Page 1312 - Small Animal Internal Medicine, 6th Edition

1284 PART XII Oncology

ventricular tachycardia, second-degree atrioventricular UROTOXICITY
blocks, and intraventricular conduction defects, can develop.
VetBooks.ir These rhythm disturbances are usually associated with the The urinary tract in small animals is rarely affected by
adverse reactions to anticancer agents. Only two specific
development of a dilated cardiomyopathy, similar to that
which occurs spontaneously in Doberman Pinschers and
nephrotoxicity and sterile hemorrhagic cystitis. Transitional
Cocker Spaniels. complications are of clinical importance in pets with cancer:
The hallmark of chronic doxorubicin toxicity is a dilated cell carcinomas of the urinary bladder associated with
cardiomyopathy that allegedly develops after a total cumu- chronic cyclophosphamide therapy have also been reported
lative dose of approximately 240 mg/m is exceeded in the in dogs.
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dog; however, we have administered higher cumulative Nephrotoxicity is rarely observed in dogs and cats undergo-
doses without overt cardiac problems in a large number of ing chemotherapy. Although several potentially nephrotoxic
dogs (see later). The histologic lesions seen in dogs with drugs are commonly used in these species, only doxorubicin
doxorubicin-induced cardiomyopathy consist of vacuola- (primarily in cats), cisplatin (in dogs), and intermediate to
tion of myocytes, with or without myofibril loss. Clinical high doses of methotrexate (in dogs) are of concern to cli-
signs of toxicity in dogs are those of congestive heart failure nicians. The author’s clinic does not use cisplatin frequently
(usually left-sided). Therapy consists of discontinuation because of its potential to induce nephrotoxicity.
of the offending drug and the administration of cardiac Doxorubicin may be a nephrotoxin in cats, and the limit-
drugs such as digitalis glycosides or nonglycoside inotro- ing cumulative toxicity in this species may be renal rather
pic agents (e.g., pimobendan). Once cardiomyopathy devel- than cardiac. This is generally seen after repeated doses of
ops, the prognosis is poor because the myocardial lesions doxorubicin in cats, and for this reason, the authors com-
are irreversible. monly monitor kidney values and urine specific gravities in
It is critical to monitor patients receiving doxorubicin cats receiving repeated doxorubicin. If increases in creati-
to prevent potentially fatal cardiomyopathy. In this respect, nine and/or SDMA concentrations, or decreases in urine
dogs (and possibly cats) with underlying rhythm distur- specific gravity develop, doxorubicin discontinuation should
bances or impaired myocardial contractility, as shown be considered. Doxorubicin may cause nephrotoxicosis in
by decreased fractional shortening on echocardiogram, dogs with preexisting renal disease and in those concomi-
should not receive doxorubicin. It is also recommended tantly receiving other nephrotoxins such as aminoglycoside
that high-risk dogs receiving doxorubicin undergo echo- antibiotics or cisplatin. The administration of cisplatin using
cardiographic evaluation every three doxorubicin cycles (9 forced diuresis protocols minimizes the prevalence of neph-
weeks) to assess myocardial contractility and that the drug rotoxicity in dogs. Due to its potential for nausea/vomiting
be discontinued if decreased fractional shortening occurs. and nephrotoxicity, the authors’ clinics do not use cisplatin.
Endomyocardial biopsy specimens are commonly obtained Sterile hemorrhagic cystitis (SHC) is a relatively common
in people receiving doxorubicin in an effort to detect sub- complication of long-term cyclophosphamide therapy in
microscopic lesions, but this is impractical in dogs. The dogs; rarely, it may also occur acutely after a single dose of
value of serum cardiac troponin I concentrations to detect cyclophosphamide. This toxicity is not clinically relevant in
early myocardial damage from doxorubicin is questionable cats. Acute clinical signs and urinalysis changes compatible
in dogs. with SHC developed after the first injection in three dogs
Several protocols have been devised in an attempt to treated at one clinic with IV cyclophosphamide, 100 mg/m ,
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minimize doxorubicin-induced cardiomyopathy in dogs. and four dogs receiving PO cyclophosphamide, 300 mg/m .
Administering the doxorubicin slowly in a diluted solution SHC results from the caustic effects of one of the cyclophos-
(≈0.5 mg/mL over 30 minutes) seems to be the most effec- phamide metabolites (acrolein) on the bladder epithelium.
tive; one of the authors (GC) has administered 8 to 10 doses It develops in approximately 5% to 25% of dogs treated with
of doxorubicin to a large number of dogs without obvious cyclophosphamide, usually after an average of 18 weeks of
cardiotoxicity. This is due to the fact that cardiotoxicity of therapy. Subjectively, it appears that the prevalence of SHC
doxorubicin is directly related to the peak plasma concentra- is higher when using cyclophosphamide in metronomic pro-
tion of the drug. tocols. Furosemide or prednisone administered concomi-
Dexrazoxane (Zinecard, Pfizer) offers a promising means tantly with cyclophosphamide appears to decrease the
of reducing the chronic cardiotoxicity induced by doxoru- prevalence of cystitis.
bicin; doxorubicin doses in excess of 500 mg/m have been Forced diuresis appears to minimize the severity of this
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administered to dogs receiving the agent without causing complication or prevent it. The authors usually recommend
significant cardiotoxicity. Recently, carvedilol (0.1-0.4 mg/ administering the cyclophosphamide in the morning, allow-
kg PO q12-24h) has been used successfully to prevent ing the pet to urinate frequently (if it is an indoor dog), and
or decrease the probability of developing doxorubicin- administering prednisone on the same day that the animal
associated cardiomyopathy in people (Kalay et al., 2006); receives the cyclophosphamide (if the protocol calls for pred-
one of the authors (GC) has successfully used carvedilol in nisone administration). In addition, if giving bolus doses of
dogs with subclinical myocardial dysfunction that needed cyclophosphamide to dogs, furosemide should be used to
doxorubicin. decrease the potential for SHC. An alternative method for