Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

Tracy T. Batchelor, Elizabeth R. Gerstner, Kyrre E. Emblem, Dan G. Duda, Jayashree Kalpathy-Cramer, Matija Snuderl, Marek Ancukiewicz, Pavlina Polaskova, Marco C. Pinho, Dominique Jennings, Scott R. Plotkin, Andrew S. Chi, April F. Eichler, Jorg Dietrich, Fred H. Hochberg, Christine Lu-Emerson, A. John Iafrate, S. Percy Ivy, Bruce R. Rosen, Jay S. Loeffler & 3 others Patrick Y. Wen, A. Greg Sorensen, Rakesh K. Jain

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti- VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic formof therapy, and these results may provide newinsight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.

Original languageEnglish (US)
Pages (from-to)19059-19064
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number47
DOIs
StatePublished - Nov 19 2013

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Glioblastoma
Perfusion
Survival
Neoplasms
Vascular Endothelial Growth Factor A
Therapeutics
Biomarkers
Phase II Clinical Trials
Vascular Endothelial Growth Factor Receptor
Angiogenesis Inhibitors
Poisons
cediranib
Interleukin-8
Protein-Tyrosine Kinases
Patient Selection

ASJC Scopus subject areas

  • General

Cite this

Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. / Batchelor, Tracy T.; Gerstner, Elizabeth R.; Emblem, Kyrre E.; Duda, Dan G.; Kalpathy-Cramer, Jayashree; Snuderl, Matija; Ancukiewicz, Marek; Polaskova, Pavlina; Pinho, Marco C.; Jennings, Dominique; Plotkin, Scott R.; Chi, Andrew S.; Eichler, April F.; Dietrich, Jorg; Hochberg, Fred H.; Lu-Emerson, Christine; Iafrate, A. John; Ivy, S. Percy; Rosen, Bruce R.; Loeffler, Jay S.; Wen, Patrick Y.; Sorensen, A. Greg; Jain, Rakesh K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 47, 19.11.2013, p. 19059-19064.

Research output: Contribution to journalArticle

Batchelor, TT, Gerstner, ER, Emblem, KE, Duda, DG, Kalpathy-Cramer, J, Snuderl, M, Ancukiewicz, M, Polaskova, P, Pinho, MC, Jennings, D, Plotkin, SR, Chi, AS, Eichler, AF, Dietrich, J, Hochberg, FH, Lu-Emerson, C, Iafrate, AJ, Ivy, SP, Rosen, BR, Loeffler, JS, Wen, PY, Sorensen, AG & Jain, RK 2013, 'Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 47, pp. 19059-19064. https://doi.org/10.1073/pnas.1318022110
Batchelor, Tracy T. ; Gerstner, Elizabeth R. ; Emblem, Kyrre E. ; Duda, Dan G. ; Kalpathy-Cramer, Jayashree ; Snuderl, Matija ; Ancukiewicz, Marek ; Polaskova, Pavlina ; Pinho, Marco C. ; Jennings, Dominique ; Plotkin, Scott R. ; Chi, Andrew S. ; Eichler, April F. ; Dietrich, Jorg ; Hochberg, Fred H. ; Lu-Emerson, Christine ; Iafrate, A. John ; Ivy, S. Percy ; Rosen, Bruce R. ; Loeffler, Jay S. ; Wen, Patrick Y. ; Sorensen, A. Greg ; Jain, Rakesh K. / Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 47. pp. 19059-19064.
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AU - Duda, Dan G.

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AU - Snuderl, Matija

AU - Ancukiewicz, Marek

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AU - Chi, Andrew S.

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AU - Lu-Emerson, Christine

AU - Iafrate, A. John

AU - Ivy, S. Percy

AU - Rosen, Bruce R.

AU - Loeffler, Jay S.

AU - Wen, Patrick Y.

AU - Sorensen, A. Greg

AU - Jain, Rakesh K.

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