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.
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.
B
B
You
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.
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M
Pollet-Villard
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins.
L
L
Fronton
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.
C
C
Labrousse
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.
A-M
AM
Schott
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.
T
T
Hajri
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins.
P
P
Girard
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.
G
G
Freyer
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins.
M
M
Tod
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; Centre Anticancéreux Léon Bérard, Lyon.
B
B
Tranchand
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins.
O
O
Colomban
EA 3738, Université de Lyon, Lyon; Université Lyon 1, Faculté de Médecine Lyon Sud, Oullins; INRIA Grenoble Rhône-Alpes, Montbonnot, Saint Ismier Cedex.
B
B
Ribba
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.
D
D
Raudrant
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.
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J
Massardier
Biostatics Department, Unité de Biostatistique et d'évaluation thérapeutique, Centre Anticancereux Léon Bérard, Lyon, France.
S
S
Chabaud
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.
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F
Golfier
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