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Epidemiology, diagnosis, and treatment of gestational trophoblastic disease: A Society of Gynecologic Oncology evidenced-based review and recommendation

Published:October 19, 2021DOI:https://doi.org/10.1016/j.ygyno.2021.10.003

      1. Introduction

      Gestational trophoblastic disease (GTD) is a group of interrelated tumors that arise from abnormal fertilization events and include both benign conditions (complete hydatidiform mole (CM) and partial hydatidiform mole (PM), placental site nodule), potentially malignant conditions (atypical placental site nodule APSN), as well as malignant conditions (invasive mole (IM), choriocarcinoma (CA), placental-site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT)). These malignancies are collectively referred to as gestational trophoblastic neoplasia (GTN). While the majority of GTN occurs after a molar pregnancy (50%), they can arise after any gestational event with 25% arising after miscarriage or tubal pregnancy and 25% after term or preterm pregnancies [
      • Ngan S.
      • Seckl M.J.
      Gestational trophoblastic neoplasia management: an update.
      ]. Unlike most malignancies, GTN can be cured even in the presence of metastatic disease. With the exception of PSTT and ETT, GTD arises from cytotrophoblasts and syncytiotrophoblasts, and produce abundant amounts of human chorionic gonadotropin (hCG), which serves as an excellent tumor marker for diagnosis, monitoring of response, and follow-up to detect recurrence. Given the rarity of this disease, management and treatment recommendations are commonly informed by data from small, retrospective single institution or collaborative studies, small prospective studies, meta-analyses, and expert opinion [
      • Lok C.
      • van Trommel N.
      • Massugar L.
      • Golfier F.
      • Seckl M.
      Practical clinical guidelines of EOTTD for the treatment and referral of gestational trophoblastic disease.
      ]. The purpose of this document is to provide a comprehensive reference for the epidemiology, management and outcomes of GTD/GTN. We carried out a systematic review of English language studies, identified through a search of MEDLINE/Pubmed, Cochrane Library, and Google Scholar from inception until June 2021. Using the terms gestational trophoblastic disease, gestational trophoblastic neoplasia, molar pregnancy, human chorionic gonadotropin, chemotherapy, we generated the references for this review and accompanying recommendations.

      1.1 Epidemiology

      Wide variations in the incidence of hydatidiform mole exist throughout the world with rates ranging from 1 to 2 per 1000 pregnancies in North America, Europe, and other developed nations, to 2–3 times higher in some Asian countries, Brazil, and India [
      • Eysbouts Y.K.
      • Bulten J.
      • Ottevanger P.B.
      • Thomas C.M.G.
      • Kate-Booij M.J.
      • van Heraarden A.E.
      • Siebers A.G.
      • FCGJ Sweep
      • LFAG Massuger
      Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.
      ]. Extremes of reproductive age and prior molar pregnancy have emerged as major risk factors for the development of molar pregnancy. Age < 15 years, and > 45 years are most strongly associated with the development of molar pregnancy, with the risk being 5–10 times greater for those over 45 [
      • Berkowitz R.S.
      • Goldstein D.P.
      Clinical practice. Molar pregnancy.
      ,
      • Sebire N.J.
      • Foskett M.
      • Fisher R.A.
      • Rees H.
      • Seckl M.
      • Newlands E.
      Risk of partial and complete hydatidiform molar pregnancy in relation to maternal age.
      ]. The risk of a second molar pregnancy after a first increases to approximately 1–2% (up from 0.1%) and after two molar pregnancies, the risk of a third molar pregnancy is 15–20% [
      • Sebire N.J.
      • Foskett M.
      • Fisher R.A.
      • Rees H.
      • Seckl M.
      • Newlands E.
      Risk of partial and complete hydatidiform molar pregnancy in relation to maternal age.
      ,
      • Vargas R.
      • Barroilhet L.M.
      • Esselen K.
      • Diver E.
      • Bernstein M.
      • Goldstein D.P.
      • Berkowitz R.S.
      Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from New England trophoblastic disease center.
      ,
      • Sand P.K.
      • Lurain J.R.
      • Brewer J.I.
      Repeat gestational trophoblastic disease.
      ]. This risk is much higher after a complete mole and interestingly, subsequent moles tend to be the same histology as the first [
      • Eagles N.
      • Sebire N.J.
      • Short D.
      • Savage P.M.
      • Seckl M.J.
      • Fisher R.A.
      Risk of recurrent molar pregnancies following complete and partial hydatidiform moles.
      ].
      Choriocarcinoma is the most common histologic GTN after a normal pregnancy. Because of its rapid growth and high propensity for metastatic disease, it is considered the most aggressive form of GTN. The incidence of choriocarcinoma is approximately 3 per 100,000 deliveries in Europe and North America, compared to approximately 23 per 100,000 in Southeast Asia [
      • Eysbouts Y.K.
      • Bulten J.
      • Ottevanger P.B.
      • Thomas C.M.G.
      • Kate-Booij M.J.
      • van Heraarden A.E.
      • Siebers A.G.
      • FCGJ Sweep
      • LFAG Massuger
      Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.
      ,
      • Smith H.O.
      Gestational trophoblastic disease epidemiology and trends.
      ]. This risk increases with increasing maternal age [
      • Savage P.
      • Winter M.
      • Parker V.
      • Harding V.
      • Sita-Lumsden A.
      • Fisher R.A.
      • Harvery R.
      • Unsworth N.
      • Sarwar N.
      • Short D.
      • Agular X.
      • Tidy J.
      • Hancock B.
      • Coleman R.
      • Seckl M.J.
      Demographis, natural history and treatment outcomes of non-molar gestational choriocarcinoma: a UK population study.
      ].
      PSTT and ETT are incredibly rare entities and most are diagnosed remotely after non-molarpregnancies. The incidence of PSTT is approximately 1 per 100,000 deliveries, and the incidence of ETT is approximately 0.1 per 100,000 deliveries [
      • Eysbouts Y.K.
      • Bulten J.
      • Ottevanger P.B.
      • Thomas C.M.G.
      • Kate-Booij M.J.
      • van Heraarden A.E.
      • Siebers A.G.
      • FCGJ Sweep
      • LFAG Massuger
      Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.
      ,
      • Horowitz N.S.
      • Goldstein D.P.
      • Berkowitz R.S.
      Placental site trophoblastic tumors and epithelioid trophoblastic tumors: biology, natural history, and treatment modalities.
      ].

