Novel and Multimodality Management Strategies for Localized Upper Tract Urothelial Carcinoma

(UroToday.com) Most patients newly diagnosed with bladder cancer have non-muscle invasive disease (NMIBC). For patients with intermediate or high-risk NMIBC and those with carcinoma in situ (CIS), adjuvant treatment with BCG is guideline-recommended on the basis of proven benefits in disease recurrence. While BCG is efficacious, many patients eventually develop BCG-unresponsive disease. For many years, there have been very limited options for these patients. While radical cystectomy has remained the gold standard for many years, there is significant interest in developing novel approaches (both initially and following BCG) which will allow patients to keep their bladders. 

To this end, the Johns Hopkins Greenberg Bladder Cancer Institute and the American Urological Association held a Translational Research Collaboration entitled “Drug Development in NMIBC from Scientific, Regulatory, Clinician, and Patient Perspectives”. The fourth session of this symposium focused on the Treatment of Non-Muscle-Invasive Urothelial Cancer of the Upper Tract. In this session, Dr. Serena Matin presented novel and multimodality management strategies in localized upper tract urothelial carcinoma (UTUC).

By way of overview, he highlighted the roles of local therapy, systemic therapy, and potential future directions.

NMIBC_2021__Matin_1.png

Before getting to discussing treatment approaches, he first emphasized challenges in the management of UTUC, particularly in the case of low-grade disease. These issues are manifold including the risk of upgrade due to undersampling and tumor heterogeneity; issues with overtreatment of low-volume low-grade disease with nephroureterectomy; issues with a lack of kidney-sparing options for patients with high-grade disease; the requirement for frequency endoscopic procedures as a result of tumor recurrence; the risk of ureteral strictures due to tumors and treatment; and the lack of high level data to drive treatment decision making in this disease space.

In particular, while ureteroscopic management is commonly utilized in the management of low-grade UTUC, there are relatively high rates of upper tract recurrence, bladder recurrence, and the need for multiple procedures. However, overall and cancer specific survival are relatively high with good rates of kidney function preservation.

In the past year, Jelmyto has been approved as primary chemo-ablation, in addition to adjuvant therapy for patients with low-grade UTUC, in part on the basis of proven efficacy with a complete response rate of 58%. There is ongoing work assessing durability of this response with preliminary data of 80% at 1 year among initial responders. While there remain concerns for ureteral narrowing and stricture affecting nearly one in three patients treated with Jelmyto, this study established this treatment as a new standard of care allowing for reduced overtreatment associated with nephroureterectomy and decreased risk of recurrence associated with endoscopic management alone.

In addition to these issues among patients with low-grade disease, there are further challenges among patients with high-grade disease. These include inadequate staging on the basis of ureteroscopic evaluation and imaging; the risk of recurrence and progression when kidney preserving strategies are used; the renal impairments associated with nephroureterectomy which may preclude use of adjuvant cisplatin chemotherapy in many patients; and that, driven by issues with inadequate pre-operative staging, neoadjuvant chemotherapy is overtreatment in a consequential subset of patients.

In patients with high-grade disease, Dr. Matin suggested that a multimodality approach is likely warranted, to optimize both local and regional/metastatic disease control. This is driven in part because ureteroscopic treatment is limited to the mucosal layer, an technical approach which is much more limited than TURBT where resection to the muscle is routinely feasible.

NMIBC_2021__Matin_2.png


Dr. Matin emphasized that there are strong data to support peri-operative chemotherapy, both topically and systemically. In terms of topical use, two randomized trials have established a significant benefit in bladder recurrence free survival, with minimal associated toxicity. Systemically, the phase III POUT trial provides level 1 evidence for a DFS benefit of adjuvant chemotherapy. Further level 2 data from the EA8141 trial and from MSKCC suggest a benefit to neoadjuvant treatment with pathologic complete responses in 14-19% of patients and downstaging in approximately 60% of patients.

Dr. Matin emphasized that a comparison of neoadjuvant versus adjuvant chemotherapy is a false dichotomy. Rather than being wed to one approach or the other, we can consider circumstances to maximize patient outcomes on the basis of maximizing treatment benefits for those who stand to benefit while reducing overtreatment
NMIBC_2021__Matin_3.png

Beyond these questions, there are many subsets of patients for whom standard, guideline-based recommendations are not clear. In particular, he highlighted the value of an adaptive approach in patients with high risk UTUC and poor kidney function or performance status which would preclude nephroureterectomy. Among 14 patients, the MD Anderson group undertook ureteroscopy, biopsy and laser ablation followed by chemotherapy (64%) or immune checkpoint inhibitors (36%). Overall, 50% of patients were able to achieve the trifecta with no dialysis, no nephroureterectomy, and no metastasis.

Among patients with Lynch syndrome, Dr. Matin described data from MD Anderson in which 10 patients with unresectable UTUC and mismatch repair deficiency or microsatellite instability received immune checkpoint inhibition. With a median follow-up of 15 months, no patients had disease progression and the objective response rate was 90% with 8 achievings complete response.

Moving forward, Dr. Matin highlighted a proposed phase II trial from Drs. Chang and Smelser from Vanderbilt assessing the efficacy, safety, and tolerability of pembrolizumab in combination with endoscopic treatment in patients who are unsuitable for nephroureterectomy.

NMIBC_2021__Matin_4.png

Looking forward, there are a number of future approaches which Dr. Matin highlighted. The first of these is a planned phase III trial of vascular photodynamic therapy. This is being assessed with a trial design similar to MitoGel but, given differences in the mechanism, it’s hoped that lower rates of stricture disease may be observed making this a preferred treatment approach.

There are preclinical data supporting the use of a polymeric paste-drug formulation with gemcitabine for local treatment of UTUC though phase I data remain to be forthcoming. Nadofaragene has recently been shown to be efficacious in patients with BCG unresponsive NMIBC. While we await FDA approval for this indication, Dr. Matin suggested that it may be particularly advantageous in the UTUC space given its relatively infrequent (single or q3 month) dosing.


Presented by: Surena F. Matin, MD, Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter during the 4th annual bladder cancer translational research meeting, co-sponsored by the American Urological Association (AUA) and the Johns Hopkins Greenberg Bladder Cancer Institute, March 4-6, 2021