Management of Bladder/Prostate Tumors for the General Practitioner

Diagnostic Techniques

1. AVOID percutaneous FNA!! Percutaneous FNA carries a risk of tumor seeding, which can be a devastating complication in these patients. TCC is notorious for its ability to seed following FNA, and you’d be hard-pressed to find an oncologist who hasn’t seen this clinically. In addition to that significant risk, we have easily accessible and far less risky ways to obtain a diagnosis.
2. BRAF mutational testing: BRAF is a cellular growth/survival signaling protein, and mutation can result in the unconstrained growth of cells. BRAF mutation is common in canine urogenital tumors (~80%), including both urothelial origin and prostate tumors. Testing for this mutation using a free-catch urine sample is now widely available, and a positive test result is considered diagnostic for urothelial carcinoma.
3. Other diagnostic options include urine cytology using a cytospin technique, traumatic catheterization, and cystoscopy.

When Is It OK to FNA?

1. When other options have been exhausted (including those that are financially out of reach for the client), and the risk has been explained to the client.
2. Your patient is a cat
   – No other good diagnostic options in cats
   – BRAF not validated
   – Cystoscopy/traumatic cath is not typically feasible

Before You Refer

1. Start an NSAID! (see below)
2. Consider staging
   – Chest x-rays
   – +/- AUS
   – Culture that urine **but don’t get it via cysto. 80% of female dogs with UCC will have a UTI during their treatment, and this can often result in acute worsening of symptoms.
3. About 30% of male dogs with UCC have a UTI. Additionally, there’s literature suggesting that these patients are more likely to develop antibiotic-resistant infections. Hence, culture and sensitivity are essential to the workup, even if visible bacteria are on your UA. Keep in mind that the presence of the tumor complicates clearance of a UTI – I typically recommend a 10 to 14-day course of antibiotics and a post-antibiotic culture to ensure the infection has cleared.

If you have an ultrasonographer you trust to identify medial iliac lymph nodes, then this might be reasonable to offer before referral. Just remember that some oncologists may prefer to have their radiologist repeat the study. If this is a patient that you won’t be referring to, also keep in mind that monitoring for the progression of the primary tumor on ultrasound can be somewhat unreliable because the apparent size varies significantly with the degree of bladder fill.

Treatment

Instead of looking at the treatment options as one or the other, we typically view this as a disease that does best with multimodal management. I usually start off the conversation for most types of cancer by saying we have two main concerns when we boil it down: the local disease and the risk of metastasis. In the case of UCC, local disease is almost always the cause of death. Metastasis does happen, and in some cases, it’s the thing that impacts QoL first, but in the vast majority, the battle is won and lost in the urinary tract.

