Upper Tract Urothelial Carcinoma: Updates in Local Treatment, Nephron Sparing Approaches, and Perioperative Chemotherapy

Upper tract urothelial carcinoma (UTUC) is a rare malignancy with an incidence of 1 case per 50,000 people in developed countries. Because symptoms are often non-specific, there are delays in presentation and diagnosis and, as a result, more than half of patients present with muscle-invasive or locally advanced disease.  The gold standard treatment for localized UTUC has been radical nephroureterectomy followed by surveillance.¹ However, as with bladder urothelial carcinoma, UTUC has a range of primary tumor aggressiveness, ranging from relatively indolent, superficial low-grade disease to the aforementioned locally invasive disease. Thus, not all patients may require nephroureterectomy. Further, due to renal dysfunction or other medical comorbidities, patients may not be fit for radical surgery. 

As a result of concerns regarding disease progression among those with more advanced tumors and over-treatment in those with less aggressive disease, there has been a simultaneous impetus for treatment intensification in those with more advanced tumors and developing less aggressive, less invasive treatment modalities.^2-4 This article will summarize advances in both domains, with a particular emphasis on nephron-sparing approaches for the management of localized disease, the utility of MitoGel in the management of localized UTUC, and the role of adjuvant chemotherapy for high-risk localized disease, including recently presented long-term follow-up and overall survival data from the POUT trial. 

Nephron Sparing Approaches

Nephron-sparing approaches in UTUC may be indicated for imperative, including patients with contraindications for radical surgery such as (i) a solitary functioning kidney, (ii) bilateral UTUC, (iii) baseline renal insufficiency, (iv) poor candidacy for hemodialysis or renal transplantation, and (v) significant comorbidities. 

Endoscopic evaluation, typically by ureteroscopy, is crucial for the initial diagnosis, risk stratification, and subsequent treatment planning for patients with UTUC. Information from endoscopy helps assess tumor location, multifocality, architecture and allows the clinician to obtain a tissue diagnosis. However, ureteroscopic biopsies can be technically challenging given the limited size and dexterity of ureteroscopic biopsy instruments that can traverse the small working channel. Some experts have advocated that the visual characteristics of the tumor may be able to predict disease aggressiveness, such as sessile-appearing tumors being more likely to be higher grade/stage ⁵. Several techniques for achieving a tissue diagnosis have been described, including multiple urine and washing samples and multiple quality biopsies to ensure sufficient tissue for pathological assessment; the most commonly used biopsy tools include the Piranha forceps (Boston Scientific, Marlborough, MA) and the biopsy forceps (Cook Medical, Bloomington, IN) ². For larger, papillary tumors, a stone basket (ie. nitinol) can be used for snaring and debulking the tumor.  

One of the benefits of a ureteroscopic approach is that a single procedure can be both diagnostic and therapeutic. When possible, use of a ureteral access sheath is ideal in that it allows atraumatic multiple insertions of the ureteroscope, especially important when encountered with a large tumor volume ⁶. Following multiple biopsies for tissue diagnosis, a laser can be used both for additional tumor resection and fulguration (for hemostasis) of the tumor bed. The most commonly used lasers are the holmium:yttrium-aluminum-garnet (YAG) laser and the neodymium-doped (Nd):YAG laser. The holmium laser is typically better suited for smaller tumors, however, it requires contact with the tissue in order to be effective. The Nd:YAG laser has a smaller wavelength, is able to penetrate deeper (5-6 mm), and does not require direct tissue contact. Although less readily available, electrocautery resection is also possible with a 10-13Fr 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 ².

Currently, there is no level I evidence assessing oncologic outcomes of patients undergoing ureteroscopic management of UTUC. Retrospective series to date are all limited to fewer than 100 patients. The largest retrospective series with more than two years of follow-up was published by Grasso and colleagues (n=82) ⁷ noting 81% recurrence rate in the upper tract, 57% in the bladder, 19% of patients progressing to surgical resection, and a 74% and 87% overall and cancer-specific survival rate, respectively. In general, ureteroscopic management of UTUC is associated with high risk of recurrence and a not insignificant rate of progression to more radical surgery.

Antegrade percutaneous endoscopic treatment of UTUC is typically reserved 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. A major benefit of percutaneous management is the ability to use larger instruments that are able to fit through a nephroscope, including loop cautery for debulking large tumors. All of the laser biopsy instruments listed above for ureteroscopic management are also feasible for the percutaneous approach. The primary risk of percutaneous management of UTUC (aside from those traditionally associated with percutaneous management of nephrolithiasis) is disruption of the urothelium, which may lead to a theoretically increased risk of tumor seeding into the retroperitoneum ².

Similar to ureteroscopic management of UTUC, oncologic outcomes have relied on retrospective studies of fewer than 100 patients. However, one study by Motamedinia et al. ⁸ identified 141 patients who underwent percutaneous resection with a median follow-up of 66 months. They noted that recurrence occurred in 37% of low-grade patients and 63% of high-grade patients, with a median time to recurrence of 71.4 vs 36.4 months, respectively. On multivariable analysis, grade was the only predictor of recurrence (HR 2.12, p = 0.018) and radical nephroureterectomy was avoided in 87% of patients. 

Local Treatment for UTUC

As a result of both high recurrence rates following endoscopic treatment and the inaccessibility of some tumors, there has been considerable interest in other local treatment approaches. While intravesical therapy (including BCG and mitomycin C) has been long established in bladder cancer, concerns with dwell time have limited its use in upper tract disease. 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 temperature⁹. 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.

Knoedler and Raman highlighted that, as of their publication in May 2018, there had been no significant advances in the topical treatment of patients with UTUC over the past two decades¹⁰. However, on December 19, 2019, UroGen Pharma Ltd. Announced that the U.S. FDA had accepted filing and granted priority review for the New Drug Application for UGN-101. As of April 15, 2020, the FDA approved mitomycin (JELMYTO^®) for the treatment of patients with low-grade UTUC based on pre-publication results from the OLYMPUS Phase III study (NCT02793128). This represents the first agent specifically approved for this approach and indication.

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 in April 2020.¹¹ OLYMPUS included patients 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 UTUC of the renal pelvis or calyces, diagnosed in the two months prior to trial screening. Importantly, patients must have had one or more low-grade lesions above the ureteropelvic junction measuring 5-15mm 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.

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 setting 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 histologic or cytologic evidence of disease. Patients who experienced a complete response were then offered ongoing monthly maintenance for 11 instillations or until first recurrence. Durability was assessed at 3-, 6-, 9-, and 12-months following initial treatment.

Among 110 patients screened, 74 were enrolled and 71 patients received treatment. As expected given the demographics of UTUC, 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 a solitary kidney 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 2 lesions (range 1 to 8). Prior to endoscopic debulking, the median diameter of the papillary tumor was 14mm (range 5 to 50mm). Median total tumor burden, calculated as the sum of the largest diameters of each lesion, was 17mm (range 5 to 65mm). Notably, 34 patients (48%) had tumor which was deemed unresectable based on being unreachable endoscopically.

Of the 71 patients who received at least one dose of the study medication, 61 completed the 6 treatments defining the initial treatment course. Among those who discontinued treatment, this was due to adverse events in 9 patients and personal reasons in the other. Among the 71 patients who received at least one dose, 42 patients (59%, 95% CI 47-71%) had a complete response at the time of primary disease evaluation. Of the remainder, 8 (11%) had a partial response, 12 (17%) had no response, 6 (8%) had newly diagnosed high-grade disease, and 3 (4%) had an indeterminate response. Central histologic and cytologic evaluation led to similar complete response results (37 of 59, 63%). Additionally, of the 42 patients with complete response, 41 entered follow-up. Of these, 29 (71%) received at least one dose of maintenance therapy and 6 (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 5 patients, tumor recurrence in 2 patients, and logistical considerations in 1 patient.

Twelve-month durability could be assessed in 20 patients. Of these, 14 (70%) showed ongoing durability of their complete response and 6 had a documented recurrence during follow-up. However, none of these patients progressed to high-grade or invasive disease. Among those with complete response at primary disease evaluation, 84% (95% CI 71-97%) remained disease-free at 12 months. Median time to recurrence was reported as 13 months (95% CI 13 months to not estimable) though should be considered highly tenuous given 6 patients at risk at 12 months and 1 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 (6 or less than 6), prior treatments for urothelial carcinoma, and prior treatments for UTUC.

