Download Management of muscle‐invasive bladder cancer

BLADDER CANCER
7
Management of muscle-invasive
bladder cancer
ANDREW MOON, HANS VAN DER VOET AND JO CRESSWELL
Cancer that has invaded the detrusor muscle can be
associated with a high degree of morbidity and mortality.
Radical treatments are required, including cystectomy,
radiotherapy and chemotherapy. These treatments can
cause short-term and long-term consequences for patients.
In this article the authors describe the current treatment
approaches to muscle-invasive bladder cancer.
© Steve Gschmeissner/Science Photo Library
B
ladder cancer can be clinically classified
by stage as either non-muscle invasive
(NMIBC) or muscle invasive (MIBC) based
on the involvement of the detrusor
muscle (Figure 1). Approximately 20% of
bladder tumours are muscle invasive at
presentation, requiring radical treatment.
Tumour grade is also a well-established
predictor of disease progression and
bladder cancer specific mortality.1,2
High-grade bladder tumours present
a significant risk in terms of disease
recurrence, local invasion and metastasis,
and are responsible for the high degree
of morbidity and mortality associated
with bladder cancer.3 High-risk NMIBC
can progress to MIBC, and the prognosis
is thought to be poorer for progressive
disease compared to primary MIBC.4
In the UK, the majority of bladder cancers
are transitional cell carcinomas, but there are
variants, such as squamous cell carcinoma,
adenocarcinoma and small cell cancer, which
require different treatment strategies.5
TREATING MUSCLE INVASIVE
BLADDER CANCER
NICE has recently published guidelines
for the management of bladder cancer.6
TRENDS IN UROLOGY & MEN’S HEALTH
The patient should be reviewed in clinic
following discussion and review of
histology and staging radiology results
at the uro-oncology MDT. A thorough
assessment of the patient’s cardiac and
respiratory function and exercise tolerance
NOVEMBER/DECEMBER 2015
Andrew Moon, Urology Specialist
Registrar; Hans Van der Voet, Consultant
Oncologist; Jo Cresswell, Consultant
Urologist, James Cook University Hospital,
Middlesbrough
www.trendsinmenshealth.com
BLADDER CANCER
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should be made, and renal function (eGFR)
should also be assessed. These assessments
will help inform both the patient and
the clinical team about the risks posed
by major surgery and the potential for
chemotherapy.
Patients should be counselled by the
bladder cancer team (comprising the
urologist performing cystectomy, a clinical
oncologist and a nurse specialist) with
regard to their treatment options, which
include radical cystectomy (RC) with an
ileal conduit or neobladder formation, or
radical chemoradiotherapy (CRT). Both
treatment options may be preceded by
neoadjuvant chemotherapy (NAC), which
has shown a 5% improvement in survival
at 5 years.7 At the present time, there are
no randomised controlled trials comparing
the effectiveness of radical cystectomy
and CRT. The patient should have the
opportunity to discuss surgery and bladder
sparing options in detail, including the
risks of each procedure.
More advanced cases may be offered
palliative radiotherapy, which can ease
symptoms such as bleeding and pain.
Metastatic disease is managed with
systemic chemotherapy.
RADICAL CYSTECTOMY
RC has long been considered the standard
method of care for MIBC. It usually includes
the complete surgical removal of the
bladder and prostate in males and the
bladder, uterus and part of the vagina in
females. Pelvic lymphadenectomy is also
performed and may provide both diagnostic
and therapeutic benefit. Two randomised
clinical trials – the LEA study in Germany
and SWOG (South West Oncology Group)
BLOG
Read Rik Bryan and Nick James’
blog on ‘The appropriate
management of muscle-invasive
bladder cancer in the elderly’:
www.trendsinmenshealth.com/blog
www.trendsinmenshealth.com
Ureters
0is or CIS
Fat
0a
Stage 1
Muscle
Stage 2
Connective tissue
Stage 3
Bladder lining
(urothelium)
Stage 4
Figure 1. Bladder cancer staging is based on the degree of invasion through the detrusor
muscle wall (reproduced with permission from Macmillan Cancer Support)
1011 study in the USA – are evaluating the
extent of lymph node dissection required
and the impact on cancer control.
RC is associated with significant morbidity
and mortality. However, improvements
in technique and perioperative care have
reduced the 90-day mortality rate to
2.1% of patients.8,9 Overall complication
rates, when collected meticulously and
prospectively, are approximately 60%.10
The procedure carries a significant risk of
bleeding requiring blood transfusion.10
In addition, infection in the surgical
wound, chest or pelvis can occur. Other
complications, including small bowel
anastomotic leak, uretero-ileal anastomotic
leakage, rectal injury, deep vein thrombosis,
pulmonary embolism, stroke, myocardial
infarction, and disease recurrence, must all
be discussed with the patient.
Recent trials with laparoscopic and
robotic RC have also been described. These
techniques appear to have similar morbidities,
oncological and functional outcomes as open
approaches.9,10 Blood loss and transfusion
rates are lower with minimally invasive
surgery, but operative times may be longer
than for open surgery. The experience of the
operator is an important factor, as with all
surgical procedures.
Figueroa et al demonstrated that elderly
patients (>70 years) with few comorbidities
recovered following RC with clinical and
functional results similar to younger
patients.11 Contemporary surgical series
(without NAC) have shown 5-year overall,
recurrence-free and cancer-specific
survival rates of 57.9%, 69.5% and
71.2%, respectively.12
URINARY DIVERSION
Following removal of the bladder during
RC, an ileal conduit or neobladder
reconstruction is formed. Ileal conduit is the
most commonly used method of urinary
diversion in the UK (80%) and involves
anastomosing the ureters to an isolated
piece of distal ileum.13 The distal end is then
mobilised and brought out as stoma on the
right side of the abdomen (Figure 2).
Patients who require an ileal conduit
need to be aware of the associated
TRENDS IN UROLOGY & MEN’S HEALTH
NOVEMBER/DECEMBER 2015
BLADDER CANCER
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Kidney
Ureter
Early
Late
Metabolic
Ileus
Stomal stenosis
Hyperchloraemic metabolic
acidosis
Bowel obstruction
Para-stomal hernia
Macrocytic anaemia
Anastomotic leakage
Uretero-ileal stenosis
Ischaemia of conduit
Skin excoriation
Table 1. Potential complications following ileal conduit formation
Stoma
Figure 2. Ileal conduit formation is the most
commonly used method of urinary diversion
in the UK, and involves anastomosing the
ureters to an isolated piece of distal ileum,
which is then mobilised and brought out as
stoma on the abdomen (reproduced with
permission from Macmillan Cancer Support)
complications (Table 1), which are
relatively frequent in the longer term
(over 15 years’ follow-up) with ureteric
obstruction reported in 14%, stoma
problems in 24%, bowel problems in 24%,
UTIs in 20% and metabolic derangement
(severe metabolic acidosis) in 1%. Renal
insufficiency developed in 27%, although
in this elderly, comorbid population it is
difficult to determine how much of this is
attributable to the diversion.14
Metabolic complications are less common
with an ileal conduit than a neobladder,
as the conduit does not act as a storage
reservoir for urine. The absorption of acid
and chloride can result in the development
of a hyperchloraemic metabolic acidosis.
Although this can occur with an ileal
conduit, it is more common in neobladders
and can be managed with sodium
bicarbonate, 1g once daily. The loss of
the terminal ileum can result in the
malabsorption of vitamin B12 and iron,
which may cause macrocytic anaemia
and neurological symptoms, although
this is rare.
The most common neobladder procedure
performed in the UK is Studer pouch
TRENDS IN UROLOGY & MEN’S HEALTH
reconstruction (Figure 3). This involves
using a section of small bowel between
45–60cm long, which is detubularised
and reconstructed into a globular shape,
forming a new reservoir that replaces the
existing bladder. The ureters are implanted
into this new reservoir, which is then
anastomosed on to the urethra, utilising the
patient’s pelvic floor sphincter mechanisms
to provide a continent reservoir.
For younger patients, neobladder formation
is increasingly offered to patients at the
time of RC. It has the advantage of not
requiring a stoma and 90% of patients are
continent by day and 70–80% by night.
The disadvantages are that it requires a
larger segment of small bowel than an ileal
conduit (60cm in the Studer neobladder
versus 15cm for an ileal conduit). As such,
the rate of metabolic complications is
proportionately higher. In more recent
studies, intermittent self-catheterisation
is required in a minority of patients (10%),
with higher rates observed in women.15
For any radical cystectomy procedure,
patients also need to be aware of the risks
of impotence, incontinence or urinary
retention, and female patients aware of the
risk of vaginal shortening.
Zippe et al found that fewer than
50% of female patients were able to
have successful vaginal intercourse
postoperatively and most female patients
described reduced satisfaction with their
sexual lives following surgery.16 In males,
RC can be performed with nerve sparing
techniques during the prostatic dissection
to preserve sexual function. In females
NOVEMBER/DECEMBER 2015
the procedure can be performed with
preservation of the vagina.
CHEMOTHERAPY
RC achieves excellent local control; however,
many patients will present with clinically
advanced and likely micro-metastatic
disease. As a result, there is a role for NAC
prior to patients undergoing RC. There is an
associated morbidity with NAC which can
result in a delay before definitive surgical
treatment can be performed, although
accelerated chemotherapy regimes have
been developed to shorten the time to
definitive treatment.
Kidney
Ureter
New bladder
Urethra
Figure 3. Neobladder formation involves
using a section of small bowel reconstructed
into a globular shape, forming a new
reservoir that replaces the existing bladder.
The ureters are implanted into this new
reservoir, which is then anastomosed on to
the urethra, utilising the patient’s pelvic floor
sphincter mechanisms to provide a continent
reservoir (reproduced with permission from
Macmillan Cancer Support)
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BLADDER CANCER
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NAC (prior to RC) is predominantly used
in patients with operable muscle-invasive
tumours, with the purpose of treating
micro-metastatic disease already present
at the time of diagnosis.
The administration of NAC may be
preferable to postoperative treatment
as tumour downstaging through
chemotherapy may enhance resectability,
metastatic disease may be treated as early
as possible, and chemotherapy may be
better tolerated than in the adjuvant setting.
Adjuvant chemotherapy is used mostly to
prevent recurrence in patients with either
advanced disease or where there is regional
lymph node involvement.
Currently, the body of evidence supporting
preoperative chemotherapy is much
stronger than the evidence supporting
postoperative chemotherapy.7 As such,
preoperative cisplatin-based combination
chemotherapy followed by RC represents
a standard therapeutic option for patients
with MIBC who are fit for chemotherapy.
EXTERNAL-BEAM RADIATION
THERAPY (EBRT)
Radiotherapy involves the use of ionising
radiation to cause fatal damage to
neoplastic cells. A typical course of radical
radiotherapy takes either 4 or 6.5 weeks.
Radiation therapy as a single curative
modality for MIBC has inferior local control
rates compared to radical cystectomy, with
5-year survival between 30-60% depending
on the stage.17,18 Radiotherapy outcomes can
be improved with concurrent chemotherapy
or with combined carbogen and nicotinamide
administration.6 When combined with
chemotherapy, although local relapse rates
can be reduced, there is no benefit in terms
of survival, mortality or quality of life.
Smith et al identified no survival advantage
following the addition of preoperative
radiation therapy to RC when compared to
RC alone in a prospective randomised trial.19
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Early
Late
Bladder
Dysuria, frequency, urgency, radiation
induced cystitis, incontinence
Haematuria, reduced bladder
volume
Bowel
Diarrhoea, cramps, radiation enteritis/
proctitis, incontinence
Chronic enteritis
General
Fatigue, skin inflammation
Subcutaneous fibrosis, sexual
dysfunction
Vaginal
Irritation, bleeding, discharge, pain
Shrinkage, adhesions
Table 2. Early and late side-effects with external beam radiotherapy
The best results with EBRT are seen in
patients with solitary bladder lesions and
without carcinoma in situ or evidence of
upper tract obstruction.
EBRT is associated with side-effects.
Up to half of patients will complain of
lower urinary tract symptoms, including
dysuria and urinary frequency, during
EBRT treatment. This tends to be resolved
several weeks after treatment. In addition,
15% of patients report bowel side-effects
secondary to EBRT.
Radiotherapy can cause early side-effects
that come on during the course, but can
settle after 4 to 6 weeks, or late and often
lasting adverse effects (Table 2).
Although the 5-year survival rates are
better with RC, this may be because
patients with significant comorbidities are
more likely to be given radical radiotherapy,
whereas patients who are stronger and
have better general health are put forward
for surgery. A staging effect may be
another possible factor, as staging is more
accurate following surgery. Management
following either RC or EBRT according to
NICE guidance is given in Table 3.
CONCLUSION
Treatment for MIBC is associated with
significant morbidity. Patients need to be
counselled extensively prior to commencing
treatment, and healthcare professionals
need to be aware of the long-term sequelae.
Following radical cystectomy
Following radical radiotherapy
Monitor upper tracts annually for
hydronephrosis, stones, cancer
Rigid cystoscopy 3 months after
completion of radiotherapy
Monitor eGFR annually
Then cystoscopy every 3 months for first
2 years
CT chest/abdomen/pelvis to assess for
local and distant recurrence at 6, 12 and
24 months post-cystectomy
Then cystoscopy every 6 months for the
next 2 years
Then annual cystoscopy thereafter
Monitor annually for metabolic acidosis,
vitamin B12 and folate deficiency
Upper tract imaging annually for 5 years
Male patients: urethral washings and
annual urethroscopy for 5 years
CT chest/abdomen/pelvis to assess for
local and distant recurrence at 6, 12 and
24 months post radiotherapy
Table 3. Follow-up after treatment for muscle-invasive bladder cancer according to
NICE guidance6
TRENDS IN UROLOGY & MEN’S HEALTH
NOVEMBER/DECEMBER 2015
BLADDER CANCER
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Declaration of interests
Jo Cresswell has received an honorarium
from Prostrakan as an invited speaker
and from Abbott as a member of an
advisory panel.
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