Background
Upper tract urothelial carcinoma (UTUC), which may affect the renal pelvis or ureter, is a relatively rare disease accounting for less than 10% of all urothelial carcinomas.1 The etiology of this uncommon cancer is discussed in more detail in a previous UroToday Center of Excellence article.
While radical nephroureterectomy remains the gold standard treatment for patients with upper tract urothelial carcinoma, this approach may not be suitable for some patients and for some tumors. Certainly, for patients with a relatively low volume of low-grade tumors, complete surgical extirpation of a renal unit is likely over treatment.
A recent UroToday Center of Excellence article examined the indications for nephron-sparing approaches, as well as a number of approaches themselves. To briefly summarize, nephron-sparing approaches may be indicated for both imperative and elective reasons. While radical nephroureterectomy should still be considered on the basis of tumor characteristics in patients for whom this will render them dialysis-dependent, most imperative indications center on the risk of renal insufficiency: (i) a solitary functioning kidney, (ii) bilateral upper tract urothelial cancer, (iii) baseline renal insufficiency, (iv) poor candidacy for hemodialysis or renal transplantation, and (v) significant comorbidities. In addition to these imperative indications, elective nephron-sparing approaches may be considered for patients with low-risk/low-grade non-muscle invasive disease. Notably, as highlighted by the 2017 European Association of Urology Guidelines on upper tract urothelial cancer,2 ureteroscopic ablation of these tumors should not be utilized for patients with a high volume of tumor, even when it is low-grade, if complete resection is not feasible.
In patients for whom nephron-sparing approaches are being considered, a variety of techniques exist,3-5 including ureteroscopic and percutaneous surgical approaches. Ureteroscopically, some tumors are relatively or completely inaccessible, particularly those in the lower calyceal system.
As with urothelial carcinoma of the bladder, patients with non-invasive upper tract urothelial carcinoma have a high risk of recurrence when managed endoscopically. This is exacerbated, compared to non-muscle invasive bladder cancer (NMIBC), with the limitations of endoscopic resection in upper tract disease. In patients managed with ureteroscopic resection, in a systematic review of small (<100 patients) retrospective studies, Petros et al. found a pooled upper tract recurrence rate of 65% at 24-58 months median follow-up.3 In addition, bladder recurrence rates were high (44%). However, progression to radical resection occurred in only 0-33%. Rates of cancer-specific survival were high (70-100%) though overall survival was not as good (35-100%), reflecting the comorbidity profile of patients selected for this approach. Similar results were observed for patients managed with percutaneous surgery: comparably high local recurrence rates (40%) though somewhat lower bladder recurrence rates (24%).3
In patients with NMIBC, topical therapy (with Bacillus Calmette–Guérin (BCG) or chemotherapy) is well established in patients with non-muscle invasive bladder cancer as treatment with BCG has been shown to decrease rates of recurrence.6 As a result, this approach is both guideline-supported and widely adopted. In contrast, topical approaches have been much less widely used in patients with non-invasive UTUC. Dr. Nepple and colleagues undertook a review of topical treatment of UTUC, highlighting that upper tract treatment with intra-luminal agents can be problematic due to technical considerations of allowing surface contact.7 They describe an approach utilizing office-based flexible cystoscopy for ureteral catheterization followed by instillation of low-dose BCG with interferon. This approach was repeated weekly for six sessions. In their review of the literature, they identified eight studies reporting on the use of adjuvant topical therapy following endoscopic treatment with variable success rates.
In addition to instillation via a ureteral catheter, others have described instillation using percutaneous nephrostomy tubes and bladder instillations in the setting of indwelling ureteral stents with reliance on passive reflux.7,8 However, this is associated with a significant patient and healthcare system burdens and questionable efficacy. One of the primary challenges is difficulty concentrating therapeutic levels of these agents in the upper tract for more than a brief period of time as a result of rapid emptying of the renal pelvis and ureter.
Among agents used in urothelial carcinoma of the bladder, mitomycin C exposure time to the urothelium is critical for its efficacy.9 In order to improve the dwell time of mitomycin C in the upper tract, MitoGel™ was developed. MitoGel™ is a combination of mitomycin C with RTGel™, a reverse-thermal hydrogel composed of a combination of polymers that allows it to exist as a liquid at cold temperatures but solidify to a gel state at body temperature.10 This product was developed to address the constraints of the upper urinary tract, where continuous urine production and ureteral peristalsis prevents drug retention (when in liquid form) in the upper tract. The hypothesis for MitoGel™ is that upon delivery to the upper urinary tract, it would gelatinize and urine would produce a slow dissolution of the gel, allowing a sustained release of mitomycin C into the upper tract allowing prolonged exposure to the urothelium.
In a preclinical swine animal model, MitoGel™ remained visible in the upper urinary tract for four to six hours on fluoroscopic and computed tomographic assessment following antegrade instillation.10 Further, there was no evidence that this approach caused urinary obstruction, acute kidney injury, sepsis, or myelosuppression. These safety results were confirmed in a study assessing six once-weekly unilateral retrograde instillations of Mitogel™.11
Up until May 2018, Knoedler and Raman highlighted that there had been no significant advances in the topical treatment of patients with upper tract urothelial carcinoma over the past two decades.12 However, on December 19, 2019, UroGen Pharma Ltd. announced that the U.S. Food and Drug Administration had accepted filing and granted priority review for the New Drug Application for UGN-101. As of April 15, 2020, the United States Food and Drug Administration approved mitomycin (JELMYTO™) for the treatment of patients with low-grade upper tract urothelial cancer based on pre-publication results from the OLYMPUS Phase III study (NCT02793128). This represents the first agent specifically approved for this approach and indication.
OLYMPUS
While preliminary data for UGN-101 were presented by Dr. Lerner at the American Urological Association 2019 Annual Meeting in Chicago, the final results were published in Lancet Oncology on April 29, 2020. The remainder of this article will discuss this publication and contextualize the results.
OLYMPUS is a Phase III, open-label, single-arm trial designed to assess the efficacy, safety, and tolerability of UGN-101 in patients with low grade, noninvasive upper tract urothelial cancer. Patients were accrued at 24 academic sites in the United States and Israel. Eligible patients were adults (18 years of age or older) with either primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma of the renal pelvis or calyces, diagnosed in the two months prior to trial screening. Patients must have had a life expectancy of at least two years and adequate performance status (Eastern Cooperative Group performance status score less than 3 or Karnofsky Performance Status score of more than 40).
Importantly, patients must have had one or more low-grade lesions above the ureteropelvic junction measuring 5-15 millimeters in greatest dimension. Patients with lesions larger than this were eligible if they underwent “downsizing” via endoscopic treatment prior to initiation of treatment.
Patients with ureteral tumors or lower urinary tract (i.e. bladder) tumors were excluded unless these were completely endoscopically treated before starting treatment. Similarly, patients with bilateral tumors were eligible for inclusion only if one renal unit was removed (via radical nephroureterectomy) or completely endoscopically treated. Patients who received BCG in the six months prior to the start of the study (visit 1) were excluded, as were patients receiving systemic or intravesical chemotherapy.
The determination of resectability was made at baseline by enrolling surgeons with unresectable tumors typically due to difficult access to the lower pole of the kidney.
Additionally, patients were required to have adequate hematologic, hepatic, and renal function as evidenced by routine laboratory testing (WBC ≥ 3000 cells per µL, ANC ≥ 1500 cells per µL, platelets ≥ 100,000 per µL, hemoglobin ≥ 9.0 mg/dL, total bilirubin ≤ 1.5 x the upper limit of normal; aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x the upper limit of normal, alkaline phosphatase ≤ 2.5 x the upper limit of normal, and estimated glomerular filtration rate ≥ 30 mL/min.
Enrolled patients received six once-weekly instillations of UGN-101 as an induction course. This was administered via retrograde instillation with ureteral catheterization. The volume of UGN-101 administered was determined using the average of three fluoroscopic assessments of renal pelvic and calyceal volume. Notably, UGN-101 treatment was administered in a variety of settings including clinics, outpatient surgical centers, and operating rooms with both general and local anesthesia based on individual surgeon preference (nearly three quarters received local anesthesia or sedation without general anesthesia). Treatment was deferred among patients experiencing adverse events.
Four to six weeks following initial treatment, patients received their primary disease evaluation including ureteroscopy, selective upper tract cytology, and for-cause biopsy where indicated. Complete response was defined as a negative endoscopic evaluation and the absence of histologic or cytologic evidence of disease.
Patients who experienced a complete response were then offered ongoing monthly maintenance is offered for 11 instillations or until the first recurrence. Durability was assessed at 3-, 6-, 9-, and 12-months following initial treatment.
Among 110 patients screening, 74 were enrolled and 71 patients received treatment. As expected given the demographics of upper tract urothelial carcinoma, patients were predominately male with a median age of 71 years. The vast majority (87%) were white and 79% were current or former smokers. While 89% had two renal units at the time of enrollment, 11% had only a single unit due to congenital or therapeutic reasons. 30% of patients had a history of previous TURBT for bladder cancer and 52% of patients had previous renal ablative surgeries. Thus, in total, 87% of patients had undergone prior surgery for urothelial carcinoma.
