Full text of DOI:10.1592/phco.20.19.1432.34861

Comparative Safety of Filgrastim versus Sargramostim in
Patients Receiving Myelosuppressive Chemotherapy
Gary Milkovich, B.S., Ronald J. Moleski, Pharm.D., John F. Reitan, Pharm.D.,
David M. Dunning, M.D., Gene A. Gibson, Pharm.D., Thomas A. Paivanas, M.H.S.A.,
Susan Wyant, Pharm.D., and R. Jake Jacobs, M.P.A.
Study Objective. To compare rates of adverse events with filgrastim versus
sargramostim when given prophylactically to patients receiving
myelosuppressive chemotherapy.
Design. Retrospective review with center crossover.
Setting. Ten United States outpatient chemotherapy centers.
Patients. Four hundred ninety patients treated for lung, breast, lymphatic
system, or ovarian tumors.
Intervention. Prophylactic use of filgrastim or sargramostim, with dosages at
investigator discretion.
Measurements and Main Results. The frequency and severity of adverse
events and the frequency of switching to the alternative CSF were assessed.
There was no difference in infectious fever. Fever unexplained by infection
was more common with sargramostim (7% vs 1%, p<0.001), as were
fatigue, diarrhea, injection site reactions, other dermatologic disorders, and
edema (all p<0.05). Skeletal pain was more frequent with filgrastim
(p=0.06). Patients treated with sargramostim switched to the alternative
agent more often (p<0.001).
Conclusion. Adverse events were less frequent with filgrastim than with
sargramostim, suggesting that quality of life and treatment costs also may
differ.
(Pharmacotherapy 2000;20(12):1432–1440)
Colony-stimulating factors (CSFs) are
recommended in certain situations to reduce the
likelihood of febrile neutropenia induced by
myelosuppressive chemotherapy.1 Recombinant
forms of granulocyte (G)-CSF and granulocyte-
macrophage (GM)-CSF are synthesized using a
variety of host expression systems. In the United
States, G-CSF is commercially available as
filgrastim, derived from bacterial cells, and GM-
CSF is available as sargramostim, derived from
yeast cells.
Only two studies directly compared the safety
of these two agents.2, 3 Reviews of safety based on
placebo-controlled trials1, 4, 5 are problematic, as
the trials often include populations with different
underlying diseases and concomitant drug
therapy. Bone pain is the most commonly
reported adverse event with filgrastim,6, 7 but
exacerbation of preexisting inflammatory
conditions,8–10 rash,11 allergic reactions,12 Sweet
syndrome,13 and injection site reactions14 have
been reported. With sargramostim, the most
common adverse event is fever.2, 4, 15 Nausea,
fatigue, headache, bone pain, chills, myalgia, and
injection site reactions also have been reported.16–20
Sargramostim is almost certainly less toxic than
GM-CSF expressed in bacterial cells (molgramostim).
Compared with molgramostim, fluid retention,
dyspepsia, fever, and myalgia and arthralgia are all
less frequent with sargramostim.21 The initial dose
of molgramostim may cause significant hypoxia
and hypotension, particularly in patients receiving

SAFETY OF FILGRASTIM VERSUS SARGRAMOSTIM Milkovich et al
1433
high dosages or intravenous administration.22
The perception that sargramostim is less safe
than filgrastim may be due to confusion
regarding data describing GM-CSF synthesized
using bacterial or mammalian cells. This was the
principal rationale for the only randomized
comparison of CSF tolerability, in which 137
patients receiving myelosuppressive chemotherapy
were assigned to filgrastim 7 µg/kg or
sargramostim 193 µg/m2, with regimens at
investigators’ discretion.2 The agents were
compared on the frequency of 11 adverse events,
graded by Eastern Cooperative Oncology Group
(ECOG) or similar criteria. The frequency of
fever, mainly 98.7–100.4°F, was 2-fold greater
with sargramostim (p=0.01). Statistically
insignificant trends were seen, indicating more
frequent bone pain, chills, and nausea with
sargramostim, and more frequent headache with
filgrastim. The comparative safety of these
agents also was assessed in a drug use evaluation,
which included 60 patients undergoing bone
marrow transplantation, dose-intensive
chemotherapy, and standard chemotherapy.3 No
differences were noted in frequencies of fever,
nausea and vomiting, musculoskeletal pain,
diarrhea, myalgia, or local reactions.
