the Departments of Chemical Endocrinology and Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen
    Amphia Medical Centre, Breda
    the Dutch Working Party on Trophoblastic Tumors, Utrecht, the Netherlands

    ABSTRACT

    PURPOSE: A generally accepted definition for resistance to first-line single-agent chemotherapy for persistent trophoblastic disease (PTD) is lacking. In the present study, a normogram for serum human chorionic gonadotropin (hCG) from patients with normalization of serum hCG after first-line single-agent chemotherapy for PTD was constructed to identify patients resistant to this chemotherapy.

    PATIENTS AND METHODS: Between 1987 and 2004, data from 2,132 patients were registered at the Dutch Central Registry for Hydatidiform Moles. A normal serum hCG regression corridor was constructed for 79 patients with low-risk PTD who were cured by single-agent methotrexate (MTX) chemotherapy (control group). Another group of 29 patients with low-risk PTD needed additional alternative therapies (dactinomycin and multiagent chemotherapy) for failure of serum hCG to normalize with single-agent chemotherapy (study group).

    RESULTS: Serum hCG measurement preceding the fourth and sixth single-agent chemotherapy course proved to have excellent diagnostic accuracy for identifying resistance to single-agent chemotherapy, with an area under the curve (AUC) for receiver operating characteristic curve analysis of 0.949 and 0.975, respectively. At 97.5% specificity, serum hCG measurements after 7 weeks showed 50% sensitivity.

    CONCLUSION: In the largest study to date, we describe the regression of serum hCG levels in patients with low-risk PTD successfully treated with MTX. At high specificity, hCG levels in the first few courses of MTX can identify half the number of patients who are extremely likely to need alternative chemotherapy to cure their disease and for whom further treatment with single-agent chemotherapy will be ineffective.

    INTRODUCTION

    A variety of pathologic types of trophoblast neoplasms are included in gestational trophoblastic disease, comprising villous malformations of trophoblast, hydatidiform mole subdivided in complete and partial hydatidiform mole, and nonvillous malformations of which choriocarcinoma is the most frequent.1 In persistent trophoblastic disease (PTD), trophoblastic activity remains after evacuation of a hydatidiform mole, as shown by subsequent unaltered high or even increasing serum human chorionic gonadotropin (hCG) concentrations. The internationally accepted definition released by the International Federation of Gynecology and Obstetrics (FIGO) defines PTD as a plateau in serum hCG for 3 weeks or an increase for 2 consecutive weeks.2 In the Netherlands, the Dutch Society for Obstetrics and Gynecology added to this definition for PTD the condition that at least one serum hCG measurement should exceed the 95th percentile (P95) of normal hCG regression after hydatidiform mole.3-5

    The reported frequency of PTD is 20% in complete hydatidiform mole6 and 0.5% to 9.9% in partial hydatidiform mole.7-10 For patients with PTD, several staging classifications and prognostic scoring systems have been developed.3 To date, the FIGO 2000 scoring system for high- and low-risk PTD is advocated by The International Society for the Study of Trophoblastic Diseases and the International Society for Gynecological Cancer to generate univocal data.2 This scoring includes serum hCG, age, antecedent pregnancy, interval between end of pregnancy and start of treatment, previous failure of chemotherapy, and the localization and number of metastases.2 The Dutch classification for high- and low-risk PTD takes the same items into account, except for the number of metastases and serum hCG concentration.3, 11

    Once diagnosed and scored, low-risk PTD is typically treated with single-agent chemotherapy (MTX or dactinomycin).12, 13 If staged as high-risk PTD, multiagent chemotherapy with etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMA/CO) is the most widely used therapy.12

    Approximately 9% to 33% of patients treated with single-agent chemotherapy for low-risk PTD will require multiagent chemotherapy because resistance to the first-line drug or toxic adverse effects occurred.14-16 Repeated administration of MTX could induce MTX resistance,17 mainly as a result of downregulation of the expression levels of the reduced folate carrier that is responsible for transport of MTX into the cell or amplification of the gene for dihydrofolate reductase. This enzyme reduces dihydrofolate in tetrahydrofolate, which is essential in DNA synthesis.18, 19 To date, an internationally accepted definition for resistance to first-line chemotherapy is lacking. In some clinics, resistance to first-line chemotherapy is defined as a plateau or increase in serum hCG and/or development of new metastases.14-16, 20, 21

