Editor’s Note: “To live or to live well?” This Shakespearean dilemma continues to haunt many patients with bladder cancer. How to provide longer-lasting disease control while preserving the bladder through safer and more tolerable strategies has become a central challenge in urologic oncology. At the 2025 ASCO Annual Meeting, Professor Yijun Shen from Fudan University Shanghai Cancer Center presented the Phase II ReBirth study, which evaluates stratified bladder-sparing treatment strategies based on whether patients achieve clinical complete response (cCR) following neoadjuvant immunochemotherapy.Investigator Insights
Oncology Frontier: With advances in medicine and diagnostic technologies, more and more patients with bladder cancer are seeking bladder-sparing treatment. Based on your clinical experience, what are the current challenges in implementing bladder preservation strategies?
Professor Yijun Shen: In recent years, we’ve seen a growing demand from bladder cancer patients for bladder-sparing treatment, but meeting this demand remains a significant clinical challenge. In fact, the concept of bladder preservation is not new—it’s been discussed in academic circles for many years. However, earlier efforts were limited by outdated treatment modalities, such as underdeveloped radiotherapy techniques and the high toxicity of conventional chemotherapeutic agents.
Today, with the rapid development and clinical application of novel therapies such as immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs), we now have more diverse options for bladder preservation.
Traditionally, bladder-sparing treatment has centered on trimodal therapy (TMT), which combines maximal transurethral resection (TURBT) with concurrent chemoradiation. However, in China, this approach remains underutilized for several reasons. First, effective bladder-sparing requires a multidisciplinary team (MDT) involving radiation oncologists, medical oncologists, radiologists, pathologists, and others. Comprehensive management across diagnosis, treatment, monitoring, and follow-up is essential, but many hospitals still lack the infrastructure for efficient MDT collaboration.
Second, there’s a conceptual gap. Many physicians—especially urologists who provide initial or primary diagnosis—still lack sufficient awareness of bladder-sparing options and often default to recommending radical cystectomy. While radical surgery has well-established survival benefits and long-term data, an increasing number of studies show that select patients—so-called “bladder-sparing candidates”—can achieve comparable long-term survival without bladder removal. Changing entrenched mindsets, however, takes time.
In recent years, the concept of neoadjuvant therapy has gained traction among both doctors and patients. Some patients who achieve clinical complete response (cCR) after neoadjuvant treatment are now proactively requesting bladder-sparing approaches rather than proceeding to cystectomy. The key challenge here lies in making the optimal treatment decision—in other words, how do we identify the patients most likely to benefit from bladder-sparing? This remains a central focus in clinical research. Beyond traditional clinicopathologic features, exploratory biomarker analysis and translational research may eventually allow us to more precisely select patients truly suited for this approach.
In summary, bladder-sparing treatment still faces multiple barriers in clinical practice—from mindset shifts and MDT collaboration to identifying the right patient population. However, with continued advances in medical science, these obstacles are gradually being addressed.
Oncology Frontier: At this year’s meeting, you and your team presented the ReBirth study, which explored a stratified bladder-sparing strategy following neoadjuvant therapy with toripalimab combined with chemotherapy. Could you tell us more about the background and main findings of this study?
Professor Yijun Shen: As mentioned earlier, traditional bladder-sparing approaches have largely relied on trimodal therapy (TMT), which still presents several limitations. For example, radiotherapy may lead to difficult-to-manage radiation-induced cystitis or enteritis. Some patients experience local recurrence or bladder-sparing failure, requiring salvage radical cystectomy. In the past, limitations in radiotherapy equipment, dosing precision, and targeting accuracy often compromised surgical outcomes, which further restricted the clinical adoption of this approach.
With these challenges in mind, our team began thinking years ago about how to optimize bladder-sparing strategies without compromising survival. Specifically, we aimed to reduce reliance on interventions with significant toxicity in order to provide patients with longer-lasting bladder preservation and better quality of life.
The ReBirth study was built on our earlier observations that patients who achieved clinical complete response (cCR) after neoadjuvant therapy tended to have favorable prognoses and low recurrence risk, suggesting they may represent ideal candidates for bladder preservation. We hypothesized a stratified approach: patients who reached cCR would undergo “treatment de-escalation,” receiving maintenance immunotherapy only, without radiotherapy; those who did not achieve cCR would undergo “treatment escalation,” receiving conventional concurrent chemoradiation followed by maintenance immunotherapy.
The study completed enrollment last year, and we presented updated results at this ASCO meeting. As of January 16, 2025, a total of 32 patients were enrolled, with a median follow-up of 14.3 months. Among them, 71% achieved cCR. Only four patients opted for surgery at the end of the first treatment phase for various reasons—one of whom was found to have achieved pathological complete response (pCR) postoperatively.
The 1-year bladder-intact event-free survival (BI-EFS) rate in this cohort was 86.9%, suggesting that most patients achieved a “dual win”—tumor control and bladder preservation. The safety profile was also favorable, with grade ≥3 adverse events occurring in only 42.3% of patients. These findings provide early evidence that using neoadjuvant response to guide subsequent bladder-sparing strategies is a feasible and promising approach. Notably, nearly 71% of patients preserved their bladder without undergoing radiotherapy, thus avoiding its associated toxicities and improving the practicality of bladder-preserving treatment.
In addition, recent years have seen significant progress in bladder cancer treatment globally—especially in the area of systemic therapy. Novel combinations such as ADCs plus ICIs have emerged as new first-line options for advanced urothelial carcinoma. Numerous clinical trials are also exploring how to integrate these therapies into bladder-preserving protocols.
We’re optimistic that with continued collaboration among domestic and international experts, multidisciplinary teams, and frontline clinicians, we’ll be able to offer safer, more durable bladder-sparing options for our patients.
Oncology Frontier: Based on this study and your clinical experience, how should post-treatment recurrence be managed in patients who undergo bladder-sparing therapy?
Professor Yijun Shen: In terms of long-term outcomes, the overall success rate of bladder-sparing treatment during the traditional TMT era was about 50%. This means that nearly half of patients might face suboptimal treatment responses, requiring salvage cystectomy or even losing the opportunity for surgery due to distant metastasis.
In our study, although the sample size was relatively small, we did observe disease recurrence in some patients during bladder-sparing treatment. Specifically, five patients experienced local high-grade recurrence, and three developed distant metastases—three with bone metastasis and two with lymph node involvement. These patterns are similar to those observed during the TMT era. However, given the relatively short follow-up, the overall recurrence and metastasis rates in our study remain low for now.
Patients with recurrence or metastasis still have further treatment options. For local recurrence, especially if non–muscle-invasive, additional maximal or radical TURBT can be followed by intravesical therapy, such as another course of BCG instillation. If the recurrence is muscle-invasive, salvage cystectomy remains the preferred option. In our study, one patient with local recurrence insisted on bladder preservation, so we administered concurrent chemoradiation again. Unfortunately, this patient later developed both bone and lymph node metastases.
For patients with distant metastasis, evidence-based guidelines recommend initiating systemic therapy appropriate for advanced disease. Given that many of these patients already received platinum-based chemotherapy during early-stage treatment, later-line therapy may involve immune checkpoint inhibitors (ICIs) combined with antibody-drug conjugates (ADCs). This includes agents like disitamab vedotin, targeting HER2, or enfortumab vedotin, targeting Nectin-4—both of which have demonstrated survival benefits in phase III trials as first-line options.
In recent years, the field of systemic therapy for advanced urothelial carcinoma has rapidly evolved, supported by growing clinical evidence and long-term survival data. Likewise, even for patients who experience unexpected recurrence or metastasis during or after bladder-sparing therapy, systemic and emerging therapies still offer the possibility of long-term survival.
Study Summary
ReBirth: A Phase II Study of Risk-Stratified Bladder-Sparing Treatment in Muscle-Invasive Bladder Cancer (MIBC) Abstract #4586
Background Trimodality therapy (TMT) has achieved long-term survival and sustained tumor control in selected patients with muscle-invasive bladder cancer (MIBC). However, there remains a lack of individualized treatment strategies based on responses to chemotherapy combined with PD-1 inhibitors. In addition, the safety and efficacy of hypofractionated radiotherapy in combination with PD-1 inhibitors and concurrent chemotherapy warrant further investigation.
Methods This was a two-stage, single-arm, phase II trial conducted in patients with clinical stage cT2-4aN0-1M0 MIBC. In the first stage, patients received neoadjuvant treatment with toripalimab (200 mg on Day 1), cisplatin (70 mg/m² on Day 1), and gemcitabine (1000 mg/m² on Days 1 and 8) every 3 weeks for 3–4 cycles. After treatment, patients were assessed using cystoscopy, urine cytology, and imaging. Those who achieved clinical complete response (cCR, defined as cT0 or cTa) received maintenance toripalimab monotherapy, while non-cCR patients underwent toripalimab combined with chemoradiation. Radiation was delivered at 44 Gy in 16 fractions to the entire bladder, with cisplatin as a radiosensitizer. For patients with nodal involvement, additional radiation could be given up to the maximum tolerated dose (e.g., nodal boost of 11 Gy in 4 fractions).
The primary endpoint was 1-year bladder-intact event-free survival (BI-EFS) in the intention-to-treat (ITT) population, defined as time from enrollment to muscle-invasive recurrence, lymph node or distant metastasis, radical cystectomy, or death. Secondary endpoints included 1-year BI-EFS in the per-protocol (PP) population, metastasis-free survival (MFS), recurrence-free survival (RFS), and safety.
Results As of January 16, 2025 (median follow-up: 14.3 months), a total of 32 patients were enrolled, with a median age of 64 years (range: 36–79). Clinical staging included cT2 (71.8%), cT3 (21.9%), cT4 (6.3%), and cN1 (6.3%). One patient withdrew consent before efficacy assessment.
In the ITT population, 71.0% achieved cCR, and 29.0% did not. Four patients underwent radical cystectomy. The 1-year BI-EFS rate was 86.9% (95% CI: 68.8–94.9) in the ITT population and 95.8% (95% CI: 73.9–99.4) in the PP population. Among PP patients, the 1-year BI-EFS was 100% in cCR patients and 80% in non-cCR patients.
Overall, five patients experienced recurrence with high-grade T1 disease. Three patients developed distant metastases, including three cases of bone metastasis and two cases of distant lymph node involvement.
Treatment-related adverse events (TRAEs) of any grade occurred in 78.1% of patients, while grade 3–4 TRAEs were reported in 42.3%. No new safety signals were observed.
Conclusion Updated results continue to support the promising efficacy and manageable toxicity of the two-stage treatment strategy. For patients who did not achieve cCR, intensified therapy with chemoradiation plus toripalimab may allow for bladder preservation and avoidance of radical cystectomy. Follow-up for long-term survival outcomes is ongoing.
Yijun Shen
