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Section 3 G-CSF in neutropenia guidelines Implementation Toolkit Guidelines Guidelines
Section 3G-CSF in neutropenia guidelines
Implementation ToolkitGuidelinesGuidelines
2
Contents
Section 3 – G-CSF in neutropenia guidelines
Introduction to Section 3
3.1 Introduction
Overall Goal
Specific Targets and Aims
The Nurse’s Role
Key Points to understand from the G-CSF in neutropenia guidelines
3.2 What is neutropenia?
Grades of neutropenia
Febrile neutropenia
3.3 How does chemotherapy lead to neutropenia?
When does chemotherapy-induced neutropenia occur?
3.4 What are the implications of neutropenia for the patient?
Risk of mortality
Potential complications of neutropenia
Impact on chemotherapy dose and cancer outcomes
Increased hospitalisation
Quality of life issues
3.5 How is neutropenia recognised?
At-risk populations
Chemotherapy and febrile neutropenia risk
Minimising the risk of infection
Controlling infection if it does occur
Sepsis and the sepsis cascade
3
3.6 How is neutropenia managed?
Granulocyte-colony stimulating factors
Recommendations for granulocyte-colony stimulating factor use
Initiating treatment with a granulocyte-colony stimulating factor
Using a granulocyte-colony stimulating factor with dose-dense chemotherapy
Regimen-specific risk of febrile neutropenia
Duration of prophylactic granulocyte-colony stimulating factor
Education for patients receiving granulocyte-colony stimulating factors
Recommendations for the use of granulocyte-colony stimulating factors – patients with ongoing febrile neutropenia
Recommendations for the use of granulocyte-colony stimulating factors – patients on chemotherapy
Side effects of granulocyte-colony stimulating factors
Other issues
3.7 Summary
Appendices
Abbreviations
References
4
3.1 Introduction
Neutropenia and febrile neutropenia (FN) are common and serious complications of anti-cancer
therapies, which can be caused by both chemotherapy and radiotherapy. Chemotherapy-induced
neutropenia (CIN) is the major dose-limiting toxicity for patients with systemic cancer undergoing
chemotherapy, and is associated with substantial morbidity, mortality and cost.1 CIN can lead to
delays in chemotherapy treatment and reduced doses, both of which may compromise long-term
survival in potentially curable cancers.1
Section 3 covers the granulocyte-colony stimulating factor (G-CSF) guidelines developed by experts
in the European Organisation for Research and Treatment of Cancer (EORTC) Guidelines Task Force.2
Their objective was to systematically review available published data and derive evidence-based
recommendations on the appropriate use of G-CSF in adult patients receiving chemotherapy for
cancer. This module also outlines the pivotal role that nurses play in identifying and managing
neutropenia.
In addition, this section makes reference to the guidelines from the two other most prominent
international bodies concerned with CIN (ASCO and NCCN).Their guidelines were produced almost
simultaneously and deal with many of the same topic areas.
Overall Goal
Specific Targets and Aims
The Nurse’s Role
3.1.1 Overall Goal
The overall goal of these guidelines is to educate healthcare professionals and propose
recommendations that help to reduce the number of neutropenia and febrile neutropenia (FN)
episodes,and improve the delivery of relative dose intensity and thereby potentially improve patient
outcomes in cancer therapy.
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3.1.2 Specific Targets and Aims
The targets and aims of this module are to:
� Update nurses on current guidelines and practice in neutropenia
� Increase nurses’ understanding of the guidelines, so they may participate in the risk assessment
and plan patient care strategy with the team
� Encourage nurses to educate patients so they can understand what standard of care to expect
� Increase nurses’ understanding of specific elements of neutropenia:
� Neutropenia risk (chemotherapy-regimen)
� Patient risk factors and patient risk assessment
� Review of the patient at the beginning of every treatment cycle
� G-CSF use – understanding which patients will gain the most benefit from
G-CSF administration
� Monitoring of blood cell counts
� G-CSF prophylaxis (primary and secondary) and antibiotic use
� Response to patient conditions – knowing when treatment should or should not be delayed,
and dose reductions should be avoided
� Encourage the successful management of a patient with neutropenia
3.1.3 The Nurse’s Role
Since nurses are among the best placed professionals to assess patients for risk by reviewing their
patients’ history and current health status (risk factors), these guidelines will highlight the role that
nurses play in CIN and will focus on the assessment and prevention of risk factors associated with
neutropenia.
Updating nursing care protocols for CIN management may allow more patients to receive
chemotherapies on schedule and at full-dose, as well as reduce potential practice variations that
could compromise care, promote cost-effectiveness and increase the quality of care for patients.3
Furthermore, nursing care protocols may improve the impaired quality of life associated with CIN.4,5
Identification of risk factors in specific patient groups, and identification of the need for primary or
secondary prophylaxis with G-CSF are part of this process. In order to achieve this, nurses need to
know the risk factors for neutropenia in order to put into practice the specific guidelines for the
different patient types.
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3.2 What is neutropenia?
By definition,neutropenia refers to a reduced neutrophil count in the blood.Normal individuals have
a neutrophil count in the blood ranging between 1,500 and 8,000 cells/mm3. When the neutrophil
count falls below the 1,500 cells/mm3 threshold, a patient is classified as neutropenic.2
Absolute neutrophil count (ANC) defines the severity of neutropenia,and is calculated by multiplying
the percentage of bands and neutrophils on a differential by the total white blood cell count.2 An
ANC should be calculated for patients with neutropenia, by multiplying the total white blood cell
(WBC) count by the percentage of neutrophils. Laboratories often provide this figure routinely in
blood counts.
Grades of neutropenia
Febrile neutropenia
3.2.1 Grades of neutropenia
Neutropenia can be graded according to the number of neutrophils in a patient’s blood sample (i.e.,
ANC). Two common methods are used in the scientific literature for grading neutropenia and are
presented below: the NCI Common Toxicity Criteria for Adverse Events (left) and the Merck Manual
(right):6,7
For full details on the Common Toxicity Criteria, please see Appendix 1.6
If the neutrophil count descends below 500 cells/mm3; there is a high risk of overwhelming infection
that will require hospitalisation and treatment with antibiotics.
