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Trophoblastic disease review for diagnosis and management

Trophoblastic disease review for diagnosis and management
Trophoblastic disease review for diagnosis and management

Trophoblastic Disease Review for Diagnosis and Management

A Joint Report From the International Society for the Study of Trophoblastic Disease,European Organisation for the Treatment of Trophoblastic Disease,and the Gynecologic Cancer InterGroup

Giorgia Mangili,MD,*Domenica Lorusso,MD,TJubilee Brown,MD,tJacobus Pfisterer,MD,§Leon Massuger,MD,||Michelle V aughan,MD,?Hextan Y.S.Ngan,MD,#Francois Golfier,MD,**

Paradan K.Sekharan,MD,TTRafael Corte ′s Charry,MD,ttAndres Poveda,MD,§§

Jae-Weon Kim,MD,||||Yang Xiang,MD,??Ross Berkowtiz,MD,##

and Michael J.Seckl,PhD,FRCP***

Objective:The objective of this study was to provide a consensus review on gestational trophoblastic disease diagnosis and management from the combined International Society for the Study of Trophoblastic Disease,European Organisation for the Treatment of Tro-phoblastic Disease,and the Gynecologic Cancer InterGroup.

Methods:A joint committee representing various groups reviewed the literature obtained from PubMed searches.

Results and Conclusions:Guidelines were constructed on the basis of literature review.After initial diagnosis in local centers,centralization of pathology review and ongoing care is recommended to achieve the best outcomes.

Key Words:Gestational trophoblastic disease,Management,Diagnosis,Review Received June 13,2014,and in revised form September 2,2014.Accepted for publication September 2,2014.(Int J Gynecol Cancer 2014;24:S109Y S116)

G

estational trophoblastic disease (GTD)is a group of dis-orders that arise from the placenta encompassing the premalignant complete (CHM)and partial (PHM)hydatidi-form moles and the malignant invasive hydatidiform mole,choriocarcinoma,placental site trophoblastic tumor (PSTT),and epithelioid trophoblastic tumor (ETT).1The malignant forms of GTD are also collectively known as gestational trophoblastic tumors or neoplasia (GTN).Gestational trophoblastic neoplasia often arises after molar (CHM/PHM)pregnancies but can also occur after any gestation including miscarriages and term

R EVIEW A RTICLE

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*Department of Gynecology and Obstetrics,IRCCS San Raffaele Hospital,Milan,Italy;?Gynecologic Oncology Department,Catholic University of the Sacred Heart,Rome/Campobasso,Italy;?Gyne-cologic Oncology Group,The University of Texas MD Anderson Cancer Center,Houston,TX;§AGO Study Group,Gynecologic On-cology Center,Kiel,Germany;||Department of Obstetrics and Gy-naecology,Radboud University Nijmegen Medical Centre,Nijmegen,The Netherlands;?ANZGOG,Camperdown,New South Wales,Australia;#Department of Obstetrics and Gynecology,University of Hong Kong,Queen Mary Hospital,Hong Kong,People’s Republic of China;**Centre de Re ′fe ′rence des Maladie Trophoblastiques,Hos-pices Civils de Lyon,Lyon,France;??Department of Obstetrics and Gynecology,Institute of Maternal and Child Health,Medical College,Calicut,India;??GTD unit,University Hospital of Caracas,Central University of Venezuela,Caracas,Venezuela;§§The Spanish Ovarian Cancer Research Group (GEICO),Fundacio ′n Instituto Valenciano de Oncolog?′a,Valencia,Spain;||||Korean Gynaecologic Oncology Group,Seoul National University Hospital,Seoul,South Korea;??De-partment of Obstetrics and Gynecology,Peking Union Medical Col-lege Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,People’s Republic of China;##Di-vision of Gynecologic Oncology,Department of Obstetrics and Gynecology,Brigham and Women’s Hospital,Dana-Farber Cancer Institute,Harvard Medical School,Boston,MA;and ***Charing Cross Trophoblastic Disease Centre,Departments of Histopathology and Medical Oncology,Charing Cross Campus of Imperial College London,London,United Kingdom.

Address correspondence and reprint requests to Michael J.Seckl,PhD,FRCP ,Director,Charing Cross Trophoblastic Disease Centre,Department of Medical Oncology,Charing Cross Hospital Campus of Imperial College London,Fulham Palace Rd,London,W68RF ,United Kingdom.E-mail:m.seckl@https://www.doczj.com/doc/c313880185.html,.The authors declare no conflicts of interest.

Copyright *2014by IGCS and ESGO ISSN:1048-891X

DOI:10.1097/IGC.0000000000000294

pregnancies.First described by Hippocrates approximately 400BC in his description of dropsy of the uterus,GTD was associated with significant morbidity and mortality before the discovery of effective chemotherapy approximately50years ago.At present,GTNs are among the most curable of all solid tumors,with survival rates approaching100%.1

EPIDEMIOLOGY

Wide regional variations in the incidence of hydatidiform mole have been reported,ranging from0.5to1per1000preg-nancies in North America and Europe,1.5to6per1000preg-nancies in South America,and as high as12per1000pregnancies in some older Southeast Asian studies.1Y3More recent analyses suggest that the Southeast Asia incidence is actually similar to that seen in Europe,1,3possibly reflecting dietary change,im-proved diagnostic accuracy,and population as opposed to hospital statistics.

