Impact of the OLYMPUS Trial on Nephron-Sparing Management for Upper Tract Disease

In a recent interview for GU Oncology Now, David Ambinder, MD, a urology resident at New York Medical College/Westchester Medical Center, spoke with Katie S. Murray, DO, of the NYU Grossman School of Medicine, an esteemed expert in upper tract urothelial carcinoma (UTUC). Dr. Murray provided valuable insight into identifying the ideal candidates for kidney-sparing management of upper tract disease. She also discussed the phase 3 OLYMPUS trial, which analyzed the use of a mitomycin-containing hydrogel for patients with UTUC, and the characteristics and advantages of that treatment.¹

Ideal Candidates for Kidney-Sparing Management

Dr. Murray provided an overview of the recently released American Urological Association (AUA)/Society of Urologic Oncology (SUO) guideline for UTUC, which offers important recommendations for identifying ideal candidates for kidney-sparing management.¹ The guideline provides criteria for risk-stratifying patients, a process that can help determine prognosis and guide treatment discussions. Dr. Murray emphasized that kidney-sparing management is most appropriate for patients with low-risk disease.²

Patients with low-risk disease have negative urine cytology, no evidence of significant disease on imaging, including no hydronephrosis, and no other evidence of obstruction. On biopsy, patients with low-risk disease have no evidence of high-grade disease.

Patients are considered to have favorable disease based on focality, with multifocal disease tending toward a more unfavorable disease process. Patients with favorable disease are most optimal for kidney-sparing management. However, Dr. Murray also mentioned there may be a role for kidney-sparing management in select patients with unifocal high-grade disease who are not ideal candidates for nephroureterectomy.

Survival and Outcome Data

Dr. Murray emphasized that kidney-sparing approaches for upper tract disease have demonstrated favorable outcomes in terms of overall survival and cancer-specific survival. While the concept of organ sparing is not new, the AUA/SUO guideline provides clear recommendations for which patients would benefit the most from such approaches. Endoscopic ablation and percutaneous resection are common, but data from the OLYMPUS trial identified a game-changing addition to the treatment landscape.

Pre-OLYMPUS Trial Kidney-Sparing Management Approaches

Dr. Murray explained that, before the OLYMPUS trial, the methods used to manage nephron sparing for upper tract disease stemmed largely from what is known about treating bladder cancer. One optimal method involved endoscopic ablation with laser treatment followed by adjuvant therapy, typically with an aqueous solution containing chemotherapy. However, its effectiveness is limited due to dwell time.

Other options include placing a ureteral stent, retrograde placement of chemotherapy, and placement via a nephrostomy tube in an antegrade fashion. The dwell time has similarly been questioned with such approaches.

These less-than-effective strategies motivated the OLYMPUS trial, which introduced mitomycin hydrogel technology in 2020. UGN-101, a mitomycin gel, received approval from the US Food and Drug Administration specifically for low-risk upper tract tumors. The gel can be used as a chemoablative or as an adjunct to laser ablation.

Mitomycin Gel Characteristics and Administration

Mitomycin gel has a liquid consistency when it is received from the pharmacy and kept on ice. The solution, while cold, is completely aqueous, Dr. Murray explained. When instilled into the upper urinary tract, it transforms into a semi-solid gel due to the patient’s body temperature. The gel’s unique characteristics enable it to reach difficult-to-access areas, such as calyces, ensuring comprehensive coverage during treatment. The gel can be administered in either a retrograde or antegrade fashion, offering versatility based on patient preference and other considerations. It is typically administered after ablation and can be given in the ambulatory or office setting. Many urologists instill it in a retrograde manner via ureteral catheter, while others use a preplaced antegrade nephrostomy tube and instill via an antegrade approach.

Monitoring and Adverse Effects

Dr. Murray emphasized the importance of monitoring and managing adverse effects associated with kidney-sparing approaches. Ureteral and upper urinary tract strictures are potential complications, and patients need to be educated about the signs and symptoms to watch for, such as flank pain, fevers, and chills. Dr. Murray suggested that the risk of stricture is reduced when using a nephrostomy tube compared with ureteral catheterization.³

Intravesical Mitomycin C Instillation

While no trial supports the use of intravesical chemotherapy at the time of ureteroscopic ablation, Dr. Murray personally uses gemcitabine for patients with bladder recurrences. Intravesical chemotherapy is not an immediate adjuvant therapy, but rather a 6-week induction course given in an outpatient setting.

Advice for Implementing Mitomycin Gel

Dr. Murray reassured urologists, and specifically surgeons, who are thinking about implementing mitomycin gel that it should be considered an addition to their current practice rather than a replacement for surgery. She emphasized that the gel offers an extra option for patients who are not ideal candidates for nephroureterectomy and are seeking alternatives to reduce recurrence rates. Dr. Murray recommended discussing the therapy with patients and giving them the option of adding mitomycin gel to their treatment plan.

Conclusion

The AUA/SUO guideline offers recommendations for identifying ideal candidates for kidney-sparing management and mitomycin gel use, ensuring better outcomes for patients with UTUC. The introduction of mitomycin gel following the pivotal OLYMPUS trial expanded the available treatment options for this patient population, and the therapy has shown favorable survival rates. Urologists can incorporate this innovative approach into their practice as a valuable alternative to nephroureterectomy.

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.

References

1. Matin SF, Pierorazio PM, Kleinmann N, et al. Durability of response to primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel: OLYMPUS trial final report. J Urol. 2022;207(4):779-788. doi:10.1097/JU.0000000000002350
2. Coleman JA, Clark PE, Bixler BR, et al. Diagnosis and management of non-metastatic upper tract urothelial carcinoma: AUA/SUO guideline. J Urol. 2023;209(6):1071-1081. doi:10.1097/JU.0000000000003480
3. Linehan J, Gottlieb J, Woldu SL, et al. Route of administration for UGN-101 and impact on oncological and safety outcomes. Eur Urol Focus. 2023. doi:10.1016/j.euf.2023.05.012