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An Update on Low-Grade Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinomas (UTUCs) are a heterogeneous group of malignancies arising from the urothelium at the level of the renal pelvis or ureter. They comprise 5% to 10% of all urothelial carcinomas and are diagnosed in approximately two per 100,000 persons in the United States annually, the majority of whom are adults older than 70 years.1-3  A significant percentage of UTUCs are low-grade; these primarily papillary tumors are substantially less aggressive than high-grade UTUCs and demonstrate a low rate of cancer-specific mortality, but hematuria and urinary obstruction are common and require management.4-6

Kidney-sparing approaches, such as endoscopic laser ablation of tumors, confer a similar rate of disease-free survival as radical nephroureterectomy among patients with low-grade UTUC, but endoscopy can be challenging to perform because of the potentially narrow ureteral lumen and the anatomic complexity of the calyceal system.6-9 Furthermore, the majority of patients develop recurrent disease that requires additional ablations and repeated anesthesia.7,9,10 For patients with multiple recurrences, the most definitive treatment alternative is radical nephroureterectomy, which increases the risk for subsequent renal insufficiency and is a more invasive procedure.10,11  Importantly, whichever treatment is taken, the contralateral upper tract and bladder remain at increased risk for developing urothelial carcinoma. 

For these reasons, chemoablation is seen as an attractive kidney-sparing option for the management of low-grade UTUC.6 In the bladder, low-grade urothelial carcinoma is known to be sensitive to the DNA alkylating agent mitomycin when used in the adjuvant setting after transurethral resection of bladder tumors (TURBT).12,13 Effective chemoablation requires an adequate period of contact time between tumor and drug, which aqueous solutions in the upper tract cannot achieve because they are rapidly diluted by continuous urine flow.14 In a recent meta-analysis of observational studies that described multiple instillation techniques and medications, patients who received adjuvant endocavitary instillations after kidney-sparing surgery for Ta-T1 UTUC had a similar rate of recurrence as previously reported rates among patients who undergo surgery without adjuvant treatment.14 Novel formulations and delivery systems that consistently address the problem of rapid dilution have not existed until recently.


JELMYTO (UGN-101) AND THE OLYMPUS TRIAL

JelmytoTM (formerly UGN-101) is the first nonsurgical therapy approved by the U.S. Food and Drug Administration (FDA) for the primary nonsurgical treatment of low-grade UTUC.15 It consists of a sustained-release formulation of 4 mg of mitomycin per mL of a sterile reverse thermal gel, a type of hydrogel that transforms from a viscous liquid when chilled to a solid gel at room temperature. This formulation enables mitomycin to be instilled into the upper urinary tract in liquid form.11 As it warms, it forms a gel depot that conforms to the renal collecting system, where it remains for approximately 4 to 6 hours before it is dissolved by normal urine flow.

The FDA approved Jelmyto based on the results of the phase III, single-arm, open-label OLYMPUS trial, which enrolled 74 adults with primary or recurrent biopsy-confirmed low-grade UTUC who had at least one papillary tumor measuring 5 to 15 mm in its longest dimension before or after debulking.11,15 (Note that this a distinct trial design in which tumors that could be resected were left in place to examine the effect of primary chemoablation.) The study, which was conducted at 24 academic sites in the United States and Israel, led to FDA fast track, breakthrough, and orphan drug designations for UGN-101.11,16

Patients in the OLYMPUS trial received six weekly instillations of UGN-101 administered under fluoroscopic guidance and were dosed based on the measured volume of the renal pelvis and calyces, with a maximum dose of 15 mL (60 mg mitomycin). Patients underwent ureteroscopy and wash cytology to assess the primary outcome of complete response, which was negative ureteroscopic evaluation at 3 months with negative cytology and negative for-cause biopsy (performed if visual inspection during ureteroscopy was suspicious for recurrent or persistent disease). Patients with complete responses were eligible to continue receiving monthly maintenance treatment with UGN-101 for up to 11 months. 

A total of 71 of the 74 patients received at least one dose of treatment, and 61 (86%) patients received all six doses. Complete responses at 3 months were observed 42 (59%) patients, of whom 41 remained on study for follow-up and 29 received at least one dose of maintenance therapy. Among 20 patients who were re-assessed at 12 months, 14 (70%) continued to show complete responses. A prespecified Kaplan-Meier analysis indicated that the median time to recurrence was 13 months.
In the OLYMPUS trial, 13% of patients stopped treatment because of adverse events. The most common treatment-emergent adverse event of any grade was ureteric stenosis (affecting 44% of patients), followed by urinary tract infection (32%), hematuria (31%), flank pain (30%), dysuria (21%), renal impairment (20%), and vomiting (20%). Most of these events were reported as transient and were graded as mild to moderate in severity. However, 50% of patients required short-term placement of a ureteral stent, 23% required long-term stent placement, and 4% (two patients) developed ureteral stenosis that would have required the placement of a permanent internal stent and instead chose to undergo radical nephroureterectomy. 

