Clinical efficacy and side effects of maintenance bacillus Calmette-Guérin in the treatment of non-muscle-invasive bladder cancer

Background: The optimal dose and duration of intravesical bacillus Calmette-Guérin (BCG) in the treatment of non muscle invasive bladder cancer (NMIBC) are controversial. Objectives: To determine if one third dose (1/3D) is not inferior to full dose (FD), if 1 year (1yr) maintenance is not inferior to 3 years (3yrs) maintenance and if 1/3D and 1yr maintenance are associated with less toxicity. Design, Setting, Participants and Intervention: After transurethral resection, intermediate and high risk NMIBC patients were randomized to one of four BCG groups: 1/3D-1 yr, 1/3D-3 yr, FD-1 yr, FD-3 yr. Outcome Measurements and Statistical Analysis: The trial was designed as a noninferiority study with the null hypothesis of a 10% decrease in the disease-free rate at 5 yr. Times to events were estimated using cumulative incidence functions and compared using the Cox proportional hazards regression model. Results: In an intent-to-treat analysis of 1355 patients with median follow up 7.1 yr, there were no significant differences in toxicity between 1/3D and FD. The null hypotheses of inferiority of the disease-free interval for both 1/3D and 1yr could not be rejected. 1/3D-1 yr is suboptimal compared to FD-3 yr (HR = 0.75, 95%CI: 0.59-0.94, p = 0.01). Intermediate risk patients treated with FD do not benefit from an additional two years of BCG. In high risk patients, 3yrs is associated with a reduction in recurrence (HR = 1.61, 95%CI: 1.13-2.30, p = 0.009), but only when given at FD. There were no differences in progression or survival. Conclusions: There were no differences in toxicity between 1/3D and FD. Intermediate risk patients should be treated with FD-1 yr. In high-risk patients, FD-3 yr reduces recurrences as compared to FD-1yr, but not progressions or deaths. The benefit of the two additional years of maintenance should be weighed against its additional costs and inconveniences. INTRODUCTION AND OBJECTIVES After initial transurethral resection (TUR), non-muscle invasive bladder cancer (NMIBC) is characterized by a high risk of recurrence and, to a lesser extent, progression to muscle invasive disease. These risks can be quantified based on a patient’s tumor characteristics using EORTC risk tables or with a simplified risk group classification [1,2]. To decrease the risk of recurrence and progression, adjuvant instillations of chemotherapy or bacillus CalmetteGuérin (BCG) are given in accordance with European Association of Urology (EAU) Guidelines [3]. In intermediate and high risk patients, the protective effects of maintenance BCG are more pronounced as compared to chemotherapy [4, 5]. The initial report by Morales et al described six weekly BCG induction instillations [6]. Afterwards, it was found that additional instillations of BCG reduced recurrences, however the optimal duration of maintenance instillations remains controversial [7-9]. Based on several meta-analyses, the EAU guidelines recommend at least 1 year of maintenance. A major disadvantage of BCG is its toxicity, leading to interruptions and premature discontinuation of maintenance. In EORTC trial 30911, isoniazid (INH) did not reduce toxicity for patients on three years of maintenance [10]. However, toxicity was reduced when two doses of ofloxacin were given shortly after each of nine BCG instillations [11]. The Club Urológico Español de Tratamiento Oncológico (CUETO) compared the effect of a reduced dose of BCG to standard dose in intermediate and in high risk patients [12-14]. These studies, where a short schedule of < 6 mo BCG was used, suggested that one third dose (1/3D) is the minimum effective dose. The current randomized phase 3 study (30962) was designed to investigate two strategies to decrease the toxicity of maintenance BCG without compromising its efficacy. The purpose is to show that 1/3D BCG is not inferior to full dose (FD) BCG and that 1 yr of maintenance is not inferior to 3 yr of maintenance with respect to efficacy and that 1/3D and 1 yr of maintenance are associated with less toxicity. MATERIAL AND METHODS Inclusion and exclusion criteria Patients with biopsy-proven, completely resected, solitary pT1G3 or multiple pTa-T1, grade 1– 3 (1973 World Health Organization [WHO] classification) urothelial carcinoma of the bladder were included. Excluded were patients with solitary tumors except T1G3, more than 10 tumors, carcinoma in situ (CIS), tumors stage T2 or higher, age > 85 yr, WHO performance status 3 or 4, previous treatment with BCG and intravesical chemotherapy during the previous 3 mo. An intravenous pyelography was performed to rule out upper tract tumors. Informed consent was obtained in accordance with the Declaration of Helsinki and/or existing national and local regulations.