Urothelial Cancer of the Bladder and Upper Tracts
Executive Summary
Urothelial cancer may occurs anywhere urine is in contact with the lining of the urinary system.
Bladder is the most common location for urothelial cancer. Urothelial cancer may also occur in the renal pelvis, ureter and urethra.
Urothelial cancers vary from ‘nuisance’ tumors that pose little risk through to aggressive cancers that may be rapidly lethal.
Treatment is highly individualized and based on assessment of risk.
Urothelial cancers that have metastasized are incurable. Treatment of cancers that have not spread is focused on preventing recurrences of cancers and progression to metastatic disease. This may require removal of the bladder.
Post-treatment surveillance is always necessary. Surveillance with cystoscopy, sometimes life-long, is necessary patients who do not require removal of their bladder.
Treatment always involves transurethral resection of the tumor. Additional treatments will vary based on the risk of the tumor and range from medications administered into the bladder through to major surgery and chemotherapy.
Background & Terminology
Kidneys filter blood and produce urine. The urine drains through a collecting system and eventually leaves the body through the urethra (the last part of the drainage system). The collecting system is a series of pipes which are much like the plumbing in a home. The collecting system starts in the kidneys and ends with the urethral meatus. The inside of these ducts are lined by a layer of cells that is called the urothelium. The individual cells are called transitional cells or urothelial cells (these terms are used interchangeably). When the lining of a hollow organ such as the bladder is in contact with fluid, we call the lining a mucosa (e.g. the lining of the mouth is also a mucosa, but is lined by a different type of cell than in the bladder). The urothelium (i.e. the mucosa) is constantly being renewed - dead cells being shed in the urine, much like the skin is always undergoing renewal. Just as sun exposure can predispose to skin cancer, the composition of the urine can predispose to urothelial cancers. Cancer is the unregulated growth of cells which cause problems with the function of the urinary system and also have the ability to spread to other organs (e.g. lung, liver, lymph nodes, etc.).
Urothelial cancer is therefore cancer that arises in the lining of the urinary system. It is also called transitional cell cancer.
Urothelial cancer may arise anywhere the urothelium exists - from the start of the collecting system in the kidney, the ureters which conduct urine from kidney to bladder, within the bladder itself to the urethra which conducts urine from the bladder to the tip of the urethral meatus.
Note: Other types of cancers involving the urinary collecting system may occur but they are much less common.. These include tumors such as squamous cell cancer, sarcomas and others. Their evaluation and management may differ significantly from urothelial cancer.
Quick Facts About Urothelial Cancer
Urothelial cancer is common. 5000 new cases per year in Canada. #4 cancer in men. #8 cancer in women.
Anyone can develop urothelial cancer. However, the major risks are age, any history of cigarette exposure, male gender, Caucasian ethnicity.
Bladder cancer (in common usage) is urothelial cancer involving bladder and is by far the most common type of urothelial cancer. Urothelial cancer of the upper tracts (renal pelvis and ureters) are much less common. The ratio of bladder to upper tract cancer is 50:1. The reason for this is that the majority of the urothelium resides in the bladder. Urothelial carcinoma of the urethra is less common but may occur as an extension from the bladder or less commonly arising from the prostatic urethra.
Causes of Urothelial Cancer
Similar to just about any other type of cancer, these tumors may result from bad luck. However, urothelial cancer is much ore common in older individuals and in those that have exposure to cigarette smoke. Urothelial carcinoma may occur in patients of any age and in the absence of a smoking history.
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Age. Older individuals have increased risk.
Male gender.
Caucasian ethnicity.
Family history. Most family history is actually related to exposure to cigarette smoke but there are some risks such as Lynch syndrome that are also associated with urothelial cancer. Most urothelial cancers do not have an inheritable genetic component.
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SMOKING: By far the most common behavior associated with urothelial carcinoma.
Cyclophosphamide/Iphosphamide (types of chemotherapy)
Carcinogens: aromatic amines, benzene, other
Pelvic radiation
Any history of smoking is a major risk factor for bladder cancer (just as it is for kidney, lung, throat, esophageal, liver, stomach, pancreatic, colon, rectal cancers). Higher exposure is correlated with increased risk - more cigarettes over a longer duration are an issue. The risk of developing cancer from smoking never goes away completely.
