| Background:Everolimus is a potent, oral inhibitor of the mammalian target of rapamycin (mTOR). It has been approved for the prophylaxis of organ transplant rejection and the treatment of patients with tuberous sclerosis complex (TSC) and other diseases. An extensive clinical development program is ongoing to establish the role of everolimus as monotherapy, or in combination with other agents, in the treatment of a broad spectrum of malignancies. As a new drug, the safety and effectiveness of everolimus has not been fully established in the field of tumor and are now in the stage of clinical trials which are under strict control and monitoring. A large number of clinical safety studies confirmed that metabolic-related adverse events (hyperglycemia, hypertriglyceridemia and hypercholesterolemia) is a common abnormal laboratory examination index in patients with everolimus. In recent years, reports about metabolic-related adverse events to everolimus varies widely and has not been closely investigated.Objectives:In this study, we sought to conduct a systematic review and a meta-analysis of the literatures to evaluate the incidence rate and risk of the metabolic-related adverse events with the use of everolimus for cancer therapy.Methods:A systemic review of all relevant literatures in English was performed by searching PubMed, Embase and the Cochrane Library to identify eligible studies regarding on the use of everolimus for solid tumors therapy. Main indicators include all grade and severe (grade 3 and 4) hyperglycemia, all grade and severe (grade 3 and 4) hypertriglyceridemia, all grade and severe (grade 3 and 4) hypercholesterolemia. In the systematic review, MetaAnalyst Beta 3.13 was used to evaluate the incidence rate of each of the metabolic adverse event with everolimus therapy. And in the meta-analysis, StataSE12.0 was used to evaluate the difference of the incidence rate of each of the metabolic adverse event between everolimus therapy and the control.Results:3704 patients with various malignancies from 27 clinical trials were included in the systematic review and 2390 patients with various malignancies from 7 randomized controlled trials were included in the meta-analysis.Results of the systematic review revealed that the average incidence rate(R) across all 27 studies (R=0.274,95%CI (0.188-0.381)) was comparatively high, while the average incidence rate of the grade 3-4 (R=0.080,95%CI (0.059-0.106)) merely amounted for 29.2% of that of the all grades. Among the 3 kinds of metabolic related adverse events, the incidence rate of hyperglycemia of all grades (R=0.257,95%CI (0.165-0.378)) was the highest and the incidence rate of grade 3-4 (R=0.068,95%CI (0.052-0.088)) only amounted for 26.5% of that of the all grades. The incidence rate of hypertriglyceridemia of all grades (R=0.074,95%CI (0.037-0.144)) was the lowest and the incidence rate of grade 3-4 was 0.013, 95%CI (0.008-0.020) which amounted for 17.6% of that of the all grades. The incidence rate of hypercholesterolemia of all grades was 0.132,95%CI (0.070-0.234) and of grade 3-4 was 0.017,95%CI (0.011-0.027) which only amounted for 12.9% of that of the all grades.Results of the Meta-analysis revealed that the incidence rate ratio (RR) of all grade metabolic adverse events (RR=4.22,95%CI (2.88-6.18)) and of grade 3-4 metabolic adverse events (RR=9.52,95%CI (4.38-20.7)) increased in patients treated with everolimus compared with control. The risk of the metabolic adverse events were calculated individually for hyperglycemia, hypercholesterolemia and hypertriglyceridemia. The incidence rate ratio of all grade hyperglycemia (RR=3.13, 95%CI (2.43-4.03)), grade 3-4 hyperglycemia (RR=8.59,95%CI (3.95-18.68)), all grade hypercholesterolemia (RR=2.02,95%CI (1.12-3.67)), grade 3-4 hypercholesterolemia (RR=8.61,95%CI (1.06-69.85)) and all grade hypertriglyceridemia (RR=2.14,95%CI (1.70-2.70)) also increased in patients treated with everolimus compared with control, while result of the analysis revealed that the difference of the incidence rate of grade 3-4 hypertriglyceridemia between everolimus therapy and the control has no statistical significance (RR=2.12,95%CI (0.23-19.70), P=0.509).Conclusions:Among all the metabolic adverse events with the use of everolimus for cancer therapy, the incidence rate of hyperglycemia is much higher than that of hypertriglyceridemia and hypercholesterolemia. Incidence rate of mild-moderate (grade 1-2) metabolic adverse events is higher than that of severe (grade 3-4) metabolic adverse events. In patients with cancer treated with everolimus, the mild-moderate metabolic adverse events are more likely to happen. In addition, the risk of all grade and grade 3-4 hyperglycemia, hypercholesterolemia and all grade hypertriglyceridemia increase in patients treated with everolimus. |
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