PROSPECTIVE OBSERVATIONAL, NON-RANDOMIZED, PARALLEL SEQUENCE STUDY FOR ASSESSMENT OF ADVERSE DRUG REACTIONS DUE TO CHEMOTHERAPEUTIC TREATMENT IN DIFFERENT TYPES OF CANCER PATIENTSABSTRACTHTML Full Text
PROSPECTIVE OBSERVATIONAL, NON-RANDOMIZED, PARALLEL SEQUENCE STUDY FOR ASSESSMENT OF ADVERSE DRUG REACTIONS DUE TO CHEMOTHERAPEUTIC TREATMENT IN DIFFERENT TYPES OF CANCER PATIENTS
Mrugank B.P. *1 and Hareesha R.P. 2
Division of Research and Development, Alembic Pharmaceuticals Limited, Vadodara, Gujarat, India
CDSCO, Zonal office, Hyderabad, Andhra Pradesh, India
Objective: To assess incidence, causality, severity, predictability and preventability of adverse drug reactions (ADRs) in hospitalised oncology patients.
Materials and Methods: A prospective observational, non-randomized, parallel sequence study was conducted at Dr B. Borooah Cancer Institute (BBCI) after getting an approval from human ethical committee. Patients hospitalised at BBCI from Aug 2010 to June 2011 were interviewed about symptoms related to their drug therapy. Patient medical records were also reviewed for data collection.
Results: Total 663 patients associated with hospitalizations were interviewed. 899 ADRs were identified in total 410 (61.84%) patients detected with ADRs. Most of all ADRs were moderate, predictable and not preventable. The most common ADRs were leucopenia, weakness, anorexia, alopecia, vomiting, diarrhoea, nausea, abdominal pain, fatigue, and anaemia in this study.
Conclusions: For definite conclusion study should be repeated. Strict drug analyzing and in vivo study is also required if feasible.
Key message: The process of defining and concluding about ADRs should be continuous and ongoing to keep a record of newly marketed drugs and medicinal products.
Adverse drug reactions, Oncology, Chemotherapy, Causality, Severity
INTRODUCTION: According to WHO, "Pharmaco-vigilance is the science and activity relating the detection, assessment, understanding and prevention of adverse effects or any other possible drug - related problems" 1.Adverse drug reaction is defined as “Any response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function” 1.
In the practice of oncology, adverse drug reactions (ADRs) of cancer treatments have become almost synonymous with the treatments themselves. The low therapeutic index of chemotherapeutic agents and the predictable and common adverse events of cancer treatments mean that these events are seen as an unavoidable component of treatment. These events are often accepted not only by the patients but also by health-care providers.
In many instances, ADRs are even used as end-points for treatment protocols. With this mindset, it is not surprising that it is not known how many of the ADRs experienced by oncology patients could be prevented.
Research on broader population groups in Sweden, the United Kingdom, Germany and the United States has found that the incidence of ADRs is high and is dominated by reactions that are predictable and preventable 2, 3, 4, 5, 6. From their review of Australian studies, Roughead and colleagues found that between 32 and 69% of drug-related admissions reported were classified as definitely or possibly preventable 7.
The magnitude of ADRs endured by oncology patients is significant. The 1992 Australian National Hospital Morbidity Data (excluding NT) reported that 11% of ADRs in Australian hospitals were associated with antineoplastic and immuno-suppressive drugs 8.
The 1995 Quality in Australian Health Care Study, which reviewed medical records of over 14,000 admissions to 28 hospitals in New South Wales and South Australia, also implicated anti-neoplastics amongst the most common agents responsible for medication-related hospitalizations 9.
Advances in the development of supportive care in oncology, for example, 5HT3 antagonists for the control of chemotherapy-induced nausea, have led to reductions in drug-related toxicity. There is evidence to show that medical perspectives do not necessarily coincide with those of patients who are being treated 10, 11.
Patients are more likely to report bothersome but not necessarily clinically important symptoms 12, 13. It is important that patients’ perspectives and psychosocial issues be considered when attempting to identify, priorities and develop strategies to combat the problem 14. Strategies to reduce the burden of ADRs and to improve the quality use of medicines in health care are clearly needed 15.
