title: Validation of the Predictive Value of Modeled Human Chorionic Gonadotrophin Residual Production in Low-Risk Gestational Trophoblastic Neoplasia Patients Treated in NRG Oncology/Gynecologic Oncology Group-174 Phase III Trial.
abstract: OBJECTIVE
  In low-risk gestational trophoblastic neoplasia, chemotherapy effect is monitored and adjusted with serum human chorionic gonadotrophin (hCG) levels. Mathematical modeling of hCG kinetics may allow prediction of methotrexate (MTX) resistance, with production parameter "hCGres." This approach was evaluated using the GOG-174 (NRG Oncology/Gynecologic Oncology Group-174) trial database, in which weekly MTX (arm 1) was compared with dactinomycin (arm 2).
  
  
  METHODS
  Database (210 patients, including 78 with resistance) was split into 2 sets. A 126-patient training set was initially used to estimate model parameters. Patient hCG kinetics from days 7 to 45 were fit to: [hCG(time)] = hCG7 * exp(-k * time) + hCGres, where hCGres is residual hCG tumor production, hCG7 is the initial hCG level, and k is the elimination rate constant. Receiver operating characteristic (ROC) analyses defined putative hCGRes predictor of resistance. An 84-patient test set was used to assess prediction validity.
  
  
  RESULTS
  The hCGres was predictive of outcome in both arms, with no impact of treatment arm on unexplained variability of kinetic parameter estimates. The best hCGres cutoffs to discriminate resistant versus sensitive patients were 7.7 and 74.0 IU/L in arms 1 and 2, respectively. By combining them, 2 predictive groups were defined (ROC area under the curve, 0.82; sensitivity, 93.8%; specificity, 70.5%). The predictive value of hCGres-based groups regarding resistance was reproducible in test set (ROC area under the curve, 0.81; sensitivity, 88.9%; specificity, 73.1%). Both hCGres and treatment arm were associated with resistance by logistic regression analysis.
  
  
  CONCLUSIONS
  The early predictive value of the modeled kinetic parameter hCGres regarding resistance seems promising in the GOG-174 study. This is the second positive evaluation of this approach. Prospective validation is warranted.
authors.affiliation: *EMR UBCL/HCL 3738, Université Claude Bernard Lyon-1, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Centre de Référence des Maladie Trophoblastiques, Hospices Civils de Lyon, Lyon, France; †NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY; and ‡Department of Oncology, Princess Margaret Hospital; and §Department of Gynecology/Oncology, Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: You
authors.forename: Wei
authors.initials: W
authors.lastname: Deng
authors.forename: Emilie
authors.initials: E
authors.lastname: Hénin
authors.forename: Amit
authors.initials: A
authors.lastname: Oza
authors.forename: Raymond
authors.initials: R
authors.lastname: Osborne
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D006063:Chorionic Gonadotropin / Q000097:blood*; D003609:Dactinomycin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D031901:Gestational Trophoblastic Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use*; D015233:Models, Statistical; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011247:Pregnancy; D011379:Prognosis; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D006063:Chorionic Gonadotropin; D003609:Dactinomycin; D008727:Methotrexate