Assessment of the business case for Positron Emission Tomography (PET) Scanning

Transcription

1 Assessment of the business case for Positron Emission Tomography (PET) Scanning May 2007 NSTR Reference 01

2 Citation: Ministry of Health. July Assessment of the Business Case for Positron Emission Tomography (PET) Scanning. Wellington: Ministry of Health. Published in July 2008 by the Ministry of Health PO Box 5013, Wellington, New Zealand ISBN (Online) This document is available on the Ministry of Health s website:

3 About NSTR The National Service & Technology Review Advisory Committee (NSTR) is part of the Service Planning and New Health Intervention Assessment (SPNIA) Framework process. NSTR is responsible for horizon scanning, coordinating business case development, and analysing and evaluating proposals for change and business cases that are developed through the SPNIA Framework. NSTR currently makes recommendations to all the District Health Board (DHB) Chief Executive Officers (CEOs) and to the Ministry of Health s Executive Leadership Team (ELT) on national service matters and new health interventions that have a national impact. NSTR s role is to: provide technical and strategic policy advice to the DHB CEOs and the Ministry s ELT on health service configuration and health interventions that have a national impact horizon scan for new health interventions that could be considered for formal assessment because of their potential value horizon scan for services and health interventions that are obsolete, ineffective or inadequate, and therefore exit or cessation is likely to be appropriate maintain a register of health interventions and potential disinvestments that have been recommended for assessment, and their status develop, over time, a precedent-based threshold against which health interventions can be ranked on their appropriateness for introduction to the New Zealand public health system, or for their provision to cease provide timely recommendations to the National Capital Committee on the service aspects of capital projects that require National Capital Committee approval co-ordinate the development of business cases, including the evidence component analyse and evaluate proposals for change and business cases and recommend their adoption or rejection to the DDG-CEO Group. Printed copies of the report can be obtained from: NSTR Convener Ministry of Health PO Box 5013 Wellington New Zealand Enquiries about the content of the report should be directed to the above address. Assessment of the Business Case for Positron Emission Tomography (PET) Scanning iii

4 Contents About NSTR iii NSTR Recommendations 1 1 Introduction Context 13 2 Development of the Options and Recommendations Overview Alternatives 15 3 Description of the technology, disease state and therapeutic interventions Basic principles of PET Technology PET applications Importance of Cancer in NZ Nature of interventions 27 4 Evidence of efficacy and effectiveness of PET Methodology Sources of evidence for the role of PET in clinical medicine Evidence for PET for cancer management 28 5 Economic assessment Overview Potential costs and benefits Costs identified Likely patient benefit 44 6 Business implications Capital expenditure and implementation costs Forecast of cost to DHBs Analysis of financial implications for provider of national service 54 7 Consultation summary Summary of medical comment Summary of research comment 57 iv Assessment of the Business Case for Poistron Emission Tomography (PET) Scanning

5 8 Specific areas of influence Community acceptability Cost-benefit assessment Equity of Access Size of the cyclotron Strategic development Next stages of analysis 65 Waikato Hospital Radiology Services - Positron Emmision Tomography (PET) Imaging Submission 8 Background 8 Key Issues 8 Demand for PET 9 C2: EVIDENCE FOR PET FOR CANCER MANAGEMENT (3) 33 Business/Programme Environment 50 Linked projects and processes 51 The objective is to provide a professional business case for PET Scanning that can be submitted to NSTR (via the Steering Group). 51 National Positron Emission Tomography Scanning Business Case Project 55 Key messages for the PET Scanning Business Case 55 National Positron Emission Tomography Scanning Business Case Project 56 Key messages for the PET Scanning Business Case 56 National Positron Emission Tomography Scanning Project in Context 61 Key messages for the PET Scanning Business Case Project 62 Project Inclusions 62 Assessment of the Business Case for Positron Emission Tomography (PET) Scanning v

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7 NSTR Recommendations The National Service and Technology Review Advisory Committee recommends that the DDG-CEO Group endorse the following: 1. Note that Positron Emission Tomography (PET) scanning is a widely adopted and proven technology, and further development will enhance its future value. 2. Note that PET scanning is currently available in New Zealand in an unco-ordinated and inequitable manner and that inaction will make the current situation worse. 3. Note that New Zealand s current regulatory environment is fully equipped to cope with the introduction of PET technology and its consequential impacts. 4. Agree to support an initial investment in PET of one cyclotron and one full ring PET scanner. 5. Note that the estimated capital cost of this option is $13 million, the estimated annual operating cost is $4.3 million, and the estimated one-off implementation cost is $2 3 million. 6. Agree the following service configuration for the recommended investment. That: a. the PET service agreed should be established at Auckland DHB and/or the University of Auckland Faculty of Medicine and Health Sciences b. Auckland DHB recommends to the National Capital Committee how ownership of the assets should be treated between Auckland DHB and the University of Auckland Faculty of Medicine and Health Sciences c. the service should be a national service d. a National PET Advisory Committee be established, initially as a subcommittee of the National Cancer Treatment Working Party and these governance arrangements be reviewed after 18 months e. savings from PET scanning should be identified and quantified as part of the business case for capital funding f. the cost to DHBs should be off-set by the proceeds of any sale of isotopes. 7. Recommend that national CEOs agree that: a. funding for the service not be volume based, but be cost based and paid by DHBs per population-based funding share b. the source of funds should be from the annual population-based funding future funding track c. the appropriateness of moving to volume based funding be reviewed after two years or as part of the report back in recommendation 9 below. 8. Recommend that national CEOs note that funding PET scanning will result in less funding being available for other services. Assessment of the Business Case for Positron Emission Tomography (PET) Scanning 1

8 9. Agree that any further investment in PET should only be undertaken following a report back to NSTR that (amongst other things): a. includes evidence from trials of PET scanning, including from New Zealand, that demonstrates level 3 to 6 proof (Fryback and Thornbury methodology, Belgian HTA, 2006), or not, of its effectiveness b. analyses the number and type of scans undertaken, the influence on decision-making, patient outcomes, costs, etc that are administered in the last year of life in New Zealand c. analyses the equity of access to the PET service in New Zealand d. identifies changes to clinical practice required to secure the best health gain from PET scanning e. identifies changes required to secure cost savings from PET, including reductions in the use of other interventions and changes to clinical practice f. advises on appropriate costs and funding for scans, including the source of funds for further investment. 10. Agree that any further investment in PET require greater evidence of health gain and efficiencies than is currently the case and must require the support of NSTR to proceed; 11. Recommend that national guidelines for oncology practice be further progressed and request the National Cancer Treatment Working Party to provide advice to the Principal Advisor Cancer Control, Ministry of Health, on this matter during 2007, with a particular focus on PET. 12. Agree that any agreements to supply isotopes to private or other users must include a public health sector first use clause. 13. Agree that following national DHB CEO support of NSTR s recommendations that the next step should be for PET scanning to proceed to completion of a capital business case for submission to the National Capital Committee, followed by the establishment of a PET scanning implementation project. 14. Note that the capital business case will be the vehicle to address and confirm final costs, models of care, private sector and research linkages and other such implementation detail. 15. Advise the project team developing the capital business case that a facility design guideline for PET scanning facilities is being developed in 2007 as part of the Australasian Health Facility Guidelines project facilitated by the Centre for Health Assets Australasia (see 2 Assessment of the Business Case for Poistron Emission Tomography (PET) Scanning

9 Business case for Positron Emission Tomography (PET) in New Zealand 28 th May 2007

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11 FOREWORD Positron Emission Tomography (PET) has become an indispensable imaging tool for the management of cancer in most developed countries. The markedly improved ability of PET to identify both the spread of cancer and the effectiveness of treatment, compared with current imaging modalities, has improved the lives of multitudes of cancer sufferers worldwide. PET scanning may indicate more extensive spread of cancer than indicated by other methods, thus sparing patients the need for futile operations or other aggressive treatments that would not be beneficial. Conversely, PET scanning may indicate that irregularities identified using other modalities may not be due to cancer spread, providing confidence that an aggressive approach to treatment is justified. The role of PET continues to expand within oncology, with more cancer types and more indications for its use becoming increasingly apparent. Although about 90% of the use of PET centres around oncology, there are developing indications in other medical disciplines such as neurology and cardiology. Failure of New Zealand to invest in PET technology will not only mean that New Zealand cancer sufferers may not be offered the correct and appropriate treatment, but will undermine the ability of New Zealand s robust and innovative biomedical research efforts to remain competitive globally. Currently there is very limited access to PET for New Zealanders and most cancer sufferers in New Zealand are treated without the benefit that PET scanning is known to provide. PET scanning is available in a limited capacity at 1-2 locations in New Zealand, using short-lived radioactive isotope imported from Australia. By contrast, most European and OECD countries are, or are planning to acquire, PET scanners in the ratio of 1 scanner per million (or less) of population. The clear advantages of PET to evaluate patients with cancer and other diseases make it inevitable that PET scanning will be recommended more widely in New Zealand. The challenges to develop a PET facility in New Zealand will be substantial, including strategic, logistic and fiscal issues. The project team considers that PET should be developed in a nationally coordinated manner in the context of multidisciplinary cancer care, as outlined in the Cancer Control Strategy. This will ensure appropriate use of this technology and equity of access for all New Zealanders. The massive global push to invest in PET technology, coupled with a global shortage of personnel of all types, has produced a highly competitive market for expertise. The ability to attract and retain suitably qualified staff will be made more difficult by the generally depressed state of nuclear medicine in New Zealand. The Project Brief was to evaluate the requirement for PET in New Zealand and to provide a framework for its implementation throughout New Zealand. On this basis I undertook to facilitate an open, transparent and inclusive process. Members of the project team were drawn from several DHBs and other institutions, including individuals with knowledge and/or experience with PET. Submissions were invited from private consortia, commercial operators and universities. Following a decision in September 2006 by NSTR to include in its work programme the development of a business case for PET scanning in New Zealand, the project team was convened in October. Members of the Team worked well together and met on several occasions. I am extremely grateful to all members of the project team for their commitment to the task. I have been privileged to act as Chair of the Group and I thank all those who have given willingly of their time, over and above their normal employment obligations. I am grateful for the opportunity to contribute to the development of a process with the potential to improve the lives of so many New Zealanders. G. Stevens Graham Stevens BSc MD FRANZCR Chair, project team i of 180

12 EXECUTIVE SUMMARY Introduction: Positron emission Tomography (PET) is a specialised technique of nuclear medicine used to detect and locate diseased tissues mainly cancers within the body. The use of PET overseas has grown dramatically in the past few years to the point where clinicians and health authorities consider PET as an indispensable tool for the assessment and management of persons with cancer. In recognition of the overseas interest in PET and increasing referral of patients to Australia, NSTR has agreed to the inclusion in its work programme the development of a business case to assess the introduction of PET in NZ. This business case indicates a requirement for PET in NZ and provides justification, estimated costings and preliminary implementation steps for a recommended option. Process: Clinical use of PET: PET technology: Equipment and facility: The project team sought information, advice and expertise from many sources, such as: published literature, Health Technology Reports from various OECD countries, the public and private sectors, site visits to PET facilities in Australia, financial consultants, and commercial suppliers and manufacturers. Approximately 90% of the use of PET is in oncology, with small but increasing use in neurology and cardiology. There is a change in treatment in 30% to 65% of the cases as a direct result of the use of PET. Uses in oncology include diagnosis, staging, early assessment of treatment response, evaluation of treatment, and localization of sites of recurrent disease. As a result of PET scanning, many patients are spared major surgery and/or protracted courses of radiation therapy which would not be beneficial. The higher sensitivity of PET compared with CT scans for many cancers allows treatment to be tailored more precisely to the individual patient. In particular, upstaging of cancers by PET has reduced rates of ultimately futile surgery for primary and recurrent cancers. This provides enhanced quality of life and cost savings. The basis of PET is the production, within a cyclotron, of radioactive isotopes that emit positrons when they undergo radioactive decay. These positron emitting isotopes are attached chemically to biological molecules that are injected into a patient and localise in areas of abnormal metabolism in the body. The affected body tissue is identified by passing the patient through a combined PET and CT scanner, which allows both PET and CT images to be obtained. These are interpreted and reported by a nuclear medicine specialist and radiologist. PET scanning requires a number of components that sequentially enable the process to occur. These are: Cyclotron, to produce the positron emitting isotope; a single cyclotron of suitable size can produce sufficient isotope to service several PET scanners. Radiochemical unit, to incorporate the isotope into a suitable biological molecule. PET/CT hybrid scanner, to detect the emitted radiation and provide ii of 180

13 a high quality CT scan to fuse with the PET images. Image software, to enable image reconstruction for interpretation and reporting. IT infrastructure, to enable distribution and storage of images. Facility to house the above, and to enable patient and staff flow. Use and availability of PET overseas: Projected requirement for PET in NZ: Current NZ use: Patient acceptability, risks, benefits and safety Maori and Pacific People issues Research: Options analysis: In most developed countries, PET is considered an indispensable imaging tool in the management of cancer. Most developed countries are planning for one PET scanner per million population. The ratio of PET scans to population in the UK is approximately 800 PET scans per million per year. Using projected cancer incidences in NZ for 2011 and making assumptions regarding the numbers of patients with specific cancer types and agreed indications for PET, approximately 4,100 PET scans will be required annually in NZ. Given the experience of other countries, this value is likely to be an underestimate and a figure within the range of 4,000-6,000 is considered probable. An estimated NZ patients are referred annually to Australian PET centres. This number does not reflect the extent of unmet need in NZ, but rather the height of the barrier for access. Small numbers of patients are scanned privately in Wellington but the capacity is severely limited by the need to import isotope from Australia. A listing of clinical indications for PET was prepared by a NZ PET Clinical Reference Group to assist DHBs and clinicians in funding and clinical decision making. PET scanning is very safe, with no reports of adverse reactions to the intravenous injection. Radiation doses received by patients are comparable to other radiological investigations that cancer patients undergo routinely. When utilised for the evidence based and agreed clinical indications, the benefits of PET outweigh the tiny risk of radiation induced cancer, which is an inherent risk with all radiation imaging techniques. Maori and Pacific Peoples have a higher incidence of many common cancers (such as lung cancer) and an increasing incidence of cancers such as colorectal cancer. Compared to other New Zealanders, Maori and Pacific Island people commonly present at a later stage of disease and have poorer survival outcomes. It is for the assessment of locally advanced and advanced cancers that PET scanning has the greatest potential to determine the appropriate treatment, to improve survival, and to improve quality of life. The availability of PET in NZ will reduce inequalities in health care. NZ has a very strong biomedical and drug development research profile internationally which would be further enhanced by availability of PET facilities in NZ. Whilst there is a strong demand for PET in the biomedical research groups in NZ, there appears little demand for PET by nonbiomedical research groups. A number of options for PET in NZ were considered by the project team, including the counterfactuals of limited private PET scanning in NZ and referral to Australian centres. These options were rejected on the basis of the clinical evidence for PET and equity of access. iii of 180

14 Options for the number and placement of cyclotrons and of PET scanners were considered in relation to population density, strategic location in cancer networks and relationship to biomedical research facilities. The type of cyclotron (high, medium, or low grade) and PET scanner (PET/CT, coincidence cameras (CoDe) and mobile units) suitable for NZ were also considered. Governance and ownership issues were considered, recognising the different requirements and complexities of isotope production versus isotope utilisation. iv of 180

15 RECOMMENDATION The major recommendation in this paper is the agreement in principle to the introduction of a national PET service, with initial purchase and installation of a research grade cyclotron and 2 PET/CT scanners, followed by acquisition of PET scanning facilities in all cancer networks and a second national cyclotron as requirements increase. Various options and configurations were considered; the recommended option was considered the most efficient in terms of the estimated volume of need, cost considerations and utilisation issues. In particular, the project team recommends the following: Equipment: Development of a PET service in NZ that includes both isotope production and scanning facilities. Scanners to be PET/CT hybrid units; CoDe cameras are not recommended. The development to be phased, with the initial phase consisting of a Group 2 (medium size) cyclotron and two PET/CT scanners. The installation of an additional two PET/CT scanners to be considered following patient build-up on the initial PET/CT scanners. A second cyclotron to be considered to provide backup for isotope production when multiple PET/CT scanners are operational and demand for isotope increases. Locations: Governance: Costing of recommended option: Funding: The initial development (Group 2 cyclotron and a PET/CT scanner) to be at Auckland City Hospital. A second PET/CT scanner to be sited at Christchurch or Wellington Hospitals. A second cyclotron to be located in Auckland, Wellington or Christchurch. Each cancer network to have a PET/CT scanner sited at the major cancer centre of the cancer network. The purchase, ownership and operation of the cyclotron(s) to be undertaken at a national level, due to the cost and complexity of isotope production and distribution. The purchase, ownership and operation of the PET/CT scanners to be undertaken by the DHBs in association with the cancer networks. The establishment of a multidisciplinary National PET Advisory Committee (NPAC) for overseeing the PET service in an ongoing manner. The approximate capital cost of a cyclotron and two PET/CT scanners is NZ$18 million. The approximate capital cost of two cyclotrons and four PET/CT scanners is NZ$37 million. Using models of throughput and build-up of workload, the cost per scan is estimated at approximately $1,700 for the initial recommendation of one cyclotron and two PET/CT scanners. This cost per scan compares favourably with current costs of NZ patients referred to Australia. The cost of PET scanning for individual DHBs has been estimated, based on these overall costings and direct proportionality to cancer incidences in DHBs. A range of funding options involving solely public, solely private and mixed models is possible. Private groups with extensive experience in cyclotron and PET operation are likely to be interested in funding partnerships, ranging from full ownership and operation through to operation alone. Private radiology groups are likely to be interested in joint ventures to fund v of 180

16 and operate PET scanning units. Implementation: An extensive and detailed implementation process is required, and this will include at least the following: Linkages: Selection of cyclotron(s) and PET/CT scanners. Workforce issues due to the lack of trained staff in NZ, and intense international competition for staff in all professional categories, staffing issues must be addressed early. Requirements for paediatric PET scanning. Impact on existing cancer services. Comprehensive educational program to inform potential referrers, develop guidelines and conduct audit. Post-implementation review, with clinical and operational audit. PET/CT scanners to be incorporated into existing nuclear medicine departments, so that PET scanning is an integral component of cancer care, with active involvement of nuclear physicians in multidisciplinary cancer forums. The requirement that all PET centres and equipment should conform to the standards prescribed by the professional body (eg ANZSNM). This recommendation was arrived at by considering a number of factors, summarised as follows. Clinical and other benefits The clinical evidence for PET is variable, depending on the clinical indication. Where effectiveness has been shown, the evidence indicates that 30-65% of therapeutic pathways are modified as against current practice. The changes in management resulting from PET scanning are numerous - in particular, major and often futile surgery can be avoided for many patients, protracted courses of radiation therapy can be avoided, and expensive treatments, including bone marrow transplantation are avoided. There are clear benefits associated with the reduction in the direct costs of operations avoided, in reduced costs of other therapies and also increased patient welfare through reduction in patient discomfort. While the stand-alone cost of the technology will exceed the immediately obvious benefits, the long-run productivity gains have been identified in assessments overseas. These productivity benefits come from the ability of the centres to raise throughput for given resources as a result of PET, as well as the overall training and workforce skills accumulated from exposure to PET technology (i.e. ability to leverage off overseas experience). Status quo A continuation of this situation would mean that the availability of PET facilities to the NZ population would be limited to those who were able to travel to Australia or access the service privately. For patients, this high barrier to access would result in inequality of provision, the exclusion of patients with particular indications, and fragmented patient care. It would also result in NZ failing to keep pace with the medical technology of other developed countries and it increases the difficulty of attracting biomedical researchers and funding to NZ. The current practice of importing PET radiopharmaceuticals from Australia to service the existing PET technology in NZ is incapable of significant growth, as only limited volumes of isotope can be imported. Strategic considerations Adoption of PET technology is consistent with the Cancer Control Strategy. The clinical evidence indicates that the primary goal of reducing the impact of cancer would be enhanced through the use of PET scanning. In addition, the need for NZ s medical community to have access to technology that is widely available overseas has many benefits for workforce development, with vi of 180

17 attraction and retention of world-class staff and researchers. It is likely patient and community confidence will increase with the adoption so of PET, although the benefits cannot be quantified. Economic and financial case not fully developed A full-scale economic evaluation was not possible in this case, due to uncertainties in data and patient management policies. Preliminary analysis of available (limited) data for lung cancer, colorectal cancer and oesophageal cancers suggests that cost savings from avoided surgery (for recurrent colorectal cancer, lung cancer, oesophageal cancer only) may be in the region of $3.6m annually. Note that this does not include potential savings from reduction in investigative tools. For many overseas centres, PET/CT has replaced mediastinoscopy (at the same financial cost but with reduced patient morbidity) and treatments including reduced need for protracted radiation treatment courses, bone marrow transplants and neck dissections for residual masses in head and neck cancer. Offsetting the potential benefits of PET are the high set up and operating costs of PET. The option of 1 cyclotron and 2 scanners entails capital costs in year 1 of $18m, and associated operating costs of $5m. Based on 2000 scans per year, this equates to a cost of approximately $1,700 per scan. Taking these costs and savings into account the net present value of this option is approximately -$17m for a 15-year period and employing 11% discount rate. Note that this is based on incomplete information, which does not include potential benefits still to be quantified, and so it is not surprising that standard economic and financial measures show poor results. Whilst these analyses are important, they are not the sole decision criterion in fields such as health. FURTHER ANALYSIS NEEDED Further work is needed as part of the development of a capital business case seeking funding, with the more immediate areas first: Capital investment- precise costings are required for the major equipment (including building fit out costs). This includes firm commitments (to the extent that these are possible) from suppliers along with contractual terms and conditions. Procurement strategy- related to above, further consideration of the optimal procurement strategy is needed. The cost advantages associated with multiple purchases and any terms need to be considered, together with whether funding for both scanners should be sought at once or separately. Detailed financial analysis- further elaboration of possible options and the costs and benefits of those. Building in dynamic assumptions and further sensitivity analyses are needed. Comprehensive cost allocation- more work is needed on terms of costs to DHBs as well as possible contributions from private sector and research interests. Implementation strategy and costs-detailed work is also required on an implementation plan and appropriate costs to support the plan. Further detail on governance options and implementation issues is contained in Appendices set 5. vii of 180

18 Table of Contents Forward Executive summary Recommendation 1 Introduction 1.1 Context 1.2 Purpose of the Business C ase. 2 Development of the Options and Recommendations 2.1 Overview 2.2 Alternatives.. 3 Description of the technology, disease state and therapeutic interventions PET overview Basic principles of PET Technology Equipment & facilities required for PET PET applications Cancer Cardiology Neurology/psychiatry Importance of Cancer in NZ.. 4 Evidence of efficacy and effectiveness of PET Methodology Sources of evidence for the role of PET in clinical medicine 4.2 Evidence for PET for cancer management Summary of levels of evidence for PET in oncology. 4.4 Analysis of evidence for PET scanning for Staging NSCLC Improved diagnostic accuracy Change in patient management Cost effectiveness Placement of radiation treatment fields Analysis of evidence for PET scanning in recurrent colorectal cancer Improved diagnostic accuracy Change in patient management. Pag e i ii v viii of 180

19 4.5.3 Cost-effectiveness Analysis of evidence for PET scanning for staging oesophageal cancer Diagnostic accuracy Change in patient management Patient outcome Analysis of evidence for PET scanning for Staging of other solid cancers. 4.8 Analysis of evidence for PET scanning for assessment of treatment response 4.9 Analysis of evidence for PET scanning for diagnosis of lung cancer (solitary pulmonary nodule SPN) 4.10 Benefit of PET/CT compared with PET alone or CT alone 4.11 Analysis of evidence for PET scanning in neurology and cardiology Neurology Cardiology Estimated number of scans in New Zealand. 5 Econom ic assessment. 5.1 Overview 5.2 Potential costs and benefits 5.3 Costs identified Costs of the current system Costs of PET scanning Likely patient benefit.. 6 Business implications. 6.1 Capital expenditure and implementation costs Capital expenditure Investment appraisal Training Other implementation costs 6.2 Forecast of cost to DHBs Analysis of financial implications for provider of national service Locations of Equipment and Service Location: cyclotrons Location: PET scanners Governance of PET service. 7 Consultation summary 7.1 Summary of medical comment Summary of research comment 8 Specific areas of influence ix of 180

20 8.1 Whanau Ora 8.2 Community acceptability Patient and Community Acceptability of PET Radiation safety of patients Ethical Considerations and Informed Consent 8.3 Impact of PET Technology on research Clinical research PET in Cancer Research Non-biomedical research uses of PET. 9 Final 65 considerations 9.1 Cost-benefit assessment Equity of Access 9.3 Size of the cyclotron Strategic development Next stages of analysis Capital business case Implementation Planning Planning for the downstream effects on services Contributors Abbreviations and Glossary Abbreviations 11.2 Glossary x of 180

21 Appendices Appendix 1: A. B. C. D. Bibliography Submissions Evidence for PET Current clinical indications list for referral to PET Appendix 2 Appendix 3 E. A. B. C. Draft terms of reference for a National Advisory Group on PET Project brief Letters sent to stakeholders and suppliers Paper written about the project to inform stakeholders Letters of support Appendix 4 A. B. C. D. E. F. Appendix 5 A. B. C. Equipment and facilities required for PET The Radiopharmaceutical laboratory Quality control system Transport system Scanners Infrastructure Implementation planning Operational issues Governance Appendix 6 An example of an economic evaluation carried out by the NHBS in 2002 for the use of PET in the staging of NSCLC. Appendix 7 Appendix 8 Results of the survey by on PET in a number of countries Feedback Summary xi of 180

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23 1 Introduction 1.1 Context PET technology for use in medical imaging has been in clinical use for the last years, and PET/CT units have been available commercially since Most developed countries have adopted the technology, with 154 PET sites in USA and 101 sites in 24 other countries (Institute for Clinical PET). Appendix 7 provides a recent listing of PET facilities across a number of European and OECD countries. Most of the countries listed are aiming for approximately one PET scanner per million population. PET scanning technology is almost non-existent and is effectively being introduced to NZ. 1 Thus, the costs associated with introducing technology can seem substantial. In any healthcare system with limited resources, priorities for investment must be set on the basis of clear evidence of benefits to patients and good value for the money spent. This report seeks to assist in that regard by setting out a description of the technology, the likely costs and benefits associated with PET scanning and other possible impacts and implications useful for decision-making. 1 Note that while there are two existing centres using PET (both commencing PET operation in 2006), one is in private hands, offering a limited number of scans, and the other is almost exclusively restricted to a clinical drug trial. Note that these are coincidence detector machines which are now recognised as unsuitable. 13 of 180

24 1.2 Purpose of the Business Case A proposal for change for PET scanning in NZ was developed jointly by the Ministry of Health and DHBs. Following consideration by the National Service and Technology Review Advisory Committee (NSTR) in July 2006, PET was included on NSTR s 2007 work programme. 2 As a national project it was necessary that a DHB was identified as the key contact and coordinator for the development of the business case. Auckland DHB was selected for this role following a discussion of key senior staff from several DHBs who had expressed an interest in the proposal. The following were to be addressed as part of the business case: Location of cyclotrons and PET scanners. Type of cyclotron and type of scanners. Expertise and availability of personnel. Partnership opportunities (at a high level only at this stage). Stakeholders (e.g. Ministry of Health, DHBNZ, DHBs, consumer representative organisations, universities, possibly industry, and private radiology providers) to be involved. The purpose of the business case was to provide sufficient information, upon which an indicative decision could be made as to whether or not PET scanning should be added to DHB service coverage requirements. In particular the business case considers the clinical evidence in support of PET scanning technology and the current and potential uses that flow from the technology. Its implementation is the subject for further work. The next stage, should DHBs agree PET scanning ought to be introduced, is to make a submission to the National Capital Committee. This will require further, and more detailed, financial and economic assessments. The options analysis in this business case has been limited by the large number of potential variables that affect the analysis, as well as the lack of some (price-based) material that is commercially sensitive. Where relevant the PHARMAC prescription has been used in this business case; reference is made through this document to the principles and material utilised. The Prescription for Pharmacoeconomic Analysis produced by PHARMAC is a useful framework for considering the merits of proposed interventions. Whilst its focus is on economic analysis, many other factors are considered in PHARMAC s final determinations. 3 The principle is the same in an environment where there are limited resources and decisions around prioritisation and the trade-offs require a consistent and coherent framework that is as value-free as possible and supports sound (and efficient) decisions. 2 NSTR was established to analyse and evaluate proposals for change and business cases and to recommend their adoption or rejection to the DDG-CEO Group. 3 See Pharmac (2006), p.13 for the list of Pharmac decision criteria. 14 of 180

25 2 Development of the Options and Recommendations 2.1 Overview This document proposes the introduction of a nationally operated PET service in NZ, with the establishment of both scanning and isotope production facilities. The development is recommended to be phased, with the initial phase consisting of a high-grade cyclotron and two PET/CT scanners. Over time, as patient numbers build up, it is proposed that two additional PET/CT scanners be installed and a second cyclotron be considered to provide backup for isotope production. 2.2 Alternatives There is currently limited availability of scanning facilities in NZ and no domestic production of the necessary isotopes. PET isotopes used in NZ are sourced from Australia in limited quantities. The volume of air-freighted FDG will always be small as the whole of a cyclotron production run can only ever deliver 6 patient doses at Wellington and Christchurch and 4 in Auckland, and possibly 1 at Hamilton 4. Therefore, the majority of NZ patients who have PET scans are referred to Australian centres. However, using this situation as the relevant counterfactual is problematic as the current number of patients referred to Australia each year (estimated to be around ) is not considered a reliable representation of actual need compared with current registrations and utilisation patterns observed overseas. There is demand for this service already in NZ as evidenced by use of overseas and domestic private arrangements, albeit to a limited extent. The counterfactual of no PET service in NZ is therefore not a comparable alternative, and this report focuses on consideration of alternatives where PET scanning is delivered. One option is to import the radiopharmaceutical from Australia for use by the existing providers of PET scans. Table 2 summarises this option, and its advantages and disadvantages. Other options centre on the proposed configuration of one cyclotron and two scanners (one initially, and one subsequent), and on the type of scanner and cyclotron. Table 3 summarises the options for acquisition of cyclotrons and Table 4 summarises the options for scanner acquisition. 4 The difference in patient doses is due to time delays transporting FDG through customs at the various airports as well as the 3+ hour flight time. 15 of 180

26 Table 2: Maintenance of status quo as counterfactual Description Advantages Disadvantages Summation No provision of radiopharmaceutical in NZ through public health system NZ would rely on the availability of PET facilities (cyclotrons and PET scanners) in Australia or privately in NZ and would not develop a PET facility in NZ public health system. No requirement to develop any PET facilities in NZ (ie no capital or recurrent costs, no staffing or training issues). Inequality of provision of PET, due to high barrier for access (eg ability to travel) or inability to pay for private PET. May exclude patients with particular indications, eg rapid assessment of treatment response (too sick/debilitated). Fragments patient care. Failure of NZ to keep pace with OECD countries. Reliance on Australian PET centres to accommodate NZ patients. Reduced ability to attract medical and biomedical research funding. Private production of isotopes in NZ will create a monopoly situation. Not a recommended solution, as discussed in text. Importation of radiopharmaceutical from Australia NZ would not develop a capability to produce PET radiopharmaceuticals but would use imported PET radiopharmaceuticals. These could be obtained only from Australia. This option presupposes that PET scanners are located in NZ. No requirement to develop a PET radiopharmaceutical facility, ie capital and recurrent costs of cyclotron, hot cell/s, QA, no staffing or training issues for PET radiopharmaceutical production (cyclotron physicists & technicians, radiochemists, radiopharmacists). No nuclear waste disposal problems. Relies on guarantee of regular supply from Australian centres this becomes a greater issue with expanding indications and increasing throughput. Severe restrictions are placed on the types of radiopharmaceutical available. Limits research applications of PET. Expensive method of delivery of radiopharmaceutical, due to loss by radioactive decay during transport, adverse weather delays, airport delays, customs clearance). Product arrives in NZ scanning centre in afternoon, inconvenient for daily scheduling. Possible option only for NZ centres with daily scheduled flights from Australian supplier. Only limited volume could ever be achieved. Impractical as a long term solution May be suitable as a short-term solution during construction and commissioning of NZ cyclotron if PET scanners are available. 16 of 180

27 Table 3: Cyclotron acquisition options Description Advantages Disadvantages Installation of one cyclotron in NZ NZ would develop a PET capacity based on local production of isotope, obtained through purchase and installation of a (Group 2, medium size) cyclotron. This provides on-site and off-site production of FDG, and on-site production of short half-life isotopes. If the cyclotron is initially commissioned for FDG production alone, it must be capable of being retro-fitted with targets for short half-life and additional isotopes. This option presupposes the provision of PET scanning facilities in NZ. No dependence on overseas supplier of product (availability, price, adverse weather, customs clearance) or private NZ supplier. Cheaper product, due to reduced activity required for same patient numbers (due to reduced transport time). Possibility for short half-life isotopes available for future clinical use and current medical/biomedical research. Ability to site cyclotron strategically (close to hospital, research centre or airport). Significant investment required (capital, recurrent costings, staff, and training). Long term disposal of cyclotron (possible radioactive waste). Single supply of product which is vulnerable (breakdown etc). Demand for product for routine use may outstrip limited supply. Possible need to compromise between clinical and research uses, due to limited product availability from a single cyclotron. Installation of two cyclotrons in NZ NZ would develop a PET capacity based on assured local production of isotope, obtained through phased purchase and installation of two cyclotrons The initial cyclotron to be a Group 2, medium sized one; the second cyclotron to be decided. This provides on-site and off-site production of FDG, and onsite production of short half-life isotopes. If one cyclotron is initially commissioned for FDG production alone, it must be capable of being retrofitted with targets for short half-life and additional isotopes. This option presupposes the provision of PET scanning facilities in NZ. No dependence on overseas supplier of product (availability, price, adverse weather, customs clearance). Cheaper product, compared with overseas procurement, due to reduced isotope activity required for same patient numbers. Ability for on-site and off-site production of FDG, and on-site production of short half-life isotopes. Possibility for short half-life isotopes available for future clinical use and for medical/biomedical research. Ability to site cyclotrons strategically (close to hospital, research centre or airport). Assurance of supply of product (redundancy). Larger base for establishing training, recruitment & retention. Significantly greater investment required (capital, recurrent costings, staff, training) than for single unit. Larger problem of long term disposal (possible radioactive waste). 17 of 180

28 Table 3 continued: Cyclotron acquisition options Summation Installation of one cyclotron in NZ Advantages of NZ location of cyclotron markedly outweigh disadvantages of counterfactual if access to PET scanning for New Zealanders is to increase. Installation of two cyclotrons in NZ Significant advantages of backup, a larger base for establishment of robust NZ facility and flexibility of locations for clinical and research purposes. Availability of short half-life isotopes at two cancer centres in NZ. 18 of 180

29 Table 4: PET scanner acquisition options Installation of full ring PET/CT scanners Combination of full ring PET/CT and CoDe scanners Use of mobile PET units, in combination with fixed scanners Description Full ring PET/CT cameras to be purchased and installed in a phased manner in Regional Cancer Centres. A small number of full ring PET/CT cameras to be purchased and located strategically, complemented by existing CoDe cameras and gamma cameras capable of conversion to CoDe. A mobile full ring PET/CT scanner, mounted on a truck, travels regularly along a defined route, stopping for 1-2 days at predetermined nuclear medicine centres to perform PET scans. Isotope (FDG) from a NZ based cyclotron is transported daily from a cyclotron to the mobile location. The mobile PET scanner could service the entire country, or could be complemented by a small number of fixed full ring PET/CT cameras to service Auckland and/or other major population centres. Advantages Internationally accepted standard of technology. Ability to scan multiple short-lived isotopes (clinical and biomedical research implications). Faster throughput than CoDe units. Introduction of full ring PET/CT scanners permits rational development of a NZ-wide PET scanning service of high quality that can be configured around the proposed cancer networks. Reduced capital costs, as some cameras will be CoDe. Combines PET scanning devices of varying sensitivity, including the internationally accepted standard. Enables wider distribution of PET scanners around NZ, facilitating patient access. Ability of full ring PET/CT scanners to use short-lived isotopes (clinical and biomedical research implications). Mobile technology allows ready access for non-urgent, routine scanning at peripheral centres. Reduced capital costs compared with fixed scanners, as a single mobile unit might substitute for >1 fixed scanner. Fixed scanners at strategic locations can be used for higher throughput in larger centres and use of short-lived isotopes (medical & biomedical research). 19 of 180

30 Table 4: PET scanner acquisition options Installation of full ring PET/CT scanners Combination of full ring PET/CT and CoDe scanners Use of mobile PET units, in combination with fixed scanners Disadvantages Expensive capital investment. Possible inequity compared with wider distribution of CoDe cameras. Requires capital investment in full ring PET/CT scanners. Possible increased inequity, as some patients would be scanned using inferior CoDe technology. Access to PET scanning by small centres may dilute experience and restrict the development of centres of excellence. Separates PET scanning from cancer network structure. No clear indication of disease conditions for which CoDe cameras are an acceptable substitute for full ring PET/CT scanners. CoDe is only suitable for centres with low patient numbers. Patients requiring urgent scanning (eg tumour staging, rapid assessment of therapeutic response) may need to travel to the mobile unit. Logistics of operation of mobile unit as yet inadequately evaluated, including patient throughput, condition of NZ road system. Limitations on volume as mobile scanner can do approx 1200 scans only. Summation This option represents the international standard for PET scanning. International recommendations suggest one PET/CT scanner per million population, ie 4-5 scanners required in NZ. This mixed option is suboptimal, as there is no clear documentation of the conditions for which CoDe cameras represent an acceptable alternative to full ring PET cameras and inequalities may arise. The combination of fixed and mobile PET/CT scanners has some merits and could be explored further. 20 of 180

31 3 Description of the technology, disease state and therapeutic interventions Basic principles of PET Technology PET technology is an imaging tool for clinical medicine and biomedical research, with limited utility in industry. The major clinical applications of PET are in oncological imaging, with neurology and cardiology as secondary but increasing areas of interest. Please refer to Appendix 4 for more detail on the technology. PET is similar to other techniques of nuclear medicine. A radioactive isotope (the tracer) is attached to a molecule of interest (the probe), which is introduced into the subject (human for clinical studies or animal for research). The choice of probe is determined by the type of investigation being undertaken. The probe localizes to the disease site or other area of interest in the body. The subject is then scanned with a radiation detector, which locates the probe by detection of the radioactive decay of the tracer. In PET, the radioactive decay is associated with emission of a positron. A positron is a particle of antimatter, being a positively charged electron. Following its emission from a radioactive atom, a positron rapidly interacts with an electron to produce a pair of gamma rays (photons) which fly off in opposite directions and may be detected by a suitable gamma camera. The detection of both gamma rays simultaneously is called coincidence detection. When many thousands of such gamma ray pairs have been detected, the computer software can compute the location of the probe within the subject. This computation is usually reconstructed as an image of the subject, showing the localization of the probe. PET and computed tomography (CT) provide complementary images of function and anatomy respectively. Due to the increased sensitivity and specificity of PET, the functional changes caused by disease are frequently detectable before any structural abnormalities become evident on CT scans. In contrast with imaging systems such as CT and magnetic resonance imaging (MRI), which primarily provide information about anatomical structure, isotopic techniques such as PET image and quantify biochemical, physiological, and functional changes. This information is particularly valuable because the functional changes caused by disease are frequently detectable before any structural abnormalities become evident. The advantage of positron emitting isotopes, compared with the more commonly used radioactive isotopes in nuclear medicine, is the ability to incorporate positron emitters into small molecules of medical and biological interest. This ability enhances and expands greatly the number of clinical and research indications for PET (refer to sections 4 and 8.3). Conversely, the major disadvantages of PET (compared with non-pet nuclear medicine techniques) are the requirement for a cyclotron, the short lifetimes ( half-lifes ) of positron emitting isotopes and the need for coincidence cameras (scanners). The following (Table 5) lists the commonly used PET isotopes and their corresponding half-lives. Although F-18, with a half-life of 2 hours, is the most commonly used PET isotope, the other isotopes in the table are very short-lived, making their use problematic. They are, however, likely to be of great utility in the future in clinical medicine. 21 of 180

32 Table 5: Some Characteristics of PET Isotopes Isotope Symbol t 1 / 2 * Comment Fluorine F 110 minutes Essentially 100% of current clinical PET scanning Oxygen-15 Nitrogen-13 Carbon O 2.2 minutes 13 N 10 minutes 11 C 20 minutes Utilised currently for medical research, but are anticipated to enter routine clinical practice in the future. *t 1 / 2 = physical half-life ie the time during which the amount of radioactivity decreases by 50% of the starting amount Equipment & facilities required for PET PET is a sophisticated technological undertaking, requiring the coordinated functioning of a number of components. The basic components are: Cyclotron: Radiochemistry facility ( hot cell ): Quality control system: Transport system: To produce positron-emitting isotopes (tracers); most commonly this is fluorine-18 ( 18 F). A cyclotron is a charged particle accelerator, used to produce positron emitting isotopes. Cyclotrons have a range of specifications, depending on the requirements of the facility. There are essentially 3 size ranges small, medium and large. During operation, cyclotrons become a source of intense ionising radiation and must be shielded either by location of the cyclotron within an appropriately shielded room (bunker) or by means of self-shielding, in which the cyclotron is constructed with a heavy and bulky metal casing. To incorporate the tracers into molecules of biological interest and produce a radio-pharmaceutical; 18F-deoxyglucose (FDG) is the most common radio-pharmaceutical used clinically. The second step in the PET process is production of a radioactively labelled probe. This involves incorporation of the tracer into a molecule of interest, usually by a chemical reaction. The most important tracer is 18Fradiolabelled fluoro-2-deoxy-d-glucose (18F-FDG, usually abbreviated to FDG), which represents over 80% of the current clinical PET studies worldwide. This is required to ensure the safety of the probe for in vivo use. Each production run from the cyclotron and hot cell must undergo quality checks, particularly for pyrogens and volatile products and sterility. This is required to ensure the rapid transfer of probes with short-lived isotopes from the production site to the PET scanner (the half-life of 18F is 110 minutes). Due to the short half-life of PET isotopes, careful consideration must be given to ensuring rapid utilization of the probe. For FDG, this is not a problem if the cyclotron and scanner are co-located. However, if the cyclotron and scanner are separated, there is general consensus that the probe should be utilized within 2-3 hours of its production. The statutory conditions for radiation safety during transportation are regulated by the 22 of 180

33 Scanner: National Radiation Laboratory (NRL). An appropriate camera is required to detect the positrons emitted from decay of the tracer. A number of options are available, including the preferred hybrid PET/CT scanner. Once the radiopharmaceutical has been injected into the patient, and sufficient time has elapsed for the probe to localize to the area of interest, a patient is passed through the scanner to detect radiation emitted from the tracer. There are several options for PET scanning. These are: Coincidence detector (CoDe) A coincidence camera contains 2 sets (heads) of radiation detectors to register the characteristic signature of positron decay, being the simultaneous emission of two photons of a particular energy (511KeV) travelling in opposite directions. Due to the long acquisition times of CoDe cameras, throughput is lower and they cannot be used to scan short lived isotopes. CoDe units are available commercially and are marketed generally for smaller centres with smaller volumes. Hybrid models with CT scanners are available (see below). CoDe cameras can also perform routine gamma scanning in nuclear medicine. There are 2 CoDe cameras in current use in NZ (Pacific Radiology in Wellington and Waikato Hospital). Some but not all existing gamma cameras in NZ are capable of being modified as CoDe cameras. Full ring PET camera This is a scanner specifically designed for the optimal detection of gamma rays from PET isotopes (511KeV). The crystal within the detector and the full ring of detector arrays (compared with limited array in CoDe cameras) allows optimal sensitivity and resolution of the radiation signal, to provide the most precise images. Full ring PET scanners are no longer produced by the major manufacturers as separate units, as production has moved entirely to hybrid PET/CT units (see below). Fusion of PET and CT images With the use of computer software, it is possible to merge both PET (or CoDe) and CT images, to produce a composite image showing the features of both scans. Image fusion is a routine procedure and provides an excellent representation of the functional data from PET (or CoDe) scans on the background of an anatomical image. The ability to merge and fuse functional and structural images has increased enormously the understanding, interpretation and utility of this technique. The PET and CT scans may be performed on separate units, with subsequent merging of the images. Hybrid PET/CT unit This is the current definitive benchmark of PET scanning globally. It consists of both a PET camera and a CT scanner mounted physically on the same frame. The patient lies on a couch which passes sequentially through both scanners. As both scans are performed whilst the patient is in the same position, anatomical correlation between the scans is excellent when the PET and CT images are fused. Currently, all manufacturers of full ring PET scanners only produce the hybrid PET/CT scanner. A further advantage of the hybrid unit is the use of the attached CT scanner to facilitate attenuation corrections. Mobile scanner PET scanners have been mounted on trucks to provide mobility. These units are a self-contained PET facility and allow PET scanning in smaller centres that could not support a fixed unit. The mobile PET scanner option poses logistic issues including availability of the radiopharmaceutical, reporting and movement of a large, heavy vehicle. Mobile units are used in USA and Europe. 23 of 180

34 Infrastructure: The similarities and differences between these options are of fundamental significance regarding the appropriate choice of equipment for development of a PET service in NZ. The clinical PET facility must contain a suitable configuration for patient and staff management and appropriate IT facilities for image construction, display and storage. The clinical PET facility has a number of requirements and must contain a suitable configuration for patient flow, staff management and appropriate IT facilities for image construction, display and storage. Patient flow As with other medical procedures, the patient must be provided with sufficient time and information to provide informed consent. This necessitates consultation rooms and the availability of appropriate staff for this purpose. The patient changes clothing at some stage. Injection of FDG intravenously is a minor procedure but must be undertaken with precautions for radioactivity. This is followed by a 60- minute uptake period prior to scanning. During this period the patient must lie or sit quietly, without muscular activity (which could alter the internal distribution of FDG and obscure the images). There must be sufficient space for this phase. The patient is positioned inside the scanner and the CT images are acquired (5-10 minutes). The couch is then moved, to locate the patient into the correct position for acquisition of the PET images. This takes approximately minutes. Staffing - Staff are required to fill multiple professional and support roles (refer section 6.1.3). Due to the significantly higher dose rate incurred in PET scanning, more staff must be available for rotation through the PET unit. This has implications for the size of centres where PET scanning should be performed. The PET facility must allocate appropriate space and resources for staff to fulfil their roles to enable a high quality service. Information flow Patient registration is mandatory for audit (clinical and operational). The clinical record must be maintained, including details of administration of a radiopharmaceutical. Data from PET and CT units are reconstructed and fused, to provide images for interpretation and clinical reporting. This requires appropriate computing facilities (software and hardware). The images are reported by medical specialists; this requires a reporting room with adequate screens to display the images. The reports and images must be available to referrers (and potentially patients GPs). The reports and images must be stored electronically for prescribed periods. Data for quality improvement must be maintained. 3.2 PET applications PET and CT provide complementary images of function and anatomy respectively. Due to the increased sensitivity and specificity of PET, the functional changes caused by disease are frequently detectable before any structural abnormalities become evident on CT scans. PET is primarily used in oncology (which accounts for 80-90% of PET usage in most centres), with secondary use in cardiology, neurology and psychiatry Cancer The specific applications of PET for cancer patients are to: a. Improve staging prior to initial treatment. b. Facilitate diagnosis. 24 of 180

35 c. Improve the locoregional anatomical localisation of cancer (i.e. enable more accurate radiation treatment). d. Provide a rapid assessment of therapeutic efficacy. e. Provide an assessment of the result of a treatment regimen. f. Improve detection and anatomical location of recurrent cancer Cardiology The applications in cardiology are: a. Assessment of cardiac metabolism in patients with chronic coronary artery disease and thereby assist in the optimal selection of candidates for coronary revascularisation (bypass surgery or angioplasty) and cardiac transplantation. b. Assessment of patients who are likely to benefit from either coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA), which is a significant advantage over existing technologies. c. Confirming the need for cardiac transplant. This has immediate benefits for the efficient use of resources, given the high cost of transplantation. Refer Appendix 1, C Neurology/psychiatry a. Focal epilepsy PET has an important role in identifying the epileptic focus when other imaging techniques (CT and MRI) are normal. b. Evaluation of dementia this is a developing area for PET scanning. The focus of this business case is the oncological applications of PET. Refer Appendix 1, C Importance of Cancer in NZ Cancer is a leading cause of death in NZ, accounting for 29 percent of deaths from all causes. About 7,500 people die from cancer each year, and this is expected to increase to about 9,000 by 2012 (16). About 16,000 people in NZ develop cancer each year, and forecasts suggest that by 2011 this number will increase to 22,000 (16). Gavin et al (8) compared NZ to Australia, Canada, the USA and Britain, and showed that NZ had the greatest increase in relative cancer mortality over the 30 years from The authors suggested that these figures may indicate that other countries have achieved greater progress than NZ in preventing cancer, effective early detection and treatment. The Ministry of Health (16) has modeled 26 specific cancers for adults. The number of registrations and deaths for 1996/97 and projections for 2011/12 are shown in the Table 6 below. 25 of 180

36 Table 6 26 of 180

37 3.4 Nature of interventions One of the six goals of the New Zealand Cancer Control Strategy is to ensure effective diagnosis and treatment to reduce cancer morbidity and mortality (17). The Cancer Control Strategy describes an intervention continuum: a. Prevention b. Early detection and cancer screening c. Diagnosis and treatment d. Support and rehabilitation e. Palliative care Cancer diagnosis involves a combination of clinical assessment and a range of investigations, such as endoscopy, imaging, histopathology, cytology and laboratory studies. Diagnostic tests are also important in identifying the extent to which the cancer may have spread. Cancer staging is necessary for determining options for treatment and assessing likely prognosis (17). PET has the potential to further enhance the diagnosis and staging of cancer, and thus may lead to changes patient treatment that will improve patient outcomes (such as qualityadjusted life years) or cost savings (such as savings from performing inappropriate surgeries). 27 of 180

38 4 Evidence of efficacy and effectiveness of PET 4.1 Methodology Sources of evidence for the role of PET in clinical medicine The evidence examined was sourced from a range of HTAs and relevant articles in the published literature. A major reference used by the project team was the Belgian HTA (3). This provides an extremely comprehensive and contemporary review of the current literature to In addition, the project team commissioned an independent rapid systematic search to reduce the possibility of bias in the selection of publications Assessment of PET clinical data (refer Appendix 1, C) The methodology used to assess therapeutic interventions involves levels of evidence escalating from expert opinion (level 4) to a meta-analysis of randomised trials (level 1). In common with most diagnostic imaging tests such as CT and MRI, there are very few randomised clinical trials of PET. In addition PET technology is a rapidly evolving field with continual development and improvement which impedes assessment by clinical trials. The vast majority of reported studies of PET relate to the diagnostic accuracy of PET and the effect of increased diagnostic accuracy on patient management, with few studies examining the higher order issues of improved patient outcomes or cost effectiveness. This difference in assessment reflects the inherent differences between diagnostic tools and therapeutic interventions, the impact of subsequent therapy on patient outcome (potentially confounding the effect of the diagnostic test), and country to country differences in health systems and cost effectiveness assessments. For diagnostic investigations such as PET, alternate systems have been developed to address the differences between assessments of therapeutic interventions and diagnostic tools. The system for evaluation of diagnostic tools, outlined by Fryback and Thornbury (6), was used by the project team to determine the efficacy and effectives of PET. The levels of evidence used in this method are summarised in the following table. Table 7: Levels of evidence for evaluation of diagnostic tools (after Fryback and Thornbury) Level Definition Explanation 1 Technical efficacy Relates to the technical quality of the images 2 Diagnostic accuracy Relates to sensitivity and specificity associated with interpretation of images 3 Diagnostic thinking Relates to whether the information produces change in the referring physician s diagnostic thinking 4 Therapeutic impact This concerns the effect on the patient s management plan 5 Patient outcome This measures effect of the information on patient outcomes 6 Cost effectiveness analysis This examines societal costs and benefits of a diagnostic imaging technology 4.2 Evidence for PET for cancer management The main cancers assessed were lung cancer, lymphoma, head and neck cancer, colorectal cancer, melanoma, breast cancer, oesophageal cancer, and brain tumours. 28 of 180

39 The evidence for the use of PET in oncology is mixed. There is evidence of efficacy (levels 1-4) for some types of cancer, and limited evidence on patient outcomes and cost effectiveness. 4.3 Summary of levels of evidence for PET in oncology The following is a summary of the levels of evidence for efficacy and effectiveness of PET presented in the Belgian HTA (3). Further documentation from the Belgian HTA is available in Appendix 1 section C2, and from other sources in Appendix 1 sections C3 to C5. The Belgian HTA report indicates that the evidence for the use of PET in oncology is good to very good for some indications and not useful for others. The evidence for the use of PET in oncology for a number of cancer types and for specific applications is detailed in Appendix 1, C2. The tables (8 and 9) below summarise the evidence and the efficacy of PET for different cancer types. 29 of 180

40 Table 8: BELGIAN HTA FINDINGS Tumour Subtype Indication Level of evidence Comment Non small cell lung At diagnosis Staging 6 Highest level reported- cost effectiveness Small cell lung At diagnosis Staging 2 At recurrence Restaging 2 Lung all types residual and recurrent Restaging 2 Pleural Staging 2 Therapy monitoring ns irradiated volume optimisation ns mediastinal disease ns Single lung nodule SPN>1 cm Diagnosis 3 Occult primary Presenting as a neck node Diagnosis 2 Metastasis outside the neck nodes Diagnosis 2 Head and neck At diagnosis Diagnosis 2 At diagnosis Staging 3 At diagnosis Distant metastases 2 At recurrence Restaging 3 Lymphoma HD and NHL Staging 2 HD and NHL Recurrence staging 2 HD and NHL Residual mass evaluation 3 30 of 180

41 Tumour Subtype Indication Level of evidence Comment HD and NHL Treatment response 2 HD and NHL Prognosis 2 HD Restaging 6 One modelling study at cost effectiveness level Melanoma At diagnosis Staging ns Evidence is conflicting Recurrence or suspected Restaging 2 Colorectal At diagnosis Diagnosis 2 At diagnosis Staging 2 After treatment Restaging no evidence Treatment monitoring no evidence Hepatic recurrence Staging 4 Second highest level noted Oesophageal Regional staging 2 Distant metastases 2 Staging at diagnosis no evidence After neoadjuvant chemotherapy Restaging 3 For patients eligible for curative surgery Pancreatic Diagnosis 2 Staging 2 Restaging no evidence Tumour Subtype Indication Level of evidence Comment Renal Diagnosis no evidence Staging 2 Cervical Staging 2 Recurrence inconclusive 31 of 180

42 Ovary Diagnosis 2 Staging no evidence Diagnosis of recurrence 2 Treatment response no evidence Breast Staging 2 If the clinical suspicion is high Recurrence Restaging 2 If the clinical suspicion is high Abnormal mammogram Diagnosis -2 Evidence against the use of PET Thyroid Restaging 2 Brain tumours Glioma high vs low grade Diagnosis 2 Biopsy targeting Diagnosis 2 Therapy planning Diagnosis 2 Recurrence or radionecrosis Restaging 2 32 of 180

43 Table 9: Summary of efficacy of PET for different cancer types from above tables Strong evidence Intermediate strength No evidence for effectiveness Not addressed in Belgian HTA Non small cell lung cancer Occult primary Prostate Bone tumours Lymphoma Small cell lung Abnormal mammogram Soft tissue sarcoma Colorectal hepatic recurrence Melanoma Mesothelioma Single lung nodule Oesophageal restaging Head and neck Pancreatic Cervix Ovary Renal Thyroid Glioma Gastric 4.4 Analysis of evidence for PET scanning for Staging non small cell lung cancer (NSCLC) Improved diagnostic accuracy Diagnostic accuracy of PET has been compared to CT, Compared with CT, PET better detects loco-regional nodal disease (42% vs 13% for hilar nodes and 58% vs 32% for mediastinal nodes). For CT node negative tumours, PET has sensitivity of 86% at the specificity of 90%. In CT node positive tumours, PET sensitivity is 92% at specificity of 76%. Refer to section 11 for brief explanation on sensitivity and specificity Change in patient management Multiple studies (including a randomised clinical trial) indicate that PET consistently upstages tumours compared to CT staging. For example, PET identifies distant metastases in 10-30% of cases deemed operable using CT alone, and indicates additional mediastinal nodal involvement in 15-50% of cases. Thus, there is a change in the management of patient treatment in 29% to 65% of the cases as a direct result of the use of PET. In most cases, patients are spared futile thoracic surgery or resection of lung tissue. Sachs & Bilfinger (26) reported that systematically applied PET imaging has a significant impact on patient management, altering diagnosis or therapeutic intervention in about 72% of patients with potentially lifesaving consequences in 2%. 33 of 180

44 4.4.3 Cost effectiveness There is evidence that adding PET to CT is cost-effective, although the incremental benefit in terms of life years gained is small, considerable costs can be saved from avoiding unnecessary surgery as well as quality of life impairments (level 6). A Canadian study concluded that FDG-PET is cost-effective in pre-operative staging of NSCLC. A strategy that includes PET in addition to CT is cost saving (about 9% of unnecessary surgery avoided with net cost saving of CA$1,455 per patient. Gambhir et al. (7) concluded that CT+PET offers a slightly better life expectancy (3 days) for a lower cost (savings US$1,154) than CT alone. A German cost-effectiveness analysis (4) concluded use of whole-body full ring PET in preoperative staging of patients with NSCLC and normal-sized lymph nodes is cost effective. The cost-utility model used by the Health Technology Board for Scotland (10) identified an algorithm which was cost effective. All patients with lung cancer were referred for a PET scan. If the PET scan did not identify any nodal or distant disease, surgery was recommended. If the PET scan identified regional nodal disease or distant metastases, non-surgical treatment was undertaken. The incremental cost-effectiveness of this strategy was 58,951/QALY compared to the current practice in CT-positive patients, and 7,909/QALY compared to sending all patients to surgery without further testing in CT-negative patients. The Agence d Evaluation des Technologies et des Modes d Intervention en Santé for Québec (1) examined CT alone versus CT followed by PET. The incremental cost-effective ratio for CT+PET is CA$ 4,689 per life year gained, the incremental effectiveness being 0.27 life years. Verboom et al (28) looked at the difference in costs and number of futile operations between patients randomly assigned to conventional work up (CWU) or CWU + PET. The number of futile surgeries was higher in the CWU alone group. The average cost per patient in the CWU alone group was 9,573, compared to 8,284 in the PET+CWU group. The median, however, was higher in the PET+CWU group than in the CWU alone group ( 7,592 versus 7,480) Placement of radiation treatment fields There is substantial evidence that PET scans enable improved placement of radiation treatment fields, ensuring improved coverage of cancerous tissue in the lungs and regional lymph nodes. This improved coverage increases the chance of cure and reduces the risk of recurrence of the cancer, which has significant advantages for patient survival and reduction of future health costs for recurrence. 4.5 Analysis of evidence for PET scanning in recurrent colorectal cancer Improved diagnostic accuracy Detection and localisation of recurrence MSAC (14) concluded that in detecting local recurrence, the concordance between PET and CT is high but that PET allows the detection of smaller lesions than CT. Detection of local recurrences - the sensitivity of PET varies from 92% to 96% and the specificity is 87%, compared to CT sensitivity of 88% and specificity of 89%, and to MRI sensitivity of 83% and specificity of 100%. Detection of hepatic metastasis - PET is better in this indication than other techniques including CT, enabling detection of smaller lesions. Detection of extrahepatic metastasis MSAC (14) concluded that PET is better than CT for this indication. AETMIS (1) concluded that identification of extrahepatic metastasis in 34 of 180

45 order to avoid surgery is that the most important added value of PET in colorectal cancer Change in patient management Recurrence of colorectal cancer is common and occurs in up to 50% of patients. For detection and localization of local, hepatic and extrahepatic recurrence, the diagnostic efficacy includes changes in patient management and therapeutic decision (level 4). The importance of the improved detection of both local recurrence and distant metastases relates to the appropriate use of major surgical resection (with its associated morbidity, mortality and cost). If local recurrence or distant metastases are isolated events, surgical resection is appropriate and can lead to prolonged survival. However, if recurrence has occurred at more than one site, surgery is usually inappropriate, as it does not improve survival. The use of PET scanning reduces the need for major surgical resection in more than 20% of patients who would be considered for surgery based on studies not involving PET Cost-effectiveness The Belgian HTA (3) identified two studies that evaluated the cost-effectiveness CT+PET compared to CT alone for the pre-operative staging of recurrent colorectal cancer. One study concluded that CT+PET offered a better outcome in terms of life expectancy and avoided surgery at a lower cost compared to CT alone (saving CA$1,758). A second study concluded that CT+PET offers a slightly better life expectancy at a higher cost (US$429). 4.6 Analysis of evidence for PET scanning for Staging oesophageal cancer Diagnostic accuracy For staging of lymph nodes (loco-regional, distal or all lymph nodes) and distant sites other than lymph nodes, evidence supports the use of PET (level 2). For nodal staging (Staging I), studies show that the specificity is high and similar for PET and CT. PET sensitivity was slightly higher than CT sensitivity in these studies. In the study with CT and oesophageal ultrasound (EUS) as comparators, PET sensitivity is significantly higher than combined CT or EUS sensitivity. Note that EUS is an invasive investigation that requires specific training and expertise. The HTA-BCBS 2002 report (3) (Staging II) assessed the diagnostic accuracy of PET in the staging of loco-regional lymph nodes in patients with biopsy proven oesophageal cancer. PET specificity and CT specificity were similar. PET sensitivity was low but still slightly higher than CT sensitivity. The HTA-BCBS 2002 report (3) (Staging III) evaluated the diagnostic accuracy of PET in the staging of distant lymph nodes in patients with biopsy proven oesophageal cancer. For two of these studies which were able to be compared, PET sensitivity was low in one study but higher than CT sensitivity. PET specificity was high in both studies and CT specificity was high in only one study. The HTA- MSAC 2001 (14) report (Staging IV) assessed the diagnostic accuracy of PET in the staging of all lymph nodes (no specific region) in patients with biopsy proven oesophageal cancer. The HTA-BCBS 2002 report (3) (Staging V) assessed the diagnostic accuracy of PET in the staging of distant sites, other than lymph nodes, in patients with biopsy proven oesophageal cancer (SCC and adenocarcinoma). PET sensitivity was higher than CT sensitivity. 35 of 180

46 In summary, when compared to CT, PET has a higher sensitivity and a similar or higher specificity Change in patient management A recent systematic review assessed the staging performance of PET in oesophageal cancer. Of the included studies, the change in patient management ranged from 3% to 20% due to the addition of PET to the preoperative work up Patient outcome The HTA-MSAC 2001 (14) report included 5 studies, with some hierarchy 4 evidence, mainly predicting surgery that would be avoided. One study assessed the 30-month survival comparing PET predicted disease state with CT predicted disease state. With PET- predicted local disease, survival was 60%; with PET-predicted distant disease, survival was only 20%. With CT-predicted local disease, survival was 52%; with CT-predicted distant disease, survival was 38%. 4.7 Analysis of evidence for PET scanning for Staging of other solid cancers Oesophageal cancer is used as an example of the use of PET that allows treatment to be tailored more accurately to the extent of the cancer. This avoids futile surgery in many cases. The same principle pertains to a number of other cancers which are treated with major surgery (stomach, pancreas, biliary). The same principles apply for a growing number of solid cancers of many types where surgery and/or radiation treatment are the dominant treatments for cure of the patient. This included head and neck cancers, melanomas, and staging of primary and recurrent breast cancer. On average, approximately 30% of patients will have their treatment changed by the addition of PET scanning to conventional staging which includes CT. 4.8 Analysis of evidence for PET scanning for assessment of treatment response A growing indication for PET in oncology is the assessment of treatment response. There are two aspects to this issue, being: i. Early assessment of the efficacy of a systemic therapy a growing body of literature indicates that a PET scan performed after 1-2 cycles of chemotherapy provides a valid indication of the ultimate tumour response. The importance of this is the ability to determine if a particular treatment should be continued, changed or discontinued. This has considerable morbidity risk and cost implications, given the cost of newer systemic agents. ii. Assessment of tumour response following treatment there are data indicating that the response of a cancer at the end of a treatment course can be predicted accurately by PET. This has been validated in treatment of lymphomas and head/neck cancer. In both cases the presence of residual PET activity in the cancer at the end of treatment indicated the need for further treatment. Conversely, the absence of PET activity is strongly suggestive that the cancer has been controlled and that further treatment is unnecessary. For head/neck cancer following radiation treatment, this reassurance from PET, which is unavailable by CT (as PET is a functional study and CT is a structural tool), avoids major morbidity risk and costly surgery. For many lymphomas, this reassurance can mean the avoidance of further intensive treatment, including bone marrow transplantation. 4.9 Analysis of evidence for PET scanning for diagnosis of lung cancer (solitary pulmonary nodule SPN) Lung cancer is the most common cause of cancer death in NZ. 36 of 180

47 In many cases the suspicion of lung cancer arises from an abnormal chest x-ray. However there are many other causes of abnormal lung shadows on chest x-rays. There are robust data which indicate that the nature of an isolated lung abnormality can be identified using PET. Lesions that are PET-negative may be watched without intervention or further investigation, and so avoiding invasive procedures such as thoracotomy in patients with smoking induced marginal lung function Benefit of PET/CT compared with PET alone or CT alone A recent compilation of data to 2006 is shown in Appendix 1, C2. This indicates that PET/CT compared with PET or CT alone, is markedly superior with staging most cancer types Analysis of evidence for PET scanning in neurology and cardiology The applications of PET in neurology and cardiology are largely investigational but are emerging areas of interest. However, the Belgian HTA (3) gives evidence of the role of PET use in these areas Neurology Alzheimer s disease: There is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). Although the possible therapeutic consequences of this diagnosis are uncertain, this is an increasingly important diagnosis. Epilepsy: There is level 2 evidence for the use of PET for diagnosis of refractory epilepsy, to identify an epileptic focus not evident on structural imaging (CT or MRI) Cardiology Myocardial viability: The Belgian HTA (3) reviewed 3 other HTA which included 164 studies for the use of PET for the diagnosis of myocardial viability. They found evidence of diagnostic efficacy to level 3 (change in diagnostic thinking). The MSAC HTA reported a change in patient management in up to 50% of the patients Estimated number of scans in New Zealand The project team attempted to determine the possible number of PET scans likely to be required in NZ. This was difficult, due to the paucity of data regarding: i. the staging of cancers in NZ (the Cancer Registry data are deficient for many cancer types). ii. marked regional differences in management policies for cancers. iii. lack of agreed management guidelines for most cancers. The numbers were estimated using the following methods: i. Extrapolation from overseas usage patterns, ii. Extrapolation from estimations in overseas HTAs, iii. Extrapolation from a UK lung cancer modelling study, iv. Estimation of a combination of expert opinion, based on tumour stage and other pathological features derived from NZ and overseas epidemiological evidence. Note the range of estimates (approximately 3,000-8,500 pa). For service planning purposes, approximately 4,000-6,000 scans per annum in NZ seems a reasonable estimate. 37 of 180

48 Table 10: Estimation of number of PET scans required in NZ, using different methods Method Number of PET scans per annum Extrapolation from Aust (Medicare rebate)* 3,000 Extrapolation from UK 2,920-6,400 Extrapolation from Ontario 7,740 Extrapolation from Quebec 8,570 Extrapolation from lung cancer modelling 5,100 Assessment by cancer site 4,088 * In Australia is the number of PET scans that met the agreed indications, following the MSAC report ( ), performed in 7 nominated PET scan centres. During this period it is estimated that a similar number of scans were performed privately. Estimation of a combination of expert opinion, based on tumour stage and other pathological features derived from NZ and overseas epidemiological evidence. The basic steps in the methodology used to make this assessment were: i. Cancer projections for 2011 as the basis for estimating the number of cancers in NZ. ii. Indications for the role of PET (diagnosis, staging, recurrence, treatment evaluation) in the listing produced by the NZ Radiation Oncology Work Group and NZACS. iii. Derivation of the number of patients within each tumour group with an indication for PET scanning by using available epidemiological data (including distribution of cancer stages and other pathological features) and expert judgement by oncologists and other clinicians. iv. Adding additional PET scans for patients who require multiple scans. Table 11 is the projected utilisation of PET scanning by tumour type. Using the above method, approximately 4,100 scans are estimated to be required in Note that breast cancers have been excluded, as there is insufficient evidence to date of a role for PET. However this is highly likely to increase demand, as there is a growing body of evidence for the role of PET scanning for initial staging and staging of recurrence in breast cancer. 38 of 180

49 Table 11: Projected utilisation of PET scanning by tumour type (excl breast cancer) Cancer type/site Projected registrations Attribute Diagnosis Staging Treatment evaluation Recurrence TOTAL Lung- any type 1684 NSCLC SPN Melanoma Colorectal 2971 Rectal Colon CEA relapse Oesophagus Stomach Pancreas Gall bladder Breast Nonhodgkins lymphoma Hodgkin s disease Head & neck Sarcomas Brain tumours Cervical Ovarian Paed oncology of 180

50 5 Economic assessment A full economic assessment of introduction of PET scanning in NZ has not been possible due to the lack of suitable data. There is little published evidence and data of cost-effectiveness or other economic techniques of analysis for PET scanning introduction and after introduction. Aspects of economic evaluations undertaken elsewhere are described below for future possible economic assessments in this area. 5.1 Overview Economic analysis is the explicit consideration of the costs and benefits of a proposed course of action, and is based on three fundamental concepts that drive many of the choices made by health professionals daily: Scarcity resources will always be insufficient to support all possible activities. Choices due to scarce resources, decisions must be made regarding how best to use them. Opportunity cost by choosing to use resources one way, the opportunities to use the same resources is lost. Based on these concepts, resources are only used efficiently if the value of what is gained from their use is greater than the value of alternative options that could have been funded. There are a range of economic analyses routinely applied to decision problems in health care, ranging from cost minimisation analysis to cost-utility analysis. As PET scanning is a service improvement, the most appropriate method is a cost-utility analysis. Cost-utility analysis (CUA) is a variant of cost effectiveness analysis in which outcomes are weighted in a common manner, usually quality-adjusted life years (QALYs). This enables comparison between the costeffectiveness of interventions treating different conditions, and takes into account benefits resulting from both decreases in mortality and decreases in morbidity. Like all economic analyses, an appropriate comparator against which to compare impacts is required. In this case, the comparator is the current situation. 5.2 Potential costs and benefits The economic issues surrounding the use of PET scanning are summarised below, with particular reference to the staging of patients with NSCLC (described above). As a result it may: i. Increase the number of correct operations in those for whom it offers a potential cure 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. iii. Avoid the mortality and morbidity associated with futile operations. iv. Reduce the number of open and close operations for which the futility of the operation is realised during operation. v. Allow improved placement of radiation fields for curative treatment. vi. Reduce the numbers of other diagnostic investigations. Offsetting these potential advantages are 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. 40 of 180

51 iii. 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). 5.3 Costs identified There is an essential difference to keep in mind between costs that are relevant for economic assessments and those that feature in financial analyses, namely that economic costs incorporate opportunity cost (the most valuable foregone alternative), whilst financial analysis generally focus on actual capital and operating costs Costs of the current system There are two basic components of the current system costs that are relevant to an economic analysis: (a) referral costs and (b) capacity and service costs. a. Referral costs: These relate to the need to send patients to Australia for scans. While there is no central recording of patient numbers, it is estimated that approximately 100 patients a year are sent to Australia for PET scans. Increasingly, DHBs are agreeing to fund patients (and carers), as the value of PET for staging of cancers is accepted. Avoidable surgery costs: PET scans performed for staging cancer can result in a decision for less aggressive treatment (usually cancellation of major surgery). The potential provided by PET scanning to avoid these costs is a key consideration, both from the perspective of patient well-being and the freeing up of resources within DHBs to be directed elsewhere. Given the current and projected pressures presented by cancer, any relief is to be valued. It may be argued that cost offsets do not need to be taken into account as often these are not realised. For example, a new technology may prevent or shorten hospital stays but the beds freed up will be occupied by another patient. Thus, DHBs may not gain direct financial savings, but rather more people with other conditions will receive treatment. However, hospital cost offsets are part of the net resource use of a particular intervention, and measuring net resource use is the goal of economic analyses such as CUA. Hence, any savings to DHBs will manifest either as discrete savings through services no longer being used, or through those resources being deployed elsewhere, and so should be included in the analysis. Avoiding protracted courses of curative radiation therapy Most curative courses of radiation treatment involve daily treatment extending for several weeks. By contrast, patients with incurable cancers usually receive shorter courses of radiation, typically a single week of treatment. The improved ability of PET to differentiate curative from palliative scenarios allows better resource management. This is of particular significance in NZ, due to the chronic protracted waiting times experienced over many years. The following caveats should be noted: i. DRG prices (often used to estimate hospitalisation costs) do not distinguish between the fixed costs necessary to run a service regardless of patient numbers (e.g. overheads, minimum staffing levels, etc.) and the marginal costs (i.e. the extra costs incurred treating each new patient). They are therefore average prices, and as such they do not provide an accurate estimate of the opportunity cost of resources (i.e. average costs are likely to overestimate the opportunity cost of hospitalisation). However, as noted by PHARMAC, average costs are often sufficient in cases where hospitalisation costs are not a significant aspect of the analysis or where a rapid costbenefit analysis is being undertaken. 41 of 180

52 ii. Guideline development and use for oncological practice in NZ is rudimentary. Current management practices are diverse, such that determination of the cost savings by the incorporation of PET is not possible currently across the spectrum of cancer. With current development of clinical guidelines occurring, the cost savings from PET will be easier to determine. iii. The likelihood of potential change of management for each of the tumour groups is not difficult to quantify with NZ clinicians who are not familiar with using PET as a diagnostic tool. iv. The number of patients whose tumours are upstaged, and who should be managed with less intensive (and less expensive) versus the number of patients whose tumours are downstaged and require more aggressive treatment (and more expensive) treatment is unknown and is difficult to quantify. v. The extent to which the availability of PET will substitute for, and reduce the requirement for, current investigations is unknown. b. Capacity and service costs The current system of referrals is thought not to be a true representation of total need due to the high barrier for access to PET caused by: Necessity to travel (social and medical barriers). Self-funding required if DHBs do not fund scans. There is an unmet need that is a cost imposed by the current system, but care is needed to not double-count in terms of the ability of PET to better meet that need. The calculations presented above have included unmet need by calculating avoidable surgery costs. The identified costs of the current system (relative to the situation of full capacity) are $3.6 million 5 (Table 12). This figure has been derived from interpolating the projected 2011 incidence rates to the current situation and pro-rating to give an accurate estimation of the current costs imposed by the system as it stands. Changes in these figures (to reflect increased throughput/scan numbers and extent to which breast cancer is included) should be considered as part of the further work. The first element is derived from multiplying the number of patients currently sent to Australia (100) by the estimated cost ($3,000, made up of $1,500 for the costs of scanning and $1,500 for travel costs). Note that the costs associated with any family members accompanying patients and the psychological cost associated with overseas travel, have not been included. Table 12: Costs of current system, based on 100 patients pa referred to Australia Description Annual estimated cost Referral costs $300,000 Unnecessary surgery $3,600,000 5 It is important to distinguish between the treatment of these costs in an economic assessment versus a financial analysis. Here we have assumed a counterfactual of full capacity (i.e scans), whereas the financial analysis assumes a phased build up to this level. For the purposes of estimating what the costs of the current system are the method used here is appropriate, while the financial analysis should take account of the actual year-by-year ability to avoid costs, rather than the full capacity consideration in the economic assessment. 42 of 180

53 Service/capacity costs NA The second element has been obtained by calculating the direct cost for surgery and inpatient stay using Auckland DHB (variable cost) figures for three situations: Staging NSCLC. Recurrence of colorectal cancer. Staging oesophageal cancer. The choice of these three situations was determined by the strength of the evidence and opinion in suggesting where PET scanning is most relevant (NSCLC and colorectal) and to illustrate a high cost option (oesophageal, where both more bed days are required, and higher surgical costs accrue). Assuming that PET scanning results in 20% fewer operations for each of the above groups we then multiplied the direct costs by the number of operations avoided (less the 100 who are currently sent to Australia) to determine the cost of unnecessary and avoidable procedures undertaken currently that PET scanning would eliminate. 6 This is more conservative than the international literature indicates (30%) but was chosen to try to avoid overstating current costs. Using the 30% figure increases these costs by half ($5.4m). Note that these are preliminary estimates and are indicative only. Their purpose is to give a flavour of the order of magnitude of costs of the current system that could be avoided by PET adoption, rather than being definitive. As there is no information on direct relationship between numbers of registrations to the number of scans for each condition, the linkage was by expert judgment. For example, the number of registrations for all lung cancer was 1,684, while the number of melanoma registrations was 1,947. However, the estimated number of PET scans for lung cancer was over twice that of melanoma. This reflects differences in the relative utility of PET scanning for diagnosis, staging, treatment and recurrence across the cancer types. Similarly, there was some variation in the costs associated with each of the three situations used to derive indicative cost estimates. As Table 13 shows, staging oesophageal cancer was responsible for only 8 per cent of scans, but 12 percent of costs. The situation is reversed in respect of the lung, where the required number of ward days is lower. Table 13: Relative comparisons across cancer types Proportion of scans Proportion of costs Oesophagus 8% 12% Colorectal 22% 26% Lung any type 70% 62% 6 There is no direct and well-defined relationship between cancer registrations and the number of scans, as such. Expert judgement and gut instinct were used to identify magnitudes, while the literature confirmed where PET scanning is most useful (staging, diagnosis, treatment and recurrence). 43 of 180

54 These costs are illustrative and have not considered savings in surgery for other cancer types, or for savings and improved treatments in non-surgical areas, such as radiation therapy, chemotherapy and haematological treatments including bone marrow transplantation. The development of strategies and protocols to incorporate PET scanning into the early assessment of chemotherapy efficacy and into the management of breast cancer (initial staging and staging at recurrence) will amplify greatly these savings in expensive and inappropriate (i.e. futile) treatments. To summarise, the exact magnitude of the costs associated with the current system which will be avoided if PET scanning is introduced is difficult to establish. The estimates may be overstated because of case-mix and clinical practice, and they could be under-stated because of the conservative nature of the assumptions and the general uncertainty/unavailability of data. Other costs, not included in the analysis, are direct non-healthcare costs (e.g. costs to other Government Departments, taxes and transfer payments), indirect healthcare costs (e.g. future healthcare costs from patients living longer and hence consuming healthcare resources), and indirect patient costs (e.g. lost productivity of a patient due to treatment, illness and death, including that of family members if they attend to patients) Costs of PET scanning The capital and operating costs associated with the introduction of PET scanning are detailed elsewhere (section 6 of this report). In terms of the opportunity costs of PET scanning, it was difficult for the project team to review competitive proposals. To the extent that there are alternatives that operate in the same environment as PET scanning (i.e. cancer) but have more readily identifiable benefits in terms of patient outcomes or are less costly, then there is obviously an opportunity cost associated with introducing PET scanning. In identifying and measuring this opportunity cost, consideration should be given to the public expectation of a high quality public health system that is not seen to be out of step with other comparable countries. New Zealanders would expect that cancer services would be at least comparable to those in Australia, Canada and the United Kingdom. These expectations place something of a premium on PET scanning in comparison with other proposals to which funding could be directed. That is, alternative proposals should have at least as much impact on public expectations as PET scanning is likely to, in order for the opportunity cost to be valid. Two possibilities that were proposed to the project team in terms of being able to measure opportunity costs were the upgrading of MRI facilities nationally and increased expenditure of pharmaceuticals. Assessing the impacts of directing up to and over $40 million towards both these possibilities is beyond the scope of this paper. However, MRI scanning is not a direct alternative to PET scanning. Although each modality is used in cancer assessment, they have different purposes, provide different types of information and are not interchangeable. 5.4 Likely patient benefit As stated previously, most studies of PET report diagnostic accuracy rather than improved patient outcomes. There have been very few studies undertaken from which it is possible to draw information about cost effectiveness from PET scanning. Appendix 6 provides an example of an economic evaluation carried out by the NHBS in 2002 for the use of PET in the staging of NSCLC. The results indicate that inclusion of PET may not be more costly than conventional staging methods alone. For staging of NSCLC, the Belgian HTA claimed that there is some evidence of effectiveness in relation to patient management, altering diagnosis or therapeutic intervention, but direct evidence of PET ability to improve patient outcome is lacking. 44 of 180

55 For head and neck cancer, the Belgian HTA stated that the evidence on cost-effectiveness is limited. Only one study that undertook cost-effectiveness and cost-utility analysis was identified. While the identified that PET is cost effective and the use of PET resulted in a reasonable cost per QALY (lower than US$10,000 per QALY gained), there were no cost savings associated with PET and the study has limitations that the authors of the Belgian HTA suggest warranted caution. In conclusion, likely patient benefits may be identified for inclusion in an economic assessment but quantification of such benefits is complex. Therefore a reliable benefit-cost ratio cannot be calculated. The literature in this area gives little indication as to the magnitude of benefit or the numbers of patients who may benefit. The types of patient benefits that are likely to result from PET scanning are: i. More accurate delineation and knowledge of the disease status of the patient. This permits a refinement of management options and selection of the treatment that is most likely to benefit the individual. ii. Patients will be spared the morbidity and mortality of major surgical procedures that are undertaken currently in the absence of PET scanning in NZ. iii. PET is minimally invasive and can avoid the requirement for invasive investigations that are required currently to determine the nature and extent of disease (mainly cancer) iv. Increased confidence in the NZ health system and in the care that they will receive. v. Patients, particularly those with cancer, will not be forced to travel overseas to access PET. However, the above does not appear immediately amenable to common economic evaluation methods of life-years or quality-of-life-gained. 45 of 180

56 6 Business implications A standard financial analysis of three options based on different cyclotron and scanner configurations is presented below. The focus is on actual costs and to a certain degree cashflows. 7 The three options are: i. Option 1-1 cyclotron, 1 scanner ii. Option 2-1 cyclotron, 2 scanners iii. Option 3-2 cyclotrons, 4 scanners These may not be discrete options, as a phased introduction of equipment to achieve option 2 may be required. It is also inefficient to have 1 cyclotron servicing one scanner. Also, it is likely that the number and nature of private PET scanning machines would increase following the placement of a cyclotron in NZ. For these reasons, the analysis below focuses on options 1 and 2. Option 2 is the project team s preferred option for immediate implementation, with phased implementation potentially to option Capital expenditure and implementation costs Capital expenditure PET scanning is frequently perceived as an expensive technology, with significant investment and operating costs. These costs are made up of a cyclotron, radiopharmaceutical facility, PET scanners, supporting infrastructure and IT. The table below presents estimates of the capital (and operating) costs required for the respective configurations. 8 While these costs are based on best estimates obtained from suppliers and have been subject to validation by experiences overseas (primarily Melbourne, Australia), they are not firm and will need to be refined and adjusted in the next stage of proceedings. In this assessment capital expenditure has been estimated in a linear fashion, with no discount for multiple purchases. 9 Any discounts available for multiple purchases or other contractual benefits will need to be considered as part of the capital business case development process. 7 Given there is effectively no cash inflow as a result of the project, financial analysis is difficult. 8 Note that the costs contained in the document relate to a research-capable cyclotron, so from a health production perspective, could be considered upper-bound in nature. 9 IT costs are an exception, where a cost reduction of 33% is assumed to accrue to IT requirements for the second scanner. Costs per scan exclude all implementation costs, estimated at $2-3 million, and training, costs estimated at $800, of 180

57 Table 14A: Capital and operating costs of major options (estimates only) Option 1 Option 2 Option 3 Capital costs Purchase price Building costs 7,150,000 10,450,000 20,900,000 3,000,000 4,000,000 8,000,000 Lab Fit Out 1,650,000 1,650,000 3,300,000 IT Costs 750,000 1,250,000 2,500,000 Contingenc y building fit out 465, ,000 1,130,000 Subtotal capital costs 13,015,000 17,915,000 35,830,000 Operating costs Fixed costs Variable costs Refer Table 14A for detail Refer 14A for detail 1,640,750 2,491,250 4,982,500 Staffing 2,280,000 3,780,000 7,560,000 Operating 311, , ,000 Other 60, , ,000 Operating costs year 1 4,291,750 6,788,250 13,576,500 Cost per scan based on 1500 scans per annum per scanner Cost per scan based on 2000 scans per annum per scanner 2,861 2,263 2,263 2,146 1,697 1,697 Excluded from operating and capital costs: implementation costs 2-3 million Training costs 800,000 Key: Option 1-1 Cyclotron, 1 Scanner; Option 2-1 Cyclotron, 2 Scanners; Option 3-2 Cyclotrons, 4 Scanners Excluded from the tables: interest is excluded from capital & operating costs; and travel and accommodation 47 of 180

58 Table 14B: PET Unit Detailed Cost Estimates $ Accelerator Accelerator Fixed Costs Accelerator Maintenance 200,000 Lab Equipment Maintenance 5,000 Power / Building Maintenance 10,000 Lab equipment Maintenance 200 Cleaning 20,000 Depreciation 524,000 Total Fixed Costs 759,200 Accelerator Variable Costs Lab Supplies 100,000 Chemicals / Target Materials 100,000 Gases 25,000 Total Variable Costs 225,000 Scanner Scanner Fixed Costs Scanner Maintenance 180,000 Computer Maintenance 5,000 Cleaning 20,000 Marketing / Training 15,000 Building Maintenance 17,800 Depreciation 643, ,550 Variable Costs Scanner Operating Scanning Supplies 36,000 Data Storage 5,000 Hard Copy & Stationery 15,000 Power 30,000 86,000 Other Training 60,000 Excluded from the tables: interest is excluded from capital & operating costs; and travel and accommodation The costs per scan recover all operating costs contemporaneously while spreading the capital costs for the cyclotron and scanner across the estimated life of the assets-15-year and 8-year periods respectively. The final building costs will be very much dependent upon the site where the cyclotron and scanner are to be located. It should be remembered however, that implementation costs (estimated cost $2-3 million) and training costs (estimated $800,000) are excluded, and are therefore excluded from the price per scan, and that fit-out costs accrue predominantly to the cyclotron. In addition, operating costs have been assumed to remain unchanged through the life of the project. To the extent that there 48 of 180

59 are price or other changes over time there will be a divergence away from the operating cost estimates, which may be reflected in the cost per scan. The initial cash outlay estimated under option one is: Table 14C: Summary of cost estimates for option 1 $/Cyclotron $/Scanner $/total Capital 7,865,000 5,150,000 13,015,000 Operating Fixed costs year 1 759, ,550 1,640,750 Variable operating costs 225,000 86, ,000 Staffing and other 2,340,000 Total operating costs 4,291,750 Total capital and operating costs for first year 17,306,750 Training and implementation estimate m Investment appraisal Discounted cashflow analysis (a commonly applied method for determining the financial merits of investment options) involves calculating the net present value (NPV). The NPV is the future stream of costs and benefits (represented as cashflows) converted into equivalent values today, using a discount rate. 10 In general a positive NPV (i.e. the sum of discounted benefits exceeds the sum of discounted costs) is a necessary (though not sufficient) condition for investing. Apart from the current expenditure on sending patients to Australia, there are effectively no actual positive cashflows resulting from the investment there is no possibility of the NPV being positive. By way of exposition, the model includes the annual savings in direct costs (of avoided surgery, only for recurrent colorectal cancer, lung cancer, and primary oesophageal cancer) identified in the analysis above, adjusted for the phased approach (i.e. the ramping up of scans to 4,000 in total by the fourth year) for option 2. It is assumed that all the costs are incurred in one initial tranche. This option generates an NPV of -$16.9m (an internal rate of return of 7.31 per cent) for a 15-year period, with a discount rate of 11%. There is some debate around what the appropriate discount rate should be. We understand that the internal rate of return required by investments in Auckland DHB is 11% (note that Auckland DHB is operating with its deficit situation and a higher threshold to test its investment models). When discounting costs and benefits for inclusion in CUA, PHARMAC recommends a discount rate of 3.5%, which is the 5 year average real risk-free long-term government bond rate. However, for budget impact analysis, which is generally used to make an investment decision (rather than determine the relative ranking of pharmaceuticals), they suggest a discount rate of 8% should be used. Table 15 shows the NPV for a number of different discount rates, over 15 years. The option of 1 cyclotron and 1 scanner would never meet the benchmark required number of 4,000 scans. Even with the unrealistic assumption that full benefits will accrue in year 1 for this option, the NPV is still strongly negative for all discount rates used in the table below. Meanwhile 10 Future values are discounted to reflect opportunity costs and the higher value placed on present consumption (cashflow) than future consumption (cashflow). 49 of 180

60 the option of 2 cyclotrons and 4 scanners performs even worse than the option shown, given that there is double the cost, but produces the same (health) benefits. Given the possibility of long horizon benefits from PET scanning (i.e. the investment is not being made with a view to short-term gains, in which case a risk premium attaches), there may be some justification for using the lower discount rate. Nevertheless the NPV is still substantially negative. Further detailed work on the benefits side (i.e. the surgery costs avoided) may result in a better NPV, but based on the information available currently, the investment decision is not justified on financial grounds alone. Whilst financial and economic analyses are important, they are not the sole decision criteria in many fields, including health. Table 15: Net present value, 1 cyclotron, 2 scanners (excludes training costs) all implementation and Discount rate NPV (m) 3.5 per cent -$ per cent -$ per cent -$ Training Considerable one-off and on-going training will be required across a range of areas, the details of which are summarised below. Exact costings have not been prepared; assuming training costs are around a third of FTE salary costs, there is an estimated additional $800,000 in costs. The development of guidelines, protocols and information packs will also entail one-off costs, although some of these may be absorbed in existing budgets. Medical specialists Currently there is one fully trained PET medical specialist in NZ. It is likely that the initial staffing of PET facilities will be from currently practicing Nuclear Medicine Physicians. Practicing, credentialed nuclear medicine specialists are able to train at selected PET centres overseas (eg Australia, UK). As access to PET training is limited and competitive (due to global shortages), it will be essential to build on existing collegial relationships to gain access to this training. Nuclear Medicine is an advanced specialty, with a three-year Advanced Training Program undertaken by medical graduates post- Fellowship of either the RACP or the RANZCR. As the demand for PET services is predicted to increase considerably in future, core training in nuclear medicine now incorporates PET. Medical Technologists There are a small number of nuclear medicine technologists in Wellington and Hamilton who have been trained, either in Australia or by their colleagues to perform PET scans. There is no current training or accreditation in NZ for technologists in PET scanning. Australia provides a useful model in terms of the regulations and requirements around appropriate training. 50 of 180

61 As the scanners recommended for introduction into NZ will be hybrid PET/CT scanners the technologists will need to be credentialed for both technologies. At present Medical Radiation Technologists (MRTs) are not permitted to perform nuclear medicine scans and nuclear medicine technicians are not certified to perform CT. To start a PET service in NZ, it will be necessary for a number of current nuclear medicine technologists to train and be credentialed for PET and also for CT to the level required for the hybrid technology The University of Sydney provides a course stream that endeavours to train nuclear medicine technologists to operate hybrid PET/CT systems. These students must undergo a three-year undergraduate course in nuclear medicine technology for certification as a nuclear medicine technologist. For further certification to operate the combine PET/CT systems only, a 16 week postgraduate course in medical radiation is offered. Physicists Physicists currently practising in nuclear medicine departments will need to extend their knowledge to include PET. At present this has not been formalised by a prescribed training structure. The ANZSNM has a very active educational program concerned with PET and SPECT. In addition there was a recent symposium about integrating CT into nuclear medicine from the physics perspective. Radiopharmacists/ Chemists This is a new workforce to NZ that will need to be recruited in a highly competitive global market. Education for Referrers Potential referrers require information and education regarding PET and its indications for use. That process has already begun with international conferences and the 2006 RANZCR ASM in Christchurch included PET as one of its main themes. A formal educational program will be required to ensure appropriate referral and use of PET An information pack could be prepared (similar to that sent to all GPs prior to the launch of the National BreastScreen Programme) Referrers will need guidance regarding incorporation of PET into clinical practice. This will be an evolving concept and will include issues such as: o o o the possibility to replace existing imaging tools by PET the possibility to use the CT component of the PET/CT unit as the sole CT study, rather than to duplicate the CT scan Protocols to ensure that individuals with suspected cancer for whom radiation treatment may be an option are scanned in the appropriate anatomical position for subsequent radiation treatment planning, to minimize duplication of PET scan requests. 51 of 180

62 6.1.4 Other implementation costs The current cost estimate for other implementation costs is $2-3 million. This includes the cost of developing and promulgating guidelines, the cost of establishment of governance over introduction of the technology, the cost of change management and project management services, and the cost of ongoing evaluation and optimisation of the technology. 6.2 Forecast of cost to DHBs High level costs to individual DHBs have been derived (Table 16). Cancer data from 2004 were used to estimate the proportion of total cancer registrations for each DHB. Assuming constant relativity, that percentage was applied to the total number of scans for a fully functioning service (with 1 cyclotron and 2 scanners capable of 4000 scans) to give an estimate of the number of scans for each DHB. Finally, the estimated cost per scan for the fully functioning service gives an estimate of the costs by individual DHBs in this scenario. The notional cost per scan at this level is $1,697. Note that the direct proportionality is an estimate based on the assumptions that: i. all DHBs have the same mix of cancer types, cancer stages, co-morbidities and treatment options, and ii. the increase in cancer registrations is the same for all DHBs. 52 of 180

63 Table 16: High level costs to individual DHBs (based on $1,697 per scan) DHB Cancer reg 2004 % Cancer reg Total scans Estimate per DHB $ Northland ,460 Waitemata ,777 Auckland ,919 Counties Manukau ,485 Waikato ,845 Lakes ,871 Bay of Plenty ,644 Tairawhiti ,955 Hawkes Bay ,920 Taranaki ,283 MidCentral ,952 Whanganui ,559 Capital and Coast ,862 Hutt Valley ,297 Wairarapa ,173 Nelson Marlborough ,145 West Coast ,072 Canterbury ,671 South Canterbury ,485 Otago ,284 Southland , $6,787,769 The costs are steady-state in nature, and represent the pricing level and quantity of scans once the system is fully functional. In the early years there will, be lower volumes and therefore higher actual unit costs. Using a linear progression over the three-year period needed to reach capacity, there is a considerable shortfall in terms of cost recovery of the operating costs and depreciation associated with a cyclotron and two scanners. This discrepancy totals $10.3 million over the three years. The first year of operation, where volumes are extremely low, accounts for approximately 50% of the gap. One possible mechanism to address the gap is a sliding price scale where fees are initially high but then transition to the $1,697 level after three years. While no detailed modelling of this mechanism is included in the analysis, preliminary examination suggests that the price per scan in the initial two years would be prohibitive, with costs per scan of around $10,000 in the first year, $3,400 in the second and $2,075 in the third. Clearly, prices per scan are sensitive to volumes and while only indicative, these figures strongly suggest that further examination and consideration of this aspect will be required in the preparation of the capital business case. Cost recovery principles and agreement around who pays are very important. The costs as presented do not take into account travel costs that may be incurred. It is likely that the majority of scans undertaken will be for patients who reside in and around where the scanners are located. Some travel will be required, and it is difficult to precisely estimate these costs. IDFs could be used to estimate numbers, but flight and/or other transport and accommodation costs will depend on several variables (time of flight and so on). Even at the 53 of 180

64 steady state cost of $1,697 per scan, when travel and accommodation costs for some patients are included, the financial comparison from a marginal cost perspective between sending patients to Australia and somewhere in NZ may not always be a favourable one. Diagnostic pathways are important when considering the possibility of cost savings resulting from PET scans replacing non-pet diagnostic scans (or other procedures). While it is considered best practice to identify and include these potential cost savings in an economic evaluation these have not been included here because any estimate those savings will rely heavily on the diagnostic pathway. The analysis is conservative and has assumed that PET will not necessarily directly replace non-pet diagnostic scans (and other procedures or treatments). It is not appropriate to include resource re-direction as a direct financial saving (though any re-direction to another area of need should be quantified and included in an economic assessment) and service delivery implications are best treated as strategic benefits in overall cancer control rather than as a number in the financial analysis. A sensitivity analysis revealed that for a throughput of 5,000 scans the cost per scan reduces to $1,358, and for a throughput of 6,000 scans the cost per scan reduces to $1,131, Note that this sensitivity analysis assumes that everything else remains the same as for a throughput of 4,000 scans, and assumes a configuration of 1 cyclotron and two scanners (operating at maximum capacity). Note that these are 'steady-state' costs and that given higher total numbers of scans the steady-state will take longer to reach, so the under recovery of costs in the initial period would be exacerbated. Note that 2 scanners would be incapable of performing 6,000 scans per annum. 6.3 Analysis of financial implications for provider of national service The above analysis has assumed that of the requirement for PET scanning and cyclotron services arises solely from DHBs. However, there is likely to be considerable interest from other parties, for example, current and future private providers of PET scanning services, and researchers. A nationally-provided service can look to four basic sources of income by which to recoup the capital and operating costs of the investment: Local demanders of scans (i.e. where the scanner is located). Other DHB demanders of scans. Research centres (for both scans and isotopes). Private providers (mainly for isotopes). There is a large range of permutations around optimal ownership and provision of the various pieces of equipment. From a pricing perspective, the appropriate form of ownership must be in place to recover costs whilst also achieving the objectives of the investment. The objectives will differ across different parties and the outcomes for each party will be difficult to compare. In theory, private ownership of a cyclotron is feasible; conversely the opportunities for research (with positive externalities and public good properties) may encourage government ownership. Similarly, ownership of the scanners will need to need to be suitable to support an appropriate price structure which reflects both need and willingness to pay. These issues are addressed below. Decisions about pricing structures and levels are dependent on decisions about ownership and governance, and require further work. 6.4 Locations of Equipment and Service Decisions on location of equipment and service will depend on a number of variables. The following describes the project team s assessment of those variables and how these can be satisfied in the NZ situation. 54 of 180

65 6.4.1 Location: cyclotrons Cyclotrons designated predominantly for clinical use should be sited: Within a major teaching hospital with a nuclear medicine department and a cancer centre, and in a city with a high population density and a large referral base, and within an average travel time of approximately 30 minutes from a domestic airport with direct scheduled flights to all cities with cancer centres. There are three locations in NZ which satisfy the above criteria: Auckland - Auckland City Hospital. Wellington - Wellington Hospital. Christchurch - Christchurch Hospital. Cyclotrons designated to include clinical and research roles should be sited: Within a major teaching hospital with a nuclear medicine department and a cancer centre, and in a city with a high population density and a large referral base, and in close proximity to a tertiary institution with a strong track record in medical and biomedical research, medical imaging and an expressed interest in PET application. There are two locations which satisfy these criteria: Auckland City Hospital and the University of Auckland. Christchurch Hospital and Canterbury University. The project team considers Auckland the preferred site, primarily due to population density. Note that discussions between members of the project team and the Faculty of Medicine and Health Sciences (FMHS), University of Auckland, indicate a strong interest in co-hosting a high-grade cyclotron and PET scanner. The FMHS has cutting edge biomedical research, drug development, a Biological Imaging Research Unit with advanced MRI Location: PET scanners In centres with cyclotrons, PET scanners must be in close proximity to the cyclotron, to enable the use of short-lived isotopes In other centres, PET scanner should be located at the principal cancer centres within the cancer networks. Auckland City Hospital, Christchurch Hospital, Wellington Hospital and Waikato Hospital meet the above criteria. This will provide the initial PET scanner in the region of highest population density and in association with the country s largest and most specialized cancer centre. In phased implementation, siting of the second scanner in Christchurch would provide geographical access for the South Island population Governance of PET service There are three considerations for governance: the service, the cyclotrons, and the scanners. a. The service: It is preferable that the introduction of this service has oversight nationally, to promote development of a high quality and well coordinated service. There is precedence for DHBs in 55 of 180

66 the establishment of national committees (eg haemophilia) which provide leadership and oversight to the sector. b. The cyclotron(s) The capital investment, staffing and operational requirements involved in the acquisition, installation and operational management of cyclotrons are costly, complex and timeconsuming. It is unreasonable and inappropriate to expect a single DHB to take on this task. Therefore a national governance model is proposed. One overseas model which might be useful for adapting to the NZ situation is the Queensland PET Service A Statewide Service (22). Queensland has the same population as NZ and a similar population density distribution, with a high concentration of people in the South-eastern corner of the state. c. PET scanners The acquisition, installation and operational management of PET/CT scanners may be undertaken at a regional level. This function should be managed by the cancer networks in conjunction with their constituent DHBs. To ensure the development of a high quality and equitable service, regional DHB Cancer Networks would be required to submit their business cases to NPAC for review, to ensure adherence to the conditions and standards proposed by NPAC. 56 of 180

67 7 Consultation summary The following processes were used to inform the project team: i. Direct contact The project team contacted individuals and organizations in NZ with knowledge, experience and/or interest in PET. This included clinical and research interests. Individuals or organisations who/that expressed interest were invited to meet with the project team and / or to write a submission for inclusion with the business case. ii. iii. iv. Mail-out to radiology practices A letter was sent to all private radiology practices in NZ outlining the project and explaining the purpose of the business case into the wider context of the decision-making process. Organisations that expressed interest were invited to meet with the project team and/or to write a submission for inclusion with the business case. Directed contact Letters were sent to the Deans of Science and Medicine in universities. Literature search Members of the project team undertook literature searches in areas of interest. In addition, NZHTA was commissioned to perform a short targeted search of peer reviewed literature and HTAs prepared in other countries. The latter included HTAs from England, Belgium, Scotland and Australia. v. Site visits Site visits were made by the Project Chairman to three PET facilities in Australia and by the GNS representative on the project team. vi. vii. viii. Contact with manufacturers & commercial operators manufacturers, suppliers and operators of cyclotrons and PET scanners provided the project team with relevant information. Financial analysis assistance this was provided by DHB financial contractors. In addition, feedback on the initial draft of the business case was received from NSTR and DHBs. 7.1 Summary of medical comment The clinical benefits associated with PET are recognised by oncologists in New Zealand as a requirement for optimal patient management.. The adoption of PET is consistent with the Cancer Control Strategy. Achieving one of the key strategy goals of reducing the impact of cancer incidence in the community would be greatly enhanced through the use of PET scanning. Professional development benefits have also been mentioned in terms of staff having access to the technology that is routinely available overseas. Also, the availability of PET technology will attract high quality professional staff. Future applications also feature in the support for PET scanning. The technology has many possibilities for expansion of existing areas (e.g. drug development, neurology) and for use in new areas, such as breast cancer. There has also been support expressed by existing private imaging groups. In particular, the possibility of PET isotope production in NZ would enable expansion of their service beyond the current low level service. 7.2 Summary of research comment There is strong support from the research community, where the Otago, Auckland, Victoria and Canterbury universities, and GNS s national isotope Centre suggested a large number of research possibilities (refer Appendix 3). Similar to the medical comments received, workforce development issues were mentioned. To a large extent, this is the driving force behind the need for a large cyclotron. Researchers have effectively framed the decision into whether NZ is looking to merely catch-up to the tail of the field or whether it is looking to be in the race. 57 of 180

68 To date, there has not been discussion around any likely financial support for the initiative from the research sector. This is another area for further deliberation in developing the funding case. There is, naturally, some reluctance by DHBs to commit Vote: Health resources toward activities that are more rightly research activities and should be funded as such. 58 of 180

69 8 Specific areas of influence Whanau Ora Cancer mortality is making an increasing contribution to the life expectancy gap for both Maori and Pacific peoples. Overall cancer mortality rates have increased over time among Maori compared to a steady decrease among non-maori and non-pacific people. Leading causes of death for Maori are lung, breast, colorectal, stomach and prostate cancer. Cancer is the leading cause of death for Maori women and the second most frequent cause of death for Maori men. Cancer is a key contributor to the decade of disparity in life expectancy that has developed in NZ between Maori and non-maori. Maori are 18% more likely to be diagnosed with cancer overall than non Maori during the period studied, they were nearly twice as likely to die from cancer. There are socioeconomic and cultural factors as well as the epidemiological factors. Although the project team did not quantify the use of PET in Maori, it is suggested that the availability of PET scanning in NZ will help to reduce inequalities in relation to cancer treatment and outcomes for the following reasons: Two major cancers in Maori are lung and colorectal cancers, for which there is significant benefit established for the use of PET. Maori are frequently diagnosed with cancer at a more advanced stage than non-maori, PET scanning will benefit Maori substantially. This is because the precise location or distribution of cancer, which is frequently best determined by PET scanning, is critically important to optimal treatment decisions. Access to timely diagnostic services is critical for appropriate diagnosis and staging of cancer, which will lead to timely treatment options. The use of PET will also benefit Maori in relation to cardiac disease, due to the higher proportion of Maori with the metabolic syndrome and its consequences, including heart disease. It is expected that the availability of PET in NZ will benefit communities with socioeconomic deprivation, as cancer sufferers from these groups will not be obliged to travel overseas and can have PET scans in NZ. 8.2 Community acceptability Community opinion was not sought in the development of the business case, as the purpose for the business case was to gather technical and clinical information useful for CEOs to decide whether or not to proceed with further investigation. The following comments reflect views from the project team on community acceptability. Community views may be sought should the business case proceed to the next phase Patient and Community Acceptability of PET The following are reasons why the public might view the development of a PET service in NZ as an appropriate use of public funds: i. The diagnosis of cancer is probably the disease most feared by the general public PET scanning is predominantly a tool for cancer management. ii. The ability to perform a minimally invasive investigation that has the potential to markedly alter management and treatment decisions for cancer. iii. The availability of a globally accepted standard of technology enhances perceptions of the high standard of the NZ health care system. 59 of 180

70 iv. Knowledge that cancer patients overseas have access to PET scanning as an integral component of cancer management, or that NZ residents are required to travel to Australia for PET scans, creates concern for patients and their families that would be alleviated by access to similar services. v. The radiation risk to the NZ population is negligible, as all steps and processes involving radiation and radioactivity are regulated by NRL, the statutory authority. This includes production, transport, use and disposal of PET isotopes, and maintenance and disposal of the cyclotron. Preliminary advice from NRL indicates that implementation and operation of a cyclotron should meet statutory and regulatory requirements in NZ Radiation safety of patients The use of PET isotopes is subject to the same requirements that govern the use of all ionizing radiation in NZ, being the Radiation Protection Act 1965 and its regulations and codes (eg Code of Safe Practice for the Use of X-rays in Medical Diagnosis and Code of Safe Practice for the Use of Unsealed Radioactive Materials in Medical Diagnosis, Therapy, and Research). Patients receive a dose of radiation from both the 511 KeV gamma rays from decay of the positron emitting radioisotope and from the x-rays from the CT scan. For patients who subsequently receive radiation treatment, the radiation dose received from radiation treatment is many thousands of times greater than the small dose received from the PET/CT scan. In addition, most cancer patients will have multiple CT scans or other radiological investigations during the course of their disease, such that the added radiation burden from the PET/CT scan is minimal Ethical Considerations and Informed Consent In considering the ethical requirements around introduction of a new technology, the following comments are relevant: i. Tens of thousands of patients have been subjected to PET scans without accident. ii. PET is a minimally invasive investigation with minimal discomfort. iii. There has never been a report of an allergic reaction to the injected material. iv. A high standard of manufacture and quality control is mandatory to ensure consistency of a safe product. v. As with other investigations involving radiation or radiopharmaceuticals, PET scans should not be performed on pregnant or potentially pregnant women. vi. As with any medical procedure, fully informed consent is required prior to undertaking a PET scan. 8.3 Impact of PET Technology on research Clinical research The following comments are in relation to clinical research in NZ. i. PET scanning has an increasing role in new drug development Ground-breaking studies with 11 C-labelled form of the drug DACA, one of the ASCRC drugs tested under the auspices of Cancer Research UK, demonstrated how the distribution, metabolism and pharmacology of a new drug can be studied at an early stage of drug development using PET. PET studies have played a significant role in the analysis of tumour blood flow changes in response to vascular disrupting agents, of which DMXAA is a leading role. 60 of 180

71 ii. The continued world leadership in new anti-cancer drug development by NZ research groups is dependent on availability of PET scanning at the preclinical and clinical phases (Appendix 3, University of Auckland letter). iii. Similarly, the continued ability of NZ research to compete successfully for commercial funding for drug development and assessment depends on the availability of PET scanning in NZ. To support this statement, the project team was informed that a major sponsor of drug development is considering abandoning projects in NZ if PET is not available. iv. It is simply not feasible to maintain the existing strong research base in NZ without PET available locally. v. The availability of PET will provide significant assistance to both the maintenance and expansion of world-leading biomedical research in NZ, and will attract talented scientists to NZ, including New Zealanders currently working overseas PET in Cancer Research PET has enormous potential to support the development of anticancer drugs. It is clear that NZ, particularly through the work the Auckland Cancer Society Research Centre (ACSRC), has a leading place in the world with respect to anticancer drug development and application to cancer patients. PET scanning, which has necessarily been carried out in countries other than NZ, has played an important part in drug development. In order for NZ to cement its international standing in the experimental and clinical development of new cancer treatments, a high quality PET scanning facility must be developed. PET/CT imaging is now recognised as an essential tool in the diagnosis and detection of cancer, but current research indicates that PET scanning will play an increasingly more important role in both the selection of optimal treatment, as well as for monitoring of response, in individual cancer patients. Some examples are: Pharmacological studies on new drugs: Metabolic resistance, whereby over-expression of metabolic enzymes in tumour or other tissue can attenuate the action of an anticancer drug, can be approached using PET studies and the appropriate probes. Multidrug resistance: The role of over-expression of drug transport proteins in resistance of tumours to a broad variety of anticancer drugs including paclitaxel, doxorubicin, etoposide and methotrexate is now well established. The development of probes to measure such resistance in individual cancer patients is now approaching the point of clinical usefulness. Blood flow: New drugs such as bevacizumab that affect angiogenesis and vascular function will have an increasing role in cancer treatment, and PET provides the best approach to the measurement of tumour blood flow. Hypoxia: The measurement of the presence and degree of hypoxia in individual tumours is important because hypoxia is associated with tumour progression, resistance to therapy and adverse prognosis. Measurement of hypoxia is also vital to the use of a new generation of anticancer drugs that target hypoxia. PET scanning is an essential technique for the measurement of tumour hypoxia, a key component for the action of PR-104 on hypoxic tumour tissue. 61 of 180

72 Proliferation: Tumour cell cycle time has long been known to be important for tumour prognosis and outcome, and varies widely for different tumours, even those with similar histology. PET provides approaches to measuring proliferation rates of individual tumours. Cell signalling: Anticancer drugs that target cell survival pathways rather than damaging DNA or mitotic spindles are showing increasing promise as a part of standard therapy. In some cases, such as with imatinib and rituximab, they have revolutionised treatment. Methods of labelling antibodies or other molecules so that they can be followed by PET scanning are now of great interest in cancer therapy research Non-biomedical research uses of PET Biological Uses Veterinary and agricultural research groups may benefit from the availability of PETisotopes, although specific interests could not be identified. It is likely that the local availability of PET in NZ will influence NZ researchers to undertake new activities in range of other disciplines. It is unlikely that a significant demand will exist commercially for PET isotopes in the short term. Outside the biomedical and veterinary research sectors, only horticultural research appears to be in the position to benefit from the availability of PET-isotopes. No other sectors in research or industry that we are aware of have made use of PET-isotopes. HortResearch has performed studies with carbon-11, synthesized into CO 2. The potential uses of such isotopes in agricultural science are: Better and much more rapid understanding of the alteration in physiology of genetically-modified plants. Understanding the effects of climate change on both native and economicallyimportant crops. Further work on the mechanisms of nutrient transport in soils. Investigation of pesticide uptake in plants and other environmental pathways. Research techniques in clinical medicine can be readily applied to veterinary medicine both in terms of fundamental research and applied research into the efficacy of new treatments. Of the four light PET-isotopes only F-18 has a long enough half-life to be distributed from the production facility to research locations elsewhere within the country. Thus any use of carbon-11, nitrogen-13, or oxygen-15 practically means co-locating the area of experimental / industrial / clinical application with the cyclotron Other uses Several major industrial research centres are advancing the basic technologies that underlie tomography with PET cameras. Image reconstruction software is still developing and so is the gamma counting hardware, in order to increase both the information extraction per unit radiation administered, and the patient throughput. 62 of 180

73 Typically, a large infrastructure is required to grow the inorganic scintillation crystals that are used in PET, and to develop the electronics that record the gamma-ray scintillation by the cameras In NZ radiation detector research and development is still in its infancy, and focuses on x-ray detection with silicon detectors. Tertiary academic departments (typically physics and imaging) have indicated that new undergraduate courses in Medical Physics and Imaging Technology will incorporate PET scanning. 63 of 180

