Continuous Bladder Irrigation Complications Evidence Based Practice
Introduction
Carcinoma of the bladder represents a worldwide health problem ranked ninth in cancer incidence [1]. In Egypt, it represents a major health problem, with an estimated rate of 37.1 per 100 000 males [2].
At diagnosis, most of these cancers are nonmuscle-invasive lesions, yet they do show a high incidence of recurrence and progression. The main goal of treatment is tumor resection with preventing recurrence and/or progression [3].
Transurethral resection of bladder tumor (TURBT) is the first step in the diagnosis and management of bladder mass. It identifies cell type, grading, as well as the depth of muscle invasion. TURBT aims to resect all visible lesions, usually followed by an immediate intravesical instillation of single-dose chemotherapy as a standard procedure in nonmuscle-invasive bladder cancer (NMIBC). There is an accumulation of data presuming that the instillation of a single dose of chemotherapy for low-grade NMIBC would have an effect on the reduction and/or prevention of tumor recurrence and progression [3], yet conflicting results are still emerging on its clinical benefit. The lifelong risk of recurrence and repeated interventions contributes to a poor physician and patient compliance, and it significantly burdens the health care system [4 5].
Intravesical chemotherapy decreases recurrence in up to 11% [3] of the cases, yet it can potentially cause several significant adverse effects, including severe lower urinary tract symptoms, persistent chronic bladder pain, and even bladder necrosis in case reports [6 7]. Furthermore, chemotherapy is contraindicated when there is a concern for bladder perforation, and when there is significant postoperative gross hematuria and/or urinary tract infection. Considering these limitations, there is an urgent need for alternative strategies to prevent the reimplantation of tumor cells following TURBT, to reduce recurrence and minimize the morbidity of the disease.
One of the mechanisms for early recurrence of NMIBC after TURBT might be seeding of tumor cells during resection [8]. Several studies have been demonstrating the potential benefits of postoperative prolonged continuous saline irrigation of the bladder to cause cytolysis of these tumor cells and prevent this seeding, with up to 17% reduction in relative risk of recurrence compared with immediate single postoperative chemotherapy installation [3 4].
In our observational study, we reviewed the results of continuous bladder irrigation (CBI) using normal saline after TURBT in terms of recurrence and progression in patients with low-risk and intermediate-risk NMIBC with up to 20 years of follow-up, comparing it with patients who received mitomycin C (MMC) as a single postoperative adjuvant intravesical instillation.
A point of consideration is the cost of chemotherapy, availability of medicine, and the status of COVID-19 pandemic in low-middle income countries and developing countries.
Patients and method
An observation study was conducted following the tenets of Helsinki declaration. Files of 2153 patients admitted to the Urology Department of Theodor Bilharz Research Institute with bladder mass were reviewed and analyzed (Fig. 1). Ethics approval and consent to participate: Written consents were obtained from all patients. The study design was approved by the Research Ethical Committee of Theodor Bilharz Research Institute; and it was designed to be in accordance with the Helsinki Declaration of 1975. The procedures were part of standard treatment in the hospital.
Patient enrollment.
Diagnosis of NMIBC was achieved by abdominal ultrasonography and computed tomography-urography, followed by urethrocystoscopy to establish the diagnosis of papillary NMIBC, which is distinct from other bladder lesions such as flat exophytic muscle invasive bladder cancer, bilharzial granuloma, and leukoplakia.
All visual tumors are resected completely, with an additional random biopsy from suspected areas to exclude carcinoma in situ. A second-look cystoscopy was done in selected cases where there was doubt of incomplete tumor resection. Diagnosis of bladder perforation during the procedure was excluded or confirmed by performing cystogram while the patient on the operation table using a mobile imaging machine.
Inclusion criteria were classified into the following.
Patient criteria:
- Age more than 18 years.
- Naive cases with no history of bladder cancer.
- Complete resection of the primary tumor.
- Single immediate installation of 40 mg MMC as a single postoperative adjuvant therapy within less than 24 h of the resection (arm 1).
- CBI with normal saline for more than 18 h postoperatively (arm 2).
- Regular follow-up more than 24 months.
Tumor criteria:
- NMIBC (Ta, T1).
- Tumor grade (I and II) according to the 1973 WHO grading system.
- Single tumor less than 3 cm in maximum diameter, or multiple tumors with the sum of their sizes being less than 3 cm.
Exclusion criteria were as follows:
- Muscle-invasive bladder cancer.
- High-grade tumor GIII and/or carcinoma in situ.
- Identified bladder perforation during TURBT.
- Tumor at the posterior urethra.
- Concomitant upper urinary tract tumors on imaging and ureterorenoscopy.
- Incomplete files or lost to follow-up.
All patients underwent cystoscopy with TURBT followed either by a single instillation of 40 mg of MMC diluted in 20 ml of saline within 24 h postoperatively (63 patients) or CBI using normal saline for more than 18 h after TURBT (76 patients).
Follow-up protocol consisted of regular check cystoscopy every 3 months for the first 2 years, every 6 months for 2 years, and then annually, with this in parallel to urine cytology twice yearly and imaging of the upper tract annually.
Statistical analysis
The Statistical Package for the Social Sciences (SPSS), version 14; SPSS Inc., IBM Corp., Armonk, New York, USA), was used for statistical analysis. Using the Student's t test (independent sample t test) descriptive statistics for continuous variables were expressed as median (minimum–maximum).
The qualitative (categorical) data of the two arms were given as number of cases and percentages and were compared using χ 2 and Fisher's exact test. Differences were considered significant at a P value less than 0.05.
