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Symptom Management and Supportive Care

Evaluating the Total Costs of Chemotherapy-Induced Febrile Neutropenia: Results from a Pilot Study with Community Oncology Cancer Patients

^aThe Robert H. Lurie Comprehensive Cancer Center and the Division of Hematology/Oncology, Northwestern University, Chicago, Illinois, USA; ^bUniversity of Illinois School of Public Health, Chicago, Illinois, USA

Key Words. Costs • Febrile neutropenia • Chemotherapy • Toxicity

Correspondence: Charles L. Bennett, M.D., Ph.D., Northwestern University, 303 E. Chicago Street, Suite 8250, Chicago, Illinois 60611, USA. Telephone: 312-503-0804; Fax: 312-503-1040; e-mail: cbenne{at}northwestern.edu

Received November 21, 2006; accepted for publication January 17, 2006.

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. Discuss the definitions of direct and indirect costs of medical care.
   
2. Describe the feasibility of obtaining information on direct and indirect medical costs associated with febrile neutropenia.
   
3. Identify clinical and nonclinical factors that are associated with larger estimates of direct and indirect medical costs for febrile neutropenia.
   

	ABSTRACT

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Purpose. While cancer chemotherapy–related febrile neutropenia affects patients' activities and medical expenditures, few studies have reported on the total costs of this condition. Here, we evaluate the feasibility of obtaining detailed and comprehensive cost information on patients who experience febrile neutropenia during cancer chemotherapy treatment.

Methods. Community oncology cancer patients who experienced chemotherapy-associated febrile neutropenia recorded information about use of medical care, tests, devices, medications, and lost productivity. Direct cost estimates were derived from Medicare Physician Fee Schedules and cost-to-charge ratios. Indirect cost estimates were based on modified Labor Force, Employment, and Earnings data for employed patients and wages earned by paid caregivers. Multivariate regression models evaluated predictors of higher direct, indirect, and total costs.

Results. Outpatients' mean direct and indirect costs were $5,704 and $1,201 (lymphoma), $1,094 and $1,530 (breast cancer), and $1,329 and $1,325 (lung cancer and myeloma), respectively. The mean direct and indirect costs were three- to tenfold and 1.5- to threefold greater for inpatients, respectively. Factors associated with higher direct costs of care included diagnosis of lymphoma and inpatient care; higher indirect costs, male versus female gender; higher total costs, lymphoma diagnosis and inpatient care.

Conclusion. Estimation of the total costs of cancer-related neutropenia is feasible. Indirect costs appear to account for as much as half of the total supportive care costs when febrile neutropenia is managed in the outpatient setting and about one fifth of the total supportive care costs in the inpatient setting.

Disclosure of potential conflicts of interest is found at the end of this article.

	INTRODUCTION

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Approaches to cancer treatment are both complex and costly [1, 2]. In response to a Congressional mandate, cancer cost estimates are summarized and reported periodically, and include three elements: direct costs, indirect morbidity costs, and indirect mortality costs. Direct costs represent expenditures for procedures, tests, and services associated with treatment and care. Indirect morbidity costs account for lost income from work disability and time spent away from the workplace. Indirect mortality costs are measured as lost income that results from early mortality because of cancer. Of the estimated $209.9 billion in direct and indirect cancer costs in 2005, $74.0 billion can be attributed to direct medical costs and $135.9 billion to indirect morbidity and mortality costs—primarily lost productivity [3]. These costs represent the societal value of oncology-related resources consumed in providing cancer care, including the costs associated with drugs and devices, consultation with physicians, and hospitalization. To date, detailed cancer cost studies report primarily on medical expenditures for treatment and few report on costs associated with treatment-related toxicities [1–11]. Myelosuppression is the major dose-limiting toxicity associated with cancer chemotherapy. Prior to widespread use of oral antibiotics and hematopoietic growth factors, chemotherapy-associated neutropenia was resource intensive, with inpatient treatment for evaluation and administration of empiric broad-spectrum antibiotics. Lyman and Kuderer [7] reported on 55,276 episodes of febrile neutropenia requiring hospitalization at 115 academic medical centers over a 6-year period. The mean hospitalization costs for chemotherapy-associated febrile neutropenia were $12,032 for persons with solid tumors and $19,061 for persons with non-Hodgkin's lymphoma or Hodgkin's disease. More recently, mean per episode direct costs as low as $2,600 have been reported when febrile neutropenia is managed in the outpatient setting, a strategy that is considered in selected low-risk patients [9].

Few studies have reported estimates of indirect morbidity costs incurred by cancer patients and their caregivers [12–16]. Indirect morbidity costs include the value of lost time from work as a result of the illness, decreased productivity while at work, time or money spent by people looking after the patient, and premature retirement. In a study of 156 Medicare or privately insured women with breast cancer who received care at a large university-affiliated comprehensive cancer center, monthly indirect costs incurred by breast cancer patients averaged $1,455, with half of this estimate being attributed to lost income by patients [12]. The most comprehensive study of indirect costs related to lost time from work evaluated administrative data for 763,527 patients with breast, colorectal, corpus uteri, gastric, head and neck, lung, melanoma of the skin, ovary, prostate, renal, and urinary bladder cancers from linked Surveillance, Epidemiology, and End Results–Medicare files [13]. Net patient time costs during the initial phase of care were $271, $842, $5,348, and $5,605, and during the last year of life were $1,509, $7,799, $7,435, and $7,388, for patients with melanoma of the skin, prostate cancer, gastric cancer, and ovarian cancer, respectively. In 2005, indirect costs resulting from lost patient time during the initial phase of cancer care were $2.3 billion [13]. This comprehensive study found that indirect costs for cancer care in the U.S. varied by tumor site and phase of care.

Our prior study of women with ovarian cancer is the only study that has reported estimates of indirect costs of chemotherapy-associated neutropenia [9]. For a cohort of women with neutropenia from ovarian cancer chemotherapy who received care at a tertiary care medical center, we reported mean indirect costs of $3,810, of which lost time from work accounted for $2,400 for patients and $710 for caregivers, and paid caregivers received a mean of $700 per toxicity episode [9]. One fifth of the employed women with advanced ovarian cancer in that study discontinued their work because of chemotherapy-associated neutropenia.

Building on our prior study, we evaluated the feasibility of obtaining detailed information from the community oncology setting on the direct, indirect, out-of-pocket, and total costs of supportive care for chemotherapy-associated febrile neutropenia. We attempted to improve on the methodology used in our prior cost of chemotherapy associated toxicity study by including detailed information from patients with diverse tumor types who were treated as outpatients, evaluating direct and indirect costs of care, and obtaining cost information from several community oncology practices.

	METHODS

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Ten community-based hematology/oncology physician practices participated in this study. Patient eligibility criteria included: age 18 years or over, diagnosis of cancer, recent treatment with chemotherapy, and documented episode of febrile neutropenia (defined as temperature 38°C and absolute neutrophil count <500/mm³. Patients who had undergone stem cell transplantation were ineligible. All patients in participating practices between July 2001 and June 2002 were identified following the occurrence of a documented febrile neutropenic event. After the treating physician determined that the event was chemotherapy related and that the patient met the eligibility criteria, study nurses informed patients about the study and queried them about their interest in the study. If a patient agreed to participate in the study and consent was obtained, patients were asked to complete a questionnaire regarding direct and indirect costs associated with management of the febrile neutropenia event. Less than 5% of patients approached refused participation in the study.

Patients were queried about resources used as a result of febrile neutropenia related to inpatient hospitalizations, outpatient visits from traditional and alternative health care providers, laboratory tests, phone calls, hospitalizations, home health visits, medications (including hematopoietic colony-stimulating factors and over-the-counter medications), medical devices, time patients missed from work, time spent by caregivers to assist with activities of daily living during episodes of toxicity, and time spent by paid caregivers. Also, a medical history case report form, based on a review of medical records, was completed by the research staff. These data included information on patient demographics, disease, treatment (including antibiotics, hematopoietic colony-stimulating factors, and site of care—inpatient versus outpatient), and medical charges. Resource utilization and charges were tracked by the patient from study entry, operationally defined as coincident with the onset of febrile neutropenia, and continued through the end of the neutropenic "episode." Economic data included a detailed listing of the medical care services received by subjects, attribution of the cause of each service, and loss of work time because of febrile neutropenia.

