Antimicrobial Prophylaxis and Outpatient Management of
Fever and Neutropenia in Adults Treated for Malignancy:
American Society of Clinical Oncology Clinical
Practice Guideline
Christopher R. Flowers, Jerome Seidenfeld, Eric J. Bow, Clare Karten, Charise Gleason, Douglas K. Hawley,
Nicole M. Kuderer, Amelia A. Langston, Kieren A. Marr, Kenneth V.I. Rolston, and Scott D. Ramsey
See accompanying article in J Oncol Pract: 10.1200/JOP.2012.000815
Christopher R. Flowers, Charise Glea-
son, and Amelia A. Langston, Emory A B S T R A C T
University School of Medicine, Atlanta,
GA; Jerome Seidenfeld, American Soci- Purpose
ety of Clinical Oncology, Alexandria, VA; To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and
Eric J. Bow, CancerCare Manitoba and on selection and treatment as outpatients of those with fever and neutropenia.
University of Manitoba, Winnipeg,
Manitoba, Canada; Clare Karten, Leuke- Methods
mia and Lymphoma Society, White A literature search identified relevant studies published in English. Primary outcomes included:
Plains, NY; Douglas K. Hawley, Onc development of fever and/or infections in afebrile neutropenic outpatients and recovery without
Heme Care, Cincinnati, OH; Nicole M. complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in
Kuderer, Duke University Comprehen- afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia,
sive Cancer Center, Durham, NC;
defervescence without regimen change, time to defervescence, infectious complications, and
Kieren A. Marr, Johns Hopkins School
of Medicine, Baltimore, MD; Kenneth
recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicro-
V.I. Rolston, University of Texas MD bials. An Expert Panel developed guidelines based on extracted data and informal consensus.
Anderson Cancer Center, Houston, TX;
and Scott D. Ramsey, Fred Hutchinson
Results
Cancer Research Center, Seattle, WA.
Forty-seven articles from 43 studies met selection criteria.
American Society of Clinical Oncology Recommendations
Clinical Practice Guideline Committee Antibacterial and antifungal prophylaxis are only recommended for patients expected to have ⬍ 100
approved: September 5, 2012. neutrophils/L for ⬎ 7 days, unless other factors increase risks for complications or mortality to similar
Editor’s note: This is the complete levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully
American Society of Clinical Oncology selected patients may be managed as outpatients after systematic assessment beginning with a
Clinical Practice Guideline and provides validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or
the recommendations with comprehen-
Talcott’s rules). Patients with MASCC scores ⱖ 21 or in Talcott group 4, and without other risk factors,
sive discussions of the relevant litera-
ture for each. The Executive Summary
can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of
of the guideline, Data Supplements empiric antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours
with evidence tables as well as other to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquin-
tables and figures, and a list of all olone plus amoxicillin/clavulanate (or plus clindamycin, if penicillin allergic) is recommended as empiric
abbreviations used in the text, tables, therapy, unless fluoroquinolone prophylaxis was used before fever developed.
and figures are available at www.asco
.org/guidelines/outpatientfn.
© 2012 by American Society of Clinical Oncology
Authors’ disclosures of potential conflicts
of interest and author contributions are
found at the end of this article. Although the CSF guideline is scheduled for an-
INTRODUCTION
Corresponding author: Jerome Seiden- other update soon, ASCO has not previously
feld, PhD, American Society of Clinical The first guideline1 published by the American addressed other measures (eg, prophylactic anti-
Oncology, 2318 Mill Rd, Suite 800,
Society of Clinical Oncology (ASCO) provided rec- microbial drugs or protective environments) to
Alexandria, VA 22314; e-mail:
. ommendations on uses of hematopoietic colony- prevent infection in outpatients who are neutro-
© 2012 by American Society of Clinical stimulating factors (CSFs), including primary penic, not yet febrile, and either continue to re-
Oncology prophylaxis of fever and neutropenia (FN) in pa- ceive or have recently completed chemotherapy
tients undergoing chemotherapy for malignancy if for malignancy. Additionally, a priority-setting
their risk was ⱖ 40%. ASCO has updated this guide- exercise of the ASCO Clinical Practice Guidelines
line periodically, most recently in 2006,2 when the Committee (CPGC) selected outpatient manage-
threshold for primary prophylaxis with a CSF was ment of febrile neutropenia as an important topic
revised to include patients at ⱖ 20% risk for FN. for a new guideline.
© 2012 by American Society of Clinical Oncology 1
, Flowers et al
Managing FN in oncology patients began to change in the late oncology patient developed FN. Presently, a wider spectrum of disorders
1960s and early 1970s, when evidence emerged that empiric antibac- than ever before is being managed on an outpatient basis. Potential ad-
terial therapy reduced deaths resulting from infection, compared with vantages of outpatient management include increased convenience for
waiting for results of microbiologic assays.3-7 The spectrum of bacte- patients and their family members, reduced costs of care, and, particularly
rial pathogens most commonly isolated from patients with FN during for those at risk of infection, decreased exposure to hospital-acquired
or after treatment for malignancy shifted from mostly Gram-negative infections, which often may be resistant to the antibiotics used most
species in the 1960s and 1970s to more Gram-positive species in the frequently. Malignancies currently being treated outside the hospital
1980s and 1990s. Currently, coagulase-negative staphylococci are the range from adjuvant systemic therapy for breast cancer to postremission
most common species identified in blood cultures, but the frequency consolidation with high-dose cytarabine for acute myeloid leukemia to
of antibiotic-resistant Gram-negative bacterial infections is increasing.
reduced-intensity conditioning stem-cell transplantation (SCT). Various
However, blood cultures and other cultures are negative and the
approaches have been studied to stratify such patients who develop FN by
causative organism and site of infection uncertain in many oncology
risk for medical complications or death.14-21 Several of these approaches
patients with fever. Because infection can progress rapidly and become
have been used to select low-risk patients for early discharge or outpatient
life threatening if patients are neutropenic, clinical practice guidelines
recommend administration of broad-spectrum antibacterials (using therapy, and a number of trials randomly assigning low-risk patients have
monotherapy or a combination regimen) soon (within an hour) after comparedoutcomesofinpatientversusoutpatientmanagement14,21-25 or
fever is documented in a neutropenic patient.7-13 oral versus IV antibacterials as empiric therapy.14,26,27 In light of the evi-
Until the late 1980s and early 1990s, empiric antibacterial therapy dence from such studies, the ASCO CPGC assembled a panel of experts to
wasalmostinvariablyadministeredintravenously(IV)inthehospitalifan address the following clinical questions.
THE BOTTOM LINE
ASCO GUIDELINE
Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated
for Malignancy
Interventions
● Antibacterial and/or antifungal prophylaxis for afebrile outpatients with neutropenia from treatment for malignancy
● Identification of oncology outpatients with fever and neutropenia (FN) at low risk for medical complications
● Initial empiric therapy in the outpatient setting to treat FN in patients at low risk for medical complications
Target Audience
● Medical oncologists, primary care physicians, and oncology nurses
Key Recommendations
● Only use antibacterial and antifungal prophylaxis if neutrophils are expected to remain ⬍ 100/L for ⬎ 7 days, unless other fac-
tors (see text and Table 2) increase risks for complications or mortality
● An oral fluoroquinolone is preferred for antibacterial prophylaxis and an oral triazole for antifungal prophylaxis
● Interventions such as footwear exchange, protected environments, respiratory or surgical masks, neutropenic diet, or nutritional
supplements are not recommended because evidence is lacking of clinical benefits to patients from their use
● Assess risk for medical complications in patients with FN using the Multinational Association for Supportive Care in Cancer (MASCC) score
(see Table 3) or Talcott’s rules; score ⱖ 21 or Talcott’s group 4 with no other risk factors (see text and Table 4) defines low risk
● An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin for those with penicillin allergy) is recommended for
initial empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed (see text for alternatives)
Methods
● An Expert Panel was convened to develop clinical practice guideline recommendations based on a review of evidence from a sys-
tematic review of the medical literature
Additional Information
● An Executive Summary of this guideline has been published in Journal of Clinical Oncology
Data Supplements, including evidence tables, and clinical tools and resources can be found at www.asco.org/guidelines/outpatientfn.
2 © 2012 by American Society of Clinical Oncology
, Antimicrobial Prophylaxis and Management of Fever and Neutropenia in Outpatients
9. Criteria for use in credentialing decisions
GUIDELINE QUESTIONS
10. Identification of areas where future research is needed
A. What interventions are appropriate to prevent infections in pa-
tients with a malignancy who have received chemotherapy in an METHODS
inpatient or outpatient setting and who are, or are anticipated to
become, neutropenic as outpatients? Panel Composition
A-1. How should risk of developing a febrile neutropenic epi- The ASCO CPGC convened an Expert Panel (hereafter referred to as the
sode (FNE) be assessed in such patients who are not yet Panel) consisting of experts in clinical medicine and research methods relevant
febrile? What clinical characteristics identify patients who to prevention and treatment of infection in patients with neutropenia after
should be offered antimicrobial prophylaxis? therapy for a malignancy and reflecting the perspectives of academic and
private practice clinicians. The experts’ fields included medical oncology,
A-2. What antimicrobial drug classes should be used to prevent hematology, infectious diseases, oncology nursing, health services research,
infection in afebrile neutropenic outpatients who should epidemiology, public health, and biostatistics. The Panel also included a pa-
be offered prophylaxis? tient representative. Panel members are listed in Appendix Table A1 (on-
A-3. What additional precautions are appropriate to prevent line only).
exposure of neutropenic but afebrile outpatients with a Literature Review and Analysis
malignancy to infectious agents or organisms? Literature search strategy. The MEDLINE database was searched using
B. Which patients with a malignancy and febrile neutropenia are PubMed for relevant evidence published from 1987 through the end of April
2011. The search included terms for malignant diseases linked to terms for
appropriate candidates for outpatient management?
