DaBlaCa 23 - The European Collaborative Study on Upper Urinary Tract Urothelial Carcinoma

Detailed description Study Overview and Scientific Rationale Upper urinary tract urothelial carcinoma (UTUC) accounts of 5-10 % of urothelial carcinomas, with an incidence of nearly two cases per 100.000 inhabitants in the western countries. It is estimated that 5-7 % of UTUC are disseminated at time of diagnosis and 60 % are invasive, with a subsequent 5 year overall survival of merely 57% for all UTUC. Age at diagnosis has been increasing over the years, a likely consequence of longer lifespan and better diagnostics, and the mean age at diagnosis is now 70-73 years. Common risk factors are male gender (2:1 ratio to female), smoking and aromatic amines.

Treatments Radical nephroureterectomy (RNU) is considered the gold standard treatment of UTUC, but kidney sparing surgery (KSS) as a treatment option has gained more ground over the years as technology and knowledge about UTUC have improved. Risk stratifications before treatment decisions comprise of imaging of the urinary tract, predominantly CT urography, selective urine cytology and flexible ureteroscopy (fURS). Histopathology assessment of a fURS biopsy can determine the grade of the tumor in more than 90% of cases. However, fURS biopsies are not without limitations, with risk of under staging especially high-grade tumors, and inconclusive biopsies due to small specimen material, since the biopsy forceps usually are 3-4 french in size.

In 2018 the European Association of Urology (EAU) changed its guidelines for low-risk UTUC and now recommend a KSS approach in all patients with low-risk UTUC independent of pre-operative renal function. Low-risk UTUC is defined as: unifocal disease, tumor size < 2 cm, negative for high-grade selected site urine cytology, low-grade fURS biopsy and no invasive aspect on CT.

KSS comprises of three distinct surgical techniques: laser treatment, percutaneous resection, segmental ureter resection (SU) with either end-to-end ureter anastomosis or neoimplantation of the ureter into the bladder. In selected cases patients with high-risk UTUC may also be treated with a KSS approach - ex. in patients with a single kidney, bilateral disease, significant comorbidity or impaired renal function. Some studies indicate that selected high-risk cases diagnosed with low-grade tumors benefit from KSS instead of RNU, regardless of imperative causes. More recently, multifocal low-grade UTUC has been proposed as an intermediate-risk category, rather than being automatically classified as high-risk. This development is reflected in the 2024 EAU UTUC guidelines, which now identify hydroureteronephrosis, multifocality, and tumor size as weak high-risk criteria. Consequently, the presence of one of these features does not automatically preclude KSS if the remaining low-risk criteria are met. It is important to note, that the current evidence base for KSS in UTUC remains limited. The available literature is still developing and largely consists of smaller, retrospective cohort studies.

KSS demands close follow up, as there is a high risk of local recurrence. One study found, that patients treated with RNU had a total of 3.18 procedures performed after a mean follow up of 37.29 months, compared to 8.76 procedures following KSS (follow up 47.81 months), which might impact on the quality of life (QoL). On the other hand, there is evidence that radical nephroureterectomy increases long-term mortality which may be a reflection of the decrease in renal function after RNU. Identification of predictors leading to a postoperative decline in renal function after RNU are mostly retrospective, but the overall consensus suggests that the largest decline is seen in patients with low preoperative eGFR, higher age, postoperative AKI and the absence of hydronephrosis. End-stage CKD can lead to hemodialysis which significantly impairs QoL, and increases morbidity and mortality. The 5-year risk of progression from CKD stage 3 to end-stage kidney disease with the need of dialysis or renal transplant is merely 1.3%. Notably patients with a eGFR of 40 ml/min/1.73m2 have a short life expectancy with a 5-year overall mortality of 25%.