VOLUME 33 䡠 NUMBER 28 䡠 OCTOBER 1 2015

JOURNAL OF CLINICAL ONCOLOGY A S C O S P E C I A L A R T I C L E

Recommendations for the Use of WBC Growth Factors:

American Society of Clinical Oncology Clinical Practice
Guideline Update
Thomas J. Smith, Johns Hopkins Sidney Thomas J. Smith, Kari Bohlke, Gary H. Lyman, Kenneth R. Carson, Jeffrey Crawford, Scott J. Cross,
Kimmel Comprehensive Cancer Center, John M. Goldberg, James L. Khatcheressian, Natasha B. Leighl, Cheryl L. Perkins, George Somlo,
Baltimore, MD; Kari Bohlke, American Soci-
James L. Wade, Antoinette J. Wozniak, and James O. Armitage
ety of Clinical Oncology, Alexandria; Scott
J. Cross, Virginia Oncology Associates,
Norfolk; James L. Khatcheressian, Virginia A B S T R A C T
Cancer Institute, Richmond, VA; Gary H.
Lyman, Fred Hutchinson Cancer Research Purpose
Center and University of Washington, Seat- To update the 2006 American Society of Clinical Oncology guideline on the use of hematopoietic
tle, WA; Kenneth R. Carson, Washington colony-stimulating factors (CSFs).
University, St Louis, MO; Jeffrey Crawford,
Duke Medicine, Durham, NC; John M. Methods
Goldberg, University of Miami Miller School The American Society of Clinical Oncology convened an Update Committee and conducted a
of Medicine, Miami, FL; Natasha B. Leighl, systematic review of randomized clinical trials, meta-analyses, and systematic reviews from
Princess Margaret Cancer Centre, Toronto, October 2005 through September 2014. Guideline recommendations were based on the review of
Ontario, Canada; Cheryl L. Perkins, patient the evidence by the Update Committee.
representative, Dallas, TX; George Somlo,
City of Hope National Medical Center, Results
Duarte, CA; James L. Wade, Cancer Care Changes to previous recommendations include the addition of tbo-filgrastim and filgrastim-sndz,
Specialists of Central Illinois, Decatur, IL; moderation of the recommendation regarding routine use of CSFs in older patients with diffuse
Antoinette J. Wozniak, Karmanos Cancer
aggressive lymphoma, and addition of recommendations against routine dose-dense chemother-
Institute, Detroit, MI; and James O. Armit-
age, University of Nebraska Medical
apy in lymphoma and in favor of high– dose-intensity chemotherapy in urothelial cancer. The
Center, Omaha, NE. Update Committee did not address recommendations regarding use of CSFs in acute myeloid
Published online ahead of print at
leukemia or myelodysplastic syndromes in adults.
www.jco.org on July 13, 2015.
Recommendations
T.J.S. and J.O.A. were Update Commit- Prophylactic use of CSFs to reduce the risk of febrile neutropenia is warranted when the risk of
tee co-chairs. febrile neutropenia is approximately 20% or higher and no other equally effective and safe regimen
Clinical Practice Guideline Committee that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of
approval: January 30, 2015. febrile neutropenia in patients who are at high risk on the basis of age, medical history, disease
Editor’s note: This American Society of characteristics, and myelotoxicity of the chemotherapy regimen. Dose-dense regimens that
Clinical Oncology clinical practice guideline require CSFs should only be used within an appropriately designed clinical trial or if supported by
provides recommendations, with compre- convincing efficacy data. Current recommendations for the management of patients exposed to
hensive review and analyses of the rele- lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death as a
vant literature for each recommendation.
result of injury to other organs, include the prompt administration of CSFs.
Additional information, including a Data
Supplement with additional evidence
tables, a Methodology Supplement, slide J Clin Oncol 33:3199-3212. © 2015 by American Society of Clinical Oncology
sets, clinical tools and resources, and links
to patient information at www.
and often require hospitalization. The risk of such
cancer.net, is available at www.asco.org/ INTRODUCTION
guidelines/wbcgf. complications increases in direct proportion to the
Authors’ disclosures of potential conflicts Neutropenia and its complications, including febrile severity and duration of neutropenia.4 Hematopoi-
of interest are found in the article online at neutropenia and infection, remain major toxicities etic colony-stimulating factors (CSFs) have been
www.jco.org. Author contributions are
associated with myelosuppressive systemic cancer shown to reduce the duration and severity of neu-
found at the end of this article.
chemotherapy.1-3 In a nationwide prospective co- tropenia and the risk of febrile neutropenia5 and
Corresponding author: American Soci-
hort study, first-cycle febrile neutropenia occurred enable delivery of more intensive or dose-dense che-
ety of Clinical Oncology, 2318 Mill Rd,
Suite 800, Alexandria, VA 22314; in 6% of adults with solid tumors being treated with motherapy when indicated. However, concerns
e-mail: [email protected]. myelosuppressive chemotherapy.2 Among patients with respect to adverse events and costs led the
© 2015 by American Society of Clinical with metastatic solid tumors, incidence of febrile American Society of Clinical Oncology (ASCO) to
Oncology neutropenia during myelosuppressive chemother- develop a clinical practice guideline for the use of
0732-183X/15/3328w-3199w/$20.00 apy ranged from 13% to 21% in a large retrospective CSFs in 1994 and updates on four occasions since
DOI: 10.1200/JCO.2015.62.3488 study.3 Neutropenic complications require prompt then. This guideline represents the first major up-
evaluation and treatment with empiric antibiotics date since 2006 and addresses the strengths and

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 Smith et al

THE BOTTOM LINE

Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical
Practice Guideline Update

Guideline Question
How should colony-stimulating factors (CSFs) be used in people with cancer?

Target Population
Adults or children with a solid tumor or lymphoma treated with chemotherapy

Target Audience
Medical oncologists, hematologists, oncology nurses, other clinicians who care for people with cancer, and patients

Methods
An Update Committee was convened to update clinical practice guideline recommendations based on a systematic review of the
medical literature.

Key Points

● Primary prophylaxis with a CSF starting with the first cycle and continuing through subsequent cycles of chemotherapy is
recommended in patients who have an approximately 20% or higher risk for febrile neutropenia based on patient-,
disease- and treatment-related factors. Primary CSF prophylaxis should also be administered in patients receiving dose-
dense chemotherapy when considered appropriate. Consideration should be given to alternative, equally effective, and safe
chemotherapy regimens not requiring CSF support when available. (Type: evidence based, benefits outweigh harms.
Evidence quality: high. Strength of recommendation: strong.)

● Secondary prophylaxis with a CSF is recommended for patients who experienced a neutropenic complication from a prior
cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose or treatment delay may
compromise disease-free or overall survival or treatment outcome. In many clinical situations, dose reduction or delay
may be a reasonable alternative. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of
recommendation: strong.)

● CSFs should not be routinely used for patients with neutropenia who are afebrile. (Type: evidence based, benefits
outweigh harms. Evidence quality: high. Strength of recommendation: strong.)

● CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia.
However, CSFs should be considered in patients with fever and neutropenia who are at high risk for infection-associated
complications or who have prognostic factors predictive of poor clinical outcomes. (Type: evidence based, benefits
outweigh harms. Evidence quality: high. Strength of recommendation: strong.)

● Dose-dense regimens with CSF support should only be used if supported by convincing efficacy data or within an
appropriately designed clinical trial. Efficacy data support the use of dose-dense chemotherapy in the adjuvant treatment
of high-risk breast cancer and the use of high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin in
urothelial cancer. There are limited and conflicting data on the value of dose-dense regimens with CSF support in non-
Hodgkin lymphoma, and it cannot routinely be recommended at this time. (Type: evidence based, benefits outweigh
harms. Evidence quality: high for breast cancer and lymphoma; intermediate for urothelial cancer. Strength of
recommendation: strong for breast cancer and lymphoma; moderate for urothelial cancer.)

● CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral-blood progenitor
cells. Choice of mobilization strategy depends in part on type of cancer and type of transplantation. (Type: evidence based,
benefits outweigh harms. Evidence quality: strong. Strength of recommendation: high.)
(continued on following page)

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 Recommendations for the Use of WBC Growth Factors

THE BOTTOM LINE (CONTINUED)

● CSFs should be administered after autologous stem-cell transplantation to reduce the duration of severe neutropenia.
(Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)

● CSFs may be administered after allogeneic stem-cell transplantation to reduce the duration of severe neutropenia. (Type:
evidence based. Evidence quality: low. Strength of recommendation: weak).
● Prophylactic CSFs for patients with diffuse aggressive lymphoma age ⱖ 65 years treated with curative chemotherapy
(cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) should be considered, particularly in the
presence of comorbidities. (Type: evidence based, benefits outweigh harms. Evidence quality: intermediate. Strength of
recommendation: moderate.)

● The use of CSFs in pediatric patients will almost always be guided by clinical protocols. As in adults, the use of CSFs is
reasonable as primary prophylaxis for pediatric patients with a high likelihood of febrile neutropenia. Similarly, the use of
CSFs for secondary prophylaxis or for therapy should be limited to high-risk patients. (Type: evidence based, benefits
outweigh harms. Evidence quality: high. Strength of recommendation: strong.)

● For pediatric indications in which dose-intense chemotherapy is known to have a survival benefit, such as Ewing sarcoma,
CSFs should be used to enable the administration of these regimens. (Type: evidence based, benefits outweigh harms.
Evidence quality: high. Strength of recommendation: strong.)

● CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or nonrelapsed acute
myeloid leukemia who do not have an infection. (Type: informal consensus. Evidence quality: intermediate. Strength of
recommendation: moderate.)

● Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used
for the prevention of treatment-related febrile neutropenia. The choice of agent depends on convenience, cost, and clinical
situation. There have been no additional data comparing granulocyte CSFs and granulocyte-macrophage CSFs since the
2006 update; therefore, there is no change in the recommendation regarding their therapeutic equivalency. (Type:
evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
● Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not
doses high enough to lead to certain death resulting from injury to other organs, include the prompt administration of
CSFs or pegylated granulocyte CSFs. (Type: formal consensus [by others], benefits outweigh harms. Evidence quality:
intermediate. Strength of recommendation: moderate.)

Qualifying Statements
The Update Committee did not provide recommendations regarding the use of CSFs in adult patients with acute myeloid leukemia or
myelodysplastic syndromes.

Additional Resources
More information, including a Data Supplement with additional evidence tables, a Methodology Supplement with information about
evidence quality and strength of recommendations, slide sets, and clinical tools and resources, is available at www.asco.org/guidelines/
wbcgf. Patient information is available at www.cancer.net.
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have
the opportunity to participate.

limitations of the use of CSFs across a range of settings in clinical

GUIDELINE QUESTIONS
oncology practice on the basis of an exhaustive review of the medical
literature. The purpose of this guideline is to foster the appropriate use
of these agents based on high-quality evidence from controlled clinical This clinical practice guideline considered the following clinical ques-
trials and a comprehensive understanding of the specific patient, dis- tions: (1) In adults treated with chemotherapy for a solid tumor or
ease, and treatment factors associated with the risk of neutropenic lymphoma, what factors should clinicians consider when selecting
complications. patients for primary prophylaxis of febrile neutropenia with a CSF? (2)

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 Smith et al

In adults treated with chemotherapy for a solid tumor or lymphoma, search and data extraction information, the recommendation development
what factors should clinicians use to select patients for secondary process, and a quality assessment.
prophylaxis of febrile neutropenia with a CSF? (3) Are there circum- The ASCO Committee and guidelines staff will work with co-chairs to
monitor the medical literature and determine the need for future updates. This
stances in which CSFs should be considered for the treatment of
is the most recent information as of the publication date. For updates, the most
neutropenia in adults with cancer? (4) In what settings should CSFs be recent information, and to submit new evidence, please visit www.asco.
used to increase chemotherapy dose density? (5) What is the role of org/guidelines/wbcgf and the ASCO Guidelines Wiki (www.asco.org/
CSFs as adjuncts to progenitor-cell transplantation? (6) What is the guidelineswiki).
role of CSFs in the setting of acute leukemia or myelodysplastic syn-
dromes? (7) Should CSFs be avoided in patients receiving concomi- Guideline Disclaimer
tant chemotherapy and radiation therapy? (8) Are there CSF This clinical practice guideline and other guidance published herein are
recommendations that apply specifically to older adults and that differ provided by ASCO to assist providers in clinical decision making. The infor-
from recommendations in younger adults? (9) How should CSFs be mation herein should not be relied on as being complete or accurate, nor
should it be considered as inclusive of all proper treatments or methods of care
used in the pediatric population? (10) What are recommendations for
or as a statement of the standard of care. With the rapid development of
the initiation, duration, dosing, and administration of CSFs? (11) Do scientific knowledge, new evidence may emerge between the time information
CSFs differ in efficacy? (12) What is the role of CSFs in the treatment of is developed and when it is published or read. The information is not contin-
radiation injury? ually updated and may not reflect the most recent evidence. The information
addresses only the topics specifically identified therein and is not applicable to
other interventions, diseases, or stages of diseases. This information does not
METHODS mandate any particular course of medical care. Furthermore, the information
is not intended to substitute for the independent professional judgment of the
Guideline Update Development Process treating provider, because the information does not account for individual
The Update Committee (members listed in Appendix Table A1, online variation among patients. Recommendations are described as having high,
only) met twice via Webinar and corresponded through e-mail. On the basis of moderate, or low confidence that a recommendation reflects the net effect of a
the consideration of the evidence, the authors were asked to contribute to the given course of action. The use of words like “must,” “must not,” “should,”
development of the guideline, provide critical review, and finalize the guideline and “should not” indicates that a course of action is recommended or not
recommendations. Members of the Update Committee were responsible for recommended for either most or many patients, but there is latitude for the
reviewing and approving the final version of guideline, which was then circu- treating physician to select other courses of action in individual cases. In all
lated for external review and submitted to Journal of Clinical Oncology for cases, the selected course of action should be considered by the treating pro-
editorial review and consideration for publication. All ASCO guidelines are vider in the context of treating the individual patient. Use of the information is
ultimately reviewed and approved by the Update Committee and the ASCO voluntary. ASCO provides this information on an as-is basis and makes no
Clinical Practice Guidelines Committee before publication. warranty, express or implied, regarding the information. ASCO specifically
The recommendations were developed by an Update Committee with disclaims any warranties of merchantability or fitness for a particular use or
multidisciplinary representation using a systematic review (October 1, 2005, purpose. ASCO assumes no responsibility for any injury or damage to persons
through September 30, 2014) of phase III randomized controlled trials or property arising out of or related to any use of this information or for any
(RCTs), meta-analyses, systematic reviews, and clinical experience. When errors or omissions.
recommended by Update Committee members, results from selected phase II
trials were considered. Articles were selected for inclusion in the systematic Guideline and Conflicts of Interest
review of the evidence on the basis of the following criteria: The Expert Panel was assembled in accordance with the ASCO Conflict
● Population: adults or children with cancer. of Interest Management Procedures for Clinical Practice Guidelines (summa-
● Intervention: granulocyte CSFs (G-CSFs) and granulocyte macro- rized at www.asco.org/rwc). Members of the panel completed the ASCO
phage CSFs (GM-CSFs) used to prevent or treat febrile neutropenia disclosure form, which requires disclosure of financial and other interests
among patients treated with chemotherapy, to allow the delivery of relevant to the subject matter of the guideline, including relationships with
dose-dense chemotherapy, to mobilize stem cells for transplanta- commercial entities that are reasonably likely to experience direct regulatory or
commercial impact as a result of promulgation of the guideline. Categories for
tion, or to treat radiation injury.
disclosure include Employment; Leadership; Stock or Other Ownership; Hon-
Articles were excluded from the systematic review if they were meeting oraria, Consulting or Advisory Role; Speaker’s Bureau; Research Funding;
abstracts not subsequently published in peer-reviewed journals; editorials, Patents, Royalties, Other Intellectual Property; Expert Testimony; Travel,
commentaries, letters, news articles, case reports, or narrative reviews; or Accommodations, Expenses; and Other Relationships. In accordance with
published in a language other than English. Excluded interventions were as these procedures, the majority of the members of the panel did not disclose
follows: topical CSFs, CSFs as immunotherapy or vaccine adjuvant, perioper- any such relationships.
ative CSFs, CSFs in allogeneic donors, CSFs for the prevention of mucositis,
and granulocyte transfusion. Also excluded were studies in which the treat-
ment arms received different anticancer drugs.
RESULTS
Outcomes of interest varied by clinical question and included
neutropenia- and infection-related outcomes, progression-free and
overall survival (OS), and outcomes related to stem-cell mobilization Characteristics of Studies Identified in the
or transplantation. Literature Search
The guideline recommendations were crafted, in part, using GLIDES A total of 66 publications met eligibility criteria and form the
(Guidelines Into Decision Support) methodology. Ratings for the type and evidentiary basis for the guideline recommendations. Evidence tables
strength of recommendation, evidence, and potential bias are provided with
each recommendation. Detailed information about the methods used to de-
for each clinical question are provided in Data Supplement 1. Forty-
velop this guideline update is available in the Methodology Supplement at one of the publications were RCTs, a majority of which were classified
www.asco.org/guidelines/wbcgf, which includes an overview (eg, Update as having either a low or intermediate risk of bias. These classifications
Committee composition, development process, and revision dates), literature are provided in Data Supplement 2.