neutropenia, fever, or infection and to terms for clinical trials, systematic
B-4. What clinical characteristics should be used to select pa- reviews, meta-analyses, or clinical guidelines. Data Supplement 1 provides the
tients for outpatient empiric therapy? full search strategy (online at www.asco.org/guidelines/outpatientfn). One
B-5. Should outpatients with FN at low risk for medical com- reviewer selected articles for full-copy retrieval and consulted a Panel cochair
plications receive their initial dose(s) of empiric antimi- when potential relevance was uncertain. Reference lists of articles retrieved in
crobial(s) in the hospital or clinic and be observed, or can full copy were searched for other relevant reports. Panel members provided
additional references from personal files.
some selected for outpatient management be discharged Inclusion and exclusion criteria. Articles were selected for inclusion in
immediately after evaluation? the systematic review if they were fully published English-language reports on:
B-6. What psychosocial and logistic requirements must be met antimicrobials for prophylaxis of infection in oncology outpatients with neu-
to permit outpatient management of patients with FN? tropenia from chemotherapy, development and/or validation of methods to
C. What interventions are indicated for patients with a malignancy stratify risk of complications in oncology patients with FN, empiric antimicro-
bial therapy for oncology outpatients with FN, or direct comparisons of out-
and febrile neutropenia who can be managed as outpatients? comes for inpatient versus outpatient management of oncology patients with
C-7. What diagnostic procedures are recommended? FN. For clinical questions addressing antimicrobials for prophylaxis of infection or
C-8. What antibacterials are recommended for outpatient em- as empiric therapy for FN, study selection criteria limited inclusion to reports from
piric therapy? randomized controlled trials (RCTs) of adult human participants, systematic re-
C-9. What additional measures are recommended for outpa- views and meta-analyses of RCTs, or evidence-based clinical practice guidelines.
Prospective or retrospective cohort studies, case-control studies, and case series
tient management? were included for questions addressing risk stratification or direct comparison of
C-10. How should persistent neutropenic fever (PNF) syn- inpatient versus outpatient management. Meeting abstracts, letters, commentar-
drome be managed? ies, editorials, case reports, and nonsystematic (narrative) reviews were excluded
from evidence tables for all questions.
Data extraction. For studies on afebrile neutropenic outpatients, pri-
mary outcomes included: 1) febrile episodes and 2) infections, whereas sec-
CLINICAL PRACTICE GUIDELINES ondary outcomes included infection-related mortality. For studies on
outpatients with FN, primary outcomes included: 1) empiric treatment suc-
Practice guidelines are systematically developed statements that assist cess (defined as recovery from FN without medical complications) and 2)
overall and infection-related mortality, whereas secondary outcomes in-
practitioners and patients in making decisions about care. Attributes cluded: 1) defervescence without regimen change, 2) time to defervescence, 3)
of good guidelines include validity, reliability, reproducibility, clinical complications from infection, and 4) relapsed or recurrent fever. Additional
applicability, flexibility, clarity, multidisciplinary process, review of secondary outcomes relevant to both sets of studies included: 1) hospital
evidence, and documentation. Guidelines may be useful in producing admissions, 2) duration of hospital stay, and 3) adverse effects of antimicrobi-
better care and decreasing cost. Specifically, use of clinical guidelines als. Data were extracted directly into evidence tables (see Data Supplement
Tables DS-3 to DS-9; online at www.asco.org/guidelines/outpatientfn) by one
may provide: reviewer and checked for accuracy by a second reviewer. Disagreements were
1. Improvements in outcomes resolved by discussion and by consultation with Panel cochairs if necessary.
2. Improvements in medical practice Guideline Development Process
3. A means for minimizing inappropriate practice variation The entire Panel met once to review results of the systematic review;
4. Decision support tools for practitioners additional work to revise the clinical questions and to draft guideline recom-
5. Points of reference for medical orientation and education mendations and a manuscript was completed by telephone conferences (when
necessary) and electronic review of documents. All members of the Panel
6. Criteria for self-evaluation participated in preparation and revision of the draft guideline document and
7. Indicators and criteria for external quality review approved the final version submitted for peer review and publication in
8. Assistance with reimbursement and coverage decisions Journal of Clinical Oncology. Additional feedback was solicited from external
© 2012 by American Society of Clinical Oncology 3
, Flowers et al
reviewers. The content of the guidelines and manuscript were reviewed and include guidelines on managing FN in patients with cancer from the
approved by the ASCO CPGC before publication. Japan Febrile Neutropenia Study Group,9 the European Society
Definition of Terms of Medical Oncology (ESMO),10 and an Australian consensus
For purposes of this guideline, the Panel defined neutropenia as an panel.13,21,28,29 Additionally, the National Comprehensive Cancer
absolute neutrophil count (ANC) ⬍ 1,000/L (equivalent to ⬍ 1.0 ⫻ 109/L), Network (NCCN) has published guidelines on prevention and treat-
severe neutropenia as ANC ⬍ 500/L (equivalent to ⬍ 0.5 ⫻ 109/L), and ment of cancer-related infections,11 and the Infectious Disease Society
profound neutropenia as ANC ⬍ 100/L (equivalent to ⬍ 0.1 ⫻ 109/L). The
of America (IDSA)7,12 and the Infectious Diseases Working Party of
Panel defined the state of being febrile as a temperature of ⱖ 38.3°C by oral or
tympanic thermometry, but it did not exclude evidence from studies that used the German Society of Hematology and Oncology8 have published
slightly different definitions (eg, core temperature ⬎ 38°C). guidelines on uses of antimicrobial drugs in neutropenic patients with
cancer. The Panel has evaluated the recommendations of these orga-
Guideline Policy
The practice guideline is not intended to substitute for the independent nizations and found them to be generally consistent with recommen-
professional judgment of the treating physician. Practice guidelines do not dations in this ASCO clinical practice guideline. Specific differences
account for individual variation among patients and may not reflect the most are highlighted and discussed in the Literature Review and Analysis
recent evidence. This guideline does not recommend any particular product or sections that follow each recommendation.
