From the Desk of the Editor: 2019 Updates in Upper Tract Urothelial Carcinoma

Sam Chang | October 08, 2019

Throughout 2019, we have continued to see progress in the diagnosis, risk assessment and genetic profiling, and possible treatment of upper tract urothelial carcinoma (UTUC). I would like to highlight some of the most exciting findings reported so far this year.

Targetable mutations in UTUC: At the Fred Hutchinson Cancer Research Center and the University of Washington, Dr. Brian R. Winters, Dr. Andrew

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Sam S. Chang, MD, MBA, Patricia and Rodes Hart Endowed Professor of Urologic Surgery and Oncology, is the Oncology Fellowship Director and Vice-Chair of Urologic Surgery at Vanderbilt University Medical Center. His clinical practice focuses on urologic oncology and he has led numerous guideline panels in prostate, bladder and kidney cancer and formerly chaired the American Joint Committee on Cancer GU Staging Task Force. Author of more than 275 articles and recipient of multiple awards such as the SUO’s first-ever Distinguished Service Award, a CaPCURE Prostate Cancer Young Investigator Award, multiple Journal of Urology Best Reviewer, and the AUA Gold Cystoscope Award, he currently serves as Assistant Secretary of the AUA.

Library Resources
Evidence based monographs by experts to define and guide clinical practice
Written by Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
December 10, 2019
The urothelium lines the urinary tract from the renal pelvis to urethra. While cancers may arise anywhere along the urothelium, the vast majority (90-95%) occur in the lower urinary tract (bladder and urethra) while the remainder (5-10%) occur in the upper tract (ureter and renal pelvis)1.
Written by Zachary Klaassen, MD, MSc
April 15, 2019
Upper tract urothelial carcinoma, comprising either the renal pelvis or ureter, is rarer than urothelial carcinoma of the bladder accounting for only 5-10% of all urothelial carcinomas. However, similar to bladder urothelial carcinoma, 
Written by Christopher J.D. Wallis, MD, PhD
January 29, 2019
Upper tract urothelial carcinoma (UTUC) comprises any malignancies arising from the urothelium between the level of the renal pelvis and the distal ureter. Owing to their relatively rarity, there is generally little data to guide the management of patients with these tumors and much of practice is extrapolated from the management of urothelial cancer of the bladder.
Expert Commentary
Evidence based monographs by experts to define and guide clinical practice
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Upper tract urothelial (UTUC) is an uncommon malignancy. Defining the impact of adjuvant chemotherapy on long term outcomes in UTUC patients is a critical clinical question. Recently, Birtle et al. reported
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
There is a need for a non-invasive for early detection of bladder cancer (BC). Telomerase reverse transcriptase (TERT) promoter mutations are common in bladder cancer patients. A recent study by Hosen
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Radical cystectomy continues to be the mainstay curative modality for bladder cancer patients. Understanding the long-term clinical outcomes of robotic and open radical cystectomy is critical for decision making.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The micropapillary and plasmacytoid variants are rare and aggressive urothelial carcinoma (UC) subtypes. The morphological features of these variants in urine cytology are not well described. A recent
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Defining the prognosis of patients who develop intravesical recurrence (IVR) after radical nephroureterectomy (RNU) is critical for the optimal management of these patients.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Effective intravesical postoperative chemotherapy can reduce the risk of bladder cancer recurrence. A recent study by Fukuokaya et al. published in Clinical Genitourinary Cancer examined
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The relationship between the baseline quality of life (QOL) and clinical outcomes for urothelial cancer (UC) patients is not well defined. A recent study published by Suppanuntaroek et al.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Intravesical recurrence (IVR) rates remain high in urothelial carcinoma of the upper urinary tract (UTUC) patients following radical nephroureterectomy
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Lynch syndrome (LS), caused by a mutation in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2). LS increases the individual’s risk of getting upper urinary tract urothelial carcinoma (UTUC).
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The optimal management of non-muscle invasive bladder cancer (NMIBC), some histologic variants, including squamous and glandular, is challenging. A recent article published by Suh et al. in Scientific
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
A significant number of patients with locally advanced and metastatic urothelial cancer (aUC) are not eligible for cisplatin-based chemotherapy.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Understanding the demographic factors which affect clinical outcomes following radical cystectomy (RC) is critical for improving oncologic outcomes for all patients. A recent study published in European Urology Oncology examined intraoperative
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Sarcomatoid urothelial bladder cancer (SARC) is an aggressive histological variant of bladder cancer. It is associated with early distant metastasis and poor survival rates. Understanding the molecular characteristics of SARC
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Non-muscle invasive bladder cancer (NMIBC) has a high recurrence rate. Understanding the risk factors for recurrence is essential. The Urokinase Plasminogen Activator (uPA)
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The American Urological Association (AUA) recommends that non-muscle invasive bladder cancer (NMIBC) patients with persistent or recurrent Ta or CIS should receive a second induction course of Bacillus Calmette-Guerin
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Treatment options available for intermediate or high-risk non-muscle invasive bladder cancer include intravesical Bacillus Calmette-Guerin (BCG) and radical cystectomy.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Point mutations in telomerase reverse transcriptase (TERT) promotor are reported in invasive and noninvasive, primary and recurrent urothelial bladder cancer (UBC). A deeper understanding of the clinical correlates