Our study was undertaken to provide
additional data on the comparative safety of
filgrastim and sargramostim in patients receiving
myelosuppressive chemotherapy. We sought to
avoid what we considered important limitations
of earlier comparative studies; namely, inade-
quate statistical power, data obtained from a
single or small number of centers, and pooling of
patients receiving CSFs prophylactically and
therapeutically.
From the School of Pharmacy, Medical College of
Virginia, Richmond, Virginia, and Northern Virginia Cancer
Center, Alexandria, Virginia (Mr. Milkovich); RJM
Associates, Guilford, Connecticut (Dr. Moleski); The Reitan
Company, Inc., Crown Point, Indiana (Dr. Reitan); Northern
Virginia Oncology Group, Fairfax, Virginia (Dr. Dunning);
the Department of Pharmacy, Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania (Dr. Gibson); the
School of Public Health and Health Services, George
Washington University Medical Center, Washington, D.C.
(Mr. Paivanas); The Dominion Group, McLean, Virginia
(Dr. Wyant); and Capitol Outcomes Research, Inc.,
Alexandria, Virginia ((Mr. Jacobs).
Methods
This was a multicenter, retrospective exami-
nation in which patients receiving CSFs for
primary or secondary prophylaxis were
identified, and their clinical experiences assessed
through medical record review. To minimize
selection bias common to retrospective studies,
we employed a center crossover design in which
participating sites substituted sargramostim for
filgrastim or vice versa as CSF of choice. We
anticipated that patients treated before and after
the policy decision would not differ system-
atically with respect to risk factors for adverse
events. By contrast, a traditional retrospective
study would be biased by self-selection if one
agent were reserved for patients at greater risk of
adverse events.
Centers
Ten U.S. outpatient chemotherapy centers
participated. All provided chemotherapy to 20 or
more patients/month and made a decision before
participation to substitute one CSF for the other
as agent of choice for patients receiving
myelosuppressive chemotherapy. Nine substituted
sargramostim for filgrastim, and one substituted
filgrastim for sargramostim. Each center was
assigned a crossover date representing the first
day of the first month during which 90% of new
patients received the subsequent agent.
Filgrastim and sargramostim eras were defined
for each center. For centers substituting
sargramostim for filgrastim, the sargramostim era
began with the crossover date and continued
through 12 months or agreement to participate in
the study, whichever was earlier; the filgrastim
era began and ended exactly 12 months earlier.
The process was reversed for the site substituting
filgrastim for sargramostim. The mean duration
of filgrastim and sargramostim eras was 8 months
(range 4–12 mo).
Patients
Records of all patients having received one or
more doses of CSF during the filgrastim and
sargramostim eras were examined. Patients were
included if they were aged 18 years or older and
received chemotherapy for a lung, breast,
lymphatic system, or ovarian tumor. Those with
a history of any autoimmune disease or disease of
the blood or blood-forming organs were
excluded, as were recent (< 90 days) recipients of
bone marrow transplants or experimental drugs.
Funded by an unrestricted research grant from Amgen
Inc., Thousand Oaks, California.
Manuscript received July 5, 2000. Accepted pending
revisions August 30, 2000. Accepted for publication in final
form September 25, 2000.
Address reprint requests to Ronald J. Moleski, Pharm.D.,
RJM Associates, 195 Maupas Road North, Guilford, CT
06437.

