Abstract
BACKGROUND: Survival-based surrogate endpoints such as progression-free survival (PFS) are commonly used in oncology clinical trials. The evaluation-time bias in the assessment of median disease progression in randomized trials has been suggested by several simulation studies, but never demonstrated in the clinic. We aimed to demonstrate the existence of potential evaluation-time bias by assessing the impact of the timing of tumor assessments on median PFS from control arms without any active treatment of randomized controlled trials involving advanced cancer patients. MATERIALS AND METHODS: A systematic literature search of English language publications from 1 January 2000 to 7 January 2021 was performed using MEDLINE (PubMed). Eligible trials for our meta-analysis included all randomized clinical trials evaluating anticancer drugs in adult patients with advanced cancers with a control arm without any anticancer drug consisting of best supportive care with or without a placebo. We performed a meta-regression analysis to analyze the correlation between the timing of the first tumor assessment and median PFS in patients randomized in the control arms without any active treatment. RESULTS: Of 3551 studies screened, 97 eligible trials were retrieved involving 36 747 patients, including 14 229 patients randomized into the control arms. A later first tumor assessment correlated with a prolonged median PFS (R(2) = 0.44, P < 10(-5)). CONCLUSIONS: Our results confirm the existence of potential evaluation-time bias in clinical research that had been suggested by simulation studies. The timing of tumor assessments should be kept the same in precision medicine trials using the PFS ratio as an efficacy endpoint.