Bladder cancerRafal Turo

William Cross

Peter Whelan

Abstract

Over 90% of malignant tumours of the bladder are urothelial cell

Rafal Turo MRCS is a Urology Research Fellow at St James University

COMMON CANCERSHospital, Leeds, UK. Conflicts of interest: none declared.

William Cross PhD FRCS is a Consultant Urological Surgeon at St James

University Hospital, Leeds, UK. Conflicts of interest: none declared.

Peter Whelan MS FRCS is a Community Urologist in Leeds, UK. Conflicts

of interest: none declared.carcinoma. Less common forms of bladder cancer include

squamous cell carcinoma, adenocarcinoma and neuroendocrine

tumours. Squamous cell carcinoma accounts for only for 5% of

bladder cancers in industrialized countries but represents more

than 50% of tumours presenting in Africa and the Middle East,

where bilharzia (Schistosoma haematobium) is endemic.

Adenocarcinoma in the bladder usually represents a metastatic

secondary lesion from another pelvic organ (prostate, ovary,

rectum). Rarer types of bladder tumour, which are associated

with aggressive behavior and worse survival outcomes, include

urachal, plasmacytoid, micropapillary and sarcomatoid

carcinomas.

Epidemiology

Annually in the UK, more than 10,000 new cases and nearly 5000

deaths are associated with bladder cancer. The disease incidence

peaks in the sixth and seventh decade of life and bladder cancerBladder cancer is the most frequently occurring tumour of the urinary tract

and the eighth-most common cause of cancer death in the UK. Urothelial

cell carcinoma of the bladder is characterized by high recurrence rate,

pathological progression and poor survival in advanced metastatic

disease. Due to the long follow-up period and associated expenses of

disease monitoring it is one of the most expensive cancers to manage.

Local therapy and surveillance are the mainstays of management of

early disease, whilst neoadjuvant chemotherapy, radical surgery and

radiotherapy are effective in advanced disease. There remains a great

need for effective tumour markers to aid diagnosis, staging, monitoring

and predicting prognosis. Novel therapies for advanced metastatic

bladder cancer are under development and assessment.

Keywords bladder cancer; chemotherapy; intravesical therapy; radical

cystectomy; radical radiotherapy; urinary markers

TerminologyMEDICINE 40:1 14is 2.5 times more common in men than in women. In the UK the

incidence rate of bladder cancer rose throughout the 1970s and

1980s and reached a peak in the early 1990s, since when it has

fallen by around 40%. This significant decrease may be attrib-

utable to reductions in smoking and exposure to occupational

carcinogens but also may be due to alterations in disease coding.1

Despite the decreasing incidence, bladder cancer remains

a significant economic burden on the NHS. One study estimated

the mean cost of patient diagnosis, treatment and follow-up was

higher for bladder cancer than prostate cancer, the most common

cancer in men in the UK (8349 vs 7294).2

Aetiology

Bladder cancer has many known risk factors, including cigarette

smoking, occupational exposure to chemicals, consumption of

analgesics containing phenacetin, chronic infection and chemo-

therapeutic agents such as cyclophosphamide. Cigarette smoking

is the strongest risk factor for developing bladder cancer. Active

cigarette smokers have a fourfold higher risk of developing

urothelial cell carcinoma than individuals who have never

smoked. It has been estimated that, after quitting smoking, it

takes nearly 20 years for the increased risk to reduce to baseline.

However, after only 4 years smoking cessation the increased risk

of bladder cancer is reduced by up to 40%, highlighting the

importance of counselling patients to stop smoking.3 Chemicals

such as aniline dyes, found in colour fabrics, and aromatic

amines (b-naphthylamine, 4-aminobiphenyl, and benzidine) are

thought to be carcinogens for bladder cancer. Occupations with

increased exposure to these carcinogens include painters,

metalworkers, paper and rubber manufacturers, foundry

workers, dry cleaners, dental technicians, hairdressers, and

marine engineers.4,5 Chronic infection and irritation of the

bladder (e.g. by indwelling catheters or calculi) have been

associated with squamous cell carcinoma, but this remains

controversial. Accumulation of many genetic changes leads to

tumour development. Characterized genomic aberrations in

bladder cancer include:

RAS oncogenes (associated with higher stage and grade) fibroblast growth factor 3 gene (FGFR3) mutations (in

more than 70% of non-invasive cancers)

deletions affecting chromosome 9 (50e60% of cases) mutations affecting the cyclin D1 gene (CCDN1) oncogenes including ERBB2 tumour suppressor genes such as TP53.

