Elsevier

European Urology

Volume 52, Issue 4, October 2007, Pages 1123-1130
European Urology

Urothelial Cancer
Long-Term Intravesical Adjuvant Chemotherapy Further Reduces Recurrence Rate Compared with Short-Term Intravesical Chemotherapy and Short-Term Therapy with Bacillus Calmette-Guérin (BCG) in Patients with Non–Muscle-Invasive Bladder Carcinoma

https://doi.org/10.1016/j.eururo.2007.02.063Get rights and content

Abstract

Objective

We present a randomised, parallel group, multicentre phase 4 trial comparing short- and long-term chemoprophylaxis with Mitomycin C (MMC) with short-term immunoprophylaxis with Bacillus Calmette-Guérin (BCG) after transurethral resection of the bladder for non–muscle-invasive bladder carcinoma.

Methods

Four hundred ninety-five patients with intermediate- to high-risk non–muscle-invasive bladder cancer (recurrent and/or multifocal pTaG1, TaG2–3, and T1G1–3) were randomised to BCG RIVM 2 × 108 CFU weekly for 6 wk, MMC 20 mg weekly for 6 wk, or MMC 20 mg weekly for 6 wk followed by monthly instillations for 3 yr.

Results

The 3-yr recurrence-free rates were 65.5% (95%CI, 55.9–73.5%) for short-term BCG, and 68.6% (59.9–75.7%) for short-term MMC, whereas recurrence-free rates were significantly increased to 86.1% (77.9–91.4%) in patients with MMC long-term therapy (log-rank test, p = 0.001).

Conclusions

Long-term MMC significantly reduced the risk of tumour recurrence without enhanced toxicity compared with both short-term BCG and MMC in patients with intermediate- and high-risk non–muscle-invasive bladder carcinoma. Our data provide a rationale for maintenance intravesical chemotherapy in this population.

Introduction

Of patients with non–muscle-invasive bladder cancer, 50–70% will develop tumour recurrence and up to 40% will progress. The cancer-related death rate is up to 36.1% [1]. Risk factors for tumour recurrence and/or progression are tumour focality, tumour size, prior recurrences, stage, grade, and concomitant carcinoma in situ (CIS) [2]. Other prognostic factors are the quality of the primary resection and the administration of adjuvant or prophylactic intravesical therapy [3], [4], [5], [6]. Intravesical adjuvant therapy with Mitomycin C (MMC) or Bacillus Calmette-Guérin (BCG) after transurethral resection (TUR) is a standard therapy for patients with intermediate- or high-risk non–muscle-invasive transitional cell cancer of the bladder [4], [7]. Although the clinical value of intravesical adjuvant therapy is well established, the optimal drug as well as the optimal regimen is still debated. A recent survey [8] has shown a wide variation in current practice for non–muscle-invasive bladder cancer.

Although, according to the guidelines of the European Association of Urology (EAU), the treatment for low-risk and high-risk tumours is well-defined, mitomycin and BCG are equally recommended for patients with intermediate-risk tumours. In contrast to these guidelines, recent meta-analyses [5], [7], [9], [10] suggest an advantage of BCG therapy over MMC, even in intermediate-risk tumours. Despite this possible advantage of BCG, its use is limited by its side-effects, because 5–20% of patients will develop a BCG intolerance [11]. Another open question is the length of intravesical therapy. According to Bouffioux et al [12] a 12-mo course of intravesical chemotherapy does not yield better results than a 6-mo course, provided that an immediate postoperative instillation was administered. In contrast other authors [4], [13], [14] presented effective long-term intravesical chemotherapy regimens.

The aim of the current parallel group, randomised, open-label multicentre trial was to compare the effectiveness of long-term adjuvant therapy with MMC with short-term protocols using BCG or MMC in patients with primary intermediate- to high-risk (recurrent, multifocal or large [>3 cm] pTaG1 tumours, and pTaG2 tumours - small, solitary pT1G3) urothelial carcinoma.

Section snippets

Patients

Patients with primary transitional cell carcinoma of the bladder or patients with tumour recurrence after TUR without prior adjuvant therapy were eligible for trial participation if the histopathologic evaluation of their completely resected tumour revealed an intermediate-risk pTaG1 tumour (size >3 cm, recurrent, or multifocal tumour) or pTaG2 up to pT1 tumour (G1–3). Patients with a pT1G3 tumour were eligible in case of a unifocal small tumour (Ø  2.5 cm). Histopathologic evaluation was done

Results

Between 1995 and 2002, 495 patients were randomised, with 179 patients randomised to receive MMC 6 wk, 153 to receive long-term MMC, and 163 to receive BCG. Demographics and disease characteristics of patients stratified by treatment arm are shown in Table 1.

In the MMC 6-wk arm all patients who started therapy received six instillations, except eight patients who discontinued prematurely. In the BCG arm, five patients did not receive the planned number of instillations.

In the MMC long-term arm.

Discussion

Although intravesical adjuvant or prophylactic treatment is well established and part of the routine in the clinical treatment of patients with non–muscle-invasive bladder cancer, the optimal treatment strategy is still under debate [7], [10]. Recent meta-analyses [5], [9], [17] indicate an advantage of BCG over MMC regarding tumour recurrence and tumour progression. However, this advantage was most pronounced in patients undergoing long-term or maintenance BCG schedules. Another problem is

Conclusions

Long-term MMC significantly reduces the risk of tumour recurrence without enhanced toxicity, compared with both short-term BCG and MMC in patients with intermediate- and high-risk non–muscle-invasive bladder carcinoma. Our data provide a rationale for maintenance intravesical chemotherapy in this population.

Conflicts of interest

None of the authors will benefit financially from the publication of the manuscript.

The work was supported in part by Fa. Medac GmbH, Wedel, Germany.

Dr Pichlmeier is an employee of Medac GmbH.

References (24)

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