    After single-agent chemotherapy with MTX, no increase in the number of second tumors has been observed.22 In contrast, patients with PTD who are treated with etoposide-containing multiagent chemotherapy have a 50% increased relative risk of developing secondary malignancies, in particular myeloid leukemia, colon carcinoma, and breast cancer, compared with an age-matched group.23 Furthermore, multiagent chemotherapy hastens the occurrence of menopause by 2 years compared with patients treated with single-agent MTX24 and can be accompanied by the occurrence of alopecia and GI symptoms. To identify patients not responding to single-agent chemotherapy in an early stage and, at the same time, to prevent unnecessary multiagent chemotherapy, we constructed a normal serum hCG regression corridor for patients successfully treated with single-agent chemotherapy.

    PATIENTS AND METHODS

    Patients

    Between 1987 and 2004, 2,132 patients were registered at the Dutch Central Registry for Hydatidiform Moles. After informed consent, patients were registered by their referring clinician. The present study included, in retrospect, all low-risk patients with proven PTD according to Dutch guidelines (histologic diagnosis of mola hydatidosa or choriocarcinoma with serum hCG plateau or increase for 3 consecutive weekly measurements, with at least one measurement > P95 of normal regression according to an uneventful hCG regression published earlier4) if serum was available in our registry. In the Netherlands, patients with low-risk PTD are treated with MTX 1 mg/kg on days 1, 3, 5, and 7 and leucovorin 15 mg rescue on days 2, 4, 6, and 8, and this schedule is repeated every 14 days.13 Exclusion criteria were hysterectomy when PTD was diagnosed; cure after a second curettage; need for alternative therapies for MTX toxicity (none in this cohort); persistent low serum hCG levels (2 to 10 μg/L) after spontaneous regression or persistent low serum hCG after MTX treatment, for which no multiagent chemotherapy was administered; and recurrence of PTD after single-agent chemotherapy. Of the 108 eligible patients, serum hCG normalized under single-agent MTX treatment in 79 patients (73%; responders). The remaining 29 patients (27%) were treated with multiagent chemotherapy after the clinician decided that the disease failed to respond to single-agent chemotherapy.

    Immunoassays

    A privately developed (in-house) radioimmunoassay (RIA) that measured total hCG (ie, intact hCG and free beta-subunit [hCG+hCG]) was used exclusively in the authors' laboratory.25 Thus, this assay has been used centrally for all measurements in sera sent to the Dutch Central Registry for Hydatidiform Moles and was used in the development of a normal hCG regression corridor for uneventful hydatidiform mole.4 The RIA was calibrated with the third International Standard (IS) Preparations for intact hCG (WHO third IS hCG 75/537 obtained from the National Institute for Biologic Standards, Potters Bar, England, United Kingdom). The measuring range for the standard line of the assay was 1 to 80 μg/L (0.027 to 2.14 nmol/L, equivalent to 9.29 to 743 U/L of the WHO third IS hCG 75/537).25 The hCG+hCG-RIA cross reacts 100% on a mol/mol basis with intact hCG and 1,000% with hCG. Serum hCG concentrations were considered to be normalized if they were less than 2 μg/L (0.053 nmol/L or 18.6 U/L of the WHO third IS hCG 75/537). The intra- and interassay coefficients of variation for means of duplicate measurements for two serum pools (means: 0.267 nmol/L, or 10 μg/L or 93 U/L, and 1.50 nmol/L, or 56 μg/L or 520 U/L) were 7.3% and 12%, respectively.

