Elsevier

European Urology

Volume 63, Issue 3, March 2013, Pages 462-472
European Urology

Platinum Priority – Bladder Cancer
Editorial by J. Alfred Witjes on pp. 473–474 of this issue
Final Results of an EORTC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guérin in Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 Years of Maintenance

https://doi.org/10.1016/j.eururo.2012.10.039Get rights and content

Abstract

Background

The optimal dose and duration of intravesical bacillus Calmette-Guérin (BCG) in the treatment of non–muscle-invasive bladder cancer (NMIBC) are controversial.

Objective

To determine if a one-third dose (1/3D) is not inferior to the full dose (FD), if 1 yr of maintenance is not inferior to 3 yr of maintenance, and if 1/3D and 1 yr of maintenance are associated with less toxicity.

Design, setting, and participants

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, and 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 and limitations

In an intention-to-treat analysis of 1355 patients with a median follow-up of 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 1 yr could not be rejected. We found that 1/3D-1 yr is suboptimal compared with FD-3 yr (hazard ratio [HR]: 0.75; 95% confidence interval [CI], 0.59–0.94; p = 0.01). Intermediate-risk patients treated with FD do not benefit from an additional 2 yr of BCG. In high-risk patients, 3 yr 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 with FD-1 yr but not progressions or deaths. The benefit of the two additional years of maintenance should be weighed against its added costs and inconvenience.

Trial registration

This study was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/record/NCT00002990.

Introduction

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 the European Organization for Research and Treatment of Cancer (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 Calmette-Guérin (BCG) are given in accordance with the European Association of Urology (EAU) guidelines [3]. In intermediate- and high-risk patients, the protective effects of maintenance BCG are more pronounced compared with chemotherapy [4], [5].

The initial report by Morales et al described six weekly BCG induction instillations [6]. Afterward, it was found that additional instillations of BCG reduced recurrences; however, the optimal duration of maintenance instillations remains controversial [7], [8], [9]. Based on several meta-analyses, the EAU guidelines recommend at least 1 yr of maintenance.

A major disadvantage of BCG is its toxicity, leading to interruptions and premature discontinuation of maintenance. In EORTC trial 30911, isoniazid did not reduce toxicity for patients on 3 yr 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 with the standard dose in intermediate- and high-risk patients [12], [13], [14]. These studies, where a short schedule <6 mo of BCG was used, suggested that a 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 was 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.

Section snippets

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, >10 tumors, carcinoma in situ (CIS), tumor 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 pyelograph was performed to rule out

Results

From March 1997 to April 2005, 1805 patients were centrally randomized at the EORTC headquarters by 57 centers from 13 countries with stratification by site. During patient entry and prior to the analysis of end point data, study coordinator central review (J.O. and M.B.) and onsite audits led to the exclusion of all data from six sites for noncompliance. After quality control exclusion of these 450 patients, patient entry continued until 1355 patients had been randomized: 341 to 1/3D-1 yr, 339

Discussion

The aim of this study was to prove that decreasing the dose of BCG from FD to 1/3D and/or shortening maintenance from 3 yr to 1 yr to reduce toxicity would not compromise treatment efficacy.

CUETO published several studies with a reduction of BCG to a 1/3D and one-sixth dose (1/6D). In one report, CUETO claimed the efficacy of 1/3D was comparable with FD [13]; however, their trial was not designed as a noninferiority study [15]. In another study, intermediate-risk patients were randomized

Conclusions

This is the largest study on the toxicity and efficacy of BCG dose reduction and duration of maintenance. There were no significant differences in toxicity between 1/3D and FD BCG. Based on the primary end point of DFI, 1/3D with 1 yr of maintenance is suboptimal compared with the standard FD during 3 yr. It is recommended to treat intermediate-risk patients with FD for 1 yr because there is no further improvement in outcome by continuing treatment to 3 yr.

In high-risk patients, FD-3 yr BCG

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