Nephron-Sparing Approaches in Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma, 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.

In parallel to how we view urothelial carcinoma of the bladder, the risk of recurrence and progression from upper tract urothelial carcinoma depends on tumor grade and stage. Unlike bladder cancer in which accurate grading and staging, distinguishing non-muscle invasive from muscle-invasive disease, can be obtained from transurethral resection of bladder tumor (TURBT), assessment of these characteristics is significantly more difficult in patients with upper tract urothelial carcinoma, due to the intrinsic limitations of ureteroscopic biopsy.2,3

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.

Nephron-sparing approaches in upper tract urothelial carcinoma may be indicated for imperative or elective reasons. Imperative indications include patients with contraindications for radical surgery such as (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. It should be noted that, in some circumstances, the approach management of a given patient will require radical extirpative surgery, rendering the patient dialysis-dependent. However, consideration should be taken whether it is feasible and safe to avoid this, taking into consideration both the oncologic risks of the tumor and the risks imposed by comorbidity. In addition to these imperative indications, patients with low-risk/low-grade non-muscle invasive upper tract urothelial cancer may be considered for nephron-sparing approaches.

According to the 2017 European Association of Urology Guidelines on upper tract urothelial cancer,4 ureteroscopic ablation of these tumors can be considered in patients with clinically low-risk cancer where the following criteria are also satisfied: (i) a laser generator and equipment is available for biopsies, (ii) when a flexible rather than rigid ureteroscope is available, (iii) the patient is informed of the need for earlier or closer surveillance, and (iv) complete tumor resection is achievable. Thus, this approach is not suitable 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.5-7 The most widely employed approach is ureteroscopic biopsy with laser ablation. This is feasible in many ureteral tumors and some in the renal pelvis. In addition, the EAU guidelines suggest that percutaneous ablation can be considered for low-risk upper tract urothelial cancer in the renal pelvis, particularly for tumors in the lower calyceal system that are inaccessible or difficult to manage by flexible ureteroscopy.

Finally, as with urothelial carcinoma of the bladder, patients with superficial high-grade upper tract urothelial carcinoma have a high risk of recurrence when managed endoscopically. This is exacerbated, compared to nonmuscle-invasive bladder cancer (NMIBC), with the limitations of endoscopic resection in upper tract disease. In patients with NMIBC, treatment with Bacillus Calmette–Guérin (BCG) has been shown to decrease rates of recurrence.8 Some authors have described BCG instillation using percutaneous nephrostomy tubes, repeated ureteral catheterization, or bladder instillations in the setting of indwelling ureteral stents with reliance on passive reflux.9,10 However, this is associated with a significant patient and healthcare system burden and questionable efficacy. To address these issues, MitoGel™ was introduced.11 MitoGel™ is a combination of mitomycin C, which has previously been used in the treatment of patients with urothelial cancer, and a polymer gel. This gel-based formulation allows for increased urothelial contact time, as compared with the instillation of liquid formulations. Each of these approaches will be discussed in more detail below.

Ureteroscopic Management

Endoscopic evaluation, typically by ureteroscopy, is crucial for the initial diagnosis, risk stratification, and subsequent treatment planning for patients with upper tract urothelial cancer. Ureteroscopy provides important information on tumor location, size, multifocality, and architecture. Further, endoscopic biopsy allows for tissue diagnosis. However, ureteroscopic biopsies can be technically challenging given the limited ureteroscopic biopsy instruments that can traverse the small working channel. Some have suggested that visual tumor characteristics may be sufficient to predict disease aggressiveness, with the notion that sessile-appearing tumors are more likely to be a higher grade and stage.12

One of the benefits of a ureteroscopic approach is that a single procedure can be both diagnostic and therapeutic. Following visual identification of the tumor and biopsy for histological diagnosis, laser resection and fulguration can be undertaken as a therapeutic approach. Although less readily available, electrocautery resection is also possible with a 10-13 Fr. rigid ureteral resectoscope (KARL STORZ Endoscopy, Tuttlingen, Germany); this scope allows resection of tumors similar to a loop used for transurethral resection of bladder tumors.5

Limited available data indicate that recurrence rates are high following endoscopic 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.5 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.

