Speaker
Description
The assessment of allogeneic stem cell transplantation (SCT) over standard continued chemotherapy in a clinical trial of childhood leukaemia is not straightforward. Standard chemotherapy will be stopped and SCT performed if a donor search identifies a suitable stem cell donor in registries of potential donors. Randomization to SCT or continued chemotherapy is usually not feasible due to ethical considerations. Nevertheless, a fair comparison can be based on the two groups formed by the availability or non-availability of suitable stem cell donors. Thereby, donor availability is a temporarily unknown external baseline variable whose actual values will become known either when a suitable stem cell donor is identified from the registry or after the end of an unsuccessful donor search. However, donor search can be prematurely ceased, e.g. due to patients’ death or deterioration of patients’ health. Unfortunately, then donor availability and thus group membership will remain unknown. There is currently no approach available to correctly illustrate survival probabilities over time for the two groups and compare them at interesting time-points, especially in case of non-proportional hazards that are mainly due to early toxicities after SCT.
For each patient with prematurely ceased donor search, it is possible to calculate the probabilities that a suitable donor might or might not be identified after the ceasing of the donor search, respectively. These probabilities are utilized to develop adjusted Kaplan-Meier curves for visual group comparison over time. These curves have a valid survival probability interpretation unlike the commonly applied Simon and Makuch curves where patients are allowed to change the group over time.
These estimated survival probabilities derived from adjusted Kaplan-Meier curves can also be used to assess group differences at selected long-term time points, which is especially interesting in case of non-proportional hazards. A corresponding statistical test is proposed and compared to other test strategies.
Data from an international study of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia are used to exemplify the satisfactory performance of the new approach. Other methods are only able to estimate survival probabilities at selected time points. Results of the different methods are compared and discussed.
The newly proposed method allows for the first time to show Kaplan-Meier curves, when group membership at baseline is unknown and becomes only partly known over time.
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