in section 6.7. The study characteristics are shown in Table 6-3 and accuracy data are displayed in Table 6-4. 6-7 Table 6-3 Study Mikhaeel et al. (2000b) Zinzani et al. (1999a) Spaepen et al. (2001a) Spaepen et al. (2001b) Study characteristics: PET accuracy post therapy Number of patients 49 High grade NHL – 45 with PET, 33 CT 44 with PET and CT (13 HD, 31 highgrade NHL) 60 HD with PET, 0 with CT 93 NHL with PET, 0 with CT Stumpe et al. (1998) 35 HD, 15 NHL Lang et al. (2001) 63 HD (47 evaluable for PET or CT) Cremerius et al. (2001) 56 (22 HD, 34 NHL) – 41 for PET, 36 for CT, 5 not evaluable Patient source Patient characteristics Design Dose (MBq) Equipment Diagnostic standard Post first therapy I-II: 30 III–IV: 19 Retrospective 350 Siemens CTI 951/31R Follow up (24 months) Post first therapy II: 20 III-IV: 24 Retrospective 444 ECAT Exact 47 Follow up (median 18 months) Post first therapy II: 25 III: 19 IV: 16 I: 8 II: 25 III: 24 IV: 36 No stage information Retrospective 150–555 ECAT 931 Retrospective 370–555 ECAT 931 Follow up (median 30 months) Follow up (median 23 months) Prospective 350 GE Advance Follow up (minimum 6 months) I: 1 II: 15 III: 10 IV: 14 Not done: 11 Retrospective 370 Exact 47 Follow up (median 22 months) I: 4 II: 24 III: 10 IV: 18 Retrospective 220 ECAT 935/15 Follow up (median 21 months) Post first therapy 54 post first therapy PET scans reported, 24 posttherapy CT scans 51 post first therapy, 4 received therapy after scanning, 12 received PET to determine recurrence 41 post first therapy, 15 received PET to determine recurrence 6-8 6.7 Accuracy of FDG-PET for post-therapy restaging (no CT) - analysis Table 6-4 Study Mikhaeel et al. (2000b) Zinzani et al. (1999a) Spaepen et al. (2001a) Spaepen et al. (2001b) Stumpe et al. (1998) Lang et al. (2001) Cremerius et al. (2001) Results: PET accuracy post therapy PET evaluation PET independent of CT True positive – PET, post therapy +ve -ve True negative – PET, post therapy +ve -ve True positive – CT, post therapy +ve -ve True negative – CT, post therapy +ve -ve Visual, 2 readers Yes 9 6 0 30 7 4 10 12 Visual, 2 readers Unclear 13 1 0 30 14 0 23 7 Visual, 2 readers Yes 5 5 0 50 Visual, 2 readers Yes 26 11 0 56 No 20 3 1 30 6 2 10 6 Yes 18 1 3 25 18 1 17 11 Yes 16 3 3 19 11 3 15 7 Visual, 2 readers Visual, 2 readers Visual, 2 readers Just as in the use of FDG-PET to evaluate residual masses, there are a number of difficulties with interpretation of the studies presented. These are: the length of follow-up is variable between studies; most of the studies present combined results for HD and NHL, although there is some (anecdotal) evidence of differences in accuracy between the two diseases; and the studies available are rather small and mostly retrospective. It should be noted, of course, that precisely the same criticisms can be made of studies of other imaging methods in this application area. The estimated sensitivity and specificity were 0.81, CI (0.63, 0.92) and 0.95 CI (0.90, 0.99), which are not essentially different from its performance when used only in CTpositive patients. There was no strong evidence that discrimination was related to the proportion of III-IV disease, but the analysis will have little power to detect such an effect. 6-9 6.8 Accuracy of CT scanning for post-therapy re-staging By way of comparison, and to inform the model discussed in section 7, a metaanalysis of studies detailing accuracy of CT scanning in assessing response to therapy was conducted. The additional studies used are shown in Table 6-5 and Table 6-6. Table 6-5 Study Devizzi et al. (1997) Smith et al. (1998) King et al. (1994) Setoain et al. (1997) Jerusalem et al. (1999a) Ha et al. (2000) Study characteristics: CT accuracy post therapy Number of patients 53 HD 47 with CT Patient source Post first therapy Patient characteristics I-IIA: 34 IIB–IV: 19 31 NHL 28 with follow-up and CT 33 HD all with CT Post first therapy Post first therapy 53 (37 HD, 16 NHL) 25 with CT 54 (19 HD, 35 NHL) all with CT (included only in CT analysis because of technically inadequate PET scanner) 79 HD all with CT Table 6-6 Diagnostic standard Follow up (median 42 months) Follow up (median not given) Design Dose Equipment Retrospective N/A N/A Not given Retrospective N/A N/A II: 12 III: 13 IV: 8 Retrospective N/A N/A Post first therapy Retrospective N/A N/A Post first therapy Prospective N/A N/A Follow up (median 21 months) Post first therapy Retrospective N/A N/A Follow up (median 12 months) Follow up (median 28 months) Follow up (median 12 months) Results: CT accuracy post therapy Study Devizzi et al. (1997) Smith et al. (1998) King et al. (1994) Setoain et al. (1997) Jerusalem et al. (1999a) Ha et al. (2000) PET evaluation PET independent of CT N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A True positive – CT, post therapy +ve 3 4 13 3 10 8 -ve 0 8 1 1 4 3 True negative – CT, post therapy +ve 24 0 14 4 14 55 -ve 20 16 5 17 26 13 6-10 6.9 Conclusions CT scanning has good sensitivity, 0.75, CI (0.58, 0.88), but poor specificity, 0.45, CI (0.27, 0.64) in detecting viable residual tumour in patients who have responded to initial induction therapy for lymphoma. FDG-PET scanning has high sensitivity, 0.80, CI (0.59, 0.94) but greater specificity, 0.89, CI (0.74, 0.97) in discriminating viable tumour from scar tissue when used in lymphoma patients who have positive CT scan results in this situation. FDG-PET scanning used alone, rather than as an adjunct to CT scanning, to detect residual tumour again has high sensitivity, 0.81, CI (0.63, 0.92) and specificity, 0.95, CI (0.90, 0.99). The majority of reported studies do not distinguish between results in HD and those in higher grade NHL; the accuracy results presented both for PET and CT therefore refer to patients with either of these forms of lymphoma. In addition, some of the studies include results from a small number of patients who were scanned on more than one occasion. Since these results may not be independent, it is possible that the metaanalysis may overestimate the accuracy of both FDG-PET and CT by a small amount. FDG-PET scanning therefore appears likely to be of substantial value in the assessment of lymphoma patients after induction therapy. Since the studies performed to date have been relatively small, it will be important to supplement them with systematic collection of the results from practical clinical experience. 6-11 7 ECONOMIC EVALUATION – RESTAGING HODGKIN’S DISEASE Summary An economic model has been used to assess the cost effectiveness of FDG-PET scanning as an adjunct to conventional imaging in deciding the further treatment of patients with HD who have achieved a partial or complete response to induction therapy. FDG-PET is more specific than CT in differentiating active residual disease and may therefore allow patients to avoid unnecessary radiotherapy (RT) and the associated mortality and morbidity. Five strategies were considered, in which patients were allocated to immediate consolidation RT or surveillance, based on the results of CT and FDG-PET imaging following induction therapy. Post-induction investigations and treatment included RT for relapse during surveillance, IVE (ifosfamide, etoposide and epirubicin) re-induction chemotherapy for relapse after RT, followed by high-dose chemotherapy (HDCT) with autologous peripheral stem cell or bone marrow support for responders. Non-responders received palliative therapy. A cost-effectiveness analysis used a Markov model to compare the different strategies in terms of changes in resource use and survival time, from the effects of accuracy on therapy selection. Cost effectiveness acceptability curves (CEAC) were used to plot the probability that the net (monetary) benefit from one strategy exceeds that from another as a function of the ‘willingness to pay’ coefficient (K). The results show that the costs are similar for all strategies and so clinical results (life years gained) play the dominant role in determining cost effectiveness. Treatment based on the results of FDG-PET scanning alone gives the largest expected life years across all patient types. Although the use of FDG-PET scanning to determine treatment only in CT-positive patients is less cost effective than the use of FDG-PET scanning in all patients, both strategies are cost effective for any value of K greater than £5000 in essentially all of the simulations, thus comparing favourably with other interventions studied in previous HTAs. The model also predicts that using CT alone, 36% of patients will receive unneccessary consolidation RT. This would be reduced to 4% for patients assessed using FDG-PET alone, or to 6% for those undergoing FDG-PET after positive CT scan. 7-1 7.1 Literature search 7.1.1 Search strategy As part of the scoping searches undertaken in July 2001, to help define the assessment question (see section 3.2), economic evaluations had been sought on a number of cancers including lymphoma. The following strategies were adopted: the NHS EED and the HEED were searched; the websites of the major health economics research centres were searched for economic evaluations; the electronic databases MEDLINE (Ovid), PreMEDLINE (Ovid) and Embase (Ovid) were searched. The search was split into three concepts: positron emission tomography, lymphoma and terms to identify economic evaluations. All relevant subject headings and free text terms were identified for each concept. The search was restricted to studies publish from 1990 onwards. No language restrictions were applied; members of the TSG and experts were consulted to check for further economic evaluations; and the bibliographies of relevant studies were scanned for further evaluations. In addition, searches were undertaken in MEDLINE, PreMEDLINE and Embase to provide inputs for the economic model relating to: the costs associated with chemotherapy for lymphoma; and toxicities associated with two chemotherapy regimens, IVE (ifosfamide, etoposide and epirubicin) and BEAM (carmustine, cytarabine, etoposide and melphalan). Further information about the search is presented in Appendix 5. 7.1.2 Criteria for inclusion and exclusion of studies The following exclusion criteria were applied when reviewing the economic literature search results: 1. Review articles not containing data in the form of a model or study. 2. Studies not carried out in a population that might be broadly relevant to Scotland (i.e. not American or European). 3. Articles not written in English. 7.1.3 Data extraction Although two previous economic modelling studies were found (Klose et al., 2000 and Hoh et al., 1997) this work was not considered directly relevant to the current model, since they were concerned with initial disease staging, and no data extraction was done. 7-2 7.2 Economic methods 7.2.1 Restriction to Hodgkin’s disease (HD) The decision was taken to restrict the economic modelling to the case of HD because of time constraints and since, following discussion with Scottish oncologists, it was believed to be likely that FDG-PET would be more clearly cost effective in HD. Although the accuracy of FDG-PET scanning is similar in both HD and NHL, clinical markers of residual disease are more effective in NHL. This restriction should not be taken as evidence that the use FDG-PET scanning to restage NHL after induction therapy is not cost effective. 7.2.2 Objectives of the economic evaluation 1. To review the existing English language literature on the economics of FDG-PET in the management of HD, in order to assess its quality and relevance to the issues facing NHSScotland. 2. To use selected literature and expert opinion as the basis for modelling the flow of patients through different investigative and treatment strategies for HD. 3. To use this model to estimate the costs and benefits of each strategy, and hence to estimate the net costs and benefits of using FDG-PET for restaging HD. 4. To assess whether the key economic results arrived at above would still hold under alternative plausible scenarios. 7.2.3 The potential for use of PET in restaging HD in NHSScotland The model described here will be used to assess the cost effectiveness of FDG-PET scanning as an adjunct to conventional imaging in deciding the further treatment of patients with HD, who have achieved a partial or complete response to induction therapy. It is expected that, since FDG-PET imaging appears to be at least as sensitive as CT scanning for the detection of residual disease, and considerably more specific (section 6), its use in this setting may allow a significant proportion of patients to avoid consolidation RT and the associated long-term toxicity. 7.2.4 Model structure Current practice mandates (Dr M Mackie, Consultant Haematologist, Western General Hospital, Edinburgh, Personal communication, 2002) that a CT scan will be undertaken for all patients after induction therapy to assess initial disease response. Therefore the economic modelling concentrates on strategies in which CT has been performed and patients are classified as CT-positive or CT-negative then further investigations and treatment are undertaken. The possibility of avoiding the use of CT scanning in some patients is discussed in section 7.4.5. 7-3 The model consists of two components; a decision tree, specifying how the results of FDG-PET and CT imaging will be used to guide initial treatment selection, and a Markov model describing the flow of patients through treatment and remission to death. Five ‘versions’ of the decision tree, corresponding to the different strategies for the use of FDG-PET and CT, are described here. The Markov ‘treatment’ model, which is common across all strategies, is described in section 7.2.5. It is assumed that for each patient, one of two possible decisions will be taken: 1 immediate consolidation RT; or 2 surveillance, with follow-up examinations; and that one of the five strategies illustrated in Figure 7-1 will be used. Although strategies 1 and 2 appear implausible, they will be used as ‘controls’ in the sense that, if either appears cost effective in the resulting assessment, this will be regarded as casting doubt on the validity of the model assumptions. Since the prevalence of active disease will differ between surveillance groups defined by different combinations of imaging tools, it is important to distinguish between these groups in the subsequent modelling. Figure 7-1 Management pathways after induction chemotherapy in HD 1. All for surveillance 2. All for consolidation –ve Surveillance +ve Consolidation 3. CT +ve +ve Consolidation -ve Surveillance FDG-PET 4. CT -ve Surveillance –ve Surveillance +ve Consolidation 5. [CT]* FDG-PET +ve : positive –ve : negative * [CT] indicates that although a CT scan is performed, the results are not used in allocating patients between surveillance and consolidation. 7-4 7.2.5 Markov treatment model The Markov (‘treatment’) model will be run for a 30-year time horizon and will represent the life experience of patients after the post-induction assessment. The model is shown schematically in simplified form in Figure 7-2 and is described in section 7.2.5.1. 7.2.5.1 Narrative description of the model and assumptions 1. Patients are selected for consolidation or surveillance based on the results of CT and FDG-PET imaging. 2. Patients selected for consolidation receive RT immediately, the others are monitored (surveillance as described in 7.2.11). 3. Patients under surveillance who relapse are assessed for salvage (either RT or further chemotherapy with Adriamycin (doxorubicin), bleomycin, vinblastine and decarbazine (ABVD) or other regimen). 4. Patients who relapse after RT, or are unsuitable for salvage, are given IVE reinduction therapy. 5. Responders to reinduction will undergo high-dose BEAM chemotherapy and autologous peripheral stem cell or bone marrow support. 6. Deaths (possibly due to toxicity) may occur during reinduction or HDCT. 7. Non-responders to reinduction therapy with IVE will be regarded as treatment failures and receive palliative therapy. 8. All patients who survive without relapse six or more years from the start of remission will be assumed to exhibit only population all-cause mortality, modified by the late toxicity of RT, salvage therapy or HDCT in those patients who received it (leukaemia, breast cancer, lung cancer and heart disease). 7-5 Figure 7-2 1. Surveillance PET negative Structure of the Markov treatment model 2. Surveillance CT positive 3. Consolidation and follow up 5. IVE 4. Salvage and follow up 7. Palliation 6. HDCT and follow up 7-6 9. Death 8. Second malignancy 7.2.6 Identification and measurement of the potential benefits and costs of PET The economic issues surrounding the use of FDG-PET scanning in the investigation of patients with HD relate to the fact that it can detect small but clinically significant metastases and is more specific than CT in differentiating active residual disease from scarring (section 6). As a result it may: 1. avoid unnecessary RT; 2. avoid the mortality and morbidity associated with long-term toxicities of RT; 3. possibly reduce the numbers of other diagnostic tests; and 4. allow appropriate systemic therapy to begin earlier. Offsetting these potential advantages might be factors such as the following: 1. the costs of setting up and running the PET scanner; and 2. since salvage therapy may be less effective than consolidation RT, patients inappropriately assigned to surveillance (false negatives) may be disadvantaged. This disadvantage is of course shared with CT scanning. 7.2.7 Assumptions 7.2.7.1 Relapse detection It is assumed that only relapses occurring in the first two years after the end of induction therapy can be predicted by any imaging device used immediately after the end of induction therapy, and that a completely accurate imaging device would predict all such relapses. 7.2.7.2 Long-term toxicity It is assumed that the long-term toxicity due to consolidation or salvage will reflect current experience. It is assumed that salvage therapy after surveillance (RT or ABVD chemotherapy) will carry the same long-term risks as consolidation RT. 7.2.7.3 No QOL loss for procedures Some authors (e.g. Dietlein et al., 2000a; Gambhir et al., 1996) have hypothesised that patients suffer reduced QOL when they are undergoing tests or treatment, for example in terms of discomfort, anxiety or the acute toxic effects of therapy. Although this is plausible, there is no published evidence to support this hypothesis. Furthermore, as PET is non-invasive and no reported adverse events have been reported in a study of 80,000 patients (section 4.6), any reduction in QOL will be minimal. 7.2.7.4 Strategies for testing and treatment are followed As discussed in section 4, much of the empirical evidence on FDG-PET relates to its accuracy, with limited uncontrolled evidence on change in patient management. The model assumes that all involved in the management of the patient follow the strategy, without ordering any other tests. 7-7 7.2.8 Methods of analysis The impact of FDG-PET is analysed by a cost-effectiveness analysis, which sets out the changes in resource use and survival from the effects of improved accuracy on therapy selection. Quality adjusted life years were not used in the analysis because of the paucity of reliable data (section 7.2.11.2) and because changes in therapy will impact survival time. Probabilistic sensitivity analysis was conducted, in which values of major inputs to the model were allowed to vary in accordance with the distributions described in 7.2.11. The results from this analysis are presented in the form of cost-effectiveness acceptability curves (CEACs) (Briggs & Tambour, 2001; van Hout et al., 1994). The CEAC for comparison of two strategies (A and B) plots the probability that the net (monetary) benefit from strategy A exceeds that for strategy B, as a function of the ‘willingness to pay’ coefficient (K). This probability is based upon the data described in section 7.2.11 and the assumptions described in section 7.3.1 and is known as a ‘posterior’ probability. If £K denotes the amount of money NHSScotland is ‘willing to pay’ for an additional life year (crudely, ‘the value of an extra year of life’), the net benefit (NB) is given by K*(Life years gained) – Cost. 7.2.9 Perspective and horizon The time horizon is assumed to approximate the lifetime of the patient; in this model a thirty-year horizon has been used. Costs relating to HD management were included (including costs to NHSScotland and patient travel costs). Given the life expectancy and age at treatment of these patients, the results may be affected by considering a societal perspective. 7.2.10 Discounting costs and benefits occurring in future years Discount rates were used as in the NSCLC analysis (section 5). 7.2.11 Model inputs The inputs for the HTBS economic model for restaging HD in Scotland are summarised in Table 7-1. 7-8 Table 7-1 Inputs to the HTBS economic model: base case and distributions Term Accuracy of CT scan Accuracy of FDG-PET scan after positive CT Accuracy of FDG-PET scan as ‘stand-alone’ Relapse percentage years 1-2 post ABVD Relapse percentage years 3-5 post ABVD Relapse percentage years 1-5 post RT Percentage of in-field relapse from RT (assumed to occur in years 1-2) Source Section 6 Section 6 Section 6 Canellos et al. (1992) Carde et al. (1993) Duggan et al. (1997) Canellos et al. (1992) Carde et al. (1993) Duggan et al. (1997) Petera et al. (2000) Yahalom et al. (1991) Mendenhall et al. (1999) Viviani et al, (1996) Petera et al. (2000) Yahalom et al. (1991) Assumption Percentage relapsing after surveillance suitable for salvage Five-year relapse free survival after salvage Percentage of patients moving from IVE re-induction to HDCT Percentage of toxic deaths under IVE Percentage of toxic deaths under HDCT Five-year survival post HDCT Relative risk of breast cancer post RT Relative risk of leukaemia post RT Value Sensitivity 0.75 (0.58 – 0.88)* Specificity 0.45 (0.27 – 0.64)* Sensitivity 0.80 (0.59 – 0.94)* Specificity 0.89 (0.74 – 0.97)* Sensitivity 0.81 (0.63 – 0.92)* Specificity 0.95 (0.90 – 0.99)* 26.5% (23% - 30%)* 6% (3% - 9%)* 11.5% (8% - 16%)* 37% (24% - 50%)* Years 1 – 2 base case 25%, distributed as Uniform (10,40) Viviani et al. (1990) Years 3 – 5 85% Viviani et al. (1990) 52% Proctor et al. (2001) Anselmo et al. (2000) Proctor et al. (2001) Anselmo et al. (2000) Chopra et al. (1993) Anselmo et al. (2000) Argiris et al. (2000) Crump et al. (1993) Linch et al. (1993) Lazarus et al. (2001) Chopra et al. (1993) Ferme et al. (2002) Bierman et al. (1993) 52% (41% - 63%)* 1% (0% - 5%)* 7% (6% - 9%)* 60% (54% - 65%) * van Leeuwen et al. (1994) 12.7 Abrahamsen et al. (1993) van Leeuwen et al. (1994) Linch et al. (2000) van Leeuwen et al. (1994) Linch et al. (2000) 24.3 (11.1 – 46.2) 34.7 (23.6 – 49.3) Low 3.7 (2.5 – 5.3) 10.3 (7 – 13.7) Relative risk of lung cancer post RT Relative risk of death from heart Hancock et al. (1993) 3.1 disease post RT * denotes that for these parameters the distribution used for the probabilistic sensitivity analysis (PSA) was the posterior distribution from a meta-analysis (see Appendix 19 and section 6). Distributions for other parameters are specified in section 7.4.1. 7-9 All relative risks are assumed to be zero in the first five years after treatment; lung and breast cancer risks are assumed also to be zero in the second five years after treatment, whereas heart disease and leukaemia risks rise immediately to the level specified. All relative risks are assumed to take the values specified in the table from year 11 post-treatment onwards. All quantities in Table 7-1 are assumed to be independent of age and sex. Although somewhat unrealistic, this assumption is made necessary by the structure of the available data. Base-case incidence and mortality rates (disease specific and all cause) refer to the Scottish population in 1998 and are taken from the ISD website (http://www.show.scot.nhs.uk/isd/). Table 7-2 Cost inputs to the model: base case Cost FDG-PET scan CT scan Source Section 9.6 Section 7.2.11.3.1 Surveillance (post ABVD) Section 7.2.11.3.2 Surveillance (post conservative/salvage) Section 7.2.11.3.2 Surveillance (post autologous PBSCT) Section 7.2.11.3.2 RT IVE re-induction HDCT therapy and autologous peripheral blood stem cell support Non-curative therapy for IVE failures Costs associated with long-term toxicities – lung cancer Costs associated with long-term toxicities - breast cancer Costs associated with long-term toxicities – leukaemia Section 7.2.11.3.3 Section 7.2.11.3.4 Value £678 £146 Year 1 £265 Year 2 £89 Year 3 £89 Year 4 £59 Year 5+ £30 Year 1 £411 Year 2 £235 Year 3 £89 Year 4 £59 Year 5+ £30 Year 1 £649 Year 2 £59 Year 3 £59 Year 4 £59 Year 5+ £30 £2494 £6832 Section 7.2.11.3.5 £19,172 Section 7.2.11.3.6 £524 p.a. Conservative assumption £500 p.a. Conservative assumption £200 p.a. Conservative assumption £1500 p.a. Distributions associated with these costs are described in section 7.3.1. 7-10 7.2.11.1 Epidemiology The model applies only to patients aged 60 or under, with advanced HD, which has apparently responded fully or partially to first-line therapy with ABVD. (Patients with a biological age greater than 60 years will not receive aggressive induction therapy and so are excluded from this model). The model will be run for six patient types: male 20 years; male 40 years; male 60 years; female 20 years; female 40 years; and female 60 years. Results from each patient ‘type’ may then be combined according to their proportional incidence in the Scottish population, although the separate results for each patient type are also of interest. 7.2.11.2 Quality of life Ideally, quality-of-life data for this study would have been derived from a survey of Scottish patients or using utility values from the Scottish public but, within the time constraints faced, the only realistic option was to search the literature for values used in previous work on HD and the associated secondary malignancies. Unfortunately there are few reliable published studies. For example, Norum et al. (1996) present a mean utility for HD survivors of 0.78. This figure was obtained from survivors roughly five years after treatment, and may well underestimate the utility experienced by long-term survivors. Interestingly, utility estimates in this paper were negatively correlated with initial disease stage (presumably merely reflecting random variation in a small sample of patients). Uyl-de Groet et al. (1995) reported that two years post-HDCT or CHOP (Cyclophosphamide, Adriamycin, Vincristine, Prednisone) chemotherapy, the Euro-QOL score of NHL survivors was close to 90/100 (again in a very small sample). In a large review, Tengs & Wallace (2000) present the following utility estimates for second primary malignancies: breast cancer 0.89; and general cancer (including leukaemia?) 0.7 – 0.9. Finally, Earle et al. (2000) and Berthelot et al. (2000) present estimates for NSCLC of between 0.65 and 0.88 depending on disease stage. In view of the considerable uncertainty surrounding these estimates and their interpretation, the primary analysis undertaken here will focus simply on life years accumulated under each of the strategies. 7-11 7.2.11.3 Resource use The following costs were sought for the economic model: CT scan; surveillance; RT; IVE chemotherapy; non-curative therapy for patients who fail IVE; autologous peripheral blood stem cell transplant (PBSCT); and costs associated with long-term toxicities (three specific diseases were identified – lung cancer, breast cancer and leukaemia). The costings in the model take overheads from the Scottish Health Services Cost Manual 2001 (Common Services Agency, Information and Statistics Division, 2001), indexed by 5% to get costs at 2002/03 prices. These are allocated overheads that cover non-direct costs. Staff costs were based on NHSScotland pay scales for the year commencing April 2002. Superannuation, national insurance and on-costs were added on. An average body size of 1.8 metres2 was used for calculating drug dosage. 7.2.11.3.1 CT scan The new English NHS Reference Costs – 2001 (NHS Executive, 2001) provide a mean cost of £139 and an interquartile range of £75. In accordance with this, CT costs (2001 level) were assumed to be random with a normal distribution, mean £139, standard deviation £75/1.349 = £55.6. These values were then indexed by 5% to convert to 2002 levels. 7.2.11.3.2 Surveillance There are no agreed strategies across Scotland for the surveillance of a patient and the working practices differ from location to location. In this model, the resource use associated with monitoring a patient over a period of five years was based on expert opinion from the Lothian University Hospitals NHS Trust. The three surveillance strategies used in this model were: post ABVD chemotherapy; post RT/salvage chemotherapy; and post autologous PBSCT. The costs and resource use over a five-year period for each of the above strategies are presented in Table 7-3 to Table 7-5. 7-12 Table 7-3 Resource CT scan (mean value) Physical examination Outpatient appointment Lab tests Mean total Table 7-4 Resource CT scan (mean value) Physical examination Outpatient appointment Lab tests Mean total Table 7-5 Resource CT scan (mean value) Physical examination Outpatient appointment Lab tests Mean total Post ABVD chemotherapy Unit cost Year 1 Year 2 Year 3 Year 4 Year 5 £145.95 1 0 0 0 0 £8.62 4 3 3 2 1 £13.65 4 3 3 2 1 £7.45 4 £264.83 3 £89.17 3 £89.17 2 £59.44 1 £29.72 Post radiotherapy/salvage chemotherapy Unit cost Year 1 Year 2 Year 3 Year 4 Year 5 £145.95 2 1 0 0 0 £8.62 4 3 3 2 1 £13.65 4 3 3 2 1 3 £89.17 2 £59.44 1 £29.72 £7.45 4 £410.78 3 £235.12 Post autologous peripheral blood stem cell transplant (PBSCT) Unit cost Year 1 Year 2 Year 3 Year 4 Year 5 £145.95 2 0 0 0 0 £8.62 12 2 2 2 1 £13.65 12 2 2 2 1 £7.45 12 £648.54 2 £59.44 2 £59.44 2 £59.44 1 £29.72 7.2.11.3.3 Radiotherapy (RT) Consolidation RT involves 20 fractions of RT administered over a four-week period (Monday to Friday). Resource use was identified based on discussions with a Consultant Oncologist (Dr N O’Rourke, Beatson Oncology Centre, Western Infirmary, Glasgow, Personal communication, 2002). The mean summary costs are listed in Table 7-6. Table 7-6 Summary costs for consolidation radiotherapy Resource Radiographer (staff time) Simulator Physicist (staff time) Linac machine Other medical time Overheads Patient travel costs Total Mean cost £178 £35 £145 £175 £315 £819 £827 £2494 7-13 Costs for the radiographer, simulator, physicist and Linac machine are the direct costs associated with administering 20 fractions of RT. ‘Other medical time’ covers initial consultation, planning appointments, consultations during the four-week period and follow- up appointments. Overheads used are the Scottish average of non-direct costs for outpatients in a RT ward. As the RT treatment is administered over a four-week period, patient travel costs will be significant. The assumptions used are based on discussion with a Consultant Oncologist (Dr N O’Rourke, Beatson Oncology Centre, Western Infirmary, Glasgow, Personal communication, 2002). It is assumed that 63% of the patients would use their own transport or public transport, 32% of patients will use the hospital patient transport service and the remaining 5% will require either an in-patient bed or a hotel room. The latter 5% of patients are assumed to be travelling from remote areas where it is not possible or cost effective to make daily return journeys. For patients using their own transport or public transport a figure of £4 per return journey has been assumed on the basis that this is what it will cost to take two bus journeys to the hospital. These patients are assumed to be local residents. Patients using hospital transport are assumed to be making a return journey of an average of 50 miles. These patients will be a mixture of local residents and residents of the surrounding areas. The cost per mile is taken as the average for Scotland as listed in the Scottish Health Service Costs Manual 2001 (Common Services Agency, Information and Statistics Division, 2001). The average cost per mile is £1.98, which has been indexed at 5% to derive costs for 2002/03. Patients travelling from further afield, such as the Highlands and Islands, will require an in-patient bed or a hotel room. The cost of an in-patient bed is based on the Scottish average non-direct overheads (it is assumed that very little nursing case or pharmacy will be needed) in an in-patient RT ward for 16 nights at £114 per night. Shetland Health Board provides an allowance of £54 per night for hotel accommodation and this figure is used for hotel costs. In addition, provision for four return flights at £300 each has been made. 7.2.11.3.4 IVE chemotherapy For each cycle of IVE treatment it was assumed that there were: four days stay as an in-patient; one outpatient visit; and 1.25 days in-patient stay for complications. Over three cycles of IVE it was assumed that 25% of patients would require standard cheaper treatment for sepsis and 10% would also require an alternative more expensive treatment for sepsis. Overhead costs were based on average overheads for a haematology ward in Scotland. Resource use, pharmacy, admission and laboratory test were based on information supplied by the Lothian University Hospitals NHS Trust. 7-14 Mean cost for IVE is £6832 per treatment (three cycles at £2063 each plus provision for treating side effects at £399). Appendix 20 outlines the components of IVE costs. 7.2.11.3.5 Autologous peripheral blood stem cell transplant (PBSCT) Assumptions used in autologous PBSCT were as follows: in-patient stay22 days; outpatient visits 8 days; and in-patient stay for complications3 days. Overhead costs were based on the Scottish average non-direct overheads for a haematology ward. Resource use, pharmacy, admission and laboratory test were based on information supplied by the Lothian University Hospitals NHS Trust. Blood products are supplied free of charge to hospitals in Scotland so they have not been included in the costing exercise. Mean costs for PBSCT are: Procedure Complications Total £18,377 £795 £19,172 Appendix 20 outlines the components of the PBSCT procedure. Autologous bone marrow transplant has also been costed at £23,990. 7-15 7.2.11.3.6 Long-term toxicities Given that each long-term toxicity is represented as a single state in the model, a conservative figure for the average cost for each toxicity was taken from the costs detailed below. This was then divided by the maximum life expectancy to get the annual cost per year. Toxicity Costing Non-curative therapy for IVE failure An annual average cost of £524 was calculated. This includes drug cost, some radiotherapy, outpatient visits and district nurse visits. Leukaemia Indicative treatment costs for secondary leukaemia were based on discussions with experts (Dr Davies, Western General Hospital, LUHT) and informed by a brief literature review. The mean cost was approximately £30,000 per patient. Breast cancer Lung cancer 7.3 Costing work on breast cancer has been done by SHPIC (Scottish Health Purchasing Information Centre, 1997). The HTBS model uses their costs for mastectomy and breast conservation with radiotherapy and first-line chemotherapy. This calculates as an indicative average £3000. Second-line chemotherapy costs used are as stated in NICE guidance on taxanes of approximately £4000 per event (NICE, 2001b). The average cost per event in breast cancer is taken to be £3000. On the basis of previous work done for this HTA (section 5), a figure of £500 per annum over the estimated average lifespan of 2.5 years was used as a conservative estimate of the cost. Results The model was constructed and run in WinBUGS 1.4 (http://www.mrcbsu.cam.ac.uk/bugs/welcome.shtml). The code used is available on request from HTBS. 7.3.1 Uncertainties Uncertainties exist in the model inputs for two reasons. First, although data exist to inform many of the inputs, those data only determine the inputs up to a distribution with some variation. For such inputs, the distributions estimated from meta-analysis and shown in Table 7-1 are used directly in the sensitivity analysis. Secondly, there exist poor or no data about some model inputs (e.g. utility weights). For such inputs the distributions shown in Table 7-7 have been used. 7-16 Table 7-7 Model inputs - sensitivity distributions Term Proportion relapsing after PET and suitable for salvage – years 1–2 Proportion relapsing after PET and suitable for salvage – years 3–5 Proportion relapse within five years post salvage Relative risk of breast cancer post RT/salvage Relative risk of breast cancer post HDCT Relative risk of breast cancer post RT/salvage and HDCT Relative risk of lung cancer post RT/salvage Relative risk of lung cancer post HDCT Relative risk of lung cancer post RT/salvage and HDCT Relative risk of leukaemia post RT/salvage Relative risk of leukaemia post HDCT Relative risk of leukaemia post RT/salvage and HDCT Relative risk of heart disease death post RT/salvage Relative risk of heart disease death post HDCT Relative risk of heart disease death post RT/salvage and HDCT Cost of CT scan Cost of salvage therapy Cost of RT Cost of IVE Cost of HDCT Cost of non-curative therapy for IVE failures Base case value Distribution 0.25 Uniform (0.1 – 0.4) 0.88 Uniform (0.75 – 1) 0.48 Uniform (0.4 – 0.55) 12 Normal (12, 1) 3 Normal (3, 1) 15 Normal (15, 1) 6 Normal (6, 1) 2 Normal (2, 1) 8 Normal (8, 1) 5 Normal (5, 1) 7 Normal (7, 1) 10 Normal (10, 1) 3.1 2 6.2 £149 £6000 £1432 £6832 £21500 £524 Normal (3.1, 0.25) Normal (2, 0.25) Normal (6.2, 0.25) Normal (149, 58.4) Normal (6000, 200) Normal (2494, 210) Normal (6832, 191) Normal (21500, 1751) Normal (524, 93) It is recognised that modern radiotherapeutic methods may present a different longterm toxicity risk profile to that observed in previous published experience. To reflect this possibility, the estimated relative risks will be multiplied by a ‘bias term’, uniformly distributed on a suitable range (0.8 – 1.2). 7-17 7.3.2 Results – Life-years analysis The results presented here represent the distribution of costs and benefits for the five strategies, generated by the input distributions described in sections 7.2.11 and 7.3.1. As the distribution of costs and benefits is too complex to calculate in a closed form, they have been obtained from an approximation based on computer simulations (specifically, Gibbs Sampling, (Carlin & Louis, 2001)). First, a set of 5,000 simulations was used to ensure that an accurate approximation was obtained. The results shown were then obtained from a further 10,000 simulations. The tables present the estimated mean of the distribution of costs and benefits given the data and assumptions. The CEACs presented for strategies 4 (FDG-PET after positive CT) and 5 (FDG-PET alone) show the probability that each of these is cost effective, relative to strategy 3 (CT alone), as a function of K, the value assigned to one additional year of life gained. In other words, the CEAC for strategy 5 plots the probability that the net benefit for strategy 5 is greater than that for strategy 3, for each value of K (the monetary value assigned to one year of life). The net benefit is given by the life years achieved by a strategy multiplied by K, minus the cost of that strategy. Overall, the model predicts that 36% of patients, CI (30.3%, 40.4%) restaged using CT alone will receive unnecessary consolidation RT. This would be reduced to 3.8%, CI (0.2%, 7%) for patients restaged using FDG-PET alone, or to 6%, CI (3.2%, 10.3%) if only CT positive patients are restaged using FDG-PET. Table 7-8 Point estimates of life years saved and total costs for female, 20 years old at end of induction therapy Strategy Life years Cost 1 – All surveillance 20.2 £5062 2 – All consolidation 20.7 £4634 3 – CT only 20.7 £4492 4 – FDG-PET after positive CT 21.1 £4304 5 – FDG-PET only* 21.4 £4069 * Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to consolidation or surveillance, although a CT scan is used to assess response. The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-3. Table 7-9 Point estimates of life years saved and total costs for male, 20 years old at end of induction therapy Strategy Life years Cost 1 – All surveillance 20.0 £5054 2 – All consolidation 20.9 £3973 3 – CT only 20.8 £4041 4 – FDG-PET after positive CT 21.1 £4062 5 – FDG-PET only * 21.5 £3805 * Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to consolidation or surveillance, although a CT scan is used to assess response. The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-5. 7-18 Table 7-10 Point estimates of life years saved and total costs for female, 40 years old at end of induction therapy Strategy Life years Cost 1 – All surveillance 19.4 £5051 2 – All consolidation 20.0 £4596 3 – CT only 20.0 £4464 4 – FDG-PET after positive CT 20.3 £4288 5 – FDG-PET only * 20.6 £4053 * Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to consolidation or surveillance, although a CT scan is used to assess response. The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-7. Table 7-11 Point estimates of life years saved and total costs for male, 40 years old at end of induction therapy Strategy Life years Cost 1 – All surveillance 18.8 £5042 2 – All consolidation 19.2 £3963 3 – CT only 19.3 £4030 4 – FDG-PET after positive CT 19.8 £4049 5 – FDG-PET only * 20.1 £3792 * Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to consolidation or surveillance, although a CT scan is used to assess response. The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-9. Table 7-12 Point estimates of life years saved and total costs for female, 60 years old at end of induction therapy Strategy Life years Cost 1 – All surveillance 15.4 £5003 2 – All consolidation 14.5 £3929 3 – CT only 15.0 £3994 4 – FDG-PET after positive CT 15.8 £4008 5 – FDG-PET only* 16.1 £3750 * Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to consolidation or surveillance, although a CT scan is used to assess response. The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-11. Table 7-13 Point estimates of life years saved and total costs for male, 60 years old at end of induction therapy Strategy Life years Cost 1 – All surveillance 13.9 £4986 2 – All consolidation 12.3 £3933 3 – CT only 13.0 £3989 4 – FDG-PET after positive CT 14.1 £3994 5 – FDG-PET only * 14.3 £3734 * Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to consolidation or surveillance, although a CT scan is used to assess response. The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-13. 7-19 7.3.3 Discussion of results The mean results show that the use of FDG-PET scanning alone, or as an adjunct to CT scanning, is cost effective for all six patient types relative to the use of CT scanning alone for any willingness to pay per life year in excess of £5000. The costs are similar for all strategies, and so clinical results (life years gained) play the dominant role in determining cost effectiveness. The use of FDG-PET alone to allocate treatment (strategy 5) uniformly gives the largest expected value of life years and lowest expected cost across all patient types and is cost effective for essentially all plausible input values, for any value of willingness to pay greater than £5000. FDG-PET following CT (strategy 4) is an inherently poorer strategy than strategy 5 because of the low overall sensitivity of combining the two procedures. However, it is still cost effective relative to the non-PET containing strategies, leads to a higher expected value of life years, and may be more acceptable to clinicians initially, until they gain experience with FDG-PET scanning. The use of FDG-PET scanning to assign patients with HD to consolidation or surveillance, whether used as the sole imaging tool or as an adjunct to CT in CTpositive patients, is cost effective in the base case, provided willingness to pay exceeds £1000, and for almost all input values considered, provided willingness to pay exceeds £5000. 7.4 Further sensitivity analysis 7.4.1 Lower accuracy from FDG-PET Although the meta-analysis presented in section 6 suggests that PET alone is both highly sensitive and highly specific, the methodological problems described there (rather small studies, generally heterogeneous groups and retrospective design) may have led to overoptimistic estimates of the accuracy of FDG-PET scanning. To investigate the effect that overestimation of the specificity, in particular, may have had, the model was rerun for 20-year-old males and females, with the specificity of PET scanning alone now drawn from a uniform distribution on (0.6,0.9) and all other input distributions unchanged. For both 20-year-old females and males, strategy 5 remains cost effective relative to strategy 3 across almost all simulations (Figure 7-9, Figure 7-10) and continues to give longer lifespans than strategy 4, although the difference is now much smaller (strategy 4 - 21.1, strategy 5 - 21.2 for females; 21.1 versus 21.2 for males). 7.4.2 Incorporation of quality weights Although as discussed in section 7.2.11.2 the assignment of quality scores to the health states in this model is subject to considerable uncertainty, in view of the substantial impacts of second malignancies on quality of life, it may be reasonable to attempt an analysis based on such assignment. Table 7-14 shows the distributions of quality weights (utilities), which have been assumed in modelling QALY gains for the 7-20 five strategies in a 20-year-old woman. All other inputs were as presented in section 7.2.11. Table 7-14 Estimated utilities in a 20-year-old woman State Any active treatment (RT, salvage, IVE, HDCT) – during period of treatment contact Five-year follow-up period post therapy Post five years and without chronic toxicity Breast cancer Leukaemia Lung cancer Utility Justification Moroff & Pauker (1983) 0.75 0.8 Norum et al. (1996) 0.9 Uyl-de Groet et al. (1995) 0.81 0.72 0.72 90% of current ‘healthy’ state 80% of current ‘healthy’ state 80% of current ‘healthy’ state The resulting QALY and cost values are shown in Table 7-15. Table 7-15 QALY analysis for 20-year-old woman Strategy 1 – All surveillance 2 – All consolidation 3 – CT only 4 – FDG-PET after positive CT 5 – FDG-PET only QALYs 14.9 15.1 15.3 15.7 16.1 Cost £5062 £4634 £4492 £4304 £4069 The corresponding CEACs are shown in Figure 7-11. Despite the uncertainty associated with utility values, this analysis of QALYs confirms the results of the life year analysis, which indicates that both strategy 4 and strategy 5 are superior to strategy 3. 7.4.3 Variations in discount rate used for clinical benefits HTBS Guidance for Manufacturers (HTBS, 2002b) states that sensitivity analyses presented should include the effects of adjusting the discount rate applied to benefits to 0% or 6%. Since it is clear that the effect of reducing the benefit discount rate to 0% would be to increase the apparent clinical advantage of PET scanning, only the results pertaining to a 6% rate will be presented here. Table 7-16 Point estimates of life years saved and total costs for female, 20 years old, 6% discount rates on benefit Strategy 1 – All surveillance 2 – All consolidation 3 – CT only 4 – FDG-PET after positive CT 5 – FDG-PET only Life years 12.0 12.4 12.4 12.5 12.7 Cost £5062 £4634 £4492 £4304 £4069 The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-12. 7-21 Table 7-17 Point estimates of life years saved and total costs for male, 20 years old, 6% discount rates on benefit Strategy 1 – All surveillance 2 – All consolidation 3 – CT only 4 – FDG-PET after positive CT 5 – FDG-PET only Life years 12.0 12.5 12.5 12.6 12.7 Cost £5054 £3973 £4041 £4062 £3805 The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-13. Table 7-18 Point estimates of life years saved and total costs for female, 40 years old, 6% discount rates on benefit Strategy 1 – All surveillance 2 – All consolidation 3 – CT only 4 – FDG-PET after positive CT 5 – FDG-PET only Life years 11.8 12.1 12.1 12.2 12.4 Cost £5051 £4596 £4464 £4288 £4053 The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-20. Table 7-19 Point estimates of life years saved and total costs for male, 40 years old, 6% discount rates on benefit Strategy 1 – All surveillance 2 – All consolidation 3 – CT only 4 – FDG-PET after positive CT 5 – FDG-PET only Life years 11.5 11.9 11.9 12.1 12.2 Cost £5042 £3963 £4030 £4049 £3792 The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-21. Table 7-20 Point estimates of life years saved and total costs for female, 60 years old, 6% discount rates on benefit Strategy 1 – All surveillance 2 – All consolidation 3 – CT only 4 – FDG-PET after positive CT 5 – FDG-PET only Life years 10.2 9.9 10.1 10.5 10.6 Cost £5003 £3929 £3994 £4008 £3750 The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-22. 7-22 Table 7-21 Point estimates of life years saved and total costs for male, 60 years old, 6% discount rates on benefit Strategy 1 – All surveillance 2 – All consolidation 3 – CT only 4 – FDG-PET after positive CT 5 – FDG-PET only Life years 9.5 8.9 9.2 9.7 9.8 Cost £4986 £3933 £3989 £3994 £3734 The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-17. 7.4.3.1 Summary Although increasing the discount rate on benefits from 1.5% to 6% has reduced the apparent superiority of PET-containing strategies relative to other approaches, there is little impact on cost effectiveness for either strategy 4 or strategy 5, except that the probability of cost effectiveness for strategy 4 in 20-year-old males now only reaches 90% if the value of a life year is greater than £15,000. 7.4.4 Discussion A considerable number of simplifications and assumptions have been made in building this model, for example: no account has been taken of the effects on quality of life of the life-long monitoring for second primaries recommended after RT (Linch et al., 2000); the costs assigned to RT, and to treatment of second malignancies, are likely to be substantial underestimates; the assumption that salvage chemotherapy treatment after surveillance is as toxic as RT may be open to debate; and no account has been taken of the impact on quality of life of the greater degree of diagnostic certainty likely to be afforded by FDG-PET results. Both patients and physicians see this as a major advantage of PET scanning. However, although the effect is undoubtedly real, there is no published evidence to allow the utility gain afforded to be assigned a value and used in a cost-effectiveness analysis. It is likely, however, that a model in which these omissions were rectified would produce results suggesting a greater advantage for the FDG-PET based strategies, and would not therefore substantially alter the conclusions of this exercise. The time horizon used (30 years) may appear long relative to those commonly used in the assessment of therapeutic technologies. However, it is well established that for both therapeutic (Linch et al., 2000) and other (Ron et al., 1993) radiation exposures the major risks of radiation exposure emerge after a lag of five to 10 years, and continue to be present for at least a further twenty years. A full societal perspective for the analysis has not been undertaken as this would require major assumptions over the 30-year time horizon and would in case undoubtedly increase the evidence for cost effectiveness. Accurate knowledge of the relative risks of late toxicity due to current treatment would substantially reduce the uncertainties associated with the model conclusions. 7-23 However, it is clear, that it is not justifiable to suggest that the introduction of FDGPET should await the conclusions of studies intended for this purpose. It is assumed throughout that all patients will receive a CT scan at the end of induction therapy, which will be used to confirm response, for radiation planning in those patients assigned to consolidation or to provide a baseline for surveillance follow up. Therefore although the optimal strategy, strategy 5, makes no use of the CT scan result in assigning patients to consolidation or surveillance, it is unlikely that this post-treatment CT scan could be avoided. 7.4.4.1 Relationship to previous work Previous studies (Klose et al., 2000; Hoh et al., 1997) have shown that FDG-PET scanning appears to be cost effective in staging/restaging HD and NHL when account is taken only of stage migrations induced by FDG-PET scanning, without reference to the long-term clinical significance of such migration. The current work confirms and extends these studies by modelling the clinical consequences of PET scanning’s superior accuracy. 7.4.5 Conclusions The use of FDG-PET to assign patients with HD to consolidation or surveillance, whether used as the sole imaging tool in all patients, or as an adjunct to CT only in patients showing residual abnormalities on CT, is cost effective in the base case provided the willingness of NHSScotland to pay exceeds £1000 per year of life, and for almost all the input values considered provided the willingness to pay exceeds £5000. The use of PET alone appears also to be cost saving compared with current practice. Even if the cost of a PET scan was increased to £1000/scan, the cost per life year would still be less than £10,000 per life year. The cost effectiveness is maintained if quality adjusted life year gains are calculated based on the available quality weights in the published literature, if very unfavourable assumptions are made about the actual false-positive rates associated with FDG-PET scanning, or if the discount rate on benefits is increased from 1.5% to 6% p.a. These results compare favourably with cost effectiveness analyses of other cancer technologies previously recommended by other agencies (for example docetaxel as second-line therapy for NSCLC, £14000 per life year gained (NICE, 2001a) and paclitaxel in addition to cisplatinum for ovarian cancer, £6500 to £10000 per life year gained (NICE, 2001b)). The use of FDG-PET scanning in this indication is therefore cost effective. Furthermore, when the model is used to evaluate benefits in terms of avoiding unnecessary radiotherapy the results show that if CT were used, 36% of patients would receive unnecessary radiotherapy, compared with approximately 5% of patients with a FDG-PET scan in strategy 4 or strategy 5. This demonstrates the immediate advantage to the patient of FDG-PET. Although the role of FDG-PET scanning in NHL has not been modelled here, the accuracy demonstrated in section 6 is likely to translate into significant patient 7-24 benefits. Since the main area of uncertainty in NHL is whether a combination of CT scanning and prognostic scores is sufficiently accurate in selecting patients for consolidation, it will be appropriate to study the comparative accuracy of FDG-PET scanning and conventional methods in a prospective study. Such a study should focus initially on the ability of FDG-PET scanning to induce important changes in patient management, but should also compare disease free survival in patients undergoing FDG-PET scanning with those restaged ‘conventionally’, either in a randomised fashion or by using historical control data. 7-25 Cost effectiveness acceptability curves (CEACs) for female, 20 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-3 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-26 Cost effectiveness acceptability curves (CEACs) for male, 20 years. Open circles - strategy 4 (PET after positive CT), solid circles strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-4 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-27 Cost effectiveness acceptability curves (CEACs) for female, 40 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-5 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-28 Cost effectiveness acceptability curves (CEACs) for male, 40 years. Open circles - strategy 4 (PET after positive CT), solid circles strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-6 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-29 Cost effectiveness acceptability curves (CEACs) for female, 60 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-7 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-30 Cost effectiveness acceptability curves (CEACs) for male, 60 years. Open circles - strategy 4 (PET after positive CT), solid circles strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-8 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-31 Cost effectiveness acceptability curves (CEACs) for female, 20 years. Strategy 5 only (PET only), relative to strategy 3 (CT only), PET specificity distributed as Uniform on (0.6,0.9) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-9 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-32 Cost effectiveness acceptability curves (CEACs) for male, 20 years. Strategy 5 only (PET only), relative to strategy 3 (CT only), PET specificity distributed as Uniform on (0.6,0.9) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-10 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-33 Cost effectiveness acceptability curves (CEACs) based on QALYs for female, 20 years. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only) both relative to strategy 3 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-11 0 5000 10000 15000 20000 25000 30000 Value per Quality Adjusted Life Year (k) in Pounds Sterling 7-34 Cost effectiveness acceptability curves for female, 20 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-12 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-35 Cost effectiveness acceptability curves for male, 20 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-13 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-36 Cost effectiveness acceptability curves for female, 40 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-14 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-37 Cost effectiveness acceptability curves for male, 40 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-15 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-38 Cost effectiveness acceptability curves for female, 60 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-16 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-39 Cost effectiveness acceptability Curves for male, 60 years, 6% discount rate on benefits. Open circles - strategy 4 (PET after positive CT), solid circles - strategy 5 (PET only), both relative to strategy 3 (CT only) 0.6 0.4 0.2 0.0 Probability 0.8 1.0 Figure 7-17 0 5000 10000 15000 20000 25000 30000 Value per Life Year (k) in Pounds Sterling 7-40 8 PATIENT ISSUES Summary PET imaging is likely to be just one part of the diagnostic work-up, so it is important to co-ordinate hospital appointments for various tests to reduce the need for patient travel and to avoid delays in treatment. Health professionals should inform patients about the process for PET imaging, associated risks and counselling, and check that patients understand the information received. Carers also require this information. Leaflets with diagrams and clear explanation of complicated terms (such as radioisotope) should be given in addition to basic information about preparation for the scan, and what can be expected during and after the scan. The potential benefits and risks associated with PET scanning should be explained in clear, simple language. The imaging environment should be comfortable and designed to alleviate patient anxieties. For example, music listening facilities should be included and adult friends should be permitted to sit with patients in the scanning room. Following consultation, there was evidence that patients value the additional information provided by PET scanning. The results of a PET scan may also provide reassurance which is valued highly by some patients. As the only PET facility in Scotland is used for research purposes, it has not been possible to obtain substantive information about patients’ views and preferences relating to PET scanning. However, professionals believe that as PET scanners are open and less noisy than some other imaging devices they may be preferred by patients. Following the introduction of PET imaging into the clinical situation in Scotland, further research will be required to understand the needs and preferences of patients and carers. 8-1 8.1 Background The consideration of patient issues is key to any HTA and accords with Scottish aims to create a patient-centred NHS. This section relies heavily on submitted evidence and on information from patients and professionals. As the only PET facility in Scotland is used for research purposes and so few patients have experienced PET scanning, it is not possible to obtain the views of patients undergoing a PET scan in a normal clinical situation in Scotland. The experience of patients undergoing other cancer diagnostic procedures, such as CT or MRI, is more readily available and will be of use when planning the establishment of a PET facility. Professionals believe that patients prefer PET to many other diagnostic procedures as the imager is open and generates very little noise. Patients’ views of any new service should be elicited early in its use, to ensure that any anxieties are discussed and lessons are learned. 8.2 The scanning process for the patient At Mount Vernon Hospital in London, patients are contacted prior to their visit to check attendance and the process is clearly explained to them. This helps to overcome anxieties and reduces the number of non-attenders. This would be good practice to follow in Scotland, but staff resources may make this difficult to achieve. It is recommended in section 9 that PET facilities in Scotland are linked with a cancer centre. In Scotland, there are four cancer centres: Glasgow; Edinburgh; Dundee; and Aberdeen. The organisation of the cancer diagnostic tests will depend on the local situation. For example, for patients travelling to Aberdeen from the Islands it would be optimal to schedule PET, CT, MRI and ultrasound scans on the same day. However, in Ayr, CT and other diagnostic procedures may be done locally on one day, with a trip to the PET scanner on another day. If PET and CT scanning need to be done in the PET centre, this may lead to delays as the time to receipt of scan is often quicker in a local centre. The funding of patient travel to the cancer clinics (where any PET facility would be situated) varies throughout Scotland. For those from the Islands who require to go to Aberdeen, travel, generally by air, is funded by NHS Boards. In some areas, voluntary organisations such as Cancer Care provide a valuable free transport service. In other areas, patients will be expected to organise and fund their own travel. MacLeod et al. (2000a) found that among women diagnosed with breast cancer in 1992 and 1993, significantly more patients from deprived areas failed to attend appointments, compared with those in affluent areas. Failure to attend appointments may be related to ease of access to hospitals rather than lack of interest in follow up. It should be recognised that it is not only those living in remote areas who experience travel difficulties. Those living on the East side of Glasgow who must rely on public transport will need to use at least two buses to get across the city to the Beatson Oncology Centre. Consequently, it is imperative that diagnostic work-ups are organised so that the patient has to make as few visits to the clinic as possible. 8-2 Avoidance of patient anxiety is also important from a technical perspective as the uptake of glucose is higher in tense muscles and this will ‘distort’ the PET image. To overcome this, St Thomas’ Hospital in London give their patients diazepam before the scanning procedure. As a general rule, most patients with breast cancer, young people with lymphoma and those with head and neck cancer will need diazepam. Any patient who is administered diazepam will be unable to drive home following the procedure and so this should be communicated clearly to the patient prior to attendance at the clinic. The scanning facilities should be designed to make the patient feel relaxed and comfortable and reduce anxiety. For example, music listening facilities could be provided. In St Thomas’ an adult friend is permitted to sit with the patient in the scanning room to provide reassurance to anxious patients. This puts the patient more at ease in a potentially stressful situation and so is recommended as standard practice. Patients undergoing studies should fast for at least four hours before the examination. The patient should partially empty his or her bladder before the scan, to reduce the size of the bladder artefact, although this will increase the uptake of the radioisotope by the bladder. Patients should not have undergone biopsy in the previous 72 hours, since inflammation round the biopsy site can cause abnormal FDG uptake (Cronin et al., 1997). 