SESAUA 2023: State-Of-The-Art Lecture: Endoscopic Management of Upper Tract Urothelial Cancer

(UroToday.com) The 2023 SESAUA annual meeting included a State-of-the-Art lecture presentation by Dr. JR Bell discussing endoscopic management of upper tract urothelial cancer. Dr. Bell started his presentation by highlighting a historical perspective, stating that endoscopy of the upper urinary tract was first described by Dr. Hugh Hampton Young in 1912.

Upper tract urothelial carcinoma makes up approximately 5-10% of all urothelial cancers, but up to 40% of urothelial carcinoma in the Balkan countries. Furthermore, upper tract urothelial carcinoma has a 2:1 male to female incidence ratio, with a peak incidence of 70-90 years of age, and Black patients are twice as likely to develop disease compared to Caucasians. Malignancy makes up 90% of upper tract urothelial carcinoma, with other histologies including squamous cell carcinoma, adenocarcinoma, and small cell carcinoma. For benign lesions, these may include fibroepithelial polyps (the most common benign tumor), inverted papillomas, fibromas, and von Brunn’s nests.

Risk factors for upper tract urothelial carcinoma include:

1. Tobacco use: RR 2.5-7x
2. Bladder cancer (2-7%): low grade tumors (longer survival), multifocality (3x risk), CIS (2-4x risk), use of ureteral stents
3. Aristolochic acid
4. Cyclophosphamide exposure
5. Arsenic exposure
6. Lynch syndrome: upper tract urothelial carcinoma prevalence is 3-28%

 With regards to signs and symptoms, upper tract urothelial carcinoma presents with hematuria in 75-82% of cases, as well as potentially with flank pain and dysuria. Additionally, up to 19% of patients are metastatic at diagnosis, with the contralateral side affected in 2-6% of cases (especially with CIS: 25% of cases), 15-50% have a history of bladder cancer, and 17% have concurrent bladder cancer. For endoscopic evaluation, this may include a retrograde pyelogram, direct visualization, cytology, and biopsy. As follows are several representative images of endoscopic evaluation of ureteral tumors:

Dr. Bell emphasized that risk stratification is crucial for upper tract urothelial carcinoma highlighting the straightforward EAU guidelines stratification schema:

• Low risk: low grade, unifocal, tumor <2 cm, no invasion seen on imaging
• High risk: high grade, positive cytology, multifocal, presence of hydronephrosis, tumor > 2 cm, invasion seen on imaging, previous cystectomy for high grade bladder cancer

When discussing kidney-sparing surgery for upper tract urothelial carcinoma, Dr. Bell notes that this is predominantly for low risk disease. However, there are also other considerations for kidney sparing surgery that include: (i) significant chronic kidney disease, (ii) solitary kidney, (iii) bilateral disease, and (iv) poor surgical candidacy for invasive procedures. Generally, there are similar rates of overall and cancer-specific survival between endoscopic compared to extirpative management. Furthermore, there are similar rates of bladder recurrence between endoscopic and extirpative management, however 20-30% of patients will progress to nephroureterectomy. There needs to be a balance between continued surveillance and renal preservation.

In a 20 year single center experience with endoscopic management of upper tract urothelial carcinoma, Cutress and colleagues treated 73 patients endoscopically between 1991 and 2011.¹ All patients underwent ureteroscopy and biopsy-confirmation of pathology was obtained in 81% (n = 59) of the patients; 14% (n = 10) of patients underwent percutaneous resection. Adjuvant mitomycin C was used in 18 patients and there was no seeding using the percutaneous approach. Over a median follow-up of 54 (1-223; 62.8) months, upper tract recurrence occurred in 68% (n = 50) of patients with 19% (n = 14) of patients proceeding to nephroureterectomy. The estimated OS and DSS were 69.7% and 88.9%, respectively, at 5 years, and 40.3% and 77.4%, respectively, at 10 years. As follows is the grade-stratified outcomes these patients, including DSS (a), upper tract RFS (b), and intravesical RFS (c):

 Dr. Bell notes that endoscopic evaluation allows for diagnosis of bladder pathology, allows for biopsy and selective cytology, as well as aides in assessing tumor stage. Furthermore, it also helps determine multifocality and can be used to evaluate for concomitant CIS. Ureteroscopic biopsies can determine grade 78-92% of the time, however tumor stage is more difficult assess with biopsy alone (it is possible to determine invasive disease in ~67% of cases, as summarized in the literature). Tumor staging is optimized when using a combination of endoscopic evaluation, biopsy, and imaging, with lamina propria present in approximately 2/3 of biopsies.

