Chemotherapeutic Drugs Reported to Produce Local Toxicities
techniques and precautions can minimize these risks?
Several factors have been associated with an increased risk of extravasation and
subsequent tissue damage after administration of cytotoxic chemotherapy. Risk
factors include generalized vascular disease commonly found in elderly and
debilitated patients or in patients who have undergone frequent venipuncture and
treatment with irritating chemotherapy (the latter causes venous fragility and
instability or decreased local blood flow); elevated venous pressure, which typically
occurs in patients with an obstructed superior vena cava or venous drainage after
axillary dissection; prior radiation therapy to the injection site; recent venipuncture in
the same vein; use of injection sites over joints, which increases the risk of needle
Tissue damage may be more severe if extravasation occurs in areas with only a
small amount of subcutaneous tissue (e.g., the back of the hand or wrist) because
wound healing is more difficult and exposure of deeper structures, such as the
103 These risks have led to the increased use of central catheters
in patients receiving vesicant chemotherapy.
C.W. has several risks for extravasation. She had an axillary lymph node
dissection for her breast cancer, which places her at higher risk for obstructed
venous drainage. Additionally, she has had multiple venous punctures, and she is a
thin woman with relatively small amounts of subcutaneous tissue.
Extravasations of agents with vesicant properties can produce devastating tissue
damage that can potentially cause loss of an extremity or death. To prevent significant
morbidity or mortality, major emphasis must be placed on prevention. All caretakers
who administer agents with vesicant or irritant properties should be skilled in IV
drug administration and receive special instruction before administering these agents.
The patient also must be told how agent administration should feel and to report
immediately any change in sensation, including pain, burning, or itching.
CASE 94-4, QUESTION 7: C.W.’s oncology nurse believes that the doxorubicin may have extravasated
Immediate management of a potential vesicant extravasation should include
stopping the injection if the entire agent has not been administered. Various other
recommended measures may minimize vesicant exposure and subsequent tissue
damage (Table 94-4). These include application of cold compresses to the
extravasation site and elevation of the extremity. Cold compresses have been shown
to cause vasoconstriction, which can help to localize the extravasation and allow
time for local vessels to displace the extravasated agent, whereas warm compresses
are thought to induce vasodilation, increase drug distribution and absorption,
therefore decreasing the concentration of the offending agent around the immediate
site. Warm compresses are recommended for vinca alkaloids and
103,104 With the exception of these two classes of agents, cooling
has been shown to be more effective than warm compresses. Specific antidotes
thought to inactivate the extravasated chemotherapy have been suggested; however,
many of these antidotes are based on observations in a few patients or animal
models, and their effectiveness, in many cases, is unsubstantiated. Antidotes
recommended in some guidelines may actually worsen tissue damage (e.g., sodium
bicarbonate for doxorubicin). Recommended treatments for suspected extravasation
of vesicant agents are outlined in Table 94-5.
Suggested Procedures for Management of Suspected Extravasation of Vesicant
well as the infiltrated area, should be aspirated
Contact a physician as soon as possible
Document the drug, suspected volume extravasated, and the treatment in the patient’s medical record
Check the site frequently for 5–7 days
ulceration begins, the surgeon can rapidly assess if surgical debridement or excision is necessary
Dexrazoxane has been established as a reliable antidote for anthracycline
extravasations. Dexrazoxane, an iron chelator, was studied based on evidence that it
protects cardiac tissue from anthracycline-induced toxicities. Two prospective,
multicenter, single-arm trials were conducted in a total of 54 evaluable patients with
anthracycline extravasations. In 98.2% of patients, surgical intervention was avoided
and 71% of patients were able to continue treatment regimen without any delays.
Hospitalization of 41% of patients was necessary secondary to their extravasation.
Toxicities included myelosuppression, increased liver function tests, nausea, and
pain at the dexrazoxane infusion site.
105 Based on these results, dexrazoxane is
approved for the treatment of anthracycline extravasations. Dexrazoxane is given
once daily for 3 days at a dose of 1,000 mg/m2
IV on days 1 and 2, and 500 mg/m2
on day 3. Administration should start within 6 hours of extravasation.
