US Pharm. 2013;38(1)(Oncology suppl):3-7.
ABSTRACT: The most common dose-limiting
toxicities of cancer chemotherapy include febrile neutropenia (FN) and
its subsequent infectious complications—anemia and thrombocytopenia. FN
is a serious medical problem that is associated with high morbidity,
mortality, and cost. Colony-stimulating factors (CSFs) are commonly used
in clinical practice to treat either primary or secondary neutropenia.
Benefits of CSFs include reduced incidence of life-threatening bacterial
and/or fungal infections, reduced hospital stays, and fewer delays in
chemotherapy. Exogenous erythrocyte-stimulating agents (ESAs) are often
required to treat more severe types of anemia resulting from cancer
treatment (chemotherapy or radiation), chronic kidney failure, and
certain drugs used to treat HIV infection, and to reduce the number of
blood transfusions during and after major surgeries.
Bone marrow suppression represents the most serious toxic
effect of antineoplastic induction therapy. Bone marrow modulators, such
as colony-stimulating factors (CSFs) and erythrocyte-stimulating agents
(ESAs), are used to treat toxicities of cancer chemotherapy.1
The most common major dose-limiting toxicities of cancer chemotherapy
include febrile neutropenia (FN) and its subsequent infectious
complications—anemia and thrombocytopenia. These conditions occur with
common chemotherapy regimens in 25% to 40% of treatment-naïve patients.1
Marrow hypoplasia from myelosuppressive regimens usually
reaches its lowest point (nadir) after 1 to 2 weeks of therapy. Its
severity depends on a number of factors, including the dose intensity of
the chemotherapy regimen, the patient’s prior history of either
radiation therapy or use of cytotoxic treatment, and comorbidities.1
It may also lengthen the hospital stay; increase monitoring,
diagnostic, and treatment costs; and reduce patient quality of life
Exogenous CSFs are often administered to patients who are
undergoing chemotherapy that may cause low white blood cell (WBC) counts
(i.e., neutropenia) and to patients with hematologic conditions that
predispose them to a greater risk of infection. Neutropenia is defined
as an absolute neutrophil count (ANC) of <500/mcL or an ANC of
<1,000/mcL with an expected decline to ≤500/mcL in 48 hours. Fever is
defined as a single temperature of 38.3°C or a temperature of 38.0°C
sustained for 1 hour without an obvious cause.2 Despite
improvements in clinical treatments, FN is a serious medical problem for
patients that is associated with high morbidity, mortality, and cost.3,4
When patients develop FN, they are usually admitted to the hospital for initiation of appropriate antibiotic therapy.4
The diagnosis of infection in neutropenic patients is complicated
because there is generally a lack of elevated WBCs, or left shift. Usual
signs and symptoms of infection in typical patients are pus, abscesses,
and infiltrates on chest x-rays, which depend on the presence of WBCs
and a healthy immune system response. However, in FN patients the most
reliable indication of infection is elevated temperature. Definitive
cultures may take days, and a septic neutropenic cancer patient may die
in a few hours if not treated. Therefore, the basic approach to the
management of the FN cancer patient is hospitalization and prompt
initiation of empiric antibiotics. The most common source of infection
in these patients is often self-infection with normal body flora, which
may include gram-negative or gram-positive bacteria and/or fungi.4
COLONY-STIMULATING FACTOR THERAPY
CSFs or granulocyte CSFs (G-CSFs) are secreted
glycoproteins that bind on the surfaces of receptor proteins, thereby
activating intracellular signaling pathways that stimulate
proliferation, differentiation, and activation of the targeted
(granulocyte) cell lines.1 CSFs are commonly used in clinical
practice as either primary or secondary prophylaxis of neutropenia.
Primary prophylaxis refers to the use of CSFs to prevent neutropenia
with the first cycle of chemotherapy. Secondary prophylaxis refers to
the use of CSFs to prevent recurrence of neutropenia in patients who
experienced neutropenia with the prior cycle of chemotherapy.1,5-7
Endogenous CSF is produced by monocytes, fibroblasts, and
endothelial cells to regulate neutrophil production in the bone marrow.
