Initial management of low-risk gestational trophoblastic neoplasia

INTRODUCTION — Gestational trophoblastic disease (GTD) defines a group of conditions that arise from an aberrant fertilization event. When GTD has local uterine invasion 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, epidemiology, clinical manifestations, and staging of GTN, in addition to the management of high-risk and persistent or recurrent GTN, are discussed separately.

●(See "Gestational trophoblastic disease: Pathology".)

●(See "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification".)

●(See "Initial management of high-risk gestational trophoblastic neoplasia".)

●(See "Management of resistant or recurrent gestational trophoblastic neoplasia".)

CLASSIFICATION OF TUMORS — 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). All patients with GTN are classified according to FIGO staging; the WHO risk scoring system (table 1) is also used for patients with invasive mole and choriocarcinoma.

Low-risk disease is characterized by any one of the following in an invasive mole or choriocarcinoma histology [1]:

●FIGO stage I GTN – This is characterized as a persistently elevated human chorionic gonadotropin (hCG) level and/or tumor confined to the uterus, or

●Stage II or III GTN with a WHO risk score <7.

The WHO risk scoring system is not used for patients with nonmetastatic placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT); such tumors have a different pathobiology and are managed differently than invasive mole and choriocarcinoma. (See 'Nonmetastatic PSTT and ETT' below.)

GTN that does not fall into these categories (ie, stage II or III with a WHO risk score >6; stage IV disease) is considered high risk. 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' and "Initial management of high-risk gestational trophoblastic neoplasia", section on 'Metastatic PSTT or ETT'.)

INVASIVE MOLE OR CHORIOCARCINOMA —  (algorithm 1)

Patients who desire future childbearing

Most patients

Single-agent chemotherapy — Most patients with low-risk GTN are of childbearing age and wish to preserve fertility; such patients may be cured with single-agent chemotherapy, using either methotrexate (MTX) or dactinomycin (ActD) [2]. MTX typically is administered with folinic acid (FA) to protect from MTX-related toxicity. (See 'Prognosis' below and "Major side effects of low-dose methotrexate".)

The duration of treatment and management of those with International Federation of Gynecology and Obstetrics (FIGO) risk score of 5 or 6 and high-risk features are discussed below. (See 'Monitoring during treatment' below and 'Select patients with WHO score of 5 or 6' below.)

National and international guidelines from the National Comprehensive Cancer Network, European Organization for Research for Treatment of Trophoblastic diseases, and FIGO support single-agent treatment [1,3-5]. Because of the overall excellent prognosis, treatment with single-agent chemotherapy is often successful and immediate treatment with multiagent regimens is generally not necessary.

In one study of 185 patients with low-risk GTN, complete remission was achieved in 88 percent of patients (90 percent of patients with stage I disease and 68 percent of patients with stages II to III disease) receiving MTX and FA [6]. 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 cured with multiagent chemotherapy or surgery [7].

Risk factors for resistance to chemotherapy include postmolar choriocarcinoma and pretreatment hCG levels >50,000 mIU/mL [8]. Body mass index ≥25 kg/m² compared with <25 kg/m² does not appear to affect the response to chemotherapy (either ActD or MTX) in low-risk GTN [9].

Methotrexate as the preferred option

●Comparative efficacy with dactinomycin — In our practice, we prefer MTX over ActD as the initial chemotherapy agent because it is effective, well tolerated, and cost effective [6,10-16]. However, there is no consensus regarding which primary single-agent regimen should be favored for the treatment of low-risk GTN and both regimens (MTX and ActD) appear to have excellent activity (table 2). ActD is discussed below. (See 'Alternatives including dactinomycin and other agents' below.)

Multiple trials have compared MTX and ActD regimens for treatment of low-risk, nonmetastatic GTN [17-20]. In a meta-analysis including seven randomized trials, 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 [21]. However, there was substantial heterogeneity in this analysis due to the various schedules of MTX (as a weekly injection, five-day injection, and eight-day schedule) and ActD (pulsed intravenous [IV] every 14 days and five-day IV dosing) included, and the number of patients included in the analysis was relatively small (667 patients). Therefore, we are not confident in the conclusiveness of this meta-analysis. In addition, one of the studies included in the meta-analysis suggested similar complete remission rates between MTX and ActD (62 patients; 78 and 80 percent, respectively, a difference that was not statistically significant); the frequency of adverse effects was also similar between the two agents [19].

