INTRODUCTION — Gestational trophoblastic disease (GTD) defines a group of conditions that arise from an aberrant fertilization event. When GTD recurs or there is evidence of metastatic disease, it is called gestational trophoblastic neoplasia (GTN) and comprises four subtypes of disease:
●Invasive mole
●Choriocarcinoma
●Placental site trophoblastic tumor (PSTT)
●Epithelioid trophoblastic tumor (ETT)
The initial treatment of low-risk GTN is discussed here. The pathology of GTN, epidemiology, clinical manifestations, and staging of GTN are discussed separately. In addition, the management of high-risk and recurrent GTN are also discussed separately.
●(See "Gestational trophoblastic disease: Pathology".)
●(See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)
●(See "Hydatidiform mole: Treatment and follow-up".)
●(See "Initial management of high-risk gestational trophoblastic neoplasia".)
DEFINITION OF LOW-RISK DISEASE — The risk for disease progression and resistance to single-agent chemotherapy for patients with GTN is defined by the International Federation of Gynecology and Obstetrics (FIGO) staging and the World Health Organization (WHO) risk scoring systems (table 1). Low-risk disease is characterized by any one of the following:
●FIGO stage I GTN – This is characterized as a persistently elevated human chorionic gonadotropin (hCG) level and/or tumor confined to the uterus.
●Stage II or III GTN with a WHO risk score <7.
Further discussion of high-risk GTN is covered separately. (See "Initial management of high-risk gestational trophoblastic neoplasia", section on 'Definition of high-risk disease'.)
APPROACH TO TREATMENT
Overview — Most patients with low-risk GTN are cured with single-agent chemotherapy, using either methotrexate (MTX) or dactinomycin (ActD) [1]. National and international guidelines from the National Comprehensive Cancer Network (NCCN) and International Federation of Gynecology and Obstetrics (FIGO) support this approach [2,3]. Because of the overall excellent prognosis, immediate treatment with multiagent regimens is generally not necessary, and, in our experience, single-agent chemotherapy is most often utilized with success. However, select patients with FIGO 5 or 6 require combination chemotherapy.
Data support combination chemotherapy in several instances in patients with FIGO score 5/6 [4]:
●No metastases and no histopathologic choriocarcinoma, but hCG >410,000
●Either metastases or histopathologic choriocarcinoma, and hCG >150,000
●Metastatic choriocarcinoma
In a multicenter retrospective, cohort study regarding predictors of single-agent resistance (>80 percent risk) in patients with FIGO score 5 or 6 GTN, about 60 percent of patients with GTN and FIGO score of 5 or 6 achieved remission with either first-line or second-line single agents. Almost all patients without metastases or choriocarcinoma (CCA) attained remission with single agents, but 4 percent of these patients with hCG >410,000 IU/L required primary combination chemotherapy. Among patients with either metastasis or CCA, with hCG >150,000 IU/L (14 percent of group), primary combination chemotherapy was required to attain remission, and all patients with metastatic CCA required primary combination chemotherapy.
In a separate report, the remission with primary first-line single-agent chemotherapy in GTN with 5 or 6 FIGO score was only 31 to 35 percent [5].
Patients with low-risk GTN have an overall excellent prognosis with survival rates approaching 100 percent after treatment, although this may require additional treatments (including the use of combination chemotherapy regimens if they become resistant to single-agent therapy) [6-8]. The principle of sequential therapy utilizes one single agent initially, then an alternate single agent if resistance to the first drug develops (as determined by a plateau or re-elevation of the human chorionic gonadotropin [hCG] level) during treatment.
The potential role of a second dilation and curettage (D&C) in lieu of chemotherapy has been evaluated in several studies, but the results are conflicting. This is discussed in detail elsewhere. (See 'Persistent uterine bleeding' below.)
Of note, because placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) are relatively resistant to chemotherapy, patients with nonmetastatic PSTT and ETT are generally treated with hysterectomy. Although there are case reports of selected patients treated successfully with local resection and preservation of fertility, hysterectomy remains the optimal treatment in most cases. (See "Initial management of high-risk gestational trophoblastic neoplasia", section on 'Placental site or epithelioid trophoblastic tumor' and 'Patients with PSTT or ETT or who do not desire fertility preservation' below.)
Methotrexate — Of the available agents, we administer MTX initially because it is effective, well tolerated, convenient for the patient, and cost effective [9-16]. MTX has been administered in a variety of schedules with or without folinic acid (FA), which is used to protect from MTX-related toxicity. (See "Major side effects of low-dose methotrexate".)
Of the regimens studied, in our practice, we administer MTX-FA as an eight-day regimen rather than other schedules because it is both effective and associated with minimal toxicities for the patient. This is based on our experience with MTX-FA in patients with low-risk GTN and the following results:
●In one study of 185 patients, complete remission was achieved in 88 percent of patients, which includes 90 percent of patients with stage I disease and 68 percent of patients with stages II to III low-risk GTN [10]. In a subsequent report, among 68 patients with low-risk GTN and resistance to MTX, 72 percent achieved remission with ActD, and the remainder were all cured with multiagent chemotherapy or surgery [17].
●After three consecutive weeks of nondetectable hCG values, only two (1.2 percent) patients with nonmetastatic disease developed tumor recurrence. Resistance was more common in patients with choriocarcinoma, metastases, and pretreatment hCG levels of >50,000 mIU/mL. In a separate report, postmolar choriocarcinoma was an independent risk factor for chemotherapy resistance in low-risk GTN [18].
●We investigated the potential influence of being overweight or obese on the clinical presentation and response to chemotherapy in low-risk GTN [19]. The presence of overweightness or obesity did not affect the response to chemotherapy in low-risk GTN [19].
In a separate study that included 250 patients, this regimen was associated with mild toxicity, and there were no cases of alopecia reported [20]. Other findings of this study included that:
●Nausea occurred in less than 15 percent of all treatment cycles, with vomiting seen in less than 5 percent.
●One-fourth of all patients developed grade 1 or 2 mucositis.
●One-fourth of these patients developed grade 1 or 2 conjunctivitis.
●Hematologic toxicity was mild and infrequent, with grade 3 or 4 neutropenia or thrombocytopenia occurring in less than 1 percent of treatment cycles.
Dosing — There is no universal consensus on the optimal dosing regimen for MTX. However, at our institution, we prefer the MTX-FA eight-day regimen for the primary therapy of low-risk GTN. In this regimen, MTX is dosed 1 mg/kg as an intramuscular (IM) or intravenous (IV) injection and administered on days 1, 3, 5, and 7. FA is administered 24 hours after each dose of MTX to protect normal cells from potential treatment-related toxicity as a result of inhibition of folate metabolism induced by MTX. The ideal FA dosing has not been established but it is critical that the dose is adequate to minimize toxicity but not too great to interfere with its effectiveness. al One study compared toxicity and outcome of eight-day MTX with FA rescue using either a fixed 15 mg FA dose or weight-based dosing of 0.1 mg/kg [21]. The fixed 15 mg FA dose had a similar primary remission rate, fewer treatment delays due to toxicity, and greater ease of administration and may therefore be preferable with the eight-day MTX regimen in the treatment of low-risk GTN. (See 'Is there an optimal regimen?' below.)
Other regimens that utilize MTX are often administered to this population. Given the lack of high-quality data comparing the different schedules for MTX administration, these are also reasonable options:
●MTX five-day regimen – The administration of MTX, 0.3 to 0.5 mg/kg, IM or IV, for five consecutive days every two weeks was originally described in 1956 [22-24] and is the regimen of choice at the Brewer Trophoblastic Disease Center in Chicago (USA) [25]. Other data emphasize that maintaining dose intensity is important to the efficacy of this regimen [26].
●Weekly MTX – Weekly IM injection of MTX at a dose of 30 to 50 mg/m2 has become a widely used regimen in the United States [27,28]. Treatment is repeated until the serum hCG level becomes undetectable (<5 mIU/mL), after which consolidation therapy is recommended. This regimen was originally introduced under the auspices of the Gynecologic Oncology Group (GOG) as the most cost-effective among alternative regimens when efficiency, toxicity, and cost were taken into consideration. The main disadvantage of this regimen is the length of time it takes to achieve remission, which in some cases has taken up to 15 to 20 weekly treatments, particularly when used to treat patients with low-risk metastatic disease.
●High-dose MTX – High-dose infusion of MTX, 100 mg/m2 IV push followed by a 12-hour continuous infusion at 200 mg/m2, has also been used as initial therapy for patients with low-risk GTN [12,29]. FA (15 mg dose) is administered orally beginning 24 hours after the start of the initial MTX dose and continued every 12 hours for six doses. Although this regimen is associated with a lower complete remission rate of 69 percent in patients with low-risk disease, it offers some advantages in terms of its shorter duration of treatment, which is particularly important for those patients who reside a long distance from the treating institution.
Is there an optimal regimen? — There are no high-quality data to establish a universally applied standard regimen. However, the available data suggest that MTX administered on a five- or eight-day schedule is more effective than either the weekly IM or intermittent infusional IV infusion regimens [12,30].
Two retrospective case studies compared five-day MTX and eight-day MTX-FA protocols in patients with low-risk GTN, and one found no difference in remission rates of approximately 76 percent [13]. Another study reported an only 72 percent remission rate in patients treated with MTX-FA as compared with a 92 percent remission rate in patients receiving MTX alone [31]. One common criticism of the eight-day schedule is the need for dosing on the weekend, and a modified schedule may be an option for some patients. In a retrospective study of over 600 patients with low-risk GTN, patients receiving the standard eight-day protocol compared with a modified schedule (ie, MTX administered on day 8 rather than day 7 to avoid Sunday administration) had similar oncologic outcomes [32].
Dactinomycin — We will generally administer ActD to patients who do not achieve remission to MTX [6,7]; it is noted that these agents have been used in this sequence since 1965 [33-35]. Although some data support the administration of ActD in the initial treatment setting, it is more often used as second-line therapy in patients with MTX resistance, or when there are contraindications to the use of MTX due to the increased toxicity associated with ActD, particularly hyperemesis, alopecia, and the risk of local tissue injury if extravasation occurs.
