Position Paper
2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours

https://doi.org/10.1016/j.ejca.2010.10.013Get rights and content

Abstract

Chemotherapy-induced neutropenia is a major risk factor for infection-related morbidity and mortality and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival.

In Europe, prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim (including approved biosimilars), lenograstim or pegfilgrastim is available to reduce the risk of chemotherapy-induced neutropenia. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. The need for generally applicable, European-focused guidelines led to the formation of a European Guidelines Working Party by the European Organisation for Research and Treatment of Cancer (EORTC) and the publication in 2006 of guidelines for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. A new systematic literature review has been undertaken to ensure that recommendations are current and provide guidance on clinical practice in Europe. We recommend that patient-related adverse risk factors, such as elderly age (⩾65 years) and neutrophil count be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. It is important that after a previous episode of FN, patients receive prophylactic administration of G-CSF in subsequent cycles. We provide an expanded list of common chemotherapy regimens considered to have a high (⩾20%) or intermediate (10–20%) risk of FN. Prophylactic G-CSF continues to be recommended in patients receiving a chemotherapy regimen with high risk of FN. When using a chemotherapy regimen associated with FN in 10–20% of patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Clinical evidence shows that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications where indicated. Filgrastim biosimilars are also approved for use in Europe. While other forms of G-CSF, including biosimilars, are administered by a course of daily injections, pegfilgrastim allows once-per-cycle administration. Choice of formulation remains a matter for individual clinical judgement. Evidence from multiple low level studies derived from audit data and clinical practice suggests that some patients receive suboptimal daily G-CSFs; the use of pegfilgrastim may avoid this problem.

Introduction

Chemotherapy-induced febrile neutropenia (FN) is a potentially fatal complication of cancer treatment, when it heralds infection and sepsis, and is seen most often during the initial cycles of myelosuppressive therapy.1, 2, 3, 4, 5, 6, 7, 8 Prevention of FN reduces hospital admissions, antibiotic usage and the need for dose reductions or delays in chemotherapy administration, which are associated with a poorer cancer outcome.9, 10, 11, 12, 13

Prophylactic administration of daily granulocyte-colony stimulating factor (G-CSF; filgrastim [Neupogen®] and lenograstim [Granocyte®]) or once per cycle administration of the pegylated form of G-CSF (pegfilgrastim, [Neulasta®])14, 15, 16, 17, 18 provides protection for patients at risk of FN. In 2005, a European Guidelines Working Party was set up by the European Organisation for Research and Treatment of Cancer (EORTC) to systematically review available published data and derive evidence-based recommendations on the appropriate use of G-CSF in adult patients receiving chemotherapy; they first published their recommendations in 2006.19 Since then, changes have occured in several areas, including our improved understanding of predisposing factors, the development of risk models and the availability of appropriate scoring systems. The risk of FN is increased by the recent trend for using dose-dense treatment schedules and the incorporation of taxanes and targeted agents into widely used chemotherapy regimens. With regard to the use of daily G-CSF versus once-per-cycle pegylated G-CSF, additional evidence has emerged since publication of the last EORTC guidelines. In addition, two further filgrastim biosimilar molecules (daily G-CSF) have been approved in Europe: XM02 and EP2006. These molecules are marketed by various companies using different trade names: Ratiograstim® (filgrastim; XM02), Filgrastim ratiopharm, Ratiopharm GmbH; Biograstim (filgrastim; XM02), CT Arzneimittel GmbH; Tevagrastim® (filgrastim; XM02), Teva Generics GmbH; filgrastim Zarzio® (EP2006), Sandoz GmbH; and filgrastim Hexal® (EP2006), Hexal Biotech Forschungs GmbH.20, 21, 22, 23, 24, 25

These developments highlight the need to reassess current evidence and to update the existing guidelines regarding the prophylactic use of G-CSF.

A stringent and standardised definition of FN helps unify patient management algorithms. Febrile neutropenia is defined as an absolute neutrophil count (ANC) of <0.5 × 109/L, or <1.0 × 109/L predicted to fall below 0.5 × 109/L within 48 h, with fever or clinical signs of sepsis.26 Currently, the European Society for Medical Oncology (ESMO) defines fever in this setting as a rise in axillary temperature to >38.5 °C sustained for at least one hour.26 It is suggested that therapy be initiated if a temperature of >38.0 °C is present for at least 1 hour or a reading of >38.5 °C is obtained on a single occasion.27

Some of the adverse consequences of chemotherapy-induced FN occur as a result of treatment delays and dose reductions. These have the potential to adversely affect tumour control.28, 29, 30, 31, 32, 33, 34, 35, 36, 37 For instance, poor outcome in cancer patients has been attributed to failure to deliver planned chemotherapy regimens for lymphoma,38 breast cancer,39 lung cancer40 and ovarian cancer.41 Prevention of chemotherapy-induced FN is, therefore, a clinical priority for patients undergoing treatment for solid tumours and lymphoma.

Progress has been made in our knowledge of what factors increase the risk of FN and in our ability to identify patients requiring G-CSF prophylaxis or antibiotic treatment or both. A variety of factors have now been implicated in the risk of developing FN, including tumour type (breast, lung, colorectal, lymphoma and ovarian), chemotherapy regimen and patient-related risk factors.42, 43, 44, 45, 46, 47 Patients who experience one episode of FN are at high risk of subsequent episodes, particularly after the occurrence of severe and prolonged neutropenia.4, 48

Recognising patients at risk for complications of FN can be achieved using risk indices, such as those developed by the Multinational Association for Supportive Care in Cancer (MASCC) (Table 1).49, 50 Using the MASCC score, patients with a score of 21 or more points are considered at low-risk, while all other patients are considered at high risk of infectious complications. Identifying patients at risk of bacteraemia facilitates appropriate initiation of antibiotics.51 Recent studies illustrate the impact of FN occurrence on hospitalisation and mortality, showing inpatient mortality rates of 9.5–12.5%.52, 53 In addition, a study of hospital practice in Pakistan has provided level IV evidence that G-CSF reduced in-hospital mortality (pneumonia or sepsis) from 20% to 4% and confirmed older age as a risk factor.54

The use of antibiotic prophylaxis to prevent infection and infection-related complications in cancer patients at risk of neutropenia55, 56 is still contentious. Though widely practiced for managing patients with haematological malignancies usually without G-CSF, the same is not true for those being treated for other cancers. Two meta-analyses57, 58 and a systematic review59 indicate that evidence is too limited to allow conclusions to be drawn regarding the relative merits of antibiotic versus CSF primary prophylaxis. A combined strategy may be appropriate in some settings. For example, in patients with breast cancer treated with docetaxel-based therapy, ciprofloxacin alone provides suboptimal prophylaxis against FN compared with pegfilgrastim plus ciprofloxacin.60 Some authors recommend fluoroquinolone prophylaxis for patients receiving chemotherapy for haematological malignancies or high-dose chemotherapy for solid tumours in which prolonged (6 weeks) neutropenia is expected.61 This cautious recommendation takes into account the finding that, in randomised controlled trials in patients receiving chemotherapy, routine fluoroquinolone prophylaxis has been shown to lead to an increase in resistance amongst Gram-positive and Gram-negative isolates compared with non-prophylaxed controls in randomised controlled trials in patients receiving chemotherapy.56 The clinical consequences of this are unclear and it is important to avoid unwarranted use of antibiotics to lower the risk of drug resistance.62

The intensity (frequency or total dose) of chemotherapy is a major factor to be taken into account when assessing the risk of FN and likely efficacy of G-CSF prophylaxis. Dose-dense (increased frequency), rather than dose-intense (increased dose) chemotherapy is increasingly used in an attempt to improve long-term clinical outcomes, often with the use of G-CSF support.63 Several studies suggest that dose-dense chemotherapy or immunochemotherapy regimens have survival benefits when compared with standard regimens.38, 64, 65, 66, 67, 68, 69, 70

