A Systematic Review of Positron Emission Tomography (PET) and Positron Emission Tomography/ Computed Tomography (PET/CT) for the Diagnosis of Breast Cancer Recurrence

AppendixHealth Technology 2 Assessment 2010; Vol. 14: No.501 Health Technology Assessment 2010; Vol. 14: No. 50 Characteristics of FDG-PET technology Abstract Appendix 3 ContentsFigures for indirect comparisons of patient-based data

AppendixList of abbreviations 4 Comparative lesion-based data Executive summary AppendixBackground 5 ObjectivesStudy data and figures for independent estimates of PET and PET/CT Methods AppendixResults 6 A systematic review of positron ConclusionsChanges in patient management Recommendations for future research emission tomography (PET) and AppendixImplications 7 for policy Sensitivity analysis positron emission tomography/ Chapter 1 AppendixIntroduction 8 computed tomography (PET/CT) BreastSubgroup cancer analysis Follow-up and treatment in the setting of recurrence for the diagnosis of breast cancer AppendixExisting 9 diagnostic strategies recurrence PETFalse-positives and PET/CT and false-negatives Current guidelines Appendix 10 ChapterProtocol 2 M Pennant, Y Takwoingi, L Pennant, Rationale and objectives Appendix 11 C Davenport, A Fry-Smith, A Eisinga, ChapterExcluded 3 studies Methods L Andronis, T Arvanitis, J Deeks HealthIdentifying Technology studies Assessment reports published to date and C Hyde Inclusion/exclusion criteria HealthData extractionTechnology Assessment programme Quality assessment Data analysis

Chapter 4 Results Included studies Test accuracy results

Chapter 5 Discussion Principal findings Strengths and limitations of the review

Chapter 6 Conclusions Recommendations for future research Implications for policy

October 2010 Acknowledgements Contribution of authors 10.3310/hta14500 References

Appendix 1 MEDLINE search strategy Health Technology Assessment NIHR HTA programme www.hta.ac.uk HTA

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The website also provides information about the HTA programme and lists the membership of the various committees. A systematic review of positron emission tomography (PET) and positron emission tomography/ computed tomography (PET/CT) for the diagnosis of breast cancer recurrence

M Pennant,1* Y Takwoingi,2 L Pennant,3 C Davenport,1 A Fry-Smith,1 A Eisinga,4 L Andronis,5 T Arvanitis,6 J Deeks2 and C Hyde7

1West Midlands Health Technology Assessment Collaboration, Unit of Public Health, Epidemiology & Biostatistics, University of Birmingham, Birmingham, UK 2Biostatistics group, Unit of Public Health, Epidemiology & Biostatistics, University of Birmingham, Birmingham, UK 3National Health Service West Midlands Deanery, UK 4UK Cochrane Centre, Oxford, UK 5Unit of Health Economics, University of Birmingham, Birmingham, UK 6School of Electronic, Electrical & Computer Engineering, University of Birmingham, Birmingham, UK 7Peninsula College of Medicine & Dentistry, University of Exeter, Exeter, UK

*Corresponding author

Declared competing interests of authors: none

Published October 2010 DOI: 10/3310/hta14500

This report should be referenced as follows:

Pennant M, Takwoingi Y, Pennant L, Davenport C, Fry-Smith A, Eisinga A, et al. A systematic review of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence. Health Technol Assess 2010;14(50).

Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch) and Current Contents/Clinical Medicine. NIHR Health Technology Assessment programme

he Health Technology Assessment (HTA) programme, part of the National Institute for Health TResearch (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. ‘Health technologies’ are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care. The research findings from the HTA programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the ‘National Knowledge Service’. The HTA programme is needs led in that it fills gaps in the evidence needed by the NHS. There are three routes to the start of projects. First is the commissioned route. Suggestions for research are actively sought from people working in the NHS, from the public and consumer groups and from professional bodies such as royal colleges and NHS trusts. These suggestions are carefully prioritised by panels of independent experts (including NHS service users). The HTA programme then commissions the research by competitive tender. Second, the HTA programme provides grants for clinical trials for researchers who identify research questions. These are assessed for importance to patients and the NHS, and scientific rigour. Third, through its Technology Assessment Report (TAR) call-off contract, the HTA programme commissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring together evidence on the value of specific technologies. Some HTA research projects, including TARs, may take only months, others need several years. They can cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence, undertaking a trial, or other research collecting new data to answer a research problem. The final reports from HTA projects are peer reviewed by a number of independent expert referees before publication in the widely read journal series Health Technology Assessment. Criteria for inclusion in the HTA journal series Reports are published in the HTA journal series if (1) they have resulted from work for the HTA programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors. Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others. The research reported in this issue of the journal was commissioned by the HTA programme as project number 08/34/01. The contractual start date was in July 2009. The draft report began editorial review in October 2009 and was accepted for publication in June 2010. As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health. Editor-in-Chief: Professor Tom Walley CBE Series Editors: Dr Martin Ashton-Key, Professor Aileen Clarke, Professor Chris Hyde, Dr Tom Marshall, Dr John Powell, Dr Rob Riemsma and Professor Ken Stein Editorial Contact: [email protected] ISSN 1366-5278 © 2010 Queen’s Printer and Controller of HMSO This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Published by Prepress Projects Ltd, Perth, Scotland (www.prepress-projects.co.uk), on behalf of NETSCC, HTA. Printed on acid-free paper in the UK by the Charlesworth Group. G DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

Abstract A systematic review of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence M Pennant,1* Y Takwoingi,2 L Pennant,3 C Davenport,1 A Fry-Smith,1 A Eisinga,4 L Andronis,5 T Arvanitis,6 J Deeks2 and C Hyde7

1West Midlands Health Technology Assessment Collaboration, Unit of Public Health, Epidemiology & Biostatistics, University of Birmingham, Birmingham, UK 2Biostatistics group, Unit of Public Health, Epidemiology & Biostatistics, University of Birmingham, Birmingham, UK 3National Health Service West Midlands Deanery UK 4UK Cochrane Centre, Oxford, UK 5Unit of Health Economics, University of Birmingham, Birmingham, UK 6School of Electronic, Electrical & Computer Engineering, University of Birmingham, Birmingham, UK 7Peninsula College of Medicine & Dentistry, University of Exeter, Exeter, UK

*Corresponding author

Background: Breast cancer (BC) accounts for Study appraisal: Quality assessment and data one-third of all cases of cancer in women in the UK. extraction were performed independently by two Current strategies for the detection of BC recurrence reviewers. Direct and indirect comparisons were include computed tomography (CT), magnetic made between PET and PET/CT and between these resonance imaging (MRI) and bone scintigraphy. technologies and methods of conventional imaging, Positron emission tomography (PET) and, more and meta-analyses were carried out. Analysis was recently, positron emission tomography/computed conducted separately on patient- and lesion-based tomography (PET/CT) are technologies that have been data. Subgroup analysis was conducted to investigate shown to have increasing relevance in the detection variation in the accuracy of PET in certain populations and management of BC recurrence. or contexts and sensitivity analysis was conducted Objective: To review the accuracy of PET and PET/ to examine the reliability of the primary outcome CT for the diagnosis of BC recurrence by assessing measures. their value compared with current practice and Results: Of the 28 studies included in the review, 25 compared with each other. presented patient-based data and 7 presented lesion- Data sources: MEDLINE and EMBASE were searched based data for PET and 5 presented patient-based from inception to May 2009. data and 1 presented patient- and lesion-based data Study selection: Studies were included if for PET/CT; 16 studies conducted direct comparisons investigations used PET or PET/CT to diagnose BC with 12 comparing the accuracy of PET or PET/CT recurrence in patients with a history of BC and with conventional diagnostic tests and 4 with MRI. if the reference standard used to define the true For patient-based data (direct comparison) PET had disease status was histological diagnosis and/or long- significantly higher sensitivity [89%, 95% confidence term clinical follow-up. Studies were excluded if a interval (CI) 83% to 93% vs 79%, 95% CI 72% to 85%, non-standard PET or PET/CT technology was used, relative sensitivity 1.12, 95% CI 1.04 to 1.21, p = 0.005] investigations were conducted for screening or staging and significantly higher specificity (93%, 95% CI 83% of primary breast cancer, there was an inadequate to 97% vs 83%, 95% CI 67% to 92%, relative specificity or undefined reference standard, or raw data for 1.12, 95% CI 1.01 to 1.24, p = 0.036) compared with calculation of diagnostic accuracy were not available. conventional imaging tests (CITs) – test performance iii

did not appear to vary according to the type of CIT Conventional imaging studies that were not compared tested. For patient-based data (direct comparison) with PET or PET/CT were excluded from the review. PET/CT had significantly higher sensitivity compared Conclusions: Available evidence suggests that for with CT (95%, 95% CI 88% to 98% vs 80%, 95% CI the detection of BC recurrence PET, in addition to 65% to 90%, relative sensitivity 1.19, 95% CI 1.03 to conventional imaging techniques, may generally offer 1.37, p = 0.015), but the increase in specificity was improved diagnostic accuracy compared with current not significant (89%, 95% CI 69% to 97% vs 77%, standard practice. However, uncertainty remains 95% CI 50% to 92%, relative specificity 1.15, 95% CI around its use as a replacement for, rather than an 0.95 to 1.41, p = 0.157). For patient-based data (direct add-on to, existing imaging technologies. In addition, comparison) PET/CT had significantly higher sensitivity PET/CT appeared to show clear advantage over CT compared with PET (96%, 95% CI 90% to 98% vs 85%, and PET alone for the diagnosis of BC recurrence. 95% CI 77% to 91%, relative sensitivity 1.11, 95% CI Future work: Future research should include: 1.03 to 1.18, p = 0.006), but the increase in specificity prospective studies with patient populations clearly was not significant (89%, 95% CI 74% to 96% vs 82%, defined with regard to their clinical presentation; a 95% CI 64% to 92%, relative specificity 1.08, 95% CI study of diagnostic accuracy of PET/CT compared with 0.94 to 1.20, p = 0.267). For patient-based data there conventional imaging techniques; a study of PET/CT were no significant differences in the sensitivity or compared with whole-body MRI; studies investigating specificity of PET when compared with MRI, and, in the possibility of using PET/CT as a replacement for the one lesion based study, there was no significant rather than an addition to CITs; and using modelling of differences in the sensitivity or specificity of PET/CT the impact of PET/CT on patient outcomes to inform when compared with MRI. the possibility of conducting large-scale intervention Limitations: Studies reviewed were generally small trials. and retrospective and this may have limited the Funding: This study was funded by the Health generalisability of findings. Subgroup analysis was Technology Assessment programme of the National conducted on the whole set of studies investigating Institute for Health Research. PET and was not restricted to comparative studies.

iv DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

Contents

List of abbreviations ...... vii Appendix 1 MEDLINE search strategy ... 41

Executive summary ...... ix Appendix 2 Characteristics of FDG-PET technology ...... 43 1 Introduction ...... 1 Breast cancer ...... 1 Appendix 3 Figures for indirect Follow-up and treatment in the setting comparisons of patient-based data ...... 47 of recurrence ...... 1 Existing diagnostic strategies ...... 1 Appendix 4 Comparative lesion- PET and PET/CT ...... 2 based data ...... 49 Current guidelines ...... 3 Appendix 5 Study data and figures 2 Rationale and objectives ...... 5 for independent estimates of PET and PET/CT ...... 51 3 Methods ...... 7 Identifying studies ...... 7 Appendix 6 Changes in patient Inclusion/exclusion criteria ...... 7 management ...... 55 Data extraction ...... 8 Quality assessment ...... 8 Appendix 7 Sensitivity analysis ...... 57 Data analysis ...... 8 Appendix 8 Subgroup analysis ...... 59 4 Results ...... 11 Included studies ...... 11 Appendix 9 False-positives and false- Test accuracy results ...... 18 negatives ...... 63

5 Discussion ...... 27 Appendix 10 Protocol ...... 65 Principal findings ...... 27 Strengths and limitations of the review ... 30 Appendix 11 Excluded studies ...... 71

6 Conclusions ...... 33 Health Technology Assessment Recommendations for future research ..... 33 reports published to date ...... 75 Implications for policy ...... 33 Health Technology Assessment Acknowledgements ...... 35 programme ...... 99

References ...... 37

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List of abbreviations

BC breast cancer NICE National Institute for Health and Clinical Excellence CI confidence interval MRI magnetic resonance imaging CITs conventional imaging tests PET positron emission tomography CT computed tomography PET/CT positron emission tomography/ CW conventional workup computed tomography

FDG 18F-fluorodeoxyglucose SROC summary receiver operating characteristic FN false-negative ROC receiver operating characteristic FP false-positive TN true-negative HSROC hierarchical summary receiver operating characteristic TP true-positive

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices, in which case the abbreviation is defined in the figure legend or in the notes at the end of the table.

vii

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Executive summary

Background if investigations were conducted for screening or staging of primary BC, if a non-standard PET Breast cancer (BC) affects 1 in 13 women in or PET/CT technology was used, if there was an their lifetime. Treatment options have developed inadequate or undefined reference standard, or significantly over the past decade and have had if raw data for calculation of diagnostic accuracy an impact on survival. The diagnosis of BC were not available. Both comparative and non- recurrence is important to allow appropriate comparative studies were included. treatment. Positron emission tomography (PET) and positron emission tomography/computed Data extraction and quality assessment were tomography (PET/CT) are technologies that have conducted independently by two reviewers with application in the detection and management of any disagreements resolved by consensus. Direct cancer. The adoption of PET or PET/CT depends and indirect comparisons were made between PET not only on their diagnostic accuracy but also and PET/CT and between these technologies and on their comparative advantage over existing methods of conventional imaging, and a meta- diagnostic approaches. analysis was performed using a bivariate random effects model. Analysis was conducted separately on patient- and lesion-based data. Subgroup Objectives analysis was conducted to investigate variation in the accuracy of PET in certain populations or This report covers the question of the effectiveness contexts and sensitivity analysis was conducted to of PET and PET/CT for diagnosing BC recurrence examine the reliability of the primary outcome and a second report (to follow) will provide measures. economic modelling to address the question of their cost-effectiveness in this context. The aim of this review was to assess the value of PET Results and PET/CT, in addition to current practice, for the diagnosis of BC recurrence. The objectives Twenty-eight studies were included in the current were: (1) to assess the diagnostic accuracy of PET review and, of these, 26 investigated the diagnostic compared with conventional diagnostic strategies; accuracy of PET. Twenty-five presented patient- (2) to assess the diagnostic accuracy of PET/CT based data and seven presented lesion-based data compared with conventional diagnostic strategies; for PET. Six studies investigated the accuracy of (3) to assess the diagnostic accuracy of PET and PET/CT, five presenting patient-based data and PET/CT compared with magnetic resonance one presenting lesion-based data. Sixteen studies imaging (MRI); (4) to compare the accuracy of PET conducted direct comparisons and, of these, 12 with PET/CT; (5) to assess the overall diagnostic compared the accuracy of PET or PET/CT with accuracy of PET and PET/CT; (6) to investigate conventional diagnostic tests and four compared the impact of PET and PET/CT on patient PET or PET/CT with an MRI technology. Quality management; and (7) to explore possible mediators varied between studies, and the major quality issue of the accuracy of PET and PET/CT. identified was the time delay between conventional tests and PET or PET/CT in comparative studies. The PET or PET/CT technology used was similar Methods across the studies.

A systematic review was conducted. A search 1. For patient-based data, in studies where direct for primary studies in MEDLINE (Ovid) and comparisons were made, PET had significantly EMBASE (Ovid) was conducted with no language higher sensitivity [89%, 95% confidence restrictions. Studies of PET or PET/CT in patients interval (CI) 83% to 93% vs 79%, 95% CI 72% with history of BC and suspicion of recurrence to 85%, relative sensitivity 1.12, 95% CI 1.04 were selected for inclusion. Studies were excluded to 1.21, p = 0.005] and significantly higher ix

specificity (93%, 95% CI 83% to 97% vs 83%, 95% CI 0.94 to 1.20, p = 0.267). The same 95% CI 67% to 92%, relative specificity 1.12, pattern of results was observed for the indirect 95% CI 1.01 to 1.24, p = 0.036), compared with comparison of all PET/CT (n = 5) and PET conventional imaging tests (CITs) (n = 10). Test (n = 25) studies. In the lesion-based analysis, performance did not appear to vary according indirect comparison of PET/CT (n = 2) and to the type of CIT that was compared with PET (n = 7) showed no significant differences PET (p = 0.500). Indirect comparisons, where in sensitivity or specificity between PET/CT all CIT (n = 11) and PET (n = 25) studies and PET. were included, gave the same findings. For 5. For overall diagnostic accuracy, on a patient lesion-based data, no significant differences basis, PET/CT (n = 5) and PET (n = 25) had in sensitivity or specificity between PET and sensitivities of 96% (95% CI 89% to 99%) and CIT were observed for studies making direct 91% (95% CI 86% to 94%) and specificities comparisons (n = 3) or for indirect comparisons of 89% (95% CI 75% to 95%) and 86% (95% for all PET (n = 7) and CIT (n = 3) studies. CI 79% to 91%) respectively. On a lesion In the sensitivity analysis of patient data, for basis, PET/CT (n = 2) and PET (n = 7) had studies in which the time period between PET sensitivities of 96% (95% CI 80% to 99%) and and comparator tests was clearly less than 89% (95% CI 78% to 95%) and specificities 1 month (n = 6), differences between PET and of 83% (95% CI 61% to 94%) and 91% (95% CIT tended to be smaller and the difference in CI 83% to 96%), respectively. There was sensitivity became non-significant. considerable heterogeneity in the spread of 2. For patient-based data, in all studies where results for PET. direct comparisons were made (n = 4), the CIT 6. Changes in patient management in study used was CT. In these studies, compared with participants ranged from 11% to 74% (median CT, PET/CT had significantly higher sensitivity 27%). These changes included initiation (95%, 95% CI 88% to 98% vs 80%, 95% CI 65% and avoidance of medical treatment such to 90%, relative sensitivity 1.19, 95% CI 1.03 to as hormone therapy and chemotherapy. 1.37, p = 0.015) but the increase in specificity In the three studies where only changes in was not significant (89%, 95% CI 69% to 97% management directly due to PET or PET/ vs 77%, 95% CI 50% to 92%, relative specificity CT were considered (patients were not 1.15, 95% CI 0.95 to 1.41, p = 0.157). Indirect correctly diagnosed by conventional imaging comparisons, where all CIT (n = 11) and PET/ techniques), estimates ranged from 11% to CT (n = 5) studies were included, gave the 25%. same findings. No lesion-based data compared 7. In subgroup analysis, the accuracy of PET PET/CT with CIT. In the sensitivity analysis did not appear to be related to the location of patient data, for studies in which the time of disease or to whether PET was conducted period between PET/CT and comparator with or without knowledge of previous clinical tests was clearly less than 1 month (n = 3) history and imaging studies. Characteristics differences between PET/CT and CT became of patient populations varied in many respects non-significant. and it was not possible to draw definite 3. For patient-based data, three studies compared conclusions about patient characteristics that PET with different types of MRI technology. In may have an impact on test accuracy. each of these studies, there were no significant differences in the sensitivity or specificity of PET compared with MRI. One study compared Conclusions PET/CT and MRI on a lesion basis and there were no significant differences in sensitivity or • For detection of BC recurrence, in addition specificity for PET/CT compared with MRI. to conventional imaging techniques, PET 4. For patient-based data, in the analysis of may generally offer improved diagnostic studies directly comparing PET/CT and PET accuracy compared with current standard (n = 4), PET/CT had significantly higher practice. Uncertainty remains around its use sensitivity (96%, 95% CI 90% to 98% vs 85%, as a replacement, rather than an add-on, to 95% CI 77% to 91%, relative sensitivity 1.11, existing imaging technologies. 95% CI 1.03 to 1.18, p = 0.006), but the increase • PET/CT appears to show a clear advantage in specificity was not significant compared over CT for the diagnosis of BC recurrence. with PET (89%, 95% CI 74% to 96% vs 82%, Although PET/CT may give an advantage 95% CI 64% to 92%, relative specificity 1.08, over other CITs, its incremental value over x DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

other tests has yet to be directly assessed in • Using modelling of the impact of PET/CT on studies. Concurrent use with, rather than patient outcomes (to be published in another replacement of, other conventional tests may report) to inform the possibility of conducting be appropriate. large-scale intervention trials to assess impacts • PET/CT appears to show a clear advantage on long-term patient outcomes. over PET and it is likely to be preferred to PET for use in this context. • PET and PET/CT appear to have some impact Implications for policy on patient management but there is currently no evidence of the effect of their use on patient PET/CT has largely superseded PET in current outcomes. practice, and the apparent advantage of PET/CT over PET found in this review supports that move. On the basis of some of the uncertainties observed, Recommendations for it may be premature to make recommendations future research about the precise diagnostic role of PET/CT in practice. However, current recommendations for • Prospective studies with patient populations its use for diagnosing metastatic BC following clearly defined with regard to their clinical equivocal findings on conventional imaging presentation. techniques appear to be justified. It appears that • Study of the diagnostic accuracy of PET/ PET/CT may be useful as an addition to current CT compared with conventional imaging practice for the diagnosis of BC recurrence but this techniques. should be reassessed in light of the analysis of its • Study of PET/CT compared with whole-body cost-effectiveness. MRI. • Studies investigating the possibility of using PET/CT as a replacement for, rather than an addition to, CITs.

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Chapter 1 Introduction

Breast cancer chemotherapy, particularly with the newer agents. Taxane-based chemotherapy is considered likely One in thirteen women in the UK will develop to increase overall survival, time to progression breast cancer (BC) in their lifetime. In women, and overall response in the second-line setting,2 BC accounts for one-third of all cases of cancer. and Herceptin (trastuzumab, Roche) is showing In the UK, from 2004–6, the incidence rate of promising results in HER (human epidermal new BC was 122 per 10,000 women.1 Most women growth factor receptor)-2-positive disease. fortunately present with early-stage breast cancer Radiotherapy, combined with appropriate (ESBC) and the UK NHS Breast Screening analgesia, may be effective in reducing persistent Programme currently offers screening at 50 years localised bone pain.2 of age. ESBC is treated with surgery and adjuvant therapy often involving combinations of hormone therapy, chemotherapy and radiation therapy.2 Existing diagnostic Treatment options have developed significantly strategies over the past decade and, with early diagnosis, rates of 5-year survival are currently > 80% and Women with a past history of BC may present have increased steadily over the past 10–20 years.1 with symptoms that may be innocent or indicate However, a number of women will develop disease. There is a range of strategies that may metastatic disease and die of their BC. be involved in patient diagnosis and the choice of tests used depends on the presenting symptoms. Conventional workup (CW) often includes Follow-up and treatment in conventional X-rays, computed tomography (CT), the setting of recurrence ultrasound, bone scintigraphy and measurement of serum tumour markers and, in a limited number In most BC units, after treatment for the initial of settings, magnetic resonance imaging (MRI) disease, patients are routinely followed up with may be available for use. clinical examination and mammography for at least 5 years,3 specifically looking for treatable local Conventional X-rays are widely available and recurrence and symptoms to suggest metastatic are routinely used for cases of suspected BC disease. Investigational screening for metastatic recurrence. X-rays may be particularly useful for disease is not performed routinely. If symptoms the diagnosis of metastases in the lung and bones suggest relapse with metastatic disease, further (chest or individual bone X-ray).6 CT scans can investigations may be conducted where there is be used to detect cancer in a range of tissue types suspicion of disease. Rates of BC recurrence have (lung, bone, soft tissue, etc.).7 Ultrasound can be been shown to be around 20%4,5 and recurrence used to detect liver metastases.6 Bone scintigraphy may be local (in the breast), regional (lymph nodes uses radionuclides of technetium-99m-labelled in the ipsilateral axilla) or distant metastases (in disphosphonates and is used for the identification tissues such as bone, liver, lungs and brain). Of of bone metastases.8 patients with BC recurrence, one study showed that 27% had bone metastases, 27% had local Several biochemical compounds in the serum/ recurrence, 16% had lung metastases and 13% had plasma may act as indicators of the presence, risk liver metastases.4 or prognosis of cancer.9 In patients with history of BC, elevated tumour marker levels may represent If metastatic disease is established, patients are cases of tumour relapse.9 It has been shown that generally not curable and treatment is aimed at increasing levels of these markers is associated with palliating symptoms and improving survival if disease recurrence and may indicate the need for possible. Useful and sometimes lengthy clinical further investigation. MRI may be used for the responses can be obtained by using hormone detection of local BC recurrence10 or, with imaging therapy in hormone-responsive disease and with of the whole body, for the additional detection of 1

bone metastases11 and other distant metastases.12 CT units installed in the UK predominantly for However, access to MRI is limited6 and it is not clinical use. Recommendations included a hub routinely used for diagnosing suspected BC and satellite system, where central hub staff and recurrence. resources would be used to maintain PET/CT scanners in more numerous satellite settings.16 In the setting of diagnosis of BC recurrence, Initially, provision was to be made for one PET/CT CW is likely to comprise a combination of these system per 1.5 million of the population,16 equating technologies (in most cases, CW will not include to ~ 40 machines for the current UK population. MRI). Patients may undergo a variety of tests depending on their presenting symptoms and on Measurement of diagnostic the basis of the results of other imaging tests. accuracy Diagnostic accuracy is usually defined as the PET and PET/CT sensitivity and specificity of a test, where sensitivity describes the ability of a test to correctly identify Positron emission tomography (PET) and, more individuals with the disease and specificity recently, positron emission tomography/computed describes the ability of a test to correctly identify tomography (PET/CT) are technologies that have individuals without the disease. The test under been increasingly shown to have application in study is referred to as the index test and the the detection and management of cancer, with results of this test are compared with the ‘reference the introduction of whole-body PET and PET/ standard’. The reference standard is a test that is CT in the late 1990s. These technologies involve considered to show the true disease status of each administration of a radioactive isotope and individual and determines which individuals are detection of photons produced in the process of classed as having or not having the disease. The radioactive decay and interaction with surrounding comparison of the index test with the reference tissues.13 In oncology, the most commonly used standard allows findings for each patient to be radionuclide is 18F-fluorodeoxyglucose (FDG) classed into one of four categories: which is taken up into cells in the same way as glucose. FDG accumulates in tumour tissue True-positive (TP) The index test detects disease owing to increased glucose requirements and and is in agreement with the reference standard therefore increased glucose uptake. Also, in that also detected disease. most tissues, FDG accumulates following uptake and phosphorylation, as, unlike glucose, it True-negative (TN) The index test does not detect cannot enter the normal glycolytic pathway.13 disease and is in agreement with the reference FDG is administered intravenously to patients standard that also did not detect disease. and, following an interval of time (usually 60–90 minutes) to allow uptake, PET scans are False-positive (FP) The index test detects disease conducted. The whole body may be imaged during but disagrees with the reference standard that did a single session14 and these technologies may be not detect disease. used to detect both local and metastatic tumours. False-negative (FN) The index test does not detect PET/CT combines information obtained from disease but disagrees with the reference standard PET with data from CT scanning.15 As these that did detect disease. technologies provide different types of data (PET gives metabolic and CT anatomical data), Findings for TP, TN, FP and FN can be used to their combination provides greater diagnostic calculate the sensitivity and specificity of the index information. CT data are also used for attenuation test, where sensitivity is the ratio of the number correction of PET images.15 An attenuation map of of people correctly identified with the disease CT can be used to estimate attenuation factors for compared with the total number of people classed PET and this correction can be applied to increase with the disease [sensitivity = TP/(TP + FN)], and the accuracy of the images produced.13 specificity is the ratio of the number of people correctly identified as not having the disease In 2005, the Royal College of Radiologists compared to the total number of people classed as published a strategy document detailing the not having the disease [specificity = TN/(TN + FP)]. provision of PET/CT instruments across the UK.16 As in the current review, where additional At that time, there were 11 fixed scanning PET/ comparator tests are also being considered, these 2 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

are assessed as if they were another index test, i.e. where assessors interpret PET or PET/CT without findings for the comparator test are compared with knowledge of these results. Where assessors those of the reference standard to class them as TP, have knowledge of previous findings, apparent TN, FP or FN. diagnostic accuracy may be anticipated to be better than when assessors do not have knowledge Results from test accuracy studies may be of previous imaging findings. This also has presented on summary receiver operating planes, implications for the applicability of study findings where each point on the graph represents the to clinical use. If PET or PET/CT is to be used diagnostic accuracy of a test found in each instead of existing diagnostic imaging tests, only particular study. Specificity is plotted on the x-axis the results of studies in which previous imaging and sensitivity on the y-axis and the results from results are unknown may be relevant, whereas, if meta-analysis of the studies are shown as summary PET and PET/CT are to be used as technologies in points. addition to standard imaging procedures, studies in which assessors have knowledge of previous Potential modifiers of the findings may be more applicable. diagnostic accuracy of PET and PET/CT Current guidelines The diagnostic accuracy of PET and PET/CT are likely to vary depending on features of the patient Guidelines have been developed by the National population, technology used and design of the Institute for Health and Clinical Excellence (NICE) investigative study. for the treatment of early/locally advanced3 and advanced17 BC. In the early BC guidance, key Features of the patient population, such as the recommendations for the follow-up of patients nature of disease, may affect the accuracy of PET with BC include provision of designated health- or PET/CT. For example, if lesions are small or care professionals, dates for review of any adjuvant particularly difficult to detect, sensitivity may therapy, surveillance with mammography and tend to be lower. Accuracy may also depend on contact points for specialist care.3 The guidance the location of disease, and PET and PET/CT may suggests that future research should involve vary in their ability to diagnose local, regional and determination of the appropriate length of follow- metastatic disease. up and suitable methods for detecting disease recurrence.3 The methods used for PET or PET/CT investigations may be important modifiers of The advanced BC guidelines give advice on the diagnostic accuracy. As these techniques use treatment of advanced/metastatic disease that is radioactive isotopes of glucose to indicate sites generally only amenable to palliative care without of increased metabolic activity, misdiagnosis curative intent. These guidelines do not specifically may result from elevated blood glucose levels. relate to the diagnosis of BC recurrence. However, It is recommended that all patients fast for at some guidance given may be applicable. The least 4–6 hours before scanning.14 The presence NICE guidelines state that ‘Positron emission of patient fasting, and exclusion of those with tomography fused with computed tomography diabetes or impaired glucose tolerance, may be (PET-CT) should only be used to make a new important mediators of diagnostic accuracy. The diagnosis of metastases for patients with breast presence of attenuation correction, using CT data cancer whose imaging is suspicious but not or another correction method, is an important diagnostic of metastatic disease.’17 In other words, predictor of diagnostic accuracy and may cause PET/CT would only be used for diagnosis in cases variation in the accuracy of PET or PET/CT in where conventional imaging techniques fail to studies. Further aspects of technology that may properly diagnose the presence or absence of affect diagnosis are features such as the length of metastases. Although these guidelines relate to radioisotope uptake, image acquisition time and the use of PET/CT, all of the evidence reviewed the mode of image interpretation. to inform them are studies or systematic reviews of PET and not PET/CT. Additionally, these The study design may also have an impact on guidelines refer only to the diagnosis of metastatic, diagnostic accuracy. A distinction may be made and not local, recurrence and the evidence base between studies where assessors have knowledge of relating to the application of PET and PET/CT for previous clinical and imaging findings and studies the detection of recurrent BC is not clear. 3

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Chapter 2 Rationale and objectives

his report covers the question of the Further aims were to assess the overall test Teffectiveness of PET and PET/CT for accuracy of PET and PET/CT, to assess the impact diagnosing BC recurrence and another report (to of PET and PET/CT on patient management and follow) will provide economic modelling to address to investigate possible determinants of variation the question of their cost-effectiveness in this in the diagnostic accuracy of PET. For clarity, context. objectives were, in the detection of BC recurrence:

We have reviewed existing systematic reviews 1. To assess the incremental diagnostic accuracy assessing the effectiveness of PET and PET/CT of PET in addition to standard practice in the diagnosis of recurrent BC. The two most compared with conventional imaging tests relevant were the Blue Cross/Blue Shield report (CITs). 200118 and Isasi et al. 2005.19 The latter provides 2. To assess the incremental diagnostic accuracy the most up-to-date assessment of test accuracy of of PET/CT in addition to standard practice PET in evaluations up to 2004, but no estimation compared with CITs. of accuracy compared with existing diagnostic 3. To assess the incremental diagnostic accuracy strategies. However, the key outstanding issue was of PET and PET/CT in addition to standard the amount of improvement that PET and PET/CT practice compared with MRI. offer over existing diagnostic approaches and this 4. To compare the diagnostic accuracy of PET was the focus of the current review. and PET/CT. 5. To obtain independent estimates of the The main aims of this review were to assess the diagnostic accuracy for PET and PET/CT in incremental diagnostic accuracy of PET and PET/ addition to standard practice. CT compared with existing diagnostic strategies 6. To examine changes in patient management and to compare the diagnostic accuracy of PET owing to the use of PET and PET/CT. and PET/CT for the diagnosis of BC recurrence. 7. To explore possible determinants of variation The accuracy of PET and PET/CT were to be in the accuracy of PET and PET/CT. considered in addition to standard practice.

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Chapter 3 Methods

he protocol was reviewed by the National Patients were to have had a previous diagnosis of TInstitute for Health Research (NIHR) Health BC and to have completed a course of primary Technology Assessment (HTA) programme (see treatment. The initial aim of this review was Appendix 10) and there were no major departures to include only studies in which patients had from it when conducting the review. previously been cleared of BC. However, it soon became evident that, in many studies, the exact patient group was unclear. It was often not fully Identifying studies clear whether patients with history of BC had Search strategy subsequently been cleared or if they had known BC and were having further imaging investigations Searches were conducted in MEDLINE (Ovid) and in order to diagnose metastatic disease. Exclusion EMBASE (Ovid) and strategies combined MeSH of these types of studies was likely to substantially (Medical Subject Headings) and text words to limit the scope of this review and restrict its define the index test (PET and PET/CT) and the application. population (suspected breast cancer recurrence) (see Appendix 1). No language restrictions were A decision was therefore made to include studies used and searches were carried out from inception investigating the diagnosis of BC recurrence in of the databases up to May 2009. patient groups that may have been cleared or not cleared of their original disease. All studies Selection of studies were to have been conducted in the context of secondary BC investigations, i.e. they did not form Titles/abstracts obtained from the literature search part of the initial BC diagnosis, BC staging or were scanned for inclusion by one reviewer. Where monitoring of response to primary BC treatment. information given in title/abstracts suggested that Included studies were required to show evidence the study (1) included patients with past history of that investigations were distinct from primary breast cancer, (2) conducted PET or PET/CT scans investigations and were conducted after completion in those patients, and (3) assessed test accuracy, of the primary course of treatment. full paper articles were retrieved for further assessment. Additionally, studies potentially Index test containing information on cost-effectiveness or one or more relevant clinical outcome measures were Included studies were to have used PET or PET/ retrieved. If there was doubt regarding inclusion CT to diagnose BC recurrence in patients with from the title and abstract, the full article was history of BC. The PET or PET/CT technology obtained for clarification. Stringent inclusion/ was required to be a dedicated machine and use a exclusion criteria were applied to full paper studies FDG tracer. Studies were excluded if coincidence in order to obtain the final set of included studies. gamma camera PET had been used or if other types of radioactive tracers had been used.

Inclusion/exclusion criteria Reference standard

Full paper articles were screened in relation to Studies were included if the reference standard the following inclusion/exclusion criteria by one used to define the true disease status was reviewer with reference to a second reviewer where histological diagnosis (operation/biopsy) and/or there was any doubt about their eligibility. long-term clinical follow-up. Studies were excluded if details of the reference standard were not given Population or if no suitable reference standard was used, e.g. other imaging studies conducted without follow-up. The patient population was to be under investigation for suspicion of BC recurrence. 7

Comparator Quality assessment This review included both studies with and without comparator groups. Within-study comparisons Quality assessment was conducted independently are more robust as they effectively eliminate by two reviewers, using relevant items from differences in potential modifiers of test accuracy the QADAS (Quality Assessment of Diagnostic between the two tests being compared. Indirect Accuracy Studies) tool,20 and differences resolved comparisons (comparison of independently pooled by consensus. Quality assessment criteria for study summary estimates across all studies) can also be methodology related to patient selection, use of the conducted on the larger set of comparative and reference standard, blinding and external validity. non-comparative studies. For studies including Additionally, the time delay between the index comparator groups, those using any diagnostic and comparator tests was assessed as an aspect of comparators were included but patients were study quality as this has potential to bias estimates also to have undergone PET or PET/CT and the of relative test accuracy. The technical quality reference standard. Studies in which PET or of the PET or PET/CT technology was assessed PET/CT and other diagnostic techniques were with reference to procedure guidelines,21 as used compared without use of a reference standard were by Isasi et al.,19 with particular reference to pre- excluded. scan blood glucose testing, the use of attenuation correction and the duration of FDG uptake. Outcomes Quality criteria were set with the specifications outlined in Table 1. Studies giving sufficient information on the diagnosis of BC recurrence to determine the number of TP, TN, FP and FN test results were Data analysis included. Recurrence could be local, regional or distant but disease was to be considered to Positron emission tomography and PET/CT be a consequence of the originally diagnosed were considered as independent technologies breast cancer. Additional studies that contained for analysis. Comparative tests considered to be information on the influence of PET or PET/CT on conventionally used for diagnosis in this setting patient management or the reasons for FP and FN were grouped together for comparison with PET results were also included. and PET/CT. CITs were defined as one or more of bone scintigraphy, CT, X-ray and general CW. Single comparators, e.g. CT or bone scintigraphy, Data extraction were classed as CIT if they were judged to be adequate diagnostic methods in the context of The number of TP, TN, FP and FN values were the study. For example, for the diagnosis of bone extracted from each study. In all studies, only data metastases, bone scintigraphy was considered as for participants who had undergone a satisfactory CIT because, despite being a single diagnostic reference standard were extracted. In studies test, it would be appropriate in the context of where there were comparator tests, where possible, diagnosing bone metastases. MRI was considered only data for participants who had undergone as a separate technology from CIT as, in many both the index and comparator tests were selected. hospitals, it may not be part of the conventional Information relating to patient management and diagnostic strategy (Professor Patricia Price, location sites of FPs and FNs on PET or PET/CT Imperial College London, 2010, personal scans was also extracted. Test accuracy data was communication). Data from studies in which PET extracted by two independent reviewers. Where or PET/CT were used in addition to other imaging there were differences in the retrieved data, these techniques and studies in which assessors were were discussed and a consensus of the true values blinded to previous imaging results were pooled was reached. Data related to patient management in the analysis. This approach was considered and sites of FPs and FNs were extracted by conservative in light of the emphasis of the review one reviewer. Authors of potentially included (to assess the diagnostic accuracy of PET and PET/ studies were contacted if relevant study data was CT in addition to standard practice). incomplete but it appeared likely to have been obtained. review manager 5.0 was used to produce a methodological quality summary table and

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TABLE 1 Quality assessment criteria

Quality item Criteria Representative spectrum Patients typical of those presenting for BC recurrence? Acceptable reference standard Histology or follow up for > 6 months? Acceptable delay between tests ≤ 1 month between PET or PET/CT and comparator test? Partial verification avoided All patients received adequate reference standard? Differential verification avoided All patients received same reference standard regardless of results of PET or PET/ CT? Incorporation avoided Results of PET or PET/CT were not used as part of the final diagnosis of BC? Index test results blinded Interpreters of PET or PET/CT were not aware of the final diagnosis of BC? Relevant clinical information Assessors of PET or PET/CT had information on patient histories and previous imaging studies?

