Clinical trial NCT05776758: Role of NAC in cT0 Muscle-invasive Bladder Cancer After Maximal TURBt
Official title: Neoadjuvant Chemotherapy Plus Cystectomy vs Cystectomy Alone for cT0 Muscle-invasive Bladder Cancer After Maximal TURBt: Multicentre Prospective Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Muscle-Invasive Bladder Carcinoma
Chemotherapy Effect
Surgery
Keywords: Bladder cancer
Muscle-invasive bladder cancer
Radical cystectomy
Survival outcomes
Lead sponsor: Regina Elena Cancer Institute
Sponsor class: OTHER
First posted: 2023-03-20
Enrollment: 236
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This prospective randomized controlled trial (RCT) is designed to provide high level evidence describing the non-inferiority of radical cystectomy (RC) alone versus neoadjuvant chemotherapy (NAC) plus RC on survival outcomes of patients with a diagnostic transurethral resection of bladder tumor (TURBt) of non-metastatic muscle invasive bladder cancer (MIBC) (T2-T4 N0 M0) and non-radiologic or endoscopic residual tumor after a maximal TURBt (cT0). Our hypothesis is that performing NAC in the absence of residual disease, after a maximal TURBt, has no survival benefit over performing an early cystectomy. Since no downstaging could be achieved in patients with no residual tumor into the bladder, the benefits of neoadjuvant chemotherapy in this setting could be not significant and it might turn into unnecessary toxicity and a substantial delay to surgical treatment.

Detailed description: Radical Cystectomy (RC) is considered the reference option for treatment of urothelial muscle invasive bladder cancer (MIBC). However, RC alone has been reported 5-year survival in about 50% of patients. Therefore, to improve survival outcomes in patients with non-metastatic MIBC, cisplatin-based neoadjuvant chemotherapy (NAC) has been introduced. On the one hand, major tolerability, higher patient compliance and lower burden of micrometastatic disease are listed as potential advantages of administering NAC before planned definitive surgery. Several phase III randomized controlled trials (RCTs) reported the potential survival benefit of NAC administration.

Moreover, the updated analysis of a large phase III RCT, globally including all patients with muscle invasive bladder cancer from T2 to T4, regardless of post transurethral resection of bladder tumor (TURBt) tumor volume, with a median follow-up of 8-yrs confirmed previous results providing additional findings:

* 16% reduction in mortality risk;
* improvement in 10-yr survival from 30% to 36% with NAC;
* Benefit with regard to distant metastases;
* the addition of NAC provided no benefit for locoregional control and locoregional disease free survival (DFS).

On the other hand, the possibility to predict patients' sensitivity to chemotherapy is still limited. Therefore, the delay in performing RC and the theoretical impact of NAC on surgical morbidity are considered significant limitations to a routine administration of neoadjuvant treatments. As a result, it is growing the interest at improving selection clinical criteria to identify the ideal candidates to NAC, in order to obtain the maximal survival benefit of NAC, minimizing its possible disadvantages. Reliable predictive markers and molecular tumour profiling might guide the use of NAC in the future, but nowadays they are not currently used in clinical practice.

Despite the evidence supporting the use of NAC, its routine administration is still limited. The risk of unresponse after NAC, with the consequent delay in surgical treatment, and the possible impact on surgical morbidity after RC, are the major limitations to the wide administration of NAC. Previous evidences supported the use of NAC in patients with T2 to T4a BCa, regardless of tumor volume at the time of NAC. It is growing the interest on a tailored approach to treat genitourinary cancer, therefore it is needed much more efforts to select which patient will benefit most from NAC rather than an early RC. To answer this question, it is needed to selectively perform RCTs aiming to test specific treatments in equally specific patients. The primary objective of the trial is to demonstrate the non-inferiority of RC alone versus NAC plus RC on survival outcomes of patients with a diagnostic TURBt of non-metastatic muscle invasive bladder cancer (MIBC) (T2-T4 N0 M0) and non-radiologic or endoscopic residual tumor after a maximal TURBt (cT0). Survival benefits of cisplatin-based NAC were already described. The SWOG trial 3 reported a 33% reduction of estimated risk of death in the NAC plus cystectomy group compared to RC alone.

