WITHDRAWN: Neoadjuvant cisplatin for advanced bladder cancer.

Abstract

Bladder cancer is the second most common malignancy of the genito-urinary system. During the past 20 years many phase II clinical trials have investigated the role of chemotherapy in patients with locally advanced bladder cancer. These studies have identified a number of active single-agent cytotoxic drugs such as cisplatin. Although promising results have also been achieved with various combinations of drugs there is no conclusive evidence that chemotherapy improves survival, irrespective of whether it is given before (neoadjuvant or pre-emptive), with (concurrent) or after (adjuvant) local treatment. Despite this, many clinicians now use neoadjuvant chemotherapy in the routine treatment of locally advanced bladder cancer. The main objective of this review was to investigate whether platinum-based chemotherapy given either before or during local treatment, improves the survival of patients with locally advanced bladder cancer. A further objective was to determine whether there is any evidence that such chemotherapy is more or less effective within well defined subgroups of patients. MEDLINE and CANCERLIT bibliographic searches were supplemented by information obtained from trial registers and, by hand searching relevant meeting proceedings, and by discussion with relevant trialists and organisations. Trials were included in the meta-analysis provided they were properly randomised, included patients with advanced bladder cancer and compared local treatment versus the same local treatment plus neoadjuvant or concurrent chemotherapy. Updated individual patient data were sought from the trialists responsible for all eligible randomised controlled trials (all were unpublished at outset of meta-analysis). Time-to-event analyses of survival were done on intention to treat basis. A sensitivity analysis including summary data from the single trial for which individual patient data were not available was also done. Pre-defined subgroup analyses by age, sex, tumour stage and grade were also carried out. Individual data on 479 patients from 4 randomised trials were available. Data extracted from a published report was used for 1 further trial (325 patients) in a supplementary analysis. Analysis of the individual patient data gave an overall hazard ratio of 1.02 in favour of local therapy alone (P = 0.845, 95% confidence interval (CI) = 0.81 to 1.26). When this analysis was supplemented by data from the only trial for which individual patient information was not available, the hazard ratio was 0.91 in favour of chemotherapy (P = 0.328, 95% confidence interval = 0.75 to 1.10). Neither analysis was conventionally significant. The only prognostic factor for which the evidence suggested a differential treatment effect (interaction) across groups was age (chi(2) test for trend = 3.833, P = 0.05), with younger age groups (< 60 years) showing a possible effect in favour or chemotherapy. There is insufficient information currently included in this meta-analysis to obtain a definitive answer to the question of whether neoadjuvant cisplatin-based chemotherapy improves the survival of patients with locally advanced bladder cancer. Since the publication of this review by the collaborative group in 1995, 4 additional trials have been completed, although none of these has yet been published in full. The next update of the meta-analysis (planned for 1999/2000) will aim to include source data from these trials and should therefore provide more definitive results.