EAU 2023: Clinical Staging for Bladder Cancer: Have Imaging Techniques Reached a Point Where We Can Avoid TURBT – at Initial Diagnosis? After Neoadjuvant Therapy?

(UroToday.com) The 2023 European Association of Urology (EAU) annual congress held in Milan, Italy between March 10^th and 13^th, 2023 was host to a rapid-fire debate session addressing common problems and controversies in bladder cancer, chaired by Dr. Ashish Kamat.

Following a case presentation by Dr. Sharokh Shariat, Dr. James Catto was tasked with debating against the need for routine transurethral resection of bladder tumor (TURBT) for initial diagnostic purposes and post-neoadjuvant therapy, given the current state of available imaging techniques. Subsequently, Dr. Alexandra Masson-Lecomte was tasked with providing the counterarguments to this approach.

Dr. Shariat presented the case of a 73-year-old patient who initially presented with gross hematuria. The patient denied any dysuria, polyuria, or flank pain. He is a smoker, with a 30- pack year history. His comorbidities include obesity (BMI: 30 kg/m²), non-insulin dependent diabetes mellitus, hypertension, gastroesophageal reflux disease, and dyslipidemia. The patient was not on any anticoagulation. Ultrasound demonstrated a large left sided bladder mass, with cystoscopy and subsequent TURBT confirming the presence of a large infiltrative high-grade lesion. His cytology was positive as expected and CT demonstrated the presence of cT3N0M0 disease. Subsequent MRI demonstrated the presence of extravesicular extension. 

Dr. Shariot next framed the goals of a TURBT:

• Perform a complete resection and make a correct staging diagnosis
  • Detect all lesions including CIS
  • Remove all papillary lesions
  • Determine the depth of invasion in papillary lesions
  • Send the pathologist an adequate specimen for evaluation

What are the current challenges of TURBTs?

• Understaging of tumors
  • Sampling error, particularly if detrusor muscle is absent
  • No difference between cT2 and cT3 for selection of neoadjuvant chemotherapy
• High variability of quality, which is not standardized and user dependent
  • Recurrence rates at first follow-up cystoscopy vary between 3 and 46%
• Significant overall complication and reoperation rates of 5% and 3%, respectively¹
• TURBT breaks all basic surgical oncologic principles
  • Cautery damage
  • Tumor fragmentation
  • Lack of spatial orientation
  • Potential inoculation of tumor cells via the hydrostatic pressure
• Invasive, labor intensive, and costly

Currently, our main goal is to potentially avoid radical cystectomy after neoadjuvant chemotherapy. Unfortunately, TURBT misses ~30% of patients with invasive cancer after neoadjuvant chemotherapy. At this point, the debate was turned over to Dr. Catto to argue against the need for routine use of TURBT, given the current state of imaging techniques. 

Given that survival rates overall are static for patients with bladder cancer, clearly, we need to do something to move the needle. Current pathways from time of referral to undergoing radical treatment (surgery or TMT) in muscle invasive bladder cancer (MIBC) patients are unnecessarily long. As demonstrated in the figure below, in the UK, the mean time from referral to treatment is 112 days. Based on data from the Surveillance, Epidemiology, and End Results database, it appears that this timeline is shorter in the US (median 69 days + referral), yet still prolonged.

As has been demonstrated in BladderPath, a randomized trial comparing risk-stratified MRI-directed care with TURBT for patients with newly diagnosed bladder cancer, the median time to “correct treatment” can be reduced from 98 days with TURBT to 53 days with MRI-guidance.²

Another issue is that TURBTs are not as good as we think. Upstaging, as high as 50%, is common and residual cancer at the time of re-resection is not uncommon. Detrusor muscle is absent in 30-40% of resections and flat urothelium resection is missed in 35-45% of patients. Furthermore, use of guideline-recommend post-operative intravesical chemotherapy remains poor.^3,4 

Other issues with TURBTs include:

• Bladder perforations occurring in 1-5% of cases, of which ~1% require a cystorrhaphy
• Hematuria requiring blood transfusions in 2 – 13%
• Infection risk with 2 – 39% receiving antibiotics for a UTI
• Damage to the ureteral orifice  reflux occurs in up to 20% of cases
• Obturator nerve stimulation in 10-11%
• Associated anesthetic risks and compression events

Furthermore, as mentioned previously by Dr. Shariot, TURBTs break basic surgical oncological principles:

• Dissemination of cancerous cells⁵
  • Pre-op cell search: 3/10 with positive circulating tumor cells (CTCs)
  • During TURBT cell search: 6/10 intravesical CTCs
  • Similar but less dramatic changes with peripheral blood 

Dr. Catto argues that utilization of the MRI VI-RADS score needs to be relied upon more often in clinical practice in order to minimize the drawbacks of over-reliance on TURBTs.

