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1150
Chemotherapy-Induced Neutropenia and Fever in
Patients with Metastatic Breast Carcinoma Receiving
Salvage Chemotherapy
Zia Rahman, M.D.
Laura Esparza-Guerra, R.N.
Hwee-Yong Yap, M.D.
Giuseppe Fraschini, M.D.
Gerald Bodey, M.D.
Gabriel Hortobagyi, M.D.
BACKGROUND. Chemotherapy-induced neutropenia and associated fever and infection are the most common complications of systemic chemotherapy. In this
retrospective analysis, the authors evaluated the incidence of neutropenic fever,
Department of Breast Medical Oncology, Division of Medicine, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas.
infection, and mortality in relation to the level of neutropenia, performance status,
course number of chemotherapy, bone marrow metastasis, and age among patients
with metastatic breast carcinoma receiving salvage chemotherapy.
METHODS. A total of 174 patients with previously treated metastatic breast carcinoma enrolled on 4 consecutive Phase II protocols were evaluated.
RESULTS. Twenty-three percent of the patients had an episode of neutropenic
fever (41 episodes among 40 patients). The incidence of neutropenic fever did not
increase until the absolute neutrophil count (ANC) had decreased to less than 500/
mL, and then fever incidence had a linear relationship with decreasing ANC (linear
trend, P õ 0.01). A source of infection was documented in 59% of the neutropenic
fever episodes. The incidence of infection did not increase significantly until the
ANC had decreased to less than 250/mL (P õ 0.01). The risk of neutropenic fever
and infection was also significantly higher when patients had poor performance
status or were undergoing the initial courses of chemotherapy. Patients with bone
marrow metastases also had a higher frequency of fever, infection, and death, but
these differences were not statistically significant.
CONCLUSIONS. For patients with metastatic breast carcinoma receiving salvage
chemotherapy, the risk of fever increases with decreasing ANC, but the risk of
infection does not increase significantly until ANC decreases to less than 250/
mL. Poor performance status, initial courses of chemotherapy, and bone marrow
metastases further increase the risk of fever, infection, and death. Cancer
1997;79:1150–7. q 1997 American Cancer Society.
KEYWORDS: neutropenic fever, breast carcinoma, drug therapy, complications.
I
Presented in part at the 1983 Annual Meeting
of the American Society of Clinical Oncology,
San Diego, California.
Address for reprints: Zia Rahman, M.D., The
University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 56, Houston, TX
77030.
Received July 29, 1996; revision received November 20, 1996; accepted November 20, 1996.
n North America, breast carcinoma is the most common malignancy
among women, accounting for 32% of their cancers.1 In 1995, there
were estimated to be approximately 183,400 new cases and 46,240
deaths from breast carcinoma in the United States.1 Almost all deaths
are from metastatic or recurrent disease, and the current standard
treatment for hormone receptor-negative and hormone-resistant
metastatic breast carcinoma consists of systemic cytotoxic chemotherapy.
Myelosuppression, especially neutropenia, is one of the most frequently encountered complications of chemotherapy. The relationship between infections and neutropenia was first described about
30 years ago in patients with acute leukemia receiving chemotherapy.2
Since then, considerable progress has been made in the management
q 1997 American Cancer Society
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W: Cancer
Neutropenic Fever in Breast Carcinoma Patients/Rahman et al.
of fever and infection in neutropenic patients.3 Empiric broad-spectrum antibiotic therapy has been the
cornerstone of the management of fever in patients
with chemotherapy-induced neutropenia.3 – 8
It is widely appreciated that patients with solid
tumors are not as severely immunocompromised as
are patients with hematologic malignancies. Unfortunately, there have been very few studies evaluating the
significance of chemotherapy-induced neutropenia
and the associated risk of fever and infection for patients with solid tumors.9,10 Almost all reported studies
of chemotherapy-induced neutropenia with fever have
been in patients with hematologic malignancies and
recipients of bone marrow transplants.4,11 – 14 The principles developed for managing disease in these patients have been applied to the management of chemotherapy-induced neutropenia and fever in patients
with solid tumors.
