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Title: VEGF Trap in Combination With Radiotherapy Improves Tumor Control in U87 Glioblastoma

Abstract

Purpose: To determine the effect of vascular endothelial growth factor VEGF Trap (Regeneron Pharmaceuticals, Tarrytown, NY), a humanized soluble vascular endothelial growth factor (VEGF) receptor protein, and radiation (RT) on tumor growth in U87 glioblastoma xenografts in nude mice. Methods and Materials: U87 cell suspensions were implanted subcutaneously into hind limbs of nude mice. VEGF Trap (2.5-25 mg/kg) was administered every 3 days for 3 weeks alone or in combination with a single dose of 10 Gy or fractionated RT (3 x 5 Gy). In addition, three scheduling protocols for VEGF Trap plus fractionated RT were examined. Results: Improved tumor control was seen when RT (either single dose or fractionated doses) was combined with the lowest dose of VEGF Trap (2.5 mg/kg). Scheduling did not significantly affect the efficacy of combined therapy. Although high-dose VEGF Trap (10 mg/kg or 25 mg/kg) significantly reduced tumor growth over that of RT alone, there was no additional benefit to combining high-dose VEGF Trap with RT. Conclusions: Vascular endothelial growth factor Trap plus radiation is clearly better than radiation alone in a U87 subcutaneous xenograft model. Although high doses of VEGF Trap alone are highly efficacious, it is unclear whether such high doses canmore » be used clinically without incurring normal tissue toxicities. Thus, information on lower doses of VEGF Trap and ionizing radiation is of clinical relevance.« less

Authors:
 [1];  [2];  [3];  [3];  [4];  [5];  [5];  [6]
  1. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA (United States). E-mail: Phyllis.Wachsberger@mail.tju.edu
  2. Department of Nutritional Sciences, University of Arizona, Tucson, AZ (United States)
  3. Department of Radiology, Thomas Jefferson University, Philadelphia, PA (United States)
  4. Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA (United States)
  5. Novartis, Emeryville, CA (United States)
  6. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA (United States)
Publication Date:
OSTI Identifier:
20951601
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 67; Journal Issue: 5; Other Information: DOI: 10.1016/j.ijrobp.2006.11.011; PII: S0360-3016(06)03394-3; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; COMBINED THERAPY; DRUGS; GLIOMAS; GROWTH; GROWTH FACTORS; IONIZING RADIATIONS; LIMBS; RADIATION DOSES; RADIOTHERAPY; RECEPTORS; TOXICITY

Citation Formats

Wachsberger, Phyllis R., Burd, Randy, Cardi, Chris, Thakur, Mathew, Daskalakis, Constantine, Holash, Jocelyn, Yancopoulos, George D., and Dicker, Adam P. VEGF Trap in Combination With Radiotherapy Improves Tumor Control in U87 Glioblastoma. United States: N. p., 2007. Web. doi:10.1016/j.ijrobp.2006.11.011.
Wachsberger, Phyllis R., Burd, Randy, Cardi, Chris, Thakur, Mathew, Daskalakis, Constantine, Holash, Jocelyn, Yancopoulos, George D., & Dicker, Adam P. VEGF Trap in Combination With Radiotherapy Improves Tumor Control in U87 Glioblastoma. United States. doi:10.1016/j.ijrobp.2006.11.011.
Wachsberger, Phyllis R., Burd, Randy, Cardi, Chris, Thakur, Mathew, Daskalakis, Constantine, Holash, Jocelyn, Yancopoulos, George D., and Dicker, Adam P. Sun . "VEGF Trap in Combination With Radiotherapy Improves Tumor Control in U87 Glioblastoma". United States. doi:10.1016/j.ijrobp.2006.11.011.
@article{osti_20951601,
title = {VEGF Trap in Combination With Radiotherapy Improves Tumor Control in U87 Glioblastoma},
author = {Wachsberger, Phyllis R. and Burd, Randy and Cardi, Chris and Thakur, Mathew and Daskalakis, Constantine and Holash, Jocelyn and Yancopoulos, George D. and Dicker, Adam P.},
abstractNote = {Purpose: To determine the effect of vascular endothelial growth factor VEGF Trap (Regeneron Pharmaceuticals, Tarrytown, NY), a humanized soluble vascular endothelial growth factor (VEGF) receptor protein, and radiation (RT) on tumor growth in U87 glioblastoma xenografts in nude mice. Methods and Materials: U87 cell suspensions were implanted subcutaneously into hind limbs of nude mice. VEGF Trap (2.5-25 mg/kg) was administered every 3 days for 3 weeks alone or in combination with a single dose of 10 Gy or fractionated RT (3 x 5 Gy). In addition, three scheduling protocols for VEGF Trap plus fractionated RT were examined. Results: Improved tumor control was seen when RT (either single dose or fractionated doses) was combined with the lowest dose of VEGF Trap (2.5 mg/kg). Scheduling did not significantly affect the efficacy of combined therapy. Although high-dose VEGF Trap (10 mg/kg or 25 mg/kg) significantly reduced tumor growth over that of RT alone, there was no additional benefit to combining high-dose VEGF Trap with RT. Conclusions: Vascular endothelial growth factor Trap plus radiation is clearly better than radiation alone in a U87 subcutaneous xenograft model. Although high doses of VEGF Trap alone are highly efficacious, it is unclear whether such high doses can be used clinically without incurring normal tissue toxicities. Thus, information on lower doses of VEGF Trap and ionizing radiation is of clinical relevance.},
doi = {10.1016/j.ijrobp.2006.11.011},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 5,
volume = 67,
place = {United States},
year = {Sun Apr 01 00:00:00 EDT 2007},
month = {Sun Apr 01 00:00:00 EDT 2007}
}
  • Purpose: Electron disequilibrium at the lung-tumor interface results in an under-dosage of tumor regions close to its surface. This under-dosage is known to be significant and can compromise tumor control. Previous studies have shown that in FFF beams, disequilibrium effects are less pronounced, which is manifested in an increased skin dose. In this study we investigate the improvement in tumor dose coverage that can be achieved with FFF beams. The significance of this improvement is evaluated by comparing tumor control probabilities of FFF beams and conventional flattened beams. Methods: The dosimetric coverage was investigated in a virtual phantom representing themore » chest wall, lung tissue and the tumor. A range of tumor sizes was investigated, and two tumor locations – central and adjacent to the chest wall. Calculations were performed with BEAMnrc Monte Carlo code. Parallel-opposed and multiple coplanar 6-MV beams were simulated. The tumor control probabilities were calculated using the logistic model with parameters derived from clinical data for non-small lung cancer patients. Results: FFF beams were not entirely immune to disequilibrium effects. They nevertheless consistently delivered more uniform dose distribution throughout the volume of the tumor, and eliminated up to ∼15% of under-dosage in the most affected by disequilibrium 1-mm thick surface region of the tumor. A voxel-by-voxel comparison of tumor control probabilities between FFF and conventional flattened beams showed an advantage of FFF beams that, depending on the set up, was from a few to ∼9 percent. Conclusion: A modest improvement in tumor control probability on the order of a few percent can be achieved by replacing conventional flattened beams with FFF beams. However, given the large number of lung cancer patients undergoing radiotherapy, these few percent can potentially prevent local tumor recurrence for a significant number of patients.« less
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