How well are you managing urinary bladder cancer?

Q. How does one diagnose and manage dogs with urinary bladder cancer?

A. Dr. Carolyn J. Henry at the 2004 Western Veterinary Conference in Las Vegas gave a lecture on diagnosis and treatment of canine bladder cancer in dogs. Some relevant points in this lecture are provided below.

Canine urinary bladder cancer presents veterinarians with treatment challenges due to its invasive nature and likelihood of metastasis. An understanding and appropriate use of available diagnostic tools is necessary for early detection of canine urinary bladder cancer. In the setting of early detection, many management options are available to provide relief of signs and prolongation of good quality of life for dogs with urinary bladder cancer.

Early detection crucial

Johnny D. HoskinsDVM, Ph.D., Dipl. ACVIM

The canine urinary bladder, usually transitional cell carcinoma (TCC), is one of the most common cancers seen in the abdomen. Because initial signs of urinary bladder cancer may be subtle, TCC is often quite invasive by the time it is clinically detectable and diagnosed.

The estimated metastatic rate at the time of diagnosis is about 20 percent, but may exceed 50 percent later in the cancer course. Thus, early diagnosis is important and should be followed by therapy that is aimed at addressing both local disease and the potential for development of metastatic lesions.

Canine TCC is more commonly diagnosed in older female dogs, with Scottish Terriers, Shelties, West Highland White Terriers, Airedale Terriers, Collies and Beagles considered at high risk. Typical presenting complaints include pollakiuria, stranguria, hematuria or tenesmus. Occasionally, lameness due to bone metastasis may be the reason for initial clinical presentation. The history of a dog with TCC often will include an apparent improvement in clinical signs after administration of antibiotics prescribed for presumed lower urinary tract infection.

Diagnostic testing for urinary bladder cancer generally begins with a urinalysis. Unfortunately, findings may be confusing and similar to those noted with lower urinary tract infection, including pyuria, hematuria and bacteriuria. Urine sediment examination may reveal tumor cells in about 30 percent of cases. However, reactive transitional cells may look very similar to TCC cells - cytologic examination should be interpreted carefully. A urine dipstick test that detects a veterinary bladder tumor antigen (VBTA) is now available to screen for canine urinary tract TCC. This test clinically functions best when run on spun urine samples and should be performed within 48 hours of urine sample collection. The initial published report indicated that this test had 90 percent specificity and 78 percent sensitivity for the diagnosis of TCC. False positive test results may occur when samples contain blood, protein or glucose. False negative test results are less common than false positive results. The VBTA test is a reasonable screening but not a definitive test. The results of the VBTA test should be interpreted with other clinical findings with further diagnostic testing pursued when positive results are obtained.

Urinalysis sometimes confusing

Urinary bladder imaging or direct tumor visualization along with cytologic or histopathologic demonstration of neoplastic cells is needed to confirm the diagnosis of TCC. Contrast cystography is a reliable method to identify bladder masses in more than 95 percent of cases. Tumor staging procedures should include sublumbar lymph node imaging and three-view thoracic radiography (right lateral, left lateral and ventrodorsal views) to assess for metastatic disease.

Take a look

Ultrasonography is a valuable tool for urinary bladder imaging and for detection of metastatic lesions in abdominal organs and lymph nodes. It is also ideal for procuring biopsy samples via urinary catheterization. Alternatively, biopsies may be obtained via cystoscopy or laparotomy.

The choice of surgery as a treatment for dogs with TCC should be based upon tumor location and invasiveness as well as owner's goals. Numerous surgical options exist, including partial cystectomy, total cystectomy with ureterocolonic or ureterourethral anastomosis or permanent cystostomy tube placement.

Surgery as treatment

Often, the least invasive techniques are chosen based on issues of quality of life and convenience. In partial cystectomy in 11 dogs, the procedure provided survival times ranging from two to more than 48 months and a 54.5 percent one-year survival rate. Importantly, visual assessment at the time of surgery is noted to be an inaccurate method for determining tumor-free margins. Accordingly, if intraoperative evaluation of surgical margins by way of cytologic examination or frozen section is not possible, margins should be taken as generously as is reasonable.

