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ASSESSMENT OF CHEMOTHERAPY OUTCOME AND ADVERSE EVENT MANAGEMENT AMONG SOLID

CANCER PATIENTS OF PENANG HOSPITAL

BASSAM ABDUL RASOOL HASSAN

UNIVERSITI SAINS MALAYSIA

2013

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ASSESSMENT OF CHEMOTHERAPY OUTCOME AND ADVERSE EVENT MANAGEMENT AMONG SOLID

CANCER PATIENTS OF PENANG HOSPITAL

By

BASSAM ABDUL RASOOL HASSAN

Thesis submitted in fulfillment of the requirements for the degree of Doctor of Philosophy

(Pharmacy)

May 2013

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ii

DEDICATION

To

My great family specifically to my lovely father Abdul Rasool and mother Basma.

My darling wife Hiba and my sweet heart daughter Shams.

My great Brothers Rafid and Bilal.

(May Great ALLAH Bless My Soul)

Bassam

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iii

ACKNOWLEDGMENTS

This research would not have been possible without the help of those whom I would like to get this chance to thank them from depth of my heart.

I would like to begin by expressing my indebtedness and grateful thanks to the greatest and mercifulness God ALLAH the Almighty for bestowing me and giving me the strength, patience and power to finish this research.

I am delighted to express my great sincere appreciation and heartfelt thanks to my supervisors Associate Professor Dr. Zuraidah Binti Mohd Yusoff, Associate Professor Saad Bin Othman and Associate Professor Dr. Mohamed Azmi Ahmad Hassali for their great guidance, intellectual supports, encouragement and unlimited advices during the different stages of my work.

I’m thankful to my field supervisor Dr. Tan Boon Seang in the Oncology Clinics at Penang Hospital, for his support and help during conducting this research.

I would like to express my grateful thanks and appreciation to University of Sains Malaysia and a special thanks to the School of Pharmaceutical Sciences for offering me the chance to do my postgraduate study.

Also I would like to thank all the medical staff of Penang Hospital especially those who work in the oncology clinic, ward C11, C19 and record office.

I would like to thank to the most and greatest support in my whole life, those who fill my life with all colorful beauties of hope and nature, those who will remain just like my soul, my great and marvelous father, mother, wife, daughter and brothers.

May ALAH (Subhanahu Wa Ta’ala) bless all those who contributed directly or indirectly to success of this research.

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iv

TABLE OF CONTENTS

Page

TITLE i

DEDICATION ii

ACKNOWLEDGMENTS iii

TABLE OF CONTENTS iv

LIST OF TABLES xxi

LIST OF FIGURES xxxii

LIST OF ABBREVIATIONS xxxiii

ABSTRAK xxxviii

ABSTRACT xl CHAPTER 1: INTRODUCTION 1.1 Cancer Background 1

1.2 Chemotherapy Background 1

1.3 Chemotherapy Side Effects 2

1.4 Main Problems Caused by Solid Cancer Diseases and Chemotherapy 3

1.4.1 Nausea and Vomiting 3

1.4.1.1 Causes of Nausea and Vomiting 4

1.4.1.2 Nausea and Vomiting in Solid Cancer Patients 4

1.4.1.3 Pathophysiology of Chemotherapy-Induced Nausea and 5

Vomiting

1.4.1.4 Major Patients Risk Factors Associated with Incidence and 7

Severity of Nausea and Vomiting

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v

1.4.1.5 Major Chemotherapy Factors Responsible For Incidence 8

and Severity of Nausea and Vomiting 1.4.1.6 Classification of Chemotherapy Induced Nausea and 9

Vomiting 1.4.1.7 Diagnosis of Incidence of Nausea and Vomiting 10

1.4.1.8 Classification and Incidence of Chemotherapy Induced 10

Nausea and Vomiting 1.4.1.9 Grading of Nausea and Vomiting Severity for Acute 11

and Delayed Phase 1.4.1.10 Association of Acute Emesis with Delayed Emesis 12

1.4.1.11 Nausea and Vomiting Treatment 12

1.4.1.11.1 Serotonin-Receptor Antagonists (5-HT

3

) 13

1.4.1.11.2 Dopamine-2- Receptor Antagonists 13

1.4.1.11.3 Corticosteroids 14

1.4.1.11.4 Neurokinin-1-Receptor Antagonists 14

1.4.1.11.5 Cannabinoids 15

1.4.1.12.6 Benzodiazepines 15

1.4.1.12 Antiemetic guidelines for Acute and Delayed Chemotherapy 16

Induced Nausea and Vomiting 1.4.1.13 Nausea and Vomiting in Breast Cancer 16

1.4.1.14 Ethnic Variation Role in Incidence of Nausea and Vomiting 18

1.4.1.15 Literature Review for Nausea and Vomiting 19

1.4.1.16 Literature review in Malaysia 31

1.4.1.17 Problem Statement 34

1.4.2 Anemia 35

1.4.2.1 Red Blood Cell (RBC) and Iron 35

1.4.2.2 Types of Anemia 36

1.4.2.3 Erythropoietin (EPO) Description and Action 37

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vi

1.4.2.4 Causes of Anemia of Chronic Diseases (ACD) 37

1.4.2.5 Diagnosis of Anemia 38

1.4.2.6 Grades of Anemia 39

1.4.2.7 Clinical Symptoms of Anemia 39

1.4.2.8 Anemia and Demographic Data 40

1.4.2.8.1 Association of Anemia with Age 40

1.4.2.8.2 Association of Anemia with Gender 41

1.4.2.8.3 Association of Anemia with Race 41

1.4.2.9 Association of Anemia with Cancer 41

1.4.2.10 Association of Anemia with Chemotherapy 42

1.4.2.11 Indications and Options for Anemia Treatments 43

1.4.2.12 Literature Review of Anemia in Cancer Patients 46

1.4.2.13 Literature Review of Studies in Malaysia on Anemia and 54

Cancer 1.4.2.14 Problem Statement 55

1.4.3 Thrombocytopenia 56

1.4.3.1 Platelets Morphology and Structure 56

1.4.3.2 Platelets Function 57

1.4.3.3 Thrombopoietin Hormone (TPO) 58

1.4.3.4 Main Causes of Thrombocytopenia 58

1.4.3.5 Association of Thrombocytopenia with Demographic Data 59

1.4.3.6 Association of Thrombocytopenia with Chemotherapy 59

1.4.3.7 Association of Thrombocytopenia with Solid Cancer 60

1.4.3.8 Diagnosis of Thrombocytopenia 60

1.4.3.9 Levels of Thrombocytopenia 61

1.4.3.10 Clinical Symptoms Associated with Thrombocytopenia 61

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vii

1.4.3.11 Thrombocytopenia Treatment 62

1.4.3.12 Literature Review for Thrombocytopenia 63

1.4.3.13 Literature Review for Thrombocytopenia in Malaysia 67

1.4.3.14 Problem Statement 68

1.4.3.15 Association of Thrombocytopenia with Neutropenia 68

1.4.4 Hypercalcemia 69

1.4.4.1 Calcium Homeostasis 69

1.4.4.1.1 Kidney Role in Calcium Homeostasis 70

1.4.4.1.2 Gut Role in Calcium Homeostasis 70

1.4.4.1.3 Bone Role in Calcium Homeostasis 71

1.4.4.2 Main Hormones Responsible for Calcium Control 71

1.4.4.3 Causes of Hypercalcemia 72

1.4.4.4 Hypercalcemia Diagnosis 73

1.4.4.5 Hypercalcemia Levels 73

1.4.4.6 Symptoms of Hypercalcemia 74

1.4.4.7 Hypercalcemia Treatment 74

1.4.4.8 Hypercalcemia with Demographic Data 78

1.4.4.9 Mechanisms of Hypercalcemia Occurrence with Malignancy 78

1.4.4.10 Hypercalcemia with Nausea and Vomiting 79

1.4.4.11 Literature Review For Hypercalcemia and Cancer 79

1.4.4.12 Literature Review For Hypercalcemia in Malaysia 85

1.4.4.13 Problem Statement 86

1.5 Rationale of the Study 87

1.6 Objectives of the Study 89

1.6.1 General Primary Objectives 89

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1.6.2 Primary Objectives (Descriptive part) 89

