Download Health Technology Board for Scotland

March 2003
Health Technology Board for Scotland
Positron emission tomography (PET) imaging in cancer management
Authors: Bradbury I, Bonell E, Boynton J, Cummins E, Facey K, Iqbal K, Laking G
McDonald C, Parpia T, Sharp P, Single A, Walker A.
With significant contributions from the Topic Specific Group (see Appendix 1)
This report should be referenced as:
Bradbury I, Bonell E, Boynton J, Cummins E, Facey K, Iqbal K, Laking G,McDonald C, Parpia T, Sharp P, Single
A and Walker A. 2002.
Positron emission tomography (PET) imaging in cancer management.
Health Technology Assessment Report 2.
Glasgow: Health Technology Board for Scotland
ISBN 1-903961-31-9
© Copyright Health Technology Board for Scotland, 2002
All rights reserved. This material may be freely reproduced for educational and not for profit puposes.
No reproduction by or for commercial organisations is permitted without the express written permission
of the Health Technology Board for Scotland.
CONTENTS
EXECUTIVE SUMMARY ............................................................................................I
Background to this assessment ...................................................................................I
Aims of this assessment ............................................................................................ II
Health Technology Assessment (HTA) evidence ..................................................... II
Clinical effectiveness - NSCLC ............................................................................... III
Economic evaluation - NSCLC ................................................................................ V
Clinical effectiveness – Lymphoma...................................................................... VIII
Economic evaluation – Restaging Hodgkin’s disease .............................................IX
Patient issues .........................................................................................................XI
Organisational issues and budget impact ............................................................... XII
Discussion
...................................................................................................... XIII
Recommendations to NHSScotland ...................................................................... XIV
1
INTRODUCTION AND OBJECTIVES ...........................................................1-1
1.1
Introduction ....................................................................................1-1
1.1.1
Previous NHS HTA research on PET imaging ..............................1-1
1.1.2
The Scottish HTA on PET imaging ...............................................1-1
1.2
Objectives and scope of this HTA ..................................................1-4
2
BACKGROUND ...............................................................................................2-1
2.1
Description of health problem in Scotland .....................................2-1
2.1.1
Cancer in Scotland ..........................................................................2-1
2.1.2
Lung cancer in Scotland .................................................................2-2
2.1.3
Lymphoma in Scotland ..................................................................2-3
2.2
Perspectives ....................................................................................2-4
2.2.1
Organisation of NHSScotland ........................................................2-4
2.2.2
Organisation of cancer services in Scotland ...................................2-5
2.3
The role of PET in oncology ..........................................................2-5
2.4
Health Technology Assessments of PET imaging .........................2-8
2.4.1
Danish HTA (DACEHTA, 2001) ...................................................2-9
2.4.1.1
Lung cancer ....................................................................................2-9
2.4.1.2
Solitary pulmonary nodules............................................................2-9
2.4.1.3
Colorectal cancer ..........................................................................2-10
2.4.1.4
Head and neck cancer ...................................................................2-10
2.4.1.5
Malignant melanoma ....................................................................2-10
2.4.1.6
Breast cancer ................................................................................2-11
2.4.1.7
Other cancers ................................................................................2-11
2.4.1.8
Alzheimer’s disease ......................................................................2-11
2.4.1.9
Epilepsy ........................................................................................2-11
2.4.1.10 Ischaemic heart disease ................................................................2-11
2.5
Description of the technology ......................................................2-12
2.5.1
Radionuclide imaging...................................................................2-12
2.5.2
PET radiopharmaceuticals ............................................................2-15
2.5.2.1
New tracers ...................................................................................2-16
2.5.3
Instrumentation for PET ...............................................................2-16
2.5.4
Image interpretation .....................................................................2-18
2.5.4.1
Quantitation ..................................................................................2-19
2.5.5
Alternatives to PET ......................................................................2-19
2.5.5.1
Gamma cameras ...........................................................................2-19
2.5.5.2
PET/CT .........................................................................................2-20
3
SOURCES OF EVIDENCE AND DEVELOPMENT OF THE
ASSESSMENT QUESTIONS ..........................................................................3-1
3.1
Sources of evidence ........................................................................3-1
3.2
Developing the assessment questions.............................................3-2
4
CLINICAL EFFECTIVENESS – NSCLC ........................................................4-1
4.1
Literature search .............................................................................4-2
4.1.1
Search strategy ...............................................................................4-2
4.1.2
Exclusion criteria ............................................................................4-2
4.2
NSCLC diagnosis in Scotland ........................................................4-3
4.2.1
NSCLC staging...............................................................................4-3
4.2.2
NSCLC diagnostic work-up in Scotland ........................................4-6
4.3
Methodology for clinical effectiveness analyses ..........................4-10
4.3.1
Evaluation of sensitivity and specificity ......................................4-10
4.3.2
Meta-analysis ................................................................................4-11
4.4
Critical appraisal of published literature ......................................4-11
4.4.1
Background ..................................................................................4-11
4.4.2
Systematic reviews .......................................................................4-12
4.4.3
Mediastinal staging.......................................................................4-13
4.4.4
Detection of distant metastases ....................................................4-14
4.4.4.1
Specific sites of metastasis ...........................................................4-15
4.4.5
Changes in patient management ...................................................4-15
4.4.5.1
Surveys of referring physicians ....................................................4-16
4.4.5.2
Prognostic significance of SUR ...................................................4-17
4.4.6
Randomised clinical trials ............................................................4-17
4.4.7
Limitations of the evidence ..........................................................4-19
4.5
Meta-analyses ...............................................................................4-19
4.5.1
Study exclusion criteria ................................................................4-20
4.5.2
FDG-PET sensitivity in CT-negative patients ..............................4-20
4.5.2.1
Sensitivity analysis .......................................................................4-21
4.5.3
PET sensitivity in CT-positive patients ........................................4-22
4.5.3.1
Sensitivity analysis .......................................................................4-23
4.5.4
CT sensitivity and specificity .......................................................4-23
4.5.4.1
Sensitivity analysis .......................................................................4-24
4.5.5
Meta-analysis conclusions ............................................................4-24
4.6
Assessment of safety in clinical practice ......................................4-25
4.7
Conclusions ..................................................................................4-25
5
ECONOMIC EVALUATION - NSCLC ...........................................................5-1
5.1
Literature search .............................................................................5-2
5.1.1
Search strategy ...............................................................................5-2
5.1.2
Criteria for inclusion and exclusion of studies ...............................5-2
5.1.3
Data extraction ...............................................................................5-2
5.2
Economic methods .........................................................................5-2
5.2.1
Background ....................................................................................5-2
5.2.2
Objectives of the economic evaluation ..........................................5-3
5.2.3
The potential for use of FDG-PET in NHSScotland ......................5-3
5.2.4
Model structure...............................................................................5-3
5.2.5
Identification and measurement of the potential benefits and
costs of FDG-PET ..........................................................................5-6
5.2.6
Constructing the economic model ..................................................5-8
5.2.7
Methods of analysis ........................................................................5-8
5.2.7.1
Delays in diagnosis and treatment ..................................................5-8
5.2.8
Perspective and horizon..................................................................5-8
5.2.9
Model inputs ...................................................................................5-9
5.2.9.1
Epidemiology ...............................................................................5-10
5.2.9.2
Quality of life ...............................................................................5-11
5.2.9.3
Resource use .................................................................................5-12
5.2.9.3.1
FDG-PET scan ..................................................................5-12
5.2.9.3.2
Mediastinoscopy................................................................5-12
5.2.9.3.3
Surgery ..............................................................................5-13
5.2.9.3.4
Non-surgical treatment (palliative treatment for
advanced disease) ..............................................................5-14
5.2.9.3.5
Follow up after surgical treatment and palliative
treatment ............................................................................5-15
5.2.10
Assumptions .................................................................................5-15
5.2.10.1 Quality of life (QOL) loss from operations ..................................5-15
5.2.10.2 Strategies for testing and treatment are followed .........................5-15
5.2.11
Discounting costs and benefits occurring in future years .............5-15
5.3
Results ..........................................................................................5-16
5.4
Diagnosis based on PET only .......................................................5-20
5.5
Model testing and savings in surgery ...........................................5-21
5.6
Sensitivity analyses ......................................................................5-22
5.6.1
Accuracy of PET scanning ...........................................................5-23
5.6.2
Increased surgical referral to non-surgical treatment ...................5-24
5.6.3
Reduced surgical morbidity..........................................................5-25
5.6.4
Increased costs of surgery ............................................................5-25
5.6.5
Conclusions of sensitivity analyses ..............................................5-26
5.7
Discussion and conclusions of economic evaluation of NSCLC .5-27
6
CLINICAL EFFECTIVENESS – LYMPHOMA ..............................................6-1
6.1
Introduction ....................................................................................6-2
6.1.1
Literature search strategy ...............................................................6-2
6.1.2
Exclusion criteria ............................................................................6-3
6.2
Lymphoma treatment in Scotland ..................................................6-3
6.3
Possible roles for FDG-PET imaging .............................................6-4
6.3.1
Initial staging ..................................................................................6-4
6.3.2
FDG-PET imaging during therapy .................................................6-4
6.3.3
FDG-PET scanning for detection of recurrence .............................6-4
6.3.4
FDG-PET in the post-treatment assessment of lymphoma ............6-4
6.4
Accuracy of FDG-PET for post-therapy restaging of patients
who are CT-positive - studies .........................................................6-5
6.5
Accuracy of FDG-PET for post-therapy restaging in patients
who are CT-positive - analysis .......................................................6-7
6.6
Accuracy of FDG-PET in post-therapy restaging (no CT) studies .............................................................................................6-7
6.7
Accuracy of FDG-PET for post-therapy restaging (no CT) analysis ...........................................................................................6-9
6.8
Accuracy of CT scanning for post-therapy re-staging .................6-10
6.9
Conclusions ..................................................................................6-11
7
ECONOMIC EVALUATION – RESTAGING HODGKIN’S DISEASE ........7-1
7.1
Literature search .............................................................................7-2
7.1.1
Search strategy ...............................................................................7-2
7.1.2
Criteria for inclusion and exclusion of studies ...............................7-2
7.1.3
Data extraction ...............................................................................7-2
7.2
Economic methods .........................................................................7-3
7.2.1
Restriction to Hodgkin’s disease (HD) ..........................................7-3
7.2.2
Objectives of the economic evaluation ..........................................7-3
7.2.3
The potential for use of PET in restaging HD in NHSScotland .....7-3
7.2.4
Model structure...............................................................................7-3
7.2.5
Markov treatment model ................................................................7-5
7.2.5.1
Narrative description of the model and assumptions .....................7-5
7.2.6
Identification and measurement of the potential benefits and
costs of PET ...................................................................................7-7
7.2.7
Assumptions ...................................................................................7-7
7.2.7.1
Relapse detection ............................................................................7-7
7.2.7.2
Long-term toxicity ..........................................................................7-7
7.2.7.3
No QOL loss for procedures ..........................................................7-7
7.2.7.4
Strategies for testing and treatment are followed ...........................7-7
7.2.8
Methods of analysis ........................................................................7-8
7.2.9
Perspective and horizon..................................................................7-8
7.2.10
Discounting costs and benefits occurring in future years ...............7-8
7.2.11
Model inputs ...................................................................................7-8
7.2.11.1 Epidemiology ...............................................................................7-11
7.2.11.2 Quality of life ...............................................................................7-11
7.2.11.3 Resource use .................................................................................7-12
7.2.11.3.1
CT scan ..............................................................................7-12
7.2.11.3.2
Surveillance .......................................................................7-12
7.2.11.3.3
Radiotherapy (RT) .............................................................7-13
7.2.11.3.4
IVE chemotherapy.............................................................7-14
7.2.11.3.5
Autologous peripheral blood stem cell transplant
(PBSCT) ............................................................................7-15
7.2.11.3.6
Long-term toxicities ..........................................................7-16
7.3
Results ..........................................................................................7-16
7.3.1
Uncertainties .................................................................................7-16
7.3.2
Results – Life-years analysis ........................................................7-18
7.3.3
Discussion of results .....................................................................7-20
7.4
Further sensitivity analysis ...........................................................7-20
7.4.1
Lower accuracy from FDG-PET ..................................................7-20
7.4.2
Incorporation of quality weights ..................................................7-20
7.4.3
Variations in discount rate used for clinical benefits ...................7-21
7.4.3.1
Summary ......................................................................................7-23
7.4.4
Discussion ....................................................................................7-23
7.4.4.1
Relationship to previous work ......................................................7-24
7.4.5
Conclusions ..................................................................................7-24
8
PATIENT ISSUES.............................................................................................8-1
8.1
Background ....................................................................................8-2
8.2
The scanning process for the patient ..............................................8-2
8.3
Communication with patients .........................................................8-3
8.3.1
Professional interactions .................................................................8-3
8.3.2
8.4
8.5
8.5.1
8.6
9
Patient information .........................................................................8-4
Consultation questions and responses ............................................8-5
Focus group ....................................................................................8-6
Results ............................................................................................8-6
Conclusions ....................................................................................8-9
ORGANISATIONAL ISSUES ..........................................................................9-1
9.1
Organisation of PET facilities in the UK .......................................9-2
9.1.1
Current facilities .............................................................................9-2
9.1.2
Planning of new facilities ...............................................................9-2
9.2
The PET centre ...............................................................................9-3
9.3
Site planning (layout, regulations) .................................................9-5
9.4
Radiopharmaceutical supply ..........................................................9-6
9.4.1
Radiopharmaceutical licensing and production..............................9-6
9.4.2
Radiopharmaceutical transportation ...............................................9-7
9.4.3
Clinical administration of radiopharmaceuticals ............................9-8
9.5
Staffing ...........................................................................................9-8
9.5.1
Cyclotron support .........................................................................9-10
9.6
Cost per scan and budget impact ..................................................9-12
9.6.1
Costings for options 1, 2 & 3 (fixed facilities) .............................9-12
9.6.1.1
Staffing levels ...............................................................................9-13
9.6.1.2
Patient throughput ........................................................................9-14
9.6.1.3
Operating costs .............................................................................9-14
9.6.1.4
Supply of FDG .............................................................................9-15
9.6.1.5
Training ........................................................................................9-16
9.6.1.6
Laboratory equipment ..................................................................9-16
9.6.1.7
Cost of a PET scanner ..................................................................9-16
9.6.1.8
Building costs ...............................................................................9-16
9.6.1.9
Location of Scottish facility .........................................................9-17
9.6.1.10 Costs not included ........................................................................9-17
9.6.1.11 Summary of annual running costs ................................................9-17
9.6.1.12 Cost per scan ................................................................................9-19
9.6.1.13 Sensitivity analysis .......................................................................9-20
9.6.2
Cost per scan option 4 (Mobile facility) .......................................9-20
9.7
Budget impact ...............................................................................9-23
9.7.1
Annual running cost .....................................................................9-23
9.7.2
Capital costs .................................................................................9-23
9.7.3
Annual cash flow projections .......................................................9-24
9.8
Budget impact discussion .............................................................9-25
9.9
Organisational issues conclusions ................................................9-26
10 DISCUSSION ..................................................................................................10-1
10.1
Scope of the HTA .........................................................................10-1
10.1.1
Clinical effectiveness - NSCLC (section 4) .................................10-1
10.1.2
Economic evaluation NSCLC (Section 5) ....................................10-2
10.1.3
Clinical effectiveness – Lymphoma (Section 6) ..........................10-3
10.1.4
Economic evaluation – Hodgkin’s disease (Section 7) ................10-3
10.1.5
Clinical effectiveness – Other clinical applications (sections
2.3 and 2.4) ...................................................................................10-4
10.1.5.1 Cancer ...........................................................................................10-4
10.1.5.2 Cardiology, neurology and psychiatry .........................................10-5
10.1.6
10.1.7
10.1.8
10.2
10.2.1
10.2.2
10.2.3
10.3
10.4
10.4.1
10.4.2
10.4.3
10.4.4
10.4.4.1
10.4.4.2
10.5
10.6
Safety (Section 4.6) ......................................................................10-5
Patient issues (Section 8) .............................................................10-5
Organisational issues and costings (Section 9) ............................10-5
Assumptions, limitations and uncertainties ..................................10-7
Assumptions .................................................................................10-7
Limitations....................................................................................10-7
Uncertainties .................................................................................10-8
Future developments ....................................................................10-9
Research .......................................................................................10-9
Exploiting the superior accuracy of FDG-PET scanning ...........10-10
Exploiting the imaging of function ............................................10-11
Facilitating research ...................................................................10-11
Approximate scan numbers in Scotland .....................................10-11
Routine clinical use ....................................................................10-11
Health services research .............................................................10-11
Summary and conclusions ..........................................................10-13
Recommendations to NHSScotland ...........................................10-15
11
ACKNOWLEDGEMENTS .............................................................................11-1
12
REFERENCES ..................................................................................................... 1
LIST OF TABLES
Table 1-1
Table 2-1
Table 3-1
Table 3-2
Table 4-1
Table 4-2
Table 5-1
Table 5-2
Table 5-3
Table 5-4
Table 5-5
Table 5-6
Table 5-7
Table 5-8
Table 5-9
Table 5-10
Table 5-11
Table 5-12
Table 6-1
Table 6-2
Table 6-3
Table 6-4
Table 6-5
Table 6-6
Table 7-1
Table 7-2
Table 7-3
Table 7-4
Table 7-5
Table 7-6
Table 7-7
Table 7-8
Table 7-9
Table 7-10
Table 7-11
Table 7-12
Table 7-13
Table 7-14
Table 7-15
Hierarchy of diagnostic efficacy .........................................................1-4
Medicare reimbursement of PET in the US ........................................2-6
Results of clinical effectiveness and economic evaluation scoping
literature searches (number of studies by cancer and functionality) ...3-3
Number of economic evaluation papers suitable for this HTA ...........3-4
Guidance on surgical judgement .........................................................4-3
Diagnostic testing ..............................................................................4-10
Comparison of estimates used in NSCLC economic models ..............5-7
Inputs to the HTBS economic model: base case .................................5-9
Distribution of lung cancer ................................................................5-10
Distribution of candidates for PET....................................................5-11
Utilities assigned: base case ..............................................................5-12
Costs and benefits for CT-positive: base case ...................................5-16
Costs and benefits for CT-negative: base case ..................................5-17
Strategies ranked by cost for CT-positive .........................................5-18
Strategies ranked by cost for CT-negative ........................................5-18
Sensitivity analyses: CT-positive ......................................................5-22
Sensitivity analyses results: CT-negative ..........................................5-23
Sensitivity analyses: reduced accuracy of PET .................................5-24
Study characteristics: FDG-PET accuracy in assessment of
residual masses ....................................................................................6-6
Results: FDG-PET accuracy in assessment of residual masses ..........6-7
Study characteristics: PET accuracy post therapy...............................6-8
Results: PET accuracy post therapy ....................................................6-9
Study characteristics: CT accuracy post therapy...............................6-10
Results: CT accuracy post therapy ....................................................6-10
Inputs to the HTBS economic model: base case and distributions .....7-9
Cost inputs to the model: base case ...................................................7-10
Post ABVD chemotherapy ................................................................7-13
Post radiotherapy/salvage chemotherapy ..........................................7-13
Post autologous peripheral blood stem cell transplant (PBSCT) ......7-13
Summary costs for consolidation radiotherapy .................................7-13
Model inputs - sensitivity distributions .............................................7-17
Point estimates of life years saved and total costs for female, 20
years old at end of induction therapy ................................................7-18
Point estimates of life years saved and total costs for male, 20
years old at end of induction therapy ................................................7-18
Point estimates of life years saved and total costs for female, 40
years old at end of induction therapy ................................................7-19
Point estimates of life years saved and total costs for male, 40
years old at end of induction therapy ................................................7-19
Point estimates of life years saved and total costs for female, 60
years old at end of induction therapy ................................................7-19
Point estimates of life years saved and total costs for male, 60
years old at end of induction therapy ................................................7-19
Estimated utilities in a 20-year-old woman.......................................7-21
QALY analysis for 20-year-old woman ............................................7-21
Table 7-16
Table 7-17
Table 7-18
Table 7-19
Table 7-20
Table 7-21
Table 9-1
Table 9-2
Table 9-3
Table 9-4
Table 9-5
Table 9-6
Table 9-7
Table 9-8
Table 9-9
Table 9-10
Point estimates of life years saved and total costs for female, 20
years old, 6% discount rates on benefit .............................................7-21
Point estimates of life years saved and total costs for male, 20
years old, 6% discount rates on benefit .............................................7-22
Point estimates of life years saved and total costs for female, 40
years old, 6% discount rates on benefit .............................................7-22
Point estimates of life years saved and total costs for male, 40
years old, 6% discount rates on benefit .............................................7-22
Point estimates of life years saved and total costs for female, 60
years old, 6% discount rates on benefit .............................................7-22
Point estimates of life years saved and total costs for male, 60
years old, 6% discount rates on benefit .............................................7-23
Cost per scan: assumptions ...............................................................9-13
Summary annual running costs .........................................................9-18
Cost per scan .....................................................................................9-19
Mobile PET model: assumptions ......................................................9-21
Mobile PET model: summary costs ..................................................9-22
Mobile PET model: cost per scan .....................................................9-22
Annual running costs (£ million) ......................................................9-23
Capital costs (£ million) ....................................................................9-23
Accumulative cash flow spending: options 1, 2 and 3 (£ million) ....9-24
Accumulative cash flow spending: option 4 (£ million) ...................9-24
LIST OF FIGURES
Figure 1-1
Figure 2-1
Figure 2-2
Figure 2-3
Figure 4-1
Figure 4-2
Figure 4-3
Figure 4-4
Figure 4-5
Figure 4-6
Figure 5-1
Figure 7-1
Figure 7-2
Figure 7-3
Figure 7-4
Figure 7-5
Figure 7-6
Figure 7-7
Figure 7-8
Figure 7-9
Figure 7-10
Health Technology Assessment (HTA) process
1-3
Outline of a PET imager
2-14
Whole body image taken using FDG
2-16
A dedicated PET imager
2-17
Lung cancer: T staging
4-4
Lung cancer: N staging
4-5
Diagnostic pathway in Scotland
4-9
False positive versus true positive and fitted SROC curve, for
CT-negative patients
4-21
False positive versus true positive and fitted SROC curve, for
CT-positive patients
4-22
False positive versus true positive and fitted SROC curve, for all
CT data
4-24
NSCLC diagnostic pathways after CT
5-5
Management pathways after induction chemotherapy in HD
7-4
Structure of the Markov treatment model
7-6
Cost effectiveness acceptability curves (CEACs) for female, 20
years. Open circles - strategy 4 (PET after positive CT), solid
circles - strategy 5 (PET only), both relative to strategy 3 (CT
only)
7-26
Cost effectiveness acceptability curves (CEACs) for male, 20
years. Open circles - strategy 4 (PET after positive CT), solid
circles - strategy 5 (PET only), both relative to strategy 3 (CT
only)
7-27
Cost effectiveness acceptability curves (CEACs) for female, 40
years. Open circles - strategy 4 (PET after positive CT), solid
circles - strategy 5 (PET only), both relative to strategy 3 (CT
only)
7-28
Cost effectiveness acceptability curves (CEACs) for male, 40
years. Open circles - strategy 4 (PET after positive CT), solid
circles - strategy 5 (PET only), both relative to strategy 3 (CT
only)
7-29
Cost effectiveness acceptability curves (CEACs) for female, 60
years. Open circles - strategy 4 (PET after positive CT), solid
circles - strategy 5 (PET only), both relative to strategy 3 (CT
only)
7-30
Cost effectiveness acceptability curves (CEACs) for male, 60
years. Open circles - strategy 4 (PET after positive CT), solid
circles - strategy 5 (PET only), both relative to strategy 3 (CT
only)
7-31
Cost effectiveness acceptability curves (CEACs) for female, 20
years. Strategy 5 only (PET only), relative to strategy 3 (CT only),
PET specificity distributed as Uniform on (0.6,0.9)
7-32
Cost effectiveness acceptability curves (CEACs) for male, 20
years. Strategy 5 only (PET only), relative to strategy 3 (CT only),
PET specificity distributed as Uniform on (0.6,0.9)
7-33
Figure 7-11
Figure 7-12
Figure 7-13
Figure 7-14
Figure 7-15
Figure 7-16
Figure 7-17
Figure 9-1
Figure 9-2
Figure 9-3
Figure 9-4
Cost effectiveness acceptability curves (CEACs) based on QALYs
for female, 20 years. Open circles - strategy 4 (PET after positive
CT), solid circles - strategy 5 (PET only) both relative to strategy
3 7-34
Cost effectiveness acceptability curves for female, 20 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
7-35
Cost effectiveness acceptability curves for male, 20 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
7-36
Cost effectiveness acceptability curves for female, 40 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
7-37
Cost effectiveness acceptability curves for male, 40 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
7-38
Cost effectiveness acceptability curves for female, 60 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
7-39
Cost effectiveness acceptability Curves for male, 60 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
7-40
A medical cyclotron
9-3
Automated radiochemistry synthesis unit
9-4
Site plan of the John Mallard Scottish Pet Centre, Aberdeen
9-5
St Thomas’ PET facility
9-9
EXECUTIVE SUMMARY
Background to this assessment
Cancer in Scotland
1. More than 26,000 people in Scotland are diagnosed with cancer every year and
cancer is now the leading cause of premature death.
2. Although survival rates in many cancers have improved, continued progress
requires greater awareness, prevention, earlier diagnosis and better, faster
treatment. This will be facilitated by the new organisation of cancer services that
has been established in Scotland with expert multidisciplinary involvement in
Managed Clinical Networks (MCN), Regional Cancer Advisory Groups and an
overarching national advisory group, the Scottish Cancer Group.
3. The most common site of disease is the lung, with approximately 4,600 patients
diagnosed each year. These are predominately non-small cell lung cancers
(NSCLC) (75%). The treatment of choice in NSCLC is surgical resection, but
only 15% of patients will have early disease suitable for potentially curative
surgery. The remaining 85% of patients will be potential candidates for
chemotherapy and/or radiotherapy.
4. Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) together account
for approximately 4% of incident cancers in Scotland, with 130 incident cases of
HD and 850 of NHL per year. In Scotland, the five-year survival from HD is
approximately 73% and that from NHL is approximately 45%. While NHL most
commonly affects older people, HD has a bimodal age distribution with an initial
peak at between 15 and 35 years. For HD, many of those affected are young
people and a large proportion will die not of lymphoma, but from the toxicity
associated with therapy. Therefore, any technology that reduces these effects is
likely to have a major positive impact.
PET scanning in oncology
1. Positron emission tomography (PET) is a non-invasive imaging procedure used
for measuring the concentrations of positron-emitting radioisotopes within tissue
in benign and malignant disease. This requires injection of a radiolabelled tracer.
In cancer, the most common radiolabelled tracer is FDG, which is glucose labelled
with 18Fluorine (2- [18F]-fluoro-2-deoxy-D-glucose).
2. Three-dimensional PET imaging provides information about the level of
biological activity in a lesion and can detect tumours due to their high rate of
glucose utilisation. This differs from other forms of imaging such as magnetic
resonance imaging (MRI), computed tomography (CT) or ultrasound techniques,
which mainly show structural (anatomical) information.
3. Malignancies can cause abnormalities of blood flow or metabolism before
anatomical changes are apparent. Therefore FDG-PET allows differentiation
between malignant and benign abnormalities. This can enable early diagnosis of
cancer and improved staging, before metastatic spread occurs.
I
Aims of this assessment
1. This Health Technology Assessment (HTA) set out with two principal objectives:


To determine the role of PET imaging in cancer management: evaluating the
clinical and cost effectiveness in terms of impact on patient mortality and
morbidity.
If PET is found to be clinically and cost effective, to consider the best
configuration of PET facilities (and cyclotrons) to serve the Scottish population.
Health Technology Assessment (HTA) evidence
1. The HTA used systematic literature searching to identify evidence published in
the scientific literature. It also used evidence submitted by professional groups,
patient groups, manufacturers, other interested parties and experts.
2. The HTA considers four components: clinical effectiveness, cost effectiveness,
patient issues and organisational issues (including budget impact).
3. To determine the value of FDG-PET, diagnostic accuracy is not sufficient and
evidence of change in patient outcomes, or a change in patient management, was
sought.
4. A review of the literature on the clinical effectiveness and economic evaluation of
FDG-PET scanning in oncology was carried out, together with an appraisal of the
questions most relevant to Scotland. The largest body of evidence is available for
the role of FDG-PET in NSCLC and this is the only indication for which there is
data on patient outcomes from randomised, controlled trials.
5. The availability of the evidence and the importance of lung cancer in Scotland,
with the largest number of deaths of any cancer, resulted in the decision initially to
focus this report on the value of FDG-PET in the staging of patients with
potentially operable NSCLC.
6. The value of FDG-PET in improving outcomes is influenced by the potential for
successful therapy. Consequently, the use of FDG-PET in lymphoma was also
assessed, because it was anticipated that a greater benefit on patient outcomes was
possible and a clear patient pathway could be constructed.
Analysis
Number of
studies
Specificity
(95% CI)
Sensitivity
(95% CI)
FDG-PET in CT-positives
15
0.76
(0.69-0.82)
0.92
(0.87-0.95)
FDG-PET in CT-negatives
15
0.90
(0.87-0.93)
0.86
(0.79-0.91)
II
Clinical effectiveness - NSCLC
1. Clinical effectiveness was evaluated by updating the summary of the literature on
the diagnostic accuracy of FDG-PET presented by the Danish Centre for
Evaluation and Health Technology Assessment (DACEHTA) in 2001. Databases
and websites were searched for literature published between January and October
2001 on FDG-PET and NSCLC. Papers were excluded from the evaluation if they
were not about NSCLC staging and did not use PET imaging with FDG as the
radiolabelled tracer.
2. The treatment offered to a patient with NSCLC and their prognosis will depend on
the stage of their disease. Patients with no lymph node involvement (N0) or
disease confined to the ipsilateral peribronchial or hilar nodes (N1) may be
candidates for surgery. Spread to the mediastinal nodes (N2, N3) precludes
surgical intervention. The current diagnostic pathway in Scotland utilises CT to
detect enlarged nodes (greater than 1 cm = CT-positive) and mediastinoscopy is
used to confirm the presence or absence of mediastinal lymph node involvement.
3. The accuracy of a diagnostic test is described by the sensitivity (probability that
the test is positive when the patient has the disease) and the specificity (probability
that the test is negative when the patient does not have the disease).
4. Thirty-three (33) papers on the use of FDG-PET in mediastinal staging were
identified. Almost all reported that FDG-PET is more accurate and more sensitive
than CT imaging. However, a number of methodological flaws were evident in the
studies. These included retrospective rather than prospective series, unclear
inclusion criteria and small numbers of patients.
5. Two meta-analyses were performed looking at the accuracy of FDG-PET
scanning in NSCLC; one to estimate the sensitivity and specificity for FDG-PET
in CT-positive nodes and one to estimate the sensitivity and specificity for PET in
CT-negative nodes. The results are shown in the above table.
6. The results demonstrate that PET appears to have substantial value in
discriminating diseased from non-diseased nodes, both for CT-positive and CTnegative patients. The estimated sensitivity and specificity are very similar to
those reported by Dietlein et al. (2000a), despite differences in the analysis
methods and study selection.
7. Nineteen (19) studies provided some data on the usefulness of FDG-PET for the
detection of distant (extra-thoracic) metastases. There is evidence that this may be
a useful tool in supplementing staging in patients believed to be free of distant
metastases. However, these results need to be confirmed in larger randomised
trials.
8. Evidence from the literature suggests that the results of FDG-PET may influence
patient management, with reports of changes in management in 10% to 40% of
patients. However, only two randomised controlled trials (RCT) presented a
randomised comparison of FDG-PET and conventional staging techniques,
evaluating change in clinical management.
III
9. The two RCTs that have been conducted compared the use of FDG-PET in
addition to conventional staging with conventional staging alone. These trials
yielded contradictory results; one suggests that the addition of FDG-PET imaging
produces a cost-effective reduction in the number of ‘futile’ operations whereas
the other shows no difference in the number of operations between the two
groups.
10. The discrepancy in results appears to be largely due to different approaches to the
management of NSCLC taken by surgeons in the two studies, given the results of
FDG-PET imaging. Specifically, surgeons in the first study regarded operations
on patients with N2 disease as ‘futile’ and avoided it. Although FDG-PET
scanning in the second trial detected a similar proportion of N2 disease, surgeons
in this study regarded patients with N2 disease as acceptable candidates for
resection.
11. In terms of safety, no studies reported any important short-term adverse effects as
a result of FDG-PET imaging. There is a risk of secondary cancers developing
posed by the radiation dose used in FDG-PET scanning, but the risk is very low
(less than 1 in 3000 for a person of normal life expectancy) and the radiation dose
is comparable with that associated with CT.
IV
Economic evaluation - NSCLC
1. Economic evaluation is the comparison of the costs and benefits of two or more
courses of action or options. It involves the identification, measurement and
valuation of resources used and benefits as seen from a stated perspective and over
a stated time horizon.
2. This economic evaluation focused on the role of different tests after a CT scan and
the use of FDG-PET in the context of the diagnostic pathway and subsequent
clinical management decisions for patients with NSCLC in Scotland. Only costs
relating to NSCLC are included.
3. The economic issues surrounding the use of FDG-PET in the investigation of
patients with NSCLC relate to the fact that it can detect small but clinically
significant metastases in the lymph nodes and in distant sites in the body.
4. The impact of FDG-PET is analysed by a cost-utility analysis. This sets out the
change in resource use and the number of quality-adjusted life years (QALY).
QALYs estimate the effect on survival and the changes in quality of life stemming
from the introduction of FDG-PET. In this model, QALYs are taken from
published studies.
5. The model assumes that for a cohort of 100 patients:
 all patients have had a chest X-ray, bronchoscopy
 and CT scan;
 all patients have a definite diagnosis of lung cancer and require staging for
decision on management;
 all patients are fit for surgery if indicated;
 30% patients have N2 or N3 disease;
 10% patients have occult metastases only
 detected by PET;
 for N0/N1 disease, 23% have enlarged lymph nodes; and
 for N2/N3 disease, 60% have enlarged lymph nodes.
The following resources are considered in the analysis:
 FDG-PET scan;
 mediastinoscopy;
 surgery (resection of lung tissue);
 follow up after potentially curative surgery;
 treatment of recurrence after potential cure;
 non-surgical treatment for advanced disease; and
 follow up after non-surgical treatment.
V
6. The cost effectiveness of seven different diagnostic and treatment strategies is
evaluated, assuming that all patients are potentially operable and have had a CT
scan. The group of seven strategies are considered separately for CT-positive and
CT-negative patients.
1
Send all patients for surgery without further testing.
2
Send all patients for non-surgical treatment (chemotherapy and/or
radiotherapy) without further testing.
3
Investigate all patients by mediastinoscopy; if negative refer for
surgery, if positive refer for non-surgical treatment (reflecting current
Scottish practice).
4
Investigate all patients by mediastinoscopy; if negative send them for
FDG-PET imaging (negative FDG-PET for surgery, positive FDGPET for non-surgical treatment), if positive refer for non-surgical
treatment.
5
Investigate all patients with FDG-PET; if negative refer for surgery, if
positive refer for non-surgical treatment.
6
Investigate all patients with FDG-PET; if negative refer for
mediastinoscopy (negative for surgery, positive for non-surgical
treatment), if positive refer for non-surgical treatment.
7
Investigate all patients with FDG-PET. If this is negative refer for
surgery. If this is positive and distant metastases are indicated (N0/1
M1) refer for non-surgical treatment, otherwise refer for
mediastinoscopy (negative for surgery, positive for non-surgical
treatment).
The first two options are unrealistic in the clinical setting and are used for model
testing purposes only.
7. The costs and QALYs per patient for CT-positive and CT-negative patients are
ranked by least cost shown in the following tables for the base-case analysis.
Strategies ranked by cost for CT-positive
Total
Total
cost
QALYs
Strategy 3
£191,295
71.86
Strategy 1
£197,247
69.81
Strategy 4
£203,720
66.03
Strategy 6
£205,157
66.16
Strategy 7
£206,098
72.11
Strategy 5
£207,690
66.17
Strategy 2
£209,538
44.45
* Incremental Cost Effectiveness Ratio
Additional
cost
£5,952
£12,425
£13,862
£14,803
£1,592
£3,440
Additional
QALYs
-2.05
-5.83
-5.71
0.25
-5.94
-27.66
ICER*
Dominated by 3
Dominated by 3
Dominated by 3
£58,951
Dominated by 7
Dominated by 7
VI
Strategies ranked by cost for CT-negative
Total
cost
Total
QALYs
Strategy 1
£293,127
189.01
Strategy 3
£304,628
189.63
Strategy 7
£318,544
190.96
Strategy 5
£321,492
181.97
Strategy 6
£336,270
181.39
Strategy 4
£337,116
181.28
Strategy 2
£400,614
95.70
* Incremental Cost Effectiveness Ratio
Additional
cost
£11,501
£13,916
£2,949
£17,727
£18,573
£82,071
Additional
QALYs
ICER*
0.62
1.33
-8.98
-9.57
-9.67
-95.26
£18,589
£10,475
Dominated by 7
Dominated by 7
Dominated by 7
Dominated by 7
8. In the base case, strategies 1, 3 and 7 stand out from the others as potentially cost
effective on grounds of cost, patient benefits or both. The base case suggests that
in CT-positive patients strategy 7 involving FDG-PET scanning may not be cost
effective compared with strategy 3, which is an accurate approximation of the
current Scottish practice. In CT-negative patients, the base case suggests that
moving from current Scottish practice to strategy 7 is cost effective. Strategy 1 (all
for surgery) cannot be ruled out in terms of QALYs. This raises doubts as to
whether the model is correctly valuing costs and utilities associated with
avoidance of futile surgery, as strategy 1 would not be used in clinical practice.
9. Strategies 1, 3 and 7 do not differ markedly in their total patient impact. Small
differences in the total quality of life under alternative strategies magnify their
differences in cost when calculating incremental cost effectiveness ratios (ICERs).
These differences in cost are also not particularly large in the context of treating
cancer. A number of modelling assumptions have been made, and uncertainties
surround a number of parameters. Not all can be formally assessed through
sensitivity analyses. The sensitivity analyses that have been undertaken show the
ICERs to be sensitive to different assumptions, particularly in CT-positive
patients.
10. Regardless of the absolute ICER values, the model results show that moving from
strategy 3 to strategy 7 is more cost effective in CT-negative patients than in CTpositive patients. It also appears that the closer the accuracy of FDG-PET in
detecting distant metastases approaches that of detecting enlarged nodes, the more
likely it is that moving from strategy 3 to strategy 7 will be cost effective. This
particularly applies to CT-positive patients.
11. From this model, it cannot be unambiguously stated which of strategies 1, 3 and 7
is the most cost effective in CT-positive or CT-negative patients. Health services
research in a clinical setting is required to address the data gaps in modelling,
particularly for detection of distant metastases and utilities associated with
avoidance of futile surgery.
VII
Clinical effectiveness – Lymphoma
1. Chemotherapy, alone or in combination with radiotherapy (RT), forms the basis of
treatment for HD and more aggressive forms of NHL.
2. Since both residual disease, after initial treatment, and recurrent disease may be
amenable to curative therapy, the assessment of response to therapy (restaging)
and monitoring for recurrence are important aspects of the management of HD
and NHL.
3. FDG-PET scanning may be useful in the initial staging of disease, re-staging after
therapy, predicting the results of therapy and monitoring for recurrence. Following
discussion with experts, the focus of this assessment is the use of FDG-PET in the
evaluation of response to treatment and, in particular, on the evaluation of residual
masses after induction therapy in patients with HD.
4. Seven published studies using optimal technology were identified and these
addressed the accuracy of FDG-PET in determining whether residual masses
visible on CT represented active disease. Seven further studies addressed the
accuracy of FDG-PET for determining residual masses irrespective of CT results
(i.e. including both those who would be negative on CT and those who would be
positive). The results of meta-analyses of sensitivity and specificity of these two
groups of studies are shown in the following table.
Number of
studies
Specificity
(95% CI)
Sensitivity
(95% CI)
FDG-PET in CT-positive
residual masses
7
0.89
(0.74 – 0.97)
0.80
(0.59 – 0.94)
FDG-PET in post-therapy
assessment
(CT-positive or CT-negative)
7
0.95
(0.90 – 0.99)
0.81
(0.63 – 0.92)
Analysis
5. These results suggest that FDG-PET may be valuable in distinguishing true
residual disease post-therapy. s with all imaging techniques, there are difficulties
in interpretation because of the absence of a ‘gold standard’ and uncertainty of the
appropriate follow-up interval.
6. By way of comparison, a meta-analysis of studies detailing the accuracy of CT
scanning in assessing response to therapy was conducted. The estimated
sensitivity and specificity were 0.75, 95% CI (0.58-0.88) and 0.45, 95% CI (0.270.64) respectively.
7. The majority of reported studies do not distinguish between results in HD and
those in NHL. Therefore, the accuracy data presented for both FDG-PET and CT
are relevant for patients with either form of lymphoma.
VIII
8. The detection and assessment of possible residual disease following first-line
therapy is of considerable importance, because patients with active residual
disease may be candidates for further therapy. The evidence clearly shows that
FDG-PET is substantially more specific and somewhat more sensitive than CT in
the detection of recurrent disease and is effective in discriminating active residual
disease from non-viable tumour.
Economic evaluation – Restaging Hodgkin’s disease
1. Following discussion with experts, the economic modelling was restricted to HD
disease; more HD sufferers are cured by initial therapy and therefore the number
of people at risk of inappropriate therapy who may benefit from PET scanning is
larger. Furthermore, the clinical markers of residual disease are more effective in
NHL.
2. The model has been used to assess the cost effectiveness of FDG-PET as an
adjunct to conventional imaging in deciding the further treatment of HD patients
who have achieved a partial or complete response to induction therapy.
3. FDG-PET can detect small but clinically significant metastases and is more
specific than CT in differentiating active residual disease. It may therefore allow
patients to avoid unnecessary RT and the associated mortality and morbidity.
4. Five strategies have been considered, which allocate patients to either immediate
consolidation RT or to surveillance (six-monthly follow up by physical
examination and CT scanning):
Strategy 1:
All for surveillance
Strategy 2:
All for consolidation
Strategy 3+:
CT-negative for surveillance
CT-positive for consolidation
Srategy 4:
CT-negative for surveillance
CT-positive for FDG-PET
FDG-PET negative for surveillance
FDG-PET positive for consolidation
Strategy 5*:
FDG-PET negative for surveillance
FDG-PET positive for consolidation
+Strategy 3 is the current Scottish practice.
*A CT scan is performed before FDG-PET but the results are not used in allocating
patients to surveillance or consolidation. CT scanning is required in all the strategies
to provide a baseline image for comparison with a follow-up CT image.
IX
5. The life experience of patients after the post-induction assessment is represented
by a Markov treatment model as follows:
 patients are selected for immediate consolidation RT or surveillance based on the
results of CT and FDG-PET imaging;
 patients under surveillance who relapse are assessed for salvage therapy (either
RT or chemotherapy);
 patients who relapse after RT, or are unsuitable for salvage therapy, are given reinduction chemotherapy;
 responders to re-induction undergo high-dose chemotherapy (HDCT) and
autologous stem cell or bone marrow support;
 deaths (possibly due to toxicity) may occur during re-induction or HDCT;
 non-responders to re-induction chemotherapy are treatment failures and receive
palliative therapy; and
 all patients who survive without relapse six or more years after beginning a
remission are assumed to exhibit only population all-cause mortality, modified by
the late toxicity of RT, salvage therapy or HDCT in those patients who received it
(leukaemia, breast cancer, lung cancer and heart disease).
6. The impact of FDG-PET is analysed by a cost-effectiveness analysis that sets out
the changes in resource use and life expectancy resulting from the introduction of
FDG-PET. QALYs are not used in this analysis because of the paucity of reliable
data. Since any advantage offered by FDG-PET is associated with the avoidance
of late toxicities that are both potentially fatal and associated with reduced quality
of life, any realistic QALY-based comparison would be more favourable to FDGPET, so the analysis presented here is conservative.
For both ‘PET-containing’ strategies (strategies 4 and 5), graphs are presented
showing the way in which the probability that the strategy is cost effective relative
to current standard practice changes as the amount of money NHSScotland is
prepared to pay for one additional life year increases.
7. The model was run for six patient types:
 Male: 20, 40 and 60 years; and
 Female: 20, 40 and 60 years.
8. Costs were sought for the following resources:
 CT;
 FDG-PET;
 surveillance;
 radiotherapy;
 re-induction chemotherapy;
 non-curative therapy for patients who fail re-induction chemotherapy;
 autologous peripheral stem cell transplant (PBSCT); and
 lung cancer, breast cancer, leukaemia – as potential long-term toxicities.
9. The results show that the costs are similar for all strategies and so clinical results
(life years gained) play the dominant role in determining cost effectiveness.
X
10. Strategy 5 (FDG-PET) uniformly gives the largest expected number of added life
years and lowest expected cost across all patient types and appears to be cost
effective for essentially all plausible input values, for any value of willingness to
pay greater than £5000 per year of life.
11. FDG-PET following CT (strategy 4) is an inherently poorer strategy than strategy
5 because of the lower overall sensitivity of combining the two procedures.
However, it is still cost effective relative to the ‘non-PET containing’ strategies,
leads to a higher expected value of life years and is a less radical change from
current practice than strategy 5.
12. The use of FDG-PET scanning to assign patients with HD to consolidation or
surveillance, whether used as the sole imaging tool or as an adjunct to CT in CTpositive patients, is cost effective in the base case provided willingness to pay
exceeds £1000, and for almost all input values considered provided willingness to
pay exceeds £5000
13. The model also predicts that 36% of patients will receive unnecessary
consolidation RT when using CT alone. This would be reduced to 4% for patients
assessed using FDG-PET alone, or to 6% for those undergoing FDG-PET after
positive CT scan.
14. Although this model has been restricted to HD, the superior accuracy of FDG-PET
is likely to translate into significant patient benefits in NHL.
Patient issues
1. As the only PET facility in Scotland is used for research purposes, it is not
possible to get patients’ views about undergoing a PET investigation in routine
clinical practice. However, the professionals believe that PET will prove
acceptable to patients as the imager is open and generates very little noise.
2. As a result of this limited experience of PET imaging in Scotland, during the
consultation period for this HTA questions were directed to people with cancer,
their family members or carers. These people were asked about their experiences
of other imaging techniques used in diagnosis and treatment of cancer. Responses
provided evidence that some patients would value the additional information
provided by PET about their condition. The importance of ensuring that the use of
PET does not result in delays in treatment was emphasised.
3. It is important to provide clear information to patients to inform them about all
aspects of the imaging process and the injection of a radiopharmaceutical. Patient
information leaflets should include diagrams and clear explanations of
complicated terms. Other media, such as video and the internet, can also be used.
However, it is essential that the consultant fully discusses all aspects of the
investigation with the patient, including any associated risks or side effects, and
ensures that the information has been understood.
4. The organisation of cancer diagnostic tests will depend on the local situation and
should be co-ordinated to reduce the need for patient travel and minimise nonattendance. The funding of patient travel varies regionally.
XI
5. PET imaging facilities should be designed to make patients feel comfortable and
reduce anxiety by, for example, providing music listening facilities and allowing
an adult friend to attend with the patient.
6. Further research into the needs and preferences of patients in relation to PET
should be undertaken following its introduction to clinical practice in Scotland.
Organisational issues and budget impact
1. The only PET facility currently available in Scotland is based within Aberdeen
Royal Infirmary for research purposes. An application is underway for a PET
facility in Glasgow. In England, there are five PET facilities in routine clinical use
and several others used for research purposes.
2. The optimal location for a PET scanner(s) in Scotland will depend on the size of
the patient population, accessibility and clinical expertise. If it were also to be
used for research purposes, then it would need to be sited near a suitably staffed
research facility.
3. All members of the multidisciplinary team that manage a cancer patient should be
educated about the benefits and issues associated with using PET.
4. Radiopharmaceutical production requires a cyclotron for the production of the
positron-emitting radionuclide, which is then used to label the chosen
pharmaceutical. The facility must comply with all radiopharmaceutical
regulations.
5. The half-life of FDG is 110 minutes and it would be feasible for the PET scanning
facility to be two to four hours by road from the production facility. However,
delivery schedules of the radiopharmaceutical may limit the working hours of the
scanner.
6. The staffing requirements for a radiopharmaceutical production facility include
radiopharmacists, radiochemists, physicists and cyclotron engineers. There is a
shortage of these trained professionals and so training of new staff will be an
essential component of the rollout of PET facilities in Scotland.
7. Four possible options for the implementation of a PET facility in Scotland have
been considered and the costs per scan and budget impact have been investigated.
These options include three different specifications for a fixed PET facility and
one mobile PET unit:
 Option 1 is a fully equipped PET unit (imager, cyclotron, radiochemistry facility)
located within a hospital, purchasing support services from the Trust, but with
dedicated staff.
 Option 2 is a fully equipped PET unit (imager, cyclotron, radiochemistry facility)
integrated with, and drawing staff skill from, other relevant hospital departments.
 Option 3 is a PET imager receiving its radiopharmaceuticals from another source.
 Option 4 is a mobile PET imager receiving its radiopharmaceuticals from another
source.
XII
8. Mobile PET results in higher long-term costs and a higher overall cost per scan.
However, capital costs are substantially lower and the facility could be operational
within a few months.
9. Option 2 has the lowest cost per scan (£677) and the lowest running costs.
However, a substantial capital outlay would be required to set up this facility
(£4.25 million) and there would be a considerable time delay before the service
could be initiated. The annual running costs are projected to be £1.02 million.
10. Option 3 would be quicker to set up than option 2 as no cyclotron or
radiochemical laboratories are needed. The cost per scan varies according to the
source of FDG. This option could be a good way of exploring the viability of PET
scanning with a lower capital outlay (£1.83 million).
11. The cost per scan is dependent on the number of patients scanned per annum. This
is unlikely to reach full capacity during the first year of service as it will take
some time to have a fully trained team of staff, to raise awareness and to promote
the service.
Discussion
1. his report restricts its conclusions to the use of full-ring FDG-PET in cancer
management.
2. Two different approaches to economic modelling have been utilised. In NSCLC,
univariate sensitivity analyses have been used. These indicate that the model is not
entirely robust and the ordering of cost effective strategies alters according to
different cost and benefit assumptions. In particular there is a need to better
determine the utilities associated with avoidance of futile surgery. For HD,
uncertainties have been formally modelled in a multivariate manner using
Bayesian techniques. This has resulted in a model that is robust to all areas of
uncertainty.
3. The results for NSCLC show that FDG-PET may be cost effective in CT-negative
patients, with PET-negatives sent for surgery and PET-positives sent for
mediastinoscopy, but that this result is dependent on model inputs. However,
FDG-PET does not appear to be cost effective in CT-positive patients.
4. In HD, FDG-PET is cost effective when used to assign patients to consolidation or
surveillance for almost all input values considered, provided the willingness to
pay per year of life exceeds £5000. The largest expected value of life years across
all patient types is seen when FDG-PET scanning is used instead of CT.
5. It should be emphasised that PET scanning in clinical practice is still largely at the
developmental stage, and all patients undergoing FDG-PET should be entered into
appropriate clinical and health services research. The collection of data must
comply with all regulations on confidentiality, security and consent. It should
include outcome data in an agreed format (Appendix 27) to fill in gaps in the
evidence base.
XIII
6. It is likely that PET will have more of an impact on patient outcomes in cancers
that have more effective treatment options available and where the alternative
techniques are unsatisfactory. In particular, its use in lung cancer (NSCLC and
solitary pulmonary nodule), recurrent head and neck cancer and malignant
melanoma looks promising and outcome and economic research should be an
early priority in these cancers.
Recommendations to NHSScotland
As a result of this HTA, HTBS has made recommendations to NHSScotland about the
clinical and cost effectiveness of PET imaging for cancer management, these are
presented in full in the Health Technology Assessment Advice on positron emission
tomography (PET) imaging in cancer management (HTBS, 2002a). Listed below is
the summary of recommendations.

