Page 673 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 30 Tumors of the Urinary System 651

The optimal length of chemotherapy for iUC has not been bone marrow suppression was noted in 10% of dogs at 90 days
defined. Although the authors continue a chemotherapy protocol and in 80% of dogs at 1 year. Most toxicity was grade 1 or 2, but
this justifies the need for careful monitoring.
as long as the cancer is controlled, quality of life is good, and no
VetBooks.ir serious adverse events are noted, other oncologists cap the number inhibitor, including the nonselective COX inhibitor piroxicam or
A more conservative treatment for iUC is a single-agent COX
of chemotherapy doses because of concerns of chronic toxicity.
The effects of discontinuing chemotherapy in dogs with PR or SD, COX-2 selective inhibitors such as deracoxib and firocoxib. 1,3,54,62
or administering COX inhibitors or metronomic chemotherapy as All three of these agents have induced remission (with most being
“maintenance therapy,” have not been determined. It is certainly PRs) in 15 to 20% of dogs with iUC, and have resulted in SD in
expected that residual iUC will progress if drugs controlling it are up to 55% of dogs. Information on 94 dogs with iUC treated with
withdrawn. Anecdotally, the authors have administered vinblas- piroxicam (0.3 mg/kg daily) has been published. Tumor responses
3
tine or mitoxantrone for well beyond a year without ill effects (D. were known in 76 dogs and included 3% CR, 18% PR, 59% SD,
Knapp, personal communication), but further study is needed. and 20% PD. The median PFI was 120 days, and MST was 244
Systemic chemotherapy agents investigated in dogs with iUC days. The MST compared favorably to that of 55 dogs in the Purdue
3
are summarized in Table 30.2. 1–3,48,55–62 Although cisplatin Comparative Oncology Program Tumor Registry that were treated
3
appears to be one of the more active agents, it is seldom used with cytoreductive surgery alone (median survival 109 days). GI
because of renal, GI, and bone marrow toxicities. 1–3,60,62 In a adverse events (due to piroxicam or comorbid conditions) were noted
3
recent report, the administration of cisplatin and piroxicam con- in 31% of dogs. Although most were grade 1 or 2, piroxicam can
currently with a chemoprotectant agent (Tavocept) was associated cause GI ulceration. It is critical for pet owners to observe their dog,
with less renal toxicity than a historic control group receiving stop piroxicam, and contact their veterinarian if anorexia, vomiting,
similar doses of cisplatin and piroxicam, but the response rate was or melena occurs. If the clinical signs are thought to be piroxicam
inferior in the dogs that received Tavocept. 60 related, it is safest to give a drug holiday and then switch to a COX-2
In recent years, vinblastine has emerged as a preferred chemo- inhibitor. Interestingly, in an expanded series of dogs with multiple
therapy agent in dogs with iUC because of very good antitumor types of cancer receiving piroxicam, the use of GI-protectant drugs
activity and a good safety profile. 58,59 After promising results in a was associated with greater GI toxicity, but the reasons for this require
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single arm trial in dogs with advanced resistant iUC, a follow-up further study. Although piroxicam can cause toxicity, the majority
trial was performed in which dogs with histologically diagnosed of dogs have notably improved quality of life on the drug. 3
2
iUC were randomly assigned to receive vinblastine (2.5 mg/m COX-2 selective inhibitors are also used in dogs with iUC.
intravenously every 2 weeks) plus piroxicam (0.3 mg/kg daily PO) In a randomized trial, firocoxib (Previcox, Merial) had antitu-
or vinblastine alone (same dose). Remission was more frequent mor activity as a single agent (20% PR and 33% SD) and greatly
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with vinblastine–piroxicam (58%) than with vinblastine alone enhanced the activity of cisplatin. Firocoxib did not worsen the
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(22%). The median PFI was 143 days with vinblastine alone and renal toxicity of cisplatin (as piroxicam does), but other toxicities
199 days with the combination. Interestingly, the MST was sig- inherent to cisplatin still limit its use. In a clinical trial of single-
nificantly longer in dogs receiving vinblastine alone followed by agent deracoxib (Deramaxx, Novartis, 3 mg/kg PO daily) in 26
piroxicam alone (531 days) than in dogs receiving the two drugs dogs with iUC, tumor responses included 17% PR, 71% SD, and
given concurrently (299 days). The longer survival was possibly 12% PD. The MST after deracoxib and subsequent therapies
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due to the dogs not developing resistance to both drugs simulta- was 323 days. Mild GI toxicity occurred in 20% of dogs.
neously. The treatment was well tolerated in both arms. Therefore Targeted therapies are also receiving considerable interest in
vinblastine combined with piroxicam (or another COX inhibitor) treating TCC and other cancers in dogs. Folate-targeted vinblas-
has become the preferred chemotherapy protocol at the authors’ tine (EC0905, Endocyte) and the BRAF targeted drug vemu-
institution. rafenib have shown good promise in iUC (D. Knapp, personal
Another commonly used chemotherapy protocol, mitoxan- communication). Toceranib combined with vinblastine and
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trone combined with piroxicam, induced remission in 35% of COX inhibitor has been studied, although responses did not
dogs with iUC with a MST was 291 days. Carboplatin combined appear better than for other vinblastine protocols. The inject-
1
27
with piroxicam induced remission in 38% of dogs, but is usually able demethylating agent 5-azacitidine resulted in PR in 22% and
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1
reserved for later use because of more frequent side effects. Other SD in 50% of treated dogs. The pharmacokinetics, toxicity, and
chemotherapy studies are summarized in Table 30.2. dosing of the oral demethylating agent zebularine in dogs with
Low-dose frequent (metronomic) chemotherapy has also been iUC have been reported, and a phase II trial is in progress (C.
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used in dogs with iUC. A clinical trial of metronomic oral chlo- Fulkerson, personal communication).
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rambucil (4 mg/m daily) was performed in 31 dogs with iUC,
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29 of which had failed prior therapy. Tumor responses included Localized Drug Delivery
PR in one dog (3%) and SD in 20 dogs (67%). The median PFI The use of localized drug delivery in dogs with iUC has been
and MST from the start of chlorambucil was 119 days and 221 limited, but has included intravesical mitomycin C and photody-
days, respectively. The quality of life was excellent. Although namic therapy (PDT). 69,70 Both have shown promise, but neither
toxicity was minimal in this study, with increased use of chlo- is used to any extent owing to the risk for systemic toxicity (when
rambucil, especially for several months in dogs, chronic myelosup- drugs instilled enter the circulation via vascularized tumors), local
pression persisting for weeks to months has emerged as a concern. irritation to the bladder, and initial inflammation and tissue swell-
2
The chlorambucil dose used in the iUC trial (4 mg/m daily) was ing after PDT. 69,70
selected because it was more effective than lower or less frequent
doses in early work. In a recent study, three different doses of Urinary Tract Infections
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2
2
chlorambucil (4 mg/m , 6 mg/m , or 8 mg/m ) were given to 78
2
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2
dogs with a variety of cancer types. Doses greater than 4 mg/m The risk of urinary tract infections (UTIs) is high in dogs with
were associated with more GI and bone marrow toxicity, but no iUC, especially in female dogs with urethral disease. 71,72 This is
2
improvement in antitumor effects. Of 34 dogs receiving 4 mg/m , due at least in part to urine retention, acquired structural defects