Despite these promising results, toxicity was not insignificant: 67 patients (94%) experienced adverse events and 26 (37%) patients experienced severe adverse events. 60 patients (85%) had adverse events which were deemed treatment-related and 19 (27%) had severe treatment-related events. 19 patients (27%) discontinued treatment due to adverse events both in the initial 6-week treatment period (9 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 2 (4%) who required nephroureterectomy due the need for permanent drainage as a result of ureteral stenosis.

Practicing Changing Adjuvant Chemotherapy for UTUC: The POUT Trial

In contrast to efforts to decrease the morbidity of treatment in patients with low-grade disease, for patients with more advanced UTUC, disease progression is a significant concern and efforts have been made to intensify care. UTUC shares similar features to muscle-invasive bladder cancer, which has seen survival improvements for patients receiving platinum-based chemotherapy in both the neoadjuvant and metastatic settings.^12-14 Because of these similarities there is interest in applying chemotherapy in the perioperative time period for those undergoing radical nephroureterectomy for UTUC. Although neoadjuvant chemotherapy for UTUC seems like an attractive option given the feasibility of receiving chemotherapy with two renal units rather than one, there are concerns regarding this approach. Most importantly, there is unreliability with preoperative staging of UTUC, primarily relying on cross sectional imaging, which would likely over treat a number of patients that are <T2 disease. 

The POUT trial was a phase III, parallel-group, open-label, randomized controlled trial done at 71 National Health Service (NHS) hospitals in the United Kingdom.¹¹ Eligible patients were ≥16 years, had received a radical nephroureterectomy for UTUC, were postoperatively staged with either muscle-invasive (pT2–pT4, pN_any) or lymph node-positive (pT_any, pN1–3) M0 disease with predominantly transitional cell carcinoma histology, and were fit to receive adjuvant chemotherapy within 90 days of surgery. Patients also had to have a glomerular filtration rate (GFR) of ≥30 mL/min. Prespecified stratification factors included platinum chemotherapy agent (cisplatin vs carboplatin), preoperative radiologically or pathologically assessed nodal involvement (N0 vs N1 vs N2 vs N3), status of surgical margins (positive vs negative), and treatment center. Patients were randomized 1:1 to receive either surveillance or adjuvant chemotherapy: four 21-day cycles of platinum-based chemotherapy (cisplatin 70 mg/m²) within 14 days of randomization; gemcitabine (1000 mg/m²) given on days 1 and 8 of each cycle. Patients with impaired renal function (GFR ≥30 mL/min but <50 mL/min) received carboplatin rather than cisplatin. 

Patients were followed at 3, 6, 9, and 12 months, then every 6 months to 36 months from randomization, and annually thereafter. The radiographic assessment included CT of the thorax, abdomen and pelvis at 3, 6, 9, 12, 18, 24, 30, and 36 months, then annually to 60 months. Cystoscopy was done every 6 months to 24 months, then annually up to 60 months after surgery. Toxicity was assessed by CTCAE v4.  Furthermore, this was the first trial in UTUC to collect patient-reported outcomes: patients filled out the EORTC quality-of-life of cancer patients questionnaire (QLQ-C30) and the EuroQol five dimensions five levels questionnaire (EQ-5D-5L) at baseline and before cycle three and at 3, 6, 12, and 24 months after randomization. The primary endpoint of this trial was DFS defined as time from randomization to either first recurrence in the tumor bed, first metastasis, or death from any cause. Secondary endpoints included metastasis-free survival, overall survival, treatment compliance, acute toxicity, late toxicity, and patient-reported quality of life. The trial was powered to detect a hazard ratio of 0.65 (i.e. improvement in 3 year DFS from 40% to 55%; 2-sided alpha=5%, 80% power) with Peto-Haybittle (p<0.001) early stopping rules for efficacy and inefficacy. 

