Single, early intravesical instillation of pirarubicin in the prevention of bladder recurrence after radical nephroureterectomy for upper tract urothelial carcinoma (JCOG1403): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND

A previous phase 2 trial of single, postoperative intravesical instillation of pirarubicin after radical nephroureterectomy for upper tract urothelial carcinoma showed promising results in reducing the risk of bladder recurrence. We aimed to further evaluate the efficacy and adverse events of pirarubicin in this setting compared with the standard-of-care treatment of no intravesical instillation.

METHODS

We did a multicentre, open-label, randomised, phase 3 trial (JCOG1403) with a two-stage registration at 44 institutes in the Urologic Oncology Study Group of the Japan Clinical Oncology Group. Eligible patients aged 20-80 years with previously untreated, clinical stage 0a-III upper tract urothelial carcinoma, and Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled in the first registration before radical nephroureterectomy. After surgery, patients underwent a second registration and were randomly assigned (1:1) to either pirarubicin (30 mg in 30 mL via intravesical instillation, received within 24 h after surgery) or observation using a central web-based minimisation method, stratified by institution, clinical T stage, and urine cytology results. Patients with pT3/T4 or pN+ status received adjuvant chemotherapy. The primary endpoint was relapse-free survival, analysed in the intention-to-treat population (all patients included in the second registration). Patients without an event were censored at the last date they were known to be alive and relapse-free; no imputation was performed. Adverse events were systematically assessed in the safety analysis population. The trial is registered with the Japan Registry of Clinical Trials, jRCTs031180121, and is complete.

FINDINGS: Between Oct 3, 2016, and June 12, 2020, 352 participants were enrolled at the first registration. Of 348 patients who had a radical nephroureterectomy, 153 were randomly assigned to the pirarubicin group and 151 to the observation group at second registration. 226 (74%) patients were male and 78 (26%) were female. Median follow-up was 4·3 years (IQR 3·4-5·1). 3-year relapse-free survival was 60·0% (95% CI 51·7-67·3) in the pirarubicin group and 47·0% (38·7-54·9) in the observation group (hazard ratio 0·67 [90·96% CI 0·50-0·88]; p=0·0066). The most common grade 3-4 adverse event was haematuria, which occurred in four (3%) patients in the pirarubicin group and none in the observation group. No treatment-related serious adverse events or deaths were observed.

INTERPRETATION: A single, postoperative pirarubicin instillation after radical nephroureterectomy is an efficacious treatment with manageable adverse events to reduce recurrence in patients with upper tract urothelial carcinoma.

FUNDING: Japan Agency for Medical Research and Development and National Cancer Centre Research and Development Fund, Japan.