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The relationship between the expression of GATA3, cytokeratin (CK) 20, CK 5/6, and p53 and survival in patients with muscle-invasive bladder cancer (MIBC) is not well characterized.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Several randomized clinical trials (RCTs) have incorporated patient-reported outcomes (PRO) to evaluate the effectiveness of new treatment modalities. Adhering to systematic and consistent
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Urine cytology plays an essential role in detecting patients who are at high risk for disease recurrence following non-muscle invasive bladder cancer (NMIBC) treatment. A recent study Gupta
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Urine cytology plays a critical role as a noninvasive tool in bladder cancer detection and surveillance. However, a substantial fraction of cytology tests is classified as atypical or indeterminate. A need for a minimally-invasive
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Radiotherapy has the potential to sensitize tumors to immune checkpoint blockade. A recent article published by Sundahl et al. in European Urology assessed
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Enfortumab Vedotin (EV) is a novel antibody-drug conjugate targeting Nectin-4, which is overexpressed in urothelial cancer. A recent study published by Takahashi et al. in Investigational New Drugs
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Bacillus Calmette-Guerin shortage is a critical access issue for patients with non-muscle-invasive bladder cancer (NMIBC). Defining the efficacy of alternative intravesical treatments is an active area of investigation.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Understanding differences in bladder cancer outcomes between men and women can help physicians tailor optimal treatment and follow-up strategies. A recent paper published by Richters et al. in Urologic Oncology: Seminars and Original Investigations studied
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Patients with muscle-invasive and high-risk non-muscle invasive urothelial carcinoma of bladder who undergo radical cystectomy (RC) and lymphadenectomy are closely monitored for recurrence. The risk of disease recurrence is highest during the first 
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The oncogene addiction model occurs when cancer cells become dependent on one mutated oncogene or pathway for the maintenance of a malignant phenotype. Withdrawal of the oncogenic signal
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The optimal treatment for cisplatin-ineligible patients with metastatic urothelial cancer is unknown.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Patients who achieved a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have a better prognosis compared to patients with pathologic residual disease (pRD).
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Carcinoma in situ (CIS) is a distinct pathological entity. The significance of histological variants associated with CIS is not well-understood. A recent paper published by Sangoi et al. in The American Journal of Surgical Pathology
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The optimal treatment for patients with metastatic urothelial carcinoma (mUC) patients who are unfit to receive the standard cisplatin-based chemotherapy is uncertain.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
FGFR3 mutations are common in urothelial carcinoma. The APOBEC mutational process is the dominant mutational mechanism in bladder cancer.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Non-muscle invasive bladder cancers (NMIBC) represent the majority of new bladder cancer diagnoses. A high recurrence rate characterizes the natural history of the disease. Understanding the risk factors for recurrence
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
The use of circulating tumor DNA (ctDNA) as an early detection tool is a promising development. However, the clinical utility of ctDNA in urothelial bladder cancer is not fully understood.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
There is a broad spectrum of bladder cancer responsiveness to treatment in the clinic. The development of practical methods to provide accurate, individualized drug sensitivity information
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Detecting muscle-invasion is a critical step that dictates treatment recommendations. A definitive assessment of muscularis propria (MP) invasion cannot be made in a small number of transurethral resections of bladder tumor
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
A shortage of the Bacillus Calmette-Guérin (BCG) Connaught strain occurred between 2013-2016. 
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Perioperative chemotherapy is frequently underutilized. Understanding the trends in the utilization of neoadjuvant or adjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer (MIBC) undergoing cystectomy is critical.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
High-resolution micro-ultrasound is a promising technology in the staging of prostate cancer but has not been well studied in bladder cancer patients. A recent paper published by Saita et al. European Urology evaluated the
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Defining the genomic landscapes that characterize the different disease states of urothelial carcinoma is an important area of investigation. A recent study by Nassar et al. recently published in Clinical Cancer
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
There is not enough data on the prognostic value of sarcopenia and nutritional indices in bladder cancer patients who receive definitive radiotherapy. A recent paper by Stangl-Kremser et al. in Urologic Oncology studied
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
