title: A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer.
abstract: BACKGROUND
  Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer.
  
  
  METHODS
  Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma.
  
  
  RESULTS
  After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%).
  
  
  CONCLUSIONS
  With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.
authors.affiliation: The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK.
authors.forename: R M
authors.initials: RM
authors.lastname: Glasspool
authors.affiliation: Department Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: R
authors.initials: R
authors.lastname: Brown
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: M E
authors.initials: ME
authors.lastname: Gore
authors.affiliation: Mount Vernon Cancer Centre, Northwood, Middlesex HA6 2RN, UK.
authors.forename: G J S
authors.initials: GJ
authors.lastname: Rustin
authors.affiliation: St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK.
authors.forename: I A
authors.initials: IA
authors.lastname: McNeish
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7AB, N. Ireland, UK.
authors.forename: R H
authors.initials: RH
authors.lastname: Wilson
authors.affiliation: Sheffield Weston Park Hospital, Whitham Road, Sheffield, South Yorkshire S10 2SJ, UK.
authors.forename: S
authors.initials: S
authors.lastname: Pledge
authors.affiliation: The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK.
authors.forename: J
authors.initials: J
authors.lastname: Paul
authors.affiliation: Edinburgh Western General Hospital, Crewe Road S, Edinburgh EH4 2XU, UK.
authors.forename: M
authors.initials: M
authors.lastname: Mackean
authors.affiliation: St James's Institute of Oncology, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: G D
authors.initials: GD
authors.lastname: Hall
authors.affiliation: Department Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: H
authors.initials: H
authors.lastname: Gabra
authors.affiliation: Drug Development Office Cancer Research UK, Angel Building, 407 Street, John Street, Islington, London EC1V 4AD, UK.
authors.forename: S E R
authors.initials: SE
authors.lastname: Halford
authors.affiliation: Analytical Services Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK.
authors.forename: J
authors.initials: J
authors.lastname: Walker
authors.affiliation: Analytical Services Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK.
authors.forename: K
authors.initials: K
authors.lastname: Appleton
authors.affiliation: Analytical Services Unit, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1QH, UK.
authors.forename: R
authors.initials: R
authors.lastname: Ullah
authors.affiliation: Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: S
authors.initials: S
authors.lastname: Kaye
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000097:blood / Q000235:genetics; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects; D019175:DNA Methylation / Q000235:genetics*; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000097:blood / Q000235:genetics; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010984:Platinum / Q000008:administration & dosage
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D010984:Platinum; D000077209:Decitabine; D016190:Carboplatin; D000070957:MutL Protein Homolog 1; D001374:Azacitidine