Review – Bladder CancerThe 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☆
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.
References (41)
- et al.
Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials
Eur Urol
(2006) - et al.
A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials
J Urol
(2004) - et al.
A combined analysis of European Organization for Research and Treatment of Cancer and Medical Research Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer
J Urol
(1996) - et al.
Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials
J Clin Epidemiol
(2000) - et al.
Apparent failure of current intravesical chemotherapy prophylaxis to influence the long-term course of superficial transitional cell carcinoma of the bladder
J Urol
(1995) - et al.
The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years of followup
J Urol
(1996) - et al.
Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment
J Urol
(1995) - et al.
Three schedules of adjuvant intravesical epirubicin in patients with non-muscle invasive bladder cancer: a comparative study
Eur Urol Suppl
(2007) - et al.
Natural history and treatment of low and high risk superficial bladder tumors
J Urol
(1988) - et al.
Effect of prophylactic treatment with intravesical epirubicin on recurrence of superficial bladder cancer—the 6th trial of the Japanese Urological Cancer Research Group (JUCRG): a randomized trial of intravesical epirubicin at dose of 20 mg/40 ml, 30 mg/40 ml, 40 mg/40 ml
Eur Urol
(2004)
Long-term intravesical adjuvant chemotherapy further reduces recurrence rate compared with short-term intravesical chemotherapy and short-term therapy with bacillus Calmette-Guerin (BCG) in patients with non–muscle-invasive bladder carcinoma
Eur Urol
Intravesical epirubicin versus doxorubicin for superficial bladder tumors (stages pTa and pT1): a randomized prospective study
J Urol
The use of intravesical thio-tepa in the management of non-invasive carcinoma of the bladder
J Urol
Intravesical instillation of epirubicin, bacillus Calmette-Guérin and bacillus Calmette-Guérin plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the bladder: a European Organization for Research and Treatment of Cancer Genito-Urinary Group randomized phase III trial
J Urol
Intravesical chemotherapy with epirubicin: a dose response study
J Urol
Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies
Eur Urol
A second-look TUR in T1 transitional cell carcinoma: why?
Eur Urol
Is a second transurethral resection necessary for newly diagnosed pT1 bladder cancer
J Urol
Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term followup
J Urol
Guidelines on TaT1 (non-muscle invasive) bladder cancer
European Association of Urology
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2022, European UrologyCitation Excerpt :Another RCT found no impact of SI with epirubicin followed by further chemotherapy or BCG instillations in a cohort of predominantly high-risk BC [98]. The length and frequency of repeat chemotherapy instillations are still controversial; however, the duration should not exceed 1 yr [96] (LE: 3). One RCT showed that adjusting the urinary pH and decreasing urinary excretion reduced the recurrence rate [99] (LE: 1b).
Clinical trial of high dose hyperthermic intravesical mitomycin C for intermediate and high-risk non–muscle invasive bladder cancer during BCG shortage
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