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Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review Xiao Jun Wang a,b , Shaun Eric Lopez a , Alexandre Chan a,b,∗ a
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore b Department of Pharmacy, National Cancer Centre Singapore, Singapore Accepted 22 December 2014
Contents 1.
2.
3.
4. 5.
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Direct, indirect and intangible cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Approaches for cost estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. General characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Data analysis of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Parameters associated with higher FN cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Quality assessment of included cost-of-illness studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Search results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. General characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Data analysis of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Comparison of inpatient and outpatient cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Comparison of direct and indirect cost within inpatient care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Incidence of cost component among direct cost within inpatient care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.4. Incidence of cost component among direct cost within outpatient care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Parameters associated with higher FN cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Quality assessment of included cost-of-illness studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
Abstract The primary objective of this review was to identify the cost components that were most frequently associated with the economic burden of febrile neutropenia (FN) among patients with lymphoma. The secondary objective was to identify any parameter associated with higher FN cost. Ten cost of illness (COI) studies were identified. General characteristics on study design, country, perspective, and patient population were extracted and systematically reported. It was observed that majority (70%) of the studies employed the perspective of healthcare provider. ∗ Corresponding author at: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Tel.: +65 6516 7814; fax: +65 6779 1554. E-mail address: [email protected] (A. Chan).
http://dx.doi.org/10.1016/j.critrevonc.2014.12.011 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Wang XJ, et al. Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.011
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20% of the studies considered long-term costs. Estimated costs were adjusted to 2013 US dollars and ranged from US$5819 to US$34,756. The cost components that were most frequently associated with economic burden were ward and medication costs. Inpatient management, male gender, discharged dead, and comorbidity were positively associated with higher FN costs. Future COI studies on FN should focus on the accurate estimation on ward and medication costs. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Febrile neutropenia; Neutropenia; Fever; Cost; Economic burden; Lymphoma; Systematic review
1. Background Febrile neutropenia (FN) is a common life-threatening complication that may arise after cancer patients undergo myelosuppressive chemotherapy [1,2]. Patients with lymphoma are highly associated with this complication of chemotherapy because these patients often receive highly myelosuppressive chemotherapy [1,3]. The complications of FN in patients with lymphoma were demonstrated by a recent study which reported that a mortality rate of 6.6% and a median length of hospital stay of 7 days [4]. Complications of FN may extend over the long term as potential chemotherapy dose reduction and dose delay may occur among lymphoma patients who experienced FN. These complications of FN can incur a considerable economic burden as patients may require additional supportive care treatments and additional hospitalization costs due to FN [5]. Therefore, the cost of FN could be substantial among patients with lymphoma. Cost-of-illness (COI) studies estimate the resources consumed and lost as a result of a particular disease [6]. Results from the COI studies can improve understanding of the economic burden that a specific disease may have on society as a whole, healthcare providers, and the individual patient [7,8]. Furthermore, COI studies typically evaluate the cost of a particular disease. This can provide a fundamental basis for some economic evaluation studies, such as cost-effectiveness analysis, cost-utility analysis and cost-benefit analysis studies [9]. 1.1. Direct, indirect and intangible cost There are three cost components estimated in a COI study. These include: (a) direct costs (medical and non-medical), (b) indirect costs, and (c) intangible costs. Direct costs estimate the opportunity costs of all kinds of resources used to treat FN. It can be further separated into direct medical costs and non-medical costs. Direct medical costs include ward charges, laboratory test charges, radiography charges, transfusion charges, medication charges, emergency room visit charges, physician visit charges, and home nursing visit charges [10]. Direct non-medical costs represent the costs incurred by patients or their family members which are directly associated with FN, but without medical nature, such as transportation charges.