Almost all anticancer agents have produced at least an isolated instance of a
hypersensitivity reaction. All types of hypersensitivity reactions can occur with
anticancer agents, although type I is the most common reaction documented. Type I
hypersensitivity reactions are immediate reactions that are most often
immunologically mediated, although there are other possible mechanisms for type I
hypersensitivities. Anaphylactic or immunoglobulin E (IgE)-mediated reactions
occur when an antigen interacts with IgE bound to a mast cell membrane, causing
degranulation of mast cells. Major signs and symptoms of type I reactions include
urticaria, angioedema, rash, bronchospasm, abdominal cramping, and hypotension.
Although many reactions associated with anticancer agents probably are
immunologically mediated, other mechanisms may cause type I reactions. Those
include the degranulation of mast cells and basophils through a direct effect on the
cell surface that releases histamine and other vasoactive substances. Activation of the
alternative complement pathway can also release vasoactive substances from mast
cells. When non-IgE-mediated mechanisms account for the symptoms of a type I
reaction, it is called an anaphylactoid reaction (see Chapter 32, Drug
Recommended Extravasation Antidotes
Recommended Specific Procedure
1/6-M solution sodium thiosulfate Mix 4 mL 10% sodium thiosulfate USP with 6 mL
of sterile water for injection, USP for a 1/6-M
solution. Into site, inject 2 mL for each mg of
mechlorethamine or 100 mg of cisplatin
Mitomycin-C Dimethylsulfoxide 99% (w/v) Apply 1–2 mL to the site every 6 hours for 14 days.
Allow to air dry; do not cover
Anthracyclines Cold compresses Apply immediately for 30–60 minutes on first day
Dexrazoxane Once daily for 3 days. First dose should be given
within the first 6 hours. Day 1: 1,000 mg/m
Apply immediately for 30–60 minutes, then alternate
off/on every 15 minutes for 1 day
a Warm compresses Apply immediately for 30–60 minutes, then alternate
off/on every 15 minutes for 1 day
Etoposide Hyaluronidase Inject 150 units into site
Taxanes Cold compresses Apply immediately for 30–60 minutes every 6 hours
Docetaxel Hyaluronidase Inject 150 units into site
IV, intravenous; w/v, weight per volume.
Infus Nurs. 2009;32:203; Totect (dexrazoxane injection) [package insert]. Rockaway NTTU, Inc.; 2011.
Many of the type I hypersensitivity reactions produced by anticancer medications
appear to be mediated by non-IgE mechanisms. Although little research has been
conducted on the mechanism of these reactions, two features suggest that they are not
mediated by IgE. First, many reactions occur during or immediately after
administration of the first dose. This is in contrast to immunologic reactions that
require prior exposure (i.e., one must be sensitized before becoming
hypersensitized). In addition, certain symptoms or symptom complexes are more
diagnostic of immunologically mediated disorders. These symptoms include
urticaria, angioedema, bronchospasm, laryngeal spasm, cytopenias, arthritis,
mucositis, vasculitic syndromes, and vesicular dermatitis. Although the spectrum of
symptoms and their severity vary widely in the case reports, most hypersensitivity
reactions that occur with anticancer agents are classified as grade 1 (transient rash,
mild) or grade 2 (mild bronchospasm, moderate) by the NCI Common Terminology
1 Furthermore, a patient who has had a reaction to an
agent that is not immunologically mediated can safely receive future courses of
anticancer therapy if he or she receives appropriate premedication. For example,
appropriate premedication allows many (>60%) patients who have previously
experienced a hypersensitivity reaction secondary to paclitaxel to continue therapy;
reactions after the first and subsequent doses of therapy.
The other types of hypersensitivity reactions are less commonly documented with
cytotoxic and targeted therapy administration. Type II is hemolytic anemia. Type III
results from deposition of antigen–antibody complexes that form intravascularly and
in tissues that can result in tissue injury. Sensitized T lymphocytes that react with
antigens causing a release of lymphokines are responsible for type IV reactions.
