title: A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer.
abstract: Standard chemotherapeutic drugs, when modified by the frequency and dose of administration, can target angiogenesis. This approach is referred to as antiangiogenic chemotherapy, low-dose chemotherapy, or metronomic chemotherapy. This study evaluated the feasibility of 6 months of metronomic chemotherapy, its toxicity and tolerability, surrogate markers of activity, and preliminary evidence of activity in children with recurrent or progressive cancer. Twenty consecutive children were enrolled and received continuous oral thalidomide and celecoxib with alternating oral etoposide and cyclophosphamide every 21 days for a planned duration of 6 months using antiangiogenic doses of all four drugs. Surrogate markers including bFGF, VEGF, endostatin, and thrombospondin were also evaluated. Therapy was well tolerated in this heavily pretreated population. Toxicities (predominantly reversible bone marrow suppression) responded to dose modifications. Sixty percent of the patients received less than the prescribed 6 months of therapy due to toxicity (one case of deep vein thrombosis), personal choice (1 patient), or disease progression (10 patients). Forty percent of the patients completed the 6 months of therapy, resulting in prolonged or persistent disease-free status. One quarter of all patients continue to be progression free more than 123 weeks from starting therapy. Sixteen percent of patients showed a radiographic partial response. Only elevated thrombospondin-1 levels appeared to correlate with prolonged response. This oral antiangiogenic chemotherapy regimen was well tolerated in this heavily pretreated pediatric population, which showed prolonged or persistent disease-free status, supporting the continued study of antiangiogenic/metronomic chemotherapy in human clinical trials.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Pediatric Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. mark_kieran@dfci.harvard.edu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Turner
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
authors.forename: Susan N
authors.initials: SN
authors.lastname: Chi
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Zimmerman
authors.forename: Christine
authors.initials: C
authors.lastname: Chordas
authors.forename: Giannoula
authors.initials: G
authors.lastname: Klement
authors.forename: Andrea
authors.initials: A
authors.lastname: Laforme
authors.forename: Amanda
authors.initials: A
authors.lastname: Gordon
authors.forename: Amanda
authors.initials: A
authors.lastname: Thomas
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Timothy
authors.initials: T
authors.lastname: Browder
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D043169:Endostatins / Q000378:metabolism; D005240:Feasibility Studies; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007223:Infant; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control*; D019699:Thrombospondins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2