Association of Chemotherapy Regimen Intensity and Use of Psychotropic Medications in Pediatric Oncology Patients

Abstract

OBJECTIVE

Pediatric oncology patients endure treatments that may include chemotherapy, surgery, radiation, and transplant. These treatment modalities often have an effect on a patient's mental health. To date, little is known or published about the association between certain cancer treatment regimens and the use of psychotropic medications. The goal of this study is to identify associations between the use of psychotropic medications in pediatric oncology patients in relation to the intensity of their oncologic treatment regimen.

METHODS

A retrospective chart review was completed for pediatric oncology patients seen between the years of 2009 and 2019 with prescriptions and/or inpatient orders for specific psychotropic medications. The intensity of the oncologic regimen was categorized using the Intensity of Treatment Rating Scale (ITR-3) tool. Association between the intensity of therapy and use of psychotropic medications were compared using Pearson χ² and Fisher exact tests as appropriate.

RESULTS

There were 172 patients identified as having inpatient and/or outpatient orders for psychotropic medications during the study period. Ninety-one pediatric oncology patients were included in data analysis. It was found that psychotropic medications were used consistently in pediatric oncology patients despite a specific ITR-3 score. There were no statistically significant associations found when comparing ITR-3 scores to psychotropic medication use or to age at diagnosis.

CONCLUSIONS

Significance was not obtained in this study; however, we found that psychotropic medications were used across the spectrum of diagnoses, age, and oncologic treatment intensity. This suggests that all pediatric oncology patients should be evaluated for psychiatric needs throughout their course of oncologic treatment.

Introduction

In pediatric patients in the United States, cancer is the leading cause of death by disease past infancy.¹ In patients up to 19 years of age, the most common cancer diagnoses include leukemias, brain and central nervous system tumors, and lymphomas.¹ The outlook for pediatric patients with cancer has vastly improved in recent decades. Between the years 2010 and 2016, 84.1% of children diagnosed with cancer had a survival rate of at least 5 years.² Despite the improvement in overall survival for these patients, a diagnosis of cancer still has a significant effect on the mental health of not only the patient but the family and caregivers as well.

A pediatric oncology patient will often go through months, even years of treatment for their disease. This is accomplished by a combination of therapies that may include chemotherapy, radiation, surgery, and/or transplant. The intensity of treatment will vary from patient to patient. This is dependent on the disease state, stage, or risk level, as well as whether this is a relapse in disease or an initial diagnosis. Although the treatment intensity can be subjectively measured by the patient or the caregiver, an objective tool exists to assist health care providers in classifying the intensity of a regimen.³ The Intensity of Treatment Rating Scale (ITR-3) is a validated tool that takes into account a number of aspects of a treatment regimen in order to give an objective intensity rating to each regimen.³

Pediatric oncology patients often face substantial mental health concerns as they go through their respective treatment regimen.⁴ As the number of pediatric cancer survivors increases, we can also expect to see these mental health concerns continue into survivorship. It is not uncommon for patients to face anxiety, depression, or concern for their own mortality when going through treatment and beyond. Research on the use of psychotropic medications such as antidepressants, antipsychotics, and anxiolytics in pediatric patients has increased in recent years; however, there is still very little known about the use of psychotropic medications in critically ill pediatric patients, specifically oncology patients. A previous study did examine pediatric oncology patients who were enrolled in clinical research trials and their use of psychotropic medications. They found that of 347 patients, 14% were prescribed at least 1 psychotropic medication at the time of trial enrollment. Overall the study concluded that pediatric oncology patients are often prescribed psychotropic medications, however, little is known about the relationship to the intensity of an oncologic treatment regimen and the use of psychotropics.⁵

This study was designed to identify an association between the intensity of a pediatric oncology patient's treatment regimen and their use of psychotropic medications. We hypothesized that higher intensity of therapy is associated with increased dose requirements and/or higher rates of combination therapy of psychotropic medications.

Materials and Methods

Study Design. This was a single-center, retrospective chart review using patient data from January 1, 2009 to December 31, 2019. Sunrise Clinical Manager (Allscripts, Raleigh, NC) is an electronic health record used in both the inpatient and outpatient setting for the pediatric oncology group at University of Kentucky, Kentucky Children's Hospital. Patients were identified within Sunrise Clinical Manager by inpatient orders and/or outpatient prescriptions for specific psychotropic medications (Table 1).

Table 1.

Psychotropic Medications

Categories and Examples
Antidepressants
Selective serotonin reuptake inhibitors (SSRI)
Sertraline
Escitalopram
Fluoxetine
Citalopram
Serotonin/norepinephrine reuptake inhibitors (SNRI)
Duloxetine
Venlafaxine
Atypical antidepressants
Bupropion
Alpha-2 antagonists
Mirtazapine
Tricyclic antidepressants
Amitriptyline
Antipsychotics
Atypical antipsychotics
Olanzapine
Risperidone
Quetiapine
Aripiprazole
Anxiolytics
Benzodiazepines
Lorazepam
Clonazepam
Alprazolam
Anxiolytics
Hydroxyzine

Demographic data were collected for each patient, including sex assigned at birth, gender identity, age at diagnosis or at relapse, height, weight, race, and ethnicity. For each psychotropic medication, the dose and instructions were collected. These were then determined to be high versus low dose using the predetermined dose categories (Table 2). A patient's psychiatric diagnoses were also included in data collection, if one had been made.

Table 2.

Dose Classifications of Psychotropic Medications *

Medication	Age or Weight Range for Weight-based Dosing	Daily Dose
		Low Dose	High Dose
Sertraline	—	≤100 mg	>100 mg
Escitalopram	—	≤10 mg	>10 mg
Bupropion Xl	—	≤150 mg	>300 mg
Fluoxetine	—	≤10 mg	>10 mg
Citalopram	—	≤20 mg	> 20 mg
Duloxetine	—	≤60 mg	>60 mg
Venlafaxine IR	—	≤37.5 mg	>37.5 mg
Venlafaxine ER	—	≤37.5 mg	≥75 mg
Mirtazapine	—	≤7.5 mg	≥15 mg
Amitriptyline†	>12 yr	≤100 mg	>100 mg
	9–12 yr	1 mg/kg/day	1.5 mg/kg/day (200 mg/day)
Olanzapine	—	≤5 mg	>5 mg
Quetiapine IR	—	≤300 mg	>300 mg
Quetiapine ER	—	≤300 mg	>300 mg
Aripiprazole	—	≤7.5 mg	>7.5 mg
Risperidone	—	≤1.5 mg	>1.5 mg
Lorazepam†	≥12 yr	≤3 mg	>3 mg
	<12 yr	≤0.05 mg/kg/dose	>0.05 mg/kg/dose (2 mg/dose)
Clonazepam†	<30 kg	≤ 0.1 mg/kg	>0.1 mg/kg (maximum 0.2 mg/kg/day)
	≥ 30 kg	≤10 mg	>10 mg
Alprazolam	—	≤1.5 mg	>1.5 mg
Hydroxyzine†	<6 yr	0.5 mg/kg/dose	0.5 mg/dose
	≥6 yr	0.5 mg/kg/dose	25 mg/dose
Bupropion IR	—	≤200 mg	>200 mg
Bupropion SR†	—	2 mg/kg up to 150 mg	—

^* Dashes indicate not applicable.

^† For weight-based dosing, if a dosage exceeds 50% of the maximum recommended, it is considered a high dose.

When analyzing the oncologic treatment regimen, the specific protocol for each patient was used to determine which treatment modalities were included in that specific protocol. This determined if surgery, radiation, or transplant were a part of the treatment plan and the specific chemotherapy that was used at the time of psychotropic initiation. Chemotherapy regimen was recorded using the patient-specific protocolized treatment plans.

The ITR-3 tool³ was used to determine the intensity of a treatment regimen, taking into account the diagnosis, stage, or risk level, and treatment modalities such as those listed above. Those with an ITR-3 score of 1 were considered the least intensive, 2 considered moderately intensive, 3 considered very intensive, and 4 considered the most intensive.

Inclusion and Exclusion Criteria. Patients were included if they were an oncology patient treated within our pediatric oncology group in the designated time frame with at least 1 order for a psychotropic medication. An age range was not predetermined, as our pediatric oncology group treats adolescent and young adult patients (>18 years) diagnosed with cancers typically found in the pediatric population.

Patients were excluded if they were a benign hematology patient seen by our pediatric hematology/oncology service, if the indication for the psychotropic was not consistent with psychiatric symptoms or if the only psychotropic medication ordered or prescribed was lorazepam monotherapy, which is commonly used as an antiemetic in our patient population. Given the retrospective nature of this study, patients were excluded if documentation was insufficient to gather the necessary data points.

