Abstract
Background: Instillation of chemotherapy after transurethral resection (TUR) has been considered as an optimal treatment for non-muscle invasive bladder cancer (NMIBC). However, controversy remains regarding the role of chemotherapy instillation. We therefore evaluated the usefulness of continuous saline bladder irrigation (CSBI) after TUR. Patients and Methods: Patients with intermediate risk NMIBC were treated by TUR followed by either CSBI (123 patients) or intravesical instillation of mitomycin C (115 patients). Recurrence-free rates were estimated using the Kaplan-Meier method. Results: No significant differences were observed in the recurrence-free rate, period to first recurrence, nor in frequency of recurrence between the CSBI and intravesical chemotherapy groups. Tumor progression rate and local toxicities were significantly higher in the intravesical chemotherapy group. Conclusion: CSBI after TUR appears to be a prophylactic treatment choice for intermediate risk NMIBC patients, in terms of its equal prophylactic effect to intravesical chemotherapy with mitomycin C, and its safety and cost benefits.
About 70% of bladder cancer patients initially present with non-muscle invasive disease. Almost all cases of non-muscle invasive bladder cancer (NMIBC) macroscopically exhibit papillary tumors, and transurethral resection (TUR) is the gold standard of treatment for these cases. However, 40-80% of tumors recur in spite of complete resection (1).
Guidelines of the European Association of Urology for the treatment of NMIBC recommend that all patients receive one immediate instillation of chemotherapy after TUR. In patients at low risk of recurrence and progression, no further treatment is recommended prior to a subsequent recurrence. In patients with high-grade tumors or carcinoma in situ (CIS), bacillus Calmette-Guerin (BCG) immunotherapy is recommended (2). The remaining patients have an intermediate risk of progression and an intermediate to high risk of recurrence depending, to a large extent, on the number of tumors (3); in patients with multiple tumors, one immediate instillation alone is insufficient treatment (4). However, there is no consensus whether further intravesical chemotherapy or immunotherapy should be given to these patients. Both intravesical chemotherapy and BCG have potential side effects which can be described as local or systemic. Local side-effects are common for both therapies and can lead to treatment cessation and incomplete treatment, resulting in suboptimal outcomes.
One of the mechanisms of recurrence of bladder tumor might be the dissemination during operation and implantation of floating cancer cells after TUR (5). Therefore, we hypothesized that continuous saline bladder irrigation (CSBI) after TUR would remove floating cancer cells and prevent these cells from attaching to the bladder wall, thus reducing tumor recurrence. The aim of the present study was to assess the efficacy of CSBI after TUR, especially in patients with intermediate risk of NMIBC.
Patients and Methods
Between January 1998 and December 2007, a total of 423 patients were newly diagnosed with NMIBC in our hospital. NMIBC patients were treated by TUR followed by either intravesical chemotherapy for 1 year with mitomycin C (MMC) diluted in 50 ml saline (4 weekly instillations starting one week after TUR followed by 11 monthly instillations to month 12), or CSBI which was started immediately after complete resection of the tumor, and continued until the next morning (2,000 ml/h for first 1 hour, then 1,000 ml/h for 3 hours, and then 250 ml/h for 14 to18 hours: a total of 8.5 to 9.5 l of saline are usually used for CSBI).
Pathological slides stained with hematoxylin and eosin were reviewed by one pathologist (TY). Results of histopathology were classified according the TNM system and graded using the World Health Organization (WHO) 1973 classification. The patients were classified into three categories, that is, low risk (single tumor, Ta, low grade, tumor diameter <3 cm), high risk (Ta or T1, high grade with/without carcinoma in situ) and intermediate group (all other tumors except lrow-and high -risk tumors) according to the Guidelines on Bladder Cancer of the European Association of Urology (2).
In 261 newly diagnosed intermediate-risk NMIBC cases, 2 patients who had a history of urothelial carcinoma of upper urinary tract, and 4 of other active neoplasms were excluded, and 8 patients who received saline irrigation after TUR because of active postoperative bleeding were removed from this study. Nine patients with residual tumor at 1 month after TUR were also excluded as having incomplete TUR, since any influence of residual tumor from incomplete TUR should be excluded for evaluation of prophylactic treatment (6). Following the above exclusion criteria, a retrospective analysis was performed on 238 intermediate-risk NMIBC patients. A total of 123 patients were treated by TUR followed by CSBI (CSBI group), and 115 patients were treated by TUR followed by intravesical instillation of chemotherapy (instillation group).