1. NSAIDs (COX-2 selective): The value of NSAIDs in treating UCC is something we’ve known for a while now. As a reminder, NSAIDs work by blocking cyclooxygenase or COX receptors — NSAIDs such as meloxicam, piroxicam, and deracoxib are COX-2 selective. Numerous publications have demonstrated the expression of COX2 receptors in UCC but NOT in normal bladder epithelium, which fits with the clinical observation that NSAIDs alone often improved both symptoms and survival in these patients.
2. Radiation therapy: As someone who has managed this disease as both a medical oncologist and a radiation oncologist, I can tell you that radiation tends to be much more gratifying. With chemotherapy, we often achieve a fairly modest tumor response; if any, with radiation, we are much more likely to see an actual decrease in tumor size. Median overall survival in patients treated with radiation and chemotherapy is >600 days.
3. Chemotherapy: Numerous chemotherapy drugs have been described for treating canine UCC, and no one agreed-upon drug is better than others. Some first-line examples include vinblastine, mitoxantrone, and carboplatin, although metronomic chlorambucil, vinorelbine, and others have been described. These chemotherapy drugs have unique tolerability profiles, dosing schedules, and other pros and cons. Ultimately, those factors weigh into clients’ decision-making, as does the efficacy over time. We take a trial-and-error approach — if we start one drug and see progression or lack of response, we may eventually transition to another.
4. Sometimes surgery: Typically with tumors where local disease is life-limiting, local therapy is the treatment of choice. Local therapy is usually going to mean surgery or radiation, so why isn’t surgery a bigger part of managing this disease? Firstly, in many cases, the location of the tumor at the trigone means that surgery would need to involve removal of the entire bladder and re-routing of the ureters directly into the urethra. While this is possible with the aid of stents and subcutaneous ureteral bypass, this is not an option that is widely available or right for every owner. That said, dogs with non-trigonal TCC may have better outcomes with surgery. Small studies combining surgery + NSAIDs (with or without chemotherapy) have reported a median survival of >700 days.
5. Stenting and laser ablation: These techniques are crucial for patients with obstruction but are not sufficient as a standalone therapy. Studies comparing laser ablation plus medical therapy to medical therapy alone showed no improvement in survival over medical therapy alone. Complications of these procedures can include incontinence, perforation, and worsening symptoms. The other thing to remember here is that even with stenting, the prognosis for obstructed patients is guarded — MST in most studies describing the use of stents is <90 days.
6. Small molecule inhibitors: Small molecule inhibitors are drugs that interfere with cellular signaling pathways. Aberrant cell signaling is a hallmark of cancer. In the case of UCC, the tyrosine kinase receptor EGFR/Her2 is frequently overexpressed. Lapatinib is an EGFR/Her-2 receptor antagonist, and a recent study showed that lapatinib/piroxicam showed survival benefits over piroxicam alone when used as a first-line therapy. Most small molecule inhibitors are orally administered, and many (including lapatinib) are available at compounding pharmacies such as Best Pet Rx.
7. Sulforaphane: This is an antioxidant/detoxifying compound produced following ingestion of cruciferous vegetables, which is chemopreventive in human models of urogenital cancers. This compound may be useful as a chemopreventive, especially in certain predisposed breeds. Its role in tumor treatment remains unknown.

Feline Urothelial Carcinoma

While urothelial carcinoma is still the most common tumor in the bladder in cats, it is overall quite rare. Additionally, other tumors are possible and can include sarcomas and lymphoma. Like canine urothelial tumors, most feline urothelial tumors are COX2-expressing. Tumors are often non-trigonal in cats, and surgical management may improve survival rates. The role of RT/chemotherapy remains largely unknown, but in my clinical experience, feline UCC tends to be much more treatment-resistant than the disease in dogs. Overall reported MST is ~9 months regardless of treatment approach.

