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BCG

Live attenuated strain of Mycobacterium bovis

 

Delivery

  • Powdered vaccine is reconstituted with 50 mL of saline and administered through a catheter
  • Should be typically held within the bladder for 1 – 2 hours, and patient rotating between supine and prone.
  • Catheter should be removed after instillation to allow bladder neck to be treated.
  • Allow at least 4 weeks after resection to allow healing and re-epithelialisation of bladder.
  • Urinalysis prior to treatment to exclude obvious infection.
  • Urine culture between treatments – active UTI traditionally considered contra-indication and treatment delayed a week to allow treatment.
  • Traumatic catheterisation with haematuria – abandon treatment and delay until next week.

 

Mechanism

Exact mechanism is unclear but:

  • Causes a robust local immune response characterised by:
    • Direct binding to fibronectin within the bladder wall
    • Induction of several cytokines (such as TNF-α and various interleukins) in the urine and bladder wall
    • Induction of a helper T cell response which is cytotoxic to the abnormal urothelium and tumour
    • Histological development of BCG granulomas

 

Contra-indications

Absolute

·       Within 2 weeks of resection

·       History of BCG sepsis

·       Gross haematuria / traumatic IDC

·       Active symptomatic UTI

 Relative

·       Immunocompromised

·       Asymptomatic bacteriuria

·       Liver disease (prevents isoniazid Rx)

·       Personal history of TB

·       Total incontinence / cannot hold

 

 

BCG side effects and toxicity

 

Local side effects

Cystitis / UTI

  • > 50 %. Work up with urine culture and antibiotics and delay BCG. Manage cystitis symptoms with anticholinergics and alkaliniser. Severe non infectious cystitis – consider steroids or LA instillations.

Haematuria

  • Exclude UTI and defer BCG until clears

Granulomatous prostatitis

  • 5 % symptomatic, up to 40 % asymptomatic. Urine cultures and treat with quinolones. If severe or not settling, no further BCG and consider isoniazid/rifampicin

Epididymo-orchitis

  • As above – cultures, quinolones, and if severe or not settling stop BCG, consider isoniazid/rifampicin or even orchidectomy

Long term local complications

  • Contracted bladder, ureteric strictures, granulomatous cystitis/orchitis/prostatitis.

 

Systemic side effects

Flu – like symptoms

  • General malaise, mild arthralgias and mild fevers in up to 25 %

Arthritis

  • True auto-immune reaction causing arthritis rare, < 5 %. Treat with NSAIDs, failing that then try steroids

Persisting high grade fevers

  • Stop treatment and consider BCGosis / BCG sepsis

Hypersensitivity / allergy

May present with rash. Probably stop treatment.

BCG sepsis

  • 0.4 % – consider diagnosis if high grade fevers for > 48 hours
  • Usually from traumatic catheter and systemic BCG
  • IV steroids, broad spectrum antibiotics and consideration of culturing for TB
  • May need long term 3 month anti TB treatment under guidance of ID
  • Not for further BCG

 

Maintenance protocol

6 week induction course

Maintenance course:

  • 3 week course at 3 months
  • 3 week course at 6 months
  • 3 week course every 6 months thereafter, until total 3 years

Total 27 doses

Only 16 % completed the total of 27 doses in the initial study due to side effects and poor tolerance.

Multiple studies show the increased efficacy of BCG at reducing recurrence in high risk NMIBC is mostly demonstrated with full maintenance schedule

Three years of maintenance is more effective at reducing recurrence cf. one year in high risk patients.

One year was not inferior cf. three years in intermediate risk.

 

Off-piste BCG (and options for consideration in BCG shortage)

No difference proven in different strains of BCG (Onco-tice, Connaught) with no evidence to suggest one over the other.

There may be a reduction in side effects and tolerance with 1/3 dose compared to full dose but this is unclear. Full dose may be more effective in multifocal tumours, with conflicting data about efficacy.

Insufficient evidence to recommend combination BCG with intravesical chemotherapy.

 

BCG failure

BCG refractory

  • Failure to achieve disease free state within 6 months of initial BCG
  • Second round of BCG (50 % response for Ta or CIS) or cystectomy (HGT1 after BCG = cystectomy)

BCG resistant

  • Disease still present at 3 months but improved, then not present at 6 months

BCG relapse

  • Recurrence of disease, after being free of disease at 6 months

BCG intolerant

  • Recurrence after an inadequate course of BCG, due to side effects

 

Alternatives for patients with BCG unresponsive disease, not fit or willing for cystectomy:

  • Clinical trials
  • Heated mitomycin
  • Alternative intravesical treatment – gemcitabine, docetaxel
  • IV pembrolizumab for CIS
  • Recombinant immunotherapies promising – nadofaragene firadenovac
  • Best endoscopic management

 

Radical cystectomy is standard of care for these patients.

 

Patients with low grade disease after BCG treatment are not considered to have BCG failure.

Adequate BCG generally defined as 5/6 induction courses and at least 2 courses of second induction or first maintenance.