An Update on Upper Tract Urothelial Carcinoma

Low-grade upper tract urothelial carcinoma (UTUC) comprises a substantial percentage of UTUCs. While mortality risk is low, diagnostic choices, therapeutic care, and continued management of these carcinomas are complex decisions. Low-grade UTUC can cause hematuria and urinary obstruction, and tumors tend to recur.  Periodic radiographic imaging is required as well as ureteroscopic interventions not only to treat disease, but also to monitor for recurrence.

Patients also are at heightened risk for bilateral disease, and standard-of-care (kidney-sparing) treatment with endoscopic laser ablation can be challenging due to the narrow ureteral lumen and the anatomic complexity of the calyceal system.1-4 Patients with multiple recurrences often end up receiving a radical nephroureterectomy.2,4

In April 2020, the U.S. Food and Drug Administration (FDA) approved JelmytoTM (mitomycin gel) as the first therapy for low-grade UTUC.5 One year later, Jelmyto is showing itself to be a valuable treatment that urologists may wish to incorporate into their clinical armamentarium. Herein, I review some useful facts and clinical pearls about Jelmyto and briefly discuss recent data on other UTUC therapies.

Jelmyto is formulated as a hydrogel, meaning that it exists in a viscous liquid state when chilled and then transforms into a solid gel when warmed to room temperature. This unique formulation enables physicians to chill the drug in an ice bath and instill it throughout the renal collection system, where it forms a gel depot as it warms that conforms to the collecting system and delivers 4 to 6 hours of chemoablation before dissolving with normal urine flow.6 General anesthesia is not required (local anesthesia and/or sedation are sufficient for most patients), providing flexibility of administration in either a surgical center or a clinic/office setting that is equipped with fluoroscopy. 

Access for Jelmyto instillation is retrograde, by means of a ureteral catheter and a retrograde pyelogram, or antegrade, with the aid of a percutaneous nephrostomy tube. Dosing is based on the measured volume of the renal pelvis and calyces.5,6 It is important to ensure an appropriate dwell time, and an appropriate volume of drug needs to be distributed throughout the entire urinary collecting system. Because Jelmyto must be kept cold to remain in a liquid state prior to instillation, all instruments should be readily to hand before Jelmyto is removed from its ice bath. 

The FDA approval of Jelmyto was based on the results of the single-arm OLYMPUS study, in which 74 patients with low-grade UTUC, consisting of at least one papillary tumor measuring 5 to 15 mm in its longest dimension before or after debulking, received weekly instillations of Jelmyto for up to six weeks (the planned treatment course).6 In this study, the average age was approximately 71 years, and at baseline, about half of patients had multiple UTUCs and/or unreachable tumors. In all, 71 of 74 patients received the full course of therapy. At 3 months, the rate of complete response (defined as a negative ureteroscopic evaluation, negative cytology, and negative for-cause biopsy) was 59%. Importantly, this rate was the same in the subgroup of patients who had endoscopically unresectable tumors at baseline. Although slightly less than half (20 of 42) of complete responders were followed through 12 months, 70% of these patients were found to maintain their complete response to Jelmyto therapy throughout follow-up. 

OLYMPUS participants with complete responses to Jelmyto therapy were eligible to receive monthly instillations of Jelmyto as maintenance therapy, but many patients did not receive them, raising questions about whether ongoing instillations are necessary to maintain response. So far, real-world clinical experience appears to indicate that many patients who respond successfully to Jelmyto therapy can maintain successful outcomes without the need for monthly maintenance therapy. To minimize possible morbidity, the use of maintenance Jelmyto therapy should be guided by a careful personal evaluation of a patient’s tumor characteristics, morbidity, symptomatology, anatomy, and treatment tolerance.

The main risk of the Jelmyto instillation procedure is ureteral stenosis. In the OLYMPUS study, the rate of grade 3 ureteral stenosis was 9%,6 and this rate may be higher in practice, at least until clinicians become adept at the procedure. The rate of stenosis also may be related to the number of repeated treatments.  Patients should be informed that serious cases of stricture could require long-term stent placement or radical nephroureterectomy; in OLYMPUS, 11% of patients still had stents placed at the time of study publication, and 3% were considered to be permanently stent-dependent (importantly, pathology of nephrectomy specimens in these patients showed no carcinomas). Complications such as ureteric stenosis are likely to become less frequent as clinicians gain more experience with Jelmyto, but stricture will always remain a risk of this procedure, and this information should be included in patient counseling. 

As with all new procedures, it is important for physicians to familiarize themselves with the Jelmyto instillation technique by carefully reviewing the detailed illustrated instructions7 and instructional videos8 made available by the manufacturer. The physician should also directly observe a procedure, if possible. Because UTUC is a relatively rare disease, it is preferable that in a group practice, a single physician takes on these procedures to maximize familiarity and expertise and optimize outcomes. Jelmyto’s manufacturer (UroGen Pharma) has provided quite good support for Jelmyto access despite the ongoing COVID-19 pandemic. The company will provide its multiuse syringe lever and chilling unit at no cost to requesting physicians and clinical institutions. Online trainings and multiple opportunities to interact with experienced physicians to help troubleshoot and anticipate likely needs will effectively prepare and support physicians as they begin to provide this care to their patients.

