Bladder recurrence remains a common clinical challenge following radical nephroureterectomy for upper tract urothelial carcinoma, occurring in approximately 20%–50% of patients. Although postoperative intravesical chemotherapy is recommended in current clinical guidelines, its uptake was limited when JCOG1403 was designed, and uncertainty remained regarding the optimal agent and timing.
Results from the phase 3 JCOG1403 trial showed that a single intravesical instillation of pirarubicin administered within 24 hours after radical nephroureterectomy significantly improved relapse-free survival compared with observation. The benefit appeared to be driven primarily by a reduction in bladder recurrence, without a corresponding improvement in overall survival.
The article, titled “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,” was published online in The Lancet Oncology on July 10, 2026.
Authors: Akihiro Ito, Yoichi Arai, Yoshiyuki Kakehi, Masayuki Yokoyama, Keita Sasaki, Motohide Uemura, Atsushi Takahashi, Kazuo Nishimura, Takashi Kawahara, Hitoshi Masuda, Koji Yoshimura, Takashi Kobayashi, Masatoshi Eto, Tsukasa Igawa, Naotaka Nishiyama, Takanori Mochizuki, Akira Yokomizo, Makito Miyake, Tomohiko Ichikawa, Katsuyoshi Hashine, Takuma Sato, Mikio Sugimoto, Hiroyuki Nishiyama, and Hiroshi Kitamura, on behalf of the Urologic Oncology Study Group of the Japan Clinical Oncology Group.
Study Design and Treatment
JCOG1403 was a multicenter, open-label, randomized phase 3 trial conducted across 44 institutions participating in the Urologic Oncology Study Group of the Japan Clinical Oncology Group.
The trial used a two-stage registration process. Eligible patients were aged 20–80 years and had previously untreated, clinical stage 0a–III upper tract urothelial carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no history or current cystoscopic evidence of bladder cancer.
Patients were initially registered before undergoing radical nephroureterectomy. Those who remained eligible following surgery were entered into the second registration and randomly assigned in a 1:1 ratio to receive:
- A single intravesical instillation of pirarubicin, administered at a dose of 30 mg in 30 mL within 24 hours after surgery and retained in the bladder for 30 minutes; or
- Observation without intravesical instillation.
Randomization was stratified according to the participating institution, clinical T stage, and urine cytology results.
Pirarubicin was not administered when patients had macroscopic haematuria requiring bladder irrigation or findings suggesting urinary leakage. Patients with pathologically confirmed pT3–T4 or node-positive disease were eligible to receive postoperative adjuvant chemotherapy with gemcitabine and cisplatin.
The primary endpoint was relapse-free survival, defined as the time from randomization to intravesical recurrence, local recurrence, distant metastasis, or death from any cause. Secondary endpoints included overall survival, intravesical relapse-free survival, non-intravesical relapse-free survival, adverse events, and serious adverse events.
The trial was registered with the Japan Registry of Clinical Trials as jRCTs031180121 and is complete.
Pirarubicin Improved Relapse-Free Survival
Between October 3, 2016, and June 12, 2020, 352 patients were enrolled at the first registration. Radical nephroureterectomy was performed in 348 patients, of whom 304 proceeded to randomization: 153 were assigned to pirarubicin and 151 to observation.
The median age was 70 years, and 74% of participants were male. Clinical stages cTa, cTis, or cT1 were present in 41% of patients, while 40% had cT2 disease and 18% had cT3 disease.
After a median follow-up of 4.3 years, relapse or death had occurred in 66 patients in the pirarubicin group and 87 patients in the observation group.
The 3-year relapse-free survival rate was:
- 60.0% with pirarubicin;
- 47.0% with observation.
This corresponded to a hazard ratio of 0.67, with a multiplicity-adjusted 90.96% confidence interval of 0.50–0.88 and a one-sided p value of 0.0066.
Post hoc sensitivity analyses supported the primary result. The hazard ratio for relapse-free survival was 0.63 in the modified intention-to-treat population and 0.62 in the per-protocol population.
