Summary
Bladder cancer forms in the cells that line the inner wall of the urinary bladder (the organ that stores urine).
The incidence in the UK is approximately 11,000 new cases per year, most of these being early cases of the disease that is controlled by local therapies performed at cystoscopy (where the doctor looks inside the bladder and treats the cancer under direct vision). In early stages of the disease, this cure is the ‘norm’, but even for more advanced cases the survival rates are improving.
Most bladder cancers are transitional cell carcinomas (cancer that begins in so-called transitional cells that normally make up the inner lining of the bladder). Other types include squamous cell carcinoma (cancer that begins in thin, flat cells that have changed from the transitional cells that normally line the bladder – perhaps following chronic irritation of the bladder by chemicals or infections such as schistosomiasis) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids).
In the UK, the disease is found predominantly in older men and often with other medical problems. This can be a potential problem for the oncologist should the patient require treatment other than straightforward local cystoscopic therapy.
Causes
Environmental factors are undoubtedly related to the incidence of the disease with smoking causing a two to six fold rise in the risk of the disease. It is thought that the aromatic amines in the tobacco smoke are the carcinogenic (cancer causing) agents. They are absorbed into the blood after inhalation into the lungs and then excreted in the urine, where the contact with the bladder wall lining (epithelium) proves the trigger for the eventual development of the cancer.
Workers in industries that involve working with aromatic amines also have a higher incidence of the disease, again due the exposure to aromatic amines (particularly the rubber industry and those workers exposed to dye stuffs).
Interestingly, recent data suggest a familial tendency to the disease and it is thought that the genetic expression of genes that metabolise the toxic substances varies between individuals and hence the excretion/concentration of carcinogenic metabolites in the urine.
In countries where the infectious disease, schistosomiasis is common e.g. Egypt, there is an increased incidence of squamous cancer of the bladder (a type which is otherwise infrequent in the UK).
Incidence
Cancer of the bladder is a relatively common cancer. It tends to occur in later life with a male preponderance and presents (usually) by blood in the urine (haematuria). The first investigation is cystoscopy (a procedure where the doctor looks into the bladder through the urethra, nowadays with a fibre optic scope) which allows the visualisation of the bladder’s internal lining, from which all bladder cancers arise.
Early bladder cancer may appear as a polyp that can be fully resected (cut out or burnt with diathermy- heat). Early stages of the cancer may require no other therapy other than repeated cystoscopies over time to check that the tumour has not recurred or new ones arisen.
There are 11,000 cases of bladder cancer diagnosed in the UK annually and most are of the early form just described. However, ultimately, the death rate from this disease in the UK is approximately 5,000 per year (and in the USA 11,000 per year) emphasising that this disease is an important health hazard.
Symptoms & diagnosis: bladder cancer (transitional cell carcinoma)
The classic presenting symptom to the doctor is blood in the urine (haematuria) or occasionally symptoms of bladder discomfort. In particular, haematuria is a symptom that is noticed very early by patients and usually brings them soon to the doctor; at this time, the disease is usually in an ‘early stage’.
However, sometimes, the symptoms referable to the bladder may not occur and then the patient may not present to the doctor until he/ she develops obstructed ureters (due to the tumours blocking the junction here the ureters lead into the bladder) or even until the disease has spread to other organs e.g. liver, lungs or bones.
Diagnosis
In the investigation of blood in the urine, the doctor images the whole of the urinary tubes and passages. A CT urogram is performed first, as this will show obvious intraluminal disease at one or more sites throughout the urinary tract (and it is not uncommon for there to be more than one site). The critical diagnostic test (and indeed the first therapy as resection (surgically removed) of all visible disease is performed at the same time) is cystoscopy (where the urologist looks into the bladder through a fibre-optic scope.
Here, the specialist (urologist) looks into the bladder of the patient and resects (surgically removes) any tumour that he can see, sending the specimens that he resects to the pathology laboratory for examination under the microscope.
