Should continuous bladder irrigation be recommended when single instillation of intravesical chemotherapy cannot be used after transurethral resection in low-risk non-muscle invasive bladder cancer?
Joaquin Chemi*, Gustavo Martin Villoldo
Urology Department, Instituto Alexander Fleming, Cramer 1180, (1426) Ciudad Autónoma de Buenos Aires, Argentina
*Corresponding author: Joaquin Chemi, MD, Urology Department, Instituto Alexander Fleming, Cramer 1180, (1426) Ciudad Autónoma de Buenos Aires, Argentina, Tel.: +54 9 1157686293, Fax.: (54-11) 3221-8999, E-mail: firstname.lastname@example.org
Conflict of interest: None
Abbreviation used: BC, bladder cancer; LR, low risk; NMIBC, Non-muscle invasive bladder cancer; TURBT, transurethral resection bladder tumor; IR, intermediate risk; SI, single instillation; MMC, CBI, Continuous bladder irrigation
Received May 2, 2022, Revision received December 30, 2022, Accepted January 5, 2023, Published xxxx
Reducing the recurrence rate in patients with low-risk non-muscle invasive bladder cancer patients is a critical concern in the urologic community. The gold standard treatment is single instillation (SI) of intravesical chemotherapy after transurethral resection of bladder tumor (TURBT), but unfortunately, it is underused. Continuous bladder irrigation (CBI) after TURBT is an alternative strategy to SI for the prevention of bladder tumor implantation and recurrence. The aim of this review was to present the evidence that supports CBI after TURBT when SI is not possible.
Keywords: low-risk, non-muscle invasive bladder cancer, continuous bladder irrigation, recurrence
Approximately 70% of new non-muscle invasive bladder cancer (BC) are classified as low risk (LR-NMIBC) [1
]. These tumors are associated with a signiﬁcant risk of recurrence requiring invasive procedures during follow-up and further treatment.
One of the possible mechanisms underlying early recurrence might be the dissemination and implantation of floating cancer cells during and after transurethral resection of bladder tumor (TURBT) [2
]. Four large meta-analyses have consistently shown that single instillation (SI) after TURBT reduces the recurrence rate compared to TURBT alone not just in LR but also in intermediate risk (IR) NMIBC (Level 1a evidence) [3
]. One randomized Phase III clinical trial, SWOG 0337, compared SI of Gemcitabine versus saline post TURBT. The study demonstrated a 34% decrease in the risk of recurrence in the gemcitabine arm (4-year estimated recurrence rate 35% versus 47%, HR 0.66,
95%CI 0.48 ‒ 0.90) [5
]. Based on those results AUA and EAU guidelines recommend instillation of chemotherapy immediately after TURBT [6
]. Despite these recommendations, SI is not universally utilized in clinical practice. Recent studies have shown that there was a marked underuse of SI of chemotherapy among urologists. Only 18% and 2% of urologists always used a single instillation of chemotherapy after TURBT, while 28% and 66% never employed it in European countries and the United States respectively [8
]. Possible reasons for the lack of wide adoption of SI could be related with urologist issues (Some believe that decreasing low-grade bladder cancer recurrences is not clinically important) or health system issues (such as increase in costs, insufficient training and inexperience in handling chemotherapeutic agents among nursing staff), pharmacy logistics, uncertainty of malignancy and tumor invasion at the time of TURBT, suspected bladder perforation with possible serious side effects [9
]. Even most complications related to Mitomycin C (MMC) extravasation are local and mild, bladder necrosis, pudendal neuritis or ureterohydronephrosis could potentially occur [10
Continuous bladder irrigation (CBI) is rarely used even with full awareness of its oncological benefit, but is commonly adopted to prevent blood clotting and catheter obstruction after TURBT. In fact, TURBT is performed in several countries in an inpatient setting, and a great many patients received CBI after surgery. Two questions present themselves: Is CBI able to prevent hematuria as effectively as described by Onishi et al
] in avoiding cancer cell implantation? Should we assume that both strategies are equally to effective in the absence of a clinical trial?
Hypothetically, CBI can be effective in preventing exfoliated tumor cells from implantation into the bladder wall, and can lower tumor recurrence rate. However, it is important to perform complete tumor resection covering sufficient surrounding and depth, including muscle tissue, since CBI has no ablative effect on residual tumor cells at the resection site.
Sylvester et al
] carried out a systematic review and reported that postoperative irrigation reduced the risk of recurrence in a non-randomized comparative study involving 1592 NMIBC patients, and adjusting for the European Organisation for Research and Treatment of Cancer (EORTC) recurrence risk score, and found that postoperative irrigation reduced the relative risk of recurrence by 21%.
In 2017, Onishi et al
] published a non-inferiority single institution clinical trial comparing CBI with saline for 18 hours versus SI with Mitomycin C in low and intermediate risk NMIBC patients. After 5 years of follow-up, CBI was not inferior to SI in terms of recurrence and progression, with a lower adverse event rate (6% in the CBI arm versus 27% in MMC arm, P
< 0.05). Another study conducted by Böhle et al
. have shown that single instillation of gemcitabine followed by CBI immediately after TURBT was not superior to CBI alone after TURBT in terms of recurrence-free survival. In the study, gemcitabine and placebo were instilled immediately after TURBT, and then continuous irrigation with saline was performed for 20 hours in both arms. The authors concluded that CBI in both arms could have diluted the benefit of SI with Gemcitabine [11
A major weakness of the evidence available regarding CBI is the long duration of the infusion. Contrariwise, at least two retrospective studies on CBI for over 2 – 3 hours have shown no reduction in recurrence compared to no CBI and a significantly shorter recurrence-free survival rate compared to SI [12
]. A large proportion of studies demonstrated the benefit of CBI with 18‒24 hours of saline infusion. However, this duration of CBI may limit its cost-effectiveness and applicability, as many bladder tumors are currently treated by outpatient procedures and long-time irrigation would end up requiring hospital admission [13
]. Further trials are needed to elucidate if 6‒8 hours of CBI could provide a prophylactic effect on bladder cancer recurrence.
Limited evidence exists regarding the use of other irrigants rather than normal saline, which is widely used in clinical practice. Reports involving distilled water may have additional benefit by causing osmotic lysis due to hypotonic effect and preventing subsequent attachment of exfoliated cancer cells to the bladder wall [14
]. Furthermore, in vitro
studies have shown that distilled water may have a cytotoxic effect equivalent to Mitomycin C on bladder cancer cells [15‒16
]. Nonetheless, several complications have been reported, involving acute hyponatremia, massive intravascular hemolysis and death after bladder irrigation with distilled water [17
]. Therefore, irrigation with saline may be superior in terms of safety especially in the case of unrecognized perforation.
Finally, two recent meta-analyses comparing CBI versus SI after TURBT concluded that CBI stands as an alternative to SI and provided a better balance between the prevention of BC recurrence and the rate of adverse events than SI [18‒19].
It has been known that bladder cancer poses a financial burden on the public health system. Because of long-term survival and the need for lifelong routine monitoring and treatment, it represents one of the most expensive cancers [20
]. In this sense, using strategies to reduce the rate of recurrence will have a positive impact in economic terms. Many authors assessed the cost-effectiveness of Mitomycin C after surgery, suggesting that the strategy of SI after TURBT lowers cost by reducing tumor recurrence [21
]. The main hurdles to use of Mitomycin C is the high cost and significant drug shortage. Conversely, other drugs like gemcitabine are readily available and considerably less expensive (average sales price for 2 g of gemcitabine is $55.70 and for 40 mg of mitomycin is $1062.72) making them an interesting alternative [5
]. To our knowledge, to date, there are no face-to-face comparison between SI and CBI in terms of economic costs but we presume that CBI will be a cheaper option than SI as an adjuvant treatment after TURBT. Further clinical studies focusing on the financial cost of the aforementioned techniques will be warranted to evaluate the real cost of both strategies.
We believe that given the scarce implementation of SI in the daily practice and in view of the evidence presented, urologic societies should promote the notion that LR-NMIBC patients should receive adjuvant treatment after TURBT to reduce bladder cancer recurrence.
Urological community should be aware that the treatment alternative for low-risk tumors can never be TURBT alone, and SI or CBI must always be an option for the prevention of not only bleeding but also the implantation of neoplastic cells, as described by Onishi et al
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