Innocent MUHIRE, B. Pharm U56/69105/2013

Transcription

1 EFFICACY AND TOLERABILITY OF GRANISETRON VERSUS ONDANSETRON IN THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING AMONG CANCER PATIENTS AT KENYATTA NATIONAL HOSPITAL Innocent MUHIRE, B. Pharm U56/69105/2013 A Research Dissertation Submitted in Partial Fulfillment for the Degree of Master of Pharmacy in Clinical Pharmacy in the School of Pharmacy of the University of Nairobi 2016

2 DECLARATION 1) I understand what plagiarism is and I am aware of the University s policy in this regard. 2) I declare that this dissertation is my original work and has not been submitted elsewhere for examination, award of a degree or publication. Where other people s work or my own work has been used, this has properly been acknowledged and referenced in accordance with the University of Nairobi s requirements. 3) I have not sought or used the services of any professional agencies to produce this work. 4) I have not allowed, and shall not allow anyone to copy my work with the intention of passing it off as his/her own work. 5) I understand that any false claim in respect of this work shall result in disciplinary action, in accordance with the University Plagiarism Policy. Principal Investigator Innocent MUHIRE U56/69105/2013 Signature Date Supervisors This research dissertation has submitted with our approval as university supervisors. DR. P. N. KARIMI, M. Pharm, M.Sc., MBA Department of Pharmaceutics and Pharmacy Practice Signature Date ii

3 DR. D. G. NYAMU, M. Pharm, Department of Pharmaceutics and Pharmacy Practice Signature Date Dr. MARANGA I.S.O, MMED (Obs/Gyn), MPH, PhD (Gyn/Oncology). Department of Reproductive Health, KNH. Signature Date This document contains confidential information that must not be disclosed to anyone other than the sponsor, the investigative team, host institution, and members of the Research Ethics Committee, unless authorized to do so. iii

4 DEDICATION I am thankful to the almighty God for the strength and knowledge offered me to carry out this work. This work is dedicated to my entire family for their constant encouragement, support and patience throughout the study, especially my wife Pamela, my daughter, son and my Parents. Special dedication to Dr. P.N. KARIMI and Rtd. Col. Dr. Ben KARENZI, may God bless them and their generous spirit. iv

5 ACKNOWLEDGEMENT To Rwanda Military Hospital for financial and moral support To my supervisors for their immense and unceasing help To all staff of Cancer Treatment Centre; Clinic 23; Wards: GFC, GFD, 1B and 8C at KNH for their assistance and cooperation during the study period To my research pharmacist Dr. Anne and the team of staff handling chemotherapy drugs at oncology pharmacy for their cooperation and help To almighty God for all that I am and I have, praise be his holy name v

6 ABREVIATION AND ACRONYMS 5-HT3 RA: A V block: ASCO: BD: BMI: BSA: CIN: CINV: CIV: Cm: DEX: ECG: HEC: HSCT: IV: KCl: Kg: KNH: M 2 : MASCC: 5-HT3 Receptors Antagonist Atrioventricular block American Society of Clinical Oncology Bis in Die (Twice daily) Body Mass Index Body Surface Area Chemotherapy Induced Nausea Chemotherapy Induced Nausea and Vomiting Chemotherapy Induced Vomiting Centimeter Dexamethasone Electrocardiogram High Emetogenic Chemotherapy Hematopoietic Stem Cell Transplantation Intravenous Potassium Chloride kilogram Kenyatta National Hospital Square meter Multinational Association of Supportive Care in Cancer vi

7 MEC: Mg SO4: N/V: Na Cl: NCCN: PO: RCTs: SPSS: STATA: TBI: U.K: U.S.A: USD: mitt: Moderate Emetogenic Chemotherapy Magnesium Sulfate Nausea and Vomiting Sodium Chloride National Comprehensive Cancer Network Per Os (Orally) Random Controlled Trials Statistical Package for the Social Sciences Statistics and Data Total Body Irradiation United Kingdom United States of America United State Dollars Modified Intention To Treat 5-HT3: 5 hydroxytryptamine 3 vii

8 TABLE OF CONTENTS DECLARATION... ii DEDICATION... iv ACKNOWLEDGEMENT...v LIST OF TABLES... xii LIST OF FIGURES... xiii OPERATIONAL DEFINITION OF TERMS... xiv ABSTRACT... xvi CHAPTER ONE: INTRODUCTION Background Problem Statement Purpose of the study Objectives General objective Specific objectives Research Questions Hypotheses Significance and anticipated output Limitation and of the study Conceptual/Theoretical framework...5 CHAPTER TWO: LITERATURE REVIEW Introduction Risk factors associated with chemotherapy induced nausea and vomiting Management of chemotherapy induced nausea and vomiting Comparison of the efficacy between ondansetron and granisetron...9 viii

9 2.5. Incidence of chemotherapy induced nausea and vomiting Adverse effects of granisetron and ondansetron Summary of literature review and knowledge gap...12 CHAPTER THREE: METHODOLOGY Introduction Research design Location of the study Target population Inclusion and exclusion criteria Inclusion criteria Exclusion criteria Sample size Sampling technique Research instruments Pre-test study Validity Reliability Recruitment of study participants Recruitment strategies Recruitment process Randomization procedure Allocation-sequence generation Allocation-concealment mechanism Allocation-implementation Blinding procedure...20 ix

10 3.13. Treatment and intervention procedure Participants follow up Data collection techniques Logistical and ethical considerations Approval to carry out the study Recruitment and consenting procedures Informed consent Confidentiality Data management Data forms and data entry Security and back-up of data Quality assurance Data analysis...26 CHAPTER FOUR: RESULTS Sociodemographic profile of the study participants Treatment interventions Incidence of nausea and vomiting Comparison of antiemetic efficacy between ondansetron and granisetron Acute nausea and vomiting Delayed vomiting and nausea Tolerability of antiemetic treatment regimens Factors associated with nausea and vomiting among cancer patients Direct cost analysis of antiemetic treatment...33 x

11 CHAPTER FIVE: DISCUSSION, CONCLUSION AND RECOMMENDATIONS Introduction Discussion Conclusion Recommendations for Policy and Practice Recommendations for Further Research...39 REFERENCES...40 APPENDICES...46 Appendix 1: Consent form...46 Appendix 2: Questionnaire...53 Appendix 3: Antiemetic treatment adverse reactions...61 Appendix 4: Relationship between CINV and different variables...62 Appendix 5: Ethical approval...68 xi

12 LIST OF TABLES Table 1: Emetogenic levels of antineoplastic drugs (2)...8 Table 2: Summary of antiemetic drugs schedule and dosing...22 Table 3: Guide for the hydration requirements for cisplatin administration based on the dose of cisplatin...21 Table 4: Sociodemographic characteristics of the study participants...27 Table 5: Treatment interventions...28 Table 6: Incidence of nausea and vomiting...29 Table 7: Effect of antiemetic treatment on acute nausea and vomiting...30 Table 8: Effect of antiemetic treatment on delayed nausea and vomiting...31 Table 9: Direct cost of preventing CINV at KNH...33 xii

13 LIST OF FIGURES Figure 1 : Conceptual/theoretical framework...6 Figure 2: Incidences of antiemetic treatment adverse reactions...32 xiii

14 OPERATIONAL DEFINITION OF TERMS 5 hydroxytryptamine 3 (5-HT3) antagonists: class of drugs that block the vomiting reflex by inhibiting 5-HT3 receptors in the vomiting center, the chemoreceptor s trigger zone and in the small intestine. Acute nausea and vomiting: Anticipatory nausea and vomiting: Breakthrough nausea and vomiting: Chemotherapy: Experienced a few minutes to hours post chemotherapy administration and lasts 24 hours. is a learned response due to previous experiences with chemotherapy that led to nausea and vomiting. Anticipatory nausea and/or vomiting starts as a person prepares for the next treatment, before the chemotherapy is actually given. Experienced during chemotherapy administration even if treatment has been given to prevent it. the treatment of disease by the use of chemical substances, especially the treatment of cancer with cytotoxic and other drugs. xiv

15 Cytotoxic drug: Delayed nausea and vomiting: Nausea: Refractory vomiting: agent that has a specific destructive action on certain cells or that may be genotoxic, oncogenic, mutagenic, teratogenic, or hazardous to cells in any way and includes most anticancer drugs. experienced after 24 hours, post chemotherapy administration. It use to be tough on 2 nd and 3 rd day. a feeling of sickness with an inclination to vomit. the type of vomiting that decline preventive medicines where patient continue to vomit although he is getting antiemetic. Vomiting: forceful discharge of stomach contents. Vomiting can be a one-time event linked to something that doesn t settle right in the stomach. xv

16 Background ABSTRACT Nausea and vomiting experienced by patients receiving cytotoxic therapy is distressing and occasionally debilitating. Differences and similarities in the effectiveness among serotonin-receptor antagonists have been reported in clinical studies and this has prompted the current study to determine whether the differences are considerable in terms of clinical efficacy and tolerability at Kenyatta National Hospital. Objective To compare the antiemetic effect of granisetron and ondansetron each combined with dexamethasone among patients receiving cisplatin based chemotherapy regimens at Kenyatta National Hospital. Methodology Thirty-four adult cancer patients scheduled to receive two consecutive three weekly cycles of cisplatin based chemotherapy regimens for the first time (at doses > 50 mg/m 2 ), were recruited into a double-blind randomized crossover study to receive ondansetron 12mg or granisetron 3mg each combined with dexamethasone 8mg as intravenous on the first day. On days 2 to 4 post chemotherapy participants received oral treatment, either ondansetron or granisetron each combined with dexamethasone as prophylaxis against delayed emesis. The frequency of nausea and vomiting were assessed daily until 5 th day post chemotherapy. Data were collected using a close ended questionnaire and reported as frequencies (%). Statistical analysis was done using STATA software version 13. Statistical significance was done using Fisher s exact test for each variable and it was termed significant when p value was less than Results There was a female predominance at 70.6%. The predominant age category was years at 47.1% and mean age was 53.5 (±11.9) years. The commonest type of cancer was cervical followed by head and neck cancer. There was no statistically significant difference between ondansetron and granisetron associated with patient s xvi

17 sociodemographic characteristics, but on the dosage of cisplatin variable at first day of the delayed phase (p values < 5%). Incidences of acute and delayed nausea and vomiting were more frequent in first compared to second cycle where most patients vomited once in five days. The peak incidence was observed on day two post chemotherapy and antiemetic administration. Complete prevention of acute and delayed vomiting/nausea was observed in about 80% of patients receiving either of the treatments. Adverse effects were not significantly different between the two antiemetic regimens, although the most frequent were malaise/fatigue and headache. Direct cost with granisetron based antiemetic treatment regimen was higher compared with the one with ondansetron at a ratio of approximately 10:1. Conclusion Ondansetron and granisetron each combined with dexamethasone have similar efficacy and tolerability in the prevention of cisplatin-induced emesis. The choice to use any of them should depend on direct cost. Recommendations Ondansetron should be preferred to granisetron in view of its lower cost and further research for complete prevention of delayed chemotherapy induced nausea and vomiting requires to be done. xvii

18 CHAPTER ONE: INTRODUCTION 1.1. Background Significant progress in cancer chemotherapy has increased the survival rate of patients with a variety of malignancies. However, antiemetic prophylaxis for anticancer cytotoxics which induce nausea and vomiting are critical for successful treatment (1). Chemotherapy induced nausea and vomiting (CINV) is divided in acute (observed in 24 hours of chemotherapy administration), delayed (observed from the second day post chemotherapy administration and may persist for 5 7 days) or anticipatory (observed before chemotherapy administration). There are two other categories recognized as breakthrough (observed during chemotherapy administration) and refractory (type that decline antiemetic drugs) nausea and vomiting (2). The supportive care offered to patients on chemotherapy has considerably improved over the past decades due to the development of effective means to prevent nausea and vomiting induced by treatment. Patients initiating chemotherapy have consistently claimed CINV as one of their common threat (3). Chemotherapy induced nausea and vomiting can impair patient s quality of health, increases the cost of health care and compromise adherence to treatment if not well controlled (3-4). Current updates about pathophysiology of CINV and the availability of stronger antiemetic agents have improved the substantial control of emesis among cancer patients on treatment (5). This study focused on the current understanding of CINV and the status of treatment interventions for their adequate management. The 5-hydroxytryptamine -3- receptor antagonists (5-HT3 RA) are considered as firstline to prevent CINV in patients on highly emetogenic chemotherapy (HEC) and radiotherapy in adults and children (2). Usually the level of occurrence of nausea and vomiting is a function of the emetogenic potential of the chemotherapy regimen used. The guidelines recommend a complete prevention of cytotoxic-induced nausea and vomiting as the main goal of antiemetic therapy. The use of the effective antiemetic agents; potential emetogenic of cytotoxic and individual patient characteristics are the 1

