Invasive transitional cell carcinoma (TCC) is the most common form of urinary tract cancer in dogs. Canine TCC is rarely amenable to surgery because of frequent trigonal location in the bladder and the presence of metastases in approximately 20% of cases at diagnosis and in 50% of cases at death. Most dogs with TCC are treated with chemotherapy, cyclooxygenase (cox) inhibitors, or combinations of these drugs. Mitoxantrone combined with piroxicam has been the most widely used treatment for TCC, resulting in remission in 35% and stable disease in 46% of cases.
Cisplatin combined with piroxicam has had greater antitumor effects in dogs with TCC (remission rate 71%), but is not recommended because of frequent renal toxicosis. The renal toxicosis is thought to be because of direct toxic effects of cisplatin on renal tubules and decreased renal blood flow related to inhibition of cox, especially cox-1, in renal blood vessels.[4, 5]
The antitumor effects of cox inhibitors are due, at least in part, to inhibition of cox enzyme activity. The isoform of cox expressed in the majority of TCC masses is cox-2. Although cox-2 is present in renal tissue, such as in the macula densa, cox-1 expression is more prominent in the kidney.[5, 8] Cox-2 inhibitors are expected to be a potentially safer choice when combined with cisplatin. In rats, cox-2 inhibitors did not worsen the renal toxicosis of cisplatin. Cox-2 inhibitors have even been reported to have a protective effect against cisplatin toxicosis in rodents, presumably through their anti-inflammatory effects.[10, 11] Cisplatin combined with the cox-2 inhibitor, celecoxib, also has been safely tolerated in humans.
This study was performed to determine the extent to which a cox-2 inhibitor, firocoxib, could enhance the antitumor activity of cisplatin in dogs with TCC while not increasing renal toxicosis. Firocoxib was chosen for its selective cox-2 inhibitory effects and excellent safety profile in dogs.[13, 14]
- Top of page
The study confirmed that a cox-2 inhibitor can significantly enhance the activity of cisplatin in dogs with TCC, similar to that reported with nonselective cox inhibitors. Cisplatin/firocoxib resulted in remission in 57% of dogs and SD in 20% of dogs for a cancer control rate of 77%. The PFI was significantly longer in dogs receiving cisplatin/firocoxib (median, 186 days) than in those receiving cisplatin alone (median, 87 days). The mechanisms by which cox inhibitors enhance the activity of cisplatin remain to be completely defined. Induction of apoptosis has been a consistent finding in previous studies of cox inhibitors in cancer, including studies of dogs and humans with invasive TCC.[18-20] Induction of apoptosis is crucial for cisplatin-induced DNA damage to cause cell death. Cox inhibitors may enhance the ability of cancer cells to undergo apoptosis, thus enabling cisplatin to kill the cancer cells. Other mechanisms are also possible.[18, 20, 21]
Although survival did not differ significantly among treatment groups, the survival in dogs receiving cisplatin alone followed by firocoxib alone (median, 338 days) compared with that of dogs receiving the 2 drugs together (median, 179 days) was intriguing. In an earlier study, dogs receiving cisplatin alone followed by piroxicam alone had a median survival of 309 days, compared with 246 days in dogs receiving cisplatin/piroxicam. The favorable survival with the sequential use of cisplatin and cox inhibitors could be, at least in part, because of decreased risk for the development of resistance to both drugs simultaneously, as well as avoiding overlapping toxicoses.
As expected, cisplatin and cisplatin/firocoxib were associated with GI, bone marrow, and renal toxicosis. In most instances, the toxicoses with cisplatin/firocoxib were no worse than those with single agent cisplatin. There were no significant differences among the groups in GI toxicosis, weight loss, bone marrow suppression, or increase in serum creatinine concentration. Although not significantly different, the decrease in iohexol clearance appeared slightly greater in dogs receiving the combination. It is likely that in dogs receiving the combination treatment, the antitumor effects would be even greater if cisplatin could be continued longer. With the combination treatment, 71% of dogs stopped receiving cisplatin because of toxicoses before cancer progression. Continued efforts to identify ways to decrease toxicoses of cisplatin/cox inhibitor therapy are indicated. Decreasing cisplatin dosage or substituting carboplatin for cisplatin could be considered, but an approach that could have more impact would be to employ emerging agents that could provide some protection from cisplatin toxicoses to the kidneys and bone marrow.
This study also was important in demonstrating antitumor activity of firocoxib as a single agent, indicating that firocoxib can be used palliatively in dogs with TCC. Partial remission occurred in 20% and SD in 33% of dogs receiving single agent firocoxib. This remission rate compares favorably to that observed with piroxicam. Although CRs have been observed with piroxicam, CR did not occur with firocoxib treatment in this study, nor have CRs been reported with other cox-2 inhibitors in dogs with TCC. It is not known if the finding of CRs in dogs treated with piroxicam is because of (1) having larger numbers of dogs treated with the drug and therefore a better chance to observe CR, (2) the longer half-life of piroxicam (40 hours) providing constant cox inhibition, (3) the inhibition of both cox-1 and cox-2 by piroxicam, or (4) other mechanisms. Although survival for dogs receiving firocoxib alone (median, 105 days) appeared shorter than survival reported with the nonselective cox inhibitor, piroxicam (195 days), this may be because of the more advanced stage cancer in dogs receiving firocoxib. Dogs receiving firocoxib had metastases in 53% of cases, urethral involvement of the TCC in 73% of cases, and prostate involvement in 80% of male dogs. The presence of TCC in these 3 areas appears higher than that reported for dogs in other studies, and TCC in any of these 3 areas has been associated with a worse prognosis. Firocoxib generally was well-tolerated. Gastrointestinal signs were noted in 5 dogs receiving firocoxib, but the likely cause of the GI upset was extensive metastases in 2 dogs, and renal failure because of cancer progression in another dog.
Another positive finding of the study was that QOL was maintained or improved in most dogs in the study. Although there were no significant differences among the treatment groups, the results related to urination and activity level in dogs receiving firocoxib alone or cisplatin/firocoxib were notable. When combining the scores across categories in dogs with follow-up available, 67% of dogs receiving firocoxib alone and 91% of dogs receiving the combination had a higher QOL score after 6 weeks of treatment than they had before treatment.
In conclusion, firocoxib had antitumor effects as a single agent and enhanced the activity of cisplatin resulting in remission in 57% of dogs with TCC receiving the combination treatment. Toxicoses inherent to cisplatin will influence the decision of whether to pursue this treatment in a given dog. Careful monitoring of renal function and other evidence of toxicoses in dogs receiving cisplatin/firocoxib is crucial. When using cisplatin/cox inhibitor treatment, decrease in cisplatin dose or withdrawal of the drug likely will become necessary in most dogs over the course of treatment.
- Top of page
The authors thank Drs Kim Selting, Nellie Owen, Dudley McCaw, and Jim Lattimer at the University of Missouri, and clinicians and staff in the Purdue Comparative Oncology Program at Purdue University for their case management and data entry related to this clinical trial. We also thank Dr Wilson Rumbeiha at the Michigan State University Diagnostic Laboratory for assisting with iohexol clearance assays, and Dr Diane Larsen at Merial Limited for manuscript and data review.
Conflict of Interest Declaration: Drs Hanson and Alva are employees of Merial Limited, Duluth, GA. Merial Limited provided funding for the study. Merial Limited manufactures and sells firocoxib.