74 9 Final considerations 9.1 Cost-benefit assessment PET scanning is a well-established medical diagnostic technology that has considerable benefits in assisting diagnostic accuracy therapeutic planning and assessment of treatment response of cancers in particular. Where effectiveness has been shown, therapeutic pathways are changed in 20-40% of cases. The changed pathways predominantly involve the avoidance of major surgery or protracted courses of radiation therapy that would not be curative, providing significant savings for both patients and the health system. Expansion of the technology however, is dependant on establishment of at least one cyclotron (for isotope production), and establishment of scanning facilities. The overall cost of the technology is likely to exceed the immediately obvious benefits of the technology, although the long-term productivity gains will be increased substantially, as the ultimate benefits are integrated into total patient management costs (such as leveraging of overseas experience in training and workforce). Although the evidence for diagnostic accuracy and a change in patient management is strong, evidence for higher endpoints (improved outcomes) remains deficient. This is due largely to the ethical and logistic problems of mounting the appropriate clinical trials to evaluate these endpoints. As with other imaging and diagnostic tools (eg CT and MRI) that represented a quantum leap in patient assessment following their introduction, it is likely these clinical trials will never be performed. There is weak evidence that patient outcomes are dramatically changed and only modest evidence of reductions in mortality and morbidity. The benefit assessment is preliminary and the possibility exists that further, targeted benefits might attach to the proposal. It is clear from the literature that there needs to be identification of where the technology both works best and provides the most benefit. The cost benefit of different pathways is considerably different. Clinical guidelines need to be developed that take this into account. 9.2 Equity of Access The main equity issue is access to the PET/CT scanner. The project team recommends agreement to two scanners. The first should be sited in Auckland, with subsequent scanning facilities established at Wellington or Christchurch. PET scanning should be implemented in conjunction with regional cancer centres within the cancer networks, to ensure integrated multidisciplinary use, and to ensure a reasonable caseload for economic efficiency and maintenance of expertise. However, there will be a degree of inequity due to the limited number of scanning facilities; this will disproportionately affect patients in other regions who are unable to travel. There are potential benefits for improvement in Maori health, though we have not been able to quantify these. Maori often present with locally advanced and metastatic lung and colorectal cancers, which PET scanning techniques have greater utility. Therefore, relative to other population groups, PET scanning may be of more value to Maori. 9.3 Size of the cyclotron The project team has recommended a medium size cyclotron, which will be required to support the isotope production needs around the country. A range of prices was received within this class of cyclotrons, and the estimate used in the financial calculations is assumed to be an adequate representation of the current and future need. That is, restricting costs now to the cheapest option (which would likely save around $800,000) may restrict the ability to expand production in future, while having only a modest impact on costs per scan. Based on the requirement of the biomedical research sector for PET facilities, a subsequent planning stage needs to consider the research community. It is acknowledged that any costs 64 of 180

75 associated with the research facility will be borne outside of Vote Health. Further, more precise analysis of the actual costs and possible contractual negotiations will need to be included in the financing decision. 9.4 Strategic development Not all the value of introducing PET scanning can be captured in cost-benefit terms. For example, PET scanning may attract skilled workers, provide the means to up-skill current workers, and lead to ground-breaking research that has positive benefits to NZ. In addition, new developments in the technology may considerably widen the scope of use for PET scanning, or augment its current applications. The perceptions of health consumers and health practitioners (in NZ and overseas) are shaped by the actions of the public health system and its commitment to improving population health; adoption of PET scanning is one example of where the public health authorities can show this commitment for a particular health need (specifically, cancer). The project team considered whether there may be a benefit in delaying the introduction of PET into NZ. The most likely potential benefits are significant imminent changes in technology, prices reductions, or newer technology with greater productivity gains. However, an horizon scan by the project team did not reveal any new technology that might displace PET or any pressing reasons to delay. The project team anticipates that servicing and upgrading clauses would be included in purchase contracts. 9.5 Next stages of analysis The purpose of this business case is to provide sufficient information for an informed decision by whether a publicly funded PET scanning service should be introduced in NZ. Funding and implementation are the subjects of further work. The following summarises key elements for the preparation of the capital business case and implementation plan Capital business case The following should be included in the capital business case: i. Capital investment - precise costings are required for the major equipment (including building fit out costs). This includes firm commitments (to the extent that these are possible) from suppliers, together with contractual terms and conditions. ii. Procurement strategy this is related to capital investment, with further consideration of the optimal procurement strategy needed, eg potential the cost savings associated with multiple purchases. iii. Refined financial analysis - further elaboration of possible options and the costs and benefits of those. Building in dynamic assumptions and further sensitivity analyses is needed. iv. Cost allocation - more work is needed on terms of costs to DHBs as well as any possible contributions from private sector and research interests. v. Implementation strategy and costs - detailed work is also required on an implementation plan and appropriate costs to support the plan. Further detail on governance options and implementation issues is contained in Appendices set Implementation Planning There will need to be a major implementation planning process for the introduction of PET to NZ, with input from individuals or groups with expertise both in project management and in PET technology. The following items need to be included in the implementation planning: i. Ownership options. 65 of 180

76 ii. Legislative requirements. iii. Quality standards that will need to be met. These include Good Laboratory Practice (GLP) facilities for isotope production and the requirement that PET facilities meet the quality standards of the appropriate professional body (eg ANZSNM). iv. Resource management processes. v. Building and site planning: Purchasing process and decisions The need to anticipate an increased need for PET scanning due to the population increase, ageing, and new indications for PET scanning Configuration and locations although PET scanners should be located in population dense regions, referral patterns need to be considered. The connections and linkages with private operators also requires further exploring (see Appendix 5). vi. Waste disposal issues need to be considered. vii. Workforce availability, development and retention - this is a major issue in NZ, as there is no existing workforce and a highly competitive global market. viii. Information system development. ix. Education of clinicians Flow on effects and impact of PET on cancer treatment services Incorporation of PET scans into patient management pathways has implications for the management of patients within all oncology services (surgery, radiation oncology, medical oncology, haematology). The likely impact for each patient service is indicated in the following Table, according to the potential roles of PET in cancer patient management is to: Facilitate diagnosis. Improve staging prior to initial treatment. Improve the locoregional anatomical localisation of cancer. Provide a rapid assessment of therapeutic efficacy. Provide an assessment of the result of a treatment regimen. Improve detection and anatomical location of recurrent cancer. 66 of 180

77 Table 17: Impact of PET on Cancer Services Role 1. Facilitate diagnosis. May reduce surgical procedures, eg PET negativity in SPN may obviate the need for thoracotomy. 2. Improve staging prior to initial treatment. Cancer service Surgery Radiation Oncology Medical Oncology Haematology Availability of PET scans must be convenient and timely Must have rapid approval process PET may reduce surgical procedures, eg mediastinoscopy. Availability of PET scans must be convenient and timely for indicated conditions. There must be a rapid approval process. Use of PET will alter the intent of treatment in ~1/3 of cases. The system must respond to this information. The availability of PET scans must be convenient and timely for indicated conditions. There must be a rapid approval process. 3. Improve the locoregional anatomical localisation of cancer. Surgical procedure may be altered by knowledge of the precise location of the PETavid focus. Radiation fields may be altered by knowledge of the location of PETavid foci. Radiation Oncology treatment planning systems must have the ability to accept and fuse PET/CT data. There must be good communication between the PET unit and radiation oncology to establish agreed protocols for PET scanning. For patients who may receive high dose radiation, the PET/CT scan must be performed on a flat couch with arms in a designated position, to reduce the need for an immediate second PET scan. 67 of 180

78 Table 17: Impact of PET on Cancer Services Role 4. Provide a rapid assessment of therapeutic efficacy. Cancer service Surgery Radiation Oncology Medical Oncology Haematology Likely to become important in future. If so, this will require rapid ability to create/alter treatment fields this will place pressure on a time delayed process Will become increasingly important in future. This will require rapid ability to respond with either a change or cessation of drugs this will place pressure on a strained system 5. Provide an assessment of the result of a treatment regimen. Main impact to decrease procedures eg neck dissections for residual PET negative masses. Growing application in radiation oncology Should not alter prescribed treatment which has been delivered. Growing application in oncology. May result in additional treatment being offered. Growing application in haematological oncology. May result in additional treatment being offered, including bone marrow replacement. 6. Improve detection and anatomical location of recurrent cancer. PET/CT scan will produce a small increase in surgical interventions by detection of site of recurrence for raised tumour markers and noncontributory CT scans. The number of additional operative procedures is difficult to estimate may be increased (added confidence of isolated recurrence) or decreased (demonstration of widespread recurrence) Some of these additional procedures may be extensive (eg hepatic resections). The ability to detect the site of recurrence may have some impact on radiation requirements. May result in increased or decreased use of chemotherapy, depending on the finding of localised or widespread recurrence. May result in increased or decreased use of chemotherapy, depending on the finding of localised or widespread recurrence. 68 of 180

79 10 Contributors Project team: Name Title Organisation Graham Stevens (Chair) Associate Professor Radiation Auckland DHB / University of Oncology Auckland Albert Zondervan Andrew Holden Scientist/Team Leader Accelerator Operations Associate Professor, Director of Interventional Radiology, Auckland City Hospital GNS Science University of Auckland / Auckland DHB David Krofcheck Senior Lecturer, Department of Physics University of Auckland David Mauger Clinical / Technical Advice Coordinator Consultant Fergus Thomson Radiological Medical Physicist Auckland DHB Hamish Fraser Nuclear Physician and Radiologist Canterbury DHB Mike Findlay Professor Oncology, Director of Auckland Cancer Society Research Centre University of Auckland / Auckland DHB Mike Rutland Nuclear Medicine Physician Auckland DHB Sam Denny Project Manager Project Portfolio Ltd Trevor Fitzjohn Chairman Pacific Radiology, Radiologist Pacific Radiology/ Capital and Coast DHB Co-opted by Chair Chris Crane Portfolio Manager DHBNZ David Moore Director LECG Limited John Brodie Financial Services Auckland DHB Roger Jarrold CFO Auckland DHB Suzanne Pohlen Health economist/finance planner Auckland DHB Conflict of interests: all members of the project team were reminded of their responsibilities with regard to conflict of interest. It is noted that any conflict issue is relatively confined at this stage. If the decision is made to proceed, either with implementation or further investigation, then steps will need to be put in place to ensure that conflicts of interest are addressed. 69 of 180

80 Acknowledgment is made to other people who provided information in development of initial business case: Name Title Organisation Allan List Clinical Director, Radiology Department Auckland DHB Anthony Butler Post-doctoral Fellow, Electrical and Computer Engineering Canterbury University Berry Allan Nuclear Medicine Scientist Waikato DHB Bruce Bagley Director, Scientist Cancer Society Laboratory Frank Bruhn General Manager, National Isotope Centre GNS Science Greg Santamaria Director Cyclotek (Aust) Pty Ltd, Melbourne Iain Martin Head of the School of Medicine University of Auckland Iain Morle Head of Radiology Hawkes Bay DHB Jason Beirne Managing Director Global Medical Solutions (NZ) Joe Manning Marketing Manager, Natural Resources, National Isotope Centre GNS Science John Childs Principal Advisor Cancer Control Ministry of Health Jon Cadwallader Urologist Mobile Surgical Services Maurice Trochei Modality Manager, Functional Imaging GE Healthcare Mike Baker Radiologist / director The Radiology Group Richard Tremewan Clinical Director, Medical Physics and Bioengineering Department Canterbury DHB Rod Hicks Director, Centre for Molecular Imaging Peter MacCallum Cancer Institute, Dept. of Medicine, University of Melbourne Russell Metcalf Radiologist, Paediatric Department Auckland DHB Steve Binckes Sales Manager, Medical Solutions Siemens Medical Solutions (NZ) Ltd 70 of 180

81 11 Abbreviations and Glossary 11.1 Abbreviations ACSRC AETMIS ALARA ANZSNM Auckland Cancer Society Research Centre Agence d'évaluation des Technologies et des Modes Intervention en Santé (Québec) As Low as Reasonably Achievable Australian and New Zealand Society of Nuclear Medicine C-11 Carbon -11 isotope CDR CGPET Ci CT CUA DHB DHBNZ DICOM EEG Clinical data repository Gamma camera PET. Curie, a measure of radioactivity Computed tomography Cost-utility analysis District Health Board District Health Boards New Zealand (inc) A standard for the computer format of medical images Electroencephalogram F-18 Fluorine-18 isotope FDG FMHS FR-PET GE GIT GMS GNS HD HEAT HPLC HTA Fluoro-deoxyglucose, the most commonly used PET radiopharmaceutical used clinically Faculty of Medicine and Health Sciences, University of Auckland Full ring PET scanner General Electric Company Gastrointestinal tract Global Medical Solutions GNS Science (Institute of Geological and Nuclear Sciences) Hodgkin s disease Health Equity Assessment Tool High Pressure Liquid Chromatography Health technology assessment 71 of 180

82 IAEA IATA ICES IT KeV MOH MRI MRT MSAC msv International Atomic Energy Agency International Air Transport Association Institute For Clinical Evaluative Sciences, Canada Information Technology Kilovoltage Ministry of Health Magnetic resonance imaging Medical Radiation Technologist Medical Services Advisory Committee, Australia millisievert N-13 Nitrogen 13 isotope NCTWP NHL NHMRC NM NPV NRL NSLC NSTR NZACS NZ NZHTA National Cancer Treatment Working Party Non-Hodgkin lymphoma National Health and Medical Research Council, Australia Nuclear medicine net present value National Radiation Laboratory Non-small cell lung cancer The National Service and Technology Review Advisory Committee. NZ Association of Cancer Specialists New Zealand New Zealand Health Technology Assessment O-15 Oxygen 15 isotope PACS PET PET/CT PTCA QA Picture archiving and communication system Positron emission tomography A combined scanner capable of producing images of both PET and CT Percutaneous transluminal coronary angioplasty Quality assurance 72 of 180

83 QALY RACP RANZCR RCT RPAC SFG SPECT SPN SPNIA framework SR quality-adjusted life years Royal Australasian College of Physicians Royal Australian and New Zealand College of Radiologists Randomised clinical trial Research Policy Advisory Committee. A subgroup of the Health Research Council of NZ Service Framework Group Single photon emission computed tomography. Single pulmonary nodule Service planning and new health intervention assessment framework Systematic review 73 of 180

84 11.2 Glossary Activity Cancer control Cancer networks Cardiology CoDe scanner Cyclotron Evidence based medicine The amount of radioactivity, measured by the atomic disintegrations in a set time interval A government strategy to reduce the incidence and impact of cancer in NZ and to reduce inequalities with respect to cancer In NZ there to be 4 cancer networks which are regional organisations of cancer providers focused around current cancer centres The study, diagnosis, treatment and management of disorders of the heart Coincidence technology. A standard nuclear medicine camera that has been modified to be able to capture PET images A charged particle accelerator used to produce the radioactive isotopes Clinical decision-making based on a systematic review of the scientific evidence of the risks, benefits and costs of alternative forms of diagnosis or treatment. Half Life The time during which the amount of radioactivity falls by 50% Hot cell Neurology Nuclear Medicine Oncology Photon Positron emission tomography Radiation Oncology Radiopharmaceut ical Sensitivity Specificity SPNIA framework A laboratory facility used to combine the isotope with a pharmaceutical compound such as FDG to produce the radiopharmaceutical The study, diagnosis, treatment and management of disorders of the brain and nerves A medical specialty which utilises radioactive isotopes to diagnose or treat disease The study, diagnosis, treatment and management of cancerous tumours A packet of electromagnetic energy similar to an X-ray A form of medical imaging where the central event is the transient generation of an atomic particle, a positron A medical specialty which predominantly utilises radiation (radiotherapy) to treat disease, mainly cancer. A chemical that is attached to a radioactive element that is changes into a stable state by releasing energy by emitting a form of radiation Sensitivity is the proportion of people that tested positive of all the positive people tested; that is (true positives) / (true positives + false negatives). It can be seen as the probability that the test is positive given that the patient is sick. The higher the sensitivity, the fewer real cases of diseases go undetected (or, in the case of the factory quality control, the fewer faulty products go to the market). Specificity is the proportion of people that tested negative of all the negative people tested; that is (true negatives) / (true negatives + false positives). As with sensitivity, it can be looked at as the probability that the test is negative given that the patient is not sick. The higher the specificity, the fewer healthy people are labelled as sick (or, in the factory case, the less money the factory loses by discarding good products instead of selling them). Service planning and new health intervention assessment framework. A 74 of 180

85 process for collective decision making for DHBs and the Ministry of Health Business case for Positron Emission Tomography (PET) in New Zealand APPENDICES May of 180

86 Appendix Contents 1 A. Bibliography B. Submissions C. Evidence for PET D. Current clinical indications list for referral to PET E. Draft terms of reference for a National Advisory Group on PET 2 A. Project brief B. Letters sent to stakeholders and suppliers C. Paper written about the project to inform stakeholders 3 Letters of support 4 A. Equipment and facilities required for PET B. The Radiopharmaceutical laboratory C. Quality control system D. Transport system E. Scanners F. Infrastructure 5 A. Implementation planning B. Operational issues C. Governance options 6 An example of an economic evaluation carried out by the NHBS in 2002 for the use of PET in the staging of NSCLC 7 Results of the survey PET in a number of countries 8 Feedback Summary 76 of 180

87 APPENDIX 1: SUPPORTING DOCUMENTATION AND IMPLEMENTATION MATERIAL Contents A. Bibliography B. Submissions C. Evidence for PET D. Current clinical indications list for referral to PET E. Draft terms of reference for a National Advisory Group on PET Appendix 1 Page 3 of 180

88 A: Bibliography 1. Agence d evaluation des Technologies et des Modes d Intervention de Sante. Positron Emission Tomography in Quebec, Australia and New Zealand Horizon scanning network Combined CT and PET scanner for carcinomas, February Centre Federal d Expertise des Soins de Sante. HTA Tomographie par Emission de Positrons en Belgique KCE reports vol. 22B, June Dietlein M, Weber K, Gandjour A, Moka D, Theissen P, Lauterbach KW, Schicha H: Cost-effectiveness of FDG- PET for the management of potentially operable nonsmall cell lung cancer: priority for a PET-based strategy after nodal-negative CT results, Eur J Nucl Med Nov;27(11): Department of Health. A Framework for the Development of Positron Emission Tomography (PET) Services in England. October Fryback D G., Thornbury J R: The Efficacy of Diagnostic Imaging, Medical Decision Making, Vol. 11, No. 2, (1991) 7. Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME. A tabulated summary of the FDG PET literature. J Nucl Med May;42(5 Suppl):1S-93S 8. Gavin J, Marshall B, Cox B. Towards a New Zealand Cancer Control Strategy A background paper prepared by the New Zealand Cancer Control Trust for the Public Health directorate of the New Zealand Ministry of Health, New Zealand Cancer Control Trust, July Haslinghuis-Bajan LM, Hooft L, van Lingen A, van Tulder M, Deville W, Mijnhout GS et al. Rapid evaluation of FDG imaging alternatives using head-to-head comparisons of full ring and gamma camera based PET scanners. Nuklearmedizin 2002; 41(5): Health Technology Board of Scotland. Implementation of HTBS Health Technology Assessment of Positron Emission Tomography in Scotland, October Health Technology Board of Scotland. Positron Emission Tomography (PET) in cancer management, November Institute for Clinical Evaluative Sciences. Health Technology Assessment of Positron Emission Tomography (PET) in Oncology A Systematic Review 4 of 180

89 Investigative Report, Quarterly Update, May Institute for Clinical Evaluative Sciences. Health Technology Assessment of Positron Emission Tomography (PET) in Oncology A Systematic Review Investigative Report, Quarterly Update, April 2004 Appendix 1 Page 5 of 180

90 14. Medical Services Advisory Committee, Australia: Positron Emission Tomography MSAC assessment report, March 2000 Positron Emission Tomography [Part 2(i)] MSAC reference 10, May 2001 Positron Emission Tomography [Part (2i)i] MSAC reference 10, August Ministry of Health and the New Zealand Health Information Service. Cancer patient survival covering the period 1994 to 2003, Ministry of Health Cancer in New Zealand: Trends and Projections, Ministry of Health New Zealand Cancer Control Strategy, National Cancer Treatment Working Party, Proposal for change. A document to NSTR, National Cancer Treatment Working Party and Radiation Oncology Working Group., National Cancer Treatment Working Party. Utility of Positron Emission Tomography (PET) in Oncology in NZ Discussion Document, Radiation Oncology Working Group, November National Cancer Treatment Working Party. Utility of positron emission tomography in New Zealand. Discussion document, prepared for the National Cancer Treatment Working Party (NCTWP) by the Radiation Oncology Working Group (ROWG) November National Institute for Clinical Excellence (NICE) The diagnosis and treatment of lung cancer, Clinical guideline 24 February Queensland Government, Queensland PET service. A statewide service, December Queensland Government Statewide positron emission tomography (PET) service- Discussion paper, December Royal College of Physicians Positron emission tomography A strategy for provision in the UK, January Royal College of Radiologists PET/CT in the UK. A strategy for the development of and integration of a leading edge technology within routine clinical practice, 6 of 180

91 August Sachs S, Bilfinger TV The Impact of Positron Emission Tomography on Clinical Decision Making in a University- Based Multidisciplinary Lung Cancer Practice Chest, 2005;128(2): The National Clinical PET Reference Group. Clinical indications for PET scanning in New Zealand. G Stevens, Chair. February Verboom P, et al Cost-Effectiveness of FDG-PET in Staging Non-Small Cell Lung Cancer: The PLUS Study, The European Journal of Nuclear Medicine and Molecular Imaging, Vol. 30, No. 11, November Working group on PET Wellington Positron emission tomographic scanning NZMOH new technology application by George Laking January 2001 Appendix 1 Page 7 of 180

92 B: Submissions 19 January 2007 Waikato Hospital Radiology Services - Positron Emmision Tomography (PET) Imaging Submission Background The Nuclear Medicine service at Waikato Hospital is among the largest imaging services of its type in New Zealand. It currently includes 3 Gamma Cameras and undertakes approximately 3,500 studies per annum. The service is lead in partnership by Dr Muthukumaraswamy, Clinical Director and Mr Berry Allen, Nuclear Medicine Scientist. In late 2004 the service installed a GE Infinia II VC Hawkeye (Integrated CT) Gamma Camera. This unit was selected due to its suitability to undertake coincidence PET (CoDe) scanning in the future. The necessary CoDe hardware and processing software were included in the purchase. This included 1 Starbright sodium iodide crystals, septa collimators, coincidence electronics and acquisition software. This unit was installed in a room with additional shielding and in close proximity to the hot lab. Additional shielding was also procured for the hot lab, isotope administration, and for staff in close proximity to the patient. Patients are rested in the departments recovery area isolated from other patient. This is currently being achieved without impact on other services as scanning is undertaken in the evenings as a result of the late delivery of the tracer. In late 2005 the service commissioned the manufacture of a set of collimators suitable for FDG PET imaging to allow the service to begin PET imaging in support of the PR-104 anit-hypoxic prechemotherapy agent clinical trial. In early 2006, following lengthy negotiations with vendors and the New Zealand National Radiation Laboratory, a supply of F-18 FDG tracer was secured from Cyclotek in Melbourne and shipping arrangements confirmed. A number of trial delivery runs were conducted to ensure delivery was viable. In 2006 Mr Berry Allen attended a PET imaging workshop at Peter MacAllum Cancer Institute in Melbourne, Australia. As a result of that visit and subsequent contact the service has, in place, a support and clinical review arrangement with Peter MacAllum Cancer Institute. It has also modelled its imaging and radiation protection protocols on those in place at Peter McAllum Cancer Institute. In July 2006 the service began providing whole body/integrated, fusion CT imaging, almost PET exclusively, for the PR-104 trial. To date the service has undertaken 17 high quality (CoDe) studies. Key Issues The establishment of CoDe PET scanning capability within the service has been faced with a number of difficulties. Most significant of these are: 1. The supply of suitable tracer currently the service has a commitment from Cyclotek (Melbourne) to produce F-198 FDG once a week to be supplied to Waikato Hospital. It appears that Cyclotek is at full production capacity and further expansion of the New Zealand market may not be able to be met by them in the short term. Tracer is currently produced a 4am (Aust time) at very high energy levels to ensure sufficient energy for diagnostic purposes follow decay associated with the lengthy delivery times. Any delay in delivery can potentially effect the image acquisition time and/or number of patients able to be imaged as a result of a single delivery. 2. The delivery of suitable tracer As stated F-18 FDG is produced at 4am transported to the Melbourne airport by 6-30am to ensure loading onto a flight departing at 8-30am. This flight arrives at Auckland Airport at 1-30pm (NZ time) and is transported by courier to Hamilton having been pre-cleared through Customs etc. This deliver chain is vulnerable at a number of points 8 of 180

93 Demand for PET Waikato District Health Board provides oncology services to the regional population of greater than 800,000. While PET imaging at Waikato is currently limited (almost exclusively) in support of the PR-104 trial, a number of patients are being referred both to Pacific Radiology and Peter McAllum Cancer Institute for PET imaging (1-2 per month). Cost being the constraining factor at this time. The Oncology Service at Waikato Hospital has estimated potential demand in the current clinical environment at between 300 and 350 cases per annum. Cardiology Services at Waikato Hospital have also expressed an interest in future access to PET imaging in support of myocardial viability studies. It is difficult to estimate this volume however this is thought not to be greater than 10% of the total demand. Coincidence Technology Coincidence technology has been available for many years. The introduction of contemporaneous CT imaging for both PET attenuation correction and co-anatomical location has significantly improved the CoDe resolution and sensitivity. Our experience to date, however, has demonstrated high quality PET coincidence-ct imaging with most studies performed. Many of these studies resulted in a significant impact on clinical management due to the detection of previously unknown secondary malignancies. The experience of the Peter McAllum Cancer Institute, performing dedicated PET, and a comparison with the CoDe image quality performed at the Alfred Hospital in Melbourne, confirms comparable image quality between dedicated PET and CoDe imaging (on an older camera) in the neck and chest. There is however agreement that dedicated PET abdominal spatial resolution is superior. The significant difference between dedicated PET and CoDe imaging is the imaging acquisition time, due to the lower CoDe imaging count ratio detection. This feature does not affect image quality, only the time to acquire the data. There is no doubt from the Waikato Hospital experience however that CoDe/CT whole body PET imaging is of considerable clinical benefit in imaging of both above and below the diaphragm. There are three gamma cameras nationally capable of hardware and software upgrade to CoDe imaging capability, which may have a positive influence on potential cyclotron vendors. The Future at Waikato Hospital In the short term PET scanning at Waikato will most likely be limited to the PR-104 and other similar trials to allow the service to manage demand within the current supply chain constraints. This will served to further enhance the skill base and build on local experience. Some clinically appropriate cases will be undertaken outside of the trial framework, where a significant clinical advantage is a likely outcome. Further growth in this area will require the service to secure further tracer. Dedicated PET scanning remains a key objective at Waikato Hospital with a dedicated PET/CT installation planned under the new Campus Redevelopment Project. It is essential that issues relating to tracer production and delivery are resolved before such services are commissioned. Appendix 1 Page 9 of 180