DISCUSSION: IMPLICATIONS AND QUESTIONS

In the OLYMPUS trial, 59% of patients with low-grade UTUC achieved complete responses to Jelmyto. The study was sufficiently powered to evaluate this primary endpoint, and the result was statistically significant (95% confidence interval, 47% to 71%; P < .0001). 

While this is an encouraging result, low-grade upper tract urothelial carcinoma tends to recur, although its chance for progression remains low. Hence, durability of response is crucial for any kidney-sparing treatment of low-grade disease. In the OLYMPUS trial, 70% of complete responders who were assessed at 12 months remained free from recurrence.11 As the investigators note, chemoablation of urothelial tumors treats the entire field of affected tissue, which might explain the high observed rate of responses at one year. However, the results need to be regarded with caution because less than half of complete responders were re-assessed at this time point. More data will be needed before we have a clear picture of response durability for Jelmyto.

Another question pertains to maintenance therapy. Because most patients in the OLYMPUS trial did not receive a full course of maintenance treatment,11 it is unclear how maintenance affects the durability of response. Some study participants demonstrated ongoing responses despite not receiving maintenance therapy, but data on these patients were not reported in detail, and the study was not designed to assess this subgroup. If patients experience a complete response to Jelmyto and are tolerating treatment, then maintenance therapy may prolong the duration of response, as is observed in urothelial carcinoma of the bladder.17,18 

However, the optimal dose, timing, and duration of maintenance treatment remain unclear. Most importantly, does every patient who responds require maintenance therapy? A corollary question would be: If a patient does not initially respond to Jelmyto, could prolonging therapy elicit a complete response?

The rate of stricture (44% overall; 9% for grade 3 or higher events) in the OLYMPUS trial is a true concern. Patients and families should be advised regarding possible treatment-emergent complications of Jelmyto therapy, particularly ureteric stenosis. They should be informed that serious cases of stricture could require long-term stent placement or even radical nephroureterectomy. It is likely that complications such as ureteric stenosis will become easier to avoid as clinicians accrue more experience with the use of Jelmyto, but stricture will remain a risk of this procedure that should be included in patient counseling.

The safety and efficacy findings of clinical studies have important implications for patient selection, especially when a therapy is newly approved for use outside the setting of clinical trials. In the OLYMPUS trial, participants had an Eastern Cooperative Oncology Group (ECOG) score of 0-2 (meaning that they were, at minimum, ambulatory and able to perform all self-care activities) and an anticipated life expectancy of at least two years.19 Patients had a median of two and up to eight papillary UTUCs; the diameter of each patient’s largest tumor was a median of 14 mm and up to 50 mm.11 Approximately half of trial participants had tumors that were unreachable for laser ablation, and the majority (62%) had recurrent UTUC. Based on these data, Jelmyto can be considered for patients with multiple UTUCs or tumors in locations that are difficult to access for laser ablation.  Based on the possible clinical risks and anticipated costs of Jelmyto therapy, laser ablation by itself may be the most appropriate initial treatment option for patients with solitary low-grade UTUCs.

Finally, clinicians should be aware of the risk for understaging and thus undertreating low-grade UTUC. Because Jelmyto is a more conservative therapy than radical nephroureterectomy, patients could be at risk for progressive disease, especially if high-grade disease is not detected. Biopsy specimens in UTUC can be quite small, increasing the risk of missing aggressive or invasive disease during pathologic examination. In a recent study of 480 patients with UTUC who underwent nephroureterectomy at the Mayo Clinic, 29% of tumors that were classified as low-grade on endoscopic biopsy were found to be high-grade on final pathology, and 38% were found to be invasive.20  Thus, patients should understand the risk of missing high-grade UTUC, which can lead to progression, and clinicians should attempt to provide as much pathologic verification of low-grade disease as possible.

PRACTICAL CONSIDERATIONS

I would like to briefly summarize a few practical points for clinicians who are considering integrating Jelmyto into their practices.
Regarding the procedure itself: Jelmyto is injected into the renal pelvis under fluoroscopic guidance with a UroJect12 Syringe Lever and a 5 or 7 French ureteral catheter with a molded Luer lock port.15,21 After Jelmyto fills and conforms to the renal collecting system, mitomycin is delivered for approximately 4 to 6 hours and excreted during normal urine flow. Treatment occurs once weekly for six weeks and can be performed in outpatient centers that are equipped with fluoroscopy. General anesthesia is not required, as local anesthesia and/or sedation is adequate for many patients.

Regarding preparation: proper setup is essential. Jelmyto must be kept cold to remain in liquid state—removing it from an ice bath and then pausing to search for instruments could result in the medication prematurely solidifying to gel form. If this occurs, the syringe must be re-cooled before it can be instilled, which will prolong the procedure time. 
Clinicians also will need to gain experience regarding the ideal location for placing and injecting the medication and determining the proper volume needed to fill the renal pelvis. The FDA-approved treatment volume is 15 to 60 mL; the average volume administered in the OLYMPUS trial was 54 mL.11,15 Clinicians should engage the experience of others, just as we do with any new procedure or medication we utilize. The manufacturer has created instructional videos on administering Jelymto that are helpful and important to view.21 In addition, it is advisable to observe a procedure, if possible. After performing a few procedures, however, clinicians should become quite adept at placing the medication in the correct location and in the proper amount. 

Finally, because low-grade UTUC is rare, no single clinician can expect to see a large number of these patients. When possible, it is ideal for a group practice to plan to have one or a few individuals who develop expertise and manage these cases for the group.

SUMMARY

Low-grade UTUC is associated with a low risk for mortality but causes hematuria and ureteral stenosis that requires treatment. Kidney-sparing endoscopic laser ablation is now a standard treatment option for this lower-risk patient group, but because many low-grade UTUCs recur, many patients ultimately undergo radical nephroureterectomy. In the multicenter, phase III OLYMPUS trial, 59% of patients with low-grade UTUC experienced complete 3-month responses when treated with multiple instillations of UGN-101 (now known as Jelmyto). Data on 12-month durability were encouraging, but loss to follow-up was a limitation of the study, and additional data on response durability and the role of maintenance therapy are needed. Most patients have tolerated Jelmyto well. The primary unique risk of treatment appears to be ureteral stenosis. The rate of grade 3 strictures in the OLYMPUS trial was 9%, and this rate could be higher, at least initially, in practice. Patients should be counseled regarding this risk and its sequelae. To optimize success, group practices may opt to have one or two individuals to develop expertise and perform these procedures for the group. The most suitable candidates for Jelmyto therapy are likely to be patients with multiple biopsy-confirmed UTUCs consisting of multiple tumors or tumors that are not accessible for laser ablation. For these patients, the availability of Jelmyto represents a step forward to preserve a kidney, avoid a major operative procedure, and help preserve renal function. 

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: August 2020.

References: 
  1. Rouprêt M, Babjuk M, Compérat E, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Cell Carcinoma: 2015 Update. Eur Urol. 2015;68(5):868-879.
  2. Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973-2005. BJU Int. 2011;107(7):1059-1064.
  3. Joshi SS, Quast LL, Chang SS, Patel SG. Effects of tumor size and location on survival in upper tract urothelial carcinoma after nephroureterectomy. Indian J Urol. 2018;34(1):68-73.
  4. 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.
  5. Syed JS, Nguyen KA, Suarez-Sarmiento A, et al. Survival outcomes for patients with localised upper tract urothelial carcinoma managed with non-definitive treatment. BJU Int. 2018;121(1):124-129.
  6. Raman J, Shore ND. Management of low-grade upper tract urothelial carcinoma: an unmet need. Rev Urol. 2020;22(1):1-8.
  7. Cutress ML, Stewart GD, Zakikhani P, Phipps S, Thomas BG, Tolley DA. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review. BJU Int. 2012;110(5):614-628.
  8. Petros FG, Li R, Matin SF. Endoscopic approaches to upper tract urothelial carcinoma. Urol Clin North Am. 2018;45(2):267-286.
  9. 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.
  10. Lin YK, Deliere A, Lehman K, Harpster LE, Kaag MG, Raman JD. Critical analysis of 30 day complications following radical nephroureterectomy for upper tract urothelial carcinoma. Can J Urol. 2014;21(4):7369-7373.
  11. 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.
  12. Au JL-S, Badalament RA, Wientjes MG, et al. Methods to improve efficacy of intravesical mitomycin C: Results of a randomized phase iii trial. JNCI: J Natl Cancer Inst. 2001;93(8):597-604.
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  14. Foerster B, D'Andrea D, Abufaraj M, et al. Endocavitary treatment for upper tract urothelial carcinoma: A meta-analysis of the current literature. Urol Oncol. 2019;37(7):430-436.
  15. U.S. Food and Drug Administration. JELMYTO™ (mitomycin) for pyelocalyceal solution. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211728s000lbl.pdf. Updated March 2020. Accessed June 24, 2020.
  16. U.S. Securities and Exchange Commission. FDA Grants Breakthrough Therapy Designation (BTD) for UroGen Pharma’s UGN-101 for the Treatment of Patients with Low-Grade Upper Tract Urothelial Cancer (LG UTUC). https://www.sec.gov/Archives/edgar/data/1668243/000119312518313813/d551584dex991.htm Published October 30, 2018. Accessed July 8, 2020.
  17. Hinotsu S, Akaza H, Naito S, et al. Maintenance therapy with bacillus Calmette-Guérin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer. BJU Int. 2011;108(2):187-195.
  18. Fukui I, Kihara K, Sekine H, et al. Intravesical combination chemotherapy with mitomycin C and doxorubicin for superficial bladder cancer: a randomized trial of maintenance versus no maintenance following a complete response. Cancer Chemother Pharmacol. 1992;30 Suppl:S37-40.
  19. ECOG-Acrin Cancer Research Group. ECOG Performance Status. https://ecog-acrin.org/resources/ecog-performance-status. Accessed July 7, 2020.
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  21. UroGen Pharma L. How to administer Jelmyto. https://www.jelmyto.com/hcp/administration/. Accessed July 6, 2020, 2020.

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