An evaluation of mitomycin-containing reverse thermal gel for the treatment of low-grade upper tract urothelial carcinoma.

INTRODUCTION: Endoscopic management of upper tract urothelial carcinoma (UTUC) is increasingly relevant with greater detection of low-grade disease and guidelines recommending kidney preservation for low-risk disease. Historically, laser or thermal ablation has served as the primary tool for endoscopic management of UTUC, however, chemoablation is rapidly being developed to serve as a primary or adjuvant treatment option, which warrants review. AREAS COVERED: The current literature was reviewed to compare the outcomes and clinical utility of endoscopic treatment modalities for low-grade UTUC, with a focus on mitomycin-containing reverse thermal gel (UGN-101). EXPERT OPINION: The overall outcomes of mitomycin-containing gel therapy are promising, but adverse effects such as ureteral stricture call for careful consideration when using this treatment. We believe it is reasonable to consider use of mitomycin-containing gel as an adjuvant chemotherapy with endoscopic laser resection of low-grade upper tract urothelial carcinoma.

First analysis of the safety and efficacy of UGN-101 in the treatment of ureteral tumors.

OBJECTIVE: UGN-101 has been approved for the chemoablation of low-grade upper tract urothelial cancer (UTUC) involving the renal pelvis and calyces. Herein is the first reported cohort of patients with ureteral tumors treated with UGN-101. PATIENTS AND METHODS: We performed a retrospective review of patients treated with UGN-101 for UTUC at 15 high-volume academic and community centers focusing on outcomes of patients treated for ureteral disease. Patients received UGN-101 with either adjuvant or chemo-ablative intent. Response rates are reported for patients receiving chemo-ablative intent. Adverse outcomes were characterized with a focus on the rate of ureteral stenosis. RESULTS: In a cohort of 132 patients and 136 renal units, 47 cases had tumor involvement of the ureter, with 12 cases of ureteral tumor only (8.8%) and 35 cases of ureteral plus renal pelvic tumors (25.7%). Of the 23 patients with ureteral involvement who received UGN-101 induction with chemo-ablative intent, the complete response was 47.8%, which did not differ significantly from outcomes in patients without ureteral involvement. Fourteen patients (37.8%) with ureteral tumors had significant ureteral stenosis at first post-treatment evaluation, however, when excluding those with pre-existing hydronephrosis or ureteral stenosis, only 5.4% of patients developed new clinically significant stenosis. CONCLUSIONS: UGN-101 appears to be safe and may have similar efficacy in treating low-grade urothelial carcinoma of the ureter as compared to renal pelvic tumors.

Advances in chemoablation in upper tract urothelial carcinoma: overview of indications and treatment patterns.

Localized upper tract urothelial carcinoma (UTUC) is a difficult disease for clinicians to treat, due to the multitude of oncological and patient factors to consider. Despite the challenges of diagnostic staging, endoscopic management, and disease recurrence, there is still a need for local therapeutic options that do not subject patients to the morbidities of radical nephroureterectomy (RNU). Intraluminal chemotherapies have allowed for improved oncological control in patients with low-grade disease receiving renal-sparing treatment approaches. This narrative review discusses the treatment modalities available for localized low-grade UTUC, with a focus on the current status of chemoablation. The OLYMPUS trial was a pivotal study that lead to the Food and Drug Administration (FDA) approval of UGN-101 (mitomycin-C) in April 2020 for the treatment of low-grade UTUC, and intraluminal chemotherapy is now a widely used modality for managing this disease. The trial reported a complete response (CR) rate of 59%, and an estimated treatment durability of 82% at 1 year. However, a concern was the reported 44% ureteral stricture rate using the retrograde approach. More research is currently underway to determine the ideal instillation method for intraluminal therapies (e.g., retrograde vs. antegrade). Lastly, we discuss upcoming treatment options. Newer novel agents like padeliporfin vascular targeted photodynamic (VTP) therapy (brand name TOOKAD) are currently being studied, which will in hope provide additional treatment options for UTUC patients.

Intravesical Therapy for Upper Urinary Tract Urothelial Carcinoma: A Comprehensive Review.

Upper tract urothelial carcinoma (UTUC) poses unique challenges in diagnosis and treatment. This comprehensive review focuses on prophylactic intravesical therapy for UTUC, summarizing key aspects of intravesical therapy in various clinical scenarios, including concurrent with or following radical nephroureterectomy, kidney-sparing surgery, ureteroscopy-guided biopsy. The incidence of intravesical recurrence in UTUC after surgical treatment is significant, necessitating effective preventive measures. Intravesical therapy plays a vital role in reducing the risk of bladder recurrence following UTUC surgery. Tailoring timing, drug selection, dosage, and frequency is vital in optimizing treatment outcomes and reducing intravesical recurrence risk in UTUC. This review provides a comprehensive summary of the history, clinical trials, guideline recommendations, and clinical applications of intravesical therapy for UTUC. It also discusses the future directions based on current clinical needs and ongoing trials. Future directions entail optimizing dosage, treatment duration, and drug selection, as well as exploring novel agents and combination therapies. Intravesical therapy holds tremendous potential in improving outcomes for UTUC patients and reducing the risk of bladder recurrence. Although advancements have been made in UTUC treatment research, further refinements are necessary to enhance efficacy and safety.

Route of Administration for UGN-101 and Impact on Oncological and Safety Outcomes.

BACKGROUND: UGN-101 can be used for chemoablation of low-grade upper tract urothelial carcinoma (UTUC). The gel can be administered via a retrograde route through a ureteral catheter or an antegrade route via a nephrostomy tube. OBJECTIVE: To report outcomes of UGN-101 by route of administration. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of 132 patients from 15 institutions who were treated with UGN-101 for low-grade UTUC via retrograde versus antegrade administration. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival outcomes are reported per patient. Treatment, complications, and recurrence outcomes are reported per renal unit. Statistical analysis was performed for primary endpoints of oncological response and ureteral stricture occurrence. RESULTS AND LIMITATIONS: A total of 136 renal units were evaluated, comprising 78 retrograde and 58 antegrade instillations. Median follow-up was 7.4 mo. There were 120 cases (91%) of biopsy-proven low-grade UTUC. Tumors were in the renal pelvis alone in 89 cases (65%), in the ureter alone in 12 cases (9%), and in both in 35 cases (26%). Seventy-six patients (56%) had residual disease before UGN-101 treatment. Chemoablation with UGN-101 was used in 50/78 (64%) retrograde cases and 26/58 (45%) antegrade cases. A complete response according to inspection and cytology was achieved in 31 (48%) retrograde and 30 (60%) antegrade renal units (p = 0.1). Clavien grade 3 ureteral stricture occurred in 21 retrograde cases (32%) and only six (12%) antegrade cases (p < 0.01). Limitations include treatment bias, as patients in the antegrade group were more likely to undergo endoscopic mechanical ablation before UGN-101 instillation. CONCLUSIONS: These preliminary results show a significantly lower rate of stricture occurrence with antegrade administration of UGN-101, with no apparent impact on oncological efficacy. PATIENT SUMMARY: We compared results for two different delivery routes for the drug UGN-101 for treatment of cancer in the upper urinary tract. For the antegrade route, a tube is inserted through the skin into the kidney. For the retrograde route, a catheter is inserted past the bladder into the upper urinary tract. Our results show a lower rate of narrowing of the ureter (the tube draining urine from the kidney into the bladder) using the antegrade route, with no difference in cancer control.

Mitomycin Gel (UGN-101) as a Kidney-sparing Treatment for Upper Tract Urothelial Carcinoma in Patients with Imperative Indications and High-grade Disease.

BACKGROUND: Intracavitary UGN-101 is approved for the treatment of low-grade noninvasive upper tract urothelial carcinoma (UTUC). Post-commercialization studies underscore the benefit of UGN-101 administration for patients with imperative indications for whom radical nephroureterectomy (RNU) is not a viable option. OBJECTIVE: To describe the use, efficacy, and safety of UGN-101 in patients with UTUC with imperative indications for renal preservation, including high-grade disease. DESIGN, SETTING, AND PARTICIPANTS: Patients receiving UGN-101 with imperative indications were retrospectively analyzed using a multicenter centralized registry from 15 high-volume academic and community centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We defined imperative indications as patients with a solitary kidney, the presence of chronic kidney disease (CKD) with a glomerular filtration rate <30 ml/min, bilateral UTUC, and patients unfit for or unwilling to undergo surgical extirpation. Tumor characteristics, disease progression/recurrence, and adverse events were recorded on a per-renal-unit basis. RESULTS AND LIMITATIONS: UGN-101 was instilled into 52 renal units (38%) in 48 patients for imperative indications, including 29 patients (56%) with a solitary kidney, 11 kidneys (21%) in the setting of bilateral UTUC, six patients (12%) with CKD, and six patients (12%) who were unfit for or unwilling to undergo RNU. Twelve renal units had biopsy-proven high-grade papillary disease. Tumors were completely ablated before induction therapy in 34% of cases, while 66% had tumor present. Following induction therapy, 17 patients (40%) had no evidence of disease (NED) on ureteroscopy, 88% of whom maintained this status at median follow-up of 10.8 mo. In the cohort with high-grade disease, five patients (45%) had NED at initial post-induction primary disease evaluation. Adverse events included pyelonephritis (8%), ureteral stenosis (8%), anemia (6%), and acute renal failure (4%). Limitations include the retrospective study design, the lack of long-term follow up, and patient selection bias. CONCLUSIONS: Intracavitary therapy with UGN-101 in patients with UTUC and imperative indications shows promise as a kidney-sparing treatment modality. While long-term follow-up is needed, this intracavitary treatment may help in prolonging time to RNU and delaying the morbidity of hemodialysis in this comorbid population. PATIENT SUMMARY: We reviewed results for patients with cancer in the upper urinary tract and an additional condition that would not allow kidney removal who received treatment with a gel called UGN-101. Our results suggest that UGN-101 shows promise as a kidney-sparing treatment. It may delay the time until kidney removal is needed in these patients and avoid the negative effects associated with dialysis.