    Statistics

    All statistical analyses were performed using the SPSS statistical software package version 12.0.1 (SPSS Inc, Chicago, IL). Normality of distributions was explored by Kolmogorov-Smirnov testing. Differences in numerical data between the control and study groups were tested nonparametrically (Mann-Whitney U test) or parametrically (Student's t test). Within each patient group, serum hCG results (obtained before the start of a new MTX course) were sorted by week from the start of MTX treatment. To approximate normal distributions, serum hCG measurements were log transformed and sorted within each week. The percentiles of 2.5% (P2.5), 50% (P50), and 97.5% (P97.5) and the standard deviation were calculated. In the control group, serum P2.5, P50, and P97.5 were plotted for each week into a normogram. To describe the complete serum hCG response of each patient, we calculated the serum hCG half-life as derived from serum hCG measurements preceding the first single-agent course until the point of normalization (cutoff, 2 μg/L). After 17 weeks (before the ninth MTX course), statistics were censored because of small numbers of patients (12 patients in control group and 11 in study group). The hCG half-life and hCG concentration in a certain week from the start of MTX treatment of the control and study groups were used to construct receiver operating characteristic (ROC) curves and to calculate areas under the curve (AUCs). All tests were considered significantly different at P < .05.

    RESULTS

    Table 1 lists age, prechemotherapy serum hCG, number of courses of single-agent chemotherapy, hCG serum half-life, and, if applicable, number of courses of multiagent chemotherapy in both the control (n = 79) and study (n = 29) groups. No difference was observed between the groups for age (median age, 30 years in both groups). Expectedly, serum hCG concentration before the first course of single-agent chemotherapy was significantly less elevated in the control group compared with the study group (251 v 2,098 μg/L, respectively; P < .001). Significantly fewer courses of single-agent chemotherapy were administered in the control group (median, five courses; range, three to 17 courses) compared with the study group (median, seven courses; range, three to 16 courses; P = .003). As expected, the median serum hCG half-life was significantly shorter in the control group (1.02 weeks; 95% CI, 0.91 to 1.13 weeks) compared with the study group (1.92 weeks; 95% CI, 1.63 to 2.27 weeks; P < .001). The median number of courses of multiagent chemotherapy administered in the study group was four (range, three to seven courses).

    For each single-agent treatment course, the P2.5, P50, and P97.5 of serum hCG concentration in the control group was calculated, and the results were plotted into a normogram (Fig 1A). In the control group, 2.5% of patients were cured after 2 weeks (after one MTX course), and 50% were cured after 8 weeks (after four MTX courses). After 17 weeks, the P97.5 of serum hCG in the control group remained at 4.3 μg/L and, thus, not less than the cutoff level of 2 μg/L. This is because, after 17 weeks, there were still some patients who needed additional MTX courses who were, at that time point, not yet normalized.

    In Figure 1B, the hCG levels of the two weekly intervals for the 29 patients in the study group were plotted into the normogram derived from the serum hCG measurements of the control group. Before the start of the first MTX course, serum hCG in the study group exceeded the P97.5 of the control group in four (13.8%) of 29 patients. After 7 weeks (before the fourth MTX course), serum hCG in the study group exceeded the P97.5 of the control group in 22 (76%) of 29 patients. After 17 weeks (before the ninth MTX course), serum hCG in the study group exceeded the P97.5 of the control group in 25 (86%) of 29 patients. These results are in line with the finding of a significantly shorter median serum hCG half-life in the control group compared with the study group, as stated previously.

    Diagnostic accuracy of serum hCG half-life was derived from the calculation of an AUC of a ROC curve (Fig 3A). In addition, the diagnostic accuracies of serum hCG levels before the first (Fig 3B), fourth (Fig 3C), and sixth (Fig 3D) first-line single-agent chemotherapy course were established by the calculation of the AUCs of these ROC curves. The corresponding AUCs for these ROC curves are listed in Table 2. The AUC for serum hCG half-life throughout single-agent treatment was 0.833. The AUC of the serum hCG concentration preceding the first-single chemotherapy course was 0.828, which increased to 0.975 preceding the sixth course (after 11 weeks) of single-agent chemotherapy. This means that, at that time point, an excellent diagnostic accuracy was obtained because, after 11 weeks, 60% of the patients needing alternative therapy could be identified at the 97.5% specificity level.

