Implications of Guideline-Based, Risk-Stratified Restaging Transurethral Resection of High-Grade Ta Urothelial Carcinoma on Bacillus Calmette-Guérin Therapy Outcomes - Beyond the Abstract

While the role of restaging transurethral resection (reTUR) for high-grade (HG) T1 bladder cancer has well-established diagnostic and therapeutic implications, and guidelines agree on the role of reTUR for HG T1 disease,1-3 this remains an area of discussion for HG Ta tumors. The AUA recommends reTUR for all ‘high-risk’ HG Ta tumors (multifocal, ≥3cm, concomitant carcinoma in situ [CIS], variant histology, lymphovascular invasion [LVI], prostatic urethral involvement);2 while the EAU guidelines reserve reTUR for patients without muscularis propria in the index tumor specimen.1


In our publication,4 we evaluated the value of reTUR in HG Ta disease in a uniformly treated patient cohort receiving adequate BCG therapy.5 reTUR was associated with improved outcomes compared to no reTUR, and this benefit was most prominent in high-risk patients without detrusor muscle in the index specimen. While these results support components of both the AUA and EAU guideline recommendations for reTUR in HG Ta disease, the data suggest that either guideline, in isolation, is insufficient to capture all high-risk patients who benefit from restaging.

In 209 patients with HG Ta disease half underwent reTUR, of which 38% (39 patients) harbored residual disease. We identified risk factors for residual disease including tumor multifocality, concomitant CIS, lack of perioperative chemotherapy instillation at the index resection, and index TUR outside our facility. Interestingly, rates of detrusor muscle sampling were similar between cohorts with and without residual tumor on reTUR. However, residual disease should not, in isolation, justify reTUR as the presence of residual tumor at reTUR was not a poor prognosticator with regards to progression-free survival (PFS) or recurrence-free survival (RFS).

The EAU recommendation regarding reTUR for HG Ta disease is largely predicated on historical data indicating a 49% under-staging risk for HG Ta tumors without detrusor muscle in the index specimen compared to 14% understaging if detrusor is present.6 While our residual disease rate of 38% on reTUR for HG Ta tumors compares with that in the literature (17-67%),7 only 1 patient (1%) was upstaged to T1 disease on reTUR and no patients to muscle-invasive disease. Our data thus suggests that the primary driver of reTUR for HG Ta tumors should not be the fear of clinical understaging per se.

Our data support a largely non-risk stratified approach to reTUR, as patients who underwent restaging exhibited more favorable PFS (medians not reached, p = 0.050) and RFS (median not reached vs 64 mo [95% confidence interval 37–106 mo], p = 0.003) compared to patients with HG Ta disease who did not undergo reTUR. When we retrospectively applied the AUA and EAU Guideline-based, risk-stratified approaches to reTUR we found higher rates of recurrence, progression (defined as any stage progression and progression to MIBC), development of BCG-unresponsive disease, and radical cystectomy in patients who did not undergo reTUR based on individual guidelines. Notably, in the 45 patients meeting both guideline criteria for reTUR (ie. AUA ‘high-risk’ and no detrusor muscle), lack of restaging was associated with over a two-fold increase in recurrence (67% vs 15%, p = 0.002) and clinical progression (defined as any stage progression; 25% vs 6%, p = 0.109).

Opponents to uniformly offering reTUR for HG Ta tumors have referenced a delay to definitive intravesical therapy. Our group recently studied the timing of initial induction BCG instillations after TUR in relation to oncologic outcomes and BCG tolerability.8 In a cohort of 518 patients treated with adequate BCG therapy, 64% of whom underwent reTUR, time from resection to BCG induction did not significantly impact response to BCG.

The benefit in BCG response of reTUR for HG Ta disease must also be placed in the context of morbidity and cost related to restaging procedures. TURBT has significant financial implications. Estimates for the cost of a TUR in the US range from $7,000 - $13,0009 – expansion of reTUR could thus lead to additional economic burden in the treatment of bladder cancer, which already has the highest lifetime treatment cost of all malignancies.10 This must, of course, be balanced with benefits to our patients.

In conclusion, our data support a non-risk stratified approach for reTUR in all patients with HG Ta disease. This most closely reflects the recommendation in the NCCN guideline which endorses reTUR in HG Ta tumors with incomplete index resection, in the absence of detrusor muscle in the index specimen, or in large, multifocal lesions.3 ReTUR may be most applicable in patients being referred to a tertiary practice after index TUR, as there is well-described surgeon variability in TUR operative standards in the literature.11 Lastly, these results have clinical trial implications. Disparate recurrence and progression rates in response to BCG immunotherapy based on receipt of reTUR can be extrapolated to emerging intravesical and systemic therapies for BCG unresponsive disease and should be strictly controlled for prior to patient enrollment and carefully considered in comparative retrospective series.

Written by: Patrick J. Hensley, MD (@pjhensley11) Kelly K. Bree, MD (@KKBree) Ashish M. Kamat, MD, MBBS (@UroDocAsh), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

References:

  1. Babjuk M, Burger M, Compérat EM, Gontero P, Mostafid AH, Palou J, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) - 2019 Update. Eur Urol. 2019;76:639-57.
  2. Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196:1021-9.
  3. Flaig TW, Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK, et al. Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18:329-54.
  4. Hensley PJ, Bree KK, Brooks N, Matulay J, Li R, Nogueras-Gonzalez GM, et al. Implications of Guideline-based, Risk-stratified Restaging Transurethral Resection of High-grade Ta Urothelial Carcinoma on Bacillus Calmette-Guérin Therapy Outcomes. Eur Urol Oncol. 2021.
  5. BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance for Industry. FDA Maryland. 2018.
  6. Herr HW. The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol. 1999;162:74-6.
  7. Cumberbatch MGK, Foerster B, Catto JWF, Kamat AM, Kassouf W, Jubber I, et al. Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol. 2018;73:925-33.
  8. Hensley PJ, Bree KK, Brooks N, Matulay J, Li R, Nogueras González GM, et al. Time interval from transurethral resection of bladder tumour to bacille Calmette-Guérin induction does not impact therapeutic response. BJU Int. 2021.
  9. Svatek RS, Hollenbeck BK, Holmäng S, Lee R, Kim SP, Stenzl A, et al. The economics of bladder cancer: costs and considerations of caring for this disease. Eur Urol. 2014;66:253-62.
  10. Mossanen M, Gore JL. The burden of bladder cancer care: direct and indirect costs. Curr Opin Urol. 2014;24:487-91.
  11. Brausi M, Collette L, Kurth K, van der Meijden AP, Oosterlinck W, Witjes JA, et al. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol. 2002;41:523-31.

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