Results
The study was designed to evaluate CBI with saline in terms of efficacy and safety and compare it with single installation of MMC as adjuvant therapy. The length of follow-up was defined as the time from the first TURBT to the last cystoscopy control. Recurrence was determined by lesions that were detected at cystoscopy and confirmed pathologically during the follow-up. Progression was defined as an upstage in either tumor stage and/or grade.
At the time of analysis, only 118 patients completed at least 24 months of follow-up and were divided into two arms. There was a male predominance, with an incidence of male : female of around 2 : 1, with no statistically significant difference in other demographic data nor tumor characteristic (Table 1).
Demographic data and tumor characteristics
Postoperative complications were evaluated subjectively during the patient hospital stay in terms of presence of gross hematuria, clot retention, need for transfusion, reoperation, development of fever, and persistent irritative urinary symptoms necessitating administration of anticholinergic drugs. The results were objectively assessed using the modified Clavien-Dindo classification for urological complications (Table 2). Overall complications occurred in 18 and nine patients in MMC and CBI arms, respectively. There was no significant difference in all complications, except the need for administration of anticholinergic drugs in 12 patients in the MMC arm (grade II complication).
Complications
The median follow-up was 65 and 68 months for MMC and CBI arms, respectively. During follow-up, recurrences developed in 22 (18.6%) of the 118 patients. Overall, 10 recurrences occurred in the MMC arm, whereas 12 occurred in the CBI one. The median time to recurrence was significantly longer in cases with immediate MMC installation in comparison with CBI (Table 3).
Recurrence and progression
Overall tumor progression occurred in 5.1% (6/118) of the patients, with three patients in each arm. In all patients, progression was an upstaging of tumor grade, with no change in tumor stage. The median time to progression was 30 and 31 months for MMC and CBI arms, respectively, with no significant difference between both arms.
Discussion
NMIBC accounts for ∼70% of new cases of urothelial bladder cancer, with a high incidence of recurrence and progression [3 5 9]; thus, it was considered as a chronic disease owing to its high risk of future complications, which necessitates frequent monitoring and surveillance [9].
Recurrence of bladder tumor was postulated to result from incomplete resection of primary tumors, invisible mucosal changes, or tumor seedling during TURBT [10].
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 [10 11].
Several chemotherapeutic agents have been used, yet MMC is the standard molecule used for immediate post-TURBT installation as adjuvant treatment in NMIBC with an objective reduction in the risk of recurrence in low-risk and intermediate-risk NMIBC, yet with reported serious morbidities [11].
The concept of surgical site irrigation using saline or distilled water to prevent local recurrence in oncological surgery was always a common practice among surgeons [12]. It is a safe procedure, with documented benefits. In 1987, Moskovitz and Levin [13] first postulated that intravesical distilled water irrigation following TURBT is associated with a lower risk of tumor recurrence. This was followed by other studies with conflicting results [14].
In our study, we retrospectively evaluated our 20 years of experience in the management of bladder cancer, and we extracted results of CBI and single MMC intravesical administration in 118 patients with low-risk and intermediate-risk NMIBC.
Both CBI and MMC showed a low risk of recurrence and progression with more than 5 years of median follow-up. This was in accordance with all large series. There was no statistically significant difference in terms of recurrence rate and/or progression between the two arms. In 2011, Onishi et al. [4] performed a nonrandomized study comparing 18–22 h of postoperative CBI with saline to a full year of induction and maintenance MMC in patients with intermediate-risk NMIBC and showed no difference in several outcomes, including recurrence-free rates, time to first recurrence, and frequency of recurrences. This was confirmed in a prospective randomized study including 250 patients with a median follow-up of 37 months [14].
In our results, we had a statistically significant shorter time to recurrence in patients undergoing CBI; this shorter time of recurrence was in discordance with other studies [4 15]. However, Kuroda et al. [11] in 2020 have demonstrated that CBI shows shorter time to recurrence in relation to intravesical post-TURBT single installation of chemotherapy, yet in our study this relatively early time to recurrence did not affect the rate of recurrence nor the incidence and time to progression.
Single post-TURBT installation of MMC was demonstrated to be superior to continuous CBI in a retrospective analysis of 205 patients with NMIBC [16] in terms of recurrence-free survival (RFS) and incidence of progression, yet in this study, median follow-up was short (16 months), it included patients with high-grade tumors and even carcinoma in situ, and CBI with saline was done for only 2 h.In a systemic review of more than 1000 patients [17] with NMIBC receiving either single post-TURBT chemotherapy installation, CBI with saline, and distilled water irrigation in terms of RFS, there was no significant difference among all arms regarding the median RFS at 1 year, with saline irrigation showed the highest median RFS among the groups.
Although there are reported cases of devastating complications following intravesical single instillation of chemotherapeutic agents including bladder necrosis [6 7], both CBI with saline and MMC administration are safe procedures, and in our results, both arms had comparable safety profile, except for the development of irritative urinary symptoms necessitating administration of bladder sedative drugs in the MMC arm.
Our study showed some points of strength yet not without limitations. We have the longest median follow-up between similar studies, yet we are a retrospective nonrandomized one with a relatively low sample size.
Conclusion
CBI following TURBT for low-risk and intermediate-risk patients with NMIBC is a valid option, with comparable efficacy and better safety profile to single post-TURBT installation to MMC. This option has to be considered especially in circumstances when the availability of drugs and access to medical care is restricted or hindered by the economic or global crisis.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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Keywords:
intravesical instillation; mitomycin C; outcome assessment; recurrence; therapeutic irrigation; urinary bladder neoplasms
Source: https://journals.lww.com/ejos/Fulltext/2021/40010/Efficacy_of_continuous_bladder_irrigation_with.36.aspx
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