Treatments for Gestational Trophoblastic Disease Cogorno

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Treatments for Gestational Trophoblastic DiseaseLaura Kenny, Michael J Seckl

Expert Rev of Obstet Gynecol. 2010;5(2):215-225.

Abstract and IntroductionAbstract

Gestational trophoblastic disease (GTD) is a relatively rare but important group of benignand malignant disorders that affect women of child-bearing potential. Most cases are nowdiagnosed earlier than previously owing to advances in our knowledge of the disease andaccuracy of ultrasonography, combined with the high analytical sensitivity of humanchorionic gonadotrophin assays, although occasionally patients with metastases present

at a late stage with life-threatening complications. Early diagnosis and referral to aspecialist center for further management is vital so that patients can receive the optimalstandard of care. Patients can be grouped into high- and low-risk categories using well-established prognostic scoring systems, enabling the minimum appropriate treatment tobe recommended. Chemotherapy regimens for the disease are now well established, sothat for the vast majority, GTD is a curable condition, and patients can be reassured thatfertility is normally preserved. Regular follow-up by human chorionic gonadotrophinmeasurement following treatment is important for the detection of early relapse.Regimens for relapsed disease are usually successful, but need to be improved for the

infrequent cases that develop multiple drug resistance. In this article the subtypes of GTD,rationale for treatment, surgery and drugs used in the condition are discussed.

Introduction

Gestational trophoblastic disease (GTD) spans a spectrum from two premalignantconditions: partial and complete hydatidiform moles, to three malignant tumors, namely:invasive mole, gestational choriocarcinoma and placental-site trophoblastic tumor(PSTT);[1] the latter three are sometimes referred to as gestational trophoblastic neoplasia.

Gestational trophoblastic tissue forms from the peripheral cells of the blastocyst a fewdays after conception. The tissue is divided into two layers: the outer syncytiotrophoblastcomposed of large mutinucelated cells and an inner layer of mononucleated cells thatmigrate out and fuse to form the cytotrophoblast. The syncytiotrophoblast subsequentlyaggressively invades the endometrium, generating an intimate connection between thefetus and the mother, known as the placenta. Normally, the growth of trophoblastic tissueis tightly regulated by as yet undefined mechanisms that prevent the development of


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distant metastases. Malignant GTD occurs when these controling mechanisms fail, whichmay result in invasion of trophoblastic tissue through the myometrium, permittinghematogenous spread and tumor emboli to form.

The revised International Federation of Gynecology and Obstetrics (FIGO) classification of GTD was developed in 2000 after many years of discussion between international expertsin the field, and is the most appropriate method for categorizing the disease into high- andlow-risk categories. [2] Successful management of GTD now means that for the vastmajority of patients the disease is curable. This has been largely dependent on acombination of centralized care leading to accumulated knowledge about the biology,pathology and natural history of the disease. Fertility can be preserved and normaloutcomes can be expected in subsequent pregnancies in most cases. [3] The tumors areextremely chemosensitive; the intensity of treatment is guided by the prognostic category(which comprises of human chorionic gonadotrophin [hCG] level, maternal age, length of time elapsed since previous pregnancy, size of uterine lesion, sites of metastases andnumber of previous chemotherapy regimens) at the time of referral. The high sensitivityand specificity of hCG assays allow the success of treatment to be followed accurately,enabling the early detection of treatment failure and relapse.

While GTD is a relatively rare diagnosis, higher incidences (up to one in 300 pregnancies)are seen in certain populations, namely Brazil, the Philippines and in native AmericanIndians. The incidence in countries such as Japan appears to be falling, possibly owing tobetter data collection and reduced dependency on hospital-based surveys as opposed to

national population data, and possibly owing to dietary influences. This article focuses onthe Charing Cross Hospital (London, UK) experience. For a comprehensive review of thegenetic abnormalities underlying GTD, readers are referred to the paper published byFisher and Hodges. [4] The various types of hCG assays, subtypes of GTD, diagnosis,management options, and potential complications of the disease and treatment will bediscussed.

HCG Assays

-subunit hCG ( HCG) circulates in a variety of isoforms (hyperglycosylated hCG, nickedhCG, nicked hyperglycosylated hCG, hCG missing the -subunit C-terminal extension, freea-subunit, free -subunit, free -subunit missing the C-terminal extension,hyperglycosylated-free -subunit [ hCG-H] and nicked-free -subunit) as a result of post-translational modifications (nicked hCG occurs owing to the action of proteolytic enzymesin the placental, molar/cancer tissue or in the circulation). [5]


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The detection of hCG in normal, early pregnancy is relatively straightforward, as themolecule is either intact or in the hyperglycosylated form (hCG-H). However, in cancer,the situation is more complex, as the assay needs to be sensitive enough to detect all hCGvariants equally well. The assays that are available commercially are licensed to detecthCG in pregnancy, but can result in significant differences in sensitivity when used incancer patients. Most centers use a commercial assay such as the Siemen Immulite 1000(Siemens, IL, USA) to measure total hCG; however, no single hCG test has been approvedfor use in cancer. At Charing Cross, we use a noncommercial radioimmunoassay (RIA) thatcan detect a site on HCG that is common to all the known forms of the hormone, andtherefore does not suffer from false negatives. Our experience in using the RIA in morethan 35,000 women with GTD has given us great confidence that we only rarely see falsepositives, and our comparative work with other assays has shown that our assay detectsall forms of hCG so far discovered equally, unlike the commercial assays examined. [6,7]

The false-positive results that can occur with hCG testing are often due to heterophileantibody production by the patient; however, these can be excluded by pairedmeasurement of hCG in the urine and serum as the antibodies are not excreted in theurine. It should be noted, however, that at low values of real hCG in the serum, there maybe no hCG detectable in the urine. This problem is overcome in our RIA by using serialdilutions of the serum; real hCG, unlike cross-reacting molecules that cause false-positiveresults, will reduce in accordance with the dilution. For commercial assays, mostmanufacturer's tests include animal serum and nonspecific animal antibodies, along withother components to prevent heterophilic antibody binding, and the incidence of false-

positive hCG tests has declined. [5] There is a wide variability between different types of commercial hCG assays with regards to the sensitivity to detect all 13 dimer and subunitvariants. [6] RIAs have limited availability outside our center, and for further informationabout hCG assays, readers are referred to a comprehensive review on this subject byCole. [8]

The half-life of hCG is 24 36 s, and the amount of hCG produced corresponds to tumorvolume. Indeed, hCG is still the most valuable tumor marker available and is moresensitive than any commonly available imaging technique (a value of 5 U/l corresponds to

a tumor volume of approximately 105

cells[9]

). It is important to remember that hCGproduction is not unique to pregnancy and GTD; for example, germ cell tumors and 15% of epithelial cell malignancies also produce the hormone. [10,11]

Partial & Complete Hydatidiform Moles


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The incidence of partial moles (PMs) and complete moles (CMs) is 3:1000 and 1:1000 of normal pregnancies, respectively. Genetically PMs are nearly all triploid and occasionallytetraploid consisting of both maternal and paternal DNA. In PMs, the uterus is often notenlarged for gestational age and vaginal bleeding tends to occur in the second trimester,and occasionally patients present with a missed or incomplete abortion. [12] In fact, thediagnosis is rarely suspected until the histology of curettings is available. Clues to thediagnosis can occasionally be obtained by ultrasound. [13] The pre-evacuation hCG is over100,000 IU/l at diagnosis in over 90% of cases. Only 0.5% of PMs require chemotherapyfor postmolar GTD. [14]

New technologies such as gene-expression microarrays may have a role in the future forpredicting which patients require hCG follow-up postevacuation. CMs are nearly alwaysandrogenetic in origin and result from the fertilization of an ovum lacking maternal genesby a single sperm, 23X, which then duplicates to form the homozygote 46XX. [15,16] Veryoccasionally the CM is biparental in origin, when the maternal nuclear DNA isretained. [17] In 25% of cases, fertilization can occur by two spermatozoa, resulting in eitherthe 46XX or 46XY genotype; [18] the 46YY genotype has not yet been reported in cases of CM.

The classical macroscopic 'bunch of grapes' appearance is usually seen when CMs presentin the second trimester, and is due to swelling of chorionic villi. Currently, CMs arenormally diagnosed in the first trimester when the villi contain little fluid and present witha threatened abortion or abnormal vaginal bleeding; the uterus is normally large for

gestational dates. Ultrasound plays an important role in helping to raise suspicion that apregnancy is abnormal and could be molar, but in the absence of histology, this imagingmodality is not diagnostic as reviewed by Sebire and Seckl. [19] Occasionally, patients maypass grape-like structures or the entire mole. Those patients with rapid trophoblasticgrowth and extremely high hCG levels often present with hyperemesis and theca luteincysts (which may be palpable above the pelvic brim). Previously, patients used to presentwith preeclamptic toxemia, although this is rarely seen now owing to earlier diagnosisusing ultrasonography. Cross-reactivity between hCG and the thyroid-stimulatinghormone receptor may lead to the development of hyperthyroidism. [20]

The disease can also present at later stages with life-threatening complications frommetastases owing to a missed diagnosis; for example, when a spontaneous abortionoccurs at home, or because full histopathological examination of elective abortionmaterial is not performed routinely in abortion centers. The development of a screeningprocedure to avoid subsequent problems in such centers would avoid thiscomplication. [21] All patients who have surgery for an ectopic pregnancy should have


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material sent for histological analysis to exclude any underlying molar pregnancy ormalignancy. In many states the in the USA and Canada, it is a legal requirement that theproducts of conception are examined by a pathologist; in contrast this is not mandatory inthe UK, where it is a Royal College of Obstetricians and Gynaecologists guideline only.Review by an experienced histopathologist in a recognized center is crucial; this isespecially true in early pregnancies where the fetal blood vessels and membranes may stillbe present.