Most metastatic solid tumors are not curable with
chemotherapy. The main objectives of chemotherapy
in this setting are to palliate symptoms and prolong
survival. In this setting, physicians try to avoid excessive risk of complications in their patients. One of the
most common side effects of chemotherapy is myelosuppression, and increased risk of fever and infections
associated with it. It has become the general practice
to reduce doses of myelosuppressive drugs for the next
cycle for patients who develop chemotherapy-induced
neutropenia. Growth factors are increasingly being
used to prevent neutropenia and associated infectious
complications.15 – 17 Both of these measures are taken
in the absence of accurate information about the risk
of complications associated with chemotherapy-induced neutropenia for patients with solid tumors receiving palliative chemotherapy.
What predicts poor outcome and increased morbidity of chemotherapy-induced neutropenia? This is
an important consideration in the palliative setting,
where quality of life is of paramount importance. This
question becomes even more critical for patients receiving second-line chemotherapy because of the cumulative toxicity of prior chemotherapy. In this study,
we retrospectively analyzed the relationship between
the degree of neutropenia and fever with and without
infection in patients with metastatic breast carcinoma
receiving standard dose salvage chemotherapy. We
also evaluated the association of these complications
with absolute neutrophil count (ANC), bone marrow
involvement with metastatic disease, course number
of chemotherapy, performance status, and age.
MATERIALS AND METHODS
The medical records of all patients with metastatic
breast carcinoma enrolled in four consecutive Phase II
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1151
trials conducted by the Department of Breast Medical
Oncology of The University of Texas M. D. Anderson
Cancer Center were reviewed. These trials utilized single-agent etoposide, teniposide, mitoxantrone, or bisantrene. All patients had measurable or evaluable
metastatic breast carcinoma; and for all of them, prior
front-line therapies, including at least one doxorubicin-containing regimen, were ineffective.
Patients had complete blood cell counts (CBCs),
including differential counts, performed at least
weekly. For the purposes of this study, neutropenia
was defined as an ANC õ1000/mL. The ANC was calculated by multiplying the white blood cell count by the
percentage of neutrophils and bands. The ANCs were
grouped in the following ranges of cells/mL: fewer than
100, 100 – 249, 250 – 499, 500 – 999, 1000 – 1999, and
2000. Fever was defined as oral temperature greater
than 38.57 C.
All patients had a physical examination, CBC, serum electrolyte measurements, hepatic and renal
function tests, chest roentgenogram, and other appropriate radiologic tests to evaluate measurable disease
prior to the start of therapy. Patients who had any
persistent abnormality of the hematologic parameters
also had bone marrow aspiration and biopsy to evaluate involvement with the metastatic breast carcinoma.
Other patients were not required to have bone marrow
evaluation. The performance status was recorded according to Zubrod’s scale.18 All CBCs and differential
counts were obtained from the patients’ medical records. Patients who presented with fever underwent a
complete physical examination and laboratory tests,
including CBC with differential count, serum electrolyte measurements, hepatic and renal function tests,
and chest roentgenogram. At least two sets of blood
cultures (one from the vascular access device and the
other from a peripheral vein) and a urine culture were
obtained. If there was another evident source of infection, then additional appropriate cultures were obtained. Patients were admitted to the hospital and
treated with broad-spectrum intravenous antibiotics.
If all cultures were reported negative, patients continued intravenous antibiotics for a minimum of 1 week
or for 4 days after defervescence, whichever period
was shorter. Patients were considered to have a source
of infection if in an appropriate clinical setting they
had positive cultures, a new infiltrate on chest radiographs, or evidence of skin or oropharyngeal infection.
Patients with documented infections were continued
on an appropriate course of antibiotics.
The statistical analysis for correlation of ANC, fever, and infectious complications with prognostic parameters, i.e., age, performance status, the presence of
bone marrow involvement, and chemotherapy course
W: Cancer
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CANCER March 15, 1997 / Volume 79 / Number 6
TABLE 1
Patient Characteristics
No. of patients
Total no. of courses
Total evaluable courses
Median age, yrs (range)
Median performance status on Zubrod’s scale (range)
Median no. of mos of prior chemotherapy
174
610
455
54 (29–74)
1 (0–3)
27
number, was performed with Sigmastat statistical software (Jandel Corporation, San Rafael, CA) using the
chi-square test and the z-test.
