Expert explains latest treatment developments in UTUC

The treatment paradigm in upper tract urothelial carcinoma (UTUC) is rapidly evolving, particularly with the FDA approving mitomycin gel (Jelmyto) in April 2020 as the first therapy to treat low-grade UTUC.

During the 2021 New York GU 14th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, hosted by Physicians’ Education Resource, LLC (PER®), Scott G. Hubosky, MD, discussed optimal treatment strategies for treating patients with upper tract transitional cell carcinomas, mostly focusing on use of mitomycin gel as adjuvant therapy, due to its ability to reach all surfaces of the luminal space of the upper urinary tract.¹

“We’re trying to see if we can extend our reach for conservative management,” said Hubosky, who is vice chair of quality improvement and safety of Jefferson University Hospitals in Philadelphia, Pennsylvania. “We were able to chemoablate these lesions; what this tells us is that we’re able to extend our reach with conservative management, and this is appealing.”

The FDA approved mitomycin gel based on results of the pivotal phase 3 OLYMPUS trial (NCT02793128),^2,3 which looked at patients with low-grade tumors who underwent weekly treatment for 6 weeks in the induction phase followed by a ureteroscopy evaluation for response. Patients were excluded if they had high-grade disease carcinoma in situ, received Bacillus Calmette-Guérin (BCG) or systemic chemotherapy, or had invasive urothelial tumors; those who were eligible had to have at least 1 papillary tumor between 5 and 15 mm in size. The primary end point was the number of patients with a complete response (CR) at the end of the treatment period.

The patient population on the study who completed therapy (n = 71) were mostly men (68%) and had a mean age of 70.7 years. About half (49%) had multiple tumors at baseline; 48% of patients were determined to have unreachable tumors at baselines.

“These patients were really optimized for this treatment to work. We measured their collecting system volume to make sure we had enough medicine for [each] unique patient,” said Hubosky. “We also alkalized their urine with sodium bicarbonate because we know that mitomycin works best in an alkaline ionized environment.”

Hubosky described the first of 6 administrations, which is done during surgery with a retrograde ureteral catheter and a retrograde pyelogram to ensure access to the collecting system appropriately. Then, a special syringe is used to inject the medication to the proper location.

At the primary disease evaluation, 42 patients achieved a CR (59%). At 12 months, 14 of 20 patients (70%) evaluated for follow-up remained disease free. In the patients who initially had tumors deemed to be endoscopically unresectable at baseline, 59% (20/34) achieved a complete response.

“Over time, as we go away from the primary disease evaluation, 3, 6, 9, and 12 months down the line, what you would expect is what you saw—that the complete response dwindled somewhat,” Hubosky said. “I just want to point out that this is just 1 years’ worth of data. We still have a lot of work to do in terms of what this is going to do over time.”

There were few (2.8%) life-threatening adverse events (AEs) of treatment noted in the trial that were not related to mitomycin-containing thermal gel or procedure. The most common AE was ureteric stenosis, leading to the need for a transient stent in 34% of patients. At the time of data publishing, 11% of patients still had stents placed, with 3% permanently stent dependent. Of noted, both patients with resulting permanent stents had nephrectomy and no residual carcinoma in pathology specimens.

According to the National Comprehensive Cancer Network guidelines, it is necessary to achieve complete or near complete endoscopic resection or ablation before administering mitomycin-containing reverse thermal gel since it is not a substitute for good endoscopic management, but rather an adjuvant therapy^.4

“I think that that needs to be appreciated because I worry that if this gets used without adhering to the guidelines, we’re not going to have outcomes that we want to see,” said Hubosky.

Other insights for UTUC management

For general management of upper tract urothelial tumors, Hubosky detailed considerations for this patient population.

A literature review representing over 1100 patients treated with endoscopic management of upper tract tumors found that the median ureter stricture rate was about 10%.⁵ “If you take a look at patients who get treated [by ureteroscopy] for kidney stones, the stricture rate is less than 1%,” Hubosky said. “It’s more than just ureteroscopic manipulation. Other things to keep in mind are the tumor locations; you’re more likely to get a stricture if you’ve got a primary ureteral tumor.”

Other concerns for avoiding ureter stricture include different energy sources, such as certain lasers that penetrate at a deeper level in the tissue. Hubosky recommended against using lasers that penetrate deeply in the ureter since many of these patients will see repeated procedures and manipulations of the tissue throughout the course of their disease.

Additionally, patients with Lynch syndrome tend to get tumors in the upper ureter more often than in the renal pelvis compared with patients who have sporadic upper tract tumors. “That’s going to put them at risk for ureteral strictures,” said Hubosky. “These patients have other things going on that really predispose them to ureteral stricture formation, such as other pelvic surgeries and pelvic radiation.” This is due to that fact that other cancers are likely present, such as colorectal cancer or endometrial cancer.

References

1. Hubosky SG. Upper urinary tract transitional cell carcinomas. Presented at: 2021 New York GU 14th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, hosted by Physicians’ Education Resource, LLC (PER®); Virtual.

2. FDA approves mitomycin for low-grade upper tract urothelial cancer. FDA. April 15, 2020. Accessed March 12, 2021. https://bit.ly/2xxaVMu.

3. 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

4. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 1.2021. Accessed March 12, 2021. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

5. Linehan J, Schoenberg M, Seltzer E, Thacker K, Smith AB. Complications associated with ureteroscopic management of upper tract urothelial carcinoma. Urology. 2021;147:87-95. doi: 10.1016/j.urology.2020.09.036