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 (CLhCG) and assessed the predictive value of CLhCG for MTX resistance. Patients and methods: A total of 154 patients with low-risk GTN treated with 8-day MTX regimen were retrospectively studied. NONMEM (TM) was used to model hCG decrease equations between day 0 and day 40 of chemotherapy. Receiver operating characteristic curve analysis defined the best CLhCG threshold. Univariate/multivariate survival analyses determined the predictive value of CLhCG 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 C-LhCG 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 CLhCG quartile (<= 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. Conclusion: In the second largest cohort of low-risk GTN patients reported to date, choriocarcinoma pathology and CLhCG <= 0.37 l/day were major independent predictive factors for MTX resistance risk.