CLINICAL REVIEW: The Management of Bladder Cancer

The essentials

* Bladder cancer is the fourth most common form of cancer in the UK.

* Smoking increases the risk of bladder cancer by up to four times.

* Haematuria should suggest bladder cancer until proven otherwise.

* Most cases of bladder cancer are superficial at the time of diagnosis.

* Treatment for invasive non-metastatic cancer remains uncertain.

1. Epidemiology and pathology of Madder cancer

In the UK, bladder cancer has an overall incidence of 4 per cent, behind breast, lung, large bowel and prostate cancer respectively, with about 10,700 people diagnosed annually. It is the fourth most common cancer in men and the tenth most common in women.

In terms of cancer-related deaths, bladder cancer is the eighth most common cause in men and seventh most common cause in women.

As well as being more prevalent in men, bladder cancer is also more common in Caucasians than in those from African-Caribbean or Asian origins. Most bladder cancers occur in Western or industrialised countries, and the risk increases with age.

Survival rates

The overall five year survival rates for patients diagnosed between 1996 and 1999 were 64 per cent in men and 56 per cent in women, but when bladder cancer is diagnosed early and treated appropriately, survival is excellent with five-year rates often exceeding 90-95 per cent. If the bladder cancer is locally advanced, then the five-year survival rates drops to around 40-50 per cent.

With metastatic disease, five-year survival rates are dismal with less than 5 per cent of patients still alive. Clearly, early detection and appropriate treatment are most important.

Pathology

Transitional cell carcinoma (TCC) is the most common histopathological subtype and accounts for up to 90 per cent of all bladder cancers. The squamous cell carcinoma (SCC) subtype accounts for 6-8 per cent of cases, and adenocarcinomas for 0.5 to 2 per cent.

Other tumour subtypes such as small cell, sarcomatous or metastatic cancers account for less than 1 per cent of cases.

TCC of the bladder may be singular or multiple, and in 5 per cent of patients there are synchronous lesions in the upper urinary tracts. Most cases are papillary and usually confined to the bladder mucosa.

Solid TCC are usually more advanced and invade the muscular wall of the bladder. Up to 10 per cent of TCC is a flat carcinoma-in- situ (CIS). This can occur in isolation, or in association with invasive TCC.

Squamous cell carcinoma

Although SCC of the bladder is not common in industrialised countries, it is the most common malignancy in the Middle East and parts of Africa where schistosomiasis (also known as bilharzia) is a widespread problem. In Egypt the incidence of SCC of the bladder rises to 70-80 per cent of cases of bladder cancer.

There is much evidence to support the association between schistosomiasis and bladder cancer including geographical correlation, distinctive patterns of gender and age at diagnosis and the clinicopathological identity of schistosome-associated bladder cancer. The causative agent is probably not a single entity but multifactorial.

However, more than 40 per cent of schistosomiasis-related bladder cancers are well-differentiated and have a better prognosis than SCCs from other causes.

SCC of the bladder is usually solid, invading muscle and are poorly differentiated. Adenocarcinoma subtypes are rare and may be associated with congenital exstrophy (‘turning inside out’ of the bladder mucosa), bowel implanted into the bladder for urinary reconstructions or endometriosis. One third originate in the urachus and are located at the dome of the bladder.

2. Risk factors for bladder cancer

There are several risk factors for bladder cancer. Some factors such as ageing and race cannot be controlled, but limiting exposure to some environmental risk factors may reduce the incidence.

Smoking

Smokers have two to four times the risk of developing bladder cancer compared to non-smokers. About half of the bladder cancers in men and one third in women are probably related to smoking, but as more women take up smoking, this may change. Smoking contains carcinogens such as 4-aminobiphenyl and 2-napthylamine. One suggested mechanism is that the carcinogens in cigarette smoke enter the circulation and are filtered and concentrated in urine, leading to damage of the urinary mucosa.

Chemicals

Prolonged exposure to certain industrial chemicals can predispose to the development of bladder cancer, such as the aromatic hydrocarbons aniline and benzidine. These chemicals have been commonly used in the paint, printing, textile, rubber, leather and petroleum industries. Most of them have now been banned in the UK, but can still produce cancers because of the long time taken for it to develop.

People working in these industries are at higher risk as well as painters, plumbers, or drivers exposed to diesel exhaust.

The use of drugs such as phenacetin and cytotoxic drugs such as cyclophosphamide are also risk factors for bladder cancer.

Age

There is an increased risk of developing bladder cancer with advancing age. Those older than 70 years have a risk of developing bladder cancer that is 15 to 20 times higher than those aged 55 years or less. A previous history of a bladder tumour also gives an increased risk of developing a second cancer.

Chronic bladder irritation

Patients with chronic bladder irritation secondary to multiple urinary tract infections, bladder stone disease or long-term in- dwelling catheters have a higher risk of developing squamous cell bladder cancer. They do not cause cancer in themselves, but the irritated bladder lining makes it more likely that the disease will develop.

Other factors that have been implicated are the consumption of Aristolochia fangchi (a herb used in some weight-loss formulas), a diet high in saturated fat and exposure to external beam radiation. A family history of bladder cancer is also relevant, and several genetic risk factors have been identified.

3. Symptoms, prognosis and staging

Most urinary symptoms and signs are non-specific for cancer and are more likely to result from non-malignant conditions such as urinary infections. Haematuria is the most suspicious symptom of cancer and this should be suspected until proven otherwise. It is often painless, may be either macroscopic or microscopic, and varies in quantity and frequency.

Other symptoms that may be significant include irritative lower urinary tract symptoms such as urgency and frequency, dysuria, and loin, suprapubic and pelvic pain or discomfort. Other symptoms relate to spread of the cancer if the disease is advanced or metastatic.

History and examination

A full clinical history and examination are essential. Initial investigations include testing urine for infection and blood. Urinary cytology can detect abnormal or malignant cells. An IVU is usually performed to exclude a space-occupying lesion in the urinary tract or bladder.

Early diagnosis and referral

Survival from bladder cancer is vastly improved when diagnosed early, so the possibility of cancer must always be borne in mind. Early referral is most important. Most major regional and even local hospitals will have a dedicated clinic for this purpose, often called a haematuria clinic, where patients are fast-tracked.

For situations where the diagnosis is in doubt, a possible diagnostic and management pathway would be to perform a bimanual examination, an ultrasound and a cystoscopy with biopsy. Superficial disease could then be treated immediately, while invasive disease would need a chest X-ray and CT, MRI or bone scans for staging, and appropriate interventions.

Prognostic factors and staging

Prognosis of bladder cancer depends on the initial clinical stage and the grade of the disease. A scale of 1-4 is usually used with Grade 1 being well-differentiated, Grade 2 being moderately differentiated, Grade 3 being poorly differentiated and Grade 4 being undifferentiated.

There is a standardised system for staging tumours called the TNM system where ‘T’ stands for tumour, ‘N’ stands for nodal involvement and ‘M’ stands for metastatic disease.

The higher the stage of disease, the worse the prognosis. Full details can be found on CancerWeb at http://cancerweb.ncl.ac.uk/ cancernet/101206.html.

4. Treating superficial disease

The selection of treatment for bladder cancer depends on the tumour grade and disease stage at diagnosis, as well as the patient’s overall state of health.

The important features in local staging are to determine if the tumour is confined to the bladder mucosa (superficial), has invaded muscle (advanced) or spread to other parts of the body (metastatic).

Most cases are superficial

Up to 70-80 per cent of bladder cancer cases present as superficial disease at the time of diagnosis. Low grade non- invasive tumours can be treated with cystoscopic resection and fulguration. However, despite complete tumour resection, up to two thirds of cases will develop a recurrence after five years, and 88 per cent of patients will develop a recurrence by 15 years.

The risk factors for recurrence or progression are high grade tumours, multi-focal lesions and carcinoma in situ cases. A progression to invasive disease is likely to occur in 15-20 per cent if one or more of these risk factors \are present.

Intravesical therapy

Intravesical therapy in the form of chemotherapy or immunotherapy is used in the management of superficial TCC of the bladder. It aims are to eradicate existing or residual disease, prevent local recurrence of the tumour, and prevent progression of the cancer to invasive disease.

Intravesical chemotherapy using drugs such as thiotepa, epirubicin, doxorubicin and mitomycin-C reduces short-term local tumour recurrence by up to 40 per cent, and long-term recurrence by about 7 per cent but does not reduce progression or cancer-related mortality.

BCG immunotherapy

Intravesical Bacillus Calmette-Guerin (BCG) immunotherapy is currently the most effective treatment in the management and prophylaxis of superficial TCC of the bladder. This treatment is usually given on a weekly basis for six weeks. BCG therapy reduces tumour recurrence by about 40-60 per cent. It has also been shown to reduce disease progression, leading to improved survival.

