Risk Factors for Bladder Recurrence After Minimally Invasive Nephroureterectomy in UTUC, Journal Club- Christopher Wallis & Zachary Klaassen

January 19, 2022

Zachary Klaassen and Christopher Wallis discuss the ROBUUST collaboration publication entitled, “Risk Factors for Intravesical Recurrence After Minimally Invasive Nephroureterectomy for Upper Tract Urothelial Cancer (Robuust Collaboration).”  The objective of this study was to assess clinicopathologic risk factors for intravesical recurrence after radical nephroureterectomy for upper tract urothelial cancer in a completely minimally invasive cohort. Dr. Wallis gives a deep background on nephroureterectomies as well as intravesical recurrence. 


Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. We are discussing a recent publication from the ROBUUST Collaboration entitled, Risk Factors for Intravesical Recurrence after Minimally Invasive Nephroureterectomy for Upper Tract Urothelial Cancer.  I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia.

This is the citation for this recent publication in the Journal of Urology. Upper tract urothelial carcinoma represents about five to 10% of all urothelial cancers, and there is significant geographic variation due to the wide range in the prevalence of the risk factors. Notably, there's a 2:1 male to female predominance, and many risk factors are shared with bladder cancer, including smoking. However, there are additional unique risk factors, including environmental exposures and genetic predispositions.

Nephroureterectomy is the gold standard treatment for patients with high-risk upper tract disease. Traditionally, this has involved open radical nephroureterectomy with a bladder cuff excision. However, minimally invasive approaches, including both laparoscopic and robotic techniques, do not appear to compromise clinical or oncologic outcomes. However, regardless of surgical approach, intravesical recurrence is relatively common, ranging between 22 and 47%, depending on the study cited.

Intravesical recurrence may occur by at least two potential mechanisms. The first is a monoclonal origin in which a tumor derived from the upper tract has antegrade descent down into the bladder and seeds the bladder's subsequent development of tumors. Alternatively, there may be metachronous carcinogenesis from a field effect of carcinogens that affects the urothelium of both the upper tract and the bladder with subsequent development of bladder cancer. Ultimately, both may contribute, and the ultimate causation of any one specific tumor or tumor in one patient is difficult to ascertain and likely does not influence clinical decision-making.

However, we know that there are a number of identified risk factors for intravesical recurrence. These include patient-specific factors including male gender and preoperative renal dysfunction, tumor-specific characteristics, including positive cytology, ureteral location, multifocality, necrosis, and invasive disease, as well as treatment-specific approaches, including extravesical bladder cuff removal and positive surgical margins.

The goal of this study is to identify risk actors for intravesical recurrence in a large multi-institutional, international cohort of patients undergoing minimally invasive radical nephroureterectomy. This was performed in the context of the ROBUUST Collaborative, a group of 17 centers. Patients were included in this study if they underwent a laparoscopic or robotic radical nephroureterectomy between 2015 and 2019. Patients were excluded if they had a prior history of bladder cancer, a concurrent cystectomy, if they have had a combined robotic and laparoscopic approach, or if there is incomplete data necessary for covariates or outcome analysis.

The authors included data on patients' baseline characteristics, treatment outcomes, pathological outcomes, and oncologic outcomes. Details of each are highlighted here. But to note, these included all of the risk factors we had previously discussed for intravesical recurrence as well as many others that may be relevant. The authors descriptively characterized the study cohort and then undertook univariate analysis using log-rank tests and Cox Proportional-Hazard models to assess the association between each of these baseline characteristics as well as treatment-related characteristics with the development of intravesical recurrence. They then derived multivariable regression models using a variable screening approach to include their covariates.

Again, you can see included covariates here, which were hypertension, tumor size, ureteroscopy, ureteroscopic biopsy, the technique of bladder cuff management, use of adjuvant intravesical chemotherapy, pathologic grade, presence of tumor necrosis, surgical margins, and the use of adjuvant systemic chemotherapy.

