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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 2  |  Page : 76-81

Prescription pattern of drugs in pediatric cancer patients in a tertiary care hospital: An observational study


1 Department of Pharmacology and Therapeutics, Seth G S Medical College and KEM Hospital, Mumbai, Maharashtra, India
2 Department of Paediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission12-May-2021
Date of Decision17-Jun-2021
Date of Acceptance01-Jul-2021
Date of Web Publication21-Aug-2021

Correspondence Address:
P S Manjesh
Department of Pharmacology and Therapeutics, Seth G S Medical College and KEM Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_20_21

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  Abstract 


Aims: The objective of the current study was to evaluate prescription pattern and to assess off-label use of drugs used in treatment of pediatric cancer patients. Subjects and Methods: This was a cross-sectional, observational study where patients who presented to the hemato-oncology and solid tumors Outpatient department at a tertiary cancer care hospital were prospectively recruited. Patients of either gender or age between 3 months and 15 years diagnosed with cancer and who has received treatment for at least 6-week duration were included. Demographic details, diagnosis, medication details, and off-label use were analyzed. Prescribing indicators and off-label use were analyzed by descriptive statistics using Microsoft Excel version 2019. Results: Of 300 patients recruited, 67% were male and 33% were female, with a median age of 75 months (interquartile range: 42–129 months). One hundred and seventy-one (57%) patients suffered from hematological cancers, while those having solid tumors were 129 (43%). Most common hematological cancer was found to be acute lymphoblastic leukemia – 126/171 (73.68%) and among 129 solid tumor patients, the most common cancer was found to be Ewing's sarcoma (29). A total number of 944 drugs were prescribed in 300 prescriptions studied. Out of 944 drugs prescribed, 346 (36.65%) were anticancer drugs and 598 (63.35%) were concomitant drugs. Most common anticancer drug prescribed in hematologic cancer was found to be vincristine (60/270), and in solid tumors also, it was vincristine in 24/76. Off-label prescriptions were found mainly in solid tumors in 80.26% (61 out of 76 anticancer drugs), whereas for hematological cancers, it was 3.33% only. The most common drug use off label in solid tumors was Cyclophosphamide. Conclusions: The study reflects the general pattern of drugs used in the treatment of various pediatric cancers and the extent of unavailability of chemotherapeutic agents – more so in the solid tumors' treatment.

Keywords: Hematological malignancy, off-label, pediatric cancer, solid tumors


How to cite this article:
Manjesh P S, Shetty YC, Chinnaswamy G, Patankar PS. Prescription pattern of drugs in pediatric cancer patients in a tertiary care hospital: An observational study. Oncol J India 2021;5:76-81

How to cite this URL:
Manjesh P S, Shetty YC, Chinnaswamy G, Patankar PS. Prescription pattern of drugs in pediatric cancer patients in a tertiary care hospital: An observational study. Oncol J India [serial online] 2021 [cited 2021 Oct 22];5:76-81. Available from: https://www.ojionline.org/text.asp?2021/5/2/76/324231




  Introduction Top


Cancer is one of the major causes of mortality and morbidity in the world. According to the WHO, it is the second leading cause of death globally. In 2018, approximately 9.6 million deaths were attributed to it globally which implies that nearly 1 in 6 deaths was due to cancer.[1] In India, about 5.3% of the total deaths reported are due to cancer. Of these, 2.6% have been attributed to the age group of 0–15 years.[2] The proportion of childhood cancers relative to all cancers reported by Indian cancer registries varied from 0.8% to 5.8% in boys and from 0.5% to 3.4% in girls. Commonly occurring pediatric cancers include leukemia and lymphoma in boys, whereas it is leukemia and brain tumors among girls of 0–15 years of age.[3] As evident, it is a substantial problem both globally and nationally which warrants effective interventional strategies.

Pediatric cancer is a specialized branch and many of the therapies are simply being extrapolated from adults' therapies. There are evidence-based medicine approaches researched and followed by the academia. However, as sponsors are not interested in conducting research in such regimens, many times everything becomes off-label therapy for pediatric cancer patients.