RESULTS
A total of 174 patients with metastatic breast carcinoma received a total of 610 courses of chemotherapy
in these 4 consecutive Phase II trials (Table 1). The
median number of courses was 3 (range, 1 – 17), and
the median age was 54 years (range, 29 – 74 years). For
455 courses of chemotherapy, CBCs with differential
counts, obtained at least weekly, were available. Only
these 455 courses were evaluated for the relationship
between ANC, fever with or without documented infection, course number of chemotherapy, bone marrow involvement by the tumor, performance status,
and age.
Neutropenia and Fever
The ANC decreased to less than 1000/mL in 54% of the
courses, less than 500/mL in 28%, less than 250/mL in
13%, and less than 100/mL in 7% (Fig. 1). Both the
incidence of neutropenia and the mean ANC were
similar during all courses of chemotherapy. There
were 51 episodes of fever, but in only 41 episodes was
the ANC less than 1000/mL, hence fulfilling the criteria
for chemotherapy-induced, neutropenia-associated
fever. These 41 episodes occurred in 40 patients; 1
patient had 2 episodes of neutropenic fever. Hence,
23% of the patients had at least one episode of neutropenic fever during their courses of this salvage chemotherapy. This constituted 9% of the chemotherapy
courses. The incidence of neutropenic fever did not
increase until the ANC was less than 500/mL and then
had a linear relationship with decreasing ANC (linear
trend, P õ 0.01). This correlation is shown in Figure
1. The incidence of neutropenic fever was 55% among
patients with ANCs of less than 100/mL.
Documented Infections
A source of infection was documented in 24 of 41 episodes of chemotherapy-induced neutropenic fever
(59%). Thirty-two episodes of documented infection
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FIGURE 1.
The relationship between absolute neutrophil count (ANC)
and neutropenic fever after salvage chemotherapy is shown for patients
with metastatic breast carcinoma. When the ANC decreases to a level
below the threshold of 500/mL, the incidence of neutropenic fever increases
in a linear trend (P õ 0.01). *:Number of courses with fever/number of
courses with nadir ANC in the same range.
occurred in 30 patients, but the ANC was less than
1000/mL during only 24 episodes (Fig. 2). The incidence of documented infection increased significantly, from 4% to 28%, when the ANC decreased to
less than 250/mL (P õ 0.01) (Fig. 3). Thirty-two percent
of patients with ANC of less than 100/mL had a documented infection during that course of chemotherapy.
Urinary tract and blood were the most common
sites of documented infections, accounting for 15 episodes each. Two patients had urinary tract infections
and bacteremia at the same time, but these conditions
were caused by two different organisms. The organisms cultured and the sources of culture are shown in
Table 2. Gram-positive (n Å 7) and gram-negative (n
Å 7) organisms were equally responsible for the bacteremia. The most common organisms cultured from
the urine were Escherichia coli (n Å 8), Klebsiella pneumoniae (n Å 3), and Pseudomonas aeruginosa (n Å 2).
Two patients had radiologically documented pneumonia, and one of them also had blood cultures that were
positive for Propionibacterium acnes. This latter patient died of overwhelming infection. The organism
causing pneumonia in the second patient could not
be determined.
W: Cancer
Neutropenic Fever in Breast Carcinoma Patients/Rahman et al.
1153
TABLE 2
Organisms Cultured and the Sources of Culture during 32 Episodes of
Documented Infections in 30 Patients
FIGURE 2.
The relationship between absolute neutrophil count (ANC)
and infection after salvage chemotherapy is shown for patients with metastatic breast carcinoma. There is a significant increase in the incidence of
infection when the ANC decreases to less than 250/mL (P õ 0.01). *:
Number of courses with documented infection/number of courses with
nadir ANC in the same range.
