# Economic burden of chemotherapy-induced febrile neutropenia in patients with lymphoma: A systematic review

Critical Reviews in Oncology/Hematology, Volume 94, Issue 2, May 2015, Pages 201 - 212

### Highlights

• We conduct a systematic review on cost-of-illness studies in FN.
• We identify the cost components frequently associated with FN cost.
• Ward costs and medication costs are most frequently associated with FN cost.

### 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. 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.

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] and [2]. Patients with lymphoma are highly associated with this complication of chemotherapy because these patients often receive highly myelosuppressive chemotherapy [1] and [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] and [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] and [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] and [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 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.

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$= 0.93US$, 1€ = 1.37 US$. 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] and [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-of-illness 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. ### 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], [22], and [23]. Four other studies [11], [24], [25], and [26] used a societal perspective. Two studies [11] and [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], [22], [23], [25], and [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. Table 1 General characteristics of included COI studies a (n = 10). Study Country Perspective Definition of FN Study design Sample size Cost data source Cost components Direct cost Indirect cost USA [12] Third party payer ICD-9-CM 288.0 or 780.6. Retrospective cohort study 373 pts; 11.3% lymphoma Ingenix LabRx, Ingenix Health Intelligence Inpatient and outpatient care for FN encounters NA USA [25] Societal b ICD-9-CM code 288. Retrospective cohort study 5990 pts; 6% lymphoma HealthCore Integrated Research Database Physician office visits, outpatient services, inpatient hospital services and pharmacy claims NA USA [21] Healthcare provider b ICD-9288.0x, 780.6x Retrospective cohort study 16,273 pts; 36% lymphoma Premier database, linked with OptimInsight database; clinical and billing records Room and board costs, ICU and non-ICU costs, laboratory costs, pharmacy costs, central supply and surgery supply costs NA USA [24] Societal b Temperature ≥ 38.0 °C and ANC < 500/mm3 Prospective cohort study 71 pts; 32% lymphoma Medicare Physician Fee Schedule, US Census Bureau Medication, MD visits, lab, medical devices, and hospitalization Productivity loss, time spent away from work, wages for hired caregiver. USA [11] Societal b Temperature of 100.5 °F and ANC < 500/μL Multicenter randomized trial 92 pts; 21% lymphoma Hospital records, patient's daily log Hospital, physician and home care Out-of-pocket expenditures and time devoted to care by informal caregivers. Canada [16] Healthcare provider ICD-10-Canadian enhancement, code D700 Prospective cohort study 46 pts; 39% lymphoma Patient records Hospital per diem cost, antibiotics, G-CSF, and other medication cost, laboratory and diagnostic test, blood bank cost NA Australia [22] Healthcare provider ICD-10 code, D70 Retrospective cohort study 158 pts; 42% lymphoma Victorian Emergency Minimum Dataset ICU, nursing, pharmacy, emergency, medical – nonsurgical, pathology, allied health, imaging and others NA Spain [23] Healthcare provider Fever >38.2 °C and ANC < 0.5*109/L, or fever > 38.5 °C and ANC < 1*109/L Retrospective cohort study 194 pts; 34.5% lymphoma SOIKOS Database, BOT Database, medical chart. Hospitalization, antibiotics, G-CSF, complementary tests; other drugs, blood transfusions NA Europe and Australia [26] Societal b An oral temperature of ≥38.3 °C or a temperature of ≥38.0 °C for ≥1 h, and a neutrophil count of <0.5*109/L Retrospective–Prospective observational study 295 pts; 100% lymphoma 2010 Unit Costs of Health and Social Care Report from the Personal Social Services Research Unit, and the British National Formulary, 60th Edition. FN inpatient care, outpatient encounter, home encounter, drug costs NA Singapore [10] Healthcare provider A temperature of ≥38.0 °C, and ANC <1.0*109/L cells/mm3 Prospective cohort study 175 pts; 32.7% lymphoma Hospital records Laboratory, radiography, medication, ward charges, and surgical charges NA a All the studies employed Incidence-based approach. b The perspective indicated is subjected to the interpretation of the reviewer as it is not specified in the study. ANC = absolute neutrophil count; COI = cost-of-illness; NA = not available. #### 3.3. Data analysis of included studies 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], and [25]. Among the studies conducted out of the US, the estimated cost ranged from $5819 to$13,823 (2013 US$) [10], [16], [22], [23], and [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], and [26] estimated their direct costs in an econometric approach, while the other studies [10], [11], [16], [21], [22], [23], and [24] estimated their direct costs in a bottom-up approach. Two studies [11] and [24] estimated the indirect costs via the human-capital approach method (HCM), in which the lost earnings were calculated as a result of mortality and morbidity of FN [8] . Table 2 Summary of the economic burden of FN related to lymphoma patients. Study Country Yea e Perspective Time Horizon Total economic burden Direct cost approach Indirect cost approach Mean (95%CI)/Median (IQR) Adjusted ($US 20130) a
[24] USA 2007 Societal d Per episode f US$28,506 (23,786–33,226) 34,756 BUM HCM [21] USA 2010 Healthcare provider d Per episode f US$ 24,218 (23,328–25,109) 26,686 BUM NA
[11] USA 2008 Societal d Per episode f US$16,341 (14,354–18,327) 19,212 BUM HCM [25] USA 2009 Societal d 17.5 months US$ 19,701 (11,543–27,287) b c 22,450 EC NA
[12] USA 2007 Third party payer Chemotherapy course: 153 (±97) days US$13,167 (9624–17,014) 16,054 EC NA [10] Singapore 2013 Healthcare provider Per episode f US$ 13,823 (11,647–15,999) 13,823 BUM NA
[22] Australia 2007 Healthcare provider Per episode f AUS$5640 c (2525–13,183) 6853 BUM NA [26] Europe and Australia 2010 Societal d Per episode f £ 5776 (4928–6713) 5819 EC NA [16] Canada 2007 Healthcare provider Per episode f CAN$ 6324 (5135–7735) 6396 BUM NA
[23] Spain 2005 Healthcare provider Per episode f € 4514 (3805–5223) 6661 BUM NA