Approximately 16% of patients with CM proceed to develop malignant disease.Metastases in the pulmonary, cervical and vaginal regions do occur, but do not mean thatthe mole is invasive, as they can resolve on the removal of the primary mole. Thedevelopment of tumor emboli leading to pulmonary metastases can be minimized byavoiding agents that promote uterine contraction.

Twin pregnancies comprising a normal fetus and hydatidiform mole do occur inapproximately 1:10,000 1:20,000 pregnancies. Some may abort in the first trimester andare undiagnosed, or present at the time of routine ultrasound screening, or may presentas a result of complications such as bleeding, large for gestational age, or symptomssecondary to a raised hCG. [22] In our experience at Charing Cross Hospital, 40% of patientswho choose to continue their pregnancy result in live births, without increasing the risk of subsequently requiring chemotherapy for malignant disease. [22]

Invasive Moles/Trophoblastic NeoplasiaThese are definitively diagnosed on the basis of myometrial invasion on histology. Thediagnosis may be suspected owing to abnormal ultrasound scan appearances (large uterusfor gestational age, theca lutein cyst >6 cm) or plateaued/rising hCG level postevacuationof a mole, or symptoms such as vaginal bleeding, abdominal distension and pain, or thosedue to complications. In reality, curettage specimens from molar evacuation rarely containmyometrium, except in hysterectomy specimens. The risk of complications is higher inpatients where the initial diagnosis of molar pregnancy was not made, and are thereforenot on hCG follow-up. It is important to differentiate an invasive mole from

choriocarcinoma (see later) and an incomplete abortion. This can be done by assessing forthe presence of chorionic villi (present in choriocarcinoma) and p57 immunostaining; asCMs are androgenetic, only the mitochondrial DNA will stain positive, the rest of the cellswill be negative.

Choriocarcinoma


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Choriocarcinoma is the most aggressive form of GTD owing to their rapid growth andmetastatic potential. They most commonly develop after a CM; the incidence of anantecedent history of CM has been reported in 29 83% of choriocarcinoma cases invarious studies across the world. [1]

Partial moles and PSTTs rarely give rise to choriocarcinoma. Choriocarcinomas can occurafter any type of pregnancy usually in the first year, although in our experience a case of choriocarcinoma has occurred after an interval of 35 years. The incidence of choriocarcinoma following term delivery without a history of CM is approximately1:50,000. The true incidence may actually be much higher as histology is often difficult toobtain, but interestingly choriocarcinoma following a full-term pregnancy is more oftenassociated with aggressive disease. Another classical presentation that has been describedin post-full-term pregnancy choriocarcinoma is of secondary postpartum hemorrhage andthe anemic neonate.

Patients present with symptoms similar to those of hydatidiform moles, but gynecologicalsymptoms can be absent in up to a third of cases in those who present withmetastases. [23,24] The disease can metastasize to any site lungs, brain, liver, skin, heartand cauda equina. Pulmonary metasases can be parenchymal, pleural or the result of tumor emboli in the pulmonary arteries. This results in symptoms of dyspnea, hemoptysisor those of pulmonary artery hypertension. Cerebral metastases present with convulsions,focal neurological signs, intracerebral hemorrhage or signs of raised intracranial pressure.Liver metastases can cause local pain or referred pain to the right shoulder tip. While

these symptoms or features are not unique to GTD, it is an important differentialdiagnosis to consider in women of child-bearing age who present with metastases of unknown primary origin and can be easily confirmed by serum hCG and tumor biopsy.The high hCG level can also cause thyrotoxicosis and ovarian theca lutea cysts.

Infantile and fetal choriocarcinoma has been reported in approximately 30 cases, both asa secondary from the mother and as a primary. [25] It appears that the disease can cross theplacenta and metastasize to the lungs, liver or brain. Treatment is with cisplatin-basedchemotherapy or excision. A diagnosis should be suspected in infants with anemia, failure

to thrive, precocious puberty or those as a result of metastases (e.g., hepatomegaly orhemoptysis). Serum or urine hCG should be measured in all infants at delivery in maternalcases of choriocarcinoma, and as the disease can present up to 6 months postdelivery,consideration should be given to extending the hCG testing period. [25 27]

Placental Site Trophoblastic Tumor


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This is a rare, slow-growing form of GTD that has been proposed to arise from theintermediate trophoblasts at the implantation site. [28] They constitute 1% of trophoblasticdisease. PSTT has been shown to follow term delivery, nonmolar abortion, CM or PM. [29] Incontrast to other forms of GTD, spread tends to occur late by local infiltration and via thelymphatics, although distant metastases can occur. It is important to differentiate fromthe benign placental-site nodule, which is also composed of intermediate trophoblastcells. A recent analysis of the entire UK experience of PSTT has shown that severalvariables, including number of mitoses per ten high-power fields, hCG level (>4 IU/l), stageand duration from the antecendent pregnancy, are all important prognostic variables onunivariate analysis. [30] The use of percentage-free HCG relative to total hCG may beuseful (although not definitive) for differentiating PSTT from choriocarcinoma and othertypes of GTD, as this has found to be secreted at a higher level. [5,31] However, onmultivariate analysis the only prognostic variable that remains significant is the durationfrom the causative pregnancy. In a series from our group, women who were more than 48months from the causative pregnancy thus far invariably die within 6 years of diagnosis of PSTT, while those within 48 months are nearly always cured. [30]

Like choriocarcinoma, the causative pregnancy may not be the immediate antecedentpregnancy. [32] PSTT displays a pattern of vascular invasion, characterized by neoplasticcells migrating through, and replacing, vessel walls, while maintaining the overall vasculararchitecture. The tumors are composed mainly of intermediate trophoblast derived fromcytotrophoblast, and so produce little hCG. hCG elevation at diagnosis has been found tobe less than 500 IU/l in over 50% of cases. [33] However, they often stain strongly for

human placental lactogen and b1-glycoprotein. In contrast to choriocarcinoma, however,metastases occur late, so the presenting symptoms are generally gynecological. The mostimportant prognostic factors for patients with PSTT are stage, myometrial invasion anddate from antecedent pregnancy (better for those with an interval


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simply represent the differentiating effects of treatment rather than a separate type of GTD.

It has been proposed that ETT arises from the intermediate trophoblasts of the chorionicleave. [28] The cells are positive for cytokeratin, epithelial membrane antigen and inhibin-a,whereas the trophoblastic markers human placental lactogen, hCG and melanoma celladhesion molecule are only focally expressed. [36]

Patients are usually of child-bearing age, although a significant number of cases have beenfound in peri- or postmenopausal women with a long interval since pregnancy. [38] Thepresenting signs are vaginal bleeding with a low level of hCG (


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nulliparous cervix is not recommended. Ergometrine is helpful to minimize bleeding aftersuction evacuation, and the chance of requiring chemotherapy. If the hCG value falls tonormal then no further treatment is necessary.

Previously, repeat evacuations in patients with molar pregnancies were commongynecological practice. This is reasonable if the initial evacuation was incomplete and thedisease is confined to the uterine cavity on ultrasound. However, analysis of our data hasshown that if the hCG is plateaued or rising, unless the hCG is less than 5000 IU/l, a secondevacuation is very unlikely to be effective, with approximately 80% of women undergoinga further evacuation subsequently requiring chemotherapy. [40] Moreover, each procedurecarries a risk of introducing infection, triggering hemorrhage and, rarely, uterineperforation. Consequently, second evacuations should only be performed in rarecircumstances where the hCG is below 5000 IU/l, the disease is confined to the uterinecavity and following discussion with a specialist GTD center. Ultrasound control can aid inthe procedure, giving useful feedback to reduce the risk of uterine perforation.

Hysterectomy This is indicated for: patients with PSTT or ETT where the disease isconfined to the uterus (i.e., no evidence on computed tomography [CT] body/MRI brain orpelvis or [ 18F]fluorodeoxyglucose-positron emission tomography [FDG-PET] scanning); forpatients with invasive GTD who have failed EMA/CO (which consists of EP, methotrexate[MTX] and actinomycin alternating weekly with cyclophosphamide and vincristine[formerly called Oncovin]) chemotherapy, which is confined to the uterus; for patientswho do not wish to preserve fertility with recurrent localized GTD; and occasionally for

patients with massive vaginal bleeding. As stated previously, hysterectomy is preferred forlocalized PSTT as it is relatively resistant to combination chemotherapy regimens andtends to metastasize late; however, there have been case reports of cure with EP/EMA(etoposide and cisplatin/etoposide, MTX and actinomycin D) chemotherapy. Themanagement of massive (life-threatening) vaginal bleeding requires a multidisciplinaryapproach between oncologists, gynecological surgeons and interventional radiologists.Potential treatment options include hysterectomy or emergency embolization of theuterine artery. Less severe cases of vaginal bleeding normally resolve with chemotherapy,transfusion and bed rest. In addition, we have found that a uterine pack can be helpful.