3.2.2 Febrile neutropenia
Febrile neutropenia (FN) refers to neutropenia (<500 cells/mm3,or <1,000 cells/mm3 with a predicted
decrease to <500 cells/mm3) in the presence of a fever (defined as fever of >38.3°C on one occasion,
or >38.3°C for more than one hour, in absence of any obvious environmental cause).8 In cancer, the
incidence of FN depends on the chemotherapy regimen, patient population and the type of cancer.
Presence of FN may indicate the development of a potentially life-threatening infection and should
be taken seriously. In fact, the presence of FN necessitates urgent patient evaluation.
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NCI Common Toxicity Criteria grade6 ANC (cells/mm3) Neutropenia grade7
Grade 2 – Moderate 1,000–1,500 Mild
Grade 3 – Severe 500–1,000 Moderate
Grade 4 – Life-threatening <500 Severe
7
3.3 How does chemotherapy lead to neutropenia?
White blood cells (WBCs) only survive for 3–4 days in the circulation, and the bone marrow is
constantly regenerating new WBCs to replenish levels in blood. Chemotherapy, however, affects the
bone marrow’s ability to regenerate WBCs, and leads to an absolute drop in neutrophil levels
(neutropenia).3
Neutropenia is the most common side effect of chemotherapy, though it is often a silent
complication. At first, patients may not display any symptoms at all or display mild symptoms, such
as fatigue, malaise, vague respiratory or urinary symptoms, sweats, fevers and chills.9 Chemotherapy-
induced neutropenia (CIN) leads to an increased susceptibility to infection and fever.
When does chemotherapy-induced neutropenia occur?
3.3.1 When does chemotherapy-induced neutropenia occur?
Patients are at increased risk of CIN during the nadir period – the lowest point for the absolute
neutrophil count (ANC) post-chemotherapy (or post-radiotherapy). The nadir usually occurs 7–10
days after chemotherapy, but the exact timing and duration of this period depends on the type and
combination of chemotherapy.2 For example, combination chemotherapy may affect the length of
nadir – typically cell-cycle specific chemotherapies have an earlier onset of nadir and non-cell-cycle
specific chemotherapies have a later nadir with a longer recovery period.2
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3.4 What are the implications of neutropenia for the patient?
Neutropenia or chemotherapy-induced neutropenia (CIN) may result in febrile neutropenia (FN),
which often necessitates hospitalisation for evaluation and broad-spectrum antibiotics,and can lead
to the severe,even life-threatening,complications.2,5,10 Neutropenia can also result in treatment delays
or dose reductions for chemotherapy, and may compromise the overall patient and clinical
outcomes. In these cases, prophylactic granulocyte-colony stimulating factors (G-CSFs) can be used
to maintain the chemotherapy dose and reduce the severity and duration of neutropenia.2,3
Risk of mortality
Potential complications of neutropenia
Impact on chemotherapy dose and cancer outcomes
Increased hospitalisation
Quality of life issues
3.4.1 Risk of mortality
FN may be associated with an increased risk of mortality.11 A recent study conducted in the US
showed that mortality was 9.5% among patients hospitalised for FN.11 Mortality was even higher
(21.4%) in patients with FN and more than one comorbidity (e.g. invasive fungal infections, Gram-
negative sepsis, pneumonia and other lung disease, cerebrovascular, renal, and liver disease).11
3.4.2 Potential complications of neutropenia
Potential complications of neutropenia can include:12
� Pneumonia
� Sepsis and severe sepsis (and subsequent sequelae of severe sepsis such as Multi-Organ
Dysfunction Syndrome)
� Bacterial infections
� Fungal and viral infections
In addition, the presence of neutropenia requires attention to/management of:
� Mucous membranes – redness, tenderness, swelling,‘fungal’ white patches
� Dysuria
� Respiratory insufficiency/complications – cough, shortness of breath, crackles, rhonchi, wheezes
� Central nervous system symptoms
� Fatigue
� Chills, fevers, rigours, sweats
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3.4.3 Impact on chemotherapy dose and cancer outcomes
Patients suffering from FN or severe neutropenia often require a chemotherapy dose reduction to
prevent further episodes. The consequences of reducing dose or delaying administration include
several possible negative effects for clinical cancer outcomes. For example:1
� Dose reductions of 20–30% have been associated with lower complete response rates and/or
survival in patients with non-Hodgkin’s lymphoma (NHL)
� Sub-optimal dose administration (<85% of planned) in patients with breast cancer has been
associated with significantly reduced relapse-free and overall survival
Due to these and other negative effects on overall cancer outcomes, the EORTC guidelines
recommend avoiding chemotherapy dose reductions and delays, particularly in patients being
treated with curative intent and/or for prolongation of survival.2
3.4.4 Increased hospitalisation
Patients who experience an episode of neutropenia often end up in the hospital. In fact, the average
hospital stay for FN can exceed 1 week.During this time, patients may undergo numerous diagnostic
procedures and receive intravenous (IV) antibiotic support, which itself increases the risk of further
complications.13
The EORTC guidelines reviewed the evidence for risk factors for prolonged hospitalisation in patients
hospitalised for the management of established FN. Factors that were significantly associated with
the length of hospitalisation included:2
� Solid tumour diagnosis
� Days since chemotherapy
� Origin of fever
3.4.5 Quality of life issues
Studies have highlighted how patient quality of life (QoL) can be significantly impaired by
neutropenia. This may be related to hospitalisation issues (including economic impact), fatigue,
interference in daily routine, negative self-evaluation, negative emotion, and social isolation.5,14,15
Neutropenia, and the adverse effects associated with it, can have a major impact on patients’ QoL,
including:5
� Loss of mobility
� Emotional distress
� Increased hospitalisation
� Out-of-pocket expense incurrence
� Reduced energy levels
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3.5 How is neutropenia recognised?
