Image directed redesign of bladder cancer treatment pathways: the BladderPath RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as award number 14/08/60. The contractual start date was in April 2016. The draft manuscript began editorial review in February 2023 and was accepted for publication in September 2023. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ manuscript and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this article.

Copyright statement

Copyright © 2024 James et al. This work was produced by James et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2024 James et al.

Staging and treatment

The pros and cons of staging and treatment techniques for BC are summarised in Table 1, including the aim of TURBT in the settings of NMIBC and MIBC.

From the above, it is clear that the main functions of TURBT in MIBC are histological diagnosis of cancer and staging. Diagnosis does not require large quantities of tissue – very small amounts are sufficient to confirm the presence of high-grade malignant cells to ascertain grade (as exemplified by the almost ubiquitous use of urine cytology). The main function of TURBT in MIBC therefore is to assess stage. Where muscle is adequately sampled and is found to contain tumour, a diagnosis of MIBC is correct by definition (although not a more comprehensive nodal or metastasis stage). The issue is the understaging of high-grade tumours due to inadequate sampling of muscle that subsequently turns out to be involved by tumour. As cystectomy is a recognised treatment for high-risk NMIBC,12 either at diagnosis or after the failure of treatments such as bacillus Calmette–Guérin (BCG), the false-negative rate with respect to distinguishing NMIBC from MIBC in the highest risk cases can be estimated – this appears to be as high as 30%,1,6 although will clearly vary depending upon the surgeon and referred case mix. Within this context, we can assess the accuracy of magnetic resonance imaging (MRI) for the same purpose. The key factor here is the split between tumours of stage pT1 and lower versus pT2 and higher.

Thus, the diagnostic function of TURBT can be substituted by a smaller biopsy obtained during outpatient flexible cystoscopy. For staging, multiparametric MRI (mpMRI) has performance characteristics that exceed those reported for TURBT, are less subject to operator variability and are amenable to external review. 22–24 Furthermore, in most cases, the therapeutic benefit for TURBT in MIBC patients remains unproven, particularly if cystectomy is the preferred definitive treatment option. The literature on staging BC has been recently reviewed by Bouchelouche and co-workers. 25–27

A role for TURBT as palliation of severe symptoms from MIBC pending a definitive treatment decision will remain. Its precise magnitude will be quantified in this study but is likely to be limited as, in most cases, symptoms such as haematuria are intermittent (one of the factors leading to delayed presentation).

Hypothesis

The purpose of the BladderPath study is to evaluate a new pathway that would eliminate TURBT from the initial staging of MIBC patients. This allows more expeditious treatments for both MIBC (by eliminating delays and improved targeting of subsequent therapy) and NMIBC (by reducing demand for TURBT in the system). Our approach integrates flexible cystoscopy, urine cytology, biopsy and detailed imaging to confirm the diagnosis and stage of disease. Appropriate definitive radical therapy can then be rapidly commenced. This could include TURBT if indicated for reasons such as diagnostic uncertainty, assessment of carcinoma in situ (CIS; e.g. for planning cystectomy) or debulking prior to radiotherapy. For the purposes of the trial, TURBT in patients with MIBC did not count as part of their definitive treatment. This is a paradigm shift in the context of BC but is standard practice in virtually every other solid tumour setting (e.g. prostate, breast, lung). Although TURBT is considered a standard part of care for NMIBC, for MIBC it is less obviously essential, particularly for patients undergoing subsequent radical surgery (cystectomy). This study tested the utility of TURBT and mpMRI as components of the initial care for MIBC patients in a randomised fashion.

Rationale

The prognosis for MIBC remains poor and has not changed for three decades. 1,3,4 Modern MRI approaches now have the ability to accurately stage bladder tumours11,28,29 and experimental urinary biomarkers show great promise in identifying MIBC from a urine test. 30,31 The platforms therefore exist to improve patient pathways, potentially leading to improved outcomes.

In order to change the current pathway, we need to show that alternatives to TURBT exist for staging, and that faster treatment will improve outcomes:

1. Do we need TURBT for histology?

   1. Flexible cystoscopy and biopsy can give accurate tumour histological diagnosis and grading but does not assess stage or muscle invasion.

2. Can we replace TURBT for detailed assessment of the bladder tumour?

   1. TURBT is frequently inaccurate and operator dependent – up to 30% of tumours assessed as high-grade NMIBC at TURBT are subsequently diagnosed as invasive (MIBC) on repeat TURBT or at cystectomy. 5,32

   2. Guidelines recommend repeat TURBT for patients staged G3pT1 because of the high incidence of understaging – further delaying correct treatment in some patients with MIBC. 5,32

   3. Sensitivity and specificity of mpMRI for separating NMIBC from MIBC are 94% and 100%, respectively. 11,27–29,33,34

   4. Introducing mpMRI ahead of TURBT (if indicated) should not compromise staging and may improve it.

3. Is TURBT an essential component of treatment?

   1. There are no randomised data on this topic – this is one of the aims of this study.

   2. Evidence exists that TURBT may increase local tumour dissemination35 and lead to increases in circulating tumour cells. 9

   3. In most other oncology settings, imaging and biopsy are sufficient for correct treatment; in some cases, imaging alone is sufficient (e.g. kidney cancer and upper tract urothelial cancer). Few tumour sites use an intermediate piecemeal debulking ahead of definitive therapy. 36

4. Does delaying the correct definitive treatment affect prognosis?

   1. Typical duration from first clinic visit to correct definitive treatment within the NHS for MIBC is around 100 days. 6,20,37 Similar delays exist worldwide. 14

   2. There is evidence that delay can affect prognosis for MIBC. 14,16,17

   3. Hence, reducing delay should improve prognosis.

Aims and objectives

The aims of the BladderPath study are to evaluate whether it is possible to expedite radical treatment for patients with MIBC using MRI rather than TURBT to diagnose and more accurately and rapidly stage their cancer. We hypothesise this may improve outcomes from MIBC by reducing the time from diagnosis to radical treatment.

Outcome measures

The primary and secondary outcomes change as we go through the study. These are summarised in Table 2.

Methods

BladderPath is a randomised trial comparing risk-stratified image-directed (mpMRI) care with TURBT for patients with newly diagnosed BC. Patients with symptoms suspicious of a new diagnosis of BC were identified via haematuria clinics and provided written informed consent for study participation. Ineligible patients were those who were unable or unwilling to undergo MRI, those with a previous BC diagnosis and those who had previously entered the study. Participants were randomised to the standard clinical pathway (Pathway 1: all patients undergo TURBT) or the investigational pathway (Pathway 2) whereby those participants with possible MIBC (Likert 3–5 as visually assessed on a 5-point Likert scale at flexible cystoscopy) undergo initial mpMRI-based assessment with flexible cystoscopy tumour biopsy.

Pathway 2 probable NMIBC (Likert 1–2) participants underwent TURBT. Primary outcomes: feasibility phase – proportion of Pathway 2 possible MIBC participants who correctly followed protocol (target: 80%); intermediate stage – time to first correct treatment (chemotherapy, radiotherapy, surgery, decision for palliative care) for participants with confirmed MIBC (target: 30-day improvement). Randomisation was achieved by using a computerised allocation program; stratification variables included participants’ sex, age and clinician’s initial visual assessment of muscle invasiveness of the tumour. Blinding of participants, caregivers and outcome assessors was not possible.

Study design

The Image Directed Redesign of BC Treatment Pathways (‘BladderPath’) study was an open-label, multistage, randomised controlled study with three overlapping stages: feasibility, intermediate and final efficacy stage. BladderPath was conducted by the Urology units in 15 UK hospitals and was sponsored by the University of Birmingham, UK, with NHS Research ethics approval (17/LO/1819, ISRCTN 35296862), funded by the UK National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) scheme. 14,38 The study protocol is available online: www.birmingham.ac.uk/research/crctu/trials/bladder-path/index.aspx.

Participants

Following the provision of dedicated patient information sheets, participants were recruited by Urology teams at hospital outpatient haematuria clinics. 39 A two-stage written informed consent process was adopted to allow prospective collection of urine samples before initial cystoscopy for a diagnostic urinary biomarker substudy (first stage),35 with confirmatory written informed consent undertaken following cystoscopy (second stage). Hence, inclusion criteria were: patients attending clinic for the investigation of symptoms suspicious of BC (initial consent process), and patients given a diagnosis of suspected BC and requiring TURBT based on visual cystoscopic examination of the bladder (confirmatory consent process following outpatient flexible cystoscopy). Excluded patients were those unable or unwilling to undergo MRI, those with a previous diagnosis of BC and previous entry in the present study.

Randomisation and masking

Participants were randomised by computer using minimisation on a 1 : 1 basis to Pathway 1 (standard of care: TURBT) or Pathway 2 (investigational: mpMRI): minimisation factors used were patient sex (male/female), age (< 75/≥ 75 years old) and clinician assessment at outpatient flexible cystoscopy (probable NMIBC/possible MIBC). A random element was incorporated into the minimisation algorithm at 20% ensuring it was not predictable. Randomisation was not blinded, with both participants and healthcare teams knowing which pathway had been allocated to participants.

Procedures

The study compared TURBT with mpMRI for the initial assessment of possible MIBC. The current SOC pathway comprises flexible cystoscopy in outpatient clinics combined with upper urinary tract imaging and, potentially, cross-sectional imaging of the bladder/pelvis followed by TURBT for participants with lesions suspicious for BC.

Participants were randomised to either Pathway 1 or 2 following visual assessment of the suspicion of NMIBC or MIBC at the time of outpatient flexible cystoscopy. The definition of likelihood of MIBC was based on a 5-point Likert scale: (1) strongly agree or (2) agree that the lesion is NMIBC, or (3) equivocal, or (4) agree or (5) strongly agree that the lesion is MIBC. Likert 1 and 2 were considered probable NMIBC and 3, 4 and 5 were considered possible MIBC.

All participants

Non-muscle-invasive bladder cancer participants underwent TURBT. In accordance with national and international guidelines, radical treatment with chemotherapy, surgery or (chemo) radiation was offered to all participants with MIBC where appropriate, based upon the results of either TURBT or mpMRI staging or both. For both groups, if unsuited to radical treatment, participants were referred for palliative care. All treatment decisions were made by the treating MDT. The study schema is shown in Figure 1.

FIGURE 1.

BladderPath Trial schema.

Assessments

Initial clinical assessments (visit 1), potentially split over more than one visit depending on local practice) comprised: medical history (including concomitant medication), full blood count (FBC), liver function tests (LFTs), urea and electrolytes (U+Es), collection of urine samples for translational research, tumour biopsy (either via flexible cystoscopy at initial visit or at a subsequent visit if randomised to pathway 2 and considered possible MIBC) and completion of a participant reported outcomes quality of life booklet. At the time of the study procedure (visit 2, for either TURBT or mpMRI), a review of adverse events (AEs) was undertaken. At the decision to treat (DTT) (visit 3, following TURBT or mpMRI and multidisciplinary review), assessments comprised: medical history, FBC, LFTs, U+Es, and review of AEs. Adjuvant therapy and follow-up were according to SOC dependent upon NMIBC risk category6 or MIBC treatment strategy. 14

Outcomes

The aims of the BladderPath study were to evaluate whether it was possible to expedite radical treatment for participants with MIBC using mpMRI rather than TURBT to more accurately and rapidly stage their cancer. We hypothesised that this may improve outcomes from MIBC by reducing the time from diagnosis to the correct (radical) treatment. The study was conceived as three stages with the primary outcomes of feasibility, time to correct therapy (TTCT) for MIBC and clinical progression-free survival.

Sample size calculation

In the feasibility stage, the target sample size was 150 participants (approximately 38 possible MIBC participants in Pathway 2). If the proportion of possible MIBC participants randomised to Pathway 2 who correctly follow pathway protocol exceeded 80%, the image-directed Pathway 2 was considered feasible in clinical practice. 38

For the Intermediate stage, the primary outcome was TTCT. We assumed that the TTCT in standard care had a median of 100 days and the effects of mpMRI would be to reduce the median TTCT to 70 days for MIBC participants. If the distribution of the TTCT for participants undergoing mpMRI followed a Weibull distribution with the same shape parameter as those receiving standard care, and that the usual proportional hazards assumption held, then a ‘hazard ratio (HR)’ of 3.6 was the effect size we wished to detect. More specifically, on average, it would be 3.6 times quicker to receive correct treatment for MIBC participants who underwent mpMRI compared to those underwent TURBT. To have 80% power to detect a HR of 3.6 using a Cox model required 20 MIBC participants. Around 20–25% of new BC participants present with de novo MIBC; hence, to recruit 20 MIBC participants, approximately 80–100 participants were required.

In the intermediate stage, the power was event driven and depended upon the number of observed events.

