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. 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.
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 (), 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.
Consolidated Standards of Reporting Trials flow chart – showing recruitment through to randomised allocation.
Outcomes following randomisation are shown in a separate diagram ().
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 (more...)
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.
Withdrawal by randomisation arm
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.
Baseline blood biochemistry results summary
Baseline haematology results summary
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).
Initial flexible cystoscopy results
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).
Transurethral resection of bladder tumour by pathway
Transurethral resection of bladder tumour pathology
Details from 172 TURBT histology reports were available (Table 11).
Transurethral resection of bladder tumour histology results
The number (and proportion) of participants in Pathway 2 who underwent TURBT after MRI-diagnosed MIBC was also monitored. (Note: participants who were diagnosed NMIBC by MRI and then underwent TURBT as the correct treatment, or where MRI diagnosis was considered inconclusive, were excluded.) Seventeen participants were diagnosed MIBC by MRI, of which eight had TURBT afterwards; two had TURBT procedures twice (including one for TURBT biopsy only). Clinician intention for carrying out TURBT following MRI for Pathway 2 participants with confirmed MIBC is summarised in Table 12 for each procedure.
Intentions of TURBT after MRI
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).
Magnetic resonance imaging data results
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.
Definitive and correct treatment received split by pathway
Four swimmer plots sorted by TTDT: 34 Pathway 1 probable NMIBC participants ), 38 Pathway 1 possible MIBC (), 32 Pathway 2 probable NMIBC () and 39 Pathway 2 possible MIBC (). Two participants in and four participants in received MRI in error.
Swimmer plot for pathway 1 probable NMIBC participants.
Swimmer plot for Pathway 2 probable NMIBC participants.
Swimmer plot for Pathway 1 possible MIBC participants.
Swimmer plot for Pathway 2 possible MIBC participants.
Four swimmer plots sorted by TTCT. Of the 143 participants, 133 (93.0%) had a confirmed NMIBC/MIBC, including 51 NMIBC in Pathway 1 (), 55 NMIBC in Pathway 2 (), 14 MIBC in Pathway 1 () and 13 MIBC in Pathway 2 (). Of note, 7/14 MIBC patients on Pathway 2 avoided the need for TURBT.
Swimmer plot for Pathway 1 NMIBC participants.
Swimmer plot for Pathway 2 NMIBC participants.
Swimmer plot for Pathway 1 MIBC participants.
Swimmer plot for Pathway 2 MIBC participants.
Summaries of types of treatment received
Intravesical therapy
Thirty-four participants received at least one intravesical BCG (Table 15); 11 participants received intravesical chemotherapy (Table 16).
Summary of participants who underwent intravesical BCG
Summary of participants who received intravesical chemotherapy
Chemotherapy
Eighteen chemotherapy treatments were received by 17 participants (one received both neo-adjuvant and synchronous chemotherapy with radiotherapy; Table 17).
Summary of participants who received systemic chemotherapy
Radiotherapy
Fifteen participants received radiotherapy (Table 18).
Summary of participants who received radiotherapy
Cystectomy
Twenty participants underwent cystectomy (Table 19). One participant underwent surgery which was immediately abandoned upon anaesthetic induction due to the participant experiencing heart arrhythmia.
Summary of participants who underwent cystectomy
Cystectomy histology
Histopathology reports were provided for all participants who underwent cystectomy. Table 20 summarises the findings. The commonest histological tumour type in this subset was transitional cell carcinoma (50%). One participant’s pathology report related to a colorectal resection involving partial cystectomy of the bladder; however, the report stated ‘no evidence of malignant neoplasm’ in the bladder.
A total of nine patients had prostate cancer diagnosed upon pathological examination of the cystoprostatectomy specimen, three in pathway 1 and six in Pathway 2, as summarised in Table 21.
Cystectomy histology–associated prostate cancer
Thirteen participants were confirmed as NMIBC (and not MIBC) by pathological examination of the cystectomy specimen, summarised in Table 22. There was no statistical difference in the number of cystectomies undertaken for NMIBC between the two pathways, Fisher’s exact test (p = 0.337). One participant experienced two recurrences of locoregional disease (on 15 April 2019 and 21 December 2019) and a new primary tumour site (prostate) confirmed (on 9 October 2020). All patients who had no invasive disease at cystectomy had prior TURBT in addition, so no patient had cystectomy due to incorrect MRI staging. It should be noted that it is well documented that post TURBT with MIBC, around 10–15% of cystectomy specimens will then show no invasive disease, presumably due to the prior endoscopic resection.
