Editor's Note: The rapid development of antibody-drug conjugates (ADCs) and immunotherapy is driving bladder-preservation strategies beyond single-modality local treatment toward an integrated approach combining systemic therapy, local treatment, and molecular stratification. Oncology Frontier – UroStream invited Professor Yijun Shen of Fudan University Shanghai Cancer Center to discuss combination bladder-preservation strategies for high-risk non-muscle-invasive bladder cancer (NMIBC), the implications of perioperative studies in muscle-invasive bladder cancer (MIBC) for traditional treatment pathways, and the potential applications of biomarkers such as circulating tumor DNA (ctDNA) and urinary tumor DNA (utDNA).High-Risk NMIBC: From Single-Modality Intravesical Therapy to Local-Systemic Treatment Integration
01
Bladder-preservation treatment for high-risk NMIBC is increasingly evolving toward a model in which systemic therapy and intravesical therapy are used in parallel. Based on your team’s research on disitamab vedotin combined with BCG, how do you assess the current state of research and future directions in this field?
Professor Yijun Shen: When discussing bladder preservation in bladder cancer, we should not focus exclusively on patients with MIBC, but also consider the much larger population with high-risk NMIBC. These patients are generally at an earlier stage of disease and often have a strong desire to preserve their bladder. Although clinical experience with BCG intravesical therapy has continued to accumulate in China, a considerable proportion of high-risk patients still experience recurrence or progression after BCG treatment. How to control oncologic risk while avoiding premature radical cystectomy remains an important clinical question.
For patients with extremely high-risk features and HER2 expression who are unwilling or unable to undergo radical cystectomy, we conducted a prospective study exploring disitamab vedotin combined with BCG. Preliminary results showed encouraging short-term efficacy, with overall manageable safety. The underlying rationale is to add HER2-targeted systemic therapy to standard local BCG treatment in an attempt to further reduce the risks of recurrence and progression.
However, the encouraging signals from early-stage studies still require validation through higher-level evidence. Future studies should involve larger, multicenter, randomized controlled trials comparing the combination strategy with standard BCG therapy, while continuing to evaluate recurrence-free survival, disease progression, bladder preservation, and long-term safety. Studies such as Formula-01 conducted by other Chinese research teams have also provided valuable evidence from different perspectives. Only when short-term responses can be translated into stable long-term benefits can combination strategies truly change clinical practice.
In the future, bladder-preservation treatment for high-risk NMIBC is likely to evolve into a diversified treatment landscape. This will include local therapies such as BCG, as well as ADCs, immunotherapy, and other novel agents. Systemic therapy combined with local treatment may be explored alongside further optimization of intravesical therapies. As treatment options become increasingly diverse, patient selection and adverse-event management will become even more important. The goal of combination therapy is not simply to add drugs, but to improve disease control while maintaining safety and, whenever possible, preserving bladder function and quality of life.
MIBC Pathway Reshaping: Perioperative Advances Do Not Mean Surgery Can Simply Be Omitted
02
Studies such as EV-303 and EV-304 have advanced ADC-plus-immunotherapy strategies into the perioperative setting for MIBC. What implications do these developments have for bladder-preservation research, and how might traditional trimodality therapy (TMT) evolve in the future?
Professor Yijun Shen: EV-303, EV-304, and other studies have attracted considerable attention because they are moving perioperative treatment for MIBC into a new stage. Compared with traditional cisplatin-based neoadjuvant chemotherapy, ADC-plus-immunotherapy strategies have demonstrated the potential to achieve deeper responses. Studies of disitamab vedotin combined with immunotherapy have likewise suggested that novel systemic therapies may further improve tumor control in some patients.
However, it is important to clarify that these perioperative studies currently still incorporate radical cystectomy as an important component of the treatment pathway. Patients receive systemic therapy and subsequently undergo surgery according to the study protocol. Therefore, these findings cannot simply be extrapolated to mean that surgery can be omitted once a patient achieves a response. A breakthrough in perioperative therapy and the establishment of a mature bladder-preservation strategy are two distinct issues.
If we want to determine whether the bladder can be safely preserved after novel systemic therapy in patients with MIBC, dedicated clinical trials are required. Such studies must first clearly define the clinical question, establish stringent patient-selection and response-assessment criteria, and ensure that participants can complete treatment, reassessment, and long-term follow-up according to protocol. Only with a sufficiently clear research pathway and rigorous implementation can we determine whether bladder preservation can truly be achieved without compromising oncologic outcomes.
From this perspective, ADCs and immunotherapy are unlikely to simply replace conventional TMT. Instead, they may prompt us to reconsider how systemic and local therapies should be combined. Future research needs to compare the appropriate patient populations, treatment intensity, and long-term outcomes of different strategies, determining which patients are suitable for standard TMT and which may be candidates for selective bladder-preservation studies following adequate systemic therapy. Whatever the pathway, conclusions must ultimately be supported by prospective evidence and standardized follow-up.
Molecular Biomarkers: From “Can the Bladder Be Preserved?” to Individualized Combination Strategies
03
In the ADC 2.0 era, what role will molecular biomarkers play in bladder-preservation strategies? Could they enable a shift from simply determining “whether to preserve the bladder” toward selecting individualized combination treatment?
Professor Yijun Shen: Biomarkers are increasingly influencing cancer diagnosis, response assessment, and treatment selection. Studies such as IMvigor011 have demonstrated the potential of ctDNA to identify patients with molecular residual disease and a high risk of recurrence after surgery for MIBC, while also helping determine the need for adjuvant treatment and the appropriate timing of intervention. These studies provide an important example of how molecular information may guide subsequent treatment decisions.
As bladder-preservation strategies enter a new phase, the range of potentially useful biomarkers is expanding. In addition to conventional urine cytology, these include circulating tumor cells (CTCs), ctDNA, urinary tumor DNA (utDNA), and personalized assays designed according to individual tumor mutations. The value of biomarkers does not lie in simply increasing the number of tests performed, but in whether their results can be integrated with imaging, cystoscopy, and pathology and ultimately alter clinical decision-making.
ctDNA is better suited to reflecting systemic tumor burden and potential minimal residual disease, but its detection and predictive capacity may be limited when disease is confined to the bladder. Because utDNA is directly derived from urine, it may have greater potential for detecting residual or recurrent local bladder disease. Therefore, future research could explore combined ctDNA and utDNA stratification—for example, comparing double-positive, single-positive, and double-negative patients—and use these results to assess whether patients should continue bladder-preservation treatment, undergo treatment intensification, or transition to another treatment pathway.
However, molecular biomarkers cannot currently be used independently of standard clinical assessment to determine treatment. Detection platforms, sample processing, positivity thresholds, sampling time points, and the relationship between dynamic molecular changes and long-term outcomes all require further clarification through prospective studies. Truly precision-based bladder preservation should integrate molecular information with clinical characteristics, imaging, cystoscopy, and pathology, moving beyond a one-time determination of “whether the bladder can be preserved” toward dynamic and individualized decision-making throughout the entire treatment course.
Summary
Professor Yijun Shen outlined three major directions in the evolution of bladder-preservation strategies. For high-risk NMIBC, treatment is moving beyond single-modality intravesical therapy toward integration of systemic therapies such as ADCs with local treatment. In MIBC, advances in perioperative therapy provide a stronger foundation for future organ-preservation research, but they do not yet justify replacing radical cystectomy or standard TMT. Meanwhile, molecular biomarkers such as ctDNA and utDNA may enable patient selection and response assessment to evolve from static evaluation toward dynamic risk stratification.
Ultimately, only through rigorous clinical research, standardized assessment, and careful safety management can therapeutic innovation translate into durable tumor control, preservation of bladder function, and meaningful improvements in quality of life.
Professor Yijun Shen
