Assessing the Efficacy and Safety of UGN-101 as an Adjuvant Therapy in UTUC

By David Ambinder, MD - Last Updated: May 1, 2023

According to a recent study published in the Journal of Urology, there may be an adjuvant indication for the use of mitomycin gel (UGN-101) in the treatment of upper tract urothelial carcinoma (UTUC).1 The European Association of Urology guidelines endorse endoscopic management as the primary treatment option for low-risk UTUC,2 but it has a high rate of disease recurrence.3 Adjuvant topical therapies such as bacillus Calmette-Guérin (BCG) and mitomycin C have been investigated in limited settings to address the high rate of recurrence.

The most studied adjuvant therapy is BCG; however, its use as an adjuvant therapy has not been shown to decrease recurrence for patients with papillary tumors.4 Intravesical mitomycin C is effective in preventing recurrence for bladder cancer,5 but its use for the management of UTUC has been questioned due to concern for dwell time within the upper tract and lack of a reservoir. Mitomycin C in a reverse thermal gel formulation, UGN-101 (JELMYTO), allows for longer contact time and has shown promise as a chemoablative agent for low-grade UTUC.6 Its use as an adjuvant treatment to complete endoscopic tumor ablation has not been described.

A multicenter, retrospective study investigated the efficacy and safety of UGN-101 as an adjuvant therapy after complete endoscopic tumor ablation and compared its outcomes with those of patients who underwent chemoablative UGN-101.

All patients enrolled in the study were diagnosed with UTUC of the ureter or renal pelvis by histology or cytology and underwent endoscopic tumor evaluation and entire ablation per operative report. Patients did not undergo confirmatory ureteroscopy prior to undergoing instillation of UGN-101. The authors noted that the number of instillations and modality, as well as surveillance, were determined by the treating physician and institution.

The study’s primary outcome was no tumor present, as seen by negative visual ureteroscopic assessment. If a biopsy was taken at the time of surveillance ureteroscopy and was negative, it was also considered to be negative for malignancy. Of note, contralateral disease or bladder recurrence was not considered to be a disease-free survival (DFS) event. The authors defined disease progression as any upgrade in tumor histology, increase in pathological staging, or development of metastatic disease. Ureteral stenosis was defined as a ureteral obstruction that required or would require stenting or nephrostomy tube placement.

The study included 132 patients, accounting for 136 renal units, who received UGN-101 therapy. A total of 115 renal units completed at least 1 post-therapy ureteroscopy and were used for primary oncologic efficacy analyses. Among them, 52 renal units had undergone complete ureteroscopic ablation before UGN-101 and were classified as adjuvant therapy. Of the patients who underwent adjuvant UGN-101, 85% had low-grade disease. A similar percentage of patients in the chemoablative intent cohort also had low-grade disease. The majority of patients (83%) undergoing adjuvant therapy received 6 instillations of UGN-101, and 25% underwent maintenance instillations, with a median of 3 additional instillations. A significantly larger percentage of patients received maintenance therapy (defined as monthly instillations after completion of induction therapy) in the adjuvant cohort than in the cohort undergoing chemoablative therapy.

The median time from beginning UGN-101 therapy to the first ureteroscopic evaluation was 2.8 months. At the primary evaluation, 69% of patients were without visible disease, and 29% had visible tumor recurrence. Two patients had indeterminate ureteroscopic findings, and 1 of those 2 patients was later confirmed to have high-grade recurrence on biopsy. Of the 9 biopsies taken at endoscopic evaluation, 2 cases had high-grade histology, 3 had low-grade recurrences, and 4 were benign. In cases where there was visual disease, the authors noted that there were no negative biopsies. The converse was also true: patients with a visually negative ureteroscopy did not have a positive biopsy or cytology. In cases with low-grade disease prior to UGN-101, 73% had no evidence of disease at the primary endoscopic evaluation compared with 50% of cases with high-grade disease.

