Section 3 G-CSF in neutropenia guidelines. Implementation Toolkit

Transcription

1 Section 3 G-CSF in neutropenia guidelines Guidelines Implementation Toolkit

2 Contents Section 3 G-CSF in neutropenia guidelines Introduction to Section 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 2

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 3

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 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. 4

5 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 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. 5

6 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/mm 3. 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 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 NCI Common Toxicity Criteria grade 6 ANC (cells/mm 3 ) Neutropenia grade 7 Grade 2 Moderate 1,000 1,500 Mild Grade 3 Severe 500 1,000 Moderate Grade 4 Life-threatening <500 Severe For full details on the Common Toxicity Criteria, please see Appendix 1. 6 If the neutrophil count descends below 500 cells/mm 3 ; there is a high risk of overwhelming infection that will require hospitalisation and treatment with antibiotics Febrile neutropenia Febrile neutropenia (FN) refers to neutropenia (<500 cells/mm 3,or <1,000 cells/mm 3 with a predicted decrease to <500 cells/mm 3 ) 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. 6

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 Chemotherapyinduced neutropenia (CIN) leads to an increased susceptibility to infection and fever. When does chemotherapy-induced neutropenia occur? 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 7

8 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 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, Gramnegative sepsis, pneumonia and other lung disease, cerebrovascular, renal, and liver disease) 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 8

9 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 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 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 9

10 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 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 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

11 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)] 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)

12 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 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. 12

13 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 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 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 13

14 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, Initiating treatment with a granulocyte-colony stimulating factor Step 1 Assess risk of FN associated with the planned chemotherapy regimen >20% 10 20% <10% Prior to chemotherapy 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) Does this increase the chance of FN such that the patient is at >20%? Yes No Would chemotherapy dose reductions or delays result in a poor prognosis? Yes No Prophylactic G-CSF recommended G-CSF use not indicated Patients with ongoing FN Yes No Does the patient have a higher than average risk of severe FN-related complications? Patient is diagnosed with FN Figure 1.Treatment algorithm for initiation of G-CSF. 2 14

15 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, 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 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 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/mm 3. 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. 15

16 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 injection 23 Administration site rotation How long the injection is stable 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 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 16

17 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 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 17

18 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 18

19 Appendix 1. Neutropenia grading:the Common Toxicity Criteria for Adverse 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/mm 3 Grade 2 Moderate AE ANC 1,000 1,500 cells/mm 3 Grade 3 Severe and undesirable AE ANC 500 1,000 cells/mm 3 Grade 4 Life-threatening or disabling AE ANC <500 cells/mm 3 Grade 5 Death related to AE N.B. Please refer to the Abbreviations section for a full list of abbreviations used. Return to text 19

20 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 nonrandomised, controlled single-group, pre-post, cohort, time or matched case control series; IV = Evidence obtained from welldesigned non-experimental studies such as comparative and correlational descriptive and case studies. 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 NHL tumours 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) IVdisease Renal III+ (NHL) Excluded disease 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 m 2 Pretreatment ANC IV + < /L Serum albumin IV + <_3.5 g/dl N.B. Please refer to the Abbreviations section for a full list of abbreviations used. Return to text 20

21 Appendix 3. Common chemotherapy regimens associated with intermediate or high-risk febrile neutropenia. 2 Low FN risk (<10%) Intermediate FN risk (10 20%) High FN risk (>20%) Chemotherapy Dose (mg/m 2, unless otherwise Risk of stated) and dosing schedule FN (%) Breast cancer FEC 90/ /90 100/500 Q3W 0 2 CMF 600/(40/600) d1 + 8 Q3W 0 3 CMF oral 100 d1 14 /(40/600) d1 + 8 Q4W 1 Doxorubicin/cyclophosphamide 60/600 Q3W 2 Doxorubicin paclitaxel cyclophosphamide ( ) Q3W 3 FAC /50/500 Q3W 5 Doxorubicin/cyclophosphamide paclitaxel (60/ ) Q3W 5 Epirubicin/cyclophosphamide ± lonidamide 120/600 ± 450mg/d Q3W 7 FEC 120 (500/60) d1 + 8 /75 d1 14 Q4W 9 14 AC 60/600 Q3W Cyclophosphamide/mitoxantrone 600/23 Q3W + G-CSF 11 Epidoxorubicin/cyclophosphamide 100/600 Q2 3W 13 Capecitabine/docetaxel 2,500 d1 14 /75 Q3W 13 CEF 75 d1 14 /60 d1 + 8 /500 d1 + 8 Q4W 14 Doxorubicin/vinorelbine 40/20 d1 + 8 Q3W 15 Docetaxel 100 Q3W AC T (60/ ) Q3W 5 25 Doxorubicin/paclitaxel 60/ Q3W TAC 75/50/500 Q3W 24 Doxorubicin/docetaxel 50/75 Q3W T AC (100 60/600) Q3W 40 Breast cancer dose dense regimens DDG* doxorubicin paclitaxel cyclophosphamide ( ) Q2W + G-CSF >20 (2) DDG* doxorubicin/cyclophosphamide paclitaxel (60/ ) Q2W + G-CSF >20 (2) DDG* epirubicin/cyclophosphamide 120/830 Q2W + G-CSF >20 (8) DD FEC 3,000 d1 3 /35 d2 4 /400 d2 4 Q3W 71(59) Colorectal cancer 5-FU/leucovorin Q2W ( /200) d1 + 2 Q2W 0 1 FOLFOX Variations on standard 0 8 IFL Various 2 7 Irinotecan Q3W or 125 d FU/leucovorin monthly (425/20) d1 5 Q4W Q5W 1 15 FOLFIRI Variations on standard Q2W