●Dosing and schedule — While there are no high-quality data to establish a universally applied standard regimen for MTX for such patients, the available data suggest that MTX administered on a five- or eight-day schedule is more effective than either the weekly intramuscular (IM) or intermittent infusional IV infusion regimens [12,22].

In our practice, we prefer the MTX-FA eight-day regimen for the primary therapy of low-risk GTN rather than other schedules; this regimen is both effective and associated with minimal toxicities for the patient.

•MTX eight-day regimen – In this regimen, MTX is typically dosed 1 mg/kg as an IM or 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. Some centers prefer to use a fixed-dose (50 mg/day) rather than weight-based regimen. In a retrospective study comparing two eight-day MTX regimens for the treatment of low-risk GTN, those receiving fixed dose (99 patients) compared with weight-based (77 patients) regimens had similar rates of remission, time to remission, resistance, and toxicities; both groups received FA 7.5 mg on days 2, 4, 6, and 8 [23].

In a cohort study including 250 patients with low-risk GTN treated with an eight-day MTX regimen (50 mg/day), complete response rate was 72 percent for first-line and 95 percent for second-line chemotherapy [24]. Treatment was associated with the following mild toxicities:

-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.

-No patients reported alopecia.

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 [25].

The ideal FA dosing has also not been established and it is critical that the dose is adequate to minimize toxicity but not too great to interfere with its effectiveness. In one retrospective study comparing toxicity and outcomes of eight-day MTX with FA rescue in patients with low-risk GTN, those treated with a fixed 15 mg FA dose compared with weight-based dosing of 0.1 mg/kg had fewer treatment delays due to toxicity and a greater ease of administration; rates of primary remission were similar between groups [26]. 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. This increased primary remission rate, however, was associated with higher toxicity [27].

Other reasonable dosing regimens include:

•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 [28-30] and is the regimen of choice at some centers [31]; FA is not administered with this regimen. Other data emphasize that maintaining dose intensity is important to the efficacy of this regimen [32]. Efficacy may be similar to the eight-day regimen. In one retrospective case study comparing five-day MTX and eight-day MTX-FA protocols in patients with low-risk GTN, remission rates were similar between groups (approximately 76 percent) [13].

•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 [33,34]. Treatment is repeated until the serum hCG level becomes undetectable (<5 mIU/mL), after which consolidation therapy is recommended. This regimen was originally introduced by the Gynecologic Oncology Group 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 [12,35]. 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.

Alternatives including dactinomycin and other agents — While we prefer MTX as initial therapy, some data support the administration of ActD in the initial treatment setting.

In our practice, we generally administer ActD to patients with MTX resistance [36,37], or when there are contraindications to the use of MTX (eg, abnormal liver function tests, renal insufficiency). ActD is less preferred as it is associated with increased toxicity (particularly hyperemesis, alopecia, and the risk of local tissue injury if extravasation occurs).

When ActD is chosen, it is generally administered in "pulsed" dosing (1.25 mg/m² IV every 14 days) to limit such toxicities, although it can also be administered as an IV push (10 to 12 mcg/kg daily for five days every other week) [38-42]. In a retrospective study including patients with MTX-resistant low-risk GTN, those receiving pulsed ActD compared with five-day ActD had similar rates of remission (overall rate: 72 percent) but lower rates of thrombocytopenia (0 versus 65 percent), grade 2 alopecia (17 versus 71 percent), and oral mucositis (17 versus 60 percent) [7]. In an earlier study including patients with nonmetastatic postmolar GTN, the primary remission rate with pulsed and five-day ActD regimens was 78 and 88 percent, respectively [43].

Other alternative agents include:

●Etoposide – Single-agent etoposide (VP-16) is an acceptable option for primary therapy for low-risk disease [44-46]. Single-agent etoposide at a dose of 100 mg/m², IV, daily for five days every 10 to 14 days has also been used as another effective monotherapy regimen for patients who progress despite MTX treatment [44,47].

Although it appears to be highly effective, its use was limited by concerns regarding the risk of secondary malignancy. Observational studies have 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 [48]. 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 [49].

