David Ambinder, MD

GU Oncology Now

In the latest American Urological Association/Society of Urologic Oncology (AUA/SUO) guideline for upper tract urothelial carcinoma (UTUC), there are 7 recommendations specific to the appropriateness of and proper technique for kidney-sparing management.<a href="https://www.auajournals.org/doi/10.1097/JU.0000000000003480" target="_blank" rel="noopener">1</a> Many of the statements focus on aiding shared decision-making and proper patient counseling.The guideline&rsquo;s first statement notes that &ldquo;tumor ablation should be the initial management option for patients with low-risk favorable UTUC.&rdquo; This statement was associated with a strong recommendation and grade B-level evidence. The basis for kidney-sparing management is that low-risk disease is correlated with low rates of metastatic progression and should be first-line if technically feasible. Due to the rarity of UTUC, there have been no randomized, controlled trials; however, 13 observational studies have compared endoscopic management with radical nephroureterectomy and found similar cancer-specific survival and improved renal functional outcomes for patients who were managed endoscopically. The panel cautioned that patient selection is a potential bias and should be considered. For patients in whom endoscopic ablation is not technically feasible (for example, because of tumor location, multifocality, or patient-specific factors), chemoablation may be an alternative. This suggestion is based on the OLYMPUS trial, an open-label, single-arm, phase 3 trial investigating a reverse thermal gel that incorporates mitomycin. Researchers found that of the 59% of patients who had an initial complete response at 1 month after a 6-week course, 56% of those patients maintained a complete response and were disease-free at 1 year.<a href="https://www.auajournals.org/doi/full/10.1097/JU.0000000000002350" target="_blank" rel="noopener">2</a> However, the panel noted that ureteral stricture is a real risk of chemoablation. Chemoablation should not be used as a substitute when complete endoscopic ablation is possible.The guideline&rsquo;s second statement says that &ldquo;tumor ablation may be the initial management option offered to patients with low-risk unfavorable UTUC and select patients with high-risk favorable disease who have low-volume tumors or cannot undergo radical nephroureterectomy.&rdquo; This statement was accompanied by a conditional recommendation and grade C-level evidence. This recommendation is not based on any randomized, controlled trials, but rather on some of the findings in the observational studies discussed above that included patients with unfavorable low-risk disease such as multifocal low-grade tumors. The authors specifically noted that Grasso et al included patients with pan-urothelial disease and large tumor burden with no higher rate of disease progression.<a href="https://bjui-journals.onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.2012.11066.x" target="_blank" rel="noopener">3</a> Tumor size is important to consider, according to the authors, as one study noted that tumors &lt;1.5 cm had a low risk of invasive disease, tumors &ge;1.5 cm had a &gt;80% risk of invasive disease, and tumors &gt;2.5 cm were associated with lower disease-specific survival.<a href="https://www.sciencedirect.com/science/article/abs/pii/S0090429507017852" target="_blank" rel="noopener">4</a> However, even in patients with tumor size &ge;2 cm, there was 10% 5-year recurrence-free survival, 65% progression-free survival, and 84% cancer-specific survival.<a href="https://okayama.elsevierpure.com/en/publications/ureteroscopic-management-of-large-2-cm-upper-tract-urothelial-car" target="_blank" rel="noopener">5</a> For &ldquo;larger tumors &ge;1.5 cm, ablation may be considered based on the provider&rsquo;s experience and assessment of the need for kidney-sparing surgery,&rdquo; the panel concluded. They also noted that patients who demonstrate disease progression should not undergo further endoscopic management and should instead be considered for segmental ureterectomy or nephroureterectomy. Patients with high-risk favorable UTUC who are being managed endoscopically and have a higher risk of disease progression should be managed with definitive surgical resection earlier, if needed, the panel cautioned.The guideline&rsquo;s third statement is related to ablation technique and is based on expert opinion. It says that &ldquo;tumor ablation may be accomplished via a retrograde or antegrade percutaneous approach and repeat endoscopic evaluation should be performed within 3 months.&rdquo; Repeat endoscopic assessment should be performed at 3-month intervals until no evidence of upper tract disease is identified. The 3-month follow-up window is based on a study showing 51.2% cancer detection at 60 days postablation,<a href="https://link.springer.com/article/10.1007/s00345-015-1753-7" target="_blank" rel="noopener">6</a> and the panel felt it reasonable to have a 30-day window before and after that 60-day time point. The panel mentioned that, if appropriate, a more conservative approach with shorter intervals can be considered. This approach would also apply to chemoablation. At times, it may be easier to perform ablation via an antegrade approach (e.g., on larger tumors or those with previous urinary diversion). The panel noted there are many energy sources available, and the use of an access sheath may be advantageous in certain situations. If using an access sheath, it is important to visualize the entire ureter prior to placing the sheath to avoid missing tumor burden.The guideline&rsquo;s fourth statement notes that, &ldquo;following ablation of UTUC tumors and after confirming there is no perforation of the bladder or upper tract, clinicians may instill adjuvant pelvicalyceal chemotherapy (conditional recommendation; evidence level: Grade C) or intravesical chemotherapy (expert opinion) to decrease the risk of urothelial cancer recurrence.