Evaluating the Total Costs of Chemotherapy-Induced Toxicity: Results from a Pilot Study with Ovarian Cancer Patients

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1 Evaluating the Total Costs of Chemotherapy-Induced Toxicity: Results from a Pilot Study with Ovarian Cancer Patients ELIZABETH A. CALHOUN, CHIH-HUNG CHANG, EMILY E. WELSHMAN, DAVID A. FISHMAN, JOHN R. LURAIN, CHARLES L. BENNETT The Institute for Health Services Research and Policy Studies, Department of Obstetrics and Gynecology, the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Department of Medicine, Division of Hematology/Oncology, Chicago, Illinois, USA and the Chicago VA Healthcare System/Lakeside Division, Chicago, Illinois, USA ABSTRACT Purpose. While chemotherapy-related toxicities affect cancer patients activities of daily living and result in large expenditures of medical care for treatment, few studies have assessed the out-of-pocket and indirect costs incurred by patients who experience toxicity. The objective of this study was to evaluate the feasibility of obtaining detailed and comprehensive cost information from patients who experienced neutropenia, thrombocytopenia, or neurotoxicity during treatment. Methods. Ovarian cancer patients who experienced chemotherapy-associated hematologic or neurologic toxicities were asked to record detailed information about hospitalization, laboratories, physician visits, phone calls, home visits, medication, medical devices, lost productivity, and caregivers. Resource estimates were converted into cost units, with direct medical cost estimates based on hospital cost-accounting data and indirect costs (i.e., productivity loss) on modified labor force, employment, and earnings data. INTRODUCTION Approaches to cancer treatment have rapidly grown complex and costly causing heightened awareness among patients, physicians, employers and insurance providers. Annual costs for cancer-related treatments are about $107 billion, accounting for 20% of all health care costs [1]. These costs represent the societal value of oncology-related resources consumed in providing cancer care, including the Key Words. Costs Toxicities Chemotherapy Results. Direct medical costs were highest for neutropenia (mean of $7,546/episode), intermediate for thrombocytopenia (mean of $3,268/episode), and lowest for neurotoxicity (mean of $688/episode). Indirect costs relating to patient and caregiver loss and payments for caregiver support were substantial, accounting for $4,220, $3,834, and $4,282 for patients who developed neurotoxicity, neutropenia, and thrombocytopenia, respectively. The total costs of chemotherapy-related neurotoxicity, neutropenia, and thrombocytopenia were $4,908, $11,830, and $7,550. Conclusion. Our study has shown that, with the assistance of patients who are experiencing toxicity, estimation of the total costs of cancer-related toxicities is feasible. Indirect costs, while not included in prior estimates of the costs of toxicity studies, accounted for 34% to 86% of the total costs of cancer supportive care. The Oncologist 2001;6: costs associated with drugs and devices, consultation with physicians, and hospital costs. However, most of the detailed information on cancer costs relates to the direct medical expenditures for cancer treatment, rather than care required for treatment-related toxicity. Very little is known about the societal value of resources used as a result of toxicity, including both the direct medical costs for supportive care and indirect costs of care. The indirect costs include Correspondence: Elizabeth A. Calhoun, Ph.D., The Institute for Health Services Research and Policy Studies, Department of Obstetrics and Gynecology, the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, 339 E. Chicago Avenue, Room 717, Chicago, Illinois 60611, USA. Telephone ; Fax: ; e-calhoun@northwestern.edu. Received June 11, 2001; accepted for publication August 30, AlphaMed Press /2001/$5.00/0 The Oncologist 2001;6:

2 Calhoun, Chang, Welshman et al. 442 the value of lost time from as a result of the illness, decreased productivity while at, time or money spent by people looking after the patient, and premature retirement or death [2-4]. It is possible that the total costs of cancer care have been markedly underestimated. In this study, we evaluated the feasibility of obtaining detailed estimates of the total direct and indirect costs of toxicities for women with a particular type of tumor ovarian cancer. Ovarian cancer is the fourth most common cancer in women. In 2000, it affected over 23,000 women and accounted for 14,000 deaths [5]. Supportive care issues are especially large for ovarian cancer, as 75% of women with this malignancy