19 basic considerations to achieve exhaustive preventive treatment of acute and delayed nausea and vomiting. Evidence in different studies suggest that co-administration of the 5-HT3 RA and corticosteroids offer more effective protection from of acute and delayed emesis (2, 6). With the standard preventive antiemetic therapy (5-HT3 RA combined with dexamethasone), it has been observed that approximately 13% of patients receiving HEC regimens experience acute and almost 50% experience delayed vomiting (6). Granisetron and ondansetron differ in their pharmacokinetic properties such as doseresponse profile, receptor affinity, potency and duration of action, although this difference is not considered in clinical use (7). This study compared efficacy and tolerability of the two antiemetic agents among cancer patients on cisplatin based regimens Problem Statement Chemotherapy induced nausea and vomiting is a common side effect experienced by patients on cancer treatment that can result in other complicated medical conditions (2). These additional complications lead to a prolonged stay of patients in hospital associated with complex medical care at elevated cost and decrease of patient s adherence to antineoplastic therapy (2, 6). At KNH the most commonly used antiemetics to prevent CINV are Ondansetron, Granisetron combined with dexamethasone and rarely Metoclopramide as oral or IV formulations. Both granisetron and ondansetron are given as intravenous bolus directly followed by chemotherapy administration. Dosages are not weight based and delayed CINVs are not controlled because patients are not prescribed oral antiemetics to take after chemotherapy administration even if they are on a high emetogenic chemotherapy regimen (HEC). There is poor patient follow up to assess efficacy and tolerance of the two antiemetics among ambulant cancer patients and their complaints are addressed only when they come back for the next chemotherapy cycle. KNH pharmacy procures both antiemetics and the choice of which one to use depends on its availability like they are considered to have equivalent efficacy and even thought their costs are different. Clinical 2

20 trials done in different countries have shown similar or contradictory efficacy of ondansetron and granisetron. The two 5-HT3 RA are usually given combined with dexamethasone to boost their efficacy. Despite the CINV prevention given, the staff receives complaints from patients having experienced nausea and vomiting episodes and it is not clear whether this depends on the type of antiemetic agent used during their chemotherapy cycle. There is no research that has been done in KNH addressing the above issues to find out if the two 5-HT3 RA have different or equivalent efficacy and how they are tolerated among cancer patients Purpose of the study 5-HT3 RA) are widely used to control chemotherapy induced nausea and vomiting in cancer chemotherapy. Several 5-HT3 RA are available and have some important considerations when selecting agents, such as efficacy, adverse events and cost. In this study, granisetron and ondansetron were evaluated for their anti-emetic efficacy and tolerability among KNH cancer patients to optimize their rational use in CINV prevention Objectives General objective To compare the efficacy between granisetron and ondansetron premedication cancer patients receiving cisplatin based chemotherapy regimens at KNH. among Specific objectives 1. To determine the incidence of CINV among cancer patients on cisplatin based chemotherapy regimens receiving ondansetron or granisetron each combined with dexamethasone. 2. To compare the adverse effects associated with granisetron and ondansetron each combined with dexamethasone among cancer patients on cisplatin based chemotherapy regimens. 3. To determine whether there is a statistically significant difference in the antiemetic efficacy between granisetron and ondansetron each combined with dexamethasone among cancer patients on cisplatin based regimen treatment at KNH. 3

21 4. To compare the cost of using ondansetron or granisetron each combined with dexamethasone to prevent nausea and vomiting among cancer patients receiving cisplatin based regimen treatment at KNH. 5. To establish factors associated with nausea and vomiting among cancer patients receiving cisplatin based chemotherapy regimens at KNH Research Questions 1. What proportions of cancer patients on cisplatin based cytotoxic regimen experience nausea and vomiting despite receiving granisetron or ondansetron each combined with dexamethasone at KNH? 2. Which adverse effects experienced by patients receiving ondansetron or granisetron each combined with dexamethasone to prevent CINV at KNH? 3. Is there a statistically significant difference in efficacy between ondansetron and granisetron each combined with dexamethasone at KNH? 4. What is the cost comparison between ondansetron and granisetron each combined with dexamethasone in the prevention of nausea and vomiting at KNH? 5. What are the factors associated with nausea and vomiting among cancer patients receiving cisplatin based chemotherapy regimens at KNH? 1.6. Hypotheses H0: There is no difference in efficacy and tolerability between ondansetron and granisetron each combined with dexamethasone. H1: There is a difference in efficacy and tolerability between ondansetron and granisetron each combined with dexamethasone Significance and anticipated output The findings of this study will help practitioners promote rational use of the two antiemetic agents, thereby decreasing the prevalence of nausea and vomiting and improving adherence to cancer treatment among patients on cisplatin based chemotherapy regimens at KNH. They will help researchers, practitioners and students to know whether there is a difference or not in efficacy between the two antiemetic agents. Patients will benefit due to decreased threat of nausea and vomiting that occasionally 4

22 affect their adherence to treatment and quality of life. They will also assist the hospital make a rational decision on which between the two drugs is more cost effective Limitation and of the study Information bias may occur.this is because patients or guardians may not be able to remember exactly when and how many episodes of delayed nausea and vomiting took place. Relying fully on the information given by patients may introduce recall and response bias. These limitations were minimized by using telephone calls for outpatients while at home up to the 5 th day (Morning and Evening) after administration of the cytotoxic and antiemetic asking them about episodes of nausea and vomiting and using a well structured questionnaire. Carry over bias may occur. The remaining antiemetic in plasma from first cycle can interfere with the dose administered on the second cycle. This was minimized by ensuring a washout period of 20 days between the two cycles Conceptual/Theoretical framework The occurrence of CINV depends on several factors described as below. Sociodemographic characteristics such as age, gender, type of cancer and whether the patient takes alcohol or not influence the incidence. Cisplatin based regimens and their respective dosages may affect the incidence of nausea and vomiting. High dosages are likely to increase these undesirable effects. The antiemetic effect of ondansetron and granisetron may differ when used alone or in combination with other antiemetics due to inherent differences in the dosages, onset of action and half lives. The similarities and difference that may exist will be seen. 5

23 EFFICACY AND TOLERABILITY OF GRANISETRON VERSUS ONDANSETRON IN THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING AMONG CANCER PATIENTS AT KNH CYTOTOXIC REGIMEN USED: Type of Chemotherapy regimens, dosage OUTCOME: Incidence of Nausea and vomiting TYPE OF ANTIEMETIC USED: -Ondansetron -Granisetron DEMOGRAPHIC CHARACTERISTICS: Age, gender, sex, alcohol consumption status, type of cancer Figure 1 : Conceptual/Theoretical Framework 6

24 CHAPTER TWO: LITERATURE REVIEW 2.1. Introduction This chapter analyses relevant studies that have been carried out to compare the efficacy and tolerability between two 5-HT3 RA. It also includes previous studies on risk factors, and management of chemotherapy induced nausea and vomiting and adverse effects associated with ondansetron and granisetron Risk factors associated with chemotherapy induced nausea and vomiting The risk to develop CINV in patients on chemotherapy treatment include emetogenic potential and dosage of cytotoxic regimen, patient s characters, psychological factors, certain substances like alcohol and genetic polymorphism (2). The emetogenicity of antineoplastic regimen depends on different factors like the type of cytotoxic agent, the dosage and the chemotherapy cycles schedule (8-9). Cisplatin is classified among highly emetogenic agents (10). Agents with high emetogenicity are considered to be less emetogenic when administered alone as revealed in different studies (8). The level of emetogenicity due to radiotherapy also depends on the treatment field and dose. Therefore, 100% of cancer patients exposed to total body irradiation (TBI) are more likely to have serious emesis compared to radiation of the cranium which counts for 10% to 30% risk of patients developing emesis (11). Patient s variables that can be linked to CINV include sex, age, alcohol, motion sickness, pregnancy, anxiety and prior exposition on chemotherapy (2, 12). Female, older patients and those who have a high pretreatment expectation of severe nausea and those with pregnancy or motion sickness are more exposed to CINV, while younger patients and those with high alcohol consumption have a lower risk of (13). 7

25 Table 1: Emetogenic levels of antineoplastic drugs (2) Emetogenicity (% of patients at high risk) High (>90%) Moderately high (60%-90%) Moderate (30%- 60%) Moderately low (10%-30%) Low (<10%) Cytotoxic agent Dosage Onset/Duration of response (in hours) Cisplatin >50mg/m Cyclophosphamide >1000mg/m Dacarbazine 4-24 Mechlorethamine Cisplatin <50mg/m Cyclophosphamide mg/m Methotrexate >1000mg/m Carboplatin 4-6 Doxorubicin >60mg/m Cyclophosphamide <750mg/m Methotrexate mg/m Doxorubicin <60mg/m Methotrexate <250mg/m Fluorouracil 3-10 Etoposide Hydroxyuracil 4-48 Vinblastine Bleomycin Tamoxifen Chlorambucil Management of chemotherapy induced nausea and vomiting Nausea and vomiting are the most common side effects observed in almost all cancer patients on chemotherapy. CINV can be prevented at a rate of 70% to 80% of patients when strong antiemetics are used rationally. The treatment must adhere to standard guidelines that have enabled physicians to adopt the latest clinical research into their practices (14). 8

26 Current standard useful guidelines for prophylaxis against CINV have been harmonized with treatment recommendations to achieve complete prevention (15). Despite the availability of such guidelines, the optimal level of adherence to treatment recommendations is not yet achieved (16). The fundamental principle of antiemetic therapy is to achieve complete prevention of CINV and is well achieved by rational use of appropriate agents and evidence based preventive treatment methods (4). The choice of antiemetic is guided by emetogenic potential of used cytotoxic agent and possible risk of delayed nausea and vomiting (4). For highly emetogenic cytotoxics a combination of a 5-HT RA and steroid (dexamethasone) has appeared effective and well toraleted in prevention of CINV. In literature many clinical trials support this combination for patients on cisplatin based regimen (4, 16). Currently, American Society of Clinical Oncology (ASCO) and Multinational Association of Supportive Care in Cancer (MASCC) guidelines recommend the triple combination (5-HT3 RA, dexamethasone, and aprepitant) for patients receiving a combination of an anthracycline and cyclophosphamide based regimen. On the other hand, the National Comprehensive Cancer Network (NCCN) guidelines recommend use of aprepitant in patients receiving moderately emetogenic cytotoxic (MEC) regimen (6, 15-16). Dexamethasone is the mostly used to prevent delayed nausea and vomiting in patients receiving MEC regimens (4, 16) Comparison of the efficacy between ondansetron and granisetron Several studies have yielded different results regarding the efficacy of granisetron and ondansetron. Stewart at al found no significant difference in efficacy between ondansetron and granisetron when evaluated by comparing the degree of nausea and distress, number of emetic episodes and overall control of emesis. The adverse effects were also comparable (17). According to Perez et al, the percentage of nausea and vomiting free patients in 24 hours using ondansetron and granisetron are approximately equivalent (18). He also concluded that granisetron is more effective than ondansetron when used in combination with a steroid (dexamethasone) to prevent both acute and delayed vomiting due to HEC (18). Ondansetron and granisetron are considered to have a 9