Due to slow recruitment (affected by COVID-19 the pandemic), it was unfeasible to reach the sample size required for a final clinical stage. A decision was made by the Trial Management Group (TMG), in discussion with the NIHR HTA, to close recruitment after sufficient participants for the first two stages had been recruited. The trial closed to recruitment on 31 December 2021. The database was locked on 20 September 2022 to allow a period of follow-up for the time-to-event outcomes. Longer-term follow-up to 2 years for all patients will be carried out via NHS digital records using methodology piloted during the study and will be reported once available in a separate publication.

Statistical analysis

The statistical analyses were carried out on an intention-to-treat basis, retaining patients in their randomised pathway groups and including patients who were protocol deviations and ineligible patients.

Proportions were calculated using the exact method and presented with 95% confidence intervals (CIs). Time-to-event estimates were assessed using Kaplan–Meier method and presented with 95% CIs. Time-to-event outcomes were analysed using a Cox regression model with stratification factors of age and sex included as covariates and study centre included as a random effect. Proportional hazards assumptions were investigated using Schoenfeld residuals and log–log plots. For instances when the Cox regression method was not appropriate due to small sample sizes, a mixed-effect Weibull survival model was utilised.

Health economics

Quality of life and health economics were outcomes for the final stage which was not completed. A basic health economic section has been added. Quality-of-life questionnaires from baseline assessment and subsequent follow-up time points were requested from consenting randomised participants. The returned data will be analysed and reported alongside the long-term follow-up data.

EuroQol-5 Dimensions data were collected but a formal health economic analysis was not carried out, as this would require the long-term outcomes data which are not yet available. We have however carried out some simple cost modelling using tariffs from NHS England40 to estimate the crude cost impact of introducing MRI into the pathway for possible muscle-invasive disease.

Oversight

Trial Management Group: The TMG consisted of the Chief Investigator (Professor Nicholas James), Co-investigator Urology (Professor James Catto, Mr Prashant Patel and Mr Kieran Jefferson), Co-investigator Patient Involvement (Ms Jean Gallagher), Co-investigator Biomarker Research (Dr Richard Bryan), Co-investigator Qualitative substudy (Dr Veronica Nanton), Co-investigator Health Informatics (Ms Alicia Jakeman), Biology Systems Co-investigator, Statistics Co-investigator, Imaging Co-investigators, Medical Oncology Co-investigator, Trial Management Team Leader, Senior Trial Coordinator, Trial Coordinator/Administrator, Lead Statistician and Trial Statistician. Notwithstanding the legal obligations of the Sponsor and Chief Investigator, the TMG were responsible for the day-to-day running and management of the trial.

Data analyses were supplied in confidence to an independent Data Monitoring Committee (DMC) who monitored patient safety and advised on whether the accumulated data justified continuation of recruitment. DMC meetings were scheduled at least annually until the study closed to recruitment.

Recruitment

Between 31 May 2018 and 31 December 2021, 15 of the 17 centres open to the BladderPath study recruited at least 1 participant; 638 patients were screened as potentially eligible, of which 309 were registered and 143 randomised (72 to Pathway 1, 71 to Pathway 2); 166 registered patients not randomised were not found to have BC during initial cystoscopy. Figure 2 shows cumulative accrual versus target recruitment during the course of the study. The graph clearly shows the impact of the COVID-19 pandemic with cessation of recruitment for most of 2020, as required by the NHS pandemic response. Post pandemic, the recruitment rate was clearly much slower than prior to the event.

FIGURE 2.

Recruitment between June 2018 and December 2021.

Recruitment targets were adjusted several times, initially aiming to improve recruitment (notably between June 2019 and February 2020) and, subsequently, to account for the devastating effect of the COVID-19 pandemic on recruitment from March 2020 onwards. The study eventually recruited 143 participants, summarised in the Consolidated Standards of Reporting Trials (CONSORT) diagram (Figure 3), close to the feasibility stage target of 150. Despite most sites having reopened to recruitment following the pandemic, fewer patients were able or willing to consider taking part in the study, and one site was unable to re-open.

FIGURE 3.

Consolidated Standards of Reporting Trials flow chart – showing recruitment through to randomised allocation.

Outcomes following randomisation are shown in a separate diagram (Figure 4).

FIGURE 4.

Illustration of the flow of participants through the study. ^aPopulation in primary outcome analysis (i.e. possible MIBC participants confirmed MIBC by TURBT/cystectomy or treated with MIBC therapy, 14 in Pathway 1 and 12 in Pathway 2). NAC, neo-adjuvant chemotherapy; Pal Care, Palliative care; SCR, synchronous chemo-radiotherapy.

Losses and exclusions

No patients were reported as being lost to follow-up during the study.

Ineligibilities

Three participants were subsequently found to be ineligible post randomisation: one in Pathway 1 and one in Pathway 2 due to estimated glomerular filtration rate (eGFR) below the accepted range and one participant in Pathway 2 due to ineligibility for MRI scanning.

Protocol deviations

Nine protocol deviations were reported by nine participants (five in Pathway 1, four in Pathway 2), mainly due to administrative error, summarised in Table 3.

Patient withdrawal of consent

Seven patients withdrew from the main trial (of which five also withdrew consent from all substudies). Of the seven withdrawals, three were found not to have cancer on histopathology, two participants felt unable to continue including one with severe dementia, one experienced delays in patient care timeline and one withdrew due to the complex nature of the diagnosis.

Six out of the seven participants who wished to withdraw from trial were not willing for further data to be supplied to the Trials Office (Table 4). One patient did not specify their wish to allow further data collection, not being able to remember consenting to take part – the clinical team withdrew the patient on discovering the participant had dementia.

Stratification factors

Participants were stratified by three factors at randomisation (Table 5).

Participant characteristics

Characteristics of the 143 randomised participants are shown in Table 6.

Research sites were asked to provide baseline biochemistry and haematology results if tested as part of standard care at the time of screening, or within a short period prior to study entry. These results, as summarised in Tables 7 and 8, were only recorded at baseline with a view to forming a baseline picture. Blood tests were not repeated at subsequent time points for analysis purposes.

Initial flexible cystoscopy

One hundred and forty-two participants underwent initial flexible cystoscopy; one participant underwent CT chest abdomen pelvis, so all flexible cystoscopy data for that patient are missing (Table 9).

Transurethral resection of bladder tumour

One hundred and thirty participants had 1 TURBT, 43 had 2, 7 had 3 and 2 had 4. In total, 182 TURBT procedures were carried out (Table 10).

Magnetic resonance imaging

Table 13 summarises the numbers of participants who underwent MRI. In all, 42 participants underwent MRI, including 6 in error (4 in Pathway 1 who were possible MIBC; 2 in Pathway 2 who were probable NMIBC).

Definitive and correct treatments

Overall, 137 (95.8%) patients received their definitive treatment. Of the six participants who did not receive definitive treatment, one did not have cancer, four were early withdrawals and one was due to an administrative error in which a Pathway 1 participant underwent MRI (but not TURBT) with MRI confirming MIBC.

As summarised in Table 14, 130 (90.9%) participants received correct treatment. Of the 13 participants who did not, 3 did not have cancer, 3 withdrew early (˂ 100 days), 1 died, 2 were probable NMIBC who had TURBT-diagnosed MIBC and were awaiting a correct treatment, and 4 were probable NMIBC participants who had no confirmed MIBC, NMIBC or were awaiting a correct treatment.

Swimmer plots: initial clinical assessment of probable non-muscle-invasive bladder cancer and possible muscle-invasive bladder cancer across arms

Four swimmer plots sorted by TTDT: 34 Pathway 1 probable NMIBC participants Figure 5), 38 Pathway 1 possible MIBC (Figure 6), 32 Pathway 2 probable NMIBC (Figure 7) and 39 Pathway 2 possible MIBC (Figure 8). Two participants in Figure 6 and four participants in Figure 7 received MRI in error.

FIGURE 5.

Swimmer plot for pathway 1 probable NMIBC participants.

FIGURE 6.

Swimmer plot for Pathway 2 probable NMIBC participants.

FIGURE 7.

Swimmer plot for Pathway 1 possible MIBC participants.

FIGURE 8.

Swimmer plot for Pathway 2 possible MIBC participants.

Swimmer plots: final assessment of non-muscle-invasive bladder cancer and muscle-invasive bladder cancer

Four swimmer plots sorted by TTCT. Of the 143 participants, 133 (93.0%) had a confirmed NMIBC/MIBC, including 51 NMIBC in Pathway 1 (Figure 9), 55 NMIBC in Pathway 2 (Figure 10), 14 MIBC in Pathway 1 (Figure 11) and 13 MIBC in Pathway 2 (Figure 12). Of note, 7/14 MIBC patients on Pathway 2 avoided the need for TURBT.

FIGURE 9.

Swimmer plot for Pathway 1 NMIBC participants.

FIGURE 10.

Swimmer plot for Pathway 2 NMIBC participants.

FIGURE 11.

Swimmer plot for Pathway 1 MIBC participants.

FIGURE 12.

Swimmer plot for Pathway 2 MIBC participants.

Summaries of types of treatment received

Outcomes

Intermediate stage

Primary outcome: time to correct treatment for participants who were initially classified as possible muscle-invasive bladder cancer and then were confirmed to have muscle-invasive bladder cancer

Of the 26 participants who were initially classified as possible MIBC and then were confirmed MIBC (14 in Pathway 1 and 12 in Pathway 2; Figure 13), 25 received a correct treatment and 1 participant did not due to death 81 days post randomisation. For this latter participant, the date last seen was used in the time-to-event analysis to account for the length of time they had waited to start treatment. Median TTCT for all participants who were initially classified as possible MIBC and then were confirmed to have MIBC (N = 26) was 77 days (95% CI 54 to 100). Median TTCT for Pathway 1 (N = 14) was 98 days (95% CI 72 to 125). Median TTCT for Pathway 2 (N = 12) was 53 days (95% CI 20 to 89, p = 0.0201), suggesting a statistical difference in TTCT between the two pathways. A Cox model, adjusted for the stratification factors of sex and age with study centre included as a random effect in the model, showed that the HR of an event for Pathway 2 versus Pathway 1 was 2.9 (95% CI 1.0 to 8.1, p = 0.04). An event in this model relates to a participant receiving a correct treatment; therefore, a HR of 2.9 indicates that participants in Pathway 2 received correct treatment 2.9 times quicker than those in Pathway 1.

FIGURE 13.

Kaplan–Meier curves of TTCT by pathway for possible MIBC participants who were confirmed MIBC and received a correct treatment.

Exploratory sensitivity analysis: the primary outcome in the intermediate stage but excluding participants whose correct treatment was palliative care

Some participants were declared as requiring palliative care, but the date of that decision depended upon on the sites’ clinical teams. Hence, careful consideration was made to account for these participants appropriately within the time-to-treatment analysis, while avoiding misleading results. This section shows a sensitivity analysis for the primary outcome, excluding participants with palliative care as their correct treatment.

There were 19 participants who were initially classified and then confirmed as having MIBC, where their correct treatment was not palliative care alone (10 in Pathway 1, and 9 in Pathway 2; Figure 14). Median TTCT for this subset of participants (N = 19) was 81 days (95% CI 54 to 100). Median TTCT for Pathway 1 (N = 10) was 81 days (95% CI 42 to 124) and median TTCT for Pathway 2 (N = 9) was 54 days (95% CI 22 to 100), log-rank p = 0.2366. Hence, the difference in TTCT between pathways became smaller when excluding participants whose correct treatment was palliative care only. In this post hoc subgroup analysis, a Cox model adjusted for the stratification factors of sex and age shows that the HR for Pathway 2 versus Pathway 1 was 1.9 (95% CI 0.6 to 5.9).

FIGURE 14.

Kaplan–Meier curves of TTCT by pathway for possible MIBC participants with confirmed MIBC and received correct treatment, excluding participants who received palliative care as their correct treatment.

It should be noted in this context that the decision to offer palliative care was made often very early in the MRI pathway, whereas it was often made very late in the standard pathway (in one case after the patient had died). This should be viewed as a very positive advantage for early MRI as patients will have likely been offered more appropriate palliative care support and are potentially spared the morbidity of a diagnostic TURBT if, for example, they are found to have locally advanced or metastatic disease.

Secondary outcome: TTCT for probable non-muscle-invasive bladder cancer participants confirmed as non-muscle-invasive bladder cancer

There were 58 participants who were initially classified as having probable NMIBC which was then confirmed (28 in Pathway 1 and 30 in Pathway 2; Figure 15); all such participants received their correct treatment of TURBT. Median TTCT for probable NMIBC participants confirmed as NMIBC (N = 58) was 16 days (95% CI 11 to 23). Median TTCT for Pathway 1 (N = 28) was 14 days (95% CI 10 to 29) and median TTCT for Pathway 2 (N = 30) was 17 days (95% CI 8 to 25, p = 0.6677). A Cox model adjusted for the stratification factors of sex and age showed that the HR for Pathway 2 versus Pathway 1 was 0.8 (95% CI 0.5 to 1.5).

FIGURE 15.

Kaplan–Meier curves of TTCT by pathway for probable NMIBC participants who were confirmed NMIBC and received a correct treatment.

Secondary outcome: TTCT for all randomised participants

Of the 143 randomised participants (72 in Pathway 1 and 71 in Pathway 2; Figure 16), 131 received a correct treatment. Participants who did not receive a correct treatment were censored at their date last seen and were included in the time-to-treatment analysis. Median TTCT for all randomised participants (N = 143) was 31 days (95% CI 22 to 37). Median TTCT for Pathway 1 (N = 72) was 37 days (95% CI 23 to 47) and median TTCT for Pathway 2 (N = 71) was 25 days (95% CI 18 to 35, p = 0.0295). A Cox model adjusted for the stratification factors of sex and age showed that the HR for Pathway 2 versus Pathway 1 was 1.4 (95% CI 0.9 to 2.0).

FIGURE 16.

Kaplan–Meier curves of TTCT by pathway for all randomised participants.

Follow-up

Length of follow-up

Overall, the median length of follow-up was 23.7 months (95% CI 23.7 to 24.0), 23.7 months (95% CI 23.7 to 24.0) for Pathway 1 (N = 72) and 24.0 months (95% CI 23.7 to 24.1) for Pathway 2 (N = 71), illustrated in Figure 17.

FIGURE 17.

Proportion of participants followed up.

Follow-up cystoscopy results are summarised in Table 26.

TABLE 26 - Summarised data from follow-up cystoscopy

Follow-up (month)	3 (131)	6 (123)	9 (115)	12 (105)	18 (97)	24 (90)	36 (22)	Overall (683)
Has the participant had a cystoscopy as part of their follow-up
No	107 (82.9)	73 (60.8)	61 (55.5)	56 (57.1)	28 (31.5)	35 (40.7)	7 (33.3)	367 (56.2)
Yes	22 (17.1)	47 (39.2)	49 (44.5)	42 (42.9)	61 (68.5)	51 (59.3)	14 (66.7)	286 (43.8)
Not known	2	3	5	7	8	4	1	30
Cystoscopy type
Flexible cystoscopy	14 (66.7)	41 (87.2)	45 (91.8)	35 (83.3)	55 (91.7)	50 (98.0)	13 (92.9)	253 (89.1)
Rigid cystoscopy	7 (33.3)	6 (12.8)	4 (8.2)	7 (16.7)	5 (8.3)	1 (2.0)	1 (7.1)	31 (10.9)
Not known	110	76	66	63	37	39	8	399
Tumour biopsies taken at the time of cystoscopy
No	13 (59.1)	41 (87.2)	43 (87.8)	33 (78.6)	45 (73.8)	40 (78.4)	9 (75.0)	224 (78.9)
Yes	9 (40.9)	6 (12.8)	6 (12.2)	9 (21.4)	16 (26.2)	11 (21.6)	3 (25.0)	60 (21.1)
Not known	109	76	66	63	36	39	10	399
Random biopsies of mucosa taken at the time of cystoscopy
No	15 (78.9)	41 (91.1)	43 (95.6)	36 (90.0)	49 (86.0)	44 (88.0)	12 (92.3)	240 (89.2)
Yes	4 (21.1)	4 (8.9)	2 (4.4)	4 (10.0)	8 (14.0)	6 (12.0)	1 (7.7)	29 (10.8)
Not known	112	78	70	65	40	40	9	414
Cystoscopy findings
No evidence of disease	14 (66.7)	36 (76.6)	32 (65.3)	31 (73.8)	41 (67.2)	33 (64.7)	10 (71.4)	197 (69.1)
No tumour seen but suggestive of CIS	2 (9.5)	1 (2.1)	0 (0.0)	1 (2.4)	3 (4.9)	3 (5.9)	0 (0.0)	10 (3.5)
Evidence of tumour	5 (23.8)	8 (17.0)	10 (20.4)	9 (21.4)	12 (19.7)	12 (23.5)	3 (21.4)	59 (20.7)
Equivocal (tumour suspected but not confirmed)	0 (0.0)	2 (4.3)	7 (14.3)	1 (2.4)	5 (8.2)	3 (5.9)	1 (7.1)	19 (6.7)
Not known	110	76	66	63	36	39	8	398

Follow-up data reporting cytology and imaging results on suspicion of recurrence are summarised in Table 27.

TABLE 27 - Summarised data from follow-up further cytology and imaging

N/A, not available.

Follow-up (month)	3 (131)	6 (123)	9 (115)	12 (105)	18 (97)	24 (90)	36 (22)	Overall (683)
Clinical examination findings suspicious of recurrence
No	95 (93.1)	87 (91.6)	64 (83.1)	58 (82.9)	61 (82.4)	65 (86.7)	18 (94.7)	448 (87.5)
Yes	7 (6.9)	8 (8.4)	13 (16.9)	12 (17.1)	13 (17.6)	10 (13.3)	1 (5.3)	64 (12.5)
Not known	29	28	38	35	23	15	3	171
Cytology
No	99 (96.1)	90 (92.8)	71 (94.7)	63 (91.3)	67 (90.5)	67 (89.3)	15 (78.9)	472 (92.2)
Yes	4 (3.9)	7 (7.2)	4 (5.3)	6 (8.7)	7 (9.5)	8 (10.7)	4 (21.1)	40 (7.8)
Not known	28	26	40	36	23	15	3	171
Cytology result
Abnormal cells suspicious	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.4)	0 (0.0)	1 (1.3)	1 (5.3)	3 (0.6)
Malignant cells present	2 (1.9)	0 (0.0)	0 (0.0)	1 (1.4)	0 (0.0)	1 (1.3)	0 (0.0)	4 (0.8)
N/A	99 (96.1)	90 (92.8)	71 (95.9)	63 (91.3)	67 (90.5)	67 (89.3)	15 (78.9)	472 (92.4)
No malignant cells	2 (1.9)	6 (6.2)	3 (4.1)	4 (5.8)	7 (9.5)	6 (8.0)	3 (15.8)	31 (6.1)
Not done	0 (0.0)	1 (1.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.2)
Not known	28	26	41	36	23	15	3	172
Further imaging
No	82 (71.3)	90 (81.1)	79 (84.9)	71 (84.5)	68 (77.3)	59 (72.8)	16 (76.2)	465 (78.4)
Yes	33 (28.7)	21 (18.9)	14 (15.1)	13 (15.5)	20 (22.7)	22 (27.2)	5 (23.8)	128 (21.6)
Not known	16	12	22	21	9	9	1	90
Further imaging detail
CT scan	28 (24.3)	19 (17.1)	13 (14.0)	12 (14.3)	16 (18.2)	19 (23.5)	5 (23.8)	112 (18.9)
MRI scan	2 (1.7)	2 (1.8)	0 (0.0)	1 (1.2)	2 (2.3)	1 (1.2)	0 (0.0)	8 (1.3)
N/A	82 (71.3)	90 (81.1)	79 (84.9)	71 (84.5)	68 (77.3)	59 (72.8)	16 (76.2)	465 (78.4)
Ultrasound	2 (1.7)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.1)	0 (0.0)	0 (0.0)	3 (0.5)
X-ray	1 (0.9)	0 (0.0)	1 (1.1)	0 (0.0)	1 (1.1)	2 (2.5)	0 (0.0)	5 (0.8)
Not known	16	12	22	21	9	9	1	90
Disease recurrence/progression
N/A	82 (71.9)	90 (81.8)	79 (84.9)	71 (84.5)	68 (77.3)	59 (72.8)	16 (76.2)	465 (78.7)
No	26 (22.8)	15 (13.6)	11 (11.8)	8 (9.5)	15 (17.0)	18 (22.2)	2 (9.5)	95 (16.1)
Yes	6 (5.3)	5 (4.5)	3 (3.2)	5 (6.0)	5 (5.7)	4 (4.9)	3 (14.3)	31 (5.2)
Not known	17	13	22	21	9	9	1	92