1.6.3 Secondary Objectives (Statistical part) 90

1.7 Significance of the Study 91

CHAPTER TWO: METHODOLOGY 93

2.1 Study Approval 93

2.2

Main Sections of The Study

93

2.3 Study Design 94

2.4 Prospective Part

2.4.1 Study Design For Prospective Part 94

2.4.2 Study Population, Sample Size and Sampling Method 96

For Prospective Part 2.4.3 Patients Inclusion and Exclusion Criteria For Prospective Part 97

2.4.3.1 General Inclusion Criteria 97

2.4.3.2 Specific Inclusion and Exclusion Criteria For Nausea 98

and Vomiting 1- Inclusion Criteria for Nausea and Vomiting 98

2- Exclusion Criteria for Nausea and Vomiting 98

2.4.4 Procedure of Collecting Information or Data Collection For 98

Prospective Part 2.4.5 Variables For The Prospective Study Nausea and Vomiting 99

2.5 Retrospective Part 100

2.5.1 Study Design For Retrospective Part 100

2.5.2 Study Population, Sample Size and Sampling Method For 101

Retrospective Part 2.5.3 Patients Inclusion and Exclusion Criteria For Retrospective Part 102

2.5.3.1 General Inclusion Criteria 102

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2.5.3.1.1 Anemia 102

1- Inclusion Criteria for Anemia 102

2- Exclusion Criteria for Anemia 102

2.5.3.1.2 Thrombocytopenia 103

1- Inclusion Criteria for Thrombocytopenia 103

2- Exclusion Criteria for Thrombocytopenia 103

2.5.3.1.3 Hypercalcemia 104

1- Inclusion Criteria for Hypercalcemia 104

2- Exclusion Criteria for Hypercalcemia 104

2.5.4 Procedure of Collecting Information or Data Collection For 104

Retrospective Part 2.5.5 Variables For Retrospective Study 105

2.5.5.1 Variables of Anemia 105

2.5.5.2 Variables of Thrombocytopenia 105

2.5.5.3 Variables of Hypercalcemia 105

2.6 Location and Time of the Study 106

2.7 Types of Data Collected and Analysis Process For This Present Study 107

2.8 Statistical Methods 107

CHAPTER 3: RESULTS and DISCUSION 110

3.1 Nausea and Vomiting 111

3.1.1 First Part (Descriptive Part) 111

3.1.1.1 Patient Demographic Data (

Patient's Gender,

111

Age and Ethnic Group)

3.1.1.2 Breast Cancer Stages 111

3.1.1.3 Chemotherapy 112

3.1.1.3.1 Chemotherapy Emetogenic Level 112

3.1.1.3.2 Chemotherapy Cycles 112

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3.1.1.3.3 Chemotherapy Schedule 112

3.1.1.3.4 Chemotherapy Status 113

3.1.1.3.5 Chemotherapy Route of Administration 113

3.1.1.3.6 Time of Chemotherapy Administration 113

3.1.1.3.7 Types of Chemotherapy Regimen 113

3.1.1.4

Patients Data

114

3.1.1.4.1 History of Chemotherapy Induce 115

Nausea and Vomiting in Previous Cycles 3.1.1.4.2

Patients Food Types, Eating Habits and

115

Amounts

3.1.1.4.3 Patients Work and House Hold Tasks 116

3.1.1.4.4 Patients Consumption of Alcohol 116

3.1.1.4.5 Taking Other Medication 117

3.1.1.5 Nausea and Vomiting Data 118

3.1.1.5.1 Types of Chemotherapy Induce 118

Nausea and Vomiting (CINV) 3.1.1.5.2 Classifications and Onset of Nausea 120

3.1.1.5.3 Classifications and Onset of Vomiting 121

3.1.1.5.4 Severity of Acute Nausea 122

3.1.1.5.5 Severity of Delayed Nausea 122

3.1.1.5.6 Severity of Acute Vomiting 123

3.1.1.5.7 Severity of Delayed Vomiting 123

3.1.1.6 Treatment of Nausea and Vomiting 124

3.1.1.6.1 Chemotherapy Status 124

3.1.1.6.2 Chemotherapy Doses 124

3.1.1.6.3 Anti Emetic Schedule 124

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3.1.1.6.4 Pre and Post Chemotherapy Anti Emetic 124 3.1.1.7 Clinical Symptoms Association with Nausea and 125 Vomiting

3.1.1.8 Effect of Nausea and Vomiting on Patients QOL 126 3.1.A.1.9 Thinking of Stopping Receiving Chemotherapy 131 Treatment

3.1.1.10

Usefulness of Antiemetic Treatment Against Acute 131 and Delayed CINV

3.1.1.11 When Did The Patients Experience Nausea 133

3.1.1.12 The Time When Nausea and/ or Vomiting was 134 The Worst

3.1.1.13 Chemotherapy Doses Used 134 3.1.2 Second Part (Statistical Analysis) 135 3.1.2.1 Analysis for Association Between Onset and Severity of 135 Nausea and Vomiting with Patients Demographic data

3.1.2.1.1 Association with Patients Gender 135 3.1.2.1.2 Association with Patients Ethnic Group and Age 135 3.1.2.2 Association Between Onset and Severity of 138 Nausea and Vomiting with Breast Cancer Stages

3.1.2.3 Association between Onset and Severity of Nausea and 139 Vomiting with Chemotherapy Data

3.1.2.3.1 Association with Emetogenic Level of 139 Chemotherapy

3.1.2.3.2 Association with Chemotherapy Cycles 139 3.1.2.3.3 Association with Chemotherapy Schedule 140 3.1.2.3.4 Association with Types of Chemotherapy 140 Regimens

3.1.2.4 Association Between Onset and Severity of Nausea 141 and Vomiting with Anti-Emetic Regimens

3.1.2.4.1 Association with Pre and Post-Chemotherapy Anti-Emetic 141

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3.1.2.5 Association Between Onset and Severity of Nausea and 142 Vomiting with Clinical Symptoms

3.1.2.6 Correlation and Association Between Acute and Delayed 143 Nausea and Vomiting with QOL

3.1.2.6.1 Correlation Between Severity of Acute Nausea with 143 Nausea Effects on QOL

3.1.2.6.2 Association Between Severity Acute Nausea with 143 Nausea Effect on QOL

3.1.2.6.3 Correlation Between Severity of Delayed Nausea 144 with Nausea Effects on QOL

3.1.2.6.4 Association Between Delayed Nausea with Nausea 145 Effect on QOL

3.1.2.6.5 Correlation Between Severity of Acute Vomiting with 145 Acute Vomiting Effects on QOL

3.1.2.6.6 Association Between Acute Vomiting with Acute 146 Vomiting Effect on QOL

3.1.2.6.7 Correlation Between Severity of Delayed Vomiting 147 with Vomiting Effects on QOL

3.1.2.6.8 Association Between Delayed Vomiting with 147 Vomiting Effects on QOL

3.1.2.7 Association Between Acute and Delayed Nausea and 148 Vomiting

3.1.2.7.1 Association Between Acute and Delayed Nausea 148 3.1.2.7.2 Association Between Acute and Delayed Vomiting 149 3.1.2.8 Association Between Chemotherapy Doses with Acute and 149 Delayed Nausea and Vomiting

3.1.2.9 Association Between Usefulness of Antiemetic 152 Treatment with Acute and Delayed Nausea and

Vomiting

3.1.2.10 Association Between Ethnicity of Patients with Their Selection 155 of Ideas of Usefulness of Antiemetic Treatment

3.1.2.11 Association between Types of CINV with Breast Cancer Stages 156

3.1.2.12 Association between Types of CINV with Chemotherapy Data 156

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3.1.2.12.1 Association with Emetogenic Level 156

3.1.2.12.2 Association with Chemotherapy Cycle 156

3.1.2.12.3 Association with Chemotherapy Schedule 157

3.1.2.12.4 Association with Chemotherapy Regimens 157

3.1.2.13 Impact of Acute and Delayed Nausea and Vomiting on QOL 158

for Breast Cancer Patients 3.1.2.14 Correlation and Association Between Severity of Acute and 162

