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SECTION 5
Bladder cancer
Case 11 Non- muscle- invasive bladder cancer
Case 12 Muscle- invasive bladder cancer
Case 13 Progression of high- grade non- muscle- invasive bladder
cancer
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11
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CASE
Non- muscle- invasive
bladder cancer
Samantha Conroy
Expert commentary Aidan P. Noon
Case history
An 82- year- old gentleman was referred to the urology department for further investigations and management of an isolated episode of visible haematuria and dysuria; no
evidence of urinary tract infection had been identified.
His past medical history included aortic stenosis with mild left ventricular systolic
dysfunction, hypertension, atrial fibrillation (for which he was anticoagulated), and
type 2 diabetes mellitus. He was an ex- smoker (with a 50 pack- year history), but had
no occupational risk factors for bladder cancer (BC). He lived alone with once- daily
carers due to limited mobility from his heart failure.
His assessment included clinical history and examination, upper tract computed
tomography (CT) urogram, and flexible cystoscopy. He was haemodynamically stable
and passing clear urine, with prior blood testing confirming a haemoglobin level of 106
g/ L and a serum creatinine level of 128 μmol/ L.
Flexible cystoscopy identified a 2.5 cm papillary tumour on the posterior wall
of the bladder, which looked suspicious for high- grade disease. He did not have a
biopsy at the time of flexible cystoscopy due to his anticoagulation. The CT urogram
revealed no evidence of synchronous upper tract disease or ureteric obstruction.
Due to this gentleman’s performance status (Eastern Co- operative Oncology Group
performance status 3), frailty, and comorbidities, he underwent a full anaesthetic assessment prior to surgical resection and was deemed high risk for surgery. A multidisciplinary decision was made to proceed in the first instance with a flexible cystoscopy
and tissue biopsy (after managing his anticoagulation).
Histology from the flexible cystoscopy revealed a high- grade G3pTa urothelial cell
carcinoma (UCC), which confirmed the diagnosis of high- risk UCC; however, formal
transurethral resection of the bladder tumour (TURBT) was required to assess the
depth of invasion. A joint decision was made to proceed with urgent TURBT, under
spinal anaesthetic, to guide future management options.
TURBT confirmed a 3.5 cm G3pT1 solitary lesion with no evidence of muscle invasion or carcinoma in situ (CIS). Figure 11.1 describes the multidisciplinary team
(MDT) approach used to make combined clinician– patient decisions in the next stages
of his care.
108 Challenging Concepts in Urological Surgery
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1. Patient wishes
regarding
investigations and
treatments
Often forgotten, yet,
the most important.
Patient ideas, concerns,
and expectations
should be evaluated
prior to decision-making
about active
investigations or radical
treatments
Combined
clinician–patient
treatment decision
3. Fitness for
radical treatment
2. Benefit of
radical treatment
A multidisciplinary approach must
weigh-up the likelihood and impact
of disease recurrence, progression,
morbidity, and mortality with the
benefits and appropriateness of
active investigations and radical
treatment options for the patient
Figure 11.1 Considerations prior to active investigation and/ or radical therapies in NMIBC.
Evidence base Treatment
patterns, morbidity, and mortality
in the elderly
A large population- based study
evaluated all newly diagnosed
BC cases. Cancer- specific and
other- cause mortality rates at
5 years were equal (19% and
19%, respectively). This suggests
that elderly patients diagnosed
with BC are just as likely to die of
other causes as they are from their
6
cancer.
Learning point Background and management
BC is the tenth most common cancer in the UK1 with approximately 10,000 newly diagnosed cases
per year.2 The majority of patients present with non- muscle- invasive tumours,3 also known as nonmuscle- invasive bladder cancer (NMIBC), which, histologically, is confined to either the urothelium or
the subepithelial connective tissues, but not invading the detrusor muscle.
The primary treatment modality for NMIBC is transurethral resection. However, due to heterogeneous
rates of recurrence and progression, adjuvant intravesical therapy or surgery is often required.
4
5
A difficulty faced by many urologists occurs when first- line treatment options fail. Synthesizing a
patient- centred treatment plan in this cohort, particularly in those who are not fit for surgery, can be
extremely difficult.
Learning point Classification of NMIBC
Recurrence and progression rates in NMIBC are heterogeneous, ranging from 15% to 78% and 0.2% to
45% within 5 years of diagnosis, respectively (Figure 11.2).7 Therefore, NMIBC is categorized into three
distinct groups: low- , intermediate- , and high- risk disease. When risk stratifying a patient, urologists
must consider tumour size, grade, multiplicity, recurrence, depth of invasion, concurrent CIS, and
histopathological variants.8 This risk stratification is essential in predicting recurrence and progression,
which aid patient- centred management decisions.