have advanced disease at presentation. Almost all of these individuals receive several cycles of multi-drug chemotherapy regimens, and the majority experience at least one episode of chemotherapy-associated toxicity [6, 7]. METHODS The objective of this study was to evaluate the feasibility of obtaining detailed information on direct and indirect costs of toxicity among a cohort of women receiving chemotherapy for ovarian cancer. We focused on three common toxicities neurotoxicity, neutropenia, and thrombocytopenia. Patients were queried about resources used as a result of the toxicity, including outpatient visits from traditional and alternative health care providers, labs, phone calls, hospitalizations, home health visits, medications (including over the counter), medical devices, time missed from, and time spent by caregivers to assist with activities of daily living during episodes of toxicity. Resource utilization was tracked from study entry, operationally defined as coincident with the onset of a toxicity and continued through the end of the toxicity episode. The Neurotoxicity Group had to meet at least one of the following: signs and symptoms of grade 2 or higher peripheral neuropathy (e.g., burning/tingling in fingers/toes, difficulty buttoning buttons); loss of feeling, numbness; signs of ototoxicity (hearing loss); and blurred vision. The Hematotoxicity Group had to meet at least one of the following: grade 3 or 4 neutropenia (neutrophil count less than 1,000/mm 3 ) in the past 2 weeks, and thrombocytopenia (Eastern Cooperative Oncology Group score for platelets less than 100,000). Prior to study initiation, the project was approved by the Cancer Research Organization of the Robert H. Lurie Comprehensive Cancer Center and the Human Subjects Protection Committee of Northwestern University. In clinic, trained research assistants obtained informed consent, reviewed the instrument instructions with each participant, and answered questions as needed. Episodes consisted of up to 9 months for the Neurotoxicity Group and up to 3 months for the hematologic toxicity groups, generally representing the time period for which gynecologic oncologist consultants felt that these toxicities might be expected to have an impact on one s life. Economic variables were collected at baseline and every 3 months during the follow-up period. All patients were recruited within 1 month of experiencing the toxicity and, by design, no patient met criteria in more than one of the toxicity groups. Most questionnaires were obtained in-person at clinic visits. Patients who were unable to complete the instruments at the time of their visit were given a postage-paid return envelope. All patients whose mailed questionnaires had not been received by Northwestern within 7 days were interviewed over the phone. Only a small number of patients were not interviewed in clinic. The economic data collected for this study included a detailed listing of the medical care services received by subjects, attribution of the cause of each service, and loss of time because of toxicities. Primary analyses included only those resources that were directly attributed to a toxicity or its treatment. Each toxicity was analyzed separately. The second part of the economic analysis assigned a value to each item. The unit costs came from standard sources, such as hospital bills for in-patient stays, the Medicare Physician Fee Schedule for outpatient services, and The Red Book for pharmaceuticals [8]. The device costs were calculated based on the average price from three national drugstores. Phone calls to medical providers were estimated to be 15 minutes to a physician or a nurse, depending upon with whom the patient spoke. 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 modified labor force, employment, and earnings data [9]. Finally, a total cost of toxicity was derived for each participant. RESULTS The study included economic information on chemotherapy-related neurotoxicity (n = 42 patients), neutropenia (n = 26 patients), and thrombocytopenia (n = 15 patients). Direct medical costs were highest for neutropenia (mean of $7,546 per episode), intermediate for thrombocytopenia (mean of $3,268 per episode), and lowest for neurotoxicity (mean of $688 per episode) (Table 1). For the hematologic toxicities, inpatient medical care accounted for the largest part of the direct medical costs ($6,204 for neutropenia [82% of the total direct costs] and $2,654 for thrombocytopenia [81% of the total costs]), followed by outpatient pharmaceuticals ($721 for neutropenia; 10% of the costs). In contrast, neurotoxicity, while disabling, was

3 443 Chemotherapy-Induced Toxicity Costs Table 1. Direct costs of chemotherapy-associated toxicity for women with ovarian cancer costs (n = 42) Direct costs costs (n = 26) Direct costs costs (n = 15) Direct costs Direct costs $688 $7,546 $3,268 Hospital inpatient $0 0% $6,204 82% $2,657 81% Physician visits $211 31% $250 3% $250 8% ER visits $0 0% $77 1% $50 1.5% Drugs/devices $432 63% $721 10% $23 <1% Home health $0 0% $0 0% $0 0% Labs $0 0% $252 3% $271 8% Phone calls to medical/ nursing providers $45 6.5% $41.5% $17 <1% Table 2. Indirect costs of chemotherapy-associated toxicity for women with ovarian cancer costs (n = 42) Indirect costs costs (n = 26) Indirect costs costs (n = 15) Indirect costs Indirect total $4,220 $3,834 $4,282 Patient loss $620 15% $2,422 63% $2,122 50% Caregiver loss $2,837 67% $711 19% $280 6% Paid caregiver $496 18% $702 18% $1,880 44% Table 3. Total costs of chemotherapy-associated toxicity for women with ovarian cancer costs (n = 42) Total costs costs (n = 26) Total costs costs (n = 15) Total costs Total costs $206,138 $295,878 $113,257 Direct total $28,878 14% $196,189 66% $49,024 43% Indirect total $177,260 86% $99,689 34% $64,233 57% Mean total per patient $4,908 $11,380 $7,550 not associated with any inpatient care and accounted for $432 in outpatient pharmaceuticals and devices (63% of the total direct costs). Indirect costs relating to patient and caregiver loss and payments for caregiver support were substantial, accounting for $4,220, $3,834, and $4,282 for ovarian cancer patients who developed neurotoxicity, neutropenia, and thrombocytopenia, respectively (Table 2). Indirect costs for hematologic toxicity were primarily associated with patient loss ($2,422 for neutropenia [63% of the total indirect costs] and $2,122 for thrombocytopenia [50% of the total costs]), while neurotoxicity was associated with $2,837 in caregiver loss (67% of the total costs). In total, the costs of chemotherapyrelated neurotoxicity, neutropenia, and thrombocytopenia were $4,908, $11,830, and $7,550, with indirect costs accounting for 86%, 34%, and 57% of the total costs of toxicity, respectively (Table 3). Figure 1 depicts the status of patients at time of study entry and at follow-up. DISCUSSION In this pilot study, we found that it was feasible to obtain detailed resource utilization information from a cohort of ovarian cancer patients during a time when chemotherapy-associated neurologic or hematologic toxicity occurred. For these 83 women, an estimated $630,000 in total costs were estimated to have been incurred as a result of chemotherapy-related toxicity, with over half of these costs being attributed to lost wages for the patient or caregiver, or direct payments to a caregiver. Our estimates of the direct costs of chemotherapy-associated toxicities can be compared to those included in prior costs of toxicity studies [6, 10-14]. These studies have focused on neutropenia, as a result of widespread adoption of the hematologic colony-stimulating factors, G-CSF and

4 Calhoun, Chang, Welshman et al Patients Neurotoxicity (n = 42) Neutropenia (n = 26) Thrombocytopenia (n = 15) 7 w/ 20 w/o 15 ing 9 w/ 15 w/o 2 ing 7 w/ 8 w/o 0 ing Figure 1. Depicts the status of patients at time of study entry and at follow-up. GM-CSF. Detailed cost analyses reports indicate a mean per episode for direct costs ranging from $2,605 when care is delivered primarily as an outpatient to $21,417, when care is delivered exclusively as an inpatient [10-14]. Our direct cost estimate for neutropenia, $7,546 per episode, was associated with care that was administered as an outpatient for about half of the individuals with this toxicity. One prior study of thrombocytopenia estimated mean direct costs of $1,818 per episode, primarily for inpatient treatment with platelet transfusions [15]. In contrast, our cost estimate of direct costs for this toxicity was $3,268. It is likely that the assessment of post-hospitalization medical resource use in our study, but not in the earlier report, accounts for some of the difference in thrombocytopenia cost estimates. There have been no studies of the direct medical costs of chemotherapy-associated neurotoxicity. While a few studies have measured indirect costs of care for cancer patients, none have included a detailed breakdown of costs [2-4]. More than 90% of cancer patients use paid caregivers for at least one activity, ranging from financial assistance to medical care to personal care. Estimates from several years ago suggest that indirect costs may be as much as $1,000 per month [3]. In our study, paid caregiver costs accounted for a mean of $496 for neurotoxicity support, $702 for thrombocytopenia support, and $1,880 for neutropenia support. Of note, two-thirds of patients with neurotoxicity discontinued