Indirect costs refer to the productivity losses due to morbidity or mortality. Productivity loss is the forgone productivity caused by work absences [11]. In most COI studies, indirect costs can account for a large proportion of the total costs [11,12]. Intangible costs refer to patients’ psychological pain, discomfort, anxiety and depression due to FN. These costs are often measured in the form of quality of life [13]. 1.2. Perspective The perspective taken is an important consideration in COI studies. Based on different perspective chosen, the cost estimation can vary. The most popular perspectives include those of the patient, the employers, the insurance company, the healthcare providers, and the government or the society. The societal perspective is the most comprehensive approach in the COI studies. This approach can avoid cost underestimation that may occur when a narrower perspective is taken [8]. 1.3. Approaches for cost estimation There are three common methods to estimate the direct costs: econometric, bottom-up and top-down approach [8,14]. Indirect costs may be estimated in three ways: the human capital approach, the friction cost approach and the willingness-to-pay approach [8]. The human capital approach is the most commonly used method, as it considers the forgone income of the patient and their caregivers and takes into account premature mortality and disability [8]. To date, the only available systematic review that evaluated the economic burden of FN was conducted in 2007 [15]. The review pooled costs from many different types of cancers, which resulted in a huge variation in the economic burden of FN [3]. In addition, the study methods used by the included COI studies including the perspectives, time horizon, and cost estimation method were not revealed. Hence, it is difficult to evaluate the validity of those cost studies. Furthermore, in that review, overall FN cost in patients with lymphoma was not breakdown into individual resource use. Therefore, the cost components that were most frequently associated with the economic burden of FN was not investigated. In view of these limitations, we have conducted a systematic review to determine the cost components that were most frequently associated with the economic burden of FN related
Please cite this article in press as: Wang XJ, et al. Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.011
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to lymphoma patients. The secondary objective of this review was to identify the parameters associated with higher FN cost. This review aims to provide a greater insight into developing a more comprehensive methodology in future COI studies with greater accuracy in determining the overall economic burden of FN in lymphoma patients.
2. Methods An electronic bibliography search was conducted through PubMed, Scopus and Web of Science to identify COI studies on FN published from 1990 to 2013, which estimated the economic burden of FN related to lymphoma patients. The following search terms (“cancer”) AND (“febrile neutropenia” OR “neutropenic fever”) AND (“costs” OR “economics”) were used according to the PICOS (Patient Population, Intervention, Comparison, Outcomes, and Setting) framework. Studies were limited to the English language and all adults aged 18 and above. COI studies that described different cost components in FN cost and provided sufficient cost breakdown were included. Editorials, case reports, and reviews were excluded from this review. Cost studies on FN in pediatric lymphoma patients, and studies exploring the costs for patients undergoing bone marrow or stem cell transplant were excluded to limit the possible variability in costs as a result of different standards of care. 2.1. General characteristics of included studies The included studies were outlined in terms of its study design, country, cost data source and perspectives used. Perspectives that were not revealed by the studies were subjected to interpretation by two investigators of this study, and if there were different opinions, the two investigators would make decisions by discussion. Studies were also summarized for the characteristics of their study population and the inclusion/exclusion criteria in order to provide a comprehensive understanding of the included studies. 2.2. Data analysis of included studies In order to allow cost estimates from COI studies of different countries to be more comparable, figures were converted to 2013 US dollars. For cost data in the United States, the medical-care component of the Consumer Price Index (CPI) was retrieved from the US Bureau of Labor Statistics and inflated to 2013 US dollars [15]. For cost data generated from non-US countries, figures were first inflated to 2013 currency value using the medical-care (or equivalent) component of that country’s CPI [15]. In the case when the medical care component was unavailable, the general CPI was used (e.g. Canada [16]). Figures were then changed to 2013 US dollars using currency exchange rates on 20 December 2013 [17]: 1 AU$ = 0.89 US$, 1 CAN$ = 0.93US$, 1D = 1.37 US$.
3
If there was no indication of the year of cost data in the study, it was assumed to be the publication year [15]. The economic burden of FN was calculated by summing up the costs from the inpatient care and outpatient care. The studies also indicated the time horizon in which these costs were incurred. A “per episode” time horizon would indicate the time taken for managing each episode of FN, from the diagnosis of FN to the resolution of the illness or mortality of the patient. To identify the cost components that were most frequently associated with the economic burden of FN, the overall cost was disaggregated into their specific resources used in the inpatient and outpatient care. The resource components were extracted from the included COI studies and categorized into a checklist format [10,18] to facilitate the comparison of the types of resources included by the COI studies in estimating the cost. The categorization of ‘resources used’ were reviewed by two investigators. Different cost components were compared within the COI study and between the studies to evaluate the cost components that were most frequently associated with the economic burden of FN, as well as its inpatient care and outpatient care.