Early assessment of neutropenia is important important to understand which patients are at risk of
developing neutropenia and to evaluate these patients closely during chemotherapy since most
overt signs of infection do not start to appear until later on (i.e. grades 3–4).
At-risk populations
Chemotherapy and febrile neutropenia risk
Recognising signs of infection
Minimising the risk of infection
Controlling infection if it does occur
Sepsis and the sepsis cascade
3.5.1 At-risk populations
Prior to administering each cycle of chemotherapy, patient-related risk factors should be evaluated
in the overall assessment of febrile neutropenia (FN) risk.The EORTC identified the risk factors most
consistently associated with an increase in FN risk. Particular consideration should be given to these
risk factors, including:2
� Age >65 years
� Advanced stage of disease
� Experience of previous episode(s) of FN
� Lack of granulocyte-colony stimulating factor (G-CSF) use
� Lack of antibiotic prophylaxis
For a full list of neutropenia risk factors, please refer to Appendix 2.
3.5.2 Chemotherapy and febrile neutropenia risk
Some chemotherapy regimens are associated with an increased risk of FN and this must also be
considered when evaluating the patient’s overall risk level.
Very careful consideration should be given to the elevated risk of FN when using certain
chemotherapy regimens. For a comprehensive list of common chemotherapy regimens associated
with intermediate or high-risk FN, please refer to Appendix 3.2
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3.5.3 Recognising signs of infection
Infection typically occurs in the more advanced grades of neutropenia (i.e. grade 3–4). It is an
extremely serious complication of neutropenia, with the risk of sepsis and the associated high
mortality rates.10 It is, therefore, very important to be able to identify any infections as early as
possible, and to become familiar with the signs of sepsis and the ‘sepsis cascade’.
To identify infection in neutropenia, look for signs of infection [in addition to possible systemic
inflammatory response syndrome (SIRS) symptoms above] at the following sites:
� Skin examination – rashes, ulcers or abscesses
� Oral mucosa – aphthous ulcers, thrush or periodontal disease
� Lymphadenopathy (a possible indication of disseminated infection or can also be associated with
certain cancers)
� Perirectal infections – abscesses or mucous membrane abnormalities
� Vaginal infections
� Perineal infections – rashes, abscesses or lymphadenopathy
� Lung infections – bacterial or fungal pneumonias
� Dysuria
� Alterations in consciousness
Aside from sepsis, patients with prolonged, severe neutropenia may be at risk of developing other
serious, life-threatening gastrointestinal or pulmonary infections [e.g. adult respiratory distress
syndrome (ARDS)].16
3.5.4 Minimising the risk of infection
The risk of infection can be minimised through patient evaluation and careful precautions, including:2
� Reviewing the medical plan for chemotherapy
� Reviewing the plan for antibiotic and granulocyte-colony stimulating factor (G-CSF) therapy
� Education regarding implementation of infection control measures
� Encouraging careful oral hygiene to prevent infections of the mucosa and teeth
� Promoting good skin care for wounds and abrasions
� Avoiding rectal temperature measurements and rectal examinations where possible
� Administering stool softeners (or aperients) for constipation
For a comprehensive list of measures for prevention/control of infection, please refer to Appendix 4
(preventive procedures) and Appendix 5 (patient education).16
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3.5.5 Controlling infection if it does occur
If a patient does suffer an episode of neutropenia, it is important to take measures to avoid infection.
If an infection does occur, there are also many factors to consider in the choice of antibiotic therapy.
Please refer to Appendix 6 for more details on antibiotic treatment of infection in FN.
3.5.6 Sepsis and the sepsis cascade
The American College of Chest Physicians/Society of Critical Care Medicine (1992) defines the sepsis
cascade as: infection, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis and
septic shock, multi-organ dysfunction.17 Nurses must be aware of their responsibility to initiate
further support (e.g. by alerting senior staff or doctors, in the event of signs of sepsis). Please refer to
Appendix 7 for further information on the sepsis cascade.
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3.6 How is neutropenia managed?
The best management of neutropenia is prevention. If a patient is at risk of becoming neutropenic,
certain preventative measures should be undertaken, including evaluating the patient’s need for
prophylactic therapy with a granulocyte-colony stimulating factor (G-CSF). In this way, many of the
negative effects of neutropenia can be avoided, including chemotherapy dose modifications.
Granulocyte-colony stimulating factors
Recommendations for granulocyte-colony stimulating factor use
Initiating treatment with a granulocyte-colony stimulating factor
Using a granulocyte-colony stimulating factor with dose-dense chemotherapy
Regimen-specific risk of febrile neutropenia
Duration of prophylactic granulocyte-colony stimulating factor
Education for patients receiving granulocyte-colony stimulating factors
Recommendations for the use of granulocyte-colony stimulating factors –
patients with ongoing febrile neutropenia
Recommendations for the use of granulocyte-colony stimulating factors –
patients on chemotherapy
Side effects of granulocyte-colony stimulating factors
Other issues
3.6.1 Granulocyte-colony stimulating factors
G-CSFs stimulate the production of white blood cells known as granulocytes, thereby helping to
decrease the depth and duration of neutropenia and reduce the chances of resulting infections.
G-CSFs are indicated for the prevention of FN and to decrease the duration of neutropenia.
The currently approved G-CSFs in Europe are:2
� Pegfilgrastim (Neulasta®, pegylated G-CSF [pegG-CSF])
� Filgrastim (Neupogen®, G-CSF)
� Lenograstim (Granocyte®, G-CSF)
� Sargramostim (Leukine®, GM-CSF) or molgrastim (not available in some EU countries)
N.B. Please refer to the detailed prescribing information for each product for a full description of
indications and dosing.
3.6.2 Recommendations for granulocyte-colony stimulating factor use
The EORTC guidelines state that pegfilgrastim, filgrastim and lenograstim have all demonstrated
clinical efficacy and that any of these are recommended to prevent FN and FN-related complications,
where indicated.2 Further clarification is required for the additional efficacy of pegfilgrastim, which
so far has been demonstrated in two separate retrospective analyses.2,18,19
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There is also strong evidence to show that G-CSF prophylaxis can be used to maintain chemotherapy
at the desired dose intensity or density and to minimise delays.2 However, there is no evidence that
G-CSF prophylaxis on its own can improve overall or progression-free survival.There is evidence that
G-CSF support allows the use of intensive chemotherapy regimens that may improve survival.2
Dose-dense or -intense chemotherapy is increasingly used in an attempt to improve long-term
clinical outcomes. Evidence has emerged that G-CSF prophylaxis can support the delivery of certain
intensive chemotherapy regimens by preventing any concomitant increase in the incidence of
prolonged neutropenia or FN.2 Furthermore, the three most prominent organisations in this field
(ASCO, EORTC and NCCN) are aligned in their recommendation for G-CSF support in all patients
receiving chemotherapy who have a risk of febrile neutropenia (FN) exceeding 20%, or in those
chemotherapy regimens with an intermediate (10–20%) risk of FN plus additional risk factors that
may contribute to overall risk of neutropenia.2,20,21
3.6.3 Initiating treatment with a granulocyte-colony stimulating factor
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Step 1 – Assess risk of FN associated with the planned chemotherapy regimen
Does the patient have a higher than average risk of severe FN-related complications?
Patient is diagnosed with FN
>20%
Prophylactic G-CSF recommended G-CSF use not indicated
10–20%
Does this increase the chance of FN such that the patient is at >20%?
Step 2 – Assess patient-related factors that could increase the risk of FN
High risk Age >65 years
Possible risk Advanced disease
Planned high- or full-dose chemotherapy
History of FN
Poor performance and/or nutritional state
No G-CSF use
No antibiotic prophylaxis
Female gender
Haemoglobin <12 g/dL
Liver, renal or cardiovascular disease (NHL)
<10%
Yes No
Yes No
Would chemotherapy dose reductions or delays result in a poor prognosis?
Yes No
Pri
or
to c
hem
oth
erap
yP
atie
nts
wit
h o
ng
oin
g F
N
Figure 1.Treatment algorithm for initiation of G-CSF.2
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The need for G-CSF support should be assessed routinely for every patient prior to each cycle of
chemotherapy.The first step in this process involves assessing FN risk for the planned chemotherapy
regimen.The next step is to identify any patient-related risk factors that could increase the risk of FN.
Following that, a judgement should be made on the overall FN risk. Finally, any other factors that
could increase the need for G-CSF prophylaxis, such as treatment for curative intent or to prolong
survival, should be considered. At this point, a decision should be made to give or withhold G-CSF
prophylaxis.2,20
3.6.4 Using a granulocyte-colony stimulating factor with dose-dense chemotherapy
In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits,
prophylactic G-CSF should be used.2 This allows dose-dense regimens to be administered for shorter
intervals, with a quicker recovery of the white blood cell (WBC) count. Therefore, without G-CSFs,
these regimens cannot be administered. Please refer to Appendix 8 for a list of chemotherapy
regimens supported by G-CSF.
3.6.5 Regimen-specific risk of febrile neutropenia
When using a chemotherapy regimen associated with >20% risk of FN, prophylactic G-CSF is
recommended by the EORTC (as well as ASCO and NCCN).2 Febrile neutropenia risk should be
assessed individually for each patient taking into account patient-related risk factors, the
chemotherapy regimen and treatment intent.When using chemotherapy regimens associated with
a 10–20% rate of FN,particular attention should be given to the assessment of patient characteristics
that may increase the overall risk of FN.2
3.6.6 Duration of prophylactic granulocyte-colony stimulating factor
Daily G-CSF: The length of treatment with daily G-CSFs varies from approximately 7–14 days but
should be continued until ANC reaches 2,000–3,000 cells/mm3.
Once-per-cycle G-CSF: Pegfilgrastim is a second generation G-CSF. Its longer duration of action
means it can be administered once per cycle.22 Recent reports show that it has efficacy similar to daily
G-CSF, as well as a similar safety and tolerability profile.22
Any decision on the dosing and duration of G-CSF should take into account efficacy data, as well as
convenience for the patient and the healthcare team.
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3.6.7 Education for patients receiving granulocyte-colony stimulating factors
Patients being prescribed G-CSF should be educated about the following important issues:2
� Why G-CSFs are used and the need for monitoring blood cell counts
� Localised skin sensitivities
� Side effects, particularly common ones such as bone pain and being aware of possible need for
analgesia
� Variations in administration (e.g.some practitioners advise patients to administer at night, so that
any short-term flu-like symptoms experienced will be minimised)
� How to prepare the injection
� How to store the injection
� Proper use of disposable syringes
� How to give the subcutaneous injection23
� Administration site rotation
� How long the injection is stable
3.6.8 Recommendations for the use of granulocyte-colony stimulating factors –
patients with ongoing febrile neutropenia
The EORTC guidelines state that treatment with G-CSF should be considered for patients with
ongoing FN, who do not respond rapidly to antibiotics, where there is an increased risk of FN-related
complications. In these cases, G-CSF use may reduce the risk of infection-related mortality or
morbidity.2 It should also be noted, however, that G-CSF use is not recommended for patients with
non-febrile neutropenia.2
3.6.9 Recommendations for the use of granulocyte-colony stimulating factors –
patients on chemotherapy
The EORTC guidelines are designed to complement previously published EORTC guidelines on the
use of G-CSFs in elderly patients with cancer.13,24 The latter suggest the routine use of G-CSFs in elderly
cancer patients undergoing chemotherapy in both first and subsequent cycles,since elderly patients
are not able to regenerate neutrophils as quickly, and take longer to recover from nadir periods.13
Patients should be evaluated during each cycle of treatment to determine their risk category.Nurses
should also evaluate the patient outcomes from each previous cycle (for example: What grade of
neutropenia did the patient experience? What was the length of their nadir? Was the patient able to
successfully self-administer G-CSF at home?)
Nurses can play a critical role in their multidisciplinary teams in assessing patient risk and deciding
whether G-CSF use is appropriate.3
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3.6.10 Side effects of granulocyte-colony stimulating factors
Nurses should educate patients that some of the side effects of G-CSF use can mimic the signs of
fever and infection (e.g.sweats).They should be made aware of when to contact health professionals
for further advice. Common side effects of G-CSFs may include:
� Headache
� Flu-like symptoms
� Bone pain
� Pain in arms or legs
� Pain in joints or muscles
� Pain in lower back or pelvis
� Skin rash or itching
Less common side effects may include:
� Dizziness or faintness after the first dose
� Flushing of face after the first dose
� Weakness
� Redness or pain at the sight of subcutaneous injection
� Fever
� Alopecia
� Shortness of breath
� Swelling of feet or lower legs
� Sudden weight gain
3.6.11 Other issues
Other issues for nurses’ consideration regarding patients’ use of G-CSFs include: whether it is easier
for patients to administer G-CSFs at home (leading to fewer visits, less out-of-pocket expenses and
perhaps improved quality of life issues), or whether it is more reassuring for the patient to have it
administered as an outpatient by a nurse or family member (e.g. if the patient is afraid of needles).
In many cases, issues like these can affect decisions like choice of therapy or dosing. Nurses, acting
within their multidisciplinary teams, can play an important role in assessing these issues and
identifying the appropriate course of action.3
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3.7 Summary
Like all healthcare professionals,nurses should strive to provide evidence-based care – ensuring that
granulocyte-colony stimulating factor (G-CSF) clinical guidelines are adhered to by:
� Assessing patients for risk factors, including both patient and treatment-risk factors
� Instituting preventative and management strategies around infection control
� Identifying with other members of their multi-disciplinary team, which patients are most at risk
� Advocating the highest quality of care for patients,so as to minimise risk and maximise outcomes
� Patient education
Evidence suggests that when guidelines such as these are successfully implemented in practice,
improvement may occur in terms of:25,26
� Febrile neutropenia (FN) episodes
� Length and extent of neutropenia
� Mortality
� Sepsis/infections
� Quality of life (QoL)
� Economic burden
� Antibiotic requirements
� Reduced hospitalisation
� Dose reductions and delays
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Appendix 1. Neutropenia grading:The Common Toxicity Criteria forAdverse Events.6
Grades of neutropenia, according to the NCI Common Toxicity Criteria for Adverse Events, range
from 0–5 (and associated ANC):
Grade 0 No adverse event (AE) ANC within normal limits
Grade 1 Mild AE ANC >1,500 cells/mm3
Grade 2 Moderate AE ANC 1,000–1,500 cells/mm3
Grade 3 Severe and undesirable AE ANC 500–1,000 cells/mm3
Grade 4 Life-threatening or disabling AE ANC <500 cells/mm3
Grade 5 Death related to AE
N.B. Please refer to the Abbreviations section for a full list of abbreviations used.
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Appendix 2. Patient-related risk factors for febrile neutropenia.2
These risk factors, from the EORTC guidelines, are also in agreement with those published in the
updated American Society of Clinical Oncology (ASCO) guidelines.
Level of evidence: I = Evidence obtained from a meta-analysis of multiple well-designed, controlled studies from high-powered,
randomised,controlled clinical trials; II = Evidence obtained from at least one well-designed,experimental study or low-powered,
randomised, controlled clinical trial; III = Evidence obtained from well-designed, quasi-experimental studies such as non-
randomised, controlled single-group, pre-post, cohort, time or matched case control series; IV = Evidence obtained from well-
designed non-experimental studies such as comparative and correlational descriptive and case studies.
N.B. Please refer to the Abbreviations section for a full list of abbreviations used.
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Lyman et al. Timmer-Bonte Tjan-Heijnen Fosså Millward Gianni Lyman & Brooks Dale (2005) et al (2005) et al (2001) et al (1998) et al (2003) et al (1995) Delgado (2003) et al (2006) et al (2004)
Cancer Various SCLC SCLC Germ cell NSCLC Breast cancer NHL NHL NHLtumours
Study design Systematic Phase III RCT Phase III RCT Phase III RCT Phase II NR Phase I NR Retrospective HE analysis Retrospective review
Patient risk factor
Older age III+ II + I + II + IV + IV+
Advanced disease/metastasis I + IV + IV- IV +
No antibiotic I +prophylaxis
Prior episode of FN II +
No G-CSF use II + IV-
Female gender III+ IV + IV+
Haemoglobin III+ (FN in IV +<12 g/dL/anaemia 1st cycle)
Cardiovascular III+ (NHL) IV-disease
