BCG Treatment for Bladder Cancer

At a glance

• What it is: Intravesical BCG (Bacillus Calmette-Guerin) is a live-attenuated strain of Mycobacterium bovis instilled directly into the bladder through a urinary catheter. It is used as immunotherapy for selected non-muscle-invasive bladder cancer (NMIBC) after the tumour has been removed by transurethral resection (TURBT).^1,2,3
• Who it suits: Patients with intermediate-risk and high-risk non-muscle-invasive bladder cancer, including most patients with high-grade Ta or T1 disease and carcinoma in situ (CIS), as defined by the European Association of Urology (EAU) and American Urological Association / Society of Urologic Oncology (AUA/SUO) NMIBC guidelines.^4,5
• What the evidence shows: In high-risk NMIBC, induction BCG followed by a defined course of maintenance BCG reduces the risk of recurrence and the risk of progression to muscle-invasive disease compared with TURBT alone or intravesical chemotherapy.^4,5,6,7 The evidence base includes randomised trials and large meta-analyses.^6,7,8
• What it is not: BCG is not chemotherapy and is not appropriate for muscle-invasive bladder cancer, where treatment is usually radical cystectomy or chemoradiation.^4,5,9
• Where Urology NSW sits: Dr Raji Kooner manages selected patients with non-muscle-invasive bladder cancer through TURBT, intravesical therapy and structured cystoscopic surveillance, with BCG offered to patients whose risk profile and overall health support intravesical immunotherapy. The recommendation in any individual case is made after histology and risk stratification, in line with international guideline frameworks.^4,5

What is BCG?

BCG stands for Bacillus Calmette-Guerin. It is a live-attenuated (weakened) strain of Mycobacterium bovis, originally developed as a vaccine against tuberculosis in the early twentieth century. When BCG is placed inside the bladder it triggers a strong, controlled local immune response in the bladder lining. That immune response also acts against any abnormal urothelial cells that remain after the tumour has been resected, reducing the chance that the cancer will return or progress.^2,3

Intravesical BCG was first reported as a treatment for superficial bladder cancer by Morales and colleagues in 1976,¹⁰ and has been the standard intravesical immunotherapy for high-risk NMIBC for several decades. Several BCG strains are used internationally (TICE, Connaught, RIVM, Tokyo and others); availability in Australia depends on supply.^2,3

BCG is given through a urinary catheter as a sterile suspension. The fluid is held in the bladder for a defined dwell time, then voided into the toilet. Nothing is injected into a vein, and BCG is not a tablet.

When is BCG used?

BCG is used after a bladder tumour has been removed by transurethral resection of the bladder tumour (TURBT) and the pathology has been reviewed. The decision to use BCG depends on how the cancer is classified.^4,5

Bladder cancers that have not invaded into the bladder muscle are grouped as non-muscle-invasive bladder cancer (NMIBC). The EAU and AUA/SUO frameworks divide NMIBC into low-risk, intermediate-risk and high-risk categories based on tumour stage (Ta, T1, CIS), grade, size, number, recurrence pattern and the presence or absence of carcinoma in situ.^4,5,11

• Low-risk NMIBC. A solitary, small, primary low-grade Ta tumour. A single dose of intravesical chemotherapy soon after TURBT is often sufficient, with cystoscopic surveillance afterwards. BCG is generally not used in this group.^4,5
• Intermediate-risk NMIBC. Recurrent or multifocal low-grade Ta tumours that do not meet high-risk criteria. Either a course of intravesical chemotherapy or a course of BCG is reasonable; choice is individualised.^4,5
• High-risk NMIBC. High-grade Ta, any T1, carcinoma in situ (CIS), or selected very-high-risk features (multiple, recurrent, large high-grade T1; variant histology; lymphovascular invasion). For these patients, induction BCG followed by maintenance BCG is the recommended bladder-preserving option, after a careful discussion of the alternative of early radical cystectomy in the very-high-risk subgroup.^4,5

Risk stratification is the single most important step before BCG is offered. The treating urologist will usually review the TURBT pathology, any prior bladder cancer history, the imaging of the upper urinary tract, and the patient's overall health before recommending BCG.

How does BCG work?

BCG is an immunotherapy, not a chemotherapy. When the BCG suspension is held in the bladder, BCG organisms attach to the bladder lining and are taken up by urothelial cells and local immune cells. This triggers a sustained, local inflammatory response involving cytokines, T cells, natural killer cells and macrophages.^2,3,12

That immune response is the active ingredient: it is the body's reaction to BCG, rather than the BCG itself, that targets residual abnormal cells. This is why the side effect profile of BCG is dominated by symptoms of bladder inflammation (frequency, urgency, dysuria) rather than the gastrointestinal or marrow-suppression side effects associated with cytotoxic chemotherapy.^2,3

Because BCG depends on a working immune system to act, patients who are significantly immunosuppressed (for example, those on high-dose immunosuppressant medication or with active untreated HIV) are usually not candidates for intravesical BCG.^4,5

BCG compared with intravesical chemotherapy

For non-muscle-invasive bladder cancer, the two main intravesical options are BCG immunotherapy and intravesical chemotherapy (most commonly mitomycin C, gemcitabine, or epirubicin in different settings).^4,5,6,8

• Single dose of chemotherapy after TURBT. A single intravesical instillation of chemotherapy given within 24 hours of TURBT is supported by meta-analysis to reduce early recurrence in selected low- and intermediate-risk NMIBC. It is not a substitute for a full course of BCG in high-risk disease.^4,5,6
• BCG vs maintenance chemotherapy in higher-risk disease. In intermediate- and high-risk NMIBC, randomised trials and meta-analyses have shown that induction plus maintenance BCG reduces recurrence and progression more effectively than intravesical chemotherapy alone, at the cost of more local urinary side effects and a small risk of systemic side effects.^4,5,6,7,8
• Where chemotherapy is preferred. Intravesical chemotherapy is sometimes chosen when BCG is contraindicated or in short supply, when the patient's risk profile sits at the lower-risk end of "intermediate", or when prior BCG has not been tolerated.^4,5

The choice between BCG and intravesical chemotherapy is not "one is universally better" - it depends on the patient's NMIBC risk category, prior treatment, fitness, immune status, and BCG availability. The discussion is held at the post-TURBT consultation.

The BCG schedule: induction and maintenance

Modern BCG protocols come from the EAU and AUA/SUO guidelines and from the SWOG 8507 trial, which established the survival benefit of maintenance BCG.^4,5,7

• Induction. An induction course is six weekly instillations, starting two to four weeks after TURBT to allow the bladder lining to heal. Each instillation is given in clinic through a small urinary catheter.^4,5,7
• Response check. A cystoscopy (and urine cytology) is usually arranged around three months after the start of induction, to confirm response and to guide what comes next.^4,5
• Maintenance. For high-risk NMIBC, the SWOG 8507 maintenance schedule is three weekly instillations given at 3, 6, 12, 18, 24, 30 and 36 months from the start of induction (a maximum of three years of maintenance). For intermediate-risk NMIBC, a shorter maintenance course (commonly one year) is supported by guideline frameworks.^4,5,7
• Dose modification. A reduced dose (for example one third dose) may be considered in intermediate-risk patients or in patients struggling with tolerability, on the basis of trials including CUETO and EORTC studies. The full standard dose is generally preferred for high-risk NMIBC where supply allows.^4,5

These are guideline-derived schedules. The exact plan for any individual patient is set by the treating urologist after the post-TURBT review, and may be adjusted based on response, tolerability, and BCG supply at the time of treatment.

What to expect at each instillation

1. Before the appointment. A urine sample is checked beforehand to make sure there is no active urinary tract infection. BCG is usually deferred if there is a UTI, traumatic catheterisation, visible blood in the urine, or recent bladder biopsy or TURBT (until healing is complete).^4,5
2. Fluid restriction. Patients are usually asked to drink very little for about four hours before the appointment so that the BCG suspension is not diluted by urine in the bladder.
3. Instillation. A small, soft urinary catheter is passed into the bladder under aseptic conditions. The bladder is drained, then the BCG suspension (typically reconstituted in about 50 mL of saline) is instilled and the catheter is removed.^2,3
4. Dwell time. The aim is to hold the BCG in the bladder for approximately two hours. Some patients find this uncomfortable; the dwell time can be shortened if needed and is still therapeutic.^2,3
5. After the dwell. The patient passes urine into the toilet at the end of the dwell time. Specific household precautions (described below) apply for about six hours after each instillation.

Most appointments take 30 to 60 minutes including check-in, the instillation itself, and a brief observation period. The patient does not need a general anaesthetic.