2.3. Parameters associated with higher FN cost Parameters associated with higher cost of FN were identified among the included studies. To be included, those parameters must be reported as statistically significant (p < 0.05) associated with a higher FN cost in those cost studies among patients with lymphoma. Those parameters would enable the identification of patients who were at greater risk for higher economic burden of FN.
2.4. Quality assessment of included cost-of-illness studies A quality assessment checklist developed by Larg and Moss [19] was adopted to evaluate the included cost-ofillness studies. In this review, each study was summarized as percentages of fulfilled criteria within the checklist [20]. Additionally, the results for each criterion in the checklist were summed in percentages to reveal the degree of fulfillment of each criterion in the checklist. Studies that fulfilled (Y) the criterion were awarded a score of 1; studies that partially fulfilled (P) the criterion were awarded a score of 0.5, while those that did not fulfill were given a score of 0. Those criteria that were not applicable (NA) to the particular study were removed from the calculation, leaving the remaining studies to be considered in the total percentage. Each criterion was assumed to be equally weighed. The purpose was not to create a hierarchy in the criteria by assigning them different weights, but to use these criteria to evaluate included cost-of-illness studies.
Please cite this article in press as: Wang XJ, et al. Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.011
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On 18 Dec 2013, 3296 articles identified from Scopus, Pubmed and Web of Science
3.3. Data analysis of included studies Excluded Non-lymphoma patients: 649 Age≤18: 454 Non-human: 52 Non-English language: 94 Reviews, editorials, guidelines: 1087 Stem cell/BM transplant: 104 Non-FN patients: 26 Studies not estimating FN cost: 675
155 articles remained after title and abstract review Excluded Non-lymphoma patients: 9 Review, editorial, guidelines: 3 Stem cell/BM transplant: 2 Non-FN patients: 4 Studies not estimating FN cost: 79 No cost breakdown: 9 Duplicate: 38 Age≤18: 1 10 articles remained after full article review
Fig. 1. Flowchart for screening articles in Scopus, PubMed and Web of Science
3. Results 3.1. Search results The search identified 3296 articles from Scopus, PubMed and Web of Science. After screening the title and abstract, 3141 articles were excluded based on inclusion and exclusion criteria. 155 studies remained for full article review. Of those, another 145 articles did not fulfill the inclusion criteria. In all, 10 articles were identified in this review (Fig. 1). These included studies estimated the cost of FN either from lymphoma patients or have lymphoma patients as part of their study population.
3.2. General characteristics In Table 1, the studies reviewed showed results from the following regions: United States (n = 5), Australia (n = 1), Singapore (n = 1), Canada (n = 1), Spain (n = 1), and Europe and Australia (n = 1). The definitions of FN were inconsistent among the studies. The majority of the studies employed a healthcare provider perspective [10,16,21–23]. Four other studies [11,24–26] used a societal perspective. Two studies [11,24] accounted for indirect costs, but used different databases to account for their indirect costs. Six studies used a retrospective cohort design analysis [12,21–23,25,26]. The source of cost data for most of the studies was from claims databases and hospital records. The study population size varied from 46 patients to cohorts of 5990 cases. There was one study [26] focused specifically on the lymphoma patients as its study population, while other cost studies included lymphoma and various other types of cancer patients in their study populations.
