Title page:
Recent advances in the diagnosis and treatment of bladder cancer
G Cheung, A Sahai, M Billia, P Dasgupta & MS Khan
Grace Cheung titles BSc MBChB MRCS dr.grace.cheung@gmail.com
Urology Centre, Guy’s Hospital, Guy’s and St Thomas’ NHS Trust, London, SE1 9RT, UK
Arun Sahai PhD, FRCS (Urol), BSc (Hons.) arun.sahai@gstt.nhs.uk
Urology Centre, Guy’s Hospital, Guy’s and St Thomas’ NHS Trust, London, SE1 9RT, UK
Michele Billia MD michele.billia@gstt.nhs.uk
Urology Centre, Guy’s Hospital, Guy’s and St Thomas’ NHS Trust, London, SE1 9RT, UK
Prokar Dasgupta MSc (Urol), MD, DLS, FRCS (Urol), FEBU prokarurol@gmail.com
Medical Research Council (MRC) Centre for Transplantation, King's College London, King’s Health Partners,
Guy’s Hospital, London, SE1 9RT, UK
Muhammad Shamim Khan* FRCS (Urol), FEBU Shamim.khan@gstt.nhs.uk
Urology Centre, Guy’s Hospital, Guy’s and St Thomas’ NHS Trust, London, SE1 9RT, UK
*Corresponding author
1
Table of contents:
Abstract
Review
Introduction
Diagnosis
Cystoscopy
Photodynamic diagnosis (PDD) / Blue-light cystoscopy (BLC)
Narrow band imaging (NBI)
Urinary markers
Non-muscle invasive bladder cancer
Bacillus Calmette-Guérin (BCG) immunotherapy / Electromotive drug administration of mitomycinC (EMDA-MMC)
Hyperthermic MMC (MMC-HT)
Intravesical gemcitabine
Muscle-invasive bladder cancer
Minimally-invasive techniques in radical cystectomy
Bladder preservation
Conclusions
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Abstract:
Cystoscopy and urine cytology are the most important tools in the diagnosis of bladder cancer. Various
alternatives have been investigated, either to reduce the frequency of cystoscopy, or improve its sensitivity
for detection of tumours. Novel techniques in diagnosis and surveillance include urine-based markers and
point-of-care tests. However, for the time being they are to be used in conjunction with, and not in
replacement of, current standard procedures. Narrow-band imaging and photodynamic diagnosis (PDD)/
blue-light cystoscopy (BLC) have shown promise in improving detection and trans-urethral resection of
bladder tumours. The majority of patients with a new diagnosis of bladder cancer have non-muscle-invasive
bladder cancer (NMIBC), which requires adjuvant intravesical chemotherapy and/ or immunotherapy.
These patients undergo regular cystoscopic surveillance, which is often life-long. For patients with muscleinvasive bladder cancer (MIBC), laparoscopic radical cystectomy (LRC) and robot-assisted radical
cystectomy (RARC) have been shown to reduce peri-operative morbidity, while oncologically equivalent to
open radical cystectomy (ORC) in the medium-term. Bladder-preserving strategies entail chemo-radiation
and in highly selected patients give equivalent results to surgery.
Keywords:
bladder cancer, narrow band imaging, photodynamic diagnosis cystoscopy, urinary markers, radical
cystectomy
Review
Introduction
Bladder cancer is the commonest malignancy of the urinary tract. Although cystoscopy remains a
fundamental investigation in the detection and surveillance of bladder cancer, small papillary tumours or
carcinoma in situ (CIS) can be easily missed by standard white-light cystoscopy (WLC), which may account
for early recurrences [1]. Approximately 75% of patients will have disease confined to the mucosa (Ta) or
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submucosa (T1) i.e. non-muscle invasive bladder cancer (NMIBC), which has a high risk of recurrence. CIS is
a high-risk disease for muscle-invasion. CIS that is refractory to bacillus Calmette-Guérin (BCG)
immunotherapy, or muscle-invasive bladder cancer (MIBC) (>T2) should be managed with radical
cystectomy. In this article, we summarise recent and evolving advances in the diagnosis and treatment of
bladder cancer.
Diagnosis
Cystoscopy
Photodynamic Diagnosis (PDD)/ Blue light Cystoscopy (BLC)
Photodynamic diagnosis (PDD) improves the ability to detect inconspicuous bladder cancer. 5aminolevulinic acid (5-ALA) dye, or its hexyl ester hexaminolevulinate (Hexvix®) (HAL), is instilled into the
bladder and absorbed by dysplastic tissue, enabling photosensitization. The abnormal tissue emits a red
colour under blue reference light. Normal tissue appears blue (figure 1). PDD is recommended to aid
diagnosis at initial TURBT, in patients with positive urine cytology but negative WLC for the assessment of
tumour recurrences in patients not previously assessed with HAL, in the initial follow-up of patients with
CIS or multifocal tumours [2].A meta-analysis has shown that the sensitivity of BLC for detecting CIS using 5ALA or HAL was 92.4%, while that of WLC was 60.5% [3].
