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      Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study

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          Angiosarcomas are rare malignant tumors of vascular origin that represent a genuine therapeutic challenge. Recently, the combination of metronomic chemotherapy and drug repositioning has been proposed as an attractive alternative for cancer patients living in developing countries.


          In vitro experiments with transformed endothelial cells were used to identify synergistic interactions between anti-hypertensive drug propranolol and chemotherapeutics. This led to the design of a pilot treatment protocol combining oral propranolol and metronomic chemotherapy. Seven consecutive patients with advanced/metastatic/recurrent angiosarcoma were treated with this combination for up to 12 months, followed by propranolol-containing maintenance therapy.


          Gene expression analysis showed expression of ADRB1 and ADRB2 adrenergic receptor genes in transformed endothelial cells and in angiosarcoma tumors. Propranolol strongly synergized with the microtubule-targeting agent vinblastine in vitro, but only displayed additivity or slight antagonism with paclitaxel and doxorubicin. A combination treatment using bi-daily propranolol (40 mg) and weekly metronomic vinblastine (6 mg/m 2) and methotrexate (35 mg/m 2) was designed and used in 7 patients with advanced angiosarcoma. Treatment was well tolerated and resulted in 100% response rate, including 1 complete response and 3 very good partial responses, based on RECIST criteria. Median progression-free and overall survival was 11 months (range 5–24) and 16 months (range 10–30), respectively.


          Our results provide a strong rationale for the combination of β-blockers and vinblastine-based metronomic chemotherapy for the treatment of advanced angiosarcoma. Furthermore, our study highlights the potential of drug repositioning in combination with metronomic chemotherapy in low- and middle-income country setting.


          This study was funded by institutional and philanthropic grants.


          • A strong synergism was identified between propranolol and vinblastine in an in vitro model of angiosarcoma.

          • Adrenergic receptor expression was detected in angiosarcoma tumors providing a molecular target for propranolol.

          • Propranolol and vinblastine-based metronomic chemotherapy led to 100% response in 7 patients with inoperable angiosarcoma.

          • This treatment resulted in prolonged survival of angiosarcoma patients and warrants further investigation in larger trials.

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          Most cited references 25

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          Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin that have a poor prognosis. They can arise anywhere in the body, most commonly presenting as cutaneous disease in elderly white men, involving the head and neck and particularly the scalp. They can be caused by therapeutic radiation or chronic lymphoedema and hence secondary breast angiosarcomas are an important subgroup. Recent work has sought to establish the molecular biology of angiosarcomas and identify specific targets for treatment. Interest is now focused on trials of vascular-targeted drugs, which are showing promise in the control of angiosarcomas. In this review we discuss angiosarcoma and its current management, with a focus on clinical trials investigating the treatment of advanced disease. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            Phase II study of sorafenib in patients with metastatic or recurrent sarcomas.

            PURPOSE Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma. PATIENTS AND METHODS We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued. Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies. CONCLUSION As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.
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              A randomized, controlled trial of oral propranolol in infantile hemangioma.

              Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited.

                Author and article information

                17 February 2016
                April 2016
                17 February 2016
                : 6
                : 87-95
                [a ]INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille University, Marseille, France
                [b ]Metronomics Global Health Initiative, Marseille, France
                [c ]Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Randwick, Australia
                [d ]Service d'Hématologie & Oncologie Pédiatrique, AP-HM, Marseille, France
                [e ]Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
                [f ]Department of Pathology, Tata Memorial Centre, Mumbai, India
                [g ]Service d'Oncologie Médicale, AP-HM, Marseille, France
                [h ]Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, UNSW Australia, Sydney, Australia
                Author notes
                [* ]Correspondence to: E. Pasquier, Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Australia, PO Box 81, High St, Randwick NSW 2031, Australia.Children's Cancer Institute Australia for Medical ResearchLowy Cancer Research CentreUNSW AustraliaPO Box 81High StRandwickNSW 2031Australia epasquier@ 123456ccia.unsw.edu.au
                [** ]Correspondence to: S. Banavali, Department of Medical and Pediatric Oncology, Tata Memorial Centre, Dr. Ernest Borges Road, Parel, Mumbai 400 012, India.Department of Medical and Pediatric OncologyTata Memorial CentreDr. Ernest Borges Road, ParelMumbai400 012India banavali_2000@ 123456yahoo.com
                © 2016 The Authors
                Original Research


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