a 1AUD = 0.89USD, 1CAN$= 0.93USD, 1€ = 1.37 USD (20 December 2013). b Cost were discounted at 3% per year. c Median cost (Interquartile Range). d Perspective was not indicated by the study and was interpreted by two reviewers. e The year of conducting the study. f A “per episode” time horizon would indicate the time taken from the diagnosis of FN to the resolution of FN or mortality of the patient. BUM = bottom-up method; EC = econometric; HCM = human-capital method; CI = confidence interval; IQR = interquartile range; NA = not available. 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], [22], and [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] and [24] included loss of productivity by the patients, and out-of-pocket costs to caregivers as their cost components. Five studies [11], [12], [24], [25], and [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. Table 3 Checklist of resource use. a Resource category [26] [25] [12] [24] [11] [10] [22] [16] [23] [21] Inpatient care x x x x x x x x x x Direct cost Direct Medical cost Ward x x x x x x Laboratory x x x x Radiography x x x x Transfusion x x Medication x x x x x x x Antibiotics x x x x G-CSF x x Direct Non-medical cost Transportation x Indirect Cost Lost productivity x Out-of-pocket cost x x Outpatient care x x x x x Direct cost Laboratory x Radiography x Medication x x x Antibiotics x x G-CSF x ER visit x Physician visit x x x Home nursing visit x Indirect cost Lost productivity x Out-of-pocket cost x x a Checkmark indicates that cost figure is provided. ER = emergency room; G-CSF = granulocyte colony-stimulating factor. ##### 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 performed to compare the costs between outpatient home treatment and inpatient treatment, the outpatient care cost was almost equivalent to that of the inpatient care cost (43% vs. 57%). The outpatient care cost included hospital costs in the patients treated in outpatient home treatment setting that were admitted in hospital, which accounted for 60% of their outpatient care costs. ##### 3.3.2. Comparison of direct and indirect cost within inpatient care Within the inpatient care setting, direct costs were compared against indirect costs from the studies. Indirect cost comprised an average of 11% of overall cost of FN. Bennett and Calhoun [24] only considered the loss of productivity in terms of wages paid to caregiver and out-of-pocket costs as part of its indirect costs. Hendricks et al. [11] considered the time loss from work as well as informal caregiving time but did not place a monetary value on them. As such, the value of indirect cost was underestimated. Moreover, long term costs due to mortality and morbidity were not accounted for as well [8] , since the time horizon for both studies [11] and [24] did not extend beyond the episode of FN. ##### 3.3.3. Incidence of cost component among direct cost within inpatient care Since direct cost was the main contributor for the inpatient care, the cost components which comprised ward stay, medication, diagnostics, and laboratory were compared with each other to investigate the main cost driver. Among those components, ward stay was the greatest cost driver for the direct inpatient care costs for the treatment of FN, averaging 70% of the total direct medial cost ( Fig. 2 ). ##### 3.3.4. Incidence of cost component among direct cost within outpatient care Most of the studies [11], [12], [24], and [25] estimating direct costs within outpatient care revealed that medication cost is the cost component most frequently associated with the economic burden of FN. Contrastingly, the study conducted by Weycker et al. [12] showed physician office visit component to be the major cost component in estimating the cost of FN in outpatient care. However, this study included other aspects such as emergency room encounters, all office and visit within that component itself, and thus overestimated the physician office visit cost. #### 3.4. Parameters associated with higher FN cost Six COI studies [10], [11], [21], [22], [24], and [25] revealed the factors associated with higher cost of FN ( Table 4 ). The study conducted by Dulisse et al. [21] showed that specific co-morbidities and infections were associated with longer length of stay, higher mortality risk and larger cost in NHL