Because of the issues associated with toxicity, ActD administered in "pulsed" dosing is generally used (1.25 mg/m2 IV every 14 days), although it can also be administered as an IV push (10 to 12 mcg/kg daily for five days every other week) [36-40]. The primary remission rate for patients with nonmetastatic postmolar GTN is 78 and 88 percent for the pulsed and five-day regimens, respectively [41].
Methotrexate versus dactinomycin — While we prefer MTX as initial therapy, there is no consensus regarding what should be the favored primary single-agent regimen in low-risk GTN. A number of different regimens utilizing MTX and ActD appear to have excellent activity (table 2).
Multiple trials have compared MTX and ActD regimens for treatment of low-risk, nonmetastatic GTN, including several randomized studies [42-45]. A 2016 meta-analysis that included seven randomized controlled trials concluded that ActD was associated with higher cure rates than MTX (relative risk [RR] 0.65, 95% CI 0.57-0.95), but possibly also with increased severe adverse events [46]. However, there was substantial heterogeneity in this analysis due to the various schedules of MTX (as a weekly injection, five-day injection, and the eight-day schedule) and ActD (pulsed IV every 14 days and the five-day IV dosing) included, and the number of patients included in the analysis was relatively small (n = 667). Therefore, we are not confident in the conclusiveness of this meta-analysis. One of the studies included in the meta-analysis, with 62 patients with low-risk gestational trophoblastic disease, suggested similar complete remission rates between MTX and ActD (78 and 80 percent, respectively, a difference that was not statistically significant). Additionally, frequency of adverse effects was similar between the two agents [44].
Both MTX and ActD are associated with hematologic toxicity, requiring that hematologic indices be carefully monitored during therapy. In addition, both agents are excreted by the kidney and as such, patients should have normal renal function confirmed prior to each treatment. MTX is hepatotoxic, however, so in the presence of abnormal liver function tests, ActD should be used preferentially.
Other agents
●Etoposide – Single-agent etoposide (VP-16) is an acceptable option for primary therapy for low-risk disease [47-49]. Single-agent etoposide at a dose of 100 mg/m2, IV, daily for five days every 10 days has also been used as another effective monotherapy regimen for patients who progress despite MTX treatment [50].
Although it appears to be highly effective, its use was limited by concerns regarding the risk of secondary malignancy. Studies conducted with the Charing Cross Hospital had reported that patients receiving more than 2000 mg/m2 have an RR of 16.6 for leukemia, 5.8 for breast cancer, 4.6 for colon cancer, and 3.4 for melanoma [51]. However, an update of data from Charing Cross Hospital based on 30,638 patient-years of follow-up indicates that this may not be the case; following treatment with etoposide, the RR for a second tumor was 0.9 [52].
Whether the concern for a secondary malignancy is justified is not necessarily clear, especially since the cumulative dose of 2000 mg/m2 is rarely required [53].
●Fluorouracil – Fluorouracil at a dose of 30 mg/kg daily for 10 days every 28 days has been the preferred single-agent regimen for low-risk GTN in China, with complete remission rates of 93 and 86 percent of patients with stage I or II disease, respectively [54]. Toxicity is reported to be mild [54-56]. It has also been used in the United States as part of combination chemotherapy for the management of high-risk disease [57].
●Carboplatin – Carboplatin has been suggested as an alternative to ActD for second-line chemotherapy after MTX. In one small study, 17 of 21 patients (81 percent) receiving second-line carboplatin achieved remission, with generally mild side effects [58]. However, in a subsequent study, remission occurred in only 11 of 23 patients (48 percent) receiving second-line carboplatin, with higher rates of lymphopenia and vomiting compared with ActD [59].
Consolidation therapy — After complete remission is attained, consolidation therapy should be administered to prevent relapse. This generally consists of three courses of the last effective regimen.
There are few data to inform the optimal number of cycles that should be administered in this setting. However, data from the Netherlands and United Kingdom comparing two versus three consolidation cycles of MTX-FA reported that patients treated with two courses had a higher relapse rate than those treated with three [60]. (See 'Defining remission' below.)
MONITORING DURING TREATMENT — All patients with GTN should be monitored with serial measurements of serum human chorionic gonadotropin (hCG) at the start of treatment and then at weekly intervals during therapy.
Defining remission — A disease remission requires three consecutive weekly normal hCG values (less than 5 mIU/mL). Treatment should then be continued for three consecutive courses of the last effective regimen to reduce the risk of relapse. (See 'Consolidation therapy' above.)
Persistent or progressive disease — Persistent or progressive GTN (or chemotherapy resistance) is defined as an increase or a plateau in two consecutive hCG values over a two-week interval [61]. Other generally accepted criteria include detection of new metastases [9].
