A placebo-controlled trial of Sertraline's effects on symptoms, well-being and survival in advanced cancer: The ZEST Trial

Abstract

9002 Background: Depression, anxiety, fatigue and impaired well-being are common, important and closely related in advanced cancer. We sought to determine the effects of sertraline (a well-tolerated, SSRI antidepressant) on these symptoms and survival in a broad cross-section of people with advanced cancer but without major depression. Methods: 189 participants (pts) were randomly allocated to sertraline 50 mg daily or placebo. Assessments were at baseline; months 1, 2, 4, 6, 9, 12; and, then 3-monthly. Outcome measures rated by pts included the: Centre for Epidemiologic Studies Depression scale (CES-D); Hospital Anxiety and Depression Scale (HADS-A, HADS-D); and the Functional Assessment of Cancer Therapy General and Fatigue scales (FACT-G and FACT-F). Clinicians completed Spitzer's Quality of Life Index (SQLI). Outcomes on all scales are expressed from 0 (worst) to 100 (best). The primary analyses of sertraline's effects on quality of life were based on scores at 4 and 8 weeks adjusted for baseline scores using generalised estimating equations. Efficacy analyses are by intention to treat; toxicity analyses by treatment received. P-values and 95% confidence intervals (CI) are 2-sided. Results: Recruitment was stopped after the first planned interim analysis of 150 pts showed a trend in overall survival favouring placebo (univariable logrank p=0.04; multivariable Cox model hazard ratio 1.61, CI 1.1 to 2.5, p=0.02). This trend was weaker at the final analysis including all 189 patients and longer follow-up (univariable logrank p=0.09); and, after accounting for baseline factors (multivariable Cox model hazard ratio 1.27, CI 0.87 to 1.8, p=0.2). Sertraline had no significant effects (scale: benefit over placebo, 95% CI) on depression (CES-D: 0.4, −2.6 to 3.4), anxiety (HADS-A: 2.0, −1.5 to 5.5), fatigue (FACT-F: 0.3, −4.3 to 4.9), overall quality of life (FACT-G: 1.7, −1.3 to 4.7) or clinicians’ ratings (SQLI: 2.0, −2.5 to 6.5). Subgroup and sensitivity analyses also excluded significant benefits. Sertraline was discontinued more often and earlier than placebo (logrank p = 0.03). The trial was closed for lack of benefit. Conclusions: Sertraline did not improve symptoms, well-being or survival and should be reserved for those with a proven indication. No significant financial relationships to disclose.