In Table 2, there was a large variation in the cost estimation on FN cost. Among the studies that were conducted in the US, the estimated cost ranged from $16,054 to $34,756 (2013 US$) [11,12,21,24,25]. Among the studies conducted out of the US, the estimated cost ranged from $5819 to $13,823 (2013 US$) [10,16,22,23,26]. The highest range of cost estimate of FN was found to be in the US, followed by Singapore, Europe, Australia, Canada and Spain. This demonstrated that different health care systems from different countries might affect the cost estimates substantially. The study conducted by Bennett and Calhoun [24] considered a comprehensive set of cost components in its direct and indirect costs from a societal perspective, hence yielded the highest estimated cost of FN. The cost estimates of other studies were not as comprehensive in terms of their direct and indirect costs. Three studies [12,25,26] estimated their direct costs in an econometric approach, while the other studies [10,11,16,21–24] estimated their direct costs in a bottom-up approach. Two studies [11,24] estimated the indirect costs via the humancapital approach method (HCM), in which the lost earnings were calculated as a result of mortality and morbidity of FN [8]. One study conducted by Michels et al. [25] estimated a relatively long-term cost of FN with a mean follow-up time of 17.5 months, and applied a discounting rate of 3% per annum to account for the future cost since the study extended beyond a year. Another study conducted by Weycker et al. [12] measured the cost of FN from the beginning of initial hospitalization for febrile neutropenia through the end of chemotherapy course, in which the mean duration was 153 (±97) days, and as such, yielded a lower FN cost. Table 3 revealed that numerous cost components from inpatient and outpatient care were included in the COI studies. All the studies included inpatient care in their cost components, but only six studies [10,11,16,21–23] revealed the breakdown of resources used in their inpatient care cost. Among the COI studies that evaluated direct medical cost, all of them considered ward and medication cost in their cost components. Hendricks et al. [11] considered the direct non-medical cost aspect as part of its inpatient care component. In terms of indirect costs, only two studies [11,24] included loss of productivity by the patients, and out-ofpocket costs to caregivers as their cost components. Five studies [11,12,24–26] have incorporated outpatient care costs in their cost estimation of FN. Medication costs were considered in most of the outpatient cost, followed by physician office visits. 3.3.1. Comparison of inpatient and outpatient cost Costs from the inpatient and outpatient care were compared against each other. Inpatient care was the greatest contributor to the economic burden of FN with an average of 79%. In the study conducted by Hendricks et al. [11], in which a multicenter trial was
Please cite this article in press as: Wang XJ, et al. Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.011
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Study Country
USA [12]
Perspective
Definition of FN
ICD-9-CM 288.0 or 780.6.
USA [21]
Healthcare providerb
USA [24]
Sample size
Cost data source
Cost components Direct cost
Indirect cost
Inpatient and outpatient care for FN encounters Physician office visits, outpatient services, inpatient hospital services and pharmacy claims Room and board costs, ICU and non-ICU costs, laboratory costs, pharmacy costs, central supply and surgery supply costs Medication, MD visits, lab, medical devices, and hospitalization
NA
Retrospective cohort study Retrospective cohort study
373 pts; 11.3% lymphoma 5990 pts; 6% lymphoma
Ingenix LabRx, Ingenix Health Intelligence HealthCore Integrated Research Database
ICD-9288.0x, 780.6x
Retrospective cohort study
16,273 pts; 36% lymphoma
Premier database, linked with OptimInsight database; clinical and billing records
Societalb
Temperature ≥ 38.0 ◦ C and ANC < 500/mm3
Prospective cohort study
71 pts; 32% lymphoma
Medicare Physician Fee Schedule, US Census Bureau
USA [11]
Societal b
Temperature of 100.5 ◦ F and ANC < 500/L
Multicenter randomized trial
92 pts; 21% lymphoma
Hospital records, patient’s daily log
Hospital, physician and home care
Canada [16]
Healthcare provider
ICD-10-Canadian enhancement, code D700
Prospective cohort study
46 pts; 39% lymphoma
Patient records
Australia [22]
Healthcare provider
ICD-10 code, D70
Retrospective cohort study
158 pts; 42% lymphoma
Victorian Emergency Minimum Dataset
Spain [23]
Healthcare provider
Retrospective cohort study
194 pts; 34.5% lymphoma
SOIKOS Database, BOT Database, medical chart.
Europe and Australia [26]
Societalb
Fever >38.2 ◦ C and ANC < 0.5*109 /L, or fever > 38.5 ◦ C and ANC < 1*109 /L An oral temperature of ≥38.3 ◦ C or a temperature of ≥38.0 ◦ C for ≥1 h, and a neutrophil count of
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Critical Reviews in Oncology/Hematology xxx (2015) xxx–xxx
Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review Xiao Jun Wang a,b , Shaun Eric Lopez a , Alexandre Chan a,b,∗ a
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore b Department of Pharmacy, National Cancer Centre Singapore, Singapore Accepted 22 December 2014
Contents 1.
