Download 2016 CCO GCSF Recommendations Report

Cancer Care Ontario GCSF Recommendations 2016
Executive Summary
The following are recommendations regarding the use of granulocyte colony-stimulating factor (G-CSF) for the
primary prophylaxis of febrile neutropenia (FN) in adult patients. Additionally, antibiotic, antifungal, and antiviral
prophylaxis will be discussed where applicable. The G-CSF Working Group is comprised of clinicians with expertise
in the management of FN in solid and hematologic malignancies from Ontario, Newfoundland and British
Columbia. The Group reviewed the current relevant guidelines (ASCO 2006, 2015, NCCN 2012, ESMO 2010,
EORTC 2010, Eastern Health 2013), primary literature and consulted clinical disease site group (DSG) oncology
experts to make comprehensive recommendations for the use of G-CSF in the primary prophylactic management
of FN based on risk classifications (high >20%, moderate = 10-20%, low < 10%). Additionally, an FN risk was
determined for all systemic chemotherapy regimens with curative intent (Appendix 2). Regimens with curative
intent includes neoadjuvant and adjuvant chemotherapy treatment. This report summarizes the G-CSF
recommendations by the Working Group. Supporting literature is presented within the body of this report.
Recommendations for primary prophylaxis in adult patients at High Risk (>20%) of FN receiving chemotherapy
with curative intent
1. A G-CSF agent should be prescribed for all regimens with a high risk of FN.
 Filgrastim 300 mcg (if < 90 kg) or 480 mcg (if ≥90 kg or <90kg with an inadequate response to 300
mcg) subcutaneously (rounded to the nearest full vial size) daily for 7 to 10 days starting 24-72 hours
post completion of chemotherapy
o Interim monitoring of ANC is generally not recommended unless the patient’s ANC is > 10 x
109/L at the subsequent cycle of treatment or if the patient experiences significant bone pain
during GCSF treatment.
 Interim monitoring may be considered for the first cycle at the clinician’s discretion
o There is insufficient evidence to recommend the use of filgrastim to elevate neutrophil counts
immediately prior to chemotherapy to achieve a minimum ANC.
OR
 Pegfilgrastim 6 mg subcutaneously once to start 24-72 hours post completion of chemotherapy. Not
to be given at less than 14 day intervals.
If infection develops, antimicrobials may be used concurrently with G-CSF therapy.
2. Where the use of G-CSF is not possible, an antimicrobial agent should be prescribed. Fluoroquinolones
are preferred over sulfamethoxazole-trimethroprim (SMX-TMP), except in the case of Pneumocystis
Jiroveci pneumonia prophylaxis (PJP) with fludarabine-based regimens. The timing of initiation of an
antimicrobial is regimen-depend and should cover the duration of the expected nadir.
 Levofloxacin 500 mg po daily x 7-10 days OR
 Ciprofloxacin 500 mg – 750 mg po q12hr x 7-10 days OR
 Sulfamethoxazole-trimethoprim 160 mg/800 mg po q12h x 7 to 10 days
Note: The dose of SMX-TMP for PJP prophylaxis is 80 mg/400 mg po daily or 160 mg/800 mg po q12h three
times a week for the duration of fludarabine-based regimens. If an antimicrobial is required, a
fluoroquinolone should be used for the prophylaxis of FN in addition to sulfamethoxazole-trimethoprim.
3. The addition of an antifungal should be considered for high-risk hematologic regimens
 Fluconazole 400 mg po once daily x duration of neutropenia OR
 Posaconazole loading dose of 300 mg (three 100 mg tablets) twice a day on the first day, then
300 mg (three 100 mg tablets) once a day thereafter OR posaconazole suspension 200 mg po TID x
duration of neutropenia (duration of use may vary according to indication)
4. Consider antiviral prophylaxis for regimens containing bortezomib and fludarabine.
 Acyclovir 400 mg po BID continuously (usually until completion of chemotherapy)
Recommendations for primary prophylaxis in patients at Moderate Risk (10% – 20%) of FN
1. If G-CSF is determined to be appropriate based on patient risk assessment (see Table 1), consider
recommendations described above for High Risk.
2. If G-CSF is determined to be appropriate based on patient risk assessment but is not possible, consider
antimicrobial prophylaxis described above for High Risk.
3. Use of antifungal prophylaxis may be considered during the period of neutropenia.
4. Consider antiviral prophylaxis for regimens containing bortezomib and fludarabine.

Acyclovir 400 mg po BID continuously (usually until completion of chemotherapy)
Recommendations for primary prophylaxis in patients at Low Risk (<10%) of FN
1. The use of G-CSF products is not recommended in this patient population.
2. Standard use of antibiotics is not recommended in this patient population.
3. Use of antifungal prophylaxis may be considered during the period of neutropenia.
4. Use of antiviral prophylaxis should be based on patient-specific history of herpes simplex viral infections
and should be considered if patient is at high risk of a reactivation of latent viral infection during period of
neutropenia.
Recommendation for secondary prophylaxis of febrile neutropenia
 If a patient experiences an episode of FN where no G-CSF was used for primary prophylaxis, G-CSF use
should be considered if further infections in the next treatment cycle are considered life-threatening; a
dose reduction would bring the dose below the studied/effective threshold; or if a lack of protocol
adherence compromises the cure rates or disease free or overall survival.