However, any potential risk of secondary cancer arising from a shift away from standard chemotherapy should be considered. The Surveillance, Epidemiology, and End Results (SEER) analysis of patients with breast cancer aged ⩾65 years showed an incidence of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) of 1.77% amongst 906 patients receiving growth factor support compared with 1.04% amongst the 4604 patients not receiving CSF. There were, however, substantial differences between the two patient populations, e.g. in this study, patients receiving growth factor tended to have positive lymph nodes and received either more intense radiation therapy or high dose cyclophosphamide treatment.71 These findings raised concern that G-CSF use in a high-dose setting amongst breast cancer patients could be associated with a high risk of secondary MDS or AML. However, an analysis of US registry data carried out to resolve this issue shows that the overall risk is small, even amongst elderly patients.72 A meta-analysis of randomised, controlled trials indicates that a small increased risk of AML/MDS (approximately 4 per 1000 cases) is associated with the use of particular chemotherapy schedules in combination with G-CSF support.73 In subgroup analyses, a significant increase in risk of AML/MDS was observed where G-CSF support was associated with a greater total dose of chemotherapy (Mantel–Haenszel relative risk [RR] = 2.334, P = 0.009) but not when the planned total dose of chemotherapy with G-CSF was the same in each study arm, such as dose-dense schedules. Furthermore, all-cause mortality was decreased in patients receiving chemotherapy with G-CSF support. Greater reductions in mortality were observed with greater chemotherapy dose-intensity.73

Current guidelines from the USA (American Society of Clinical Oncology [ASCO],74 National Comprehensive Cancer Network [NCCN]),43 Canada75 and Europe (EORTC19 ESMO76), consistently advocate a risk threshold of 20% for routine G-CSF support in patients with solid tumours and lymphoma.74 This threshold was established after the results from two large clinical trials demonstrated substantial reduction in FN incidence at this level of risk5, 66 and is supported by modelling studies.44 Another recent trend is the addition of taxanes to commonly-used regimens for many solid tumours (docetaxel, doxorubicin, cyclophosphamide [TAC], fluorouracil/epirubicin/cyclophosphamide/docetaxel FEC-D); these are associated with an increased risk of FN and grade 4 neutropenia, with studies of patients in the UK showing FN rates >20%.77, 78, 79, 80 When treating chronic lymphocytic leukaemia (CLL), the improved efficacy made possible by frontline combination therapies (fludarabine/cyclophosphamide [FC] or FC-rituximab [FCR]) is accompanied by increased myelosuppression and high rates of grade 3–4 neutropenia, which may result in increased infection-related mortality (IRM).81, 82, 83, 84

Evidence exploring these issues was gathered from the literature and is presented below, compiled with the evidence previously described.19 These updated guidelines are intended to complement previously published ESMO guidelines on the use of colony-stimulating factors for prevention of chemotherapy-induced FN in patients with cancer.26

Section snippets

Methodology

Questions considered pertinent to G-CSF use across Europe were defined prospectively by the EORTC G-CSF Guidelines Working Party (Appendix 1). The computerised searches of MEDLINE, PreMEDLINE, EMBASE and The Cochrane Library used to support the 2006 guidelines (31st December 1994 to 16th September 2005) have been previously described.19 These searches have now been extended to cover the period to 21st July 2009. Studies involving children <18 years of age or patients with leukaemia were

Commentary on recommendation 1: patient-related risk factors for increased incidence of FN and complications of FN

The previous EORTC guidelines were able to identify certain independent patient risk factors for FN, based on 11 studies.1, 4, 85, 86, 87, 88, 89, 90, 91 The updated literature search identified an additional nine studies assessing multiple patient-related risk factors.46, 92, 93, 94, 95, 96, 97, 98, 99 of which one presented level IV evidence.98 The more recent level I, II and III evidence is shown in Table 4.