Delayed CINV With QOL 3.1.3 Discussion 164

3.1.3.1 Association of Nausea and Vomiting with Patient Demographic 164

Data 3.1.3.1.1 Patients Gender 164

3.1.3.1.2 Patients Ethnic Group 164

3.1.3.1.3 Patient's Age 165

3.1.3.2 Breast Cancer Stages 166

3.1.3.3 Chemotherapy 166

3.1.3.3.1 Chemotherapy Emetogenic Level 166

3.1.3.3.2 Chemotherapy Cycles 167

3.1.3.3.3 Chemotherapy Schedule 168

3.1.3.3.4 Types of Chemotherapy Regimens 169

3.1.3.3.5 Chemotherapy Doses 170

3.1.3.4

Nausea and Vomiting Data 171

3.1.3.4.1 Types of Chemotherapy Induce Nausea and Vomiting 171

(CINV)

3.1.3.4.2 Classifications and Onset of Nausea 178

3.1.3.4.3 Classifications and Onset of Vomiting 178

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3.1.3.4.4 Severity of Acute and Delayed Nausea and Vomiting 179

3.1.3.5 Treatment of Nausea and Vomiting 180

3.1.3.5.1 Chemotherapy Status 180

3.1.3.5.2 Chemotherapy Doses 181

3.1.3.5.3 Anti Emetic Pre and Post Chemotherapy 181

3.1.3.6 Patients Data 182

3.1.3.7 Clinical Symptoms Association with Nausea and Vomiting 182

3.1.3.8 Effect, Association and Correlation of Nausea and Vomiting on/ 184

with Patients QOL 3.1.3.8.1 Effect of Acute and Delayed Nausea and Vomiting on 184

Patients QOL 3.1.3.8.2 Association and Correlation Between Acute and Delayed 185

CINV with QOL 3.1.3.9 Usefulness of Antiemetic Treatment Against Acute and Delayed 188 CINV 3.1.3.10 Thinking to Stop Chemotherapy Treatment 189

3.1.3.11 The Time That Worst Nausea and Vomiting Present 189

3.2 Anemia 196

3.2.1 (Descriptive Part) 191

3.2.1.1 Patients Demographic Data (Patients' Gender, 191

Ethnic and Age Groups) 3.2.1.2 Cancer Information 192

3.2.1.2.1 Types of Cancer Diagnosed 192

3.2.1.2.2 Stages of Cancer 193

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3.2.1.3 Chemotherapy Data 194

3.2.1.3.1 Patients and Chemotherapy 194

3.2.1.3.2 Types of Chemotherapy Drugs or Regimens 195

3.2.1.3.3 Doses of Chemotherapy regimens 197

3.2.1.4 Anemia Data 199

3.2.1.4.1 Onset or Incidence of Anemia 199

3.2.1.4.2 Severity of Anemia 200

3.2.1.4.3 Levels of Hemoglobin 201

3.2.1.5 Treatment of Anemia 202

3.2.1.5.1 Types of Treatment 203

3.2.1.5.2 Effect of Types of Treatment (Guideline) on 203

Hemoglobin Level 3.2.1.6 Clinical Symptoms Associated with Anemia 204

3.2.2 Second Part (Statistical Analysis) 205

3.2.2.1 Association Between Onset and Severity of Anemia with 205

Patients Demographic Data 3.2.2.2 Association with Cancer Data 206

3.2.2.2.1 Association with Cancer Type and Stages 206

3.2.2.3 Association with Chemotherapy Data 208

3.2.3.3.1 Association with Chemotherapy Cycles, Schedule and 208

Chemotherapy Type and Regimen 3.2.2.3.2 Association with Chemotherapy Doses 210

3.2.2.4 Association Between Anemia Treatment with Anemia Onset, 214

Severity and Hemoglobin Levels

3.2.2.5 Association Between Clinical Symptoms with Anemia Onset and 217

Severity

3.2.3 Discussion 219

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xvi

3.2.3.1 Association of Anemia with Patient Demographic Data 219

3.2.3.1.1 Patients Gender 219

3.2.3.1.2 Patients Ages 219

3.2.3.1.3 Patients Ethnic Group 220

3.2.3.2 Association with Cancer Data 221

3.2.3.2.1 Association with Cancer Type 221

3.2.3.2.2 Association with Cancer Stages 222

3.2.3.3 Association with Chemotherapy Data 224

3.2.3.3.1 Association with Chemotherapy Cycles 224

3.2.3.3.2 Association with Chemotherapy Schedule 226

3.2.3.3.3 Association with Type of Chemotherapy 226

3.2.3.3.4 Association with Chemotherapy Doses 228

3.2.3.4 Association Between Anemia Treatment with Anemia 233

Onset, Severity and Hemoglobin Levels 3.2.3.5 Association Between Clinical Symptoms with Anemia 238

Onset and Severity 3.3 Thrombocytopenia 240

3.3.1 Descriptive Part 240

3.3.1.1 Patient Demographic Data (Patients Gender, Ethnic 240

Group and Patient's Age) 3.3.1.2 Cancer Information 241

3.3.1.2.1 Types of Cancer Diagnosed 241

3.3.1.2.2 Stages of Cancer 241

3.3.1.3 Chemotherapy Data 242

3.3.1.3.1 Patients and Chemotherapy 242

3.3.1.3.2 Types of Chemotherapy Drugs or Regimens 244

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xvii

3.3.1.3.3 Doses of Chemotherapy Regimens 246

3.3.1.4 Thrombocytopenia Data 248

3.3.1.4.1 Onset of Thrombocytopenia 248

3.3.1.4.2 Severity of Thrombocytopenia 249

3.3.1.4.3 Levels of Platelets 250

3.3.1.4.4 Bleeding Characteristic 251

3.3.1.5 Treatment of Thrombocytopenia 251

3.3.1.5.1 Pattern of Treatment and Chemotherapy Status 251

3.3.1.5.2 Type of Treatments 252

3.3.1.5.3 Effect of Types of Treatment (Guideline) on 253

Platelets Level 3.3.1.6 Clinical Symptoms Associated with Thrombocytopenia 254

3.3.1.7 Thrombocytopenia Patients with Neutropenia 254

3.3.2 Second Part (Statistical Analysis) 256

3.3.2.1 Association Between Onset and Severity of 256

Thrombocytopenia With Patients Demographic Data 3.3.2.1.1 Association With Patients Gender, Age and Race 256

3.3.2.2 Association with Cancer Information 258

3.3.2.2.1 Association with Cancer Type and Stages 258

3.3.2.3 Association with Chemotherapy Data 259

3.3.2.3.1 Association with Chemotherapy Cycles, Schedule 259

and Types 3.3.2.3.2 Association with Chemotherapy Doses 261

3.3.2.4 Association Between Thrombocytopenia Treatment with 265

Thrombocytopenia Onset, Severity and Platelets levels

3.3.2.5 Association Between Clinical Symptoms with 268

Thrombocytopenia Onset and Severity

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3.3.3 Discussion 270

3.3.3.1 Analysis of Association Between Onset and Severity of 270

Thrombocytopenia with Patient Demographic Data 3.3.3.2 Association Between Onset and Severity of Thrombocytopenia 271

and Cancer Information

3.3.3.2.1 Association with Cancer Type and Stages 271

3.3.3.3 Association with Chemotherapy Data 272

3.3.3.3.1 Association with Chemotherapy Cycles 272

3.3.3.3.2 Association

of Thrombocytopenia

with Chemotherapy 274

Schedule 3.3.3.3.3 Association

of Thrombocytopenia

with Chemotherapy Types 274

3.3.3.3.4 Association with Chemotherapy Doses 279

3.3.3.4 Association Between Thrombocytopenia Treatment with 281

Thrombocytopenia Onset, Severity and Platelets levels 3.3.3.5 Association Between Clinical Symptoms with 285

Thrombocytopenia Onset and Severity 3.3.3.6 Patients with Thrombocytopenia and Neutropenia 286

3.4 Hypercalcemia 287

3.4.1 First Part (Descriptive Part) 287

3.4.1.1 Patient Demographic Data (Patients Gender, Ethnic Group 287

and Age Group) 3.4.1.2 Cancer Information 288

3.4.1.2.1 Types of Cancer Diagnosed 288

3.4.1.2.2 Stages of Cancer 288

3.4.1.2.3 Types of Lung Cancer 289

3.4.1.2.4 Metastasis of Solid Cancer 289

3.4.1.3 Chemotherapy Data 290

3.4.1.3.1 Chemotherapy Status, Schedule and Types of Chemotherapy 290

Regimens

3.4.1.3.2 Doses of Chemotherapy Regimens 294

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3.4.1.4 Hypercalcemia Data 295