patients. Apart from individual co-morbidities, this study also revealed that the higher the number of co-morbidities cancer patients had, the larger the cost of FN. Other factors associated with higher FN cost included inpatient management, discharge dead, males, longer duration of neutropenia, therapeutic use of granulocyte-colony stimulating factor (G-CSF), longer length of stay in the hospital, lower absolute neutrophil count (ANC), lower ANC nadir, and longer duration of antibiotics use. Table 4 Parameters associated with higher FN cost. Studies Parameters associated with higher cost Category [24] •Inpatient management Management Location •Male Gender [21] •Lung disease, Liver disease, Renal disease, •Septicemia/bacteremia, Pneumonia Comorbidity and Infection •Discharge dead Discharge status •Male Gender [11] •Inpatient management Management Location •Longer duration of neutropenia Duration of low ANC •Use of therapeutic growth factor Therapeutic use of G-CSF [22] •Longer length of stay Length of stay [25] •Inpatient management Management Location •Discharge dead Discharge status [10] •Longer duration of antibiotics use Antibiotics use •Lower ANC nadir ANC nadir •Invasive pulmonary aspergillosis, CMV reactivation Comorbidity and Infection FN = febrile neutropenia; ANC = absolute neutrophil count; G-CSF = granulocyte colony-stimulating factor; CMV = cytomegalovirus. #### 3.5. Quality assessment of included cost-of-illness studies All the included studies were assessed for quality. The COI studies fulfilled 44–84% of the listed criteria in the checklist ( Table 5 ). The study conducted by Hendricks et al. [11] fulfilled the most number of criteria (84%), while Weycker et al. [26] fulfilled the least number of criteria. Table 5 Checklist for the evaluation of cost-of-illness studies [19] . Checklist [26] [25] [12] [10] [22] [16] [23] [21] [24] [11] Percentage (%) # 1. Analytical framework a. Is there a defined perspective of the study? N N Y N Y Y Y N N N 40 b. Was the appropriate epidemiologic approach taken? Y Y Y Y Y Y Y Y Y Y 100 c. Was the study question well specified? P P P P P P P P P P 50 2. Methodology and data a. Was the appropriate method(s) of resource quantification used? P Y P P P P P P P Y 60 b. Was the resource quantification method(s) valid? N Y P Y Y P Y Y P Y 75 c. Were there appropriate valuation of healthcare resources? N Y N Y N Y Y Y Y Y 70 d. Was the approach for valuing indirect costs justified and assumptions valid? N N N NA N NA N N Y Y 25 e. Was there appropriate inclusion of intangible costs? N N N NA N NA N N N N 0 3. Analysis and reporting a. Was the study question addressed in the analysis? Y Y Y Y Y Y Y Y Y Y 100 b. Was there a range of cost estimates presented? Y Y Y Y Y Y Y Y Y Y 100 c. Were the main uncertainties identified? Y Y Y Y Y Y Y Y Y Y 100 d. Were sensitivity analyses performed on important parameter estimates, key assumptions and point estimates? N Y Y N N Y N N N Y 40 e. Was sufficient documentation and justification made for cost components, data and sources, assumptions and methods? N Y N Y Y Y Y Y N Y 70 f. Was uncertainty of the estimates and its implications sufficiently discussed? Y Y Y Y Y Y Y Y Y Y 100 g. Were limitations of the analysis discussed regarding its cost components, data, assumptions and methods? Y Y Y Y Y Y Y Y Y Y 100 h. Was there an appropriate degree of detail in the results presented to answer the study question? N Y N Y Y Y N Y N Y 60 Percentage (%) * 44 72 59 79 69 82 63 69 59 84 # Percentage of studies that fulfilled the respective criterion. * Percentage of criteria each study fulfilled. Y = fulfilled; N = not fulfilled; P = partially fulfilled; NA = not applicable. ### 4. Discussion In this review, we have found that there was a large variation in the cost estimates among the COI studies in lymphoma patients experiencing FN, ranging from$5819 to $34,756 (2013 US$) per episode of FN. The cost components that were most frequently associated with the economic burden of FN among patients with lymphoma were ward costs and hospitalization costs. Also, the included COI studies revealed that inpatient costs were more substantial than the outpatient costs of FN. Parameters associated with higher FN cost included inpatient management, male gender, discharged dead, and comorbidity and infection.

