"The Latest Information on Bladder Tumors!" TUMOR TIDBITS, A BIWEEKLY VETERINARY ONCOLOGY E-LETTER Volume 2; Number 16; September 24, 2001. Editor: Kevin A. Hahn, DVM, PhD, Dipl - ACVIM (Oncology) & Overall Nice Guy! ONGOING ANNOUNCEMENTS FROM ONCOLOGY (www.gcvs.com) Thanks for your support of our Tomball Office. Dr. Hahn is available there every other Monday (713-693-1166). Don't forget our San Antonio Office (210-822-1913) every Thursday. in Houston. THIS WEEK'S TUMOR TIDBIT: THE LATEST INFORMATION ON BLADDER TUMORS! The following are notes obtained from: CURRENT DIAGNOSTIC AND THERAPEUTIC APPROACH FOR CANINE TRANSITIONAL CELL CARCINOMA OF THE BLADDER Presented at the 2001 Annual Forum of the American College of Veterinary Internal Medicine by Dr. Carolyn Henry, DVM, MS, Diplomate ACVIM (Oncology). OVERVIEW Transitional cell carcinoma (TCC) is the most common urinary bladder tumor of dogs. In contrast to the early-stage bladder cancer detected in people, dogs more often present with advanced stage, invasive tumors at the time of initial evaluation. In fact, over 50 percent of canine patients with bladder tumors may have metastatic disease at the time of diagnosis. Therefore, some options for successful treatment utilized in human oncology (e.g. intravesicular BCG, surgery, and radiation therapy) are unlikely to provide complete remissions and cures in dogs. Recently, veterinary clinical trial research has focused on chemotherapeutic options for canine TCC of the bladder. Other areas of investigation have included new diagnostic techniques, surgical alternatives, radiation therapy, and photodynamic therapy. This review summarizes current diagnostic recommendations and treatment options applicable in a private practice setting and provides insight into future treatment alternatives. CLINICAL PRESENTION AND DIAGNOSIS Presenting complaints for patients with TCC of the bladder may include pollakiuria, stranguria, hematuria, and tenesmus. These signs may resolve temporarily with antibiotic therapy. Occasionally, dogs may first present for signs related to metastatic disease, rather than urologic symptoms. The typical signalment is an older animal (average age = 10 years) and females may be predisposed. Breeds thought to be at higher risk of developing TCC include Shetland sheepdogs, Scottish terriers, Airedale terriers, collies, and beagles. Urinalysis is often the first step toward diagnosis of TCC, although results may be similar to those noted with cystitis. Care should be taken when obtaining a urine sample, as transplantation of tumor cells may occur with manipulation of TCC. For this reason, the author does not recommend cystocentesis in cases where TCC is suspected. [Dr. Hahn's Note: This observation is anecdotal and not universally accepted by all veterinary oncologists]. Urine sediment examination may reveal neoplastic cells in 30% or greater of cases, but must be interpreted with caution, as reactive transitional cells may look quite similar to neoplastic cells. Other urinalysis findings may be consistent with cystitis, including white blood cells, red blood cells, and bacteria. Urine samples may be evaluated with a newly marketed bladder tumor antigen test (VBTA, Bion Diagnostics) as a quick screening test for TCC. In one study that included 20 dogs with TCC, 19 healthy controls, and 26 dogs with non-neoplastic urologic disease, the test had a 90% specificity and a 78% sensitivity for the diagnosis of TCC. A limitation of this test includes false positive results with hematuria, proteinuria, and glucosuria. Further evaluation of the VBTA test is underway. At the present time, it seems prudent to interpret test results in light of other clinical findings and to pursue definitive diagnostic testing in cases with positive test results. Urine concentration of basic fibroblastic growth factor has been shown to be increased in dogs with bladder cancer, as compared to normal dogs and those with urinary tract infection. The peptide has been detected via a commercially available enzyme-linked immunosorbent assay kit (Quantikine HS; R&D Systems, Minneapolis, MN). While the technique is not widely used, it may represent another test that can be used with the VBTA to improve our ability to detect early TCC lesions. Definitive diagnosis of TCC is based on demonstration of a bladder mass via imaging or direct visualization and cytological or histopathological demonstration of neoplastic cells. Bladder tumor imaging may be accomplished via contrast cystography. In one study of dogs with bladder and urethral tumors, 96% of all cases had a mass or filling defect that could be demonstrated via this method. The sublumbar lymph nodes should be evaluated for enlargement, which may denote metastasis. Three-view thoracic radiographs are recommended, as pulmonary metastasis is occasionally detectable at the time of diagnosis. Abdominal ultrasound is another useful tool for imaging bladder masses, as well as for evaluating for intrabdominal metastasis. A biopsy sample may be obtained via a urinary catheter, using ultrasound guidance where available. When sufficient samples cannot be obtained via this method, biopsy samples should be obtained via cystoscopy or laparotomy. SURGERY FOR TCC OF THE BLADDER Surgical options for treatment of TCC depend upon the disease location and extent, as well as the goals of the client. These options include partial cystectomy, total cystectomy and ureterocolonic anastamosis, or placement of a permanent cystostomy catheter. The least invasive of these techniques