Download A Review of Current Guidelines and Best Practice

A Review of Current Guidelines and Best Practice Recommendations for the
Management of Nonmuscle Invasive Bladder Cancer by the International
Bladder Cancer Group
Maurizio Brausicorrespondence†,email, J. Alfred Witjes‡, Donald Lamm§, Raj Persad†, Joan
Palou∥, Marc Colombel§, Roger Buckley†, Mark Soloway¶, Hideyuki Akaza†, Andreas
Böhle†
Purpose
Although the European Association of Urology, First International Consultation on Bladder
Tumors, National Comprehensive Cancer Network and American Urological Association
guidelines all provide an excellent evidence-based framework for the management of nonmuscle
invasive bladder cancer, these guidelines vary with respect to important issues such as risk level
definitions and management strategies for these risk categories. Therefore, we built on the
existing framework provided by current guidelines, and provide consensus on the definitions of
low, intermediate and high risk nonmuscle invasive bladder cancer, as well as practical
recommendations for the treatment of patients in each of these risk categories.
Materials and Methods
An international committee of experts on bladder cancer management identified and analyzed the
European Association of Urology, First International Consultation on Bladder Tumors, National
Comprehensive Cancer Network and American Urological Association guidelines as well as the
published English language literature related to the treatment and management of nonmuscle
invasive bladder cancer available as of April 2010.
Results
Based on review of the current guidelines and literature, the International Bladder Cancer Group
developed practical recommendations for the management of nonmuscle invasive bladder
cancer.
Conclusions
Complete transurethral bladder tumor resection is recommended for all patients with nonmuscle
invasive bladder cancer. For low risk disease a single, immediate chemotherapeutic instillation
after transurethral bladder tumor resection is recommended. For intermediate or high risk disease
there is no significant benefit from an immediate, postoperative chemotherapeutic instillation.
For intermediate risk disease intravesical bacillus Calmette-Guérin with maintenance or
intravesical chemotherapy is recommended. For high risk disease bacillus Calmette-Guérin
induction plus maintenance is recommended. The appropriate management of recurrence
depends on the patient level of risk as well as previous treatment, while the management of
treatment failure depends on the type of failure as well as the level of risk for recurrence and
disease progression.
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Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer Overview of
BCG Immunotherapy
Author: Gary David Steinberg, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO,
FACS
Overview of BCG Immunotherapy
Currently, bacillus Calmette-Guérin (BCG) is a live attenuated strain of Mycobacterium bovis
and is the only agent approved by the US Food and Drug Administration as the primary therapy
of carcinoma in situ (CIS; see image below) of the bladder. BCG supplanted cystectomy as the
treatment of choice for CIS in the mid 1980s.BCG therapy also reduces the risk of recurrence
and BCG therapy with ongoing maintenance therapy reduces the risk of progression in patients
with high-grade nonmuscle invasive bladder cancer.[1]
Bladder cancer is the only cancer in which BCG is commonly used. Other agents have been used
in bladder cancer, but none has surpassed the effectiveness of BCG.
For BCG to be effective, the host should be immunocompetent, the tumor burden should be
small, direct contact with the tumor should occur, and the dose should be adequate to incite a
reaction. Studies have consistently shown that BCG treatment can eradicate this cancer in 70%
of patients with CIS who meet these criteria. To prevent cancer recurrence, long-term
maintenance therapy following the induction phase is necessary.
Typically, BCG is administered in either an induction (once weekly for 6 weeks) or maintenance
(once weekly for 3 weeks) course. Another 6-week course may be administered if a repeat
cystoscopy (see image above) reveals tumor persistence or recurrence. Recent evidence indicates
that induction therapy combined with maintenance therapy every 3-6 months for 1-3 years may
provide more lasting results. Periodic bladder biopsies are usually necessary to assess response.
Mechanism of Action of BCG
The mechanism of action of BCG therapy is incompletely understood. Some early studies
purported that an immune response against bacillus Calmette-Guérin (BCG) surface antigens
cross-reacted with putative bladder tumor antigens, and this was proposed as the mechanism for
the therapeutic effect of BCG; however, multiple subsequent studies refute this claim.