      1.2 Molar pregnancy

      There are two histologically distinct subtypes of hydatidiform moles, complete (CM) and partial (PM). The majority of CM result from fertilization of an ovum lacking maternal nuclear DNA, with subsequent duplication of the haploid genome from a single sperm (80%) or dispermic fertilization (20%). The resulting karyotypes are diploid, either 46 XX or 46 XY, and are completely paternally derived [
      • Lawler S.D.
      • Fisher R.A.
      • Dent J.
      A prospective genetic study complete and partial hydatidiform moles.
      ,
      • Lage J.M.
      • Mark S.D.
      • Roberts D.J.
      • et al.
      A flow cytometric study of 137 fresh hydropic placentas: correlation between types of hydatidiform moles and nuclear DNA ploidy.
      ]. PM are almost always triploid, resulting from dispermic fertilization of an ovum retaining its maternal DNA [
      • Lawler S.D.
      • Fisher R.A.
      • Dent J.
      A prospective genetic study complete and partial hydatidiform moles.
      ,
      • Lage J.M.
      • Mark S.D.
      • Roberts D.J.
      • et al.
      A flow cytometric study of 137 fresh hydropic placentas: correlation between types of hydatidiform moles and nuclear DNA ploidy.
      ]. Although rare, if a woman has 2 or 3 consecutive moles familial recurrent hydatidiform mole syndrome (FRHM)) should be suspected [
      • Fisher R.A.
      • Hodges M.D.
      • Newlands E.S.
      Familial recurrent hydatidiform mole: a review.
      ]. CM related to FRHM are diploid and genetically biparental rather than androgenic and result from sporadic mutations in NLRP7 (70% of cases), KHDC3L (5–10%% of cases), or from gene(s) unidentified to date. [
      • Fisher R.A.
      • Hodges M.D.
      • Newlands E.S.
      Familial recurrent hydatidiform mole: a review.
      ,
      • Murdoch S.
      • Djuric U.
      • Mazhar B.
      • et al.
      Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans.
      ,
      • Wang C.M.
      • Dixon P.H.
      • Decordova S.
      • et al.
      Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region.
      ]. If FRHM is confirmed, egg donation from an unaffected individual is a way to enable a successful non-molar pregnancy [
      • Fisher R.A.
      • Maher G.J.
      Genetics of gestational trophoblastic disease.
      ].
      Hydatidiform moles are characterized by unregulated trophoblastic proliferation, resulting in increased production of hCG. Elevated hCG levels above 100,000 IU/L are commonly observed with CM, but these levels are rare in PM given the less prominent trophoblastic hyperplasia [
      • Berkowitz R.S.
      • Goldstein D.P.
      Clinical practice. Molar pregnancy.
      ,
      • Genest D.R.
      • Laborde O.
      • Berkowitz R.S.
      • et al.
      A clinicopathologic study of 153 cases of complete hydatidiform mole (1980-1990): histologic grade lacks prognostic significance.
      ]. Ultrasonographic findings of a vesicular pattern, indicating hydropic villi, and theca lutein cysts are strongly suggestive of the diagnosis of CM [
      • Benson C.B.
      • Genest D.R.
      • Bernstein M.R.
      • et al.
      Sonographic appearance of first trimester complete hydatidiform moles.
      ]. Ultrasonographic features suggestive of a PM include focal cystic changes in the placenta, presence of a nonviable fetus, and an elevated ratio of the transverse to anteroposterior dimension of the gestational sac [
      • Fine C.
      • Bundy A.L.
      • Berkowitz R.S.
      • et al.
      Sonographic diagnosis of partial hydatidiform mole.
      ].
      The use of sensitive hCG assays and early ultrasound have shifted detection of molar pregnancy into the first trimester and therefore the classic presenting symptoms (excessive uterine size, anemia, pre-eclampsia, hyperemesis, hyperthyroidism, and respiratory failure) are rarely encountered [
      • Curry S.L.
      • Hammond C.B.
      • Tyrey L.
      • et al.
      Hydatidiform mole: diagnosis, management and long-term follow-up of 347 patients.
      ,
      • Kohorn E.I.
      Molar pregnancy: presentation and diagnosis.
      ,
      • Szulman A.E.
      • Surti U.
      The clinicopathological profile of the partial hydatidiform mole.
      ,
      • Soto-Wright V.
      • Bernstein M.
      • Goldstein D.P.
      • Berkowitz R.S.
      The changing clinical presentation of complete molar pregnancy.
      ]. This shift to earlier detection and evacuation has necessitated the use of additional diagnostics such as flow cytometry to determine ploidy, and immunohistochemistry staining for the cyclin dependent kinase inhibitor, p57 [
      • Fisher R.A.
      • Maher G.J.
      Genetics of gestational trophoblastic disease.
      ]. As a paternally imprinted and maternally expressed gene, p57 can differentiate between CM (p57 negative) and either a PM (p57 positive) or non-molar hydropic abortions [
      • Genest D.R.
      • Dorfman D.M.
      • Castrillon D.H.
      Ploidy and imprinting in hydatidiform moles: complementary use of flow cytometry and immunohistochemistry of the imprinted gene product p57KIP2 to assist molar classification.
      ]. These additional diagnostics are performed on tissue obtained at evacuation, not separate biopsies.
      The initial treatment of hydatidiform moles in women who wish to preserve fertility is suction dilation and curettage (D&C), preferably performed with the largest cannula that is easily introduced and with uterotonic agents administered as necessary [
      • Ngan H.Y.S.
      • Seckl M.J.
      • Berkowitz R.S.
      • et al.
      Update on the diagnosis and management of gestational trophoblastic disease.
      ,
      • Padron L.
      • Rezende F.
      • Amim J.
      • Sun S.Y.
      • Charry R.C.
      • Maesta I.
      • et al.
      Manual compared with electric vaccum aspiration for treatment of molar pregnancy.
      ]. Ultrasound guidance may be used at the discretion of the surgeon but may increase the rate of complete evacuation. Uterine evacuation by medication only methods is discouraged due to high failure rates, risk of hemorrhage, and increased development of GTN requiring chemotherapy [
      • Tidy J.A.
      • Gillespie A.M.
      • Bright N.
      • et al.
      Gestational trophoblastic disease: a study of mode of evacuation and subsequent need for treatment with chemotherapy.
      ]. RhD factor is expressed on trophoblastic tissue, therefore RhD immunoglobulin should be administered at the time of uterine evacuation in Rh negative women [
      • Eysbouts Y.K.
      • Bulten J.
      • Ottevanger P.B.
      • Thomas C.M.G.
      • Kate-Booij M.J.
      • van Heraarden A.E.
      • Siebers A.G.
      • FCGJ Sweep
      • LFAG Massuger
      Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.
      ]. Given the earlier gestational age of diagnosis, complications during or after evacuation are uncommon, but surgeons should be prepared to manage excessive bleeding and pulmonary compromise. For those who have completed childbearing and have a presumed molar pregnancy, hysterectomy provides an alternative method of management. In one study, compared to uterine evacuation, hysterectomy has a significant advantage in preventing post-molar GTN with an approximately 80% reduction in risk [
      • Zhao P.
      • Lu Y.
      • Huang W.
      • Tong B.
      • Lu W.
      Total hysterectomy versus uterine evacuation for preventing post-molar gestational trophoblastic neoplasia in patients who are at least 40 years old: a systemic review and meta-analysis.
      ]. Although hysterectomy eliminates any locally invasive disease, some women will have occult metastases at the time of diagnosis and therefore hCG monitoring is still warranted after hysterectomy [
      • Zhao P.
      • Lu Y.
      • Huang W.
      • Tong B.
      • Lu W.
      Total hysterectomy versus uterine evacuation for preventing post-molar gestational trophoblastic neoplasia in patients who are at least 40 years old: a systemic review and meta-analysis.
      ].
      Post-evacuation surveillance with hCG is critical in identifying the development of post-molar GTN. Ideally, an assay that can detect all forms of hCG (beta-hCG, core hCG, C-terminal hCG, nicked-free beta, beta-core, and hyperglycosylated) equally well should be used and are often referred to as “total hCG assays” [
      • Cole L.A.
      Human chorionic gonadotropin and associated molecules.
      ,
      • Muller C.Y.
      • Cole L.A.
      The quagmire of hCG and hCG testing in gynecologic oncology.
      ]. hCG is routinely monitored weekly until normalization or diagnosis of GTN, however, appropriate duration of hCG surveillance varies considerably by histologic subtype and the institution performing the surveillance. Current guidelines for the duration of surveillance from various organizations and trophoblastic reference centers are noted in Table 1 [