THE BEST THING TO DO IS TO NEVER SMOKE OR IF YOU SMOKE TO QUIT OR SMOKE AS LITTLE AS POSSIBLE. IF YOU HAVE BLADDER CANCER AND SMOKE YOU MUST QUIT RIGHT NOW.
Structure of the Bladder Wall
It is helpful to understand the structure of the bladder wall because invasion into and beyond that wall is critical in how bladder cancer is managed. Urothelial carcinomas that show invasion into the underlying structures are almost high risk high grade and pose a significant risk of spreading.
To use an analogy, one can think of the bladder wall as being similar to a carpeted floor. The surface of the floor is the side which is in contact with the urine (and forms the inside of the bladder). Starting from from the inside-out, the layers of the bladder are:
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The superficial layers of the bladder is the innermost layer. It is composed of the:
Urothelium (the mucosa) which sits like a carpet upon the …
Lamina propria which is like the underlay for a carpet.
Tumor start in the mucosal layer and may start to invade into the underlay if the tumor is high grade.
The mucosa and lamina propria represent the limits of what can reliably be removed from the inside during transurethral resections.
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The muscular layer of the bladder provides the force required to push urine out when one wishes to urinate.
It can be thought of as the ‘subfloor’ on which the mucosa (‘carpet’) and lamina propria (‘underlay’) sit.
There are 2 layers of muscle (subfloor - like wood or concrete)
Superficial muscle. Denoted on staging as T2a.
Deep muscle. Denoted on staging as T2b.
Tumors which have invaded into muscle are invariably high grade. Once in the muscle, these tumors gain access to the lymphatic channels and blood vessels which permit spread to lymph nodes and everywhere else in the body, respectively.
Muscle invasive tumors cannot reliably be removed from the inside using TURBT. Radical treatments, most importantly radical cystectomy but also radiation, provide the only real hopes of cure.
Transurethral resection of tumors is the only reliable way to tell if there is early invasion into the muscle.
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Tumors that have invaded through the full thickness of the bladder wall would be analogous to having the subfloor completely compromised.
The bladder sits within the abdominal cavity - it is not ‘free floating’. Therefore, when cancers go through the entire thickness of the bladder wall, they can continue to invade into the surrounding structures.
Perivesical fat - the fat directly outside the bladder
Other organs: bladder cancer can spread anywhere in the body, but the regional pelvic lymph nodes, lungs and liver are the most common areas.
Tumors that have invaded through the full thickness of the bladder wall have often metastasized.
Diagnosis
Bladder cancer is most commonly diagnosed when there is blood in the urine (hematuria). Virtually all patients who have hematuria require evaluation. In fact, urologists generally approach the work up of evaluation by assuming that urothelial cancer is present and then doing the testing to exclude it.
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The most common symptom by far is blood in the urine (hematuria). Hematuria can be visible or microscopic (invisible to the naked eye but visible under a microscope). ANY blood may be from bladder cancer. This holds regardless of whether the blood is visible or if the patient is taking antiplatelet (e.g. ASA, Plavix) or anticoagulant (e.g. coumadin, apixaban).
Hematuria may be intermittent. That is, urothelial cancers do not need to bleed every day or on a repeated basis at least to start. Waiting until the bleeding is frequent or severe results in delayed diagnosis and worse outcomes.
Some patients may present with urinary symptoms such as urgency, frequency and pain.
Urothelial cancer rarely presents incidentally during routine exam or after death. This type of cancer will make itself known one way or another.
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Urine testing:
Urine analysis is essential to confirm the presence of red blood cells. It may also indicate other diagnoses such as infection. Urothelial carcinoma is uncommon in the absence of microscopic blood in the urine.
Urine cytology. This tests looks for abnormal cells shed in the urine. It cannot be relied upon to exclude the presence of urothelial carcinoma. It is not recommended in the routine evaluation of hematuria.
Other: specialized testing purported to be sensitive for detection or surveillance of bladder cancer have been introduced but not have supplanted cystoscopy and the other recommended tests.
Other tests.
Kidney function tests are routinely ordered.
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Cystoscopy is the most critical test in the evaluation of hematuria. It is complemented by imaging tests.
Because most urothelial cancers occur in the bladder, cystoscopy should be performed as soon as possible, especially when the bleeding is visible. Up to 40% of patients with blood in the urine have bladder cancer.
There is no substitute for cystoscopy.
Urine tests cannot reliably exclude bladder cancer.
Imaging studies (e.g. ultrasound, CT, MRI) cannot reliably exclude bladder cancer.
Some patients try and avoid cystoscopy during the evaluation of hematuria. The reasons given include thinking that intermittent hematuria is not serious, that the absence of other symptoms means that bladder cancer is not present or that the absence of a cancer on imaging is good enough proof that cancer is not present. These are life-threatening errors in judgement and unfounded by that evidence. Every professional organization recommends cystoscopy for hematuria. There are rare exceptions where hematuria does not require cystoscopy and your urologist will be aware of these.
Ureteroscopy is the act of using a scope to evaluate the upper tracts. It is not part of the routine evaluation of hematuria but may be performed if there is suspicion of an upper tract urothelial cancer. Upper tract urothelial cancer are most commonly identified on imaging but can be challenging to diagnose.
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Imaging is utilized to evaluate the upper tracts - the urinary system upstream of the bladder.
During the initial evaluation of hematuria, this may be an ultrasound or special type of CT scan (i.e. CT IVP). Ultrasound may be satisfactory when there is a low risk of urothelial cancer. CT IVP is done in most other circumstances and almost always when the blood can be seen with the naked eye.
In patients with a diagnosis of urothelial carcinoma a CT is always performed and the type of CT will depend on the circumstances. CT IVP is the routine test and a CT of the chest will be added if the cancer is at risk of having spread (metastasized).
There are other specialized tests that may be used including retrograde pyelography, nuclear renograms, MRI scans, and PET scans. These are not part of the routine diagnostic or staging evaluation.
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A sample of tissue for analysis under a microscope and specialized testing is always required to make a final diagnosis. Taking a sample is usually the last step after completing lab tests, cystoscopy and imaging
There are a few ways to obtain tissue. None involve cutting the skin and are done endoscopically - utilizing the normal passages within the body.
Transurethral resection of bladder tumor (TURBT). Surgery most commonly performed for bladder cancer. Both diagnostic and therapeutic.
Bladder biopsy. Used when the tumor is small. This may be done at the time of cystoscopy and can be considered a limited form of a TURBT.
Ureteroscopy and biopsy. Surgery utilized to sample tumors in the upper tract. Mainly for diagnostic purposes since the most common treatment for upper tract urothelial cancer is removal of the kidney and the ureter (nephroureterectomy). In select circumstances, cancer may be ablated with laser or other means.
Repeat samples are taken in the following cases:
Immediate re-TURBT: repeat surgery within 2-4 weeks of the first surgery is done when the tumor is high-grade or the tumor was so large that it could not be removed in a single surgery. Repeat TURBT is considered a standard of care because residual cancer is found in about 1 in 4 patients and initially unrecognized muscle invasion is found in about 1 in 50 patients.
Post-treatment re-TURBT: to assess response to treatment. Especially after intravesical adjuvant treatment (see elsewhere).
Possible recurrence: anytime a recurrence is suspected.
Risk Assessment
Just like any cancer, urothelial cancers may be life-threatening. However, some may be more nuisance and non-life-threatening. Assessing risk is essential in management. Regardless of the level of risk, all urothelial cancers should be treated so that the risk can be fully assessed.
Urothelial cancers that have metastasized (spread outside the urinary system) are invariably high grade and are incurable. The prognosis is months to a a few years at best. Metastatic urothelial cancer is a terrible disease and the primary goal in the management of urothelial cancer is to prevent this occurrence.
Risk assessment means:
Assessing the current state of affairs.
Predicting the likely future behavior of the tumor: the risk of recurrence (the cancer comes back) and progression (the tumor invades more deeply into the surrounding tissues or metastases).
Assessment of bladder cancers is often ore straight forward than for upper tract urothelial cancer
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Knowing what one is dealing with the the best of one’s ability is the cornerstone of treatment. There are 2 components.