A recent study published by Guo et al. in BMC Systems Biology investigated the relationship between AURKA expression, clinicopathologic characteristics and overall survival in patients with bladder cancer using sequential gene expression profiling.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Micropapillary (MP) is a histological variant of bladder cancer. As with most other histological variants of bladder cancer, the available data is derived from small case series and treatment is based on expert opinion.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Bladder cancer is a ‘field’ disease in which early-events occurring in morphologically-normal urothelium eventually give rise to urothelial carcinoma.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Chromosomal damage, breakage, loss, and rearrangement are early events in cancer initiations.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Frequent long-term monitoring is required for non-muscle-invasive bladder cancer (NMIBC) patients due to the high rate of recurrence.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Bladder cancer takes an enormous physical, emotional and economic toll on patients.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Neoadjuvant chemotherapy followed by radical cystectomy (RC) with lymph node dissection is the standard of care in patients with muscle-invasive urothelial bladder carcinoma (MIBC).
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Although urothelial carcinomas of the bladder and upper tract urothelial carcinoma (UTUC) can have similar histology, they significantly differ in prevalence and risk factors.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Upper tract urothelial carcinoma (UTUC) is a distinct clinical entity with poor clinical outcomes.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Immune checkpoints inhibitors (ICIs) are approved as a second line of treatment for metastatic urothelial carcinoma (mUC) patients with progression on cisplatin-based chemotherapy.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Primary carcinoma in situ (P-CIS) of the bladder is rare. Adjuvant intravesical Bacillus Calmette-Guérin (BCG) immunotherapy has been reported to be effective in reducing recurrence rates in CIS and P-CIS patients 
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Patients with muscle-invasive bladder cancer  (MIBC) who are treated with neoadjuvant chemotherapy (NAC) before cystectomy have a survival advantage.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Although hematuria is the most common symptoms of bladder cancer (BC), it can be caused by many non-malignant conditions.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Radical cystectomy (RC) is currently the gold standard operative treatment for localized (T2-T4a) muscle-invasive bladder cancer (MIBC) or recurrent high-risk non-MIBC.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Downstaging of muscle-invasive bladder cancer (MIBC) following neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) has been correlated with higher survival rates.  
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
To achieve progress against Urinary bladder cancer (UBC), studies are needed to understand to understand the racial differences in the incidence, presentation, outcomes, and biology of UBC.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Lynch Syndrome (LS) is a common hereditary cancer syndrome that is characterized by mutations in the mismatch repair (MMR) genes.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Due to the very high risk of recurrence, bladder cancer patients require periodic screening and monitoring.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Non-muscle-invasive bladder cancer (NMIBC) has a high recurrence rate. Although the BCG therapy is recommended as an immune targeting treatment in high-risk NMIBC tumors, 
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Currently, intermediate or high-risk non-muscle-invasive bladder cancer patients (NMIBC) require intensive follow-up.
Written by Zhamshid Okhunov, MD
Department of Urology, University of California, Irvine Urology
Though nephrectomy is the gold standard treatment for renal cell carcinoma, 20%-40% of patients have a recurrence and 20-30% of patients present with metastatic disease1.
Written by Zhamshid Okhunov, MD
Department of Urology, University of California, Irvine Urology
As men get older, starting at the age of 30 years, their testosterone levels decrease by an average of 3.1 to 3.5ng/dL per year.
Written by Zhamshid Okhunov, MD
Department of Urology, University of California, Irvine Urology
Partial nephrectomies are the standard of care with treatment of T1a or T1b tumors due to their better functional outcomes and decrease cardiovascular morbidity.
Written by Zhamshid Okhunov, MD
Department of Urology, University of California, Irvine Urology
Laparoscopic renal surgery (LRS) has long been recognized for its improvements over open renal surgery for patient quality of life.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Neoadjuvant chemotherapy is a standard of care for patients with cisplatin-eligible muscle-invasive urothelial carcinoma.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Platinum-resistant urothelial carcinoma is a lethal disease. After a long period of therapeutic stagnation, the last two years have witnessed an explosion in the development of new second-line therapies.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Neoadjuvant chemotherapy is a standard of care for patients with urothelial muscle-invasive bladder cancer.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Bladder preservation therapy is a definitive treatment option for clinically localized bladder cancer.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Circulating tumor cells (CTCs) are cancer cells shed from the tumor that enter the circulation.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Clinically-localized bladder cancer is amenable to local treatments because of its accessibility.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Upper tract urothelial carcinoma is less common than bladder urothelial carcinoma. The biological characteristics of this form of the disease is not completely understood.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Patients with advanced platinum-resistant urothelial carcinoma have limited therapeutic options.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) neoadjuvant chemotherapy is a standard of care for muscle-invasive urothelial bladder cancer.
Written by Bishoy M. Faltas, MD
Englander Institute for Precision Medicine, Weill Cornell Medicine
Neoadjuvant chemotherapy is a standard of care for muscle-invasive bladder cancer (MIBC).
Upper Tract Urothelial Carcinoma Today
 