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PHARMACOTHERAPY Volume 20, Number 12, 2000
Table 1. Baseline Characteristics
Variable
Filgrastim
Sargramostim
p Value
No. of patients (by initial CSF)
239
251
Mean (SD) age, yrsa
62 (14)
176 (74)
1.8 (0.2)
26 (48)
115 (51)
6 (3)
61 (14)
176 (71)
1.8 (0.3)
19 (36)
122 (47)
10 (4)
0.43b
0.56d
0.38b
0.62b
0.49d
0.33d
0.07d
No. (%) womenc
Mean (SD) body surface area,e m2
Mean (SD) months since cancer diagnosisf
No. (%) of patients covered by Medicareg
No. (%) of patients covered by managed careg
No. (%) of patients by tumor type
Breast
Lung
Lymphoma
Ovarian
97 (41)
52 (22)
56 (23)
34 (14)
88 (35)
84 (33)
48 (19)
31 (12)
No. (%) of patients by study center
0.41d
A
B
C
D
E
F
G
H
I
10 (4)
31 (13)
22 (9)
19 (8)
10 (4)
8 (3)
9 (4)
5 (2)
70 (29)
55 (23)
20 (8)
39 (16)
26 (10)
16 (6)
12 (5)
7 (3)
18 (7)
6 (2)
61 (24)
46 (18)
J
aMissing data for one sargramostim recipient.
bWilcoxon rank sum test.
cMissing data for four sargramostim recipients.
␹2 test.
d
eMissing data for 15 filgrastim and 20 sargramostim recipients.
fMissing data for 13 filgrastim and 21 sargramostim recipients.
gMissing data for 12 filgrastim and 19 sargramostim recipients.
Chemotherapy and CSF Cycles
monitored beginning with the first CSF dose
through 24 hours after the last dose. Most
patients received one CSF dose/day on
consecutive days, as evidenced by the similarity
between mean (SD) doses/cycle [7.5 (3.1)] and
cycle duration [8.0 days (3.3 days)]. During
occasional gaps of 1 or more days between doses,
adverse event monitoring was suspended.
Clinical monitors recorded information explicitly
stated in medical records, including verbatim
description of adverse events.
Two reviewers blinded to CSF reviewed adverse
event reports and classified them into
predetermined categories: fever, fatigue, chills,
headache, skeletal pain, nausea and vomiting,
constipation, diarrhea, other digestive disorder,
injection site reaction, other dermatologic
disorder, chest discomfort, edema, hematologic
reaction, central nervous system disorder, or
other. Disagreement between reviewers on
adverse event classification was rare (9/555
cases) and resolved through consultation with
the prescribing physician or nursing staff.
Febrile episodes were defined as a single reading
of 100.4°F or greater obtained by any health
professional and were subclassified as being of
Data describing chemotherapy regimens, CSF
dosing, blood counts, and adverse events were
recorded for all cycles, to a maximum of
six/patient. Daily CSF doses were established at
investigators’ discretion. Mean doses were 369
µg (5.5 µg/kg) for filgrastim and 474 µg (6.9
µg/kg) for sargramostim. Eligible cycles were
those beginning within 7 days of the most recent
chemotherapy dose, if the patient was afebrile (<
100.0°F) and did not otherwise meet criteria for
therapeutic administration of CSFs.1 If inclusion
and exclusion criteria no longer were met during
follow-up, all subsequent cycles were excluded.
