Upper tract urothelial carcinoma is a relatively rare disease, accounting for 5-10% of
urothelial malignancies. Following radical nephroureterectomy (RNU), recurrence of
urothelial carcinoma in the bladder (UCB) is reported in up to 50% of cases. Although the
mechanism of bladder cancer recurrence following RNU is still controversial, recent
evidence suggest that these tumors have similar clonal origin to upper tract tumors,
supporting the theory of downstream seeding; specifically, that manipulation of the upper
tract during surgery results in shedding of tumor cells which then implant in the bladder
and give rise to bladder tumors.
Different strategies have been suggested to reduce UCB recurrence rates following RNU.
Early clipping of the ureter distal to the tumor may prevent seeding and reduce UCB
recurrence, while the correct technique for bladder cuff resection remains debatable. A
single, post-operative, prophylactic intravesical chemotherapy instillation (pIVC) has
been shown to reduce recurrence rates following resection of UCB. Specifically, two
prospective studies have evaluated the use of pIVC using mitomycin-C (MMC) or pirarubicin
(THP) following RNU, showing a 11-25% absolute reduction in the risk of UCB recurrence.
The safety of pIVC has previously been reported by Moriarty et al. with no directly
associated adverse events. The investigators' group also compared bladder recurrence
rates in patients who received intraoperative or postoperative pIVC. In this cohort, 12-
and 24-month recurrence rates in the I-pIVC groups were 10.8% and 14.4%, respectively,
with a favorable safety profile. Current practice at this institution, which is widely
employed at many centers but is not supported by Level I evidence, is to instill
gemcitabine into the bladder intraoperatively and to allow it to dwell within the bladder
until excision of the ureter, at which time the gemcitabine is drained prior to entry
into the bladder.
Despite its demonstrated benefits, there appears to be considerable underutilization of
pIVC for various reasons. Based on a national survey in the United States, less than 50%
of urologic oncologists use pIVC, mainly due to concerns including lack of evidence, fear
of extravasation and office infrastructure. While educational measures should be taken to
increase urologists' awareness of the importance and high level evidence supporting the
use of pIVC, other concerns, such as extravasation and logistical issues (which may
include office infrastructure, availability of chemotherapeutic agents outside of a
hospital setting, availability of trained personnel, etc.).
A possible alternative to pIVC that would circumvent logistical, availability-, and
toxicity-based concerns is the use of intravesical continuous bladder irrigation (CBI)
with sterile water. In this method, a multi-way urinary catheter is placed in the bladder
which allows water to be irrigated into the bladder while simultaneously and freely
draining out via a separate lumen, allowing the bladder to be continuously irrigated with
sterile fluid. In this setting, irrigation would be initiated at the start of the
surgical procedure and would be terminated and the bladder drained immediately prior to
entry into the bladder at the time of excision of the distal ureter. There have been
several studies that have demonstrated the ability of hypotonic fluid (e.g., sterile
water) to kill bladder tumor cells. Distilled water irrigation has shown to delay tumor
recurrence of bladder cancer by osmolysis of tumor cells. A prospective, randomized,
open-label, two-arm, single-center, pilot study compared continuous sterile water
irrigation to a single dose intravesical of mitomycin C after transurethral resection of
bladder tumors (TURBT) and found recurrence-free rates for MMC and continuous sterile
water irrigation groups were 47.1% and 52.6%, respectively. Another study investigated
the results of bladder irrigation with water for injection after TURBT. A total of 239
patients (158 with single tumors, group A, and 81 with multiple tumors, group B) received
continuous intravesical postoperative irrigation with water. Recurrence-free rate for
those patients who received only intravesical irrigation with water was 75.8%, 66.2% and
63.2% at the 1st, 2nd and 3rd year of follow up, respectively. A systemic review of the
literature evaluated bladder irrigation after TURBT. There were 6 studies, including 1515
patients of which 361 had saline irrigation and 463 had sterile water. There was no
significant difference between IVT chemotherapy, saline and sterile water groups
regarding to the median RFS at 1 year [IVT: 81%, IQR (77.70, -81.00), sterile water: 74%,
IQR (63.3-74.9), saline: 76.7% IQR (76.0, 77.7), p = 0.21]. Adverse events were more
frequent amongst patients in the IVT chemotherapy group in comparison to the saline or
water groups.
In this study, it is hypothesized that intraoperative continuous bladder irrigation with
sterile water is noninferior to intravesical instillation of gemcitabine. If the two
regimens are substantially equivalent, irrigation with water would be considered a
superior option due to greater simplicity, wider availability, and reduced risk of toxic
exposure to the patient and operating room staff.