 A dose reduction may be a reasonable alternative to using G-CSF in secondary prophylaxis if the threshold
for efficacy is not reached, or in the case of chemotherapy with a low FN risk.
 If a patient experiences FN despite receiving primary FN prophylaxis with G-CSF, it is recommended to
continue G-CSF use with the following chemotherapy cycles as well as consideration of dose reduction or
change in treatment regimen.
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Cancer Care Ontario GCSF Recommendations 2016
Background/Introduction
Febrile neutropenia (FN) is a common complication of treatment with myelosuppressive chemotherapy.1 There
are a number of clinical implications that impact treatment outcomes for a patient who develops FN including but
not limited to: decreased total chemotherapy dose, delayed chemotherapy treatment schedule,
hospitalization/prolonged hospitalization and broad-spectrum antimicrobial exposure.1 Risk of FN is stratified
according to high (>20%), moderate (10-20%) and low (<10%) risk through consideration of patient,
chemotherapy, and cancer related characteristics to determine each patient’s overall risk.1 Treatment with
granulocyte colony-stimulating factor (G-CSF) is one way to help prevent a patient’s first FN episode (primary
prophylaxis).1
The Cancer Quality Counsel of Ontario (CQCO), an advisor to Cancer care Ontario and the Ministry of Health and
Long-Term Care on cancer care in Ontario, assesses many quality indicators including number of unplanned
hospital visits, emergency visits and the indications for these visits in Ontarians after receiving adjuvant
chemotherapy.2 In 2014, 42% and 45% of patients receiving adjuvant chemotherapy for breast or colon cancer,
respectively, had an unplanned visit to the emergency department (ED); 2% of each group being directly admitted
to hospital for medical treatment.2 Of the patients presenting to the ED in each of these disease groups, one third
of patients were admitted to hospital after physician assessment and about 47% had a second visit to the ED
during a course of chemotherapy treatment.2 The most common reasons for hospital visits were neutropenia,
fever or infection in breast cancer and colon cancer patients (43% and 23% respectively).
In 2012, the American Society of Clinical Oncology (ASCO) released a “Top Five” list of procedures and/or
treatments that physicians and patients should question due to their common clinical use despite a lack of
support in the current literature.3 Among these five procedures/treatments is the use of G-CSF for the prevention
of FN in patients with < 20% risk of this complication.3 G-CSF products are expensive medications and have a
number of potentially serious adverse events, including moderate to severe bone pain and has been associated
with an increased risk of Acute Myeloid Leukemia/Myelodysplastic Syndrome (AML/MDS), making unnecessary
use ill-advised in a person centered care model.1,4
As highlighted by CQCO and ASCO, there is a great need for guidance in the area of appropriate G-CSF use in
Ontario, across Canada, and worldwide. This report makes recommendations to improve the rates of G-CSF use in
patients at high risk of FN, provides guidance for G-CSF use in patients at moderate risk of FN, and reduces
inappropriate G-CSF use in patients at low risk of FN. This report will not discuss: FN risk of stem cell transplant
specific chemotherapy, treatment of FN, or extensive review of secondary prophylaxis of FN. Recommendations
for the use of antimicrobials, antifungals and antivirals will be outlined where appropriate.
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Recommendations for the Prevention of Febrile Neutropenia in Adult Patients
Receiving Chemotherapy with Curative Intent
High FN Risk (>20%)
1. A G-CSF agent should be prescribed for all regimens with a high risk of FN.
 Filgrastim 300 mcg (if < 90 kg) or 480 mcg (if ≥90 kg or <90kg with an inadequate response to 300
mcg) subcutaneously (rounded to the nearest full vial size) daily for 7 to 10 days starting 24-72 hours
post completion of chemotherapy
o Interim monitoring of ANC is generally not recommended unless the patient’s ANC is > 10 x
109/L at the subsequent cycle of treatment or if the patient experiences significant bone pain
during GCSF treatment.
 Interim monitoring may be considered for the first cycle at the clinician’s discretion
o There is insufficient evidence to recommend the use of filgrastim to elevate neutrophil counts
immediately prior to chemotherapy to achieve a minimum ANC.
OR
 Pegfilgrastim 6 mg subcutaneously once to start 24-72 hours post completion of chemotherapy. Not
to be given at less than 14 day intervals.
If infection develops, antimicrobials may be used concurrently with G-CSF therapy.
3. Where the use of G-CSF is not possible, an antimicrobial agent should be prescribed. Fluoroquinolones
are preferred over sulfamethoxazole-trimethroprim (SMX-TMP), except in the case of Pneumocystis
Jiroveci Pneumonia prophylaxis (PJP) with fludarabine-based regimens. The timing of initiation of an
antimicrobial is regimen-depend and should cover the duration of the expected nadir.
 Levofloxacin 500 mg po daily x 7-10 days OR
 Ciprofloxacin 500 mg – 750 mg po q12hr x 7-10 days OR
 sulfamethoxazole-trimethoprim 160 mg/800 mg po q12h x 7 to 10 days
Note: The dose of SMX-TMP for PJP prophylaxis is 80 mg/400 mg po daily or 160 mg/800 mg po q12h three
times a week for the duration of fludarabine-based regimens. If an antimicrobial is required, a
fluoroquinolone should be used for the prophylaxis of FN in addition to sulfamethoxazole-trimethoprim.