2.
3.
4. 5.
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Direct, indirect and intangible cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Approaches for cost estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. General characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Data analysis of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Parameters associated with higher FN cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Quality assessment of included cost-of-illness studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Search results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. General characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Data analysis of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Comparison of inpatient and outpatient cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Comparison of direct and indirect cost within inpatient care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. Incidence of cost component among direct cost within inpatient care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.4. Incidence of cost component among direct cost within outpatient care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Parameters associated with higher FN cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Quality assessment of included cost-of-illness studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract The primary objective of this review was to identify the cost components that were most frequently associated with the economic burden of febrile neutropenia (FN) among patients with lymphoma. The secondary objective was to identify any parameter associated with higher FN cost. Ten cost of illness (COI) studies were identified. General characteristics on study design, country, perspective, and patient population were extracted and systematically reported. It was observed that majority (70%) of the studies employed the perspective of healthcare provider. ∗ Corresponding author at: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Tel.: +65 6516 7814; fax: +65 6779 1554. E-mail address: [email protected] (A. Chan).
http://dx.doi.org/10.1016/j.critrevonc.2014.12.011 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Wang XJ, et al. Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.011
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20% of the studies considered long-term costs. Estimated costs were adjusted to 2013 US dollars and ranged from US$5819 to US$34,756. The cost components that were most frequently associated with economic burden were ward and medication costs. Inpatient management, male gender, discharged dead, and comorbidity were positively associated with higher FN costs. Future COI studies on FN should focus on the accurate estimation on ward and medication costs. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Febrile neutropenia; Neutropenia; Fever; Cost; Economic burden; Lymphoma; Systematic review
1. Background Febrile neutropenia (FN) is a common life-threatening complication that may arise after cancer patients undergo myelosuppressive chemotherapy [1,2]. Patients with lymphoma are highly associated with this complication of chemotherapy because these patients often receive highly myelosuppressive chemotherapy [1,3]. The complications of FN in patients with lymphoma were demonstrated by a recent study which reported that a mortality rate of 6.6% and a median length of hospital stay of 7 days [4]. Complications of FN may extend over the long term as potential chemotherapy dose reduction and dose delay may occur among lymphoma patients who experienced FN. These complications of FN can incur a considerable economic burden as patients may require additional supportive care treatments and additional hospitalization costs due to FN [5]. Therefore, the cost of FN could be substantial among patients with lymphoma. Cost-of-illness (COI) studies estimate the resources consumed and lost as a result of a particular disease [6]. Results from the COI studies can improve understanding of the economic burden that a specific disease may have on society as a whole, healthcare providers, and the individual patient [7,8]. Furthermore, COI studies typically evaluate the cost of a particular disease. This can provide a fundamental basis for some economic evaluation studies, such as cost-effectiveness analysis, cost-utility analysis and cost-benefit analysis studies [9]. 1.1. Direct, indirect and intangible cost There are three cost components estimated in a COI study. These include: (a) direct costs (medical and non-medical), (b) indirect costs, and (c) intangible costs. Direct costs estimate the opportunity costs of all kinds of resources used to treat FN. It can be further separated into direct medical costs and non-medical costs. Direct medical costs include ward charges, laboratory test charges, radiography charges, transfusion charges, medication charges, emergency room visit charges, physician visit charges, and home nursing visit charges [10]. Direct non-medical costs represent the costs incurred by patients or their family members which are directly associated with FN, but without medical nature, such as transportation charges.
