Economic analysis of granulocyte colony stimulating factor as adjunct therapy for older patients with acute myelogenous leukemia (AML): estimates from a Southwest Oncology Group clinical trial.

Considerable morbidity, mortality, and economic costs result during remission induction therapy for elderly patients with acute myeloid leukemia (AML). In this study, the economic costs of adjunct granulocyte colony stimulating factor (G-CSF) are estimated for AML patients > 55 years of age who received induction chemotherapy on a recently completed Southwest Oncology Group study (SWOG). Clinical data were based on Phase III trial information from 207 AML patients who were randomized to receive either placebo or G-CSF post-induction therapy. Analyses were conducted using a decision analytic model with the primary source of clinical event probabilities based on in-hospital care with or without an active infection requiring intravenous antibiotics. Estimates of average daily costs of care with and without an infection were imputed from a previously reported economic model of a similar population. When compared to AML patients who received placebo, patients who received G-CSF had significantly fewer days on intravenous antibiotics (median 22 vs. 26, p = 0.05), whereas overall duration of hospitalization did not differ (median 29 days). The median cost per day with an active infection that required intravenous antibiotics was estimated to be $1742, whereas the median cost per day without an active infection was estimated to be $1467. Overall, costs were $49,693 for the placebo group and $50,593 for the G-CSF patients. G-CSF during induction chemotherapy for elderly patients with AML had some clinical benefits, but it did not reduce the duration of hospitalization, prolong survival, or reduce the overall cost of supportive care. Whether the benefits of G-CSF therapy justify its use in individual patients with acute leukemia for the present remains a matter of clinical judgment.

Economic analysis of a phase III study of G-CSF vs placebo following allogeneic blood stem cell transplantation.

Hematopoietic colony-stimulating factors (CSF) decrease the duration of neutropenia following stem cell transplantation (SCT). With CSF-mobilized allogeneic blood SCT (alloBSCT), the yields of CD34+ cells are several-fold higher than in other SCT settings, raising concern that post-transplant CSF use may be unnecessary. In this study, we estimate the resource and cost implications associated with CSF use following alloBSCT. A cost identification analysis was conducted for 44 patients on a randomized, double-blind placebo-controlled trial of G-CSF following alloBSCT. Study drug was given daily until an absolute neutrophil count (ANC) > or = 1000 cells/microl. Billing information from the time of transplant to day +100 was analyzed. The median number of days to an ANC > or = 500 cells/microl was shorter in the G-CSF arm, 10.5 days vs 15 days (P < 0.001), while platelet recovery and rates of acute graft-versus-host disease (GVHD) and survival were similar. Resource use was similar, including days hospitalized, days on antibiotics, blood products transfused and outpatient visits. Total median post-transplant costs were $76577 for G-CSF patients and $78799 for placebo patients (P = 0.93). G-CSF following allogeneic blood SCT decreased the median duration of absolute neutropenia and did not incur additional costs, but did not result in shorter hospitalizations, or less frequent antibiotic use.

Evaluating the financial impact of clinical trials in oncology: results from a pilot study from the Association of American Cancer Institutes/Northwestern University clinical trials costs and charges project.

PURPOSE: Medical care for clinical trials is often not reimbursed by insurers, primarily because of concern that medical care as part of clinical trials is expensive and not part of standard medical practice. In June 2000, President Clinton ordered Medicare to reimburse for medical care expenses incurred as part of cancer clinical trials, although many private insurers are concerned about the expense of this effort. To inform this policy debate, the costs and charges of care for patients on clinical trials are being evaluated. In this Association of American Cancer Institutes (AACI) Clinical Trials Costs and Charges pilot study, we describe the results and operational considerations of one of the first completed multisite economic analyses of clinical trials. METHODS: Our pilot effort included assessment of total direct medical charges for 6 months of care for 35 case patients who received care on phase II clinical trials and for 35 matched controls (based on age, sex, disease, stage, and treatment period) at five AACI member cancer centers. Charge data were obtained for hospital and ancillary services from automated claims files at individual study institutions. The analyses were based on the perspective of a third-party payer. RESULTS: The mean age of the phase II clinical trial patients was 58.3 years versus 57.3 years for control patients. The study population included persons with cancer of the breast (n = 24), lung (n = 18), colon (n = 16), prostate (n = 4), and lymphoma (n = 8). The ratio of male-to-female patients was 3:4, with greater than 75% of patients having stage III to IV disease. Total mean charges for treatment from the time of study enrollment through 6 months were similar: $57,542 for clinical trial patients and $63,721 for control patients (1998 US$; P =.4) CONCLUSION: Multisite economic analyses of oncology clinical trials are in progress. Strategies that are not likely to overburden data managers and clinicians are possible to devise. However, these studies require careful planning and coordination among cancer center directors, finance department personnel, economists, and health services researchers.

Cost analyses of adjunct colony stimulating factors for acute leukemia: can they improve clinical decision making.

Colony stimulating factors reduce the duration of neutropenia following intensive chemotherapy in a variety of settings, but the advantages in the management of leukemia are inconclusive. The variations in clinical results and the high costs of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) have led to confusion over appropriate use for leukemia patients. In this paper, we reviewed published information on costs and cost-effectiveness of growth factors for childhood and adult leukemia patients. Medline and Healthstar databases were searched for original research articles that contain cost or cost-effectiveness analyses of G-CSF (filgrastim) and GM-SCF (sargramostim) in oncology cooperative group trials. Published manuscripts and abstracts presented at national or international oncology conferences were included. The cost of adjunct treatment was evaluated in two studies of pediatric ALL, one study of adult AML, and two studies of AML in older adults (>55 years). The use of G-CSF for children with ALL was associated with reductions in days to ANC recovery, fewer documented infections, a shorter duration of hospitalization, and small (but not significant) additional costs. In adult AML patients, benefits included a shortening of the duration of neutropenia and hospital stays, a lower incidence of infection and febrile episodes, less use of antibiotics, and cost savings of $2,230 and $2,310 in two studies and an increase if $120 in the third study. This summary suggests that economic analyses can provide useful information to assist clinical decision-making. For pediatric ALL patients, this information indicates that G-CSF use is unlikely to have significant cost implications, and its use should be based on clinical considerations. In studies of adult and older adult AML patients, both GM-CSF and G-CSF have clinical benefits and can be expected to lead to a decrease in overall costs.

Cost analysis of filgrastim for the prevention of neutropenia in pediatric T-cell leukemia and advanced lymphoblastic lymphoma: a case for prospective economic analysis in cooperative group trials.

BACKGROUND: Growth factor use has been shown to ameliorate chemotherapy-induced neutropenia, leading to shorter hospital stays and lower use of parenteral antibiotics, two costly areas of cancer treatment. Prior reports on pediatric patients have shown evidence of cost savings in some studies, but no such evidence in others. In this study a retrospective analysis compared the costs of inpatient supportive care for pediatric patients with T-cell leukemia and advanced lymphoblastic lymphoma enrolled in a Pediatric Oncology Group trial. PROCEDURE: Patients 1-22 years of age were randomized to receive either granulocyte colony-stimulating factor (G-CSF; n = 45) or no G-CSF (n = 43) following induction and two cycles of maintenance therapy. There were no significant differences in neutropenia-related outcomes during the induction phase. During maintenance therapy, G-CSF patients had significantly fewer days to an ANC >500 cells/microl and a trend towards fewer days of hospitalization. Data on resource utilization were tabulated from case report forms. Costs were imputed from national data on hospitalization costs, average wholesale prices of pharmaceuticals, and patient billing information from a single institution. RESULTS: Total median costs of supportive care were $34,190 for patients receiving G-CSF and $28,653 for patients not receiving G-CSF (P > 0. 05 for the cost difference). Sensitivity analyses demonstrated that the total cost difference was not statistically significant, even in scenarios that included reasonable variations in estimates of the range of the length of stay, antibiotic regimen, and dosage and cost of G-CSF. CONCLUSIONS: In the setting of pediatric leukemia, the cost of growth factor may offset potential savings from shorter hospital stays or lower antibiotic use, a finding consistent with that from the Children's Cancer Study Group.