Prescription studies related to cancer are limited in India. Furthermore, there have been no studies involving the off-label use of anticancer drugs and other drugs used to treat cancer patients in India, whereas it is a known fact that such practice is widespread, more so in the pediatric population.[4] Off-Label use essentially means the clinical practice of prescribing medicines outside the terms approved by the regulatory authority in the prescribing information (PI). Off-Label use of drugs may be in terms of dose, dosage form, route of administration, age, or indication.[5]

A study conducted in China revealed that off-label use of anticancer drugs was common in their hospitals and that prescribing physicians should duly consider the adverse drug reactions and contraindications before prescribing and also to increase the drug security monitoring.[6] In USA, such studies have been done and reported that though there is increased off-label prescribing, most often such use of anticancer drugs is supported by the National Comprehensive Cancer Network.[7],[8] Hence, rates of off-label use vary with the country of labeling, the type of tumor, the evolution of the disease, the availability of effective marketed treatments, and the anticancer agent. Off-label drug use in cancer therapy is commonly practiced but outcomes could vary significantly. Hence, greater scrutiny about its use and based on it, clinical guidance is needed to establish the favorable benefit-risk ratio for patients at the time of prescribing at each level of oncology care to facilitate rational off-label prescribing.[9]

In India, a questionnaire-based survey on the prescribing practices of ten important drugs used in cancer has been done which yielded limited information.[10] Apart from it, no observational study has been conducted on the current subject. Hence, an observational study was planned to evaluate the prescription pattern and the off-label use of drugs used in treatment of pediatric cancer patients in a tertiary cancer care facility.


  Subjects and Methods Top


The study was a cross-sectional and observational study conducted in a tertiary cancer care hospital after getting approval from IECs with IEC approval numbers IEC EC/99/2017 and IEC/0318/1976/001. The Clinical Trials Registry-India (CTRI) registration number is CTRI/2018/01/011263. Patients of either gender or age between 3 months and 15 years diagnosed with cancer and who has received treatment for at least 6 weeks duration were included. The sample size calculated was as per the principles of the rational use of medicines (n = 300).[11] Patients, who came to the hemato-oncology outpatient department (OPD) and solid tumors OPD in morning hours between 9 am and 12 am for consultation and fulfilled the eligibility criteria, were approached by the investigator, were counseled about the study and consent obtained. The study duration was for 18 months (May 2018–October 2019) which included screening, recruitment of participant, and data analysis. Patient details were anonymized and demographic details such as registration number, age, and gender were captured. Diagnosis with the stage of the disease and medication details as listed in the OPD case notes were recorded in the case record form. His/her prescription was reviewed for the profile of drugs and its details with the diagnosis were determined. Prescribing indicators were evaluated as per WHO prescribing indicators.

Off-label use of drugs was analyzed by referring to the PI on the package insert of the drug approved by Drugs Controller General of India. Off-label use was analyzed in terms of indication, dose, dosage form, frequency, and route of administration. All the study records were kept confidential, and the privacy of participants' data was maintained.

Statistical analysis plan

Demographic data that were continuous (age) expressed as median and range. Categorical data (Gender) were expressed as percentage. Prescribing indicators and off-label use were analyzed by descriptive statistics using Microsoft Excel v16.0, Microsoft, Redmond, Washington, US.


  Results Top


A total of 300 pediatric cancer patients were part of the study. One hundred and seventy-one (57%) patients suffered from hematological cancers, while those having solid tumors were 129 (43%). Overall, the median age was found to be 75 months with interquartile range (Q3–Q1) of 87 (129–42) months. Age of the participants is summarized in [Table 1]. Out of 300 patients, 200 were boys and 100 were girls. Similar trend was seen when hematological malignancies, and solid tumors were analyzed separately.
Table 1: Age of the participants expressed in months

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A total number of 944 drugs were prescribed in the 300 prescriptions studied. The prescribing indicators are summarized in [Table 2].
Table 2: Prescribing indicators (n=300)

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Hematological malignancies

Diagnosis

The most common hematological cancer was found to be acute lymphoblastic leukemia (ALL) – 126 (73.68%) out of 171 patients. Other cancers were acute myeloid leukemia (AML) – 15 (8.77%), Hodgkin's lymphoma – 15 (8.77%), Burkitt's lymphoma – 9 (5.26%), chronic myeloid leukemia – 5 (2.92%), and one case of mixed phenotype leukemia.

Drugs prescribed

Anticancer drugs

Out of 270, the most common anticancer drug prescribed in hematologic cancer was found to be vincristine (60) followed by 6-mercaptopurine (48), L-asparaginase (42), and methotrexate (36). The drugs are summarized in [Figure 1].
Figure 1: Anticancer drugs prescribed in hematological malignancies

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Concomitant drugs

Out of 327 concomitant drugs prescribed in hematological cancers, the most common was found to be ondansetron (n = 41) followed by dexamethasone (36), ranitidine (30), Granisetron (28), and Azithromycin (15).

Off label use of anti-cancer drugs

In hematological cancers, out of 270 drugs prescribed, only on nine instances, off-label use was recorded. Thus, percentage of off-label prescribing of anticancer drugs in hematological cancers was found to be around 3.33% only. The medication which was used off-label on nine instances was Etoposide. Etoposide is not indicated for the treatment of ALL, CML, or AML. Yet, it was used in six prescriptions of ALL, two prescriptions of CML, and one prescription of AML.

