Abstract

ObjectivesTo examine the presence of the time-dependent effect of metronomic chemotherapy for the treatment of older patients with acute myeloid leukemia (AML) who were unfit for standard chemotherapy and to reanalyze the data using an appropriate statistical approach in the presence of non-proportional hazards, the restricted mean survival time (RMST).ResultsThis was a secondary analysis of a multi-center, open-label, randomized controlled trial, which was conducted in seven tertiary care hospitals across Thailand. A total of 81 unfit AML patients were randomized into two treatment groups, metronomic chemotherapy and palliative treatment. The hazard ratio of metronomic chemotherapy over palliative treatment was time-dependent. At three landmark time points of 90, 180, 365 days, the restricted mean survival time differences were 13.3 (95% CI 1.9–24.7) days, 28.9 (95% CI 3.3–54.4) days, and 40.4 (95% CI − 1.3 to 82.0) days, respectively. With non-proportional hazards modeling and RMST analysis, we were able to conclude that metronomic chemotherapy is a potentially effective alternative treatment for elderly AML patients who were medically unfit for intensive chemotherapy. In the future clinical trials, non-proportional hazards should be carefully inspected and properly handled with appropriate statistical methods.Trial registration Randomized clinical trial TCTR20150918001; registration date: 15/09/2015. Retrospectively registered

Highlights

  • Proper therapeutic choices for elderly patients with acute myeloid leukemia (AML) remains controversial [1]

  • The efficacy and safety of metronomic chemotherapy in AML patients who were unfit for standard chemotherapy were addressed for the first time in our prior work [4]

  • It was revealed that the overall survival was higher in patients who were allocated to metronomic chemotherapy compared to those allocated to palliative treatment

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Summary

Introduction

Proper therapeutic choices for elderly patients with acute myeloid leukemia (AML) remains controversial [1]. The efficacy and safety of metronomic chemotherapy in AML patients who were unfit for standard chemotherapy were addressed for the first time in our prior work [4]. It was revealed that the overall survival was higher in patients who were allocated to metronomic chemotherapy compared to those allocated to palliative treatment. Phinyo et al BMC Res Notes (2021) 14:3 as the survival curves merged. This could suggest the violation of proportional hazards (PH) assumption. In this situation, reporting a single hazard ratio (HR) is misleading, as there was evidence that the treatment effect is time-dependent [5]

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