&rdquo; This statement is based on what is known about bladder urothelial carcinoma. Based on a limited body of evidence for UTUC, this approach is still considered to be optional, but some studies have used a single upper tract instillation of mitomycin C<a href="https://www.liebertpub.com/doi/10.1089/end.2019.0750" target="_blank" rel="noopener">7</a> and, more recently, mitomycin gel. The authors noted there are 3 techniques used to administer chemotherapy: antegrade via nephrostomy tube, retrograde via ureteral catheter, or bladder irrigation with refluxing through a double-J ureteral stent. For the last option, the panel recommended a cystogram to demonstrate reflux prior to chemotherapy administration. They concluded that while bacillus Calmette-Gu&eacute;rin (BCG) therapy is the mainstay, mitomycin C, gemcitabine, docetaxel, epirubicin, doxorubicin, thiotepa, and BCG with interferon have been described.The guideline&rsquo;s fifth statement is based on expert opinion and supported by limited evidence. It says that &ldquo;pelvicalyceal therapy with BCG may be offered to patients with high-risk favorable UTUC after complete tumor ablation or patients with upper tract carcinoma in situ.&rdquo; A 6-week induction course is typical and should be considered in patients with a solitary kidney, bilateral tumor burden, or risk of end-stage renal disease (ESRD).The guideline&rsquo;s sixth statement says, &ldquo;when tumor ablation is not feasible or evidence of risk group progression is identified in patients with low-risk UTUC, surgical resection of all involved sites, either by radical nephroureterectomy or segmental resection of the ureter, should be offered.&rdquo; This statement is accompanied by a moderate recommendation of grade C-level evidence and is based on 13 retrospective studies. The recommendation includes patients who experienced treatment failure or histologic or clinicopathologic changes.The guideline&rsquo;s final statement is based on expert opinion and says, &ldquo;clinicians may offer watchful waiting or surveillance alone to select patients with UTUC with significant comorbidities, competing risks, or mortality, or at significant risk of ESRD with any intervention resulting in dialysis.&rdquo; Two large database studies have lent evidence to the theory that nonsurgical management has worse overall survival and cancer specific survival compared with surgical management.<a href="https://pubmed.ncbi.nlm.nih.gov/31012833/" target="_blank" rel="noopener">8</a>,<a href="https://bjui-journals.onlinelibrary.wiley.com/doi/abs/10.1111/bju.14042" target="_blank" rel="noopener">9</a> However, in certain patient populations, including those with very limited life expectancy, it is appropriate to manage disease by addressing symptomatic progression and with palliative care.David Ambinder, MD is a urology&nbsp;resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU&nbsp;oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.&nbsp;References<ol>
<li>Coleman JA, Clark PE, Bixler BR, et al. Diagnosis and management of non-metastatic upper tract urothelial carcinoma: AUA/SUO guideline.J Urol. 2023;209(6):1071-1081. doi:<a href="https://www.auajournals.org/doi/10.1097/JU.0000000000003480" target="_blank" rel="noopener">10.1097/JU.0000000000003480</a></li>
<li>Matin SF, Pierorazio PM, Kleinmann N, et al. Durability of response to primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel: OLYMPUS trial final report. J Urol. 2022; 207:779-788. doi:<a href="https://www.auajournals.org/doi/full/10.1097/JU.0000000000002350" target="_blank" rel="noopener">10.1097/JU.0000000000002350</a></li>
<li>Grasso M, Fishman AI, Cohen J, Alexander B. Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15-year comprehensive review of 160 consecutive patients. BJU Int. 2012;110(11):1618-1626. doi:<a href="https://bjui-journals.onlinelibrary.wiley.com/doi/abs/10.1111/j.1464-410X.2012.11066.x" target="_blank" rel="noopener">10.1111/j.1464-410X.2012.11066.x</a></li>
<li>Cho KS, Hong SJ, Cho NH, Choi YD. Grade of hydronephrosis and tumor diameter as preoperative prognostic factors in ureteral transitional cell carcinoma. Urology. 2007;70(4):662-666. doi:<a href="https://www.sciencedirect.com/science/article/abs/pii/S0090429507017852" target="_blank" rel="noopener">10.1016/j.urology.2007.06.1106</a></li>
<li>Scotland KB, Kleinmann N, Cason D, et al. Ureteroscopic management of large &ge;2 cm upper tract urothelial carcinoma: a comprehensive 23-year experience. Urology. 2018; 121:66-73. doi:<a href="https://okayama.elsevierpure.com/en/publications/ureteroscopic-management-of-large-2-cm-upper-tract-urothelial-car" target="_blank" rel="noopener">10.1016/j.urology.2018.05.042</a></li>
<li>Villa L, Cloutier J, Letendre J, et al. Early repeated ureteroscopy within 6-8 weeks after a primary endoscopic treatment in patients with upper tract urothelial cell carcinoma: preliminary findings. World J Urol. 2016;34(9):1201-1206. doi:<a href="https://link.springer.com/article/10.1007/s00345-015-1753-7" target="_blank" rel="noopener">10.1007/s00345-015-1753-7</a></li>
<li>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;34(5):573-580. doi:<a href="https://www.liebertpub.com/doi/10.1089/end.2019.0750" target="_blank" rel="noopener">10.1089/end.2019.0750</a></li>
<li>Syed JS, Nguyen KA, Suarez-Sariemento A, et al. Outcomes of upper tract urothelial cancer managed non-surgically. Can J Urol. 2019;26(2):9699-9707. PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/31012833/" target="_blank" rel="noopener">31012833</a></li>
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</ol>

Kidney-Sparing Management for UTUC: A Review of the 2023 AUA/SUO Guideline

Upper Tract Urothelial Carcinoma

In the latest AUA/SUO guideline for UTUC, there are 7 recommendations specific to the appropriateness of and proper technique for kidney-sparing management.