Circulating tumour cells to drive the use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer

Nick Beije ,J Alfred Witjes,E Te Slaa,J Van Der Hoeven,H Bickerstaffe,Diederik M Somford ,Antoine G Van Der Heijden ,Harm H.e Van Melick ,John W.m Martens ,Stefan Sleijfer ,L Fossion ,Ronald De Wit ,Jaco Kraan ,Sjoerd Klaver ,Rebecca Jacobs ,Peter De Vries ,Ingeborg E De Kruijff ,Carl Wijburg ,Egbert R Boevé ,Joep J De Jong ,Joost L Boormans

doi:10.1016/j.esmoop.2022.100416

Abstract

BackgroundGuidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of nonmetastatic muscle-invasive bladder cancer (MIBC). NAC is, however, underutilized in practice because of its associated limited overall survival (OS) benefit and significant treatment-related toxicity. We hypothesized that the absence of circulating tumour cells (CTCs) identifies MIBC patients with such a favourable prognosis that NAC may be withheld.Patients and methodsThe CirGuidance study was an open-label, multicentre trial that included patients with clinical stage T2-T4aN0-N1M0 MIBC, scheduled for radical cystectomy. CTC-negative patients (no CTCs detectable using the CELLSEARCH system) underwent radical surgery without NAC; CTC-positive patients (≥1 detectable CTCs) were advised to receive NAC, followed by radical surgery. The primary endpoint was the 2-year OS in the CTC-negative group with a prespecified criterion for trial success of ≥75% (95% confidence interval (CI) ±5%).ResultsA total of 273 patients were enrolled. Median age was 69 years; median follow-up was 36 months. The primary endpoint of 2-year OS in the CTC-negative group was 69.5% (N = 203; 95% CI 62.6%-75.5%). Two-year OS was 58.2% in the CTC-positive group (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).ConclusionThe absence of CTCs in MIBC patients was associated with improved cancer-related mortality and a lower risk of disease relapse after cystectomy; however, their absence alone does not justify to withhold NAC. Exploratory analyses suggested that CTC-positive MIBC patients might derive more benefit from NAC.Trial registrationNetherlands Trial Register NL3954; https://www.trialregister.nl/trial/3954

Highlights

Radical cystectomy with pelvic lymph node dissection and urinary diversion is the mainstay of treatment for patients with nonmetastatic muscle-invasive bladder cancer (MIBC)
The circulating tumour cells (CTCs)-negative group comprised 203 patients (74.4%) and these patients were per protocol required to undergo immediate radical cystectomy without neoadjuvant chemotherapy (NAC)
The CTC-positive group comprised 70 patients (25.6%) with a median of 1 CTC/7.5 ml; it was advised to treat these patients with NAC followed by radical cystectomy

Summary

Introduction

Radical cystectomy with pelvic lymph node dissection and urinary diversion is the mainstay of treatment for patients with nonmetastatic muscle-invasive bladder cancer (MIBC). Despite this extensive surgery, MIBC patients have a poor 5year overall survival (OS) of 57.9%.1. CTC-positive patients had a higher rate of cancer-related mortality [hazard ratio (HR) 1.61, 95% CI 1.05-2.45, P 1⁄4 0.03] and disease relapse (HR 1.87, 95% CI 1.28-2.73, P 1⁄4 0.001) than CTC-negative patients. Conclusion: The absence of CTCs in MIBC patients was associated with improved cancer-related mortality and a lower risk of disease relapse after cystectomy; their absence alone does not justify to withhold NAC. Trial registration: Netherlands Trial Register NL3954; https://www.trialregister.nl/trial/3954

Objectives

Results

Conclusion