advances in upper tract urothelial carcinoma: starting to
TRANSCRIPT
Advances in Upper Tract Urothelial Carcinoma:Starting To Get Attention
For The Right Reasons
Sam S. Chang, MD, MBAPatricia and Rodes Hart Professor of Urologic Surgery
Chief Surgical OfficerVanderbilt Ingram Cancer Center, Vanderbilt University Medical Center
Nashville, TN
Vanderbilt University
Vanderbilt University
VUMC
VUMC
VUMC
Tennessee Wine
Upper Tract Urothelial Ca Epidemiology
• Account for 5% of urothelial malignancies, <10% of renal tumors
• Includes carcinoma of the renal pelvis and ureter (4:1), most superficial and low grade
• 1-2 cases per 100,000 people BUT each year incidence increasing over time
Kleinmann, et al Bladder Cancer 5:21, 2019
Risk Factors
• Smoking (60-70%)• Prior bladder cancer (range 7-0.8%)• Chronic inflammation• Cyclophosphamide• Occupational exposures• Lynch Syndrome (F>M) up to 15%; consider yearly UA starting at age 30• Balkan nephropathy• Aristocholic acid• Use of Double J stents prior to RC?
What To Know About Lynch Syndrome Patients
Upper tract:-more prone to be bilateral
-associated with MSH2 mutation
-ureteral tumors more common
What To Do About Lynch Syndrome PatientsScreening
NCCN Guidelines from 2020
“There is no clear evidence to support surveillance for urothelial carcinomas in LS…Surveillance options may include annual urinalysis starting at age 30-35 years. However, there is insufficient evidence to recommend a particular surveillance strategy…”
NCCN Guidelines, 2020, Genetic/Familial High-Risk Assessment
What To Do About Lynch Syndrome PatientsScreening
Goldberg H, et al UROLOGY, 2019
Evaluation
EAU Guidelines, 2020
Management• Nephroureterectomy
– First described in 1934 by Kimball and Ferris– Remains the gold standard– Single randomized trial comparing Open versus Laparascopic approaches
• Lap: superior for perioperative outcomes (e.g. blood loss, LOS )• Equivalent from bladder cancer control and cancer-specific survival standpoint
• Segmental ureterectomy• SEER review of approx 2000 patients with upper tract urothelial carcinoma (T1 – T4 N0)
– 28% underwent segmental ureterectomy– 5 year cancer specific survival was 86%, not significantly different from
nephroureterectomy patients– Caveats exist, especially selection bias
• Endoscopic Resection/Ablation– Percutaneous approach– Ureteroscopy
Rai B, et al Cochrane Review, 2011Jeidres C, et al J Urol. 2010 Apr;183(4):1324-9
Radical Nephroureterectomy
Pros• Definitive cure• No need for further intervention• Lower recurrence rates
Cons• Parenchymal loss• May result in CRI or need for HD• Greater morbidity• Risk of bilateral disease
Endoscopic Treatment
Pros• Preservation on renal function• Less morbid• Can be done as outpatient
• Cons• Rigorous, lifelong follow-up
schedule• Higher recurrence rates
LOCALIZED?GRADE?
Risk Stratification Guided Treatment
Endoscopic Treatment Radical Nephroureterectomy
BUT THIS IS INCOMPLETE—
Have to consider patient
characteristics (e.g. renal
function, location of tumor, etc) and
patient wishes
Advances in Low Grade Disease
UGN-101: A novel mitomycin polymer: To treat low grade/low risk disease
Karim Chamie, MD – Leading investigator
UGN-101
Liquid at low temperature
Solid at body temperature
• Poloxamer 407 based inverse thermosensitivity– Block co-polymer PEO-PPO-PEO
– MMC 4mg/1ml gel• Instilled as a liquid, converts to semi solid gel
• Releases mitomycin for 4-6 hours
Methodology – Procedures• UGN-101 treatment (4mg MMC per mL gel) q weekly x 6
– Instilled via retrograde ureteral catheter (possibly a percutaneous tube?)– Volume determined by average of three fluoroscopic measurements
• Settings: OR or office using GA/local anesthesia
Other supplies needed:• Flexible or rigid cystoscope• Guide wire• Syringe with contrast • Ice to chill UGN-101
UGN-101 supplied as: 2 vials of sterile,
lyophilized mitomycin
1 vial of sterile hydrogel
Primary outcome results: UGN-101• For patients with CR,
median f/u = 11 months
• 41 of 42 patients with CR underwent follow-up
• 29 of 41 patients received at least 1 maintenance dose
• 6 of 41 patients were still receiving maintenanceat the time of data cut-off
Complete Responders
• At data cut-off, 20 of 41 patients reached 12 month assessment
• 14 of 20 assessed patients had durable CR (at one year mark)• 6 of 20 assessed patients had documented recurrence—but
none of these patients progressed to high-grade or invasive disease
Safety data• Adverse events of special interest:
– Impaired renal function: 14 patients (20%)• 9 recovering• 5 not recovering
– Anemia: 9 patients (13%) self-limited– Thrombocytopenia: 3 patients (4%)
• 48 of 71 patients had urinary related AE– 11 patients did not require stenting– 24 patients required transient placement of stent– 11 patients required long-term stent placement– 2 patients opted for nephroureterectomy instead
of permanent stenting
Jelmyto
The FDA indication is quite broad—
“for the treatment of adult patients with
low-grade upper tract urothelial
cancer (LG-UTUC).”