Reporting and dissemination of industry versus non-profit sponsored economic analyses of six novel drugs used in oncology.

PURPOSE: Our prior study found that pharmaceutical-sponsored and non-profit sponsored analyses differed in their published assessments of the economic value of six new oncology drugs. In this study, we expand on our earlier findings and evaluate the association between funding source and 1) characteristics of the published study report and 2) journal type for dissemination of the previously evaluated economic studies. METHODS: We reviewed the published cost-effectiveness literature for hematopoietic colony stimulating factors, 5-HT3 antagonist antiemetics. and taxanes. Two blinded investigators rated specific aspects of study reporting based on the US Public Health Service Panel on Cost-effectiveness in Health and Medicine criteria. Dissemination strategies were evaluated using impact factor scores from the Science Citation Index. RESULTS: The operational aspects of pharmaceutical-sponsored study reporting were better overall than those associated with non-profit sponsored studies. Specifically, pharmaceutical-sponsored studies were more likely to be reported based on data obtained from randomized clinical trials or detailed cost-models (90% vs. 70%), to include descriptions of the source of cost differences (90% vs. 79%), to state whether the study was carried out from a societal, governmental, or insurer perspective (70% vs. 42%), and to clearly indicate the time-period over which costs were evaluated (65% vs. 50%). Nonprofit sponsored studies were more likely than pharmaceutical sponsored studies to report the generalizability of the findings, including being more likely to include information about how the data could be extrapolated to other clinical settings (58% vs. 35%), to include statements on the statistical significance of the findings (38% vs. 20%), and to clearly outline the cost per unit and data sources for the cost analyses (67% vs. 45%). A similar percent of pharmaceutical and non-profit sponsored studies reported background and conclusions with about 80% providing literature comparisons of the results (about 80%) and two thirds to three fourths discussing the limitations of the finding (75% for pharmaceutical-sponsored and 67% for non-profit sponsored studies). Most studies were published in low impact factor peer-reviewed journals, and journal impact factor scores were similar between pharmaceutical and nonprofit sponsored studies. CONCLUSIONS: Upon reviewing the entire pharmacoeconomic literature for six new oncology drugs, we identified differences in study reporting, but not in types of journals where studies were published, between pharmaceutical-sponsored and non-profit sponsored studies. These results, particularly the observed differences in data generalizability, may account in part for our previous finding of lower likelihood of reporting unfavorable conclusions in pharmaceutical-sponsored studies.

Comparing cost-effectiveness analyses for the clinical oncology setting: the example of the Gynecologic Oncology Group 111 trial.

For the practicing oncologist, balancing quality of care with cost containment has become an unavoidable challenge. The development of new technologies, increased patient awareness, growth of managed care, and aging of our population represent conflicting interests in this endeavor. Medical literature has recently been inundated with economic analyses in an effort to approach some of these difficult questions, but often times it is difficult to see how this research applies to any particular oncologist's practice. This article identifies many of the key issues raised in the critical evaluation of cost-effectiveness analyses as they relate to the practicing oncologist. We offer suggestions on the interpretation of these studies to the clinical setting, using the recently published Journal of Clinical Oncology articles on cost-effectiveness analyses of paclitaxel-cisplatin as first-line therapy for ovarian cancer as examples.

Cost analysis of second-line therapies for platinum-refractory ovarian cancer: reimbursement dilemmas for Medicare patients.

Currently used options for salvage therapy for epithelial ovarian cancer include intravenously administered paclitaxel or topotecan and orally administered altretamine or etoposide. The response rates for these agents are similar (14-26%), whereas the type and incidence of adverse events differ. Under current legislation, Medicare will reimburse intravenous outpatient chemotherapy regimens only or oral regimens with a marketed intravenous formulation, despite that 89% of cancer patients prefer oral therapies. To compare the out-of-pocket costs and costs to the Medicare system, a cost minimization analysis of treatment with these agents was conducted using published phase II and phase III data. The total cost of treatment was $15,767 for paclitaxel, $18,635 for topotecan, $4477 for altretamine, and $5016 for etoposide. The out-of-pocket costs to the patient were $83, $37, $4477, and $6, respectively. Although a physician's first consideration in choosing a therapy is efficacy and toxicity, current Medicare reimbursement policies restrict patient options for cancer care. Because Medicare adopts managed care and health maintenance organizations into the management of patient care, cost effectiveness will likely become an important consideration in the treatment of cancer.

Evaluation of conflict of interest in economic analyses of new drugs used in oncology.

CONTEXT: Recent studies have found that when investigators have financial relationships with pharmaceutical or product manufacturers, they are less likely to criticize the safety or efficacy of these agents. The effects of health economics research on pharmaceutical company revenue make drug investigations potentially vulnerable to this bias. OBJECTIVE: To determine whether there is an association between pharmaceutical industry sponsorship and economic assessment of oncology drugs. DESIGN: MEDLINE and HealthSTAR databases (1988-1998) were searched for original English-language research articles of cost or cost-effectiveness analyses of 6 oncology drugs in 3 new drug categories (hematopoietic colony-stimulating factors, serotonin antagonist antiemetics, and taxanes), yielding 44 eligible articles. Two investigators independently abstracted each article based on specific criteria. MAIN OUTCOME MEASURE: Relationships between funding source and (1) qualitative cost assessment (favorable, neutral, or unfavorable) and (2) qualitative conclusions that overstated quantitative results. RESULTS: Pharmaceutical company-sponsored studies were less likely than nonprofit-sponsored studies to report unfavorable qualitative conclusions (1/20 [5%] vs 9/24 [38%]; P = .04), whereas overstatements of quantitative results were not significantly different in pharmaceutical company-sponsored (6/20 [30%]) vs nonprofit-sponsored (3/24 [13%]) studies (P = .26). CONCLUSIONS: Although we did not identify bias in individual studies, these findings indicate that pharmaceutical company sponsorship of economic analyses is associated with reduced likelihood of reporting unfavorable results.

Economic analysis of a randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia. Eastern Cooperative Oncology Group (E1490).

PURPOSE: Considerable morbidity and mortality and costs occur during induction therapy for acute myeloid leukemia (AML). Colony-stimulating factors (CSFs) can shorten neutropenia, and may lower costs. We performed a cost-minimization analysis of granulocyte macrophage colony stimulating factor (GM-CSF) for AML patients > 55 to 70 years of age during an Eastern Cooperative Oncology Group Study. PATIENTS AND METHODS: Clinical data were from a randomized double-blind phase III trial of 117 AML patients. Estimates of costs were from financial accounts from seven participating institutions. Costs were reported from the third party payor perspective. Analyses were conducted utilizing a decision analytic model. The primary source of event probabilities was in-hospital care with or without an active infection. Sensitivity analyses were also reported. RESULTS: When compared to AML patients who received placebo. GM-CSF patients had fewer grade 4-5 infections (9.6% versus 36.2%, P = 0.002) and grade 3-5 infections (52% versus 70%. P = 0.07) and $2.310 in savings. Sensitivity analyses indicated that similar cost estimates applied over a range of clinical and economic assumptions. CONCLUSIONS: This analysis can serve as a template for cooperative group cost analyses. Cooperation on study methodologies may allow for results that are relevant to both clinicians and policy makers.

The effect of reimbursement policies on the management of Medicare patients with refractory ovarian cancer.

