What is BCG? 

Means BCG Bacillus Calmette-Guérin and is the vaccine used for tuberculosis since 1921. Bacilli is attenuated (weakened) of Mycobacterium bovis (germ that causes tuberculosis in cows). Since 1929 it is known that the tubercle bacillus has antitumor properties when it was observed that a group of patients who developed tuberculosis had fewer tumors than a group of individuals without tuberculosis. Antitumor optimum result is obtained in tumors with the following characteristics: 1 – small tumor, 2 – is essential that there is direct contact between BCG and tumor cells, appropriate dose, the tumor must be located in the body (not effective in metastasis). These characteristics are especially true in the superficial bladder tumor. The BCG was first used in bladder tumor by Morales in 1976. Today after 25 years of use, BCG is fully implemented as a treatment in cases of bladder carcinoma in situ, grade III superficial tumors, residual tumor after incomplete resection of the same, as prevention of tumor recurrence (appearance of new tumors) or progression (tumor more advanced).

How does the BCG?

The mode of action of BCG into the bladder tumor is as stimulating immunity (natural defenses of the individual) to release cytokines (IL1, IL6, IL8) and the multiplication of tumor cells (macrophages, lymphocytes, natural killer and lymphokine activated killer ). Though several routes have been investigated for managing BCG instillations considered the best.

What bladder tumors should be treated with BCG?

 

BCG should be used in patients with tumors of intermediate and high risk of recurrence (occurrence of new tumors) or progression (appearance of more advanced tumor). These tumors are: 1 – the multiple, 2 – invading the submucosa of the bladder (T1), 3 – those that reproduce very quickly (2-3 times a year), 4 – the grade of differentiation 3 ( Grade 3), 5 – the greater than 3 cm and 6 – which are associated with carcinoma in situ. In these tumors, BCG has proven superior to Thiotepa Adriamycin and probably also exceeds mitomycin C. 

BCG should not be used in low-risk tumors such as unique Grade 1, only affecting the bladder mucosa (Ta). In low-risk tumors, the most widely accepted treatment is applied after the operation (RTU) a single dose intravesical chemotherapeutic agent such as mitomycin C.

Format and application of BCG

 

BCG is dispensed as a lyophilized vial requiring reconstitution with 50 ml saline before use. There are several strains of BCG: Connaught (81 mg) (Toronto), Tice (50 mg) (Chicago), Pasteur (Paris), RIVM (Netherlands), Glaxo (England), Armand-Frapier (Toronto) and Moreau (Brazil) though the most used are the first two. Although not set the suitable dose, required at least 106 colony forming units (CFU) to achieve antitumor effect. All strains provide between 100 million and one billion CFU. Wait at least 15 days after the operation to perform the treatment. 

Before each application of BCG should conduct a urinalysis to rule out infection, because if there is, delay BCG treatment until the infection has been treated. 

For application of BCG into the bladder is placed very thin probe through which apply 50 ml of serum in which reconstituted. The instillation should be performed smoothly without much pressure to the syringe. You should avoid excessive use of lubricants because they may decrease the viability of BCG. Should also avoid the use of antibiotics instillation day because they reduce the effectiveness of BCG for their antimicrobial effect. Other substances that may interfere with the mechanisms of action of BCG are aspirin, indomethacin and anticoagulants. If tube placement is difficult and causes bleeding in the bladder or urethra instillation should be postponed because of the risk of adverse effects.

Recommendations for patients treated with BCG

 

The patient should keep the solution of BCG in the bladder for 2 hours and then urinate to empty the bladder. Although not observed the spread of the couple or family, you should consider the following recommendations: 

 

1 – It is recommended that during the first 24 hours the patient urinate sitting to avoid contamination of other people using the same basin. 

2 – should postpone sexual activity for the first 48 hours of installation. 

3 – It is advisable to use condoms throughout treatment with BCG. 

 

It should take the temperature on the day of infusion and the next and should be consulted if the temperature reaches 38.5 ° C.

Therapeutic Scheme

Even though the use of BCG for over 25 years, no one knows the scheme that provides the most benefit with the lower incidence of side effects. The most accepted scheme is instillation weekly for 6 consecutive weeks (unless a dose delay due by the appearance of intolerance or side effects). Recently some studies have shown that the application of maintenance treatment reduces the appearance of tumor recurrence. Maintenance treatment involves the application of three weekly instillations at 3 and 6 months and then every six months to three years. Recurrence was observed after a mean follow up of 7 years in 52% of patients treated only with the cycle of 6 weeks while those who received more treatment (maintenance) only 25% relapsed. However, patients who received maintenance therapy had a higher number of adverse effects. 

Contraindications to BCG

BCG should not be used in patients with reduced immunity such as AIDS patients, active tuberculosis, transplanted, myeloproliferative disorders, Hodgkin’s disease, pregnant or breast-feeding anticoagulant therapy, urinary infection, urinary bleeding active fever over 38.5 ° C and severe urinary symptoms.

Side effects of BCG treatment

The BCG administration produces more side effects that instillation of chemotherapeutic substances such as mitomycin C, thiotepa, Adriamycin or epirubicin. Side effects were classified as local (bladder) or systemic (whole body) and also in terms of severity are considered as mild, moderate or severe. It is considered that 90% of patients treated with BCG present mild or moderate symptoms while severe effects were observed between 2 and 5% of cases and observed complications that may endanger the life of the patient in less than 1 % of cases.

Local effects (bladder) of BCG 

Are observed in about 90% of cases and consist essentially of type cystitis urinary symptoms (urinary frequency, pain, stinging or burning when urinating, urinating very frequently or blood in the urine. These noninfectious cystitis symptoms, begin after 2-4 hours of making instillation. If you do a urine culture undetected germs. In most cases, the symptoms disappear within 48 hours. Treating these symptoms is performed with analgesics and inflammatory or anticholinergics. If symptoms remain at the time of the next instillation is recommended delayed until the complete disappearance of them. The drilling necessary to implement the BCG can cause bacterial cystitis (approximately 20% of cases). If urine culture detects germs and antibiotics should be used should be delayed until the next instillation new urine culture shows that germs are gone. The presence of blood in the urine is a common sign in noninfectious cystitis and should instillation delay if the blood is plentiful.

 

Much less frequently can be seen contracture or contraction of the bladder, ureter obstruction, pus in the urine or inability to urinate.

In the few patients who presented bladder contracture, this appears months to years following treatment with BCG. It is extremely rare occurrence of epididymitis (inflammation of the tube that carries sperm out of the testis) or prostatic granulomas (0.9%), testis (0.4%) and kidney (0.1%).

Systemic effects of BCG

 

The most common systemic effects of BCG are flu-like symptoms (decay, malaise, fatigue, fever less than 38.5 ° C) that resolve spontaneously in the first 24-36 hours after instillation. Less can be observed frequently nausea, vomiting, muscle and joint pain and much less common effects are allergic reactions, hepatitis, pneumonitis, polyarthritis or choroiditis. The most severe systemic effect and is fortunately very rare BCG sepsis which may be fatal (there have been 11 fatal cases in the world literature)

In cases with fever over 39 ° C, if this is not resolved with 12 hours of treatment with antipyretics should begin treatment with substances antituberculosis (isoniazid 300 mg daily, rifampicin 600 mg daily and ethambutol 1200 mg per day for 3 to 6 months) about the risk of being in the presence of a BCG sepsis and should discontinue treatment with BCG. The use of corticosteroids (prednisone 40 mg per day) may be indicated.