94 From Pacific Radiology Pacific Radiology Wellington Pacific Radiology, commenced performing Coincidence Detection (CoDe) PET/CT in late Jan This was NZ's first PET Scanner and relies on imported F18FDG from Melbourne until a NZ based cyclotron is operational. Pacific Radiology has a strong interest in multimodality body imaging with high investment in top end CT and MRI scanners in both Wellington and Christchurch (64 slice and 3T MRI) as well as diagnostic nuclear medicine. Pacific at Wakefield, Wellington has provided nuclear medicine for over 15 years and has invested heavily in new equipment. Prior to the CoDe PET capability Pacific invested early in SPECT/CT and image fusion. PET/CT was therefore a logical development. The type of equipment was dictated by the lack of infrastructure. CoDe/CT as supplied by GE the Infinia has imaging specifications that match the proposed full ring criteria except throughput. (To overcome its low CoDe flux in 2D mode, extra acquisition time is needed), however this relative drawback is amply offset currently when the clinical demand for PET scanning is low, by its dual role being also used for SPECT/CT. This dual ability is also important when the FDG is sourced from Australia as the first flights do not arrive before mid afternoon hence a dedicated scanner would be idle during the usually most productive part of the day. Given the long flight in relation to its half life (5 half lives) combined with the CoDe slowness, limits scanning per evening session to 3 patients covering 80 cm per patient ( the usual coverage - skull base to inguinal nodes station). It also results in a high cost per delivery FDG dose. Pacific Radiology works closely with the Peter MacCallum Cancer Institute PET centre and the radiologist was trained in PET there. The Wakefield Hospital campus is built in a concrete building and has sufficient shielding for the higher energy positron emissions. The hot lab was remodelled to the PET standard with readily available items sourced from Australia and USA. However Pacific's medium term plan is to move to a full ring platform when a) A NZ based source of isotope is available and b) patient numbers increase to satisfy the investment of this sole use machine. Clinical demand in NZ based PET has been good despite the initial lack of funding from DHBs and private insurance although that is changing, and opposition to CoDe based PET/CT. We have now scanned over 100 patients and as presented at the NZ meeting of ANZSNM have achieved significant clinical value in the patients scanned. Requests for scanning are now showing strong growth and we are now providing 2 PET/CT sessions per week. i.e. a doubling in scanning volume. Of the hundred studies to date 2/3rds have been from DHBs most have sent at least one, CCDHB the most. Others have been from private with Southern Cross, Tower and Police Protection Plan insurance cover. Referrals have been from all over NZ. Recent clinical evidence for CoDE A study has been identified, and a paper written, but not yet published, with regard to CoDE. The first author of this paper is Dr Kate Moodie from the Alfred Hospital in Melbourne. The study was been presented at the Australia and New Zealand Society for Nuclear Medicine conference in As comparison between full ring PET and CoDe scanners was part of the Project Brief, the summaries of these two publications are included in full below. Dr Moodie s study from the Alfred Hospital, Melbourne 10 of 180

95 Kate Moodie, Martin Cherk, Eddie Lau, Alla Turlakow, Sarah Skinner, Rod Hicks, Michael J Kelly, Victor Kalff. Evaluation of Pulmo nary Nodules and Lung Cancer With One Inch Crystal Gamma Coincidence PET/CT versus Dedicated PET/CT Dedicated PET/CT scanners employing BGO detectors (d-pet) has become the current standard imaging modality in many malignancies. Hybrid gamma camera systems utilizing NaI detectors in co-incidence mode (g-pet) have been compared to d-pet but reported clinical usefulness has been variable when gamma cameras with ½ - 5 / 8 thick crystals have been used without CT. Our aim was to compare the diagnostic performance of g-pet with a 1 thick crystal and inbuilt CT for lesion localization and attenuation correction (g-pet/ct) and d-pet/ct in patients presenting with potential and confirmed lung malignancies. Methods One hour post injection of 18 F-FDG, each patient underwent BGO d-pet/ct from jaw to proximal thigh. This was followed by 1-2 bed position coincidence g-pet/ct 194 ± 27 min post FDG. Each study pair was then independently analyzed with concurrent CT. d-pet/ct was interpreted by a Radiologist experienced in both PET and CT, and g-pet/ct by consensus reading of an experienced PET Physician and PET Physician with an experienced CT Radiologist. A TNM score was then assigned, recording the location and number of lesions on standardized forms. Studies were then unblinded and compared. Results 57 patients (39 men), mean age 66 (range yrs) underwent 58 scan pairs over 2 years. 89% concordance was demonstrated between g-pet/ct and d-pet/ct for the assessment of intrapulmonary lesions, with 100% concordance for intrapulmonary lesions >10mm (36/36) and 55% for intrapulmonary lesions <10mm (6/11). 90% concordance was demonstrated between g- PET/CT and d-pet/ct for TNM staging. Conclusion: Coincidence imaging using an optimized dual-head 1 thick crystal gamma camera with inbuilt CT compares well with dedicated PET/CT for assessment of intrapulmonary lesions, with 100% agreement for intrapulmonary lesions > 10 mm in size. 90% concordance was seen between g- PET/CT and d-pet/ct for TNM staging, providing some support for the use of g-pet/ct for staging of pulmonary malignancy in institutions where d-pet/ct is not readily available. Image quality of CoDe scanners and ANZSNM technical standards An evaluation of the CoDe GE scanner at Pacific Radiology to compare with the ANZSNM recommendations for PET scanners was carried out in December 2006 by Dr Alex Mitchell, Consulting Health Physicist. His table is reproduced below. P a r a m e t e r A N Z S N M C o D e s p e c Appendix 1 Page 11 of 180

96 i f i c a t i o n T r a n s v e r s e r e s o l u t i o n < 6. 5 m m < 6. 0 m m a t 1 c m 12 of 180

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99 Appendix 1 Page 15 of 180 s u t n a t 1 0 c m r a d i u s m r e m o l i o S y s t e m s e n s i t > 4. 0 c p s / d B c p s / k B q

100 16 of 180 i i q v t y N o i s e e q e c t t u i v a l n t o u n r a e > k c p s k c p s M a x i < m 1 N o t 0 s

101 Appendix 1 Page 17 of 180 c r e i u m % p c o u n t f i e d a t e e r r o r E r o r i n r e c o v e r i n g < r 1 0 % N o t s p e c i f i e d

102 a c t i v i t y c o n c Dr Mitchell s summary The specification of the CoDe scanner meets the ANZSNM requirements for resolution. The system sensitivity is lower but this can to some extent be compensated for my longer scanning times. The use of a CoDe scanner with an integrated CT scanner may give a diagnostic advantage over a dedicated PET scanner without CT 18 of 180

103 Submission from The Radiology Group (TRG) PET/CT SCANNING in AUCKLAND January 2007 SUMMARY This paper has been invited by the National PET Business Case Project Team to outline TRG Group s progress with setting up a molecular imaging service in New Zealand. The TRG Group and an experienced nuclear medicine partner, Global Medical Solutions, have identified a need for a cyclotron and Positron Emission Tomography (PET) scanner combined with a computed tomography (CT) scanner facility in Auckland. Significant work has been carried out on the project for a cyclotron and PET/CT scanner to date including bringing together interested parties, preliminary plans and costing for the facilities and equipment. A comprehensive and detailed business case has been developed including the planning process, resource consent issues, building sites, financial interests and an extensive financial analysis. A cyclotron in the MeV range is planned which will have the capacity to supply the Auckland PET/CT scanner as well as other New Zealand sites. A cyclotron of this size will be able to produce isotopes capable for research. A state-of-the-art PET/CT scanning suite is planned for central Auckland to open in The consortium wishes to work with the National Service and Technology Review Committee to assist the combined DHBs to develop a PET/CT service based in Auckland. The TRG Group and Global Medical Solutions would be happy to assist the DHBs to reduce the risk in the introduction of PET/CT scanning in New Zealand. It is in no-ones interest to duplicate this expensive technology in the public and private sectors. The consortium offers the combined DHBs the opportunity to partner this venture. This could include a financial interest, siting the machine(s), management, clinical input and research trials involving the cyclotron and/or the PET/CT scanning service. BACKGROUND This paper outlines the development of a molecular imaging service, or functional imaging, in Auckland using a cyclotron and PET/CT scanner. The consortium partners are: TRG Group - own or joint venture the PET/CT scanner as well as manage the PET/CT business Global Medical Solutions - own or joint venture the cyclotron as well as manage the production and distribution of radiopharmaceuticals The partners have been developing the project for the last two years. Auckland University, through its commercial arm UniServices, were involved from an early stage and pulled out in February 2006 due to property issues. Global Medical Solutions (NZ) Limited Global Medical Solutions (GMS) is a provider of nuclear medicine and diagnostic imaging products and services in Asia-Pacific as well as South America. GMS owns, operates and manages PET Appendix 1 Page 19 of 180

104 cyclotrons and scanners in Taiwan and Australia. It has a New Zealand company providing nuclear medicine imaging in Auckland and Hamilton and radiopharmaceutical supply services throughout the country. Global Medical Solutions will own and manage the cyclotron and the laboratory and be responsible for managing and staffing both. At start up, it is anticipated that the radiopharmaceutical FDG only will be produced with the roll out of other isotopes as required for research or for new clinical indications as they arise. GMS aims to secure research contracts through its industry network and will assist with the worldwide commercialisation of tracers developed within the facility. TRG Group Limited TRG Group is a New Zealand owned radiology company formed in 2004 with the merging of The Radiology Group in Auckland, Northern Radiology in Northland and Lakes Radiology in Rotorua, Taupo and Gisborne. Since this time, TRG Group has acquired regional companies in Hawkes Bay and Hamilton. TRG Group owns and operates CT and MRI scanners, including the MRI scanners situated in North Shore Hospital and Whangarei Hospital servicing the public and private sectors. TRG Group wishes to introduce new high technology molecular imaging in the form of PET/CT scanning to the Auckland region. TRG Group believes it has the technical expertise, professional network and business know-how to install and manage this rapidly developing technology. STRATEGIC ANALYSIS The consortium partners wish to be market leaders and install the first cyclotron in New Zealand and the have the highest quality PET/CT scanning service. The lack of PET/CT in New Zealand presents a unique opportunity to set the standard for this form of imaging in this country. A wealth of information in now available that indicates PET studies as the ideal test in diagnosis, staging and monitoring disease. The number of indications continues to grow, with the Medicare system in the United States now funding indications in cancer, cardiology and neurology. We are aware of the Ministry of Health initiative looking at a standard set of evidence based indications for PET scanning which we support. The Auckland Initiative Auckland is the obvious site for the first cyclotron and PET/CT scanner with over half of New Zealand s population being in the upper half of the North Island. Also, there is a large sub specialised oncology service based in the region for cancer diagnosis and treatment. In addition, there is potential for medical and scientific research based at Auckland University. PET capable hybrid gamma cameras have recently been trialled elsewhere in New Zealand. Due to their hybrid nature, these systems are not optimised for PET. They do not qualify for Medicare reimbursement in either Australia or the United States. A hybrid system in Auckland would put all clinical trials involving PET at risk. Choice of Cyclotron For the production of commercial quantities of 18 F ( FDG) to suit the New Zealand market, a smaller unit in the 9-10 MeV will be sufficient to supply several PET cameras. These smaller units, however, are unable to produce significant quantities of other isotopes such as 11 C, 13 N and 15 O, which at present are used primarily in research. 20 of 180

105 Previous discussions had indicated that Auckland University may wish to have access to research isotopes and other research capabilities which will require the installation of a larger cyclotron in the MeV range. The additional investment required is in the order of $500,000 for the cyclotron plus additional costs for the installation and building requirements. The additional costs of purchasing and installing the larger research capable cyclotron could present a possible area of partnership and collaboration. Choice of PET/CT Scanner The scanner will be a state-of-the-art PET/CT machine. TRG Group will purchase radiopharmaceuticals from Global Medical Solutions and scan patients for diagnostic purposes. TRG Group also wishes to participate in clinical trials. The PET/CT scanner will be sited in central Auckland close to oncology services and to the Medical School. Machine selection will take into account radiotherapy planning requirements. OTHER PET SERVICES IN NEW ZEALAND Wakefield Radiology in Wellington and Waikato DHB are currently trialling PET imaging with FDG imported from Melbourne. Limitations of Imported Isotopes There are currently several cyclotrons operating on the east coast of Australia producing FDG commercially. Supply from these centres has been explored in the past and small quantities are shipped into NZ. This supply option is not suitable for a dedicated PET facility as supply is extremely limited and the available logistics do not allow for a patient to be injected before 3pm at best. The main reason importation of PET isotopes is not realistic is due to the extremely short half life of the tracers involved. As shown in the table, 18 F, the longest lived isotope, still has a half life of just under 2 hours. With at least 5 and probably 6 hours between production and delivery from Australia, 8 times the injected activity must be manufactured. The problem is compounded if more than one patient is to be injected. The other isotopes involved have even shorter half lives and therefore are impossible to import and must be produced very close to the site of the PET scanner. Isotope Half Life 11 C 20.5 minutes 13 N 10 minutes 15 O 122 seconds 18 F 110 minutes Other Cyclotron Initiatives We understand that the University of Canterbury in conjunction with Canterbury District Health Board has been evaluating cyclotron options. A private cyclotron company has discussed a similar initiative in Wellington. Only one cyclotron is required for New Zealand s needs. Research capability needs to be factored in with the choice of cyclotron. BUSINESS STRUCURE TRG Group and Global Medical Solutions will install a cyclotron and PET/CT scanner in Whilst we are very comfortable funding this project and carrying the business risk ourselves, we Appendix 1 Page 21 of 180

106 would be happy to offer the combined DHBs the opportunity to partner this venture. This could include a financial interest, siting the machine(s), management, clinical input and research trials involving the cyclotron and/or the PET/CT scanning service. Dr Mike Baker Managing Director and Radiologist TRG Group Limited P O Box Milford Auckland Tel. (09) Mobile (021) of 180

107 Submission from Mobile Medical Technology CONSIDERATION OF A MOBILE PET/CT SCANNER AS PART OF THE NATIONAL SERVICE Internationally mobile PET/CT scanners have been part of respective countries oncology services for a number of years. Countries that have developed this service include the United Kingdom, EU communities of France, Germany, Spain and Italy, and certain states of USA. NZ is suitable for mobile technologies with its longitudinal geography, and widely distributed population. Oncology centres are linear through the country, based around radiation facilities, with medical and surgical oncology support, from Auckland, Waikato, Palmerston North, Wellington, Christchurch, Dunedin. Other centres of possible oncology service investigagion include Whangarei, Tauranga. Whilst it is not possible, for a number of logistical reasons, for a mobile PET/CT system to provide an adequate service alone, it could support and provide an adequate service to some centres, in conjunction with one or more fixed site facilities. For example a fixed-site facility in Auckland, with a mobile service to the remainder of the North Island oncology centres. THE LOGIC OF MOBILE PET/CT Within NZ mobile systems have been functioning for the last 10yrs. Mobile Medical Technology, and its associated company of Mobile Surgical Services introduced and currently run a mobile shockwave lithotriptor for treating renal calclui, and for the last 6yrs, a mobile operating theatre for delivering multidisciplinary rural surgery. The lithotriptor deals with patients from both the public and private sector. The mobile theatre is a government, MOH initiative solely for unmet surgical need in the rural and some urban communities. These are both examples of the benefits of mobile services: Efficient utilisation by sharing high capital cost technologies Sharing of the cost of such high cost capital technologies Improving equity of access to care Maintaining care at point of patient contact LIMITATIONS OF MOBILE PET/CT From international data, both UK and USA, the number of PET/CT investigations are approximately 1000/Population Million/annum. In NZ that would equate to nearly 3000 procedures per annum or more. From our experience of running mobile systems throughout the country, moving the vehicle, maintenance requirements, 4/7 working week, and working weeks/annum, 7-8 investigations per day, a mobile unit could only service approx investigations per annum. That is a fixed-site PET/CT would be essential to meet the expected service nationally. Demographically Auckland is a logical site. A mobile service could meet the need of lower population centres such as Tauranga, Waikato, Palmerston North. Our current technologies service both the North and South Island, generally within a 4-5 week cycle. STANDARDS AND RELIABILITY OF MOBILE PET/CT Both our mobile systems have been designed and built in NZ. However the companies that manufacture PET/CT, Siemens, Philips and GE, are stringent in the oversight and comissioning of Appendix 1 Page 23 of 180

108 buildin g units for mobile PET/CT. This relates to radiation legislation requirements, radiation safety, managing the 'hot' patient, the sensitivity of the technology to being mobile, and specific transport construction design. Such modern, sensitive technology has been found to be very reliable within the transport mode. Radiation legislation varies from county to country, the most stringent being Germany, the lesser the USA (v aries from state to state) with the UK in the middle. NZ would probably be similar to that of the UK. The significance of the legislation relates to the impact on vehicle and axle weight. The grea ter the requirements, the heavier the vehicle. Lighter vehicles could be built in the USA, heavier vehicles Antwerp Belgium. In both these centres, the entire manufacture and commissio ning is strictly supervised by the respective PET/CT manufacturer. The process of commissioning is repeated on delivery to the respective country. Design of the vehicle must also comply with the local transport legislation for heavy vehicles. CONCLUS ION This submission was invited by the committee of the PET/CT Project. It is a brief summary of a presentation made in November '06 to the committee. A mobile PET/CT system can provide equity of access to a number of centres of cancer care. It allows t he sharing of such high cost technologies to communities which would not be justified based upon their population density. Particularly in oncology it would allow continued point of contact care, and decision making in the management of cancers, with patients and their physician s. This can be a significant cost-benefit, both financially and of stress in patient care. Such mobile systems are reliable technically. There is considerable experience in providing mobile services within NZ. A mobile PET/C T service would be a valuation asset in supporting a National programme of PET/CT investigations. Jon A Cadwallader FRACS Urological Surgeon Director MMT, MSS of 180

109 Letter from NZACS New Zealand Association of Cancer Specialists Dr Andy Simpson (Chair) C/- Wellington Blood & Cancer Centre Wellington Hospital Private Bag 7902 Wellington Tel: (04) Mob: Fax: (04) Jan 2007 A/Prof Graham Stevens Chair PET Business Case Project Group C/- Oncology Department Auckland Hospital Park Road, Grafton Auckland Dear Graham Re: Business case for PET scanning The New Zealand Association of Cancer Specialists strongly advocates the development of PET scanning services within New Zealand. Effective and judicious use of PET scanning is becoming increasingly important and instrumental for the appropriate and efficient delivery of health care to cancer patients. Previously the Radiation Oncology Working Group (ROWG) convened the Clinical PET Reference Group, with the support of NZACS, which reviewed the evidence for PET scanning at that time. Their report on national indications for PET scanning was endorsed by our professional body and was subsequently submitted to the National Cancer Treatment Working Party. The indications for PET scanning, at that time, were highlighted in the ROWG report. PET scanning has utility in several areas of patient assessment, treatment planning, and treatment assessment. Th ese areas include: Diagnosis e.g. determination of malignancy of sol itary pulmonary nodules that are not amenable to other diagnostic approaches. In these patients PET enables appropriate treatment decisions to be made and prevents ongoing duplication of other investigations (eg serial CT scans) or potentially unnecessary surgery for diagnostic purposes Staging e.g. determination of the extent of malignant spread in non-small cell lung cancer in patients undergoing evaluation for potentially curative surgery. PET scans can determine whether there is evidence of metastatic spread to regional lymph nodes or other organs with a greater sensitivity than other inv estigational modalities. This has lead to avoidance of surgery in those with PET documented disseminated disease that was not evident with other investigations thereby limiting patient morbidity and saving resource. Treatment assessment e.g. in patients receiving potentially curative treatment for lymphomas, PET scanning assesses tu mour activity in any residual masses post chemotherapy. This enables appropriate planning of ongoing treatment. For those with ongoing tumour activity Appendix 1 Page 25 of 180

110 further treatment is required, however for those with no tumour activity ongoing treatment can be revised. This has lead to avoidance of high dose chemotherapy (with stem cell support) for some patients. Diagnosis of Relapse The examples above are only a small part of the utility of PET scanning. The indications within the ROWG report are a baseline for ongoing expansion as more evidence and experience is gained globally in the effective use of PET scanning. Likely future indications will include staging of breast cancer, as well as using PET to rapidly assess treatment response by assessing changes in tumour activity (within days to weeks) in contrast to delayed assessment by standard imaging whic h requires waiting for changes in tumour size (weeks to months). This rapid assessment has the potential to stop ineffective treatments, limiting treatment costs and patient morbidity far earlie r than we are able to do so with conventional means of assessment. Judicious use of PET scanning has the potential to improve patient outcomes, limit morbidity, and increase healthcare efficiency by guiding optimal treatment. As the professional body representing the oncology specialists within New Zealand, we fully endorse the preparation of the busin ess case for PET scanning in New Zealand, and look forward to its rapid implementation. Yours sincerely Andy Simpson Chair 26 of 180

111 Letter from National Radiation Laboratory (Unable to include NRL letterhead) Comments to Graham Stevens chair of the project group writing a business case for positron emission tomography (PET) in New Zealand In your dated 3 December 2006 you wrote: Re PET scanning: I am chairing a project group writing a business case for PET in NZ. We need to canvass all options, including - importing isotope from Australia for use in various NZ centres - having a cyclotron here in NZ. Can you tell me t he NRL/radiation protection issues relating to these options. Thanks, Graham Stevens In response NRL has the following comments: Comments on the specific radiation safety issues associated with importing radionuclides from abroad for use in medical maging in New Zealand General The specific radiation protection issue here relates to the safety, security and reliability of the international transport of radioactive material by air. The transport of radioactive material by road is a regular occurrence within New Zealand and is briefly discussed in the section discussing radiation protection issues associated with operating a medical cyclotron dedicated to the production of radionuclides for use in PET imaging (referred to in this document as a PET cyclotron). Almost all artificially produced radioactive sources used in New Zealand, both sealed and unsealed 13, are brought into the country by air. Certain types of shipments occur on a regular basis. For instance, there are weekly shipments from Australia of molybdenum a radionuclide produced at the Lucas Heights Research Reactor and used in nuclear medicine imaging. Section 12 (1) of the Radiation Protection Act 1965 requires all radioactive material prior to it being brought into New Zealand to be the subject of an import consent by the Minister of Health. The consent process is administered by the National Radiation Laboratory (NRL) acting under delegated authority from the Minister. At present, under a general consent allowing repeat i mportations two licensees (one in Wellington and one in Hamilton) are importing the positron emitting radionuclide fluorine-18 from a production facility in Melbourne. The most commonly used radionuclides used in PET imaging, all produced using a PET cyclotron, are fluorine-18 (halftes), oxygen-15 (half-life of 2 minutes), nitrogen-13 (half-life of 10 minutes), life 15 of 110 minu and carbon-11 (half-life of 20 minutes). Of these only fluorine-18, due to its relatively long halflife, can be transport any appreciable distance prior to use Sealed radioactive source: radioactiv e material that is (a) permanently sealed in a capsule or (b) closely bounded and in a solid form. The capsule or material of a sealed source shall be strong enough to maintain leak tightness under the conditions of use and wear for which the source was designed, also under foreseeable mishaps. Unsealed radioactive source: a source that does not meet the definition of a sealed source. Molybdenum-99 is produced through neutron capture in a neutron flux from a nuclear reactor. Radioactive materials are characterised by the time it takes the initial amount of material to decay to half of its original activity. This time period is called the half-life. After 10 half-lives initial amounts of radioactive material are usually considered to no longer present any appreciable radiation hazard. Appendix 1 Page 27 of 180

112 Among the organisations in the United Nations system, the International Atomic Energy Agency (IAEA) has the statutory function to establish or adopt standards of safety for the protection of health from the effects of ionising radiation. This includes standards of safety for the transport of radioactive material. Since the first edition was published in 1961, the IAEA s Regulations for the Safe Transp ort of Radioactive Material (IAEA Transport Regulations) 16 have served as the basis f or safety in the transport of radioactive material worldwide. Provisions compatible (in New Zealand s case identical) 17 with the IAEA Transport Regulations have been incorporated into domestic requirements by most of the IAEA Member States. In addition, the IAEA Transport Regulations serve as the basis for the United Nations model regulations on the Transport of Dangerous Goods. These in turn serve as the basis for the international regulatory documents issued by International Civil Aviation Organisation (ICAO) for transported by air 18. The application of the regulatory requirements by the transport industry (consignors, carriers 19 and consignees) has resulted in a good safety record for the transport of radioactive material. Having said this radiation incidents do occur such as one, reported in the press, which occurred in June 2004 at Auckland Airport involving the temporary loss of a shipment of the radioactive material samarium-153. Although of small concern in relation to the benefits, the simple fact that radioactive material is being transported by air means additional sources of radiation exposure (eg through the associated handling) are being created with the associated risk of the radioactive material being lost or stolen 20. Also, the short half-life of fluorine-18 means a relatively large activity (much greater than would be needed for a 2 or 3 hour road journey) is required to be initially consigned. The reliability of air transport has become an issue of concern in the past few years. A number of airlines, out of what would seem principally to be concerns over the regulatory consequences and liabilities in the event of an incident, have policies of not transporting any radioactive material (such as British Airways) or apply very restrictive conditions to its transport. Also, pilots c an and have refused to carry radioactive material for reasons such as the aeroplane will also be carrying live animals in the hold. Summary The transport of radionuclides used in medical imaging from suppliers outside the country is an established and necessary occurrence with a good safety record. The necessity to import medical radionuclides arises out of the lack of a production facility in New Zealand. The short lived radionuclide fluorine-18 is the only radionuclide used in PET imaging that can be transported. Consequently, this limits the type of imaging that can take place. Also, its utilisation is particularly susceptible to any type of transport delay and the recent denials of shipment by major airlines are of concern in relation to the security of supply. As a final point, although of small concern in relation to the benefits, reducing the number of movements of radioactive material is desirable as part of a risk avoidance strategy. Comments on specific radiation protection issues associated with operating a PET cyclotron in New Zealand International Atomic Energy Agency. Regulations for the safe transport of radioactive material Edition. Publication No. TS-R-1. IAEA, Vienna, Regulation 3 of the Radiation Protection Regulations 1982 requires that no person shall transport radioactive material into or through New Zealand unless the radioactive material is packed, labelled, marked and transported in accordance with the IAEA Transport Regulations. The International Air Transport Association annually produces a set of Dangerous Goods Regulations based on the ICAO Technical Instructions for the Safe Transport of Dangerous Goods by Air. It was stated in the summary and findings of the IAEA International Conference on the Safety of Transport of Radioactive Material (Vienna 2003) that, over several decades of transport, there has never been an in-transit accident with serious human health, economic, or environmental consequences attributable to the radioactive nature of the goods. The short half life of positron emitting radionuclides means that the radioactive material has no potential for use in a radiological dispersion device. 28 of 180

113 General The proposed installation and operation of a medical cyclotron dedicated to the production of positron emitting radionuclides represents for New Zealand new sources 21 of actual and potential exposure and new types of exposure situations (planned and emergency) 22. Consequently, following established procedure NRL will carry out a so-called regulatory assessment following the receipt of a written a pplication and prior to the granting of any licences. The purpose of the assessment is to identify specific mandatory requirements, identify and obtain necessary information relating to radiation safety, consider the need for consultations and pre- and establish the likely position that NRL will take in relation to key emptive briefings operational and safety issues. A summary of specific regulatory requirements applying prior to the first use (i.e. not including regulations applying only during use) in New Zealand of a PET cyclotron are included at the end of this document. PET cyclotrons commonly rely on the acceleration of negative ions of hydrogen. The use of negative ions (rather than positive ions) has the advantage that the beam extraction efficiency is close to 100% and that two beams can be produced. Typical particle energy ranges are between 10 and 18 MeV. Charged particles with an energy o f between 5 and 10 MeV can produce neutrons through nuclear interactions with concomitant induction of radioactivity in accelerator structures and components. However, as very little of the beam current is lost when accelerating negative ions activation of th e internal components of the cyclotron is minimised making servicing and maintenance easier. PET cyclotrons are a relatively mature technology (there are a few hundred in use world-wide) and those available commercially are compact in design (due to the relatively low energies used and technological advances) and are mostly self-shielded with lead blocks. Also, they now operate with automated devices for the synthesis of radiopharmaceuticals thereby avoiding potential high levels of radiation exposure to persons carrying out the synthesis. Particle-accelerator radiological safety has much in common with other broader and more diverse radiological safety programmes (NCRP, 2003). Specifically in relation to PET cyclotrons the radiation safety issues are comparable (excepting for servicing and maintenance) in many ways 23 with those faced when operating a high energy linear accelerator and a conventional nuclear medicine radiopharmacy. In the absence of a relevant NRL Code of Safe Practice specific licence requirements for users, in addition to standard conditions such as the requirement to devise and implement a comprehensive radiation safety plan, are likely to include: The term source here has the same meaning as used in the International Commission on Radiological Protection s Report No. 60, 1990 i.e. the term is used to indicate the source of an exposure, not necessarily a physical source of radiation. These situations arise as a consequence of new practices not previously encountered in New Zealand. The term practices has the same meaning as used in the International Commission on Radiological Protection s Report No. 60, 1990 i.e. human activities increasing the overall exposure to radiation. 23 Activation of components, neutron doses, handling unsealed sources etc. Appendix 1 Page 29 of 180