Pathology

Tumour grade and stage are the strongest predicting factors for

disease behaviour and prognosis. Bladder cancers are tradition-

ally graded from one to three (G1e3), based upon cell anaplasia,

with higher-grade lesions being at a greater risk for tumour

recurrence and progression. In 2004, a new histologic classifi-

cation system was developed with the aim of improving stan-

dardized interpretation of pathological samples, and to better

characterize disease behaviour. The WHO/International Society

of Urological Pathology introduced the terms urothelial neoplasm

of low malignant potential (UNLMP) and papillary carcinoma of

low and high grade. Application of this system still remains

controversial and is not widespread. The universal staging 2011 Published by Elsevier Ltd.

system is the TNM classification based on the depth of invasion

(T), involvement of regional lymph nodes (N) (Tables 1 and 2)

and presence or absence of metastases (M) (Figure 1).

Diagnosis

Bladder cancer may be diagnosed incidentally or because of

symptoms. Painless and usually intermittent, macroscopic hae-

maturia (frank or gross haematuria) is the commonest finding,

occurring in about 75% of patients. However, haematuria can

also be a sign of many other conditions, such as urinary tract

infection, nephrolithiasis and benign prostatic hyperplasia.

Patients presenting with haematuria (macroscopic or micro-

scopic) should be appropriately investigated. This includes

a diagnostic cystoscopy, to identify lesions within the bladder or

urethra, and imaging of the upper urinary tract by ultrasonog-

Further management

Further management is based upon the risk factors discussed

above and the stage/grade of the disease. Depending on these,

a patient may need only surveillance, single installation of

intravesical chemotherapy, a course of intravesical chemo-

therapy or immunotherapy, or further surgery. Up to 30% of

those found to have high-risk T1 disease have residual disease,

often invading the bladder muscle. For all cases of newly diag-

nosed T1 G3 tumours, a second cystoscopy and resection is

COMMON CANCERSraphy, intravenous urogram or CT, to identify lesions within the

ureter, renal pelvis and renal parenchyma. Dysuria or storage

voiding symptoms, such as urinary urgency or frequency, can

occasionally be the only presenting symptoms of bladder cancer

(less than 30% of patients). In patients with more advanced

disease, common presenting symptoms are weight loss, abdom-

inal pain and renal impairment secondary to ureteric obstruction.

An approach to the management of bladder cancer is summa-

rized in Figure 2.

Prognosis

Seventy-five per cent of patients present with tumours that are

described as superficial. The term superficial is misleading

because it implies a more benign process. Superficial bladder

tumours are more appropriately referred to as non-muscle

invasive. These tumours include lesions that are confined to

the mucosa (Ta and carcinoma in situ) and those that invade

through the basement membrane into the lamina propria (T1).

Carcinoma in situ (CIS) is a flat, high-grade, non-invasive

bladder cancer with a very high rate of recurrence and progres-

sion within 5 years. It usually appears as a red velvety patch on

the bladder wall and is less well detected by white-light cystos-

copy compared to papillary urothelial cell carcinoma. CIS often

occurs in association with high-grade papillary and invasive

tumours. In isolation, CIS accounts for 5% of non-muscle inva-

sive tumours. Because of poor cell cohesion in CIS, urine

cytology is often positive (the test has high sensitivity and

Lymph nodes (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastases

N1 Metastasis to a single lymph node, 2 cm or less

in greatest dimension

N2 Metastasis in a single lymph node, more than 2 cm

but not more than 5 cm in greatest dimension;

or multiple lymph nodes, none more than 5 cm in

greatest dimension

N3 Metastasis in a lymph node, more than 5 cm in greatest

dimension

Table 1MEDICINE 40:1 15specificity). In contrast, reported urine cytology sensitivity in G1/

2 tumours is very variable (17e72%).