Recording the Response
Case report forms were completed by four
clinical monitors, and their accuracy was
confirmed by center investigators. Data were
recorded covering inclusion and exclusion
criteria, demographic and clinical characteristics,
CSF dosages and cycle duration, and adverse
events including symptom description, onset and
resolution dates, and assessments of severity and
relationship to CSF. Adverse events were

SAFETY OF FILGRASTIM VERSUS SARGRAMOSTIM Milkovich et al
1435
Table 2. Chemotherapy Regimensa
Variable
Filgrastim
239
Sargramostim
251
p Value
No. of patients (by initial CSF)
No. (%) receiving each agent
Bleomycin
Carboplatin
Cisplatin
Cyclophosphamide
Cytarabine
Dacarbazine
9 (4)
51 (21)
24 (10)
104 (44)
6 (3)
5 (2)
73 (29)
22 (9)
90 (36)
6 (2)
0.24b
0.05b
0.63b
0.08b
0.93b
1.0c
3 (1)
4 (2)
Docetaxel
Doxorubicin
Etoposide
21 (9)
93 (39)
42 (18)
9 (4)
39 (16)
2 (1)
20 (8)
81 (32)
35 (14)
5 (2)
42 (17)
15 (6)
10 (4)
0 (0)
23 (9)
12 (5)
1 (< 1)
73 (29)
1(< 1)
2 (1)
0.74b
0.13b
0.27b
0.24b
0.90b
<0.01b
0.71b
0.49c
0.63b
0.93b
1.0c
Fludarabine
Fluorouracil (5-FU)
Gemcitabine
Ifosfamide
8 (3)
Melphalan
1 (< 1)
19 (8)
11 (5)
0 (0)
52 (22)
1 (< 1)
0 (0)
20 (8)
6 (3)
39 (16)
7 (3)
Methotrexate
Mitoxantrone
Nitrogen mustard
Paclitaxel
Procarbazine
Rituximab
Topotecan
Vinblastine
Vincristine
Vinorelbine
0.06b
1.0c
0.50c
0.22b
0.85b
0.46b
0.39b
14 (6)
7 (3)
35 (14)
11 (4)
aIncludes agents administered during any of up to six chemotherapy cycles.
␹2 test.
b
cFisher’s exact test.
presumed infectious cause or unexplained by
infection, based on the presence or absence of
documented pathogen(s) or other clinical signs
of infection (e.g., dark, cloudy urine; positive
chest radiograph).
9% difference in frequency of fever unexplained
by infection, with anticipated fever risk derived
from an earlier comparative study2 adjusted to
reflect an expected three cycles/patient. We
intended to conduct analyses on a per-patient
basis and determined 245 patients in each arm
would provide 80% power, assuming an ␣ of 0.05
and a two-tailed test. Patients first prescribed
sargramostim frequently switched to filgrastim,
requiring modification of the analysis because
duration of follow-up differed between CSFs. We
therefore assessed adverse event frequency on a
per-cycle basis, assigning cycles after a switch to
the alternative CSF. Based on the actual numbers
of 958 filgrastim and 644 sargramostim cycles,
the sample provided abundant statistical power
to detect meaningful differences. For adverse
events occurring in one arm at rates of 3%, 4%,
and 5%/cycle, the sample provides 82%, 91%,
and 96% power to detect 2-fold greater rates in
the other arm.
Adverse events other than fever were rated for
severity. They were considered at least moderate
if drug therapy or other intervention was
required, and severe if intervention included a
narcotic, invasive procedure, or hospitalization.
Otherwise, they were categorized based on
expressions in medical records and considered
mild unless evidence was recorded to the
contrary. Relationship to CSF was categorized
based on World Health Organization definitions23
as probably, possibly, or probably not related.
The last category included conditions present
before CSF was begun or attributed in medical
records to an underlying disease or concomitant
drug. Otherwise, events were considered
possibly related unless medical records indicated
a stronger association.
Categoric data were compared by ␹2, unless a
low frequency of adverse events required Fisher’s
exact test. For interval data, the normality of
distributions was determined by Kolmogorov D
test. Student’s t test was used when data were
Statistical Methods
The study was powered to detect a 3% versus

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PHARMACOTHERAPY Volume 20, Number 12, 2000
Table 3. Numbers of CSF Cycles and Doses
Variable
Filgrastim
239
Sargramostim
251
p Valuea
No. of patients (by initial CSF)
Use of either CSF
Mean (SD) cycles
Mean (SD) doses
3.5 (1.9)
24.1 (15.9)
3.4 (1.9)
25.1 (17.1)
0.76
0.65
Use of first prescribed CSF
Mean (SD) cycles
Mean (SD) doses
3.4 (1.9)
23.9 (16.0)
2.6 (1.6)
19.5 (15.3)
<0.001
<0.001
Use of alternative CSF
Mean (SD) cycles
Mean (SD) doses
aWilcoxon rank sum test.