It is recommended that a PET imaging facility including a cyclotron, dedicated to
clinical use and specific health services research applications, should be set up in
Scotland to allow Scottish patients and researchers to realise the potential benefits
of FDG-PET imaging in cancer management as rapidly as possible. It should be
linked to an existing cancer centre, with functional links to the existing PET
facility in Aberdeen.

It will take approximately two years to build such a
facility, so interim
solutions for the provision of PET imaging should be considered, particularly for
the re-staging of patients with Hodgkin’s disease. Possible options are the use of
the John Mallard Scottish PET Centre in Aberdeen, other UK facilities, or the use
of a mobile PET facility in a fixed location in Scotland.

All patients who require restaging of Hodgkin’s disease should be sent for a FDGPET scan. Extension to the restaging of all patients with lymphoma should be
investigated by further research.

Appropriate research should be undertaken to inform economic modelling in order
to produce a robust assessment of the value of FDG-PET imaging in the staging of
patients with NSCLC who are CT-negative in the regional lymph nodes.

For other cancers, FDG-PET is likely to add most value where existing
diagnostic/monitoring techniques have poor accuracy and information from PET
imaging can substantially improve prognosis. This should be evaluated through
health services research, taking account of the clinical effectiveness results from
other international HTAs. Research priorities should be agreed with
multidisciplinary expert groups, Regional Cancer Advisory Groups, the Scottish
Cancer Group, the NHS HTA programme and other international research
organisations. All research should be coordinated with the Scottish Cancer
Clinical Trials Network.

All patients undergoing FDG-PET should have outcomes recorded, either through
participation in a national or international trial to confirm and extend the current
applications of FDG-PET imaging or through health services research designed to
allow costs and patient outcomes to be recorded for economic modelling.
XIV
1
INTRODUCTION AND OBJECTIVES
1.1
Introduction
1.1.1
Previous NHS HTA research on PET imaging
In the late 1990s the UK NHS Research and Development programme recognised that
there was still uncertainty regarding the clinical role of positron emission tomography
(PET) imaging and so research was undertaken to review the current and potential
role of PET, in order to establish research priorities for the future (Robert & Milne,
1999).
A literature review to ascertain the level of knowledge regarding the clinical
applications of PET was undertaken. Alongside this, a three-round Delphi study
involving 41 interested individuals was performed to inform the key Health
Technology Assessment (HTA) research questions relating to the use of PET in the
UK.
Four possible PET modalities were considered: full-ring PET scanners operating in
two or three dimensions; partial-ring rotating PET scanners; coincidence imaging with
modified gamma camera technology (section 2.5.5.1); and high-energy collimator
imaging of 511 keV photons with modified gamma camera technology.
The clinical applications advocated for PET were in oncology, cardiology and
neurology. However, Robert & Milne (1999) concluded that there was a paucity of
evidence relating to the cost effectiveness of the various PET modalities in all of these
clinical applications. Although there were many studies of diagnostic accuracy of
PET, many were small and subject to bias. They concluded that evidence is needed to
show that using PET as a diagnostic technique will alter actual patient management.
The Delphi research identified that the key questions of interest related to the
evaluation of the cost effectiveness of full-ring PET to determine staging in lung
cancer, staging and monitoring treatment response in breast cancer, and assessing
myocardial viability when selecting patients for revascularisation surgery.
1.1.2
The Scottish HTA on PET imaging
This HTA from the Health Technology Board for Scotland (HTBS) focuses on the use
of full-ring PET scanners in cancer management in Scotland, with the
radiopharmaceutical 2-[18F]-fluoro-2-deoxy-D-glucose, also known as FDG.
Scotland has one PET scanner, which is used for research purposes, but not for
routine clinical use. Cancer in Scotland: Action for change (Scottish Executive Health
Department, 2001a) highlighted the fact that new imaging techniques such as PET
imaging appear to be making a significant contribution to cancer clinical care in the
United States but future investment decisions need to take account of the HTBS
Advice arising from this HTA.
The full objectives of this HTA are presented in section 1.2.
HTBS uses the internationally recognised definition of HTA (INAHTA, 2000), which
describes it as a multidisciplinary field of policy analysis that studies the medical,
1-1
social, ethical and economic implications of the development, diffusion and use of
health technology.
The HTA considers four components as identified in Figure 1-1: clinical
effectiveness, economic evaluation, patient issues and organisational considerations.
This assessment report presents the evidence relating to each of these sections and a
final discussion, and recommendations that bring together the key aspects from each
section.
This HTA follows the process published by HTBS (HTBS, 2001a). This involves the
submission of evidence from a wide variety of sources, expert staff to undertake the
analyses, a multidisciplinary expert Topic Specific Group (TSG) to collect and
critique evidence and analyses, quality assurance (QA) by the HTBS Governance
Board and wide-ranging open consultation and expert review.
In this HTA, national and international evidence is critically appraised, taking account
of Scottish circumstances, so that clear, practical recommendations can be made to the
National Health Service in Scotland (NHSScotland). This HTA report is accompanied
by two other summary documents. The Health Technology Assessment Advice is
aimed at policy makers, NHS Board decision makers and healthcare professionals.
An Understanding HTBS Advice document is published explaining to patients, carers
and the public how the evidence was reviewed and the reasons for the HTBS
recommendations. All products are available on the HTBS website www.htbs.co.uk.
1-2
Figure 1-1
Health Technology Assessment (HTA) process
Topic proposal & filtration
Selection by HTBS Board:
Definition of the policy question(s) & objective
Determination of background information
Planning: scoping & protocol development
Definition of evidence question(s)
Assessment Report
Working with
Evidence
Clinical
Effectiveness
Epidemiology
Economic
Evaluation
Organisational
Issues
Patient
Issues
Scottish Interpretation with Topic Specific Group
Board & external review including Open Consultation
Conclusions & Recommendations
Final Assessment Report
Dissemination of Report, Advice, Understanding
Implementation of HTA by NHS Boards
Review of the HTA by HTBS
1-3
1.2
Objectives and scope of this HTA
This HTA set out with two principal objectives:
1. To determine the role of PET imaging in cancer management by evaluating the
clinical and cost effectiveness in terms of impact on patient outcome
(morbidity/mortality).
2. If PET is found to be clinically and cost effective, to consider the best
configuration of PET facilities and cyclotrons to serve the Scottish population.
The detailed assessment questions outlined at the start of the HTA are presented in
Appendix 2.
Fryback & Thornbury (1991) explained that the utility of a diagnostic test might be
described on one or more levels in a hierarchy, with higher levels of the hierarchy
relating more closely to the social impacts of the technology.
Table 1-1
Hierarchy of diagnostic efficacy
1
Technical
2
Diagnostic accuracy
3
4
5
6
Diagnostic thinking
Therapeutic
Patient outcome
Societal
Technical imaging quality
Sensitivity, specificity, positive predictive value,
negative predictive value
Likelihood ratio
Changes in therapeutic choices (patient management)
Improvement in morbidity/mortality
Cost-benefit analysis
The aim of this HTA was to focus on levels 5 and 6, that is evaluating outcomes of
importance to patients and undertaking an economic evaluation that was relevant to
Scotland.
In an economic evaluation it is necessary to consult with experts to determine the
precise patient pathway for a cancer in Scotland, to estimate all the benefits and
resources used on that pathway (to the end of the patient’s life) and to determine
strategies in which PET might be used. This model will be different for every
individual cancer and for each stage of cancer and is extremely complex to construct.
Therefore it is necessary to choose a particular cancer and question to study. For this
HTA, the initial approach was to identify the cancer that was thought to have the
strongest evidence base.
Initial literature searches identified that the strongest evidence for the effect of PET on
patient outcomes was available for the staging of non-small cell lung cancer (NSCLC)
(section 3.2). Furthermore, NSCLC is common in Scotland (section 2.1.2). Therefore,
this HTA was initially focused on staging in NSCLC.
The value of PET in improving outcomes is influenced by the potential for successful
therapy. Patient outcomes in NSCLC are poor and it was recognised that an
evaluation of the use of PET in another cancer, in which the benefits may be more
apparent and which had not been extensively studied, would be of value in the
assessment of this technology. Following discussion with Scottish Experts (Scottish
Cancer Group, Personal communication, 2002), an evaluation of the clinical and cost
1-4
effectiveness of PET scanning in lymphoma (restaging Hodgkin’s disease) was
undertaken for this HTA.
Further detail of the rationale for choosing these two cancers for assessment is
presented in section 3.2.
Although this HTA has only considered two cancers in detail in terms of clinical and
cost effectiveness, the patient issues and organisational issues apply to all uses of
PET. Furthermore, other recent HTAs are reported (section 2.4), which summarise the
clinical effectiveness of PET for other cancers and in certain cardiology and
neurology indications. Unfortunately these focus mainly on diagnostic accuracy and
few cost effectiveness studies are available.
1-5
2
BACKGROUND
2.1
Description of health problem in Scotland
2.1.1
Cancer in Scotland
Our National Health: A plan for action, a plan for change (Scottish Executive Health
Department, 2000) states that more than 26,000 people in Scotland are diagnosed with
cancer every year. In Scotland, there have been improvements in cancer survival rates,
but further progress requires continued effort on a number of fronts. Better awareness
and prevention, earlier diagnosis and better, faster treatment all have a part to play in
reducing both the incidence of cancer and the number of deaths. In 2002, a major
service re-design initiative was initiated to improve the patient journey from referral
to treatment establishing Managed Clinical Networks (MCN) for all cancer services
(section 2.2.2).
Cancer in Scotland: Action for change (Scottish Executive Health Department,
2001a) the ‘Cancer Strategy’ indicates that cancer is now the leading cause of
premature death amongst the Scottish population, with 14,740 dying of cancer in
1999. Since the national cancer registration system began in 1959, records show that
there has been a year-on-year increase in the total number of new cases of cancer
diagnosed in Scotland. This is largely due to the ageing of the population. Compared
with the rest of western Europe, the age-standardised incidence of and mortality from
cancer in Scotland are high. Examination of outcomes for particular types of cancer
almost always shows low case-survival in Scotland (and the rest of the UK) compared
with other western European countries.
The outcome for an individual patient is also determined by where the cancer
develops and how it is treated. In contrast to the increasing incidence of many
cancers, deaths from cancer are falling. More Scots are being diagnosed with cancer
but fewer under the age of 75 are dying from it. This is due to improved secondary
prevention and treatment.
Factors influencing the outcome of cancer care include the extent of disease at the
time of diagnosis and co-existing illness. Both of these factors are probably
influenced by deprivation.
The Cancer Scenarios: An aid to planning cancer services in Scotland (Scottish
Executive Health Department, 2001b) presents models of cancer incidence and
mortality trends from 1960-1996, with projections of numbers of incident cancer
cases and deaths expected up to the period 2010-2014. Different projections are
provided for various scenarios of developments in cancer management strategies.
The most important factors that could reduce the incidence of, and mortality from,
cancer are a reduction in smoking prevalence and changes in diet.
However, prompt investigation and appropriate patient management are also noted as
essential to improve outcomes. This was also identified in the Cancer Strategy
(Scottish Executive Health Department, 2001a), in which it was proposed that, by
2005, the maximum wait from urgent referral to treatment will be two months for all
cancers.
2-1
2.1.2
Lung cancer in Scotland
Approximately 4,600 patients were diagnosed with lung cancer in Scotland in 1998
and 75% of these (3,450 patients) had NSCLC (Scottish Executive Health
Department, 2001b). The treatment of choice in NSCLC is surgical resection.
However, only approximately 15-20% of patients will have local disease that is
suitable for this potentially curative surgery. The remaining 85% of patients will be
possible candidates for chemotherapy or radiotherapy (RT), although many will be
unfit to receive chemotherapy or will decline it when offered. Scottish Cancer
Registry statistics suggest that only around 10% of patients with NSCLC receive
chemotherapy (Clinical Resource and Audit Group, 2002).
Scotland leads the international tables in both incidence and mortality of lung cancer.
This has been due, historically, to a high prevalence of smoking, perhaps coupled with
poor diet and some industrial exposures (Scottish Executive Health Department,
2001b).
Survival from lung cancer is poor in Scotland when compared internationally, and
factors that may account for this include:








late presentation;
more co-morbidity;
different tumour biology/behaviour;
delays in investigation;
delays in treatment;
lack of access to specialist advice and treatment;
under-treatment/therapeutic nihilism;
more complete follow up in cancer registration data.
It seems unlikely that more accurate cancer registration data can explain the
significant survival differences, especially in comparison to the Nordic countries,
which also have high-quality registration data. It is not inconceivable that patients in
Scotland may have tumours of different biology and/or behaviour since, even within
Scotland, evidence is emerging of biological differences between breast cancers in
women from deprived areas compared with those from affluent areas (Thomson et al.,
2001). Higher levels of co-morbidity may also be a consideration, along with late
presentation and delays in investigation and treatment.
Exposure to known occupational carcinogens, including asbestos, radon, chromium,
nickel and inorganic arsenic compounds, increase the risk of lung cancer. The most
common occupational cause of lung cancer in Scotland relates to asbestos exposure
(particularly the crocidolite or blue type). In the west of Scotland, where there has
been a large amount of industrial exposure to asbestos, about 6% of all lung cancers in
men may be related directly to asbestos (De Vos Irvine et al., 1993).
In 1998, there were 3,948 deaths registered due to lung cancer (General Register
Office for Scotland, 2000). The survival from lung cancer remains very poor and has
not changed during the last 25 years. Fifty per cent (50%) of patients are dead within
four months of the diagnosis with more than 80% of patients dead at one year. Only
6% of lung cancer patients are alive at five years (Scottish Cancer Intelligence Unit,
2000). Almost all of the surviving patients have been treated with curative surgery.
2-2
The Scottish Executive Health Department (2001c) has highlighted that for the lung
cancer (and colorectal cancer) pathway there needs to be a re-design of the service to
improve the patient journey through diagnosis, treatment and follow up (section2.2.2).
2.1.3
Lymphoma in Scotland
Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL), both now recognised
as lymphomata, jointly account for approximately 4% of cancer incidence in Scotland.
Although NHL is predominantly a disease of older people (median age of onset is 65
years), both NHL and HD can also affect younger people. Indeed the age distribution
of HD is bimodal, with a peak incidence between 15 and 35 years but 25% of people
affected being over 60 years (Scottish Executive Health Department, 2001b).
The incidence of NHL in Scotland and other parts of the UK, Europe and the USA,
has increased by approximately 4% per annum over the last two decades. There is no
obvious aetiology in the majority of cases seen, although there are some known
associations, including HIV infection and immunosuppression after transplantation
(Scottish Executive Health Department, 2001b).
Since both HD and some subtypes of NHL are highly sensitive to chemotherapy, a
large proportion of patients survive beyond five years. In Scotland, the five-year
relative survival for HD is 73% (Scottish Executive Health Department, 2001b) and
data from the Scotland and Newcastle Lymphoma Group (SNLG) database indicate a
five-year survival of 80% in patients under 60 years (compared with 86% in USA).
For NHL, the Scottish Cancer Registry data show a five-year relative survival of 45%
(55-60% in patients under 60 years) (Scottish Executive Health Department, 2001b).
New multidrug chemotherapy regimens are being developed for lymphoma and
treatment initiatives focus on ensuring that patients receive optimal treatment with the
highest efficacy-to-toxicity ratio. A particular issue in this context is the appropriate
treatment of patients with apparent residual disease after induction therapy (Dr M
Mackie, Consultant Haematologist, Western General Hospital, Edinburgh, Personal
communication, 2002). Patients in remission following induction chemotherapy may
be offered consolidation RT for the treatment of residual masses. However, radiation
treatment is itself associated with toxicity, including the development of other
malignancies and cardiotoxicity. Some residual masses detected after treatment are
due to dead tissue and scarring and do not represent active disease (Segall, 2001).
Furthermore some patients may have active disease outside the radiation fields and
will not benefit from RT. In order to minimise unnecessary exposure to potentially
toxic radiation treatment, further investigations are needed to identify those patients
who will receive no benefit from RT at this point. Magnetic resonance imaging (MRI)
and Gallium scanning have been used to discriminate residual active disease but
neither modality is universally successful in achieving this goal (Front et al., 1997).
There is evidence that PET may have a useful role to play (Cremerius et al., 2001)
and this is investigated in detail in the new economic modelling presented in section 7
of this report.
2-3
2.2
Perspectives
2.2.1
Organisation of NHSScotland
NHSScotland, like the NHS in other parts of the UK, provides comprehensive health
care for its citizens, and is free at the point of use. It is funded mainly by direct
taxation in the form of income tax and National Insurance Contributions, with a small
proportion of funding coming from patient charges, such as for dental care and
prescriptions. A key advantage of the UK’s funding system is its fairness, providing
maximum separation between an individual’s financial contributions and their use of
health care. After social security payments, health is the biggest single component of
public expenditure (Wanless, 2001).
Mortality and morbidity rates are higher in Scotland than in England, reflecting
differences in their populations and environmental and socio-economic factors.
However, alongside these greater health needs, Scotland has more health care
resources. Funding per head, the number of hospital beds and professional health care
staff are all above the levels in England (Wanless, 2001). NHSScotland has core aims
of improving the health of the population and reducing inequalities in health. There
are currently five priority topics: coronary heart disease/stroke, cancer, mental health,
children and young people, and older people (Scottish Executive Health Department,
2000).
In 1998 the UK health expenditure per capita was £1,510 or 6.8% of the gross
domestic product (GDP) (5.7% publicly funded and 1.1% privately funded).
The European Union (EU) weighted average figures were £1,824 and 8.4% of GDP
(6.4% publicly funded and 2.1% privately funded) (Wanless, 2001). Scotland has
higher public health service expenditure per capita than the UK average (Wanless,
2001).
NHSScotland has around 132,000 staff, including more than 63,000 nurses, midwives
and health visitors and over 8,500 doctors. There are also more than 7,000 general
practitioners, including doctors, dentists, opticians and community pharmacists, who
are independent contractors providing a range of services within the NHS in return for
various fees and allowances (www.show.scot.nhs.uk/public/publicindex.htm).
The Scottish Executive Health Department (SEHD) leads the central management of
NHSScotland. It oversees the work of 15 NHS Boards responsible for planning
health services for people in their area and, through the boards, the activities of the 28
acute and primary care NHS Trusts responsible for providing services to patients and
the community (www.show.scot.nhs.uk/public/publicindex.htm). Primary Care Trusts
have been developing Local Health Care Co-operatives (LHCCs), which initially
involved only general practitioners but are now evolving into multiprofessional
organisations. The aim of LHCCs is to allow local decision making (with
involvement of local communities) to improve health and health care (Hopton & Hill,
2001).
A number of special Health Boards also exist which have Scotland-wide remits for
specific functions. For example, NHS Education for Scotland commissions education
and training for some NHS staff and HTBS provides advice on the clinical and cost
effectiveness of new and existing health technologies.
2-4
More information about the health service in Scotland can be obtained from
www.show.scot.nhs.uk and http://www.show.scot.nhs.uk/publicationsindex.htm.
2.2.2
Organisation of cancer services in Scotland
The Cancer Strategy (Scottish Executive Health Department, 2001a) heralded a more
organised approach to cancer care across Scotland, recognising the value of a
multidisciplinary approach to patient care.
To better coordinate cancer care, MCNs covering the three regions of Scotland were
put in place during 2002. These multidisciplinary groups agree care protocols and
audit the outcome of treatment.
Three Regional Cancer Advisory Groups (RCAG) (Scottish Executive Health
Department, 2001c) were established in Scotland (North, South East and West) during
2001 to work with NHS Boards to plan investment in equipment, chemotherapy and
staff on the basis of regional clinical need. They are intended to focus, stimulate and
facilitate change and implementation of the Cancer Strategy. RCAGs provide reports
to local NHS Boards on the MCN audit data in their area and work closely with the
Boards to agree investment plans based on priorities that are agreed across the region.
The Scottish Cancer Group is an advisory group of the Scottish Executive whose
remit includes oversight of the implementation of the Cancer Strategy; they work
closely with the RCAGs. Overall responsibility for monitoring and steering
implementation centrally lies with the SEHD Implementation Steering Group.
2.3
The role of PET in oncology
Diagnostic strategy and quality is vitally important in the treatment of cancer and
necessitates close collaboration between radiologists, nuclear medical staff and
clinicians. Accurate staging is important for determining treatment, since local
treatment of curative intent, such as surgery or RT, is only realistic when no distant
metastases are present. Accurate diagnostic methods are necessary for evaluating the
effects of treatment and following treatment any recurrence needs to be detected as
soon as possible to achieve the best results.
PET is an innovative technology that has been in use since the 1970s. In contrast to
computed tomography (CT) or MRI which both provide images based upon anatomy,
PET creates images that reflect biochemical processes and blood flow. Most
radioisotopes used in clinical PET are combined with organic compounds. The most
commonly used isotope is 2-[18F]-fluoro-2-deoxy-D-glucose (FDG), which competes
with glucose for absorption and metabolism in a wide variety of cells. Because cancer
cells often use glucose at higher rates than normal or benign tissue, FDG can
potentially identify a primary or metastatic cancer before structural evidence of
disease is present, and can differentiate malignant from benign structural
abnormalities (Phelps, 2000). Similarly, metabolic activity within the brain, heart and
other organs can be reflected by uptake of FDG. A detailed description of PET and
associated technology is given in section 2.5.
2-5
Many cancer patients have metastases at the time of initial diagnosis and this includes
some who are diagnosed with only primary cancer. Detection of disease at a late
stage, when metastases are present, leads to complicated therapies, poor prognosis and
increased medical care costs. If PET, or any other diagnostic test, could identify
cancer before the gene that enables malignant metastatic spread is expressed, more
patients would be shifted from the group with metastases to the group with only
primary cancer. Improved patient outcomes should then result as many primary
cancers are curable whereas patients with metastases have a poor prognosis.
A number of roles for the use of PET scanning in patients with cancer, or a suspected
diagnosis of cancer, have been proposed (O’Doherty & Marsden, 2000):






diagnosis;
staging;
provision of quantitative or qualitative information on whether chemotherapy
actually arrives at a tumour site;
evaluation of treatment response;
whether there are features about the tumour that may make treatment less
effective (e.g. hypoxia, poor blood flow);
identification of disease recurrence during follow up.
Table 2-1
Medicare reimbursement of PET in the US
Lung cancer
(Non-small cell)
Solitary pulmonary nodules
(SPNs)
Lymphoma
Lymphoma
Colorectal cancer
Colorectal cancer
Head and neck cancers
(excluding central nervous
system and thyroid)
Initial staging, diagnosis, staging and restaging
Characterisation
Staging and restaging only when used as an
alternative to Gallium scan
Diagnosis, staging and restaging
Determining location of tumours if rising
carcinoembryonic antigen level suggests
recurrence
Diagnosis, staging and restaging
Diagnosis, staging and restaging
Evaluating recurrence prior to surgery as an
alternative to a Gallium scan
Diagnosis, staging and restaging (but not
Melanoma
reimbursed for evaluating regional nodes)
Oesophageal cancer
Diagnosis, staging and restaging
Staging, restaging and monitoring tumour response
Breast cancer
to treatment
Medicare Coverage Issues Manual,
http://www.cms.hhs.gov/manuals/06_cim/ci50.asp#_50_36; Centers for Medicare
and Medicaid Services, 2002
Melanoma
As shown in Table 2-1, in the US, Medicare permits use of PET in several cancers.
However, for each cancer, Medicare is quite specific about when PET should be used.
Taking NSCLC as an example, Medicare reimburses the following:
2-6
Initial staging: PET performed with a concurrent CT scan on a primary cancerous
lung tumour that is pathologically confirmed.
Diagnosis: In clinical situations where PET may assist in avoiding an invasive
diagnostic procedure, or in where PET may assist in determining the optimal
anatomical location to perform an invasive diagnostic procedure.
Staging: Where the staging is in doubt after a standard diagnostic work-up PET may
be used or if PET could potentially replace a standard imaging test when it is expected
that conventional tests will be insufficient for patient management.
European countries also use PET extensively in oncology, with the greatest number of
scanners and the greatest use in Germany (Confidential evidence submission, 2001).
Germany regularly hosts consensus conferences on PET, which establish ‘indications’
for PET. At the 2000 conference, a systematic literature review was presented
identifying 533 papers relevant to oncology (Reske & Kotzerke, 2001). This led to
the following recommendations for uses of PET imaging in cancer management.
The following indications were considered as ‘established clinical use’:
















nodal (N)-staging NSCLC (Section 4.2.1);
extrathoracic metastatic (M)-staging (Section 4.2.1) (except brain metastases) in
lung cancer;
recurrence in lung cancer;
differential diagnosis (benign/malignant) of pulmonary lesions in patients with
increased surgical risk in lung cancer;
therapy control in high-grade (aggressive) NHL;
diagnosis of recurrence or follow up in malignant melanoma in pT3 and pT4
tumours or following metastases;
restaging in radioiodine-negative lesions in endocrine/neuro-endocrine tumours;
staging of lymph nodes and distant metastases in oesophageal cancer;
differential diagnosis (inflammation versus malignancy) in pancreatic cancer;
restaging in suspected relapse in colorectal cancer;
N-staging in head and neck cancer;
diagnosis of recurrence in head and neck cancer;
carcinoma of unknown primary origin;
differentiation of recurrence and scar in high-grade gliomas;
detection of tumour dedifferentiation in brain tumour relapse; and
localisation of brain tumour site for biopsy.
2-7
The following indications were considered as ‘probable clinical use’:













differential diagnosis (benign/malignant) of pulmonary lesions in patients without
increased surgical risk in lung cancer;
staging in HD;
therapy control in HD;
staging in high-grade (aggressive) NHL;
M- and N-staging in malignant melanoma (Breslow
>1.5 mm
or known lymph node involvement);
diagnosis of relapse in pancreatic cancer;
therapy control in colorectal cancer;
N-staging in breast cancer (without value in small tumours);
radioiodine-positive lesions in differentiated thyroid carcinoma;
differential diagnosis (benign/malignant) in bone and soft tissue tumours of the
primary or biological aggressiveness for planning the surgical procedure;
brain tumour grading;
estimation of residual brain tumour mass following surgery; and
differentiation of cerebral lymphoma and toxoplasmosis.
The following indications were considered as ‘useful in individual cases’:





therapy control in lung cancer tumours;
differential diagnosis (benign/malignant) in breast cancer;
M-staging in breast cancer;
recurrence in ovarian cancer; and
in case of second tumour in head and neck cancer.
For other indications there was considered to be a paucity of data.
As will be discussed in section 4, it is likely that these indications have been
considered on the basis of the diagnostic accuracy of PET and not considering the
effects on patient management or patient outcomes, or cost effectiveness, which are
the objectives of this report.
2.4
Health Technology Assessments of PET imaging
PET scanning has been the subject of HTAs by many international HTA Agencies.
All HTAs focused on literature reviews of clinical effectiveness and in a few cases,
cost effectiveness analyses were also reviewed. DIMDI (2000), another German
government agency, did a comprehensive literature review to find cost-effectiveness
studies of FDG-PET. They found 14 oncological studies (six studies alongside
clinical trials, eight modelling studies), seven cardiology studies (all modelling
studies) and one in neurology. No other Government HTA Agencies have undertaken
full economic evaluations to model the value of FDG-PET imaging in terms of patient
outcomes.
2-8
Overall, the HTAs concluded that FDG-PET was more accurate than conventional
technologies in diagnosis and that this had the potential to translate into improvements
in therapeutic benefit, particularly in pinpointing areas for RT and identifying distant
metastases. All HTA reports agreed that the quality of evidence available supporting
routine clinical application of FDG-PET is generally very poor. Indeed, the ICES
group in Canada found no Grade A evidence articles for the use FDG-PET in any
cancer, with studies often based on case series of highly selected patients (ICES,
2001). All agree that further well-designed, prospective studies are essential. In
particular, Australia (MSAC, 2000, 2001) has recommended limited reimbursement
of FDG-PET in some indications, on the proviso that data are collected in studies
specifically to inform future decisions about the use of PET.
As an example of the conclusions from one of these reports, HTBS has translated the
Danish HTA (DACEHTA, 2001) and conclusions from the report are presented in
section 2.4.1. HTBS has built upon the work of DACEHTA in NSCLC augmenting
their literature review to update the evidence on clinical effectiveness (section 4) and
undertaking an economic model in this cancer (section 5). We have also taken another
of the cancers for which DACEHTA identified that more work was needed,
lymphoma, and undertaken definitive analyses of clinical and cost effectiveness
(sections 6 and 7).
2.4.1
Danish HTA (DACEHTA, 2001)
The following text is taken verbatim from the HTBS translation of the Danish HTA
and reproduced with the kind permission of DACEHTA.
2.4.1.1 Lung cancer
Gradually considerable data become available which indicates that PET is superior to
other investigations in diagnosing NSCLC, pinpointing primary tumours, mediastinal
staging and identifying distant metastases. However, it is difficult to compare the
results of the various investigations, since all are patient series with internal controls.
Methods of evaluating PET results vary greatly and there is a need for these to be
standard. Investigations using both qualitative assessment (visual analyses) and semiquantitative assessment have found no significant differences. Most investigations
use an internal histological control, but CT evaluation varies, as does the degree of
lymph node sampling. One Dutch randomised investigation however shows that at
the highest evidence level, PET is superior to CT in mediastinal staging and appears
to be cost effective. In the USA and Australia, attempts are currently being made to
reproduce these results in the form of randomised investigations.
2.4.1.2 Solitary pulmonary nodules
The published data all agree that PET provides very high diagnostic accuracy and can
improve diagnosis of solitary pulmonary nodules (SPNs). However, no prospective or
retrospective investigations have been published containing data on survival.
Investigations cannot be directly compared on account of their differing inclusion
criteria, and the high prevalence of malignancy suggests a serious election bias, which
might encourage too much being read into diagnostic accuracy. All the investigations
were patient series with internal controls.
2-9
2.4.1.3 Colorectal cancer
The overall evidence for use of FDG-PET in colorectal cancer is still sparse, and there
is a need for large well-conducted investigations, with bigger control groups to
minimise selection bias. Unblinded image analysis is also required. It is possible that
PET can provide important information in certain cases where recurrence remains
suspected after negative initial investigations. As long as diagnostic accuracy from
existing data can be confirmed in larger future investigations, PET will probably be
the most precise method for assessing recurrence in colorectal cancer. It is not known
whether the diagnostic benefits will have therapeutic implications, since recurrent
colorectal cancer can only be cured in rare instances. Nevertheless, it is expected that
operations for solitary metastases will be performed on a better selection basis, since
surgery can be spared on patients in whom PET indicates a wider spread of the
disease.
2.4.1.4 Head and neck cancer
The existing data suggests that PET may be particularly useful in diagnosing
suspected recurrence after radiation treatment, where clinical investigation and
CT/MR are uncertain because of cicatricial tissue. The method is simple to use, but
expensive in resources. It is not known whether diagnostic benefits will have
therapeutic implications, but a prospective Danish investigation is now underway.
PET’s potential to identify unknown primary tumours and lymph node metastases
seems clear. This group of patients can be cured by radiation treatment alone, but this
is often given over a large area. Identification of the primary lesion can have the
therapeutic consequence that either the area radiated is reduced, or radical treatment
cannot be offered. However, there is still too little data available and larger
prospective investigations are awaited. Conditions are roughly similar for staging of
head and neck cancer with FDG-PET. More precise demarcation of tumours and
lymph node regions may involve more optimal radiation treatment, besides assisting
surgeons in the possible dissection of lymph nodes. At the moment too little data is
available, and no investigations have yet been published containing a systematic
analysis of the therapeutic implications. Larger prospective investigations into
survival time, lymph node recurrence and the side effects of radiation treatment are
awaited. Much is expected of combined PET/CT, which will utilise the increased
sensitivity of PET and the high structural resolution of CT. However, this data has not
yet been published.
2.4.1.5 Malignant melanoma
The included published results show that PET has greatest diagnostic value when
evaluating localised melanoma for major surgical intervention. PET is best used for
diagnosing lymph node metastases and visceral metastases. The value of the method
appears to be definite, as the finding of metastatic disease makes major surgical
intervention obsolete, which saves the patient from unnecessary operations and is
thought to reduce the overall expense.
2-10
2.4.1.6 Breast cancer
PET appears to be a promising method for detection or exclusion of axillary lymph
node metastases, but the existing data is however encumbered with a certain amount
of uncertainty because of several serious sources of error and methodological points
of uncertainty.
The provisional results indicate a high negative predictive value, but before we can
draw any conclusions from this, larger prospective investigations should be conducted
with higher levels of evidence. Future investigations might show if the method is
superior to other methods, but this should be evaluated using harder outcome
measures, such as survival, costs and patient stress.
2.4.1.7 Other cancers
Clinical development is also being pursued in the following oncological areas:





lymphoma
oesophageal cancer
primary brain tumours
occult primary tumours
testicular cancer.
2.4.1.8 Alzheimer’s disease
(This text has been edited slightly to make it more understandable in translation.)
There is selection bias with the investigations of PET in Alzheimer’s disease (AD).
There is little evidence from prospective investigations in patients with possible AD,
but some evidence in probable AD. However, there is no evidence that PET increases
diagnostic certainty compared with perfusion investigations using single photon
emission computed tomography (SPECT), which is a more readily available imaging
technique. Perfusion investigations with dedicated PET and for example, O15-H2O,
may possibly be a supplement, but this tracer is very short-lived and therefore cannot
be distributed outside departments with their own cyclotron.
2.4.1.9 Epilepsy
The results are still too preliminary and too few to give an overall picture of the
diagnostic value of PET for epilepsy. There appears to be no evidence that PET can
replace perfusion investigations with SPECT, which is much more easily accessible.
As the affected patient group in Denmark is relatively small, there appears to be no
need [for] clinical use of PET in assessing the operation indication with uncontrolled
complex, partial epilepsy. PET may possibly be a supplement to SPECT after MR
scanning and electroencephalogram, if the location of the trigger zone is still
unresolved.
2.4.1.10 Ischaemic heart disease
Many of the included studies were unblended and without control groups. All of the
studies were case series with indirect diagnostic tests and a low evidence level,
corresponding to category III for clinical evidence. The larger scale investigations
2-11
were unable to retrieve the high sensitivity and specificity of studies published earlier.
On the basis of the smaller investigations with 20-40 patients, concordance appears to
exist between PET and other studies such as SPECT and low-dose dobutamine
echocardiography regarding sensitivity.
The positive predictive values of 46-95% and negative predictive values of 66-96% are very
unreliable, since KAG control is lacking. The fluctuating results with FDG uptake can be due to
fluctuating inclusion criteria and varying evaluation methods. It is possible that the contractile
reserve cannot be described on the basis of single metabolic investigations. Intensive research is
being conducted within this area, and increased knowledge of pathophysiological mechanisms may
possibly lead to the development of new, better diagnostic methods.
Large scale, multi centre investigations with a higher evidence level are necessary before the
ultimate role of PET for ischaemic heart disease can be determined. However, it is doubtful
whether these studies will be carried out since very ill patients are involved, who in many instances
are in urgent need of revascularization.
2.5
Description of the technology
(from text provided by Professor P Sharp)
2.5.1
Radionuclide imaging
PET imaging is a form of radionuclide imaging, which uses radioactively-labelled
pharmaceuticals (radiopharmaceuticals) for diagnostic purposes. This is a well
established technique in modern health care and a detailed description of the
technique, known as nuclear medicine, can be found in many textbooks (see for
example, Sharp et al., 1998). For cancer, increased metabolic activity at a cancer
tumour site results in increased uptake of a radiopharmaceutical and so there are many
potential uses of PET imaging in oncology
While the spatial resolution and image noise achieved with PET is worse than with
other diagnostic techniques, such as X-ray imaging or MRI, its strength is in
producing images of the biochemistry of the tissue or organ as opposed to anatomy.
PET provides functional information about activity and processes, unlike
conventional X-rays, MRI, CT and ultrasound, which provide predominantly
anatomical information.
Images of the distribution of the pharmaceutical are formed by detecting the gamma
rays emitted by the decay of the radioactive label, while the diagnostic information
depends upon the pharmaceutical employed. Conventional nuclear medicine uses
radioactive elements that emit gamma ray photons, this being the only radiation
sufficiently energetic to penetrate through tissue and so be detected externally.
Imaging is carried out with a gamma camera and can be either planar or tomographic,
the latter being known as SPECT.
PET also employs radiopharmaceuticals, but in this case the label is a positronemitting radionuclide. Positron-emitting radionuclides were first discovered in the
1940s. The positron is a positively-charged electron emitted from nuclei that are
unstable due to an excess of protons. The emitted positron carries with it energy,
which it loses in interacting with conventional negatively-charged electrons in the
2-12
material through which it passes. When it has lost almost all of its energy it is
captured by an electron and the resulting pair of positive and negative electrons is
known as positronium. These two particles rapidly annihilate, reappearing as two
gamma rays. In order to conserve energy the two gamma rays will each carry an
energy of 511 keV, the total energy being equal to the mass of the two electrons. If the
positron carried no energy at the time it was captured, then the gamma rays would
travel in diametrically opposed directions, otherwise the angle between them will be
slightly less than 180 degrees. Thus compared with normal decay, the positron decay
produces a pair of gamma rays rather than a single one.To produce an image of the
distribution of the radiopharmaceutical, the gamma camera not only has to detect the
presence of gamma rays but also locate from where in the body they were emitted.
Gamma rays cannot be focused by a lens, and instead a collimator is used. This is a
lead plate through which several thousand holes run from the front to the back face.
Gamma rays can only pass through the collimator if they travel parallel to the axes of
the holes; radiation travelling in any other direction will be absorbed by the lead.
While the lens forms an image by focusing light, the collimator does so by excluding
all radiation except that travelling in a particular direction. Thus, one of the major
drawbacks of radionuclide imaging is its low sensitivity, with only about one in a
thousand of the emitted gamma rays actually being used to form the image.
PET imaging does not need such collimation.
By detecting the simultaneous arrival of a pair of gamma rays, the position of
emission can be computed as lying on the line connecting the two rays. By looking at
points of intersection of thousands of such lines, an image can be formed and the
source accurately located. A typical PET imager is shown in Figure 2-1. It consists of
a ring detector, which surrounds the patient and collects a high proportion of the pairs
of gamma rays emitted, connected to electronics that record the coincident arrival of
pairs of gammas.
2-13
Figure 2-1
Outline of a PET imager
Imaging ring
Detector
Point of
Positron
Emission
Gamma
ray 1
Image
produced
Gamma
ray 2
Coincidence
Detector
Circuit
Detector geometries other than the full-ring system (such as gamma cameras) are in
use (section 2.5.5).
The spatial resolution of a PET imager is better than that of a gamma camera;
typically 3 to 6 mm in clinical applications, or down to 1.5 mm in ideal conditions.
It is ultimately determined by the energy of the positron emission. However, the
strength of the technique does not lie primarily in its better resolution, which is still
not competitive with that of other techniques. Conventional, single photon nuclear
medicine is limited by the fact that no biologically important element has a
radioisotope suitable for imaging and that the ability to quantify the amount of
radiopharmaceutical in an organ is restricted by the effects of attenuation of the
radiation. However, biologically important elements such as 11Carbon, 13Nitrogen,
15Oxygen and 18Fluorine, do have positron-emitting isotopes and so can be used to
label a wide variety of pharmaceuticals for PET imaging.
By combining emission with transmission imaging, PET also permits the accurate
measurement of the amount of radiopharmaceutical at a point in the body. Since PET
uses very small amounts of positron-labelled molecules, it can measure the function of
biological processes, such as blood flow, with minimal disturbance. To do so requires
a compartmental model that describes the process and the way the labelled molecules
mimic or trace it. The PET imager measures the changing tissue concentration of the
labelled molecule over time, or the accumulated concentration at a given time, which
is determined by the rate of transport and chemical reactions in which the
radiopharmaceutical participates. For this reason PET has been called molecular
imaging (Phelps, 2000).
2-14
However, there are disadvantages. The biologically interesting positron emitters all
have a short lifetime. The longest one in routine imaging is 18Fluorine with a half-life
of 110 minutes. The other tracers have half-lives as short as two minutes for
15Oxygen. Thus it is necessary to have a production facility, a cyclotron, for
positron-emitting radionuclides located close to the imaging facility and a
radiochemistry laboratory for rapid labelling of the pharmaceutical. For 18Fluorine,
transportation from a cyclotron within two hours journey time is possible (section
9.4.2), but for other isotopes, on-site production is necessary.
2.5.2
PET radiopharmaceuticals
Currently the main PET tracer in oncology is glucose labelled with 18Fluorine
(FDG). Neoplastic degeneration is associated with increases in glycolysis because of a
progressive loss of the tricarboxylic acid cycle (TCA) (Weber, 1977). Glucose is also
used to provide the carbon backbone to meet the high cell replication rates of tumours
(Weber, 1977). A complete loss of the TCA cycle can amplify glucose consumption
19-fold per adenosine triphosphate molecule (ATP). This is because only two ATP
molecules are generated when a molecule of glucose is metabolised to lactate,
whereas 38 ATP molecules are generated when a molecule of glucose is completely
metabolised to carbon dioxide and water in the TCA cycle. Glucose consumption is
further increased by the activation of the hexose monophosphate shunt. These two
factors increase glucose consumption as neoplastic degeneration progresses (Phelps,
2000). Thus neoplasms are differentiated from surrounding tissue by their high
uptake of FDG. These properties appear to be common for all malignancies.
FDG was first synthesized by Ido et al. (1978).
FDG undergoes glycolysis in tumours but the dephosphorylation of FDG-6-phosphate
is relatively slow, so FDG gradually accumulates within the cells (Figure 2-2). The
concentration of FDG reaches a plateau when the rate of dephosphorylation equals the
rate of uptake into the cell. In experimental studies, this occurs about 45-60 minutes
after injection, so clinical imaging is normally carried out after this interval.
The kidney does not recognise FDG as glucose, so it is largely excreted by glomerular
filtration, although there is some reabsorption in the proximal tubule. In a normal
subject about half of the injected dose is excreted in the urine 2 to 2.5 hours after
injection.
2-15
Figure 2-2
Whole body image taken using FDG
(Metastatic deposits can be seen in the area of the lungs and spine.)
In clinical practice it is found that absolute measurement of glucose uptake into
lesions or specific organs is difficult because of differences in the size and body
composition of patients, and individual variations in glucose metabolism. When
required, approximate quantitation is achieved by using the standardised uptake value
(SUV), which is an estimate of the uptake of FDG into the lesion or organ of interest,
compared with the mean uptake in the rest of the body.
However, some concerns have been expressed about the robustness of SUV as a
measure of FDG uptake (Keyes, 1995).
2.5.2.1 New tracers
Currently, most PET oncology studies use FDG. This is likely to continue for some
time but some interesting new tracers are under assessment. These include 11Carbon
Thymidine (Strauss, 1997) and a 18Fluorine Fluorothymidine (FLT) for cell
proliferation, a 18Fluorine Metronidazole derivative for tumour hypoxia and
18Fluorine fluoro-estradiol as an oestrogen receptor (ER) tracer. This allows depiction
of ER heterogeneity within breast cancers and also detection of loss of ER expression
with treatment or disease progression. 11Carbon and 18Fluorine choline tracers are
being used to look at membrane synthesis and these show considerable promise in
prostate cancer, where FDG is less effective.
2.5.3
Instrumentation for PET
Positron decay gives rise to two 511 keV photons travelling in diametrically opposed
directions. It is the recognition of such coincident pairs of photons by detectors
placed on opposite sides of the body that allows the position of the source of the
radiation to be determined. Since collimators are not needed, the efficiency of
detection is considerably improved compared with the conventional gamma camera
approach. However, as the imaging process depends on detecting both of each pair of
photons, effective imaging involves surrounding the patient with the radiation detector
(Figure 2-3) and consequently such dedicated PET systems are expensive.
2-16
Figure 2-3
A dedicated PET imager
The high-energy photons are stopped in a scintillation crystal. Such crystals need to
have good ‘stopping power’, and bismuth germanate oxide (BGO) has been the
standard for the last few years. The recent introduction of lutetium based detectors,
together with faster electronics, offers an increase in sensitivity so that examination
times can be considerably reduced.
A typical block detector consists of a single crystal of BGO, which has been sawn into
an array of 8x8 distinct crystal elements. The depth of the saw-cuts determines the
amount of light directed to each of four photomultiplier tubes. These blocks then form
the ring around the patient.
The axial field of view, i.e. along the length of the patient, depends upon the number
of detector rings employed. A two-ring system (16 detectors deep) would give 31
slices and a three ring system, 47 slices. Typically each slice would be 3.4 mm thick,
giving a field of view of 11 cm for a two ring and 16.2 cm for a three ring system. By
moving the patient through the detector ring, larger fields of view can be achieved.
In addition to a true coincidence, the image may be degraded by artefactual
coincidences, which will result in incorrect spatial information. Thus the coincidence
system must be designed to keep processing time to a minimum and to reduce the
effect of false coincidences. This is done both electronically and by using lead or
tungsten discs, known as septa, inserted between detector planes to reduce scatter.
2-17
With the septa in place, data are acquired as a series of two dimensional (2D) slices.
With the inter-plane septa retracted all possible coincidences are acquired creating a
three dimensional (3D) volume of data from which slices may be extracted (Bendriem
& Townsend, 1998). It increases the sensitivity by a factor of about 10, allowing
lower doses and/or shorter acquisition times to be used. There are, however, a number
of problems with the 3D technique and, in general it does not lend itself to imaging of
extended sources, such as the trunk, although it is advantageous for the brain.
One of the strengths of PET is its ability to accurately quantify the amount of
radioactivity in an organ or region of interest. This requires that a correction be made
for attenuation of radiation in the patient. This is done by the acquisition of a
‘Transmission Image’ when the patient is in position, using an external positron
source, usually 68Germanium (68Ge) with a half-life of 275 days. The process takes
about 20 minutes, and is in addition to the time required for the emission image.
One of the major limitations of PET is the lack of anatomical landmarks, particularly
in the thorax, abdomen and pelvis. Therefore for applications in oncology, PET
images need to be interpreted in conjunction with CT or MRI anatomy. Although coregistration of images obtained from separate examinations can be carried out on an
image processing workstation, the advantages of simultaneous acquisition of
anatomical and functional data are self-evident. Mounting both a spiral CT and a
partial ring PET device on a single imaging gantry offers the possibility of combining
functional and anatomical data in the same examination (section 2.5.5.2). Typically,
the CT acquisition is performed first followed by PET acquisition. The anatomical
CT data can then be used to apply attenuation correction for the PET data and the
resulting images can be displayed separately or fused together, obviating the need for
the 68Ge system.
2.5.4
Image interpretation
Although PET scanners can have a very high sensitivity, this can often be
accompanied by a large amount of unwanted background data arising from two
sources. The first of these is scatter where one or both of the 511 keV photons has
scattered in the patient; this is significant for large patients and when imaging the
torso. Scatter is particularly troublesome in PET because many current detectors have
poor energy resolution. Also, many photons interact via a Compton scatter and
deposit only a fraction of their energy in the detector. As a result, energy thresholds
are usually set at approximately 300 keV and scatter fractions are high. The second
form of noise is not encountered in single photon systems. Random coincidences
arise when two single photons from different annihilations are detected within the
very short (approximately 10 nanoseconds) window that is used to define a
coincidence event.
The scanner has no way of discriminating between these random coincidences and
true coincidences. There are various schemes to correct for the systematic effects of
scatter and random events; however, the noise that is introduced into the image cannot
be removed and depends on the basic design of the scanner.
2-18
The noise due to scatter and random events is a particular problem for scanners that
operate in 3D mode. To keep random and scatter coincidences to a minimum, many
scanners restrict coincidences to pairs of photons that lie within transaxial planes of
the scanner, and thin lead or tungsten septa are placed between these planes. In 3D
mode, the inter-slice septa are removed and coincidences are permitted between all
detector rings with the result that the sensitivity is much increased but so are the
scatter and randoms.
Image reconstruction of PET data is usually performed using the standard filtered
back projection algorithm and modified versions of this that are applicable to data
acquired in 3D mode. Increasingly, iterative reconstruction techniques are being
used. These can take account of the statistical properties of the data and result in
higher quality reconstructions.
2.5.4.1 Quantitation
In the majority of clinical cases, PET scanning is just used to detect lesions (tumours).
For this purpose Bleckmann et al. (1999) and Lonneux et al. (1999) have shown that
images not corrected for attenuation show better contrast between the lesion and the
background. However, there are other factors, besides plain contrast, that influence
the ability to perform an accurate diagnosis. These factors include consistency of
lesion detection across a number of scans, differences between clinical examiner, and
size and shape of the lesion. It has been suggested that these factors may outweigh
contrast as cues for visual detection of lesions (Lonneux et al., 1999). Furthermore
Bai et al. (2000) have shown that the attenuation artefact is non-linear and may
produce both locally enhanced and decreased contrast depending on the position of
the lesion (i.e. it may not be detected in some cases). They suggest that both corrected
and uncorrected images should be used for diagnosis.
While questions remain about the need for attenuation correction for lesion detection,
there is little doubt that it is required for absolute (or even relative) quantification of
lesion uptake (Bailey, 1998), which may be required when assessing response to
therapy, for example.
2.5.5
Alternatives to PET
2.5.5.1 Gamma cameras
As an alternative to full PET imaging, two or more planar detector, multi-headed
gamma cameras could be used. Using a dual- or multi-headed gamma camera for PET
has the obvious advantage that the same instrument can also be used for single photon
imaging as well.
However, there are relatively few studies available that can be used to evaluate the
specificity and predictive value of gamma cameras and most are small case series,
which are subject to bias. Initial comparisons have shown that dedicated PET and
gamma cameras perform equally well in detecting lesions larger than about 2 cm, but
dedicated PET systems are more accurate for the detection of small lesions (Yutani et
al., 1999; Tatsumi et al., 2001). Consequently it was decided to focus this HTA on
dedicated PET systems.
2-19
A study is currently underway at the Royal Hallamshire Hospital, Sheffield looking at
the diagnostic accuracy of a combined gamma camera/CT system in the diagnosis of
positive lymph nodes in NSCLC. It will be interesting to evaluate the results of this
trial once it is completed.
2.5.5.2 PET/CT
PET images lack anatomical detail and a transmission image is required to calculate
the attenuation correction of the radiation in the patient. This takes approximately 20
minutes in addition to the imaging scan. The use of a CT scanner allows the
attenuation data to be acquired in a shorter time while also providing diagnostically
useful CT images.
There have been recent advances in the development of combined PET/CT scanners,
which may help to address these issues by producing combined images. Costs of
PET/CT scanners are greater than PET imagers alone (of the order of 50% higher) and
maintenance costs are also higher. However, it is hoped that diagnostically superior
images may be produced and that scan time will be reduced, thus allowing higher
patient throughput. However, there is no published evidence of this to date, and no
such evidence was submitted to HTBS.
Images from individual PET/CT scans are provided in Appendix 3. Phelps (2000)
proposes that PET/CT scanners could be used for the following:





