title: Early prediction of treatment resistance in low-risk gestational trophoblastic neoplasia using population kinetic modelling of hCG measurements.
abstract: BACKGROUND
  In low-risk gestational trophoblastic neoplasia (GTN) patients, a predictive marker for early identification of methotrexate (MTX) resistance would be useful. We previously demonstrated that kinetic modelling of human chorionic gonadotrophin (hCG) measurements could provide such a marker. Here we validate this approach in a large independent patient cohort.
  
  
  METHODS
  Serum hCG measurements of 800 low-risk GTN patients treated with MTX were analysed. The cohort was divided into Model and Test data sets. hCG kinetics were described from initial treatment day to day 50 using: '(hCG(time))=hCG0*exp(-k*time)+hCGres', where hCGres is the modelled residual production, hCG0 is the baseline hCG level, and k is the rate constant. HCGres-predictive value was investigated against previously reported predictors of MTX resistance.
  
  
  RESULTS
  Declining hCG measurements were well fitted by the model. The best discriminator of MTX resistance in the Model data set was hCGres, categorised by an optimal cut-off value of >20.44 IU l(-1): receiver-operating characteristic (ROC) area under the curve (AUC)=0.87; Se=0.91; Sp=0.83. The predictive value of hCGres was reproducible using the Test data set: ROC AUC=0.87; Se=0.88; Sp=0.86. Multivariate analyses revealed hCGres as a better predictor of MTX resistance (HR=1.01, P<0.0001) and MTX failure-free survival (HR=13.25, P<0.0001) than other reported predictive factors.
  
  
  CONCLUSIONS
  hCGres, a modelled kinetic parameter calculated after fully dosed three MTX cycles, has a reproducible value for identifying patients with MTX resistance.
authors.affiliation: EMR UBCL/HCL 3738, Université Claude Bernard Lyon-1, Hospices Civils de Lyon, Lyon, France. benoit.you@chu-lyon.fr
authors.forename: B
authors.initials: B
authors.lastname: You
authors.forename: R
authors.initials: R
authors.lastname: Harvey
authors.forename: E
authors.initials: E
authors.lastname: Henin
authors.forename: H
authors.initials: H
authors.lastname: Mitchell
authors.forename: F
authors.initials: F
authors.lastname: Golfier
authors.forename: P M
authors.initials: PM
authors.lastname: Savage
authors.forename: M
authors.initials: M
authors.lastname: Tod
authors.forename: M
authors.initials: M
authors.lastname: Wilbaux
authors.forename: G
authors.initials: G
authors.lastname: Freyer
authors.forename: M J
authors.initials: MJ
authors.lastname: Seckl
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D006063:Chorionic Gonadotropin / Q000097:blood*; D019008:Drug Resistance, Neoplasm; D005260:Female; D031901:Gestational Trophoblastic Disease / Q000188:drug therapy*; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use*; D015999:Multivariate Analysis; D011247:Pregnancy; D012372:ROC Curve; D017211:Treatment Failure
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D006063:Chorionic Gonadotropin; D008727:Methotrexate