SUO 2018: Topical Agents for Upper Tract Urothelial Carcinoma - How to Do It?

Phoenix, Arizona  ( Upper tract urothelial carcinoma (UTUC) is associated with a worse prognosis than bladder UC, and while extirpative surgery is the mainstay of treatment for high grade and large volume disease, there has been an increase in utilization of endoscopic treatments over time particularly for low-grade tumors. European Association of Urology (EAU) 2017 guidelines advocate for categorization of UTUC into low and high-risk groups in order to guide treatment.

Low-risk UTUC is characterized by tumors that are unifocal, small <2 cm, low-grade on cytology and ureteroscopic (URS) biopsy, and non-invasive on axial imaging. High-risk UTUC is associated with hydronephrosis, tumor size > 2cm, high grade cytology or URS biopsy, multifocality, prior cystectomy, and variant histology. Renal-sparing surgery for appropriately selected low-risk UTUC reduces the morbidity of radical surgery without compromising oncological outcomes .1

Dr. Chamie reviewed his recently published study which evaluated treatment utilization and survival of radical nephroureterectomy as compared with endoscopic management of UTUC.2 The study reported that there was an overall increasing trend to endoscopic management for tumors of the renal pelvis (6% to 11%) and ureter (17% to 20%) between 2004 and 2012, and that there was not a statistically significant difference in overall survival for patients with small tumors ≤ 1.5 cm who underwent either radical nephroureterectomy or endoscopic management. The reliability of endoscopic biopsies for UTUC staging is poor; 45% of tumors classified as non-invasive Ta are actually invasive. Conversely, the reliability of biopsies for tumor grading is better. Low-grade tumor on biopsy corresponds to a non-invasive ≤ pT1 tumor in > 70% of cases, and high-grade tumor on biopsy corresponds to an invasive tumor in ≥ 60% of cases. A useful adjunct to biopsy is voided urinary cytology which has been shown to have sensitivity 35-65% and specificity > 90%, with positive cytology predicting an invasive tumor with sensitivity of 62%.3,4  A recent study by Cutress and colleagues compared outcomes of endoscopic surgery to laparoscopic nephroureterectomy and found that for grade 1 UTUC, endoscopic management can produce effective oncologic control and help avoid the morbidity of radical nephroureterectomy, but should not be used for higher grade disease except for in very select cases.5

Given the recurrence rates after endoscopic treatment for UTUC, adjuvant treatments as adjuncts have been increasingly explored. Adjuvant BCG after percutaneous resection has not shown statistically significant improvements in recurrence or progression, and instillations of mitomycin C have been associated with relatively high recurrence rates, though a significant proportion of renal units have been spared with the combined approach.6 Two recent studies have evaluated chemoprophylaxis during nephroureterectomy. One study found that 16% of the mitomycin arm compared to 27% of the placebo arm had a recurrence at 1 year (p=0.03), and the second study showed that of patients who received pirarubicin, 17% had a recurrence at 1 and 2 years compared to 32% and 42% of those who didn’t at 1 and 2 years, respectively.7 The best instillation approach appears to be via a retrograde catheter based on work by Pollard and colleagues. Lastly, recent work is being done on Urogen Pharma UGN101 (MitogelTM), a substance that is liquid at room temperature and solid at body temperature once instilled. The substance is instilled antegrade or retrograde and maintained in the upper urinary tract for 5-7 hours without obstruction or systemic absorption. An OLYMPUS trial of Mitogel showed that six weekly installations in 34 evaluable patients with low-grade disease was associated with 59% complete and 15% partial response which is promising.

Adoption of endoscopic treatment for UTUC is slowly increasing. The adoption has been generally slow because of unreliable staging of UTUC and high recurrence rates after endoscopic treatment even with adjuvant BCG or mitomycin therapies. Adjuvant treatment has been increasingly explored and various topical approaches have been introduced. It appears that retrograde ureteral catheter instillation results in greatest surface area coverage, but retrograde instillation is inconvenient and comes with a small but real risk of systemic absorption through pyelovenous backflow. Topical therapy with agents such as Mitogel is promising for low grade tumors and BCG is beneficial for high grade tumors in terms of complete response rates despite high recurrence rates. Additional studies are ongoing.

Presented by: Karim Chamie, MD, MSHS, University of California, Los Angeles, California 

1. EAU Guidelines 2017 Update.
2. Upfill-Brown, A., et al., Treatment utilization and overall survival in patients receiving radical nephroureterectomy versus endoscopic management for upper tract urothelial carcinoma: evaluation of updated treatment guidelines. World J Urol, 2018.
3. Brown, G.A., et al., Ability of clinical grade to predict final pathologic stage in upper urinary tract transitional cell carcinoma: implications for therapy. Urology, 2007. 70(2): p. 252-6.
4. Cutress, M.L., et al., Long-term endoscopic management of upper tract urothelial carcinoma: 20-year single-centre experience. BJU Int, 2012. 110(11): p. 1608-17.
5. Cutress, M.L., et al., Endoscopic versus laparoscopic management of noninvasive upper tract urothelial carcinoma: 20-year single center experience. J Urol, 2013. 189(6): p. 2054-60.
6. Metcalfe, M., et al., Induction and Maintenance Adjuvant Mitomycin C Topical Therapy for Upper Tract Urothelial Carcinoma: Tolerability and Intermediate Term Outcomes. J Endourol, 2017. 31(9): p. 946-953.
7. Ito, A., et al., Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial. J Clin Oncol, 2013. 31(11): p. 1422-7.

Written By: Selma Masic, MD, Urologic Oncology Fellow (SUO), Fox Chase Cancer Center, @selmasic at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona