Transcript Document

New
irections in
Managing Febrile Neutropenia
林建廷
Overview
Clinical Definitions
Causes
Risk
Management
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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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