Doctor talking a with patient in hospital exam room. Photo courtesy: 2019 Fotolia
Doctor talking a with patient in hospital exam room. Photo courtesy: 2019 Fotolia

Treatment of low-grade upper tract urothelial cancer, also known as UTUC, a subset of urothelial cancer that is found in the renal pelvis of the ureter, usually involves radical surgery to remove the kidney and ureter, highlighting the need for improved treatments.

The disease corresponds to a subset of urothelial cancers that arise in the lining of the kidney (the renal pelvis) or the ureter (the long, thin tube connecting the kidney to the bladder). Because of the lining of the bladder, kidney, and ureter are the same, there are many similarities between UTUCs and bladder cancers. For example, both forms of cancer may present with hematuria (blood in the urine). However, UTUCs may also block the ureter or kidney, which causes hydronephrosis (swelling) and infections. In some patients, they can even affect kidney function.

Challenging
Treatment of low-grade upper tract urothelial cancer is challenging due to the complex anatomy of the urinary tract system. Today, the current standard of care includes multiple surgeries, and most patients require a radical nephroureterectomy, which includes the removal of the renal pelvis, kidney, ureter, and bladder cuff.[2] Treatment is further complicated by the fact that patients diagnosed with the disease are, in most cases, over 70 years of age. These patients may already have a compromised kidney function and may suffer further complications as a result of major surgery, creating a major unmet medical need.

“The current approach to treating low-grade upper tract urothelial cancer includes multiple endoscopic surgeries, high risk of disease recurrence and for many patients, the eventual removal of a kidney, which can present a whole new set of challenges that can adversely impact long-term health,” noted Seth Paul Lerner, M.D., FACS, professor of urology and Beth and Dave Swalm Chair in Urologic Oncology at Baylor. Lerner is also the principal investigator of the OLYMPUS trial and the corresponding and senior author of the study.

A different approach
An international team led by researchers at Baylor College of Medicine reports in the journal The Lancet Oncology that a new form of local chemotherapy using a mitomycin-containing reverse thermal gel offers a kidney-sparing treatment option for this rare cancer, which, according to the American Cancer Society, affects between 6,000 to 8,000 new patients in the United States every year.[1]

“Urothelial cancer refers to a cancer of the lining of the urinary system. While about 9 of 10 urothelial cancers arise in the bladder (lower tract), a small subset arises in the upper tract, in the lining of the kidney or the ureter, the long, thin tube that connects that kidney to the bladder,” Lerner noted.

Limiting radical kidney surgery
To spare patients having to undergo radical kidney surgery, physicians treated cancer with a novel formulation of mitomycin, a form of chemotherapy that urologists use to treat low-grade cancers of the bladder. Standard formulations of mitomycin are administered in a water-based solution that is washed away by the urine produced by the kidney, shortening the time the drug is in direct contact with the urothelium, which lessens the effect of the treatment.

To overcome the shortcomings of standard mitomycin treatment, Lerner and his colleagues evaluated a mitomycin-containing reverse thermal gel or pyelocalyceal solution known as UGN-101 (Jelmyto®, UroGen Pharma).

“UGN-101 is semi-solid at body temperature and becomes a viscous liquid at colder temperatures that can be injected via a catheter passed from the bladder into the renal pelvis where these tumors occur,” Lerner explained.

“The reverse thermal properties of UGN-101 allow for local administration of mitomycin as a liquid, which subsequently transforms into a semi-solid gel depot as it warms up following instillation into the urinary upper tract. Normal urine flow dissolves the gel depot, allowing tissue exposure to mitomycin over a period of 4 to 6 hours,” he added.

“Data from the OLYMPUS trial suggest UGN-101 is associated with a higher than expected initial complete response rate and strong durability without additional endoscopic surgery, which represents significant progress for patients living with this rare and difficult-to-treat type of cancer,” Lerner further noted.

Proof-of-concept
The team of researchers previously reported proof-of-concept and preliminary safety data for UGN-101 in treating 22 patients with upper tract urothelial cancer in a compassionate-use program. In the current study, Lerner and his colleagues conducted a phase III single-arm clinical trial to further evaluate the efficacy of the innovative reverse gel delivery of mitomycin in low-grade upper tract urothelial cancer.

In this phase III clinical trial, seventy-one patients received six weekly treatments with mitomycin-containing reverse thermal gel. Patients who had a complete response (complete disappearance of the tumor) were offered monthly treatments for up to 11 additional months. Efficacy of the treatment was evaluated using urine cytology, ureteroscopy, and, if warranted, biopsy three months following the initiation of therapy.

Beneficial treatment
Following the initial six weekly treatments, 59% of the patients had no residual tumors, including patients with cancer deemed unresectable at diagnosis, who represented 48% of the overall treatment population.

Although common adverse events were reported in ≥ 20% of patients, including urinary tract infection, hematuria, flank pain, and nausea, the severity and frequency were as expected from patients who are undergoing similar interventions. In addition, clinically relevant adverse reactions were observed in < 10% and ≥ 2% of patients  and included urinary tract inflammation, bladder spasm, urosepsis, hypersensitivity, and instillation site pain.

The study will continue to monitor the durability of the initial response out to 12 months.

Drug approval
The treatment has been recently approved by the U.S. Food and Drug Administration and became the first and only approved non-surgical treatment available for patients with low-grade upper tract urothelial cancer.

“The clear benefit is that patients get to keep their kidney. For people who have one kidney, this option also removes the need for dialysis,” Lerner noted.

“Other potential beneficiaries would be patients for whom, because of other conditions, it would be too risky to perform an operation to remove the kidney. Now they have an option for treatment,” he concluded.

Clinical trials
The OLYMPUS Study – Optimized DeLivery of Mitomycin for Primary UTUC Study (Olympus) – NCT02793128

Reference
[1] Kleinmann N, Matin SF, Pierorazio PM, Gore JL, Shabsigh A, Hu B, Chamie K, Godoy G, Hubosky S, 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. The Lancet Oncology, April 29, 2020, Online first. DOI:https://doi.org/10.1016/S1470-2045(20)30147-9
[2] Browne BM, Stensland KD, Moynihan MJ, Canes D. An Analysis of Staging and Treatment Trends for Upper Tract Urothelial Carcinoma in the National Cancer Database. Clin Genitourin Cancer. 2018;16(4):e743‐e750. doi:10.1016/j.clgc.2018.01.015