Table 11.1 One- year and 5- year predicted recurrence and progression risks based
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on the patient’s flexible cystoscopy and TURBT findings
109Case 11 Non-muscle-invasive bladder cancer
EORTC risk calculator Flexible cystoscopy staging
(2.5 cm, G3pTa)
1- year recurrence 24% 38%
1- year progression 1% 5%
5- year recurrence 46% 62%
5- year progression 6% 17%
Using the European Organisation for Research and Treatment of Cancer (EORTC) NMIBC risk
stratification calculator, Table 11.1 depicts the change in recurrence and progression risk when a
patient is histologically upstaged from pTa to pT1 disease in NMIBC. Hence, highlighting the need for
accurate and timely staging.
TURBT staging
(3.5 cm, G3pT1)
The patient was reviewed in a specialist BC clinic. A joint decision was made not to
attempt re- resection of his tumour given his frailty and comorbidities. As he was not
fit for radical cystoprostatectomy (RC), he was offered intravesical bacillus Calmette–
Guérin (BCG).
Learning point Recommended management of high- risk NMIBC
High- risk NMIBC can be further subdivided into either high- risk or highest- risk disease. Highest- risk
NMIBC displays the following clinical and/ or histological characteristics9:
● pT1 tumour with evidence of lymphovascular invasion.
● Multiple, large, or recurrent high- grade G2/ G3pT1 tumours.
● All high- grade G2/ G3pT1 tumours with concurrent CIS.
● CIS in the prostatic urethra.
● Some histological variants of UCC.
For patients with highest- risk disease, RC is the recommended first- line treatment option. However,
due to the increasing comorbidity and polypharmacy that parallels an ageing population, alternative
approaches to RC are becoming more widely accepted. Intravesical BCG is an acceptable alternative
in such circumstances, but in a climate of BCG manufacturing shortages10 and high volume of BCG
failures, it is essential to identify more alternative and successful adjuvant therapies.
Learning point BCG regimen and efficacy
BCG is a live attenuated vaccine that has been used as an intravesical agent to treat BC for many years.
Intravesical BCG’s mechanism of action on BC cells is not yet fully understood, although it is thought
to activate acquired and innate immune responses, facilitating the recognition and destruction of BC
cells. The optimal intravesical schedule for BCG should include induction, followed by 1– 3 years of
maintenance. An example of a 3- year schedule9 is shown here:
● Induction: 6× weekly instillations of BCG.
● Maintenance: 3× weekly instillations given at 3, 6, 12, 18, 24, 30, and 36 months.
● Regular check cystoscopies throughout.
Intravesical BCG is effective as an adjuvant immunotherapeutic agent, where meta- analysis data have
confirmed reductions in the risk of recurrence and progression in NMIBC compared to controls.11 Its
effect is superior to other chemotherapeutic agents, such as ambient mitomycin C (MMC), for high- risk
NMIBC and CIS; however, the true benefit is usually only seen in those who complete both induction
and maintenance treatment.11 Unfortunately, it is estimated that only one- third of patients will complete
the full 3- year induction and maintenance schedule,12 due to side effects, toxicity, and failure.
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Learning point BCG side effects, complications, and contraindications
Due to BCG’s mechanism of action, patients usually develop inflammatory side effects that manifest
in the form of lower urinary tract symptoms (dysuria, frequency, urgency, and haematuria) and urinary
tract infections. These symptoms can occasionally be severe, relentless, and intolerable for patients.
The most clinically significant complication to be aware of is localized or systemic granulomatous
infection. Patients typically present with high fever, confusion, and clinical signs of sepsis. BCG sepsis—
Learning point Classifying
BCG failures
BCG failures can be subclassified as
one of the following9:
1. Muscle- invasive tumour
detected during follow- up
period.
2. BCG- refractory tumour:
- High- grade non- muscle-
invasive tumour identified
at 3- month endoscopic
check— further BCG therapy is
linked with increased risk of
progression.
- CIS present at 3- and 6-
month checks— additional
BCG can achieve complete
response in >50%.
- New high- grade tumour
identified during BCG
treatment (note: low- grade
tumours not considered
BCG failure).
Future directions The role
of AS in NMIBC
AS is not currently recommended
in high- risk NMIBC , but is currently
being evaluated in a non- inferiority
phase III randomized controlled
trial in Japan14 as an alternative
strategy to intravesical BCG after
complete TURBT resection (pT0 on
re- resection). For low- risk NMIBC,
AS has been advocated as a
potential strategy in a well- defined,
compliant population with low- risk,
low- volume, pTa disease.15 AS
aims to reduce the morbidity of
repeated surgical procedures and/
or adjuvant treatments.
a rare and potentially life- threatening condition— requires prompt identification, resuscitation, and
involvement of the infectious diseases team, who often initiate lengthy antitubercular therapy with or
without supportive steroids in the acute phase.