Conclusions

The mpMRI-directed pathway (Pathway 2) led to a substantial reduction in TTCT for MIBC participants without detriment to the TTCT for NMIBC participants. The initial Likert scale assessment at flexible cystoscopy accurately identified lower-risk NMIBC who all required TURBT and suggest no benefit from MRI in this lower-risk setting. Higher-risk patients identified at flexible cystoscopy benefited from MRI prior to any further intervention. Consideration should be given to the incorporation of mpMRI ahead of TURBT in the standard pathway for all patients with suspected MIBC. The improved decision-making accelerated time to treatment, even though many patients subsequently needed TURBT as part of their treatment plan. It also allowed around half of the MIBC patients to avoid TURBT completely and to proceed, with combined histological (for tissue diagnosis) and radiological confirmation of invasion or metastasis, to correct treatment for their MIBC, saving resources and reducing patient morbidity.

Discussion

We undertook the BladderPath study to investigate whether suspected MIBC participants may be safely expedited to correct treatment using initial mpMRI for initial local staging rather than TURBT. We have shown that it is feasible to introduce mpMRI for a proportion of participants visually diagnosed with possible MIBC at outpatient diagnostic flexible cystoscopy45 and, in doing so, MIBC participants receive their correct treatment significantly (over 6 weeks) quicker. We also show that deploying mpMRI in this way also allowed NMIBC participants to receive their correct treatment (TURBT) more rapidly, perhaps by reducing operating theatre demand through avoiding inappropriate TURBT for MIBC. As noted, many of these higher-risk patients also required TURBT, for example to resolve diagnostic uncertainty, to debulk patients prior to chemoradiation or to assess factors such as CIS or variant histology. Despite this, the Pathway 2 patients still received their definitive treatment faster than those assessed solely with TURBT.

Delays in administering the correct treatment for MIBC participants are internationally widespread and contribute to worsening prognosis. 14,21,45–47 The shortcomings of TURBT are well-reported and delay the correct treatment for MIBC participants by radical therapies, lead to incorrect therapy choices and possibly contribute to tumour spread. 45 Over the last decade, multiple studies have confirmed that mpMRI has higher sensitivity and specificity for more accurate discrimination of NMIBC and MIBC than TURBT,22,23 and so potentially offering a safer and faster route to staging and hence correct treatment. Although the relationship between delay and survival in BC is complex,48 it is reasonable to suggest that administering correct treatment to MIBC participants more than 6 weeks earlier than the current SOC can only be beneficial. Several studies report adverse outcomes associated with delays of over 3 months between BC diagnosis and RC;49,50 the mpMRI-guided pathway (Pathway 2) undercut this by a considerable margin (median TTCT 53 days), whereas the standard pathway did not (median TTCT 98 days).

Transurethral resection of bladder tumour has been the cornerstone of the MIBC pathway for nearly 100 years. 51 Advocates suggest it is important to resect the luminal BC component to allow full histological categorisation (including the identification of variant histology) to obtain pathological proof of muscle invasion prior to commencing systemic chemotherapy/radical treatment and for reduction in tumour volume (perhaps to facilitate bladder sparing radical treatment). 52 However, the literature clearly shows that TURBT and cystectomy histology are often discordant with respect to variant and subtyping,53,54 understaging of muscle invasion in TURBT samples is common,11,55 and there are few data to suggest that tumour debulking is a necessary component of radiotherapy regimens. It should be noted that debulking is prognostic in many series, with incomplete debulking being associated with worse outcomes. However, this is likely to reflect completeness of debulking as being a surrogate for stage rather than a direct therapeutic effect. Indeed, the operator dependency of TURBT56 may confuse the identification of complete chemotherapy response (stage ypT0) and so mean that cystectomy is used in many participants where bladder sparing would be possible. 57 Although not yet routine, modern technologies allow complex RNA expression profiling and DNA mutation analysis to be undertaken on small biopsies or on tumour DNA from urine. 35,58 There is thus no need for large excision biopsies for detailed molecular subtyping. Small tumour biopsies obtained during flexible cystoscopy yield enough material to permit both histopathological diagnosis of cancer and molecular subtyping (cf. prostate cancer59); liquid biopsy approaches may contribute additional risk stratification. 35,60,61

An important component of this new pathway is the ability of urologists to accurately triage patients as probable NMIBC or possible MIBC at the time of outpatient diagnostic flexible cystoscopy based upon the macroscopic appearances of suspicious bladder lesions. Building upon previous evidence,62 we have shown that such initial triage is accurate, demonstrating that 89% of lesions where the initial cystoscopic assessor strongly agreed or agreed the likely diagnosis was NMIBC were subsequently confirmed as NMIBC and accounted for around 50% of all cases. For the remaining 50%, where the initial urological assessment was less certain, the addition of mpMRI provided rapid, accurate triage with an approximately equal split between NMIBC and MIBC. Such an approach dovetails neatly with standard practice for prostate cancer diagnostics in the same units. 63 With initial outpatient cystoscopic triage, plus the lower numbers of cases of BC versus prostate cancer, any impact on departmental MRI workload would be relatively modest. Notwithstanding, it should be noted that a proportion of participants in Pathway 2 underwent TURBT for a range of reasons post MRI (e.g. to ascertain presence of histological variants, debulking pre-radiotherapy) without compromising TTCT. Of 14 TURBTs undertaken after mpMRI scanning in Pathway 2, only 3 (21%) were undertaken due to ‘lack of confidence that the MRI shows MIBC’, all from the same hospital. Hence, for the majority of patients, mpMRI provided staging information such that these TURBT procedures could be assigned to the correct surgeon for the correct indication (e.g. to debulk tumour prior to radical therapy) and be given high priority to reflect the needs of MIBC participants.

