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.