Summary
Re-transurethral resection of bladder tumors (reTURBTs) improves staging and local control in high-risk bladder cancer, posing the clinical challenge of determining the most effective adjuvant intravesical regimen. In this multicenter retrospective study, 174 patients undergoing reTURBT between 2010 and 2024 received either Bacillus Calmette-Guérin (BCG) or pirarubicin/epirubicin (THP/EPI) intravesical therapy, delivered as post-reTURBT instillations alone (PIT) or combined with interval instillations before and after reTURBT (IIT + PIT). We compared recurrence-free survival (RFS) and adverse events across regimens and performed subgroup analyses by tumor characteristics. IIT + PIT significantly prolonged RFS: BCG IIT + PIT conferred a 2.93-fold lower recurrence risk versus BCG PIT (p = 0.03), while THP/EPI IIT + PIT achieved a 2.61-fold reduction versus THP/EPI PIT (p < 0.001). The greatest benefit appeared in high-grade, cT1 lesions. Our findings endorse IIT + PIT—particularly with BCG—as an effective strategy to reduce recurrence in high-risk bladder cancer.
Subject areas: Therapeutics, Cancer
Graphical abstract
Highlights
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Interval intravesical therapy reduced recurrence in patients with high-risk BLCA
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BCG IIT + PIT showed superior efficacy in patients with larger or invasive tumors
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THP/EPI IIT + PIT was more effective in smaller, non-invasive BLCA cases
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Stratified analysis revealed distinct benefits of IIT + PIT across tumor subgroups
Therapeutics; Cancer
Introduction
Bladder cancer (BLCA) is one of the most prevalent malignancies of the urinary system, with high recurrence and progression rates posing significant challenges to effective management.1 To achieve optimal therapeutic outcomes, a second transurethral resection of bladder tumor (reTURBT) is typically recommended within 2–6 weeks following the initial procedure in specific clinical scenarios.2 These include cases where the initial TURBT is incomplete, where the detrusor muscle is absent in the pathological specimen despite a seemingly complete resection (except for Ta-LG/G1 tumors and primary carcinoma in situ), or where T1 tumors are fully resected but the detrusor muscle is present in the specimen.3,4 The primary objectives of reTURBT include evaluating the completeness of the initial resection, identifying residual tumors, and detecting potential tumor upstaging. Evidence also suggests that reTURBT may positively influence long-term outcomes by reducing recurrence and progression risks while improving cancer-specific and overall survival rates.
Despite the effectiveness of reTURBT in removing visible tumors, the high recurrence rate necessitates adjuvant therapies to reduce the risk of relapse. Intravesical instillation treatments, such as Bacillus Calmette-Guérin (BCG) therapy or chemotherapy agents such as Pirarubicin (THP) and Epirubicin (EPI), are commonly used in an attempt to prevent recurrence and eliminate any residual cancer cells in the bladder.5,6 BCG therapy is regarded as the standard intravesical treatment for non-muscle invasive bladder cancer (NMIBC) due to its ability to significantly reduce recurrence rates and improve patient’s progression-free survival (PFS).7 However, its side effects and the potential for resistance have prompted the investigation of alternative chemotherapeutic agents, including THP and EPI, which also show efficacy in preventing tumor recurrence. Although THP and EPI have both demonstrated promising efficacy in preventing recurrence, existing studies indicate no significant difference in their effects on recurrence-free survival (RFS) when compared to each other.8
The timing of intravesical instillation therapy is another critical factor influencing treatment outcomes. Several studies have demonstrated the benefit of immediate postoperative intravesical chemotherapy (IVC) in reducing the risk of recurrence. For instance, a systematic review and meta-analysis by Sylvester et al. of 13 randomized trials found that immediate IVC following TURBT decreased the risk of recurrence by 35%, reducing the 5-year recurrence rate from 58.8% to 44.8%.9 Lately, Messing et al. showed that intravesical gemcitabine instillation, compared to saline, was particularly effective in reducing recurrence rates in patients with low-grade tumors.10
Traditionally, instillation therapy is performed after the second TURBT. Our study is the first to demonstrate that intravesical therapy administered between the first and second TURBT more effectively eliminates residual tumor cells and reduces recurrence risk. These findings provide valuable insights into the benefits of interval-based therapy and offer guidance for optimizing clinical outcomes.
Results
Baseline characteristics of the patients
The baseline characteristics of the 174 patients included in the present study (Figure 1), stratified by recurrence status, are presented in Table 1. Among the patients, 54 (31.0%) experienced recurrence, while 120 (69.0%) remained recurrence-free during the follow-up period.
Figure 1.
Study flow diagram
BCG: Bacillus Calmette-Guérin; THP: Pirarubicin; EPI: Epirubicin; IIT + PIT: Interval Intravesical Therapy + Post-reTURBT Intravesical Therapy; PIT: Post-reTURBT Intravesical Therapy Only.
Table 1.
Patient characteristics and disease profiles at baseline
| Characteristics | Total (N = 174) | Recurrence |
||
|---|---|---|---|---|
| Yes (N = 54) | No (N = 120) | p value | ||
| Gender | ||||
| Male | 152 (87.4%) | 50 (92.6%) | 102 (85.0%) | 0.22 |
| Female | 22 (12.6%) | 4 (7.4%) | 18 (15.0%) | |
| Age | ||||
| <65 | 83 (47.7%) | 26 (48.1%) | 57 (47.5%) | 1 |
| ≧65 | 91 (52.3%) | 28 (51.9%) | 63 (52.5%) | |
| BMI | ||||
| Mean±SD | 25.20 ± 3.53 | 24.92 ± 3.62 | 25.33 ± 3.49 | 0.48 |
| Smoking | ||||
| Yes | 117 (67.2%) | 38 (70.4%) | 79 (65.8%) | 0.68 |
| No | 57 (32.8%) | 16 (29.6%) | 41 (34.2%) | |
| Hematuria | ||||
| Yes | 144 (82.8%) | 43 (79.6%) | 101 (84.2%) | 0.61 |
| NO | 30 (17.2%) | 11 (20.4%) | 19 (15.8%) | |
| Grade | ||||
| PUNLMP | 4 (2.3%) | 1 (1.9%) | 3 (2.5%) | 0.18 |
| Low | 35 (20.1%) | 14 (25.9%) |
21 (17.5%) |
|
| High | 121 (69.5%) | 32 (59.3%) | 89 (74.2%) | |
| Unknow | 14 (8.1%) | 7 (13.0%) | 7 (5.8%) | |
| Invasion | ||||
| Non-invasive | 57 (32.8%) | 20 (37.0%) | 37 (30.8%) | 0.36 |
| Invasive | 103 (59.2%) | 28 (51.9%) | 75 (62.5%) | |
| unknown | 14 (8.1%) | 6 (11.1%) | 8 (6.7%) | |
| Stage | ||||
| cTa | 41 (23.6%) | 16 (29.6%) | 25 (20.8%) | 0.006 |
| cT1 | 101 (58.0%) | 22 (40.7%) | 79 (65.8%) | |
| cT2 | 16 (9.2%) | 16 (9.2%) | 8 (6.7%) | |
| Unknow | 16 (9.2%) | 8 (14.8%) | 8 (6.7%) | |
| Tumor number | ||||
| Single | 81 (46.6%) | 28 (51.9%) |
53 (44.2%) |
0.59 |
| Multiple | 88 (50.6%) | 25 (46.3%) | 63 (52.5%) | |
| unknow | 5 (2.9%) | 1 (1.9%) | 4 (3.3%) | |
| Tumor size | ||||
| Mean±SD | 2.52 ± 1.24 | 2.42 ± 1.26 | 2.56 ± 1.23 | 0.53 |
Bold values represented statistically significant results with a p-value of less than 0.05.
The recurrence group showed a higher proportion of high-grade tumors and invasive tumors; however, these differences were not statistically significant, as indicated by tumor grade (p = 0.18) and invasion status (p = 0.36). Interestingly, the distribution of tumor stage differed significantly (p = 0.006), with patients in the recurrence group more likely to have cTa stage tumors (29.6%) compared to 20.8% in the non-recurrence group. Conversely, cT1 stage tumors were more frequent in the non-recurrence group (65.8%) than in the recurrence group (38.9%). Among the 17 (9.8%) clinically staged T2 (cT2) patients, all had solitary tumors less than 7 cm in diameter, with no or unilateral hydronephrosis and no evidence of extensive carcinoma in situ, confirming their status as candidates for an initial bladder-preserving approach. Tumor number (single vs. multiple) and tumor size were similar between the two groups (p = 0.59 and p = 0.53, respectively). It is important to note that, as per the inclusion criteria, all patients in the final cohort had a pathologically negative reTURBT, meaning no residual tumor was detected during the second resection.
Recurrence-free survival analysis between different treatment groups
The schema of the intravesical therapy regimen significantly influenced the recurrence of bladder cancer (p = 0.02, Table 2). In the THP/EPI post-reTURBT intravesical therapy (PIT) group, 48.6% of patients experienced recurrence, while only 36.4% of patients receiving BCG PIT relapsed. A different treatment strategy, THP/EPI interval intravesical therapy + post-reTURBT intravesical therapy (IIT + PIT), reduced the recurrence rate to 29.6%, while the BCG IIT + PIT regimen significantly lowered the relapse rate to 15.9%. These results suggest that IIT + PIT is associated with lower recurrence rates compared to standard PIT alone, with BCG treatment showing a significantly better outcome than THP/EPI.
Table 2.