Thirteen participants underwent cystectomy but were later diagnosed with NMIBC after histopathological examination of the cystectomy specimen (six in Pathway 1 and seven in Pathway 2); there was no significant difference in the number of cystectomies undertaken for NMIBC between the two pathways. All 13 of these participants underwent TURBT prior to cystectomy, with TURBT diagnosing NMIBC in all but 1 participant. This latter participant (Pathway 2, possible MIBC) had MIBC confirmed at TURBT and then pTis in the cystectomy specimen, indicating a complete resection of tumour at the initial TURBT. Hence, there was no evidence that early use of MRI for staging led to NMIBC patients undergoing ‘unnecessary’ cystectomy. As detailed in the introduction, cystectomy is a potentially appropriate treatment for high-grade or extensive NMIBC and the similar numbers in both pathways reflect this. We were unable to determine in more detail the decision-making process at the MDT meeting following first TURBT. We suggest that future studies in this setting should set out to capture such data.

Experience with the introduction of MRI into the prostate cancer pathway has been that, after initial scepticism, there has been widespread acceptance of the paradigm that more accurate imaging can improve clinical decision-making. 64 Notably, this adoption has occurred in the absence of randomised studies linked to clinical outcomes beyond the initial biopsy findings. To apply similar considerations to the BC pathway, generally managed via the same teams, is likely to be potentially more straightforward. Experience with setting up BladderPath suggests that clinicians rapidly become comfortable with using MRI to guide downstream decisions.

Regarding the cost associated with Pathway 2, a simple analysis demonstrates that saving 1 : 10 patients from needing a TURBT pays the crude costs of the additional nine MRI scans. Around 1 : 6 patients avoided a MRI scan in BladderPath making it likely that the pathway can be self-funding at the very least. The faster time to definitive therapy for NMIBC, but also for MIBC, is likely to improve outcomes which in itself may be cost saving. A full health economic analysis to examine these effects will require access to the long-term follow-up data which will become available in around 18 months’ time and will be analysed separately. We conclude that it is feasible to add mpMRI for those participants visually diagnosed with possible MIBC at outpatient diagnostic cystoscopy. By doing so, possible MIBC participants receive their correct therapy significantly quicker, potentially leading to improved long-term outcomes, even if these patients require TURBT as part of their further assessments prior to definitive treatment. The initial radiological staging data which MRI adds over and above the urinary tract imaging that is routinely carried out in haematuria clinics thus leads to accelerated access to correct treatment. Anecdotally, where patients are undergoing TURBT post MRI, the procedure may be different and more targeted than the standard full diagnostic procedure on Pathway 1. Additionally, separating the lower-risk NMIBC from the higher-risk NMIBC and MIBC allows triage of cases to appropriate levels of surgical expertise. This is more difficult on the standard pathway where all patients need to have a TURBT for staging in order to plan further therapy.

The BC diagnostic and staging pathway has followed a largely unchanged pattern for nearly a century with rigid cystoscopy forming the mainstay of both histological diagnosis and initial staging. For patients with NMIBC, TURBT is also the mainstay of treatment. Unfortunately, TURBT is not the main treatment for the most lethal form of BC and may even be pro-metastatic. In the main, most cancers are staged with a biopsy to confirm histology and imaging to determine stage ahead of definitive treatment. For patients with MIBC, the TURBT pathway is frequently inaccurate with the need for repeat TURBT to assess muscle invasion with consequent delay – a minimum delay of 6 weeks between initial and re-do TURBT is standard.

Patient participation and involvement

Patient participation and involvement in this study are summarised in Table 30.

Equality, diversity and inclusion

Registration into the study was open to any adult patient of 18 years or more attending haematuria clinic for investigation of blood in their urine. If initial examination found evidence of potential BC, then randomised entry into the main study was offered to the patient. During the course of the trial only one registered participant was under the age of 20 years, and they were not found to have cancer during initial examination. Lowering the age of entry to 16 years was considered in 2020, but with the approaching end of recruitment and the unlikely prospect of a 16- to 17-year-old presenting with BC, this was decided against.

One recruiting site reported that sending out the invitation letter and participant information sheet to patients due to attend the haematuria clinic for initial investigation was found to be upsetting to some of the patients, which also upset the research staff. The site’s research team explained that the biggest barrier and upset for potential patients was the term ‘Cancer’ in the information sent to them prior to clinic, when approximately 80% of patients attending for investigation of their haematuria do not typically have cancer. At the same time, an investigator at another recruiting site pointed out that eligible patients might be discovered through alternative routes, such as inpatient investigations. Further to these early comments from sites, the protocol was amended to allow sites to approach patients about the study after their being given an initial diagnosis of suspicious tumours suitable for TURBT, which would in turn permit other patients found to be eligible for TURBT and treatment of BC to be recruited.

The difference between participants being registered prior to their initial bladder examination or registered and randomised into the study after the examination was that a biopsy of any tumour found might be obtained. Most of the sites were not able to obtain a biopsy during the initial examination (flexible cystoscopy) due to the procedure being carried out by a clinical nurse specialist rather than a urologist or that the surgical kit required to obtain the biopsy was not available. Participants who were both registered and randomised after flexible cystoscopy and found to have possible MIBC and randomised to Pathway 2 had to return for a repeat cystoscopy with biopsy in order that a histological diagnosis could be made.

These changes made it easier both for the recruiting sites to recruit, and reduced some of the stress experienced by patients awaiting examination.

Pictures and diagrams used in the participant information sheet were of body parts common to all, rather than having any link to a particular part of society.

The study management group is composed of clinicians, academics and academic and support research staff and patient representatives of various ethnicities, ages and abilities – as is the University of Birmingham in general.

Contributions of authors

Nicholas James (https://orcid.org/0000-0002-7314-8204) [Chief Investigator, Institute of Cancer Research (ICR) and Principal Investigator (PI) at The Royal Marsden Hospital, London] substantially contributed to the conception and design of the work, revising this report critically for important intellectual content and had final approval of the version to be published. NDJ is also accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Sarah Pirrie (https://orcid.org/0000-0002-2894-2230) [Principal Statistician at the Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham] substantially contributed to the design of the work and analysis of trial data.

