Update on the Management of Febrile Neutropenia

European Oncology & Haematology, 2011;7(4):263-269

Abstract:

Febrile neutropenia (FN) is a potentially life-threatening complication of chemotherapy. Supportive measures and diagnostic tools in the management of FN are constantly evolving. Recent evidence has validated the need for risk stratification. With the increasing use of dose-intense chemotherapy and evidence to show the detrimental effects of dose delay in the outcomes of cancer treatment, strategies, including the use of colony-stimulating factors and biosimilars to prevent FN, are being developed. This review is an update on the management of FN in adults undergoing chemotherapy.
Keywords: Neutropenia, febrile neutropenia, infection, myelosuppression, colony-stimulating factors
Disclosure: The authors have no conflicts of interest to declare.
Received: March 28, 2011 Accepted July 04, 2011 Citation European Oncology & Haematology, 2011;7(4):263-269
Correspondence: John A Liu Yin, Consultant Haematologist, Department of Haematology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. E: john.yin@cmft.nhs.uk

Neutropenic sepsis is a serious and potentially life-threatening complication of cancer chemotherapy. It is the leading cause of infectious complications in patients receiving chemotherapy, accounting for most chemotherapy-associated morbidity and mortality, and compromising treatment outcomes by causing dose reductions and treatment delays. Frequent use of dose-intense and dose-dense chemotherapy, especially in the older population, has escalated the risk of neutropenic sepsis. Prompt recognition and management with antimicrobial therapy reduces mortality but, increasingly, focus is shifting towards prevention using targeted antimicrobial or antifungal prophylaxis and supportive strategies such as the use of growth factors. However, challenges remain with respect to the most appropriate empirical treatment regimen adapted to an evolving and changing epidemiology of infections as well as to resistance rates, the development of early markers of bacterial or fungal infections, the risk stratification of patients and the establishment of targeted empirical or pre-emptive antifungal therapy.1 This review is an update on the management of febrile neutropenia (FN) in adults and highlights recent developments that are likely to have an impact on patient care.
Definitions and Risk Factors
FN is a clinical syndrome and, as defined by the Infectious Diseases Society of America (IDSA) and the Immunocompromised Host Society (ICHS), refers to fever in patients who have an absolute neutrophil count (ANC)<0.5 x 109/l or <1 x 109/l that is predicted to fall below 0.5 x 109/l within 48 hours of onset of fever or signs of sepsis. Fever is defined as temperatures of ≥38 °C (100.4 °F) for at least one hour or a single record of ≥38.3 °C (101 °F).2 The ICHS and other scientific societies have also added, as a criterion of fever, the presence of an oral temperature of ≥38 °C measured twice in 12 hours.3
FN represents a medical emergency. Clinical evidence of a focus of infection is present in 20–30 % of febrile episodes, whereas bacteraemia is present in 10–25 % of patients.2 Prompt initiation of antimicrobial therapy, especially within the first hour of onset of fever, has contributed to a significant reduction in mortality, from 60–70 % in the 1970s to 4–6 % in adults and 0.4–1 % in children currently.4–6
References:
  1. Antoniadou A, Giamarellou H, Fever of unknown origin in febrile leukopenia, Infect Dis Clin N Am, 2007;21(4):1055–90.
  2. Freifeld AG, Bow EJ, Sepkowitz KA, et al., Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America, Clin Infect Dis, 2011;52(4):e56–93.
  3. Link H, Böhme A, Cornely OA, et al., Antimicrobial therapy of unexplained fever in neutropenic patients. Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG – German Cancer Society), Ann Hematol, 2003;82(Suppl. 2):S105–17.
  4. Hann I, Viscoli C, Paesmans M, et al., A comparison of outcome from febrile neutropenic episodes in children compared with adults: results from four EORTC studies. International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC), Br J Haematol, 1997;99(3):580–8.
  5. Malik IA, Khan WA, Karim M, Self-administered antibiotic therapy for chemotherapy-induced, low-risk febrile neutropenia in patients with nonhematologic neoplasms, Clin Infect Dis, 1994;19(3):522–7.
  6. Klaassen RJ, Goodman TR, Pham B, Doyle JJ, Low-risk prediction rule for pediatric oncology patients presenting with fever and neutropenia, J Clin Oncol, 2000;18(5):1012–9.
  7. Oude Nijhuis CS, Daenen SM, Vellenga E, et al., Fever and neutropenia in cancer patients: the diagnostic role of cytokines in risk assessment strategies, Crit Rev Oncol Hematol, 2002;44(2):163–74.
  8. Dompeling EC, Donnelly JP, Raemaekers JM, et al., Evolution of the clinical manifestations of infection during the course of febrile neutropenia in patients with malignancy, Infection, 1998;26(6):349–54.
