Long-Term Side Effects of BCG Treatment For Bladder Cancer

Introduction

TICE® BCG is an attenuated, live culture preparation of the Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium Bovis.¹ The BCG immunotherapy drug was initially a vaccine for the prevention of tuberculosis (TB), introduced in 1921, but since 1977 it has proved effective in treating non-invasive bladder cancers.² The drug is given directly into the bladder (intravesical immunotherapy) to provoke an immune response that destroys tumour cells.

About bladder cancer

Bladder cancer is the most common cancer in the urinary tract and the 10th most common cancer worldwide.^3,4In 2018, newly-diagnosed cases of bladder cancer were an estimated 549,000, with 200,000 fatalities.⁴ Bladder cancer is more common in men than women, with incidence and mortality rates of 9.6 and 3.2 per 100,000, respectively.⁴ Prevalence rates of bladder cancer amongst men and women are most significant in Southern Europe (Greece, with the highest global incidence rate in men; Spain; Italy). Like all cancers, bladder cancer has several risk factors, with cigarette smoking posing the most significant risk.⁵ The second most common risk factor is occupational exposure to chemical contaminants.⁶ Whilst the mechanisms are not entirely understood, inflammation and previous chemotherapy may increase the risk of developing bladder cancer.^7,8 

In most cases, bladder cancer will present as a tumour in the epithelial lining of the urinary tract. Most of these tumours form in the bladder, but they can manifest anywhere along the urinary tract, including the ureter, kidney, or renal pelvis.⁹ Blood in the urine (haematuria) is the most common sign of bladder cancer, occurring in 80% of diagnosed patients.⁸ Bleeding is either microscopic or visible in the urine, and the severity of such bleeding does not reflect the severity or stage of one’s bladder cancer. 

How BCG is used for the treatment of bladder cancer?

Treatment for bladder cancer via BCG is accompanied by intravesical chemotherapy and radiation therapy. Patients receiving such treatments are then given BCG doses to help fight any remaining cancer. BCG helps prevent cancer from coming back after treatment of the bladder lining. It is given when there is a high possibility of relapse from treatment, particularly when cancer starts growing into the bladder’s muscle lining (becomes muscle-invasive, stage II [T2]). 

BCG immunotherapy involves a combination of direct effects and an induced immune response. Upon insertion directly into the bladder (intravesical), the dose of BCG triggers an immune response. Immune cells, named cytotoxic T lymphocytes, natural killer cells, neutrophils, and macrophages recognise and destroy the cancer cells, subsequently minimising the cancerous site.¹⁰ 

During treatment, a catheter is used to insert the BCG into the bladder. Firstly, patients must ensure that they are lying down, are comfortable, and have a limited amount of fluid in the bladder. Once the BCG has been introduced, patients must lie on their front for 15 minutes. Those treated should not pass urine for 2 hours post-insertion to allow the BCG treatment to be fully effective. The effectiveness of BCG treatment is maximised when conducted on an empty bladder, which increases the concentration of BCG. 

Complications of BCG treatment 

Local Complications

Bladder

The most common complications of BCG treatment are associated with the bladder and lower urinary tract, with 80% of patients reporting cystitis-like symptoms.⁶ In addition, complaints of BCG-induced cystitis made up 35% of the experienced side effects in the EORTC study.¹¹ Traumatic instillation of BCG doses can lead to urethral irritation, complications in bladder contracture, inflammation, and possible urethral perforation.^12,13 

Prostate

BCG can invade the prostate gland and seminal vesicles up to the epididymis, inducing an inflammatory response that forms the basis of Prostatitis.¹⁴ In rare cases where an obstruction is caused by BCG application, possible transurethral resection of the prostate may be necessary.¹² 

Scrotum

Epididymal-orchitis is inflammation of the epididymis and the adjacent testis. Patterns of TB-induced (from the BCG dose) epididymitis have been described, often recognised by a visible enlargement of the scrotal area.¹⁵ Many cases have been reported following intravesical BCG therapy.¹⁴ 

Upper urinary tract

Renal complications from BCG therapy are rare yet significant. Nephritis (inflammation of the kidney), ureteral obstruction, acute renal failure and acute renal injury have been noted following intravesical BCG for non-invasive bladder cancer cases.^14,16,17 Interestingly, a 2017 study demonstrated the advanced stages of chronic kidney disease in a female patient following administration of BCG for non-muscle-invasive bladder cancer.¹⁷ 

Penis

Penile complications of BCG administration include localised bacterial infection that manifests as inflammation, both superficially and deep to the penis.^12,14 In severe cases, papules or plaques have developed on the glans following repeated BCG instillation therapy.¹⁸ 

Systemic complications

Musculoskeletal

Severe musculoskeletal complications of BCG therapy include osteomyelitis (inflammation of bone or bone marrow due to infection), reactive arthritis, Reiter’s syndrome, infected orthopaedic prosthesis, and polyarthritis.¹⁴ Many musculoskeletal complications are challenging to diagnose because of the delay in symptoms. 

Vascular

There have been several cases where BCG therapy has induced inflammation in one or more blood vessels.^14,19 In severe cases where patients may undergo vascular surgery, long-duration anti-mycobacterial therapy can impair the effectiveness of drug-induced bladder cancer treatment.

Pulmonary

Two main pulmonary complications have been reported.^12,14 Pulmonary hypersensitivity (interstitial pneumonitis) refers to inflammation of the lung tissue. Similarly, BCG therapy can lead to mycobacterial pneumonia, an inflammatory infection of the alveoli characterised by a phlegmy cough.

