The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia  G.H. Lyman, N.M. Kuderer  Critical Reviews in Oncology / Hematology  Volume 50, Issue 2, Pages 129-146 (May 2004) DOI: 10.1016/j.critrevonc.2004.01.001

Fig. 1 Triangle representing the dimensions of healthcare outcome measures including clinical (survival), quality-of-life and economic (costs). Combined measures of clinical, quality-of-life and economic outcome are illustrated on the sides of the triangle including quality-adjusted life years (QALYs), time without symptoms of disease and toxicity of treatment (Q-TWIST), cost-effectiveness (cost per life year gained) and cost utility (cost per quality-adjusted life year gained) [32]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 2 Bar graph illustrating the frequency of treatment delays ≥7 days, dose reductions ≥15% and RDI <85% in approximately 20,000 women with breast cancer receiving various adjuvant chemotherapy regimens from a large practice-based survey [48]. AC: adriamycin + cyclophosphamide; ACT: adriamycin + cyclophosphamide followed by taxol; ATC: adriamycin + cyclophosphamide + taxotere; CAF: cyclophosphamide + adriamycin + 5-fluyorouracil; CMF: cyclophosphamide + methotrexate + 5-fluorouracil; SEQ: sequential agents [48]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 3 Hazard plot of the time in days to the first episode of FN in 577 patients with non-Hodgkin’s lymphoma treated with CHOP chemotherapy stratified by age 65 and over vs. less than 65 years (P=0.0002) [50]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 4 Diagram summarizing the results of a systematic review of 19 prognostic or risk factor studies for severe or febrile neutropenia (top) as well as serious medical consequences including bacteremia, prolonged hospitalization or death (bottom). Shown are those factors associated with these outcomes in multivariate analysis in two or more reported studies [52]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 5 Bar graph displaying the cumulative proportion of patients with FN or any subsequent neutropenic complication (FN, dose reduction or treatment delay) based on a composite risk score based on age ≥65 or first cycle events including FN, ANC <500/mm3 or a hemoglobin decrease ≥1g/dl (P<0.001) [57]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 6 Frequency distribution of the length of stay in days among adults excluding bone marrow transplantation patients hospitalized for FN in institutions reporting to the University Health System Consortium, 1995–2000 [60]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 7 Distribution of cost per day (mean±S.E.M., $) for patients admitted with FN to institutions reporting to the University Health System Consortium from 1995 to 2000 [60]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 8 Bar chart of total cost of hospitalization among patients with solid tumors, lymphoma and leukemia admitted for FN to institutions reporting to the University Health System Consortium between 1995 and 2000 [60]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 9 Forrest plot of the Peto odds ratios for FN among the eight randomized controlled trials of prophylactic G-CSF vs. control along with a weighted summary measure across trials (OR=0.38, P<0.001) [17]. The size of the point estimate rectangles are in proportion to the weight and inversely proportional to the variance associated with each study. Also shown are the 95% confidence limits for each estimate. All studies demonstrate an effect estimate below 1.0 favoring G-CSF. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 10 Forrest plot of the relative risk based on Mantel–Haenszel for duration of hospitalization among the nine randomized controlled trials of therapeutic G-CSF vs. control along with a weighted summary measure across trials (RR=0.704, P=0.01) [18]. The size of the point estimate rectangles are in proportion to the weight and inversely proportional to the variance associated with each study. Also shown are the 95% confidence limits for each estimate. Point estimates to the left of 1.0 favor G-CSF while those above 1.0 favor control. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 11 Forrest plot of the relative risk based on Mantel–Haenszel for FN among the four controlled trials of prophylactic filgrastim vs. pegfilgrastim along with a weighted summary measure across trials (RR=0.66, P=0.0536). The size of the point estimate rectangles are in proportion to the weight and inversely proportional to the variance associated with each study. Also shown are the 95% confidence limits for each estimate. All studies demonstrate an effect estimate below 1.0 favoring pegfilgrastim. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 12 Decision tree for a cost minimization model of the use of prophylactic G-CSF or no G-CSF in chemotherapy patients at risk for FN. Model assumes all patients with FN are hospitalized, the risk of hospitalization for FN in those receiving prophylactic G-CSF is reduced by 50%, equal duration of hospitalization and mortality among those hospitalized for FN in both groups. Cost considerations are limited to those related to hospitalization for FN (average length of stay × average cost per day ($)) and G-CSF (average duration of administration × average cost per day for drug and administration). Patients not hospitalized and not receiving G-CSF have no associated costs [19]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 13 One-way sensitivity analysis of the expected total cost associated with FN for varying levels of risk with and without G-CSF prophylaxis. The expected cost associated with each strategy is based on the model shown in Fig. 12 and increases as the control risk of febrile neutropenia increases. The threshold represents the level of risk at which the costs associated with each strategy is the same [19]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 14 Two-way sensitivity analysis of the threshold for cost associated with febrile neutropenia and G-CSF use based on the decision model shown in Fig. 12 [16]. The horizontal axis varies the cost per day ($) for hospitalization while the vertical axis varies the risk of febrile neutropenia. The threshold curve demonstrates lower thresholds for cost saving use of the CSFs with increasing cost of hospitalization. Combinations of risk and cost above the threshold hold are associated with a reduction in cost with the use of prophylactic CSF while those below the threshold curve are associated with greater cost with the use of CSF. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 15 Two-way sensitivity analysis based on the original cost model but incorporating a third option with stratification into low risk and high risk patients. After an initial 48h of observation and evaluation, low risk patients are then be discharged to complete their antibiotic course as an outpatient. Risk threshold estimates are seen to vary little across a range of estimated hospital costs per day as most of the cost is associated with the longer length of stay observed in high-risk patients. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 16 Two-way sensitivity analysis varying the relative risk associated with the use of pegfilgrastim prophylaxis and the risk of febrile neutropenia. The threshold curve represents conditions under which the total expected cost associated with the prophylactic use of pegfilgrastim is the same as the total cost in control subjects. The use of pegfilgrastim is favored based on lower comparative costs as the risk of febrile neutropenia and relative risk reduction increase. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 17 One-way sensitivity analysis representing the cost savings associated with the therapeutic use of G-CSF in patients hospitalized for established febrile neutropenia for varying proportions of patients hospitalized for 10 days or more. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 18 Two-way sensitivity analysis of a decision model comparing a strategy of targeted G-CSF for the one-half of breast cancer adjuvant chemotherapy patients at greatest risk for future dose-limiting neutropenic complications based on a conditional risk model compared to a strategy of standard dose reduction without G-CSF support. The horizontal axis varies the proportion of patients planned to receive G-CSF (50% at baseline). The vertical axis presents the associated cost-effectiveness in terms of cost per life-year saved by avoiding decreased dose intensity with the targeted use of G-CSF in high risk women [55,91]. LYS: life year saved. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)

Fig. 19 Actuarial plot of the time to first FN event in patients with non-Hodgkin’s lymphoma receiving CHOP chemotherapy based on the method of Kaplan and Meier [49]. Patients were stratified into high risk [>3 factors, n=218] or low risk (≤3 factors, n=314] based on an unconditional model for increased risk based on older age, female gender, heart or renal disease, pretreatment hemoglobin <12g/dl, intended dose intensity >80% and the absence of G-CSF prophylaxis. High risk patients had a significantly greater cumulative risk of FN than patients in the low risk group (P<0.0001) [50]. Critical Reviews in Oncology / Hematology 2004 50, 129-146DOI: (10.1016/j.critrevonc.2004.01.001)