Introduction

Transitional cell carcinoma (TCC) of the urinary bladder is common in dogs, particularly in certain breeds such as the Scottish terrier, West Highland white terrier, beagle, and Shetland sheepdog.^1,2 TCC in dogs is commonly muscle invasive within the bladder, with more variable prostatic and urethral involvement.¹ TCC has a moderate metastatic rate, ranging from 21 to 51% based on previous studies.^1,3 At the time of diagnosis, ∼16% of dogs had lymph node metastasis and another 14% had distant metastasis.¹ Local tumor progression, rather than metastatic disease, is most commonly life limiting as a consequence of urethral and/or ureteral obstruction.^1,3

Although intensity-modulated and image-guided radiation therapy has recently shown promise in improving outcome in dogs with bladder tumors, systemic medical therapy remains the mainstay of treatment for dogs.⁴ This typically involves a nonsteroidal anti-inflammatory drug (NSAID) combined with administration of cytotoxic chemotherapy.¹ Numerous chemotherapeutic agents have been investigated for the treatment of canine TCC including cisplatin, carboplatin, mitoxantrone, and others.^5–12 In general, response rates are low to moderate, ranging from 3 to 38%.^5–12 The combination of cisplatin with either firocoxib or piroxicam led to higher response rates but was associated with an increased risk of renal toxicity.^13,14 Median response durations with NSAIDs and chemotherapy range from 93 to 194 days, with overall survival (OS) times of 161–350 days reported for TCC treated with chemotherapy.^5–12

Toceranib (TOC) phosphate^a is a receptor tyrosine kinase inhibitor that competitively inhibits adenosine triphosphate binding. This prevents tyrosine kinase receptor activation and downstream signaling.¹⁵ TOC has the greatest affinity for vascular endothelial growth factor receptor, platelet-derived growth factor receptor, stem cell factor receptor, and McDonough feline sarcoma-like-tyrosine kinase 3.^15,16 TOC phosphate is FDA approved for the treatment of canine mast cell tumors. It has also shown preliminary biologic activity in apocrine gland anal sac adenocarcinoma, metastatic osteosarcoma, thyroid carcinoma, squamous cell carcinoma, and nasal carcinoma.¹⁵ In addition to directly inhibiting receptor tyrosine kinase signaling pathways, TOC may also exhibit immunomodulatory and other “off-target” effects in some tumor types.¹⁷

There has been limited study of TOC in the treatment of dogs with TCC. However, the expression of platelet-derived growth factor receptor-β in TCC tumors compared with the expression in cystitis and normal bladder supports the possibility of clinical activity of this drug.¹⁸ Two preliminary studies have used TOC in the treatment of canine TCC. The first was a phase 1 trial evaluating tolerability in a variety of spontaneous canine malignancies that showed stable disease (SD) in three out of four dogs with TCC.¹⁹ The second study evaluated the combination of TOC and vinblastine in 10 patients with TCC with no improvement in response rate seen over vinblastine alone.²⁰ Also, the analogous drug sunitinib has shown marked inhibitory activity against bladder cancer cells in vitro and is currently undergoing clinical trials in combination with gemcitabine and cisplatin for the treatment of advanced urothelial carcinoma in humans.^21,22 The purpose of this study was to determine the clinical activity of TOC as a single therapeutic agent in a larger number of dogs with bladder tumors. The hypotheses were (1) TOC would provide a clinical benefit in the treatment of bladder tumors, thereby prolonging survival times, and (2) TOC would be well tolerated with manageable adverse events.

Materials and Methods

Results

Thirty-seven dogs receiving TOC for the treatment of TCC were identified through a retrospective search of medical records. The mean age was 10.4 yr (range 6.1–15.6 yr), with a mean weight of 12.9 kg. There were 23 spayed females, 13 neutered males, and 1 intact male. Dogs were of various breeds including 7 beagles, 3 Shetland sheepdogs, 3 Yorkshire terriers, 2 dachshunds, 2 Labrador retrievers, 2 mixed-breed dogs, 2 Pomeranians, 2 toy poodles, and 1 each of various other purebreed dogs. There was no significant difference in outcome associated with age, weight, or sex.

Common presenting clinical signs included pollakiuria in 12 dogs, hematuria in 23 dogs, and stranguria in 16 dogs. Thirty-one dogs had at least one of these signs. Seven dogs also had urinary tract infections at the time of diagnosis. The most common laboratory abnormality at the time of presentation was an elevated blood urea nitrogen (BUN), which occurred in 9 dogs. Two dogs with grade 4 elevations in BUN also had elevated creatinine. Three dogs were anemic, and 12 dogs had elevated liver enzymes at the time of diagnosis. Three dogs had elevated alanine aminotransferase, 5 had elevated alkaline phosphatase, and 3 dogs had both enzymes elevated. One additional dog had elevated bilirubin.