27 required effectiveness to prevent acute CINV but granisetron is claimed to be stronger in the delayed phase of CINV. Dexamethasone is used to boost efficacy of 5-HT3 RA (18-19). Ondansetron at the dosage of 8mg and granisetron 3 mg, each combined with dexamethasone, demonstrated similar efficacy and tolerability in prophylaxis of cisplatin induced emesis (3).There is no statistically significant difference observed between the two antiemetic drugs for acute and delayed emesis (17, 19). Other clinical trials have shown granisetron to be effective and well tolerated agent in management of nausea and vomiting (20). Due to its pharmacokinetic properties (safe profile and minimal drug-drug interactions), it is considered to be more effective and well tolerated in special populations, such as patients with refractory properties, those with hepatic or renal defects, children and elderly (20).In a double blind cross over trial done on two antiemetics each combined with dexamethasone, granisetron proved to be more efficacious than ondansetron in acute and delayed vomiting due to HEC (18). Other comparable studies have not yielded convincing data on clinically significant differences (17)(38). A meta-analysis of randomized controlled trials conducted to check if the data available can show any therapeutic difference between ondansetron and granisetron revealed that both antiemetics have similar efficacy and tolerability in prophylaxis of CINV (21). But number of comparative trials that addressed the delayed phase of CINV was low and therefore further RCTs are still needed to confirm these results (21) Incidence of chemotherapy induced nausea and vomiting A prospective study conducted in Mexico showed that healthcare providers can underestimate the incidence of CINV after HEC (22). There is a need for a better understanding of the incidence of nausea and emesis, which remains to be a common side-effect of chemotherapy (22). 10

28 On the other hand, a study done in Taiwan observed a significant misestimating of the incidence of acute vomiting in patients on HEC and MEC compared to that of delayed vomiting. However, rates of both acute and delayed nausea were correctly estimated in patients receiving HEC compared to those on MEC treatment regimen (23). A study conducted to determine the incidence of CINV in patients on MEC treatment, found that despite receiving preventive treatment, 31 % of patients failed to achieve complete response and 38 % got complete protection (24). Results also found that the delayed phase was less controlled than the acute phase. Healthcare providers overestimated the effectiveness of preventive antiemetics (24) Adverse effects of granisetron and ondansetron The most common side effect of ondansetron and granisetron include abdominal pain, diarrhea, constipation, headache, fatigue, weakness and vomiting (25). The less common ones include agitation, dizziness, drowsiness, anxiety, heartburn, indigestion, drowsiness, sour stomach, insomnia and unusual taste in the mouth. Nervous system side effects have been reported as the most frequent in several studies (20)(49). Granisetron induced headache is generally mild. Gastrointestinal side effects include nausea, constipation, vomiting, diarrhea, abdominal pain, dyspepsia, flatulence, dry mouth, and taste disturbances. Hepatic side effects are rare and they include elevations in serum transaminases. Acute pancreatitis has also been noted (50). Cardiovascular side effects that have been reported include hypertension in 1% of patients. Atrial fibrillation, angina pectoris, and syncope are rare. Hypotension, sinus bradycardia, A-V block, ventricular ectopy, QT prolongation, and ECG changes have been observed as well, although causality is unknown (51). Hypersensitivity manifesting as skin rashes, facial flushing, anaphylactoid reactions, and shortness of breath, hypotension, and urticaria may occur. Other side effects includes asthenia and fever (26). 11

29 2.7. Summary of literature review and knowledge gap The literature review demonstrates that several studies concerning granisetron and ondansetron have been done. However, researchers have noted either equivalence or differences between the two antiemetics in prevention of nausea and vomiting and recommended further studies. Additionally, the incidence of vomiting among patients on cisplatin based cancer treatment and granisetron or ondansetron has been a challenge where studies done resulted in either over or under estimation. Lack of local studies on the efficacy of these two antiemetics creates a gap that limits the choice and therefore this study will provide information that will be useful when choosing either ondansetron or granisetron for patients receiving cisplatin based chemotherapy regimens. 12

30 CHAPTER THREE: METHODOLOGY 3.1. Introduction This part covers the methods used to conduct the study. They include; description of the research design, population sampling, and the blinding procedure. This is followed by an explanation of the experimental procedure and a detailed description of data collection, data management and data analysis. The part ends with a discussion of the ethical considerations and measures to provide validity and reliability Research design A prospective double-blind, randomized crossover trial was conducted in cancer patients receiving cisplatin based chemotherapy regimen at KNH. Eligible patients were those starting treatment and the study considered only the first two chemotherapy cycles for each patient. Patients were crossed over from one treatment to another during the trial with a washing period of 21 days (3 weeks) between two chemotherapy cycles considered. This design is suitable since each patient serve as his/her own control and therefore the effects of confounders are minimized (27) Location of the study The research was conducted at Kenyatta National Hospital. The hospital was suitable for the study because it has a high number of cancer patients that are on chemotherapy treatment. Kenyatta National Hospital is the oldest hospital in Kenya founded in 1901 with a bed capacity of 40 as the Native Civil Hospital. It was renamed the King George VI Hospital in At that time the settler community was served by the nearby European Hospital (now the Nairobi Hospital). It was renamed Kenyatta National Hospital after Jomo Kenyatta following independence from the British. It is currently the largest referral and teaching hospital in Kenya, which receives patients from all over the country and region. It is the main public hospital offering comprehensive cancer treatment in Kenya. It has a capacity of 1,800 beds and has over 6,000 staff members and covers an area of 45.7 hectares. The University of Nairobi College of Health Sciences, and several government agencies are located within the vicinity. 13

31 Kenyatta National Hospital has 50 wards, 22 outpatient clinics, 24 theatres and Accident & Emergency department. This study was conducted specifically at the following sites: cancer treatment centre (CTC); oncology wards GFD and GFC; oncology pharmacy; medical ward 8C and gynecology ward 1B. The oncology ward GFD is located on the ground floor of KNH and serves inpatient oncology patients. The ward has a bed capacity of 30 and a staff capacity of 18 nurses, 4 registrars and 2 cleaners. The oncology ward GFC is located on the ground floor of KNH and serves outpatient oncology patients who come to receive their chemotherapy during their prescribed clinic days. GFC handles 50 patients in a day and is served by 8 nurses, 3 medical officers, 2 registrars and 2 cleaners. Ward 1B is located on the first floor of KNH and serves inpatient adult gynecology patients. This ward has a bed capacity of 32 and a staffing level of 18 nurses, 4 medical officers, 3 registrars and 2 cleaners. Ward 8C is located on the eighth floor of KNH and serves adult oncology patients. The ward has a bed capacity of 20 and a staffing level of 20 nurses, 1 medical officer, 4 registrars and 6 cleaners. The oncology pharmacy is located in ward GFC on the ground floor of KNH and is responsible for compounding and dispensing cytotoxic medicines for all oncology units in KNH except private wing. The oncology pharmacy has a staff capacity of 3 pharmacists and 4 pharmaceutical technologists and 1 cleaner Target population All cancer patients aged 18 years and older starting cisplatin chemotherapy based regimen at KNH were eligible including inpatients and outpatients. This group of patients was appropriate because most cancer patients in Kenya are adults. Cervical and breast cancers are most common in women while cancers of the prostate and esophagus are common in men. 14

32 3.5. Inclusion and exclusion criteria Inclusion criteria Cancer patients who: 1. Were 18 years and older attending KNH and starting chemotherapy treatment on regimens that contain cisplatin; 2. Did not have any disease that can induce vomiting; 3. Were not on radiation therapy courses; 4. Were having normal liver and renal function; 5. Had consented to participate in the study Exclusion criteria 1. Hypersensitivity to ondansetron, granisetron or related substances, 2. Patients with previous exposure to cisplatin based chemotherapy regimen 3. Patients who were too sick to give informed consent 3.6. Sample size The sample size was determined on the basis of the primary hypothesis that the occurrence of CINV among patients receiving the first course of standard cisplatin based chemotherapy and receiving iv ondansetron is significantly different from that among patients on a standard cisplatin based chemotherapy receiving granisetron. In this regard, occurrence of CINV was chosen as the primary outcome of interest. In order to calculate the target sample size, the estimated proportions of CINV occurrence in the two groups were needed. These figures were obtained from previous studies on ondansetron and granisetron by Linda Stewart et al (52). According to the study the incidence of CINV for the patients receiving ondansetron was 50% compared to 18% for those receiving granisetron. With regard to type I and type II errors, a two-tailed α of 0.05 and a 1- β of 0.8 was chosen. At this level, potential error and statistical power of 80% are conventionally considered acceptable in routine health care research. The sample size for this study was calculated using the formula below described by Chan (53-54) for estimating sample sizes for superiority trials with a dichotomous outcome of interest: 15

33 m (size per group) = C x (π1 (1 π1) + π2 (1 π2)) / (π1 π2) 2 Where: C = 7.9 for 80% power π1 and π2 are the proportion estimates, π1 = 0.50 and π2 = 0.18 Therefore, for an 80% power: m (size per group) = 7.9 X [0.50 (1 0.50) (1 0.18)] / ( ) 2 m = Hence a minimum of 31 x 2 = 62 patients were required for this study, 31 in each comparison group. This number was adjusted upwards to 68 to account for an expected 10% loss to follow up. Thirty-four (34) patients were selected and each received both granisetron and ondansetron in two consecutive chemotherapy cycles with a washing period of 20 days using a randomized, double blind crossover design where each patient acted as both test and its own control (Two in One wherein one patient represents two patients thus 34 patients represents 34x2 = 68 patients) Sampling technique This was a consecutive sampling, where eligible participants in the study were being recruited when coming for first chemotherapy cycle and were followed up for the first two cycles only Research instruments A closed-ended questionnaire was used by research investigators during the interview at the hospital followed by daily phone call interviews for ambulant patients (Appendix2). The questionnaire was constructed according to the information required. Patients who met the inclusion/exclusion criteria received an explanation about the purpose of the study and consent was sought before the interview. Those who consented were interviewed by the investigator or research assistant and their responses entered in the questionnaire. 16

34 3.9. Pre-test study The questionnaire was given to colleagues and supervisors to check if the questions and responses were valid, reliable, appropriate, necessary and sufficient. Then it was administered to 10 cancer patients starting cisplatin based chemotherapy regimen to determine how much time it took to complete each questionnaire. A debriefing for the respondents and the interviewers was done after completing the questionnaire. Analysis of the information provided for clarity of directions, question wording, or response categories was done where necessary. Revision was done as needed Validity The validity of the questionnaire was established by checking: 1. If it measured what it intended to measure; having appropriate phrases and responding options. 2. If it represented the content of the entire study. 3. If it was appropriate for the sample/population. 4. If it was enough comprehensive to capture all needed information to meet the study objectives. Internal and external validity were ensured by using randomization of the sample and appropriate care when allocating controls which were the same individuals as recommended in crossover clinical trial design Reliability Reliability of the questionnaire was established by carrying out a pre-test to find out whether the questionnaire consistently measured whatever was required. The process was achieved by analysis of data collected from 10 patients not included in the sample to provide two key pieces of information: correlation matrix and view alpha if item deleted" column. The reliability coefficient (alpha) range was from 0 (questionnaire with several errors) to 1 (absence of error in the questionnaire). A reliability coefficient is acceptable when alpha is 0.70 or higher (22). The reliability coefficient (alpha) of this study was

35 3.10. Recruitment of study participants Recruitment strategies Before starting recruitment, an announcement of the study was displayed to the oncology physicians and pharmacists at Cancer treatment centre; Cancer wards 8C, 1B and GFD, Oncology clinic No 23 and GFC and Oncology pharmacy. After this announcement, sensitization meetings were held with study staff at the study sites to improve their understanding of the study aims and protocols, thus ensuring the cooperation and buy in of the investigators. In addition, posters were hanged at the trial sites to inform patients about the study Recruitment process Participant candidates for the study were initially approached for enrollment. At the oncology consultation sites the physicians initially identified potential patients ready to receive their first 3-weekly cycle of cisplatin based chemotherapy regimen. At this point, the initial awareness about the study was made to patients by the physician with subsequent counselling by the principal investigator. The second venue was at the research office. The potentially suitable patients for the study were selected by the principal investigator based on patient files as having a confirmed diagnosis of cancer and a documented cisplatin based regimen prescribed. These patients were approached and counseled about enrollment in the study. Patients were then given time to consider the issues and discuss it privately with their relatives. Participants were made aware that study involvement was voluntary and that they could decline to participate or withdraw at any time without any consequence. Patients willing to take part in the study were invited to sign the consent form and a copy of it was given to each participant. Any patient who expressed any misgivings about enrollment was not recruited. Consenting participants were provided with details of the study, then assessed for eligibility by the principal investigator. Thereafter, all recruited patients were checked if they were suitable to start treatment and their eligibility confirmed. The participants were then randomly assigned to one of the two antiemetics sequentially. Seventeen patients were started on granisetron combined with dexamethasone, while the other seventeen were started on ondansetron combined with 18

