TY - JOUR
T1 - Inflammatory breast cancer as a model disease to study tumor angiogenesis
T2 - Results of a phase IB trial of combination SU54 16 and doxorubicin
AU - Overmoyer, Beth
AU - Fu, Pingfu
AU - Hoppel, Charles
AU - Radivoyevitch, Tomas
AU - Shenk, Robert
AU - Persons, Marjie
AU - Silverman, Paula
AU - Robertson, Kelly
AU - Ziats, Nicholas P.
AU - Wasman, Jay K.
AU - Abdul-Karim, Fadi W.
AU - Jesberger, John A.
AU - Duerk, Jeffrey
AU - Hartman, Paul
AU - Hanks, Shelli
AU - Lewin, Jonathan
AU - Dowlati, Afshin
AU - McCrae, Keith
AU - Ivy, Percy
AU - Remick, Scot C.
PY - 2007/10/1
Y1 - 2007/10/1
N2 - Purpose: We used inflammatory breast cancer (IBC) as amodel disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin. Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 andd oxorubicin for induction therapy. The dose of SU5416 (administered on days 1and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalatedin cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy. Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached( 50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival. Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.
AB - Purpose: We used inflammatory breast cancer (IBC) as amodel disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin. Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 andd oxorubicin for induction therapy. The dose of SU5416 (administered on days 1and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalatedin cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy. Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached( 50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival. Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=35348849126&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35348849126&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-07-0688
DO - 10.1158/1078-0432.CCR-07-0688
M3 - Article
C2 - 17908980
AN - SCOPUS:35348849126
SN - 1078-0432
VL - 13
SP - 5862
EP - 5868
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -