Targeted Oncology

, Volume 9, Issue 3, pp 273–277 | Cite as

Low level of baseline circulating VEGF-A is associated with better outcome in patients with vascular sarcomas receiving sorafenib: an ancillary study from a phase II trial

  • Nicolas Penel
  • Isabelle Ray-Coquard
  • Christine Bal-Mahieu
  • Christine Chevreau
  • Axel Le Cesne
  • Antoine Italiano
  • Emmanuelle Bompas
  • Stéphanie Clisant
  • Brigitte Baldeyrou
  • Amélie Lansiaux
  • Yves-Marie Robin
  • Jacques-Olivier Bay
  • Sophie Piperno-Neumann
  • Jean-Yves Blay
  • Charles Fournier
Original Research


We have carried out a stratified phase II study of sorafenib (So) in patients with advanced angiosarcoma (n = 32) and epithelioid hemangioendothelioma (n = 13). This report concerns the correlative analysis of the predictive values of circulating pro/anti-angiogenetic biomarkers. Using the ELISA method (R&D Systems), circulating biomarkers (VEGF-A, in picograms per milliliter), thrombospondin-1 (TSP1, in micrograms per milliliter), stem cell factor (SCF, in picograms per milliliter), placental growth factor (PlGF, in picograms per milliliter), VEGF-C (in picograms per milliliter), and E-selectin (in nanograms per milliliter) were measured before So treatment and after 7 days. VEGF-A (mean value 475 vs. 541, p = 0.002), TSP1 (16 vs. 24, p = 0.0002), and PlGF (20.9 vs. 40.7, p = 0.0001) significantly increased during the treatment. Treatment did not affect the levels of SCF, VEGF-C, and E-selectin. Only two biomarkers were associated with better outcome as follows: VEGF-A and PlGF. Best objective response and non-progression at 180 days were associated with low level of VEGF-A at baseline (p = 0.04 and 0.03, respectively). There was a correlation between the circulating level of VEGF-A and time to progression (TTP) (r = −0.47, p = 0.001). Best objective response and non-progression at 180 days were not associated with baseline level of PIGF, but there was a correlation between the circulating level of PIGF at baseline and TTP. Low level of VEGF-A at baseline (<500) was significantly associated with better outcome.