Pathology Assessment
Pathologic assessment involves analyzing a sample of the tumor taken at the time of surgery. The analysis results in a pathology report. Information gleaned from the analysis provides information on the nature of the tumor and is also utilized to assess stage (see below).
Important details:
Tumor grade. This is the most important piece of information because only high grade tumors are capable burrowing into the underlying muscle. Muscle invasion is prerequisite for the cancer spreading elsewhere in the body and becoming incurable. High grade tumors have the potential to be or to become lethal.
Depth of invasion. Tumors which are capable of invading the wall of the bladder also have the ability to metastasize and become incurable. Tumor grade and depth of invasion go hand in hand.
Variant (divergent) histology. Some urothelial cancers exhibit secondary changes. All of these are associated with more aggressive behavior. Examples: sarcomatoid, plasmacytoid, neuroendocrine (small cell and large cell), micropapillary, nested.
Staging Assessment
‘Staging a cancer’ is the process of knowing how where and how much cancer is present. Staging typically combines physical examination, pathology reports and imaging studies.
Broadly speaking, urothelial carcinomas of the bladder may be classified as:
Clinically localized. There is not evidence that the cancer has spread based on a full assessment. Clinically localized bladder cancer is further subdivided into non-muscle invasive (NMIBC) and muscle invasive bladder cancer (MIBC). While both are concerning, MIBC is particularly concerning because these cancers are at very high risk of becoming incurable if they have not already done so.
Metastatic. The may also be called systemic and indicates that the tumor has spread beyond the bladder. These are rarely curable and the prognosis is guarded. Urothelial carcinoma may spread anywhere in the body. Lung, liver, lymph nodes are the most common
A very important caveat is that tumors that appear not to have spread (metastasized) may already have done so but the amount metastatic tumor may currently below the threshold of detection. This is relevant to high-grade tumors and especially to high-grade tumors that are showing evidence of invasion into the bladder wall.
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Once the current state of affairs has been completed and addressed, the focus changes to predicting future behavior.
Predicting future behavior is most relevant to urothelial cancers which are clinically localized - that is, the cancers that have the potential to be cured. Tumors that have metastasized are still treatable but the prognosis is guarded. Treatment of metastatic tumors largely fall under the purview of medical oncologists with surgeons and radiation oncologists providing assistance where necessary. Furthermore, tumors that are muscle invasive are most commonly managed with surgery (radical cystectomy, often combined with chemotherapy though sometimes radiation plus chemotherapy). Predicting the behavior of muscle invasive and metastatic urothelial carcinoma is far less complicated - the cancer has already shown itself to be a lethal or potentially lethal tumor as the case may be. The response to such a threat is appropriately ‘radical’.
Therefore, prediction of behavior is largely relevant to tumors that are clinically localized and not invasive into the muscular layers.
NIMBC are those confied to the mucosa or lamina propria (the 'carpet or underlay'). They are designated by the stages Ta or T1, respectively. These tumors are frequently curable without major surgery but can, none the less, progress to very dangerous muscle-invasive disease. In many cases, the tumors are more 'nuisance' than 'life threatening', but knowing exactly what sort of risk the tumor brings with it will help individualize treatment.
There are 2 types of risk associated with the non-muscle invasive bladder cancers.
Progression: progression of bladder cancer takes 2 forms.
Tumors can progress in terms of stage - that being from a superficial to a muscle-invasive tumor (i.e. it invades more deeply into the bladder wall).
Tumors can also progress from low to high grade (grade is something established by looking at the cancer cells under a microscope.
Recurrence: bladder cancer has a prediliction for recurrence even if removed. Detecting recurrent tumor before it has the opportunity to progress can reduce the chances of requiring more extensive surgery and death from bladder cancer.
The tumors with the highest risks of progression are also the ones with the highest risk of recurrence.
Risk factors for progression and recurrence include:
Grade. Grade is the strongest predictor of progression. High grade tumors are at high risk of recurrence and progression.
CIS. The presence of carcinoma in situ (CIS) indicated high grade tumor.
Stage: tumors that invade into the lamina propria are staged T1 and have an increased risk of progression to muscle-invasive or systemic disease. All T1 tumors are high grade with rare exception. Technically speaking, T1 tumors are invasive (but not into the muscle).