4. The addition of an antifungal should be considered for high-risk hematologic regimens
 Fluconazole 400 mg po once daily x duration of neutropenia OR
 Posaconazole loading dose of 300 mg (three 100 mg tablets) twice a day on the first day, then
300 mg (three 100 mg tablets) once a day thereafter OR posaconazole suspension 200 mg po TID x
duration of neutropenia (duration of use may vary according to indication)
5. Consider antiviral prophylaxis for regimens containing bortezomib and fludarabine.
 Acyclovir 400 mg po BID continuously (usually until completion of chemotherapy)
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Duration of Filgrastim Use
The optimal duration of filgrastim use will likely vary depending on the regimen and patient response. The
product monograph recommends administration for 10 – 14 days while clinical practice suggests that 7 to 10 days
may be sufficient.
A study using American healthcare claims data found that less than 7 days of filgrastim was associated with an
increased risk of chemotherapy-induced neutropenic complications versus ≥7 days of treatment.5 A single-centre
retrospective Canadian trial of women who received anthracycline- or taxane-containing chemotherapy noted a
higher than expected FN incidence of 28% among patients who received primary prophylaxis with filgrastim for a
median of 7 days.6 Similarly, 6 days of daily G-CSF as primary prophylaxis did not significantly reduce FN
compared with primary antibiotic prophylaxis in a large study of women receiving cycles of doxorubicincyclophosphamide-docetaxel. In contrast, pegfilgrastim use was associated with significantly less FN.7 Therefore
the Working Group suggests using filgrastim for at least 7 days.
Despite the scarcity of studies comparing 7 to 9 days of filgrastim treatment to ≥10 days, longer treatment
courses are uncommon in more recent clinical practice. Among the 5477 patients included in the American
healthcare claims data study, 95% of patients received less than 10 days of filgrastim prophylaxis despite the 1011 days of treatment used in the pivotal clinical trials.5 Patients must be evaluated individually to determine if use
beyond 10 days is warranted.
The 2006 ASCO Guideline recommends continuing G-CSF until the ANC is at least 2 to 3 x 109/L.8 However, in
ambulatory practice, it is not common to have patients return for interim blood work unless there is clinical
justification for this action. Instead, the G-CSF Working Group does not recommend that interim monitoring of
ANC be done unless the patient’s ANC is > 10 x 109/L at the subsequent cycle of treatment or if the patient
experiences significant bone pain during G-CSF treatment. Consideration may be made for interim monitoring
with the first cycle for patients who may be at higher risk of complications of febrile neutropenia.
Docetaxel-Containing Regimens
The area of largest disparity between the G-CSF guidelines is the FN risk classification of docetaxel-containing
regimens for breast cancer. AC-DOCE+TRAS and FEC-D were rated as having a moderate risk for patients
developing FN when treated with these regimens in the NCCN, or NCCN and EORTC, respectively.1,9 There was no
classification recommendation provided by ASCO or EORTC for AC-DOCE+TRAS.
The NCCN guidelines classify AC-DOCE+TRAS as an intermediate risk regimen based on a trial by Slamon et al.,
which reported that the rate of FN in patients receiving AC-DOCE+TRAS was 10.9% (n=1068), with AC-DOCE
showing similar rates at 9.3% (n=1050).10 This trial allowed the use of G-CSF but did not report the rate of use in
each of the groups studied.9 This is a large discrepancy in reporting that needs to be taken into consideration
when classifying these regimens. In 2003, Bear et al. reported the risk of FN associated with use of AC-DOCE
(without prophylactic use of G-CSF) to be 21.2%; suggesting the regimen to have a high risk of FN.11 The ASCO
2006, EORTC 2010, NCCN 2012 and CCO 2015 recommend AC-DOCE FN classification as high risk.8,9,1 The addition
of trastuzumab (TRAS) to AC-DOCE is unlikely to contribute to increased risk of FN. Thus, it is appropriate to
extrapolate AC-DOCE literature to AC-DOCE+TRAS in the face of a general lack of data for AC-DOCE+TRAS in
chemotherapy naïve patients without the addition of G-CSF with the initial treatment. The similar rate of FN
between AC-DOCE and AC-DOCE+TRAS regimens when G-CSF use was allowed by Slamon et al. is support for a
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
similar risk.9 Cancer Care Ontario is extending this recommendation of high FN risk with AC-DOCE to ACDOCE+TRAS based on the above information despite its moderate risk classification from NCCN.
FEC-D received a FN risk classification from NCCN of moderate.1 Early literature by Roche and Cousin reported
rates of FN with FEC-D usage in breast cancer to be low to moderate.12,13 The rates of G-CSF use in these trials are
unclear based on available literature.9,12 A 2011 trial by Madarnas et al. reported the rates of FN in patients
receiving FEC-D to be 22.7%, despite use of G-CSF for primary FN prophylaxis in 35% of the included patients.14
This study was not included in any of the above mentioned G-CSF guidelines, likely due to the later completion
date of this trial. A retrospective before-and-after study and a meta-analysis both found FN rates with FEC-D
treatment to be approximately 30% without the use of G-CSF, providing additional support for the Cancer Care
Ontario classification of this regimen as high risk.15,16
Moderate FN Risk (10-20%)
1. For chemotherapy regimens that carry an FN risk between 10 – 20%, the use of G-CSF should be
determined at the discretion of the prescriber based on patient risk assessment (see Table 1).
 If G-CSF is determined to be appropriate, consider recommendations described above for High Risk.
 If G-CSF is determined to be appropriate based on patient risk assessment but is not possible, consider
antimicrobial prophylaxis described above for High Risk.
Table 1. Risk Factors for the Development of Febrile Neutropenia1,8,17
Risk Factors
High level of
supporting evidence
Intermediate level of
supporting evidence
Low level of
supporting evidence
Other/unclear level of
supporting evidence
Clinical Factors





















≥85% relative intensity
Extensive prior chemotherapy
Prior radiation to bone marrow
Age greater than 65 years
Bone marrow involvement with tumor
Poor performance status
Low albumin/high LDH
Pulmonary disease
Cardiovascular disease
Liver disease
Diabetes mellitus
Open wounds or active infection
Poor nutritional status
Hgb < 120 g/L
Female sex (smaller BSA)
Preexisting neutropenia
Advanced cancer
Leukemia
Lymphoma
Lung cancer
Decreased immunity
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Age greater than 65 years
The NCCN 2014 and EORTC 2010 guidelines recommend that older age is a significant risk factor when
determining the risk of FN for patients receiving intermediate risk regimens. There is data for increased FN risk in
patients aged ≥ 60 or 65 years in urothelial cancer, Non-Hodgkin’s lymphoma, lung cancer, breast cancer and
ovarian cancer.
Urothelial Cancer: In the EORTC Cancer in the Elderly Task Force guidelines, prophylactic use of G-CSF was found
to reduce the risk of FN and infections in urothelial cancer patients over the age of 60 years, based on metaanalysis of clinical trials.18
Non-Hodgkin’s Lymphoma: The EORTC Elderly Task Force also concluded that there was evidence demonstrating
benefit of prophylactic use of G-CSF in NHL patients over the age of 60 years.18 More recently, a prospective multicentered randomized trial found the use of prophylactic G-CSF in NHL patients over the age of 65 years reduced
the FN risk to 15% compared to 37% when physician-discretion was used.19
Lung Cancer: Both the EORTC Elderly Task Force and the randomized trial from Balducci and colleagues found
evidence in support of the use of prophylactic G-CSF in lung cancer patients older than 60 or 65 years,
respectively.18,19
Ovarian Cancer: The prospective study completed by Balducci and colleagues included elderly patients with
ovarian cancer and found benefit with the use of prophylactic G-CSF in this patient population.19 A retrospective
chart analysis also found that age over 60 years was a predictor of FN.20
Breast Cancer: There is some data pertaining to the use of G-CSF in elderly breast cancer patients. The EORTC
Elderly Task Force did not find sufficient data to support primary prophylaxis of FN in elderly breast cancer
patients.18 However, the more recent randomized trial from Balducci and colleagues observed a reduction in FN
when G-CSF was used.19 A systematic review of four randomized controlled trials of breast cancer patients
receiving taxane-containing neoadjuvant or adjuvant chemotherapy observed no difference in FN risk based on
age (< 60 years, 60-64 years, or >65 years).21 However, the majority of patients received G-CSF prophylaxis, and
patients with comorbidities were excluded. Finally, a sub-analysis of a systematic review found that primary
prophylaxis with pegfilgrastim resulted in lower incidence of FN in elderly patients on chemotherapy with a ≥15%
risk of FN compared to current practice G-CSF use, where approximately 27% of patients received G-CSF in cycle
1.22
Tools for predicting FN Risk
The NCCN 2014 guidelines base their list of risk factors on a risk model developed by Lyman and colleagues. This
model incorporates baseline variable information to predict an individual patient’s risk of severe or febrile
neutropenia. The model was derived from the first cycle data of 2425 patients and then validated from the data of
1213 patients. It was observed that chemotherapy dose intensity, history of previous chemotherapy, elevated
bilirubin and type of cancer were significantly associated with cycle 1 severe or febrile neutropenia. The model
had a 90% sensitivity, 59% specificity, 34% positive predictive value, and 96% negative predictive value. The model
was undergoing additional validation testing in independent institutions and patient populations at the time of
publication.23
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Low FN Risk (<10%)
1.
2.
3.
4.
G-CSF should not be used for primary prophylaxis of FN
Standard use of antibiotics is not recommended in this patient population.
Use of antifungal prophylaxis may be considered during the period of neutropenia.
Use of antiviral prophylaxis should be based on patient specific history of herpes simplex virus and should
be considered if patient is at high risk of a reactivation of latent viral infection during period of
neutropenia.