One and 2 year recurrence rates are significantly decreased in patients undergoing BLC compared with WLC
[4]. However, a multi-centre, randomised, double-blind, placebo-controlled trial [5] failed to show that BLC
led to improved outcomes. Although more tumours per patient were detected in the BLC group, the higher
detection rate did not translate into differences in long-term outcome.
Narrow-band imaging
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Narrow-band imaging (NBI) cystoscopy enhances the fine structure of the bladder mucosal surface without
the use of dyes. Longer wavelengths of light enable deeper penetration. NBI cystoscopy improves detection
of recurrent NMIBC over standard WLC, with a comparative false-positive rate [6]. TURBT performed in the
NBI modality reduces the recurrence risk of NMIBC by at least 10% at 1 yr [7].
Urinary markers
The most widely adopted non-invasive urine test is cytology, which has good specificity and sensitivity for
the detection of high-grade tumours, but poor sensitivity for low-grade tumours [8], and has a delay in
result availability. Numerous urinary markers have been investigated (Table 1) [9]. We discuss two of the
most promising.
Fluorescence in situ hybridization (FISH) assay using UroVysion® detects aneuploidy in chromosomes 3, 7,
and 17 as well as loss of the 9p21 locus of the P16 tumour suppressor gene [10]. In most comparative
studies, FISH outperformed cytology across all stages and grades of bladder cancer [11,12,13]. FISH results can
identify patients at risk for tumour recurrence and progression during BCG immunotherapy [14]. This
information may be used to counsel patients about alternative treatment strategies.
Nuclear mitotic apparatus protein 22 (NMP22) is another marker that can be detected in voided urine.
NMP22® Bladderchek® is a point-of-care test approved by the USA Food and Drug Administration for
bladder cancer surveillance. In patients with both negative cystoscopy and NMP22® Bladderchek®, very
few cancers are missed, and cytology is ineffective in detection [15]. However, for clinicians who have a low
threshold for performing a cystoscopy to detect recurrence or progression in patients, NMP22 did not aid
clinical decision-making [16].
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Treatment
Non-muscle invasive bladder cancer
Transurethral resection of bladder tumours (TURBT) is the first-line treatment in patients with NMIBC.
Unfortunately, the high rate of recurrence and progression after TURBT necessitates the use of adjuvant
treatments [17,18,19]. This entails instillation of chemotherapeutic, usually mitomycin-C (MMC), or
immunotherapapeutic agents such as BCG, either alone or in various combinations. A single dose of
intravesical chemotherapy given the same day post-TURBT significantly reduces tumour recurrence [20],
although it is significantly underutilized [21]. Intravesical BCG is the standard treatment for high-grade
NMIBC, particularly CIS, and should be given in a maintenance schedule [22]. Unfortunately, some patients
are unable to tolerate the side-effects of urgency and frequency and/ or are refractory to treatment.
BCG/ Electromotive drug administration (EMDA®) Mitomycin C
To reduce BCG toxicity, some groups suggest reduced dose instillations of BCG. One-third dose has similar
efficacy to full-dose BCG but with significantly less toxicity. However, full-dose BCG is more effective in
multifocal tumours [23,24]. Di Stasi et al have demonstrated that intravesical, sequential BCG and
electromotive administration of mitomycin C – EMDA-MMC – for patients with high-risk superficial bladder
leads to higher disease-free interval, lower recurrence and progression, and to improved overall survival
and disease-specific survival compared with BCG alone [25]. More recently, the same group showed that
intravesical EMDA-MMC before TURBT is feasible and safe. Importantly, it reduced recurrence rates and
enhanced the disease-free interval compared with intravesical passive diffusion of MMC after TURBT, and
TURBT alone [26].
Hyperthermic MMC
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A combined regimen of intravesical MMC and microwave-induced bladder wall hyperthermia (HT) for Ta/
T1 bladder cancer was first introduced in 1995 [27]. A small randomised controlled trial (RCT) comparing
MMC-HT vs. MMC alone has since shown a significantly improved disease-free survival rate at 10 years [28].
A systematic review suggests a 59% relative reduction in NMIBC recurrence when MMC-HT is administered,
compared with MMC alone [29]. In the future, MMC-HT may become standard therapy for high-risk patients
with recurrent tumours, for patients who are unsuitable for radical cystectomy, and in cases for which BCG
treatment is contraindicated.
Intravesical gemcitabine
Administration of intravesical gemcitabine is being explored. A Cochrane review of the current evidence
base of randomised trials is limited but promising, and it may be suitable for high-risk BCG-refractory
patients. Multiple doses would be required, rather than a single shot after surgery [30].
Muscle-invasive bladder cancer
Minimally-invasive techniques in radical cystectomy
Open radical cystectomy (ORC) is the current gold-standard treatment for MIBC, or high-risk, recurrent
NMIBC. Ideally, all patients with MIBC should receive platinum-based neo-adjuvant chemotherapy [31].
ORC has a perioperative complication rate of 25-62% [32].