The British Audit Commission’s 2001 report “Spoonful of Sugar” highlighted the important proactive role that pharmacists play in medicine management 16. The 2002 report by the Clinical Oncological Society of Australia, The Cancer Council Australia and the National Cancer Control Initiative similarly highlighted the contribution of pharmacists to the quality of cancer treatment and patient care 17.
An increased understanding of the prevalence and nature of ADRs, as well as an appreciation of patients’ perspectives on quality of life, would enable us as a profession to identify and target specific areas for vigorous pharmaceutical care.
MATERIALS AND METHODS: A prospective observational, non randomized, parallel sequence study was conducted after getting an approval from human ethical committee. Study was conducted for 11 months from Aug 2010 to June 2011 at Dr B Borooah Cancer Institute (Regional Institute for Treatment and Research), Guwahati, Assam, India.
Male and female patients of all age group who were receiving chemotherapeutic treatment for various cancers at medical or paediatric oncology ward were interviewed about symptoms related to their drug therapy for data collection till they visit to the hospital for different cycles of treatment. Patient medical records were also reviewed for data collection. The prescriptions containing incomplete information or patients attending at surgical or radiation or preventive oncology departments were excluded for the interview.
Method for assessment of Adverse Drug Reactions: The total numbers of adverse drug reactions were assessed for the causality, severity, preventability and predictability.
- Causality criteria: The Naranjo Algorithm or Adverse Drug Reaction Probability Scale (Table 1) was used to evaluate the causality relationship between a likely ADR and a drug18.It was a questionnaire which contains 10 questions with the options yes, no, and do not know and for each option score was given. The total score calculated from this questionnaire defines the category as >9: Definite, 5-8: Probable, 1-4: Possible (Table 1).
TABLE 1: NARANJO ALGORITHM OR ADVERSE DRUG REACTION PROBABILITY SCALE - THE TOTAL SCORE CALCULATED FROM THIS TABLE DEFINES THE CATEGORY AS: POSSIBLE (TOTAL SCORE 1–4), PROBABLE (TOTAL SCORE 5–8), DEFINITE (TOTAL SCORE >9)
|S. No.||Questionnaires||Yes||No||Do not know||Score|
|1||Are there previous conclusive reports on this reaction?||1||0||0|
|2||Did adverse drug reaction (ADR) appear after the suspected drug was administered?||2||-1||0|
|3||Did ADR improve when the drug was discontinued or a specific antagonist was administered?||1||0||0|
|4||Did the adverse reaction appear when the drug was readministered?||2||-1||0|
|5||Are there any alternative causes (other than the drug) that could have caused the reaction?||-1||2||0|
|6||Did the reaction reappear when placebo was given?||-1||1||0|
|7||Was the drug detected in the blood (or other fluids) in concentration known to be toxic?||1||0||0|
|8||Was the ADR more severe when dose was increased or less severe when dose was decreased?||1||0||0|
|9||Did the patient have a similar reaction to the same or similar drugs in any previous exposure?||1||0||0|
|10||Was the adverse event confirmed by any objective evidence?||1||0||0|
Severity criteria: The severity of the reaction as mild, moderate and severe was determined according to Hartwig Scale et al., 19 as given below (Table 2). Mild ADRs (Level 1, 2) were self limiting and able to resolve over time without treatment and do not contribute to prolongation of length of stay. Moderate ADRs (Level 3, 4, 5) were required therapeutic intervention and hospitalization prolonged by 1 day but resolved in 24 hrs or change in drug therapy or specific treatment to prevent a further outcome. Severe ADRs (Level 6, 7) were life threatening, producing disability and those that prolonged hospital stay or lead to hospitalization, required intensive medical care, or lead to the death of the patient (Table 2).