because of toxicity versus only 20% for neutropenia and 0% for thrombocytopenia. Specific examples of neurotoxicity loss include a woman who was no longer able to perform her duties as a bank teller and several women unable to perform job-related computer activities. As cancer treatment is primarily administered on an outpatient basis, informal caregivers assume a large responsibility for patient care at home. One of the greatest worries of cancer patients is lost income, resulting from the use of sick and vacation time or from lost for people who are self-employed. Although cancer treatment often results in fatigue and weakness, a quick return to is crucial for many. One study from the early 1990s reported a three-month average of $1,258 in lost earnings for patients [4]. In contrast, in our study, mean lost wages for patients ranged from $2,100 to $2,400 for hematologic toxicities and $620 for neurotoxicity. Of note, 52% of the ovarian cancer patients in our study were not ing at the time of diagnosis and did not incur any lost wages as a result. There are limitations to this pilot study. First, our data collection methods relied upon patient reporting of many of the outpatient costs of care. This method has been used in other comprehensive cost-of-illness studies of persons with serious medical illnesses and has been validated where possible against medical bills. Second, only women with ovarian cancer were included in this pilot study. This allowed for efficiencies of recruitment and data collection, with one research assistant spending most of her time in the gynecologic oncology clinic setting. Despite being in the middle of treatment with chemotherapy, the patients readily complied with the study interview and follow-up assessments. We are now extending the study methods to include costs of cancer care for persons with lung, prostate, breast, and colon cancer, in order to provide a broader estimate of the total costs of cancer care. Together, these malignancies account for over 60% of all new cancer diagnoses annually. In conclusion, this study has shown that, with the involvement of patients engaged in active treatment programs, evaluation of the total direct and indirect costs of cancer-associated toxicities is feasible. These studies are likely to be important to policymakers as indirect costs, which accounted for 34% to

5 445 Chemotherapy-Induced Toxicity Costs 86% of the total costs of cancer supportive care in this study, have rarely been included in the few prior estimates of the cost of chemotherapy-related toxicities. ACKNOWLEDGMENT Supported in part by unrestricted grants from Amgen Inc. and ALZA Inc. REFERENCES 1 Pfister DG. Importance of economic evaluation in oncology. New economic challenges in oncology practice. World Health CME 1997; Moore K. Breast cancer patients out-of-pocket expenses. Cancer Nurs 1999;22: Houts P, Lipton A, Harvey HR et al. Nonmedical costs to patients and their families associated with outpatient chemotherapy. Cancer 1984;53: Given B, Given C, Stommel M. Family and out-of-pocket costs for women with breast cancer. Cancer Pract 1994;2: American Cancer Society [database online]: Cancer Facts and Figures Atlanta, GA: American Cancer Society, Inc., Bennett, CL, Golub R, Calhoun EA et al. Cost-utility assessment of amifostine as first-line therapy for ovarian cancer. Int J Gynecol Cancer 1998:8: Christian M, Trimble E. Salvage chemotherapy for epithelial ovarian carcinoma. Gynecol Oncol 1994;55:S143-S Red Book, Medical Economics Company, Inc. Montvale, NJ: 1999: Statistical Abstract of the United States 1999, 119th Edition, U.S. Department of Commerce Economics and Statistics Administration, U.S. Census Bureau. 10 Hutton J, Brown R, Borowitz M et al. A new decision model for cost-utility comparisons of chemotherapy in breast cancer. Pharmacoeconomics 1996:9(suppl 2): Dranitsaris G. A pilot study to evaluate the feasibility of using willingness to pay as a measure of value in cancer supportive care: an assessment of amifostine cytoprotection. Support Cancer Care 1997;5: Souetre E, Quing W. Economic analysis of lenogastrim in the correction of neutropenia following chemotherapy for non-hodgkin s lymphoma. Pharmacoeconomics 1994;6 (suppl 2): Lyman GH, Kuderer NM, Green J. The economics of febrile neutropenia. Blood 1996;88(suppl 1):346a. 14 Lyman GH, Kuderer NM, Balducci L. Thresholds for the use of recombinant human colony stimulating factors based on revised cost estimates incorporating indirect medical, nonmedical, and intangible cost considerations. Blood 1996;88(suppl 1):346a. 15 Malone D, Sullivan S, Black D et al. The cost of treating chemotherapy-induced thrombocytopenia. Proc Am Soc Clin Oncol 1995;14:305a.