At baseline enrollment, most patients had multifocal disease with a median of two lesions (range 1 to 8). Prior to endoscopic debulking, the median diameter of the papillary tumor was 14 millimeters (range 5 to 50 millimeters). Median total tumor burden, calculated as the sum of the largest diameters of each lesion, was 17 millimeters (range 5 to 65 millimeters). Notably, 34 patients (48%) had a tumor that was deemed unresectable based on being unreachable by laser.
Of the 71 patients who received at least one dose of the study medication, 61 completed the six treatments defining the initial treatment. Among those who discontinued treated, this was due to adverse events in nine patients and personal reasons in the remaining one.
Among the 71 patients who received at least one dose, 42 patients (59%, 95% confidence interval [CI] 47-71%) had a complete response at the time of primary disease evaluation. Of the remainder, eight (11%) had a partial response, 12 (17%) had no response, six (8%) had newly diagnosed high-grade disease, and three (4%) had an indeterminate response. The central histologic and cytologic evaluation led to similar complete response results (37 of 59, 63%).
Of the 42 patients with complete response, 41 entered follow-up. Of these, 29 (71%) received at least one dose of maintenance therapy and six (15%) were continuing on maintenance therapy at the time of data cut-off. Of the 23 patients who started but were no longer receiving maintenance therapy, reasons for discontinuation included adverse events in 10 patients, investigator discretion in 10 patients, patient non-compliance with the treatment regime in five patients, tumor recurrence in two patients, and logistical considerations in one patient.
Twelve-month durability could be assessed in 20 patients. Of these 20 patients, 14 (70%) showed ongoing durability of their complete response and six had a documented recurrence during follow-up. However, none of these patients progressed to high-grade or invasive disease. Among those with a complete response at primary disease evaluation, 84% (95% CI 71-97%) remained disease-free at 12 months. The median time to recurrence was reported as 13 months (95% CI 13 months to not estimable) though should be considered highly tenuous given six patients at risk at 12 months and one patient at risk at 13 months.
Subgroup analyses demonstrated stability of effect across patient demographics (age, gender, and body mass index), tumor characteristics (number of lesions before and after debulking, size of lesions before and after debulking, total tumor burden before and after debulking, tumor resectability), number of treatments received at initial induction (six or less than six), prior treatments for urothelial carcinoma, and prior treatments for upper tract urothelial carcinoma.
Despite these promising results, toxicity was not insignificant: 67 patients (94%) experienced adverse events, and 26 (37%) patients experienced severe adverse events. Sixty patients (85%) had adverse events that were deemed treatment-related and 19 (27%) had severe treatment-related events. Nineteen patients (27%) discontinued treatment due to adverse events both in the initial six-week treatment period (nine patients, 13%) and during maintenance (10 patients, 14%). Among adverse events of particular interest, renal functional impairment was noted in 14 patients (20%). There was also a significant burden of urinary tract morbidity: among 71 patients who received at least one dose of study medication, 48 patients (68%) had an adverse event related to the urinary system including 11 (23%) who did not require surgical intervention, 24 (50%) who required transient stent placement, 11 (23%) who required long-term stent placement (still in place at the time of data cut-off), and two (4%) who required nephroureterectomy due to the need for permanent drainage as a result of ureteral stenosis.
Conclusions
Radical nephroureterectomy, despite being the historical gold standard for patients with upper tract urothelial carcinoma, results in renal functional impairment as significant oncologic overtreatment in many patients with low-grade disease. However, endoscopic management of upper tract urothelial cancer, while technically feasible and offering a nephron-sparing approach, is associated with high rates of recurrence and non-insignificant rates of progression necessitating radical surgical treatment. Further, a significant proportion of tumors will be unresectable ureteroscopically due to anatomic location. Intra-luminal therapy is a mainstay in the treatment of non-muscle invasive bladder cancer but has not been widely used in patients with upper tract disease. The recently published Phase III OLYMPUS trial demonstrates both the feasibility of treatment with UGN-101, a unique hybrid of mitomycin-C and RTGel™, and promising oncologic outcomes. However, treatment with UGN-101 was associated with significant urinary tract morbidity.
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia
Published Date: May 2020
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Watch: Nephron-Sparing Management of Low-Grade UTUC with UGN-101 (Mitomycin Gel) for Instillation: The Olympus Trial Experience - Seth Lerner