Medical and Pediatric Oncology 34:92–96 (2000)
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
Charles L. Bennett, MD, PhD,1,2* Tammy J. Stinson, MS,1 David Lane, BA,2
Michael Amylon, MD,3 Vita J. Land, MD,4 and Joseph H. Laver, MD5
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 evi-
dence in others. In this study a retrospective
analysis compared the costs of inpatient sup-
portive care for pediatric patients with T-cell
leukemia and advanced lymphoblastic lym-
phoma 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 sig-
nificantly fewer days to an ANC >500 cells/µl
and a trend towards fewer days of hospitaliza-
Key words: costs; cost effectiveness; granulocyte colony-stimulating factor; pediatric
leukemia and lymphoma
INTRODUCTION
In recent years the event-free survival for pediatric
patients with T-cell disease has improved from 20% to
65% owing to new developments in intensive chemo-
therapy regimens and supportive care [1–4]. However,
this treatment can be highly toxic, causing severe and
prolonged neutropenia and delays in therapy and/or re-
peated hospitalizations. Studies have been published in-
vestigating the use of colony-stimulating factors (CSFs)
as prophylactic or adjunct therapy for chemotherapy-
induced neutropenia in pediatric patients [5–7]. The aim
of this treatment is to reduce the length of time and
severity of neutropenia and the risk of infection. This
should subsequently reduce the total costs of care by
minimizing hospitalization and the use of parenteral an-
tibiotics. However, there is uncertainty whether use of
CSFs will result in meaningful improvements in clinical
outcomes and whether these benefits will be worth the
additional costs associated with routine use of CSFs in
the pediatric setting [5–7].
Increasing emphasis has been placed on the costs and
© 2000 Wiley-Liss, Inc.
tion. Data on resource utilization were tabu-
lated from case report forms. Costs were im-
puted from national data on hospitalization
costs, average wholesale prices of pharmaceu-
ticals, and patient billing information from a
single institution. Results. Total median costs of
supportive care were $34,190 for patients re-
ceiving G-CSF and $28,653 for patients not re-
ceiving 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 pediat-
ric leukemia, the cost of growth factor may off-
set potential savings from shorter hospital stays
or lower antibiotic use, a finding consistent
with that from the Children’s Cancer Study
Group. Med. Pediatr. Oncol. 34:92–96, 2000.
© 2000 Wiley-Liss, Inc.
cost effectiveness of novel treatments for cancer. Man-
aged care organizations, assuming greater responsibility
for coverage of cancer care, evaluate these parameters in
addition to clinical and toxicological outcomes [8]. The
use of CSFs in particular is often scrutinized because of
1
Chicago VA Healthcare System-Lakeside, Chicago, Illinois
2
Division of Hematology/Oncology and the Robert H. Lurie Compre-
hensive Cancer Center, Northwestern University, Chicago, Illinois
3
Dept. of Pediatrics, Stanford University, Stanford, California
4
Dept. of Pediatrics, Children’s Memorial Hospital, Chicago, Illinois
5
Division of Hematology/Oncology, Medical University of South
Carolina, Charleston, South Carolina
Grant sponsor: Pediatric Oncology Group; Grant numbers: CA-30969,
CA-33603; Grant sponsor: National Cancer Institute; Grant number:
CA69177; Grant sponsor: AMGEN Inc.
*Correspondence to: Dr. Charles L. Bennett, Chicago VA Healthcare
System-Lakeside, 400 East Ontario Street Suite 205, Chicago, IL 60611.
E-mail: cbenne@nwu.edu.
Received 2 July 1998; Accepted 31 August 1999

high acquisition costs and expanding roles in clinical
medicine. The prophylactic use of CSFs following my-
eloablative chemotherapy has been well studied in adult
patients and is recommended when the risk of febrile
neutropenia is greater than 40% [9]. Significant cost sav-
ings have been demonstrated resulting from lower inci-
dence and duration of febrile neutropenia, infections,
hospitalizations, and antibiotic usage [10–14].