improve the PET image through fast and accurate attenuation correction;
improve localisation of abnormalities detected using PET;
radiotherapy and surgery planning;
evaluation of therapy outcome by localising regions of oedema and scarring; and
produce the highest possible quality PET and CT information with the least
inconvenience.
Comments have been received from a number of interested parties claiming that, as
well as reducing the time required for a transmission scan, PET/CT systems may be
more accurate than PET alone in the staging and diagnosis of cancer. To assess the
evidence currently available for this claim, a literature search was conducted for peerreviewed papers addressing the use of PET/CT fusion images in mediastinal staging
of NSCLC.
The search identified three papers reporting the use of PET/CT fusion images in
mediastinal staging of NSCLC, and two additional papers reporting the use of PET
and CT images that were ‘visually coordinated’. The results given in these papers are
described in Appendix 4. From the small number of published studies, it would seem
that some sort of correlation between PET and CT is useful, but that fusion images
actually add little or nothing in this application in NSCLC.
2-20
Some of the questions that would need to be answered before deciding whether
PET/CT will be effective in practice are:
1. What percentage of PET scans require quantitation? In some cases the aim is to
detect the spread of a cancer. While correcting for attenuation may improve the
accuracy of the image, there is conflicting evidence (from the few studies that
have been done) on whether it improves the ability to detect the spread. If
quantitation is not required then a combined PET/CT scanner does not offer any
improvement in throughput, thus negating one of its advantages.
2. What percentage of scans require anatomical registration? In some cases the fact
that a tumour has spread is enough to change the management of the patient (i.e.
make them unsuitable for surgery). In these cases there is no need for any
anatomical registration.
3. Is the registration that can be obtained on the combined scanner significantly
better than that using two separate scans? Clearly it is easier to co-register a PET
and a CT image if they are taken with the patient in the same position. However,
even in this case, co-registration may not be perfect. For example in order to get
good diagnostic CT images patients are often asked to hold their breath during the
CT scan. This is not possible for the PET scan since it takes too long. Therefore
breathing motion will introduce some error. Also in some cases the CT scan may
be taken with the arms above the head (to improve quality) and this position may
be too uncomfortable for the longer PET scan so the arms may be placed by the
patients side, thereby changing the position of internal organs.
The results of the literature review show that there is much less evidence available for
assessment of PET/CT than there is for PET alone. This is not surprising as PET/CT
scanners are a relatively new technology, but it means that there is insufficient
evidence to attempt a robust economic evaluation. Hence this report has focused on
dedicated PET imagers.
2-21
3
SOURCES OF EVIDENCE AND DEVELOPMENT OF THE
ASSESSMENT QUESTIONS
3.1
Sources of evidence
The HTAs undertaken by HTBS use international evidence from a range of sources:
published literature, grey literature (e.g. academic and government reports, conference
abstracts) and information submitted from a variety of interested parties.
The following interested parties were invited to submit evidence for this assessment
(those marked * did not reply and those marked + did not have anything additional to
contribute):
Professional/Specialist Groups
British Institute of Radiology*
College of Radiographers*
Royal College of Radiologists
Scottish Council of the Society of Radiographers+
Institute of Physics and Engineering in Medicine
Medical Research Council+
British Nuclear Medicine Society
Society of Radiographers
Royal College of Physicians (London)
European Association of Nuclear Medicine
Intercollegiate Standing Committee
on Nuclear Medicine
Patient Groups
British Lung Foundation (Scotland)*
Scottish Breast Cancer Campaign*
Imperial Cancer Research Fund*
McMillan Cancer Relief*
Sargent Cancer Care of Children (Scotland)*
Scottish and Newcastle Lymphoma Group
Scottish Association of Prostate Cancer Support Groups*
Breast Cancer Care*
Colon Cancer Care+
Manufacturers
ADAC Laboratories
Alliance Medical
CTI PET systems
GEM Systems USA
Marconi*
Marken Time Critical Express
Amersham Health
Siemens Medical Solutions
Strand Transport Service Limited+
Synektix
Trionix*
3-1
Manufacturers were asked to respond to the following questions:
1. Summarise the evidence for clinical and cost effectiveness of gamma cameras
versus dedicated PET scanners in the provision of PET as part of cancer
management.
2. In your view would it be necessary for the effective use of PET in cancer
management to have an on-site cyclotron?
3. Summarise developments in the field of PET imaging technology that may, in the
next two years, have an important impact on the effectiveness of PET imagers in
cancer management.
The TSG submitted a range of technical and operational materials about existing PET
facilities in the UK, general technical information and patient information leaflets.
For clinical effectiveness and the economic evaluation a systematic literature review
was undertaken. As explained in sections 1.2 and 3.2, this focused on the staging of
NSCLC and lymphoma. For NSCLC, the literature review built on a recently
published high quality HTA from Denmark (DACEHTA, 2001).
For organisational and patient issues the focus was placed on submitted evidence,
selected literature references and grey literature from a variety of sources.
3.2
Developing the assessment questions
At the outset it was realised that there is substantial literature on the diagnostic
accuracy of FDG-PET. However, it was agreed that, in order to determine the value of
FDG-PET, evidence of change in patient outcomes should be obtained (section 1.2). If
this was not available, change in patient management may be considered a sufficient
surrogate. Diagnostic accuracy would not be sufficient. So the first step in the HTA
was to determine which cancer might have sufficient patient outcome or management
data for evaluation.
The HTBS TSG highlighted seven cancers (lung, head and neck, prostate, colorectal,
breast, lymphoma and melanoma) where FDG-PET imaging may be of potential use
and summarised five main areas of FDG-PET application by functionality (diagnosis,
staging, functional information for prognosis, evaluation of early response to
treatment and evaluation of sub-clinical response). This formed the basis of literature
searches undertaken in MEDLINE (July 2001) to assist in scoping the assessment
questions.
The scoping searches resulted in a total of 1811 clinical articles and 190 economic
articles for all cancers. A summary of the number of papers identified is presented in
Table 3-1.
3-2
Table 3-1
Results of clinical effectiveness and economic evaluation scoping
literature searches (number of studies by cancer and functionality)
Lung
Diagnosis
Staging
Prognosis
Early
response
Sub-clinical
response
Total*
Head and
neck
Prostate
Colorectal
Clinical papers
88
88
90
64
50
37
189
205
93
210
188
156
14
14
9
3
23
0
2
0
3
0
0
580
37
490
Breast
Lymphoma
Melanom
a
58
77
38
38
49
14
7
4
0
0
0
0
230
196
Economic papers
Total
67
49
1
31
18
*
Note: Papers may be duplicated within functionality criteria.
177
101
10
14
The results of the searches were reviewed and the following broad exclusion criteria
were applied:
4. 1. Duplicate references within the list
5. 2. Articles not specifically on the individual cancer
6. 3. Studies not using FDG as the radiolabelled tracer
7. 4. Review articles or letters describing general use of PET
8. 5. Studies not specifically using PET
9. 6. Articles not written in English
10. 7. Animal studies.
This reduced the number of relevant papers and the studies included for consideration
were corroborated by the reviews done by other HTA organisations; in particular a
recent report produced by the Danish Centre for Evaluation and Health Technology
Assessment (DACEHTA, 2001) which summarises the literature on the use of FDGPET in oncology, cardiology and neurology and a report prepared by the Medical
Services Advisory Committee (MSAC) for the Commonwealth Minister for Health
and Aged Care in Australia (MSAC, 2000).
3-3
The HTBS appraisals team subsequently held discussions with a subgroup of the TSG
members to define specific questions for assessment, based on the results of this
literature search. The following HTBS questions were proposed in order of
importance to Scotland:
1. What is the role of FDG-PET in the evaluation of the SPN?
2. What is the role of FDG-PET in selecting patients presenting with NSCLC for
surgical resection?
3. What is the role of FDG-PET in recurrent lymphoma?
4. What is the role of FDG-PET in squamous cell head and neck cancer recurrence
after major surgery (excluding thyroid)?
5. What is the role of FDG-PET in assessing patients for recurrent colorectal cancer:
(a) when there is a single site of known recurrence, does it help the decision on
surgical resectability?
(b) when tumour markers are rising but no recurrent site is evident, does it aid in
localising the recurrence?
The HTBS appraisals team considered the feasibility of assessing these five cancers
against the evidence questions that were to be applied to all cancers (Appendix 2 –
questions 4.1, 4.2, 4.3, 4.5), relating to the:



quality of clinical effectiveness evidence;
availability of economic modelling information; and
importance of the cancer in Scotland.
On the first factor, the HTBS appraisals team considered the reports produced by the
DACEHTA (2001) and the MSAC (2000) to provide a good summary of the evidence
available on the role of FDG-PET in oncology to May 2001. It was clear that the
largest body of evidence is available for the role of FDG-PET in lung cancer. It was
also determined that the only randomised trials that evaluated patient outcomes were
in NSCLC and were to be published in 2001/2002. Information from randomised
trials did not appear to be available for any other cancers.
Table 3-2
Number of economic evaluation papers suitable for this HTA
Lung: SPN
Lung: NSCLC
Lymphoma
Head and neck
Colorectal
3
3
2
0
0
Table 3-2 shows that, of the eight relevant published economic evaluations, six related
to lung cancer, three to the role of FDG-PET in evaluating SPNs (HTBS question 1),
and three to the role of FDG-PET in surgical resection of NSCLC (HTBS question 2).
3-4
The lack of studies that could act as a basis for the economic evaluation of HTBS
questions 3-5, together with the poor quality of clinical data on the role of FDG-PET
in patient management within lymphoma, head and neck and colorectal cancers,
resulted in the initial decision to concentrate on the staging of NSCLC for this HTA.
The importance of NSCLC, which is the most common cause of cancer death in
Scotland, was an additional factor in this decision.
However, it was subsequently recognised that the value of PET is influenced by the
potential for successful therapy and patient outcomes in NSCLC are poor (section
2.1.2). Consequently FDG-PET was assessed for another cancer, in which greater
treatment benefit was possible, for which a clear patient pathway could be determined
and which had not been extensively studied by other organisations, namely Hodgkin’s
disease.
Consequently, this HTA presents analyses of clinical effectiveness and cost
effectiveness that compare the addition of FDG-PET with current standard diagnostic
work-ups for the staging of NSCLC (section 4 and 5) and restaging of Hodgkin’s
disease after induction therapy (sections 6 and 7). Clinical effectiveness evidence
from other HTAs is used in the discussion to consider the value of FDG-PET in other
cancers (section 10). Patient and organisational issues relate to all patients who may
undergo a PET scan and these are presented in sections 8 and 9.
3-5
CLINICAL EFFECTIVENESS – NSCLC
4
Summary

A systematic review and critical appraisal of the literature was undertaken to
determine the effectiveness of FDG-PET in NSCLC with regard to mediastinal
staging, the detection of distant metastases, changes in patient management
and clinical outcomes.

A meta-analysis of diagnostic accuracy was performed, using a summary
receiver operating characteristic curve (SROC) to estimate the sensitivity and
specificity in CT negative patients, CT-positive patients and both groups
combined.

Meta-analysis shows that, for NSCLC patients who are CT negative, the
estimated specificity
of FDG-PET scanning is 0.9, 95% confidence
interval (CI) (0.87, 0.93), with sensitivity at this specificity of 0.86, CI (0.79,
0.91).

Meta-analysis shows that, in NSCLC patients who are CT positive, the
estimated specificity of FDG-PET scanning is 0.76, CI (0.69, 0.82), with
sensitivity at this specificity of 0.92, CI (0.87, 0.95).

Published studies conclude that FDG-PET is superior to CT and other
conventional tools in the mediastinal staging of NSCLC, in the investigation
of possible distant metastases in NSCLC
and in other selected
areas of oncology.

Two randomised controlled trials comparing diagnostic strategies in NSCLC,
with and without FDG-PET, have been reported. The two trials produced
contradictory results. One trial (van Tinteren et al., 2002) demonstrated that
the addition of FDG-PET produces a cost-effective reduction in the number of
futile thoracotomies, whereas the other (Boyer et al., 2001) found no
difference between the strategies. This appears largely due to different
approaches to the management of NSCLC, given the results of FDG-PET
scanning.

No randomised trials report evidence on quality-of-life outcomes following
use of FDG-PET for staging NSCLC.

The published studies suffer from a number of deficiencies and further welldesigned research is needed.

Potential risks associated with PET imaging relate mainly to the administration
of the
radiopharmaceutical. However, in all published literature no
adverse events have been reported as a result of PET scanning. There is a risk
of second cancers posed by the radiation dose in PET scanning, but this is very
low.
4-1
4.1
Literature search
4.1.1
Search strategy
Scoping searches were undertaken in July 2001, as part of the process to help define
the assessment question. This included a search for HTAs, systematic reviews and
other evidence-based reports on the application of PET in cancer management. In
addition, exploratory searches of MEDLINE were undertaken to try and establish the
quantity and the quality of the evidence on the impact of PET on patient management,
vis-à-vis diagnostic accuracy.
Section 3.2 presents the results of these literature searches and describes how the
decision was reached that HTBS would focus on NSCLC and update the systematic
literature search on the diagnostic accuracy of FDG-PET presented by the DAHCETA
(DACEHTA, 2001).
To update the Danish HTA the following approaches were adopted:




The databases MEDLINE (Ovid), PreMEDLINE (Ovid) and Embase (Ovid) were
searched. The search was split into two concepts: positron emission tomography
and non-small-cell lung cancer (NSCLC) with all relevant subject headings and
free text terms identified for each concept. The search was limited to records
added to the databases from January 2001 onwards. No language restrictions
were applied.
Attempts were made to identify additional randomised controlled trials and
ongoing research, not indexed in MEDLINE or Embase, by searching sources
such as the Cochrane Controlled Trials Register, Current Controlled Trials
(mRCT) and the websites of professional organisations.
Members of the TSG and Experts were consulted to check for completeness of
the included studies and, in particular, to help identify unpublished (grey)
literature and ongoing research.
The bibliographies of relevant studies were scanned for further studies.
Further information about the search and a flow chart detailing the systematic
literature selection process are presented in Appendix 5.
4.1.2
Exclusion criteria
Clinical effectiveness papers were excluded from review according to the following
criteria:





duplicate references within the list;
articles not about NSCLC staging;
studies not using PET;
studies not using FDG as the radiolabelled tracer;
review articles or letters describing general use of PET, with no formal metaanalysis; and animal studies.
For the meta-analysis, further exclusion criteria were used. These are described in
section 4.5.1.
4-2
4.2
NSCLC diagnosis in Scotland
4.2.1
NSCLC staging
The treatment offered to patients with NSCLC (and their outcome) will depend on the
stage of their disease. To lay the foundations for the clinical effectiveness and
economic evaluation, detailed information is needed about the current diagnostic
pathway used to stage NSCLC in Scotland. On this basis, the potential value of FDGPET in the Scottish clinical setting can be evaluated.
The TNM classification of lung cancer (Sobin and Wittekind, 1997) considers the
extent of the primary tumour (T status), condition of regional nodes (N status) and
presence (1) or absence (0) of distant metastases (M status). Diagrammatic
representation of T and N status is presented in Figures 4-1 and 4-2.
The Scottish Intercollegiate Guidelines Network guideline on lung cancer (SIGN,
1998a) recommends staging patients (Stage 0 to Stage IV) according to the TNM
classification, as follows:
Stage 1A
Stage 1B
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Stage IV
T1
T2
T1
T2
T3
T1
T2
T3
Any T
T4
Any T
N0
N0
N1
N1
N0
N2
N2
N1, N2
N3
Any N
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1.
As shown in Table 4-1, other professional organisations recommend similar staging
categories. There is agreement that those with M1 (distant metastases) or N3
(involving contralateral mediastinal or hilar, scalene or supraclavicular nodes) disease
rule out surgery, but N2 (involving ipsilateral mediastinal, subcranial nodes) are a
matter for clinical judgement (see section 4.2.2).
Table 4-1
Guidance on surgical judgement
BTS
Operable
Stage I (T1 N0, T2 N0)
Stage II (T1 N1, T2 N1, T3 N0)
Surgical judgement or
only in trial
Stage IIIA (T3 N1, T1-3 N2)
English cancer
guideline*
Stage I
Stage IIA
Stage IIB
Stage IIIA
SIGN
Stage I, II
Stage IIIA
Stage IIIB (anyT N3, T4 N2) or
Stage IIIB, IV
Stage IIIB, IV
IV (anyT anyN M1)
*NHS Executive document: Guidance on Commissioning Cancer Services – Improving Outcomes in
Lung Cancer
Not operable
4-3
Figure 4-1
Lung cancer: T staging
Reproduced with permission from Hanson J, Armstrong P, Lung cancer. In: Imaging
in Oncology (eds JES Husband, RH Reznek). London: Isis Medical Media, 1998: 4566.
4-4
Figure 4-2
Lung cancer: N staging
Reproduced with permission
from Hanson J, Armstrong
P, Lung cancer. In: Imaging
in Oncology (eds JES
Husband, RH Reznek).
London: Isis Medical Media,
1998: 45-66.
4-5
4.2.2
NSCLC diagnostic work-up in Scotland
Consultation with lung cancer experts in Scotland indicates that to accurately stage
patients with NSCLC, the following diagnostic procedures are involved:









history and physical examination (including assessment of performance status,
weight and weight loss);
chest X-ray, if this is normal, but clinical suspicion is high, further investigations
should be undertaken;
haematology and biochemistry, including serum calcium, alkaline phosphatase
and liver function tests to determine metastatic status;
fibre-optic bronchoscopy (day case under topical anaesthesia) in those who are
sufficiently fit (this will yield a positive histological diagnosis in up to 80% of
cases; those who are unfit may receive sputum cytology);
CT of the thorax with contrast medium;
biopsy of mediastinal lymph nodes more than 1 cm
in the short
axis, by superior mediastinoscopy or
anterior
mediastinotomy;
pathological diagnosis by bronchoscopic biopsy, brush or bronchoalveolar lavage
cytology, percutaneous fine needle aspirate or image-guided needle biopsy;
ultrasound or other organ specific scans if there is clinical or biochemical
evidence to suggest metastatic disease (if tests are normal, incidence of occult
metastatic disease outside the chest is less than 5%); and
pulmonary function tests.
Following this, appropriate treatment of the patient is decided. Surgery,
chemotherapy, RT and palliative care are possible, with surgery (lobectomy or
pneumonectomy) being the treatment that offers the best chance of cure in patients
with NSCLC. The diagnostic/staging work-up outlined above is in line with the
recommendations in the SIGN guideline (SIGN, 1998a), the Scottish standards on
management of lung cancer (CSBS, 2001) and the BTS guideline on selection of
patients with lung cancer for surgery (BTS, 2001). However, in practice there are
regional differences in the way staging is performed, the order of tests and the
resulting treatment decisions.
CT is used for T and N staging, but false-positive and false negative results can occur.
Other conditions may cause one or more lymph nodes to be enlarged and thus be
interpreted as cancerous when in fact they are not, and metastases in a node may be so
small that the CT image is interpreted as benign when it is cancerous.
To determine where FDG-PET might be used, HTBS has had detailed conversations
with lung cancer experts in Scotland to determine the flow of diagnostic work-up and
clinical decision-making process.
4-6
Patients with suspected NSCLC can be referred to a chest physician by their general
practitioner (GP) and may already have a suspicious chest X-ray (especially if an open
access service is available locally). Relatively few patients who do not have lung
cancer are referred; an important consideration in view of the fact that the early signs
and symptoms are not so specific. A small number of cases are referred as incidental
findings during other health care e.g. on a routine chest X-ray prior to elective surgery
for another condition. Other referral patterns are also possible and still probably not
uniform across Scotland. The pattern of referral and subsequent management of
patients on the cancer register in Yorkshire, England during 1993 has been evaluated
and also identifies self-referral through Accident and Emergency departments. The
conclusion is that patients without a suspicious chest X-ray are less likely to have
specialist care and lower rates of chemotherapy, RT or surgery (Melling et al., 2002).
From the surgical viewpoint, the strategy is to establish the tissue diagnosis, then to
establish resectability (T and N status), the presence of distant metastases (M status)
and fitness for surgery. For non-clinicians, thinking in terms of these four tasks can
be helpful. In practice, however, the process is not divided up into a neat sequence.
The literature talks of an index of suspicion (usually for diagnosis of cancer) but a
more accurate understanding of the clinician's thought-process might be one index for
each of the four problems, with new information becoming available at each contact
with the patient. For example, when the patient attends for a test on their lymph
nodes they might be complaining of new pain suggestive of distant site metastases.
Following referral, the next investigation would ideally be a CT scan but, given
waiting times, bronchoscopy may be undertaken first. This has the advantage of
allowing biopsy samples to be taken for histology and random washings and
brushings for cytology.
By this stage, about 60% of cases can be diagnosed as NSCLC. Image-guided needle
biopsy can give a definite diagnosis in a further 20 to 30%. Of the remaining 10 to
20% a small number might be referred for surgery on the basis of a suspicious chest
X-ray showing a solitary tumour strongly suggestive of cancer. However, most
patients who do not have obvious advanced disease will go on for further
investigation.
Resectability depends on size, extension to ribs and pleura, and the extent of nodal
disease. CT of the lungs and abdomen (notably the liver and adrenal glands) is a
reliable guide to tumour size and will also show obvious metastases beyond the lymph
nodes in the area scanned. It also shows the size of lymph nodes, a factor that has
some prognostic value. It is common practice to regard lymph nodes that are more
than 1 cm in diameter as ‘enlarged’ or CT-positive and lymph nodes of less than 1 cm
as ‘normal’ or CT-negative. Enlarged nodes have a much higher probability of tumour
spread to that node.
4-7
Patients with lymph nodes that are not enlarged are candidates for surgery (subject to
fitness). For those with enlarged lymph nodes, mediastinoscopy is the next line of
investigation. This investigation is (close to) definitive for lymph nodes that can be
reached but, in about a quarter of cases with affected lymph nodes, mediastinoscopy
cannot detect disease. Where there is no suggestion of lymph node involvement,
patients are candidates for surgery. Where lymph node disease is detected, however,
clinical judgement is required. Small primary cancers with lymph node involvement
on the same side of the body (T1N2 disease) might be candidates for surgery but
ideally this would be in the context of a trial. Those with more extensive disease
(especially N3 disease) are very unlikely to be surgical candidates.
There appears to be one major alternative to this general work-up in Scotland, with
one centre that undertakes percutaneous image-guided biopsy of lymph nodes or of
adrenal gland/liver for metastatic disease instead of mediastinoscopy and which
reserves mediastinoscopy for cases where such a biopsy is not possible or cannot be
performed.
It is important to screen for metastases in distant parts of the body, typically by CT
scan or MRI of the brain and radionuclide bone scans. SIGN (1998a) guidance
suggests only investigating patients with symptoms that are indicative of secondary
disease in the brain and skeleton. However, it should be noted that patients with
obvious advanced disease would be identified and referred on throughout the
diagnostic process and not only at the final stage.
Similar comments apply to the assessment of patient fitness to undergo surgery. The
doctor responsible for the diagnostic investigation strategy may be able to identify
patients who are obviously unfit, even before they see an anaesthetist. For patients
with no other obvious contraindications, the anaesthetist makes a final assessment
when the patient is admitted before surgery.
In practice, treatment decisions will be complex and are now facilitated by the
multidisciplinary MCNs (section 2.2.2) being established in Scotland. For example, a
meeting of surgeons, physicians, radiologists, oncologists and palliative care
specialists might review evidence from chest X-ray, bronchoscopy, CT of lungs and
abdomen, and mediastinoscopy. In some cases decisions must be made on the
balance of probabilities. For example, CT might show enlarged lymph nodes that
cannot be reached by mediastinoscopy. Surgery can reveal the extent of lymph node
involvement. Either more accurate staging will be made at the start of the operation
or sampling of lymph nodes following resection of the primary tumour will show the
'true' extent of spread.
A typical diagnostic and treatment pathway for NSCLC in Scotland is shown in
Figure 4-3. Despite initiatives to achieve standardisation across Scotland, as
highlighted in section 5.2.3, there is still variability in the diagnostic approaches.
These will be investigated in further detail in the economic evaluation.
4-8
Figure 4-3
Diagnostic pathway in Scotland
CT
(sometimes
with fine
needle
aspiration)
NONSURGICAL
TREATMENT
ENLARGED
NODES
NORMAL
NODES
(CT-positive)
(CT-negative)
MEDIASTINOSCOPY
POSITIVE
LYMPH
NODE
NONSURGICAL
TREATMENT
SURGERY
MEDIASTINOSCOPY
NEGATIVE
LYMPH
NODE
POSITIVE
LYMPH
NODE
SURGERY
NON-SURGICAL
TREATMENT
NEGATIVE
LYMPH
NODE
SURGERY
To determine how FDG-PET might help in this diagnostic process, consultation with
Scottish experts suggested that it has four possible roles in the pre-operative staging of
NSCLC:
1. to investigate lymph nodes inaccessible after mediastinoscopy;
2. to replace mediastinoscopy in the investigation of normal or enlarged lymph
nodes;
3. to investigate the 10% of patients in whom bronchoscopy/fine needle biopsy does
not give a definite diagnosis; and
4-9
Ultrasound/CT/isotope scans for bone and brain occult metastases on the basis of
haematology/biochemistry or signs and symptoms
Patient considered fit for surgery undergoes chest X-ray, haematology,
biochemistry, bronchoscopy (fine needle aspiration)
4. as an additional procedure in the investigation of distant metastases where
sensitivity for occult metastases is around 90%.
This list is not definitive. For example, patients could be referred for FDG-PET after
bronchoscopy without having CT. However, a number of experts have indicated that
in these circumstances they would still wish to see CT results even if they had PET
for the anatomical detail.
These are not the only ways in which FDG-PET might contribute to NSCLC
management. For example, it might be used as an additional procedure to stage
patients for radical RT, helping to plan therapy by defining site of tumour, especially
in the mediastinum, as well as allowing assessment of response to this therapy. In
addition, FDG-PET may have a role in solving difficult palliative problems e.g.
causes of pain.
4.3
Methodology for clinical effectiveness analyses
4.3.1
Evaluation of sensitivity and specificity
The particular diagnostic decision of interest is the decision about whether a patient
presenting with primary NSCLC and no evidence of distant metastases has metastatic
spread to N2 or N3 lymph nodes.
This is assumed to take the form of a simple yes/no decision, which may of course be
correct or not (relative to the patient’s ‘true state’), as shown in Table 4-2.
Table 4-2
Diagnostic testing
True disease state
Imaging result
Yes
(N2/N3)
No
(N0/N1)
Yes
(N2/N3)
TP
True Positive
FN
False Negative
No
(N0/N1)
FP
False Positive
TN
True Negative
The ‘accuracy’ of a diagnostic test is normally described by two quantities, the
sensitivity and specificity (or equivalently the true positive rate (= sensitivity) and the
false positive rate (=1 – specificity)).
Sensitivity is the probability that a test result is positive given the subject has the
disease. In a suitable experiment the sensitivity can be estimated by: TP/(TP+FN).
Specificity is the probability that a test result is negative given the subject does not
have the disease. In a suitable experiment the specificity can be estimated by:
TN/(TN+FP).
In this HTA, because of the structure of the economic model used, the sensitivity and
specificity of FDG-PET was estimated for CT-negative and CT-positive patients
separately.
4-10
4.3.2
Meta-analysis
Data allowing the estimation of sensitivity and specificity are available from a number
of studies (section 4.5) and have been combined using a meta-analysis approach
(DerSimonian & Laird, 1986). The specificity and sensitivity for a particular study are
not independent, but ‘traded off’ depending on specific local rules for the
interpretation of PET images. Consequently the relationship between sensitivity and
specificity has been estimated by construction of a summary receiver operating
characteristic (SROC) curve using the unweighted regression method described in
Moses et al. (1993), and in Appendix 6. This technique allows display of the
‘estimated relationship’ in the form of a graph plotting the FP rate against the TP rate,
see for example, Figure 4-4. The pooled specificity has then been calculated by
standard meta-analysis techniques (DerSimonian & Laird, 1986).
Although, in principle, a SROC curve could be summarised by ‘reading off’ the
specificity at any desired sensitivity (or vice versa) it is not obvious that the reading of
PET scans can, in fact be ‘tuned’ in such a fashion (see also Samson et al., 2001). In
this report, therefore, the results are summarised by presenting the pooled specificity
from a random-effects meta-analysis (DerSimonian & Laird, 1986) or a fixed-effects
meta-analysis if this was not calculable. The sensitivity was estimated from the ROC
curve at this specificity.
A pooled specificity estimate was calculated by combining the logit transformed FP
rates, using inverse variance weighting and confidence intervals calculated assuming
normality (DerSimonian & Laird, 1986). Confidence intervals for the sensitivity
estimate were calculated as in Moses et al. (1993). See Appendix 6 for further details.
As part of the meta-analysis, a test was done to determine whether the SROC curve
was symmetric (this is referred to below as the test for constant odds ratios, since the
equivalent condition is that the ratio [odds (TP)/odds (FP)] be constant between
studies). Figures 4-4 to 4-6 display plots of the TP rate against the FP rate for each of
the studies, in each of the three meta-analyses, together with the fitted ROC curves. If
the model (as shown in Appendix 6) is a completely accurate description of the data,
the points will all fall close to the fitted line (as in Figure 4-6). A poor fit, with points
falling well away from the line (as in Figure 4-5) suggests that patient populations or
machine performance may differ between studies (which is, indeed, quite likely).
4.4
Critical appraisal of published literature
4.4.1
Background
This section reviews the wide variety of published material reporting on various
aspects of the use of FDG-PET in NSCLC. In addition to reports of studies of
accuracy in mediastinal staging (section 4.4.3), a number of other reports have been
published under the following headings:




systematic reviews (section 4.4.2);
detection of extra-thoracic metastases (section 4.4.4);
changes in patient management resulting from the use of FDG-PET (section
4.4.5); and
randomised clinical trials (RCTs) (section 4.4.6).
4-11
There is considerable overlap between the groups of studies dealing with mediastinal
staging, detection of extra-thoracic metastases and changes in patient management.
However, it appears worthwhile to describe separately the three types of outcome.
4.4.2
Systematic reviews
Three systematic reviews which included meta-analyses of the diagnostic
performance of FDG-PET for NSCLC were found in the literature search (Dwamena
et al., 1999; Fischer et al., 2001 and Hellwig et al., 2001). These reviews all conclude
that FDG-PET has higher sensitivity and specificity than CT for the staging of
mediastinal lymph nodes. The reviews are discussed in detail in Appendix 8. Their
conclusions were that:



FDG-PET was both more sensitive and more specific than CT in lymph node
staging;
the quality of evidence available was generally low; and
no evidence was available on patient outcomes.
Two further review articles (Haberkorn, 2001; Vansteenkiste & Stroobants, 2001)
containing narrative summaries of the available evidence were also identified.
Haberkorn (2001) claims that FDG-PET scanning is likely to be of great value in the
initial staging of NSCLC, in the planning of therapy and in monitoring response to
that therapy. In the area of staging, he suggests that a chest X-ray should be followed
immediately by a PET scan, with CT scanning used only if the FDG-PET scan is
positive. Haberkorn (2001) also claims that FDG-PET scanning is valuable in the
staging of breast and colorectal cancers, and in detecting recurrent disease in these
tumours. He concludes that the most important task for the future is to develop
diagnostic algorithms to allow optimal therapy on the basis of FDG-PET and other
imaging tools.
The review of Vansteenskiste & Stroobants (2001) concentrates on NSCLC, and
covers a wide variety of topics within this area. Specifically, they argue that:





since FDG-PET has a high sensitivity for N2/N3 disease, a negative scan will
exclude the need for mediastinoscopy. However, they also argue that
mediastinoscopy is appropriate following a positive FDG-PET scan.
They state that in their experience this strategy reduces the number of
mediastinoscopies by 50%; there is as yet insufficient data to be sure of the value
of FDG-PET in detecting distant metastatic disease;
FDG-PET may have a useful role in combination with CT in planning
radiotherapy;
in a pilot study (Vansteenkiste et al., 1998a) PET appeared valuable in selecting
patients whose mediastinal (N2) disease had been successfully treated by
induction chemotherapy. They state that a larger study is in progress to confirm
these results, and that if successful this may allow appropriate selection of
candidates for radical surgery after induction chemotherapy; and
they conclude by stating that the value of FDG-PET in NSCLC requires
validation by large-scale randomised studies, focusing on outcome parameters
(survival, quality of life and cost effectiveness).
4-12
4.4.3
Mediastinal staging
The HTBS literature search identified a total of 33 papers reporting studies of
mediastinal staging. Brief details of the study designs are shown in Appendix 9.
The results of these studies are summarised in a series of meta-analyses which are
presented in section 4.5.
A number of methodological flaws and problems affect the majority of these studies,
and make it difficult to draw conclusions about the accuracy of FDG-PET from any
meta-analysis or overview. Specific problems identified include:





many of the studies are retrospective case series;
the ‘gold standard’ for mediastinal disease is (except for one paper) nodal
dissection or sampling, but the dissection/sampling protocols vary between
papers and are not clearly described in some of them;
some of the studies considered ‘all patients referred for PET scanning’. It is
unclear whether such patients are representative of the general population of
(early stage) NSCLC patients;
many of the studies are based on quite small groups (12 of the 33 studies contain
fewer than 50 ‘evaluable’ patients); and
methods of interpreting PET images differ between studies, with the majority
using some form of visual assessment and a small number using SURs, either
alone or as an aid to interpretation. Studies relying on visual interpretation varied
in the number of readers (between one and three). In general, no assessment of
inter-observer variation was presented.
Three further points relate to the utility of these studies in informing the economic
model. First, only studies reporting results for differentiation of N2/N3 disease from
N0/N1 disease are useful in determining accuracy in pre-surgical staging; secondly
only studies which allow the three-way cross-tabulation of PET results, CT results and
‘surgical truth’ are useful here because of the structure of the economic model used
(section 5.2.4). Finally and more generally, although the study authors have generally
been careful to report that PET scans were read independently of clinical data, they
are generally less clear in reporting whether PET scans were read independently of the
CT images. In fact, since in clinical use these tools would likely be used together, it
would be appropriate, if possible, to confine analysis to studies in which they were
read together. Unfortunately it is not, generally, possible to decide whether specific
studies meet this condition.
The authors of some papers acknowledge these problems, but regard these issues as
simply part of the problems of clinical studies. From another perspective, of course,
they are simply part of the strong argument for basing decisions on RCTs whenever
possible.
When evaluating papers for clinical effectiveness, it was clear that two distinct
approaches are taken to interpretation of the PET scan results; the majority involve
‘visual interpretation’ by one or more experienced people (in some studies this
involved the grading of regions of increased uptake on a (subjective) 5 point scale
4-13
(1 = minimal uptake, 2 = lower than mediastinal blood pool, 3 = same intensity as
mediastinal blood pool, 4 = greater intensity than mediastinal blood pool, 5 = much
greater intensity than mediastinal blood pool) with 4 or 5 read as malignant, in others
a simple binary decision was taken). The others calculate standardised uptake values
(SUV) and assign as malignant any region with an SUV exceeding some cut-off
value. Vansteenkiste et al. (1998b) report that for an appropriate choice of cut-off they
obtain very similar results with visual and SUV- based approaches. For further
discussion of standardised uptake ratios (SURs), see section 4.4.5.2.
Additionally, all the reported prospective series excluded patients with ‘obvious bulky
mediastinal disease’. The papers reporting retrospective series do not state whether
such exclusions were performed, but it seems unlikely that such patients would have
been referred for PET scanning.
In summary, the majority of these studies report that FDG-PET is both more specific
and more sensitive than CT imaging, but a number of methodological flaws were
evident in the studies. None of them report any form of randomised comparison
between the methods.
4.4.4
Detection of distant metastases
Nineteen studies provide some data on the usefulness of FDG-PET scanning in
detecting distant (extra-thoracic) metastases. Details of these studies are given in
Appendix 10 and Appendix 11.
Appendix 12 presents numerical data on the incidence of ‘unexpected’ (i.e. not
conventionally detected) metastases found by FDG-PET. Some studies used nonoptimal sodium iodide (NaI) detectors (those shown in normal font in Appendices 10,
11 and 12). Despite this, these studies generally show good agreement to studies with
the optimal detectors, concluding that between 10 and 20% more distant metastases
are detected by FDG-PET imaging than by other techniques.
In general, these studies have similar limitations to those noted in section 4.4.3.
Additionally:


inclusion criteria differed between studies (Appendix 10). For example some
studies (e.g. Changlai et al., 2001; Bury et al., 1997 and Valk et al., 1995)
included all patients referred for FDG-PET scanning with suspected or proven
NSCLC, whereas other studies (e.g. MacManus et al., 2001a; Weder et al., 1998
and Lewis et al., 1994) explicitly included only patients thought suitable for
radical therapy on the basis of clinical investigation; and
FDG-PET results are generally compared with those obtained using ‘standard’
methods, but the standard varies between studies and is not tightly defined.
In summary, although there is evidence that FDG-PET may be useful in
supplementing conventional staging in patients without clinical evidence of distant
metastases, there is again a need for well-controlled trials to demonstrate conclusively
the value of the tool in this setting.
4-14
4.4.4.1 Specific sites of metastasis
Three papers deal in more detail with the application of FDG-PET scanning to detect
metastases at specific sites. Erasmus et al. (1997) and Gupta et al. (2001a) examined
the accuracy of FDG-PET scanning relative to CT scanning in assessing adrenal
masses. Erasmus et al. (1997) examined the results of FDG-PET scanning 33 adrenal
masses found on CT scan. On biopsy, 23/33 (70%) were found to be cancerous, hence
10 were falsely positive on CT scan. FDG-PET scans were positive for all 23 of the
cancerous lesions, and negative for 8/10 (80%) non-cancerous lesions.
Gupta et al. (2001a) examined 30 patients with adrenal abnormalities seen on either
FDG-PET or CT scan. In 7/30 patients the adrenal mass was biopsied, the rest were
followed over a minimum of one year using repeat CT scan, and assigned to be
cancerous or otherwise on the basis of changes in lesion size and appearance over this
period. Eighteen patients were found to have a cancerous lesion by these criteria. Five
false-negative findings and four false-positive results occurred with CT, compared
with one false positive and one false negative for FDG-PET.
Bury et al. (1998) report a comparison of bone scintigraphy and FDG-PET scanning
in 110 NSCLC patients. Areas that appeared positive on either scan were investigated
by further radiography or biopsy. The diagnostic standard used was ‘considered by
the clinician in charge to be positive’. Twenty-one areas of patients were found to
have metastatic disease (note that to be ‘discovered’, an area had to be positive on at
least one of bone scintigraphy or FDG-PET, therefore the true sensitivity of both
methods cannot be determined from these data). Both FDG-PET and scintigraphy had
true-positive rates of 19/21 (90%), however the false- positive rate for scintigraphy
was 45/89 (51%), as against 2/89 (2%) for FDG-PET. Since this work was performed
using a non-optimal NaI detector, it is possible that these results may understate the
value of FDG-PET in detecting bony metastases.
In summary, it appears that FDG-PET may have value in detecting or ruling out
metastatic spread to the adrenals or bone, but that as Gupta et al. (2001a) conclude
‘these results require confirmation in larger prospective studies’.
4.4.5
Changes in patient management
Many of the papers reviewed claims that PET scanning resulted in changes in patient
management. majority of patients, the changes described involve moving from
curative to palliative treatment, because PET detected previously unsuspected distant
or regional metastatic spread. This result is somewhat exaggerated because many of
the studies were specifically confined to patients believed to be candidates for
curative surgery or RT (e.g. MacManus et al., 2001a; Kalff et al., 2001 and Lewis et
al., 1994).
Conversely, reports of changes in management from non-resectable to resectable tend
to be sporadic notes in papers whose major focus is mediastinal staging, e.g. Changlai
et al. (2001) report that 39/156 (25%) patients were moved from resectable to nonresectable as a result of PET scanning, whereas 22/156 (14%) became resectable after
PET scanning. Similarly, Gupta et al. (1999) report that in 5/63 (8%) patients PET
showed that distant metastases apparent on conventional images were negative for
cancer.
4-15
Although interesting, these reports do not provide sufficient evidence of the value of
PET for patient management, for the following reasons:



in none of the studies was a randomised comparison performed between PET and
conventional staging techniques, which would provide the clearest evidence of
benefit;
since the studies focused on patients referred for PET scanning, the referring
physicians presumably anticipated that some changes would occur, and may have
been using PET to confirm their ‘clinical suspicions’, thus overstating the likely
effect of PET in unselected patients; and
changes in management following PET scanning may be very dependent on local
preferences, reimbursement policies, and experience with the technique. Again,
the effect of such issues on the apparent difference between PET results and
‘conventional’ results may best be controlled in a randomised trial.
MacManus et al. (2001a, 2001b) have undertaken a prospective study in patients with
nonresectable NSCLC who were potential candidates for radical chemoradiation. This
shows that PET may have the potential to improve the selection of patients for radical
chemoradiation, but that there is no evidence to show that this improves patient
survival or quality of life. A full appraisal of this study is presented in Appendix 13.
4.4.5.1 Surveys of referring physicians
Two further papers, McCain et al. (2000) and Tucker et al. (2001) report the results of
surveys of referring physicians’ views on the usefulness of PET in patient
management.
McCain et al. (2000) carried out two surveys, one covering all physicians who
referred patients with known or suspected thoracic malignancies to the Wake Forest
University Baptist Medical Center Comprehensive Cancer Center for PET scanning
between April 1998 and February 1999, asking them to indicate whether the scan
results had influenced treatment decisions, and to rate the usefulness of PET scans in
management on a five-point scale (with 1 being not at all useful and 5 being
extremely useful). Of 126 questionnaires, 98 were returned. The respondents rated
PET’s usefulness in management of 4.28 (s.d. 0.74), and in 64 cases PET was said to
have influenced treatment. The authors also sent questionnaires to 488 chest clinicians
across the US, asking whether PET was available to them, if so to rate its usefulness,
and if not whether they would like to have it available. Only 129 responses were
received, of which 51 were from physicians with access to PET. The average rating
from this group was 2.77. The authors conclude that it is important for future uses of
PET to define more closely the subgroups of patients in whom it is genuinely valuable
(they believe this to explain the discrepancy between Wake Forest and national
findings).
Tucker et al. (2001) attempted to assess the value of PET in clinical care in the first
year of use at a centre in Honolulu. They also undertook two surveys, the first
covering all referring physicians, the second restricted to two physicians (a
pneumonologist and a surgical oncologist) who referred most frequently. In the first
survey they received 464 responses from 517 mailed questionnaires (they mailed one
questionnaire per patient, so it is not clear how many physicians replied). Forty
percent of the cases covered were of lung cancer, 18% head and neck and 11%
4-16
colorectal. Two hundred and eight responses (45%) stated that the PET scan had
changed patient management, 204 (44%) that it had ‘decision making value’ and 51
(11%) that it had no value.
The second survey covered a total of 53 cases, 43 of them lung cancer. In 70% of
cases ‘therapy was affected’ (in 20 cases surgery was cancelled, in 11 cases surgery
was undertaken despite having been thought futile before the PET scan). No data were
available on the outcomes of these patients.
Although these two surveys provide an interesting picture of the use of PET in two
US centres, they clearly do not provide convincing evidence that the advantages
perceived by the respondents are real, nor that they would be realised in other clinical
settings.
4.4.5.2 Prognostic significance of SUR
Ahuja et al. (1998) reported on the prognostic significance of SUR in NSCLC. They
considered a series of 149 patients who had both a PET scan and pathologically
confirmed diagnosis of NSCLC, with the scan and diagnosis no more than eight
weeks apart. Sixty-nine patients were stage I/II, 55 stage III and 31 stage IV. The
patients were followed up using institutional tumour registry data (median follow up
21 months).
The authors assessed the association of SUR for the primary lesions by choosing a
cut-off value (they state that the log rank test was used to determine a statistically
significant cut-off) of 10. Presumably this was found as the value yielding the most
significant difference between the two groups. They state that, in this database, an
SUR value greater than 10 remained a significant predictor of survival in a
proportional hazards model even after adjustment for lesion size and stage. They go
on to suggest that SUR could be used as a prognostic tool, for example to select
patients for post-operative chemotherapy.
However, the authors make no attempt to replicate their results on independent data,
and since it is well known that the test procedure they appear to have used is likely to
inflate the apparent significance of an effect, such replication should precede any
clinical application of the approach.
One further study (Vansteenkiste et al., 1999) relates prognosis to SUR value,
unfortunately using a different cut-off value (7). However, the results of these two
studies do indeed suggest that the SUR value may be of prognostic significance.
4.4.6
Randomised clinical trials
There are two randomised trials of the use of FDG-PET imaging in NSCLC. The first
of these (van Tinteren et al., 2000) has recently been reported in The Lancet (van
Tinteren et al., 2002). One hundred and eighty-eight NSCLC patients who were
medically fit for operation and apparently clinically resectable were randomised
between a conventional work-up (CWU), based on current guidelines (e.g. National
Comprehensive Cancer Network (Ettinger et al., 1996)) and to conventional work-up
plus FDG-PET to detect locoregional or distant metastasis. Ninety-six patients were
4-17
randomised to CWU alone and 92 to CWU + PET, of whom 90 actually underwent a
scan.
Pre-treatment characteristics and work-up procedures were similar between the two
groups; 70% of patients in each group had clinical stage I/II disease. Work-up for all
patients included a chest CT scan, and 58% of patients (very similar between groups)
had at least one test to identify distant metastatic disease.
The primary outcome was the number of ‘futile’ thoracotomies performed, i.e. the
number of thoracotomies found to be definitely non-curative at operation. The
difference in futile thoracotomy rates between the CWU group (39/96) and CWU +
PET group (19/92) was significant, with p=0.003 (Chi-squared test).
Additionally, the reduction in futile surgery was relatively independent of clinical
stage (31/68 versus 16/64 in stage I/II and 8/28 versus 3/27 in stage III). The authors
commented that positive FDG-PET results, which were not confirmed by biopsy or
other imaging techniques, were not definitive for tumour and were ignored when the
decision to operate was made. They also note that the need for such confirmation may
impose additional costs and delays on the patient.
Finally, they note that the design of their study allows the effect of FDG-PET
scanning on final outcomes to be evaluated in a way that reflects the importance of the
complete diagnostic profile. For example, one patient underwent surgery despite a
negative scan result for the primary lesion, an action that was justified by the
diagnosis of NSCLC. Such interactions between FDG-PET and other diagnostic tools
are difficult to model (Kosuda et al., 2000).
Boyer et al. (2001), currently reported only in abstract and American Society of
Clinical Oncology (ASCO) conference slides, performed a similar study in Australia,
in which 179 clinical stage I/II patients were randomised to conventional staging with
or without FDG-PET. This study was designed to assess the ability of FDG-PET to
reduce the rate of ‘futile’ thoracotomies by detecting distant metastatic disease in
these apparently early stage patients.
At the time of reporting 164 patients were evaluable, 80 in the conventional arm and
84 in the FDG-PET arm. The thoracotomy rate in the conventional arm was 98%,
compared with that in the FDG-PET arm of 96% (no significant difference). The
futile surgery rates are not quoted. The death rates in the two groups after 10- months
median follow up were also extremely similar (16% versus 15%). As in van Tinteren
et al. (2002), patient management was only affected by FDG-PET finding distant
metastatic disease confirmed by other imaging or biopsy. However, in Boyer et al.
(2001), the proportion of patients with distant metastases detected by FDG-PET was
very small compared with other studies.
There were three major differences between the two studies. First, Boyer et al.
enrolled only patients who were at clinical stage I or II, whereas van Tinteren et al.
enrolled stage I, II and III. Secondly, the surgical policy used in Boyer et al. indicated
that patients with N2 disease should undergo thoracotomy, whereas operations on
patients with N2 were viewed as ‘futile’ in van Tinteren et al. Finally, in van Tinteren
et al. FDG-PET scanning was used to exclude benign lesions, whereas this was not
done in Boyer et al.
4-18
It is likely that the apparent differences in results between the studies are explained, at
least in part, by these three differences in design. First, five of the 20 ‘prevented’
thoracotomies in van Tinteren et al. (2002) were due to the detection of a benign
primary lesion and secondly Boyer et al. (2001) note that FDG-PET scanning did
detect N2 disease in 13 patients. Finally, in Boyer et al. (2001), the occurrence rate of
(FDG-PET detectable) distant metastases was very low
in the early stage group.
Unfortunately neither randomised controlled trial collected quality-of-life data,
arguing that the short-term psychological advantage of surgery, which the patient
believed might be curative would ‘bias’ this comparison. However, such data would
have been invaluable to inform the economic evaluation.
4.4.7
Limitations of the evidence
As noted by DACEHTA (2001), although there is accumulating evidence that FDGPET scanning appears to be more sensitive and specific than CT scanning in
mediastinal staging, and to be of value in detecting or investigating possible distant
metastases, there are methodological weaknesses and problems with much of the
published research.
Most crucially, the majority of published work does not involve randomised trials,
and is focused on diagnostic accuracy rather than patient outcomes such as surgery
rates, survival and quality of life.
The ‘unexpected’ results of Boyer et al. (2001) help illustrate why outcome-based
RCTs are preferable tools for the evaluation of diagnostic techniques such as PET.
First, by allowing the effect of PET scanning to be compared with genuinely
standardised alternatives and by ensuring comparability of patient groups, they
remove many potential sources of bias. Secondly, they allow the actual behaviour of
patients and clinicians when confronted with the information provided by PET
scanning to be studied, rather than relying on the assumptions underpinning model
based approaches.
4.5
Meta-analyses
Three meta-analyses have been performed, to estimate sensitivity and specificity for
CT scanning overall, to estimate sensitivity and specificity of FDG-PET in CTnegatives and CT-positives. These analyses were undertaken to inform the economic
evaluation (section 5).
4-19
4.5.1
Study exclusion criteria
The following exclusion criteria were used to exclude trials from the meta-analysis:




studies reporting only nodal-based results were excluded. Although the papers of
Wahl et al. (1994); Patz et al. (1995) and Valk et al. (1995) were included in the
Dietlein et al. (2000a) economic model and other systematic reviews, they have
been excluded from this analysis because they are based on nodal results, rather
than patient results;
studies reporting results only for N0 versus N positive were excluded;
studies which did not allow FDG-PET results to be determined for CT-negative
and CT-positive patients separately were excluded from the analyses in sections
4.5.2 and 4.5.3; and
four of the papers included (Chin et al., 1995; Vansteenkiste et al., 1998a;
Vansteenkiste et al., 1998b and Vansteenkiste et al., 1997) used a different
definition of enlarged lymph nodes from those in the remaining papers (1.5 cm
versus 1 cm). The data from these papers have been retained in the main analyses,
but are excluded in a sensitivity analysis.
The studies selected are a subset of those displayed in Appendix 9 and are shown in
Appendix 14. This latter table contains additional data extraction columns needed for
the meta-analyses presented in sections 4.5.2 and 4.5.3.
Professor P. Sharp, Chair of the TSG, reviewed all the selected studies for technical
adequacy and concluded that all the studies, with the possible exception of Bury et al.
(1996a) were technically adequate. Details are presented in Appendix 15. Since the
results of the Bury et al. (1996a) study were similar to the remaining studies, it has
been retained in the meta-analyses.
4.5.2
FDG-PET sensitivity in CT-negative patients
The 15 papers included in the analysis of CT-negative patients are shown in Appendix
13. The paper of Liewald et al. (2000) is excluded from this analysis because it only
reports data on CT-positive patients. The analysis was conducted as described in
Appendix 6.
The results of this analysis are as follow:
Total number of patients = 547
Total number of studies = 15
Pooled specificity estimate 0.9,
95% Confidence Interval (0.87, 0.93).
Estimated sensitivity at specificity 0.9 is 0.86,
95% Confidence Interval (0.79, 0.91).
The estimated SROC is plotted in Figure 4-4.
This is a fixed effects estimate because the between- study variance estimate was
negative. There was no evidence of non-constant odds ratios (Appendix 7).
4-20
False positive versus true positive and fitted SROC curve, for
CT-negative patients
0.0
0.2
0.4
True
0.6
0.8
1.0
Figure 4-4
0.0
0.2
0.4
0.6
0.8
1.0
False
Corrected, with SROC
4.5.2.1 Sensitivity analysis
The results obtained after removing the four papers that used a different threshold for
defining enlarged lymph nodes (Chin et al., 1995; Vansteenkiste et al., 1998a;
Vansteenkiste et al., 1998b and Vansteenkiste et al., 1997) were extremely similar
Pooled specificity estimate 0.9, 95% Confidence Interval (0.86, 0.93).
Estimated sensitivity at specificity 0.9 is 0.85, 95% Confidence Interval (0.77, 0.91).
This is a fixed effects estimate because the between study variance estimate was
negative. There was no evidence of non-constant odds ratios (Appendix 7).
4-21
4.5.3
PET sensitivity in CT-positive patients
The data from 15 studies were available for the analysis of CT-positive patients. The
details were essentially as in section 4.5.2, except that the paper of Liewald et al.
(2000) could be included, and that of Farrell et al. (2000) was excluded, because these
authors only considered CT-negative patients.
Results from all studies:
Total number of patients = 357
Total number of studies = 15
Pooled specificity estimate 0.76,
95% Confidence Interval (0.69, 0.82).
Estimated sensitivity at specificity 0.76 is 0.92,
95% Confidence Interval (0.87, 0.95).
The estimated SROC is plotted in Figure 4-5.
This is a fixed effects estimate because the between- study variance estimate was
negative. There was no evidence of non-constant odds ratios (Appendix 7).
False positive versus true positive and fitted SROC curve, for
CT-positive patients
0.0
0.2
0.4
True
0.6
0.8
1.0
Figure 4-5
0.0
0.2
0.4
0.6
0.8
1.0
False
Corrected, with SROC
4-22
4.5.3.1 Sensitivity analysis
Again, similar results were obtained when the four papers that used a different
threshold for defining large lymph nodes were excluded.
Pooled specificity estimate 0.75, 95% Confidence Interval (0.67, 0.82).
Estimated sensitivity at specificity 0.75 is 0.92, 95% Confidence Interval (0.86, 0.96).
This is a fixed effects estimate because the between- study variance estimate was
negative. There was no evidence of non-constant odds ratios (Appendix 7).
4.5.4
CT sensitivity and specificity
The data from 17 studies were available for the analysis of all patients (CT-positive
and negative). All the studies shown in Appendix 14 were included, except the studies
of Liewald et al. (2000) and Farrell et al. (2000). Additionally, data from the studies
of Dunagan et al. (2001), Hagberg et al. (1997) and Steinert et al. (1997) were
included, as they supplied patient-based data sufficient to calculate specificity and
sensitivity for CT screening of mediastinal lymph nodes.
The results of this analysis are as follow:
Total number of patients = 863
Total number of studies = 17
Pooled specificity estimate 0.76,
95% Confidence Interval (0.70, 0.81).
Estimated sensitivity at specificity 0.76 is 0.65,
95% Confidence Interval (0.61, 0.69).
The estimated SROC is plotted in Figure 4-6.
This is a random effects estimate. There was no evidence of non-constant odds ratios
(Appendix 7).
4-23
False positive versus true positive and fitted SROC curve, for all
CT data
0.0
0.2
0.4
True
0.6
0.8
1.0
Figure 4-6
0.0
0.2
0.4
0.6
0.8
1.0
False
Corrected, with SROC
4.5.4.1 Sensitivity analysis
A sensitivity analysis performed by removing the four studies reporting results with a
different threshold for defining enlarged lymph nodes gave very similar results:
Pooled specificity estimate 0.78, 95% Confidence Interval (0.71, 0.83).
Estimated sensitivity at specificity 0.76 is 0.63, 95% Confidence Interval (0.59, 0.68).
This is a random effects estimate. There was no evidence of non-constant odds ratios
(Appendix 7).
4.5.5
Meta-analysis conclusions
Although the plots suggest some inadequacy in the fit, there is no evidence that any
available study level covariates are able to explain the observed heterogeneity, and the
summaries appear to adequately reflect the observed sensitivity and specificity. Note
that in the analysis of CT-negative patients (section 4.5.2), the range of false-positive
rates is restricted, which may exaggerate the apparent lack of fit seen in Figure 4-4.
Additionally, the two most outlying studies in this group Magnani et al. (1999) and
Weng et al. (2000) both contribute very small numbers of patients (three and four,
respectively) to this analysis. The results are essentially unaltered if they are removed.
4-24
Consequently, the meta-analyses of sensitivity and specificity demonstrate that FDGPET appears to discriminate diseased from non-diseased nodes, both for normal sized
(section 4.5.2) and enlarged (section 4.5.3) mediastinal lymph nodes.
Interestingly, the estimated sensitivity and specificity for FDG-PET in both CTnegative and CT-positive patients are very similar to those found by Dietlein et al.
(2000a), despite the differences in both analysis methods (no account taken of the
joint distribution of sensitivity and specificity) and study selection.
4.6
Assessment of safety in clinical practice
Potential risks associated with PET imaging relate to the administration of the
radiopharmaceutical and the dose of radiation delivered by the PET tracer, but this is
relatively small.
There is a very small risk of secondary cancers posed by the radiation dose used in
PET scanning. One FDG-PET scan delivers a radiation dose of 7 mSv, which is
similar to that associated with CT and according to the National Radiological
Protection Board (1998a) corresponds to a lifetime cancer risk of less than 1 in 3000
for a person of normal life expectancy.
Silberstein (1998) states that there were no reported adverse events from 80 000 PET
scans undertaken in 22 US PET centres. No adverse events related to FDG-PET
scanning were reported in any of the studies reviewed for this HTA. Also, a
systematic review of PET in all cancers (Reske & Kotzerke, 2001), evaluating 533
papers in detail, did not identify any radiopharmaceutical-related complications or
adverse events.
Therefore, it is reasonable to conclude that PET scanning is essentially free from
short-term adverse effects, as the data are incompatible with anything except an
extremely low rate of adverse effects.
4.7
Conclusions
FDG-PET imaging appears to produce superior specificity and sensitivity compared
with CT scanning in staging mediastinal lymph node involvement in potentially
operable NSCLC patients. However, it is notable that in CT-positive patients (with
enlarged nodes), the pooled estimate of specificity of FDG-PET is only 0.76, CI (0.69,
0.82), so for one in four of these patients the test result will be a false positive, e.g.
indicating that they have distant metastases, when they do not. For CT-negative
patients the specificity of FDG-PET is much higher 0.9, CI (0.87, 0.93) and in fact the
confidence intervals for CT-negative and CT-positive patients do not overlap.
It also appears to be more accurate for the assessment of some distant sites of
metastatic disease (specifically, evidence exists for adrenal glands and bone
metastases).
In both cases the available evidence consists of data from generally rather small, nonrandomised studies, many of which focus on selected patient groups. However, the
studies present a reasonably consistent picture and suggest an advantage for FDGPET over CT in these applications.
4-25
There is some evidence that the results of FDG-PET scanning can cause changes in
patient management. In two studies patient management was changed in over 60% of
patients (Kalff et al., 2001 and Kutlu et al., 2001), but both of these studies used sub–
optimal PET technology. Other studies report such changes in between approximately
10% and 40% of patients.
Only two studies employed a randomised, simultaneous comparison between patient
management with and without FDG-PET (van Tinteren et al., 2000; Boyer et al.,
2001). These two studies provide contradictory results, suggesting that the value of
FDG-PET scanning, as measured by final patient outcomes, is dependent on the
treatment decision-making protocol. In this case, the type of patients scanned, whether
PET is used to detect benign primary lesions and what is considered a futile
thoracotomy all have an important part to play.
There remains a need for large well-controlled trials to demonstrate conclusively the
benefits of FDG-PET in staging potentially operable NSCLC patients.
Other possible applications of FDG-PET, such as determination of prognosis and
assessment of treatment response lack a conclusive evidence base.
The available evidence (Section 4.6) suggests that FDG-PET is essentially safe, i.e.
essentially without clinically observable adverse events.
4-26
5
ECONOMIC EVALUATION - NSCLC
Summary

A number of possible strategies for the utilisation of FDG-PET based on diagnostic
pathways used in Scotland for NSCLC have been explored. All but one focus on the
use of FDG-PET following CT scanning.

Economic evaluation of the introduction of FDG-PET involves estimating the change
in resource use, impact on survival and changes in quality of life for the whole patient
journey through each of the strategies to end of life or sustained cure. It has not
proved possible to obtain reliable data for all parts of the model, particularly for
utilities. However, model testing indicates that the model’s prediction of the number
of operations avoided by the use of FDG-PET is similar to estimates from the van
Tinteren et al. (2002). This gives some confidence in the model.

The results from the model suggest that three strategies are not strongly differentiated
by their average patient benefits and costs: strategy 1 of sending all patients to
surgery, strategy 3 of mediastinoscopy with surgery for negatives and non-surgical
treatment for positives, and strategy 7 of FDG-PET with surgery for negatives and
mediastinoscopy for positives.

In CT-positive patients, strategy 1 shows a worse patient outcome and slightly higher
cost than strategy 3. In CT-negative patients, strategy 3 is more costly but slightly
more effective than strategy 1, to give an incremental cost effectiveness ratio (ICER)
of £18,589. This raises doubts as to whether the model is correctly valuing costs and
utilities associated with surgery. Strategy 7 is the most costly of the three, with
slightly higher patient benefits. The base case suggests that the additional benefits of
strategy 7 are small relative to their higher costs in CT-positive patients (ICER
£58,951). However, it appears more likely that strategy 7 is cost effective in CTnegative patients (ICER £10,475).

Sensitivity analysis shows a lower accuracy of FDG-PET increases the ICER of
moving from strategy 3 to strategy 7 in CT-positive patients, but has less impact in
CT-negative patients. The ability of FDG-PET to detect distant metastases is
uncertain. If this is similar to its accuracy in detecting enlarged nodes, the ICER of
moving to strategy 7 in CT-positive patients is considerably improved.

