Bladder cancer (bladder tumor) is a malignant disease of the bladder. Bladder tumor is a common disease among urological cancers. It is more common in men. Smoking is one of the most important reasons. It is common after 65 years of age. The most important symptom is painless blood in the urine (painless macroscopic hematuria). Treatment varies according to the stage of the disease.

Treatment planning is made according to the stage of bladder cancer. Pathological examination and pathological evaluation (grade, stage) of cancer are important in determining the treatment modality. According to the staging and pathology, performing BCG in appropriate patients is effective treatment. We also administer BCG treatment to our eligible patients. Since 1990, our results have been quite successful. In this article, I will give information about BCG therapy (immunotherapy) in bladder cancer patients, taking into account my own experience.

What is BCG therapy in bladder cancer treatment?

BCG is short for Bacillus Galmette Guerin. BCG is a vaccine made to protect against tuberculosis disease. This vaccine is prepared by reducing the viability of the tuberculosis microbe. BCG prepared from Mycobacterium bovis strain is used for this purpose. In this way, the patient’s immune system is strengthened by giving the tuberculosis microbe with reduced vitality. By giving the BCG vaccine into the bladder in bladder cancer, we strengthen the body’s immune system against cancer. Immune enhancement here is local, not a general condition.

Why is BCG treatment performed in bladder cancer?

Recurrence is a very common problem in bladder cancer. Even if all superficial bladder cancer is removed with TUR, recurrence is seen in approximately 50% of cases. The aim of BCG treatment after TUR is to prevent these recurrences. In other words, BCG is given to prevent the recurrence and regeneration of the disease.

How is BCG treatment performed in bladder cancer?

BCG must be given into the bladder. It should never be given intravenously. Intravenous cases result in death. This point must be paid attention to. Patients who will undergo BCG stop taking excess water a few hours before the procedure. In this way, BCG is prevented from being diluted with excess water. Before the application, the patient urinates or the urine is drained with a catheter.

BCG is normally found in a dry bottle and should be kept in the cold chain. It is diluted with sterile saline (50cc) and given through a catheter placed in the bladder. The patient is kept in the bladder for 2 hours without urinating. The patient lies in different positions in order to contact all parts of the bladder. It is recommended that patients not drink too much fluid before and after administering BCG into the bladder. In this way, it is aimed to keep the urine in the bladder at higher rates and time.

How long is BCG treatment in bladder cancer?

BCG administration in bladder cancer takes place in two stages: induction therapy and maintenance therapy. Induction therapy is given once a week for 6 weeks and in 6 doses. After that, maintenance treatment is started for varying durations according to the risk group of the patient. BCG treatment is not required in the low-risk group, BCG treatment is given for 1 year to the patients in the medium-risk group and for 3 years to the patients in the high-risk group.

In the intermediate risk group, after 6 weeks of induction treatment, three doses of BCG are administered at 3, 6 and 12 months, one week apart.

Patients in the high-risk group are administered BCG in three doses with one-week intervals at the 3rd, 6th, 12th, 18th, 24th, 30th and 36th months following the 6-week induction treatment. This is called the “SWOG protocol” (South West Oncology Group).

When is BCG treatment started in bladder cancer?

BCG treatment is started 10-15 days (2 weeks) after TUR surgery. The reason for this is to wait for the bleeding due to surgery to stop completely. BCG is not applied when there is bleeding from the urine. If done, BCG mixes with the blood and sepsis occurs. Another reason is that the level of fibronectin increases in the urine due to bleeding, BCG binds to fibronectin and is excreted in the urine and its effectiveness decreases. For these reasons, we expect the bleeding in the urine to stop in patients who will undergo BCG. 2 weeks is enough for this.

What should patients who receive BCG treatment pay attention to?

Since BCG is a TB microbe with reduced viability, these patients should pay attention to some issues. These:

• Hands should be washed thoroughly after urinating.
• Care should be taken to clean the toilets used.
• Sexual intercourse should not be done for the first 48 hours after BCG
• Condom should be used during sexual intercourse for 1 month after BCG application.
• Female patients should not become pregnant until BCG treatment is completed.
• The baby should not be breastfed during this treatment.