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 [50].

●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 [51]. Toxicity is reported to be mild [51-53]. It has also been used in the United States as part of combination chemotherapy for the management of high-risk disease [54].

●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 [55]. However, in a subsequent study including patients from Brazil, remission occurred in only 11 of 23 patients (48 percent) receiving second-line carboplatin, with higher rates of lymphopenia and vomiting compared with ActD [56].

Limited role for second curettage — 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 to patients with persistent uterine bleeding in whom transvaginal ultrasound demonstrates residual molar tissue [57].

Although some data suggest that a second D&C may eliminate or reduce the need for subsequent chemotherapy among a subset of patients with stage I GTN (table 1), data are conflicting, and this is not standard practice. In one randomized trial including 62 patients with low-risk GTN, those assigned to a second D&C compared with MTX 50 mg/m² experienced human chorionic gonadotropin (hCG) normalization six weeks earlier (3.2 versus 9.2 weeks); half the patients in the second D&C group were able to avoid chemotherapy [58]. Overall cure rates were similar between groups, and no patients in the second D&C group experienced uterine perforation. By contrast, in a subsequent randomized trial including patients with low-risk GTN receiving treatment with MTX, the number of chemotherapy cycles needed to reach hCG normalization was similar for those assigned to a second D&C and no D&C [59,60].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 [57,61-64].

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 [62,63]. 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 [65]. No studies to date have shown such high cure rates.

Select patients with WHO score of 5 or 6

Combination chemotherapy — Combination chemotherapy is appropriate for patients with FIGO risk score of 5 or 6 (table 1) in whom other high risk features are also present:

●No metastases and no histopathologic choriocarcinoma (CCA), but hCG >410,000

●Either metastases from non-CCA or histopathologic CCA, and hCG >150,000

●Metastatic CCA

Rates of remission are much lower in such patients and thus single-agent chemotherapy is not used [66].

Choice of combination therapy follows a similar approach as for high-risk GTN and is discussed separately. (See "Initial management of high-risk gestational trophoblastic neoplasia", section on 'Approach to treatment'.)

In a retrospective study including 80 patients with GTN and International Federation of Gynecology and Obstetrics (FIGO) risk score 5 or 6, remission with primary first-line single-agent chemotherapy was only 31 to 35 percent [67]. However, in a subsequent multicenter retrospective study which included 431 patients with low-risk GTN and a FIGO risk score of 5 or 6, approximately 60 percent achieved remission with either first-line or second-line single-agent chemotherapy [66]. While almost all patients without metastases or CCA attained remission with single agents, almost all patients with metastatic CCA required primary combination chemotherapy [67]. Furthermore, modeling studies suggest that most (approximately 80 percent) patients with nonmetastatic and non-CCA histology with hCG >410,000 IU/L would require primary combination chemotherapy to attain remission; among patients with either CCA or metastatic non-CCA, most patients (approximately 80 percent) with an hCG >150,000 IU/L would require primary combination chemotherapy [66].

Monitoring during treatment — All patients with GTN should be monitored with serial measurements of serum hCG at the start of treatment and then on day 1 of each subsequent cycle.

Hematologic indices should also be monitored during chemotherapy, as both MTX and ActD are associated with hematologic toxicity. As MTX can cause hepatotoxicity, liver function tests should also be monitored. In addition, both agents are excreted by the kidney and as such, patients should have normal renal function confirmed prior to each treatment.

Remission and consolidation treatment — In our practice, we consider disease remission as three consecutive weekly normal hCG values (less than 5 mIU/mL).

After complete remission is attained, we suggest consolidation therapy in order to prevent relapse. This generally consists of three courses of the last effective regimen. For patients treated with chemotherapy and hysterectomy, and in whom normal hCG values following the procedure have been attained, withholding consolidation cycles is also reasonable.

There are few data to inform the optimal number of cycles that should be administered. However, in a retrospective study including 951 patients with GTN receiving MTX-FA consolidation therapy in the Netherlands and United Kingdom, those treated with two compared with three courses of consolidation therapy had a higher rate of disease relapse (8.3 versus 4 percent) [68].

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 [69]. Other generally accepted criteria include detection of new metastases [10]. 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 [70-72].