Many potential factors account for the large variation in estimating the cost of FN, such as the year of pricing, the perspective employed, and the cost estimation approach used. In addition, different healthcare systems may also be a factor for the cost variation. Despite using CPI to standardize the cost estimates, the cost of FN varied largely among countries. The studies conducted by Dulisse et al. [21] , Zhou et al. [10] and Mayordomo et al. [23] employed the same perspective of a healthcare provider, had the same time horizon, and used bottom-up method to estimate its cost. However, the overall cost varied greatly of US$26,686, US$13,823 and US\$6661 respectively. Upon closer examination, all these studies were conducted in different countries, elucidating that the large variation in the cost of FN was because these studies were conducted in different countries. The public healthcare system is unique for each country, with different standards of care as well as different costing of health care resources [27] . For instance, when drug prices were compared between the US and Canada, the price was 69% higher in the US than in Canada [28] . The drug price is also 7% higher in the UK than Canada [28] . The highest cost of FN was documented in the US, followed by Europe, and Canada could be due to the higher cost of health care resources and services provided. Therefore, future cost evaluation studies should compare the cost of FN and intervention costs within the same healthcare system, not between countries, so as to determine more accurately if the intervention is cost-effective.

Several methodological considerations were required in order to improve the cost estimates of FN in cost-of-illness studies. For example, all of the studies included in this review utilized an incidence-based approach to estimate the cost of FN. Incidence-based approach was more appropriate for the calculation of cost estimates as FN is an acute condition and this approach allowed the cost of FN to be estimated from the onset of the illness to its resolution. Incidence-based approach also considered costs over a long term. Considering how FN may potentially affect the chemotherapy regimen by delaying, reducing or discontinuing the dose [23], [29], [30], and [31], direct substantial hospitalization costs from the relapse of lymphoma cancer and indirect costs due to mortality and morbidity may be incurred as well. Future cost-of-illness studies should use an incidence-based approach with a time horizon that begins from the onset of FN and extends beyond the acute episode of FN to account for the downstream consequences of this complication.

It is noted that the indirect costs were often overlooked in the included COI studies. A study by Cosler et al. [32] indicated that indirect costs comprised a major proportion of the healthcare costs, up to 70% of overall cancer care, but such was not the case in our included studies. The studies [11] and [24] considered a human-capital method to evaluate the indirect costs [7] . Since FN is an acute condition, and typically produces temporary complete disability, the cost involved from the patient time lost from work may not be significant [11] . Our review has shown that indirect costs comprised an average of 11% of overall cost of FN. Therefore, future COI studies may consider focusing more on the direct costs, rather than indirect costs, which contribute more to the economic burden of FN.

