Page 217 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

196 PART 3 Therapeutic Modalities for the Cancer Patient

Epipodophyllotoxins (Etoposide and Teniposide) displacement reactions resulting in bifunctional lesions and inter-
Basic Pharmacology. Etoposide (VP-16) and teniposide (VM-26) or intrastrand cross-links. 331 Intrastrand adducts, in particular
by stabi-
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N -d(GpG) and N -d(ApG) account for the majority of plati-
both inhibit the catalytic activity of topoisomerase II
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322
VetBooks.ir lizing a protein–DNA cleavage complex 323 that ultimately results num-DNA damage and are highly correlated with drug-induced
Reactions with water are an important compo-
in the generation of single- and double-strand DNA breaks.
332
324
cell killing.
These compounds enter tumor cells by simple diffusion across the nent of the pharmacology of cisplatin (CDDP) owing to some
cell membrane, and increased levels of topoisomerase II in prolif- of the aquated species potentially crossing cell membranes more
erating tumor cells increases selectivity. 325 rapidly. 333
Clinical Pharmacology. Etoposide has been evaluated in dogs Clinical Pharmacology. Both CDDP and carboplatin are
both IV and orally. Etoposide administered IV is associated with administered intravenously. Metabolism of both CDDP and
severe histamine release in dogs associated with the polysorbate 80 carboplatin occurs primarily through reactions with water and
vehicle as described earlier with the use of IV DTX. Oral dosing elimination by binding to plasma and tissue proteins. Urinary
has shown low and highly variable bioavailability in dogs, making elimination of unbound and bound forms accounts for nearly
this route of delivery difficult to use. 326 Etoposide is eliminated 50% of the cisplatin dose 5 days after administration. Carbopl-
after dosing by hepatic metabolism, and renal elimination of both atin is predominantly excreted in the urine with approximately
parent drug (30%–40% of the dose) and glucoronide metabolites. 65% of the dose recovered in the urine 24 hours after adminis-
The major DLT of IV etoposide in the dog is hypersensitivity. 327 tration. 333 Strong correlations exist between carboplatin exposure
Clinical Use. Based on the hypersensitivity reactions experi- and renal function such that simple formulas have been derived in
enced in dogs after IV etoposide and the low bioavailability of both humans 334 and cats 335 for dosing calculations based on renal
orally administered etoposide, it is not recommended for use. function. The DLTs associated with CDDP are GI (nausea and
Strategies to overcome the vehicle induced hypersensitivity by vomiting) and renal. Pretreatment with antiemetics, and vigor-
reformulation or to improve bioavailability are required to con- ous saline diuresis is required. CDDP is contraindicated in cats
tinue evaluating etoposide. No studies have been reported in cats. because of fatal pulmonary vasculitis and edema. 336 In contrast,
the DLT associated with carboplatin is myelosuppression. GI AEs
Corticosteroids are less common and less severe, the drug is not nephrotoxic, and
it can be safely administered to cats.
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Clinical Use. CDDP (50–70 mg/m IV infusion administered
Prednisone with saline diuresis and antiemetics every 3 weeks) is indicated pri-
Basic Pharmacology. Prednisone and prednisolone are cortico- marily for canine OSA. It also has activity against bladder TCC,
steroids that presumably induce killing of hematopoietic cancer mesothelioma, carcinomatosis, and germinal cell tumors. 337,338
cells through interaction with the glucocorticoid receptor 328 and A variety of other tumor types have been reported to be marginally
the induction of apoptosis. 329 Mechanisms of apoptosis induction sensitive to CDDP.
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by corticosteroids in hematologic cancers is still not completely In dogs, carboplatin (300 mg/m or 10 mg/kg IV as a slow
understood and multiple mechanisms exist whereby tumor cells of bolus every 3 weeks) often is preferred to CDDP because of its
hematopoietic origin resist steroid-induced killing. 330 more favorable toxicity profile and ease of delivery. Although no
Clinical Pharmacology. Prednisone is generally well tolerated formal comparisons exist, carboplatin appears to have similar
in dogs over short time periods (weeks) when administered as a efficacy to CDDP for canine OSA but is inferior for TCC. 73,339
tapering schedule to a tolerable baseline dose dependent on the Carboplatin also is used for anal sac adenocarcinoma, SCC,
response of the patient and the cancer. The adrenal–pituitary axis intestinal carcinoma, prostatic carcinoma, mesothelioma, and
can become suppressed with, signs of iatrogenic hyperadrenocorti- carcinomatosis. 271,340–342
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cism causing severe disease in dogs if prednisone is continued at The traditional dose of carboplatin in cats is 200 to 240 mg/m
immunosuppressive doses. Cats tolerate exogenous steroids well IV as a slow bolus every 3 weeks. 343 A significant proportion
for prolonged periods. of cats require every 4 week regimens owing to prolonged neu-
Clinical Use. Prednisone is widely used for management of tropenia. As in humans, an individualized dose of carboplatin
lymphoid malignancies, MCTs, insulinoma, and brain tumors in may be calculated based on GFR and a targeted area under
dogs and cats. It is also useful for the management of paraneoplas- the concentration versus time curve (AUC Target ). 77,344 When
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tic hypercalcemia. Dogs are often dosed at 2 mg/kg (or 40 mg/m ) GFR is measured using serum iohexol clearance (commer-
PO daily at the beginning of multiagent protocols for lymphoma cially available through Michigan State University), the dosing
and are weaned off the drug over 3 to 4 weeks. Cats are tolerant of equation is:
prednisone or prednisolone and are maintained at 5 mg PO q24h
or BID as needed. Prednisone is also used to manage signs and Carboplatin dose = AUC Target × [(1.3 × GFR) + 1.4]
side effects of chemotherapy-induced toxicity such as hypersensi- × Body weight(kg)
tivities or hemorrhagic cystitis. Antiinflammatory doses are used Based on a phase I study, the maximum tolerated AUC Target
in dogs (0.5–1.0 mg/kg) PO once daily and reduced as indicated is 2.75 min × mg/mL. 345 Limited efficacy information is avail-
by signs. able with either dosing strategy, but clinical responses have been
reported in cats with injection site sarcoma, HSA, colonic adeno-
Others carcinoma, and oral SCC. 77,343,346
Hydroxyurea
Platinum (Carboplatin and Cisplatin) Basic Pharmacology. Hydroxyurea (HU) enters cells via pas-
Basic Pharmacology. The activity of platinum containing sive diffusion 347 and is an inhibitor of ribonucleotide reduc-
antitumor agents is through covalent binding to DNA through tase, 348 resulting in depletion of deoxyribonucleotide pools. 349