This study analyzed the resource use and costs of pe-
diatric patients receiving granulocyte CSF (G-CSF) to
determine whether the same cost savings were accom-
plished. A retrospective cost analysis of a randomized,
multisite Pediatric Oncology Group trial was conducted
to determine the effects of G-CSF on costs of inpatient
supportive care for T-cell leukemia (T-ALL) and ad-
vanced-stage lymphoblastic lymphoma (ASLL) patients
[15].
MATERIALS AND METHODS
Patients and Treatment Plan
The details of the clinical trial have been published
previously [15]. Briefly, 89 patients between 1 and 22
years of age with previously untreated T-ALL (n ⳱ 56)
or ASLL (n ⳱ 33) were randomized to receive (n ⳱ 46)
or not receive (n ⳱ 43) open-label G-CSF (10 ␮g/kg, s.c.
from 24 hr postchemotherapy to an ANC >10,000 after
the nadir) following induction and the first two cycles of
maintenance therapy. Forty-five patients in the G-CSF
arm and forty-three patients in the no–G-CSF arm were
determined to be eligible for treatment. The patient char-
acteristics did not differ between groups: The median age
of the patients was 9 years, the male to female ratio was
2:1, and the ratio of patients with T-ALL vs. ASLL was
29:16 for G-CSF patients and 26:17 for the no–G-CSF
patients. The induction phase included two combinations
of chemotherapy, vincristine, prednisone, cyclophospha-
mide, and adriamycin (days 1–21) followed by a con-
tinuous infusion of high-dose ara-C and asparaginase
(days 22–42). Maintenance phases of therapy included
the same combinations of treatment. All patients had a
central line placed for administration of chemotherapy,
blood products, and other supportive care therapies. Prior
to induction, patients received intravenous fluids and
were placed on allopurinol. Erythrocyte transfusions
were given for symptomatic anemia and platelet transfu-
sions for bleeding from thrombocytopenia; all blood
products were irradiated. The protocol included support-
ive care guidelines for participating institutions, although
specific antibiotics were not mandated. Patients with fe-
ver (>101°F) and neutropenia (ANC <500 cells/␮l) were
hospitalized and treated with broad-spectrum parenteral
antibiotics after appropriate cultures were taken. If fever
persisted beyond 6 days of antibiotic therapy, amphoteri-
cin B was initiated. Chemotherapy treatment was re-
93
started once the patient’s ANC was >500 cells/␮l for 48
hr off G-CSF. In the G-CSF group, 91% of patients
achieved remission during induction, as did 81% of the
no–G-CSF patients. During maintenance phases, 76% of
the G-CSF patients and 70% of the no–G-CSF patients
achieved remission. Neither of these differences was sta-
tistically significant.
Clinical trial endpoints included duration of neutrope-
nia, days of hospitalization, and delays in therapy. No
significant differences in outcomes were seen between
the G-CSF and no–G-CSF groups during the induction
phase of therapy. The median number of days to ANC
recovery was 4.5, median number of days of delays in
therapy was 0, and median number of days hospitalized
was 9 in both groups. During the first two cycles of
maintenance, G-CSF patients had fewer days to an ANC
>500 cells/␮l (6 days vs. 11 days for the no–G-CSF
group; P ⳱ 0.02) and a trend toward fewer delays in
therapy (5.5 days vs. 7 days for no–G-CSF; P ⳱ 0.16)
and hospital days for neutropenia (8.5 days vs. 10.5 days
for no–G-CSF patients; P ⳱ 0.22). Comparisons of days
hospitalized for neutropenic episodes following each
type of regimen (vincristine, prednisone, cyclophospha-
mide, and adriamycin vs. continuous infusion of high-
dose ara-C and asparaginase) determined that G-CSF did
not significantly lower the duration of hospital stay for
either specific type of treatment. Following the vincris-
tine combination regimen in the induction phase, G-CSF
patients were hospitalized for a median of 7 days com-
pared to 8 days for no–G-CSF patients (P ⳱ 0.56); in the
maintenance phase both groups of patients were hospi-
talized for an equal number of days (3). Following the
high-dose ara-C regimen in the induction phase, G-CSF
patients were hospitalized for 7 days compared to 5.5
days for no–G-CSF patients (P ⳱ 0.27) and, in the main-
tenance phase, 3 days compared to 6 days (P ⳱ 0.13).