3.4.1.4.1 Onset of Hypercalcemia 295

3.4.1.4.2 Severity of Hypercalcemia and Level of Calcium Level 296

3.4.1.5 Treatment of Hypercalcemia 297

3.4.1.5.1 Pattern of Treatment 297

3.4.1.5.2 Types of Treatment 297

3.4.1.5.3 Effect of Types of Treatment (Guideline) on Calcium Level 298

3.4.1.5.4 Bone Scan 299

3.4.1.6 Clinical Symptoms Associated With Hypercalcemia 300

3.4.1.7 Hypercalcemia Effect on Biochemistry Profile 301

3.4.2 Second Part (Statistical Analysis) 303

3.4.2.1 Association Between Onset and Severity of Hypercalcemia with 303

Patients Demographic data 3.4.2.1.1 Association with Patients Gender, Ethnic Group and Age 303

Group 3.4.2.2 Association with Cancer Information 304

3.4.2.2.1 Association with Cancer Type and Stages 304

3.4.2.3 Association with Chemotherapy Data 306

3.4.2.3.1 Association with Chemotherapy Type 306

3.4.2.3.2 Association of Cancer Stages and Metastasis with 307

Chemotherapy Type 3.4.2.3.3 Association of Cancer Stages (primary and advanced) 310

with Chemotherapy Doses 3.4.2.4 Association of Hypercalcemia with Clinical Symptoms 314

3.4.2.5 Association of Hypercalcemia with Biochemistry Profile 316

3.4.2.6 Association Between Hypercalcemia Treatment with 317

Hypercalcemia Onset and Severity 3.4.2.7 Sub Types of Lung Cancer 318

3.43 Discussion 319

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3.4.3.1 Association Between Onset and Severity of Hypercalcemia with 319

Patients Demographic Data 3.4.3.1.1 Association with Patients Gender 319

3.4.3.1.2 Association with Patients Race 319

3.4.3.1.3 Association with patients Ages 321

3.4.3.2 Association with Cancer Information 321

3.4.3.2.1 Association with Cancer Type 321

3.4.3.2.2 Association with Cancer Stages 322

3.4.3.3 Association with Chemotherapy Data 325

3.4.3.3.1 Association with Chemotherapy Type 325

3.4.3.3.2 Association of Cancer Stages and Metastasis with 328

Chemotherapy Type 3.4.3.3.3 Association of Cancer Stages (Primary and Advanced i.e., 335

Metastases) and Calcium Level with Chemotherapy Doses 3.4.3.4 Association of Hypercalcemia with Clinical Symptoms 339

3.4.3.5 Association of Hypercalcemia with Biochemistry Profile 341

3.4.3.6 Association Between Hypercalcemia Treatment with 342

Hypercalcemia Onset and Severity 3.4.3.7 Sub Types of Lung Cancer 345

CHAPTER 4: CONCLUSION, RECOMMENDATIONS AND 346

LIMITATIONS 4.1 Conclusion 346

4.2 Recommendations 349

4.3 Limitations 351

REFERENCES 352

APPENDICES 387

LIST OF PUBLICATIONS 403

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LIST OF TABLES

Table No. Title Page

Table 1.1 Grading of Chemotherapy Induced Nausea and Vomiting 11 Severity for Both Acute and Delayed

Table 1.2 Antiemetic Guideline for Acute and Delayed Nausea and 16 Vomiting

Table 1.3 Clinical Tests Used to Differentiate ACD From IDA 39 Table 1.4 Grades of Anemia 39

Table 1.5 Clinical Signs and Symptoms Associated with Anemia

40 Table 3.1

Demographic Data of Breast Cancer Patients Admitted to 111 Oncology Clinic, Ward C11 and C19 (n=158) Who

Experienced Nausea and Vomiting

Table 3.2 Breast Cancer Stages of Patients Admitted to Penang 111 Hospital who Suffered From Nausea and Vomiting

(n=158)

Table 3.3 Chemotherapy Cycles at Which Nausea and Vomiting 112 Occurred (n=158)

Table 3.4 Chemotherapeutics Drugs or Regimens Used (n=158) to 113 Treat The Breast Cancer Patients

Table 3.5

Breast Cancer Patients Data (n=158)

114

Table 3.6

History of Chemotherapy Induced Nausea and Vomiting in

115

Previous Chemotherapy Cycles (n=133)

Table 3.7

Food Consumption, Eating Habits and Amount Eating by

116

Breast Cancer Patients (n=158) on Chemotherapy

Table 3.8 Effect of Nausea and Vomiting on Patients (n=158) 116 Work and House Hold Tasks

Table 3.9

Consumption and Pattern of Consumption of Alcohol Among 117 Breast Cancer Patients (n=158) Who Experienced Nausea

and Vomiting

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Table 3.10 Nausea and Vomiting Effect on Consumption of Other 117 Medication Among Breast Cancer Patients (n=158)

Table 3.11 Types of Chemotherapy Induce Nausea and Vomiting 118 (CINV)Observed in 158 Breast Cancer Patients

Table 3.12 Types of Chemotherapy Induce Nausea and Vomiting 119 (CINV)Among Chinese Patients (n=101)

Table 3.13 Types of Chemotherapy Induce Nausea and Vomiting 119 (CINV) Among Malay Patients (n=35)

Table 3.14 Types of Chemotherapy Induce Nausea and Vomiting 120 (CINV) Seen in Indian Patients (n=22)

Table 3.15

Classification and Onset of Nausea Among Breast Cancer 121 Patients (n=158)

Table 3.16 Classification and Onset of Vomiting among Breast Cancer 121

Patients (n=158)

Table 3.17 Severity of Acute Nausea Among Breast Cancer Patients 122 (n=158)

Table 3.18 Severity of Delayed Nausea Among Breast Cancer Patients 122 (n=158)

Table 3.19 Severity of Acute Vomiting Among Breast Cancer Patients 123 (n=158)

Table 3.20 Severity of Delayed Vomiting Among Breast Cancer Patients 123 (n=158)

Table 3.21 Different Types of Clinical Symptoms Observed in Breast 125 Cancer Patients (n=137) who Suffered from Nausea and

Vomiting in Penang Hospital

Table 3.22 Scores of Acute Nausea Effect on Quality of Life (QOL) of 126 Breast Cancer Patients (n=158)

Table 3.23 Scores of Acute Vomiting Effect on Quality of Life (QOL) of 127 Breast Cancer Patients (n=158)

Table 3.24 Scores of Delayed Nausea Effect on Quality of Life (QOL) of 128

Breast Cancer Patients (n=158)

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Table 3.25 Scores of Delayed Vomiting Effect on Quality of Life (QOL) 129 of Breast Cancer Patients (n=158)

Table 3.26 Effect of CINV on Quality of Life (QOL) of Breast Cancer 130 Patients (n=158)

Table 3.27 Patients Thinking of Stop Chemotherapy Treatment (n=158) 131 Table 3.28

Usefulness of Antiemetic Treatment Against Acute and Delayed 132 Nausea and Vomiting (n=158)

Table 3.29

Time of Experiencing Nausea and Vomiting (n=158)

133 Table 3.30

The Time When Nausea and/ or Vomiting was The Worst

134

(n=158)

Table 3.31 Chemotherapy Doses Used (n=158) 135 Table 3.32 Statistical Analysis of The Ethnic Group and Patient’s Age 137 with Nausea and Vomiting

Table 3.33 Statistical Analysis of the Cancer Stages with Nausea and 138 Vomiting

Table 3.34 Statistical Analysis of the Chemotherapy Cycles with Nausea 139 and Vomiting

Table 3.35 Statistical Analysis of the Chemotherapy Regimens with Nausea 140 and Vomiting

Table 3.36 Statistical Analysis of the Pre- and Post- Chemotherapy 141 Antiemetic with Nausea and Vomiting

Table 3.37 Statistical Analysis of the Clinical Symptoms with Nausea and 142 Vomiting

Table 3.38 Statistical Analysis for Correlation Between the Severity of 143 Acute Nausea with Nausea Effect on QOL

Table 3.39 Statistical Analysis of the Acute Nausea with Nausea Effect on 144 QOL