At this point in time, I'm going to hand it over to Zach to walk us through the results of this study.

Zachary Klaassen: Thanks Chris. So this is the PRISMA flow chart of the selection criteria for this study. There were 870 patients in the ROBUUST database. There were 237 patients that were excluded for history of bladder cancer, 49 patients that were excluded for concurrent cystectomy, 86 patients that were excluded for incomplete records, ultimately resulting in 396 patients that underwent robotic radical nephroureterectomy, and 89 patients that had a laparoscopic approach.

These are the patient characteristics as you can see here in this Table 1. This is stratified by no recurrence versus recurrence. You can see that the mean age of these patients was roughly about 70 years of age. About two-thirds of patients were male, about 60% of patients were white and interestingly, almost 40% to 45% of patients claim that they were never tobacco users. In terms of ECOG performance status, pretty standard for this population, the majority were ECOG 0 or 1. Of note, I've highlighted in this box here that in patients with hypertension, 69% of those were in the recurrence group compared to 57% in the no recurrence group, which was statistically significant. In terms of diabetes, approximately 20% had diabetes, and the majority of patients had some level of chronic kidney disease.

This is the Kaplan-Meier survival curve for intravesical recurrence. You can see here that the intravesical recurrence rate was 22.7% over a mean follow-up of 20.5 months. The mean time to recurrence among these patients was 15.2 months with a standard deviation of 15.5.

This table looks at tumor characteristics and disease management in the univariable Cox Proportional-Hazard regression model. I've highlighted the key findings in this table with the red boxes. Looking at ureteroscopic biopsy, yes versus no, a hazard ratio of 1.49 and a 95% confidence interval of 1.00 to 2.20. When looking at transurethral resection of the bladder cuff, this was statistically significant looking at a hazard ratio of 1.95 and a 95% confidence interval of 1.03 to 3.66. Not surprisingly, surgical margins were also associated with intravesical recurrence positive versus negative with a hazard ratio of 3.36 and a 95% confidence interval of 1.36 to 8.33.

This is a multiple variable analysis looking at risk factors for intravesical recurrence. Putting all of these variables in the model, you can see here several important points in terms of hypertension with a hazard ratio of 1.99 and a 95% confidence interval of 1.06 to 3.71. Again, we see that transurethral resection had a hazard ratio of 2.73 and a 95% confidence interval of 1.10 to 6.76. Not quite statistically significant was again, the ureteroscopic biopsy with a hazard ratio of 1.93. And in the multivariable model, surgical margins had a hazard ratio of 2.43 but were not statistically significant.

So several discussion points from this ROBUUST analysis. This is the first large multi-institutional study to evaluate intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma in an exclusively robotic or laparoscopic cohort. They found that the intravesical recurrence rate was 22.7%, which is consistent with previous reports in the literature. As we noted, diagnostic ureteroscopy +/- biopsy remains controversial and may be associated with an increased risk of intravesical recurrence. So in these patients, we must weigh the risks and benefits of the benefit of this approach. Transurethral resection of the bladder cuff led to an increased risk of intravesical recurrence of 95%, a nearly threefold increased risk on the multivariable analysis. And possible mechanisms of this may be due to incomplete resection of the distal ureter or tumor spillage.

As we note in this study, hypertension for the first time was associated with intravesical recurrence. This has not been shown in the literature for the upper tract before, but it has been shown that diltiazem and ACE inhibitors have been associated with the risk of bladder cancer.

So in conclusion, in this minimally invasive cohort, several risk factors for intravesical recurrence were identified; patient-specific risk factors included a history of hypertension; treatment-specific risk factors included a ureteroscopic biopsy as well as transurethral resection of the bladder cuff; pathological risk factors included positive surgical margins, and ultimately, identifying and mitigating risk factors for intravesical recurrence is critical for oncological success in these patients with upper tract urothelial carcinoma.

Thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion.