3. Introduction
• Over 30 years’ successful application of Bacillus Calmette
Guerin (BCG) to the clinical treatment of bladder cancer has
proved it one of the most promising immunotherapies for cancer
1
• Intravesical BCG results in a robust local immune response 2
• directly reacts to the tumor cells, causing apoptosis,
necrocytosis, oxidative stress, 1
1. Jiansong Han et al, 2020 ; Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect
2. Shen et al., 2008
4. • Intravesical BCG is a live, attenuated mycobacteria and therefore has the
potential risk for transmission.
• Urine Routine and culture should be done before installation
• The preparation, handling and disposal should bring with it the same
precautions of other biohazardous materials.
• BCG powdered vaccine 80mg is reconstituted with 50 mL of saline
• Fluid, diuretic, and caffeine restriction before instillation limits dilution of the
agent by urine and facilitates adequate retention of the agent for 2 hours
1. Lamm et al. 2011
2. Herr, 2012
3. Lamm et al., 2000b
5. Administration procedure:
1. Assemble equipment on trolley as above.
2. Reconstitute BCG using closed system equipment as per manufacturers’
instructions. BCG should always be given within 2 hours of mixing.
3. Place both plastic and linen draw sheet underneath patient’s buttocks.
4. Insert urethral catheter as per policy and drain bladder
5. A plastic backed sheet should be placed under the catheter connection and
across the patient to prevent the spillage of BCG onto the patient or bedding if
there is a leak.
6. 6. Instil BCG into patient’s bladder in adherence to the manufacturer’s
instructions for using closed system products.
7. Remove catheter carefully and advise the patient they are to retain
liquid in bladder for up to two hours following instillation.
8. All efforts should be made to ensure the intravesical drugs do not
come into contact with the skin, clothing or other surfaces.
7. 9. Following insertion of intravesical therapeutic agents, the patient should lie prone,
supine left lateral and right lateral for 15 minutes each. The drug needs to remain
in the patient’s bladder for at least 1 hour (to a maximum of 2 hours).
10. equipment, in contact with cytotoxic material, should be disposed of into 2
cytotoxic waste bags, labelled and secured closed with cytotoxic tape and
disposed of in the clinical waste for incineration.
11. Following completion of the treatment, the patient should be advised to void into
the designated toilet.
12. The toilet should not be flushed. Two cups of bleach should be poured into the
toilet bowl and left for 20 minutes prior to flushing. Patients should be advised to
continue to use bleach in the toilet bowl with each void for 6 hours following
treatment.
8. 13. The patient should be encouraged to drink 2-3 litres of fluid for the
first 24 hours following treatment to encourage elimination of
absorbed drugs.
14. Urine samples should not routinely be sent to the laboratory within
72 hours of treatment.
15. The patient should be given instructions on after care, their next
appointment and contact details should they encounter any
problems prior to leaving the department.
9. Mechanism of action
• Initial step is direct binding to fibronectin within the bladder wall leading to direct
stimulation of cell-based immunologic response 1
• Numerous cytokines involved in the initiation or maintenance of inflammatory
processes including TNF-α, GM-CSF, IFN-γ, and IL-1, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12,
and IL-18 have been detected in the urine of patients treated with intravesical BCG.1
• cytokine induction with preferential upregulation of IFN-γ, IL-2, and IL-12 reflects
induction of a T-helper type-1 (Th1) response 2
• This immunologic response activates cell-mediated cytotoxic mechanisms believed to
underlie the efficacy of BCG and other agents in the prevention of recurrence and
progression 2
1. Ludwig et al., 2004
2. Bohle and Brandau, 2003
10. Jiansong Han et al, 2020 ; Biomedicine & Pharmacotherapy Journal
Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect
The model of mechanisms of BCG in bladder cancer.
When BCG is exposed to tumor microenviroment, it attaches to the cell surface and be internalized by tumor cells to
active different pathways such as NF-KB. Cytokines will be released by some immune cells like nuetrophils and
macrophages to attend immune cascade or kill the tumor cells directly
11. BCG Prophylaxis to Prevent Recurrence and
Progression
Conclusion:
• In NMIBC several intravesical therapies are associated with a decreased risk
of recurrence and Progression vs transurethral bladder tumor resection
alone
12. Conclusion
In 403 patients with CIS, BCG reduced the risk of progression by 35%
compared with intravesical chemotherapy.
15. Symptoms of cystitis and LUTS
• frequency, dysuria and occasional mild haematuria. These symptoms
usually subside within 24 to 48 hours
• Phenazopyridine, or non-steroidal anti-inflammatory drugs (NSAIDs).
• If symptoms improve within a few days: continue instillations.
• If symptoms persist or worsen:
• Postpone the instillation
• Perform a urine culture
• Start empirical antibiotic treatment
16. If symptoms persist even with antibiotic treatment:
• With positive culture: adjust antibiotic treatment according to
sensitivity
• With negative culture: quinolones and potentially analgesic anti-
inflammatory instillations once daily for 5 days (repeat cycle if
necessary) .
• If symptoms persist: anti-tuberculosis drugs + corticosteroids.
• If no response to treatment and/or contracted bladder: radical
cystectomy.
17. Haematuria
• Perform urine culture to exclude haemorrhagic cystitis, if other
symptoms present.
• If haematuria persists, perform cystoscopy to evaluate presence of
bladder tumour
18. Symptomatic granulomatous prostatitis
• Symptoms rarely present: perform urine culture.