Seventeen dogs were diagnosed with TCC based on histopathology, and 8 were cytologically diagnosed with carcinoma. The remaining 12 dogs had a presumptive diagnosis based on abdominal ultrasound. Seventeen dogs had a trigonal mass, 11 had an apical tumor, and 8 had multifocal disease. One dog did not have an initial ultrasound because it went straight to surgery for diagnosis. Based on abdominal ultrasound performed in the other 36 dogs, 12 dogs had urethral involvement, and 5 of the 14 male dogs had prostatic involvement. Additionally, 3 dogs had presumed metastasis to sublumbar lymph nodes identified on abdominal ultrasound. This was confirmed via cytology for only 1 dog. Of the 24 dogs with thoracic radiographs performed at the time of diagnosis, 4 had suspected metastasis. In 2 dogs, there was a solitary pulmonary nodule, 1 had multiple nodules, and 1 had sternal lymphadenopathy. The dog with sternal lymphadenopathy also had sublumbar lymphadenopathy.

Thirty-four dogs received chemotherapy prior to TOC, and 3 dogs were naïve to chemotherapy treatment (Table 1). These 34 dogs had received a variety of agents including mitoxantrone, carboplatin, cyclophosphamide, vinblastine, vinorelbine, and chlorambucil. The mean number of chemotherapy drugs used prior to receiving TOC was two (range 1–4), with a mean of seven (range 0–19) total chemotherapy treatments. Six dogs received chemotherapy concurrently with TOC; of those 6 dogs, 3 received vinblastine, 1 received mitoxantrone, 1 received carboplatin, and 1 received vinorelbine. Thirty-five dogs had received an NSAID prior to TOC treatment including carprofen, meloxicam, deracoxib, or piroxicam for a median of 160 days. Twelve dogs had surgical excision of their tumors, with 3 documented as complete excision based on histopathology. One had intensity-modulated radiation therapy concurrently with initiation of mitoxantrone chemotherapy, and 1 had a palliative course of radiation therapy.

TABLE 1 Prior Therapy Received in Dogs Treated with TOC for Bladder Tumors

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The median dosage of TOC given was 2.44 mg/kg (range 1.34–4.88 mg/kg). Twenty-eight dogs received TOC three times a week, whereas 7 dogs received every-other-day treatment. One dog received TOC twice weekly, and 1 dog received TOC once weekly. The median duration of TOC treatment in all dogs was 45 days. Twenty-one dogs received an NSAID concurrently with the TOC, which was administered only on days when TOC was not given. NSAIDs used concurrently included carprofen, piroxicam, and deracoxib. Five dogs experienced improvement in clinical signs while receiving TOC based on client reports, but 1 of these dogs was also receiving mitoxantrone.

Thirty-two dogs were available for evaluation of adverse events (Table 2). All dogs had at least one adverse event, but most were transient and mild (grades 1 and 2). Most severe (grades 3 and 4) adverse events involved progression of azotemia, which occurred in 56% of dogs. In 9 dogs, gastrointestinal adverse events were documented to be at least partially responsible for discontinuation of therapy. However, only 3 dogs were given dose delays (as a result of one event each of grade 4 BUN elevation/grade 2 creatinine elevation, grade 2 anorexia, and grade 1 neutropenia), and 3 dogs received dose reductions (as a result of grade 2 anorexia in 2 dogs and weight loss in 1 dog).

TABLE 2 Adverse Events Following Toceranib Administration to 32 Dogs with Primary Urinary Bladder Tumors

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Fifteen dogs were available for evaluation of tumor response. The median dosage of TOC administered in this group was 2.56 mg/kg (range 1.34–3.39 mg/kg). Thirteen had received the drug three times weekly, with 1 dog receiving TOC every other day and 1 dog receiving TOC once weekly. Thirteen dogs were also treated concurrently with an NSAID. Among the 15 dogs, there was one PR; this dog had been heavily pretreated with mitoxantrone, chlorambucil, vinblastine, and carboplatin. This dog had received treatment for 476 days prior to starting TOC, and the duration of the PR to TOC was 264 days. Twelve of 15 (80%) had SD for a median duration of 128.5 days (range 34–310 days); the other 3 had progressive disease. The median TTP for all 15 dogs was 96 days (range 30–599 days; Figure 1).

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Survival time was evaluated for all 37 dogs. The OS from the start of TOC therapy was 149 days (range 5–710 days; Figure 2). Sixteen dogs received further chemotherapy following TOC administration; these drugs included gemcitabine, vinorelbine, vinblastine, chlorambucil, mitoxantrone, paclitaxel, and cyclophosphamide. None of the variables evaluated were found to have significantly influenced TTP or OS.

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Discussion

The purpose of this study was to evaluate the potential clinical benefit and tolerability of TOC in the treatment of bladder tumors in dogs. The characteristics of the dogs in this study were similar to other reports of canine TCC, with an overrepresentation of females and certain breeds such as beagles and Shetland sheepdogs.^1,3 At the time of the start of the study, three dogs had lymph node metastasis (8%) and three (8%) had pulmonary metastasis, similar to previous reports.¹ However, the lack of complete staging in all patients could have biased these results.

