Page 1294 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 95: Toxicities of Chemotherapy 901

Anaphylaxis is an immune-mediated reaction secondary to preformed Extravasation of chemotherapeutic agents occurs in up to 22% of
IgE antibodies from prior exposure to the agent. An anaphylactoid adults and can cause local inflammation (agents with irritant proper-
reaction is non-IgE mediated but may result in identical symptomatol- ties) or tissue necrosis and blistering (agents with vesicant properties).
ogy and does not require past exposure. Cytokine release syndrome is Vesicant agents include anthracyclines, vinca alkaloids, and taxanes
another nonimmune-mediated reaction to the monoclonal antibody while irritants include alkylating agents, platinums, and topoisomerase II
class of drugs that can result in similar anaphylactoid reactions. An inhibitors. Treatment is supportive (elevation and warm or cold com-
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infusion reaction is merely a hypersensitivity reaction that occurs during presses) and in some instances an antidote may be available that can
or immediately after administration of the drug infusion. Depending prevent tissue necrosis by mitigating the chemical effects of the drug on
on the severity of the reaction, agents may be continued as part of the soft tissue (ie, prevention or scavenging of free radicals). Anthracycline
patient’s treatment regimen at lower dosages and with premedication extravasation may be particularly severe due to the drugs tendency to
with steroids, antihistamines, and histamine blockers. Desensitization bind fat and surgical intervention may be warranted.
has been utilized successfully without adverse effects on the antineoplas-
tics efficacy. Otherwise, in severe, life-threatening reactions, use of a dif- ■ THROMBOTIC COMPLICATIONS
ferent agent with similar efficacy should be entertained. While most all Venous thromboembolism is a well-known complication of malignancy
antineoplastics have been shown to cause hypersensitivity reactions, the with studies revealing >50% of cancer patients with VTE on autopsy. In
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most common include paclitaxel, docetaxel, platinums, epipodophyllo- addition, several anticancer therapies have been shown to further increase
toxins, monoclonal antibodies, as well as bacterial-derived asparaginase. risk of VTE. For patients receiving tamoxifen, there was a relative risk of
The severity of a hypersensitivity reaction can be graded by clinical 2.4 for the development of DVT/PE in a large population-based study with
manifestations. Mild reactions may include transient facial flushing, fever, a long-term follow-up of 10 years. The risk for DVT/PE was found to
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rash, urticaria, and dyspnea. A more severe reaction can include the previ- be greatest in the first 2 years of therapy (3.5 times the risk of women not
ous symptoms in addition to bronchospasm and hypotension. Anaphylaxis receiving tamoxifen) while the risk was not significantly increased during
is a life-threatening reaction and can rapidly lead to death if not recognized year 3 to 10 of follow-up. Other contributing factors may further increase
and treated aggressively. Severe reactions, including anaphylaxis, will have this risk such as age, obesity, immobility, smoking, and hypertension.
immediate onset, whereas milder reactions may occur during the infusion Cisplatin-based chemotherapies have also been shown to increase
or be delayed for up to 24 to 72 hours after administration. 88 risk of vascular events including cerebrovascular events, arterial
In general, if a patient experiences a hypersensitivity reaction, the thromboses, superficial phlebitis, angina pectoris, as well as DVT/PE.
infusion should be discontinued and the patient monitored for signs In a study by Czaykowski et al of 271 consecutive patients, 35 (12.9%)
and symptoms of anaphylaxis while providing supportive therapy with experienced a vascular event, 77% of which were during the first two
oxygen, bronchodilators, and IV fluids in addition to histamine blockade cycles. Chemotherapy was prematurely discontinued in 24%, and there
with diphenhydramine and ranitidine. Treatment of anaphylaxis includes were 3 deaths (9%). A phase II trial examining the use of combination
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hemodynamic and respiratory support with rapid, large volume fluid gemcitabine, 5-FU and thalidomide in patients with metastatic renal
administration, epinephrine and endotracheal intubation with mechanical cell carcinoma was suspended after enrollment of 21 patients due to
ventilation. One should anticipate a difficult intubation due to significant an unexpectedly high rate of DVT/PE (43%) and no improvement in
soft tissue edema which may obscure adequate visualization of the vocal response rate compared to historical controls treated with gemcitabine
cords. Attempts to intubate that are unsuccessful may lead to complete and 5-FU. While this study was small due to early suspension, simi-
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airway obstruction and need for emergency surgical airway. For this lar risks of DVT/PE associated with thalidomide have been shown in
reason, collaboration between the intensivist, anesthesiologist, and otolar- patients treated for multiple myeloma. 96
yngologist may be advised. Concomitant with hemodynamic and respira- Thrombotic thrombocytopenic purpura has been most commonly
tory stabilization, antihistamines should be administered with intravenous associated with mitomycin, cisplatin, and more recently, gemcitabine. The
diphenhydramine 50 mg and H blocker such as ranitidine 50 mg every proposed mechanism for chemotherapy-induced TTP is direct endothelial
2
6 hours in addition to hydrocortisone 100 mg or methylprednisolone at cell dysfunction due to the chemotherapeutic agent and resultant generation
1.0 to 2.0 mg/kg/day to prevent a biphasic reaction which occurs in up to of small immune complexes and platelet aggregates. The term thrombotic
one-quarter of patients who experience true anaphylactic shock. microangiopathic syndrome has also been used to describe chemotherapy-
To avoid potentially life-threatening reactions, premedication is related development of microangiopathic hemolytic anemia, thrombo-
typically administered with histamine blockers and corticosteroids. cytopenia, and renal insufficiency. Depending on the severity of renal
■ DERMATOLOGIC TOXICITY dysfunction, the term HUS may also be used. Despite different terminology
used, the underlying histology of all three is characterized by platelet laden
The nature of traditional chemotherapeutic agents to target cells with microthrombi within the glomeruli and afferent arterioles with subsequent
high mitotic rates makes the skin, hair, and nail particularly vulnerable thickening of the glomerular basement membrane due to fibrin deposition.
to side effects. Most of these reactions are not life-threatening though As a result, patients will present with new or worsening hypertension and
may be dose limiting due to painful effects. Even with the advent of progressive renal dysfunction. Compared to classic TTP-HUS, TTP that
newer targeted agents, dermatotoxicity remains a concern. is chemotherapy related is typically more insidious in onset, neurologic
Acral erythrodysesthesia, known as hand-foot syndrome, has been symptoms are less common, and it does not respond well to plasma
associated with high doses of 5-FU, doxorubicin, and cytarabine, as exchange. Incidence ranges from 8.5% to 15% for cases of mitomycin-
well as tyrosine kinase inhibitors. The syndrome is characterized by related disease, 2.6% secondary to cisplatin, and 0.015% to 1.4% due to
progressive tingling and burning pain in the palms and soles which sub- gemcitabine. Mitomycin-related TTP is dose related and most cases
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sequently become edematous and erythematous and in some instances report a cumulative dose >60 mg. The onset ranges 4 to 9 weeks after
desquamated. The onset of hand-foot syndrome ranges from 24 hours treatment though in some cases onset may be delayed up to 15 months.
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to 10 months after initiation of treatment and management requires The risk of gemcitabine-induced TTP appears to increase at cumulative
treatment interruption or dose reduction. Topical emollients and adjunc- doses >20,000 mg/m and has a relatively later onset of 7 months compared
2
tive treatment with pyridoxine or cyclo-oxegenase-2-inhibitors have to mitomycin. Renal failure in most cases is progressive and requires renal
shown symptomatic improvement when compared to placebo. Due to loss replacement therapy while mortality ranges from 9% to 100% depending
of skin integrity, affected patients may be at increased risk of infection. 89 on the chemotherapeutic agent; however, these estimates are based on small
Other examples of dermatologic patterns of toxicity include radiation case reviews. Plasma exchange has been utilized in both mitomycin- and
recall (inflammatory dermatitis at site of prior radiation after exposure to gemcitabine-induced TTP with mixed results (response rates only 30%
chemotherapy); hyperpigmentation; hidradenitis; and photosensitivity. 90 compared to 80% in classical TTP) and its role remains controversial.

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