TABLE 2: HARTWIG SEVERITY SCALE - ACCORDING TO THIS SCALE ADRS WERE ASSESSED AS MILD (LEVEL 1, 2), MODERATE (LEVEL 3, 4, 5) AND SEVERE (LEVEL 6, 7)
|Level 1||An ADR occurred but required no change in treatment with the suspected drug.|
|Level 2||The ADR required that treatment with the suspected drug be held, discontinued, or otherwise changed. No antidote or other treatment requirement was required No increase in length of stay (LOS)|
|Level 3||The ADR required that treatment with the suspected drug be held, discontinued, or otherwise changed. AND/OR An antidote or other treatment was required. No increase in length of stay (LOS).|
|Level 4||(A) Any level 3 ADR which increases length of stay by at least 1 day. OR
(B) The ADR was the reason for the admission.
|Level 5||Any level 4 ADR which requires intensive medical care.|
|Level 6||The adverse reaction caused permanent harm to the patient.|
|Level 7||The adverse reaction either directly or indirectly led to the death of the patient.|
Predictability criteria: The Council for International Organizations of Medical Sciences guidelines for preparing core clinical-safety information on drugs was adapted for assessment of predictability 20. Patients who have had the drug on previous occasion(s): If the drug was previously well-tolerated at the same dose and route of administration, the ADR is not predictable; if there was a history of allergy or previous reactions to the drug, the ADR is predictable. Patients who have never had the drug previously: Incidence of the ADR reported in product information or other literature determines its predictability (Table 3).
- Preventability criteria: The criteria of Schumock and Thornton were modified to assess and categorize ADRs into definitely, probably or not preventable (Table 4) 21. The factor “toxic serum drug level” was omitted from the original criteria, and two questions (4 and 5, section B) on the use of preventative measures were added (Table 4).
TABLE 3: CRITERIA FOR DETERMINING PREDICTABILITY OF AN ADVERSE DRUG REACTION (ADR)
|S. No.||Incidence rate||Incidence Description||Predictability|
|2||≥1/100 and <1/10||Common||Predictable|
|3||≥1/1000 and <1/100||Uncommon||Not predictable|
|4||≥1/10,000 and <1/1000||Rare||Not predictable|
|5||<1/10,000||Very rare||Not predictable|
TABLE 4: CRITERIA FOR DETERMINING PREVENTABILITY OF AN ADVERSE DRUG REACTION (ADR) - MODIFIED SCHUMOCK AND THRONTON PREVENTABILITY SCALE
Answering “yes” to one or more of the following implies that an ADR is DEFINITELY preventable.
1. Was there a history of allergy or previous reactions to the drug?
2. Was the drug involved inappropriate for the patient’s clinical condition?
3. Was the dose, route, or frequency of administration inappropriate for the patient’s age, weight, or disease state?
If answers are all negative to the above, then proceed to Section B
Answering “yes” to one or more of the following implies that an ADR is PROBABLY preventable
1. Was required therapeutic drug monitoring or other necessary laboratory tests not performed?
2. Was a documented drug interaction involved in the ADR?
3. Was poor compliance involved in the ADR?
4. Was a preventative measure not administered to the patient?
5. If a preventative measure was administered, was it inadequate and/or inappropriate? Answer ‘NO’ if this question is nonapplicable.
If answers are all negative to the above, then proceed to Section C
The ADR is NOT preventable
Interview Sample: Total 663 patients associated with admissions were interviewed for this study. The interview sample comprised admissions of 277 women and 386 men whose age ranged from 1 to 76 years. The proportions and types of cancer at the time of admission were as below (Table 5).
TABLE 5 DIAGNOSIS DISTRIBUTION AT TIME OF ADMISSION
|Digestive system cancers||30.77%|
|Breast and Gynecology cancers||27.90%|
|Head & neck cancers||13.12%|
|Blood & Lymphatic system cancers||9.20%|
|Respiratory tract cancers||8.29%|
|Cancers of urinary system||4.37%|
Number of ADRs identified: Out of total 663 patients, 410 (61.84%) patients were detected with total 899 types of ADRs. Incidence of ADRs occurrence was higher in female patients – 68.23% (189 out of 277) than male patients – 57.25% (221 out of 386).
Types of ADRs identified: Total 53 different types of ADRs were detected from 23 drug categories. Out of those the most common reaction types (n=261) comprised 79.57% of ADRs identified (Fig. 1).
FIG. 1 THE MOST COMMON ADVERSE DRUG REACTIONS (ADRS)
Causality of ADRs: Majority of ADRs (68.41%) were assessed as probable in its causality. Causality of most common ADRs was as illustrated below (Fig. 2).
