Highlights
- •The assumption of uninformative censoring does not hold in many randomised trials.
- •The reverse Kaplan–Meier and reverse hazard ratio are useful for censoring analysis.
- •Excessive treatment arm censoring is specific to positive trials with no survival gain.
- •Fifty percent of trials with imbalanced censoring lose significance after restoring the balance.
- •Informative censoring explains inconsistencies in trials with discordant outcomes.
Abstract
Background
Kaplan–Meier (K-M) analysis, the cornerstone of cancer clinical trial interpretation,
assumes that censored patients are no more or less likely to experience an event than
those followed. We sought to investigate the patterns of censoring in surrogate end-points
of oncology randomised controlled trials (RCTs) and examine the relationship between
censoring in practice-changing treatments that failed to demonstrate survival gain.
Methods
In this cross-sectional study of phase III RCTs published in the New England Journal
of Medicine, Lancet, and JAMA, between 2010 and 2020, K-M curves of surrogate end-points
with statistical significance were extracted. The reverse K-M method (i.e., events
and censoring are flipped) was used to examine differential censoring using the analogous
reverse hazard ratio and restricted mean survival time. Sensitivity analysis was performed
by partially restoring the balance in censoring between study arms.
Results
Of the 73 eligible studies with significant surrogates, 33 (45%) reported significant
overall survival benefit (concordant trials), and 40 (55%) did not (discordant trials).
The proportion of studies with significant differential censoring in surrogates was
43% (17/40) and 51% (17/33) in discordant and concordant trials, respectively. Trials
with a significant censoring imbalance in the experimental arm occurred only in discordant
trials (15% vs 0%, odds ratio [OR] = 12.62, P = 0.033), compared to excessive censoring in the control arm which occurred more
in concordant trials (28% vs 52%; OR = 0.36, P = 0.036). Although censoring imbalance occurred in both groups, after sensitivity
analysis, 50% of the discordant trials lost their statistical significance, compared
to 15% of concordant trials (OR = 5.6, P = 0.0018).
Conclusion
Censoring imbalance between study arms of RCTs suggests a potential systemic bias
and raises uncertainty regarding the validity of the results. Informative censoring
may explain the inconsistency between therapies that seem to improve disease outcomes
without concomitant survival benefit and should trigger further investigation.
Keywords
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Article info
Publication history
Published online: June 26, 2021
Accepted:
April 30,
2021
Received in revised form:
April 25,
2021
Received:
March 4,
2021
Identification
Copyright
© 2021 Elsevier Ltd. All rights reserved.