Once in the bladder, the live organisms enter macrophages, where they induce the same type of
histologic and immunologic reaction as found in patients with tuberculosis. BCG vaccine also
has been shown to have a predilection for entering bladder cancer cells, where the proteins are
broken down and fragments are combined with histocompatibility antigens and displayed on the
cell surface. This induces a cytokine and direct cell-to-cell cytotoxicity response, which targets
these cells for destruction.
The overall response to BCG is limited if the patient is immunosuppressed.
Contraindications to BCG
Contraindications to bacillus Calmette-Guérin (BCG) vaccine therapy include
immunosuppression, cancer invading the bladder muscle, and large tumor volume. Because BCG
is a live attenuated organism, it can cause an acute disseminated tuberculosislike illness if it
enters the bloodstream (BCG sepsis), possibly resulting in death. Reports have described BCG
vaccine organisms identified on vascular grafts in patients who have died following BCG
vaccine sepsis. Therefore, the use of BCG is contraindicated in patients with gross hematuria,
traumatic catheterization, and recent bladder tumor resection. Additionally, total bladder
incontinence is a contraindication, as patients cannot retain the BCG solution.
BCG Strains
The original bacillus Calmette-Guérin (BCG) strain was developed at the Pasteur Institute from
an attenuated strain of Mycobacterium bovis. Subcultures were made and sent to other parts of
the world. Two BCG products are commercially available in the United States. The Tice strain,
which is a substrain of the original Pasteur product, is manufactured by Organon
Pharmaceuticals. The TheraCys strain is made by Aventis/Pasteur. These products, in addition to
the Tokyo 172 substrain and the Danish substrain, are available in countries other than the
United States.
No one product has been shown to have consistent clinical superiority. BCG viability is an
important consideration for the vaccine to be effective. This viability is measured in colonyforming units (CFUs). A vaccine that contains no or very few live organisms would be clinically
ineffective. One dose, either an ampule or vial, may vary in weight from one product to another,
but the CFU should be similar. Tice BCG has 1-8×10-8 CFUs. TheraCys has 10.5 +/-8.7×10-8
CFUs.
In a study that compared Tokyo172 with the Connaught vaccines, Ikeda et al found that the
Tokyo172 vaccine had 48.77 +/-5.43 CFUs per dose, while the Connaught strain had 3.77 +/-
1.45 CFUs.[2] This implies that a smaller dose of Tokyo172 is likely to be as effective as a much
larger dose of the Connaught strain.
BCG Immunotherapy Technique
Preparation
The BCG solution is prepared by initially dissolving the freeze-dried powder with the diluent
that comes with the preparation. This solution is diluted further with saline, so that the total
volume is approximately 30 mL
The individuals who prepare and administer BCG should wear gloves and avoid spilling or
touching the vaccine. BCG may cause a strong local reaction in a sore or a cut. If the vaccine is
splashed into an eye, it should immediately be washed. This is a preparation that contains live
organisms; care should be taken during preparation, administration, and disposal of the supplies.
The BCG solution should be used within 2-3 hours. It is instilled into the bladder via a small
catheter by gravity or a slow drip (not forced into the bladder).
The solution should be retained for 1.5-2 hours, after which time the patient voids. The patient is
encouraged to move positions every 30-45 minutes to allow the BCG solution to contact all
portions of the bladder lumen. If the patient’s bladder ordinarily retains more than 60 mL of
urine, the bladder may need to be drained after the BCG solution is retained for 2 hours.
Patients do not have to remain in the office during the retention time. Patients should not be
given antibiotics at the time of the instillation. These medications can kill the live organisms and
negate the effect of the treatment.
The patient should wash out the toilet with bleach following the next 3 urinations to avoid
exposing other family members to the vaccine.
BCG induction therapy
To a BCG reaction, multiple instillations of BCG are required. Typically, 6 weekly instillations
constitute the induction phase, although some patients respond with fewer instillations and
some require more. Each patient's response should be assessed each time the patient comes for
an instillation.