The second part of the economic analysis assigned a cost to each item. Unit costs came from the Medicare Physician Fee Schedule for outpatient services, Medicare cost-to-charge ratios, and The Red Book for pharmaceuticals [17]. Device costs were calculated based on the average price from three national drug stores. Phone calls to medical providers were estimated to be 15 minutes to a physician or a nurse; costs were allocated depending on whom the patient spoke with. Standard unit costs were multiplied by the average number of visits, labs, hospitalizations, medications, and medical devices to calculate an estimate of the average cost per person in each of the three study groups. Indirect costs (i.e., productivity loss) were based on wages paid to hired caregivers and modified Labor Force, Employment, and Earnings data based on job category for patients who were employed during the evaluation period [18].

Multivariate analysis of variance was used to evaluate the association between direct, indirect, and total costs and patient age (65 versus >65 years old), tumor type (breast, lymphoma, or other), site of care (outpatient versus some or all in the inpatient setting), race/ethnicity (white versus non-white), insurance (commercial versus Medicare), and gender. Cost estimates were transformed using the natural logarithm because these values were highly skewed. The natural logarithm of costs was included as the dependent variable.

	RESULTS

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Community oncology practices in California (n = 2 practices), Washington DC (n = 1), Maryland (n = 2), New York (n = 2), and Virginia (n = 3) agreed to participate in the study. Economic information was obtained for 71 patients who developed cancer chemotherapy–associated febrile neutropenia, including 23 patients with lymphoma, 22 patients with breast cancer, seven patients with lung cancer, and five patients with multiple myeloma. Forty-five patients were female (63%) and 24 were 65 years of age or older (35%).

Febrile neutropenia–associated costs varied according to diagnosis and whether treatment was provided as an inpatient or outpatient (Table 1). For persons treated as an outpatient (n = 43 individuals), the mean direct and indirect costs were $5,704 and $1,201 for lymphoma patients, $1,094 and $1,530 for breast cancer patients, and $1,329 and $1,325 for patients with lung cancer/myeloma, respectively. Medications accounted for the largest percentage of the direct costs (84% for lymphoma patients, 66% for breast cancer patients, and 58% for patients with lung cancer and myeloma), while work loss accounted for >95% of the indirect costs for persons in each of the three diagnostic groups (Fig. 1). In contrast, for persons who received some inpatient care (n = 28 individuals), the mean direct costs were three to tenfold greater and the mean indirect costs were 1.5- to threefold greater: $17,869 and $3,732 for lymphoma patients, $10,354 and $2,832 for breast cancer patients, and $10,311 and $1,839 for patients with lung cancer and myeloma, respectively. Hospitalizations accounted for 76%–80% of the total direct costs, while patient work loss accounted for 83%–97% of the total indirect costs of each of the three diagnostic groups (Fig. 2). We also evaluated the association of sociodemographic, clinical, and site of care factors with costs of care (data not shown). Factors associated with higher direct costs of care were a diagnosis of lymphoma (p = .006) and receiving care in the inpatient setting (p = .001); factors associated with higher indirect costs were male versus female gender (p = .02); and factors associated with higher total costs were a lymphoma diagnosis (p = .02) and receiving some care in the inpatient setting (p = .001).

View larger version (17K): [in this window] [in a new window]   Figure 1. Direct and indirect costs of febrile neutropenia for cancer patients treated entirely as outpatients.

View larger version (22K): [in this window] [in a new window]   Figure 2. Direct and indirect costs of febrile neutropenia for cancer patients who receive some or all of their care in the inpatient setting.

	DISCUSSION

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Our findings on direct costs of cancer care are remarkably similar to those reported in prior studies of direct costs of cancer-associated neutropenia [7–10]. Among cancer patients who receive inpatient care, both the Lyman and Kuderer [7] study and this study estimate that mean direct costs are between $10,000 and $20,000, with lymphoma being 50%–60% more costly than breast cancer and other nonhematologic malignancies. In both studies, much of this difference is likely to be related to the older mean age of patients with lymphoma, compared with those with breast cancer, the greater extent of comorbid medical illnesses, and the greater intensity of care used to treat febrile neutropenia for patients with lymphoma than for patients with breast cancer. For direct costs of care for persons who were not hospitalized, Hutton et al. [10] and our study reported costs that are 10%–20% as great as those reported for patients who receive inpatient care. With respect to indirect costs, we reported previously that, for ovarian cancer patients with chemotherapy-associated neutropenia, indirect costs accounted for 34%–86% of the total costs. In the more recent era covered in this study, indirect costs continue to be high, accounting for 17%–58% of the total costs of patients who receive outpatient care only and 17%–50% of the total costs of patients who are hospitalized for treatment of febrile neutropenia [9]. In contrast, in this study, the estimated mean indirect costs were $1,200–$1,500 for patients who received outpatient care only and $1,840–$3,730 for patients who received inpatient care for this toxicity. In both pilot studies, lost income for the patient accounted for the largest percentage of the indirect costs (63% in the prior study versus 83%–96% in this study). Of note, the prior study included estimates of the costs of lost income for caregivers ($710), which, if excluded, would result in an estimate of foregone patient wages accounting for 78% of the mean total indirect costs associated with chemotherapy-associated neutropenia.

Our prior study of ovarian cancer patients who received care at a tertiary care medical center is the only prior report to include detailed information on clinical, sociodemographic, and site of care factors associated with higher costs of care for febrile neutropenia [9]. In that study, as in this study, a diagnosis of lymphoma was an important predictor of higher direct costs associated with febrile neutropenia. It is likely that lymphoma patients have received many cycles of chemotherapy and, as a result, have longer periods of neutropenia and longer mean lengths of stay when hospitalized for this complication. Our study is the first to evaluate the relationship between these factors and indirect costs. Compared with women, men with febrile neutropenia had markedly higher estimates of lost wages, which is the primary component of the indirect cost estimates. With respect to total costs of febrile neutropenia, as expected, receipt of care in the inpatient setting was the most important factor associated with higher cost estimates. Programs and strategies that support outpatient treatment may have important clinical and economic impacts on the overall burden of neutropenia [19–21]. However, it is possible that these patients are selected for outpatient treatment because of their lower risk for complications, and similar savings may not be achieved by managing all patients in the outpatient setting.

As with all pilot studies, there are limitations that should be identified. Our data-collection methods relied upon patient reporting of many of the costs of care. This method has been used in other comprehensive cost-of-illness studies of persons with serious medical illnesses as well as in the prior costs of chemotherapy-associated toxicity studies, and has been validated where possible against medical bills [9, 22]. Second, only cancer patients who received care in 10 community oncology practices were included in this pilot study. However, after the introduction of the Health Insurance Portability and Accountability Act, it may be more expensive to recruit patients to cost of toxicity studies, because health care personnel, rather than research assistants, may be required to identify eligible patients [23]. Third, the choice of the inpatient versus outpatient setting and approach to treatment of febrile neutropenia was based primarily on physician preference, taking into consideration such factors as patient comorbidities and physical examination and laboratory findings. Few patients with febrile neutropenia received hematopoietic growth factors as a supportive care treatment. Fourth, the range of patients evaluated in this feasibility study (primarily patients with lymphoma or cancer of the breast or lung) is not representative of the general oncology setting, where there are large numbers of patients with gastrointestinal cancers. Additional studies that include a broader range of patients are needed. Finally, our estimates of indirect costs were conservative, because other aspects of indirect costs, such as parking, meals out of the house, and child care costs, were not included in our study.

In conclusion, this study has shown that, with the involvement of cancer patients who receive care in community oncology settings, evaluation of the direct, indirect, and total costs of one of the most common cancer-associated toxicities, neutropenia, is feasible. Comprehensive costs of toxicity studies are likely to be important to patients, physicians, and policy makers. Indirect costs, which accounted for over half of the total costs of supportive care for persons who received outpatient care and as much as one fifth of the total supportive care costs for persons who receive inpatient care, have rarely been included in the few prior estimates of the cost of chemotherapy-related neutropenia.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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Research for this manuscript was supported by an unrestricted grant from Amgen. C.L.B. has acted as a consultant for Amgen, Sanofi, and Millenium.

	ACKNOWLEDGMENTS

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Supported by an unrestricted grant from Amgen.

	REFERENCES

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