Technology Assessment Report commissioned by the NHS R&D HTA Programme on behalf of the National Institute for Health and Clinical Excellence – Assessment Report Guide The use of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer Produced by The School of Health and Related Research (ScHARR) Authors Abdullah Pandor Research Fellow, ScHARR Simon Eggington Operational Research Analyst, ScHARR Suzy Paisley Research Scientist, ScHARR Paul Tappenden Senior Cost-effectiveness Modeller, ScHARR Paul Sutcliffe Research Associate, ScHARR Correspondence to Abdullah Pandor, ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield, S1 4DA. Date completed 8 August 2005 Expiry date Expiry date Information from academic submissions was submitted in confidence to the National Institute for Health and Clinical Excellence, this information was made available to the NICE Appraisals Committee but has been removed from this version of the report. A note in the relevant portion of the text shows where this has occurred. Publication information About ScHARR The School of Health and Related Research (ScHARR) is one of the four Schools that comprise the Faculty of Medicine at the University of Sheffield. ScHARR brings together a wide range of medical- and health-related disciplines including public health, general practice, mental health, epidemiology, health economics, management sciences, medical statistics, operational research and information science. It includes the Sheffield unit of the Trent Institute for Health Services Research, which is funded by NHS R&D to facilitate high-quality health services research and capacity development. The ScHARR Technology Assessment Group (ScHARR-TAG) synthesises research on the effectiveness and cost-effectiveness of healthcare interventions for the NHS R&D Health Technology Assessment Programme on behalf of a range of policy makers, including the National Institute for Health and Clinical Excellence. ScHARR-TAG is part of a wider collaboration of six units from other regions. The other units are: Southampton Health Technology Assessment Centre (SHTAC), University of Southampton; Aberdeen Health Technology Assessment Group (Aberdeen HTA Group), University of Aberdeen; Liverpool Reviews & Implementation Group (LRiG), University of Liverpool; Peninsular Technology Assessment Group (PenTAG), University of Exeter; NHS Centre for Reviews and Dissemination, University of York; and West Midlands Health Technology Assessment Collaboration (WMHTAC), University of Birmingham. Contributions of authors Abdullah Pandor, Research Fellow, coordinated the review. Suzy Paisley, Research Scientist, developed the search strategy and undertook searches; Abdullah Pandor, Paul Sutcliffe, Research Associate, Simon Eggington, Operational Research Analyst, and Paul Tappenden, Senior Cost-effectiveness Modeller, screened the search results. Abdullah Pandor, Paul Sutcliffe, Simon Eggington and Paul Tappenden screened retrieved papers against inclusion criteria, appraised the quality of papers and abstracted data from papers. Abdullah Pandor and Simon Eggington wrote to authors of papers for additional information. 2 Abdullah Pandor, Simon Eggington, Paul Tappenden and Paul Sutcliffe analysed the data. Abdullah Pandor wrote the background section, Abdullah Pandor and Paul Sutcliffe wrote the section on clinical effectiveness. Simon Eggington and Paul Tappenden wrote the section on cost-effectiveness. Declared competing interests of authors None Source of Funding This report was commissioned by the NHS R&D HTA Programme as project number 04/18 Relationship of reviewer(s) with sponsor Neither the authors nor the unit know of any pecuniary relationship with sponsors, specific or non-specific. Acknowledgements Mark Saunders, Consultant Clinical Oncologist, Christie Hospital NHS Trust, John Scholefield, Professor of Surgery, University Hospital, Paul Skinner, Consultant Colorectal Surgeon, Northern General Hospital, Moyez Jiwa, Lecturer, Institute of General Practice & Primary Care, University of Sheffield and Maria Marples, Senior Lecturer in Medical Oncology, Weston Park Hospital provided clinical advice. Andrea Shippam, Project Administrator, ScHARR, organised the retrieval of papers and helped in preparing and formatting the report. The authors wish to thank all of the above. Rider on responsibility of report The views expressed in this report are those of the authors and not necessarily those of the NHS R&D HTA Programme. Any errors are the responsibility of the authors. 