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Myelosuppression is one of the most common toxicities of cytotoxic
anticancer therapy. Cytotoxic therapy may affect any one or all of the
bone marrow cell lines including erythrocytes, neutrophils, and platelets.
Complications from anemia, neutropenia, and thrombocytopenia can
cause significant morbidity and mortality, including complications from
bleeding and infections. Prophylactic administration of growth factors
may protect against the myelosuppressive effects of chemotherapy.
The upper and lower gastrointestinal (GI) tract is highly susceptible to
cytotoxic chemotherapy, and toxicities can include nausea and vomiting,
mucositis, xerostomia, constipation, and diarrhea. Efficacy of preventive
strategies is limited; thus, supportive treatment is a foundation for
managing adverse effects in patients.
Dermatologic toxicities from anticancer therapies include alopecia, nail
changes, hyperpigmentation, radiation sensitivities, hand-foot syndrome,
dry skin, and papular–pustular (acneiform) rash. Most of the toxicities
are cosmetic and resolve upon discontinuation of the agent. Onset and
duration of dermatologic toxicities depend on the causative agent.
Extravasation is the unintended infiltration of an agent into the tissue
area surrounding the vein during an infusion. Several anticancer agents
demonstrate vesicant properties that can cause tissue necrosis and
permanent damage to the extravasated area. Cases of extravasation
require emergency treatment that is agent-specific, including elevation
of the extremity, extraction of the agent, hot or cold treatment, and
rituximab, trastuzumab, cetuximab, and ofatumumab are among some of
the agents most commonly associated with reactions. Reactions
commonly occur with the first dose, and they may be minimized with
premedications such as acetaminophen, diphenhydramine, and
Multiple types of central nervous system (CNS) toxicity, including
encephalopathy, cerebellar toxicity, and peripheral neuropathy, are
associated with anticancer agents and differ in presentation between
various agents. Most of the symptoms of neurotoxicity are reversible
over time, but modifications to regimens including discontinuation of
agents or reduction of doses may be necessary.
Cardiomyopathy, arrhythmias, and hypertension are common types of
cardiotoxicity observed in patients receiving infusion and oral anticancer
therapies. Anthracycline-induced cardiomyopathy is closely linked to a
patient’s cumulative dose and may be treated with current heart failure
Several anticancer agents carry severe risks of nephrotoxicity and
bladder toxicity for which preventive measures are necessary. Cisplatin
is one of the most nephrotoxic agents. Preventive strategies for cisplatin
nephrotoxicity include normalsaline hydration, mannitol, and amifostine,
and methotrexate-induced nephrotoxicity may be prevented with
alkalinization of the urine and leucovorin rescue. Ifosfamide-induced
hemorrhagic cystitis may be prevented with concomitant use of mesna.
Many anticancer medications demonstrate organ-specific toxicities, such
as pulmonary fibrosis caused by bleomycin and transaminitis caused by
cytarabine. Specific treatments for resolution of these toxicities do not
exist; rather, supportive care for symptoms is necessary. If adverse
effects do not resolve, discontinuation of therapy or dose modifications
Many anticancer agents cause long-term complications after therapy,
including treatment-related acute myeloid leukemia, lymphomas, bladder
cancer, and bone sarcoma. The risks of secondary malignancies should
be considered in assessing the adverse effect profile within the risks and
benefits of specific types of therapy.
Cytotoxic chemotherapy is potentially gonadotoxic with use of specific
agents. Sex, age, agent, and cumulative dose are factors in determining
the risk of infertility. Methods of preserving fertility should be discussed
with patients before initiating therapy.
Cytotoxic, targeted anticancer and immunotherapy agents are toxic to cancer cells and
also to various host tissues and organs. The adverse effects of anticancer therapies
are considered for both infusional and oral therapies and can be classified as
common and acute toxicities, specific organ toxicities, and long-term complications.
Common and acute toxicities generally occur as a result of inhibition of host-cell
division. Host tissues most susceptible to cytotoxic agents include tissues with
renewal cell populations, such as lymphoid tissues, bone marrow, and epithelium of
the GI tract and skin. Some other common and acute toxicities (e.g., nausea and
vomiting, hypersensitivity reactions) frequently occur in patients shortly after
therapy. Specific organ toxicities often are attributed to a unique uptake or a selective
toxicity of the anticancer agent to the organ. Long-term complications are toxicities
that occur months to years after anticancer therapy. These long-term toxicities occur
secondary to continued immunodeficiencies or from permanent damage to the organ
cells from the specific therapy. Regardless of the type of toxicities observed, most
are classified for severity by the National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events. This classification creates a common
method for classification of events in clinical trials and for management of toxicities
that occur for patients receiving standard of care regimens.
