In the previous episode, we reviewed the full evolution of the HOPE series from HOPE-01 through HOPE-04. Among all its design features, one detail may represent the most distinctive — and perhaps boldest — aspect of the HOPE program within the global bladder-preservation landscape: its enrollment criteria.HOPE-02 enrolled patients with cT2-4b, N0-3, M0-1a disease. This means the study included not only the traditionally recognized “ideal candidates” for bladder preservation (such as T2N0 patients), but also patients with T4b disease, N2-3 lymph node involvement, and even M1a metastatic disease.
In almost all international bladder-preservation studies, cN+ disease (lymph node-positive status) has been regarded as an unspoken contraindication. The NIAGARA trial, for example, limited enrollment to cN0-1 disease, while the RETAIN series excluded all cN+ patients entirely. HOPE-02/03 broke this long-standing taboo.
What clinical rationale supported this decision? And how did radiotherapy provide the technical foundation for such a strategy? In this episode, we explore these two central questions directly.
Expert Perspectives
Professor Zhang Peng
“We want to demonstrate that, in the modern treatment era, the indications for bladder preservation can actually be expanded.”
Professor Shen Yali
“If chemotherapy fails, and even targeted therapy combined with immunotherapy fails, then bladder preservation is unlikely to produce good outcomes for those patients either.”
Professor Zhang Ruiyun
“Expanding the boundaries without abandoning caution — that is the essence of the HOPE series enrollment philosophy.”
I. Clinical Reality: Patients in Western China Cannot Afford to Wait
Professor Zhang Peng’s explanation was direct and candid: this was not simply a “design choice,” but rather a response driven by real-world clinical challenges.
“In the HOPE-02 and HOPE-03 cohorts, only about 20% of patients had T2 disease. The remainder were predominantly T3-T4 cases, including some node-positive patients,” Professor Zhang explained. “Many patients in western China present at an advanced stage at initial diagnosis. Even with aggressive neoadjuvant therapy followed by radical surgery, the five-year survival rate for these patients remains below 50%.”
In other words, for these high-risk patients, the conventional radical cystectomy pathway alone had already failed to provide satisfactory answers. The bladder was removed, yet tumor control often remained inadequate, while patients permanently lost quality of life.
“So we started asking ourselves: if outcomes are already poor and bladder removal further compromises quality of life, could we adopt a more comprehensive treatment strategy that preserves the bladder without sacrificing efficacy?” Professor Zhang said.
II. Redefining the “Ideal Candidate” for Bladder Preservation
The traditional definition of “ideal candidates” for trimodal therapy (TMT: transurethral resection of bladder tumor + chemotherapy + radiotherapy) — namely patients with T2 disease or below, no carcinoma in situ, and no hydronephrosis — was established during the era of chemotherapy plus radiotherapy alone.
However, Professor Zhang believes these criteria now require re-evaluation.
“The current definition of ideal bladder-preservation candidates still largely reflects recommendations from the traditional TMT era,” he stated frankly. “We want to show that, in the modern era, the indications for bladder preservation can indeed be broadened.”
The core philosophy of the HOPE series is not merely to identify patients who are naturally suitable for bladder preservation, but rather to use intensive systemic therapy to convert “non-ideal candidates” into potential bladder-preservation candidates, followed by consolidative and definitive radiotherapy.
This represents a paradigm-level shift:
from “selecting suitable patients” to “creating the conditions necessary for bladder preservation.”
III. “No Progressive Disease (PD)” — A Critical Selection Threshold
Expanding enrollment criteria did not mean abandoning all boundaries. HOPE-02/03 established one crucial selection threshold: only patients who did not develop progressive disease (PD) after neoadjuvant therapy were eligible to proceed to sequential radiotherapy and bladder-preservation treatment.
(Progressive disease was defined as a ≥20% increase in target lesion size or the appearance of new lesions.)
Professor Shen Yali explained the rationale behind this design in detail.
“Why did we establish ‘no PD’ as a prerequisite? If chemotherapy is ineffective, and if targeted therapy combined with immunotherapy also fails, then the overall prognosis for these patients remains poor,” she explained. “We believe such patients are unlikely to benefit from bladder preservation either, so they were excluded.”
She further emphasized that even among patients with N2, N3, or M1a disease, enrollment remained selective rather than indiscriminate.
“We were still selective. Although metastases may have reached those sites, we excluded patients with bulky disease. If a patient had extensive chains of lymph node metastases across N1, N2, N3, or even M1 regions, and still demonstrated large residual nodal disease after neoadjuvant induction therapy, then the overall prognosis was unlikely to be favorable. In such situations, the value of bladder preservation would be greatly diminished by systemic progression.”
Expanding the boundaries while maintaining caution — this is the core philosophy underlying the HOPE enrollment strategy.
IV. Radiotherapy: The Technical Backbone Supporting Expanded Enrollment
Why did HOPE-02/03 dare to include cN+ patients? Beyond the efficacy of systemic therapy, radiotherapy provided another critical pillar of support.
Professor Shen described the radiotherapy target design and dose strategy in detail.
“In both HOPE-02 and HOPE-03, the complete clinical response (cCR) rates after neoadjuvant treatment reached 51% and 64%, respectively. This meant that radiotherapy target volumes became relatively consistent, allowing us to plan treatment according to cCR-based principles,” she explained. “For lymph node regions, we delivered a prophylactic dose of approximately 50 Gy, while the whole bladder generally received 56–60 Gy.”
For patients with residual positive lymph nodes, radiotherapy techniques allowed for even further dose escalation.
“If residual lymph node disease remained, our radiotherapy approach was fully capable of covering those areas and safely escalating visible nodal lesions to doses exceeding 60 Gy,” she emphasized. “For residual local lesions or suspicious residual disease, we delivered doses consistent with traditional TMT standards — typically above 64 Gy. In some cases, we escalated to 65 or 66 Gy. So far, both the safety and efficacy of this approach have been well validated in our studies.”
It is precisely because radiotherapy provides such strong local control that the HOPE series had the confidence to include cN+ patients — a population traditionally regarded as outside the acceptable boundaries for bladder preservation.
Systemic therapy first achieves downstaging, followed by radiotherapy to eradicate residual disease — together forming a complete and mutually reinforcing therapeutic strategy.
Key Takeaways
- The primary driving force behind the expanded enrollment criteria in the HOPE series was clinical reality: many patients in western China present with advanced-stage disease, and traditional surgical approaches alone provide limited benefit.
- The field is shifting from “selecting ideal candidates” toward “creating the conditions necessary for bladder preservation.”
- “No progressive disease (PD)” following neoadjuvant therapy served as the critical gateway into the bladder-preservation pathway, ensuring that ineffective treatment was not pursued in non-responders.
- Even among high-risk patients, enrollment remained selective; patients with bulky residual nodal disease were excluded.
- Radiotherapy provided indispensable technical support for expanded enrollment through prophylactic nodal irradiation and definitive dose escalation to residual disease, achieving both safety and efficacy.
