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.

Conclusion: hCGres, a modelled kinetic parameter calculated after fully dosed three MTX cycles, has a reproducible value for identifying patients with MTX resistance.

Figure 1

Flowchart of analysed patients in the three-time strategy. *WHO–FIGO score (classified between 0 and 6); choriocarcinoma (yes vs no); hCG level measured 1 week after treatment start; hCG level in the seventh week.

Figure 2

Internal qualification of the model in Model data set patients (n=418 patients). (A) Observed vs individual predicted hCG titres (blue circles), identity line (black line), smooth line of the cloud of points (red line). (B) Visual predictive checks of hCG concentrations. The observations are symbolised by the blue circles, and the median, 5% and 95% of observations are represented by red lines. Blue areas represent the 95% prediction interval for the median, 5% and 95%, computed from1000 simulated replicates. A full colour version of this figure is available at the British Journal of Cancer journal online.

Figure 3

Examples of four typical patients of Model data set. The blue dots are the observed hCG values while the green line represents the individual predicted values. Resistances to MTX are specified. A full colour version of this figure is available at the British Journal of Cancer journal online.

Figure 4

Predictive value of modelled kinetic parameters. (A) Predictions of MTX resistance offered by two modelled kinetic parameters K (AUC=0.69, 95% CI=0.64–0.74) and hCGres (AUC=0.94, 95% CI=0.91–0.96). (B) Predictive values of hCGres (>20.44 IU l⁻¹: AUC=0.86, 95% CI=0.83–0.89) against previously reported predictors: hCG values on week 7 (>737 IU l⁻¹: AUC=0.66; 95% CI=0.62–0.70; >520.24 IU l⁻¹: AUC=0.69, 95% CI=0.65–0.74; >500 IU l⁻¹: AUC=0.70, 95% CI=0.65–0.74) and the WHO–FIGO score (AUC=0.66, 95% CI=0.62–0.70). (C) Predictive value of modelled hCGres categorised by 20.44 cut-off value regarding MTX failure-free survival. Three-year MTX failure-free survival=89.7% vs 21.8%, hCGres <0.0001.