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 Recommendations for the Use of WBC Growth Factors

in which all study arms received the same chemotherapy or SCT

RECOMMENDATIONS
conditioning regimen were included. On the basis of the 80 trials with
all-cause mortality results, short-term all-cause mortality was 7.6%
CLINICAL QUESTION 1 with primary prophylaxis and 8.0% without primary prophylaxis (RR,
In adults treated with chemotherapy for a solid tumor or lym- 0.95; 95% CI, 0.84 to 1.08). Results for infection-related mortality
phoma, what factors should clinicians consider when selecting pa- were also null (RR, 0.82; 95% CI, 0.66 to 1.02).19 In contrast, the
tients for primary prophylaxis of febrile neutropenia with a CSF? addition of a G-CSF was associated with a statistically significant
reduction in infection-related mortality in a 2011 meta-analysis of 12
Recommendation 1 RCTs in adults with a solid tumor or lymphoma; risk was 1.5% among
Primary prophylaxis with a CSF starting in the first cycle and patients who received primary prophylaxis with a CSF, compared with
continuing through subsequent cycles of chemotherapy is recom- 2.8% among patients who did not receive primary prophylaxis (RR,
mended in patients who have an approximately 20% or higher risk for 0.55; 95% CI, 0.34 to 0.90).12
febrile neutropenia on the basis of patient-, disease-, and treatment- Adverse effects of CSFs include bone pain, but a randomized trial
related factors. Primary CSF prophylaxis should also be administered of naproxen versus placebo suggested that nonsteroidal anti-
in patients receiving dose-dense chemotherapy when considered ap- inflammatory drugs may reduce the incidence, duration, and severity
propriate. Consideration should be given to alternative, equally effec- of bone pain among CSF-treated patients.11 Naproxen was adminis-
tive, and safe chemotherapy regimens not requiring CSF support tered at a dose of 500 mg twice per day starting on the day of pegfil-
when available. (Type: evidence based, benefits outweigh harms. Evi- grastim administration and continuing for 5 to 8 days.
dence quality: high. Strength of recommendation: strong.)
Clinical Interpretation
Literature Review Update and Analysis In addition to the risk of neutropenic complications associated
Of the 16 publications that addressed primary prophylaxis (eight with chemotherapy regimens in patients who are eligible for clinical
meta-analyses, three clinical practice guidelines, three RCTs, and two trials, the risk and consequences of neutropenic complications may be
systematic reviews), none prompted a change in the level of febrile increased in the elderly, those previously treated with chemotherapy
neutropenia risk warranting primary prophylaxis with a CSF.6-21 The or radiation therapy, and those with medical comorbidities (Table 1).
20% cutoff for febrile neutropenia risk has been maintained from Primary CSF prophylaxis has been consistently associated with signif-
the 2005 guideline based on the evidence from randomized trials, icant reductions in the risk of febrile neutropenia and infectious com-
especially the trial of CSFs in patients with breast cancer,22 in which the plications and also enables delivery of full-dose chemotherapy on
baseline risk for febrile neutropenia was 17%. Independent systematic schedule when considered important in patient management.14 Find-
reviews of eight trials with 2,156 patients with breast cancer confirmed ings regarding infection-related and all-cause mortality have been less
that CSFs reduce the risk of febrile neutropenia, with possible reduc- consistent. The ASCO Panel looks forward to reviewing validated and
tions in the need for hospitalization and all-cause mortality, but with tested, user-friendly risk prediction tools when they are available, but
no effect on infection-related mortality.18 Subsequent studies have at present, none can be fully recommended.
shown that CSFs can reduce the risk of hospitalization for febrile
neutropenia in elderly patients (age ⬎ 65 years) with solid tumors CLINICAL QUESTION 2
from 9% in all cycles to 5%,7 but no other differences, such as in Among adults treated with chemotherapy for a solid tumor or
mortality, have been reported to justify treating a large number of lymphoma, what factors should clinicians use to select patients for
patients who would not benefit and would experience potential tox- secondary prophylaxis of febrile neutropenia with a CSF?
icities and costs.
However, recent publications have provided additional informa-
tion about the likely benefits of primary prophylaxis. Meta-analyses of
RCTs conducted in varying patient populations have confirmed that Table 1. Patient Risk Factors for Febrile Neutropenia
primary prophylaxis with a CSF reduces the risk of febrile neutropenia
Risk Factor
during chemotherapy for a solid tumor or lymphoma.8,9,12,13,18,19
In addition to chemotherapy regimen and type of malignancy, consider the
Primary prophylaxis may also reduce the risk of hospitalization18 and following factors when estimating patient’s overall risk of febrile
infection.8,19 Results for all-cause or infection-related mortality are neutropenia23-25:
less consistent. A meta-analysis of 59 RCTs among patients with solid Age ⱖ 65 years
tumors or lymphoma reported that primary prophylaxis with a Advanced disease
Previous chemotherapy or radiation therapy
G-CSF was associated with a modest reduction in all-cause mortality
Preexisting neutropenia or bone marrow involvement with tumor
compared with no primary prophylaxis (risk ratio [RR], 0.93; 95% CI, Infection
0.90 to 0.96; absolute risk difference, ⫺3.2%; 95% CI, ⫺2.1% to Open wounds or recent surgery
⫺4.2%).14 The greatest benefit was observed among patients who Poor performance status or poor nutritional status
received dose-dense chemotherapy. In studies that evaluated the same Poor renal function
dose and schedule of chemotherapy in different treatment arms, pri- Liver dysfunction, most notably elevated bilirubin
mary prophylaxis did not have a statistically significant effect on mor- Cardiovascular disease
Multiple comorbid conditions
tality.14 Another large meta-analysis considered 148 RCTs of primary
HIV infection
prophylaxis in children or adults who were receiving cancer chemo-
therapy or undergoing stem-cell transplantation (SCT).19 Only RCTs

