Presentation

Treatment

• BCG was originally developed by Calmette and Guérin in 1921 as a vaccine to prevent tuberculosis in endemic regions, derived from Mycobacterium bovis. 

• BCG treatment, implemented in the 1970s, is the main immunotherapy for early-stage bladder cancer (3).

• Commonly used along with transurethral resection of bladder tumors (TUBIT).

• Most effective treatment for NMIBC, especially high-grade Ta/T1 tumors and carcinomas in situ, not metastatic (4).

• BCG activates the immune system to target and destroy malignant cells, offering a more localized and specific alternative to chemotherapy

Procedure

• Local anesthesia is used while a catheter is inserted into the urethra to instill the liquid BCG solution into the bladder.

• The solution is held in the bladder for about two hours before urination.

• Induction therapy is once a week for six weeks.

• Maintenance therapy is once a week for three weeks at three, six, and twelve months; may continue up to three years (4).

Effectiveness and Recurrence

• Cancer recurs in up to 40% of people treated with BCG.

• If cancer returns, it may not necessarily progress to a more advanced stage (4).

Known mechanism 1

• BCG binds to Toll-like receptor 7 (TLR7) and TLR3 on tumor cells; induces signaling involving IRAK1 and 4 molecules to activate caspase-8 and promote the apoptosis.

Known Mechanism 2

• BCG internalization within tumor cells:

  • Production of ROS, increasing the activity of iNOS, which causes ROS-mediated cell injury.

  • Activation of CB within the lysosome:

    • Capsase-9 signaling and apoptosis.

    • Truncation of BID to increase MOMP and release AF from mitochondria.

Known mechanism 3

• BCG adhesion to integrin inhibits the cell cycle transition from the G1 to the S phase. This may be due to the downregulation of synthesis of cyclin D1 and cyclin E which promotes cell death.

Unclear mechanism 1

Cell membrane rupture post-BCG exposure due to the increased release of protease from the mitochondria.

Unclear mechanism 2

• HMGB (necrosis marker) released in high amount from bladder tumor cells; mitochondrial rupture following activation of RIPK1 mediator may cause cell membrane damage and thus necrosis.

Risk Factors

• Common in older patients with comorbidities; less common in immunosuppression (~1.8%)

• Different substrains vary in genetics and immunogenicity (7).

Adverse reactions

• Expected side effects are low grade fever, polyuria, dysuria, and hematuria.

• 23-63% experience local complications; up to 30.6% experience systemic.

• 8% discontinue treatment due to toxicity.

• Only 29% complete full 3-year therapy (5).

• Disseminated BCG infections include (Table 1):

  • 25.2% miliary tuberculosis

  • 6.7% fever associated with bone marrow and/or liver infiltration

  • 2.5% sepsis with multiorgan failure (8)

Significance

• A hypersensitivity reaction is a systemic reaction that can present with many different systemic related issues (list off a few)

• But, hypersensitivity reactions can closely mimic disseminated BCG infections.

• Diffuse miliary nodules often correlate with active infection; microbiology studies are indicated.

• When microbiology studies are negative, and the patient is clinically stable (Fig. 2), a hypersensitivity reaction is more likely (7).

• Differentiating between these entities is critical as management differs significantly.

• Figure 2: CT (left) and chest x-ray (right) showing diffuse, uniform miliary nodules. Patient is a 70-year-old man presenting with no clinical illness (i.e., hypersensitivity reaction) (7).

Mechanism of Adverse Reaction 1

Colonization – M. bovis becomes pathogenic when there is a barrier disruption (biopsy, TURBIT, catheterization) or increased bacterial load.

Mechanism of Adverse Reaction 2

Extravasation – M. bovis crosses the mucosal membrane via endocytosis, passing between cells, or destroying cells (6).

Mechanism of Adverse rection 3

• Dissemination – M. bovis penetrates the blood vessel and evades the immune response.

  • Prevents phagocytosis (capsules), neutrophil respiratory burst, nitric oxide production, and lymphocytic proliferation

  • Inhibits monocyte and macrophage apoptosis but promotes lymphocyte apoptosis in response to mitogens

  • Induces anti-inflammatory factors, leading to apoptosis of peripheral blood mononuclear cells (10)

Mechanism of adverse reactions 4

Seeding other organs – M. bovis can reside in the macrophages of lungs, lymph nodes, bones, and skin and create granulomas (2, 10).

Type IV (Delayed) Hypersensitivity

An antigen-presenting cell presents an antigen, causing T-cell activation.

CD4+ T cells release cytokines, causing macrophage activation, while CD8+ T cells are involved in direct cell killing (9).

Conclusion

BCG immunotherapy remains a cornerstone in the management of NMIBC due to its unique ability to stimulate the immune system and target tumor cells.

While it has proven to be beneficial, its use is not without risk, as complications ranging from mild, local symptoms to rare, but serious, systemic effects can occur.

Understanding the underlying mechanisms of both therapeutic action and adverse reactions is essential for accurate diagnosis and appropriate clinical management.

Continued research into the variability of patient responses may further improve safety, optimize outcomes, and support more individualized approaches to therapy.

iNOS

CB

BID

MOMP

AF

HMGB1

RIPK1

IRAK 1

1. iNOS - induce-NO synthase 

2. CB - cathepsin B

3. BID - Bcl-2 protein 

4. MOMP - mitochondrial outer membrane permeability

5. AF - Apoptotic factors

6. HMGB1 - High mobility group box 1 

7. RIPK1 - Receptor-interacting protein kinase 1

8. IRAK 1 - interleukin 1 receptor-associated kinases