Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.11596
Title: Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer
Authors: Wong A.L.A. 
Sundar R.
Wang T.-T. 
Ng T.-C. 
Zhang B. 
Tan S.-H. 
Soh T.I.P.
Pang A.S.L.
Tan C.-S.
Ow S.G.W.
Wang L. 
Mogro J.
Ho J.
Jeyasekharan A.D. 
Huang Y.
Thng C.-H. 
Chan C.-W. 
Hartman M. 
Iau P.
Buhari S.A. 
Goh B.-C. 
Lee S.-C. 
Keywords: cyclophosphamide
doxorubicin
sunitinib
anthracycline
antineoplastic agent
contrast medium
cyclophosphamide
doxorubicin
indole derivative
pyrrole derivative
sunitinib
tumor marker
adult
aged
anemia
Article
breast cancer
cancer chemotherapy
clinical article
controlled study
drug efficacy
drug response
drug safety
febrile neutropenia
female
fever
human
human tissue
immunohistochemistry
lethargy
leukopenia
lymph vessel
multiple cycle treatment
neutropenia
nuclear magnetic resonance imaging
phase 1 clinical trial
phase 2 clinical trial
randomized controlled trial
stomatitis
breast tumor
clinical trial
disease free survival
drug administration
middle aged
neoadjuvant therapy
preoperative period
treatment outcome
Adult
Aged
Anthracyclines
Antineoplastic Agents
Biomarkers, Tumor
Breast Neoplasms
Contrast Media
Cyclophosphamide
Disease-Free Survival
Doxorubicin
Drug Administration Schedule
Female
Humans
Immunohistochemistry
Indoles
Magnetic Resonance Imaging
Middle Aged
Neoadjuvant Therapy
Preoperative Period
Pyrroles
Treatment Outcome
Issue Date: 2016
Citation: Wong A.L.A., Sundar R., Wang T.-T., Ng T.-C., Zhang B., Tan S.-H., Soh T.I.P., Pang A.S.L., Tan C.-S., Ow S.G.W., Wang L., Mogro J., Ho J., Jeyasekharan A.D., Huang Y., Thng C.-H., Chan C.-W., Hartman M., Iau P., Buhari S.A., Goh B.-C., Lee S.-C. (2016). Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer. Oncotarget 7 (39) : 64089-64099. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.11596
Abstract: Background: Prolonged anti-angiogenic therapy destroys tumor vasculature, whereas vascular-normalizing doses may enhance intra-tumoral drug delivery. We hypothesize that low-dose, short-course sunitinib normalizes vasculature, enhancing chemotherapy efficacy. Patients and Methods: In phase Ib, treatment-naïve breast cancer patients received four cycles of pre-operative doxorubicin/cyclophosphamide, with sunitinib before each cycle. The optimal dose of sunitinib leading to tumor vessel normalization on immunohistochemistry was identified. In phase II, subjects were randomized to chemotherapy alone or chemotherapy plus sunitinib at the recommended phase II dose (RP2D). Primary endpoint was pathological complete response (pCR) rate. Tumor and functional imaging biomarkers were evaluated serially. Results: In phase Ib (n=9), sunitinib 12.5 mg daily for 7 days before each chemotherapy was established as RP2D. In phase II, patients receiving chemotherapy plus sunitinib (n=24) had similar pCR rates (5.0% versus 4.3%, p=1.00), but a higher incidence of chemotherapy dose delays (33.3% versus 8.7%, p=0.04), compared to those receiving chemotherapy alone (n=25). The addition of sunitinib to chemotherapy significantly increased vascular normalization index (VNI) and decreased lymphatic vessel density (D2-40) on immunohistochemistry [VNI:25.50±27.94% versus 49.29±31.84%, p=0.034; D2-40:3.29±2.70 versus 1.29±1.54, p=0.014, baseline versus post-cycle 1], and improved perfusion on DCE-MRI (Ktrans:12.6±9.6 mL/100 g/min versus 16.3±10.7 mL/100 g/min, baseline versus post-cycle 1, p=0.015). Conversely, immunohistochemical and DCE-MRI parameters were not significantly altered by chemotherapy alone. Conclusion: Low-dose, short-course sunitinib prior to anthracycline-based chemotherapy in breast cancer patients did not improve pCR and increased chemotherapy dose delays. However, the addition of sunitinib induced compelling pharmacodynamic evidence of vascular normalization. Further studies with alternative cytotoxic regimens should be explored.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174106
ISSN: 19492553
DOI: 10.18632/oncotarget.11596
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