Additional technology-specific criteria Measurement of blood glucose Exclusion of patients with blood glucose levels ≥ 130 mg/dl? Attenuation correction Was attenuation correction used for PET or PET/CT scans? Uptake > 60 minutes Were patients given doses of FDG glucose > 60 minutes prior to scanning?

forest plots of sensitivity and specificity for each logistic regression models for sensitivity and test from the extracted 2 × 2 data and to present specificity separately. meta-analytic results in receiver operating characteristic (ROC) space. In order to make Data presented on a patient and lesion basis were inferences about the relative accuracy of the tests considered separately in the analysis. Patient- in terms of sensitivity and specificity (instead of based data were used as the basis for the main the diagnostic odds ratio), a bivariate method, analysis and for the investigation of heterogeneity. rather than the [7]hierarchical summary receiver As limited patient data were available on a operating characteristic (HSROC) method, as location-specific basis, lesion data were used to specified in the protocol, was used for statistical inform investigation of relative test accuracy analysis. A meta-analysis was done for each pair- in different sites. For patient-based data, each wise comparison of imaging modalities to estimate patient constituted the unit of analysis and, for ratios of sensitivity and specificity. The bivariate lesion-based data, each lesion suspected of disease random effects approach described by Reitsma constituted the unit of analysis. et al.22 was used to obtain summary estimates of sensitivity, specificity and ratios of values between The primary outcomes of interest were the tests (relative sensitivity and specificity). This accuracy of PET and PET/CT compared with approach preserves the two-dimensional nature conventional technologies and the accuracy of PET of the data by incorporating the correlation compared with PET/CT. Using patient- and lesion- between sensitivity and specificity. It also takes into based data (where available), comparisons were account both within-study sampling variability in made for: estimates of sensitivity and specificity and between- study variability in test performance through the • PET compared with CIT inclusion of random effects. All models were fitted • PET/CT compared with CIT using the NLMIXED procedure in sas based on • PET compared with PET/CT. the formulation proposed by Chu and Cole.23 Estimations of the differences in test accuracy To investigate differences in test performance were first made using only studies in which PET according to type of CIT (CT, CW and bone or PET/CT had been compared directly with other scintigraphy), a second covariate was introduced technologies or with each other (referred to as into the analytical model comparing PET with CIT. direct comparisons). Indirect comparisons were To achieve convergence, this model was simplified also made by pooling estimates for each test across by setting the correlation parameter equal to zero. all included studies before making between-test This is equivalent to fitting two random effects comparisons. 9

Sensitivity analysis Subgroup analysis Sensitivity analysis was conducted to examine the Subgroup analyses were conducted to reliability of findings for comparisons among PET, investigate factors that may have been sources PET/CT and CIT. As the emphasis of this review of heterogeneity. The limited number of direct was on studies directly comparing tests, sensitivity comparison studies (10 for PET vs CIT and 4 for analysis was applied only to direct comparisons. PET/CT vs CIT) limited subgroup analysis within Issues of quality related to individual studies, e.g. this set but subgroup analysis was conducted on the representativeness of patient spectrum, quality of larger set of studies in which PET (with or without the reference standard, etc., were unlikely to have a comparator group; n = 25) had been performed. affected the comparisons and these factors were Subgroup analysis was not performed for PET/ therefore not included in the sensitivity analysis. CT owing to the limited amount of data available. However, aspects that could have differed between Subgroup analysis was conducted to compare tests under investigation were eligible for sensitivity studies of: analysis. The area of potential concern, where conditions for different tests may have varied, • PET in patients with negative results for was the time delay between the index (PET or previous imaging studies versus PET in PET/CT) and comparator tests and the reference patients with positive or suspicious previous standard. In the sensitivity analysis, to remove the imaging results bias associated with different time lapses between • PET in different locations of the body tests and the reference standard, studies were • PET for investigation of those cleared of BC removed if PET or PET/CT investigations were not versus PET for those not cleared/where disease conducted within 1 month of comparator tests or if status is unclear the period of time between tests was unclear. • PET in addition to standard practice versus PET instead of standard practice.

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Chapter 4 Results

total of 2526 citations were retrieved from the CT compared with MRI (n = 4) or with more Asearch of the databases, of which 522 were conventional diagnostic strategies (CW, CT and duplicates. After title/abstract screening, a total bone scintigraphy) (n = 12). In most studies, data of 185 full papers was ordered for review. Thirty- were presented on a patient basis (n = 26). In nine two studies were included in the final review, 28 studies, lesion data were presented and seven provided quantitative data and the reasons for full studies presented both patient and lesion data paper exclusions are given in Figure 1. (Table 2). The numbers of patients for the main groups for analysis are shown in Table 2.

Included studies Three studies contained information on changes in patient management owing to PET or PET/CT. Twenty-eight studies were identified as containing These were excluded from quantitative synthesis information on diagnostic accuracy relevant to the because there was no test accuracy data,52,53 a less current review. Most of these studies investigated sophisticated PET technology54 or an unsatisfactory PET (n = 26) and fewer assessed PET/CT (n = 6) reference standard,55 but information from these (four studies investigated both PET and PET/CT). studies was included in the patient management Sixteen studies were direct comparisons and 12 part of the review (see Chapter 4, Changes in were non-comparative (Table 2). Direct comparison patient management). studies investigated the accuracy of PET or PET/

2004 distinct records 1819 records excluded identified

153 full-text articles excluded: primary BC diagnosis n = 26 primary BC staging n = 32 data include other cancers n = 25 185 full-text articles review n = 11 assed for eligibility not current PET or PET/CT technology n = 12 no relevant outcome n = 8 monitoring response to treatment n = 7 not satisfactory reference standard n = 7 not FDG tracer n = 5 other n = 12

32 studies included in 4 studies excluded from qualitative synthesis quantitative synthesis

28 studies included in quantitative synthesis (meta-analysis)

FIGURE 1 PRISMA diagram. 11

TABLE 2 Numbers of studies and patients/lesions in the main groups for analysis

Analysis Number of studiesa Number of patients/lesions

Patient data PET vs CIT 10 456 patients PET/CT vs CIT 4 167 patients PET vs PET/CT 4 188 patients PET 25 1379 patients PET/CT 5 225 patients

Lesion data PET vs CIT 3 449 lesions (154 patients) PET 7 690 lesions (331 patients) PET/CT 2 443 lesions (79 patients)

a Numbers do not add up to 28 because some studies contain data for PET and PET/CT or patient and lesion data.

Population characteristics The majority of studies used an acceptable The characteristics of patient populations in the reference standard (n = 21) (histology or follow-up included studies are shown in Table 4 (comparative > 6 months) but in three studies in some patients studies) and Table 5 (non-comparative studies). follow-up was < 6 months,28,32,41 in two studies the The size of study samples ranged from 10 to 291 duration of follow-up was unclear,34,42 and in one patients (median 45). In most cases the reference study changes in tumour markers were used to standard was a combination of histology and define the reference standard in some patients.25 clinical follow-up including conventional imaging techniques. In the majority of comparative studies, PET or PET/CT were conducted after the comparator. In all studies, patients were being investigated for The time delay between PET or PET/CT BC disease distinct from primary investigations. and the comparator was < 1 month in 11 In 16 of the studies25,30–36,38–40,42,43,46–48 it studies24,27,28,30,32,33,41,44,46,48,51 but, in the rest of the appeared that all patients had previously been comparative studies, the time delay was either not cleared of BC, whereas in the remaining 12 reported or appeared to be longer than 1 month. studies,24,26–29,37,41,44,45,49–51 investigations were for the diagnosis of metastases in patients with a diagnosis In most studies (n = 19), it was reported that all of BC or where the diagnosis of patients was patients received a reference standard (avoiding unclear. partial verification bias). However, it was often not clear whether this was a criterion for enrolment Quality of study methodology into the study, i.e. patients without reference standard data (follow-up, histology, etc.) were In the assessment of study quality excluded from the study and not mentioned (Figure 2), approximately one-third (n = 10) of in the reporting of results. Studies in which the studies29–31,35,43,45–48,50 were considered to exclusions for incomplete follow-up were explicit, have investigated a representative spectrum of and were therefore considered to be at risk of patients. In these studies, patients were selected partial verification bias n( = 8),27,28,30,34,36,44,47,48 may in a consecutive series or all patients examined therefore not have been of poorer study quality but within a certain period of time were selected may have simply been more transparent in their for investigation. In other studies, the method reporting of study methods. for patient selection was unclear or it appeared that the patients being investigated were not The results of PET or PET/CT may have had some representative of those that might typically present influence on the mode or intensity of subsequent for diagnosis of BC recurrence. patient follow-up (differential verification bias).

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TABLE 3 Included studies with diagnostic accuracy data

Index test Comparator Data

PET PET/CT CIT MRI Patient Lesion Abe 200524  Bone scintigraphy   Aide 200725  –  Bender 199726  –   Dirisamer 201027   CT  Fueger 200528   –  Gallowitsch 200329  CW   Goerres 200330  –   Guillemard 200631  –  Hathaway 199932  –   Haug 200733   CT  Hubner 200034  CT  Kamel 200335  –   Kim 200136  –   Lin 200237  –   Liu 200238  –  Lonneux 200039  –  Moon 199840  –   Ohta 200141  Bone scintigraphy  Pecking 200442  –  Radan 200643  CT   Raileanu 200444  Bone scintigraphy  Santiago 200645  –  Schmidt 200846  –   Suarez 200247  –  Veit-Haibach 200748   CT  Vranjesevic 200249  CW  Wolfort 200650  CW  Yang 200251  Bone scintigraphy 

In most studies this was thought to have been Blinding of the interpretation of PET or PET/ likely or uncertain. In one study,50 follow-up was CT to the results of the reference standard histology in all patients and therefore differential (index test blinding) clearly took place in nine verification was not considered to have been a studies.24,25,27,28,30,35,40,48,49 In the remaining studies source of bias in this study. the presence of blinding was unclear. The interpretation of PET or PET/CT will be naturally Incorporation bias, the inclusion of index test blinded in prospective studies as the reference results as part of the reference standard, may standard diagnosis is assigned after PET or PET/ have played some role in most studies. Findings CT during follow-up. In retrospective studies, if from PET or PET/CT may have influenced final results are those of PET or PET/CT reassessed at diagnosis. However, the relative influence of PET a later date (after the reference standard), without or PET/CT findings compared with subsequent blinding to final patient diagnosis, there is risk follow-up examinations may have been small and of bias. In the remaining studies, it was often limited the size of this bias. unclear whether (1) studies were prospective or 13

months)

months, mean

months,

months months, 1–42 12 months, mean 24

months) months with MRI CT, or PET months) 6 months)

12 months for years 3–5) Histology patients) (15 and clinical 15 (mean follow-up 5–31 Reference standardReference Histology follow-up clinical or Pathology (23%) and imaging follow- up (mean 17.2 Clinical follow up (exam every 3 months for 3 years, then every 6 up Histology follow clinical or > Biopsy or clinical follow-up (> Histology follow-up clinical or examinations and imaging (6 follow-up clinical Histology and/or (8–54 Histology clinical/radiological and follow-up > Confirmationby one or more imaging follow-up techniques on 6 over follow-up Clinical (> follow-up Clinical 21 Whole Whole body Location of test Whole body Whole body Whole body Bone Bone Whole body Whole body Whole body Bone Bone Whole body 43 Prevalence Prevalence (%) 66 54 70 Lesion basis 81 69 32 55 76 17 35 32), clinicaln = 32), n = 29) 10) and/orn = 10) equivocal 16) or suspiciousn = 16) conventional imaging n = 9) 15) or suspiciousn = 15) conventional imaging ( n = 48) increasedn = 42), tumour markers ( Reason for investigation with PET or PET/CT Suspected BC recurrence (reason for referral not specified) Suspected recurrence based on elevated serum tumour markers Suspicion of BC recurrence due to increased tumour markers ( Clinical suspicion (symptoms) of recurrence or systemic disease BC patients with suspicion of bone metastases BC patients with suspicion of bone metastases Restaging due to elevated tumour markers ( deterioration ( ( Suspected recurrence/metastases based on suspicious or markers tumour in increase or CIT inconclusive Suspicion of recurrence on basis of increased tumour markers CIT) previous (negative BC patients with suspicion of bone metastases BC patients with suspicion of bone metastases Examined for residual or recurrent disease for: no reason ( CIT ( b f d e c a Data n 44 52 62 34 64/44 51 37 20 44 61 18 127 n 44 52 62 34 57 51 46 20 44 61 23 48

Age (years) (range) 56 (35–81) 61 (40–84) 58 (range NR) 51 (28–73) 59 49 (29–79) 60 (32–79) 53 (range NR) 56 (36–80) 54 (32–91) NR 38–67 27 44 34 43 33 41 51 24 Characteristics of study populations for studies comparing PET and/or PET/CT with other imaging tests

50 29 49 48 Vranjesevic 2002 CIT comparator CIT 2005 Abe Ohta 2001 Raileanu 2004 2002 Yang Study and and Study date Haug 2007 Wolfort 2006 Dirisamer 2010 Dirisamer Gallowitsch 2003 2000Hubner Radan 2006 Veit-Haibach 2007

14 TABLE 4 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50 months)

= 4) or n months 12 months) Reference standardReference clinical or Cytology/histology (17) follow-up of > (15) Surgical confirmation ( PET studies (2–24 follow-up follow radiological and Clinical up > 6 months (mean months, 14 6–37 Histology (95%) or clinical follow-up Location of test Local Local Whole body Whole Whole body Prevalence Prevalence (%) 44 86 NR 19 n = 9), 14), newlyn = 14), elevated n = 10) Reason for investigation with PET or PET/CT contralateral or Suspected BC recurrence local/regional or signs clinical on based local-regional of Suspicion recurrence symptoms examination ( clinical to due recurrence of Suspicion findings on conventional imaging ( tumour markers ( Suspected recurrent or metastatic disease f g a h Data n 75 32 7 263 n 75 49 10 33 Age (years) (range) 46 (32–74) 57 (32–76) 58.4 (45–71) 55 (24–79) 32 30 46 26 Data that were used for analysis. Sixty-four PET scans patients, in 57 only 44 had CT. Only of 46 37 patients had comparative CT data available. In this study data for restaging were presented on a patient basis and could therefore be interpreted in terms of diagnosticcorrectly accuracy: down-staged correctly up-staged patients TN, patients under-staged TP, patients FN, over-staged patients This interpretation FP. patient gave a conservative diagnosis may be achieved assessment without of necessarily test accuracy correct as correct patient staging. Only of 23 patients 18 had results for conventional PET, imaging and the reference standard. Only of 32 49 patients had follow-up data and PET and MRI results. Excluding patients being investigated for initial staging in the setting of primary diagnosis. Lesions. Hathaway 1999 Hathaway NR, not reported. a b c d e f g h MRI comparator Bender 1997 Schmidt 2008 Study and and Study date Goerres 2003 Goerres 15

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Results months months months with months) months or 12 6 months months 12 12 Conventional imaging and imaging and Conventional pathology over 2 follow-up at 6 and 12 Histology or imaging and clinical follow up over > Biopsy, other imaging and follow-up clinical Histology follow-up and 6 months)(> Histology clinical/ and for radiological follow-up > 6 months Histology and/or biopsy or follow-up > Histiology imaging clinical or follow-up > Histology, other imaging or clinical follow-up for months> 12 Follow-up (12–24 Follow-up for > imaging conventional Reference standardReference Histopathology imaging/ or for follow-up clinical 6–30 months Follow-up imaging studies for > 6 months Whole Whole body Whole Whole body Whole body Whole body Whole body Local Whole body Whole body Whole body Whole body Location of test Whole body Whole Whole body 92 85 74 80 57 57 63 11 93 68 Prevalence Prevalence (%) 52 51 n = 31) 10), massn = 10), months before n = 13) 63) orn = 63) elevated tumour markers n = 5) n = 33) n = 25) 10) andn = 10) increased tumour markers ( n = 34) and clinical symptoms ( or staging/restagingn = 15) ( n = 35) and abnormal CIT ( Suspected BC recurrence based on elevated tumour markers malignancies) of evidence any (without Suspected recurrence based on increased tumour marker CA 15–3. No abnormality at conventional imaging 3 Restaging due to elevated tumour markers, symptoms or findings imaging conventional equivocal/suspicious Suspicion of recurrence based on increased tumour markers. imaging results Asymptomatic conventional with inconclusive Clinical suspicion of recurrence or systemic disease based on imaging studies examination or physical Suspected local recurrence or systemic disease Suspected recurrence based on increased tumour marker levels, all patients negative for conventional imaging Suspicion of recurrence based on elevated tumour markers examinations) clinical negative and (asymptomatic Clinical suspicion of recurrence based on symptoms ( Suspicion of recurrence based on increased tumour markers ( ( recurrence/metastases suspicion of Suspicion clinical to due imaging ( conventional equivocal ( lesions ( Reason for investigation with PET or PET/CT examination physical on based recurrence of suspicion Clinical ( b a 291 35 58 14 46/57 27 36 30 38 57 39 133 Data n 291 35 58 14 60 27 36 30 38 57 39 133 n

51 (31–79) 61 (42–84) 53 (29–80) 62 (49–76) 55 (30–79) 46 (28–62) 48 (35–68) (mean NR) (38–65) 58 (35–80) 55 (30–80) 57 (36–78) 55 (34–82) Age (years) (range)

45 42 28 47 35 40 25 36 Characteristics of study populations for studies not comparing PET and/or PET/CT with other imaging tests 37 38

39 31 Forty-six examined for loco-regional recurrence, examined 57 for metastasis. Santiago 2006Santiago Liu 2002 Suarez 2002 Study and and Study date Fueger 2005 Fueger Guillemard 2006 Kamel 2003 Lin 2002 1998 Moon CA, cancer antigen; NR, not reported. a Data that were used for analysis. b Pecking 2004 Aide 2007 Kim 2001 Lonneux Lonneux 2000

16 TABLE 5 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

retrospective, (2) results were for scans assessed at imaging results).26,29,36–39,43,45,50,51 In 10 studies the time of investigation or those of reassessment assessors were blinded to previous relevant at a later date, and (3) whether blinding was used clinical information.24,25,27,30,33,34,41,46,48,49 In these if scans were being reassessed. There was therefore studies, the assessment of incremental diagnostic some uncertainty around this item of quality. accuracy of PET or PET/CT in addition to standard practice was likely to be underestimated. In In 10 studies, PET or PET/CT were interpreted eight studies,28,31,32,35,40,42,44,47 it was unclear what with knowledge of relevant clinical information information was available to assessors. (knowledge of previous patient history and a Representative spectrum? Representative standard? Acceptable reference tests? between Acceptable delay avoided? Partial verification avoided? verification Differential Incorporation avoided? blinded? Index test results clinical information? Relevant of blood glucose? Measurement correction? Attenuation time >60 minutes? Uptake Abe 200524 ? + + + ? – + – + + + Aide 200725 ? – + – – + – + + + Bender 199726 ? + ? + ? ? ? + – + – Dirisamer 201029 + + + – ? ? + – – ? – Fueger 200528 + ? + – ? ? + ? – + + Gallowitsch 200329 + + – + – – ? + + + + Goerres 200330 + + + – – – + – – + – Guillemard 200631 + + + ? – ? ? + + + Hathaway 199932 ? – + + – – ? ? + + – Haug 200733 ? + + + ? – ? – + + + Hubner 200034 ? ? ? – ? ? ? – – + ? Kamel 200335 + + + ? – + ? – + – Kim 200136 ? + – ? – ? + – + + Lin 200237 ? + + ? – ? + – – ? Liu 200238 ? + + ? – ? + – + – Lonneux 200039 ? + + ? – ? + – – + Moon 199840 ? + + ? – + ? – – – Ohta 200141 ? – + + ? – ? – – ? – Pecking 200442 – ? + ? – ? ? – + + Radan 200643 + + – + ? – ? + + + + Raileanu 200444 – + + – ? – ? ? – ? + Santiago 200645 + + + ? – ? + – ? – Schmidt 200846 + + + + ? – ? – – + + Suarez 200247 + + – ? – ? ? + + + Veit-Haibach 200748 + + + – ? – + – + ? – Vranjesevic 200249 ? + – ? ? – + – – – – Wolfort 200650 + + – + + – ? + ? ? ? Yang 200251 ? + + + ? – ? + – ? –

FIGURE 2 Quality assessment of all included studies. (a) Quality item was applied to studies where diagnostic accuracy of tests was compared. 17

Characteristics and quality of Test accuracy results PET or PET/CT technology The characteristics and quality determinants of For each of the objectives, results for patient and the PET and PET/CT technologies used are given then lesion data are presented. in Appendix 2. Quality findings for three specific factors, identified as particularly important aspects PET compared with CITs of technical quality, are shown in Figure 2. PET and PET/CT machines were considered standard in all Patient data of the included studies, but attenuation correction Ten studies investigated the diagnostic accuracy of was only used in 19 studies. Attenuation correction conventional imaging techniques compared with was not used or not reported in the remaining nine PET on a patient basis.24,27,29,33,34,41,44,48–50 Figure 3 studies.27,37,40,41,44,45,49–51 Interpretation of scans was provides individual study data, Table 6 gives pooled predominantly by visual inspection. Standardised summary estimates, Figure 4 gives quality scores uptake values were used for sole classification in and Figure 5 displays the SROC plane for studies one study42 and, in seven studies, both visual and directly comparing PET with CITs. In these quantitative methods were used.27,32,34,36,46–48 In studies, PET had significantly higher sensitivity almost all studies it was reported that patients [89%, 95% confidence interval (CI) 83% to 93% vs were asked to fast at the time of PET, but in only 79%, 95% CI 72% to 85%, relative sensitivity 1.12, nine studies blood glucose levels were measured 95% CI 1.04 to 1.21, p = 0.005] and significantly before the test and used as criteria for entry higher specificity (93%, 95% CI 83% to 97% vs 83%, into the study.24,25,29,31–33,43,47,48 The dose of FDG 95% CI 67% to 92%, relative specificity 1.12, 95% ranged from 101 MBq to 740 MBq. In 18 studies CI 1.01 to 1.24, p = 0.036) (Table 6). The relative dose appeared to have been adjusted on the basis accuracy of PET did not appear to vary according of body weight, and in nine studies dose was to the type of CIT (bone scintigraphy, CW, CT) constant.27,29,30,33,37–39,48,51 Dose was not reported in with which it was compared (p = 0.50). one study.50 Visual inspection of the three technical aspects of PET and PET/CT quality revealed no For all studies of PET (n = 25) or CIT (n = 11) relationship between these aspects of quality and (indirect comparison), PET had significantly the diagnostic accuracy of PET or PET/CT. higher sensitivity (91%, 95% CI 87% to 93% vs 81%, 95% CI 73% to 87%, relative sensitivity 1.12, 95%

Sensitivity Specificity Study n TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Abe 200524 44 PET 14 1 0 29 1.00 (0.77 to 1.00) 0.97 (0.83 to 1.00) BS 11 0 3 30 0.79 (0.49 to 0.95) 1.00 (0.88 to 1.00) Ohta 200141 51 PET 7 1 2 42 0.78 (0.40 to 0.97) 0.98 (0.88 to 1.00) BS 7 8 2 34 0.78 (0.40 to 0.97) 0.81 (0.66 to 0.91) Raileanu 200444 20 PET 6 0 1 13 0.86 (0.42 to 1.00) 1.00 (0.75 to 1.00) BS 7 3 0 10 1.00 (0.59 to 1.00) 0.77 (0.46 to 0.95) Dirisamer 201027 52 PET 34 0 8 10 0.81 (0.66 to 0.91) 1.00 (0.69 to 1.00) CT 28 0 14 10 0.67 (0.50 to 0.80) 1.00 (0.69 to 1.00) Haug 200733 34 PET 23 1 3 7 0.88 (0.70 to 0.98) 0.88 (0.47 to 1.00) CT 24 2 2 6 0.92 (0.75 to 0.99) 0.75 (0.35 to 0.97) Hubner 200034 44 PET 36 6 6 16 0.86 (0.71 to 0.95) 0.73 (0.50 to 0.89) CT 22 6 9 7 0.71 (0.52 to 0.86) 0.54 (0.25 to 0.81) Veit-Haibach 200748 44 PET 17 6 2 19 0.89 (0.67 to 0.99) 0.76 (0.55 to 0.91) CT 17 6 2 19 0.89 (0.67 to 0.99) 0.76 (0.55 to 0.91) Gallowitsch 200323 62 PET 33 5 1 23 0.97 (0.85 to 1.00) 0.82 (0.63 to 0.94) CW 28 13 6 15 0.82 (0.65 to 0.93) 0.54 (0.34 to 0.72) Vranjesevic 200249 61 PET 39 3 3 16 0.93 (0.81 to 0.99) 0.84 (0.60 to 0.97) CW 33 6 9 13 0.79 (0.63 to 0.90) 0.68 (0.43 to 0.87) Wolfort 200650 23 PET 13 0 3 7 0.81 (0.54 to 0.96) 1.00 (0.59 to 1.00) CW 11 0 4 7 0.73 (0.45 to 0.92) 1.00 (0.59 to 1.00) 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

18 FIGURE 3 Patient data for the diagnostic accuracy of PET and CITs in comparative studies. BS, bone scintigraphy. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

TABLE 6 Patient data: direct and indirect comparisons of the sensitivity and specificity of PET compared with CITs

PET CIT Relative PET CIT Relative sensitivity % sensitivity % sensitivity specificity % specificity % specificity Comparison (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Direct PET vs 89 (83 to 93) 79 (72 to 85) 1.12 (1.04 to 93 (83 to 97) 83 (67 to 92) 1.12 (1.01 to CIT n = 10 n = 10 1.21) p = 0.005 1.24) p = 0.036 Indirect PET vs 91 (87 to 93) 81 (73 to 87) 1.12 (1.04 to 86 (79 to 91) 73 (59 to 83) 1.18 (1.03 to CIT n = 25 n = 11 1.21) p = 0.005 1.36) p = 0.017

CI 1.04 to 1.21, p = 0.005) and significantly higher significant differences in sensitivity (relative specificity (86%, 95% CI 79% to 91% vs 73%, 95% sensitivity 0.93, 95% CI 0.76 to 1.13, p = 0.447) or CI 59% to 83%, relative specificity 1.18, 95% CI specificity (relative specificity 1.29, 95% CI 0.57 1.03 to 1.36, p = 0.017) compared with CIT (Table 6 to 2.90, p = 0.540) for PET compared with CIT and Appendix 3, Figure 13). (Appendix 4, Figures 17 and 18). In the indirect comparison of PET studies presenting lesion data Sensitivity analysis (n = 7) with CIT studies presenting lesion data When the comparison between PET and CIT was (n = 3), there were no significant differences in conducted with only studies in which PET and sensitivity (relative sensitivity 0.98, 95% CI 0.90 to CIT (patient data) were done within a 1-month 1.07, p = 0.624) or specificity (relative specificity time period (n = 6),24,27,33,41,44,48 PET was no longer 2.57, 95% CI 0.41 to 16.07, p = 0.313) for PET significantly more sensitive than CIT (p = 0.4797) compared with CIT (Appendix 4, Table 9 and but the significant increase in specificity remained Figure 18). (p = 0.022) (Appendix 7, Table 11a and Figure 27). PET/CT compared with CITs Lesion data For lesion-based data, three studies directly Patient data compared the diagnostic accuracy of PET with Four studies compared the accuracy of PET/CT CIT. 24,29,51 For these studies, there were no with CIT on a patient basis27,33,43,48 and, in each Representative spectrum? Representative standard? Acceptable reference tests? between Acceptable delay avoided? Partial verification avoided? verification Differential Incorporation avoided? blinded? Index test results clinical information? Relevant of blood glucose? Measurement correction? Attenuation time >60 minutes? Uptake

Abe 200524 ? + + + ? – + – + + + Dirisamer 201027 + + + – ? ? + – – ? – Gallowitsch 200329 + + – + – – ? + + + + Haug 200733 ? + + + ? – ? – + + + Hubner 200034 ? ? ? – ? ? ? – – + ? Ohta 200141 ? – + + ? – ? – – ? – Raileanu 200444 – + + – ? – ? ? – ? + Veit-Haibach 200748 + + + – ? – + – + ? – Vranjesevic 200249 ? + – ? ? – + – – – – Wolfort 200650 + + – + + – ? + ? ? ?

FIGURE 4 Quality assessment for studies comparing PET with CITs. 19

1.0

0.9

0.8

0.7

0.6

0.5

Sensitivity 0.4

0.3

0.2

0.1

0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Specificity

FIGURE 5 Summary receiver operating characteristic plane for studies directly comparing the diagnostic performance of PET (□) and CITs (◊) for patients with suspected BC recurrence.

Sensitivity Specificity Study n TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Dirisamer 201027 52 PET/CT 40 0 2 10 0.95 (0.84 to 0.99) 1.00 (0.69 to 1.00) CT 28 0 14 10 0.67 (0.50 to 0.80) 1.00 (0.69 to 1.00) Haug 200733 34 PET/CT 24 1 1 8 0.96 (0.80 to 1.00) 0.89 (0.52 to 1.00) CT 24 2 2 6 0.92 (0.75 to 0.99) 0.75 (0.35 to 0.97) Radan 200643 37 PET/CT 17 4 3 13 0.85 (0.62 to 0.97) 0.76 (0.50 to 0.93) CT 14 9 6 8 0.70 (0.46 to 0.88) 0.47 (0.23 to 0.72) Veit-Haibach 200748 44 PET/CT 19 4 0 21 1.00 (0.82 to 1.00) 0.84 (0.64 to 0.95) CT 17 6 2 19 0.89 (0.67 to 0.99) 0.76 (0.55 to 0.91)

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

FIGURE 6 Patient data for the diagnostic accuracy of PET/CT and CT in comparative studies.

case, the conventional imaging technique was CT. in specificity was not significant (89%, 95% CI Figure 6 provides individual study data, Table 7 76% to 96% vs 79%, 95% CI 65% to 88%, relative gives pooled summary estimates, Figure 7 gives specificity 1.13, 95% CI 0.99 to 1.29, p = 0.063) quality scores and Figure 8 displays the SROC (Table 7). plane for studies directly comparing PET/CT with CT. In these studies, in comparison with Sensitivity analysis CT, PET/CT had significantly higher sensitivity One study in which CT was not conducted at (95%, 95% CI 88% to 98% vs 80%, 95% CI 65% to the same time as PET/CT was removed in the 90%, relative sensitivity 1.19, 95% CI 1.03 to 1.37, sensitivity analysis.43 Despite the continued pattern n = 4, p = 0.015) but the increase in specificity of advantage of PET/CT over CT in the remaining was not significant (89%, 95% CI 69% to 97% vs studies (n = 3), PET/CT was no longer significantly 77%, 95% CI 50% to 92%, relative specificity 1.15, more sensitive (p = 0.063) or specific (p = 0.367) 95% CI 0.95 to 1.41, p = 0.157) (Table 7). For all compared with CIT (Appendix 7, Table 11b and studies of patient-basis PET/CT (n = 5) and CIT Figure 28). (n = 11) in indirect comparisons, the sensitivity was significantly higher (95%, 95% CI 89% to 97% vs Lesion data 78%, 95% CI 72% to 84%, relative sensitivity 1.21, No studies comparing the accuracy of PET/CT with 95% CI 1.11 to 1.31, p < 0.0001) but the increase CIT presented lesion-based data. 20 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

TABLE 7 Patient data: direct comparison of the sensitivity and specificity of PET/CT compared with CT and indirect comparison of PET/CT compared with a range of CITs

PET/CT CIT Relative PET/CT CIT Relative sensitivity% sensitivity % sensitivity specificity % specificity % specificity Comparison (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Direct PET/CT 95 (88 to 98), 80 (65 to 90), 1.19 (1.03 89 (69 to 97) 77 (50 to 92) 1.15 (0.95 to vs CT n = 4 n = 4 to 1.37) 1.41) p = 0.157 p = 0.015 Indirect PET/CT 95 (89 to 97), 78 (72 to 84), 1.21 (1.11 89 (76 to 96) 79 (65 to 88) 1.13 (0.99 to vs CIT n = 5 n = 11 to1.31) 1.29) p = 0.063 p < 0.0001 Representative spectrum? Representative standard? Acceptable reference tests? between Acceptable delay avoided? Partial verification avoided? verification Differential Incorporation avoided? blinded? Index test results clinical information? Relevant of blood glucose? Measurement correction? Attenuation time >60 minutes? Uptake

Dirisamer 201027 + + + – ? ? + – – ? – Haug 200733 ? + + + ? – ? – + + + Radan 200643 + + – + ? – ? + + + + Veit-Haibach 200748 + + + – ? – + – + ? –

FIGURE 7 Quality assessment of studies comparing PET/CT and CIT (CT).

1.0

0.9

0.8

0.7

0.6

0.5

Sensitivity 0.4

0.3

0.2

0.1

0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Specificity

FIGURE 8 Summary receiver operating characteristic curve for studies directly comparing the diagnostic performance of PET/CT (□) and CT (◊) for patients with suspected BC recurrence.

PET and PET/CT compared PET/CT compared with PET with MRI Patient data Patient data Four studies compared the accuracy of PET Three studies investigated the diagnostic and PET/CT on a patient basis.27,28,33,48 Figure 10 accuracy of PET and MRI on a patient basis, provides individual study data, Table 8 gives but the MRI technologies used in these studies pooled summary estimates, Figure 11 shows quality were quite distinct. In one study32 auxiliary and scores and Figure 12 displays the SROC planes for supraclavicular MRI was used to diagnose local studies directly comparing PET with PET/CT. In recurrence. In the second study26 whole-body MRI these studies, PET/CT had significantly higher and/or CT was used to detect local recurrence and sensitivity (96%, 95% CI 90% to 98% vs 85%, 95% distant metastases, and in the third study30 breast CI 77% to 91%, relative sensitivity 1.11, 95% CI 1.03 MRI was used for local recurrence. Results for to 1.18, p = 0.006) but the increase in specificity these studies are shown in Figure 9. There were no was not significant (89%, 95% CI 74% to 96% vs significant differences in sensitivity or specificity 82%, 95% CI 64% to 92%, relative specificity 1.08, between PET and MRI in any of these studies and, 95% CI 0.94 to 1.20, p = 0.267) compared with because of the differences in the MRI technologies, PET (Table 8 and Figure 12). For all patient-based results from the studies were not combined. studies of PET/CT (n = 5) and PET (n = 25), in indirect comparisons PET/CT had significantly Lesion data higher sensitivity (96%, 95% CI 91% to 98% vs One lesion-based study compared PET/CT with 90%, 95% CI 86% to 93%, relative sensitivity 1.06, MRI46 and there was no significant difference in 95% CI 1.01 to 1.10, p = 0.009) but the increase sensitivity and specificity for PET/CT compared in specificity was not significant (89%, 95% CI with MRI (Appendix 4, Figure 19). 77% to 95%, vs 86%, 95% CI 79% to 91%, relative specificity 1.04, 95% CI 0.95 to 1.13, p = 0.377) compared with PET (Table 8 and Appendix 3, Figure 15).

Sensitivity Specificity Study n TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Bender 199726 64 PET 10 2 4 48 0.71 (0.42 to 0.92) 0.96 (0.86 to 1.00) 74 MRI 13 2 1 58 0.93 (0.66 to 1.00) 0.97 (0.88 to 1.00) Goerres 200330 32 PET 11 1 3 17 0.79 (0.49 to 0.95) 0.94 (0.73 to 1.00) MRI 14 5 0 13 1.00 (0.77 to 1.00) 0.72 (0.47 to 0.90) Hathaway 199932 7 PET 6 0 0 1 1.00 (0.54 to 1.00) 1.00 (0.03 to 1.00) MRI 6 0 0 1 1.00 (0.54 to 1.00) 1.00 (0.03 to 1.00) 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

FIGURE 9 Patient data for the diagnostic accuracy of PET and MRI in comparative studies. No studies compared the diagnostic accuracy of PET/CT with MRI on a patient basis.

