Adverse Events in Randomized Clinical Trials for Targeted Therapies High in Placebo Groups

Patients enrolled in clinical trials of targeted and immunotherapy cancer agents should be better educated that adverse events (AEs) may occur even if they receive an inert substance, according to a systematic review and meta-analysis published in the JAMA Network Open. Investigators found that placebo administration was associated with a substantial proportion of grade 3 to 4 AEs in double-blind randomized clinical trials (RCTs) in the adjuvant setting.¹

“Our study was started after noticing that many clinical trials reported elevated rates of higher-grade adverse events in patients who were not receiving anticancer treatment and were assumed to be free of disease. After reviewing existing evidence, we observed that the nocebo effect is not well described in cancer patients,” explained medical oncologist Diego Enrico, MD, who is with the research department, Argentine Association of Clinical Oncology, Buenos Aires, Argentina.

When patients receive an inert agent or procedure and experience symptom improvement, this is referred to as the placebo phenomenon. A number of theories explain what may be occurring, such as changes in neurobiological pathways, the physician-patient relationship, or the patient’s psychosocial context. Adverse effects after receiving a placebo are called nocebo effects. Dr Enrico said these types of AEs have been studied in other areas of medicine, but there has been little investigation in the field of oncology.

THE STUDY

Dr Enrico and his colleagues examined the incidence of placebo AEs reported in randomized clinical trials of modern cancer drugs in the adjuvant setting. Using MEDLINE, they conducted a systematic literature search of English-language publications from January 1, 2000, through April 15, 2018.

The review included only phase 3 double-blind, randomized, placebo-controlled studies that enrolled patients who had undergone macroscopically complete resections. No other anticancer treatments in addition to placebo were allowed in the control group. In addition, the analysis included only trials involving a targeted therapy (tyrosine kinase, BRAF, or MEK inhibitors) or immunotherapy-related drugs. Trials using chemotherapy, interferon, and endocrine therapies were excluded.

The researchers examined the incidence of grade 3 to 4 placebo AEs in the placebo groups of 731 studies. They found 10 eligible trials that included 4 tumor types (melanoma, non-small cell lung cancer, gastrointestinal stromal tumor, and renal cell carcinoma). The trials included 11,143 patients, of whom 6270 (56.3%) were in the treatment groups and 4873 (43.7%) were in the placebo groups. Mean ages were 55.6 years and 55.9 years in the treatment and placebo groups, respectively.