Evidence or Prejudice? Critical Re-Analysis of Randomized Controlled Trials Comparing Overall Survival After Cisplatin Versus Carboplatin-Based Regimens in Advanced Urothelial Carcinoma

• Published in: Clinical genitourinary cancer Vol. 20; no. 4; pp. e346 - e352
• Main Authors: Richters, Anke, Kiemeney, Lambertus A.L.M., Mehra, Niven, Westgeest, Hans M., Birtle, Alison, Bryan, Richard T., Aben, Katja K.H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2022
• Subjects: Advanced urothelial carcinoma; Chemotherapy; Overall survival; Secondary analysis; Survival analysis; Urothelial cancer; Advanced urothelial carcinoma; Urothelial cancer; Survival analysis; Chemotherapy; Secondary analysis; Overall survival
• ISSN: 1558-7673; 1938-0682
• DOI: 10.1016/j.clgc.2021.12.017

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) 2 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. Individual patient data (IPD) were reconstructed from the 2 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. In each study individually, and in both studies combined, the survival benefit of cisplatin versus carboplatin was less than 1 month and not significant in a follow-up window of 12 months. This was also the case when an alternative censoring scenario was applied. 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. Guidelines recommend cisplatin over carboplatin for treatment of advanced urothelial carcinoma since 2008. This recommendation is based on (a meta-analysis of) two small RCTs, one with a questionable censoring approach. Secondary analysis of individual patient data from these RCTs did not demonstrate overall survival benefit from cisplatin over carboplatin. Considering lower toxicity and larger population eligibility for carboplatin, guideline recommendations should be reconsidered.