What is the recommended treatment approach for Carcinoma In Situ (CIS) using Bacillus Calmette-Guérin (BCG)?

From the Guidelines

Intravesical BCG immunotherapy is the recommended treatment approach for Carcinoma In Situ (CIS) of the bladder, with a strong recommendation based on high-quality evidence. The treatment involves an induction course of weekly BCG instillations for 6 weeks, followed by maintenance therapy for 1-3 years 1. For the induction phase, a full dose of BCG is instilled into the bladder via a catheter and retained for 1-2 hours before voiding. After completing induction, maintenance therapy consists of 3 weekly instillations at months 3,6,12,18,24,30, and 36. This maintenance schedule is crucial as it significantly reduces recurrence rates and improves disease-free survival compared to induction alone.

Key Considerations

• The evidence level for this recommendation is 1a-1b, indicating high-quality evidence from randomized controlled trials and systematic reviews 1.
• The strength of recommendation is strong, indicating that the benefits of intravesical BCG immunotherapy outweigh the risks and burdens for most patients with CIS.
• Patients should be monitored with regular cystoscopy and urine cytology every 3 months for the first 2 years, then every 6 months for years 3-4, and annually thereafter.

Side Effects and Management

• Common side effects of BCG therapy include urinary frequency, dysuria, and mild hematuria, which typically resolve within 48 hours 1.
• More severe complications like BCG sepsis are rare but require immediate discontinuation and antibiotic treatment.
• Management of side effects includes postponing instillations, reducing the dose of BCG, and administering empirical antibiotic treatment or anti-tuberculosis drugs as needed.

Evidence Summary

• A meta-analysis of 9 RCTs (11 studies) with a total of 1231 patients and a maximum follow-up time of 148.8 months showed that intravesical BCG immunotherapy significantly reduced the 72-month recurrence rate and the 143-month recurrence rate compared with intravesical chemotherapy 1.
• The EORTC study 30,993, a randomized phase II trial of 96 patients with CIS, compared sequential mitomycin and BCG with BCG alone and found similar complete response and disease-free rates in both groups 1.

From the FDA Drug Label

To evaluate the efficacy of intravesical administration of TICE® BCG in the treatment of carcinoma in situ, patients were identified who had been treated with TICE BCG under 6 different Investigational New Drug (IND) applications in which the most important shared aspect was the use of an induction plus maintenance schedule Patients received TICE BCG (50 mg; 1 to 8 x 108 CFU) intravesically, once weekly for at least 6 weeks and once monthly thereafter for up to 12 months. TICE® BCG is indicated for: the treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder

The recommended treatment approach for Carcinoma In Situ (CIS) using Bacillus Calmette-Guérin (BCG) is intravesical administration of TICE BCG, with an induction plus maintenance schedule. The typical treatment regimen consists of:

• Induction: TICE BCG (50 mg; 1 to 8 x 10^8 CFU) intravesically, once weekly for at least 6 weeks
• Maintenance: once monthly thereafter for up to 12 months 2. TICE BCG is indicated for the treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder 2.

From the Research

Treatment Approach for Carcinoma In Situ (CIS) using Bacillus Calmette-Guérin (BCG)

• The recommended treatment approach for CIS using BCG is intravesical instillation, which has been shown to be effective in reducing recurrence and delaying progression of the disease 3, 4.
• Studies have demonstrated that BCG is the intravesical treatment of choice for CIS, with complete response rates ranging from 66.7% to 75.6% 3.
• The use of sequential chemoimmunotherapy with mitomycin C (MMC) plus BCG has also been explored, with similar complete response rates to BCG alone 3.
• A meta-analysis of randomized clinical trials comparing intravesical BCG to intravesical chemotherapy found that BCG significantly reduces the risk of short and long-term treatment failure compared to chemotherapy 4.

Treatment Modalities for BCG-Unresponsive CIS

• For patients with BCG-unresponsive CIS, alternative treatment modalities such as intravesical CG0070 adenovirus or hyperthermic intravesical chemotherapy with MMC may be considered 5.
• Other options include intravesical radiofrequency-induced chemohyperthermia or electromotive drug administration of MMC 5.
• In patients who have failed second-line therapies, a combination of gemcitabine, cabazitaxel, and cisplatin may be used as an alternative regimen 5.

Adherence to First-Line Intravesical BCG Therapy

• A study evaluating adherence to first-line intravesical BCG therapy in US patients with high-risk non-muscle invasive bladder cancer found that most patients received adequate BCG induction, but less than half had adequate BCG maintenance 6.
• Patients with CIS had higher adherence to guidelines compared to those without CIS, but still had inadequate BCG maintenance 6.
• The study highlights the need for additional treatment options for patients with non-muscle invasive bladder cancer, including those with CIS 6.

Special Considerations

• Intravesical BCG has been shown to be a feasible treatment option for patients with CIS involving prostatic ducts, with a response rate of 82% in the prostatic urethra and 64% in the bladder 7.
• However, progression was encountered in 18% of patients, emphasizing the need for careful follow-up and prompt cystectomy in patients with persistent disease 7.