Patients were followed up by cystoscopy and urine cytology monthly for one year, and three-month intervals thereafter. Recurrence was defined as tumor identified at cystoscopy. Progression was defined as an increase in tumor grade or stage. The primary criterion for treatment efficacy was recurrence-free survival. The frequency of tumor recurrence and disease progression was also assessed. Both local toxicities, such as macrohematuria and irritative bladder symptoms (micturition pain and frequency of urination) and systemic toxicities were also monitored after CSBI or bladder instillation of chemotherapy. Standard chi-square tests were used to compare the two groups. The recurrence-free interval was estimated by Kaplan-Meier methods and the resulting distribution was compared by log-rank test. Differences were considered statistically significant at p<0.05.
Results
A total of 238 eligible patients were investigated in this study (123 patients in the CSBI group, 115 in the instillation group). The median follow-up period was 58 (range 32 to 84) months for the CSBI group, and 66 (range 42 to 96) months for the instillation group. No significant differences were seen between the groups in terms of age, sex, stage, tumor grade, number of tumors, and tumor size (Table I).
To evaluate the treatment efficacy of CSBI, recurrence-free survival rate, the period to first recurrence, frequency of recurrence, and progression rate in the CSBI group were compared to those of the instillation group. The recurrence free rate at 1, 3 and 5 years for the CSBI group were 76.7%, 67.3%, and 61.3%, respectively. In instillation group, recurrence-free rate at 1, 3 and 5 years were 81%, 58%, and 58% respectively (Figure 1). No significant difference was observed in the recurrence-free rate, the period to first recurrence (13.9 months vs. 16 months) and frequency of recurrence (1.9 times vs. 2.2 times) between the two groups. Tumor progression was seen in 9 (7.3%) and 16 patients (13.9%) in the CSBI and instillation groups, respectively. Tumor progression rate was significantly higher in the instillation group than in the CSBI group (p=0.01). Of intermediate-risk patients, 3 (2.4%) in the CSBI group, and 5 (4.3%) in the instillation group died of bladder cancer (Table II).
Intermediate-risk patient characteristics.
Adverse events were assessed in all 238 eligible patients. No severe systemic toxicities were observed in either group. The rates of local toxicities were significantly higher in the instillation group than in the CSBI group (Table III).
The yearly medical cost per person for CSBI is apparently lower than that in our instillation schedule (the cost of 30 mg of MMC is about 7,000 yen, and that of 9 l of saline is about 2,000 yen).
Discussion
Recurrence of bladder tumor might occur through residual tumor left after an incomplete TUR, by implantation of circulating tumor cells, and by de novo tumor. The effect of intravesical instillation chemotherapy may be explained either by its destroying circulating tumor cells, or as having an ablative effect (chemo-resection) of residual tumor cells at the resection site (4). Thus it is clear that one immediate instillation of chemotherapy has benefits in terms of efficacy, negligible side-effects and cost savings compared to long-term instillation of chemotherapy. This strategy can be performed without problems in most case. However, it is not always completely harmless. When a bladder perforation or near-perforation is present after TUR, an immediate instillation of a cytostatic drug may lead to leakage outside the bladder into the retroperitoneal or intraperitoneal space. Several case reports have been published of severe complications after an early instillation with MMC and epirubicin, and one of these patients died due to a number of consecutive complications (7-9).
The initial high peak of tumor recurrence after TUR of Ta/T1 bladder cancer was detected at 100-200 days after operation (10). It might be surmised that the initial high peak may be a result of dissemination of tumor cells during TUR and/or microscopic residual tumor. In theory, CSBI after TUR could be effective in preventing free tumor cells from implanting in the bladder wall, followed by reduction of tumor recurrence. However it is important to perform complete tumor resection with surrounding and sufficient depth including muscle tissue, since CSBI has no ablative effect on residual tumor cells at the resection site. Using distilled water for bladder irrigation instead of saline might have an additive effect of destroying circulating tumor cells by the change of osmotic pressure caused. Although the prophylactic effect of CSBI has not generally been established yet, Whelan et al. reported that the 2-year recurrence-free rate was significantly higher in patients with postoperative irrigation with saline or glycine than those with no irrigation (11). Another of our investigations also showed relatively good results for recurrence-free survival in 63 patients of a low-risk CSBI group (recurrence-free rate at 1, 3 and 5 years were 87.5%, 87.5%, and 84.3%, respectively; data not shown).
Recurrence-free survival in the continuous saline bladder irrigation group (CSBI), and bladder instillation of chemotherapy group (Instillation). There was no significant difference between the survival of the two groups.
One immediate instillation reduces the recurrence rate, not only in good-risk patients with single tumors but also in patients with multiple tumors; however, one immediate instillation by itself has been shown to be insufficient treatment after TUR in patients with multiple tumors (4). Although there is no consensus as to whether further intravesical chemotherapy or BCG should be given for these patients, additional instillation may further reduce the recurrence rate. If one immediate instillation is not given, a minimum of 12 months of treatment appears to be necessary to achieve the same prophylactic effect on recurrence as compared to one immediate instillation, either without or with additional instillation (12). Therefore the prophylactic effect of our instillation schedule could be comparable to one immediate instillation. Furthermore, 3 years of treatment with MMC is more effective than that of 6 weeks (13), but it is unknown if this difference leads to fewer cystectomies, progression, and deaths due to bladder cancer.
Treatment efficacy comparing CSBI to instillation therapy.
Local toxicity experienced by patients under therapy.
In this study, there was no significant difference in the recurrence-free rate, period to first recurrence, and number of recurrences between the CSBI and instillation groups, suggesting that the prophylactic effect of CSBI is comparable to that of intravesical chemotherapy with MMC, although our study has several limitations – this was a retrospective study, with a relatively small number of patients, and our instillation regimen was not an immediate instillation but delayed therapy with maintenance.
Meta-analysis data comparing intravesical chemotherapy to TUR alone demonstrated that intravesical chemotherapy prevents recurrence but not progression (14). Our results also showed that rates of both tumor progression and cancer-specific death were significantly higher in the instillation group, suggesting the risk of intravesical chemotherapy masking tumor progression before the tumor itself is visible. Furthermore, long-term intravesical chemotherapy has certain demerits including its costs, inconvenience, toxicity, and possible carcinogenicity (15). Sylvester et al. carried out a systemic review of the published results of randomized clinical trials and reported that for low-risk patients, no further treatment is recommended before recurrence. For patients with multiple tumors, one immediate instillation is insufficient, and additional instillations may further reduce the recurrence rate, although no recommendations can be given concerning their optimal duration (12). We totally agree with their considerations. Together with our data of equal prophylactic effect of CSBI and intravesical chemotherapy with MMC, prophylactic intravesical chemotherapy after TUR might be overtreatment, especially for intermediate risk patients. Our current treatment strategy for newly diagnosed low- and intermediate-risk NMIBC is complete resection of the tumor followed by CSBI instead of intravesical chemotherapy. CSBI after complete resection of bladder cancer is easy to administer, has little toxicity, and has the benefit of cost savings. Thus it has potential as an alternative prophylactic strategy for intermediate-risk NMIBC patients. We are planning to perform a randomized case–control study with three arms: intermediate-risk NMIBC patients treated with TUR followed by i) CSBI, ii) no irrigation (no treatment), or iii) one immediate instillation, in order to determine the efficacy and usefulness of CSBI.
In conclusion, continuous saline bladder irrigation after TUR may be a treatment choice for intermediate-risk patients with non-muscle invasive bladder tumor, in terms of its equal prophylactic effect to intravesical chemotherapy with MMC, and its safety and cost benefits.
Footnotes
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Conflict of Interest Statement
The Authors have no conflicts of interest to declare.
- Received December 29, 2010.
- Revision received March 10, 2011.
- Accepted March 11, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved