2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Initial Management of Low-Risk Pediatric
Fever and Neutropenia: Efficacy and
Safety, Costs, Quality-of-Life Considerations,
and Preferences
Overview: Initial management options for pediatric low-risk
fever and neutropenia (FN) include outpatient compared with
inpatient management and oral compared with intravenous
therapy. Single-arm and randomized trials have been conducted
in children. Meta-analyses provide support for the
equivalence of outpatient and inpatient approaches. Outpatient
oral management may be associated with a higher risk of
readmission compared with outpatient intravenous management
in children with FN, although other outcomes such as
treatment failure and discontinuation of the regimen because
of adverse effects were similar. Importantly, there have been
no reported deaths among low-risk children treated as outpatients
or with oral antibiotics. Costs, whether derived directly
or through cost-effectiveness analysis, are consistently reduced
when an outpatient approach is used. Quality of life
FEVER AND neutropenia (FN) is a common and potentially
fatal complication of intensive chemotherapy in
children with cancer. 1 Over the last 4 decades, outcomes of
FN have improved dramatically related to hospitalization
and prompt initiation of empiric antibiotic therapy. 2,3 However,
children with FN are heterogeneous. 4 Based on characteristics
at presentation, some of these children are
predicted to be at low risk of mortality and adverse events,
and these children may be managed less intensively. 5 Currently,
there are several validated prediction rules designed
to identify the low-risk child with FN. 6 These rules vary in
terms of their specific characteristics, but all rules identify
children with an anticipated short duration of neutropenia.
The ability to identify such patients has led to the consideration
and design of clinical trials to evaluate less intensive
strategies for low-risk FN and, ultimately, to their implementation
in clinical practice.
The most relevant lesser intensity strategies relate to site
of care (outpatient compared with inpatient) and mode of
antibiotic administration (oral compared with intravenous).
In adult patients with low-risk FN, oral therapy is associated
with similar outcomes to intravenous treatment, 7-9 and
there is increasing evidence that outpatient management of
this population is a safe approach. 10,11 As a result, adultbased
guidelines for the management of FN now recommend
outpatient management and oral antibiotics for selected
low-risk patients. 12,13 However, there has been reluctance to
adopt these strategies for children with FN. 14 The following
sections summarize the existing literature related to outpatient
management and oral antibiotic therapy in children
with FN with respect to efficacy and safety, costs, and QoL
and preferences.
Efficacy and Safety of Outpatient Management and
Oral Antibiotic Administration
Outpatient Compared with Inpatient Management
Successful outpatient management of children with FN is
predicated on several important considerations related to
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By Lillian Sung, MD, PhD
(QoL) and preferences should be considered in order to
evaluate different strategies, plan programs, and anticipate
uptake of outpatient programs. Using parent-proxy report,
child QoL is consistently higher with outpatient approaches,
although research evaluating child self-report is limited. Preferences
incorporate estimated QoL, but, in addition, factor in
issues such as costs, fear, anxiety, and logistical issues. Only
approximately 50% of parents prefer outpatient management.
Future research should develop tools to facilitate outpatient
care and to measure caregiver burden associated with this
strategy. Additional work should also focus on eliciting child
preferences for outpatient management. Finally, studies of
effectiveness of an ambulatory approach in the real-world
setting outside of clinical trials are important.
the child, family, and local infrastructure. First, the child
must be identified as having low-risk features using one of
the validated clinical prediction rules. 6 Family considerations
include a history of compliance with other medical
procedures, rapid accessibility to hospital, ability to communicate
reliably by telephone, and ability to provide continual
observation and assessment of the child. The local health
care team must also have the infrastructure to support
outpatient management, which includes clinics that can
assess outpatients and professionals who can be in contact
with families on a regular basis and who are readily available
if problems arise.
Outpatient therapy can be initiated at the onset of FN
or after a short period of inpatient treatment followed by
discharge to the home (step-down management). Outpatient
programs may deliver antibiotics by different routes of
administration, including entirely oral administration, entirely
intravenous administration, or step-down management
in which treatment begins with intravenous and then
transitions to oral therapy. In the outpatient setting,
follow-up assessments may occur in clinics, in the home, by
telephone, or a combination of approaches. The frequency of
follow-up assessments may vary considerably depending on
the specific outpatient model of care.
There has been a single meta-analysis of randomized
controlled trials (RCTs) that compared outpatient compared
with inpatient management of FN. 15 Six studies were included:
four were adult studies and two were pediatric
studies. Two studies consisted of an entirely outpatient
approach whereas four consisted of a step-down approach in
From the Division of Haematology/Oncology, and Program in Child Health Evaluative
Sciences, The Hospital for Sick Children, Toronto, ON, Canada.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Lillian Sung MD, PhD, Division of Haematology/Oncology,
The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G1X8; email:
lillian.sung@sickkids.ca
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10