title: Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer.
abstract: BACKGROUND
  Combined therapy of metronomic cyclophosphamide, methotrexate and high-dose celecoxib targeting angiogenesis was used in a phase II trial.
  
  
  METHODS
  Patients with advanced cancer received oral cyclophosphamide 50 mg o.d., celecoxib 400 mg b.d. and methotrexate 2.5 mg b.d. for two consecutive days each week. Response was determined every 8 weeks; toxicity was evaluated according to CTC version 2.0. Plasma markers of inflammation, coagulation and angiogenesis were measured.
  
  
  RESULTS
  Sixty-seven of 69 patients were evaluable for response. Twenty-three patients had stable disease (SD) after 8 weeks, but there were no objective responses to therapy. Median time to progression was 57 days. There was a low incidence of toxicities. Among plasma markers, levels of tissue factor were higher in the SD group of patients at baseline, and levels of both angiopoietin-1 and matrix metalloproteinase-9 increased in the progressive disease group only. There were no changes in other plasma markers.
  
  
  CONCLUSIONS
  This metronomic approach has negligible activity in advanced cancer albeit with minimal toxicity. Analysis of plasma markers indicates minimal effects on endothelium in this trial. These data for this particular regimen do not support basic tenets of metronomic chemotherapy, such as the ability to overcome resistant tumours by targeting the endothelium.
authors.affiliation: University of Oxford Department of Medical Oncology, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: O A
authors.initials: OA
authors.lastname: Khan
authors.forename: A D
authors.initials: AD
authors.lastname: Blann
authors.forename: M J
authors.initials: MJ
authors.lastname: Payne
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
authors.forename: A S
authors.initials: AS
authors.lastname: Protheroe
authors.forename: D C
authors.initials: DC
authors.lastname: Talbot
authors.forename: M
authors.initials: M
authors.lastname: Taylor
authors.forename: O
authors.initials: O
authors.lastname: Kirichek
authors.forename: C
authors.initials: C
authors.lastname: Han
authors.forename: M
authors.initials: M
authors.lastname: Patil
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042683:Angiopoietin-1 / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068579:Celecoxib; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D011720:Pyrazoles; D013449:Sulfonamides; D003520:Cyclophosphamide; D020780:Matrix Metalloproteinase 9; D000068579:Celecoxib; D008727:Methotrexate