Elsevier

European Urology

Volume 53, Issue 4, April 2008, Pages 709-719
European Urology

Review – Bladder Cancer
The Schedule and Duration of Intravesical Chemotherapy in Patients with Non–Muscle-Invasive Bladder Cancer: A Systematic Review of the Published Results of Randomized Clinical Trials

https://doi.org/10.1016/j.eururo.2008.01.015Get rights and content

Abstract

Objectives

Intravesical chemotherapy has been studied in randomized clinical trials for >30 yr; however, the optimal schedule and duration of treatment are unknown. The objective is to determine the effect of schedule and duration of intravesical chemotherapy on recurrence in patients with stage Ta T1 bladder cancer.

Methods

A systematic review was conducted of the published results of randomized clinical trials that compared intravesical instillations with respect to their number, frequency, timing, duration, dose, or dose intensity.

Results

One immediate instillation after transurethral resection (TUR) is recommended in all patients. In low-risk patients, no further treatment is recommended before recurrence. In patients with multiple tumors, one immediate instillation is insufficient treatment. Additional instillations may further reduce the recurrence rate; however, no recommendations can be made concerning their optimal duration. A short intensive schedule of instillations within the first 3–4 mo after an immediate instillation may be as effective as longer-term treatment schedules (grade C). Instillations during ≥1 yr in intermediate-risk patients seem advisable only when an immediate instillation has not been given (grade C). Higher drug concentrations and optimization of the drug's concentration in the bladder may provide better results (grade C).

Conclusions

The optimal schedule and duration of intravesical chemotherapy after an immediate instillation remain unknown. Future studies should focus on the eradication of residual disease after TUR and the prevention of late recurrences.

Introduction

Guidelines of the European Association of Urology for the treatment of stage Ta–T1 (non–muscle-invasive) bladder cancer recommend that all patients receive one immediate instillation of chemotherapy after transurethral resection (TUR) [1]. Further treatment depends on the patient's risk of recurrence and progression to muscle-invasive disease [2]. In patients at low risk of recurrence and progression, no further treatment is recommended prior to a subsequent recurrence. In patients at high risk of progression, that is, those with high-grade tumors or carcinoma in situ (CIS), 1–3 yr of maintenance bacillus Calmette-Guérin (BCG) is recommended.

The remaining patients have an intermediate risk of progression and an intermediate to high risk of recurrence, with the risk of recurrence depending, to a large extent, on the number of tumors [2]. One immediate instillation by itself has been shown to be insufficient treatment after TUR in patients with multiple tumors [3]; however, there is no consensus whether further intravesical chemotherapy or intravesical BCG should be given in these patients.

Meta-analyses have shown that intravesical chemotherapy reduces the recurrence rate as compared to TUR alone [4], [5], [6], with a decrease of 8% in the percentage of patients who have recurrence [4]. However, the optimal frequency and duration of treatment remain unknown. Although one meta-analysis suggested that longer instillation schedules may be associated with greater treatment benefit [5], another meta-analysis questioned whether there was a long-term benefit beyond one immediate instillation [7].

To determine the effect of schedule and duration of intravesical chemotherapy on recurrence in patients with non–muscle-invasive bladder cancer, a systematic review of the published results of randomized clinical trials has been carried out. Because of the heterogeneity of the various treatment schedules within some of the groups being compared, it was not always justified to pool together the results from the different studies to get an overall quantitative estimate of the size of the treatment effect. Hence, meta-analyses have been carried out for only a limited number of comparisons.

Section snippets

Methods

All randomized trials in patients with stage Ta–T1 bladder cancer that compared different schedules or durations of intravesical chemotherapy after TUR were considered. Trials published or accepted for publication before May 2007 that compared intravesical instillations with respect to their number, frequency, timing, duration, dose, or dose intensity were identified by searching MEDLINE, reference lists in trial publications and review articles, and annual meeting abstracts in the Journal of

Results

Results are presented as answers to different questions about the schedule and duration of intravesical chemotherapy taking into account whether or not an immediate instillation of chemotherapy was given after TUR.

Discussion

Although the schedule and duration of intravesical chemotherapy have been the subjects of many studies, the optimal instillation scheme remains unknown. Controversy exists because underpowered trials have produced inconsistent results. Comparisons of different treatment durations have been diluted because patients have had recurrences and gone off the study before the time when additional long-term instillations should have started. The benefit of continuing treatment in patients who were free

Conclusions

One immediate instillation after TUR reduces the recurrence rate and is recommended in all patients with papillary tumors except in the case of a perforated bladder or extended TUR (grade A). In patients at low risk of recurrence, no further treatment is recommended prior to recurrence.

In patients with multiple tumors for whom one instillation is insufficient treatment, the results of this systematic review are inconclusive and firm recommendations cannot be provided. The effect of one

Conflicts of interest

The authors have nothing to disclose.

Acknowledgments

This research project was supported by the EORTC Charitable Trust through a grant from the Fondation contre le Cancer (Belgium). This publication was supported by grant number 5U10 CA11488-37 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.

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