title: Dynamic modeling in ovarian cancer: an original approach linking early changes in modeled longitudinal CA-125 kinetics and survival to help decisions in early drug development.
abstract: OBJECTIVE
  Early prediction of the expected benefit of treatment in recurrent ovarian cancer (ROC) patients may help in drug development decisions. The actual value of 50% CA-125 decrease is being reconsidered. The main objective of the present study was to quantify the links between longitudinal assessments of CA-125 kinetics and progression-free survival (PFS) in treated recurrent ovarian cancer (ROC) patients.
  
  
  METHODS
  The CALYPSO randomized phase III trial database comparing two platinum-based regimens in ROC patients was randomly split into a "learning dataset" and a "validation dataset". A parametric survival model was developed to associate longitudinal modeled CA-125 changes (ΔCA125), predictive factors, and PFS. The predictive performance of the model was evaluated with simulations.
  
  
  RESULTS
  The PFS of 534 ROC patients were properly characterized by a parametric mathematical model. The modeled ΔCA125 from baseline to week 6 was a better predictor of PFS than the modeled fractional change in tumor size. Simulations confirmed the model's predictive performance.
  
  
  CONCLUSIONS
  We present the first parametric survival model quantifying the relationship between PFS and longitudinal CA-125 kinetics in treated ROC patients. The model enabled calculation of the increase in ΔCA125 required to observe a predetermined benefit in PFS to compare therapeutic strategies in populations. Therefore, ΔCA125 may be a predictive marker of the expected gain in PFS and an early predictive tool in drug development decisions.
authors.affiliation: EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France. Electronic address: melanie.wilbaux@gmail.com.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Wilbaux
authors.affiliation: EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Hénin
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Amit
authors.initials: A
authors.lastname: Oza
authors.affiliation: EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Colomban
authors.affiliation: Hôpital Hôtel Dieu, Place du Parvis Notre-Dame, 75004 Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Pujade-Lauraine
authors.affiliation: EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France; Service d'Oncologie Médicale, Investigational Center for Treatments in Oncology and Hematology of Lyon, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, F-69310 Pierre-Bénite, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
authors.affiliation: EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tod
authors.affiliation: EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France; Service d'Oncologie Médicale, Investigational Center for Treatments in Oncology and Hematology of Lyon, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, F-69310 Pierre-Bénite, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: You
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018394:CA-125 Antigen / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D055808:Drug Discovery; D005260:Female; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D015233:Models, Statistical; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D017239:Paclitaxel / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D016190:Carboplatin; D017239:Paclitaxel
keywords: CA-125; Drug development; Ovarian cancer; Progression-free survival