Sensitivity Specificity Study n TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Dirisamer 201027 52 PET/CT 40 0 2 10 0.95 (0.84 to 0.99) 1.00 (0.69 to 1.00) PET 34 0 8 10 0.81 (0.66 to 0.91) 1.00 (0.69 to 1.00) Fueger 200528 58 PET/CT 31 4 2 21 0.94 (0.80 to 0.99) 0.84 (0.64 to 0.95) PET 28 7 5 18 0.85 (0.68 to 0.95) 0.72 (0.51 to 0.88) Haug 200733 34 PET/CT 24 1 1 8 0.96 (0.80 to 1.00) 0.89 (0.52 to 1.00) PET 23 1 3 7 0.88 (0.70 to 0.98) 0.88 (0.47 to 1.00) Veit-Haibach 200748 44 PET/CT 19 4 0 21 1.00 (0.82 to 1.00) 0.84 (0.64 to 0.95) PET 17 6 2 19 0.89 (0.67 to 0.99) 0.76 (0.55 to 0.91)

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

22 FIGURE 10 Patient data for the diagnostic accuracy of PET and PET/CT in comparative studies. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

TABLE 8 Patient data: direct and indirect comparisons of the relative sensitivity and specificity of PET/CT compared with PET

PET/CT PET Relative PET/CT PET Relative sensitivity % sensitivity % sensitivity specificity % specificity % specificity Comparison (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Direct PET/ 96 (90 to 98), 85 (77 to 91), 1.11 (1.03 to 89 (74 to 96) 82 (64 to 92) 1.08 (0.94 to CT vs PET n = 4 n = 4 1.18) p = 0.006 1.20) p = 0.267 Indirect PET/ 96 (91 to 98), 90 (86 to 93), 1.06 (1.01 to 89 (77 to 95) 86 (79 to 91) 1.04 (0.95 to CT vs PET n = 5 n = 25 1.10) p = 0.009 1.13) p = 0.377

Representative spectrum? Representative standard? Acceptable reference tests? between Acceptable delay avoided? Partial verification avoided? verification Differential Incorporation avoided? blinded? Index test results clinical information? Relevant of blood glucose? Measurement correction? Attenuation time >60 minutes? Uptake

Dirisamer 201027 + + + – ? ? + – – ? – Fueger 200528 + ? + – ? ? + ? – + + Haug 200733 ? + + + ? – ? – + + + Veit-Haibach 200748 + + + – ? – + – + ? –

FIGURE 11 Quality assessment of studies comparing the diagnostic accuracy of PET and PET/CT.

1.0

0.9

0.8

0.7

0.6

0.5

Sensitivity 0.4

0.3

0.2

0.1

0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Specificity

FIGURE 12 Summary receiver operating characteristic plane for studies directly comparing the diagnostic performance of PET (□) and PET/CT (◊) for patients with suspected BC recurrence.

Sensitivity analysis influence test accuracy. Subgroup analysis was not In all studies in which PET/CT was compared with conducted for PET/CT as these data were limited. PET, tests were undertaken simultaneously and no studies were therefore removed in the sensitivity PET and location of disease analysis. Table 12 and Figure 29 in Appendix 8 show the Lesion data relative accuracy of PET in different locations of No studies comparing the accuracy of PET and the body with lesion-based data (limited location- PET/CT presented lesion-based data. specific patient-based data were available). There were no significant differences in the sensitivity Diagnostic accuracy of PET and or specificity of PET for the detection of local PET/CT recurrence, distant metastases or disease in lymph nodes. Patient data Patient data were presented for PET in 25 studies PET and previous imaging and for PET/CT in five studies. Sensitivity and results specificity for PET were 91% (95% CI 86% to 94%) and 86% (95% CI 79% to 91%) respectively and Comparisons were made between studies of PET for PET/CT were 96% (95% CI 89% to 99%) and where all patients had previously had positive or 89% (95% CI 75% to 95%) respectively. Study data equivocal results on other imaging modalities used for the calculation of overall sensitivity and and studies in which previous imaging had been specificity and figures for test accuracy findings are negative in all patients (Appendix 8, Table 13a and given in Appendix 5 (Figures 20–23). Figure 30). Sensitivity was not significantly different in studies with negative compared with positive/ Lesion data equivocal previous diagnostic imaging (relative On a lesion basis, mean sensitivity and specificity sensitivity 0.99, 95% CI 0.899 to 1.093, p = 0.859) for PET (n = 7 studies) were 89% (95% CI 78% to but specificity was significantly lower (relative 95%) and 91% (95% CI 83% to 96%). Two studies specificity 0.734, 95% CI 0.560 to 0.960, p = 0.024). assessed the accuracy of PET/CT on a lesion basis and pooled sensitivity and specificity were 96% PET and disease status at the (95% CI 80% to 99%) and 83% (95% CI 61% to time of investigation 94%) respectively (no model could be fitted to the data). Study data used for the calculation of In 14 studies,25,27,28,31–35,38–40,42,47,48 PET was overall sensitivity and specificity and figures for exclusively used for the detection of recurrent BC test accuracy findings are given in Appendix 5 in patients who had been cleared of initial disease. (Figures 24–26). In the remaining 11 studies,24,26,29,30,36,37,41,44,45,49,50 PET was used to investigate further metastases in Changes in patient management patients with known BC or, in some studies, the disease status of the patient group was a mixture Changes in patient management in individual of known and unknown BC diagnosis. There was studies are given in Appendix 6. Overall, the no difference in sensitivity (relative sensitivity estimated numbers of patients with changes in 1.004, 95% CI 0.924 to 1.092, p = 0.920) but management in studies ranged from 11% to 74% specificity was significantly lower for studies in (median 27%). In the three studies where only which patients were cleared of initial disease at changes in management directly owing to PET the time of investigation compared with studies in or PET/CT were considered (patients were not patients with diagnosed BC or in mixed diagnosis correctly diagnosed by conventional imaging populations (relative specificity 0.844, 95% CI techniques),48,49,55 estimates tended to be lower 0.734 to 0.971, p = 0.018) (Appendix 8, Table 13b (11–25%). and Figure 31).

Variation in the diagnostic PET and assessors knowledge of accuracy of PET previous clinical findings Further investigation of the diagnostic accuracy of In nine studies,24,25,27,30,33,34,41,48,49 assessors of PET was conducted to investigate factors that may PET were blinded to information on previous clinical examination and imaging. In eight 24 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

studies26,29,36,37,38,39,45,50 assessors had access FP and FN PET results to previous clinical results, and in eight The numbers of FPs and FNs for PET and PET/ studies28,31,32,35,40,42,44,47 it was unclear whether CT are given for studies where data was available assessors had knowledge of previous findings. (Appendix 9, Tables 14 and 15). FPs fell largely There was no difference in sensitivity (relative into three categories: infections and inflammation sensitivity 0.962, 95% CI 0.886 to 1.043, p = 0.346) (41%), physiological muscle uptake (29%) and or specificity (relative specificity 1.045, 95% CI degenerative process/old fracture sites (10%), while 0.910 to 1.201, p = 0.533) between studies where the remaining 20% were assigned to other artifacts assessors did not have information on previous of measurement. FNs were most commonly lesions findings compared with studies where assessors in the lymph nodes or bone. had information or where access to previous information was unclear (Appendix 8, Table 13c).

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Chapter 5 Discussion

Principal findings PET and CIT was reduced and became non- significant (Appendix 7, Table 11a and Figure 27), PET compared with CITs although the difference in specificity remained. In the patient-based analysis, absolute estimates of sensitivity and specificity were around 10% There may also be uncertainty around the higher for PET compared with CIT and differences magnitude of advantage of PET over different were statistically significantly for both direct and types of existing diagnostic tests. Relative indirect comparisons (Table 6). Lesion-based results accuracy may vary depending on the location of were inconsistent with results for patient-based investigation and the accuracy of the particular data and no significant differences were found in comparative test conventionally used for diagnosis sensitivity or specificity for comparisons of PET in that location. Included comparator groups with CIT (Appendix 4, Table 9). Lesion data are classed as CIT fell into three categories: CW (a considered to be less reliable than patient data56 range of examination and imaging techniques), and may also relate more to the ability of tests to CT and bone scintigraphy. Further inspection stage, rather than diagnose, disease. There was a identified that, for the three studies investigating high degree of heterogeneity between comparative the diagnosis of bone metastases,24,41,44 a less studies presenting lesion data (Appendix 4, consistent pattern of effect was observed, with Figure 16) and, for the study in which PET had very variable advantage in sensitivity and specificity poor lesion-based sensitivity (56%),29 patient-based over bone scintigraphy. A recent systematic review data indicated a typical to high level of sensitivity compared the diagnostic accuracy of PET with (97%). Lesion-based data were not used for bone scintigraphy.57 In that review, for patient- primary interpretation, not only owing to the small based data, PET had similar sensitivity to bone sample size and seemingly erratic nature of the scintigraphy (81%, 95% CI 70% to 89% and 78%, data but also because of the wide recognition that 95% CI 67% to 68%, respectively) and higher patient-based data are a more true representation specificity but not significantly so (93%, 95% of the accuracy of patient diagnosis. From patient- CI 84% to 97% and 79%, 95% CI 40% to 95% based data, it appears that PET may give improved respectively). However, in formal statistical testing, diagnostic accuracy compared with CIT for the there was no difference in the relative accuracy diagnosis of BC recurrence, but there may be some of PET when compared with CW, CT and bone constraints and uncertainties related to this. scintigraphy (p = 0.50), suggesting that PET may have similar benefit when used in different In many of the included studies, sources of bias contexts. may bring some uncertainty around the apparent advantage of PET over CIT. In many of the studies The absence of comparisons of PET with individual comparing PET and CIT, it was unclear whether conventional diagnostic tests may be a limitation the patients selected were representative of those of this review. However, to some extent this may that might normally be examined in this context be counteracted by the benefit of making some (Figure 4). Inclusion criteria were often not stated estimation of the general advantage of adding and it was unclear whether consecutive patients PET to standard practice. The decision to combine were enrolled or whether investigators selected studies of different conventional tests was made not particular individuals to take part in the study. only because of the limited number of available Another aspect of quality identified as potentially studies for each individual test but also so that important was the time delay between comparator the review might be more applicable to current tests and PET. Differences observed in some practice. In practice it may be difficult to make studies may be due partly to PET being conducted distinctions in the use of PET for specific case at a later time point, when disease was likely to presentations and there may be value in assessing be further developed and more detectable. In the whether there is likely to be a general advantage sensitivity analysis including only studies in which for its use for patients presenting with suspected PET and CIT were conducted within a 1-month recurrence. time period, the difference in sensitivity between 27

It is likely that any potential advantage of PET four studies but, in the other study, a separate should be considered in the context of its use CT was conducted earlier and the time interval in addition to, rather than instead of, existing before PET/CT in some of the patients was more strategies. The aim of this review was to assess than 1 month. After removal of this study in the comparative diagnostic accuracy in addition to sensitivity analysis, the increase in sensitivity standard practice but, in some of the included compared with CT became non-significant studies, assessors of PET were blinded to (Appendix 7, Table 11b and Figure 28). However, a the results of previous imaging tests. This is consistent pattern of effect was still observed for displayed in the quality assessment as ‘relevant the remaining studies. clinical information?’, i.e. were assessors blinded to previous clinical results? (Figure 4). In the The poor availability of studies comparing the subgroup analysis, the accuracy PET did not diagnostic accuracy of PET/CT with other imaging appear to be affected by whether assessors had tests may to some extent limit the interpretation knowledge of previous patient investigations of findings. In comparative studies of PET/CT, (Appendix 8, Table 13c). Also, although the the only CIT used was CT and there may be some specificity of PET was lower in studies where uncertainty around the relative advantage of PET/ previous imaging tests had shown negative CT over different individual CITs. In the indirect compared with positive/equivocal findings, the comparison, when PET/CT was compared with level of sensitivity was similar (Appendix 8, the range of conventional diagnostic tests (Table Table 13a) suggesting that PET may be useful for 7 and Appendix 3, Figure 14), sensitivity was 20% disease diagnosis where previous imaging tests higher for PET/CT than for CIT (p < 0.0001). have failed. However, despite some suggestion However, as this analysis was not based on direct that PET may be useful as a replacement comparison studies, the finding may be interpreted technology, uncertainty remains around its with caution, and uncertainty remains around the comparative advantage in every setting and this variation in benefit of PET/CT when compared does not warrant the recommendation of PET as a with different conventional tests. replacement to conventional imaging procedures. In three of the four studies, assessors of PET/ Overall, PET appears to give improved diagnostic CT were blind to CT results and previous clinical accuracy compared with CIT. However, there may findings Figure( 7) and it may be that, in situations be some uncertainty around these findings. There where the choice of CIT is CT, PET/CT can be is currently insufficient evidence for the use of PET used as a replacement test. However, the presence as a replacement for existing imaging technologies of uncertainty around the comparative advantage but, in addition to standard practice, it may give of PET/CT over other CITs is likely to make a improved diagnostic accuracy compared with conservative approach more appropriate. As for conventional imaging. PET, it may be prudent to consider PET/CT in addition to, rather than instead of, conventional PET/CT compared with CITs diagnostic tests.

Positron emission tomography/computed Despite the small number of available studies, tomography was compared with CT in four studies. the consistent improvement in test accuracy for PET/CT showed significantly improved sensitivity PET/CT compared with CT provides reasonable for both direct and indirect patient-based evidence for an advantage of PET/CT over CT. comparisons (absolute sensitivity was ~ 15% higher) PET/CT may give diagnostic advantage over other but the absolute increase in specificity (~ 10%) was CITs but currently there is no direct evidence of not statistically significant Table( 7). Differences the comparative advantage of PET/CT over other were consistency shown across all of the four imaging tests. studies (Figure 8), with increases in sensitivity and specificity in each case where it could be achieved PET and PET/CT compared (in one study specificity was 100% for both PET/CT with MRI and CT). In the current review only three studies compared In three of the four studies, patient samples PET and MRI on a patient basis and, as the types appeared to be a representative spectrum of those of MRI technology used were different, results that might be typical in clinical practice. CTs were of these studies could not be combined. There performed as part of the PET/CT in three of the were no significant differences in sensitivity or 28 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

specificity between PET and MRI in any of these Theodoros Arvanitis, University of Birmingham, studies and further research may be required 2009, personal communication). This review to assess their comparative diagnostic accuracy. supports the suggestion that PET technology has Only one study compared the diagnostic accuracy reached a consistent level and confirms previous of PET/CT with MRI and, for this study, data findings. No previous systematic review has were presented on a lesion basis. Sensitivity and attempted to meta-analyse the accuracy of PET/ specificity were similar for PET/CT and MRI and CT and the current review gives no indication as to further patient-based studies may be important to whether the diagnostic accuracy of this technology establish the comparative accuracy of PET/CT and has changed, or is likely to change, during its MRI. evolution.

PET/CT compared with PET Inspection of the individual results for PET studies (Appendix 5, Figure 20) shows heterogeneity in In this review, for all studies comparing the estimates of sensitivity and specificity (for some diagnostic accuracy of PET with PET/CT (n = 4), studies 95% CIs do not overlap). This was not PET/CT was consistently shown to have improved observed with studies of PET/CT (Appendix 5, sensitivity compared with PET (Figure 12). Figure 21) but the number of these studies was Differences in sensitivity were significant for both smaller. It appears likely that there are differences direct and indirect comparisons, but differences in in the patient groups, study methods or mode of specificity were not Table( 8). In these studies, PET/ investigation in studies of PET and this may bring CT was used for the diagnosis of local disease and uncertainty around the overall estimates for test metastases in different locations and the advantage accuracy in this context. of PET/CT over PET appears to be true when considered for the detection of disease over a range Changes in patient management of locations. and outcome In three of the four studies, patient samples Despite the reasonable data available to determine appeared to be representative of patients that the diagnostic accuracy of PET and PET/CT, might be typical in clinical practice. All studies their impact on patient management is uncertain. interpreted PET images obtained during the Individual studies assert that these technologies do course of conducting PET/CT and, as tests were lead to changes in management, but it is difficult conducted simultaneously, none needed to be to determine to what extent these changes would removed in the sensitivity analysis. have taken place with conventional diagnostic procedures and, more importantly, whether they Despite the limited number of PET/CT studies, resulted in changes in final patient outcome. there appears to be reasonable evidence that PET/ CT gives improved sensitivity compared with Some sense about impact on patient management PET over the whole body. If it is found to be more may be gained by considering the consequences cost-effective, PET/CT may be considered for use of FN and FP results, both of which appear to be instead of PET in this context. reduced when comparing PET with conventional imaging and PET/CT with PET. FN results Diagnostic accuracy of PET and generally lead to delayed treatment, which is PET/CT likely to be important where the condition is life threatening. In distantly recurring BC delaying In the current review, the sensitivity and specificity treatments with palliative intent will make a of PET are very similar to those obtained in considerable impact on quality of life over the short the most recently conducted systematic review19 to medium term. For systemic treatments aiming (sensitivity 91% compared with 90% and specificity to alter the course of metastatic disease, there 86% compared with 87%), suggesting that more are also likely to be modest gains in survival and recent studies, not included in the previous review, thus FN CITs will delay these treatments. Some have not influenced overall estimates of diagnostic patients will suffer a sufficient fall in performance accuracy. The criterion for inclusion in both of status by the time of diagnosis for there to be these reviews was that a dedicated PET machine fewer appropriate treatment options available. was to have been used but, since the development The consequences of avoidance of FPs, which also of these types of instruments, there have been appears to be achieved by the use of PET and PET/ no major changes in the technology of PET (Dr CT, are clearer. Avoiding unnecessary exposure 29

to costly and potentially harmful, occasionally applied in the specific case of local recurrence life-threatening, treatment such as chemotherapy and this may help to better predict the potential is clearly desirable and could be anticipated to benefits from the use of PET. Data for the use of bring about improvements in quality of life, if PET/CT for diagnosis in different locations were not survival. Avoiding the anxiety associated with limited, and location-specific analysis could not treatment and the fact that BC has recurred adds be conducted. However, it may be anticipated to this. This prediction of impact on the patient that similar findings would be shown and PET/ assumes that there are no further steps in the CT may have similar diagnostic accuracy for local diagnostic pathway beyond conventional imaging recurrence as for metastatic disease. with or without PET/CT. Biopsies of possible BC recurrences following CITs are sometimes PET had similar sensitivity in studies where performed. In these cases, FNs can result in patients had been negative on previous imaging significant unnecessary risk and morbidity to tests compared with studies where previous patients. Overall, there appears to be a clear findings were positive/equivocal but specificity potential value for a diagnostic technique that was significantly reduced (Appendix 8, Table 13a). reduces both the rate of FPs and FNs. Specificity was also significantly reduced for studies in which patients were cleared of BC at the Of primary interest is the impact of PET and time of investigation compared with other studies PET/CT on patient prognosis and survival. If (Appendix 8, Table 13b). Selective patient sampling detection of recurrence by PET or PET/CT gives by previous imaging testing in these studies may patients additional quality of life or extends have had some impact on apparent specificity. survival, these technologies may be important However, it is difficult to ascertain whether diagnostic tools. In order to directly assess the these observations are due to random statistical effects of PET or PET/CT on long-term outcomes, significance of if they may be confounded by other large-scale intervention studies may be required. potentially moderating factors. As numerous Owing to the intensive follow-up and the large factors are likely to be involved in determining sample sizes required, these types of studies are diagnostic accuracy of PET, it is difficult to identify expensive, and modelling work may be used to specific factors responsible for the heterogeneity provide information on whether these trials are observed. Also, as subgroup analysis was not worthwhile. The construction of models relating restricted to the group of comparative studies, diagnostic accuracy and features of disease it was not possible to examine whether these progression to long-term patient outcomes would observations would result in a comparative give information on the potential impact of PET difference in test accuracy between PET and CIT. and PET/CT on patient outcome. Where modelling findings suggest a potential benefit of PET or PET/ CT, this may support the implementation of large- Strengths and limitations of scale interventional studies to investigate long-term the review impacts. One strength of the current review was that it was Variation in the diagnostic likely to have included the majority of the relevant accuracy of PET literature. This review included 14 of the 18 studies included in the most recent previous systematic The variation in estimates of test accuracy for PET review.19 The current review was restricted to was investigated by conducting subgroup analysis studies performed in the secondary diagnostic on this group of studies, but no conclusive pattern setting and this led to the exclusion of the other emerged to explain the variability. There was four studies.58–61 The current report includes an no apparent difference in the accuracy of PET additional 14 studies, not covered by the previous in different locations of the body, although this review and, for the first time, reviews evidence for analysis was conducted using lesion-based data the diagnostic accuracy of PET/CT. (may be less reliable than patient-based data). The diagnosis of local disease may be considered A second strength of this work was the comparative more valuable than the diagnosis of disease in nature of the review. Estimations of individual lymph nodes or distant metastases as surgical values for diagnostic accuracy may give some treatment may more realistically be employed for information on the likely benefit of these local recurrence. Findings suggest that the overall technologies. However, comparative analysis allows estimates of diagnostic accuracy for PET can be proper investigation of the possible advantage 30 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

of adopting PET or PET/CT over conventional analysis of differences in the diagnostic accuracy diagnostic strategies. of PET or PET/CT in different settings or groups relative to conventional tests may be useful to A further strength of this review may be the use inform decision-making about specific contexts for of direct comparisons. The large spread of results their use. for test accuracy, particularly for PET, suggests that there are other important mediators of A limitation in the interpretation of this review test accuracy that influence results. In indirect may be the distinction of results for direct and comparisons, where results from different studies indirect comparisons. It should be noted that, are compared, the comparison of PET and PET/ particularly for PET/CT, studies included in CT with CIT may be affected by many factors the direct comparison analysis also largely associated with the populations, study methods constituted the studies included in the indirect and technologies used. In direct comparisons, comparison analysis. Because some of the study some of these moderating factors are avoided as data are used in both analyses, although indirect index and comparator tests are conducted in the comparisons may be taken to some extent to same populations and the same study methods are support comparative results, findings are not used. independent. Although they may be useful for corroborating findings, results for direct and Although direct comparisons are desirable and indirect comparisons should not be interpreted as can eliminate between-study variability associated independent outcomes. with indirect comparisons, methods currently recommended for meta-analysis of test accuracy A further limitation of indirect comparisons in studies do not exploit the paired nature of the the current review is the exclusion of conventional data when all patients receive each of the two tests imaging studies that were not compared with PET under evaluation as well as the reference standard. or PET/CT. Studies of CIT were only included in For such analyses to be possible, test accuracy this review if they contained a comparison with data from primary studies must be presented in PET or PET/CT, and it is unclear whether this a suitable format, i.e. joint classification of the could have had an impact on findings. In order to results of the tests, but this is rarely the case. Only make true independent comparisons, an additional six of the studies in this review presented data in systematic review of all CIT studies would be this format, one comparing PET with PET/CT28 necessary. However, owing to the large volume of two comparing PET with MRI,30,32 one comparing evidence relating to each conventional diagnostic PET with bone scintigraphy44 and two comparing strategy, the workload involved would be sizable. PET with CW.49,50 Methods that combine evidence from both direct and indirect comparisons, such A further limitation of this review is the small as the adjusted indirect comparison method and size of the majority of included studies. The network meta-analysis techniques for comparing average (median) size of studies was 45 (10–291) health-care interventions, make optimal use of all and only 456 and 167 patients constituted the relevant data but such methods are lacking for test analysis groups for PET and PET/CT versus CIT comparisons. Current methodology may result in respectively. Although sample sizes were adequate a more conservative estimate of relative differences for testing statistical significance, they may, to in test accuracy when analysis is restricted to direct some extent, limit the generalisability of these comparisons and this may be a limitation of this findings. review. The short duration over which this review was A limitation of this review was that subgroup conducted to some extent limited the number of analysis was conducted on the whole set of studies included studies. As some studies appeared to investigating PET (n = 25) and not on comparative have recorded the relevant information but not studies for PET (n = 10) and PET/CT (n = 4). This included it in publications, authors were contacted was necessary as the number of comparative to request raw data for inclusion in the review. One studies was limited. However, it is difficult to investigator provided the relevant data33 but, in interpret subgroup findings because within-test other cases, data were not retrieved and further analysis does not give information on the actual follow-up may have proved successful in obtaining diagnostic advantage in different settings and data and increasing the information available in patient populations. If more data were available, this review.

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Chapter 6 Conclusions

• For the detection of BC recurrence, in addition to assess the comparative advantage of PET/CT to conventional imaging techniques, PET over different CITs. may generally offer improved diagnostic • Further research may inform the use of PET/ accuracy compared with current standard CT as a replacement technology. In future practice. Uncertainty remains around its use research, reading of scans with assessors both as a replacement, rather than an add-on, to blinded and unblinded to previous results existing imaging technologies. would allow assessment of the comparative • PET/CT appears to show a clear advantage accuracy of PET/CT as a replacement over CT for the diagnosis of BC recurrence. compared with an add-on technology. This Although PET/CT may give an advantage may help to determine whether PET/CT may over other conventional imaging strategies, potentially be used as a replacement to tests its incremental value over other tests has yet currently used in clinical practice. to be assessed in studies directly. Concurrent • Further research may investigate the use with, rather than replacement of, other application of MRI of the whole body conventional tests may be appropriate. compared with PET/CT in this context. • PET/CT appears to show a clear advantage • Modelling work (to be published in another over PET and, if found to be more cost- report) may be used to examine the potential effective, it may be preferred to PET for use in impact of PET/CT on long-term patient this context. outcomes. This work may be used to inform • PET and PET/CT appear to have some impact the implementation of large-scale intervention on patient management but there is currently studies to examine the long-term impact of no evidence of the effects of their use on PET/CT. patient outcome. Recommendations for Implications for policy future research Positron emission tomography/computed Future research studies should ideally be large tomography has largely superseded PET in current and prospective, avoiding some sources of bias practice and the apparent advantage of PET/CT associated with retrospective studies. Studies over PET found in this review supports this move. should be comparative and, where possible, any On the basis of some of the uncertainties observed, comparator tests used should be conducted close in it may be premature to make recommendations time to PET or PET/CT. Patient populations should about changes in the precise diagnostic role of be clearly defined with regard to their clinical PET/CT in current practice. However, current presentation, e.g. only patients with suspected BC recommendations for its use following equivocal recurrence on the basis of previous conventional findings on conventional imaging techniques may imaging findings. be justified. It appears that PET/CT may be useful as an addition to current practice for the diagnosis • Further study of the diagnostic accuracy of of BC recurrence but this should be reassessed in PET/CT compared with specific CITs may help light of the analysis of its cost-effectiveness.

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Acknowledgements

e would like to thank Professor Pat Price analysis and reviewed the report. Lucy Pennant Wand Dr Peter Clark for providing clinical conducted the data extraction. Clare Davenport comments and guidance on this report. contributed to the interpretation of findings and reviewed the report. Anne Fry-Smith and Anne Eisinga devised the search strategy and Anne Fry- Contribution of authors Smith carried out the searches. Lazaros Andronis reviewed the protocol and the report. Theo Mary Pennant contributed to the development of Arvanitis gave technical guidance on imaging the protocol, conducted abstract and full-paper technologies and reviewed the report. Jon Deeks screening, data extraction and quality assessment, gave guidance for statistical analysis and reviewed contributed to the interpretation of findings and the report. Chris Hyde developed the protocol, was responsible for writing the report. Yemisi conducted quality assessment, contributed to the Takwoingi was responsible for the statistical interpretation of findings and reviewed the report.

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28. Fueger BJ, Weber WA, Quon A, Crawford TL, 38. Liu CS, Shen YY, Lin CC, Yen RF, Kao CH, len-Auerbach MS, Halpern BS, et al. Performance Liu CS, et al. Clinical impact of [(18)F]FDG-PET of 2-deoxy-2-[F-18]fluoro-D-glucose positron in patients with suspected recurrent breast cancer emission tomography and integrated PET/CT in based on asymptomatically elevated tumor marker restaged breast cancer patients. Mol Imaging Biol serum levels: a preliminary report. Jpn J Clin Oncol 2005;7(5):369–76. 2002;32(7):244–7.

29. Gallowitsch HJ, Kresnik E, Gasser J, Kumnig G, 39. Lonneux M, Borbath I, I, Berliere M, Kirkove C, Igerc I, Mikosch P, et al. F-18 fluorodeoxyglucose Pauwels S. The place of whole-body pet fdg for the positron-emission tomography in the diagnosis diagnosis of distant recurrence of breast cancer. of tumor recurrence and metastases in the Clin Positron Imaging 2000;3(2):45–9. follow-up of patients with breast carcinoma: a comparison to conventional imaging. Invest Radiol 40. Moon DH, Maddahi J, Silverman DH, Glaspy JA, 2003;38(5):250–6. Phelps ME, Hoh CK, et al. Accuracy of whole- body fluorine-18-FDG PET for the detection of 30. Goerres GW, Michel SCA, Fehr MK, Kaim AH, recurrent or metastatic breast carcinoma. J Nucl Steinert HC, Seifert B, et al. Follow-up of women Med 1998;39(3):431–5. with breast cancer: Comparison between MRI and FDG PET. Eur Radiol 2003; 13(7):1635–44. 41. Ohta M, Tokuda Y, Suzuki Y, Kubota M, Makuuchi H, Tajima T, et al. Whole body PET for 31. Guillemard S, Eberle Pouzeratte MC, Lamy P-J, the evaluation of bony metastases in patients with Romieu G, Rossi M, Artus JC. 18FDG PET/CT and breast cancer: comparison with 99Tcm-MDP bone CA 15–3 in the early diagnosis of recurrent breast scintigraphy. Nucl Medi Commun 2001;22(8):875–9. cancer. [French]. Méd Nucl 2006;30(4):209–16. 42. Pecking AP, Corone-Mechelany C, Alberini JL, 32. Hathaway PB, Mankoff DA, Maravilla KR, Gutman F, Sarandi F, Bertrand-Kermorgant F, et al. Austin-Seymour MM, Ellis GK, Gralow JR, et al. Positrons Emission Tomography (PET) using 18FDG Value of combined FDG PET and MR imaging in and occult diseases in cancerology: the experiment the evaluation of suspected recurrent local-regional of the Rene Huguenin Center. [French]. Immuno- breast cancer: preliminary experience. Radiology anal Biol Spéc 2004;19(5):269–73. 1999;210(3):807–14. 43. Radan L, Ben-Haim S, Bar-Shalom R, Guralnik L, 33. Haug AR, Schmidt GP, Klingenstein A, Israel O, Radan L, et al. The role of FDG-PET/CT 38 Heinemann V, Stieber P, Priebe M, et al. F-18- DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

in suspected recurrence of breast cancer. Cancer 53. Belohlavek O, Kantorova I. Influence of positron 2006;107(11):2545–51. emission tomography (PET) on therapeutic decision at breast cancer – Preliminary report. 44. Raileanu I, Grahek D, Montravers F, Kerrou K, [Czech]. Klinicka Onkologie 2002;15(5):189–91. Aide N, Younsi N, et al. Comparison of [18F]- fluorodeoxyglucose positron emission tomography 54. Grahek D, Montravers F, Kerrou K, Aide N, and technetium bisphosphonate bone scintigraphy Lotz JP, Talbot JN, et al. [18F]FDG in recurrent to detect bone metastases in patients with breast breast cancer: diagnostic performances, clinical cancer. [French]. Méd Nucl 2004;28(7):297–303. impact and relevance of induced changes in management. Eur J Nucl Med Mol Imaging 45. Santiago JF, Gonen M, Yeung H, Macapinlac H, 2004;31(2):179 –88. Larson S, Santiago JFY, et al. A retrospective analysis of the impact of 18F-FDG PET scans on 55. Eubank WB, Mankoff D, Bhattacharya M, Gralow J, clinical management of 133 breast cancer patients. Linden H, Ellis G, et al. Impact of FDG PET on Q J Nucl Med Mol Imaging 2006;50(1):61–7. defining the extent of disease and on the treatment of patients with recurrent or metastatic breast 46. Schmidt GP, Baur-Melnyk A, Haug A, cancer. AJR Am J Roentgenol 2004;183(2):479–86. Heinemann V, Bauerfeind I, Reiser MF, et al. Comprehensive imaging of tumor recurrence in 56. Gould MK, Kuschner WG, Rydzak CE, Maclean CC, breast cancer patients using whole-body MRI at 1.5 Demas AN, Shigemitsu H, et al. Test performance and 3 T compared to FDG-PET-CT. Eur J Radiol of positron emission tomography and computed 2008;65(1):47–58. tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. 47. Suarez M, Perez-Castejon MJ, Jimenez A, Ann Intern Med 2003;139(11):879–92. Domper M, Ruiz G, Montz R, et al. Early diagnosis of recurrent breast cancer with FDG-PET in 57. Shie P, Cardarelli R, Brandon D, Erdman W, patients with progressive elevation of serum Abdulrahim N. Meta-analysis: comparison of F-18 tumor markers. Q J Nucl Med Mol Imaging Fluorodeoxyglucose-positron emission tomography 2002;46(2):113–21. and bone scintigraphy in the detection of bone metastases in patients with breast cancer. Clin Nucl 48. Veit-Haibach P, Antoch G, Beyer T, Stergar H, Med 2008;33(2):97–101. Schleucher R, Hauth EA, et al. FDG-PET/CT in restaging of patients with recurrent breast cancer: 58. Smith IC, Ogston KN, Whitford P, Smith FW, possible impact on staging and therapy. Br J of Sharp P, Norton M, et al. Staging of the axilla in Radiol 2007;80(955):508–15. breast cancer: Accurate in vivo assessment using positron emission tomography with 2-(fluorine- 49. Vranjesevic D, Filmont JE, Meta J, Silverman DH, 18)-fluoro-2-deoxy-D- glucose. Ann Surg Phelps ME, Rao J, et al. Whole-body (18)F-FDG 1998;228(2):220–7. PET and conventional imaging for predicting outcome in previously treated breast cancer 59. Van der Hoeven JJ, Krak NC, Hoekstra OS, patients. J Nucl Med 2002;43(3):325–9. Comans EF, Boom RP, Van GD, et al. 18F-2-fluoro- 2-deoxy-d-glucose positron emission tomography 50. Wolfort RM, Li BDL, Johnson LW, Turnage RH, in staging of locally advanced breast cancer. J Clin Lilien D, Ampil F, et al. The role of whole-body Oncol 2004;22(7):1253–9. fluorine-18-FDG positron emission tomography in the detection of recurrence in symptomatic patients 60. Rostom AY, Powe J, Kandil A, Ezzat A, Bakheet S, with stages II and III breast cancer. World J Surg El-Khwsky F, et al. Positron emission tomography in 2006;30(8):1422–7. breast cancer: A clinicopathological correlation of results. Br J Radiol 1999;72:1064–8. 51. Yang SN, Liang JA, Lin FJ, Kao CH, Lin CC, Lee CC, et al. Comparing whole body (18)F-2- 61. Dose J, Bleckmann C, Bachmann S, deoxyglucose positron emission tomography Bohuslavizki KH, Berger J, Jenicke L, et al. and technetium-99m methylene diphosphonate Comparison of fluorodeoxyglucose positron bone scan to detect bone metastases in patients emission tomography and ‘conventional diagnostic with breast cancer. J Cancer Res Clin Oncol procedures’ for the detection of distant metastases 2002;128(6):325–8. in breast cancer patients. Nucl Med Commun 2002;23(9):857–64. 52. Yap CS, Seltzer MA, Schiepers C, Gambhir SS, Rao J, Phelps ME, et al. Impact of whole-body 62. Siggelkow W, Zimny M, Faridi A, Petzold K, 18F-FDG PET on staging and managing patients Buell U, Rath W. The value of positron emission with breast cancer: the referring physician’s tomography in the follow-up for breast cancer. perspective. J Nucl Med 2001;42(9):1334–7. Anticancer Res 2003;23(2C):1859–67. 39

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Appendix 1 MEDLINE search strategy

Database: Ovid MEDLINE 1950 8. (positron adj2 emission adj2 tomograph$).tw. to Week 2 May 2009 (21399) 9. (pet or petct).tw. (30218) 1. exp tomography, emission-computed/ (52882) 10. or/1–9 (65938) 2. (emission adj2 comput$ adj2 tomograph$).tw. 11. exp breast neoplasms/ (162433) (9710) 12. (breast$ adj5 (cancer$ or carcinoma$ or 3. (tomograph$ adj2 emission adj2 comput$).tw. adenocarcinoma$ or carcinogen$ or sarcoma$ (9941) or malignan$ or tumo?r$ or neoplas$)).tw. 4. (radionuclide-comput$ adj2 tomograph$).tw. (149035) (19) 13. or/11–12 (191059) 5. (radionuclide adj2 cat scan$).tw. (4) 14. 10 and 13 (1422) 6. (radionuclide adj2 ct scan$).tw. (29) 15. (recur$ or relaps$ or metasta$ or restag$ or 7. (scintigraph$ adj2 comput$ adj2 tomograph$). re-stag$).mp. (633461) tw. (373) 16. 14 and 15 (730)

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Appendix 2 Characteristics of FDG-PET technology

© 2010 Queen’s Printer and Controller of HMSO. All rights reserved. Appendix 2 minutes minutes minutes minutes10 positionper 4 minutes 10 minutes 10 NR Acquisition Acquisition time 9 minutes 7 NR ~ 2 minutes 3 4 minutes 2 4 minutes per field of view 6 minutes, 30 minutes if evidence minutes minutes minutes minutes minutes minutes minutes minutes minutes minutes 45–60 50 45–60 minutes NR Uptake time 60 60 70 60 60 45 60 minutes 45 60 MBq/ MBq MBq MBq MBq MBq MBq FDG dose 2 MBq/kg 185– 370 7.77 kg 200 MBq 300– 520 200 MBq 300– 400 MBq 101– 434 MBq 370 386 MBq 260– 370 185– 370 370– 555 BG testing fastingand BG mg/dl, < 120 fast > 6 hour Given BG test, don’t give fasting results, Only those < 200 mg/dl fast included, > 6 hours BG mg/dl, < 130 fasting BG controlled before, > 6-hour fast ensureTested mg/dl,< 120 > 6-hour fast fast 4-hour BG measured as mg/dl, 87–135 > 4-hour fast BG mg/dl, < 150 fasting 4 hours fasting BG > 80 mg/dl, < 140 > 4-hour fast recorded BG but not given, fast 4-hour Overnight fast Positive Positive scan definition given? N Y Y N Y Y N Y Y Y Y Y Image reconstruction Image Iterative Filtered back projection Filtered backprojection for IterativeCT. algorithms (OSEM) for PET Iterative NR NR Iterative and some standard filtered back projection Ordered-subset Ordered-subset maximisation expectation (OSEM) algorithm Unclear OSEMIterative algorithm Filtered back-projection Using 0.4 Hann filter and 1.5 zoom NR Interpretation Visual Visual Visual Visual Visual Visual and SUV Visual Visual Visual and SUV Visual Visual and SUV Visual and SUV Visual and SUV Attenuation correction Y Y Y Y Y Y Y Y NR Y Y Y Y Camera HR+ CTIHR+ siemens EACTECAT 927/47 REVEAL RT scanner PET/CT ECAT SiemensART CTI MS Biograph PET/ SiemensCT, AG Phillips Gemini GE Advance ECAT EXACTECAT HR+ LS Discovery GE Advance GE Advance ECAT/EACT 921 EXACTECAT 47 31 27 32 30 34 26 28 35 33 25 24 36 29 Dirisamer 2010 Dirisamer Fueger 2005 Fueger Haug 2007 Kamel 2003 Study and date Abe 2005 Abe Goerres 2003 Goerres Bender 1997 Gallowitsch 2003 1999 Hathaway 2000Hubner Kim 2001 44 Aide 2007 Guillemard 2006 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50 minutes minutes minutes minutes minutes minutes minutes 30 7 7 4 NR 3 Acquisition Acquisition time 5 minutes 20 NR NR 6 NR 4 minutes or (931) 6 minutes (961) minutes minutes minutes minutes minutes minutes minutes minutes minutes minutes minutes NR 30–45 45 60 60 30–45 Uptake time 60 60 1 hour 1 hour NR 45–60 45–60 60 40 MBq MBq MBq MBq MBq MBq MBq MBq MBq FDG dose 370 370 MBq370 260– 370 296– 407 MBq 370– 666 2 MBq/kg 340 MBq 370– 555 NR 370– 555 370– 550 202– 378 2 MBq/kg 370 4-hour fast BG testing fastingand 4-hour fast 4-hour Fast > 4 hours > 6-hour fast ?, > NR BG mmol/l, < 11 fasting 4–6 hours NR BG measured to ensure normal, fast 4 hours > 6-hour fast NR No exclusions, > 6-hour fast BG < 200 mg/dl, > 6-hour fast Fast > 6 hours BG mg/dl, < 120 > 6-hour fast > 4-hour fast Positive Positive scan definition given? N Y Y N Y Y N Y N NR N Y Y Y Image reconstruction Image Standard filtered back projection NR Filteredbackprojection (no correction) attenuation or attenuation-weighted OSEM NR NR expectation subsets Order maximisation NR Iterative Filtered backprojection NR NR Filtered backprojection actionRow maximum algorithmlikelihood Iterative NR Interpretation Visual Visual Visual Visual SUV Visual Visual Visual and SUV Visual NR Visual Visual Visual + SUV Visual and SUV Visual Attenuation correction N Y Y, N NR Y Y NR Y N (20% with) NR N NR Y Y NR Camera GE Advance bodywhole CTI-Siemens ECAT HR + EXACTECAT HR, CTI ECAT EXACT47 LS Discovery LS Discovery ADAC-philips CT -Somatom emotion PET -ECAT HR+ EXACTECAT or HR + NR ECAT 931 (67%) (67%) 931 ECAT 961 and ECAT GE Advance row 2-detector scanner (Gemini) ADAC C-PET-250 ECAT HR + 39 44 45 50 46 42 47 43 40 41 51 37 38 49 48 Radan 2006 Liu 2002 2000Lonneux Pecking 2004 Raileanu 2004 Suarez 2002 BG, blood glucose; N, no; NR, not reported; SUV, standardised uptake value; yes Y, Study and date Lin 2002 Moon 1998 Moon 2006Santiago Vranjesevic 2002 Wolfort 2006 2002 Yang Schmidt 2008 Veit-Haibach 2007 Ohta 2001 45

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Appendix 3 Figures for indirect comparisons of patient-based data

PET versus conventional imaging tests

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FIGURE 13 Summary receiver operating characteristic plane for indirect comparison of the diagnostic performance of PET (□) and CIT (◊) for patients with suspected BC recurrence.

