title: Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response.
abstract: PURPOSE Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). PATIENTS AND METHODS Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for > or = 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. CONCLUSION Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.
authors.affiliation: Sunnybrook Odette Cancer Centre, Ontario Clinical Oncology Group, University of Toronto, 2075 Bayview Ave, Toronto M4N3M5, Ontario, Canada.
authors.forename: Nan Soon
authors.initials: NS
authors.lastname: Wong
authors.forename: Robert A
authors.initials: RA
authors.lastname: Buckman
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
authors.forename: Shailendra
authors.initials: S
authors.lastname: Verma
authors.forename: Susan
authors.initials: S
authors.lastname: Dent
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Trudeau
authors.forename: Kathie
authors.initials: K
authors.lastname: Roche
authors.forename: John
authors.initials: J
authors.lastname: Ebos
authors.forename: Robert
authors.initials: R
authors.lastname: Kerbel
authors.forename: Gerrit E
authors.initials: GE
authors.lastname: Deboer
authors.forename: Donald J A
authors.initials: DJ
authors.lastname: Sutherland
authors.forename: Urban
authors.initials: U
authors.lastname: Emmenegger
authors.forename: Joyce
authors.initials: J
authors.lastname: Slingerland
authors.forename: Sandra
authors.initials: S
authors.lastname: Gardner
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D003520:Cyclophosphamide / Q000008:administration & dosage; D017985:Dalteparin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009864:Ontario / Q000453:epidemiology; D011241:Prednisone / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood*
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003520:Cyclophosphamide; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D017985:Dalteparin; D011241:Prednisone; D008727:Methotrexate