36 dexamethasone at first cycle and reversed in the second cycle as per their prescribing papers Randomization procedure After obtaining written consent and baseline information from study participants, those who fulfilled the eligibility criteria and agreed to participate in the study were then randomly allocated treatment intervention regimens as prescribed by physicians Allocation-sequence generation The Biostatistician used a computer program to generate the random allocation sequence using block randomization, whereby random numbers were generated and allocated in a one-to-one ratio to a sequence of permuted blocks Allocation-concealment mechanism Once the randomization schedule was generated, the Biostatistician used it to create sequential numbers for patients corresponding to their respective coded antiemetic treatment intervention. A sealed and opaque envelope containing a list of coded antiemetic treatments allocations and two sealed decoding slips (one for each antiemetic) was provided to the research pharmacist at oncology pharmacy where all treatment interventions were prepared. The coded allocation schedule was held by the research pharmacist until the end of data collection Allocation-implementation The envelope was opened by the research pharmacist to decode treatment allocations by picking one of the two sealed slips containing antiemetic names from the envelope. The envelope with treatment allocation paper was then kept under lock and key by the research pharmacist independently and concealed from the patient, principal investigator, and study personnel till completion of data collection. Once the treatment allocation for each patient was made, the research pharmacist prepared and labeled the corresponding drugs as described in prepared protocol. Infusion bags containing cytotoxic were labeled as usual, but those containing either ondansetron or granisetron each combined with dexamethasone were labeled with the word 19

37 ANTIEMETIC. The infusion bags were availed to the research nurses immediately for administration as indicated in the protocol developed by the principal investigator. The research pharmacist ensured that the administration of drugs was done as per protocol Blinding procedure In this study a double-blinding method was applied to Latin square random allocation design in sets of two by two (2X2). Computer software was used to generate randomized intervention treatments for patients. The two antiemetics were encoded as A and B (by research pharmacist) while patients were encoded in Arabic numbers (1 to 34). The codes were handled only by the research pharmacist who prepared all intervention drugs independently to principal investigator, research assistants and patients to reveal them to the principal investigator for data entry at the end of data collection. The two antiemetics were prepared in the same volume and similar containers so that the investigator could not identify any difference between them. Neither patient nor investigator was aware of which type of antiemetic was being administered and the research pharmacist who prepared the drugs was not aware which patient received the drugs Treatment and intervention procedure The experimental manoeuvre in this trial was the administration of antiemetic prophylaxis, including ondansetron and granisetron each combined with dexamethasone. Research participants were randomized to receive the intervention from blinded investigators. Day 1 Antiemetic Treatment Patients were sequentially randomized to receive an antiemetic prophylaxis of either 12 mg ondansetron (Zofran) or 3mg granisetron (Kytril) each combined with 8mg of dexamethasone and mixed in 50 ml of NaCl 0.9% administered as 15 minutes i.v. infusion, 30 minutes before administration of chemotherapy regimen. Preparation of drugs was done by qualified research pharmacists and administration was done by KNH medical and nursing staff. 20

38 Cisplatin Hydration schedule Good hydration and urine output prevents retention of cisplatin in the kidneys and is essential for minimizing damage to the kidneys. Approximately 80% of cisplatin is excreted within 24 hours of administration, therefore hydration should continue for this period. Recently, a randomized clinical trial demonstrated that sodium chloride 0.9% alone or with furosemide provides better renal protection than sodium chloride 0.9% plus mannitol(27). In this study, patients have been prehydrated with ml of sodium chloride 0.9% infusion. Table 2: Guide for the hydration requirements for cisplatin administration based on the dose of cisplatin (28-29) Cisplatin dose mg/m 2 Pre-Hydration Cisplatin Post-Hydration > ml Na Cl 0.9% iv over 1 hour Cisplatin in 500 ml Sodium Chloride 0.9% infused over 2 hours Patient advised to take at least 1000ml of water day for 2 weeks days ml NaCl 0.9% iv over 1 hour ml Na Cl 0.9% iv over 30 minutes <40 500ml Na Cl 0.9% iv over 30 minutes Cisplatin in 500 ml Sodium Chloride 0.9% infused over 2 hours Cisplatin in 500 ml Sodium Chloride 0.9% iv over 2 hours Cisplatin in 500mL of Na Cl 0.9% iv over 1 hour Patient advised to take at least 1000ml of water day for 5 days Patient advised to take at least 500ml of water per day for 5 days Patient advised to take at least 500ml of water per day for 5 days 21

39 NB: 1. If another drug is being given in the regimen, e.g. Etoposide then this may be used as pre hydration (Etoposide in 1000ml of sodium Chloride 0.9%) (28). 2. Patient should be advised to take more than 1.5 liters of fluid in the 24 hours following chemotherapy (55-56). Chemotherapy Treatment All patients received only cisplatin-based chemotherapy regimens as per the prescription. The cytotoxic drugs were prepared as per manufacturer s instructions by qualified research pharmacist and administered as per prescription by KNH well trained medical staff. Cisplatin was mixed in 500 ml of 0.9% Na Cl (sodium chloride) solution and administered as iv infusion over 90 minutes. All patients had received a cisplatin dosage of mg/m 2. On day 2-5 Oral antiemetics for delayed CINV prophylaxis were started from 2 nd day after chemotherapy administration as dexamethasone tablet 4 mg plus ondansetron tablet 8 mg or granisetron tablet 1mg, both twice a day, respectively, depending on whether the patient received ondansetron iv or granisetron iv on the first day and continued up to the 5th day. Table 3: Summary of antiemetic drugs schedule and dosing Antiemetic drug Day 1 Day 2-5 Ondansetron Granisetron -Ondansetron 12mg IV -Dexamethasone 8mg IV -Granisetron 12mg IV -Dexamethasone 8mg IV -Ondansetron 8mg PO BD -Dexamethasone 4mg PO BD -Granisetron 1mg PO BD -Dexamethasone 4mg PO BD 22

40 3.14. Participants follow up Each patient was observed from the time after being given chemotherapy and nausea; vomiting or other side effects were registered. Admitted patients were followed up morning and evening in the wards. Ambulant patients were called on their phone or through relatives in the morning and evening and responses entered in the questionnaire Data collection techniques A closed-ended questionnaire was used as a research instrument to collect data from participants. Patients were sampled while coming for their first chemotherapy cycle and those who met the inclusion/exclusion criteria received explanations about the purpose of the study and written consent sought before the interview. Participants were interviewed about their social demographic characteristics and their responses recorded in the questionnaires. The study covered only the first two chemotherapy cycles and data were collected during consecutive 5 days including the one of chemotherapy administration. For inpatients, investigator recorded data directly from their wards while for outpatients data was recorded directly from the drug administration room and continued through telephone interviews from their domiciles. The number of nausea and vomiting episodes in the first 24 h (acute nausea and vomiting) and the following 4 days (delayed nausea and vomiting) after each chemotherapy cycle were reported. Antiemetic efficacy was assessed as complete response (no vomiting), major response (1-2 vomiting episodes) minor response (3-5 vomiting episodes) and failure (more than 5 vomiting episodes); no nausea (0 episode), mild nausea (1-2 nausea episodes), moderate nausea (3-5 nausea episodes) and severe (> 5 nausea episodes), any other adverse drug reaction due to antiemetic treatment was reported by patients and recorded. 23

41 3.16. Logistical and ethical considerations Approval to carry out the study Authorisation to carry out the study was sought from the Kenyatta National Hospital/ University of Nairobi Ethical and Research Committee (KNH/UoN/ERC) and also from the KNH administration and an approval letter reference number KNH-ERC/A/182 was given Recruitment and consenting procedures After going through the files of the patients and clinic day bookings, the Principal investigator approached and interviewed the patients who met inclusion/exclusion criteria when immediately they were through with the doctor`s consultation and ready to get their first chemotherapy cycle. Patients received explanations about the study in English, Kiswahili or any other language they understood well. This was done before they got their antiemetic premedication. Consent was sought from patients or guardians after the explanation on the purpose of the study. Information on the risks and their prevention involved in the study was discussed with the patient. Patients were further informed about their right to decline or abandon the process at any moment they felt uncomfortable. Information that to participate in the study was voluntary was paramount and any other benefit to the patient was communicated. Patients were free to opt out of the trial at any moment without jeopardizing their treatment care Informed consent Consent from patients / guardians who met the inclusion criteria were sought. Each Patient was requested to sign a consent form before enrolment into the study. This was after the patient was made aware of the risks involved in the study and benefits were fully understood by the patient. The principal investigator requested the patients to paraphrase their understanding of what was in the consent form and discussion they have had with the principal investigator. This was a way to ensure that the patients were fully aware and informed about the study benefits, risks and their rights before signing the consent form. 24

42 Confidentiality The Patients were informed privately on how medication administration is done, its benefits and risks, then the purpose and benefits of study in a private room. All the information was treated with confidentiality. Serial numbers of their questionnaires were used instead of the patient s name to protect their identity Data management Data forms and data entry Completed questionnaires were cross-checked by the study data clerk to ensure completion of responses and alert the principal investigator in case of incompleteness. The patient s questionnaires were kept safe up to the end of data collection before data entry. Data were entered electronically into a specific computer software (STATA: Statistics and Data, version 13) and any change documented after information captured from completed questionnaire was checked for completeness and accuracy by the principal investigator against the source data. The principal investigator was responsible for all information collected on patients enrolled in this study Security and back-up of data Access to the database was limited by the use of the password and only the principal investigator, outcome assessor and administrative assistant were allowed access. Once updates needed to be done, the database was backed up on separate media. All the forms related to study data were stored in a locked cabinet. Only the administrative assistant at the trial site and the principal investigator were having access to the cabinet Quality assurance All research assistant personnel were the usual personnel of KNH having sufficient trainings in clinical practice were used in the study. Data entry techniques, explanation of data discrepancy queries and other information about the quality of data were ensured by a covered one-day training session of research assistants on how to conduct the trial before the commencement. 25

43 3.18. Data analysis Statistical analyses were conducted on a modified intention to treat (mitt) basis. All participants who were enrolled and randomized to receive the allocated intervention as described by the study protocol were included in the evaluation of the primary and secondary outcomes. The baseline characteristics data were presented as frequencies and percentages for categorical variables and means and standard deviations according to the normality of the distribution for continuous variables. The efficacy and tolerability were compared between the two antiemetics using Fisher s exact test. A value of P < 0.05 was considered statistically significant. All analyses were performed using STATA software, version

44 CHAPTER FOUR: RESULTS During the study, data were collected from eligible and consenting patients, and analyzed using STATA software version13. This facilitated presentation and description of findings that are going to be considered in this chapter Sociodemographic profile of the study participants Out of 34 participants, 24 (70.90%) were females and 16 (47.1%) were in age category of years with mean age of 53.5 (+/-11.9) years (Table 4). Twenty-one (61.8%) patients had a normal body mass index (BMI); 2 (5.9) patients were overweight and 5 (14.7%) patients were under weight. The mean weight of the study was 61.8 (+/-14.6) Kg. The most prevalent disease was cervical cancer 14 (41.2%) followed by head and neck cancer 10 (29.4%). Table 2: Sociodemographic characteristics of the study participants Variable Frequency (N=34) Percentage (%) Gender Male Female Age category in years Above BMI (Kg/m 2 ) Below Above Type of cancer Cervical Breast Ovarian Head and neck Lung BMI: Body Mass Index 27