General Discussions
1. Filgrastim vs pegfilgrastim
A number of studies have compared filgrastim and pegfilgrastim. Shi et al. found that there was no significant
difference in rates of grade 4 neutropenia, incidence of FN or antibiotic administration rates. The absolute
neutrophil count (ANC) nadir was earlier (7 vs 9 days) and duration of neutropenia was shorter with pegfilgrastim
vs filgrastim but the depth of the nadir was not significantly different between treatments.24 In another
comparative study, patients receiving pegfilgrastim 100 ug/kg vs filgrastim 5 ug/kg/day as primary prophylaxis
after treatment with doxorubicin and docetaxel were reported to have similar rates of cycle-one grade-four
neutropenia (74% vs 76%), duration of neutropenia (1.3 days vs 1.6 days), FN (7% vs 4%), and mild-moderate bone
pain (35% vs 36%).25 Pegfilgrastim 30 ug/kg and 60 ug/kg were also evaluated in this study but were not as
effective as either the pegfilgrastim 100 ug/kg or filgrastim treatments in preventing grade-four neutropenia or FN
episodes.16 There was large variation in the sample size (25;19;60;46 for filgrastim; pegfilgrastim 30 ug/kg;
pegfilgrastim 60 ug/kg; pegfilgrastim 100ug/kg respectively) of the treatment groups of this study so significance
of these results needs to be interpreted with extreme caution.17
There is some evidence that pegfilgrastim may be more effective than filgrastim. Weycker et al. identified a
difference between the two agents, observing a lower risk of hospitalization for neutropenic complications during
cancer chemotherapy with pegfilgrastim compared to filgrastim.26 A number of meta-analyses have suggested
that pegfilgrastim may be superior to filgrastim in reducing FN rates with similar incidence of bone pain.27,28
A number of cost-effectiveness assessments have been done comparing filgrastim and pegfilgrastim in the current
model of practice. A Canadian cost-effectiveness assessment found that neither of these medications is costeffective with the current funding and usage practices, with cost estimates of CAD$1740/10 day course of
filgrastim, CAD$2422/pegfilgrastim 6 mg dose, CAD$1012/day of hospitalization for FN (2012 costs).29 At this time,
cost-benefit is being analyzed in quality-adjusted life years instead of survival as a clear survival benefit has not
been seen with these medications.24 If a survival benefit is identified, or medication coverage is made available for
appropriate patient groups, these medications may prove to be cost-effective from a health systems perspective,
without adversely effecting clinical outcomes.24 This analysis highlights the importance of eliminating
inappropriate use of G-CSF prophylaxis in low FN risk patients and selective use in moderate risk FN patients. At
this time there have not been any cost-effectiveness analyses conducted in only high FN risk patients but it is
likely that use in this patient population would prove to be cost effective.
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Despite the meta-analyses suggesting decreased FN risk with pegfilgrastim, the G-CSF Working Group does not
advocate for one G-CSF product over another. The decision of product selection will need to incorporate patient
preference, access and convenience.
Cost4,26
 $192/filgrastim 300 mcg dose (DIN 01968017)
 $308/filgrastim 480 mcg dose (DIN 09853464)
 $2422/pegfilgrastim 6 mg dose (DIN 02249790)
The Ontario Drug Benefit Program (ODB) funds both strengths of filgrastim under Limited Use criteria for
prophylaxis of FN in patients receiving chemotherapy with curative intent. It does not currently fund
pegfilgrastim.
o Primary G-CSF prophylaxis: Patients with cancer receiving a curative chemotherapy who are expected to
have incidence of FN of more than or equal to 20% (e.g., due to highly myelosuppressive regimen, patient
co-morbidities, pre-existing severe neutropenia, etc.).
o Secondary G-CSF prophylaxis: For secondary prophylaxis of FN (i.e. patient has
experienced an episode of sepsis or FN or neutropenia such that treatment has had to be delayed for at
least one week) for patients with cancer receiving a curative chemotherapy
o Exclusion: non-curative cancer with palliative intent.
o Dosage reduction: <90kg: 300mcg, ≥90kg or patient who was unable to achieve adequate response from
300mcg: 480mcg.
2. Curative Intent vs Palliative Chemotherapy
The goal of curative chemotherapy treatment is to induce remission or cure of the cancer, prolonging the
patient’s life. In cases where reduced dose density or intensity has been shown to lead to poor prognosis, the use
of G-CSF is justified with the goal of preventing or reducing the need for these dose changes.11 The need for dose
changes may be prevented with G-CSF use through its ability to decrease the duration, severity and complications
of neutropenia experienced by the patient.11
The goal of palliative chemotherapy treatment is to extend and improve the patient’s quality of life as much as
possible and not to necessarily cure the disease. In this case, increased intensity or density of chemotherapy
regimens has not been proven to lead to improved quality of life for these patients.8 In this setting, a decrease in
dose density or intensity of chemotherapy to decrease the duration, severity and risk of complications of
neutropenia is preferred over accomplishing these outcomes with the use of G-CSF products.8 G-CSF is not
recommended for prevention of grade four neutropenia or FN when the goal of chemotherapy is palliative unless
dose density or intensity are unable to be decreased. If these measures are not effective in preventing grade four
neutropenia or FN, consideration should be given to secondary FN prophylaxis with antibiotic therapy.