Percutaneous Management

Less commonly, antegrade percutaneous endoscopic treatment of upper tract urothelial carcinoma may be undertaken, particularly for patients with low-grade, large volume tumors that are either anatomically or technically challenging for ureteroscopic management, ie. lower pole tumors. This approach is particularly advantageous for patients that have had a prior cystectomy and urinary diversion in whom retrograde ureteral access is difficult. Additionally, the ability to use larger instruments, including a nephroscope with loop cautery, is beneficial. However, there are concerns regarding a theoretically increased risk of tumor seeding into the retroperitoneum.5

Data are similarly limited for this approach with comparably high recurrence rates (40%) though somewhat lower bladder recurrence rates (24%).5  

Emerging Novel Treatments

Perhaps the most interesting and exciting advances in the care of patients with upper tract urothelial carcinoma relate to the ability to provide intraluminal chemotherapy to reduce the risk of recurrence. Further, ureteroscopic and percutaneous approaches are poorly suited to patients with carcinoma in situ or diffuse multifocal disease.

In bladder cancer, the use of intravesical therapy has been proven to be particularly advantageous in this population. However, unlike the bladder in which intravesical instillation through a catheter is simple, it has taken much work to develop approaches for delivering topical agents in the upper urinary tract. 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.13 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 temperature11. 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, MitoGel 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.11 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™.14

Moving to the clinical space, MitoGel™ (UGN-101) is now being assessed in a prospective, single-arm randomized clinical trial, the OLYMPUS study (NCT02793128), designed to assess the efficacy, safety, and tolerability of MitoGel™ in patients with low grade, noninvasive upper tract urothelial cancer. Patients receive six weekly retrograde instillations. For those who demonstrate a complete response, ongoing monthly maintenance is offered for 11 instillations or until the first recurrence.

The trial reached accrual and is now awaiting publication. Early results were presented at the American Urological Association 2019 Annual Meeting in Chicago. To summarize Dr. Lerner’s presentation, the authors successfully accrued 71 patients. As expected with this disease, the majority (68%) were men, the mean age was 70.7 years, and many patients had multiple tumors (49%) and unreachable tumors (48%) at baseline. Among the 71 patients on trial, a complete response was seen in 42 (59%). Twenty-seven of these patients (66% of those experiencing a complete response) underwent six months of surveillance (of a planned 12 months) and 24 (89%) remained disease-free during these six months. Of the endoscopically unresectable cohort (34 patients, 48% of the cohort), 59% achieved a complete response and 85% remained disease-free at six-month follow-up. Mild adverse events (predominately hematuria) were experienced by 19 patients (27%); moderate adverse events (UTI and flank pain) by 17 patients (24%); and severe adverse events by 24 (34%). These severe events included patients who developed ureteral stenosis or hydronephrosis. Two patients had life-threatening events and three died while on trial (stroke, failure to thrive, sudden death).

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. Data presented in the press release indicate that, in addition to the data presented above, complete responses were sustained at 84% at 12 months (in addition to the previously reported rate of 89% at six months). The median time to recurrence was 13 months. Additionally, ureteral stenosis was reported in 47.3% of patients, with severe stenosis occurring in 8.5% of patients.

Conclusions

Endoscopic management of upper tract urothelial cancer is technically feasible and offers a nephron-sparing approach, at the risk of high rates of recurrence and non-insignificant rates of progression necessitating radical surgical treatment. The as-yet-unpublished Phase III OLYMPUS trial, along with other ongoing research, offers promise as a non-surgical treatment for patients with low-grade upper tract urothelial carcinoma.

Written by: Christopher J.D. Wallis, MD, PhD, Urology Resident and Epidemiologist, University of Toronto, Toronto, Ontario; Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia

Published Date: April 15th, 2020

Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
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