A single intravesical dose of the antracycline pirarubicin administered within 24 hours after radical nephroureterectomy significantly improved relapse-free survival in patients with upper tract urothelial carcinoma. The benefit was driven mainly by fewer new bladder tumors after surgery, while overall survival was unchanged. The phase III JCOG1403 trial was reported by Ito et al in The Lancet Oncology.
New bladder tumors are common after radical nephroureterectomy, occurring in an estimated 20% to 50% of patients with upper tract urothelial carcinoma.
Study Details
The multicenter, open-label, randomized trial was conducted at 44 institutions in Japan and used a two-stage registration process. Eligible patients were aged 20 to 80 years and had previously untreated clinical stage 0a to III upper tract urothelial carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with a history of bladder cancer were excluded. The phase III trial followed an earlier phase II study in which a single postoperative intravesical dose of pirarubicin reduced the risk of recurrence after radical nephroureterectomy.
A total of 352 patients were enrolled before radical nephroureterectomy. After surgery, 304 patients who remained eligible proceeded to the second registration and were randomly assigned to pirarubicin or observation. Patients in the pirarubicin group received a single 30-mg intravesical dose within 24 hours after surgery and retained it in the bladder for 30 minutes. Patients with high-risk pathologic features, including pT3-T4 or node-positive disease, could also receive adjuvant chemotherapy.
The primary endpoint was relapse-free survival, which included bladder recurrence, local recurrence, distant metastasis, or death from any cause. Secondary endpoints included overall survival, intravesical relapse-free survival, non-intravesical relapse-free survival, and safety.
Of the 304 randomly assigned patients, 153 were assigned to pirarubicin and 151 to observation. The median age was 70 years, 74% of patients were male, and the median follow-up was 4.3 years.
Key Findings
At 3 years, relapse-free survival was 60% with pirarubicin vs 47% with observation (hazard ratio [HR] = 0.67, P = .0066). A total of 66 relapse events or deaths occurred in the pirarubicin group compared with 87 in the observation group.
The relapse-free survival benefit appeared to be driven largely by fewer bladder recurrences. There were 40 intravesical recurrences in the pirarubicin group and 55 in the observation group. At 3 years, the cumulative incidence of bladder recurrence was 25% with pirarubicin and 34% with observation, an absolute reduction of 8.9 percentage points. The investigators estimated that 12 patients would need to receive pirarubicin to prevent one bladder recurrence.
Non-intravesical relapse-free survival did not differ between groups, suggesting that the benefit was confined mainly to reducing bladder recurrence. Overall survival was also similar. At 3 years, overall survival was 89.3% with pirarubicin and 88.4% with observation (HR = 0.82, P = .48).
Adverse events were generally manageable. Grade 3 hematuria occurred in 3% of patients receiving pirarubicin and in none of those assigned to observation. No treatment-related serious adverse events or deaths were reported.
The investigators concluded that the benefit appeared to be limited to preventing recurrence in the bladder. “Our findings will further strengthen guideline recommendations for preventing intravesical recurrence after radical nephroureterectomy,” they wrote.
Akihiro Ito, MD, of the Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Japan, is the corresponding author of the article in The Lancet Oncology.
DISCLOSURE: The study was funded by the Japan Agency for Medical Research and Development and the National Cancer Centre Research and Development Fund, Japan. For full disclosures of the study authors, visit thelancet.com.