The approach to measure direct costs also required further evaluation. Most of the studies used bottom-up method (BUM) to evaluate the direct costs [10], [11], [16], [21], [22], [23], and [24]. However, the cost estimated in those studies may not be specific to FN since there may be other costs included regardless of FN incidence. It may include costs that were associated with FN through confounding factors but were not caused by FN. One such confounding factor was age, as a study by Chrischilles et al. [33] revealed that older NHL patients were at higher risk of hospitalization for FN. Therefore, the costs of utilization of resources should be matched by various demographic characteristics with patients who experience FN to those who did not, so that only FN-specific costs may be identified. This is known as the mean difference approach [8], [34], and [35]. As such, confounding variables may potentially be eliminated as the two cohorts are paired with common characteristics to determine the incremental difference due to FN. Thus, instead of measuring the total cost estimate, it would be more appropriate to provide the FN-specific costs for future COI studies.

It was interesting to note that specific co-morbidities were associated with higher mortality and higher costs. Moreover, higher number of co-morbidities and infections such as septicemia and pneumonia were also associated with higher cost of FN in NHL patients [21] . Some studies have shown that co-morbidities such as cardiovascular diseases in lymphoma patients were associated with an increased risk of FN [2] and [36]. Therefore, these findings may enable better identification of lymphoma patients who are not only at higher risk of FN events, but also at elevated risk for higher cost of FN to be provided with preventive treatment against FN. The use of prophylactic G-CSF and antibiotics may possibly be cost-saving in patients with elevated risk for higher cost of FN. Future prediction risk models should not only include risk factors of FN to be considered for use of prophylactic therapies but also the predictors of higher cost of FN as well. Currently, the MASCC scoring system is widely used to prognosticate the severity of FN among cancer patients [37] . However, there is room to improve the sensitivity and specificity of the prognostic model. Considered that the management strategies of low-risk and high-risk FN are different, improving the current prognostic model to predict the severity of FN is worth to further explore in future studies.

The cost of medications was identified as a large component of the economic burden in patients manifesting FN. Several meta-analysis have demonstrated that prophylactic use of G-CSF significantly reduce patients’ risk to experience FN [38] and [39]. However, several studies [40] and [41] have also suggested that the primary prophylaxis with G-CSF throughout all chemotherapy cycles may not be cost-effective. Hence, other prophylaxis strategies are being explored in the literature, which include limiting primary prophylaxis to the first two cycles of chemotherapy only [40] . In addition, biosimilars of G-CSF have appeared in clinical practice [42] . Several studies have demonstrated that the biosimilar G-CSF is equivalent in terms of efficacy and safety when compared against G-CSF [43] and [44]. Adoption of the biosimilar G-CSF in the clinical practice may reduce healthcare costs and the economic burden on patients. However, there is still a need for longer follow up studies to confirm the safety, efficacy as well as cost effectiveness of these biosimilars [42] .

Ward cost was found to be the cost component to be most frequently associated with the cost of FN. Since costing can take substantial time and effort, future COI studies can focus on estimating the main cost drivers even more accurately. Different levels of precision in hospital costing may be applied to different cost items [45] . For example, as the radiology cost is less than 5% of overall inpatient care [10], [11], and [22], it may not be worthwhile to collect considerable detail on trivial cost component as an average radiology charge would suffice. Conversely, ward costs covers more than 50% of total inpatient care cost in all the studies. Thus, it may be important to apply micro-costing by noting the numbers and grades of ward as well as the days of stay of lymphoma patients who encounter FN. By doing so, the cost components that are most frequently associated with the economic burden are made more accurate in estimating and influencing the overall inpatient costs. In addition, different studies may account for ward fees in different manners. For example, studies [10], [24], [25], and [26] that did not specify the how the ward costs were estimated may incorporate drug administration fee, physician visit fee or nursing fee into the ward costs, but other studies [11] do not. Therefore, future COI studies should clarify what is considered in the ward cost and medication cost so as to enhance the internal validity as well as improve the accuracy of the cost components that were most frequently associated with the economic burden for future COI studies [45] and [46].

