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Medication Burden Among Pediatric Cancer Survivors: Analysis of a Population-Wide Electronic Database in Hong Kong

Abstract Background Few studies have evaluated the medication burden borne by survivors of pediatric cancer. This study aimed to describe the drug utilization pattern of chronic medications in a cohort of young pediatric cancer survivors. Methods This was a population-based study of patients diagnosed with cancer at age 18 years or younger between 2000 and 2013 in Hong Kong and who had survived at least 5 years postdiagnosis. The primary outcome is the use of any chronic medication (medications that were prescribed for ≥30 consecutive days within a 6-month period). Multivariable log-binomial models were used to identify factors associated with chronic medication use. Kaplan-Meier analysis was used to present the cumulative proportion of survivors initiated on a chronic medication across time from cancer diagnosis. Results Of the 2444 survivors (median age = 22 years, interquartile range = 16-27 years), 669 (27.4%) required at least 1 chronic medication at least 5 years postdiagnosis. Survivors who developed a chronic health condition (CHC) had a 5.48 (95% confidence interval [CI] = 4.49 to 6.71) times higher risk of taking a chronic medication than those without CHC. At 10 years postdiagnosis, the cumulative proportion of survivors being initiated a chronic medication was 33.4% (95% CI = 31.1% to 35.6%) for the overall cohort. Higher cumulative proportions were observed in survivors with endocrine (74.6%, 95% CI = 68.4% to 79.6%), renal (68.8%, 95% CI = 54.2% to 78.7%), neurological (58.6%, 95% CI = 46.1% to 68.1%), and cardiovascular (54.7%, 95% CI = 44.0% to 63.4%) disorders. Conclusion Survivors with certain CHCs had a higher risk of starting a prescription medication in the early phase of survivorship. Future studies include examining the impact of medication burden on survivors’ functional status.

monitored closely for adverse health outcomes that may result from the use of multiple chronic medications.
Previous studies have typically focused on evaluating the association of chronic disease burden with functional outcomes and health-care utilization in survivors of pediatric cancer (3,4,(11)(12)(13)(14). However, few epidemiological studies have evaluated the medication burden borne by these patients. Studies on this topic have been either single-center studies (15) or confined to specific cancer diagnoses (10) or drug classes (16,17) (eg, the long-term use of psychoactive medications). To address these research gaps, the primary objective of this study was to describe the pattern of chronic medication use by a cohort of young Chinese pediatric cancer survivors, using a populationbased electronic medical database in Hong Kong. The secondary objective was to identify patient characteristics associated with chronic medication use.

Study Design
This was a population-based observational study of survivors of pediatric cancer within the Hospital Authority health-care system in Hong Kong. The Hospital Authority is the sole public health-care provider in Hong Kong, and it serves more than 90% of Hong Kong residents. We conducted our study using data from the Clinical Data Analysis and Reporting System (CDARS), which is a centralized clinical data repository for all 43 public hospitals, 49 specialist outpatient clinics, and more than 70 general outpatient clinics within the Hospital Authority (18). CDARS captures patients' clinical and treatment information and has previously been validated as a data source for epidemiological studies in Hong Kong (19). This study was reviewed and approved by the Joint Chinese University-New Territories East Cluster Clinical Research Ethics Committee (reference number 2018.427).

Study Population
The study population comprised patients aged 18 years or younger who were registered with an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code of 140.00 to 209.79 between January 1, 2000, and December 31, 2013. Both incident and prevalent cases of cancer were included. Patients were excluded if they were aged older than 18 years at the time of cancer diagnosis (ie, when the ICD-9 code for cancer was first registered) or with ambiguous or uncertain diagnosis.

Medication Use
The definition used for a chronic medication was a medication that was prescribed to a patient with an intended duration of 30 or more consecutive days within a 6-month period or a medication that was prescribed to be used as needed but with an intended cumulative duration of 180 or more days within a 12month period (15).
The primary outcome was the use of any newly prescribed chronic medications at 5 years or more postdiagnosis, as well as chronic medications that were prescribed at the end of therapy and were continued for more than 5 years postcancerdiagnosis. Medications were excluded from this category if they 1) were not filled or dispensed by the pharmacy, 2) had no active pharmaceutical ingredients, 3) were parenterally administered and required inpatient admission, or 4) had no valid start date. As this analysis is focused on medications with a curative intent in survivors, medications that were dispensed 6 months prior to death were also excluded. We did not exclude chronic medications that were prescribed before cancer diagnosis because it is often difficult to tease apart preexisting health conditions or symptoms from the cancer-or treatment-related conditions.
Medications were categorized according to the British National Formulary (BNF) classification (20). The BNF is a widely accepted framework for the drug management of common diseases. All drugs within the BNF are organized by the body systems and therapeutic drug classifications. For simplicity, the drugs used by survivors of this study are presented by the therapeutic drug classifications.
The secondary outcomes were medication burden (the number of chronic prescription medications) and polypharmacy (the use of 5 concurrent chronic medications). These were descriptive outcomes as our previous work had shown that the rate of polypharmacy among young survivors is low (5.3%) (15).

Predictive Variables
Based on a literature review (1,8,10,(15)(16)(17), several predictive factors for medication burden were identified a priori, namely primary cancer diagnosis, chronic health conditions (CHCs), and history of relapse. Primary cancer diagnoses were classified based on the Surveillance, Epidemiology and End Results Program of the National Cancer Institute classification system (21). The information on CHCs was captured electronically from CDARS. A CHC was defined as a condition with chronic implications requiring long-term management (eg, gonadal dysfunction, on-treatment epilepsy, stroke, and heart failure) or a condition that was first registered at least 5 years postdiagnosis (22).

Statistical Analysis
Descriptive statistics were used to summarize the distribution of relevant outcome variables and covariates according to reasonable groupings based on previous reports on childhood cancer (11,12,14,15,23). Multivariable models were used to identify clinical factors associated with chronic medication use, after adjustment for sex, time since diagnosis, and age at diagnosis. Consistent with other studies evaluating health outcomes in childhood cancer survivors (16,24,25), the log-binomial models (generalized linear models with Poisson error and log-link function) were used to minimize biased estimates after adjusting for confounders in cohort studies (26,27). The corresponding relative risk (RR) estimates and 95% confidence intervals (CIs) were reported. Because cancer relapse and its treatment are associated with a higher burden of comorbidities (4,28,29), a sensitivity analysis was conducted to evaluate the association between the clinical factors and chronic medication use in the cohort excluding relapsed patients.
Finally, to illustrate descriptively medication utilization from early survivorship (5 to 10 years postcancer diagnosis) to long-term survivorship (10 years postdiagnosis), the cumulative proportion of survivors who were initiated a chronic medication across time since diagnosis was estimated using Kaplan-Meier analysis in the overall cohort and by the type of CHC. Events including death and loss to follow-up were censored. The Schoenfeld residuals were calculated for each variable to ensure that they independently satisfied the assumptions of the Cox model. A P value less than .05 was considered statistically significant, and all tests were 2-sided. All analyses were conducted using the R program.

Study Population
Between January 1, 2000, and December 31, 2013, a total of 3123 patients who were aged 18 years or younger had an ICD-9 diagnosis code of 140.00 to 209.79 registered on their records (Supplementary Figure 1, available online). Among them, 81 subjects were excluded from subsequent analyses because of the ambiguous or uncertain nature of their diagnoses. After further excluding 598 subjects who passed away and thus were lost to follow-up within 5 years postdiagnosis, 2444 subjects were included in the final analyzed cohort (Table 1).
Leukemia was the most common cancer diagnosis (37.8%), followed by lymphoma (11.2%) and CNS tumors (7.4%) ( Table 1). At 5 years or more postdiagnosis, at least 1 diagnosis of CHC was documented in 774 (31.7%) survivors ( Table 2). The most common CHCs were endocrine (12.3%), behavioral (6.6%), and musculoskeletal complications (6.6%). Survivors with CNS tumors were most likely to develop at least 1 CHC (58.2%), followed by survivors of sarcoma and leukemia (Supplementary Figure 2, available online). An analysis of the distribution of CHCs across cancer diagnoses showed that endocrine disorders were the most common diagnoses among survivors of CNS tumors, lymphoma, and leukemia, and musculoskeletal disorders were the most prevalent in survivors of sarcoma (Supplementary Figure 3, available online).
One-fifth of the cohort developed a relapse (19.1%; Supplementary Table 1, available online). Among survivors who relapsed, cancer recurrence occurred within 10 years from primary cancer diagnosis (77.5%). More than half of the relapsed survivors had developed a CHC (47.3%) during the time of evaluation.

