The Danish Bladder Cancer Group 23 Study - A Nordic Study on Cancer in the Upper Urinary Tract
- Conditions
- Upper Urinary Tract Urothelial Carcinoma
- Registration Number
- NCT07077447
- Lead Sponsor
- Zealand University Hospital
- Brief Summary
This is a study looking at how patients with a rare type of cancer in the pelvis and ureter of the kidney - called upper urinary tract urothelial carcinoma (UTUC) - is currently treated. The gold standard treatment of UTUC is the complete removal of the kidney, renal pelvis and ureter. The use of kidney-sparing surgery, which preserves the kidney while treating the cancer, was only considered for patients who were too frail to undergo kidney removal, had a solitary functioning kidney, or suffered from severe chronic kidney disease. Since 2018 international guidelines have incorporated kidney sparing surgery for all patients but only offered to patients that have been diagnosed with very low risk tumors to ensure the safety of the patients. The latest update of the UTUC Guidelines from the European Association of Urology has revised the criteria, so that certain features previously classified as high-risk are no longer considered high-risk on their own, provided the tumor otherwise appears benign. Nonetheless, ongoing research is essential to support this evolving approach and to further enhance the guidelines.
Kidney sparing surgery comprise of a strict follow up schedule that often demands supplemental surgeries under general anesthesia, which can cause strain on patients.
Preservation of the kidney is important since a decrease in kidney function can result in increased risk of cardiovascular disease and death.
The main question we want to answer is:
Can more patients with superficial non-invasive UTUC safely be treated with kidney-sparing surgery instead of the more aggressive surgery that removes the entire kidney and ureter without increasing the risk of the cancer coming back and while maintaining quality of life? Furthermore, we are interested in learning more about patients who later develop bladder cancer after treatment of UTUC (intravesical recurrences), the affection of kidney function over time and a subgroup of UTUC patients that are diagnosed with Lynch syndrome (a genetic condition that increases cancer risk and development of UTUC is the third most common cancer) where UTUC presents differently than other patients.
Participants Anyone diagnosed with UTUC can take part in the study. We will collect information from their medical records when they join and again after one, three, five, and ten years. Danish participants will also be asked to fill out quality-of-life questionnaires at the beginning of entering the study and at one, three and five years.
- Detailed Description
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 (1). 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 (2). 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 (2,3). Common risk factors are male gender (2:1 ratio to female), smoking and aromatic amines (3).
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 (2-4).
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 (5).
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 (6,7). More recently, multifocal low-grade UTUC has been proposed as an intermediate-risk category, rather than being automatically classified as high-risk (8). 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 (5). 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 (6,9).
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) (6). 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 (9,10). 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 (11). End-stage CKD can lead to hemodialysis which significantly impairs QoL, and increases morbidity and mortality (10,11). 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% (12,13).
Lynch syndrome Lynch syndrome, also known as hereditary non polyposis colorectal cancer, is caused by the germline mutation of one of four mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) or the EPCAM gene, which can cause inactivation of the MSH2 tumor suppressor gene (14). These genetic altercations lead to a spectrum of cancers in which UTUC is the third most frequent cancer. Patients with Lynch syndrome have a 14-22 times higher risk of developing UTUC and are diagnosed 10-15 years earlier than the background population. Additionally, UTUC in Lynch patients are more likely to occur in the ureter than in the renal pelvis (15). In contrast to the general population where men are twice as likely to be diagnosed with UTUC, the gender ratio is 1:1and there is an increased risk of developing bilateral UTUC (16). The percentage of patients with UTUC related to Lynch syndrome differs in the literature with rates between 1-20% of Lynch Syndrome related UTUC (3,14,17).
As formerly stated, UTUC is a rare disease and patients with UTUC and Lynch syndrome are even more of a rarity, thus the literature of this corner of UTUC is very scarce. When treating these patients the risk of subsequent contralateral disease must be taken into consideration, thus favoring KSS, but without comprising the oncological outcome for this patient group (14).
It is recommended that all primary UTUC pathology specimens are screened for the expression of the mismatch repair genes MLH1, MSH2, MSH6 and PMS2 and patients diagnosed with Lynch syndrome follow yearly screenings with an ultrasound, urinary dipstick and cytology (18).
