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Mitomycin Gel for Low-Grade Upper Tract Urothelial Cancer: Seth P. Lerner, MD, FACS

Seth P. Lerner, MD, FACS.

Upper-tract urothelial cancer (UTUC) is a rare cancer that often needs to be treated with radical surgery, typically entailing complete removal of the affected kidney, ureter, and bladder cuff. Mitomycin C formulated with a reverse thermal hydrogel (JelmytoTM, UroGen Pharma), recently approved by the FDA as the first agent specifically indicated for the treatment of low-grade UTUC, will now allow some patients to keep a kidney that would otherwise have needed to be removed. In this interview with i3 Health, Seth P. Lerner, MD, FACS, principal investigator of the OLYMPUS study, on which the approval was based, discusses the benefits and adverse events of mitomycin C hydrogel as a treatment option for low-grade UTUC. 

Can you comment on the significance of the FDA's approval of mitomycin C hydrogel for patients with low-grade UTUC?

Seth P. Lerner, MD, FACS: This really represents the first approved treatment for patients with low-grade urothelial carcinoma of the renal pelvis, and it's delivering a chemotherapy drug, mitomycin C, with which urologists have a lot of experience in the lower urinary tract, treating similar tumors in the bladder. The novelty of this approval is that it addresses one of the challenges that we have in treating these tumors in the kidney pelvis: while we have an effective drug, it has been impossible to ensure retention of the drug for any length of time that would assure efficacy in ablating tumors that are often in difficult-to-reach regions of the kidney collecting system. That's the innovation and novelty of the reverse thermal hydrogel which is admixed with mitomycin: the drug is retained for somewhere between four to six hours, so it can be effective as a chemotherapy agent with minimal risk of systemic exposure.

Another significant benefit for patients is that these tumors are often very difficult to manage or ablate, even with our current state-of-the-art endoscopic techniques. We have the ability to navigate pretty easily with a small scope from the bladder to the ureter and up to the kidney, and we can visualize really well, but because of some of the limitations both of instrumentation and of the geography of the renal pelvis, a lot of these tumors are in very difficult-to-access locations. Often because of that alone, we have to remove the kidney, or in other circumstances, we need to remove the kidney because of a large-volume tumor that simply can't be managed endoscopically.

So the real benefit of mitomycin gel is that it gives patients who previously have not really had an option for endoscopic management or effective chemotherapy the opportunity to keep their kidney.

That's a tremendously important benefit! Would you like to comment on anything regarding the trial?

Dr. Lerner: We had a fantastic multicenter group of experts in endoscopic management of upper urinary tract tumors who were incredibly supportive and enthusiastic. These world-leading authorities and their patients who volunteered to participate really made this trial happen. It is a very positive reflection on the expert community, who came together to solve a very complex problem in a way that was incredibly professionally run and executed from start to finish. The sponsor UroGen had the foresight to develop this treatment concept for a rare disease and build and support a tremendous collaboration.

So let's discuss adverse events. Ureteric obstruction is a frequent adverse event with mitomycin gel. How should that risk be handled, and how is ureteric obstruction best managed when it does occur?

Dr. Lerner: There is an inherent risk of ureteric obstruction that is to be expected in patients who are getting repeated instrumentation. What does that mean? Ureteroscopy (URS) is used for visualization, biopsy for diagnosis, and ablation of low-grade tumors in the upper urinary tract using a variety of methods, including laser and electrocautery. This may require multiple procedures and often frequent surveillance with URS. Treatment in this trial was performed most frequently by passing a catheter from the bladder to the kidney weekly for six weeks, then monthly for up to 12 months for patients who had a complete response at the first URS evaluation. Every time the ureter is instrumented, there is always a risk of minor injury that may lead to scarring. So some of this ureteric obstruction risk with mitomycin C hydrogel is a reflection of that. There is also a chance that mitomycin may contribute to risk of edema or scarring.

