Background: Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an\nantitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a\ntolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was\nto assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and\ntremelimumab).\nMethods: A systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane\ndatabases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted\ndata. Pooled incidence was calculated using RÃ?©, package meta.\nResults: Overall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included\nin the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently\nhepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-BarrÃ?© syndrome,\nimmune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 %\n(95 % CI, 65ââ?¬â??79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18ââ?¬â??30 %). The risk of developing\nirAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56ââ?¬â??66 %) for\nipilimumab 3 mg/kg and 79 % (95 % CI, 69ââ?¬â??89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 %\nof patients.\nThe median time of onset of irAEs was about 10 weeks (IQR, 6ââ?¬â??12) after the onset of treatment, corresponding with\nthe first three cycles but varied according to the organ system involved. Such immune activation could also be\nindicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4\nblocking in 60 % of patients.\nConclusion: The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting\nthe mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a\nmultidisciplinary approach will help to reduce morbidity and therapy interruptions.
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