Improving treatment pathways in muscle-invasive bladder cancer

There has been a significant lack of progress in improving survival rates for muscle-invasive bladder cancer, even with radical treatment, and delays in receiving definitive treatment are common. Professors Rik Bryan and Nicholas James – collaborators on the recent BladderPath trial – explain how incorporating an image-directed pathway prior to standard care significantly reduces the time to correct treatment and improves outcomes for these patients.

Bladder cancer is the tenth most common cancer worldwide, responsible for 3% of annual cancer cases and 2.1% of cancer-related deaths, while also imposing high healthcare costs.^1–3

Standard management approaches include outpatient flexible cystoscopy, followed by transurethral resection of bladder tumour (TURBT),⁴ which is derived from a pathway established over a century ago.⁵

TURBT is the preferred treatment for non-muscle-invasive bladder cancer (NMIBC), frequently removing the tumour(s) completely and followed by single or multiple doses of adjuvant intravesical therapy directly into the bladder.⁴

However, for patients with muscle-invasive bladder cancer (MIBC), TURBT is a hybrid diagnostic and partial staging procedure (See Table 1) that needs to be followed by correct treatment with more radical therapies such as systemic chemotherapy, chemoradiotherapy or cystectomy.^6,7

Table 1: Staging conventions for non-invasive and invasive bladder cancer

T = tumour

While TURBT is generally well-tolerated, a minority of patients experience significant complications –including bladder perforation or haemorrhage – with the need for extended hospitalisation. TURBT also frequently under-stages the depth of invasion, with up to 30% of MIBCs initially staged as NMIBC.⁸ There are also concerns that TURBT could lead to tumour dissemination through bladder perforation or venous emboli generated by the piecemeal resection process.⁹  

Lack of improvement in survival rates for MIBC

In contrast to many cancers, the survival rates for MIBC have not improved in over 30 years.² These poor outcomes may reflect, in part, slow diagnostic pathways. TURBT significantly contributes to this delay, regardless of the healthcare structure.

For instance, in the UK, patients with MIBC waited an average of 144 days from GP referral to radical therapy between 2013 and 2016, according to NHS data.¹⁰ Additionally, a national audit reported that 48% of patients waited more than 180 days from diagnosis to cystectomy between 2017 and 2019.¹¹

In the US, patients waited an average of 69 days from TURBT to starting radical treatment (the time from referral to TURBT is unknown),¹² whereas in Canada, the wait was up to 56 days to see a urologist before TURBT,¹³ followed by an additional 65 days from TURBT to cystectomy.¹⁴

The situation is worse for women, who are frequently initially misdiagnosed with bacterial cystitis and see their GP up to five-times more than men before urological referral.^13,15

In stark contrast, UK patients with breast cancer averaged 40 days from referral to treatment between 2013 and 2018.¹⁶ These delays contribute to worse prognoses for patients with MIBC.^12,17

Improving MIBC survival rates

A better approach could be to separate NMIBC from MIBC patients early in the care pathway. MIBC patients could then receive faster, more accurate modalities for local staging and expedited correct treatment.¹⁸ This could improve outcomes and reduce clinical costs.

Imaging advances show that multiparametric magnetic resonance imaging (mpMRI) enables precise differentiation between NMIBC and MIBC,^19,20 theoretically providing a safer and faster path to the appropriate treatment than TURBT.

With cystoscopic assessment of tumours accurate in predicting lower grade and stage NMIBCs,²¹ triage of patients into likely NMIBC or possible MIBC early in the diagnostic pathway is possible and complemented by small tumour biopsies obtained during flexible cystoscopy that yield enough material to permit histopathological diagnosis. Such an approach is rational and aligns with the diagnostic pathways of other malignancies

The BladderPath trial for MIBC

We undertook the BladderPath randomised controlled trial to investigate whether MIBC patients can be safely expedited to correct treatment using an outpatient biopsy and mpMRI for local staging rather than TURBT. The primary outcome of the trial was time to correct treatment (TTCT).²²

The study’s novel aspects included the randomised comparison of clinical pathways, rather than comparing the sensitivity and specificity of TURBT or mpMRI. It also emphasised the use of clinicians’ expertise in distinguishing NMIBC from MIBC during cystoscopy to facilitate early patient management in the clinical pathway.

The study randomised 143 patients with suspected MIBC to one of two pathways:

• Pathway 1: The conventional clinical pathway, in which all patients underwent TURBT for staging
• Pathway 2: An imaging-guided mpMRI investigational pathway, in which patients underwent mpMRI for disease staging and then definitive treatment – potentially without TURBT.

In an initial feasibility stage of the study, 36 of 39 possible MIBC participants (92%) in Pathway 2 underwent mpMRI post-randomisation and the overall proportion of participants who correctly followed their respective protocol pathway was 96% in each pathway.

Given the potential benefits of an outpatient-based diagnostic pathway during the Covid-19 pandemic, feasibility data from the BladderPath trial were published online in February 2021.¹⁸

In the main stage of the study, the median TTCT for the mpMRI pathway was 53 days – some 45 days sooner than the median TTCT for the conventional TURBT pathway (98 days; P = 0.02).²²

Importantly, this time reduction occurred without affecting NMIBC patients whose TTCTs were no different between the two pathways (P = 0.668).²²

Furthermore, when evaluating the TTCT for all patients, the mpMRI pathway was again significantly quicker. The median time for the mpMRI pathway was 25 days compared to 37 days for the TURBT pathway (P = 0.030).²²

What has the BladderPath trial shown?