Table 3.40 Statistical Analysis for Correlation Between the Severity of 144 Delayed Nausea with Delayed Nausea Effect on QOL

Table 3.41 Statistical Analysis of the Delayed Nausea with Delayed Nausea 145

Effect on QOL

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Table 3.42 Statistical Analysis for Correlation Between the Severity of 146 Acute Vomiting with Acute Vomiting Effect on QOL

Table 3.43 Statistical Analysis of the Acute Vomiting with Acute Vomiting 146 Effect on QOL

Table 3.44 Statistical analysis for Correlation Between the Severity of 147 Delayed Vomiting with Delayed Vomiting Effect on QOL

Table 3.45 Statistical Analysis of the Delayed Vomiting with Vomiting 148 Effects on QOL

Table 3.46 Statistical Analysis of Association Between Onset and Severity 148 of Acute Nausea with Severity of Delayed Nausea (n=158)

Table 3.47 Statistical Analysis of Association Between Onset and Severity 149 of Acute Vomiting with Severity of Delayed Vomiting

(n=158)

Table 3.48 Association Between Chemotherapy Doses with Acute and 150

Delayed Nausea and Vomiting

Table 3.49 Logistic Regression Test of Chemotherapy Doses with Onset 151 and Severity of Acute and Delayed Nausea and Vomiting

Table 3.50 Statistical Analysis of Association Between Perception of 153 Patients on the Usefulness of Antiemetic Treatment Against

Acute and Delayed Nausea and Vomiting (n=158)

Table 3.51 Logistic Regression Analysis of Perception of Patients on the 154 Usefulness of Antiemetic Treatment Against Acute and

Delayed Nausea and Vomiting (n=158)

Table 3.52 Association Between Cancer Patients Races with Opinions of 155 Usefulness of Antiemetic Treatments Against Acute and

Delayed CINV (n=158)

Table 3.53 Statistical Analysis Results of Association Between CINV and 156 Breast Cancer Stages

Table 3.54 Statistical Analysis Results of Association Between CINV and 157 Chemotherapy Cycles

Table 3.55 Statistical Analysis Results of Association Between CINV and 158 Chemotherapy Regimen

Table 3.56 Impact Effect of Acute CINV on Breast Cancer Patients QOL 159

(n=158)

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Table 3.57 Impact of Delayed Nausea and Vomiting on QOL for Breast 161

Cancer Patients

Table 3.58 The Correlation and Association of Severity of Acute and 163 Delayed of CINV with Impact Effect of Acute and

Delayed CINV on Breast Cancer QOL (n=158)

Table 3.59 Gender, Ethnic and Age Group of Cancer Patients with Anemia 191 (n=534) Admitted to the Oncology Ward From 2003-2009

Table 3.60 Types of Cancer Diagnosed Among Anemic Patients Admitted 193 to Penang Hospital Between 2003-2009 (n=534)

Table 3.61 Cancer Stages Among the Anemic Patients Admitted (n=534) 194 Table 3.62 Chemotherapy Data of Anemic Patients (n=534) Admitted to 194 Ward C19 Between 2003-2009

Table 3.63 Types of Chemotherapy Used in Anemic Patients (n=408) 196 Admitted to Ward C 19 Between 2003-2009

Table 3.64 Chemotherapy Doses Administered to Anemic Patients 198 Table 3.65 Onset or Incidence of Anemia Detected Among Cancer Patients 199 Before Chemotherapy (n=126)

Table 3.66 Onset of Anemia Among Cancer Patients After Chemotherapy 200 Administration (n=408)

Table 3.67 Severity of Anemia among Cancer Patients Prior to 201 Chemotherapy Administration (n=126)

Table 3.68 Severity of Anemia Which Developed After Chemotherapy 201 (n=408) Among Cancer Patients Admitted to Ward C19

Table 3.69 The level of Hemoglobin Among the Cancer Patients with 202 Anemia Admitted to Ward C19 Between 2003-2009

Table 3.70 Anemia Treatment (n=534) Employed for the Cancer Patients 202 with Anemia and Chemotherapy Status

Table 3.71 Types of Treatment Used for Anemia (n=534) 203 Table 3.72 Effect of Anemia Treatments Guidelines on Hemoglobin Level 204 for Anemic Patients in Penang Hospital (n=534)

Table 3.73 Clinical Symptoms Associated with Anemia (n=2091) 205

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Table 3.74 Association Between Patient Demographic Data with Anemia 206 Onset and Severity (n=534)

Table 3.75 Association Between Types and Stages of Solid Cancers with 207 Onset and Severity of Anemia Before and After

Chemotherapy (n=534)

Table 3.76 Association Between Chemotherapy Cycles, Schedules and 209 Types with Anemia Onset and Severity

Table 3.77 Logistic Regression of Chemotherapy Regimens with Anemia 209

Onset (n=408)

Table 3.78 Logistic Regression of Chemotherapy Regimens with Anemia 210

Severity (n=408)

Table 3.79 Correlation of Chemotherapy Doses with Anemia Onset (n=408) 211 Table 3.80 Correlation of Chemotherapy Doses with Anemia Severity 212 (n=408)

Table 3.81 Liner regression of Chemotherapy Doses with Anemia Onset 213 (n=408)

Table 3.82 Liner Regression of Chemotherapy Doses with Anemia Severity 213 (n=408)

Table 3.83 Association of Anemia Treatment with Onset and Severity of 215 Anemia Before and After Chemotherapy

Table 3.84 Association of Anemia Treatment with Hemoglobin Levels 215 Onset and Severity Before and After Chemotherapy

Table 3.85 Logistic Regression Test Between Anemia Treatment with 216 Anemia Severity and Hb Levels

Table 3.86 Association of Clinical Symptoms with Onset and Severity of 217 Anemia

Table 3.87 Logistic Regression of Clinical Symptoms with Anemia Onset 217 and Severity

Table 3.88 Demographic Data of Thrombocytopenic Patients Admitted to 240 Penang Hospital (n=341)

Table 3.89 Types of Cancer Diagnosed Among Thrombocytopenic Patients 241

Studied (n=341)

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Table 3.90 Cancer Stages When Thrombocytopenia Occurred Among 242 Patients Studied (n=341)

Table 3.91 Chemotherapy Data for Thrombocytopenic Patients (n=341) 243 Table 3.92 Types of Chemotherapy Used in Thrombocytopenic Patients 245 (n=320)

Table 3.93 Chemotherapy Doses Administered to Thrombocytopenic 247 Patients

Table 3.94 Onset of Thrombocytopenia Among Cancer Patients Before 248 Chemotherapy (n=21)

Table 3.95 Onset of Thrombocytopenia Among Cancer Patients After 249 Chemotherapy (n=320)

Table 3.96 Thrombocytopenia Severity Among Cancer Patients Before 249 Chemotherapy (n=21)

Table 3.97 Thrombocytopenia Severity Among Cancer Patients After 250 Chemotherapy (n=320)

Table 3.98 Platelets Levels Found Among Thrombocytopenic Patients 250 (n=341)

Table 3.99 Degree of Bleeding Happened With Severe Thrombocytopenia 251 Patients (n=51)

Table 3.100 Thrombocytopenia Treatment Pattern (n=51) 252

Table 3.101 Effect of Thrombocytopenia Treatments Guidelines on Platelets 253 Level for Thrombocytopenic Patients in Penang Hospital

(n=274)

Table 3.102 Clinical Symptoms Associated With Thrombocytopenia (n=1311) 254 Table 3.103 Incidence of Thrombocytopenia After Receiving G-CSF 255 (filgrastim)

Table 3.104 Association Between Patient Demographic Data with 257 Thrombocytopenia Onset and Severity (n=341)

Table 3.105 Association Between Solid Cancer Types and Stages with Onset 259 and Severity of Thrombocytopenia Before and After

Chemotherapy

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Table 3.106 Association Between Chemotherapy Cycles, Schedules and 260 Types with Thrombocytopenia Onset and Severity

Table 3.107 Logistic Regression of Chemotherapy Regimens with 260 Thrombocytopenia Onset

Table 3.108 Logistic Regression of Chemotherapy Regimens with 261 Thrombocytopenia Severity

Table 3.109 Correlation of Chemotherapy Doses with Thrombocytopenia 262 Onset

Table 3.110 Correlation of Chemotherapy Doses with Thrombocytopenia 263 Severity

Table 3.111 Linear Regression of Chemotherapy Doses with 264 Thrombocytopenia Onset

Table 3.112 Linear Regression of Chemotherapy Doses with 264 Thrombocytopenia Severity

Table 3.113 Association of Thrombocytopenia Treatment with Onset and 266 Severity of Thrombocytopenia Before and After

Chemotherapy

Table 3.114 Association of Thrombocytopenia Treatment with Platelets 266 Levels Onset and Severity Before and After Chemotherapy

Table 3.115 Association of Treatment with Thrombocytopenia and Platelets 267 Levels Severity After Chemotherapy

Table 3.116 Association of Clinical Symptoms with Onset and Severity of 268 Thrombocytopenia

Table 3.117 Logistic Regression of Clinical Signs with Thrombocytopenia 269 Onset and Severity

Table 3.118 Demographic Data of Hypercalcemic Patients Admitted to 287 Penang Hospital (n=292)

Table 3.119 Types of Cancer Diagnosed Among Hypercalcemic Patients 288 Studied (n=292)

Table 3.120

Breast (n=174) and Lung (n=118) Cancer Stages During The 288 Occurrence of Hypercalcemia

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Table 3.121 Types of Lung Cancer Associated with Hypercalcemia (n=118) 288 Table 3.122 Breast and Lung Cancer Metastasis (n=292) 288 Table 3.123

Chemotherapy Status, Schedules and Types of Regimens Received 290 by Patients Who Developed Hypercalcemia (n=292)

Table 3.124a Effect of Chemotherapy Regimens on Breast and Lung Cancer 291 Size and Metastasis (cancer size depend on cT=

clinical staging)

Table 3.124b Effect of Chemotherapy on Calcium Levels of Breast and Lung 292 Cancer with Hypercalcemia (HC)

Table 3.125 Chemotherapy Doses Received by Hypercalcemic Patients 295 Table 3.126 Onset of Hypercalcemia Among Cancer Patients (n=292) 296 Table 3.127a Severity of Hypercalcemia Among Cancer Patients (n=292) 296 Table 3.127b Calcium Level Among Hypercalcemic Patients (n=292) 297

Table 3.128 Hypercalcemia Treatment Pattern (n=292) 297

Table 3.129 Types of Treatment Used for Hypercalcemia (n=292) 298

Table 3.130 Effects of Types of Treatment on Calcium Level 299

Table 3.131 Bone Scan Performed Among Hypercalcemic Patients (n=292) 300 Table 3.132 Clinical Symptoms Associated with Hypercalcemia 301

Table 3.133

Biochemistry Profile Changes in Presence of Hypercalcemia

302

Table 3.134 Effects of Hypercalcemia on Cancer Patients

Biochemistry Profile

302

Table 3.135 Association of Hypercalcemia Onset and Severity with Patients 303 Demographic Data (n=292)

Table 3.136 Logistic Regression Test of Gender and Race Association 304 with Hypercalcemia Onset

Table 3.137 Association of Cancer Types and Stages with Hypercalcemia 305

Onset and Severity

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Table 3.138 Logistic Regression for Association of Hypercalcemia Onset 305 with Breast and Lung Cancer (n=292)

Table 3.139 Logistic Regression for Association of Hypercalcemia Onset 306 with Breast and Lung Cancer Stages (n=292)

Table 3.140 Association of Type of Chemotherapy with Onset and Severity 306 of Hypercalcemia (n=292)

Table 3.141 Logistic Regression for Association of Chemotherapy Types 307 with Hypercalcemia Onset and Severity

Table 3.142 Association of Chemotherapy Type with Cancer Stages 308

Table 3.143 Logistic Regression for Association of Chemotherapy Types 308 with Early and Advanced Cancer Stages

Table 3.144 Association of Chemotherapy Types with Solid Cancer Sizes/ 309 Differences Between Calcium Level Before and After

Chemotherapy Uses

Table 3.145a Logistic Regression of Chemotherapy Types with Solid Cancer 309 Sizes (Breast)

Table 3.145b Logistic Regression of Chemotherapy Types with Solid Cancer 309 Sizes (Lung)

Table 3.146 Correlation of chemotherapy Doses with Cancer Stages (primary 310 and advanced based on cancer size in cm) (n=292)

Table 3.147 Association of Chemotherapy Doses with Cancer Stages 311 (primary and advanced) (n=292)

Table 3.148a Correlation of Chemotherapy Doses with Calcium Level 312 Table 3.148b Association of Chemotherapy Doses with Calcium Level 313 Table 3.149 Association of Clinical Symptoms with Hypercalcemia Onset 314 and Severity

Table 3.150 Logistic Regression for Association of Clinical Symptoms with 315 Hypercalcemia Onset

Table 3.151 Logistic Regression for Association of Clinical Symptoms with 315 Hypercalcemia Severity

Table 3.152 Association of

Biochemistry Profile

with Hypercalcemia 316

Onset and Severity

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Table 3.153 Logistic for

Biochemistry Profile

Association with Hypercalcemia 317 Severity

Table 3.154 Association of Treatment with Hypercalcemia Onset and Severity 318 (n=292)

Table 3.155 Logistic Regression for Treatment Used in Severe Hypercalcemic 318 Patients (n=292)

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LIST OF FIGURES

Title Page Figure 1.1: Responsible Neurotransmission Pathways for Chemotherapy Induce 6 Nausea and Vomiting (CINV)

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LIST OF ABBREVIATIONS

μg Micro gram

μl Microliter

dl Deciliter

Kg Kilogram

gm (g) Gram

L Litter

mg Milligram

m2 Square Meter

ml Milliliter

U Unit

1st cycle First Cycle 2nd cycle Second Cycle 3rd cycle Third cycle 4th cycle Fourth cycle 5th cycle Fifth cycle 6th cycle Sixth cycle

ACD Anemia of Chronic Diseases ADH Antidiuretic Hormone ANS Autonomic Nervous System aPTT Thromboplastin Time

ASCO American Society of Clinical Oncology

ASHP American Society of Health-System Pharmacist ATP Adenosine Triphosphate

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CAF Cyclophosphamide, Adriamycin and 5-Flurouracil cAMP Cyclic Adenosine Monophosphate

CBC Complete Blood Count

cDNA Cyclic Deoxyribonucleic Acid

CEF or FEC Cyclophosphamide + Epirubicin + 5-Flourouracil CFU-E Colony Forming Unit-Erythroid

CINV Chemotherapy Induce Nausea and Vomiting CMV Cytomegalovirus

CNS Central Nervous System

CMF Cyclophosphamide + Methotrexate + 5-Flourouracil CRC Clinical Research Centre

CT Computed Tomography CTZ Chemoreceptor Trigger Zone CYP Cytochrome P450 Enzymes DNA Deoxyribonucleic Acid D2 Dopamine-2 Receptor

ECAS European Cancer Anaemia Survey ESA Erythropoiesis-Stimulating Agents EPO Erythropoietin

ESR Erythrocyte Sedimentation Rate FAO Food and Agriculture Organization

FDA United State Federal and Drug Administration (FDA) FLIE Functional Living Index- Emesis (FLIE) Questionnaire GIT Gastrointestinal Tract

Hb Hemoglobin

HC Hypercalcemia

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Hct Hematocrit

HEC Highly Emetogenic Chemotherapy HHM Humoral Hypercalcemia of Malignancy HIT Heparin Induced Thrombocytopenia HPE Histopathological Examination IDA Iron Deficiency Anemia

IDIS Medline and Iowa Drug Information Services IMR Institute for Medical Research

INF-γ Interferon

IHM Institute for Health Management IHBR Institute for Health Behavioral Research IHSR Institute for Health Systems Research IPH Institute of Public Health

ITP Idiopathic Thrombocytopenic Purpura I.V. Intravenous

LOH Local Osteolytic Hypercalcemia

MASCC Multinational Association of Supportive Care in Cancer MANE The Morrow Assessment of Nausea and Emesis

MCV Mean Corpuscular Volume

MEC Moderately Emetogenic Chemotherapy Meg-CFC Megakaryocyte Colony Forming Cells MOH Ministry of Health of Malaysia MRI Magnetic Resonance Imaging

NCCN National Comprehensive Cancer Network NIH National Institutes of Health

NICE National Institute for Clinical Excellence

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xxxvi NK-1 Neurokinin Receptors

