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Bladder Preservation after Neoadjuvant Therapy for Muscle-invasive Bladder Cancer in the Current Era: Myth and Reality - Beyond the Abstract

Bladder preservation strategies after perioperative therapy (PoT) in muscle-invasive bladder cancer (MIBC) represent a promising but still developing approach. Early prospective studies suggest that, in carefully selected patients, clinical complete responses after neoadjuvant therapy may allow short-term deferral of radical cystectomy (RC). At the same time, the durability, reproducibility, and generalizability of these findings remain uncertain. Our European Urology Focus debate examines this landscape through the lens of “myth versus reality.”

The myth component stems from the assumption that response to PoT alone is sufficient to justify routine omission of RC. Most bladder-preservation attempts originate from small, single-arm phase 2 studies, often restricted to highly selected populations and supported by intensive restaging and surveillance programs.1–3 Reported clinical complete response (cCR) rates can be encouraging, but estimates of bladder-intact event-free survival remain imprecise, and none of these trials establishes oncologic equivalence to RC. Technical heterogeneity, including variable definitions of maximal TURBT, differences in cCR criteria, inconsistent use of re-TURBT, and divergent imaging/biopsy standards, further limits interpretation and prevents cross-study comparability.4 Moreover, the limitations of restaging remain a central obstacle. Cystoscopy and systematic biopsies may miss residual ≥T2 disease; imaging often cannot reliably differentiate post-treatment effects from persistent tumor; and micrometastatic nodal disease is frequently undetected. Contemporary series show that cCR correlates only partially with pT0 at RC, meaning that a proportion of patients classified as tumor-free endoscopically still harbor invasive disease at cystectomy. Even when salvage RC is feasible and potentially curative, it is technically more challenging after prior radiation or delayed local failure, with the risk of narrower curative windows in real-world settings.5

The reality is that bladder preservation is not a speculative or unstructured concept. Modern trimodality therapy (TMT), combining maximal TURBT, concurrent chemoradiation, and timely salvage RC, has matured into a reproducible, guideline-supported approach in experienced centers. Long-term data from BC2001, RTOG protocols, and multi-institutional series show that, in appropriately selected patients, TMT can deliver durable local control and cancer-specific survival comparable to RC.6,7 Emerging biomarkers, including multiparametric MRI, ctDNA, and urine-based tumor DNA assays, may enhance patient selection, although none currently justifies RC omission independently. Importantly, recent consensus statements have harmonized definitions of cCR, endorsed event-free survival as a more rigorous endpoint, and proposed structured pathways for candidate selection and post-treatment surveillance.8

A new contextual factor is the FDA approval of perioperative enfortumab vedotin plus pembrolizumab (EVP) for cisplatin-ineligible, surgery-fit MIBC.9 KEYNOTE-905/EV-303 is the first perioperative trial to demonstrate a survival advantage over RC alone. Although EVP was evaluated exclusively in patients undergoing RC, it raises the systemic benchmark against which future bladder-preservation strategies must be assessed.

Written by:

  • Emanuele Crupi, MD, Department of GU Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • Andrea Necchi, MD, Department of Medical Oncology, IRCCS San Raffaele University Hospital, Milan, Italy
  • Ashish M. Kamat, MD, MBBS, FACS, Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
References:

  1. Galsky MD, Daneshmand S, Izadmehr S, Gonzalez-Kozlova E, Chan KG, Lewis S, et al. Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial. Nat Med. novembre 2023;29(11):2825–34.
  2. Geynisman DM, Abbosh PH, Ross E, Zibelman MR, Ghatalia P, Anari F, et al. Phase II Trial of Risk-Enabled Therapy After Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer (RETAIN 1). J Clin Oncol. 20 marzo 2025;43(9):1113–22.
  3. Ghatalia P, Ross EA, Zibelman MR, Anari F, Abbosh P, Tester WJ, et al. A phase 2 trial of risk enabled therapy after neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer (RETAIN-2). J Clin Oncol. 10 febbraio 2025;43(5_suppl):815–815.
  4. Laukhtina E, Moschini M, Teoh JYC, Shariat SF. Bladder sparing options for muscle-invasive bladder cancer. Curr Opin Urol. 1 novembre 2024;34(6):471–6.
  5. Zlotta AR, Ballas LK, Niemierko A, Lajkosz K, Kuk C, Miranda G, et al. Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis. Lancet Oncol. giugno 2023;24(6):669–81.
  6. Hall E, Hussain SA, Porta N, Lewis R, Crundwell M, Jenkins P, et al. Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial. Eur Urol. settembre 2022;82(3):273–9.
  7. Dahl DM, Karrison TG, Michaelson MD, Pham HT, Wu CL, Swanson GP, et al. Long-term Outcomes of Chemoradiation for Muscle-invasive Bladder Cancer in Noncystectomy Candidates. Final Results of NRG Oncology RTOG 0524-A Phase 1/2 Trial of Paclitaxel + Trastuzumab with Daily Radiation or Paclitaxel Alone with Daily Irradiation. Eur Urol Oncol. febbraio 2024;7(1):83–90.
  8. Gupta S, Hensley PJ, Li R, Choudhury A, Daneshmand S, Faltas BM, et al. Bladder Preservation Strategies in Muscle-invasive Bladder Cancer: Recommendations from the International Bladder Cancer Group. Eur Urol [Internet]. 22 aprile 2025 [citato 5 ottobre 2025]
  9. Research C for DE and. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA [Internet]. 21 novembre 2025 [citato 26 novembre 2025]; Disponibile su: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer
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