The approximate biologic half-life of hCG is 1.5 to 3 days, and serum levels should fall exponentially (by at least one log within 18 days). A slower rate of decline suggests the possibility of chemoresistance, although there is no consensus or clear guideline as to the optimal cutoff for determining chemoresistance or the management of patients with a slower than expected tumor marker decline [62-64].
POSTTREATMENT SURVEILLANCE — After remission is achieved, serum human chorionic gonadotropin (hCG) should be measured monthly in asymptomatic patients until one year of normal hCG levels has been documented, in agreement with International Federation of Gynecology and Obstetrics (FIGO) guidelines [65-67]. However, if following completion of one year of hCG surveillance the patient develops new symptoms, such as abnormal bleeding, then recurrence should be considered, and an hCG value should be obtained.
This approach is supported by a large series showing the low risk of recurrence beyond this time period. In a population-based cohort study from the United Kingdom including 154 recurrences among patients with low-risk GTN, 73 percent of recurrences occurred within one year after treatment cessation, 85 percent occurred within two years, and 96 percent occurred within three years [68]. The risk of recurrence in years 2, 3, 4 to 7, and beyond year 7 was 1/179, 1/199, 1/560, and 0, respectively.
Although the authors of the study suggest monitoring for 10 years instead of the lifelong surveillance suggested by United Kingdom guidelines, we do not agree because of limitations of these data. For example, a rise in hCG was considered a recurrence but could have represented an unrecognized intercurrent gestation as many patients beyond a year of normal hCG values are likely attempting to conceive and 1.5 percent will have another molar pregnancy [69]. In addition, the relapse risk was not stratified according to type of chemotherapy, which changed over the time period of the study (1958 to 2015), and positive hCGs due to pituitary hCG were not identified. Furthermore, it is unclear how many patients with recurrence were symptomatic, which would have been detected with an hCG measurement at the time of evaluation for bleeding or other symptoms [70].
FERTILITY AND PREGNANCY — Given that GTN affects patients in their reproductive years, it is important that issues related to fertility and pregnancy be part of the subsequent management of patients after treatment has completed.
Contraception — Following successful treatment, all patients should be monitored using serial human chorionic gonadotropin (hCG) for at least 12 months [65,66]. A new pregnancy during this period would make it difficult or impossible to interpret hCG results and would complicate management. Therefore, it is essential that patients use contraception for the entire duration of surveillance.
Estrogen-progestin contraceptives are preferred because of their low failure rate and relatively low incidence of irregular bleeding, since this symptom may raise concern about recurrence. Two randomized trials found no increase in the risk of GTN in patients who used estrogen-progestin pills following a molar pregnancy [71]. There is also no evidence that the use of oral contraceptives influences the course of GTN [72]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)
Barrier methods may be used, but have less contraceptive efficacy. In addition, in our practice, we advise against use of intrauterine devices because there is a risk of uterine perforation with intrauterine contraceptive devices, particularly in patients in whom there is uterine invasion.
Subsequent pregnancy — Patients who achieve a sustained remission after treatment for low-risk GTN can expect normal reproductive function, and we advise that patients may attempt to achieve pregnancy after 12 or more months of normal hCG levels [69,73-75].
In a review from the New England Trophoblastic Disease Center (NETDC) between July 1965 and December 2013 of 667 pregnancies in patients who subsequently became pregnant after treatment for GTN, pregnancy outcomes were as follows (table 3) [69]:
●Live term births (66.9 percent)
●Spontaneous abortions (18.3 percent)
●Premature deliveries (6.6 percent)
●Therapeutic abortions (4.2 percent)
●Stillbirths (1.5 percent)
●Repeat molar pregnancies (1.5 percent)
●Ectopic pregnancies (1 percent)
Importantly, the use of chemotherapy for low-risk GTN does not appear to be associated with an increase in congenital malformations [69,73,75-83]. In the experience of the NETDC reported above, congenital anomalies (major and minor) were detected in only 12 of 500 births (1.4 percent); these values are comparable with the general gestational population.
For patients with a prior history of GTN, following completion of a pregnancy, we advise that all patients have an hCG level measured at the six-week postpartum (or postabortal) check-up to ensure complete remission and the absence of occult GTN. The placenta should be examined carefully and sent for evaluation by a pathologist if any abnormality is suspected.
Pregnancy before completion of follow-up — Patients occasionally become pregnant before their follow-up has been completed, despite advice to use contraception.
Early pregnancy after treatment for GTN can delay diagnosis of disease recurrence, as most recurrences occur between three and six months after completing treatment [84,85]. When this occurs and the pregnancy is desired, we monitor the developing fetus and placenta with sonograms at 6 and 10 weeks of gestation. If the 10-week sonogram appears normal, there is little likelihood of recurrence [86]. Furthermore, pregnancies occurring before hCG follow-up is complete appear to have no increased risk of abnormalities [87].
