Peripheral Mechanisms Underlying Bacillus Calmette-Guerin-Induced Lower Urinary Tract Symptoms (LUTS)

Abstract

Non-muscle invasive bladder cancer (NMIBC) accounts for approximately 70-75% of all bladder cancer cases. The standard treatment for high-risk NMIBC involves transurethral tumour resection followed by intravesical Bacillus Calmette-Guerin (BCG) immunotherapy. While BCG immunotherapy is both safe and effective, it frequently leads to the development of lower urinary tract symptoms (LUTS) such as urinary urgency, frequency, dysuria, and pelvic discomfort. These symptoms can significantly diminish patients' quality of life and may result in the discontinuation of BCG treatment, adversely affecting oncological outcomes. Despite the considerable clinical impact of BCG-induced LUTS, the underlying mechanisms remain unclear, hindering the implementation or development of effective treatments. This review provides novel insights into the potential mechanisms underlying BCG-induced LUTS, focusing on the integrated roles of afferent and efferent nerves in both normal and pathological bladder sensation and function. Specifically, this review examines how the body's response to BCG-through the development of inflammation, increased urothelial permeability, and altered urothelial signalling-might contribute to LUTS development. Drawing from known mechanisms in other common urological disorders and data from successful clinical trials involving NMIBC patients, this review summarises evidence supporting the likely changes in both sensory nerve signalling and bladder muscle function in the development of BCG-induced LUTS. However, further research is required to understand the intricate mechanisms underlying the development of BCG-induced LUTS and identify why some patients are more likely to experience BCG intolerance. Addressing these knowledge gaps could have profound implications for patients' quality of life, treatment adherence, and overall outcomes in NMIBC care.

Keywords: Bacillus Calmette–Guérin (BCG); LUTSs; NMIBC; afferent sensitisation; bladder cancer (BCa); cystitis.

Figure 1

Structure and innervations of the bladder wall. The bladder is innervated by a complex network of sensory (afferent) and efferent nerves. Bladder afferent nerves terminate throughout the bladder wall, with endings located in the detrusor smooth muscle, lamina propria, and urothelium. As the bladder fills with urine, the bladder wall stretches, and mechanosensory afferent fibres embedded within the detrusor smooth muscle are activated. These afferent nerves, with cell bodies located in the dorsal root ganglia (DRG), travel through the pelvic and hypogastric/splanchnic nerves, synapsing in the dorsal horn of the lumbosacral (LS, L5-S1) and thoracolumbar (TL, T10-L2) regions of the spinal cord. Sensory signals arriving at the spinal cord synapse are transduced by second-order neurons to terminate in the periaqueductal gray (PAG), a brainstem hub for integrating sensory inputs from the spinal cord and descending input from higher brain centres. Changes in the excitability of bladder-innervating sensory nerves can thus directly impact bladder sensation and bladder function. Created in BioRender. Grundy, L. (2024) [53] www.BioRender.com/h79i418.

Figure 2

Proposed peripheral mechanisms underlying BCG-induced bladder hypersensitivity and dysfunction. Following BCG instillation into the bladder (1), live BCG attaches to the urothelium via the fibronectin present on tumour cells (2). BCG adherence to the urothelium triggers the release of cytokines and chemokines (3), stimulating immune cell infiltration into the urothelium (4) to initiate tumour cell death. Inflammation in the urothelium promotes GAG layer dysfunction and urothelial barrier breakdown (5), allowing urine, BCG, and commensal bacteria to reach the bladder interstitium. The urinary solutes and inflammatory mediators released from urothelial and immune cells have the potential to sensitise bladder afferent (6) and efferent (7) endings. Bladder afferent hypersensitivity increases peripheral drive to the spinal cord, leading to exaggerated bladder sensation and function. Exaggerated bladder sensation and function are proposed as key mechanisms underlying the development of LUTS. Created in BioRender. Grundy, L. (2024) [53] www.BioRender.com/a16d912.