External validation of serum hCG cutoff levels for prediction of resistance to single-agent chemotherapy in patients with persistent trophoblastic disease

Abstract

Van Trommel et al have previously shown that serum human chorionic gonadotropin (hCG) cutoff levels can provide early prediction of resistance to first-line methotrexate (MTX) in patients with persistent trophoblastic disease (PTD). In this study, we validate this approach of prediction of resistance to single-agent chemotherapy in an independent and larger cohort of PTD patients using a different hCG assay. Receiver operating characteristics (ROC) curves were constructed to determine hCG cutoff levels and sensitivity between patients cured on single-agent chemotherapy (control group) and patients requiring change to combination chemotherapy (study group). Receiver operating characteristics analysis identified an hCG cutoff value of 737 IU l À1 that enabled us to predict the subsequent development of single-agent chemotherapy resistance in 52% of patients before their fourth MTX course at 97.5% specificity. This would have enabled an earlier switch to combination chemotherapy reducing the MTX exposure by an average of 2.5 courses. The present findings confirm that serum hCG cutoff levels predict resistance to single-agent therapy earlier than traditional methods. Change to combination chemotherapy should be considered for patients whose serum hCG levels exceed these hCG cutoff values. For patients not exceeding the hCG cutoff levels, static or rising hCG levels should still be included in the criteria for change of chemotherapy.

Early prediction of treatment resistance in low-risk gestational trophoblastic neoplasia using population kinetic modelling of hCG measurements

“…The only significant independent predictors of MTX failure-free survival were as follows: high-modelled individual hCGres categorised by >20.44 threshold (HR=14.51, 95% CI=9.78–21.09); high hCG titre at week 1 categorised by >2000 IU l −1 cut-off value defined by Growdon et al (2009a; HR=0.62, 95% CI=0.45–0.83) and high hCG at week 7 categorised by >737 IU l −1 threshold defined by Kerkmeijer et al (2009; HR=2.19, 95% CI=1.65–2.90).…”

“…Using a binomial logistic regression model, including the WHO–FIGO score (HR=1.17, 95% CI=0.99–1.38), choriocarcinoma (yes vs. no, HR=1.02, 95% CI=0.36–2.87), high hCG titre at week 1 categorised by >2000 IU l −1 cut-off value defined by Growdon et al (2009a; HR=1, 95% CI=1–1), high hCG at week 7 categorised by >737 IU l −1 threshold defined by Kerkmeijer et al (2009; HR=1, 95% CI=1–1.01) and hCGres, the only significant independent predictive factor of MTX resistance was hCGres (HR=1.009, 95% CI=1.007–1.011, P <0.0001).…”

“…Other previously reported predictive factors for chemoresistance considered in the comparative analysis were: WHO–FIGO score (classified between 0 and 6); choriocarcinoma (yes vs no; You et al , 2010); hCG level measured 1 week after treatment start, categorised according to Growdon et al (2009b) cut-offvalue >2000 IU l −1 (Growdan et al , 2009b) or hCG level in the seventh week, categorised according to different thresholds, ⩽520.24 vs >520.24 IU l −1 (van Trommel et al , 2006); ⩽500 vs >500 IU l −1 (Savage et al , 2008); and ⩽737 vs >737 IU l −1 (Kerkmeijer et al , 2009). …”

“…Patients diagnosed with low-risk gestational trophoblastic neoplasias (GTN), comprising ∼95% of malignant GTD forms (including invasive mole, choriocarcinoma, epitheliod trophoblastic and placental site trophoblastic tumours) have International Federation of Gynecology and Obstetrics (FIGO) 2000 risk scores ranging from 0 to 6 and are treated using single-agent chemotherapy (Kohorn, 2001; Chalouhi et al , 2009). The 8-day methotrexate (MTX) protocol modified by Bagshawe et al , 1989 is the most commonly used regimen in Europe (Savage et al , 2008; Chalouhi et al , 2009; Kerkmeijer et al , 2009). MTX treatment is continued until either normalisation of serum hCG concentration and further three cycles or resistance to MTX therapy is detected (Seckl et al , 2010).…”

“…Several previous studies have attempted to develop new methods to enable earlier identification of patients that will develop MTX resistance (van Trommel et al , 2006; Savage et al , 2008; Kerkmeijer et al , 2009; Growdon et al , 2009a). Among these, a previous study led by the French reference centre for treatment of GTN (Centre de Référence des Maladies Trophoblastiques, Lyon, France), showed that mathematical modelling of individual declining hCG measurements using a population kinetic approach is feasible, and that derived parameters were strong early predictors of MTX resistance (You et al , 2010).…”