Page 1290 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 95: Toxicities of Chemotherapy 897

occur within 72 hours of the first cycle. Depending on study size, the VEGF-targeted tyrosine kinase inhibitors sunitinib and sorafenib
incidence of 5-FU cardiotoxicity ranges from 1.6% to 10%. Saif et al have demonstrated a 20% incidence in asymptomatic LVEF decline as
reviewed the data of 377 patients from previously published clinical well as a 4% incidence of LVEF decline of greater than 20%. 54
studies and case reports of 5-FU–induced cardiotoxicity to better identify Finally, radiation therapy is also damaging to the heart and this risk
its incidence and risk factors. The median age of the patients was 57 increases with fractional dose as well as concomitant administration of
43
years while 14% and 37% of them were identified as having preexisting cardiotoxic systemic anticancer therapies mentioned above. The cardio-
cardiac disease or cardiac risk factors (smoking, diabetes, hyperlipid- toxic effects of radiation develop at a mean interval of 82 months after
emia), respectively, and half of them received combination chemother- therapy and most commonly manifests as pericardial disease (effusion or
apy. Manifestations of cardiotoxicity included angina (45%), MI (22%), pericarditis) which can later lead to fibrosis and constrictive physiology.
50
arrhythmia (23%), pulmonary edema (5%), heart failure (2%), and Of particular concern is the frequency with which combination
cardiac arrest and pericarditis (1.4%). Sixty-nine percent experienced radiation and chemotherapy are used in treatment regimens and their
transient ECG findings consistent with ischemia. Risk factors associated potential for synergistic cardiotoxic effects.
with increased incidence of these cardiac events were advanced age, a The American College of Cardiology and American Heart Association
history of CAD, and administration of 5-FU via a continuous infusion 2003 guidelines for the use of cardiac radionuclide imaging recommend
(>24 hours) versus IV bolus dosing (<3 hours). Capecitabine is an orally baseline EF assessment with a multigated acquisition scan, or MUGA,
administered prodrug of 5’-deoxy-5-fluorouridine which is converted to in all patients prior to receiving doxorubicin (IA). Serial LVEF assess-
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5-FU in the liver and tumor cells. Its use has been increasing due to its ments have been advocated based on an early study by Alexander et al,
effectiveness and convenience of administration. Initially, hopes were which demonstrated serial MUGA during treatment with doxorubin
that capecitabine had milder toxicity profile; however, a retrospective was able to detect preclinical moderate declines in LVEF. However,
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analysis by Van Cutsem et al found the incidence of cardiotoxicity of MUGA and echocardiograms are felt to lack adequate sensitivity for
capecitabine to be comparable to that of 5-FU. This is perhaps due to the detection of preclinical cardiotoxicity. The most sensitive indicator
44
the metabolites ultimately produced by 5-FU which have been shown of early myocardial toxicity, however, is endomyocardial biopsy, which
to be directly toxic to myocardial cells in animal studies. given its invasive nature, limits its utility. Serum markers such as
The alkylating agent, cyclophosphamide, has also been shown to exert troponin and BNP have been shown to be predictive of cardiac
a dose-related cardiotoxicity in cancer patients within 10 days of the first events; however, there are no established values that demonstrate good
dose. Patients receiving high-dose (≥150 mg/kg) preparative regimens sensitivity and specificity due to limited studies. 50
for stem cell transplants are particularly at risk. Toxicity may manifest as
failure with an incidence of LV dysfunction ranging from 7% to 28%. ■ GASTROINTESTINAL AND HEPATIC TOXICITIES
myocarditis, pericarditis, cardiomyopathy, pericardial effusion, or heart
45
The proposed mechanism of cyclophosphamide toxicity is believed to The incidence of clinically significant grade 3-4 oral mucositis (pain-
be mediated by neurohumoral activation as shown by increased BNP ful erythema or ulcers preventing swallowing with inability to take PO
levels in 23 patients treated with 4 g/m cyclophosphamide for multiple or handle oral secretions that may require prophylactic endotracheal
2
myeloma in anticipation of autologous stem cell transplant. 46 intubation) is 1% to 10% when associated with anthracycline-based regi-
