DEFINITIONS: Neutropenia is defined as an Absolute Neutrophil Count (ANC) of 500 or less per microL or ANC less than 1000/microL and a predicted decline to 500 or less per microL over the next 48 hours. Febrile Neutropenia (FN) is defined as a temperature of 38.0 degrees C orally in a Neutropenic patient.
RISK FACTORS: The risk for of Febrile Neutropenia is not only dependent on the treatment regimen and delivered dose intensity but also on the overall condition of the patient. It is important that all these risk factors be taken into consideration before considering Primary Prophylaxis with CSF (Colony Stimulating Factors given prior to first chemotherapy cycle).
Patients at a risk of developing Febrile Neutropenia include
1) Patients 65 years of age or older
2) Poor Performance Status
3) Previous chemotherapy or radiation therapy
4) Preexisting Neutropenia
5) Tumor involving the bone marrow
6) Poor Liver function with elevated bilirubin
7) Poor renal function
8) Recent surgery
9) Preexisting Infection
10) Open wounds
Based on the treatment regimen and patient related risk factors, patients can fall in one of the three risk groups to develop Febrile Neutropenia (FN)
High Risk: More than 20% risk of FN
Intermediate Risk: 10-20% risk of FN
Low Risk: Less than 10% risk
Approximately 25%-40% of patients who had no prior chemotherapy develop FN with commonly prescribed chemotherapy regimens1. A notable group falling in the high risk category are those in whom dose intensity has to be maintained, in spite of a Neutropenic complication in the immediate previous chemotherapy cycle. The risk of FN associated with various chemotherapy regimens has been extensively published2 and is beyond the scope of this review.
BENEFITS OF CSF:
1) Use of G-CSF (Granulocyte – Colony Stimulating Factor) as recommended, reduces the incidence, severity and duration of chemotherapy induced Neutropenia. Neutropenic colitis or Typhlitis can be associated with prolonged neutropenia in patients with hematologic malignancies. The decreased duration of WBC (White Blood Cell) nadir in turn can decrease the chance of infectious complications including infection related mortality and improve quality of life3
2) There can be potential cost savings, preventing patient hospitalization4
3) G-CSF can facilitate delivery of full dose intensity of chemotherapy on schedule5
RISKS ASSOCIATED WITH CSF:
1) Mild to moderate bone pain
2) Rare cases of Splenic rupture
3) Allergic reactions involving the skin, cardiovascular and respiratory system with Filgrastim
FDA APPROVED MYELOID GROWTH FACTORS:
LEUKINE® (Granulocyte Macrophage-CSF, Sargramostim)
The first three are currently approved for use in preventing chemotherapy induced Neutropenia, whereas LEUKINE® is indicated for use in patients with Acute Myeloid Leukemia following induction therapy and in Stem Cell Transplantation
PREVENTION OF NEUTROPENIC COMPLICATIONS:
1) Primary prophylaxis (Prior to start of the first cycle of chemotherapy) with CSF’s is recommended for all patients who are considered to be at high risk for FN6, regardless of whether the treatment intent is palliative or curative
2) CSF’s should be considered on an individualized basis for patients who fall in the Intermediate risk category.
3) CSF’s are not usually recommended for patients considered to be at low risk for FN. The exception however will be for those patients who are being treated with a curative intent or receiving adjuvant therapy who cannot risk FN as this could lead to fatal complications.
4) Research in the area of pharmacogenomics may help us better understand how Neutropenic complications could be prevented
NEUTROPENIA AFTER FIRST CYCLE OF CHEMOTHERAPY:
1) FN or dose limiting Neutropenia (Unable to give treatment on schedule) following first cycle of chemotherapy warrants use of CSF
2) If a patient experiences dose limiting Neutropenia or FN inspite of primary prophylaxis with CSF’s, dose reductions or change in treatment regimen has to be considered
3) For a patient hospitalized with FN, CSF’s may be considered if the patient is deemed to be at high risk, provided the patient did not receive prophylactic NEULASTA® following chemotherapy. NEULASTA® is only indicated for the prevention of chemotherapy induced Neutropenia but not for therapy, when a patient presents with Neutropenia.
ADMINISTRATION OF CSF:
1) Start NEUPOGEN® within 24-72 hours after completion of chemotherapy and continue until post nadir ANC is normal or close to normal
2) NEULASTA® is administered 24 hours after completion of chemotherapy and is not recommended for administration on a schedule less than 2 weeks.
3) NEULASTA® is not recommended following weekly chemotherapy2.
MANAGEMENT of Febrile Neutropenia – OTHER ASPECTS:
1) Hospitalization is recommended
2) Patients should be started on broad spectrum antibiotics, following appropriate cultures
3) Start CSF if appropriate
4) Good hand hygiene
5) If prolonged Neutropenia is anticipated, minimize exposure to pets and live plants
1. Dale DC. Colony-stimulating factors for the management of neutropenia in cancer patients. Drugs 2002;62 Suppl 1:1-15.
2. Crawford J, Allen J, Armitage J et al. Myeloid growth factors. J Natl Compr Canc Netw 2011;9(8):914-932.
3. Fortner BV, Schwartzberg L, Tauer K, Houts AC, Hackett J, Stolshek BS. Impact of chemotherapy-induced neutropenia on quality of life: a prospective pilot investigation. Support Care Cancer 2005;13(7):522-528.
4. Lyman GH, Kuderer NM. The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia. Crit Rev Oncol Hematol 2004;50(2):129-146.
5. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21(8):1431-1439.
6. Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187-3205.