Statistical Analysis. Descriptive statistics were used for demographic information. Pearson χ² and Fisher exact tests were used to compare ITR-3 scores and use of specific psychotropic medication classes. They were also used to compare ITR-3 scores with use of combinations of psychotropic medications. Analysis of variance was used to compare age across ITR-3 scores. Analysis was completed using SPSS Statistics version 27 (IBM, Armonk, NY).

Results

Within the study period, 172 pediatric oncology patients were identified through inpatient and/or outpatient orders for the designated psychotropic medications. This included relapses in disease that were considered separate patient encounters. Of those 172 patient encounters, 91 patients were included for data analysis excluding 81 patients (Supplemental Figure). Of the 91 included patients, 93.4% (n = 85) were Caucasian and the majority of the patients were male, 61.5% (n = 56). The age (mean ± SD) at diagnosis was 14.8 years ± 6.8 (Table 3). The most common diagnoses were pre-B acute lymphoblastic leukemia and osteosarcoma along with Ewing sarcoma, rhabdomyosarcoma, and T-cell acute lymphoblastic leukemia (Table 4).

Table 3.

Demographic Data and Characteristics of Total Sample

Parameter	Total Sample (N = 91)
Race or ethnicity, n (%)
Caucasian	85 (93.4)
African American	3 (3.3)
Asian	2 (2.2)
Hispanic	1 (1.1)
Sex/Gender identity, n (%)
Male	56 (61.5)
Female	34 (37.4)
Transgender male	1 (1.1)
Age at diagnosis, mean ± SD	14.8 ± 6.8

Table 4.

Cancer Diagnoses of Study Patients

Diagnosis (%)	Patients, n (N = 91)
Leukemia (31)
Pre-B acute lymphoblastic leukemia	17
T-cell lymphoblastic leukemia	6
Acute myeloid leukemia	4
APML	1
Hodgkin lymphoma (2)	2
Non-Hodgkin lymphoma (9)
B-cell lymphoma	3
Burkitt lymphoma	1
Gray zone lymphoma	1
T-cell lymphoma	3
Bone and joint (26)
Alveolar rhabdomyosarcoma	6
Ewing sarcoma	6
Osteosarcoma	12
Solid abdominal tumor (9)
Ovarian tumor	3
Wilms tumor	1
Neuroblastoma	3
Hepatoblastoma	1
Soft tissue (14)
Synovial cell sarcoma	2
Sarcoma not otherwise specified	4
Germ cell tumor	2
Granular cell tumor	1
Desmoplastic small round cell tumor	2
Rhabdoid tumor	2
CNS (9)
CNS tumors (not specified)	3
Medulloblastoma	3
Anaplastic ependymoma	2

APML, acute promyelocytic leukemia; CNS, central nervous system

Of the 91 patients included in data analysis, 14 (15.4%) patients received an ITR-3 score of 2, 17 (18.7%) received a score of 4, and 60 (65.9%) patients received an ITR-3 score of 3. Of those with a score of 4, indicating the most intense regimens, 11 (64.7%) were relapsed disease and 6 (35.3%) received stem cell transplants in their treatment course. Age was compared across ITR-3 scores and a statistically significant difference was not found between the 3 groups (Table 5).

Table 5.

Comparison of Age at Cancer Diagnosis and ITR-3 Score

ITR-3 Score	Patients, n	Age, Mean ± SD, yr	p value*
2	14	16.6 ± 8.9	0.118
3	60	15.2 ± 6.3
4	17	11.9 ± 6.0

ITR-3, Intensity of Treatment Rating Scale

^* Based on analysis of variance test.

The use of antidepressants, antipsychotics, and anxiolytics did not differ between ITR-3 scores (Table 6). The percentage of patients in each ITR-3 scoring category had a similar percentage of patients on antidepressants (p = 0.827). There was no difference in use of antipsychotics between the 3 groups (p = 0.375), and the lowest intensity group with ITR-3 score of 2 had the highest percentage of use of antipsychotics at 14.3%. There was also not a significant difference between the use of antipsychotics between the 3 groups (p = 0.585) and the use trended down as the intensity score increased.

Table 6.