Curated content of advancements in upper tract urothelial carcinoma

Upper Tract Urothelial Carcinoma Today: 2019

Upper tract urothelial carcinoma (UTUC) comprises 5% to 10% of urothelial carcinomas, is distinct from bladder cancer, and often carries a worse prognosis — roughly 60% of patients present with invasive disease. Until recently, the relative rarity of UTUC and difficulties with accurate pre-operative staging impeded clinical trials and therapeutic progress.

Conference Coverage
Recent data from conferences worldwide
Presented by Chana Weinstock, MD
Washington, DC (UroToday.com) The expert panel of providers and FDA discussed ongoing and future collaborations with the FDA and bladder cancer. The FDA Oncology Center of Excellence (OCE) leverages the combined skills of regulatory scientists and reviewers. The panel reviewed the structure of the OCE and how expedited programs within the FDA strive to accelerate drug development and approval.
Presented by Seth Lerner, MD, FACS
Chicago, IL (UroToday.com) Low grade upper tract urothelial carcinoma (LG UTUC) can be managed with endoscopic resection/ablation however, the associated high recurrence rate requires repetitive intervention and intercavitary therapy for the frequently recurrent and multifocal disease.
Presented by Srikala (Kala) Sridhar, MD, MSc, FRCPC
Barcelona, Spain (UroToday.com)  Dr. Kala Sridhar, a medical oncologist from the University of Toronto, provided a summary of the current status of chemotherapy for upper tract urothelial carcinoma (UTUC).  UTUC accounts for 5-10% of urothelial malignancies, of which 60% are invasive at disease presentation. Radical nephroureterectomy remains the standard of care for localized and invasive disease.
Presented by Juan Palou, MD, PhD
Barcelona, Spain (UroToday.com) Upper tract urothelial carcinoma (UTUC) is a rare condition, making large clinical trials difficult to accrue for. More importantly, known concerns with the accuracy of pre-operative staging, and therefore, difficulties in accurately identifying high-risk patients...
Presented by Morgan Roupret, MD, Ph.D
Barcelona, Spain (UroToday.com) Upper tract urothelial carcinoma (UTUC) is a rare condition, making large clinical trials difficult to accrue for. More importantly, known concerns with the accuracy of pre-operative staging, and therefore, difficulties in accurately identifying high-risk patients make clinical trial accrual and accuracy difficult. As such, much of the data for UTUC is often extrapolated
Presented by Seth Paul Lerner, MD, FACS
San Francisco, CA (UroToday.com) -- UroGen Pharma Ltd., a clinical-stage biopharmaceutical company developing treatments to address unmet needs in the field of urology, with a focus on uro-oncology,  announced a new data presentation from an interim analysis of the ongoing pivotal Phase 3 OLYMPUS clinical trial of UGN-101 (MitoGel™),
Presented by Alison J. Birtle, MD, MRCP, FRCR
San Francisco, CA (UroToday.com) The management of patients with upper tract urothelial carcinoma (UTUC) is challenging due to the lack of high-level evidence, which results from the disease’s overall rarity. The standard of care for patients with high-grade disease or those suspected to have invasive disease is a radical nephroureterectomy,