Maintenance Bacillus Calmette-Guerin for Ta T1 Bladder Tumors Is Not Associated with Increased Toxicity: Results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial
Introduction
From the many randomized trials published, it has become clear that intravesical bacillus Calmette-Guerin (BCG) is the therapy of choice for high risk Ta, T1 papillary carcinomas as well as for carcinoma in situ (CIS). Recent meta-analyses have shown that intravesical BCG reduces the risk of both recurrence and progression in patients with superficial bladder cancer [1], [2]. However, reductions in the risks of recurrence and progression were only observed if maintenance therapy was used, with the duration of maintenance varying between 18 weeks and 3 years. Since intravesical BCG provokes more side effects than intravesical chemotherapy [1], [3], [4], [5], [6], some urologists are still reluctant to use BCG.
Patients may not complete the entire BCG maintenance regimen for a number of reasons. One of the assumptions is that the occurrence of adverse events is one of the most frequent reasons to stop treatment and that as more BCG is administered, the more likely it is that side effects will appear. In other words, the longer the instillations are given, the more likely it is that the patient will develop severe toxicity [7].
Since maintenance instillations are necessary to reduce the risk of recurrence and progression, it is of utmost importance to know whether or not adverse effects increase with time during maintenance. Few data in the literature exist where the severity of BCG side effects has been investigated during both the 6 week induction course and later on during the maintenance schedule which can last up to 3 years.
The purpose of this paper is to assess the type, frequency and time at which adverse events are reported in patients receiving maintenance BCG treatment and to determine if the percent of patients stopping BCG due to side effects increases with time.
Section snippets
Selection of patients
Patients with intermediate and high risk superficial bladder tumors were included in the trial [6]. Patients had to have single or multiple, primary or recurrent, completely resectable Ta–T1, grade 1–3, biopsy proven transitional cell carcinoma of the bladder. Exclusion criteria were: a primary solitary tumor, tumor stage ≥T2 or CIS, age older than 85 years, WHO performance status 3 or 4, previous treatment with adriamycin, epirubicin or BCG, and intravesical treatment within the previous 3
Results
957 patients were randomized by 44 institutions between January 1992 and February 1997 to receive prophylactic intravesical instillations after TUR: 318 to epirubicin, 320 to BCG Tice and 319 to BCG Tice plus isoniazid. 487 eligible patients who started BCG treatment (247 BCG alone and 240 BCG+INH) were evaluated for BCG toxicity and are included in this analysis.
The median duration of treatment was 12 months during which time 15 instillations were administered (Table 1). The total number of
Discussion
Intravesical immunotherapy with BCG has been used now for more than 25 years for the treatment of carcinoma in situ and the adjuvant treatment of Ta T1 bladder cancer after TUR. Intravesical BCG is more effective than both TUR alone [9] and intravesical chemotherapy [1] with respect to reducing tumor recurrence. Contrary to intravesical chemotherapy [10], a meta-analysis has shown that intravesical BCG does reduce the risk of progression, however maintenance therapy is required [2]. In the 20
Conclusions
BCG therapy is effective in reducing the risk of disease progression only when maintenance schedules are used, however the fear of increased toxicity during the maintenance treatment period is not justified. Local side effects of BCG do not increase during maintenance therapy. Systemic side effects are more frequent during the first 6 months of treatment after which time they decrease. Although 20% of the patients stopped BCG due to side effects, two thirds of those patients stopped BCG already
Acknowledgements
This project was supported by grant numbers 2U10 CA11488-22, 5U10 CA11488-23, 5U10 CA11488-24, 2U10 CA11488-25, 5U10 CA11488-26, 5U10 CA11488-27, 2U10 CA11488-28, 5U10 CA11488-29, 5U10 CA11488-30, 2U10 CA11488-31, 5U10 CA11488-32 and 5U10 CA11488-33 from the National Cancer Institute (Bethesda, MD, USA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Participating members of the European Organisation
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