Serum interleukin-6 as a prognostic biomarker in patients with metastatic melanoma.
ABSTRACT Interleukin-6 (IL-6) is an immunomodulatory cytokine produced by both normal cells and tumor cells, including melanoma cells. The specific biological function of IL-6 in melanoma is unknown. The present study examined whether the serum concentration of IL-6 can predict prognosis in patients with metastatic melanoma. IL-6 was measured by ELISA in serum samples from 103 patients with metastatic melanoma obtained before IL-2-based immunotherapy. Patients with metastatic melanoma had higher serum IL-6 than healthy individuals (median 3.4 ng/l, range 0.3-93 ng/l vs. median 1.4 ng/l, range 0.25-22.5 ng/l, P<0.0001). Pretreatment serum IL-6 was elevated in 43% of the patients. Patients with elevated pretreatment serum IL-6 had shorter overall survival (OS) compared with patients with normal serum IL-6 (P<0.0002). The median OS was 10.8 months [95% confidence interval (CI): 8.86-13.46] in patients with normal serum IL-6 compared with 4.5 months (95% CI: 3.04-7.39) in patients with elevated serum IL-6. Multivariate Cox analysis showed that serum IL-6 [hazard ratio (HR)=1.82, 95% CI: 1.19-2.78, P=0.006] and serum lactate dehydrogenase (HR=2.02, 95% CI: 1.31-3.11, P=0.001) were independent prognostic biomarkers of OS. A combination variable of elevated serum IL-6 and elevated serum lactate dehydrogenase almost quadrupled the risk of early death (HR=3.67, 95% CI: 2.17-6.20, P<0.0001) compared with patients with normal serum levels of these two biomarkers. Elevated serum IL-6 is an independent prognostic biomarker of short OS in patients with metastatic melanoma. A larger retrospective study is ongoing to confirm the findings. To validate serum IL-6 further as a prognostic biomarker, a prospective study is required.
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ABSTRACT: Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).New England Journal of Medicine 06/2011; 364(26):2507-16. · 51.66 Impact Factor
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ABSTRACT: Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group. Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).New England Journal of Medicine 06/2011; 364(26):2517-26. · 51.66 Impact Factor
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ABSTRACT: Recent discoveries involving the cytokine interleukin (IL)-6 have originated from diverse disciplines, revealing roles in biological processes that are likewise varied. The most novel findings suggest a connection between inflammation and diseases, such as insulin resistance associated with diabetes mellitus and cancer, which had not or only weakly been appreciated previously. The IL-6 pathway is one of the mechanisms linking inflammation to these disease processes. In addition, new evidence points toward IL-6 as one of the mediators coordinating the interface between adaptive and innate immunity. Here, we review the evidence linking IL-6 to inflammatory diseases and cancer.Trends in Molecular Medicine 04/2008; 14(3):109-19. · 9.57 Impact Factor