COMMENTARY
clinical review
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Copyright © 2024 American Society of Clinical Oncology. All rights reserved.
ASSOCIATED
CONTENT
See accompanying
article on page 19
Author affiliations
and support
information (if
applicable) appear
at the end of this
article.
Accepted on
November 30, 2018:
DOI https://doi.org/10.
1200/JOP.18.00718
Clinical Implications of Febrile Neutropenia
Guidelines in the Cancer Patient Population
Catherine C. Braga, MSN1; Randy A. Taplitz, MD1; and Christopher R. Flowers, MD1
Febrile neutropenia is a medical emergency that re-
quires urgent evaluation, the timely administration of
empiric broad-spectrum antimicrobials, and careful
monitoring to optimize patient outcomes and mitigate
the risk of complications. Fever in the setting of
neutropenia can affect subsequent chemotherapy
dosing and scheduling, which, in turn, affects treat-
ment efficacy and overall prognosis. Febrile neu-
tropenia remains a significant cause of morbidity,
mortality, and cost burden in patients with cancer.1
ASCO and the Infectious Disease Society of America
(IDSA) have published clinical practice guidelines for
the effective triage, risk stratification, and standardized
management of this vulnerable patient population with
a focus on patients who can safely be managed in the
outpatient setting.2,3 The IDSA guideline on the general
management of neutropenic patients with cancer was
first published in 1997 and last updated in 2011.4 In
the article that accompanies this commentary, Zimmer
and Freifeld5 address an important gap in the literature
regarding the management of most patients who will
require inpatient care. As the authors note, there is no
set of diagnostics or grading criteria that can precisely
distinguish bacteremia from uninfected febrile neu-
tropenia; therefore, treatment is indicated in all cases.
Antibiotic regimens must primarily target gram-negative
pathogens that carry the highest risk for morbidity and
mortality.
In specific groups, such as patients undergoing high-
dose cytotoxic chemotherapy and hematopoietic stem
cell transplantation, antimicrobial prophylaxis is in-
dicated for patients with cancer who are at high risk of
infection during prolonged neutropenia to prevent
febrile neutropenia and reduce infectious risk. Another
recent IDSA/ASCO clinical practice guideline de-
lineates the judicious application of such measures.6,7
Risk for febrile neutropenia should be assessed on the
basis of patient characteristics, underlying malig-
nancy, and treatment-related criterion, with pro-
phylactic antimicrobial selection, timing, and duration
administered accordingly.2,5,8,9 However, as Zimmer
and Freifeld note, fluoroquinolone prophylaxis is in-
creasingly associated with multidrug resistance and
potential toxicity, which must be considered in both
the use of prophylactic regimens and the diagnos-
tic workup and treatment selection when febrile
neutropenia occurs in the setting of prophylaxis.
Prophylaxis regimens vary by institutional practice as
there is no uniform evidence that suggests enhanced
survival with use. Supportive measures, including
respiratory hygiene/cough etiquette, hand hygiene,
vaccination administration, and limiting hazardous
environmental exposures, are modalities that are
intended to augment infection prevention.
Upon evaluating patients with febrile neutropenia,
clinicians must differentiate between patients who can
be safely treated and monitored as outpatients versus
individuals who require inpatient hospitalization.
ASCO/IDSA recently published updated recommen-
dations for the identification of patients with febrile
neutropenia who may be considered for outpatient
management. This approach was endorsed by
Zimmer and Freifeld. Validated tools, such as Talcott’s
rules, the Multinational Association for Supportive Care
in Cancer score, and the Clinical Index of Stable Fe-
brile Neutropenia, support risk stratification for de-
cision making.2,5,8,9 In treatment centers that have the
resource capacity to provide prompt triage, empiric
treatment, and ongoing evaluation, an empiric oral
and/or outpatient antibiotic management strategy is
possible for low-risk patients with solid tumors who
have undergone mild- to moderate-intensity chemo-
therapy and otherwise seem to be clinically stable.
Patients with hematologic malignancies or who un-
dergo hematopoietic stem cell transplantation are
unlikely to be appropriate candidates for outpatient
therapy, nor are patients known or suspected to be
infected by fluoroquinolone-resistant or other resistant
pathogens, such as methicillin-resistant Staphylo-
coccus aureus, vancomycin-resistant Enterococcus,
and extended-spectrum b-lactamase gram-negative
organisms. Multiorgan system involvement with ac-
companying derangements in examination findings or
laboratory diagnostics also exclude patients from
outpatient management. As the authors recommend,
site-specific antibiograms and susceptibility patterns
related to a patient’s presenting history and physical
examination should guide differential diagnosis and
treatment.
The initial diagnostic approach for patients with fe-
brile neutropenia must include timely and thorough
evaluation and laboratory, microbiologic, and
Volume 15, Issue 1 25
 Braga, Taplitz, and Flowers

radiologic diagnostics as indicated with expanded as hemodynamic instability, or if antimicrobial resistance

workup in the setting of hematologic malignancy and
hematopoietic stem cell transplantation. Time from
triage to the delivery of antibiotics should not exceed
1 hour as delays are associated with complications
and decreased survival. For patients who develop fe-
brile neutropenia while receiving oral fluoroquinolone
prophylaxis, monotherapy with an antipseudomonal
B-lactam agent is recommended, with the addition of
other antimicrobials if other complications arise, such
is suspected or proven. Consideration of logistic and
psychosocial support, access to 24/7 emergency ser-
vices, transportation, compliance, and mutually de-
veloped patient-provider understanding of the care plan
must be ensured. Although the article by Zimmer and
Freifeld fills an important gap, an updated, evidence-
based guideline specifically geared toward the inpatient
management of febrile neutropenia for patients with
cancer is needed.

AFFILIATION AUTHOR CONTRIBUTIONS

1
Emory University Hospital, Atlanta, GA Conception and design: Christopher R. Flowers
Financial support: Christopher R. Flowers
Administrative support: Christopher R. Flowers
CORRESPONDING AUTHOR
Data analysis and interpretation: All authors
Christopher R. Flowers, MD, Winship Cancer Institute, Department of
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Hematology and Oncology, Emory University, Health Science Research Manuscript writing: All authors
Building, 1760 Haygood Dr NE, 2nd Floor, W220, Atlanta, GA 30322; Final approval of manuscript: All authors
e-mail: crflowe@emory.edu. Accountable for all aspects of the work: All authors
Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST ACKNOWLEDGMENT

AND DATA AVAILABILITY STATEMENT Supported by National Cancer Institute Grant No. K24-CA208132. The
Disclosures provided by the authors and data availability statement (if content is solely the responsibility of the authors and does not necessarily
applicable) are available with this article at DOI https://doi.org/10.1200/ represent the official views of the National Institutes of Health.
JOP.18.00718.

REFERENCES
1. Kuderer NM, Dale DC, Crawford J, et al: Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 106:2258-2266, 2006
2. Taplitz RA, Kennedy EB, Bow EJ, et al: Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology
and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol 36:1443-1453, 2018
3. Taplitz RA, Kennedy EB, Flowers CR: Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology
and Infectious Diseases Society of America clinical practice guideline update summary. J Oncol Pract 14:250-255, 2018
4. Freifeld AG, Bow EJ, Sepkowitz KA, et al: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the
Infectious Diseases Society of America. Clin Infect Dis 52:e56-e93, 2011
5. Zimmer AJ, Freifeld AG: Optimal management of neutropenic fever in patients with cancer. J Oncol Pract 15:19-24, 2019
6. Taplitz RA, Kennedy EB, Bow EJ, et al: Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice
guideline update. J Clin Oncol 36:3043-3054, 2018
7. Taplitz RA, Kennedy EB, Flowers CR: Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice
guideline update summary. J Oncol Pract 14:692-695, 2018
8. Klastersky J, Paesmans M, Rubenstein EB, et al: The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for
identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 18:3038-3051, 2000
9. Talcott JA, Siegel RD, Finberg R, et al: Risk assessment in cancer patients with fever and neutropenia: A prospective, two-center validation of a prediction rule.
J Clin Oncol 10:316-322, 1992

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26 © 2019 by American Society of Clinical Oncology Volume 15, Issue 1

 Commentary

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Clinical Implications of Febrile Neutropenia Guidelines in the Cancer Patient Population
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held
unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about
ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jop/site/ifc/journal-policies.html.

Randy A. Taplitz Christopher R. Flowers

Consulting or Advisory Role: Merck Consulting or Advisory Role: OptumRx, Seattle Genetics, Bayer, Gilead
Sciences, Spectrum Pharmaceuticals, AbbVie, Celgene, Denovo Biopharma,
BeiGene, AstraZeneca, Karyopharm Therapeutics, Pharmacyclics, Janssen
Pharmaceuticals
Research Funding: Acerta Pharma (Inst), Infinity Pharmaceuticals (Inst), Onyx
Pharmaceuticals (Inst), Janssen Oncology (Inst), Gilead Sciences (Inst), Celgene
(Inst), TG Therapeutics (Inst), Genentech (Inst), Pharmacyclics (Inst), AbbVie
(Inst), Immune Design (Inst), BeiGene (Inst)
Travel, Accommodations, Expenses: Gilead Sciences, Celgene, Genentech

No other potential conflicts of interest were reported.

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Copyright © 2024 American Society of Clinical Oncology. All rights reserved.

Journal of Oncology Practice