Phase III JCOG1403 Trial: Single-Dose Intravesical Pirarubicin Cuts Bladder Recurrence After Nephroureterectomy
Key Insights
A single intravesical instillation of pirarubicin within 24 hours of radical nephroureterectomy improved 3-year relapse-free survival to 60% versus 47% with observation (HR 0.67, p=0.0066).
The benefit was driven by a reduction in bladder recurrence, with a 3-year cumulative incidence of 25% for pirarubicin versus 34% for observation, yielding an absolute risk reduction of 8.9% and NNT of 12.
No significant improvement was observed in overall survival (89.3% vs 88.4%, HR 0.82, p=0.48), indicating the intervention provides bladder-specific disease control rather than a systemic survival effect.
A single intravesical instillation of pirarubicin administered within 24 hours after radical nephroureterectomy significantly improves relapse-free survival in patients with upper tract urothelial carcinoma (search) (UTUC), according to results from the multicenter, open-label, randomized phase III JCOG1403 trial published in The Lancet Oncology.
The trial, conducted across 44 institutions in Japan under the Urologic Oncology Study Group of the Japan Clinical Oncology Group, enrolled 304 patients with previously untreated clinical stage 0a–III UTUC and no history of bladder cancer (search). Participants were randomly assigned in a 1:1 ratio to receive either a single intravesical dose of pirarubicin (30 mg in 30 mL, retained for 30 minutes) within 24 hours of surgery or observation alone.
Relapse-Free Survival: A 13-Point Absolute Improvement
After a median follow-up of 4.3 years, the 3-year relapse-free survival rate reached 60.0% in the pirarubicin group compared with 47.0% in the observation group, corresponding to a hazard ratio of 0.67 (multiplicity-adjusted 90.96% CI, 0.50–0.88; one-sided p=0.0066). Post hoc sensitivity analyses reinforced the primary result, with hazard ratios of 0.63 in the modified intention-to-treat population and 0.62 in the per-protocol population.
The benefit was driven predominantly by a reduction in bladder recurrence. At 3 years, the cumulative incidence of intravesical recurrence was 25% with pirarubicin versus 34% with observation. A post hoc analysis estimated an absolute risk reduction of 8.9 percentage points (95% CI, –1.4 to 19.3), with a number needed to treat of 12 to prevent one bladder recurrence. Intravesical relapse-free survival favored pirarubicin with a hazard ratio of 0.67 (95% CI, 0.44–1.00; two-sided p=0.048 from Gray's test).
By contrast, non-intravesical relapse-free survival did not differ significantly between groups. Local or distant recurrence occurred in 23 patients receiving pirarubicin and 27 patients under observation (HR 0.82; two-sided p=0.46).
Overall Survival Unchanged
A total of 52 deaths occurred during follow-up—24 in the pirarubicin group and 28 in the observation group. The 3-year overall survival rates were 89.3% and 88.4%, respectively (HR 0.82; 95% CI, 0.48–1.42; two-sided p=0.48). The absence of a survival difference underscores that the intervention provides bladder-specific disease control rather than a systemic anticancer effect.
Safety Profile
The overall incidence of early postoperative adverse events was 24% in the pirarubicin group and 31% in the observation group. Grade 3 haematuria occurred in four patients (3%) receiving pirarubicin and in none under observation. No grade 4 early postoperative adverse events, treatment-related serious adverse events, or treatment-related deaths were reported. The investigators noted that early instillation could potentially affect the bladder wall following bladder cuff resection and contribute to severe haematuria in a small proportion of patients, though the safety profile was considered clinically manageable.
Clinical Context and Limitations
Bladder recurrence remains a common challenge after radical nephroureterectomy, occurring in approximately 20%–50% of patients. While postoperative intravesical chemotherapy is recommended in current guidelines, uptake was limited when JCOG1403 was designed, and uncertainty persisted regarding the optimal agent and timing.
The investigators emphasized that no head-to-head randomized trial has established the superiority of pirarubicin over other intravesical chemotherapy agents. Prior studies, including the ODMIT-C trial evaluating mitomycin C after the seventh postoperative day and an earlier Japanese phase II trial of pirarubicin within 48 hours, differed in both agent selection and timing. JCOG1403 now provides phase III evidence specifically supporting pirarubicin within the first 24 hours.
Several limitations warrant consideration. The trial included only Japanese patients, which may limit generalizability across different racial or ethnic populations. Preoperative ureteroscopy was performed in only 37% of participants, and eight randomized patients were subsequently found not to have urothelial carcinoma on pathological examination. The primary analysis was conducted after 153 events rather than the 166 events anticipated in the original sample-size calculation, though the timing was prospectively defined and the treatment effect remained significant across sensitivity analyses. Subgroup findings should be interpreted cautiously given their exploratory nature.
Rishabh Jain, Medical Oncologist at AIIMS, commented on the findings: "The challenge is no longer the evidence. It is ensuring the dose is actually delivered. Practice changing? I would say practice reinforcing, with strong phase III confirmation."
The study was funded by the Japan Agency for Medical Research and Development and the National Cancer Centre Research and Development Fund, Japan. The trial is registered as jRCTs031180121 and is complete.