PET/CT versus conventional imaging tests

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FIGURE 14 Summary receiver operating characteristic plane for indirect comparison of the diagnostic performance of PET/CT (□) and CIT (◊) for patients with suspected BC recurrence. 47

PET versus PET/CT

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FIGURE 15 Summary receiver operating characteristic plane for indirect comparison of the diagnostic performance of PET (□) and PET/CT (◊) for patients with suspected BC recurrence.

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Appendix 4 Comparative lesion-based data

Sensitivity Specificity Study n Test TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Abe 200524 187 PET 38 2 7 140 0.84 (0.71 to 0.94) 0.99 (0.95 to 1.00) Abe 200524 CIT 36 2 9 140 0.80 (0.65 to 0.90) 0.99 (0.95 to 1.00) Gallowitsch 200329 135 PET 61 3 47 24 0.56 (0.47 to 0.66) 0.89 (0.71 to 0.98) Gallowitsch 200329 CIT 97 7 11 20 0.90 (0.83 to 0.95) 0.74 (0.54 to 0.89) Yang 200251 127 PET 100 2 5 20 0.95 (0.89 to 0.98) 0.91 (0.71 to 0.99) Yang 200251 CIT 98 20 7 2 0.93 (0.87 to 0.97) 0.09 (0.01 to 0.29) 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

FIGURE 16 Lesion data for the diagnostic accuracy of PET and CITs in comparative studies. Note: no studies comparing the accuracy of PET/CT and CIT presented lesion data.

TABLE 9 Lesion data for direct and indirect comparisons of PET compared to CITs

Relative Relative PET CIT sensitivity PET CIT specificity sensitivity sensitivity % (95% CI), specificity% specificity % (95% CI), Comparison % (95% CI) (95% CI) p-value (95% CI) (95% CI) p-value Direct PET vs 83 (56 to 95), 90 (84 to 94), 0.93 (0.76 to 95 (87 to 98) 74 (10 to 99) 1.29 (0.57 to CIT: lesion data n = 3 n = 3 1.13) p = 0.447 2.90) p= 0.540 Indirect PET vs 89 (78 to 95), 91 (86 to 94), 0.98 (0.90 to 91 (83 to 95) 35 (3 to 91) 2.57 (0.41 to CIT: lesion data n = 7 n = 3 1.07) p = 0.624 6.07) p = 0.313

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FIGURE 17 Summary receiver operating characteristic plane for studies directly comparing the diagnostic performance of PET (□) and CITs (◊) for lesions with suspected disease.

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FIGURE 18 Summary receiver operating characteristic plane for indirect comparison of the diagnostic performance of PET (□) and CITs (◊) for lesions with suspected disease.

TABLE 10 Lesion data for the indirect comparison of PET with PET/CT

PET/CT PET Relative PET/CT PET Relative sensitivity% sensitivity % sensitivity specificity% specificity% specificity Comparison (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Indirect PET/CT 97 (86 to 99), 89 (78 to 95), 1.1 (1.0 to 1.2) 84 (62 to 94) 91 (83 to 95) 0.9 (0.8 to 1.1) vs PET: lesion n = 2 n = 7 p = 0.137 p = 0.414 basis

Sensitivity Specificity Study n Test TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Schmidt 200846 263 PET/CT 170 8 16 69 0.91 (0.86 to 0.95) 0.90 (0.81 to 0.95) MRI 172 11 14 66 0.92 (0.88 to 0.96) 0.86 (0.76 to 0.93)

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

FIGURE 19 Lesion data for the diagnostic accuracy of PET/CT and MRI in the comparative study of PET/CT and MRI. Note: no studies comparing the accuracy of PET and MRI presented lesion data.

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Appendix 5 Study data and figures for independent estimates of PET and PET/CT

Patient data

Sensitivity Specificity Study TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Abe 200524 14 1 0 29 1.00 (0.77 to 1.00) 0.97 (0.83 to 1.00) Aide 200725 21 2 7 5 0.75 (0.55 to 0.89) 0.71 (0.29 to 0.96) Bender 199726 13 2 1 58 0.93 (0.66 to 1.00) 0.97 (0.88 to 1.00) Dirisamer 201027 34 0 8 10 0.81 (0.66 to 0.91) 1.00 (0.69 to 1.00) Fueger 200528 28 7 5 18 0.85 (0.68 to 0.95) 0.72 (0.51 to 0.88) Gallowitsch 200329 33 5 1 23 0.97 (0.85 to 1.00) 0.82 (0.63 to 0.94) Goerres 200330 14 5 0 13 1.00 (0.77 to 1.00) 0.72 (0.47 to 0.90) Guillemard 200631 7 0 1 6 0.88 (0.47 to 1.00) 1.00 (0.54 to 1.00) Hathaway 199932 6 0 0 1 1.00 (0.54 to 1.00) 1.00 (0.03 to 1.00) Haug 200733 23 1 3 7 0.88 (0.70 to 0.98) 0.88 (0.47 to 1.00) Hubner 200034 36 6 6 16 0.86 (0.71 to 0.95) 0.73 (0.50 to 0.89) Kamel 200335 25 2 2 23 0.93 (0.76 to 0.99) 0.92 (0.74 to 0.99) Kim 200136 16 2 1 8 0.94 (0.71 to 1.00) 0.80 (0.44 to 0.97) Lin 200237 4 1 0 31 1.00 (0.40 to 1.00) 0.97 (0.84 to 1.00) Liu 200238 27 2 1 0 0.96 (0.82 to 1.00) 0.00 (0.00 to 0.84) Lonneux 200039 31 3 2 3 0.94 (0.80 to 0.99) 0.50 (0.12 to 0.88) Moon 199840 27 6 2 22 0.93 (0.77 to 0.99) 0.79 (0.59 to 0.92) Ohta 200141 7 1 2 42 0.78 (0.40 to 0.97) 0.98 (0.88 to 1.00) Pecking 200442 260 12 7 12 0.97 (0.95 to 0.99) 0.50 (0.29 to 0.71) Raileanu 200444 6 0 1 13 0.86 (0.42 to 1.00) 1.00 (0.75 to 1.00) Santiago 200645 68 7 30 28 0.69 (0.59 to 0.78) 0.80 (0.63 to 0.92) Suarez 200247 24 3 2 9 0.92 (0.75 to 0.99) 0.75 (0.43 to 0.95) Veit-Haibach 200749 17 6 2 19 0.89 (0.67 to 0.99) 0.76 (0.55 to 0.91) Vranjesevic 200250 39 3 3 16 0.93 (0.81 to 0.99) 0.84 (0.60 to 0.97) Wolfort 200651 13 0 3 7 0.81 (0.54 to 0.96) 1.00 (0.59 to 1.00) 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

FIGURE 20 Study data for the accuracy of PET on a patient basis.

Sensitivity Specificity Study TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Dirisamer 201027 40 0 2 10 0.95 (0.84 to 0.99) 1.00 (0.69 to 1.00) Fueger 200528 31 4 2 21 0.94 (0.80 to 0.99) 0.84 (0.64 to 0.95) Haug 200733 24 1 1 8 0.96 (0.80 to 1.00) 0.89 (0.52 to 1.00) Radan 200643 17 4 3 13 0.85 (0.62 to 0.97) 0.76 (0.50 to 0.93) Veit-Haibach 200748 19 4 0 21 1.00 (0.82 to 1.00) 0.84 (0.64 to 0.95) 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

FIGURE 21 Study data for the accuracy of PET/CT on a patient basis.

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FIGURE 22 Summary receiver operating characteristic plane for studies measuring the diagnostic performance of PET (□) for patients with suspected BC recurrence.

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FIGURE 23 Summary receiver operating characteristic plane for studies measuring the diagnostic performance of PET/CT (□) for patients with suspected BC recurrence.

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Lesion data

Sensitivity Specificity Study TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Abe 200524 38 2 7 140 0.84 (0.71 to 0.94) 0.99 (0.95 to 1.00) Gallowitsch 200329 61 3 47 24 0.56 (0.47 to 0.66) 0.89 (0.71 to 0.98) Kamel 200335 43 3 2 13 0.96 (0.85 to 0.99) 0.81 (0.54 to 0.96) Kim 200136 46 2 2 11 0.96 (0.86 to 0.99) 0.85 (0.55 to 0.98) Lin 200237 8 2 1 28 0.89 (0.52 to 1.00) 0.93 (0.78 to 0.99) Moon 199840 35 8 6 31 0.85 (0.71 to 0.94) 0.79 (0.64 to 0.91) Yang 200251 100 2 5 20 0.95 (0.89 to 0.98) 0.91 (0.71 to 0.99) 0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

FIGURE 24 Study data for the accuracy of PET on a lesion basis.

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0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Specificity

FIGURE 25 Summary receiver operating characteristic plane for studies measuring the diagnostic performance of PET (□) for lesions with suspected disease.

Sensitivity Specificity Study TP FP FN TN (95% Cl) (95% Cl) Sensitivity Specificity Radan 200643 151 5 2 13 0.99 [0.95 to 1.00] 0.72 [0.47 to 0.90] Schmidt 200846 179 8 16 69 0.92 [0.87 to 0.95] 0.90 [0.81 to 0.95]

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0

FIGURE 26 Study data for the accuracy of PET/CT on a lesion basis.

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Appendix 6 Changes in patient management

Start/ Patients with changed Changed Avoided overall changes in medical to medical Avoided Additional management therapy surgery treatment surgery gain n n (%) n (%) n (%) n (%) n (%) Dirisamer 201027 N 52 7 (13%) 3 (6%) 4 (8%) Bĕlohlávek 200253 N 51 31 (60%) Eubank 200455 N 125 40 (32%) 22 (18%) 2 (2%) 2 (2%) 14 (11%) Eubank 200455 Ya 20 5 (25%) 4 (16%) 1 (4%) Gallowitsch N 62 13 (21%) 6 (3%) 2 (3%) 200329 Grahek 200454 N 75 25 (33%) 10 (13%) 5 (7%) 4 (5%) 3 (4%) Kim 200136 N 27 13 (48%) 6 (22%) 7 (26%) Radan 200643 N 47 24 (51%) 17 (36%) 2 (4%) 1 (2%) Santiago 200645 N 133 99 (74%) Veit-Haibach Ya 44 5 (11%) 200748 Vranjesevic Ya 61 10 (16%) 10 (16%) 200249 bYap 200152 N 50 29 (58%) 22 (44%) 4 (8%) 3 (6%)

N, no; Y, yes. a In patients not correctly identified by conventional imaging. b Half of patients referred for initial staging of BC.

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Appendix 7 Sensitivity analysis

TABLE 11a Diagnostic accuracy of PET and CIT for studies in which tests were conducted within a 1-month time period

Relative Relative PET CIT sensitivity PET CIT specificity sensitivity % sensitivity % (95% CI), specificity % specificity % (95% CI), Comparison (95% CI) (95% CI) p-value (95% CI) (95% CI) p-value Direct PET vs 87 (79 to 93) 84 (72 to 91) 1.04, (0.92 to 96 (83 to 99) 87 (75 to 94) 1.10, (1.01 to CIT n = 6 n = 6 1.15) p = 0.4797 1.17) p = 0.022

TABLE 11b Diagnostic accuracy of PET/CT and CIT for studies in which tests were conducted within a 1-month time period

Relative Relative PET/CT CIT sensitivity PET/CT CIT specificity sensitivity % sensitivity % (95% CI), specificity % specificity % (95% CI), Comparison (95% CI) (95% CI) p-value (95% CI) (95% CI) p-value Direct PET/CT 97 (90 to 99) 84 (66 to 94) 1.13 (0.99 to 93 (65 to 99) 86 (59 to 97) 1.07 (0.91 to vs CIT (CT) n = 3 n = 3 1.26), p = 0.063 1.22) p = 0.367

TABLE 11c Diagnostic accuracy of PET/CT and PET for studies in which tests were conducted within a 1-month time period

Relative Relative PET/CT PET sensitivity PET/CT PET specificity sensitivity % sensitivity % (95% CI), specificity % specificity % (95% CI), Comparison (95% CI) (95% CI) p-value (95% CI) (95% CI) p-value Direct PET/CT 96 (90 to 98) 85 (77 to 91) 1.11 (1.03 to 89 (74 to 96) 82 (64 to 92) 1.08 (0.94 to vs PET n = 4 n = 4 1.18) p = 0.006 1.20) p = 0.267

1.0

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FIGURE 27 Summary receiver operating characteristic plane for direct comparison of the diagnostic performance of PET (□) and CITs (◊) for patients with suspected BC recurrence for studies where PET and CIT were conducted within a 1-month time period.

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FIGURE 28 Summary receiver operating characteristic plane for direct comparison of the diagnostic performance of PET/CT (□) and CT (◊) for patients with suspected BC recurrence for studies where PET/CT and CT were conducted within a 1-month time period.

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Appendix 8 Subgroup analysis

TABLE 12 Indirect comparison of the diagnostic accuracy of PET for detecting lesions of disease in different locations in the body

Local (n = 4 Lymph nodes Distant metastases studies) p (n = 3 studies) p (n = 7 studies) p

Relative specificity (95% CI) Local – 1.01 0.936 1.02 0.744 (0.81 to 1.17) (0.9 to 1.12) Lymph nodes 0.99 0.936 – 0.98 0.874 (0.83 to 1.19) (0.75 to 1.17) Distant 0.98 0.744 1.02 0.874 – metastases (0.88 to 1.10) (0.83 to 1.25)

Relative sensitivity (95% CI) Local – 0.91 0.334 0.93 0.442 (0.69 to 1.09) (0.74 to 1.09) Lymph nodes 1.09 0.334 – 1.02 0.822 (0.91 to 1.31) (0.89 to 1.16) Distant 1.07 0.442 0.98 0.822 – metastases (0.91 to 1.26) (0.84 to 1.11)

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FIGURE 29 Indirect comparison of the diagnostic accuracy of PET for the detection of local (□), lymph node (○) or distant metastatic (◊) lesions.

Variability of PET with study characteristics

TABLE 13a Indirect comparisons of the variability of PET with the outcome of previous imaging investigations

Relative PET positive on previous imaging PET negative on previous sensitivity/ (n = 5) imaging (n = 5) specificity p Sensitivity 94% 93% 0.99 0.859 (95% CI) (82 to 98) (84 to 97) (0.90 to 1.09) Specificity 90% 66% 0.73 0.024 (95% CI) (77 to 96) (48 to 80) (0.56 to 0.96)

TABLE 13b Indirect comparisons of the variability of PET with patient disease status at the time of investigation

Relative PET in patients with known BC or PET in patients cleared of sensitivity/ diagnosis unclear (n = 11) BC (n = 14) specificity p Sensitivity 91% 91% 1.00 0.920 (95% CI) (82 to 95) (86 to 94) (0.92 to 1.09) Specificity 92% 77% 0.84 0.018 (95% CI) (85 to 95) (66 to 86) (0.73 to 0.97)

TABLE 13c Indirect comparisons of the variability of PET with assessors knowledge of previous clinical and imaging investigations at the time of study

PET assessors with knowledge Relative of previous findings/knowledge PET assessors blinded to sensitivity/ unclear (n = 16) previous findings n( = 9) specificity p Sensitivity 92% 88% 0.96 0.346 (95% CI) (87 to 95) (81 to 93) (0.87 to 1.04) Specificity 85% 88% 1.05 0.533 (95% CI) (75 to 91) (76 to 95) (0.91 to 1.20)

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1.0

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Sensitivity 0.4

0.3

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FIGURE 30 Summary receiver operating characteristic plane for comparison of the diagnostic performance of PET in studies where all patients had been positive or equivocal (□) or negative (◊) for breast cancer recurrence in previous imaging tests.

1.0

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FIGURE 31 Summary receiver operating characteristic curve for comparison of the diagnostic performance of PET in studies of patients previously cleared of BC (□) or of patients with known BC or where disease status was unclear (◊).

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Appendix 9 False-positives and false-negatives

TABLE 14 Causes of FPs in PET and PET/CT studies

Infection/ Physiological Degenerative process/ inflammation activity old fractures Other artefacts Bender 199726 4 2 Dirisamer 201027 2 Fueger 200528 5 1 1 Gallowitsch 200329 3 1 1 Goerres 200330 2 3 Grahek 200454 2 1 1 Hubner 200034 2 1 1 Kamel 200335 2 1 Kim 200136 1 1 Lin 200237 4 1 Liu 200238 2 Lonneux 200039 1 1 1 Moon 199840 4 5 9 Ohta 200141 1 Radan 200643 2 2 Suarez 200247 1 4 1 Veit-Haibach 200748 2 Vranjesevic 200249 1 1 1 41% 29% 10% 20%

TABLE 15 Sites of FNs in PET and PET/CT scans

Cutaneous/ Local/ subcutaneous/ Lymph regional soft tissue Peritoneal node Lung Bone Liver Brain Bender 199726 4 1 Dirisamer 201027 4 Gallowitsch 200329 1 Grahek 200454 1 2 2 2 2 Hubner 200034 1 3 1 1 Kamel 200335 1 2 Kim 200136 1 1 Liu 200238 2 1 Lonneux 200039 1 1 Moon 199840 1 5 Radan 200643 1 1 1 Siggelkow 200362 1 5 1 Suarez 200247 1 1 Veit-Haibach 200748 2 2 Vranjesevic 200249 1 2 1 Wolfort 200650 1 1 1

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Appendix 10 Protocol

Positron emission ¹Department of Public Health, Epidemiology & tomography (PET) and Biostatistics, University of Birmingham ²Department of Health Economics, University of PET/CT in breast cancer Birmingham recurrence: draft protocol 3UK Cochrane Centre 4Cancer Sciences Clinical Trials Unit, University of Produced by West Midlands Health Technology Birmingham Assessment Collaboration, Department of Public 5Electronic & Electrical Engineering, University of Health, Epidemiology & Biostatistics, University of Birmingham Birmingham, Edgbaston, Birmingham B15 2TT, UK Correspondence to: Chris Hyde

Authors: Mary Pennant,1 Yemisi Takwoingi,1 Date completed: June 2009 Lazaros Andronis,2 Anne Fry-Smith,1 Anne Eisinga,3 Daniel Rea,4 Theo Arvanitis,5 Jon Deeks,1 This report was commissioned by the National Chris Hyde1 Institute for Health Research HTA programme, HTA no. 08/34. Details of review team

Lead/senior reviewer Hyde, Chris, Dr Senior Lecturer/Director of WMHTAC Main reviewer Pennant, Mary, Dr Systematic Reviewer Administrator Farren, Janet, Mrs Project Administrator Senior statistical advisor Deeks, Jon, Professor Professor of Health Statistics Statistical advisor Yemisi Takwoingi, Mrs Research Fellow Health economist Andronis, Lazaros, Mr Research Associate Information specialist Fry-Smith, Anne, Ms Information Specialist Information specialist Eisinga, Anne, Mrs Information Specialist Clinical advisor Rea, Dan, Dr Senior Lecturer and Honorary Consultant in Medical Oncology Technical advisor Arvanitis, Theodoros, Dr Senior Lecturer

Background 20012 and Isasi et al. 20053. The latter provides Breast cancer is a serious life-threatening disease. the most up-to-date assessment of test accuracy Treatment options have developed significantly in evaluations up to 2004, with pooled sensitivity over the past decade, and have impacted on and specificity for PET both in the region of survival. Inevitably, recurrence of breast cancer has 90%. Although this review could be up-dated and increased and its diagnosis is important, as early improved on, the key outstanding issue is the appropriate treatment also has small but clear amount of improvement PET and PET/CT offer associated advantage for survival. over existing diagnostic approaches and this is the focus of the research proposed in this protocol. For women who have suffered with breast cancer, following clearance, NICE recommends continued Objectives access to a breast cancer nurse for an indefinite period of time.1 This nurse is to provide advice, 1. To assess the diagnostic accuracy of PET and support and counselling via the telephone PET/CT in the diagnosis of breast cancer and, where appropriate, to arrange additional recurrence. hospital appointments. Women also undergo the –– The primary aim is to assess the normal population-wide screening programme incremental diagnostic accuracy of (mammography every 3 years for those aged PET and PET/CT compared to existing 50–64 years1). diagnostic strategies. –– If there are insufficient within-study Breast cancer recurrence may be local (in the comparisons to assess incremental breast), regional (lymph nodes, collar bone, etc., diagnostic accuracy, basic test accuracy same side of body as original cancer) or distant values will be reported. (in other body organs such as bone, liver, lungs 2. To assess the impact of PET and PET/CT on and brain) and is associated with symptoms the type of patient diagnosis, treatment and such as weight loss, abdominal pain, respiratory outcome. symptoms, bone pain and neurological signs. 3. To assess the cost-effectiveness of PET and Women with a past history of breast cancer may PET/CT in the diagnosis and treatment of present with symptoms which may be innocent breast cancer recurrence. or the first indication of recurrence. The nature of these symptoms will dictate the nature of the A further objective, to be met by conducting an investigation but tests will often include bone scans, additional modelling review, is: chest X-ray, CT scans, MRI scans and ultrasound. 4. To model the effectiveness and cost- PET and, more recently, PET/CT are new tools that effectiveness of PET and PET/CT relative to may be used to diagnose breast cancer recurrence. existing diagnostic strategies in suspected These technologies trace radioactive isotopes in breast cancer recurrence. the body. Isotopes of glucose, most commonly fluorodeoxyglucose (FDG), are used for the Population detection of tumours since glucose is taken up and retained in tumour tissue, making it visible in PET The population to be studied are patients with images. Whether PET or PET/CT offer advantages a history of breast cancer but who have been over existing diagnostic approaches depends in the cleared of having the disease and, at the time of first instance on whether their diagnostic accuracy study, have not been diagnosed with breast cancer is good. However, ultimately, these need to be recurrence. Breast cancer recurrence may or may translated into more appropriate applications of not be suspected at the time of study and tests may effective treatment strategies, leading in turn to be conducted as part of follow-up examinations or improved patient outcomes. As well as detecting in response to presentation of symptoms suggestive recurrence, a new diagnostic tool may also be able of breast cancer recurrence. to improve outcomes by correctly differentiating solitary recurrences from multiple metastases. Studies will be excluded if:

We have reviewed existing systematic reviews • Patients have confirmed breast cancer. assessing the effectiveness of PET and PET/CT • Patients have never suffered from breast in the diagnosis of recurrent breast cancer. The cancer. two most relevant were Blue Cross/Blue Shield 66 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

• Populations include both patients with and (calculated from additional test accuracy and without breast cancer but data from the two additional test cost). patient types cannot be differentiated. • Populations include patients undergoing tests Where there are sufficient studies that use a to diagnose primary breast cancer and breast comparator test (in addition to the reference cancer recurrence but data from the two standard), these will be used to assess the patient types cannot be differentiated. incremental diagnostic accuracy of PET and • Patients may have impaired glucose tolerance/ PET/CT. The tests for comparison may be diabetes or may not have been fasting at the existing diagnostic strategies (as defined by UK time of PET or PET/CT scanning. treatment guidelines) such as clinical examination, mammography, bone scan, chest x-ray, liver Index tests ultrasound and CT. Studies will be excluded if:

The index tests under assessment are PET and • No comparator tests were undertaken. PET/CT and these will be considered separately. • Not all the patients have undergone both the They may be used in addition to standard tests, index and comparator test. e.g. in combination with clinical examination/ • Index tests and comparator tests were not bone scanning, etc., and also instead of standard undertaken during the same investigation tests. Studies where whole body PET and PET/ period. CT are conducted as well as studies using only breast imaging may be considered. Studies will be If sufficient studies with comparator groups are not excluded if: available then it is anticipated that the emphasis of the review will be changed to include studies • FDG is not the radioactive tracer used. with no additional comparator test (but still with a • Planar (not tomographic) imaging is used. reference standard).

Reference standard Target condition

The reference standard used to define the true The outcome to be assessed by studies is breast disease status of patients may be histological cancer recurrence as defined by the reference diagnosis (operation/biopsy) or long term clinical standard (see above). Recurrence may be local, follow-up/autopsy findings. Studies will be excluded regional or distant but must be considered to be if: a consequence of the originally diagnosed breast cancer. It is anticipated that, in the majority of • Other diagnostic tests, e.g. CT, are used as the studies, PET or PET/CT will have been used to reference standard. detect distant recurrence. Studies will be excluded • It is not clear what reference standard has been if they investigate: used. • The diagnosis of primary breast cancer in Comparator previously disease-free individuals. • Diagnosis of lymph node/distant metastases In order to be able to directly compare the in breast cancer patients who have not been accuracy of PET and PET/CT for the detection cleared of having breast cancer. of recurrent breast cancer with other diagnostic • Diagnosis of tumours that are not considered strategies, in the first instance, studies investigating to be related to the initial breast cancer. both PET or PET/CT and another method of detection (and both compared to the same Study design reference standard – see above), will be included. There is evidence that these types of studies exist Studies in which subjects undergo the index since some are included in the review by Isasi et test (PET or PET/CT), a comparison test (e.g. al. 2005. This approach is preferential as it allows mammography) and the reference standard direct comparison of PET or PET/CT test accuracy (histology/long-term follow-up) will be included. If with the accuracy of other detection methods there are insufficient tests with comparator groups, and it allows a more simple and direct modelling studies where subjects only undergo the index test approach for the calculation of cost-effectiveness and the reference standard will also be included.

All study designs assessing test accuracy will be accuracy for breast cancer recurrence in the bone, considered for inclusion. Additionally, all study liver, lung and brain. designs providing information on cost-effectiveness or relevant outcomes related to diagnosis, PET scans may be interpreted by quantitative treatment or outcome will also be considered. (using standard uptake values) or qualitative (visual Studies will be excluded if: assessment) methods. The mode of interpretation may influence diagnostic accuracy and subgroup • Data is not available to determine test analysis may include comparison of PET and PET/ accuracy, cost-effectiveness or other relevant CT diagnostic accuracy using quantitative versus outcomes. qualitative methodology. • They are not published in peer-reviewed journals The methodological quality, e.g. presence of • They are case-control studies comparing blinding, length of reference standard follow-up test results in diseased versus non-diseased etc, of included studies may affect the apparent individuals. accuracy. Other possible subgroup analysis are to examine the diagnostic accuracy of PET and Subgroup analysis PET/CT in studies that differ for aspects of methodological quality. Subgroup analysis may be conducted to assess the differential diagnostic accuracy of PET and PET/ Method CT in different patient groups, settings or methods of use. A systematic review of the literature will be conducted to identify studies assessing: PET and PET/CT may have different diagnostic accuracy depending on the mode of presentation. 1. The test accuracy of PET and PET/CT. In The primary focus for subgroup analysis may be the first instance, only studies in which differentiation on the basis of presentation at the PET or PET/CT are compared to existing time of the index test. Groups have been identified methodologies will be included in the review. as: If there are insufficient studies to provide useful information, the review will be extended • Patients undergoing a follow-up examination to include studies of PET or PET/CT without with no clinical symptoms of recurrence. comparator groups. • Patients presenting with clinical symptoms 2. The impact of PET and PET/CT on patient suggestive of breast cancer recurrence, e.g. diagnosis, treatment and outcome. bone pain, shortness of breath, weight loss and 3. The cost-effectiveness of PET and PET/CT. neurological symptoms. • Patients with a rise in tumour marker levels. In a separate piece of work, the results of this • Patients testing positive for other imaging review will be used to devise a simple decision techniques (mammography, ultrasonography, tree model to explore health effects and costs CT or bone scintigraphy) associated with changes in diagnostic error. A further protocol will be developed to detail Studies may present patient or lesion-based data, methodology for this modelling review, including i.e. either recurrence in one patient or one lesion of further targeted searches to identify best available recurrence in a patient can be taken as the unit of parameters, e.g. effects of treatments, side-effects measurement. If this is the case, studies presenting and costs. patient and lesion based data will be separated in the analysis of data. Standard Cochrane and diagnostic test accuracy methods will be used to conduct the review. The Other possible subgroup analysis possibility of this work being conducted as a The diagnostic accuracy of PET and PET/CT may Cochrane review will also be explored. depend on the location of recurrence. It may be that studies do not differentiate between patients Search strategy on the basis of recurrence location, especially Relevant primary studies will be sought in where whole-body scans have been conducted. MEDLINE (Ovid) and EMBASE (Ovid). Search However, where possible, subgroup analysis may strategies will be devised by combining index and be conducted to assess the differential diagnostic text words defining the index test: PET and PET/ 68 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

CT; and the population: suspected breast cancer • Studies of the relative cost-effectiveness of PET recurrence. There will be no language restrictions or PET/CT versus other comparator tests will and searches will be done from inception of be subjected to narrative synthesis. the databases up to the current date. Details of the proposed search strategy for MEDLINE is References available in the appendix. 1. National Institute for Clinical Excellence. Guidance Selection of studies on cancer services: Improving outcomes in breast Titles/abstracts obtained from the literature search cancer, Manual update; 2002. http://www.nice. will be scanned for inclusion. Full articles will be org.uk/nicemedia/pdf/Improving_outcomes_ retrieved for further assessment if the information breastcancer_manual.pdf given suggests that the study: 1) includes patients 2. Samson D, Redding Flamm C, Aronson N. FDG who have had breast cancer in the past, 2) conducts positron emission tomography for evaluating breast PET or PET/CT scans in those patients, and 3) cancer. Blue Cross and Blue Shield Association, assesses test accuracy, cost-effectiveness or one or Technology Evaluation Center; 2001 http://www. more relevant clinical outcome measure. If there mrw.interscience.wiley.com/cochrane/cldare/ is any doubt regarding inclusion from the title articles/DARE-12003008146/frame.html and abstract, the full article will be retrieved for clarification. Full paper articles will be screened 3. Isasi C R, Moadel R M, Blaufox M D. A meta- with another checklist, using inclusion/exclusion analysis of FDG-PET for the evaluation of breast criteria as detailed in this protocol. cancer recurrence and metastases. Breast Cancer Research and Treatment 2005;90(2):105–112. Quality assessment 4. Leeflang MMG, Deeks JJ, Gatsonis C, Quality assessment will be conducted using the Bossuyt PMM and on behalf of the Cochrane QADAS tool that includes criteria relating to Diagnostic Test Accuracy Working Group. patient selection, use of the reference standard, Systematic Reviews of Diagnostic Test Accuracy. detail of reporting, blinding, follow-up and Ann Intern Med 2008; 889–897. external validity. Since this quality assessment tool does not address issues related to the use of 5. Rutter CM, Gatsonis CA. A hierarchical regression an additional comparator test, a small number of approach to meta-analysis of diagnostic test additional quality criteria will be added. accuracy evaluations. Stat Med 2001;20:2865–84.