Early experience with UGN-101 for the treatment of upper tract urothelial cancer - A multicenter evaluation of practice patterns and outcomes.

BACKGROUND: UGN-101 is a novel delivery system for intracavitary treatment of upper tract urothelial cancer (UTUC). UGN-101 was approved based on a pivotal trial for small volume residual low-grade UTUC. Our aim was to report our experience with UGN-101 in a more heterogenous and real-world setting. METHODS: We performed a retrospective review of all UGN-101 cases from 15 institutions with a focus on practice patterns, efficacy, and adverse effects. We include UGN-101 utilization in both the chemoablative and adjuvant setting. RESULTS: There were a total 136 renal units treated from 132 patients. The majority of cases were biopsy proven low-grade UTUC. Practice patterns varied considerably - the most common administration technique was antegrade instillation via a percutaneous nephrostomy. When utilized in the adjuvant setting, 69% of patients were disease free at the time of their first endoscopic evaluation, while in the chemoablative setting, 37% were endoscopically clear on the first evaluation (P < 0.001). Complete response was higher in patients with smaller tumor size prior to UGN-101 induction; low volume (<1 cm) residual disease was associated with a 70% complete response, similar to disease free rate at first endoscopic evaluation when UGN-101 was used in the adjuvant setting. The use of maintenance doses of UGN-101 was reported in 27% of cases. The overall incidence of new onset, clinically significant ureteral stenosis was 23%. CONCLUSIONS: This study represents the largest review of patients treated with UGN-101 and can serve as a basis of ongoing hypotheses regarding treatment with UGN-101 for UTUC.

Pharmacokinetics of UGN-101, a mitomycin-containing reverse thermal gel instilled via retrograde catheter for the treatment of low-grade upper tract urothelial carcinoma.

PURPOSE: To evaluate the pharmacokinetic properties of UGN-101, a mitomycin-containing reverse thermal gel used as primary chemoablative treatment for low-grade upper tract urothelial carcinoma (UTUC), in a subset of patients participating in a phase 3 clinical trial. METHODS: Pharmacokinetic parameters (Cmax, Tmax, AUC(0-6), λz, t½, and AUCinf) were evaluated in six participants (male or female, ≥ 18 years) with biopsy-proven, low-grade UTUC who received the first of 6 once-weekly instillations of UGN-101 to the renal pelvis and calyces via retrograde ureteral catheter. Plasma samples were collected prior to instillation and 30 min, 1, 2, 3, 4, 5, and 6 h post-instillation. Safety was assessed by laboratory evaluations, physical exam, and adverse event monitoring. RESULTS: The mean age of the six participants was 69 years; most were male (5/6) and Caucasian (5/6). Mean (SD) Cmax was 6.24 (4.11) ng/mL and mean Tmax was 1.79 (1.89) hours after instillation. Mean apparent t½ following instillation was 1.27 (0.63) hours. Mean total systemic exposure to mitomycin up to 6 h post-instillation was 20.30 (19.69) ng h/mL. At 6 h post-instillation, mitomycin plasma concentrations of 5/6 participants were < 2 ng/mL. There were no clinically important adverse events or changes in laboratory values in any participant after a single instillation of UGN-101. CONCLUSION: The reverse thermal gel formulation of UGN-101 is associated with higher concentration and extended dwell time of mitomycin in contact with the urothelium of the upper urinary tract while limiting systemic absorption of mitomycin. REGISTRATION: NCT02793128; registered June 8, 2016.

An evaluation of UGN-101, a sustained-release hydrogel polymer-based formulation containing mitomycin-C, for the treatment of upper urothelial carcinomas.

INTRODUCTION: The treatment of low-grade upper tract urothelial carcinomas (UTUCs) after either surgery, or nephron-sparing techniques remains an unmet need in Genitourinary (GU) Oncology. UGN-101 is a novel drug in development for the treatment of UTUCs; it is composed of a sustained-release hydrogel polymer-based formulation containing the antitumor antibiotic mitomycin-C (MM-C); cold UGN-101 is liquid, but at body temperature, it becomes a gel, and thus, when administered through a ureteral catheter, it sticks to the upper tract urothelium, slowly releasing MM-C. AREAS COVERED: Here, the authors review the preclinical rationale for the development of UGN-101, as well as presently available clinical results for the treatment of low-grade UTUCs. EXPERT OPINION: The positive results of the recently completed OLYMPUS trial suggest the feasibility, activity (59% of complete responses, with just 6 of these complete responders on follow-up who recurred), and safety (68% of patients experiencing mild to moderate urinary adverse events) of UGN-101 instillations into the upper urinary tract. Our expectations are that UGN-101 will soon become a standard of treatment for low-grade UTUC at risk of relapse after either surgery, or nephron-sparing techniques.