Severe adverse events from the treatment of advanced melanoma: A systematic review of severe side effects associated with ipilimumab, vemurafenib, interferon alfa-2b, dacarbazine and interleukin-2

Background: Current immunomodulatory agents for stage III and IV melanoma exert different mechanisms of action that manifest in distinct adverse events. Objective: This systematic review aims to synthesize safety data from clinical trials on ipilimumab, vemurafenib, interferon (IFN) alfa-2b, dacarbazine and interleukin (IL)-2 to elucidate the severe adverse events associated with each melanoma therapy. Methods: Through a systematic search using MEDLINE, EMBASE and the Cochrane Central Register between January 1, 2010 and June 1, 2012, we identified 32 clinical trials with 5802 subjects that met the inclusion criteria. Results:Ipilimumab was associated with immune-mediated diarrhea and colitis, with an incidence rate of 0.0017 cases per 100 person-years. Patients receiving vemurafenib developed keratoacanthomas and cutaneous squamous cell carcinoma at an incidence rate of 0.0025 cases per 100 person-years. Treatment with IFN alfa-2b precipitated depression at an incidence rate of 0.0002 cases per 100 person-years. Dacarbazine was associated with respiratory toxicity and dyspnea, with incidence rates of 0.0001 and 0.00008 cases per 100 person-years, respectively. IL-2 treatment induced vascular leak syndrome (VLS), with symptoms of hypotension and oliguria, was observed at incidence rates of 0.17 and 0.15 cases per 100 person-years, respectively. Findings may serve as a foundation for future research in this area and guide clinical recommendations.