Drug utilization pattern and adverse drug reactions of chemotherapy in pediatric patients at Muhimbili National Hospital, Tanzania

Introduction

Cancer is a non-communicable disease (NCD) that reduces the quality of life.¹ It is a group of diseases that involves abnormal cell growth that invades or spreads to other parts of the body.² Cancer is a disease of public health importance, and it is reported to be among the leading causes of death globally in both developing and developed countries.³ As per the World Health Organization (WHO) survey report, the global cancer incidence in 2012 increased to 14 million new cases. It is estimated that the incidence may rise to 19.3 million by 2025.⁴ Worldwide, an estimated number of 250,000 children are diagnosed with cancer yearly, whereby most diagnoses occur in low and middle-income countries.⁵

In Tanzania, the incidence of pediatric cancer is unknown due to the lack of a national cancer registry, but it has been estimated to be at 134 occurrences per million.⁶ The likelihood of surviving a diagnosis of childhood cancer depends on the country; more than 80% of children with cancer are cured in high-income countries while in low-middle income countries only 30% are cured.^7,8 Cancer has contributed to 5.1% of all in-hospital deaths in Tanzania in 2006-2015. The mortality rate was 47.8 per 100000 population and the number of deaths was high among individuals 15-59 years of age.⁹

Most used chemotherapy agents in cancer are cytotoxic, meaning that they function by killing fast-dividing cells. The most immediate adverse drug reactions (ADRs) of chemotherapy are due to the cytotoxic effect on the normal cells. Cancer chemotherapy's common ADRs include hair loss, nausea and vomiting, anemia, febrile neutropenia, thrombocytopenia, tiredness, confusion, mood changes, tingling, burning, weakness, numbness, and pain in the hands and feet and mucositis.¹⁰

The utilization pattern of anticancer drugs has changed significantly in recent years because of better enhancement in carcinomas' pathophysiology and the introduction of newer drugs. Significant inter-individual variability in the response rate of anticancer drugs, availability of different regimens, and combination regimens intolerability necessitate monitoring and evaluation of cancer chemotherapy.

Like many other low- and middle-income countries, the pediatric cancer outcomes in Tanzania are poor, and there are limited diagnostic and treatment capacities.⁵ Moreover, it is unknown whether pediatric cancer patients are being managed rationally in Tanzania. Poor drug utilization among pediatric cancer patients will increase the occurrence of drug toxicity and ADRs hence decreasing the survival rates even further.¹¹ Therefore, this study assessed the drug utilization pattern and reported ADRs among pediatric cancer patients at Muhimbili National Hospital (MNH).

Methods

Results

Baseline characteristics

Overall, 240 patients were potentially eligible for the study. Systematic random sampling using Microsoft Excel was used to select 126 patients. Of the 126 patients, 123 were eligible and included in the final analysis and 3 patients were excluded.²⁸ Of the 3 excluded one refused to participate in the study and 2 had incomplete information in their files (Figure 1).

Figure 1. Study flow chart.

Out of the 123 patients, the majority (62.6%, n = 77) were male. The median age was 5.2 (IQR = 6.4) years with half of patients (50.4%, n = 62) in the range of 0 – 5 years. The median weight was 16.7 (IQR = 10.4) kg, and almost half of the patients (48.8%, n = 60) were diagnosed in 2020. Based on hematological parameters, the median hemoglobin (Hb) level was 9.6 (IQR = 2.9) g/dl, median absolute neutrophil count (ANC) was 2.3 (IQR = 3.5) and the median platelet count (PLT) was 288 (IQR = 251). Most patients (79.3%, n = 98) were from regions outside of Dar es salaam (Table 1).

Table 1. Demographic and clinical characteristics of the study patients (n = 123).

Characteristics	Number of patients (%)
Residence
Dar es Salaam	25 (20.7)
Tanga	14 (11.6)
Pwani	10 (8.3)
Other regions	74 (59.4)
Sex
Male	77 (62.6)
Female	23 (37.4)
Age category
0 – 5 Years	62 (50.4)
6 – 10 Years	41 (33.3)
11 – 18 Years	20 (16.3)
Diagnosis year
2018	1 (0.8)
2019	5 (4.1)
2020	60 (48.8)
2021	57 (46.3)
Age in years (Median, IQR)	5.2 (6.4)
Weight in kg (Median, IQR)	16.7 (10.4)
Hb Levels in g/dl (Median, IQR)	9.6 (2.9)
ANC (Median, IQR)	2.3 (3.5)
PLT (Median, IQR)	288 (251)

Most patients (64.1%) had bone marrow and kidney malignancies with the prevalence of 30.1% (n = 37) and 27.6% (n = 34), respectively. The most dominant tumors were Wilms Tumor with 23.6% (n = 29) followed by B Cell Acute Lymphoblastic Leukemia (B Cell ALL) (17.1%) and Burkitt Lymphoma (17.1%) (Table 2).

Table 2. Clinical characteristics of the study patients (n = 123).

Characteristic	Number of patients (%)
Diagnosis
Wilms Tumor	29 (23.6)
B cell ALL	21 (17.1)
Burkitt Lymphoma	21 (17.1)
Retinoblastoma	18 (14.6)
T cell ALL	15 (12.2)
Hodgkin Lymphoma	12 (9.8)
Astrocytoma	4 (3.3)
Neuroblastoma	3 (2.4)
Ewing sarcoma	3 (2.4)
Xeroderma Pigmentosa	3 (2.4)
Rhabdomyosarcoma	2 (1.6)
Sacrococcygeal Teratoma	2 (1.6)
Squamous Cell Carcinoma	2 (1.6)
ALCL	1 (0.8)
Dysgerminoma	1 (0.8)
Hepatoblastoma	1 (0.8)
Nasopharyngeal Carcinoma	1 (0.8)
Disease site
Bone Marrow (BM)	37 (30.1)
Kidney	34 (27.6)
Orbit	16 (13.0)
Neck	13 (10.6)
CNS	4 (3.3)
Jaw	5 (4.1)
Abdomen	1 (0.8)
Other (Bones, Genital, Muscles and Skin)	13 (10.6)

Drug utilization pattern

The average number of drugs prescribed per prescription was 7 and the average number of cytotoxic drugs prescribed per prescription was 4. The percentage of drugs prescribed from the National Essential Medicines List (NEMLIT) and WHO Model Lists of Essential Medicines was 66.4% and 93%, respectively. More than a quarter (30.4%) of the prescribed drugs were injectables, 93.9% were prescribed using generic names and 19.0% of the medications were antibiotics. The most used class of anticancer agents were the antimetabolites (31.9%, n = 138) followed by vinca alkaloids (17.6%, n = 76) and antitumor antibiotics (17.4%, n = 75) (Figure 2). Enzyme cytotoxic drugs were the least used 5.1% (n = 22). The commonly used anticancer drugs were Vincristine (55.3%, n = 68), followed by Cytarabine (44.7%, n = 55) and Methotrexate Injection (42.3%, n = 54) (Table 3).

Figure 2. Cytotoxic drugs used in cancer treatment (n = 432).

Table 3. Functional classification of chemotherapy medications (n = 432 prescriptions).

Functional classification	Frequency (%)	Chemotherapy medication	Frequency (%)
Alkylating agents	49 (11.3)	Cyclophosphamide	33 (26.83)
		Darcabazine	8 (6.50)
		Ifosfamide	8 (6.50)
Antitumor antibiotics	75 (17.4)	Doxorubicin	40 (32.52)
		Actinomycin D	15 (12.2)
		Bleomycin	10 (8.13)
		Actinomycin B	2 (1.63)
		Daunorubicin	8 (6.50)
Antimetabolites	109 (31.9)	Cytarabine	55 (44.71)
		Methotrexate	54 (42.28)
Enzyme	22 (5.1)	L-asparaginase	22 (17.89)
Platinum compounds	37 (8.6)	Carboplatin	30 (24.39)
		Cisplatin	7 (5.69)
Topoisomerase	35 (8.1)	Etoposide	35 (28.46)
Vinca alkaloids	76 (17.6)	Vincristine	68 (55.28)
		Vinblastine	8 (6.50)

Various adjuvants were given whereby the most commonly used adjuvants were antiemetic ondansetron injection (30.9%, n = 38), followed by steroids hydrocortisone injection (27.6%, n = 34) and cytoprotective agents such as dexrazoxane 24 (19.5%, n = 24) and mesna (21.9%, n = 27) (Table 4).

Table 4. Functional classification of adjuvant medications (n = 432 prescriptions).

Functional classification	Adjuvant medication	Number of prescriptions (%)
Antibiotics	Piperacillin/tazobactam	29 (23.58)
Antiemetics	Ondansetron	38 (30.89)
Antihistamines	Cetirizine	14 (11.38)
Cytoprotective	Mesna	27 (21.95)
	Dexrazoxane	24 (19.51)
Laxatives	Lactulose	19 (15.45)
Proton Pump Inhibitor (PPI)	Pantoprazole	7 (5.69)
Steroids	Hydrocortisone	34 (27.64)
	Dexamethasone	12 (9.76)
	Prednisolone	6 (4.88)
Supplements	Folinic acid	7 (5.69)
Others	Benylin cough syrup, Maalox antacid syrup and Xylocaine local anaesthetic (BMX*)	11 (8.94)
	Furosemide	1 (0.81)

* Compounded in ratio of 4:4:1, Benylin cough syrup 100 mls, Maalox antacid syrup 100 mls and Xylocaine local anaesthetic 25 mls.

Reported adverse drug reactions

Over three-quarters of the patients (87%) reported having experienced ADRs upon using chemotherapy medications. The most prevalent ADRs were nausea and vomiting reported by almost half of the study patients (45.8%) followed by hair loss and neutropenia with the prevalence of 33.6% and 32.7%, respectively (Figure 3).

Figure 3. Side effects reported among pediatric cancer patients (n = 123).

Discussion

Assessment of drug utilization pattern is important as it provides information that will help in promoting the rational use of medication. Unlike the adult population, there is limited information on drug utilization pattern and ADRs experienced by pediatrics undergoing cancer chemotherapy in Tanzania. Therefore, this study assessed drug utilization pattern and reported ADRs of chemotherapy among pediatric cancer patients undergoing chemotherapy at MNH.

In this study the most predominant malignancies were Wilms Tumor, B Cell Acute Lymphoblastic Leukemia, Burkitt Lymphoma and Retinoblastoma. This is comparable to a study by Schroeder et al. which reported on the most prevalent pediatric cancers in northern Tanzania were Burkitt Lymphoma 18% and Wilms tumor 14%.⁵ Similar malignancy types among pediatric patients have also been reported in other African countries.^14,15

The average number of drugs prescribed per prescription in this study was 7 which is higher than the WHO recommended range of 1.6 – 1.8.¹⁶ This is comparable with the range of 6.0-6.9 which was reported in previous studies.^12,13 The average number of cytotoxic drugs prescribed per prescription was 3.5 which is higher than a study by Sandeep et al. and Bepari et al. in which it was 1.94 and 1.27, respectively.^12,13 This could be explained by differences in prescribing pattern from country to country influenced by existing cancer management guidelines, medicines availability, clinicians’ preferences, cost of medicines, diseased population, and disease status in the area.¹⁷

The percentage of drugs prescribed from NEMLIT and WHO Model Essential Medicines List were 66.4% and 93.0%, respectively. The discrepancy observed in compliance to these two lists is attributed by the fact that the NEMLIT used during the study was not updated since 2017 compared to the WHO Essential Medicines List which has been updated in 2019.^18,19 After the study completion there was a release of updated NEMLIT in 2021 whereby most drugs have now been included in the management of cancer in pediatric patients.

In this study vincristine was the most used anticancer drug, followed by cytarabine and methotrexate which are both antimetabolites. Vincristine is the drug for most pediatric malignancies which was the target population in this study.²⁰ Similar findings were reported in Ethiopia whereby 85.4% of the pediatric patients were using vincristine.¹⁴ The results differ from those obtained from the adult population in India in which carboplatin was the most prescribed drug, followed by paclitaxel and gemcitabine.¹² Also, they differ to those in another study conducted in India by Vijayalakshmi et al. on drug utilization pattern reported that cisplatin 58% and 5-fluorouracil 41% were most prescribed among all anticancer drugs, followed by doxorubicin.²¹

In our study the most used adjuvant drugs were ondansetron, hydrocortisone and piperacillin/tazobactam. This is comparable to other studies in which similar adjuvants were also found to be commonly used for reduction of the ADRs of chemotherapy medications.^12,13,22

In the present study, over three-quarters (87%) of the study patients, reported to have experienced at least one side effect upon using chemotherapy medications. This is comparable to a study by Pearce et al. which looked at the incidence and severity of self-reported chemotherapy side effects in routine care in which 86% of the study patients reported at least one side effect during the study period.²³ The findings are also comparable to a cross-sectional national survey done in the U. S by Henry et al. in which 88% of the study patients reported at least one side effect.²⁴ Furthermore, a study done in Kenya by Opanga et al. looking at side effects of chemotherapy 93 % of the study reported to have experienced at least one side effect during chemotherapy treatment.²⁵

In our study the most prevalent side effects were nausea and vomiting, which were reported by about half of the study patients, followed by hair loss and neutropenia. This is comparable to the studies conducted in Malaysia and India, where the most common side effects of anticancer drugs included nausea and vomiting, hair loss, loss of appetite, and tiredness or weakness.^26,27 This could be explained by the fact that most anticancer drugs are associated with nausea and vomiting.

This study is limited in its scope to a single institution. However, MNH being the only national hospital has capacity in terms of human resources and technology required in management of cancer patients in the country. Therefore, information obtained from this center provide the best indicator of the drug utilization pattern and ADRs experienced by pediatric cancer patients in the country. Some important information was missing in the patients’ files and prescriptions like duration of treatment, height and weight of patients, hence limiting patients’ enrollment in the study. Moreover, factors influencing prescription patterns by the clinicians were not examined.

Conclusions and recommendations

The prescribing pattern among the pediatric cancer patients at MNH was highly adherent to the WHO Model Essential Medicines List. However, the average number of drugs per prescription was very high. Vincristine was the most used anticancer drug and ondansetron was the most used adjuvant drug. The prevalence of side effects was very high indicating a need for improvement in prescribing for pediatric cancer patients to avoid ending up in irrational medicine use which could hinder the achievement of the treatment goals.

Since the average number per prescription was very high, we recommend multidisciplinary teamwork between prescribers and dispensers to reduce polypharmacy which could in turn can improve the management of pediatric cancer patients. Moreover, high prevalent of ADRs among these patients requires a vigilant ADR monitoring system to ensure early detection, management and reporting of ADRs experienced by pediatric cancer patients.

Data availability