Bladder urothelial cell carcinoma is characterized by

a tendency to recur (polychronotropism) with a variable rate of

progression;more than 50%of patients experience recurrence, yet

only 10e15% of urothelial cell carcinomas subsequently progress

to invade the bladdermuscle wall. Increasing tumour grade, stage,

size and multifocality have been associated with an increased risk

of progression and have been used to stratify Ta/T1 tumours into

risk groups. The European Urological Association guidelines of

2010 define low-risk tumours as single Ta G1 transitional cell

carcinomas of less than 3-cm diameter without CIS; TaT1 high-

grade tumours with or without CIS, multifocal high-risk

tumours, and all others as intermediate risk. In one study, of

a cohort of patients with T1G3 bladder cancers followed for 15

years, about one-third died from the disease, one-third survived,

but without their bladder, and one-third survived intact.6

Primary management: surgery

Primary treatment of non-muscle invasive urothelial cell carci-

noma is endoscopic resection of the bladder tumour. This is

usually performed under general or regional anaesthesia using

a rigid cystoscope. The bladder is illuminated from an external

light source via fibre optics within the scope. The image is

transmitted along the optical rod-lens system at the core of the

instrument. Electric energy to cut or coagulate tissue is generated

in the diathermy machine, usually via monopolar circuit. The

current travels via a pad on the patients thigh and is concen-

trated at the tip of the electrode attached to the cystoscope. The

bladder is continuously irrigated with non-ionic glycine. Care

must be taken to avoid perforating the bladder wall, which may

be very thin, particularly around the dome in elderly women.

Stimulating the obturator nerve lying adjacent to the lateral

bladder walls results in a strong kick. Muscle should be included

in the resection specimen to stage the disease accurately.

Although modern imaging has reduced its importance, bimanual

palpation should also be performed. If the tumour is palpable

after resection, the tumour is staged as cT3, or cT4 if bladder is

fixed.

Distant metastasis (M)

MX Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

Table 2 2011 Published by Elsevier Ltd.

fat

ular

mus

2a

bl

COMMON CANCERShighly recommended. A repeat resection will provide further

bladder tissue and allow more accurate staging information (the

probability of under-staging high-grade tumours ranges from

20% to 70%, depending on presence of muscle fibres in the

initial sample). European guidelines recommend early re-biopsy

in all T1 lesions; if muscle layer is not identified in the specimen;

Tis

Perivesical

Deep musc

Superficial

Submucosa

Mucosa

Ta

T1T

T-stages of transitional cell carcinoma

Figure 1if primary resection was incomplete; or in bulky or multiple

tumours.

Intravesical chemotherapy and immunotherapy

The majority of molecular studies of recurrent tumours suggest

a monoclonal origin, implying that recurrent tumours are

descendants of a single progenitor cell. Recurrences may arise

from the seeding of free-floating tumour cells at the time of the

initial resection. To reduce the risk of recurrence, perioperative

intravesical therapy is given at the time of tumour resection. It

has been shown that single installation of intravesical chemo-

therapy (mitomycin or epirubicin) within 6 hours of resection

reduces the recurrence rate by 50%. A meta-analysis of over

2500 patients with Ta/T1 transitional cell carcinoma suggested

equal efficacy for all agents used and that recurrence rates were

reduced after a median follow-up of nearly 8 years, but

progression and survival were unaltered.7

The bacillus CalmetteeGuerin (BCG) remains the most effective

intravesical treatment in non-muscle invasive bladder cancer.