22 Chemotherapy Dose (mg/m 2, unless otherwise Risk of stated) and dosing schedule FN (%) Pancreatic cancer Gemcitabine/irinotecan 1,000 d1 + 8 /300 d8 Q3W 17 Non-small-cell lung cancer Paclitaxel/carboplatin /AUC6 Q3W 0 9 Gemcitabine/cisplatin 1,250 d1 + 8 / Q3W 1 7 Gemcitabine/cisplatin 1,000 d /100 Q4W 4 Vinorelbine/cisplatin 25/100 Q4W 1 10 Docetaxel/cisplatin 75/75 Q3W 5 11 Paclitaxel/cisplatin 135/75 d2 Q3W 16 VIG (25 d d4 )/3,000/(1,000 d ,000 d4 ) Q3W 25 Docetaxel/carboplatin 75/AUC6 Q3W 26 Etoposide/cisplatin (200/35) d1 3 Q4W 54 Small-cell lung cancer CAV PE (800/50/ /100 d1 3 ) Q3W 3 9 Paclitaxel/carboplatin 200/AUC6 Q3W 9 Etoposide/carboplatin 100 d1 3 /300 Q3W CAV 750/40/1.3 Q3W 14 CODE 25/1 (not W3,5,7 9) /40 (not W2,4,6,8) /80 d1 3 (not W2,4,6,8) QW + G-CSF 19 Topotecan/cisplatin 0.75 d1 5 /60 Q3W 19 Topotecan/paclitaxel 1 d1 5 /135 d5 Q4W > 20 ICE 5,000/300/180 d1 + 2 Q4W 24 ACE 45 50/1,000/ d1 3 Q3W Topotecan 1.5 d1 5 Q3W 28 VICE 1mg d15 /5,000/300/120 d d3 Q2 6W 70 Small-cell lung cancer dose-dense regimens DDG* CAV PE (500/30/1 50/75 d1 + 2 ) QW >20 (4) DDG* CE 5,000/300/180 d1 + 2 Q2W + G-CSF >20 (18) DDG* ACE 55/1,250/125 d1 3 Q2W + G-CSF >20 (34 56) Ovarian cancer Paclitaxel/carboplatin /AUC5 6 Q3W 3 8 Gemcitabine/cisplatin 1,000 d1 + 8 /AUC5 Q3W 9 Topotecan 1.5 d1 5 Q3W Paclitaxel Q3W 22 Docetaxel Q3W 33 Cervical cancer Paclitaxel/cisplatin /75 d2 Q3W 28 Endometrial cancer Doxorubicin/cisplatin 60/50 Q3W 2 TAP 160 d2 /45/50 + G-CSF Q3W 3 22

23 Chemotherapy Dose (mg/m 2, unless otherwise Risk of stated) and dosing schedule FN (%) Urothelial cancer Paclitaxel/carboplatin /AUC6 Q3W 25 MVAC 30 d /3 d /30 d2 /70 Q4W 26 Urothelial cancer dose-dense regimens DDG* MVAC 30 d1 + 8 /3 d1 + 8 /30 d2 /70 + G-CSF Q2W >20 (10) Germ cell tumours Cisplatin/etoposide (20/100) d1 5 Q3W 10 BEP EP 30U d /100 d1 5 /20 d1 5 Q3W 100 d1 5 /20 d1 5 Q3W 13 BOP VIP-B 30U/2mg/50 d1 + 2 Q10d 20 d1 5 /1,000 d1 5 /100 d /30U d Q3W 46 VeIP 0.11mg/kg d1 + 2 /1,200 d1 5 /20 d1 5 Q3W 67 Head and neck cancer TIC 175/1,000 d1 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) d Q4W 4 Stanford V Standard 14 Non-Hodgkin s lymphoma ACOD 25/500/1.2 d1 + 8 /50 mg d1 + 8 Q3W 11 Fludarabine/mitoxantrone 25 d1 3 /10 Q4W 11 R-CHOP /(750/50/1.4) d3 /100 mg d3 7 Q3W 19 CHOP /50/1.4/ mg d1 5 Q3W ESHAP d1 4 /500 mg d1 5 / 2,000 d5 /25 d1 4 Q3W Q4W DHAP 100/2 x 2,000 d2 /40 mg d1 4 Q3W Q4W 48 Non-Hodgkin s lymphoma dose-dense regimens DD VAPEC-B 1.4/35/0 50 mg d1 7 /100 d1 5 /350/10 QW 44(23) DD A(N)CVB 75(12)/1,200/2 d1 + 5 /10 mg d1 + 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 23