45 4.2. Treatment interventions Cisplatin combined with paclitaxel was the predominant chemotherapy regimen given to the participants at the 22 (64.7%) as shown in table 5. Twenty-seven (79.4%) patients received a dose of 75mg/m 2 of cisplatin. Both combinations of antiemetics (Ondasetron+Dexamethasone and Granisetron+Dexamethasone) were administered at equal frequencies (50%) in both cycles I and II respectively. Table 3: Treatment interventions Variable Frequency (N=34) Percentage (%) Chemotherapy regimens Cisplatin Cisplatin/Paclitaxel Cisplatin/5 FU Cisplatin/Epirubicin/Capecitabine Dose of cisplatin (mg/m 2 ) Antiemetics used in Cycle I Ondansetron+ Dexamethasone Granisetron+ Dexamethasone Antiemetics used in Cycle II Ondansetron+ Dexamethasone Granisetron+ Dexamethasone Key: 5-FU: 5-Fluorouracil 4.3. Incidence of nausea and vomiting The incidences of acute nausea and vomiting were more frequent in first than second cycle of chemotherapy (Table 6). Most patients vomited once within five days after chemotherapy and preventive antiemetic administration. The frequency of delayed nausea and vomiting was high in first cycle compared to second cycle and decreased from second to fifth day. The incidence was highest on day two and day three after chemotherapy administration. 28

46 Table 4: Incidence of nausea and vomiting Sign/Symptom Cycle I Cycle 2 Acute period Frequency (n, %) Frequency (n, %) Acute nausea 10 (29.4) 4 (11.8) Acute vomiting 7 (20.6) 2 (5.9) Frequency of delayed nausea Day 2 18 (52.9) 13 (38.2) Day 3 12 (35.3) 4 (11.8) Day 4 9 (26.5) 1 (2.9) Frequency of delayed vomiting Day 2 15 (44.1) 13 (38.2) Day 3 12 (35.3) 4 (11.8) Day 4 9 (26.5) 1 (2.9) Day 5 5 (14.7) 0 Frequency of vomiting in 5 days One 27 (79.4) 32 (94.1) Two 4 (11.8) 2 (5.9) Three 2 (5.9) 0 Above 5 1 (2.9) Comparison of antiemetic efficacy between ondansetron and granisetron The efficacy of ondansetron and granisetron each combined with dexamethasone was compared in prevention of acute and delayed CINV and the results are shown in tables 7 and Acute nausea and vomiting No acute nausea appeared in 27 (79.4%) patients on Ondansetron+Dexamethasone and 28 (82.4%) patients on Granisetron+Dexamethasone. Severe nausea appeared in 1 (2.9%) patient with Ondansetron+ Dexamethasone but none with Granisetron + Dexamethasone. Major efficacy to prevent acute vomiting (complete response or no vomiting) was achieved in 29 (85.3%) patients on Ondansetron+ Dexamethasone and 30 (88.2%) patients on Granisetron + Dexamethasone. No failure of treatment was observed and the p value was above 0.05 in all comparisons indicating therefore the difference between the two regimens was not statistically significant. 29

47 Table 5: Effect of antiemetic treatment on acute nausea and vomiting Response Ondansetron + Dexamethasone Granisetron + Dexamethasone p value Number of treatment cycles Acute nausea No nausea 27 (79.4%) 28 (82.4%) Mild nausea 6 (17.6%) 6 (17.6%) Moderate nausea 0 (0%) 0 (0%) NA Severe nausea 1 (2.9%) 0 (0%) Acute vomiting Complete response 29 (85.3%) 30 (88.2%) Major response 5 (14.7%) 4 (11.8%) Minor response 0 (0%) 0 (0%) NA Failure 0 (0%) 0 (0%) NA Key: NA: Not Applicable After the initial administration of intravenous antiemetics and chemotherapy drugs in acute phase, patients continued with oral preventive antiemetics up to fifth day in delayed phase and the results are shown in table 8 below. 30

48 Delayed vomiting and nausea Table 6: Effect of antiemetic treatment on delayed nausea and vomiting Day Response Ondansetron+ Dexamethasone Granisetron+ Dexamethasone p value Day 2 Delayed nausea No nausea 17 (50%) 21 (61.8%) Mild nausea 13 (38.2%) 10 (29.4%) Moderate nausea 3 (8.8%) 3 (8.8%) Severe nausea 1 (2.9%) 0 (0%) Delayed vomiting Complete response 19 (55.9%) 21 (61.8%) Major response 11 (32.4%) 10 (29.4%) Minor response 3 (8.8%) 3 (8.8%) Failure 1 (2.9%) 0 (0%) Day 3 Delayed nausea No nausea 25 (73.5%) 27 (79.4%) Mild nausea 7 (20.6%) 4 (11.8%) Moderate nausea 2 (5.9%) 2 (5.9%) Severe nausea 0 (0%) 1 (2.9%) Delayed vomiting Complete response 25 (73.5%) 28 (82.4%) Major response 7 (20.6%) 3 (8.8%) Minor response 2 (5.9%) 2 (5.9%) Failure 0 (0%) 1 (2.9%) Day 4 Delayed nausea No nausea 30 (88.2%) 28 (82.4%) Mild nausea 3 (8.8%) 2 (5.9%) Moderate nausea 1 (2.9%) 4 (11.8%) Delayed vomiting Complete response 30 (88.2%) 28 (82.4%) Major response 3 (8.8%) 2 (5.9%) Minor response 1 (2.9%) 4 (11.8%) Day 5 Delayed nausea No nausea 33 (97.1%) 31 (91.2%) Mild nausea 1 (2.9%) 1 (2.9%) Moderate nausea 0 (0%) 2 (5.9%) Delayed vomiting Complete response 33 (97.1%) 31 (91.2%) Major response 1 (2.9%) 1 (2.9%) Minor response 0 (0%) 2 (5.9%)

49 No nausea was observed in more than 50% of the patients in the second day and the percentage increased progressively up to the fifth day. Vomiting was absent in more than half of the patients during the second day and again the number increased until the end of follow up. Comparison between the two combinations of drugs yielded p values above 0.05 and therefore the difference in efficacy was not statistically significant between the two antiemetic regimens Tolerability of antiemetic treatment regimens Although Ondansetron antiemetic combination regimen was associated with more adverse drug reactions compared to Granisetron antiemetic combination regimen the difference was not statistically significant (P>0.05). Figure 2: Incidences of antiemetic treatment adverse reactions The most common adverse drug effect was malaise/fatigue, which occurred more frequently with Ondansetron combination in 30 (88.2%) patients compared to Granisetron combination at 25 (73.5%) patients as shown in figure 2 and table in appendix 3. 32

50 The headache was more common with Granisetron combination in 21 (61.8%) patients compared to the Ondansetron combination in 19 (55.9%) patients. Urticaria was the less frequent in 5 (14.7%) patients with Ondansetron combination compared to 1(2.9%) patient receiving Granisetron combination Factors associated with nausea and vomiting among cancer patients The statistical analysis was done between incidence of nausea and vomiting with gender, age, type of cancer, chemotherapy regimen used and dosage of cisplatin (Appendix 3). No significant difference among most variables in enhancing nausea and vomiting in acute and delayed phases was observed because all p values generated were greater than 5%, except for the dosage of cisplatin where delayed nausea and vomiting on day 2 reflected p values less than 5% (p = and p = respectively) with significant difference associated in cisplatin dosage Direct cost analysis of antiemetic treatment Direct cost analysis of the two combinations of antiemetic for preventing chemotherapy induced nausea and vomiting, using KNH prices is shown in table 11. Table 7: Direct cost of preventing CINV at KNH Combination O + D G + D Duration Drug Total quantity Unit cost (KSh) Day1 Ondansetron 4mg iv Dexamethasone 4mg iv 2 10 Normal saline 50ml 1 20 Day 2-5 Oral Ondansetron 4mg Oral Dexamethasone 0.5mg 64 1 Day 1 Granisetron 3mg iv 1 1,610 Dexamethasone 4mg iv 2 10 Normal saline 50ml 1 20 Total cost (KSh) 694 7,074 Day 2-5 Oral Granisetron 1mg Oral Dexamethasone 0.5mg 64 1 Key: O: Ondansetron G: Granisetron KSh: Kenyan Shilling 33

51 Patients spent KSh 694 for five days of treatment using Ondansetron+Dexamethasone (O+D) compared to KSh 7,074 while using Granisetron+Dexamethasone (G+D) during the same treatment period. The ratio of the cost was approximately 10:1 in favor of Granisetron+Dexamethasone. 34

52 CHAPTER FIVE: DISCUSSION, CONCLUSION AND RECOMMENDATIONS 5.1. Introduction This chapter discusses the findings comparing them with other similar studies to come out with valuable and applicable conclusion and different recommendations. The conclusion and recommendations are also given Discussion Female gender was predominant at 70.6%, which correlates with other studies done in Kenya, Nigeria, Cameroun and USA (30-33). The leading type of cancer were cervical cancer followed by head and neck cancer. This is in line with the ICO Information Centre on HPV (Human Papilloma Virus) and Cancer (HPV Information Centre) which ranks cervical cancer as the most prevalent in Kenya at an incidence of 22.4%, and reports evidence linking HPV with anogenital cancers (anus, vulva, vagina and penis) and head and neck cancers). The most common age category where cancers were more prevalent was years with mean age of 53.5 (+/-11.9) years. These are elderly patients and advanced age is associated with chronic diseases such as cancer (34). More than a half of the patients had normal BMI, with 14.7% being underweight suggesting that at the time of diagnosing, the disease had caused a significant weight reduction among patients. The most frequently used chemotherapy regimen was cisplatin/paclitaxel since patients receiving this regimen can be treated on an outpatient basis and has demonstrated broad clinical activity in a variety of malignancies (35-37). The most frequently administered dosage of cisplatin was 75 mg/m 2 as it is mostly used in cervical cancer which was the predominant diagnosis. The incidence of acute and delayed nausea and vomiting due to HEC included cisplatin when appropriate antiemetic therapy was administered have been reported to be more than 35% for acute nausea; 13%, acute vomiting and 60% for delayed nausea; 50%, delayed vomiting. Delayed CINV was more commonly observed and poorly controlled than acute CINV (38-39). Similarly, in this study the incidence of nausea and vomiting were well controlled in acute than in delayed period. This is not also different from other 35

53 studies which have shown that it is generally difficult to control delayed CINV with conventional antiemetic therapy (39). In addition, prevention and treatment of the delayed CINV remain a challenge and many antiemetic agents have been less successful to prevent them than acute CINV (39). A good number of patients experienced nausea and vomiting on second day post treatment but this declined progressively up to the fifth day in both cycles I and II suggesting that the antiemetic properties of the drugs were slow. Perhaps this was also due to progressive tolerance of treatment interventions (cytotoxics and antiemetics) by patients However, since most of patients vomited once in five days in both cycles I and II, the antiemetic treatment was effective. Globally, the incidence of CINV was higher in the first cycle than in the second cycle for each patient during the entire treatment period. In this study, there was no appreciable difference in the tolerability of antiemetic treatment regimens among the patients as observed by Gregory et al (40) although there were more adverse drug reactions of malaise/fatigue followed by headache with ondansetron compared to granisetron regimen. Separate findings from some other studies observed that the most common side effects were constipation and headache, which were more frequently observed with ondansetron than with granisetron (3). This dissimilarity could be due to the fact that malaise/fatigue may have been confused with cisplatin adverse effects and headache could have massively reported. Both adverse effects could have been associated with the illnesses themselves (head and neck cancers, psychological stress, and increased metabolism). However, the adverse drug reactions were not severe and not significantly different between the two antiemetic treatment regimens. Studies have revealed that CINV may be influenced by two major categories of risk factors: chemotherapy agents and patient characteristics(41). However, we found that cisplatin as a HEC with its relative elevated dosage were associated with worse CINV; also female gender and young age were associated with an elevated frequency of CINV. This study was conducted in heterogeneous patients of both genders and different types of malignancy treated with different cytotoxic regimens and those variations might affect the study findings as revealed elsewhere (7, 42). 36