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
The toxicities associated with anticancer therapies are the most important factors
limiting the use of potentially curative doses. Therefore, all discussions regarding the
benefits of anticancer agents must include a discussion of toxicities associated with
their use. Concerns regarding the toxicities of therapy include the incidence,
predictability, severity, and reversibility of the adverse effects. In addition, the
specific agent, dose intensity, and treatment duration can influence the incidence of
several adverse effects. Although the incidence and predictability may be well
defined in specific patient populations, the incidence often varies depending on
individual susceptibility. The specific adverse effects that an individual patient will
experience may be difficult to predict. Because several toxicities have well-defined
characteristics, clinicians should be aware of the most common adverse effects.
Clinicians should also be aware of patient-specific factors, such as the stage of
disease, concomitant illnesses, and concurrent medications, which could cause signs
or symptoms that mimic the adverse effects associated with anticancer therapy. Many
patients have disease involvement which may impair organ function. In addition,
most patients with cancer receive many other medications, including antibiotics and
analgesics, which may cause additional adverse effects or interact with anticancer
agents. When a patient reports a new symptom, it may be difficult to determine
whether it is secondary to anticancer therapy, concurrent medications, or disease
either the myeloid or the lymphoid cell line. The myeloid stem cell further commits to
developing into an erythrocyte (red blood cell (RBC)), megakaryocyte (platelet), or
granulocyte (white blood cell (WBC)). Multiple types of granulocytes exist including
neutrophils, basophils, and eosinophils, although neutrophils are the most common
After committing to a particular cell line, bone marrow precursor cells undergo a
series of divisions (mitosis) to increase the number of cells. The cells then undergo
several developmental stages to mature and differentiate into their final forms
(postmitotic) and leave the bone marrow. The total time required for a cell to pass
through the mitotic and postmitotic pool under normal resting conditions is
approximately 10 to 14 days. This process is regulated by several cytokines; although
many cytokines have been identified, only a few growth factors are now produced
through recombinant DNA technology. These growth factors can expand the mitotic
pool and accelerate maturation and differentiation. Ultimately, these growth factors
decrease the total time spent in these stages to approximately 5 to 7 days.
The development and circulating life span of hematopoietic cell lines determine
the severity of the depression of that cell line (nadir, lowest point) and the time
course of peripheral cytopenias. Because RBCs survive approximately 120 days in
the peripheral blood, clinically significant anemia is unlikely if production is
impaired for a short period of time. Instead, anemia usually develops slowly after
several courses of cytotoxic therapy. In contrast, platelets survive approximately 10
days, and granulocytes survive only 6 to 8 hours. Hence, neutropenia generally
occurs before thrombocytopenia, but both may be observed after the first or
subsequent courses of cytotoxic chemotherapy. The clinician may have to adjust the
minimize the risk of adverse effects with additional courses of cytotoxic
chemotherapy. To diminish these effects, one can reduce the dose, delay therapy until
recovery, or administer colony-stimulating factors (CSFs). The availability of CSFs
provides an alternative approach to preventing severe neutropenia.
QUESTION 1: J.T., a 68-year-old, 59-kg man with no significant past medical history, presents to the
time curve (AUC) of 6 mg/mL × minute and paclitaxel 135 mg/m
2 on day 1. Discuss the toxicities that might be
can J.T. expect these effects to occur?
Although several toxicities are commonly associated with carboplatin and
paclitaxel, the most predictable and severe toxicity associated with this regimen is
myelosuppression. This chemotherapy regimen can significantly affect any cell line,
including RBCs, neutrophils, and platelets, and the cytopenias can cause significant
morbidity or mortality. Decreased RBCs can cause anemia, and patients usually
present with fatigue and decreased exercise tolerance. Having low neutrophil counts
significantly increases a patient’s risk for bacterial infections. Moreover, reduced
platelets can cause thrombocytopenia, which can cause bleeding from the GI and
Both patient-related and agent-related factors can significantly influence the degree
of cytopenia a patient faces after cytotoxic therapy. Agent-related factors include the
specific agent, dose intensity, and dose density. Because most anticancer treatments
are not given as a single agent, the effects of concurrent cytotoxic therapies may
intensify the myelosuppressive effect of an individual agent. Host factors that
specifically may affect the cellularity of the bone marrow compartment also influence
the degree of cytopenia. They include the following:
Patient age. Younger patients are generally better able to tolerate cytotoxic
chemotherapy than elderly patients because they have a more cellular marrow with
a decreased percentage of marrow fat.
