Neoadjuvant and adjuvant treatments in muscle-invasive bladder cancer: Where are we?

Objectives: Fifty percent of muscle-invasive bladder cancer (MIBC) patients succumb from metastatic disease despite radical cystectomy (RC). Neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (ACT) randomized clinical trials (RCT) investigated whether peri-operative chemotherapy improves survival. More recently, immune checkpoint inhibitors (ICI) are explored as peri-operative single agent, ICI-ICI or ICI-chemotherapy combinations. Our goal is to provide the status of neoadjuvant and adjuvant treatment in MIBC.

Methods: The literature on NAC and ACT trials in MIBC was reviewed.

Results: Since the 1980s, NAC RCTs were performed in cisplatin-fit patients, mainly using cisplatin combination chemotherapy. Meta-analyses indicated a small, but significant 5% improvement in overall survival in T2-T4N0M0 MIBC patients. Mostly MVAC or gemcitabine-cisplatin (GC) regimens were used without clear benefit of one regimen over the other. NAC value in N+MIBC is not established and predictive value of associated~25-40% complete downstaging (pathologically confirmed complete regression, pCR) not unequivocally demonstrated. Adjuvant cisplatin-based chemotherapy RCTs were smaller, some prematurely stopped for poor accrual, and underpowered to demonstrate clear statistical evidence for a 5% overall survival advantage in pT3-T4N1-3M0 MIBC. Novel neoadjuvant immune checkpoint inhibitors, alone or with chemotherapy, phase 2 trials demonstrate down staging and encouraging clinical results.

Conclusions: Neoadjuvant MVAC or GC in cT2-T4N0 MIBC patients fit for cisplatin is still recommended based on OS benefit shown in meta-analyses, butreal-world adherence to NAC is low as ~40-50% ofpatients are unfit for cisplatin. The value of neoadjuvant treatment in node-positive MIBC is not clearly demonstrated requiring more accurate clinical staging and prospective studies. Adjuvant cisplatin-based chemotherapy may be considered in selected, chemo-naïve pT3-T4N+patients. Results from prospective checkpoint inhibitor immunotherapy RCTs are needed before immunotherapy becomes a recommended alternative for peri-operative treatment. Molecular tumour subtyping will support selecting novel agents for neoadjuvant or adjuvant strategies.