Guideline sources The following summarized guidelines for the evaluation and management of upper urinary tract urothelial carcinoma (UTUC) are prepared by our editorial team based on guidelines from the American Urological Association (AUA/SUO 2023), the European Association of Urology (EAU 2023), and the American Urological Association (AUA 2021). 1 2 3 Calculator Calculator Calculat Eastern Cooperative Oncology G Karnofsky performance status s TNM cl Guidelines 1. Classification and risk stratification Risk assessment: As per AUA 2023 guidelines: https://web.pathway.md/diseases/recbQQMwanj5s105i 1/6 6/29/23, 3:48 AM Upper urinary tract urothelial carcinoma Pathway Obtain a standardized assessment documenting clinically meaningful endoscopic (focality, location, appearance, size) and radiographic (invasion, obstruction, and lymphadenopathy) features to facilitate clinical staging and risk assessment at the time of identified UTUC. B Stratify patients as low or high risk for invasive disease ( pT2) following standardized assessment based on obtained endoscopic, cytologic, pathologic, and radiographic findings. Obtain further stratification into favorable and unfavorable risk groups based on standard identified features. B As per EAU 2023 guidelines, use prognostic factors to risk-stratify patients for therapeutic guidance. B 2. Diagnostic investigations Clinical assessment: As per AUA 2023 guidelines, elicit a personal and family history to identify known hereditary risk factors for familial diseases associated with Lynch syndrome (colorectal, ovarian, endometrial, gastric, biliary, small bowel, pancreatic, prostate, skin, and brain cancer) in patients with suspected/diagnosed UTUC, and offer referral for genetic counseling if identified. E As per EAU 2023 guidelines: Elicit a medical and family history based on the Amsterdam criteria to identify patients with UTUC. B Elicit a history of exposure to smoking and aristolochic acid. B Diagnostic imaging: As per AUA 2023 guidelines, obtain contrast-enhanced cross-sectional imaging of the upper tract, including delayed images of the collecting system and ureter, in patients with suspected UTUC. B Obtain pyeloureterography if good quality imaging, such as CT or magnetic resonance urography, cannot be obtained. B As per EAU 2023 guidelines: Obtain CT urography for diagnosis and staging of UTUC. A Consider obtaining magnetic resonance urography or 18F-FDG-positron emission tomography/CT to assess for nodal metastasis if CT is contraindicated. C Laboratory testing: obtain a comprehensive metabolic panel, CBC, and urinalysis in patients with suspected renal malignancy. B 3. Diagnostic procedures Diagnostic endoscopy: As per AUA 2023 guidelines, perform a cystoscopy in patients with suspected UTUC. B Show 4 more As per EAU 2023 guidelines: Perform urethrocystoscopy to rule out bladder tumor. A https://web.pathway.md/diseases/recbQQMwanj5s105i 2/6 6/29/23, 3:48 AM Upper urinary tract urothelial carcinoma Pathway Perform ureteroscopy (preferably without biopsy) if imaging and/or voided urine cytology is not sufficient for the diagnosis and/or risk stratification of patients with suspected UTUC. A Urinary tract washing: Perform cytologic washing from the urinary tract system being inspected during ureteroscopy. B Consider performing selective urinary tract washing or barbotage for cytology if ureteroscopy cannot be safely performed or is not possible. C Histopathology: obtain universal histologic testing of upper tract urothelial carcinoma with additional studies, such as immunohistochemistry or MSI, to identify patients with a high probability of Lynch-related cancers, and offer referral for genetic counseling and germline testing. B 4. Medical management Wantchful waiting: consider offering watchful waiting or surveillance alone in selected patients with upper tract urothelial carcinoma with significant comorbidities, competing risks of mortality, or significant risk of end-stage renal disease with any intervention resulting in dialysis. E Neoadjuvant therapy: offer cisplatin-based neoadjuvant chemotherapy in patients undergoing radical nephroureterectomy or ureterectomy with high-risk upper tract urothelial carcinoma, particularly if postoperative eGFR is expected to be < 60 mL/min/1.73m or in patients with other medical comorbidities precluding postoperative platinum-based chemotherapy. B Adjuvant therapy: As per AUA 2023 guidelines: Offer adjuvant platinum-based chemotherapy in patients with advanced pathological stage (pT2-T4 pN0-N3 M0 or pTany N1-3 M0) UTUC after radical nephroureterectomy or ureterectomy not received neoadjuvant platinum-based therapy. B Consider offering adjuvant nivolumab therapy in patients received neoadjuvant platinum- based chemotherapy (ypT2-T4 or ypN+) or ineligible for or refusing perioperative cisplatin (pT3, pT4a, or pN+). C As per EAU 2023 guidelines, offer adjuvant platinum-based chemotherapy after radical nephroureterectomy in patients with pT2-T4 and/or pN+ disease. A Show 2 more Definitive therapy, first-line therapy: As per SUO/AUA 2023 guidelines, offer initial systemic therapy in patients with clinical, regional node-positive (cN1-3, M0) UTUC. Consider performing consolidative radical nephroureterectomy or ureterectomy with lymph-node dissection in patients with a partial or complete response. E As per EAU 2023 guidelines, offer platinum combination chemotherapy in platinum-eligible patients. A Show 4 more https://web.pathway.md/diseases/recbQQMwanj5s105i 3/6 6/29/23, 3:48 AM Upper urinary tract urothelial carcinoma Pathway Definitive therapy (second-line