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 Smith et al

Recommendation 2
Table 2. Patient Risk Factors for Poor Clinical Outcomes Resulting From
Secondary prophylaxis with CSFs is recommended for patients Febrile Neutropenia or Infection28
who experienced a neutropenic complication from a previous cycle of
Risk Factor
chemotherapy (for which primary prophylaxis was not received), in
Sepsis syndrome
which a reduced dose or treatment delay may compromise disease-
Age ⬎ 65 years
free or OS or treatment outcome. In many clinical situations, dose Profound neutropenia (absolute neutrophil count ⬍ 0.1 ⫻ 109/L)
reduction or delay may be a reasonable alternative. (Type: evidence Neutropenia expected to last ⬎ 10 days
based, benefits outweigh harms. Evidence quality: high. Strength of Pneumonia
recommendation: strong.) Invasive fungal infection
Other clinically documented infections
Literature Review Update and Analysis Hospitalization at time of fever
Prior episode of febrile neutropenia
The systematic review provided no new data. In particular,
there were no new data supporting the use of CSFs to maintain
dose-intensity in the treatment of metastatic disease, and the re-
view found no demonstrable benefit in patients with metastatic
lung, small-cell lung, colorectal, hormone-refractory prostate, or
breast cancer.26 To date, there have been no improvements in Clinical Interpretation
disease-free or OS reported for any common cancer with the use of No changes have been made to the 2006 recommendations.
CSFs to maintain dose-intensity, instead of dose reduction. The Table 2 lists factors associated with poor clinical outcomes or compli-
ASCO Panel recognizes that there may be individual patients who cations resulting from febrile neutropenia or infection.28
will not tolerate effective doses of chemotherapy without CSFs, as
noted in the Guideline Disclaimer section. CLINICAL QUESTION 4
In what settings should CSFs be used to increase chemotherapy
Clinical Interpretation dose density?
No changes have been made to the 2006 recommendations.
Recommendation 4
CLINICAL QUESTION 3 Dose-dense regimens with CSF support should only be used
Are there circumstances in which CSFs should be considered for within an appropriately designed clinical trial or if supported by con-
the treatment of neutropenia in adults with cancer? vincing efficacy data. Efficacy data support the use of CSFs with dose-
dense chemotherapy in the adjuvant treatment of high-risk breast
Recommendation 3.1 cancer and with high– dose-intensity methotrexate, vinblastine, doxo-
Therapy for patients with afebrile neutropenia. CSFs should not rubicin, and cisplatin (HD-M-VAC) in urothelial cancer. There are
be routinely used for patients with neutropenia who are afebrile. limited and conflicting data on the value of dose-dense regimens with
(Type: evidence based, benefits outweigh harms. Evidence quality: CSF support in non-Hodgkin lymphoma (NHL), and this cannot
high. Strength of recommendation: strong.) routinely be recommended at this time. (Type: evidence based, bene-
fits outweigh harms. Evidence quality: high for breast cancer and
Recommendation 3.2 lymphoma; intermediate for urothelial cancer. Strength of recom-
Therapy for febrile patients with neutropenia. CSFs should not be mendation: strong for breast cancer and lymphoma; moderate for
routinely used as adjunctive treatment with antibiotic therapy for urothelial cancer.)
patients with fever and neutropenia. However, CSFs should be con-
sidered in patients with fever and neutropenia who are at high risk for Literature Review Update and Analysis
infection-associated complications or who have prognostic factors Twenty publications were identified (16 RCTs, two meta-
that are predictive of poor clinical outcomes. High-risk features in- analyses, one clinical practice guideline, and one single-arm phase II
clude expected prolonged (⬎ 10 days) and profound (⬍ 0.1 ⫻ 109/L) trial).14,16,29-46 In nonmetastatic breast cancer, a 2010 meta-analysis
neutropenia, age ⬎ 65 years, uncontrolled primary disease, pneumo- reported that dose-dense chemotherapy (administered with CSFs)
nia, hypotension and multiorgan dysfunction (sepsis syndrome), in- improves disease-free and OS, particularly among women with hor-
vasive fungal infection, or hospitalization at the time of fever mone receptor–negative disease.30 A benefit was observed in three
development. (Type: evidence based, benefits outweigh harms. Evi- trials of so-called conserved dose-dense chemotherapy (similar doses
dence quality: high. Strength of recommendation: strong.) of drugs in two treatment arms; HR, 0.84; 95% CI, 0.72 to 0.98) and in
six trials of so-called modified dose-dense chemotherapy (different
Literature Review Update and Analysis drugs or doses in two arms; HR, 0.85; 95% CI, 0.75 to 0.96). A survival
New data regarding therapeutic use of CSFs were provided by a benefit of dose-dense chemotherapy was also observed in a phase III
single 2014 meta-analysis.27 Treatment of febrile neutropenia with clinical trial among women with ⱖ four positive lymph nodes.41
antibiotics plus a CSF did not reduce overall mortality compared with Compared with conventionally scheduled epirubicin and cyclophos-
antibiotics alone (hazard ratio [HR], 0.74; 95% CI, 0.47 to 1.16).27 phamide followed by paclitaxel every 3 weeks, an intense dose-dense
However, the addition of a CSF did shorten the duration of neutrope- schedule of sequential epirubicin, paclitaxel, and cyclophosphamide
nia, fever, and antibiotic use and reduce the number of hospital stays every 2 weeks increased the toxicity of treatment but improved event-
⬎ 10 days. free and OS (OS: HR, 0.76; 95% CI, 0.59 to 0.97). More recently,

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 Recommendations for the Use of WBC Growth Factors

doxorubicin plus cyclophosphamide every 2 weeks followed by pacli- dose-dense chemotherapy in lymphoma, lung cancer, ovarian cancer,
taxel every 2 weeks was compared with continuous doxorubicin plus osteosarcoma, and sarcoma have been negative.
cyclophosphamide and/or weekly paclitaxel in the phase III SWOG
(Southwest Oncology Group) S0221 trial. Disease-free survival was CLINICAL QUESTION 5
similar across treatment arms, but OS was highest with dosing every 2 What is the role of CSFs as adjuncts to progenitor-
weeks.31 However, not all studies have reported a benefit of dose- cell transplantation?
dense chemotherapy in nonmetastatic breast cancer. Dose-dense se-
quential epirubicin and paclitaxel followed by intensified CMF
Recommendation 5.1
treatment did not improve disease-free or OS compared with con-
CSFs may be used alone, after chemotherapy, or in combination
comitant epirubicin and paclitaxel followed by intensified CMF treat-
with plerixafor to mobilize peripheral-blood progenitor cells. Choice
ment37; dose-intense neoadjuvant fluorouracil, doxorubicin, and
of mobilization strategy depends in part on type of cancer and type of
cyclophosphamide did not improve pathologic complete response
transplantation. (Type: evidence based, benefits outweigh harms. Ev-
rate compared with conventional neoadjuvant fluorouracil, doxoru-
idence quality: strong. Strength of recommendation: high.)
bicin, and cyclophosphamide29; and neoadjuvant weekly doxorubicin
and daily oral cyclophosphamide did not improve survival or patho-
logic complete response rate compared with standard neoadjuvant Literature Review Update and Analysis
doxorubicin and cyclophosphamide.35 Plerixafor, a CXCR4 receptor antagonist approved by the US
Among patients with newly diagnosed diffuse large B-cell lym- Food and Drug Administration in 2008, is administered in combina-
phoma (DLBCL), two phase III clinical trials reported that a CSF- tion with a G-CSF for the mobilization of stem cells for autologous
supported 14-day cycle of rituximab plus cyclophosphamide, transplantation in patients with NHL and multiple myeloma. The
doxorubicin, vincristine, and prednisolone or prednisone (R-CHOP- combination of a G-CSF and plerixafor has been evaluated in two
14) was not more effective than the standard 21-day cycle (R-CHOP- phase III clinical trials.47,48 Compared with a G-CSF alone, the com-
21). In a UK study of patients age ⱖ 18 years, 2-year OS was 82.7% in bination of a G-CSF and plerixafor increased the number of patients
the R-CHOP-14 group and 80.8% in the R-CHOP-21 group (HR, who reached optimal CD34⫹ cell targets within a specified number of
0.90; 95% CI, 0.70 to 1.15).33 Similarly, in a multinational study of apheresis days. The most common adverse events related to plerixafor
older patients (age 60 to 80 years) with DLBCL, 3-year OS was 69% in were GI disorders and injection site reactions.
the R-CHOP-14 group and 72% in the R-CHOP-21 group (HR, 0.96;
95% CI, 0.73 to 1.26).34 R-CHOP-14 also failed to improve Clinical Interpretation
progression-free or OS in a phase II/III trial of patients with untreated The updated recommendation adds the option of a CSF in com-
indolent B-cell NHL.46 bination with plerixafor for the mobilization of peripheral-blood pro-
A single phase III study assessed dose-intensified chemotherapy genitor cells.
in lung cancer. Among patients with extensive-stage small-cell lung
cancer, dose-intensified carboplatin plus etoposide every 21 days did
Recommendation 5.2
not improve OS or progression-free survival compared with conven-
CSFs should be administered after autologous SCT to reduce
tional carboplatin plus etoposide every 28 days.38 Dose-dense or dose-
the duration of severe neutropenia. (Type: evidence based, benefits
intense therapy supported by G-CSFs also failed to improve OS or
outweigh harms. Evidence quality: high. Strength of recommenda-
progression-free survival in studies of metastatic and locally advanced
tion: strong.)
soft tissue sarcoma (standard v dose-intensified doxorubicin, ifosf-
amide, and dacarbazine),38 high-grade osteosarcoma (3- v 2-week
cycles of cisplatin and doxorubicin),40 and advanced ovarian cancer Recommendation 5.3
(standard v intensified cyclophosphamide combined with epirubicin CSFs may be administered after allogeneic SCT to reduce the
and cisplatin).42 duration of severe neutropenia. (Type: evidence based. Evidence qual-
Promising results with higher dose density or dose-intensity were ity: low. Strength of recommendation: weak.)
reported in urothelial cancer. In a 7-year update of a phase III clinical
trial, HD-M-VAC improved OS and progression-free survival among Literature Review Update and Analysis
patients with advanced urothelial tract tumors. Median and 5-year OS Concerns about use of CSFs after allogeneic transplantation were
were 15.1 months and 21.8% in the HD-M-VAC arm, compared with raised by retrospective studies that reported an increased risk of acute
14.9 months and 13.5% in the M-VAC arm (HR, 0.76; 95% CI, 0.58 to graft-versus-host disease (GVHD) or treatment-related mortality
0.99).43 In a more recent single-arm phase II trial, neoadjuvant dose- among CSF recipients.49-51 However, a 2006 meta-analysis of RCTs
dense M-VAC resulted in significant downstaging among patients found that CSF use after allogeneic SCT reduced the risk of docu-
with muscle-invasive urothelial cancer.32 mented infections and did not have a statistically significant effect on
grade 2 to 4 acute GVHD or treatment-related mortality.52 In the
Clinical Interpretation combined group of autologous and allogeneic transplantation re-
There are now several trials that support the use of CSFs in the cipients, CSF use reduced duration of hospitalization, days of
setting of adjuvant dose-dense chemotherapy for high-risk breast can- parenteral antibiotics, and risk of documented infection, although
cer and one large study supporting CSF use with HD-M-VAC in the association with documented infection was of borderline sta-
urothelial cancer. Outside of a clinical trial, CSF-supported dose- tistical significance (P ⫽ .05). CSFs did not reduce the risk of
dense chemotherapy should be restricted to these settings. Trials of infection-related mortality.

