Transcript Document
New
irections in
Managing Febrile Neutropenia
林建廷
Overview
Clinical Definitions
Causes
Risk
Management
2
Neutropenic Complications
C/T
R/T
Neutropenia
Dz Process
FEBRILE NEUTROPENIA
Complicated Infections
Prolonged Hospitalization
DEATH
Adapted from Lyman GH. Oncology. 2003:17(suppl):8-13.
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Clinical Impact of Neutropenia
May result in:
Hospitalization
QoL decrease
C/T dose reductions or treatment delay
Inpatient mortality rate= 6.8%
100
80
Empirical Abx Tx
60
40
20
0
1950
1960
1970
1980
Caggiano V, et al. Cancer. 2005;103:1916-1924.
1990
2000
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Impact of Neutropenia
Complaint
Frequency
per Patient
Fatigue
91%
Decreased social contacts and activity
59%
Inability to engage in normal physical activities
56%
Difficulties with household activities
56%
Fortner BV, et al. BMC Nursing. 2005;4:4.
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Definitions of Febrile Neutropenia (FN)
Neutropenia
Fever
ANC <500/μL
or
Oral BT >38.3°C
(single reading)
or
>38.0°C (>1 h)
ANC <1000/μL and
a predicted decline to
≤500/μL
over the next 48 h
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Neutropenia and Infection Risk
53
50
40
37
30
22
20
10
11
10
0
39
40
<100 100500
ANC(/μL)
500- 1000- >1500
1000 1500
Patients With FN (%)
Patient-Days
With Infection (%)
60
35
30
25
19
20
15
11
10
5
0
0
0
3
1
2
3
>4
Duration of Severe
Neutropenia (days)
Adapted from Bodey GP, et al. Ann Intern Med. 1966;64:328-340; Meza L, et al.
ASCO 2002. Abstract 2840.
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Overview
Clinical Definitions
Causes
Risk
Management
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Risk Factors for Febrile Neutropenia
Patient-related
Old age
Female
Poor PS
Poor nutritional status
Comorbidities
COPD
Cardiovascular disease
Liver disease
Kidney disease
DM
Conditions associated with
risk of serious infection
Open wounds
Active tissue infection
NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005.
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Risk Factors for Febrile Neutropenia (cont’d)
Treatment-related
Type of C/T
Hx of severe neutropenia
with similar C/T
Planned RDI >80%
Preexisting neutropenia or
lymphocytopenia
Extensive prior C/T
R/T to marrow-containing
bone
Cancer-related
Hema malignancy
BM involved
Advanced or
uncontrolled cancer
Elevated LDH
NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005.
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Incidence of Neutropenia and FN
Regimen
FN
Neutropenia Risk
Other
SCLC
Etoposide, cisplatin
Topotecan, paclitaxel
18%
21%
G3/4 neutropenia: 85%1
G4 neutropenia: 96%2
4%
16%
G3/4 neutropenia: 63%3
G3/4 neutropenia: 75%3
14%
G3/4 neutropenia: 47%-48%4
Hospitalization:
<age 65: 7.9%
≥age 65: 13.8%5
G3/4 leukopenia:
34%-72%6,7
NSCLC
Carboplatin, paclitaxel
Cisplatin, paclitaxel
Colorectal
Irinotecan
NHL
CHOP
FN = febrile neutropenia; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone. 1. Pujol JL, et al. J Natl
Cancer Inst. 2001;93:300-308; 2. Jacobs SA. ASCO 1999. Abstract 1814; 3. Schiller JH, et al. N Engl J Med.
2002;346:92-98; 4. Rougier P, et al. J Clin Oncol. 1997;15:251-260; 5. Morrison VA, et al. Clin Lymphoma. 2001;2:4756. 6. Pfreundschuh M, et al. Blood. 2004;104:626-633. 7. Pfreundschuh M, et al. Blood. 2004;104:634-641.
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Overview
Clinical Definitions
Causes
Risk
Management
Initial Evaluation
ttt
Initial Therapy
Day 1
{
Empiric Abx
Documented infection
Subsequent Therapy
Days 3-7
Fever unknown origin (FUO)
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Recognition of potential pathogens
Central Catheter:
G(+)/ G(-)/ fungus
Abd/perianal:
enterococci/ G(-)/ anaerobes
Diarrhea: C. difficile
Gingiva, teeth, mucosa,
sinus—
G(+)/ anaerobes/ HSV/
Candida
Pulmonary:
bacteria, PCP, virus,
fungi
Even with a comprehensive evaluation, an infectious
etiology is demonstrated in 50 to 70% of cases
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Initial Evaluations
Hx & PE
Some sites easily be neglected…
S/S directed lab/ image exam
CBC, CRP, Cre, BUN, AST, ALT…
B/C (2 sets, a vein and/or a catheter)
CXR
U/A, U/C, and Gram staining and/or culture of
specimens from the potential infectious foci
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Febrile Neutropenia-- Etiology
NTUH, 1996-2001
G(+)
Fungus
(%)
80
G(-)
Anaerobes
57
60
40
32
20
7
3
0
1996
1997
1998
1999
2000
Chen CY et al. J Formos Med Assoc 2004;103:526-32.
2001
19962001
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Febrile Neutropenia– Etiology
738 isolates, 1996-2001, NTUH
GNB: 57%
GPC: 32%
S. aureus
Viridans streptococci
S. maltophilia
A. baumannii
P. aeruginosa
Candida spp.
Enterobacter spp.
K. pneumoniae
E. coli
CoNS
MRSA, 67%
C, tropicalis. C. albicans
0
5
10
Chen CY et al. J Formos Med Assoc 2004;103:526-32.
%
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Algorithm for Initial Management of FN
IDSA
FN
Low risk
Oral
High risk
IV
Ciprofloxacin
+
Amoxicillin-clavulanate
(adults only)
Vancomycin
Not needed
Vancomycin
needed
Monotherapy
Two Drugs
Vancomycin +
Cefepime,
Ceftazidime,
or
Carbapenem
Aminoglycoside
+
Antipseudomonal
penicillin, Cef
Cefepime,
Ceftazidime, or
carbapenem
Vancomycin
+
Cefepime,
ceftazidime or
Carbapenem
aminoglycoside
Reassess after 3-5 days
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Hughes WT et al. Clin Infect Dis 2002;34:730-51.
Factors that favor a Low Risk for severe infections during
Neutropenia
ANC > 100 cells/mm3
AMC >100 cells/mm3
Normal CXR
Nearly normal RFT and LFT
Duration of neutropenia < 10 days
No CVC infection
Malignancy in remission
BT <39 °C
No neurological or mental status changes
No abd pain
No appearance of illness
No co-morbidity
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Immediate Vancomycin?
Suspected catheter infections
Known colonization with organisms
GPC blood cultures
Hypotension
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New
irections in
Managing Febrile Neutropenia
But, does IDSA guideline
work in Taiwan?
(%)
Resistant Gram (-) Blood Pathogens
1996-2001, NTUH
70
E. coli (n=93)
E. cloacae (n=48)
A. baumannii (n=36)
60
K. pneumoniae (n=87)
P. aeruginosa (n=46)
50
40
30
20
10
0
Ceftazidime
Pip-Taz
Cefepime
Imipenem
Chen CY et al. J Formos Med Assoc 2004;103:526-32.
Amikacin
Ciprofloxacin
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Resistant Gram (-) Blood Pathogens
2002-2003, Six Taiwan Hospitals
(%)
K. pneumoniae (n = 49)
P. aeruginosa (n = 33)
E. coli (n = 40)
E. cloacae (n = 35)
80
70
60
50
40
30
20
10
0
Ceftazidime
Ticarcillinclavulanate
Pip-Taz
Cefepime
Imipenem
Amikacin
Ciprofloxacin
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Taiwan Resistance Patterns- Summary
High rates (>30%) of resistance
Ciprofloxacin: E. coli
Ceftazidime: E. cloacae
Timentin: Enterobacteriaceae
Gentamicin: E. coli, E. cloacae
Low rates of ESBL (+)- E. coli or KP
Other analogues (in vitro activities)
Vancomycin = teicoplanin
Cefepime = cefpirome (except for P. aeruginosa)
Isepamicin = amikacin >gentamicin
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Algorithm for Initial Management of FN
FN
Low risk
Oral
A fluoroquinolone a
+
Amoxicillinclavulanate or
Ampicillin-sulbactam
(adults)
High risk
Glycopeptided
Not needed
IV
A
cephalosporinb
An
aminoglycoside
Monotherapy
(A)
Cefepime,
Cefpirome,
Piperacillintazobactam,
A
carbapeneme
Two Drugs (B)
An aminoglycosidec
+
Ceftazidime,
Piperacillin-tazobactam,
Cefepime, Cefpirome
or
A carbapenemc
Glycopeptide
needed
A
d
glycopeptide
+
A or B
Reassess after 3-5 days
a Includes ciprofloxacin, levofloxacin, or moxifloxacin
b Includes a first-, second-, or third-generation cephalosprin
c Includes amikacin or isepamicin
d Includes vancomycin or teicoplanin
e Includes imipenem or meropenem
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Reassessment – Afebrile patient
ffffffffffffffffffffffffff
Afebrile within the first 3-5 days of treatment
ffffffffffffffffffffffffffffff
No etiology
Low Risk
High risk
Consider
PO antibiotics
Continue same
IV antibiotics
Etiology identified
Adjust
therapy
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Reassessment – Febrile Patient
ffffffffffffffffffffffffff
Febrile for the first 3-5 days of treatment
Or new onset fever
Continue same
Antibiotics
If no change
in patient
condition
D/C vanco
Change Antibiotics
If progressive
disease
If criteria for
Vancomycin
Cover
ESBL Type 1
lactamase
Add antifungal
drug
• Review all cultures
• Meticulous Physical exam
• CXR/ Image for suspected
infection (CT/US/TTE)
• Status of CVC/port-A
• Aspergillus galactomannan Ag
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Amphotericin B: Safety
Adequate hydration 1 L/m2 of body surface containing 1
L of 0.9 saline, and sodium load (to maintain serum Na
135-145 mEq/L)
Infusion-related S/E and nephrotoxicity of AmB may be
reduced significantly by the prolongation of AmB application
to 24 h, without compromising the response rates
If sCr >2 mg/dL for 2 consecutive days, AmB was replaced
with alternative agent
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Central Line Infections
Keep Line
Most Staph. Epi
Some Staph. Aureus
Afebrile in 48-72hrs.
Line Removal Required
Tunnel or peri-port infection
Septic emboli
Febrile after 48-72hrs.
Candida
Pseudomonas etc.
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G-CSF Prophylaxis for First and All
Subsequent Cycles: NCCN Guidelines
If pt’s
risk for
FN:
If the patient is receiving:
Curative intent or
adjuvant therapy
Tx to prolong survival Palliative therapy
or improve QOL
>20%
(high)
Use G-CSF
Use G-CSF
Consider G-CSF (discuss
high-risk C/T with pt)
10%-20%
(intermediate)
Consider G-CSF
Consider G-CSF
(discuss high-risk
C/T with pt)
Consider G-CSF (discuss
high-risk C/T with pt)
<10%
(low)
G-CSF is not
recommended for
most pts†
G-CSF is not
recommended
G-CSF is not
recommended
NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005.
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G-CSF Prophylaxis
Filgrastim
5 µg/kg/day until post-nadir ANC recovery
Start 1-3 days after completion of C/T
Pegfilgrastim
One dose of 6 mg per cycle of treatment
There is evidence to support use for chemotherapy
regimens given every 3 weeks
Phase 2 studies demonstrate efficacy in
chemotherapy regimens given every 2 weeks
NCCN. Myeloid Growth Factors in Cancer Treatment. V2.2005.
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Impact of Antibiotic or G-CSF Prophylaxis
on Febrile Episodes
80
Placebo
P = .001
70
60
50
40
30
P = .01
20
10
Febrile Episodes* (%)
Febrile Episodes (%)
90
Levofloxacin
90
Pegfilgrastim
80
Placebo
70
60
P <.001
50
40
30
20
10
0
0
Cullen, et al. 2005 Bucaneve, et al. 2005
Vogel, et al. 2005
*Cycle 1.
Cullen M, et al. N Engl J Med. 2005;353:988-998; Bucaneve G, et al. N Engl J Med.
2005;353:977-987; Vogel CL, et al. J Clin Oncol. 2005;23:1178-1184.
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