The induction phase is considered complete when the immunologic reaction has occurred. This is
evident when the patient has irritative bladder symptoms, the urine contains WBCs without
evidence of infection, and microscopic hematuria is present. Once the patient has been induced
or vaccinated, this phase of therapy has been completed.
BCG maintenance therapy
When induction is completed, a course of immunoprophylaxis or maintenance therapy is begun.
Prolonging the course of therapy has been shown to reduce the frequency of recurrence and
progression. These intervals have varied from instillations administered monthly to every 3
months or every 6 months. The optimum frequency and duration of this therapy seems to vary,
but a Southwest Oncology study found that 2-3 instillations every 3 months is effective.
Most experts agree that a maintenance program of at least 1 year is necessary. From the
immunologic point of view, establishing this interval is difficult because patient variability is
great and this is a biologic product whose dose may differ slightly with each instillation. The
products also vary. Antigenic stimulation becomes greater with consecutive instillations but
decreases dramatically when the stimulation is excessive.
Data from a small study conducted by Palou et al indicated that patients who are tumor-free after
6 months of therapy are likely to remain so indefinitely and do not need additional maintenance.
Most studies have shown the benefit of using maintenance therapy for at least one year.
Tolerability of therapy
Patients often have difficulty completing long-term therapy because of irritative adverse effects
in the bladder. In such cases, the intervals between instillations should be lengthened; in
addition, dose modification may also be necessary. Generally, a full ampule is administered, but
some patients respond just as well to half or even one third of a dose and seem to have fewer
adverse effects. The dose selection depends on the degree of reaction in the patient. Patients
treated with the Tokyo172 substrain need only a 25% dose because of the potency of this
product. The intent of the treatment is to elicit an immune response without overwhelming the
immune system.
Adverse Effects of BCG
Usually, the first 1-3 instillations of bacillus Calmette-Guérin (BCG) vaccine cause very few
adverse effects, unless the patient has been previously vaccinated with BCG vaccine or has a
history of tuberculosis. After the third instillation, patients usually begin experiencing irritative
bladder symptoms and/or flulike symptoms that last 24-72 hours. These symptoms are usually
mild and can be controlled with bladder antispasmodics, NSAIDs, and antihistamines, and they
are often perceived as favorable immunological responses to the therapy. Nearly 80% of patients
can expect to experience this type of reaction.
A study by Rosevear et al found that a poor response to BCG plus interferon-α therapy in
patients with carcinoma in situ were associated with prior tumor stage, 2 or more prior BCG
failures, and a BCG failure pattern.[5]
Patients who develop a fever of higher than 39°C (102.2°F) and those who have gross hematuria,
severe irritative symptoms lasting more than 72 hours, a urinary tract infection, elevated liver
enzyme levels, arthritis, epididymoorchitis, or acute prostatitis should not receive additional
BCG vaccine therapy until these findings have resolved. These are symptoms of a systemic BCG
reaction, and further administration is unnecessary, immunosuppressive, and potentially lethal.
BCG therapy should be administered at reduced doses half or a quarter dose can be administered.
Severe reactions to BCG vaccine, including high-grade fevers (ie, temperature >40°C [104°F]),
hepatotoxicity, respiratory distress, chills, hemodynamic instability, and mental status changes,
suggest life-threatening septicemia. These are emergencies, and patients should be hospitalized.
A urine culture should be obtained because many cases of septicemia following BCG vaccine
instillation are caused by more common uropathogens, rather than the organisms in the BCG
vaccine. Tuberculosis organisms from the urine or tissues are usually difficult to culture.
Treatment should be initiated without waiting for culture results. Broad-spectrum antibiotics
should be administered intravenously, and the patient should be started on antituberculosis
therapy, including rifampin, isoniazid, and cycloserine, which is the only antituberculosis drug to
reach bactericidal levels within 24 hours of administration. Corticosteroids are also
recommended in some patients.
When BCG vaccine therapy was introduced, several deaths were reported, all of which could be
attributed to improper use of this agent. Today, a death is extraordinary because clinicians have
learned how to administer this agent and to stop therapy before a patient becomes ill.
(BS Nguyễn Ngọc Hiền tổng hợp)