Median follow-up after beginning adjuvant UGN-101 therapy was 6.9 months, and 37% of patients experienced recurrence after the primary ureteroscopic evaluation. Patients with high-grade disease had a recurrence rate of 62.5%. Disease progression was seen in 1 patient. No patients underwent nephroureterectomy, developed metastasis, or died of other causes during the follow-up period at time of database lock.

Multifocality was seen in 53% of patients in both the chemoablative and adjuvant cohorts and was investigated as a risk factor for ipsilateral DFS after UGN-101 in the adjuvant setting. Multifocality was associated with a higher risk of tumor recurrence, particularly in low-grade tumors.

After chemoablative UGN-101 therapy, 37% of patients were free of visible disease. When patients with visible or indeterminate disease were included, 40% had no evidence of disease after biopsy. There were significantly fewer evaluations with no evidence of disease in the chemoablative therapy cohort compared with the adjuvant cohort. When comparing renal units with incomplete tumor ablation prior to UGN-101 therapy, there were significantly fewer tumor events (persistent disease or recurrence) after adjuvant therapy.

Disease progression was seen in 19 cases in the chemoablative cohort and in 1 case in the adjuvant cohort. No patients underwent nephroureterectomy after complete endoscopic ablation followed by UGN-101, while 7 patients in the chemoablation arm underwent nephroureterectomy. Of the 23 cases receiving salvage therapy after UGN-101, 6 had undergone complete endoscopic ablation compared with 17 in the chemoablation arm. Four patients in the chemoablation arm died of urothelial carcinoma after disease progression.

Patients receiving adjuvant UGN-101 had fewer treatment delays (18% vs 35%) and lower rates of infectious complications compared with those receiving chemoablative therapy. Urinary tract infections were diagnosed in 4% of patients in the adjuvant cohort compared with 23% of patients in the chemoablative cohort. The use of antibiotic prophylaxis and indwelling ureteral stents was similar between the 2 groups. Administration of therapy was performed via percutaneous nephrostomy tube (adjuvant, 54% vs chemoablative, 34%) or retrograde ureteral catheter (adjuvant, 46% vs chemoablative, 66%). The incidence of ureteral stenosis (adjuvant, 19% vs chemoablative, 27%) and serious adverse events (adjuvant, 13% vs chemoablative, 11%) was similar between the 2 groups.

The study reviewed the use of mitomycin C in reverse thermal gel (UGN-101) as an adjuvant after complete endoscopic ablation of UTUC. The results showed that patients undergoing complete endoscopic ablation followed by UGN-101 had a higher rate of tumor-free first endoscopic evaluation and longer DFS compared with those undergoing a chemoablative approach. The study also found that there was no significant difference in ureteral stenosis rate surrounding therapy, and there were fewer urinary tract infections than with chemoablative treatment.

The authors emphasized that data reported in this paper “represent one of the largest adjuvant UTUC series to date and the largest using mitomycin C.” They observed an encouraging rate of complete response/no evidence of disease at first endoscopic evaluation and a low rate of recurrence in the limited follow-up. These findings are consistent with data from the OLYMPUS trial7, although monthly maintenance therapy after adjuvant UGN-101 was more frequent after complete endoscopic ablation, and it is unclear how significant that is. Further follow-up is needed to determine if the response after endoscopic ablation with adjuvant UGN-101 will have similar durability.

Multifocality was a risk factor for recurrence in patients with UTUC who underwent endoscopic ablation and adjuvant UGN-101. Multifocal tumors had an increased risk of recurrence compared with unifocal tumors, with unifocal low-grade tumors having the highest disease-free rates at primary ureteroscopy and while under surveillance. The authors suggested that this may be due to an increased per-patient likelihood of recurrence related to multiple tumor sites at risk for recurrence, or it could be potentially reflective of a field defect more apt for de novo tumor formation.

The study also reported a low rate of progression in patients treated by complete endoscopic ablation and adjuvant UGN-101, a finding that agrees with a contemporary series of total endoscopic ablation of low-grade UTUC with a progression-free survival of 93%. The authors concluded that further research is needed to determine the efficacy and long-term outcomes of UGN-101 as an adjuvant therapy after complete endoscopic ablation.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.



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