A New Resource for Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma is a heterogeneous disease that can be challenging to diagnose, treat, and survey. Its relative rarity has hampered its study in large prospective trials, and therapy has been guided primarily by retrospective data or by trials of urothelial bladder cancer, which we now know to be genetically and molecularly distinct.1-4 The location of upper tract urothelial carcinoma has made it difficult to collect high-quality biopsy specimens. Moreover, it is an insidious disease—the least obvious tumors can be the most dangerous, and those that appear obvious can be the most benign. For all these reasons, patients often are overtreated or undertreated, undermining quality of life and disease-free survival.

Fortunately, we are starting to see real progress in upper tract urothelial carcinoma. Our diagnostic realm has expanded from detection of gross or microscopic hematuria and a filling defect seen on urogram to current options for next-generation sequencing and molecular subtyping of visually biopsied tumor samples.5-10 Technical advances and improved training have made it possible to collect larger and higher-quality biopsies.11 We have hope from studies such as POUT, in which adjuvant chemotherapy improved disease-free survival in pT2-T4 N0-3 M0 disease, and URANUS, which will compare neoadjuvant versus adjuvant chemotherapy.12,13 Such studies have shown that it is possible to accrue upper tract urothelial carcinoma trials and have spurred interest in studies of novel diagnostics and more tolerable therapies, such as immune checkpoint inhibitors and FGFR3 inhibitors.14 Hopefully, we will soon be able to optimally combine surgery with medical therapy and adapt treatment based on risk of recurrence, progression, and metastasis.

As vice-chair of urologic surgery at Vanderbilt University Medical Center, my practice focuses on urologic cancers, predominantly of the prostate, bladder, and kidney. I have helped create AUA and SUO guidelines for each of these diseases, and yet in the United States, we so far lack corresponding guidelines for upper tract urothelial carcinoma. As urologists and medical oncologists, we are left grappling with many questions. Are there helpful urinary biomarkers for upper tract urothelial carcinoma? What is the best way to diagnose disease and determine the risk of progression and recurrence? How do genetic and molecular variants affect risk and therapeutic options? Which are the best surgical therapies to avoid both under and overtreatment? What about neoadjuvant versus adjuvant chemotherapy? How should we manage other organs that contain urothelial cells? 

These are complex decisions that often require input from both medical and surgical disciplines. To help guide practice, this new Center of Excellence will serve as a hub that rapidly and accurately shares the latest data from published and recently presented studies. Using a variety of formats such as video, expert articles, and meeting summaries, we will cover typical and atypical cases, treatment nuances, complications of therapy, and best-practice approaches, including multidisciplinary care models. As the Center’s editor, I will provide an interface between physicians, advanced practice providers, specialty nurses, and patients and caregivers, helping them stay current on diagnostics, prognostics, treatment algorithms, controversies, and the latest advances. My hope is that this Center of Excellence will help fill the sizable gap that we as clinicians face across the spectrum of genitourinary care when managing this complex disease. I look forward to working with and hearing from you.

Written by: Sam S. Chang, MD, FACS, Professor of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee

Published Date: April 15th, 2019

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.
2. Soria F, Shariat SF, Lerner SP, et al. Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC). World J Urol. 2017;35(3):379-387.
3. Kikuchi E, Oya M. Clinical practice patterns for upper tract urothelial carcinoma: a nationwide survey in Japan. Jpn J Clin Oncol. 2016;46(8):768-774.
4. Mandalapu RS, Remzi M, De reijke TM, et al. Update of the ICUD-SIU consultation on upper tract urothelial carcinoma 2016: treatment of low-risk upper tract urothelial carcinoma. World J Urol. 2017;35(3):355-365.
5. Zhang L, Xiong G, Fang D, et al. Contralateral upper tract urothelial carcinoma after nephroureterectomy: the predictive role of DNA methylation. J Exp Clin Cancer Res. 2015;34:5.
6. Guo RQ, Xiong GY, Yang KW, et al. Detection of urothelial carcinoma, upper tract urothelial carcinoma, bladder carcinoma, and urothelial carcinoma with gross hematuria using selected urine-DNA methylation biomarkers: A prospective, single-center study. Urol Oncol. 2018;36(7):342.e15-342.e23.
7. Krabbe LM, Bagrodia A, Haddad AQ, et al. Multi-institutional validation of the predictive value of Ki-67 in patients with high grade urothelial carcinoma of the upper urinary tract. J Urol. 2015;193(5):1486-1493.
8. Moss TJ, Qi Y, Xi L, et al. Comprehensive genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2017 Oct;72(4):641-649.
9. Glaser AP, Fantini D, Shilatifard A, et al. The evolving genomic landscape of urothelial carcinoma. Nat Rev Urol. 2017;14(4):215-229.
10. Skala SL, Liu TY, Udager AM, et al. Programmed death-ligand 1 expression in upper tract urothelial carcinoma. Eur Urol Focus. 2017;3(4-5):502-509.
11. Browne BM, Stensland KD, Moynihan MJ, et al. An analysis of staging and treatment trends for upper tract urothelial carcinoma in the National Cancer Database. Clin Genitourin Cancer. 2018;16(4):e743-e750.
12. Birtle AJ, Lewis R, Johnson M, et al. Time to define an international standard of postoperative care for resected upper urinary tract transitional cell carcinoma (TCC) - opening of the peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (POUT) Trial. BJU Int. 2012;110(7):919-921.
13. Clinicaltrials.gov. Feasibility of neo-adjuvant versus adjuvant chemotherapy in upper tract urothelial carcinoma (URANUS). https://clinicaltrials.gov/ct2/show/NCT02969083 Accessed April 8, 2019.
14. Liem EI, Freund JE, Baard J, et al. Confocal laser endomicroscopy for the diagnosis of urothelial carcinoma in the bladder and the upper urinary tract: protocols for two prospective explorative studies. JMIR Res Protoc. 2018;7(2):e34.

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Watch: The Diagnostic and Therapeutic Challenges Associated with UTUC - Sam Chang