Treatment regimen distribution and recurrence status comparison
| Treated | Total | Recurrence | No-recurrence | p value |
|---|---|---|---|---|
| THP/EPI PIT | 22 (12.6%) | 18 (48.6%) | 19 (51.4%) | 0.02 |
| BCG PIT | 71 (40.8%) | 8 (36.4%) | 14 (63.6%) | |
| THP/EPI IIT + PIT | 44 (25.3%) | 21 (29.6%) | 50 (70.4%) | |
| BCG IIT + PIT | 37 (21.3%) | 7 (15.9%) | 37 (84.1%) |
Bold values represented statistically significant results with a p-value of less than 0.05.
BCG, Bacillus Calmette-Guérin; THP, Pirarubicin; EPI, Epirubicin; IIT + PIT, Interval Intravesical Therapy + Post-reTURBT Intravesical Therapy; PIT, Post-reTURBT Intravesical Therapy Only.
The analysis of RFS, as shown in Table 3 and Figure 2, highlighted notable differences among the various treatment regimens. Specifically, BCG IIT + PIT demonstrated a significant reduction in recurrence risk compared to BCG PIT (HR = 2.93, 95%CI: 1.05–8.12, p = 0.03). Additionally, the combination of THP/EPI IIT + PIT showed a significantly lower recurrence risk compared to THP/EPI PIT alone (HR = 2.61, 95% CI: 1.37–4.95, p < 0.001). However, no significant difference in recurrence risk was found between BCG PIT and THP/EPI IIT + PIT, or between THP/EPI PIT and BCG PIT. We further explored the potential of the intensive THP/EPI IIT+PIT regimen as an alternative to BCG. In a direct comparison with BCG PIT, the THP/EPI IIT+PIT regimen showed a consistent, non-significant trend toward superior recurrence-free survival across nearly all patient subgroups, including those with high-grade, invasive, and cT1-stage tumors (Table S1). Although these comparisons did not reach statistical significance, the uniform direction of the hazard ratios (HR > 1) suggests that the intensive chemotherapy schedule may mitigate the efficacy gap between chemotherapy and immunotherapy. These results suggest that combining interval therapy with post-TURBT intravesical therapy, particularly with BCG IIT + PIT, may be more effective in preventing recurrence than post-TURBT therapy alone.
Table 3.
Survival analysis between different treatment groups
| Treated | Control | HR (95%CI) | p value |
|---|---|---|---|
| THP/EPI IIT + PIT | BCG IIT + PIT | 2.2 (95% CI: 0.93–5.22) | 0.07 |
| BCG PIT | BCG IIT + PIT | 2.93 (95% CI: 1.05–8.12) | 0.03 |
| THP/EPI PIT | BCG IIT + PIT | 5.12 (95% CI: 2.09–12.55) | <0.01 |
| BCG PIT | THP/EPI IIT + PIT | 1.46 (95% CI: 0.64–3.31) | 0.37 |
| THP/EPI PIT | THP/EPI IIT + PIT | 2.61 (95% CI: 1.37–4.95) | <0.01 |
| THP/EPI PIT | BCG PIT | 1.71 (95% CI: 0.74–3.95) | 0.20 |
Bold values represented statistically significant results with a p-value of less than 0.05.
BCG, Bacillus Calmette-Guérin; THP, Pirarubicin; EPI, Epirubicin; IIT + PIT, Interval Intravesical Therapy + Post-reTURBT Intravesical Therapy; PIT, Post-reTURBT Intravesical Therapy Only.
Figure 2.
Recurrence-free survival curve of the various treatment regimens
(A) Overall Kaplan-Meier curves for the four treatment regimens.
(B) Kaplan-Meier curves between different treatment groups.
Construction of nomograms for Bacillus Calmette-Guérin and pirarubicin/epirubicin treatment
Nomograms were constructed separately for the BCG (Figures 3A–3C) and THP/EPI (Figures 3D–3F) treatment groups to predict RFS in patients with BLCA. Nomograms were constructed separately for the BCG (Figures 3A–3C) and THP/EPI (Figures 3D–3F) treatment groups to predict RFS in patients with BLCA. The discriminative ability was quantified by the Concordance Index (C-index). The BCG nomogram achieved a C-index of 0.897 (95% CI: 0.817–0.977, p < 0.001), indicating outstanding performance, while the THP/EPI nomogram showed good discrimination with a C-index of 0.741 (95% CI: 0.643–0.839, p < 0.001). The contribution of the treatment regimen is explicitly quantified within the nomogram (Figures 3A and 3D). For instance, in the BCG nomogram, the BCG IIT+PIT regimen was assigned the fewest points, reflecting its association with the most favorable prognosis. This allows clinicians to visually appreciate the significant prognostic impact of the treatment strategy. A patient’s total point score—and thus their predicted recurrence risk—changes substantially based on the planned treatment, providing a powerful tool for personalized risk assessment and therapeutic planning.
Figure 3.
Construction of nomograms for BCG and THP/EPI treatment
(A–C) Nomogram (A), decision curve (B), and calibration curve (C) for predicting the recurrence-free survival of patients with BLCA with BCG intravesical therapies.
(D–F) Nomogram (D), decision curve (E), and calibration curve (F) for predicting the recurrence-free survival of patients with BLCA with THP/EPI intravesical therapies.
The clinical utility of the nomograms was evaluated using decision curve analysis (DCA). The DCA (Figures 3B and 3E) compared the net benefit of three models: a model based on demographic factors alone, a model based on tumor characteristics alone, and the full model incorporating both patient/tumor factors and the treatment regimen. The results demonstrated that the full model provided a superior net benefit across the vast majority of clinically reasonable risk thresholds. This indicates that incorporating the treatment regimen into the decision-making process provides tangible clinical value, enabling more effective identification of patients who would benefit from intensive therapy.
Stratified analysis based on tumor characteristics
A stratified analysis was performed based on key tumor characteristics, including tumor grade, tumor stage, tumor number, and tumor size, to evaluate the impact of different intravesical therapy regimens on RFS (Table 4, Figure 4). This stratification allowed us to assess the heterogeneity in outcomes and identify subgroups that might benefit more from specific intravesical therapies. In the high-grade tumor subgroup, IIT + PIT was significantly more effective than PIT, resulting in lower recurrence rates and better RFS, suggesting that interval therapy is beneficial in patients with high-grade tumors. For cT1 stage tumors, IIT + PIT was again associated with better outcomes, indicating that interval therapy may help reduce recurrence in more aggressive tumor stages. For tumor size, BCG IIT + PIT was significantly more effective in patients with tumors ≥3 cm, as evidenced by a markedly reduced hazard ratio (HR = 12, 95% CI: 0.73–197.44, p = 0.03). In contrast, THP/EPI IIT + PIT demonstrated significantly better outcomes in patients with tumors <3 cm (HR = 3.08, 95% CI: 1.35–7.05, p < 0.001). Similarly, for invasion status, BCG IIT + PIT showed a marked reduction in recurrence in patients with invasive tumors (HR = 8.71, 95% CI: 1.68–45.10, p < 0.001), while THP/EPI IIT + PIT exhibited superior efficacy in patients with non-invasive tumors, suggesting that THP/EPI may be particularly beneficial for lower-risk cases (HR = 4.01, 95% CI: 1.26–12.74, p = 0.01). This stratified analysis underscores the importance of pathological characteristics in treatment response, with IIT + PIT proving more effective in controlling recurrence across most subgroups, particularly in high-grade and cT1-stage tumors. Additionally, these results indicate that BCG IIT + PIT is particularly effective in treating high-risk patients with larger or invasive tumors, whereas THP/EPI IIT + PIT may be more beneficial for patients with smaller or non-invasive tumors. The result further emphasized the importance of tailoring intravesical therapy to the individual pathological characteristics of patients to optimize recurrence-free survival.
Table 4.
Recurrence-free survival-stratified analysis
| Characteristics | BCG |
THP/EPI |
||||||
|---|---|---|---|---|---|---|---|---|
| PIT (patients, n) | IIT+PIT (patients, n) | HR | p Value | PIT (patients, n) | IIT+PIT (patients, n) | HR | p Value | |
| Overall | 22 | 44 | 2.93 (95%CI: 1.05–8.12) | 0.03 | 37 | 71 | 2.61 (95% CI: 1.37–4.95) | <0.001 |
| Grade | ||||||||
| Low | 3 | 8 | 1.16 (95%CI: 0.12–11.20) | 0.9 | 7 | 17 | 2.16 (95%CI: 0.61–7.73) | 0.22 |
| High | 18 | 28 | 3.54 (95%CI: 0.89–14.18) | 0.06 | 25 | 50 | 3.27 (95%CI: 1.39–7.66) | <0.001 |
| Invasion | ||||||||
| Non-invasive | 9 | 12 | 1.58 (95%CI: 0.34–7.33) | 0.56 | 12 | 24 | 4.01 (95%CI: 1.26–12.74) | 0.01 |
| Invasive | 11 | 29 | 8.71 (95%CI: 1.68–45.10) | <0.001 | 21 | 42 | 1.98 (95%CI: 0.81–4.84) | 0.13 |
| Tumor number | ||||||||
| Single | 10 | 15 | 0.26 (95%CI: 0.05–1.44) | 0.1 | 19 | 37 | 3.39 (95%CI: 1.44–7.99) | <0.001 |
| Multiple | 12 | 28 | 2.32 (95%CI: 0.62–8.71) | 0.2 | 16 | 32 | 1.81 (95%CI: 0.64–5.11) | 0.26 |
| Tumor size | ||||||||
| <3 | 19 | 21 | 1.88 (95%CI: 0.59–5.92) | 0.28 | 18 | 36 | 3.08 (95%CI: 1.35–7.05) | <0.001 |
| ≧3 | 2 | 18 | 12 (95%CI: 0.73–197.44) | 0.03 | 14 | 26 | 2.07 (95%CI: 0.57–7.51) | 0.26 |
| Stage | ||||||||
| cTa | 8 | 8 | 0.92 (95%CI: 0.14–5.90) | 0.93 | 11 | 14 | 0.39 (95%CI: 0.11–1.41) | 0.14 |
| cT1 | 12 | 29 | 5.26 (95%CI: 0.96–28.72) | 0.03 | 15 | 45 | 3.10 (95%CI: 1.09–8.82) | 0.03 |
| cT2 | 2 | 3 | -(95%CI: 0.0e+0, NaN) | 0.04 | 5 | 6 | 2.73 (95%CI: 0.43–17.39) | 0.27 |
Bold values represented statistically significant results with a p-value of less than 0.05.
BCG, Bacillus Calmette-Guérin; THP, Pirarubicin; EPI, Epirubicin.
Figure 4.
Stratified analysis based on tumor characteristics
Stratified analysis based on tumor characteristics to evaluate the impact of BCG (A) or THP/EPI (B) intravesical therapies on RFS.
Adverse events associated with bladder irrigation
Table 5 summarizes the adverse events associated with bladder irrigation in patients receiving BCG and THP/EPI intravesical therapies. For urethral-related symptoms, urinary tract infections were more common in the BCG IIT + PIT and THP/EPI IIT + PIT groups, affecting 43.2% and 32.4% of patients, respectively, compared to the PIT groups. Urinary frequency, urgency, and pain were reported in over 90% of patients in both IIT + PIT groups, showing the significant discomfort associated with these treatments. Additionally, chemical cystitis and hematuria were common across all groups, but more frequent in those receiving the combined therapy regimen (IIT + PIT). In terms of systemic symptoms, fever was observed in a greater proportion of patients receiving BCG IIT + PIT (68.2%) and THP/EPI IIT + PIT (43.7%) compared to their respective PIT groups. Overall, while IIT + PIT regimens showed potential efficacy in improving RFS, they were also linked to a higher frequency of certain adverse events, making the trade-off between benefits and side effects an important consideration in clinical decision-making.
Table 5.
Adverse events associated with bladder irrigation
| Adverse event | BCG |
THP/EPI |
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|---|---|---|---|---|
| PIT (n = 22) | IIT+PIT (n = 44) | PIT (n = 37) | IIT+PIT (n = 71) | |
| Urethral related symptoms | ||||
| Urinary tract infection | 27.3% (n = 6) | 43.2% (n = 19) | 21.6% (n = 8) | 32.4% (n = 23) |
| Pyelonephritis | 4.5% (n = 1) | 6.8% (n = 3) | 0 | 1.4% (n = 1) |
| Urinary frequency, urgency, and pain | 90.9% (n = 20) | 97.7% (n = 43) | 81.1% (n = 30) | 91.5% (n = 65) |
| Chemical cystitis | 59.1% (n = 13) | 54.5% (n = 24) | 64.9% (n = 24) | 66.2% (n = 47) |
| Hematuria | 27.3% (n = 6) | 43.2% (n = 19) | 18.9% (n = 7) | 23.9% (n = 17) |
| Dysuria | 18.2% (n = 4) | 22.7% (n = 10) | 10.8% (n = 4) | 16.9% (n = 12) |
| Local skin irritation | 40.9% (n = 9) | 43.2% (n = 19) | 35.1% (n = 13) | 32.3% (n = 23) |
| Urethral stricture | 0 | 4.5% (n = 2) | 0 | 0 |
| Systemic symptoms | ||||
| Fever | 54.5% (n = 12) | 68.2% (n = 30) | 37.8% (n = 14) | 43.7% (n = 31) |
| Allergic reactions | 0 | 2.3% (n = 1) | 2.7% (n = 1) | 0 |
| Joint or muscle pain | 9.1% (n = 2) | 11.4% (n = 5) | 2.7% (n = 1) | 4.2% (n = 3) |
BCG, Bacillus Calmette-Guérin; THP, Pirarubicin; EPI, Epirubicin.
Discussion
ReTURBT is widely recognized as a critical component in the optimal management of high-risk BLCA, with its inclusion in numerous international guidelines, such as those from the EAU and the AUA.11 This procedure is typically followed by intravesical adjuvant chemotherapy or immunotherapy to further reduce the risk of recurrence, particularly in NMIBC. While the combination of TURBT and intravesical therapy has long been the cornerstone of treatment for NMIBC, the timing and regimen of intravesical therapy for patients who underwent reTURBT remain subjects of ongoing debate.
Current clinical practice generally employs either BCG or chemotherapeutic agents such as THP and EPI, with the goal of eradicating residual tumor cells in the bladder and preventing recurrence.12 The timing of intravesical therapy, particularly whether it should be administered immediately after reTURBT or whether an interval therapy approach is preferable, remains a key question in the management of these patients.
In addition to the long-term maintenance therapies with intravesical agents, there is substantial evidence supporting the use of IVC following TURBT.13,14 The rationale for this is to target circulating tumor cells within the bladder lumen and any residual cancerous cells at the site of resection, thus reducing recurrence. However, there are also studies that question this benefit, particularly those that administered IVC the day after TURBT, rather than immediately postoperatively, which might highlight the importance of the timing of IVC instillation.
While clear evidence supports the use of immediate postoperative IVC in certain patients, its inconsistent application-shaped by factors such as physician awareness, biases, recurrence risk, and institutional practices-reflects the broader insufficiency of existing literature to definitively establish its benefits, particularly in reTURBT cases.15 This study explored the potential benefit of IIT, delivered between the first and second TURBT procedures, in combination with PIT.
Our findings are consistent with previous studies that have shown the importance of early and sustained intravesical therapy in reducing recurrence rates. In our study, IIT + PIT demonstrated superior efficacy, particularly in patients with high-grade and cT1 stage tumors, where the baseline risk of recurrence is notably higher. This suggests that interval therapy, which is administered between the first and second TURBT procedures, may provide additional benefit by allowing for more complete eradication of remaining tumor cells, thus reducing the risk of recurrence. It was worth noting that the THP/EPI IIT + PIT group showed a significantly higher risk of recurrence compared to BCG IIT + PIT. This observation suggests that while THP/EPI may offer some therapeutic benefit in specific settings, such as in cases where BCG is contraindicated, it does not achieve the same level of efficacy in preventing recurrence in high-risk patients. These findings further corroborate the established clinical consensus that BCG remains the gold standard for intravesical therapy in patients with high-risk NMIBC, particularly those with high-grade, cT1 tumors, and carcinoma in situ (CIS).
BCG’s superior efficacy can be attributed to its robust immunological mechanisms, including the activation of local immune responses and the enhancement of anti-tumor immunity.16 BCG induces a complex immune cascade involving the activation of T-cells, neutrophils, macrophages, and dendritic cells, which work together to target and eliminate residual tumor cells.17,18 This immune-mediated mechanism of action, while highly effective, does carry the risk of local inflammation and systemic side effects, such as fever, hematuria, and, in rare cases, severe adverse events such as sepsis or granulomatous reactions.19 However, despite these potential risks, BCG continues to outperform alternative treatments, such as THP/EPI, in high-risk patients, as it offers superior long-term recurrence-free survival rates.
Furthermore, the stratified analysis of treatment regimens based on tumor size and invasion status provides valuable insights into the differential effectiveness of BCG IIT + PIT and THP/EPI IIT + PIT. Notably, BCG IIT + PIT was significantly more effective in patients with larger (≥3 cm) and invasive tumors, highlighting its potential superiority in high-risk subgroups. This could be attributed to the robust immunological mechanism of BCG, which may be particularly advantageous in eliminating larger and more aggressive tumor cells. On the other hand, THP/EPI IIT + PIT appeared to be more effective in patients with smaller (<3 cm) tumors or non-invasive tumors, though the benefit was less pronounced in patients with invasive disease. These findings underscore the importance of tailoring intravesical therapy regimens based on tumor characteristics, as BCG remains highly effective in more advanced cases, while THP/EPI may be better suited for less aggressive forms of BLCA.
Notably, our study also included a select group of patients with cT2 managed under a bladder-preservation paradigm. This reflects evolving clinical practice where tri-modality therapy (TMT) has emerged as an effective alternative to radical cystectomy in carefully selected cohorts.20,21,22 Indeed, contemporary evidence from large comparative studies demonstrates comparable survival outcomes between TMT and radical cystectomy in patients with similar baseline characteristics.22 The patients with cT2 in our cohort mirrored standard bladder-preservation eligibility criteria (e.g., solitary tumors <7 cm, no hydronephrosis, absence of extensive carcinoma in situ), wherein an aggressive local approach involving reTURBT and intensive intravesical therapy aims to maximize local control and potentially delay or avoid cystectomy. However, our T-stage stratified analysis confirmed that the significant reduction in recurrence risk associated with IIT+PIT was primarily driven by the robust effect in patients with T1-stage, who constituted the majority of our cohort. The effect of this therapy in a highly selected cT2 population within a bladder-sparing paradigm remains an area for future validation in larger, prospective studies.
The safety profile of IIT + PIT was generally consistent with expectations. While patients receiving IIT + PIT reported more frequent urinary symptoms, such as dysuria, urinary frequency, and hematuria, as well as systemic symptoms such as fever, these adverse events were generally mild and resolved upon the completion of the treatment course. This is consistent with previous reports of BCG and THP/EPI intravesical therapy, which often cause temporary local irritation or systemic responses such as fever and malaise, but these side effects are typically not serious enough to warrant discontinuation of therapy.23,24,25
Looking forward, liquid biopsy technologies, particularly urinary tumor DNA (utDNA) analysis, hold promise for further personalizing intravesical therapy. Recent evidence suggests that utDNA assays can detect minimal residual disease with high sensitivity, potentially identifying patients at highest risk for recurrence who would benefit most from intensive regimens such as IIT+PIT.26 Moreover, utDNA monitoring could guide intravesical therapy selection and duration by providing real-time feedback on treatment response, enabling a more personalized approach.27 This could ultimately lead to a dynamic, biomarker-driven framework for intravesical management, optimizing outcomes while minimizing overtreatment.