  9. Vusirikala M, Supportive care in hematologic malignancies. In: Greer JP, Foerster J, Rodgers GM, et al. (eds), Wintrobe’s Clinical Hematology, Philadelphia: Lippincott Williams & Wilkins, 2009;1747–90.
  10. Giamarellou H, Antoniadou A, Infectious complications of febrile leukopenia, Infect Dis Clin North Am, 2001;15(2):457–82.
  11. Pizzo PA, Fever in immunocompromized patients, N Engl J Med, 1999;341(12):893–900.
  12. Chrischilles EA, Link BK, Scott SD, et al., Factors associated with early termination of CHOP, and its association with overall survival among patients with intermediate-grade non- Hodgkin’s lymphoma, Cancer Control, 2003;10(5):396–403.
  13. Talcott JA, Siegel RD, Finberg R, Goldman L. Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule, J Clin Oncol, 1992;10(2):316–22.
  14. Klastersky J, Paesmans M, Rubenstein EB, et al., The multinational association for supportive care in cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients, J Clin Oncol, 2000;18(16):3038–51.
  15. Baskaran ND, Gan GG, Adeeba K, Applying the Multinational Association for Supportive Care in Cancer risk scoring in predicting outcome of febrile neutropenia patients in a cohort of patients, Ann Hematol, 2008;87(7):563–9.
  16. Cohen J, Drage S, How I manage haematology patients with septic shock, Br J Haematol, 2011;152(4):380–91.
  17. Fätkenheuer G, Buchheidt D, Cornely OA, et al., Central venous catheter(CVC)-related infections in neutropenic patients, Ann Hematol, 2003;82(Suppl. 2):S149–57.
  18. Rintala E, Incidence and clinical significance of positive blood cultures in febrile episodes of patients with hematological malignancies, Scand J Infect Dis, 1994;26(1):77–84.
  19. Sakr Y, Sponholz C, Tuche F, et al., The role of procalcitonin in febrile neutropenic patients: review of the literature, Infection, 2008;36(5):396–407.
  20. Chen SCA, Kontoyiannis DP, New molecular and surrogate biomarker-based tests in the diagnosis of bacterial and fungal infection in febrile neutropenic patients, Curr Opin Infect Dis, 2010;23(6):567–77.
  21. Mato AR, Luger SM, Heitjan DF, et al., Elevation in serum lactate at the time of febrile neutropenia in hemodynamically stable patients with hematologic malignancies is associated with the development of septic shock within 48 hours, Cancer Biol Ther, 2010;9(8):585–9.
  22. Aapro MS, Bohlius J, Cameron DA, et al., 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapyinduced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours, Eur J Cancer, 2011;47(1):8–32.
  23. Wheatley K, Goldstone AH, Littlewood T, et al., Randomized placebo-controlled trial of granulocyte colony stimulating factor (G-CSF) as supportive care after induction chemotherapy in adult patients with acute myeloid leukaemia: a study of the United Kingdom Medical Research Council Adult Leukaemia Working Party, Br J Haematol, 2009;146(1):54–63.
  24. Heil G, Hoelzer D, Sanz MA, et al., A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group, Blood, 1997;90(12):4710–8.
  25. Mey UJM, Maier A, Schmidt-Wolf IG, et al., Pegfilgrastim as hematopoietic support for dose-dense chemoimmunotherapy with R-CHOP-14 as first-line therapy in elderly patients with diffuse large B cell lymphoma, Support Care Cancer, 2007;15(7):877–84.
  26. Brusamolino E, Rusconi C, Montalbetti L, et al., Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity. Haematologica, 2006;91(4):496–502.
  27. European Medicines Agency. Assessment report for Tevagrastim. Nonproprietary name: filgrastim (EMEA/H/C/827). Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000827/WC500036667.pdf (accessed 10 October 2011).
  28. European Medicines Agency. Assessment report for Ratiograstim. Nonproprietary name: filgrastim (EMEA/H/C/825). Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000825/WC500047793.pdf (accessed 10 October 2011).
  29. European Medicines Agency. Assessment report for Biograstim. Nonproprietary name: filgrastim (EMEA/H/C/826). Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000826/WC500053904.pdf (accessed 10 October 2011).
  30. European Medicines Agency. Assessment report for Filgrastim ratiopharm. Nonproprietary name: filgrastim (EMEA/H/C/824). Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000824/WC500022727.pdf (accessed 10 October 2011).
  31. European Medicines Agency. CHMP assessment report for Zarzio. International nonproprietary name: filgrastim (EMEA/H/C/000917). Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000917/WC500046528.pdf (accessed 10 October 2011).
  32. European Medicines Agency. CHMP assessment report for Filgrastim Hexal. International nonproprietary name: filgrastim (EMEA/H/C/918). Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000918/WC500022471.pdf (accessed 10 October 2011).
  33. European Medicines Agency. Assessment report for Nivestim. Nonproprietary name: filgrastim (EMEA/H/C/001142). Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001142/WC500093664.pdf (accessed 10 October 2011).
  34. Engert A, del Giglio A, Bias P, et al., Incidence of febrile neutropenia and myelotoxicity of chemotherapy: a metaanalysis of biosimilar G-CSF studies in breast cancer, lung cancer, and non-Hodgkin’s lymphoma, Onkologie, 2009;32(10):599–604.
  35. Gascon P, Fuhr U, Sörgel F, et al., Development of a new G-CSF product based on biosimilarity assessment, Ann Oncol, 2010;21(7):1419–29.
  36. European Medicines Agency. Questions and Answers on biosimilar medicines (similar biological medicinal products), October 2008. Available at: www.ema.europa.eu/pdfs/human/pcwp/7456206en.pdf (accessed 10 October 2011).
  37. Bow EJ, Laverdière M, Lussier N, et al., Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials, Cancer, 2002;94(12):3230–46.
  38. Rotstein C, Bow EJ, Laverdiere M, et al., Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group, Clin Infect Dis, 1999;28(2):331–40.
  39. Ullmann AJ, Lipton JH, Vesole DH, et al., Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease, N Engl J Med, 2007;356(4):335–47.
  40. Zinner SH, Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria, Clin Infect Dis, 1999;29(3):490–4.
  41. Paul M, Soares-Weiser K, Grozinsky S, Leibovici L, Beta-lactam versus betalactam-aminoglycoside combination therapy in cancer patients with neutropaenia, Cochrane Database Syst Rev 2003:CD003038.
  42. Zavascki AP, Goldani LZ, Li J, Nation RL, Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review, J Antimicrob Chemother, 2007;60(6):1206–15.
  43. Huang J, Tang YQ, Sun JY, Intravenous colistin sulfate: a rarely used form of polymyxin E for the treatment of severe multidrug-resistant Gram-negative bacterial infections, Scand J Infect Dis, 2010;42(4):260–5.
  44. Wingard JR, Empirical antifungal therapy in treating febrile neutropenic patients, Clin Infect Dis, 2004;39(Suppl. 1):S38–43.
  45. Sipsas NV, Bodey GP, Kontoyiannis DP, Perspectives for the management of febrile neutropenic patients with cancer in the 21st century, Cancer, 2005;103(6):1103–13.
  46. Empiric antifungal therapy in febrile granulocytopenic patients. EORTC International Antimicrobial Therapy Cooperative Group, Am J Med, 1989;86(6 Pt 1):668–72.
  47. Walsh TJ, Teppler H, Donowitz GR, et al., Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia, N Engl J Med, 2004;351(14):1391–402.
  48. Walsh TJ, Pappas P, Winston DJ, et al., Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever, N Engl J Med, 2002;346(4):225–34.
  49. Vigouroux S, Morin O, Moreau P, et al., Zygomycosis after prolonged use of voriconazole in immunocompromised patients with hematologic disease: attention required, Clin Infect Dis, 2005;40(4):e35–7.
  50. Maertens J, Marchetti O, Herbrecht R, et al., European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3 – 2009 Update, Bone Marrow Transplant, 2011;46(5):709–18.
  51. Leventakos K, Lewis RE, Kontoyiannis DP, Fungal infections in leukemia patients: how do we prevent and treat them? Clin Infect Dis, 2010;50(3):405–15.
  52. Mermel LA, Allon M, Bouza E, et al., Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America, Clin Infect Dis, 2009;49(1):1–45.
  53. Elting LS, Rubenstein EB, Rolston K, et al., Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care, J Clin Oncol, 2000;18(21):3699–706.
  54. Chamilos G, Marom EM, Lewis RE, et al., Predictors of pulmonary zygomycosis versus invasive pulmonary aspergillosis in patients with cancer, Clin Infect Dis, 2005;41(1):60–6.
  55. Vellenga E, Uyl-de Groot CA, de Wit R, et al., Randomized placebo controlled trial of granulocyte–macrophage colonystimulating factor in patients with chemotherapy-related febrile neutropenia, J Clin Oncol, 1996;14(2):619–27.
  56. Stanworth S, Massey E, Hyde C, et al., Granulocyte transfusions for treating infections in patients with neutropenia or neutrophil dysfunction, Cochrane Database System Rev, 2005;(3):CD005339.
  57. Schiffer CA, Granulocyte transfusion therapy 2006: the comeback kid?, Med Mycol, 2006;44:S383–6.
Keywords: Neutropenia, febrile neutropenia, infection, myelosuppression, colony-stimulating factors