Intravesical recurrence The risk of intravesical recurrence (IVR) after surgical treatment for UTUC, primarily after RNU, is between 21-50 %, with 82% occurring within the first two years after diagnosis (19,20).
IVR is primarily treated with transurethral resection of bladder tumor (TURBT). The follow-up is according to bladder cancer guidelines which are adjusted according to the stage and grade of the tumor. One study presented a mean of 2.3 recurrences/patient (19). Therefore, follow-up extends for an extra five years beyond the initial diagnosis of IVR. Although studies on treatment for non-muscle invasive bladder cancer may not apply to treatment for IVR after KSS for UTUC, it has been shown that the risk of overall death is 14% higher is patients who have undergone 2-4 TURBTs compared to patients who have only undergone 1 (21).
The role of Mitomycin C (MMC) in preventing IVR is to eradicate any residing tumor cells from the bladder by damaging the DNA of the tumor cells (20,22). The ODMID-C trial, a prospective randomized study concluded that a single instillation of MMC after RNU reduces the risk of IVR with absolute risk reduction of 11% and relative risk reduction of 40% (23).
Rationale and objectives
To our knowledge only one prospective UTUC database study exists, The CROES-UTUC registry, which terminated inclusion in 2019 (24). The development of treatment options for UTUC has improved over the years. Thus, there is need for further knowledge within the treatment field of UTUC to provide true personalized treatments options to our patients. The Nordic countries have a well-known and internationally respected tradition within health registry-based research, and we believe that a prospective multicenter multinational Nordic UTUC study is needed. The collected data will be used to validate the current prediction tools and explore novel tools within the following areas:
1. Prediction on oncological outcomes after RNU or KSS.
2. Prediction of the long-term preservation of renal function after KSS compared to RNU
3. Prediction of IVR after bladder instillation with chemotherapy
4. Prediction of the oncological outcomes for UTUC patients diagnosed with Lynch Syndrome
5. Prediction of patient related outcome measures of patients treated with RNU or KSS.
We hypothesize that we can accommodate these aims and provide further development of the current prediction tools to provide personalized well documented treatment options to our patients.
Study design summary NorCUT is a prospective, multicenter observational cohort study. No randomization or experimental intervention is applied; clinical management follows routine practice and is determined by the treating physician. Patients are invited to participate in the study at the time of a confirmed histopathology of UTUC.
The study is expected to commence in Denmark by summer/autumn 2025 and expand throughout the Nordic countries within 2025 and 2026. The study is expected to terminate inclusion by December 2030 and follow up in 2040.
Data are collected at baseline and during follow-up at 1, 3, 5, and 10 years. For Danish patients, a QoL questionnaire will be distributed electronically, and responses will be automatically integrated into the electronic case report form (eCRF) in REDCap.
Statistical Considerations NorCUT is designed as a non-inferiority study of KSS ('experimental' arm) compared to RNU ('standard of care' arm) with the primary endpoint of overall survival. The expected 5-year cancer specific mortality after RNU for patients with T0/Ta tumors is 6% (24). With a 15% mortality due to other causes makes an overall mortality rate of 21% with pT0/pTa tumors (25). In order to show non-inferiority in patients with a pTa tumor classified as high-risk tumor according to guidelines but imperatively treated with KSS compared to patients who undergo RNU with less than 5% increased risk of overall death, a sample size of 206 patients per arm is required, in order to achieve a power of 80% and a 5% type I error.
Categorical variables will be reported as counts and percentages, and continuous as medians with interquartile range. Test for independence will be performed with the chi-square test for categorical variables and the Wilcox test for numeric variables. Kaplan-Meier, competing-risk and uni- and multivariable COX regression analyses will be applied to assess the probability of recurrence, progression to invasive or metastatic disease, and cancer-specific and overall survival. All tests are planned as two sided with the significance level is set at p \< 0.05.
Patient inclusion, data collection and management The recording of data from patient records will be collected prospectively. Primary- or sub-investigators will document updates from the patient records at baseline and follow-up according to the study protocol. No further information will be collected after 10 years, progression to disseminated disease or death.
Data will be reported to the eCRF in the online REDCap web application. The eCRF is stored on a secure server under the responsibility of Zealand University Hospital, Roskilde. REDCap is a secure web application for building and managing online surveys and databases. The study will oblige to the laws and regulations of the Danish Data Protection Agency and EU regulations (GDPR).
