Beyond composite endpoints analysis: Semicompeting risks as an underutilized framework for cancer research

Background: Composite endpoints (CEP), such as progression-free survival, are commonly used in cancer research. Notwithstanding their popularity, however, CEP analyses suffer from a number of drawbacks, especially when death is combined with a nonterminal event (ie, progression or recurrence), exemplifying the semicompeting risks setting. We investigated the semicompeting risks framework as a complementary analysis strategy that avoids certain drawbacks of CEPs. Methods: The illness-deathmodel under the semicompeting risks framework was compared with standard analysis approaches: CEP analyses and (separate) univariate analyses for each component endpoint. Data froma previously published phase III randomized clinical trial inmetastatic colon cancer including 1419 participants in the N9741 trial (conducted between 1997 and 2003) were used to determine the impact of the loss of information associated with combiningmultiple endpoints, as well as of ignoring the potentially informative role of death. A simulation study was conducted to further explore these issues. Results: Failure to account for critical features of semicompeting risks data can lead to potentially severely misleading conclusions. Advantages of semicompeting risks analyses include a clear delineation of treatment effects on both events, the ability to draw conclusions about a patient's joint risk of the two events, and an assessment of the dependence between the two event types. Conclusions: Embedding and analyzing component outcomes in the semicompeting risks framework, either as a supplement or alternative to CEP analyses, represents an important, underutilized, and feasible opportunity for cancer research.