There were 261 patients included in the trial between June 19, 2012 and November 8, 2017 at 57 of the 71 participating centers in the UK, including 129 patients randomized to surveillance and 132 to chemotherapy; 260 patients were included in the intention to treat analysis. In October 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected to date met the early stopping rule for efficacy. Included patients were a median 68.5 years of age (IQR 62.0-74.1 years). With respect to tumor characteristics, 94% of patients had pT2-T3 disease and 91% were N0. The median follow-up was 30.3 months (IQR 18.0-47.5 months). There were 7 of 131 patients allocated to chemotherapy that did not start treatment and 75% of those that started chemotherapy received four cycles. There were 60 (47%) DFS events in the surveillance cohort and 35 (27%) in the chemotherapy cohort; as such, the unadjusted HR was 0.45 (95%CI 0.30-0.68) in favor of chemotherapy (log-rank p = 0.0001). The three-year disease-free survival rate was 46% for surveillance (95%CI 36-56) and 71% for chemotherapy (95%CI 61-78). Metastasis free survival also favored chemotherapy, with a HR of 0.48 (95%CI 0.31-0.74, log-rank p = 0.0007), and the three-year event-free rates were 53% (95% CI 42-63) for those on surveillance and 71% (95% CI 60-79) for those receiving chemotherapy. 

Grade ≥3 toxicities were reported in 44% of chemotherapy patients and 4% of surveillance patients (p < 0.0001). During the treatment period, the most common grade ≥3 toxicities in chemotherapy patients were neutropenia (36%) and thrombocytopenia (10%). Analysis of late toxicity is planned after 2-year follow-up of all patients. Quality of life questionnaires were returned by 95% of patients at baseline (95% of those allocated to surveillance and 95% of those allocated to chemotherapy), 82% at 3 months (81% of those allocated to surveillance and 82% of those allocated to chemotherapy), and 70% at 12 months (70% of those allocated to surveillance and 70% of those allocated to chemotherapy). The mean overall global health status score at baseline was 77% (standard deviation 19) for the chemotherapy group and 76% (standard deviation 19) for the surveillance group. Subsequently, the overall global health status was lower during chemotherapy (before cycle 3) and immediately afterward (at 3 months) in participants allocated chemotherapy versus surveillance, however, the difference resolved by 6 months of follow-up.

Updated Follow-up and Overall Survival Data from the POUT Trial

At the 2021 GU ASCO annual meeting, Dr. Birtle and colleagues presented updated results of the POUT trial.¹⁵ Over a median follow-up of 48.1 months (IQR: 36.0-60.1), the unadjusted hazard ratios for disease-free survival was 0.51 (95% CI 0.35-0.76; p = 0.0006) and for metastasis-free survival was 0.52 (95% CI 0.36-0.77; p = 0.0007). There were 93/260 (35.8%) patients that died (52/129 [40.3%] surveillance and 41/131 [31.3%] chemotherapy) during follow-up. Chemotherapy conferred a non-statistically significant 30% reduction in relative risk of death (HR 0.70, 95% CI 0.46-1.06; p = 0.09):

The 3-year overall survival rate for surveillance patients was 67% (95% CI 58-75%) and 79% for chemotherapy (95% CI 71%-86%). There was no evidence of long-term toxicity associated with chemotherapy, and the most common grade 2+ adverse events were hypertension (10.4%), lethargy (10.4%), and hearing loss (5.4%). There was no evidence of statistically or clinically relevant differences in quality of life 12 months after treatment (EORTC Q30 global health status mean difference 4.1 and 4.8 at 12 and 24 months, respectively, in favor of chemotherapy). This updated analysis of POUT confirmed the benefit of adjuvant chemotherapy on disease-free and metastasis-free survival with longer-term follow-up, as well as demonstrating a non-statistically significant improvement in overall survival. 

Conclusion

Endoscopic management of UTUC is technically feasible but associated with high rates of recurrence and non-insignificant rates of progression necessitating radical surgical treatment. Endoscopic management should be reserved for low-grade tumors and patients that have contraindications to radical nephroureterectomy. Publication of the OLYMPUS trial has demonstrated the feasibility of MitoGel for patients with low-grade UTUC, however, the ureteral stricture rate for these patients is not insignificant. The POUT trial showed an improved disease-free survival benefit for adjuvant chemotherapy, showing durability with extended follow-up and a signal for overall survival benefit (although not statistically significant). Encouragingly, the last several years have demonstrated that clinical trials are feasible in UTUC, both in the local, nephron-sparing space and in the adjuvant chemotherapy setting.