      Gestational Trophoblastic Neoplasia, NCCN Guidelines version1. 2022

      ,
      • Coyle C.
      • Short D.
      • Jackson L.
      • et al.
      What is the optimal duration of human chorionic gonadotropin surveillance following evacuation of a molar pregnancy? A retrospective analysis of over 20,000 consecutive patients.
      ,
      • Tidy J.
      • Seck M.
      • Hancock B.W.
      On behalf of the royal college of obstetricians and gynaecologists. Management of Gestational Trophoblastic Disease.
      ,
      • Albright B.B.
      • Shorter J.M.
      • Mastroyannis S.A.
      • Ko E.M.
      • Schreiber C.A.
      • Sonalkar S.
      ]. A recent meta-analysis by Albright et al. [
      • Albright B.B.
      • Shorter J.M.
      • Mastroyannis S.A.
      • Ko E.M.
      • Schreiber C.A.
      • Sonalkar S.
      ] confirmed that the overall incidence of post-molar GTN is approximately 20% for CM and 4% for PM. For those patients who normalize their hCG <56 days after evacuation, the risk of developing GTN is 0.03% following CM and 0.02% after PM. For those that normalize ≥56 days the rate is still low, 0.3% and 0.03% respectively. This data is very reassuring and supports the recommendation that once hCG normalization is achieved follow up should continue until 3 months after CM and 1 month after PM, while maintaining patient safety [
      • Albright B.B.
      • Shorter J.M.
      • Mastroyannis S.A.
      • Ko E.M.
      • Schreiber C.A.
      • Sonalkar S.
      ,
      • Berkowitz R.S.
      • Horowitz N.S.
      • Elias K.M.
      Hydatidiform Mole: Treatment and Follow Up.
      ].
      Table 1Current guidelines for hCG follow up after molar pregnancy.
      1. ACOG monthly hCG x 6 months for both complete and partial mole (4).
      2. National Comprehensive Cancer Network (NCCN) - 3 consecutive normal hCG levels followed by 2 hCG assays in 3-month intervals (32)
      3. FIGO - hCG monitoring every 1–2 weeks until normal followed by a single confirmatory normal hCG in a month for partial moles and monthly hCG for 6 months for complete moles (26)
      4. United Kingdom (UK) - monthly hCG for six months for both CM starting from the date of evacuation if normalization took ≤56 days or from the date of normalization if this took >56 days. For PM only one confirmatory normal hCG is needed 1 month after the first normal (34)
      5. New England Trophoblastic Disease Center (NETDC) - After normalization of weekly hCG for partial mole one confirmatory hCG a month after normalization and 3 monthly hCG for complete moles (36).
      Despite earlier diagnosis, the incidence of post-molar GTN has remained constant over time [
      • Sun S.Y.
      • Melamed A.
      • Goldstein D.P.
      • et al.
      Changing presentation of complete hydatidiform mole at the New England trophoblastic disease center over the last three decades: does early diagnosis alter risk for gestational trophoblastic neoplasia?.
      ]. Risk factors for developing post-molar GTN include hCG at diagnosis >100,000 IU/L, excessive uterine size, theca lutein cysts, and age > 40 years. Women aged 40–49 with initial hCG levels exceeding 175,000 mIU/mL represent an especially at risk group, with 85% developing post-evacuation GTN [
      • Elias K.M.
      • Shoni M.
      • Bernstein M.R.
      • et al.
      Complete hydatidiform mole in women aged 40–49 years.
      ]. In women older than 50 years, the risk of post-evacuation GTN may be as high as 60%, regardless of presenting hCG level [
      • Elias K.M.
      • Goldstein D.P.
      • Berkowitz R.S.
      Complete hydatidiform mole in women older than age 50.
      ], though population based studies place this risk for older women around 30% [
      • Savage P.
      • Winter M.
      • Parker V.
      • Harding V.
      • Sita-Lumsden A.
      • Fisher R.A.
      • Harvery R.
      • Unsworth N.
      • Sarwar N.
      • Short D.
      • Agular X.
      • Tidy J.
      • Hancock B.
      • Coleman R.
      • Seckl M.J.
      Demographis, natural history and treatment outcomes of non-molar gestational choriocarcinoma: a UK population study.
      ]. For these women, or for those in whom reliable hCG follow up cannot be obtained, hysterectomy should be considered [
      • Elias K.M.
      • Goldstein D.P.
      • Berkowitz R.S.
      Complete hydatidiform mole in women older than age 50.
      ,
      • Zhao P.
      • Chen C.
      • Lu W.
      Comparison of different therapeutic strategies for complete hydatidiform mole in women at least 40 years old: a retrospective cohort study.
      ,
      • Sugrue R.
      • Foley O.
      • Elias K.M.
      • Growdon W.B.
      • et al.
      Outcomes of minimally invasive versus open abdominal hysterectomy in patients with gestational trophoblastic disease.
      ]. Although use of prophylactic chemotherapy at the time of hysterectomy for molar pregnancy has been shown to decrease the risk of developing GTN, for those that do develop GTN despite prophylactic chemotherapy, there is often a delayed diagnosis, increase drug resistance, exposure to toxicity, and worse outcome [
      • Limpongsanurak S.
      Prophylactic actinomycin D for high-risk complete hydatidiform mole.
      ,
      • Wang Q.
      • Fu J.
      • Hu L.
      • et al.
      Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia.
      ]. Therefore it is not recommended in this setting.
      Development of a new gestation prior to the completion of post-molar surveillance poses a diagnostic dilemma, and as such reliable contraception during this period is strongly advised. Importantly, recent data suggests that the use of hormonal contraception during post-molar follow-up does not increase the risk of developing or the severity of GTN and does not postpone normalization of hCG [
      • Stone M.
      • Bagshawe K.D.
      An analysis of the influences of maternal age, gestational age, contraceptive method, and the mode of primary treatment of patients with hydatidiform moles on the incidence of subsequent chemotherapy.
      ,
      • Dantas P.R.S.
      • Maesta I.
      • Filho J.R.
      • et al.
      Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk-factors?.
      ,
      • Braga A.
      • Maesta I.
      • Short D.
      • Savage P.
      • Harvey R.
      • Seckl M.J.
      Hormonal contraceptive use before hCG remission does not increase the risk of gestational trophoblastic neoplasia following complete hydatidiform mole: a historical database review.
      ].

      1.3 Human chorionic gonadotropin (hCG)

      Human chorionic gonadotropin (hCG) is part of the glycoprotein hormone family along with luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). These hormones are heterodimers, sharing a common alpha subunit and different, but with varying degrees of homology, betasubunits. The intact heterodimeric form of hCG is produced almost exclusively by cytotrophoblast and syncytiotrophoblast of the placenta, GTN, germ cell, and other somatic tumors, such as bladder or lung, with trophoblastic elements [
      • Harvey Richard
      Measurement of Human Chorionic Gonadotrophin (hCG) in the management of trophoblastic disease.
      ]. In addition to the intact heterodimer, there is another isoform, hyperglycosolated hCG (hCG H) which contains more sugar residues than regular hCG, is predominately produced by cytotrophoblasts, and promotes trophoblastic growth and invasion [
      • Cole L.A.
      Hyerglycosolated hCG.
      ]. In addition, multiple variants are produced by enzymatic degradation in the tissue and circulation. The most common variants include free beta subunit, free alpha subunit, nicked hCG, nicked hCG beta, and hCG beta subunit core fragment [
      • Harvey Richard
      Measurement of Human Chorionic Gonadotrophin (hCG) in the management of trophoblastic disease.
      ].
      All common commercially available hCG assays are sandwich-type immunoassays that measure the beta-subunit, the intact hCG, and almost all the major variants described above. These sandwich assays are highly sensitive and can detect serum hCG levels as low as 1–2 IU/L and in urine as low as 10–50 IU/L [
      • Harvey Richard
      Measurement of Human Chorionic Gonadotrophin (hCG) in the management of trophoblastic disease.
      ]. Fortunately, hCG is an exquisitely sensitive tumor marker thus allowing for easy diagnosis, monitoring response to treatment, and identifying recurrence of GTN. This is most successful if the same assay is used consistently throughout the course of care as there can be great variation between assays.
      False negative and false positive results for hCG can occur at the extremes of value. Markedly elevated hCG, usually when hCG > 1000,000 IU/L can produce a phenomenon known as the “hook effect”, in which the fixed, solid phase antibodies and the labeled, soluble antibodies are saturated preventing sandwich formation and a negative result. If hook effect is suspected, the true value can be obtained with serial dilutions of the sample before analysis [
      • Al-Mahdili H.A.
      • Jones G.R.
      High-dose hook effect in six automated human chorionic gonadotropnin assays.
      ,
      • Winder A.D.
      • Suarez Mora Am Betty E.
      • Lurain J.R.
      The “hook effect” causing a negative pregnancy test in a patient with an advanced molar pregnancy.
      ]. Additionally, false negative results can occur if the tumor secretes a form of hCG not detected or under-detected by a particular assay. When there is a persistently low but positive hCG level, defined as an hCG < 1000 IU/L with no more than a two-fold variation over at least a 3-month period and in the absence of tumor on imaging, one must consider false positive results, phantom hCG, or other sources of hCG such as the pituitary [
      • Cole L.A.
      • Khanlian S.A.
      • Giddings A.
      • Butler S.A.
      • Muller C.Y.
      • Hammond C.
      • Kohorn E.
      Gestational trophoblastic diseases: 4. Presentation with persistent low positive human chorionic gonadotropin test results.
      ]. Phantom hCG results from heterophile antibodies that interfere with the immunoassay. This can be confirmed if hCG elevation is noted only in serum and not in urine, by using two separate commercial assays in which the results vary greatly or are negative in repeat assay, or by persistent elevated hCG despite serial dilution of the serum. The pituitary gland produces a small amount of hCG which becomes more pronounced around menopause or in women in whom multi-agent, high dose chemotherapy has temporarily stopped ovarian function. Pituitary hCG can be distinguished from real trophoblastic hCG by placing the patient on higher dose oral contraceptive or GnRH agonist which will suppress pituitary hCG production [
      • Cole L.A.
      • Khanlian S.A.
      • Giddings A.
      • Butler S.A.
      • Muller C.Y.
      • Hammond C.
      • Kohorn E.
      Gestational trophoblastic diseases: 4. Presentation with persistent low positive human chorionic gonadotropin test results.
      ].

