Urinary bladder cancer is a common cancer. In the Nordic countries annually 5.500-6.000 individuals are diagnosed with bladder cancer ( Nordcan). Risk factors include smoking, male gender, exposure to certain industrial chemicals, and certain medical treatments (especially pelvic radiotherapy).
Approximately two thirds of new bladder cancer cases are well differentiated and have low risk of progression and metastasis, but recurrences are frequent and therefore is demanding both for the patients and health-care system. The rest of the cases are poorly differentiated and harbor invasive and metastatic potential. Especially muscle-invasive bladder cancer is an aggressive cancer needing radical treatment. The treatment process is complex, requiring centers to have expertise in urology, oncology, radiotherapy, pathology, radiology, anesthesiology etc.
High risk non-invasive (TaT1) bladder cancer may be treated and cured without radical surgery (TUR-BT and intravesical instillations of BCG or chemotherapy), but in some cases radical cystectomy is needed. In the case of muscle-invasive bladder cancer, radical cystectomy with pelvic lymphadenectomy is the treatment of choice ( www.uroweb.org)
Radical cystectomy and pelvic lymphadenectomy may be performed with open surgery or with laparoscopic approach, the latter with or without robotic assistance. Next to the cystectomy, urinary diversion is also an integral part of the surgery. Urinary conduit (stoma) or construction of a new bladder (neobladder) are the most commonly used methods for urinary diversion. This surgery is one of the most complex cancer operations and is associated with significant risk of complications, including mortality. Furthermore, the process with major surgery, recovery period and adaptation to the new diversion is challenging for the patients and requires significant resources from the hospitals to support the patient’s journey.
Radical surgery alone is not always curative and there is a risk for disease recurrences after the operation. This risk may be decreased with addition of chemotherapy to the treatment regimen. Currently the recommended method for the delivery of the chemotherapy is neoadjuvant approach, i.e. chemotherapy is given prior to the surgery. With this approach significant improvement to the survival is achieved.
Recently, the quality of bladder cancer treatment has improved in many ways in the Nordic countries. With the recognition of relationship of improved treatment outcome and treatment volume, radical bladder cancer surgery has been centralized to expert centers in all Nordic countries. Currently this type of surgery is offered in less than 25 centers in the Nordics.
Other improvements include introduction of minimally invasive surgery (especially robotic assisted radical cystectomy) and ERAS (enhanced recovery after surgery) -protocols. All these improvements have likely resulted in decreased complication rates, decreased surgical morbidity and improved cancer survival, but unfortunately scientific publications of outcomes are few and often of low quality. There is a clear unmet need to know on national and international (Nordic) level the results of the radical bladder cancer care. In order to achieve this, we need well designed prospective studies measuring and reporting the outcome of the treatment with high population coverage.
Other unmet needs include need to identify risk factors for complications from the surgery as well as factors associated with survival. With this, the uro-oncological oncology may focus on improving of the most significant aspects of the care for the benefit of patients with bladder cancer.
The scientific aim is to collect high-quality data for research purposes. This allows various research projects to be conducted where the effect of specific details of care pathway is analyzed. Also, the data collected in the study allows reporting of outcome data on national and international level and this allows in the setting of Nordic standards of bladder cancer care.
In the urological literature there is numerous reports of various factors associated with outcome of the treatment. Despite this, in the routine clinical practice, we do not use any prognostic or predictive data apart from traditional tumor and patient characteristics. The main reason for this is the fact that majority of the publication are of low quality (retrospective, single institution etc.) and not properly validated. In order to improve this situation, we have designed prospective studies to validate the previous reports. These NorCys- substudies have been selected by the study board members and in the future, new substudies are welcomed.
The NorCys-study is conducted in all Nordic countries and each country. The study is led by the study board which includes all NUF Urothelial Bancer Group Members (two from each county apart from Iceland which has one member). The aim of the study is to include all centers performing radical bladder surgery in the Nordic countries. Each country has a has a national principal investigator (PI), who is responsible for the national coordination between the centers and authorities. Also, each center has a contact person for study related matters. In the table national PIs and centers which have confirmed participation are listed. Additional centers will be joining the study in near future.