< 0.1 (0.2)
0.1 (1.5)
0.8 (1.5)
5.5 (10.8)
<0.001
<0.001
Table 4. Frequency of Fever
Variable
No. of cycles
Filgrastim
958
Sargramostim
644
p Valuea
No. (%) of cycles with report of
Fever ≥ 100.4˚F
39 (4)
25 (3)
14 (1)
57 (9)
15 (2)
42 (7)
<0.001
0.72
<0.001
Fever of presumed infectious origin
Fever unexplained by infection
a
␹2 test.
normally distributed, and Wilcoxon rank sum
test when the distribution was not normal. All
tests were two-tailed, and a p value below 0.05
was considered statistically significant.
We found no differences in numbers of
chemotherapy-CSF cycles (p=0.76) or CSF doses
(p=0.65) between patients initially prescribed
filgrastim versus sargramostim (Table 3). The
proportions of filgrastim recipients proceeding to
second, third, fourth, fifth, and sixth CSF cycles
were 80%, 58%, 44%, 29%, and 18%, versus 77%,
58%, 41%, 28%, and 21% for sargramostim (all
NS). Patients first prescribed sargramostim were
more likely to be switched to filgrastim than vice
versa. Consequently, they received fewer cycles
(2.6 vs 3.4, p<0.001) and doses (19.5 vs 23.9,
p<0.001) of their initial CSF.
Table 4 shows the frequency of fever during
filgrastim and sargramostim cycles. Febrile
episodes occurred more than twice as frequently
with sargramostim (9% vs 4%, p<0.001), with the
entire difference represented by fever
unexplained by infection (7% vs 1%, p<0.001).
Among the 56 febrile episodes, no differences
were seen between CSFs in fever duration or
maximum recorded temperature. Fever
unexplained by infection was most common
during the first sargramostim cycle (10% vs 1%
with filgrastim, p<0.001), although a lesser
relationship persisted during subsequent cycles
(4% vs 2%, p<0.01).
Results
There were no significant differences in
baseline characteristics between patients initially
receiving filgrastim versus sargramostim (Table 1).
Patients were typical of those seen in office-based
oncology practices. The sargramostim arm had
proportionally more patients with lung cancer,
and the filgrastim arm had more with breast
cancer and lymphoma. No differences in disease
stage were detected between arms (data not
shown).
Patients received 24 chemotherapeutic agents
(Table 2), with cyclophosphamide, doxorubicin,
paclitaxel, carboplatin, and etoposide most
common in both groups. Those in the
sargramostim arm were most likely to receive
carboplatin (29% vs 21%, p=0.05) and
gemcitabine (6% vs 1%, p<0.01). Given the large
number of comparisons, these differences
approximate what would be expected by chance.
We found no differences between arms with
respect to combinations of chemotherapeutic
agents or chemotherapy dosages (data not
shown).