Solid tumors

Diagnosis

Among 129 solid tumor patients, the most common cancer was found to be Ewing's sarcoma (29) followed by other Primitive neuroectodermal tumors (PNET) (19), Wilms tumor (16), osteogenic sarcoma (14), rhabdomyosarcoma (10), hepatoblastoma (7), medulloblastoma (6), small round cell tumors (6), retinoblastoma (RB) (4), hemangioma (4), glioma (3), astrocytoma (3), primitive embryonal tumors (3), germ cell tumors (3), undifferentiated sarcoma of liver (1), and nasopharyngeal cancer (1).

Drugs prescribed

Anticancer drugs

Out of 76 anticancer drugs prescribed, the most common was found to be vincristine (24) followed by cyclophosphamide (16), etoposide (14), vinblastine (7), cisplatin (6), carboplatin (3), ifosfamide (3), and dactinomycin (3)

Concomitant drugs

Out of 271 concomitant drugs prescribed, the most common was found to be ondansetron (38) followed by paracetamol (35), granulocyte colony-stimulating factor (34), cefoperazone + Sulbactam (25), ranitidine (20), and dexamethasone (17).

Off-label use of anticancer drugs

In solid tumors, out of 76 drugs prescribed, in 61 instances, off-label use was recorded. Thus, percentage of off-label prescribing of anticancer drugs in solid tumors was found to be around as high as 80.26%. The most common off-label use was seen with cyclophosphamide (16), followed by vincristine (15), etoposide (14), vinblastine (7), cisplatin (6), and Carboplatin (3).


  Discussion Top


The present study evaluated the prescription pattern of drugs used for the treatment of pediatric cancer patients and the off-label use of drugs, if any in a tertiary cancer care hospital.

Our demographic finding simulated with the finding of Conroy et al., where about 80% of patients had hematological cancers and remaining had solid tumors. However, the study had inherent limitation of having a small sample size (not more than 100 in each study),[12] whereas the present study had 300 patients evaluated.

In our study, the cancer prevalence in age group and gender distribution was like a study reported by Sharma et al.[13] where a retrospective analysis of epidemiological characteristics of 303 children with solid tumors was done at a regional cancer institute in India and Pearce and Parker[14] in their study on childhood cancer registrations in developing world. In childhood cancers, males are generally diagnosed more than females, and this holds true even in case of adult cancers. In India, cancer registries also have shown similar finding.[15] This can be attributed to the general paternalistic society and thinking trend. Preferential treatment for male child which includes medical care also cannot be denied. In general hospital registrations too, male preponderance is seen.[16]

The literature available on the epidemiology of leukemia in children[17] showed the ALL as the most common hematological cancer in children. We also found ALL as the predominant hematological cancer in children.

The finding of solid tumors in the study conducted by Qureshi et al.[18] in India had reported that soft-tissue tumors were most common followed by neuroblastoma and renal tumors, which was not the case in our study, but this could be because bone tumors and central nervous system (CNS) tumors were excluded from their analysis, so there was a relative increase in the soft-tissue tumor numbers. In the study conducted by Sharma et al., Ewing sarcoma/PNET were the third most common tumor after CNS tumors and germ cell tumors.[13]

In Indian backdrop, many of the drugs are not available in generic as against the western world, so the patient ends up being prescribed brand-named drugs as happened in the present study. This enhances the cost for treatment as a majority of the patients pay from their pocket. Prescribing drug by their generic name helps the patients to get medications at an affordable price and avoid any potential confusion when brand names are similar.[19] In developing country like India, practitioners have no other option than prescribing in brand names because 90% of the drugs are available in branded generics.[19] In the tertiary cancer care hospital, these drugs were available for the patient free of cost. Hence, the patient was not obligated to make out of pocket expenses. However, we cannot make any comments in this direction, as cost analysis was not the objective of the current study, which is one of the limitations of our research. In support to the practice of prescribing drugs by brand names, in the present study, most of the drugs were administered on site at the tertiary care itself by qualified personnel. Hence, the problem of confusion in the patients was greatly reduced. Being a center where e-prescribing was in place, oncologists had the chance to select and prescribe drugs – both generic and branded – from the central hospital formulary. This also ensured that oncologists prescribed the most appropriate brand drug required for the patient which was available in the formulary. Another limitation of our study was, we were not able to access the e-prescribing software used by the physicians. Hence, comment regarding availability of the drugs was made based on the discussions done with the treating physicians.

Most prescribed anticancer drug was found to be vincristine in both hematological cancer and solid tumor patients. In majority of the cancers, vincristine is one of the drugs in many chemotherapy regimens. The evidence for vincristine usage in pediatric cancer is established in many studies.[20],[21]

Along with anticancer medications, important classes of concomitant medications such as antiemetics, antiulcer agents, antibiotics, analgesics, and growth factors were also prescribed. Among the concomitant drugs, in both the cancer types, ondansetron was the most prescribed agent.