3 Table of contents Definition of Terms and List of Abbreviations 10 Executive Summary 13 1. Aim of the Review 23 2. Background 24 2.1. Description of underlying health problem 24 2.1.1. Introduction 24 2.1.2. Epidemiology 24 2.1.3. Aetiology 25 2.1.4. Pathology 26 2.1.5. Prognosis 26 2.1.6. Significance in terms of ill-health (burden of disease) 28 2.2. Current service provision 29 2.2.1. Management of disease and national guidelines 29 2.2.2. Current service cost 30 2.2.3. Variation in services 33 2.3. Description of technology under assessment 33 2.3.1. Summary of interventions 34 3. Assessment of Clinical Effectiveness 39 3.1 Methods for reviewing effectiveness 39 3.1.1. Identification of studies 39 3.1.2. Inclusion and exclusion criteria 40 3.1.3. Data abstraction strategy 41 3.1.4. Critical appraisal strategy 41 3.1.5. Methods of data synthesis 41 3.1.6. Handling of the company submission 42 3.2. Results: Oxaliplatin 42 3.2.1. Quantity and Quality of research available 42 3.2.2 Assessment of effectiveness 43 3.2.3. Summary of effectiveness data for oxaliplatin 64 3.3. Results: Capecitabine 66 3.3.1. Quantity and Quality of research available 66 3.3.2 Assessment of effectiveness 67 3.3.3. Summary of effectiveness data for capecitabine 82 3.4. Bolus or infusional 5-FU for the adjuvant treatment of colon 84 4 cancer? 3.4.1. Introduction 84 3.4.2. Quantity and quality of research available 84 3.4.3 Assessment of effectiveness 85 3.4.4. Summary of effectiveness data for bolus or infusional 5-FU 94 4. Assessment of Cost Effectiveness 96 4.1. Systematic review of existing economic literature 96 4.1.1. Identification of studies 96 4.1.2. Inclusion / exclusion criteria 97 4.1.3. Quality assessment 97 4.1.4. Results of cost-effectiveness review 97 4.1.5. Cost-effectiveness review 98 4.1.6. Evidence from industry submissions 102 4.2. Independent Economic Assessment 110 4.2.1. Economic methodology 112 4.3. Results of economic assessment 130 4.3.1. Estimated overall survival benefits 131 4.3.2. Central estimates of cost-effectiveness for overall survival period 132 4.3.3. Sensitivity analysis results 133 4.3.4. Probabilistic sensitivity analysis results 138 4.3.5. Cost-effectiveness analysis using indirect comparisons 141 4.3.6. Budget impact analysis results 142 5. Assessment of Factors Relevant to the NHS and Other Parties 143 5.1. Implications for other parties 143 5.1.1. Patient education 143 5.1.2. Support of Families and Friends 143 5.1.3. Transportation 144 5.2. Factors relevant to NHS 144 5.2.1. Outreach clinics 144 5.2.2. Cost incentives within the NHS 144 5.2.3. Pharmacy and nursing time 145 5.2.4. Drug administration 146 5.2.5. Training for doctors and nurses 146 5.2.6. Compliance 147 5.2.7. Availability of alternative therapies 147 5 5.2.8. Age 148 5.2.9. Off-licence use 148 6. Discussion 149 6.1. Principle findings 149 6.2. Limitations of the assessment 150 6.3. Uncertainties 151 6.4. Other relevant factors 151 6.5. Further research 152 6.5.1. Ongoing trials 152 6.5.2. Suggested research priorities 152 7. Conclusion 154 8. Appendices 156 Appendix 1. Summary of 5-FU/LV regimens 156 Appendix 2. BNF general guidance on use of cytotoxic drugs 157 Appendix 3. Identification of studies for the review of clinical 159 effectiveness Appendix 4. Studies excluded from the review of clinical effectiveness 169 Appendix 5. Quality assessment scale for randomised controlled trials 171 (adapted) Appendix 6. QUORUM trial flow chart (clinical effectiveness) 173 Appendix 7. Data extraction tables 174 Appendix 8. Meta-analysis of oxaliplatin (in combination with 5-FU/LV) 229 versus 5-FU/LV alone: Disease-free survivala,b Appendix 9. Identification of studies for review of cost-effectiveness 230 Appendix 10. Critical appraisal of economic evidence using the Drummond 237 checklist Appendix 11. QUORUM trial flow chart (cost-effectiveness) 258 Appendix 12. Studies excluded from the review of cost-effectiveness 259 Appendix 13. Identification of sources of evidence - economic model 260 Appendix 14. Disease-free survival analysis and results 282 Appendix 15. Fitted Weibull functions for patients with relapse 286 Appendix 16. Fitted overall survival curves 289 Appendix 17. Overview of ongoing adjuvant therapy trials in stage III colon 291 cancer 9. References 293 6 Tables Table 1 Colorectal cancer incidence, 2002 25 Table 2 Staging of colorectal cancer, with five year survival 27 Table 3 Colorectal cancer mortality, 2002 29 Table 4 Summary of design and study characteristics – MOSAIC trial 45 and NSABP C-07 trial Table 5 Summary of patient characteristics – MOSAIC trial and NSABP 47 C-07 trial Table 6 Trial quality assessment: Oxaliplatin 49 Table 7 Disease-free and overall survival for the MOSAICa and NSABP 53 C-07b trial Table 8 Adverse events (toxicities)a during treatment 57 Table 9 Summary of design and study characteristics – X-ACT study 68 Table 10 Summary of patient characteristics – X-ACT study 70 Table 11 Trial quality assessment: Capecitabine