When to Use Jelmyto?
Balance: Primary chemoablation of low-grade UTUC and avoidance of nephroureterectomy and/or multiple ureteroscopic procedures with procedure requirements and possible risk of stenosis and learning curve
My Concerns• Cost?• Learning curve?• Risk stratification inaccuracy?• Long term side effects?• Ability to give in outpatient setting?• Long term side effects, esp in patients with aggressive
resection?• When do we really need to use it?
Advances for High Grade Disease
Intravesical chemotherapy and Radical Nephroureterectomy
EAU guideline 2017
Approximately 20 % to 50 % patients have bladder
recurrence after nephroureterectomy for
upper tract urothelial carcinoma
Habuchi T: Lancet 1993, Takahashi T: J Urol 2001
ODMIT-C Trial
• Prospective, randomized non blinded trial
• 284 pt undergoing radical nephroureterectomy– 144 received single dose of
MMC perioperative or when foley removed
– 140 had standard of care
O’Brien T et al. Eur Urol, 2011
83%
72%
ODMIT-C Trial
• Single, postoperative dose– Absolute risk reduction 11%– Relative risk reduction 40%
• BUT– Intent to treat: p = 0.05– Per protocol analysis: p = 0.03– Lack of standardization of the treatment administration– Do not know pathology of recurrences within the bladder
O’Brien T et al. Eur Urol, 2011
Cochrane Meta-Analysis…single-dose intravesical chemotherapy instillation may reduce the risk of bladder cancer recurrence over time compared to no instillation (hazard ratio [HR]: 0.51, 95% confidence interval [CI]: 0.32 to 0.82, low-certainty evidence). After 12 months follow-up, this would result in 127 fewer bladder cancer recurrences (95% CI: 182 to 44 fewer bladder cancer recurrences) per 1000 participants.
Hwang EC, Sathianathen NJ, Jung JH, Kim MH, Narayan V, Hwang JE, Spiess PE, Dahm P. Cochrane Database of Systematic Reviews 2020, Issue 3. Art. No.: CD013567. DOI: 10.1002/14651858.CD013567.
GEMINI: Phase II Trial of IntraoperativeGEMcitabine INtravesical Instillation inPatients Undergoing RNU for UTUC
• Primary outcome: 1 year intravesical RFS• Accrual goal 90 patients• Opening at Mayo then other sites
Courtesy Vig Packiam
Perhaps We Can Do a Better Job of Predicting Nature of Bladder Ca Recurrence?
83 UTUC, 59 HG UTUC102 UBC
UTUCBLADDER
Bottom Line: Those with Bladder Recurrences
• Those upper tract with secondary bladder recurrences OFTEN share the same mutations
• So can we sample the upper tract reliably for mutation analysis without nephroureterectomy?
Audenet F. et al. Clin Can Res. 2018;e213
Major Limitations of Tissue-Based Molecular Characterization in UTUC
Small samplesDifficult Locations to sampleTumor HeterogeneityInvasive Instrumentation
Biopsy mutation
Radical Nephro U mutation
“Furthermore, subtyping of UTUC and BUC has identified similar expression subtypes, but UTUC is more often luminal with more T-cell depletion. Clonal studies indicate that BUC after UTUC is also likely luminal, while UTUC after BUC is often basal. “
Sfakianos JP, et al, Eur Urol Oncol, 2021
Sfakianos JP, et al, Eur Urol Oncol, 2021
Advances in Advanced Disease
Targeting Mutations: Erdafitinib
Advances for High Grade Disease
Adjuvant Chemotherapy: POUT Trial
Neoadjuvant vs Adjuvant Chemotherapy for UTUC
Points to Consider Neoadjuvant AdjuvantAccurate staging sometimes yes
Early treatment of micrometastatic disease
yes no
Renal function baseline may be compromised
Platinum and/or chemo-sensitivity
yes no
Benefit Probably/maybe/bias yes
WHAT DID WE DO? WHAT DO WE DO? WHAT WILL WE DO?
Sometimes you have a hit….
Sometimes you have a miss….
Improved disease-free survival--YES
Improved metastasis-free survival--YES
ChemoSurveillance
ChemoSurveillance
What Next?
Future Direction
• Improved biomarkers—perhaps urine-based?– Non-Invasive– Potential for longitudinal monitoring– Can look at DNA, RNA, proteomics, etc– But cytology is not very good: poor sensitivity and specificity
• Improved diagnostic instrumentation• Genetic screening and adaptive therapies
Thank You…In 2019