L’irrigation continue de sérum salé après une resection transurétrale de tumeur de vessie à la lumière bleue augmente la survie sans récidive des tumeurs de vessie de risque faible à intermédiaire

16 mai 2021

Auteurs : B. Gondran-Tellier, R. Abdallah, P.C. Sichez, A. Akiki, H. Toledano, S. Gaillet, V. Delaporte, G. Karsenty, C. Bastide, L. Daniel, S. Garcia, D. Rossi, E. Lechevallier, R. Boissier, M. Baboudjian
Référence : Prog Urol, 2021, 6, 31, 316-323




 




Introduction


Bladder cancer is the seventh most commonly diagnosed cancer in the male population worldwide [1]. At diagnosis, more than 75% of tumors are non-muscle invasive bladder cancer (NMIBC), and 5-year survival for these tumors is>90% [2, 3]. Although cancer specific survival is favorable, bladder recurrence and progression rates up to 78% and 45% respectively have been reported after transurethral resections (TURBT) [3].


One of the mechanisms of recurrence might be the dissemination during operation and implantation of floating cancer cells after TURBT [4, 5]. Immediate chemotherapy instillation is recommended in NMIBC that are presumed to be at low-risk or intermediate-risk with low recurrence rate as it proved to reduce significantly bladder recurrence [6]. However, immediate instillation of chemotherapy is associated to many drawbacks, from the selection of patients, the perioperative identification of contraindications (bladder perforation) and potential morbidity. Recently, Onishi et al. demonstrated in a prospective randomized study similar bladder recurrence rate between CSBI and a single immediate instillation of Mitomycin C (MMC) [7]. Another mechanism of bladder recurrence could be the persistence of undiagnosed tumors with white light TURBT. As photodynamic diagnosis using violet light after intravesical instillation of hexaminolaevulinic acid proved to decrease the bladder recurrence in the short and long term, this technique is systematically performed in every TURBT done in our institution [8].


Taking into account on the results of Onishi et al. [7], we aimed to demonstrate the benefit of CSBI in combination with photodynamic diagnosis in the treatment of low- to intermediate-risk NMIBC.


Materials and method


Study population


Ethical approval was obtained from the Ethics Committee of the French Association of Urology (CERU_2020002). Consecutive blue light TURBT in two urological departments of l’Assistance Publique des Hôpitaux de Marseille , between January 2017 and December 2018 have been considered. Patients who underwent blue light TURBT for low- to intermediate-risk NMIBC and a minimal follow-up of 12 months were included. Patients with high-risk NMIBC, muscle-invasive bladder cancer, absence of malignant tumor or unusual (variant) histology on pathology examination were excluded from the analysis. The experimental group (CSBI group) included patients who had postoperative CSBI and corresponded to patients from the urology department of La Conception academic hospital (Center 1) where CSBI is systematically performed. The control group consisted of patients who didn’t receive postoperative CSBI and corresponded to patients from the urology department of the Nord academic hospital where CSBI after TURBT is not performed.


Management of NMIBC


The management of NMIBC was identical in both centers, in accordance with national recommendations [9]. All TURBT were performed under general anesthesia. Complete resection was achieved by fractioned or en-bloc resection using monopolar or bipolar resection. Photodynamic diagnosis was systematically performed using violet light after intravesical instillation of hexaminolaevulinic acid. Blue light TURBTs were performed using the KARL STORZ D-Light C Photodynamic Diagnostic system which enables both white light and blue light cystoscopy. Reported data included tumor location, appearance, size and multifocality, as well as extent and completeness of resection. Two senior uropathologists reviewed and described all the resected tumors. The pathological report specified the tumor location, tumor grade and stage, lymphovascular invasion, presence of CIS and detrusor muscle. In patients with intermediate-risk tumors and high recurrence rate (more than one per year), adjuvant MMC instillation (40mg/40mL) treatment was administered. In patients having low risk or intermediate risk with previous low recurrence rate (less than one recurrence per year), surveillance by cystoscopy and urine cytology was performed because we do not perform, as recommended [6], single immediate postoperative instillations of MMC in our centers.