Measurement of Resource Utilization and Estimation
of Costs
Resource use was determined for each patient by tabu-
lation from study case report forms. The following cost
drivers were considered: days of hospitalization for neu-
tropenia, days on intravenous and oral antibiotics, units
of packed red blood cells and single donor platelet prod-
ucts transfused, and days of G-CSF administration. Data
acquisition began after treatment with chemotherapy (the
first day of G-CSF administration) and ended after the
completion of the second maintenance cycle of treat-
ment. Median total resource utilization profiles per pa-
tient were calculated. Costs for each resource were im-
puted from national data on the average daily cost of
room and board at a U.S. children’s hospital [16], aver-
age wholesale prices of pharmaceuticals, and detailed
costs from patient billing records at a single study insti-
tution (for blood products). Patient dosage calculations
94
TABLE I. Derivation of Costs per Day (Based on a Mean TABLE II. Median Resource Counts per Cost Driver Category
Patient Weight of 37.3 kg)
G-CSF No G-CSF
Description Cost Variable (range) (range) P value
Average cost of stay in U.S. childrens hospital in 1996 $1,574.73 Induction
IV antibiotics (ceftazidime, 40 mg/kg, IV) $70.57 Days hospitalized 9 (0–40) 9 (0–47) 0.96
Broad-spectrum antibiotic (bactrim, 8 or 40 mg/kg) $37.80 Days IV antibiotics 7 (0–27) 4 (0–27) 0.38
G-CSF (10 ␮g/kg, SC) $189.00 RBC transfusions 1 (0–5) 0 (0–7) 0.53
Unit irradiated RBC $138.75 Platelet transfusions 1 (0–8) 0 (0–5) 0.57
Unit single-donor irradiated platelets $555.50 Days bactrim 2 (0–49) 0 (0–20) 0.80
Days G-CSF 8 (0–24) — —
Maintenance
were based on an average mass of 37.3 kg. Centralized Days hospitalized 8.5 (0–45) 10.5 (0–39) 0.22
pharmacy dispensation of G-CSF was assumed, allowing Days IV antibiotics* 1 (0–17) 4 (0–43) 0.02
multiple usage per vial and calculation of the cost of RBC transfusions 2 (0–9) 2 (0–7) 0.53
Platelet transfusions 2 (0–10) 1.5 (0–13) 0.18
treatment per milligram, not per vial. The cost analysis Days bactrim 0 (0–84) 0 (0–66) 0.29
was based on daily costs for a pediatric patient of $1,575 Days G-CSF 18 (3–65) — —
room cost for each in-hospital day, $71 per day for in-
*Statistically significant at >95% confidence level, Wilcoxon rank-
travenous antibiotics, $38 per day for oral antibiotics, sum test.
$139 per unit of leukocyte reduced packed red blood
cells, $556 per unit of leukocyte-reduced single donor
apheresis platelets, and $189 per day for G-CSF admin- RESULTS
istration (Table I). Only direct medical costs were in-
cluded, exclusive of costs of supplies and radiology, The cost analysis determined that median resource use
laboratory, and physician fees. and costs were similar during both induction ($13,296 for
Total costs, cost per treatment phase (induction and the G-CSF group and $11,404 for the no–G-CSF group;
maintenance), and cost per resource category were cal- P ⳱ 0.57) and maintenance phases ($21,687 for the G-
culated as medians (owing to the skewed distribution of CSF group and $17,898 for the no–G-CSF group; P ⳱
cost data resulting from a small percentage of patients 0.70; Tables II, III). There was a significantly lower use
with extremely high costs). Medians provide an estimate and cost of intravenous antibiotics in the G-CSF arm
of the costs of a typical patient and not an average (such during maintenance phase (1 day vs. 4 days, P ⳱ 0.02;
as one would use for budgetary purposes, in order to $141 vs. $423, P ⳱ 0.04). Overall the median cost dif-
accommodate the costs of outliers). Differences in me- ference between treatment arms was $34,190 for G-CSF
dian costs were evaluated using Wilcoxon rank sum test- vs. $28,653 for no–G-CSF but was not significant (P ⳱
ing, and bootstrapping was used to calculate 95% confi- 0.43) Ninety-five percent confidence intervals of these
dence intervals. Power analyses indicate that this study values demonstrate the large degree of variance in these
had 14% power to detect a difference of $5,000, and 49% numbers, $24,460–46,191 for G-CSF and $17,596–
power to detect a difference of $10,000 with the available 49,608 for no–G-CSF (Table III). G-CSF represents 10%
sample sizes. The high variance inherent in cost analyses of the cost of treatment during induction phase and
often results in a requirement of sample sizes that are not 17.5% during maintenance phases.
compatible with clinical endpoints or are prohibitive (for Sensitivity analyses confirmed these findings. When
a two-tailed test with 80% power at P < 0.05, this analy- the patient hospital length of stay was varied by 20%, the
sis would require 490 patients per arm). As with all pilot total median cost in the G-CSF arm was $28,993 (−20%)
clinical and economic analyses, nonsignificant results or $38,802 (+20%), compared to $23,535 (−20%) or
should be viewed as inconclusive and not as evidence of $33,771 (+20) in the no–G-CSF arm (P ⳱ 0.29 and 0.43,
equivalence. respectively). If G-CSF administration was discontinued
Univariate sensitivity analyses were conducted to at an ANC 500 (closer to typical clinical parameter than
evaluate the cost of treatment. Assumptions were varied the 10,000 cells/␮l used in this study), the total median
to accommodate potential practice differences, including cost for the G-CSF arm was $31,279 vs. $28,653 for the
the length of hospitalization, criteria for discontinuing no–G-CSF arm (P ⳱ 0.91). If the dosage of G-CSF was
growth factor, alternative growth factor dosage, and ad- 5 ␮g/kg/day (a more commonly used amount), the total
dition of an aminoglycoside as part of the antibiotic regi- median cost would be $31,744 for the G-CSF arm and
men for neutropenic fever. Analyses of variation in $28,653 for the no–G-CSF arm (P ⳱ 0.86). Finally, if an
length of stay (overall and with potential decreases with aminoglycoside (amikacin) were added to the parenteral
G-CSF use) and the cost of growth factors were plotted antibiotic regimen for febrile neutropenia, total median
vs. total costs to illustrate these effects and provide costs for G-CSF patients would be $35,647 vs. $30,171
‘break-even’ values. for no–G-CSF patients (P ⳱ 0.62). Graphical represen-
 95
TABLE III. Median Costs by Phase of Treatment and
Cost Category
Variable G-CSF No G-CSF P value
Induction
Hospitalization 9,448 9,448 0.96
IV antibiotics 494 353 0.49
RBC transfusions 184 0 0.33
Platelet transfusions 556 0 0.48
Bactrim 38 0 0.52
G-CSF 1,323 — —
Subtotal 13,296 11,404 0.57
Maintenance
Hospitalization 14,173 16,535 0.42
IV Antibiotics* 141 423 0.04
RBC transfusions 278 278 0.55
Platelet transfusions 1,111 556 0.18
Bactrim 0 0 0.52
G-CSF 3,806 — —
Subtotal 21,687 17,898 0.70
Total $34,190 $28,653 0.43
95% Conf. interval $24,460–46,191 $17,896–49,608
*Statistically significant at >95% confidence level, Wilcoxon rank-
sum test.

tations of sensitivity analyses that vary decreases in pa-

tient hospital length of stay because of G-CSF use and
the cost of G-CSF demonstrate that an additional de-
crease in days of hospitalization of 20% (or a decrease of
6.5 days in comparison to no–G-CSF, as opposed to the
reported difference of 2.5 days) or zero costs of G-CSF
would result in equivalent costs between treatment arms
(Fig. 1).