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. Return to text 24

25 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. Return to text 25

26 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 Return to text 26

27 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. Return to text 27

28 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 and withdrawal of doxorubicin III * 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 28

29 Abbreviations 5-FU ABVD AC ACE ACOD AC T ANC A(N)CVB ARDS ASCO AUC BEACOPP BEP BOP CAV CAV PE CE CEF CHOP-21 CIN CMF CMV CODE DD DDG DHAP EORTC EP ESHAP FAC FEC FN FOLFIRI 5-fluorouracil doxorubicin/bleomycin/vinblastine/dacarbazine doxorubicin/cyclophosphamide doxorubicin/cyclophosphamide/etoposide doxorubicin/cyclophosphamide/vincristine/prednisolone doxorubicin/cyclophosphamide followed by docetaxel absolute neutrophil count doxorubicin/mitoxantrone/cyclophosphamide/vindesine/bleomycin adult respiratory distress syndrome American Society of Clinical Oncology area under the curve bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone bleomycin/etoposide/cisplatin bleomycin/vincristine/cisplatin cyclophosphamide/ doxorubicin/vincristine cyclophosphamide/ doxorubicin/vincristine followed by cisplatin/etoposide cyclophosphamide/epirubicin cyclophosphamide/epirubicin/5-fu cyclophosphamide/doxorubicin/vincristine/prednisone chemotherapy-induced neutropenia cyclophosphamide/methotrexate/fluorouracil cytomegalovirus cisplatin/vincristine/doxorubicin/etoposide dose dense dose-dense regimen supported by primary prophylactic G-CSF cisplatin/cytarabine/dexamethasone European Organisation for Research and Treatment of Cancer etoposide/cisplatin etoposide/methylprednisolone/cytarabine/cisplatin fluorouracil/doxorubicin/cyclophosphamide cyclophosphamide/epirubicin/fluorouracil febrile neutropenia 5-FU/l-folinic acid/d,l-folinic acid/irinotecan 29

30 FOLFOX G-CSF GM-CSF HD ICE IFL MAID M,C&S MMM MODS MVAC NCCN NCI NHL NR NSCLC PCP PE pegg-csf PVM QoL Q10d QW Q2W Q3W Q4W Q5W 5-FU/folinic acid/oxaliplatin granulocyte-colony stimulating factor granulocyte macrophage-colony stimulating factor Hodgkin s disease ifosfamide/carboplatin/etoposide irinotecan/5-fu/calcium folinate mesna/doxorubicin/ifosfamide/dacarbazine microscopy, culture and sensitivity mitoxantrone/methotrexate/mitomycin Multiple Organ Dysfunction Syndrome methotrexate/vinblastine/doxorubicin/cisplatin National Comprehensive Cancer Network National Cancer Institute non-hodgkin s lymphoma non-randomised non-small-cell lung cancer pneumocystis carinii pneumonia cisplatin/etoposide pegylated G-CSF cisplatin/vindesine/mitomycin C quality of life once every 10 days once weekly once every 2 weeks once every 3 weeks once every 4 weeks once every 5 weeks R-CHOP-21 rituximab/chop RCT SCLC SIRS Stanford V STAT T AC TAC randomised controlled trial small-cell lung cancer systemic inflammatory response syndrome mustard/doxorubicin/vinblastine/vincristine/bleomycin/etoposide/prednisolone a common medical abbreviation that means now or rush docetaxel followed by doxorubicin/cyclophosphamide docetaxel/doxorubicin/cyclophosphamide 30

31 TAP TB TIC U VAPEC-B VeIP VICE VIG VIP-B WBC WHO paclitaxel/oxorubicin/cisplatin tuberculosis paclitaxel/ifosfamide/carboplatin ungraded vincristine/doxorubicin/prednisolone/etoposide/cyclophosphamide/bleomycin vinblastine/ifosfamide/cisplatin vincristine/ifosfamide/carboplatin/etoposide vinorelbine/ifosfamide/gemcitabine cisplatin/ifosfamide/etoposide/bleomycin white blood cells World Health Organisation 31

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