At home after each instillation

BCG is a live organism, and small amounts are passed in the urine for several hours after each instillation. Standard household precautions for the first six hours after each instillation are:^1,2,3

• Sit down to pass urine to reduce splash, regardless of gender.
• Add ordinary household bleach (about a cup of household bleach) to the toilet bowl after passing urine, leave for 15 to 20 minutes, then flush. Do this for each void in the first six hours.
• Wash hands and the genital area thoroughly with soap and water after each void.
• Drink plenty of fluids for the rest of the day to flush the bladder.
• Avoid sexual intercourse for 24 to 48 hours after each instillation, and use a barrier method (condom) for at least one week to protect the partner from contact with BCG-containing urine.

These precautions are conservative and reflect international patient information for intravesical BCG. They are not a sign that BCG is dangerous to be near; rather, they are a sensible way to keep BCG out of the eyes, broken skin, and the partner's mucous membranes during the period when BCG can still be detected in the urine.

Side effects

BCG is an active treatment and most patients have at least some side effects. The pattern is dominated by symptoms of bladder inflammation. Severity usually increases through an induction course and tends to be greatest after the third or fourth instillation.^2,3,13

Common (often expected)

• Urinary frequency, urgency and burning for one to three days after each instillation.
• Blood-tinged urine, usually settling within 24 to 48 hours.
• Mild flu-like symptoms (low-grade fever under 38.5 degrees Celsius, mild fatigue, mild aches) on the day of instillation.
• Pelvic discomfort.

These symptoms are usually managed with simple oral analgesia (paracetamol), good fluid intake and short courses of bladder-soothing measures. Anticholinergic medication may be added for prominent urgency.

Less common

• Higher fever (38.5 degrees Celsius or above) lasting more than 24 hours.
• Joint pain (arthralgia or arthritis), usually self-limiting.
• Skin rash.
• Granulomatous prostatitis or epididymo-orchitis in men, with localised pain or swelling.
• Symptomatic urinary tract infection from a different organism.

Higher fever, joint inflammation, an unusual rash or significant local pain after BCG should be reported to the rooms or to the patient's general practitioner. Many of these reactions can be managed with a short delay between instillations and simple symptom treatment, but some require formal anti-tuberculous medication.^2,3,13

Serious (uncommon, but important)

• BCG sepsis (disseminated BCG infection). A rare but serious complication, where BCG enters the bloodstream and sets up a systemic infection. Risk factors include traumatic catheterisation, BCG given through a fresh wound (recent TURBT or bladder biopsy), and patients who are significantly immunosuppressed. Disseminated BCG can present with persistent high fever, chills, hypotension, breathlessness, jaundice, or signs that resemble severe sepsis. It requires urgent assessment and treatment with combination anti-tuberculous antibiotics; patients sometimes need hospital admission and intensive care support.^13,14
• BCG involvement of other organs. Granulomatous infection of the lungs, liver, kidneys, vertebrae, or vascular grafts has been reported in case series. Patients with vascular grafts or prosthetic heart valves should ensure their treating team is aware before BCG is given.¹³

When to seek urgent medical attention

BCG is generally well tolerated when the patient is selected appropriately and the precautions above are followed. The patient (or their family) should seek urgent medical attention - present to an emergency department - for any of the following after a BCG instillation:

• Fever of 38.5 degrees Celsius or higher that does not settle within 24 hours, or any fever associated with shaking chills, confusion, low blood pressure, or severe pain.
• Heavy or persistent blood in the urine, or inability to pass urine.
• Significant breathlessness, chest pain, or jaundice.
• Persistent severe pain in the back, joints, lungs, or testicles.

Patients should tell the treating doctor that they have recently had intravesical BCG, because the differential diagnosis and the choice of antibiotic are different from a standard urinary infection. A simple medical alert card (or note in the patient's phone) is helpful.

Follow-up cystoscopy and surveillance

BCG is part of a wider surveillance program; the cystoscopic checks are as important as the instillations themselves.^4,5

• First check. A cystoscopy (and usually urine cytology) is performed around three months after the start of induction BCG, to look at the bladder lining and confirm response.
• Frequency thereafter. For high-risk NMIBC, cystoscopy every three months for the first two years, then every six months to year five, then annually, is a typical guideline-aligned schedule. Intermediate-risk patients can usually be checked less often once they remain disease-free.^4,5
• Upper tract imaging. Periodic imaging of the kidneys and ureters is included in the high-risk follow-up plan, because the same urothelial cancer can develop in the lining of the upper urinary tract.^4,5
• Repeat TURBT. Where there is concern about residual disease (particularly for high-grade T1 tumours), an early second TURBT may be planned before BCG starts, in line with EAU and AUA/SUO recommendations.^4,5

The exact follow-up schedule for any individual patient is set by the treating urologist on the basis of risk category, response to induction, and the clinical findings at each cystoscopy.

If BCG is not enough: BCG-unresponsive disease

Most patients with high-risk NMIBC respond to a full course of induction and maintenance BCG. A subset of patients have disease that does not respond, recurs early, or progresses despite BCG; this is grouped under the heading BCG-unresponsive NMIBC, defined by international consensus criteria.^4,5,15

The standard options at that point are:

• Radical cystectomy. Removal of the bladder, with either a neobladder constructed from bowel or an ileal conduit, is the recommended bladder-removing option for fit patients with BCG-unresponsive high-risk NMIBC.^4,5,9
• Bladder-sparing alternatives. Where cystectomy is declined or not appropriate, options include further intravesical therapy with different agents (for example intravesical gemcitabine plus docetaxel in some centres), or, where access is available, newer therapies such as intravesical nadofaragene firadenovec or systemic pembrolizumab, which have been studied in BCG-unresponsive disease and have approvals in some jurisdictions.^15,16,17 Availability of these newer options in Australia varies and should be confirmed locally.
• Clinical trials. Trial enrolment is appropriate for selected patients; the local investigator team can advise on currently open trials.

The decision in BCG-unresponsive disease is usually made together with the patient at a multidisciplinary discussion, balancing oncological control against quality of life and the implications of bladder removal.

BCG at Urology NSW

Dr Raji Kooner manages selected patients with non-muscle-invasive bladder cancer through TURBT, intravesical therapy and structured cystoscopic surveillance, in line with the international NMIBC frameworks summarised above. Where BCG is the right intravesical option, the schedule, household precautions and follow-up plan are explained in person before treatment begins, and the patient is given written information including the BAUS leaflet linked below.

Patients who would like to discuss whether BCG is appropriate for them, or who have already started BCG elsewhere and would like a second opinion on the plan, are welcome to request a second opinion or to telephone the rooms to arrange a consultation.

Frequently asked questions

Will BCG give me tuberculosis?

BCG is a live but weakened strain of Mycobacterium bovis. It does not cause classical pulmonary tuberculosis in healthy people. It can, very rarely, set up a granulomatous infection in the bladder, prostate, lungs or other organs (see "BCG sepsis" above). Patients who are significantly immunosuppressed are not usually offered BCG for this reason.^2,3,13

Why are the bathroom precautions necessary?

BCG is a live organism. For about six hours after each instillation, small amounts can be present in the urine. Adding household bleach to the toilet for that period, sitting to pass urine, and washing hands afterwards keeps BCG out of the household environment and protects other people in the home.^1,2,3

Can I have sex during a BCG course?

Sexual activity is reasonable between instillations, but it is recommended to avoid intercourse for 24 to 48 hours after each instillation and to use a condom for at least one week, to avoid contact between BCG-containing urine and the partner's mucous membranes.^1,2,3

What should I do if I get a fever after BCG?

A low-grade fever (under 38.5 degrees Celsius) on the evening of the instillation, settling within 24 hours, can be managed at home with paracetamol and rest. A higher fever, a fever lasting more than 24 hours, shaking chills, low blood pressure, breathlessness, or feeling unusually unwell are reasons to present to an emergency department urgently and to mention that you have had intravesical BCG so the team uses the right antibiotics.^13,14

How long do the side effects last?

Local urinary symptoms (frequency, urgency, burning, pelvic ache) are usually most noticeable in the day or two after each instillation and tend to settle by the next instillation. Symptoms can become more prominent through an induction course; the rooms can adjust timing or dose if symptoms become limiting.^2,3

What if BCG does not work?

BCG-unresponsive NMIBC has its own treatment pathway, including radical cystectomy, alternative intravesical regimens, and newer agents in some jurisdictions (see "If BCG is not enough" above). The plan is individualised after the relevant cystoscopy, biopsy and imaging.^4,5,15

Is BCG used for muscle-invasive bladder cancer?

No. BCG is for non-muscle-invasive disease only. Muscle-invasive bladder cancer is generally treated with radical cystectomy (with neoadjuvant chemotherapy where appropriate) or with bladder-preserving chemoradiation in selected patients.^4,5,9

Will BCG be available?

BCG supply has been intermittent worldwide over the past decade. Where there is a shortage, dose-reduction, prioritisation of high-risk patients, alternative strain use, or substitution with intravesical chemotherapy may be required. The treating team will advise on the current Australian supply position at the time of treatment.³