Inflammatory breast cancer as a model disease to study tumor angiogenesis: results of a phase IB trial of combination SU5416 and doxorubicin.
OBJECTIVE
We used inflammatory breast cancer (IBC) as a model disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin.


METHODS
Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 and doxorubicin for induction therapy. The dose of SU5416 (administered on days 1 and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalated in 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.
Overmoyer
Beth
B
Connecticut Oncology & Hematology Associates/US Oncology, Torrington, Connecticut 06790, USA. beth.overmoyer@usoncology.com
Fu
Pingfu
P
Hoppel
Charles
C
Radivoyevitch
Tomas
T
Shenk
Robert
R
Persons
Marjie
M
Silverman
Paula
P
Robertson
Kelly
K
Ziats
Nicholas P
NP
Wasman
Jay K
JK
Abdul-Karim
Fadi W
FW
Jesberger
John A
JA
Duerk
Jeffrey
J
Hartman
Paul
P
Hanks
Shelli
S
Lewin
Jonathan
J
Dowlati
Afshin
A
McCrae
Keith
K
Ivy
Percy
P
Remick
Scot C
SC
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D007249:Inflammation; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011758:Pyrroles / Q000008:administration & dosage*; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D004317:Doxorubicin