Renal III+ (NHL) Excludeddisease
Abnormal liver III+ (NHL) Excluded IV +transaminases
Planned high (>_80%) III+ IV +chemotherapy dose intensity
Poor performance III+ IV+and/or nutritional status
>_1 comorbidity IV + IV +
Lymphoma histology IV +
Asian origin IV +
Body surface IV +area <2.0 m2
Pretreatment ANC IV +<1.5 109/L
Serum albumin IV +<_3.5 g/dL
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Appendix 3. Common chemotherapy regimens associated withintermediate or high-risk febrile neutropenia.2
Low FN risk (<10%)
Intermediate FN risk (10–20%)
High FN risk (>20%)
Chemotherapy Dose (mg/m2, unless otherwise Risk ofstated) and dosing schedule FN (%)
Breast cancer
FEC 90/100 500/90–100/500 Q3W 0–2
CMF 600/(40/600)d1 + 8 Q3W 0–3
CMF oral 100d1–14/(40/600)d1 + 8 Q4W 1
Doxorubicin/cyclophosphamide 60/600 Q3W 2
Doxorubicin�paclitaxel�cyclophosphamide (60�175�600) Q3W 3
FAC 50 500/50/500 Q3W 5
Doxorubicin/cyclophosphamide�paclitaxel (60/600�175) Q3W 5
Epirubicin/cyclophosphamide ± lonidamide 120/600 ± 450mg/d Q3W 7
FEC 120 (500/60)d1 + 8/75d1–14 Q4W 9–14
AC 60/600 Q3W 10–20
Cyclophosphamide/mitoxantrone 600/23 Q3W + G-CSF 11
Epidoxorubicin/cyclophosphamide 100/600 Q2–3W 13
Capecitabine/docetaxel 2,500d1–14/75 Q3W 13
CEF 75d1–14/60d1 + 8/500d1 + 8 Q4W 14
Doxorubicin/vinorelbine 40/20d1 + 8 Q3W 15
Docetaxel 100 Q3W 16–17
AC�T (60/600�100) Q3W 5–25
Doxorubicin/paclitaxel 60/125–200 Q3W 21–32
TAC 75/50/500 Q3W 24
Doxorubicin/docetaxel 50/75 Q3W 33–48
T�AC (100�60/600) Q3W 40
Breast cancer – dose dense regimens
DDG* doxorubicin�paclitaxel�cyclophosphamide (60�175�600) Q2W + G-CSF >20 (2)†
DDG* doxorubicin/cyclophosphamide�paclitaxel (60/600�175) Q2W + G-CSF >20 (2)†
DDG* epirubicin/cyclophosphamide 120/830 Q2W + G-CSF >20 (8)†
DD FEC 3,000d1–3/35d2–4/400d2–4 Q3W 71(59)†
Colorectal cancer
5-FU/leucovorin Q2W (400–600/200)d1 + 2 Q2W 0–1
FOLFOX Variations on standard 0–8
IFL Various 2–7
Irinotecan 300–350 Q3W or 125d1 + 7 + 14 + 21 2–7
5-FU/leucovorin monthly (425/20)d1–5 Q4W–Q5W 1–15
FOLFIRI Variations on standard Q2W 3–14
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Chemotherapy Dose (mg/m2, unless otherwise Risk ofstated) and dosing schedule FN (%)
Pancreatic cancer
Gemcitabine/irinotecan 1,000d1 + 8/300d8 Q3W 17
Non-small-cell lung cancer
Paclitaxel/carboplatin 175–225/AUC6 Q3W 0–9
Gemcitabine/cisplatin 1,250d1 + 8/75–100 Q3W 1–7
Gemcitabine/cisplatin 1,000d1 + 8 +15/100 Q4W 4
Vinorelbine/cisplatin 25/100 Q4W 1–10
Docetaxel/cisplatin 75/75 Q3W 5–11
Paclitaxel/cisplatin 135/75d2 Q3W 16
VIG (25d1 + 20–25d4)/3,000/(1,000d1 +800–1,000d4) Q3W 25
Docetaxel/carboplatin 75/AUC6 Q3W 26
Etoposide/cisplatin (200/35)d1–3 Q4W 54
Small-cell lung cancer
CAV�PE (800/50/1.4�80–100/100d1–3) Q3W 3–9
Paclitaxel/carboplatin 200/AUC6 Q3W 9
Etoposide/carboplatin 100d1–3/300 Q3W 10–20
CAV 750/40/1.3 Q3W 14
CODE 25/1 (not W3,5,7–9)/40 (not W2,4,6,8)/80d1–3 (not W2,4,6,8) QW + G-CSF 19
Topotecan/cisplatin 0.75d1–5/60 Q3W 19
Topotecan/paclitaxel 1d1–5/135d5 Q4W > 20
ICE 5,000/300/180d1 + 2 Q4W 24
ACE 45–50/1,000/100–120d1–3 Q3W 24–57
Topotecan 1.5d1–5 Q3W 28
VICE 1mgd15/5,000/300/120d1 + 2+240d3 Q2–6W 70
Small-cell lung cancer – dose-dense regimens
DDG* CAV�PE (500/30/1�50/75d1 + 2) QW >20 (4)†
DDG* CE 5,000/300/180d1 + 2 Q2W + G-CSF >20 (18)†
DDG* ACE 55/1,250/125d1–3 Q2W + G-CSF >20 (34–56)†
Ovarian cancer
Paclitaxel/carboplatin 175–185/AUC5–6 Q3W 3–8
Gemcitabine/cisplatin 1,000d1 + 8/AUC5 Q3W 9
Topotecan 1.5d1–5 Q3W 10–18
Paclitaxel 135–175 Q3W 22
Docetaxel 75–100 Q3W 33
Cervical cancer
Paclitaxel/cisplatin 135–170/75d2 Q3W 28
Endometrial cancer
Doxorubicin/cisplatin 60/50 Q3W 2
TAP 160d2/45/50 + G-CSF Q3W 3
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Chemotherapy Dose (mg/m2, unless otherwise Risk ofstated) and dosing schedule FN (%)
Urothelial cancer
Paclitaxel/carboplatin 150–225/AUC6 Q3W 25
MVAC 30d1 + 8 + 15/3d1 + 8 + 15/30d2/70 Q4W 26
Urothelial cancer – dose-dense regimens
DDG* MVAC 30d1 + 8/3d1 + 8/30d2/70 + G-CSF Q2W >20 (10)†
Germ cell tumours
Cisplatin/etoposide (20/100)d1–5 Q3W 10
BEP�EP 30Ud2 + 9+ 16/100d1–5/20d1–5 Q3W�100d1–5/20d1–5 Q3W 13
BOP�VIP-B 30U/2mg/50d1 + 2 Q10d�20d1–5/1,000d1–5/100d1 + 3 + 5/30Ud8 + 15 Q3W 46
VeIP 0.11mg/kgd1 + 2/1,200d1–5/20d1–5 Q3W 67
Head and neck cancer
TIC 175/1,000d1–3/AUC6 Q3–4W 30
Sarcoma
MAID (3,000/20/2,500/300)d1–3 Q3W 58
Hodgkin’s disease
ABVD (25/10/6/375)d1 + 15 Q4W 4
Stanford V Standard 14
Non-Hodgkin’s lymphoma
ACOD 25/500/1.2d1 + 8/50 mgd1 + 8 Q3W 11
Fludarabine/mitoxantrone 25d1–3/10 Q4W 11
R-CHOP-21 375/(750/50/1.4)d3/100 mgd3–7 Q3W 19
CHOP-21 750/50/1.4/50–100 mgd1–5 Q3W 17–50
ESHAP 40–60d1–4/500 mgd1–5/ 2,000d5/25d1–4 Q3W–Q4W 30–64
DHAP 100/2 x 2,000d2/40 mgd1–4 Q3W–Q4W 48
Non-Hodgkin’s lymphoma – dose-dense regimens
DD VAPEC-B 1.4/35/0–50 mgd1–7/100d1–5/350/10 QW 44(23)†
DD A(N)CVB 75(12)/1,200/2d1 + 5/10 mgd1 + 5 Q2W 78(52)†
* DDG indicates dose-dense regimens supported by primary prophylactic G-CSF to reduce the
incidence of neutropenia.
