Predicting Chemotherapy-Induced Febrile Neutropenia Outcomes in Adult Cancer Patients: An Evidence-Based Prognostic Model Yee Mei, Lee Cert Nursing (S’pore), RN, Adv. Dip. (Oncology) in Nursing (S’pore), Bsc of Nursing (Monash), Master of Nursing (S’pore) Thesis submitted for the Doctor of Philosophy School of Translational Health Science The University of Adelaide Adelaide, South Australia Australia November 2013 Table of Contents TABLE OF CONTENTS -------------------------------------------------------------------- II LIST OF TABLES ------------------------------------------------------------------------ VII LIST OF FIGURES ---------------------------------------------------------------------- VIII LIST OF ABBREVIATIONS --------------------------------------------------------------- XI ABSTRACT ----------------------------------------------------------------------------- XII DECLARATION ----------------------------------------------------------------------- XIIII ACKNOWLEDGEMENTS-- ------------------------------------------------------------ IXV PUBLICATIONS ------------------------------------------------------------------------ XV 1 INTRODUCTION TO THE THESIS ---------------------------------------------------- 15 1.1 CLINICAL CONTEXT -------------------------------------------------------------------------------- 15 1.2 CLINICAL IMPACT OF CHEMOTHERAPY-INDUCED FEBRILE NEUTROPENIA -------------------- 16 1.3 ECONOMIC IMPLICATIONS OF CHEMOTHERAPY-INDUCED FEBRILE NEUTROPENIA ---------- 18 1.4 EVOLVING PRACTICE IN THE MANAGEMENT OF FEBRILE NEUTROPENIA ---------------------- 18 1.5 PROGNOSTIC FACTORS AND PROGNOSTIC MODELS ------------------------------------------ 21 1.6 PROGNOSTIC FACTORS AND MODELS FOR RISK STRATIFICATION OF FEBRILE NEUTROPENIA PATIENTS -------------------------------------------------------------------------------------------- 22 1.7 CURRENT STATE OF PROGNOSTIC FACTORS AND MODELS FOR RISK STRATIFICATION OF FEBRILE NEUTROPENIA PATIENTS ------------------------------------------------------------------ 23 1.8 OPTIMAL PROGNOSTIC MODEL FOR RISK STRATIFICATION OF FEBRILE NEUTROPENIA PATIENTS ------------------------------------------------------------------------------------------------------ 25 1.9 SIGNIFICANCE OF THE RESEARCH ---------------------------------------------------------------- 25 1.10 STRUCTURE OF THE THESIS ------------------------------------------------------------------------- 26 2 BACKGROUND -------------------------------------------------------------------- 27 2.1 INTRODUCTION TO THE CHAPTER ----------------------------------------------------------------- 27 2.2 NEUTROPHILS AND THE BODY IMMUNE SYSTEM ------------------------------------------------- 27 2.3 GRADES OF NEUTROPENIA ----------------------------------------------------------------------- 29 2.4 CHEMOTHERAPY-INDUCED NEUTROPENIA ------------------------------------------------------ 30 2.5 CHALLENGES IN THE MANAGEMENT OF CHEMOTHERAPY-INDUCED FEBRILE NEUTROPENIA 32 2.6 CHEMOTHERAPY-INDUCED NEUTROPENIA AND FEBRILE NEUTROPENIA – RISK FACTORS AND PREVENTIVE MEASURES ---------------------------------------------------------------------------- 34 2.6.1 Use of colony-stimulating factors in patients with neutropenia ---- 35 2.6.2 Use of antimicrobial prophylaxis in patients with neutropenia ----- 37 2.7 FACTORS PREDICTIVE OF FEBRILE NEUTROPENIA OUTCOMES ---------------------------------- 39 2.7.1 Patient-related factors ----------------------------------------------------------- 39 2.7.2 Disease-related factors ---------------------------------------------------------- 43 2.7.3 Treatment–related factors ------------------------------------------------------ 45 2.7.4 Febrile episode-related factors ----------------------------------------------- 47 2.7.5 Diagnostic / Laboratory markers --------------------------------------------- 53 ii 2.8 SUMMARY OF PROGNOSTIC FACTORS FOR THE RISK STRATIFICATION OF PATIENTS WITH FEBRILE NEUTROPENIA ----------------------------------------------------------------------------- 58 2.9 PROGNOSTIC MODELS FOR RISK STRATIFICATION OF PATIENTS WITH FEBRILE NEUTROPENIA 59 2.9.1 Talcott model ----------------------------------------------------------------------- 60 2.9.2 MASCC risk-index score --------------------------------------------------------- 62 2.9.3 Risk model for patients with haematology malignancies ------------ 63 2.9.4 Summary of the prognostic models ----------------------------------------- 65 2.10 CURRENT STATE OF EVIDENCE -------------------------------------------------------------------- 65 3 SYSTEMATIC REVIEW OF PROGNOSTIC FACTORS FOR FEBRILE NEUTROPENIA OUTCOMES IN ADULT CANCER PATIENTS --------------------------------------- 67 3.1 INTRODUCTION TO THE CHAPTER ----------------------------------------------------------------- 67 3.2 EVIDENCE-BASED PRACTICE ---------------------------------------------------------------------- 67 3.3 BARRIERS OF EVIDENCE-BASED HEALTHCARE ADOPTION -------------------------------------- 69 3.4 THE JOANNA BRIGGS INSTITUTE MODEL OF EVIDENCE-BASED HEALTHCARE ---------------- 70 3.4.1 Framework of the Joanna Briggs Institute model ----------------------- 71 3.5 SYSTEMATIC REVIEW ------------------------------------------------------------------------------- 74 3.6 SCOPE OF REVIEW FOR FACTORS ASSOCIATED WITH FEBRILE NEUTROPENIA OUTCOMES -- 76 3.7 CHALLENGES ASSOCIATED WITH SYSTEMATIC REVIEW OF PROGNOSTIC FACTORS --------- 78 3.8 META-ANALYSIS OF INDIVIDUAL PATIENT DATA ------------------------------------------------- 80 3.9 SYSTEMATIC REVIEW PROTOCOL ----------------------------------------------------------------- 82 3.9.1 Statement of the review question ------------------------------------------- 82 3.9.2 Objectives of the review -------------------------------------------------------- 82 3.9.3 Review Questions: ----------------------------------------------------------------- 82 3.9.4 Inclusion criteria -------------------------------------------------------------------- 82 3.9.5 Search strategy -------------------------------------------------------------------- 87 3.9.6 Method of the review ------------------------------------------------------------ 89 3.9.7 Results of the systematic review ---------------------------------------------- 91 3.9.8 Review findings --------------------------------------------------------------------- 98 3.9.9 Patient-related factors --------------------------------------------------------- 100 3.9.10 Disease-related factors -------------------------------------------------------- 101 3.9.11 Treatment-related factors ---------------------------------------------------- 101 3.9.12 Febrile neutropenia episode-related factors --------------------------- 103 3.9.13 Laboratory markers ------------------------------------------------------------- 106 3.9.14 Factors summarised according to the odd ratios -------------------- 108 3.9.15 Summary of the review findings -------------------------------------------- 111 3.9.16 Discussion --------------------------------------------------------------------------- 112 3.9.17 Limitations of the Review ------------------------------------------------------ 121 3.9.18 Conclusions to the systematic review ------------------------------------ 123 3.9.19 Implications for practice ------------------------------------------------------ 123 3.9.20 Implications for research ------------------------------------------------------ 124 iii 4 PRIMARY STUDY TO ESTABLISH CANDIDATE FACTORS FOR THE PROGNOSIS OF FEBRILE NEUTROPENIA ----------------------------------------------------------- 126 4.1 INTRODUCTION TO THE CHAPTER --------------------------------------------------------------- 126 4.2 PROGNOSIS AND ITS UTILITY IN DECISION MAKING ------------------------------------------- 126 4.3 SINGLE VERSUS MULTIPLE PREDICTORS IN PROGNOSTICATION ------------------------------ 127 4.4 TYPES OF PROGNOSTIC STUDIES ---------------------------------------------------------------- 129 4.5 PROGNOSTIC FACTORS AND MODEL DEVELOPMENT ---------------------------------------- 131 4.6 QUALITY OF PROGNOSTIC STUDIES ------------------------------------------------------------- 132 4.6.1 Study design: prospective compared with retrospective designs --- ----------------------------------------------------------------------------------------- 133 4.6.2 Selection of candidate variables ------------------------------------------ 135 4.6.3 Choice of appropriate outcome measures ---------------------------- 136 4.6.4 Sample size and events in analysis – some limitations --------------- 137 4.6.5 Reporting of results -------------------------------------------------------------- 138 4.7 PRIMARY STUDY: DESIGN AND METHODS ---------------------------------------------------- 139 4.7.1 Justification for primary study ------------------------------------------------ 139 4.7.2 Purpose of the study ------------------------------------------------------------ 140 4.7.3 Study questions: ------------------------------------------------------------------ 140 4.7.4 Site of study ------------------------------------------------------------------------ 141 4.7.5 Study design ----------------------------------------------------------------------- 141 4.7.6 Sampling ---------------------------------------------------------------------------- 143 4.7.7 Study population ---------------------------------------------------------------- 144 4.7.8 Sample Size ------------------------------------------------------------------------ 144 4.7.9 Operational