Sample size calculation for the proportional hazards cure model.

In clinical trials with time-to-event endpoints, it is not uncommon to see a significant proportion of patients being cured (or long-term survivors), such as trials for the non-Hodgkins lymphoma disease. The popularly used sample size formula derived under the proportional hazards (PH) model may not be proper to design a survival trial with a cure fraction, because the PH model assumption may be violated. To account for a cure fraction, the PH cure model is widely used in practice, where a PH model is used for survival times of uncured patients and a logistic distribution is used for the probability of patients being cured. In this paper, we develop a sample size formula on the basis of the PH cure model by investigating the asymptotic distributions of the standard weighted log-rank statistics under the null and local alternative hypotheses. The derived sample size formula under the PH cure model is more flexible because it can be used to test the differences in the short-term survival and/or cure fraction. Furthermore, we also investigate as numerical examples the impacts of accrual methods and durations of accrual and follow-up periods on sample size calculation. The results show that ignoring the cure rate in sample size calculation can lead to either underpowered or overpowered studies. We evaluate the performance of the proposed formula by simulation studies and provide an example to illustrate its application with the use of data from a melanoma trial.