DISCUSSION
This analysis determined that G-CSF use for pediatric
patients with T-ALL or ASLL is unlikely to result in
significant cost savings, despite the shorter time to ANC
recovery during the maintenance phase. This study con-
firms the findings of the recently published article by Pui
et al. [5] that reported shorter hospital stays and fewer
documented infections in pediatric patients with ALL
who received G-CSF during induction than in those who
received placebo. Despite these clinical improvements
the median costs of supportive care were similar, $8,678
for the G-CSF arm and $8,616 for the placebo arm. In
contrast, one other report in the literature found a cost
savings for G-CSF use in the pediatric setting. Riikonen
et al. demonstrated a $1,033 savings per chemotherapy
cycle for 16 pediatric cancer patients (mainly hemato-
logic malignancies) receiving G-CSF as treatment for
febrile neutropenia [6,7]. Clearly the use of growth fac-
tors, though seeming to provide some clinical benefit, for
pediatric leukemia requires further investigation and op-
timization.
Limitations exist in this study. First, these analyses
were based on measurements of direct costs and did not
Fig. 1. Graphical representation of selected sensitivity analyses.
include indirect costs or direct nonmedical costs to the
patient’s family. Likewise, the analyses were not ad-
justed for effects on quality of life. Although the impact
of shorter hospital stays, febrile episodes, and daily sub-
cutaneous injections are unknown in this set of patients,
these outcomes are difficult to measure retrospectively
and have not been included in prior studies of the costs
and cost effectiveness of CSFs [5,11–14,16]. More recent
studies evaluating CSFs are prospectively assessing qual-
ity of life and will be useful for the purpose of quality-
adjusting both clinical and economic outcome assess-
ments [17]. Second, although practice patterns related to
chemotherapy administration were identical among all
the study sites, supportive care strategies may have var-
ied between centers. However, supportive care guide-
lines were part of the POG protocol (as discussed in
Materials and Methods), and the use of antibiotics and
duration of hospitalization were determined to be similar
at the different study sites. Third, this was an open-label
study (without placebo administered to control patients).
This may influence some physician practices, but the
clinical endpoints, supportive care protocols, and dis-
charge criteria were based on definitive values, such as
days with fever and absolute neutrophil counts, limiting
the extent of bias. Fourth, this study was underpowered
96
to provide a quantitative value for the difference in costs.
This is a common problem encountered when conducting
economic analyses of trials designed for clinical end-
points. The lack of statistical power stems from the wide
degree of variance for these values. Although these cost
data may have some practical significance for medical
professionals comparing treatment strategies, they should
be viewed discerningly.
The current economic study was conducted retrospec-
tively by an external health economics research team,
requiring minimal efforts from the cooperative group
personnel. Copies of case report forms were sent to the
economic research personnel, and cost elements were
determined and abstracted and analyses performed. Re-
source utilization data for the primary cost drivers were
limited to those provided in the case report forms. To
conduct a prospective study, case report forms can be
designed to include necessary information for economic
analyses with little additional workload to the data-
collection personnel. During the drafting process of the
case report forms, clinical and economic investigators
would have to determine the important cost drivers to the
specific situation to ensure that data requirements are
kept to a minimum. Financial and administrative contacts
can be readily established at the start of a study in a
prospective manner, rather than having to determine
sources and decipher data once billing records have been
merged into permanent storage files. A summary com-
paring the resources used to complete the retrospective
analysis (approximately 68 working hours) and the pos-
tulated time to conduct the same analysis collecting data
prospectively alongside the cooperative group trial (ap-
proximately 49 working hours) determined that a pro-
spective analysis would be cost- and time-effective for
this type of study. Our study provides additional evi-
dence that economic assessments of phase III clinical
trials of cooperative groups are feasible, a finding that
has been reported previously by investigators from the
Southwest Oncology Group and the Eastern Cooperative
Oncology Group [18,19]. As suggested by the recent
National Cancer Institute/American Society of Clinical
Oncology Economics Workgroup, economic assessments
can be readily incorporated into prospective cooperative
group trial design and conducted in a manner that is
cost-effective, feasible, and likely to result in clinically
meaningful results.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the assistance of
Ms. Rachel Stroman in organizing the data transfer.
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