The compiled results from the 2006 and 2009 searches confirm that older age

Conclusion

In conclusion, we have produced up-to-date recommendations for G-CSF use that are relevant to current European clinical practice, as summarised in Fig. 1.

These may help to optimise local protocols and patient management strategies in hospitals across Europe and, in turn, improve patient care and clinical outcomes. This review has allowed alignment of the 2010 EORTC guidelines with evidence available until end of 2009, including review of the 2009 NCCN and 2006 ASCO guidelines. The guidelines

Disclaimer

The EORTC offers no guarantees of any kind nor can it be held liable for any consequences which might derive from using these guidelines. Constant developments in the field mean that some recent information might be missing. Thus a third biosimilar, nivestim was recently approved by the European Medicines Agency (EMA).252

Conflict of interest statement

Julia Bohlius, Lissandra Dal Lago, Nora Kearney, Ruth Pettengell, Vivianne C. Tjan-Heijnen, Jan Walewski, and Damien Weber have no conflict of interest.

J. Peter Donnelly has received research grants, lectureship and consultancy honoria from Gilead Sciences, MSD, Pfizer and Schering Plough and consultancy honoria from Astellas and Basilea. Matti Aapro has received lectureship honoraria from Amgen Hexal/Sandoz and Roche and Christoph Zielinski has received lectureship honoraria from Amgen and

Acknowledgements

The EORTC G-CSF Guidelines committee was provided with independent medical writing and organisational support from Janet Stephenson, Steven Walker and Elizabeth Hollowayof Bioscript Stirling Limited, London, UK. Funding was by means of an unrestricted grant from Amgen (Europe) GmbH, Zug, Switzerland. Comments on early drafts of the manuscript were received from Nicole Kuderer and on the final draft of the manuscript from Amgen GmbH, Chugai Sanofi Aventis, Ratiopharm GmbH, Sandoz International

References (252)

  • M. Bonadio et al.

    Fluoroquinolone resistance in hematopoietic stem cell transplant recipients with infectious complications

    Biomed Pharmacother

    (2005)
  • A. Younes et al.

    Safety and efficacy of once-per-cycle pegfilgrastim in support of ABVD chemotherapy in patients with Hodgkin lymphoma

    Eur J Cancer

    (2006)
  • S.A. Gregory et al.

    Chemotherapy dose intensity in non-Hodgkin’s lymphoma: is dose intensity an emerging paradigm for better outcomes?

    Ann Oncol

    (2005)
  • M. Pfreundschuh et al.

    Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL

    Blood

    (2004)
  • M. Pfreundschuh et al.

    Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL

    Blood

    (2004)
  • G. Fountzilas et al.

    Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00

    Ann Oncol

    (2008)
  • L.F. Verdonck et al.

    Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON)

    Blood

    (2007)
  • R. Greil et al.

    Hematopoietic growth factors: ESMO recommendations for the application

    Ann Oncol

    (2007)
  • C.S. Tam et al.

    Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia

    Blood

    (2008)
  • M.J. Millward et al.

    Docetaxel and carboplatin is an active regimen in advanced non-small-cell lung cancer: a phase II study in Caucasian and Asian patients

    Ann Oncol

    (2003)
  • V.C. Tjan-Heijnen et al.

    Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study

    Ann Oncol

    (2001)
  • F. Hilpert et al.

    Feasibility, toxicity and quality of life of first-line chemotherapy with platinum/paclitaxel in elderly patients aged > or=70 years with advanced ovarian cancer – a study by the AGO OVAR Germany

    Ann Oncol

    (2007)
  • M. Moreau et al.

    A general chemotherapy myelotoxicity score to predict febrile neutropenia in hematological malignancies

    Ann Oncol

    (2009)
  • P. Jenkins et al.

    Pretreatment haematological laboratory values predict for excessive myelosuppression in patients receiving adjuvant FEC chemotherapy for breast cancer

    Ann Oncol

    (2009)
  • D.C. Dale et al.

