Abstract
Selumetinib is a promising and interesting targeted therapy agent as it may reverse radioiodine uptake in patients with radioiodine-refractory differentiated thyroid cancer. We conduct this meta- analysis to compare the efficacy and safety of selumetinib with current therapies in patients with advanced cancer. An electronic search was conducted using PubMed/ Medicine, EMBASE and Cochrane library databases. Statistical analyses were carried out using either random-effects or fixed-effects models according to the heterogeneity of eligible studies. Six eligible trials involved 601 patients were identified. Compared with current therapies, treatment schedules with selumetinib did not improve progression free survival (hazard ratio, 0.91; 95%CI 0.70-1.17, P= 0.448), but did identify better clinical benefits (odds ratio, 1.24; 95%CI 0.69- 2.24, P = 0.472) and less disease progression (hazard ratio, 0.72; 95%CI 0.51-1.00, P = 0.052) though its impact was not statistically significant. Sub-group analysis resulted in significantly improved progression free survival (hazard ratio, 0.61; 95%CI 0.49-0.57, P = 0.00), clinical benefits (odds ratio, 3.04; 95%CI 1.60-5.77, P = 0.001) and reduced disease progression (hazard ratio, 0.35; 95%CI 0.18-0.67, P = 0.001) in patients administrated selumetinib. Dermatitis acneiform (risk ratio, 9.775; 95%CI 3.143-30.395, P = 0.00) and peripheral edema (risk ratio, 2.371; 95%CI 1.690-3.327, P = 0.00) are the most frequently observed adverse effects associated with selumetinib. Compared with current chemotherapy, selumetinib has modest clinical activity as monotherapy in patients with advanced cancer, but combinations of selumetinib with cytotoxic agents in patients with BRAF or KRAS mutations hold great promise for cancer treatment. Dermatitis acneiform and peripheral edema are the most frequently observed adverse effects in patients with selumetinib.
Highlights
The mitogen-activated protein kinases (MAPKs) are important signal transducing enzymes, evolutionarily conserved, which respond to various extracellular stimuli and play critical roles in a vast number of fundamental cellular processes including growth, proliferation, differentiation, motility, stress response, survival, apoptosis and angiogenesis via a series of phosphorylation events and protein-protein interactions (Shaul et al, 2007; Raman et al, 2007; Pimienta et al, 2007; Krishna et al, 2008)
After screening titles and abstracts, 157 irrelevant articles were excluded because they involved other treatment agents, duplicates, review articles, case reports, abstracts presented at meetings, letters or commentaries
In addition to the cancer sites in the studies we analyzed in the current meta-analysis, there have been many other clinical studies estimating the clinical benefits of selumetinib in other types of malignancy including thyroid carcinoma
Summary
The mitogen-activated protein kinases (MAPKs) are important signal transducing enzymes, evolutionarily conserved, which respond to various extracellular stimuli and play critical roles in a vast number of fundamental cellular processes including growth, proliferation, differentiation, motility, stress response, survival, apoptosis and angiogenesis via a series of phosphorylation events and protein-protein interactions (Shaul et al, 2007; Raman et al, 2007; Pimienta et al, 2007; Krishna et al, 2008). MEK1 and MEK2, closely related, are dual specificity enzymes that phosphorylate threonine and tyrosine residues (in the activation sequence Thr-Glu-Tyr of ERK1/2) within the activation loop of their MAP kinase substrates (Pearson et al, 2001) Their key position within the Ras/Raf/MEK/ERK signal cascades (Wortzel et al, 2011), which is one of the most frequently dysregulated pathways involved in the process of human tumorigenesis (Peyssonnaux et al, 2001), provides a strong rationale for the development of small molecule inhibitors of MEK1/2 in the treatment modality of human cancer. Treatment schedules with selumetinib did not improve progression free survival (hazard ratio, 0.91; 95%CI 0.70–1.17, P= 0.448), but did identify better clinical benefits (odds ratio, 1.24; 95%CI 0.69– 2.24, P = 0.472) and less disease progression (hazard ratio, 0.72; 95%CI 0.51–1.00, P = 0.052) though its impact was not statistically significant. Dermatitis acneiform and peripheral edema are the most frequently observed adverse effects in patients with selumetinib
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