Number. Multiple tumors (multifocal) are at higher risk for recurrence
Size. Larger tumors (over about 3 cm) are associated with a higher risk of recurrence
Prior recurrence. Tumors that have a recur more frequently are more likely to do so in the future
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After assessment of current and predicted future risk is completed, urothelial tumors can be classified into general groups. This permits for individualized management of bladder cancer (see below).
Clinically localized. No evidence that the tumor has spread elsewhere in the body. Potentially curable.
Non-muscle invasive bladder cancer (NMIBC). Many shades of risk from low to high risk. There are many variations when it comes to treatment.
Muscle invasive bladder cancer (MIBC). Usually require radical surgery or radiation.
Systemic/metastatic bladder cancer. These are incurable. A medical oncologist will manage with support from a surgeon and radiation oncologist.
Management of Bladder Cancer
All patients with bladder cancer start with:
Imaging (CT or MRI or other type).
Transurethral resection of bladder tumor (TURBT).
Untreated bladder cancer, especially high grade tumors, may be lethal. This section addresses what happens after that the initial evaluation and TURBT have been completed..
The treatment of bladder cancer is individualized based on the risk associated with the tumor with further consideration of the patient's circumstances. Bladder cancers are highly variable - some are associated with much more aggressive behavior than others. The following are general guidelines and your treatment may differ based on your circumstances.
See above: ‘Classification - Putting It All Together’.
All patients require surveillance (periodic rechecks) after initial treatment. Cystoscopy is the cornerstone of surveillance - there is no substitute. Urine tests cannot replace cystocopy.
Clinically Localized: Non-Muscle Invasive Bladder Cancer (NMIBC)
NIMBC are those confined to the mucosa or lamina propria (the 'carpet or underlay') - they do not invade into the muscular layer of the bladder. They are designated by the stages Ta or T1, respectively. These tumors are frequently curable without major surgery but can, none the less, progress to very dangerous muscle-invasive disease. In many cases, the tumors are more 'nuisance' than 'life threatening', but knowing exactly what sort of risk the tumor brings with it will help individualize treatment.
The goals of treatment are to prevent recurrence (tumor comes back) and progression (tumor becomes high grade or muscle invasive) of the cancer (see Predicting Future Behavior above). Preventing cancer progression is the most important goal since progression in bladder cancer may be lethal and almost always requires radical treatment.
Patients with NMIBC are split into 3 groups for the purposes of management:
Low risk NMIBC: first presentation, stage Ta, low grade, less than 3 cm, no CIS.
Intermediate risk NMIBC: anything that is not low or high risk.
High risk NMIBC: any of stage T1, high grade (grade 3/3), any CIS, a mix of criteria (need all of multiple, recurrent and large (>3 cm), Ta, grade 1 or grade 2 tumor).
Very high risk NMIBC: high risk patients who have multiple high risk features or those with additional factors including age >70, multiple papillary tumors, tumor diameter >3 cm
Recommendations for intravesical treatment and the frequency and nature of surveillance are what vary between treatments. With increasing risk, the intensity of surveillance and the use of additional (adjuvant treatments) increase as well.
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If a patient smokes, they need to stop NOW.
Transurethral resection of bladder cancer (TURBT) is necessary in all patients.
Immediate post-operative adjuvant intravesical therapy (IVT) may be appropriate.
The prognosis is excellent though careful monitoring is necessary to ensure the cancer does not become intermediate or high risk.
Surveillance is always necessary.
Cystoscopy: at 3 months and then every 6-12 months to a minimum of 5 years. Most patients will be followed indefinitely.
Imaging: optional.
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Individualized. Surveillance schedule typically between low and high risk tumors.
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If a patient smokes, they need to stop NOW.
Transurethral resection of bladder cancer (TURBT) is necessary in all patients.
Immediate post-operative adjuvant intravesical therapy (IVT) may be appropriate.
Adjuvant IVT with BCG is usually indicated.
All patients must be aware that they are at risk for needing radical cystectomy or other radical treatment.
Surveillance:
Cystoscopy: performed at 3 months and usually every 3 months for at least 2-3 years and decreasing frequency thereafter.
Surveillance cystoscopy should occur life-long because late recurrences (after 10 years) do occur.
Imaging: generally at 1 year and then periodically.
Urine cytology: every 6 months or so.
Risk of Progression
1 in 7 patients will progress to muscle invasive disease over the course of 10 years and require radical treatment.
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The management of very high risk tumors is similar to the high risk group but in addition recognizes the roughly 1 in 2 risk of disease progression.
Early cystectomy should be considered.
Intravesical Treatment for NMIBC: Medication Instilled Into The Bladder
Intravesical means ‘into the bladder’. Intravesical treatment (IVT) is a treatment where medication is placed into the bladder by way of a temporary catheter. The medication coats the inner surface of the bladder with the goal of reducing the risk of recurrence and progression. Treatments that are given after the primary treatment (in this case TURBT) are known as adjuvant treatments. Therefore, short hand for this treatment is ‘adjuvant IVT’.
Adjuvant IVT is almost exclusively used in non-muscle invasive bladder cancer. It is almost never used for muscle invasive bladder cancer.
There are a variety of adjuvant IVT’s that are in use. The primary ones are BCG and gemcitabine. IVT’s not using BCG are sometimes administered at the time of surgical removal of the tumor and are called ‘post-operative intravesical installation of chemotherapy’.
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Bacillus Calmette-Guerin (BCG) BCG is an attenuated (weakened) strain of the tuberculosis bacteria (Mycobacterium tuberculosis) which can cause lung infections.
The bladder is intentionally inoculated with this bacteria. BCG induces a very specific immune reaction which happens to not only eradicate the bacteria but has the side-benefit of killing cancer cells as well. One can think of this is an immunization against bladder cancer, though technically it is not.
This treatment was introduced in the 1970's by a Canadian urologist and is the mainstay of treatment higher risk NMIBC.
BCG is commonly used for NMIBC of intermediate or high risk. BCG is not helpful with low risk tumors.
The first series of BCG treatment is called induction. To achieve maximal effect, induction should be followed by a series of repeated treatments called maintenance. The duration of maintenance is usually a total of 1 year for intermediate risk and 3 years for high risk bladder cancers.
Benefits of BCG Treatment
Treatment reduces the risk of progression by 35%. Those who can tolerate 3 years of maintenance are just under half as likely to be free of recurrence than if they were only to receive induction (41% vs. 60% recurrence).
Timing of BCG Treatment.
BCG treatment is typically withheld until:
The blood has visibly cleared following tumor resection.
For 2 weeks after resection.
After traumatic catheterization.
Patients with symptomatic bladder infection (pus or asymptomatic bacteria are not contraindications)
BCG should not be used in the following circumstances.
Pregnant or lactating patients.
Active TB.
Immunosuppressed patients (e.g. AIDs, leukemia, lymphoma), chemotherapy or immunosuppressive drugs.
Fever.
Receiving antibiotics that interfere with the action of BCG (e.g. fluoroquinolones).
Prior adverse reaction or allergy to BCG.
Bladder perforation.
Sexual activity during BCG treatment.
Avoid intercourse for 2 days after instillation. Use barrier protection (e.g. condoms) during the entire course of treatment (AUA Guideline).
BCG Administration: How it is Done
Occurs at the hospital on an outpatient basis. Usually takes about 1 hour.
Catheter placed temporarily in the bladder.
Small volume of the active bacteria in instilled through the catheter.
The treatment is always administered at a frequency of once a week.
How often are treatments given?BCG treatments are administered on a weekly basis. The frequency and dose may be modified based on response.
Induction: 6 weeks of weekly 1 hour treatments.
Maintenance: 3 weeks of weekly 1 hour treatments. May last up to 3 years. Given at 3, 6, 12, 18, 24, 30 and 36 months after induction.
Checking Response To Treatment
Response to treatment is assessed 3-6 months after the 6 week induction course with cystoscopy and/or TURBT.
Side-Effects of BCG Treatment
While BCG is generally well tolerated, as with any treatment, BCG may cause side effects. Most side effects will resolve on their own. Most side-effects are similar to a bladder infection and show that the medication is working. Real infections may occur and a urine culture will tell the difference.
Side effects of BCG.
Dysuria
Urgency
Frequency
Malaise
Arthralgia/flu-like symptoms
Low-grade Fever/chills
Skin rash/eruptions
Loss of appetite
Nausea/vomiting
Urinary Incontinence
Bladder Spasm
Blood in the urine
Complications of BCG (much less common).