course of medical treatment. Use of the practice guideline is voluntary. The
Executive Summary and additional information are available at www.asco
.org/guidelines/outpatientfn. GUIDELINE RECOMMENDATIONS
Guideline and Conflicts of Interest
The Expert Panel was assembled in accordance with the ASCO Conflict Each of the 10 recommendations (Table 1) considers issues relevant to
of Interest Management Procedures for Clinical Practice Guidelines (Proce- one of the guideline key questions. Recommendations A-1 to A-3
dures; summarized at http://www.asco.org/guidelinescoi). Members of the address issues relevant to Key Question A on preventing infection in
Panel completed the ASCO disclosure form, which requires disclosure of oncology outpatients who have or are expected to develop neutrope-
financial and other interests that are relevant to the subject matter of the nia but are without fever or evidence of infection. These include
guideline, including relationships with commercial entities that are reasonably
assessing risk for infection and selecting candidates for prophylaxis
likely to experience direct regulatory or commercial impact as the result of
promulgation of the guideline. Categories for disclosure include employment (Recommendation A-1), choosing prophylactic antimicrobials for
relationships, consulting arrangements, stock ownership, honoraria, research appropriate patients (Recommendation A-2), and other precautions
funding, and expert testimony. In accordance with the Procedures, the major- to consider (Recommendation A-3). Recommendations B-4 to B-6
ity of the members of the Panel did not disclose any such relationships. address selection of individuals with FN who can remain outpatients
Revision Dates (Key Question B), including assessing risk of medical complications (Rec-
At annual intervals, the Panel cochairs and two Panel members desig- ommendation B-4), evaluation and observation after initial dose(s) (Rec-
nated by the cochairs will determine the need for revisions to the guideline ommendation B-5), and psychosocial and logistic requirements for
based on an examination of current literature. If necessary, the entire Panel or outpatientmanagement(RecommendationB-6).Finally,Recommenda-
an update committee will be reconvened to discuss potential changes. When tions C-7 to C-10 focus on managing oncology patients with FN outside
appropriate, the Panel will recommend revised guidelines to the ASCO CPGC
for review and approval.
the hospital (Key Question C), including diagnostic procedures (Recom-
mendation C-7), empiric antibacterial therapy (Recommendation C-8),
additional measures to be considered (Recommendation C-9), and man-
RESULTS agement of PNF (Recommendation C-10).
The MEDLINE search identified a total of 4,863 unique records. Clinical Key Question A
Review of titles and abstracts eliminated 4,397 as either not relevant to What interventions are appropriate to prevent infections in pa-
the clinical questions of the guideline or not meeting study selection tients with a malignancy who have received chemotherapy in an inpa-
criteria (Data Supplement 2; online at www.asco.org/guidelines/ tient or outpatient setting and who are, or are anticipated to become,
outpatientfn). Of 466 articles selected for full-text retrieval, 45 met neutropenic as outpatients?
study selection criteria for data extraction. Hand-searching of refer-
ence lists from included articles and input from Panel members iden- Question A-1
tified 140 additional articles retrieved in full, of which two met How should risk of developing an FNE be assessed in such pa-
selection criteria. tients who are not yet febrile? What clinical characteristics identify
Of the 47 articles extracted, none addressed guideline Key Ques- patients who should be offered antimicrobial prophylaxis?
tion A (preventing infection in neutropenic adult outpatients who are Because evidence to address Question A-1 was unavailable from
not febrile); 25 addressed Key Question B (selecting adult patients trials limited to outpatients, the Panel considered evidence from stud-
with FN who are eligible for outpatient management; Data Supple- ies on inpatients or mixed populations. The following recommenda-
ment Tables DS-3 to DS-6), and 22 addressed Key Question C (com- tions on risk assessment (A-1a) and patient selection for antibacterial
paring interventions used to manage FN in the outpatient setting). (A-1b), antifungal (A-1c), anti-Pneumocystis (A-1d), and antiviral
Data extracted from the 47 reports that met selection criteria are listed (A-1e to A1g) prophylaxis are based on the evidence summarized here
in Data Supplement Tables DS-3 to DS-9. and Panel members’ expert opinion.