The neutrophils produced are involved in the following physiological
processes: 1) phagocytosis, 2) respiratory burst, 3) antibody-dependent
killing, and 4) increased expression of surface antigens.7
When patients develop an infection, the immune system responds by
releasing G-CSF into the bloodstream. The bone marrow responds by
stimulating the growth and maturation of stem cells into neutrophils
that enhance the immune system and increase phagocytosis of infectious
The term colony-stimulating factors, also known as hematopoietic growth factors,
is derived from the method by which they were discovered. Hematopoietic
stem cells were cultured on a semisolid matrix, which prevents cells
from moving around, so that if a single cell starts proliferating, all
cells derived from it will remain clustered around the spot in the
matrix where the first cell was originally located.6 These clusters are referred to as colonies.
Therefore, it was possible to add various substances to cultures to see
which kinds of colonies were “stimulated.” Currently, the CSF family
includes filgrastim (Neupogen), pegfilgrastim (Neulasta), and
sargramostim (Leukine).8-10 Both filgrastim and pegfilgrastim are G-CSFs derived from Escherichia coli, and sargramostim is a granulocyte-macrophage CSF
(GM-CSF) derived from Saccharomyces cerevisiae yeast (see TABLE 1
for a comparison). Initially, clinicians feared that because myeloid
blast cells carry receptors for G-CSF and GM-CSF, using CSFs might
stimulate regrowth of the myeloid leukemia. However, this outcome is not
supported by clinical studies.11
Recently, a new CSF, tbo-filgrastim (Neutroval), received FDA approval.12
XM02 or tbo-filgrastim is the first biosimilar G-CSF, marketed as safe
and effective in reducing the duration of severe neutropenia and the
incidence of FN in patients with small cell or non-small cell lung
cancer receiving platinum-based chemotherapy.13-15 The drug
is a short-acting recombinant G-CSF agent that is marketed as
Tevagrastim in Europe, where tbo-filgrastim is classified as biosimilar
to Amgen’s G-CSF product Neupogen. Tbo-filgrastim was approved through
the standard FDA process for new drugs and some biological agents.
Tbo-filgrastim is reported to be superior to placebo and equivalent to
filgrastim in reducing the duration of severe neutropenia and the
incidence of FN in cycle 1 in breast cancer patients receiving
docetaxel-doxorubicin chemotherapy. The manufacturer, Teva
Pharmaceuticals, announced that it does not expect to market
tbo-filgrastim until November 2013 at the earliest.12,13
The term biosimilar refers to products that are
marketed after expiration of drug patents and are claimed to have very
similar properties to existing biological products. But due to the
complexity of newer biologics, a biosimilar product can only be made
that is close, not identical, to another, and clinical results from the
use of biosimilars may vary from those of the original product.12
Indications and Potential Uses
Clinically important uses of CSFs in oncology include
prevention of FN after chemotherapy treatment of FN episodes, support
following bone marrow transplantation, and collection of CSF-mobilized
peripheral blood progenitor cells.1,5,8-10 Other potential
uses include combination therapy with stem cell factors and other
cytokines to boost progenitor cell development; maintenance of dose
intensity of salvage therapy in metastatic cancer patients; and
application in patients with pneumonia, Crohn’s fistulas, breast cancer,
lung cancer, non-Hodgkin’s lymphoma, Hodgkin’s disease, diabetic foot
infections, and a variety of other infectious conditions.
The high cost of CSFs may limit their widespread use.16,17
Current American Society of Clinical Oncology (ASCO) and National
Comprehensive Cancer Network (NCCN) guidelines recommend primary
prophylaxis, or first cycle use, only for patients with a 20% or higher
risk of FN; primary prophylaxis with special circumstances, which may
include elderly and other high-risk patients; and secondary prophylaxis.2,5
Clinical risk factors that may increase patient risk for complications
include age >65 years; concurrent chemotherapy and radiotherapy; poor
nutritional status; advanced cancer; decreased immune function in
patients who are already at an increased risk of infection; preexisting
neutropenia due to disease, extensive prior chemotherapy, or previous
irradiation to the pelvis or other areas containing large bone marrow
reserve; infection or open wound; and other comorbidities.1,2
Toxicities and Adverse Drug Reactions
The most common toxicity and adverse effects of CSFs
include musculoskeletal bone pain (25%-45%), particularly in the large
bones, thighs, hips, sternum, and lower spine; acidic diarrhea;
headache; lethargy; fever; nausea; vomiting; and diarrhea. Other side
effects include an increase in lactate dehydrogenase, alkaline
phosphatase, and uric acid levels. Serious adverse effects include
effects in the hematologic (sickle cell anemia with crisis and bone
marrow leukemia), immunologic (anaphylaxis), and respiratory (acute
respiratory distress syndrome) systems; alveolar hemorrhage (manifested
as pulmonary infiltrates and hemoptysis); rupture of the spleen; and
urinary tract infections.8-10
Counseling Considerations for Patients Taking CSFs8-10:
- Do not shake prefilled syringe/vial before using.
- Do not freeze but refrigerate syringes/vials (2°-8°C or 36°-45°F) in original carton.
- Discard unused syringes stored at room temperature for longer than 48 hours. Protect from light.
- Allow the CSF product to reach room temperature (this takes about 30 minutes) before administering.
- Rotate subcutaneous (SC) injection sites. Use a
different place on your arms, stomach, hips, or legs each time you give
the injection. Do not inject into the same place two times in a row.
- Do not use the medication if it has changed colors or has particles in it.
- The needle cover on the single-use prefilled syringe
contains dry natural rubber (latex), which should not be handled by
persons sensitive to this substance.
- Treatment for bone pain can usually be managed by acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs).
- If a dose is missed, use it as soon as you remember, but
not within the 24-hour period before or after you receive chemotherapy.
Skip the missed dose if it is almost time for your next scheduled dose.
Do not use extra medicine to make up the missed dose.
Generally, CSF therapy should not begin sooner that 24
hours after the last dose of chemotherapy and should be continued until
the ANC exceeds a safe level following the expected chemotherapy nadir.
To avoid the potential risks of excessive leukocytosis (WBC >50,000
cells/mm3; ANC >20,000 cells/mm3), CSF therapy may be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Administering doses of CSF when the ANC exceeds 10‚000/mm3 may not result in any additional clinical benefit. CBCs will be routinely conducted to monitor CSF therapy results.8-10
Patients may have delays or dose reductions in
chemotherapy treatment, which have the potential to impact their QOL, as
well as their survival. The occurrence of FN often causes subsequent
chemotherapy delays or dose reductions. It may also lengthen hospital
stay, increase monitoring, diagnostic, and treatment costs, and reduce
Information Specific to Sargramostim: The
first dose of sargramostim may cause difficulty breathing, flushing,
fainting, dizziness, or fast or irregular heartbeat. These signs usually
resolve and usually do not occur again. This effect may get worse if
the drug is taken with alcohol or certain medications. Patients should
not drive or perform other possibly unsafe tasks until they know how
they will react to sargramostim.10
For patients with diabetes, sargramostim may affect blood
glucose levels, so blood glucose should be checked regularly. Patients
should be advised to discuss any dosing changes to their diabetes
medications with their physician. Laboratory tests, including liver
function, kidney function, blood counts, body weight, and fluid and
serum electrolyte levels, may be performed while using sargramostim.
These tests may be used to monitor the condition or check for side
effects. Adverse drug effects such as edema, capillary leak syndrome,
and pleural and/or pericardial effusions have been reported in patients
after administration of the drug.10
ERYTHROCYTE-STIMULATING AGENT THERAPY
Conventional therapy (e.g., iron, folic acid, vitamin B12)
is often effective in treating common types of anemia. For more severe
types of anemia, exogenous ESAs are often required. Anemias requiring
ESAs include those from cancer treatment (chemotherapy or radiation),
chronic kidney failure, and the use of antiretroviral agents; ESAs are
also used to reduce the number of blood transfusions during and after
major surgeries.18 In addition, preexisting anemia may be
exacerbated by myelosuppressive cancer treatment, particularly in
patients who undergo intensive chemotherapy or combined modality
treatment with both chemotherapy and radiation therapy. Erythropoiesis
is the development process by which new red blood cells (RBCs), or
erythrocytes, are produced. Erythropoietin (EPO) is a naturally
occurring substance, and about 90% is produced by the kidneys.19,20
Kidneys can detect low oxygen levels in blood or tissue and respond by
releasing EPO into the plasma, which travels to the red bone marrow to
stimulate stem cells to differentiate into proerythroblasts, increase
the rate of mitosis, increase the release of reticulocytes, and induce
Human erythrocytes, are produced through a process termed erythropoiesis, developing from committed stem cells to mature erythrocytes in about 7 days.21,22
When matured, these cells exist in blood circulation for about 100 to
120 days (80-90 days in a full-term infant). Through this process
erythrocytes are continuously produced in the red bone marrow of large
bones (the vertebrae, sternum, ribs, and pelvis), at a rate of about 2
million per second in a healthy adult. Just before and after leaving the
bone marrow, immature RBCs are known as reticulocytes; these cells constitute about 1% of circulating RBCs.