Use of Chronic Medications
A subgroup of 669 survivors (27.4%) required at least 1 chronic medication ( Table 2). The most commonly prescribed class of chronic medication was thyroid replacement therapy (22.7%), followed by antihistamines (17.6%) and sex hormones (15.4%). A minority (3.8%) of patients were prescribed at least 5 chronic medications (ie, polypharmacy) during the study period (Supplementary Table 2, available online).  More than one cancer diagnosis may be present in a patient. CNS ¼ central ner- Defined as either acute complication that occurred after the date of cancer diagnosis and chronic implications requiring long-term management (eg, gonadal dysfunction, on-treatment epilepsy, stroke, heart failure) or a condition that was first registered at 5 or more years postdiagnosis.
Survivors who had developed a relapse demonstrated a higher risk of being prescribed a chronic medication than survivors who did not (RR ¼ 2.97, 95% CI ¼ 2.38 to 3.71). The sensitivity analysis showed that the predictors of chronic medication use among survivors without any history of relapse (Supplementary Table 3, available online) were similar to the primary analysis on the overall cohort.
At 10 years postdiagnosis (ie, when survivors transit into long-term survivorship), the proportion of survivors with a chronic medication was 33.4% (95% CI ¼ 31.1% to 35.6%) for the overall analyzed cohort. Figure 2 summarizes the cumulative proportion of survivors who were initiated a chronic medication, stratified by the type of CHC. For those survivors without a CHC, the proportion was small (20