    Using serum hCG before the start of single-agent chemotherapy as a diagnostic tool to identify patients who will need alternative chemotherapeutic treatment for PTD resulted in the identification of 14% of patients who needed alternative therapy at the 97.5% specificity level (hCG serum cutoff, 9,600 μg/L). Serum hCG levels obtained before the start of the fourth course of therapy to predict the need for alternative therapy would identify as much as 50% of patients at the 97.5% specificity level (cutoff, 56 μg/L; Table 2).

    DISCUSSION

    The objective of this study was to clarify whether it is possible to identify, at an early stage and from a single hCG measurement, patients with PTD who will not be cured by single-agent chemotherapy. For this reason, we established a serum hCG normogram with data from 79 patients with low-risk PTD who were cured by single-agent MTX chemotherapy. This normogram was applied to hCG measurements from 29 PTD patients who needed alternative therapy after single-agent chemotherapy failed to establish normalization of serum hCG. Using this normogram, we found that it is possible to identify 14% of patients who will need alternative therapy before the start of first-line single-agent chemotherapy with 97.5% specificity. Likewise, on the basis of serum hCG measurements obtained just before the fourth MTX course, we were able to identify 50% of patients who would not respond to single-agent chemotherapy at 97.5% specificity.

    The international criteria used to diagnose PTD include an abnormal serum hCG regression, with a plateau for 3 weeks or an increase for 2 weeks.2 Normal serum hCG regression corridors for uneventful hydatidiform moles have been constructed, with 50% of patients having normalized serum hCG measurements between 6 and 14 weeks after evacuation.4, 20, 21, 26, 27 The Dutch Society for Obstetrics and Gynecology included the extra condition in the diagnosis for PTD that, in addition to a serum hCG plateau or increase for 3 consecutive weeks, at least one serum hCG measurement should exceed the P95 of normal hCG regression, as derived from an hCG normogram constructed from data of 130 patients with uneventful hydatidiform mole.4 There are two reasons for the inclusion of this additional condition. First, PTD, as defined by exceeding the P95 of normal regression, is diagnosed 2 weeks earlier than if the definition for PTD of an hCG plateau or increase for 3 consecutive measurements is used.21, 27 Second, use of a normal hCG regression corridor prevents overtreatment. One study indicated that 15% of patients with a plateau or increase for 3 weeks but without a serum hCG measurement exceeding the P95 will have spontaneous serum hCG remission afterwards.4 Two retrospective studies showed that, in patients treated for PTD on the basis of a plateau or increase in serum hCG for 3 consecutive weeks, 29% had serum hCG measurements less than the P90 of normal regression20 8% had measurements less than the P95 of normal regression.4

    Although firm criteria for the diagnosis of PTD exist and the use of a normogram for normal serum hCG regression identifies patients with PTD earlier and prevents overtreatment, no firm criteria for the diagnosis of resistance to first-line single-agent therapy exist. A generally accepted definition for resistance to first-line chemotherapy is lacking, although some clinics define resistance to chemotherapy by a plateau or increase in serum hCG or by detection of (new) metastases.14, 15, 20, 21

    Rotmensch et al20 described the only normogram for normalization of hCG in 21 patients with nonmetastatic trophoblastic disease treated with MTX. They reported that the median time for serum hCG to normalize in successfully treated patients with PTD is 50 days. The authors stated that, in successfully treated patients with low-risk PTD, the median time to normalization is comparable to patients with uncomplicated regression of serum hCG after hydatidiform mole (50 days). Our results are in line with their results because we found that serum hCG normalizes in 50% of patients after five 2-week courses of MTX. Our group previously developed a normogram for serum hCG regression after uneventful hydatidiform mole.4 In that study, median time for normalization was 11 weeks, which is comparable to the five 2-week courses that 50% of patients needed for normalization of hCG after successful single-agent chemotherapy.

    Serum hCG in two patients in the study by Rotmensch et al20 failed to normalize after primary chemotherapy. Serum hCG of these two patients was greater than the P90 of the normal regression with MTX at the start of the MTX treatment. These investigators did not explore the diagnostic accuracy of serum hCG levels to detect resistance to single-agent chemotherapy in low-risk PTD. Shigematsu et al,21 in their study comprising 24 patients with PTD, indicated that woman who would show resistance to single-agent chemotherapy later on (as concluded from increasing hCG for 2 weeks, a plateau for 3 weeks, or the development of new metastases) exceeded the P95 of normal hCG regression significantly earlier than patients who would respond well to single-agent chemotherapy.

    With the presented serum hCG regression corridor for patients treated with first-line single-agent MTX, we have an excellent diagnostic tool to identify patients with resistance to first-line single-agent chemotherapy at an early stage with great certainty. Before the fourth course of single-agent chemotherapy (after 7 weeks), serum hCG identifies 50% of patients needing alternative therapy at the 97.5% specificity level.

    The birthrate in the Netherlands is approximately 200,000 persons per year. With an estimated incidence of hydatidiform mole of 1 per 1,000 to 2,000 pregnancies,28 the 18-year period of our study could yield 1,800 to 3,600 patients with hydatidiform mole, of whom we would expect 180 to 360 to have PTD. Registration with the Dutch Central Registry for Hydatidiform Moles is on a voluntary basis, and we registered 2,132 patients with hydatidiform mole throughout the entire study period, of whom 108 patients with PTD were eligible for inclusion in our study. Because of the low incidence of PTD and, in particular, the need for alternative therapy, it is not feasible to perform a prospective study, and we used our retrospective data for a proposal for a new treatment regimen for patients with PTD.

    In analogy with the regression curve for serum hCG after evacuation of uneventful hydatidiform mole as earlier published by our group,4 we developed a curve for the early detection of resistance to first-line single-agent MTX chemotherapy. Because overtreatment with multiagent chemotherapy is highly undesirable, we increased the cutoff from P95 to P97.5 for normal regression of patients successfully treated with first-line single-agent chemotherapy. If before the fourth course of single-agent chemotherapy the serum hCG concentration exceeds the P97.5 of this normal regression curve, it can be concluded with 50% sensitivity that a change of treatment is mandatory to gain cure (Fig 2, lightly hatched area). In line with the internationally accepted criteria for treatment of PTD, the course of hCG (plateau or increase) should also be included in the decision to start alternative therapy. The choice of second-line chemotherapy could be multiagent chemotherapy with EMA/CO. In the United Kingdom, McNeish et al15 described a successful regimen in which patients with resistance to MTX-leucovorin were administered either dactinomycin if serum hCG was less than 100 U/L or EMA/CO if serum hCG exceeded 100 U/L. In this study, 58 of 67 patients treated secondarily with dactinomycin were cured by this drug.

    In conclusion, in the largest study to date, we describe the regression of serum hCG levels in patients with low-risk PTD treated with MTX. From these data, it can be concluded that serum hCG levels before the fourth course of MTX can identify half the number of patients who are highly likely to need alternative therapy to cure their disease and for whom further treatment with single-agent chemotherapy will be ineffective.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Nienke E. van Trommel, Chris M. Thomas

    Administrative support: Charles P. Schijf, Marianne J. ten Kate-Booij, Chris M. Thomas

    Provision of study materials or patients: Charles P. Schijf, Marianne J. ten Kate-Booij, Chris M. Thomas

    Collection and assembly of data: Charles P. Schijf, Marianne J. ten Kate-Booij, Chris M. Thomas

    Data analysis and interpretation: Nienke E. van Trommel, Leon F. Massuger, Fred C. Sweep, Chris M. Thomas

    Manuscript writing: Nienke E. van Trommel, Leon F. Massuger, Fred C. Sweep, Chris M. Thomas

    Final approval of mauscript: Nienke E. van Trommel, Leon F. Massuger, Charles P. Schijf, Marianne J. ten Kate-Booij, Fred C. Sweep, Chris M. Thomas

    Acknowledgment

    We thank Dr Paul N. Span for his expert advice.

    NOTES

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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