In conclusion, the addition of interval intravesical therapy appears to offer significant benefits in preventing recurrence in patients with high-risk BLCA who accept re-TURBT. While IIT + PIT, especially BCG, was associated with a higher incidence of adverse events, these effects were generally transient and did not outweigh the therapeutic benefits, making it a promising option for patients with high-risk BLCA. A prospective, randomized controlled trial represents the next critical step to validate this strategy and refine its application in clinical practice.
Limitations of the study
Despite the valuable findings, this study has several limitations. First, although we adjusted for known risk factors such as tumor stage and grade, the choice of treatment regimen may have been influenced by physician preference, and variations in data collection and follow-up procedures across different institutions could introduce additional bias. Second, despite a robust median follow-up of 42 months for the entire cohort, the inclusion of patients until October 2024 meant that a subset, particularly those enrolled later, had limited follow-up, potentially leading to an underestimation of the true long-term recurrence risk. Additionally, while the sample size of 174 patients is relatively robust, it remains small in certain treatment subgroups, particularly in those receiving therapies such as THP/EPI PIT or BCG PIT. Lastly, this study did not conduct a comprehensive assessment of adverse events and their impact on patients' quality of life.
Resource availability
Lead contact
Requests for further information and resources should be directed to and will be fulfilled by the lead contact, Lei Yan (yanlei5309@sdu.edu.cn).
Materials availability
This study did not generate new unique reagents.
Data and code availability
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The de-identified data reported in this article will be shared by the lead contact upon request.
-
•
This article does not report original code.
-
•
Any additional information required to reanalyze the data reported in this article is available from the lead contact upon request.
Acknowledgments
This work was supported by the Postdoctoral Innovation Program of Shandong Province (No. SDCX-ZG-202502072), the Youth Project of Shandong Provincial Natural Science Foundation (No. ZR2024QH575), the Shandong Provincial Natural Science Foundation General Program (No. ZR2025MS1463), the Shandong University (No. 2019GSF108255), and the Shandong Pingzheng Biotechnology Co., Ltd. (No. 6010123019).
Author contributions
C.D., data curation, formal analysis, project administration, funding acquisition, and writing – original draft; L.Z., conceptualization, data curation, formal analysis, visualization, and writing – original draft; S.Y., conceptualization, data curation, and writing – original draft; Z.Y., conceptualization, data curation, formal analysis, and writing – original draft; C.H., resources, visualization, and writing – original draft; Q.L., data curation, formal analysis, methodology, and writing – original draft; Y.L., data curation, formal analysis, methodology, and writing – original draft; L.S., formal analysis, methodology, and writing – original draft; W.Z., conceptualization and writing – original draft; C.S., formal analysis, investigation, and writing – original draft; Z.C., conceptualization, data curation, formal analysis, investigation, funding acquisition, and writing – review and editing; Y.L., conceptualization, data curation, formal analysis, funding acquisition, investigation, and writing – review and editing.
Declaration of interests
The authors declare no competing interests.
STAR★Methods
Key resources table
| REAGENT or RESOURCE | SOURCE | IDENTIFIER |
|---|---|---|
| Software and algorithms | ||
| EndNote | https://support.clarivate.com/Endnote/s/article/Download-EndNote?language=zh_CN | Endnote 19 |
| R | https://www.r-project.org/ | Version 4.4.1 |
| IBM SPSS | https://www.ibm.com/cn-zh/products/spss | Version 27.0 |
Experimental model and study participant details
Our study does not use experimental models typical in the life sciences. This multicenter, retrospective cohort study analyzed data from 174 adult human patients who underwent repeat transurethral resection of bladder tumors (reTURBT) between January 1, 2010, and October 1, 2024. Patient data were collected from Qilu Hospital of Shandong University, Beijing Chaoyang Hospital Affiliated with Capital Medical University, and the Affiliated Hospital of Xuzhou Medical University. All patients received standard reTURBT procedures and completed a full course of intravesical therapy with either Bacillus Calmette-Guérin or pirarubicin/epirubicin according to established treatment guidelines. The potential influence of patient sex on recurrence-free survival was evaluated, and no significant association was found in our cohort. The study was approved by the Ethics Committee of Qilu Hospital of Shandong University (Approval No. KYLL-202501-043-1), and a waiver of informed consent was granted due to the retrospective nature of the research.
