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Avastin causes regression of tumour vasculature

Preclinical models and clinical observations have indicated that Avastin can cause regression(A characteristic of diseases to show lighter symptoms without completely disappearing. At a later point, symptoms may return ) of existing tumour(An abnormal growth of cells, forming a mass of tissue) vasculature. Significant reductions in tumour vascular volume and density following a single infusion of Avastin alone have been reported.1,2

In a preclinical model(A study to test a drug, procedure or medical treatment in animals. Preclinical studies are required before clinical trials can be started) using human tumour xenografts, a single bolus(The administration of a drug, medication or other substance in the form of a single, large dose) (0.2mL) infusion of Avastin resulted in an 80% decrease in tumour vascular volume.1 This reduction was observed rapidly, within 24 hours of infusion.

Reduction in MVD following administration of Avastin has also been observed in the clinical setting. In a phase I evaluation, a single infusion of Avastin significantly (p<0.05) decreased MVD in patients with rectal cancer.2

In terms of clinical significance, regression of tumour vasculature by Avastin can increase tumour response to cytotoxic(Refers to an agent that acts by causing the death of cells in the body, thus causing a reduction in cell numbers) chemotherapy.

Regression of tumour vasculature by Avastin increases tumour response

Preclinical studies of Avastin have reported significant reductions in tumour vascular volume and density.1,3

The removal of tumour vasculature prevents the delivery of oxygen and nutrients to regions of the tumour, arresting tumour growth and potentially inducing shrinkage

  • In a preclinical study, VEGF(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour) blockade significantly reduced MVD, resulting in regression of both tumours and metastases.4

In clinical trials, Avastin therapy has resulted in significant improvements in tumour response.5–11

Avastin has an anti-permeability(Anti-permeability is the decrease in vessel permeability that results from the blockade of VEGF by anti-VEGF agents) effect on tumour vasculature

  • Human umbilical vein endothelial cell (HUVEC) monolayers were exposed to VEGF with or without Avastin.
  • The addition of Avastin significantly reduced HUVEC monolayer permeability.
  • New Zealand rabbits were given intravenous Avastin or vehicle, followed by intrapleural injections of talc or silver nitrate after 30 minutes.
  • Pleural vascular permeability and fluid volume were determined at regular intervals up to seven days after injection.
  • Avastin significantly reduced vascular permeability within three days.
  • Avastin significantly reduced plural fluid volumes.

Avastin inhibits new and recurrent vessel growth

In preclinical models, Avastin alone resulted in nearly complete inhibition of new vessel growth,18,19 which is required for tumour growth and metastasis(The spread of a disease from one organ or part to another non-adjacent organ or part).20 The inhibition of neovascularisation(The formation of functional microvascular networks with red blood cell perfusion) with Avastin has been correlated with decreased tumour growth and metastatic(Pertaining to the spread of a disease, usually cancer, from one organ or part to another non-adjacent organ or part) potential.21 In addition, Avastin may result in ongoing inhibition of recurrent tumour vessel growth.18,19 In terms of clinical significance, inhibition of recurrent tumour vessel growth by Avastin can provide continued disease control.

Inhibition of new and recurrent vessel growth provides continued disease control

Although existing vasculature is essential for tumour survival, tumours are unable to grow and spread without the generation of new vasculature.22 Inhibition of neovascularisation by Avastin inhibits the growth of the tumour and prevents metastasis

  • In clinical trials, patient survival is extended and PD is delayed.6–11,23

Sustained control of tumour growth by Avastin can translate into clinical benefit regardless of patients’ objective response to therapy

  • In a phase III trial in CRC, objective response did not predict the magnitude of PFS(The time from trial entry to disease progression or death from any cause) or OS(The time from trial entry to death from any cause) benefit achieved following the addition of Avastin to chemotherapy; significant increases in both PFS and OS were reported in patients with complete/partial response(A 30% decrease in the sum of the longest diameter of target lesions following treatment), stable disease(Description of a tumour that is neither growing nor shrinking. Stable disease also means that no new tumours have developed, and that the cancer has not spread to any new regions of the body (the cancer is not getting better or worse)) or no response, alike.24

References

  1. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Proc Natl Acad Sci USA 1996;93:14765–70.
  2. Willett CG, Boucher Y, di Tomaso TE, et al. Nat Med 2004;10:145–7.
  3. Gerber HP, Ferrara N. Cancer Res 2005;65:671–80.
  4. Huang J, Frischer JS, Serur A, et al. Proc Natl Acad Sci USA 2003;100:7785–90.
  5. Avastin Summary of Product Characteristics. Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/avastin/emea-combined-h582en.pdf
  6. Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. J Clin Oncol 2009;27:4966–72.
  7. Reck M, von Pawel J, Zatloukal P, et al. J Clin Oncol 2009;27:1227–34.
  8. Sandler A, Gray R, Perry MC, et al. N Engl J Med 2006;355:2542–50.
  9. Escudier B, Pluzanska A, Koralewski P, et al. Lancet 2007;370:2103–11.
  10. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med 2004;350:2335–42.
  11. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol 2007;25:1539–44.
  12. Senger DR, Galli SJ, Dvorak AM, et al. Science 1983;219:983–5.
  13. Brasch R, Pham C, Shames D, et al. J Magn Reson Imaging. 1997;7(1):68-74. Review.
  14. Gossmann A, Helbich TH, Mesiano S, et al. Am J Obstet Gynecol.
  15. 2000;183(4):956-63.
  16. Pham CD, Roberts TP, van Bruggen N, et al. Cancer Invest. 1998;16(4):225-30.
  17. Prager GW, Lackner EM, Krauth MT, et al. Mol Oncol. 2010;4(2):150-60.
  18. Ribeiro SC, Vargas FS, Antonangelo L, et al. Respirology. 2009;14(8):1188-93.
  19. Borgström P, Hillan KJ, Sriramarao P, Ferrara N. Cancer Res 1996;56:4032–9.
  20. Borgström P, Bourdon MA, Hillan KJ, Sriramarao P, Ferrara N. Prostate 1998;35:1–10.
  21. Bergers G, Benjamin LE. Nat Rev Cancer 2003;3:401–10.
  22. Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. J Clin Invest 1995;95:1789–97.
  23. Hicklin DJ, Ellis LM. J Clin Oncol 2005;23:1011–27.
  24. Pivot X, Verma S, Thomssen C, et al. J Clin Oncol 2009;27(May 20 Suppl.):64s (Abstract 1094 and associated poster presentation).
  25. Grothey A, Hedrick EE, Mass RD, et al. J Clin Oncol 2008;26:183–9.

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