Data analysis Appendix: MEDLINE search PET and PET/CT will be considered as separate strategy technologies in data analysis. For the stated Database: Ovid MEDLINE 1950 to May research objectives, data analysis will be Week 2 2009 undertaken as follows: 1. exp tomography, emission-computed/ (52882) 2. (emission adj2 comput$ adj2 tomograph$).tw. • Hierarchical methods are recommended4 (9710) for meta-analyses of diagnostic test accuracy 3. (tomograph$ adj2 emission adj2 comput$).tw. studies. The HSROC model5 which takes (9941) account of both within- and between-study 4. (radionuclide-comput$ adj2 tomograph$).tw. variation in test performance will be used (19) to quantitatively combine data from eligible 5. (radionuclide adj2 cat scan$).tw. (4) studies. The relative accuracy of PET and 6. (radionuclide adj2 ct scan$).tw. (29) PET/CT compared to the comparator tests 7. (scintigraph$ adj2 comput$ adj2 tomograph$). will be determined and potential sources of tw. (373) heterogeneity investigated using extensions of 8. (positron adj2 emission adj2 tomograph$).tw. this model where possible. (21399) • Narrative synthesis will be used to combine 9. (pet or petct).tw. (30218) information from studies assessing the impact 10. or/1–9 (65938) of PET or PET/CT on patient diagnosis (e.g. 11. exp breast neoplasms/ (162433) differentiating solitary recurrences and 12. (breast$ adj5 (cancer$ or carcinoma$ or multiple metastases), treatment and outcome. adenocarcinoma$ or carcinogen$ or sarcoma$

or malignan$ or tumo?r$ or neoplas$)).tw. 15. (recur$ or relaps$ or metasta$ or restag$ or (149035) re-stag$).mp. (633461) 13. or/11–12 (191059) 16. 14 and 15 (730) 14. 10 and 13 (1422)

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Appendix 11 Excluded studies

Reason for Referencea exclusion Al-Husaini H, Amir E, Fitzgerald B, Wright F, Dent R, Fralick J, et al. Prevalence of overt No relevant outcomes metastases in locally advanced breast cancer. Clin Oncol 2008;20(5):340–4 Andrieux A, Switsers O, Chajari MH, Jacob JH, Delozier T, Gervais R, et al. Clinical impact of No reference standard fluorine-18 fluorodeoxyglucose positron emission tomography in cancer patients. A comparative study between dedicated camera and dual-head coincidence gamma camera. Q J Nucl Med Mol Imaging 2006;50(1):68–77 Basu S, Mavi A, Cermik T, Houseni M, Alavi A. Implications of standardized uptake value In patients with newly measurements of the primary lesions in proven cases of breast carcinoma with different degree diagnosed BC of disease burden at diagnosis: Does 2-deoxy-2-[F-18]fluoro-d-glucose-positron emission tomography predict tumor biology? Mol Imaging Biol 2008;10(1):62–6

Beer AJ, Niemeyer M, Carlsen J, Sarbia M, Nahrig J, Watzlowik P, et al. Patterns of alphavbeta3 Patients with primary expression in primary and metastatic human breast cancer as shown by 18F-galacto-RGD PET. or suspected primary J Nucl Med 2008;49(2):255–9 BC Bellon JR, Livingston RB, Eubank WB, Gralow JR, Ellis GK, Dunnwald LK, et al. Evaluation of the Part of staging in initial internal mammary lymph nodes by FDG-PET in locally advanced breast cancer (LABC). A J Clin BC diagnosis Oncol 2004;27(4):407–10 Belohlavek O, Kantorova I. Influence of positron emission tomography (PET) on therapeutic No test accuracy data decision at breast cancer – preliminary report. [Czech]. Klinicka Onkologie 2002;15(5);189–91 (included for data on patient management) Bos R, Van der Hoeven JJ, van der WE, van Der GP, Van Diest PJ, Comans EF, et al. Biologic Pre-operative PET, correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron primary setting emission tomography. J Clin Oncol 2002;20(2):379–87 Brix G, Henze M, Knopp MV, Lucht R, Doll J, Junkermann H, et al. Comparison of Diagnosis of primary pharmacokinetic MRI and 18F fluorodeoxyglucose PET in the diagnosis of breast cancer: Initial BC experience. Eur Radiol 2001;11(10):2058–70 Buchmann I, Riedmuller K, Hoffner S, Mack U, Aulmann S, Haberkorn U, et al. Comparison of Primary BC diagnosis 99mtechnetium-pertechnetate and 123-iodide SPECT with FDG-PET in patients suspicious for breast cancer. Cancer Biother Radiopharm 2007;22(6):779–89 Can N, Kapucu LO, Uner A, Unlu M. The role of 18F-FDG PET/CT in follow up of advanced stage No relevant outcomes breast cancer. [Turkish]. Uluslararasi Hematoloji-Onkoloji Dergisi 2008;18(1):9–15 Carkaci S, Macapinlac HA, Cristofanilli M, Mawlawi O, Rohren E, Gonzalez Angulo AM, et Unclear reasons for al. Retrospective study of 18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: patient referral Preliminary data. J Nucl Med 2009;50(2):231–8 Chae BJ, Bae JS, Kang BJ, Kim SH, Jung SS, Song BJ. Positron emission tomography-computed For primary staging tomography in the detection of axillary lymph node metastasis in patients with early stage breast cancer. Jpn J Clin Oncol 2009;39(5):284–9 Chin K, Finger PT, Kurli M, Tena LB, Reddy S, Chin K, et al. Second cancers discovered by (18) Diagnosis of second FDG PET/CT imaging for choroidal melanoma. Optometry 2007;78(8):396–401 primary tumours Danforth DN, Jr., Aloj L, Carrasquillo JA, Bacharach SL, Chow C, Zujewski J, et al. The role of For primary staging 18F-FDG-PET in the local/regional evaluation of women with breast cancer. Breast Cancer Res Treat 2002;75(2):135–46 Dehdashti F, Mortimer JE, Siegel BA, Griffeth LK, Bonasera TJ, Fusselman MJ, et al. Positron Incomplete reference tomographic assessment of estrogen receptors in breast cancer: Comparison with FDG-PET and standard, data not in vitro receptor assays. J Nucl Med 1995;36(10):1766–74 extractable Dizendorf EV, Baumert BG, Von Schulthess GK, Lutolf UM, Steinert HC, Dizendorf EV, et al. Staging in primary Impact of whole-body 18F-FDG PET on staging and managing patients for radiation therapy. J Nucl setting Med 2003;44(1):24–9

Reason for Referencea exclusion Dose J, Bleckmann C, Bachmann S, Bohuslavizki KH, Berger J, Jenicke L, et al. Comparison of Data merged for fluorodeoxyglucose positron emission tomography and ‘conventional diagnostic procedures’ for patients in the the detection of distant metastases in breast cancer patients. Nucl Med Commun 2002;23(9):857– setting of primary 64 and secondary investigation Eby PR, Partridge SC, White SW, Doot RK, Dunnwald LK, Schubert EK, et al. Metabolic No relevant outcomes and vascular features of dynamic contrast-enhanced breast magnetic resonance imaging and (15)O-water positron emission tomography blood flow in breast cancer. Acad Radiol 2008;15(10):1246–54 Eubank WB, Mankoff D, Bhattacharya M, Gralow J, Linden H, Ellis G, et al. Impact of FDG PET Unsatisfactory on defining the extent of disease and on the treatment of patients with recurrent or metastatic reference standard breast cancer. AJR Am J Roentgenol 2004;183(2):479–86 (included for data on patient management) Fuster D, Duch J, Paredes P, Velasco M, Munoz M, Santamaria G, et al. Preoperative staging Pre-operative staging of large primary breast cancer with [18F]fluorodeoxyglucose positron emission tomography/ in primary setting computed tomography compared with conventional imaging procedures. J Clin Oncol 2008;26(29):4746–51 Garcia JR, Simo M, Soler M, Perez G, Lopez S, Lomena F, et al. Relative roles of bone scintigraphy Assessing response to and positron emission tomography in assessing the treatment response of bone metastases. Eur treatment J Nucl Med Mol Imaging 2005;32(10):1243–4 Grahek D, Montravers F, Kerrou K, Aide N, Lotz JP, Talbot JN, et al. [18F]FDG in recurrent PET gamma camera breast cancer: diagnostic performances, clinical impact and relevance of induced changes in used (included for management. Eur J Nucl Med Mol Imaging 2004;31(2):179– 88 data on patient management) Heinisch M, Gallowitsch HJ, Mikosch P, Kresnik E, Kumnig G, Gomez I, et al. Comparison of Confirmation of FDG-PET and dynamic contrast-enhanced MRI in the evaluation of suggestive breast lesions. primary diagnosis Breast 2003;12(1):17–22 prior to surgery Heusner TA, Kuemmel S, Umutlu L, Koeninger A, Freudenberg LS, Hauth EAM, et al. PET for primary Breast cancer staging in a single session: Whole-body PET/CT mammography. J Nucl Med diagnosis 2008;49(8):1215–1222. Hoh CK, Hawkins RA, Glaspy JA, Dahlbom M, Tse NY, Hoffman EJ, et al. Cancer detection with Data not separated whole-body PET using 2-[18F]fluoro-2-deoxy-D-glucose. J Comput Assist Tomogr 1993;17(4):582–9 for PETs done for primary diagnosis and recurrence Iagaru A, Masamed R, Keesara S, Conti PS, Iagaru A, Masamed R, et al. Breast MRI and 18F FDG PET/CT for initial PET/CT in the management of breast cancer. Ann Nucl Med 2007;21(1):33–8 staging or postoperative assessment Ide M. Cancer screening with FDG-PET. Q J Nucl Med Mol Imaging 2006;50(1):23–7 BC screening in asymptomatic people Imbriaco M, Caprio MG, Limite G, Pace L, De FT, Capuano E, et al. Dual-time-point Primary diagnosis of 18F-FDG PET/CT versus dynamic breast MRI of suspicious breast lesions. AJR Am J Roentgenol BC 2008;191(5):1323–30 Inoue T, Kim EE, Wallace S, Yang DJ, Wong FC, Bassa P, et al. Positron emission tomography Unclear if patients in using [18F]fluorotamoxifen to evaluate therapeutic responses in patients with breast cancer: primary or secondary preliminary study. Cancer Biother Radiopharm 1996;11(4):235–45 treatment setting Inoue T, Yutani K, Taguchi T, Tamaki Y, Shiba E, Noguchi S, et al. Preoperative evaluation of Pre-operative staging prognosis in breast cancer patients by [(18)F]2-Deoxy-2-fluoro-D-glucose-positron emission tomography. J Cancer Res Clin Oncol 2004;130(5):273–8 Kitajima K, Nakamoto Y, Okizuka H, Onishi Y, Senda M, Suganuma N, et al. Accuracy of whole- Mixed for different body FDG-PET/CT for detecting brain metastases from non-central nervous system tumors. Ann primary cancers Nucl Med 2008;22(7):595–602 Klaeser B, Wiederkehr O, Koeberle D, Mueller A, Bubeck B, Thuerlimann B, et al. Therapeutic Initial staging impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography in the pre- and postoperative staging of patients with clinically intermediate or high-risk breast cancer. Ann Oncol 2007;18(8):1329–34 Kumar R, Zhuang H, Schnall M, Conant E, Damia S, Weinstein S, et al. FDG PET positive lymph Mixed population for nodes are highly predictive of metastasis in breast cancer. Nucl Med Commun 2006;27(3):231–6 primary diagnosis and staging 72 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

Reason for Referencea exclusion Landheer ML, Steffens MG, Klinkenbijl JH, Westenberg AH, Oyen WJ, Landheer MLEA, et al. No proper reference Value of fluorodeoxyglucose positron emission tomography in women with breast cancer. Br standard, no results J Surg 2005;92(11):1363–7 for TN and FNs Mahner S, Schirrmacher S, Brenner W, Jenicke L, Habermann CR, Avril N, et al. Comparison Raw data not provided between positron emission tomography using 2-[fluorine-18]fluoro-2-deoxy-D-glucose, conventional imaging and computed tomography for staging of breast cancer. Ann Oncol 2008;19(7):1249–54 Moy L, Ponzo F, Noz ME, Maguire J, Murphy-Walcott AD, Deans AE, et al. Improving specificity No results for PET, of breast MRI using prone PET and fused MRI and PET 3D volume datasets. J Nucl Med only for MRI/PET 2007;48(4):528–37 fused Pecking A-P, Corone MC, Alberini JL, Bertrand KF, Pallud C, Floiras JL, et al. FDG-PET Coincidence PET and detection of occult disease in oncology. [French]. Immuno-Analyse et Biologie Specialisee gamma camera 2002;17(5):287–92 Piperkova E, Raphael B, Altinyay ME, Castellon I, Libes R, Sandella N, et al. Impact of PET/CT in Cannot separate data comparison with same day contrast enhanced CT in breast cancer management. Clin Nucl Med for staging, restaging 2007;32(6):429–34 and evaluating therapy response Roman CD, Martin WH, Delbeke D. Incremental value of fusion imaging with integrated PET-CT No proper reference in oncology. Clin Nucl Med 2005;30(7):470–7 standard Rostom AY, Powe J, Kandil A, Ezzat A, Bakheet S, El-Khwsky F, et al. Positron emission Mixed population tomography in breast cancer: A clinicopathological correlation of results. B J Radiol 1999;72: with PET for primary 1064–8 diagnosis, staging and suspected recurrence Schirrmeister H, Guhlmann A, Kotzerke J, Santjohanser C, Kuhn T, Kreienberg R, et al. Early F-18-PET (not FDG) detection and accurate description of extent of metastatic bone disease in breast cancer with fluoride ion and positron emission tomography. J Clin Oncol 1999;17(8):2381–9 Schirrmeister H, Kuhn T, Guhlmann A, Santjohanser C, Horster T, Nussle K, et al. Fluorine-18 Predominantly 2-deoxy-2-fluoro-D-glucose PET in the preoperative staging of breast cancer: Comparison with patients having PET the standard staging procedures. Eur J Nucl Med Mol Imaging 2001;28(3):351–8 for primary diagnosis Schwarz-Dose J, Untch M, Tiling R, Sassen S, Mahner S, Kahlert S, et al. Monitoring primary Measuring response to systemic therapy of large and locally advanced breast cancer by using sequential positron emission chemotherapy tomography imaging with [18F]fluorodeoxyglucose. J Clin Oncol 2009;27(4):535–41 Siggelkow W, Zimny M, Faridi A, Petzold K, Buell U, Rath W, et al. The value of positron emission Data unclear and tomography in the follow-up for breast cancer. Anticancer Res 2003;23(2C):1859–67 cannot be extracted Smith IC, Ogston KN, Whitford P, Smith FW, Sharp P, Norton M, et al. Staging of the axilla in Staging in primary breast cancer: Accurate in vivo assessment using positron emission tomography with 2-(fluorine- breast cancer 18)-fluoro-2-deoxy-D- glucose. Ann Surg 1998;228(2):220–7 assessment Specht JM, Tam SL, Kurland BF, Gralow JR, Livingston RB, Linden HM, et al. Serial 2-[18F] fluoro- Referred for staging 2-deoxy-D-glucose positron emission tomography (FDG-PET) to monitor treatment of bone- dominant metastatic breast cancer predicts time to progression (TTP). Breast Cancer Res Treat 2007;105(1):87–94 Stecco A, Romano G, Negru M, Volpe D, Saponaro A, Costantino S, et al. Whole-body diffusion- Mixed results for weighted magnetic resonance imaging in the staging of oncological patients: Comparison with different cancers positron emission tomography computed tomography (PET-CT) in a pilot study. Radiologia Medica 2009;114(1):1–17 Taira N, Ohsumi S, Takabatake D, Hara F, Aogi K, Takashima S, et al. Determination of indication Primary staging for sentinel lymph node biopsy in clinical node-negative breast cancer using preoperative 18F- for lymph node fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging. Jpn metastases J Clin Oncol 2009;39(1):16–21 Tatsumi M, Cohade C, Mourtzikos KA, Fishman EK, Wahl RL, Tatsumi M, et al. Initial experience No proper reference with FDG-PET/CT in the evaluation of breast cancer. Eur J Nucl Med Mol Imaging 2006;33(3):254– standard, PET/CT vs 62 CT compared Terauchi T, Murano T, Daisaki H, Kanou D, Shoda H, Kakinuma R, et al. Evaluation of whole- Primary screening body cancer screening using 18F-2-deoxy-2-fluoro-D-glucose positron emission tomography: a investigations preliminary report. Ann Nucl Med 2008;22(5):379–85

Reason for Referencea exclusion Tran A, Pio BS, Khatibi B, Czernin J, Phelps ME, Silverman DH, et al. 18F-FDG PET for staging PET for staging breast cancer in patients with inner-quadrant versus outer-quadrant tumors: comparison with long-term clinical outcome. J Nucl Med 2005;46(9):1455–9 Uematsu T, Yuen S, Yukisawa S, Aramaki T, Morimoto N, Endo M, et al. Comparison of Patients referred for FDG PET and SPECT for detection of bone metastases in breast cancer. AJR Am J Roentgenol staging or restaging 2005;184(4):1266–73 Uematsu T, Kasami M, Yuen S. Comparison of FDG PET and MRI for evaluating the tumor extent Setting of primary BC of breast cancer and the impact of FDG PET on the systemic staging and prognosis of patients staging who are candidates for breast-conserving therapy. Breast Cancer 2009;16(2):97–104 Van der Hoeven JJ, Krak NC, Hoekstra OS, Comans EF, Boom RP, Van GD, et al. 18F-2-fluoro-2- Investigations in deoxy-d-glucose positron emission tomography in staging of locally advanced breast cancer. J Clin primary BC staging Oncol 2004;22(7):1253–9 Weir L, Worsley D, Bernstein V. The value of FDG positron emission tomography in the PET for staging or management of patients with breast cancer. Breast 2005;11(3):204–9 unclear reason for referral Yap CS, Seltzer MA, Schiepers C, Gambhir SS, Rao J, Phelps ME, et al. Impact of whole-body No test accuracy data 18F-FDG PET on staging and managing patients with breast cancer: the referring physician’s (included for data on perspective. J Nucl Med 2001;42(9):1334–7 patient management) Zornoza G, Garcia-Velloso MJ, Sola J, Regueira FM, Pina L, Beorlegui C, et al. 18F-FDG PET PET for staging complemented with sentinel lymph node biopsy in the detection of axillary involvement in breast cancer. Eur J Surg Oncol 2004;30(1):15–19 a A full list of the 185 excluded hard-copy references with reasons for exclusion can be provided on request.

74 DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

Health Technology Assessment reports published to date

Volume 1, 1997 No. 11 No. 6 Newborn screening for inborn errors of Effectiveness of hip prostheses in metabolism: a systematic review. primary total hip replacement: a critical No. 1 By Seymour CA, Thomason MJ, review of evidence and an economic Home parenteral nutrition: a systematic Chalmers RA, Addison GM, Bain MD, model. review. Cockburn F, et al. By Faulkner A, Kennedy LG, Baxter By Richards DM, Deeks JJ, Sheldon K, Donovan J, Wilkinson M, Bevan G. TA, Shaffer JL. No. 12 Routine preoperative testing: a No. 7 No. 2 systematic review of the evidence. Antimicrobial prophylaxis in colorectal Diagnosis, management and screening By Munro J, Booth A, Nicholl J. surgery: a systematic review of of early localised prostate cancer. randomised controlled trials. A review by Selley S, Donovan J, No. 13 By Song F, Glenny AM. Faulkner A, Coast J, Gillatt D. Systematic review of the effectiveness of laxatives in the elderly. No. 8 No. 3 By Petticrew M, Watt I, Sheldon T. The diagnosis, management, treatment Bone marrow and peripheral and costs of prostate cancer in England blood stem cell transplantation for and Wales. No. 14 malignancy. A review by Chamberlain J, Melia J, When and how to assess fast-changing A review by Johnson PWM, Moss S, Brown J. technologies: a comparative study of Simnett SJ, Sweetenham JW, Morgan GJ, medical applications of four generic Stewart LA. No. 4 technologies. Screening for fragile X syndrome. A review by Mowatt G, Bower DJ, No. 9 A review by Murray J, Cuckle H, Brebner JA, Cairns JA, Grant AM, McKee Screening for speech and language Taylor G, Hewison J. L. delay: a systematic review of the literature. No. 5 By Law J, Boyle J, Harris F, A review of near patient testing in Volume 2, 1998 Harkness A, Nye C. primary care. By Hobbs FDR, Delaney BC, No. 10 Fitzmaurice DA, Wilson S, Hyde CJ, Resource allocation for chronic Thorpe GH, et al. No. 1 Antenatal screening for Down’s stable angina: a systematic review of syndrome. effectiveness, costs and cost-effectiveness No. 6 of alternative interventions. Systematic review of outpatient services A review by Wald NJ, Kennard A, By Sculpher MJ, Petticrew M, for chronic pain control. Hackshaw A, McGuire A. Kelland JL, Elliott RA, Holdright DR, By McQuay HJ, Moore RA, Eccleston Buxton MJ. C, Morley S, de C Williams AC. No. 2 Screening for ovarian cancer: a No. 7 systematic review. No. 11 Neonatal screening for inborn errors of By Bell R, Petticrew M, Luengo S, Detection, adherence and control of metabolism: cost, yield and outcome. Sheldon TA. hypertension for the prevention of A review by Pollitt RJ, Green A, stroke: a systematic review. McCabe CJ, Booth A, Cooper NJ, No. 3 By Ebrahim S. Leonard JV, et al. Consensus development methods, and their use in clinical guideline No. 12 No. 8 development. Postoperative analgesia and vomiting, Preschool vision screening. A review by Murphy MK, Black NA, with special reference to day-case A review by Snowdon SK, Lamping DL, McKee CM, Sanderson surgery: a systematic review. Stewart-Brown SL. CFB, Askham J, et al. By McQuay HJ, Moore RA. No. 9 No. 4 No. 13 Implications of socio-cultural contexts Choosing between randomised and for the ethics of clinical trials. A cost–utility analysis of interferon beta nonrandomised studies: a systematic A review by Ashcroft RE, Chadwick for multiple sclerosis. review. DW, Clark SRL, Edwards RHT, Frith L, By Parkin D, McNamee P, Jacoby A, Hutton JL. Miller P, Thomas S, Bates D. By Britton A, McKee M, Black N, McPherson K, Sanderson C, Bain C. No. 10 No. 5 A critical review of the role of neonatal Effectiveness and efficiency of methods No. 14 hearing screening in the detection of of dialysis therapy for end-stage renal Evaluating patient-based outcome congenital hearing impairment. disease: systematic reviews. measures for use in clinical trials. By Davis A, Bamford J, Wilson I, By MacLeod A, Grant A, Donaldson A review by Fitzpatrick R, Davey C, Ramkalawan T, Forshaw M, Wright S. C, Khan I, Campbell M, Daly C, et al. Buxton MJ, Jones DR. 75

No. 15 No. 4 No. 15 Ethical issues in the design and conduct A randomised controlled trial of Near patient testing in diabetes clinics: of randomised controlled trials. different approaches to universal appraising the costs and outcomes. antenatal HIV testing: uptake and By Grieve R, Beech R, Vincent J, A review by Edwards SJL, Lilford RJ, acceptability. Annex: Antenatal HIV Braunholtz DA, Jackson JC, Hewison J, testing – assessment of a routine Mazurkiewicz J. Thornton J. voluntary approach. By Simpson WM, Johnstone FD, No. 16 No. 16 Boyd FM, Goldberg DJ, Hart GJ, Positron emission tomography: Qualitative research methods in health Gormley SM, et al. establishing priorities for health technology assessment: a review of the technology assessment. No. 5 literature. A review by Robert G, Milne R. By Murphy E, Dingwall R, Methods for evaluating area-wide and Greatbatch D, Parker S, Watson P. organisation-based interventions in health and health care: a systematic No. 17 (Pt 1) review. The debridement of chronic wounds: a No. 17 By Ukoumunne OC, Gulliford MC, systematic review. The costs and benefits of paramedic Chinn S, Sterne JAC, Burney PGJ. By Bradley M, Cullum N, Sheldon T. skills in pre-hospital trauma care. No. 6 By Nicholl J, Hughes S, Dixon S, No. 17 (Pt 2) Turner J, Yates D. Assessing the costs of healthcare technologies in clinical trials. Systematic reviews of wound care A review by Johnston K, Buxton MJ, management: (2) Dressings and topical No. 18 Jones DR, Fitzpatrick R. agents used in the healing of chronic Systematic review of endoscopic wounds. ultrasound in gastro-oesophageal No. 7 By Bradley M, Cullum N, Nelson EA, cancer. Cooperatives and their primary care Petticrew M, Sheldon T, Torgerson D. By Harris KM, Kelly S, Berry E, emergency centres: organisation and Hutton J, Roderick P, Cullingworth J, impact. No. 18 By Hallam L, Henthorne K. et al. A systematic literature review of spiral and electron beam computed No. 19 No. 8 tomography: with particular reference Screening for cystic fibrosis. to clinical applications in hepatic Systematic reviews of trials and other A review by Murray J, Cuckle H, studies. lesions, pulmonary embolus and Taylor G, Littlewood J, Hewison J. coronary artery disease. By Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. No. 9 By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al. A review of the use of health status No. 20 measures in economic evaluation. No. 19 Primary total hip replacement surgery: By Brazier J, Deverill M, Green C, a systematic review of outcomes Harper R, Booth A. What role for statins? A review and and modelling of cost-effectiveness economic model. associated with different prostheses. No. 10 By Ebrahim S, Davey Smith Methods for the analysis of quality- A review by Fitzpatrick R, Shortall G, McCabe C, Payne N, Pickin M, of-life and survival data in health Sheldon TA, et al. E, Sculpher M, Murray D, Morris R, technology assessment. Lodge M, et al. A review by Billingham LJ, No. 20 Abrams KR, Jones DR. Factors that limit the quality, number and progress of randomised controlled Volume 3, 1999 No. 11 Antenatal and neonatal trials. haemoglobinopathy screening in the A review by Prescott RJ, Counsell CE, UK: review and economic analysis. Gillespie WJ, Grant AM, Russell IT, No. 1 By Zeuner D, Ades AE, Karnon J, Kiauka S, et al. Informed decision making: an Brown J, Dezateux C, Anionwu EN. annotated bibliography and systematic No. 21 review. No. 12 Antimicrobial prophylaxis in total hip By Bekker H, Thornton JG, Assessing the quality of reports of replacement: a systematic review. randomised trials: implications for the Airey CM, Connelly JB, Hewison J, By Glenny AM, Song F. Robinson MB, et al. conduct of meta-analyses. A review by Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, No. 22 No. 2 Jones A, et al. Health promoting schools and health Handling uncertainty when performing promotion in schools: two systematic economic evaluation of healthcare No. 13 reviews. interventions. ‘Early warning systems’ for identifying By Lister-Sharp D, Chapman S, A review by Briggs AH, Gray AM. new healthcare technologies. Stewart-Brown S, Sowden A. By Robert G, Stevens A, Gabbay J. No. 3 No. 23 No. 14 The role of expectancies in the placebo A systematic review of the role of Economic evaluation of a primary effect and their use in the delivery of human papillomavirus testing within a care-based education programme for health care: a systematic review. cervical screening programme. patients with osteoarthritis of the knee. By Crow R, Gage H, Hampson S, By Cuzick J, Sasieni P, Davies P, A review by Lord J, Victor C, 76 Hart J, Kimber A, Thomas H. Adams J, Normand C, Frater A, et al. Littlejohns P, Ross FM, Axford JS. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

Volume 4, 2000 No. 11 No. 21 Cost and outcome implications of the Systematic reviews of wound care organisation of vascular services. management: (3) antimicrobial agents No. 1 By Michaels J, Brazier J, for chronic wounds; (4) diabetic foot ulceration. The estimation of marginal time Palfreyman S, Shackley P, Slack R. preference in a UK-wide sample By O’Meara S, Cullum N, Majid M, (TEMPUS) project. No. 12 Sheldon T. A review by Cairns JA, Monitoring blood glucose control in No. 22 van der Pol MM. diabetes mellitus: a systematic review. By Coster S, Gulliford MC, Seed PT, Using routine data to complement and enhance the results of randomised No. 2 Powrie JK, Swaminathan R. controlled trials. Geriatric rehabilitation following No. 13 By Lewsey JD, Leyland AH, Murray fractures in older people: a systematic GD, Boddy FA. review. The effectiveness of domiciliary By Cameron I, Crotty M, Currie C, health visiting: a systematic review of international studies and a selective No. 23 Finnegan T, Gillespie L, Gillespie W, Coronary artery stents in the treatment et al. review of the British literature. By Elkan R, Kendrick D, Hewitt M, of ischaemic heart disease: a rapid and Robinson JJA, Tolley K, Blair M, et al. systematic review. No. 3 By Meads C, Cummins C, Jolly K, Screening for sickle cell disease and Stevens A, Burls A, Hyde C. thalassaemia: a systematic review with No. 14 The determinants of screening uptake supplementary research. No. 24 By Davies SC, Cronin E, Gill M, and interventions for increasing uptake: a systematic review. Outcome measures for adult critical Greengross P, Hickman M, Normand C. care: a systematic review. By Jepson R, Clegg A, Forbes C, Lewis R, Sowden A, Kleijnen J. By Hayes JA, Black NA, Jenkinson C, No. 4 Young JD, Rowan KM, Daly K, et al. Community provision of hearing aids No. 15 and related audiology services. No. 25 The effectiveness and cost-effectiveness A review by Reeves DJ, Alborz A, A systematic review to evaluate the Hickson FS, Bamford JM. of prophylactic removal of wisdom teeth. effectiveness of interventions to promote the initiation of breastfeeding. A rapid review by Song F, O’Meara S, No. 5 By Fairbank L, O’Meara S, Wilson P, Golder S, Kleijnen J. False-negative results in screening Renfrew MJ, Woolridge M, Sowden AJ, programmes: systematic review of Lister-Sharp D. No. 16 impact and implications. Ultrasound screening in pregnancy: By Petticrew MP, Sowden AJ, No. 26 a systematic review of the clinical Lister-Sharp D, Wright K. Implantable cardioverter defibrillators: effectiveness, cost-effectiveness and arrhythmias. A rapid and systematic women’s views. No. 6 review. By Bricker L, Garcia J, Henderson J, By Parkes J, Bryant J, Milne R. Costs and benefits of community Mugford M, Neilson J, Roberts T, et al. postnatal support workers: a randomised controlled trial. No. 27 No. 17 By Morrell CJ, Spiby H, Stewart P, Treatments for fatigue in multiple A rapid and systematic review of the Walters S, Morgan A. sclerosis: a rapid and systematic review. effectiveness and cost-effectiveness of By Brañas P, Jordan R, Fry-Smith A, the taxanes used in the treatment of Burls A, Hyde C. No. 7 advanced breast and ovarian cancer. Implantable contraceptives (subdermal By Lister-Sharp D, McDonagh MS, No. 28 implants and hormonally impregnated Khan KS, Kleijnen J. intrauterine systems) versus other Early asthma prophylaxis, natural history, skeletal development and forms of reversible contraceptives: two No. 18 systematic reviews to assess relative economy (EASE): a pilot randomised Liquid-based cytology in cervical effectiveness, acceptability, tolerability controlled trial. screening: a rapid and systematic and cost-effectiveness. By Baxter-Jones ADG, Helms PJ, review. By French RS, Cowan FM, Russell G, Grant A, Ross S, Cairns JA, By Payne N, Chilcott J, McGoogan E. Mansour DJA, Morris S, Procter T, et al. Hughes D, et al. No. 19 No. 29 No. 8 Randomised controlled trial of non- Screening for hypercholesterolaemia directive counselling, cognitive– An introduction to statistical methods versus case finding for familial behaviour therapy and usual general for health technology assessment. hypercholesterolaemia: a systematic practitioner care in the management of review and cost-effectiveness analysis. A review by White SJ, Ashby D, depression as well as mixed anxiety and Brown PJ. By Marks D, Wonderling depression in primary care. D, Thorogood M, Lambert H, By King M, Sibbald B, Ward E, Humphries SE, Neil HAW. No. 9 Bower P, Lloyd M, Gabbay M, et al. Disease-modifying drugs for multiple No. 30 sclerosis: a rapid and systematic review. No. 20 A rapid and systematic review of By Clegg A, Bryant J, Milne R. Routine referral for radiography of the clinical effectiveness and cost- patients presenting with low back pain: effectiveness of glycoprotein IIb/ No. 10 is patients’ outcome influenced by GPs’ IIIa antagonists in the medical Publication and related biases. referral for plain radiography? management of unstable angina. A review by Song F, Eastwood AJ, By Kerry S, Hilton S, Patel S, By McDonagh MS, Bachmann LM, Gilbody S, Duley L, Sutton AJ. Dundas D, Rink E, Lord J. Golder S, Kleijnen J, ter Riet G. 77

No. 31 Volume 5, 2001 No. 11 A randomised controlled trial Effectiveness of autologous chondrocyte of prehospital intravenous fluid transplantation for hyaline cartilage replacement therapy in serious trauma. No. 1 defects in knees: a rapid and systematic review. By Turner J, Nicholl J, Webber L, Clinical and cost-effectiveness Cox H, Dixon S, Yates D. of donepezil, rivastigmine and By Jobanputra P, Parry D, Fry-Smith galantamine for Alzheimer’s disease: a A, Burls A. No. 32 rapid and systematic review. No. 12 Intrathecal pumps for giving opioids in By Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al. Statistical assessment of the learning chronic pain: a systematic review. curves of health technologies. By Williams JE, Louw G, By Ramsay CR, Grant AM, Wallace No. 2 Towlerton G. SA, Garthwaite PH, Monk AF, Russell IT. The clinical effectiveness and cost- effectiveness of riluzole for motor No. 33 No. 13 neurone disease: a rapid and systematic Combination therapy (interferon review. The effectiveness and cost-effectiveness alfa and ribavirin) in the treatment of temozolomide for the treatment of By Stewart A, Sandercock J, Bryan S, of chronic hepatitis C: a rapid and recurrent malignant glioma: a rapid Hyde C, Barton PM, Fry-Smith A, et al. systematic review. and systematic review. By Shepherd J, Waugh N, By Dinnes J, Cave C, Huang S, No. 3 Hewitson P. Major K, Milne R. Equity and the economic evaluation of healthcare. No. 34 No. 14 By Sassi F, Archard L, Le Grand J. A systematic review of comparisons of A rapid and systematic review of the clinical effectiveness and cost- effect sizes derived from randomised No. 4 and non-randomised studies. effectiveness of debriding agents in Quality-of-life measures in chronic treating surgical wounds healing by By MacLehose RR, Reeves BC, diseases of childhood. secondary intention. Harvey IM, Sheldon TA, Russell IT, By Eiser C, Morse R. By Lewis R, Whiting P, ter Riet G, Black AMS. O’Meara S, Glanville J. No. 5 No. 35 Eliciting public preferences for No. 15 Intravascular ultrasound-guided healthcare: a systematic review of Home treatment for mental health interventions in coronary artery techniques. problems: a systematic review. disease: a systematic literature review, By Ryan M, Scott DA, Reeves C, Bate By Burns T, Knapp M, Catty J, with decision-analytic modelling, of A, van Teijlingen ER, Russell EM, et al. Healey A, Henderson J, Watt H, et al. outcomes and cost-effectiveness. By Berry E, Kelly S, Hutton J, No. 6 No. 16 Lindsay HSJ, Blaxill JM, Evans JA, et al. General health status measures for How to develop cost-conscious people with cognitive impairment: guidelines. No. 36 learning disability and acquired brain By Eccles M, Mason J. A randomised controlled trial to injury. evaluate the effectiveness and cost- By Riemsma RP, Forbes CA, No. 17 effectiveness of counselling patients Glanville JM, Eastwood AJ, Kleijnen J. The role of specialist nurses in multiple with chronic depression. sclerosis: a rapid and systematic review. By Simpson S, Corney R, No. 7 By De Broe S, Christopher F, Fitzgerald P, Beecham J. An assessment of screening strategies Waugh N. for fragile X syndrome in the UK. No. 18 No. 37 By Pembrey ME, Barnicoat AJ, Systematic review of treatments for Carmichael B, Bobrow M, Turner G. A rapid and systematic review atopic eczema. of the clinical effectiveness and cost-effectiveness of orlistat in the No. 8 By Hoare C, Li Wan Po A, management of obesity. Williams H. Issues in methodological research: By O’Meara S, Riemsma R, perspectives from researchers and Shirran L, Mather L, ter Riet G. No. 38 commissioners. Bayesian methods in health technology By Lilford RJ, Richardson A, Stevens No. 19 A, Fitzpatrick R, Edwards S, Rock F, et al. assessment: a review. The clinical effectiveness and cost- By Spiegelhalter DJ, Myles JP, effectiveness of pioglitazone for Jones DR, Abrams KR. No. 9 type 2 diabetes mellitus: a rapid and Systematic reviews of wound systematic review. No. 39 care management: (5) beds; By Chilcott J, Wight J, Lloyd Jones (6) compression; (7) laser therapy, M, Tappenden P. The management of dyspepsia: a therapeutic ultrasound, electrotherapy systematic review. and electromagnetic therapy. 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No. 21 No. 31 No. 4 Systematic reviews of the effectiveness Design and use of questionnaires: a A systematic review of discharge of day care for people with severe review of best practice applicable to arrangements for older people. mental disorders: (1) Acute day hospital surveys of health service staff and By Parker SG, Peet SM, McPherson versus admission; (2) Vocational patients. A, Cannaby AM, Baker R, Wilson A, et al. rehabilitation; (3) Day hospital versus By McColl E, Jacoby A, Thomas L, outpatient care. Soutter J, Bamford C, Steen N, et al. No. 5 By Marshall M, Crowther R, The clinical effectiveness and cost- Almaraz-Serrano A, Creed F, Sledge W, No. 32 effectiveness of inhaler devices used Kluiter H, et al. in the routine management of chronic A rapid and systematic review of asthma in older children: a systematic the clinical effectiveness and cost- No. 22 review and economic evaluation. effectiveness of paclitaxel, docetaxel, The measurement and monitoring of By Peters J, Stevenson M, Beverley C, surgical adverse events. gemcitabine and vinorelbine in non- small-cell lung cancer. Lim J, Smith S. By Bruce J, Russell EM, Mollison J, By Clegg A, Scott DA, Sidhu M, Krukowski ZH. No. 6 Hewitson P, Waugh N. The clinical effectiveness and cost- No. 23 effectiveness of sibutramine in the Action research: a systematic review and No. 33 management of obesity: a technology guidance for assessment. Subgroup analyses in randomised assessment. By Waterman H, Tillen D, Dickson R, controlled trials: quantifying the risks By O’Meara S, Riemsma R, Shirran de Koning K. of false-positives and false-negatives. L, Mather L, ter Riet G. By Brookes ST, Whitley E, Peters TJ, No. 24 Mulheran PA, Egger M, Davey Smith G. No. 7 A rapid and systematic review of The cost-effectiveness of magnetic the clinical effectiveness and cost- No. 34 resonance angiography for carotid effectiveness of gemcitabine for the artery stenosis and peripheral vascular treatment of pancreatic cancer. Depot antipsychotic medication in the treatment of patients with disease: a systematic review. By Ward S, Morris E, Bansback N, schizophrenia: (1) Meta-review; (2) By Berry E, Kelly S, Westwood ME, Calvert N, Crellin A, Forman D, et al. Patient and nurse attitudes. Davies LM, Gough MJ, Bamford JM, et al. No. 25 By David AS, Adams C. A rapid and systematic review of the No. 8 No. 35 evidence for the clinical effectiveness Promoting physical activity in South and cost-effectiveness of irinotecan, A systematic review of controlled Asian Muslim women through ‘exercise oxaliplatin and raltitrexed for the trials of the effectiveness and cost- on prescription’. treatment of advanced colorectal effectiveness of brief psychological By Carroll B, Ali N, Azam N. cancer. treatments for depression. By Lloyd Jones M, Hummel S, By Churchill R, Hunot V, Corney R, No. 9 Bansback N, Orr B, Seymour M. Knapp M, McGuire H, Tylee A, et al. Zanamivir for the treatment of No. 26 influenza in adults: a systematic review No. 36 and economic evaluation. Comparison of the effectiveness of Cost analysis of child health inhaler devices in asthma and chronic By Burls A, Clark W, Stewart T, surveillance. obstructive airways disease: a systematic Preston C, Bryan S, Jefferson T, et al. review of the literature. By Sanderson D, Wright D, Acton C, By Brocklebank D, Ram F, Wright J, Duree D. No. 10 Barry P, Cates C, Davies L, et al. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and No. 27 Volume 6, 2002 The cost-effectiveness of magnetic health economic models. resonance imaging for investigation of By Richards RG, Sampson FC, the knee joint. Beard SM, Tappenden P. By Bryan S, Weatherburn G, Bungay No. 1 H, Hatrick C, Salas C, Parry D, et al. A study of the methods used to select No. 11 review criteria for clinical audit. Screening for gestational diabetes: No. 28 By Hearnshaw H, Harker R, a systematic review and economic A rapid and systematic review of Cheater F, Baker R, Grimshaw G. evaluation. the clinical effectiveness and cost- By Scott DA, Loveman E, McIntyre effectiveness of topotecan for ovarian No. 2 L, Waugh N. cancer. Fludarabine as second-line therapy for No. 12 By Forbes C, Shirran L, Bagnall A-M, B cell chronic lymphocytic leukaemia: a Duffy S, ter Riet G. technology assessment. The clinical effectiveness and cost- effectiveness of surgery for people with By Hyde C, Wake B, Bryan S, Barton No. 29 morbid obesity: a systematic review and P, Fry-Smith A, Davenport C, et al. Superseded by a report published in a economic evaluation. later volume. By Clegg AJ, Colquitt J, Sidhu MK, No. 3 Royle P, Loveman E, Walker A. No. 30 Rituximab as third-line treatment for The role of radiography in primary refractory or recurrent Stage III or IV No. 13 care patients with low back pain of at follicular non-Hodgkin’s lymphoma: The clinical effectiveness of least 6 weeks duration: a randomised a systematic review and economic trastuzumab for breast cancer: a (unblinded) controlled trial. evaluation. systematic review. 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No. 14 No. 23 No. 32 The clinical effectiveness and cost- A systematic review and economic The measurement of satisfaction with effectiveness of vinorelbine for breast evaluation of pegylated liposomal healthcare: implications for practice cancer: a systematic review and doxorubicin hydrochloride for ovarian from a systematic review of the economic evaluation. cancer. literature. By Lewis R, Bagnall A-M, King S, By Forbes C, Wilby J, Richardson G, By Crow R, Gage H, Hampson S, Woolacott N, Forbes C, Shirran L, et al. Sculpher M, Mather L, Riemsma R. Hart J, Kimber A, Storey L, et al.