8.3 Communication with patients 8.3.1 Professional interactions There is a need to show sensitivity to the needs of the patient and their family. Patients are often acutely aware of time pressures on busy clinicians and so do not ask questions. Consequently contact with other patients, health professionals and voluntary organisations is recommended and so it will be important for NHS Boards to provide voluntary organisations with details of a new facility, such as a PET imaging centre. The following sections are taken from the SIGN guideline on lung cancer (SIGN, 1998a) and can be applied to all cancers and major diseases: Communication between health professionals and patient is a central clinical function. The establishment of relationships which can support patients and carers through their illness begin with unconditional listening and effective information provision. Lack of information can increase anxiety, uncertainty, distress and dissatisfaction (Audit Commission, 1993), and there is evidence to suggest that the level of psychological distress in patients with serious illness is less when they perceive themselves to have received adequate information about diagnosis and treatment options (Fallowfield et al., 1986; Fallowfield et al., 1990). With few exceptions, patients should be informed of the diagnosis of lung cancer and the options for treatment discussed with them (Sell et al., 1993). This information should be shared with appropriate close relatives if the patient consents. The environment of the diagnostic consultation and the way in which the diagnosis and treatment plan is conveyed to the patient should be conducive to establishing trust and confidence. The presence of a family member or friend is usually helpful. It is very important that other professionals involved, especially GP, should be informed as soon as possible exactly what information has been given. 8-3 A survey of 65,337 NHS patients with cancer - including 5,604 people with NHL and 4,011 with lung cancer - commissioned by the Department of Health (2002), identified the need for health professionals to ensure patients not only receive sufficient information about their condition, treatment, tests and possible outcomes, but also understand this information. The survey found that approximately one in five people (18%) with lung cancer or NHL would have preferred to be given more information about the outcome of their first treatment. Additionally, 13% of respondents believed that on one or more occasion doctors or nurses withheld information from them. This percentage increased to 16% among people with NHL. People with NHL were also less likely to understand their diagnosis or the purpose of tests they were given. For example, 84% of people with lung cancer stated that they completely understood their diagnosis, while only 70% of people with NHL made this statement. 8.3.2 Patient information Scanning often triggers anxiety in cancer patients and with PET there may be fears related to the injection of a radiopharmaceutical. Patients may have important questions (such as ‘am I radioactive to the rest of my family’) that they are too embarrassed or scared to discuss with anyone. There may also be a concern about repeat injections and a fear of radioactive accumulation. The amount of information given to patients about imaging procedures in cancer appears to be highly variable and dependent upon the individual professional. Leaflets with diagrams and clear explanations of complicated terms (such as radioisotope) should be given in addition to basic information about what can be expected during and after the scan. The potential benefits, risks and the procedures associated with PET scanning should be explained in clear, simple language. When evaluating papers for clinical effectiveness, a number of practical issues relating to patient eligibility were identified, which should be communicated clearly to patients and their carers. Published studies indicate that the following are not eligible for FDG-PET scans: patients with high fasting levels of glucose (e.g. above 5.8 mmol/l, Vansteenkiste et al., 1998b); patients unable to lie down for one hour (e.g. patients with congestive cardiomyopathy); and patients who have not fasted for between four and six hours before the scan. Some of the studies (e.g. Vansteenkiste et al., 1998b) exclude any patients with diabetes mellitus, whereas other studies (e.g. Poncelet et al., 2001) exclude only patients with uncontrolled diabetes mellitus. A document with frequently asked questions displayed in simple terms might be helpful. Such information should be made available to the patient sufficiently in advance of the procedure so that they have time to assimilate it, ask questions and discuss areas of concern. Some examples of patient information leaflets about PET scanning are presented in Appendix 21. These leaflets have been reproduced by kind permission of the centres outlined on the first page of the Appendix 21. 8-4 Some US sites also provide patient information in other media, such as on video (see the Louisiana PET centre: www.louisianapet.com/). 8.4 Consultation questions and responses As PET imaging is currently confined to use within one research facility in Scotland, few health service users in Scotland are able to advise on its use based on their experiences. For this reason, information was sought about the broader issues surrounding diagnosis, treatment, and quality of life following treatment. Patient representative and voluntary organisations were sent copies of the consultation questions with an easy-to-read summary of the Consultation Assessment Report. Additionally, the Lymphoma Association promoted the consultation in its newsletter. During consultation the following questions were asked: 1. Few people in Scotland have had a PET scan, but from your experience of attending tests (perhaps CT scans or MRI scans) what issues do you think should be considered regarding using PET scanners in Scotland. For example, what are your ideas about timing of the scans, access and counselling and finding out the results? 2. As with several procedures associated with cancer management, PET scanning involves the use of radiation. Have you had any experience of these other procedures and was the use of radiation explained adequately? What concerns do you have about the use of radiation and how do you think these could be addressed? 3. If PET scanners were to be used, what information would you like, when would you like to receive it and how would you like to receive it? 4. From your experience of diagnostic tests for cancer, are there any other issues that you think HTBS should be aware of? Respondents to the consultation questions indicated that they valued the additional information provided by the PET scan. One respondent had had a PET scan at the Aberdeen facility after his oncologist gained funding for the scan from a charity. He especially valued the technology because it resulted in the prevention of unnecessary biopsy and provided reassurance during a treatment which otherwise offered him ‘no guarantees’ or clear answers: ‘This was the only time that I felt I had been given a clear answer, which was in great contrast to the ambiguous results from CT scans which often added to the frustration and strain of dealing with cancer’. The respondent indicated that the PET scan took away doubt and allowed him to get on with his life without unnecessary worry. The response from this patient is reproduced in full in Appendix 22. Health service users did not raise concerns about radiation, but two health professionals responded on these issues. One was concerned that the radiation dose should not be played down and the other stressed the need to consider the risks and benefits in each case. A need for information, both oral and written, to explain what the PET scanner does, why it is used, and what people may experience during the scan was identified. 8-5 Additionally, there is a need for results to be communicated as soon as possible and each person should be asked about their information needs. Respondents also identified the need for people to be treated as individuals and the importance of ensuring that scanning does not result in delays to treatment that may be intolerable to health service users. 8.5 Focus group A focus group was conducted with people who had been treated for lymphomas, including those who had experience of PET imaging. The primary objective of the focus group was to gain an understanding of the patient’s perspective, and the views of their families and carers, on the issues surrounding treatment and investigation. Participants were asked about their experience and the questions from consultation (section 8.4) were also used to facilitate discussion. The second objective of the focus group was to explore the issues surrounding the role of PET imaging in helping to reassure a patient and issues about quality of life raised in section 7.2.11.2 (i.e. whether quality of life is reduced due to discomfort, anxiety or toxicity associated with undergoing tests or treatments). Three focus groups were planned, however, recruitment of participants was difficult. Potential participants were invited to take part in ‘discussion’ groups by advertisement and by advertising in the Lymphoma Association newsletter. One focus group comprised four people (three males and one female) with experience of treatment for NHL and one carer (female) and the members met in Glasgow for a discussion session. Three of the participants had been diagnosed with NHL in the past year and one had been diagnosed with NHL eight years ago. The youngest participant was 17 years old. During the focus group, participants used a wall chart to create a timeline which summarised their experiences since diagnosis. Participants requested a separate wall chart to summarise some key points from their experiences before diagnosis, for example their interactions with health services which led to a diagnosis being made. Participants were given three different coloured pieces of paper to record their experiences. One colour represented ‘good’ experiences, another colour represented ‘bad’ experiences, and a third colour was called ‘gap’ which was intended to prompt participants to share their reflections about what might have been missing from their journey of care. 8.5.1 Results The focus group provided a few examples of people’s experiences of treatment and their needs and preferences. These examples indicated that participants: valued the timeous treatment they currently received; valued survival above risks and access to treatments; thought consultants played a vital role in providing information; felt that good quality information about current services, counselling and risks should be provided without people having to ask for it, and checked with patients to ensure it has been understood; 8-6 felt information about risks was sought on the grounds of ‘right to know’ rather than because it would change their decisions about treatment; and thought that reassurance is an ongoing need, but sources of reassurance differ. Participants shared a belief that once a person was diagnosed with lymphoma, their treatment was prioritised and met their needs for speed, however prior to diagnosis, the investigations may have been too slow and they perceived that the system was ‘bottlenecked’ at the initial diagnosis stage. As a result of the difficulties in diagnosing NHL, some participants said diagnosis could be a ‘relief’. Once diagnosed, one participant considered the journey is better described as a ‘roller coaster ride’ than a pathway. Treatment for lymphomas had had differing impacts on the participants’ lives. One participant had been able to continue a relatively ‘normal’ life, as close access to the hospital allowed her still to attend school regularly. For another, treatment had required large amounts of travel which resulted in his wife giving up work for six months to take him to appointments. The participants were generally in agreement that the consultant plays the key role in providing them with information about their condition. Attempts to gain further information – for example from the internet, medical journals and friends – were described as unhelpful. One participant described most written information as ‘too scientific’. Participants questioned the quality of information they found on the internet and one participant suggested there was a need for good information to carry some sort of certification so that patients could identify it. Participants had found that information, received from sources other than health professionals, could cause further worry. Some asked that health professionals give information to patients without them having to request it. Information should be provided about the services that exist, side effects and counselling. Two issues were raised about information on the side effects of radiation. Three participants indicated that they had been given insufficient information on side effects of treatments, especially in relation to scans and radiation. Participants said that this information would not have changed their decisions to attend, but they believed they should have been given the information. The second issue raised was their understanding of the information they had been given. ‘I don’t think I was told an awful lot about the risks. I have a good relationship with my doctor but unless you ask you don’t get told. I didn’t know anything about the radiation thing’. Health service user A ‘If somebody said ‘tomorrow you’re going to have a CT, MRI and PET scan’, I’d say ‘I’m going and I’m not worried too much about the consequences because survival is the name of the game’’. 8-7 Health service user B The second issue raised was their understanding of the information they had been given. One participant had been given information about radioactivity following a PET scan, but was unsure if he had interpreted it correctly or had been overly alarmed. ‘I was wandering about Aberdeen for several hours trying to keep back from people you know. I was like radioactive man kind of thing. I honestly don’t know if….really there was a danger. I did worry if I was being alarmed unnecessarily’. Health service user E Participants’ views about the use of scans to provide reassurance differed. One participant had found the results of a PET scan ‘reassuring’ because they had identified a residual mass as scar tissue. ‘That’s where the PET scan made the difference, because I knew for definite that that part of tissues was no longer active and that made a huge difference…if offered the certainty of knowledge that I was in the clear as much as I could be. CTs don’t reduce the uncertainty and that’s the worse thing’. Health service user E Another person – who had not had experience of a PET scan – said that ‘nothing will supersede the feeling inside’. He indicated that an examination of every cell in his body would be less reassuring than ‘feeling well’. ‘No matter how far we go down the road of technological advancement, nothing is going to supersede the feeling you’ve got inside. Even if they want to look at every cell I’ve got in my body, that is still not sufficient assurance. It’s the feeling of being well, thinking well’. Health service user B Participants indicated that they had an ongoing need for reassurance because once diagnosed with non-Hodgkin’s disease they were never completely free from worry or concern. They indicated that every ailment, whether connected to their diagnosis or not, increased their anxiety. ‘You’re very positive and you say ‘I’m going to beat this thing’, but you don’t get a sore throat anymore. You know, a sore back is not a sore back, it’s a possible lump’. Health service user D ‘People have given me statistics but they don’t actually mean anything…I mean what’s the chances of a 17-year- old getting cancer in the first place’. 8-8 Health service user A The participant who had been diagnosed with lymphoma for more than eight years said that the intensity of his anxiety decreased after the first year because if it had continued to remain as high he would have suffered from mental health problems. He described his diagnosis as an ‘old friend’. The results of this focus group indicate that PET should be organised to allow timely availability for patients and for consultants to have a role in providing clear information about its benefits and risks. The results of a PET scan may also provide reassurance which is valued highly by some patients. 8.6 Conclusions There is no experience of the use of PET in routine clinical practice in Scotland, however anecdotal reports of experience in England indicate that patients prefer PET to CT because the imager is open and generates very little noise. In Scotland, travel to specialist health care facilities from urban, rural and island areas can act as a barrier to attendance, both in terms of convenience and because of the financial implications. Therefore diagnostic tests should be scheduled to coincide wherever possible. All PET imaging facilities should be specially designed to make the patient feel comfortable and reduce anxiety by, for example, providing music listening facilities and allowing an adult friend to attend with the patient. Diagnostic work-ups for cancer can involve several tests, spaced over many weeks and lack of information during this process can lead to increased anxiety and distress for the patient. Patients should be informed of the imaging process to be undertaken and given clear literature explaining the process. Several good examples of patient information leaflets available in the US are available and may provide useful models for use in the UK. Patient information leaflets may be valued as supplements to communication between health professionals, particularly doctors, and patients if they contain information about the process, its purpose, any associated risks, and possible outcomes. However, it is essential that health professionals check with patients to ensure they understand all written and verbal information given and discuss any anxieties. 8-9 9 ORGANISATIONAL ISSUES Summary PET facilities and cyclotrons should be organised to provide appropriate provision and equitable access for all patients with cancer who may benefit from imaging. PET facilities should be linked to cancer centres and PET imaging should be coordinated with other diagnostic tests to minimise delays in treatment. Four possible options for the implementation of a PET facility in Scotland have been considered and the cost per scan and budget impact of each have been investigated. These options include three fixed facilities and various configurations of mobile units. Mobile PET results in higher long-term costs and a higher overall cost per scan. However, capital costs are substantially lower and the facility could be operational in a few months. The lowest cost per scan and lowest running costs are associated with a fully equipped PET unit integrated with other relevant hospital departments and drawing on staff skills from these departments (£677/scan). This option requires a capital outlay of £4.25 million and incurs annual running costs of £1.02 million. The layout of the facility and production and transportation of radiopharmaceuticals must comply with legal requirements. Appropriate training and accreditation must be created for radiopharmacists, radiochemists and cyclotron engineers. This would be best achieved on a national (UK) basis. All staff in the cancer team should understand the value and uncertainties associated with PET in decision- making for cancer management. 9-1 9.1 Organisation of PET facilities in the UK This organisational issues section has been written with major input from the experts on the TSG, who have provided much of the specialist text herein. 9.1.1 Current facilities The only PET facility currently available in Scotland is based within Aberdeen Royal Infirmary and is currently used for research purposes only and not for routine clinical use. An application is underway for a PET facility in Glasgow. In England, there are five PET facilities, which are used for routine clinical use. These are all in London; in Harley Street and at St Thomas’/Guy’s, Middlesex, Mount Vernon and Hammersmith Hospitals. These facilities are also used for research purposes; this amounts to 25% of use at St Thomas’ and Middlesex and 10% at Mount Vernon. Other PET research facilities are also available in England at the MRC/IRSL unit at Hammersmith, the Functional Imaging Laboratory at Queen’s Square, the Wolfson Brain Imaging Centre at Cambridge and the MANPET facility in Manchester. A Wolfson Molecular Imaging Centre, which will be a national oncology research centre, is also about to be built in Manchester. 