54 The study evaluated the association of gender, age, type of cancer, chemotherapy regimen and dosage of cisplatin with episodes of nausea and vomiting. Female and younger patients were more nauseated and vomited more often than male and older patients, but there was no statistically significant difference. A study done by Hilarius et al found out that CINV is worse in women and in younger patients (41, 43). Women compared to men have lower body weight and organ size (e.g. Kidney), more body fat, faster gastric motility and lower glomerular filtration rate. These differences can affect the way the body deals with drugs by altering the pharmacokinetics and pharmacodynamic of the drugs including drug absorption (faster), distribution (wider), metabolism (faster) and elimination (slow); reason why they are more exposed to many adverse drug reactions than men as found in a study done by Alomar (44). Patients with cervical, head and neck cancers appeared to have nauseated and vomited more during follow up due to high dose of cisplatin in their chemotherapy combination but still the difference was not statistically significant. Patients taking a combination regimen of cisplatin/paclitaxel presented a higher number of those that nauseated and vomited. This was due to the higher dose of cisplatin (75mg/m2) administered in the chemotherapy regimen as concluded studies, that concomitant administration of higher doses of chemotherapy agents and repeated cycles have increased risk for CINV (2, 11, 41, 45). Significant difference associated with cisplatin dosage was observed only on second day post treatment in both cycles I and II, perhaps due to the usual tough CINV associated with a progressive increase of tissue distribution of cytotoxic and decrease of antiemetic drug activity of the first dose. Many comparative studies using different dosages, regimens and routes of administration have been done with 5-HT3 RA including granisetron and ondansetron. Most of the studies showed equal efficacy between the two antiemetic agents (40, 46) and the addition of steroid (dexamethasone) appears to improve treatment outcome (47). As the 5-HT3 RAs perform similarly clinically, pharmacological differences do not seem to translate into therapeutic differences. In this study, there was no significant difference in antiemetic efficacy in acute or delayed nausea and vomiting between ondansetron and granisetron each combined with dexamethasone among KNH cancer patients. The 37

55 complete response rate for acute vomiting was 88.2% with granisetron and 85.3% with ondansetron compared to the rates for delayed vomiting of 79.5% with granisetron and 78.7% with ondansetron, similar to the trial done by Italian Group for Antiemetic Research on HEC (48). Given the above rates of vomiting, control of delayed nausea and vomiting was still less satisfactory but, better compared to the use of the either of the two antiemetic drugs alone as found in other different studies (3, 14, 48-49). Although the two antiemetic combinations didn t show any significant difference in prevention of CINV there is a considerable difference in the terms of their direct costs for the five days of CINV treatment. The combination including granisetron was almost ten times more expensive than the one with ondansetron similarly to the study done in Malaysia (45) Conclusion The study showed that both antiemetic combinations (Ondansetron+ Dexamethasone or Granisetron+ Dexamethasone) were effective in controlling CINV in cancer patients receiving cisplatin based chemotherapy regimens. In addition, the antiemetic control is better in acute compared to delayed phase. It has been revealed that ondansetron and granisetron; each combined with dexamethasone have similar efficacy and tolerability in prevention of cisplatin induced nausea and vomiting. This suggests that determination of clinical choice between the two antiemetics may then be only dictated by direct cost Recommendations for Policy and Practice 1. Complete prevention of emesis is not achieved by a single dose of antiemetic drug, therefore; patients follow up should be encouraged in order to monitor the effectiveness of an antiemetic. 2. As delayed phase of CINV is poorly controlled, continued oral antiemetic drugs are necessary for all patients on HEC. 3. Finally, instead of procuring both granisetron and ondansetron, which have similar antiemetic properties and tolerability profiles, the hospital should consider using the one that is cost affordable (ondansetron). 38

56 5.5. Recommendations for Further Research Prospective cohort study is needed to find out the optimal antiemetic regimen for the delayed phase of chemotherapy induced nausea and vomiting. 39

57 REFERENCES 1. Takeuchi H, Saeki T, Aiba K, Tamura K, Aogi K, Eguchi K, et al. Japanese Society of Clinical Oncology clinical practice guidelines 2010 for antiemesis in oncology: executive summary. International journal of clinical oncology Jun Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. The oncologist. 2003;8(2): Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of cisplatin-induced emesis. Italian Group of Antiemetic Research. Ann Oncol Oct; 6 (8): Hesketh PJ. Chemotherapy-induced nausea and vomiting. The New England journal of medicine Jun 5;358 (23): Roila F, Palladino MA, Ciccarese G, Basurto C. [Recent improvements in antiemetic therapy]. Tumori. 1997;83 (2 Suppl): S Gomez-Raposo C, Feliu-Batlle J, Gonzalez-Barona M. [Prevention and control of chemotherapy-induced nausea and vomiting]. Medicina clinica Feb 4;126 (4): Poon RT, Chow LW. Comparison of antiemetic efficacy of granisetron and ondansetron in Oriental patients: a randomized crossover study. British journal of cancer May; 77 (10): Doherty KM. Closing the gap in prophylactic antiemetic therapy: patient factors in calculating the emetogenic potential of chemotherapy. Clin J Oncol Nurs Jul; 3 (3): Bilgrami S, Fallon BG. Chemotherapy-induced nausea and vomiting. Easing patients' fear and discomfort with effective antiemetic regimens. Postgrad Med Oct; 94 (5): 55-8, Hesketh PJ, Kris MG, Grunberg SM, Beck T, Hainsworth JD, Harker G, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology Jan; 15 (1):

58 11. Gralla RJ, Osoba D, Kris MG, Kirkbride P, Hesketh PJ, Chinnery LW, et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. Journal of clinical oncology: official journal of the American Society of Clinical Oncology Sep; 17 (9): Pollera CF, Giannarelli D. Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model. Cancer Sep 1;64(5): Roscoe JA, Bushunow P, Morrow GR, Hickok JT, Kuebler PJ, Jacobs A, et al. Patient expectation is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer Dec 1;101(11): Grunberg SM. Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy, and tolerability analysis. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO Feb; 18 (2): Durand JP, Madelaine I, Scotte F. [Guidelines for prophylaxis and treatment of chemotherapy-induced nausea and vomiting]. Bulletin du cancer Oct; 96 (10): Jordan K, Sippel C, Schmoll HJ. Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present, and future recommendations. The oncologist Sep; 12 (9): Stewart A, McQuade B, Cronje JD, Goedhals L, Gudgeon A, Corette L, et al. Ondansetron compared with granisetron in the prophylaxis of cyclophosphamideinduced emesis in out-patients: a multicentre, double-blind, double-dummy, randomized, parallel-group study. Emesis Study Group for Ondansetron and Granisetron in Breast Cancer Patients. Oncology May-Jun; 52 (3): Perez EA, Hesketh P, Sandbach J, Reeves J, Chawla S, Markman M, et al. Comparison of single-dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randomized parallel study. Journal of 41

59 clinical oncology: official journal of the American Society of Clinical Oncology Feb; 16 (2): Ruff P, Paska W, Goedhals L, Pouillart P, Riviere A, Vorobiof D, et al. Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomized, parallel-group study. The Ondansetron and Granisetron Emesis Study Group. Oncology Jan-Feb; 51 (1): Aapro M. Granisetron: an update on its clinical use in the management of nausea and vomiting. The oncologist. 2004;9(6): Del Giglio A, Soares HP, Caparroz C, Castro PC. Granisetron is equivalent to ondansetron for prophylaxis of chemotherapy-induced nausea and vomiting: results of a meta-analysis of randomized controlled trials. Cancer Dec 1;89(11): Erazo Valle A, Wisniewski T, Figueroa Vadillo JI, Burke TA, Martinez Corona R. Incidence of chemotherapy-induced nausea and vomiting in Mexico: healthcare provider predictions versus observed. Curr Med Res Opin Dec; 22 (12): Liau CT, Chu NM, Liu HE, Deuson R, Lien J, Chen JS. Incidence of chemotherapy-induced nausea and vomiting in Taiwan: physicians' and nurses' estimation vs. patients' reported outcomes. Support Care Cancer May;13(5): Escobar Y, Cajaraville G, Virizuela JA, Alvarez R, Munoz A, Olariaga O, et al. Incidence of chemotherapy-induced nausea and vomiting with moderately emetogenic chemotherapy: ADVICE (Actual Data of Vomiting Incidence by Chemotherapy Evaluation) study. Support Care Cancer Sep; 23 (9): Abali H, Celik I. Tropisetron, ondansetron, and granisetron for control of chemotherapy-induced emesis in Turkish cancer patients: a comparison of efficacy, side-effect profile, and cost. Cancer Invest Apr-May; 25 (3):

60 26. Joss RA, Dott CS. Clinical studies with granisetron, a new 5-HT3 receptor antagonist for the treatment of cancer chemotherapy-induced emesis. The Granisetron Study Group. Eur J Cancer. 1993;29A Suppl 1:S Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci Aug; 334 (2): Sakaida E, Iwasawa S, Kurimoto R, Ebata T, Imai C, Oku T, et al. Safety of a short hydration method for cisplatin administration in comparison with a conventional method-a retrospective study. Jpn J Clin Oncol Jan Miller RP, Tadagavadi RK, Ramesh G, Reeves WB. Mechanisms of Cisplatin nephrotoxicity. Toxins (Basel) Nov; 2 (11): Korir A, Okerosi N, Ronoh V, Mutuma G, Parkin M. Incidence of cancer in Nairobi, Kenya ( ). Int J Cancer Nov 1;137 (9): Jedy-Agba E, Curado MP, Ogunbiyi O, Oga E, Fabowale T, Igbinoba F, et al. Cancer incidence in Nigeria: a report from population-based cancer registries. Cancer Epidemiol Oct; 36 (5): e Jensen OM, Tuyns AJ, Ravisse P. Cancer in Cameroon: a relative frequency study. Rev Epidemiol Sante Publique. 1978;26(2): Devesa SS, Silverman DT, Young JL, Jr., Pollack ES, Brown CC, Horm JW, et al. Cancer incidence and mortality trends among whites in the United States, J Natl Cancer Inst Oct;79(4): White MC, Holman DM, Boehm JE, Peipins LA, Grossman M, Jane Henley S. Age and Cancer Risk: A Potentially Modifiable Relationship. American Journal of Preventive Medicine. 2014;46(3, Supplement 1):S7-S Jin Y, Shi YX, Cai XY, Xia XY, Cai YC, Cao Y, et al. Comparison of five cisplatin-based regimens frequently used as the first-line protocols in metastatic nasopharyngeal carcinoma. J Cancer Res Clin Oncol Oct; 138 (10): Kornek GV, Raderer M, Schüll B, Fiebiger W, Gedlicka C, Lenauer A, et al. Effective combination chemotherapy with paclitaxel and cisplatin with or without human granulocyte colony-stimulating factor and/or erythropoietin in patients with advanced gastric cancer. British journal of cancer. 2002;86(12):

61 37. Scatchard K, Forrest JL, Flubacher M, Cornes P, Williams C. Chemotherapy for metastatic and recurrent cervical cancer. Cochrane Database Syst Rev. 2012;10: CD Grunberg SM, Deuson RR, Mavros P, Geling O, Hansen M, Cruciani G, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer May 15;100 (10): Markman M. Progress in preventing chemotherapy-induced nausea and vomiting. Cleve Clin J Med Aug; 69 (8): , 12, Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical efficacy. Drugs Feb; 55 (2): Dodd MJ, Onishi K, Dibble SL, Larson PJ. Differences in nausea, vomiting, and retching between younger and older outpatients receiving cancer chemotherapy. Cancer Nurs Jun; 19 (3): Sekine I, Segawa Y, Kubota K, Saeki T. Risk factors of chemotherapy-induced nausea and vomiting: index for personalized antiemetic prophylaxis. Cancer Sci Jun; 104 (6): Hilarius DL, Kloeg PH, van der Wall E, van den Heuvel JJ, Gundy CM, Aaronson NK. Chemotherapy-induced nausea and vomiting in daily clinical practice: a community hospital-based study. Support Care Cancer Jan; 20 (1): Alomar MJ. Factors affecting the development of adverse drug reactions (Review article). Saudi Pharm J Apr; 22 (2): Keat CH, Ghani NA. Cost-effectiveness analysis of granisetron-based versus standard antiemetic regimens in low-emetogenic chemotherapy: a hospital-based perspective from Malaysia. Asian Pac J Cancer Prev. 2013;14(12): Chua DT, Sham JS, Kwong DL, Kwok CC, Yue A, Foo YC, et al. Comparative efficacy of three 5-HT3 antagonists (granisetron, ondansetron, and tropisetron) plus dexamethasone for the prevention of cisplatin-induced acute emesis: a randomized crossover study. American journal of clinical oncology Apr; 23 (2):