What do “induction therapy” and “maintenance therapy” mean in BCG therapy?

A correct application is very important to obtain the most effective result from BCG in the immunotherapy of bladder cancer. BCG treatment is started 2 weeks after the TUR operation and is done weekly for 6 weeks. This 6-week practice is called “induction therapy”. In this way, maximum immune system stimulation takes place. Immune system stimulation is adversely affected in long-term applications. Long-term treatment, which is started from the end of the 6th week, is also called “maintenance treatment”. Purpose of maintenance therapy. It is to maintain the immune system stimulated in the first 6 weeks for a long time. After that, a long-term treatment called “maintenance therapy” is applied. There are different protocols applied for maintenance therapy.

What is the success rate of BCG therapy (immunotherapy)?

Studies have reported that BCG treatment prevented the recurrence of the disease by 75.3% in 3-year follow-ups, and 96.1% of the patients continued their healthy lives without disease. The complication rate of varying degrees is 81.5%.

Is BCG a chemotherapy or immunotherapy agent?

No, BCG is not a chemotherapy drug. BCG therapy is an “immunotherapy”. It is given into the bladder. Although chemotherapy drugs are given into the bladder, their effects are different from BCG. Instead of killing cancer cells directly, BCG exerts its effect indirectly by strengthening the immune system.

What is chemotherapy and immunotherapy, what is the difference between them?

Chemotherapy and immunotherapy are different concepts. Chemotherapy is the administration of drugs that directly affect cancer cells and kill them. Agents used in immunotherapy do not directly affect cancer cells, they stimulate the body’s immune system and thus kill cancer cells. BCG does not systemically activate the immune system. It is effective by stimulating the immune system locally in the bladder. The immune system has two main components: humoral immunity and cellular immunity. It is cellular immunity that is effective against cancer. BCG shows its effectiveness by increasing cellular immunity.

Is there a more effective alternative than BCG in preventing bladder cancer recurrences?

New results were obtained in a study from the University of Iova comparing the efficacy of BCG therapy with a combination of gemcitabine and docetaxel into the bladder in the treatment of 312 high-risk patients with non-muscle invasive bladder cancer. Accordingly, combination chemotherapy was found to be more effective than BCG (JAMA Netw Open. 2023 Feb; 6 (2): e230849).

How does BCG affect bladder cancer?

In the treatment of cancer, if the disease is in an advanced stage and the stage of treatment with surgery has passed, chemotherapy is applied. With chemotherapy, cancer cells are tried to be eliminated directly. Recurrence is common after endoscopic removal of the tumor in patients with bladder cancer confined to the bladder. BCG is given into the bladder to prevent these recurrences. This is called immunotherapy. BCG acts by binding to a protein called “fibronectin” found in the structure of the bladder wall in the bladder TUR area. In this region, cells effective in the cellular immune system are collected and increase cellular immunity in a local way. As a result, damage and death occur in cancer cells. In this way, BCG shows its effect immunologically. Because of this effect, BCG is known as an immunotherapeutic agent. The effects of BCG in bladder cancer are as follows:

• Activation of the immune system
• Antitumoral effect on direct tumor cells
• Apoptosis
• Necrocytosis
• Increase in oxidative stress within the cancer cell
• Cytokines such as IL-1, IL-2, IL-6, IL-8, IL-10, 1L-12, tumor necrosis factor-alpha and interferon increase in urine
• Increased level of Interferon gamma in urine

In which cases should patients receiving BCG treatment call their doctor?

Some complaints may be excessive in patients receiving BCG therapy. Patients in this situation should definitely contact their doctor. Patients should inform their doctor in the following cases:

• If there is a long-term high fever of 38 degrees and above
• Complaints such as chills, shivering
• If there is macroscopic bleeding in the urine
• Excessive bladder spasms

Why and how is BCG maintenance therapy performed in bladder cancer?

