The administration of hematopoietic colony-stimulating factors (CSFs) to reduce the severity and duration of neutropenia associated with systemic chemotherapy has become widespread, although the appropriate use of
The administration of hematopoietic colony-stimulating factors (CSFs) to reduce the severity and duration of neutropenia associated with systemic chemotherapy has become widespread, although the appropriate use of these agents has not yet been fully defined. A cost model based on decision theory is presented for three therapeutic choices in these patients: no CSF, prophylactic CSF, and therapeutic CSF. Baseline probabilities were derived from a prospective, randomized, placebo-controlled trial of G-CSF in patients receiving systemic chemotherapy. Application of the model to institutionally generated cost figures provides comparative estimates of excess cost favoring the prophylactic use of CSFs. Model thresholds were calculated based on sensitivity analysis comparing no CSF to prophylactic CSF, and therapeutic CSF to prophylactic CSF. Guidelines are provided based on this model that are consistent with those adopted by the American Society of Clinical Oncology.
Myelosuppression remains the major dose-limiting toxicity of systemic cancer chemotherapy. The risk of infection and infection-related mortality increases in direct proportion to the degree and duration of neutropenia observed . The onset of fever in the setting of neutropenia generally requires immediate hospitalization and administration of broad-spectrum antibiotic therapy . Previous efforts to enhance hematologic recovery following systemic chemotherapy have had only limited success .
Several hematopoietic colony-stimulating factors (CSFs) have been characterized over the past decade , and two are now readily available: human recombinant granulocyte-colony stimulating factor (G-CSF, filgrastim, Neupogen) and yeast-derived granulocyte-macrophage colony-stimulating factor [GM-CSF, sargramostim, Leukine] [5,6]. Several studies have shown that these agents can reduce the severity and duration of neutropenia associated with cancer chemotherapy [7-11]. A prospective, double-blind, placebo-controlled trial of G-CSF utilized prophylactically has demonstrated a significant reduction in the risk of febrile neutropenia and need for hospitalization in patients with solid malignancies receiving combination chemotherapy . Randomized clinical trials have demonstrated that CSFs administered after the onset of febrile neutropenia accelerate myeloid recovery, reducing the duration of neutropenia . It remains uncertain, however, to what degree CSFs so administered reduce duration of fever or hospitalization.
The approval of the hematopoietic CSFs for use in patients receiving cancer chemotherapy has resulted in widescale use of these agents in a variety of clinical settings, contributing to increasing health care costs. As further studies define additional indications for CSFs, even greater utilization of these agents can be anticipated. Nevertheless, clinical and economic uncertainty exists as to the optimal use of CSFs in patients receiving different cancer chemotherapy regimens in each tumor type, considering the wide variation in patients' risk for neutropenia. Recent cost studies have been conducted in an effort to define, measure, and compare the relevant positive and negative economic consequences of the use of CSFs to prevent infections in patients receiving chemotherapy [14-16].
The American Society of Clinical Oncology (ASCO) has recently adopted general guidelines for the use of CSFs based on these and other studies in the literature . This paper reviews and extends the cost model previously presented for the use of hematopoietic CSFs in patients receiving cancer chemotherapy and presents specific guidelines based on this model. The administration of hematopoietic CSFs may be associated with a reduction in health care costs for hospitalization due to febrile neutropenia if utilized within the specific guidelines presented.
A standard model based on decision theory was developed for this cost analysis of the use of hematopoietic CSFs in patients receiving systemic cancer chemotherapy (Table 1). The decision choices consisted of no CSF; CSF
administered prophylactically after the completion of chemotherapy with continuation through the period of neutropenia; and CSF administered therapeutically only if febrile neutropenia occurs. The model assumes that all patients experiencing febrile neutropenia will be hospitalized and treated empirically with parenteral antibiotics. The role for outpatient management of selected patients with febrile neutropenia has not yet been fully defined.
Baseline probabilities for hospitalization risk and survival with and without CSF, along with the durations of hospitalization and CSF administration, were based on the prospective randomized trial of G-CSF in patients with small-cell lung cancer receiving systemic chemotherapy . Baseline probabilities of hospitalization and survival in patients with febrile neutropenia receiving therapeutic CSF are assumed to be the same as for patients receiving no CSF (Table 2). Since there was no reduction in the median duration of hospitalization in patients treated with G-CSF in either the prophylactic or therapeutic randomized trials, no reduction in hospitalization duration was assumed at baseline with either choice [12,13]. As with all variables studied in this model, this baseline assumption was then varied over the range of possible values in a sensitivity analysis.
Costs considered in this model include the cost of hospitalization for febrile neutropenia and the cost of CSF per treatment cycle. Baseline daily costs of hospitalization were estimated from data available at our own institution, based on fixed daily costs for room, antibiotics, fluids and tubing, and professional fees. These represent minimal cost estimates, since they do not reflect the cost of diagnostic and monitoring tests (x-rays, scans, blood tests), cultures, drug levels, and consultations, which can increase the hospitalization costs substantially. Baseline CSF costs include agent and administration costs derived from our own institution.
The expected excess cost for each specific choice was calculated from the sum of the products of the costs and probabilities of each outcome. The expected cost per treatment cycle represents the excess cost associated with hospitalization for febrile neutropenia and treatment with CSFs. Chemotherapy costs and other items likely to be identical in the three treatment choices were not considered.
Sensitivity analysis provides an estimate of the expected cost for a range of values of one or more variables for each decision choice. Sensitivity analysis permits the calculation of thresholds when the expected cost for two treatment options are the same. In multiway sensitivity analysis, each function or curve represents a series of thresholds for a combination of two variables indicated on the axes. A family of threshold curves may be generated as the value of a third factor is varied.
Using Monte Carlo analysis, the model was analyzed repeatedly, each time sampling from the assumed distributions of the main variables. Probability distributions for the main variables were derived from the randomized controlled trial and local institutional data. Monte Carlo simulations consisted of 1,000 sequential samples. In this study, the distributions of outcomes or thresholds then serve as a measure of variability upon which to base a level of confidence in the decision outcome or threshold estimate. The distribution function of the differences in outcome between two choices is distributed as sample mean differences, allowing for statistical inference. Tests of significance were based on a t statistic with n-1 degrees of freedom, with n representing the number of samples in the simulation.
Utilizing the baseline probability and cost assumptions in Table 2, the model generated an expected excess cost per treatment cycle of $5,500 for no CSF, $4,750 for prophylactic CSF, and $6,875 for therapeutic CSF. Sensitivity analyses for the three choices were performed for each of the study variables. Figure 1 displays one-way sensitivity analyses for the control probability of hospitalization (Figure 1A) and for the cost of hospitalization per day (Figure 1B). The excess cost associated with prophylactic CSF increases at a slower rate than with the other two strategies for both variables. The thresholds for each variable are the values at the point where the cost line for prophylactic CSF crosses each of the other lines. At these points, the total excess cost is the same for each group being compared.
Model thresholds for the decision between no CSF and prophylactic CSF are presented in Table 3, and those for the decision between prophylactic CSF and therapeutic CSF are shown in Table 4. The strategy favored on a cost basis at values above the threshold is indicated in the tables to the right of the thresholds, while the strategy favored at values below the threshold is indicated to the left of the thresholds.
Figure 2 displays three-way sensitivity analyses based on variations in daily hospital cost and duration of hospitalization. The region above each threshold curve represents values of the variables favoring the use of the hematopoietic CSFs on a cost basis. Figure 2A varies the risk of hospitalization in the prophylactic group as a proportion of the control risk. Conditions favoring the use of CSF represented by the area above each curve increase as the risk of hospitalization in patients receiving CSF decreases. Alternatively, as the proportional risk of hospitalization with prophylactic CSF increases, the conditions associated with a net cost advantage for CSF lessen. The incremental change in the area above the threshold curve is greater with higher proportional risk of hospitalization. Figure 2B varies the cost of CSFs per day. The conditions favoring the use of CSF on a cost basis increase as the daily cost of CSF lessens. The area above the threshold curves favoring the use of CSF in this setting increases at approximately equal increments as the daily cost of CSF decreases.