No. 15 No. 24 No. 33 A systematic review of the effectiveness A systematic review of the effectiveness The effectiveness and cost-effectiveness and cost-effectiveness of metal-on- of interventions based on a stages-of- of imatinib in chronic myeloid metal hip resurfacing arthroplasty for change approach to promote individual leukaemia: a systematic review. treatment of hip disease. behaviour change. By Garside R, Round A, Dalziel K, By Vale L, Wyness L, McCormack K, By Riemsma RP, Pattenden J, Bridle Stein K, Royle R. McKenzie L, Brazzelli M, Stearns SC. C, Sowden AJ, Mather L, Watt IS, et al. No. 34 No. 16 No. 25 A comparative study of hypertonic saline, daily and alternate-day rhDNase The clinical effectiveness and cost- A systematic review update of the in children with cystic fibrosis. effectiveness of bupropion and nicotine clinical effectiveness and cost- replacement therapy for smoking effectiveness of glycoprotein IIb/IIIa By Suri R, Wallis C, Bush A, cessation: a systematic review and antagonists. Thompson S, Normand C, Flather M, economic evaluation. By Robinson M, Ginnelly L, Sculpher et al. By Woolacott NF, Jones L, Forbes CA, M, Jones L, Riemsma R, Palmer S, et al. No. 35 Mather LC, Sowden AJ, Song FJ, et al. No. 26 A systematic review of the costs and effectiveness of different models of No. 17 A systematic review of the effectiveness, paediatric home care. A systematic review of effectiveness cost-effectiveness and barriers to implementation of thrombolytic and By Parker G, Bhakta P, Lovett CA, and economic evaluation of new drug Paisley S, Olsen R, Turner D, et al. treatments for juvenile idiopathic neuroprotective therapy for acute arthritis: etanercept. ischaemic stroke in the NHS. By Cummins C, Connock M, By Sandercock P, Berge E, Dennis M, Fry-Smith A, Burls A. Forbes J, Hand P, Kwan J, et al. Volume 7, 2003 No. 27 No. 18 A randomised controlled crossover trial Clinical effectiveness and cost- No. 1 of nurse practitioner versus doctor- effectiveness of growth hormone in How important are comprehensive led outpatient care in a bronchiectasis children: a systematic review and literature searches and the assessment clinic. economic evaluation. of trial quality in systematic reviews? By Caine N, Sharples LD, By Bryant J, Cave C, Mihaylova B, Empirical study. Hollingworth W, French J, Keogan M, Chase D, McIntyre L, Gerard K, et al. By Egger M, Jüni P, Bartlett C, Exley A, et al. Holenstein F, Sterne J. No. 19 No. 28 Clinical effectiveness and cost- No. 2 Clinical effectiveness and cost – Systematic review of the effectiveness effectiveness of growth hormone consequences of selective serotonin in adults in relation to impact on and cost-effectiveness, and economic reuptake inhibitors in the treatment of evaluation, of home versus hospital or quality of life: a systematic review and sex offenders. economic evaluation. satellite unit haemodialysis for people By Adi Y, Ashcroft D, Browne K, with end-stage renal failure. By Bryant J, Loveman E, Chase D, Beech A, Fry-Smith A, Hyde C. Mihaylova B, Cave C, Gerard K, et al. By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al. No. 29 No. 20 Treatment of established osteoporosis: No. 3 Clinical medication review by a a systematic review and cost–utility Systematic review and economic pharmacist of patients on repeat analysis. evaluation of the effectiveness of prescriptions in general practice: a By Kanis JA, Brazier JE, Stevenson infliximab for the treatment of Crohn’s randomised controlled trial. M, Calvert NW, Lloyd Jones M. disease. By Zermansky AG, Petty DR, Raynor By Clark W, Raftery J, Barton P, DK, Lowe CJ, Freementle N, Vail A. No. 30 Song F, Fry-Smith A, Burls A. Which anaesthetic agents are cost- No. 21 effective in day surgery? Literature No. 4 The effectiveness of infliximab and review, national survey of practice and A review of the clinical effectiveness etanercept for the treatment of randomised controlled trial. and cost-effectiveness of routine anti-D rheumatoid arthritis: a systematic By Elliott RA, Payne K, Moore JK, prophylaxis for pregnant women who review and economic evaluation. Davies LM, Harper NJN, St Leger AS, are rhesus negative. By Jobanputra P, Barton P, Bryan S, et al. By Chilcott J, Lloyd Jones M, Wight Burls A. J, Forman K, Wray J, Beverley C, et al. No. 31 No. 22 Screening for hepatitis C among No. 5 A systematic review and economic injecting drug users and in Systematic review and evaluation of the evaluation of computerised cognitive genitourinary medicine clinics: use of tumour markers in paediatric behaviour therapy for depression and systematic reviews of effectiveness, oncology: Ewing’s sarcoma and anxiety. modelling study and national survey of neuroblastoma. By Kaltenthaler E, Shackley P, current practice. By Riley RD, Burchill SA, Stevens K, Beverley C, Parry G, By Stein K, Dalziel K, Walker A, Abrams KR, Heney D, Lambert PC, 80 Chilcott J. McIntyre L, Jenkins B, Horne J, et al. Jones DR, et al. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

No. 6 No. 15 No. 25 The cost-effectiveness of screening for Early thrombolysis for the treatment The clinical and cost-effectiveness of Helicobacter pylori to reduce mortality of acute myocardial infarction: a pulsatile machine perfusion versus cold and morbidity from gastric cancer and systematic review and economic storage of kidneys for transplantation peptic ulcer disease: a discrete-event evaluation. retrieved from heart-beating and non- simulation model. heart-beating donors. By Boland A, Dundar Y, Bagust A, By Roderick P, Davies R, Raftery J, Haycox A, Hill R, Mujica Mota R, et al. By Wight J, Chilcott J, Holmes M, Crabbe D, Pearce R, Bhandari P, et al. Brewer N. No. 16 No. 7 No. 26 The clinical effectiveness and cost- Screening for fragile X syndrome: a Can randomised trials rely on existing effectiveness of routine dental checks: literature review and modelling. electronic data? A feasibility study to a systematic review and economic By Song FJ, Barton P, Sleightholme explore the value of routine data in evaluation. V, Yao GL, Fry-Smith A. health technology assessment. By Davenport C, Elley K, Salas By Williams JG, Cheung WY, C, Taylor-Weetman CL, Fry-Smith A, No. 17 Cohen DR, Hutchings HA, Longo MF, Bryan S, et al. Systematic review of endoscopic sinus Russell IT. surgery for nasal polyps. No. 8 No. 27 A multicentre randomised controlled By Dalziel K, Stein K, Round A, Garside R, Royle P. Evaluating non-randomised trial assessing the costs and benefits intervention studies. of using structured information and By Deeks JJ, Dinnes J, D’Amico R, analysis of women’s preferences in the No. 18 Sowden AJ, Sakarovitch C, Song F, et al. management of menorrhagia. Towards efficient guidelines: how to By Kennedy ADM, Sculpher MJ, monitor guideline use in primary care. No. 28 Coulter A, Dwyer N, Rees M, Horsley S, By Hutchinson A, McIntosh A, et al. A randomised controlled trial to assess Cox S, Gilbert C. the impact of a package comprising a patient-orientated, evidence-based self- No. 9 No. 19 help guidebook and patient-centred Clinical effectiveness and cost–utility consultations on disease management Effectiveness and cost-effectiveness of photodynamic therapy for wet and satisfaction in inflammatory bowel of acute hospital-based spinal cord age-related macular degeneration: disease. a systematic review and economic injuries services: systematic review. By Kennedy A, Nelson E, Reeves D, evaluation. By Bagnall A-M, Jones L, Richardson Richardson G, Roberts C, Robinson A, By Meads C, Salas C, Roberts T, G, Duffy S, Riemsma R. et al. Moore D, Fry-Smith A, Hyde C. No. 20 No. 29 No. 10 Prioritisation of health technology The effectiveness of diagnostic tests for Evaluation of molecular tests for assessment. The PATHS model: the assessment of shoulder pain due prenatal diagnosis of chromosome methods and case studies. to soft tissue disorders: a systematic abnormalities. review. By Grimshaw GM, Szczepura A, By Townsend J, Buxton M, By Dinnes J, Loveman E, McIntyre L, Hultén M, MacDonald F, Nevin NC, Harper G. Waugh N. Sutton F, et al. No. 21 No. 30 No. 11 Systematic review of the clinical First and second trimester antenatal effectiveness and cost-effectiveness of The value of digital imaging in diabetic screening for Down’s syndrome: tension-free vaginal tape for treatment retinopathy. the results of the Serum, Urine and of urinary stress incontinence. By Sharp PF, Olson J, Strachan F, Ultrasound Screening Study (SURUSS). Hipwell J, Ludbrook A, O’Donnell M, By Cody J, Wyness L, Wallace S, et al. By Wald NJ, Rodeck C, Hackshaw Glazener C, Kilonzo M, Stearns S, et al. AK, Walters J, Chitty L, Mackinson AM. No. 31 No. 22 No. 12 Lowering blood pressure to prevent The effectiveness and cost-effectiveness The clinical and cost-effectiveness of myocardial infarction and stroke: a new of ultrasound locating devices for patient education models for diabetes: preventive strategy. central venous access: a systematic a systematic review and economic By Law M, Wald N, Morris J. review and economic evaluation. evaluation. By Calvert N, Hind D, McWilliams By Loveman E, Cave C, Green C, No. 32 RG, Thomas SM, Beverley C, Royle P, Dunn N, Waugh N. Clinical and cost-effectiveness of Davidson A. capecitabine and tegafur with uracil for No. 23 the treatment of metastatic colorectal No. 13 The role of modelling in prioritising cancer: systematic review and economic A systematic review of atypical and planning clinical trials. evaluation. antipsychotics in schizophrenia. By Ward S, Kaltenthaler E, Cowan J, By Chilcott J, Brennan A, Booth A, By Bagnall A-M, Jones L, Lewis R, Brewer N. Karnon J, Tappenden P. 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No. 34 Volume 8, 2004 No. 10 Literature searching for clinical and A systematic review and economic cost-effectiveness studies used in health evaluation of magnetic resonance cholangiopancreatography compared technology assessment reports carried No. 1 with diagnostic endoscopic retrograde out for the National Institute for What is the best imaging strategy for Clinical Excellence appraisal system. cholangiopancreatography. acute stroke? By Kaltenthaler E, Bravo Vergel Y, By Royle P, Waugh N. By Wardlaw JM, Keir SL, Seymour J, Chilcott J, Thomas S, Blakeborough T, Lewis S, Sandercock PAG, Dennis MS, Walters SJ, et al. No. 35 et al. Systematic review and economic No. 11 decision modelling for the prevention No. 2 The use of modelling to evaluate and treatment of influenza A and B. 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By Garside R, Stein K, Wyatt K, No. 37 By Pandor A, Eastham J, Beverley C, Round A, Price A. Chilcott J, Paisley S. Redesigning postnatal care: a randomised controlled trial of protocol- No. 4 No. 13 based midwifery-led care focused A systematic review of the role of Clinical effectiveness and cost- on individual women’s physical and bisphosphonates in metastatic disease. effectiveness of pioglitazone and psychological health needs. By Ross JR, Saunders Y, rosiglitazone in the treatment of type By MacArthur C, Winter HR, Edmonds PM, Patel S, Wonderling D, 2 diabetes: a systematic review and Bick DE, Lilford RJ, Lancashire RJ, Normand C, et al. economic evaluation. Knowles H, et al. By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, No. 5 No. 38 Cowan J. Systematic review of the clinical Estimating implied rates of discount in effectiveness and cost-effectiveness No. 14 healthcare decision-making. ® of capecitabine (Xeloda ) for locally Routine examination of the newborn: By West RR, McNabb R, Thompson advanced and/or metastatic breast the EMREN study. Evaluation of an AGH, Sheldon TA, Grimley Evans J. cancer. extension of the midwife role including By Jones L, Hawkins N, Westwood M, a randomised controlled trial of No. 39 Wright K, Richardson G, Riemsma R. appropriately trained midwives and Systematic review of isolation policies paediatric senior house officers. in the hospital management of No. 6 By Townsend J, Wolke D, Hayes J, methicillin-resistant Staphylococcus Effectiveness and efficiency of guideline Davé S, Rogers C, Bloomfield L, et al. aureus: a review of the literature dissemination and implementation with epidemiological and economic strategies. No. 15 modelling. By Grimshaw JM, Thomas RE, Involving consumers in research and development agenda setting for the By Cooper BS, Stone SP, Kibbler CC, MacLennan G, Fraser C, Ramsay CR, Vale L, et al. NHS: developing an evidence-based Cookson BD, Roberts JA, Medley GF, approach. et al. By Oliver S, Clarke-Jones L, Rees R, No. 7 Milne R, Buchanan P, Gabbay J, et al. No. 40 Clinical effectiveness and costs of the Treatments for spasticity and pain in Sugarbaker procedure for the treatment No. 16 multiple sclerosis: a systematic review. of pseudomyxoma peritonei. A multi-centre randomised controlled By Beard S, Hunn A, Wight J. By Bryant J, Clegg AJ, Sidhu MK, trial of minimally invasive direct Brodin H, Royle P, Davidson P. coronary bypass grafting versus percutaneous transluminal coronary No. 41 No. 8 angioplasty with stenting for proximal The inclusion of reports of randomised Psychological treatment for insomnia stenosis of the left anterior descending trials published in languages other than in the regulation of long-term hypnotic coronary artery. English in systematic reviews. drug use. By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al. By Moher D, Pham B, Lawson ML, By Morgan K, Dixon S, Mathers N, Klassen TP. Thompson J, Tomeny M. No. 17 Does early magnetic resonance imaging No. 42 No. 9 influence management or improve The impact of screening on future Improving the evaluation of outcome in patients referred to health-promoting behaviours and therapeutic interventions in multiple secondary care with low back pain? 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No. 18 No. 27 No. 36 The clinical and cost-effectiveness Methods for expected value of Review of guidelines for good practice of anakinra for the treatment of information analysis in complex health in decision-analytic modelling in health rheumatoid arthritis in adults: a economic models: developments on technology assessment. systematic review and economic the health economics of interferon-β By Philips Z, Ginnelly L, Sculpher M, analysis. and glatiramer acetate for multiple Claxton K, Golder S, Riemsma R, et al. By Clark W, Jobanputra P, Barton P, sclerosis. Burls A. By Tappenden P, Chilcott JB, No. 37 Eggington S, Oakley J, McCabe C. Rituximab (MabThera®) for aggressive non-Hodgkin’s lymphoma: systematic No. 19 No. 28 review and economic evaluation. 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By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the No. 39 By Karnon J, Peters J, Platt J, VenUS Team. Pegylated interferon α-2a and -2b Chilcott J, McGoogan E, Brewer N. in combination with ribavirin in the No. 30 treatment of chronic hepatitis C: No. 21 Systematic review of the effectiveness a systematic review and economic Systematic review of the long-term and cost-effectiveness, and economic evaluation. effects and economic consequences of evaluation, of myocardial perfusion By Shepherd J, Brodin H, Cave C, treatments for obesity and implications scintigraphy for the diagnosis and Waugh N, Price A, Gabbay J. for health improvement. management of angina and myocardial By Avenell A, Broom J, Brown TJ, infarction. No. 40 Poobalan A, Aucott L, Stearns SC, et al. By Mowatt G, Vale L, Brazzelli M, Clopidogrel used in combination with Hernandez R, Murray A, Scott N, et al. aspirin compared with aspirin alone No. 22 in the treatment of non-ST-segment- No. 31 elevation acute coronary syndromes: Autoantibody testing in children A pilot study on the use of decision a systematic review and economic with newly diagnosed type 1 diabetes theory and value of information evaluation. mellitus. analysis as part of the NHS Health By Main C, Palmer S, Griffin S, Jones By Dretzke J, Cummins C, Technology Assessment programme. L, Orton V, Sculpher M, et al. Sandercock J, Fry-Smith A, Barrett T, By Claxton K, Ginnelly L, Sculpher Burls A. M, Philips Z, Palmer S. No. 41 Provision, uptake and cost of cardiac No. 23 No. 32 rehabilitation programmes: improving Clinical effectiveness and cost- The Social Support and Family Health services to under-represented groups. effectiveness of prehospital intravenous Study: a randomised controlled trial By Beswick AD, Rees K, Griebsch I, fluids in trauma patients. and economic evaluation of two Taylor FC, Burke M, West RR, et al. By Dretzke J, Sandercock J, Bayliss alternative forms of postnatal support S, Burls A. for mothers living in disadvantaged No. 42 inner-city areas. Involving South Asian patients in By Wiggins M, Oakley A, Roberts I, clinical trials. No. 24 Turner H, Rajan L, Austerberry H, et al. By Hussain-Gambles M, Leese B, Newer hypnotic drugs for the short- Atkin K, Brown J, Mason S, Tovey P. term management of insomnia: a No. 33 systematic review and economic Psychosocial aspects of genetic No. 43 evaluation. screening of pregnant women and Clinical and cost-effectiveness of By Dündar Y, Boland A, Strobl J, newborns: a systematic review. continuous subcutaneous insulin Dodd S, Haycox A, Bagust A, et al. By Green JM, Hewison J, Bekker HL, infusion for diabetes. Bryant LD, Cuckle HS. By Colquitt JL, Green C, Sidhu MK, No. 25 Hartwell D, Waugh N. Development and validation of No. 34 methods for assessing the quality of Evaluation of abnormal uterine No. 44 diagnostic accuracy studies. bleeding: comparison of three Identification and assessment of By Whiting P, Rutjes AWS, Dinnes J, outpatient procedures within cohorts ongoing trials in health technology Reitsma JB, Bossuyt PMM, Kleijnen J. defined by age and menopausal status. assessment reviews. By Critchley HOD, Warner P, Lee AJ, By Song FJ, Fry-Smith A, Davenport Brechin S, Guise J, Graham B. C, Bayliss S, Adi Y, Wilson JS, et al. No. 26 EVALUATE hysterectomy trial: No. 35 No. 45 a multicentre randomised trial Coronary artery stents: a rapid Systematic review and economic comparing abdominal, vaginal and systematic review and economic evaluation of a long-acting insulin laparoscopic methods of hysterectomy. evaluation. analogue, insulin glargine By Garry R, Fountain J, Brown J, By Hill R, Bagust A, Bakhai A, By Warren E, Weatherley-Jones E, Manca A, Mason S, Sculpher M, et al. Dickson R, Dündar Y, Haycox A, et al. Chilcott J, Beverley C. 83

No. 46 No. 4 No. 13 Supplementation of a home-based Randomised evaluation of alternative Cervical screening programmes: can exercise programme with a class- electrosurgical modalities to treat automation help? Evidence from based programme for people bladder outflow obstruction in men systematic reviews, an economic with osteoarthritis of the knees: a with benign prostatic hyperplasia. analysis and a simulation modelling randomised controlled trial and health By Fowler C, McAllister W, Plail R, exercise applied to the UK. economic analysis. Karim O, Yang Q. By Willis BH, Barton P, Pearmain P, By McCarthy CJ, Mills PM, Pullen R, Bryan S, Hyde C. Richardson G, Hawkins N, Roberts CR, No. 5 et al. No. 14 A pragmatic randomised controlled Laparoscopic surgery for inguinal trial of the cost-effectiveness of No. 47 hernia repair: systematic review of palliative therapies for patients with effectiveness and economic evaluation. Clinical and cost-effectiveness of once- inoperable oesophageal cancer. By McCormack K, Wake B, Perez J, daily versus more frequent use of same By Shenfine J, McNamee P, Steen N, Fraser C, Cook J, McIntosh E, et al. potency topical corticosteroids for Bond J, Griffin SM. atopic eczema: a systematic review and No. 15 economic evaluation. No. 6 Clinical effectiveness, tolerability and By Green C, Colquitt JL, Kirby J, Impact of computer-aided detection cost-effectiveness of newer drugs for Davidson P, Payne E. prompts on the sensitivity and epilepsy in adults: a systematic review specificity of screening mammography. and economic evaluation. No. 48 By Taylor P, Champness J, Given- By Wilby J, Kainth A, Hawkins N, Acupuncture of chronic headache Wilson R, Johnston K, Potts H. Epstein D, McIntosh H, McDaid C, et al. disorders in primary care: randomised controlled trial and economic analysis. No. 7 No. 16 By Vickers AJ, Rees RW, Zollman CE, A randomised controlled trial to Issues in data monitoring and interim McCarney R, Smith CM, Ellis N, et al. compare the cost-effectiveness of analysis of trials. tricyclic antidepressants, selective By Grant AM, Altman DG, Babiker No. 49 serotonin reuptake inhibitors and AB, Campbell MK, Clemens FJ, lofepramine. Generalisability in economic evaluation Darbyshire JH, et al. studies in healthcare: a review and case By Peveler R, Kendrick T, Buxton M, studies. Longworth L, Baldwin D, Moore M, et al. No. 8 By Sculpher MJ, Pang FS, Manca A, Lay public’s understanding of equipoise No. 17 Drummond MF, Golder S, Urdahl H, and randomisation in randomised Clinical effectiveness and cost- et al. controlled trials. effectiveness of immediate angioplasty By Robinson EJ, Kerr CEP, for acute myocardial infarction: No. 50 Stevens AJ, Lilford RJ, Braunholtz DA, systematic review and economic Virtual outreach: a randomised Edwards SJ, et al. evaluation. controlled trial and economic By Hartwell D, Colquitt J, Loveman evaluation of joint teleconferenced No. 9 E, Clegg AJ, Brodin H, Waugh N, et al. medical consultations. Clinical and cost-effectiveness of By Wallace P, Barber J, Clayton W, No. 18 electroconvulsive therapy for depressive Currell R, Fleming K, Garner P, et al. A randomised controlled comparison of illness, schizophrenia, catatonia alternative strategies in stroke care. and mania: systematic reviews and By Kalra L, Evans A, Perez I, economic modelling studies. Knapp M, Swift C, Donaldson N. Volume 9, 2005 By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S. No. 19 The investigation and analysis of No. 1 No. 10 critical incidents and adverse events in Randomised controlled multiple Measurement of health-related quality healthcare. treatment comparison to provide a cost- of life for people with dementia: By Woloshynowych M, Rogers S, effectiveness rationale for the selection development of a new instrument Taylor-Adams S, Vincent C. of antimicrobial therapy in acne. (DEMQOL) and an evaluation of By Ozolins M, Eady EA, Avery A, current methodology. No. 20 Cunliffe WJ, O’Neill C, Simpson NB, By Smith SC, Lamping DL, Banerjee Potential use of routine databases in et al. S, Harwood R, Foley B, Smith P, et al. health technology assessment. By Raftery J, Roderick P, Stevens A. No. 2 No. 11 No. 21 Do the findings of case series studies Clinical effectiveness and cost- vary significantly according to effectiveness of drotrecogin alfa Clinical and cost-effectiveness of newer immunosuppressive regimens in renal methodological characteristics? (activated) (Xigris®) for the treatment transplantation: a systematic review and By Dalziel K, Round A, Stein K, of severe sepsis in adults: a systematic review and economic evaluation. modelling study. Garside R, Castelnuovo E, Payne L. By Woodroffe R, Yao GL, Meads C, By Green C, Dinnes J, Takeda A, Bayliss S, Ready A, Raftery J, et al. No. 3 Shepherd J, Hartwell D, Cave C, et al. Improving the referral process No. 22 for familial breast cancer genetic No. 12 A systematic review and economic counselling: findings of three A methodological review of how evaluation of alendronate, etidronate, randomised controlled trials of two heterogeneity has been examined in risedronate, raloxifene and teriparatide interventions. systematic reviews of diagnostic test for the prevention and treatment of By Wilson BJ, Torrance N, accuracy. postmenopausal osteoporosis. Mollison J, Wordsworth S, Gray JR, By Dinnes J, Deeks J, Kirby J, By Stevenson M, Lloyd Jones M, De 84 Haites NE, et al. Roderick P. Nigris E, Brewer N, Davis S, Oakley J. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

No. 23 No. 32 No. 40 A systematic review to examine Longer term clinical and economic A randomised controlled trial and the impact of psycho-educational benefits of offering acupuncture care to cost-effectiveness study of systematic interventions on health outcomes patients with chronic low back pain. screening (targeted and total and costs in adults and children with population screening) versus routine By Thomas KJ, MacPherson difficult asthma. practice for the detection of atrial H, Ratcliffe J, Thorpe L, Brazier J, fibrillation in people aged 65 and over. By Smith JR, Mugford M, Holland Campbell M, et al. R, Candy B, Noble MJ, Harrison BDW, The SAFE study. et al. By Hobbs FDR, Fitzmaurice DA, No. 33 Mant J, Murray E, Jowett S, Bryan S, No. 24 Cost-effectiveness and safety of et al. An evaluation of the costs, effectiveness epidural steroids in the management and quality of renal replacement of sciatica. No. 41 therapy provision in renal satellite units By Price C, Arden N, Coglan L, Displaced intracapsular hip fractures in England and Wales. Rogers P. in fit, older people: a randomised By Roderick P, Nicholson T, Armitage comparison of reduction and fixation, A, Mehta R, Mullee M, Gerard K, et al. No. 34 bipolar hemiarthroplasty and total hip arthroplasty. The British Rheumatoid Outcome By Keating JF, Grant A, Masson M, No. 25 Study Group (BROSG) randomised Scott NW, Forbes JF. Imatinib for the treatment of patients controlled trial to compare the with unresectable and/or metastatic effectiveness and cost-effectiveness of gastrointestinal stromal tumours: aggressive versus symptomatic therapy No. 42 systematic review and economic in established rheumatoid arthritis. Long-term outcome of cognitive evaluation. By Symmons D, Tricker K, Roberts C, behaviour therapy clinical trials in By Wilson J, Connock M, Song F, Davies L, Dawes P, Scott DL. central Scotland. Yao G, Fry-Smith A, Raftery J, et al. By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, No. 35 No. 26 Major KA, et al. Indirect comparisons of competing Conceptual framework and systematic interventions. review of the effects of participants’ No. 43 and professionals’ preferences in By Glenny AM, Altman DG, Song F, randomised controlled trials. The effectiveness and cost-effectiveness Sakarovitch C, Deeks JJ, D’Amico R, of dual-chamber pacemakers compared et al. By King M, Nazareth I, Lampe F, with single-chamber pacemakers for Bower P, Chandler M, Morou M, et al. bradycardia due to atrioventricular No. 27 block or sick sinus syndrome: systematic Cost-effectiveness of alternative No. 36 review and economic evaluation. strategies for the initial medical The clinical and cost-effectiveness of By Castelnuovo E, Stein K, Pitt M, management of non-ST elevation acute implantable cardioverter defibrillators: Garside R, Payne E. coronary syndrome: systematic review a systematic review. and decision-analytical modelling. By Bryant J, Brodin H, Loveman E, No. 44 By Robinson M, Palmer S, Sculpher Payne E, Clegg A. Newborn screening for congenital heart M, Philips Z, Ginnelly L, Bowens A, et al. defects: a systematic review and cost- effectiveness analysis. No. 37 No. 28 By Knowles R, Griebsch I, Outcomes of electrically stimulated A trial of problem-solving by Dezateux C, Brown J, Bull C, Wren C. gracilis neosphincter surgery. community mental health nurses for anxiety, depression and life difficulties By Tillin T, Chambers M, Feldman R. among general practice patients. The No. 45 CPN-GP study. The clinical and cost-effectiveness of No. 29 left ventricular assist devices for end- By Kendrick T, Simons L, stage heart failure: a systematic review The effectiveness and cost-effectiveness Mynors-Wallis L, Gray A, Lathlean J, and economic evaluation. of pimecrolimus and tacrolimus for Pickering R, et al. atopic eczema: a systematic review and By Clegg AJ, Scott DA, Loveman E, economic evaluation. Colquitt J, Hutchinson J, Royle P, et al. No. 38 By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al. The causes and effects of socio- No. 46 demographic exclusions from clinical The effectiveness of the Heidelberg trials. No. 30 Retina Tomograph and laser diagnostic Systematic review on urine albumin By Bartlett C, Doyal L, Ebrahim S, glaucoma scanning system (GDx) in testing for early detection of diabetic Davey P, Bachmann M, Egger M, et al. detecting and monitoring glaucoma. complications. By Kwartz AJ, Henson DB, Harper By Newman DJ, Mattock MB, No. 39 RA, Spencer AF, McLeod D. Dawnay ABS, Kerry S, McGuire A, Is hydrotherapy cost-effective? Yaqoob M, et al. A randomised controlled trial of No. 47 combined hydrotherapy programmes Clinical and cost-effectiveness of No. 31 compared with physiotherapy land autologous chondrocyte implantation Randomised controlled trial of the cost- techniques in children with juvenile for cartilage defects in knee joints: effectiveness of water-based therapy for idiopathic arthritis. systematic review and economic lower limb osteoarthritis. By Epps H, Ginnelly L, Utley M, evaluation. By Cochrane T, Davey RC, Southwood T, Gallivan S, Sculpher M, By Clar C, Cummins E, McIntyre L, Matthes Edwards SM. et al. Thomas S, Lamb J, Bain L, et al. 85

No. 48 No. 6 No. 15 Systematic review of effectiveness of Systematic review and evaluation Measurement of the clinical and cost- different treatments for childhood of methods of assessing urinary effectiveness of non-invasive diagnostic retinoblastoma. incontinence. testing strategies for deep vein By McDaid C, Hartley S, Bagnall By Martin JL, Williams KS, Abrams thrombosis. KR, Turner DA, Sutton AJ, Chapple C, A-M, Ritchie G, Light K, Riemsma R. By Goodacre S, Sampson F, et al. Stevenson M, Wailoo A, Sutton A, No. 49 Thomas S, et al. Towards evidence-based guidelines No. 7 for the prevention of venous The clinical effectiveness and cost- No. 16 thromboembolism: systematic effectiveness of newer drugs for reviews of mechanical methods, oral children with epilepsy. A systematic Systematic review of the effectiveness anticoagulation, dextran and regional review. and cost-effectiveness of HealOzone® anaesthesia as thromboprophylaxis. By Connock M, Frew E, Evans B-W, for the treatment of occlusal pit/fissure By Roderick P, Ferris G, Wilson K, Bryan S, Cummins C, Fry-Smith A, et al. caries and root caries. Halls H, Jackson D, Collins R, et al. By Brazzelli M, McKenzie L, Fielding No. 8 S, Fraser C, Clarkson J, Kilonzo M, et al. No. 50 Surveillance of Barrett’s oesophagus: The effectiveness and cost-effectiveness exploring the uncertainty through No. 17 of parent training/education systematic review, expert workshop and Randomised controlled trials of programmes for the treatment economic modelling. conventional antipsychotic versus of conduct disorder, including By Garside R, Pitt M, Somerville M, new atypical drugs, and new atypical oppositional defiant disorder, in Stein K, Price A, Gilbert N. drugs versus clozapine, in people with children. schizophrenia responding poorly to, or By Dretzke J, Frew E, Davenport C, No. 9 intolerant of, current drug treatment. Barlow J, Stewart-Brown S, Sandercock J, Topotecan, pegylated liposomal et al. doxorubicin hydrochloride and By Lewis SW, Davies L, Jones PB, paclitaxel for second-line or subsequent Barnes TRE, Murray RM, Kerwin R, treatment of advanced ovarian cancer: et al. Volume 10, 2006 a systematic review and economic evaluation. No. 18 By Main C, Bojke L, Griffin S, Diagnostic tests and algorithms used Norman G, Barbieri M, Mather L, et al. in the investigation of haematuria: No. 1 systematic reviews and economic The clinical and cost-effectiveness of No. 10 evaluation. donepezil, rivastigmine, galantamine Evaluation of molecular techniques and memantine for Alzheimer’s By Rodgers M, Nixon J, Hempel S, in prediction and diagnosis Aho T, Kelly J, Neal D, et al. disease. of cytomegalovirus disease in By Loveman E, Green C, Kirby J, immunocompromised patients. Takeda A, Picot J, Payne E, et al. By Szczepura A, Westmoreland D, No. 19 Vinogradova Y, Fox J, Clark M. Cognitive behavioural therapy in No. 2 addition to antispasmodic therapy for FOOD: a multicentre randomised trial No. 11 irritable bowel syndrome in primary evaluating feeding policies in patients Screening for thrombophilia in high- care: randomised controlled trial. admitted to hospital with a recent risk situations: systematic review By Kennedy TM, Chalder T, stroke. and cost-effectiveness analysis. The McCrone P, Darnley S, Knapp M, By Dennis M, Lewis S, Cranswick G, Thrombosis: Risk and Economic Jones RH, et al. Forbes J. Assessment of Thrombophilia Screening (TREATS) study. No. 20 No. 3 By Wu O, Robertson L, Twaddle S, A systematic review of the The clinical effectiveness and cost- Lowe GDO, Clark P, Greaves M, et al. clinical effectiveness and cost- effectiveness of computed tomography effectiveness of enzyme replacement screening for lung cancer: systematic No. 12 therapies for Fabry’s disease and reviews. A series of systematic reviews to inform mucopolysaccharidosis type 1. By Black C, Bagust A, Boland A, a decision analysis for sampling and Walker S, McLeod C, De Verteuil R, et al. treating infected diabetic foot ulcers. By Connock M, Juarez-Garcia A, By Nelson EA, O’Meara S, Craig D, Frew E, Mans A, Dretzke J, Fry-Smith A, No. 4 Iglesias C, Golder S, Dalton J, et al. et al. A systematic review of the effectiveness and cost-effectiveness of neuroimaging No. 13 No. 21 assessments used to visualise the seizure Randomised clinical trial, observational Health benefits of antiviral therapy for focus in people with refractory epilepsy study and assessment of cost- mild chronic hepatitis C: randomised being considered for surgery. effectiveness of the treatment of controlled trial and economic By Whiting P, Gupta R, Burch J, varicose veins (REACTIV trial). evaluation. Mujica Mota RE, Wright K, Marson A, By Michaels JA, Campbell WB, By Wright M, Grieve R, Roberts J, et al. Brazier JE, MacIntyre JB, Palfreyman SJ, Main J, Thomas HC, on behalf of the Ratcliffe J, et al. UK Mild Hepatitis C Trial Investigators. No. 5 Comparison of conference abstracts No. 14 No. 22 and presentations with full-text articles The cost-effectiveness of screening for in the health technology assessments of oral cancer in primary care. Pressure relieving support surfaces: a rapidly evolving technologies. By Speight PM, Palmer S, Moles DR, randomised evaluation. By Dundar Y, Dodd S, Dickson R, Downer MC, Smith DH, Henriksson M, By Nixon J, Nelson EA, Cranny G, 86 Walley T, Haycox A, Williamson PR. et al. Iglesias CP, Hawkins K, Cullum NA, et al. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

No. 23 No. 31 No. 40 A systematic review and economic Etanercept and infliximab for the What are the clinical outcome and cost- model of the effectiveness and cost- treatment of psoriatic arthritis: a effectiveness of endoscopy undertaken effectiveness of methylphenidate, systematic review and economic by nurses when compared with doctors? dexamfetamine and atomoxetine evaluation. A Multi-Institution Nurse Endoscopy for the treatment of attention deficit By Woolacott N, Bravo Vergel Y, Trial (MINuET). hyperactivity disorder in children and Hawkins N, Kainth A, Khadjesari Z, By Williams J, Russell I, Durai D, adolescents. Misso K, et al. Cheung W-Y, Farrin A, Bloor K, et al. By King S, Griffin S, Hodges Z, No. 32 Weatherly H, Asseburg C, Richardson G, No. 41 et al. The cost-effectiveness of testing for hepatitis C in former injecting drug The clinical and cost-effectiveness of oxaliplatin and capecitabine for the No. 24 users. adjuvant treatment of colon cancer: The clinical effectiveness and cost- By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, systematic review and economic effectiveness of enzyme replacement evaluation. therapy for Gaucher’s disease: a et al. systematic review. By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P. By Connock M, Burls A, Frew E, No. 33 Fry-Smith A, Juarez-Garcia A, McCabe C, Computerised cognitive behaviour et al. therapy for depression and anxiety No. 42 update: a systematic review and A systematic review of the effectiveness economic evaluation. No. 25 of adalimumab, etanercept and By Kaltenthaler E, Brazier J, Effectiveness and cost-effectiveness infliximab for the treatment of De Nigris E, Tumur I, Ferriter M, rheumatoid arthritis in adults and of salicylic acid and cryotherapy for Beverley C, et al. cutaneous warts. An economic decision an economic evaluation of their cost- effectiveness. model. No. 34 By Chen Y-F, Jobanputra P, Barton P, By Thomas KS, Keogh-Brown MR, Cost-effectiveness of using prognostic Jowett S, Bryan S, Clark W, et al. Chalmers JR, Fordham RJ, Holland RC, information to select women with breast Armstrong SJ, et al. cancer for adjuvant systemic therapy. By Williams C, Brunskill S, Altman D, No. 43 No. 26 Briggs A, Campbell H, Clarke M, et al. Telemedicine in dermatology: a A systematic literature review of the randomised controlled trial. effectiveness of non-pharmacological No. 35 By Bowns IR, Collins K, Walters SJ, interventions to prevent wandering in Psychological therapies including McDonagh AJG. dementia and evaluation of the ethical dialectical behaviour therapy for implications and acceptability of their borderline personality disorder: a No. 44 use. systematic review and preliminary Cost-effectiveness of cell salvage and By Robinson L, Hutchings D, Corner economic evaluation. alternative methods of minimising L, Beyer F, Dickinson H, Vanoli A, et al. By Brazier J, Tumur I, Holmes M, perioperative allogeneic blood Ferriter M, Parry G, Dent-Brown K, et al. transfusion: a systematic review and No. 27 economic model. A review of the evidence on the effects No. 36 and costs of implantable cardioverter Clinical effectiveness and cost- By Davies L, Brown TJ, Haynes S, defibrillator therapy in different effectiveness of tests for the diagnosis Payne K, Elliott RA, McCollum C. patient groups, and modelling of cost- and investigation of urinary tract effectiveness and cost–utility for these infection in children: a systematic No. 45 groups in a UK context. review and economic model. Clinical effectiveness and cost- By Buxton M, Caine N, Chase D, By Whiting P, Westwood M, Bojke L, effectiveness of laparoscopic surgery Connelly D, Grace A, Jackson C, et al. Palmer S, Richardson G, Cooper J, et al. for colorectal cancer: systematic reviews and economic evaluation. No. 28 No. 37 By Murray A, Lourenco T, de Verteuil Adefovir dipivoxil and pegylated Cognitive behavioural therapy R, Hernandez R, Fraser C, McKinley A, interferon alfa-2a for the treatment of in chronic fatigue syndrome: a et al. chronic hepatitis B: a systematic review randomised controlled trial of an outpatient group programme. and economic evaluation. No. 46 By O’Dowd H, Gladwell P, Rogers By Shepherd J, Jones J, Takeda A, CA, Hollinghurst S, Gregory A. Etanercept and efalizumab for the Davidson P, Price A. treatment of psoriasis: a systematic No. 38 review. No. 29 A comparison of the cost-effectiveness By Woolacott N, Hawkins N, An evaluation of the clinical and cost- of five strategies for the prevention Mason A, Kainth A, Khadjesari Z, Bravo effectiveness of pulmonary artery of nonsteroidal anti-inflammatory Vergel Y, et al. catheters in patient management in drug-induced gastrointestinal toxicity: intensive care: a systematic review and a a systematic review with economic No. 47 randomised controlled trial. modelling. Systematic reviews of clinical decision By Harvey S, Stevens K, Harrison D, By Brown TJ, Hooper L, Elliott RA, tools for acute abdominal pain. Young D, Brampton W, McCabe C, et al. Payne K, Webb R, Roberts C, et al. By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al. No. 30 No. 39 Accurate, practical and cost-effective The effectiveness and cost-effectiveness assessment of carotid stenosis in the of computed tomography screening No. 48 UK. for coronary artery disease: systematic Evaluation of the ventricular assist By Wardlaw JM, Chappell FM, review. device programme in the UK. Stevenson M, De Nigris E, Thomas S, By Waugh N, Black C, Walker S, By Sharples L, Buxton M, Caine N, Gillard J, et al. McIntyre L, Cummins E, Hillis G. Cafferty F, Demiris N, Dyer M, et al. 87