114 a requirement for substantial professional input and advice relating to radiation safety from a medical physics expert during the design and commissioning of any facility and on an ongoing basis during the operation of the PET cyclotron. mandatory personal monitoring by passive and direct readout personal monitors, radioactive contamination monitoring, and area radiation monitoring. In addition, a facility is likely to be scheduled for an on-site compliance visit by NRL staff within twelve months of it first becoming operational. The transport of radioactive material by road in New Zealand is a routine occurrence with a good safety record. Radiation safety concerns related to the inter-centre transport of fluorine-18 by road are no different to those already encountered with other radionuclides and hence require no additional consideration. Summary A lthough there are new radiation sources involved the complexity of radiation safety issues (excepting those involved with installation and servicing) associated with the use of a modern commercially available PET cyclotron equipped with an automated device for the synthesis of radiopharmaceuticals should be no greater than those associated with the operation of linear accelerators and conventional nuclear medicine radiopharmacies. With this in mind utilising skills already available in the country there is no reason to believe that from a radiation protection perspective a PET cyclotron cannot be operated safely within New Zealand. 30 of 180

115 C: Evidence for PET C1. Comments on Assessment Measures of Evidence The system most commonly used in clinical practice is shown below: Level of evidence 1a Systematic review (SR) with homogeneity of Randomised Controlled Trials (RCT) 1b Individual RCT with narrow confidence level 1c All or non case series 2a SR with homogeneity of cohort studies 2b Individual cohort studies 2c Outcomes research (not applicable to diagnostic studies 3a SR with homogeneity of case control studies 3b Individual case control studies 4 Case series 5 Expert opinion A system with some crossover to the above was used in the Commonwealth of Australia MSAC report entitled Positron emission tomography in March MSAC report I II III-1 III-2 III-3 IV Evidence obtained from a systematic review of all relevant randomised controlled trials. Evidence obtained from at least one properly designed randomised controlled trial. Evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies or interrupted time series with control group Evidence obtained from comparative studies with historical control, two and more single arm studies or interrupted time series without a parallel control group. Evidence obtained from case-series, either post-test or pre-test and post-test. Source: NHMRC (1999) A grading system for diagnostic studies developed by the Institute for Clinical Evaluative Sciences Canada was used in the paper of the NZ Clinical PET Reference Group, Clinical indications for PET scanning in New Zealand. Grading system for diagnostic studies (after ICES) A B C D Prospective studies with broad generalizability to a variety of patients and no significant deficiencies in research methods. Prospective studies with a narrower spectrum of generalizability and with only a few deficiencies that are well described (and impact on conclusions can be assessed). Studies with several methods deficiencies (e.g., small sample size (<35) and retrospective) Studies with multiple deficiencies in methods (e.g., no credible reference standard for diagnosis) Appendix 1 Page 31 of 180

116 Efficacy and effectiveness of diagnostic tests a. The PET Business Case Project Team was particularly impressed with the quality and technical excellence of the report HTA Tomographie par Emission de Positrons en Belgique. The report uses a different method of assessing the evidence and introduces the concept of Efficacy, as compared to Evidence. b. Fryback and Thornbury described a hierarchy of diagnostic efficacy, which is used as the basis of the Belgian HTA report. c. Efficacy is defined as the probability of benefit from a medical technology to individuals in a defined population under ideal c onditions of use. In other words: can the diagnostic test work? d. This is not the same as effectiveness, which assesses the test s ability to work in the real world: does it work in clinical pract ice? e. Finally, efficiency is where the test s financial implications are considered: is it worth it? f. The model is characterized by a change in perceived goals. It is hierarchical: on one extreme are endpoints describing only the technical performance of the test, on the other extreme are endpoints pertaining to the value of the diagnostic technology to society. If a test performs poorly at one level, it is unlikely to perform well at a higher level. The reverse, however, is not true: increases in the technical performance of a test will not necessarily guarantee improvement at a higher level, for example effect on patient outcome. g. A diagnostic test does not necessarily have to demonstrate effectiveness at each level before it can be used in clinical practice, but the possible gain and remaining uncertainty on the test s efficacy is clearly presented by this approach. Levels of Evidence and Levels of Efficacy The level of evidence and grading systems referred to above have the highest level of evidence as 1 or A. In the Fryback and Thornbury hierarchy of efficacy level 1 is the lowest level and level 6 is the highest, ie this is the reverse of the other systems in common use. Summary: Fryback and Thornbury hierarchy of efficacy Level Description Area of concern 1 Technical efficacy Technical qual ity of the images 2 Diagnostic accuracy Diagnostic accuracy, sensitivity and specificity associated with interpretation of images. Sensitivity and specificity are the commonest measures used throughout the PET diagnostic literature to sh ow how PET compares to other imaging, usually CT. Significant specificity and sensitivity have been the measures used to support conclusions that PET is effective. Attainment of level 2 efficacy is enough to show that PET has value in a particular clinical situation. 3 Diagnostic thinking Whether the informatio n produces change in the referring physician s diagnostic thinking 4 Therapeutic impact Effect on the patient management plan 5 Patient outcome Effect of the information on patient outcomes 6 Cost effectiveness analysis Societal costs and benefits of a diagnostic imaging technology 32 of 180

117 C2: EVIDENCE FOR PET FOR CANCER MANAGEMENT (3) Lung Cancer a. The evidence for the use of PET in oncology is good to very good for some ind ications. For some indications, it is not useful at all. The value a number of other potential indications is intermediate but it is a very active area of clinical research with new information becoming availab le, which usually supports the use of this technology. b. This report will comment on the use of PET in lung cancer, lymphoma, head and neck cancer, colorectal cancer, malignant melanoma, breast cancer, oesophageal cancer, thyroid cancer, pancreatic cancer, liver cancer, cervical cancer, ovarian cancer, renal cancer, testicular cancer and bra in tumours. c. A comment on the use of the technology used in the studies appraised is appropriate. The largest and most recent comprehensive review is the Belgian HTA. This includes studies published up until April The actual patients studied and reported on will have been scanned dating from the 1990 s. Almost all of the scans will have been with full ring PET. Current and recent scanners are CT/PET machines. We do not have data include d that compare PET with PET/CT, but it is commonly accepted that PET/CT has advantages over PET alone. Non Small Cell Lung Cancer (NSLC) Diagnosis Staging Residual and recurrent disease Restaging Treatment monitoring Irradiated volume optimisation Pleural disease Mediastinal disease Comment This is the strongest indication for the use of PET. Several previous reports and proposals in New Zealand and elsewhere base almost the entire case on the management of NSCLC. Diagnosis of a single pulmonary nodule (SPN) The Belgian HTA rated the use of PET in SPN at level 3. This means that it changed the diagnostic thinking of the clinicians managing the patient. The expert opinion of the Business Case Project Team was that it did more in current practice, that it changed the actual patient management in a significant number of patients. It was stated that the use of PET allowed the invasive procedures of FNAB or thoractomy to be avoided. For the initial staging of a Non Small Cell lung Cancer, there is evidence of diagnostic accuracy. In addition, there is evidence that adding PET to CT is cost-effective, although the incremental benefit in terms of life years gained is small (level 6). For residual and recurrent disease, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity ( level 2). For residual and recurrent disease, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity ( level 2). For therapy monitoring, there is a lack of evidence for diagnostic efficacy. For irradiated volume optimization, there is a lack of evidence for diagnostic efficacy. For pleural disease, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). For mediastinal disease, there is no evidence. For mediastinal disease, there is no evidence This evidence is very strong and has been the primary justification for the introduction of PET scanning in several countries. Appendix 1 Page 33 of 180

118 Other lung cancer indications, including small cell Evidence for efficacy at level 2 No evidence for efficacy Residual and recurrent disease Staging and restaging of SCLC Assessment of pleural disease Therapy monitoring Mediastinal disease Other Cancers Malignant Melanoma Diagnosis Staging Lymphoma Planning local aggressive therapy Comment Staging Early response to treatment Residual mass evaluation Prognosis Comment There is agreement that PET has no role in the initial diagnosis of malignant melanoma. Diagnosis is made by inspection, biopsy or surgical excision and histopathology. The main value is in detecting distant metatases. PET is relatively insensitive to early nodal spread. There is agreement between the Belgian and Australian HTA s that PET appears to have improved diagnostic accuracy over conventional imaging the detection of metastatic lesions at level 2, specificity and sensitivity. In addition, it is of value in the staging of single or oligo metastases where metastatectomy is being considered. This makes the technology potentially useful in the staging of locally advanced melanoma in order to determine the appropriateness of aggressive locoregional therapy. In addition, it is of value in the staging of single or oligo metastases where metastatectomy is being considered. This is an important application of PET for triaging metastatic and extensive disease. This includes Hodgkin Lymphoma (HD) and non Hodgkin Lymphoma (NHL) For staging of Hodgkin s and NHL as above, PET is highly sensitive and specific, more so than CT, gallium or technecium bone scintigraphy at level 2. Assessment by PET within days of commencement of chemotherapy shows great promise of becoming a valuable method to determine whether the lymphoma will respond to the chemotherapy. This application of the technology is currently the subject of clinical trials. There is clinical evidence up to the diagnostic thinking level (level 3) because PET allows directing of the medical decision on the follow up strategy. PET is an excellent method to assess the efficacy of treatment and is a good predictor or relapse. (Level 2) PET is proving to be an excellent tool in the staging and management of intermediate and high grade lymphomas in adults and children 34 of 180

119 Head and Neck Cancer Diagnosis Staging Restaging Comment For diagnosis of primary head and neck cancer, limited evidence seems supportive for the use of PET in the diagnosis of primary head and neck cancer when CT/MRI results are indeterminate (level 2) For staging in head and neck cancer, i.e. assessment of regional lymph node involvement, there is evidence of diagnostic efficacy up to diagnostic thinking based on calculated positive and negative likelihood ratios (level 3). For staging in head and neck cancer, i.e. detection of distant metastases and synchronous primary tumours, there is some evidence of diagnostic accuracy (level 2). For restaging in head and neck cancer, i.e. assessment of residual or recurrent disease during follow up after treatment, there is evidence of diagnostic efficacy up to diagnostic thinking based on calculated positive and negative likelihood ratios (level 3). PET has a vital role in evaluation of residual neck masses following radiation treatment, with excellent discrimination between residual disease and fibrosis. This is of particular importance, as the risks of neck dissection in the heavily irradiated neck are substantial. Occult Primary Cancer Diagnosis Comment From a cervical lymph node metatasis. For diagnosis of an Occult Primary Tumour suspected from a cervical lymph node metastasis when clinical examination, panendoscopy with biopsy and/or conventional imaging modalities (CT/MRI) have failed to identify a primary tumour, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). From a metastatic tumour outside the cervical lymph nodes. As well as for the detection or exclusion of additional metastases following an unsuccessful initial diagnostic work up for an Occult Primary Tumour when local or regional therapy is considered as part of a treatment plan for a single metastatic carcinoma outside the cervical lymph nodes, there is evidence of diagnostic accuracy (level 2). PET has become an excellent new tool for difficult diagnosis. Location of the primary tumour is important for management, as surgery or radiation can be targeted to the primary tumour, avoiding treatment to normal tissues. Colorectal Cancer Diagnosis For initial diagnosis and staging of colorectal cancer, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). Restaging Restaging at recurrence Treatment monitoring Comment For restaging after chemo/radiotherapy, there is no evidence. For detection and localization of local, hepatic and extrahepatic recurrence, the diagnostic efficacy includes changes in patient management and therapeutic decision (level 4). In addition, there is limited evidence for cost-effectiveness. For treatment monitoring, there is no evidence. The use of PET to identify patients suitable for major surgery following upper abdominal recurrence is one of the most important applications of this technology. It was given an efficacy score in the Belgian HTA of 4, the highest well validated level in the report. In one Appendix 1 Page 35 of 180

120 study of 102 patients, the addition of PET altered management in a significant manner in 50%. There is agreement that the higher sensitivity of full ring PET is necessary for this indication. Oesphageal Cancer Diagnosis Staging Treatment response for patients eligible for curative surgery Comment For diagnosis, i.e. the initial detection of a primary tumour, there is lack of evidence. For staging in oesophageal cancer, i.e. staging of lymph nodes (loco-regional, distal or all lymph nodes) and distant sites other than lymph nodes, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity. Evidence, although limited, seems supportive for the use of PET (level 2) For staging in oesophageal cancer, i.e. staging of distant sites, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). For assessment of treatment response after patients, eligible for curative surgery, have received neoadjuvant therapy (comparative with initial staging PET result), there is evidence up to diagnostic thinking based on diagnostic accuracy and prognosis (level 3). The use of PET adds considerably in the selection of patients suitable for high cost surgical procedures. Level 3 efficacy as above. Pancreatic Cancer Diagnosis Staging Restaging Comment For diagnosis, i.e. the detection of pancreatic cancer, there is limited evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). The clinical utility and advantage over other imaging techniques remain to be established. For staging, i.e. detection of metastatic disease, there is limited evidence of diagnostic accuracy including determination of sensitivity and specificity (level 2). The clinical utility and advantage over other imaging techniques remain to be established. For restaging, i.e. detection of residual or recurrent disease, there is lack of evidence. Evidence of efficacy is present, but more studies would add to knowledge. Cervical Cancer Staging Residual mass evaluation Recurrence diagnosis Comment For staging, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). Evidence to level 2 Evidence to level 2, but some is conflicting PET is of value in staging locally advanced cancer. It can identify hot spots outside the standard RT fields which are then modified to include them. 36 of 180

121 Ovarian Cancer Diagnosis Staging Treatment response Diagnosis of recurrence Comment For diagnosis, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). For initial staging, there is no evidence. For evaluation of treatment response, there is no evidence. For diagnosis of recurrence, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). The use of PET at diagnosis can identify areas of potentially resectable disease. Breast Cancer Diagnosis Staging Restaging Treatment response Comment Thyroid cancer Restaging For diagnosis in patients referred for breast biopsy with abnormal mammogram or palpable breast mass, there is evidence of diagnostic inaccuracy. Benefits do not appear to outweigh risks (level 2 against the use of PET). For staging/restaging in breast cancer, i.e. detection of distant metastatic disease if clinical suspicion for metastatic disease is high at initial diagnosis or when recurrent breast cancer is suspected, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). Evidence seems supportive for the use of PET. For staging in breast cancer, i.e. staging of axillary lymph nodes in patients with no palpable axillary lymph nodes metastases and no evidence of distant metastases, there is evidence of diagnostic inaccuracy. Benefits do not appear to outweigh risks (level 2 against the use of PET). For restaging in breast cancer, i.e. detection of loco-regional recurrence, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). There is inconclusive evidence that PET is superior to CT/MRI. For assessment of treatment response, further diagnostic studies are needed There is evidence to support the use of PET in staging and restaging. The evidence that this is superior to other modalities is not strong. Expert opinion is that the use of PET for breast cancer will increase as new evidence, currently in trials, is published. The applications of PET for thyroid cancer are all restaging, and all reach significance. For restaging, i.e. detection of recurrence of epithelial thyroid cancer in previously treated patients with elevated biomarkers not confirmed by 131I scintigraphy, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). For restaging, i.e. detection of recurrence of medullary thyroid cancer in previously treated patients with elevated biomarkers not confirmed by other imaging, there is some evidence of diagnostic accuracy (level2). For restaging, i.e. detection of recurrence of thyroid cancer (no differentiation between epithelial and medullary) in previously treated patients without elevated biomarkers and no evidence of disease by 131I scintigraphy but with clinical suspicion of recurrence, there is some evidence of diagnostic accuracy (level2). For restaging, i.e. detection of recurrence of thyroid cancer (no differentiation between epithelial and medullary) in patients with otherwise established neoplastic foci, there is some evidence of diagnostic accuracy (level2). Appendix 1 Page 37 of 180

122 Renal Cancer Diagnosis Staging Diagnosis of recurrence Comment For initial diagnosis, there is a lack of evidence for diagnostic accuracy. For staging, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). For detection of recurrence, there is a lack of evidence for diagnostic accuracy. PET is of value in staging at diagnosis. Testicular Cancer Staging Residual mass detection Treatment response Diagnosis of recurrence For staging there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). For residual mass detection, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2). For therapeutic response, there is a lack of evidence for the use of PET. For the detection of occult recurrence, there is a lack of evidence for the use of PET. Comment PET is of v alue in staging at diagnosis and the detection of residual masses after chemotherapy. Brain Tumours Diagnosis Restaging Comment For diagnosis, i.e. distinguishing high-grade from low-grade glioma, there is evidence of diagnostic accuracy including the determination of sensitivity and specificity (level 2) For diagnosis, i.e. biopsy targeting and delineation of lesion for therapy planning, there is some evidence of diagnostic accuracy (level 2) For restaging, i.e. distinguishing recurrent malignancy from radiation necrosis, there is some evidence of diagnostic accuracy (level 2) PET is of value for biopsy targeting, monitoring tumour transformation and to distinguish recurrence from radiation necrosis. 38 of 180

123 The following table clinical performance of PET/CT compared with PET alone or CT alone. It has been adapted from Czernin J, Allen-Auerbach M, Schelbert HR: Improvements in Cancer Staging with PET/CT:Literature-Based Evidence as of September 2006, The Journal of Nuclear Medicine Vol. 48 (No. 1) (Suppl) January This summarises the clinical evidence to Clinical Performance of PET/CT: Direct Comparison with PET or CT Cancer Study No. of subjects enrolled Method with which PET/CT was compared P Head and neck Branstetter et al. (6), T/N staging by PET NS T/N staging by CT <0.05 Schoeder et al. (7), Lesion detection by PET <0.05 Gordin et al. (8), Staging by PET NS Staging by CT <0.05 Chen et al. (10), Staging by PET <0.05 Staging by CT <0.05 Thyroid Palmedo et al. (12), Diagnosis by PET <0.05 SPN and lung Yi et al. (15), PET <0.05 Lardinois et al. (1), T staging by PET 0.01 N staging by PET <0.05 Antoch et al. (18), T staging by PET N staging by PET NS Halpern et al. (19), T staging by PET <0.05 N staging by PET NS Shim et al. (20), T staging by CT NS N staging by CT <0.001 Cerfolio et al. (27), Restaging or monitoring by CT <0.05 Breast Fueger et al. (28), Restaging by PET 0.06 (NS) Tatsumi et al. (29), Restaging by CT <0.05 Esophageal Bar-Shalom et al. (30), Staging <0.05 Yuan et al. (31), N staging by PET <0.05 Appendix 1 Page 39 of 180

124 TABLE 1: Clinical Performance of PET/CT: Direct Comparison with PET or CT Cancer Study No. of subjects enrolled Method with which PET/CT was compared P Colorectal Co hade e t al. (33), Restaging by PET <0.01 Kim et al. (35), Restaging by PET <0.01 Votrubova et al. (36), Restaging by PET <0.05 Even-Sap ir et al. (37), Restaging by PET <0.05 Selzner et al. (38), Detection of liver metastases by CT Detection of extrahepatic disease by CT NS <0.05 Pancreatic Heinrich et al. (40), Diagnosis by CT 0.07 (NS) Biliary tract Petrowsky et al. (41), Diagnosis by CT NS Detection of distant metast ases by CT Regional N staging by C T <0.05 NS GIST Go erres et al. (43), Prognosis by CT <0.05 An toch et al. (44), Prognosis by PET <0.05 Lymphoma Allen-Auerbach et al. ( 45), Restaging by PET <0.05 Freudenberg et al. (46), Restaging by PET NS Restaging by CT <0.05 Schaefer et al. ( 47), Restaging by CT <0.05 la Fougere et al. (49), Side-by-side PET and CT NS Melanoma Reinha rdt et al. (55), M/N staging by CT <0.05 M/N staging by PET <0.05 Unknown primary Gu tzeit et al. (56), Detection by PET Detection by CT NS NS SPN 5 solitary pulmonary nodules. 40 of 180

125 C3: The NICE guideline for the management of lung cancer (The NHS National Institute for Clinical Excellence) The NICE guideline for the management of lung cancer makes several recommendations for the use of PET, which are reproduced below. Every cancer network should have a system of rapid access to FDG-PET scanning for eligible patients. Patients who are staged as candidates for surgery on CT should have an FDG-PET scan to look for involved intrathoracic lymph nodes and distant metastases. Patients who are otherwise surgical candidates and have, on CT, limited (1 2 stations) N2/3 disease of uncertain pathological significance should have an FDG-PET scan. Patients who are candidates for radical radiotherapy on CT should have an FDG-PET scan. Patients who are staged as N0 or N1 and M0 (stages I and II) by CT and FDG-PET and are suitable for surgery should not have cytological/histological confirmation of lymph nodes before surgical resection. Histological/cytological investigation should be performed to confirm N2/3 disease where FDG-PET is positive. This should be achieved by the most appropriate method. Histological/cytological confirmation is not required: where there is definite distant metastatic disease or where there is a high probability that the N2/N3 disease is metastatic (for example, if there is a chain of high FDG uptake in lymph nodes). Appendix 1 Page 41 of 180

126 C4: GA STRIC CANCER Gastric cancer was not included in the HTA s that were available to us. There are no published systematic reviews. A Medline search returned 9 citations, none of which reached level 2 efficacy. Using other criteria they would have been rated either as level 4 (case series) or 5 (expert opinion) on the Sackett scale. This evidence is not enough to support t he use of PET for this indication, although new information will certainly be published. Gastric cancer is included in the NZ indications for PET under Upper GIT C5: PAEDIATRIC ONCOLOGY The use of PET in paediatric oncology was not included in the core HTA s available to the Project Team. It was included in the brief for the literature search conducted by the NZHTA, and the single systematic literature search summary is reproduced below. The Project T eam was a ble to provide expert advice as there were two members of the team working or recently working in the field. Although there is little published about PET for paediatric oncology, the commonest use of it for NZ patients has been for lymphoma, either for patient management or because it was required for a clinical trial. The adult experience can be extrapolated as Hodgkin Lymphoma in childhood is biologically very similar to that in adults. Practically all Non Hodgkin lymphoma s in childhood are high grade, and the value of the technology already demonstrated for adults has been show n in clinical practice to also apply to children. The summary of the review found by the NZHTA search follows: Little is known about the clinical value of FDG PET for assessing treatment response in paediatric oncology. After systematic review of literature, the very few publications concerning response control in paediatric oncology using FDG PET are summarized. There were only 4 studies concerning FDG PET in the assessment of therapy response in paediatric patients. None of the publications fulfilled the requirements for high quality studies because of the small number of patients studied. The clinical value of FDG PET in the assessment of therapy response in paediatric oncology is likely in osseous sarcomas and possibly in high-grade brain tumo urs. In other paediatric tumour entities such as lymphomas, soft-tissue sarcomas, germ cell tumours, or neuroblastomas, the clinical usefulness of FDG PET can either be assumed analogous to adults, or can be assumed from staging studies, or is still unknown. There is a need for large, systematic studies evaluating FDG PET in therapy monit oring, but also in grading, staging, and in the diagnosis of recurrences in paediatric malignancies. C6: NEUROLOGY a. Alzmeimer Disease For Alzheimer disease, there is evidence of diagnostic accurac y including the determin ation of sensitivity and specificity ( leve l 2). 42 of 180

127 Possible therapeutic consequences are uncertain. The effectiveness of pharmacological treatment of Alzheimer disease, e.g. by cholinesterase inhibitors, is being questioned. b. Epilepsy The Belgian HTA rated the use of PET for diagnosis of refractory epilepsy as level 2. Dr Peter Bergin for the Auckland epilepsy group commented There are some patients who have refractory partial seizures but have normal MR scans, and in some of them, an abnormal FDG-PET scan result can be the critical factor in determining whether or not a patient should undergo surgery. His full submission follows. Comment by Dr Peter Bergin, Neurologist, Auckland City Hospital a. Epilepsy is a common neurological problem. There are many different types of epilepsy and different reasons why patients develop epilepsy. Essentially any insult to the brain can result in seizures. Seizures can be generalised, meaning they involve the entire brain, or partial (also termed focal or localisation related), meaning that they arise from a restricted area (part) of the brain. Many patients have a genetic predisposition to seizures, though other patients develop seizures because of a structural abnormality affecting the brain. b. Although there is not good epidemiological data regarding New Zealand specifically, the prevalence of epilepsy in other Western countries is approximately 0.5%. If these figures are extrapolated to the New Zealand situation, it would mean that there are approximately 20,000 patients with epilepsy in New Zealand. c. Approximately 70 to 80 % of patients with epilepsy have their seizures controlled adequately with anti-epileptic drugs. However, this means that 20 to 30% of patients continue to have refractory seizures despite optimal treatment with drugs. A proportion of these patients are candidates for resective brain surgery. d. If it is possible to identify the area of the brain from which seizures arise, then it is sometimes possible to resect the damaged tissue and thereby prevent the seizures. Some patients with drug-resistant epilepsy can be effectively cured by this surgery. Seizures can arise in any part of the brain, although the most common group of patients in whom surgery is performed are those who have temporal lobe epilepsy. It is obviously critically important that the correct region of the brain is resected. PET scanning is one of the tools that can be very useful in identifying where a patient s seizures arise, and guiding the surgical resection. e. FDG-PET scanning has been undertaken in large epilepsy centres around the world for many years now. FDG-PET typically shows an area of hypometabolism involving the area from which seizures arise in patients with focal (partial) seizures. f. At present all patients in New Zealand who are being considered for surgery undergo MR scanning, and they have one or more EEGs recorded. Nearly all patients are also admitted to hospital for a period of video-monitoring, during which we attempt to record seizures. Typically patients spend a week in hospital undergoing video- shows a monitoring, though some patients need a longer admission. If an MR scan well defined lesion, and the video-eeg confirms that seizures arise from this region, then a decision regarding surgery is often straight forward. FDG-PET scans are likely to be abnormal in these patients, but the PET scan does not contribute greatly, since it merely confirms that the area of hypometabolism corresponds with the abnormality seen on the MR scan. However there are some patients who have refractory partial seizures but have normal MR scans, and in some of them, an abnormal FDG-PET scan result can be the critical factor in determining whether or not a patient should undergo surgery. If the FDG-PET scan shows a focal area of hypometabolism that corresponds with the EEG findings, then surgery may be a realistic option. Other Appendix 1 Page 43 of 180

128 patients have lesions seen on their MR scans, but the EEG does not show any focal abnormality, or they have multiple lesions on MR, and it may not be clear which of them is actually the epileptogenic lesion. Some of these patients will have abnormal FDG-PET scans. If the FDG-PET scan shows a restricted area of hypometabolism that corresponds with a lesion seen on MRI, then these patients, too, may be candidates for resective surgery. In other patients, a PET scan may show a very extensive or diffuse area of abnormality, indicating that surgery is not a realistic option. In this setting, the PET scan may save the patient a fruitless week-long admission for video monitoring. g. Over the past 3 years the Auckland Epilepsy Group have sent a small number of patients (approximately 5 patients) to Australia for PET scans. These were patients whose investigations had suggested a focal origin for their seizures, but we had not been able to confirm this with sufficient certainty that we were prepared to recommend surgery. For these patients the PET scan was the critical test. A further group of patients (approximately 20) have been sent to Melbourne for a work up towards surgery. Most of these patients have had PET scans as part of this workup in Melbourne. h. We anticipate that PET scanning will only be required for relatively small numbers of patients with epilepsy. Following discussion with other Neurologists, we would anticipate that, if we had easier access, we would request PET scans in 10 to 20 patients per year. For these patients, the PET scan may well be decisive in determining whether they could undergo surgery for their epilepsy. C7: CARDIOLOGY Submission by Dr Sue O Malley, Cardiologist and Physician in Nuclear Medicine a. While the cornerstone of PET is its application in oncology, PET has a secure role in managing cardiac patients. b. PET is able to provide clinically useful diagnostic data to determine accurately and non-invasively the extent and severity of any myocardial ischemia. It achieves this by use of radioactive tracers that can demonstrate both myocardial blood flow and myocardial metabolic activity. The most common radiotracer used in cardiac PET is 18 F-deoxyglucose (FDG) which indicates the presence of myocardial metabolism at the cellular level. This technique is then able to differentiate between viable and nonmyocardium. viable c. This data is pivotal in managing patients and triaging those who are likely to benefit from revasularisation, by either coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). If there is sufficient uptake of FDG, then this has proven to be a highly predictive tool that the patient will benefit from that procedure with improved outcome. d. If there is extensive non-viable myocardium, then the patient is triaged for either medical management or cardiac transplant (should that be a clinically appropriate). e. Prior to cardiac PET, the investigations available to provide this functional data were nuclear cardiology techniques utilizing radio isotopes such as thallium and technetium based radiopharmaceuticals, along with stress echocardiography. It is not difficult to understand how much more sensitive cardiac PET is at providing data on metabolic activity, reflecting what is occurring at the cellular level. f. Nuclear cardiology has a secure place in cardiac management due to its accuracy and highly predictive role in cardiac outcomes. Different protocols and different radioisotopes have expanded its application in acute and chronic settings in investigation of patients with chest pain. Most of the commonly used radioisotopes can provide data of myocardial ischaemia and viability. Data is digitally acquired and can be presented in internationally standardised formats and readily exported for 44 of 180