In this study, 1 dog (6.7%) had a partial response, based on measurements using serial abdominal ultrasound. This response rate is lower than reported response rates to mitoxantrone, vinblastine, and gemcitabine, but it is similar to other chemotherapeutics used in the treatment of canine TCC.^5–12 More importantly, 12 dogs (80%) had SD for a median duration of 128.5 days; thus, TOC resulted in a clinical benefit in 86.7% of dogs. This result is consistent with the previous pilot study evaluating TOC for canine TCC, in which 3 out of 4 dogs had SD for 11, 17, and 26 wk duration.¹⁹ The study evaluating TOC administered concurrently with vinblastine reported a 40–60% partial response rate.²⁰ Although this response rate is higher than the one in the present study, these dogs were receiving multiagent therapy rather than TOC alone. Only 5 (13.5%) of the 37 dogs evaluated here demonstrated improvement in urinary clinical signs. Unfortunately, the retrospective nature of this study may have led to inconsistent assessment and documentation of this important clinical sign. A prospective study design including a client questionnaire would be undoubtedly superior in addressing response to TOC therapy.

Although the 6.7% response rate is low and the median TTP of 96 days is short, it is important to note that all but three dogs had received a mean of two chemotherapy drugs prior to starting TOC, with a mean of seven chemotherapy doses. Because TOC inhibits growth factor signaling rather than causing direct deoxyribonucleic acid damage, it may be more likely to result in SD rather than tumor regression.^15,16 In this population, 80% of dogs had SD for a median of 128.5 days.

Only 25 of the dogs in this study had a definitive diagnosis of bladder carcinoma. Among the 15 dogs evaluated for response to TOC, 11 had a definitive diagnosis of bladder carcinoma. The lack of definitive diagnosis in the remaining dogs may have falsely elevated the TTP and OS data reported here because inflammation and polyps can mimic neoplasia in the bladder.³

Most dogs in this study received an NSAID concurrently with TOC, which may have impacted TTP and OS favorably; however, all dogs had received NSAID therapy well before initiating TOC. Because the dogs had been refractory to chemotherapy including the NSAID prior to starting TOC, responses in this study could reflect the activity of TOC or a synergistic activity between TOC and the NSAID. The effect of concurrent NSAID treatment with TOC on TTP could not be statistically evaluated because only 3 dogs did not receive an NSAID.

TOC was generally well tolerated in this patient population. The most common significant (grades 3 and 4) adverse events were elevated BUN and creatinine, which occurred in 56% of dogs. Earlier studies with TOC for the treatment of mast cell tumors reported only a 1.4% incidence of grades 3 and 4 elevations in creatinine and no elevations in BUN in 145 dogs.¹⁹ Although azotemia is likely attributable to disease progression in the majority of patients in this population, careful monitoring of kidney values in dogs receiving TOC for TCC seems warranted. Gastrointestinal side effects were also common in our study, but most of these were described as mild and transient. Grades 3 and 4 gastrointestinal side effects occurred in 12.5% of dogs in this study, which is similar to the findings of previous studies.¹⁹ Because renal and gastrointestinal toxicity are also possible with NSAID treatment, caution is warranted when combining these with TOC.

A weakness of this study was the use of abdominal ultrasound for measurement of bladder tumors. Monitoring tumors with abdominal ultrasound has inherent limitations as a result of variation in measurement technique by different ultrasonographers and variability with degree of bladder filling and patient positioning. With the exception of one patient, the same ultrasonographer evaluated the bladder tumor serially in all dogs from this study. Although more advanced imaging (contrast cystography, computed tomography, MRI) may offer greater reliability in monitoring bladder tumors, these techniques require general anesthesia and are associated with increased risk and cost and therefore are not routinely performed.^5–14 Other shortcomings of this study include the lack of complete staging in all cases, lack of standard prior therapies, variability in follow-up, variability in timing of repeat staging, inherent differences in clinician management of adverse events, and small sample size. The small number of cases in this study may hinder the value of the statistical analysis, and a type II error may be responsible for the lack of prognostic factors evaluated to exhibit an effect on TTP or OS. Despite these limitations, the results of the dogs evaluated here support the use of TOC as a reasonable rescue treatment option for TCC in dogs. Further studies to prospectively compare TOC with more traditional chemotherapeutics either as a first-line treatment or when used in combination with other drugs are clearly needed.

Conclusion

The results of this retrospective study indicate that TOC may be considered as a rescue treatment option for canine TCC. TOC was generally well tolerated; however, careful monitoring of renal function is warranted. Further prospective studies are needed to evaluate the most effective treatment protocol and most appropriate role of TOC in the treatment of TCC.