No. 49 No. 7 No. 16 A systematic review and economic Glucocorticoid-induced osteoporosis: Additional therapy for young model of the clinical and cost- a systematic review and cost–utility children with spastic cerebral palsy: a effectiveness of immunosuppressive analysis. randomised controlled trial. therapy for renal transplantation in By Kanis JA, Stevenson M, children. McCloskey EV, Davis S, Lloyd-Jones M. By Weindling AM, Cunningham CC, Glenn SM, Edwards RT, Reeves DJ. By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al. No. 8 Epidemiological, social, diagnostic and No. 17 economic evaluation of population No. 50 screening for genital chlamydial Screening for type 2 diabetes: literature Amniocentesis results: investigation of infection. review and economic modelling. anxiety. The ARIA trial. By Low N, McCarthy A, Macleod J, By Waugh N, Scotland G, McNamee By Hewison J, Nixon J, Fountain J, Salisbury C, Campbell R, Roberts TE, P, Gillett M, Brennan A, Goyder E, et al. Cocks K, Jones C, Mason G, et al. et al. No. 18 No. 9 Methadone and buprenorphine for the The effectiveness and cost-effectiveness Volume 11, 2007 management of opioid dependence: of cinacalcet for secondary a systematic review and economic hyperparathyroidism in end-stage renal evaluation. disease patients on dialysis: a systematic review and economic evaluation. No. 1 By Connock M, Juarez-Garcia A, et al. Pemetrexed disodium for the treatment Jowett S, Frew E, Liu Z, Taylor RJ, By Garside R, Pitt M, Anderson R, of malignant pleural mesothelioma: Mealing S, Roome C, Snaith A, et al. a systematic review and economic No. 10 Exercise Evaluation Randomised evaluation. No. 19 Trial (EXERT): a randomised trial By Dundar Y, Bagust A, Dickson R, comparing GP referral for leisure The clinical effectiveness and cost- Dodd S, Green J, Haycox A, et al. centre-based exercise, community-based effectiveness of gemcitabine for walking and advice only. metastatic breast cancer: a systematic No. 2 By Isaacs AJ, Critchley JA, See Tai review and economic evaluation. A systematic review and economic S, Buckingham K, Westley D, Harridge By Takeda AL, Jones J, Loveman E, model of the clinical effectiveness SDR, et al. Tan SC, Clegg AJ. and cost-effectiveness of docetaxel in combination with prednisone or No. 11 prednisolone for the treatment of Interferon alfa (pegylated and non- No. 20 hormone-refractory metastatic prostate pegylated) and ribavirin for the A systematic review of duplex cancer. treatment of mild chronic hepatitis ultrasound, magnetic resonance By Collins R, Fenwick E, Trowman R, C: a systematic review and economic angiography and computed Perard R, Norman G, Light K, et al. evaluation. tomography angiography for By Shepherd J, Jones J, Hartwell D, the diagnosis and assessment of Davidson P, Price A, Waugh N. symptomatic, lower limb peripheral No. 3 arterial disease. A systematic review of rapid diagnostic No. 12 By Collins R, Cranny G, Burch J, tests for the detection of tuberculosis Systematic review and economic Aguiar-Ibáñez R, Craig D, Wright K, infection. evaluation of bevacizumab and et al. By Dinnes J, Deeks J, Kunst H, cetuximab for the treatment of Gibson A, Cummins E, Waugh N, et al. metastatic colorectal cancer. By Tappenden P, Jones R, Paisley S, No. 21 No. 4 Carroll C. The clinical effectiveness and cost- The clinical effectiveness and cost- effectiveness of treatments for children effectiveness of strontium ranelate for No. 13 with idiopathic steroid-resistant the prevention of osteoporotic fragility A systematic review and economic nephrotic syndrome: a systematic fractures in postmenopausal women. evaluation of epoetin alfa, epoetin review. beta and darbepoetin alfa in anaemia By Stevenson M, Davis S, Lloyd-Jones associated with cancer, especially that By Colquitt JL, Kirby J, Green C, M, Beverley C. attributable to cancer treatment. Cooper K, Trompeter RS. By Wilson J, Yao GL, Raftery J, No. 5 Bohlius J, Brunskill S, Sandercock J, No. 22 et al. A systematic review of quantitative and A systematic review of the routine qualitative research on the role and monitoring of growth in children of effectiveness of written information No. 14 primary school age to identify growth- available to patients about individual A systematic review and economic related conditions. medicines. evaluation of statins for the prevention By Fayter D, Nixon J, Hartley S, By Raynor DK, Blenkinsopp of coronary events. Rithalia A, Butler G, Rudolf M, et al. A, Knapp P, Grime J, Nicolson DJ, By Ward S, Lloyd Jones M, Pandor A, Pollock K, et al. Holmes M, Ara R, Ryan A, et al. No. 23 No. 15 No. 6 A systematic review of the effectiveness Systematic review of the effectiveness of Oral naltrexone as a treatment for and cost-effectiveness of different preventing and treating Staphylococcus relapse prevention in formerly opioid- models of community-based respite aureus carriage in reducing peritoneal dependent drug users: a systematic care for frail older people and their catheter-related infections. review and economic evaluation. carers. By McCormack K, Rabindranath K, By Adi Y, Juarez-Garcia A, Wang D, By Mason A, Weatherly H, Spilsbury Kilonzo M, Vale L, Fraser C, McIntyre L, 88 Jowett S, Frew E, Day E, et al. K, Arksey H, Golder S, Adamson J, et al. et al. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

No. 24 No. 33 No. 41 The clinical effectiveness and cost The clinical effectiveness and cost- The clinical effectiveness and cost- of repetitive transcranial magnetic effectiveness of inhaled insulin in effectiveness of screening for open stimulation versus electroconvulsive diabetes mellitus: a systematic review angle glaucoma: a systematic review therapy in severe depression: a and economic evaluation. and economic evaluation. multicentre pragmatic randomised By Black C, Cummins E, Royle P, By Burr JM, Mowatt G, Hernández controlled trial and economic analysis. Philip S, Waugh N. R, Siddiqui MAR, Cook J, Lourenco T, By McLoughlin DM, Mogg A, Eranti et al. S, Pluck G, Purvis R, Edwards D, et al. No. 34 No. 42 No. 25 Surveillance of cirrhosis for A randomised controlled trial and hepatocellular carcinoma: systematic Acceptability, benefit and costs of early economic evaluation of direct versus review and economic analysis. screening for hearing disability: a study of potential screening tests and models. indirect and individual versus group By Thompson Coon J, Rogers G, modes of speech and language therapy Hewson P, Wright D, Anderson R, By Davis A, Smith P, Ferguson M, for children with primary language Cramp M, et al. Stephens D, Gianopoulos I. impairment. By Boyle J, McCartney E, Forbes J, No. 35 No. 43 O’Hare A. Contamination in trials of educational The Birmingham Rehabilitation interventions. No. 26 Uptake Maximisation Study (BRUM). Hormonal therapies for early breast Homebased compared with hospital- By Keogh-Brown MR, Bachmann cancer: systematic review and economic based cardiac rehabilitation in a multi- MO, Shepstone L, Hewitt C, Howe A, evaluation. ethnic population: cost-effectiveness Ramsay CR, et al. By Hind D, Ward S, De Nigris E, and patient adherence. Simpson E, Carroll C, Wyld L. By Jolly K, Taylor R, Lip GYH, No. 44 Greenfield S, Raftery J, Mant J, et al. Overview of the clinical effectiveness of No. 27 positron emission tomography imaging Cardioprotection against the toxic No. 36 in selected cancers. effects of anthracyclines given to By Facey K, Bradbury I, Laking G, A systematic review of the clinical, children with cancer: a systematic Payne E. review. public health and cost-effectiveness of rapid diagnostic tests for the detection By Bryant J, Picot J, Levitt G, No. 45 Sullivan I, Baxter L, Clegg A. and identification of bacterial intestinal pathogens in faeces and food. The effectiveness and cost-effectiveness of carmustine implants and No. 28 By Abubakar I, Irvine L, Aldus CF, temozolomide for the treatment of Adalimumab, etanercept and infliximab Wyatt GM, Fordham R, Schelenz S, et al. newly diagnosed high-grade glioma: for the treatment of ankylosing a systematic review and economic spondylitis: a systematic review and No. 37 evaluation. economic evaluation. A randomised controlled trial By McLeod C, Bagust A, Boland A, By Garside R, Pitt M, Anderson R, examining the longer-term outcomes Rogers G, Dyer M, Mealing S, et al. Dagenais P, Dickson R, Dundar Y, et al. of standard versus new antiepileptic drugs. The SANAD trial. No. 29 No. 46 Prenatal screening and treatment By Marson AG, Appleton R, Baker Drug-eluting stents: a systematic review strategies to prevent group B GA, Chadwick DW, Doughty J, Eaton B, and economic evaluation. et al. streptococcal and other bacterial By Hill RA, Boland A, Dickson R, infections in early infancy: cost- Dündar Y, Haycox A, McLeod C, et al. effectiveness and expected value of No. 38 information analyses. Clinical effectiveness and cost- No. 47 By Colbourn T, Asseburg C, Bojke L, effectiveness of different models The clinical effectiveness and Philips Z, Claxton K, Ades AE, et al. of managing long-term oral anti- cost-effectiveness of cardiac coagulation therapy: a systematic resynchronisation (biventricular pacing) No. 30 review and economic modelling. for heart failure: systematic review and Clinical effectiveness and cost- By Connock M, Stevens C, Fry-Smith effectiveness of bone morphogenetic economic model. A, Jowett S, Fitzmaurice D, Moore D, By Fox M, Mealing S, Anderson R, proteins in the non-healing of fractures et al. and spinal fusion: a systematic review. Dean J, Stein K, Price A, et al. By Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al. No. 39 No. 48 A systematic review and economic Recruitment to randomised trials: No. 31 model of the clinical effectiveness strategies for trial enrolment and A randomised controlled trial of and cost-effectiveness of interventions participation study. The STEPS study. for preventing relapse in people with postoperative radiotherapy following By Campbell MK, Snowdon C, bipolar disorder. breast-conserving surgery in a Francis D, Elbourne D, McDonald AM, minimum-risk older population. The By Soares-Weiser K, Bravo Vergel Y, Knight R, et al. PRIME trial. Beynon S, Dunn G, Barbieri M, Duffy S, By Prescott RJ, Kunkler IH, Williams et al. LJ, King CC, Jack W, van der Pol M, et al. No. 49 Cost-effectiveness of functional No. 40 No. 32 cardiac testing in the diagnosis and Current practice, accuracy, effectiveness Taxanes for the adjuvant treatment of management of coronary artery and cost-effectiveness of the school early breast cancer: systematic review disease: a randomised controlled trial. entry hearing screen. and economic evaluation. The CECaT trial. By Bamford J, Fortnum H, Bristow K, By Ward S, Simpson E, Davis S, Hind By Sharples L, Hughes V, Crean A, Smith J, Vamvakas G, Davies L, et al. D, Rees A, Wilkinson A. Dyer M, Buxton M, Goldsmith K, et al. 89

No. 50 No. 5 No. 14 Evaluation of diagnostic tests when A multi-centre retrospective cohort A randomised controlled trial of there is no gold standard. A review of study comparing the efficacy, safety cognitive behaviour therapy in methods. and cost-effectiveness of hysterectomy adolescents with major depression By Rutjes AWS, Reitsma and uterine artery embolisation for treated by selective serotonin reuptake JB, Coomarasamy A, Khan KS, the treatment of symptomatic uterine inhibitors. The ADAPT trial. Bossuyt PMM. fibroids. The HOPEFUL study. By Goodyer IM, Dubicka B, Wilkinson By Hirst A, Dutton S, Wu O, Briggs A, P, Kelvin R, Roberts C, Byford S, et al. Edwards C, Waldenmaier L, et al. No. 51 No. 15 Systematic reviews of the clinical No. 6 effectiveness and cost-effectiveness of The use of irinotecan, oxaliplatin proton pump inhibitors in acute upper Methods of prediction and prevention and raltitrexed for the treatment of gastrointestinal bleeding. of pre-eclampsia: systematic reviews of advanced colorectal cancer: systematic accuracy and effectiveness literature review and economic evaluation. By Leontiadis GI, Sreedharan A, with economic modelling. Dorward S, Barton P, Delaney B, Howden By Hind D, Tappenden P, Tumur I, By Meads CA, Cnossen JS, Meher S, CW, et al. Eggington E, Sutcliffe P, Ryan A. Juarez-Garcia A, ter Riet G, Duley L, et al. No. 16 No. 52 No. 7 A review and critique of modelling in Ranibizumab and pegaptanib for The use of economic evaluations in the treatment of age-related macular prioritising and designing screening NHS decision-making: a review and programmes. degeneration: a systematic review and empirical investigation. economic evaluation. By Karnon J, Goyder E, Tappenden P, By Williams I, McIver S, Moore D, By Colquitt JL, Jones J, Tan SC, McPhie S, Towers I, Brazier J, et al. Bryan S. Takeda A, Clegg AJ, Price A. No. 53 No. 8 No. 17 An assessment of the impact of the Stapled haemorrhoidectomy Systematic review of the clinical NHS Health Technology Assessment (haemorrhoidopexy) for the treatment effectiveness and cost-effectiveness Programme. of haemorrhoids: a systematic review and economic evaluation. of 64-slice or higher computed By Hanney S, Buxton M, Green C, tomography angiography as an By Burch J, Epstein D, Baba-Akbari Coulson D, Raftery J. alternative to invasive coronary A, Weatherly H, Fox D, Golder S, et al. angiography in the investigation of coronary artery disease. No. 9 Volume 12, 2008 By Mowatt G, Cummins E, Waugh N, The clinical effectiveness of diabetes Walker S, Cook J, Jia X, et al. education models for Type 2 diabetes: a systematic review. No. 18 No. 1 By Loveman E, Frampton GK, Structural neuroimaging in psychosis: A systematic review and economic Clegg AJ. a systematic review and economic model of switching from evaluation. nonglycopeptide to glycopeptide No. 10 antibiotic prophylaxis for surgery. Payment to healthcare professionals for By Albon E, Tsourapas A, Frew E, Davenport C, Oyebode F, Bayliss S, et al. By Cranny G, Elliott R, Weatherly H, patient recruitment to trials: systematic Chambers D, Hawkins N, Myers L, et al. review and qualitative study. By Raftery J, Bryant J, Powell J, No. 19 No. 2 Kerr C, Hawker S. Systematic review and economic analysis of the comparative effectiveness of ‘Cut down to quit’ with nicotine No. 11 different inhaled corticosteroids and replacement therapies in smoking their usage with long-acting beta Cyclooxygenase-2 selective non- 2 cessation: a systematic review of agonists for the treatment of chronic effectiveness and economic analysis. steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, asthma in adults and children aged By Wang D, Connock M, Barton P, rofecoxib, etoricoxib, valdecoxib and 12 years and over. Fry-Smith A, Aveyard P, Moore D. lumiracoxib) for osteoarthritis and By Shepherd J, Rogers G, Anderson rheumatoid arthritis: a systematic review R, Main C, Thompson-Coon J, No. 3 and economic evaluation. Hartwell D, et al. A systematic review of the effectiveness By Chen Y-F, Jobanputra P, Barton P, of strategies for reducing fracture risk Bryan S, Fry-Smith A, Harris G, et al. No. 20 in children with juvenile idiopathic Systematic review and economic analysis arthritis with additional data on long- No. 12 of the comparative effectiveness of term risk of fracture and cost of disease The clinical effectiveness and cost- different inhaled corticosteroids and management. effectiveness of central venous catheters their usage with long-acting beta2 By Thornton J, Ashcroft D, O’Neill T, treated with anti-infective agents in agonists for the treatment of chronic Elliott R, Adams J, Roberts C, et al. preventing bloodstream infections: asthma in children under the age of a systematic review and economic 12 years. No. 4 evaluation. By Main C, Shepherd J, Anderson R, Does befriending by trained lay workers By Hockenhull JC, Dwan K, Boland Rogers G, Thompson-Coon J, Liu Z, et al. improve psychological well-being and A, Smith G, Bagust A, Dundar Y, et al. quality of life for carers of people No. 21 with dementia, and at what cost? A No. 13 Ezetimibe for the treatment of randomised controlled trial. Stepped treatment of older adults on hypercholesterolaemia: a systematic By Charlesworth G, Shepstone L, laxatives. The STOOL trial. review and economic evaluation. Wilson E, Thalanany M, Mugford M, By Mihaylov S, Stark C, McColl E, By Ara R, Tumur I, Pandor A, Duenas 90 Poland F. Steen N, Vanoli A, Rubin G, et al. A, Williams R, Wilkinson A, et al. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

No. 22 No. 31 No. 3 Topical or oral ibuprofen for chronic The effectiveness and cost-effectivness Surgical procedures and non-surgical knee pain in older people. The TOIB of minimal access surgery amongst devices for the management of non- study. people with gastro-oesophageal reflux apnoeic snoring: a systematic review of By Underwood M, Ashby D, Carnes disease – a UK collaborative study. The clinical effects and associated treatment D, Castelnuovo E, Cross P, Harding G, reflux trial. costs. et al. By Grant A, Wileman S, Ramsay C, By Main C, Liu Z, Welch K, Weiner G, Bojke L, Epstein D, Sculpher M, et al. Quentin Jones S, Stein K. No. 23 A prospective randomised comparison No. 4 of minor surgery in primary and No. 32 Continuous positive airway pressure secondary care. The MiSTIC trial. Time to full publication of studies of devices for the treatment of obstructive anti-cancer medicines for breast cancer By George S, Pockney P, Primrose J, sleep apnoea–hypopnoea syndrome: a and the potential for publication bias: a Smith H, Little P, Kinley H, et al. systematic review and economic analysis. short systematic review. By McDaid C, Griffin S, Weatherly H, No. 24 By Takeda A, Loveman E, Harris P, Durée K, van der Burgt M, van Hout S, A review and critical appraisal Hartwell D, Welch K. Akers J, et al. of measures of therapist–patient interactions in mental health settings. No. 33 No. 5 By Cahill J, Barkham M, Hardy G, Performance of screening tests for Gilbody S, Richards D, Bower P, et al. Use of classical and novel biomarkers child physical abuse in accident and as prognostic risk factors for localised emergency departments. No. 25 prostate cancer: a systematic review. The clinical effectiveness and cost- By Woodman J, Pitt M, Wentz R, By Sutcliffe P, Hummel S, Simpson E, effectiveness of screening programmes Taylor B, Hodes D, Gilbert RE. Young T, Rees A, Wilkinson A, et al. for amblyopia and strabismus in children up to the age of 4–5 years: No. 34 No. 6 a systematic review and economic Curative catheter ablation in atrial The harmful health effects of recreational evaluation. fibrillation and typical atrial flutter: ecstasy: a systematic review of By Carlton J, Karnon J, Czoski- systematic review and economic observational evidence. Murray C, Smith KJ, Marr J. evaluation. By Rogers G, Elston J, Garside R, By Rodgers M, McKenna C, Palmer S, Roome C, Taylor R, Younger P, et al. No. 26 Chambers D, Van Hout S, Golder S, et al. A systematic review of the clinical No. 7 effectiveness and cost-effectiveness and Systematic review of the clinical economic modelling of minimal incision No. 35 effectiveness and cost-effectiveness total hip replacement approaches in Systematic review and economic of oesophageal Doppler monitoring the management of arthritic disease of modelling of effectiveness and cost in critically ill and high-risk surgical the hip. utility of surgical treatments for men patients. By de Verteuil R, Imamura M, Zhu S, with benign prostatic enlargement. Glazener C, Fraser C, Munro N, et al. By Mowatt G, Houston G, Hernández By Lourenco T, Armstrong N, N’Dow R, de Verteuil R, Fraser C, Cuthbertson J, Nabi G, Deverill M, Pickard R, et al. B, et al. No. 27 A preliminary model-based assessment No. 36 of the cost–utility of a screening No. 8 programme for early age-related Immunoprophylaxis against respiratory The use of surrogate outcomes in model- macular degeneration. syncytial virus (RSV) with palivizumab based cost-effectiveness analyses: a survey By Karnon J, Czoski-Murray C, Smith in children: a systematic review and of UK Health Technology Assessment K, Brand C, Chakravarthy U, Davis S, economic evaluation. reports. et al. By Wang D, Cummins C, Bayliss S, By Taylor RS, Elston J. Sandercock J, Burls A. No. 28 No. 9 Intravenous magnesium sulphate Controlling Hypertension and and sotalol for prevention of atrial Volume 13, 2009 Hypotension Immediately Post Stroke fibrillation after coronary artery (CHHIPS) – a randomised controlled bypass surgery: a systematic review and trial. economic evaluation. By Potter J, Mistri A, Brodie F, By Shepherd J, Jones J, Frampton No. 1 Chernova J, Wilson E, Jagger C, et al. GK, Tanajewski L, Turner D, Price A. Deferasirox for the treatment of iron overload associated with regular No. 10 No. 29 blood transfusions (transfusional Routine antenatal anti-D prophylaxis Absorbent products for urinary/faecal haemosiderosis) in patients suffering for RhD-negative women: a systematic incontinence: a comparative evaluation with chronic anaemia: a systematic review and economic evaluation. of key product categories. review and economic evaluation. By Pilgrim H, Lloyd-Jones M, Rees A. By Fader M, Cottenden A, Getliffe K, By McLeod C, Fleeman N, Kirkham Gage H, Clarke-O’Neill S, Jamieson K, J, Bagust A, Boland A, Chu P, et al. et al. No. 11 Amantadine, oseltamivir and zanamivir No. 2 No. 30 for the prophylaxis of influenza A systematic review of repetitive Thrombophilia testing in people with (including a review of existing guidance functional task practice with modelling venous thromboembolism: systematic no. 67): a systematic review and of resource use, costs and effectiveness. review and cost-effectiveness analysis. economic evaluation. By French B, Leathley M, Sutton C, By Simpson EL, Stevenson MD, By Tappenden P, Jackson R, Cooper McAdam J, Thomas L, Forster A, et al. Rawdin A, Papaioannou D. K, Rees A, Simpson E, Read R, et al. 91

No. 12 No. 21 No. 29 Improving the evaluation of therapeutic Neuroleptics in the treatment of Sensitivity analysis in economic interventions in multiple sclerosis: the aggressive challenging behaviour for evaluation: an audit of NICE current role of new psychometric methods. people with intellectual disabilities: practice and a review of its use and By Hobart J, Cano S. a randomised controlled trial value in decision-making. (NACHBID). By Andronis L, Barton P, Bryan S. No. 13 By Tyrer P, Oliver-Africano P, Romeo R, Knapp M, Dickens S, Bouras N, et al. Treatment of severe ankle sprain: a Suppl. 1 pragmatic randomised controlled trial Trastuzumab for the treatment of comparing the clinical effectiveness No. 22 primary breast cancer in HER2-positive and cost-effectiveness of three types of Randomised controlled trial to women: a single technology appraisal. mechanical ankle support with tubular determine the clinical effectiveness By Ward S, Pilgrim H, Hind D. bandage. The CAST trial. and cost-effectiveness of selective Docetaxel for the adjuvant treatment By Cooke MW, Marsh JL, Clark M, serotonin reuptake inhibitors plus of early node-positive breast cancer: a Nakash R, Jarvis RM, Hutton JL, et al., supportive care, versus supportive care single technology appraisal. on behalf of the CAST trial group. alone, for mild to moderate depression with somatic symptoms in primary By Chilcott J, Lloyd Jones M, care: the THREAD (THREshold for Wilkinson A. No. 14 AntiDepressant response) study. Non-occupational postexposure By Kendrick T, Chatwin J, Dowrick C, The use of paclitaxel in the prophylaxis for HIV: a systematic review. Tylee A, Morriss R, Peveler R, et al. management of early stage breast By Bryant J, Baxter L, Hird S. cancer. No. 23 By Griffin S, Dunn G, Palmer S, No. 15 Diagnostic strategies using DNA testing Macfarlane K, Brent S, Dyker A, et al. for hereditary haemochromatosis in Blood glucose self-monitoring in type 2 Rituximab for the first-line treatment at-risk populations: a systematic review diabetes: a randomised controlled trial. of stage III/IV follicular non-Hodgkin’s and economic evaluation. By Farmer AJ, Wade AN, French DP, lymphoma. By Bryant J, Cooper K, Picot J, Clegg Simon J, Yudkin P, Gray A, et al. By Dundar Y, Bagust A, Hounsome J, A, Roderick P, Rosenberg W, et al. McLeod C, Boland A, Davis H, et al. No. 16 How far does screening women for No. 24 Bortezomib for the treatment of domestic (partner) violence in different Enhanced external counterpulsation multiple myeloma patients. health-care settings meet criteria for for the treatment of stable angina and By Green C, Bryant J, Takeda A, a screening programme? Systematic heart failure: a systematic review and Cooper K, Clegg A, Smith A, et al. reviews of nine UK National Screening economic analysis. Committee criteria. By McKenna C, McDaid C, Suekarran Fludarabine phosphate for the first- line treatment of chronic lymphocytic By Feder G, Ramsay J, Dunne D, Rose S, Hawkins N, Claxton K, Light K, et al. leukaemia. M, Arsene C, Norman R, et al. No. 25 By Walker S, Palmer S, Erhorn S, Brent S, Dyker A, Ferrie L, et al. No. 17 Development of a decision support tool for primary care management of Spinal cord stimulation for chronic Erlotinib for the treatment of relapsed patients with abnormal liver function pain of neuropathic or ischaemic non-small cell lung cancer. tests without clinically apparent liver origin: systematic review and economic By McLeod C, Bagust A, Boland A, evaluation. disease: a record-linkage population cohort study and decision analysis Hockenhull J, Dundar Y, Proudlove C, By Simpson EL, Duenas A, Holmes (ALFIE). et al. MW, Papaioannou D, Chilcott J. By Donnan PT, McLernon D, Dillon Cetuximab plus radiotherapy for the JF, Ryder S, Roderick P, Sullivan F, et al. No. 18 treatment of locally advanced squamous cell carcinoma of the head and neck. The role of magnetic resonance imaging No. 26 in the identification of suspected By Griffin S, Walker S, Sculpher M, A systematic review of presumed White S, Erhorn S, Brent S, et al. acoustic neuroma: a systematic review consent systems for deceased organ of clinical and cost-effectiveness and donation. Infliximab for the treatment of adults natural history. By Rithalia A, McDaid C, Suekarran with psoriasis. By Fortnum H, O’Neill C, Taylor R, S, Norman G, Myers L, Sowden A. By Loveman E, Turner D, Hartwell D, Lenthall R, Nikolopoulos T, Lightfoot Cooper K, Clegg A. G, et al. No. 27 Paracetamol and ibuprofen for the No. 30 No. 19 treatment of fever in children: the Psychological interventions for postnatal Dipsticks and diagnostic algorithms in PITCH randomised controlled trial. depression: cluster randomised trial urinary tract infection: development By Hay AD, Redmond NM, Costelloe and economic evaluation. The PoNDER and validation, randomised trial, C, Montgomery AA, Fletcher M, trial. economic analysis, observational cohort Hollinghurst S, et al. By Morrell CJ, Warner R, Slade P, and qualitative study. Dixon S, Walters S, Paley G, et al. By Little P, Turner S, Rumsby K, No. 28 Warner G, Moore M, Lowes JA, et al. A randomised controlled trial to No. 31 compare minimally invasive glucose The effect of different treatment No. 20 monitoring devices with conventional durations of clopidogrel in patients Systematic review of respite care in the monitoring in the management of with non-ST-segment elevation acute frail elderly. insulin-treated diabetes mellitus coronary syndromes: a systematic review By Shaw C, McNamara R, Abrams K, (MITRE). and value of information analysis. Cannings-John R, Hood K, Longo M, By Newman SP, Cooke D, Casbard A, By Rogowski R, Burch J, Palmer S, 92 et al. Walker S, Meredith S, Nunn A, et al. Craigs C, Golder S, Woolacott N. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

No. 32 No. 40 Adalimumab for the treatment of Systematic review and individual patient Breastfeeding promotion for infants in psoriasis. data meta-analysis of diagnosis of heart neonatal units: a systematic review and By Turner D, Picot J, Cooper K, failure, with modelling of implications economic analysis. Loveman E. of different diagnostic strategies in By Renfrew MJ, Craig D, Dyson L, Dabigatran etexilate for the prevention primary care. McCormick F, Rice S, King SE, et al. of venous thromboembolism in patients By Mant J, Doust J, Roalfe A, Barton undergoing elective hip and knee P, Cowie MR, Glasziou P, et al. No. 41 surgery: a single technology appraisal. The clinical effectiveness and cost- By Holmes M, Carroll C, No. 33 effectiveness of bariatric (weight loss) Papaioannou D. surgery for obesity: a systematic review and A multicentre randomised controlled economic evaluation. Romiplostim for the treatment trial of the use of continuous positive of chronic immune or idiopathic airway pressure and non-invasive By Picot J, Jones J, Colquitt JL, thrombocytopenic purpura: a single positive pressure ventilation in the early Gospodarevskaya E, Loveman E, Baxter technology appraisal. treatment of patients presenting to the L, et al. emergency department with severe By Mowatt G, Boachie C, Crowther acute cardiogenic pulmonary oedema: No. 42 M, Fraser C, Hernández R, Jia X, et al. the 3CPO trial. Rapid testing for group B streptococcus Sunitinib for the treatment of By Gray AJ, Goodacre S, Newby during labour: a test accuracy study with gastrointestinal stromal tumours: a DE, Masson MA, Sampson F, Dixon evaluation of acceptability and cost- critique of the submission from Pfizer. S, et al., on behalf of the 3CPO study effectiveness. By Bond M, Hoyle M, Moxham T, investigators. By Daniels J, Gray J, Pattison H, Napier M, Anderson R. Roberts T, Edwards E, Milner P, et al. No. 34 No. 45 Early high-dose lipid-lowering therapy No. 43 Vitamin K to prevent fractures in older to avoid cardiac events: a systematic Screening to prevent spontaneous women: systematic review and economic review and economic evaluation. preterm birth: systematic reviews of evaluation. accuracy and effectiveness literature By Stevenson M, Lloyd-Jones M, By Ara R, Pandor A, Stevens J, Rees with economic modelling. Papaioannou D. A, Rafia R. By Honest H, Forbes CA, Durée KH, Norman G, Duffy SB, Tsourapas A, et al. No. 46 No. 35 The effects of biofeedback for the Adefovir dipivoxil and pegylated No. 44 treatment of essential hypertension: a interferon alpha for the treatment The effectiveness and cost-effectiveness systematic review. of chronic hepatitis B: an updated of cochlear implants for severe to By Greenhalgh J, Dickson R, systematic review and economic profound deafness in children and Dundar Y. evaluation. adults: a systematic review and By Jones J, Shepherd J, Baxter L, economic model. No. 47 A randomised controlled trial of the Gospodarevskaya E, Hartwell D, Harris By Bond M, Mealing S, Anderson R, use of aciclovir and/or prednisolone for P, et al. Elston J, Weiner G, Taylor RS, et al. the early treatment of Bell’s palsy: the No. 36 BELLS study. Suppl. 2 By Sullivan FM, Swan IRC, Donnan Methods to identify postnatal Gemcitabine for the treatment of PT, Morrison JM, Smith BH, McKinstry depression in primary care: an metastatic breast cancer. B, et al. integrated evidence synthesis and value By Jones J, Takeda A, Tan SC, Cooper of information analysis. K, Loveman E, Clegg A. Suppl. 3 By Hewitt CE, Gilbody SM, Brealey S, Lapatinib for the treatment of HER2- Paulden M, Palmer S, Mann R, et al. Varenicline in the management of overexpressing breast cancer. smoking cessation: a single technology By Jones J, Takeda A, Picot J, von No. 37 appraisal. Keyserlingk C, Clegg A. A double-blind randomised placebo- By Hind D, Tappenden P, Peters J, controlled trial of topical intranasal Kenjegalieva K. Infliximab for the treatment of corticosteroids in 4- to 11-year-old ulcerative colitis. Alteplase for the treatment of acute children with persistent bilateral otitis By Hyde C, Bryan S, Juarez-Garcia A, ischaemic stroke: a single technology media with effusion in primary care. Andronis L, Fry-Smith A. appraisal. By Williamson I, Benge S, Barton S, By Lloyd Jones M, Holmes M. Rimonabant for the treatment of Petrou S, Letley L, Fasey N, et al. overweight and obese people. Rituximab for the treatment of By Burch J, McKenna C, Palmer S, No. 38 rheumatoid arthritis. Norman G, Glanville J, Sculpher M, et al. By Bagust A, Boland A, Hockenhull The effectiveness and cost-effectiveness Telbivudine for the treatment of chronic J, Fleeman N, Greenhalgh J, Dundar Y, of methods of storing donated kidneys hepatitis B infection. from deceased donors: a systematic et al. By Hartwell D, Jones J, Harris P, review and economic model. Cooper K. By Bond M, Pitt M, Akoh J, Moxham Omalizumab for the treatment of severe T, Hoyle M, Anderson R. persistent allergic asthma. Entecavir for the treatment of chronic By Jones J, Shepherd J, Hartwell D, hepatitis B infection. Harris P, Cooper K, Takeda A, et al. No. 39 By Shepherd J, Gospodarevskaya E, Frampton G, Cooper K. Rehabilitation of older patients: day Rituximab for the treatment of relapsed hospital compared with rehabilitation at or refractory stage III or IV follicular Febuxostat for the treatment of home. A randomised controlled trial. non-Hodgkin’s lymphoma. hyperuricaemia in people with gout: a By Parker SG, Oliver P, Pennington By Boland A, Bagust A, Hockenhull J, single technology appraisal. M, Bond J, Jagger C, Enderby PM, et al. Davis H, Chu P, Dickson R. By Stevenson M, Pandor A. 93