Optimum use of BCG intravesical therapy is as maintenance therapy, and this seems to improve long-term results. It is most effective when combined with transurethral resection or fulgation. Failure to control superficial disease often leads to patients having a radical cystectomy.

5. Treating invasive disease

The optimum treatment for invasive non-metastatic bladder cancer remains uncertain. The conventional method of treatment is surgery, particularly for SCC and adenocarcinoma subtypes where radiotherapy and chemotherapy are less effective. A well-localised tumour could be treated with a partial cystectomy, otherwise a radical cystectomy is performed. In men this entails the removal of the prostate, while in women the uterus, ovaries, fallopian tubes, and part of the vagina are usually removed. Various urinary diversion techniques are available such as ileal conduits, neobladders and continence pouches.

Radiotherapy

Radiotherapy was traditionally the treatment choice for those patients who were unsuitable for surgery or general anaesthesia, and in the elderly or those with locally advanced non-metastatic disease.

Results were poorer than surgery because of inherent patient selection bias and clinical staging criteria. More recently, modern techniques allow accurate delivery of higher irradiation doses and this has improved local control rates.

The use of simultaneous chemoradiation regimes has also improved results to the extent that equivalent outcomes to radical surgery are now being reported. The added advantage of these approaches is the possibility of good quality bladder preservation and improved quality of life.

Metastatic disease

Chemotherapy is the mainstay of treatment for patients with metastatic bladder cancer. The most commonly used have been the multi-agent regimes using methotrexate, vinblastine, adriamycin and cisplatin (MVAC), or cisplatin, methotrexate and vinblastine. These offer survival times of 12-13 months compared to the eight to nine months with single agents. Recently the combination of gemcitabine and cisplatin has shown equivalent results to MVAC but with reduced toxicity. Another new agent with promising results is paclitaxel.

Further resources

Further reading

Improving Outcomes in Umlogical Cancers published by NICE, 2002

Websites

See Medicine on the Web, page 42

Previously in Clinical Review

You can produce your own re-prints of Clinical Reviews published in the past year by logging on to GPonline.com. Recent issues have covered the following conditions:

* Managing depression (18 February)

* Childhood infections part 2 (11 February)

* Childhood infections part 1 (4 February)

* Contraception: first requests (J28 January)

Bladder cancer: 10, 700 cases diagnosed annually

Key points

* Bladder cancer is twice as common in men than in women.

* If detected early, survival rates can exceed 90 percent.

* Transitional cell carcinoma accounts for 90 per cent of all bladder cancers.

* Squamous cell carcinoma is common in regions where schistosomiasis is widespread.

* Adenocarcinoma subtypes are rare and may be associated with bladder reconstruction.

Chronic irritation from bladder stones can lead to SCC

Key points

* Limiting exposure to some environmental risk factors may reduce incidence.

* Chemicals used in the paint, printing, textile, rubber, leather and petroleum industries increase the risk.

* There is an increased risk of developing bladder cancer with advancing age.

* Chronic bladder irritation can lead to SCC of the bladder.

Tumour classification indicates the degree of invasiveness of bladder tumours, starting with carcinoma in situ

Key points

* Most urinary symptoms and signs are nonspecific for cancer.

* Especially with haematuria, the possibility of of cancer must always be borne in mind.

* Grade and tumour stage at diagnosis are the most important prognostic factors.

* The higher the grade or tumour stage (TNM stagingsystem), the worse the prognosis.

Only low-grade tumours can be treated cystoscopically

Key points

* Low grade non-invasive tumours can be treated with cystoscopic resection and fulguration.

* Up to two thirds of cases will develop a recurrence after five years.

* Intravesical BCG immunotherapy is the most effective prophylactic treatment.

Total cystectomy involves urinary diversion techniques

Key points

* Conventional treatment for invasive disease is surgery, particularly with SCC.

* Radical cystectomy may be required.

* Simultaneous chemoradiation regimes can now give similar outcomes to radical surgery.

* Chemotherapy is the mainstay of treatment for patients with metastatic bladder cancer.

Contributed by Dr Vincent Khoo, consultant in clinical oncology at the Royal Marsden Hospital and honorary senior lecturer at the Institute of Cancer Research

Copyright Haymarket Business Publications Ltd. Feb 25, 2005