are often preferred for veterinary patients due to quality of life and convenience issues. Clinical outcome for dogs undergoing partial cystectomy was evaluated in one clinical study. Eleven dogs with solitary bladder masses (10 TCC and 1 rhabdomyosarcoma) that did not invade the urethra were considered eligible for study enrollment. Cystotomy sites were planned to preserve maximal bladder volume, yet provide 1 to 2-cm tumor-free margins. Regional lymph nodes were also excised and submitted for histopathological examination if they were grossly abnormal at the time of surgery. When ureteral stoma excision and anastamosis was performed, a 3.5 French catheter that was positioned in the ureter to exit through the urethra was maintained for at least 72 hours after surgery. Seven dogs received adjuvant chemotherapy (70 mg/m2 cisplatin or 350 to 400 mg/m2 carboplatin) and two dogs received radiation therapy in addition to surgery and carboplatin. The percentage of total bladder tissue excised ranged from 40 to 70%. Despite attempts to excise all visible tumor tissue with 1 to 2-cm margins, five dogs had histopathological evidence of tumor extending to surgical margins. Tumor recurrence was diagnosed (n=5) or presumed (n=4) in nine dogs. Metastasis was confirmed in three of five dogs with visibly abnormal medial iliac lymph nodes. Postoperative complications included bladder incision dehiscence (n=2), hematuria (n=3), and pollakiuria (n=6). Both dogs experiencing dehiscence had not had ureteral or urethral catheters placed at the time of surgery. Survival times ranged from two months to greater than 48 months. Two dogs were alive at the time of publication, with survival times of 17 and 27 months. The overall one-year survival rate was 54.5%. Based on the results of this study, partial cystectomy appears to be a reasonable treatment for localized TCC. Ureteral-urethral catheter placement may prevent bladder incision dehiscence. Lymph node biopsy was described as useful for disease staging and for identifying dogs likely to benefit from adjuvant therapy. However, because lymph node biopsy was performed only when tissue was grossly abnormal, its true value for staging purposes was not determined. Perhaps the most important finding was that gross visual assessment at the time of surgery was inaccurate for determining tumor-free margins. Therefore, when intraoperative pathological assessment of surgical margins is not possible, margins should be taken as generously as possible. MEDICAL THERAPY/CHEMOTHERAPY Several chemotherapy protocols have been investigated for the treatment of TCC in the past decade. Drugs evaluated include doxorubicin and cyclophosphamide, cisplatin, carboplatin, mitoxantrone, and piroxicam. Treatment outcomes and current recommendations are described below: Doxorubicin and Cyclophosphamide In a retrospective study reported in 1994, combination therapy using doxorubicin and cyclophosphamide provided a median survival time of 259 days (n=11), compared to 86 days with surgery alone (n=14) and 57 days with intravesicular thiotepa (n=6). Although no reports since that time have critically evaluated doxorubicin or cyclophosphamide for treatment of canine TCC, the study results compare favorably to those obtained using other protocols in terms of overall survival. Piroxicam The nonsteroidal anti-inflammatory agent, piroxicam (Feldene), has shown promise in the treatment of TCC, both as a single agent and in combination therapy. The mechanism of action has been attributed to inhibition of cyclooxygenase-2 (COX-2), as immunohistochemical evaluation has shown that TCC cells express COX-2 whereas normal urinary bladder epithelium does not. However, more recent work suggests that there is no association between COX-2 expression and tumor response to piroxicam. Although the mechanism is unclear, at a dose of 0.3 mg/kg/day orally (PO), piroxicam provided two complete remissions and four partial remissions in 34 dogs for a median of seven months. Side effects may include gastrointestinal irritation and nephrotoxicity. The prostaglandin analogue, misoprostol, may be administered (3 µg/kg PO q8h) to reduce the likelihood of gastrointestinal ulceration. Piroxicam has been evaluated in combination with chemotherapeutic agents, and results are summarized below. Cisplatin The first report of single-agent cisplatin (50 mg/m2 IV q21d) for treatment of canine TCC was a retrospective study of 15 dogs with urinary bladder or urethral TCC. Three dogs experienced acute toxicity and were not included in the evaluation of drug efficacy. Of the 12 remaining dogs, none had complete responses, three had partial responses and six had disease stabilization. Median survival time was 180 days. A second retrospective study evaluated a higher dose of cisplatin (60 mg/m2) in 18 dogs with TCC. Eleven dogs had disease invasive into bladder wall (Stage T2) and seven dogs had tumors that invaded surrounding tissue or organs (Stage T3). Of the dogs for which thoracic radiographs were evaluated (n=17), five had evidence of pulmonary metastasis. Cisplatin was administered every 21 days using a six-hour saline diuresis protocol for up to six doses. Treatment protocols were modified when there was disease progression or azotemia. Partial responses were noted in only 4/18 (22%) dogs and there were no complete responses. Four dogs had disease stabilization and the others had disease progression despite chemotherapy. Tumor restaging was not performed in two dogs. The median time to treatment failure was 75 days, with a median survival time of 130 days. Four of the ten dogs undergoing necropsy examination had lung metastases and none had regional node metastases. This is in contrast to regional node metastases noted in three dogs in the cystectomy study referenced previously. Although the dose of cisplatin used was higher than previously reported , it was ineffective in producing complete responses and resulted in few partial responses. This was again confirmed in a randomized clinical trial evaluating single-agent cisplatin versus the combination of cisplatin and piroxicam. Of the eight dogs receiving single agent cisplatin (60 mg/m2 IV), none experienced clinical remission, four had stable disease, and four had disease progression. The combination of cisplatin and piroxicam has been evaluated in attempts to improve response rates over those resulting from single-agent therapy. One study evaluated the combination in 14 dogs with TCC. Dogs received cisplatin (60 mg/m2 IV q 21d) and piroxicam (0.3 mg/kg/day PO). While the response rate was greatly improved over cisplatin alone (two complete remissions and four partial remission versus none in the single-agent group), renal toxicity was frequent (12/14 dogs; 87%) and dose limiting. Dosage modifications are currently under investigation in hopes of developing a safe and effective combination protocol. Carboplatin Carboplatin is an alternative to cisplatin when nephrotoxicity is of concern and when six-hour saline diuresis is impractical. In a Phase II clinical trial, carboplatin and piroxicam combination therapy provided five partial remissions in 13 dogs and did not cause nephrotoxicity. This 38% remission rate was an improvement over the lack of remissions seen in 14 dogs with single-agent carboplatin in a study by the same authors. Interestingly, the median survival time achieved with the combination therapy (93 days) was not an improvement over that noted with single-agent carboplatin (132 days) or piroxicam (180 days). Mitoxantrone Mitoxantrone is an anthracycline that has shown some promise in the treatment of canine TCC. Used as a single agent, mitoxantrone provided a partial remission for 63 days in one of six treated dogs. A prospective clinical trial evaluating the efficacy of mitoxantrone (5 mg/m2 IV q21d for four treatments) and piroxicam (0.3 mg/kg PO daily) in dogs with confirmed measurable bladder TCC has recently been completed. Data analysis is currently underway, but the initial response rate exceeded 35%. Even in dogs without measurable decrease in tumor size by 50% or greater (required to be considered a partial remission), most showed clinical improvement. Diarrhea and azotemia were the most common adverse effects noted with this drug combination. FUTURE DIRECTIONS Curative therapy for canine TCC of the bladder is unlikely until early detection becomes a reality. Improved imaging techniques and screening tests may make this goal a reality in this decade. It is likely that optimum therapy will involve a combined modality approach including surgery, chemotherapy, and immunotherapy. If early diagnosis is achieved, intravesicular therapy may become more commonplace. The pharmacokinetics of compounds such as taxol, gemcitabine, and 5-fluouridine have been evaluated via this route in dogs and may provide treatment alternatives for select cases. Other treatments including photodynamic therapy and radiation are also under investigation and may be appropriate choices for multimodality therapy. However, the relatively high metastatic rate of this cancer suggests that systemic therapy will be an integral part of successful treatment protocols. WHAT'S THE PROTOCOL AT GULF COAST VETERINARY ONCOLOGY? Although cure is unlikely for TCC in dogs, significant long-term control of clinical signs may be achieved using a combination of radiation therapy and chemotherapy. At Gulf Coast we irradiate the bladder tumor and associated lymph nodes using a 3-day-per-week irradiation protocol (7 weeks) with concurrent Mitoxantrone chemotherapy (every 21 days for 5 treatments). Side effects are extremely few and the protocol is well tolerated. In our preliminary evaluation of patient records, more than 75% of the dogs finish the assigned protocol and >60% of dogs are still alive with minimal complications or symptoms 1 year or longer. Reasons for treatment failure are 1) no response to radiation or chemotherapy (it's still a bad tumor folks), 2) colonic irritation from radiation and severe diarrhea, and 3) urinary tract obstruction by tumor necrosis. Choices we give owners in our clinic include: 1. Palliation (median time 6-9 months) with Piroxicam. 2. Palliation (median time 9-12 months) with Piroxicam and Radiation (once every 14 days for 3 treatments Eto relieve pain and obstruction). 3. Palliation (median time 9-12 months) with Piroxicam and Mitoxantrone (chemo every 21 days for 3 treatments). 4. Palliation (median time 12-15 months) with Piroxicam, Mitoxantrone (3 treatments) and Radiation (3 treatments). 5. Intent for long-term control (median time 15-24 months) using Piroxicam, Mitoxantrone (5 treatments), and Radiation (21 treatments). ANY OTHER QUESTIONS ABOUT BLADDER TUMORS? Don't hesitate to call or email us at Gulf Coast Veterinary Oncology! We can forward additional info by email if needed. ALL THE BEST, Kevin Hahn Kevin A. Hahn, DVM, PhD Diplomate ACVIM (Oncology) & Overall Nice Guy Gulf Coast Veterinary Specialists 1111 West Loop South, Suite 150 Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 www.gcvs.com drhahn@g...