Rivaroxaban for the prevention of No. 54 Volume 14, 2010 venous thromboembolism: a single Randomised controlled trial of the use technology appraisal. of three dressing preparations in the By Stevenson M, Scope A, Holmes M, management of chronic ulceration of No. 1 Rees A, Kaltenthaler E. the foot in diabetes. Multicentre randomised controlled By Jeffcoate WJ, Price PE, Phillips CJ, trial examining the cost-effectiveness of Cetuximab for the treatment of Game FL, Mudge E, Davies S, et al. recurrent and/or metastatic squamous contrast-enhanced high field magnetic cell carcinoma of the head and neck. resonance imaging in women with No. 55 primary breast cancer scheduled for By Greenhalgh J, Bagust A, Boland A, VenUS II: a randomised controlled trial wide local excision (COMICE). Fleeman N, McLeod C, Dundar Y, et al. of larval therapy in the management of By Turnbull LW, Brown SR, Olivier C, leg ulcers. Mifamurtide for the treatment of Harvey I, Brown J, Drew P, et al. osteosarcoma: a single technology By Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, appraisal. No. 2 et al. By Pandor A, Fitzgerald P, Stevenson Bevacizumab, sorafenib tosylate, M, Papaioannou D. sunitinib and temsirolimus for renal No. 56 cell carcinoma: a systematic review and Ustekinumab for the treatment of A prospective randomised controlled economic evaluation. moderate to severe psoriasis. trial and economic modelling of antimicrobial silver dressings versus By Thompson Coon J, Hoyle M, By Gospodarevskaya E, Picot J, Green C, Liu Z, Welch K, Moxham T, Cooper K, Loveman E, Takeda A. non-adherent control dressings for venous leg ulcers: the VULCAN trial. et al. No. 48 By Michaels JA, Campbell WB, King BM, MacIntyre J, Palfreyman SJ, No. 3 Endovascular stents for abdominal Shackley P, et al. The clinical effectiveness and cost- aortic aneurysms: a systematic review effectiveness of testing for cytochrome and economic model. No. 57 P450 polymorphisms in patients By Chambers D, Epstein D, Walker S, Communication of carrier status with schizophrenia treated with Fayter D, Paton F, Wright K, et al. information following universal antipsychotics: a systematic review and newborn screening for sickle cell economic evaluation. No. 49 disorders and cystic fibrosis: qualitative By Fleeman N, McLeod C, Bagust A, Clinical and cost-effectiveness of study of experience and practice. Beale S, Boland A, Dundar Y, et al. epoprostenol, iloprost, bosentan, By Kai J, Ulph F, Cullinan T, sitaxentan and sildenafil for pulmonary Qureshi N. No. 4 arterial hypertension within their Systematic review of the clinical licensed indications: a systematic review No. 58 effectiveness and cost-effectiveness of and economic evaluation. Antiviral drugs for the treatment of photodynamic diagnosis and urine By Chen Y-F, Jowett S, Barton P, influenza: a systematic review and biomarkers (FISH, ImmunoCyt, Malottki K, Hyde C, Gibbs JSR, et al. economic evaluation. NMP22) and cytology for the detection By Burch J, Paulden M, Conti S, Stock and follow-up of bladder cancer. No. 50 C, Corbett M, Welton NJ, et al. By Mowatt G, Zhu S, Kilonzo M, Cessation of attention deficit Boachie C, Fraser C, Griffiths TRL, et al. hyperactivity disorder drugs No. 59 in the young (CADDY) – a Development of a toolkit and glossary No. 5 pharmacoepidemiological and to aid in the adaptation of health Effectiveness and cost-effectiveness of qualitative study. technology assessment (HTA) reports arthroscopic lavage in the treatment By Wong ICK, Asherson P, Bilbow A, for use in different contexts. of osteoarthritis of the knee: a mixed Clifford S, Coghill D, DeSoysa R, et al. By Chase D, Rosten C, Turner S, methods study of the feasibility of Hicks N, Milne R. conducting a surgical placebo-controlled No. 51 trial (the KORAL study). ARTISTIC: a randomised trial of No. 60 By Campbell MK, Skea ZC, human papillomavirus (HPV) testing in Colour vision testing for diabetic Sutherland AG, Cuthbertson BH, primary cervical screening. retinopathy: a systematic review of Entwistle VA, McDonald AM, et al. By Kitchener HC, Almonte M, diagnostic accuracy and economic Gilham C, Dowie R, Stoykova B, Sargent evaluation. No. 6 A, et al. By Rodgers M, Hodges R, Hawkins A randomised 2 × 2 trial of community J, Hollingworth W, Duffy S, McKibbin versus hospital pulmonary rehabilitation No. 52 M, et al. for chronic obstructive pulmonary The clinical effectiveness of glucosamine disease followed by telephone or and chondroitin supplements in slowing No. 61 conventional follow-up. or arresting progression of osteoarthritis Systematic review of the effectiveness By Waterhouse JC, Walters SJ, of the knee: a systematic review and and cost-effectiveness of weight Oluboyede Y, Lawson RA. economic evaluation. management schemes for the under By Black C, Clar C, Henderson R, fives: a short report. No. 7 MacEachern C, McNamee P, Quayyum By Bond M, Wyatt K, Lloyd J, Welch The effectiveness and cost-effectiveness Z, et al. K, Taylor R. of behavioural interventions for the prevention of sexually transmitted No. 53 No. 62 infections in young people aged 13–19: Randomised preference trial of medical Are adverse effects incorporated in a systematic review and economic versus surgical termination of pregnancy economic models? An initial review of evaluation. less than 14 weeks’ gestation (TOPS). current practice. By Shepherd J, Kavanagh J, Picot J, By Robson SC, Kelly T, Howel D, By Craig D, McDaid C, Fonseca T, Cooper K, Harden A, Barnett-Page E, 94 Deverill M, Hewison J, Lie MLS, et al. Stock C, Duffy S, Woolacott N. et al. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

No. 8 No. 16 No. 24 Dissemination and publication of Randomised controlled trials for policy A systematic review and economic research findings: an updated review of interventions: a review of reviews and evaluation of the clinical effectiveness related biases. meta-regression. and cost-effectiveness of aldosterone By Song F, Parekh S, Hooper L, Loke By Oliver S, Bagnall AM, Thomas J, antagonists for postmyocardial YK, Ryder J, Sutton AJ, et al. Shepherd J, Sowden A, White I, et al. infarction heart failure. By McKenna C, Burch J, Suekarran S, Walker S, Bakhai A, Witte K, et al. No. 9 No. 17 Paracetamol and selective and The effectiveness and cost-effectiveness non-selective non-steroidal anti- No. 25 of biomarkers for the prioritisation inflammatory drugs (NSAIDs) for the Avoiding and identifying errors in of patients awaiting coronary reduction of morphine-related side health technology assessment models: revascularisation: a systematic review effects after major surgery: a systematic qualitative study and methodological and decision model. review. review. By Hemingway H, Henriksson By McDaid C, Maund E, Rice S, By Chilcott JB, Tappenden P, Rawdin M, Chen R, Damant J, Fitzpatrick N, Wright K, Jenkins B, Woolacott N. A, Johnson M, Kaltenthaler E, Paisley S, Abrams K, et al. et al. No. 18 No. 10 A systematic review of outcome No. 26 Comparison of case note review measures used in forensic mental health BoTULS: a multicentre randomised methods for evaluating quality and research with consensus panel opinion. controlled trial to evaluate the clinical safety in health care. By Fitzpatrick R, Chambers J, Burns effectiveness and cost-effectiveness of By Hutchinson A, Coster JE, Cooper T, Doll H, Fazel S, Jenkinson C, et al. treating upper limb spasticity due to KL, McIntosh A, Walters SJ, Bath PA, stroke with botulinum toxin type A. et al. No. 19 By Shaw L, Rodgers H, Price C, van The clinical effectiveness and cost- Wijck F, Shackley P, Steen N, et al., on behalf of the BoTULS investigators. No. 11 effectiveness of topotecan for small cell lung cancer: a systematic review and Clinical effectiveness and cost- No. 27 effectiveness of continuous economic evaluation. Weighting and valuing quality-adjusted subcutaneous insulin infusion for By Loveman E, Jones J, Hartwell D, life-years using stated preference diabetes: systematic review and Bird A, Harris P, Welch K, et al. methods: preliminary results from the economic evaluation. Social Value of a QALY Project. No. 20 By Cummins E, Royle P, Snaith A, By Baker R, Bateman I, Donaldson C, Antenatal screening for Greene A, Robertson L, McIntyre L, et al. Jones-Lee M, Lancsar E, Loomes G, et al. haemoglobinopathies in primary care: No. 12 a cohort study and cluster randomised trial to inform a simulation model. The Suppl. 1 Self-monitoring of blood glucose in type Screening for Haemoglobinopathies in Cetuximab for the first-line treatment of 2 diabetes: systematic review. First Trimester (SHIFT) trial. metastatic colorectal cancer. By Clar C, Barnard K, Cummins E, By Dormandy E, Bryan S, Gulliford By Meads C, Round J, Tubeuf S, Royle P, Waugh N. MC, Roberts T, Ades T, Calnan M, et al. Moore D, Pennant M, Bayliss S. Infliximab for the treatment of acute No. 13 No. 21 exacerbations of ulcerative colitis. North of England and Scotland Study of Early referral strategies for By Bryan S, Andronis L, Hyde C, Tonsillectomy and Adeno-tonsillectomy management of people with markers of Connock M, Fry-Smith A, Wang D. in Children (NESSTAC): a pragmatic renal disease: a systematic review of the randomised controlled trial with a evidence of clinical effectiveness, cost- Sorafenib for the treatment of advanced parallel non-randomised preference effectiveness and economic analysis. hepatocellular carcinoma. study. By Black C, Sharma P, Scotland G, By Connock M, Round J, Bayliss S, By Lock C, Wilson J, Steen N, Eccles McCullough K, McGurn D, Robertson Tubeuf S, Greenheld W, Moore D. M, Mason H, Carrie S, et al. L, et al. Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B No. 14 No. 22 A randomised controlled trial of infection. Multicentre randomised controlled trial cognitive behaviour therapy and By Jones J, Colquitt J, Shepherd J, of the clinical and cost-effectiveness of motivational interviewing for people Harris P, Cooper K. a bypass-surgery-first versus a balloon- with Type 1 diabetes mellitus with angioplasty-first revascularisation persistent sub-optimal glycaemic Prasugrel for the treatment of acute strategy for severe limb ischaemia due control: A Diabetes and Psychological coronary artery syndromes with to infrainguinal disease. The Bypass Therapies (ADaPT) study. percutaneous coronary intervention. versus Angioplasty in Severe Ischaemia By Greenhalgh J, Bagust A, Boland of the Leg (BASIL) trial. By Ismail K, Maissi E, Thomas S, Chalder T, Schmidt U, Bartlett J, et al. A, Saborido CM, Fleeman N, McLeod By Bradbury AW, Adam DJ, Bell J, C, et al. Forbes JF, Fowkes FGR, Gillespie I, et al. No. 23 Alitretinoin for the treatment of severe A randomised controlled equivalence chronic hand eczema. No. 15 trial to determine the effectiveness By Paulden M, Rodgers M, Griffin S, A randomised controlled multicentre and cost–utility of manual chest Slack R, Duffy S, Ingram JR, et al. trial of treatments for adolescent physiotherapy techniques in the anorexia nervosa including assessment management of exacerbations of Pemetrexed for the first-line treatment of cost-effectiveness and patient chronic obstructive pulmonary disease of locally advanced or metastatic non- acceptability – the TOuCAN trial. (MATREX). small cell lung cancer. By Gowers SG, Clark AF, Roberts C, By Cross J, Elender F, Barton G, By Fleeman N, Bagust A, McLeod C, Byford S, Barrett B, Griffiths A, et al. Clark A, Shepstone L, Blyth A, et al. Greenhalgh J, Boland A, Dundar Y, et al. 95

Topotecan for the treatment of No. 34 No. 38 recurrent and stage IVB carcinoma of Exploring the needs, concerns and Towards single embryo transfer? the cervix. behaviours of people with existing Modelling clinical outcomes of potential By Paton F, Paulden M, Saramago P, respiratory conditions in relation to the treatment choices using multiple data Manca A, Misso K, Palmer S, et al. H1N1 ‘swine influenza’ pandemic: a sources: predictive models and patient multicentre survey and qualitative study. perspectives. Trabectedin for the treatment of By Caress A-L, Duxbury P, Woodcock By Roberts SA, McGowan L, Hirst advanced metastatic soft tissue sarcoma. A, Luker KA, Ward D, Campbell M, et al. WM, Brison DR, Vail A, Lieberman BA. By Simpson EL, Rafia R, Stevenson MD, Papaioannou D. Influenza A/H1N1v in pregnancy: an No. 39 Sugammadex for the reversal of muscle investigation of the characteristics and Azacitidine for the treatment of relaxation in general anaesthesia: management of affected women and the myelodysplastic syndrome, chronic a systematic review and economic relationship to pregnancy outcomes for myelomonocytic leukaemia and acute assessment. mother and infant. myeloid leukaemia. By Chambers D, Paulden M, Paton F, By Yates L, Pierce M, Stephens S, Mill By Edlin R, Connock M, Tubeuf S, Heirs M, Duffy S, Craig D, et al. AC, Spark P, Kurinczuk JJ, et al. Round J, Fry-Smith A, Hyde C, et al. No. 40 The impact of communications about No. 28 Systematic review and economic swine flu (influenza A H1N1v) on public The safety and effectiveness of modelling of the effectiveness and cost- responses to the outbreak: results from different methods of earwax removal: effectiveness of non-surgical treatments 36 national telephone surveys in the a systematic review and economic for women with stress urinary UK. incontinence. evaluation. By Rubin GJ, Potts HWW, Michie S. By Imamura M, Abrams P, Bain C, By Clegg AJ, Loveman E, Buckley B, Cardozo L, Cody J, et al. Gospodarevskaya E, Harris P, Bird A, The impact of illness and the impact Bryant J, et al. of school closure on social contact No. 41 patterns. A multicentred randomised controlled No. 29 By Eames KTD, Tilston NL, White PJ, trial of a primary care-based cognitive Systematic review of the clinical Adams E, Edmunds WJ. behavioural programme for low back effectiveness and cost-effectiveness pain. The Back Skills Training (BeST) of rapid point-of-care tests for the Vaccine effectiveness in pandemic trial. detection of genital chlamydia infection influenza – primary care reporting By Lamb SE, Lall R, Hansen Z, in women and men. (VIPER): an observational study to Castelnuovo E, Withers EJ, Nichols V, et al. By Hislop J, Quayyum Z, Flett G, assess the effectiveness of the pandemic Boachie C, Fraser C, Mowatt G. influenza A (H1N1)v vaccine. No. 42 By Simpson CR, Ritchie LD, No. 30 Recombinant human growth hormone Robertson C, Sheikh A, McMenamin J. School-linked sexual health services for for the treatment of growth disorders in children: a systematic review and young people (SSHYP): a survey and Physical interventions to interrupt or systematic review concerning current economic evaluation. reduce the spread of respiratory viruses: By Takeda A, Cooper K, models, effectiveness, cost-effectiveness a Cochrane review. Bird A, Baxter L, Frampton GK, and research opportunities. By Jefferson T, Del Mar C, Dooley L, Gospodarevskaya E, et al. By Owen J, Carroll C, Cooke J, Ferroni E, Al-Ansary LA, Bawazeer GA, Formby E, Hayter M, Hirst J, et al. et al. No. 43 A pragmatic randomised controlled No. 31 No. 35 trial to compare antidepressants with Systematic review and cost-effectiveness Randomised controlled trial and a community-based psychosocial evaluation of ‘pill-in-the-pocket’ strategy parallel economic evaluation of intervention for the treatment of for paroxysmal atrial fibrillation conventional ventilatory support versus women with postnatal depression: the compared to episodic in-hospital extracorporeal membrane oxygenation RESPOND trial. treatment or continuous antiarrhythmic for severe adult respiratory failure By Sharp DJ, Chew-Graham C, Tylee drug therapy. (CESAR). A, Lewis G, Howard L, Anderson I, et al. By Martin Saborido C, Hockenhull J, By Peek GJ, Elbourne D, Mugford M, No. 44 Bagust A, Boland A, Dickson R, Todd D. Tiruvoipati R, Wilson A, Allen E, et al. Group cognitive behavioural therapy for postnatal depression: a systematic No. 32 No. 36 review of clinical effectiveness, cost- Chemoprevention of colorectal cancer: Newer agents for blood glucose control effectiveness and value of information systematic review and economic in type 2 diabetes: systematic review and analyses. evaluation. economic evaluation. By Stevenson MD, Scope A, Sutcliffe By Cooper K, Squires H, Carroll C, By Waugh N, Cummins E, Royle P, PA, Booth A, Slade P, Parry G, et al. Papaioannou D, Booth A, Logan RF, et al. Clar C, Marien M, Richter B, et al. No. 45 No. 33 No. 37 Screening for hyperglycaemia in Cross-trimester repeated measures Barrett’s oesophagus and cancers of the pregnancy: a rapid update for the testing for Down’s syndrome screening: biliary tract, brain, head and neck, lung, National Screening Committee. an assessment. oesophagus and skin. By Waugh N, Royle P, Clar C, By Wright D, Bradbury I, Malone F, By Fayter D, Corbett M, Heirs M, Fox Henderson R, Cummins E, Hadden D, 96 D’Alton M, Summers A, Huang T, et al. D, Eastwood A. et al. DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

No. 46 Virus shedding and environmental No. 49 Open-label, randomised, parallel- deposition of novel A (H1N1) pandemic Relapse prevention in UK Stop group, multicentre study to evaluate the influenza virus: interim findings. Smoking Services: current practice, safety, tolerability and immunogenicity By Killingley B, Greatorex J, systematic reviews of effectiveness and of an AS03B/oil-in-water emulsion- Cauchemez S, Enstone JE, Curran M, cost-effectiveness analysis. adjuvanted (AS03B) split-virion versus Read R, et al. By Coleman T, Agboola S, Leonardi- non-adjuvanted wholevirion H1N1 Bee J, Taylor M, McEwen A, McNeill A. influenza vaccine in UK children Neuraminidase inhibitors for 6 months to 12 years of age. preventing and treating influenza in By Waddington CS, Andrews N, healthy adults: a Cochrane review. Hoschler K, Walker WT, Oeser C, Reiner By Jefferson T, Jones M, Doshi P, Del A, et al. Mar C, Dooley L, Foxlee R.

Evaluation of droplet dispersion during No. 47 non-invasive ventilation, oxygen Intensity-modulated radiotherapy therapy, nebuliser treatment and chest for the treatment of prostate cancer: physiotherapy in clinical practice: a systematic review and economic implications for management of evaluation. pandemic influenza and other airborne By Hummel S, Simpson EL, infections. Hemingway P, Stevenson MD, Rees A. By Simonds AK, Hanak A, Chatwin M, Morrell MJ, Hall A, Parker KH, et al. No. 48 Computerised decision support systems Evaluation of triage methods used to in order communication for diagnostic, select patients with suspected pandemic screening or monitoring test ordering: influenza for hospital admission: cohort systematic reviews of the effects and study. cost-effectiveness of systems. By Goodacre S, Challen, K, Wilson R, By Main C, Moxham T, Wyatt JC, Kay Campbell M. J, Anderson R, Stein K.

DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

Health Technology Assessment programme

Director, Deputy Director, Professor Tom Walley, Professor Jon Nicholl, Director, NIHR HTA Director, Medical Care Research programme, Professor of Unit, University of Sheffield Clinical Pharmacology, University of Liverpool

Prioritisation Strategy Group Members Chair, Dr Andrew Cook, Professor Paul Glasziou, Ms Lynn Kerridge, Professor Tom Walley, Consultant Advisor, NETSCC, Professor of Evidence-Based Chief Executive Officer, Director, NIHR HTA HTA Medicine, University of Oxford NETSCC and NETSCC, HTA programme, Professor of Clinical Pharmacology, Dr Peter Davidson, Dr Nick Hicks, Professor Ruairidh Milne, University of Liverpool Director of NETSCC, Health Consultant Adviser, NETSCC, Director of NETSCC External Technology Assessment HTA Relations Deputy Chair, Professor Jon Nicholl, Professor Robin E Ferner, Dr Edmund Jessop, Ms Kay Pattison, Director, Medical Care Research Consultant Physician and Medical Adviser, National Senior NIHR Programme Unit, University of Sheffield Director, West Midlands Centre Specialist, National Manager, Department of for Adverse Drug Reactions, Commissioning Group (NCG), Health Dr Bob Coates, City Hospital NHS Trust, Department of Health, London Consultant Advisor, NETSCC, Birmingham Ms Pamela Young, HTA Specialist Programme Manager, NETSCC, HTA

HTA Commissioning Board Members Programme Director, Professor Deborah Ashby, Professor Freddie Hamdy, Professor Ian Roberts, Professor Tom Walley, Professor of Medical Statistics, Professor of Urology, Professor of Epidemiology & Director, NIHR HTA Queen Mary, University of University of Sheffield Public Health, London School programme, Professor of London of Hygiene and Tropical Clinical Pharmacology, Professor Allan House, Medicine University of Liverpool Professor John Cairns, Professor of Liaison Psychiatry, Professor of Health Economics, University of Leeds Professor Mark Sculpher, Chairs, London School of Hygiene and Professor of Health Economics, Professor Sallie Lamb, Tropical Medicine Dr Martin J Landray, University of York Director, Warwick Clinical Trials Reader in Epidemiology, Unit Professor Peter Croft, Honorary Consultant Physician, Professor Helen Smith, Director of Primary Care Clinical Trial Service Unit, Professor of Primary Care, Professor Hywel Williams, Sciences Research Centre, Keele University of Oxford University of Brighton Director, Nottingham Clinical University Trials Unit Professor Stuart Logan, Professor Kate Thomas, Professor Nicky Cullum, Director of Health & Social Professor of Complementary & Deputy Chair, Director of Centre for Evidence- Care Research, The Peninsula Alternative Medicine Research, Dr Andrew Farmer, Based Nursing, University of Medical School, Universities of University of Leeds Senior Lecturer in General York Exeter and Plymouth Practice, Department of Professor David John Primary Health Care, Professor Jenny Donovan, Dr Rafael Perera, Torgerson, University of Oxford Professor of Social Medicine, Lecturer in Medical Statisitics, Director of York Trials Unit, University of Bristol Department of Primary Health University of York Professor Ann Ashburn, Care, University of Oxford Professor of Rehabilitation Professor Steve Halligan, and Head of Research, Professor of Gastrointestinal Southampton General Hospital Radiology, University College Hospital, London

Observers Ms Kay Pattison, Dr Morven Roberts, Section Head, NHS R&D Clinical Trials Manager, Programme, Department of Medical Research Council Health 99

Diagnostic Technologies and Screening Panel Members Chair, Dr Dianne Baralle, Professor Anthony Robert Mrs Una Rennard, Professor Paul Glasziou, Consultant & Senior Lecturer Kendrick, Service User Representative Professor of Evidence-Based in Clinical Genetics, Human Professor of Primary Medicine, University of Oxford Genetics Division & Wessex Medical Care, University of Ms Jane Smith, Clinical Genetics Service, Southampton Consultant Ultrasound Deputy Chair, Southampton, University of Practitioner, Ultrasound Dr David Elliman, Southampton Dr Susanne M Ludgate, Department, Leeds Teaching Consultant Paediatrician and Director, Medical Devices Hospital NHS Trust, Leeds Honorary Senior Lecturer, Dr Stephanie Dancer, Agency, London Great Ormond Street Hospital, Consultant Microbiologist, Dr W Stuart A Smellie, London Hairmyres Hospital, East Dr Anne Mackie, Consultant, Bishop Auckland Kilbride Director of Programmes, UK General Hospital Professor Judith E Adams, National Screening Committee Consultant Radiologist, Dr Ron Gray, Professor Lindsay Wilson Manchester Royal Infirmary, Consultant, National Perinatal Dr David Mathew Turnbull, Central Manchester & Epidemiology Unit, Institute of Service User Representative Scientific Director of the Centre for Magnetic Resonance Manchester Children’s Health Sciences, University of Dr Michael Millar, Lead University Hospitals NHS Oxford Investigations and YCR Consultant in Microbiology, Professor of Radiology, Hull Trust, and Professor of Department of Pathology & Diagnostic Radiology, Imaging Professor Paul D Griffiths, Royal Infirmary Professor of Radiology, Microbiology, Barts and The Science and Biomedical London NHS Trust, Royal Dr Alan J Williams, Engineering, Cancer & Academic Unit of Radiology, University of Sheffield London Hospital Consultant in General Imaging Sciences, University of Medicine, Department of Manchester Mr Martin Hooper, Mr Stephen Pilling, Thoracic Medicine, The Royal Service User Representative Director, Centre for Outcomes, Bournemouth Hospital Mr A S Arunkalaivanan, Research & Effectiveness, Honorary Senior Lecturer, University College London University of Birmingham and Consultant Urogynaecologist and Obstetrician, City Hospital

Observers Dr Tim Elliott, Dr Catherine Moody, Dr Ursula Wells, Team Leader, Cancer Programme Manager, Principal Research Officer, Screening, Department of Neuroscience and Mental Department of Health Health Health Board

Disease Prevention Panel Members Chair, Dr Elizabeth Fellow-Smith, Dr Chris McCall, Professor Ian Roberts, Dr Edmund Jessop, Medical Director, West London General Practitioner, The Professor of Epidemiology and Medical Adviser, National Mental Health Trust, Middlesex Hadleigh Practice, Corfe Public Health, London School Specialist Commissioning Mullen, Dorset of Hygiene & Tropical Medicine Advisory Group (NSCAG), Dr Colin Greaves Department of Health Senior Research Fellow, Miss Nicky Mullany, Professor Carol Tannahill, Peninsular Medical School Service User Representative Glasgow Centre for Population Deputy Chair, (Primary Care) Health Professor Margaret Dr Julie Mytton, Thorogood, Dr John Jackson, Locum Consultant in Public Mrs Jean Thurston, Professor of Epidemiology, General Practitioner, Parkway Health Medicine, Bristol Service User Representative University of Warwick Medical Medical Centre, Newcastle Primary Care Trust upon Tyne Professor David Weller, School, Coventry Professor Irwin Nazareth, Head, School of Clinical Dr Robert Cook Dr Russell Jago, Professor of Primary Care Science and Community Clinical Programmes Director, Senior Lecturer in Exercise, and Director, Department of Health, University of Bazian Ltd, London Nutrition and Health, Centre Primary Care and Population Edinburgh for Sport, Exercise and Health, Sciences, University College University of Bristol London

Observers Ms Christine McGuire, Ms Kay Pattison Dr Caroline Stone, Research & Development, Senior NIHR Programme Programme Manager, Medical Department of Health Manager, Department of Research Council Health

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Current and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk) DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

External Devices and Physical Therapies Panel Members

Chair, Dr Dawn Carnes, Dr Peter Martin, Dr Pippa Tyrrell, Dr John Pounsford, Senior Research Fellow, Barts Consultant Neurologist, Stroke Medicine, Senior Consultant Physician North and the London School of Addenbrooke’s Hospital, Lecturer/Consultant Stroke Bristol NHS Trust, Bristol Medicine and Dentistry, Cambridge Physician, Salford Royal London Foundation Hospitals’ Trust, Deputy Chair, Dr Lorraine Pinnigton, Salford Professor E Andrea Nelson, Dr Emma Clark, Associate Professor in Reader in Wound Healing and Clinician Scientist Fellow Rehabilitation, University of Dr Sarah Tyson, Director of Research, University & Cons. Rheumatologist, Nottingham, Nottingham Senior Research Fellow & of Leeds, Leeds University of Bristol, Bristol Associate Head of School, Dr Kate Radford, University of Salford, Salford Professor Bipin Bhakta Mrs Anthea De Barton-Watson, Division of Rehabilitation and Charterhouse Professor in Service User Representative Ageing, School of Community Dr Nefyn Williams, Rehabilitation Medicine, Health Sciences. University of Clinical Senior Lecturer, Cardiff University of Leeds, Leeds Professor Christopher Griffiths, Nottingham, Nottingham University, Cardiff Professor of Primary Care, Mrs Penny Calder Barts and the London School Mr Jim Reece, Service User Representative of Medicine and Dentistry, Service User Representative London Professor Paul Carding, Professor Maria Stokes, Professor of Voice Pathology, Dr Shaheen Hamdy, Professor of Newcastle Hospital NHS Trust, Clinical Senior Lecturer Neuromusculoskeletal Newcastle and Consultant Physician, Rehabilitation, University of University of Manchester, Southampton, Southampton Manchester

Observers Dr Phillip Leech, Ms Kay Pattison Dr Morven Roberts, Dr Ursula Wells Principal Medical Officer for Senior NIHR Programme Clinical Trials Manager, MRC, PRP, DH, London Primary Care, Department of Manager, Department of London Health , London Health

Interventional Procedures Panel Members Chair, Mr Seamus Eckford, Dr Nadim Malik, Dr Ashish Paul, Professor Jonathan Michaels, Consultant in Obstetrics & Consultant Cardiologist/ Medical Director, Bedfordshire Consultant Surgeon & Gynaecology, North Devon Honorary Lecturer, University PCT Honorary Clinical Lecturer, District Hospital of Manchester University of Sheffield Dr Sarah Purdy, Professor David Taggart, Mr Hisham Mehanna, Consultant Senior Lecturer, Mr David P Britt, Consultant Cardiothoracic Consultant & Honorary University of Bristol Service User Representative, Surgeon, John Radcliffe Associate Professor, University Cheshire Hospital Hospitals Coventry & Mr Michael Thomas, Warwickshire NHS Trust Consultant Colorectal Surgeon, Mr Sankaran Dr Matthew Hatton, Bristol Royal Infirmary ChandraSekharan, Consultant in Clinical Dr Jane Montgomery, Consultant Surgeon, Colchester Oncology, Sheffield Teaching Consultant in Anaesthetics and Professor Yit Chiun Yang, Hospital University NHS Hospital Foundation Trust Critical Care, South Devon Consultant Ophthalmologist, Foundation Trust Healthcare NHS Foundation Royal Wolverhampton Hospitals Dr John Holden, Trust NHS Trust Professor Nicholas Clarke, General Practitioner, Garswood Consultant Orthopaedic Surgery, Wigan Dr Simon Padley, Mrs Isabel Boyer, Surgeon, Southampton Consultant Radiologist, Chelsea Service User Representative, University Hospitals NHS Trust & Westminster Hospital London

101

Pharmaceuticals Panel Members Chair, Dr Peter Elton, Dr Dyfrig Hughes, Dr Martin Shelly, Professor Imti Choonara, Director of Public Health, Reader in Pharmacoeconomics General Practitioner, Leeds, Professor in Child Health, Bury Primary Care Trust and Deputy Director, Centre and Associate Director, NHS University of Nottingham for Economics and Policy in Clinical Governance Support Professor Robin Ferner, Health, IMSCaR, Bangor Team, Leicester Deputy Chair, Consultant Physician and University Dr Lesley Wise, Director, West Midlands Centre Dr Gillian Shepherd, Unit Manager, for Adverse Drug Reactions, Dr Yoon K Loke, Director, Health and Clinical Pharmacoepidemiology City Hospital NHS Trust, Senior Lecturer in Clinical Excellence, Merck Serono Ltd Research Unit, VRMM, Birmingham Pharmacology, University of Medicines & Healthcare East Anglia Mrs Katrina Simister, Products Regulatory Agency Dr Ben Goldacre, Assistant Director New Research Fellow, Division of Professor Femi Oyebode, Medicines, National Prescribing Mrs Nicola Carey, Psychological Medicine and Consultant Psychiatrist Centre, Liverpool Senior Research Fellow, Psychiatry, King’s College and Head of Department, School of Health and Social London University of Birmingham Mr David Symes, Care, The University of Service User Representative Reading Dr Bill Gutteridge, Dr Andrew Prentice, Medical Adviser, London Senior Lecturer and Consultant Mr John Chapman, Strategic Health Authority Obstetrician and Gynaecologist, Service User Representative The Rosie Hospital, University of Cambridge

Observers Ms Kay Pattison Mr Simon Reeve, Dr Heike Weber, Dr Ursula Wells, Senior NIHR Programme Head of Clinical and Cost- Programme Manager, Principal Research Officer, Manager, Department of Effectiveness, Medicines, Medical Research Council Department of Health Health Pharmacy and Industry Group, Department of Health

Psychological and Community Therapies Panel Members Chair, Dr Steve Cunningham, Ms Mary Nettle, Dr Howard Ring, Professor Scott Weich, Consultant Respiratory Mental Health User Consultant, Consultant & University Professor of Psychiatry, Paediatrician, Lothian Health Gloucestershire Lecturer in Psychiatry, University of Warwick Board University of Cambridge Professor John Potter, Professor Jane Barlow, Dr Anne Hesketh, Professor of Ageing and Stroke Dr Karen Roberts, Professor of Public Health in Senior Clinical Lecturer in Medicine, University of East Nurse/Consultant, Dunston Hill the Early Years, Health Sciences Speech and Language Therapy, Anglia Hospital, Tyne and Wear Research Institute, Warwick University of Manchester Medical School Dr Greta Rait, Dr Karim Saad, Dr Yann Lefeuvre, Senior Clinical Lecturer and Consultant in Old Age Dr Sabyasachi Bhaumik, GP Partner, Burrage Road General Practitioner, University Psychiatry, Coventry & Consultant Psychiatrist, Surgery, London College London Warwickshire Partnership Trust Leicestershire Partnership NHS Trust Dr Jeremy J Murphy, Dr Paul Ramchandani, Dr Alastair Sutcliffe, Consultant Physician & Senior Research Fellow/Cons. Senior Lecturer, University Mrs Val Carlill, Cardiologist, County Durham & Child Psychiatrist, University of College London Service User Representative, Darlington Foundation Trust Oxford Gloucestershire Dr Simon Wright, Mr John Needham, GP Partner, Walkden Medical Service User, Buckingmashire Centre, Manchester

Observers Ms Kay Pattison Dr Morven Roberts, Professor Tom Walley, Dr Ursula Wells, Senior NIHR Programme Clinical Trials Manager, MRC, HTA Programme Director, Policy Research Programme, Manager, Department of London Liverpool DH, London Health

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Current and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk) DOI: 10.3310/hta14500 Health Technology Assessment 2010; Vol. 14: No. 50

Expert Advisory Network Members Professor Douglas Altman, Mr Jonothan Earnshaw, Professor Allen Hutchinson, Professor Miranda Mugford, Professor of Statistics in Consultant Vascular Surgeon, Director of Public Health and Professor of Health Economics Medicine, Centre for Statistics Gloucestershire Royal Hospital, Deputy Dean of ScHARR, and Group Co-ordinator, in Medicine, University of Gloucester University of Sheffield University of East Anglia Oxford Professor Martin Eccles, Professor Peter Jones, Professor Jim Neilson, Professor John Bond, Professor of Clinical Professor of Psychiatry, Head of School of Reproductive Professor of Social Gerontology Effectiveness, Centre for Health University of Cambridge, & Developmental Medicine & Health Services Research, Services Research, University of Cambridge and Professor of Obstetrics University of Newcastle upon Newcastle upon Tyne and Gynaecology, University of Tyne Professor Stan Kaye, Liverpool Professor Pam Enderby, Cancer Research UK Professor Professor Andrew Bradbury, Dean of Faculty of Medicine, of Medical Oncology, Royal Mrs Julietta Patnick, Professor of Vascular Surgery, Institute of General Practice Marsden Hospital and Institute National Co-ordinator, NHS Solihull Hospital, Birmingham and Primary Care, University of of Cancer Research, Surrey Cancer Screening Programmes, Sheffield Sheffield Mr Shaun Brogan, Dr Duncan Keeley, Chief Executive, Ridgeway Professor Gene Feder, General Practitioner (Dr Burch Professor Robert Peveler, Primary Care Group, Aylesbury Professor of Primary Care & Ptnrs), The Health Centre, Professor of Liaison Psychiatry, Research & Development, Thame Royal South Hants Hospital, Mrs Stella Burnside OBE, Centre for Health Sciences, Southampton Chief Executive, Regulation Barts and The London School Dr Donna Lamping, and Improvement Authority, of Medicine and Dentistry Research Degrees Programme Professor Chris Price, Belfast Director and Reader in Director of Clinical Research, Mr Leonard R Fenwick, Psychology, Health Services Bayer Diagnostics Europe, Ms Tracy Bury, Chief Executive, Freeman Research Unit, London School Stoke Poges Project Manager, World Hospital, Newcastle upon Tyne of Hygiene and Tropical Confederation for Physical Medicine, London Professor William Rosenberg, Therapy, London Mrs Gillian Fletcher, Professor of Hepatology Antenatal Teacher and Tutor Mr George Levvy, and Consultant Physician, Professor Iain T Cameron, and President, National Chief Executive, Motor University of Southampton Professor of Obstetrics and Childbirth Trust, Henfield Neurone Disease Association, Gynaecology and Head of the Northampton Professor Peter Sandercock, School of Medicine, University Professor Jayne Franklyn, Professor of Medical Neurology, of Southampton Professor of Medicine, Professor James Lindesay, Department of Clinical University of Birmingham Professor of Psychiatry for the Neurosciences, University of Dr Christine Clark, Elderly, University of Leicester Edinburgh Medical Writer and Consultant Mr Tam Fry, Pharmacist, Rossendale Honorary Chairman, Child Professor Julian Little, Dr Susan Schonfield, Growth Foundation, London Professor of Human Genome Consultant in Public Health, Professor Collette Clifford, Epidemiology, University of Hillingdon Primary Care Trust, Professor of Nursing and Professor Fiona Gilbert, Ottawa Middlesex Head of Research, The Consultant Radiologist and Medical School, University of NCRN Member, University of Professor Alistaire McGuire, Dr Eamonn Sheridan, Birmingham Aberdeen Professor of Health Economics, Consultant in Clinical Genetics, London School of Economics St James’s University Hospital, Professor Barry Cookson, Professor Paul Gregg, Leeds Director, Laboratory of Hospital Professor of Orthopaedic Professor Rajan Madhok, Infection, Public Health Surgical Science, South Tees Medical Director and Director Dr Margaret Somerville, Laboratory Service, London Hospital NHS Trust of Public Health, Directorate Director of Public Health of Clinical Strategy & Public Learning, Peninsula Medical Dr Carl Counsell, Bec Hanley, Health, North & East Yorkshire School, University of Plymouth Clinical Senior Lecturer in Co-director, TwoCan Associates, & Northern Lincolnshire Neurology, University of West Sussex Health Authority, York Professor Sarah Stewart-Brown, Aberdeen Professor of Public Health, Dr Maryann L Hardy, Professor Alexander Markham, Division of Health in the Professor Howard Cuckle, Senior Lecturer, University of Director, Molecular Medicine Community, University of Professor of Reproductive Bradford Unit, St James’s University Warwick, Coventry Epidemiology, Department Hospital, Leeds of Paediatrics, Obstetrics & Mrs Sharon Hart, Professor Ala Szczepura, Gynaecology, University of Healthcare Management Dr Peter Moore, Professor of Health Service Leeds Consultant, Reading Freelance Science Writer, Research, Centre for Health Services Studies, University of Professor Robert E Hawkins, Ashtead Dr Katherine Darton, Warwick, Coventry Information Unit, MIND – The CRC Professor and Director Dr Andrew Mortimore, Mental Health Charity, London of Medical Oncology, Christie Public Health Director, Mrs Joan Webster, CRC Research Centre, Southampton City Primary Consumer Member, Southern Professor Carol Dezateux, Christie Hospital NHS Trust, Care Trust Derbyshire Community Health Professor of Paediatric Manchester Council Epidemiology, Institute of Child Dr Sue Moss, Health, London Professor Richard Hobbs, Associate Director, Cancer Professor Martin Whittle, Head of Department of Primary Screening Evaluation Unit, Clinical Co-director, National Mr John Dunning, Care & General Practice, Institute of Cancer Research, Co-ordinating Centre for Consultant Cardiothoracic University of Birmingham Sutton Women’s and Children’s Surgeon, Papworth Hospital Health, Lymington NHS Trust, Cambridge Professor Alan Horwich, Dean and Section Chairman, The Institute of Cancer Research, London

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