Sequential single-agent chemotherapy or combination chemotherapy regimens are required for such patients [36,37,73]. 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 hCG level) during treatment. The approach to patients with persistent GTN is discussed separately. (See "Management of resistant or recurrent gestational trophoblastic neoplasia".)

Higher rates of chemotherapy resistance have been demonstrated in patients with choriocarcinoma than with other histologic subtypes [8].

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 in the absence of any 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'.)

Patients for whom hysterectomy is appropriate

●Stage I low-risk GTN – Patients with FIGO stage I (nonmetastatic) GTN who do not wish to preserve fertility are typically treated with primary hysterectomy with or without chemotherapy. In our practice, we administer one cycle of chemotherapy (as a prophylactic treatment) at the time of hysterectomy; there is a high risk of occult pulmonary disease in GTN in general (estimated to occur in 40 percent of patients with presumed nonmetastatic disease [74-76]), and invasive mole or choriocarcinoma is chemosensitive. Chemotherapy for such patients is with either IV MTX and folinic acid or bolus ActD. However, we recognize that use of chemotherapy in patients with stage I low-risk GTN is variable, and some experts avoid this practice (eg, due to theoretical concerns of promoting chemotherapy resistance) and reserve chemotherapy only for patients in whom hCG levels fail to normalize postoperatively. (See 'Posttreatment surveillance' below.)

In a case series of 33 patients with low-risk GTN, treatment with hysterectomy and one cycle of single-agent chemotherapy resulted in sustained remission in all patients [77]. Chemotherapy can be safely administered without increasing perioperative morbidity [78]. A subsequent study confirmed the utility of first-line hysterectomy for patients with stage I GTN who no longer wish to conceive [79].

Mode of surgery (ie, laparotomy, minimally invasive surgery [MIS]) does not appear to affect oncologic outcomes. In a retrospective study including 39 patients with GTN, those undergoing minimally invasive hysterectomy (56 percent) compared with open abdominal hysterectomy had similar rates of recurrence and five-year survival; MIS was associated with less blood loss and shorter hospital stays [80].

●Other patients – While chemotherapy alone is appropriate for most patients with low-risk GTN, some patients are treated with both hysterectomy and chemotherapy. Examples of such patients include those with heavy or bothersome uterine bleeding, or substantial uterine tumor burden with low tumor burden elsewhere. The choice of chemotherapy in such patients is detailed above. (See 'Most patients' above and 'Select patients with WHO score of 5 or 6' above.)

NONMETASTATIC PSTT AND ETT — Placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) are relatively resistant to chemotherapy. As such, for most patients with nonmetastatic PSTT and ETT (stage I disease) we suggest hysterectomy alone (algorithm 2). Observational data suggest high cure rates with hysterectomy alone without chemotherapy, supporting this approach [77,81,82]. While case reports indicate that local resection may be successful in carefully selected patients who wish to preserve fertility [83-86], hysterectomy remains the optimal treatment in most cases.

However, for patients who develop stage I PSTT or ETT >48 months after the antecedent pregnancy, we suggest hysterectomy plus chemotherapy and immunotherapy. These patients are at particularly high risk of recurrence and poor survival. For choice of chemotherapy, we suggest etoposide plus cisplatin with etoposide, methotrexate (MTX) plus dactinomycin (ActD; EP/EMA). Treatment is administered for up to 12 weeks, and if tolerated, followed by pembrolizumab for six months. If the patient is unable to tolerate EP/EMA, pembrolizumab may be administered alone. This regimen is based on the practice of a specialty center with experience in treatment of this rare clinical entity [87].

The approach to patients with metastatic disease (stage II to IV) is discussed separately. (See "Initial management of high-risk gestational trophoblastic neoplasia", section on 'Metastatic PSTT or ETT'.)

POSTTREATMENT SURVEILLANCE — All patients with low-risk GTN are followed with weekly human chorionic gonadotropin (hCG) levels until normal (<5 mIU/mL) for three weeks and then monthly; surveillance is discontinued after 12 months of normal hCG levels have been documented. This is consistent with International Federation of Gynecology and Obstetrics (FIGO) guidelines [88-90]. However, if following completion of one year of hCG surveillance the patient develops new symptoms (eg, 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 [91]. 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 (and United Kingdom guidelines suggest lifelong surveillance), 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 new pregnancy as many patients beyond a year of normal hCG values are likely attempting to conceive and 1.5 percent will have another molar pregnancy [92]. 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 hCG values 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 [93].

