Importance: Several reports have associated the placebo effect with objective response and improvement of a clinical condition in oncology, but only a few studies have analyzed the adverse events (AEs) in the placebo groups of the clinical trials.
Objective: To determine the incidence of placebo AEs reported in randomized clinical trials of modern cancer drugs in the adjuvant setting.
Data sources: Based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, a systematic literature search of English-language publications from January 1, 2000, through April 15, 2018, was performed using MEDLINE (PubMed). The following search terms were used to retrieve all trials from the PubMed library: adjuvant, maintenance, consolidation, and placebo, in addition to specific cancer type-related keywords.
Study selection: A double-blind, randomized, placebo-controlled, phase 3 design was mandatory for study inclusion. Only studies enrolling patients who had undergone macroscopically complete resections were included. No other anticancer treatments in addition to placebo were allowed in the control group. Only trials involving a targeted therapy (tyrosine kinase, BRAF, or MEK inhibitors) or immunotherapy-related drugs were included. Trials using chemotherapy, interferon, and endocrine therapy were excluded. Two authors (D.H.E. and F.D.W.) independently reviewed the studies for inclusion.
Data extraction and synthesis: Data were extracted by investigators, and random-effects meta-analysis was performed to estimate the proportion of grade 3 to 4 placebo AEs in the included studies.
Main outcomes and measures: Incidence of grade 3 to 4 placebo AEs in the placebo groups.
Results: Of 731 studies screened, 10 eligible trials were found including 4 tumor types (melanoma, non-small cell lung cancer, gastrointestinal stromal tumor, and renal cell carcinoma). Overall, 11 143 patients (6270 [56.3%] in the treatment group with mean [SD] age of 55.6 [4.2] years and 4873 patients [43.7%] in the placebo group with mean [SD] age of 55.9 [4.3] years) were included. The mean incidence of any-grade placebo AEs was 85.1% (95% CI, 79.2%-91.0%). The most frequent (mean [SD]) grade 3 to 4 placebo AEs in patients were hypertension (2.8% [2.2%]), fatigue (1.0% [0.9%]), and diarrhea (0.8% [0.6%]). The overall, random-effects pooled incidence of grade 3 to 4 placebo AEs was 18% (95% CI, 15%-21%), with a high level of heterogeneity (I2 = 86%). Frequency of grade 3 to 4 placebo AEs was found to be correlated in the treatment and placebo groups (ρ = 0.7; P = .03). Mean study drug discontinuation owing to placebo AEs was 3.9% (95% CI, 2.7%-5.2%).
Conclusions and relevance: Placebo administration was associated with a substantial incidence of grade 3 to 4 placebo AEs in modern cancer adjuvant trials. This finding should be considered by investigators, sponsors, regulatory authorities, and patient support groups.