Bladder cancer is the fourth most common cancer among men and accounts for 8% of all new male cancer cases. Urinary bladder cancer is less common among women (ranked 11th) and accounts for less than 3% of all new female cancer cases. Statistics Canada estimates that in 2022 there will be approximately 13,300 new cases of bladder cancer and 2,500 deaths associated with bladder cancer in Canada. 1 Upper tract disease represents approximately 5-10% of all urothelial malignancies. 2 Upper tract tumours can be graded, in order to distinguish those with a low risk or recurrence from those with a high risk. The grading system was developed by the World Health Organization (WHO) in 2004. 3 Papillary urothelial neoplasms of low malignant potential (PUNLMP) have a low rate of recurrence (36%) and stage progression (3.7%) as compared to low grade papillary urothelial carcinomas (50% and 10%, respectively). High grade papillary urothelial carcinomas have a high rate of recurrence and stage progression. The progression rate ranges from 15 to 40%. 4,5 Guideline Questions 1. What staging investigations are required for patients with upper tract tumours? 2. What are the appropriate treatment options (i.e., surgery, systemic therapy, etc.) for patients with upper tract tumours? 3. What is a reasonable follow-up strategy for patients who have completed treatment for upper tract tumours?

# Search Strategy
This guideline was reviewed and endorsed by the Alberta Provincial Genitourinary Tumour Team. Members of the Alberta Provincial Genitourinary Tumour Team include medical oncologists, radiation oncologists, urologists, pathologists, nurses, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Genitourinary Tumour Team and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Utilization Unit Handbook.
This guideline was originally developed in April, 2013 and updated in December 2020.

# Target Population
These guideline recommendations apply to adult patients with transitional cell carcinoma (urothelial carcinoma) of the ureter and/or renal pelvis.
Due to the small number of patients that present with primary transitional cell carcinoma (TCC) of the ureter and renal pelvis, there is a lack of high level evidence (i.e., randomized controlled trials) to inform the treatment strategies for this disease. For this reason, many of the recommendations are based on findings from studies involving patients with TCC of the bladder. Physicians should take into account specific clinical characteristics of each patient with regard to renal function, comorbidities, tumour location, stage and grade when determining the optimal treatment for their patients. 7
If the tumour is operable, surgical excision is recommended. Nephroureterectomy with cuff of bladder excision is recommended, or if possible, a nephron-sparing procedure for low-grade disease. Lymph node dissection is recommended in high-grade cases. An analysis of the SEER database compared the cancer-specific mortality of patients with pT1-4 (any N, M0) disease who underwent a nephroureterectomy with a bladder cuff excision versus those who had a nephroureterectomy alone.
The results indicated that the cancer-specific mortality was higher at 2 and 5 years among patients in the nephroureterectomy only group (17.7% and 28.1% versus 12.2% and 22.4%). However, patients that underwent bladder cuff excision were significantly younger. 8 A single institution retrospective study, comparing outcomes associated with nephroureterectomy versus nephron-sparing endoscopic surgery, among 96 patients with upper tract TCC, showed that the 5-year overall survival rate was comparable between treatment groups (i.e., 72% for nephroureterectomy and 75% for nephronsparing approach). Patients with low grade disease treated with a nephron-sparing approach had a higher 5-year metastases-free survival (94% versus 88%) and 5-year cancer-specific survival (100% versus 89%), along with a lower complication rate (9.3% versus 29%). The authors concluded that endoscopic management provides cancer related and overall survival equivalent to that of nephroureterectomy in patients with low-grade disease. 9 An abstract presented at the American Urological Association meeting in May 2012 analyzed the outcomes of 1029 patients with upper tract TCC from the Canadian UTUC database. 10 In multivariate analyses, no differences were found in overall survival or disease-specific survival based on surgical approach (extravesical management, open bladder cuff excision or endoscopic management). Furthermore, open bladder cuff excision was found to reduce tumour recurrence compared with extravesical management (HR=0.628, 95% CI 0.491-0.801, p=0.0002). 10

# Neoadjuvant Therapy
Cases in which systemic therapy is being considered should be brought to and discussed at local tumour board meetings. Neoadjuvant chemotherapy can be considered in high grade patients, if the degree of invasiveness can be established prior to surgery. There is no strong evidence that neoadjuvant chemotherapy is effective in the treatment of TCC of the renal pelvis and ureter due to the rarity of the disease and lack of literature. 7,11 A retrospective comparative study comparing patients with biopsy-proven high-grade disease who received neoadjuvant chemotherapy followed by nephrouterectomy with patients who underwent initial nephroureterectomy (N=150) demonstrated significant downstaging with neoadjuvant chemotherapy (p =.004). The incidence of tumors classified as pathologic T2 (pT2) or as pT3 or higher was significantly lower in the study group (pT2, 65.4% vs 48.8%; P =.043; pT3 or higher, 47.7% vs 27.9%; P =.029). 12 Based on this data, the European Guidelines on Upper Tract Urothelial Carcinomas recommend this strategy. 12 Furthermore, because of the comparable etiology between TCC of the bladder and that of the upper tract, findings from studies involving patients with invasive bladder cancer can be extrapolated to patients with highgrade upper tract urothelial carcinoma. 13,14 A meta-analysis by the Advanced Bladder Cancer (ABC) Meta-analysis Collaboration (2005) of 11 trials (N=3005) found a significant survival benefit with platinum-based combination chemotherapy (HR=0.86, 95% CI 0.77-0.95, p=.003), equivalent to a 5% absolute improvement in survival at 5 years. A significant disease-free survival benefit was also noted in those patients that received neoadjuvant platinum-based chemotherapy (HR=0.78, 95% CI 0.71-0.86, p<.0001). 15 Another meta-analysis of eight trials of neoadjuvant cisplatinum-based combination chemo-therapy for TCC of the bladder published similar results; the pooled HR was 0.87 (95%, CI 0.78-0.96, p=.006), consistent with an absolute overall survival benefit of 6.5%. 16 A more recent retrospective study that included patients with upper tract TCC who received neoadjuvant chemotherapy following by laparoscopic nephroureterectomy showed that, as compared to nephroureterectomy alone, neoadjuvant chemotherapy was associated with a significantly higher complete response rate (15% versus 1.7%); however, complications were higher in the neoadjuvant chemotherapy group (58% versus 45%). 17 Similar results have been reported elsewhere. 18

# Adjuvant Therapy
The open-label phase 3 POUT trial compared adjuvant chemotherapy to surveillance after nephroureterectomy with curative intent in UTUC patients. Chemotherapy was cisplatin or carboplatin (for GFR <50 mL/min) plus gemcitabine. A total of N=261 patients were enrolled from 57 sites. Adjuvant chemotherapy significantly improved disease-free survival (HR: 0.45; 95%CI: 0.330-0.68; p<0.001) after a median follow-up of 30.3 months. Treatment associated adverse events were reported in 44% of patients who underwent chemotherapy. 19 T4b Extravesical tumor invades pelvic wall, abdominal wall