DIAGNOSIS OF RECURRENT DISEASE — Patients with low-risk GTN have a less than 5 to 10 percent risk of recurrence [94,95]. 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 [96].

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 were noncompliant with follow-up.

For patients diagnosed with recurrence, reimaging with chest, abdominal, and pelvic computed tomography scans and brain magnetic resonance imaging should be performed. Positron emission tomography scanning may be used 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 [97,98].

The approach to patients with recurrent GTN is discussed separately. (See "Management of resistant or recurrent gestational trophoblastic neoplasia".)

PROGNOSIS — The prognosis for patients with low-risk GTN is excellent, and cure rates approach 100 percent [12,34,35,99], although this number includes patients receiving subsequent treatment(s).

In an analysis of 664 patients treated for stage I GTN between July 1965 and December 2018, 84 percent achieved complete remission with primary single-agent chemotherapy. Cure was obtained with additional therapy in all other patients and included primary hysterectomy (7 percent) and subsequent multiagent chemotherapy with or without surgical intervention (16 percent). These results are summarized in the table (table 3).

In a separate analysis of 178 patients with low-risk stage II and III GTN, all patients ultimately were cured. However, 21 percent required subsequent line multiagent regimens for resistant disease to attain remission. These results are summarized in the table (table 4).

POSTTREATMENT ISSUES

Contraception — Following successful treatment, all patients should be monitored using serial human chorionic gonadotropin (hCG) for at least 12 months (see 'Posttreatment surveillance' above). A new pregnancy during this period makes it difficult or impossible to interpret hCG results and complicates management. Therefore, it is essential that patients use contraception for the entire duration of surveillance.

Estrogen-progestin contraceptives are preferred over other contraceptive methods because of their low failure rate and relatively low incidence of irregular bleeding, since this symptom may raise concern for disease recurrence. Two randomized trials found no increase in the risk of GTN in patients who used estrogen-progestin pills following a molar pregnancy [100]. There is also no evidence that the use of oral contraceptives influences the course of GTN [101]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

In our practice, we advise against use of an intrauterine device because of the risk of uterine perforation, particularly in patients in whom there is uterine invasion. Barrier methods may be used but have less contraceptive efficacy.

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 months of normal hCG levels [92,102-104].

In one review of 667 pregnancies between July 1965 and December 2013 in patients previously treated for GTN, pregnancy outcomes were as follows [92]:

●Live term births (66.9 percent)

●Spontaneous pregnancy loss (18.3 percent)

●Premature births (6.6 percent)

●Pregnancy termination (4.2 percent)

●Stillbirths (1.5 percent)

●Repeat molar pregnancies (1.5 percent)

●Ectopic pregnancies (1 percent)

Higher rates of spontaneous pregnancy loss may occur if pregnancy occurs <6 months after treatment. In a meta-analysis including 19 studies (2925 patients) evaluating first pregnancy outcomes after treatment for GTN, the incidence of spontaneous pregnancy loss was 15.3 percent; those with pregnancy ≤6 compared with ≥12 months posttreatment had higher rates of spontaneous pregnancy loss (53.9 [two studies] versus 8.9 [five studies] percent, respectively) [105].

Importantly, the use of chemotherapy for low-risk GTN does not appear to be associated with an increase in congenital malformations [92,102,104,106-113]. In the observational study cited above, congenital anomalies (major and minor) were detected in only 12 of 500 births (1.4 percent) [92]; in the meta-analysis reported above, congenital anomalies were detected in 3.3 percent of patients (11 studies) [105]. These values are comparable with the general gestational population.

Following delivery, the placenta (or, in the case of pregnancy loss/termination, any products of conception) should be examined carefully and sent for evaluation by a pathologist if any abnormality is suspected. We also advise that patients with a history of GTN have an hCG level measured six to eight weeks after delivery (or pregnancy loss/termination) to ensure complete remission and the absence of occult GTN.

