Elsevier

European Urology

Volume 57, Issue 5, May 2010, Pages 766-773
European Urology

Platinum Priority – Bladder Cancer
Editorial by Marko Babjuk on pp. 774–776 of this issue
Long-Term Efficacy Results of EORTC Genito-Urinary Group Randomized Phase 3 Study 30911 Comparing Intravesical Instillations of Epirubicin, Bacillus Calmette-Guérin, and Bacillus Calmette-Guérin plus Isoniazid in Patients with Intermediate- and High-Risk Stage Ta T1 Urothelial Carcinoma of the Bladder

https://doi.org/10.1016/j.eururo.2009.12.024Get rights and content

Abstract

Background

Intravesical chemotherapy and bacillus Calmette-Guérin (BCG) reduce the recurrence rate in patients with stage Ta T1 urothelial bladder cancer; however, the benefit of BCG relative to chemotherapy for long-term end points is controversial, especially in intermediate-risk patients.

Objective

The aim of the study was to compare the long-term efficacy of BCG and epirubicin.

Design, setting, and participants

From January 1992 to February 1997, 957 patients with intermediate- or high-risk stage Ta T1 urothelial bladder cancer were randomized after transurethral resection to one of three treatment groups in the European Organization for Research and Treatment of Cancer Genito-Urinary Group phase 3 trial 30911.

Intervention

Patients received six weekly instillations of epirubicin, BCG, or BCG plus isoniazid (INH) followed by three weekly maintenance instillations at months 3, 6, 12, 18, 24, 30, and 36.

Measurements

End points were time to recurrence, progression, distant metastases, overall survival, and disease-specific survival.

Results and limitations

With 837 eligible patients and a median follow-up of 9.2 yr, time to first recurrence (p < 0.001), distant metastases (p = 0.046), overall survival (p = 0.023), and disease-specific survival (p = 0.026) were significantly longer in the two BCG arms combined as compared with epirubicin; however, there was no difference for progression. Three hundred twenty-three patients with stage T1 or grade 3 tumors were high risk, and the remaining 497 patients were intermediate risk. The observed treatment benefit was at least as large, if not larger, in the intermediate-risk patients compared with the high-risk patients.

Conclusions

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.

Trial registration

This study was registered with the US National Cancer Institute clinical trials database [protocol ID: EORTC-30911]. http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=77075&version=HealthProfessional&protocolsearchid=6540260.

Introduction

The European Association of Urology (EAU) guidelines on non–muscle-invasive urothelial carcinoma of the bladder provide recommendations for the adjuvant treatment of patients after transurethral resection (TUR) based on their risk of recurrence and progression to muscle-invasive disease [1], [2]. In patients at low risk of recurrence and progression, one immediate instillation of chemotherapy is recommended as the complete adjuvant treatment. In patients at high risk of progression, at least 1 yr of intravesical bacillus Calmette-Guérin (BCG) is recommended after an immediate instillation of chemotherapy. In the remaining intermediate-risk patients, the guidelines recommend that either further instillations of chemotherapy or a minimum of 1 yr of BCG be given after an immediate instillation of chemotherapy [1].

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 [3], [4], [5]. Although two literature-based meta-analyses comparing BCG with mitomycin C (MMC) or other therapies concluded that BCG with maintenance prevents or at least delays progression to muscle-invasive disease [6], [7], a recent individual patient data meta-analysis comparing BCG with MMC could not confirm these results [5].

Intravesical chemotherapy and intravesical BCG both reduce the recurrence rate in patients with stage Ta T1 urothelial bladder cancer; however, the benefit of BCG relative to chemotherapy for long-term end points in the intermediate-risk patients, approximately 50% of whom recur but only about 10% progress to muscle-invasive disease, remains controversial because any advantage in efficacy with BCG must be weighed against its increased risk of toxicity [8].

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 [9]. In 1992, the European Organization for Research and Treatment of Cancer (EORTC) launched a trial to compare, after TUR, the efficacy of six weekly intravesical instillations of epirubicin, BCG, and BCG plus isoniazid (INH) followed by three weekly maintenance instillations at months 3, 6, 12, 18, 24, 30, and 36 in patients with intermediate- and high-risk stage Ta T1 urothelial bladder cancer without carcinoma in situ (CIS). The first results, dealing mainly with recurrence and side-effects, were published in 2001 [10]. The present paper presents the final long-term efficacy results, taking into account patient risk groups.

Section snippets

Material and methods

EORTC phase 3 trial 30911 included patients with biopsy-proven, completely resected, single or multiple, primary or recurrent, stage Ta T1, grades 1–3 urothelial carcinoma of the bladder.

Exclusion criteria were a solitary primary tumor; CIS; stage T2 or higher tumors; age >85 yr; World Health Organization (WHO) performance status 3 or 4; previous treatment with doxorubicin, epirubicin, or BCG; and intravesical treatment during the previous 3 mo. Patient informed consent was obtained in

Results

Nine hundred and fifty-seven patients were centrally randomized by 44 institutions at the EORTC headquarters between January 1992 and February 1997, with stratification by primary/recurrent tumors, solitary/multiple tumors, and institution using the minimization technique. One hundred and twenty ineligible patients were excluded from the comparisons of treatment efficacy (Fig. 1). Reasons for ineligibility were mainly related to an inappropriate tumor stage because histology was available only

Discussion

The long-term results of this study comparing epirubicin with BCG have confirmed BCG’s superiority for the time to first recurrence (Fig. 2). In addition, BCG favorably influenced the long-term end points of time to distant metastases (Fig. 4), overall duration of survival (Fig. 5), and time to death due to bladder cancer (Fig. 6). It was unexpected, however, that the treatment effect appeared to be larger in the intermediate-risk patients than in the high-risk patients. These results raise

Conclusions

In patients with intermediate- and high-risk stage Ta and T1 bladder cancer, this trial confirms the superiority of intravesical BCG with or without INH as compared with intravesical epirubicin not only for the time to first recurrence but also for the long-term end points of time to distant metastases, overall survival, and disease-specific survival. This study, however, shows that the benefit of BCG is not limited just to high-risk patients; intermediate-risk patients also benefit from BCG.

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