Absolute contraindications to intravesical BCG treatment include:
● Immunocompromised patients or those on immunosuppressive medication
● Symptomatic urinary tract infection; or, patients with a breach of the urothelium, suggested by
having had a recent TURBT (within the last 14 days)
● Recent catheter- related trauma, or visible haematuria.
Note: a relative contraindication to intravesical BCG therapy is complete incontinence, which reduces
intravesical dwelling time and, therefore, efficacy of treatment.
After completing BCG induction, a flexible check cystoscopy was performed to
avoid the anaesthetic risk associated with rigid cystoscopy. A new, concerning patchy
erythematous area was identified and biopsied, as the patient had been pre- warned
about stopping anticoagulation.
Histology confirmed a high- grade G3pTa UCC and a re- staging CT scan showed no
evidence of muscle- invasive or metastatic disease. The patient, therefore, had BCGrefractory disease. Because he was asymptomatic, and unfit for RC, he was offered the
following management strategies:
● Intravesical hyperthermic MMC.
● Active surveillance (AS).
Expert comment Watchful waiting in high- risk NMIBC in patients unfit for RC
Watchful waiting is another relatively novel concept in NMIBC. When managing unfit or frail patients,
an MDT decision should be made (Figure 11.1), with active patient involvement about the need for
and benefit of repeated investigations and treatments.
When managing low- volume, asymptomatic disease, in patients with a short life expectancy
or significant comorbidity, clinicians must consider the benefits and risks of TURBT to identify
progression to muscle- invasive disease. If the patient is unsuitable for or unwilling to undergo radical
treatment (surgery or chemoradiotherapy), watchful waiting seems a reasonable management strategy
for those failing first- line bladder- preserving therapies.
Learning point Alternative chemotherapy agents 1: standard MMC therapy
Mechanism of action
● Cytotoxic.
● Alkylates DNA.
Recommendation
Adjuvant therapy in those with intermediate- risk disease.
13
111Case 11 Non-muscle-invasive bladder cancer
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Comparison with BCG
A large meta- analysis has shown16:
● Higher risk of recurrence in MMC (but lower recurrence rates when compared to induction- only
BCG patients)
● No observed significant differences in progression or survival.
Dosing schedule
Induction and maintenance phases (no definitive recommended schedule):
● Induction phase: 6– 8 weekly instillations (60– 120- minute duration).
● Maintenance phase: 3 weekly instillations.
● The need for ongoing maintenance therapy is dictated by tolerability and response (can be repeated
to a maximum duration of 1 year).
Adverse effects
Clinical tip Alternative
treatment strategies
for unfit patients in the context
of BCG failure
There has been growing motivation
among urologists to identify more
novel therapies and/ or devices
that can provide a feasible and
efficacious alternative to intravesical
BCG therapy in those unfit for
RC. Current alternatives include
use of intravesical chemotherapy,
device- assisted therapy, alternative
immunotherapies, and conservative
management with either AS or
watchful waiting.
● Dysuria, frequency, haematuria, urinary tract infection, allergic skin rash, urethral stricture (2– 50%).
● Severe allergic reaction, bladder fibrosis (<1%).
Learning point Alternative chemotherapy agents 2: epirubicin (and other anthracyclines such
as doxorubicin)
Mechanism of action
● Anthracycline.
● Inhibits DNA replication, transcription, and repair.
Recommendation
Not currently recommended in isolation over MMC or BCG.
Comparison with BCG
● Inferior disease- specific survival and higher progression, when used in isolation.
● In combination with BCG, has shown promising effects on disease recurrence and progression
(without significantly increasing toxicity).
Dosing schedule
17
Similar schedule to intravesical MMC.
Adverse effects
Similar to MMC.
Mechanism of action
● Cytotoxic.
● Antimetabolite (impairs DNA synthesis).
Learning point Alternative chemotherapy agents 3: gemcitabine
Recommendation
● Traditionally used systemically for locally advanced or metastatic BC (in combination with cisplatin
or carboplatin).
● Ongoing research into its intravesical use, although early data are promising.
Comparison with BCG
A recent meta- analysis, comparing five randomized controlled trials with follow- up of 1– 4 years,
highlighted no significant difference between intravesical BCG and gemcitabine for risk of recurrence
or progression.
18
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Dosing schedule
● No definitive schedule defined. Similar to MMC.
