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The Use of an Evidence Based Approach to Guide Optimal Surgical Management of Colorectal Liver Metastases

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The Use of an Evidence Based Approach to Guide Optimal Surgical Management of Colorectal Liver Metastases 1 THE USE OF AN EVIDENCE BASED APPROACH TO GUIDE OPTIMAL SURGICAL MANAGEMENT OF COLORECTAL LIVER METASTASES Dr Constantinos Simillis BSc, MBBS, MA, MRCS Supervisors Mr Kurinchi Gurusamy Professor Brian Davidson Division of Surgery & Interventional Science University College London (UCL) THESIS SUBMITTED TO UNIVERSITY COLLEGE LONDON FOR THE DEGREE OF MD (RES) JUNE 2015 2 Declaration of own work I, Dr Constantinos Simillis confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. It should be noted that the scientific studies presented in this thesis reflect the contributions of a team of researchers, and I have conducted most steps of study design, data collection, data analysis, and interpretation of the results. Signature 3 ACKNOWLEDGEMENTS I would like to thank my supervisors Mr Kurinchi Gurusamy and Professor Brian Davidson for their constant support and inspiring guidance throughout the course of this thesis. This thesis is dedicated to the memory of my beloved father, Panayiotis Simillis, who passed away while I was writing this thesis. Father, I miss you so much, and I am grateful for every moment we spent together. It is your shining example that I try to emulate in all that I do. Also, dedicated to my mother Maroulla, my brother Michalis, and to Thalia for their unconditional love and support. 4 ABSTRACT The aim of this thesis was to validate the optimal surgical management of colorectal liver metastases (CLM) by using an evidence based approach. A meta-analysis comparing combined and sequential resection for synchronous CLM demonstrated that combined resection is associated with reduced hospital stay and with comparable perioperative mortality and morbidity, operative blood loss, and survival rates as sequential resection. Nevertheless, combined resection was associated with lower metastatic disease severity compared to sequential resection. A meta-analysis assessed liver resection for CLM in the presence of hepatic lymph node involvement and demonstrated that survival rates are lower in node positive disease patients compared to node negative disease patients, irrespective of whether the positive disease nodes were detected by routine or selective lymphadenectomy, or whether nodal involvement was microscopic or macroscopic. A network meta-analysis comparing different treatment strategies aiming to decrease operative blood loss found no difference in mortality, length of hospital stay or ITU stay between the treatment strategies. The use of radiofrequency dissecting sealer resulted in more serious adverse events compared to the clamp-crush method in the absence of vascular occlusion and fibrin sealant. Simple methods, such as clamp-crush method, gave overall equivalent outcomes to methods which require special equipment. Not reporting the period of follow-up was investigated as a potential source of study bias. Overall analysis did not identify a significant difference in mortality and disease recurrence, but sensitivity analysis of more recent reviews and larger reviews showed that the trials reporting the period of follow-up had a significantly lower hazard ratio for disease recurrence compared to trials not reporting the period of follow-up. A network meta-analysis comparing interventions aiming to decrease ischaemia- reperfusion injury during liver resection, demonstrated that ischaemic preconditioning resulted in fewer serious adverse events, lower operative blood loss, fewer transfusion proportions, and shorter operative time. 5 TABLE OF CONTENTS DECLARATION OF OWN WORK ................................................................................ 2 ACKNOWLEDGEMENTS .............................................................................................. 3 ABSTRACT ...................................................................................................................... 4 TABLE OF CONTENTS .................................................................................................. 5 LIST OF ABBREVIATIONS ........................................................................................... 8 CHAPTER 1: INTRODUCTION ................................................................................... 10 1.1 Colorectal liver metastases .................................................................................... 11 1.2 Liver resection ....................................................................................................... 14 1.3 Evidence-based approach ...................................................................................... 22 1.4 Thesis hypothesis and aim ..................................................................................... 27 CHAPTER 2: PAIRWISE META-ANALYSIS ............................................................. 28 2.1 Definition ............................................................................................................... 29 2.2 Advantages and disadvantages .............................................................................. 29 2.3 Methods ................................................................................................................. 33 CHAPTER 3: NETWORK META-ANALYSIS ............................................................ 41 3.1 Definition ............................................................................................................... 42 3.2 Advantages and disadvantages .............................................................................. 42 3.3 Methods ................................................................................................................. 48 3.4 WinBUGS codes ................................................................................................... 53 3.5 Raw data ................................................................................................................ 64 CHAPTER 4: PAIRWISE META-ANALYSIS COMPARING COMBINED VERSUS SEQUENTIAL RESECTION FOR SYNCHRONOUS COLORECTAL LIVER METASTASES ............................................................................................................... 66 4.1 Introduction ........................................................................................................... 67 4.2 Methods ................................................................................................................. 69 4.3 Results ................................................................................................................... 74 4.4 Discussion ............................................................................................................ 111 4.5 Conclusions ......................................................................................................... 117 6 CHAPTER 5: PAIRWISE META-ANALYSIS COMPARING THE SURVIVAL OF NODE POSITIVE VERSUS NODE NEGATIVE DISEASE AFTER HEPATECTOMY FOR COLORECTAL LIVER METASTASES ............................................................ 118 5.1 Introduction ......................................................................................................... 119 5.2 Methods ............................................................................................................... 123 5.3 Results ................................................................................................................. 130 5.4 Discussion ........................................................................................................... 152 5.5 Conclusions ......................................................................................................... 157 CHAPTER 6: A NETWORK META-ANALYSIS COMPARING TREATMENT STRATEGIES USED DURING LIVER RESECTION AIMING TO DECREASE BLOOD LOSS AND BLOOD TRANSFUSION ......................................................... 158 6.1 Introduction ......................................................................................................... 159 6.2 Methods ............................................................................................................... 167 6.3 Results ................................................................................................................. 177 6.4 Discussion ........................................................................................................... 248 6.5 Conclusions ......................................................................................................... 255 CHAPTER 7: REVIEW OF THE LITERATURE TO ASSESS WHETHER NOT REPORTING THE PERIOD OF FOLLOW-UP IS A SOURCE OF BIAS IN TRIALS COMPARING LONG-TERM OUTCOMES ............................................................... 256 7.1 Introduction ......................................................................................................... 257 7.2 Methods ............................................................................................................... 260 7.3 Results ................................................................................................................. 264 7.4 Discussion ........................................................................................................... 280 7.5 Conclusions ......................................................................................................... 284 CHAPTER 8: OVERALL DISCUSSION AND FUTURE STUDIES ........................ 285 8.1 Overall discussion and future studies ..............................................................
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