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A Cost Analysis of Hematopoietic Colony-Stimulating Factors

A Cost Analysis of Hematopoietic Colony-Stimulating Factors

ABSTRACT: 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. [ONCOLOGY 9(Suppl):85-91, 1995]

Introduction

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 [1]. The onset of fever in the setting
of neutropenia generally requires immediate hospitalization and
administration of broad-spectrum antibiotic therapy [2]. Previous
efforts to enhance hematologic recovery following systemic chemotherapy
have had only limited success [3].

Several hematopoietic colony-stimulating factors (CSFs) have been
characterized over the past decade [4], 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
[12]. Randomized clinical trials have demonstrated that CSFs administered
after the onset of febrile neutropenia accelerate myeloid recovery,
reducing the duration of neutropenia [13]. 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 [17]. 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.

Methods

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 [12]. 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.

Results

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.

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