All data are kept confidential in a pseudo anonymized form, according to the GDPR and the Danish Data Protection Agency's guidelines. Sponsor will assure that each participant enrolled in the study is coded with a unique patient identification number.
Registry Quality Assurance Measures A structured data dictionary has been developed to align with the eCRF implemented in REDCap. Each variable is defined with a clear name, label, data type (e.g., numeric, categorical, date), permissible values and specified units of measurement where applicable (e.g., serum creatinine in µmol/L).
To ensure data accuracy and consistency, built-in data validation rules are applied within REDCap, including:
* Range checks, used in e.g. height and weight measurement.
* Logic checks (e.g., date of surgery must occur after date of diagnosis etc.)
* Required field enforcement for critical variables
* Conditional branching to prevent irrelevant or contradictory entries throughout the eCRF.
* Format checks (e.g., dates must follow DD-MM-YYYY format) These rules are mirrored in the data dictionary to ensure transparency and traceability. In addition, automated queries are triggered when values fall outside expected ranges or violate logic rules.
The REDCap system is thoroughly tested prior to patient inclusion to ensure reliability and data integrity. A preliminary data extraction has been conducted to confirm that the collected data is suitable for meaningful statistical analysis.
Handling of Missing Data Missing data will be recorded and reported as "Not Available (NA)" in the study dataset and documentation. The primary analyses will be conducted using available data. If the extent or pattern of missing data warrants further consideration, appropriate statistical imputation methods (e.g., multiple imputation) may be employed for selected variables. Any use of imputation will be clearly specified in the statistical analysis plan, and sensitivity analyses will be performed to assess the robustness of the results.
Reference list
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7. Shvero A, Abu-Ghanem Y, Laufer M, Dotan ZA, Zilberman DE, Mor Y, m.fl. Endoscopic Treatment for Large Multifocal Upper Tract Urothelial Carcinoma. J Urol. april 2021;205(4):1039-46.
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9. Jung H, Giusti G, Fajkovic H, Herrmann T, Jones R, Straub M, m.fl. Consultation on UTUC, Stockholm 2018: aspects of treatment. World J Urol. november 2019;37(11):2279-87.
10. Hasan MN, Rouprêt M, Keeley F, Cracco C, Jones R, Straub M, m.fl. Consultation on UTUC, Stockholm 2018 aspects of risk stratification: long-term results and follow-up. World J Urol. november 2019;37(11):2289-96.
11. Tafuri A, Marchioni M, Cerrato C, Mari A, Tellini R, Odorizzi K, m.fl. Changes in renal function after nephroureterectomy for upper urinary tract carcinoma: analysis of a large multicenter cohort (Radical Nephroureterectomy Outcomes (RaNeO) Research Consortium). World J Urol. 2022;40(11):2771-9.
12. Webster AC, Nagler EV, Morton RL, Masson P. Chronic Kidney Disease. The Lancet. marts 2017;389(10075):1238-52.
13. Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, m.fl. Chronic Kidney Disease and Mortality Risk: A Systematic Review. Journal of the American Society of Nephrology. juli 2006;17(7):2034.
14. Lonati C, Moschini M, Simeone C, Spiess PE, Necchi A. Lynch syndrome in urological practice: diagnosis, therapeutic strategies, and screening for upper tract urothelial carcinoma. Current Opinion in Urology. januar 2022;32(1):40.
15. Lonati C, Necchi A, Gómez Rivas J, Afferi L, Laukhtina E, Martini A, m.fl. Upper Tract Urothelial Carcinoma in the Lynch Syndrome Tumour Spectrum: A Comprehensive Overview from the European Association of Urology - Young Academic Urologists and the Global Society of Rare Genitourinary Tumors. European Urology Oncology. 1. februar 2022;5(1):30-41.
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19. Raman JD, Ng CK, Boorjian SA, Vaughan Jr ED, Sosa RE, Scherr DS. Bladder cancer after managing upper urinary tract transitional cell carcinoma: predictive factors and pathology. BJU International. 2005;96(7):1031-5.
20. Seisen T, Granger B, Colin P, Léon P, Utard G, Renard-Penna R, m.fl. A Systematic Review and Meta-analysis of Clinicopathologic Factors Linked to Intravesical Recurrence After Radical Nephroureterectomy to Treat Upper Tract Urothelial Carcinoma. European Urology. juni 2015;67(6):1122-33.