Hepatic

BCG-therapy-induced hepatitis has been shown to be fatal in some cases.^14,20 Patients diagnosed with hepatitis demonstrated elevated inflammatory markers and transaminitis (elevated liver enzymes), where symptoms were so intense that patients were given antibiotics and steroids to alleviate symptoms.²⁰

Lymphatic

In rare cases, intravesical BCG immunotherapy has induced lymphatic inflammation and fibrosis. In 2013, an individual treated for superficial bladder cancer had completed a course of BCG immunotherapy, and CT scanning revealed inflammation of the lymph nodes in the aortic region.²¹ 

Sepsis and other Complications

Sepsis is a life-threatening condition resulting from the presence of microorganisms (in the case of BCG, bacteria) in the blood and organs. Infections trigger an immune response that damages one’s tissues, organs, and systems.²² Despite high tolerance rates, BCG-induced sepsis occurs in a small number of patients. BCG sepsis can occur acutely after intravesical BCG therapy, where mycobacteria (bacteria that cause TB) have been found in the urine and bladder several months post-treatment^.23 Symptoms of BCG sepsis include chills, an altered mental state, hypotension, jaundice, and respiratory issues.²³ 

BCG sepsis in those receiving treatment for bladder cancer has also been linked to multiple organ failure. Systemic BCG infection has been linked to a deterioration in liver function, blood deficiencies, and abnormal coagulation.²⁴ 

Long-term side effects of BCG treatment

As established, BCG perfusion therapy is used to treat cell carcinoma in situ of the bladder. A 2004 study found the initial responses to treatment as “excellent”. However, 50% experienced failure of BCG treatment, resulting in recurrence and subsequent death.²⁵ Long-term data about the efficacy of BCG treatment in preventing bladder cancer progression and its impact on mortality is severely lacking. 

Hayashida et al. found bladder irritation in all patients several months after cessation of BCG therapy.²⁵ Frequent side effects observed were:

• Hydronephrosis (one or more of the kidneys become stretched and swollen in response to the internal build-up of urine)
• Persistent lower back pain (lumbago)
• A recurring fever greater than 38 degrees Celsius ²⁵

Generally, BCG treatment is regarded as highly safe with excellent response rates. However, the collection of long-term results is unsatisfactory, necessitating further long-term studies.

A 2002 journal successfully concluded that BCG treatment increases the median survival time for bladder cancer but does not provide a cure, except in those with carcinoma in situ.²⁶  BCG treatment can potentially cause secondary diseases, namely urothelial cancer. Further studies have recorded relapses in bladder cancer and metastasis in 50% of patients.²⁷ 

Diagnosis and treatment of BCG-related complications

In those treated for high-grade bladder cancer, 30% are at risk of progression, and thus associated complications must be considered.²⁸ 

If side effects occur shortly after administration of BCG therapy, instillation was likely the root cause of such developments. Therefore it is highly advocated to inform patients of potential complications, symptoms, and side effects. However, complications do not appear until later, sometimes after treatment cessation. Symptoms may show elsewhere in the body, which may prove challenging to treat if the supervising practitioner is unfamiliar with BCG-therapy-induced side effects.

Cookson et al.found that after 15 years of follow-up post-BCG therapy, 53% of patients with high-risk non-muscle-invasive bladder cancer (NMIBC) had progressed to muscle-invading bladder cancer.²⁷ Radical cystectomy (surgical bladder removal) may be necessary in extreme cases. Renal complications should instigate biopsy to ensure cancer has not spread beyond the urinary tract. In the case of renal, hepatic, and rheumatologic complications and BCG persistence, steroids, anti-mycobacterial therapy and short-term hemodialysis (dialysis of the kidney) could prove effective.¹⁴

Differences in adverse events among different BCG strains

The side effects appear similar for all strains of BCG used in physical therapy.¹² Whether all BCG strains are equal in their mechanisms and efficacy or if some induce more adverse side effects than other strains was investigated in a 2020 study. Despite the differences observed in the genetic composition of BCG strains, patients, and the induced immune response, there was no suggestion that different BCG strains induced adverse effects or negatively impacted bladder cancer treatment outcomes.²⁹ Another study found that the progression rate of bladder cancer was not statistically different between different strains of BCG.³⁰ 

Prevention strategies to reduce the side effects of BCG treatment

Several strategies can alleviate the side effects of treatment:

• NSAIDs: anti-inflammatory drugs such as ibuprofen, aspirin or diclofenac are all effective for minimising pain, inflammation and fever associated with BCG-therapy side effects.
• Corticosteroids: steroids that suppress the immune system to decrease swelling and relieve inflammation.
• Avoid factors that directly favour side effects: some side effects directly result from traumatic instillation of BCG or instillation after transurethral resection. Avoid treatment (direct instillation) for no less than two weeks post-resection and post-urethral perforation.
• Administration of TB drugs: a 2006 study found that administration of the antibiotic Ofloxacin reduced moderate-severe side effects by up to 18.5%.³¹ 

Conclusion

Bladder cancer is one of the most common forms of cancer. BCG therapy has proved successful in treating, preventing and managing bladder cancer for decades. Despite its widely advocated success, BCG treatment has demonstrated regional and systemic side effects. Thus, severity influences the efficacy of treatment outcomes. Future long-term studies must be conducted to build a comprehensive understanding of the mechanisms and effects of this life-saving treatment.