For the most part, the majority of these ureteric obstructions were grade 1 or 2 events, which were generally manageable by placing a stent; some required dilation, and some patients required leaving a stent in for an extended period of time. These are procedures that are standard for urologists. Some of the investigators used a short course of steroids to try to ameliorate the stricture, thereby avoiding the potential for a more serious complication that could ultimately require kidney removal. There were some patients, however, who had refractory or recalcitrant strictures that were not amenable to these interventions, ultimately necessitating removal of the kidney. This means that it's very important for urologists to discuss this risk with patients who will be treated with mitomycin gel: how they will be monitored, what interventions may be required, and the fact that there is a small risk that ureteral obstruction could lead to a requirement to remove the kidney even if the treatment is effective in eliminating the cancer.

So this is something that we'll pay very close attention to post approval, and we will continue to work on strategies to minimize that risk. Some surgeons have preferentially used a size 5 French catheter for administration of the mitomycin gel, which is perfectly acceptable, although we did allow using up to a size 7 French catheter. Is it possible that the larger catheter somehow contributed to this? I don't know.

Are there any other adverse events that are of particular concern?

Dr. Lerner: There was very little in the way of evidence of systemic absorption, although a handful of patients developed low platelet counts, for example, which could be an effect of the chemotherapy drug on their bone marrow. Those were relatively infrequent, however. The main issue whenever we're dealing with instrumentation of the upper urinary tract is the risk of urinary tract infection. Meticulous attention to detail regarding verifying sterile urine before treatment and before any instrumentation will go a long way towards minimizing that risk.

About Dr. Lerner

Seth P. Lerner, MD, FACS, is Professor of Urology, Beth and Dave Swalm Chair of Urologic Oncology, and Vice Chair for Faculty Affairs in the Scott Department of Urology of Baylor College of Medicine, where he is also Director of Urologic Oncology. Dr. Lerner established and directs the multi-disciplinary Bladder Cancer Research Program at Baylor. His research interests include the use of selective estrogen receptor modulators for treatment of bladder cancer, gene therapy, integrated genomic analysis of bladder and upper urinary tract cancers, and outcomes of radical cystectomy and pelvic lymphadenectomy. He is the Chair of the Local Bladder Cancer Committee of the Southwest Oncology Group (SWOG), the founding and former Cochair of the NCI Bladder Cancer Task Force, and the current Cochair of the NCI Cancer Therapy Evaluation Program (CTEP) Genitourinary Steering Committee. In addition, he cochaired the Analysis Working Group of The Cancer Genome Atlas Project for muscle-invasive bladder cancer. He is a member of the Board of Directors and past Chair of the Bladder Cancer Think Tank of the Bladder Cancer Advocacy Network (BCAN), Cochair of the Management Committee of the Bladder Cancer Research Network, and a member of the American Association of Genitourinary Surgeons. Dr. Lerner has authored over 200 peer-reviewed articles and served as co-editor of a comprehensive Textbook of Bladder Cancer. He is a founding Coeditor-in-Chief of the journal Bladder Cancer.

For More Information

Kleinmann N, Matin S, Pierorazio P, et al (2019). Nephron-sparing management of low grade (LG) UTUC with UGN-101 (mitomycin gel) for instillation: the OLYMPUS trial experience. J Urol (AUA Annual Meeting Abstracts), 201(suppl_4). Abstract LBA-16. DOI:10.1097/01.JU.0000557508.23335.0a

Kleinmann N, Wirth G, Lin JS, et al (2019). Thermo reversible hydrogel based delivery of mitomycin C (UGN-101) for treatment of upper tract urothelial carcinoma (UTUC). Bladder Cancer, 5(1):21-29. DOI:10.3233/BLC-180182

Clinicaltrials.gov (2019). The OLYMPUS study - optimized delivery of mitomycin for primary UTUC study (Olympus). NLM identifier: NCT02793128.

JelmytoTM (mitomycin gel) prescribing information (2020). UroGen Pharma, Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211728s000lbl.pdf

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health or of the trial sponsor, UroGen.


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