When the kidneys cannot produce enough EPO to maintain the
RBCs and hemoglobin needed, ESAs may be prescribed. ESAs act like
natural EPO and can be given to increase RBCs and hemoglobin production.23-25
ESAs are administered either subcutaneously or intravenously, and are
given in many dosing schedules, ranging from once a week to several
times a week to once a month, depending on the ESA selected, the dose
needed, and the reason it is being given.23-25 It may take
several weeks to raise the RBCs and hemoglobin levels and relieve
symptoms. Currently, exogenous EPOs approved by the FDA are produced by
recombinant DNA technology in cell culture, and include epoetin alfa
(Procrit/Epogen) and darbepoetin alfa (Aranesp) (see TABLE 2 for a
comparison). Darbepoetin alfa has a longer duration of action than
epoetin alfa and can usually be administered less often.18,26
ESAs are structurally and biologically similar to naturally occurring
EPO, and they stimulate erythropoiesis by the same mechanism as EPO.18,27-29
Recently, the FDA approved peginesatide (Omontys), a novel
ESA for the treatment of anemia due to chronic kidney disease (CKD) in
adult patients on dialysis. It is a synthetic peptide that mimics the
structure of EPO.12
Toxicities and Adverse Drug Effects of ESAs
Side effects that occur most often with ESA use include
high blood pressure, swelling, fever, dizziness, nausea, and pain at the
site of the injection. These drugs also have black box warnings of
increased risk of death, myocardial infarction, stroke, venous
thromboembolism, and tumor recurrence.30
Counseling Considerations for Patients Taking ESAs18,27-29:
- ESAs increase the risk of venous thromboembolism (blood
clots in the veins), and a blood clot can break away from one location
and travel to the lungs (pulmonary embolism), where it can block
- Use ESAs with caution in patients who have the following
conditions: heart disease; high blood pressure, especially uncontrolled
hypertension; porphyria (a group of diseases that are caused by enzyme
deficiencies); seizures; and an allergy to epoetin alfa or any other
part of this medicine; also in women who are pregnant, planning to
become pregnant, or breastfeeding.
- Inform patients that blood transfusions may improve
symptoms of anemia right away, but ESAs may take from weeks to months to
provide noticeable relief of the symptoms of anemia.
- Determine if the patient is allergic to ESAs or to
products containing human albumin, or if the patient has any other
- Some products may contain inactive ingredients (e.g.,
polysorbate, latex), which can cause allergic reactions or other
problems. The needle cover of prefilled syringes may contain dry natural
rubber (a derivative of latex), which can cause allergic reactions.
- Do not shake prefilled syringes or vials. Do not use products that have been shaken or frozen.
- Protect vials and prefilled syringes from light.
- Do not use any vials or prefilled syringes exhibiting particulate matter or discoloration.
- Discard unused portions of vials or prefilled syringes. Do not re-enter vial.
- Do not dilute darbepoetin alfa and do not administer in conjunction with other drug solutions.
CSFs help reduce the duration of neutropenia and the
incidence of FN episodes in patients receiving myelosuppressive
chemotherapy. Since common signs of systemic infections are often not
present, unexplained fever and an ANC <500/mcL are considered key
indicators of FN. Due to the high morbidity of FN, it is important to
begin G-CSF treatment and appropriate antibiotic therapy. Currently, the
ASCO and NCCN guidelines recommend the use of G-CSF when patients have a
20% or greater risk of developing FN from chemotherapy.2,5 Benefits of CSFs include reduced incidence of serious infections, shorter hospital stays, and fewer delays in chemotherapy.
Conventional medications and ESAs are available to help
correct anemias and may at times be used concurrently. ESAs have been
administered successfully to millions of patients worldwide and are
becoming the standard of care for cancer and HIV medication–induced
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30. Epogen/Procrit (epogen alfa) and Aranesp (darbepoetin alfa). MedWatch. August 11, 2011. www.fda.gov/Safety/MedWatch/SafetyInformation/ucm267698.htm. Accessed November 18, 2012.
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