| 15th Shanghai Urologic Oncology Academic ConferencePlay
Editor’s Note: With the continuous evolution of treatment concepts and the advancement of therapeutic strategies, the management landscape of muscle-invasive bladder cancer (MIBC) has undergone significant transformation. Among these advances, treatment regimens combining antibody–drug conjugates (ADCs) with immune checkpoint inhibitors (ICIs) have substantially increased pathologic complete response (pCR) rates, opening new possibilities for bladder preservation in selected patients.
However, despite these promising outcomes, several critical challenges remain unresolved—most notably, how to accurately identify patients who are most likely to benefit, and how to effectively control intravesical recurrence and metastatic risk following bladder-sparing approaches.
At the recently held 15th Shanghai Urologic Oncology Academic Conference, Oncology Frontier – UroStream invited Andrea Necchi, Director of the Genitourinary Oncology Center at Vita-Salute San Raffaele University, to provide an in-depth analysis of the current status, unmet needs, and future directions of bladder-sparing strategies in MIBC.
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Oncology Frontier- UroStream: Professor, do intensive treatment strategies based on ADCs and ICIs have the potential to change the standard of care for high-risk bladder cancer patients and perhaps even replace radical cystectomy in the future? What are the primary scientific and clinical challenges involved?
Dr. Necchi：The field of bladder cancer treatment is entering an exciting phase. With the successive emergence of ICIs and ADCs (such as enfortumab vedotin), we have begun exploring their combination in both clinical trials and practice. Existing data indicate that ADCs combined with ICIs as a neoadjuvant strategy can yield high pCR rates. This has led us to consider: can patients who achieve a deep response be spared from undergoing radical cystectomy?
As systemic treatment outcomes improve, an increasing number of patients hope to retain their bladder when they respond well to therapy. However, the critical challenge lies in the uncertainty of recurrence patterns. Even if patients respond well to systemic therapy, those who choose bladder preservation still face the risk of intravesical recurrence, most of which are high-grade non-muscle invasive recurrences. Consequently, the core clinical issues are how to precisely screen suitable candidates for bladder preservation and how to effectively manage intravesical recurrence to prevent progression into metastatic disease. The consensus meeting held in Milan last year aimed specifically to clarify concepts such as “clinical complete response (cCR)” to provide a standardized basis for patient screening.
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Oncology Frontier- UroStream: Can precision tools such as circulating tumor DNA (ctDNA), urinary tumor DNA (utDNA), or artificial intelligence (AI) imaging analysis provide guidance for bladder preservation? Is it possible to establish reliable biomarker models in the future to provide a basis for individualized patient choices between bladder preservation and radical cystectomy?
Dr. Necchi：In the field of efficacy monitoring, we have entered a new stage. A significant advancement is the assessment of minimal residual disease (MRD), a concept that is still relatively novel in bladder cancer. Currently, common MRD assessment methods include two types of “liquid biopsy”:Individualized ctDNA analysis based on the patient’s tumor mutation profile and utDNA detection based on the same principle.
ctDNA refers to small fragments of DNA released into the blood by tumor cells, carrying genetic information related to the primary tumor. Detecting ctDNA enables early diagnosis, treatment monitoring, and recurrence risk assessment. Currently, ctDNA has been confirmed as a prognostic biomarker for bladder cancer and can predict the efficacy of adjuvant immunotherapy (such as atezolizumab after cystectomy). utDNA refers to tumor-derived DNA fragments detected in urine samples. As a non-invasive biomarker similar to ctDNA, utDNA also carries tumor-specific mutation information; however, because it originates from urine, it may offer advantages in certain contexts.
Nevertheless, in the perioperative neoadjuvant or adjuvant setting—particularly regarding the guidance of bladder preservation decisions—the application of ctDNA and utDNA still requires more reliable data for support. Theoretically, if both ctDNA and utDNA turn negative following neoadjuvant therapy, the patient may be an ideal candidate for attempting bladder preservation. However, there is currently a lack of high-level evidence to define the guiding significance of these biomarkers in bladder preservation decision-making. What is certain is that, regardless of the neoadjuvant regimen used, MRD assessment is gradually transforming patient management strategies.
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Oncology Frontier- UroStream: Many clinical studies on bladder preservation have been reported, but there is still a lack of compelling evidence sufficient to change clinical practice. What do you believe are the primary limitations of current clinical trial designs for bladder preservation, and how should they be optimized?
Dr. Necchi：Current bladder preservation strategies typically involve systemic therapy for eligible patients, followed by a decision on bladder management based on efficacy. Multiple clinical trials have shown that even for patients who achieve deep remission and successfully retain their bladder, intravesical recurrence remains possible—primarily as high-grade non-muscle invasive recurrence—despite subsequent maintenance immunotherapy or active surveillance.
The RETAIN study was a prospective, multicenter Phase II clinical trial designed to evaluate the feasibility and efficacy of an active surveillance strategy instead of immediate radical cystectomy for MIBC patients following dose-dense MVAC (ddMVAC) neoadjuvant chemotherapy. The results showed that among patients who achieved cCR and chose active surveillance, the study successfully achieved high short-term bladder preservation rates. However, recurrences still occurred in some patients. While most recurrences were localized to the bladder (non-muscle invasive), a certain proportion of these patients eventually progressed to metastatic disease.
This reveals a core challenge: even in patients with a good initial response whose recurrence is localized to the bladder, high-grade recurrence itself may indicate aggressive underlying biology and a risk of metastasis. Existing clinical assessment tools (such as imaging and cystoscopic follow-up) may be insufficient to accurately identify patients who, despite reaching cCR, still face a high risk of long-term metastasis. Currently, we lack tools to precisely predict the risk of intravesical recurrence at the individual level. The sensitivity of conventional MRD methods (like ctDNA) for detecting minute intravesical recurrences may be inadequate; utDNA may hold more potential, though further data validation is required.
Consequently, future clinical trials should be improved in two areas: Optimizing patient screening strategies: Incorporating more sensitive biomarkers like utDNA to enhance recurrence risk prediction.Strengthening local consolidation: In the context of effective systemic therapy, exploring ways to reinforce local bladder treatment—such as through novel intravesical drug instillations or radiotherapy—to reduce intravesical recurrence rates and improve the overall success and safety of bladder preservation strategies。
Andrea Necchi
