Adjuvant chemotherapy for invasive bladder cancer (individual patient data)

Abstract

Background: Controversy exists as to whether adjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite a number of randomised controlled trials.

Objectives: To evaluate the effect of adjuvant chemotherapy in invasive bladder cancer. We conducted a systematic review and meta-analysis of updated individual patient data from all available randomised controlled trials comparing local treatment plus adjuvant chemotherapy versus the same local treatment alone.

Search strategy: MEDLINE and Cancerlit searches were supplemented with information from registers and hand searching meeting proceedings and also by discussion with relevant trialists and organisations. They have been regularly updated until September 2004.

Selection criteria: Trials that aimed to randomise patients with biopsy proven invasive (i.e. clinical stage T2-T4a) transitional cell carcinoma of the bladder to receive local definitive treatment with or without adjuvant chemotherapy were eligible for inclusion.

Data collection and analysis: We collected, validated and re-analysed updated data on all randomised patients from all available randomised trials, including 491 patients from 6 RCTs. For all outcomes, we obtained overall pooled hazard ratios using the fixed effects model. To explore the potential impact of trial design, we pre-planned analyses that grouped trials by important aspects of their design that might influence the treatment effect. To investigate any differences in effect by pre-defined patient sub-groups, we used a stratified logrank analysis on the primary endpoint of survival.

Main results: Analyses were based on 491 patients from six trials, representing 90% of all patients randomised in cisplatin-based combination chemotherapy trials and 66% of patients from all eligible trials. The power of this meta-analysis is clearly limited. The overall hazard ratio for survival of 0.75 (95%CI 0.60-0.96, p=0.019) suggests a 25% relative reduction in the risk of death for chemotherapy compared to that on control. Cox regression suggests that small imbalances in patient characteristics do not bias the results in favour of chemotherapy. However, the impact of trials that stopped early, of patients not receiving allocated treatments or not receiving salvage chemotherapy is less clear.

Authors' conclusions: This IPD meta-analysis provides the best evidence currently available on the role of adjuvant chemotherapy for invasive bladder cancer. However, at present there is insufficient evidence on which to reliably base treatment decisions. These results highlight the urgent need for further research into the use of adjuvant chemotherapy. The results of appropriately sized randomised trials, such as the ongoing EORTC-30994 trial are needed before any definitive conclusions can be drawn.

1

Survival Curve (all trials)

2

Recurrence and treatment for recurrence flow diagram 
 * Otto et al (unpublished) supplied overall survival data only. Patients who recurred on the control arm received 2 cycles of MVEC (PJ Goebell, pers comm.). 
 † Treatment on recurrence data not available for 3 trials [4‐6]. However, for one trial [6] patients randomised to control were treated with standard CMV on first evidence of recurrence and for another trial [5] there was no restriction on patients randomised to control arm receiving chemotherapy on recurrence / progression. For the final trial [4] patients randomised to the control arm were not recommended to receive chemotherapy on recurrence.

1.1. Analysis

Comparison 1 Adjuvant chemotherapy + local treatment vs. local treatment alone, Outcome 1 Overall Survival.

1.2. Analysis

Comparison 1 Adjuvant chemotherapy + local treatment vs. local treatment alone, Outcome 2 Disease‐free survival.