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      Circulating Biomarkers in Advanced Colorectal Cancer Patients Randomly Assigned to Three Bevacizumab-Based Regimens

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          Abstract

          The need to identify biomarkers for bevacizumab-based treatment in advanced colorectal cancer is imperative. The aim of this study was to investigate the prognostic role of circulating VEGF, PDGF, SDF-1, osteopontin and CEA in patients randomly assigned to three bevacizumab-based regimens. Plasma samples from 50 patients treated at a single Institution were analysed using the multiplex assay BioPlex™ 2200 (Bio-Rad Laboratories, Inc, Berkeley, CA, USA) at baseline, before first three cycles and subsequently every three cycles until disease progression. Prognostic analyses of baseline values were performed using multivariable Cox models, including disease extension >10 cm or ≤10 cm (measured as the sum of the diameters for all target lesions) as adjustment factor. The association between progression-free and overall survival and biomarkers modulation during treatment was studied using multivariable Cox models, which included summary statistics synthesizing during-treatment modulation together with disease extension. The biomarkers significantly associated with disease extension were baseline CEA ( p = 0.012) and SDF-1 ( p = 0.030). High values of VEGF and SDF-1 tended to be associated with worse prognosis, especially in terms of overall survival. The negative prognostic trend was more marked for baseline CEA as compared to other biomarkers; increasing values during treatment was significantly related to worse prognosis independently of disease extension ( p = 0.007 and 0.016 for progression-free and overall survival, respectively). VEGF is related to bevacizumab pharmacodynamics and is associated to other angiogenic cytokines; some of the proposed biomarkers such as SDF-1 and CEA should be further validated for prognosis assessment and monitoring of bevacizumab-based treatment of advanced colorectal cancer.

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          Most cited references 28

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          Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.

          Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis associated with tumors and other pathological conditions, including proliferative diabetic retinopathy and age-related macular degeneration. The murine anti-human VEGF monoclonal antibody (muMAb VEGF) A.4.6.1 has been shown to potently suppress angiogenesis and growth in a variety of human tumor cells lines transplanted in nude mice and also to inhibit neovascularization in a primate model of ischemic retinal disease. In this report, we describe the humanization of muMAb VEGF A.4.6.1. by site-directed mutagenesis of a human framework. Not only the residues involved in the six complementarity-determining regions but also several framework residues were changed from human to murine. Humanized anti-VEGF F(ab) and IgG1 variants bind VEGF with affinity very similar to that of the original murine antibody. Furthermore, recombinant humanized MAb VEGF inhibits VEGF-induced proliferation of endothelial cells in vitro and tumor growth in vivo with potency and efficacy very similar to those of muMAb VEGF A.4.6.1. Therefore, recombinant humanized MAb VEGF is suitable to test the hypothesis that inhibition of VEGF-induced angiogenesis is a valid strategy for the treatment of solid tumors and other disorders in humans.
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            Information Theory and an Extension of the Maximumlikelihood Principle

             H. AKAIKE,  Akaike,  H Akaike (1973)
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              Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial.

               J. Hecht,  W Novotny,  J Hamm (2005)
              Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan. Patients had metastatic CRC and one of the following characteristics: age > or = 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin < or = 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed. Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation. Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                29 August 2014
                September 2014
                : 6
                : 3
                : 1753-1768
                Affiliations
                [1 ]Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, Milan 1-20133, Italy; E-Mails: elisa.sottotetti@ 123456istitutotumori.mi.it (E.S.); maria.dibartolomeo@ 123456istitutotumori.mi.it (M.D.B.); filippo.debraud@ 123456istitutotumori.mi.it (F.B.); arpine.gevorgyan@ 123456istitutotumori.mi.it (A.G.); katia.dotti@ 123456istitutotumori.mi.it (K.F.D.); giacomo.bregni@ 123456gmail.com (G.B.); filippo.pietrantonio@ 123456istitutotumori.mi.it (F.P.)
                [2 ]Medical Statistics, Biometry and Bioinformatics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, Milan 1-20133, Italy; E-Mail: rosalba.miceli@ 123456istitutotumori.mi.it
                [3 ]Medical Oncology Unit, IDO Policlinico di Monza, Via Amati, Monza 111-20900, Italy; E-Mail: emilio.bajetta@ 123456policlinicodimonza.it
                [4 ]Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian, Milan 1-20133, Italy; E-Mails: manuela.campiglio@ 123456istitutotumori.mi.it (M.C.); francesca.bianchi@ 123456istitutotumori.mi.it (F.B.)
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: antonia.martinetti@ 123456istitutotumori.mi.it ; Tel.: +39-02-2390-3045; Fax: +39-02-2390-2149.
                Article
                cancers-06-01753
                10.3390/cancers6031753
                4190566
                25256831
                94e6c2b2-e0f7-42bf-ac9b-737f1b361794
                © 2014 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

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