Specifically, Authors reported that survival benefit of NAC appeared to be strongly related to downstaging of the tumor to pT0: 38% and 15% in NAC plus RC and RC alone cohorts, respectively (p\<0.001). At 5yr, 85% of the patients with a pT0 surgical specimen were alive. Analysis of survival according to treatment group (NAC plus cystectomy vs cystectomy alone) and pathologically free of cancer (pT0) or residual disease at the time of cystectomy evidenced comparable outcomes between groups in pT0 patients (2yr OS: 90% vs 94% in NAC plus RC and RC alone cohorts, respectively) while a slight difference occurred in patients with residual disease at the time of cystectomy (2yr OS: 66% vs 52% in NAC plus RC and RC alone cohorts, respectively). As a result, the impact of NAC seems to play a negligible role in pT0 patients, while major benefits were observed in presence of residual disease. However, all the available RCTs did not discuss the endoscopically feasibility to achieve a cT0 stage, after a maximal TURBt, prior to RC. Moreover, systematic therapies are not devoid of limitations and they need to be carefully administered, in order to reduce toxicity, to minimize the risk of cystectomy delay in patients not sensitive to chemotherapy and to reduce the impact of NAC on surgical and health related quality of life (HRQoL) outcomes. Therefore, it is necessary to improve the selection criteria of patients' candidates for NAC plus cystectomy.

The hypothesis of investigators is that performing NAC in the absence of residual disease, after a maximal TURBt, has no survival benefit over performing an early cystectomy. Whenever endoscopically feasible, the complete resection of MIBC during TURB, particularly for T2 bladder cancer, will define a condition of cT0 stage, where probably no benefits would be observed in terms of downstaging for patients receiving NAC plus RC than those undergoing an early RC alone.

Eligibility criteria: Inclusion Criteria:

* diagnostic TURBt with cT2-4, cN0, cM0;
* non-radiologic or endoscopic residual tumor after a maximal TURBt (cT0);
* patients eligible to curative intent, candidate to surgical treatment and/or NAC (all patients must meet all the criteria required to be able to undergo RC and/or NAC);
* ≥ 18 yrs old;
* compliants patients able to follow the study protocol and fill in EORTC quality of life questionnaires;
* patients able to provide a written informed consent for the trial

Exclusion criteria:

* anaesthesiologic contraindications to surgery;
* palliative intent;
* patients ineligible for cisplatin-combination chemotherapy

Primary outcomes:
measure: To demonstrate the non-inferiority of radical cystectomy (RC) alone versus neoadjuvant chemotherapy plus RC on 2 years Overall Survival (OS) rates, defined as the length of time from surgery until death from any cause.
timeFrame: 2 years
Secondary outcomes:
measure: To compare disease free survival (DFS) rates, defined as the length of time from surgery to local disease recurrence
timeFrame: 6 months, 1 year, 2 years
measure: To evaluate metastasis free survival (MFS) rates, defined as the length of time from surgery to metastasis recurrence.
timeFrame: 6 months, 1 year, 2 years
measure: To evaluate recurrence free survival (RFS), rates defined as the length of time from surgery to disease recurrence.
timeFrame: 6 months, 1 year, 2 years
measure: To evaluate impact of NAC on perioperative complications rate (described accordingly to Clavien Dindo classification into minor o major complications)
timeFrame: Within hospital stay
measure: To evaluate impact of NAC on postoperative complications rate described accordingly to Clavien Dindo classification into minor o major complications)
timeFrame: 30 days, 90 days and 180 days
measure: To evaluate impact of NAC on readmission rates (defined as postoperative rehospitalization)
timeFrame: 30 days, 90 days and 180 days
measure: To compare health-related quality of life (HRQoL) outcomes, using EORTC self-assessed questionnaires
timeFrame: 3 months, 6 months, 1 year and 2 years
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Riccardo Mastroianni
Study officials:
affiliation: IRCCS "Regina Elena" National Cancer Institute
name: Giuseppe Simone, MD
role: PRINCIPAL_INVESTIGATOR
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