Elsevier

European Urology

Volume 65, Issue 1, January 2014, Pages 69-76
European Urology

Platinum Priority – Bladder Cancer
Editorial by Joan Palou on pp. 77–78 of this issue
Side Effects of Bacillus Calmette-Guérin (BCG) in the Treatment of Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Bladder: Results of the EORTC Genito-Urinary Cancers Group Randomised Phase 3 Study Comparing One-third Dose with Full Dose and 1 Year with 3 Years of Maintenance BCG

https://doi.org/10.1016/j.eururo.2013.07.021Get rights and content

Abstract

Background

Although bacillus Calmette-Guérin (BCG) has proven highly effective in non–muscle-invasive bladder cancer (NMIBC), but it can cause severe local and systemic side effects.

Objectives

The objective was to determine whether reducing the dose or duration of BCG was associated with fewer side effects. Efficacy comparisons of one-third dose versus full dose BCG given for 1 yr versus 3 yr have previously been published.

Design, setting, and participants

After transurethral resection, patients with intermediate- and high-risk NMIBC without carcinoma in situ were randomised to one-third dose or full dose BCG and 1 yr or 3 yr of maintenance.

Outcome measurements and statistical analysis

Local and systemic side effects were recorded at every instillation and divided into three time periods: during induction, during the first year after induction, and during the second and third years of maintenance.

Results and limitations

Of the 1316 patients who started BCG, 826 (62.8%) reported local side effects, 403 (30.6%) reported systemic side effects, and 914 (69.5%) reported local or systemic side effects. The percentage of patients with at least one side effect was similar in the four treatment arms (p = 0.41), both overall and in the different time periods. The most frequent local and systemic side effects were chemical cystitis in 460 (35.0%) patients and general malaise in 204 patients (15.5%); 103 patients (7.8%) stopped treatment because of side effects. No significant difference was seen between treatment groups (p = 0.74). In the 653 patients randomised to 3 yr of BCG, 35 (5.4%) stopped during the first year, and 21 (3.2%) stopped in the second or third year.

Conclusions

No significant differences in side effects were detected according to dose or duration of BCG treatment in the four arms. Side effects requiring stoppage of treatment were seen more frequently in the first year, so not all patients are able to receive the 1–3 yr of treatment recommended in current guidelines.

This study was registered at ClinicalTrials.gov with identifier NCT00002990 (http://clinicaltrials.gov/ct2/show/record/NCT00002990).

Introduction

After transurethral resection (TUR), intravesical immunotherapy with bacillus Calmette-Guérin (BCG) is considered the most effective prophylactic treatment for patients with intermediate- and high-risk urothelial non–muscle-invasive bladder cancer (NMIBC) [1], [2]. BCG induction instillations are classically given according to the empirical 6-wk schedule that Morales introduced >35 yr ago [3]. Several randomised trials and meta-analyses published thereafter suggested that maintenance BCG instillations during 1–3 yr is superior to both chemotherapy and induction BCG alone in reducing recurrences and even progression to muscle-invasive disease [4], [5], [6], [7], [8]. As a result, current clinical practice guidelines recommend BCG with 1–3 yr of maintenance as the intravesical therapy of choice for high-risk disease [1], [2].

Although BCG has proved effective in Ta–T1 high-grade tumours and carcinoma in situ (CIS), it can produce moderate to severe local and systemic side effects. In the report by Lamm et al. on maintenance BCG, only 16% of patients were able to receive all instillations of the 3-yr treatment, mainly because of side effects [5]. More recently, in the report on European Organisation for Research and Treatment of Cancer (EORTC) trial 30911 comparing maintenance BCG with and without isoniazid (INH) versus epirubicin, 19% of patients in the BCG group had to stop treatment because of side effects, but 29% completed all 3 yr of treatment [9].

The occurrence of side effects is one of the main reasons why urologists try to avoid the use of BCG, particularly in intermediate-risk patients, for whom chemotherapeutic agents are often prescribed. A reduction in side effects might be achieved in several different ways, for example, with the administration of the antituberculosis drug INH [9], [10], [11] or the antibiotic ofloxacin [12] or by reducing the BCG dose [13], [14], [15]. After EORTC trial 30911 showed that INH did not reduce the side effects of BCG, EORTC study 30962 was designed with the primary objective of determining whether one-third dose was inferior to full dose, whether 1 yr of maintenance was inferior to 3 yr of maintenance, and whether one-third dose and 1 yr of maintenance was associated with fewer side effects. As the efficacy results have already been reported [16], this article focuses on 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 Organisation [WHO] classification) urothelial carcinoma (UC) of the bladder were included. Patients with solitary tumours except T1G3, >10 tumours, CIS, tumours stage ≥T2, those >85 yr of age, WHO performance status 3 or 4, previous treatment with BCG, and intravesical chemotherapy during the previous 3 mo were excluded. An intravenous pyelography was performed to rule out

Results

After the quality control exclusion of 450 patients from six institutions, 1355 patients were centrally randomised by 51 institutions from 13 European countries between March 1997 and April 2005. Seventy-five patients (5.5%) were ineligible. Delay between TUR and randomisation (>21 d) and type of tumour were the most common reasons for ineligibility. Three hundred forty-one patients were randomised to 1/3D-1yr BCG, 339 to FD-1yr BCG, 337 to 1/3D-3yr BCG, and 338 to FD-3yr BCG (Fig. 1). Patient

Discussion

Maintenance BCG has been advocated by many investigators as the therapy of choice for patients with Ta–T1 high-grade UC of the bladder or CIS. This is reflected in the various guidelines on NMIBC that include BCG as first-line adjuvant therapy after TUR in high-risk patients [1], [2].

The most widely used maintenance schedule is based on the Southwest Oncology Group regimen, starting with a series of six weekly inductions followed by three weekly instillations at 3 mo and 6 mo, and then every 6

Conclusions

No significant differences in toxicity were detected according to dose (one-third dose vs full dose) or duration (1 yr vs 3 yr) of BCG treatment in the four arms. Neither reducing the dose nor shortening the duration of maintenance decreased the percentage of patients who stopped treatment because of side effects. Side effects requiring stoppage of treatment were seen more frequently in the first year of therapy, preventing some patients from receiving the 1–3 yr of treatment recommended in

References (20)

There are more references available in the full text version of this article.

Cited by (0)

Please visit www.eu-acme.org/europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.

View full text