Recently, the Beijing Academic Exchange Conference for Young Physicians in Urologic Oncology was successfully held in Beijing. The meeting focused on the latest frontiers in urologic oncology and brought together many leading mid-career and young experts from across China, aiming to elevate clinical practice through intellectual exchange.At the conference, Yige Bao, Professor from West China Hospital of Sichuan University, delivered a keynote lecture entitled “Post-Neoadjuvant Management of Patients with Muscle-Invasive Bladder Cancer (MIBC)”. Drawing on classical Tang and Song dynasty poetry, Professor Bao vividly illustrated the dramatic paradigm shift in MIBC treatment and the complex clinical challenges that have emerged in its wake.
Based on Professor Bao’s presentation, this article systematically summarizes his core viewpoints, his in-depth interpretations of landmark studies (EV-303, NIAGARA), and his sober reflections on future therapeutic strategies, with the aim of providing practical reference for clinicians.
“New Leaves Spur the Old”: A New Perioperative Landscape in MIBC
At the beginning of his lecture, Professor Bao quoted Liu Yuxi’s Tang dynasty verse: “New leaves in fragrant woods press on the old; the forward wave yields to the one behind.” He used this imagery to capture the profound transformation currently unfolding in the treatment of MIBC.
In recent years, MIBC management has entered an entirely new era. Compared with the former paradigm of neoadjuvant chemotherapy followed by radical surgery alone, modern perioperative treatment now incorporates antibody–drug conjugates (ADCs), immune checkpoint inhibitors, and various precision-based strategies. The traditional treatment framework has been fundamentally dismantled.
Breakthrough trials such as EV-303 and NIAGARA represent these “new leaves of the medical forest,” bringing unprecedented survival benefits to patients. Yet, as Yang Wanli famously wrote, “Just when one mountain opens, another blocks the way.” Professor Bao emphasized that every major leap in clinical research inevitably gives rise to new questions. When neoadjuvant strategies undergo radical change, how should subsequent treatment pathways be designed? This remains an unresolved academic question and an urgent clinical dilemma.
The “Reverse Conflict” Between Drug Development and Clinical Pathways:
A Post-Line Treatment Vacuum**
Professor Bao astutely identified a fundamental contradiction between drug development logic and clinical treatment logic.
New drugs are typically developed by advancing from later lines to earlier lines, eventually securing positions in first-line or even perioperative settings. In contrast, clinical treatment planning proceeds from early to late, first determining neoadjuvant therapy, then adjuvant therapy, and finally systemic salvage options.
This mismatch creates an awkward reality: once highly effective agents—such as disitamab vedotin or enfortumab vedotin—are successfully moved into neoadjuvant therapy, they effectively eliminate themselves as later-line rescue options. When patients relapse or metastasize after receiving the most potent agents upfront, a large therapeutic void emerges downstream.
As the strongest weapons have already been deployed, clinicians may find themselves “brandishing the sword yet gazing in confusion,” uncertain how to proceed. This post-line vacuum is a key underlying reason why neoadjuvant innovation has triggered such profound downstream challenges.
Prognostic Value of Neoadjuvant Response and the Rigidity Paradox of the “Sandwich” Model
One core value of neoadjuvant therapy lies in its role as an in vivo drug-sensitivity test. Professor Bao reviewed the long-standing consensus since the SWOG 8710 trial: patients who respond well to neoadjuvant therapy generally have superior prognoses.
This principle has led to response-adapted strategies, such as:
- CheckMate-274, which recommends adjuvant nivolumab for patients with residual disease (ypT2 or node-positive) after neoadjuvant chemotherapy;
- IMvigor 010, which explored post-operative adjustment based on ctDNA status.
However, Professor Bao raised concerns about the rigid “sandwich” designs used in current high-profile trials such as EV-303, EV-304, and VOLGA, in which identical regimens are mandated both before and after surgery for fixed durations. While commercially efficient, these designs may abandon one of neoadjuvant therapy’s greatest advantages—using treatment response to guide subsequent decisions.
He posed a series of critical questions:
- If neoadjuvant therapy achieves an excellent response (e.g., pCR), is it necessary to rigidly complete all planned post-operative ADC cycles?
- Can treatment be de-escalated, radiotherapy avoided, or bladder preservation considered?
- Conversely, if response is poor, should the same regimen be continued unchanged?
- Does the current “one-size-fits-all” model truly serve individual patients, or does it constrain clinical judgment?
Deep Dive into NIAGARA and EV-303:
Heterogeneity of pCR and the True Value of Adjuvant Therapy**
Professor Bao provided a technical dissection of the NIAGARA trial (neoadjuvant chemo-immunotherapy plus adjuvant immunotherapy). Although data suggest that even patients achieving pCR benefit from continued post-operative immunotherapy compared with neoadjuvant chemotherapy alone, Professor Bao highlighted a key logical limitation.
Because immunotherapy was administered pre-operatively in the experimental arm, and immune checkpoint inhibitors have a prolonged tail effect, it is difficult to isolate the independent contribution of adjuvant immunotherapy. Drawing on lung cancer data and pharmacokinetic evidence, PD-1/PD-L1 receptor occupancy may persist for months or even a year after treatment cessation.
Thus, NIAGARA does not purely prove the value of adjuvant immunotherapy; rather, it demonstrates the advantage of an integrated perioperative immunotherapy strategy, or the biological distinction between immunotherapy-induced pCR and chemotherapy-induced pCR.
Further, EV-303 data underscore that not all pCRs are equal. Local pCR achieved by transurethral resection of bladder tumor (TURBT) alone is associated with inferior prognosis compared with systemic therapy–induced pCR (EV + pembrolizumab). This indicates that the ultimate goal of neoadjuvant therapy is not merely local pathological response, but eradication of micrometastatic disease. Simply stacking local treatments to inflate pCR rates may not translate into long-term survival benefit.
ctDNA-Guided Precision Therapy:
An Attractive Ideal, a Harsh Reality?**
Circulating tumor DNA (ctDNA) has been widely heralded as a future guide for precision therapy. However, Professor Bao urged caution based on NIAGARA data.
After neoadjuvant therapy, most patients convert to ctDNA-negative status. In NIAGARA, only three patients achieved pCR while remaining ctDNA-positive, and only fourteen patients were ctDNA-positive without pCR.
This severely narrows the actionable window for ctDNA-guided escalation or de-escalation strategies. Designing trials that subdivide patients into six to eight subgroups based on pCR and ctDNA status would be extraordinarily challenging. Whether ctDNA can truly function as a navigational “compass” for post-neoadjuvant management therefore remains an open question.
Conclusion: Escaping the “Mountain Maze” and Pursuing True Individualization
Professor Bao’s presentation was not merely a data review, but a profound interrogation of contemporary clinical thinking. He cautioned against becoming confined by rigid, commercially driven trial designs in the era of rapidly advancing immunotherapy and ADCs.
Given the marked heterogeneity of patients with T3/T4 disease or nodal involvement, more refined stratification is essential. Treating these populations as homogeneous risks obscuring meaningful biological differences.
Although the road ahead may feel like being “surrounded by mountains,” each obstacle also drives medical progress. The future lies in dismantling inflexible “sandwich” paradigms and developing dynamic, biology-guided treatment strategies that balance efficacy with toxicity reduction, ultimately maximizing patient benefit.
As Professor Bao concluded, these reflections may be informal in tone, but they represent the indispensable intellectual pathway toward truly precision-driven oncology care.
Professor Yige Bao