Anticancer agents most frequently reported to produce hypersensitivity reactions and
their characteristic reactions are listed in Table 94-6.
information stems from patient series and case reports. However, they often provide
conflicting and contradictory information, particularly with respect to incidence,
severity, characteristic symptoms, time course, and the success of rechallenge. If a
patient experiences a hypersensitivity reaction and the clinician decides to continue
therapy with this regimen, a full review of all of the relevant literature as well as
manufacturer’s data is advised. Several reviews are available to assist in this
cycles of FOLFOX (oxaliplatin 85 mg/m
IV on day 1, leucovorin 100 mg/m
IV bolus, followed by 600 mg/m
IV for 22 hours on days 1 and 2) plus bevacizumab 5
mg/kg. He also recently progressed after two cycles of second-line FOLFIRI (irinotecan 180 mg/m
IV on days 1 and 2, and fluorouracil 400 mg/m
IV bolus, followed by 600 mg/m
IV weekly). Discuss the toxicities that S.R. may expect and when they might
appear. How should these side effects be managed? S.R. asks how these side effects can be prevented.
Cancer Chemotherapeutic Agents Commonly Causing Hypersensitivity
Drug Frequency Risk Factors Manifestations Mechanism Comments
126–128 Common Lymphoma Fever (up to
130 First None known Chills, fever, Unknown, Manage with
6.8% None known Flushing, SOB,
intravenous; PRN, as needed; SC, subcutaneous; SOB, shortness of breath.
The most common toxicities observed in patients receiving cetuximab include
rash, diarrhea, hypomagnesemia, headache, nausea, and hypersensitivity reactions.
Infusion-related reactions occur in 15% to 20% of patients receiving their first
infusion. However, severe hypersensitivity reactions (including allergic and
anaphylactic reactions) occur in 1% to 3% of patients. The reactions are related to
the infusion of cetuximab and generally occur during or within 1 hour of completing
the first dose. Patients should be premedicated with diphenhydramine before the
infusion. The infusion can be stopped or the rate decreased if S.R. begins
experiencing these effects. The skin rash and dry skin occurring after cetuximab
administration are related to the inhibition of EGFR and were the most common side
effect seen in clinical trials. The rash occurred in approximately 80% of patients and
appeared in the first 1 to 3 weeks of therapy. Grade 3 or 4 skin rashes occurred in
Several of the monoclonal antibodies (e.g., rituximab, trastuzumab, cetuximab,
ofatumumab) are associated with a higher incidence of hypersensitivity reactions than
traditional cytotoxic agents. These agents are genetically engineered humanized
monoclonal antibodies containing foreign proteins that can trigger the reaction.
During the first infusion with trastuzumab, approximately 40% of patients experience
a symptom complex, mild to moderate in severity, which consists of chills, fever, or
both. These symptoms usually do not recur with subsequent injections.
comparison, approximately 80% of patients receiving rituximab may experience an
infusion-related reaction ranging from fever, chills, and rigors to severe reactions
(7%) characterized by hypoxia, pulmonary infiltrates, adult respiratory distress
syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock with
the first dose. Approximately 40% of patients receiving rituximab experience
infusion-related reactions with subsequent infusions (5%–10% severe).
of these reactions follows the recommendations for treatment of hypersensitivity
reactions that occur with more traditional agents.
Recommended treatment of hypersensitivity reactions is reviewed in Table 94-7. If a
patient experiences a severe type I hypersensitivity reaction to any anticancer agent,
the treatment should be stopped. If a structural analog or another agent in the same
chemical class is an effective treatment for the same cancer, subsequent therapy
should use the analog or other agent to minimize the risk of future reactions. If the
reaction is mild or moderate, the patient may continue with the same therapy if
treatment is preceded by methods to prevent or minimize hypersensitivity reactions.
General recommendations for preventing hypersensitivity reactions are found in
Table 94-7. Pretreatment with corticosteroids and diphenhydramine significantly
decreases the frequency and severity of hypersensitivity reactions; however, the
receptor antagonists and epinephrine remains controversial. Because the
success of these preventive measures depends on the cause of the reaction
(immunologic or anaphylactoid), the aforementioned characteristics of type I
reactions should be used to assess the underlying pathogenesis. In addition, other
chemicals present in the formulation or other agents administered concomitantly with
the chemotherapy can cause the hypersensitivity reaction. Potential allergens
included in the diluent or formulation of chemotherapy agents include Cremophor EL
(present in paclitaxel), polysorbate 80 (present in docetaxel and etoposide), benzyl
alcohol (present in the parenteral form of methotrexate, cytarabine, and etoposide),
and methoxypolyethylene glycol (present in liposomal doxorubicin). Recognizing
potential allergens can significantly affect treatment of the current reaction and
minimize the risk of future reactions.