† Scores in parentheses indicate the risk of neutropenia for the dose-dense regimen when
supported by G-CSF.
N.B. Please refer to the Abbreviations section for a full list of abbreviations used.
Return to text
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24
Appendix 4. Procedures for infection prevention/control.2,17
There are a number of preventative procedures that you can do to prevent/control infection:
� Hand washing
� Correct cleaning preparation for any invasive procedure
� Meticulous IV line maintenance and avoiding indwelling urinary catheter, if possible
� Good central line care, including push-pull technique for flushing after medication, fluids, blood
products or blood sampling
� Starting ordered antibiotics STAT (immediately)
� Full physical examination and monitoring for the following potential infections:
� Pneumonia
� Skin and soft tissue
� Urinary tract infections
� Gastrointestinal infections
� Pharyngitis/oesophagitis
� Mucositis
� Perianal/vaginal/perineal infections
� Generalised sepsis
� Blood cultures (at >38.5°C, or >38°C for more than 1 hour), ensuring all secretions and excretions
are sent for M,C&S
� Being aware of the ‘high’ risk patients as well as:
� Patients already in hospital when becoming febrile
� Patients requiring hospitalisation for other reasons
� Patients with progressive and advancing disease
� Patients with pneumonia
� Patients with previous stem cell transplant
� Patients with abnormal liver and kidney function.
� Close observation of patients vital signs (haemodynamic observations)
� Avoidance of enemas, rectal temperatures and anything invasive to mucosal membranes
N.B. Please refer to the Abbreviations section for a full list of abbreviations used.
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Appendix 5. Patient education for the prevention/control of infection.2,17
In addition, infection can be controlled/avoided through simple patient education, including
teaching patients about basic hygiene measures:
� Frequent and thorough hand washing
� Daily showers or baths
� Frequent and gentle mouth care – before and after meals
� Gentle daily exercise
� Deep breathing exercises (to prevent atelectasis and stasis of secretions in the lungs in unwell
patients)
� Avoiding uncooked food or food that cannot be washed*
� Avoiding contact with people exposed to infectious diseases, or with known infections
� Avoiding people recently vaccinated with live vaccines for 30 days
� Avoiding the ‘flu jab’ and live vaccines at the time of CIN
� Using barrier protection during sexual intercourse at severe neutropenia
� Avoiding sharing of cutlery or toothbrushes
� Avoiding contact with cat litter, pet excretia
� Being aware of nosocomial infections
* Precautions remain contentious regarding the practice of peeling fruit/vegetable peeling since
the evidence doesn’t support it entirely. Some units still recommend use of filtered water. In high
dose and transplant patients this practice is common.
N.B. Please refer to the Abbreviations section for a full list of abbreviations used.
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Appendix 6. Antibiotic treatment of infection in febrile neutropenia.2,16,27,28
Patients with neutropenic complications following chemotherapy are usually hospitalised and given
broad-spectrum intravenous (IV) antibiotics.
Timing of infection
� Atypical bacterial infections usually manifest around 4–7 days.
� Invasive fungal infections (particularly those caused by Aspergillus species) appear in prolonged
neutropenia (>7 days).27
Important considerations
� It is important for nurses to take certain factors into account when preparing for the
administration of antibiotics in patients with neutropenia:2,16
� Age of the patient
� Potential hospitalisation duration
� Patient co-morbidities (e.g. renal impairment limits the drugs that will be used)
� Type of cancer (e.g. avoiding aminoglycosides in teratoma patients)
� Blood culture results
� Correct dose and timing of dose
� Nurses should also review the results of blood cultures once established to ensure the right
antibiotic therapy is maintained
� Each antibiotic is associated with contraindications (e.g.hypersensitivity) and precautions (e.g.
renal function monitoring, liver function, haematopoietic function) and resistant infections
may occur with prolonged or repeated antibiotic therapy
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Appendix 7. Sepsis and the sepsis cascade.28
The symptoms of systemic inflammatory response syndrome (SIRS) include:
� Heart rate: >90
� Temperature: >38°C or <36°C
� Respiratory rate: >20 (or PaC0 <4.3kPa)
� WBC: <4, >12, or >10% immature bands
Sepsis cascade:
Sepsis: SIRS plus the presence of infection (documented by positive culture for organisms from that
site). Blood cultures (presence of bacteraemia) do NOT need to be positive. Or, SIRS in presence of
haematological failure
Severe sepsis: Sepsis associated with organ dysfunction, hypoperfusion abnormalities or
hypotension. Hypoperfusion abnormalities include, but are not limited to:
� Lactic acidosis
� Oliguria
� Acute alteration in mental status
Septic shock: Sepsis-induced hypotension despite fluid resuscitation, PLUS hypoperfusion
abnormalities (may be evident as early signs of organ dysfunction in lungs,kidneys, liver,GI tract,skin,
heart, haematological and neurobiological systems).