Comparison of ITR-3 Scores and Use of Psychotropic Medication Classes

Therapeutic Class,	ITR-3 Score, n (%)			p value*
	2	3	4
Antidepressant
Yes	10 (76.9)	42 (70.0)	13 (76.5)	0.827
No	3(23.1)	18 (30.0)	4 (23.5)
Antipsychotic
Yes	2 (14.3)	3 (5.0)	1 (5.9)	0.375
No	12 (85.7)	57 (95.0)	16 (94.1)
Anxiolytic
Yes	10 (71.4)	39 (65.0)	9 (52.9)	0.585
No	4 (28.6)	21 (35.0)	8 (47.1)

ITR-3, Intensity of Treatment Rating Scale

^* Based on χ² and Fisher exact tests.

In comparing the use of high dose psychotropic medications, there was not a statistically significant difference between the 3 intensity groups (Table 7). Use of high dose antidepressants was similar across the 3 groups (p = 0.909) as was use of high dose anxiolytics (p = 0.521). The use of high dose antipsychotics could not be evaluated as there were not any patients in any of the intensity groups using a high dose antipsychotic throughout their oncologic treatment regimen.

Table 7.

Comparison of ITR-3 Score and Use of Large Dose Psychotropic Medications

Therapeutic Class	ITR-3 Score, n			p value*
	2	3	4
Antidepressant	3	9	3	0.909
Antipsychotic	0	0	0	—
Anxiolytic	3	15	5	0.521

ITR-3, Intensity of Treatment Rating Scale

^* Based on χ² and Fisher exact tests.

Discussion

In this study, we looked at the use of psychotropic medications in pediatric oncology patients seen at the University of Kentucky, Kentucky Children's Hospital. The overall demographic data was representative of the patient population that is seen regularly at our institution. Our data demonstrated that pediatric oncology patients are often prescribed psychotropic medications throughout their course of therapy, regardless of how intense their oncologic treatment plan is considered. Although not statistically significant across the ITR-3 intensity scores, the use of psychotropic medications was consistent across the spectrum of patients indicating that all pediatric oncology patients should be evaluated for the need of psychiatric treatment and resources.

Of the patients included in data analysis, 38 had a concurrent psychiatric diagnosis. Anxiety and depression were the most common, but patients were also diagnosed with adjustment disorder, opposition defiant disorder, mood disorders, attention deficit disorder, and autism spectrum disorder. These diagnoses are consistent with previous studies that have demonstrated common disorders requiring hospitalization and medication management in pediatric patients.⁶

The majority of psychotropics were managed by an oncologist or advanced practice provider from the oncology clinic in 67 of the 91 patients (73.6%). Twenty-four (26.4%) patients had involvement from the child psychiatry team at the University of Kentucky and 3 (3.3%) patients were managed by an outside physician. Some patients' psychotropic medication therapy was managed by a combination of providers. It has been found that many pediatric primary care providers are comfortable providing assessment of mental health, but then prefer to give a referral for further treatment.⁷ The oncology group at the University of Kentucky frequently reaches out to the child psychiatry group and will refer patients to their group or to outside mental health resources.

Our study is limited by its retrospective methods and the small sample size. The nature of chart review revealed inconsistencies in documentation over the time period including how home medications were documented as well as the documentation of oncologic treatment plan. Although paper charts related to the oncologic treatment plans were available for some patients, the extensiveness of the study period did not allow for paper chart review of all patients. Patients were only included based upon a list of psychotropic medications that were determined based on the more commonly seen psychotropic medication in pediatric patients and other psychotropic medications could have been missed such as long-acting injectable antipsychotics. Lorazepam, which was excluded from our study based on common non-anxiolytic usage in pediatric oncology patients, may have influenced psychiatric medication usage in our patients. We did not evaluate lorazepam dosing, which could have had varying effects.

Conclusion

Although statistical significance was not reached when comparing psychotropic medication use and intensity of oncologic treatment regimens, this study demonstrates the need for evaluation of all pediatric oncology patients for psychiatric concerns throughout their treatment course. Our data indicate that patients across the spectrum of oncologic treatment intensity are prescribed psychotropic medications to manage a number of conditions such as depression and anxiety. When treating pediatric oncology patients, treatment teams should consider the psychiatric needs of the patient and facilitate the necessary resources to ensure treatment of those needs.

ABBREVIATIONS

ITR-3

Intensity of Treatment Rating Scale

Funding Statement

Disclosures. The authors declare no financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Natalie Gray had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The project described was supported by the National Institutes of Health (NIH) National Center for Advancing Translational Sciences through grant number UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.