The most frequently reported adverse event
was skeletal pain (Table 5), which tended to
occur more frequently with filgrastim (11% vs

SAFETY OF FILGRASTIM VERSUS SARGRAMOSTIM Milkovich et al
1437
Table 5. Frequency of Adverse Events other than Fever
Adverse Event
Adverse Event
Possibly or Probably
Related to Cytokine
of Moderate or
Greater Severity
Any Adverse Event
Variable
Filg
Sarg
Filg
Sarg
Filg
Sarg
% of cycles with report of
Fatigue
Chills
Headache
Skeletal pain
Nausea, vomiting
Constipation
Diarrhea
Other digestive disorder
Injection site reaction
Other skin disorder
Chest discomfort
Edema
2
< 1
< 1
11
3
4a
1
1
8
3
1
< 1
< 1
11
2
4b
1
1
8
2
< 1
< 1
< 1
7
2
< 1
1
< 1
0
< 1
< 1
< 1
0
3b
< 1
1
6
2
1
2
1
1
1
1
3
1
2
3a
1
< 1
< 1
< 1
< 1
< 1
0
< 1
< 1
< 1
< 1
< 1
0
1
1
6b
3b
1
6b
2b
1
5b
1b
1
2b
1
2b
< 1
1
2b
< 1
< 1
1
Hematologic reaction
CNS disorder
Other adverse event
2
1
1
1
1
< 1
1
< 1
1
Filg = filgrastim; Sarg = sargramostim; CNS = central nervous system.
ap<0.05, ␹2 or Fisher’s exact test.
bp<0.01, ␹2 or Fisher’s exact test.
Table 6. Switching between CSFs
Variable
No. of patients (by initial CSF)
No. (%) of patients switching CSF for any reason
Filgrastim
239
Sargramostim
251
74 (29)
p Value
<0.001a
2 (1)
No. (%) of patients switching CSF due to
Adverse event
0 (0)
0 (0)
0 (0)
2 (1)
45 (18)
11 (4)
2 (1)
<0.001a
<0.001a
0.50b
Poor ANC response
Formulary restriction
Undetermined reason
Frequency of switching by cyclec
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
17 (7)
<0.001a
0/239 (0)
1/192 (1)
1/138 (1)
0/104 (0)
0/ 69 (0)
0/ 43 (0)
11/251 (4)
33/193 (17)
16/146 (11)
8/103 (8)
4/ 71 (6)
<0.001a
<0.001a
<0.001a
<0.01b
0.12b
Cycle 6
2/ 53 (4)
0.50b
ANC = absolute neutrophil count.
a
␹2 test.
bFisher’s exact test.
cPatients switched during cycle/patients beginning cycle (%).
8%, p=0.06). Several adverse events occurred
significantly more frequently with
remained higher with sargramostim. Results
were similar when the analysis was limited to
adverse events rated moderate or severe. The
lone injection site reaction attributed to
filgrastim was rated mild. With sargramostim, 4
of 41 injection site reactions were severe and 29
were moderate.
Switching from filgrastim to sargramostim was
uncommon, whereas more than one-fourth of
sargramostim recipients switched to filgrastim
(p<0.001; Table 6). Adverse events were the
most frequent reason for switching, with
sargramostim—fatigue (4% vs 2%, p<0.05),
diarrhea (3% vs 2%, p<0.05), injection site
reaction (6% vs < 1%, p<0.01), other
dermatologic disorders (3% vs < 1%, p<0.01),
and edema (2% vs < 1%, p<0.01). Limiting the
analysis to adverse events judged probably or
possibly related to CSFs lowered total event rates,
but the frequency of fatigue (p<0.01), injection
site reactions (p<0.01), other dermatologic
disorders (p<0.01), and edema (p<0.01)

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PHARMACOTHERAPY Volume 20, Number 12, 2000
injection site reactions (10), fever (8), skeletal
pain (6), and other dermatologic disorders (5)
being most common. Although the reason for
CSF switching was considered undetermined
unless medical record notations were specific,
adverse events were probably most often
responsible in these cases as well. In the
undetermined category, both switches of
filgrastim to sargramostim and 8 of 17 switches
of sargramostim to filgrastim followed cycles
with adverse events. The determination that
switching was due to poor absolute neutrophil
count (ANC) response was based on medical
record notations (e.g., “ANC still falling after X
days sargramostim”). In 9 of 11 cases the ANC
was below baseline after 5–14 days of
sargramostim. We investigated whether
suboptimal dosages were responsible for poor
ANC response but found mean daily doses were
similar for these (6.7 µg/kg) and other (6.9
µg/kg) sargramostim cycles. Switching was most
frequent during the second and third cycles.