Focal Resection of Uterine Disease

There are some women with focal uterine lesions from PSTT who wish to preserve theirfertility, for whom a fertility sparing focal uterine resection may be appropriate; however,the multifocality of the disease can often be difficult to diagnose as it may be missed byimaging technologies such as ultrasound, MRI and FDG-PET. To date, this approach hasonly been reported to successfully conserve fertility in three out of four cases. [41]


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AP MoleAbortion or unknown

Term

Interval (end of AP tochemotherapy in months)

12

hCG IU/l 10 3 104 10 5

Number of metastases 0 1 3 4 8 >8

Site of metastases None, lung,vagina

Spleen, kidney GI tractBrain,liver

Largest tumor mass 5 cm

Prior chemotherapySingledrug

two

drugs

AP: Antecedent pregnancy; hCG: Human chorionic gonadotrophin.

Figure 1.

Chemotherapy treatment of low- and high-risk gestational trophoblastic disease.

EMA/CO: see Table 3 for explanation.

CO: Cyclophosphamide and vincristine; EMA: Etoposide, methotrexate, actinomycin; GTD:Gestational trophoblastic disease; hGC: Human chorionic gonadotrophin.

Histological evidence of choriocarcinoma

Metastases to brain, liver, GI tract or radiological opacities above 2 cm on chest x-ray(CXR)

Pulmonary vulval, or vaginal metastases unless hCG falling (in these cases themeasurement of HCG-H may be useful for determining the presence of active disease)

Heavy vaginal bleeding, gastrointestinal or intraperitoneal hemorrhage

Rising hCG postevacuation


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Serum hCG above 20,000 IU/l more than 4 weeks postevacuation (risk of uterineperforation)

Raised hCG 6 months after evacuation even if falling (in these cases the measurementof HCG-H may be useful for determining the presence of active disease)

All patients requiring chemotherapy are admitted to hospital for at least 1 week todetermine whether significant hemorrhage is going to occur and to deal with any sideeffects. This enables us to monitor the patients for hemorrhagic or other complications,and allows time for the patients to become familiar with their treatment. Patients withlow-risk disease are initially treated at Charing Cross, but once discharged continuetherapy locally and are monitored by serial hCG levels at Charing Cross and by clinicreviews every 6 weeks. Serum hCG levels are checked twice-weekly during therapy untilthe value normalizes, and then both serum and urine levels are checked once-weekly untiltreatment stops 6 8 weeks later and, subsequently, at intervals (the normal range forserum hCG in our laboratory is 4 IU/l and urine 25 IU/l).

Low-risk PatientsLow-risk patients are treated with cycles of single-agent MTX 50 mg given byintramuscular injection on alternate days for four doses, combined with folinic acid (15mg) given orally 30 h post each dose of MTX (). Generally, this treatment is well tolerated;the potential side effects include mucositis, serositis, hepatitis and pneumonitis. Mucositis

can be managed by ensuring good oral hygiene and starting the folinic acid at 24 h post-MTX. Adequate fluid intake (3 l/day) also helps to prevent against complications. In ourexperience, significant MTX toxicity occurs in 2% of patients, and this can warrantswitching to actinomycin D (). MTX can cause significant delayed photosensitivity;therefore patients are advised to avoid sun exposure for 1 year following treatment.Actinomycin D tends to cause more nausea and myelosuppression than is seen with MTX,and has the additional effect of alopecia.

Box 1. Low-risk gestational trophoblastic disease: first- and second-line treatment.

Treatment Repeated every 14 days

Low-risk disease first-line treatment:

Methotrexate50 mg by intramuscular injection repeated every 48 h for a total of four doses

Calcium 15 mg orally 30 h after each injection of methotrexate (folinic acid)


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folinate

Low-risk disease second-line treatment:

Actinomycin D 0.5 mg by intravenous injection daily for 5 days

Box 1. Low-risk gestational trophoblastic disease: first- and second-line treatment.