21. Erikson MS, Petersen AC, Andersen KK, Jacobsen FK, Mogensen K, Hermann GG. Do repeated transurethral procedures under general anesthesia influence mortality in patients with non-invasive urothelial bladder cancer? A Danish national cohort study. Scand J Urol. august 2020;54(4):281-9.
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23. Noennig B, Bozorgmehri S, Terry R, Otto B, Su LM, Crispen PL. Evaluation of Intraoperative Versus Postoperative Adjuvant Mitomycin C with Nephroureterectomy for Urothelial Carcinoma of the Upper Urinary Tract. Bladder Cancer. 29. oktober 2018;4(4):389-94.
24. Kealey J, Snider R, Hayne D, Davis ID, Sengupta S. The utility of clinical registries for guiding clinical practice in upper tract urothelial cancer: a narrative review. Transl Androl Urol. 31. marts 2023;12(3):497-507.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 2500
- Patients with confirmed histopathology of UTUC
- Age ≥ 18 years
- Informed patient consent
- Patient not willing or able to give informed consent
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Overall survival From the end of enrollement until 10 years after inclusion or time of death At each follow-up (after 1, 3, 5, and 10 years), we will record whether each participant is alive or has passed away. If a participant has died, we will register whether the cause of death was due to their upper urinary tract cancer or from another cause. This information will be entered into the electronic case report form (eCRF). By doing this, we can better understand how different treatments affect survival related specifically to the cancer.
- Secondary Outcome Measures
Name Time Method Recurrences From enrollement until five years either after diagnosis or last recurrence according to current follow up guidelines. We record the following types of recurrence:
Any recurrence (local or distant) following radical nephroureterectomy (RNU) or kidney-sparing surgery (KSS).
Recurrence is documented based on follow-up imaging studies and/or histopathological confirmation.
Intravesical recurrence following RNU or KSS. All bladder recurrences identified during surveillance cystoscopy are recorded. Additionally, we document any prior or concomitant bladder cancer, in order to differentiate between pre-existing bladder cancer and secondary bladder cancer potentially related to UTUC.Progression From enrollment until five years of follow up Progression after KSS Progression will be assessed based on histopathological evaluation of local biopsy specimens or subsequent radical nephroureterectomy (RNU) specimens. Both grade progression and stage progression will be recorded according to the WHO 2004/2016 grading system for UTUC.
Cancer specific survival From the end of enrollement until 10 years after inclusion or time of death Cancer specific survival will be assessed by recording the cause of death for all enrolled patients throughout the follow-up period. At each scheduled follow-up time point (1, 3, 5, and 10 years), survival status will be updated, and if applicable, the cause of death will be registered in the electronic case report form (eCRF) as either UTUC-related or due to other causes. This distinction allows for accurate estimation of cancer-specific mortality and evaluation of the oncological safety of different treatment strategies, including kidney-sparing surgery (KSS) versus radical nephroureterectomy (RNU).
Renal function from enrollment until ten years Renal function is monitored using serum creatinine (µmol/L) measurements at baseline and at follow-up scheduled at 1, 3, 5, and 10 years. Creatinine values obtained within 3 months prior to each follow-up time point are accepted for analysis.
The endpoint is the development of chronic kidney disease (CKD) stage ≥3b, defined as an estimated glomerular filtration rate (eGFR) \<45 mL/min/1.73 m². eGFR is calculated using standard formulas (CKD-EPIkrea), without adjustment for race.Patient reported outcome measures Enrollment until five years or death. Patient-reported outcomes are assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30). All Danish participants complete the questionnaire at the time of enrollment. Follow-up assessments are administered electronically at 1, 3, and 5 years after inclusion. All responses are included directly into REDCap.
Trial Locations
- Locations (3)
Herlev Gentofte Hospital
🇩🇰Herlev, Denmark
Department of Urology, Copenhagen University Hospital - Rigshospitalet
🇩🇰København Ø, Denmark
Department of Urology, Zealand University Hospital
🇩🇰Roskilde, Denmark
Herlev Gentofte Hospital🇩🇰Herlev, DenmarkGitte W Lam, MDContact+45 38682813Gitte.Wrist.Lam@regionh.dkIda B Ebbensgaard, MDPrincipal Investigator