Indirect costs refer to the productivity losses due to morbidity or mortality. Productivity loss is the forgone productivity caused by work absences [11]. In most COI studies, indirect costs can account for a large proportion of the total costs [11,12]. Intangible costs refer to patients’ psychological pain, discomfort, anxiety and depression due to FN. These costs are often measured in the form of quality of life [13]. 1.2. Perspective The perspective taken is an important consideration in COI studies. Based on different perspective chosen, the cost estimation can vary. The most popular perspectives include those of the patient, the employers, the insurance company, the healthcare providers, and the government or the society. The societal perspective is the most comprehensive approach in the COI studies. This approach can avoid cost underestimation that may occur when a narrower perspective is taken [8]. 1.3. Approaches for cost estimation There are three common methods to estimate the direct costs: econometric, bottom-up and top-down approach [8,14]. Indirect costs may be estimated in three ways: the human capital approach, the friction cost approach and the willingness-to-pay approach [8]. The human capital approach is the most commonly used method, as it considers the forgone income of the patient and their caregivers and takes into account premature mortality and disability [8]. To date, the only available systematic review that evaluated the economic burden of FN was conducted in 2007 [15]. The review pooled costs from many different types of cancers, which resulted in a huge variation in the economic burden of FN [3]. In addition, the study methods used by the included COI studies including the perspectives, time horizon, and cost estimation method were not revealed. Hence, it is difficult to evaluate the validity of those cost studies. Furthermore, in that review, overall FN cost in patients with lymphoma was not breakdown into individual resource use. Therefore, the cost components that were most frequently associated with the economic burden of FN was not investigated. In view of these limitations, we have conducted a systematic review to determine the cost components that were most frequently associated with the economic burden of FN related
Please cite this article in press as: Wang XJ, et al. Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.011
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to lymphoma patients. The secondary objective of this review was to identify the parameters associated with higher FN cost. This review aims to provide a greater insight into developing a more comprehensive methodology in future COI studies with greater accuracy in determining the overall economic burden of FN in lymphoma patients.
2. Methods An electronic bibliography search was conducted through PubMed, Scopus and Web of Science to identify COI studies on FN published from 1990 to 2013, which estimated the economic burden of FN related to lymphoma patients. The following search terms (“cancer”) AND (“febrile neutropenia” OR “neutropenic fever”) AND (“costs” OR “economics”) were used according to the PICOS (Patient Population, Intervention, Comparison, Outcomes, and Setting) framework. Studies were limited to the English language and all adults aged 18 and above. COI studies that described different cost components in FN cost and provided sufficient cost breakdown were included. Editorials, case reports, and reviews were excluded from this review. Cost studies on FN in pediatric lymphoma patients, and studies exploring the costs for patients undergoing bone marrow or stem cell transplant were excluded to limit the possible variability in costs as a result of different standards of care. 2.1. General characteristics of included studies The included studies were outlined in terms of its study design, country, cost data source and perspectives used. Perspectives that were not revealed by the studies were subjected to interpretation by two investigators of this study, and if there were different opinions, the two investigators would make decisions by discussion. Studies were also summarized for the characteristics of their study population and the inclusion/exclusion criteria in order to provide a comprehensive understanding of the included studies. 2.2. Data analysis of included studies In order to allow cost estimates from COI studies of different countries to be more comparable, figures were converted to 2013 US dollars. For cost data in the United States, the medical-care component of the Consumer Price Index (CPI) was retrieved from the US Bureau of Labor Statistics and inflated to 2013 US dollars [15]. For cost data generated from non-US countries, figures were first inflated to 2013 currency value using the medical-care (or equivalent) component of that country’s CPI [15]. In the case when the medical care component was unavailable, the general CPI was used (e.g. Canada [16]). Figures were then changed to 2013 US dollars using currency exchange rates on 20 December 2013 [17]: 1 AU$ = 0.89 US$, 1 CAN$ = 0.93US$, 1D = 1.37 US$.
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If there was no indication of the year of cost data in the study, it was assumed to be the publication year [15]. The economic burden of FN was calculated by summing up the costs from the inpatient care and outpatient care. The studies also indicated the time horizon in which these costs were incurred. A “per episode” time horizon would indicate the time taken for managing each episode of FN, from the diagnosis of FN to the resolution of the illness or mortality of the patient. To identify the cost components that were most frequently associated with the economic burden of FN, the overall cost was disaggregated into their specific resources used in the inpatient and outpatient care. The resource components were extracted from the included COI studies and categorized into a checklist format [10,18] to facilitate the comparison of the types of resources included by the COI studies in estimating the cost. The categorization of ‘resources used’ were reviewed by two investigators. Different cost components were compared within the COI study and between the studies to evaluate the cost components that were most frequently associated with the economic burden of FN, as well as its inpatient care and outpatient care.
