Introduction
Background
Objective
Methods
Study design
Study population
-
Adult patients,
-
Histologically proven locally confined or locally advanced MIBC, i.e., cT2-T4a 0-N1M0,
-
Predominantly urothelial cell bladder carcinoma,
-
Scheduled for cisplatin-based NAC prior to RC with extended pelvic lymph node dissection (ePLND),
-
Prior to NAC, no evidence of regional or distant metastases on staging 2-Deoxy-2-[18F] fluorodeoxyglucose (18F-FDG) position emission tomography/computed tomography (PET/CT), albeit a single node in the surgical template of the ePLND (cN0–1 M0) is allowed
-
Carcinoma in situ (CIS) in the urethra prostatica at diagnosis
-
Patients with concomitant tumours of the upper urinary tract, tumours of the urachus or an additional malignancy that is progressing or has required active treatment within the past three years are excluded. Exceptions to these include patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or carcinoma in situ (e.g., breast carcinoma in situ, cervical carcinoma in situ), who have undergone potentially curative therapy. Participants with low-risk early-stage prostate cancer defined as follows will not be excluded: Stage T1c or T2a with an International Society of Urological Pathology (ISUP) grade 1 and prostate-specific antigen < 10 ng/mL either treated with definitive intent or on active surveillance that has been stable for the past year prior to study allocation.
-
Clinical response evaluation (CRE) by CT scanning during NAC shows progression of local disease or pulmonary, osseous, hepatic, or non-regional lymph-node metastases.
Study algorithm (Table 1, Fig. 1)
Overview
Pre-treatment | NACe week 3–15 | Surgery | Follow-up | ||||
---|---|---|---|---|---|---|---|
Visit | Visit 0 | Visit 1 | Visit 2 | Visit 4 | Visit 5 | Visit 6 | Visit 7 |
Week | -2 | 0 | 2 | 7–8 or 11–12 | 15–16 | 20–22 | 32–35 |
Informed consent | X* | ||||||
Inclusion | X* | ||||||
ECOG performance status | X | ||||||
Liquid biopsya | X* | X* | |||||
Urine cytology | X | X* | |||||
Blood hematologyb and biochemistryc | X | X | |||||
Staging 18F-FDG-PET/CTd | X | ||||||
CRE1f | X | ||||||
(optional) CRE2f | X | ||||||
BME, cystoscopy and TURg | X* | ||||||
RC with ePLND | X | ||||||
CRE3f | X |
Liquid biopsies
Clinical response evaluation during NAC
Surgery
Follow-up
Radiology
Pathology
Biomarker analyses
Study parameters/endpoints
-
The number of patients with pCR after NAC. pCR is defined as the absence of tumour cells in the RC specimen and in the resected pelvic lymph nodes (ypT0N0) or the presence of a non-invasive papillary tumour in the bladder without tumour cells in the resected pelvic lymph nodes (ypTaN0).
-
The number of participants in whom RC could have been withheld, i.e., the number of patient who could have undergone a bladder-sparing approach, if imaging, urine cytology, histological examination on re-staging TUR and molecular biomarker analyses was not followed by RC.
-
Perioperative complications of the re-staging TUR, such as perforation of the bladder wall, major bleeding in the bladder where haemostasis is not achieved with coagulation alone or any other surgical complications directly related to the re-staging TUR.
-
The number of participants who had ≥cN2Mx or cNxM1 disease on the staging FDG-PET/CT and were therefore counselled for a different treatment strategy than NAC plus RC.
Interim analysis and (serious) adverse events
Statistical analyses
Sample size calculation
-
After staging with 18F-FDG-PET/CT scan, 20 (95% CI 14–26) patients will have disseminated disease and are not candidates for curative NAC and RC.
-
After CRE during NAC, approximately 10 (95% CI 6–16) patients will have disseminated disease or progression of local disease after NAC. These patients are either candidates for palliative therapy or immediate RC;
-
After CRE, 60 (95% CI 40–90) and 90 (95% CI 70–110) patients will have a complete radiological response or stable disease/partial radiological response, respectively, and are candidates for RC.