Alleviating breathlessness in patients with cancer with dexamethasone (ABCD): A parallel-group, double-blind, randomized clinical trial (RCT).
Authors: Hui David , Puac Veronica , Shelal Zeena , Dev Rony , Hanneman Sandra , Jennings Kristofer , Ma Hilary Y. , Urbauer Diana L. , Shete Sanjay , Fossella Frank V. , Liao Zhongxing X. , Blumenschein George R. , Chang Joe Y. , O'Reilly Michael , Gandhi Saumil , Tsao Anne S. , Mahler Donald , Bruera Eduardo 
Published: June 2022

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Background: Systemic corticosteroids are commonly prescribed for palliation of dyspnea in patients with cancer; however, evidence to support their use is limited. A small RCT suggested that dexamethasone may be efficacious. In this confirmatory RCT, we compared the effect of high dose dexamethasone and placebo on dyspnea in patients with cancer. Methods: This NCI-funded, multi-site, double-blind, parallel group RCT enrolled ambulatory patients with cancer, age ≥18, dyspnea ≥4/10 and randomly assigned them to receive dexamethasone 8 mg orally every 12 hours for 7 days followed by 4 mg orally every 12 hours for 7 days or matching placebo capsules. Permuted block randomization (block size = 6, 2:1) was conducted, stratified by baseline dyspnea and study site. Patients, research staff and clinicians were blinded. The primary outcome was change in average dyspnea intensity assessed with a 0-10 numeric rating scale (0 = none, 10 = worst) between baseline and day 7. Secondary outcomes included the Edmonton Symptom Assessment Scale (ESAS) and adverse effects (CTCAE v4.02). Intention-to-treat analysis was conducted with linear models to compare between groups. The planned sample size of 201 patients provided 80% power to detect a mean difference of 1.0 between treatment groups with a two-sided α of 5%, assuming a standard deviation of 2.0 and 15% attrition. (Clinicaltrials.gov NCT03367156). Results: Between 1/11/2017 and 4/23/2021, we enrolled 149 patients and 128 received the blinded study interventions (dexamethasone n = 85, placebo n = 43). Enrollment was terminated early by the Data Safety Monitoring Board when futility criterion was met in pre-planned interim analysis. The mean change in dyspnea NRS intensity between baseline and day 7 was -1.6 (95% CI -2, -1.2) in the dexamethasone group and -1.6 (95% CI -2.3, -0.9) in the placebo group, with no significant between-group difference (mean 0, 95% CI -0.8, 0.7; P = 0.91). Secondary analyses showed that the dexamethasone group had a significantly better ESAS appetite (mean difference -1.2, 95% CI -2.2, -0.1; P = 0.03) and well being (mean -1, 95% CI -1.8, -0.2; P = 0.02), and worse ESAS anxiety (mean 1.1, 95% CI 0.3, 1.9; P = 0.01) and depression (mean 0.9, 95% CI 0.1, 1.7; P = 0.02) compared to placebo. Similar magnitude of changes in dyspnea and ESAS symptoms were observed by day 14. Adverse effects were reported more frequently in the dexamethasone group (any grade): insomnia (38% v. 12%), neuropsychiatric symptoms (31% vs. 7%), infections (21% v. 12%), dyspepsia (26% v. 12%), edema (18% v. 9%), hiccups (12% v. 7%), flushing (9% v. 5%) and respiratory distress (6% v. 0%). More patients in the dexamethasone group required hospitalization within 30 d of last study medication (25% vs. 7%, P = 0.02). Conclusions: High dose dexamethasone did not improve dyspnea in patients with cancer more than placebo and was associated with more adverse events. Clinical trial information: NCT03367156.