• Quinolones is treatment of choice
• If quinolones are not effective: isoniazid (300 mg/day) and rifampicin
(600 mg/day) for three months.
• Cessation of intravesical therapy.
19. Epididymo-orchitis
• Perform urine culture and administer quinolones.
• Cessation of intravesical therapy.
• Orchidectomy if abscess or no response to treatment.
20. Arthritis
• Rare complication and considered autoimmune reaction.
• Arthralgia and arthritis : treatment with NSAIDs.
• If no/partial response, proceed to corticosteroids, high-dose
quinolones or antituberculosis drugs.
21. Persistent high-grade fever
• (> 38.5°C for > 48 h)
• Permanent discontinuation of BCG instillations.
• Immediate evaluation: urine culture, blood tests, chest X-ray.
• Prompt treatment with more than two antimicrobial agents while
diagnostic evaluation is conducted.
• Consultation with an infectious diseases specialist.
22. BCG sepsis
• Evaluation: total count, urine culture, chest X-ray, ESR, CRP
• Cessation of BCG.
• For severe infection:
• High-dose quinolones or isoniazid, rifampicin and ethambutol
• Start ATT for 6 months
• Early, high-dose corticosteroids as long as symptoms persist.
• Consider an empirical non-specific antibiotic to cover Gram-negative
bacteria and/or Enterococcus.
23. Allergic reactions
• Antihistamines and anti-inflammatory agents.
• Consider high-dose quinolones or isoniazid and rifampicin for
persistent symptoms.
• Delay therapy until reactions resolve
24. Bacille Calmette-Guérin: Treatment Schedule
• Several studies and AUA guidelines suggest that a 6-week induction course 1
• Durations of maintenance therapy based on risk stratification of the tumor 2
• Southwest Oncology Group (SWOG) reported the most significant impact of
maintenance therapy. Patients received a 6-week induction course followed by 3
weekly instillations at 3 and 6 months and every 6 months thereafter for 3 years.1
• intermediate-risk disease, a 1-year course of maintenance BCG was administered at
months 3, 6, and 12. 2
1. Chang et al., 2016
2. Oddens et al. 2013
25.
26.
27. BCG-refractory tumour
• If T1G3/HG tumour is present at 3 months . Further conservative
treatment with BCG is associated with an increased risk of
progression
• If TaG3/HG tumour is present after 3 months and/or at 6 months,
after either re-induction or first course of maintenance.
• If CIS (without concomitant papillary tumour) is present at 3 months
and persists at 6 months after either re-induction or first course of
maintenance. If patients with CIS present at 3 months, an additional
BCG course can achieve a complete response in > 50% of cases
• If HG tumour appears during BCG maintenance therapy
28. BCG-relapsing tumour
• Recurrence of G3/HG tumour after completion of BCG maintenance,
despite an initial response
• Radical cystectomy or repeat BCG course according to individual
situation.
• Bladder-preserving strategies
29. BCG unresponsive tumour
• BCG refractory or T1Ta/HG BCG recurrence within 6 months of
completion of adequate BCG exposure
• or
• Development of CIS within 12 months of completion of adequate BCG
exposure
• Radical cystectomy or bladder preservation strategy
non–muscle-invasive bladder cancer (NMIBC) is the term commonly applied to malignant urothelial tumors that have not invaded the detrusor muscle of the bladder .
The terminology of NMIBC encompasses the relatively benign course of low-grade papillary tumors, the more aggressive clinical course of high-grade tumors including urothelial carcinoma in situ (CIS), and high-grade Ta and T1 tumors
BCG not only works on bladder cancer by activating the immune system, but also
Commercially available strains include Pasteur, Connaught, and Tice
Should the BCG come into contact with the patient’s skin at the time of administration, an absorbent cloth should be placed over the spillage, which is then disposed of into the cytotoxic waste bag. The area should then be washed thoroughly with copious amounts of soap and water.
and should then be allowed to move freely to ensure the drug has the opportunity to bathe all parts of the bladder mucosa.
Release of tumor necrosis factor–related apoptosis inducing ligand (TRAIL) also appears to be a key event in propagation of the BCG response and is associated with response to BCG
FAP on BCG surface binds to fibronectin on the cell surface for adsorption after intravesical instillation of BCG; then, the repaired bladder epithelial cells and tumor cells internalize BCG. Through a variety of cell surface receptors and intracellular signal transduction pathways, on the one hand, cell apoptosis, cell necrosis, oxidative stress, and others directly induce tumor cell death; On the other hand, the induced cytokines cause an immune cascade that facilitates the host’s immune system to kill tumor cells. BCG can directly act on many cells in the entire tumor immune microenvironment, such as tumor cells, macrophages, neutrophils, T cells, dendritic cells, and other cells. These cells interact with each other, relying on released cytokines of IL-6 and IL-8 at an early stage to generate cascade reactions and heighten the effect.
Prevention: initiate BCG at least 2 weeks post-transurethral resection of the bladder (if no signs and symptoms of haematuria).
several studies and AUA guidelines suggest that a 6-week induction course alone is insufficient to obtain an optimal response in many patients and that maintenance therapy is requisite
Adequate BCG is defined as the completion of at least 5 of 6 doses of an initial induction course plus at least 2 out of 6 doses of a second induction course or 2 out of 3 doses of maintenance therapy.