Platinum Priority – Bladder CancerEditorial by Marko Babjuk on pp. 774–776 of this issueLong-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
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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