Estimates of excess cost per treatment cycle based on Monte Carlo analysis were $7,923 ± $484 (SEM), $6,612 ± $289, and $9,812 ± $533 for the control, prophylactic, and therapeutic CSF arms, respectively. The distribution of cost differences based on Monte Carlo analysis favors prophylactic CSF over no CSF, with a median difference of $1,070 (Figure 3A). The distribution of cost differences also favors prophylactic CSF over therapeutic CSF, with a median difference of $2,671 (Figure 3B). Neither of these differences was statistically significant, however, based on the assumed variability of each parameter.
Threshold analysis based on Monte Carlo simulation also demonstrated considerable variability in threshold measures of the main variables (Table 5). The distribution of threshold estimates for each of the variables in the model was studied. Each of the distributions was skewed, suggesting that the median probably represents a better measure of central tendency than the mean.
The introduction of recombinant hematopoietic CSFs has had a major impact on the management of patients receiving cancer chemotherapy. Increasing overall health care costs in patients with cancer raise concern about the appropriate use of these agents. The study reported here updates a previous report assessing those factors influencing the cost associated with the use of CSFs in patients receiving cancer chemotherapy. Based on the decision model described and the baseline conditions utilized, a net cost reduction was estimated for chemotherapy patients receiving CSFs prophylactically. This net cost savings is due primarily to a reduction in the risk of hospitalization for febrile neutropenia in patients receiving CSF. Sensitivity analysis suggests that the estimate of net cost savings for prophylactic CSF use is relatively robust under reasonable assumptions for each of the variables utilized in this model.
This analysis suggests that the most important factors influencing the cost associated with the use of CSFs in patients receiving cancer chemotherapy are the control risk of hospitalization with febrile neutropenia, the proportional risk of febrile neutropenia in those receiving CSF, and the daily cost of hospitalization. As the control risk of hospitalization for febrile neutropenia decreases, the cost advantage with CSFs falls, with a net loss under a control hospitalization risk of 40%. Since only more intensive regimens are associated with a 40% or greater risk of febrile neutropenia, the indications for CSF based solely on cost are somewhat restrictive. Once a patient on a given regimen has experienced febrile neutropenia, the conditional risk for febrile neutropenia with future cycles may justify the use of CSFs. Although CSFs may increase health care costs when used in individuals at lower risk for febrile neutropenia or when given only after hospitalization for febrile neutropenia, many other considerations may influence this decision. If a role for the outpatient management of a substantial proportion of patients with febrile neutropenia becomes established, this will have a major effect on the cost advantage of CSFs.
Guidelines for the use of the CSFs were developed by the authors based on the analysis of this decision model (Table 6). Until other studies demonstrate a meaningful reduction in the duration of hospitalization for febrile neutropenia or a survival advantage with CSFs, these agents cannot be recommended for routine use on a cost basis after the onset of febrile neutropenia. The potential benefit of CSF use in this setting must be determined by the treating physician knowledgeable about the patient's condition and the use of these agents.
Prophylactic use of CSFs can result in a net cost savings in patients treated with regimens of known high potential for febrile neutropenia (greater than 40%), including those who have previously required hospitalization for febrile neutropenia. Studies in the transplantation setting clearly demonstrate that CSF use is associated with a reduction in hematologic recovery time after allogeneic, autologous, and peripheral stem cell transplantation [18-21]. Prophylactic use of CSFs may be considered in patients receiving less intensive regimens if the clinical situation suggests a greater than usual infection risk, if local costs or hospitalization duration exceed those assumed in this model, or if local costs of CSFs are less than those assumed here. Clinical situations that may increase the risk of febrile neutropenia include advanced age, previous radiation or chemotherapy, and previous or current infection. Hospital costs can increase with complicated infections requiring multiple laboratory tests and prolonged treatment. CSFs may also be justified on a selected basis when treatment delay or dose reduction is anticipated in disease categories in which the benefit of dose intensity has been clearly established.
The use of CSFs only after hospitalization for febrile neutropenia requires further study. The model presented suggests that such a strategy is unlikely to demonstrate a cost savings, compared with controls, unless there is a reduction in the duration of hospitalization of greater than 20%. While this may be an achievable reduction with therapeutic CSF, a similar reduction in the duration of hospitalization would be anticipated for individuals receiving CSF prophylactically who require hospitalization for febrile neutropenia. Sensitivity analysis indicates that prophylactic CSF would remain the optimal strategy from a cost standpoint if the control risk of hospitalization is 33% or greater. If a reduction in the duration of hospitalization with CSFs of 20% is demonstrated, therapeutic CSFs would represent the least costly strategy for regimens associated with a risk of hospitalization of less than 33%.