Molar pregnancies are more frequent at the extremes of maternal age,and a prior mole increases the risk for another molar pregnancy to1%.1,4Many other possible risk factors for CHM have been studied,among which an increased risk has been associated with reduced dietary beta carotene and animal fat.1Data for choriocarcinoma incidence rates are more limited often because the diagnosis is made clinically rather than on biopsy material,to avoid life-threatening haemorrhage.1 Consequently,estimates vary widely,but it is likely that cho-riocarcinoma is commonest after CHM,is rare after PHM,and may occur in2to7per100,000other pregnancies.The fre-quency of PSTT is estimated to be0.2%of all GTD.5

PATHOLOGY

Complete and Partial Hydatidiform Moles Most CHM and PHM can be distinguished by their spe-cific microscopic features.Thus,CHMs show a characteristic abnormal budding villous structure with nonpatchy trophoblast hyperplasia,stromal karyorrhectic debris,and collapsed villous blood vessels.Early PHMs are quite distinct,demonstrating patchy villous hydrops with scattered abnormally shaped ir-regular villi,trophoblastic pseudoinclusions,and patchy tro-phoblast hyperplasia.The pathological distinction of nonmolar miscarriage from early molar pregnancies may pose diagnostic problems.Fortunately,immunostaining for P57KIP2,an im-printed gene expressed by the maternal allele,shows nuclear staining of cytotrophoblast and villous mesenchyme in placenta of all gestations apart from androgenetic complete mole.1Con-sequently,negative staining is indicative of a CHM.In addition, ploidy analysis by in situ hybridization or flow cytometry can distinguish diploid from triploid conceptions,helping to diag-nose PHM that are triploid.However,this cannot distinguish PHM from nonmolar triploidy,so further genetic investigations may be required(see below).

Invasive Mole

Invasive mole is probably best regarded as a malignant form of GTD and is usually a clinical rather than pathological diagnosis based on persistent human chorionic gonadotropin (hCG)elevation after molar evacuation.1Choriocarcinoma

Choriocarcinoma is a malignant disease characterized by abnormal trophoblastic hyperplasia and anaplasia,absence of chorionic villi,hemorrhage,and necrosis,with direct in-vasion into the myometrium and vascular invasion resulting in spread to distant sites,most commonly to the lungs,brain, liver,pelvis and vagina,kidney,intestines,and spleen.Ap-proximately25%of cases follow abortion or tubal pregnancy, 25%are associated with term or preterm gestation,and the remaining50%arise from hydatidiform moles,although only 2%to3%of hydatidiform moles are estimated to progress to choriocarcinoma.1

Placental Site Trophoblastic

Tumor/Epithelioid Trophoblastic Tumor Placental site trophoblastic tumor arises from the placental implantation site and consists predominantly of mononuclear intermediate trophoblasts without chorionic villi infiltrating in sheets or cords between myometrial fibers.It is associated with less vascular invasion,necrosis,and hemorrhage than chorio-carcinoma,and it has a propensity for lymphatic metastasis. Cytogenic studies have revealed that PSTTs are more often diploid than aneuploid.Most PSTTs follow nonmolar gesta-tions.5Epithelioid trophoblastic tumor is a rare variant of PSTT that simulates carcinoma.On the basis of morphologic and his-tochemical features,it seems to differentiate toward chorionic-type intermediate trophoblast.1

GENETICS

The genetics of CHM and PHM has recently been re-viewed.6Approximately80%of CHM are46,XX resulting from duplication of the haploid genome of a single sperm after fertilization of an ovum in which the maternal chromo-somes are lost during meiosis or as a consequence of postzygotic diploidization of a triploid conception.Approximately20%of CHMs arise by dispermic fertilization of an ovum and may be 46,XX or46,XY.6However,whereas CHMs are androgenetic (AnCHM),the nuclear DNA being paternally derived,mito-chondrial DNA is still maternal in origin.Partial hydatidiform moles are almost always triploid usually resulting from fertili-zation of an apparently normal ovum by2sperms or occa-sionally a diploid sperm and may therefore be69XXX,69XXY, or69XYY.6Most reported cases of diploid PHM probably represent misdiagnosed CHM,hydropic abortions,or twin preg-nancies.Some patients with recurrent CHM have diploid bi-parental CHM rather than AnCHM.These women often have a family history of recurrent molar pregnancies.The condition is autosomal recessive,associated with mutations in NLRP7 in70%and KHDC3L in approximately5%of cases.Unlike AnCHM,patients with biparental CHM,also known as familial recurrent hydatidiform mole syndrome,rarely achieve a normal live birth.Fortunately,egg donation from unaffected women seems to provide a successful solution to this problem.7 Because postmolar GTN is treated on a clinical rather than pathological diagnosis,tumor tissue is rarely available for genetic analysis.However,where tumor DNA is available, the genotype will reflect that of the causative pregnancy.1