Only 11 (4%) sargramostim recipients switched
during the first cycle, and the rate of switching
declined consistently between cycles 2 and 6.
detected no relationship between age and
frequency of adverse events.
Our decision to limit the study to prophylactic
CSF may have affected results, but the extent and
direction of such an effect are unclear. In other
studies, 18–28% of patients received CSFs
therapeutically,2, 3 and results were not stratified
by therapeutic versus prophylactic administration.
It is unclear how earlier studies examined fever
frequency for patients already febrile at the first
CSF dose.
Our study used passive adverse event
surveillance, similar to the other retrospective
study.3 By contrast, the prospective CSF safety
trial2 included rigorous monitoring. Patients
completed evaluation forms and home diaries,
and were telephoned every 1–2 days to review
adverse events. Although passive surveillance
probably provides more false negative results,
this is unlikely to have impaired our ability to
assess comparative safety. Active surveillance
seems to increase the number of mild adverse
events rather than moderate or severe events. In
our study, for example, only 26% of reports of
nausea and vomiting were rated mild, versus 67%
in the prospective trial. Corresponding data for
reports of skeletal pain and chills were 31% and
43% in our study versus 57% and 75% in the
prospective trial. Unfortunately, medical records
did not provide sufficient information to allow us
to categorize adverse events by ECOG or similar
criteria, as was done in the prospective trial.2
Although we cannot determine whether our
methods caused more or fewer adverse events to
be identified, we see no reason why either
method would cause more events to be detected
with one cytokine versus the other.
This study most likely detected differences not
found in prior research due to its greater
statistical power. We studied 490 patients
through 1602 chemotherapy-CSF cycles, whereas
other studies included 60 and 137 patients, all
followed through a single cycle.2, 3 Given the
frequency of grade 2 fever with filgrastim in the
prospective trial, the study had only 9% power to
detect a 2-fold increase with sargramostim.
Our most important results relate to switching
between CSFs, and frequencies of injection site
reactions and fever unexplained by infection.
Whereas switching from sargramostim to
filgrastim was common, this partially may reflect
study design; 9 of 10 centers substituted
sargramostim for filgrastim, thereby being
experienced with both agents when patients in
the sargramostim arm were treated. They may
Discussion
In the 6 years since the American Society of
Clinical Oncology called for more investigation
of the comparative toxicity of filgrastim and
sargramostim,1 few data have been published on
the subject. Adverse events were assessed in a
retrospective cohort study considering 680 days
of CSF administration3 and a randomized trial
that included 820 days of CSFs.2 Neither study
detected differences between CSFs, with the
exception of more grade 1 fever (98.7–100.4°F)
with sargramostim.2 We assessed adverse events
during 12,060 days of CSF treatment and found
important differences that generally favored
filgrastim over sargramostim.
The dissimilarity between our results and those
of other studies may be due to several factors,
including our exclusion of patients receiving
CSFs therapeutically, passive surveillance for
adverse event reporting, method of categorizing
adverse events, and greater statistical power. It is
unlikely to be due to differences in composition
of patient samples. Although our study was
limited to patients with lung, breast, lymphatic
system, or ovarian tumors, these diagnoses
represented 65–80% of patients in earlier
studies.2, 3 Our sample was somewhat older, but
this was unlikely to have had an effect, as we

SAFETY OF FILGRASTIM VERSUS SARGRAMOSTIM Milkovich et al
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Support Care Cancer 1997;5:289–98.
have been inexperienced with sargramostim
during the filgrastim era, making a switch to
sargramostim in the face of efficacy or safety
concerns unusual. Unlike earlier studies that
reported no differences in local reactions, we
identified just 1 (< 1%) injection site reaction
during 958 filgrastim cycles, but 41 (6%) during
644 sargramostim cycles. Most were rated
moderate or severe, and in 10 patients (24%) led
to a switch to filgrastim. Like the prospective
trial, fever unexplained by infection was more
common with sargramostim in this series of
patients. With a threshold of 100.4°F, we found a
difference of 7% versus 1%. In the prospective
trial, the difference in fever 100.5°F or greater
was 4% versus 2%.
