Upper tract urothelial carcinoma is a heterogeneous disease presenting multiple challenges to diagnosis and treatment. It remains relatively understudied in large prospective trials, and therapy has been guided primarily by retrospective data or by trials of urothelial bladder cancer (which is genetically and molecularly distinct).¹ The location of upper tract urothelial carcinoma also complicates collection of high-quality biopsy specimens.

“I have focused my clinical and research efforts on prostate and bladder cancer, but many times patients with urothelial cancer of the kidney and/or ureters, the so-called upper tract, can be the most challenging to treat.” said Sam Chang, M.D., Patricia and Rodes Hart Professor and vice chair of urologic surgery at Vanderbilt University Medical Center. “The least obvious tumors can be the most dangerous, and those that appear obvious can be the most benign. Patients often are overtreated or undertreated, undermining quality of life and disease-free survival.”

Chang recently announced in UroToday that he will serve as editor of a new Center of Excellence section on upper tract urothelial carcinoma for the website. The section will provide a resource on the latest study data and will cover typical and atypical cases, treatment nuances, complications of therapy, and best-practice approaches, including multidisciplinary care models.

Progress in Diagnosis, New Research

“Now more than ever, we are able to combine surgery with medical therapy and adapt treatment.”

Progress is accelerating in diagnosing upper tract urothelial carcinoma. Diagnostics have evolved from imaging only to next-generation sequencing and molecular subtyping of visually biopsied tumor samples.² Technical advances and improved training have made it possible to collect larger and higher-quality biopsies.³

“As the AUA Guidelines Chair for Bladder Cancer and past Chair of the SUO Guidelines on Advanced Prostate Cancer, I have carefully monitored significant inroads in detecting and treating these tumors. Now more than ever, we are able to combine surgery with medical therapy and adapt treatment based on risk of recurrence, progression and metastasis for upper tract cancers,” Chang said.

Studies such as POUT, in which adjuvant chemotherapy improved disease-free survival in pT2-T4 N0-3 M0 disease, and URANUS, which is comparing neoadjuvant versus adjuvant chemotherapy, have shown that it is possible to accrue upper tract urothelial carcinoma trials. They have spurred interest in other studies of novel diagnostics and more tolerable therapies, such as immune checkpoint inhibitors and FGFR3 inhibitors.4

Resolving Knowledge Gaps

Without treatment guidelines for upper tract urothelial carcinoma, urologists and medical oncologists are grappling with many questions. Are there helpful biomarkers for upper tract urothelial carcinoma? How do genetic disease processes and variants affect risk, surveillance, and therapeutic options? Which are the best surgical therapies and chemotherapies to avoid both under or overtreatment? How should other organs that contain urothelial cells, namely the bladder and prostatic urethra, be managed for patients with this diagnosis?

Chang hopes that developing the Center of Excellence resource for UroToday will be a step toward resolving these questions, and may inform future practice guidelines.

“It is our 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,” Chang said. “This Center will engage leaders on the forefront of important translational and clinical work that will help shape and define how we can improve our care for these patients.”

About the Expert

Sam Chang, M.D.

Sam S. Chang, M.D., M.B.A., F.A.C.S., is Patricia and Rodes Hart Professor of Urologic Surgery and Oncology, urologic oncology fellowship director and vice chair of the Department of Urologic Surgery at Vanderbilt University Medical Center. His clinical practice focuses on urologic oncology and he has led the American Joint Committee on Cancer GU Staging Task Force as well as numerous national guideline panels in prostate, bladder and kidney cancer. He currently serves as assistant secretary of the American Urological Association.

FOOTNOTES

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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.
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.
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.

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.
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.
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.
Moss TJ, Qi Y, Xi L, et al. Comprehensive genomic characterization of upper tract urothelial carcinoma. Eur Urol. 2017 Oct;72(4):641-649.
Glaser AP, Fantini D, Shilatifard A, et al. The evolving genomic landscape of urothelial carcinoma. Nat Rev Urol. 2017;14(4):215-229.
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.

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.

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.