Stages
In the investigation of blood in the urine, the doctor images the whole of the urinary tubes and passages. An intravenous urogram is performed first, as this will show obvious intraluminal disease at one or more sites (and it is not uncommon for there to be more than one site) and abdomino-pelvic scanning.
The critical diagnostic test (and indeed the first therapy as resection of all visible disease is performed at the same time) is cystoscopy. Here, the specialist (urologist) looks into the bladder of the patient and resects (surgically removes) any tumour that he can see, sending the specimens that he resects to the pathology laboratory for examination under the microscope.
After resection, the urologist bi-manually feels the bladder to see if there is palpable abnormality (which is a feature of locally invasive/muscle invasive cancers) but, more accurately, he ensures that there is muscle in the deeper biopsies that he performs from the bladder wall tumour. Based on the pathological/ histological findings, the patient is staged according to the system that is shown in the figure. The earliest stage is where the tumour is confined to the bladder lining and does not invade deep (pT1) and the highest stage (pT4) is where there is invasion of the tumour deep and into adjacent tissues.
Treatment and outcomes: Bladder cancer (transitional cell carcinoma)
Early bladder cancer (e.g. pT1 disease) is treated by the urologist by resection or diathermy, aiming to totally destroy/ surgically excise the entire tumour; this is often possible as the tumour is superficial in the bladder and growing out into the bladder lumen.
After this procedure, and when the pathologist has confirmed that there is no ‘deep invasion’ of the bladder wall, (which implies that there will be disease left behind and further therapy is needed) the urologist will repeat serial follow-up cystoscopies to be sure there is no recurrence at increasing intervals over many years.
Where there is a superficial ‘carpet’ of tumour across the lining of the bladder some instillations of toxic chemicals (e.g. the chemotherapeutic agents, doxorubicin or mitomycin C) or BCG, (the attenuated tubercle bacillus species) into the bladder may be very useful in clearing the disease by causing a chemical ‘burn’ or a local immunotherapy reaction in the case of BCG.
For more advanced disease (where there is involvement of the bladder muscular wall) where there is no evidence of spread beyond the bladder, then there are several curative treatment options:
In the younger and fitter patient, then cystectomy (the removal of the bladder with reconstruction of some substitute conduit for the urine) is the standard and often best treatment – often preceded by some chemotherapy.
For the older patient who would not stand this large operation, then radical radiotherapy (an external beam course lasting 5-6 weeks) is chosen – again with chemotherapy as an option.
Radiotherapy (or chemo-radiotherapy – see below) is also chosen when the disease is through the bladder wall and therefore not potentially curable by cystectomy e.g pT4 disease. Often, the Oncologist will start with chemotherapy (say two or three cycles of cisplatin and gemcitabine chemotherapy) followed by radical radiotherapy to a curative dose.
The modern radiation system is with high energy linear accelerators and using conformal technology/ IMRT. The high radiation dose is carefully ‘moulded’ around the bladder (which is treated empty) as the patient lies on his back on the radiotherapy treatment couch. Each treatment takes up to 15 minutes (the majority of this being due to the time taken for the patient to be set-up in the correct position) and the patient feels nothing as the body cannot sense the absorption of this x-radiation. He/she returns the next day (Monday to Friday) for the next treatment (‘fraction’ in radiotherapy parlance)
There is no doubt that modern chemotherapy, using drugs such as cis-platinum and gemcitabine can cause a good regression in transitional carcinoma of the bladder and for younger and fitter patients many would now employ it in conjunction with local therapy (surgery or radiotherapy).
Sometimes, as has been said above, the use of chemotherapy might come first, with one to three courses of chemotherapy used before the radiotherapy to shrink the tumour and hence maybe make it more radiocurable. Sometimes, chemotherapy is used during radiotherapy in an attempt to get synergy between the two modalities of therapy to enhance the cure chance. There are data to support both points of view but the optimal chemotherapy regime and timing of administration are still subjects of controversy and trial data.