What is the ability of MRI to stage non-muscle invasive (i.e. Ta-T1) versus MIBC? The pooled sensitivity and specificity for MRI was 0.92 (95% CI: 0.88 – 0.95) and 0.88 (95% CI: 0.78 – 0.94), respectively, for discriminating between non-muscle invasive and muscle invasive disease.⁶ 

It thus appears that the performance of MRI in this setting may be even better than TURBT. As such, Dr. Catto concluded his presentation by again advocating for the increased utilization of MRI in this setting at the expense of less frequent TURBTs. At this point, the debate was turned over to Dr. Masson-Lecomte to argue in favor of routine use of TURBT, despite the current state of imaging techniques. 

Dr. Masson-Lecomte argued that TURBT is unavoidable (in most cases). The benefits/advantages of a TURBT are numerous and have been previously discussed.

Although the prognosis of patients with MIBC has not sufficiently improved over the past 30 years, this is not a valid reason to remove the first therapeutic step in the current bladder cancer paradigm. Improving the treatment of bladder cancer will require the combination of innovative diagnostic procedures/therapies.

A complete local response in patients with MIBC still matters. Tumor downstaging is central to improving survival, irrespective of the local treatment chosen. As demonstrated by Efstathiou et al. in 2012, among patients who had a visually complete TURBT the rate of complete responders was 79%. Conversely, in patients who do not achieve a visually complete resection, the rate of complete responders was substantially lower at 57%.⁷ This was similarly demonstrated by Rodel et al. previously in 2002. The local response has significant implications even within the context of prior neoadjuvant chemotherapy⁸ with complete responders having a much better prognosis. As such, TURBT is the first step to a complete response. 

Dr. Masson-Lecomte argued that mpMRI is not good enough at the current time. Real life specificity is a concern. As demonstrated below, an ROC curve based on the results of a systematic review/meta-analysis of retrospective studies demonstrated that the diagnostic accuracy of the MRI VI-RADS system is impressively/artificially high. 

However, in the prospective “real life” BladderPath trial, of the 14 patients with MIBC on mpMRI, 5 had a TURBT, of which all were NMIBC. As such, in the “real life” setting, the true specificity is 61%, which remains inadequate in this setting.

What other applications does MRI have in this setting? The role of MRI in predicting the presence of MIBC in patients undergoing a repeat TURBT for T1 disease was recently evaluated and was demonstrated to have a sensitivity and specificity of 92% and 91%, respectively. However, such a comparison would assume that a repeat TURBT’s only value is to diagnose muscle invasive disease, which is inaccurate, as resection of residual disease in this scenario is critical to improving oncologic outcomes. 

The MRI delta ADC may also have interesting applications for the prediction of responders to neoadjuvant chemotherapy as demonstrated in the waterfall plot below. However, Dr. Masson-Lecomte argues that these results are not sufficient enough to allow for routine MRI use alone in this setting as of yet.

Dr. Masson-Lecomte concluded her presentation with the following take home message:

Presented by:

• Professor James Catto, MBChB, PhD, FRCS, Professor of Urologic Surgery at the University of Sheffield, Sheffield, United Kingdom 
• Professor Alexandra Masson-Lecomte, MD, PhD, Professor of Urology at Hôpital Saint Louis, Université Paris Cité, Paris, France

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3. Mariappan et al. Good quality white-light transurethral resection of bladder tumours (GQ-WLTURBT) with experienced surgeons performing complete resections and obtaining detrusor muscle reduces early recurrence in new non-muscle-invasive bladder cancer: validation across time and place and recommendation for benchmarking. BJU Int 2012. (11):1666-73.
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