Other Guidelines and Consensus Statements Recommendation A-1a
Other organizations have published guidelines or consensus Risk for developing an FNE should be systematically assessed (in
statements addressing clinical questions also addressed here. These consultation with infectious disease specialists as needed), including
4 © 2012 by American Society of Clinical Oncology
Fever and Neutropenia in Adults Treated for Malignancy:
American Society of Clinical Oncology Clinical
Practice Guideline
Christopher R. Flowers, Jerome Seidenfeld, Eric J. Bow, Clare Karten, Charise Gleason, Douglas K. Hawley,
Nicole M. Kuderer, Amelia A. Langston, Kieren A. Marr, Kenneth V.I. Rolston, and Scott D. Ramsey
See accompanying article in J Oncol Pract: 10.1200/JOP.2012.000815
Christopher R. Flowers, Charise Glea-
son, and Amelia A. Langston, Emory A B S T R A C T
University School of Medicine, Atlanta,
GA; Jerome Seidenfeld, American Soci- Purpose
ety of Clinical Oncology, Alexandria, VA; To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and
Eric J. Bow, CancerCare Manitoba and on selection and treatment as outpatients of those with fever and neutropenia.
University of Manitoba, Winnipeg,
Manitoba, Canada; Clare Karten, Leuke- Methods
mia and Lymphoma Society, White A literature search identified relevant studies published in English. Primary outcomes included:
Plains, NY; Douglas K. Hawley, Onc development of fever and/or infections in afebrile neutropenic outpatients and recovery without
Heme Care, Cincinnati, OH; Nicole M. complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in
Kuderer, Duke University Comprehen- afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia,
sive Cancer Center, Durham, NC;
defervescence without regimen change, time to defervescence, infectious complications, and
Kieren A. Marr, Johns Hopkins School
of Medicine, Baltimore, MD; Kenneth
recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicro-
V.I. Rolston, University of Texas MD bials. An Expert Panel developed guidelines based on extracted data and informal consensus.
Anderson Cancer Center, Houston, TX;
and Scott D. Ramsey, Fred Hutchinson
Results
Cancer Research Center, Seattle, WA.
Forty-seven articles from 43 studies met selection criteria.
American Society of Clinical Oncology Recommendations
Clinical Practice Guideline Committee Antibacterial and antifungal prophylaxis are only recommended for patients expected to have ⬍ 100
approved: September 5, 2012. neutrophils/L for ⬎ 7 days, unless other factors increase risks for complications or mortality to similar
Editor’s note: This is the complete levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully
American Society of Clinical Oncology selected patients may be managed as outpatients after systematic assessment beginning with a
Clinical Practice Guideline and provides validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or
the recommendations with comprehen-
Talcott’s rules). Patients with MASCC scores ⱖ 21 or in Talcott group 4, and without other risk factors,
sive discussions of the relevant litera-
ture for each. The Executive Summary
can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of
of the guideline, Data Supplements empiric antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours
with evidence tables as well as other to determine suitability for outpatient management or be admitted to the hospital. An oral fluoroquin-
tables and figures, and a list of all olone plus amoxicillin/clavulanate (or plus clindamycin, if penicillin allergic) is recommended as empiric
abbreviations used in the text, tables, therapy, unless fluoroquinolone prophylaxis was used before fever developed.
and figures are available at www.asco
.org/guidelines/outpatientfn.
© 2012 by American Society of Clinical Oncology
Authors’ disclosures of potential conflicts
of interest and author contributions are
found at the end of this article. Although the CSF guideline is scheduled for an-
INTRODUCTION
Corresponding author: Jerome Seiden- other update soon, ASCO has not previously
feld, PhD, American Society of Clinical The first guideline1 published by the American addressed other measures (eg, prophylactic anti-
Oncology, 2318 Mill Rd, Suite 800,
Society of Clinical Oncology (ASCO) provided rec- microbial drugs or protective environments) to
Alexandria, VA 22314; e-mail:
. ommendations on uses of hematopoietic colony- prevent infection in outpatients who are neutro-
© 2012 by American Society of Clinical stimulating factors (CSFs), including primary penic, not yet febrile, and either continue to re-
Oncology prophylaxis of fever and neutropenia (FN) in pa- ceive or have recently completed chemotherapy
tients undergoing chemotherapy for malignancy if for malignancy. Additionally, a priority-setting
their risk was ⱖ 40%. ASCO has updated this guide- exercise of the ASCO Clinical Practice Guidelines
line periodically, most recently in 2006,2 when the Committee (CPGC) selected outpatient manage-
threshold for primary prophylaxis with a CSF was ment of febrile neutropenia as an important topic
revised to include patients at ⱖ 20% risk for FN. for a new guideline.
