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Neoadjuvant sorafenib treatment of clear cell renal cell carcinoma and release of circulating tumor fragments.
Kats-Ugurlu, G, Oosterwijk, E, Muselaers, S, Oosterwijk-Wakka, J, Hulsbergen-van de Kaa, C, de Weijert, M, van Krieken, H, Desar, I, van Herpen, C, Maass, C, et al
Neoplasia (New York, N.Y.). 2014;(3):221-8
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) is characterized by high constitutive vascular endothelial growth factor A (VEGF-A) production that induces a specific vascular phenotype. We previously reported that this phenotype may allow shedding of multicellular tumor fragments into the circulation, possibly contributing to the development of metastasis. Disruption of this phenotype through inhibition of VEGF signaling may therefore result in reduced shedding of tumor fragments and improved prognosis. To test this hypothesis, we investigated the effect of neoadjuvant sorafenib treatment on tumor cluster shedding. PATIENTS AND METHODS Patients with renal cancer (n = 10, of which 8 have ccRCC) received sorafenib for 4 weeks before tumor nephrectomy. The resection specimens were perfused, and the perfundate was examined for the presence of tumor clusters. Effects of the treatment on the tumor morphology and overall survival were investigated (follow-up of 2 years) and compared with a carefully matched control group. RESULTS Neoadjuvant sorafenib treatment induced extensive ischemic tumor necrosis and, as expected, destroyed the characteristic ccRCC vascular phenotype. In contrast to the expectation, vital groups of tumor cells with high proliferation indices were detected in postsurgical renal venous outflow in 75% of the cases. Overall survival of patients receiving neoadjuvant treatment was reduced compared to a control group, matched with regard to prognostic parameters. CONCLUSIONS These results suggest that neoadjuvant sorafenib therapy for ccRCC does not prevent shedding of tumor fragments. Although this is a nonrandomized study with a small patient group, our results suggest that neoadjuvant treatment may worsen survival through as yet undefined mechanisms.
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Hepatocellular carcinoma with portal vein tumor thrombus: treatment with transarterial chemoembolization combined with sorafenib--a retrospective controlled study.
Zhu, K, Chen, J, Lai, L, Meng, X, Zhou, B, Huang, W, Cai, M, Shan, H
Radiology. 2014;(1):284-93
Abstract
PURPOSE To determine the safety and efficacy of transarterial chemoembolization (TACE) combined with sorafenib (hereafter, TACE-sorafenib) in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). MATERIALS AND METHODS This study was approved by the institutional review board, and the requirement for informed consent was waived. The medical records of consecutive patients with HCC and PVTT who underwent TACE-sorafenib or TACE alone from January 2010 to December 2012 were retrospectively evaluated. Sorafenib (400 mg) was administered twice daily. Outcomes of patients who underwent TACE-sorafenib were compared with outcomes of patients who underwent TACE by using the Kaplan-Meier method according to types of PVTT PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). RESULTS Ninety-one patients were included in the analysis; 46 patients underwent TACE-sorafenib and 45 underwent TACE. TACE-sorafenib showed significant survival benefits compared with TACE in patients with type B (median survival, 13 months vs 6 months; P = .002) or type C (median survival, 15 months vs 10 months; P = .003) PVTT. TACE-sorafenib and main PVTT were the independent prognostic factors for survival at uni- and multivariate analysis. Liver function after TACE-sorafenib worsened only in patients with main PVTT. Sorafenib-related adverse events of grade 3 or higher occurred in 16 patients (35%). CONCLUSION TACE-sorafenib side effects were acceptable, and this treatment may improve overall survival in patients with HCC with first-order or lower-branch PVTT when compared with patients who underwent TACE alone.
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Technical considerations in the development of circulating peptides as pharmacodynamic biomarkers for angiogenesis inhibitors.
Thomeas, V, Chow, S, Gutierrez, JO, Karovic, S, Wroblewski, K, Kistner-Griffin, E, Karrison, TG, Maitland, ML
Journal of clinical pharmacology. 2014;(6):682-7
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Abstract
To determine the biological reproducibility and estimate relevant covariates for candidate circulating biomarkers of angiogenesis, we conducted 3 sub-studies with ≤15 subjects each. In study 1, 6 healthy subjects provided 13 blood samples across 14-24 days. In study 2, 15 advanced solid tumor patients provided single blood samples before, and approximately 8 and 40 days after sorafenib treatment. In study 3, 4 healthy subjects provided blood samples on 3 occasions over 14 days, processed simultaneously in 2 different laboratories at a single institution. Vascular endothelial growth factor (VEGFA), soluble VEGF receptor-2 (sVEGFR2), and angiopoietin-2 (Ang2) concentrations in plasma and serum were determined by standard immunoassays. Ang2 and sVEGFR2 demonstrated low variance within and high variance across individuals reflected by the high intraclass correlation coefficient (for Ang2: 0.86 for plasma, 0.89 for serum; for sVEGFR2: 0.91 for plasma, 0.87 for serum). Repeated measures linear modeling from 15 patients demonstrated increased Ang2 (P ≤ 0.05) and decreased sVEGFR2 (P ≤ 0.05) after exposure to sorafenib. VEGFA had high intraindividual variance, and study 3 demonstrated the laboratory to have significant effects on plasma measurements (P ≤ 0.05). The biological reproducibility of sVEGFR2 and Ang2 support further use of these markers in studies of vasculature-targeted therapeutics.
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Early response to anti-tumoral treatment in hepatocellular carcinoma--can quantitative contrast-enhanced ultrasound predict outcome?
Knieling, F, Waldner, MJ, Goertz, RS, Zopf, S, Wildner, D, Neurath, MF, Bernatik, T, Strobel, D
Ultraschall in der Medizin (Stuttgart, Germany : 1980). 2013;(1):38-46
Abstract
PURPOSE In order to detect an early response to anti-angiogenic therapy, this study aims at analyzing specific effects of a sorafenib-based regime on intra-tumoral D-CEUS flow parameters of patients with HCC. MATERIALS AND METHODS Videos of the arterial phase were captured before initiation of a therapy with sorafenib and 1 and 3 months after (n = 9). Patients receiving a non-anti-angiogenic therapy (TACE, n = 10) served as a comparison group. Cross-sectional imaging was performed at the same time points and patients were followed up for 1 year. RESULTS In the responder group (RE), the absolute (percentage) TTP was 11.28 s ± 2.03 s (1.00) before treatment, 13.60 s ± 1.52 s (1.53 ± 0.08) after one month (p = 0.0405), and 16.17 s ± 2.35 s (1.46 ± 0.07) after three months of treatment (p = 0.0071). The TTP increased significantly in the RE group as early as 1 month after initiation of sorafenib compared to the non-responder group. There were no significant differences in the non-responder group or between the NR and the TACE group at any time point. D-CEUS values from all sorafenib-treated patients showed good accordance with RECICL (response evaluation criteria in cancer of the liver) criteria (R2 = 0.7154, p = 0.0001). CONCLUSIONS Quantitative CEUS reveals variations of dynamic parameters of blood flow during anti-tumoral therapy in liver cancer patients. Further investigations and clinical trails have to confirm that the TTP is a promising parameter in the prediction of early response to sorafenib-based therapy.