There were several limitations associated with this review. Firstly, there were relatively limited COI studies that were dedicated to review the cost of FN in lymphoma patients. Among the ten studies identified, only three studies [21], [23], and [24] estimated their costs specifically for lymphoma patient populations within their studies, while the rest of the studies estimated cost of FN from their study population, which consisted of lymphoma patients among other types of cancer patients. Due to these challenges, no definite inference was possible to provide the average cost of FN related to lymphoma patients. Nevertheless, the cost of FN among lymphoma patients revealed in those COI studies proved to be considerable. Secondly, only papers written in English were included, which restricted the number of studies screened and may potentially introduce selection bias. However, we expected these included studies to be of higher methodological quality since most of the high quality studies would be published in English. In addition, we are uncertain whether the primary studies adhere to any specific guidelines for management of NHL and FN. However, considering that different management pathways may affect the estimation of economic burden of FN, it should be noted that such variation might limit the interpretability of the findings in this review. At last, in addition to comorbidities, being elderly may also serve as an important prognostic factor that is associated with high morbidity and mortality, hence leading to higher economic burden of FN. Future studies should evaluate how age affects the economic burden of FN.

### 5. Conclusions

Our review has highlighted ward and medication costs of inpatient care were most frequently identified to be associated with the cost of FN related to lymphoma patients. Future studies should place greater emphasis on improving the accuracy of costing of those costs, as determining the true cost of FN is important in clinical decision-making. Our review has also highlighted predictors of higher cost of FN among lymphoma patients. Future cost evaluation studies may be conducted to consider cost-containment strategies for these predictors, including the use of prophylactic G-CSF and antibiotics, to reduce the economic burden of FN among those lymphoma patients.

### Conflict of interest

The authors have declared no conflict of interest for this article. No funding has been received for the conduct of this study and preparation of this manuscript.

### Reviewers

Jean Klastersky, Ph.D.: Professor, Institut Jules Bordet, Department of Medicine, 121 Boulevard de Waterloolaan, B-1000 Brussels, BELGIUM

Bernardo Rapoport MD: Medical Oncologist In-Charge, The Medical Oncology Centre of Rosebank, Parklands 2121, SOUTH AFRICA

Rosanna Tarricone, PhD: Associate Professor, Bocconi University, Public Management, Via Roentgen, 1, I-20136 Milan, ITALY

### Author contributions

XJW, SEL and AC conceived of the study, participated in the design of the study, participated in the literature search and data extraction, interpreted data, and drafted the manuscript. All authors read and approved the final manuscript.