CSBI protocol


In both groups, immediately after TURBT, a 20 or 22 Fr three-way Foley catheter was inserted and manual bladder irrigation with saline was carried out several times using a 50mL syringe catheter tip. CSBI was started after the surgery in absence of bladder perforation, using physiological saline solution at a rate of 500–1000mL/h, for a duration of 24 hours (Center 1). In case of significant hematuria, saline irrigation could be maintained until 48 or 72 hours after TURBT. In the control group (Center 2), after immediate manual irrigation with a Toomey syringe, CSBI was never performed. Intermittent bladder wash with bolus of saline in case of clot was performed without CSBI.


Follow-up and endpoint


The frequency of cystoscopy follow-up, according to the guidelines, was adapted to the individual patient's degree of risk [6, 9]. All patients underwent cystoscopy at 3-months. If negative, subsequent cystoscopy was performed at 12-months in patients with low-risk Ta tumors, and at 6- and 12-months in patients with intermediate-risk of tumor recurrence. Blue light TURBT was performed when office cystoscopy showed suspicious findings.


The primary endpoint was recurrence free-survival which was defined as the time between initial TURBT and the date of bladder recurrence, proved with positive pathology report. Secondary outcomes included: progression-free survival, time to first recurrence and safety of CSBI which was evaluated according to the Clavien–Dindo classification of surgical complications [10].


Statistical analysis


Descriptive statistics were delineated for the available variables. Quantitative variables were reported in median, interquartile range [IQR] and analyzed by Mann–Whitney test. Categorical variables were described as numbers and percentages and were analyzed by Chi2 test. For each variable, the recurrence-free intervals were estimated by Kaplan–Meier methods, and the resulting distribution was compared using a log-rank test. Variables with P <0.20 were then considered to be included in a Cox proportional hazard regression analyses with a stepwise backward elimination to calculate the adjusted ORs and 95% CIs. The final model included the following variables: tumor risk stratification, CSBI and MMC. Statistical analyses were performed using R Version 4.0.2 (The R Foundation for Statistical Computing). For all tests, a two-side P <0.05 was considered statistically significant.


Results


Between January 2017 and December 2018, 375 patients underwent blue light TURBT and were assessed for eligibility in two urology centers. In the Center A (CSBI protocol), 141 patients were excluded because of either a muscle-invasive bladder cancer (n =42), high-risk NMIBC (n =98), or bladder perforation (n =1). In the Center B (control group), 60 patients were excluded due to invasive-muscle bladder cancer (n =17) or high-risk NMIBC (n =43). Completed 12 months of follow-up post-TURBT was achieved in 95 and 72 patients, respectively in CSBI and Control groups (Figure 1). The median follow-up was 14 months in both groups.


Figure 1
Figure 1. 

Flow diagram. TURBT: transurethral resections of bladder tumor; NMIBC: non-muscle invasive bladder cancer.




Patient and tumor characteristics are summarized in Table 1. The median (IQR) age in the study cohort was 71 (64–77) years, 33 female patients (20%) were included and the median (IQR) charlson score was 4 (2–5). All patients underwent blue light TURBT. The two groups were compared in terms of tumor characteristics including grade, stage, number, size and EORTC recurrence risk scores. The results showed no significant differences. In the study group, median duration of CSBI was 1 (1-1) day. No complication related to CSBI was reported.


In Kaplan–Meier analyses (Figure 2), 55 patients experienced bladder recurrence and 12-month recurrence-free survival in overall cohort was 67.1% (95% CI 60.3–74.6%). In the control group, recurrence at 1 year postoperatively was 45.8% (n =33) versus 23.1% (n =22) in the CSBI group (P =0.002). The median time to recurrence was shorter in the control group (168 [147–200] vs. 214 [182–280] days) but the difference did not reach statistical significance (P =0.07). Tumor progression was seen in one case (1%) in the CSBI group while none case was reported in the control group. There was no treatment difference in progression-free survival (P =1).


Figure 2
Figure 2. 

Kaplan–Meier estimates of recurrence-free survival in overall cohort.




Table 2 shows the univariable Cox regression model to identify factors associated with bladder tumor recurrence. Adjuvant intravesical chemotherapy instillations (P =0.04) and CSBI (P <0.01) were significantly associated with reduced risk of recurrence (Figure 3). Multivariate stepwise logistic regression analysis with backward selection revealed that CSBI (HR 0.47 [0.27–0.81]; P =0.006) and MMC (HR 0.55 [0.31–0.95]; P =0.034) were significantly associated with reduced risk of bladder recurrence (Figure 4).