Discussion
Using real-world data from electronic health records, we sought to characterize the medication burden in a population of pediatric cancer survivors who were treated in the health-care system of Hong Kong after 2000. A subgroup (27.4%) of survivors were taking at least 1 chronic prescription medication. Overall, only a minority (3.8%) of survivors had polypharmacy. Survivors with endocrine, musculoskeletal, respiratory, and behavioral complications had the highest risk of starting a prescription medication early in the cancer survivorship continuum. This is one of the first studies to report the treatment burden of late effects borne by survivors of pediatric cancer.
Our results concur with findings from the literature showing that even contemporary treatment protocols carry a risk of late effects and may have implications on the medication burden during the early survivorship period (3). Survivors who developed at least 1 CHC were 5.48 times more likely to take a chronic medication than those who did not. The use of multiple medications in young survivors may have clinical implications, as physiological processes and neurodevelopment may be sensitive to the effects of pharmacological interventions during adolescence and young adulthood (30). For example, a previous study showed that the use of psychoactive medications during adolescence is associated with neurocognitive impairment and poorer social attainment later in life (16). Other studies have also reported worse functional outcomes in childhood cancer survivors with endocrine complications, although the comparative contribution of hormonal and metabolic abnormalities vs medications on adverse outcomes is often hard to distinguish (13,14,31). Admittedly, the lifelong use of chronic medications is likely warranted in certain conditions, such as hormonal replacement therapy in cancer survivors with hypothalamic or gonadal dysfunction. However, the screening and early identification of modifiable risk factors for certain late effects (eg, cardiovascular diseases, diabetes, and behavioral disorders) may facilitate timely lifestyle interventions before the condition becomes chronic and requires pharmacological interventions. A higher medication burden was observed in survivors of CNS tumors and leukemia compared with survivors of other cancers. A similar observation was found in survivors who had a relapse. This finding is consistent with previous findings that these groups of survivors demonstrate the highest cumulative burden of CHCs (4,12,15,22,32); hence, they require the use of multiple medications. It is also important to note that concurrent medication use may confound the study of cancer-related symptoms in these survivors. For example, anticonvulsants and hormonal replacement therapy may exacerbate neurological and behavioral symptoms in CNS tumor survivors (32,33). Our results reinforce the need for closer monitoring of adverse health outcomes from multiple medications in these high-risk groups. Future studies should also evaluate the welldocumented burden associated with multiple medications in patients with chronic diseases, such as nonadherence to  medication therapy (34,35) and inappropriate drug prescribing and drug interactions (36,37), as well as increased health-care utilization costs (9,38). The steep slope observed on the Kaplein-Meier curves within 5 years postdiagnosis seemed to suggest that survivors tended to be prescribed a chronic medication during the early posttherapy period rather than at a later phase of the survivorship period (ie, 10 years postdiagnosis). This is contrary to wellestablished evidence that the incidence of chronic morbidities increases as survivors age (22). Our findings may reflect the initiation of medications to treat chronic conditions that occur early in the posttreatment period (eg, hormonal replacement therapy for secondary endocrinopathy). A longer follow-up time on our cohort is required to assess medication utilization in survivors as they age and as late-occurring chronic conditions emerge. Respiratory chronic conditions were recorded in 5% of our survivors, hence, the use of prescribed systemic antihistamines may be for the symptomatic relief of respiratory conditions, or it may reflect the high prevalence of allergies in the local pediatric population due to environmental factors (39). As we do not expect the prevalence of allergic conditions to differ between cancer survivors and the general population (40), these conditions might be present even prior to the cancer diagnosis and may not be related to the cancer or its treatment. Future studies should include prospectively capturing the specific indications of chronic medications and the verification with consultation notes to characterize medication use patterns in individuals with preexisting conditions. According to a landmark study, impaired pulmonary, cardiac, endocrine, and nervous system functions were most prevalent (detected in 20% of participants at risk) (22). Our results showed that patients with endocrine, respiratory, and neurological conditions were at the highest risk of being prescribed a chronic medication. However, cardiovascular conditions were not associated with chronic medication use in our multivariable analysis. Our cohort is still relatively young. The estimated prevalence of clinically significant cardiovascular conditions in survivors aged 40 years and younger was around 5% (22,41). Therefore, the non-statistically significant finding should be interpreted in light of the low proportion of survivors with documented cardiovascular conditions (5.6%) and with consideration that 54% of these survivors were on a chronic medication by the time they were 10 years postdiagnosis. On the contrary, even though the prevalence of renal late effects (5%) was substantially less common (22), our study found that the medication burden in this minority is high; 68% of patients with a renal condition were initiated a chronic medication at long-term survivorship. The medication burden for this group is likely to be higher when their renal health declines as they age. Future studies with a longer follow-up should investigate the evolving profile of morbidities and medication burden in highrisk groups of survivors.
The major strength of this study is the use of a large sample size of pediatric patients diagnosed with cancer in the public health-care network of Hong Kong. However, the findings of this study should be considered in the context of several limitations. First, this study did not include an age-matched healthy comparison control group. However, the prevalence of CHCs identified here (13.0%) is higher than the rates reported by the latest Hong Kong Census and Statistics Department (3.5% to 5.1% for individuals aged 15 to 39 years) (42). Given the high prevalence of CHCs reported in childhood cancer survivors (4,7,22), it is reasonable to speculate that the medication burden may be considerably higher in cancer survivors than in the agematched general population. Notably, our reported prevalence of CHCs was substantially lower than previously published estimates, as most previous studies have performed systematic screening of late effects (4,22) or captured self-reported late effects (11,23). The confounding effects of the different chemotherapy drugs cannot be accounted for. This is because although CDARS has a high reported level of completeness for demographic and prescription data (19), there may be a certain degree of inaccuracy in cancer treatment data because of the use of paper forms for chemotherapy orders in the pediatric wards of some hospitals in the early 2000s. Therefore, some chemotherapy drugs may not have been captured electronically. Moreover, CDARS does not include dosimetry data; hence, we were unable to evaluate the effects of radiation on late effects and chronic medication use. This is the first study harnessing population-based electronic health data to examine drug use patterns in a cohort of relatively young Chinese survivors of childhood cancer. Although polypharmacy was observed in a minority of the survivors in this study, chronic medication use was a common occurrence and has the potential to contribute to the future medical burden, particularly in survivors with endocrine, behavioral, and musculoskeletal late effects, as well as individuals who survived a relapse. These high-risk groups should be monitored closely for drug-drug interactions and adverse events during follow-up care, as well as nonadherence to drug therapy and increased cost associated with health-care services utilization. Future studies should also include examining the impact of multiple chronic medication use on the health status of survivors as they age.

Funding
No funding was received for conducting this study.

Notes
Role of the funder: Not applicable.
Disclosures: All authors do not have any conflict of interest to declare that are relevant to the content of this article.

Data Availability
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to identifiers in the dataset and are hence restricted from sharing by the Hospital Authority of Hong Kong.