Abstract
Background: To assess the prophylactic efficacy of postoperative single intravesical instillation with pirarubicin (THP) and mitomycin C (MMC) for low-risk non-muscle-invasive bladder cancer (NMBC). Patients and Methods: A total of 103 clinically low-risk NMBC patients were preoperatively randomized into either THP (n=49) or MMC (n=54) groups. The primary endpoint was recurrence-free survival. Results: The median follow-up periods of the THP and MMC groups were 955 and 1008 days, respectively (p=0.76). Twelve patients (24.5%) in the THP group and 7 (13%) in the MMC group had bladder cancer recurrences. The two-year recurrence-free survival of the THP group and the MMC group was 77.8% and 86.4%, respectively (p=0.20). Neither groups had severe toxicity. Conclusion: In low-risk NMBC, the prophylactic effect against postoperative single intravesical instillation with THP was not superior to that with MMC.
In non-muscle-invasive bladder cancer (NMBC), the biggest problem is the high intravesical recurrence rate after transurethral resection of bladder tumor (TUR-BT). Therefore, TUR-BT alone is insufficient as curative treatment and intravesical chemotherapy is necessary after TUR-BT for most NMIBC patients (1). In particular, a single instillation of a chemotherapeutic agent immediately after TUR-BT is necessary for low- and intermediate-risk bladder cancers (2). Many reports have demonstrated the efficacy of a single instillation of a chemotherapeutic agent immediately after TUR-BT in preventing intravesical recurrence in cases with low- and intermediate-risk bladder cancers (3-11).
A single instillation of epurubicin (3, 5, 6, 8) mitomycin C (MMC) (4, 9-11), pirarubicin (THP) (7), or thiotepa (12) after TUR-BT have been employed to prevent intravesical recurrence in the case of low-risk bladder cancer. In a meta-analysis, all of these agents except thiotepa were demonstrated to reduce the first intravesical recurrence after TUR-BT (2). However, there are no definitive data yet indicating the best agent for a single instillation after TUR-BT.
In this context, we conducted a multicenter, prospective, randomized study to compare the efficacy and safety of THP and MMC (the most popular agents for intravesical chemotherapy in Japan) used in a single instillation manner to prevent intravesical recurrence.
Patients and Methods
Patients. Between November 2007 and July 2012, a total of 160 patients with clinically low-risk NMIBC on cystoscopy from six institutions were randomized into either THP or MMC groups using a random number table before TUR-BT. Written informed consent was obtained from all patients. The study was approved by the ethical committee of the Cancer Institute Hospital (authorization number: 2007-1013). Patients who were randomly (1:1 ratio) assigned into the THP or MMC group received a single intravesical instillation of THP (30 mg in 50 ml of normal saline) or MMC (30 mg in 50 ml of normal saline) after TUR-BT, respectively. This study was performed as single blind test. The instillations were administered through a bladder catheter within 6 h of TUR-BT. The catheter was clamped for 30 min in the THP group and for 2 h in the MMC group after the instillation of each agent. In the final pathological results after TUR-BT, only patients with pathological Ta and Grade 1 or 2 were analyzed in this study.
Inclusion and exclusion criteria. Inclusion criteria were age between 20 and 80 years old, primary, solitary lesion smaller than 3 cm, histologically proven urothelial carcinoma of the bladder without carcinoma in situ and grade 3 components. Exclusion criteria were a history of upper urinary tract tumor and performance status above 2. Pathological diagnosis was performed based on UICC 6th edition (13) by pathologists in each hospital.
Follow-up. Cystoscopy and urinary cytology were performed at 3-month intervals for the first 2 years, and at 6-month intervals thereafter. Recurrence was defined as a finding at cystoscopy, regardless of histology.
Endpoints. The primary endpoint was recurrence-free survival after TUR-BT, and the second endpoint was adverse events related to the two agents. The sample size was calculated assuming that the two-year recurrence-free survival rates of the THP and MMC groups would be 80% (7) and 40% (14), respectively. Thirty-six patients in each group were required for a 90% chance of detection at a significance of 5%. We decided to enroll at least 40 patients in each group to allow for possible drop-outs.
Statistics. Recurrence-free survival was calculated using the Kaplan-Meier method and the log-rank test was used for comparing recurrence-free survival rates between the two arms. The patient characteristics and adverse events of the two arms were compared by the Fisher exact test or the Student t-test. All p-Values were two-sided. A p-value of less than 0.05 was considered statistically significant. Statistical analyses were performed with JMP version 9.0.2. (SAS Institute Inc, Cary, NC, USA).
Results
Patient characteristics. Patient characteristics are shown in Table I. Of the 160 randomized patients, 57 were excluded from this study, because of pathological results and consent withdrawal (Figure 1). A total of 103 patients (THP group: 49, MMC group: 54) were eligible for the final analysis. There was no significant difference in age, male/female ratio, tumor dimension, and tumor grade between the two groups (age: p=0.59, male/female ratio: p=1.00, tumor dimension: p=0.83, tumor grade: p=0.61). The median follow-up periods of the THP and MMC groups were 955 and 1008 days, respectively (p=0.76).
