title: Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) plays an important role in the biology of ovarian cancer (OC). Inhibitors of VEGF suppress tumor growth in OC models. Metronomic chemotherapy, defined as frequent administration of low doses of cytotoxic chemotherapy, suppresses tumor growth, possibly by inhibiting angiogenesis. A phase II trial was conducted to evaluate the antitumor activity and adverse effects of bevacizumab and metronomic oral cyclophosphamide in women with recurrent OC.
  
  
  METHODS
  Patients with measurable disease and prior treatment with a platinum-containing regimen were eligible. Up to two different regimens for recurrent disease were allowed. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks and oral cyclophosphamide 50 mg/d. The primary end point was progression-free survival at 6 months. Plasma levels of VEGF, E-selectin, and thrombospondin-1 were obtained serially.
  
  
  RESULTS
  Seventy patients were enrolled. The probability of being alive and progression free at 6 months was 56% (+/- 6% SE). A partial response was achieved in 17 patients (24%). Median time to progression and survival were 7.2 and 16.9 months, respectively. The most common serious toxicities were hypertension, fatigue, and pain. Bevacizumab-related toxicities included four episodes of gastrointestinal perforation or fistula, two episodes each of CNS ischemia and pulmonary hypertension, and one episode each of gastrointestinal bleeding and wound healing complication. There were three treatment-related deaths. Levels of VEGF, E-selectin, and thrombospondin-1 were not associated with clinical outcome.
  
  
  CONCLUSIONS
  The combination of bevacizumab and metronomic cyclophosphamide is active in recurrent OC. Further study of this combination is warranted.
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA. aagarcia@usc.edu
authors.forename: Agustin A
authors.initials: AA
authors.lastname: Garcia
authors.forename: Hal
authors.initials: H
authors.lastname: Hirte
authors.forename: Gini
authors.initials: G
authors.lastname: Fleming
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Denice D
authors.initials: DD
authors.lastname: Tsao-Wei
authors.forename: Lynda
authors.initials: L
authors.lastname: Roman
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: Steve
authors.initials: S
authors.lastname: Swenson
authors.forename: Frank
authors.initials: F
authors.lastname: Markland
authors.forename: David
authors.initials: D
authors.lastname: Gandara
authors.forename: Sidney
authors.initials: S
authors.lastname: Scudder
authors.forename: Robert
authors.initials: R
authors.lastname: Morgan
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002140:California; D002641:Chicago; D003520:Cyclophosphamide / Q000008:administration & dosage; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019040:E-Selectin / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D019700:Thrombospondin 1 / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019040:E-Selectin; D019700:Thrombospondin 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D003520:Cyclophosphamide