Strategies have been differentiated by cost. It has not been possible to differentiate
patient life expectancies or utilities to the same degree. Modelling shows limited
differences in aggregate patient benefits between strategies 1, 3 and 7. Small absolute
changes to these aggregates would significantly affect the reported ICERs. Accurately
addressing this requires clinical data as to FDG-PET accuracy in detecting metastases
as well as enlarged nodes, and greater differentiation of life expectancies after
treatment. Better patient utility data during and after treatment is also needed.
Modelling conclusions should be confirmed through the collection of health services
research data.
5-1
5.1
Literature search
5.1.1
Search strategy
Searches were undertaken, in July 2001, as part of the scoping to help define the
assessment question (see section 3.2). The NHS Economic Evaluation Database (NHS
EED), the Health Economic Evaluations Database (HEED) and the websites of major
health economics research centres were searched for economi c evaluations.
In addition:
 the databases MEDLINE (Ovid), PreMEDLINE (Ovid) and Embase (Ovid) were
searched. The search was split into three concepts: positron emission
tomography, non-small cell lung cancer (NSCLC) and terms to identify economic
evaluations. All relevant subject headings and free text terms were identified for
each concept. The search was restricted to studies published from 1990 onwards.
No language restrictions were applied;
 members of the TSG and experts were consulted to check for further economic
evaluations; and
 the bibliographies of relevant studies were scanned for further evaluations.
Further information about the search is presented in Appendix 5.
5.1.2
Criteria for inclusion and exclusion of studies
The following exclusion criteria were applied when reviewing the economic literature
search results:
1. review articles not containing data in the form of a model or study;
2. studies not carried out in a population that might be broadly relevant to Scotland (i.e.
American or European); and
3. articles not written in English.
5.1.3
Data extraction
The studies used in the economic modelling are described in Appendix 16. Critique of
these studies appears in the development of the HTBS economics model in section
5.2.10.
5.2
Economic methods
5.2.1
Background
Economic evaluation is the comparison of the costs and benefits of two or more
courses of action or options. It involves the identification, measurement and valuation
of resources used and benefits as seen from a stated perspective and over a stated time
horizon. The results quantify the costs and benefits to allow comparisons with other
uses of the resources. The most efficient option is the one that gives the greatest
benefit from the resources. Economic evaluation has been applied extensively in
health care and 'good practice' guidance is available, including guidance from HTBS
(HTBS, 2002b). This economic evaluation was carried out with this guidance in mind
and sought to create a model that clearly reflects the diagnosis and treatment of
patients in NHSScotland.
5-2
For diagnostic technologies, Sassi et al. (1997) note that one of the main deficiencies
of economic evaluations is a failure to consider how diagnostic information impacts
on patient management and final outcomes. Commonly, evaluations implicitly
assume that more accurate tests lead to health gain. Instead, they advocate a threestage process that includes:
(i)
assessing how the sensitivity and specificity of a technology varies across
types of disease and patient;
(ii)
taking explicit account of the response of clinical decision-makers to further
diagnostic information either by modelling the decision-making process or by
observing the use of the technology in practice (studying the empirical
relationship between information inputs and treatment outputs from the 'black
box' of decision-making); and
(iii) explicitly modelling the impact of change in management on final outcomes.
In Section 4 of this report, the evidence available for these three components has been
critically appraised and will be used as a basis for the economic modelling.
5.2.2
Objectives of the economic evaluation
1. To review the existing English-language literature on the economics of FDG-PET
in staging NSCLC in order to assess the quality and relevance to the issue facing
NHSScotland.
2. To use the selected literature as the basis for constructing a simple spreadsheet
that models the flow of patients through different diagnostic and treatment
strategies for NSCLC.
3. To use this model to estimate the costs and benefits of each strategy, and hence to
estimate the net costs and benefits of introducing FDG-PET for this specific
indication.
4. To assess whether the key economic results arrived at above would still hold
under alternative plausible scenarios.
5.2.3
The potential for use of FDG-PET in NHSScotland
The use of FDG-PET must be considered in the context of the diagnostic pathway and
subsequent treatment management decisions used for patients with NSCLC in
Scotland. A ‘standard pathway’ was identified following initial discussion with lung
cancer experts in Scotland. This is outlined in section 4.2.2. However, further
questioning of the detail of the pathway showed that there is variation across Scotland
in the diagnostic procedures that are undertaken and subsequent management of
patients (Appendix 17). This has led to the identification of five possible diagnostic
strategies that are plausible for NSCLC in Scotland, four of which involve FDG-PET.
5.2.4
Model structure
Most experts believe that CT would always be needed in the diagnostic pathway given
the lack of anatomical detail provided by PET. Hence the economic modelling
concentrates on strategies in which CT has been performed and patients are classified
5-3
as CT-positive (enlarged nodes) or CT-negative (normal nodes) then further
investigations and treatment are undertaken.
The five possible diagnostic strategies are compared with two options that will test the
economic model at its limits, but which would not be used in clinical practice
(strategies 1 and 2).
Strategies after CT:
1. Send all patients for surgery without further testing.
2. Send all patients for non-surgical treatment (chemotherapy and/or RT) without
further testing.
3. Investigate all patients by mediastinoscopy – if this is negative refer for
surgery and if positive refer for non-surgical treatment.
4. Investigate all patients by mediastinoscopy – if this is negative send them for a
FDG-PET scan (negative FDG-PET for surgery, positive FDG-PET for nonsurgical treatment) and if positive refer for non-surgical treatment.
5. Investigate all patients by FDG-PET scan – if this is negative refer for surgery,
if this is positive refer for non-surgical treatment.
6. Investigate all patients by FDG-PET scan – if FDG-PET is negative refer for
mediastinoscopy (and if this is negative then for surgery, if positive then for
non-surgical treatment), if FDG-PET is positive refer for non-surgical
treatment.
7. Investigate all patients by FDG-PET scan - if FDG-PET is negative refer for
surgery. If FDG-PET is positive and distant metastases are indicated (N0/1
M1) refer for non-surgical treatment, otherwise refer for mediastinoscopy
(negative for surgery, positive for non-surgical treatment).
These options are presented schematically in Figure 5-1. Note that in Figure 5-1,
‘non-surgical treatment’, refers to chemotherapy and/or RT.
In addition, a strategy of using FDG-PET before CT is considered in the sensitivity
analysis (section 5.4).
One expert noted that PET could be useful in decision- making for radical RT
treatment (CHART). However, as discussed in section 4.4.5 there is insufficient
evidence to determine long-term resource use and patient outcomes (Appendix 13) for
this use of FDG-PET in this situation. Hence it has not been considered in this report,
but this will clearly be an important area for consideration when more data
accumulate.
CT scanning is not a perfect test for regional disease but the division of patients into
those with normal and enlarged lymph nodes does create ‘low-risk’ and ‘high-risk’
groups. Since these differ, each of the seven strategies was run for each group
separately.
5-4
Figure 5-1
NSCLC diagnostic pathways after CT
1. All for surgery
2. All for non-surgical
treatment
–ve
Surgery
+ve
Non-surgical
treatment
3. Mediastinoscopy
–ve
–ve
Surgery
+ve
Non-surgical
treatment
–ve
Surgery
+ve
Non-surgical
treatment
PET
4. Mediastinoscopy
+ve
Non-surgical
treatment
–ve
Surgery
+ve
Non-surgical
treatment
–ve
Mediastinoscopy
5. FDG-PET
6 FDG-PET
+ve
Non-surgical
treatment
–ve
Surgery
7. FDG-PET
+ve (N0/1 M1)
+ve
(other)
Non-surgical treatment
–ve
Surgery
+ve
Non-surgical
treatment
Mediastinoscopy
+ve : positive
–ve : negative
‘Non-surgical treatment’ – chemotherapy and/or radiotherapy.
5-5
On the basis of the seven strategies following CT, the economic model has been
constructed as follows:
 an estimate made of the underlying (‘true’) staging distribution in the population
who may be eligible for PET;
 sensitivity, specificity, mortality and cost estimated for each type of test;
 assumptions made about clinicians decision-making following staging results;
 conversion of these changes in management into health outcomes; and
 diagnostic strategies compared in terms of resource use and health gain.
5.2.5
Identification and measurement of the potential benefits and costs of FDGPET
The economic issues surrounding the use of FDG-PET in the investigation of patients
with NSCLC relate to the fact that FDG-PET can detect small but clinically
significant metastases in the lymph nodes and in distant sites in the body. As a result
it may:
(i)
increase the number of correct operations in those for whom it offers a
potential cure (N0/1 M0) and reduce the number of missed operations
within this group;
(ii)
avoid the resource cost of futile operations in patients for whom it does
not offer a potential cure (N2/3 and M1 patients);
(iii)
avoid the mortality and morbidity associated with futile operations;
(iv)
by altering the number of futile operations, alter the number of ‘open and
shut operations’ where N2/3 or M1 patients are operated upon, the futility
of the operation realised during operation and patients referred on to
appropriate palliation;
(v)
allow palliative treatment to be offered at an earlier stage of the disease
when symptom control may be more effective in N2/3 and M1 patients
who are not operated upon;
(vi)
allow more appropriate palliative care to be offered to N2/3 M1 patients
who are not operated upon; and
(vii) reduce the numbers of other diagnostic investigations.
Offsetting these potential advantages might be factors such as:
(i)
the costs of setting up and running the PET scanner;
(ii)
changes to the number of correct operations among N0/1 M0 patients due
to the specificity of PET and false positive results;
(iii)
additional costs of palliative treatment if patients are being referred at an
earlier stage;
(iv)
additional side effects from a longer period of palliative treatment; and
(v)
loss of the hope which potentially curative surgery offers (even if this
subsequently proves to have been false hope because the patient had
advanced disease and the operation was futile).
5-6
Table 5-1
Comparison of estimates used in NSCLC economic models
Variable
Base case patient
Prevalence of N2/N3
CT sensitivity
for N2/N3
CT specificity
for N2/N3
FDG-PET
sensitivity
FDG-PET
specificity
Mediastinoscopy:
Specificity
Sensitivity
CT mortality
PET mortality
Biopsy mortality
Mediastinoscopy
mortality
Surgery mortality
Surgery morbidity
Biopsy morbidity
Mediastinoscopy
morbidity (years)
Gambhir et al. (1996)
Otherwise healthy
64-year-old
white man
31%
Dietlein et al. (2000a)
62-year-old, ASA okay,
bronchoscopy and
thoracic CT already
30%
67%
60%
73%
77%
90%
91%
CT-negative 76%
CT-positive 89%
CT-negative 97%
CT-positive 81%
CT-negative 74%
CT-positive 95%
CT-negative 96%
CT-positive 76%
0.0025%
0%
0.3%
100%
78%
0
0
-
-
0.5%
3%
1 month
2.5 days
3.7%
0.1 year
-
-
0.02
Life expectancy
after surgery
7 years if ‘cure’
Life expectancy
after palliation
1 year ‘unresectable’
Cost of thoracic CT
Cost of thoracic
FDG-PET
Cost of biopsy
Cost of
mediastinoscopy
Cost of surgery
Non-surgical
treatment
Discount rate
Scott et al. (1998)
Otherwise healthy
64-year-old
white man
$700 (£467)
$378 (£252)
$1,200 (£800)
$2,000 (£1,333)
$3,000 (£2,000)
$4,360 (£2,907)
$30,000 (£20,000)
$0
N/A
$18,500 (£12,333)
N0/1, M0 4.5 years
N2/3, M0 1.8 years
M1
0.5 years
N0/1, M0 2.6 years
(resectable)
N2/3, M0 1.8 years
M1
0.5 years
585 EURO (£364)
1,227 EURO
(whole body) (£763)
1,138 EURO
(£708)
11,656 EURO (£7,249)
11,378 EURO
(£7,077)
5%
5-7
5.2.6
Constructing the economic model
The Scottish economic model started with an assessment of the economic models of
Gambhir et al. (1996), Scott et al. (1998) and Dietlein et al. (2000a). The key inputs
to these economic models are presented in Table 5-1.
The estimates used in the three models are broadly similar, apart from the cost of
procedures, with FDG-PET ranging from £763-£1,333 and surgery ranging from
£7,429-£20,000. As may be anticipated, the cheaper costs occur in the German study
(Dietlein) and more expensive costs occur in the US study (Gambhir).
These models all used cost-utility analysis with QALYs. QALYs are appropriate for
this disease given the different morbidities associated with the different stages of the
disease and with the associated treatments. However, caveats associated with the
QALY calculations are discussed in section 5.2.9.2.
Dietlein et al. (2000a) have constructed the most detailed model, with clear
explanations of the source of the inputs to the model and the estimates of benefit that
seem plausible for the Scottish situation. However, this study has some limitations:
 it does not consider all plausible options for the use of FDG-PET (as outlined in
section 5.2.4);
 the simple approach taken of combining original data from the literature on the
sensitivity and specificity of tests independently is inappropriate; and
 costs are taken from German national reimbursement rates and charges, and
hence cannot be assumed to be representative of Scotland.
Despite the limitations, the Dietlein model is still useful to confirm the main costs and
benefits associated with NSCLC, to give an outline for an economic model structure
that is appropriate Scotland, and to provide a basis for some of the data inputs.
5.2.7
Methods of analysis
The impact of FDG-PET is analysed by a cost-utility analyses, which sets out the
resource use and calculates the number of QALYs from the effect on survival and the
changes in quality of life for each strategy.
Sensitivity analyses were performed to make allowance for the uncertainty in inputs
to the model. This involves varying the data inputs in the base case to assess the
impact on the results, indicating which of the data inputs contribute most to the main
findings of the economic evaluation.
5.2.7.1 Delays in diagnosis and treatment
The number of investigations was assumed not to delay treatment or to alter the
patient’s prognosis (except through changes to staging).
5.2.8
Perspective and horizon
HTBS guidance (HTBS, 2002b) indicates that a HTA is undertaken from a full
societal perspective considering social and ethical issues alongside the issues of the
clinical and cost effectiveness of the health technology. However, it is recognised that
5-8
in the economic evaluation it may not be possible to quantify all the consequences and
resources associated with such a wide perspective. Consequently, for the base case,
the economic evaluation should assess changes from the stance of NHSScotland,
patients, families and carers, with quantification of other costs and consequences as
far as possible. It also states that the time horizon should be sufficient for the main
health outcomes and resource uses to be explored, with any use of extrapolation fully
explained.
In this analysis, only NHS costs relating to NSCLC management were included, as
this would cover the key costs given the short life expectancy and intensity of
treatment received by these patients. Similarly, the time horizon is assumed to be the
lifetime of the patient.
5.2.9
Model inputs
The inputs for the HTBS economic model for Scotland are summarised in Table 5-2,
with a more detailed explanation of their source in the following sections.
Table 5-2
Inputs to the HTBS economic model: base case
Variable
Base case patient
Prevalence of N2/N3
True staging distribution
FDG-PET sensitivity
FDG-PET specificity
Mediastinoscopy:
Specificity
Sensitivity
CT and PET mortality
Mediastinoscopy mortality
Surgery mortality
Life expectancy (LE) after surgery
LE after palliation
Utilities to reflect health-related
quality of life
Cost of thoracic FDG-PET
Cost of mediastinoscopy
Cost of surgery
Non-surgical treatment:
Radical radiotherapy
Chemotherapy
Best supportive care
Input / assumption
62-year-old fit for either surgery or
non-surgical treatment (Dietlein et al., 2000a)
30% (Dietlein)
See section 5.2.9.1 on ‘Epidemiology’
CT-negative 86%
CT-positive 92%
(Section 4.5)
CT-negative 90%
CT-positive 76%
(Section 4.5)
100% (Dietlein)
72% (Dietlein)
0% (Dietlein)
0.5% (Dietlein)
3.7% (Dietlein)
N0/1, M0 4.5 years
N2/3, M0 1.8 years
M1
0.5 years
(Dietlein)
N0/1, M0 2.6 years
N2/3, M0 1.8 years
M1
0.5 years
(Dietlein)
See section 5.2.9.2 on ‘Health-related quality of life’
£677
(HTBS calculation, see chapter 9)
£375
(based on Scottish data on stay and cost)
£3,419
(based on Scottish data on resource use and cost)
£2,102
£4,003
£3,371
(HTBS Comment, 2001b and HTBS radiotherapy costs)
5-9
It is interesting to note that the Scottish costs for procedures are even cheaper than the
German costs. This is discussed further in section 5.2.9.3.3.
5.2.9.1 Epidemiology
It is necessary to determine which patient group is likely to be affected if FDG-PET
were to be introduced. The base-case analysis assumes the patient is a 62-year- old
man with no co-morbidities of relevance to operative risk or prognosis.
Ideally, the economic evaluation would be carried out with knowledge of the true
staging distribution of the patients. Data from three Scottish audits of patients with a
diagnosis of lung cancer were identified (Gregor et al., 2001; Kesson et al., 1998 and
Fergusson et al., 1996) and help determine the epidemiological inputs to the model.
Data from Gregor et al. (2001) suggest the distribution shown in Table 5-3.
Table 5-3
Distribution of lung cancer
All lung cancers1
Definite NSCLC2
Localised
33%
41%
Regional spread
25%
28%
Distant metastases
31%
25%
Unknown
11%
6%
1 Excludes 9% of the original sample for which records could not be traced.
2 Excludes small cell lung cancer and 29% of patients who had no histology.
It should be emphasised that this is not definitive because the data reflect
imaging/staging practices in the mid-1990s. The study also showed that many patients
were not fully investigated. If PET had been available and it had detected small foci
of secondary disease, then the proportions would be more evenly allocated across the
three stages listed.
The other problem is that the audit applies to the whole cohort of lung cancer patients;
it is not specific to the group who might be eligible for PET. For example, many
patients with clear metastatic disease will have been excluded as will those obviously
unfit for major surgery.
To overcome this, the model assumptions have been based on the model of Dietlein et
al. (2000a). These are as follows:
 patients have a definite diagnosis of lung cancer and require staging;
 assume that patients have already had chest X-ray, bronchoscopy and CT;
 patients would be fit for surgery if this were indicated;
 30% of patients have N2 or N3 disease;
 10% have occult metastases that are only detected by PET;
 for N0/N1 disease, 23% have enlarged lymph nodes; and
 for N2/N3 disease, 60% have enlarged lymph nodes.
The underlying staging distribution for the patients who might be candidates for PET
can be determined from Table 5-4. This table shows the estimated proportion of
patients at each stage of disease compared with CT scan results – either normal lymph
nodes (CT-negative) or enlarged lymph nodes (CT-positive).
5-10
Table 5-4
Distribution of candidates for PET
Normal lymph nodes
Enlarged lymph nodes
N0/1, M0
48.4
14.6
N0/1, M1
5.4
1.6
N2/3, M0
10.7
16.3
N2/3, M1
1.2
1.8
The assumptions from Dietlein et al. (2000a) are consistent with a rate of metastases
at distant sites of 5% (M1 disease). Advice received during consultation was that the
figure in UK clinical practice is likely to be nearer to 10%. To reflect this, the figures
in the Table 5-4 were doubled for M1 disease in the base case and the figures for other
stages were reduced on a pro rata basis.
5.2.9.2 Quality of life
The data to reflect quality of life are effectively weights attached to the survival
figures in Table 5-2. Taking one as being equivalent to full health and zero as a state
that is as bad as being dead, other health states can be ranked and valued (including
potential negative values) according to their inherent unpleasantness. There are no
Scottish utility values for this disease, so literature estimates have been used.
Three relevant studies were identified from the literature that calculated utilities.
Berthelot et al. (2000) considered metastatic NSCLC and took values from 24
oncologists using a visual analogue scale. The following utilities were derived:
 best supportive care: utility 0.53 (survival 0.49 years); and
 chemotherapy: utility 0.52 to 0.65 depending on which regimen used (survival
0.76 – 1.06 years).
Values in a paper by Marshall et al. (2001) were derived from Earle et al. (2000), but
this source does not clearly identify who made the utility judgements, but it appears to
be the authors themselves. These values are:
 local disease: utility 0.88;
 regional disease: utility 0.8; and
 distant metastases: utility 0.69.
Table 5-5 sets out the utilities used in the base case.
Major assumptions have had to be made in this step of the model. Firstly, utility
values have had to be drawn from different and questionable sources for the current
context. Secondly, while it has been possible to differentiate costs for different stages
of treatment, it has not been possible similarly to differentiate utility values for
different stages of treatment beyond that stated in Table 5-5. Little is known about the
utilities in those sent for correct or for futile operations, or about the effect upon
utility of RT, chemotherapy and other supportive care packages for the three distinct
stages of disease.
5-11
Table 5-5
Stage of disease
N0/N1, M0
Utilities assigned: base case
Treatment
Surgery
Utility*
0.88
N2/N3, M0
Surgery
0.65
N0-3, M1
Surgery
0.65
N0/N1, M0
N2/N3, M0
N0-3, M1
Non-surgical
treatment
Non-surgical
treatment
Non-surgical
treatment
0.65
0.65
0.65
Based on
Earle’s figure for local disease
Berthelot’s figure for advanced disease which
responds to treatment
Berthelot’s figure for advanced disease which
responds to treatment
Berthelot’s figure for advanced disease which
responds to treatment
Berthelot’s figure for advanced disease which
responds to treatment
Berthelot’s figure for advanced disease which
responds to treatment
*An additional adjustment was made to assume that the last month of survival before
a lung cancer death would be 0.52 based on Berthelot’s figure for advanced disease
that does not respond well to treatment.
5.2.9.3 Resource use
The resource use of relevance for each strategy is as follows:
 FDG-PET scan;
 mediastinoscopy;
 surgery (resection of lung);
 follow up after potentially curative surgery;
 treatment of recurrence after potential cure;
 palliative treatment for advanced disease; and
 follow up after palliative treatment.
All the costs stated here are at 2002/03 prices.
5.2.9.3.1 FDG-PET scan
HTBS has calculated the cost of a FDG-PET scan in section 9.6 using a bottom-up
approach. A complex PET scan (high resolution with attenuation correction) would
cost around £677. The FDG-PET Centre at St. Thomas's Hospital, London also
indicated their PET scan charges to other NHS trusts. This was £784 for a body scan
(scan with no attenuation correction) and £873 for a complex scan.
Although there is a difference in costs here, it is important to note that the cost per
scan calculated by HTBS is modelled on a PET facility operating in Scotland.
However, the difference between the estimated costs per scan will have little impact
on the results presented here.
5.2.9.3.2 Mediastinoscopy
The cost of mediastinoscopy was estimated on the basis that 50% were day cases and
50% required one night stay in hospital. The time in theatre is assumed to be 15
minutes (Professor J McKillop, Muirhead Professor of Medicine, University of
Glasgow, Personal communication, 2001). It is feasible to carry out more procedures
as a day case but patients often receive other investigations at the same time.
However, this also means that not all of the costs are attributable to mediastinoscopy
and the cost used is thus a slight overestimate.
5-12
From Scottish Health Service Costs (Common Services Agency, Information and
Statistics Division, 2001), and indexing at 5% for 2002/03 prices, a surgical day case
costs £393 and a night in hospital costs £357 (this includes £78 for theatre). It is thus
assumed that the cost of a mediastinoscopy is £375.
5.2.9.3.3 Surgery
The cost of surgery reflects several potential operations. The type of surgery depends
on the site of the primary tumour. In some cases lobectomy is adequate but in the
remainder a pneumonectomy is required. The cost of surgery was based on a median
stay of eight days (Mr A Kirk, Consultant Cardiothoracic Surgeon, Western
Infirmary, Glasgow, Personal communication, 2002). It is assumed that 5% of
patients require Intensive Therapy Unit (ITU) admission and the remainder go to the
High Dependence Unit (HDU) for one night.
The Scottish Health Service Costs (Common Services Agency, Information and
Statistics Division, 2001) show the average cost per case in a general surgical ward in
a Scottish acute hospital to be £1697 with an average stay of five days. Indexing this
at 5% for 2002/03 prices, this is £1782. This implies an average cost per day of £357.
This includes allowances for medical staff time, nursing staff time, pharmacy, other
health care workers (Allied Health Professions: AHPs), theatre time and laboratory
costs as well as overheads. Thus a seven-day stay would cost as follows:
Medical staff
Nursing staff
Pharmacy
AHPs
Other direct care
Theatre
Laboratory
“Overheads”
TOTAL
£318
£669
£180
£124
£22
£623
£155
£765
£2,856
A stay of eight days involves seven days on the ward at £357 per day as above, plus
one day in HDU at £835 for 95%, plus one night in ITU at £1312 for 5%. Note that
the HDU cost is calculated as the average of general surgical ward and intensive care
costs. In addition, it is assumed that after discharge the patient consults their GP (or
practice nurse) four times at a cost of £15.30 per consultation. The cost including
follow-up is thus £3,419. This estimated cost is much lower than that used by Dietlein
et al. (2000a).
The Dietlein et al. (2000a) figure for surgery includes an allowance for 12 days on a
surgical ward, three days in intensive care, plus a special payment for the surgery
carried out. By contrast, the Scottish figures would be seven days on a surgical ward,
one day in intensive care and no special allowance for surgery (although it could be
argued that theatre costs might be underestimated by this method).
The German cost per day for general surgery is 321 euros and for intensive care 1218
euros. At an exchange rate of one euro equals 63.3 pence; this converts to £203 and
£772 respectively. The Scottish figures are £357 and £1312. Therefore, the Dietlein
et al. (2000a) figure is higher because of:
5-13
assumed longer hospital stay, especially in
(i)
(ii)
(iii)
intensive care;
use of ITUs rather than HDUs as in Scotland; and
a special remuneration allowance of 4350 euros (£2,754) for carrying out
the procedure. This is partly offset by lower costs per day for ward and
intensive care.
Those correctly undergoing surgery (N0/1 M0) are assumed to incur only the cost of
surgery of £3,419. While this figure does make an allowance for theatre time, this
may be low for lung resection. Similarly, some correctly operated upon will relapse.
Arriving at accurate average costs for these events has not proved possible, but they
are addressed in the sensitivity analysis with the cost of surgery being increased by
50%, coupled with 50% of those correctly operated upon receiving Best Supportive
Care (BSC) as described below.
‘Open and shut’ operations where enlarged lymph nodes (N2/3) or metastatic disease
(M1) are revealed are assumed to be referred for non-surgical treatment as described
below. Surgery is assumed to identify 10% of those with N2/3 disease, and an
additional 1% with M1 disease.
Those with N2/3 disease or M1 disease who are operated upon but not identified as
such, i.e. futile operations that are not ‘open and shut’, are assumed to present again
with advanced disease and be treated with chemotherapy as described below.
5.2.9.3.4 Non-surgical treatment (palliative treatment for advanced disease)
The costs of non-surgical treatment are based on costs estimated in the recent HTBS
comment on NICE guidance regarding the role of chemotherapy in advanced (stage
III and IV) NSCLC (HTBS, 2001b). The lowest chemotherapy cost was £4,003
(£3,812 indexed at 5%) for cisplatin plus vinorelbine (VNB). The guidance also
calculates BSC without chemotherapy to cost £3,371 (£3,210 indexed at 5%).
In addition, radical RT costs for a course of 20 fractions have been calculated by
HTBS at £2,102, through a bottom-up approach. Included is a provision for patient
travel time, assuming that 63% of patients use public/own transport and 32% use the
hospital transport service.
Those identified as having N2/3 disease, including those identified as such during
‘open and shut’ operations, are assumed to be offered radical RT. The base case
assumes that all accept radical RT, but that they subsequently also present for VNB. It
is recognised that this is likely to overestimate the number that will receive radical
RT. However, changing this to only 50% of those identified with N2/3 disease with
the remainder only incurring VNB does not markedly affect average costs per patient.
Those identified as having M1 disease, including those identified as such during ‘open
and shut’ operations, are assumed to be offered VNB. The base case assumes that all
accept. It is recognised that this is likely to overestimate the number that will accept
chemotherapy. However, reducing this to only 50% of those identified as having M1
disease with the remainder only incurring BSC again does not markedly affect
average costs per patient.
5-14
For modelling purposes, further assumptions have to be made about the ability of PET
to differentiate between N2/3 and M1 disease in N2/3 M1 patients. Sensitivities and
specificities for PET have been calculated on the basis of detecting N2/3 disease.
Consequently, the base case assumes that a positive PET scan for N2/3 M1 patients
results in them being seen as and treated as N2/3 patients. The sensitivity analysis
alters this assumption; a PET positive result for N2/3 M1 patients being seen and
treated as having M1 disease.
5.2.9.3.5 Follow up after surgical treatment and palliative treatment
Subsequent costs of follow up are assumed to be the same whatever the initial
treatment, the NICE (2001a) guidance indicating a figure for terminal care of £1,408
(£1,341 indexed at 5%). These are assumed to be common to all treatment options,
and have been omitted from the analysis. This may not be appropriate for major
surgery as downstream support costs following discharge from hospital might not be
insignificant. However, it has not been possible to quantify what the resource use for
this might be.
5.2.10
Assumptions
5.2.10.1 Quality of life (QOL) loss from operations
Some authors (e.g. Dietlein et al., 2000a; Gambhir et al., 1996) have hypothesised
that patients suffer reduced QOL when they are undergoing tests or surgery, for
example in terms of discomfort or anxiety. They make arbitrary reductions from life
expectancy to reflect a QALY ‘penalty’ for the inherent unpleasantness of consuming
health care. It was assumed that undergoing and surviving surgery involved a loss of
0.15 QALYs, but major uncertainty surrounds the appropriate value for this.
Given the uncertainty surrounding the appropriate value for the QOL loss from
operations, this is explored in the sensitivity analyses by setting the QOL loss for
correct operations to zero and reducing it for futile operations to 0.1 QALYs.
5.2.10.2 Strategies for testing and treatment are followed
As discussed in section 4, much of the empirical evidence on PET relates to its
accuracy, with limited uncontrolled evidence on change in patient management. The
model assumes that all involved in the management of the patient follow the strategy,
without ordering any other tests. In fact, the RCTs were designed so that clinicians
could not act on PET results without confirmation (van Tinteren et al., 2002; Boyer et
al., 2001).
5.2.11
Discounting costs and benefits occurring in future years
It is common practice in economic evaluations to allow for the timing of effects by
assuming a positive rate of time preference. Thus, events occurring in the future have
a lower weight when viewed from the present perspective. The HTBS economic
guidance (HTBS, 2002b) recommends that costs should be discounted according to
the UK Treasury discount rate (currently 6.0%) and health effects should be
discounted using the time preference part of the Treasury discount rate (currently
1.5%).
5-15
Dietlein et al. (2000a) report undiscounted average life expectancies in summary
form. These have been used as the basis for calculating patient benefits. It has not
been possible to disaggregate these figures, with Dietlein’s reported averages being
used as the basis for calculating patient benefits. Given the immediacy of progression
through to death in those not successfully operated upon and the limited life
expectancy of those correctly operated upon, it is felt that the effect of applying a
1.5% discount rate to benefits would be minor.
The majority of treatment costs are incurred immediately or soon after diagnosis.
Only ongoing and terminal care costs among those N0/1 M0 patients successfully
operated upon are likely to be materially affected by discounting. Given the
uncertainty surrounding post-operative follow up costs and the terminal care costs
among N0/1 M0 patients who have successful operations, costs have not been
discounted because this would have only a minor effect upon aggregated costs.
5.3
Results
The model was constructed and run in an EXCEL spreadsheet for a representative
cohort of 100 patients, 34.3% being CT-positive and 65.6% being CT-negative. To
illustrate how the data inputs are used to derive costs and QALYs, an example of the
calculation for one diagnostic strategy is shown in Appendix 18.
The results of the base case evaluation are presented for CT-positive patients in Table
5-6. Within the cohort of 100, about a third of patients (34.3) were CT-positive, with
14.5 suitable for surgery (N0/1 M0) and the remaining 19.8 suitable for non surgical
treatment, as described in Section 5.2.9.3.4.
Table 5-6
Costs and benefits for CT-positive: base case
34.3 patients of which 14.5 are suitable for operation
Strategy 1
Strategy 2
Strategy 3
Strategy 4
Strategy 5
Strategy 6
Strategy 7
Correct
operations
14.55
0.00
14.48
11.00
11.06
11.00
14.53
Missed
operations
0.00
14.55
0.07
3.55
3.49
3.55
0.02
Futile
operations
19.77
0.00
6.67
0.53
1.58
0.53
6.24
Mean
cost
£5,747
£6,105
£5,573
£5,935
£6,051
£5,977
£6,004
Mean QALY
2.03
1.30
2.09
1.92
1.93
1.93
2.10
Mean life
years
93.04
68.96
93.38
87.67
88.04
87.86
93.59
Strategy 1 sends all patients to surgery, while strategy 2 sends all to non-surgical
treatment on an initial assumption of all being N2/3 M0. All other strategies involve
further diagnostics, with only those not being indicated as having enlarged nodes or
metastasis going to surgery. Strategy 3 uses mediastinoscopy, strategy 4 augmenting
this with FDG-PET for those indicated as being suitable for surgery. The other
strategies initially test patients with PET, with strategy 5 relying solely upon FDGPET. Strategy 6 sends those indicated as suitable for surgery for a confirmatory
mediastinoscopy, while strategy 7 sends those indicated as unsuitable for operating
upon for a confirmatory mediastinoscopy.
5-16
The simple strategies of sending all to surgery (strategy 1) or all to palliative care
(strategy 2) have the obvious implications for the numbers of correct and incorrect
operations undertaken. Strategies 4, 5 and 6 have the attraction of incurring around
five fewer futile operations in CT-positive patients relative to strategies 3 and 7.
However, this is at the expense of missing more than three patients who should have
been operated upon. Strategies 3 and 7 are similar in terms of the number of correct
operations and missed operations, though the number of futile operations avoided is
slightly better for strategy 7.
For CT-positive patients strategies 1, 3 and 7 have a higher mean QALY per patient
and a higher mean life expectancy, but the mean cost per patient is similar among
strategies. Consequently, the base case analysis suggests that strategies 1, 3 and 7
offer the greatest patient benefits, coupling these with a lower cost per patient.
The results of the base-case evaluation are presented for CT-negative patients in Table
5-7. The remaining two-thirds of the cohort (65.6 patients) were CT-negative, with
48.4 suitable for surgery and the remaining 17.2 suitable for non-surgical treatment.
Table 5-7
Costs and benefits for CT-negative: base case
65.6 patients of which 48.4 are suitable for operation
Strategy 1
Strategy 2
Strategy 3
Strategy 4
Strategy 5
Strategy 6
Strategy 7
Correct
operations
48.41
0.00
48.17
43.35
43.57
43.35
48.35
Missed
operations
0.00
48.41
0.24
5.06
4.84
5.06
0.06
Futile
operations
17.21
0.00
8.64
1.21
2.41
1.21
4.41
Mean
cost
£4,467
£6,105
£4,642
£5,137
£4,899
£5,124
£4,854
Mean QALY
2.88
1.46
2.89
2.76
2.77
2.76
2.91
Mean
life years
3.53
2.26
3.52
3.39
3.41
3.40
3.53
As for CT-positive patients, the simple strategies of 1 and 2 have the obvious
implications for the number of correct and incorrect operations. Similarly, strategies
4, 5 and 6 have the attraction of incurring fewer incorrect operations, avoiding
between six and seven futile operations relative to strategy 3 but only between two
and three operations relative to strategy 7. However, again, this is at the expense of
missing around five patients who should have been operated upon. Strategies 3 and 7
remain similar in terms of the number of correct operations and missed operations, but
for CT-negative patients the high specificity of PET (0.90) causes strategy 7 to avoid
four futile operations relative to strategy 3.
The above suggests that strategy 3 of sending patients for a mediastinoscopy and
strategy 7 of sending patients for a PET scan with those apparently unsuitable for
surgery being sent for a confirmatory mediastinoscopy are likely to offer the greatest
patient benefits, though these are not strongly distinguished from strategy 1 in CTnegative patients. The principal distinction between strategies 3 and 7 and strategy 1
is the additional number of futile operations avoided.
Strategies 2, 4, 5 and 6 appear to offer poorer patient outcomes than strategies 1, 3 or
7, and have higher average costs per patient, though strategy 4 is marginal less costly
5-17
than strategy 7 for CT-positive patients. However, the differences in terms of patient
outcomes and costs are not especially large between patients, apart from strategy 2 of
sending all to palliation which performs poorly.
Table 5-8 and Table 5-9 give the incremental cost effectiveness ratios (ICERs). An
ICER examines the additional cost that one strategy incurs compared with another,
evaluating this against the additional patient benefits. The formal calculation of an
ICER divides the difference in costs by the difference in patient benefits, to give the
incremental cost per incremental QALY. Where a number of strategies are being
compared, the ICERs are calculated using the following process:
 strategies are ranked in terms of cost from the least expensive to the most
expensive;
 the least expensive strategy is compared with the next least expensive strategy. If
the next least expensive strategy results in lower patient benefits this strategy is
said to be ‘dominated’ as it requires additional expense but results in lower
patient benefits. The dominated strategy is excluded from subsequent calculation
of ICERs;
 the ICERs are calculated for each successive alternative, from the cheapest to the
most expensive. If the ICER for a given strategy is higher than that of the next
most effective strategy then this strategy is ruled out on the basis of ‘extended
dominance’; and
 finally the ICERs are recalculated excluding all the strategies that are ruled out
using the notions of dominance and extended dominance.
Applying these principles strategies 1-7 are ranked in Table 5-8 and Table 5-9.
Table 5-8
Strategy 3
Strategy 1
Strategy 4
Strategy 6
Strategy 7
Strategy 5
Strategy 2
Table 5-9
Strategy 1
Strategy 3
Strategy 7
Strategy 5
Strategy 6
Strategy 4
Strategy 2
Strategies ranked by cost for CT-positive
Total cost
Total QALYs
£191,295
£197,247
£203,720
£205,157
£206,098
£207,690
£209,538
71.86
69.81
66.03
66.16
72.11
66.17
44.45
Additional
cost
£5,952
£12,425
£13,862
£14,803
£1,592
£3,440
Additional
QALYs
-2.05
-5.83
-5.71
0.25
-5.94
-27.66
ICER
Dominated by 3
Dominated by 3
Dominated by 3
£58,951
Dominated by 7
Dominated by 7
Strategies ranked by cost for CT-negative
Total cost
Total QALYs
£293,127
£304,628
£318,544
£321,492
£336,270
£337,116
£400,614
189.01
189.63
190.96
181.97
181.39
181.28
95.70
Additional
cost
£11,501
£13,916
£2,949
£17,727
£18,573
£82,071
Additional
QALYs
0.62
1.33
-8.98
-9.57
-9.67
-95.26
ICER
£18,589
£10,475
Dominated by 7
Dominated by 7
Dominated by 7
Dominated by 7
5-18
The results suggest that in CT-positive patients the current Scottish practice of
mediastinoscopy prior to surgery (strategy 3) is superior to sending all for surgery, as
would be anticipated given the relatively low proportion of CT-positive patients who
should get surgery. Strategy 7 of sending all patients for a FDG-PET scan and sending
FDG-PET positive patients for a confirmatory mediastinoscopy1 requires
approximately £60,000 per additional QALY and thus is unlikely to be considered
cost effective.
The economic model indicates that among CT-negative patients the option of sending
all for surgery cannot be ruled out on grounds of patient impact alone. It results in all
who are suitable for surgery receiving a correct operation, but this is at the expense of
roughly double the number of futile operations (17.21 or 26% of CT-negative
patients) compared with strategy 3. However, Strategy 1 will not be used in clinical
practice and is used here as a test of the economic model. This raises doubt as to
whether the model is correctly valuing the costs and utilities associated with surgery.
However, for CT-negative patients the results suggest that the current Scottish
practice of mediastinoscopy is likely to be cost effective compared with sending all
patients for surgery. Furthermore, it is even more cost effective to use FDG-PET as
outlined in strategy 7, compared with strategy 3. This result appears to differ from
that in CT-positive patients because a greater proportion of CT-negative patients are
suitable for surgery and the specificity of FDG-PET is greater in CT-negative patients.
The base case of the model strongly suggests that strategy 2 is dominated by other
strategies. It also indicates that strategies 4, 5 and 6 are dominated, though this should
be interpreted with some caution given the difficulties in assigning life expectancies
and utility values, together with the other uncertainties surrounding the model. The
differences between strategies in average QALY values are not large, though greater
differentiation is reported between strategies in CT-positive patients than between
strategies in CT-negative patients. However, relative to strategies 1, 3 and 7, strategies
4 to 6 perform poorly. They miss around 3 and 5 patients suitable for surgery in CTpositive and CT-negative patients respectively, which is only marginally less than
their reduction in futile operations relative to strategies 3 and 7.
Concentrating upon strategies 1, 3 and 7 the base case modelling suggests that:
 the principal potential benefit of FDG-PET scanning is to limit the number of
futile operations carried out. Within CT-positive patients the specificity of FDGPET is relatively low at 0.76, compared with the specificity of mediastinoscopy
of 1.00 for N2/3 disease. As a consequence, only around 1% of CT-positive
patients would avoid futile operations if strategy 7 is employed instead of strategy
3. There is virtually no effect upon the number of missed operations among
those suitable for surgery;
 within CT-negative patients, the specificity of FDG-PET is much better at 0.90.
As a consequence around 6% of CT-negative patients would avoid futile
operations if strategy 7 is employed instead of strategy 3. There may also be a
small increase in the number of correct operations undertaken;
 the base case of surgery suggests that strategy 3 of sending all for
mediastinoscopy is cost effective relative to strategy 1 of surgery for all patients;
and
 FDG-PET only appears to be potentially cost effective in strategy 7. This is not
clear cut in CT-positive patients. Given the higher proportion of these patients
5-19
who are not suitable for surgery, the current Scottish practice of sending all for
mediastinoscopy cannot be ruled out given its 100% specificity for N2/3 disease.
The findings of the ECRI report (ECRI, 1998) conclude that FDG-PET is cost
effective when used to replace mediastinal biopsy (by mediastinoscopy or
mediastinotomy) after a negative CT scan in patients with confirmed NSCLC who are
candidates for resection. The set of strategies considered by ECRI involved using
FDG-PET to replace direct mediastinal examination, rather than as an adjunct to
mediastinoscopy, and so is not directly comparable with the results obtained here.
ECRI took careful account of the post-surgery costs of treating lung cancer, the
financial and morbidity costs of operative complications and of the costs of rebiopsy
for technical failures. They also conducted a number of sensitivity analyses, taking
account of the wide cost ranges presented for all the diagnostic tools, and including in
the set of strategies one in which FDG-PET replaces CT completely. They conclude
that their analysis is superior to previous work, because of the broader range of issues
accounted for, and that the results are robust to plausible changes in input values.
However, direct comparison of the ECRI findings with those of the model presented
here would only be possible by rerunning their model with a strategy including the
use of both mediastinoscopy and FDG-PET.
The base-case results of the HTBS model suggest that FDG-PET is cost effective as a
diagnostic test subsequent to patients being found to be CT negative, but that FDGPET should only replace mediastinoscopy if the FDG-PET scan result is negative. The
model suggests those CT-negative patients who receive a positive result from a FDGPET scan should still be sent for a confirmatory mediastinoscopy given its 100%
specificity for N2/3 disease. Among those patients found to be CT positive, the
evidence that PET is cost effective is more muted than in the base case.
5.4
Diagnosis based on PET only
The seven strategies considered so far in this chapter have all assumed that PET
scanning would be performed following CT scanning. An alternative would be to use
FDG-PET as soon as the diagnosis of NSCLC has been confirmed and the patient has
been assessed for suitability for surgery.
Therefore a further, potential patient pathway has PET coming first followed by CT to
provide the additional anatomical detail necessary for treatment. This requires further
modelling assumptions as to what happens to true FDG-PET negatives which are
subsequently seen by CT to be positive, and false FDG-PET positives which are
subsequently seen by CT to be negative. In the absence of evidence about the
combined sensitivity and specificity of this combination of diagnostic tools, it has
been assumed that the combined sensitivity and specificity is that of FDG-PET alone.
As a consequence, the patient impact of the ‘all for FDG-PET’ strategy is the
summation of the patient impact of strategy 5 in CT-enlarged and CT-normal patients.
Similarly, the cost of strategy 5 is the same summation, minus the number of CT
scans avoided. One CT scan would be avoided in each patient not undergoing surgery
and undergoing palliation, as all palliation costs include an allowance for any CT
scans necessary to them. (In this model, the cost of a CT is £97, calculated from the
5-20
Scottish Health Services Costs (Common Services Agency, Information and Statistics
Division, 2001) with indexing at 5%.)
This yields a total patient impact from the all for PET strategy of 248 QALYs (in 100
patients), coupled with a total cost of £525,183. The parallel figures for strategy 7 are
263 QALYs and £524,642. As a consequence, it appears that the all for PET strategy
is dominated by strategy 7.
5.5
Model testing and savings in surgery
The HTBS model was tested to see if it would predict the results of the van Tinteren
et al. (2002) trial.
In the control group of the Dutch trial, 78 of 96 patients (81%) had surgery compared
with 60 of 92 in the PET group (65%). Sixty-six per cent of the control group had a
mediastinoscopy whereas 25 patients went straight to surgery. In the PET group 73%
had a mediastinoscopy. This suggests there was a mixture of the seven strategies of
the HTBS model being used. To try to approximate this, the following was assumed:
Control group: 66% of patients are following strategy 3 and 34% are following the
‘straight to surgery’ path.
FDG-PET group: 73% are following strategy 6 (PET with mediastinoscopy for
negatives and non-surgical treatment for positives) and 27% are sent for surgery after
FDG-PET.
The HTBS model predicts equivalent to 85 operations in the control group and 68 in
the FDG-PET group. The difference is 17 operations per 100, whereas the Dutch trial
showed a difference of 16 per 100. The conclusion drawn from this is that the HTBS
model can adequately predict the number of operations avoided in a real clinical trial.
While the exact impact upon patient quality of life of avoiding these futile operations
is difficult to quantify, there is little controversy that such an effect exists. Patients
would welcome the increased likelihood that if offered surgery this is likely to be the
correct course of action for them as opposed to a false hope. At a time when skilled
surgical time is in very short supply, freeing up resources by reducing the numbers of
futile operations is also especially valuable.
5-21
5.6
Sensitivity analyses
Published models for the use of FDG-PET scanning in NSCLC have been used and
modified following extensive input from Scottish lung cancer experts. Despite this,
there are major gaps in our knowledge about resource use and benefits at different
stages in the disease process. These gaps have been filled by assumptions, some of
which have been tested by one-way sensitivity analyses.
Sensitivity analyses can be used to evaluate how conclusions arising from the
economic model vary depending on assumptions. The results of some of the
sensitivity analyses undertaken by HTBS are presented in Table 5-10 and Table 5-11,
for the three most favourable strategies: 1, 3 and 7. These report the change in the
absolute values, together with the percentage change in relation to the base case
values.
Table 5-10
Sensitivity analyses: CT-positive
Mean cost
Mean QALYs
Base case
Strategy 3
£5,573
2.09
Strategy 1
£5,747
2.03
Strategy 7
£6,004
2.10
FDG-PET accuracy: Lower CI bounds for sensitivity and specificity
Strategy 3
£5,573
0.0%
2.09
0.0%
Strategy 1
£5,747
0.0%
2.03
0.0%
Strategy 7
£6,040
0.6%
2.10
-0.2%
FDG-PET accuracy: Upper CI bounds for sensitivity and specificity
Strategy 3
£5,573
0.0%
2.09
0.0%
Strategy 1
£5,747
0.0%
2.03
0.0%
Strategy 7
£5,980
-0.4%
2.10
0.1%
FDG-PET accuracy: +ve in N2/3 M1 treated as M1
Strategy 3
£5,573
0.0%
2.09
0.0%
Strategy 1
£5,747
0.0%
2.03
0.0%
Strategy 7
£5,867
-2.3%
2.10
0.1%
Open and shut: 50% of N2/3 surgery and 5% of M1 surgery
Strategy 3
£5,692
2.1%
2.09
0.0%
Strategy 7
£6,148
2.4%
2.10
0.0%
Strategy 1
£6,175
7.5%
2.03
0.0%
Surgery morbidity: Nil for N0/1 M0 surgery, others -0.1 QALY
Strategy 3
£5,573
0.0%
2.16
3.4%
Strategy 1
£5,747
0.0%
2.12
4.4%
Strategy 7
£6,004
0.0%
2.17
3.3%
Surgery costs: +50% and 50% of N0/1 M0 surgery require BSC
Strategy 3
£7,311
31.2%
2.09
0.0%
Strategy 7
£7,726
28.7%
2.10
0.0%
Strategy 1
£8,144
41.7%
2.03
0.0%
ICER
Dominated by 3
£58,951
Dominated by 3
£153,948
Dominated by 3
£40,623
Dominated by 3
£30,881
£62,329
Dominated by 7
Dominated by 3
£62,116
£56,746
Dominated
5-22
Table 5-11
Sensitivity analyses results: CT-negative
Mean cost
Mean QALYs
Base case
Strategy 1
£4,467
2.88
Strategy 3
£4,642
2.89
Strategy 7
£4,854
2.91
FDG-PET accuracy: Lower CI bounds for sensitivity and specificity
Strategy 1
£4,467
0.0%
2.88
0.0%
Strategy 3
£4,642
0.0%
2.89
0.0%
Strategy 7
£4,892
0.8%
2.91
-0.1%
FDG-PET accuracy: Upper CI bounds for sensitivity and specificity
Strategy 1
£4,467
0.0%
2.88
0.0%
Strategy 3
£4,642
0.0%
2.89
0.0%
Strategy 7
£4,827
-0.6%
2.91
0.1%
FDG-PET accuracy: +ve PET scan in N2/3 M1 treated as M1
Strategy 1
£4,467
0.0%
2.88
0.0%
Strategy 3
£4,642
0.0%
2.89
0.0%
Strategy 7
£4,806
-1.0%
2.91
0.0%
Open and shut: 50% of N2/3 surgery and 5% of M1 surgery
Strategy 1
£4,613
3.3%
2.88
0.0%
Strategy 3
£4,683
0.9%
2.89
0.0%
Strategy 7
£4,903
1.0%
2.91
0.0%
Surgery morbidity: Nil for N0/1 M0 surgery, others -0.1 QALY
Strategy 1
£4,467
0.0%
3.00
4.1%
Strategy 3
£4,642
0.0%
3.00
3.9%
Strategy 7
£4,854
0.0%
3.02
3.8%
Surgery costs: +50% and 50% of N0/1 M0 surgery require BSC
Strategy 3
£7,313
57.5%
2.89
0.0%
Strategy 1
£7,373
65.1%
2.88
0.0%
Strategy 7
£7,424
53.0%
2.91
0.0%
5.6.1
ICER
£18,589
£10,475
£18,589
£14,264
£18,589
£8,347
£18,589
£7,836
£7,400
£10,892
£67,353
£12,083
Dominated
£5,502
Accuracy of PET scanning
To explore the effects of the accuracy of FDG-PET scanning being lower than the
central estimates for sensitivity and specificity as used in the base case, these can be
replaced by the relevant lower bounds of the 95% confidence intervals as reported in
the clinical effectiveness section. In addition to affecting the mean patient cost and
QALYs of strategy 7 as shown in Table 5-10 and Table 5-11, this also impacts upon
the numbers of operations, as shown below in Table 5-12. Table 5-12 also shows the
impact if a positive PET scan result leads to N2/3 M1 patients avoiding
mediastinoscopy and being referred to the appropriate palliative regimen.
The main patient impact of the lower accuracy of FDG-PET in strategy 7 falls
principally upon the increase in false negatives who are incorrectly sent for surgery.
This is greatest among CT-positive patients with a little under one futile operation, or
slightly over 2% of the CT-positive patient population. While the absolute increase in
futile operations is around the same in CT-negative patients, this is only slightly over
1% of the CT-negative patient population.
5-23
Table 5-12
Sensitivity analyses: reduced accuracy of PET
CT-positive
Correct operations
Base case
Strategy 7
14.53
Lower CI bounds for sensitivity and specificity
Strategy 7
14.53
-0.04%
Upper CI bounds for sensitivity and specificity
Strategy 7
14.54
0.03%
Positive FDG-PET scan in N2/3 M1 treated as M1
Strategy 7
14.53
0.00%
CT-negative
Correct operations
Base case
Strategy 7
48.35
Lower CI bounds for sensitivity and specificity
Strategy 7
48.34
-0.04%
Upper CI bounds for sensitivity and specificity
Strategy 7
48.37
0.03%
Positive FDG-PET scan in N2/3 M1 treated as M1
Strategy 7
48.35
0.00%
Incorrect operations
6.24
6.97
11.80%
5.79
-7.08%
5.77
-7.46%
Incorrect operations
4.41
5.11
15.76%
4.00
-9.45%
4.11
-6.95%
Note that there is also an impact from the increase in false positives, with more
patients being sent for unnecessary mediastinoscopy. This increases costs slightly,
with the attendant risk of a slight increase in deaths from mediastinoscopy.
Given the limited differences in average patient QALYs between the strategies, these
changes have a major effect upon the likely cost effectiveness of strategy 7. For CTpositive patients the ICER of moving from strategy 3 to strategy 7 roughly trebles to
£153,948. The effect is more muted among CT-negative patients, but the ICER of
moving from strategy 3 to strategy 7 still increases by around 40% to £14,264.
Note that the effect of using the upper bounds of the confidence intervals for the
accuracy of FDG-PET is not symmetric to using the lower bounds. The costeffectiveness ratios of moving from strategy 3 to strategy 7 are affected less, falling to
£40,623 and £8,347 for CT-positive and CT-negative patients respectively.
If the accuracy of PET in detecting metastases is similar to that for detecting N2/3
disease, this would greatly affect the number of patients in the N2/3 M1 group being
treated appropriately under strategy 7. In the CT-positive group the prevalence of
patients with N2/3 M1 disease is roughly treble that in the CT-negative group. As a
consequence, greater differentiation of N2/3 disease into M0 and M1 disease by PET
would have the greatest impact in the CT-positive group. The ICER would fall from
£58,951 to £30,881 in the CT-positive group, and from £10,475 to 7,836 in the CTnegative group.
5.6.2
Increased surgical referral to non-surgical treatment
The base-case analysis assumes that 10% of operations on N2/3 patients and 1% of
operations in N0/1 M1 patients are ‘open and shut’ operations, these patients being
referred to the relevant non-surgical intervention. If these percentages are increased to
50% and 5% respectively the average cost of treatment for CT-positive patients
increases by around 2% for strategies 3 and 7, while the increase for strategy 1 is
5-24
greater at 7.5% as would be expected. Proportionately fewer CT-negative patients are
affected by this, and the increases in costs are correspondingly lower, at around 1%
for strategies 3 and 7, and 3.3% for strategy 1.
Given the model structure, patient benefits are unaffected by this. As a consequence,
the cost effectiveness of moving from strategy 3 to strategy 7 is reduced slightly
among CT-positive patients, with strategy 1 remaining dominated. Among CTnegative patients strategy 1 remains the least costly, but the cost effectiveness of
moving from strategy 1 to strategy 3 is markedly increased.
5.6.3
Reduced surgical morbidity
The base case analysis assumes that all patients undergoing surgery incur a 0.15
QALY detriment. This detriment may be related to whether surgery is correct or
futile. Removing this detriment from those correctly operated upon (N0/1 M0) and
reducing it to 0.1 QALY for the remainder being operated upon increases the average
QALY value for patients under all strategies.
This affects patient morbidity in correct operations as no additional operative
morbidity is applied, and reduces the morbidity associated with incorrect operations
by 33%. Among CT-positive patients, these effects increase the patient benefits of
strategy 1 more than for strategy 3, but this remains insufficient for strategy 1 not to
be dominated by strategy 3. Strategy 3 is also less penalised for its greater number of
incorrect operations, and the cost effectiveness of moving to strategy 7 reduced.
Strategy 7 remains apparently cost effective among CT-negative patients assuming a
reduced utility penalty of sending all for surgery.
5.6.4
Increased costs of surgery
Surgical costs may be underestimates, as outlined in section 5.2.9.3.3. For those
correctly operated upon the base case analysis also assumes a cure. Increasing the
costs of surgery by 50% and allowing for 50% of those correctly operated upon
requiring BSC naturally impact more upon the cost of strategy 1 than strategies 3 or 7,
making strategy 1 increasingly less attractive. Given the proportionately greater
numbers undergoing surgery in the CT-negative group under strategies 3 and 7 than in
the CT-positive group, the cost effectiveness of moving from strategy 3 to strategy 7
is more affected for them, improving to £5,502 per incremental QALY.
Since the strategies 1, 3 and 7 involve greater surgery their costs increase more than
the costs of strategies involving more direct referrals to palliation, even though this
palliation is often incorrect. However, this does not affect the cost effectiveness
conclusions. For CT-positive patients, strategy 4 is the most attractive of the other
strategies, but the cost-effectiveness of moving from it to strategy 3 is £1,655 cost per
QALY. For CT-negative patients, strategy 5 is the most attractive of the other
strategies, but the cost effectiveness of moving from it to strategy 3 is £1,190 cost per
QALY. Note that this is the only sensitivity analysis under which strategies other the
1, 3 and 7 are not dominated.
5-25
5.6.5
Conclusions of sensitivity analyses
The sensitivity analyses have focused upon the three strategies: the hypothetical
strategy 1 of sending all to surgery; current Scottish practice being strategy 3 of
sending all for mediastinoscopy, with mediastinoscopy negatives receiving surgery;
and strategy 7 of sending all for FDG-PET, FDG-PET positives receiving a
confirmatory mediastinoscopy with all negative results receiving surgery.
For CT-positive patients, the base-case analysis suggested that strategy 7 was unlikely
to be cost effective relative to strategy 3 (£58,951 per additional QALY). The cost
effectiveness of strategy 7 reduces if the lower confidence intervals for the accuracy
of FDG-PET are applied, though applying the upper confidence intervals causes the
ICER to reduce to £40,623 per QALY. Assuming improved accuracy of FDG-PET in
detecting M1 disease has the greatest effect upon this ICER. If FDG-PET is as
accurate at detecting M1 disease as it is at detecting N2/3 disease the ICER of moving
from strategy 3 to strategy 7 in CT-positive patients is £30,881 per QALY.
For CT-negative patients, the costs of strategy 1 are affected if there are increased
referrals from incorrect operations to radical RT. The effects of this are more muted
for strategies 3 and 7, and strategy 1 appears less attractive. The opposite effect is
observed from lower surgical morbidity. This increases the average patient quality of
life for strategy 1 more than that of strategies 3 and 7. As a consequence, the cost
effectiveness of strategy 3 is called into question. However, it should be noted that
the impact of a reduced surgical morbidity upon the average patient quality of life of
strategy 1 relative to strategy 3 is extremely small, and it is difficult to have
confidence in this result. Within all the sensitivity analyses, it still appears likely that
strategy 7 is cost effective compared with strategy 3 for CT-negative patients.
5-26
5.7
Discussion and conclusions of economic evaluation of NSCLC
Seven different diagnostic and treatment strategies for the use of FDG-PET after CT
in staging NSCLC have been compared in an economic evaluation, using estimates of
benefits and resource use from Scotland wherever these were available.
Three strategies appear to stand out in terms of either better patient impact, lower
cost, or both:
 the hypothetical strategy 1 of sending all to surgery; used as a test of the model;
 strategy 3 of sending all for a mediastinoscopy, negatives being sent for surgery
and positives to non-surgical interventions; and
 strategy 7 of sending all for FDG-PET, negatives being sent to surgery and
positives for a confirmatory mediastinoscopy2, mediastinoscopy negatives being
sent to surgery and positives to non-surgical interventions.
The most reliable reported outcomes from the model relate to the number of correct
operations, the number of missed operations and the number of futile operations under
each strategy. On these grounds, among CT-positive patients in the base case, strategy
1 is unattractive as it incurs treble the number of futile operations (57% of CTpositive patients) compared with strategies 3 and 7, which have a very small increase
in the number of correct operations.
For patients who are CT-negative the number of futile operations in the base case for
strategy 1 is still roughly double (26% of CT-negative patients) that of strategy 3, and
this is coupled with only a slight increase in the number of correct operations.
Strategy 3 is also differentiated from strategy 7 in CT-negative patients, due to the
specificity of FDG-PET being much better than in CT-positive patients. In the base
case, strategy 3 produces roughly double the number of futile operations and slightly
fewer correct operations than strategy 7.
None of the formal sensitivity analyses cause the number of correct, missed and futile
operations to alter much in any of the strategies. As a consequence, it appears robust
that the cost effectiveness of FDG-PET in CT-negative patients will be better than the
cost effectiveness of PET in CT-positive patients. Similarly, it appears robust that the
greater the accuracy of FDG-PET in differentiating N2/3 patients into those with M1
disease and those without, the more likely it is that FDG-PET will be cost effective.
However, formal calculation of cost effectiveness and ICERs requires that costs be
attached to treatments, with treatments conferring patient benefits in terms of both life
expectancies and patient utilities. It has been possible to differentiate the costs of
treatment into broad categories, though the follow-up costs of those correctly operated
upon have not been modelled beyond a sensitivity analysis. The greater these followup costs are the less attractive is strategy 1, and the less attractive is strategy 7 relative
to strategy 3 though this latter effect would be minor. It has not been possible to
differentiate the life expectancies and the patient utilities that result from treatments to
the same degree as treatment costs.
The principal differentiation of patient impacts that have been modelled is the
increased life expectancy from a correct operation, the higher patient utility after a
correct operation and the patient utility detriment associated with undergoing an
operation. When these are aggregated and compared across the different strategies,
5-27
differences in the lifetime utility accruing to those correctly undergoing surgery
largely cancel out the differences in any utility detriment not being applied to those
avoiding futile surgery.
As a consequence, the differences in the total patient utilities under strategies 1, 3 and
7 are small. Items that would affect these totals would have a major impact upon
ICERs. Such items clearly include the life expectancies from the different treatments
and the patient utilities associated with these treatments.
Some of the uncertainties associated with these inputs have been studied in the
sensitivity analyses presented in Section 5.6, in particular, the utility penalty for
surgery, the proportion of patients undergoing ‘open and shut’ surgery, the proportion
of patients undergoing chemotherapy/RT after surgery and the cost of surgery.
However, some important inputs cannot be addressed in this analysis. The model
structure has been driven by the available data, and it has not been possible to
differentiate life expectancies from the various treatments and patient utilities to the
same degree as it has been for costs.
The model would be improved:
 by better activity-based accounting;
 with better data on clinical outcomes, such as survival rates, by stage of disease
and treatment; and
 using utilities elicited from patients or the general public.
This could be achieved by targeted health services research in Scotland (or the UK).
As these uncertainties remain largely unquantified it is unknown whether changes to
the model inputs would make FDG-PET more or less cost effective. Concentrating
upon the numbers of correct operations and futile operations in the correct model still
suggests that ICER of FDG-PET in CT-negative patients is likely to be better than
that in CT-positive patients. However, further research is needed to obtain the
required evidence from pragmatic clinical settings.
5-28
6
CLINICAL EFFECTIVENESS – LYMPHOMA
Summary

A systematic review and critical appraisal of the literature was undertaken to
determine the accuracy of FDG-PET in detecting possible residual disease following
induction chemotherapy in patients with lymphoma (restaging lymphoma).

Bayesian meta-analysis indicated that for post-induction chemotherapy in patients
who showed residual masses on CT, the sensitivity of FDG-PET was 0.80, CI (0.59,
0.94), with a specificity of 0.89, CI (0.74, 0.97).

Bayesian meta-analysis indicated that the sensitivity of FDG-PET to detect residual
masses following induction chemotherapy (with no CT results) was 0.81, CI (0.63,
0.92), with a specificity of 0.95, CI (0.90, 0.99).

Bayesian meta-analysis of CT scanning to detect residual masses following inducation
therapy found a sensitivity of 0.75, CI (0.58, 0.88) and specificity of 0.45, CI (0.27,
0.64).

Although the studies of accuracy in restaging lymphoma after induction therapy are
generally retrospective and involve heterogeneous patient groups and variable followup times, FDG-PET is substantially more specific and somewhat more sensitive than
CT for the detection of recurrent disease and is effective in discriminating active
residual disease from non-viable tumour.
6-1
6.1
Introduction
It has been proposed that FDG-PET may be useful in the initial staging of disease, the
assessment of response to therapy (restaging), predicting the results of therapy early
during treatment and monitoring for possible recurrence (Kostakoglu & Goldsmith,
2000).
Following discussion with Scottish haematologists, it was decided that the assessment
of FDG-PET in lymphoma should focus on its use in the assessment of response to
therapy and, in particular, on the assessment of residual masses. A brief overview of
the literature relating to other possible applications of FDG-PET scanning in
lymphoma is presented in sections 6.3.1 to 6.3.4.
Following critical appraisal of published literature meta-analyses of combined
sensitivity and specificity have been undertaken. To allow direct input into the
economic model in section 7, this has used the Bayesian methods of Rutter &
Gatsonis (1995) implemented in WinBUGS 1.3 (http://www.mrcbsu.cam.ac.uk/bugs/welcome.shtml). Further details of the modelling methodology
are presented in Appendix 19.
6.1.1
Literature search strategy
A systematic literature search on the role of PET, and comparators, in the assessment
of post-treatment residual mass was undertaken in March/April 2002.
The following approaches were adopted:
 health technology assessments, systematic reviews and other evidence-based
reports were identified, to establish the current evidence base;
 the databases MEDLINE (Ovid), PreMEDLINE (Ovid) and Embase (Ovid) were
searched to identify primary studies. The search was split into three concepts:
positron emission tomography, lymphoma and detection of residual mass with all
relevant subject headings and free text terms identified for each concept. The
databases were searched from their start date. No language restrictions were
applied;
 attempts were made to identify additional RCTs and ongoing research, not
indexed in MEDLINE or Embase, by searching sources such as the Cochrane
Controlled Trials Register, Current Controlled Trials (mRCT) and the websites of
professional organisations;
 members of the TSG and experts were consulted to check for completeness of the
included studies and,in particular, to help identify unpublished (grey) literature
and ongoing research; and
 the bibliographies of relevant studies were scanned for further studies.
Further information about the search and a flow chart detailing the systematic
literature selection process are presented in Appendix 5.
6-2
6.1.2
Exclusion criteria
The following exclusion criteria were applied:
 studies using obsolete (NaI) detector technology, gamma camera PET or nonstandard technology;
 studies concerned solely with the accuracy of Gallium 67 scanning; and
 multiple studies found dealing with the same patients (only the most recent was
included).
6.2
Lymphoma treatment in Scotland
Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) together account for
approximately 4% of incident cancers in the UK (Scottish Executive Health
Department, 2001b).
NHL is most common in older people, with a median age of onset of 65 years, while
HD has a bimodal age distribution, which peaks at between 15 and 35 years and again
at 65 years. The incidence of NHL has increased at approximately 4% per annum over
the past two decades; the reason for this is unclear (Scottish Executive Health
Department, 2001b).
In Scotland, the five-year survival from HD is approximately 73% (compared with
86% in the US) and that from NHL is approximately 45%, which is slightly lower
than the corresponding US figure (Scottish Executive Health Department , 2001b).
Chemotherapy, alone or in combination with RT, forms the basis of treatment for HD
and more aggressive forms of NHL.
A wide variety of treatment regimens have been employed (Eghbali et al., 2000) with
the joint objectives of maximising the cure rate and minimising the acute and longterm toxicity experienced by patients. Since both residual disease, after initial
treatment, and recurrent disease may still be amenable to curative therapy, restaging
of disease after initial treatment and monitoring for recurrence are important aspects
of the management of HD and NHL.
This part of the assessment focuses specifically on the role of FDG-PET scanning in
lymphoma management and only treatment options considered in the economic
evaluation will be described in detail.
6-3
6.3
Possible roles for FDG-PET imaging
6.3.1
Initial staging
The results available from the use of FDG-PET (and other imaging tools) pose two
substantial problems of interpretation. First, since biopsy confirmation of lesions is
frequently impossible, the diagnostic accuracy can usually only be confirmed by
follow up. It is not clear, however, what duration of follow up is appropriate, or how
the confounding effects of treatment should be allowed for. Secondly, since systemic
chemotherapy is the treatment of choice for many patients, it is unclear how valuable
increased accuracy of staging is likely to be. However, Segall (2001) notes that FDGPET may be valuable in confirming or ruling out the possibility of administering
radiation to patients whose disease appears confined to a small region.
The reviews by Talbot et al. (2001) and Kostakoglu & Goldsmith (2000) suggest that
FDG-PET has similar accuracy to CT in staging nodal involvement of lymphoma and
may have superior sensitivity in detecting abdominal and central nervous system
disease (e.g. Rodriguez, 1998; Hoffman et al., 1999).
However, the majority of studies reported are retrospective and contain relatively
small numbers of patients (all studies contained fewer than 100 patients). Coiffier
(2001) comments that the small changes in staging seen in the studies are unlikely to
cause significant changes in management, whereas Willkomm et al. (1998) concluded
that FDG-PET resulted in the upstaging of a large number of patients and may thus
have a significant impact on management.
6.3.2
FDG-PET imaging during therapy
Jerusalem et al. (2000) and Romer et al. (1998) both show that the change in FDG
uptake six weeks after the start of therapy is strongly correlated with the relapse- free
interval after completion of therapy. In principle, this result could be used to allow
the selection of patients to receive intensified therapy, or treatment with different
drugs. However, such a trial has not yet been performed.
6.3.3
FDG-PET scanning for detection of recurrence
According to Talbot et al. (2001), Bar-Shalom et al. (2001) and Kostakoglu &
Goldsmith (2000), FDG-PET is more accurate than CT for detecting recurrent
disease, especially in differentiating recurrent disease from residual scarring.
However, the original studies on which this conclusion is based are rather small and,
in common with the other imaging studies, are handicapped by the absence of a ‘gold
standard’. Kostakoglu & Goldsmith (2000) argue however that, because of the
sensitivity of FDG-PET demonstrated in primary staging, it should also be included in
long-term follow-up strategies to detect recurrence.
6.3.4
FDG-PET in the post-treatment assessment of lymphoma
The peer-reviewed reports of original work in this area are described in section 6.4.
This section outlines the important issues and the qualitative conclusions proposed by
previous reviews.
6-4
The detection and assessment of possible residual disease following first-line therapy
is of considerable importance, because patients with active residual disease may be
candidates for further therapy. A particular problem is posed by patients with residual
masses evident on CT, which may occur in 60% of patients with mediastinal
involvement at presentation (Israel et al., 1990). Bar-Shalom et al. (2001) and Talbot
et al. (2001) both conclude that FDG-PET has significant value in discriminating
between active disease and residual scarring/fibrosis in such patients.
According to Bar-Shalom et al. (2001) PET appears to have similar accuracy to
Gallium SPECT for these applications, and is, therefore, likely to be preferred on the
grounds of convenience, both by patients and health care providers.
The use of Gallium SPECT as a comparator has not been considered further in this
report for the following reasons (Professor J McKillop, Muirhead Professor of
Medicine, University of Glasgow and Professor PF Sharp, Chair of the TSG
(Professor of Medical Physics, University of Aberdeen & Grampian Hospitals NHS
Trust), Personal communication, 2002):
SPECT with high dose Gallium 67 citrate (Ga-67) has been used in evaluation of
lymphoma (King et al., 1994). It has proven to be successful in assessment of
recurrence or residual disease after primary therapy in the mediastinum in patients
whose pretreatment scan shows uptake. Gallium 67 SPECT does, however, suffer
from shortcomings, which preclude its widespread use in lymphoma patients:
 the high-energy emissions of Ga-67 require a high-energy collimator. Many
departments in Scotland do not have such a collimator and, more importantly,
some SPECT cameras are unable to perform satisfactorily with such a heavy
collimator;
 following injection of the tracer, the patient must be imaged 48 and/or 72 hours
later. This necessitates multiple outpatient visits by the patient or admission for
the duration of the study;
 a significant proportion of untreated lymphomas do not show Ga-67 uptake and
thus a post-treatment study is of no value; and
 the large bowel excretes a substantial fraction of the injected Ga-67. This makes
the evaluation of abdominal and pelvic lymph nodes very difficult.
6.4
Accuracy of FDG-PET for post-therapy restaging of patients who are
CT-positive - studies
Eight published studies were identified that addressed the accuracy of FDG-PET for
restaging HD post induction therapy in patients who showed residual masses on CT
scan.
The paper by Maisey et al. (2000) was excluded because the scanner used was
recognised to have substandard performance. The remaining studies are summarised
here. The study characteristics are shown in Table 6-1 and accuracy data are displayed
in Table 6-2.
6-5
Table 6-1
Study
Dittmann et
al. (2001)
Mikhaeel et
al. (2000a)
Naumann et
al. (2001)
Study characteristics: FDG-PET accuracy in assessment of
residual masses
Number
of
patients
40 HD
24
evaluable,
16 had
scans for
recurrence
32
(15 HD,
17 NHL)
58
(43 HD,
15 NHL)
Patient
source
Design
Dose
(MBq)
Equipment
Diagnostic
standard
26
evaluations
of residual
masses
I: 2
II: 12
III: 6
IV: 6
Retrospective
400
GE Advance
Follow up
(no median
reported,
minimum
6 months)
32 with
residual
masses
62
evaluations
of residual
masses
I-II:
13
III–IV: 19
Retrospective
350
ECAT
951R
I:
II:
III:
IV:
1
23
12
22
Prospective
300-370
ECAT
EXACT
HR+
Follow up
(median
38 months)
Follow up
(median
30 months)
I:
1
II: 9
III: 7
IV: 2
Relapse: 11
I:
3
II: 15
III: 9
IV: 9
I:
7
II: 13
III: 5
IV: 9
Prospective
370
ECAT
EXACT
HR+
Follow up
(median
28 months)
Prospective
270
ECAT
EXACT
Follow up
(median
28 months)
Weihrauch
et al. (2001)
28 HD
patients
29
evaluations
of residual
masses
Bangerter et
al. (1999)
36
(14 HD,
22 NHL)
36 with
residual
masses
de Wit et al.
(1997)
34
(17 HD,
17 NHL)
31
evaluable,
3 received
chemothr’
py post
PET
37 HD
34 with
residual
masses
de Wit et al.
(2001)
Patient
characteristics
50
evaluations
of residual
masses
Retrospective
250-400
ECAT
EXACT 47
Follow up
(median
62 weeks)
Retrospective
250-400
ECAT
EXACT 47
Follow up
(median
25 months)
6-6
6.5
Accuracy of FDG-PET for post-therapy restaging in patients who are
CT-positive - analysis
Table 6-2
Study
Dittmann et al.
(2001)
Mikhaeel et al.
(2000a)
Naumann et al.
(2001)
Weihrauch et al.
(2001)
Bangerter et al.
(1999)
de Wit et al.
(1997)
de Wit et al.
(2001)
Results: FDG-PET accuracy in assessment of residual masses
PET
evaluation
Visual
Visual
(2 readers)
Visual +
SUV
Visual
Visual, read
with clinical
history
Visual ‘part
of daily
routine’
Visual ‘part
of daily
routine’
PET
independent
of CT
True positive – PET,
residual mass
True negative – PET,
residual mass
+ve
-ve
+ve
-ve
No
7
1
1
17
No
8
2
1
21
No
5
2
3
48
No
6
3
4
16
No
5
2
4
25
No
9
0
5
17
No
10
1
12
27
As with all imaging techniques, there are difficulties in interpretation because of the
absence of a ‘gold standard’ and uncertainty as to the appropriate follow-up interval.
Furthermore, it has been suggested (Bar-Shalom et al., 2001) that the accuracy of
FDG-PET may vary with the pretreatment stage. However, there is no evidence for
this from a between-study comparison but, with only five studies, such a test will be
very weak.
The meta-analysis indicates that for patients who have residual masses on CT, FDGPET has a sensitivity of 0.80, CI (0.59, 0.94) and specificity of 0.89, CI (0.74, 0.97),
which suggests that FDG-PET may be valuable in distinguishing true residual disease
post-therapy.
6.6
Accuracy of FDG-PET in post-therapy restaging (no CT) - studies
FDG-PET may also be used to assess post-induction therapy response without using
the results of a CT scan, this may be done by ignoring CT scan results that have been
taken or in patients for whom no CT results are available.
The review identified 10 published papers on this topic, three of which were
excluded; two because a non-optimal scanner using NaI detection was used
(Jerusalem et al., 2001 and Jerusalem et al., 1999b), and one because it recapitulated
two other studies (Spaepen & Mortelmans, 2001). The remaining papers are combined
using meta-analysis in section 6.7. The study characteristics are shown in Table 6-3
and accuracy data are displayed in Table 6-4.
6-7
Table 6-3
Study
Mikhaeel
et al.
(2000b)
Zinzani
et al.
(1999a)
Spaepen
et al.
(2001a)
Spaepen
et al.
(2001b)
Study characteristics: PET accuracy post therapy
Number
of
patients
49 High
grade
NHL – 45
with PET,
33 CT
44 with
PET and
CT
(13 HD,
31 highgrade
NHL)
60 HD
with PET,
0 with CT
93 NHL
with PET,
0 with CT
Stumpe
et al.
(1998)
35 HD,
15 NHL
Lang et al.
(2001)
63 HD
(47
evaluable
for PET or
CT)
Cremerius
et al.
(2001)
56
(22 HD,
34 NHL)
– 41 for
PET, 36
for CT, 5
not
evaluable
Patient
source
Patient
characteristics
Design
Dose
(MBq)
Equipment
Diagnostic
standard
Post first
therapy
I-II: 30
III–IV: 19
Retrospective
350
Siemens CTI
951/31R
Follow up
(24 months)
Post first
therapy
II: 20
III-IV: 24
Retrospective
444
ECAT Exact
47
Follow up
(median
18 months)
Post first
therapy
II: 25
III: 19
IV: 16
I: 8
II: 25
III: 24
IV: 36
No stage
information
Retrospective
150–555
ECAT 931
Retrospective
370–555
ECAT 931
Follow up
(median
30 months)
Follow up
(median
23 months)
Prospective
350
GE Advance
Follow up
(minimum
6 months)
I: 1
II: 15
III: 10
IV: 14
Not done: 11
Retrospective
370
Exact 47
Follow up
(median
22 months)
I: 4
II: 24
III: 10
IV: 18
Retrospective
220
ECAT
935/15
Follow up
(median
21 months)
Post first
therapy
54 post
first
therapy
PET scans
reported,
24 posttherapy CT
scans
51 post
first
therapy, 4
received
therapy
after
scanning,
12 received
PET to
determine
recurrence
41 post
first
therapy,
15 received
PET to
determine
recurrence
6-8
6.7
Accuracy of FDG-PET for post-therapy restaging (no CT) - analysis
Table 6-4
Study
Mikhaeel
et al.
(2000b)
Zinzani et
al.
(1999a)
Spaepen
et al.
(2001a)
Spaepen
et al.
(2001b)
Stumpe et
al. (1998)
Lang et al.
(2001)
Cremerius
et al.
(2001)
Results: PET accuracy post therapy
PET
evaluation
PET
independent
of CT
True positive
– PET, post
therapy
+ve
-ve
True
negative –
PET, post
therapy
+ve
-ve
True positive
– CT, post
therapy
+ve
-ve
True
negative –
CT, post
therapy
+ve
-ve
Visual,
2 readers
Yes
9
6
0
30
7
4
10
12
Visual,
2 readers
Unclear
13
1
0
30
14
0
23
7
Visual,
2 readers
Yes
5
5
0
50
Visual,
2 readers
Yes
26
11
0
56
No
20
3
1
30
6
2
10
6
Yes
18
1
3
25
18
1
17
11
Yes
16
3
3
19
11
3
15
7
Visual,
2 readers
Visual,
2 readers
Visual,
2 readers
Just as in the use of FDG-PET to evaluate residual masses, there are a number of
difficulties with interpretation of the studies presented. These are:
 the length of follow-up is variable between studies;
 most of the studies present combined results for HD and NHL, although there is
some (anecdotal) evidence of differences in accuracy between the two diseases;
and
 the studies available are rather small and mostly retrospective.
It should be noted, of course, that precisely the same criticisms can be made of studies
of other imaging methods in this application area.
The estimated sensitivity and specificity were 0.81, CI (0.63, 0.92) and 0.95 CI (0.90,
0.99), which are not essentially different from its performance when used only in CTpositive patients. There was no strong evidence that discrimination was related to the
proportion of III-IV disease, but the analysis will have little power to detect such an
effect.
6-9
6.8
Accuracy of CT scanning for post-therapy re-staging
By way of comparison, and to inform the model discussed in section 7, a metaanalysis of studies detailing accuracy of CT scanning in assessing response to therapy
was conducted. The additional studies used are shown in Table 6-5 and Table 6-6.
Table 6-5
Study
Devizzi et
al. (1997)
Smith et
al. (1998)
King et al.
(1994)
Setoain et
al. (1997)
Jerusalem
et al.
(1999a)
Ha et al.
(2000)
Study characteristics: CT accuracy post therapy
Number of
patients
53 HD
47 with CT
Patient
source
Post first
therapy
Patient
characteristics
I-IIA: 34
IIB–IV: 19
31 NHL
28 with
follow-up
and CT
33 HD
all with CT
Post first
therapy
Post first
therapy
53
(37 HD,
16 NHL)
25 with CT
54
(19 HD,
35 NHL)
all with CT
(included
only in
CT analysis
because of
technically
inadequate
PET
scanner)
79 HD
all with CT
Table 6-6
Diagnostic
standard
Follow up
(median
42 months)
Follow up
(median not
given)
Design
Dose
Equipment
Retrospective
N/A
N/A
Not given
Retrospective
N/A
N/A
II: 12
III: 13
IV: 8
Retrospective
N/A
N/A
Post first
therapy
Retrospective
N/A
N/A
Post first
therapy
Prospective
N/A
N/A
Follow up
(median
21 months)
Post first
therapy
Retrospective
N/A
N/A
Follow up
(median
12 months)
Follow up
(median
28 months)
Follow up
(median
12 months)
Results: CT accuracy post therapy
Study
Devizzi et al. (1997)
Smith et al. (1998)
King et al. (1994)
Setoain et al. (1997)
Jerusalem et al. (1999a)
Ha et al. (2000)
PET
evaluation
PET
independent
of CT
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
True positive –
CT, post therapy
+ve
3
4
13
3
10
8
-ve
0
8
1
1
4
3
True negative –
CT, post therapy
+ve
24
0
14
4
14
55
-ve
20
16
5
17
26
13
6-10
6.9
Conclusions
CT scanning has good sensitivity, 0.75, CI (0.58, 0.88), but poor specificity, 0.45, CI
(0.27, 0.64) in detecting viable residual tumour in patients who have responded to
initial induction therapy for lymphoma.
FDG-PET scanning has high sensitivity, 0.80, CI (0.59, 0.94) but greater specificity,
0.89, CI (0.74, 0.97) in discriminating viable tumour from scar tissue when used in
lymphoma patients who have positive CT scan results in this situation.
FDG-PET scanning used alone, rather than as an adjunct to CT scanning, to detect
residual tumour again has high sensitivity, 0.81, CI (0.63, 0.92) and specificity, 0.95,
CI (0.90, 0.99).
The majority of reported studies do not distinguish between results in HD and those in
higher grade NHL; the accuracy results presented both for PET and CT therefore refer
to patients with either of these forms of lymphoma. In addition, some of the studies
include results from a small number of patients who were scanned on more than one
occasion. Since these results may not be independent, it is possible that the metaanalysis may overestimate the accuracy of both FDG-PET and CT by a small amount.
FDG-PET scanning therefore appears likely to be of substantial value in the
assessment of lymphoma patients after induction therapy. Since the studies performed
to date have been relatively small, it will be important to supplement them with
systematic collection of the results from practical clinical experience.
6-11
7
ECONOMIC EVALUATION – RESTAGING HODGKIN’S DISEASE
Summary

An economic model has been used to assess the cost effectiveness of FDG-PET
scanning as an adjunct to conventional imaging in deciding the further treatment of
patients with HD who have achieved a partial or complete response to induction
therapy.

FDG-PET is more specific than CT in differentiating active residual disease and may
therefore allow patients to avoid unnecessary radiotherapy (RT) and the associated
mortality and morbidity.

Five strategies were considered, in which patients were allocated to immediate
consolidation RT or surveillance, based on the results of CT and FDG-PET imaging
following induction therapy.

Post-induction investigations and treatment included RT for relapse during
surveillance, IVE (ifosfamide, etoposide and epirubicin) re-induction chemotherapy
for relapse after RT, followed by high-dose chemotherapy (HDCT) with autologous
peripheral stem cell or bone marrow support for responders. Non-responders received
palliative therapy.

A cost-effectiveness analysis used a Markov model to compare the different strategies
in terms of changes in resource use and survival time, from the effects of accuracy on
therapy selection. Cost effectiveness acceptability curves (CEAC) were used to plot
the probability that the net (monetary) benefit from one strategy exceeds that from
another as a function of the ‘willingness to pay’ coefficient (K).

The results show that the costs are similar for all strategies and so clinical results (life
years gained) play the dominant role in determining cost effectiveness. Treatment
based on the results of FDG-PET scanning alone gives the largest expected life years
across all patient types.

Although the use of FDG-PET scanning to determine treatment only in CT-positive
patients is less cost effective than the use of FDG-PET scanning in all patients, both
strategies are cost effective for any value of K greater than £5000 in essentially all of
the simulations, thus comparing favourably with other interventions studied in
previous HTAs.

The model also predicts that using CT alone, 36% of patients will receive
unneccessary consolidation RT. This would be reduced to 4% for patients assessed
using FDG-PET alone, or to 6% for those undergoing FDG-PET after positive CT
scan.
7-1
7.1
Literature search
7.1.1
Search strategy
As part of the scoping searches undertaken in July 2001, to help define the assessment
question (see section 3.2), economic evaluations had been sought on a number of
cancers including lymphoma. The following strategies were adopted:
 the NHS EED and the HEED were searched;
 the websites of the major health economics research centres were searched for
economic evaluations;
 the electronic databases MEDLINE (Ovid), PreMEDLINE (Ovid) and Embase
(Ovid) were searched. The search was split into three concepts: positron emission
tomography, lymphoma and terms to identify economic evaluations. All relevant
subject headings and free text terms were identified for each concept. The search
was restricted to studies publish from 1990 onwards. No language restrictions
were applied;
 members of the TSG and experts were consulted to check for further economic
evaluations; and
 the bibliographies of relevant studies were scanned for further evaluations.
In addition, searches were undertaken in MEDLINE, PreMEDLINE and Embase to
provide inputs for the economic model relating to:
 the costs associated with chemotherapy for lymphoma; and
 toxicities associated with two chemotherapy regimens, IVE (ifosfamide,
etoposide and epirubicin) and BEAM (carmustine, cytarabine, etoposide and
melphalan).
Further information about the search is presented in Appendix 5.
7.1.2
Criteria for inclusion and exclusion of studies
The following exclusion criteria were applied when reviewing the economic literature search
results:
1. Review articles not containing data in the form of a model or study.
2. Studies not carried out in a population that might be broadly relevant to
Scotland (i.e. not American or European).
3. Articles not written in English.
7.1.3
Data extraction
Although two previous economic modelling studies were found (Klose et al., 2000
and Hoh et al., 1997) this work was not considered directly relevant to the current
model, since they were concerned with initial disease staging, and no data extraction
was done.
7-2
7.2
Economic methods
7.2.1
Restriction to Hodgkin’s disease (HD)
The decision was taken to restrict the economic modelling to the case of HD because
of time constraints and since, following discussion with Scottish oncologists, it was
believed to be likely that FDG-PET would be more clearly cost effective in HD.
Although the accuracy of FDG-PET scanning is similar in both HD and NHL, clinical
markers of residual disease are more effective in NHL.
This restriction should not be taken as evidence that the use FDG-PET scanning to
restage NHL after induction therapy is not cost effective.
7.2.2
Objectives of the economic evaluation
1. To review the existing English language literature on the economics of FDG-PET
in the management of HD, in order to assess its quality and relevance to the issues
facing NHSScotland.
2. To use selected literature and expert opinion as the basis for modelling the flow of
patients through different investigative and treatment strategies for HD.
3. To use this model to estimate the costs and benefits of each strategy, and hence
to estimate the net costs and benefits of using FDG-PET for restaging HD.
4. To assess whether the key economic results arrived at above would still hold
under alternative plausible scenarios.
7.2.3
The potential for use of PET in restaging HD in NHSScotland
The model described here will be used to assess the cost effectiveness of FDG-PET
scanning as an adjunct to conventional imaging in deciding the further treatment of
patients with HD, who have achieved a partial or complete response to induction
therapy. It is expected that, since FDG-PET imaging appears to be at least as sensitive
as CT scanning for the detection of residual disease, and considerably more specific
(section 6), its use in this setting may allow a significant proportion of patients to
avoid consolidation RT and the associated long-term toxicity.
7.2.4
Model structure
Current practice mandates (Dr M Mackie, Consultant Haematologist, Western
General Hospital, Edinburgh, Personal communication, 2002) that a CT scan will be
undertaken for all patients after induction therapy to assess initial disease response.
Therefore the economic modelling concentrates on strategies in which CT has been
performed and patients are classified as CT-positive or CT-negative then further
investigations and treatment are undertaken. The possibility of avoiding the use of CT
scanning in some patients is discussed in section 7.4.5.
7-3
The model consists of two components; a decision tree, specifying how the results of
FDG-PET and CT imaging will be used to guide initial treatment selection, and a
Markov model describing the flow of patients through treatment and remission to
death. Five ‘versions’ of the decision tree, corresponding to the different strategies for
the use of FDG-PET and CT, are described here. The Markov ‘treatment’ model,
which is common across all strategies, is described in section 7.2.5.
It is assumed that for each patient, one of two possible decisions will be taken:
1
immediate consolidation RT; or
2
surveillance, with follow-up examinations;
and that one of the five strategies illustrated in Figure 7-1 will be used.
Although strategies 1 and 2 appear implausible, they will be used as ‘controls’ in the
sense that, if either appears cost effective in the resulting assessment, this will be
regarded as casting doubt on the validity of the model assumptions.
Since the prevalence of active disease will differ between surveillance groups defined
by different combinations of imaging tools, it is important to distinguish between
these groups in the subsequent modelling.
Figure 7-1
Management pathways after induction chemotherapy in HD
1. All for surveillance
2. All for consolidation
–ve
Surveillance
+ve
Consolidation
3. CT
+ve
+ve
Consolidation
-ve
Surveillance
FDG-PET
4. CT
-ve
Surveillance
–ve
Surveillance
+ve
Consolidation
5. [CT]* FDG-PET
+ve : positive
–ve : negative
* [CT] indicates that although a CT scan is performed, the results are not used in allocating patients
between surveillance and consolidation.
7-4
7.2.5
Markov treatment model
The Markov (‘treatment’) model will be run for a 30-year time horizon and will
represent the life experience of patients after the post-induction assessment. The
model is shown schematically in simplified form in Figure 7-2 and is described in
section 7.2.5.1.
7.2.5.1 Narrative description of the model and assumptions
1. Patients are selected for consolidation or surveillance based on the results of CT
and FDG-PET imaging.
2. Patients selected for consolidation receive RT immediately, the others are
monitored (surveillance as described in 7.2.11).
3. Patients under surveillance who relapse are assessed for salvage (either RT or
further chemotherapy with Adriamycin (doxorubicin), bleomycin, vinblastine and
decarbazine (ABVD) or other regimen).
4. Patients who relapse after RT, or are unsuitable for salvage, are given IVE
reinduction therapy.
5. Responders to reinduction will undergo high-dose BEAM chemotherapy and
autologous peripheral stem cell or bone marrow support.
6. Deaths (possibly due to toxicity) may occur during reinduction or HDCT.
7. Non-responders to reinduction therapy with IVE will be regarded as treatment
failures and receive palliative therapy.
8. All patients who survive without relapse six or more years from the start of
remission will be assumed to exhibit only population all-cause mortality, modified
by the late toxicity of RT, salvage therapy or HDCT in those patients who
received it (leukaemia, breast cancer, lung cancer and heart disease).
7-5
Figure 7-2
1. Surveillance
PET negative
Structure of the Markov treatment model
2. Surveillance
CT positive
3. Consolidation and follow up
5. IVE
4. Salvage and follow up
7. Palliation
6. HDCT and follow up
7-6
9. Death
8. Second malignancy
7.2.6
Identification and measurement of the potential benefits and costs of PET
The economic issues surrounding the use of FDG-PET scanning in the investigation
of patients with HD relate to the fact that it can detect small but clinically significant
metastases and is more specific than CT in differentiating active residual disease from
scarring (section 6). As a result it may:
1. avoid unnecessary RT;
2. avoid the mortality and morbidity associated with long-term toxicities of
RT;
3. possibly reduce the numbers of other diagnostic tests; and
4. allow appropriate systemic therapy to begin earlier.
Offsetting these potential advantages might be factors such as the following:
1. the costs of setting up and running the PET scanner; and
2. since salvage therapy may be less effective than consolidation RT, patients
inappropriately assigned to surveillance (false negatives) may be
disadvantaged. This disadvantage is of course shared with CT scanning.
7.2.7
Assumptions
7.2.7.1 Relapse detection
It is assumed that only relapses occurring in the first two years after the end of
induction therapy can be predicted by any imaging device used immediately after the
end of induction therapy, and that a completely accurate imaging device would predict
all such relapses.
7.2.7.2 Long-term toxicity
It is assumed that the long-term toxicity due to consolidation or salvage will reflect
current experience. It is assumed that salvage therapy after surveillance (RT or
ABVD chemotherapy) will carry the same long-term risks as consolidation RT.
7.2.7.3 No QOL loss for procedures
Some authors (e.g. Dietlein et al., 2000a; Gambhir et al., 1996) have hypothesised
that patients suffer reduced QOL when they are undergoing tests or treatment, for
example in terms of discomfort, anxiety or the acute toxic effects of therapy.
Although this is plausible, there is no published evidence to support this hypothesis.
Furthermore, as PET is non-invasive and no reported adverse events have been
reported in a study of 80,000 patients (section 4.6), any reduction in QOL will be
minimal.
7.2.7.4 Strategies for testing and treatment are followed
As discussed in section 4, much of the empirical evidence on FDG-PET relates to its
accuracy, with limited uncontrolled evidence on change in patient management. The
model assumes that all involved in the management of the patient follow the strategy,
without ordering any other tests.
7-7
7.2.8
Methods of analysis
The impact of FDG-PET is analysed by a cost-effectiveness analysis, which sets out
the changes in resource use and survival from the effects of improved accuracy on
therapy selection. Quality adjusted life years were not used in the analysis because of
the paucity of reliable data (section 7.2.11.2) and because changes in therapy will
impact survival time.
Probabilistic sensitivity analysis was conducted, in which values of major inputs to
the model were allowed to vary in accordance with the distributions described in
7.2.11. The results from this analysis are presented in the form of cost-effectiveness
acceptability curves (CEACs) (Briggs & Tambour, 2001; van Hout et al., 1994). The
CEAC for comparison of two strategies (A and B) plots the probability that the net
(monetary) benefit from strategy A exceeds that for strategy B, as a function of the
‘willingness to pay’ coefficient (K). This probability is based upon the data described
in section 7.2.11 and the assumptions described in section 7.3.1 and is known as a
‘posterior’ probability.
If £K denotes the amount of money NHSScotland is ‘willing to pay’ for an additional
life year (crudely, ‘the value of an extra year of life’), the net benefit (NB) is given by
K*(Life years gained) – Cost.
7.2.9
Perspective and horizon
The time horizon is assumed to approximate the lifetime of the patient; in this model a
thirty-year horizon has been used. Costs relating to HD management were included
(including costs to NHSScotland and patient travel costs). Given the life expectancy
and age at treatment of these patients, the results may be affected by considering a
societal perspective.
7.2.10
Discounting costs and benefits occurring in future years
Discount rates were used as in the NSCLC analysis (section 5).
7.2.11
Model inputs
The inputs for the HTBS economic model for restaging HD in Scotland are
summarised in Table 7-1.
7-8
Table 7-1
Inputs to the HTBS economic model: base case and distributions
Term
Accuracy of CT scan
Accuracy of FDG-PET scan
after positive CT
Accuracy of FDG-PET scan as
‘stand-alone’
Relapse percentage years 1-2
post ABVD
Relapse percentage years 3-5
post ABVD
Relapse percentage years 1-5
post RT
Percentage of in-field relapse
from RT (assumed to occur in
years 1-2)
Source
Section 6
Section 6
Section 6
Canellos et al. (1992)
Carde et al. (1993)
Duggan et al. (1997)
Canellos et al. (1992)
Carde et al. (1993)
Duggan et al. (1997)
Petera et al. (2000)
Yahalom et al. (1991)
Mendenhall et al. (1999)
Viviani et al, (1996)
Petera et al. (2000)
Yahalom et al. (1991)
Assumption
Percentage relapsing after
surveillance suitable for salvage
Five-year relapse free survival
after salvage
Percentage of patients moving
from IVE re-induction to HDCT
Percentage of toxic deaths
under IVE
Percentage of toxic deaths under
HDCT
Five-year survival post HDCT
Relative risk of breast cancer
post RT
Relative risk of leukaemia
post RT
Value
Sensitivity 0.75 (0.58 – 0.88)*
Specificity 0.45 (0.27 – 0.64)*
Sensitivity 0.80 (0.59 – 0.94)*
Specificity 0.89 (0.74 – 0.97)*
Sensitivity 0.81 (0.63 – 0.92)*
Specificity 0.95 (0.90 – 0.99)*
26.5% (23% - 30%)*
6% (3% - 9%)*
11.5% (8% - 16%)*
37% (24% - 50%)*
Years 1 – 2 base case 25%,
distributed as Uniform (10,40)
Viviani et al. (1990)
Years 3 – 5 85%
Viviani et al. (1990)
52%
Proctor et al. (2001)
Anselmo et al. (2000)
Proctor et al. (2001)
Anselmo et al. (2000)
Chopra et al. (1993)
Anselmo et al. (2000)
Argiris et al. (2000)
Crump et al. (1993)
Linch et al. (1993)
Lazarus et al. (2001)
Chopra et al. (1993)
Ferme et al. (2002)
Bierman et al. (1993)
52% (41% - 63%)*
1% (0% - 5%)*
7% (6% - 9%)*
60% (54% - 65%) *
van Leeuwen et al. (1994)
12.7
Abrahamsen et al. (1993)
van Leeuwen et al. (1994)
Linch et al. (2000)
van Leeuwen et al. (1994)
Linch et al. (2000)
24.3 (11.1 – 46.2)
34.7 (23.6 – 49.3)
Low
3.7 (2.5 – 5.3)
10.3 (7 – 13.7)
Relative risk of lung cancer
post RT
Relative risk of death from heart
Hancock et al. (1993)
3.1
disease post RT
* denotes that for these parameters the distribution used for the probabilistic sensitivity analysis (PSA)
was the posterior distribution from a meta-analysis (see Appendix 19 and section 6). Distributions for
other parameters are specified in section 7.4.1.
7-9
All relative risks are assumed to be zero in the first five years after treatment; lung
and breast cancer risks are assumed also to be zero in the second five years after
treatment, whereas heart disease and leukaemia risks rise immediately to the level
specified. All relative risks are assumed to take the values specified in the table from
year 11 post-treatment onwards.
All quantities in Table 7-1 are assumed to be independent of age and sex. Although
somewhat unrealistic, this assumption is made necessary by the structure of the
available data.
Base-case incidence and mortality rates (disease specific and all cause) refer to the
Scottish population in 1998 and are taken from the ISD website
(http://www.show.scot.nhs.uk/isd/).
Table 7-2
Cost inputs to the model: base case
Cost
FDG-PET scan
CT scan
Source
Section 9.6
Section 7.2.11.3.1
Surveillance (post ABVD)
Section 7.2.11.3.2
Surveillance
(post conservative/salvage)
Section 7.2.11.3.2
Surveillance
(post autologous PBSCT)
Section 7.2.11.3.2
RT
IVE re-induction
HDCT therapy and autologous
peripheral blood stem cell
support
Non-curative therapy for IVE
failures
Costs associated with long-term
toxicities – lung cancer
Costs associated with long-term
toxicities - breast cancer
Costs associated with long-term
toxicities – leukaemia
Section 7.2.11.3.3
Section 7.2.11.3.4
Value
£678
£146
Year 1 £265
Year 2 £89
Year 3 £89
Year 4 £59
Year 5+ £30
Year 1 £411
Year 2 £235
Year 3 £89
Year 4 £59
Year 5+ £30
Year 1 £649
Year 2 £59
Year 3 £59
Year 4 £59
Year 5+ £30
£2494
£6832
Section 7.2.11.3.5
£19,172
Section 7.2.11.3.6
£524 p.a.
Conservative assumption
£500 p.a.
Conservative assumption
£200 p.a.
Conservative assumption
£1500 p.a.
Distributions associated with these costs are described in section 7.3.1.
7-10
7.2.11.1 Epidemiology
The model applies only to patients aged 60 or under, with advanced HD, which has
apparently responded fully or partially to first-line therapy with ABVD. (Patients with
a biological age greater than 60 years will not receive aggressive induction therapy
and so are excluded from this model).
The model will be run for six patient types:
 male 20 years;
 male 40 years;
 male 60 years;
 female 20 years;
 female 40 years; and
 female 60 years.
Results from each patient ‘type’ may then be combined according to their
proportional incidence in the Scottish population, although the separate results for
each patient type are also of interest.
7.2.11.2 Quality of life
Ideally, quality-of-life data for this study would have been derived from a survey of
Scottish patients or using utility values from the Scottish public but, within the time
constraints faced, the only realistic option was to search the literature for values used
in previous work on HD and the associated secondary malignancies.
Unfortunately there are few reliable published studies. For example, Norum et al.
(1996) present a mean utility for HD survivors of 0.78. This figure was obtained from
survivors roughly five years after treatment, and may well underestimate the utility
experienced by long-term survivors. Interestingly, utility estimates in this paper were
negatively correlated with initial disease stage (presumably merely reflecting random
variation in a small sample of patients). Uyl-de Groet et al. (1995) reported that two
years post-HDCT or CHOP (Cyclophosphamide, Adriamycin, Vincristine,
Prednisone) chemotherapy, the Euro-QOL score of NHL survivors was close to
90/100 (again in a very small sample).
In a large review, Tengs & Wallace (2000) present the following utility estimates for
second primary malignancies:
 breast cancer 0.89; and
 general cancer (including leukaemia?) 0.7 – 0.9.
Finally, Earle et al. (2000) and Berthelot et al. (2000) present estimates for NSCLC of
between 0.65 and 0.88 depending on disease stage.
In view of the considerable uncertainty surrounding these estimates and their
interpretation, the primary analysis undertaken here will focus simply on life years
accumulated under each of the strategies.
7-11
7.2.11.3 Resource use
The following costs were sought for the economic model:
 CT scan;
 surveillance;
 RT;
 IVE chemotherapy;
 non-curative therapy for patients who fail IVE;
 autologous peripheral blood stem cell transplant (PBSCT); and
 costs associated with long-term toxicities (three specific diseases were identified
– lung cancer, breast cancer and leukaemia).
The costings in the model take overheads from the Scottish Health Services Cost
Manual 2001 (Common Services Agency, Information and Statistics Division, 2001),
indexed by 5% to get costs at 2002/03 prices. These are allocated overheads that cover
non-direct costs. Staff costs were based on NHSScotland pay scales for the year
commencing April 2002. Superannuation, national insurance and on-costs were added
on. An average body size of 1.8 metres2 was used for calculating drug dosage.
7.2.11.3.1 CT scan
The new English NHS Reference Costs – 2001 (NHS Executive, 2001) provide a
mean cost of £139 and an interquartile range of £75. In accordance with this, CT costs
(2001 level) were assumed to be random with a normal distribution, mean £139,
standard deviation £75/1.349 = £55.6. These values were then indexed by 5% to
convert to 2002 levels.
7.2.11.3.2 Surveillance
There are no agreed strategies across Scotland for the surveillance of a patient and the
working practices differ from location to location. In this model, the resource use
associated with monitoring a patient over a period of five years was based on expert
opinion from the Lothian University Hospitals NHS Trust. The three surveillance
strategies used in this model were:
 post ABVD chemotherapy;
 post RT/salvage chemotherapy; and
 post autologous PBSCT.
The costs and resource use over a five-year period for each of the above strategies are
presented in Table 7-3 to Table 7-5.
7-12
Table 7-3
Resource
CT scan
(mean value)
Physical
examination
Outpatient
appointment
Lab tests
Mean total
Table 7-4
Resource
CT scan
(mean value)
Physical
examination
Outpatient
appointment
Lab tests
Mean total
Table 7-5
Resource
CT scan
(mean value)
Physical
examination
Outpatient
appointment
Lab tests
Mean total
Post ABVD chemotherapy
Unit cost
Year 1
Year 2
Year 3
Year 4
Year 5
£145.95
1
0
0
0
0
£8.62
4
3
3
2
1
£13.65
4
3
3
2
1
£7.45
4
£264.83
3
£89.17
3
£89.17
2
£59.44
1
£29.72
Post radiotherapy/salvage chemotherapy
Unit cost
Year 1
Year 2
Year 3
Year 4
Year 5
£145.95
2
1
0
0
0
£8.62
4
3
3
2
1
£13.65
4
3
3
2
1
3
£89.17
2
£59.44
1
£29.72
£7.45
4
£410.78
3
£235.12
Post autologous peripheral blood stem cell transplant (PBSCT)
Unit cost
Year 1
Year 2
Year 3
Year 4
Year 5
£145.95
2
0
0
0
0
£8.62
12
2
2
2
1
£13.65
12
2
2
2
1
£7.45
12
£648.54
2
£59.44
2
£59.44
2
£59.44
1
£29.72
7.2.11.3.3 Radiotherapy (RT)
Consolidation RT involves 20 fractions of RT administered over a four-week period
(Monday to Friday). Resource use was identified based on discussions with a
Consultant Oncologist (Dr N O’Rourke, Beatson Oncology Centre, Western
Infirmary, Glasgow, Personal communication, 2002). The mean summary costs are
listed in Table 7-6.
Table 7-6
Summary costs for consolidation radiotherapy
Resource
Radiographer (staff time)
Simulator
Physicist (staff time)
Linac machine
Other medical time
Overheads
Patient travel costs
Total
Mean cost
£178
£35
£145
£175
£315
£819
£827
£2494
7-13
Costs for the radiographer, simulator, physicist and Linac machine are the direct costs
associated with administering 20 fractions of RT. ‘Other medical time’ covers initial
consultation, planning appointments, consultations during the four-week period and
follow- up appointments. Overheads used are the Scottish average of non-direct costs
for outpatients in a RT ward.
As the RT treatment is administered over a four-week period, patient travel costs will
be significant. The assumptions used are based on discussion with a Consultant
Oncologist (Dr N O’Rourke, Beatson Oncology Centre, Western Infirmary, Glasgow,
Personal communication, 2002).
It is assumed that 63% of the patients would use their own transport or public
transport, 32% of patients will use the hospital patient transport service and the
remaining 5% will require either an in-patient bed or a hotel room. The latter 5% of
patients are assumed to be travelling from remote areas where it is not possible or cost
effective to make daily return journeys.
For patients using their own transport or public transport a figure of £4 per return
journey has been assumed on the basis that this is what it will cost to take two bus
journeys to the hospital. These patients are assumed to be local residents.
Patients using hospital transport are assumed to be making a return journey of an
average of 50 miles. These patients will be a mixture of local residents and residents
of the surrounding areas. The cost per mile is taken as the average for Scotland as
listed in the Scottish Health Service Costs Manual 2001 (Common Services Agency,
Information and Statistics Division, 2001). The average cost per mile is £1.98, which
has been indexed at 5% to derive costs for 2002/03.
Patients travelling from further afield, such as the Highlands and Islands, will require
an in-patient bed or a hotel room. The cost of an in-patient bed is based on the
Scottish average non-direct overheads (it is assumed that very little nursing case or
pharmacy will be needed) in an in-patient RT ward for 16 nights at £114 per night.
Shetland Health Board provides an allowance of £54 per night for hotel
accommodation and this figure is used for hotel costs. In addition, provision for four
return flights at £300 each has been made.
7.2.11.3.4 IVE chemotherapy
For each cycle of IVE treatment it was assumed that there were:
 four days stay as an in-patient;
 one outpatient visit; and
 1.25 days in-patient stay for complications.
Over three cycles of IVE it was assumed that 25% of patients would require standard
cheaper treatment for sepsis and 10% would also require an alternative more
expensive treatment for sepsis.
Overhead costs were based on average overheads for a haematology ward in Scotland.
Resource use, pharmacy, admission and laboratory test were based on information
supplied by the Lothian University Hospitals NHS Trust.
7-14
Mean cost for IVE is £6832 per treatment (three cycles at £2063 each plus provision
for treating side effects at £399).
Appendix 20 outlines the components of IVE costs.
7.2.11.3.5 Autologous peripheral blood stem cell transplant (PBSCT)
Assumptions used in autologous PBSCT were as follows:
 in-patient stay22 days;
 outpatient visits 8 days; and
 in-patient stay for complications3 days.
Overhead costs were based on the Scottish average non-direct overheads for a
haematology ward. Resource use, pharmacy, admission and laboratory test were based
on information supplied by the Lothian University Hospitals NHS Trust.
Blood products are supplied free of charge to hospitals in Scotland so they have not
been included in the costing exercise.
Mean costs for PBSCT are:
Procedure
Complications
Total
£18,377
£795
£19,172
Appendix 20 outlines the components of the PBSCT procedure.
Autologous bone marrow transplant has also been costed at £23,990.
7-15
7.2.11.3.6 Long-term toxicities
Given that each long-term toxicity is represented as a single state in the model, a
conservative figure for the average cost for each toxicity was taken from the costs
detailed below. This was then divided by the maximum life expectancy to get the
annual cost per year.
Toxicity
Costing
Non-curative therapy for
IVE failure
An annual average cost of £524 was calculated. This includes drug cost,
some radiotherapy, outpatient visits and district nurse visits.
Leukaemia
Indicative treatment costs for secondary leukaemia were based on
discussions with experts (Dr Davies, Western General Hospital, LUHT) and
informed by a brief literature review. The mean cost was approximately
£30,000 per patient.
Breast cancer
Lung cancer
7.3
Costing work on breast cancer has been done by SHPIC (Scottish Health
Purchasing Information Centre, 1997). The HTBS model uses their costs
for mastectomy and breast conservation with radiotherapy and first-line
chemotherapy. This calculates as an indicative average £3000. Second-line
chemotherapy costs used are as stated in NICE guidance on taxanes of
approximately £4000 per event (NICE, 2001b). The average cost per event
in breast cancer is taken to be £3000.
On the basis of previous work done for this HTA (section 5), a figure of
£500 per annum over the estimated average lifespan of 2.5 years was used
as a conservative estimate of the cost.
Results
The model was constructed and run in WinBUGS 1.4 (http://www.mrcbsu.cam.ac.uk/bugs/welcome.shtml). The code used is available on request from
HTBS.
7.3.1
Uncertainties
Uncertainties exist in the model inputs for two reasons. First, although data exist to
inform many of the inputs, those data only determine the inputs up to a distribution
with some variation. For such inputs, the distributions estimated from meta-analysis
and shown in Table 7-1 are used directly in the sensitivity analysis.
Secondly, there exist poor or no data about some model inputs (e.g. utility weights).
For such inputs the distributions shown in Table 7-7 have been used.
7-16
Table 7-7
Model inputs - sensitivity distributions
Term
Proportion relapsing after PET
and suitable for salvage –
years 1–2
Proportion relapsing after PET
and suitable for salvage –
years 3–5
Proportion relapse within
five years post salvage
Relative risk of breast cancer
post RT/salvage
Relative risk of breast cancer
post HDCT
Relative risk of breast cancer
post RT/salvage and HDCT
Relative risk of lung cancer
post RT/salvage
Relative risk of lung cancer
post HDCT
Relative risk of lung cancer
post RT/salvage and HDCT
Relative risk of leukaemia
post RT/salvage
Relative risk of leukaemia
post HDCT
Relative risk of leukaemia
post RT/salvage and HDCT
Relative risk of heart disease
death post RT/salvage
Relative risk of heart disease
death post HDCT
Relative risk of heart disease
death post RT/salvage and
HDCT
Cost of CT scan
Cost of salvage therapy
Cost of RT
Cost of IVE
Cost of HDCT
Cost of non-curative therapy for
IVE failures
Base case value
Distribution
0.25
Uniform (0.1 – 0.4)
0.88
Uniform (0.75 – 1)
0.48
Uniform (0.4 – 0.55)
12
Normal (12, 1)
3
Normal (3, 1)
15
Normal (15, 1)
6
Normal (6, 1)
2
Normal (2, 1)
8
Normal (8, 1)
5
Normal (5, 1)
7
Normal (7, 1)
10
Normal (10, 1)
3.1
2
6.2
£149
£6000
£1432
£6832
£21500
£524
Normal (3.1, 0.25)
Normal (2, 0.25)
Normal (6.2, 0.25)
Normal (149, 58.4)
Normal (6000, 200)
Normal (2494, 210)
Normal (6832, 191)
Normal (21500, 1751)
Normal (524, 93)
It is recognised that modern radiotherapeutic methods may present a different longterm toxicity risk profile to that observed in previous published experience. To reflect
this possibility, the estimated relative risks will be multiplied by a ‘bias term’,
uniformly distributed on a suitable range (0.8 – 1.2).
7-17
7.3.2
Results – Life-years analysis
The results presented here represent the distribution of costs and benefits for the five
strategies, generated by the input distributions described in sections 7.2.11 and 7.3.1.
As the distribution of costs and benefits is too complex to calculate in a closed form,
they have been obtained from an approximation based on computer simulations
(specifically, Gibbs Sampling, (Carlin & Louis, 2001)). First, a set of 5,000
simulations was used to ensure that an accurate approximation was obtained. The
results shown were then obtained from a further 10,000 simulations.
The tables present the estimated mean of the distribution of costs and benefits given
the data and assumptions. The CEACs presented for strategies 4 (FDG-PET after
positive CT) and 5 (FDG-PET alone) show the probability that each of these is cost
effective, relative to strategy 3 (CT alone), as a function of K, the value assigned to
one additional year of life gained.
In other words, the CEAC for strategy 5 plots the probability that the net benefit for
strategy 5 is greater than that for strategy 3, for each value of K (the monetary value
assigned to one year of life). The net benefit is given by the life years achieved by a
strategy multiplied by K, minus the cost of that strategy.
Overall, the model predicts that 36% of patients, CI (30.3%, 40.4%) restaged using
CT alone will receive unnecessary consolidation RT. This would be reduced to 3.8%,
CI (0.2%, 7%) for patients restaged using FDG-PET alone, or to 6%, CI (3.2%,
10.3%) if only CT positive patients are restaged using FDG-PET.
Table 7-8
Point estimates of life years saved and total costs for female, 20
years old at end of induction therapy
Strategy
Life years
Cost
1 – All surveillance
20.2
£5062
2 – All consolidation
20.7
£4634
3 – CT only
20.7
£4492
4 – FDG-PET after positive CT
21.1
£4304
5 – FDG-PET only*
21.4
£4069
* Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to
consolidation or surveillance, although a CT scan is used to assess response.
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-3.
Table 7-9
Point estimates of life years saved and total costs for male, 20 years
old at end of induction therapy
Strategy
Life years
Cost
1 – All surveillance
20.0
£5054
2 – All consolidation
20.9
£3973
3 – CT only
20.8
£4041
4 – FDG-PET after positive CT
21.1
£4062
5 – FDG-PET only *
21.5
£3805
* Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to
consolidation or surveillance, although a CT scan is used to assess response.
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-5.
7-18
Table 7-10
Point estimates of life years saved and total costs for female, 40
years old at end of induction therapy
Strategy
Life years
Cost
1 – All surveillance
19.4
£5051
2 – All consolidation
20.0
£4596
3 – CT only
20.0
£4464
4 – FDG-PET after positive CT
20.3
£4288
5 – FDG-PET only *
20.6
£4053
* Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to
consolidation or surveillance, although a CT scan is used to assess response.
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-7.
Table 7-11
Point estimates of life years saved and total costs for male, 40 years
old at end of induction therapy
Strategy
Life years
Cost
1 – All surveillance
18.8
£5042
2 – All consolidation
19.2
£3963
3 – CT only
19.3
£4030
4 – FDG-PET after positive CT
19.8
£4049
5 – FDG-PET only *
20.1
£3792
* Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to
consolidation or surveillance, although a CT scan is used to assess response.
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-9.
Table 7-12
Point estimates of life years saved and total costs for female, 60
years old at end of induction therapy
Strategy
Life years
Cost
1 – All surveillance
15.4
£5003
2 – All consolidation
14.5
£3929
3 – CT only
15.0
£3994
4 – FDG-PET after positive CT
15.8
£4008
5 – FDG-PET only*
16.1
£3750
* Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to
consolidation or surveillance, although a CT scan is used to assess response.
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-11.
Table 7-13
Point estimates of life years saved and total costs for male, 60 years
old at end of induction therapy
Strategy
Life years
Cost
1 – All surveillance
13.9
£4986
2 – All consolidation
12.3
£3933
3 – CT only
13.0
£3989
4 – FDG-PET after positive CT
14.1
£3994
5 – FDG-PET only *
14.3
£3734
* Strategy 5 – ‘PET only’ implies that only the PET scan results are used to assign patients to
consolidation or surveillance, although a CT scan is used to assess response.
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-13.
7-19
7.3.3
Discussion of results
The mean results show that the use of FDG-PET scanning alone, or as an adjunct to
CT scanning, is cost effective for all six patient types relative to the use of CT
scanning alone for any willingness to pay per life year in excess of £5000.
The costs are similar for all strategies, and so clinical results (life years gained) play
the dominant role in determining cost effectiveness.
The use of FDG-PET alone to allocate treatment (strategy 5) uniformly gives the
largest expected value of life years and lowest expected cost across all patient types
and is cost effective for essentially all plausible input values, for any value of
willingness to pay greater than £5000.
FDG-PET following CT (strategy 4) is an inherently poorer strategy than strategy 5
because of the low overall sensitivity of combining the two procedures. However, it
is still cost effective relative to the non-PET containing strategies, leads to a higher
expected value of life years, and may be more acceptable to clinicians initially, until
they gain experience with FDG-PET scanning.
The use of FDG-PET scanning to assign patients with HD to consolidation or
surveillance, whether used as the sole imaging tool or as an adjunct to CT in CTpositive patients, is cost effective in the base case, provided willingness to pay
exceeds £1000, and for almost all input values considered, provided willingness to
pay exceeds £5000.
7.4
Further sensitivity analysis
7.4.1
Lower accuracy from FDG-PET
Although the meta-analysis presented in section 6 suggests that PET alone is both
highly sensitive and highly specific, the methodological problems described there
(rather small studies, generally heterogeneous groups and retrospective design) may
have led to overoptimistic estimates of the accuracy of FDG-PET scanning. To
investigate the effect that overestimation of the specificity, in particular, may have
had, the model was rerun for 20-year-old males and females, with the specificity of
PET scanning alone now drawn from a uniform distribution on (0.6,0.9) and all other
input distributions unchanged.
For both 20-year-old females and males, strategy 5 remains cost effective relative to
strategy 3 across almost all simulations (Figure 7-9, Figure 7-10) and continues to
give longer lifespans than strategy 4, although the difference is now much smaller
(strategy 4 - 21.1, strategy 5 - 21.2 for females; 21.1 versus 21.2 for males).
7.4.2
Incorporation of quality weights
Although as discussed in section 7.2.11.2 the assignment of quality scores to the
health states in this model is subject to considerable uncertainty, in view of the
substantial impacts of second malignancies on quality of life, it may be reasonable to
attempt an analysis based on such assignment. Table 7-14 shows the distributions of
quality weights (utilities), which have been assumed in modelling QALY gains for the
7-20
five strategies in a 20-year-old woman. All other inputs were as presented in section
7.2.11.
Table 7-14
Estimated utilities in a 20-year-old woman
State
Any active treatment
(RT, salvage, IVE, HDCT) –
during period of treatment contact
Five-year follow-up period post
therapy
Post five years and without
chronic toxicity
Breast cancer
Leukaemia
Lung cancer
Utility
Justification
Moroff & Pauker (1983)
0.75
0.8
Norum et al. (1996)
0.9
Uyl-de Groet et al. (1995)
0.81
0.72
0.72
90% of current ‘healthy’ state
80% of current ‘healthy’ state
80% of current ‘healthy’ state
The resulting QALY and cost values are shown in Table 7-15.
Table 7-15
QALY analysis for 20-year-old woman
Strategy
1 – All surveillance
2 – All consolidation
3 – CT only
4 – FDG-PET after positive CT
5 – FDG-PET only
QALYs
14.9
15.1
15.3
15.7
16.1
Cost
£5062
£4634
£4492
£4304
£4069
The corresponding CEACs are shown in Figure 7-11.
Despite the uncertainty associated with utility values, this analysis of QALYs
confirms the results of the life year analysis, which indicates that both strategy 4 and
strategy 5 are superior to strategy 3.
7.4.3
Variations in discount rate used for clinical benefits
HTBS Guidance for Manufacturers (HTBS, 2002b) states that sensitivity analyses
presented should include the effects of adjusting the discount rate applied to benefits
to 0% or 6%. Since it is clear that the effect of reducing the benefit discount rate to
0% would be to increase the apparent clinical advantage of PET scanning, only the
results pertaining to a 6% rate will be presented here.
Table 7-16
Point estimates of life years saved and total costs for female, 20
years old, 6% discount rates on benefit
Strategy
1 – All surveillance
2 – All consolidation
3 – CT only
4 – FDG-PET after positive CT
5 – FDG-PET only
Life years
12.0
12.4
12.4
12.5
12.7
Cost
£5062
£4634
£4492
£4304
£4069
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-12.
7-21
Table 7-17
Point estimates of life years saved and total costs for male, 20 years
old, 6% discount rates on benefit
Strategy
1 – All surveillance
2 – All consolidation
3 – CT only
4 – FDG-PET after positive CT
5 – FDG-PET only
Life years
12.0
12.5
12.5
12.6
12.7
Cost
£5054
£3973
£4041
£4062
£3805
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-13.
Table 7-18
Point estimates of life years saved and total costs for female, 40
years old, 6% discount rates on benefit
Strategy
1 – All surveillance
2 – All consolidation
3 – CT only
4 – FDG-PET after positive CT
5 – FDG-PET only
Life years
11.8
12.1
12.1
12.2
12.4
Cost
£5051
£4596
£4464
£4288
£4053
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-20.
Table 7-19
Point estimates of life years saved and total costs for male, 40 years
old, 6% discount rates on benefit
Strategy
1 – All surveillance
2 – All consolidation
3 – CT only
4 – FDG-PET after positive CT
5 – FDG-PET only
Life years
11.5
11.9
11.9
12.1
12.2
Cost
£5042
£3963
£4030
£4049
£3792
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-21.
Table 7-20
Point estimates of life years saved and total costs for female, 60
years old, 6% discount rates on benefit
Strategy
1 – All surveillance
2 – All consolidation
3 – CT only
4 – FDG-PET after positive CT
5 – FDG-PET only
Life years
10.2
9.9
10.1
10.5
10.6
Cost
£5003
£3929
£3994
£4008
£3750
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-22.
7-22
Table 7-21
Point estimates of life years saved and total costs for male, 60 years
old, 6% discount rates on benefit
Strategy
1 – All surveillance
2 – All consolidation
3 – CT only
4 – FDG-PET after positive CT
5 – FDG-PET only
Life years
9.5
8.9
9.2
9.7
9.8
Cost
£4986
£3933
£3989
£3994
£3734
The CEACs for strategies 4 and 5 relative to strategy 3 are shown in Figure 7-17.
7.4.3.1 Summary
Although increasing the discount rate on benefits from 1.5% to 6% has reduced the
apparent superiority of PET-containing strategies relative to other approaches, there is
little impact on cost effectiveness for either strategy 4 or strategy 5, except that the
probability of cost effectiveness for strategy 4 in 20-year-old males now only reaches
90% if the value of a life year is greater than £15,000.
7.4.4
Discussion
A considerable number of simplifications and assumptions have been made in
building this model, for example:
 no account has been taken of the effects on quality of life of the life-long
monitoring for second primaries recommended after RT (Linch et al., 2000);
 the costs assigned to RT, and to treatment of second malignancies, are likely to be
substantial underestimates;
 the assumption that salvage chemotherapy treatment after surveillance is as toxic
as RT may be open to debate; and
 no account has been taken of the impact on quality of life of the greater degree of
diagnostic certainty likely to be afforded by FDG-PET results. Both patients and
physicians see this as a major advantage of PET scanning. However, although the
effect is undoubtedly real, there is no published evidence to allow the utility gain
afforded to be assigned a value and used in a cost-effectiveness analysis.
It is likely, however, that a model in which these omissions were rectified would
produce results suggesting a greater advantage for the FDG-PET based strategies, and
would not therefore substantially alter the conclusions of this exercise.
The time horizon used (30 years) may appear long relative to those commonly used in
the assessment of therapeutic technologies. However, it is well established that for
both therapeutic (Linch et al., 2000) and other (Ron et al., 1993) radiation exposures
the major risks of radiation exposure emerge after a lag of five to 10 years, and
continue to be present for at least a further twenty years.
A full societal perspective for the analysis has not been undertaken as this would
require major assumptions over the 30-year time horizon and would in case
undoubtedly increase the evidence for cost effectiveness.
Accurate knowledge of the relative risks of late toxicity due to current treatment
would substantially reduce the uncertainties associated with the model conclusions.
7-23
However, it is clear, that it is not justifiable to suggest that the introduction of FDGPET should await the conclusions of studies intended for this purpose.
It is assumed throughout that all patients will receive a CT scan at the end of
induction therapy, which will be used to confirm response, for radiation planning in
those patients assigned to consolidation or to provide a baseline for surveillance
follow up. Therefore although the optimal strategy, strategy 5, makes no use of the CT
scan result in assigning patients to consolidation or surveillance, it is unlikely that this
post-treatment CT scan could be avoided.
7.4.4.1 Relationship to previous work
Previous studies (Klose et al., 2000; Hoh et al., 1997) have shown that FDG-PET
scanning appears to be cost effective in staging/restaging HD and NHL when account
is taken only of stage migrations induced by FDG-PET scanning, without reference to
the long-term clinical significance of such migration. The current work confirms and
extends these studies by modelling the clinical consequences of PET scanning’s
superior accuracy.
7.4.5
Conclusions
The use of FDG-PET to assign patients with HD to consolidation or surveillance,
whether used as the sole imaging tool in all patients, or as an adjunct to CT only in
patients showing residual abnormalities on CT, is cost effective in the base case
provided the willingness of NHSScotland to pay exceeds £1000 per year of life, and
for almost all the input values considered provided the willingness to pay exceeds
£5000. The use of PET alone appears also to be cost saving compared with current
practice. Even if the cost of a PET scan was increased to £1000/scan, the cost per life
year would still be less than £10,000 per life year.
The cost effectiveness is maintained if quality adjusted life year gains are calculated
based on the available quality weights in the published literature, if very unfavourable
assumptions are made about the actual false-positive rates associated with FDG-PET
scanning, or if the discount rate on benefits is increased from 1.5% to 6% p.a.
These results compare favourably with cost effectiveness analyses of other cancer
technologies previously recommended by other agencies (for example docetaxel as
second-line therapy for NSCLC, £14000 per life year gained (NICE, 2001a) and
paclitaxel in addition to cisplatinum for ovarian cancer, £6500 to £10000 per life year
gained (NICE, 2001b)).
The use of FDG-PET scanning in this indication is therefore cost effective.
Furthermore, when the model is used to evaluate benefits in terms of avoiding
unnecessary radiotherapy the results show that if CT were used, 36% of patients
would receive unnecessary radiotherapy, compared with approximately 5% of patients
with a FDG-PET scan in strategy 4 or strategy 5. This demonstrates the immediate
advantage to the patient of FDG-PET.
Although the role of FDG-PET scanning in NHL has not been modelled here, the
accuracy demonstrated in section 6 is likely to translate into significant patient
7-24
benefits. Since the main area of uncertainty in NHL is whether a combination of CT
scanning and prognostic scores is sufficiently accurate in selecting patients for
consolidation, it will be appropriate to study the comparative accuracy of FDG-PET
scanning and conventional methods in a prospective study. Such a study should focus
initially on the ability of FDG-PET scanning to induce important changes in patient
management, but should also compare disease free survival in patients undergoing
FDG-PET scanning with those restaged ‘conventionally’, either in a randomised
fashion or by using historical control data.
7-25
Cost effectiveness acceptability curves (CEACs) for female, 20
years. Open circles - strategy 4 (PET after positive CT), solid
circles - strategy 5 (PET only), both relative to strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-3
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-26
Cost effectiveness acceptability curves (CEACs) for male, 20 years.
Open circles - strategy 4 (PET after positive CT), solid circles strategy 5 (PET only), both relative to strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-4
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-27
Cost effectiveness acceptability curves (CEACs) for female, 40
years. Open circles - strategy 4 (PET after positive CT), solid
circles - strategy 5 (PET only), both relative to strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-5
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-28
Cost effectiveness acceptability curves (CEACs) for male, 40 years.
Open circles - strategy 4 (PET after positive CT), solid circles strategy 5 (PET only), both relative to strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-6
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-29
Cost effectiveness acceptability curves (CEACs) for female, 60
years. Open circles - strategy 4 (PET after positive CT), solid
circles - strategy 5 (PET only), both relative to strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-7
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-30
Cost effectiveness acceptability curves (CEACs) for male, 60 years.
Open circles - strategy 4 (PET after positive CT), solid circles strategy 5 (PET only), both relative to strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-8
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-31
Cost effectiveness acceptability curves (CEACs) for female, 20
years. Strategy 5 only (PET only), relative to strategy 3 (CT only),
PET specificity distributed as Uniform on (0.6,0.9)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-9
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-32
Cost effectiveness acceptability curves (CEACs) for male, 20 years.
Strategy 5 only (PET only), relative to strategy 3 (CT only), PET
specificity distributed as Uniform on (0.6,0.9)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-10
0
5000
10000
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20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-33
Cost effectiveness acceptability curves (CEACs) based on QALYs
for female, 20 years. Open circles - strategy 4 (PET after positive
CT), solid circles - strategy 5 (PET only) both relative to strategy 3
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-11
0
5000
10000
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20000
25000
30000
Value per Quality Adjusted Life Year (k) in Pounds Sterling
7-34
Cost effectiveness acceptability curves for female, 20 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-12
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-35
Cost effectiveness acceptability curves for male, 20 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-13
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-36
Cost effectiveness acceptability curves for female, 40 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-14
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-37
Cost effectiveness acceptability curves for male, 40 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-15
0
5000
10000
15000
20000
25000
30000
Value per Life Year (k) in Pounds Sterling
7-38
Cost effectiveness acceptability curves for female, 60 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-16
0
5000
10000
15000
20000
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30000
Value per Life Year (k) in Pounds Sterling
7-39
Cost effectiveness acceptability Curves for male, 60 years, 6%
discount rate on benefits. Open circles - strategy 4 (PET after
positive CT), solid circles - strategy 5 (PET only), both relative to
strategy 3 (CT only)
0.6
0.4
0.2
0.0
Probability
0.8
1.0
Figure 7-17
0
5000
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Value per Life Year (k) in Pounds Sterling
7-40
8
PATIENT ISSUES
Summary

PET imaging is likely to be just one part of the diagnostic work-up, so it is important
to co-ordinate hospital appointments for various tests to reduce the need for patient
travel and to avoid delays in treatment.