9.1.2 Planning of new facilities Scotland currently has cancer centres in Glasgow, Edinburgh, Dundee and Aberdeen. If implementation of a PET scanning service is undertaken, PET facilities should be organised across Scotland (and the UK) according to the size of the patient population, accessibility and availability of clinical expertise to ensure patients across Scotland have access to a PET scanner. In addition, for research purposes the scanner would need to be sited near to a suitably staffed research facility. Therefore it is important to consider the location of current scanners and cyclotrons. A PET facility may be integrated into an imaging department (as in the Glasgow proposal) or standalone (as proposed by some Public Private Partnership (PPP) initiatives). If the facility is combined with an imaging department, it may be possible to achieve economies of scale, particularly through sharing of staff, information, etc. In the US, mobile PET facilities are in operation. When considering service configuration in Scotland, such a facility may provide a useful resource to manage the difficulties caused by access in remote areas, or it could serve more than one cancer centre (e.g. Aberdeen and Dundee). However, it is likely that a patient would have to travel to the nearest cancer centre for other diagnostic tests and treatment, so the value of this is not entirely clear. As mobile PET facilities can be established more quickly than building a totally new fixed site, they might also be considered as an interim solution for provision of the technology in a cancer site pending establishment of the fixed facility. Any PET scanning provision would have to guarantee a reasonable service to patients from across Scotland without disadvantaging those from the more rural and remote areas such as the Southwest or the Highlands and Islands. Furthermore it would be important to ensure that the inclusion of PET scanning in the diagnostic work-up did not create new delays to the initiation of treatment. Current standards state that at least 9-2 90% of patients considered for curative therapy (surgery, radical RT and combined modality treatment) should receive a CT scan within two weeks, but in a recent review this criterion was met by two of the 28 hospitals in Scotland (Clinical Standards Board for Scotland, 2002). There are no data available on the effect of PET on the time to diagnosis and treatment, but the risk that the provision of PET scanning might further slow down the progress from initial diagnosis to definitive treatment, by introducing a further rate limiting step in the patient’s journey, should be recognised. Any such delay is likely to impinge more on patients having to travel significant distances for the investigation and might further exaggerate the inequality of health care provision for more remote and rural populations. These issues would be tackled in Scotland by regional planning groups, in particular the Regional Cancer Advisory Groups (section 2.2.2) and local NHS Boards. 9.2 The PET centre A PET Centre has three main components: the facility for production of the positron emitting radionuclide; an area for rapid labelling of the chosen pharmaceutical by the radionuclide; and the imaging area. Radionuclides are produced by a cyclotron in which a non-radioactive target material is bombarded with high-energy charged particles to transform it to a radioactive form (Figure 9-1) (Sorenson & Phelps, 1987). Figure 9-1 A medical cyclotron Medical cyclotrons are designed specifically for the efficient production of the four main PET radionuclides; 18Fluorine, 11Carbon, 13Nitrogen and 15Oxygen. Most of these machines are negative ion, with dual irradiation, numerous target ports and beam energies of 10-20 MeV. While many of them are self-shielded for radiation, UK radiation regulations normally require the machine to be located in a shielded vault. 9-3 While the reliability of such devices is high, servicing and the employment of an engineer should be considered. Given the short lifetime of the radionuclide, it is desirable to locate the radiochemistry laboratory adjacent to the cyclotron vault. To achieve the necessary levels of activity on the final labelled radiopharmaceutical, the labelling process starts with high levels of radioactivity. Thus the labelling has to be carried out in a shielded chamber using an automated synthesis unit as shown in Figure 9-2. For the commonly produced radiopharmaceuticals, automated synthesis units that are designed to be user-friendly, reliable, easy to maintain, high yielding and with a rapid synthesis time are commercially available. Figure 9-2 Automated radiochemistry synthesis unit Such laboratories are supplemented with a quality assurance (QA) facility. Obviously there is not sufficient time for conventional pharmaceutical QA to be performed on the final product. Therefore stringent production protocols are required. Such units require staffing by a trained radiochemist/radiopharmacist. Further details of requirements for radiopharmaceutical production are presented in section 9.4.1. The design of the imaging room is similar to that for a conventional gamma camera room. It should be located close to the radiochemistry facility if short-lived radionuclides are to be used. Given the complexity of the radiopharmaceutical production process, many centres choose to purchase the product from a central production facility. This limits the radiopharmaceuticals to those labelled with long-lived radionuclides, which at present is 18Fluorine. 9-4 9.3 Site planning (layout, regulations) Planning of a PET facility requires careful consideration of the legal and technical requirements for managing the radiochemical production and associated information technology (IT) requirements, alongside the need for patients to feel comfortable with the administration of the radiopharmaceutical and the scan itself. The diagram in Figure 9-3 shows the site plan for the John Mallard Scottish PET Centre in Aberdeen. This is reproduced by kind permission of WS Atkins. Figure 9-3 Site plan of the John Mallard Scottish Pet Centre, Aberdeen 9-5 Prior to setting up a PET unit, a range of licences must be obtained. In order to hold and dispose of radioactive materials, applications must be made to the Scottish Environmental Protection Agency (SEPA). The RSA1 and RSA3 forms must be accompanied by an environmental impact assessment. Following granting of the authorisations, a 28-day period of notice must be observed prior to the commencement of operations. The authorisations must be displayed prominently in the unit. The clinician in medical charge of the unit must hold a licence from the Administration of Radioactive Substances Advisory Committee (ARSAC). He/she will be either a nuclear medicine consultant or a consultant in radiology with an interest in radionuclide imaging. Specialist training is required before a certificate will be issued in respect of PET studies. Countersignatures from the scientists responsible for radiopharmaceutical supply and scientific support and from the Radiation Protection Adviser (RPA) are required. Note that these authorisations are specific to the site, other staff and facilities; particular investigations and permissible administered activities are also stated. A RPA must be appointed for the unit and must be consulted in the preparation of the above applications. Locally, a member of staff must be appointed as Radiation Protection Supervisor (RPS) and there must be a designated medical physics expert, with at least six years experience in nuclear medicine. Under the new Ionising Radiation (Medical Exposure) Regulations (IRMER) legislation, those who will be permitted to refer patients for investigation must be specified and notified that they have been so recognised; referral criteria must be made available. Staff who will operate the scanner must be trained and designated in writing. A system must be in place to vet study requests. There must be a set of standard operating procedures (SOP) available which specify the details of each study type, including patient identification procedures, data acquisition, data analysis, reporting and emergency procedures. 9.4 Radiopharmaceutical supply 9.4.1 Radiopharmaceutical licensing and production If the unit is producing radiopharmaceuticals, the requirements will vary according to whether only research studies are proposed or routine service investigations are undertaken. In the latter case, it will depend on whether materials are to be supplied to another NHS health care facility. For research studies only, there are no restrictions at present, although this will alter in 2004. For routine investigation, a unit may prepare radiopharmaceuticals under the direction of a pharmacist (the so-called Section 10 exemption) or may apply to the Medicines Control Agency (MCA) for a Manufacturing (Specials) Licence. If materials are to be supplied to another NHS health care facility, the latter route is the only option. 9-6 The Notice to Applicants (http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm) outlines pharmaceutical regulatory reporting requirements to manufacturers and Volume 2b, Part II, presents the chemical, pharmaceutical and biological documentation required for radiopharmaceuticals (http://pharmacos.eudra.org /F2/eudralex/vol-2/B/pdfs-en/Part2_2en.pdf). The regulations state that if there is a licensed source for a pharmaceutical, then other production sites must get a licence also, or purchase from the licensed source. Research facilities, such as those in Aberdeen, do not need a licence for production of radiopharmaceuticals for their own purposes, but if they were to supply other centres, then a licence would be required. This may allow income generation, but this has not been evaluated in this HTA. In the Aberdeen PET centre every radiopharmaceutical is tested for purity immediately after radiochemical synthesis. All radiopharmaceutical preparations and purity tests comply with the requirements of the latest (3rd) Edition of the European Pharmacopoeia (Council of Europe, 1996) and exposure to ionising radiation is kept to a minimum (Appendix 23). 9.4.2 Radiopharmaceutical transportation As the half-life of FDG is 110 minutes, it is possible to transport it between PET scanning facilities, so that not all sites need a cyclotron (and associated radiation infrastructure and special staffing). Most say that the maximum travel time for FDG is two hours from the manufacturing facility. However, one expert believes that it can be up to four hours. The means of transport is anything that is legally acceptable for the carrying of radioactive substances. Substantial experience of the production and transportation of radiopharmaceuticals has been gained over the past 30 years at the Radionuclide Dispensary (RND) sited at the Western Infirmary, Glasgow. It produces approximately 45,000 patient doses per year distributed throughout the West of Scotland. In addition, it acts as a central supplier to many laboratories (both NHS and university) utilising radiochemicals. The only possible mode of transport is by road. Small sprinter trains that serve much of Scotland do not have guards vans and are thus not suitable. Likewise the planes that serve local flights in Scotland are too small to handle the radioactive materials. For transportation of radioactive materials, the RND uses five vans. There are four drivers who have to undertake a statutory training course and are subject to continuing training updates. The vehicles are fitted with the necessary signage and are modified internally to provide secure transport. These vehicles provide supplies to nuclear medicine departments in five NHS Board areas. Most areas only receive one delivery a day, which is despatched around 08:00am, to optimise use in the target department. Only Greater Glasgow receives two deliveries, the second being at 11:15am. However, emergency materials can be transported as required at other times of day; more easily in the afternoon when the critical morning runs have finished. 9-7 9.4.3 Clinical administration of radiopharmaceuticals Notes for Guidance on the Clinical Administration of Radiopharmaceuticals and Use of Sealed Radioactive Sources (National Radiological Protection Board, 1998b) provides guidance, based on national and international recommendations, to medical practitioners. The guidance is not mandatory and does not have the force of statutory regulations. However, it does provide a summary of the relevant legislation and is a guide to good clinical practice for nuclear medicine in the UK. 9.5 Staffing The organisational structure of the PET facility at St Thomas’ is presented in Figure 9-4. PET scanning is a sophisticated enterprise, requiring highly trained personnel. This includes radiation chemists, nuclear medicine technicians, physicists and nuclear medicine physicians. Physicians will need to be trained to interpret the scans and it is important that this training be of sufficient length and quality. Furthermore, all members of the multidisciplinary team involved in the treatment of a cancer patient should be educated about the benefits and risks associated with using PET. Consequently, personnel training should be a top priority. 9-8 Figure 9-4 St Thomas’ PET facility Organisational Structure PET Management Committee PET Centre Director Senior Scientist Clinical Manager Senior Clinician Radiochemistry Physics & Computing Technical Administration Clinical Radiochemist x2 Laboratory Assistant Research Associate x2 System Administrator Radiographers x4 Secretary Senior Registrar x0.5 Registrar x0.5 Cyclotron Techs x2 9-9 It must also be recognised, that at the outset it is likely that the clinical team will want to see PET scans in addition to the standard diagnostic work-up, but as experience is gained it is likely that there will be greater confidence in the use of PET scans. This is demonstrated in the survey of lung cancer diagnostic pathways. Scottish experts indicated the need for CT but St Thomas’ staff were happy to use PET instead of CT. Those working in the PET facility need special training and must be accredited on an ongoing basis. As there is currently a shortage of staff in many of the key disciplines, it may be necessary to train existing staff. For nuclear physicians, this can be achieved as an addition to current skills and ARSAC indicates that a period of training and experience will be necessary before competency is achieved. 9.5.1 Cyclotron support One of the key considerations relating to the establishment of a radiopharmaceutical production facility is the staffing requirement for radiopharmacists, radiochemists, physicists and electronic engineers. Aberdeen currently has a core staff of one cyclotron engineer, two chemists, a chemistry technician, one scanner operator, one physicist and four postdoctoral researchers who cover some of the roles (such as scanner operator). In practice, recruitment of radiochemists can be difficult and an alternative may be to employ organic chemists and train them to work with radiation. The radiation levels involved are quite low and the ability to synthesise novel compounds is more important than experience of working with high levels of radiation. The radiochemist in a PET facility performs the following functions: Routine work: provision of a reliable supply of short-lived radiolabelled compounds (e.g. FDG); quality control; dispensing; environmental monitoring; and documentation, radiation monitoring, maintenance, etc. Research: development of new synthetic strategies for the production of well-known or novel radiopharmaceuticals; development and construction of remotely controlled chemistry modules for the production of radiopharmaceuticals; and development of novel or well-known analytical methods for the routine synthesis of radiopharmaceuticals, etc. 9-10 The radiopharmacist in a PET facility undertakes the following functions: preparation and dispensing of radiopharmaceuticals used for patient diagnosis and therapy; verification that specified radioactive substances and reagents will give desired results in examination or treatment procedures, utilising knowledge of radiopharmaceutical preparation and principles of drug biodistribution; and conducting research to develop or improve radiopharmaceuticals, etc. The balance between routine work and research depends on a number of factors: the staffing levels and time available for research, given that routine work should take priority; the number of patients to be scanned on a daily basis; and the number of different scans being performed (and therefore the number of different radiopharmaceuticals being produced). The routine work required in a PET chemistry laboratory may be undertaken by a radiochemist or radiopharmacist. However, if research is undertaken, both of these professions are required. There is a shortage of these trained professionals and so training of new staff will be an essential component of the rollout of PET facilities in the UK. One course, hosted by the University of Leeds, provides an introduction to radiopharmacy. It consists of 30 hours of residential teaching and 120 hours of private study time, covering a series of lectures, seminars and orientation practicals relating to basic nuclear sciences, radiation safety and legalisation. 9-11 9.6 Cost per scan and budget impact Four options for providing a FDG-PET service were considered. These were: 1. A fully equipped FDG-PET unit (imager, cyclotron, radiochemistry facility) located within a hospital. This unit would benefit from support services purchased from the Trust such as maintenance, pharmacy and radiation protection advice. 2. A fully equipped FDG-PET unit (imager, cyclotron, radiochemistry facility) integrated with other relevant hospital departments such as nuclear medicine and radiology. This unit will draw on staff skill from other departments. 3. A FDG-PET unit receiving its radiopharmaceuticals from another source and integrated with other relevant hospital departments. This unit will draw on staff skills from other departments. 4. A mobile FDG-PET imager unit receiving its radiopharmaceuticals from another source. Various staffing options are considered here. Options 1, 2 and 3 are a ‘fixed’ facility. Costs per scan are calculated for these options in section 9.6.1. Option 4 is a mobile facility. Cost per scan values are calculated for a mobile facility used in a variety of ways across Scotland in section 9.6.2. 9.6.1 Costings for options 1, 2 & 3 (fixed facilities) The PET centre at Guy’s and St Thomas’ is a fully equipped unit, with a cyclotron and radiochemistry laboratory located within an NHS hospital. Costs have been obtained from them based on their current resource use (M Dakin, PET Manager, Guy’s and St Thomas’ Clinical PET Centre, Personal communication, 2002). The only staff shared with the rest of the hospital are the nuclear medicine clinicians as their posts are funded jointly by the hospital and the PET centre. This is considered as a case example similar to HTBS option 1, but with recognition that the St Thomas’ PET imager is several years old and patient throughput can now be increased. The tables presented in Appendix 24 set out full details of the costs of staffing and running the three fixed PET facility scenarios in Scotland. Option 1 would be a brand new fully equipped Scottish PET facility drawing on support services purchased by the Trust. Option 2 assumes that a PET facility will be located in a hospital environment where it will be possible to gain from synergies with other departments such as nuclear medicine and radiology for example sharing staff for illness and holiday cover. Option 3 also assumes that the PET facility is in an integrated hospital environment but that the facility will acquire its radiopharmaceuticals from an external source. It is possible to have a PET scanning unit located in a hospital with an existing cyclotron and radiochemistry facility in this option. Scottish resource use estimated for options 1, 2 and 3 were derived from experts in Scotland (Prof AT Elliot, Prof PF Sharp, Dr A Welch, Members of the TSG, Personal communication, 2002). They are principally modelled on the resource use structure at the Guy’s and St Thomas’ Clinical PET Centre. 9-12 Options 1, 2, 3 and Guy’s and the case example of St Thomas’ Clinical PET Centre are based on the assumptions presented in Table 9-1. Table 9-1 Cost per scan: assumptions Location Costs based on prices at Patient throughput per annum Average number of patients per day Number of working days per year Scanner age and specification Staffing costs VAT Depreciation of capital equipment Cost of adapting buildings for scanner or radiochemistry lab Provision for specialist training Number of FDG deliveries per day Option 1 (FDG on-site, separate unit) Scotland 2002/03 (2000/01 prices indexed at 5%) Option 2 (FDG on-site, shared staff) Scotland 2002/03 (2000/01 prices indexed at 5%) Option 3 (FDG delivered, shared staff) Scotland 2002/03 (2000/01 prices indexed at 5%) Case example Guy’s and St Thomas’ London 1500 1500 1300 1200 6.25 6.25 5.4 5 240 240 240 240 New 3-ring scanner NHS Scotland pay scales April 2002 Midpoint of grading band Inc. NI, on-costs and superannuation Included where applicable New 3-ring scanner NHS Scotland pay scales April 2002 Midpoint of grading band Inc. NI, on-costs and superannuation Included where applicable New 3-ring scanner NHS Scotland pay scales April 2002 Midpoint of grading band Inc. NI, on-costs and superannuation Included where applicable 10 years 2-ring scanner NHS pay scales April 2000 Inc. London weighting and on- costs Included Included Included Included Included Included Included Not included Included Included Included Not included N/A N/A 2 N/A 2000/01 Included where applicable 9.6.1.1 Staffing levels Staffing levels have been listed separately for the PET scanning unit and for the cyclotron and radiochemistry unit. The staffing levels have been based on the current staff use at St Thomas’. A lower staffing level has been agreed for options 2 and 3 compared with option 1. This reflects the differences in operational structure between options 1, 2 and 3. For example, in options 2 and 3 holiday cover would be provided by staff from other departments, whereas the staffing levels for option 1 have been calculated on the basis that holiday cover will be provided in-house. 9-13 9.6.1.2 Patient throughput On a newer three-ring scanner, time taken for a clinical scan is estimated to be one hour per patient (J Lowe, PET Superintendent, Paul Strickland Scanner Centre, Middlesex, Personal communication, 2002). In an optimal situation in options 1 and 2, using the staffing levels stated in Appendix 24, a maximum of seven patients could be scanned in a normal working day, a maximum annual throughput of 1700 patients, based on 240 working days in a year. However, a patient throughput of 1500 per annum has been assumed for options 1 and 2. This reflects the possibility that the unit will not be operating at optimal capacity at all times and also allows for set-up time prior to start of scanning each day. Where the radiopharmaceuticals are being purchased from an external source, this will probably mean a delayed start to the working day thereby limiting the number of patient slots. Taking this into consideration lower annual patient throughput of 1300 (average of 5.5 per day) has been assumed for option 3. There is the possibility of increasing patient throughput in option 3 if the risk of late delivery of the radiopharmaceuticals can be eliminated. This is addressed in the sensitivity analysis of the cost per scan model. Both the patient throughput and staffing levels have been crosschecked for consistency by another UK PET facility (J Lowe, PET Superintendent, Paul Strickland Scanner Centre, Middlesex, Personal communication, 2002). 9.6.1.3 Operating costs Other areas of operating costs to highlight are: i) Maintenance contracts The estimate for scanner maintenance is for full comprehensive cover, which includes software maintenance. However, existing UK PET centres have judged that the scanner software maintenance and development aspect of the maintenance service provided by manufacturers is not optimal or costeffective. Therefore it is assumed that for options 1, 2 and 3 that this aspect of maintenance will be done in-house and will be covered by the software developer/system administrator. This person will also be responsible, together with support from the clinical scientist, for other systems maintenance tasks. Cyclotron maintenance is estimated at £33,075 for option 2 compared with £55,125 for option 1. A full maintenance contract will be about £115,000 so both options assume a degree of in-house maintenance, the difference being that option 2 assumes a lower level, ‘parts only’ maintenance contract compared with a more fuller level of maintenance contract in option 1. 9-14 ii) Power/buildings maintenance Power and buildings maintenance has been allocated on a 40:60 basis to the PET scanning unit and cyclotron facility. A combined total of £14,884 has been assumed for option 2 and £16,538 for option 1. This reflects the difference in operating structures between the options. 9.6.1.4 Supply of FDG The viability of option 3 depends on the availability of FDG, either from another NHS facility or from a commercial entity. Cost estimates (at current prices) for two scenarios were sought: i) Supply of FDG from a NHS facility Price per dose of 350 MBq is approximately £353 including VAT (commercially confidential communication). The maximum distance coverable for transporting batches of FDG was indicated at 70 miles at a cost of approximately £100 per delivery. If a PET scanning unit is located within a hospital with a cyclotron and radiochemistry facility then there will be no additional transport costs. ii) Supply from a commercial entity Price per dose of 350 MBq is approximately £376 including VAT (commercially confidential communication). A range of coverable distances were indicated for transporting batches of FDG (50 miles at a total cost of £80 per delivery, 100 miles at a total cost of £141 per delivery, 150 miles at a total cost of £188 per delivery and 200 miles at a total cost of £258 per delivery). The maximum distance coverable was indicated to be 200 miles subject to terrain. The costs of FDG stated here are based on information supplied by facilities located in the South-East of England. Another confidential quote received during the final stages of the assessment supports these figures. The range of distance coverable for the transportation of FDG is consistent with expert opinion of two to four hours travelling time. The differences in cost and the differences in distances coverable between an NHS facility and a commercial facility reflect the fact that NHS facilities operate on a costrecovery basis whereas commercial facilities will operate on a profit basis. Costs for option 3 presented here are for FDG purchased from a NHS source, with and without transportation. (No transportation would model the case in which a cyclotron is available on an NHS facility but not actually part of the NHS PET centre). The purchase of FDG from a commercial source with 100 miles transportation is also costed. A full list of option 3 costs are detailed in Appendix 24. 9-15 9.6.1.5 Training The provision for training at St Thomas’ is estimated at £4,000, with most training being undertaken by Continual Professional Development. This amount is intended to cover basic and general training for all staff, as there are currently no formal training courses for PET. This figure is quite low and as the use of PET develops in the UK it is hoped that more formal training will be available. Funding one person through an MSc programme, if available, would typically cost around £15,000. It is important to note that the cost of training will vary from site to site depending on the number and existing skill of the personnel recruited. Communication with the Paul Strickland Scanner Centre indicates that a possible estimate for training would be around £20,000. After discussions with experts in Scotland (Prof AT Elliot, Prof PF Sharp, Dr A Welch, Members of the TSG, Personal communication, 2002) a training figure of £8,000 has been deemed appropriate for the purposes of this assessment. 9.6.1.6 Laboratory equipment Laboratory equipment for the PET scanning unit includes a protected bench, trolley, equipment for transporting, storing and administering FDG and office furniture. Laboratory equipment for the radiochemistry and cyclotron facility includes hot cells and chemistry modules for both FDG and 11Carbon and radiation safety monitoring equipment. Equipment required for the radiopharmaceutical QA function has also been included. 9.6.1.7 Cost of a PET scanner The manufacturers list price for a three-ring scanner has been used in the cost per scan model. It may be possible to negotiate a lower price with the manufacturer should a PET facility be set up in Scotland. 9.6.1.8 Building costs Building costs are included in this model and are based on the actual costs paid to build the PET facility at Aberdeen Royal Infirmary. Building works at Aberdeen commenced in 1997 and cost £738,628 (excluding VAT). The radiochemistry and cyclotron unit are more expensive to build due to the nature of their function. From the information supplied by Aberdeen it has been possible to estimate the individual costs of building the radiochemistry and cyclotron unit and for the PET scanning unit. Specific costs relating to the radiochemistry and cyclotron unit were identified where possible (roof for the plant room, special ground works, special electrical and mechanical services). These were deducted from the total cost and the remainder was apportioned between the two units on the basis of the floor area they occupied (see Figure 9-2). The radiochemistry and cyclotron unit are estimated to occupy 60% of the floor area and the PET scanning unit 40%. Costs are indexed at 5% per annum and VAT has been included where applicable. Building costs are classed as capital costs. 9-16 The same values for building costs of the PET unit and cyclotron facility have been used for options 1 to 3. 9.6.1.9 Location of Scottish facility The costs presented for a PET facility in Scotland are not for a specific location. The location will have no impact on the costs for option 2. However, an impact can be expected for option 3. This is addressed by presenting costs for various distances that the radioisotope can be transported. 9.6.1.10 Costs not included A number of costs have not been included in the model. These include costs for local authority rates, site and equipment insurance, telephone bills, stationery and security costs. Costs to the Trusts of providing staff cover for holidays/illness as in option 2 and 3 have not been included. 9.6.1.11 Summary of annual running costs Summary costs for 1, 2 and 3 and St Thomas’s are shown in Table 9-2. 9-17 Table 9-2 Summary annual running costs Staffing – PET scanning unit (inc. training) Staffing – cyclotron and radiochemistry unit (inc. training) Total staffing cost Scanning unit operating costs - Fixed Cyclotron unit operating costs – Fixed Scanning unit operating costs - Variable Cyclotron unit operating costs – Variable Purchase of FDG (NHS no transport) Purchase of FDG (NHS 70 miles inc. transport) Purchase of FDG (Commercial 100 miles inc. transport) Total annual running costs Total annual running costs; purchase of FDG from NHS source (no transport) Total annual running costs; purchase of FDG (NHS 70 miles) Total annual running costs; purchase of FDG (Commercial 100 miles) Case example St Thomas’ Option 1 Option 2 Option 3 £324,980 £220,691 £220,691 £309,957 £144,635 £115,123 £0 £140,700 £469,615 £335,814 £220,691 £450,657 £311,354 £310,693 £310,693 £268,884 £301,312 £278,269 £0 £244,489 £23,625 £23,625 £20,475 £18,000 £67,380 £67,380 £0 £64,000 N/A N/A £458,900 N/A N/A N/A £506,900 N/A N/A N/A £556,480 N/A £1,173,286 £1,015,781 £1,046,030 £1,010,759 £1,058,759 £1,108,339 9-18 9.6.1.12 Cost per scan The following cost per scan can be estimated for each of the options. Listed here are costs based on purchasing the FDG from a NHS facility with no transportation costs and allowing for 70 miles transportation, and purchasing FDG tracer from a commercial supplier allowing for 50 to 200 miles transportation. Option 2 has the lowest cost per scan at £677. In option 3, purchasing FDG from a NHS source offers the best value for money at £777 per scan without transport and £814 with transport. As the distance that the FDG has to be transported increases so does the cost per scan (£833 to £896). The German PET study by Klose et al. (2000) states that a PET scan, including production of FDG on-site, costs 960.5 euros (1998 prices). Using an exchange rate of 1 euro equals 63.3 pence and indexing at 5% per annum, the cost per PET scan at 2002/03 prices is £739. This is close to the midpoint cost per scan of options 1 and 2. Note that the cost per scan depends on the annual level of patient throughput. In the first year of a PET facility being operational it is unlikely that the levels of patient throughput stated in this model’s assumptions could be achieved. This can be due to training staff and raising awareness of the service. Table 9-3 Cost per scan Cost per scan Option 1 Cost £782 FDG bought from NHS source (no transport) FDG bought from NHS source (70 miles transport) FDG bought from commercial source (50 miles transport) FDG bought from commercial source (100 miles transport) FDG bought from commercial source (150 miles transport) FDG bought from commercial source (200 miles transport) Option 2 1500 patients/yr Option 3 1300 patients/yr £677 Case example St Thomas’s 1200 patients/yr £872 at 2000/01 prices £961 at 2002/03 prices £777 £814 £833 £853 £870 £896 9-19 9.6.1.13 Sensitivity analysis As the Scottish estimates for staffing levels, patient throughput and price of FDG were lower than some other estimates, sensitivity analyses were performed to assess the impact of increasing the cost of these components and increasing throughput. Details of these analyses are presented in Appendix 25. If staffing levels had to increase to the same levels as in option 1 then this will have the biggest impact on the cost per scan prices, increasing by around £80 for option 3. Increasing patient throughput to 1500 in option 3 lowers the cost per scan price by around £105. Decreasing patient throughput by 100 increases the cost per scan by around £65. Increasing staffing levels and increasing patient throughput in option 3 increases the cost per scan price by around £40. 9.6.2 Cost per scan option 4 (Mobile facility) Indicative costs for four options were sought (‘contractor’ means the company supplying the mobile PET unit): A. Mobile PET scanner situated at a single site throughout the year. Unit staffed by NHSScotland. B. Mobile PET scanner situated at a single site throughout the year. Unit staffed by three fully trained staff supplied by contractor. C. Mobile PET scanner situated at five different sites throughout the year with 30 moves per year. Unit staffed by NHSScotland. D. Mobile PET scanner situated at five different sites throughout the year with 30 moves per year. Unit staffed by three fully trained staff supplied by contractor. In options A and B, the scanner is situated at a single site. This would give the hospital the flexibility to use the equipment without having to spend a large capital amount building a purpose built PET unit. There is no doubt that accommodating a mobile unit will incur building costs however these are unlikely to be of the same magnitude as setting up a fixed site PET unit. The time taken for a mobile unit provided by a contactor to be operational will be significantly less than building a unit in a hospital. Assumptions used for the mobile PET model are presented in Table 9-4. 9-20 Table 9-4 Mobile PET model: assumptions Patient throughput per year Number of working days per year Maximum number of patients per day Maximum operating hours per day Set-up time for unit Fully trained staff provided by: Training and equipment maintenance provided by: FDG provided by: Power supply provided by: Site licences provided by: VAT Cost of adapting buildings/site Number of batches of FDG deliveries per day Option A Option B Option C Option D 1300 1300 1300 1300 240 (NHS standard) 250 (set by contractor) 250 (set by contractor) 240 (NHS standard) 5.4 5.2 5.2 5.4 Included in operating hours 6 (this is set by the contractor) Included in operating hours Included in operating hours 6 (this is set by the contractor) Included in operating hours NHS Contractor NHS Contractor Contractor Contractor Contractor Contractor NHS NHS NHS NHS NHS NHS NHS NHS NHS NHS NHS NHS Included where applicable Included where applicable Included where applicable Included where applicable Not included Not included Not included Not included 2 2 2 2 7 7 It is assumed that set-up time for the unit is included in the number of operating hours per day. Appendix 26 presents in full the costs involved in the four different options of providing a mobile PET service. These costs are based on the contractor providing the scanner unit only; the hospital will be required to provide all the laboratory equipment associated with a fully functioning scanner. Note that no provisions have been made for the costs of acquiring site licences that will be necessary to handle radioactive material or for adapting buildings/site for the mobile service. The contractor will provide training in all options. A small provision of £1,000 has been made to cover uniforms and ad-hoc basic training. Other costs used for fixed and variable operating costs are the same as for option 2 in a fixed PET facility. Summary costs for a mobile PET service are listed in Table 9-5. Costs for purchasing FDG from a NHS source, with and without transport and from a commercial source 9-21 (100 miles transport) are provided. A complete list of options of purchasing FDG is included in Appendix 26. Option B and D result in the same annual cost. This is because the contractor has quoted the same service charge for the two options despite the facts that option B is for a PET unit to remain stationary at one site throughout the year and option D is for a PET unit to make 30 moves between five sites per year. It is important to note that the contractor charges make up the bulk of a mobile option’s operating costs so any variation of these can have a significant impact on the cost per scan value. Figures for a cost per scan for each of the four mobile PET options are listed in Table 9-6. Table 9-5 Mobile PET model: summary costs Staff Operating costs – Fixed per annum Operating costs – Variable per annum Purchase of FDG (NHS no transport) Purchase of FDG (NHS 70 miles) Purchase of FDG (commercial 100 miles) Total (FDG NHS no transport) Total (FDG NHS 70 miles) Total (FDG commercial 100 miles) Table 9-6 Option A £213,691 Option B £124,594 Option C £213,691 Option D £124,594 £656,814 £809,564 £703,814 £809,564 £20,475 £20,475 £20,475 £20,475 £458,900 £458,900 £458,900 £458,900 £506,900 £506,900 £506,900 £506,900 £556,480 £556,480 £556,480 £556,480 £1,349,880 £1,413,533 £1,396,880 £1,413,533 £1,397,880 £1,461,533 £1,444,880 £1,461,533 £1,447,460 £1,511,113 £1,494,460 £1,511,113 Mobile PET model: cost per scan Where FDG is purchased from NHS source (70 miles) Where FDG is purchased from commercial source (100 miles) Option A Option B Option C Option D £1,075 £1,124 £1,111 £1,124 £1,113 £1,162 £1,150 £1,162 9-22 9.7 Budget impact 9.7.1 Annual running cost The annual running costs for options 2 to 4 are presented in Table 9-7 and in more detail in Appendices 24 and 26. A range is presented for options 3 and 4 covering FDG transportation of 70 to 200 miles. Note that the income generation element of a NHS facility supplying FDG to another NHS facility has not been taken into account in the annual cash flow projections or the budget impact to NHSScotland. Table 9-7 Annual running costs (£ million) Option 1 1.173 9.7.2 Option 2 1.016 Option 3 1.011-1.165 Option 4 (mobile) 1.398-1.567 Capital costs Capital costs for options 1, 2, 3 and mobile PET are detailed in Table 9-8. Different financing options can be explored such as leasing and hire purchase of the PET scanner and/or cyclotron. However, this is beyond the remit of this study. Table 9-8 Capital costs (£ million) PET scanner Lab equipment for scanner room Computer equipment for scanning unit Cyclotron Lab equipment for radiochemistry unit Computer equipment for radiochemistry lab Buildings – PET scanning unit Buildings – cyclotron and radiochemistry lab Total Option 1 1.410 Option 2 1.410 Option 3 1.410 Mobile 0 0.1016 0.1016 0.1016 0.1016 0.040 0.040 0.040 0.040 1.175 1.175 0 0 0.543 0.543 0 0 0.0187 0.0187 0 0 0.2831 0.2831 0.02831 0 0.6789 0.6789 0 0 4.250 4.250 1.834 0.1413 9-23 9.7.3 Annual cash flow projections Annual cash flow projections over a 20-year period at 2002/03 prices are listed in Appendices 24 and 26 for the following: Option 1 Option 2 Option 3 where FDG is purchased from a NHS source (70 miles) Option 3 where FDG is purchased from a commercial source (100 miles) Option 4 mobile PET options A to C It is assumed that capital equipment is replaced at the end of its life. Staff costs are indexed at 2% per annum using year one as the base. No other costs are indexed. For options 1, 2 and 3, accumulative cash flow spending at one, five, 10, 15 and 20 years is listed in Table 9-9. Table 9-9 Year 1 5 10 15 20 Accumulative cash flow spending: options 1, 2 and 3 (£ million) Option 1 4.97 7.95 11.97 18.32 22.92 Option 2 4.81 7.14 10.26 15.65 19.19 Option 3 FDG purchased from a NHS source (70 miles) 2.67 6.04 10.41 16.44 21.07 Option 3 FDG purchased from a commercial source (100 miles) 2.72 6.29 10.91 17.17 22.06 For option 4 mobile PET, accumulative cash flow spending at one, five, 10, 15 and 20 years is listed in Table 9-10. Table 9-10 Year 1 5 10 15 20 Accumulative cash flow spending: option 4 (£ million) Option A FDG FDG NHS source commercial (70 miles) source (100 miles) 1.52 1.57 7.07 7.32 14.16 14.65 21.47 22.22 28.83 29.82 Option B FDG FDG NHS source commercial (70 miles) source (100 miles) 1.58 1.63 7.37 7.62 14.71 15.21 22.22 22.97 29.72 30.71 Option C FDG FDG NHS source commercial (70 miles) source (100 miles) 1.57 1.62 7.31 7.55 14.63 15.12 22.18 22.92 29.77 30.76 9-24 9.8 Budget impact discussion Option 2 (fully equipped PET facility integrated with cancer centre using their staff) has the lowest annual running cost at £1.016 million even though this option has the highest patient throughput of 1500. Option 1 (fully equipped PET facility but with separate staff) costs £1.173 million to operate every year. Running costs for option 3 (fixed PET facility, remote FDG) vary from £1.011 million to £1.165 million. Mobile PET (option 4) has the highest running costs at £1.398 million to £1.567 million. A fully equipped PET scanning facility with its own radiochemistry and cyclotron will cost in the region of £4.2 million in capital outlay. A PET unit without the cyclotron would cost £1.8 million. A mobile facility will require around £141,000 in capital outlay. Although the initial capital outlay is much higher for options 1 and 2, a full PET facility as in option 2 demands less cash outlay in the longer run (see annualised cash flow projections). At the end of year 20, option 2 would have cost £19.19 million and option 3 (FDG from NHS) £21.07 million or (FDG from commercial) £22.07 million. At the end of 20 years the cash outlay for mobile PET ranges from £28.83 million to £30.76 million. Running costs do not vary significantly when using a mix of the options in setting up and providing a PET scanning network across Scotland. However, there is a significant impact on capital outlay. Capital outlay required for option 2 is over twice as much than that required for option 3. In the future, private companies may manage PET facilities and have capacities to sell scans to the NHS or supply FDG. As no such facilities are currently established in the UK it has not been possible to cost this option. 9-25 9.9 Organisational issues conclusions PET facilities and cyclotrons should be organised to provide appropriate provision and equitable access for all patients with cancers who may benefit from scanning. The layout of the facility and production and transportation of radiopharmaceuticals must comply with legal requirements. Appropriate training and accreditation must be created for radiopharmacists, radiochemists and cyclotron engineers. This would be best achieved on a national (UK) basis. Budget impact calculations demonstrate that it is cheaper to have a fixed PET facility with cyclotron integrated into an established clinical centre, with sharing of cancer centre staff (option 2). With an estimated throughput of 1500 patients per year, the estimated cost/scan of such a facility is £677. However, the capital outlay needed to set up this type of facility is substantial. Furthermore, building a new facility will mean that there will be a significant time delay before the services come on stream. If FDG is purchased remotely (option 3), the capital cost is lower, but the cost per scan is estimated to be between approximately £800 and £900 with 1300 patient throughput per annum, depending on transportation distance and supplier. Mobile PET has higher long-term costs and a higher overall cost per scan of approximately £1130 with 1300 patient throughput per annum. This needs to be offset against the fact that a mobile facility can be operational within months and at a fraction of the capital that either options 2 or 3 will require. However, it is important to stress that costs for mobile PET are less robust, because there is currently no mobile PET service provided in the UK that can be used as a basis for cost estimates. It is important to acknowledge that the cost per scan estimated is dependent on the number of patients that can be scanned per annum. However, during the first year of operation, it is unlikely that the level of patient throughput assumed in the HTBS model will be achieved in a new PET facility, as it will take some time to have a fully trained team of staff and to raise awareness and promote the service. Furthermore, in section 10.4 health services research is recommended to inform further economic modelling to determine the value of PET in other cancers. The cost of this research has not been considered in these budget impact calculations. 9-26 10 DISCUSSION 10.1 Scope of the HTA This HTA evaluates the issues of clinical effectiveness, cost effectiveness, patients’ needs and preferences, and organisational issues that pertain to the introduction and development of PET imaging facilities for the management of cancer in Scotland. As outlined in section 1, this report has focused on full-ring PET scanners and on the use of the radiopharmaceutical FDG. This is appropriate as gamma cameras and combined PET/CT machines have a weaker evidence base than full-ring PET and most oncology applications use FDG. This HTA has taken data and evidence from a broad range of sources (including, but not limited to, peer-reviewed literature, preprints and manufacturer submissions) and critically appraised it to ensure that analyses of clinical and cost effectiveness are as robust as possible. 10.1.1 Clinical effectiveness - NSCLC (section 4) There is clear evidence from the systematic review and meta-analysis conducted by HTBS that FDG-PET imaging is both more sensitive and more specific than CT scanning in mediastinal staging for N2/N3 lymph nodes in patients with potentially operable NSCLC. There is some evidence from less robust studies that FDG-PET more accurately detects previously unsuspected metastatic disease. In terms of changes in patient management, published studies indicate that after FDG-PET, between approximately 10% and 40% of patients had management altered. However, these results arise from case series that may specifically select patients and so may be biased. Three studies have reported the findings of surveys of the use of FDG-PET in NSCLC in routine clinical settings. The most recent of these (Seltzer et al., 2002) illustrates the problematic nature of these surveys and the danger of attempting to draw conclusions from them. They sent survey questionnaires to 292 physicians, who referred 744 consecutive lung cancer patients for FDG-PET. Only 48% of the physicians responded to the questionnaire and this covered just 37% of the lung cancer patients. Two randomised controlled clinical trials (Boyer et al., 2001 and van Tinteren et al., 2002) have been performed to assess the effect of FDG-PET scanning in NSCLC. In both trials patients were randomised between conventional staging for mediastinal involvement and conventional staging plus FDG-PET scanning. The primary outcome in both cases was the number of ‘futile’ thoracotomies avoided. The trials produced apparently conflicting results; van Tinteren et al. (2002) reported a 50% reduction in the number of ‘futile’ operations, whereas Boyer et al. (2001) reported no difference between the two groups. This discrepancy appears to be caused by a difference in approach to patient management between the two groups of investigators. Specifically, Boyer et al. (2001) report that, in their institution, patients with early N2 disease undergo surgery and that a similar number of operations would have been avoided had the policy of avoiding surgery for N2 patients, as in the Dutch study, been in place. Neither of these studies reported quality of life measurements. 10-1 10.1.2 Economic evaluation NSCLC (Section 5) Cost-utility analysis was used to compare seven diagnostic strategies for patients who have undergone chest X-ray and biopsy and are thought to have potentially operable NSCLC. Strategies 1 and 2 consider sending all patients to surgery or all to oncology and were included for model testing purposes. Strategy 3 reflects current standard practice in Scotland (without FDG-PET). Strategies 4 to 7 included FDG-PET in the diagnostic pathway in a variety of ways, before or after mediastinoscopy. In line with other economic models of NSCLC and anticipated use of PET in Scotland, it is assumed that all patients have undergone a CT scan prior to implementing any of the strategies. Of the plausible clinical strategies (strategies 3 to 7), 3 and 7 were shown to be cost effective in the base case model for CT-negative patients, but strategy 7 was not cost effective for CT-positive patients. In strategy 7 those who are FDG-PET negative are sent to surgery, while FDG-PET positives are sent for a confirmatory mediastinoscopy and then to surgery or non-surgical treatment and it is notable that the greater value is achieved in this strategy for those patients who have better prognosis, i.e. the CT-negatives. It also appears that the closer FDG-PET accuracy in detecting M1 disease approaches that in detecting N2/3 disease the greater will be the cost effectiveness of moving to strategy 7, particularly among CT-positive patients. Strategy 1, all for surgery, also appeared to be promising in the model, but this strategy is associated with a large number of futile operations and so would not be appropriate in clinical practice. However, this highlights a weakness in the model, that it was not possible to quantify the utilities associated with avoidance of futile surgery. Another strategy of sending all patients for FDG-PET, prior to CT, is not cost effective compared with strategy 7. This is not surprising as it is not possible to differentiate the CT-negative and CT-positive patients in advance in this strategy and the value of PET in CT-positive patients is less clear. In CT-negative patients, the base-case analysis suggests that moving from strategy 3 to strategy 7 is cost effective (ICER £10,475). However, in CT-positive patients, the case for moving from strategy 3 to strategy 7 is weak (ICER £58,951) due to the poor specificity of FDG-PET in these patients. Even for CT-negative patients, strategies 3 and 7 were not strongly differentiated by patient impact as measured by QALYs, and different utility values could lead to different rankings between these two strategies. Thus the value of using FDG-PET added to the current standard of diagnostic workup in terms of QALYs is not clear. Another way of evaluating the strategies is to consider the number of correct operations undertaken and the number of futile operations avoided. Among CTnegative patients, strategy 7 avoids an additional 6% of patients undergoing futile surgery compared with strategy 3. This is due to the superior specificity of FDG-PET in CT-negative patients. Among CT-positive patients only an additional 1% of patients avoid futile surgery with strategy 7 compared with strategy 3. 10-2 It cannot be unambiguously stated which of strategies 3 and 7 is the more cost effective, nor is it possible to estimate the probability of the individual strategies being cost effective. The principal conclusion is that FDG-PET is most likely to be cost effective when followed by a confirmatory mediastinoscopy in patients who are FDG-PET positive in mediastinal lymph nodes. It is also more likely to be cost effective in CT-negative than in CT-positive patients. However, the information gaps render a definitive conclusion on the cost effectiveness of using FDG-PET in NSCLC inappropriate at this time. Health services research in a clinical setting is required to address the data gaps in diagnostic accuracy, particular for distant metastases, in treatment life expectancies, and in determining patient utilities associated with avoiding futile surgery. 10.1.3 Clinical effectiveness – Lymphoma (Section 6) Although the studies of accuracy in restaging lymphoma after induction therapy are generally retrospective and include heterogeneous patient groups (the majority of series include both HD and NHL patients), a consistent picture emerges of FDG-PET being at least as sensitive, and substantially more specific, than CT for the detection of viable residual disease. 10.1.4 Economic evaluation – Hodgkin’s disease (Section 7) The cost-effectiveness modelling was restricted to restaging HD. The model examined the value of using FDG-PET as an adjunct to, or a replacement for, CT scanning for the assignment of patients to consolidation therapy or surveillance after induction therapy. The base-case analysis suggested that the use of FDG-PET after a positive CT scan (strategy 4) and the use of FDG-PET to replace CT (strategy 5) were both cost effective relative to the use of CT alone, provided the willingness to pay per life year exceeded £1,000. Strategy 5, replacing CT by PET, was both clinically more effective and less expensive than strategy 4. Sensitivity analyses showed that both strategy 4 and strategy 5 remained cost effective for at least 95% of simulations from the joint distribution of input values, provided that the willingness to pay per life year exceeded £5,000. The probability of cost effectiveness for strategy 5 at a specificity of 70% exceeded 95%, provided the willingness to pay exceeded £5000. Increasing the discount rate on benefits from 1.5% to 6% reduced the apparent superiority of FDG-PET containing strategies relative to other approaches. However, there was little impact on cost effectiveness for either strategy 4 or strategy 5, except that the probability of cost effectiveness for strategy 4 in 20-year-old males reached 90% only if the value of a life year exceeded £15,000. Overall, the model predicts that 36% of patients restaged using CT alone will receive unnecessary consolidation RT. This would be reduced to approximately 5% with either FDG-PET strategy. 10-3 The robustness of the modelling results to uncertainties and altered assumptions, alongside the low cost per life year gained and benefits in terms of avoidance of unnecessary RT, indicate that FDG-PET provides substantial value in the restaging of HD. Although the role of FDG-PET scanning in NHL has not been modelled in this HTA, the accuracy demonstrated in section 6 is likely to translate into significant patient benefits in this indication. Since the main area of uncertainty in NHL is whether a combination of CT and prognostic scores is sufficiently accurate in selecting patients for consolidation, it will be appropriate to study the comparative accuracy of FDGPET and conventional methods in a prospective study. 10.1.5 Clinical effectiveness – Other clinical applications (sections 2.3 and 2.4) 10.1.5.1 Cancer In the USA, Medicare currently reimburses FDG-PET imaging for specific management decisions in NSCLC, SPN, lymphoma, colorectal cancer, head and neck cancers, melanoma, oesophageal cancer and breast cancer and is considering extending its reimbursement to include some central nervous system tumours. A number of countries have undertaken HTAs of FDG-PET in cancer. Most have reached similar conclusions that FDG-PET is more accurate than conventional technologies, but that the evidence for translating this into patient benefit, even just change in patient management, is weak and often relies on case series of selected patients. Consequently definitive conclusions cannot be drawn about the clinical and cost effectiveness of PET in these various indications at this time and further evaluation of the technology is necessary. In Australia, MSAC (2000 and 2001) concluded that there was insufficient evidence to recommend unrestricted funding, but that FDG-PET is safe, and potentially clinically and cost effective in a number of cancers (NSCLC, melanoma, recurrent colorectal cancer, recurrent ovarian cancer, cervical cancer, oesophageal cancer, gastric cancer, lymphoma, head and neck cancer, sarcoma). They recommended that interim funding be made available for use of FDG-PET in these cancers, according to MSAC-approved prospectively designed studies, with all data sent to a central coordinating body, to better determine the clinical and cost effectiveness of FDGPET. The cancers highlighted by MSAC are wide ranging and some have a weaker evidence base than others. Other HTAs would imply that the strongest evidence of clinical effectiveness is available for NSCLC, SPN, recurrent head and neck cancer and malignant melanoma (DACEHTA, 2001). DACEHTA concluded that the evidence for the value of FDG-PET in recurrent colorectal cancer was sparse; it may be ‘important’ but was probably influenced by poor prognosis in this cancer. For breast cancer, it was noted that there were a number of sources of error in the presented trials but that it looked ‘promising’. They note that clinical development is also being pursued in lymphoma, oesophageal, brain and testicular cancer. 10-4 10.1.5.2 Cardiology, neurology and psychiatry There is general agreement that, so far, the evidence of benefit in cardiology, psychiatry and neurology is weaker. Furthermore, there are good alternative techniques to aid clinical decision-making in cardiology. In dementia, the benefit achieved would probably be small due to the modest benefit of currently available treatments. Consequently more research is needed of the value of PET in these conditions before it is brought into routine clinical use. 10.1.6 Safety (Section 4.6) The literature shows no evidence of any important short-term adverse events related to PET scanning. Therefore, it is reasonable to conclude that PET is essentially free from short-term adverse effects. There is a risk of second cancers posed by the radiation dose used in PET scanning, but this is very small (a lifetime cancer risk of less than one in 3000 for a person of normal life expectancy) and comparable with that associated with CT. 10.1.7 Patient issues (Section 8) Patients need to be fully informed about the imaging process and any side effects. Information given by consultants is valued but checks are needed to ensure that information has been understood by the patient. Advice about current services, counselling and any risks should be provided without people having to ask for it. Information for carers is also needed. There is evidence from lymphoma patients that some value the additional information provided by an FDG-PET investigation and the reassurance that this provides. Patients also value the timeous treatment they currently receive once the diagnosis has been made. However, there is a perception that the system is ‘bottlenecked’ at the initial diagnosis stage. Therefore it is important that the addition of a PET scan to the diagnostic work-up does not lead to additional delays in the initiation of treatment. PET imaging should be coordinated with other diagnostic procedures to minimise travelling, disruption and anxiety. The facilities should be created to make the patient feel comfortable and at ease with the process. Following the introduction of clinical PET in Scotland, further research is required to understand the needs and preferences of patients and carers. 10.1.8 Organisational issues and costings (Section 9) PET facilities and cyclotrons should be organised to provide appropriate provision and equitable access for all patients with cancers that may benefit from imaging. The layout of the facility and production and transportation of radiopharmaceuticals must comply with legal requirements. Specialist training and accreditation must be created for radiopharmacists, radiochemists and cyclotron engineers and appropriate training must be given to all those involved in the multidisciplinary cancer team. 10-5 Any PET facility would have to guarantee a reasonable service to patients from across Scotland, without disadvantaging those in the more rural and remote areas, such as the rural Southwest and the Highlands and Islands. The risk that the provision of PET scanning might further slow down the progress from initial diagnosis to definitive treatment, by introducing a further rate-limiting step in the patient’s journey, should be recognised and addressed. A PET facility incorporating a cyclotron to produce its own radiopharmaceuticals and integrated with other nuclear medicine facilities has the lowest running costs and cost per scan (£677). However, the capital outlay for such a facility is substantial (approximately £4.25 million) and there would be a time delay to build the new facility. Capital outlay may be reduced (£1.83 million) if the radiopharmaceuticals are available from an alternative source and a cost per scan of £777 to £900 is estimated, depending on distance from source and provider (NHS or commercial). Both these facilities have a total annual running cost of just over £1 million. It will take approximately two years to build a PET facility and a further year until it is operating at full capacity. Interim solutions should therefore be considered, particularly for the restaging of patients with HD. One possible interim option is the use of the John Mallard Scottish PET Centre in Aberdeen, which is currently used as a research facility but could potentially provide a service element for 2 or 2.5 days a week, with an estimated throughput of 300 to 400 patients per annum. The use of other UK facilities for HD staging could also be considered. An alternative mode of delivery would be the use of a mobile facility. This would be more expensive on a cost per scan basis (approximately £1,130) and for annual running costs (approximately £1.5 million), but would be quicker to establish and would involve very little capital outlay. However, there is little experience of such mobile PET facilities in the UK and FDG would need to be sourced. 10-6 10.2 Assumptions, limitations and uncertainties It may be argued that PET is being judged more stringently than previous diagnostic tests. However, given the substantial capital and running costs associated with a PET facility and the competing demands for limited health care resources, it is entirely appropriate to subject it to evaluations that will determine its value in routine clinical practice. In summarising the Medicare reimbursement process for diagnostic tests, Newman (2001) identified that reimbursement depends not only on the sensitivity and specificity of the test, but also evidence of change in patient management or outcomes. The value of a test must be considered in terms of its impact on clinical treatment. This highlights the difficulty in assessing a diagnostic procedure. With the exception of two trials in lung cancer (van Tinteren et al., 2002 and Boyer et al., 2001), and a small number of economic modelling studies, the research literature has focused on the issue of superior diagnostic accuracy, with little attention paid to ‘higher level’ outcomes (Fryback & Thornbury, 1991) such as the outcome of the patient’s disease. The evidence available of superior diagnostic performance, although important, does not directly answer the key questions about final patient outcomes and quality of life. The analyses attempted in this review are therefore necessarily based on modelling, and on assumptions that are sometimes difficult to verify. A common criticism of models is that the wide freedom of action given to the analyst may cause bias (Buxton et al., 1997; Kassirer & Angell, 1994). Certainly, any largescale analysis of a problem risks bias, and in this respect an ambitious model is more at risk than the dataset from a single randomised, controlled, trial. However, models usually address larger problems than trials, considering how evidence can be translated into clinical practice given a much longer time horizon than it would be practicable to study in a trial. 