I would like to emphasize that even though the OLYMPUS study had a unique trial design in which resectable low-grade UTUCs were left in place to examine the effect of primary chemoablation,6 laser ablation does remain the standard kidney-sparing treatment option for managing low-grade UTUC, and hence Jelmyto serves as an adjuvant to laser ablation.9 In my view, the ideal candidate for Jelmyto is a patient with biopsy-confirmed low-grade, upper tract recurrent tumors and/or tumors that are not easily accessible for laser ablation. For these patients, Jelmyto therapy can potentially help preserve a kidney, forgo or postpone major surgery, and preserve renal function.

The development and regulatory approval of Jelmyto reflects the recent trend of increased focus on developing kidney-sparing therapies for low and intermediate-grade UTUC. For example, in March 2021, the FDA granted an Orphan Drug designation to the investigational agent padeliporfin Immune Photo Activated Cancer Therapy (ImpACT) for patients with UTUC.10 Padeliporfin is a vascular-targeted photodynamic therapy delivered intravenously in an inactive form and then activated by non-thermal light from a low-energy laser. This activation induces targeted tumor necrosis by decreasing tumor blood supply, which in turn increases antitumor immunity. The Orphan Drug designation was based on the phase 1 study data that remains unpublished, and a phase 3 UTUC trial is planned (NCT04620239). It is far too early to draw any conclusions about the safety and efficacy of padeliporfin for treating UTUC, but this agent may have promise. 

We also are seeing important data on optimizing outcomes for higher-grade or recurrent UTUC for which patients undergo radical nephroureterectomy with curative intent. Previously, the phase 3, parallel-group, open-label, randomized controlled POUT trial confirmed that systemic adjuvant platinum-based chemotherapy significantly improves disease-free survival and metastasis-free survival compared with surveillance only after radical nephroureterectomy. At the GU ASCO 2021 annual meeting, POUT investigators presented the findings of pre-planned subgroup analyses confirming clinically meaningful and statistically significant improvements in the primary survival endpoints.11,12 (In addition, overall survival at 3 years was 12% greater in the chemotherapy arm, even though the study was not powered to assess this outcome.) The POUT study was a practice-changing trial, and these updated results confirm the role of platinum-based adjuvant chemotherapy for the management of fit patients undergoing radical nephroureterectomy for UTUC.

Written by: Sam S. Chang, MD, MBA, Patricia and Rodes Hart Endowed Professor of Urologic Surgery and Oncology, is the Oncology Fellowship Director and Vice-Chair of Urologic Surgery at Vanderbilt University Medical Center. 

Published Date: March 2021


1.Raman J, Shore ND. Management of low-grade upper tract urothelial carcinoma: an unmet need. Rev Urol. 2020;22(1):1-8.
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3. Petros FG, Li R, Matin SF. Endoscopic approaches to upper tract urothelial carcinoma. Urol Clin North Am. 2018;45(2):267-286.
4. Upfill-Brown A, Lenis AT, Faiena I, et al. Treatment utilization and overall survival in patients receiving radical nephroureterectomy versus endoscopic management for upper tract urothelial carcinoma: evaluation of updated treatment guidelines. World J Urol. 2019;37(6):1157-1164.
5. U.S. Food and Drug Administration. JELMYTO™ (mitomycin) for pyelocalyceal solution. Updated March 2020. Accessed March 23, 2021.
6. 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.
7. UroGen Pharma.  Instructions for administration: JELMYTO. Accessed March 21, 20201.
8. UroGen Pharma. How to administer Jelmyto. Accessed March 23, 2021.
9. National Comprehensive Cancer NEtwork. Clinical Practice Guidelines in Oncology. Bladder cancer, version 2.2021. March 23, 2021. 
10. Intrado Global Newswire. Steba Biotech receives FDA Orphan Drug Designation for Padeliporfin ImPACT in Upper Tract Urothelial Cancer. Accessed March 23, 2021. 
11. Birtle AJ, Chester JD, Jones RJ, et al. Updated outcomes of POUT: A phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). J Clin Oncol 2021 39:6_suppl, 455-455.
12. UroToday. A Brief History of POUT & Three-year Updated Outcomes from A Phase III Randomized Trial of Peri-Operative Chemotherapy Vs. Surveillance in UTUC - Alison Birtle.  Accessed March 23, 2021.

Related Content:
Watch: Lancet Oncology OLYMPUS Trial Review: Primary Chemoablation for the Treatment of Low-Grade Upper Tract Urothelial Carcinoma
Watch: A Brief History of POUT & Three-year Updated Outcomes from A Phase III Randomized Trial of Peri-Operative Chemotherapy Vs. Surveillance in UTUC - Alison Birtle

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