FIG. 2 CAUSALITY OF ADRS
Severity of ADRs: Majority of ADRs (69.30%) were assessed as mild in its severity. Severity of most common ADRs was as illustrated below (Fig. 3).
FIG. 3 SEVERITY OF ADRS
Preventability of ADRs: Over half (54.95%) of ADRs were assessed as not preventable, 43.05% probably preventable and 2% definitely preventable. For the most common ADRs, only three cases were assessed as definitely preventable - two cases of abdominal pain, which were caused by inappropriate NSAIDs doses, and one case of diarrhoea, which was caused by simultaneous use of three laxatives. High proportions of constipation, nausea, vomiting, diarrhoea and mucositis were assessed as probably preventable. Alopecia and anorexia were always assessed as not preventable (Fig. 4).
FIG. 4 PREVENTABILITY OF ADRS
Predictability of ADRs: Majority of ADRs (87.54%) were assessed as predictable. Predictability of most common ADRs was as illustrated below. (Fig. 5)
FIG. 5: PREDICTABILITY OF ADRS
DISCUSSION: It is clear from the results that ADRs are common in hospitalised oncology patients. Comparatively, figures from this study are higher than those reported in the 1992 Australian National Hospital Morbidity Data because of the difference in methods of event identification 8.
The national database is a collection of confidential summary records for admitted patients separated from public and private hospitals in Australia, while the data from this study were obtained through personal interviews with patients and comprehensive review of patients’ medical records. This method clearly resulted in the identification of more ADRs.
When a predictable ADR occurs, questions should be raised about whether it is preventable and if so, whether known preventative measures have been used in an appropriate, adequate and timely manner. Using the modified Schumock and Thornton criteria, very few ADR incidents in this study were definitely preventable, and reactions such as fatigue, alopecia and anorexia were mostly assessed as not preventable. On the other hand, almost half of the ADRs were probably preventable, for example, constipation, nausea, vomiting, dermatological reactions, diarrhoea and mucositis. Opiates were the apparent cause of the majority of the constipation incidents, all of which were predictable and almost 90% classified as probably preventable.
It was very clear from the study data that constipation was common as a result of opiates being initiated or administered without a concurrent prophylactic laxative or in some cases; prophylactic laxatives were being administered at too low a dose. The situation was similar with nausea and vomiting. Anti-neoplastics were the apparent cause of the majority of the nausea and vomiting incidents (69.4%), all of which were predictable and almost 60% of which were probably preventable.
In contrast, although the majority of the fatigue incidents (81.1%) caused by the administration of antineoplastic were predictable, over 90% were not preventable. Of significance in terms of improving patient care is the finding that common reasons for ADRs to be assessed as probably preventable were omission of or inappropriate or inadequate use of known preventative measures.
CONCLUSION: Chemotherapeutic drugs have narrow therapeutic index and the dosage needed to achieve a therapeutic response usually proves toxic to the body’s rapidly proliferating cells. So, the ADR is common in most of the cancer patients.
There are however many occasions where improved use of preventive measures has the potential to contribute to reducing the severity of ADR. An understanding and appreciation of patient’s perceptions of these events will help health care professionals prioritize targeted interventions and prevention strategies.
Results of this study further emphasized the need of ADR monitoring in a Day care chemotherapy department at cancer institute. The process of defining and concluding about ADRs should be continuous and ongoing to keep a record of newly marketed drugs and medicinal products. More over strict drug analyzing and in vivo study is also required if feasible.
ACKNOWLEDGEMENT: I would like to express my sincere gratitude to the Dean of GMCH & BBCI who allowed me for this research work. I dedicate this work to my project partner, who supported me deeply till the completion of project.
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How to cite this article:
Mrugank BP and Hareesha RP: Prospective Observational, Non-Randomized, Parallel Sequence study for assessment of Adverse Drug Reactions due to Chemotherapeutic treatment in different types of Cancer patients. Int J Pharm Sci Res. 2013; 4(1); 386-391.
Mrugank B.P. *and Hareesha R.P.
Clinical Research Scientist, Division of Research and Development, Alembic Pharmaceuticals Limited, Vadodara, Gujarat, India
19 September, 2012
12 October, 2012
27 December, 2012
01 January, 2013