129 remote reporting or viewing. One of the new developments is the use of SPECT, rather than planar images alone which has increased scan interpretation accuracy. To further enhance the breadth of the investigation, the studies now are routinely gated to provide detail about ventricular volume, left ventricular ejection fraction and wall motion. Images can be aligned to demonstrate interval change. Some of the nuclear medicine scanners in New Zealand can co-register anatomical and functional images. SPECT reversible inferior wall defect g. In locations where nuclear cardiology has not developed, stress echocardiography emerged to provide data on myocardial ischaemia and viability. It achieved this by looking at ventricular wall motion at rest and how stressing the heart (either by physiological means or pharmacological means) affects the ventricular volume, and wall motion. In a positive study for myocardial ischaemia, typically the ventricular volume would increase with stress and there would be a decrease in left ventricular wall thickening and contractility relative to the rest study. Because these parameters depend in turn on blood flow, stress echocardiography is regarded as less sensitive than nuclear cardiology techniques. h. What has cardiac PET to offer over and above current technologies? i. The really important advance that cardiac PET has brought is in identification of viable versus non viable myocardium with FDG. The medical management for patients is dependant on these results. It is vital therefore that chronically underperfused myocardium (but metabolically active) not be misinterpreted as non viable myocardium. If there is poor or absent myocardial perfusion, but preserved metabolism (flow: metabolism mismatch), then these patient respond well to revasularisation and the do not require the scarce resource of cardiac transplantation. If however there is matched absent flow and metabolism of the myocardium then a different strategy can be employed such as cardiac drug treatment, biventricular pacemakers and other ventricular support means. It is the accuracy of the results that sets this apart. All cardiac transplant patients would ideally have a cardiac PET study to confirm the need for that highly specialised and scarce treatment option. Appendix 1 Page 45 of 180

130 Cardiac PET showing viable myocardium; poorly perfused myocardium with preserved myocardial metabolism j. The use of cardiac PET to look for myocardial ischaemia requires a different radioisotope, one with a very short half life. This would necessitate an onsite cyclotron for thi s purpose. Because of the very short half life of the positron, then an adequate dose can be given to provide good quality images without a significant radioactivity burden. k. The technology of cardiac PET is well established globally because it is Accurate Non-invasive Rapid Provides clinically useful prognostic data l. There is a need to have a cardiac PET centre is New Zealand, so that patients can be appropriately managed in a contemporary manner with an established track record. m. Key points: FDG-PET has significant advantages over existing technologies in assessing patients who are likely to benefit from either coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). All potential cardiac transplant patients should have a PET scan to confirm the need for the procedure. This has obvious benefits for the efficient use of resources, given the high cost of transplantation. 46 of 180

131 D: Current clinical indications list for referral to PET The following is a list of indications prepared by the PET Reference Group to assist DHB s in their consideration for referral of patients for PET scans Clinical indications for referral to PET Tumour Indication Purpose Implication of PET result Grades of studies Lung Diagnosis of solitary pulmonary nodule not amenable to other diagnosis Determine PET status (po sitive = malign ant; cold = benign) Advise resection if PET positive Observe if PET negative B Non small cell lung cancer Staging prior to initial management decision Identify hot spots in mediastinum Identify hot spots indicating haematogenous spread Avoid surgery if extensive mediastinal disease Avoid high dose radia tion if disseminated. A B Melanoma Staging locally advanced melanoma Identify hot spots indicating haematogenous spread Staging of single or oligo metastatic Identify hot spots indicating extensive metastatic disease Avoid aggressive locoregional therapy if disseminated Avoid futile metastectomy if widely disseminated B B Occult primary (neck node presentation) Identify primary site Allow tailored therapy to primary and neck Avoid morbid wide field RT C Head/neck cancer Staging Identify o ccult disease not evident on clinical and CT examination Determine suitability of morbid surgery and/or RT B Re -staging Determine PET status of residual mass/es post RT Advise resection if PET positive Observe if PET negative B,C Recurrent colorectal cancer Re-staging Identify o ccult site of CEA production with negative CT/MRI Possible curative surgery if single metastatic site B Identify m ultiple hot spots in patients with isolated pelvic recurrence or oligo metastases (liver, lung, brain) Avoid futile hepatic, pulmonary, cerebral or pelvic resection B Initial staging Determine extent of disease Lymphoma (Hodgkin s & Non Hodgkin's) Re-staging following initial chemotherapy Determine PET status of residual mass/es post chemo Cervical cancer Staging locally advanced cancer Identify hot spots outside standard RT fields Determine staging to decide treatment protocol Determine need for further therapy (systemic or local, including bone marrow transplantation) Modify RT fields B A C Appendix 1 Page 47 of 180

132 Clinical indications for referral to PET Tumour Indication Purpose Implication of PET result Grades of studies Ovarian cancer Staging recurrence Identify potentially resectable intraabdominal disease Identify extensive disease Improve outcome through targeted surgery Avoid futile surgery B,C Upper GIT (oesophagus Stomach, pancreas, biliary tract) Staging Determine extent of disease Determine appropriateness of curative therapy (mainly morbid surgery) B,C Paediatric oncology Staging Determine extent of disease Modify type/ aggr essiveness of systemic & local therapies B,C Low grade brain tumours Determine tumour heterogeneity Monitor tumour transformation Identify metabolically active focus for biopsy Identify development of metabolically active focus Determine need for immediate aggressive local therapy (surgery/rt) vs observation Determine timing of intervention B,C Brain tumours Recurrent symptoms with equivocal CT/MRI Distinguish recurrence from RT-induced brain necrosis Inform decision re further surgery B,C Epilepsy Focal seizure activity Identify focus of epilepsy Inform decision re surgery to remove focus C Grading Scheme for Diagnostic Studies (after ICES) A Prospective studies with broad generalizability to a variety of patients and no significant deficiencies in research methods. B Prospective studies with a narrower spectrum of gen eralizability, and with only a few deficiencies that are well described ( and impact on conclusions can be assessed). C Studies with several methods deficiencies (e.g., small sample size (<35) and retrospective) D Studies with multiple deficiencies in methods (e.g., no credible reference standard for diagnosis) 48 of 180

133 E: Draft Terms of Reference for a National PET Advisory Committee (NPAC) Proposed composition of NPAC a. Oncologist representative b. Neurologist representative c. Cardiologist representative d. Research and industry representative(s) e. Nuclear medicine physician f. Nuclear medicine physicist g. Radiologist representative h. Manager of Cancer Service representative i. Manager of Imaging Service representative j. DHB representative k. NRL representative Note: MOH, Maori and consumer input into NPAC is assured through their proposed membership NCTWP. Draft Terms of Reference of NPAC 1. Development and implementation phase: a. ensure compatibility, integration etc of all components b. ensure legislative compliance c. define and ensure maintenance of standards d. develop QA indicators, outcome measures and audit tool e. develop guidelines for prioritisation of access within and between specialties, indications and research f. assess and advise on issues of risk management g. develop protocols for adoption nationally 2. Ongoing oversight phase a. ongoing review of clinical indications b. manage audit process including performance indicators c. determine national requirements for infrastructure d. maintain watching brief and advise on workforce and training issues e. advise regarding requirements for new/replacement equipment of Appendix 1 Page 49 of 180

134 APPENDICES SET 2: BUSINESS CASE PROCESSES Contents: A. Project brief B. Letters sent to stakeholders and suppliers C. Paper written about the project to inform stakeholders A: Project Brief / Draft Project Plan Business/Programme Environment The Service Planning and New Health Intervention Assessment framework (SPNIA framework) aims to help District Health Boards (DHBs) and the Ministry of Health with health service changes that require a collective decision. National Service and Technology Review Group (NSTR) is part of the SPNIA framework, and has been established to analyse and evaluate proposals for change and business cases and to recommend their adoption or rejection to the DDG-CEO Group. NSTR endorsed the change proposal for PET scanning at their August (2006) meeting. The change proposal was a joint Ministry/DHB approach and did not therefore require a lead DHB to bring the case forward. The development of a business case does require a DHB to take responsibility for coordination. At a teleconference on Sept 6 th proposals from several DHBs were evaluated with the agreement that Auckland DHB take the coordination role with support and advice from other DHBs. It was subsequently suggested that the DHBs involved in that decision- the draft business case and to making could have a useful advisory role to review provide advice as necessary on any issues arising during the development of the business case. Auckland DHB s proposal included Oncology Radiation Specialist Graham Stevens as Project Chair, contracting with Project Portfolio Ltd to supply project manager expertise of Sam Denny. GMs Funding and Planning were also informed and invited to advise Chris Crane, SFG Portfolio Manager, DHBNZ (in lieu of a project manager) if they wish to participate in the business case development. Several DHBs responded to this invitation Waikato Hawkes Bay Capital Coast Canterbury Project Opportunity Cancer Control is a priority for NZ. It is one of the thirteen health areas targeted by the NZ Health Strategy. PET scanning is now a routine component of cancer management and treatment in most developed countries. Any requirement to increase capacity for CT scanning by DHBs will need to include consideration of the merit of CT versus PET/CT and the effect that the introduction of PET/CT to NZ would have on their volume projections for CT scanning The new SPNIA Framework and NSTR provide the appropriate forum to assess proposed new services and technology Appendix 2 Page 50 of 180

135 Linked projects and processes Some DHBs have already begun to consider the need for CT PET Scanning in NZ eg Canterbury DHB have had a working group considering this which put up a bid in 2004 for Enterprise funding as a joint venture between CDHB, Canterbury University and a private radiology firm. Some DHBs are experiencing waiting times for diagnostic and staging procedures including CT Scans and MRI and may be in various stages of considering the need for additional capacity. Capital investment projects such as these will need to be considered in the light of this project and vice versa. The team / resources needed /available The successful team will have the assistance of the Ministry of Health, NSTR, DHBs and DHBNZ to deliver the final output to a standard able to be published. It is noted that a strong partnership between all these parties is required for the project to be a success. Risks of not addressing the problem Clinical risk: not assessing the merits of developing a PET/CT facility in NZ may be deemed to be compromising the treatment, survival, and quality of life of NZ cancer sufferers Financial risk: continuing to diagnose and treat inappropriately poses an ongoing financial risk to DHBs. The business case will also include assessment of the possibility and cost of continuing to send patients to Australia for PET scans. Risks in addressing the problem Competing priorities for funding: New high tech capital investment can be perceived as very inappropriately taking funding from low tech, community based priorities. This is the first business case under the new SPNIA Framework and for NSTR. PROJECT FRAMEWORK General Description of Project The purpose of this project is to write a business case in order to credibly plan the delivery of a service change (PET scanning). The business case is a stand-alone document. A business case is a comprehensive document that provides all the necessary detailed information and analysis required for informed decision-making about a service planning initiative or a new health intervention, and for planning the successful implementation of a project. Objectives The objective is to provide a professional business case for PET Scanning that can be submitted to NSTR (via the Steering Group). A business case must be developed in order to credibly plan the delivery of a service change or new health intervention. The business case will be a stand-alone document. To ensure that the funding and affordability section is accurate, the clinical effectiveness assumptions will be reflected in both the financial modelling and cost-effectiveness analysis. Appendix 2 Page 51 of 180

136 Stakeholder requirements A business case must be developed in order to credibly plan the delivery of a service change or new health intervention. The business case will be a stand-alone document. To ensure that the funding and affordability section is accurate, the clinical effectiveness assumptions will be reflected in both the financial modelling and cost-effectiveness analysis. NSTR reviews the proposals for change and business cases using a standard evaluation methodology. That methodology assesses the strength of the business case in the following areas: 1. Expert clinical evidence and health technology assessment, including challenges to the evidence 2. Population health gain 3. Cost effectiveness 4. Equity and opportunity cost 5. Funding stream and affordability 6. Community acceptability and ethical issues 7. Service configuration and implementation planning 8. Priority in relation to other proposals in the annual decision round and against past precedents. SPNIA Framework - Business case development The PET business case needs to include information on the following: Information on referrals to Australia (directly approaching the Australian providers may be the easiest way to gain this information) Population gain Workforce issues Community acceptability and ethical issues Societal impact, included as part of the economic analysis Implementation issu es, in particular projected Austral ian capacity and understanding of the Australian environ ment in relation to New Zealand Service configuration, in particular options for the location and number of cyclotrons and ownership or partne rship with the privat e sector for the cyclotron(s) Key internal and external stakeholders Key stakeholders are identified as Minister of Health, MOH, DHBNZ, DHBs, Consumer Representative organisations such as Cancer Society. The Project Charter The Project Charter is as outlined in the DHBNZ memo of 30th August Scope This proj ect will include the following: Framing the question and options analysis Effectiveness and safety Cost 52 of 180

137 Cost-effectiveness/value for money Funding and affordability including inter-district flows and opportunity cost Equity Whanau ora Information flows Constraints including workforce Community acceptability including ethical issues Implementation planning, risk management and post-implementation review Completeness Consultation Summary and recommendations Exclusions From SPNIA Framework, A business case as required by NSTR does not replace the requirement for a business case for capital investment as set out in the Ministry of Health Guidelines for Capital Investment. However, where service change or new intervention implementation requires a capital business case, the health service business case should be incorporated in the capital business case so that the two documents are compatible. Constraints Timeframe: The change proposal included a very tight timeframe in order to report before the end of the year. It has been agreed by NSTR that this needs to be explored as part of the scoping of the project. Budget : A budget has been set which relates to the short timeframe schedule. NSTR infrastructure does not enable development of business cases in-house and therefore a new team has to be brought together. Requirement for sector agreement within short timeframes. Lack of PET/CT experience in NZ other than overseas experience by individual clinicians Appendix 2 Page 53 of 180

138 PET/CT Project Governance/ Reporting Structure Ministry of Health National CEOs DDG/CEOs Decision-making National Service and Technology Review Group via Convenor Ricarda Vandervorst Business case development DHBNZ SFG via Chris Crane Project Team Chair: Graham Stevens PM: Sam Denny Re fer section 10 of busines s ca se for membership PET Project Reference Group Provided feedback on first draft Win Bennett (Hawkes Bay DHB) Megan Bolvin (Otago DHB) Jan Hewitt (Waikato DHB) Sandra Williams (Capital and Coast DHB) Stephen Munn (Auckland DHB) Chris Hoar (Canterbury DHB) 54 of 180

139 B: Letter to all Radiology practices in NZ Dear Radiology Practice, National Positron Emission Tomography Scanning Business Case Project The purpose of this letter is to inform you about the National Positron Emission Tomography (PET) Scanning business case project. As you may be aware, the Service Planning and New Health Intervention Assessment (SPNIA) Framework has been developed jointly by District Health Boards and the Ministry of Health to help with health service changes that require a collective decision. The SPNIA Framework covers regional and national collaborative decision making in two related areas: new health interventions (including a new method of delivering an existing treatment) service reconfiguration (including the introduction of a new service, cessation of a service, service expansion, quality change or change of providers). The National Service and Technology Review (NSTR) Advisory Committee (set up to consider proposals that have a national impact) considered a Proposal for Change on PET Scanning in July 2006 and agreed to include PET Scanning on its work programme. Auckland District Health Board (DHB) is the lead DHB for the development of the PET Scanning business case. Graham Stevens (Radiation Oncologist) is Project Chair. Project Portfolio Ltd is providing project management and clinical expertise for the project. The project / expert team has a number of people from Auckland, Wellington and Christchurch with expertise in both clinical and scientific use of PET technology. The purpose of this current project is to write a business case on PET scanning. The business case is required to be a comprehensive document that provides all the necessary detailed information and analysis required for informed decision-making about a service planning initiative or a new health intervention, and for planning the successful implementation of a project. Key messages for the PET Scanning Business Case Cancer Control is a priority for New Zealand. It is one of the thirteen priority population health objectives in by the New Zealand Health Strategy. PET scanning is now a routine component of cancer management and treatment in most developed countries. The business case is to explore all options including public/private partnerships. Options for partnership will be explored at high level only with no preferred partner or supplier arrangements implied or intended at this business case stage. The business case is to be completed and provided to NSTR by mid February This letter is to ensure all New Zealand radiology practices with an interest in PET scanning are kept abreast with the process and to invite comment or discussion with the business case project tea m who can be contacted as below. The project team are available through the holiday period except for the statutory public holidays. Yours sincerely, Graham Stevens Project Chair Appendix 2 Page 55 of 180

140 Letter to Universities Dear Sir, National Positron Emission Tomography Scanning Business Case Project The purpose of this letter is to inform you about the National Positron Emission Tomography (PET) Scanning business case project and to gauge the level of interest from your university. The health sectors Service Planning and New Health Intervention Assessment (SPNIA) Framework has been developed jointly by District Health Boards and the Ministry of Health to help with health service changes that require a collective decision. The National Service and Technology Review (NSTR) Advisory Committee (set up as part of the SPNIA Framework to consider proposals that have a national impact ) considered a Proposal for Change on PET Scanning in July 2006 and agreed to include PET Scanning on its work programme. Auckland District Health Board (DHB) is the lead DHB for the development of the PET Scanning business case. Graham Stevens (Radiation Oncologist) is Project Chair. The project / expert team has a number of people from Auckland, Wellington and Christchurch with expertise in both clinical and scientific use of PET technology including representatives of Auckland and Canterbury University. The purpose of this current project is to write a business case on PET scanning. The business case is required to be a comprehensive document that provides all the necessary detailed information and analysis required for informed decision-making about a service planning initiative or a new health intervention, and for planning the successful implementation of a project. Key messages for the PET Scanning Business Case Cancer Control is a priority for New Zealand. It is one of the thirteen priority population health objectives in by the New Zealand Health Strategy. PET scanning is now a routine component of cancer management and treatment in most developed countries. The business case is to explore all options including public/ private partnerships. Options for partnership will be explored at high level only with no preferred partner or supplier arrangements implied or intended at this business case stage. The business case is to be completed and provided to NSTR by mid February This letter is to ensure New Zealand university departments, with an interest in PET scanning, are kept abreast with this process and to invite comment or discussion with the business case project team who can be contacted as below. We have attached a paper which describes this project and puts it into context. If you wish to demonstrate interest a letter of support from your university could be included with the business case. Yours sincerely, Graham Stevens Project Chair 56 of 180

141 Letter to suppliers 12 January 2007 Dear Ms/Mr, On behalf of the project team that is formulating the business case for the establishment of PET in New Zealand (see Appendix on pages 7-8), I am seeking more detailed information about your company s PET product line. I or one of my team colleagues have already approached you earlier in some form and have received some information on the isotope production system(s) that your company offers. That has been helpful. However, the project team strives for completeness and a greater degree of comparability amongst competitor companies, in order to come to well researched recommendations. The range of PET instruments on which we look for your input now covers everything from accelerator system, targetry, and synthesis units to PET/CT camera/scanner system. Where applicable in the questionnaire, I would like you to draw sufficient distinction between two modalities: 1. clinical application of PET, versus 2. research and development of PET techniques. There is enough interest amongst New Zealand clinicians and other researchers to establish capability and capacity to pursue both modalities. The minimum set of PET isotopes that your answers should cover are that of the four light PET isotopes C-11, N-13, O-15, and F-18. We would appreciate if you could provide extra details on capabilities to cover other PET isotopes (eg. I-124, Br-76, Ga-68, Rb-82, and Cu-64) and SPECT isotopes (eg. Tl-201, I-123, Tc-99m). We request that you provide the information in a fixed format. The table-formatted questionnaire is shown on pages 2-6, with my questions under column 1. You are kindly asked to populate columns 2 and 3. Providing additional comments under column 4 is optional. Your company s response would be greatly appreciated by Friday, 19 th of January. Yours sincerely, Albert Zondervan PhD nuclear physics Specialist in accelerator mass spectrometry Appendix 2 Page 57 of 180

142 A. Your identification: A1 company representative other contact details B. Your particle accelerator system: column #1: my questions column #2: your answers for the column #3: your answers for the column #4: your additional B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13 B14 B15 What nuclear reactions and beam energies are used to provide the isotopes? What target systems do you offer for each isotope? What are typical activity yields of each isotope at end-of-bombardment (~2 half-lifes)? Please comment if this is target dependent. How much time does it take to switch production from one isotope to another and are separate beamlines involved? Can the system be upgraded to produce also (one or more of the) heavier PET isotopes? What radiation shielding is provided? Please supply original technical specification requirements for radiation shielding rather than sole references to an (inter)national standard. What are the total space requirements (m 2 ), including all shielding? Please comment on optimal configuration of this space given the design of your equipment and customer experiences. What percentage of uptime can be expected from existing facilities? What are typical length and frequency of downtime intervals? What are the most common reasons for downtime? How many staff (fte percentages) are required for operation, and what are their functions and required competencies / qualifications? What form of backup support does your company provide in case non-standard technical problems are encountered? What are the benefits of bundling the purchase of your accelerator with other components of PET products that you offer (eg. synthesis module, PET camera, QAQC system, and conversely, what are the risks of not bundling with these other products? Please indicate the capital cost of the accelerator, broken down to include (i) planning and consultation, and (ii) installation, testing, and training. What do you suggest for managing hazard and waste issues around operation? Please comment on specific issues, solutions, and costs. What are the accelerator s operating costs, in terms of consumables, replacement parts, and services (mains power, climate control, water cooling, etc.)? If New Zealand cost estimates are unknown to you, please provide base information to enable NZ cost derivation by us. clinical application modality research modality comments (optional) 58 of 180

143 B16 B17 B18 What is the life expectancy of the accelerator, if properly maintained? What cost percentage should be reserved for decommissioning the plant (accelerator plus shield ing), and what potential risks / issues are involved (eg. remanent radiation)? What are the alternative uses for decommissioned equipment? Please comment on the present state of markets for these uses. C. Your radiochemistry equipment: column #1: my questions column #2: your answers for the column #3: your answers for the column #4: your additional comments C1 What chemistry modules do you offer for synthesizing each PET isotope? C2 What are the total space requirements (m 2 ), including shielding? clinical application modality research modality (optional) C3 What are their capital and operating costs? C4 How much overlap in staffing can there be in reality between operating the accelerator and performing the radiochemistry? Appendix 2 Page 59 of 180

144 D. Your PET/CT scanning system: column #1: my questions column #2: your answers for the column #3: your answers for the column #4: your additional comments D1 Which systems does your company offer? clinical application modality research modality (optional) D2 Which type of scintillator is used? Please comment on its value specific to your scanner(s). D3 What detector arrangement is provided? D4 Are both the 2-D and the 3-D modes available D5 D6 What is the camera count rate capacity equivalent with patient throughput? Will it offer time-of-flight (TOF) reconstruction D7 What is the construction of the PET and CT arrays, ie. distance between them? D8 What algorithm is used to reconstruct and combine images from the raw data? D9 Is respiratory gating supplied, to avoid mismatching between PET and CT images? D10 Do the image-file formats comply to the Dicom standard? D11 How are the multiple images displayed? D12 What is a typical scanning rate, in terms of patients per hour? D13 What make and model of CT is available with the PET system? D14 What multidetector CT options are available (eg. 4/16/32/64 slice) D15 What are the capital and operating costs? E. General: column #1: my questions column #2: your answers for the column #3: your answers for the column #4: your additional comments E1 E2 E3 What is your upgrade path for hard- and software? Which facilities can be approached to showcase your PET equipment? Please provide contact details of the listed facilities. Which research developments are around the corner for inclusion in your line of PET products? Please indicate likely estimated release date. clinical application modality research modality (optional) 60 of 180

145 C: Paper written about the project to inform stakeholders National Positron Emission Tomography Scanning Project in Context The purpose of this project is to write a business case on the introduction of Positron Emission Tomography (PET) scanning. A business case is a comprehensive document that provides all the necessary detailed information and analysis required for informed decision-making about a service planning initiative or a new health intervention, and for planning the successful implementation of a project. Background The Service Planning and New Health Intervention Assessment framework (SPNIA framework) aims to help District Health Boards (DHBs) and the Ministry of Health with health service changes that require a collective decision. The National Service and Technology Review Advisory Committee (NSTR) is part of the SPNIA framework. NSTR analyses and evaluates proposals for change and business cases that have a national impact. It makes recommendations to the Ministry of Health Deputy Director General and District Health Board Chief Executive Officer Group (DDG-CEO Group) on national service matters and new health interventions that have a national impact. The PET Scanning proposal for change was developed jointly by the Ministry of Health and DHBs. After considering the PET Scanning proposal for change, NSTR agreed at its July 2006 meeting to include PET Scanning on its work programme. The development of a business case required a lead DHB. Proposals from several DHBs were considered by District Health Boards New Zealand (DHBNZ) with the recommendation that Auckland District Health take the lead role with support and advice from other DHBs. Waikato, Hawkes Bay, Capital Coast, and Canterbury DHBs are involved as a reference group to review the draft PET Scanning business case and to provide advice as necessary on any issues arising during the development of the business case. DHB General Managers Funding and Planning were also informed and invited to advise DHBNZ if they wished to participate in the business case development. ADHB s proposal to be the lead DHB included Oncology Radiation Specialist Graham Stevens as Project Chair, contracting with Project Portfolio Ltd to supply project manager expertise of Sam Denny and clinical expertise of Dr David Mauger. PET Scanning Technology PET scanning is expensive and complex technology. The basic components are: a cyclotron to produce a range of suitable positron-emitting isotopes mainly 18 F, though other isotopes are being produced for specific purposes a radiochemistry facility ( hot cell ) to produce the required radio-pharmaceutical; 18 F- deoxyglucose (FDG) is the most common tracer used clinically, but others will be used increasingly in the future a transport system to enable rapid transfer of short-lived isotopes from the cyclotron to the PET scanner (the half-life of 18 F is 110 minutes). Issues to consider include: appropriate location of PET scanners sufficient numbers of trained personnel for each of the above steps. PET scanning technology is used in both the clinical and research setting and to a limited degree in industry. Cyclotrons have a range of specifications and those capable of generating a range of Appendix 2 Page 61 of 180

146 isotopes are not only a useful source of shorter lived isotopes for PET scanning but can also be used in other areas of biomedical and physics research by universities. Key messages for the PET Scanning Business Case Project Cancer Control is a priority for New Zealand. It is one of the thirteen priority population health objectives in the New Zealand Health Strategy. PET scanning is now a routine component of cancer management and treatment in most developed countries. The new SPNIA framework and NSTR provide the appropriate forum to assess national service matters and new health interventions that have a national impact. ADHB is the lead DHB for the development of a national business case for the introduction of PET scanning technology. The PET scanning business case is to explore all options including partnerships with other parties. Options for partnership will be explored at a high level only with no preferred partner or supplier arrangements implied or intended at this business case stage. The business case is to be completed and provided to NSTR by the end of February Project Inclusions NSTR agreed to the following matters being addressed as part of the PET Scanning business case development. 1. Requisition a specific local Health Technology Assessment to answer questions on implementation options eg No. 4 below 2. Investigate possibilities for public, private and /or university joint ventures 3. Assume PET scanning technology will be utilised for research and/or industry 4. Consider full ring PET and gamma camera PET 5. One cyclotron and x number of scanners in NZ and use of short half life isotopes allowing for greater accuracy and increased detection. Stakeholders Stakeholders include the Ministry of Health, DHBNZ, DHBs, consumer representative organisations, universities, possibly industry, and private radiology providers. A database of stakeholders / contacts will be commenced. The project team will make its best endeavours, within resource and timeframe constraints of the project, to: Identify and make contact with potential users of PET technology. Make initial contact with manufacturers/agents of PET technology-research, industry and clinical. Make initial contact with possible partners in PET technology to establish possibilities of partnership, consortium arrangements. Describe at the level of detail possible financial arrangements with partners while recognising that this will be limited by commercial sensitivity and the explicit absence of a mandate for the project team to enter any relationship with potential partners. Process and indicative timeframe following presentation of business case to NSTR. NSTR considers the PET Scanning business case and makes recommendations to the DDG-CEO Group in March DDG-CEO Group and national DHB CEOs consider NSTR s recommendations in March April of 180

147 Subject to national DHB CEOs decision (and Ministerial approval, if required), implementation process to supply PET scanners developed in May June For further information Graham Stevens Project Chair Sam Denny Project Manager Appendix 2 Page 63 of 180

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