PSYCHOSOCIAL ISSUES — Patients who develop GTN may experience significant mood disturbance, marital and sexual problems, and concerns over future fertility. Because GTN is a consequence of pregnancy, patients and their partners must confront the loss of a pregnancy at the same time they face concerns regarding malignancy. Patients can experience clinically significant levels of anxiety, fatigue, anger, confusion, sexual problems, and concern for future pregnancy that last for protracted periods of time. Patients with metastatic disease are particularly at risk for psychological disturbances and need assessments and interventions both during treatment and after remission is attained [88-90].
SPECIAL SCENARIOS — While most patients with low-risk GTN will be cured with single-agent chemotherapy, there are a few scenarios where chemotherapy may not be necessary. These are reviewed below.
Persistent elevated hCG levels (quiescent GTN) — Some patients with a history of GTN or nonmolar pregnancy have a consistently low level of human chorionic gonadotropin (hCG; <200 mIU/mL) with low levels of hyperglycosylated hCG without detectable disease. This condition is often referred to as quiescent GTN and is discussed in detail separately. (See "Hydatidiform mole: Treatment and follow-up", section on 'Plateaued hCG levels'.)
Persistent uterine bleeding — While a dilation and curettage (D&C) is initially performed for diagnosis of a molar pregnancy, performing a second D&C may be indicated for management of persistent uterine bleeding. In our practice, we typically limit performance of a repeat D&C for management of persistent uterine bleeding to when there is transvaginal ultrasound evidence of residual molar tissue [91].
Although some data suggest that a second D&C may reduce the need for subsequent chemotherapy among a subset of patients with stage I GTN (table 1), data are conflicting, and this is not our standard practice. In one randomized trial of 62 patients with low-risk postmolar GTN managed with either a second D&C or weekly low-dose intramuscular methotrexate (MTX; 50 mg/m2), 50 percent (13 of 26) of patients managed with a second D&C were able to avoid chemotherapy, and the time to hCG normalization was six weeks faster among those receiving a second D&C compared with the MTX group (3.2 versus 9.2 weeks) [92]. Overall cure rates were similar between groups, and no patients in the second D&C group experienced uterine perforation. A subsequent randomized trial, however, did not demonstrate differences, and the mean number of chemotherapy cycles was comparable between groups [93,94].
Observational data also show conflicting results; remission rates after a second D&C range between 20 and 68 percent, and surgical complications (eg, uterine perforation) occur in up to 8 percent of patients [91,95-98]. Risk factors for failure of second curettage include a World Health Organization (WHO) score of 5 or 6, age <19 or >39 years, histologic evidence of persistent GTN, and hCG levels above 1500 mIU/mL [96,97].
Weighing the possible reductions in chemotherapy exposure with the potential surgical complications of a second D&C, a cost-effectiveness analysis suggested that a second D&C compared with MTX would only be cost-effective if the second D&C had a cure rate >98 percent [99]. No studies to date have shown such high cure rates.
Patients with PSTT or ETT or who do not desire fertility preservation — Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I (nonmetastatic) GTN (table 1) who do not wish to preserve fertility may be treated with primary hysterectomy.
However, there is high risk of occult pulmonary disease (estimated to occur in 40 percent of patients with presumed nonmetastatic disease [100-102]) in GTN in general, and invasive mole or choriocarcinoma is chemosensitive. In a case series of 33 patients with GTN from our practice, treatment with hysterectomy and one cycle of single-agent chemotherapy resulted in sustained remission in all patients [103]. Chemotherapy can be safely administered without increasing perioperative morbidity [104]. Based on these factors, for patients with stage I choriocarcinoma or invasive mole treated with hysterectomy, we suggest one cycle of single-agent chemotherapy (either intravenous [IV] infusion of MTX and folinic acid or bolus dactinomycin [ActD]). A French study confirmed the utility of first-line hysterectomy for patients with stage I GTN who no longer wish to conceive [105].
Patients treated with primary hysterectomy should be followed with hCG levels postoperatively and treated with chemotherapy if hCG is persistently elevated. (See 'Posttreatment surveillance' above.)
Placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) are relatively resistant to chemotherapy, and patients with stage I disease are generally treated with hysterectomy [103,106]. Based on observational data, it appears that patients with PSTT or ETT confined to the uterus may be cured with primary hysterectomy alone without adjuvant chemotherapy, making this a reasonable option for primary management in these patients. There are growing data to suggest patients who develop stage I PSTT or ETT greater than 48 months after the antecedent pregnancy are at particularly high risk of recurrence and poor survival. Although there are no published data showing that chemotherapy changes this outcome, some experts are recommending adjuvant chemotherapy for these patients with high-risk, stage I disease. Case reports indicate that local resection may be successful in carefully selected patients who wish to preserve fertility [107-110].
PROGNOSIS — The prognosis for patients with low-risk GTN is excellent, and cure rates approach 100 percent [12,28,29,111], although this may require subsequent treatment to achieve cure. This is shown in the following studies:
●In an analysis of 664 patients treated for stage I GTN at the New England Trophoblastic Disease Center (NETDC) between July 1965 and December 2018, 83.9 percent achieved complete remission with primary single-agent chemotherapy. Cure was obtained with additional therapy in all other patients and included primary hysterectomy (n = 40) and subsequent multiagent chemotherapy with or without surgical intervention (n = 107). These results are summarized in the table (table 4).