Figure 3
Figure 3. 

Kaplan–Meier plot comparing the recurrence-free survival according to the CSBI variable. CSBI: continuous saline bladder irrigation.




Figure 4
Figure 4. 

Forest plot of the HRs with 95% CIs based on different covariates included in multivariate analysis.





Discussion


In a retrospective study that included patients with low- to intermediate-risk NMIBC and systematic use of photodynamic diagnosis with hexaminolaevulinic acid, we demonstrated that CSBI could improve the prognosis of patients and reduce the risks of early cancer recurrence. Given the different rates of MMC instillation between both groups, adjusted multivariate analysis was performed and CSBI remained an independent protective factor for bladder recurrence regardless of MMC instillations. The tolerance of CSBI was also excellent as no complications related to irrigation were reported.


After the primary resection, tumor recurrence may be due to the persistence or re-growth of residual tumor in the bladder after an incomplete TURBT, a lesion that has been overlooked during the TURBT, a new occurrence caused by either the growth of a microscopic lesion to a macroscopic one, or it may result from a high aggressive biology of the neoplasm [11]. Furthermore, one of the mechanisms for early recurrence of NMIBC after TURBT might be the dissemination during surgery and implantation of floating cancer cells after TURBT [6]. Cancer cells from the primary tumor may be implanted at areas of the urothelium that were damaged at the time of resection. Tumor cell implantation has been described in experimental animal models [12]. It has been shown that trauma to the mucosal surface is required for seeding to occur. Thus, the prevention of tumor cell implantation should be initiated within the first hours after cell seeding. Within a few hours, the cells are implanted firmly and are covered by extracellular matrix [13]. Continuous saline bladder irrigation, as a well-known perfusion protocol, is rarely applied with full awareness of its oncologic benefit but is very frequently adopted as a safety maneuver after surgery to prevent catheter obstruction by clots [14]. It was hypothesized that CSBI after TURBT would remove floating cancer cells and prevent these cells from attaching to the bladder wall, which would result in a reduction in tumor recurrence [13]. However, CSBI has no effect on the removal of residual cancer cells at the resected site; whole tumor resection is required at sufficient depth around the tumor including muscle tissue.


The diagnostic methods and transurethral resection techniques have developed recently, especially in the universal use of photodynamic diagnosis and re-TURBT [15, 16]. Only one retrospective study found that CSBI after white light TURBT could reduce early recurrence of NMIBC and it was expected to be more widely used because it could be a safe, and easy-to-perform technique [17]. Our data supports the results of this previous study, by reaffirming the interest of irrigation in the era of the most recent practices by using, in association with irrigation, methods which have already proven to be effective in reducing risks of recurrence like photodynamic diagnosis. Several other studies have compared the efficacy of CSBI with postoperative instillations and reported comparable recurrence-free survival rate between both groups reinforcing the oncological interest of CSBI [7, 18, 19]. The authors concluded that saline irrigation was easy to handle, inexpensive, and had potential as a prophylactic strategy for patients with NMIBC while preventing catheter obstruction in patients with significant hematuria.


Several studies reported the feasibility of TURBT in a one-day case surgery [20, 21, 22]. However, TURBT is becoming an increasingly complex procedure, as there is mounting evidence that several interventions at the time of the first TURBT will reduce the long-term recurrence rate. These include the instillation of a single dose of chemotherapy [23] and photodynamic diagnosis [24], which showed to decrease the rate of residual tumor. In addition, CSBI could now be combined with previous measures to prevent recurrence. Omitting these treatments is likely to result in a higher recurrence rate and hence lower patient acceptability. The widespread use of day-case TURBT is probably not justified until it has been shown to be equivalent to inpatient TURBT in terms of recurrence rates and staging accuracy. Once one-day case TURBT will be generalized, it will be then necessary to assess whether shorter duration CSBI protocols are equivalent to the usual 24-hour protocols.


