Background

Upper tract urothelial carcinoma (UTUC) remains a rare yet challenging disease to manage. Although overall population incidence is low at about 2 cases per 100,000 adults, among patients with urothelial tumors, upper tract tumors make up about 5% to 10% of diagnoses. Incidence is highest in men 70 to 90 years of age.¹ Radical nephroureterectomy with excision of the bladder cuff is the current standard of care for localized UTUC.² However, further complicating management is the estimated 22% to 47% risk of development of metachronous bladder cancer after treatment for UTUC.^1,3,4 Prior investigation by Svatek and colleagues demonstrates that this increases the overall cost of care due to increased intensity of postoperative surveillance and treatment in patients who develop later recurrence of urothelial carcinoma in the bladder.⁵ Many of us can envision this specific patient in our practice who has had a prior nephroureterectomy and now has burdensome disease in the bladder. However, data regarding factors associated with recurrence in this setting now point to receipt of intravesical chemotherapy in the perioperative period as a protective factor for bladder recurrence.

Evidence Supporting the Use of Perioperative Chemotherapy

Because of the risk of metachronous development of bladder cancer after nephroureterectomy, current National Comprehensive Cancer Network© (NCCN©) guidelines recommend consideration of perioperative intravesical chemotherapy at the time of nephroureterectomy.² This recommendation is informed by 2 contemporary studies. First, the results of the ODMIT-C (One Dose Mitomycin C) Trial published in 2011 demonstrated that a single postoperative dose of intravesical mitomycin C (MMC) reduces the risk of metachronous bladder cancer within a year of nephroureterectomy by an absolute risk reduction of 11% and a relative risk reduction of 40%. In this study, a single dose of MMC (40 mg in 40 ml of saline) was instilled into the bladder postoperatively at the time of urinary catheter removal. This therapy was well-tolerated overall with only 4% of patients unable to retain the intravesical chemotherapy for the required 1 hour indwelling time.⁶ Furthermore, a similar trial by Ito and colleagues published in 2013 examined the use of pirarubicin within 48 hours of nephroureterectomy versus no instillation in a randomized phase II clinical trial.⁷ This trial again demonstrated an advantage to perioperative instillation of chemotherapy, with recurrences occurring in 16.9% of patients at 1 year who received intravesical chemotherapy vs 31.8% in the control group.⁷ However, a 2017 study by Lu and colleagues demonstrated that 44% of surveyed urologists did not use intravesical chemotherapy at the time of nephroureterectomy, highlighting the lack of adoption of this treatment.⁸

Figure. Three-way Foley catheter set-up for intravesical chemotherapy instillation during nephroureterectomy. Use of a heavy clamp on the outflow tubing allows chemotherapy to be instilled safely through the catheter side port with a Luer lock syringe, and then flushed from the bladder later using a 3-liter saline bag attached to the inflow port. Photos courtesy of Dr. Jeffrey Holzbeierlein, Chairmain, University of Kansas Medical Center.

Current Investigation

At present, a third trial utilizing intravesical chemotherapy at the time of nephroureterectomy is underway. GEMINI is a multicenter, single-arm phase II study (NCT#04398368) that aims to enroll 90 patients with cTa-T4N0M0 UTUC. Enrolled patients will receive intravesical gemcitabine at the time of nephroureterectomy, and the primary end point will be 1-year intravesical recurrence-free survival. This end point will be assessed by cystoscopy at 3, 6, 12, 18 and 24 months and compared to historical rates of relapse for no treatment (30%). An important secondary end point will be time to recurrence in order to assess if use of intravesical gemcitabine delays recurrence in the bladder.⁹ This trial is expected to be fully accrued by 2023 and will likely add to the prior studies supporting use of intravesical chemotherapy. Use and benefit of intravesical gemcitabine at the time of nephroureterectomy is being extrapolated from randomized clinical trials in the nonmuscle invasive bladder cancer space which have shown excellent tolerability and similar response rates with gemcitabine compared to MMC.¹⁰

Method of Intravesical Instillation

At our institution and at many others, utilization of a 3-way Foley catheter apparatus can aid in perioperative instillation of intravesical chemotherapy. We typically perform these procedures either robotically or laparoscopically, and we begin preoperatively by placing a 3-way Foley catheter in a sterile fashion after anesthesia induction, as shown in the figure. This is then attached to a 3 L sterile saline bag for inflow using standard Y-tubing, and the catheter is attached to a drainage bag for outflow. Additionally, the outflow tubing is clamped with a heavy Kelly clamp. Once the patient has been fully positioned and laparoscopic access is established, the intravesical chemotherapy can then be instilled through the side port on the drainage tubing to fill the bladder in a retrograde fashion using a Luer lock syringe, and 100 to 200 cc of sterile saline can also be instilled to allow the bladder to fill. The catheter is then left clamped for 60 minutes during renal and ureteral manipulation and dissection. After 1 hour, the tubing can be unclamped under the drape allowing the bladder to drain, and the bladder can be irrigated with the remaining sterile saline. This allows uninterrupted operating and timely chemotherapy delivery with the assistance of perioperative staff. This method also limits the risk of chemotherapy spills or staff exposure with instillation and drainage into a completely closed system.

Recommendations

For patients undergoing nephroureterectomy, consider single-dose instillation of either mitomycin (40 mg in 40 ml of saline) or gemcitabine (2 g in 100 ml of saline) at the time of surgery. Data from prior studies demonstrates a benefit out to at least 10 days, although the perioperative period seems to offer the greatest opportunity for instillation with fewer logistical barriers. At our institution we favor gemcitabine due to safer handling, better tolerability and overall more favorable cost profile. Furthermore, use of a closed system during surgery with a 3-way Foley catheter can prevent drug delivery delay or omission and allows minimal handling of chemotherapy safeguarding perioperative staff. However, the best method for delivery is the one that ensures receipt of intravesical therapy, and I encourage you to examine your current practice patterns and make room for this high-yield intervention.