Editorial Comment on: “Adjuvant Single-Dose Upper Urinary Tract Instillation of Mitomycin C After Therapeutic Ureteroscopy for Upper Tract Urothelial Carcinoma: A Single-Centre Prospective Non-Randomized Trial” by Gallioli et al.

Paucity of Data Supporting Intraluminal Therapy for UTUC

The use of mitomycin in the upper tract has been reported by several small series with widely variable recurrence rates ranging from 14% to 68%. ^{2 –7} The largest series of mitomycin patients to date was published by Metcalfe et al. in 2007. ⁸ Their cohort consisted of 28 renal units who, after endoscopic resection, were treated with induction followed by maintenance using both retrograde instillation through ureteral catheter and antegrade through nephrostomy tube. Despite this dual delivery method, the authors reported a 39% recurrence rate in their series of Ta/T1 patients.

There has been similar variability among patients receiving Bacille Calmette-Guerin (BCG). Rastinehad et al. ⁹ built upon the original series of percutaneous resection of upper tract urothelial cancers by Orihuela and Smith ¹⁰ and published the largest comparative study (133 renal units for 20 years) with adjuvant antegrade BCG therapy administered through a nephrostomy tube after percutaneous resection. ⁹ Despite the lengthy follow-up and study population size, the team demonstrated no benefit in terms of recurrence and progression rates with adjuvant BCG. A retrospective review has shown benefit only for patients with proven carcinoma in situ. These results were replicated and supported by a later series from Thalmann et al. using the same technique of 6 weekly perfusions of BCG through a 10F nephrostomy tube. ¹¹ However, other series using BCG as a topical adjuvant treatment failed to realize a benefit in decreasing recurrence for papillary tumors.

Selection Bias Affecting Results

The authors of the preceding study present some rather interesting results and conclusions that may be optimistic and a stretch considering existing data. ¹² The concern that arises when reading this study relates to selection bias when reviewing those treated with ASDM (a single dose of mitomycin) vs control. A critical reading of the methods and results reveals significant selection biases, which the authors do not sufficiently and convincingly discuss. Indeed, the study is not randomized, but the authors do not give enough details as to how the patients were selected for treatment or control. It appears from review of table that the patients with the most favorable parameters were more likely to be selected for adjuvant treatment (i.e., higher propensity for multifocal tumors to be relegated to control group, higher proportion of ureteral tumor location). In addition, when assessing multifocality, it may be best to provide an estimate of total tumor burden (i.e., aggregate size of tumors). As a result of the perhaps ideal patient population noted in the ASDM group, there was unsurprisingly a lower recurrence rate noted in the ASDM group vs that of the control. The authors of this study fail to explain the exclusion of five patients in the ASDM group who were selected for weekly upper tract instillations—as this may have contributed to poorer oncologic outcomes after only a single dose of intraluminal therapy (three of five patients included for weekly instillations after ASDM were noted to have “urothelial recurrence”). When including these patients, the urothelial recurrence rate of 31.8% appears more consistent with that previously discussed. Regardless, the results presented in this study will need to be replicated for a larger study population with lengthier follow-up to demonstrate benefit for adjuvant intraluminal therapy.

Variables in Endoscopic UTUC Management

Ultimately, the question that needs to be addressed is why the same advantages and efficacy realized with adjuvant bladder instillations are not replicated in the upper tract. Several variables come to light when examining this question: agent selection, agent dosage, agent delivery frequency/dwell time, and method of delivery. Another possibility includes inherent anatomic differences between the bladder and the upper tract: specifically functional differences (i.e., bladder as a storage organ vs the collecting system as a transit system) and/or perfusion patterns (i.e., higher propensity of variable perfusion and watershed areas in the collecting system vs richly perfused bladder urothelium).

Two studies have evaluated the questions of which method is best for delivery of anticarcinogenic agents into the collecting system. Pollard et al. published their results comparing retrograde infusion through an open-ended ureteral catheter, antegrade infusion through a nephrostomy tube, and reflux delivery through a double-pigtail stent in an ex vivo porcine model. Retrograde infusion through an open-end ureteral catheter resulted in the highest staining intensity in all six predefined points in the urinary tract. Their results showed that the mean percentage of surface area stained for the nephrostomy tube, double-pigtail stent, and open-ended ureteral catheter groups was 65.2%, 66.2%, and 83.6%, respectively (p = 0.002). ¹³ Likewise, Liu et al. performed a similar experiment comparing all three modalities in an in vivo porcine model and demonstrated similar results. ¹⁴ Although both studies suggest that retrograde infusion through ureteral catheter may be the best delivery method, human clinical studies have yet to confirm these experimental results.

Future Directions

One future treatment that has shown promise based on initial trials is sustained-release mitomycin gel (Mitogel Urogen Pharma, Princeton, NJ). Although it exists as a liquid thermosensitive polymer at low temperatures, it forms a viscous gel at body temperature resulting in sustained slow release allowing for prolonged contact of the mitomycin with the treated surface (Olympus Trial, Kleinmann et al., 2019) ¹⁵ The initial phase III trial consisted of six instillations through a ureteral catheter demonstrated a 59% complete response rate in patients with low-grade UTUC. In a preclinical study, the same agent (Mitogel) was shown to remain in the pelvicaliceal system for up to 6 hours. ¹⁶ Liourdi et al. evaluated tissue drug distribution after application of a paclitaxel drug-eluting stent in a porcine ureter model. They showed penetration into the muscle layer on immunohistochemistry and nuclear magnetic resonance spectroscopy analysis. ¹⁷

Another promising concept that has been published is biodegradable ureteral stent impregnated with commonly used anticancer drugs such as paclitaxel, epirubicin, doxorubicin, and gemcitabine. In vitro testing of the impregnated drugs showed 100% release in the first 72 hours for all but gemcitabine, and stent dissolution after 9 days. A cancer cell line (T24) exposed to the impregnated stent confirmed the antitumoral effect of all four drugs tested, reducing about 75% of the viability of the T24 cell line after 72 hours and minimal cytotoxic effect on human umbilical vein cell lines. ¹⁸ The further development of these devices may represent better ways of delivering the commonly used chemotherapeutic agents than the currently available methods.