Sites of infection/organisms
No. of casesa
Urinary tract
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Morganella morganii
a-hemolytic streptococcus
Blood (bacteremia)
Staphylococcus
epidermidis
a-hemolytic streptococcus
Klebsiella pneumoniae
Escherichia coli
Bacillus species
Propionibacterium acnes
Streptococcus pneumoniae
Candida albicans
Skin
Staphylococcus aureus
Klebsiella pneumoniae
Pseudomonas
Oropharynx
Candida albicans
15
8
3
2
1
1
15
3
3
2
2
2
1
1
1
3
1
1
1
1
1
a
Two patients had urinary tract infections and bacteremia at the same time from different organisms,
and two patients each had two episodes of documented infections.
Course Number of Chemotherapy
The frequency of fever and infection was highest during the initial three courses of chemotherapy. There
were 19 episodes of chemotherapy-induced, neutropenia-associated fever during the first course, 12 during the second, and 5 during the third (Fig. 3)(Table
3). With each course of chemotherapy, the percentage
of patients who developed neutropenia decreased
slightly and median ANC increased slightly, while the
incidence of fever and infection decreased dramatically more (Fig. 3). The total number of patients decreased with each successive course; the patients with
progressive disease or unacceptable toxicity were removed from the study (Fig. 3).
FIGURE 3. The relationship between the course number of chemotherapy and the incidence of neutropenia, fever, and infection is shown for
patients with metastatic breast carcinoma receiving salvage chemotherapy.
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Deaths
Four patients (2%) died of documented infections. All
four had an ANC of less than 100/mL and positive
blood cultures on admission. Two patients had multiple-organism septicemia documented by blood and
catheter tip cultures, one patient had septicemia and
radiologically documented pneumonia, and the fourth
patient had septicemia and a urinary tract infection
caused by two different organisms (Table 4). All patients had advanced disease with extensive visceral
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CANCER March 15, 1997 / Volume 79 / Number 6
TABLE 3
Details of Myelosuppression and Associated Fever and Infection by Course Number of Chemotherapy
Course no.
No. of patients
Median ANC/mL
No. (%) of patients with neutropenia
No. (%) of neutropenic patients with:
fever
Documented infection
1
2
3
4
143
792
85 (60)
107
783
62 (58)
62
909
36 (58)
46
972
24 (53)
19 (22)
13 (15)
12 (19)
7 (11)
5 (14)
3 (8)
1 (4)
1 (4)
ANC: absolute neutrophil count.
TABLE 4
Course Number of Chemotherapy, Bone Marrow Metastasis, Site of Infection, and Organisms Cultured for the Four Patients with Metastatic
Breast Carcinoma Who Died during Chemotherapy
Patient
no.
Course
no.
Bone marrow
metastasis
1
2
1
1
No
No
3
4
2
4
Yes
Yes
Type of infection
Organisms cultured
Septicemia
Septicemia
Pneumonia
Septicemia
Septicemia
Urinary tract infection
Staphylococcus aureus, Bacillus species
Propionibacterium acnes
Escherichia coli, Staphylococcus epidermidis
Candida albicans
Escherichia coli
metastases and had previously been treated with three
to six chemotherapy regimens for metastatic disease.
Two patients had bone marrow involvement with metastatic disease. Two patients died during the first chemotherapy course, one died during the second course,
and one died during the fourth course.
TABLE 5
Association among Performance Status, Neutropenic Fever, and
Documented Infection
Performance Status
There was a statistically significant association between poor performance status and both episodes of
chemotherapy-induced neutropenic fever and documented infections (P õ 0.008 and P õ 0.014, respectively) (Table 5). The rates of chemotherapy-induced,
neutropenia-associated fever and documented infection were approximately 14% and 6%, respectively,
among the 80 patients with good performance status
(0 or 1 on Zubrod’s scale) and approximately 32% and
20%, respectively, among the 94 patients with poor
performance status (2 or 3 on Zubrod’s scale).
No. of patients
No. of cycles
Neutropenic fever
With infection
Without infection
Bone Marrow Involvement
Thirty patients had documented bone marrow
involvement with metastatic breast carcinoma, and
the other 144 patients did not have bone marrow evaluation. The patients with known bone marrow metas-
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Performance statusa
0 or 1
2 or 3
80
247
11 (13.8%)b
5 (6.2%)c
6 (7.5%)
94
208
30 (31.9)b
19 (20.2%)c
11 (11.7%)
a
Performance status was measured on Zubrod’s scale.