Health professionals should inform patients about the process for PET imaging,
associated risks and counselling, and check that patients understand the information
received. Carers also require this information.

Leaflets with diagrams and clear explanation of complicated terms (such as
radioisotope) should be given in addition to basic information about preparation for
the scan, and what can be expected during and after the scan. The potential benefits
and risks associated with PET scanning should be explained in clear, simple language.

The imaging environment should be comfortable and designed to alleviate patient
anxieties. For example, music listening facilities should be included and adult friends
should be permitted to sit with patients in the scanning room.

Following consultation, there was evidence that patients value the additional
information provided by PET scanning.

The results of a PET scan may also provide reassurance which is valued highly by
some patients.

As the only PET facility in Scotland is used for research purposes, it has not been
possible to obtain substantive information about patients’ views and preferences
relating to PET scanning. However, professionals believe that as PET scanners are
open and less noisy than some other imaging devices they may be preferred by
patients.

Following the introduction of PET imaging into the clinical situation in Scotland,
further research will be required to understand the needs and preferences of patients
and carers.
8-1
8.1
Background
The consideration of patient issues is key to any HTA and accords with Scottish aims
to create a patient-centred NHS. This section relies heavily on submitted evidence and
on information from patients and professionals.
As the only PET facility in Scotland is used for research purposes and so few patients
have experienced PET scanning, it is not possible to obtain the views of patients
undergoing a PET scan in a normal clinical situation in Scotland. The experience of
patients undergoing other cancer diagnostic procedures, such as CT or MRI, is more
readily available and will be of use when planning the establishment of a PET facility.
Professionals believe that patients prefer PET to many other diagnostic procedures as
the imager is open and generates very little noise. Patients’ views of any new service
should be elicited early in its use, to ensure that any anxieties are discussed and
lessons are learned.
8.2
The scanning process for the patient
At Mount Vernon Hospital in London, patients are contacted prior to their visit to
check attendance and the process is clearly explained to them. This helps to overcome
anxieties and reduces the number of non-attenders. This would be good practice to
follow in Scotland, but staff resources may make this difficult to achieve.
It is recommended in section 9 that PET facilities in Scotland are linked with a cancer
centre. In Scotland, there are four cancer centres: Glasgow; Edinburgh; Dundee; and
Aberdeen.
The organisation of the cancer diagnostic tests will depend on the local situation. For
example, for patients travelling to Aberdeen from the Islands it would be optimal to
schedule PET, CT, MRI and ultrasound scans on the same day. However, in Ayr, CT
and other diagnostic procedures may be done locally on one day, with a trip to the
PET scanner on another day. If PET and CT scanning need to be done in the PET
centre, this may lead to delays as the time to receipt of scan is often quicker in a local
centre.
The funding of patient travel to the cancer clinics (where any PET facility would be
situated) varies throughout Scotland. For those from the Islands who require to go to
Aberdeen, travel, generally by air, is funded by NHS Boards. In some areas,
voluntary organisations such as Cancer Care provide a valuable free transport service.
In other areas, patients will be expected to organise and fund their own travel.
MacLeod et al. (2000a) found that among women diagnosed with breast cancer in
1992 and 1993, significantly more patients from deprived areas failed to attend
appointments, compared with those in affluent areas. Failure to attend appointments
may be related to ease of access to hospitals rather than lack of interest in follow up. It
should be recognised that it is not only those living in remote areas who experience
travel difficulties. Those living on the East side of Glasgow who must rely on public
transport will need to use at least two buses to get across the city to the Beatson
Oncology Centre. Consequently, it is imperative that diagnostic work-ups are
organised so that the patient has to make as few visits to the clinic as possible.
8-2
Avoidance of patient anxiety is also important from a technical perspective as the
uptake of glucose is higher in tense muscles and this will ‘distort’ the PET image. To
overcome this, St Thomas’ Hospital in London give their patients diazepam before the
scanning procedure. As a general rule, most patients with breast cancer, young people
with lymphoma and those with head and neck cancer will need diazepam. Any patient
who is administered diazepam will be unable to drive home following the procedure
and so this should be communicated clearly to the patient prior to attendance at the
clinic.
The scanning facilities should be designed to make the patient feel relaxed and
comfortable and reduce anxiety. For example, music listening facilities could be
provided. In St Thomas’ an adult friend is permitted to sit with the patient in the
scanning room to provide reassurance to anxious patients. This puts the patient more
at ease in a potentially stressful situation and so is recommended as standard practice.
Patients undergoing studies should fast for at least four hours before the examination.
The patient should partially empty his or her bladder before the scan, to reduce the
size of the bladder artefact, although this will increase the uptake of the radioisotope
by the bladder. Patients should not have undergone biopsy in the previous 72 hours,
since inflammation round the biopsy site can cause abnormal FDG uptake (Cronin et
al., 1997).
8.3
Communication with patients
8.3.1
Professional interactions
There is a need to show sensitivity to the needs of the patient and their family.
Patients are often acutely aware of time pressures on busy clinicians and so do not ask
questions. Consequently contact with other patients, health professionals and
voluntary organisations is recommended and so it will be important for NHS Boards
to provide voluntary organisations with details of a new facility, such as a PET
imaging centre.
The following sections are taken from the SIGN guideline on lung cancer (SIGN,
1998a) and can be applied to all cancers and major diseases:
Communication between health professionals and patient is a central clinical function. The
establishment of relationships which can support patients and carers through their illness begin with
unconditional listening and effective information provision.
Lack of information can increase anxiety, uncertainty, distress and dissatisfaction (Audit Commission,
1993), and there is evidence to suggest that the level of psychological distress in patients with serious
illness is less when they perceive themselves to have received adequate information about diagnosis
and treatment options (Fallowfield et al., 1986; Fallowfield et al., 1990).
With few exceptions, patients should be informed of the diagnosis of lung cancer and the options for
treatment discussed with them (Sell et al., 1993). This information should be shared with appropriate
close relatives if the patient consents. The environment of the diagnostic consultation and the way in
which the diagnosis and treatment plan is conveyed to the patient should be conducive to establishing
trust and confidence. The presence of a family member or friend is usually helpful.
It is very important that other professionals involved, especially GP, should be informed as soon as
possible exactly what information has been given.
8-3
A survey of 65,337 NHS patients with cancer - including 5,604 people with NHL and
4,011 with lung cancer - commissioned by the Department of Health (2002),
identified the need for health professionals to ensure patients not only receive
sufficient information about their condition, treatment, tests and possible outcomes,
but also understand this information. The survey found that approximately one in five
people (18%) with lung cancer or NHL would have preferred to be given more
information about the outcome of their first treatment. Additionally, 13% of
respondents believed that on one or more occasion doctors or nurses withheld
information from them. This percentage increased to 16% among people with NHL.
People with NHL were also less likely to understand their diagnosis or the purpose of
tests they were given. For example, 84% of people with lung cancer stated that they
completely understood their diagnosis, while only 70% of people with NHL made this
statement.
8.3.2
Patient information
Scanning often triggers anxiety in cancer patients and with PET there may be fears
related to the injection of a radiopharmaceutical. Patients may have important
questions (such as ‘am I radioactive to the rest of my family’) that they are too
embarrassed or scared to discuss with anyone. There may also be a concern about
repeat injections and a fear of radioactive accumulation.
The amount of information given to patients about imaging procedures in cancer
appears to be highly variable and dependent upon the individual professional.
Leaflets with diagrams and clear explanations of complicated terms (such as
radioisotope) should be given in addition to basic information about what can be
expected during and after the scan. The potential benefits, risks and the procedures
associated with PET scanning should be explained in clear, simple language.
When evaluating papers for clinical effectiveness, a number of practical issues
relating to patient eligibility were identified, which should be communicated clearly
to patients and their carers. Published studies indicate that the following are not
eligible for FDG-PET scans:
 patients with high fasting levels of glucose (e.g. above 5.8 mmol/l, Vansteenkiste
et al., 1998b);
 patients unable to lie down for one hour (e.g. patients with congestive
cardiomyopathy); and
 patients who have not fasted for between four and six hours before the scan.
Some of the studies (e.g. Vansteenkiste et al., 1998b) exclude any patients with
diabetes mellitus, whereas other studies (e.g. Poncelet et al., 2001) exclude only
patients with uncontrolled diabetes mellitus.
A document with frequently asked questions displayed in simple terms might be
helpful. Such information should be made available to the patient sufficiently in
advance of the procedure so that they have time to assimilate it, ask questions and
discuss areas of concern.
Some examples of patient information leaflets about PET scanning are presented in
Appendix 21. These leaflets have been reproduced by kind permission of the centres
outlined on the first page of the Appendix 21.
8-4
Some US sites also provide patient information in other media, such as on video (see
the Louisiana PET centre: www.louisianapet.com/).
8.4
Consultation questions and responses
As PET imaging is currently confined to use within one research facility in Scotland,
few health service users in Scotland are able to advise on its use based on their
experiences. For this reason, information was sought about the broader issues
surrounding diagnosis, treatment, and quality of life following treatment. Patient
representative and voluntary organisations were sent copies of the consultation
questions with an easy-to-read summary of the Consultation Assessment Report.
Additionally, the Lymphoma Association promoted the consultation in its newsletter.
During consultation the following questions were asked:
1. Few people in Scotland have had a PET scan, but from your experience of
attending tests (perhaps CT scans or MRI scans) what issues do you think should
be considered regarding using PET scanners in Scotland. For example, what are
your ideas about timing of the scans, access and counselling and finding out the
results?
2. As with several procedures associated with cancer management, PET scanning
involves the use of radiation. Have you had any experience of these other
procedures and was the use of radiation explained adequately? What concerns do
you have about the use of radiation and how do you think these could be
addressed?
3. If PET scanners were to be used, what information would you like, when would
you like to receive it and how would you like to receive it?
4. From your experience of diagnostic tests for cancer, are there any other issues that
you think HTBS should be aware of?
Respondents to the consultation questions indicated that they valued the additional
information provided by the PET scan. One respondent had had a PET scan at the
Aberdeen facility after his oncologist gained funding for the scan from a charity. He
especially valued the technology because it resulted in the prevention of unnecessary
biopsy and provided reassurance during a treatment which otherwise offered him ‘no
guarantees’ or clear answers:
‘This was the only time that I felt I had been given a clear answer, which was in great
contrast to the ambiguous results from CT scans which often added to the frustration
and strain of dealing with cancer’.
The respondent indicated that the PET scan took away doubt and allowed him to get
on with his life without unnecessary worry. The response from this patient is
reproduced in full in Appendix 22.
Health service users did not raise concerns about radiation, but two health
professionals responded on these issues. One was concerned that the radiation dose
should not be played down and the other stressed the need to consider the risks and
benefits in each case.
A need for information, both oral and written, to explain what the PET scanner does,
why it is used, and what people may experience during the scan was identified.
8-5
Additionally, there is a need for results to be communicated as soon as possible and
each person should be asked about their information needs.
Respondents also identified the need for people to be treated as individuals and the
importance of ensuring that scanning does not result in delays to treatment that may
be intolerable to health service users.
8.5
Focus group
A focus group was conducted with people who had been treated for lymphomas,
including those who had experience of PET imaging. The primary objective of the
focus group was to gain an understanding of the patient’s perspective, and the views
of their families and carers, on the issues surrounding treatment and investigation.
Participants were asked about their experience and the questions from consultation
(section 8.4) were also used to facilitate discussion. The second objective of the focus
group was to explore the issues surrounding the role of PET imaging in helping to
reassure a patient and issues about quality of life raised in section 7.2.11.2 (i.e.
whether quality of life is reduced due to discomfort, anxiety or toxicity associated
with undergoing tests or treatments).
Three focus groups were planned, however, recruitment of participants was difficult.
Potential participants were invited to take part in ‘discussion’ groups by advertisement
and by advertising in the Lymphoma Association newsletter. One focus group
comprised four people (three males and one female) with experience of treatment for
NHL and one carer (female) and the members met in Glasgow for a discussion
session. Three of the participants had been diagnosed with NHL in the past year and
one had been diagnosed with NHL eight years ago. The youngest participant was 17
years old.
During the focus group, participants used a wall chart to create a timeline which
summarised their experiences since diagnosis. Participants requested a separate wall
chart to summarise some key points from their experiences before diagnosis, for
example their interactions with health services which led to a diagnosis being made.
Participants were given three different coloured pieces of paper to record their
experiences. One colour represented ‘good’ experiences, another colour represented
‘bad’ experiences, and a third colour was called ‘gap’ which was intended to prompt
participants to share their reflections about what might have been missing from their
journey of care.
8.5.1
Results
The focus group provided a few examples of people’s experiences of treatment and
their needs and preferences. These examples indicated that participants:




valued the timeous treatment they currently received;
valued survival above risks and access to treatments;
thought consultants played a vital role in providing information;
felt that good quality information about current services, counselling and risks
should be provided without people having to ask for it, and checked with patients
to ensure it has been understood;
8-6


felt information about risks was sought on the grounds of ‘right to know’ rather
than because it would change their decisions about treatment; and
thought that reassurance is an ongoing need, but sources of reassurance differ.
Participants shared a belief that once a person was diagnosed with lymphoma, their
treatment was prioritised and met their needs for speed, however prior to diagnosis,
the investigations may have been too slow and they perceived that the system was
‘bottlenecked’ at the initial diagnosis stage. As a result of the difficulties in
diagnosing NHL, some participants said diagnosis could be a ‘relief’. Once
diagnosed, one participant considered the journey is better described as a ‘roller
coaster ride’ than a pathway.
Treatment for lymphomas had had differing impacts on the participants’ lives. One
participant had been able to continue a relatively ‘normal’ life, as close access to the
hospital allowed her still to attend school regularly. For another, treatment had
required large amounts of travel which resulted in his wife giving up work for six
months to take him to appointments.
The participants were generally in agreement that the consultant plays the key role in
providing them with information about their condition. Attempts to gain further
information – for example from the internet, medical journals and friends – were
described as unhelpful. One participant described most written information as ‘too
scientific’. Participants questioned the quality of information they found on the
internet and one participant suggested there was a need for good information to carry
some sort of certification so that patients could identify it.
Participants had found that information, received from sources other than health
professionals, could cause further worry. Some asked that health professionals give
information to patients without them having to request it. Information should be
provided about the services that exist, side effects and counselling.
Two issues were raised about information on the side effects of radiation. Three
participants indicated that they had been given insufficient information on side effects
of treatments, especially in relation to scans and radiation. Participants said that this
information would not have changed their decisions to attend, but they believed they
should have been given the information. The second issue raised was their
understanding of the information they had been given.
‘I don’t think I was told an awful lot about the risks. I have a good relationship with
my doctor but unless you ask you don’t get told. I didn’t know anything about the
radiation thing’.
Health service user A
‘If somebody said ‘tomorrow you’re going to have a CT, MRI and PET scan’, I’d say
‘I’m going and I’m not worried too much about the consequences because survival is
the name of the game’’.
8-7
Health service user B
The second issue raised was their understanding of the information they had been
given. One participant had been given information about radioactivity following a
PET scan, but was unsure if he had interpreted it correctly or had been overly
alarmed.
‘I was wandering about Aberdeen for several hours trying to keep back from people
you know. I was like radioactive man kind of thing. I honestly don’t know if….really
there was a danger. I did worry if I was being alarmed unnecessarily’.
Health service user E
Participants’ views about the use of scans to provide reassurance differed. One
participant had found the results of a PET scan ‘reassuring’ because they had
identified a residual mass as scar tissue.
‘That’s where the PET scan made the difference, because I knew for definite that that
part of tissues was no longer active and that made a huge difference…if offered the
certainty of knowledge that I was in the clear as much as I could be. CTs don’t reduce
the uncertainty and that’s the worse thing’.
Health service user E
Another person – who had not had experience of a PET scan – said that ‘nothing will
supersede the feeling inside’. He indicated that an examination of every cell in his
body would be less reassuring than ‘feeling well’.
‘No matter how far we go down the road of technological advancement, nothing is
going to supersede the feeling you’ve got inside. Even if they want to look at every cell
I’ve got in my body, that is still not sufficient assurance. It’s the feeling of being well,
thinking well’.
Health service user B
Participants indicated that they had an ongoing need for reassurance because once
diagnosed with non-Hodgkin’s disease they were never completely free from worry or
concern. They indicated that every ailment, whether connected to their diagnosis or
not, increased their anxiety.
‘You’re very positive and you say ‘I’m going to beat this thing’, but you don’t get a
sore throat anymore. You know, a sore back is not a sore back, it’s a possible lump’.
Health service user D
‘People have given me statistics but they don’t actually mean anything…I mean
what’s the chances of a 17-year- old getting cancer in the first place’.
8-8
Health service user A
The participant who had been diagnosed with lymphoma for more than eight years
said that the intensity of his anxiety decreased after the first year because if it had
continued to remain as high he would have suffered from mental health problems. He
described his diagnosis as an ‘old friend’.
The results of this focus group indicate that PET should be organised to allow timely
availability for patients and for consultants to have a role in providing clear
information about its benefits and risks. The results of a PET scan may also provide
reassurance which is valued highly by some patients.
8.6
Conclusions
There is no experience of the use of PET in routine clinical practice in Scotland,
however anecdotal reports of experience in England indicate that patients prefer PET
to CT because the imager is open and generates very little noise.
In Scotland, travel to specialist health care facilities from urban, rural and island areas
can act as a barrier to attendance, both in terms of convenience and because of the
financial implications. Therefore diagnostic tests should be scheduled to coincide
wherever possible.
All PET imaging facilities should be specially designed to make the patient feel
comfortable and reduce anxiety by, for example, providing music listening facilities
and allowing an adult friend to attend with the patient.
Diagnostic work-ups for cancer can involve several tests, spaced over many weeks
and lack of information during this process can lead to increased anxiety and distress
for the patient. Patients should be informed of the imaging process to be undertaken
and given clear literature explaining the process. Several good examples of patient
information leaflets available in the US are available and may provide useful models
for use in the UK.
Patient information leaflets may be valued as supplements to communication between
health professionals, particularly doctors, and patients if they contain information
about the process, its purpose, any associated risks, and possible outcomes. However,
it is essential that health professionals check with patients to ensure they understand
all written and verbal information given and discuss any anxieties.
8-9
9
ORGANISATIONAL ISSUES
Summary

PET facilities and cyclotrons should be organised to provide appropriate provision
and equitable access for all patients with cancer who may benefit from imaging.
PET facilities should be linked to cancer centres and PET imaging should be
coordinated with other diagnostic tests to minimise delays in treatment.

Four possible options for the implementation of a PET facility in Scotland have been
considered and the cost per scan and budget impact of each have been investigated.
These options include three fixed facilities and various configurations of mobile
units.

Mobile PET results in higher long-term costs and a higher overall cost per scan.
However, capital costs are substantially lower and the facility could be operational
in a few months.

The lowest cost per scan and lowest running costs are associated with a fully
equipped PET unit integrated with other relevant hospital departments and drawing
on staff skills from these departments (£677/scan). This option requires a capital
outlay of £4.25 million and incurs annual running costs of £1.02 million.

The layout of the facility and production and transportation of radiopharmaceuticals
must comply with legal requirements.

Appropriate training and accreditation must be created for radiopharmacists,
radiochemists and cyclotron engineers. This would be best achieved on a national
(UK) basis. All staff in the cancer team should understand the value and
uncertainties associated with PET in decision- making for cancer management.
9-1
9.1
Organisation of PET facilities in the UK
This organisational issues section has been written with major input from the experts
on the TSG, who have provided much of the specialist text herein.
9.1.1
Current facilities
The only PET facility currently available in Scotland is based within Aberdeen Royal
Infirmary and is currently used for research purposes only and not for routine clinical
use. An application is underway for a PET facility in Glasgow.
In England, there are five PET facilities, which are used for routine clinical use. These
are all in London; in Harley Street and at St Thomas’/Guy’s, Middlesex, Mount
Vernon and Hammersmith Hospitals. These facilities are also used for research
purposes; this amounts to 25% of use at St Thomas’ and Middlesex and 10% at Mount
Vernon. Other PET research facilities are also available in England at the MRC/IRSL
unit at Hammersmith, the Functional Imaging Laboratory at Queen’s Square, the
Wolfson Brain Imaging Centre at Cambridge and the MANPET facility in
Manchester. A Wolfson Molecular Imaging Centre, which will be a national oncology
research centre, is also about to be built in Manchester.
9.1.2
Planning of new facilities
Scotland currently has cancer centres in Glasgow, Edinburgh, Dundee and Aberdeen.
If implementation of a PET scanning service is undertaken, PET facilities should be
organised across Scotland (and the UK) according to the size of the patient
population, accessibility and availability of clinical expertise to ensure patients across
Scotland have access to a PET scanner. In addition, for research purposes the scanner
would need to be sited near to a suitably staffed research facility. Therefore it is
important to consider the location of current scanners and cyclotrons.
A PET facility may be integrated into an imaging department (as in the Glasgow
proposal) or standalone (as proposed by some Public Private Partnership (PPP)
initiatives). If the facility is combined with an imaging department, it may be possible
to achieve economies of scale, particularly through sharing of staff, information, etc.
In the US, mobile PET facilities are in operation. When considering service
configuration in Scotland, such a facility may provide a useful resource to manage the
difficulties caused by access in remote areas, or it could serve more than one cancer
centre (e.g. Aberdeen and Dundee). However, it is likely that a patient would have to
travel to the nearest cancer centre for other diagnostic tests and treatment, so the value
of this is not entirely clear. As mobile PET facilities can be established more quickly
than building a totally new fixed site, they might also be considered as an interim
solution for provision of the technology in a cancer site pending establishment of the
fixed facility.
Any PET scanning provision would have to guarantee a reasonable service to patients
from across Scotland without disadvantaging those from the more rural and remote
areas such as the Southwest or the Highlands and Islands. Furthermore it would be
important to ensure that the inclusion of PET scanning in the diagnostic work-up did
not create new delays to the initiation of treatment. Current standards state that at least
9-2
90% of patients considered for curative therapy (surgery, radical RT and combined
modality treatment) should receive a CT scan within two weeks, but in a recent
review this criterion was met by two of the 28 hospitals in Scotland (Clinical
Standards Board for Scotland, 2002).
There are no data available on the effect of PET on the time to diagnosis and
treatment, but the risk that the provision of PET scanning might further slow down the
progress from initial diagnosis to definitive treatment, by introducing a further rate
limiting step in the patient’s journey, should be recognised. Any such delay is likely
to impinge more on patients having to travel significant distances for the investigation
and might further exaggerate the inequality of health care provision for more remote
and rural populations.
These issues would be tackled in Scotland by regional planning groups, in particular
the Regional Cancer Advisory Groups (section 2.2.2) and local NHS Boards.
9.2
The PET centre
A PET Centre has three main components:
 the facility for production of the positron emitting radionuclide;
 an area for rapid labelling of the chosen pharmaceutical by the radionuclide; and
 the imaging area.
Radionuclides are produced by a cyclotron in which a non-radioactive target material
is bombarded with high-energy charged particles to transform it to a radioactive form
(Figure 9-1) (Sorenson & Phelps, 1987).
Figure 9-1
A medical cyclotron
Medical cyclotrons are designed specifically for the efficient production of the four
main PET radionuclides; 18Fluorine, 11Carbon, 13Nitrogen and 15Oxygen. Most of
these machines are negative ion, with dual irradiation, numerous target ports and
beam energies of 10-20 MeV. While many of them are self-shielded for radiation, UK
radiation regulations normally require the machine to be located in a shielded vault.
9-3
While the reliability of such devices is high, servicing and the employment of an
engineer should be considered.
Given the short lifetime of the radionuclide, it is desirable to locate the radiochemistry
laboratory adjacent to the cyclotron vault. To achieve the necessary levels of activity
on the final labelled radiopharmaceutical, the labelling process starts with high levels
of radioactivity. Thus the labelling has to be carried out in a shielded chamber using
an automated synthesis unit as shown in Figure 9-2. For the commonly produced
radiopharmaceuticals, automated synthesis units that are designed to be user-friendly,
reliable, easy to maintain, high yielding and with a rapid synthesis time are
commercially available.
Figure 9-2
Automated radiochemistry synthesis unit
Such laboratories are supplemented with a quality assurance (QA) facility. Obviously
there is not sufficient time for conventional pharmaceutical QA to be performed on
the final product. Therefore stringent production protocols are required. Such units
require staffing by a trained radiochemist/radiopharmacist. Further details of
requirements for radiopharmaceutical production are presented in section 9.4.1.
The design of the imaging room is similar to that for a conventional gamma camera
room. It should be located close to the radiochemistry facility if short-lived
radionuclides are to be used.
Given the complexity of the radiopharmaceutical production process, many centres
choose to purchase the product from a central production facility. This limits the
radiopharmaceuticals to those labelled with long-lived radionuclides, which at present
is 18Fluorine.
9-4
9.3
Site planning (layout, regulations)
Planning of a PET facility requires careful consideration of the legal and technical
requirements for managing the radiochemical production and associated information
technology (IT) requirements, alongside the need for patients to feel comfortable with
the administration of the radiopharmaceutical and the scan itself.
The diagram in Figure 9-3 shows the site plan for the John Mallard Scottish PET
Centre in Aberdeen. This is reproduced by kind permission of WS Atkins.
Figure 9-3
Site plan of the John Mallard Scottish Pet Centre, Aberdeen
9-5
Prior to setting up a PET unit, a range of licences must be obtained. In order to hold
and dispose of radioactive materials, applications must be made to the Scottish
Environmental Protection Agency (SEPA). The RSA1 and RSA3 forms must be
accompanied by an environmental impact assessment. Following granting of the
authorisations, a 28-day period of notice must be observed prior to the
commencement of operations. The authorisations must be displayed prominently in
the unit.
The clinician in medical charge of the unit must hold a licence from the
Administration of Radioactive Substances Advisory Committee (ARSAC). He/she
will be either a nuclear medicine consultant or a consultant in radiology with an
interest in radionuclide imaging. Specialist training is required before a certificate
will be issued in respect of PET studies. Countersignatures from the scientists
responsible for radiopharmaceutical supply and scientific support and from the
Radiation Protection Adviser (RPA) are required. Note that these authorisations are
specific to the site, other staff and facilities; particular investigations and permissible
administered activities are also stated.
A RPA must be appointed for the unit and must be consulted in the preparation of the
above applications. Locally, a member of staff must be appointed as Radiation
Protection Supervisor (RPS) and there must be a designated medical physics expert,
with at least six years experience in nuclear medicine.
Under the new Ionising Radiation (Medical Exposure) Regulations (IRMER)
legislation, those who will be permitted to refer patients for investigation must be
specified and notified that they have been so recognised; referral criteria must be
made available. Staff who will operate the scanner must be trained and designated in
writing. A system must be in place to vet study requests.
There must be a set of standard operating procedures (SOP) available which specify
the details of each study type, including patient identification procedures, data
acquisition, data analysis, reporting and emergency procedures.
9.4
Radiopharmaceutical supply
9.4.1
Radiopharmaceutical licensing and production
If the unit is producing radiopharmaceuticals, the requirements will vary according to
whether only research studies are proposed or routine service investigations are
undertaken. In the latter case, it will depend on whether materials are to be supplied to
another NHS health care facility. For research studies only, there are no restrictions at
present, although this will alter in 2004. For routine investigation, a unit may prepare
radiopharmaceuticals under the direction of a pharmacist (the so-called Section 10
exemption) or may apply to the Medicines Control Agency (MCA) for a
Manufacturing (Specials) Licence. If materials are to be supplied to another NHS
health care facility, the latter route is the only option.
9-6
The Notice to Applicants (http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm)
outlines pharmaceutical regulatory reporting requirements to manufacturers and
Volume 2b, Part II, presents the chemical, pharmaceutical and biological
documentation required for radiopharmaceuticals (http://pharmacos.eudra.org
/F2/eudralex/vol-2/B/pdfs-en/Part2_2en.pdf).
The regulations state that if there is a licensed source for a pharmaceutical, then other
production sites must get a licence also, or purchase from the licensed source.
Research facilities, such as those in Aberdeen, do not need a licence for production of
radiopharmaceuticals for their own purposes, but if they were to supply other centres,
then a licence would be required. This may allow income generation, but this has not
been evaluated in this HTA.
In the Aberdeen PET centre every radiopharmaceutical is tested for purity
immediately after radiochemical synthesis. All radiopharmaceutical preparations and
purity tests comply with the requirements of the latest (3rd) Edition of the European
Pharmacopoeia (Council of Europe, 1996) and exposure to ionising radiation is kept
to a minimum (Appendix 23).
9.4.2
Radiopharmaceutical transportation
As the half-life of FDG is 110 minutes, it is possible to transport it between PET
scanning facilities, so that not all sites need a cyclotron (and associated radiation
infrastructure and special staffing).
Most say that the maximum travel time for FDG is two hours from the manufacturing
facility. However, one expert believes that it can be up to four hours. The means of
transport is anything that is legally acceptable for the carrying of radioactive
substances.
Substantial experience of the production and transportation of radiopharmaceuticals
has been gained over the past 30 years at the Radionuclide Dispensary (RND) sited at
the Western Infirmary, Glasgow. It produces approximately 45,000 patient doses per
year distributed throughout the West of Scotland. In addition, it acts as a central
supplier to many laboratories (both NHS and university) utilising radiochemicals. The
only possible mode of transport is by road. Small sprinter trains that serve much of
Scotland do not have guards vans and are thus not suitable. Likewise the planes that
serve local flights in Scotland are too small to handle the radioactive materials.
For transportation of radioactive materials, the RND uses five vans. There are four
drivers who have to undertake a statutory training course and are subject to continuing
training updates. The vehicles are fitted with the necessary signage and are modified
internally to provide secure transport. These vehicles provide supplies to nuclear
medicine departments in five NHS Board areas. Most areas only receive one delivery
a day, which is despatched around 08:00am, to optimise use in the target department.
Only Greater Glasgow receives two deliveries, the second being at 11:15am.
However, emergency materials can be transported as required at other times of day;
more easily in the afternoon when the critical morning runs have finished.
9-7
9.4.3
Clinical administration of radiopharmaceuticals
Notes for Guidance on the Clinical Administration of Radiopharmaceuticals and Use
of Sealed Radioactive Sources (National Radiological Protection Board, 1998b)
provides guidance, based on national and international recommendations, to medical
practitioners. The guidance is not mandatory and does not have the force of statutory
regulations. However, it does provide a summary of the relevant legislation and is a
guide to good clinical practice for nuclear medicine in the UK.
9.5
Staffing
The organisational structure of the PET facility at St Thomas’ is presented in Figure
9-4.
PET scanning is a sophisticated enterprise, requiring highly trained personnel. This
includes radiation chemists, nuclear medicine technicians, physicists and nuclear
medicine physicians. Physicians will need to be trained to interpret the scans and it is
important that this training be of sufficient length and quality. Furthermore, all
members of the multidisciplinary team involved in the treatment of a cancer patient
should be educated about the benefits and risks associated with using PET.
Consequently, personnel training should be a top priority.
9-8
Figure 9-4
St Thomas’ PET facility
Organisational Structure
PET Management Committee
PET Centre Director
Senior Scientist
Clinical Manager
Senior Clinician
Radiochemistry
Physics & Computing
Technical
Administration
Clinical
Radiochemist x2
Laboratory Assistant
Research Associate x2
System Administrator
Radiographers x4
Secretary
Senior Registrar x0.5
Registrar x0.5
Cyclotron Techs x2
9-9
It must also be recognised, that at the outset it is likely that the clinical team will want
to see PET scans in addition to the standard diagnostic work-up, but as experience is
gained it is likely that there will be greater confidence in the use of PET scans. This is
demonstrated in the survey of lung cancer diagnostic pathways. Scottish experts
indicated the need for CT but St Thomas’ staff were happy to use PET instead of CT.
Those working in the PET facility need special training and must be accredited on an
ongoing basis. As there is currently a shortage of staff in many of the key disciplines,
it may be necessary to train existing staff. For nuclear physicians, this can be
achieved as an addition to current skills and ARSAC indicates that a period of training
and experience will be necessary before competency is achieved.
9.5.1
Cyclotron support
One of the key considerations relating to the establishment of a radiopharmaceutical
production facility is the staffing requirement for radiopharmacists, radiochemists,
physicists and electronic engineers. Aberdeen currently has a core staff of one
cyclotron engineer, two chemists, a chemistry technician, one scanner operator, one
physicist and four postdoctoral researchers who cover some of the roles (such as
scanner operator).
In practice, recruitment of radiochemists can be difficult and an alternative may be to
employ organic chemists and train them to work with radiation. The radiation levels
involved are quite low and the ability to synthesise novel compounds is more
important than experience of working with high levels of radiation.
The radiochemist in a PET facility performs the following functions:
Routine work:
 provision of a reliable supply of short-lived radiolabelled compounds (e.g. FDG);
 quality control;
 dispensing;
 environmental monitoring; and
 documentation, radiation monitoring, maintenance, etc.
Research:
 development of new synthetic strategies for the production of well-known or
novel radiopharmaceuticals;
 development and construction of remotely controlled chemistry modules for the
production of radiopharmaceuticals; and
 development of novel or well-known analytical methods for the routine synthesis
of radiopharmaceuticals, etc.
9-10
The radiopharmacist in a PET facility undertakes the following functions:
 preparation and dispensing of radiopharmaceuticals used for patient diagnosis and
therapy;
 verification that specified radioactive substances and reagents will give desired
results in examination or treatment procedures, utilising knowledge of
radiopharmaceutical preparation and principles of drug biodistribution; and
 conducting research to develop or improve radiopharmaceuticals, etc.
The balance between routine work and research depends on a number of factors:
 the staffing levels and time available for research, given that routine work should
take priority;
 the number of patients to be scanned on a daily basis; and
 the number of different scans being performed (and therefore the number of
different radiopharmaceuticals being produced).
The routine work required in a PET chemistry laboratory may be undertaken by a
radiochemist or radiopharmacist. However, if research is undertaken, both of these
professions are required.
There is a shortage of these trained professionals and so training of new staff will be
an essential component of the rollout of PET facilities in the UK. One course, hosted
by the University of Leeds, provides an introduction to radiopharmacy. It consists of
30 hours of residential teaching and 120 hours of private study time, covering a series
of lectures, seminars and orientation practicals relating to basic nuclear sciences,
radiation safety and legalisation.
9-11
9.6
Cost per scan and budget impact
Four options for providing a FDG-PET service were considered. These were:
1. A fully equipped FDG-PET unit (imager, cyclotron, radiochemistry facility)
located within a hospital. This unit would benefit from support services purchased
from the Trust such as maintenance, pharmacy and radiation protection advice.
2. A fully equipped FDG-PET unit (imager, cyclotron, radiochemistry facility)
integrated with other relevant hospital departments such as nuclear medicine and
radiology. This unit will draw on staff skill from other departments.
3. A FDG-PET unit receiving its radiopharmaceuticals from another source and
integrated with other relevant hospital departments. This unit will draw on staff
skills from other departments.
4. A mobile FDG-PET imager unit receiving its radiopharmaceuticals from another
source. Various staffing options are considered here.
Options 1, 2 and 3 are a ‘fixed’ facility. Costs per scan are calculated for these options
in section 9.6.1. Option 4 is a mobile facility. Cost per scan values are calculated for a
mobile facility used in a variety of ways across Scotland in section 9.6.2.
9.6.1
Costings for options 1, 2 & 3 (fixed facilities)
The PET centre at Guy’s and St Thomas’ is a fully equipped unit, with a cyclotron
and radiochemistry laboratory located within an NHS hospital. Costs have been
obtained from them based on their current resource use (M Dakin, PET Manager,
Guy’s and St Thomas’ Clinical PET Centre, Personal communication, 2002). The
only staff shared with the rest of the hospital are the nuclear medicine clinicians as
their posts are funded jointly by the hospital and the PET centre.
This is considered as a case example similar to HTBS option 1, but with recognition
that the St Thomas’ PET imager is several years old and patient throughput can now
be increased.
The tables presented in Appendix 24 set out full details of the costs of staffing and
running the three fixed PET facility scenarios in Scotland.
Option 1 would be a brand new fully equipped Scottish PET facility drawing on
support services purchased by the Trust.
Option 2 assumes that a PET facility will be located in a hospital environment where
it will be possible to gain from synergies with other departments such as nuclear
medicine and radiology for example sharing staff for illness and holiday cover.
Option 3 also assumes that the PET facility is in an integrated hospital environment
but that the facility will acquire its radiopharmaceuticals from an external source. It is
possible to have a PET scanning unit located in a hospital with an existing cyclotron
and radiochemistry facility in this option.
Scottish resource use estimated for options 1, 2 and 3 were derived from experts in
Scotland (Prof AT Elliot, Prof PF Sharp, Dr A Welch, Members of the TSG, Personal
communication, 2002). They are principally modelled on the resource use structure at
the Guy’s and St Thomas’ Clinical PET Centre.
9-12
Options 1, 2, 3 and Guy’s and the case example of St Thomas’ Clinical PET Centre
are based on the assumptions presented in Table 9-1.
Table 9-1
Cost per scan: assumptions
Location
Costs based on
prices at
Patient
throughput per
annum
Average number
of patients per
day
Number of
working days
per year
Scanner age
and specification
Staffing costs
VAT
Depreciation of
capital equipment
Cost of adapting
buildings for
scanner or
radiochemistry
lab
Provision for
specialist training
Number of FDG
deliveries per day
Option 1
(FDG on-site,
separate unit)
Scotland
2002/03
(2000/01 prices
indexed at 5%)
Option 2
(FDG on-site,
shared staff)
Scotland
2002/03
(2000/01 prices
indexed at 5%)
Option 3
(FDG delivered,
shared staff)
Scotland
2002/03
(2000/01 prices
indexed at 5%)
Case example
Guy’s and St
Thomas’
London
1500
1500
1300
1200
6.25
6.25
5.4
5
240
240
240
240
New
3-ring scanner
NHS Scotland pay
scales April 2002
Midpoint of
grading band
Inc. NI,
on-costs and
superannuation
Included where
applicable
New
3-ring scanner
NHS Scotland pay
scales April 2002
Midpoint of
grading band
Inc. NI, on-costs
and
superannuation
Included where
applicable
New
3-ring scanner
NHS Scotland pay
scales April 2002
Midpoint of
grading band
Inc. NI, on-costs
and
superannuation
Included where
applicable
10 years
2-ring scanner
NHS pay scales
April 2000
Inc. London
weighting and
on- costs
Included
Included
Included
Included
Included
Included
Included
Not included
Included
Included
Included
Not included
N/A
N/A
2
N/A
2000/01
Included where
applicable
9.6.1.1 Staffing levels
Staffing levels have been listed separately for the PET scanning unit and for the
cyclotron and radiochemistry unit.
The staffing levels have been based on the current staff use at St Thomas’. A lower
staffing level has been agreed for options 2 and 3 compared with option 1. This
reflects the differences in operational structure between options 1, 2 and 3. For
example, in options 2 and 3 holiday cover would be provided by staff from other
departments, whereas the staffing levels for option 1 have been calculated on the basis
that holiday cover will be provided in-house.
9-13
9.6.1.2 Patient throughput
On a newer three-ring scanner, time taken for a clinical scan is estimated to be one
hour per patient (J Lowe, PET Superintendent, Paul Strickland Scanner Centre,
Middlesex, Personal communication, 2002). In an optimal situation in options 1 and
2, using the staffing levels stated in Appendix 24, a maximum of seven patients could
be scanned in a normal working day, a maximum annual throughput of 1700 patients,
based on 240 working days in a year. However, a patient throughput of 1500 per
annum has been assumed for options 1 and 2. This reflects the possibility that the unit
will not be operating at optimal capacity at all times and also allows for set-up time
prior to start of scanning each day.
Where the radiopharmaceuticals are being purchased from an external source, this
will probably mean a delayed start to the working day thereby limiting the number of
patient slots. Taking this into consideration lower annual patient throughput of 1300
(average of 5.5 per day) has been assumed for option 3.
There is the possibility of increasing patient throughput in option 3 if the risk of late
delivery of the radiopharmaceuticals can be eliminated. This is addressed in the
sensitivity analysis of the cost per scan model.
Both the patient throughput and staffing levels have been crosschecked for
consistency by another UK PET facility (J Lowe, PET Superintendent, Paul
Strickland Scanner Centre, Middlesex, Personal communication, 2002).
9.6.1.3 Operating costs
Other areas of operating costs to highlight are:
i)
Maintenance contracts
The estimate for scanner maintenance is for full comprehensive cover,
which includes software maintenance. However, existing UK PET
centres have judged that the scanner software maintenance and
development aspect of the maintenance service provided by
manufacturers is not optimal or costeffective. Therefore it is assumed
that for options 1, 2 and 3 that this aspect of maintenance will be done
in-house and will be covered by the software developer/system
administrator. This person will also be responsible, together with
support from the clinical scientist, for other systems maintenance tasks.
Cyclotron maintenance is estimated at £33,075 for option 2 compared
with £55,125 for option 1. A full maintenance contract will be about
£115,000 so both options assume a degree of in-house maintenance,
the difference being that option 2 assumes a lower level, ‘parts only’
maintenance contract compared with a more fuller level of
maintenance contract in option 1.
9-14
ii)
Power/buildings maintenance
Power and buildings maintenance has been allocated on a 40:60 basis
to the PET scanning unit and cyclotron facility. A combined total of
£14,884 has been assumed for option 2 and £16,538 for option 1. This
reflects the difference in operating structures between the options.
9.6.1.4 Supply of FDG
The viability of option 3 depends on the availability of FDG, either from another NHS
facility or from a commercial entity.
Cost estimates (at current prices) for two scenarios were sought:
i)
Supply of FDG from a NHS facility
Price per dose of 350 MBq is approximately £353 including VAT
(commercially confidential communication). The maximum distance
coverable for transporting batches of FDG was indicated at 70 miles at
a cost of approximately £100 per delivery.
If a PET scanning unit is located within a hospital with a cyclotron and
radiochemistry facility then there will be no additional transport costs.
ii)
Supply from a commercial entity
Price per dose of 350 MBq is approximately £376 including VAT
(commercially confidential communication). A range of coverable
distances were indicated for transporting batches of FDG (50 miles at a
total cost of £80 per delivery, 100 miles at a total cost of £141 per
delivery, 150 miles at a total cost of £188 per delivery and 200 miles at
a total cost of £258 per delivery). The maximum distance coverable
was indicated to be 200 miles subject to terrain.
The costs of FDG stated here are based on information supplied by facilities located
in the South-East of England. Another confidential quote received during the final
stages of the assessment supports these figures.
The range of distance coverable for the transportation of FDG is consistent with
expert opinion of two to four hours travelling time.
The differences in cost and the differences in distances coverable between an NHS
facility and a commercial facility reflect the fact that NHS facilities operate on a costrecovery basis whereas commercial facilities will operate on a profit basis.
Costs for option 3 presented here are for FDG purchased from a NHS source, with
and without transportation. (No transportation would model the case in which a
cyclotron is available on an NHS facility but not actually part of the NHS PET
centre). The purchase of FDG from a commercial source with 100 miles
transportation is also costed. A full list of option 3 costs are detailed in Appendix 24.
9-15
9.6.1.5 Training
The provision for training at St Thomas’ is estimated at £4,000, with most training
being undertaken by Continual Professional Development. This amount is intended to
cover basic and general training for all staff, as there are currently no formal training
courses for PET. This figure is quite low and as the use of PET develops in the UK it
is hoped that more formal training will be available. Funding one person through an
MSc programme, if available, would typically cost around £15,000. It is important to
note that the cost of training will vary from site to site depending on the number and
existing skill of the personnel recruited. Communication with the Paul Strickland
Scanner Centre indicates that a possible estimate for training would be around
£20,000.
After discussions with experts in Scotland (Prof AT Elliot, Prof PF Sharp, Dr A
Welch, Members of the TSG, Personal communication, 2002) a training figure of
£8,000 has been deemed appropriate for the purposes of this assessment.
9.6.1.6 Laboratory equipment
Laboratory equipment for the PET scanning unit includes a protected bench, trolley,
equipment for transporting, storing and administering FDG and office furniture.
Laboratory equipment for the radiochemistry and cyclotron facility includes hot cells
and chemistry modules for both FDG and 11Carbon and radiation safety monitoring
equipment. Equipment required for the radiopharmaceutical QA function has also
been included.
9.6.1.7 Cost of a PET scanner
The manufacturers list price for a three-ring scanner has been used in the cost per scan
model. It may be possible to negotiate a lower price with the manufacturer should a
PET facility be set up in Scotland.
9.6.1.8 Building costs
Building costs are included in this model and are based on the actual costs paid to
build the PET facility at Aberdeen Royal Infirmary. Building works at Aberdeen
commenced in 1997 and cost £738,628 (excluding VAT). The radiochemistry and
cyclotron unit are more expensive to build due to the nature of their function. From
the information supplied by Aberdeen it has been possible to estimate the individual
costs of building the radiochemistry and cyclotron unit and for the PET scanning unit.
Specific costs relating to the radiochemistry and cyclotron unit were identified where
possible (roof for the plant room, special ground works, special electrical and
mechanical services). These were deducted from the total cost and the remainder was
apportioned between the two units on the basis of the floor area they occupied (see
Figure 9-2). The radiochemistry and cyclotron unit are estimated to occupy 60% of
the floor area and the PET scanning unit 40%.
Costs are indexed at 5% per annum and VAT has been included where applicable.
Building costs are classed as capital costs.
9-16
The same values for building costs of the PET unit and cyclotron facility have been
used for options 1 to 3.
9.6.1.9 Location of Scottish facility
The costs presented for a PET facility in Scotland are not for a specific location. The
location will have no impact on the costs for option 2. However, an impact can be
expected for option 3. This is addressed by presenting costs for various distances that
the radioisotope can be transported.
9.6.1.10 Costs not included
A number of costs have not been included in the model. These include costs for local
authority rates, site and equipment insurance, telephone bills, stationery and security
costs. Costs to the Trusts of providing staff cover for holidays/illness as in option 2
and 3 have not been included.
9.6.1.11 Summary of annual running costs
Summary costs for 1, 2 and 3 and St Thomas’s are shown in Table 9-2.
9-17
Table 9-2
Summary annual running costs
Staffing – PET scanning
unit (inc. training)
Staffing – cyclotron and
radiochemistry unit
(inc. training)
Total staffing cost
Scanning unit operating
costs - Fixed
Cyclotron unit operating
costs – Fixed
Scanning unit operating
costs - Variable
Cyclotron unit operating
costs – Variable
Purchase of FDG
(NHS no transport)
Purchase of FDG (NHS
70 miles inc. transport)
Purchase of FDG
(Commercial 100 miles
inc. transport)
Total annual running
costs
Total annual running
costs; purchase of FDG
from NHS source
(no transport)
Total annual running
costs; purchase of FDG
(NHS 70 miles)
Total annual running
costs; purchase of FDG
(Commercial 100 miles)
Case example St Thomas’
Option 1
Option 2
Option 3
£324,980
£220,691
£220,691
£309,957
£144,635
£115,123
£0
£140,700
£469,615
£335,814
£220,691
£450,657
£311,354
£310,693
£310,693
£268,884
£301,312
£278,269
£0
£244,489
£23,625
£23,625
£20,475
£18,000
£67,380
£67,380
£0
£64,000
N/A
N/A
£458,900
N/A
N/A
N/A
£506,900
N/A
N/A
N/A
£556,480
N/A
£1,173,286
£1,015,781
£1,046,030
£1,010,759
£1,058,759
£1,108,339
9-18
9.6.1.12 Cost per scan
The following cost per scan can be estimated for each of the options. Listed here are
costs based on purchasing the FDG from a NHS facility with no transportation costs
and allowing for 70 miles transportation, and purchasing FDG tracer from a
commercial supplier allowing for 50 to 200 miles transportation.
Option 2 has the lowest cost per scan at £677. In option 3, purchasing FDG from a
NHS source offers the best value for money at £777 per scan without transport and
£814 with transport. As the distance that the FDG has to be transported increases so
does the cost per scan (£833 to £896).
The German PET study by Klose et al. (2000) states that a PET scan, including
production of FDG on-site, costs 960.5 euros (1998 prices). Using an exchange rate of
1 euro equals 63.3 pence and indexing at 5% per annum, the cost per PET scan at
2002/03 prices is £739. This is close to the midpoint cost per scan of options 1 and 2.
Note that the cost per scan depends on the annual level of patient throughput. In the
first year of a PET facility being operational it is unlikely that the levels of patient
throughput stated in this model’s assumptions could be achieved. This can be due to
training staff and raising awareness of the service.
Table 9-3
Cost per scan
Cost per scan
Option 1
Cost
£782
FDG bought from NHS
source (no transport)
FDG bought from
NHS source
(70 miles transport)
FDG bought from
commercial source
(50 miles transport)
FDG bought from
commercial source
(100 miles transport)
FDG bought from
commercial source
(150 miles transport)
FDG bought from
commercial source
(200 miles transport)
Option 2
1500 patients/yr
Option 3
1300 patients/yr
£677
Case example St Thomas’s
1200 patients/yr
£872
at 2000/01 prices
£961
at 2002/03 prices
£777
£814
£833
£853
£870
£896
9-19
9.6.1.13 Sensitivity analysis
As the Scottish estimates for staffing levels, patient throughput and price of FDG
were lower than some other estimates, sensitivity analyses were performed to assess
the impact of increasing the cost of these components and increasing throughput.
Details of these analyses are presented in Appendix 25.
If staffing levels had to increase to the same levels as in option 1 then this will have
the biggest impact on the cost per scan prices, increasing by around £80 for option 3.
Increasing patient throughput to 1500 in option 3 lowers the cost per scan price by
around £105. Decreasing patient throughput by 100 increases the cost per scan by
around £65. Increasing staffing levels and increasing patient throughput in option 3
increases the cost per scan price by around £40.
9.6.2
Cost per scan option 4 (Mobile facility)
Indicative costs for four options were sought (‘contractor’ means the company
supplying the mobile PET unit):
A. Mobile PET scanner situated at a single site throughout the year.
Unit staffed by NHSScotland.
B. Mobile PET scanner situated at a single site throughout the year.
Unit staffed by three fully trained staff supplied by contractor.
C. Mobile PET scanner situated at five different sites throughout the year
with 30 moves per year.
Unit staffed by NHSScotland.
D. Mobile PET scanner situated at five different sites throughout the year
with 30 moves per year.
Unit staffed by three fully trained staff supplied by contractor.
In options A and B, the scanner is situated at a single site. This would give the
hospital the flexibility to use the equipment without having to spend a large capital
amount building a purpose built PET unit. There is no doubt that accommodating a
mobile unit will incur building costs however these are unlikely to be of the same
magnitude as setting up a fixed site PET unit. The time taken for a mobile unit
provided by a contactor to be operational will be significantly less than building a unit
in a hospital.
Assumptions used for the mobile PET model are presented in Table 9-4.
9-20
Table 9-4
Mobile PET model: assumptions
Patient throughput
per year
Number of
working days per
year
Maximum number
of patients per day
Maximum
operating hours
per day
Set-up time
for unit
Fully trained staff
provided by:
Training and
equipment
maintenance
provided by:
FDG provided by:
Power supply
provided by:
Site licences
provided by:
VAT
Cost of adapting
buildings/site
Number of
batches of FDG
deliveries per day
Option A
Option B
Option C
Option D
1300
1300
1300
1300
240
(NHS standard)
250
(set by contractor)
250
(set by contractor)
240
(NHS standard)
5.4
5.2
5.2
5.4
Included in
operating hours
6
(this is set by the
contractor)
Included in
operating hours
Included in
operating hours
6
(this is set by the
contractor)
Included in
operating hours
NHS
Contractor
NHS
Contractor
Contractor
Contractor
Contractor
Contractor
NHS
NHS
NHS
NHS
NHS
NHS
NHS
NHS
NHS
NHS
NHS
NHS
Included where
applicable
Included where
applicable
Included where
applicable
Included where
applicable
Not included
Not included
Not included
Not included
2
2
2
2
7
7
It is assumed that set-up time for the unit is included in the number of operating hours
per day.
Appendix 26 presents in full the costs involved in the four different options of
providing a mobile PET service. These costs are based on the contractor providing the
scanner unit only; the hospital will be required to provide all the laboratory equipment
associated with a fully functioning scanner.
Note that no provisions have been made for the costs of acquiring site licences that
will be necessary to handle radioactive material or for adapting buildings/site for the
mobile service.
The contractor will provide training in all options. A small provision of £1,000 has
been made to cover uniforms and ad-hoc basic training.
Other costs used for fixed and variable operating costs are the same as for option 2 in
a fixed PET facility.
Summary costs for a mobile PET service are listed in Table 9-5. Costs for purchasing
FDG from a NHS source, with and without transport and from a commercial source
9-21
(100 miles transport) are provided. A complete list of options of purchasing FDG is
included in Appendix 26.
Option B and D result in the same annual cost. This is because the contractor has
quoted the same service charge for the two options despite the facts that option B is
for a PET unit to remain stationary at one site throughout the year and option D is for
a PET unit to make 30 moves between five sites per year.
It is important to note that the contractor charges make up the bulk of a mobile
option’s operating costs so any variation of these can have a significant impact on the
cost per scan value.
Figures for a cost per scan for each of the four mobile PET options are listed in Table
9-6.
Table 9-5
Mobile PET model: summary costs
Staff
Operating costs –
Fixed per annum
Operating costs –
Variable per annum
Purchase of FDG
(NHS no transport)
Purchase of FDG
(NHS 70 miles)
Purchase of FDG
(commercial 100 miles)
Total
(FDG NHS no transport)
Total
(FDG NHS 70 miles)
Total
(FDG commercial 100 miles)
Table 9-6
Option A
£213,691
Option B
£124,594
Option C
£213,691
Option D
£124,594
£656,814
£809,564
£703,814
£809,564
£20,475
£20,475
£20,475
£20,475
£458,900
£458,900
£458,900
£458,900
£506,900
£506,900
£506,900
£506,900
£556,480
£556,480
£556,480
£556,480
£1,349,880
£1,413,533
£1,396,880
£1,413,533
£1,397,880
£1,461,533
£1,444,880
£1,461,533
£1,447,460
£1,511,113
£1,494,460
£1,511,113
Mobile PET model: cost per scan
Where FDG is purchased
from NHS source
(70 miles)
Where FDG is purchased
from commercial source
(100 miles)
Option A
Option B
Option C
Option D
£1,075
£1,124
£1,111
£1,124
£1,113
£1,162
£1,150
£1,162
9-22
9.7
Budget impact
9.7.1
Annual running cost
The annual running costs for options 2 to 4 are presented in Table 9-7 and in more
detail in Appendices 24 and 26. A range is presented for options 3 and 4 covering
FDG transportation of 70 to 200 miles.
Note that the income generation element of a NHS facility supplying FDG to another
NHS facility has not been taken into account in the annual cash flow projections or
the budget impact to NHSScotland.
Table 9-7
Annual running costs (£ million)
Option 1
1.173
9.7.2
Option 2
1.016
Option 3
1.011-1.165
Option 4 (mobile)
1.398-1.567
Capital costs
Capital costs for options 1, 2, 3 and mobile PET are detailed in Table 9-8.
Different financing options can be explored such as leasing and hire purchase of the
PET scanner and/or cyclotron. However, this is beyond the remit of this study.
Table 9-8
Capital costs (£ million)
PET scanner
Lab equipment for
scanner room
Computer equipment
for scanning unit
Cyclotron
Lab equipment for
radiochemistry unit
Computer equipment
for radiochemistry lab
Buildings –
PET scanning unit
Buildings – cyclotron
and radiochemistry lab
Total
Option 1
1.410
Option 2
1.410
Option 3
1.410
Mobile
0
0.1016
0.1016
0.1016
0.1016
0.040
0.040
0.040
0.040
1.175
1.175
0
0
0.543
0.543
0
0
0.0187
0.0187
0
0
0.2831
0.2831
0.02831
0
0.6789
0.6789
0
0
4.250
4.250
1.834
0.1413
9-23
9.7.3
Annual cash flow projections
Annual cash flow projections over a 20-year period at 2002/03 prices are listed in
Appendices 24 and 26 for the following:





Option 1
Option 2
Option 3 where FDG is purchased from a NHS source (70 miles)
Option 3 where FDG is purchased from a commercial source (100 miles)
Option 4 mobile PET options A to C
It is assumed that capital equipment is replaced at the end of its life. Staff costs are
indexed at 2% per annum using year one as the base. No other costs are indexed.
For options 1, 2 and 3, accumulative cash flow spending at one, five, 10, 15 and 20
years is listed in Table 9-9.
Table 9-9
Year
1
5
10
15
20
Accumulative cash flow spending: options 1, 2 and 3 (£ million)
Option 1
4.97
7.95
11.97
18.32
22.92
Option 2
4.81
7.14
10.26
15.65
19.19
Option 3 FDG purchased
from a NHS
source (70 miles)
2.67
6.04
10.41
16.44
21.07
Option 3 FDG purchased
from a commercial
source (100 miles)
2.72
6.29
10.91
17.17
22.06
For option 4 mobile PET, accumulative cash flow spending at one, five, 10, 15 and 20
years is listed in Table 9-10.
Table 9-10
Year
1
5
10
15
20
Accumulative cash flow spending: option 4 (£ million)
Option A
FDG FDG NHS source
commercial
(70 miles)
source
(100 miles)
1.52
1.57
7.07
7.32
14.16
14.65
21.47
22.22
28.83
29.82
Option B
FDG FDG NHS source
commercial
(70 miles)
source
(100 miles)
1.58
1.63
7.37
7.62
14.71
15.21
22.22
22.97
29.72
30.71
Option C
FDG FDG NHS source
commercial
(70 miles)
source
(100 miles)
1.57
1.62
7.31
7.55
14.63
15.12
22.18
22.92
29.77
30.76
9-24
9.8
Budget impact discussion
Option 2 (fully equipped PET facility integrated with cancer centre using their staff)
has the lowest annual running cost at £1.016 million even though this option has the
highest patient throughput of 1500. Option 1 (fully equipped PET facility but with
separate staff) costs £1.173 million to operate every year. Running costs for option 3
(fixed PET facility, remote FDG) vary from £1.011 million to £1.165 million. Mobile
PET (option 4) has the highest running costs at £1.398 million to £1.567 million.
A fully equipped PET scanning facility with its own radiochemistry and cyclotron
will cost in the region of £4.2 million in capital outlay. A PET unit without the
cyclotron would cost £1.8 million. A mobile facility will require around £141,000 in
capital outlay.
Although the initial capital outlay is much higher for options 1 and 2, a full PET
facility as in option 2 demands less cash outlay in the longer run (see annualised cash
flow projections). At the end of year 20, option 2 would have cost £19.19 million and
option 3 (FDG from NHS) £21.07 million or (FDG from commercial) £22.07 million.
At the end of 20 years the cash outlay for mobile PET ranges from £28.83 million to
£30.76 million.
Running costs do not vary significantly when using a mix of the options in setting up
and providing a PET scanning network across Scotland. However, there is a
significant impact on capital outlay. Capital outlay required for option 2 is over twice
as much than that required for option 3. In the future, private companies may manage
PET facilities and have capacities to sell scans to the NHS or supply FDG. As no such
facilities are currently established in the UK it has not been possible to cost this
option.
9-25
9.9
Organisational issues conclusions
PET facilities and cyclotrons should be organised to provide appropriate provision
and equitable access for all patients with cancers who may benefit from scanning. The
layout of the facility and production and transportation of radiopharmaceuticals must
comply with legal requirements.
Appropriate training and accreditation must be created for radiopharmacists,
radiochemists and cyclotron engineers. This would be best achieved on a national
(UK) basis.
Budget impact calculations demonstrate that it is cheaper to have a fixed PET facility
with cyclotron integrated into an established clinical centre, with sharing of cancer
centre staff (option 2). With an estimated throughput of 1500 patients per year, the
estimated cost/scan of such a facility is £677. However, the capital outlay needed to
set up this type of facility is substantial. Furthermore, building a new facility will
mean that there will be a significant time delay before the services come on stream.
If FDG is purchased remotely (option 3), the capital cost is lower, but the cost per
scan is estimated to be between approximately £800 and £900 with 1300 patient
throughput per annum, depending on transportation distance and supplier.
Mobile PET has higher long-term costs and a higher overall cost per scan of
approximately £1130 with 1300 patient throughput per annum. This needs to be offset
against the fact that a mobile facility can be operational within months and at a
fraction of the capital that either options 2 or 3 will require. However, it is important
to stress that costs for mobile PET are less robust, because there is currently no
mobile PET service provided in the UK that can be used as a basis for cost estimates.
It is important to acknowledge that the cost per scan estimated is dependent on the
number of patients that can be scanned per annum. However, during the first year of
operation, it is unlikely that the level of patient throughput assumed in the HTBS
model will be achieved in a new PET facility, as it will take some time to have a fully
trained team of staff and to raise awareness and promote the service. Furthermore, in
section 10.4 health services research is recommended to inform further economic
modelling to determine the value of PET in other cancers. The cost of this research
has not been considered in these budget impact calculations.
9-26
10
DISCUSSION
10.1
Scope of the HTA
This HTA evaluates the issues of clinical effectiveness, cost effectiveness, patients’
needs and preferences, and organisational issues that pertain to the introduction and
development of PET imaging facilities for the management of cancer in Scotland. As
outlined in section 1, this report has focused on full-ring PET scanners and on the use
of the radiopharmaceutical FDG. This is appropriate as gamma cameras and
combined PET/CT machines have a weaker evidence base than full-ring PET and
most oncology applications use FDG.
This HTA has taken data and evidence from a broad range of sources (including, but
not limited to, peer-reviewed literature, preprints and manufacturer submissions) and
critically appraised it to ensure that analyses of clinical and cost effectiveness are as
robust as possible.
10.1.1
Clinical effectiveness - NSCLC (section 4)
There is clear evidence from the systematic review and meta-analysis conducted by
HTBS that FDG-PET imaging is both more sensitive and more specific than CT
scanning in mediastinal staging for N2/N3 lymph nodes in patients with potentially
operable NSCLC. There is some evidence from less robust studies that FDG-PET
more accurately detects previously unsuspected metastatic disease. In terms of
changes in patient management, published studies indicate that after FDG-PET,
between approximately 10% and 40% of patients had management altered. However,
these results arise from case series that may specifically select patients and so may be
biased.
Three studies have reported the findings of surveys of the use of FDG-PET in NSCLC
in routine clinical settings. The most recent of these (Seltzer et al., 2002) illustrates
the problematic nature of these surveys and the danger of attempting to draw
conclusions from them. They sent survey questionnaires to 292 physicians, who
referred 744 consecutive lung cancer patients for FDG-PET. Only 48% of the
physicians responded to the questionnaire and this covered just 37% of the lung
cancer patients.
Two randomised controlled clinical trials (Boyer et al., 2001 and van Tinteren et al.,
2002) have been performed to assess the effect of FDG-PET scanning in NSCLC. In
both trials patients were randomised between conventional staging for mediastinal
involvement and conventional staging plus FDG-PET scanning. The primary outcome
in both cases was the number of ‘futile’ thoracotomies avoided. The trials produced
apparently conflicting results; van Tinteren et al. (2002) reported a 50% reduction in
the number of ‘futile’ operations, whereas Boyer et al. (2001) reported no difference
between the two groups. This discrepancy appears to be caused by a difference in
approach to patient management between the two groups of investigators.
Specifically, Boyer et al. (2001) report that, in their institution, patients with early N2
disease undergo surgery and that a similar number of operations would have been
avoided had the policy of avoiding surgery for N2 patients, as in the Dutch study,
been in place. Neither of these studies reported quality of life measurements.
10-1
10.1.2
Economic evaluation NSCLC (Section 5)
Cost-utility analysis was used to compare seven diagnostic strategies for patients who
have undergone chest X-ray and biopsy and are thought to have potentially operable
NSCLC. Strategies 1 and 2 consider sending all patients to surgery or all to oncology
and were included for model testing purposes. Strategy 3 reflects current standard
practice in Scotland (without FDG-PET). Strategies 4 to 7 included FDG-PET in the
diagnostic pathway in a variety of ways, before or after mediastinoscopy. In line with
other economic models of NSCLC and anticipated use of PET in Scotland, it is
assumed that all patients have undergone a CT scan prior to implementing any of the
strategies.
Of the plausible clinical strategies (strategies 3 to 7), 3 and 7 were shown to be cost
effective in the base case model for CT-negative patients, but strategy 7 was not cost
effective for CT-positive patients. In strategy 7 those who are FDG-PET negative are
sent to surgery, while FDG-PET positives are sent for a confirmatory
mediastinoscopy and then to surgery or non-surgical treatment and it is notable that
the greater value is achieved in this strategy for those patients who have better
prognosis, i.e. the CT-negatives.
It also appears that the closer FDG-PET accuracy in detecting M1 disease approaches
that in detecting N2/3 disease the greater will be the cost effectiveness of moving to
strategy 7, particularly among CT-positive patients.
Strategy 1, all for surgery, also appeared to be promising in the model, but this
strategy is associated with a large number of futile operations and so would not be
appropriate in clinical practice. However, this highlights a weakness in the model, that
it was not possible to quantify the utilities associated with avoidance of futile surgery.
Another strategy of sending all patients for FDG-PET, prior to CT, is not cost
effective compared with strategy 7. This is not surprising as it is not possible to
differentiate the CT-negative and CT-positive patients in advance in this strategy and
the value of PET in CT-positive patients is less clear.
In CT-negative patients, the base-case analysis suggests that moving from strategy 3
to strategy 7 is cost effective (ICER £10,475). However, in CT-positive patients, the
case for moving from strategy 3 to strategy 7 is weak (ICER £58,951) due to the poor
specificity of FDG-PET in these patients. Even for CT-negative patients, strategies 3
and 7 were not strongly differentiated by patient impact as measured by QALYs, and
different utility values could lead to different rankings between these two strategies.
Thus the value of using FDG-PET added to the current standard of diagnostic workup
in terms of QALYs is not clear.
Another way of evaluating the strategies is to consider the number of correct
operations undertaken and the number of futile operations avoided. Among CTnegative patients, strategy 7 avoids an additional 6% of patients undergoing futile
surgery compared with strategy 3. This is due to the superior specificity of FDG-PET
in CT-negative patients. Among CT-positive patients only an additional 1% of
patients avoid futile surgery with strategy 7 compared with strategy 3.
10-2
It cannot be unambiguously stated which of strategies 3 and 7 is the more cost
effective, nor is it possible to estimate the probability of the individual strategies
being cost effective. The principal conclusion is that FDG-PET is most likely to be
cost effective when followed by a confirmatory mediastinoscopy in patients who are
FDG-PET positive in mediastinal lymph nodes.
It is also more likely to be cost effective in CT-negative than in CT-positive patients.
However, the information gaps render a definitive conclusion on the cost
effectiveness of using FDG-PET in NSCLC inappropriate at this time. Health services
research in a clinical setting is required to address the data gaps in diagnostic
accuracy, particular for distant metastases, in treatment life expectancies, and in
determining patient utilities associated with avoiding futile surgery.
10.1.3
Clinical effectiveness – Lymphoma (Section 6)
Although the studies of accuracy in restaging lymphoma after induction therapy are
generally retrospective and include heterogeneous patient groups (the majority of
series include both HD and NHL patients), a consistent picture emerges of FDG-PET
being at least as sensitive, and substantially more specific, than CT for the detection
of viable residual disease.
10.1.4
Economic evaluation – Hodgkin’s disease (Section 7)
The cost-effectiveness modelling was restricted to restaging HD. The model examined
the value of using FDG-PET as an adjunct to, or a replacement for, CT scanning for
the assignment of patients to consolidation therapy or surveillance after induction
therapy.
The base-case analysis suggested that the use of FDG-PET after a positive CT scan
(strategy 4) and the use of FDG-PET to replace CT (strategy 5) were both cost
effective relative to the use of CT alone, provided the willingness to pay per life year
exceeded £1,000. Strategy 5, replacing CT by PET, was both clinically more effective
and less expensive than strategy 4.
Sensitivity analyses showed that both strategy 4 and strategy 5 remained cost effective
for at least 95% of simulations from the joint distribution of input values, provided
that the willingness to pay per life year exceeded £5,000. The probability of cost
effectiveness for strategy 5 at a specificity of 70% exceeded 95%, provided the
willingness to pay exceeded £5000.
Increasing the discount rate on benefits from 1.5% to 6% reduced the apparent
superiority of FDG-PET containing strategies relative to other approaches. However,
there was little impact on cost effectiveness for either strategy 4 or strategy 5, except
that the probability of cost effectiveness for strategy 4 in 20-year-old males reached
90% only if the value of a life year exceeded £15,000.
Overall, the model predicts that 36% of patients restaged using CT alone will receive
unnecessary consolidation RT. This would be reduced to approximately 5% with
either FDG-PET strategy.
10-3
The robustness of the modelling results to uncertainties and altered assumptions,
alongside the low cost per life year gained and benefits in terms of avoidance of
unnecessary RT, indicate that FDG-PET provides substantial value in the restaging of
HD.
Although the role of FDG-PET scanning in NHL has not been modelled in this HTA,
the accuracy demonstrated in section 6 is likely to translate into significant patient
benefits in this indication. Since the main area of uncertainty in NHL is whether a
combination of CT and prognostic scores is sufficiently accurate in selecting patients
for consolidation, it will be appropriate to study the comparative accuracy of FDGPET and conventional methods in a prospective study.
10.1.5
Clinical effectiveness – Other clinical applications (sections 2.3 and 2.4)
10.1.5.1 Cancer
In the USA, Medicare currently reimburses FDG-PET imaging for specific
management decisions in NSCLC, SPN, lymphoma, colorectal cancer, head and neck
cancers, melanoma, oesophageal cancer and breast cancer and is considering
extending its reimbursement to include some central nervous system tumours.
A number of countries have undertaken HTAs of FDG-PET in cancer. Most have
reached similar conclusions that FDG-PET is more accurate than conventional
technologies, but that the evidence for translating this into patient benefit, even just
change in patient management, is weak and often relies on case series of selected
patients. Consequently definitive conclusions cannot be drawn about the clinical and
cost effectiveness of PET in these various indications at this time and further
evaluation of the technology is necessary.
In Australia, MSAC (2000 and 2001) concluded that there was insufficient evidence
to recommend unrestricted funding, but that FDG-PET is safe, and potentially
clinically and cost effective in a number of cancers (NSCLC, melanoma, recurrent
colorectal cancer, recurrent ovarian cancer, cervical cancer, oesophageal cancer,
gastric cancer, lymphoma, head and neck cancer, sarcoma). They recommended that
interim funding be made available for use of FDG-PET in these cancers, according to
MSAC-approved prospectively designed studies, with all data sent to a central
coordinating body, to better determine the clinical and cost effectiveness of FDGPET.
The cancers highlighted by MSAC are wide ranging and some have a weaker
evidence base than others. Other HTAs would imply that the strongest evidence of
clinical effectiveness is available for NSCLC, SPN, recurrent head and neck cancer
and malignant melanoma (DACEHTA, 2001). DACEHTA concluded that the
evidence for the value of FDG-PET in recurrent colorectal cancer was sparse; it may
be ‘important’ but was probably influenced by poor prognosis in this cancer. For
breast cancer, it was noted that there were a number of sources of error in the
presented trials but that it looked ‘promising’. They note that clinical development is
also being pursued in lymphoma, oesophageal, brain and testicular cancer.
10-4
10.1.5.2 Cardiology, neurology and psychiatry
There is general agreement that, so far, the evidence of benefit in cardiology,
psychiatry and neurology is weaker. Furthermore, there are good alternative
techniques to aid clinical decision-making in cardiology. In dementia, the benefit
achieved would probably be small due to the modest benefit of currently available
treatments. Consequently more research is needed of the value of PET in these
conditions before it is brought into routine clinical use.
10.1.6
Safety (Section 4.6)
The literature shows no evidence of any important short-term adverse events related
to PET scanning. Therefore, it is reasonable to conclude that PET is essentially free
from short-term adverse effects.
There is a risk of second cancers posed by the radiation dose used in PET scanning,
but this is very small (a lifetime cancer risk of less than one in 3000 for a person of
normal life expectancy) and comparable with that associated with CT.
10.1.7
Patient issues (Section 8)
Patients need to be fully informed about the imaging process and any side effects.
Information given by consultants is valued but checks are needed to ensure that
information has been understood by the patient. Advice about current services,
counselling and any risks should be provided without people having to ask for it.
Information for carers is also needed.
There is evidence from lymphoma patients that some value the additional information
provided by an FDG-PET investigation and the reassurance that this provides.
Patients also value the timeous treatment they currently receive once the diagnosis has
been made. However, there is a perception that the system is ‘bottlenecked’ at the
initial diagnosis stage. Therefore it is important that the addition of a PET scan to the
diagnostic work-up does not lead to additional delays in the initiation of treatment.
PET imaging should be coordinated with other diagnostic procedures to minimise
travelling, disruption and anxiety. The facilities should be created to make the patient
feel comfortable and at ease with the process.
Following the introduction of clinical PET in Scotland, further research is required to
understand the needs and preferences of patients and carers.
10.1.8
Organisational issues and costings (Section 9)
PET facilities and cyclotrons should be organised to provide appropriate provision
and equitable access for all patients with cancers that may benefit from imaging. The
layout of the facility and production and transportation of radiopharmaceuticals must
comply with legal requirements. Specialist training and accreditation must be created
for radiopharmacists, radiochemists and cyclotron engineers and appropriate training
must be given to all those involved in the multidisciplinary cancer team.
10-5
Any PET facility would have to guarantee a reasonable service to patients from across
Scotland, without disadvantaging those in the more rural and remote areas, such as the
rural Southwest and the Highlands and Islands. The risk that the provision of PET
scanning might further slow down the progress from initial diagnosis to definitive
treatment, by introducing a further rate-limiting step in the patient’s journey, should
be recognised and addressed.
A PET facility incorporating a cyclotron to produce its own radiopharmaceuticals and
integrated with other nuclear medicine facilities has the lowest running costs and cost
per scan (£677). However, the capital outlay for such a facility is substantial
(approximately £4.25 million) and there would be a time delay to build the new
facility. Capital outlay may be reduced (£1.83 million) if the radiopharmaceuticals are
available from an alternative source and a cost per scan of £777 to £900 is estimated,
depending on distance from source and provider (NHS or commercial). Both these
facilities have a total annual running cost of just over £1 million.
It will take approximately two years to build a PET facility and a further year until it
is operating at full capacity. Interim solutions should therefore be considered,
particularly for the restaging of patients with HD. One possible interim option is the
use of the John Mallard Scottish PET Centre in Aberdeen, which is currently used as a
research facility but could potentially provide a service element for 2 or 2.5 days a
week, with an estimated throughput of 300 to 400 patients per annum. The use of
other UK facilities for HD staging could also be considered.
An alternative mode of delivery would be the use of a mobile facility. This would be
more expensive on a cost per scan basis (approximately £1,130) and for annual
running costs (approximately £1.5 million), but would be quicker to establish and
would involve very little capital outlay. However, there is little experience of such
mobile PET facilities in the UK and FDG would need to be sourced.
10-6
10.2
Assumptions, limitations and uncertainties
It may be argued that PET is being judged more stringently than previous diagnostic
tests. However, given the substantial capital and running costs associated with a PET
facility and the competing demands for limited health care resources, it is entirely
appropriate to subject it to evaluations that will determine its value in routine clinical
practice.
In summarising the Medicare reimbursement process for diagnostic tests, Newman
(2001) identified that reimbursement depends not only on the sensitivity and
specificity of the test, but also evidence of change in patient management or
outcomes. The value of a test must be considered in terms of its impact on clinical
treatment.
This highlights the difficulty in assessing a diagnostic procedure. With the exception
of two trials in lung cancer (van Tinteren et al., 2002 and Boyer et al., 2001), and a
small number of economic modelling studies, the research literature has focused on
the issue of superior diagnostic accuracy, with little attention paid to ‘higher level’
outcomes (Fryback & Thornbury, 1991) such as the outcome of the patient’s disease.
The evidence available of superior diagnostic performance, although important, does
not directly answer the key questions about final patient outcomes and quality of life.
The analyses attempted in this review are therefore necessarily based on modelling,
and on assumptions that are sometimes difficult to verify.
A common criticism of models is that the wide freedom of action given to the analyst
may cause bias (Buxton et al., 1997; Kassirer & Angell, 1994). Certainly, any largescale analysis of a problem risks bias, and in this respect an ambitious model is more
at risk than the dataset from a single randomised, controlled, trial. However, models
usually address larger problems than trials, considering how evidence can be
translated into clinical practice given a much longer time horizon than it would be
practicable to study in a trial.
10.2.1
Assumptions
Models require specification of the patient pathway and prediction of response along
that pathway until the death of the patient. Such modelling inevitably depends on a
number of assumptions. These have been obtained by discussion with experts and
literature-based estimates.
10.2.2
Limitations
This HTA has focused on the use of FDG-PET within oncology, and specifically in
the areas of preoperative mediastinal staging of NSCLC and restaging of HD. As
explained in section 1, this has been necessary to allow detailed economic modelling.
However, the conclusions stated here should be considered alongside the other HTA
work presented in section 2, which presents evidence on clinical effectiveness in other
areas of oncology, and for cardiology and neurology, and the need for structured
clinical research (see section 10.4).
10-7
As this HTA has focused on the ‘patient and societal’ outcomes of the technology
(Fryback & Thornbury, 1991) it has not looked at the more speculative ‘researchorientated’ uses of FDG-PET, such as monitoring response to therapy and following
the distribution of appropriately labelled cytostatic drugs (e.g. Strauss, 1997;
Jerusalem et al., 2000; Smith et al., 1998). Arguably, in doing so, it may understate
the future value of PET scanning to Scotland’s health.
Knowledge about the patient experience and patients’ needs and preferences in
relation to PET imaging is weak. Lack of published research in this area, the absence
of patient experience of PET in clinical practice in Scotland and difficulties in
recruiting participants for patient issues focus groups have resulted in a limited
understanding of these issues. This information needs to be gathered from a diverse
group of patients.
As the utility value of different health states for patients or members of the public is
not known, the economic model could not be informed by this information.
Additionally, it would seem reasonable that PET may provide knowledge that has a
role in reassuring patients and reducing anxiety and that, as individuals, patients will
value treatment differently. This has been considered in the assessment, but could not
be quantified. Furthermore, appropriately using this qualitative information in an
economic model poses a considerable challenge.
It has not been possible to determine whether undertaking a PET investigation would
increase the time to diagnosis and subsequent treatment. Clearly this should be
avoided and so careful consideration should be given to the scheduling of PET scans.
The existence of such delays should be monitored as part of continuing health services
research in the use of PET in NHSScotland, by comparing times to diagnosis and
treatment for cancers in which PET scanning is, and is not, offered as part of the
management pathway. Similar research should be directed at ensuring that
geographical and socioeconomic equity of access to PET facilities is maximised.
10.2.3
Uncertainties
In NSCLC, univariate and bivariate sensitivity analyses have been used to draw out
the uncertainties in the model. These have been sufficient to identify the instability in
the model and the need to determine key pieces of information more clearly,
particularly valuation of avoidance of futile surgery.
For HD, uncertainties have been formally modelled in a multivariate manner using
Bayesian techniques and these have shown that the model is robust to all areas of
uncertainty.
10-8
10.3
Future developments
The information on imaging time used in this report has been obtained from St
Thomas’ Hospital and is based on a PET scanner that is nine years old. There is
anecdotal information that recent advances in technology have resulted in reduced
scanning times and increased patient throughput, with a corresponding impact on the
cost per investigation. However, currently there are no published data to support this
(see also the discussion of PET/CT in section 2.5.5.2).
The current assessment is based on full-ring PET systems using BGO scintillation
crystals. New crystals are being developed that may improve the image quality of
PET scanners in the future. However, it is likely that these systems will be more
expensive.
10.4
Research
Close cooperation is required among all those involved in cancer care to determine
which clinical areas might benefit most from PET imaging investigations. This
applies both to future scientific studies, to the evaluation of published data and to the
planning of diagnostic and treatment guidelines.
It is recommended that all patients undergoing a FDG-PET scan should have
outcomes recorded, either through participation in national or international clinical
trials to confirm and extend the current applications of FDG-PET, or through health
services research constructed to allow costs and patient outcomes to be recorded to
inform economic modelling. It will be particularly valuable to identify cancers with a
good prognosis where the accuracy of alternative diagnostic or response monitoring
mechanisms is poor. Appendix 27 recommends data that should be collected for the
ongoing clinical and economic evaluation of FDG-PET imaging in NHSScotland.
Additionally, as indicated in section 8, information about the patients’ experiences,
preferences and needs in relation to PET imaging needs to be recorded.
The collection of all data must, of course, comply with all regulations on
confidentiality and security of patient information and patient consent as presented in
the report on Protecting Patient Confidentiality (CSAGS, 2002).
It is clear that for most, if not all cancers, such trials cannot be confined to Scotland,
but must take place collaboratively across the UK, or possibly across Europe.
However, it is vitally important that Scottish patients are encouraged to enter clinical
trials. A recent review shows that only 2.4% of patients of all newly diagnosed lung
cancer patients in Scotland (small cell and non-small cell), were recruited into clinical
trials in 1997-1998 (Scottish Executive Health Department, 2001c).
It is noted that the costings for the PET facility do not include research costs, so it will
be essential to obtain funding from elsewhere.
The National Cancer Research Institute (NCRI) is a UK body comprising the main
cancer research funders and is responsible for the strategic leadership of cancer
research in the UK. The National Cancer Research Network (NCRN) was established
in April 2001 by the Department of Health to improve the quality, speed and
integration of cancer clinical trials and thus to improve patient care. The NCRN is
10-9
expected to double recruitment into clinical trials in England within the next five
years. It will do this through the creation of cancer research networks, closely aligned
to NHS cancer service networks, and in close collaboration with NCRI on a range of
issues that impact on the quality and management of cancer research. The
establishment of a Scottish Cancer Clinical Trials Network is currently underway and
it is proposed that this organisation will work in partnership with NCRN (and
therefore within NCRI). It is envisaged that the Scottish network will map onto the
three existing regional networks, which are established in the north, south, east and
west of Scotland. These networks provide an ideal framework on which to build
research governance requirements, including peer review and protocol development.
In the UK, the NHS HTA programme is also considering proposals for primary HTA
research in PET imaging. HTBS recommends that this be focused on the cancers
determined by DACEHTA to have promising evidence of clinical effectiveness
(NSCLC, SPN, recurrent head and neck cancer and malignant melanoma) and on
lymphoma.
Three main areas of clinical and economic evaluation can be identified:
 translation of the superior accuracy of FDG-PET into clear patient benefits or
cost savings;
 translation of the ability of FDG-PET to image metabolism into clear patient
benefits or cost savings; and
 methods of using FDG-PET to facilitate other research in oncology.
These three areas are discussed in the following sections.
10.4.1
Exploiting the superior accuracy of FDG-PET scanning
Although there is considerable evidence that FDG-PET scanning is more accurate
than CT scanning in many forms of cancer, there are few published studies that
establish the impact of the superior diagnostic accuracy of FDG-PET on patient
outcomes, such as survival and quality of life in NSCLC. Trials of this kind will need
to be designed and justified by the detailed modelling of possible patient outcomes
and associated costs and benefits.
Studies using Markov models, as described for example, in Fenwick et al. (2000), can
be used to support the development of clinical studies. This type of approach, firmly
based on a combination of clinical knowledge and modelling, is likely to yield novel
approaches to the use of FDG-PET to improve patient survival and quality of life, and
will be vital if the promise of FDG-PET is to be realised.
Trials focusing on improving the delivery of effective treatment to patients rather than
diagnostic accuracy, are essential in proving and realising the value of PET scanning
to the NHS. In addition to trials focused on the ‘avoidance of futile therapy’ (e.g. van
Tinteren et al., 2002) FDG-PET may, more positively, help to improve survival by
improving the planning of radical RT.
10-10
10.4.2
Exploiting the imaging of function
In addition to better diagnostic accuracy, FDG-PET is able to give visual
representations of changes in the tumour that occur as a result of treatment.
Consequently, FDG-PET may be useful in identifying response early in a course of
treatment (Smith et al., 2000), for example in neoadjuvant therapy for breast cancer or
in treatment of high-grade NHL. This may enable an early change of treatment in nonresponders, but this clearly needs to be proven in a randomised trial.
10.4.3
Facilitating research
PET scanning may be of value in a number of ways in cancer research:
 in defining response to treatment in early phase studies (e.g. van Oosterom et al,
2001);
 ‘proof of principle’ studies to demonstrate that tumour response as determined by
pre- and post- treatment PET scans can serve as a surrogate outcome variable
(Prentice, 1989; Lin et al., 1997) for long-term survival in cancer trials;
 facilitating development through pharmacodynamic studies in clinical trials
(Aboagye et al., 2001); and
 improving selection of patients for clinical trials by better staging.
10.4.4
Approximate scan numbers in Scotland
Using a PET facility for a mix of routine clinical use for restaging HD and health
services research to inform economic models, the following calculations may provide
a rough guide to capacity requirements in Scotland. The recommendations for health
services research are based on DACEHTA’s clinical effectiveness conclusions
(10.1.5.1) (DACEHTA, 2001) and are estimates of the number of patients who might
be eligible for scanning if these recommendations were adopted in Scotland.
Estimates of incident cases are taken from the ISD website figures, which quotes for
1998 <http://www.show.scot.nhs.uk/isd/cancer/facts_figures/facts_figures.htm>.
When choosing cancers to be evaluated, it should be remembered that the maximum
capacity for a PET facility is estimated to be approximately six patients per day
(approximately 1500 patients per year). Combining the reasonably conservative
estimates presented here, approximately 1600 patients per annum would require
scans.
10.4.4.1 Routine clinical use
Restaging HD: 130 incident cases, 75% receive chemotherapy, 90% response implies
approximately 90 patients.
10.4.4.2 Health services research
Restaging NHL: 1020 incident cases, approximately 50% receive chemotherapy, 90%
response rate implies 450 patients.
10-11
Staging NSCLC: In 1997, 880 patients underwent surgery for NSCLC, so it may be
estimated that 1000 FDG-PET scans may be required for those potentially eligible for
surgery in 2003. If FDG-PET scanning is restricted to CT-negative patients only, this
figure would be reduced to approximately 640 patients.
SPN: No Scottish incidence data, but comparison with imaging figures from US
centers suggests that up to 200 patients may require scans (MSAC recommends that
PET scanning be restricted to patients with low pre test probability of malignancy or
who are unsuitable for fine-needle aspiration biopsy). However, only between 80 and
120 of these patients are likely to have potentially resectable CT-negative malignant
disease, therefore the additional number of scans required is unlikely to exceed 120
patients (and may well be fewer).
Recurrent head and neck cancer: Scottish incidence of this cancer is approximately
1100 cases per annum, and estimates of five-year recurrence rate are as high as 50%
(Sidransky et al., 1998). In practice the number of patients requiring FDG-PET will
be lower than the 550 this suggests because some patients will be too sick to benefit
from further treatment and some will clearly have distant metastases. Hence in the
summary calculation a figure of 150 patients is assumed for recurrent head and neck
cancer.
Malignant melanoma: The draft SIGN guideline on melanoma suggests that PET is
only likely to be of value in stage III or IV disease. There are roughly 600 incident
cases per year in Scotland. US data (Coleman, 2002) suggest that 12% of cases are
stage III/IV, data from New Zealand’s Ministry of Health (1999) suggest that ~ 20%
are stage III/IV. Consequently, the number of scans needed is unlikely to exceed 100.
10-12
10.5
Summary and conclusions
HTAs from around the world agree that there is insufficient evidence to fully
recommend FDG-PET imaging as a standard technique in cancer management at this
time. However, improvements in diagnostic accuracy compared with other imaging
modalities and weak evidence of change in patient management from case series,
indicate that FDG-PET is ‘potentially’ clinically and cost effective. Cancers for which
there is general agreement of potential value are NSCLC, SPN, recurrent head and
neck cancer and malignant melanoma.
There are only two good quality clinical studies that evaluate how FDG-PET has
improved patient outcomes. Both of these are in NSCLC, but they give somewhat
conflicting results as to the value of FDG-PET in avoiding futile surgery and are
dependent on the decisions taken by surgeons after FDG-PET, with benefit only
demonstrable if an operation on N2 patients is considered futile.
The economic modelling work undertaken in this HTA is particularly valuable for
assessing the role of PET in restaging HD where potential benefit (avoiding long-term
morbidity associated with unnecessary RT) is large, but also occurs a long time after
the scan. Collection of such outcome data is difficult in a clinical trial and this is a
good example of where a detailed model quantifying all associated uncertainties is
helpful. This model showed that either FDG-PET strategy was more cost effective
than the current practice, with use of FDG-PET instead of CT being most cost
effective. This shows the value of modelling work that can link changes in accuracy,
with patient management and long-term outcomes using evidence from a variety of
sources and sophisticated analyses of uncertainty to provide reassurance about the
robustness of the model.
The economic evaluation for staging NSCLC contains inherent uncertainties in the
input assumptions and indicates that FDG-PET is cost effective in CT-negative
patients; if those who are negative are sent for surgery and those who are positive are
sent for mediastinoscopy. Other possible uses for FDG-PET scanning, such as to
replace mediastinoscopy completely, do not appear cost-effective in this setting.
However, this model is less robust than that for HD and further work is needed to
ensure that the value of avoiding futile surgery is captured in the model.
The economic models both indicate that the value of FDG-PET would appear to be
greatest where the accuracy of other imaging or diagnostic techniques is poor and
where knowledge from FDG-PET imaging can lead to substantially better prognosis
for the patient. It is this finding that should drive future work with FDG-PET into its
potential clinical role.
Overall following the synthesis of evidence on clinical and cost effectiveness,
organisational issues and patient needs and preferences, HTBS believes that FDGPET can be a valuable tool in cancer management.
10-13
Claxton et al. (2002) suggest four possible recommendations from an HTA ‘implement, implement with further research, do not implement but conduct further
research, do not implement’. In the vocabulary of this article the recommendation
from HTBS for FDG-PET scanning is in the second category, i.e. that FDG-PET
imaging should be implemented in Scotland and that further research should be
undertaken to confirm and extend its usefulness.
FDG-PET is recommended for routine clinical use in restaging HD, in properly
organised health services research for other high-grade lymphomas, and in patients
with NSCLC who are CT-negative. Its use in SPN, recurrent head and neck cancer
and malignant melanoma looks promising from the viewpoint of diagnostic accuracy
and research into the specific value of FDG-PET in terms of patient outcomes and
economic value in these cancers should be determined as an early priority.
10-14
10.6
Recommendations to NHSScotland
As a result of this HTA, HTBS has made recommendations to NHSScotland about the
clinical and cost effectiveness of PET imaging for cancer management, these are
presented in full in the Health Technology Assessment Advice on positron emission
tomography (PET) imaging in cancer management (HTBS, 2002a). Listed below is
the summary of recommendations.

It is recommended that a PET imaging facility including a cyclotron, dedicated to
clinical use and specific health services research applications, should be set up in
Scotland to allow Scottish patients and researchers to realise the potential benefits
of FDG-PET imaging in cancer management as rapidly as possible. It should be
linked to an existing cancer centre, with functional links to the existing PET
facility in Aberdeen.

It will take approximately two years to build such a facility, so interim solutions
for the provision of PET imaging should be considered, particularly for the restaging of patients with Hodgkin’s disease. Possible options are the use of the
John Mallard Scottish PET Centre in Aberdeen, other UK facilities, or the use of a
mobile PET facility in a fixed location in Scotland.

All patients who require re-staging of Hodgkin’s disease should be sent for a
FDG-PET scan. Extension to the restaging of all patients with lymphoma should
be investigated by further research.

Appropriate research should be undertaken to inform economic modelling in order
to produce a robust assessment of the value of FDG-PET imaging in the staging of
patients with NSCLC who are CT-negative in the regional lymph nodes.

For other cancers, FDG-PET is likely to add most value where existing
diagnostic/monitoring techniques have poor accuracy and information from PET
imaging can substantially improve prognosis. This should be evaluated through
health services research, taking account of the clinical effectiveness results from
other international HTAs. Research priorities should be agreed with
multidisciplinary expert groups, Regional Cancer Advisory Groups, the Scottish
Cancer Group, the NHS HTA programme and other international research
organisations. All research should be coordinated with the Scottish Cancer
Clinical Trials Network.

All patients undergoing FDG-PET should have outcomes recorded, either through
participation in a national or international trial to confirm and extend the current
applications of FDG-PET imaging or through health services research designed to
allow costs and patient outcomes to be recorded for economic modelling.
10-15
11
ACKNOWLEDGEMENTS
HTBS is grateful to all members of the TSG who have contributed to the appraisal of
the evidence in relation to the Scottish situation and writing many of the technical
sections this report.
Thanks to all those who submitted evidence at the outset and those who have provided
access to information, particularly grey literature during the assessment. The special
advisers are also thanked for reading earlier drafts of the report at a time when
evidence was still emerging.
Scottish lung cancer experts are thanked for responding to various enquiries about
lung cancer diagnosis and treatment in Scotland.
We are indebted to Drs Mackie and O’Rourke for explaining the intricacies of treating
HD and for spending many hours checking what became a very complicated model.
11-1
12
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