ONEM The Osoba Nausea and Emesis PO or p.o. Per Oral

PONV Postoperative Nausea and Vomiting PS Power and Sample Size Program PT Prothrombin Time

PTH Parathyroid Hormone

PTHrP Parathyroid Hormone-Related Protein QOL Quality Of Life

RBC Red Blood Cells

rhIL-11 Recombinant Human Interleukin-11 rhTPO Recombinant Human Thrombopoietin rHuEPO Recombinant Erythropoietin

RNA Ribonucleic Acid

rs Spearman Correlation coefficient () SCF Stem Cell Factor

SCC Squamous Cell Carcinoma

SCCOHT Small Cell Carcinoma of The Ovary and Hypercalcemic Type

TB Tuberculosis

TNF-α Tumor Necrosis Factor TPO Thrombopoietin

TT Thrombin Time

TTP Thrombotic Thrombocytopenic Purpura

UNICEF United Nations International Children's Emergency Fund USA United State of America

USM Universiti Sains Malaysia

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xxxvii VC Vomiting Center

WBC White Blood Cell

WHO World Health Organization

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PENILAIAN HASIL KEMOTERAPI DAN PENGURUSAN PERISTIWA ADVERS DI KALANGAN PESAKIT KANSER PEPEJAL HOSPITAL PULAU PINANG

ABSTRAK

Dalam abad ini, kanser telah menjadi salah satu masalah dan penyakit utama yang telah menyebabkan banyak kematian dan akan melebehi penyakit jantung.

Penyakit kanser dan rawatan kemoterapi mempunyai banyak kesan sampingan yang berbahaya yang boleh menjejaskan kualiti hidup (QOL) pesakit-pesakit kanser.

Oleh itu kajian ini dilakukan untuk mengesan faktor-faktor risiko utama berkaitan dengan loya dan muntah, anemia, trombositopenia dan hiperkalsemia dan untuk menilai keberkesanan garis panduan rawatan masing-masing. Di samping itu QOL pesakit kanser payudara yang mengalami loya dan muntah juga dinilai. Kajian prospektif dan retrospektif telah dijalankan keatas pesakit-pesakit kanser pepejal yang dimasukkan ke Hospital Pulau Pinang. Data telah dikumpulkan dengan menggunakan kaedah temuduga secara bersemuka untuk bahagian prospektif (loya dan muntah-muntah) dan dengan menggunakan lembaran data khusus untuk bahagian retrospektif (anemia, trombositopenia dan hiperkalsemia). Maklumat telah dikumpul daripada fail-fail pesakit yang disimpan di klinik onkologi dan pejabat rekod hospital.

Kajian prospektif tertumpu terhadap faktor-faktor risiko dan QOL pesakit kanser payudara (n=158) yang mengalami loya dan muntah setelah rawatan kemoterapi. Faktor- faktor risiko ini termasuk data demografik pesakit, maklumat kanser payudara, data kemoterapi, data ciri-ciri pesakit dan rawatan loya dan muntah. Faktor-faktor utama berkaitan dengan loya dan muntah aruhan kemoterapi (CINV) tertangguh dan akut ialah etnik pesakit, kitaran dan jenis kemoterapi serta rawatan pra dan pasca antiemetik yang digunakan. CINV tertangguh mempunyai kesan negatif terhadap QOL pesakit kanser

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payudara yang lebeh besar berbanding kesan CINV akut. Di samping itu, kajian menunjukkan bahawa terdapat kepincangan dalam garis panduan rawatan antiemetik yang mungkin disebabkan oleh perbezaan etnik dikalangan pelbagai bangsa.

Bahagian kedua adalah kajian retrospektif observasional ke atas pesakit kanser yang dimasukkan ke hospital di antara tahun 2003 dan 2009 yang mengalami anemia atau trombositopenia atau hiperkalsemia. Menurut kajian ini, faktor risiko utama berkaitan dengan anemia, trombositopenia dan hiperkalsemia adalah jenis dan tahap penyakit kanser;

jenis kemoterapi; skedul kemoterapi, kitaran kemoterapi dan dos (tinggi) kemoterapi serta rawatan. Satu lagi hasil kajian penting yang diperolehi berkaitan dengan anemia (n=534 pesakit) ialah garis panduan rawatan yang digunakan adalah tidak cukup berkesan dan hanya bersifat sementara. Hasil kajian yang sama turut diperolehi untuk trombositopenia (n=341 pesakit) dan hiperkalsemia (n=292 pesakit), menunjukkan garis panduan rawatan tidak berkesan. Oleh yang demikian, garis panduan rawatan dan cadangan-cadangan baru digubal berdasarkan daripada hasil kajian ini.

Katakunci: Loya dan Muntah, Loya dan Muntah Tertangguh, Loya dan Muntah Akut, QOL, Anemia, Trombositopenia, Hiperkalsemia, Garis Panduan Rawatan.

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ASSESSMENT OF CHEMOTHERAPY OUTCOME AND ADVERSE EVENT MANAGEMENT AMONG SOLID CANCER PATIENTS OF PENANG HOSPITAL

ABSTRACT

During this century, cancer has become one of the major problem and diseases which has caused predominant death and will even surpass heart diseases. Both cancer diseases and chemotherapy have many hazardous side effects which could also affect the quality of life (QOL) of cancer patients.

Thus this study was performed to detect the main risk factors associated with nausea and vomiting, anemia, thrombocytopenia and hypercalcemia and to evaluate effectiveness of respective treatment guidelines. In addition QOL of breast cancer patients with nausea and vomiting was also evaluated. Prospective and retrospective studies were conducted on solid cancer patients admitted to Penang, Hospital. Data were collected by using direct person-to- person interview for the prospective part (nausea and vomiting) and by using specific data sheet for the retrospective part (anemia, thrombocytopenia and hypercalcemia). The required data were collected from patients’ files kept in the oncology clinic and the record office of the hospital.

The prospective study focused on risk factors and QOL of breast cancer patients (n=158) suffering from nausea and vomiting after chemotherapy administration. These risk factors include patient's demographic data, breast cancer information, chemotherapy data, patients’ characteristic data and treatment of nausea and vomiting. The main risk factors associated with delayed and acute chemotherapy induced nausea and vomiting (CINV) are patients ethnicity, chemotherapy cycles and types, as well as pre and post antiemetic treatments used. As for the effect on QOL, delayed CINV has a higher negative effect on breast cancer patients QOL than acute CINV. Moreover it shows that there is a defect in the antiemetic treatment guideline which might be due to ethnic variation among the different races.

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The second part is an observational retrospective study among solid cancer patients admitted between 2003 and 2009 who developed anemia or thrombocytopenia or hypercalcemia. According to this study, the main risk factors associated with anemia, thrombocytopenia and hypercalcemia are types and stages of solid cancer disease, chemotherapy type, chemotherapy schedule, chemotherapy cycle, and chemotherapy dose (high) as well as the treatment. Other important result related to anemia (n=534 patients) is that the treatment guidelines employed is not effective enough and was only temporary.

Similar findings were obtained with thrombocytopenia (n= 341 patients) and hypercalcemia (n= 292 patients), indicating ineffectiveness of treatment guideline. Thus new treatment guidelines and recommendations are developed based on the findings.

Keywords: Nausea and Vomiting, Acute Nausea and Vomiting , Delayed Nausea and Vomiting, QOL, Anemia, Thrombocytopenia, Hypercalcemia, Treatment Guidelines.

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1

CHAPTER 1 INTRODUCTION

1.1 Cancer Background

During this century, cancer has become one of the major problem and diseases which has caused predominant death and it will even surpass heart diseases. Many of the researchers begin to use the term lifetime risk for cancer patients which refer to the time that cancer will progress and developed or the time that the patient will die because of cancer.

Cancer does not represents only one disease but it is a group involving about 100 diseases.

Cancer is characterized by two things. Firstly there is no control for the growth of cancer cells and secondly is the ability of the cancer cells to metastasis and migrate from the original site to different parts of the body. There are two types of tumors which are malignant and benign cancer. Cancer can attack any person and its occurrence increases as the age of the individual increase too (Carson-De Witt, 2002; Markman, 2002). There are many problems (i.e., side effects) associated with cancer diseases either solid or hematological cancer such as nausea, vomiting, diarrhea, constipation, hypercalcemia, pain, lost of appetite, anemia, fatigue, cachexia, leucopenia, neutropenia and thrombocytopenia.

