Page 216 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 12 Cancer Chemotherapy 195

action involving interference with the polymerization or depoly- a semisynthetic derivative and metabolite of VBL, vindesine, and
merization of the microtubules that play critical roles in cell func- the semisynthetic derivative of VBL, vinorelbine. These agents all
share a similar mechanism of action and focus will be on VCR and
tion and division.
VetBooks.ir Taxanes (Paclitaxel and Docetaxel) VBL in this section because of their use in veterinary medicine.
Basic Pharmacology. The vinca alkaloids bind to a distinct site
Basic Pharmacology. The clinically used taxanes (paclitaxel on tubulin 308 and inhibit microtubule assembly. 309 This inhibi-
[PTX] and docetaxel [DTX]) both act by stabilizing microtubules tion of microtubule function leads to a disruption in the mitotic
against depolymerization and thus inhibit reorganization dynam- spindle apparatus resulting in metaphase arrest and cytotoxic-
ics required for carrying out cellular functions. 295–297 This altera- ity. 310,311 The vinca alkaloids enter cells by a simple diffusion
tion in microtubule function causes an abnormal organization of process. Exposure time and concentration seem to be important
spindle microtubules involved in chromosome segregation during variables in determining cytotoxicity.
mitosis, leading to mitotic arrest. 298 PTX and DTX share identi- Clinical Pharmacology. The vinca alkaloids are administered
cal mechanisms with the increased potency of DTX 299 attribut- by IV infusion, rapidly distribute to tissues, and are slowly elimi-
able to an approximately 2-fold higher affinity for tubulin binding nated primarily by hepatic metabolism and biliary excretion of
compared with PTX. 300 parent drug and metabolites. Urinary excretion of parent drug and
Clinical Pharmacology. The clinical use of the taxanes is com- metabolites is relatively low: 10% to 20%. One of the metabolites
plicated by their poor solubility and the use of excipients including of VBL is desacetylvinblastine (vindesine), which is active and has
cremophor EL (PTX) and polysorbate 80 (DTX) to allow for intra- been identified in dogs. 312 VBL and VCR differ in their respective
venous administration. Both PTX and DTX are rapidly distributed toxicities, with VCR being less myelosuppressive than VBL but
throughout the body and eliminated slowly, primarily by hepatic causing more peripheral neurotoxic and GI effects, including sig-
metabolism and biliary excretion. Renal elimination is 10% or less nificant ileus. All vinca alkaloids are vesicants. If extravasated, 5 to
for both compounds. Toxicities associated with taxanes include 10 mL saline can be infused around the affected area. The addition
hypersensitivity reactions that are attributable to the cremophor EL of hyaluronidase (150 U/1 mL extravasated drug) to the saline
and polysorbate 80 utilized in formulation. Diarrhea and neutrope- has been reported but is not widely available. Warm compresses
nia are the major dose-limiting taxane-specific toxicities observed. should be applied as well. A solution of DMSO and flucinolone
Clinical Use. The use of PTX has not been frequently described acetonide (Synotic) mixed with 10 mg of flunixin meglumine
in either dogs or cats. This is likely because of the requirement should be applied topically after each heat application.
for significant pretreatment with antihistamines and corticoste- Clinical Use. VCR is used predominantly as a component in
roids followed by a prolonged infusion that must be monitored multiagent protocols for dogs and cats with lymphoma. It is also
for acute hypersensitivity. One report evaluated dogs treated with used as a single agent for dogs with transmissible venereal tumor.
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PTX at a dose of 165 mg/m slow IV infusion every 3 weeks. 103 The dose for VCR is 0.5 to 0.75 mg/m IV bolus weekly in both
Although a few measurable responses were identified for various dogs and cats, or as defined in the protocol.
tumor types, hypersensitivity was frequent (64%) despite pre- VBL is most often used to manage canine MCT either as a
treatment, and significant bone marrow toxicity was observed, single agent or in combination with other agents. It also is used
leading to the conclusion that the recommended dose for further to treat canine bladder TCC, 313 as a rescue for lymphoma, 314 and
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evaluation is 132 mg/m as a slow IV infusion every 3 weeks. As in place of VCR in multiagent protocols to help minimize adverse
discussed earlier in the section on pharmaceutics, a water-soluble GI AEs. 315 Several dose-schedule variations exist in dogs. When
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micellar preparation is effective for nonresectable MCT, but at the given weekly, starting dosages of 2.0 to 2.67 mg/m IV are used
time this chapter was written it was no longer commercially avail- most commonly, but dosage escalations up to 3.0 mg/m have
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able. 301 PTX in cats has been used at 80 mg/m slow IV infusion been reported. 316,317 Doses as high as 3.0 to 3.5 mg/m IV are well
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every 3 weeks with similar need for pretreatment. 302 tolerated when the dose interval is extended to q2 weeks. 100,313 In
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Hypersensitivity is more manageable with DTX as opposed cats, VBL has been administered at a dosage of 1.5 mg/m IV as
to PTX. In a small group of dogs with mammary carcinoma, part of a COP-based protocol. 315
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DTX was administered at a dosage of 30 mg/m IV over 30 min- Vinorelbine is administered at a starting dosage of 15 mg/m
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utes with routine pretreatment (steroids, diphenhydramine). 303 IV over 5 minutes once weekly in dogs, and 11.5 mg/m in
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Low-grade cutaneous hypersensitivities were reported but easily cats. 318–321 There is preliminary evidence to support activity
managed. Similarly, cats were successfully treated at a dosage of against primary lung tumors, histiocytic sarcoma, and MCTs, but
2.25 mg/kg IV over 1 hour with pretreatment. 304 To overcome insufficient numbers of patients have been evaluated to accurately
hypersensitivity reactions a strategy was developed to administer quantify tumor response at this time.
DTX orally with cyclosporine as an absorption aid. This strategy
was investigated in phase I studies in dogs and cats with cancer Topoisomerase Inhibitors
where the MTD of DTX was 1.63 mg/kg and 1.75 mg/kg PO
(by gavage) every 2 to 3 weeks, respectively, when combined with The topoisomerase inhibitors represent classes of drugs that
cyclosporine (5 mg/kg PO). 305,306 Although no hypersensitivity inhibit either the type I or type II topoisomerase enzymes that are
reactions were reported, diarrhea was the DLT. Subsequent phase involved in the unlinking and unwinding of the DNA strand for
II evaluation of this dosing strategy in dogs demonstrated modest replication and transcription. The major classes of topoisomerase
activity against oral squamous cell carcinoma (SCC). 307 II inhibitors used in veterinary oncology are the anthracyclines,
which have already been discussed, and the epipodophyllotoxins
Vinca Alkaloids (Vinblastine, Vincristine, Vindesine, of which etoposide and teniposide are the clinically relevant mem-
Vinorelbine) bers. The major class of topoisomerase I inhibitors used in human
The vinca alkaloids as a class of antitumor agents consist of the oncology are the camptothecins, which have found little use so far
naturally occurring vincristine (VCR) and vinblastine (VBL) and in veterinary medicine and will not be discussed here.