Title: BladderPath: Image Directed Redesign of Bladder Cancer Treatment Pathways
Funder: Department of Health and Social Care

Abstract: Bladder cancer outcomes and treatment pathways have not changed significantly in 30 years. Following initial assessment in a haematuria clinic, standard management involves initial rigid cystoscopic transurethral resection of bladder tumour (TURBT), followed by further treatment for muscle invasive disease (MIBC) such as cystectomy or chemo-radiotherapy. TURBT has the dual purpose of staging and, for non-muscle invasive disease (NMIBC), removal of the tumour. For MIBC, TURBT is frequently sub-optimal for staging, delays definitive appropriate therapy and may contribute to dissemination of the tumour either extravesically by bladder perforation, or systemically by increasing circulating tumour cells. Additionally, post-TURBT, cross-sectional pelvic imaging is hard to interpret due to post-procedure artefacts such as perivesical inflammation or reactive lymph nodes interpreted as nodal spread. Delay in treatment may adversely affect prognosis. The ideal pathway would therefore separate NMIBC patients from MIBC patients early in the pathway. We are testing a modified pathway in which we use a combination of i) tumour appearance ii) histology and iii) initial radiology to stratify care. Each of these parameters can independently discriminate MIBC from NMIBC. By combining these three factors, we can partition patients into probable NMIBC (low-grade tumour, papillary/narrow stalk appearance) and possible MIBC (high grade tumour, solid appearance, CT suggestive of invasion). Those with proven histological high-grade or probable clinical/radiological muscle invasion (up to 50%) will proceed to multi-parametric MRI (mpMRI), which has a high sensitivity and specificity for distinguishing NMIBC from MIBC. Patients with no evidence of MIBC will proceed to standard endoscopic resection. Patients with probable MIBC will proceed to definitive therapy (chemotherapy, surgery or radiotherapy according to patient characteristics). These patients will have avoided a TURBT, had imaging unaffected by prior surgical procedures and a shorter pathway to definitive therapy. In addition, subsequent MRI scanning could more accurately assess patients’ responses to chemotherapy and radiotherapy. The trial is randomised at presentation. The randomisation is standard pathway 1 versus image-directed pathway 2. The trial has 3 stages: feasibility; intermediate and definitive stage. Feasibility Stage Duration: 1 year in 3 centres (total c. 150 patients, assuming 33% recruitment). Endpoints: • Feasibility of pathway 2 • Proportions of possible MIBC patients randomised to pathway 2 who undergo mpMRI as per protocol Intermediate Stage Aim: To assess time to MIBC-appropriate definitive treatment (TTDT). Our target is a minimum reduction of 30 days on pathway 2 for MIBC patients measured from 1st informed consent to 1st definitive treatment. Endpoints: • for MIBC: time to first of chemotherapy, radiotherapy or surgery Definitive Stage Assuming feasibility, an acceptably small rate of protocol violation and a reduction in TTDT on pathway 2 for MIBC, we will continue recruitment to the trial with the following endpoints: • Primary outcome: time to disease progression (loco-regional or metastatic) • Secondary outcomes: overall and disease-specific survival, health economics, TTDT for NMIBC

Lay abstract: Bladder cancer treatment and outcomes have not changed significantly in 30 years. Standard management comprises local anaesthetic inspection of the bladder with a small endoscope – termed flexible cystoscopy. If a bladder tumour is seen, the patient then proceeds to general anaesthetic removal of the tumour via a larger, rigid cystoscope - transurethral resection of bladder tumour (TURBT). The removed tumour is assessed to decide if it is confined to the bladder lining (non-muscle-invasive bladder cancer – NMIBC) or invading bladder muscle (muscle-invasive bladder cancer – MIBC). For NMIBC, the procedure should successfully remove all tumour; nonetheless further drug treatment into the bladder is usually given to reduce the risk of recurrence. For MIBC, removal is generally incomplete and further treatment required. This may be with cystectomy (to remove the bladder) or radiotherapy with or without chemotherapy. A major concern with the current pathway is that TURBT delays the definitive treatment - in the UK the typical delay from presentation to treatment is over 100 days. TURBT may also actively spread tumour into tissues around the bladder or into the blood stream. We believe that the prolonged pathway and potentially unnecessary TURBT may contribute to the poor outcomes seen with bladder cancer – around 50% will die of the disease within 5 years. The ideal pathway would therefore separate NMIBC from MIBC early, with treatment tailored more appropriately and rapidly according to disease stage. We are testing a modified pathway in which we are using flexible cystoscopy plus biopsy as initial assessment. The very small biopsy obtainable by this procedure is sufficient to confirm the presence of cancer and also the grade of tumour (high or low). Most muscle-invasive tumours are high grade. Non-muscle invasive tumours may be high or low grade. The urologist can also assess the overall appearance of the tumour. Combining these factors, we can partition patients into probable NMIBC (low grade tumour, sea anemone-like appearance) and possible MIBC (high grade tumour, solid appearance). Probable NMIBC (around 50% of the total) will continue with current standard therapy. Those with possible muscle-invasion will proceed to MRI scan and be further separated into MIBC and NMIBC. Patients with no evidence of muscle-invasion will proceed to standard TURBT. Patients with evidence of muscle-invasion will proceed directly to definitive therapy, avoiding TURBT and reducing delay. Patients entering the trial will be randomly assigned to either the current standard pathway 1 or the image-directed pathway 2. The trial has 3 stages: feasibility, intermediate and definitive clinical outcomes. Feasibility stage: This is carried out in three centres and is testing the ability to introduce pathway 2. The key endpoint is proportions of MIBC patients who undergo mpMRI as per protocol on pathway 2. Intermediate stage: Assuming feasibility, we will also seek to measure impact on time taken to receive MIBC-appropriate definitive treatment (chemotherapy, radiotherapy or cystectomy). Target outcome will be a reduction in time from 1st informed consent to definitive treatment from 100 to 70 days for MIBC. Final clinical outcomes: Assuming a reduction in time to treatment for muscle-invasive disease, we will continue with the aim of seeing reductions in relapse rates.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS