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Granulocyte colony-stimulating factor (G-CSF, Filgrastim) after or during an intensive remission induction therapy for adult acute lymphoblastic leukaemia: effects, role of patient pretreatment characteristics, and costs |
Bassan R, Lerede T, Di Bona E, Rossi G, Pogliani E, Rambaldi A, Buelli M, Viero P, Rodeghiero F, Izzi T, Corneo G, Barbui T |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology An intensive remission induction therapy based on a 14 day regimen with idarubicin-vincristine-L-asparaginase-prednisone (IVAP), for adult acute lymphoblastic leukaemia (ALL). Idarubicin (IDA) was given on days 2 and 3. As IDA is known to be a strongly myelo-suppressive agent, human recombinant granulocyte colony-stimulating factor (G-CSF) was used as an adjunct to the IVAP therapy in the hope of counteracting this effect by accelerating neutrophil recovery and thereby attenuating the risk of infection. Initially in the series, G-CSF was given from day 15 (the end of the IVAP therapy) at the rate of 5 microg/kg/d until neutrophils > 1.5x10?9/l for 3 consecutive days. Later in the series G-CSF was given from day 4 in the treatment regimen at the same rate until the same conditions were fulfilled. To combat infection all patients received prophylactic oral ciprofloxacin and fluconazole from day 1 but in the presence of fever or other signs of infection intravenous ceftazidme plus amikacin were commenced. Vancomycin was added after 48 hours if needed and imipenemcilastatin substituted for ceftazidme plus amikacin if necessary.
Type of intervention Treatment; Secondary prevention.
Economic study type Cost-effectiveness analysis.
Study population Adult patients with de novo and previously untreated ALL who were undergoing an intensive remission therapy including IDA (IVAP).
Setting Hospital. The economic study was carried out in Italy.
Dates to which data relate Patients were entered into the clinical study between October 1991 and December 1993. Price dates were not given.
Source of effectiveness data Evidence for final outcomes was based on a single study.
Link between effectiveness and cost data Costing was undertaken prospectively on the same patient sample as that used in the effectiveness study.
Study sample During the study period 80 consecutive adults with ALL were treated with the IVAP therapy at participating institutions. Of these, 10 were not treated with G-CSF and 5 were excluded from the analysis owing to inadequate data. The 10 who were not given G-CSF were not suitable as a control group because they were not comparable in age and disease presentation. Of the remaining sample of 65, the first 28 were given G-CSF from day 15 and the remaining 37 from day 4.
Study design The study was a multi-centred non-randomized controlled trial. It was not stated specifically how many centres participated in the study but there were co-authors from 4 hospitals. It was not stated how many patients were treated at each centre or which groups they were in. Follow up was not mentioned.
Analysis of effectiveness It was not stated whether analysis was based on intention to treat. Primary health outcomes were: complete remission rates; the neutrophil recovery pattern and incidence of neutropenic complications (infections, fever and use of antibiotics). The endpoints measured were: complete remission rates, days with neutropenia less than 0.5x10?9/l, number of cases of abnormally long neutropenia (PSN), days to neutrophils greater than 0.5x10?9/l, patients with documented infections, patients with fever >38?C, days with fever >38?C, patients on iv antibiotics, days on iv antibiotics, patients on iv amphotericin-B. There were no statistically significant differences between the group receiving late G-CSF and that receiving early G-CSF in age, sex or disease presentation.
Effectiveness results Complete remission rates were globally high, 96% (26/27) in the late G-CSF group and 86% (32/37) in the early G-CSF group.
Days (median) with neutropenia less than 0.5x10?9/l were 17 (range: 5 - 26) in the late G-CSF group and 9 (range: 0 - 23) in the early G-CSF group, p<0.001.
Number of cases of abnormally long neutropenia (PSN) were 18 (64%) in the late G-CSF group and 9 (24%) in the early G-CSF group, p=0.002.
Days (median) to neutrophils more than 0.5x10?9/l were 21 (range: 17 - 35) in the late G-CSF group and 17 (range: 15 - 31) in the early G-CSF group, p<0.001.
Numbers of patients with documented infections were 20 (71%) in the late G-CSF group and 13 (35%) in the early G-CSF group, p=0.007.
Numbers of patients with fever >38?C were 9 (32%) in the late G-CSF group and 15 (40%) in the early G-CSF group, (difference not significant).
Days (median) with fever >38?C were 3 (range: 1 - 14) in the late G-CSF group and 2 (range: 1 - 10) in the early G-CSF group, (difference not significant).
Numbers of patients on iv antibiotics were 22 (78.5%) in the late G-CSF group and 16 (43%) in the early G-CSF group, p=0.008.