P õ 0.008.
c
P õ 0.014.
b
tases received 77 courses of chemotherapy and had
11 episodes of neutropenic fever and 7 episodes of
documented infection. Two of the patients with
known bone marrow metastases and documented infections died. There was an increased frequency of
neutropenic fever, infection, and septic death in patients with known bone marrow metastases, compared
with patients whose bone marrow status was unknown
W: Cancer
Neutropenic Fever in Breast Carcinoma Patients/Rahman et al.
1155
TABLE 6
Association between Age and Neutropenic Fever with and without Infection
Neutropenic fever
Age group
No. of
patients
Without infection
With infection
Total no. (%)
õ50 yrs
50–65 yrs
ú65 yrs
71
80
23
6
10
2
11
12
1
17 (24%)
22 (27.5%)
3 (13%)
(fever, 37% vs. 21%; infection, 24% vs. 12%; septic
death, 7% vs. 1%). These differences were not statistically significant. The patients with bone marrow metastases also had a higher probability of developing
neutropenia and lower median ANCs than patients
with unknown bone marrow status; these differences
also were not statistically significant.
Age
There was no association between age and chemotherapy-induced, neutropenia-associated fever and infection. The incidence of chemotherapy-induced, neutropenia-associated fever was 24% in the 71 patients
younger than 50 years, approximately 27% in the 80
patients age 50 – 65 years, and 13% in the 23 patients
older than 65 years. The number of documented infections is shown in Table 6. These numbers were too
small for definitive conclusions to be drawn.
DISCUSSION
This is the first report to evaluate chemotherapy-induced neutropenia and its associated fever and infection in patients with metastatic breast carcinoma receiving chemotherapy. Patients with metastatic breast
carcinoma routinely receive multiple regimens of palliative chemotherapy, and there is cumulative myelosuppression with each subsequent chemotherapy regimen. A substantial proportion of patients become
neutropenic and are exposed to increased risk of fever,
infection, and death.
Among the patients with metastatic breast carcinoma in this study, there was an inverse relationship
between ANC and fever with and without infection,
as previously shown by Bodey et al., in patients with
leukemia.2 The incidence of fever seems to have a
threshold and did not increase until the ANC decreased to less than 500/mL (Fig. 1). The incidence of
infection did not significantly increase until the ANC
decreased to less than 250/mL (Fig. 2). This is different
from the observation in patients with leukemia, in
whom the risk of infection increases significantly when
the ANC decreases to less than 1000/mL.2 Bodey et al.,
in their original article, also reported that for any given
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ANC level, the frequency of infection was higher in
patients with active acute leukemia than in patients
in remission. A much smaller number of neutrophils
in breast carcinoma patients than in patients with leukemia seems to protect patients against spontaneous
infections. The total number of neutrophils is important in preventing spontaneous infections, but it is
apparent that some other factor or factors, yet undetermined, also play an important role in preventing
these infections. Whether it is abnormal intrinsic neutrophil function in patients with leukemia or altered
cytokine production needs to be determined. Pizzo
et al. reported a large prospective series of pediatric
patients with cancer who presented with fever.19 There
was no difference in the patients with hematologic
malignancies or solid tumors with respect to the types
of infection or the percentage of patients who were
neutropenic on presentation.19 The authors did not
evaluate whether the relationships between ANC and
infections in these two groups of patients were similar
or not.
In this study, a source of infection was documented in 59% of the chemotherapy-induced, neutropenia-associated fever episodes. The most common
types of infection identified were septicemia and urinary tract infection. Nobbenhuis and Cleton reported
on 90 patients with solid tumors who received chemotherapy on European Organization for Research and
Treatment of Cancer protocols.10 A source of infection
was documented in a similar proportion of chemotherapy-induced, neutropenia-associated fever episodes (33 of 51). The common sites of documented
infection were also the blood and the urinary tract.
Pizzo et al also reported a similar percentage (52%) of
documentation of the source of infection in patients
with neutropenic fever.19 Curtin et al. reported 56 episodes of chemotherapy-induced, neutropenia-associated fever in 43 patients with ovarian carcinoma who
received platinum-based chemotherapy.9 In 12 of the
56 episodes (21%), septicemia was documented by
positive blood cultures. The exact incidence of infection at other sites was not reported.
It has been an anecdotal clinical experience that
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CANCER March 15, 1997 / Volume 79 / Number 6
the risk of neutropenic fever and infection is highest
during the initial courses of chemotherapy. This
study is the first documentation of this clinical observation. The most noteworthy finding was that this
risk did not correlate with the percentage of the patients developing neutropenia or with the median
ANC (Fig. 3). The patients who developed neutropenic fever or infection had dose reduction in the
next cycle, but that did not change the myelosuppression profile of the entire population at risk, and
very similar percentages of patients in each cycle
developed neutropenia (Fig. 3). This could be due
to cumulative myelotoxicity in the entire group compensating for any reduced myelosuppression
achieved by the dose reduction in some patients.
Why more patients develop neutropenic fever during the first course of chemotherapy is not known.
One possible explanation is that some patients are
intrinsically at higher risk for developing neutropenic fever and infection. When they declare themselves during the initial courses of chemotherapy, in
the subsequent courses either the drug doses are
reduced or colony-stimulating factors are administered to reduce the risk of neutropenic fever and
infection. Another possibility is that some patients
already have a subclinical infection that becomes
evident as a fever or a documented infection with the
onset of neutropenia. When these patients receive
antibiotics, the subclinical infection is eradicated in
some of them. The patients who had progressive disease or excessive toxicity were removed from this
study, and only patients with responding disease
who tolerated chemotherapy well remained. This selection bias is shown by the decrease in the number
of patients with each successive course and might
also explain increased incidence of fever and infection during initial courses of chemotherapy (Table
3). The mortality rate was also higher during the
initial courses of chemotherapy.
Bone marrow involvement by metastatic breast
carcinoma has been reported to be associated with
an increased risk of infectious complications.20 In
a prior report from the University of Texas M. D.
Anderson Cancer Center, patients with bone marrow
involvement by metastatic breast carcinoma had a
higher incidence of neutropenia and infectious complications than did patients without bone marrow
involvement.20 In this report, we also found a higher
incidence of neutropenia and its associated fever,
infection, and death in patients with bone marrow
metastases, although these differences were not statistically significant, probably because of the sample
size. Dose reduction in women with bone marrow
involvement by metastatic breast carcinoma has
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also been shown to result in lower response rates
and survival.20 Patients with bone marrow involvement should be treated with full doses in those centers where aggressive supportive measures are easily
available, or doses should be reduced in the initial
courses (when the rate of fever and infection is highest) and then rapidly escalated to full doses.
In a study of more than 5000 patients entered
into the Veterans Administration Lung Group protocols, performance status at the start of therapy was
shown to be the most important prognostic factor
for survival.21 Poor performance status has been associated with increased risk of complications and
poor survival in a number of other tumor types.22–24
In this study, poor performance status was also associated with increased risk of neutropenic fever and infection (Table 5).
The older patients had the same risk of chemotherapy-induced neutropenia, fever, and infection as
the younger patients (Table 6). Ibrahim et al. reported
on the relationship between age and efficacy and toxicity of doxorubicin-based chemotherapy in patients
with metastatic breast carcinoma and found that the
incidence of neutropenia, infection, response rate,
time to progression, and survival were similar for patients older than 65 years and patients age 50 – 65
years.25
With the increasing awareness that patients
with solid tumors are not as immunocompromised
as patients with hematologic malignancies, and
with changing medical economics, a large number
of centers are managing ‘‘low risk’’ solid tumor patients with neutropenic fever in outpatient settings
or discharging them early to continue antibiotics at
home. 6,26 – 30 In these patients, ANC of less than 250/
m L, poor performance status, initial courses of chemotherapy, and bone marrow involvement by the
malignancy also signifies increased risk of infection
and death and should be taken into account when
decisions are made about outpatient management.
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