Urinary tract infection
Epididymitis/Orchitis
Abscess formation
Hematuria with clot retention
Fever >38.5 Celsius
Myelosuppression
Ureteral obstruction
Bladder contracture/necrosis
BCG sepsis
Neutropenia
Tissue necrosis with extravasation
Pneumonitis
Hepatitis
Death
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Gemcitabine is a chemotherapy that mimics abuilding blocks of DNA and RNA (cytosine). When the body mistakenly uses gemcitabine the process of copying the DNA or RNA grinds to a halt and the cell dies.
Because cancer cells are replicating more rapidly than normal cells, cancer cells are more likely to die.
Gemcitabine IVT on its own is only useful for low grade tumors. It can reduce the 4-year risk of recurrence from 1 in 2 down to 1 in 3.
Side-Effects
Gemcitabine is remarkably well tolerated when given in the bladder.
Early data suggest that side-effects do not seem to be any different than placebo. That is, the additional risk of not giving the medication is minimal to none.
References:
SWOG SO337 doi:10.1001/jama.2018.4657
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There are a number of adjuvant IVT’s including:
Mitomycin C (almost completely replaced by gemcitabine).
Epirubicin
Doxorubicin
Adriamycin
Investigational agents
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BCG intravesical treatment is not guaranteed to work. Persistent or recurrent cancer despite treatment with BCG is serious and requires discussion of radical surgery or radiation.
BCG is administered to patients who are at higher risk of recurrence and progression. Progression to muscle invasive disease is the primary concern but persistence or recurrence despite BCG treatment are markers for aggressive cancer.
Not all cancers that persist following treatment with BCG are treated the same. Also, it may take up to 6 months for a full response after induction is completed. About 1 in 4 patients who have a small amount of cancer at 3 months will not have cancer at 6 months.
Most patients should have radical surgery or radiation but there may be a role trying other intravesical treatments before doing radical treatments.
Clinically Localized: Muscle-Invasive Bladder Cancer
Bladder cancers that have invaded into the muscle layer may still be curable. Muscle-invasive bladder cancers (MIBC) are invariably high grade and have a high risk of spreading if not treated aggressively. About 1 in 3 to as many as 1 in 2 patients who do not appear to have evidence of spread at the time of initial assessment will in reality have cancer that has already spread but is not yet detectable because the amount of cancer that has spread is below the threshold of detection. What this means is that about up to 1 in 2 patients who appear to have clinically localized bladder cancer will die from their cancer within 5 years despite best efforts at cure. Muscle invasive bladder cancer is a life-threatening disease.
The 2 primary options for treatment of MIBC are:
Radical cystectomy: Removal of the bladder and surrounding organs (prostate in males and uterus in females) plus pelvic lymph nodes plus urinary diversion/reconstruction is considered the standard treatment for muscle invasive bladder cancer. Often combined with chemotherapy before surgery (neoadjuvant chemotherapy) and sometimes chemotherapy after surgery (adjuvant chemotherapy). There are rare circumstances where removal of part of the bladder is possible (partial cystectomy).
Radiation combined with adjuvant chemotherapy after TURBT. This is also known as ‘trimodal therapy’ or ‘TMT’ and is an option only in very selective circumstances. In those select circumstances it can be as effective as radical cystectomy.
Chemotherapy is not capable of curing bladder cancer on its own. It is always used as an adjunct to radiation or surgery. Chemotherapy utilized on its own is restricted to patients who are incurable.
Management of patients with MIBC is highly specialized and it is beyond the scope of this website to describe all of the important nuances. Some general information follows.
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Radical cystectomy (RC) is considered the standard of care for muscle invasive bladder cancer.
It is a major surgery associated with a high risk of complications even in experienced hands. Despite this, RC is the most attractive option in patients with muscle invasive bladder cancer since inaction invariably results in death (the 5 year survival for metastatic bladder cancer approaches 0) and RC outperforms trimodal therapy (see below) in almost all circumstances.
Neoadjuvant Systemic Therapy
Neoadjuvant systemic therapy is medication administered prior to radical surgery for cancer.