●In a separate analysis of 178 patients with low-risk stage II and III GTN treated at the NETDC, all patients ultimately were cured. However, 21 percent required second-line multiagent regimens for resistant disease to attain remission. These results are summarized in the table (table 5).
DIAGNOSIS OF RECURRENT DISEASE — Patients with low-risk GTN have a less than 5 to 10 percent risk of recurrence [84,85]. This is usually marked as a rise in the human chorionic gonadotropin (hCG) level at a median time of six months since end of therapy, irrespective of the International Federation of Gynecology and Obstetrics (FIGO) stage [112]. Risk factors for recurrence in most studies appear to be related to a large initial tumor burden, inadequate primary therapy, and in patients who defaulted on potential treatments or noncompliant follow-up.
For patients diagnosed with relapse, re-imaging with chest, abdominal, and pelvic computed tomography (CT) scans and brain magnetic resonance imaging (MRI) should be performed. Consideration should be given to the use of positron emission tomography (PET) scanning to distinguish active disease from fibrotic tumor nodules. In addition to re-establishing a baseline for future treatment, these studies are important to determine if surgery is an option [113,114]. The approach to patients with persistent or recurrent GTN is discussed separately. (See "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gestational trophoblastic disease".)
SUMMARY AND RECOMMENDATIONS
●Gestational trophoblastic disease (GTD) defines a group of conditions that arise from an aberrant fertilization event. When GTD recurs or there is evidence of metastatic disease, it is called gestational trophoblastic neoplasia (GTN). (See 'Introduction' above.)
●Low-risk disease is characterized by any one of the following: International Federation of Gynecology and Obstetrics (FIGO) stage I GTN, which is characterized as a persistently elevated human chorionic gonadotropin (hCG) level and/or tumor confined to the uterus or FIGO stage II or III GTN with a World Health Organization (WHO) risk score <7. (See 'Definition of low-risk disease' above.)
●For patients with low-risk GTN, for most patients, we recommend single-agent chemotherapy rather than combination chemotherapy (Grade 1B) (see 'Approach to treatment' above). We suggest single-agent methotrexate (MTX) rather than dactinomycin (Grade 2C). We suggest MTX be administered on an eight-day regimen, alternating with folinic acid (Grade 2C). (See 'Methotrexate' above.)
•However, for select patients with FIGO score 5 or 6 and high-risk features, we suggest combination chemotherapy (Grade 2C). High-risk features are described above. (See 'Overview' above.)
●All patients with GTN should be monitored with serial measurements of serum hCG at the start of treatment and then at weekly intervals during therapy. (See 'Monitoring during treatment' above.)
•A disease remission requires three consecutive weekly normal hCG values (less than 5 mIU/mL). For patients who achieve a remission, we suggest consolidation therapy (Grade 2C). In our practice, this consists of three cycles of the last effective regimen to reduce the risk of relapse. (See 'Consolidation therapy' above.)
•Persistent or progressive GTN (or chemotherapy resistance) is defined as an increase or a plateau in two consecutive hCG values over a two-week interval or the detection of new metastases. (See 'Persistent or progressive disease' above and "Management of resistant or recurrent gestational trophoblastic neoplasia".)
●After remission is achieved, serum hCG should be measured monthly until monitoring has shown one year of normal hCG levels. (See 'Posttreatment surveillance' above.)
●Contraception is required for the entire duration of posttreatment hCG follow-up. Estrogen-progestin contraceptives are an effective option and do not appear to impact the course of GTN. (See 'Contraception' above.)
●For patients with persistent/invasive GTN solely on the basis of a persistently elevated hCG six months after molar evacuation, we observe, provided they are willing and able to follow a careful schedule of surveillance with blood tests every week. Patients who are not candidates for observation for whatever reason should be treated with single-agent chemotherapy. (See 'Persistent elevated hCG levels (quiescent GTN)' above.)
●For patients with stage I placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT), we suggest primary hysterectomy alone rather than primary chemotherapy (Grade 2C). However, local resection is reasonable in patients who wish to preserve fertility. (See 'Patients with PSTT or ETT or who do not desire fertility preservation' above.)
●For those with stage I choriocarcinoma or invasive mole, hysterectomy is a reasonable option. For those who choose hysterectomy, we suggest one course of single-agent chemotherapy at the time of hysterectomy rather than no chemotherapy (Grade 2C). (See 'Patients with PSTT or ETT or who do not desire fertility preservation' above.)
●The prognosis for patients with low-risk GTN is excellent, and cure rates approach 100 percent, although this may require subsequent treatment to achieve cure. (See 'Prognosis' above.)
●The diagnosis of recurrent disease is usually marked as a rise in the hCG level. The median time for recurrence is six months, irrespective of the FIGO stage. (See 'Diagnosis of recurrent disease' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Donald Peter Goldstein, MD, who contributed to an earlier version of this topic review.
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16 : Effectiveness and toxicity of first-line methotrexate chemotherapy in low-risk postmolar gestational trophoblastic neoplasia: The New England Trophoblastic Disease Center experience.