References

1. Blackburn, Amanda L., et al. “Evaluation of outcome following urethral stent placement for treating obstructive carcinoma of the urethra in dogs: 42 cases (2004–2008).” Journal of the American Veterinary Medical Association 242.1 (2013): 59-68.
2. Breen, Matthew, and Claire Wiley. “Canine Transitional Cell Carcinoma: What’s New?.“
3. Budreckis, D. M., et al. “Bacterial urinary tract infections associated with transitional cell carcinoma in dogs.” Journal of veterinary internal medicine 29.3 (2015): 828-833.
4. Cerf, Dean J., and Eric C. Lindquist. “Palliative ultrasound-guided endoscopic diode laser ablation of transitional cell carcinomas of the lower urinary tract in dogs.” Journal of the American Veterinary Medical Association 240.1 (2012): 51-60.
5. Clerc‐Renaud, Benoit, et al. “Treatment of genitourinary carcinoma in dogs using nonsteroidal anti‐inflammatory drugs, mitoxantrone, and radiation therapy: A retrospective study.” Journal of Veterinary Internal Medicine 35.2 (2021): 1052-1061.
6. Clerc‐Renaud, Benoit, et al. “Treatment of genitourinary carcinoma in dogs using nonsteroidal anti‐inflammatory drugs, mitoxantrone, and radiation therapy: A retrospective study.” Journal of Veterinary Internal Medicine 35.2 (2021): 1052-1061.
7. Fulkerson, Christopher M., and Deborah W. Knapp. “Management of transitional cell carcinoma of the urinary bladder in dogs: a review.” The veterinary journal 205.2 (2015): 217-225.
8. Higuchi, Takashi, et al. “Characterization and treatment of transitional cell carcinoma of the abdominal wall in dogs: 24 cases (1985–2010).” Journal of the American Veterinary Medical Association 242.4 (2013): 499-506.
9. Kaiser, Anna E., et al. “Sulforaphane: A broccoli bioactive phytocompound with cancer preventive potential.” Cancers 13.19 (2021): 4796.
10. Kaye, M. E., et al. “Vinorelbine rescue therapy for dogs with primary urinary bladder carcinoma.” Veterinary and Comparative Oncology 13.4 (2015): 443-451.
11. Kaye, M. E., et al. “Vinorelbine rescue therapy for dogs with primary urinary bladder carcinoma.” Veterinary and Comparative Oncology 13.4 (2015): 443-451.
12. Kennelley, Gabrielle E., et al. “Mechanistic review of sulforaphane as a chemoprotective agent in bladder cancer.” American Journal of Clinical and Experimental Urology 11.2 (2023): 103.
13. Khan, K. Nasir M., et al. “Expression of cyclooxygenase-2 in transitional cell carcinoma of the urinary bladder in dogs.” American journal of veterinary research 61.5 (2000): 478-481.
14. Khan, K. Nasir M., et al. “Expression of cyclooxygenase-2 in transitional cell carcinoma of the urinary bladder in dogs.” American journal of veterinary research 61.5 (2000): 478-481.
15. Kim, Jung-Hyun. Chemopreventive potential of Se-enriched broccoli and kale sprouts in vitro and in a human prostate cancer xenograft model. Diss. 2010.
16. Leone, Andrew, et al. “Sulforaphane for the chemoprevention of bladder cancer: molecular mechanism targeted approach.” Oncotarget 8.21 (2017): 35412.
17. Maeda, Shingo, et al. “Lapatinib as first-line treatment for muscle-invasive urothelial carcinoma in dogs.” Scientific Reports 12.1 (2022): 4.
18. Marvel, S. J., et al. “Clinical outcome of partial cystectomy for transitional cell carcinoma of the canine bladder.” Veterinary and comparative oncology 15.4 (2017): 1417-1427.
19. Marvel, S. J., et al. “Clinical outcome of partial cystectomy for transitional cell carcinoma of the canine bladder.” Veterinary and comparative oncology 15.4 (2017): 1417-1427.
20. McMillan, Sarah K., et al. “Outcome of urethral stent placement for management of urethral obstruction secondary to transitional cell carcinoma in dogs: 19 cases (2007–2010).” Journal of the American Veterinary Medical Association 241.12 (2012): 1627-1632.
21. Milovancev, Milan, et al. “Partial cystectomy with a bipolar sealing device in seven dogs with naturally occurring bladder tumors.” Veterinary Surgery 49.4 (2020): 794-799.
22. Nyland, Thomas G., Seth T. Wallack, and Erik R. Wisner. “Needle‐tract implantation following US‐guided fine‐needle aspiration biopsy of transitional cell carcinoma of the bladder, urethra, and prostate.” Veterinary Radiology & Ultrasound 43.1 (2002): 50-53.
23. Upton, Melinda L., C. H. Tangner, and Mark E. Payton. “Evaluation of carbon dioxide laser ablation combined with mitoxantrone and piroxicam treatment in dogs with transitional cell carcinoma.” Journal of the American Veterinary Medical Association 228.4 (2006): 549-552.
24. Vail, David M., Douglas H. Thamm, and Julius M. Liptak, eds. Withrow and MacEwen’s Small Animal Clinical Oncology: 6th edition. Elsevier Health Sciences, 2020.
25. Wilson, Heather M., et al. “Clinical signs, treatments, and outcome in cats with transitional cell carcinoma of the urinary bladder: 20 cases (1990–2004).” Journal of the American Veterinary Medical Association 231.1 (2007): 101-106.