First bladder cancer recurrence after TUR-BT in the two groups. During the follow-up period, 12 patients (24.5%) in the THP group and 7 (13.0%) in the MMC group had bladder cancer recurrences. The mean interval to initial recurrence was 431 days in the THP group and 425 days in the MMC group (p=0.98). The two-year recurrence-free survival of the THP group and the MMC group were 77.8% and 86.4%, respectively (p=0.20) (Figure 2).
Adverse events. Table II shows the adverse events observed after instillation. No patients in either group had life-threatening toxicity. Six patients (12.2%) in the THP group and 3 (5.6%) in the MMC group had adverse events, most of which were Grade 1 or 2 macroscopic hematuria according to Clavien-Dindo classification (15). One patient in the THP group required emergent transurethral coagulation for postoperative bleeding from the bladder. The number of adverse events in both groups was not statistically significant, despite the Grade (p=0.189 in Grade 1, p=1.00 in Grade 2 and p=0.471 in Grade 3).
Discussion
This prospective study was unable to confirm that the prophylactic effect against postoperative recurrence of a single instillation immediately after TUR-BT using THP was superior to that of using MMC in low-risk NMBC. The toxicity of the two drugs was almost the same. Although the etiology of the intravesical recurrence of NMIBC is not fully understood, it has been suggested that tumor cells are implanted on the bladder epithelium that is injured by TUR-BT (16). Pan et al. demonstrated that the immediate intravesical instillation of single-dose thiotepa after TUR-BT prevented recurrence caused by possible tumor implantation using murine bladder tumor models (16). They reported that recurrence rates were significantly lower in groups in which thiotepa was instilled immediately or 1h after TUR-BT, compared to the group that received thiotepa-instillation 24 h after TUR-BT or the control group. Based on their findings, they concluded that thiotepa should be instilled as soon as possible after TUR-BT (16). Sylvester et al. also reported that a single instillation reduced the risk of bladder cancer recurrence by 35% for low- and intermediate-risk NMIBC patients in meta-analysis randomized trials (2). A single instillation of THP and MMC has been demonstrated to be effective for reducing intravesical recurrence after TUR-BT. Okamura et al. conducted a prospective randomized study to assess the efficacy and safety of pirarubicin that was instilled as prophylaxis against recurrence following TUR-BT for NMIBC patients. The three-year recurrence-free rates of the THP and placebo groups were 78.8 % and 52.6%, respectively. The results suggested that a single instillation of THP after TUR-BT was effective for suppressing intravesical recurrence (7). Similarly, De Nunzio et al. conducted a prospective randomized trial to examine the benefit of a single instillation of MMC after TUR-BT, and reported that 10% of patients in the MMC group and 43% in the control group experienced recurrence (p=0.0001) during the median follow-up period of 90 months. In our study, the two-year recurrence-free survival rates in the THP and the MMC groups were 77.8% and 86.4%, respectively. These results are compatible with those of previous reports (10). Although, there have been some studies the comparison on a single drug versus no treatment (7, 10, 14), no randomized study has compared the prophylactic efficacy of a single instillation of anticancer agents, including THP and MMC. To our knowledge, this is the first study comparing the prophylactic effects of a single instillation of THP and MMC immediately after TUR-BT, and may contribute to decision making in clinical practice.
THP was developed in Japan and is absorbed rapidly into tumor cells. As such, the effect of the agent is exhibited by storing the agent in the bladder for only a short time (17, 18). THP is an effective prophylactic instillation agent after TUR-BT. Okamura et al. have also demonstrated the prophylactic effect of THP instillation and concluded that a comparative study between THP and MMC was needed (7).
Although the efficacy and indication of a single instillation of anticancer drugs as prophylaxis for bladder cancer recurrence after TUR-BT has already been established (3-11), the appropriate dose of the agents has not yet been determined. Based on the previous reports (7, 9-11), we set the dose at 30 mg for both MMC and THP in this study. Further studies are needed to determine the optimal doses in this context.
In this study, severe toxicity was not observed in either group, which is consistent with the toxicity profiles reported in other studies (19). It can thus be concluded that the instillation of THP or MMC after TUR-BT is safe and has acceptable toxicity.
This study has a few limitations. First, TUR-BT was performed by different surgeons which may have compromised the consistent quality of the operations. Second, pathological diagnosis was made in each hospital and no review by a central pathologist was conducted. Despite these limitations, we are confident the findings of this study. The findings of this study will contribute significantly to the decision making of physicians engaged in the management of low-risk NMIBC.
Acknowledgements
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Footnotes
Authors' Contributions
Study design: YF; Manuscript writing: SY; Statistical analysis: SY; Coordination of the team and final corrections: IF; Patient's management: SY, YK, TA, SU and IF. All Authors approved the final manuscript.
Conflicts of Interest
All Authors have no conflicts of interest to declare regarding this study.
- Received June 6, 2020.
- Revision received July 18, 2020.
- Accepted July 21, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved