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
Author(s)
Type
Journal Article
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-20
-
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.
ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-20
-
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.
Date Issued
2014-03-18
Date Acceptance
2014-02-09
Citation
British Journal of Cancer, 2014, 110 (8), pp.1923-1929
ISSN
1532-1827
Publisher
Cancer Research UK
Start Page
1923
End Page
1929
Journal / Book Title
British Journal of Cancer
Volume
110
Issue
8
Copyright Statement
© 2014 Cancer Research UK.This work is published under the standard license to publish agreement. 12 months after publication the work will become freely available and
the license terms will switch to a Creative Commons AttributionNonCommercial-Share
Alike 3.0 Unported License.
the license terms will switch to a Creative Commons AttributionNonCommercial-Share
Alike 3.0 Unported License.
Subjects
Science & Technology
Life Sciences & Biomedicine
Oncology
ONCOLOGY
5-aza-2 '-deoxycytidine
carboplatin
drug resistance
DNA methylation
ovarian cancer
DRUG-RESISTANCE
CISPLATIN RESISTANCE
HMLH1 EXPRESSION
CLINICAL-TRIALS
SOLID TUMORS
METHYLATION
PROMOTER
GENES
CHEMOTHERAPY
Publication Status
Published