Transitional Cell Carcinoma: Options Beyond NSAIDs Julie Marie Gillem, DVM, DACVIM (Oncology) Overview ✦ Background ✦ Surgical Options ✦ Pathology ✦ Medical Options ✦ Location and staging ✦ Radiation Therapy ✦ Behavior Options ✦ Etiology and risk factors ✦ Palliative care ✦ Work up and diagnosis ✦ What about cats? Objectives ✦ How do we determine when NSAIDs fail? ✦ When should we intervene with surgery, chemotherapy, radiation therapy, and additional palliative care? Pathology ✦ ~2% of canine cancer ✦ Invasive transitional cell carcinoma (TCC) most common ✦ Others: SCC, adenocarcinoma, undifferentiated carcinoma, rhabdomyosarcoma, fibroma, and other mesenchymal tumors Location and Staging ✦ TCC in dogs most often found in the trigone of the bladder ✦ Series of 102 dogs at PUVTH ✦ Urethra and bladder in 56% ✦ Prostate involvement in 29% male dogs ✦ Lymph node mets in 16% at diagnosis ✦ Distant mets in 14% at diagnosis ✦ Distant mets in 50% at death Location ✦ TCC in dogs most often is found in the trigone region of the bladder. ✦ In a series of dogs with TCC examined at the PUVTH, the tumor involved the urethra as well as the bladder in 57 of 102 dogs (56%), and it involved the prostate in 11 of 38 (29%) male dogs. WHO Staging ✦ 78% T2 tumors ✦ 20% T3 tumors Biological Behavior ✦ At diagnosis: ✦ Regional lymph node metastasis in 12-46 % (Norris et al 1992, Knapp et al 2000, Blackburn et al 2013) ✦ Distant metastasis in 16- 23% (Norris et al 1992, Blackburn et al 2013) ✦ Distant metastasis in 50% at death (Norris et al 1992, Knapp et al 2000,) ✦ Locally aggressive! Etiology and Risk factors ✦ Identified risk factors : ✦ Exposure to topical insecticides and herbicides (Glickman et al 1989, Glickman et al 2004) ✦ Obesity (Glickman et al 1989) ✦ Possibly cyclophosphamide (Weller et al 1979, Macy et al 1983) ✦ Female gender (Knapp et al 2000, Mustaers et al 2003) ✦ Certain breeds (Knapp et al 2000) ✦ Vegetables may decrease risk (Raghavan et al 2005) Work Up and Diagnosis ✦ Initial Diagnostics ✦ Abdominal ultrasound ✦ Positive, or double contrast cystourethogram ✦ Chest radiographs Diagnosis ✦ Free Catch Cytospin (Knapp 2000) ✦ Traumatic catheterization±US guidance (Lamb 1996) ✦ Cystoscopy and surgical biopsy(Childress 2011) ✦ V-BTA test (Borjesson 1999) ✦ CADET BRAF Mutation detection assay (Mochizuki 2015) Diagnosis ✦ Caution with FNA Surgical Options ✦ Total cystectomy with re-routing of the urinary system ✦ Severe Complications ✦ 9/10 neurologic dysfunction ✦ 5/10 hyperchloremic metabolic acidosis ✦ 5/10 pyelonephritis ✦ Survival 1-5 months (MST not given) Kudnig and Seguin 2010 ✦ Not recommended due to the complications ✦ Attempted 1-2 cm margins ✦ 4/11 had microscopic dirty margins ✦ 9/11 dogs had tumor recurrence ✦ MST not evaluated ✦ En-bloc resection of trigone and proximal urethra discouraged due to major potential complications (incontinence, bladder necrosis) ✦ Technique involving complete resection of bladder neck, including trigone and proximal urethra, but preserving neurovascular pedicles to bladder and urethra ✦ Preserves LUT function and maintains continence ✦ ST for two dogs was 280 and 580 days ✦ Recurrence noted in both patients ✦ Continence achieved in both patients ✦ 37 dogs with partial cystectomy +/- additional therapies ✦ 60% had microscopic dirty margins ✦ 76% dogs had tumor recurrence ✦ Abdominal wall seeding in 11% ✦ PFI 235 d and MST 348 d ✦ MST for partial cystectomy + daily piroxicam +/- chemo- 772 d ✦ Non-trigonal location and frequency of piroxicam prognostic Cyto-reductive surgery ✦ Incomplete removal of a tumor (planned or unplanned) or debulking ✦ Removing 99.9% of 1-cm tumor (one billion cells) still leaves one million cancer cells ✦ Theoretical indication to enhance efficacy of other treatments ✦ Chemotherapy ✦ Radiation therapy ✦ Cryotherapy ✦ Few well-controlled clinical trials have shown benefit in vet med Surgical Debulking in TCC ✦ Surgical cure virtually impossible with “debulking” ✦ Various studies evaluate survival with surgery alone: ✦ Norris et al 1992: ✦ Survival dependent on perceived amount of tumor removed ✦ Determined location was important for prognosis ✦ 100% - MST 365 days ✦ 50-99% - MST 120 days ✦ <50% - MST 75 days ✦ Helfand et al 1994: ✦ MST - 86 days ✦ Data from the PCOP tumor registry: ✦ MST - 106 days Cyto-reductive Surgery with adjunctive therapy ✦ Norris et al 1992: ✦ MST for dogs with cytoreductive surgery and RT- 105 days ✦ MST for dogs with cytoreductive surgery and chemo- 30 days ✦ Knapp et al 2000: 102 dogs with TCC ✦ MST with surgical debulking plus medical therapy (piroxicam or chemotherapy) was 272 days ✦ MST for surgery for biopsy only plus medical therapy- 195 days ✦ MST for medical therapy alone- 150 days ✦ Josel et al 2002: 122 dogs with TCC ✦ MST with surgical debulking and chemo- 350 days ✦ MST with medical therapy alone- 207 days Cyto-reduction with a MIS approach ✦ Liptak et al 2004: Transurethral resection ✦ Not recommended in female dogs ✦ Upton et al 2006: CO2 laser ablation ✦ MST- 299 days ✦ Cerf et al 2012: Endoscopically utilized Diode laser ✦ MST 380 days Medical Options Medical Treatment ✦ COX inhibitors, chemotherapy, or combo ✦ Goal is palliation ✦ Can obtain remission or SD ✦ Therapy continued as long as TCC is controlled, SEs are acceptable, and QOL is good NSAIDs ✦ Inhibit cyclooxygenase (COX) ✦ Useful palliative treatment for dogs with TCC ✦ Watch for GI toxicities: vomiting, melena, anorexia ✦ COX-2 inhibitors (i.e. deracoxib) may be a little safer Uremicfrost.com Piroxicam ✦ 62 dogs at PUVTH w/ single agent piroxicam for TCC ✦ 18% ORR including 2 CRs via cystography ✦ MST 195 days ✦ 2 dogs with CR lived 2.1 and 3.3 years COX-2 Inhibitors • 17% ORR via ultrasonography w/ consistent degree of bladder distention • MST 323 days • 8 dogs had received prior tx with piroxicam and/ or chemotherapy How Do We Determine When NSAIDs Fail? ✦ Majority of treatment is palliative ✦ Response endpoints: ✦ Progression or development of clinical signs ✦ Objective increase in tumor measurements ✦ Urinary obstruction Tumor Measurements ✦ Traditional ultrasonography may not be most reliable measure of response Chemotherapy ✦ Many combos of single agent chemotherapy and NSAIDs used ✦ Mitoxantrone and piroxicam one of most common ✦ Benefit of multi-agent chemotherapy protocols not yet determined Zazzle.com Study Results re: Medical Therapy of Transitional Cell Carcinoma in Dogs Metastasis Drug Dogs (#) (%) ORR (%) CR (%) PR (%) SD (%) PD (%) PFI (days) MST (days) Single Arm Trials Piroxicam 34 23 18 6 12 53 29 NA 181 Deracoxib 26/24 15 17 0 17 71 12 133 323 Mitoxantrone/ piroxicam 55/48 11 35 2 33 46 19 (194) 160 (350) 291 Vinblastine 28 28 36 0 36 50 14 122 147 Cisplatin (40-50 mg/m2)/ piroxicam 14 7 7 0 7 36 57 78 307 Carboplatin 14/12 28 0 0 0 8 92 41 132 Carboplatin/ piroxicam 31/29 19 38 0 38 45 17 NA 161 Intravesical Mitomycin C 13/12 0 42 0 42 58 0 120 223 Gemcitabine/ piroxicam 38/37 11 27 5 22 51 22 NA 230 Metronomic chlorambucil 31/30 32 3 0 3 67 30 119 221 Vinblastine (1.6 mg/m2)/ tocerinib (2.5-2.75 mg/kg) 5/10 20 40 0 40 60 0 NA NA Randomized Trials Cisplatin (60 mg/m2) 8 12 0 0 0 50 50 84 300 Cisplatin (60 mg/m2)/ piroxicam 14 43 14 14 57 28 0 124 246 Cisplatin (60 mg/m2) 15 33 13 0 13 53 27 87 338 Firocoxib 15 53 20 0 20 33 27 105 152 Cisplatin (60 mg/m2)/ firocoxib 14 29 57 0 57 21 0 186 179 Mitoxantrone/ piroxicam 26 8 8 0 8 69 23 106 248 Carboplatin/ piroxicam 24 41 13 0 13 54 33 74 263 Vinblastine (2.5 mg/m2) 27 11 58 0 58 33 8 143 407 Vinblastine (2.5 mg/m2)/ piroxicam 24 4 22 0 22 70 4 199 299 Retrospective Studies Doxorubicin/ piroxicam 34/23 29 9 0 9 60.5 30.5 103 168 Vinorelbine 14/12 0 14 0 14 57 14 93 187 Cisplatin (60 mg/m2) 18/16 33 19 0 19 25 56 75 130 Cistplatin (50 mg/m2) 15/12 40 25 0 25 50 25 NA 105 ✦ Nonrandomized one armed prospective clinical trial with 55 dogs ✦ 34.5% ORR via cystosonography ✦ Subjective improvement in 75% via owner observation ✦ PFI 194/ 160 days ✦ MST 350/ 291 days ✦ 9% ORR via cystosonography ✦ 1 dog had subjective response based on CSs and QOL, but no imaging ✦ PFI 103 days ✦ MST 168 days ✦ Well tolerated but modest response rates ✦ OS significantly improved in patients who underwent cytoreductive sx Platinums ✦ Cisplatin ✦ Higher reported remission rates (50-70%), but limited by renal damage ✦ ORR 57% with combination via cystography (13% for cisplatin alone and 20% for firocoxib alone) ✦ Renal and GI toxicosis common ✦ Carboplatin ✦ 38% ORR via cystography and cystosonography ✦ MST 161 days ✦ GI and hematologic toxicities; no renal toxicity ✦ No response difference between groups ✦ Mitoxantrone group (26): 8% PR and 69% SD ✦ Carboplatin group (24): 13% PR and 54% SD ✦ 106 d PFI for mitoxantrone versus 73.5 d PFI for carboplatin- not sign ✦ Prostatic involvement- shorter MST- 109 d vs 300 d (urethral), 190 d (trigonal), and 645 d (apical) ✦ 38 dogs evaluated ✦ 27% ORR via ultrasonography w/ consistent bladder distension and single ultrasonographer ✦ MST 230 days ✦ Limited adverse effects ✦ Prospective clinical trial of 28 dogs ✦ 18 dogs had tx prior to trial ✦ 36% ORR via ultrasonography w/ single ultrasonographer ✦ MST 147 days ✦ Maj. (27/28) did not have clinically relevant adverse effects ✦ Prospective and retrospective clinical trial with 14 dogs (13 relapsed, 1 naïve) ✦ 14% ORR via ultrasonography ✦ Subjective improvement in CSs in 11/14 ✦ Mild adverse effects ✦ PFI 93 days ✦ MST 187 days ✦ Dogs receiving dose reduction had MST of 130 d vs 222 d ✦ 8 dogs received additional tx after, but no