Bone marrow reserve. Certain diseases might present with tumor cells in the bone
marrow, such as leukemias and some lymphomas, in which case the bone marrow
does not have a healthy reserve of normal hematopoietic cells to help in the
The degree of myelosuppression from previous cytotoxic chemotherapy, radiation
therapy, or both. Prior cytotoxic chemotherapy and radiation therapy to fields
involving marrow-producing bone (pelvic bone and sternum) reduce bone marrow
The ability of the liver or kidney to metabolize and excrete the compounds
administered. If agents are administered to patients with specific organ
insufficiencies (i.e., renal or hepatic), slower clearance, resulting in increased
systemic exposure, can occur. This can cause greater toxicities, including longer
These factors, along with the kinetics of the stem cells, can help clinicians predict
the severity and duration of cytopenia observed after therapy.
With most myelosuppressive agents, the patient’s WBC and platelet counts begin
to fall within 5 to 7 days of cytotoxic therapy administration, reach a nadir within 7
to 10 days, and recover within 14 to 26 days. Phase-specific cytotoxic chemotherapy
agents, such as the vinca alkaloids and antimetabolites, cause a fairly rapid onset of
understood reasons, nitrosoureas typically produce severe, delayed neutropenia and
thrombocytopenia 4 to 6 weeks after therapy. Other agents that exhibit this pattern
include mitomycin and mechlorethamine. All of these anticancer agents exert their
cytotoxic effects during the resting phase of the cell cycle. The nitrosoureas, as well
as mitomycin and mechlorethamine, can cause two neutropenic nadirs; the first nadir
occurs at the conventional time expected for phase-nonspecific agents and the second
nadir occurs approximately 4 to 6 weeks after therapy. Many combination regimens
with these agents are therefore given for 6-week cycles to avoid treatment before the
second nadir. However, most other myelosuppressive regimens can be safely given
every 3 to 4 weeks. The majority of the targeted therapies do not suppress bone
marrow production, because they are designed to inhibit a specific molecular
pathway rather than proliferating cells in general. Because of their minimal
myelosuppressive effects, they may be desirable agents to add to regimens that are
Each of the agents included in J.T.’s regimen has marked myelosuppressive
activity. His elderly age may place him at higher risk for exhibiting
myelosuppression. J.T. should be carefully counseled to contact his physician or
report to the emergency department if he experiences signs or symptoms of an
infection (including fever) or bleeding. Typically, these symptoms occur 10 to 14
days after the first day of chemotherapy.
he receive the same doses he was given initially?
One option would be to reduce (usually by 25%) the dose of each agent for all
subsequent cycles. Although a dose reduction can clearly cause less neutropenia, it
chemosensitive and potentially curable, a dosage reduction is undesirable. To
minimize the risk of neutropenia with future therapy, CSFs can be administered to
J.T. to prevent potential complications associated with neutropenia.
Prophylactic administration of CSFs can be used to reduce the myelosuppressive
effects of cytotoxic chemotherapy. Several CSFs—granulocyte colony-stimulating
long-acting form of filgrastim, pegfilgrastim—are available in the United States.
Pegfilgrastim was developed with the aim of providing the same pharmacologic
benefit as filgrastim while offering the advantage and convenience of fewer
injections. The FDA approved filgrastim-sndz as the first biosimilar in the United
States in March 2015. Although tbo-filgrastim was FDA-approved in 2012, it is not
considered a biosimilar because it was filed as a Biologics License Application,
prior to the establishment of the FDA biologics approval pathway. Clinical safety,
particularly related to immunogenicity, is a concern with new approval of
biosimilars, and assessment of tolerability and safety should occur in clinical
2 The evidence-based clinical practice guidelines for the use of CSFs have
been developed by the American Society of Clinical Oncology (ASCO).
guidelines recommend primary prophylaxis for all patients receiving chemotherapy
regimens that have been previously reported to cause a febrile neutropenia incidence
of approximately 20%. A CSF used in these patients can reduce both the incidence of
febrile neutropenia and need for hospitalizations and broad-spectrum antibiotics.