### References

• J.H. Ng, X.Y. Ang, S.H. Tan, M. Tao, S.T. Lim, A. Chan. Breakthrough febrile neutropenia and associated complications in Non-Hodgkin's lymphoma patients receiving pegfilgrastim. Acta Haematol. 2011;125:107-114
• R. Pettengell, A. Bosly, T.D. Szucs, et al. Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study. Br J Haematol. 2009;144:677-685
• M.S. Aapro, J. Bohlius, D.A. Cameron, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer (Oxf, Engl: 1990). 2011;47:8-32
• M. Wong, J. Jin, M.H. Tan, et al. Prospective audit of post-chemotherapy febrile neutropenia in patients with solid cancer and lymphoma in two Singaporean cancer centres. Ann Acad Med Singap. 2012;41:287-293
• R. Pettengell, H.E. Johnsen, P.J. Lugtenburg, et al. Impact of febrile neutropenia on R-CHOP chemotherapy delivery and hospitalizations among patients with diffuse large B-cell lymphoma. Support Care Cancer. 2012;20:647-652
• R. Tarricone. Cost-of-illness analysis. What room in health economics?. Health Policy (Amst, Neth). 2006;77:51-63
• T.A. Hodgson, M.R. Meiners. Cost-of-illness methodology: a guide to current practices and procedures. Milbank Meml Fund Q Health Soc. 1982;60:429-462
• J.E. Segel. Cost-of-illness studies—a primer. (RTI-UNC Center of Excellence in Health Promotion Economics, 2006) 1-39
• A. Ament, S. Evers. Cost of illness studies in health care: a comparison of two cases. Health Policy (Amst, Neth). 1993;26:29-42
• Y.P. Zhou, J. Jin, Y. Ding, et al. Direct costs associated with febrile neutropenia in inpatients with hematological diseases in Singapore. Support Care Cancer. 2014;22(6):1447-1451
• A.M. Hendricks, E.T. Loggers, J.A. Talcott. Costs of home versus inpatient treatment for fever and neutropenia: analysis of a multicenter randomized trial. J Clin Oncol. 2011;29:3984-3990
• D. Weycker, J. Malin, J. Edelsberg, A. Glass, M. Gokhale, G. Oster. Cost of neutropenic complications of chemotherapy. Ann Oncol. 2008;19:454-460
• R. Karen. Measuring and estimating costs. Essentials of pharmacoeconomics (Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA, 2009) 250
• T. McLinden. A scoping review of component costs of foodborne illness and analysis of the association between study methodologies and component costs to the cost of a foodborne illness. (, 2013)
• S.Y. Liou, J.M. Stephens, K.T. Carpiuc, W. Feng, M.F. Botteman, J.W. Hay. Economic burden of haematological adverse effects in cancer patients: a systematic review. Clin Drug Investig. 2007;27:381-396
• N. Lathia, N. Mittmann, C. DeAngelis, et al. Evaluation of direct medical costs of hospitalization for febrile neutropenia. Cancer. 2010;116:742-748
• A. Chan, Q.X. Wong, M.K. Ali, M. Wong, L.Y. Hsu. Clinical efficacy of adjunctive G-CSF on solid tumor and lymphoma patients with established febrile neutropenia. Support Care Cancer. 2014;22:1105-1112
• C. Kriza, M. Emmert, P. Wahlster, C. Niederlander, P. Kolominsky-Rabas. Cost of illness in colorectal cancer: an international review. Pharmacoeconomics. 2013;31:577-588
• A. Larg, J.R. Moss. Cost-of-illness studies: a guide to critical evaluation. Pharmacoeconomics. 2011;29:653-671
• N. Stuhldreher, A. Konnopka, B. Wild, et al. Cost-of-illness studies and cost-effectiveness analyses in eating disorders: a systematic review. Int J Eat Disord. 2012;45:476-491
• B. Dulisse, X. Li, J.A. Gayle, et al. A retrospective study of the clinical and economic burden during hospitalizations among cancer patients with febrile neutropenia. J Med Econ. 2013;16:720-735
• P.M. Livingston, M. Craike, M. Slavin. Clinical and economic burden of emergency department presentations for neutropenia following outpatient chemotherapy for cancer in Victoria Australia. Oncologist. 2012;17:998-1004
• J.I. Mayordomo, A. Lopez, N. Vinolas, et al. Retrospective cost analysis of management of febrile neutropenia in cancer patients in Spain. Curr Med Res Opin. 2009;25:2533-2542
• C.L. Bennett, E.A. Calhoun. Evaluating the total costs of chemotherapy-induced febrile neutropenia: results from a pilot study with community oncology cancer patients. Oncologist. 2007;12:478-483
• S.L. Michels, R.L. Barron, M.W. Reynolds, K. Smoyer Tomic, J. Yu, G.H. Lyman. Costs associated with febrile neutropenia in the US. Pharmacoeconomics. 2012;30:809-823
• D. Weycker, A. Danel, A. Marciniak, K. Bendall, M. Lipsitz, R. Pettengell. Economic costs of chemotherapy-induced febrile neutropenia among patients with non-Hodgkin's lymphoma in European and Australian clinical practice. BMC Cancer. 2012;12:362
• E.B.R. Jakubowski, G.R. Chambers. Health care systems in the EU a comparative studyPN European Parliament. (, 1998) Available from: http://www.europarl.europa.eu/workingpape