There are some limitations in this study. First, the main limitation is its retrospective design with relatively small sample size. Prospective randomized study is needed to confirm these results. Second, CSBI was performed without standardization of flow, volume and duration. Nevertheless, it was systematically carried out for a minimum duration of 24 hours with a decreasing flow. Our CSBI protocol, which has been simplified compared to that of Onishi et al. [7], can easily be transposed to daily practice. Third, longer term follow-up is required to fully realize the differences between both groups. Fourth, patients were included in two urological centers who had exactly the same management of NMIBC, limiting the risk of selection bias. Although immediate instillation of chemotherapy proved to significantly reduce bladder recurrence [6], no patient received this therapy in each group and therefore did not influence the rate of recurrence. Five, outcomes relate only patients with low- to intermediate-risk NMIBC and should not be generalized to high and very high-risk tumor. Finally, the value of en bloc resection of the bladder tumor to reduce bladder recurrence is still highly debated [25]. Some patients in our study were operated on with an en-bloc technique during the study period, but we were unable to determine who benefited from it and this limitation could be regarded as a major drawback.


Conclusion


Continuous Saline Bladder Irrigation was well tolerated after blue light TURBT. It seems to reduce the risk of bladder recurrence in patients affected with low- to intermediate-risk NMIBC while being safe. A prospective randomized study is needed to confirm these results.


Disclosure of interest


The authors declare that they have no competing interest.




Table 1 - Baseline characteristics.
  Overall cohort
(n =167) 
Control group
(n =72) 
CSBI group
(n =95) 
P  
Female sex, n (%)  33 (20)  14 (19)  19 (20)  0.93 
Median (IQR) age, years  71 (64–77)  70 (64–76)  72 (64–78)  0.85 
Median (IQR) body mass index  26 (24.2–28)  26.4 (25.7–28)  25.6 (23.9–29)  0.17 
Median (IQR) Charlson score  4 (2–5)  4 (2–5)  4 (3–5)  0.91 
Smoking history, n (%)   115 (69)  52 (72)  63 (66)  0.41 
Tumor stage (TMN 2017), n (%)
Ta
T1 

167 (100)
0 (0) 

72 (100)
0 (0) 

95 (100)
0 (0) 
Tumor grade (WHO 2016), n (%)
Low
High 

167 (100)
0 (0) 

72 (100)
0 (0) 

95 (100)
0 (0) 
Tumor number, n (%)
Single
Multiple 

72 (43)
95 (57) 

28 (39)
44 (61) 

44 (46)
51 (54) 
0.34 
Tumor diameter, n (%)
<3cm
≥3cm 

149 (89)
18 (11) 

61 (85)
11 (15) 

88 (93)
7 (7) 
0.10 
Prior recurrence rate, n (%)
Primary
<1 recurrence/year
>1 recurrence/year 

66 (39.5)
47 (28.2)
54 (32.3) 

24 (33.3)
26 (36.1)
22 (30.6) 

42 (44.2)
32 (33.7)
21 (22.1) 
0.12 
Tumor risk stratification, n (%)
Low
Intermediate 

25 (15)
142 (85) 

8 (11)
64 (89) 

17 (18)
78 (82) 
0.22 
Photodynamic diagnosis, n (%)  167 (100)  72 (100)  95 (100) 
MMC, n (%)  80 (48)  30 (42)  50 (53)  0.16 



Légende :
CSBI: continuous saline bladder irrigation; MMC: mitomycin C.



Table 2 - Kaplan–Meier analysis testing the effect of different variables on the probability of bladder recurrence.
  Recurrence free-survival
95% CI 
P  
Smoking history
No
Yes 

65.4% (53.7–79-7)
67.8% (59.8–76.9) 
0.54 
Tumor number
Single
Multiple 

66.7% (56.6–78.5)
67.4% (58.6–77.5) 
0.74 
Tumor diameter
<3cm
≥3cm 

69.1% (62.1–77)
50% (31.5–79.4) 
0.05 
Prior recurrence rate
Primary
<1 recurrence/year
>1 recurrence/year 

69.7% (59.4–81.7)
72.2% (61.2–85.2)
57.4% (44.9–73.5) 
0.25 
Tumor risk stratification
Low
Intermediate 

80% (65.8–97.3)
64.8% (57.4–73.1) 
0.15 
CSBI
No
Yes 

54.2% (43.8–67)
76.8% (68.8–85.8) 
<0.01 
MMC
No
Yes 

60.9% (51.5–72.1)
73.8% (51.5–72.1) 
0.04 



Légende :
CI: Confidence Interval; CSBI: continuous saline bladder irrigation; MMC: mitomycin C. The following demographic characteristics were not associated with bladder recurrence: age (P =0.92), gender (P =0.62), Charlson score (P =0.57), and Body Mass Index (P =0.24).


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