AUA 2022: Case-Based Debate: Do I need to do Repeat TUR for all High Grade NMIBC Patients? Pro

(UroToday.com) The 2022 Annual Meeting of the American Urological Association (AUA) was host to The International Bladder Cancer Group (IBCG) AUA Bladder Cancer Forum which featured a case-based debate regarding the role of repeat transurethral resection of bladder tumors (TURBT) for all high grade non-muscle invasive bladder cancers (NMIBC). This session was expertly moderated by Dr. Neal Shore, and Dr. Trinity Bivalacqua was tasked with arguing in favor of repeat TURBT in this setting.

Dr. Shore began the session by presenting the following debate considerations:

• 70-year-old presents with high grade NMIBC to your clinic - when is repeat TURBT needed?
• NMIBC stage: TaG3 versus CIS versus TI
• Who performed the initial TURBT: you versus your known versus unknown colleague? Does technique/operative note make a difference?
• Who reads the histopathology (muscle included)? Is a 2^nd opinion read needed?
• Does time from initial resection matter?
• If a repeat TURBT is recommended, do patient comorbidities matter? Does patient opinion matter regarding repeat anesthesia, morbidity, and cost?

Dr. Bivalacqua began his discussion by highlighting the importance of TURBT for determination of:

• Configuration (flat, sessile or papillary)
• Location (trigone, prostate, base, dome, or lateral walls)
• Size
• Number of tumors
• Pathology: stage, grade, lymphovascular invasion (LVI), variant histology, depth of invasion

NMIBC is a highly heterogenous disease with varying rates of recurrence and progression:

• Low grade Ta
  • Recurrence rate ~55%, stage progression ~5%
• High grade T1
  • Recurrence rate ~50%, ~20% progression to MIBC
• Risk stratification enables personalized treatment decisions
• Current predictive models are based on the pathologic features of the tumor but underperform

Dr. Bivalacqua went on to present the current recommendations for re-staging TURBT as per current guidelines. There is a consensus among the guidelines that repeat TURBT is needed for:

• Incomplete initial TURBT
• No muscle in specimen except for LGTa and primary CIS
• T1 tumors
• Recommendations vary from weak to strong

Currently the AUA guidelines recommend:

13. n a patient with high-risk, high-grade Ta tumors, a clinician should consider performing repeat transurethral resection of the primary tumor site within six weeks of the initial TURBT. (Moderate Recommendation; Evidence Strength: Grade C)
14. In a patient with T1 disease, a clinician should perform repeat transurethral resection of the primary tumor site to include muscularis propria within six weeks of the initial TURBT. (Strong Recommendation; Evidence Strength: Grade B)

The rationale of re-TUR is concern for:

• Incomplete resection, residual tumors
• Upstaging
• Recurrence
• Progression
• Facilitate response to intravesical therapy
• Predictive of outcomes

In his practice, Dr. Bivalcqua performs:

• Repeat TURBT for high risk NMIBC, including HGTa (all sizes), HGT1 and CIS
  • Less debate about HGT1 +/- CIS
  • HGTa – people may have differing opinions
  • Within 4-6 weeks of initial TURBT and uses enhanced cystoscopy (blue light cystoscopy) for all patients with high risk NMIBC
• Pathology re-review

Why perform a re-staging TURBT? Herr et al. demonstrated in 2015 among patients with Ta and T1 bladder tumors undergoing a re-staging TURBT that the risk of residual disease in HGTa patients was 65% (50% HGTa/CIS, 10%, T1, 5% T2 or worse). For T1 patients, this is particularly crucial for those without muscles in the specimen:

• T1 with muscle: 75% residual disease
  • 31% HGTa/CIS
  • 29% T1
  • 15% T2
• T1 without muscle: 70% residual disease
  • 15% HGTa/CIS
  • 20% T1
  • 45% T2

Overall, for HGTa undergoing re-TURBT:

• 17-67% have residual tumors
• Upstaging rate: 0-15%
• One study with 12 months follow-up showed recurrence rate of 16% with re-TURBT and 58% without re-TURBT
• Another study with 48 months follow-up showed progression rate of 7% with re-TURBT versus 31% without re-TURBT

Sfakianos et al. have also demonstrated that among patients with high risk NMIBC, a single TURBT was a significant predictor of recurrence odds during a 5 year follow up (OR 2.1, 95% CI 1.3-3.3).

With regards to T1 disease, the debate is less controversial. Dalbagni et al. performed a retrospective review of 523 patients between 1990 and 2007 who had initial T1 disease with subsequent re-staging TURBT. Muscle was present in 47% of the initial specimens and 84% of re-TURBT specimens. 20% of patient were upstaged to T2 or worse disease. The results of the re-staging TURBT were highly predictive of cancer specific mortality outcomes:

• 8% for <T1
• 10% for T1
• 44% for T2 disease

Divrik et al performed a randomized controlled trial between 2001 and 2005 of 142 patients with HGT1 disease on initial TURBT with all patients receiving Mitomycin adjuvantly. Patients were randomized to repeat TURBT versus surveillance. The recurrence free survival was superior in the re-TURBT group at 1 (86% versus 47%), 2 (78% versus 42%) and 3 years (69% versus 37%).

The value of repeat TURBT in those with true T1 disease is further re-enforced by results from European Urology in 2009 that demonstrated that true T1 disease who had repeat TUR and underwent immediate cystectomy or local therapy and surveillance had no significant difference in cancer-specific survival.¹

The importance of pathology re-review at a tertiary center was demonstrated by the team at Columbia University. 91 patients underwent a pathology re-review and the number of clinically significant discrepancies was 61.5%.

Despite the obvious advantages of repeat TURBT, once must remember that TURBT can be a morbid operation:

• Readmission rates of 3.7% and 30-day complications rates of grade 3 or worse of 5%
• Surveillance cystoscopy and TURBT are expensive and contribute to financial toxicity
• Anesthesia can cause cognitive decline in the elderly

Finally, Dr. Bivalcqua presented results from the phase III study comparing the efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer patients. Among 304 patients referred, 103 were noted to have lesions concerning for malignancy and 63 were noted to have confirmed malignancy. In 13 of 63 patients (20.6%) recurrence was only seen with blue light flexible cystoscopy. Of these 63 patients, 26 (41%) were noted to have carcinoma in situ, 9 (34.6%) of which could only be detected with blue light cystoscopy. The false positive rate was 9.1% for both cystoscopy modalities.²

Trinity Bivalacqua, MD, PhD, Professor of Urology and Oncology, Department of Urology, University of Pennsylvania, Philadelphia, PA

Written by: Rashid Sayyid, MD, MSc – Urology Chief Resident, Augusta University/Medical College of Georgia, @rksayyid on Twitter during the 2022 American Urological Association (AUA) Annual Meeting, New Orleans, LA, Fri, May 13 – Mon, May 16, 2022.