10.2.1 Assumptions Models require specification of the patient pathway and prediction of response along that pathway until the death of the patient. Such modelling inevitably depends on a number of assumptions. These have been obtained by discussion with experts and literature-based estimates. 10.2.2 Limitations This HTA has focused on the use of FDG-PET within oncology, and specifically in the areas of preoperative mediastinal staging of NSCLC and restaging of HD. As explained in section 1, this has been necessary to allow detailed economic modelling. However, the conclusions stated here should be considered alongside the other HTA work presented in section 2, which presents evidence on clinical effectiveness in other areas of oncology, and for cardiology and neurology, and the need for structured clinical research (see section 10.4). 10-7 As this HTA has focused on the ‘patient and societal’ outcomes of the technology (Fryback & Thornbury, 1991) it has not looked at the more speculative ‘researchorientated’ uses of FDG-PET, such as monitoring response to therapy and following the distribution of appropriately labelled cytostatic drugs (e.g. Strauss, 1997; Jerusalem et al., 2000; Smith et al., 1998). Arguably, in doing so, it may understate the future value of PET scanning to Scotland’s health. Knowledge about the patient experience and patients’ needs and preferences in relation to PET imaging is weak. Lack of published research in this area, the absence of patient experience of PET in clinical practice in Scotland and difficulties in recruiting participants for patient issues focus groups have resulted in a limited understanding of these issues. This information needs to be gathered from a diverse group of patients. As the utility value of different health states for patients or members of the public is not known, the economic model could not be informed by this information. Additionally, it would seem reasonable that PET may provide knowledge that has a role in reassuring patients and reducing anxiety and that, as individuals, patients will value treatment differently. This has been considered in the assessment, but could not be quantified. Furthermore, appropriately using this qualitative information in an economic model poses a considerable challenge. It has not been possible to determine whether undertaking a PET investigation would increase the time to diagnosis and subsequent treatment. Clearly this should be avoided and so careful consideration should be given to the scheduling of PET scans. The existence of such delays should be monitored as part of continuing health services research in the use of PET in NHSScotland, by comparing times to diagnosis and treatment for cancers in which PET scanning is, and is not, offered as part of the management pathway. Similar research should be directed at ensuring that geographical and socioeconomic equity of access to PET facilities is maximised. 10.2.3 Uncertainties In NSCLC, univariate and bivariate sensitivity analyses have been used to draw out the uncertainties in the model. These have been sufficient to identify the instability in the model and the need to determine key pieces of information more clearly, particularly valuation of avoidance of futile surgery. For HD, uncertainties have been formally modelled in a multivariate manner using Bayesian techniques and these have shown that the model is robust to all areas of uncertainty. 10-8 10.3 Future developments The information on imaging time used in this report has been obtained from St Thomas’ Hospital and is based on a PET scanner that is nine years old. There is anecdotal information that recent advances in technology have resulted in reduced scanning times and increased patient throughput, with a corresponding impact on the cost per investigation. However, currently there are no published data to support this (see also the discussion of PET/CT in section 2.5.5.2). The current assessment is based on full-ring PET systems using BGO scintillation crystals. New crystals are being developed that may improve the image quality of PET scanners in the future. However, it is likely that these systems will be more expensive. 10.4 Research Close cooperation is required among all those involved in cancer care to determine which clinical areas might benefit most from PET imaging investigations. This applies both to future scientific studies, to the evaluation of published data and to the planning of diagnostic and treatment guidelines. It is recommended that all patients undergoing a FDG-PET scan should have outcomes recorded, either through participation in national or international clinical trials to confirm and extend the current applications of FDG-PET, or through health services research constructed to allow costs and patient outcomes to be recorded to inform economic modelling. It will be particularly valuable to identify cancers with a good prognosis where the accuracy of alternative diagnostic or response monitoring mechanisms is poor. Appendix 27 recommends data that should be collected for the ongoing clinical and economic evaluation of FDG-PET imaging in NHSScotland. Additionally, as indicated in section 8, information about the patients’ experiences, preferences and needs in relation to PET imaging needs to be recorded. The collection of all data must, of course, comply with all regulations on confidentiality and security of patient information and patient consent as presented in the report on Protecting Patient Confidentiality (CSAGS, 2002). It is clear that for most, if not all cancers, such trials cannot be confined to Scotland, but must take place collaboratively across the UK, or possibly across Europe. However, it is vitally important that Scottish patients are encouraged to enter clinical trials. A recent review shows that only 2.4% of patients of all newly diagnosed lung cancer patients in Scotland (small cell and non-small cell), were recruited into clinical trials in 1997-1998 (Scottish Executive Health Department, 2001c). It is noted that the costings for the PET facility do not include research costs, so it will be essential to obtain funding from elsewhere. The National Cancer Research Institute (NCRI) is a UK body comprising the main cancer research funders and is responsible for the strategic leadership of cancer research in the UK. The National Cancer Research Network (NCRN) was established in April 2001 by the Department of Health to improve the quality, speed and integration of cancer clinical trials and thus to improve patient care. The NCRN is 10-9 expected to double recruitment into clinical trials in England within the next five years. It will do this through the creation of cancer research networks, closely aligned to NHS cancer service networks, and in close collaboration with NCRI on a range of issues that impact on the quality and management of cancer research. The establishment of a Scottish Cancer Clinical Trials Network is currently underway and it is proposed that this organisation will work in partnership with NCRN (and therefore within NCRI). It is envisaged that the Scottish network will map onto the three existing regional networks, which are established in the north, south, east and west of Scotland. These networks provide an ideal framework on which to build research governance requirements, including peer review and protocol development. In the UK, the NHS HTA programme is also considering proposals for primary HTA research in PET imaging. HTBS recommends that this be focused on the cancers determined by DACEHTA to have promising evidence of clinical effectiveness (NSCLC, SPN, recurrent head and neck cancer and malignant melanoma) and on lymphoma. Three main areas of clinical and economic evaluation can be identified: translation of the superior accuracy of FDG-PET into clear patient benefits or cost savings; translation of the ability of FDG-PET to image metabolism into clear patient benefits or cost savings; and methods of using FDG-PET to facilitate other research in oncology. These three areas are discussed in the following sections. 10.4.1 Exploiting the superior accuracy of FDG-PET scanning Although there is considerable evidence that FDG-PET scanning is more accurate than CT scanning in many forms of cancer, there are few published studies that establish the impact of the superior diagnostic accuracy of FDG-PET on patient outcomes, such as survival and quality of life in NSCLC. Trials of this kind will need to be designed and justified by the detailed modelling of possible patient outcomes and associated costs and benefits. Studies using Markov models, as described for example, in Fenwick et al. (2000), can be used to support the development of clinical studies. This type of approach, firmly based on a combination of clinical knowledge and modelling, is likely to yield novel approaches to the use of FDG-PET to improve patient survival and quality of life, and will be vital if the promise of FDG-PET is to be realised. Trials focusing on improving the delivery of effective treatment to patients rather than diagnostic accuracy, are essential in proving and realising the value of PET scanning to the NHS. In addition to trials focused on the ‘avoidance of futile therapy’ (e.g. van Tinteren et al., 2002) FDG-PET may, more positively, help to improve survival by improving the planning of radical RT. 10-10 10.4.2 Exploiting the imaging of function In addition to better diagnostic accuracy, FDG-PET is able to give visual representations of changes in the tumour that occur as a result of treatment. Consequently, FDG-PET may be useful in identifying response early in a course of treatment (Smith et al., 2000), for example in neoadjuvant therapy for breast cancer or in treatment of high-grade NHL. This may enable an early change of treatment in nonresponders, but this clearly needs to be proven in a randomised trial. 10.4.3 Facilitating research PET scanning may be of value in a number of ways in cancer research: in defining response to treatment in early phase studies (e.g. van Oosterom et al, 2001); ‘proof of principle’ studies to demonstrate that tumour response as determined by pre- and post- treatment PET scans can serve as a surrogate outcome variable (Prentice, 1989; Lin et al., 1997) for long-term survival in cancer trials; facilitating development through pharmacodynamic studies in clinical trials (Aboagye et al., 2001); and improving selection of patients for clinical trials by better staging. 10.4.4 Approximate scan numbers in Scotland Using a PET facility for a mix of routine clinical use for restaging HD and health services research to inform economic models, the following calculations may provide a rough guide to capacity requirements in Scotland. The recommendations for health services research are based on DACEHTA’s clinical effectiveness conclusions (10.1.5.1) (DACEHTA, 2001) and are estimates of the number of patients who might be eligible for scanning if these recommendations were adopted in Scotland. Estimates of incident cases are taken from the ISD website figures, which quotes for 1998 <http://www.show.scot.nhs.uk/isd/cancer/facts_figures/facts_figures.htm>. When choosing cancers to be evaluated, it should be remembered that the maximum capacity for a PET facility is estimated to be approximately six patients per day (approximately 1500 patients per year). Combining the reasonably conservative estimates presented here, approximately 1600 patients per annum would require scans. 10.4.4.1 Routine clinical use Restaging HD: 130 incident cases, 75% receive chemotherapy, 90% response implies approximately 90 patients. 10.4.4.2 Health services research Restaging NHL: 1020 incident cases, approximately 50% receive chemotherapy, 90% response rate implies 450 patients. 10-11 Staging NSCLC: In 1997, 880 patients underwent surgery for NSCLC, so it may be estimated that 1000 FDG-PET scans may be required for those potentially eligible for surgery in 2003. If FDG-PET scanning is restricted to CT-negative patients only, this figure would be reduced to approximately 640 patients. SPN: No Scottish incidence data, but comparison with imaging figures from US centers suggests that up to 200 patients may require scans (MSAC recommends that PET scanning be restricted to patients with low pre test probability of malignancy or who are unsuitable for fine-needle aspiration biopsy). However, only between 80 and 120 of these patients are likely to have potentially resectable CT-negative malignant disease, therefore the additional number of scans required is unlikely to exceed 120 patients (and may well be fewer). Recurrent head and neck cancer: Scottish incidence of this cancer is approximately 1100 cases per annum, and estimates of five-year recurrence rate are as high as 50% (Sidransky et al., 1998). In practice the number of patients requiring FDG-PET will be lower than the 550 this suggests because some patients will be too sick to benefit from further treatment and some will clearly have distant metastases. Hence in the summary calculation a figure of 150 patients is assumed for recurrent head and neck cancer. Malignant melanoma: The draft SIGN guideline on melanoma suggests that PET is only likely to be of value in stage III or IV disease. There are roughly 600 incident cases per year in Scotland. US data (Coleman, 2002) suggest that 12% of cases are stage III/IV, data from New Zealand’s Ministry of Health (1999) suggest that ~ 20% are stage III/IV. Consequently, the number of scans needed is unlikely to exceed 100. 10-12 10.5 Summary and conclusions HTAs from around the world agree that there is insufficient evidence to fully recommend FDG-PET imaging as a standard technique in cancer management at this time. However, improvements in diagnostic accuracy compared with other imaging modalities and weak evidence of change in patient management from case series, indicate that FDG-PET is ‘potentially’ clinically and cost effective. Cancers for which there is general agreement of potential value are NSCLC, SPN, recurrent head and neck cancer and malignant melanoma. There are only two good quality clinical studies that evaluate how FDG-PET has improved patient outcomes. Both of these are in NSCLC, but they give somewhat conflicting results as to the value of FDG-PET in avoiding futile surgery and are dependent on the decisions taken by surgeons after FDG-PET, with benefit only demonstrable if an operation on N2 patients is considered futile. The economic modelling work undertaken in this HTA is particularly valuable for assessing the role of PET in restaging HD where potential benefit (avoiding long-term morbidity associated with unnecessary RT) is large, but also occurs a long time after the scan. Collection of such outcome data is difficult in a clinical trial and this is a good example of where a detailed model quantifying all associated uncertainties is helpful. This model showed that either FDG-PET strategy was more cost effective than the current practice, with use of FDG-PET instead of CT being most cost effective. This shows the value of modelling work that can link changes in accuracy, with patient management and long-term outcomes using evidence from a variety of sources and sophisticated analyses of uncertainty to provide reassurance about the robustness of the model. The economic evaluation for staging NSCLC contains inherent uncertainties in the input assumptions and indicates that FDG-PET is cost effective in CT-negative patients; if those who are negative are sent for surgery and those who are positive are sent for mediastinoscopy. Other possible uses for FDG-PET scanning, such as to replace mediastinoscopy completely, do not appear cost-effective in this setting. However, this model is less robust than that for HD and further work is needed to ensure that the value of avoiding futile surgery is captured in the model. The economic models both indicate that the value of FDG-PET would appear to be greatest where the accuracy of other imaging or diagnostic techniques is poor and where knowledge from FDG-PET imaging can lead to substantially better prognosis for the patient. It is this finding that should drive future work with FDG-PET into its potential clinical role. Overall following the synthesis of evidence on clinical and cost effectiveness, organisational issues and patient needs and preferences, HTBS believes that FDGPET can be a valuable tool in cancer management. 10-13 Claxton et al. (2002) suggest four possible recommendations from an HTA ‘implement, implement with further research, do not implement but conduct further research, do not implement’. In the vocabulary of this article the recommendation from HTBS for FDG-PET scanning is in the second category, i.e. that FDG-PET imaging should be implemented in Scotland and that further research should be undertaken to confirm and extend its usefulness. FDG-PET is recommended for routine clinical use in restaging HD, in properly organised health services research for other high-grade lymphomas, and in patients with NSCLC who are CT-negative. Its use in SPN, recurrent head and neck cancer and malignant melanoma looks promising from the viewpoint of diagnostic accuracy and research into the specific value of FDG-PET in terms of patient outcomes and economic value in these cancers should be determined as an early priority. 10-14 10.6 Recommendations to NHSScotland As a result of this HTA, HTBS has made recommendations to NHSScotland about the clinical and cost effectiveness of PET imaging for cancer management, these are presented in full in the Health Technology Assessment Advice on positron emission tomography (PET) imaging in cancer management (HTBS, 2002a). Listed below is the summary of recommendations. It is recommended that a PET imaging facility including a cyclotron, dedicated to clinical use and specific health services research applications, should be set up in Scotland to allow Scottish patients and researchers to realise the potential benefits of FDG-PET imaging in cancer management as rapidly as possible. It should be linked to an existing cancer centre, with functional links to the existing PET facility in Aberdeen. It will take approximately two years to build such a facility, so interim solutions for the provision of PET imaging should be considered, particularly for the restaging of patients with Hodgkin’s disease. Possible options are the use of the John Mallard Scottish PET Centre in Aberdeen, other UK facilities, or the use of a mobile PET facility in a fixed location in Scotland. All patients who require re-staging of Hodgkin’s disease should be sent for a FDG-PET scan. Extension to the restaging of all patients with lymphoma should be investigated by further research. Appropriate research should be undertaken to inform economic modelling in order to produce a robust assessment of the value of FDG-PET imaging in the staging of patients with NSCLC who are CT-negative in the regional lymph nodes. For other cancers, FDG-PET is likely to add most value where existing diagnostic/monitoring techniques have poor accuracy and information from PET imaging can substantially improve prognosis. This should be evaluated through health services research, taking account of the clinical effectiveness results from other international HTAs. Research priorities should be agreed with multidisciplinary expert groups, Regional Cancer Advisory Groups, the Scottish Cancer Group, the NHS HTA programme and other international research organisations. All research should be coordinated with the Scottish Cancer Clinical Trials Network. All patients undergoing FDG-PET should have outcomes recorded, either through participation in a national or international trial to confirm and extend the current applications of FDG-PET imaging or through health services research designed to allow costs and patient outcomes to be recorded for economic modelling. 10-15 11 ACKNOWLEDGEMENTS HTBS is grateful to all members of the TSG who have contributed to the appraisal of the evidence in relation to the Scottish situation and writing many of the technical sections this report. Thanks to all those who submitted evidence at the outset and those who have provided access to information, particularly grey literature during the assessment. The special advisers are also thanked for reading earlier drafts of the report at a time when evidence was still emerging. Scottish lung cancer experts are thanked for responding to various enquiries about lung cancer diagnosis and treatment in Scotland. 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