Treatment pathway for participants who did not have MIBC confirmed by cystectomy
Accuracy of magnetic resonance imaging
Nine Pathway 2 participants underwent both MRI diagnosis and subsequent cystectomy with available histology (Table 23).
Comparison of MRI diagnosis with cystectomy histological tumour staging
Accuracy of transurethral resection of bladder tumour
Eight participants in each pathway had both TURBT and cystectomy tumour staging available (see Tables 24 and 25).
Comparison of TURBT tumour staging with cystectomy for Pathway 1
Comparison of TURBT tumour staging with cystectomy for Pathway 2
Outcomes
Feasibility stage
Primary outcome: proportion of possible muscle-invasive bladder cancer participants randomised to Pathway 2 who correctly followed the protocol pathway
In total, there were 39 possible MIBC participants in Pathway 2, of which 36 (92%, 95% CI 79% to 98%) received MRI as per protocol. Three Pathway 2 possible MIBC participants did not undergo MRI after randomisation, including one who was found to have a metal fragment in his eye prior to undergoing the MRI examination, one who cancelled their MRI as the participant withdrew from the trial (29 days post randomisation) and one who underwent MRI prior to being entered into the trial (the scan was requested by the surgeon independently of the study). Of the 36 participants who underwent MRI, 17 were diagnosed as having MIBC, 16 were NMIBC and for 3 the mpMRI images were inconclusive.
Secondary outcome: overall proportion of all randomised participants who correctly followed the protocol pathway in their respective pathways
For Pathway 1, this was defined as the number of probable NMIBC and possible MIBC participants randomised to the pathway who received a TURBT at the appropriate pathway stage as a proportion of all participants randomised to Pathway 1.
For Pathway 2, it was defined as the number of probable NMIBC participants in the pathway who had a TURBT plus the number of possible MIBC participants in the pathway who underwent MRI as a proportion of all participants randomised to Pathway 2.
The overall proportion of participants who correctly followed their respective pathway protocol was 96% CI (88% to 99%) in each pathway. No statistical difference between the pathways was found.
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; ), 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.
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; ). 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).
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.
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; ); 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).
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; ), 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).
Kaplan–Meier curves of TTCT by pathway for all randomised participants.
Health economics
Pre-trial costing suggested that the pathway may be cost-saving depending on the numbers of TURBT procedures that were removed by the earlier use of MRI and biopsy. The NHSE (NHS England) tariff cost of TURBT is £2183 (LB13D) and the tariff cost of mpMRI is £200 (RD05Z). There may be a small additional charge if biopsy is carried out during flexible cystoscopy but pre trial we ascertained that in many sites this was already common standard practice.
Based on these tariffs, we can estimate that bypassing TURBT in cases where it is not required is likely to be cost saving if only > 1 : 10 MRI scans lead to this outcome. Our data show that 7/36 patients had either definitive therapy or palliative care that did not require TURBT, a saving of approximately £8000–9000 on the £78,000 that would have been spent had all these patients had a TURBT. There are thus unlikely to be significant cost barriers to implementing the pathway. Separate issues apply within trusts concerning the relative availability of scanning capacity and operating theatre or surgical capacity which are likely to vary from hospital to hospital.
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 .
Proportion of participants followed up.
Follow-up cystoscopy results are summarised in Table 26.
Summarised data from follow-up cystoscopy
Follow-up data reporting cytology and imaging results on suspicion of recurrence are summarised in Table 27.
Summarised data from follow-up further cytology and imaging
Recurrence/progression/new primary/death
There were 70 recurrence, progression or new primary events from 47 participants (26 in Pathway 1 and 21 in Pathway 2), summarised in Table 28.
Recurrence, metastatic disease and new primary cancer
Twenty participant deaths were reported (10 in each pathway), summarised in Table 29.
Summary of causes of death
Substudies
Urinary DNA substudy
The trial included a translational study evaluating the use of a urinary DNA test in the haematuria clinic. The aim was to test the ability of mutational analysis of urinary DNA to non-invasively detect BC within the context of haematuria investigations and NMIBC surveillance. The initial BladderPath screening patients were offered entry into this biomarker study which had separate funding and eventually 176 participants were recruited. It should be noted that these patients only partially overlap with the main trial patients as most did not have BC and hence did not proceed to the main study. The DNA substudy was also supplemented with other patients from haematuria clinics, separate from BladderPath recruitment. The results summarised below have been separately published.30
In brief, pre-cystoscopy mid-stream urine specimens (up to 50 ml) were collected in Norgen Urine Collection and Preservation Tubes (Norgen Biotek, Thorold, ON, Canada) on the day of clinic attendance and transferred to the Human Biomaterials Resource Centre (HBRC) at the University of Birmingham at ambient temperature by post (in UN3373 packaging). On receipt at HBRC, samples were centrifuged at 1000 g for 10 minutes; cell pellets and supernatants were then separated and frozen at –80 °C. The non-BC patients were determined to be ‘normal’ or with diagnoses including calculi, benign prostatic hyperplasia, cystitis, inflammation, urinary tract infection, prostate cancer and kidney cancer. A ‘panel of normals’ and ‘confirmatory controls’ were randomly selected from this cohort.
Deoxyribonucleic acid was extracted from cell pellets (cp) using Quick-DNA Urine Kits (Zymo Research, Irving, CA, USA) and quantitated using high-sensitivity double-stranded DNA Qubit kits (Thermo Fisher, Waltham, MA, USA). Laboratory staff were unaware of patient diagnoses. Libraries were prepared from 25 ng urine cell pellet DNA (cpDNA; extracted from an average of 23 ml of urine) using Nonacus Cell3 Target enrichment. DNA was enzymatically sheared, end-repaired and A-tailed, and adapters (including Unique Molecular Identifiers) ligated to the fragments. Libraries were amplified and pooled in batches of 12 prior to overnight hybridisation with biotinylated probes and subsequent capture and final amplification of the next generation sequencing libraries. The probes targeted hotspots or regions of 23 genes. All libraries were 2 × 150 bp sequenced on a NovaSeq (Illumina, San Diego, CA, USA).
Sequencing data were demultiplexed and aligned to hg19 using bwa (version 0.7.15-r1140). Consensus reads were built using fgbio (version 1.1.0) requiring ≥ 3 reads to produce a consensus as described previously36 and re-aligned to the reference. Average raw and consensus read depths were 27,100 × and 3000 ×, respectively. Samples with consensus read depth < 500 at ≥ 10 loci were excluded (35 out of 919, 3.8%). Base calls with quality ≥ 30 were extracted using bam-readcount and used to calculate VAFs at 443 predefined genomic coordinates (a refined set of single nucleotide variants from our study of 956 BCs36). An optimal variant calling strategy was developed based on the maximum variant allele frequencies observed in a panel of 100 BC-negative haematuria patients and confirmed on a further 62 BC-negative haematuria patients.
A ‘positive test’ was defined as detection of any one of the 443 mutations in a cpDNA sample at > 0.9% VAF for chr5:129528A/G or > 0.5% VAF at all other coordinates. This combination provided 89.9% specificity in the ‘panel of normals’ and 91.2% specificity in a further 62 ‘confirmatory controls’ (non-BC haematuria clinic cpDNAs).
Applying the assay to the prospectively collected haematuria clinic cohort, including BladderPath patients, achieved 86.8% sensitivity at 81.0% specificity.30 Combining two haematuria clinic cohorts to derive test positivity and VAFs across grades and stages of disease, 144/165 BCs tested positive [87.3% (95% CI 81.2 to 92.0) sensitivity] and 223/264 non-BCs tested negative [84.8% (95% CI 79.9 to 89.0) specificity].30 Mutations were detected significantly more commonly (and with higher VAFs) in cpDNA from patients with all stages and grades of BC compared with non-BC patients (p < 0.001). Sensitivity was 97.4% (95% CI 91.4 to 99.7) for grade 3 BC, 86.5% (95% CI 74.2 to 94.4) for grade 2 BC and 70.8% (95% CI 48.9 to 87.4) for grade 1 BC. Sensitivity was 79.3% (95% CI 69.3 to 87.2) for pTa, 100% (95% CI 90.0 to 100.0) for pT1 and 91.7% (95% CI 78.1 to 98.3) for MIBC; all three cases of solitary CIS were detected. The median maximum VAF in incident BCs was 18.7%, versus 0.28% in non-BC patients (p < 0.001), with a median of three mutations per BC cpDNA. The most commonly detected mutations were TERT, TP53, FGFR3, PIK3CA, ERCC2, ERBB2 and RHOB, mirroring previous tumour tissue data.36,41,42
The study concluded that ultra-deep sequencing of somatic mutations in a 23 gene panel in urinary DNA had the potential to detect new cases of BC with high sensitivity and specificity and could reduce reliance on cystoscopy in the haematuria clinic setting. The test also has a potential role in post-diagnosis surveillance, and this is being evaluated further.35
Routine data use
The trial initially intended to use access to routine data to reduce the need for conventional data collection via case record forms. The methodology was developed as part of a PhD thesis and the findings have been separately published.43 This data model could be used as part of a future Commissioning through Evaluation (CTE)-based evaluation. It was not unfortunately possible to use the data collected in this way for the primary trial analysis as NHS Digital wished to charge around £3000 for each data extraction, even though these data extractions were multiple repeats of the same query, rather than each being a new bespoke query. As this was potentially monthly for up to 5 years, these costs were prohibitive.44 The Chief Investigator met with the Chair of NHS Digital to explore ways of reducing these costs. While he agreed that it made no sense to levy these high charges for simple repeat queries, there did not seem to be any mechanism to waive them. In the end, we were forced to collect data the ‘traditional’ way via local case record forms, research nurses and data managers, thereby depleting valuable local trial resources within trusts. A positive end note to this is that the HTA have agreed to fund a one-off NHS Digital data sweep to correspond with the last entered patient completing 2 years of follow-up. This has allowed us to close all the trial sites to further follow-up and still to perform an event-driven and survival analysis using this methodology as a future analysis.
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.
Interpretation
A modified pathway with initial triage based on appearance at flexible cystoscopy correctly identified lower-risk NMIBC patients requiring TURBT. For higher-risk patients, use of a MRI scan allowed identification of NMIBC patients for TURBT while accelerating the identification of very high-risk patients requiring more complex therapy, which may include TURBT but equally allowed some patients to bypass this stage and proceed to definitive treatment more rapidly. The impact of the MRI on TTCT for these patients is substantial with no evidence of a detrimental effect on NMIBC care.
Limitations
There are various limitations to the current study. Unfortunately, there were substantial interruptions to recruitment due to COVID-19 and so we were unable to enrol sufficient participants to evaluate our a priori progression free survival-based outcomes.
Secondly, the exact pathological stage in participants who underwent systemic chemotherapy, radiotherapy or palliation for mpMRI-diagnosed MIBC was unknown and so it is impossible to conclusively know whether these were correct treatments. However, TURBT has been shown to have substantial error rates, with many NMIBC patients upstaged to MIBC at subsequent cystectomy.11,65 Hence, there is no perfect ‘ground truth’ on either side of the randomisation – this would require a trial in which all participants undergo cystectomy. Thirdly, the development of a mpMRI grading system, VI-RADS,22 occurred during the conduct of our study (two of the trial team were part of the VI-RADS group) and provides a separate, peer-reviewed classification system for implementation. Work to validate the VI-RADS system with the BladderPath images is ongoing. Notwithstanding, the VI-RADS mpMRI sequences are analogous to those in widespread use for prostate cancer diagnosis by the same clinical teams. Hence, roll-out of a mpMRI-based pathway incorporating VI-RADS should be straightforward.
Further work to cross-correlate with the VI-RADS system22 will improve accuracy and aid dissemination. Longer follow-up to examine the effect of the pathway on outcomes is also required.
A comprehensive health economic analysis was not feasible in the absence of longer-term outcomes data. However, a simple cost: consequence analysis shows that the MRI-based pathway is likely to be cost saving.
Generalisability
The MRI sequences used are similar to those in widespread use for prostate cancer diagnosis by the same teams and hence roll out should be relatively straightforward. The trial was carried out in a range of NHS units and thus broader roll out should be feasible.
Overall evidence
The trial was carried out at a time when image-directed treatment decisions have become standard practice in prostate cancer. The development of a MRI grading system, VI-RADS,22 occurred during the conduct of the trial and provides a separate, peer-reviewed, classification system for implementation. Taken with the work on VI-RADS, a move to the pathway examined in the BladderPath trial appears to be both feasible and desirable.
Research recommendations
Key areas for further research:
A large, randomised trial to look at failure-free survival is unlikely to be feasible given the issues faced by BladderPath and the current very difficult research and broader NHS environment. However, part of the BladderPath programme included the development of tools to extract the key end points of interest from NHS Digital records. This would allow broader evaluation of a MRI-based pathway via the CTE programme. As our costings indicate, this is likely to be cost saving and will free up around 10% of
TURBT slots, participation in such a programme may be attractive to Trusts.
A CTE programme looking at
MRI should also evaluate the role of VI-RADS specifically as a decision-making tool. Studies examining the role of biomarkers, particularly liquid DNA biomarkers in blood and urine, are required. These may further improve the diagnostic accuracy and therapeutic decision-making provided by
MRI (± TURBT) as well as providing non-invasive tools for follow-up and response assessment reducing the need for invasive check cystoscopy.
Patient participation and involvement
Patient participation and involvement in this study are summarised in Table 30.
Guidance for Reporting Involvement of Patients and the Public 2 short form
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.