      1.4 GTN

      Unlike other malignancies, GTN does not necessarily need histologic confirmation, (although choriocarcinoma is occasionally seen on a D&C or hysterectomy), and is the only malignancy diagnosed based on a serum assay. In 2018, FIGO/WHO updated criteria for diagnosing post-molar GTN (Table 2) [
      • Ngan H.Y.S.
      • Seckl M.J.
      • Berkowitz R.S.
      • et al.
      Update on the diagnosis and management of gestational trophoblastic disease.
      ]. Prior to 2018, hCG persistence for 6 months after evacuation was a diagnostic criterion, however, recent data suggests ≥80% of those with a persistently elevated but falling hCG 6 months after evacuation, who are managed expectantly without initiation of chemotherapy, ultimately achieve undetectable levels. For those that do not achieve undetectable levels, there is no worsening of outcome [
      • Braga A.
      • Torres B.
      • Burla M.
      • Maesta I.
      • Sun S.Y.
      • Lin L.
      • Madi J.M.
      • Uberti E.
      • Viggiano M.
      • Elias K.M.
      • Berkowitz R.S.
      Is chemotherapy necessary for patients with molar pregnancy and human chorionic gonadotropin serum levels raised but falling at 6 months after uterine evacuation?.
      ,
      • Agarwal R.
      • Teoh S.
      • Short D.
      • Harvey R.
      • Salvage P.M.
      • Seckl M.J.
      Chemotherapy and human chorionic gonadotropin concentrations 6 months after uterine evacuation of molar pregnancy: a retrospective cohort study.
      ]. For GTN diagnosed after a non-molar pregnancy, a single elevated hCG with exclusion of any other explanation other than GTN is sufficient for diagnosis. This is particularly true if there is unexplained metastatic disease. Importantly, biopsies should be avoided as the highly vascular nature of GTN can lead to significant bleeding complications.
      Table 2FIGO /WHO criteria for diagnosis of post-molar GTN (26).
      1. Plateauing of hCG +/− 10% for 4 consecutive values over 3 weeks (i.e., days 1, 7, 14, 21)
      2. A rise in hCG levels of ≥10% for 3 values over 2-week period (i.e., days 1, 7, 14)
      3. Histologic diagnosis of choriocarcinoma or clinical and/or radiologic evidence of metastases
      Once criteria are met, patients must be evaluated for extent of disease and assigned a FIGO anatomic stage (Table 3) and WHO risk score (Table 4) to determine the likelihood of disease progression and/or resistance to treatment with single agent chemotherapy [
      Gestational Trophoblastic Neoplasms (Female Reproductive Organs).
      ]. Evaluation should include a complete physical examination including a pelvic examination and a chest radiograph as lung and vaginal metastases are the most common site of disease. FIGO expressly recommends chest radiograph rather than chest computed tomography (CT) for staging as micrometastases are detected on CT scans in approximately 40% of patients with negative chest X-rays. These micrometastases do not affect overall survival and can unnecessarily increase the use of multi-agent chemotherapy [
      • Frijstein M.M.
      • Lok C.A.R.
      • van Trommel N.E.
      • ten Kate-Booij M.J.
      • Massuger L.F.A.G.
      Lung metastases in low-risk gestational trophoblastic neoplasia: a retrospective cohort study.
      ]. If there is evidence of metastatic disease on the initial evaluation, CT scan of abdomen and pelvis as well as MRI of the brain are warranted. Other investigations should include routine laboratory tests (complete blood count, hepatic, renal, thyroid tests, chemistry, blood group, and hCG) and a pelvic ultrasound to exclude intrauterine pregnancy, asses uterine size, and estimate intrauterine tumor size and/or invasion. When calculating WHO score it is important to use the hCG at time of GTN diagnosis, not hCG at time of mole evacuation, as this can lead to an inappropriately elevated WHO score. Additionally, WHO risk scores do not apply to PSTT or ETT. Treatment for these histologies is based on the independent adverse prognostic factors FIGO stage (III/IV) and the time from the antecedent pregnancy, with ≥48 months considered high-risk disease warranting chemotherapy [
      • Frijstein M.M.
      • Lok C.A.R.
      • van Trommel N.E.
      • Ten Kate-Booji M.J.
      • Massuger L.F.A.G.
      • et al.
      Management and prognostic factors of epithelioid trophoblastic tumors: results from the International Society for the Study of trophoblastic diseases database.
      ,
      • Froeling F.E.M.
      • Ramaswami R.
      • Papanastasopoulos P.
      • Kaur B.
      • Sebire N.J.
      • Short D.
      • Fisher R.A.
      • et al.
      Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours.
      ].
      Table 3FIGO staging (54):
      Stage IDisease confined to uterine corpus
      Stage IIGTN extends outside of uterus, but is limited to the genital structures (adnexa, vagina, broad ligament)
      Stage IIIGTN extends to the lungs, with or without known genital tract involvement
      Stage IVAll other metastatic sites
      Table 4WHO Risk Score (54).
      Scores
      0124
      Age (yr)<40≥40
      Antecedent pregnancyMoleAbortionTerm
      Interval months from index pregnancy<44–<77–<13≥13
      Pretreatment serum hCG (International Unit/L)<103103–<104104–<105>105
      Largest tumor size (including uterus)3–<5 cm≥5 cm
      Site of metastasesLungKidney/spleenGastrointestinal/liverBrain
      Number of metastases1–45–8>8
      Previous failed chemotherapySingle drug2 or more drugs
      Format for reporting to FIGO Annual Report: In order to stage and allot a risk factor score, a patient's diagnosis is allocated to a stage as represented by a Roman numeral I, II, III, and IV. This is then separated by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals for example, stage II:4, stage IV:9. This stage and score will be allotted for each patient.
      Definition of Risk Categories:
      Low Risk - Stage I or Stage II/III with a WHO prognostic score < 7.
      High Risk - Stage IV disease or any stage and WHO score ≥ 7.
      Ultra-high Risk - Any stage with WHO score > 12.
      Women with stage I or stage II/III with a WHO prognostic score < 7 are considered to have low-risk disease and are treated with single agent chemotherapy while those with stage IV disease or WHO score ≥ 7 have high-risk disease and receive multi-agent chemotherapy. A separate category of ultra- high-risk, defined as WHO score > 12, identifies women at high risk of early death and poor outcome who should be treated with low dose induction chemotherapy before initiating multi-agent chemotherapy [
      • Alifrangis C.
      • Agarwal R.
      • Short D.
      • Fisher R.A.
      • Sebire N.J.
      • Harvey R.
      • et al.
      EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis.
      ].