Although the precise mechanism of BCG is not fully understood, it

has been suggested that the key element of antitumour activity

resides in its ability to initiate extensive local inflammatory reaction

in the bladder wall. The complex immunologic cascade starts with

the initial adherence of live attenuated mycobacteria to the urothe-

lial lining, and proceeds to an immune response with natural killer

cells andT lymphocytes as criticalmediators.Due to this strong local

MEDICINE 40:1 16inflammatory reaction patients very often experience adverse

effects, especially irritative voiding symptoms, and only about 16%

of patients complete the course of therapy.8 To reduce the risk of

serious complications it is a standard practice to commence BCG

treatment after 2 weeks of interval from the surgery. The superiority

of BCG treatment over epirubicin in terms of time to first recurrence,

is propria

cularis propria

T4-contiguous organs

T2bT3

T4

adder cancer (TNM classification)time to distant metastases, disease-specific survival and overall

survival has been demonstrated in a phase 3 randomized study

performed by the European Organization for Research and Treat-

ment of Cancer (EORTC).9 Additional immunological agents (e.g.

interferon-a-2-B) are under investigation to augment BCG or as

salvage treatments if BCG therapy fails.

Disease surveillance

Bladder cancer is a disease characterized by high risk of recur-

rence and progression, and patients should be subject to a period

of endoscopic surveillance. Many studies have been conducted to

develop scales to predict the recurrence and progression of

bladder cancer and to aid in disease follow up. One of the

commonly used protocols to stratify bladder cancer risk for

recurrence and progression was developed by EORTC in 2008.

This scoring system is part of European guidelines and considers

clinical and pathological factors, including number of tumours,

tumour size, prior recurrence rate, T category, concomitant CIS

and tumour grade. According to this scoring system, patients

with non-muscle invasive disease are divided into three different

risk groups (low, intermediate and high). It is a usual practice to

undertake cystoscopy at 3 months after resection for interme-

diate and high-risk patients. The endoscopic surveillance is

usually performed as a day case procedure under local anaes-

thesia using a white-light flexible cystoscope. It is associated with

minimal discomfort and is well tolerated in majority of cases. A

2011 Published by Elsevier Ltd.

ymturincyeig

atiory imble gy

COMMON CANCERSPresenting sHaema

Urinary frequePelvic pain, w

InvestigUpper urina

Diagnostic flexiUrine bacteriolo

Approaches to DCS and DCRDCSdisadvantage of conventional cystoscopy is the difficulty in

detecting flat lesions such as CIS. Fluorescent agents have been

recently introduced to increase rate of detection of such lesions.

Non-invasive surveillance

There is a need for tumour markers that can detect bladder cancer

earlier and decrease the need for cystoscopic surveillance. Urine

cytology has a high sensitivity (70e80%) and specificity (90e95%)

for detecting high-grade disease but is poor at diagnosing well-

differentiated bladder cancers. Other bladder tumour markers

have been developed and evaluated, including protein-based

Urine cytology tumo

Low-risk cancerpTa G1/G2 and

treatment (partial cystectomy, close surveillance or chemo-

COMMON CANCERSradiation) is offered to small subset of patients with low stage,

single, small tumours and no associated CIS or hydronephrosis.

However, these approaches remain controversial and are not

routine practice. The debate is about whether bladder preserva-

tion can occur while obtaining the same survival rates that are

achieved with radical cystectomy.

Metastatic disease

Despite advances in chemotherapy, treatment outcomes forpatients

with metastatic bladder cancer continue to be poor. Metastatic

bladder cancer has a very poor prognosis with a 5e10% 5-year

survival rate. Common metastatic sites for bladder cancer include

pelvic lymph nodes, liver, lung, bone and intestines. A multidrug,

cisplatin-based regimen (methotrexate, vinblastine, cisplatin, dox-

orubucin) has generally been the gold-standard treatment for

metastatic bladder cancer. Alternatives to cisplatin for those

considered unsuitable (e.g. patients with poor renal function)

include carboplatin, gemcitabine or paclitaxel. The response rates

are up to 35% and median survival of 6 months.