Treatment Repeated every 14 days

Low-risk disease first-line treatment:

Methotrexate50 mg by intramuscular injection repeated every 48 h for a total of four doses

Calciumfolinate

15 mg orally 30 h after each injection of methotrexate (folinic acid)

Low-risk disease second-line treatment:Actinomycin D 0.5 mg by intravenous injection daily for 5 days

Methotrexate produces hCG normalization in approximately 67% of low-risk patientsoverall (i.e., WHO score: 0 6; Charing Cross prognostic score: 0 8). [42] Drug-resistantdisease is defined as patients with two rising or plateaued hCG values during treatment. Inthe study by McNeish et al. , MTX-resistant patients with a hCG level of less than 100 IU/lwere treated with actinomycin D, and patients with a hCG above 100 IU/l were treatedwith EMA/CO. Of the patients who changed to actinomycin D (owing to resistance or MTXtoxicity), only 6% relapsed after completion of therapy, and for patients who receivesecond-line treatment with EMA/CO, the relapse-rate postcompletion is only 1%. [42]

High-risk PatientsOwing to the risk of drug resistance in this group, patients have been treated since 1979 atCharing Cross with an intensive chemotherapy regime EMA/CO (). The regimen ismyelosupressive, but dose intensity can be maintained by using granulocyte colony-stimulating factors to prevent neutropenia and neutropenic sepsis, continuing treatmentunless the total white cell count is less than 2, neutrophils less than 1 and platelets less

than 75 when dose delays may be required. Patients with liver metastases are treatedwith EP/EMA chemotherapy (), and may require a dose reduction depending on liverfunction tests.

Table 3. Etoposide, methotrexate and actinomycin/cyclophosphamide and vincristinechemotherapy for high-risk patients.


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Regimen Drug Dosage

EMA

Day 1 Etoposide 100 mg/m 2 by iv. infusion over 30 min

Actinomycin D 0.5 mg iv. bolus

Methotrexate 300 mg/m 2 by iv. infusion over 12 h

Day 2 Etoposide 100 mg/m 2 by iv. infusion over 30 min


Folinic acid rescue15 mg orally every 12 h for four doses (starting 24 h after commencing the methotrexate infusion)

CO

Day 8 Vincristine 1 mg/m 2 iv. bolus (maximum 2 mg)

Cyclophosphamide 600 mg/m 2 iv. infusion over 30 min

For patients with brain metastases the methotrexate dose is increased to 1 g/m 2 withfolinic acid rescue 30 mg given 8 h intravenously for 3 days, commencing 32 h after thestart of the methotrexate infusion. Intrathecal methotrexate 12.5 mg is given on the COweek provided there is no raised intracranial pressure with 15 mg folinic acid until thehuman chorionic gonadotrophin normalizes.

CO: Cyclophosphamide and vincristine; EMA: Etoposide, methotrexate and actinomycin D;iv.: Intravenous.

Table 4. Etoposide and cisplatin/etoposide, methotrexate and actinomycin Dchemotherapy.

Day Drug Dosage

1 Etoposide 100 mg/m 2 by iv. infusion over 30 min



2Folinic acidrescue

15 mg orally every 12 h for four doses (starting 24 h after commencing the methotrexate infusion)

8 Etoposide 150 mg/m 2 iv. bolus

Cisplatin 75 mg/m 2 iv. bolus


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iv.: Intravenous.

There is a risk of respiratory failure in patients with large-volume lung metastases, or thiscan also occasionally occur owing to massive pulmonary embolism. Careful attentionshould be paid to patients' respiratory function, with regular monitoring of the respiratoryrate and pulse oximetry with arterial blood gases taken if necessary to check for anychange from baseline after initiating chemotherapy. Occasionally, we may start treatmentwith only one or two drugs in patients with very poor respiratory function to preventperitumoral edema and inflammation that may occur around tumor deposits in the lungs,and then introduce the other drugs once the respiratory function has stabilized.Intubation should be avoided, as the high ventilatory pressures can trigger fatalintrapulmonary hemorrhage from the friable tumor vasculature; other strategies that maybe considered are continuous positive-pressure ventilation or extracorporeal oxygenation.

The cumulative 5-year survival of patients treated with this schedule is 86.2%, with nodeaths from GTD beyond 2 years after the initiation of chemotherapy. [43] The earlymortality was due to respiratory failure, brain metastases, liver failure and pulmonaryembolism in patients who presented with extensive disease at first presentation. The factthat previous chemotherapy was a good prognostic factor (5-year survival 88.9 vs 84.2%)is likely to be due to patients being on follow-up so that relapse was detected early, asmost of the deaths in the chemotherapy-naive group occurred early after the initiation of treatment due to the extent of disease at the time of diagnosis. [43] The adverse prognosticfactors were: liver metastases, longer interval from antecedent pregnancy, cerebral

metastases and term delivery in the antecedent pregnancy. A total of 83% of women whowere in remission and had fertility-preserving surgery were able to become pregnant aftereither MTX or EMA/CO. [44] However, the paper by Bower et al. shows that treatment withEMA/CO can bring forward the date of the menopause by 3 years. [43]

The long-term sequelae of this regimen includes an increased risk of second tumors suchas acute myeloid leukemia (due to EP), melanoma, breast cancer and colorectal cancer.The overall incidence of second tumors is estimated to be 1.5-times that of the generalpopulation. [45]

CNS DiseaseAt Charing Cross, low-risk patients with lung metastases and all high-risk patients (even inthe absence of lung metastases) are assumed to be at risk of CNS disease and so undergoMRI brain scans. If this is negative then the patients are still considered to be at risk of occult disease and so have a lumbar puncture to measure the cerebrospinal fluid


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(CSF):serum hCG ratio and to give the first dose of intrathecal MTX (12.5 mg) followed byoral folinic acid 24 h later. If the ratio of CSF:serum hCG is 1:60 or less then two furtherdoses of intrathecal MTX are given, usually with the CO arm of EMA/CO chemotherapy.This completes prophylaxis for potential occult CNS disease.

Patients with overt CNS disease on MRI, or where the serum:CSF hCG ratio exceeds 1:60require more intensive therapy. Management of overt CNS disease is potentiallyhazardous, owing to the risk of cerebral hemorrhage and death after starting treatment.Despite this, the long-term survival rate (30+ months) for patients with brain metastases is80%. [46] The first 3 weeks provide a useful prognostic indicator; 86 89% of patients whosurvive this period are cured. [46 48]Early resection of a solitary lesion may be appropriate inpatients with serious neurological signs. High-dose dexamethasone (24 mg in divideddoses) can be given to reduce cerebral edema prior to chemotherapy. The chemotherapyregime is EMA/CO with a higher dose of MTX (1 g/m 2 given as a 24 h infusion on day 1)than for patients without brain metastases. Provided there is no evidence of raisedintracranial pressure, patients at this center are treated with intrathecal MTX 12.5 mgwith each CO treatment for three doses only. The use of intrathecal MTX is controversial,and while used at Charing Cross, is not advocated in other centers such as Sheffield. [49]

Patients who develop CNS metastases during treatment have a poor prognosis, as this isindicative of drug resistance. However, immediate surgery to remove intracerebral lesionsand modified chemotherapy can be curative in this situation. [47,48] Stereotacticradiotherapy may have a role to treat isolated lesions that are inoperable, and which are

present at the end of chemotherapy. Whole-brain radiotherapy, in our experience, isnever curative and substantially adds to long-term toxicity, and so is avoided except inrare cases where palliation is required.

Drug ResistanceHigh-risk patients who develop resistance to EMA/CO chemotherapy are treated withEP/EMA alternating with 1 day EMA chemotherapy (see , note the second day of the EMAetoposide, MTX and actinomycin is omitted to minimize toxicity). The indications for

changing treatment are similar for those low-risk patients who change from MTX toactinomycin D; that is, hCG plateau or rise, and inappropriately slow fall. Alternativechemotherapy regimes for this patient group and those intolerant of MTX includepaclitaxel/etoposide alternating with paclitaxel/cisplatin (), [50] gemcitabine/cisplatin,single-agent paclitaxel and high-dose chemotherapy using Carbop-EC-T (carboplatin,etoposide, cyclophosphamide, paclitaxel and prednisolone) or CEM (carboplatin,etoposide and melphalan) or ICE (ifosfamide, carboplatin and etoposide) with autologous


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bone marrow or peripheral stem cell transplantation. This can also be complemented bysurgery to remove any residual lesions. Of this group, 70% will be cured. A study byWang et al. evaluated paclitaxel/etoposide alternating with the paclitaxel/cisplatin regimein patients who had failed chemotherapy previously or had treatment-related toxicity, andfound that the overall survival was 70% (if cisplatin-resistant patients were excluded, and75% for the two groups, respectively. [51]

Table 4. Etoposide and cisplatin/etoposide, methotrexate and actinomycin Dchemotherapy.

Day Drug Dosage

1 Etoposide 100 mg/m 2 by iv. infusion over 30 min



2Folinic acidrescue

15 mg orally every 12 h for four doses (starting 24 h after commencing the methotrexate infusion)

8 Etoposide 150 mg/m 2 iv. bolus

Cisplatin 75 mg/m 2 iv. bolus

iv.: Intravenous.

Table 5. Relapse regimen.

Day Drug Dosage

1 Paclitaxel 135 mg/m 2 by iv. infusion over 3 h

Cisplatin 60 mg/m 2 iv. infusion over 3 h

15 Paclitaxel 135 mg/m 2 by iv. infusion over 3 h

Etoposide 150 mg/m 2 iv. infusion over 1 h

iv.: Intravenous.

Surveillance & Follow-upPatients who have an evacuation only for molar pregnancy are registered and have serialhCG in blood and urine samples every 2 weeks. This continues until the hCG level hasnormalized (0 4), following which urine samples are monitored every 4 weeks. Themonitoring can be discontinued at 6 months postevacuation if the hCG normalized within


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8 weeks postevacuation, or if the hCG falls more slowly, monitoring can be stopped at 6months postnormalization. A plateau or rise in hCG levels is indicative of residual/invasivedisease.

Patients who require chemotherapy are reviewed 6 weeks postcompletion of treatment(i.e., 12 weeks after hCG levels have normalized) for a repeat ultrasound scan of pelvis andother imaging (CXR/CT/MRI if abnormal at baseline). At this point, most women will havea normal appearance, but a few will have persisting defects. These are of no consequenceprovided that hCG remains normal. The hCG levels are then monitored for life as shown in.

Table 6. Human chorionic gonadotrophin follow-up of patients who have receivedchemotherapy for gestational trophoblastic disease.

Year Time of follow-up Urine Blood1 Week 1 6 after chemotherapy Weekly Weekly

Months 2 6 Every 2 weeks Every 2 weeks

Months 7 12 Every 2 weeks

2 Every 4 weeks

3 Every 8 weeks

4 Every 3 months

5 Every 4 months

After year 5 Every 6 months

Contraception & PregnancyThe hormones in the contraceptive pill are thought to act as growth factors fortrophoblastic tissue. For that reason, use of the contraceptive pill and hormone-replacement therapy should be avoided following evacuation of a molar pregnancy untilthe hCG value has normalized. This also applies to patients receiving chemotherapy

(where there is an added risk of thromboembolism). A retrospective study of 611 patientswithin 2 months of molar evacuation found that oral contraceptive pill users were 2.6-times more likely to develop recurrent GTD than nonusers. [52] However, a smallerprospective study by the Gynaecological Oncology Group of 266 patients postevacuationof hydatidiform moles found that there was no increased risk of relapse using oralcontraception compared with barrier methods. [53]


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We advocate against pregnancy until after the completion of the surveillance period inthose patients who have had evacuation only, or 12 months after chemotherapy has beencompleted mainly to avoid potential teratogenic effects of chemotherapy and confusionregarding hCG values. If a patient does become pregnant, it is important for an ultrasoundscan to be performed early to confirm that the pregnancy is normal. Patients who havehad evacuation only of their molar pregnancy should have hCG checked at 3 weeks and 3months postdelivery owing to the increased risk of molar pregnancy. [54]Chemotherapypatients have follow-up temporarily discontinued during pregnancy until 3 weekspostdelivery.

Treatment with chemotherapy can result in an earlier onset of menopause. In ourexperience, with single-agent MTX this is by approximately 1 year, and approximately 3years with EMA/CO. [55]

PSTT

Patients with PSTT are often cured by hysterectomy if the disease is limited to theuterus. [33,56,57] In the presence of metastatic disease we currently use EP/EMA, as PSTTstend to be less chemosenstive than choriocarcinomas. [30] For this reason, unlike otherforms of gestational trophoblastic neoplasia where resection of residual masses appearsto be unnecessary, [58] in PSTT we recommend the removal of residual masses and a totalabdominal hysterectomy after completion of chemotherapy. As the disease representsonly 0.2% of GTD overall, further studies are needed to optimize its treatment.

Expert CommentaryAll patients with suspected GTD should be discussed with a GTD center and have theirhistology centrally reviewed early accurate diagnosis is essential in the management of this condition. While outcomes have clearly improved over the past 20 years, late and'missed' diagnoses must be avoided to prevent deaths from this highly treatable disease.One of the key features in the treatment success of GTD has been the development of accurate serum and urine hCG measurements to allow clinicians to follow the diseasecourse and select the appropriate treatment. However, recent work has shown that care

is required in the interpretation of hCG values obtained from commercial kit assays owingto the risk of false positives and false negatives. The most reliable hCG assays for cancershould detect all hCG types equally well. Currently, the RIA used at Charing Cross appearsto be very good at this, but there is an obvious need to develop new assays that can bereadily implemented elsewhere.


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The development of centers with experts in the biology, pathology, biochemistry,radiology, surgery and oncology of GTD, with access to large databases of patients providean essential resource for both patients, and referring physicians. There have beenachievements in international collaborative efforts to establish a standard of care forpatients with GTD. Further efforts are necessary to determine the best strategies forpatients with rarer forms of GTD, drug-resistant disease and management of cerebralmetastases.

Five-year ViewIn the next 5 years, by assembling an international database of PSTT, we should expandour knowledge about this rare variant, helping to identify new prognostic variables andrefine therapy. We also need to develop new techniques to distinguish malignant from thebenign moles just after evacuation. Novel therapeutic approaches are required for those

patients who develop multiple-drug resistance.

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Treatments for Gestational Trophoblastic Disease Cogorno