Despite lack of documented pathogens, the
febrile episodes we detected were costly. Those
occurring with filgrastim resulted in 15 days of
inpatient care and 115 doses of antiinfective
drugs/1000 chemotherapy-CSF cycles. Episodes
occurring with sargramostim resulted in 93 days
of inpatient care and 634 doses of antiinfective
drugs/1000 cycles. Blood chemistries, micro-
biology tests, and radiologic examinations were
commonly performed.
3. Rotella DL. A medication use evaluation of adverse events
associated with colony-stimulating factors. Hosp Pharm
1999;34:286–91.
4. Root RK, Dale DC. Granulocyte colony-stimulating factor and
granulocyte-macrophage colony-stimulating factor: compar-
isons and potential for use in treatment of infections in
nonneutropenic patients. J Infect Dis 1999;179(suppl
2):S342–52.
5. Kellihan MJ. Drug formulary review process for sargramostim
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colony-stimulating factor of fever and neutropenia induced by
chemotherapy in patients with small-cell lung cancer. N Engl J
Med 1991;325:164–70.
7. Pettengell R, Gurney H, Radford JA, et al. Granulocyte
colony-stimulating factor to prevent dose-limiting neutropenia
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Blood 1992;80:1430–6.
8. Ross HJ, Moy LA, Kaplan R, Figlin RA. Bullous pyoderma
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Assessments of CSF prophylaxis should
consider the agents’ ability to extend survival,
improve quality of life, and reduce use of other
health care services. In certain populations, CSFs
have lowered antibiotic requirements6, 24, 25 and
hospitalization for febrile neutropenia.6, 24–26
These end points are reasonable markers for both
cost savings and quality of life. Based on the
experience of this series, filgrastim may offer
benefits of less fever, fatigue, diarrhea, local
reactions, other dermatologic disorders, and
edema. Whether such differences significantly
affect survival, quality of life, and costs in the
presence of considerable background toxicity
from chemotherapy has not been determined and
warrants further study.
12. Hudis C, Lebwohl D, Crown J, et al. Feasibility of adjuvant
dose-intensive cyclophosphamide with G-CSF after
doxorubicin in women with high-risk stage II/III resectable
breast cancer [abstr]. Proc Am Soc Clin Oncol 1992;11:55.
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Sweet syndrome during therapy with granulocyte colony-
stimulating factor. Ann Intern Med 1988;116:996–8.
14. Mueller BU, Jacobsen F, Butler KM, Husson RN, Lewis LL,
Pizzo PA. Combination treatment with azidothymidine and
granulocyte colony-stimulating factor in children with human
immunodeficiency virus infection. J Pediatr 1992;121:
797–802.
15. Peters WP, Shogan J, Shpall EJ, Jones RB, Kim CS.
Recombinant human granulocyte-macrophage colony-
stimulating factor produces fever [letter]. Lancet
1998;1(8591):950.
16. Neidhart JA, Mangalik A, Stidley CA, et al. Dosing regimen of
granulocyte-macrophage colony-stimulating factor to support
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Acknowledgments
18. Ganser A, Volkers B, Gerher J, et al. Recombinant human
granulocyte-macrophage colony-stimulating factor in patients
with myelodysplastic syndromes: a phase I/II trial. Blood
1989;73:31–7.
We are grateful to Lisa Lynch, R.N., and Nancy
Black, R.N., for their careful review of patient records.
19. Nemunaitis J, Singer J, Buckner C, et al. Use of recombinant
human granulocyte-macrophage colony-stimulating factor in
graft failure after bone marrow transplantation. Blood
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20. Jones SE, Schottstaedt MW, Duncan LA, et al. Randomized
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