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 [94,95]. 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 [114]. Pregnancies occurring before hCG follow-up is complete appear to have no increased risk of abnormalities [115].

Psychosocial issues — Patients with GTN and their partners must confront the loss of a pregnancy at the same time they face concerns regarding malignancy. Patients can thus experience clinically significant levels of anxiety, fatigue, anger, confusion, sexual dysfunction, and concern for future pregnancy that can 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 [116-118].

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

●Terminology

•Gestational trophoblastic disease (GTD) arises from an aberrant fertilization event. When GTD has local uterine invasion or metastases, it is called gestational trophoblastic neoplasia (GTN). (See 'Introduction' above.)

•Low-risk GTN is characterized by invasive mole or choriocarcinoma with either of the following: International Federation of Gynecology and Obstetrics (FIGO) stage I GTN, or FIGO stage II or III GTN with a World Health Organization (WHO) risk score <7 (table 1). WHO prognostic scoring does not apply to nonmetastatic placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). (See 'Classification of tumors' above.)

●Invasive mole or choriocarcinoma (algorithm 1)

•Treatment for patients who desire future childbearing

-For most patients who desire future childbearing, we suggest intramuscular (IM) methotrexate (MTX) on an eight-day regimen alternating with folinic acid (FA; MTX-FA) rather than other regimens (Grade 2C). (See 'Methotrexate as the preferred option' above.)

-However, for select patients with WHO score 5 or 6 and high-risk features (table 1), we suggest combination chemotherapy (Grade 2C). High-risk features are described above. (See 'Select patients with WHO score of 5 or 6' above.)

•Treatment for patients in whom hysterectomy is appropriate

-For patients with stage I invasive mole or choriocarcinoma who desire hysterectomy, we suggest hysterectomy with one cycle of (prophylactic) chemotherapy at time of surgery (Grade 2C). However, other experts avoid prophylactic chemotherapy, and administer chemotherapy only if human chorionic gonadotropin (hCG) levels fail to normalize. (See 'Patients for whom hysterectomy is appropriate' above.)

-Some patients who are candidates for single-agent or combination chemotherapy are also treated with hysterectomy; such patients include those with heavy or bothersome uterine bleeding, or substantial uterine tumor burden with low tumor burden elsewhere. (See 'Patients for whom hysterectomy is appropriate' above.)

•Monitoring during chemotherapy – Serum hCG is checked on day 1 of each cycle. (See 'Monitoring during treatment' above.)

-Disease remission requires three consecutive weekly normal hCG values. For patients in remission, we suggest three cycles of consolidation therapy (Grade 2C), using the last effective regimen. (See 'Remission and consolidation treatment' above.)

-Persistent or progressive GTN is defined as an increase or a plateau in two consecutive hCG values over a two-week interval or new metastases. (See 'Persistent or progressive disease' above and "Management of resistant or recurrent gestational trophoblastic neoplasia".)

●PSTT or ETT (algorithm 2)

•For most patients with stage I PSTT or ETT, we suggest hysterectomy alone rather than hysterectomy and chemotherapy (Grade 2C). Local resection is an alternative in highly selected patients desiring fertility preservation. (See 'Nonmetastatic PSTT and ETT' above.)

•However, for patients who develop stage I PSTT or ETT >48 months after the antecedent pregnancy, we suggest that hysterectomy be followed by chemotherapy and immunotherapy (Grade 2C), and suggest, as choice of regimen, etoposide plus cisplatin with etoposide, MTX, plus dactinomycin (ActD; EP/EMA) followed by pembrolizumab (Grade 2C). If the patient is unable to tolerate EP/EMA, pembrolizumab may be administered alone. (See 'Nonmetastatic PSTT and ETT' above.)

●Posttreatment surveillance – All patients with low-risk GTN are followed with weekly hCG levels until normal (ie, <5 mIU/mL) for three weeks and then monthly; surveillance is discontinued after 12 months of normal hCG levels have been documented. (See 'Posttreatment surveillance' above.)

●Prognosis – The prognosis of low-risk GTN is excellent, with cure rates approaching 100 percent, although this may require subsequent treatment(s) to achieve cure. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Donald Peter Goldstein, MD, who contributed to earlier versions of this topic review.