There are several strategies to minimize the risk of bladder cancer recurrence and progression following the initial transurethral resection. These treatments are called 'adjuvant'. The medications are all administered through a urethral catheter into the bladder (intravesical). Commonly used treatments include:
- Mitomycin-C (MMC)
- Bacillus Calmette Guerein (BCG)
- Ohter: Epirubicin, Gemcitabine, Doxorubicin, adriamycin
Indications for Induction Intravesical Therapy are
- Intermediate risk patients: usually just a 6 week course of MMC
- All high risk patients should receive BCG induction and maintenance
Bacillus Calmette-Guerin (BCG)
BCG is an attenuated (weakened) strain of tuberculosis. The bladder is intentionally innoculated with bacteria. BCG induces a very specific immune reaction - the goal of the body's immune reaction is to clear the BCG from the bladder. While the goal of the body is to clear the BCG infection, a beneficial side-effect is clearance of the cancer cells. While this process is not technically an immunization, it is simple to think of it as such with an 'induction' course of treatment followed by 'booster' courses.
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 (as defined above). BCG is not helpful with low risk tumors. To achieve maximal effect, the induction should be followed by maintenance - usually a total of 1 year for intermediate risk and 3 years for high risk bladder cancers. It reduces the risk of progression by 35%. Those who could tolerate the 3 years of maintenance were more likely to be free of recurrence (60%) compared to induction alone (41%)
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 bacteriurea are not contraindications)
BCG is contraindicated for
- Pregnant or lactating patients
- Active TB
- Immunosuppressed patients (e.g. AIDs, leukemia, lymphoma), chemotherapy or immunosuppressive drugs
- Febrile illness
- 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).
Administration occurs at the hospital with placement of a catheter into the bladder and then instillation of a small volume of the active bacteria. The treatment is always administered at a frequency of once a week.
- Induction: This is a 6 week course (once per week) following which a bladder biopsy is usually performed to confirm complete response. The biopsy typically occurs 6 weeks after completion of the induction course. induction is the most important component of BCG treatment
- Maintenance: this can reduce the frequency of recurrence is but is not always tolerated. These are 3 week treatments given at 3, 6, 12, 18, 24, 30 and 36 months
Response to treatment is assessed 3-6 months after the 6 week induction course with cystoscopy and/or TURBT.
Side effects are generally well tolerated but can be similar to infection. A urine culture is generally used to differentiate BCG reaction (which is the intent of treatment) from non-BCG type infections (which are not the intended effect).
There are a number of uncommon side effects which will be discussed with you by the medical oncologist. The vast majority of patients tolerate treatment well but there are rare side effect that may occur and that you should be aware of. Many of these apply to other types of intravesical treatments such as Mitomycin C.
Side Effects |
Complications |
Dysuria
Urgency
Frequency
Malaise
Arthralgia/flu-like symptoms
Low-grade Fever/chills
Skin rash/eruptions
Anoreia
Nause/vomiting
Urinary Incontinence
Bladder Spasms
Hematuria
|
Urinary tract infection
Epididymitis/Orchitis
Abscess formation
Hematuria with clot retention
Fever >38.5 celcius
Myelosuppression
Ureteral obstruction
Bladder contracture/necrosis
BCG sepsis
Neutropenia
Tissue necrosis with extravasation
Pneumonitis
Hepatitis
Death
|
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. It is progression to muscle invasive disease which is the primary concern but persistence or recurrence despite BCG treatment are markers for disease progression and need to be handled carefully. Not all bladder cancer following treatment with BCG is treated the same and it is important to note that after the induction course it may take up to 6 months for a full response. Having said that, if there has not been eradicated of the disease at 3 months, there is only a small chance (roughly 25%) that further response will be seen by waiting an additional 3 months.
There are 3 ways to think about bladder cancer in the context of BCG treatment
- BCG Refractory: No response to BCG - tumor is the same or worse than before treatment. The disease process despite induction. most patients should underggo cystectomy or chemoradiation (NB: radiation not a good option for CIS). Salvage treatment withanother course of BCG is an option for those who decline upfront cystectomy - generally only if frail or 2 old to tolerate cystectomy.the respponse rate is abbout 30%-50%. A third course of BCG is successful less than 20% of the time.
- BCG Resistant: recurrence or persistent disease but lower volume, lower stage or grade. A second course of BCG or BCG and interferon can be considered with a response rate of about 60%. Often a lower dose of BCG is combined wwith interferon and after 6 weeks of induction maintenance is 3 week courses at 3, 9 and 15 months
- BCG Relapsing: recurrence after an initial complete response. A second course of BCG or BCG and interferon can be considered with a response rate of about 60%. often a lower dose of BCG is combined wwith interferon and after 6 weeks of induction maintenance is 3 week courses at 3, 9 and 15 months
Investigational treatments for recurrence after BCG include intravesical Gemcitabine (2 grams in 100 mL NS for post-operative instillation) and clinical trial (e.g. atezolizumab).
The bottom line is that patients with BCG refractory disease nneed too be managed with great care as this can progress rapidly. Cystectomy should always be discussed.
Mitomycin C (MMC)
Mitomycin C is a chemotherapy which is instilled into the bladder either at the time of bladder tumour resection or following treatment in a series of instillations. It is most effective in reducing the risk of recurrence when the tumor is:
- Low grade
- Solitary
- Smaller
- If there have been
While generally well tolerated, there are a number of serious side effects which can occur including
- Myelosuppression with neutropenia
- Bladder contracture/necrosis
- Extravasation
Most intravesical treatments are well tolerated and importantly can provide a reduction in the risk of progression to lethal disease or recurrences. However, the side-effects can be severe and there are reported cases of complications resulting in death (especially in cases of extravasation).