PMID- 30646278
OWN - NLM
STAT- MEDLINE
DCOM- 20190930
LR  - 20200309
IS  - 2574-3805 (Electronic)
IS  - 2574-3805 (Linking)
VI  - 1
IP  - 8
DP  - 2018 Dec 7
TI  - 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.
PG  - e185617
LID - 10.1001/jamanetworkopen.2018.5617 [doi]
LID - e185617
AB  - 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 (rho = 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.
FAU - Chacon, Matias Rodrigo
AU  - Chacon MR
AD  - Research Department, Argentine Association of Clinical Oncology, Buenos Aires, 
      Argentina.
FAU - Enrico, Diego Hernan
AU  - Enrico DH
AD  - Research Department, Argentine Association of Clinical Oncology, Buenos Aires, 
      Argentina.
FAU - Burton, Jeannette
AU  - Burton J
AD  - Research Department, Argentine Association of Clinical Oncology, Buenos Aires, 
      Argentina.
FAU - Waisberg, Federico Daniel
AU  - Waisberg FD
AD  - Research Department, Argentine Association of Clinical Oncology, Buenos Aires, 
      Argentina.
FAU - Videla, Viviana Marina
AU  - Videla VM
AD  - Research Department, Argentine Association of Clinical Oncology, Buenos Aires, 
      Argentina.
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Systematic Review
DEP - 20181207
PL  - United States
TA  - JAMA Netw Open
JT  - JAMA network open
JID - 101729235
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Placebos)
SB  - IM
MH  - Antineoplastic Agents/therapeutic use
MH  - Clinical Trials, Phase III as Topic
MH  - Diarrhea
MH  - Drug-Related Side Effects and Adverse Reactions/*epidemiology
MH  - Fatigue
MH  - Humans
MH  - Hypertension
MH  - *Immunotherapy
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Placebos/*adverse effects/therapeutic use
MH  - Randomized Controlled Trials as Topic
PMC - PMC6324542
COIS- Conflict of Interest Disclosures: None reported.
EDAT- 2019/01/16 06:00
MHDA- 2019/10/01 06:00
PMCR- 2018/12/07
CRDT- 2019/01/16 06:00
PHST- 2019/01/16 06:00 [entrez]
PHST- 2019/01/16 06:00 [pubmed]
PHST- 2019/10/01 06:00 [medline]
PHST- 2018/12/07 00:00 [pmc-release]
AID - 2717560 [pii]
AID - zoi180239 [pii]
AID - 10.1001/jamanetworkopen.2018.5617 [doi]
PST - epublish
SO  - JAMA Netw Open. 2018 Dec 7;1(8):e185617. doi: 10.1001/jamanetworkopen.2018.5617.