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 Smith et al

Clinical Interpretation Given the low risk of febrile neutropenia in this group, most would not
The updated recommendation adds the option of administering have qualified for CSFs outside of the clinical trial. For these patients at
CSFs after allogeneic transplantation. Studies published since the 2006 low risk of febrile neutropenia, CSFs should not be routinely pre-
recommendation have not confirmed previous reports of increased scribed. However, among patients with NHL, risk of febrile neutrope-
risk of grade 2 to 4 GVHD or mortality in association with CSF use nia across all cycles was 37% in the physician-discretion arm and 15%
after allogeneic transplantation. Data are limited, however, and bene- in the arm receiving pegfilgrastim in all cycles (P ⫽ .004), justifying the
fits of CSF use in this setting seem to be modest. A strong recommen- use of a CSF as primary prophylaxis to prevent febrile neutropenia and
dation regarding CSF use after allogeneic transplantation was not hospitalization. However, the use of pegfilgrastim in all cycles did not
possible at this time. result in fewer chemotherapy dose reductions or delays.

CLINICAL QUESTION 6 Clinical Interpretation

What is the role of CSFs in the setting of acute leukemia or The study by Balducci et al7 provides support for the administra-
myelodysplastic syndromes? tion of pegfilgrastim in patients age ⱖ 65 years who have a high
enough risk of febrile neutropenia to justify CSF use, such as those
Recommendation 6 with lymphoma. Whether patients would achieve as good or better
The Update Committee did not provide recommendations re- results with prophylactic antibiotics is uncertain.53-55
garding the use of CSFs in adults with acute myeloid leukemia or
myelodysplastic syndromes. CLINICAL QUESTION 9
How should CSFs be used in the pediatric population?
CLINICAL QUESTION 7
Should CSFs be avoided in patients receiving concomitant che- Recommendation 9.1
motherapy and radiation therapy? The use of CSFs in pediatric patients will almost always be guided
by clinical protocols. As in adults, a CSF is reasonable as the primary
Recommendation 7 prophylaxis for pediatric patients with a high likelihood of febrile
CSFs should be avoided in patients receiving concomitant che- neutropenia. Similarly, a CSF as secondary prophylaxis or therapy
motherapy and radiation therapy, particularly involving the medias- should be limited to high-risk patients. (Type: evidence based, benefits
tinum. In the absence of chemotherapy, therapeutic use of CSFs may outweigh harms. Evidence quality: high. Strength of recommenda-
be considered in patients receiving radiation therapy alone if pro- tion: strong.)
longed delays secondary to neutropenia are expected. (Type: evidence
based. Evidence quality: high. Strength of recommendation: strong.) Literature Review Update and Analysis
A single meta-analysis evaluated the efficacy of prophylactic
Literature Review Update and Analysis G-CSFs among children with a range of tumor types.56 Prophylactic
There were no new data. G-CSFs reduced the incidence of febrile neutropenia and the duration
of severe neutropenia, hospitalization, and antibiotic use among chil-
Clinical Interpretation dren treated with myelosuppressive chemotherapy. However, pro-
No changes have been made to the 2006 recommendations. phylactic G-CSFs did not decrease documented infections.

CLINICAL QUESTION 8 Clinical Interpretation

Are there CSF recommendations that apply specifically to older The 2006 study continues to be the benchmark for children
adults and that differ from recommendations in younger adults? receiving myelosuppressive chemotherapy. Although there were no
differences in the rates of infection on the basis of CSF use, many
Recommendation 8 pediatric regimens and pediatric clinical trials depend on rapid count
Prophylactic CSFs for patients with diffuse aggressive lymphoma recovery to allow for intensive treatment. For such regimens and such
age ⱖ 65 years treated with curative chemotherapy (CHOP-R) should trials, CSFs should still be used if appropriate.
be considered, particularly in the presence of comorbidities. (Type:
evidence based, benefits outweigh harms. Evidence quality: interme- Recommendation 9.2
diate. Strength of recommendation: moderate.) For pediatric indications in which dose-intense chemotherapy is
known to have a survival benefit, such as Ewing sarcoma, CSFs should
Literature Review Update and Analysis be used to enable the administration of these regimens. (Type: evi-
A single RCT evaluated the efficacy of primary prophylaxis dence based, benefits outweigh harms. Evidence quality: high.
among older patients. The trial enrolled patients age ⱖ 65 years with Strength of recommendation: strong.)
performance status of 0 to 2 and either a solid tumor or NHL.7 Patients
received either pegfilgrastim starting with cycle one for all cycles or Literature Review Update and Analysis
pegfilgrastim initiated after cycle one at the physician’s discretion. Chemotherapy intensification through interval compression was
Pegfilgrastim administered during all cycles reduced the risk of febrile evaluated in an RCT of patients age ⬍ 50 years with newly diagnosed,
neutropenia. Among patients with a solid tumor, the risk of febrile localized Ewing sarcoma.57 Chemotherapy consisted of alternating
neutropenia across all cycles was 10% in the physician-discretion arm cycles of vincristine, doxorubicin, and cyclophosphamide and of ifos-
and 4% in the arm receiving pegfilgrastim in all cycles (P ⫽ .001). famide plus etoposide administered every 21 or 14 days. All patients

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 Recommendations for the Use of WBC Growth Factors

received filgrastim. Primary tumor treatment was provided after four dence for or against the use of CSFs in ALL, although we can extrap-
cycles in the standard arm and after six cycles in the intensified arm. olate from the AML experience. There is a theoretic concern that CSF
Intensified treatment improved event-free survival; 5-year event-free use could stimulate the growth of leukemic blasts or leukemic stem
survival was 73% in the intensified arm and 65% in the standard arm cells, particularly in AML, and increase resistance to therapy and
(P ⫽ .048). OS was also higher in the intensified arm, although this disease progression or relapse in both ALL and AML. The 2007 study58
result was of borderline statistical significance; 5-year OS was 83% in did not demonstrate an increased risk of relapse with CSF use among
the intensified arm and 77% in the standard arm (P ⫽ .056). Toxicity pediatric patients with AML, but exclusion criteria limit the general-
was similar in the two groups. izability of these results. Furthermore, CSF use did not decrease the
risk for infectious complications. The routine use of CSF cannot be
Clinical Interpretation recommended for children with de novo AML and, by extension, for
In North America, as a result of these findings, the current stan- children with ALL.
dard of care for pediatric patients with Ewing sarcoma outside of a
clinical trial is myelosuppressive chemotherapy every 2 weeks when CLINICAL QUESTION 10
tolerated. This is not feasible without CSF support. What are recommendations for the initiation, duration, dosing,
and administration of CSFs?
Recommendation 9.3
CSFs should not be used in pediatric patients with nonre- Recommendations
lapsed acute lymphoblastic leukemia (ALL) or nonrelapsed acute Recommendations for the administration of filgrastim, tbo-
myeloid leukemia (AML) who do not have an infection. (Type: filgrastim, filgrastim-sndz, pegfilgrastim, and sargramostim are sum-
informal consensus. Evidence quality: intermediate. Strength of marized in Table 3.
recommendation: moderate.)
Literature Review Update and Analysis
Literature Review Update and Analysis Recent randomized trials have addressed issues related to the
Evidence regarding the effects of prophylactic G-CSFs in pediat- duration and timing of G-CSF prophylaxis. The importance of con-
ric ALL or AML is limited, but a 2007 randomized trial reported few tinuing prophylaxis through all cycles of chemotherapy was assessed
benefits with prophylactic G-CSFs after induction therapy for de novo among women with breast cancer. Women who received pegfilgras-
pediatric AML. G-CSFs shortened the duration of neutropenia but did tim prophylaxis during only the first two cycles of chemotherapy were
not decrease the risk of febrile neutropenia, microbiologically docu- more likely to develop febrile neutropenia than women who received
mented infections, or infection-related mortality.58 In the intent-to- pegfilgrastim prophylaxis during all six cycles of chemotherapy (36%
treat analysis, 5-year event-free survival was 58% with G-CSFs and v 10%, respectively).59 The timing of pegfilgrastim (same day as che-
59% without G-CSFs (P ⫽ .66). motherapy v next day) was evaluated in randomized phase II trials of
patients with breast cancer and lymphoma. Same-day pegfilgrastim
Clinical Interpretation resulted in a longer but statistically noninferior duration of severe
The previous ASCO guideline noted that use of CSFs in children neutropenia compared with next-day pegfilgrastim.60 Administration
with ALL should be considered with caution. There is little new evi- of pegfilgrastim on day 2 versus day 4 was evaluated in a small trial

Table 3. Dosing and Administration of CSFs

Agent Dosing and Administration

Filgrastim Filgrastim should be started 1 to 3 days after administration of myelotoxic chemotherapy; in setting of high-dose therapy and autologous
stem-cell rescue, filgrastim can be started 1 to 5 days after administration of high-dose therapy; filgrastim should be continued until
reaching ANC ⱖ 2 to 3 ⫻ 109/L; for PBPC mobilization, filgrastim should be started ⱖ 4 days before first leukapheresis procedure
and continued until last leukapheresis
In adults, recommended filgrastim dose is 5 ␮g/kg per day for all clinical settings other than PBPC mobilization; in setting of PBPC
mobilization, dose of 10 ␮g/kg per day may be preferable; preferred route of filgrastim administration is subcutaneous
Filgrastim-sndz Same as for filgrastim
Tbo-filgrastim Tbo-filgrastim should be started 1 to 3 days after administration of myelotoxic chemotherapy; in adults, recommended tbo-filgrastim
dose is 5 ␮g/kg per day; preferred route of tbo-filgrastim administration is subcutaneous
Pegfilgrastim Pegfilgrastim 6 mg should be administered once 1 to 3 days after chemotherapy if possible; because some patients will not be able to
return for dose of pegfilgrastim because of distance or immobility, for instance, alternatives to consider may include self-administered
filgrastim or tbo-filgrastim or same-day pegfilgrastim, recognizing that although same-day pegfilgrastim is not as effective as later
pegfilgrastim, it is better than no pegfilgrastim; pegfilgrastrim is also available in a timed automated-inject device that delivers 6 mg
of pegfilgrastrim subcutaneously, 27 hours after it is placed on skin and activated; pegfilgrastim is not currently indicated for stem-cell
mobilization; 6-mg formulation should not be used in infants, children, or small adolescents who weigh ⬍ 45 kg
Sargramostim Because GM-CSFs have been licensed specifically for use in mobilization and after transplantation of autologous PBPCs, after autologous or
allogeneic bone marrow transplantation, and for AML, manufacturer’s instructions for administration are limited to those clinical settings;
GM-CSFs should be initiated on day of bone marrow infusion and not ⬍ 24 hours after last chemotherapy and 12 hours after most recent
radiotherapy; GM-CSFs should be continued until ANC ⬎ 1.5 ⫻ 109/L for 3 consecutive days is achieved; drug should be discontinued early
or dose reduced by 50% if ANC increases to ⬎ 20 ⫻ 109/L; recommended dose for adults is 250 ␮g/m2 per day

Abbreviations: AML, acute myeloid leukemia; ANC, absolute neutrophil count; CSF, colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating
factor; PBPC, peripheral-blood progenitor cell.