To reduce the hypersensitivity reactions observed with paclitaxel, paclitaxel
protein-bound particles (Abraxane), an albumin-bound formulation of paclitaxel, has
been created. Because paclitaxel protein-bound particles formulation is Cremophor
EL-free and less likely to cause hypersensitivity than traditional paclitaxel, it is not
necessary to premedicate patients with steroids and antihistamines. Doses between
the two agents are not comparable. Although fewer hypersensitivity reactions are
associated with this formulation, myelosuppression remains a dose-limiting
Prophylaxis and Treatment of Hypersensitivity Reactions from Anticancer
BP monitoring must be available
Dexamethasone 20 mg PO and diphenhydramine 50 mg PO 12 and 6 hours before treatment, then the same
dose IV immediately before treatment
antagonist with schedule similar to dexamethasone
Have epinephrine and diphenhydramine readily available for use in case of a reaction
Observe the patient up to 2 hours after discontinuing treatment
Discontinue the drug (immediately if being administered IV)
Administer epinephrine 0.3 mg IM or SC minutes until reaction subsides
Administer diphenhydramine 50 mg IV
If hypotension is present that does not respond to epinephrine, administer IV fluids
If wheezing is present that does not respond to epinephrine, administer nebulized albuterolsolution
BP, blood pressure; IV, intravenous; PO, orally.
for induction chemotherapy. Methotrexate 3 g/m
IV once on day 1, cytarabine 2 g/m
Methotrexate, Cytarabine, and Vincristine
Methotrexate causes little or no neurotoxicity when administered orally or
intravenously in doses less than 1 g/m2
; however, high-dose IV methotrexate (usually
) can occasionally cause acute encephalopathy. The encephalopathy that
occurs after therapy with methotrexate is usually transient and reversible. Some
patients may experience a progressive leukoencephalopathy after high-dose IV
methotrexate. The risk of leukoencephalopathy increases with higher cumulative
doses of methotrexate and concomitant cranial radiation therapy.
reversible encephalopathy syndrome has also been associated with high-dose
methotrexate and intrathecal methotrexate. Chemical meningitis can occur with
intrathecal administration of methotrexate and, less frequently, myelopathy or
(see Chapter 95, Pediatric Malignancies). Patients
receiving intrathecal therapy or high-dose methotrexate should be carefully
monitored for signs and symptoms associated with neurotoxicity.
High doses of cytarabine (>1 g/m2
in multiple doses) are associated with CNS
toxicity in 8% to 37% of patients.
142,143 These neurotoxicities are dose-related and
schedule-related. Doses greater than 18 g/m2 per course increase the frequency of
neurotoxicity. Older patients are more susceptible than younger patients, and the
prevalence seems higher in subsequent versus initial courses of therapy. As
illustrated by A.L., neurotoxicity may become evident within a few days after
treatment with cytarabine and, most commonly, the neurotoxicity is manifested by a
generalized encephalopathy with symptoms such as confusion, obtundation, seizures,
and coma. Cerebellar dysfunction, presenting as ataxia, gait and coordination
difficulties, and dysmetria (inability to arrest muscular movement when desired and
lack of harmonious action between muscles when executing voluntary movement), is
also commonly observed in patients receiving high-dose cytarabine therapy. These
neurologic symptoms may partially resolve over days to weeks after discontinuation
of therapy. Other neurologic toxicities reported with cytarabine include progressive
leukoencephalopathy and chemical meningitis. Intrathecal administration of
cytarabine, including the liposomal formulation, may also cause a chemical
141,144 Leukoencephalopathy typically presents with
progressive personality and intellectual decline, dementia, hemiparesis, and,
sometimes, seizures. These neurotoxicities also can occur after treatment with other
Asparaginase and pegaspargase can cause encephalopathy, which presents most
commonly as lethargy and confusion. These agents are used in acute lymphocytic
leukemia regimens. Severe cerebral dysfunction occurs occasionally, and patients
may present with stupor, coma, excessive somnolence, disorientation, hallucination,
or severe depression. Symptoms can occur early (within days of administration of
asparaginase) or late, depending on the treatment schedule.