      1.5 Low-Risk GTN

      Low-risk GTN is primarily treated and cured with one of two single agent drugs, methotrexate (MTX) or Dactinomycin (Act-D) [
      • Lok C.
      • van Trommel N.
      • Massugar L.
      • Golfier F.
      • Seckl M.
      Practical clinical guidelines of EOTTD for the treatment and referral of gestational trophoblastic disease.
      ,
      • Ngan H.Y.S.
      • Seckl M.J.
      • Berkowitz R.S.
      • et al.
      Update on the diagnosis and management of gestational trophoblastic disease.
      ,
      • Lawrie T.A.
      • Alazzam M.
      • Tidy J.
      • Hancock B.W.
      • Osborne R.
      First-line chemotherapy in low-risk gestational trophoblastic neoplasia.
      ,
      • Osborne R.J.
      • Filiaci V.
      • Schink J.C.
      • Mannel R.S.
      • Alvarez Secord A.
      • et al.
      Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study.
      ,
      • Braga A.
      • Araujo C.
      • Mora P.
      • Paulino Ede Melo A.
      • Velarde G.
      • et al.
      Comparison of treatment for low-risk GTN with standard 8-day MTX/FA regimen versus modified MTX/FA regimen without chemotherapy on the weekend.
      ,
      • Maesta I.
      • Nitecki R.
      • Horowitz N.S.
      • Goldstein D.P.
      • et al.
      Effectiveness and toxicity of first-line methotrexate chemotherapy in low-risk postmolar gestational trophoblastic neoplasia: the New England trophoblastic disease center experience.
      ,
      • Lurain J.R.
      • Elfstrand E.P.
      Single-agent methotrexate chemotherapy for the treatment of nonmetastatic gestational trophoblastic tumors.
      ,
      • Schink J.C.
      • Filiaci V.
      • Huang H.Q.
      • Tidy J.
      • Winter M.
      • Carter J.
      • et al.
      An international randomized phase III trial of pulse actinomycin-D versus multi-day methotrexate for the treatment of low risk gestational trophoblastic neoplasia; NRG/GOG275.
      ,
      • Mangili G.
      • Cioffi R.
      • Danese S.
      • Frigerio L.
      • Ferrandina G.
      • Cormio G.
      • Rabaiotti E.
      • Scarfone G.
      • Gadducci A.
      • Bergamini A.
      • Pisano C.
      • Candiani M.
      Does methotrexate (MTX) dosing in a 8-day MTX/FA regimen for the treatment of low-risk gestational trophoblastic neoplasia affect outcome? The MITO-9 study.
      ]. A variety of doses and infusion schedules for these drugs have been utilized but multi-day MTX (either 8-day or 5-day) and pulse Act-D seem to be the most efficacious (Table 5) [
      • Lawrie T.A.
      • Alazzam M.
      • Tidy J.
      • Hancock B.W.
      • Osborne R.
      First-line chemotherapy in low-risk gestational trophoblastic neoplasia.
      ]. Weekly methotrexate has been used secondarily for ease of schedule and low toxicity but it is not as effective as multi-day regimens [
      • Osborne R.J.
      • Filiaci V.
      • Schink J.C.
      • Mannel R.S.
      • Alvarez Secord A.
      • et al.
      Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study.
      ]. New data suggests that modifying the 8-day MTX regimen to avoid a weekend administration (treatment on the 8th day rather than 7th) does not compromise oncologic outcome [
      • Braga A.
      • Araujo C.
      • Mora P.
      • Paulino Ede Melo A.
      • Velarde G.
      • et al.
      Comparison of treatment for low-risk GTN with standard 8-day MTX/FA regimen versus modified MTX/FA regimen without chemotherapy on the weekend.
      ]. To date, there is not a clearly superior regimen between these two drugs, with complete remission rates ranging between 75 and 90% and rare grade 3 or 4 toxicities, for both agents [
      • Lawrie T.A.
      • Alazzam M.
      • Tidy J.
      • Hancock B.W.
      • Osborne R.
      First-line chemotherapy in low-risk gestational trophoblastic neoplasia.
      ,
      • Osborne R.J.
      • Filiaci V.
      • Schink J.C.
      • Mannel R.S.
      • Alvarez Secord A.
      • et al.
      Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study.
      ,
      • Braga A.
      • Araujo C.
      • Mora P.
      • Paulino Ede Melo A.
      • Velarde G.
      • et al.
      Comparison of treatment for low-risk GTN with standard 8-day MTX/FA regimen versus modified MTX/FA regimen without chemotherapy on the weekend.
      ,
      • Maesta I.
      • Nitecki R.
      • Horowitz N.S.
      • Goldstein D.P.
      • et al.
      Effectiveness and toxicity of first-line methotrexate chemotherapy in low-risk postmolar gestational trophoblastic neoplasia: the New England trophoblastic disease center experience.
      ,
      • Lurain J.R.
      • Elfstrand E.P.
      Single-agent methotrexate chemotherapy for the treatment of nonmetastatic gestational trophoblastic tumors.
      ,
      • Schink J.C.
      • Filiaci V.
      • Huang H.Q.
      • Tidy J.
      • Winter M.
      • Carter J.
      • et al.
      An international randomized phase III trial of pulse actinomycin-D versus multi-day methotrexate for the treatment of low risk gestational trophoblastic neoplasia; NRG/GOG275.
      ,
      • Mangili G.
      • Cioffi R.
      • Danese S.
      • Frigerio L.
      • Ferrandina G.
      • Cormio G.
      • Rabaiotti E.
      • Scarfone G.
      • Gadducci A.
      • Bergamini A.
      • Pisano C.
      • Candiani M.
      Does methotrexate (MTX) dosing in a 8-day MTX/FA regimen for the treatment of low-risk gestational trophoblastic neoplasia affect outcome? The MITO-9 study.
      ]. Treatment therefore is often determined by institutional preference. However, in 2016, a Cochrane Review including over 600 patients in 7 randomized controlled trials showed Act-D appeared to be superior to MTX (RR 0.65, 95%CI 0.57–0.75) [
      • Lawrie T.A.
      • Alazzam M.
      • Tidy J.
      • Hancock B.W.
      • Osborne R.
      First-line chemotherapy in low-risk gestational trophoblastic neoplasia.
      ]. Alternative single drug options for low-risk GTN include etoposide or fluorouracil [
      • Matsui H.
      • Itsuka Y.
      • Seki K.
      • Sekiya S.
      Comparison of chemotherapies with methotrexate, VP-16 and actinomycin D in low risk gestational trophoblastic disease. Remission rates and drug toxicities.
      ,
      • Sung H.C.
      • Wu P.C.
      • Yang H.Y.
      Reevaluation of 5-fluorouracil as a single therapeutic agent for gestational trophoblastic neoplasms.
      ], though these are not typically used outside of Asia.
      Table 5Single-agent regimens for low-risk gestational trophoblastic neoplasia (59–65).
      Methotrexate RegimensPrimary remission rates
      Weekly IM 30–50 mg/m249–74%
      Multi-day every 2 weeks
       5-day IV or IM 0.3–0.5 mg/kg87–93%
       8-day IV or IM 1 mg/kg on days 1,3,5,7
      Leucovorin 15 mg PO on days 2, 4, 6,8.
      74–90%
       8-day IM 50 mg on days 1,3, 5, 7
      Leucovorin 15 mg PO on days 2, 4, 6,8.
      70–80%
      High dose IV
      Leucovorin 15 mg PO every 12 h × 6 doses beginning 24 h after starting MTX.
      69–90%
       100 mg/m2 over 30 min
       200 mg/m2 over 12 h
      Dactinomycin Regimens
      Maximum dose 2 mg (2000 micrograms).
      Pulse 1.25 mg/m2 IV every 2 weeks69–90%
      5- day 10–12 micrograms IV every 5 days77–94%
      low asterisk Leucovorin 15 mg PO on days 2, 4, 6,8.
      low asterisklow asterisk Leucovorin 15 mg PO every 12 h × 6 doses beginning 24 h after starting MTX.
      low asterisklow asterisklow asterisk Maximum dose 2 mg (2000 micrograms).
      Women with low-risk GTN with scores 5 or 6 are a particularly challenging group with only approximately 30% responding to single agent chemotherapy [
      • Sita-Lumsden A.
      • Short D.
      • Lindsay I.
      • Sebire N.J.
      • Adjogatse D.
      • Seckl M.J.
      • Savage P.M.
      Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at Charing cross hospital, 2000-2009.
      ]. A recent multicenter retrospective study identified predictors of single agent resistance. In the study approximately 60% of patients achieved complete remission after first or second line single agent therapy. All women with metastatic choriocarcinoma needed multi-agent chemotherapy. For those without metastases or choriocarcinoma, and hCG was >410,000 IU/L and for those patients with metastases or choriocarcinoma and hCG >150,000 IU/L combination chemotherapy was also necessary to obtain remission [
      • Braga A.
      • Paiva G.
      • Ghorani E.
      • Freitas F.
      • Guillermo Coca Velande G.
      • Kour B.
      • Unsworth N.
      • Lozano-Kuehne J.
      • Viena dos Santos Esteves A.
      • FilhoJ Rezende
      • Amim J.
      • Aguiar X.
      • Sarwar N.
      • Elias K.M.
      • Horowitz N.S.
      • Berkowtiz R.S.
      • Seckl M.J.
      Predictors for single-agent resistance in FIGO score 5 or 6 gestational trophoblastic neoplasia: a multicenter retrospective cohort study.
      ].
      After complete remission is obtained, consolidation therapy, using the last effective regimen should be delivered to prevent relapses. Lybol and colleagues showed that 3 rather than 2 cycles of consolidation decreased the risk of relapse (4 vs 8%) [
      • Lybol C.
      • Sweep F.C.
      • Harvey R.
      • Mitchell H.
      • Short D.
      • Thomas C.M.
      • et al.
      Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia.
      ]. The chemotherapy cycle delivered at first hCG normalization is considered the first consolidation cycle.
      Survival for women with low-risk GTN is excellent with rates approaching 100%. To achieve this high rate of success, additional chemotherapy regimens or surgical intervention may be necessary. Patients can have primary resistant disease (rising hCG after two cycles of treatment or hCG plateau (<10% change) over three cycles) or may develop acquired resistance (hCG plateau over two course or rising hCG over 2 weeks after an initial response) [
      • Lok C.
      • van Trommel N.
      • Massugar L.
      • Golfier F.
      • Seckl M.
      Practical clinical guidelines of EOTTD for the treatment and referral of gestational trophoblastic disease.
      ]. New areas of metastases would also qualify as resistance/progression. Depending upon the hCG level at the time of resistance or if toxicity prevents adequate dosing/schedule, switching to the alternate single agent (ActD or MTX) or other single agent chemotherapy such as Carboplatin should be considered [
      • Winter M.C.
      • Tidy J.A.
      • Hilts A.
      • Ireson J.
      • Gillett S.
      • Singh K.
      • Hancock B.W.
      • Coleman R.E.
      Risk adapted single-agent dactinomycin or carboplatin for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia.
      ,
      • Mora P.A.R.
      • Sun S.Y.
      • Velarde G.C.
      • Filho J.R.
      • Uberti E.H.
      • dos Santos Esteves A.P.V.
      • Elias K.M.
      • Horowitz N.S.
      • Braga A.
      • Berkowitz R.S.
      Can carboplatin or etoposide replace actinomycinod for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia?.
      ]. If there is an inadequate response to the initial single agent,if there are new metastases, and/or if hCG plateaus at a high level (>3000 IU/L), then multi-agent chemotherapy regimens should be employed [
      • Lok C.
      • van Trommel N.
      • Massugar L.
      • Golfier F.
      • Seckl M.
      Practical clinical guidelines of EOTTD for the treatment and referral of gestational trophoblastic disease.
      ]. Additionally, for those with resistant disease, hysterectomy or resection of persistent metastatic disease could be considered, especially for those who no longer desire to preserve their fertility [
      • Sugrue R.
      • Foley O.
      • Elias K.M.
      • Growdon W.B.
      • et al.
      Outcomes of minimally invasive versus open abdominal hysterectomy in patients with gestational trophoblastic disease.
      ,
      • Eysbouts Y.K.
      • Massuger L.F.A.G.
      • IntHout J.
      • Lok C.A.R.
      • Sweep F.C.G.J.
      • Ottewanger F.B.
      The added value of hysterectomy in management of gestational trophoblastic neoplasia.
      ].
      Second dilation and curettage has been investigated as an alternative to chemotherapy for low-risk GTN. In appropriately selected patients, approximately 40% of patients are cured, avoiding toxicity of chemotherapy altogether [
      • Osborne R.J.
      • Filiaci V.L.
      • Schink J.C.
      • Mannel R.S.
      • Behbackht K.
      • et al.
      Second curettage for low -risk nonmetastatic gestational trophoblastic neoplasia.
      ]. Although the ideal candidate for attempt at second curettage could not be easily defined, patients at extremes of reproductive age and those with WHO score of 5 or 6 were less likely to respond to second curettage. Similarly, for those women with stage I low-risk GTN who are done with child bearing, hysterectomy, with or without a single dose of Act-D at the time of surgery, offers an excellent cure rate [41 73].
      Monitoring hCG during treatment should occur on a weekly basis or with day 1 of each cycle, both are acceptable. Although consolidation chemotherapy starts with the first normal hCG, remission is defined as three consecutive normal hCG. Posttreatment surveillance consists of monthly hCG for one year. In a recent population-based cohort study, 73% of recurrences occurred within 1 year of remission and the risk of recurrence beyond this was <1% per year [
      • Balachandran K.
      • Salawu A.
      • Ghorani E.
      • Kaur B.
      • Sebire N.J.
      • Short D.
      • Harvey R.
      • et al.
      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.
      ]. If new symptoms such as vaginal bleeding develop after the year of surveillance, recurrence needs to be considered and hCG evaluated.

      1.6 High-risk GTN

      The management of patients with high-risk metastatic or recurrent GTN remains a clinically difficult scenario. In an effort to cure patients with high-risk disease, and salvage those with persistent/recurrent GTN, several multi-agent chemotherapy regimens have been identified (Table 6) [
      • Lurain J.R.
      • Sing D.K.
      • Schink J.C.
      Management of high-risk gestational trophoblastic neoplasia: FIGO stages II-IV:risk factor score > or = 7.
      ,
      • Alazzam M.
      • Tidy J.
      • Osborne R.
      • Coleman R.
      • Hancock B.W.
      • Lawrie T.A.
      Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia.
      ,
      • Bower M.
      • Newlands E.S.
      • Holden L.
      • et al.
      EMA/CO for high-risk gestational trophoblastic tumours: results from a cohort of 272 patients.
      ,
      • Newlands E.S.
      • Mulholland P.J.
      • Holden L.
      • Seckl M.J.
      • Rustin G.J.
      Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumors.
      ,
      • Lurain J.R.
      • Schink J.C.
      Importance of salvage therapy in the management of high-risk gestational trophoblastic neoplasia.
      ,
      • Mao Y.
      • Wan X.
      • Lv W.
      • Xie X.
      Relapsed or refractory gestational trophoblastic neoplasia treated with the etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EP-EMA) regimen.
      ,
      • Wang J.
      • Short D.
      • Sebire N.J.
      • Lindsay I.
      • Newlands E.S.
      • Schmid P.
      • et al.
      Salvage chemotherapy of relapsed or high-risk gestational trophoblastic neoplasia (GTN) with paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE).
      ,
      • Yang J.
      • Xiang Y.
      Wan Xirun, Feng F, Ren Tong. Primary treatment of stage IV gestational trophoblastic noeplasia with floxuridine, dactinomycin, etoposide, and vincristine (FAEV): a report based on our 10-year clinical experience.
      ]. However, given the low prevalence of the disease, it is unclear which multi-agent regimen is most effective and least toxic, as randomized controlled trials have not been conducted.
      Table 6Salvage chemotherapy regimens for high-risk, persistent/recurrent, or refractory GTN (76–83, 87,89, 90).
      1. EMA-CO - Etoposide with methotrexate, actinomycin D (EMA) and vincristine and cyclophosphamide (CO)
      Day 1Etoposide100 mg/m2 IV bolus
      Actinomycin-D500 μg IV push
      Methotrexate100 mg/m2 IV push
      200 mg/m2 IV over 12 h
      Day 2
      Some centers omit day 2 etoposide, Act-D.
      Actinomycin-D500 μg IV push
      Etoposide100 mg/m2 IV bolus
      Leucovorin15 mg PO q 12 h
      Day 8Vincristine1.0 mg/m2
      Cyclophosphamide600 mg/m2
      2. EMA-EP – Etoposide, methotrexate, actinomycin-D, and cisplatin
      Day 1Etoposide100 mg/m2 IV bolus
      Actinomycin-D500 μg IV push
      Methotrexate100 mg/m2 IV push
      200 mg/m2 IV over 12 h
      Day 2
      Some centers omit day 2 etoposide, Act-D.
      Actinomycin-D500 μg IV push
      Etoposide100 mg/m2 IV bolus
      Leucovorin15 mg PO q 12 h
      Day 8Etoposide150 mg/m2 IV bolus
      Cisplatin75 mg/m2 IV bolus
      3. TE-TP – Paclitaxel + etoposide alternating Paclitaxel + cisplatin
      4. ACE – Actinomycin-D, cisplatin, etoposide
      5. VIP – Etoposide, ifosphamide cisplatin
      6. BEP – Bleomycin, etoposide, cisplatin
      7. ICE – Ifosphamide, carboplatin, etoposide
      8 Gemcitabine
      9. Capcetabine or 5 FU containing regimen such as FAEV – floxuridine, dactinomycin, etoposide, and vincristine
      10. Liposomal doxorubicin
      11. High dose chemotherapy with stem cell support
      12. Immune check point inhibitors
      Methotrexate dose increased to 1 g/m2 if brain metastases.
      low asterisk Some centers omit day 2 etoposide, Act-D.
      Developed at Charing Cross in 1979, EMA-CO has become the preferred regimen in the management of patients with high-risk disease [
      • Alazzam M.
      • Tidy J.
      • Osborne R.
      • Coleman R.
      • Hancock B.W.
      • Lawrie T.A.
      Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia.
      ]. In a report of 272 consecutive women with high-risk GTN, the cumulative 5-year survival rate was 86.2%. This was more efficacious in the chemotherapy naïve population. Seventy-eight percent achieved complete remission with EMA-CO, 17% developed drug resistance of whom 70% were salvaged with other chemotherapy, while 11 patients (4%) experienced early deaths [
      • Bower M.
      • Newlands E.S.
      • Holden L.
      • et al.
      EMA/CO for high-risk gestational trophoblastic tumours: results from a cohort of 272 patients.
      ]. Many other groups have shown similar responses to this multi-drug regimen [
      • Lurain J.R.
      • Sing D.K.
      • Schink J.C.
      Management of high-risk gestational trophoblastic neoplasia: FIGO stages II-IV:risk factor score > or = 7.
      ,
      • Alazzam M.
      • Tidy J.
      • Osborne R.
      • Coleman R.
      • Hancock B.W.
      • Lawrie T.A.
      Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia.
      ]. As with low-risk disease, chemotherapy for high-risk disease is continued for at least 3 consolidation courses after the first hCG normalization [
      • Lurain J.R.
      • Sing D.K.
      • Schink J.C.
      Management of high-risk gestational trophoblastic neoplasia: FIGO stages II-IV:risk factor score > or = 7.
      ,
      • Alazzam M.
      • Tidy J.
      • Osborne R.
      • Coleman R.
      • Hancock B.W.
      • Lawrie T.A.
      Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia.
      ].
      Despite the established efficacy of the EMA-CO regimen, approximately 30% of women will develop resistance, or experience relapse after remission, necessitating salvage chemotherapy [
      • Lurain J.R.
      • Schink J.C.
      Importance of salvage therapy in the management of high-risk gestational trophoblastic neoplasia.
      ]. In these patients, alternate regimens containing etoposide and platinum, with or without surgical resection, can usually affect cure. In EMA-CO failures, the most commonly employed regimen is EMA-EP (substituting etoposide and cisplatin for cyclophosphamide and vincristine in the EMA-CO regimen), with cure rates ranging from 66 to 85% [
      • Newlands E.S.
      • Mulholland P.J.
      • Holden L.
      • Seckl M.J.
      • Rustin G.J.
      Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumors.
      ,
      • Mao Y.
      • Wan X.
      • Lv W.
      • Xie X.
      Relapsed or refractory gestational trophoblastic neoplasia treated with the etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EP-EMA) regimen.
      ]. In an effort to mitigate the significant hematologic toxicity encountered using EMA-EP, investigators have also examined a taxane containing regimen, TE/TP (paclitaxel and etoposide alternating weekly with paclitaxel and cisplatin), with a 70% cure rate, in patients who were etoposide and platinum naïve, and reduced hematologic adverse events [
      • Wang J.
      • Short D.
      • Sebire N.J.
      • Lindsay I.
      • Newlands E.S.
      • Schmid P.
      • et al.
      Salvage chemotherapy of relapsed or high-risk gestational trophoblastic neoplasia (GTN) with paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE).
      ]. Alternate salvage treatment programs, with response rates of 20–75% are listed in Table 6 80, 83. Uniformly these multi-agent regimens have significant hematologic toxicity. Administering granulocyte colony stimulating factors (G-CSF) as primary prophylaxis can decrease morbidity, treatment delays and dose reductions [
      • Kanis M.J.
      • Sobecki-Rausch J.
      • Greendyk R.
      • Dayno M.E.
      • Lurain J.R.
      Use of granulocyte colony stimulating factors (G-CSF) with multiagent chemotherapy for gestational trophoblastic neoplasia.
      ]. Given the significant chemosensitivity of GTN, the prognosis for women with stage II or III high-risk disease remains very good with approximately 70–80% achieving complete remission with primary therapy and another 10–15% cured with additional lines of chemotherapy or surgery [
      • Alazzam M.
      • Tidy J.
      • Osborne R.
      • Coleman R.
      • Hancock B.W.
      • Lawrie T.A.
      Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia.
      ,
      • Lurain J.R.
      • Schink J.C.
      Importance of salvage therapy in the management of high-risk gestational trophoblastic neoplasia.
      ].

      1.7 Ultra high-risk disease

      For those patients with ultra high-risk disease (WHO score > 12), experts advocate using induction chemotherapy to reduce the risk of life-threatening complications, predominantly hemorrhage from metastatic implants. The use of an induction regimen, with combination low dose etoposide and cisplatin (EP on days 1 and 2, weekly x 2–3 weeks), has been shown to significantly reduce the risk of early death, as reported in the Charing Cross experience [
      • Alifrangis C.
      • Agarwal R.
      • Short D.
      • Fisher R.A.
      • Sebire N.J.
      • Harvey R.
      • et al.
      EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis.
      ]. When patients present with central nervous system metastatic lesions, in addition to low-dose induction EP, the MTX dose in the EMA-CO or EMA-EP regimen should be increased to 1 g/m2. Intrathecal (IT) methotrexate (12.5 mg) can be considered and is typically administered during the CO or EP portion of the multi-agent regimens. Survival rates of 80–85% have been reported with these regimens and IT MTX [
      • Savage P.
      • Kelpanides I.
      • Tuthill M.
      • SHrt D.
      • Seckl M.J.
      Brain metastases in gestational trophoblastic neoplasia: an update on incidence, management, and outcome.
      ,
      • Xiao C.
      • Yang J.
      • Xiang Y.
      Clinical Management of GTN with brain metastasis: A 20 year experience in Peking Union Medical College Hospital, China; in Hancock BW, Seckl MJ, Berkowitz RS (eds). Chapter 19.
      ]. Furthermore, there may be utility to gamma-knife, stereotactic radiotherapy, and surgical resection to control CNS disease. Whole-brain radiation is controversial given the long- term cognitive toxicities. For these ultra high-risk patients, consolidation with 3–4 cycles of therapy should be considered.
      Active areas of investigation include the utilization of high-dose chemotherapy (HDC), with stem cell support and use of immune checkpoint inhibitors. Prior investigators have shown sustained complete responses to high-dose chemotherapy with stem cell support in patients with disease refractory to multiagent regimens. In a review of 32 patients treated with HDC at 2 referral centers, 41% (N = 13) remained disease free after HDC with or without additional treatment [
      • Frijstein M.M.
      • Lok C.A.R.
      • Short D.
      • Singh K.
      • Fisher R.A.
      • Hancock B.W.
      • et al.
      The results of treatment with high-dose chemotherapy and peripheral blood stem cell support for gestational trophoblastic neoplasia.
      ]. All patients who survived had hCG values ≤12 IU/L before HDC. In an effort to capitalize on elevated programmed death ligand 1 (PD-L1) expression levels identified in GTN specimens [
      • Bolze P.A.
      • Patrier S.
      • Massardier J.
      • Hajri T.
      • Abbas F.
      • Schott A.M.
      • et al.
      PD-L1 expression in premalignant and malignant trophoblasts from gestational trophoblastic diseases is ubiquitous and independent of clinical outcomes.
      ], use of single agent pembrolizumab has been explored. In a small cohort of 4 previously treated patients (2 with choriocarcinoma and 2 with placental site trophoblastic tumor), 3 experienced durable remissions with single agent pembrolizumab, highlighting the potential utility of immunotherapy in these disease settings [
      • Ghorani E.
      • Kaur B.
      • Fisher R.A.
      • Short D.
      • Joneborg U.
      • Carlson J.W.
      • et al.
      Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia.
      ]. Furthermore, in a recent small phase II study, avelumab was shown to cure 8 out of 15 women (53%) with low-risk GTN whose disease progressed after first line therapy with MTX or ActD with minimal and mild toxicity. Importantly, there was also one documented pregnancy after avelumab treatment [
      • You B.
      • Bolze P.A.
      • Lotz J.P.
      • Massardier J.
      • Gladieff L.
      • Jody F.
      • et al.
      Avelumab in patients with gestational trophoblastic tumors with resistance to single-agent chemotherapy: cohort Aof the TROPHIMMUN phase II trial.
      ]. The DART trial (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors; NCT02834013) is currently examining the utility of dual agent immunotherapy in patients with recurrent GTN.

      1.8 Surgery

      Despite therapeutic advances and approaches, the importance of surgery in the management of GTN should not be over looked. Hysterectomy as well as resection of oligometastatic extra-uterine disease plays an important role in the management of those with isolated chemoresistant disease or those with uterine confined disease who no longer desire to preserve fertility [
      • Doll K.M.
      • Soper J.T.
      The role of surgery in the management of gestational trophoblastic neoplasia.
      ,
      • Lehman E.
      • Gershenson D.M.
      • Burke T.W.
      • Levenback C.
      • Silva E.G.
      • Morris M.
      Salvage surgery for chemorefractory gestational trophoblastic disease.
      ]. Furthermore, salvage hysterectomy, rather than use of multi-agent chemotherapy, should be considered in patients with evidence of persistent uterine disease despite single agent chemotherapy [
      • Sugrue R.
      • Foley O.
      • Elias K.M.
      • Growdon W.B.
      • et al.
      Outcomes of minimally invasive versus open abdominal hysterectomy in patients with gestational trophoblastic disease.
      ,
      • Eysbouts Y.K.
      • Massuger L.F.A.G.
      • IntHout J.
      • Lok C.A.R.
      • Sweep F.C.G.J.
      • Ottewanger F.B.
      The added value of hysterectomy in management of gestational trophoblastic neoplasia.
      ]. Surgery may also be necessary to deal with disease-related hemorrhage complications when embolization is not available or has failed.

      1.9 PSTT/ETT

      Given that PSTT and ETT arise from intermediate trophoblast, it is not surprising that these histologies behave similarly to each other but are different clinically from other GTN and therefore have unique management. [
      • Frijstein M.M.
      • Lok C.A.R.
      • van Trommel N.E.
      • Ten Kate-Booji M.J.
      • Massuger L.F.A.G.
      • et al.
      Management and prognostic factors of epithelioid trophoblastic tumors: results from the International Society for the Study of trophoblastic diseases database.
      ,
      • Froeling F.E.M.
      • Ramaswami R.
      • Papanastasopoulos P.
      • Kaur B.
      • Sebire N.J.
      • Short D.
      • Fisher R.A.
      • et al.
      Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours.
      ]. Surgery is the mainstay of treatment for these diseases and consists of hysterectomy with lymphadenctomy reserved for those with grossly enlarged lymph nodes [
      • Lan C.
      • Li Y.
      • He J.
      • Liu J.
      Placental site trophoblastic tumor: lymphatic spread and possible target markers.
      ]. There are case reports of local uterine resection with preservation of fertility [
      • Shen X.
      • Xiang Y.
      • Guo L.
      • Feng F.
      • Wan X.
      • Xiao Y.
      • et al.
      Fertility preserving treatment in young patients with placental site trophoblastic tumors.
      ]. Although they are not chemotherapy resistant, compared to choriocarcinoma or post-molar GTN, they are not as sensitive. First line treatment with multi-agent regimens like EMA-CO or EMA-EP is often reserved for those that present with advanced stage disease or have ≥48 months from the antecedent pregnancy [
      • Frijstein M.M.
      • Lok C.A.R.
      • van Trommel N.E.
      • Ten Kate-Booji M.J.
      • Massuger L.F.A.G.
      • et al.
      Management and prognostic factors of epithelioid trophoblastic tumors: results from the International Society for the Study of trophoblastic diseases database.
      ,
      • Froeling F.E.M.
      • Ramaswami R.
      • Papanastasopoulos P.
      • Kaur B.
      • Sebire N.J.
      • Short D.
      • Fisher R.A.
      • et al.
      Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours.
      ]. These risk factors are the same for both PSTT and ETT. A relatively new entity, atypical placental site nodule (APSN), has been associated with concurrent PSTT/ETT or the development of PSTT/ETT within 16 months of diagnosis in approximately 10–15% of cases. This is based on small numbers but suggests patients with APSN should have a thorough clinical evaluation and consider hysterectomy. Larger series and longer follow up is necessary however in order to best counsel patients [
      • Kaur B.
      • Short D.
      • Fisher R.A.
      • Savage P.M.
      • Seckl M.
      • Sebire N.J.
      Atypical placental site nodule (APSN) and association with malignant gestational trophoblastic disease; a clinicopathologic study of 21 cases.
      ].