© 2012 by American Society of Clinical Oncology 1
, Flowers et al
Managing FN in oncology patients began to change in the late oncology patient developed FN. Presently, a wider spectrum of disorders
1960s and early 1970s, when evidence emerged that empiric antibac- than ever before is being managed on an outpatient basis. Potential ad-
terial therapy reduced deaths resulting from infection, compared with vantages of outpatient management include increased convenience for
waiting for results of microbiologic assays.3-7 The spectrum of bacte- patients and their family members, reduced costs of care, and, particularly
rial pathogens most commonly isolated from patients with FN during for those at risk of infection, decreased exposure to hospital-acquired
or after treatment for malignancy shifted from mostly Gram-negative infections, which often may be resistant to the antibiotics used most
species in the 1960s and 1970s to more Gram-positive species in the frequently. Malignancies currently being treated outside the hospital
1980s and 1990s. Currently, coagulase-negative staphylococci are the range from adjuvant systemic therapy for breast cancer to postremission
most common species identified in blood cultures, but the frequency consolidation with high-dose cytarabine for acute myeloid leukemia to
of antibiotic-resistant Gram-negative bacterial infections is increasing.
reduced-intensity conditioning stem-cell transplantation (SCT). Various
However, blood cultures and other cultures are negative and the
approaches have been studied to stratify such patients who develop FN by
causative organism and site of infection uncertain in many oncology
risk for medical complications or death.14-21 Several of these approaches
patients with fever. Because infection can progress rapidly and become
have been used to select low-risk patients for early discharge or outpatient
life threatening if patients are neutropenic, clinical practice guidelines
recommend administration of broad-spectrum antibacterials (using therapy, and a number of trials randomly assigning low-risk patients have
monotherapy or a combination regimen) soon (within an hour) after comparedoutcomesofinpatientversusoutpatientmanagement14,21-25 or
fever is documented in a neutropenic patient.7-13 oral versus IV antibacterials as empiric therapy.14,26,27 In light of the evi-
Until the late 1980s and early 1990s, empiric antibacterial therapy dence from such studies, the ASCO CPGC assembled a panel of experts to
wasalmostinvariablyadministeredintravenously(IV)inthehospitalifan address the following clinical questions.
THE BOTTOM LINE
ASCO GUIDELINE
Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated
for Malignancy
Interventions
● Antibacterial and/or antifungal prophylaxis for afebrile outpatients with neutropenia from treatment for malignancy
● Identification of oncology outpatients with fever and neutropenia (FN) at low risk for medical complications
● Initial empiric therapy in the outpatient setting to treat FN in patients at low risk for medical complications
Target Audience
● Medical oncologists, primary care physicians, and oncology nurses
Key Recommendations
● Only use antibacterial and antifungal prophylaxis if neutrophils are expected to remain ⬍ 100/L for ⬎ 7 days, unless other fac-
tors (see text and Table 2) increase risks for complications or mortality
● An oral fluoroquinolone is preferred for antibacterial prophylaxis and an oral triazole for antifungal prophylaxis
● Interventions such as footwear exchange, protected environments, respiratory or surgical masks, neutropenic diet, or nutritional
supplements are not recommended because evidence is lacking of clinical benefits to patients from their use
● Assess risk for medical complications in patients with FN using the Multinational Association for Supportive Care in Cancer (MASCC) score
(see Table 3) or Talcott’s rules; score ⱖ 21 or Talcott’s group 4 with no other risk factors (see text and Table 4) defines low risk
● An oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin for those with penicillin allergy) is recommended for
initial empiric therapy, unless fluoroquinolone prophylaxis was used before fever developed (see text for alternatives)
Methods
● An Expert Panel was convened to develop clinical practice guideline recommendations based on a review of evidence from a sys-
tematic review of the medical literature
Additional Information
● An Executive Summary of this guideline has been published in Journal of Clinical Oncology
Data Supplements, including evidence tables, and clinical tools and resources can be found at www.asco.org/guidelines/outpatientfn.
2 © 2012 by American Society of Clinical Oncology
, Antimicrobial Prophylaxis and Management of Fever and Neutropenia in Outpatients
9. Criteria for use in credentialing decisions
GUIDELINE QUESTIONS
10. Identification of areas where future research is needed
A. What interventions are appropriate to prevent infections in pa-
tients with a malignancy who have received chemotherapy in an METHODS
inpatient or outpatient setting and who are, or are anticipated to
become, neutropenic as outpatients? Panel Composition
A-1. How should risk of developing a febrile neutropenic epi- The ASCO CPGC convened an Expert Panel (hereafter referred to as the
sode (FNE) be assessed in such patients who are not yet Panel) consisting of experts in clinical medicine and research methods relevant
febrile? What clinical characteristics identify patients who to prevention and treatment of infection in patients with neutropenia after
should be offered antimicrobial prophylaxis? therapy for a malignancy and reflecting the perspectives of academic and
private practice clinicians. The experts’ fields included medical oncology,
A-2. What antimicrobial drug classes should be used to prevent hematology, infectious diseases, oncology nursing, health services research,
infection in afebrile neutropenic outpatients who should epidemiology, public health, and biostatistics. The Panel also included a pa-
be offered prophylaxis? tient representative. Panel members are listed in Appendix Table A1 (on-
A-3. What additional precautions are appropriate to prevent line only).
exposure of neutropenic but afebrile outpatients with a Literature Review and Analysis
malignancy to infectious agents or organisms? Literature search strategy. The MEDLINE database was searched using
B. Which patients with a malignancy and febrile neutropenia are PubMed for relevant evidence published from 1987 through the end of April
2011. The search included terms for malignant diseases linked to terms for
appropriate candidates for outpatient management?
neutropenia, fever, or infection and to terms for clinical trials, systematic
B-4. What clinical characteristics should be used to select pa- reviews, meta-analyses, or clinical guidelines. Data Supplement 1 provides the
tients for outpatient empiric therapy? full search strategy (online at www.asco.org/guidelines/outpatientfn). One
B-5. Should outpatients with FN at low risk for medical com- reviewer selected articles for full-copy retrieval and consulted a Panel cochair
plications receive their initial dose(s) of empiric antimi- when potential relevance was uncertain. Reference lists of articles retrieved in
crobial(s) in the hospital or clinic and be observed, or can full copy were searched for other relevant reports. Panel members provided
additional references from personal files.
some selected for outpatient management be discharged Inclusion and exclusion criteria. Articles were selected for inclusion in
immediately after evaluation? the systematic review if they were fully published English-language reports on:
B-6. What psychosocial and logistic requirements must be met antimicrobials for prophylaxis of infection in oncology outpatients with neu-
to permit outpatient management of patients with FN? tropenia from chemotherapy, development and/or validation of methods to
C. What interventions are indicated for patients with a malignancy stratify risk of complications in oncology patients with FN, empiric antimicro-
bial therapy for oncology outpatients with FN, or direct comparisons of out-
and febrile neutropenia who can be managed as outpatients? comes for inpatient versus outpatient management of oncology patients with
C-7. What diagnostic procedures are recommended? FN. For clinical questions addressing antimicrobials for prophylaxis of infection or
C-8. What antibacterials are recommended for outpatient em- as empiric therapy for FN, study selection criteria limited inclusion to reports from
piric therapy? randomized controlled trials (RCTs) of adult human participants, systematic re-
C-9. What additional measures are recommended for outpa- views and meta-analyses of RCTs, or evidence-based clinical practice guidelines.
Prospective or retrospective cohort studies, case-control studies, and case series
tient management? were included for questions addressing risk stratification or direct comparison of
C-10. How should persistent neutropenic fever (PNF) syn- inpatient versus outpatient management. Meeting abstracts, letters, commentar-
drome be managed? ies, editorials, case reports, and nonsystematic (narrative) reviews were excluded
from evidence tables for all questions.
Data extraction. For studies on afebrile neutropenic outpatients, pri-
mary outcomes included: 1) febrile episodes and 2) infections, whereas sec-
CLINICAL PRACTICE GUIDELINES ondary outcomes included infection-related mortality. For studies on
outpatients with FN, primary outcomes included: 1) empiric treatment suc-
Practice guidelines are systematically developed statements that assist cess (defined as recovery from FN without medical complications) and 2)
overall and infection-related mortality, whereas secondary outcomes in-
practitioners and patients in making decisions about care. Attributes cluded: 1) defervescence without regimen change, 2) time to defervescence, 3)
of good guidelines include validity, reliability, reproducibility, clinical complications from infection, and 4) relapsed or recurrent fever. Additional
applicability, flexibility, clarity, multidisciplinary process, review of secondary outcomes relevant to both sets of studies included: 1) hospital
evidence, and documentation. Guidelines may be useful in producing admissions, 2) duration of hospital stay, and 3) adverse effects of antimicrobi-
better care and decreasing cost. Specifically, use of clinical guidelines als. Data were extracted directly into evidence tables (see Data Supplement
Tables DS-3 to DS-9; online at www.asco.org/guidelines/outpatientfn) by one
may provide: reviewer and checked for accuracy by a second reviewer. Disagreements were
1. Improvements in outcomes resolved by discussion and by consultation with Panel cochairs if necessary.
2. Improvements in medical practice Guideline Development Process
3. A means for minimizing inappropriate practice variation The entire Panel met once to review results of the systematic review;
4. Decision support tools for practitioners additional work to revise the clinical questions and to draft guideline recom-
5. Points of reference for medical orientation and education mendations and a manuscript was completed by telephone conferences (when
necessary) and electronic review of documents. All members of the Panel
6. Criteria for self-evaluation participated in preparation and revision of the draft guideline document and
7. Indicators and criteria for external quality review approved the final version submitted for peer review and publication in
8. Assistance with reimbursement and coverage decisions Journal of Clinical Oncology. Additional feedback was solicited from external
© 2012 by American Society of Clinical Oncology 3
, Flowers et al
reviewers. The content of the guidelines and manuscript were reviewed and include guidelines on managing FN in patients with cancer from the
approved by the ASCO CPGC before publication. Japan Febrile Neutropenia Study Group,9 the European Society
Definition of Terms of Medical Oncology (ESMO),10 and an Australian consensus
For purposes of this guideline, the Panel defined neutropenia as an panel.13,21,28,29 Additionally, the National Comprehensive Cancer
absolute neutrophil count (ANC) ⬍ 1,000/L (equivalent to ⬍ 1.0 ⫻ 109/L), Network (NCCN) has published guidelines on prevention and treat-
severe neutropenia as ANC ⬍ 500/L (equivalent to ⬍ 0.5 ⫻ 109/L), and ment of cancer-related infections,11 and the Infectious Disease Society
profound neutropenia as ANC ⬍ 100/L (equivalent to ⬍ 0.1 ⫻ 109/L). The
of America (IDSA)7,12 and the Infectious Diseases Working Party of
Panel defined the state of being febrile as a temperature of ⱖ 38.3°C by oral or
tympanic thermometry, but it did not exclude evidence from studies that used the German Society of Hematology and Oncology8 have published
slightly different definitions (eg, core temperature ⬎ 38°C). guidelines on uses of antimicrobial drugs in neutropenic patients with
cancer. The Panel has evaluated the recommendations of these orga-
Guideline Policy
The practice guideline is not intended to substitute for the independent nizations and found them to be generally consistent with recommen-
professional judgment of the treating physician. Practice guidelines do not dations in this ASCO clinical practice guideline. Specific differences
account for individual variation among patients and may not reflect the most are highlighted and discussed in the Literature Review and Analysis
recent evidence. This guideline does not recommend any particular product or sections that follow each recommendation.
course of medical treatment. Use of the practice guideline is voluntary. The
Executive Summary and additional information are available at www.asco
.org/guidelines/outpatientfn. GUIDELINE RECOMMENDATIONS
Guideline and Conflicts of Interest
The Expert Panel was assembled in accordance with the ASCO Conflict Each of the 10 recommendations (Table 1) considers issues relevant to
of Interest Management Procedures for Clinical Practice Guidelines (Proce- one of the guideline key questions. Recommendations A-1 to A-3
dures; summarized at http://www.asco.org/guidelinescoi). Members of the address issues relevant to Key Question A on preventing infection in
Panel completed the ASCO disclosure form, which requires disclosure of oncology outpatients who have or are expected to develop neutrope-
financial and other interests that are relevant to the subject matter of the nia but are without fever or evidence of infection. These include
guideline, including relationships with commercial entities that are reasonably
assessing risk for infection and selecting candidates for prophylaxis
likely to experience direct regulatory or commercial impact as the result of
promulgation of the guideline. Categories for disclosure include employment (Recommendation A-1), choosing prophylactic antimicrobials for
relationships, consulting arrangements, stock ownership, honoraria, research appropriate patients (Recommendation A-2), and other precautions
funding, and expert testimony. In accordance with the Procedures, the major- to consider (Recommendation A-3). Recommendations B-4 to B-6
ity of the members of the Panel did not disclose any such relationships. address selection of individuals with FN who can remain outpatients
Revision Dates (Key Question B), including assessing risk of medical complications (Rec-
At annual intervals, the Panel cochairs and two Panel members desig- ommendation B-4), evaluation and observation after initial dose(s) (Rec-
nated by the cochairs will determine the need for revisions to the guideline ommendation B-5), and psychosocial and logistic requirements for
based on an examination of current literature. If necessary, the entire Panel or outpatientmanagement(RecommendationB-6).Finally,Recommenda-
an update committee will be reconvened to discuss potential changes. When tions C-7 to C-10 focus on managing oncology patients with FN outside
appropriate, the Panel will recommend revised guidelines to the ASCO CPGC
for review and approval.
the hospital (Key Question C), including diagnostic procedures (Recom-
mendation C-7), empiric antibacterial therapy (Recommendation C-8),
additional measures to be considered (Recommendation C-9), and man-
RESULTS agement of PNF (Recommendation C-10).
The MEDLINE search identified a total of 4,863 unique records. Clinical Key Question A
Review of titles and abstracts eliminated 4,397 as either not relevant to What interventions are appropriate to prevent infections in pa-
the clinical questions of the guideline or not meeting study selection tients with a malignancy who have received chemotherapy in an inpa-
criteria (Data Supplement 2; online at www.asco.org/guidelines/ tient or outpatient setting and who are, or are anticipated to become,
outpatientfn). Of 466 articles selected for full-text retrieval, 45 met neutropenic as outpatients?
study selection criteria for data extraction. Hand-searching of refer-
ence lists from included articles and input from Panel members iden- Question A-1
tified 140 additional articles retrieved in full, of which two met How should risk of developing an FNE be assessed in such pa-
selection criteria. tients who are not yet febrile? What clinical characteristics identify
Of the 47 articles extracted, none addressed guideline Key Ques- patients who should be offered antimicrobial prophylaxis?
tion A (preventing infection in neutropenic adult outpatients who are Because evidence to address Question A-1 was unavailable from
not febrile); 25 addressed Key Question B (selecting adult patients trials limited to outpatients, the Panel considered evidence from stud-
with FN who are eligible for outpatient management; Data Supple- ies on inpatients or mixed populations. The following recommenda-
ment Tables DS-3 to DS-6), and 22 addressed Key Question C (com- tions on risk assessment (A-1a) and patient selection for antibacterial
paring interventions used to manage FN in the outpatient setting). (A-1b), antifungal (A-1c), anti-Pneumocystis (A-1d), and antiviral
Data extracted from the 47 reports that met selection criteria are listed (A-1e to A1g) prophylaxis are based on the evidence summarized here
in Data Supplement Tables DS-3 to DS-9. and Panel members’ expert opinion.
Other Guidelines and Consensus Statements Recommendation A-1a
Other organizations have published guidelines or consensus Risk for developing an FNE should be systematically assessed (in
statements addressing clinical questions also addressed here. These consultation with infectious disease specialists as needed), including
4 © 2012 by American Society of Clinical Oncology