However the major problems are nausea and vomiting, neutropenia, anemia, thrombocytopenia and hypercalcemia. Hence due to these reasons cancer is considered as one of the major diseases that will effect the quality of life (Dolan, 2005; Henry, 2005;

Sitamvaram, 2005; Stephens, 2005).

1.2 Chemotherapy Background

Chemotherapy was developed and used since the Word War I from the chemical weapon program of the United State of America (USA). Since then chemotherapy has became as one of the most important and significant treatment of cancer. Its main

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2

mechanism of action is by killing the cancer cells which are characterized by their high multiplication and growth rate. It will also kill all the cancer cells that had broken off from the main tumor and spread to the blood or lymphatic system or any part of the body. This killing process of cells is either by a direct effect on deoxyribonucleic acid (DNA) or an effect on the factors involved in mitosis by inhibition of its synthesis or production or uses (Weir-Hughes, 2005; Scurr et al., 2005; Kelland, 2005). Chemotherapy drug may lead to complete cure for some types of cancers or may suppress the growth of others or may prevent their spread to other parts of the body. So many types of new therapies have emerged over the past 20 years. Some of them were straight forward, effective and safe and some have many side effects. However when comparing chemotherapy with other types of treatments, it still remain potentially high risk with many side effects which are difficult to manage. Chemotherapy used required the involvement of various clinical professionals during its various stages of administration and enormous patient health care is needed to overcome its side effects (Weir-Hughes, 2005; Rizzo and Closs, 2002).

1.3 Chemotherapy Side Effects

The goal of chemotherapy is to be as effective as possible with tolerable side effects, since the dose of chemotherapy will be toxic to the cancer cells as well as to the normal cells.

A proportion of the cancer patients suffer from only mild side effects whereas others may suffer from serious side effects (Abrams, 2001; Koda-Kimble et al., 2002; Rizzo and Cloos, 2002). These side effects are classified as:

1- Acute, which develop within 24 hours after chemotherapy administration.

2- Delayed, which developed after 24 hours and up to 6 to 8 weeks after chemotherapy treatments.

3- Short term, combination of both acute and delayed effect.

4- Late/ long term, which developed after months or years of chemotherapy treatment.

5- Expected, which developed among 75% of the patients.

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6- Common, occurred in 25%-75% of the patients.

7- Uncommon, happened is less than 15% of the patients.

8- Rare, occur in only 5% of the patients.

9- Very rare, occur with less than 1% of the patients (Abrams, 2001; Koda-Kimble et al., 2002; Rizzo and Cloos, 2002).

Occurrence of specific side effects will vary according to the chemotherapy used. The most common side effects experienced are nausea and vomiting, anemia, hair lost, bleeding, thrombocytopenia, hyperuricemia, bone marrow depression, alopecia and mucositis. So different parameters must be taken into consideration to prevent, reduce and overcome these side effects (Abrams, 2001; Koda-Kimble et al., 2002; Rizzo and Cloos, 2002).

1.4 Main Problems Caused by Solid Cancer Diseases and Chemotherapy 1.4.1 Nausea and Vomiting

Both nausea and vomiting are recognized as two separate and distinct conditions.

Nausea is an unpleasant sensation of being vomit or urge to vomit which may or may not result in vomiting. While, vomiting or emesis is the process of expelling of digested and undigested food through the mouth. Nausea and vomiting can arises from a different or wide spectrum of etiologies which are either directly associated to cancer disease itself or its treatment. According to the new ranking of chemotherapy side effects, nausea is the number one or the most disturbing side effect, followed by fatigue, neutropenia, anemia or thrombocytopenia, hair losing while vomiting is the third and sometimes the fifth disturbing chemotherapy side effects. Even so, not all cancer patients suffer from nausea and/ or vomiting because not all of them were treated with emetogenic chemotherapy (Haggert, 1999; Oberleitner, 2002; Coates et al., 1983; Lebourgeois et al., 1999; Morrow et al., 2005;

Hesketh, 2005; Rudd and Andrews, 2005).

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1.4.1.1 Causes of Nausea and Vomiting

There are several factors involved in the stimulation of nausea and vomiting and these factors included stress, pregnancy, motion sickness, migraine headache, cancer stages, radio therapy and chemotherapy.

The main focus of this part of the study will be on the factors causing nausea and vomiting related with solid cancers specifically breast cancer and chemotherapy. Nausea and vomiting is one of the major problems that is associated with cancer patients and 50%-55% of cancer patients suffer from both nausea and vomiting even with the use of antiemetic drugs. The main causes for this are either due to the chemotherapy or because of the cancer progression.

Some of the cancer patients who were treated with chemotherapy did not suffer from nausea or vomiting because the chemotherapy used were not significantly emetogenic. Nausea and vomiting still remain the major side effects that occur and is associated with chemotherapy and cancer diseases (Haggerty, 1999; Oberleitner, 2002; Mitchell and Schein, 1984; Bartlett and Koczwara, 2002).

1.4.1.2 Nausea and Vomiting in Solid Cancer Patients

Both nausea and vomiting are very common problems especially with advanced stages of solid cancer diseases like breast cancer and stomach cancer where 50 to 60% of the patients are mainly female under 65 years of age (Molassiotis and Böjeson, 2006). In this situation, nausea and vomiting occur because of the advanced stages of solid cancer diseases characterized by more severe complications than that caused by chemoradiotherapy or other treatments. The main causes for those problems are gastric stasis, obstruction of the intestine, opioid use, constipation caused by morphine uses, hypercalcemia, brain metastasis, renal failure, hyponatremia, increases in the intracranial pressure and tumor burden (Molassiotis and Böjeson, 2006). With regards to solid tumor burden, breast cancer causes nausea and vomiting especially at its advance stages is by metastasis to the abdomen (mainly stomach or liver) or central nervous system (CNS). So emphasis on the details of the effect of advance

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stages of cancer on nausea and vomiting should be made which up to now was given only little attention (Molassiotis and Böjeson, 2006).

1.4.1.3 Pathophysiology of Chemotherapy-Induced Nausea and Vomiting

Chemotherapy cause nausea by stimulating the autonomic nervous system (ANS), while vomiting is triggered when afferent impulses from chemoreceptor trigger zone (CTZ), pharynx, cerebral cortex and vagal afferent fiber stimulate the vomiting center (VC) located in the medulla. The stimulation of the VC leads to contraction of muscles of abdomen, chest wall and diaphragm, so this will lead to an expulsion of stomach and intestine contents (Haggerty, 1999; Oberleitner, 2002; Mitchell and Schein, 1984; Bartlett and Koczwara, 2002; Navari, 2007). Nausea and vomiting associated with surgery, chemotherapeutic agents, radiotherapy and pregnancy are thought to be induced by stimulating the dopamine-2 (D2), acetylcholine, histamine, and serotonin-3 (5-HT3) neuro-receptors involved in activating specific areas of the brain that coordinate the act of vomiting (Beckley, 2005).

Also some studies have reported the involvement of neurokinin receptors (NK-1) especially in delayed emesis, while histamine and muscarinic receptors have lesser role in emesis associated with motion sickness (Hesketh et al., 2003; Grunberg and Hesketh, 1993). The main mechanism of chemotherapy induced vomiting is the stimulation of the entrochromaffin cells lining the wall of the gastrointestinal tract (GIT) hence causes the release of the serotonin. The serotonin will then bind to the vagal afferent 5-HT3 receptors in the GIT which will send impulses to the CTZ and VC. This is illustrated in Figure 1.1.

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Figure 1.1 Responsible Neurotransmission Pathways for Chemotherapy Induce Nausea and Vomiting (CINV) (ASHP, 1999).

Chemotherapy Serotonin release from

Enterochromaffin cells

CTZ 5-HT3, D2, NK1, M Cortex

GIT 5-HT3, NK1

Nucleus Tractus Solitarius 5-HT3, D2, H, NK1, M

Vomiting Center

CNS Centers Salivatory Respiratory Vasomotor

Abdominal Muscles Diaphragm

Stomach Esophagus

Emesis

CINV Receptors:

5-HT3= Serotonin Type 3 H = Histamine D2 = Dopamine Type 2 NK1 = Neurokinin Type 1 M = Muscarinic

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