62 47. Morrow GR, Hickok JT, Rosenthal SN. Progress in reducing nausea and emesis. Comparisons of ondansetron (Zofran), granisetron (Kytril), and tropisetron (Navoban). Cancer Aug 1;76 (3): Gebbia V, Cannata G, Testa A, Curto G, Valenza R, Cipolla C, et al. Ondansetron versus granisetron in the prevention of chemotherapy-induced nausea and vomiting. Results of a prospective randomized trial. Cancer Oct 1;74 (7): Delayed emesis induced by moderately emetogenic chemotherapy: do we need to treat all patients? The Italian Group for Antiemetic Research. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO Jun; 8 (6): Diehl V, Marty M "Efficacy and safety of antiemetics." Cancer Treat Rev 20, 1994: "Product Information. Kytril (granisetron)." SmithKline Beecham, Philadelphia, PA. 52. Linda Stewart, MPharm, MRPharmS, S. M. Crawford, FRCP, and P. A. Taylor, MPharm, MRPharmS. The comparative effectiveness of ondansetron and granisetron in a once daily dosage in the prevention of nausea and vomiting caused by cisplatin: a double-blind clinical trial. The Pharmaceutical Journal Vol 265 No 7104p59-62 July 8, 2000 Original Papers 53. Y H Chan. Randomized Controlled Trials (RCTs) Sample Size: The Magic Number? Singapore Med J2003; 44 (4): Piantadosi Steven. (2005) Crossover Designs. In: Piantadosi Steven. Clinical Trials: A Methodologic Perspective. 2nd ed. Hobaken, NJ: John Wiley and Sons, Inc. 55. Vincent Launay -Vacher et al. Prevention of cisplatin nephrotoxicity: state of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care. Cancer Chemother Pharmacol (2008) 61: North East Yorkshire and Humber Cancer Alliance. Policy for Cisplatin Hydration (2014) [accessed on the 3rd March 2015] 45

63 APPENDICES APPENDIX 1: CONSENT FORM (a) English version Title: Efficacy of granisetron versus ondansetron in the prevention of chemotherapy induced nausea and vomiting among cancer patients at Kenyatta National Hospital Institution: Department of Pharmaceutics and Pharmacy Practice, School of Pharmacy, University of Nairobi, P.O BOX , Nairobi. Investigator: Dr. MUHIRE Innocent, Tel: Supervisors: 1 st. Dr. P. N. KARIMI, Department of Pharmaceutics and Pharmacy Practice; Tel: nd. Dr. DR. D. G. NYAMU, Department of Pharmaceutical and Pharmacy Practice Tel: rd. Dr. MARANGA I.S.O, Department of Reproductive Hearth, KNH Tel: Ethical Approval Board: Kenyatta National Hospital/ University of Nairobi Ethical and Research Committee, P.O BOX , Nairobi. Tel: / Ext Permission is requested from you to enroll in this medical research study. The following general principles which apply to all participants in a medical research: 46

64 i. Your agreement to participate in this study is voluntary. ii. You may withdraw from the study at any time without necessarily giving a reason for your withdrawal. iii. After you have read the explanation, please feel free to ask any questions that will enable you to understand clearly the nature of the study. Introduction The purpose of this study is to compare two commonly used anti-vomiting drugs by evaluating their efficacy in preventing vomiting without causing side effects and how they can be used more effectively among cancer patient attending chemotherapy at KNH. These two drugs are usually part of routine treatment every time one receives anti-cancer drugs. Procedure With your permission I kindly request you to accept to be administered an intravenous (iv) single dose of a drug before to be administered iv infusion cisplatin based cytotoxic regimen as prescribed by your primary doctor. This drug administration will be done at KNH by our well trained staff to ensure appropriate good practice of drugs administration and safety. The drug administered the 1 st is to prevent you against nausea and vomiting caused by the one that will be administered the 2 nd. All your information will be handled with confidentiality and will only be used for the purpose of this study. While at your home, we request that you allow us to call you on phone for next 5 days at 6 7:00 am and 6 7:00 pm daily or any other convenient time for you, to find out your well being especially status regarding nausea and vomiting. Benefits After pre-treatment interview you will be injected the 1 st drug to prevent you against nausea and vomiting induced by chemotherapy treatment based on cisplatin to treat your disease. We will brief you on everything that is going to be done to you instantaneously. Any case of complication will be managed in the right way by KNH staff safe. 47

65 Risks There will be pain at the injection site, but all precautions will be taken to ensure that no infection or spillage will take place. There may be also risk of the common side effects of administering drugs which, the investigating team will be ready to address. Assurance of confidentiality All information obtained from you will be kept in confidence. At no point will you or your name be mentioned or used during data handling or in any resulting publications. Codes and numbers will be used instead of names to identify patients. Contacts: In case you need to contact me, my academic department or the Kenyatta National Hospital/ University of Nairobi Ethics and Research Committee concerning this study please feel free to use the contacts provided above. I kindly request you to sign the consent form attached. I patient/parent/guardian of Agree to enroll him/her into the study as explained to me by Dr.. I patient/parent/guardian of agree to allow Dr.. to call me through my mobile phone at the agreed time following administration of the drugs during the study. My signature is confirmation that I have understood the nature of the study and that whatever information that I give will remain confidential and that I have not given up my legal rights as a participant. 48

66 I also confirm that no monetary or material gains have been promised or given to me for participating in the study. I willingly give consent to participate in this research. Signed.. Relationship (Patient/patient/guardian) Tel. (1). (2) (3) Date:.. / /.. Signature of principal investigator. Date:.. / /. 49

67 (b) Swahili version KIAMBATISHO 1 IDHINI FOMU Title: Linganishi juu ya ufanisi wa Granisetron na ondansetron katika kuzuia kichefuchefu na kutapika miongoni mwa wagonjwa wa saratani katika Hospitali ya Taifa ya Kenyatta Taasisi: Idara ya pharmaceutics na Pharmacy Mazoezi, Shule ya Pharmacy, Chuo Kikuu cha Nairobi, SLP , Nairobi. Mpelelezi: Dk MUHIRE Innocent, Simu: Wasimamizi 1. Dk. P. N. Karimi, Idara ya pharmaceutics na Pharmacy na Pharmacy Mazoezi; Simu: Dk. D. G. Nyamu, Idara ya Madawa na Pharmacy Mazoezi Simu: Dk. Maranga I.S.O, Idara ya Uzazi Makaa, KNH Simu: Kimaadili kibali Kenyatta National Hospital / Chuo Kikuu cha Nairobi kimaadili na Kamati ya Utafiti, SLP , Nairobi. Simu: / Ext Ruhusa ni ombi kutoka kwenu kujiandikisha katika utafiti huu utafiti wa matibabu. kufuatia kanuni za jumla ambayo yanahusu washiriki wote katika utafiti wa matibabu i. makubaliano yako na kushiriki katika utafiti huu ni wa hiari. ii. Unaweza kuondoa kutoka utafiti wakati wowote bila lazima kutoa sababu kwa ajili ya uondoaji yako. iii. Baada ya kusoma maelezo maelezo tafadhali jisikie huru kuuliza maswali yoyote ambayo itawezesha wewe kuelewa wazi asili ya utafiti. 50

68 Kuanzishwa Lengo la somo hili ni kulinganisha granisetron na ondansetron kwa kufanya tathmini ya kupambana na utapishi zao ufanisi na uvumilivu na jinsi inaweza kuboreshwa kwa kuongeza matumizi yao rationale katika kansa kike mgonjwa kuhudhuria chemotherapy hapa KNH. Utaratibu Kwa ruhusa yako mimi kuuliza wewe kuwa unasimamiwa iv dozi moja ya madawa ya kulevya kabla ya kuwa unasimamiwa iv infusion cisplatin msingi cytotoxic regimen katika kipimo cha 50mg - 75mg / m2.this madawa utawala itafanyika katika KNH na wafanyakazi wetu vizuri mafunzo ya kuhakikisha sahihi mazoezi mazuri ya dawa za utawala na usalama. madawa ya kulevya kusimamiwa 1 ni kuzuia wewe dhidi ya kichefuchefu na kutapika unasababishwa na moja kwamba utasimamiwa 2. Taarifa zote itakuwa kubebwana usiri na itakuwa tu kutumika kwa madhumuni ya utafiti huu. Mimi kesi wewe ni kwenda nyumbani, tutafanya wewe kupiga simu na wewe kwa muda wa siku 7 katika 6-7 0:00 na :00 kila siku au nyingine yoyote wakati unaofaa na wewe. Faida Baada ya mahojiano kabla ya matibabu utakuwa sindano madawa ya kulevya 1 ili kuzuia wewe dhidi ya kichefuchefu na kutapika ikiwa na matibabu ya kidini msingi cisplatin kutibu ugonjwa wako. Sisi itakuwa mafupi juu ya kila kitu kinachoendelea kufanywa ili wewe instantaneous. Katika kesi ya matatizo yoyote, itakuwa imeweza katika njia ya haki na KNH mambo salama. Hatari Kutakuwa na maumivu kwenye tovuti ya sindano lakini mbinu aseptic zitatumika ili kuhakikisha kwamba hakuna maambukizi au extravasation utafanyika. Kutakuwa na pia hatari ya madhara ya kawaida upande wa dawa unasimamiwa lakini kama mbaya zaidi, timu ya uchunguzi itakuwa tayari kuingilia kati. 51

69 Uhakika wa usiri Taarifa zote zilizopatikana kutoka kwenu yatawekwa katika kujiamini. Wakati hakuna uhakika itakuwa wewe au jina lako na waliotajwa au kutumika wakati wa utunzaji data au katika machapisho yoyote kusababisha. idadi Posta zitatumika badala ya majina kutambua wagonjwa. Mawasiliano Katika kesi unahitaji kuwasiliana na mimi, idara yangu taaluma au Kenyatta National Hospital / Chuo Kikuu cha Nairobi Maadili na Kamati ya Utafiti kuhusu somo hili tafadhali jisikie huru kutumia mawasiliano zinazotolewa hapo juu. Mimi sasa ombi wewe kusaini fomu ya idhini masharti. Mimi... mgonjwa / mzazi / mlezi wa... Kubali kujiandikisha yake / zake katika utafiti kama nilivyoeleza kwangu na Dk... sahihi yangu ni uthibitisho kwamba mimi kuelewa asili ya utafiti na kwamba taarifa yoyote kwamba mimi kutoa kubaki siri. Mimi pia kuthibitisha kwamba hakuna faida ya fedha au vifaa ahidiwa au kutolewa na mimi kwa ajili ya kushiriki katika utafiti. Saini... (Mgonjwa / mgonjwa / mlezi) Uhusiano... Tel. (1)... (2)... (3)... Tarehe..... /... /..... Saini ya mkuu wa uchunguzi... Tarehe..... /... /... 52

70 APPENDIX 2: QUESTIONNAIRE Study: EFFICACY AND TOLERABILITY OF GRANISETRON VERSUS ONDANSETRON IN THE PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING AMONG CANCER PATIENTS AT KNH Date.. /.. /.. IP/OP No: Patient code number A. Sociodemographic characteristics 1. Gender: Male (0) Female (1) 2. Age (Years).. 3. Age category Age category in years Code Above Weight:.. Kg 5. Height:.. M 6. BMI BMI- kg/m 2 Code Below Above

71 7. BSA:.. M 2 8. Taking alcohol: Yes (0) No (1) 9. Diagnosis Type of cancer Code Cervical 1 Breast 2 Ovarian 3 Stomach 4 Bladder 5 Head and neck 6 Esophagus 7 Lungs 8 Osteogenic sarcoma 9 Gastric 10 Endometrial 11 Hodgkin s lymphoma 12 Non Hodgkin s lymphoma 13 Colorectal 14 Prostate 15 Others (Specify) 16 B. Treatment interventions 10. Chemotherapy regimen used Chemotherapy regimen administered Code Cisplatin 1 Cisplatin/Gemcitabine 2 Cisplatin/Docetaxel 3 Cisplatin/Paclitaxel 4 Cisplatin/Etoposide 5 54

