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 difference in MST ✦ Vinblastine alone (27)- 22.2% PR
✦ Median PFI 143 d
✦ Vinblastine/ piroxicam (24)- 58.3% PR
✦ Median PFI 199 d
✦ MST longest in dogs with vinblastine alone that followed with piroxicam alone (20)- 531 d vs combo- 299 d ✦ 5 dogs completed protocol
✦ 2 PR, 1 SD based on AUS
✦ 2 PR, 3 SD based on CT
✦ GI AEs most common
✦ Did not seem to improve response ✦ 5 dogs completed protocol
✦ 2 PR, 1 SD based on AUS
✦ 2 PR, 3 SD based on CT
✦ GI AEs most common
✦ Did not seem to improve response ✦ Antitumor activity in variety of dogs w/ naturally occurring cancers
✦ Prospective clinical trial of 31 dogs w/ TCC
✦ 29 dogs had failed prior tx
✦ 3% ORR via cystosonography w/ single evaluator and similar bladder distension
✦ 67% SD
✦ PFI 119 days
✦ MST 221 days
✦ Few associated toxicities Systemic Chemotherapy: Summary
✦ Palliative
✦ Almost all dogs also on an NSAID
✦ Response rates affected by response criteria
✦ Similar survival times
✦ Most effective chemotherapy limited by renal toxicity Intra-Arterial Chemotherapy
✦ Fluoroscopic guided catheterization of arteries feeding the tumor
✦ Theoretically reduces systemic toxicities and improves response rates
✦ Higher concentration of chemotherapy to tumor
✦ Several studies in humans, often combined with radiotherapy ✦ Retrospective of IVC versus IAC
✦ Sign decrease in tumor measurements in IAC group after 2 chemo treatments
✦ IAC group sign more likely to have tumor response (36% PR vs 13%)
✦ Dogs in IAC group significantly less likely to develop anemia, lethargy, and anorexia ✦ Retrospective of IVC versus IAC
✦ Sign decrease in tumor measurements in IAC group after 2 chemo treatments
✦ IAC group sign more likely to have tumor response (36% PR vs 13%)
✦ Dogs in IAC group significantly less likely to develop anemia, lethargy, and anorexia Intravesicular Therapy
✦ Phase I clinical trial of 12 dogs
✦ Determined MTD
✦ ORR 42% via cystosonography +/- CT and cystography
✦ 2 dogs had severe myelosuppression and GI upset
✦ Limited by suspected systemic absorption • 5 dogs
• Pretreated orally with 5-aminolevulinic acid (ALA)
• Laser delivery system passed retrograde via urethra
• Ultrasound guidance
• PFI 42 days (28-238 days)
• AEs: hematuria, stranguria, and vomiting after receiving ALA
• Outcomes not improved compared to standard therapy Radiation Therapy
✦ Limited information for TCC
Mydogscancer.blogspot.com ✦ TCC of bladder & prostate, AGASACA
✦ 6-MV linear accelerator w/ varying fractionation schemes
✦ Colitis in 56%
✦ 3 had GI perforation
✦ All had 3 or 3.3 Gy per fraction
✦ Many had implantable chemo as a radiation potentiator
✦ RT can be given to pelvic region w/ minimal risk of late effects to colon
✦ Smaller doses per fraction
✦ Avoiding systemic radiation potentiators ✦ Retrospective of 21 dogs
✦ Tumors in prostate (10), urinary bladder (9), and urethra (2)
✦ Total RT dose 54-58 Gy delivered in 20 daily fractions
✦ Mild acute toxicities
✦ 4/21 late grade III gastrointestinal or genitourinary toxicities
✦ ORR subjectively 60% based on owner perceived improved QOL
✦ Median event free survival 317 days
✦ MST 654 days
✦ Neither local tumor control or overall survival statistically dependent upon location of the primary tumor
✦ Variable adjuvant and neoadjuvant therapies ✦ Retrospective of 21 dogs
✦ Tumors in prostate (10), urinary bladder (9), and urethra (2)
✦ Total RT dose 54-58 Gy delivered in 20 daily fractions
✦ Mild acute toxicities
✦ 4/21 late grade III gastrointestinal or genitourinary toxicities
✦ ORR subjectively 60% based on owner perceived improved QOL
✦ Median event free survival 317 days
✦ MST 654 days
✦ Neither local tumor control or overall survival statistically dependent upon location of the primary tumor
✦ Variable adjuvant and neoadjuvant therapies ✦ 13 dogs- 10 daily (M-F) fractions of 2.7 Gy
✦ 8% CR
✦ 54% PR
✦ 39% SD
✦ MST 150 d from RT
✦ 31% acute Aes; no sign late AEs Multimodal Approaches
✦ Retrospective study of 10 dogs
✦ Minimal SEs
✦ 22% ORR via ultrasonography
✦ 90% subjective response
✦ PFI 91 days
✦ MST 326 days