2.3. Parameters associated with higher FN cost Parameters associated with higher cost of FN were identified among the included studies. To be included, those parameters must be reported as statistically significant (p < 0.05) associated with a higher FN cost in those cost studies among patients with lymphoma. Those parameters would enable the identification of patients who were at greater risk for higher economic burden of FN.
2.4. Quality assessment of included cost-of-illness studies A quality assessment checklist developed by Larg and Moss [19] was adopted to evaluate the included cost-ofillness studies. In this review, each study was summarized as percentages of fulfilled criteria within the checklist [20]. Additionally, the results for each criterion in the checklist were summed in percentages to reveal the degree of fulfillment of each criterion in the checklist. Studies that fulfilled (Y) the criterion were awarded a score of 1; studies that partially fulfilled (P) the criterion were awarded a score of 0.5, while those that did not fulfill were given a score of 0. Those criteria that were not applicable (NA) to the particular study were removed from the calculation, leaving the remaining studies to be considered in the total percentage. Each criterion was assumed to be equally weighed. The purpose was not to create a hierarchy in the criteria by assigning them different weights, but to use these criteria to evaluate included cost-of-illness studies.
Please cite this article in press as: Wang XJ, et al. Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.011
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On 18 Dec 2013, 3296 articles identified from Scopus, Pubmed and Web of Science
3.3. Data analysis of included studies Excluded Non-lymphoma patients: 649 Age≤18: 454 Non-human: 52 Non-English language: 94 Reviews, editorials, guidelines: 1087 Stem cell/BM transplant: 104 Non-FN patients: 26 Studies not estimating FN cost: 675
155 articles remained after title and abstract review Excluded Non-lymphoma patients: 9 Review, editorial, guidelines: 3 Stem cell/BM transplant: 2 Non-FN patients: 4 Studies not estimating FN cost: 79 No cost breakdown: 9 Duplicate: 38 Age≤18: 1 10 articles remained after full article review
Fig. 1. Flowchart for screening articles in Scopus, PubMed and Web of Science
3. Results 3.1. Search results The search identified 3296 articles from Scopus, PubMed and Web of Science. After screening the title and abstract, 3141 articles were excluded based on inclusion and exclusion criteria. 155 studies remained for full article review. Of those, another 145 articles did not fulfill the inclusion criteria. In all, 10 articles were identified in this review (Fig. 1). These included studies estimated the cost of FN either from lymphoma patients or have lymphoma patients as part of their study population.
3.2. General characteristics In Table 1, the studies reviewed showed results from the following regions: United States (n = 5), Australia (n = 1), Singapore (n = 1), Canada (n = 1), Spain (n = 1), and Europe and Australia (n = 1). The definitions of FN were inconsistent among the studies. The majority of the studies employed a healthcare provider perspective [10,16,21–23]. Four other studies [11,24–26] used a societal perspective. Two studies [11,24] accounted for indirect costs, but used different databases to account for their indirect costs. Six studies used a retrospective cohort design analysis [12,21–23,25,26]. The source of cost data for most of the studies was from claims databases and hospital records. The study population size varied from 46 patients to cohorts of 5990 cases. There was one study [26] focused specifically on the lymphoma patients as its study population, while other cost studies included lymphoma and various other types of cancer patients in their study populations.