Method details
Patient population
We conducted a retrospective study by collecting data from 256 patients who underwent reTURBT procedures between January 1, 2010, and October 1, 2024, at Qilu Hospital of Shandong University, Beijing Chaoyang Hospital Affiliated Capital Medical University and the Affiliated Hospital of Xuzhou Medical University. ReTURBT is defined by the European Association of Urology (EAU) as a procedure recommended within 2 to 6 weeks after the initial TURBT in certain clinical situations.3 All patients completed the full course of BCG or THP/EPI therapy (defined as ≥5/6 induction and ≥8/10 maintenance doses for BCG; ≥6/8 induction and ≥4/6 maintenance doses for THP/EPI), ensuring intravesical treatment consistency within the cohort. The study cohort included patients with NMIBC and a selected group of patients with clinical T2 stage (cT2) muscle-invasive bladder cancer (MIBC) who were managed under a bladder-preservation strategy. The clinical staging was based on preoperative cross-sectional imaging and the initial TURBT pathology confirming muscle invasion. The inclusion of cT2 patients was justified by their eligibility for bladder preservation, characterized by favorable tumor features (e.g., solitary tumor <7 cm, no hydronephrosis, no extensive CIS) and/or presence of comorbidities precluding radical cystectomy, reflecting real-world clinical scenarios where effective intravesical therapy plays a crucial role in local disease control. After excluding cases that did not meet the inclusion criteria, a total of 174 patients were included in the present study (Figure 1). The study was approved by the local medical ethics committee (Approval No. KYLL-202501-043-1). As this study is retrospective in nature, the Ethics Committee granted a waiver of informed consent.
Inclusion and exclusion criteria
Inclusion criteria: 1. Patients who underwent reTURBT procedures within 2 to 6 weeks after the initial TURBT procedures between January 1, 2010, and October 1, 2024; 2. Patients with a pathologically confirmed negative reTURBT finding (no residual tumor); 3. Patients who completed the full course of intravesical therapy with either BCG or THP/EPI following the first TURBT, as per the guidelines for treatment regimens; 4. Patients who had complete clinical data, including tumor stage, grade, tumor size, and tumor number and other important clinical-pathological information.
Exclusion criteria: 1. Patients who had incomplete resection during the initial or second TURBT; 2. Patients who did not complete the full course of prescribed intravesical therapy (BCG or THP/EPI); 3. Patients who received different classes of intravesical agents (e.g., BCG and THP/EPI) before and after the reTURBT procedure; 4. Patients with significant contraindications to intravesical therapy, including active urinary tract infections or bladder perforation; 5. Patients with insufficient clinical data for outcome analysis, including lack of follow-up or missing information on recurrence status.
Follow up
The cut-off date for follow-up was Mar 1, 2025. RFS was calculated from the date of reTURBT to the date of first recurrence or the last follow-up. The median follow-up time for the entire cohort was 42.0 months (95% CI: 38.0 - 49.9 months). The median follow-up time for each treatment group was as follows: BCG IIT+PIT (50.6 months, 95% CI: 36.4 - 90.5), THP/EPI IIT+PIT (44.2 months, 95% CI: 38.7 - 55.8), BCG PIT (42.5 months, 95% CI: 39.1 - 68.3), and THP/EPI PIT (36.1 months, 95% CI: 27.2 - 45.5).
Observation indicators
The primary observation indicators in this study included demographic factors such as age, gender, smoking history, hematuria, and body mass index (BMI). Tumor-related characteristics included tumor size (measured as the diameter of the largest tumor), number of tumors, pathological tumor grade, tumor stage, and invasion status. Additionally, treatment-related factors were analyzed, which included the type of intravesical therapy administered (BCG or THP/EPI) and the timing of therapy.
Outcomes
The primary outcome of this study was RFS, which was defined as the time from the reTURBT to the first documented recurrence of bladder cancer. Recurrence was confirmed either through cystoscopy with histopathological examination in cases of suspected tumor regrowth.
Secondary outcomes included the assessment of treatment-related adverse events and treatment completion rate of intravesical therapy.
Quantification and statistical analyses
Statistical analysis was performed using SPSS software (version 28.0, NY, USA) and R software (version 4.4.1, Vienna, Austria). Continuous variables were presented as mean ± standard deviation (SD). Pearson’s chi-square test or Fisher’s exact test were used for categorical variables. Wilcoxon rank-sum test was used to compare non-parametric data between two independent groups. RFS was analyzed using the ' survival ' package in R, employing the Kaplan-Meier method to estimate survival curves. A p value < 0.05 was considered statistically significant for all analyses. All statistical analyses were two-tailed.
Published: November 19, 2025
Footnotes
Supplemental information can be found online at https://doi.org/10.1016/j.isci.2025.114152.
Contributor Information
Cong Zhang, Email: 873060642@qq.com.
Lei Yan, Email: yanlei5309@sdu.edu.cn.
Supplemental information
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
-
•
The de-identified data reported in this article will be shared by the lead contact upon request.
-
•
This article does not report original code.
-
•
Any additional information required to reanalyze the data reported in this article is available from the lead contact upon request.