title: Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study.
abstract: OBJECTIVE
  To elucidate the effect of a doubled carboplatin dose-intensity in epithelial ovarian cancer in combination with a fixed dose of cyclophosphamide.
  
  
  METHODS
  A total of 222 patients with epithelial ovarian cancer stages II to IV were included in the study. Following surgery, patients were randomly assigned to receive carboplatin at an area under the concentration-versus-time curve (AUC) of 4 (AUC4) or carboplatin at an AUC of 8 (AUC8) and cyclophosphamide 500 mg/m2 given every 4 weeks for six courses. The AUC was calculated according to Calvert's formula. In 123 patients, the carboplatin AUC was also measured based on a single-sample method and the results were compared with the calculated AUC. The end points of the trial were complete pathologic remission (CPR) and crude survival.
  
  
  RESULTS
  Approximately 50% of patients in both arms underwent second-look surgery. The frequency of CPR was 32% and 30%, respectively. The survival curves showed no significant difference (P = .84). The dose-intensity of cyclophosphamide was almost identical in the two arms, whereas that of carboplatin was different. In the AUC8 arm, the dose-intensity was 1.86 times that of the AUC4 arm. The results also demonstrated good agreement between the calculated and the measured AUC in most patients. Bone marrow toxicity was significantly higher in the AUC8 arm.
  
  
  CONCLUSIONS
  A doubling of the carboplatin dose-intensity did not result in any significant improvement of pathologic remission or survival. Calvert's formula can be used to give a fairly accurate estimate of the carboplatin AUC. Bone marrow toxicity increased with higher dose-intensity, and a further increase of dose is only feasible with growth-factor or stem-cell support.
authors.affiliation: Department of Oncology, Odense University Hospital, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Jakobsen
authors.forename: K
authors.initials: K
authors.lastname: Bertelsen
authors.forename: J E
authors.initials: JE
authors.lastname: Andersen
authors.forename: H
authors.initials: H
authors.lastname: Havsteen
authors.forename: P
authors.initials: P
authors.lastname: Jakobsen
authors.forename: K A
authors.initials: KA
authors.lastname: Moeller
authors.forename: K
authors.initials: K
authors.lastname: Nielsen
authors.forename: E
authors.initials: E
authors.lastname: Sandberg
authors.forename: I
authors.initials: I
authors.lastname: Stroeyer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D012086:Reoperation
chemical_list: D003520:Cyclophosphamide; D016190:Carboplatin