The estimand framework had implications in time to patient-reported outcomes deterioration analyses in cancer clinical trials

Abstract

ObjectivesTo apply the estimand framework in time to deterioration (TTD) analysis of patient-reported outcomes (PROs), and identify the appropriate statistical methods to deal with intercurrent event (IEs) such as death. Study Design and SettingData from phase II randomized trial were used. We estimated TTD using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 questionnaire with death as the IE, by applying Kaplan–Meier (K.M.) estimator and Cox proportional hazards (PH) model. The Fine–Gray approach was explored, accounting for death as a competing risk. The estimands targeted by the aforementioned methods were defined. ResultsWe analyzed the data of 64 patients with available questionnaires at baseline. The most notable differences in TTD estimates were observed for deterioration in physical functioning: the hazard ratios were 0.44 [95% CI 0.22–0.90] and 0.62 [95% CI 0.36–1.07] by either ignoring death (31 events) or considering it as deterioration (58 events), respectively (Cox-PH model). When considering death as a competing event (Fine–Gray model), the sub-HRs was 0.51 [95% CI 0.26–1.01]. ConclusionDepending on the proportion and distribution of deaths occurring before deterioration between arms, the Fine–Gray competing risks model should be considered rather than KM estimator and Cox PH model to reflect the patient's experience of the disease and treatment burden.