WHAT WAS LEARNED
The researchers found that mean incidence of any-grade placebo AEs was 85.1%, and the most frequently occurring at grade 3 to 4 were hypertension (2.8%), fatigue (1.0%), and diarrhea (0.8%). The analysis showed that the overall, random-effects pooled incidence of grade 3 to 4 placebo AEs was 18%, with a high level of heterogeneity.
“We were surprised to find that almost 1 in 5 patients who received placebo presented with a high-grade adverse event. Under these circumstances, we notice that there is a high rate of patients who may develop non-specific symptoms based on contextual factors, such as data provided during informed consent process, suggestions, expectations, cancer-information seeking, and interaction with symptomatic patients,” Dr Enrico told Oncology Nurse Advisor.
In this review, the mean study drug discontinuation rate in the placebo AEs group was 3.9%. The authors write that these findings should be considered by investigators, trial sponsors, and regulatory authorities, as well as patient support groups.
IMPLICATIONS FOR NURSES
The meta-analysis suggests a greater need for educating patients entering adjuvant clinical trials about potential risks, even if they ultimately receive the placebo. The investigators report that time from surgical resection to randomization was 12 to 13 weeks in all the trials. For this reason, the authors theorize that any possible AEs overlapped by surgical procedures were the same for the entire population.
Dr Enrico and his colleagues contend these findings raise issues of informed consent because many patients may be unaware of the potential for severe AEs with the placebo in RCTs. However, these results may be limited to the heterogeneous population included in the analysis.
The authors did not have data for the full text and supplemental appendixes of some trials. Subsequently, they were unable to draw any associations between sex, ethnic/racial characteristics, age, cancer stage, comorbidities, or placebo composition and the occurrence of grade 3 to 4 placebo AEs. In addition, the researchers were not able to control for the different local cancer treatment types that patients had undergone before entering the trials.
The researchers concluded that further investigation is warranted with much larger numbers of RCTs to obtain a better understanding of the potential factors that contribute to placebo AEs.
1. Chacón MR, Enrico DH, Burton J, Walsberg FD, Videla VM. Incidence of placebo adverse events in randomized clinical trials of targeted and immunotherapy cancer drugs in the adjuvant setting: a systematic review and meta-analysis. JAMA Network Open. doi: 10.1001/jamanetworkopen.2018.5617