THE PREVENTION OF ORAL SIDE EFFECTS OF CANCER TREATMENT VOLUME I of II A thesis submitted to The University of Manchester for the degree of Doctor of Philosophy in the Faculty of Biology, Medicine and Health 2017 PHILIP RILEY SCHOOL OF MEDICAL SCIENCES Division of Dentistry 1 CONTENTS VOLUME I OF II: ABSTRACT ................................................................................................................. 6 DECLARATION ......................................................................................................... 7 COPYRIGHT STATEMENT .................................................................................... 7 ACKNOWLEDGEMENTS ........................................................................................ 8 THE AUTHOR ............................................................................................................ 8 1 INTRODUCTION ............................................................................................... 9 1.1 Overview of side effects caused by cancer treatment .............................................9 1.2 Oral mucositis .............................................................................................................9 1.3 Salivary gland dysfunction ......................................................................................19 1.4 Importance of systematic reviews ...........................................................................21 1.5 Importance of clinical guidelines ............................................................................24 1.6 What are the gaps? ..................................................................................................27 2 AIMS .................................................................................................................. 29 3 INTERVENTIONS FOR PREVENTING ORAL MUCOSITIS IN PATIENTS WITH CANCER RECEIVING TREATMENT: ORAL CRYOTHERAPY ...... 30 3.1 Abstract .....................................................................................................................30 3.2 Background ...............................................................................................................33 3.3 Objectives ..................................................................................................................36 3.4 Methods .....................................................................................................................36 3.5 Results .......................................................................................................................44 3.5.1 Description of studies ..................................................................................... 44 3.5.2 Risk of bias in included studies ...................................................................... 53 3.5.3 Effects of interventions .................................................................................. 57 3.6 Summary of findings tables .....................................................................................79 1 Cryotherapy versus control for preventing oral mucositis in adults receiving fluorouracil-based treatment for solid cancers ........................................................ 79 2 Cryotherapy versus control for preventing oral mucositis in adults receiving high- dose melphalan-based treatment prior to haematopoietic stem cell transplantation for haematological cancers ........................................................................................... 81 3.7 Discussion ..................................................................................................................84 3.8 Authors' conclusions ................................................................................................89 4 INTERVENTIONS FOR PREVENTING ORAL MUCOSITIS IN PATIENTS WITH CANCER RECEIVING TREATMENT: CYTOKINES AND GROWTH FACTORS .................................................................................................................. 91 2 4.1 Abstract .....................................................................................................................91 4.2 Background ...............................................................................................................93 4.3 Objectives ..................................................................................................................97 4.4 Methods .....................................................................................................................97 4.5 Results .....................................................................................................................105 4.5.1 Description of studies ................................................................................... 105 Excluded studies.................................................................................................... 118 4.5.2 Risk of bias in included studies .................................................................... 119 4.5.3 Effects of interventions ................................................................................ 123 4.6 Summary of findings tables ...................................................................................157 1 KGF compared to placebo for preventing oral mucositis in adults with cancer receiving treatment ................................................................................................ 157 2 GM-CSF compared to placebo/no treatment for preventing oral mucositis in adults with cancer receiving treatment ............................................................................ 160 3 G-CSF compared to placebo/no treatment for preventing oral mucositis in adults with cancer receiving treatment ............................................................................ 163 4.7 Discussion ................................................................................................................165 4.8 Authors' conclusions ..............................................................................................171 5 PHARMACOLOGICAL INTERVENTIONS FOR PREVENTING DRY MOUTH AND SALIVARY GLAND DYSFUNCTION FOLLOWING RADIOTHERAPY .................................................................................................. 173 5.1 Abstract ...................................................................................................................173 5.2 Background .............................................................................................................175 5.3 Objectives ................................................................................................................177 5.4 Methods ...................................................................................................................177 5.5 Results .....................................................................................................................184 5.5.1 Description of studies ................................................................................... 184 5.5.2 Risk of bias in included studies .................................................................... 189 5.5.3 Effects of interventions ................................................................................ 193 5.6 Summary of findings tables ...................................................................................245 1 Pilocarpine compared to no treatment/placebo for preventing salivary gland dysfunction following radiotherapy ...................................................................... 245 2 Amifostine compared to no treatment/placebo for preventing salivary gland dysfunction following radiotherapy ...................................................................... 248 3 Palifermin compared to placebo for preventing salivary gland dysfunction following radiotherapy........................................................................................................... 251 5.7 Discussion ................................................................................................................252 5.8 Authors' conclusions ..............................................................................................256 6 THE QUALITY OF CLINICAL GUIDELINES ON MOUTH CARE FOR CANCER PATIENTS ............................................................................................. 258 6.1 Abstract ...................................................................................................................258 3 6.2 Background .............................................................................................................258 6.3 Objective .................................................................................................................259 6.4 Methods ...................................................................................................................259 6.5 Results .....................................................................................................................265 6.6 Discussion ................................................................................................................276 6.7 Conclusion ...............................................................................................................278 7 DISCUSSION .................................................................................................. 279 8 REFERENCES ...............................................................................................