72 Cisplatin/Doxorubicin 6 Cisplatin/Daunorubicin 7 Cisplatin/Epirubicin 8 Cisplatin/5-FU 9 Cisplatin/Trastuzumab/Capectabine 10 Cisplatin/Epirubicin/Capecitabine 11 Others (specify) Cisplatin dosage: Dose (mg/m 2 ) Code C. Onset and frequency of nausea and vomiting CYCLE I 12. Antiemetic used Drug Code Ondansetron 1 Granisetron Combination antiemetic used Drug combination Code Ondansetron+ Dexamethasone 1 Granisetron +Dexamethasone 2 a. Acute nausea and vomiting (within 24 hours) 14. Did you feel nausea? Yes (0) No (1) 15. Did you vomit? Yes (0) No (1) 55

73 16. If Yes in question No. 14, how many times: Number of times Code None 1 One 2 Two 3 Three 4 Four 5 Five 6 Above If Yes in 15, how many times: Number of times Code None 1 One 2 Two 3 Three 4 Four 5 Five 6 Above 5 7 b. Delayed nausea and vomiting (from 2 nd day) Did you feel nauseated today? S/No Day Response Yes No 18 Day Day Day Day

74 Did you vomit today? S/No Day Response Number of vomiting Yes No episodes per day 22 Day Day Day Day Vomiting episodes categories Number of vomiting episodes in 5 days Code >5 4 CYCLE II 27. Antiemetic used Drug Code Ondansetron 1 Granisetron Combination antiemetic used Drug combination Code Ondansetron+ Dexamethasone 1 Granisetron +Dexamethasone 2 57

75 a. Acute nausea and vomiting (within 24 hours) 29. Did you feel nausea? Yes (0) No (1) 30. Did you vomit? Yes (0) No (1) 31. If Yes in question No. 29, how many times: Number of times Code None 1 One 2 Two 3 Three 4 Four 5 Five 6 Above If Yes in 30, how many times: Number of times Code None 1 One 2 Two 3 Three 4 Four 5 Five 6 Above

76 b. Delayed nausea and vomiting (from 2 nd day) Did you feel nauseated today? S/No Day Response Yes No 33 Day Day Day Day Did you vomit today? S/No Day Response Number of vomiting Yes No episodes 37 Day Day Day Day Vomiting episodes categories Number of vomiting episodes in 5 days Code >5 4 59

77 Did you experience any of the following conditions today? S/No Adverse effects of drugs Response Yes No 42 Constipation Diarrhoea Headache Fever Malaise/Fatigue Abdominal pain Dizziness Urticaria Somnolence

78 APPENDIX 3: ANTIEMETIC TREATMENT ADVERSE REACTIONS Adverse reaction Ondansetron+Dexamethasone Granisetron+Dexamethasone p effect (n, %) (n, %) value Constipation 17 (50.0%) 12 (35.3%) Diarrhoea 6 (17.6%) 6 (17.6%) Headache 19 (55.9%) 21 (61.8%) Fever 15 (44.1%) 16 (47.1%) Malaise/Fatigue 30 (88.2%) 25 (73.5%) Abdominal pain 12 (35.3%) 11 (32.4%) Dizziness 17 (50.0%) 13 (38.2%) Urticaria 5 (14.7%) 1 (2.9%) Somnolence 6 (17.6%) 11 (32.4%)

79 APPENDIX 4: RELATIONSHIP BETWEEN CINV AND DIFFERENT VARIABLES Variable Acute nausea p value Yes (n, %) No (n, %) Gender Male 3 (8.8%) 7 (20.6) Female 7 (20.6%) 17 (50%) Age category (2.9%) (11.8%) 9 (26.5%) (11.8%) 12 (35.3%) Above 70 2 (5.9%) 2 (5.9%) Type of cancer Cervical 5 (14.7%) 9 (26.5%) Breast 0 2 (5.9%) Ovarian 0 1 (2.9%) Head and neck 4 (11.8%) 6 (17.6%) Lungs 1 (2.9%) 6 (17.6%) Chemo. regimen Cisplatin 4 (11.8%) 6 (17.6%) Cisplatin/Paclitaxel 6 (17.6%) 16 (47.1%) Cisplatin/5-FU 0 1 (2.9%) Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (5.9%) 4 (11.9%) (2.9%) 75 8 (23.5%) 19 (55.9%) Acute vomiting Yes No Gender Male 2 (5.9%) 8 (23.5%) Female 5 (14.7%) 19 (55.9%) Age category (2.9%) (8.8%) 10 (29.4%) (8.8%) 13 (38.2) Above 70 1 (2.9%) 3 (8.8%) Type of cancer Cervical 4 (11.8%) 10 (29.4%) Breast 0 2 (5.9%) Ovarian 0 1 (2.9%) 62

80 Head and neck 3 (8.8%) 7 (20.6%) Lungs 0 7 (20.6%) Chemo. regimen Cisplatin 3 (8.8%) 7 (20.6%) Cisplatin/Paclitaxel 4 (11.8%) 18 (52.9%) Cisplatin/5-FU 0 1 (2.9%) Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (2.9%) 5 (14.7%) (2.9%) 75 6 (17.6%) 21 (61.8%) Variable Delayed nausea (Day 2) p value Yes No Gender Male 5 (14.7%) 5 (14.7%) Female 13 (38.2%) 11 (32.4) Age category (2.9%) (17.6%) 7 (20.6%) (29.4%) 6 (17.6%) Above 70 1 (2.9%) 3 (8.8%) Type of cancer Cervical 5 (14.7%) 9 (26.5%) Breast 0 2 (5.9%) Ovarian 1 (2.9%) 0 Head and neck 8 (23.5%) 2 (5.9%) Lungs 4 (11.8%) 3 (8.8%) Chemo. regimen Cisplatin 5 (14.7%) 5 (14.7%) Cisplatin/Paclitaxel 13 (38.2%) 9 (26.5%) Cisplatin/5-FU 0 1 (2.9%) Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (2.9%) 5 (14.7%) (2.9%) (50%) 10 (29.4%) Delayed nausea (Day 3) p value Yes No Gender Male 2 (5.9%) 8 (23.5%) Female 10 (29.4%) 14 (41.2%) Age category (2.9%)

81 (11.8%) 9 (26.5%) (20.6%) 9 (26.5%) Above (11.8%) Type of cancer Cervical 5 (14.7%) 9 (26.5%) Breast 0 2 (5.9%) Ovarian 0 1 (2.9%) Head and neck 6 (17.6%) 4 (11.9%) Lungs 1 (2.9%) 6 (17.6%) Chemo. regimen Cisplatin 4 (11.9%) 6 (17.6%) Cisplatin/Paclitaxel 7 (20.6%) 15 (44.1%) Cisplatin/5-FU 1 (2.9%) 0 Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (17.6%) (2.9%) (35.3%) 15 (44.1%) Delayed nausea (Day 4) Yes No Gender Male 3 (8.8%) 7 (20.6%) Female 6 (17.6%) 18 (52.9%) Age category (2.9%) (8.8%) 10 (29.4%) (14.7%) 11 (32.4) Above (11.9%) Type of cancer Cervical 2 (5.9%) 12 (35.3%) Breast 0 2 (5.9%) Ovarian 0 1 (2.9%) Head and neck 6 (17.6%) 4 (11.9%) Lungs 1 (2.9%) 6 (17.6%) Chemo. regimen Cisplatin 4 (11.9%) 6 (17.6%) Cisplatin/Paclitaxel 5 (14.7%) 17 (50%) Cisplatin/5-FU 0 1 (2.9%) Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (17.6%) (2.9%) 75 9 (26.5%) 18 (52.9%) 64

82 Delayed nausea (Day 5) Yes No Gender Male 3 (8.8%) 7 (20.6%) Female 2 (5.9%) 22 (64.7%) Age category (2.9%) (5.9%) 11 (32.4%) (8.8%) 13 (38.2%) Above (11.9%) Type of cancer Cervical 0 14 (41.2%) Breast 0 2 (5.2%) Ovarian 0 1 (2.9%) Head and neck 3 (8.8%) 7 (20.6%) Lungs 2 (5.9%) 5 (14.7%) Chemo. regimen Cisplatin 1 (2.9%) 9 (26.5%) Cisplatin/Paclitaxel 4 (11.9) 18 (52.9%) Cisplatin/5-FU 0 1 (2.9%) Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (17.6) (2.9%) 75 5 (14.7%) 22 (64.7%) Delayed vomiting (Day 2) Yes No Gender Male 4 (11.9%) 6 (17.6%) Female 12 (35.3%) 12 (35.3%) Age category (2.9%) (17.6%) 7 (20.6%) (23.5%) 8 (23.5%) Above 70 1 (2.9%) 3 (8.8%) Type of cancer Cervical 4 (11.9%) 10 (29.4%) Breast 0 2 (5.9%) Ovarian 1 (2.9%) 0 Head and neck 8 (23.5%) 2 (5.9%) Lungs 3 (8.8%) 4 (11.9%) Chemo. regimen Cisplatin 4 (11.9%) 6 (17.6%) Cisplatin/Paclitaxel 12 (35.3%) 10 (29.4%) 65

83 Cisplatin/5-FU 0 1 (2.9%) Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (17.6%) (2.9%) (47.1) 11 (32.4%) Delayed vomiting (Day 3) Yes No Gender Male 3 (8.8%) 7 (20.6%) Female 9 (26.5%) 15 (44.1%) Age category (2.9%) (11.9%) 9 (26.5%) (20.6%) 9 (26.5%) Above (11.9%) Type of cancer Cervical 4 (11.9%) 10 Breast 0 2 (5.9%) Ovarian 0 1 (2.9%) Head and neck 6 (17.6%) 4 (11.9%) Lungs 2 (5.9%) 5 (14.7%) Chemo. regimen Cisplatin 4 (11.9%) 6 (17.6%) Cisplatin/Paclitaxel 8 (23.5%) 14 (41.2%) Cisplatin/5-FU 0 1 (2.9%) Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (17.6%) (2.9%) (35.3%) 15 (44.1%) Delayed vomiting (Day 4) Yes No Gender Male 3 (8.8%) 7 (20.6%) Female 6 (17.6%) 18 (52.9%) Age category (2.9%) (8.8%) 10 (29.4%) (14.7%) 11 (32.4%) Above (11.9%) Type of cancer Cervical 2 (5.9%) 12 (35.3%) 66

84 Breast 0 2 (5.9%) Ovarian 0 4 (11.9%) Head and neck 6 (17.6%) 1 (2.9%) Lungs 1 (2.9%) 6 (17.6%) Chemo. regimen Cisplatin 4 (11.9%) 6 (17.6%) Cisplatin/Paclitaxel 5 (14.7%) 17 (50%) Cisplatin/5-FU 0 1 (2.9%) Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (17.6%) (2.9%) 75 9 (26.5%) 18 (52.9%) Delayed vomiting (Day 5) Yes No Gender Male 3 (8.8%) 7 (20.6%) Female 2 (5.9%) 22 (64.7%) Age category (2.9%) (5.9%) 11 (32.4%) (8.8%) 13 (38.2%) Above (11.9%) Type of cancer Cervical 0 14 (41.2%) Breast 0 2 (5.9%) Ovarian 0 1 (2.9%) Head and neck 3 (8.8%) 7 (20.6%) Lungs 2 (5.9%) 5 (14.7%) Chemo. regimen Cisplatin 1 (2.9%) 9 (26.5%) Cisplatin/Paclitaxel 4 (11.9%) 18 (52.9%) Cisplatin/5-FU 0 1 (2.9%) Cisplatin/Epirubicin/Capecitabine 0 1 (2.9%) Cisplatin dosage mg/m (17.6%) (2.9%) 75 5 (14.7%) 22 (64.7%) 67

85 APPENDIX 5: ETHICAL APPROVAL 68

86 69