In the present study, most of the anticancer drugs used to treat hematological cancer were found to be on label. Out of the 270 anticancer drugs prescribed, only on nine instances, it was found off-label where etoposide was prescribed for the treatment of ALL, CML, and AML. Etoposide is indicated only for the treatment of refractory testicular tumors and small-cell lung cancer.[22] The efficacy of etoposide in ALL and AML has been demonstrated in various Phase 1 and Phase 2 trials with many complete responses reported for it. However, because of the leukemogenic potential, the use of etoposide in leukemia remains controversial and hence not on label for various hematological cancers.[23]

In solid tumors, most common off-label drug was found to be cyclophosphamide and vincristine with maximum such prescriptions were seen in Wilms tumor patients. The algorithm for treating Wilms tumor according to National Wilms Tumour Study Group (NWTS) includes Vincristine in all stages – from Stage I to Stage IV – and Cyclophosphamide in Stage 4 of Wilms tumor. The overall survival rates of 90% have been found in patients treated by these agents.[24] Hence, in practice, pediatric oncologists are using these drugs for Wilms tumor. Vincristine in Ewing sarcoma was the second most common off-label drug prescribed. For Ewing Sarcoma, recommended treatment consists of vincristine, ifosfamide, doxorubicin, and etoposide. With intensive multimodal therapy, event-free survival of 50% can be achieved with these agents.[25]

Etoposide was used off label in Wilms tumor. According to NWTS protocols, etoposide is recommended to be used as the chemotherapeutic agent in Stage II to Stage IV Wilms tumor patients.[24] Etoposide was also used off label in RB. Chemotherapy is used in both extraocular and intraocular RB. Due to good intraocular penetration, standard chemotherapeutic agents such as vincristine, etoposide, and carboplatin are used – VEC protocol.[26]

Vinblastine was used as an off-label drug in CNS tumors such as astrocytoma and glioma. In a clinical trial conducted on 54 patients, vinblastine was found to be well tolerated in children with treatment-naive pediatric low grade glioma. Overall survival and progression-free survival were comparable to current therapies, with a favorable toxicity profile and a maintained quality of life.[27]

Cisplatin was used off label in osteogenic sarcoma. In a study conducted by Meyers et al., patients treated with standard arm of therapy (cisplatin, doxorubicin, and high-dose methotrexate) had 3-year event-free survival of 71% in newly diagnosed patients with osteosarcoma.[28]

Apart from the anticancer drugs, among concomitant drugs which were given, no off-label use was found.

Regulators have adopted methods to approve drugs in pediatric population. Food and Drug Administration (FDA) has allowed industry to undertake additional clinical trials and submit a supplemental new drug application (sNDA). The advantage of sNDA is that the average approval time is shorter as compared to NDA. They can skip the preclinical phase and rely on one/few Phase three trials. Second, an arrangement of pediatric exclusivity provision in FDA as a marketing incentive is existing, because 75% of pediatric prescriptions are off label. It provides 6 months of patent and marketing exclusivity for approved drugs in return for conducting pediatric studies. This has increased the number of trials in pediatric population in the US. Furthermore, sNDA applicants are given 3 years of marketing exclusivity for their own products to promote off-label use of the drugs.[29]

All these can potentially make off-label drugs change in their label with the help of manufacturers and regulators. Such arrangements are not existing at present in India.


  Conclusions Top


The most common anticancer drug prescribed in pediatric cancer patients was vincristine and concomitant drug prescribed was ondansetron. The off-label use of anticancer drugs is commonly seen in solid tumors whereas rarely used in hematological malignancies. Studies on off-label use of drugs should be conducted to see the implications in terms of benefit to the patient population and also in terms of ADR incidence in them. Creating a drug therapeutic committee in tertiary care hospital is ideal, which looks for discrepancy in the prescribing practices and can make changes and recommendations accordingly. Such committees can also make periodic reviews of the drugs being used off label at the hospital and generate quality evidence – either in support or against such practice – based on the benefit-risk analysis.

Regulators can call for expert panels which look into the various academic trials and also the published evidence regarding the off-label use of drugs. If such use is found efficacious on the lines of evidence-based medicines, there should be provision for such drug to be made on label. Pharmaceutical industries should be encouraged to take up off-label drugs and see for the potential use of the drug by conducting clinical trials by utilizing the various concessions provided by the drug-regulating bodies.

Financial support and sponsorship

Financial support provided by Diamond Jubilee Society Trust of Seth G S Medical College and KEM Hospital, Mumbai.

Conflicts of interest

There are no conflicts of interest.



 
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