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 Smith et al

of older patients with aggressive NHL61 and a larger trial of women filgrastim.68-71 In a meta-analysis of the three trials, the adjusted dif-
with node-positive breast cancer.62 Although the NHL trial sug- ference in the rate of first-cycle febrile neutropenia between tbo-
gested that day-4 pegfilgrastim may reduce the incidence of severe filgrastim and filgrastim was 1.7% (95% CI, ⫺3.8% to 7.1%), again
leukocytopenias, the breast cancer trial reported that day-2 and demonstrating no statistically significant difference between the two
day-4 pegfilgrastim produced similar rates of febrile neutropenia, drugs for this outcome.71
infection, and grade 4 leukopenia. Filgrastim-sndz, approved in March 2015, was the first biosimilar
product approved in the United States. Approval was based on struc-
Clinical Interpretation tural and functional characterization, animal data, human pharmaco-
The recommendation for pegfilgrastim administration includes kinetic and pharmacodynamic data, clinical immunogenicity data,
off-label use (administration of pegfilgrastim on same day as chemo- and other clinical safety and effectiveness data. Filgrastim and
therapy in certain circumstances). Evidence suggests that pegfilgras- filgrastim-sndz were compared in a phase III noninferiority trial. Full
tim administered 1 to 3 days after chemotherapy results in a lower risk results from the trial had not been published at the time the ASCO
of infection than pegfilgrastim administered on the same day as che- guideline was submitted for publication. However, an abstract was
motherapy,60 but clinicians should not be prohibited from using published as part of the 56th Annual Meeting of the American Society
same-day pegfilgrastim if it provides the only feasible means of CSF of Hematology (online publication only).72 The study enrolled
administration for certain patients. women who were eligible for neoadjuvant or adjuvant docetaxel,
doxorubicin, and cyclophosphamide chemotherapy for breast cancer.
CLINICAL QUESTION 11 Study participants were randomly assigned to one of four groups:
Do CSFs differ in efficacy? filgrastim-sndz in all cycles; filgrastim-sndz in cycle one, then alternat-
ing filgrastim and filgrastim-sndz in subsequent cycles; filgrastim in
Recommendation 11 cycle one, then alternating filgrastim-sndz and filgrastim in subse-
Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and quent cycles; or filgrastim in all cycles. Filgrastim-sndz was noninfe-
other biosimilars as they become available) can be used for the preven- rior to filgrastim with respect to duration of severe neutropenia after
tion of treatment-related febrile neutropenia. The choice of agent cycle one chemotherapy. Switching between the two drugs did not
depends on convenience, cost, and clinical situation. There have been seem to affect efficacy or safety.
no additional data comparing G-CSF and GM-CSF since the 2006
update; therefore, there has been no change in the recommendation Clinical Interpretation
regarding their therapeutic equivalency. (Type: evidence based, bene- Filgrastim, tbo-filgrastim, filgrastim-sndz, and pegfilgrastim
fits outweigh harms. Evidence quality: high. Strength of recommen- are all effective in the reduction of the risk of febrile neutropenia.
dation: strong.) Choice of agent will depend on factors such as convenience and
cost and may in some cases be dictated by the patient’s treatment
Literature Review Update and Analysis plan (eg, weekly chemotherapy).
In a 2011 meta-analysis of primary G-CSFs in adults undergoing
chemotherapy for a solid tumor or lymphoma, filgrastim, pegfilgras- CLINICAL QUESTION 12
tim, and lenograstim (which is not currently available in United What is the role of CSFs in the treatment of radiation injury?
States) each significantly reduced the risk of febrile neutropenia.9 A
comparison of pegfilgrastim and filgrastim was based on five clinical Recommendation 12
trials and suggested that pegfilgrastim was more effective than filgras- Current recommendations for the management of patients ex-
tim at reducing the risk of febrile neutropenia (RR, 0.66; 95% CI, 0.44 posed to lethal doses of total-body radiotherapy, but not doses high
to 0.98).9 A number of small RCTs comparing pegfilgrastim and enough to lead to certain death as a result of injury to other organs,
filgrastim have also been conducted in other patient populations, include the prompt administration of CSFs or pegylated G-CSFs.73-75
including pediatric patients63,64 and adults who have undergone au- (Type: formal consensus [by others], benefits outweigh harms. Evi-
tologous SCT.65-67 A statistically significant benefit of pegfilgrastim dence quality: intermediate. Strength of recommendation: moderate.)
over filgrastim in the incidence of febrile neutropenia was reported
after a study of patients with multiple myeloma who had under- Literature Review Update and Analysis
gone autologous peripheral-blood SCT, but the sample size and the This question has not been addressed by placebo-controlled trials
differing timing of G-CSF administration limit the conclusions in humans and, because of ethical considerations, is unlikely to be
that can be drawn from this study; pegfilgrastim was started on day addressed. An expert panel convened by the WHO in 2009 considered
1 after stem-cell infusion, and filgrastim was started on day 5 after data from animal experiments, case series and case reports, and studies
stem-cell infusion.67 of patients treated with chemotherapy and made a strong consensus
Tbo-filgrastim, a nonglycosylated recombinant methionyl hu- recommendation for the administration of GM-CSFs or G-CSFs in
man granulocyte colony-stimulating growth factor, was approved by the management of hematopoietic syndrome resulting from exposure
the US Food and Drug Administration in 2012 for reduction in the to ionizing radiation.73 The panel noted that health care providers
duration of severe neutropenia in patients with nonmyeloid malig- “should consider initiating cytokine therapy for exposures of ⱖ 2 Gy
nancies receiving myelosuppressive anticancer drugs associated with a and/or a significant decrease in the absolute lymphocyte count, or
clinically significant incidence of febrile neutropenia. RCTs conducted when it is anticipated that neutropenia of less than 0.5 ⫻ 109 cells per
in patients with breast cancer, lung cancer, and NHL have suggested liter will persist for ⱖ 7 days.”73p6 The recommended timing of cyto-
that the safety and efficacy of tbo-filgrastim are similar to those of kine initiation was within 24 hours of exposure.

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 Recommendations for the Use of WBC Growth Factors

Clinical Interpretation use among women with breast cancer is less common in nonwhites88
Accidental or intentional (eg, resulting from terrorist attack or and women of low socioeconomic status89 and varies substantially by
war) total-body radiation leads to probable or certain death resulting geographic region.88 Awareness of these disparities in access to care
from bone marrow failure at doses of 3 to 10 Gy without supportive should be considered in the context of this clinical practice guideline,
care, CSFs, and/or bone marrow transplantation.76-78 Doses below and health care providers should strive to deliver the highest level of
that level are almost always survivable with excellent nursing care; cancer care to these vulnerable populations.
higher doses are lethal because of injury to other organs, such as the GI
tract. The chance of mortality from any radiation dose rises with
combined injuries to the skin, lungs, and so on.79 MULTIPLE CHRONIC CONDITIONS
Hematopoietic growth factors can increase the survival, prolifer-
ation, amplification, and differentiation of granulocyte progenitors to Creating evidence-based recommendations regarding the treatment
produce neutrophils. Although no prospective randomized trials have of patients with multiple chronic conditions can be challenging. Pa-
been carried out to determine the benefit of hematopoietic growth tients with multiple chronic conditions are a complex and heteroge-
factors in humans exposed to accidental or intentional radiation in- neous population and are frequently excluded from clinical trials.
jury, they have been used in radiation accident victims, and neutrophil In the case of febrile neutropenia, observational studies have
recovery seems to have been hastened in 25 of 28 patients (from provided important information about the impact of comorbidity. A
Radiation Emergency Assistance Center/Training Site registry). In 2014 systematic review reported that the presence of comorbid con-
animal models, prompt administration of hematopoietic growth fac- ditions increased the risk of febrile neutropenia among patients with
tors after otherwise lethal total-body radiation exposure has dramati- cancer treated with chemotherapy.23 Both the number and types of
cally increased survival.80-85 comorbidities may be important to consider. Among patients with
breast, lung, prostate, or colorectal cancer in the SEER-Medicare da-
tabase, the risk of febrile neutropenia increased with the number of
PATIENT AND CLINICIAN COMMUNICATION comorbid conditions.24 Compared with patients with no comorbid
For adults with a solid tumor or lymphoma who receive chemother- conditions, patients with ⱖ three comorbid conditions had an 81%
apy regimens that carry a high risk of febrile neutropenia (ⱖ 20%), increased risk of febrile neutropenia. The presence of renal, hepatic, or
primary prophylaxis substantially reduces the risk of a serious treat- cardiovascular disease has been associated with febrile neutropenia or
ment complication and is recommended for most patients. However, febrile neutropenia–related hospitalization in patients with NHL
for many commonly used chemotherapy regimens, the risk of febrile treated with CHOP-based chemotherapy.90,91 The optimal approach
neutropenia is ⬍ 20%, and more individualized decisions about CSF to incorporating comorbidity information in risk prediction tools
use are required. The risk of neutropenic complications and the im- continues to be explored, but comorbidity remains an important
portance of primary prophylaxis will vary with factors such as age, predictor of febrile neutropenia, even after accounting for factors such
comorbidity, and other treatment-related considerations. It is impor- as cancer type and age.25
tant that in addition to understanding the evidence-based benefits and
other risks of treatment, patients learn about the risk of febrile neutro-
penia as part of routine chemotherapy education. COST IMPLICATIONS
The most common adverse effect of G-CSFs is bone pain, and
patients should be encouraged to report this and other adverse effects Although the 2006 Update Committee extensively discussed the cost
to their treatment team. Acetaminophen and nonsteroidal anti- of CSFs, it recommended CSF use when the febrile neutropenia rate
inflammatory drugs are common first-line options for the prevention was approximately ⱖ 20% based on clinical impact alone, because of
or treatment of G-CSF–related bone pain in adults. Other approaches the consensus that reduction in febrile neutropenia itself was an im-
that may be considered include antihistamines, opioids, and G-CSF portant clinical outcome. Since the 2006 update, original data from
dose reduction.86 randomized trials have been limited.
Cost-effectiveness analyses of primary versus secondary prophy-
laxis with G-CSFs have produced varying results. In a model that
HEALTH DISPARITIES considered three different strategies (no primary prophylaxis, 10 days
of filgrastim, or one dose of pegfilgrastim) among patients receiving
Although ASCO clinical practice guidelines represent expert recom- R-CHOP-21 for DLBCL, primary prophylaxis was not cost effective
mendations on the best practices in disease management to provide from the perspective of a publicly funded health care system. Costs
the highest level of cancer care, it is important to note that many associated with no primary prophylaxis, filgrastim prophylaxis, and
patients have limited access to medical care. Racial and ethnic dispar- pegfilgrastim prophylaxis were Canadian $7,314, $13,947, and
ities in health care contribute significantly to this problem in the $16,290, respectively.92 The incremental cost effectiveness for primary
United States. Patients with cancer who are members of racial/ethnic prophylaxis with filgrastim versus no primary prophylaxis was Cana-
minorities disproportionately experience comorbidities, experience dian $5,796,000 per quality-adjusted life-year, far outside accepted
more substantial obstacles to receiving care, are more likely to be bounds. In a United Kingdom– based model of cost among patients
uninsured, and are at greater risk of receiving care of poor quality than with breast cancer, the most cost-effective strategy (primary prophy-
other Americans.87 Many other patients lack access to care because of laxis, secondary prophylaxis, or no G-CSFs) depended on patient
their geographic location or distance from appropriate treatment fa- characteristics and risk of febrile neutropenia. Of the three types of
cilities. Analyses of SEER-Medicare data suggest that first-cycle CSF G-CSFs evaluated, pegfilgrastim seemed to be more cost effective than