3. Secondary FN Prophylaxis
Secondary FN prophylaxis is treatment to help prevent a future episode of FN after an initial FN episode has
already been experienced by that patient.11 The occurrence of a previous FN episode predisposes a patient to
further episodes of FN.11 If a patient experiences an episode of FN where no G-CSF was used for primary
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
prophylaxis, G-CSF use should be considered in secondary prophylaxis of FN if further infections in the next
treatment cycle are considered life-threatening; a dose reduction would bring the dose below the
studied/effective threshold; FN may lead to a delay in chemotherapy; or if a lack of protocol adherence
compromises the cure rates or disease free or overall survival.1,30
A dose reduction may be a reasonable alternative to using G-CSF in secondary prophylaxis if the threshold for
efficacy is not reached, or in the case of chemotherapy with a low FN risk. The ASCO 2015 guidelines report that
there is no data to support improvements in disease-free or overall survival for common cancers with the use of
G-CSFs to maintain dose-intensity instead of dose reduction.31
If a patient experiences FN despite receiving primary FN prophylaxis with G-CSF, it is recommended to continue GCSF use with the following chemotherapy cycles as well as consideration of dose reduction or change in treatment
regimen.1
4. Risk of neutropenic infection by hematological vs solid malignancy
The mechanism of infection and infection risk in hematological malignancies is fundamentally different than with
solid tumour malignancies. Patients with hematological malignancies are at increased risk for infection due to
leukopenia secondary to infiltration of the marrow with malignant cells, potential for hypogammaglobulinemia,
restriction of antibody production, and common use of multiple treatment cycles.32
Patients with solid tumours are at increased infection risk due to potential anatomical abnormalities caused by
the tumour itself, necrotized tumours acting as a nidus of infection, tumours impairing the body’s natural
defenses (i.e. postobstructive pneumonias in endotracheal tumours, facilitated bacterial gut translocation with GI
mucosal tumours, etc), and surgical removal of tumours in immune compromised or non-immune compromised
patients.30
Both hematological and solid tumours carry their own individual risk factors for infection as described above. This
highlights the importance of taking malignancy type and characteristics into consideration, in addition to the FN
risk classification of the chemotherapy regiment to be given, when determining the patient’s overall risk for FN.
This is especially important in patients scheduled to receive moderate FN risk chemotherapy treatment.
5. Efficacy of G-CSF vs antimicrobial for FN primary prophylaxis.
There is a large composite of data available to assess the efficacy of G-CSF and antibiotics monotherapy in
preventing FN episodes. Takabatake et al. prospectively assessed docetaxel 75 mg/m2 + cyclophosphamide 600
mg/m2 every three weeks for the treatment of breast cancer, using no primary prophylactic G-CSF or antibiotics
for the prevention of FN.33 An FN event rate of 28%, all events being grade 3 in severity, was reported.32
Ngamphaiboon et al. looked at the same regimen with 100% use of primary prophylactic G-CSF, with no primary
prophylactic antibiotic use, and saw an FN event rate of 7%.34 Indirectly comparing the safety results of these two
studies, there was an absolute risk reduction (ARR) of 21% in FN episodes when G-CSF is used as primary
prophylaxis. These results were echoed in the before-and-after retrospective study by Mullard et al. study using
FEC-D, which saw an FN event rate pre-G-CSF (without antibiotic use) of 30% and FN event rates post-G-CSF
(without antibiotic use) of 11%, an ARR of 19%.15
The question of whether to choose antibiotic(s) or G-CSF to prevent infection or FN in oncology patients receiving
chemotherapy was addressed by a 2009 Cochrane Systematic Review that concluded there is insufficient evidence
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
to support the use of either antibiotics or G-CSF over the other for the prevention of fever or hospitalization for
FN.35 Due to FN and other infectious complications associated mortality rates of 2-21%,34 patients at high risk of
FN should receive both antibiotics and G-CSF for prevention as the combination has been seen to be better than
either treatment alone.7,36 Caution should be used when prescribing an antibiotic for prophylactic use since the
development of resistance is increasing, putting patients at risk of subsequent infections with antibiotic-resistant
organisms.37 Patients at moderate risk of FN should receive patient specific assessment to determine the
appropriateness of antibiotic and/or G-CSF FN prophylaxis based on the characteristics described in Table 1.
The G-CSF Working Group recommends the use of G-CSF where possible due to concerns over antibiotic overuse.
When an antibiotic is necessary, the use of a fluoroquinolone is preferred over sulfamethoxazole-trimethoprim
due to the hematologic toxicities associated with sulfonamides (e.g. agranulocytosis).
Process for Assigning FN Risk to Chemotherapy Regimens with Curative Intent
Table 2 summarizes the FN risk assigned to each chemotherapy regimen with curative intent by the GCSF Working
Group. These include neoadjuvant and adjuvant regimens that are part of the Systemic Treatment Funding
Model. The process for arriving at the FN risk was a combined effort of published literature and expert clinical
consensus of the Disease Site Leads or their delegates. The GCSF Working Group proposed FN risk classifications
to those regimens where a classification was available by international guidelines (e.g. ASCO, NCCN, EORTC) or in
clinical trials where the study was accessible by the Group. The list of disease-site-specific regimens were then
vetted through to the Disease Site Leads or Clinical Leads for verification and for additional classification of
regimens based on clinical experience and best practice. Consensus was achieved between Disease Site Leads
where there were multiple clinicians assigning FN risk classification to each regimen.
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Table 1: GCSF Recommendations for the Prophylaxis of Febrile Neutropenia
High Risk (Risk of FN > 20%)
A G-CSF agent should be prescribed for all regimens with a high risk of FN.
 Filgrastim 300 mcg (if < 90 kg) or 480 mcg (if ≥90 kg or <90kg with an inadequate response to
300 mcg) subcutaneously (rounded to the nearest full vial size) daily for 7 to 10 days starting 2472 hours post completion of chemotherapy OR
 Pegfilgrastim 6 mg subcutaneously once to start 24-72 hours post completion of chemotherapy cycle.
Not to be given less than 14-day intervals.
Where the use of G-CSF is not possible, an antimicrobial agent should be prescribed.
 Ciprofloxacin 500 mg – 750 mg oral q 12 hr x 7-10 days OR
 Levofloxacin 500 mg oral daily x 7-10 days.