The aim of post-induction maintenance therapy in bladder cancer is to prevent recurrence of the disease. Maintenance therapy ranges from 1-3 years. With maintenance therapy, it is aimed to maintain the maximum immune system formed as a result of induction therapy. For this reason, long-term treatment given after induction therapy is called “maintenance therapy”. There are different protocols. The most preferred maintenance treatment protocol with a high success rate is the SWOG (South West Oncology Group) protocol.

What are the side effects of bladder cancer BCG treatment?

Some complications occur during the treatment of bladder cancer with BCG. Their severity is of varying degrees. The most common complications are:

Common cold-flu-like symptoms, fever, pain, chills, chills and fatigue are seen. It improves in 2-3 days after treatment. Frequent urination, hematuria, painful urination are common.

The side effects of BCG in the treatment of bladder cancer are examined in two groups: Local, that is, bladder-related complaints (side effects) and systemic complaints. Or we can classify it as urinary system and systemic side effects.

Bladder-related side effects of BGG therapy include:

• Cystitis
• Hematuria (blood in the urine)
• Decreased bladder volume (contracted bladder)
• Painful urination (burning while urinating, dysuria)
• Frequent urination
• Reduction of bladder capacity (bladder contracture)

Side effects of BCG on the upper urinary system

• If there is VUR, the kidneys are infected and there is a risk of sepsis.
• Kidney abscess
• Granuloma in the kidneys
• Ureteral strictures

Side effects related to the lower urinary system

• Side effects on the penis
• Balanitis
• BCG-induced prostatitis
• Epididymitis
• Orchitis
• Urethral strictures

Systemic (general) effects and side effects

• Swelling in regional lymph nodes
• Osteomyelitis
• Systemic infection (BCG sepsis)
• Swelling in regional lymph nodes
• Osteomyelitis
• Systemic infection (BCG sepsis)
• Nausea, vomiting and weakness
• Urinary incontinence
• Neutropenia
• Pneumonia

In which cases BCG is not performed in bladder cancer patients?

BCG therapy is a very effective application in the prevention of bladder cancer recurrences. This treatment cannot be applied to all patients, so some patients have contraindications. BCG is not performed in patients with non-muscle invasive high-grade bladder cancer:

• If the patient has visible bleeding (macroscopic hematuria)
• If the insertion of a catheter into the bladder has been traumatic and there is bleeding
• 7-14 days before TUR surgery
• In very old patients
• People with a very weak immune system (HIV patients)
• People with suppressed immune system (kidney transplant)
• If there is an active urinary tract infection
• If the patient has VUR (vesicoureteral reflux)
• If there is pregnancy
• Breastfeeding mothers
• Pediatric patients
• Those with active tuberculosis disease
• Patients sensitive to BCG

What are the drugs (antibiotics) that reduce the effectiveness of BCG?

BCG is actually a reduced viability tuberculosis bacillus. So it’s a tuberculosis microbe. This is very important for BCG to stimulate the immune system and be effective. For this reason, BCG must be kept in the cold chain. A BCG that loses its vitality loses its effect. Urinary tract infections can also be seen in patients receiving BCG. Antibiotics to be used in the treatment of these should be considered. Otherwise, these antibiotics will also kill the micro-organisms in BCG, and as a result, the effectiveness of BCG will be reduced or not at all. Antibiotics that adversely affect the effectiveness of BCG by killing the tuberculosis bacillus when used during BCG therapy and that should be considered are:

• Aminoglycoside group drugs (amikacin, kanamycin, gentamicin)
• Quinolone group antibiotics

What does BCG deficiency/ineffectiveness mean?

The desired effects may not always be seen in all patients in whom BCG is administered. In this case, it is said that there is no BCG activity. BCG failure is seen at a rate of 30-50%. BCG deficiency is mentioned when:

• If cancer is detected in the follow-ups
• If cancer is detected in the 3rd and 6th month controls
• If a worsening of the course of the disease is detected during the BCG treatment during the follow-ups (increase in the grade and stage of the cancer, CIS detection)

Does BCG treatment show the same effect in everyone?

BCG vaccine, which is used to prevent recurrences due to bladder cancer, does not show the same effect in every patient. Appropriate patient selection is very important in order to achieve the desired effect. In addition, BCG treatment should be given appropriately and a cold chain should be provided. If antibiotics are to be given to patients receiving BCG due to urinary tract infection, appropriate antibiotics should be selected. The desired effect cannot be achieved in patients with insufficient immune system and in elderly patients.

How long does BCG treatment take?

In patients with non-muscle invasive bladder cancer, the most effective treatment for preventing recurrence of the disease and for a longer life is to apply BCG therapy after TUR. Today, this treatment is accepted as the “gold standard treatment” method. BCG therapy continues with maintenance therapy after 6 weeks of induction therapy, lasting approximately 3 years.

How are patients receiving BCG immunotherapy followed up?

Patients receiving BCG immunotherapy for bladder cancer should be checked at regular intervals.

• Urine microscopy: If there is an infection and symptomatic in urine microscopy, treatment should be performed. The negative effects of antibiotics given in the treatment on BCG should be considered.
• Blood count: When deemed necessary, blood count should be done in patients. Because neutropenia (low white blood cells) can be seen in some of these patients.
• Cystoscopy: Cystoscopy is performed every 3 months in the first year, every 6 months in the second year, and then annually. If a tumor is seen on cystoscopy, it should be evaluated for recurrence and appropriate treatment should be given.
• Urinary system USG: Evaluation of the upper urinary system and bladder by ultrasonography gives information about the bladder and kidneys.
• PSA: BCG administration increases the PSA level and this may be confused with prostate cancer. In this respect, it may be appropriate to examine male patients for PSA before treatment.

Is BCG treatment given together with chemotherapy?

Recent studies have shown that the success rate is higher when BCG therapy is combined with chemotherapy (combined therapy). We also recommend combined treatment to our patients when appropriate.

What to do if bladder cancer BCG treatment fails?

If relapses occur in the early period, ie within 12 months, before the end of BCG treatment in patients receiving BCG therapy, a second BCG treatment should be started in these patients. For this, the grade of the recurrent tumor and whether it is carcinoma in situ (CIS) are important. If the recurrent cancer is of high grade and there is no CIS, then a second BCG treatment is started. If these conditions exist, radical cystectomy should be performed. That is, the bladder must be completely removed.

Briefly: In cases where BCG therapy is not effective, there are different treatment alternatives. Appropriate treatment should be applied to these patients. In the case of BCG deficiency, there are mainly two types of treatment options:

• BCG repetition
• Radical cystectomy

Is BCG used for bladder cancer of all stages?

BCG therapy is an immunotherapy method used to prevent recurrences after removal of early-stage cancer with TUR. BCG treatment is not used in advanced stage (metastatic) cancers outside the bladder.

Is there a recurrence in bladder cancer patients receiving BCG therapy?

BCG therapy is a very important and effective treatment method in the prevention of bladder cancer recurrences. Despite this, the disease may recur in 30-50% (40%) of the patients. Appropriate treatment protocol should be selected for patients with relapse.

Is BCG as effective as chemotherapy in preventing bladder cancer recurrence?

Studies conducted to prevent recurrence of bladder cancer have shown that the combination of BCG and chemotherapy is more effective than BCG alone. There are not many studies comparing the effectiveness of BCG with chemotherapy administered into the bladder. In a study conducted in 2023, the combination of gemcitabine and docetaxel was found to be more effective than BCG.

In summary: In the treatment of non-muscle invasive bladder cancers, BCG therapy administered into the bladder is very effective in preventing cancer recurrence. As a result of the complete endoscopic removal of the cancer in the bladder, these patients are treated with BCG. It is a very successful treatment method in preventing recurrences. We always give our patients maintenance therapy. Maintenance treatment lasts up to 3 years. Appropriate treatment and regular follow-up are important. In cases resistant to BCG therapy, appropriate treatment is given to the patient. Cystectomy (bladder removal, radical cystectomy) is one of the methods we prefer in cases of recurrence.

Prof. Dr. Emin ÖZBEK

Urology Specialist

Istanbul- TURKEY