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 Smith et al

filgrastim or lenograstim.93 A cost benefit may be more apparent in the equivalent efficacy without the need for CSF support, these alternative
United States, as a result of higher health care costs,94 but cost effec- regimens should be used.
tiveness will vary by factors such as the risk of febrile neutropenia.
Randomized trials have assessed the efficacy of reduced dosages GUIDELINE IMPLEMENTATION
or less frequent administration of prophylactic G-CSFs. A study in the
United Kingdom randomly assigned 172 patients with breast cancer ASCO guidelines are developed for implementation across health
to primary prophylaxis with a G-CSF during all six cycles of chemo- settings. Barriers to implementation include the need to increase
therapy or during just the first two cycles. Prophylactic G-CSF during awareness of the guideline recommendations among front-line prac-
only the first two cycles of chemotherapy was cost saving but titioners and survivors of cancer and caregivers and also to provide
resulted in a higher rate of febrile neutropenia than a G-CSF during adequate services in the face of limited resources. The guideline Bot-
all cycles (36% v 10%, respectively).95 A reduced dose of lenogras- tom Line Box was designed to facilitate implementation of recom-
tim (50 ␮g/body) was evaluated in a small cross-over study of mendations. This guideline will be distributed widely through the
patients with NHL in Japan and compared favorably with a 75-␮g/ ASCO Practice Guideline Implementation Network. ASCO guide-
body dose of filgrastim.96 In the absence of more definitive data, lines are posted on the ASCO Web site and most often published in
the consensus of the 2015 Update Committee is that clinicians Journal of Clinical Oncology and Journal of Oncology Practice.
should adhere to current product labeling.
There do seem to be opportunities to improve G-CSF use in ADDITIONAL RESOURCES
the community. The overuse of CSFs was one of the 2012 ASCO
Choosing Wisely recommendations: “Don’t use white cell stimu- More information, including a Data Supplement with additional evi-
lating factors for primary prevention of febrile neutropenia for dence tables, a Methodology Supplement with information about
patients with less than 20% risk for this complication.”97p3 To evidence quality and strength of recommendations, slide sets, and
reduce CSF use in patients receiving low-risk chemotherapy regi- clinical tools and resources, is available at www.asco.org/
mens, Fishman et al98 instituted real-time peer-to-peer consulta- guidelines/wbcgf. Patient information is available at www.cancer.net.
tion regarding pegfilgrastim use. Among patients receiving low- Visit www.asco.org/guidelineswiki to provide comments on the
risk chemotherapy regimens, pegfilgrastim use decreased from 52 guideline or to submit new evidence.
units in the fourth quarter of 2009 to 15 units in the third quarter of
2010 (71% decrease) with no adverse consequences. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
Although questions remain about the cost effectiveness of OF INTEREST
G-CSFs in certain settings, the 2015 Update Committee has reiterated
the position that G-CSF prophylaxis should be driven by clinical Disclosures provided by the authors are available with this article at
considerations and not by cost. CSF use is recommended when the www.jco.org.
febrile neutropenia rate is ⱖ 20% based on clinical impact alone,
because of the consensus that reduction in febrile neutropenia itself is AUTHOR CONTRIBUTIONS
an important clinical outcome. The 2015 Update Committee has
recognized, again, that these are expensive agents with the potential for Manuscript writing: All authors
overuse. As stated, when alternative regimens are available that offer Final approval of manuscript: All authors

colony stimulating factor to reduce the incidence of Community Oncology Program research base. J Clin
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 Recommendations for the Use of WBC Growth Factors

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ 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 jco.ascopubs.org/site/ifc.
Thomas J. Smith Travel, Accommodations, Expenses: Roche
Stock or Other Ownership: United Healthcare
James Khatcheressian
Kari Bohlke No relationship to disclose
No relationship to disclose
Natasha Leighl
Gary Lyman Research Funding: Novartis Canada (Inst)
Consulting or Advisory Role: Dendreon
Research Funding: Amgen (Inst) Cheryl Perkins
No relationship to disclose
Kenneth Carson
Honoraria: Genentech, Spectrum Pharmaceuticals, Celgene, Millennium George Somlo
Pharmaceuticals Consulting or Advisory Role: Pfizer, Genentech, Novartis, Abbvie,
Consulting or Advisory Role: Celgene, Spectrum Pharmaceuticals, Celgene, Quest Diagnostics, NanoString Technologies
Millennium Pharmaceuticals, Genentech Speakers’ Bureau: Jansen, Millennium Pharmaceuticals
Speakers’ Bureau: Genentech Research Funding: Celgene (Inst), Genentech (Inst)
Research Funding: Millennium Pharmaceuticals, Kyowa-Hakko Kirin Other Relationship: Abbvie (steering committee)
Expert Testimony: Abbvie James Wade
Travel, Accommodations, Expenses: Spectrum Pharmaceuticals,
Employment: Johnson & Johnson (I)
Celgene, Genentech
Stock or Other Ownership: Seattle Genetics, Celgene
Jeffrey Crawford
Antoinette Wozniak
Consulting or Advisory Role: Amgen, Bayer, Boehringer Ingelheim, Eli
Honoraria: Xcenda, Biodesix
Lilly, Gilead, Hospira, Ono Pharmaceutical, Aveo, Merck, Novartis
Consulting or Advisory Role: Genentech/Roche, Boehringer Ingelheim,
Research Funding: Amgen (Inst), AstraZeneca (Inst), GTx (Inst),
Novartis, AstraZeneca
MedImmune (Inst), Morphotek (Inst), Clovis (Inst), Fibrogen (Inst)
Speakers’ Bureau: Biodesix
Scott Cross Research Funding: Astex Therapeutics
No relationship to disclose
James O. Armitage
John Goldberg Leadership: Tesaro Bio
Consulting or Advisory Role: Health Affairs Consulting or Advisory Role: GlaxoSmithKline, Roche, Spectrum
Research Funding: ArQule Pharmaceuticals, ZIOPHARM Oncology, Conatus IDMC, Celgene

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 Smith et al

Acknowledgment
We thank Supriya Mohile, Mariana Chavez Mac Gregor, Benjamin Djulbegovic, and the Clinical Practice Guidelines Committee for their
thoughtful reviews of and insightful comments on this guideline document.

Appendix

Table A1. Update Committee Membership

Member Affiliation/Location
Thomas J. Smith, MD (co-chair) Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
James O. Armitage, MD (co-chair) University of Nebraska Medical Center, Omaha, NE
Gary H. Lyman, MD, MPH Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA
Kenneth R. Carson, MD, PhD Washington University, St Louis, MO
Jeffrey Crawford, MD Duke Medicine, Durham, NC
Scott J. Cross, MD Virginia Oncology Associates, Norfolk, VA
John M. Goldberg, MD University of Miami Miller School of Medicine, Miami, FL
Natasha B. Leighl, MD, MMSc Princess Margaret Cancer Centre, Toronto, Ontario, Canada
James L. Khatcheressian, MD (PGIN representative) Virginia Cancer Institute, Richmond, VA
Cheryl L.Perkins, MD (patient representative) Dallas, TX
George Somlo, MD City of Hope National Medical Center, Duarte, CA
James L. Wade, MD Cancer Care Specialists of Central Illinois, Decatur, IL
Antoinette J. Wozniak, MD Karmanos Cancer Institute, Detroit, MI

NOTE. American Society of Clinical Oncology staff: Kari Bohlke, ScD.

Abbreviation: PGIN, Practice Guideline Implementation Network.

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