The goal is to ‘clean up’ small amounts of cancer that may already have spread - remember that up to 1 in 2 patients who seem to have cancer limited to the bladder itself will actually have spread to other areas of the body.
The medication regimen most commonly uses cisplatin. The use of cisplatin based regimens result in about 1-2 more patients out of 20 patients being alive at 5 years after treatment. Stated another way, cisplatin based chemotherapy improves the 5-year survival by 5-8%.
Adjuvant Systemic Therapy
Adjuvant systemic therapy is medication administered after radical surgery for cancer.
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Radiation plus chemotherapy following transurethral resection of bladder cancer is an attractive option to radical cystectomy because one gets to keep their bladder and avoid major surgery. However, it cannot be done in many common circumstances.
Any of the following preclude trimodal therapy (TMT) - these make the vast majority of patients ineligible for TMT.
Multiple tumors.
Large tumors (>3 cm or so).
Carcinoma-in-situ (CIS): multifocal or extensive CIS.
Obstruction of the kidneys.
Poor bladder function.
It can be considered outside these parameters for patients who are not fit for surgery.
The early (1-2 years) of trimodal therapy can approach those of radical cystectomy, however, the long-term results appears to be worse even considering that TMT is restricted to a select group of patients.
Quantitative Risk Assessment Tools
Sometimes classifying patients with NMIBC into low, intermediate and high risk is not satisfactory. These tools can be used in those circumstances.
TAT1 TUMORS - NMIBC PREDICTION OF RECURRENCE AND PROGRESSION
The European Association of Urology has provided a set of tools for predicting recurrence and progression. It utilizes a scoring system based on the 6 most significant clinical and pathological factors.
IMPORTANT: This tool does NOT take into account the beneficial effects of adjuvant intravesical therapy. The Cueto risk tool does take this into account.
| Factor | Recurrence | Progression |
|---|---|---|
| Number of tumours | ||
| Single | 0 | 0 |
| 2-7 | 3 | 3 |
| ≥8 | 6 | 3 |
| Tumour diameter | ||
| <3 cm | 0 | 0 |
| ≥3 cm | 3 | 3 |
| Prior recurrance | ||
| Primary | 0 | 0 |
| ≤ 1 recurrance/year | 2 | 2 |
| > 1 recurrance/year | 4 | 2 |
| category | ||
| Ta | 0 | 0 |
| T1 | 1 | 4 |
| Concurrent CIS | ||
| No | 0 | 0 |
| Yes | 1 | 6 |
| Grade | ||
| G1 | 0 | 0 |
| G2 | 1 | 0 |
| G3 | 2 | 5 |
| Total Score | 0-17 | 0-23 |
| Recurrence Score | Probability of recurrence at 1 year | Probability of recurrence at 5 years | ||
|---|---|---|---|---|
| % | (95% CI) | % | (95% CI) | |
| 0 | 15 | (10-19) | 31 | (24-37) |
| 1-4 | 24 | (21-26) | 46 | (42-49) |
| 5-9 | 38 | (35-41) | 62 | (58-65) |
| 10-17 | 61 | (55-67) | 78 | (73-84) |
| Progression Score | Probability of progression at 1 year | Probability of progression at 5 years | ||
|---|---|---|---|---|
| % | (95% CI) | % | (95% CI) | |
| 0 | 0.2 | (0-0.7) | .8 | (0-1.7) |
| 2-6 | 1 | (0.4-1.6) | 6 | (5-8) |
| 7-13 | 5 | (4-7) | 17 | (14-20) |
| 14-23 | 17 | (10-24) | 45 | (35-55) |
Note that we offer the full spectrum of bladder cancer surgery and treatments:
Transurethral reconstruction
The full spectrum of urinary diversion including Ileal Conduit and Studer Pouch
On the Web
General Information on Cancer
BC Cancer Agency: Good general website from the British Columbia Cancer Agency. Has contact information on locations.
National Cancer Institute: Excellent source of understandable and mainly unbiased information. Several very good brochures on every stage of prostate cancer.
National Comprehensive Cancer Network: peer-reviewed expert content/prostate cancer guidance on evidence-based cancer diagnosis and management. Best for Prostate and Kidney Cancer. The most in-depth information is located in the physician section and requires registration.