17 : Effectiveness and toxicity of second-line actinomycin D in patients with methotrexate-resistant postmolar low-risk gestational trophoblastic neoplasia.
18 : Postmolar choriocarcinoma: An independent risk factor for chemotherapy resistance in low-risk gestational trophoblastic neoplasia.
19 : Response to chemotherapy in overweight/obese patients with low-risk gestational trophoblastic neoplasia.
20 : Low-risk persistent gestational trophoblastic disease treated with low-dose methotrexate: efficacy, acute and long-term effects.
21 : Folinic acid rescue during methotrexate treatment for low-risk gestational trophoblastic neoplasia - How much is just right?
22 : Five year's experience with the chemotherapy of metastatic choriocarcinoma and related trophoblastic tumors in women.
23 : Treatment of metastatic trophoblastic disease: good and poor prognosis.
24 : Primary chemotherapy for nonmetastatic gestational trophoblastic neoplasms.
25 : Single-agent methotrexate chemotherapy for the treatment of nonmetastatic gestational trophoblastic tumors
26 : Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: factors associated with resistance to single-agent methotrexate chemotherapy.
27 : Rapid escalation of weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease: a Gynecologic Oncology Group study.
28 : Weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease.
29 : Methotrexate infusion in low-risk gestational trophoblastic disease.
30 : Evaluating methotrexate treatment in patients with low-risk postmolar gestational trophoblastic neoplasia.
31 : Treatment of nonmetastatic gestational trophoblastic disease: results of methotrexate alone versus methotrexate--folinic acid.
32 : Comparison of treatment for low-risk GTN with standard 8-day MTX/FA regimen versus modified MTX/FA regimen without chemotherapy on the weekend.
33 : SEQUENTIAL USE OF METHOTREXATE AND ACTINOMYCIN D IN THE TREATMENT OF METASTATIC CHORIOCARCINOMA AND RELATED TROPHOBLASTIC DISEASES IN WOMEN.
34 : Actinomycin D in the treatment of methotrexate-resistant trophoblastic disease in women.
35 : Actinomycin D as the primary agent for gestational trophoblastic disease.
36 : Pulse actinomycin D scheduling in nonmetastatic gestational trophoblastic neoplasia: cost-effective chemotherapy.
37 : Single-dose actinomycin-D treatment for nonmetastatic gestational trophoblastic disease. A prospective phase II trial of the Gynecologic Oncology Group.
38 : Actinomycin D toxicity in the treatment of trophoblastic disease: a comparison of the five-day course to single-dose administration.
39 : Single-dose actinomycin D in the treatment of postmolar trophoblastic disease.
40 : Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--state of the art.
41 : Decision making for chemotherapy administration in patients with low-risk gestational trophoblastic neoplasia
42 : Actinomycin d versus methotrexate-folinic acid as the treatment of stage I, low-risk gestational trophoblastic neoplasia: a randomized controlled trial.
43 : Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study.
44 : Five-Day Intravascular Methotrexate Versus Biweekly Actinomycin-D in the Treatment of Low-Risk Gestational Trophoblastic Neoplasia: A Clinical Randomized Trial.
45 : An international randomized phase III trial of pulse actinomycin-D versus multi-day methotrexate for the treatment of low risk gestational trophoblastic neoplasia; NRG/GOG 275.
46 : First-line chemotherapy in low-risk gestational trophoblastic neoplasia.
47 : Comparison of chemotherapies with methotrexate, VP-16 and actinomycin-D in low-risk gestational trophoblastic disease. Remission rates and drug toxicities.
48 : Single agent etoposide in gestational trophoblastic tumours. Experience at Charing Cross Hospital 1978-1987.
49 : Primary oral etoposide therapy in gestational trophoblastic disease. An update.
50 : Management of low-risk gestational trophoblastic tumors with etoposide (VP16) in patients resistant to methotrexate.
51 : Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors.
52 : Effects of single-agent and combination chemotherapy for gestational trophoblastic tumors on risks of second malignancy and early menopause.
53 : Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours.
54 : Reevaluation of 5-fluorouracil as a single therapeutic agent for gestational trophoblastic neoplasms.
55 : Forty-five year's experience of the treatment of choriocarcinoma and invasive mole.
56 : What is the best regimen for low-risk gestational trophoblastic neoplasia? A review.
57 : Management of high-risk gestational trophoblastic disease--the Memorial Hospital experience.
58 : Risk adapted single-agent dactinomycin or carboplatin for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia.
59 : Can carboplatin or etoposide replace actinomycin-d for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia?
60 : Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia.
61 : [Evaluation of treatment relating to gestational trophoblastic tumor registered to the French Trophoblastic Disease Reference Center (TDRC) in Lyon from 1999 to 2005].
62 : Early identification of resistance to first-line single-agent methotrexate in patients with persistent trophoblastic disease.
63 : Predictive values of hCG clearance for risk of methotrexate resistance in low-risk gestational trophoblastic neoplasias.
