Evidence or prejudice? Critical re-analysis of randomized controlled trials comparing overall survival after cisplatin versus carboplatin-based regimens in advanced urothelial carcinoma

Abstract

Background
For many years EAU guidelines have recommended the use of cisplatin-based regimens over carboplatin for treatment of advanced urothelial cell carcinoma (UCC) in eligible patients. The claim of an overall survival (OS) benefit is based on (a meta-analysis of) two RCTs totalling 190 patients, of which one study has methodological flaws. These studies warrant secondary analysis to substantiate the evidence for an OS benefit of cisplatin- versus carboplatin-based regimens.

Patients and Methods
Individual patient data (IPD) were reconstructed from the two RCTs, assessing OS in both treatment arms. IPD of both studies were then jointly reanalysed to assess an OS estimate with Kaplan-Meier methods, with and without an alternative censoring scenario to assess the impact of the original biased censoring approach. Kaplan-Meier curves were compared by calculating restricted mean survival time (RMST) differences.

Results
In each study individually, and in both studies combined, the survival benefit of cisplatin vs carboplatin was less than one month and not significant in a follow-up window of 12 months. This was also the case when an alternative censoring scenario was applied.

Conclusions
Careful scrutiny of the data on which guidelines base the recommendation of cisplatin-based chemotherapy for the treatment of advanced UCC does not uphold the finding that cisplatin leads to an OS benefit when compared to carboplatin. This conclusion, combined with higher toxicity in cisplatin-based regimens warrants a reconsideration of this guideline recommendation.