Therefore, minimally invasive techniques in radical cystectomy have been explored. The majority of existing
data comprises cohort studies. The advantages of laparoscopic radical cystectomy (LRC) include decreased
blood loss, reduced postoperative pain, early return of bowel function and shorter hospital stay [33,34].
However, the data should be interpreted with caution, given the problem of selection bias in most series.
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Overall, current evidence suggests that LRC has good early oncologic outcomes with low morbidity in large
cohorts with up to 5 years follow-up [35]. Nevertheless, LRC is considered an advanced laparoscopic
procedure, because it has multiple difficult steps and fewer degrees of freedom.
In 2001 the da Vinci® robot (Intuitive Surgical Inc., CA, USA) was introduced as an innovative system for
minimally invasive surgery. View of the operative field is improved by binocular 3-D high definition
endoscopic vision. ‘Endowrists’ on the tip of each instrument can reproduce movements of the human
hand. An RCT by Nix et al has shown that robot-assisted radical cystectomy (RARC) allows for reduced
operative blood loss, time for return of bowel function and analgesic requirements compared with ORC,
with equivalent lymph node yields [36]. A group of motivated robotic surgeons have formed the
International Robotic Radical Cystectomy Consortium (IRCC). Their collaborative datasets have also
demonstrated comparable lymph node yields and positive surgical margin rates to ORC [37,38]. Short-term
outcomes of RARC are promising, with 70-90% overall survival (OS) rate in 2-3 years of follow-up [39,40,41].
Increasing experience has enabled intra-corporeal reconstruction of urinary diversion, whether this be ileal
conduit or orthotopic neobladder formation. Clearly, the learning curve is steep. Operative times are
longer, although patients have lower inpatient narcotic requirement and comparable short-term clinical
outcomes to extra-corporeal diversion [42,43,44,45].
Bladder preservation
Strategies for bladder preservation have been investigated in selected patients who decline surgery or are
not fit for surgery. A Phase III trial of chemotherapy (fluorouracil + mitomycin) combined with radiotherapy
was shown to improve 2-year disease-free survival, compared with radiotherapy alone; and also decreased
salvage cystectomy rate, with good long-term bladder function [46]. Long-term data from Massachusetts
General Hospital, USA has shown that combined multi-modal therapy in the form of concurrent cisplatinbased chemotherapy and radiotherapy after maximal TURBT achieves a complete response and preserves
the native bladder in >70% of patients, while offering long-term survival rates comparable to contemporary
8
cystectomy series [47]. However, a number of different protocols were used in their centre, and so the
optimal therapy regimen is still uncertain.
Conclusions
Although mortality from bladder cancer is improving, the challenge now is to reduce the morbidity
associated with NMIBC and reduce recurrence rates. BLC enhances detection of bladder tumours and may
prolong recurrence-free survival. As yet, no urinary markers exist that have substantial enough specificity or
sensitivity to replace regular cystoscopic surveillance of NMIBC. The initial outcomes from RARC appear
promising. However, there is a distinct lack of randomised-controlled trials to compare RARC with ORC.
There are several that are currently underway, including the randomised CORAL radical cystectomy trial
[48]; Open Vs Robotic-Assisted Radical Cystectomy: A Randomised Trial, University of Texas Health Science
Centre, USA [49]; and BOLERO, Cardiff University, UK [50]. The long-term outcomes of the first cohort of
patients who underwent RARC should be available in the next 1-2 years. Whilst the long-term benefits of
RARC are awaited, ORC remains the gold-standard treatment for MIBC. Patients at high risk for
complications from surgery may well benefit from bladder preservation with combined chemotherapy and
radiotherapy regimens.
List of abbreviations
NBI – narrow band imaging
BCG – bacillus Calmette-Guérin
MMC – mitomycin C
MMC-HT – hyperthermic mitomycin C
NMIBC – non-muscle-invasive bladder cancer
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MIBC – muscle-invasive bladder cancer
ORC – open radical cystectomy
LRC – laparoscopic radical cystectomy
RARC – robot-assisted radical cystectomy
Competing interests
Financial competing interests
Prokar Dasgupta acknowledges financial support from the Department of Health via the National Institute
for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS
Foundation Trust in partnership with King's College London and King’s College Hospital NHS Foundation
Trust.
Non-financial competing interests
None
Authors’ contributions
GC and MB wrote the initial version of the manuscript. AS conceived the outline of the manuscript,
reviewed the manuscript and made final changes. PD and MSK critically reviewed the manuscript. All
authors read and approved the final manuscript.
Authors’ information
GC is a research fellow in Urology at Guy’s Hospital. AS is an academic clinical lecturer and specialist trainee
in Urology at Guy’s Hospital. MB is a robotic fellow in Urology at Guy’s Hospital. PD is Professor of
Urological Innovation for the Medical Research Council (MRC) Centre for Transplantation, King's College
London, and a Consultant Urological Surgeon at Guy’s Hospital. MSK is a Reader and Consultant Urological
10
Surgeon at Guy’s Hospital.
Acknowledgements
The authors wish to acknowledge Kathryn Chatterton, Bladder Cancer Nurse Specialist, Guy’s Hospital, for
providing images of white light and blue light endoscopy.
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