Bladder Cancers: What is Low-Grade Upper Tract Urothelial Carcinoma?

In 2020, bladder cancer was the sixth most¹ common cancer type in the United States, behind breast, lung, prostate, colon, and skin cancers.

The American Cancer Society² estimates 81,180 new diagnoses of bladder cancer in 2022—61,700 in men and 19,480 in women—and 17,100 deaths.

Bladder cancers are more common in men and the incidence and death rates for women with bladder cancers appears to be trending downwards.² The risk of contracting bladder cancer is for men is about 1 in 27, or 1 in 89 for women.

While more than 50% of bladder-related cancers occur in the bladder itself, upper tract urothelial carcinoma (UTUC) is a specific subset of urothelial cancer that primarily affects the lining of the kidney or renal pelvis and the ureter.^2-4 Approximately 5% to 10% of urothelial cancer cases³ are attributed to UTUC, making it qualify as rare.

Risk factors are very similar to bladder cancer and include race/ethnicity (White people are at higher risk compared with Black, Hispanic, Asian American, and Native American), increased age, gender, family history, smoking, and exposure to certain chemicals.²

Johns Hopkins Medicine’s Greenberg Bladder Cancer Institute explains: “As the lining of the bladder, kidney and ureter are the same, there are many similarities and some differences between UTUCs and bladder cancers. For instance, both bladder cancers and UTUCs can present with hematuria (blood in the urine). However, UTUCs can block the ureter or kidney, causing swelling (known as hydronephrosis) and infections, and they can even affect kidney function in some patients.”

Symptoms related to UTUC could also include flank pain if the tumor is causing an obstruction. Patients with low-grade UTUC may also present no signs or symptoms and are only detecting when looking for other health-related problems with radiology tests or scans.⁵

Two main types of UTUC include noninvasive and invasive. Tumor development can be classified as low- or high grade with different treatment strategies for each. High-grade UTUCs can spread and typically result in a radical nephrouretectomy. While low-grade UTUCs tend to be less invasive and remain in the kidney or ureter, they tend to reoccur prompting additional management and need to preserve the urinary tract.³

Surena F. Matin, MD, urologist, MD Anderson Cancer Center, in a recent webinar⁶ explained that while bladder cancer is about a 4 to 1 ratio for men and women, UTUC occurs in 2 to 1 ratio, respectively. He continued to explain some of the unique risks, limitations, and points of interest associated with UTUC which include:

• Lynch syndrome: an inheritable genetic syndrome that increases the risk of certain cancers that occurs in an estimated 4% of patients with UTUC
• Limited imaging technology: UTUC are growing by the millimeter, imaging for smaller organs can be challenging
• Intracavitary therapy: Compared to the bladder, which is built for storage, the upper tract works more similarly to a funnel so treatments do not “stick around” very long to be efficient enough.
• Many patients with UTUCs have FGFR3 genetic mutations

Treatment strategy is determined primarily by the risk and grade levels for individual patients. In the case of low-grade UTUC, the primary goals are to reduce tumor growth, avoid radical surgery, and maintain quality of life.

Upon clinical presentation or suspected bladder cancer/UTUC diagnosis, the National Comprehensive Cancer Network Guidelines for Bladder Cancer⁷ recommend a trans urethra resection of the bladder tumor (TURBT).

Kate Murray, DO, University of Missouri Medical Center, explained in a webinar⁶ how TURBT is used to determine the grade of the tumor and determine next steps. Depending on the grade and risk characterization for the patient, treatment options can include:

• Nephroureterectomy with lymph node dissection
• Primary ureterectomy with lymph node dissection
• Endoscopic tumor ablations (antegrade or retrograde)
• Primary chemoablation
• Clinical trials
• Chemotherapy or immunotherapy

Another important distinction between therapy options from the NCCN Guidelinesfor Upper GU Tract Tumors that Dr Matlin points out is how staging for this disease is very difficult, but if qualified as metastatic, there is no staging in the recommendations chart.

Dr Murray emphasized how treatment and goals are evolving to fight to save the kidneys because of the potential implications on patients such as metachronous disease, potential blood pressure related problems, and other comorbidities.

Relating to Dr Matin, Dr Murray discussed the importance of kidney-saving treatment options for low-grade UTUCs—particularly a newly FDA-approved chemoablation “reverse hydrogel technology for installation of a mitomycin C chemotherapy within the upper urinary tract within the renal pelvis” called Jelmyto.⁶

Jelmyto, or mitomycin, was approved by the FDA⁸ on April 15, 2020, for adult patients with low grade UTUC, based on results from an ongoing, single arm, multicenter trial of 71 patients, of which 58% achieved a complete response rate after 3 months following treatment initiation. Treatment with Jelmyto has an estimated 82% (95% CI: 66, 91) durability of response rate.^9,10

Dr Murray went on to explain how chemoablation is one of her top choices for low-risk patients, “It’s familiar to us as urologists. It’s quite tolerable for the patients, and it can avoid repetitive surgeries, repetitive anesthetics for our patients, if possible.”

Chemoablation with Jelmyto also removes concern related to kidney pressures and irrigations during ureteroscopic laser ablations, creates an opportunity for faster results or outcomes, and helps avoid bleeding, stents, and anesthesia for treatments, explained Dr Murray in an webinar.⁶

References:

1. Cancer statistics. National Cancer Institute. Updated September 25, 2020. Accessed September 15, 2022. https://www.cancer.gov/about-cancer/understanding/statistics
2. American Cancer Society. Key statistics for bladder cancer. Updated January 12, 2022. Accessed September 15, 2022. https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html
3. Johns Hopkins Medicine. Greenberg Bladder Cancer Institute. Upper tract urothelial cancer. 2022. Accessed September 15, 2022. https://www.hopkinsmedicine.org/greenberg-bladder-cancer-institute/utuc/
4. Urothelial cancer. National Cancer Institute. Accessed September 15, 2022. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/urothelial-cancer
5. Bladder Cancer Advocacy Network. What is upper tract urothelial carcinoma (UTUC)? December 16. 2021. Accessed September 15, 2022. https://bcan.org/what-is-upper-tract-urothelial-carcinoma-utuc/
6. Bladder Cancer Advocacy Network. Understanding upper tract urothelial carcinoma. April 25, 2022. Webinar available at: https://bcan.org/understanding-upper-tract-urothelial-carcinoma/
7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Bladder Cancer. Version 2.2022-May 20, 2022. Accessed September 15, 2022. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdfUS Food & Drug Administration.
8. FDA approves mitomycin for low-grade upper tract urothelial cancer. April 15, 2020. Accessed September 15, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mitomycin-low-grade-upper-tract-urothelial-cancer
9. US Food and Drug Administration. JELMYTO™ (mitomycin) for pyelocalyceal solution. April 2020. Accessed September 15, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211728s000lbl.pdf
10. Kleinmann N, Matin SF,  Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol. 2020;21(6):776-785. doi:10.1016/S1470-2045(20)30147-9