The addition of an antifungal should be considered for high-risk hematologic regimens
 Fluconazole 400 mg po once daily x duration of neutropenia OR
 Posaconazole 300 mg po BID (3 x 100 mg tablets) on Day 1 then 300 mg po daily thereafter OR
posaconazole suspension 200 mg po TID OR x duration of neutropenia.
Consider antiviral prophylaxis based on patient history for the duration of neutropenia and for regimens
containing bortezomib and fludarabine.
 Acyclovir 400 mg po BID continuously (usually until completion of chemotherapy).
Moderate Risk: Additional Risk Factors
Risk Factors
Clinical Factors
High level of
supporting
evidence
-≥85% relative intensity.
-Extensive prior
chemotherapy.
-Prior radiation to bone
marrow.
-Age greater than 65 years.
-Bone marrow involvement
with tumor.
Intermediate
-Poor performance status.
-Low albumin/high LDH.
level of
-Pulmonary disease.
supporting
-Cardiovascular disease.
evidence
-Liver disease.
-Diabetes mellitus.
Low level of
-Open wounds or active
infection.
supporting
-Poor nutritional status.
evidence
-Hgb < 120 g/L.
-Female sex (smaller BSA).
Other/unclear -Preexisting neutropenia.
-Advanced cancer.
level of
-Leukemia.
supporting
-Lymphoma.
evidence
-Lung cancer.
-Immunocompromised.
Moderate Risk (Risk of FN 10-20%)
Consider treatment based on risk factors listed in “Additional risk factors column”
 Consider filgrastim OR pegfilgrastim dosed as above.
 Consider ciprofloxacin OR levofloxacin dosed as above.
 Consider fluconazole OR posaconazole dosed as above.
 Consider antiviral therapy based on patient specific history of viral infections/chemotherapy regimen.
Low FN Risk (Risk of FN < 10%)
 Filgrastim OR pegfilgrastim are not recommended in this patient population.
 Antibiotic prophylaxis is not standard recommendation in this patient population.
 Antifungal prophylaxis is not standard recommendation in this patient population.
 Consider antiviral therapy as needed.
Note: Interim monitoring of ANC is generally not recommended unless the patient’s ANC is > 10 x 109/L at the subsequent cycle of treatment or
if the patient experiences significant bone pain during GCSF treatment
Table 2: Febrile Neutropenia Risk Classification of CCO Drug Formulary Regimens with Curative Intent
Disease Site Group
Breast
Central Nervous System
Gastrointestinal
Regimen
AC
AC-DOCE
AC-DOCE+TRAS
AC-PACL
AC-PACL(DD)
AC-PACL(DD)+TRAS
AC-PACL(W)
AC-PACL(W)+TRAS
AC-PACL+TRAS
CRBPDOCETRAS
CYCLDOCE
CYCLDOCE+TRAS
FEC100
FEC-D
FEC-D+TRAS
TRAS
PCV
CAPE
CAPE(RT)
CAPECISP
CAPECISP(RT)
CISPETOP(3D)
CISPFU
CISPFU(RT)
CISPGEMC
CRBPETOP
CRBPFU
CRBPPACL(RT)
ECARBOF
ECARBOX
ECF
ECX
FLOX
FU(CIV-RT)
FU(IV-CIV)LCVR
FULCVR
FULCVR(RT)
FULCVR(RT-GAST)
FULCVR(W)
FUMTMC(RT)
GEMC
CCO Risk Classification
Low
High
High
Low
High
High
Low
Low
Low
High
High
High
Moderate
High
High
Low
Low
Low
Low
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Low
Low
Low
Low
Low
Moderate
Moderate
Moderate
Low
Low
Low
Low
Low
Low
Low
Low
Gastrointestinal (cont.)
IMAT
Low
MFOLFOX6
Low
OXALRALT
Low
RALT
Low
XELOX
Low
CAPEMTMC(RT)
Moderate
FU(IV-CIV)LCVR (MODIFIED DE GRAMONT)
Low
FU(IV-CIV)LCVR( DE GRAMONT)
Low
Genitourinary
BEP(3D)
High
BEP(5D)
High
CISP
Low
CISP(RT)
Low
CISP(RT-W)
Low
CISPETOP(3D)
Moderate
CISPETOP(5D)
Moderate
CISPFU
Moderate
CISPGEMC
Moderate
CISPGEMCPACL
Moderate
CMV
Moderate
CRBP
Low
CRBP(RT)
Low
CRBPETOP
Moderate
CRBPGEMC
Moderate
FUMTMC(RT)
Low
MTTN
Low
MVAC
High
MVAC(HD)
High
TIP
High
VEIP
High
VIP
High
Gynecological
BEP(5D)
High
CISP
Low
CISP(RT-W)
Low
CISPDOXO
Moderate
CISPETOP(3D)
Moderate
CISPETOP(5D)
Moderate
CISPFU
Moderate
CISPPACL
Low
CISPPACL(IP)
Low
CRBP
Low
CRBP(RT)
Low
CRBPDOCE
Moderate
CRBPDOXO
Low
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
CRBPETOP
CRBPPACL
CRBPPACL(IP)
CRBPPACL(W)
FUMTMC(RT)
Gynecological (cont.)
Head and Neck
Hematological
DCTN
EMA-CO
EP-EMA
ETOPPAC-CISPPACL
MTRX
MTRX(5D)
CETU(RT)
CISP(RT)
CISP(RT-D)
CISP(RT-W)
CISPDOCEFU
CISPETOP(3D)
CISPFU
CISPFU(RT)
CRBP(RT)
CRBPETOP
CRBPFU(RT)
ABVD
BEACOPP
CEPIOP
CEPIOP+RITU
CEPP
CEPP+RITU
CHOP
CHOP+R
CHOP14+R
CNOP
COPP
CYCLETOP
DHAP
EPOCH+RITU
DA-EPOCH+RITU
ESHAP
GDP
GDP+RITU
ICE
MINIBEAM
Moderate
Low
Low
Low
Low
Low
High
High
Low
Low
Low
Low
Low
Low
Low
High
Moderate
Moderate
Moderate
Low
Moderate
Low
Moderate
High
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
High
Moderate
Low
Low
High
High
High
High
Moderate
Moderate
High
High
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Hematological (Cont.)
CEOP
CEPIOP
CEPIOP+RITU
CEPP+RITU
CHOEP
CHOEP+RITU
ICE
HYPERCVA
HYPERCVAD+RITU
Lung
Sarcoma
CISP(RT-D)
CISPETOP(3D)
CISPETOP(RT)
CISPETOP(PO)
CISPGEMC
CISPPEME
CISPVINO
CISPVINO(MOD)
CISPVINO(RT)
CISPVINO(W)
CISPVNBL
CISPVNBL(RT)
CISPVNBL(RT)
CRBPETOP(RT)
CRBPPACL
CRBPETOP(RT)
CRBPPACL(RT)
CRBPPEME
CRBPVINO
CRBPVNBL
CISP(RT-W)
CISPDOXO
CISP(RT-W)
CRBPDOCE
DOCEGEMC
CRBPPACL
DOXO
DOXOIFOS
EPIRIFOS
ETOPIFOS
MTRXVINO
MTRXVNBL
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
High
High
High
Low
Moderate
High
High
Moderate
Low
Moderate
Moderate
Moderate
Moderate
Low
Low
Low
Moderate
Moderate
Moderate
Moderate
Low
Low
Low
Low
Moderate
Low
Low
Moderate
Low
Low (50 - 70mg/m2);
Moderate >70mg/m2
High
High
Moderate
Low
Low
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Appendix 3: Febrile Neutropenia G-CSF Prophylaxis Working Group Members
Member
Role
Affiliation(s)
Dr. Maureen Trudeau
Co-chair; Medical Oncologist
Odette Cancer Centre
Dr. Kathy Vu
Co-chair; Pharmacist
Cancer Care Ontario, University of Toronto
Dr. Tom Kouroukis
Hematologist
Juravinski Cancer Centre
Dr. Nicole Laferriere
Hematologist
Thunderbay Regional Health Sciences Centre
Dr. Winson Cheung
Medical Oncologist
BC Cancer Care
Mary Doherty
Nurse
Princess Margaret Cancer Centre
Andrea Crespo
Pharmacist
University Health Network
Dr. Carlo DeAngelis
Pharmacist
Sunnybrook Odette Cancer Centre
Dr. Scott Edwards
Pharmacist
Dr H. Bliss Murphy Cancer Centre
Annie Cheung
Pharmacist
Cancer Care Ontario
Nita Lakhani
Pharmacist
Cancer Care Ontario
Brenda Ferris
Patient
Patient Advisor
Appendix 4: Acknowledgements: Reviewers
Dr. Leonard Kaizer
Dr. Monika Krzyzynowska
Dr. David Warr
Dr. Peter Ellis
Dr. John Goffin
Dr. Julie Francis
Dr. Helen Mackay
Dr. Sebastien Hotte
Dr. Eric Winquist
Dr. Warren Mason
Dr. Shailendra Verma
Dr. Kelvin Chan
Dr. Teresa Petrella
Dr. Tara Baetz
Dr. Susan Dent
Provincial Head, Cancer Care Ontario; Oncologist/Hematologist, Trillium
Health Partners
Clinical Lead, Cancer Care Ontario; Medical Oncologist, Princess Margaret
Cancer Centre
Medical Oncologist, Princess Margaret Cancer Centre
Medical Oncologist, Juravinski Cancer Centre
Medical Oncologist, Juravinski Cancer Centre
Medical Oncologist, Kingston General Hospital
Medical Oncologist, Princess Margaret Cancer Centre
Medical Oncologist, Juravinski Cancer Centre
Medical Oncologist, London Health Sciences Centre
Medical Oncologist, Princess Margaret Cancer Centre
Medical Oncologist, The Ottawa Hospital Cancer Centre
Medical Oncologist, Sunnybrook Health Sciences Centre
Medical Oncologist, Sunnybrook Health Sciences Centre
Medical Oncologist, Kingston Regional Cancer Centre
Medical Oncologist, The Ottawa Hospital Cancer Centre
Appendix 5: Acknowledgements: Significant Contributors
Kimberley Vu
Drug Formulary Pharmacist, Cancer Care Ontario
Lauren Hutton
University of Toronto PharmD Student
John Cao
University of Toronto PharmD Student
Michael Wan
University of Toronto PharmD Student
Date of original version: January 18, 2016
Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)
Matthew Dytoc
University of Toronto PharmD Student
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Modified: February 16, 2016 (posaconazole dose; added DA-EPOCH+RITU and HYPERCVAD)
Modified: March 21, 2016 (SMX-TMP dose)