Vascular sarcoma Sorafenib Angiogenesis VEGF Placenta growth factor 


  1. 1.
    Penel N, Marreaud S, Robin YM, Hohenberger P (2011) Angiosarcoma: state of the art and perspectives. Crit Rev Oncol Hematol 80:257–263PubMedCrossRefGoogle Scholar
  2. 2.
    Penel N, Bui BN, Bay JO, Cupissol D, Ray-Coquard I, Piperno-Neumann S, Kerbrat P, Fournier C, Taieb S, Jimenez M, Isambert N, Peyrade F, Chevreau C, Bompas E, Brain EG, Blay JY (2008) Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX study. J Clin Oncol 26:5269–5274PubMedCrossRefGoogle Scholar
  3. 3.
    Mehrabi A, Kashfi A, Fonouni H, Schemmer P, Hallscheidt P, Schirmacher P, Weitz J, Friess H, Buchler MW, Schmidt J (2006) Primary malignant hepatic epithelioid hemangioendothelioma. Cancer 107:2108–2121PubMedCrossRefGoogle Scholar
  4. 4.
    Kitaichi M, Nagai S, Nishimura K, Itoh H, Asamoto H, Izumi T, Dail DH (1998) Pulmonary epithelioid haemangioendothelioma in 21 patients, including three with partial spontaneous regression. Eur Respir J 12:89–96PubMedCrossRefGoogle Scholar
  5. 5.
    Flaherty KT (2007) Sorafenib: delivering a targeted drug to the right targets. Expert Rev Anticancer Ther 7:617–626PubMedCrossRefGoogle Scholar
  6. 6.
    Adnane L, Trail PA, Taylor I, Wilhelm SM (2006) Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol 407:597–612PubMedCrossRefGoogle Scholar
  7. 7.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109PubMedCrossRefGoogle Scholar
  8. 8.
    Brown L, Tognazzi K, Dvorak HF, Harrist TJ (1996) Strong expression of kinase insert domain-containing receptor, a vascular permeability factor/vascular endothelial growth factor receptor in AIDS-associated Kaposi and cutaneous angiosarcoma. Am J Pathol 148:1065–1074PubMedCentralPubMedGoogle Scholar
  9. 9.
    Naito S, Shimizu K, Nakashima M, Ito T, Ito M, Yamashita S, Sekine I (2000) Overexpression of Ets-1 transcription factor in angiosarcoma of the skin. Pathol Res Pract 196:103–109PubMedCrossRefGoogle Scholar
  10. 10.
    Itakura E, Yamaoto H, Oda Y, Tsuneyoshi M (2008) Detection and characterization of vascular endothelia growth factors and their receptors in a series of angiosarcoma. J Surg Oncol 97:74–81PubMedCrossRefGoogle Scholar
  11. 11.
    LaMontagne KR Jr, Moses MA, Wiederschain D, Mahajan S, Holden J, Ghazizadeh H, Frank DA, Arbiser JL (2000) Inhibition of MAP kinases causes morphological reversion and dissociation between soft agar growth and in vivo tumorigenesis in angiosarcoma cells. Am J Pathol 157:1937–1945PubMedCrossRefGoogle Scholar
  12. 12.
    Antonescu CR, Yoshida A, Guo T, Chang NE, Zhang L, Agaram NP, Qin LX, Brennan MF, Singer S, Maki RG (2009) KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibition. Cancer Res 69:71–79CrossRefGoogle Scholar
  13. 13.
    Lahat G, Dhuka AR, Hallevi H, Xiao L, Zou C, Smith KD, Phung TL, Pollock RE, Benjamin R, Hunt KK, Lazar AJ, Lev D (2010) Angiosarcoma: clinical and molecular insights. Ann Surg 251:1098–1106PubMedCrossRefGoogle Scholar
  14. 14.
    Emamaullee JA, Edgar R, Toso C, Thiesen A, Bain V, Bigam D, Kneteman N, Shapiro AM (2010) Vascular endothelial growth factor expression in hepatic epithelioid hemangioendothelioma: implications for treatment and surgical management. Liver Transpl 16:191–197PubMedCrossRefGoogle Scholar
  15. 15.
    Hatva E, Böhling T, Jääskeläinen J, Persico MG, Haltia M, Alitalo K (1996) Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Am J Pathol 148:763–775PubMedCentralPubMedGoogle Scholar
  16. 16.
    Ray-Coquard I, Italiano A, Bompas E, Le Cesne A, Robin YM, Chevreau C, Bay JO, Bousquet G, Piperno-Neumann S, Isambert N, Lemaitre L, Fournier C, Gauthier E, Collard O, Cupissol D, Clisant S, Blay JY, Penel N, French Sarcoma Group (GSF/GETO) (2012) Sorafenib for patients with advanced angiosarcoma : a phase II trial from the French Sarcoma Group (GSF/GETO). Oncologist 17:260–266PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Chevreau C, Le Cesne A, Ray-Coquard I, Italiano A, Cioffi A, Isambert N, Robin YM, Fournier C, Clisant S, Chaigneau L, Bay JO, Bompas E, Gauthier E, Blay JY, Penel N (2013) Sorafenib in patients with progressive epithelioid hemangioendothelioma: a phase 2 study by the Fench Sarcoma Group (GSF/GETO). Cancer. doi:10.1002/cncr.28109 PubMedGoogle Scholar
  18. 18.
    Tokuyama W, Mikami T, Masuzawa M, Okayasu I (2010) Autocrine and paracrine roles of VEGF/VEGFR-2 and VEGF-C/VEGFR63 signaling in angiosarcomas of the scalp and face. Hum Pathol 41:407–414PubMedCrossRefGoogle Scholar
  19. 19.
    Lovet JM, Pena CE, Lathia CD, Shan M, Meinherdt G, Bruix J, SHARP Investigators Study Group (2012) Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res 18:2290–2300CrossRefGoogle Scholar
  20. 20.
    Pena C, Lathia C, Shan M, Escudier B, Bukowski RM (2010) Biomarkers predicting outcome in patients with advanced renal cell carcinoma: results from sorafenib phase III treatment approaches in renal cancer global evaluation trial. Clin Cancer Res 16:4853–4863PubMedCrossRefGoogle Scholar
  21. 21.
    Raut CP, Boucher Y, Duda DG, Morgan JA, Quek R, Ancukiewicz M et al (2012) Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948). PLoS One 7:e26331PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Sleijfer S, Gorlia T, Lamers C, Burger H, Blay JY, Le Cesne A et al (2012) Cytokine and angiogenic factors associated with efficacy and toxicity of pazopanib in advanced soft tissue sarcoma: an EORTC-STBSG study. Eur J Cancer 107:639–645Google Scholar
  23. 23.
    Sleijfer S, Ouali M, Van Glabbeke M, Krarup-Hansen A, Rodenhuis S, Le Cesne A et al (2010) Prognostic and predictive factors for outcome to first-line ifosfamide-containing chemotherapy for adult patients with advanced soft tissue sarcomas: an exploratory, retrospective analysis on large series from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG). Eur J Cancer 46:72–83PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag France 2013

Authors and Affiliations

  • Nicolas Penel
    • 1
    • 2
  • Isabelle Ray-Coquard
    • 3
  • Christine Bal-Mahieu
    • 4
  • Christine Chevreau
    • 5
  • Axel Le Cesne
    • 6
  • Antoine Italiano
    • 7
  • Emmanuelle Bompas
    • 8
  • Stéphanie Clisant
    • 9
  • Brigitte Baldeyrou
    • 4
  • Amélie Lansiaux
    • 4
  • Yves-Marie Robin
    • 10
  • Jacques-Olivier Bay
    • 11
  • Sophie Piperno-Neumann
    • 12
  • Jean-Yves Blay
    • 3
  • Charles Fournier
    • 13
  1. 1.Medical Oncology DepartmentCenter Oscar LambretLille CedexFrance
  2. 2.EA 2694, Medical SchoolLille Hospital UniversityLilleFrance
  3. 3.Medical Oncology DepartmentCenter Léon BérardLyonFrance
  4. 4.Pharmacology UnitCenter Oscar LambretLilleFrance
  5. 5.Medical Oncology DepartmentInstitut Claudius RegaudToulouseFrance
  6. 6.Medical Oncology DepartmentInstitut Gustave RoussyVillejuifFrance
  7. 7.Medical Oncology DepartmentInstitut BergoniéBordeauxFrance
  8. 8.Medical Oncology DepartmentInstitut René GauducheauNantesFrance
  9. 9.Clinical Research UnitCenter Oscar LambretLilleFrance
  10. 10.Pathology UnitCenter Oscar LambretLilleFrance
  11. 11.Medical Oncology DepartmentCenter Jean PerrinClermont-FerrandFrance
  12. 12.Medical Oncology DepartmentInstitut CurieParisFrance
  13. 13.Biostatistics UnitCenter Oscar LambretLilleFrance

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