✦ Results similar to those with medical therapy alone Multimodal Approaches
✦ Retrospective study of 10 dogs
✦ Minimal SEs
✦ 22% ORR via ultrasonography
✦ 90% subjective response
✦ PFI 91 days
✦ MST 326 days
✦ Results similar to those with medical therapy alone Multimodal Approaches Palliative Care • Results:
• Resolution of obstruction in 41/42 (97.6%)
• MST after SEMS placement - 78 d
• Complications: http://www.amcny.org/node/342#Urethral_Stenting
• Urinary incontinence in 27/42 (64%)
• Tenesmus in 13/42 dogs (31%)
• UTI in 8/42 dogs (19%)
• Re-obstruction due to tumor regrowth 9/42 (21.5%) • Results:
• Resolution of obstruction in 41/42 (97.6%)
• MST after SEMS placement - 78 d
• Complications: http://www.amcny.org/node/342#Urethral_Stenting
• Urinary incontinence in 27/42 (64%)
• Tenesmus in 13/42 dogs (31%)
• UTI in 8/42 dogs (19%)
• Re-obstruction due to tumor regrowth 9/42 (21.5%) ✦ Metastasis was confirmed in 4/12 prior to treatment
✦ 3/12 had bilateral stents
✦ Complications:
✦ Renal pelvis rupture
✦ Migration
✦ MST 57 d Cystostomy Tube
✦ Complications in 37/76 (49%)
✦ Inadvertent removal/ displacement in 12/76
✦ Chewing of tube (2)
✦ Breakage of the mushroom tip during removal (2)
✦ Fistula formation (2)
✦ Irritation or inflammation around tube exit site (7)
✦ Urine leakage around the tube (7)
✦ UTIs in 24/76 animals after placement Human Muscle Invasive Bladder TCC
✦ Radical cystectomy and lymphadenectomy
✦ Neoadjuvant chemotherapy in certain cases
✦ Adjuvant chemotherapy within clinical trials or in patients with metastatic disease
✦ Cisplatin containing combination chemotherapy
✦ Vinflunine as second line chemotherapeutic
✦ Multi-modal bladder preserving treatments in localized disease for well-informed patients
✦ Bisphosphonates for metastatic bone disease (MBD)
✦ Checkpoint inhibitors showing promise What About Cats? Pathology, Location and Behavior
✦ 46% of bladder tumors in cats are epithelial
✦ 30% of bladder tumors in cats are TCC (Schwarz et al 1985)
✦ Other tumor types: SCC (15%), adenocarcinoma (11%), benign mesenchymal (19%), sarcomas (26%)
✦ 5% lymph node mets and 15% pulmonary mets reported (Wilson et al 2007)
✦ Median age 14-15 years (Wilson et al 2007, Bommer et al 2012)
✦ 45% trigonal
✦ 64-65% male Prognosis
✦ MST 311 d (Bommer et al 2012)
✦ Partial cystectomy and meloxicam- 375 d
✦ Meloxicam alone- 123 d
✦ 1 year survival 50%
✦ COX2 positive cases- 123 s
✦ COX2 negative cases- 375 d
✦ MST 261 d (Wilson et al 2007)
✦ Survival not reached for cats receiving surgery with or without other therapies ✦ Doxorubicin and cyclophosphamide in 1 cat- survived 38 d
✦ Piroxicam alone in 3 cats- survivals 1, 23, and 208 d
✦ Surgery in 10 cats
✦ 2 died peri-op
✦ Median PFI 89 d
✦ 8 had additional therapies: piroxicam, meloxicam, carboplatin, doxorubicin
✦ 6 no treatment- 5 euthanized within 24 h, 1 survived 276 d ✦ Meloxicam in all 11 at mean initial dose of 0.09 mg/kg/day initially then maintenance dose of 0.04 mg/kg/day
✦ Partial cystectomy in 4 cats- MST 375 d vs 123 d for meloxicam alone
✦ 1 cat switched to piroxicam and treated with cystostomy tube ✦ Meloxicam in all 11 at mean initial dose of 0.09 mg/kg/day initially then maintenance dose of 0.04 mg/kg/day
✦ Partial cystectomy in 4 cats- MST 375 d vs 123 d for meloxicam alone
✦ 1 cat switched to piroxicam and treated with cystostomy tube Conclusions
✦ Treatment of TCC involves palliation of clinical signs
✦ Surgical options have not shown improvement of long term outcomes in dogs
✦ Individual chemotherapy options have not shown significant differences between treatment groups
✦ Response rates are affected by inconsistent response criteria
✦ Less known about cats, but NSAIDs and surgery may play a role Questions Left Unanswered
✦ Knowing that our treatment goals for TCC are primarily palliation, how should we be defining response rate?
✦ Imaging studies
✦ Cystography
✦ Cystosonography
✦ CT
✦ Clinical signs
✦ Quality of life measures
✦ How can we incorporate multi-modal therapy to extend quality and quantity of life in the treatment for TCC? References
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