• RGE. Drug pricing: a comparison between Canada and other countries. Toronto, Ontario. (, 2002) Available from: http://www.pmprb-cepmb.gc.ca/english/view.asp?.x=138&mid=90 [accessed 11.02.14]
• J. Chang. Chemotherapy dose reduction and delay in clinical practice. Evaluating the risk to patient outcome in adjuvant chemotherapy for breast cancer. Eur J Cancer (Oxf, Engl: 1990). 2000;36(Suppl. 1):S11-S14
• G.H. Lyman, N.M. Kuderer. Epidemiology of febrile neutropenia. Support Cancer Ther. 2003;1:23-35
• G.H. Lyman, V.A. Morrison, D.C. Dale, J. Crawford, D.J. Delgado, M. Fridman. Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin's lymphoma receiving CHOP chemotherapy. Leuk Lymphoma. 2003;44:2069-2076
• L.E. Cosler, E.A. Calhoun, O. Agboola, G.H. Lyman. Effects of indirect and additional direct costs on the risk threshold for prophylaxis with colony-stimulating factors in patients at risk for severe neutropenia from cancer chemotherapy. Pharmacotherapy. 2004;24:488-494
• E. Chrischilles, D.J. Delgado, B.S. Stolshek, G. Lawless, M. Fridman, W.B. Carter. Impact of age and colony-stimulating factor use on hospital length of stay for febrile neutropenia in CHOP-treated non-Hodgkin's lymphoma. Cancer Control. 2002;9:203-211
• H.G. Birnbaum, R.C. Kessler, S.W. Lowe, et al. Costs of attention deficit-hyperactivity disorder (ADHD) in the US: excess costs of persons with ADHD and their family members in 2000. Curr Med Res Opin. 2005;21:195-206
• L.M. Rubenstein, E.A. Chrischilles, M.D. Voelker. The impact of Parkinson's disease on health status, health expenditures, and productivity. Estimates from the National Medical Expenditure Survey. Pharmacoeconomics. 1997;12:486-498
• A. Chan, C.P. Lee, J. Chiang, R. Ng. Breakthrough febrile neutropenia and associated complications among elderly cancer patients receiving myelosuppressive chemotherapy for solid tumors and lymphomas. Support Care Cancer. 2013;21:2137-2143
• J. Klastersky, M. Paesmans, E.B. Rubenstein, et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000;18:3038-3051
• K.L. Cooper, J. Madan, S. Whyte, M.D. Stevenson, R.L. Akehurst. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer. 2011;11:404
• N.M. Kuderer, D.C. Dale, J. Crawford, G.H. Lyman. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007;25:3158-3167
• M.J. Aarts, J.P. Grutters, F.P. Peters, et al. Cost effectiveness of primary pegfilgrastim prophylaxis in patients with breast cancer at risk of febrile neutropenia. J Clin Oncol. 2013;31:4283-4289
• N. Lathia, P.K. Isogai, C. De Angelis, et al. Cost-effectiveness of filgrastim and pegfilgrastim as primary prophylaxis against febrile neutropenia in lymphoma patients. J Natl Cancer Inst. 2013;105:1078-1085
• K. Welte. G-CSF: filgrastim, lenograstim and biosimilars. Expert Opin Biol Ther. 2014;14:983-993
• C.F. Waller, V.F. Semiglazov, S. Tjulandin, D. Bentsion, S. Chan, R. Challand. A phase III randomized equivalence study of biosimilar filgrastim versus Amgen filgrastim in patients receiving myelosuppressive chemotherapy for breast cancer. Onkologie. 2010;33:504-511
• U. Gatzemeier, T. Ciuleanu, M. Dediu, E. Ganea-Motan, H. Lubenau, A. Del Giglio. XM02, the first biosimilar G-CSF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or non-small cell lung cancer receiving platinum-based chemotherapy. J Thorac Oncol. 2009;4:736-740
• M.F.S.M. Drummond, G.W. Torrance, B.J. O’Brien, G.L. Stoddart. Methods for the economic evaluation of health care programmes. 3rd ed (Oxford University Press, 2005)
• J. Ruof, J.L. Hulsemann, T. Mittendorf, et al. Costs of rheumatoid arthritis in Germany: a micro-costing approach based on healthcare payer's data sources. Ann Rheum Dis. 2003;62:544-549

Xiao Jun Wang is a Doctor of Philosophy candidate at Department of Pharmacy, National University of Singapore. His research interest includes supportive care, pharmacoeconomics, and outcomes research.

Shaun Eric Lopez was a candidate for the Bachelor of Science (Hons) (Pharmacy) degree at the National University of Singapore.

Alexandre Chan is an Associate Professor at Department of Pharmacy, National University of Singapore. He is also a specialist pharmacist (oncology pharmacy) at Department of Pharmacy, National Cancer Centre Singapore. His research interest includes supportive care in cancer patients, clinical relevance of drug interactions in cancer patients and clinical pharmacy education.

### Footnotes

a Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore

b Department of Pharmacy, National Cancer Centre Singapore, Singapore

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.

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