mechanism is the direct neurocytotoxic effect of aspartic acid, glutamic acid, and
ammonia. The neurotoxicity is usually reversible with the acute syndrome clearing
rapidly and a delayed syndrome lasting several weeks.
agents is complicated because omitting a dose or decreasing the dose of either of
these agents could compromise the likelihood of a complete remission. High-dose
cytarabine cerebellar toxicity may be irreversible. Therefore, the clinician may
decide to discontinue cytarabine in A.L.’s future regimens. Additionally,
modifications of methotrexate including dose reductions may be necessary in future
Multiple other anticancer agents including fluorouracil, fludarabine, nelarabine,
procarbazine, and ifosfamide produce an encephalopathic toxicity (Table 94-8).
Recognition of neurotoxicity resulting from cytotoxic chemotherapy is often difficult
because of comorbid conditions such as metastatic disease and other paraneoplastic
syndromes, but it is important in assessing the need for potential dose modifications
or even discontinuation of the agent. Several reviews provide detailed explanations
of signs and symptoms, mechanisms, and potential treatments for chemotherapyinduced neurotoxicities.
145,147 When a patient presents with any signs or symptoms of
neurotoxicity, the patient should receive a neurologic examination followed by a
dose reduction or discontinuation of therapy.
Neurotoxicity of Selected Chemotherapeutic Agents
Encephalopathic Cerebellar Peripheral Cranial
Encephalopathy Syndrome Neuropathy Neuropathy Neuropathy Therapy) Neuropathy
Asparaginase Cytarabine Cytarabine Bortezomib Fluorouracil Cytarabine Vinblastine
Cisplatin Methotrexate Cisplatin Brentuximab Ifosfamide Methotrexate Vincristine
Cytarabine Nelarabine Fludarabine Cisplatin Thiotepa Vinorelbine
Fludarabine Thiotepa Fluorouracil Docetaxel
Ifosfamide Ifosfamide Fluorouracil
SIADH, syndrome of inappropriate secretion of antidiuretic hormone.
Fluorouracil can cause acute cerebellar dysfunction characterized by the rapid onset
of gait ataxia, limb incoordination, dysarthria, and nystagmus. Cerebellar dysfunction
occurs in approximately 5% to 10% of patients receiving fluorouracil at all treatment
schedules in common use and can present weeks to months after beginning therapy. A
more diffuse encephalopathy presenting as headache, confusion, disorientation,
lethargy, and seizures can also occur. These symptoms can be reversed if
fluorouracil is discontinued or the dose is reduced. Reports of cerebellar ataxia have
also been reported with capecitabine, an oral prodrug of fluorouracil.
Fludarabine can cause severe neurotoxicity when used at doses greater than 90 mg/m2
145,151,152 Symptoms include altered mental status, photophobia,
amaurosis (blindness that usually is temporary without change in the eye itself),
generalized seizures, spastic or flaccid paralysis, quadriparesis, and coma. Patients
may progress to death even when therapy is discontinued. This neurotoxicity,
however, is not common with the current recommended dosage of 20-30 mg/m2
for 5 days. Mild neurologic symptoms are typically reported, but severe
145,151 and optic demyelination occurs only occasionally.
signs or symptoms suggestive of significant neurotoxicity should receive a neurologic
examination and, if warranted, therapy should be discontinued without rechallenging
with a dose reduction. Nelarabine, another purine analog has dose-limiting
neurotoxicity, and 18% to 37% of patients in Phase II trials showed severe grade 3
154,155 The clinical presentation includes severe somnolence,
convulsions, and peripheral neuropathy ranging from paresthesias to motor weakness.
Several cases of ascending peripheral neuropathies and demyelination have been
156 Therapy should be stopped if grade 2 toxicity is present because some
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