Wenyu Liu (https://orcid.org/0000-0002-6682-2053) [Senior Statistician at the Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham] substantially contributed to the design of the work and analysis of trial data.

James Catto (https://orcid.org/0000-0003-2787-8828) (Co-investigator, Consultant Urological Surgeon and PI at Department of Urology, Sheffield Teaching Hospitals NHS Foundation Trust, UK) substantially contributed to the conception and design of the work, drafting and revising this report critically for important intellectual content.

Kieran Jefferson (https://orcid.org/0000-0002-0029-8359) (Co-investigator, Consultant Urological Surgeon and PI at Department of Urology, University Hospitals Coventry and Warwickshire NHS Trust, UK) substantially contributed to the conception and design of the work, drafting and revising this report critically for important intellectual content.

Prashant Patel (https://orcid.org/0000-0002-2882-5990) (Co-investigator, Consultant Urological Surgeon and PI at University Hospitals Birmingham recruiting site) substantially contributed to the conception and design of the work, drafting and revising this report critically for important intellectual content.

Ana Hughes (https://orcid.org/0000-0001-7274-9422) (Senior Trial Coordinator at CRCTU, Institute of Cancer & Genomic Sciences, University of Birmingham) contributed to the drafting and revising this report critically for important intellectual content.

Ann Pope (https://orcid.org/0000-0001-7458-3294) (Trial Coordinator at CRCTU, Institute of Cancer & Genomic Sciences, University of Birmingham) contributed to the drafting and revising this report critically for important intellectual content.

Veronica Nanton (https://orcid.org/0000-0002-9553-822X) (Co-investigator, based at the Medical School, University of Warwick) contributed to the qualitative research section.

Harriet P Mintz (https://orcid.org/0000-0003-1583-6268) (Research Associate) contributed to the design of the work.

Allen Knight (https://orcid.org/0000-0001-8123-9547) (Patient and Public Involvement Representative on the Trial Management Group) contributed to the design and concept and has been involved in drafting the report.

Jean Gallagher (https://orcid.org/0009-0007-6308-2292) (Patient and Public Involvement Representative on the Trial Management Group) contributed to the design and concept and has been involved in drafting the report.

Richard T Bryan (https://orcid.org/0000-0003-2853-4293) (Co-investigator and Director of the Bladder Cancer Research Centre, Institute of Cancer & Genomic Sciences, University of Birmingham) substantially contributed to the conception and design of the work, drafting and revising this report critically for important intellectual content. He also obtained funding for and led the diagnostic urinary biomarker sub-study of BladderPath.

Acknowledgements

The study was sponsored by University of Birmingham and run by the Cancer Research UK Clinical Trials Unit (CRCTU). Staff at the CRCTU are supported by a core funding grant from Cancer Research UK (C22436/A25354). The trial was initiated and conducted independently by the trial investigators. We thank the participants who took part in the trial and their families; the principal investigators and co-investigators from the 15 recruiting centres, and their research staff. We would also like to acknowledge the contribution of the Trial Steering Committee and Data Monitoring Committee. Additional biomarker research on samples derived from the trial was funded by Cancer Research UK.

Patient data statement

This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people’s patient records, to understand more about disease, develop new treatments, monitor safety and plan NHS services. Patient data should be kept safe and secure, to protect everyone’s privacy, and it is important that there are safeguards to make sure that they are stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.

Data-sharing statement

Participant data and the associated supporting documentation will be available within 6 months after the publication of the study results in a peer-reviewed journal. Details of our data request process are available on the CRCTU website. Only scientifically sound proposals from appropriately qualified research groups will be considered for data sharing. All data requests should be submitted to the corresponding author for consideration.

Ethics statement

The BladderPath study was conducted in accordance with the World Medical Association (WMA) Declaration of Helsinki (1964) amended by the 48th WMA General Assembly, Somerset West, Republic of South Africa, 1996 [World Medical Association. WMA Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. 6 September 2022. URL: www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ (accessed 14 July 2023)]. The study was also conducted in accordance with applicable UK Statutory Instruments (including the Data Protection Act 1998 and Human Tissue Act 2004 and Good Clinical Practice (GCP). The study protocol and patient information and consent documents were peer reviewed and ethically approved prior to the study opening (NIHR London Bridge Research Ethics Committee, UK project reference 17/LO/1819; approval date 4 December 2017). It was the responsibility of Principal Investigators at the recruiting sites that local approvals were in place and maintained, and to take immediate clinical action if thought necessary to protect the health and interest of individual patients.

Information governance statement

The University of Birmingham is the data controller and its Cancer Research Clinical Trials Unit (CRCTU) the data processor of all study participants’ personal data handled throughout the BladderPath study. As per the EU General Data Protection Regulation and the UK Data Protection Act 2018, all trial/study participants were provided with additional details regarding the legal basis that allows us to hold and process their personal data, available on the study’s web page [bladderpath-patient-info-sheet-v5.0a-10-sep-2020.pdf (birmingham.ac.uk)].

Disclosure of interests

Full disclosure of interests: Completed ICMJE forms for all authors, including all related interests, are available in the toolkit on the NIHR journals Library report publication page at https://doi.org/10.3310/DEHT5407.

Primary conflicts of interest: Nicholas James received funding for this project from the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme and was a member of HTA General Committee. He is also a NIHR Senior Investigator. Richard T Bryan received research funding for this project from the National Institute of Health and Care Research Health Technology Assessment program. His research is also funded by grants from Cancer Research UK (Early Detection & Diagnosis), Cancer Research UK (Data Innovation Award), Janssen, University Hospitals Birmingham Charity (UK), Cancer Research UK (Biospecimen Collection), UroGen Pharma (USA). He receives consulting fees from Cystotech (Denmark) and is an unpaid charity trustee for Action Bladder Cancer UK. James Catto receives consulting fees from Astra Zeneca, BMS, Gilead, QED Therapeutics, Roche, Ferring, Steba biotech, UroGen, Jansenn, Photocure, and also received honoraria payments from BMS, Astra Zeneca and Roche. He is an unpaid trustee for Fight Bladder Cancer UK and member of BMS advisory board. Allen Knight was a member of EME Strategy Group, PHR Research Funding Board and EME Funding Committee Member, he is an unpaid Trustee of Action Bladder Cancer UK, unpaid Director of the World Bladder Cancer Patient Coalition and unpaid Birmingham Bladder Cancer Research Centre advisory board member.

Publications

Disclaimers

This article presents independent research funded by the National Institute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care.