A Single Dose of Intravesical Chemotherapy After Nephroureterectomy: The JCOG1403 Phase 3 Trial

KEY FINDINGS

• Trial: A multicentre, open-label, randomized phase 3 trial conducted at 44 centres in Japan (JCOG1403 / UTUC THP Phase III); the results were published in The Lancet Oncology.
• Relapse-free survival: 3-year relapse-free survival was 60.0% versus 47.0% (HR 0.67; p=0.0066).
• Bladder recurrence: The 3-year cumulative incidence of bladder recurrence was 25% versus 34% (an absolute difference of 8.9 points).
• NNT: The number of patients needing treatment to prevent one bladder recurrence was 12.
• Overall survival: No difference (3-year 89.3% versus 88.4%; HR 0.82; p=0.48).
• Number of patients: 304 randomized patients, median follow-up 4.3 years.

Background: Why Is Bladder Recurrence After Nephroureterectomy So Common?

Upper tract urothelial carcinoma (UTUC) is a relatively rare but potentially aggressive disease arising from the urothelial surface of the renal collecting system and ureter. In high-risk cases, the standard treatment is radical nephroureterectomy, in which the kidney, the entire ureter and a bladder cuff are removed together.

Even when surgery is completed successfully, the most frequent problem encountered in follow-up is the development of a new tumour in the bladder. Rates of 20% to 50% are reported in the literature. The underlying mechanisms can be summarised under two headings:

• Field effect: Shared carcinogenic exposure along the urothelium leads to premalignant changes not only in the upper tract but throughout the urinary tract.
• Intraluminal tumour cell implantation: Tumour cells shed from the upper tract are carried downwards by the urinary stream and can attach to the bladder mucosa, particularly to surfaces damaged during surgery.

The second mechanism provides the rationale for a single dose of intravesical chemotherapy given in the early postoperative period: shed cells are brought into contact with a cytotoxic agent before they can settle in the bladder. This approach has been used for many years after TURBT in non-muscle-invasive bladder cancer; in UTUC, however, the level of evidence had until now remained more limited.

What is pirarubicin (THP)? Pirarubicin, an anthracycline derivative, is the tetrahydropyranyl analogue of doxorubicin. Because of its rapid entry into cells and low systemic absorption on intravesical administration, it is widely used for intravesical chemotherapy, particularly in Japan.

Study Design

The trial used a two-stage registration method. 352 patients were registered before surgery; the 304 patients who remained eligible after radical nephroureterectomy were entered into the second registration and randomized.

The primary endpoint was relapse-free survival; bladder recurrence, local recurrence, distant metastasis or death from any cause were counted as events. Secondary endpoints were overall survival, intravesical relapse-free survival, non-intravesical relapse-free survival and safety.

Key Results

HR: hazard ratio; NNT: number needed to treat. No significant difference between the groups was found in non-intravesical relapse-free survival.

The most critical point in interpreting the results is where the benefit comes from. The 13-point improvement in relapse-free survival is explained by the reduction in bladder recurrences; no difference was found between the arms in extravesical recurrence (local recurrence, distant metastasis), and overall survival was unchanged.

Safety Profile

The safety profile was favourable. The most frequent grade 3 adverse event was haematuria, seen in 4 patients (3%) in the pirarubicin arm; none were reported in the observation arm. No treatment-related serious adverse events or treatment-related deaths were reported.

Because of the risk of extravasation, administration should not be performed without confirming the integrity of the bladder cuff closure; this is the common safety principle for all early intravesical chemotherapy administration.

Implications for Clinical Practice

1. A low-cost, single-dose, easy-to-administer intervention

Most of the innovations setting the agenda in modern uro-oncology - radioligand therapies, immunotherapy combinations, antibody-drug conjugates - are high-cost approaches requiring infrastructure. JCOG1403, by contrast, shows that a meaningful clinical gain can be achieved by administering an existing generic cytotoxic agent once, on the first day after surgery. Administration requires no additional anaesthesia, hospital stay or session.

2. Raising the evidence level of guideline recommendations

The EAU and other major guidelines already recommend a single dose of intravesical chemotherapy after nephroureterectomy; however, that recommendation rested largely on smaller randomized trials and meta-analyses. JCOG1403 is one of the most robust pieces of evidence strengthening this recommendation, with phase 3-level data and long follow-up.

3. Managing expectations: recurrence control, not survival

A single dose of intravesical chemotherapy does not change the systemic course of the disease; it does not prolong overall survival. The gain it provides is a reduction in the probability of a new tumour developing in the bladder and, consequently, a relative reduction in exposure to repeated cystoscopy, repeat resection and anaesthesia. This is a valuable gain in terms of quality of life, but one with clear limits.

4. The follow-up protocol does not change

Although the risk of bladder recurrence is reduced, it is not eliminated - even in the pirarubicin arm, a quarter of patients experienced bladder recurrence within three years. Regular cystoscopic follow-up and upper urinary tract imaging after nephroureterectomy must therefore be maintained consistently.

5. Notes on administration practice

In the trial the drug was given within the first 24 hours after surgery and retained for 30 minutes; timing is critical given the rationale of preventing tumour cell implantation. Because patients with a history of bladder cancer were excluded, the results cannot be directly generalised to that group. In addition, the study population came from a single country (Japan); pirarubicin is not licensed in some countries, where similar strategies are applied with alternative agents such as mitomycin C.

Glossary

• Upper tract urothelial carcinoma (UTUC): Cancer arising from the urothelium lining the inner surface of the renal collecting system and ureter.
• Radical nephroureterectomy: Removal of the kidney, the entire ureter and the bladder cuff at the point where the ureter opens into the bladder.
• Intravesical administration: Delivery of a drug directly into the bladder via a catheter; systemic absorption is low.
• Relapse-free survival (RFS): The time elapsed without disease recurrence at any site or death.
• NNT: The number of patients who need to be treated to prevent one adverse event; a lower value indicates a more effective intervention.

Conclusion

JCOG1403 recalls a truth often overlooked in uro-oncology: not every meaningful clinical gain requires a new and expensive molecule. A single dose of intravesical pirarubicin given within the first 24 hours after radical nephroureterectomy raised three-year relapse-free survival from 47% to 60% and reduced the risk of bladder recurrence by approximately nine points - with an acceptable side effect profile.

The finding does not translate into overall survival, and this limit must be stated clearly. From the patient's perspective, however, not returning to the operating theatre, avoiding repeated resections and facing fewer interventions during follow-up are valuable gains in themselves. Given the simplicity and low cost of administration, this single dose should be expected to become a routine part of standard surgical care in appropriate patients.

References

• Ito A, et al. 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. The Lancet Oncology. 2026.
• PubMed record. JCOG1403 phase 3 trial - PMID: 42435772.
• Barbor M. Early Intravesical Pirarubicin Improves Relapse-Free Survival in Upper Tract Urothelial Carcinoma. The ASCO Post, 17 August 2026.
• OncoDaily. JCOG1403: Early Intravesical Pirarubicin Improves Relapse-Free Survival After Nephroureterectomy for UTUC. August 2026.
• Ito A, et al. JCOG1403 (UTUC THP Phase III) study protocol. Japanese Journal of Clinical Oncology.