Keywords
nonmuscle-invasive bladder cancer - recurrence - transurethral resection of bladder
tumor
Introduction
Transurethral resection followed by intravesical Bacillus Calmette-Guerin (BCG) therapy has been the standard of care for T1 bladder tumors.
Historically, a single transurethral resection was performed followed by intravesical
BCG therapy.[1] The residue left behind during the transurethral resection of bladder tumor (TURBT)
was meant to be taken care by intravesical immunotherapy. Later, it was observed that
the disease recurrence was very early in some set of patients (within 3 months). The
reason behind the early recurrences was found out to be the status of residual tumor
that was left behind after the TURBT.[2] Patients with significant residual tumor following TURBT had early recurrence. In
fact, those were actually due to persistence of the disease rather than a true recurrence.
Hence, not having a residual disease was considered a prognostic factor for disease-free
survival, thus evolved the need for improving the quality of initial TURBT and measures
to assess its completeness. We conducted a study to analyze the impact of repeat TURBT
(ReTURBT) in detecting residual disease and in restaging the disease following complete
TURBT. We also evaluated the benefit of performing the procedure as a routine in a
developing country scenario, considering its morbidity.
Materials and Methods
It was a combined retrospective and prospective study that included a total of 152
patients with superficial bladder cancer who were treated at Cancer Institute (WIA)
from January 2005 to December 2013. It included all patients with newly detected cancer
and those diagnosed at an outside facility who may have undergone TURBT elsewhere.
Patients treated at an outside facility for superficial bladder cancer and presenting
to the institute with recurrence were also included.
All newly diagnosed patients were evaluated by computed tomography (CT) of the abdomen
and pelvis with urographic reconstruction along with urine cytology from three consecutive
early morning samples. Patients who had undergone TURBT elsewhere and presented to
the institute for further management were evaluated by reviewing the upfront imaging.
The TURBT operation notes were reviewed, and completeness of the resection was ensured.
Cystoscopy was performed in all the patients presenting after undergoing TURBT at
an outside facility to ensure that no gross residue was left behind. If there was
an obvious residue, then a second-staged TURBT was performed.
TURBT was performed under spinal or general anesthesia. After adequately distending
the bladder with saline, the bladder was completely visualized. Resectoscope fitted
with 30-degree lens was then introduced, and resection was performed piecemeal using
a loop with the aid of cutting current.
Ultrasound of the abdomen and pelvis was performed before ReTURBT. As in the TURBT,
the entire bladder was visualized and thoroughly checked for any residue and resected
appropriately. If no residue is found, then the tumor bed was reresected, and the
resection was performed especially at the margins of the previous resected sites also.
In our institute, only the carefully selected patients who had low-grade solitary
lesion that had been completely resected in initial TURBT and no residual tumor/CIS
was found in the ReTURBT specimen were not offered intravesical BCG therapy. ReTURBTwas
performed for all nonmuscle-invasive bladder cancers including Ta histology.
Intravesical BCG is administered to T1 bladder tumors, commencing 3 to 4 weeks following
ReTURBT. The treatment schedule followed at our institute was administration of intravesical
BCG once a week for 6 weeks followed by maintenance dose of once a month administration
for 6 months. A check cystoscopy was performed once after completing the weekly regimen
and again after completing the maintenance therapy.
Follow-Up
The follow-up protocol for nonmuscle-invasive bladder tumors included a 3 monthly
follow-up for the first 3 years and then every 6 monthly for the next 2 years. Follow-up
was annual after the completion of 5 years. Every follow-up visit included clinical
history and physical examination and urine cytology and flexible cystoscopy under
local anesthesia. Annual investigations included chest X-ray and ultrasound of the
abdomen and pelvis apart from the routine follow-up investigations.
The study protocol was approved by the local Institution Review Board at the authors’
affiliated institution and meets the standards of the Declaration of Helsinki.
Statistical Analysis
All data were analyzed using SPSS statistics software Version 15 (SPSS Inc., Chicago,
Illinois, United States). Chi-square test and binary logistic model analysis were
also used. Statistical significance was at p < 0.01.
Results
Initial TURBT was performed in our institute in 88 (57.9%) out of 152 cases, and 64
(42.1%) patients had undergone TURBT elsewhere and presented to our institute for
further management.
The mean age at diagnosis was 57.7 years. The most elderly patient was 80 years old,
and the youngest was 27 years old. Males were predominant in the group, occupying
86.1% (131 patients) of the total and females comprising only approximately 13.9%
(21 cases). The mean age of presentation was almost similar among both sexes: 60 years
among females and 57.4 years among the males.
Out of 152 patients, 83 (54.6%) had unifocal disease and the remaining 69 (45.4%)
patients had multifocal disease. Complete resection of visible tumor was performed
in 145 (95.4%) of 152 patients. Seven (4.6%) cases who had large volume tumor had
incomplete resection and underwent a second-stage TURBT before ReTURBT. Of 152 patients,
Ta histology was seen in 14 (9.3%) cases. These patients with Ta histology were also
included because they all got reassigned to a higher T status in ReTURBT. T1 histology
without deep muscle identification was seen in 74 cases (48.6%) and T1 with deep muscle
identification was seen in 64 cases (42.1%).
Of 152 patients, 7 (5%) had low-grade/grade 1 tumors, 110 (71%) had intermediate/grade
2 tumors, and 35 (24%) patients had high-grade/grade 3 tumors.
Deep muscle was identified in 71 (46.7%) of 152 patients and was absent in the resected
specimen in 81 (53.3%) patients. In the subgroup of patients who underwent TURBT at
an outside facility, only 17% had deep muscle identified in the TURBT specimen, whereas
68% of patients had deep muscle identified in the TURBT performed in our institute.
Out of 152 patients, 100 (65%) underwent ReTURBT within 6 weeks of initial surgery
and 52 (34.2%) patients underwent ReTURBT after 6 weeks. There was considerable delay
in the patients who had undergone TURBT elsewhere due to delay in presenting to our
institute and in completing the evaluations.
Of the 152 cases who underwent ReTURBT, 47 (31%) patients had residue in the final
histopathology of the resected specimen. Of the 47 cases with histologically positive
residue in ReTURBT, 42 (89.4%) patients had pT1 tumors. The rest of the five (10.6%)
patients had pT2 tumor and underwent radical surgeries.
Deep muscle was identified in 144 (96%) out of 152 cases who underwent ReTURBT. Of
that, five (3.3%) patients had involvement of the deep muscle by the tumor.
Eleven patients got assigned to a higher grade by ReTURBT, thereby leaving 7.2% of
upgrading by ReTURBT. Ten of the 14 Ta tumors got restaged to T1, 1 of the Ta tumors
got restaged to T2 (7.1%), and 3 of 64 T1 tumors were upstaged to T2 tumor following
ReTURBT (4.7%). The overall rate of upstaging to muscle-invasive disease following
ReTURBT was 3.3%.
Of the 152 patients, 147 patients were followed up for a median follow-up of 47.13
months, of which 25 (17%) who underwent ReTURBT had disease recurrence. Also, 17 out
of 69 cases of multifocal tumor developed recurrence (24.6%), whereas only 8 out of
83 patients with upfront unifocal tumor developed recurrence (9.6%) (p = 0.013). The timing of ReTURBT, presence of residue at ReTURBT, and administration
of BCG had no significant impact on recurrence rate.
The 3-year disease-free survival following ReTURBT was 73.7%, with 56% of the recurrences
occurring within the first year.
Discussion
Accurate histological staging is essential for the management for bladder cancers.
Following TURBT, deep muscle could not be identified in 81 (53.3%) patients, and accurate
T status could not be exactly ascertained in 74 (48.6%). Deep muscle was identified
in 144 (96%) out of 152 cases who underwent ReTURBT. Of those, five (3.3%) patients
had involvement of the deep muscle by the tumor. As emphasized by Zurkirchen et al,
resecting deep muscle is a technique of expertise and directly correlates with the
learning curve.[3] Rate of identifying deep muscle is higher in our study compared with the other study
because all the ReTURBT was performed by experienced surgeons.
In our study, ReTURBT upstaged 5 out of 137 patients; 3% of the patients got upstaged
from T1 to T2 stage as compared with 24 to 32% conversion rate in other studies. Similarly,
7% got upstaged from Ta to T2 compared with 5.5 to 14%, as found in other studies.[4]
[5] Reason for low percentage of upstaging in our study may be that other studies did
not have “complete” gross tumor resection as criteria in initial TURBT. The concept
of leaving behind some residue for the intravesical therapy to take care was prevalent
in the 1990s. It is, in fact, after these studies that the importance of complete
resection in the disease recurrence and progression was understood, and the quality
control for TURBT began to be emphasized and followed in various centers across the
world.
ReTURBT has significant influence on tumor recurrence. Sfakianos et al retrospectively
analyzed 894 patients who were treated in the same method as followed by our study
and reported a recurrence rate of 57.5% over 5 years.[6] They concluded that the recurrence rate following single TURBT is almost twofold
at 5 years when compared with those who had undergone ReTURBT, and the greatest difference
in the recurrence rate (4.5-fold) was during the initial 3 months, which is mainly
due to tumor persistence. This surge can be excluded by performing a ReTURBT. In our
study, in 152 patients who underwent ReTURBT, 16.4% had recurrence over a median follow-up
of 47 months.
Patients having multifocal disease at the entry level had higher rates of residual
tumor and higher rates of tumor recurrence following ReTURBT and intravesical therapy.
Brausi et al, in their combined analysis for seven EORTC studies, inferred similar
results with single TURBT and intravesical therapy. They have observed an 18.9% recurrence
rate for multifocal tumors following single TURBT and intravesical therapy and 5%
recurrence rate for unifocal tumors. However, they calculated the recurrence of the
tumor when detected at the first follow-up by cystoscopy, thereby emphasizing that
despite intravesical therapy, multifocal disease tends to recur and thereby a ReTURBT
becomes mandatory.[7]
Similarly, tumor grade was also found to be an important predictor of recurrence;
25.7% of high-grade tumors had recurrence, whereas only 13.6% of low-grade tumor had
recurrence. Divrik et al directly correlated the presence of residual disease with
tumor grade. In their study, residual cancer was detected in 62% of high-risk tumors.[8]
Other parameters, namely administration of BCG or presence of residue in ReTURBT,
did not reveal any statistical significance in the recurrence pattern.
Effect of timing of ReTURBT on picking up residual disease was studied. It was 16%
as compared with 17.2% for patients in which ReTURBT got delayed by <6 weeks. Exact
timing of ReTURBT is still not standardized. Klän et al did not observe any advantage
in delaying the ReTURBT by <14 days. Most authors quote 4 to 8 weeks as the standard
time interval following initial TURBT for performing ReTURBT.[9]
ReTURBT is relatively a safe procedure carrying less operative time and comparable
morbidity rate as that of TURBT. [Table 1] depicts a comparison between the two procedures. Duration of the procedure is less
compared with TURBT, which is statistically significant: 115.2 minutes versus 64 minutes
(p = 0.015). The duration of postoperative bladder irrigation (2 vs. 1.2 days), duration
of retaining Foley’s catheter (2.9 vs. 1.6 days), and duration of hospital stay (3.2
vs. 2.1 days) were all shorter for ReTURBT compared with initial TURBT. Hence, it
is a safe procedure to perform as a routine.
Table 1
Comparison of transurethral resection of bladder tumor with repeat transurethral resection
of bladder tumor
|
TURBT
|
ReTURBT
|
|
Abbreviations: ReTURBT, repeat transurethral resection of bladder tumor; TURBT, transurethral
resection of bladder tumor.
|
|
Mean duration of surgery (minutes)
|
115
|
64
|
|
Mean duration of hospital stay (days)
|
3.2
|
2.1
|
|
Mean duration of bladder irrigation (days)
|
2
|
1.2
|
|
Mean duration of retaining catheter (days)
|
2.9
|
1.6
|
|
Major complications
|
1
|
2
|
|
Minor complications
|
7
|
3
|
The study is limited by its retrospective–prospective nature, which restricts the
analysis. Furthermore, at our institute, we perform ReTURBT for Ta histology as we
believe that any upstaging/ upgrading will significantly affect management, especially
when a considerable number of TURBT are referred from other centers.
Conclusion
The study reaffirms that in Tl bladder cancers, ReTURBT comprehensively confirms the
completeness of initial resection, treats the residual tumor effectively, and picks
up the missed muscle-invasive tumors that need radical treatment. Tumor characteristics
such as multifocality and high grade were associated with higher recurrences. The
complications in ReTURBT are not significantly high compared with TURBT. The procedure
when performed with utmost care in experienced hands in selected patients remains
a very safe procedure to be followed as a routine and standard even in developing
countries.