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Clinical Presentation

Complete and Partial Hydatidiform Moles Molar pregnancies most commonly present with vagi-nal bleeding in the first or early second trimester.Previous classic clinical signs and symptoms,such as excessive uterine enlargement for gestational dates,hyperemesis,thyrotoxicosis, preeclampsia,and toxemia,are rarely seen because of earlier diagnosis aided by ultrasonography.8

Gestational Trophoblastic Neoplasia

Gestational trophoblastic neoplasia arising after evac-uation of a molar pregnancy is most commonly diagnosed biochemically because all patients should be regularly mon-itored with serum hCG assessments.8A plateaued or rising hCG indicates malignant change(the development of GTN) often previously referred to as persistent trophoblastic dis-ease.Irregular vaginal bleeding is frequently present because of a vascular uterine mass or,occasionally,vaginal metastasis.

Choriocarcinoma after a nonmolar gestation may present in many different ways depending on metastatic disease sites. Thus,pulmonary metastases may induce cough,hemoptysis, shortness of breath,and chest pains,whereas brain involvement may present with headaches,seizures,visual impairment,and the like.Systemic features of malignancy such as loss of ap-petite and weight may occur.In one third of cases,no vaginal bleeding is present.In contrast,PSTTs and ETTs almost always cause irregular uterine bleeding because the disease remains localized in the uterus longer,before causing metastatic or other symptoms.5Unlike other forms of GTN,serum hCG levels are often only modestly elevated for the volume of disease present,8 and in some,the serum hCG is normal.

Diagnosis

Ultrasonography

The classic ultrasonography‘‘snowstorm’’appearance of CHM is now rarely seen because the diagnosis is often made in the first trimester when less or no hydropic change has developed.Instead,a mixed echogenic vascular mass may be present,which is less marked with PHM where,in addition,a variable amount of fetal parts may also be seen.Importantly, these patterns,although suggestive,are not diagnostic of molar pregnancies and histological examination of the evacuated ma-terial is essential for the diagnosis.1

Human Chorionic Gonadotropin

Human chorionic gonadotrophin is a glycoprotein hor-mone composed of an>subunit shared with other hormones and a A subunit unique to trophoblastic tissue.In normal pregnancy,hCG is usually intact(both subunits together)and is hyperglycosylated in the first trimester.In cancers including GTN,hCG can exist in a variety of forms and/or fragments including free A subunit,nicked free A subunit,c-terminal peptide and A-core,as well as hyperglycosylated forms.9It is therefore essential that the assays used to measure hCG in cancer recognize all the different forms of hCG equally well.Most commercial hCG assays only work well for pregnancy hCG, and many either fail or significantly overdetect or underdetect certain hCG isoforms.This can result in false-negative read-ings.1Moreover,some assays are also prone to false-positive results usually because of cross-reacting heterophile anti-bodies.1The latter are too large to pass through the renal glo-merulus,so only real hCG is found in the urine.Consequently,a positive urine hCG excludes a false positive in serum.In ad-dition,real hCG will appropriately serially dilute and is positive on another hCG assay,whereas heterophile antibodies are most unlikely to do this.So,which hCG assays are safe in GTN? Several homemade assays exist,which seem to work very well but are not generally available.Of the commercial assays,the Siemens IMMULITE is probably one of the best.10How-ever,none are completely perfect,so a working party within the European Organisation for the Treatment of Tropho-blastic Disease(EOTTD)is currently addressing this issue.In the meantime,if there are concerns regarding hCG measure-ments in a given patient,then their samples can be referred to the nearest hCG reference laboratory for further analysis. Pathologic Diagnosis

Complete hydatidiform mole and PHM are diagnosed by examination of curettage specimens as described previously. Histological diagnosis of invasive mole and choriocarcinoma is rarely made because of the risk for promoting life-threatening hemorrhage upon biopsy.In contrast,PSTT and ETT are usu-ally diagnosed by examination of curettage,biopsy,or hyster-ectomy specimens.

Management of Molar Pregnancies Hydatiform Mole

Hydatidiform moles are removed by suction and cu-rettage ideally under ultrasound control to ensure adequate evacuation and avoid uterine perforation.Medical induction of labor or hysterotomy is not recommended for several rea-sons,including an increased risk for developing postmolar GTN requiring chemotherapy.3Hydatidiform moles of gesta-tional age greater than16weeks should be evacuated at a tro-phoblast center because of the risk for pulmonary embolization of molar tissue.Hysterectomy can rarely be used in patients who have completed their family and are free of metastatic disease, but such women still require careful hCG surveillance because a significant risk for developing GTN remains.1After evacu-ation,patients with PHM should be given anti-D prophylaxis.

The risk for developing GTN is15%to20%and0.5% to1%after CHM and PHM,respectively.1To reduce this, some have advocated prophylactic chemotherapy such as meth-otrexate or actinomycin D at the time of or immediately after evacuation of CHM.Although this may reduce post-CHM GTN to3%to8%,it exposes more than80%of patients to unnecessary toxicity,does not eliminate the need for surveil-lance,and may induce drug-resistant disease.Moreover,for patients on hCG surveillance,nearly all will have their GTN detected and subsequently cured with chemotherapy.Thus,the use of prophylactic chemotherapy is controversial and should be limited to very special situations where adequate hCG and patient follow-up are not possible.11

Definitive follow-up after evacuation of CHM or PHM requires serial serum quantitative hCG measurements every1

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to2weeks until at least2consecutive tests show normal levels,after which,hCG levels should be determined monthly for up to6months in patients with CHM but can be stopped in those with PHM because the risk for subsequent GTN is less than1:3000(presented at the International Society for the Study of Trophoblastic Disease[ISSTD]meeting2013).

During hCG follow-up,patients should use contra-ception for at least6months.Oral contraceptives are helpful because they have the advantage of suppressing endogenous luteinizing hormone,which may interfere with the measure-ment of hCG at low levels.12The use of the oral contraceptive pill before hCG normalization was previously linked with an increased risk for developing GTN.1However,modern lower-dose progestin(desogestrel)pills do not seem to cause this problem(ISSTD2013Chicago meeting).Other factors linked with an increased risk for GTN after a CHM include a pre-evacuation hCG level greater than100,000IU/L,excessive uterine growth(920-week size),theca lutein cysts greater than 6cm in diameter,and age older than40years.3,4

Co-Twin Pregnancy(CHM or PHM and Healthy Fetus)

A healthy co-twin can develop alongside a CHM or PHM in1per20,000to100,000pregnancies.Some in-vestigators have suggested that such pregnancies should be terminated because of the low probability of successful out-come and an increased risk for developing GTN.However,a population-based case series of77twin pregnancies suggests that approximately38%of women will deliver a healthy baby without a significant increase in the risk for malignant trans-formation of CHM.13Importantly,there were no maternal deaths despite a slightly higher risk for pregnancy-related complica-tions including hemorrhage,preeclampsia,thyroxicosis,and preterm delivery.13Similar results were recently reported in90 new cases but with an increased successful delivery rate of57% (ISSTD2013).Consequently,after appropriate counseling re-garding the increased risks for obstetric complications,these twin pregnancies can be allowed to continue. Indications for Chemotherapy

Table1summarizes the International Federation of Gy-necology and Obstetrics(FIGO)criteria14,15for commencing chemotherapy for postmole GTN.The commonest reason is a rising or plateaued hCG level.An elevated but falling hCG 6months after molar evacuation is no longer an absolute requirement for commencing chemotherapy because patients undergoing continued surveillance all seem to spontaneously normalize their hCG levels.16Other criteria for chemotherapy in some institutions include a serum hCG level greater than 20,000IU/L more than4weeks after evacuation because of the risk for uterine perforation and uterine or intra-abdominal hemorrhage requiring transfusion.1For postpartum GTN,che-motherapy is indicated either when a histological diagnosis of choriocarcinoma is established or when there are worrying clinical features such as unexplained widespread metastasis in a woman of childbearing age with elevated hCG values. Risk Stratification for Chemotherapy

Several scoring systems based on a variety of prognostic factors were developed to enable the classification of patients with GTN into low-and high-risk groups for the development of disease that will become resistant to single-agent metho-trexate(MTX)or dactinomycin(ActD)chemotherapy.Among these,the FIGO(FIGO2000)scoring/staging system is the most commonly used and is summarized in Table2.15,17A score of0to6indicates a low risk for developing resistance to single-agent therapy.Patients scoring higher than6are at high risk for developing disease resistant to single-agent therapy and therefore receive combination-agent chemotherapy straightaway. In this system,patients are also assigned a stage(Table2).

This stratification system is good but not perfect.Thus, whereas nearly all patients scoring0to3will be cured with single-agent therapy,70%will fail this treatment with a score of5to6and require combination therapy.10Fortunately,all failures can be salvaged,so it is reasonable to start with the much less toxic single-agent therapies for patients scoring5 to6.10Various approaches may help refine risk stratification. Thus,Doppler ultrasonography to measure uterine vascularity through the pulsatility index is an independent predictor of methotrexate-resistant disease.10

Once patients are on therapy,the use of hCG regression nomograms and/or hCG kinetics can predict the onset of resistance to therapy at an earlier time point.18,19However, none of these refinements are yet in routine practice.An ISSTD working party is now looking at this issue. Imaging and Chemotherapy of Low-Risk GTN After Molar Pregnancy

Most women developing GTN after CHM or PHM are detected early by hCG monitoring,so a detailed investigation is rarely needed.Often,therapy decisions can be based on clinical history,examination,serum hCG,pelvic ultrasound to exclude pregnancy,measured uterine size/volume and spread of disease within the pelvis,and chest x-ray(CXR).If the CXR is suggestive of lung metastases,a confirmatory computed tomographic(CT)chest scan can be helpful,but only visible lesions on CXR should be scored.20Patients with lung metastases are at an increased risk for central nervous system(CNS)involvement,so a magnetic resonance imaging (MRI)of the brain is then needed because CNS disease changes scoring and chemotherapy(see section on CNS management below).10

TABLE1.Indications for chemotherapy after a molar

pregnancy

Weekly hCG rising*for at least3consecutive measurements

for a period of at least2wk(days0,7,and14)

Weekly hCG plateauing?for at least4consecutive

measurements for a period of at least3wk(days0,7,14,

and21)

Persistence of hCG more than6months after evacuation

Histological diagnosis of choriocarcinoma

*A rising hCG is usually defined as a more than10%increase

over the previous weekly value.

?A plateauing hCG concentration is defined as a less than10%

change over the previous weekly value.

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Low-risk GTN (evidence IB)is treated with either MTX with or without folinic acid (FA)rescue or ActD.Many dif-ferent schedules have been devised,all of which seem to have activity,but comparison of results is hampered by differences in patient inclusion criteria among other issues.21In Europe and many centers internationally,MTX/FA (Table 3)is preferred because it is less toxic.Thus,unlike ActD,it causes no hair loss,induces less nausea and vomiting,and is less myelosuppressive.However,ActD may be simpler togive and some suggest that it is more effective as primary therapy,although the only randomized trial compared a low-dose (30mg/m 2)MTX regimen not widely used with a more optimal schedule of ActD.22Importantly,all patients can expect to be cured regardless of whether they need to switch to second-or,even occasionally,third-line treatments.10Table 3summarizes the low-risk treatment schedules most widely used.Data from the ongoing Gynecologic Oncology Group 0275,comparing pulsed ActD with IV MTX or MTX/FA (Table 3),should provide further information regarding comparative tox-icity,efficacy,and quality-of-life data.

Response to therapy is assessed by serial serum hCG measurements.Different centers monitor with varying intensity,but it should be done no less frequently than every 1to 2weeks to enable the early detection of resistance or complete response.

Generally accepted criteria for the definition of resis-tance to first-line therapy are an hCG plateau over 3con-secutive samples or rising hCG titer on 2consecutive samples usually for more than 2weeks.Detection of resistance may be identified earlier by using either hCG regression normograms or kinetics,although these approaches are not yet in routine practice.18,19Once the hCG is normal,3consolidation treat-ments for 6weeks are required to minimize the risk for recur-rence.Lybol et al 24compared 2versus 3cycles of MTX/FA showing a doubling in relapse rates in those patients receiving only 2consolidation courses.

Salvage Chemotherapy

For women who become refractory/resistant to first-line single-agent chemotherapy,polychemotherapy can be ad-ministered (evidence grade 2C).10However,to limit toxicity,it is possible to stratify patients to receiving another single-agent

therapy depending on the hCG level at the point of resistance.10Thus,in the case of an 8-day MTX/FA regimen,with hCG values less than either 100IU/L or 300IU/L,100.5-mg 5-day intravenous ActD every 14days is highly effective,and in the small percentage failing this,all are still salvaged with combination-agent chemotherapy.Consequently,the overall cure rate for patients with low-risk disease can be expected to be virtually 100%.10

Imaging and Management of Suspected High-Risk GTN

For those patients with a histological diagnosis of cho-riocarcinoma or suspected GTN after a nonmolar pregnancy,much more intensive imaging is required,including a CT scan of the chest and abdomen,MRI of the brain and pelvis,as well as an ultrasound of the pelvis.Fluorodeoxyglucose-positron emission tomography-CT suffers both false-positive and negative prob-lems and is most helpful in imaging relapsed patients to identify the location of active disease before attempted curative surgical resection.10The value of a lumbar puncture to measure the ce-rebrospinal fluid:serum hCG ratio,which should be less than 1:60,10in the era of high-resolution (3T)MRI of the CNS is unclear but is still practiced by some centers.1

TABLE 3.Most widely used treatment schedules of low-risk GTN

-*MTX 8-d regimen (50-mg total dose intramuscular days 1,3,5,7with FA rescue 15mg given 24or 30h later on (days 2,4,6,8)repeated every 14d termed the MTX/F A regimen .10Some centers prefer to adjust the MTX dose by weight and give as 1mg/kg.

-*Pulsed ActD 1.25mg/m 2biweekly 22

-5d of ActD (0.5mg intravenous)repeated every 14d 21-Low-dose MTX (30/50mg/m 2intramuscular)repeated weekly,21but 30mg/m 2can no longer be recommended.22-MTX IV 0.4mg/kg days 1Y 5(maximum,25mg/d)repeated every 14d 23

TABLE 2.FIGO 2000scoring system for GTN Score Prognostic Factor

0124Age,y G 40Q 40V V AP

Mole Abortion Term V Interval (end of AP to chemotherapy in months)G 44Y 67Y 12912hCG (IU/L)G 103103Y 104104Y 1059105No.metastases 01Y 4

5Y 898Site of metastases Lung Spleen,kidney GI tract Brain,liver Largest tumor mass V 3Y 5cm 95cm Prior chemotherapy

V

V

Single drug

Q 2drugs

The total score for a patient is obtained by adding the individual scores for each prognostic factor.Low risk,0Y 6;high risk,Q 7.Placental site trophoblastic tumor/ETT should not be scored and instead requires staging.Stage I,disease confined to the uterus;stage II,disease extending into the pelvis;stage III,disease spread to lungs and/or vagina;stage IV ,all other metastatic sites including liver,kidney,spleen,and brain.AP ,antecedent pregnancy;GI,gastrointestinal.

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High-risk patients without brain or liver involvement who do not have extensive metastases can be managed with multiagent chemotherapy.The most frequently used regimen comprises etoposide,MTX,and ActD(EMA)alternating weekly with cyclophosphamide and vincristine(Oncovin)(CO) (grade2C).10

After hCG normalization,6weeks of consolidation therapy equivalent to3additional cycles are usually admin-istered.If the disease is refractory to EMA/CO(Table4a),or subsequently relapses,many patients can still be salvaged with various alternative platinum-based regimens25including the following:EMA(omitting day2etoposide and ActD) alternating weekly with etoposide and cisplatin(EP)26;pac-litaxel and etoposide(TE)alternating twice weekly with pac-litaxel and cisplatin(TP)10;etoposide(VP16),ifosfamide,and cisplatin given thrice weekly25;as well as bleomycin,etoposide, and cisplatin given thrice weekly.25

Probably the2most frequently used regimens are EMA/ EP and TE/TP(Table4b,c).The former is highly active salvaging in excess of75%of EMA/CO failures but is very toxic.The latter may be equally efficacious and seems much less toxic,so a randomized trial comparing these regimens has been proposed. Management of Ultrahigh-Risk Disease Some patients present with very advanced disease ei-ther causing or at high-risk for organ failure.Patients may also have poor prognostic factors such as liver with or without CNS/brain involvement.10Commencing such individuals on standard EMA/CO or other multiagent chemotherapy can cause severe hemorrhage or worsening organ failure resulting in early deaths.27This can be avoided by using gentle in-duction therapy with low-dose etoposide100mg/m2and cisplatin20mg/m2on days1and2repeated every week up to 3times if necessary before commencing standard chemo-therapy.27In those patients with liver and brain metastases who have the worst long-term outcome,the subsequent uses of EP/EMA seem sensible.10Patients with poor risk features may benefit from8rather than6weeks of consolidation therapy with a normal hCG.10

Management of CNS Disease and

Role of Radiotherapy

The main therapeutic options for CNS metastasis comprise escalated-dose EMA/CO in which the MTX is in-creased to1g/m2and intrathecal MTX12.5mg is given with the CO or whole-brain radiotherapy(20Y30Gy in2daily fractions)concurrent with chemotherapy.10,28Neurosurgery to remove and/or control bleeding metastases and/or relieve raised intracranial pressure can be lifesaving.

The use of whole-brain radiotherapy is controversial, given the long-term toxicity issues and lack of evidence that it significantly improves survival.A less toxic alternative is the delivery of stereotactic radiotherapy or F-knife treatment at the end of chemotherapy for any residual lesions left that are unsuitable for resection.10

Role of Surgery

Residual lesions after chemotherapy for low-risk GTN are not predictive of an increased risk for recurrence,29so surgical resection is not indicated.However,the importance of surgery in the management of GTN should not be under-estimated.Patients with drug-resistant disease in a single or, perhaps,just2or3sites can be surgically cured.10In this setting, fluorodeoxyglucose-positron emission tomography/CT imag-ing can help to identify active residual disease sites for resec-tion.30In nonmetastastic patients who do not desire to preserve fertility,hysterectomy may also be useful to reduce the duration of chemotherapy.Finally,surgical intervention may be required

TABLE4.Chemotherapy schemes

a.EMA-CO

Day1actinomycin-D0.5mg iv

Etoposide100mg/m2iv

Methotrexate300mg/m2iv

Day2actinomycin-D0.5mg iv

Etoposide100mg/m2iv

Folinic acid15mg postoperatively12hourly?4doses

Starting24hours after methotrexate

Day8vincristine0.8mg/m2(maximum,2mg)

Cyclophosphamide600mg/m2

b.EP/EMA

Day1actinomycin-D0.5mg iv

Etoposide100mg/m2iv

Methotrexate300mg/m2iv

Day2folinic acid15mg po12hourly?4doses

Starting24h after methotrexate week2

Day8etoposide150mg/?iv

Cisplatin75mg/m2iv

c.TP/TE schedule for relapsed GTN

Regimen Schedule

Day1

Dexamethasone20mg oral(12h before paclitaxel)

Dexamethasone20mg oral(6h before paclitaxel)

Cimetidine30mg in100-mL NS for30min iv

Chlorphenamine10-mg bolus iv

Paclitaxel135mg/m2in250-mL NS for3h iv

Mannitol10%in500mL for1h iv

Cisplatin60mg/m2in1-L NS for3h iv

Posthydration1-L NS+KCl20mmol+1-g MgSO4

for2h iv

Day15

Dexamethasone20mg oral(12h before paclitaxel)

Dexamethasone20mg oral(6hours before paclitaxel)

Cimetidine30mg in100-mL NS for30min iv

Chlorphenamine10-mg bolus iv

Paclitaxel135mg/m2in250-mL NS for3h iv

Etoposide150mg/m2in1-L NS for1h iv

iv,intravenous;NS,normal saline.

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to deal with bleeding complications,particularly where selec-tive angiographic embolization is not possible or has failed. Role of High-Dose and Other

Salvage Therapies

For those patients failing third-line chemotherapy with, for example,EP/EMA,some investigators have tried high-dose chemotherapy.Data presented at the ISSTD in2013 suggest that this might salvage approximately one third of cases either alone or in combination with subsequent surgery. Centers using this experimental approach are now doing tan-dem high dose,and the most frequently used regimen comprises carboplatin,etoposide,cyclophosphamide,and paclitaxel.10 Other drugs with activity include capecitabine and gemcitabine used either alone or in combination with other agents.10 Placenta Site Trophoblastic Tumor and Epithelioid Trophoblastic Tumors

Placental site trophoblastic tumor may be less respon-sive to chemotherapy than choriocarcinoma does but is still a chemosensitive tumor in many patients.The FIGO prognostic scoring system is not used for determining therapy in these patients.Instead,although several prognostic factors have been identified,including mitotic index,disease stage,and hCG levels,the only one that remains highly significant on multivariate analysis is the duration from the last known and presumed causative pregnancy.In the United Kingdom,pa-tients presenting within4years had a98%(48/49)long-term survival,whereas all13who presented beyond4years even-tually died regardless of their stage.5In those patients presenting within4years of their last known pregnancy,hysterectomy alone seemed sufficient for localized disease,whereas patients with metastatis responded well to either EP/EMA or EMA/CO often followed by resection of residual disease sites and a hysterectomy.5Given the reduction in chemosensitivity of PSTT compared with choriocarcinomas,EP/EMA is favored by some investigators.Patients with focal uterine disease who still desire children may be considered for focal resection with or without adjuvant chemotherapy.However,this approach is experimental and carries risks for missing microscopic multi-focal uterine disease and/or disseminating disease,thereby compromising long-term outcomes.10For those patients pre-senting beyond4years from their last known pregnancy,given the very poor outcomes,experimental therapies should be considered,including the use of high-dose treatment even when the disease seems localized.5,10

Epithelioid trophoblastic tumor is a comparatively new entity and may or may not behave distinctly from PSTT. Currently,most investigators manage ETT like PSTT until more data are available.In this regard,the combined PSTT/ ETT ISSTD database may help to provide further information in due course(https://https://www.doczj.com/doc/c313880185.html,/).

Fertility and Longer-Term Outlook

After Chemotherapy

After treatment,hCG surveillance in serum and/or urine is necessary to monitor for relapse.The frequency and duration of hCG tests are not standardized.Some centers measure hCG just once monthly up to18months,and others adopt more frequent testing initially that slowly tapers to just6monthly urine samples for life.10

Because most relapses occur in the first12months, avoiding pregnancy during this period seems sensible unless other reasons for an earlier pregnancy exist,such as advancing age.Fortunately,existing data suggest that early pregnancy does not increase the risk for GTN recurrence,that for miscarriage,or that for malformed children.10Reassuringly,83%of women who have had single-or multiagent chemotherapy have a further pregnancy.10However,EMA/CO does induce meno-pause3years early,so women need to be warned of this.10The previously reported slight increased risk for second cancers after combination-agent chemotherapies10was no longer seen with EMA/CO treatment in a more recent analysis,and single-agent MTX/F A remains without effect(ISSTD2013Chicago meeting).Several survivorship issues still need addressing, including short-and longer-term psychosocial and sexual problems experienced by patients,their partners,and other family members.

ACKNOWLEDGMENTS

The authors thank the additional members of the writing group representing EOTTD and ISSTD,including Isa Niemann (Denmark),Nienke van Trommel(Holland),John Lurain(United States),Faye Cagyan(Philippines),and Robert Coleman(United Kingdom)as well as all participants of the London meeting validating all Gynecological Cancer InterGroup(GCIG)reviews in November2013.

Isabelle Ray Coquard(GINECO),Jonathan Ledermann (MRC NCRI),Monica Bacon(GCIG Canada),Eric Pujade-Lauraine(GINECO),Michael Quinn(ANZGOG),William Small (RTOG),Gavin Stuart(NCIC CTG),Jan V ermorken(EORTC).

AGO Australia:Regina Berger,Christian Marth, Karl Tamussino.

AGO Germany:Klaus Baumann,Jacobus Pfisterer, Alexander Reuss,Gabriele Elser,Philip Harter.

ANZGOG:Alison Brand,Linda Mileshkin,Clare Scott.

COGi:Jonathan Berek,Ashley Powell,Wendy Fantl.

DGOG:Rudd Bekkers,Carien Creutzberg,Els Witteveen.

GEICO:Andres Poveda,Ignacio Romero.

GICOM:David Isla,Dolores Gallardo.

GINECO:Benedicte V otan,Emmanuel Kurtz,Fabrice Lecuru,Florence Joly.

GOG:Mark Brady,David Gershenson,David Miller.

GOTIC:Keiichi Fujiwara,Kosei Hasegawa,Yuji Takei.

ICORG:Dearbhaile O’Donnell,Noreen Gleeson, Paula Calvert.

JGOG:Satoru Sagae,Aoki Okamoto,Tadao Takano.

KGOG:Jae Weon Kim,Byung Ho Nam,Sang Ryu.

MaNGO:Nicoletta Colombo,Roldano Fossati, Dionyssios Katsaros.

MITO:Domenica Lorusso,Georgia Mangili,Delia Mezzanzanica,Jane Bryce.

MRC-NCRI:Charles Gourley,Iain McNeish,Melanie Powell,Max Parmar.

NCIC CTG:Hal Hirte,Marie Plante,Diane Provencher.

NOGGO:Jalid Sehouli,Elena Braicu,Mani Nassir.

NSGO:Gunnar Kristensen,Johanna Maenpaa, Mansoor Mirza.

International Journal of Gynecological Cancer&Volume24,Number S3,November2014

Trophoblastic Disease Diagnosis and Management

*2014IGCS and ESGO S115

PMHC:Amit Oza,Helen MacKay,Steven Welch.

RTOG:Patricia Eifel,Anuja Jhingran.

SGCTG:Ros Glasspool,David Millan,Nick Reed, Jim Paul.

NCI-US:Thomas Gross,Elise Kohn.

ISSTD:Michael Seckl.

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16.Agarwal R,Teoh S,Short D,et al.Chemotherapy and human

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critical assessment.Int J Gynecol Cancer.2001;11:73Y77. 18.van Trommel NE,Massuger LF,Schijf CP,et al.Early

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Mangili et al International Journal of Gynecological Cancer&Volume24,Number S3,November2014 S116*2014IGCS and ESGO

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电话:传真:邮政编码: 日期:_2016年_4月_27日 二、投标报价一览表 投标报价一览表 三、申请人一般情况表及 资格证明文件 1、申请人一般情况:

2、资格证明文件

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管理规范化:公司根据国家法律法规规定,结合众多专家顾问的操作经验,制订了针对派遣员工切实可行的管理制度、详细的服务流程和协议合同文本,包括劳务派遣、招聘、工资发放、社会保险缴纳、工伤处理、劳动合同终止解除等流程和表格,以及劳务派遣协议、劳动合同以及员工手册等,从根本上降低了用人风险,保证了派遣服务的规范化。同时我们制定了一套完整的服务标准,即在工资、保险的误差率、事务处理的速度与效率,走访频度,客户与员工的满意度等方面提出了明确要求与承诺。 三、劳务派遣的好处 劳务派遣是近年我国人力资源市场根据市场需求而开办的新的人力资源外包服务项目。具体地说,就是派遣单位与劳动者签定劳动合同,建立劳动关系,再将该劳动者派遣到用工单位从事劳动的一种特殊用工形式。在这种形式下,派遣单位只管人而不用人,被派遣单位只用人而不管人,从而达到规范劳动关系、转移用工风险、降低用人成本的目的。它的好处在于: (一)用工方式灵活:《劳动合同法》规定了多种情况单位应当与劳动者签定无固定期限劳动合同,如连续签定两次固定期限合同应当转为无固定期限合同,而通过派遣的方式将有效解决这一问题。而一些制造类、信息类企业存在季节性用工问题,使用劳务派遣这种用工模式明科公司就可根据贵公司实际情况,设立短期临时性用工、非全日制工或承包某项特殊工作等。 (二)降低招工费用:用工单位采用劳务派遣用工方式,不需要制定招工方案和计划,也不需要发布招工广告,只需要根据本单位需要招收员工的数量、工种、技能和基本条件要求等与劳务派遣机构签订一份协议书,所有招工事宜均由劳务派遣机构办理,这样就可以不用支付人力费、广告费等支出。。

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