64 : External validation of serum hCG cutoff levels for prediction of resistance to single-agent chemotherapy in patients with persistent trophoblastic disease.
65 : ACOG Practice Bulletin #53. Diagnosis and treatment of gestational trophoblastic disease.
66 : Society of Gynecologic Oncologists Clinical Practice Guidelines. Practice guidelines: gestational trophoblastic disease.
67 : Gestational trophoblastic neoplasia, FIGO 2000 staging and classification.
68 : When to stop human chorionic gonadotrophin (hCG) surveillance after treatment with chemotherapy for gestational trophoblastic neoplasia (GTN): A national analysis on over 4,000 patients.
69 : Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Trophoblastic Disease Center.
70 : Continued hCG surveillance following chemotherapy for gestational trophoblastic neoplasia: When is enough enough?
71 : Influence of oral contraceptives in the development of post-molar trophoblastic neoplasia--a systematic review.
72 : Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk factors?
73 : Subsequent reproductive experience after treatment for gestational trophoblastic disease.
74 : Pregnancy after chemotherapy for gestational trophoblastic disease.
75 : Return of fertility after successful chemotherapy treatment of gestational trophoblastic tumors.
76 : Maternal and perinatal outcomes of first pregnancy after chemotherapy for gestational trophoblastic neoplasia in Brazilian women.
77 : Pregnancies after chemotherapy of trophoblastic neoplasms.
78 : Reproductive performance of patients with gestational trophoblastic disease in Hong Kong.
79 : Pregnancy outcomes after successful chemotherapy for choriocarcinoma and invasive mole: long-term follow-up.
80 : Malignant trophoblastic tumors in Norway: Fertility rate after chemotherapy
81 : Influence of chemotherapy for gestational trophoblastic disease on subsequent pregnancy outcome.
82 : Pregnancy after EMA/CO for gestational trophoblastic disease: a report from The Netherlands.
83 : Early pregnancy outcomes after chemotherapy for gestational trophoblastic tumor.
84 : Recurrent gestational trophoblastic disease. Experience of the Southeastern Regional Trophoblastic Disease Center.
85 : Revised FIGO staging system for gestational trophoblastic tumors. Recommendations regarding therapy.
86 : Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy.
87 : Effect of early pregnancy following chemotherapy on disease relapse and fetal outcome in women treated for gestational trophoblastic neoplasia.
88 : Quality of life of gestational trophoblastic neoplasia survivors: a study of patients at the Philippine General Hospital trophoblastic disease section.
89 : Quality of life after gestational trophoblastic disease.
90 : Quality of life after gestational trophoblastic disease.
91 : The role of repeat uterine evacuation in the management of persistent gestational trophoblastic disease.
92 : A pilot randomized controlled clinical trial of second uterine curettage versus usual care to determine the effect of re-curettage on patients' need for chemotherapy among women with low risk, nonmetastatic gestational trophoblastic neoplasm in Urmia, Iran.
93 : Second Uterine Curettage and the Number of Chemotherapy Courses in Postmolar Gestational Trophoblastic Neoplasia: A Randomized Controlled Trial.
94 : Second Uterine Curettage and the Number of Chemotherapy Courses in Postmolar Gestational Trophoblastic Neoplasia: A Randomized Controlled Trial.
95 : The curative effect of a second curettage in persistent trophoblastic disease: a retrospective cohort survey.
96 : The role of repeat uterine evacuation in the management of persistent gestational trophoblastic disease.
97 : Second Curettage for Low-Risk Nonmetastatic Gestational Trophoblastic Neoplasia.
98 : Diagnostic and therapeutic curettage in gestational trophoblastic disease.
99 : Cost-effectiveness of second curettage for treatment of low-risk non-metastatic gestational trophoblastic neoplasia.
100 : Significance of chest computed tomography findings in the evaluation and treatment of persistent gestational trophoblastic neoplasia.
101 : Clinical outcome of micrometastasis in the lung in stage IA persistent gestational trophoblastic disease.
102 : The Role of Computed Tomography Scanning of the Thorax in the Initial Assessment of Gestational Trophoblastic Neoplasia.
103 : Current management of gestational trophoblastic neoplasia.
104 : The evolving role of hysterectomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center.
105 : First-line hysterectomy for women with low-risk non-metastatic gestational trophoblastic neoplasia no longer wishing to conceive.
106 : Epithelioid trophoblastic tumor: A single institution case series at the New England Trophoblastic Disease Center.
107 : Twenty-five years' clinical experience with placental site trophoblastic tumors.
108 : Advances in the understanding of placental site trophoblastic tumor.
109 : Epithelioid trophoblastic tumor: a review of the literature.
110 : Fertility-preserving treatment in young patients with placental site trophoblastic tumors.
111 : Treatment of low-risk metastatic gestational trophoblastic tumors with single-agent chemotherapy.
112 : Current management of gestational trophoblastic diseases
113 : Surgical therapy for gestational trophoblastic disease.
114 : The prognosis of gestational trophoblastic neoplasia patient with residual lung tumor after completing treatment.