We demonstrated that an mpMRI-based pathway resulted in patients with MIBC receiving correct treatment over six weeks sooner without negatively impacting the TTCT for NMIBC patients.²²

It would be reasonable to surmise that this ‘expedited’ management of MIBC patients would lead to survival advantages, potentially reversing the 30-year stagnation in outcomes for bladder cancer patients.

With initial outpatient cystoscopic triage, any impact on departmental MRI workload remains relatively modest. It should also be noted that a proportion of patients in the mpMRI pathway still underwent TURBT for various reasons following mpMRI, such as assessment of carcinoma in situ and debulking prior to radiotherapy, without compromising TTCT.

With accurate staging information before TURBT, these procedures can be assigned to the appropriate surgeon and prioritised to meet the needs of MIBC patients.

Conclusion

We recommend considering the incorporation of mpMRI ahead of TURBT into the clinical pathway for all patients with suspected MIBC. This approach may allow TURBT to be avoided in some patients and enhance decision-making, resulting in faster treatment initiation. Consequently, this could lead to improved long-term outcomes, and we await further data on this.

Authors

Richard Bryan MBChB PhD MRCS FAcadTM
Professor in urothelial cancer research and director of the Bladder Cancer Research Centre at the University of Birmingham, UK

Nicholas James MBBS PhD FRCP FRCR
Professor of prostate and bladder cancer research at the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK

References

1. Sung H et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209–49.
2. Catto JWF et al. Diagnosis, treatment and survival from bladder, upper urinary tract, and urethral cancers: real-world findings from NHS England between 2013 and 2019. BJU Int 2023;131(6):734–44.
3. Svatek RS et al. The economics of bladder cancer: costs and considerations of caring for this disease. Eur Urol 2014;66:253–62.
4. Gontero P et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) – A Summary of the 2024 Guidelines Update. Eur Urol 2024;86:531–49.
5. Beer E. Landmark article May 28, 1910: Removal of neoplasms of the urinary bladder. By Edwin Beer. JAMA 1983;250:1324–5.
6. Babjuk M et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ). Eur Urol 2022;81:75–94.
7. Witjes JA et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines. Eur Urol 2021;79:82–104.
8. Kulkarni GS et al. An updated critical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladder cancer. Eur Urol 2010;57:60–70.
9. Engilbertsson H et al. Transurethral bladder tumor resection can cause seeding of cancer cells into the bloodstream. J Urol 2015;193:53–7.
10. Harrison S. Urology: GIRFT Programme National Specialty Report. NHS England, 2018.
11. Jefferies ER et al. Open radical cystectomy in England: the current standard of care – an analysis of the British Association of Urological Surgeons (BAUS) cystectomy audit and Hospital Episodes Statistics (HES) data. BJU Int 2018;121:880–5.
12. Chu AT et al. Delays in radical cystectomy for muscle-invasive bladder cancer. Cancer 2019;125:2011–17.
13. Santos F et al. Urologist referral delay and its impact on survival after radical cystectomy for bladder cancer. Curr Oncol 2015;22:e20–26.
14. Kulkarni GS et al. Longer wait times increase overall mortality in patients with bladder cancer. J. Urol 2009;182:318–24.
15. Lyratzopoulos G et al. Gender inequalities in the promptness of diagnosis of bladder and renal cancer after symptomatic presentation: evidence from secondary analysis of an English primary care audit survey. BMJ Open 2013;3:e002861.
16. National Disease Registration Service. Median pathway analysis by patient demographics, stage at diagnosis, route to diagnosis, and geography. 2018. https://digital.nhs.uk/ndrs/data/data-outputs/cancer-data-hub/cancer-median-pathways [Accessed March 2025].
17. Russell B et al. A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients. Eur Urol Oncol 2020;3:239–49.
18. Bryan RT et al. Comparing an Imaging-guided Pathway with the Standard Pathway for Staging Muscle-invasive Bladder Cancer: Preliminary Data from the BladderPath Study. Eur Urol 2021;80(1):12–15.
19. Del Giudice F et al. The accuracy of Vesical Imaging-Reporting and Data System (VI-RADS): an updated comprehensive multi-institutional, multi-readers systematic review and meta-analysis from diagnostic evidence into future clinical recommendations. World J Urol 2022;40:1617–28.
20. Panebianco V et al. Multiparametric Magnetic Resonance Imaging for Bladder Cancer: Development of VI-RADS (Vesical Imaging-Reporting And Data System). Eur Urol 2018;74:294–306.
21. During VA et al. Prediction of histological stage based on cytoscopic appearances of newly diagnosed bladder tumours. Ann R Coll Surg Engl 2016;98:547–51.
22. Bryan RT et al. Randomized Comparison of Magnetic Resonance Imaging Versus Transurethral Resection for Staging New Bladder Cancers: Results From the Prospective BladderPath Trial. J Clin Oncol 2025;Jan 14:JCO2302398.