Advanced and metastatic bladder cancer.
For patients with metastatic bladder cancer, treatment usually starts with chemotherapy such as outlined above – cisplatin (providing the patient’s kidney function is reasonable) is partnered with another drug or two – gemcitabine and methotrexate being two active drugs.
For chemoresistant cancer, it has become appreciated that this type of cancer may be sensitive to immunotherapy – particularly the immune check-point inhibitors (the rationale and mechanism of action of which has been outlined in the Melanoma treatment section of this website).
PD1 inhibitors such as pembrolizumab and nivolumab are active immunotherapy anti-cancer agents in metastatic bladder cancer and more recently the PDL1 inhibitor : atezolizumab has been show to have good activity.
This immunotherapy has brought a new dimension to the therapy and longevity of these patients with advanced bladder cancer.
What to do when all the foregoing therapies have been trialled and still the cancer relapses?
It is worthwhile obtaining next generation sequencing of the cancer at this time-point. This can be done by a new biopsy specimen of the cancer or by a blood draw and NGS analysis of the cell-free cancer DNA. The latter method (if there is significant amounts of the cfDNA circulating) allows the analysis of the new mutations that may be ‘driving’ the cancer cells to divide and hopefully bring up options to inhibit the downstream effector pathways of these mutated driver oncogenes.
The immunotherapy options should be fully explored, as this line of treatment has definitely improved the outlook of advanced bladder cancer patients in the last few years. FGFR inhibitors are currently in research and some look promising for therapy in advanced and metastatic bladder cancer.
Credit: P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics).
Outcomes
Overall, the vast majority of patients with early bladder cancer are in remission after first resection but require careful and prolonged cystoscopic follow-up as there is a chance of both local recurrence and of new tumours developing.
Local relapse in the bladder after conservative therapy (i.e. chemotherapy and radiotherapy) is an indication for the doctor to recommend cystectomy with a high chance of cure.
Once the cancer is muscle invasive (pT3+) the overall chance of cure falls substantially, but improved by the addition of adjuvant chemotherapy and, perhaps in the future: immunotherapy (trials in progress).
Where the tumour has spread to other organs, and the bones and later the liver and lungs are at particular risk, is an indication for chemotherapy; however, such chemotherapy is not curative; with the recent introduction of immunotherapy options, there is now a better chance of durable second remissions in this disease.
What to do if there is relapse despite all the forgoing?
In this situation it is worthwhile obtaining a new tissue biopsy for next generation sequencing (NGS) for genomic analysis (or obtaining cell-free DNA: cfDNA) from a blood draw (as frequently there are DNA fragments suitable for NGS released into the blood.
The search is for new mutations of activating oncogenes (that are, via their mutated downstream products, causing constant stimulation to the cells to divide) – that are ‘druggable’ with inhibitors.
Exploring the new mutations that are arising during cancer evolution (and signalling to cells to constantly divide) and then trying to inhibit this process – is the key to future success in Oncology.
The new realisation of the sensitivity of bladder cancer to immunotherapy also opens up new methods of treating resistant disease – not least because, at the time of this refractoriness to the foregoing therapies, the cancer is likely to be more antigenic (as it is much further down the road of mutations) and theoretically at least more prone to immunotherapy options. FGFR inhibitors are looking promising.
P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics).
Screening
It is possible to send urine for cytology. This is where a specialist pathologist looks under the microscope for tumour cells in the urine sediment. This screening test does not have a use on a population wide basis but may have a role in perceived higher risk patients.
Once the patient has been diagnosed and treated for a superficial bladder cancer, it is behoven for the Urologist to keep and routine cyctoscopic ‘eye’ on the bladder (and indeed the rest of the urological tracts – right up to the renal pelves – as the whole tract is at risk of new tumours).