Next to the investigators, Dr. Otto Ettala and Dr. Ilkka Nikulainen from Turku University, Finland, are running the RedCap data collection system and coordinating access privileges to the system.
The study is run by the Nordic Urothelial Cancer Group and all Nordic hospitals performing radical cystectomies are welcomed to participate in the study. All >18 year old individuals with histologically confirmed urinary bladder cancer who are planned to have radical cystectomy with or without neoadjuvant chemotherapy may be included in the study and patients with planned palliative cystectomy are eligible as well. Patients who undergo cystectomy for other reason than bladder cancer are not eligible. Other exclusion criteria include other bladder cancer surgeries than radical cystectomy and lack of signed informed consent.
The trial will be conducted in compliance with the “Principles of Good Clinical Practice” (ICH-GCP). The investigator is responsible that the trial is carried out in accordance with the Declaration of Helsinki in the revised version of Somerset West, South Africa 1996 and the “Principles of Good Clinical Practice“ (ICH-GCP), 1997. National PI´s have processed national ethical boards permissions and centers their own study approval processes.
In practice, patients are introduced with the study with verbal and written patient information at the time decision of radical cystectomy and may be included after receipt of the signed consent.
Data collection is done through RedCap – data collection platform ( www.project-redcap.org) with pseudonymized data.
As the study starts in Q3 2020, the trial starts with three substudies, designed to validate three different clinical parameters suggested to be associated with various outcome measures after radical cystectomy for bladder cancer
NorCys I-study is designed to validate the prognostic value of neutrophil-lymphocyte ratio (NLR) to estimate oncological outcome of BC after RC. Leucocyte ratios reflect the immunological status of the patients and relative leucocyte quantities have widely been studies for prognostic and predictive value in oncology. In bladder cancer, NLR have been reported in retrospective studies to predict cancer survival after radical cystectomy, both with and without neoadjuvant chemotherapy.
For our study, based on previous evidence we have decided to use the NLR cut-off value 3.0. According to the results, patients will be allocated into two groups: low NLR ratio (NLR<3), and high NLR ratio (NLR≥3). The primary end-point is bladder-cancer specific survival, and secondary endpoints include progression-free, and overall survival. For patients receiving NAC, additional secondary end-point is complete pathological response (pT0N0) rate at RC. Based on previous studies, high NLR patients have hazard risk of 1.88 for BC specific mortality compared to patients with low NLR. Having alpha level of 0.05 and beta of 0.20, a total of 192 patients is needed.
NorCys II-study is designed to validate the prognostic role of low albumin level to estimate complication risk after radical cystectomy. Low albumin level is a marker for poor nutritional status and available evidence from retrospective studies suggest that low albumin level is a predictor of complications after RC. The cut-off for low albumin has consistently been <3,5 mg/l across the studies.
The primary end-point is the 90-day major (Clavien 3-5) complication rate. The secondary end-points include total 90-day complication (Clavien 1-5) and 90-mortality rate (Clavien 5) for all patients and complication rate during NAC for patients receiving chemotherapy. In order to observe OR of 1.65 in 90-day complication rate comparing patients with low pre-operative albumin (S-Alb<3.7d/L, prevalence of 14%) and high pre-operative albumin (S-Alb ³3.7d/L, prevalence of 86%) with alpha level of 0.05 and beta of 0.20, a total of 1163 patients is needed.
NorCys III-study is designed to validate previous studies suggesting that blood transfusions during radical cystectomy and in-hospital period after surgery affect cancer survival negatively. The transfusion rate is recorded and patients without transfusions are compared to those receiving transfusions.
The primary end-point is bladder cancer specific mortality at 24 months. In order to observe HR of 1.31 when comparing BC specific mortality at 24 months between patients having no perioperative blood transfusions (CSS 0.80) and those having perioperative blood transfusions (CSS 0.71) and having alpha level of 0.05 and beta of 0.20, a total of 1754 patients is needed.
The NorCys study officially opens for recruitment on Q3 and patient data may be uploaded to RedCap system starting October 5th 2020. After inclusion, patients will be followed for five years. Substudy accrual will proceed based on specific substudy sample size targets.