title: The strong prognostic value of KELIM, a model-based parameter from CA 125 kinetics in ovarian cancer: data from CALYPSO trial (a GINECO-GCIG study).
abstract: BACKGROUND
  Unexpected results were recently reported about the poor surrogacy of Gynecologic Cancer Intergroup (GCIG) defined CA-125 response in recurrent ovarian cancer (ROC) patients. Mathematical modeling may help describe CA-125 decline dynamically and discriminate prognostic kinetic parameters.
  
  
  METHODS
  Data from CALYPSO phase III trial comparing 2 carboplatin-based regimens in ROC patients were analyzed. Based on population kinetic approach, serum [CA-125] concentration-time profiles during first 50 treatment days were fit to a semi-mechanistic model with following parameters: "d[CA-125]/dt=(KPROD∗exp (BETA∗t))∗Effect-KELIM∗[CA-125]" with time, t; tumor growth rate, BETA; CA-125 tumor production rate, KPROD; CA-125 elimination rate, KELIM and K-dependent treatment indirect Effect. The predictive values of kinetic parameters were tested regarding progression-free survival (PFS) against other reported prognostic factors.
  
  
  RESULTS
  Individual CA-125 kinetic profiles from 895 patients were modeled. Three kinetic parameters categorized by medians had predictive values using univariate analyses: K; KPROD and KELIM (all P<0.001). Using Cox multivariate analysis, 5 independent predictors of PFS remained significant: GCIG CA-125 response (favoring carboplatin-paclitaxel arm), treatment arm, platinum free-interval, measurable lesions and KELIM (HR=0.53; 95% CI 0.45-0.61; P<0.001).
  
  
  CONCLUSIONS
  Mathematical modeling of CA-125 kinetics in ROC patients enables understanding of the time-change components during chemotherapy. The contradictory surrogacy of GCIG-defined CA-125 response was confirmed. The modeled CA-125 elimination rate KELIM, potentially assessable in routine, may have promising predictive value regarding PFS. Further validation of this predictive marker is warranted.
authors.affiliation: National Cancer Institute of Canada-Clinical Trial Group, Canada. benoit.you@chu-lyon.fr
authors.forename: Benoit
authors.initials: B
authors.lastname: You
authors.forename: Olivier
authors.initials: O
authors.lastname: Colomban
authors.forename: Mark
authors.initials: M
authors.lastname: Heywood
authors.forename: Chee
authors.initials: C
authors.lastname: Lee
authors.forename: Margaret
authors.initials: M
authors.lastname: Davy
authors.forename: Nicholas
authors.initials: N
authors.lastname: Reed
authors.forename: Sandro
authors.initials: S
authors.lastname: Pignata
authors.forename: Nenzi
authors.initials: N
authors.lastname: Varsellona
authors.forename: Günter
authors.initials: G
authors.lastname: Emons
authors.forename: Khalid
authors.initials: K
authors.lastname: Rehman
authors.forename: Karina Dahl
authors.initials: KD
authors.lastname: Steffensen
authors.forename: Alexander
authors.initials: A
authors.lastname: Reinthaller
authors.forename: Eric
authors.initials: E
authors.lastname: Pujade-Lauraine
authors.forename: Amit
authors.initials: A
authors.lastname: Oza
mesh_terms: D018394:CA-125 Antigen / Q000097:blood*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007700:Kinetics; D008962:Models, Theoretical; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D018394:CA-125 Antigen
keywords: CA-125 antigen; Computer simulation; Kinetics; Ovarian epithelial cancer; Survival analysis