The value of neoadjuvant versus adjuvant chemotherapy

continues to be of great interest and investigation. Currently, there

is greater evidence supporting the use of neoadjuvant chemo-

therapy than there is in favour of adjuvant chemotherapy. A

prospective randomized trial performed by the EORTC in 1989,

and updated in 2002, of neoadjuvant cisplatin, methotrexate, and

vinblastine before cystectomy or external-beam radiotherapy re-

ported a significant improvement in 5-year survival among

patients who have been given neoadjuvant treatment. This was

supported by a meta-analysis performed by the Advanced Bladder

Cancer Collaboration group who combined data from 11 trials.

They showed a 5% absolute improvement in survival after 5

years.11bladder wall (T2), perivesical tissue (T3) or adjacent pelvic organs

(T4) is managed differently to non-muscle invasive disease. Before

adecisionabout treatment ismade, bladder cancer requiresa careful

staging processwith cross-sectional imaging of the bladder and sites

of possible metastases (particularly the chest). The investigation of

choice for staging purposes is CT, although pelvic MRI is occa-

sionally used in combination with abdominal and chest CT.

Unfortunately these investigations are not highly sensitive in iden-

tifying lymph node metastases, as only the size and shape of the

lymph nodes determine the probability of lymphatic metastasis

Between 30%and 50%of patients are clinically under-staged at the

time of cystectomy,10 and there is a need for more accurate staging

technologies and tools. One of these is MR lymphangiography,

which uses superparamagnetic iron oxide nanoparticles to identify

lymph node metastases as small as 2 mm. These particles are

ingested by macrophages in normal lymph nodes resulting in low

nodal signal intensity. In metastatic nodes, particles are not

concentrated, resulting in high signal intensity. Application of this

technology is promising, with a sensitivity of 96%and specificity of

95% for detection of lymph node metastases. Positron emission

tomographyusinga radiolabelled tracer suchasfluorodeoxyglucose

(FDG-PET) is another novel imaging technique used to improve the

accuracy of pretreatment staging.

The standard approach for invasive bladder cancer in UK is

radical cystectomy or radical radiotherapy. A bladder-sparingMEDICINE 40:1 18Targeted therapies

The aim of targeted therapies is to interfere with molecular

pathways characteristic only for tumours and therefore to spare

normally dividing cells and reduce treatment morbidity. On the

basis of preclinical and clinical evidence, targets such as

epidermal growth factor receptor (EGFR), FGFR3, human

epidermal growth factor receptor 2 (HER2) and many others are

validated for cancer therapy and remain the subject of intense

investigation. Examples of targeted therapies include cetuximab

(anti-EGFR monoclonal antibody), gefitinib and erlotinib (EGFR-

specific tyrosine kinase inhibitors), trastuzumab (anti-EGFR type

2-related monoclonal antibody), lapatinib and bevacizumab.

Some of these agents have already entered clinical trials in

bladder cancer patients; trials of gefitinib in combination with

chemotherapy in first-line metastatic bladder cancer and trastu-

zumab in combination with chemotherapy in metastatic bladder

cancer patients with HER2 expression are under way. An

improved understanding of the molecular pathology of bladder

cancer will help us to predict which patients will progress to

more advanced disease and allow targeted therapy for patients

with metastatic disease.

Conclusions

Bladder cancer imposes a significant clinical and economic

burden upon the NHS with the highest lifetime treatment costs

per patient of all cancers. Efforts to reduce the recurrence and

progression rates of Ta/T1 bladder cancers with intravesical

therapy have made a small, but definite, improvement in clinical

outcome, but have not significantly reduced the overall cost/

spend on bladder cancer among any health service system. New

treatment agents and technologies are required to manage this

costly malignancy. Further trials investigating new therapies

will hopefully improve both oncologic outcomes and quality of

life for patients with bladder cancer. A

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COMMON CANCERSMEDICINE 40:1 19 2011 Published by Elsevier Ltd.

Bladder cancer Terminology Epidemiology Aetiology Pathology Diagnosis Prognosis Primary management: surgery Further management Intravesical chemotherapy and immunotherapy Disease surveillance Non-invasive surveillance T2+ muscle invasive bladder cancer Metastatic disease Targeted therapies Conclusions References