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

Background: Cancer is a highly debilitating non-communicable disease and an essential contributor to the global burden of disease. Pediatric patients are highly exposed to multiple drugs for the management of cancer. Monitoring drug utilization patterns helps to provide feedback to healthcare providers to ensure the rational use of medicines; as a result, it increases the therapeutic efficacy and decreases the frequency and severity of adverse drug reactions (ADRs). Therefore, this study assessed the utilization pattern and ADRs of chemotherapy in pediatric patients at Muhimbili National Hospital (MNH). Methods: A descriptive cross-sectional study was conducted for three months from February to April 2021 in pediatric cancer patients undergoing chemotherapy at MNH. A total of 123 children diagnosed with cancer and on chemotherapy were enrolled in this study. Patients’ socio-demographics, clinical information, chemotherapy status, prescribed medications, and prevalence of ADRs were collected. Descriptive statistics was used in data analysis, whereby frequency and proportions were used to summarize data. Results: Out of 123 patients, 62.6% were male. Most patients received an average of four anticancer drugs. Vincristine (55.3%) was the most used anticancer drug, followed by cytarabine (44.7%) and methotrexate (42.3%). The most used adjuvant drugs were ondansetron (30.9%), hydrocortisone (27.6%), and piperacillin/tazobactam (23.6%). The percentage of drugs prescribed from the Tanzania Essential Medicine List (TEML) and World Health Organization (WHO) list was 66.4% and 93%. Most (87%) of the patients reported having experienced ADRs whereby nausea and vomiting (45.8%), hair loss (33.6%), and neutropenia (32.7%) were more prevalent ADRs reported. Conclusions: This study found the drug prescribing pattern to be in line with the essential medicine list, but the average number of drugs prescribed was higher than recommended. ADRs were prevalent among pediatric cancer patients.

methotrexate (42.3%).The most used adjuvant drugs were ondansetron (30.9%), hydrocortisone (27.6%), and piperacillin/tazobactam (23.6%).The percentage of drugs prescribed from the Tanzania Essential Medicine List (TEML) and World Health Organization (WHO) list was 66.4% and 93%.Most (87%) of the patients reported having experienced ADRs whereby nausea and vomiting (45.8%), hair loss (33.6%), and neutropenia (32.7%) were more prevalent ADRs reported.Conclusions: This study found the drug prescribing pattern to be in line with the essential medicine list, but the average number of drugs prescribed was higher than recommended.ADRs were prevalent among pediatric cancer patients.

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. 3As 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 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. 6The 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. 7,8Cancer 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. 9st 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. 10e 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. 5Moreover, 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. 11Therefore, this study assessed the drug utilization pattern and reported ADRs among pediatric cancer patients at Muhimbili National Hospital (MNH).

Study design
This hospital-based descriptive cross-sectional study was conducted from February to April 2021.

Study area
The study was conducted at MNH which is the National Referral Hospital, a research center and university teaching hospital with 1,500 bed facility, attending 1,000 to 1,200 outpatients per day, admitting 1,000 to 1,200 inpatients per week.There are five government referral hospitals for dealing with cancer which are Muhimbili National Hospital, Ocean Road Cancer Institute, The Benjamin Mkapa Hospital, Mbeya Zonal Referral Hospital, Kilimanjaro Christian Medical Centre and Bugando Medical Centre which are mainly specialized in adult and pediatric malignancies.MNH has a special ward known as the Pediatric oncology ward that attends 60 to 70 pediatric cancer patients per month.

Study population
The study was carried out on pediatric cancer patients admitted to the pediatric oncology ward and diagnosed with malignancy during the study period.The list of eligible participants was obtained from Tumaini and Upendo wards registers at MNH.These patients were then followed in their admission cubes whereby the parents or guardians who attend to them were told the details of the study.The consent was requested from parents followed by assent from children.

Inclusion and exclusion criteria
All pediatric cancer patients receiving chemotherapy, aged less than 18 years old were included in the study.Exclusion criteria were patients whose diagnosis has not been well established and those with incomplete records in their files.

Sample size and sampling
A total of 126 patients were enrolled in the study.The estimated sample size N was computed using Kish and Leslie formula given below: Z is percentage point of the normal distribution corresponding to the level of significance <5%, Therefore, Z = 1.96.P = Proportion of pediatric cancer patients on chemotherapy, from a study done in northern Tanzania on pediatric cancer patients, whereby a proportion of 93% was reported. 5= margin of error, which is approximately 5%.
Systematic random sampling was used to select 126 patients out of the 240 patients.The IDs of 240 patients fulfilling the inclusion criteria were entered in Microsoft Excel followed by systematic random sampling whereby the sampling interval was 2.