Days (median) on iv antibiotics were 9.5 (range: 4 - 24) in the late G-CSF group and 7 (range: 2 - 38) in the early G-CSF group, (difference not significant).
Numbers of patients on iv amphotericin-B were 11 (39%) in the late G-CSF group and 2 (5%) in the early G-CSF group p=0.002.
Clinical conclusions The complete remission rate was globally high and not affected by G-CSF timing. Results from the first phase of the study (late G-CSF) were rather disappointing with a pattern of slow neutrophil recovery associated with a high rate of infectious complications. Experience with early G-CSF was more positive. The incidence of abnormally prolonged severe neutropenia and associated infections was reduced.
Measure of benefits used in the economic analysis The measure of benefits were the number of documented infectious episodes.
Direct costs The only costs give were those for medications used: mean cost per patient of G-CSF and of antibiotic and antifungal treatments( ciprofloxaxin + fluconazole, ceftazidime/amikacin +/- anti-Gram + antibiotic and Amphotericin).
Statistical analysis of costs Costs were given as the mean cost per patient of the medications used. No confidence interval or range was given. Selected variables in the study were compared using the student t test and Fisher's exact test but it was not stated which was used for the costing. P values were given where differences were significant.
Indirect Costs Indirect costs were not considered.
Currency European Currency Unit (ECU). Converted from Italian lira at 1 ECU = 1.812 Lira (the mean exchange rate obtained in January 1993).
Sensitivity analysis No sensitivity analysis was performed.
Estimated benefits used in the economic analysis The numbers of patients with documented infections were 20 (71%) in the late G-CSF group and 13 (35%) in the early G-CSF group, p=0.007.
Cost results The mean costs per patient expressed in ECU from day 1 of IVAP to outcome were:
G-CSF, late group:882
G-CSF, early group: 1,478 (significant increase p < 0.0001).
Ciprofloxaxin + fluconazole, late group: 263
Ciprofloxaxin + fluconazole, early group: 203.
Ceftazidime/amikacin +/- anti-Gram + antibiotic, late group: 670
Ceftazidime/amikacin +/- anti-Gram + antibiotic, early group: 324 (significant reduction p = 0.01).
Amphotericin, late group:3
Amphotericin, early group:1 (significant reduction p= 0.03).
Total 1,812 in the late group and 2,006 in the early group. The difference between totals was not significant.
Synthesis of costs and benefits Costs and benefits were not combined because the cost difference between the two groups was not statistically significant.
Authors' conclusions Early G-CSF limited the incidence of severe neutropenia and related complications following the IVAP induction regime for adult ALL without short term side effects and it could, therefore, be considered cost-effective. However, the cost was high, there was uncertainty about long term effects and benefits could vary according to pretreatment features.
CRD COMMENTARY - Selection of comparators The authors explained their reasons for not using a control group with no G-CSF.
Validity of estimate of measure of benefit The authors stated that long term effects were not yet known. They presented a large number of short term endpoints but failed to show that the one they used in their discussion of cost-effectiveness (incidence of infections) had any particular clinical significance.
Validity of estimate of costs The only costs presented were the costs of drugs. The authors did not show that there were no other costs involved. Important cost items in the care of patients may have been omitted.
Other issues The numbers in this study were not large enough to detect a difference in costs. Since this was not a randomised trial, differences in benefits between the two groups may have other explanations. There may have been differences between the results in different centres but the numbers treated and group allocation between participating institutions was not given.
Bibliographic details Bassan R, Lerede T, Di Bona E, Rossi G, Pogliani E, Rambaldi A, Buelli M, Viero P, Rodeghiero F, Izzi T, Corneo G, Barbui T. Granulocyte colony-stimulating factor (G-CSF, Filgrastim) after or during an intensive remission induction therapy for adult acute lymphoblastic leukaemia: effects, role of patient pretreatment characteristics, and costs. Leukemia and Lymphoma 1997; 26(1-2): 153-161 Indexing Status Subject indexing assigned by NLM MeSH Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols /therapeutic use; Asparaginase /administration & Cost-Benefit Analysis; Female; Filgrastim; Granulocyte Colony-Stimulating Factor /economics /therapeutic use; Humans; Idarubicin /administration & Male; Middle Aged; Patient Selection; Precursor Cell Lymphoblastic Leukemia-Lymphoma /drug therapy /economics; Prednisolone /administration & Prospective Studies; Recombinant Proteins; Remission Induction /methods; Treatment Outcome; Vincristine /administration & dosage; dosage; dosage; dosage AccessionNumber 21997001098 Date bibliographic record published 30/11/1998 Date abstract record published 30/11/1998 |
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