Predictive values of hCG clearance for risk of methotrexate resistance in low-risk gestational trophoblastic neoplasias.
BACKGROUND
Early identification of patients at high risk for chemoresistance among those treated with methotrexate (MTX) for low-risk gestational trophoblastic neoplasia (GTN) is needed. We modeled human chorionic gonadotropin (hCG) decline during MTX therapy using a kinetic population approach to calculate individual hCG clearance (CL(hCG)) and assessed the predictive value of CL(hCG) for MTX resistance.


METHODS
A total of 154 patients with low-risk GTN treated with 8-day MTX regimen were retrospectively studied. NONMEM was used to model hCG decrease equations between day 0 and day 40 of chemotherapy. Receiver operating characteristic curve analysis defined the best CL(hCG) threshold. Univariate/multivariate survival analyses determined the predictive value of CL(hCG) and compared it with published predictive factors.


RESULTS
A monoexponential equation best modeled hCG decrease: hCG(t) = 3900 x e(-0.149 x t). Median CL(hCG) was 0.57 l/day (quartiles: 0.37-0.74). Only choriocarcinoma pathology [yes versus no: hazard ratio (HR) = 6.01; 95% confidence interval (CI) 2.2-16.6; P < 0.001] and unfavorable CL(hCG) quartile (< or =0.37 versus >0.37 l/day: HR = 6.75; 95% CI 2.7-16.8; P < 0.001) were significant independent predictive factors of MTX resistance risk.


CONCLUSIONS
In the second largest cohort of low-risk GTN patients reported to date, choriocarcinoma pathology and CL(hCG) < or =0.37 l/day were major independent predictive factors for MTX resistance risk.
You
B
B
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Medical Oncology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France; Medical Oncology Department, Drug Development Program, Princess Margaret Hospital, Toronto, Ontario, Canada. Electronic address: benoit.you@laposte.net.
Pollet-Villard
M
M
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Gynecology-Obstetrics Department, Hospices Civils de Lyon, Hôtel Dieu, Centre de Référence des Maladies Trophoblastiques, Lyon; Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite.
Fronton
L
L
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins.
Labrousse
C
C
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Gynecology-Obstetrics Department, Hospices Civils de Lyon, Hôtel Dieu, Centre de Référence des Maladies Trophoblastiques, Lyon; Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite.
Schott
A-M
AM
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; EA 4129, Université Lyon 1; Hospices Civils de Lyon, Réseau d'Epidémiologie Clinique International Francophone, Lyon.
Hajri
T
T
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Gynecology-Obstetrics Department, Hospices Civils de Lyon, Hôtel Dieu, Centre de Référence des Maladies Trophoblastiques, Lyon; Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite.
Girard
P
P
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins.
Freyer
G
G
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Medical Oncology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.
Tod
M
M
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins.
Tranchand
B
B
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Centre Anticancéreux Léon Bérard, Lyon.
Colomban
O
O
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins.
Ribba
B
B
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; INRIA Grenoble Rhône-Alpes, Montbonnot, Saint Ismier Cedex.
Raudrant
D
D
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Gynecology-Obstetrics Department, Hospices Civils de Lyon, Hôtel Dieu, Centre de Référence des Maladies Trophoblastiques, Lyon; Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite.
Massardier
J
J
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Gynecology-Obstetrics Department, Hospices Civils de Lyon, Hôtel Dieu, Centre de Référence des Maladies Trophoblastiques, Lyon; Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite.
Chabaud
S
S
Biostatics Department, Unité de Biostatistique et d'évaluation thérapeutique, Centre Anticancereux Léon Bérard, Lyon, France.
Golfier
F
F
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Gynecology-Obstetrics Department, Hospices Civils de Lyon, Hôtel Dieu, Centre de Référence des Maladies Trophoblastiques, Lyon; Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite.
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D006063:Chorionic Gonadotropin / Q000493:pharmacokinetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D031901:Gestational Trophoblastic Disease / Q000188:drug therapy*; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use*; D011247:Pregnancy; D012372:ROC Curve; D012189:Retrospective Studies; D012306:Risk; D016019:Survival Analysis
D000964:Antimetabolites, Antineoplastic; D006063:Chorionic Gonadotropin; D008727:Methotrexate