Multiple Organ Dysfunction Syndrome (MODS): Presence of organ dysfunction in an acutely ill
patient – to the extent that homeostasis cannot be maintained without critical care support.
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Appendix 8. Intensive chemotherapy regimens supported by G-CSF.2
Malignancy Chemotherapy regimen and level of evidence
Dose-dense regimens (increased frequency)*
Breast cancer FEC I
Epirubicin/cyclophosphamide
Doxorubicin�paclitaxel�cyclophosphamide
Doxorubicin/cyclophosphamide�paclitaxel
R-CHOP II
R-CHOP
MMM III
SCLC ACE II
CAV�PE (alternating weekly)
VICE (>_Q2W, not fixed)
CODE (QW)
Cisplatin/epirubicin/paclitaxel IV
NSCLC Cisplatin/vindesine/mitomycin C (PVM) II
Urothelial cancer MVAC II
Dose-intense regimens (increased dose)
HD BEACOPP II
Ovarian cancer Paclitaxel II
SCLC ACE II
Dose-modified regimens (withdrawal of one drug and increase in the dose of the remainder)
Breast cancer Epirubicin/cyclophosphamide with withdrawal of 5-FU I
Cyclophosphamide with high-dose mitoxantrone III
and withdrawal of doxorubicin
* The dose-dense regimens were given every 2 weeks, unless otherwise specified.
N.B. Please refer to the Abbreviations section for a full list of abbreviations used.
Return to text
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29
Abbreviations
5-FU 5-fluorouracil
ABVD doxorubicin/bleomycin/vinblastine/dacarbazine
AC doxorubicin/cyclophosphamide
ACE doxorubicin/cyclophosphamide/etoposide
ACOD doxorubicin/cyclophosphamide/vincristine/prednisolone
AC�T doxorubicin/cyclophosphamide followed by docetaxel
ANC absolute neutrophil count
A(N)CVB doxorubicin/mitoxantrone/cyclophosphamide/vindesine/bleomycin
ARDS adult respiratory distress syndrome
ASCO American Society of Clinical Oncology
AUC area under the curve
BEACOPP bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone
BEP bleomycin/etoposide/cisplatin
BOP bleomycin/vincristine/cisplatin
CAV cyclophosphamide/ doxorubicin/vincristine
CAV�PE cyclophosphamide/ doxorubicin/vincristine followed by cisplatin/etoposide
CE cyclophosphamide/epirubicin
CEF cyclophosphamide/epirubicin/5-FU
CHOP-21 cyclophosphamide/doxorubicin/vincristine/prednisone
CIN chemotherapy-induced neutropenia
CMF cyclophosphamide/methotrexate/fluorouracil
CMV cytomegalovirus
CODE cisplatin/vincristine/doxorubicin/etoposide
DD dose dense
DDG dose-dense regimen supported by primary prophylactic G-CSF
DHAP cisplatin/cytarabine/dexamethasone
EORTC European Organisation for Research and Treatment of Cancer
EP etoposide/cisplatin
ESHAP etoposide/methylprednisolone/cytarabine/cisplatin
FAC fluorouracil/doxorubicin/cyclophosphamide
FEC cyclophosphamide/epirubicin/fluorouracil
FN febrile neutropenia
FOLFIRI 5-FU/l-folinic acid/d,l-folinic acid/irinotecan
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FOLFOX 5-FU/folinic acid/oxaliplatin
G-CSF granulocyte-colony stimulating factor
GM-CSF granulocyte macrophage-colony stimulating factor
HD Hodgkin’s disease
ICE ifosfamide/carboplatin/etoposide
IFL irinotecan/5-FU/calcium folinate
MAID mesna/doxorubicin/ifosfamide/dacarbazine
M,C&S microscopy, culture and sensitivity
MMM mitoxantrone/methotrexate/mitomycin
MODS Multiple Organ Dysfunction Syndrome
MVAC methotrexate/vinblastine/doxorubicin/cisplatin
NCCN National Comprehensive Cancer Network
NCI National Cancer Institute
NHL non-Hodgkin’s lymphoma
NR non-randomised
NSCLC non-small-cell lung cancer
PCP pneumocystis carinii pneumonia
PE cisplatin/etoposide
pegG-CSF pegylated G-CSF
PVM cisplatin/vindesine/mitomycin C
QoL quality of life
Q10d once every 10 days
QW once weekly
Q2W once every 2 weeks
Q3W once every 3 weeks
Q4W once every 4 weeks
Q5W once every 5 weeks
R-CHOP-21 rituximab/CHOP
RCT randomised controlled trial
SCLC small-cell lung cancer
SIRS systemic inflammatory response syndrome
Stanford V mustard/doxorubicin/vinblastine/vincristine/bleomycin/etoposide/prednisolone
STAT a common medical abbreviation that means ‘now’ or ‘rush’
T�AC docetaxel followed by doxorubicin/cyclophosphamide
TAC docetaxel/doxorubicin/cyclophosphamide
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TAP paclitaxel/oxorubicin/cisplatin
TB tuberculosis
TIC paclitaxel/ifosfamide/carboplatin
U ungraded
VAPEC-B vincristine/doxorubicin/prednisolone/etoposide/cyclophosphamide/bleomycin
VeIP vinblastine/ifosfamide/cisplatin
VICE vincristine/ifosfamide/carboplatin/etoposide
VIG vinorelbine/ifosfamide/gemcitabine
VIP-B cisplatin/ifosfamide/etoposide/bleomycin
WBC white blood cells
WHO World Health Organisation
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