Page 212 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 12 Cancer Chemotherapy 191

studies showing similar exposure to the active 4-OHCP metab- Clinical Pharmacology. Chlorambucil is orally bioavailable
olite. 119,120 The major DLT of CP is neutropenia. GI toxicity with rapid absorption. Hepatic metabolism is extensive, with
121
the pharmacologically active phenylacetic acid being the primary
(nausea and vomiting) is not common but has been observed.
VetBooks.ir In dogs, sterile hemorrhagic cystitis (SHC) can result from the metabolite and presumably responsible for much of the clinical
It is uncommon with conventional IV dos-
The major DLT is myelosuppression, including
activity.
metabolite acrolein.
122
145,146
ing, but there are reports after even just a single IV administra- granulocytopenia and thrombocytopenia.
tion. 123,124 The incidence is higher with chronic oral dosing, and a Clinical Use. Chlorambucil is used primarily for chronic lym-
cumulative dose is a risk factor. 125,126 Concurrent treatment with phocytic leukemia, Waldenström’s macroglobulinemia and feline
furosemide (1–2 mg/kg PO or IV) significantly reduces the risk of low-grade (small cell) GI lymphoma. It also is used as part of
SHC. 123,125 CP should be discontinued permanently in patients metronomic therapy for a variety of cancers, including bladder
that develop SHC. Chlorambucil is often a suitable replacement. transitional cell carcinoma (TCC) (see Chapter 15, Section C). 147
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Treatment for SHC is largely symptomatic with nonsteroidal Chronic oral dosing typically begins at 3 to 6 mg/m once daily.
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antiinflammatory drugs (NSAIDs), oxybutynin (0.2–0.3 mg/kg Doses as high as 4 mg/m /d are well tolerated long term in dogs,
PO q8–12 h), and/or pentosan polysulfate sodium (20 mg/kg but often the dose can be lowered based on control of cancer. 148 In
PO twice weekly for 5 weeks, then once weekly for 12 weeks). cats, to maintain dose intensity without splitting tablets, a dosage
In extreme cases, intravesicular dimethyl sulfoxide (DMSO) or of 2 mg every-other-day or Monday–Wednesday–Friday is com-
dilute formalin, or surgery can be considered. 127,128 monly used. An oral bolus dose of 20 mg/m every 2 weeks also
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Clinical Use. CP is commonly included in multiagent proto- has been reported with excellent response in feline low-grade GI
cols for lymphoma in both dogs and cats. Standard bolus dosages lymphoma. 149
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are 200 to 250 mg/m in both dogs and cats. Bone marrow abla-
tion protocols in dogs have used doses in the range of 500 to 750 Nitrosoureas
mg/m before hematopoietic cell transplantation. 129–131 CP has Lomustine (Cyclohexylchloroethylnitrosurea)
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also been dosed using a fractionated schedule (50–75 mg/m PO Basic Pharmacology. Cyclohexylchloroethylnitrosurea
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for 3–4 consecutive days) in both dogs and cats in combination (CCNU, CeeNU) is a nitrosourea-based agent that is highly lipid
protocols for sarcomas and mammary carcinoma. 132–136 The use soluble and enters cells by passive diffusion. 150 Under aqueous
of CP in low-dose continuous (metronomic) chemotherapy pro- conditions and at physiologic pH, CCNU will spontaneously
tocols is discussed in detail in Chapter 15, Section C of this text. decompose to a reactive center capable of DNA alkylation 151,152
and DNA–DNA and DNA–protein cross-links. 153
Ifosfamide Clinical Pharmacology. The highly lipophilic properties of
Basic Pharmacology. Ifosfamide is a nitrogen mustard–con- CCNU allows for rapid crossing of biologic membranes includ-
taining prodrug that, like CP, requires metabolic activation by ing the blood–brain barrier. CCNU undergoes extensive hepatic
microsomal mixed function oxidases before generating the isofos- metabolism, 154 predominantly by hydroxylation of the cyclohexyl
foramide mustard metabolite capable of bifunctional alkylation. 137 ring, to metabolites with at least equivalent alkylating activity that
Clinical Pharmacology. The major difference between the clini- presumably play an important role in the cytotoxic activity. 155
cal use of ifosfamide and CP is a result of differences in the relative This extensive hepatic metabolism is presumably responsible for
metabolism of the parent drugs, with dechloroethylation account- the lack of oral bioavailability of the parent compound but rapid
ing for up to 25% of the metabolism of ifosfamide, 138 whereas appearance of metabolites after oral dosing. 156 The major DLT
this number is much smaller for CP. This difference in metabolism is myelosuppression with acute neutropenia followed by cumu-
accounts for an increase in the formation of the neurotoxic metabo- lative and potentially irreversible thrombocytopenia. 157 In cats,
lite chloracetaldehyde after ifosfamide dosing and potentially for the the neutrophil nadir can occur anywhere from 1 to 4 weeks post-
less favorable metabolism profile observed with ifosfamide after oral treatment. 158 In dogs, and much less commonly in cats, chronic
dosing. 139 The primary DLT associated with ifosfamide treatment administration may result in hepatic enzyme elevations and pos-
is a dose-related myelosuppression, but nephrotoxicity and damage sible hepatic dysfunction requiring discontinuation of the drug
to the bladder epithelium are not uncommon. Vigorous hydration temporarily (i.e., drug holiday) or permanently. 159–161 The most
is required with ifosfamide administration, and mesna, a urinary consistent and dramatic hematologic abnormality is a marked
epithelial protectant, must be administered to avoid severe cystitis. elevation in alanine aminotransferase (ALT). Concurrent admin-
Clinical Use. Ifosfamide has been evaluated in dogs and cats istration with Denamarin TM , a product that increases glutathione
with cancer and is recommended primarily for management of levels and provides antioxidant properties, reduces the risk of
sarcomas. The recommended dose for dogs is 375 mg/m IV and ALT elevation, and decreases the magnitude of elevations in ALT,
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for cats is 900 mg/m IV, both as slow infusions and saline diure- aspartate aminotransferase (AST), alkaline phosphatase (ALKP),
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sis, every 3 weeks. 140,141 The basis for such discrepancies in the and bilirubin. 162 Pulmonary fibrosis has been reported rarely in
MTD between species is not understood but reflects profound cats. 163
and interesting differences in metabolism pathways and most Clinical Use. CCNU (70–90 mg/m PO every 3 weeks) is most
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likely reduced generation of bioactive metabolites. A phase II often used alone or in multiagent protocols for canine lymphoma,
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study in feline injection site sarcomas (ISSs) reported moderate MCTs, and histiocytic sarcoma. In cats, CCNU (40–60 mg/m
objective response rates. 142 PO or 10 mg per cat every 4–6 weeks) is used primarily for MCTs
and lymphoproliferative disorders.
Chlorambucil
Basic Pharmacology. Chlorambucil (p-bis[chloro-2-ethyl] amino- Streptozotocin
phenyl-4-butanoic acid) is a nitrogen mustard derivative that enters Basic Pharmacology. Streptozotocin is a naturally occurring
cells via passive diffusion and has direct bifunctional alkylating nitrosourea capable of DNA alkylation and inhibition of DNA
143
144
ability responsible for the cytotoxic activity. synthesis in both bacteria and mammalian cells. 164,165 Cellular