therapy): offer a checkpoint inhibitor (pembrolizumab) in patients with disease progression during or after platinum-based combination chemotherapy for metastatic disease. A Show 2 more Definitive therapy (subsequent-line therapy): Offer vinflunine as third- or subsequent-line therapy. A Offer erdafitinib as subsequent-line therapy in platinum-refractory patients with FGFR deoxyRNA genomic alterations (FGFR2/3 mutations or FGFR3 fusions). B Palliative care: As per AUA 2023 guidelines, offer enrollment in a clinical trial or best supportive care, including palliative management (radiation, systemic approach, endoscopic, or ablative), for refractory symptoms (such as hematuria) in patients with unresectable UTUC, including patients ineligible or refusing surgery (radical nephroureterectomy or ureterectomy). E As per EAU 2023 guidelines, perform nephroureterectomy as a palliative treatment in symptomatic patients with resectable locally-advanced tumors. B 5. Inpatient care General counseling: Provide patients with a description of the short- and long-term risks associated with recommended diagnostic and therapeutic options, including the need for endoscopic follow- up, clinically significant strictures, toxicities associated with surgical treatment, and side effects from neoadjuvant and adjuvant therapies. B Discuss disease-related stresses and risk factors and encourage patients with urothelial cancer to adopt healthy lifestyle habits, including smoking cessation, exercise, and a healthy diet, to promote long-term health benefits and quality of life. E 6. Therapeutic procedures Kidney-sparing interventions: As per AUA 2023 guidelines, perform tumor ablation as the initial management option in patients with low-risk favorable UTUC. B Show 3 more As per EAU 2023 guidelines: Offer kidney-sparing management as the primary treatment in patients with low-risk tumors. A Offer kidney-sparing management in high-risk patients with imperative indication on a case-by-case basis, in consultation with the patient. A Pelvicalyceal chemotherapy: Consider offering adjuvant pelvicalyceal chemotherapy C or intravesical chemotherapy, after confirming there is no bladder or upper tract perforation, to decrease the risk of recurrence following ablation of UTUC. E https://web.pathway.md/diseases/recbQQMwanj5s105i 4/6 6/29/23, 3:48 AM Upper urinary tract urothelial carcinoma Pathway Offer a single dose of perioperative intravesical chemotherapy in eligible patients undergoing radical nephroureterectomy or segmental ureterectomy (including distal ureterectomy) for UTUC to reduce the risk of bladder recurrence. A Pelvicalyceal bacillus Calmette-Gu rin: consider offering pelvicalyceal therapy with BCG in patients with high-risk favorable UTUC after complete tumor ablation or in patients with upper urinary tract carcinoma in situ. E 7. Surgical interventions Radical nephroureterectomy: As per AUA 2023 guidelines, assess for the risk of post-nephroureterectomy CKD or dialysis before surgery in patients with UTUC. E Show 7 more As per EAU 2023 guidelines, perform radical nephroureterectomy in patients with high-risk non-metastatic UTUC. A Show 3 more 8. Follow-up and surveillance Surveillance after kidney-sparing management: As per AUA 2023 guidelines, perform a follow-up cystoscopy and upper urinary tract endoscopy within 1-3 months to confirm successful treatment in low-risk patients managed with kidney-sparing treatment. Obtain continued cystoscopic surveillance of the bladder, once successful treatment is confirmed, at least every 6-9 months for the first 2 years and at least annually thereafter. Repeat endoscopy at 6 months and 1 year. Obtain upper urinary tract imaging at least every 6-9 months for 2 years, then annually for up to 5 years. Obtain surveillance after 5 years in the absence of recurrence based on shared decision-making between the patient and clinician. E Show 2 more As per EAU 2023 guidelines: Perform cystoscopy and obtain CT urography at 3 and 6 months and then yearly for 5 years in low-risk patients. Perform ureteroscopy at 3 months if no second-look ureteroscopy was performed. B Perform ureteroscopy and urinary cytology in situ at 3 and 6 months in high-risk patients. B Surveillance after nephroureterectomy: As per AUA 2023 guidelines, consider referring patients with reduced or deteriorating renal function following nephroureterectomy or other intervention to nephrology. E Show 2 more As per EAU 2023 guidelines, perform cystoscopy at 3 months in low-risk patients. Repeat subsequent cystoscopy 9 months later and then yearly for 5 years. B Show 2 more https://web.pathway.md/diseases/recbQQMwanj5s105i 5/6 6/29/23, 3:48 AM Upper urinary tract urothelial carcinoma Pathway Clinical findings Symptoms Past medical history Fatigue Bone metastasis Fever Liver metastasis Flank pain Lung metastasis Hematuria Imaging findings Loss of appetite Malaise Hydronephrosis Night sweats Renal mass Weight loss Ureteral mass Lab findings serum creatinine serum urea References 1. Jonathan A Coleman, Peter E Clark, Brooke R Bixler et al. Diagnosis and Management of Non- Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline. J Urol. 2023 Apr 25;101097JU0000000000003480. Open 2. Morgan Roupr t, Thomas Seisen, Alison J Birtle et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update. Eur Urol. 2023 Mar 24;S0302 2838 23 02652 0. Open 3. Steven C Campbell, Peter E Clark, Sam S Chang et al. Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow-Up: AUA Guideline: Part I. J Urol. 2021 Aug;206 2 199 208. Open https://web.pathway.md/diseases/recbQQMwanj5s105i 6/6