Partial cystectomy is a viable option for treatment of localized TCC. Partial cystectomy does not address metastatic disease and is poor treatment for advanced TCC. As the entire urinary bladder mucosa is likely to have been exposed to the inciting carcinogen that led to tumor development, multifocal lesions or diffuse disease may limit the ability to achieve complete surgical excision. In one study, only two of 67 dogs undergoing surgery for TCC had complete surgical excision of their disease and both later had tumor recurrence/progression.

A multitude of medical therapies and combination chemotherapy protocols have been evaluated for the treatment of canine TCC. The nonsteroidal anti-inflammatory drug (NSAID), piroxicam, has shown efficacy, both as a single agent and in combination therapy, against canine TCC. Although the mechanism of action of piroxicam is still unclear, it may relate to inhibition of cyclooxygenase 2 (COX-2) expressed on TCC cells and to inhibitory effects on tumor angiogenesis.

Treatment

In the first prospective evaluation of piroxicam for treatment of canine TCC, piroxicam-induced responses were noted in six of 34 dogs for a median of seven months. Side effects may include gastrointestinal (GI) irritation and nephrotoxicity.

Regular evaluation of PCV, BUN, creatinine and urine specific gravity are advised in order to monitor for renal toxicity and GI bleeding. The dosage for piroxicam is 0.3 mg/kg PO SID, always administered with food.

Although not evaluated prospectively, the combination of doxorubicin and cyclophosphamide provided a median survival time of 259 days for dogs with TCC, compared to 57 days with intravesicular thiotepa and 86 days with surgery alone in one retrospective study. Because these results compare favorably to those obtained using other protocols, and the drugs are relatively inexpensive, it may be worthwhile to prospectively evaluate this combination therapy for canine TCC.

Cisplatin has been disappointing as a single agent for the treatment for canine TCC. Response rates have been less than 25 percent, with median survival times of six months or less. When single-agent cisplatin was compared to the combination of cisplatin and piroxicam, none of the dogs receiving cisplatin alone experienced remission.

Only 10 of 14 dogs receiving the combination protocol responded favorably. Unfortunately, renal toxicity was frequent (12/14 dogs; 87 percent) and dose limiting in the combination protocol group. Until dosage modifications or substitution of other NSAIDs are found to result in a safe and effective combination protocol, the routine use of cisplatin and NSAIDs together in clinical practice for treatment of TCC is not recommended.

In a prospective clinical trial, the combination of carboplatin and piroxicam provided five partial remissions in 13 dogs and did not cause nephrotoxicity. While this 38 percent remission rate compared favorably to that of dogs treated with carboplatin alone, the median survival time of dogs treated with the combination (93 days) was not better than what has been achieved with either single-agent carboplatin (132 days) or piroxicam (180 days).

Combinations

The synthetic anthracycline, mitoxantrone, in combination with piroxicam is currently the protocol uses for first-line therapy of canine TCC. Mitoxantrone (5 mg/m2 IV) is administered every three weeks for four treatments and piroxicam (0.3 mg/kg PO) is given daily.

In a prospective multi-institutional study, the initial response rate was 35 percent, with subjective improvement in 75 percent of all animals treated and a median survival time of 350 days.

When considering this protocol, one should ensure that dogs have normal renal function prior to treatment. Monitoring for GI and renal side effects is necessary, although the rate of toxicity is less than 15 percent.

Radiation therapy is reasonable treatment in the palliative or adjuvant setting for select TCC cases. While intraoperative radiation therapy has provided promising results, it is a technically challenging alternative that requires facilities and personnel adept at coordinating the surgical and radiation treatments during one anesthetic event. Initial results with external beam radiation therapy and chemotherapy for canine TCC suggest that relief of signs may be superior to that achieved with chemotherapy alone, although overall survival times have been similar to chemotherapy alone.

Selective radiation