Circulating tumor cell-driven use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer.

4523 Background: International guidelines for the treatment of non-metastatic muscle-invasive bladder cancer (MIBC) recommend neoadjuvant chemotherapy (NAC), which, however, is underutilized in practice. We hypothesized that the absence of circulating tumour cells (CTCs), an established prognostic marker in MIBC, may identify patients with such a favourable prognosis that NAC may be withheld. Methods: The CirGuidance study included adults with clinical stage T2-T4aN0-N1M0 muscle-invasive urothelial carcinoma of the bladder who were fit to undergo radical cystectomy. CTCs were enumerated using the CellSearch system. CTC-negative patients (no CTCs detectable) underwent radical surgery without NAC; CTC-positive patients (≥1 detectable CTCs) were advised to receive NAC followed by radical surgery, but NAC could be withheld at the discretion of the treating physician. The primary endpoint was the two-year overall survival (OS) in the CTC-negative group, analysed in the intention-to-treat population. The prespecified criterion for trial success was a two-year OS of minimally 75% (95% confidence interval (CI) ±5%) in the CTC-negative group. Results: Of 315 patients screened for eligibility, 273 were enrolled in the study. The median age was 69 years; the median follow-up was 36 months. The two-year OS in the CTC-negative group was 69.5% (n = 203; 95% CI 62.6%-75.5%); in the CTC-positive group it was 58.2% (n = 70; 95% CI 45.5%-68.9%). CTC-positive patients had a higher rate of cancer-related mortality (hazard ratio (HR) 1.61, 95% CI 1.05-2.45, p = 0.03) and disease relapse (HR 1.87, 95% CI 1.28-2.73, p = 0.001) than CTC-negative patients. Explorative analyses suggested that CTC-positive patients who had received NAC (n = 22) survived longer than CTC-positive patients who had not (n = 48), with a two-year OS of 74.8% (95%CI 49.5%-88.8%) versus 52.0% (95% CI 37.2%-65.0%), respectively. Conclusions: The two-year OS in the CTC-negative group did not meet the prespecified criterion for trial success. However, given the trial population’s advanced age and high rate of non-cancer related mortality, the benefit of NAC is likely to be limited in CTC-negative MIBC patients. CTC enumeration at the moment of diagnosis could aid in the decision to prescribe neoadjuvant chemotherapy for a muscle-invasive bladder cancer patient as a criterion in addition to clinical characteristics. Clinical trial information: NL3954.