However, CSF usage has not been shown to lead to better tumor response or higher
overall survival. Two randomized Phase III clinical trials have shown that the risk of
neutropenic fever is reduced when primary prophylaxis is used in regimens with a
known neutropenia incidence of approximately 20%. In one trial, 928 patients with
breast cancer receiving docetaxel 100 mg/m2 every 21 days were randomly assigned
to receive placebo or pegfilgrastim 6 mg subcutaneously (SC) 24 hours after
chemotherapy. Patients who received pegfilgrastim had a lower incidence of febrile
neutropenia (1% vs. 17%, respectively) and hospitalizations (1% vs. 14%,
4 A trial in patients (n = 171) with small-cell lung cancer (SCLC)
receiving a dose-intense regimen containing cyclophosphamide 1,000 mg/m2 on day
1, doxorubicin 45 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 to 3 every 21
days was conducted. Patients were randomly assigned to receive prophylactic
antibiotics with or without filgrastim. The rate of febrile neutropenia over all five
cycles was 32% with prophylactic antibiotics without filgrastim versus 18% with
5 A meta-analysis of 17 randomized trials including 3,493
adult patients with solid tumors and lymphomas showed that the use of filgrastim as
primary prophylaxis reduced the risk of febrile neutropenia and improved the rate of
full-dose cytotoxic chemotherapy given on schedule. Additionally, the investigators
in the meta-analysis observed a significant reduction in the risk of infection-related
6 The use of CSFs for secondary prophylaxis is recommended by ASCO for
those patients who experience a neutropenic complication from the prior cycle,
where primary CSF was not used, when a reduced dose or treatment delay may
negatively impact the survival/treatment outcome.
3 Because the regimen J.T. received
does not typically produce a 20% incidence of febrile neutropenia, a CSF was not
recommended for him after his first course of cytotoxic chemotherapy. Now that J.T.
has experienced febrile neutropenia and he has a potentially curable malignancy, a
CSF is indicated with subsequent courses of chemotherapy to prevent additional
Dosing of Colony-Stimulating Factors
The recommended initial dose of filgrastim, tbo-filgrastim or filgrastim-sndz, is 5
mcg/kg/day as a single daily subcutaneous (SC) injection, and of sargramostim, 250
/day SC beginning 24 to 72 hours following the administration of myelotoxic
convenience and reduce cost without clinical detriment. Because commercially
available vials or syringes contain either 300 or 480 mcg of filgrastim, adult patients
weighing less than 75 kg should receive 300 mcg daily and adult patients weighing
more than 75 kg should receive 480 mcg daily.
commercially available vial sizes, the weight break point for sargramostim is slightly
different; patients who weigh more than 60 kg should receive 500 mcg daily and
patients who weigh less than 60 kg should receive 250 mcg daily. Pegfilgrastim is
given once per cycle, 24 to 72 hours following administration of myelotoxic
chemotherapy and not less than 14 days prior to the next treatment, as 6 mg SC in
adult patients regardless of patient weight. A new formulation of pegfilgrastim was
recently approved that is a timed automated-inject device that delivers the
medication 27 hours after it is activated.
The ASCO guidelines also recommend a shorter duration of treatment than the
manufacturers. The manufacturers recommend that therapy with filgrastim or
sargramostim continues until the patient’s neutrophil count is greater than 10,000
cells/μL after the expected chemotherapy nadir. This is based on the observation that
the neutrophil count falls roughly 50% after discontinuing a CSF. The risk of
bacterial infection is highest, however, in patients with neutrophil counts of less than
500 to 1,000 cells/μL; patients with neutrophil counts greater than that are not thought
to be at high risk for experiencing bacterial infections. Thus, many clinicians elect to
discontinue the CSF when the neutrophil count reaches 2,000 to 4,000 cells/μL after
the chemotherapy nadir. This reduces the number of treatment days and the cost
associated with therapy while concurrently reducing the excessive risk for bacterial
infections. The ASCO guidelines support this recommendation to discontinue CSF
In summary, J.T. should be given either filgrastim, tbo-filgrastim or filgrastim-sndz
300 mcg/day, or sargramostim 250 mcg/day SC beginning the day after his last dose
of chemotherapy. Treatment should continue until the ANC is greater than 2,000 to
4,000 cells/μL. Filgrastim is used much more widely than sargramostim.
Alternatively, J.T. could receive a single 6-mg injection of pegfilgrastim the day after
chemotherapy administration. This more convenient administration is due to
pegfilgrastim’s favorable pharmacokinetics. Self-regulation of pegfilgrastim serum
levels, related to its pegylation, is almost entirely dependent on neutrophil receptor-
mediated clearance. Serum levels of pegfilgrastim will remain elevated during
neutropenia induced by chemotherapy, and decline on recovery of neutrophil counts.
Aside from high cost and inconvenience, the only negative effect of filgrastim or
sargramostim therapy is mild transient bone pain. Bone pain is most commonly
experienced when patients begin to recover peripheral blood cells after their nadir.
The proposed mechanism suggests the stimulatory effect of CSF on granulopoiesis
causes the pain. Most patients commonly report pain in bone marrow-rich areas, such
as the sternum and pelvic regions. They should be advised that the bone pain
experienced during marrow recovery is normal and usually is relieved with
Treatment of Fever and Neutropenia with a Colony-Stimulating Factor
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