Ovarian cancer patients who are covered by Medicare are faced with therapeutic decisions that require consideration of out-of-pocket costs for oral anticancer agents and complete reimbursement for more expensive intravenous and often more toxic medications. The response rates for oral agents such as altretamine or etoposide are similar to those for intravenous paclitaxel or topotecan (14% to 26%), but the economic considerations differ markedly. Under current legislation, Medicare will completely cover the costs for the two intravenous outpatient chemotherapy regimens, but does not provide any financial support for oral regimens that do not have associated injectable formulations. This is a matter of concern for patients, as 89% prefer oral therapies. We compared the out-of-pocket costs and costs to the Medicare system of oral and intravenous agents used for refractory ovarian cancer, using published phase II and phase III data. The total cost of treatment was $18,635 for topotecan, $15,767 for paclitaxel, $7,721 for etoposide, and $4,477 for altretamine. Conversely, out-of-pocket costs for Medicare patients without Medigap coverage were highest for altretamine, at the full cost of $4,477, whereas Medicare covered all but $83 for topotecan, $37 for paclitaxel, and $66 for etoposide. Current Medicare reimbursement policies may affect patient options for cancer care. These policies are changing and should continue to change as Medicare adopts more managed care strategies.

Cost-effectiveness analysis comparing liposomal anthracyclines in the treatment of AIDS-related Kaposi's sarcoma.

Liposomal formulations have been shown to alter the efficacy and toxicity profiles of anthracylines for patients with HIV-related advanced Kaposi's sarcoma (KS). Using decision-analysis models, the costs and cost-effectiveness of the two U.S. Food and Drug Administration (FDA)-approved liposomal formulations of these agents were estimated. Estimates of costs, effectiveness, and cost-effectiveness were derived from clinical trial data of separate, randomized phase III trials of pegylated liposomal doxorubicin (20 mg/m2 every 3 weeks) and liposomal daunorubicin (40 mg/m2 every 2 weeks). Clinical response rates were 59% for pegylated liposomal doxorubicin and 25% for liposomal daunorubicin. Despite higher acquisition costs for pegylated liposomal doxorubicin, total estimated costs of treatment for KS and chemotherapy-related hematologic toxicities were similar ($7,066 U.S. compared with $6,621 U.S. for liposomal daunorubicin). Cost-effectiveness profiles, defined as average costs per responder, favored pegylated liposomal doxorubicin ($11,976 U.S./responder versus $26,483 U.S./responder for liposomal daunorubicin), reflecting the higher reported response rate in the phase III trial. Sensitivity analyses suggested that the costs and cost-effectiveness results would not differ markedly when evaluated over a range of assumptions, including response rate, neutropenia rate, and dosage variations.

The relationship between nickel chloride-induced peroxidation and DNA strand breakage in rat liver.

Inorganic nickel chloride induces hepatic DNA strand breaks, chromosome aberrations, and lipid peroxidation under in vitro and in vivo conditions. The objective of this research was to determine if a relationship exists between NiCl2 genotoxicity and lipid peroxidation in vivo. Male Sprague-Dawley rats (210-250 g) were dosed with 0.56 or 0.75 mmol/kg NiCl2 subcutaneously and euthanized after specific time periods, ranging from 30 min to 24 hr. Livers were perfused and excised for the measurement of nickel content using atomic absorption spectrometry, lipid peroxidation using a thiobarbituric acid assay, and DNA strand breakage using single-stranded DNA extraction and the diaminobenzoic acid assay. The lower dose (0.56 mmol/kg) did not induce lipid peroxidation or strand breakage. The higher dose (0.75 mmol/kg) induced DNA strand breakage at 4 hr and lipid peroxidation at 12 hr in rat liver. Nickel was seen to accumulate in liver nuclei of rats receiving 0.75 mmol/kg. Deferoxamine (1 g/kg, ip, 15 min before the NiCl2 injection) completely inhibited DNA strand breakage at 4 hr but had no effect on lipid peroxidation. This suggests that lipid peroxidation is not causally related to genetic damage. NiCl2-induced DNA strand breakage may be caused by the induction of the Fenton reaction, generating hydroxyl radicals.