TY - JOUR
T1 - Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation
AU - Batchelor, Tracy T.
AU - Gerstner, Elizabeth R.
AU - Emblem, Kyrre E.
AU - Duda, Dan G.
AU - Kalpathy-Cramer, Jayashree
AU - Snuderl, Matija
AU - Ancukiewicz, Marek
AU - Polaskova, Pavlina
AU - Pinho, Marco C.
AU - Jennings, Dominique
AU - Plotkin, Scott R.
AU - Chi, Andrew S.
AU - Eichler, April F.
AU - Dietrich, Jorg
AU - Hochberg, Fred H.
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.
PY - 2013/11/19
Y1 - 2013/11/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84887419886&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887419886&partnerID=8YFLogxK
U2 - 10.1073/pnas.1318022110
DO - 10.1073/pnas.1318022110
M3 - Article
C2 - 24190997
AN - SCOPUS:84887419886
SN - 0027-8424
VL - 110
SP - 19059
EP - 19064
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 47
ER -