Data collection
A structured questionnaire was used to collect data.This tool was adapted from previous studies by Bepari et al and Kamlekar et al 12,13 with addition of demographic information to reflect the Tanzania context.The questionnaire consisted of socio-demographic information, clinical characteristics of the patients, drugs used, and reported ADRs.Patient sociodemographics included age, gender and residence.Clinical characteristics included the admission date, referral status, diagnosis, comorbidities, body mass index (BMI), hemoglobin levels.In addition, both anticancer, adjuvants drugs used and side effects at the time of data collection were recorded.The data collection tool can be found as Extended data. 28ta management and statistical analysis Data collected was entered, cleaned, and analyzed using Statistical Package for Social Sciences (SPSS, RRID: SCR_016479) version 24, and R statistical software version 4.0.3(RRID:SCR_001905) was used for plotting.The data was summarized using frequency distribution and proportion.The continuous variables were summarized using median and interquartile range (IQR).The R scripts used in the analysis can be found as Extended data.

Ethical considerations
Ethical clearance with reference number DA.25/11/01/dated 28 th January 2021 was obtained from the Muhimbili University of Health and Allied Sciences (MUHAS) Institutional Review Board (IRB).Permission to collect data from the hospital was obtained from the MNH administration.A signed informed consent was obtained from all parents/ guardians before interview followed by assent obtained verbally from older children who were asked whether they would like to participate in the study and they said either a yes or no as an assent.For younger children 1-6 years which were majority of the study population, consent from the patient was enough for participation.Privacy and confidentiality were highly observed in data collection and person identifying information was not collected from the patient's files.

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. 28Of the 3 excluded one refused to participate in the study and 2 had incomplete information in their files (Figure 1).

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).

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).

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. 14,15e 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. 16This is comparable with the range of 6.0-6.9 which was reported in previous studies. 12,13The 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. 12,13This 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. 17e 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. 18,19After 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. 20imilar findings were reported in Ethiopia whereby 85.4% of the pediatric patients were using vincristine. 14The results differ from those obtained from the adult population in India in which carboplatin was the most prescribed drug, followed by paclitaxel and gemcitabine. 12Also, 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 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 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. 23The 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. 24Furthermore, 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 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. 26,27This 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.

Paola Muggeo
Department of Pediatric Oncology and Hematology, University Hospital of Policlinic, Bari, Italy The Authors report data about childhood cancer in Tanzania and the use of antineoplastic drugs, together with the ADRs.The importance of this paper is to report incidence and outcome of childhood cancer in a developing Country, which is the first step to work for a better medical support and outcome.However the paper needs major adjustment to be improved.First of all, about methods.Diagnosis: the authors report that the most frequent diagnosis is Wilms' tumor, which is a noteworthy result since it may depend on differences in genetic background, being this tumor a genetically influenced cancer.However diagnosis should be categorized according to international WHO classification.Moreover how is the diagnosis and staging of disease performed?This should be reported in the methods.The modality of drug association and delivery should be detailed.Are there any prescribed protocols to administer polychemotherapy?which is the basis to deliver polychemotherapy?usually standardized protocols should be used.If this is the case, they should be cited in the methods.
Results: The authors conclude about irrational medicine use, however in the field of polychemotherapy detailed protocols guide the correct use of antitumor drugs based on mechanism of action, pharmacokinetics, and pharmacodynamics.Is the 30% survival rate caused by poor response to chemotherapy or to severe side effects (such as infectious complication or other severe side effects).In other words, is there any possibility to check the tumor response after chemotherapy?
The paper needs major reorganization to offer a key of interpretation of an important and urgent problem in developing Countries.

Is the work clearly and accurately presented and does it cite the current literature? Partly
Is the study design appropriate and is the work technically sound?

Are sufficient details of methods and analysis provided to allow replication by others? Partly
If applicable, is the statistical analysis and its interpretation appropriate?I cannot comment.A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?Partly

Are the conclusions drawn adequately supported by the results? No
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: pediatric hematolgy and oncology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.Results: 2.
It would be good to know what proportion of patients were underweight or malnourished rather than the median weight.

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The term bone marrow malignancy is vague as solid tumors like neuroblastoma and lymphomas can disseminate to marrow too.The term 'leukemias' may be better and also represent the disease site well.

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It is interesting to note that Wilms tumor surpassed B cell ALL in being the commonest malignancy.Do the authors have an explanation for this? ○ Was any grading system like CTCAE used for adverse events?It would be good to know the proportion of severe or grade 3 or 4 toxicity.

○
All scientific terms in results must be predefined in methods.For example, anemia and neutropenia must be defined with the cut-off used.Again, this reiterates the need to use a classification system like CTCAE or an indigenous system if used by the center, for all toxicity events.
○ Since the study is aimed at evaluating drug utilization and capacity building there should be more details on the route of administration and doses.This is particularly relevant for drugs such as methotrexate which can be administered orally, intravenously, and intrathecally.Drugs such as methotrexate and cytarabine can be administered at high doses and low doses, and the corresponding vial strengths needed would be different.

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With this large sample size, one would like to know of treatment-related mortality during the study period.How many patients succumbed to adverse events of chemotherapy and what were the specific etiologies?

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The term 'adjuvant therapy' in oncology typically refers to the cytotoxic therapy that follows local therapy in a solid tumor.'Supportive care' medication is an alternative term.Again, the authors must define what constitutes adjuvant therapy in the methods section, with a brief description of the center's supportive care protocols.There is no mention of antimicrobial prophylaxis such as co-trimoxazole which would be an indispensable part of supportive care.The indication of steroids such as hydrocortisone must be mentioned, as they can be part of the chemotherapy regimen too.

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Figure 3: the side effects that comprise 'others' must be listed in the legend or in the main text.A singular unexpected or severe adverse event would be as important as a common adverse event.○ 3.It would be interesting to see if there was an unavailability of any specific drug during the study period that led to a delay in therapy, or a need to modify the regimen to exclude or replace the unavailable drug.

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility?

Are the conclusions drawn adequately supported by the results? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Pediatric Hematology Oncology practice in a low-and middle-income country, supportive care, thalassemia, common childhood cancers I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Divya Subramonian
Department of Pediatrics, Division of Hematology-Oncology, University of California, San Diego, CA, USA In this article, the authors have addressed a critical and important issue by looking at drug utilization and adverse drug reactions in pediatric cancer patients.The authors have provided a clear and sound introduction covering relevant literature.The paper is well presented and could be used as a good tool for clinicians and researchers while prescribing drugs to pediatric patients.

Methods:
Although the study was done only in one hospital, the sample size, distribution between male and female, and distribution of age group seems reasonable.The process of sample collection is clear with inclusion and exclusion criteria.However, it would be great if the authors can address this: Is there a reason for collecting data during the mentioned 3-month period (Feb-April 2021)?Is it possible to include/get data for a longer period of time? ○

Results:
The tables are well presented, taking into consideration the demographic and clinical characteristics of the patients.The chemotherapy and adjuvant medications are well tabulated indicating the frequency of intake.The figures give a clear representation of the cytotoxic drugs used in the study pointing out the most commonly used ones.The most common side effects are also shown in Figure 3.All of this information can be used as a reference for physicians and researchers alike.
Nevertheless, it would be nice to have a couple of things addressed/discussed.In Table 1, the number of males and females does not add up to 123.I believe the numbers 77 males and 23 females should be revisited.
○ This is probably beyond the scope of the paper, but it would be nice to see the number or percentage of pediatric patients recovering from the disease given the adverse effects.
○ Discussion: As the clinical treatment of pediatric patients has changed significantly over the last few decades, this study points out the adverse effects the drugs have on patients.
It would be useful if the authors can address how long the side effects last and discuss a little bit about the risk-benefit analysis for the most commonly used chemotherapy drugs.

○
It is alarming to note that the average number of drugs prescribed per prescription is 7, which is several times higher than recommended by WHO.Finally, do the authors have a hypothesis for this discrepancy and if that is true in other parts of Tanzania and the world?A little more insight on this would be a great eye-opener.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound?Yes

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate?I cannot comment.A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?Yes

Are the conclusions drawn adequately supported by the results? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Pediatric Cancer -Neuroblastoma I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
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Reviewer Report 13
April 2024 https://doi.org/10.5256/f1000research.121654.r261864Introduction: The first paragraph on cancer can focus more on childhood cancer rather than describing what cancer is.It would be good to mention the global initiative for childhood cancer from the World Health Organization to set the stage for a study on children being treated for cancer.1.

Reviewer
Report 05 May 2022 https://doi.org/10.5256/f1000research.121654.r136029© 2022 Subramonian D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Table 2 .
Clinical characteristics of the study patients (n = 123).
ALL Acute Lymphoblastic Leukemia, ALCL Anaplastic Large Cell Lymphoma.