EORTC-30911: BCG or Epirubicin for Urothelial Carcinoma of the Bladder
PubMed • Full text
Clinical Question
In patients with intermediate or high risk stage Ta T1 urothelial bladder cancer, does Bacillus Calmette-Guerin BCG, epirubicin or BCG + Isoniazid in six weekly instillations followed by three weekly maintenance instillations at months 3, 6, 12, 18, 24, 30 and 36 months, achieve the best time to recurrence, progression distant metastases, overall survival and disease specific survival?
Bottom Line
In patients with intermediate and high-risk stage Ta and T1 urothelial bladder cancer, intravesical BCG with or without INH is superior to intravesical epirubicin not only for time to first recurrence but also for time to distant metastases, overall survival, and disease-specific survival. The benefit of BCG is not limited to just high-risk patients; intermediate-risk patients also benefit from BCG.
Major Points
• Meta-analyses have shown that adjuvant BCG with a maintenance schedule is superior to both TUR alone and TUR plus adjuvant chemotherapy in preventing recurrence
• Meta-analysis are not completely conclusive regarding BCG preventing or delaying progression to muscle invasive disease
• Concern about BCG for maintenance therapy long term is the toxicity
• As an alternative to MMC, epirubicin has been commonly used in the intravesical treatment of non–muscle-invasive bladder cancer after TUR in both Europe and in Japan
• The main reasons for prematurely stopping treatment were treatment inefficacy, including second recurrence or progression, in 166 patients and toxicity in 115 patients: 16 (6%) on epirubicin and 99 (19%) on the two BCG arms
Guidelines
AUA, NCCN and EAU all provide guidelines relevant to this paper. The guidelines site a number of RCT papers (including this one) and also meta-analyses (level 1a evidence).
Generally, in intermediate risk patients, an induction course of BCG or chemotherapy is recommended, followed by a maintenance course of BCG for 36 months.
Design
- Multicenter, double-blind, parallel-group, randomized, controlled trial
- 957 randomised patients.
- Epirubicin – 318 patients, 279 eligible.
- BCG alone – 320 patients, 281 eligible.
- BGG + isoniazid – 319 patients, 277 eligible.
- No control group.
- Setting: 44 institutions in Europe.
- Enrollment: Jan 1992 to Feb 1997.
- Mean follow-up: Median follow-up time of 9.2yrs. Maximum follow-up of 14.3yrs.
- Analysis: modified intention to treat.
- Primary outcome: Time to first bladder cancer recurrence
Population
Inclusion Criteria
• Urothelial carcinoma of the bladder
• Biopsy proven
• Completely resected
• Single or multiple, primary or recurrent
• Stage Ta, T1, grades 1-3
Exclusion Criteria
• Solitary primary tumour
• CIS
• Stage T2 or higher
• >85 years old
• WHO performance status 3 or 4
• Previous treatment
Baseline Characteristics
Overall population (characteristics were balanced between groups)
- Median age: 67 years
- Prior recurrence rate: (primary) 45.3%
- n tumours: 15%
- Median tumour size : 1.0 cm
- T Category: Ta 63.6%
- WHO 1973 grade: G1 38.3%
- Risk group : intermediate 60.6%
Interventions
Within 24 hours after TUR and prior to receipt of the histology report, patients were randomized to one of three treatment groups:
1. Epirubicin, 50 mg in 50 ml of saline weekly for 6 consecutive weeks starting within 24 h after TUR
2. BCG (Tice), 5 x 108 colony-forming units weekly for 6 consecutive weeks starting 7–15 d after transurethral resection
3. BCG (Tice) as above plus INH, 300 mg orally, the day before, the same day as, and the day after instillation
In all three treatment groups, this initial treatment was followed by three weekly instillations at months 3, 6, 12, 18, 24, 30, and 36 for a total of 27 instillations for 3 years
Outcomes
Comparisons were made between epirubicin and BCG. (For most outcomes reporting, the BCG arm and the BCG + INH were combined)
Primary Outcomes
Cancer recurrence: HR 0.62, p<0.001 (95% CI not reported)
Secondary Outcomes
Distant metastases: HR 0.55, p=0.046 (95% CI not reported)
Death: HR 0.76, p=0.023 (95% CI not reported)
Bladder cancer death: 0.47, p=0.026 (95% CI not reported)
Time to progression: HR 0.84, p=0.55 (95% CI not reported)
Non bladder cancer death: p=0.21 (95% CI not reported)
Subgroup Analysis
1. Time to progression to muscle-invasive disease (T2 or higher), Compared to epirubicin, with BCG there was no significant difference in the time to progression (HR: 0.84; p = 0.55; Fig. 3) or in non–bladder cancer mortality ( p = 0.21). BCG does appear to reduce the risk of progression. Intermediate Risk HR: 0.56 (95% CI 0.26–1.23); p 0.14 High Risk HR 0.92 (95% CI 0.47–1.82); p 0.93 Total HR 0.84 (95% CI 0.51–1.39) p 0.55 However, there are too few progressions (25) to make meaningful comparisons (p 0.55)
2. Time to distant metastases, Compared to epirubicin BCG reduced the risk of the development of distant metastases. Total HR: 0.55 (95% CJ 0.32–0.94); p = 0.046 Possibly due to effect of BCG on micrometastases via a systemic immune response.
3. Overall duration of survival, a. Kaplan-meier technique. Compared using two-sided log-rank test. disease-specific survival (HR, 0.35; 95% CI, 0.14–0.86; p=0.02) 4. Time to death due to bladder cancer. a. Estimated by cumulative incidence functions Compared to epirubicin BCG reduced the risk of the risk of death HR: 0.76 (95% CI (0.59–0.96); p = 0.023 b. Then compared using the two-sided Gray’s test - To take into account patients who died of unrelated causes (competing risks) Compared to epirubicin BCG reduced the risk of death due to bladder cancer (HR: 0.47 (95% CI (0.25–0.89); p = 0.026.
Adverse Events
The main reasons for prematurely stopping treatment were treatment inefficacy, including second recurrence or progression, in 166 patients and toxicity in 115 patients: 16 (6%) on epirubicin and 99 (19%) on the two BCG arms.
Criticisms
- Patients enrolled in the 90s had different treatments compared to current practice
- Changes to pathological grading of bladdder cancer have been made
- High risk patients did not get a 2nd TURBT
- Use of photodynamic diagnosis and resection may reduce overall recurrence and need for BCG
- Inclusion of mitomycin treatment arm would be useful. Some suggestion mitomycin may be more effective than epirubicin. Meta-analysis showing no difference in longterm end points BCG vs mitomycin
- Didn’t look at side effects (BCG associated with higher cystitis, haematuria, systemic toxicity)
- No details provided about randomisation or blinding
- No justification provided for ample size and statistical power
- The exclusion criteria may include the very patients who would be considered for this therapy (as they are not fit for surgery)
Funding
EORTC Charitable trust. BCG Tice and epirubicin were supplied by Organon Teknika and Farmitalia Carlo Erba respectively, where drugs were not registered when administered.
Further Reading
- Duchek M, Johansson R, Jahnson S, et al. Bacillus Calmette-Gueurin is superior to a combination of epirubicin and interferon-alpha2b in the intravesical treatment of patients with stage T1 urinary bladder cancer. A prospective, randomized, Nordic study. Eur Urol 2010;57:25–31.
- Jarvinen R, Kaasinen E, Sankila A, Rintala E. Long-term efficacy of maintenance bacillus Calmette-Gue´ rin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur Urol 2009;56:260–5.