    The Severe Chronic Neutropenia International Registry: 10-Year follow-up report

    Support Cancer Ther

    (2006)
  • J.N. Timmer-Bonte et al.

    Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: a Dutch Randomized Phase III Study

    J Clin Oncol

    (2005)
  • G.H. Lyman et al.

    Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study

    J Clin Oncol

    (2004)
  • G.H. Lyman et al.

    Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin’s lymphoma receiving CHOP chemotherapy

    Leuk Lymphoma

    (2003)
  • G.H. Lyman et al.

    Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma

    Cancer

    (2003)
  • C.L. Vogel et al.

    First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study

    J Clin Oncol

    (2005)
  • D. Wolff et al.

    Risk of neutropenic complications based on a prospective nationwide registry of cancer patients initiating systematic chemotherapy

    Proc Am Soc Clin Oncol

    (2004)
  • D. Wolff et al.

    J Support Oncol

    (2005)
  • J. Crawford et al.

    Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice

    J Natl Compr Canc Netw

    (2008)
  • W.T. Hughes et al.

    2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer

    Clin Infect Dis

    (2002)
  • D. Cameron

    Management of chemotherapy-associated febrile neutropenia

    Br J Cancer

    (2009)
  • G. Padilla et al.

    Quality of life and chemotherapy-induced neutropenia

    Cancer Nurs

    (2005)
  • L.I. Wagner et al.

    Measuring health-related quality of life and neutropenia-specific concerns among older adults undergoing chemotherapy: validation of the Functional Assessment of Cancer Therapy-Neutropenia (FACT-N)

    Support Care Cancer

    (2008)
  • D. Krell et al.

    Impact of effective prevention and management of febrile neutropenia

    Br J Cancer

    (2009)
  • F.A. Holmes et al.

    Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer

    J Clin Oncol

    (2002)
  • C. Gisselbrecht et al.

    Placebo-controlled phase III study of lenograstim (glycosylated recombinant human granulocyte colony-stimulating factor) in aggressive non-Hodgkin’s lymphoma: factors influencing chemotherapy administration. Groupe d’Etude des Lymphomes de l’Adulte

    Leuk Lymphoma

    (1997)
  • EMEA. Committee for medicinal products for human use summary of positive opinion for Hexal....
  • EMEA. Committee for medicinal products for human use summary of positive opinion for Zarzio....
  • EMEA. Committee for medicinal products for human use summary of positive opinion for tevagrastim....
  • EMEA. Committee for medicinal products for human use summary of positive opinion for filgrastim ratiopharm....
  • EMEA. Committee for medicinal products for human use summary of positive opinion for ratiograstim....
  • EMEA. Committee for medicinal products for human use summary of positive opinion for biograstim....
  • Chauhan R, Morgan S, Potter V. Guidelines for the management of febrile neutropenia in oncology patients....
  • D.R. Budman et al.

    Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B

    J Natl Cancer Inst

    (1998)
  • L.W. Kwak et al.

    Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis

    J Clin Oncol

    (1990)
  • G. Bonadonna et al.

    Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up

    N Engl J Med

    (1995)
  • Cited by (944)

    View all citing articles on Scopus
    m

    Member of the EORTC Task Force Elderly.

    n

    Methodology Expert.

    o

    Representative of the EORTC Breast Cancer Group.

    p

    Representative of the EORTC Headquarters.

    q

    Representative of the EORTC Infectious Disease Group.

    r

    Nursing Expert, mandated by EONS (European Oncology Nursing Society).

    s

    US Expert.

    t

    Member of the EORTC and Lymphoma Expert.

    u

    Representative of the EORTC Lung Cancer Group.

    v

    Representative of the EORTC Lymphoma Group.

    w

    Central European Cooperative Oncology Group (www.cecog.org).

    x

    Representative of the EORTC Radiation Oncology Group.

    View full text