The benefits of retrograde endoscopic evaluation are minimization of tumor seeing, whereas several challenges include small scopes, visualization being difficult, biopsy and resection is difficult with small instruments, and the inability to orient the specimen. Enhanced endoscopic imaging options include narrow band imaging (OLYMPUS) and image IS system (Storz), which has the benefit of improved detection of tumors with enhanced imaging, especially for CIS. However, to date, this has not translated to a benefit with regards to overall survival or disease specific survival. Optical coherence tomography also has the potential to improve visualization of the tumor. Bus et al. prospectively evaluated the diagnostic accuracy of optical coherence tomography for the grading and staging of 26 patients with upper tract urothelial carcinoma:²

In 83% of patients, the staging of lesions was in accordance with final histopathology, and sensitivity and specificity for tumor invasion was 100% and 92%, respectively. As follows is the comparison between biopsy and optical coherence tomography results with regards to staging (A) and grading (B):

Indications for percutaneous resection is primarily larger tumors in the renal pelvis, as well as low risk tumors that are inaccessible via a retrograde approach. The benefits of a percutaneous approach are that there may be a lower risk of recurrence compared to a ureteroscopic approach with the main (theoretical) concern being tumor seeding. For ureteroscopic techniques, these include the following:

• Access sheath: recommended, as this allows for multiple passes and biopsies, minimizing the theoretical risk of downstream spreading and lowering intrarenal pressure
• Ureteroscopic biopsy: basket versus biopsy forceps
• Selective washings/cytology
• Ablation: monopolar coagulation versus laser

One of the most common baskets Dr. Bell uses is the Segura basket, named after Endourological Society founding member Dr. Joseph Segura, which is made by Boston Scientific and ranges from 2.4-4.5 Fr in diameter. The Piranha biopsy forcep is also an option, made by Boston Scientific, 3 Fr in diameter, and has a “scissor-like” handle. The BIGopsy is made by Cook, is 2.4 Fr in diameter, and needs to be backloaded into the scope and then assembled. Lasers can be used to excise tumors and/or ablate, with the 3 most common lasers as follows:

• Ho:YAG – depth of penetration is <0.5 mm, with the settings typically 0.6-1 J x 8-10 Hz
• Thulium – depth of penetration is <0.5 mm, with the settings typically 0.6-1 J x 8-10 Hz
• ND:YAG – works by coagulative necrosis, has a depth of penetration of 5-6 mm, has excellent hemostasis, with the settings typically 5-15 watts

Monopolar cautery is also an option, using the Gyrus ACMI 2 Fr fulgurating electrode, with the settings typically 20-30, requiring water as an irrigant.

Dr. Bell then discussed the utility of immediate adjuvant therapy, highlighting the prospective non-randomized trial from Gallioli et al. of which 52 patients were treated by endoscopic ablation, of whom 26 were selected for adjuvant single-dose upper urinary tract instillation of mitomycin.³ Adjuvant single-dose upper urinary tract instillation of mitomycin was administered through a Single-J (19/25, 76%) or a Double-J (6/25, 24%) in 25/26 (96%) patients. Over a median follow-up of 18 months (IQR 10-29), the urothelial recurrence rate was 23.5% and 55.5% in the adjuvant group and controls, respectively (p = 0.086):

Clavien grade ≤II complications occurred in 32% (8/25) and 30.7% (8/26) of the patients in the adjuvant and control group, respectively (p = 0.9), with two Clavien III complications occurring in the adjuvant single-dose upper urinary tract instillation of mitomycin group.

In a 2019 meta-analysis, Foerster et al. assessed the oncologic impact of adjuvant endocavitary instillation after kidney-sparing surgery.⁴ Among 27 studies including 438 patients, 154 (35%) patients developed upper tract recurrence during a median follow-up of 30 months. The overall pooled estimates for adjuvant instillations in Ta-T1 patients were 40% for upper tract recurrence, 94% for cancer-specific survival, and 71% for OS. Subanalyses stratified by regimen used and instillation approach did not show any significant differences. In patients with upper tract carcinoma in situ treated with BCG, the pooled estimates for cytology response, upper tract recurrence, and progression were 84%, 34%, and 16%, respectively:

Dr. Bell summarized delayed adjuvant upper tract therapy by noting that the benefits are that we can draw on success we have seen in the treatment of bladder cancer, with an opportunity to preserve kidneys. However, there are several challenges, including difficulty to deliver treatment (and need for ureteral catheter or nephrostomy tube), and difficulty achieving significant dwell time. One solution includes hydrogel formulations, which are liquids at room temperature that convert to gel at body temperature (urine flow then dissolves the gel within 4-6 hours).

BCG is best used for CIS in the upper tract, however there is a recurrence rate of 40% and progression rate of 5%. For Ta/T1 lesions, there is a 59% recurrence rate and 41% progression rate. Other options include mitomycin C and gemcitabine. Mitomycin C treatment has been largely extrapolated from bladder cancer data, has a risk of systemic absorption, and has a viscous state that has limited dwell time. Gemcitabine has comparable efficacy in the bladder, is cheap, and has less toxicity compared to other agents.

To conclude his presentation, Dr. Bell highlighted the OLYMPUS trial, which included patients with either primary or recurrent biopsy-proven low-grade upper tract urothelial cancer of the renal pelvis or calyces, diagnosed in the two months prior to trial screening.⁵ Importantly, patients must have had one or more low-grade lesions above the ureteropelvic junction measuring 5-15mm in greatest dimension. Enrolled patients received six once-weekly instillations of UGN-101 as an induction course, which was administered via retrograde instillation with ureteral catheterization. Four to six weeks following initial treatment, patients received their primary disease evaluation including ureteroscopy, selective upper tract cytology, and for-cause biopsy where indicated. Complete response was defined as a negative endoscopic evaluation and the absence histologic or cytologic evidence of disease. Patients who experienced a complete response were then offered ongoing monthly maintenance for 11 instillations or until first recurrence. Durability was assessed at 3-, 6-, 9-, and 12-months following initial treatment.

Among 110 patients screened, 74 were enrolled and 71 patients received at least one dose of the study medication, and 61 completed the 6 treatments defining the initial treatment course. Among the 71 patients who received at least one dose, 42 patients (59%, 95% CI 47-71%) had a complete response at the time of primary disease evaluation. Of the remainder, 8 (11%) had a partial response, 12 (17%) had no response, 6 (8%) had newly diagnosed high-grade disease, and 3 (4%) had an indeterminate response. Additionally, of the 42 patients with complete response, 41 entered follow-up. Of these, 29 (71%) received at least one dose of maintenance therapy and 6 (15%) were continuing on maintenance therapy at the time of data cut-off.

Twelve-month durability could be assessed in 20 patients. Of these, 14 (70%) showed ongoing durability of their complete response and 6 had a documented recurrence during follow-up. However, none of these patients progressed to high-grade or invasive disease. Among those with complete response at primary disease evaluation, 84% (95% CI 71-97%) remained disease free at 12 months. Median time to recurrence was reported as 13 months (95% CI 13 months to not estimable) though should be considered highly tenuous given 6 patients at risk at 12 months and 1 patient at risk at 13 months.

Despite these promising results, toxicity was not insignificant: 67 patients (94%) experienced adverse events and 26 (37%) patients experienced severe adverse events. There were 60 patients (85%) that had adverse events which were deemed treatment-related, and 19 (27%) had severe treatment related events. There were 19 patients (27%) that discontinued treatment due to adverse events both in the initial 6-week treatment period (9 patients, 13%) and during maintenance (10 patients, 14%). Among adverse events of particular interest, renal functional impairment was noted in 14 patients (20%). There was also a significant burden of urinary tract morbidity: among 71 patients who received at least one dose of study medication, 48 patients (68%) had an adverse event related to the urinary system including 11 (23%) who did not require surgical intervention, 24 (50%) who required transient stent placement, 11 (23%) who required long-term stent placement (still in place at the time of data cut-off), and 2 (4%) who required nephroureterectomy due the need for permanent drainage as a result of ureteral stenosis.

Dr. Bell provided the following advice with regards to endoscopic treatment of upper tract urothelial carcinoma:

• Assess tumors generally in a retrograde fashion (preferred), but do not be afraid to use an antegrade technique if necessary
• Use a ureteral access sheath for tumors in the proximal to the distal ureter
• Snare papillary tumors with a basket
• Use biopsy forceps for more sessile and smaller tumors
• A thulium laser works well for ablation

Dr. Bell concluded his presentation discussing endoscopic management of upper tract urothelial cancer with the following take-home messages:

• Proper staging of upper tract urothelial carcinoma is best done with imaging and endoscopic techniques
• There is significant variation in reported techniques for management
• Consider enhanced endoscopic imaging for patients with positive cytology with no visible tumor
• Post-procedural administration of mitomycin C or BCG is not needed routinely, but one can consider for recurrent disease
• Consider Jelmyto for tumors that are small and low grade, especially if the patient is frail, or if it is difficult to access the tumor 

Presented by: John R. Bell, University of Kentucky, Lexington, KY 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 Southeastern Section of the American Urological Association (SESAUA) Annual Meeting, Amelia Island, FL, Wed, Mar 15 – Sat, Mar 18, 2023.

References:

1. Cutress ML, Stewart GD, Wells-Cole S, et al. Long-term endoscopic management of upper tract urothelial carcinoma: 20-year single-centre experience. BJU Int. 2012 Dec;110(11):1608-1617.
2. Bus MTJ, de Bruin DM, Faber DJ, et al. Optical Coherence Tomography as a Tool for In Vivo Staging and Grade of Upper Urinary Tract Urothelial Carcinoma: A Study of Diagnostic Accuracy. J Urol. 2016 Dec;196(6): 1749-1755.
3. Gallioli A, Boissier R, Territo A, et al. Adjuvant single-dose upper urinary tract instillation of mitomycin C after therapeutic ureteroscopy for upper tract urothelial carcinoma: A single-centre prospective non-randomized trial. J Endourol. 2020 May;34(5):573-580.
4. Foerster B, D’Andrea D, Abufaraj M, et al. Endocavitary treatment for upper tract urothelial carcinoma: A meta-analysis of the current literature. Urol Oncol. 2019 Jul;37(7):430-436.
5. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): An open-label, single-arm, phase 3 trial. Lancet Oncol 2020 Jun;21(6):776-785.