      1.10 Survivorship issues

      The majority of women with molar pregnancies or GTN will be cured with treatment, and counseling regarding future pregnancies is critical. History of GTN or use of single agent chemotherapy has not been associated with an increased risk of infertility and patients can expect normal reproductive function [
      • Joneborg U.
      • Coopmans L.
      • van Trommel N.
      • Seckl M.J.
      • Lok C.A.R.
      Fertility and pregnancy outcome in gestational trophoblastic disease.
      ]. Use of multi-agent chemotherapy however, was shown to induce early menopause (<45 years) in approximately 35% of women and this risk increased with increasing age at the start of treatment [
      • Savage P.
      • Cooke R.
      • O’Nions J.
      • Krell J.
      • Kwan A.
      • Camarata M.
      • et al.
      Effects of single-agent and combination chemotherapy for gestational trophoblastic tumors on risk of second malignancy and menopause.
      ]. In women who subsequently become pregnant after molar pregnancy or treatment for GTN, there are good data to reassure them that the rate of live births, and other pregnancy outcomes such as spontaneous abortions and obstetrical complications, are no different than the general population, regardless of whether or not chemotherapy was administered [
      • Vargas R.
      • Barroilhet L.M.
      • Esselen K.
      • Diver E.
      • Bernstein M.
      • Goldstein D.P.
      • Berkowitz R.S.
      Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from New England trophoblastic disease center.
      ]. The one difference is the risk of a second molar pregnancy [
      • Sebire N.J.
      • Fisher R.A.
      • Foskett M.
      • et al.
      Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy.
      ]. When patients subsequently conceive, obtaining an early ultrasound in the first trimester to confirm a non-molar pregnancy is recommended. Additionally, hCG should be measured approximately 6–8 weeks after the completion of any gestational event (miscarriage, ectopic, term pregnancy) to ensure that it has normalized and to exclude the development of choriocarcinoma. Though the risk of non-molar GTN is incredibly small, an hCG evaluation is a simple, inexpensive, and relatively non-invasive test to insure this has not developed Examination of the placenta can be considered but is not mandatory [
      • Lok C.
      • van Trommel N.
      • Massugar L.
      • Golfier F.
      • Seckl M.
      Practical clinical guidelines of EOTTD for the treatment and referral of gestational trophoblastic disease.
      ].
      In an analysis of approximately 1900 patients and over 32,000 person-years of follow up, Savage and his colleagues showed that MTX carried no substantial long- term risk of secondary malignancies. Even after EMA-CO or other alkylating agent containing regimens, the risk of secondary malignancies such as leukemia was minimally increased and was associated with prolonged exposure [
      • Savage P.
      • Cooke R.
      • O’Nions J.
      • Krell J.
      • Kwan A.
      • Camarata M.
      • et al.
      Effects of single-agent and combination chemotherapy for gestational trophoblastic tumors on risk of second malignancy and menopause.
      ].

      1.11 Recommendations

      Women with presumed hydatidiform mole should undergo evacuation with suction curettage and ultrasound guidance if necessary. Uterotonics should be administered after evacuation. Given the increased risk of GTN, hysterectomy is an acceptable alternative in women with risk factors for GTN, ≥40 years old or those who have completed child bearing. Medically induced evacuations of known molar pregnancies should be avoided. (Level II-2).
      Weekly hCG monitoring is recommended after evacuation of a complete (CM) or partial mole (PM). Once hCG normalization is achieved, hCG follow up should continue until 3 months after CM and 1 month after PM. (Level I).
      Patients who meet criteria for GTN (Table 1) must undergo staging per FIGO and WHO Prognostic Scoring System. Staging should include physical exam, serum hCG (from diagnosis of GTN not the initial hCG value at the time of molar pregnancy diagnosis), pelvic ultrasound, and chest x-ray. For those with vaginal metastases or pulmonary metastases on chest x-ray, a CT of the chest, abdomen, pelvis and a brain MRI should be obtained. (Level II-2).
      Either single agent multi-day MTX or bolus Act-D is recommended for treatment of low-risk GTN. Second curettage is an acceptable alternative for those wishing to avoid chemotherapy. (Level I and II-1).
      For patients with low-risk GTN who develop resistance to or relapse after single agent chemotherapy treatment with the alternative single agent (if hCG ≤3000 IU/L) or with EMA-CO (if hCG >3000 IU/L) is recommended. (Level II-3).
      Hysterectomy should be considered for those with stage I choriocarcinoma or invasive mole who no longer desire fertility preservation. Hysterectomy should also be considered as management of complete mole for women aged 40–49 with an initial hCG > 175,000 IU/L or age ≥ 50 with any hCG value. Furthermore, for women with GTN, a dose of single agent chemotherapy at the time of hysterectomy should be administered to treat occult metastases. (Level II-2).
      For patients with high-risk GTN, EMA-CO is the recommended first line treatment while those with ultra high-risk GTN should receive induction low dose EP followed by either EMA-CO or EMA-EP. (Level I and II-1).
      For those patients with brain metastases, the MTX dose should be increased to 1 g /m2. Other treatments to consider include neurosurgical consultation, radiation, and intrathecal MTX. (Level II-2).
      G-CSF primary prophylaxis should be used in etoposide and platinum containing regimens and as needed to maintain treatment schedule and dose intensity of other regimens. (Level II-2).
      For those whose disease is resistant to or relapses after multi-agent chemotherapy consider consultation or referral to a high volume trophoblastic disease center. Management for these women should include surgery, when appropriate, and salvage chemotherapy including immune checkpoint inhibitors or high dose chemotherapy with stem cell transplant, in selected patients. (Level II-3).
      Three cycles of consolidation chemotherapy, consisting of the last effective regimen, should be given after normalization of the hCG (Level II-2).
      Surveillance for low and high-risk GTN should consist of monthly hCG x 12 months after completion of consolidation chemotherapy. Furthermore, for patients with ultra high-risk disease hCG x 24 months after completion of chemotherapy is recommended. (Level II-3).
      For patients with presumed stage I PSTT and ETT hysterectomy with removal of suspicious lymph nodes, and cytoreduction for those with metastatic disease, should be performed. Furthermore, chemotherapy with EMA-EP should be administered to those diagnosed with advanced stage disease or diagnosis ≥48 months from antecedent pregnancy. (Level II-3).
      For those with persistent low level hCG (< 200 IU/L), non-gestational tumors, false positive hCG, and pituitary hCG should be excluded by measuring hCG on a different assay and in the urine, by obtaining a CT of chest, abdomen, pelvis and a brain MRI with pituitary views, checking menopausal hormones, and trialing high dose oral contraceptive pills or GnRH agonist. (Level II-3).
      For women with a history of GTD, a first trimester ultrasound should be performed and a hCG should be assessed 6–8 weeks after conclusion of any pregnancy event. Examination of the placenta can be considered but is not mandatory. (Level II-3).

      Author contributions

      Dr. Neil Horowitz developed the practice statement outline, contributed to the practice statement, reviewed and edited the final draft.
      Drs. Ramez Eskander and Marisa Adelman contributed to the practice statement and reviewed the final draft.
      Dr. William Burke reviewed the outline, practice statement draft and oversaw the practice statement development.

      Declaration of Competing Interest

      Dr. Burke reports other from Titan Medical, outside the submitted work.
      Dr. Adelman reports personal fees from AbbVie, outside the submitted work.
      Dr. Horowitz reports personal fees from Up to Date, outside the submitted work.
      Dr. Eskander reports other from AstraZeneca, other from Clovis Oncology, other from Eisai, outside the submitted work.

      Acknowledgements

      Dr. Horowitz's research is supported by the Donald P. Goldstein, M.D. Trophoblastic Tumor Registry Endowment and The Dyett Family Trophoblastic Disease Research and Registry Endowment. These endowments had no direct role in the generation of the data or the manuscript.

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