Cisplatin infusion can be associated with acute-onset chest pain and mens while 5-FU–related mucositis approaches rates of >15%. Taxane-
elevated cardiac enzymes, as well as late onset complications including and platinum-based regimens also have an incidence of oral mucositis
hypertension, LV hypertrophy, and myocardial ischemia up to 20 years in the range of 3% to 13%; however, concomitant XRT increases the risk
following remission. 47 up to sevenfold. Stem cell transplant recipients (largely acute leukemia
Paclitaxel has been reported to potentiate heart failure when used in and lymphoma patients) have the highest rates of mucositis as a result of
combination with anthracyclines in addition to an estimated 29% inci- high-dose chemotherapy regimens (30%-50% and >60% when accom-
dence of transient asymptomatic bradycardia possibly due to massive panied by whole body irradiation) followed by head and neck patients
histamine release. 32,48 The antitumor mechanism of action of paclitaxel (approximately 40%). 57,58
and docetaxel exerts a negative ionotropic effect by reducing calcium The onset of mucositis typically occurs 5 to 7 days after treatment with
release from the sarcoplasmic reticulum, leading to both brady- and chemotherapy or radiation and may resolve in 2 to 3 weeks in the absence
tachyarrhythmias, as well as myocardial ischemia or infarction sec- of myelosuppression. Treatment is largely supportive with adequate
ondary to coronary vasospasm. Reports of the incidence myocardial hydration, topical anesthetics such as lidocaine and systemic analgesia
ischemia following taxane treatment range 1.7% to 5% and myocardial with morphine via PCA. Present guidelines do not recommend chlorhex-
infarction 0.5% in patients with a known history of CAD. For this idine to treat established oral mucositis. The painful nature of muco-
45
reason, cardiac monitoring is recommended during treatment in patients sitis limits oral intake and leads to malnutrition that may require total
with known history of conduction defects or ventricular dysfunction. 48,49 parenteral nutrition (TPN). In severe cases, patients may be unable to
Newer biologic agents including monoclonal antibodies and tyrosine handle their oral secretions and require intubation for airway protection.
kinase inhibitors also have cardiotoxic potential. The incidence of car- Mucositis involving the gastrointestinal tract can result in clinically
diac dysfunction due to the monoclonal antibodies trastuzumab and significant diarrhea leading to hypovolemia and electrolyte abnormalities.
bevacizumab ranges 0.8% to 16%; however, in most studies these agents Subcutaneous octreotide (100 µg) is recommended when first-line
were combined with an anthracycline. 34,45 Bevacizumab can also cause therapy with loperamide is unsuccessful. Radiation-induced proctitis
severe hypertension in up to 5% of patients, resulting in complications accompanied by rectal bleeding can be treated with sucralfate enemas. 59,60
such as hypertensive encephalopathy and subarachnoid hemorrhage. At least 70% of patients receiving cancer chemotherapy will experi-
50
The tumor cell target of trastuzumab, ErbB2, is also present on cardiac ence nausea and vomiting that can lead to dehydration, malnourish-
myocytes and serves a presumed cardioprotective role; thus inhibition of ment, and electrolyte abnormalities. Chemoreceptors in the fourth
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ErbB2 may predispose to anthracycline-induced cardiotoxicity. 51,52 The ventricle of the brain mediate the individual’s emetogenic response to
clinical manifestations of cardiotoxicity that may occur in 2% to 3% of cytotoxic drugs. Some of the chemotherapeutics agents with highest
patients treated with the EGFR inhibitor cetuximab include acute MI, emetogenic potential (>60%) include carmustine, cisplatin cyclophos-
arrhythmias, myopericarditis, cardiomyopathy, CHF, hypotension, and phamide (especially at higher doses), dacarbazine, procarbazine (oral),
nonspecific ECG changes. Hypomagnesemia is a common side effect dactinomycin, doxorubicin, methotrexate, and pentostatin. Treatment
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of cetuximab that should be aggressively treated in order to avoid poten- is largely supportive with IV hydration and/or nutrition as well as
tially exacerbating cardiotoxic effects such as conduction disturbances aggressive electrolyte replacement in combination with attempts at
such as prolongation of QTc interval. chemoreceptor blockade via 5-HT3 receptor antagonists (ondansetron,

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