In Table 2, there was a large variation in the cost estimation on FN cost. Among the studies that were conducted in the US, the estimated cost ranged from $16,054 to $34,756 (2013 US$) [11,12,21,24,25]. Among the studies conducted out of the US, the estimated cost ranged from $5819 to $13,823 (2013 US$) [10,16,22,23,26]. The highest range of cost estimate of FN was found to be in the US, followed by Singapore, Europe, Australia, Canada and Spain. This demonstrated that different health care systems from different countries might affect the cost estimates substantially. The study conducted by Bennett and Calhoun [24] considered a comprehensive set of cost components in its direct and indirect costs from a societal perspective, hence yielded the highest estimated cost of FN. The cost estimates of other studies were not as comprehensive in terms of their direct and indirect costs. Three studies [12,25,26] estimated their direct costs in an econometric approach, while the other studies [10,11,16,21–24] estimated their direct costs in a bottom-up approach. Two studies [11,24] estimated the indirect costs via the humancapital approach method (HCM), in which the lost earnings were calculated as a result of mortality and morbidity of FN [8]. One study conducted by Michels et al. [25] estimated a relatively long-term cost of FN with a mean follow-up time of 17.5 months, and applied a discounting rate of 3% per annum to account for the future cost since the study extended beyond a year. Another study conducted by Weycker et al. [12] measured the cost of FN from the beginning of initial hospitalization for febrile neutropenia through the end of chemotherapy course, in which the mean duration was 153 (±97) days, and as such, yielded a lower FN cost. Table 3 revealed that numerous cost components from inpatient and outpatient care were included in the COI studies. All the studies included inpatient care in their cost components, but only six studies [10,11,16,21–23] revealed the breakdown of resources used in their inpatient care cost. Among the COI studies that evaluated direct medical cost, all of them considered ward and medication cost in their cost components. Hendricks et al. [11] considered the direct non-medical cost aspect as part of its inpatient care component. In terms of indirect costs, only two studies [11,24] included loss of productivity by the patients, and out-ofpocket costs to caregivers as their cost components. Five studies [11,12,24–26] have incorporated outpatient care costs in their cost estimation of FN. Medication costs were considered in most of the outpatient cost, followed by physician office visits. 3.3.1. Comparison of inpatient and outpatient cost Costs from the inpatient and outpatient care were compared against each other. Inpatient care was the greatest contributor to the economic burden of FN with an average of 79%. In the study conducted by Hendricks et al. [11], in which a multicenter trial was
Please cite this article in press as: Wang XJ, et al. Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2014.12.011
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Study Country
USA [12]
Perspective
Definition of FN
ICD-9-CM 288.0 or 780.6.
USA [21]
Healthcare providerb
USA [24]
Sample size
Cost data source
Cost components Direct cost
Indirect cost
Inpatient and outpatient care for FN encounters Physician office visits, outpatient services, inpatient hospital services and pharmacy claims Room and board costs, ICU and non-ICU costs, laboratory costs, pharmacy costs, central supply and surgery supply costs Medication, MD visits, lab, medical devices, and hospitalization
NA
Retrospective cohort study Retrospective cohort study
373 pts; 11.3% lymphoma 5990 pts; 6% lymphoma
Ingenix LabRx, Ingenix Health Intelligence HealthCore Integrated Research Database
ICD-9288.0x, 780.6x
Retrospective cohort study
16,273 pts; 36% lymphoma
Premier database, linked with OptimInsight database; clinical and billing records
Societalb
Temperature ≥ 38.0 ◦ C and ANC < 500/mm3
Prospective cohort study
71 pts; 32% lymphoma
Medicare Physician Fee Schedule, US Census Bureau
USA [11]
Societal b
Temperature of 100.5 ◦ F and ANC < 500/L
Multicenter randomized trial
92 pts; 21% lymphoma
Hospital records, patient’s daily log
Hospital, physician and home care
Canada [16]
Healthcare provider
ICD-10-Canadian enhancement, code D700
Prospective cohort study
46 pts; 39% lymphoma
Patient records
Australia [22]
Healthcare provider
ICD-10 code, D70
Retrospective cohort study
158 pts; 42% lymphoma
Victorian Emergency Minimum Dataset
Spain [23]
Healthcare provider
Retrospective cohort study
194 pts; 34.5% lymphoma
SOIKOS Database, BOT Database, medical chart.
Europe and Australia [26]
Societalb
Fever >38.2 ◦ C and ANC < 0.5*109 /L, or fever > 38.5 ◦ C and ANC < 1*109 /L An oral temperature of ≥38.3 ◦ C or a temperature of ≥38.0 ◦ C for ≥1 h, and a neutrophil count of