Studies are currently underway to incorporate patient preferences into this decision model. Preliminary observations suggest a substantial patient preference favoring the use of hematopoietic CSFs to reduce the risk of hospitalization for febrile neutropenia. Incorporation of such preferences into the model alters the associated thresholds in a direction favoring the use of CSFs in this setting.
1. Bodey GP, Buckley M, Sathe YS, et al: Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64:328-340, 1966.
2. Pizzo PA, Hathorn JW, Heimenz J, et al: A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with neutropenia and fever. N Engl J Med 315:552-558, 1986.
3. Lyman GH, Williams CC, Preston D: The use of lithium carbonate to reduce infection and leukopenia during systemic chemotherapy. N Engl J Med 302:257-259, 1980.
4. Laver J, Moore MAS: Clinical use of recombinant human hematopoietic growth factors. J Natl Cancer Inst 81:1370-1382, 1989.
5. Groopman JE, Molina JM, Scadden DT: Hematopoietic growth factors: Biology and clinical applications. N Engl J Med 321:1449-1459, 1989.
6. Lieschke GJ, Burgess AW: Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor: Parts I and II. N Engl J Med 327:28-35, 99-106, 1992.
7. Gabrilove JL, Jakubowski A, Scher H, et al: Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med 318:1414-1422, 1988.
8. Morstyn G, Campbell L, Lieschke G, et al: Treatment of chemotherapy-induced neutropenia by subcutaneously administered granulocyte colony-stimulating factor with optimization of dose and duration of therapy. J Clin Oncol 7:1554-1562, 1989.
9. Sheridan WP, Wolf M, Lusk J, et al: Granulocyte colony stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet 2:891-894, 1989.
10. Neidhart J, Mangalik A, Kohler W, et al: Granulocyte colony-stimulating factor stimulates recovery of granulocytes in patients receiving dose-intensive chemotherapy without bone marrow transplantation. J Clin Oncol 7:1685-1692, 1989.
11. Gulati SC, Bennett CL: Granulocyte-macrophage colony stimulating factor (GM-CSF) as adjunct therapy in relapsed Hodgkin's disease. Ann Intern Med 116:177-182, 1992.
12. Crawford J, Ozer H, Stoller R, et al: Reduction in the incidence of chemotherapy-induced febrile neutropenia in patients with small-cell lung cancer. N Engl J Med 325:164-170, 1991.
13. Maher DW, Lieschke GJ, Green N, et al: Filgrastim in patients with chemotherapy-induced febrile neutropenia: A double-blind, placebo controlled trial. Ann Intern Med 121:492-501, 1994.
14. Finley RS: Measuring the cost-effectiveness of hematopoietic growth factor therapy. Cancer 67:2727-2730, 1993.
15. Lyman GH, Lyman CG, Sanderson RA, et al: Decision analysis of hematopoietic growth factor use in patients receiving cancer chemotherapy. J Natl Cancer Inst 85:488-493, 1993.
16. Nichols CR, Fox EP, Roth BJ, et al: Incidence of neutropenic fever in patients treated with standard-dose combination chemotherapy for small-cell lung cancer and the cost impact of treatment with granulocyte colony-stimulating factor. J Clin Oncol 12:1245-1250, 1994.
17. American Society of Clinical Oncology: American Society of Clinical Oncology recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 12:2471-2508, 1994.
18. Nemunaitis J, Singer JW, Buckner CD, et al: Use of recombinant human granulocyte-macrophage colony-stimulating factor in graft failure after bone marrow transplantation. Blood 76:245-253, 1990.
19. Nemunaitis J, Rabinowe SN, Singer JW, et al: Recombinant granulocyte macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med 324:1773-1778, 1991.
20. Advani R, Chao NJ, Homing SJ, et al: Granulocyte-macrophage colony stimulating factor (GM-CSF) as an adjunct to autologous hemopoietic stem cell transplantation for lymphoma. Ann Intern Med 116:183-189, 1992.
21. Appelbaum FR: The use of colony stimulating factors in marrow transplantation. Cancer 72:3387-3392, 1993.