● Once- weekly instillations for 6– 8 weeks.
● Maintenance therapy proposed as a once- monthly dose for up to 1 year.
Adverse effects
● Similar to MMC.
● Significantly lower incidence of haematuria and dysuria than BCG.
18
Learning point Alternative chemotherapy agents 4: device- assisted thermochemotherapy
with MMC
Mechanism of action
Thermochemotherapy is thought to increase urothelial permeability to allow for greater depth of drug
delivery. It can be delivered via:
● SYNERGIO device: electromagnetic radiation is transmitted via a catheter to produce homogeneous
heating of the bladder tissues, along with concomitant instillation of MMC
● COMBAT BRS device: external dry aluminium conduction system that recirculates the MMC
solution at a given temperature.
Comparison with BCG
Early research has suggested:
● Better recurrence- free survival for high- grade disease and equivocal response rates for CIS, when
compared to patients who have only undergone 1 year of BCG therapy.
19
● More data are required for to compare outcomes with maintenance BCG.
Dosing schedule
Similar to standard MMC.
Adverse effects
● Similar to standard MMC.
● Significantly higher rates of frequency, haematuria, and bladder spasm.
20
Learning point Combination immunotherapy: durvalumab and BCG therapy
(POTOMAC study)
Mechanism of action
● Durvalumab is an immunoglobulin G1 monoclonal antibody that targets and binds to the
programmed death- ligand 1 (PD- L1) and programmed cell death- 1 (PD- 1) receptors.
● Binding of these receptors is thought to initiate pathways that activate antitumour immune
responses.
● BCG mechanism has been explained earlier in the case.
● Note: systemic durvalumab has shown promising overall survival results for metastatic urothelial
carcinoma in those who have previously progressed despite first- line therapy.
21
Dosing schedule
To be confirmed after the results of the POTOMAC trial.
22
113Case 11 Non-muscle-invasive bladder cancer
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Adverse effects
● Adverse effects of BCG have been described earlier in the case.
● Systemic durvalumab may cause the following general and immune- mediated side effects:
- General: fatigue, musculoskeletal pain, nausea, constipation, and acute kidney injury.
- Immune mediated: pneumonitis, hepatitis, colitis, endocrinopathies, dermatitis and
immunocompromise.
Evidence base POTOMAC trial
The POTOMAC trial is a phase III randomized, open- label, multicentre, global study of durvalumab
and BCG administered as combination therapy versus BCG alone in high- risk, BCG- naïve NMIBC
22
patients.
It is currently recruiting to compare combined and standard immunotherapy:
● BCG induction and maintenance + durvalumab versus
● BCG induction + durvalumab versus
● BCG induction and maintenance.
The trial aims to recruit almost 1000 patients worldwide, with the primary outcome being disease- free
survival. Secondary outcomes will assess side effects, tolerability, health- related quality of life, disease
progression, and overall survival.
Learning point Alternative immunotherapy
An example is interferon alpha (IFNα) therapy.
Mechanism of action
23
IFNα has been shown to increase T- cell and natural killer recognition of tumour cells by control/
manipulation of antigen presentation and dendritic maturation.
Recommendation
Phase III trial data are required prior to widespread use.
Comparison with BCG
A recent phase II randomized controlled trial, evaluating IFNα with a surfactant- enhanced
recombinant adenovirus vector rAd– IFNα/ Syn3, has shown promising efficacy in BCG- refractory
disease, with 35% of patients being recurrence free at 12 months.
Dosing schedule
● Dose not yet confirmed.
● Proposed schedule: one 60- minute instillation, repeated at 4, 7, and 10 months if confirmed as
disease free on cystoscopy.
Adverse effects
● Limited available data; however, usually well tolerated.
● Urgency, dysuria, haematuria, nocturia, and pollakiuria (often transient and self- limiting).
23
Expert comment
Checkpoint inhibitors
Advances in our understanding of
UCC and the complex molecular
pathways by which it evades
antitumour responses have played
an important role in developing
targeted immunotherapies.
In particular, the binding and
inhibition of PD- L1 and PD- 1
checkpoint molecules.
Between the choice of AS and hyperthermic MMC, the patient chose active treatment.
He completed induction hyperthermic MMC, which was well tolerated, but cystoscopic
assessment showed minimal change in the patchy, erythematous area (graded G3pTa).
He was initiated on a maintenance cycle of hyperthermic MMC; however, during his
second instillation he developed a palmar rash and opted out of further treatment.
These novel immunotherapies are a
very promising treatment modality
for high- risk NMIBC patients.
Investigation of their use both in
isolation and in conjunction with
existing therapies will play a vital
role for targeted BC therapy in the
future.
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