Reduction in Bladder Recurrence Drove the Benefit
A total of 95 intravesical recurrences were reported during follow-up: 40 in the pirarubicin group and 55 in the observation group.
At 3 years, the cumulative incidence of bladder recurrence was:
- 25% in the pirarubicin group;
- 34% in the observation group.
In a post hoc analysis, the absolute reduction in the 3-year cumulative incidence of bladder recurrence was estimated at 8.9 percentage points, with a 95% confidence interval of –1.4 to 19.3. The corresponding number needed to treat was 12 to prevent one intravesical recurrence.
Intravesical relapse-free survival favored pirarubicin, with a hazard ratio of 0.67 and a 95% confidence interval of 0.44–1.00. The two-sided p value from Gray’s test was 0.048.
By contrast, non-intravesical relapse-free survival did not differ significantly between the treatment groups. Local or distant recurrence occurred in 23 patients receiving pirarubicin and 27 patients undergoing observation, with a hazard ratio of 0.82 and a two-sided p value of 0.46.
These findings indicate that the improvement in the trial’s primary endpoint was predominantly attributable to better control of recurrence within the bladder rather than a reduction in local recurrence or distant metastasis.
No Overall Survival Difference
A total of 52 deaths occurred: 24 in the pirarubicin group and 28 in the observation group.
At 3 years, overall survival was:
- 89.3% with pirarubicin;
- 88.4% with observation.
The hazard ratio for death was 0.82, with a 95% confidence interval of 0.48–1.42 and a two-sided p value of 0.48.
The absence of an overall survival difference suggests that the benefit of a single postoperative pirarubicin instillation is confined primarily to bladder-specific disease control rather than systemic cancer control.
Safety Findings
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 no patients undergoing observation. No grade 4 early postoperative adverse events, treatment-related serious adverse events, or treatment-related deaths were reported.
The investigators considered the adverse-event profile clinically manageable, although they 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.
Clinical Context and Limitations
Previous randomized studies had shown that postoperative intravesical chemotherapy could reduce bladder recurrence after nephroureterectomy. However, these trials differed in the chemotherapy agents used and the timing of administration.
The ODMIT-C trial evaluated mitomycin C administered after the seventh postoperative day, whereas an earlier phase 2 trial from the same Japanese research group evaluated pirarubicin within 48 hours of surgery. JCOG1403 provides phase 3 evidence supporting pirarubicin administration within the first 24 hours after radical nephroureterectomy.
The investigators emphasized that no head-to-head randomized trial has established the superiority of pirarubicin over other intravesical chemotherapy agents.
Several limitations should also be considered. The trial included only Japanese patients, which could limit the generalizability of its findings 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 also conducted after 153 events rather than the 166 events anticipated in the original sample-size calculation. Nevertheless, the timing of the analysis had been prospectively defined, and the treatment effect remained statistically significant across sensitivity analyses.
Subgroup findings should be interpreted cautiously because the analyses were exploratory, were not powered for formal interaction testing, and involved multiple unadjusted comparisons. The investigators stressed that no patient subgroup should be excluded from postoperative pirarubicin based on these analyses alone.
Conclusion
The phase 3 JCOG1403 trial showed that a single intravesical instillation of pirarubicin administered within 24 hours after radical nephroureterectomy improved relapse-free survival in patients with stage 0a–III upper tract urothelial carcinoma.
The treatment reduced the incidence of subsequent bladder recurrence and had a manageable safety profile, although grade 3 haematuria occurred in a small proportion of patients. No significant improvements were observed in non-intravesical relapse-free survival or overall survival.
These results strengthen the evidence supporting early postoperative intravesical chemotherapy as a strategy to prevent bladder recurrence following radical nephroureterectomy.
The study was funded by the Japan Agency for Medical Research and Development and the National Cancer Centre Research and Development Fund, Japan.
The full article is available in The Lancet Oncology.
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