Bladder preservation in localized, muscle-invasive bladder cancer: Current state of affairs

Introduction

Daniel S. Roberson, MD

In 2024, cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) with pelvic lymph node dissection (PLND) remains the gold standard, curative treatment for eligible patients with nonmetastatic muscle-invasive bladder cancer (MIBC).¹ The risks of mortality, morbidity, and quality of life (QOL) degradation stemming from bladder removal cannot be overstated. Thus, a critical unmet need exists for effective MIBC treatments that avoid radical surgery while preserving oncologic outcomes.

Leilei Xia, MD

Historically, individuals who elect bladder-preserving treatment for MIBC fall into 1 of 2 groups: those medically unfit for major surgery or those with a strong preference to avoid RC. The concept of bladder-preserving therapy (BPT) in localized MIBC is not new. Various protocols have been employed and studied in this population for over 25 years.² In all comers with nonmetastatic MIBC, oncologic outcomes of organ-preserving treatments remain inferior to those of radical surgery but seem to approach noninferiority in particular populations. Current evidence suggests that QOL may be superior with BPT in all comers, but this does not hold in all subgroups of patients with MIBC. More effective systemic therapies, further individualized treatment, and improved staging and surveillance may allow more patients with MIBC to receive effective, durable treatment while retaining their bladder.

Patient selection

Trinity J. Bivalacqua, MD, PhD

Regarding patient selection for bladder preservation in MIBC, the literature supports specific disease- and patient-level factors that lead to superior outcomes. Patients with normal or near-normal performance status and bladder function are better candidates for BPT. Disease-specific factors contributing to improved outcomes include clinical T2 disease, small and solitary tumors that are amenable to complete transurethral resection (TUR), and disease that does not result in hydroureteronephrosis and is not associated with carcinoma in situ or regional lymph node spread.³

Treatment selection

To achieve optimal outcomes in organ-preserving MIBC treatment, the components of a therapy regimen are as crucial as patient selection. The modalities in a clinician’s arsenal include systemic therapy, radiation, and surgery in the form of TUR or partial cystectomy with PLND. The strongest evidence exists for multimodal therapy in the form of either trimodal therapy (TMT), consisting of maximal TUR, chemotherapy, and chemoradiation, or maximal TUR and chemotherapy followed by local consolidation with partial cystectomy and PLND.^4-6 Utilization of a single modality in organ-preserving treatment is not recommended by contemporary evidence-based guidelines nor considered standard of care.1 When utilizing radiation therapy as part of a BPT regimen, concurrently administered sensitizing chemotherapy has demonstrated superior outcomes to radiation alone.⁷

The evidence appraising the effectiveness of bladder-preserving MIBC treatments is not significant. The only randomized controlled trial (RCT) comparing TMT against RC in this population was published in 1991, and although it demonstrated similar overall survival (OS) in both arms, there was increased locoregional failure in the organ preservation arm; more importantly, the results were highly confounded, and the validity of the findings has consistently been called into question.² Subsequent efforts to perform RCTs have been unsuccessful, the most recent being the failure to accrue in the phase 3 SPARE trial (NCT00867347).⁸ We thus rely on nonrandomized prospective and retrospective case series to draw conclusions. Meta-analyses of such series quote BPT 5-year OS at around 55% and disease-
specific survival (DSS) at around 70%, which does approach that of RC, but only in a small, select subset of nonmetastatic patients with MIBC.^9,10

Several other prospective and retrospective studies employing chemotherapy and partial cystectomy after maximal TUR support a similar theme: Oncologic outcomes in BPT approach that of radical surgery only in the highly selected patient. One prospective study out of Japan demonstrated excellent 5-year outcomes (93% DSS, 91% OS) with “tetramodal therapy,” which included maximal transurethral resection of bladder tumor, induction chemoradiation, and consolidative partial cystectomy with PLND. “Tetramodal therapy” touts the best oncologic outcomes to date in this space, although this study had incredibly stringent inclusion criteria and comprised a few patients.¹¹

Regardless of the organ-preserving regimen, patients must be closely monitored with cystoscopy, cross-sectional imaging, and urine cytology.¹ If MIBC recurs, which happens in an estimated 30% of cases,¹² patients should proceed to RC if medically fit.¹ If patients recur with superficial bladder cancer (non–muscle-invasive bladder cancer [NMIBC]), they may be treated as if they developed de novo NMIBC, although even recurrence with NMIBC confers inferior outcomes in this population.¹³ Published surveillance protocols recommend beginning with endoscopic examinations every 3 months and cross-sectional, contrast-enhanced imaging every 6 months, although no one surveillance protocol has demonstrated a superior survival benefit over another.^14,15

Future directions

As the field of bladder cancer evolves, the future of organ-preserving treatment in MIBC likely will be shaped by individualization of diagnostics and care, improved clinical staging and risk stratification, novel predictive biomarkers, and more effective and tailored systemic therapies. The bladder MRI is hypothesized to stage patients more accurately than conventional CT scans. Standardization efforts in the form of the Vesical Imaging-Reporting and Data System (VI-RADS), similar to what has been developed in prostate cancer, are a significant focus of ongoing research efforts.¹⁶ VI-RADS scoring has shown some promise in clinical applications in patients with localized MIBC electing BPT.17 A recent multi-institutional, phase 2 study, HCRN GU16-257 (NCT03558087), investigated the addition of immunotherapy (nivolumab [Opdivo]) to a cisplatin-based NAC regimen, provided an individualized risk-adapted approach by using VI-RADS scoring, and explored the ability to surveil patients with novel biomarkers including whole exosome sequencing of tissue and circulating tumor DNA from urine and plasma specimens.¹⁸

Another contemporary phase 2 trial, the RETAIN study (NCT02710734), took an individualized, risk-adapted approach to this clinical problem by offering BPT to patients who demonstrated specific molecular profiles on pre-NAC TUR specimens and demonstrated no evidence of disease following systemic therapy. The 2-year metastasis-free survival in RETAIN was 72%, and 50% of active surveillance patients were able to avoid RC at 41 months; however, the study did not meet its prespecified noninferiority conditions.¹⁹

In the highly selected patient with localized MIBC, an organ-preserving approach to treatment may produce similar oncologic outcomes to radical surgery with a potential for improved QOL, although there is insufficient evidence to recommend bladder preservation therapy as a standard of care. No individual bladder preservation therapy or surveillance protocol has demonstrated superiority. The future in this space likely will include enhanced diagnostics and therapies to individualize care.

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