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