Original Research| Volume 130, P228-240, May 2020

Download started.


Practical clinical guidelines of the EOTTD for treatment and referral of gestational trophoblastic disease

Published:April 01, 2020DOI:


      • GTD is rare and treatment protocols vary within Europe.
      • The European Organisation for treatment of GTD aims to harmonise treatment.
      • Clinical guidelines were formulated by consensus and based on available literature.
      • Flow diagrams were created for easy clinical use.
      • New definitions of recurrence and chemotherapy resistance were formulated.


      Background and aim

      Gestational trophoblastic disease (GTD) is a heterogeneous group of disorders characterised by abnormal proliferation of trophoblastic tissue. Since GTD and its malignant sequel gestational trophoblastic neoplasia (GTN) are rare diseases, little evidence is available from randomised controlled trials on optimal treatment and follow-up. Treatment protocols vary within Europe, and even between different centres within countries. One of the goals of the ‘European Organisation for Treatment of Trophoblastic Diseases’ (EOTTD) is to harmonise treatment in Europe. To provide a basis for European standardisation of definitions, treatment and follow-up protocols in GTD, we composed a set of guidelines for minimal requirements and optimal management of GTD.


      Members from each EOTTD country attended multiple workshops during annual EOTTD meetings. Clinical guidelines were formulated by consensus and evidence where available. The following guidelines were discussed: diagnostics of GTD and GTN, treatment of low-risk GTN, high-risk GTN, ultra-high-risk GTN, placental site and epithelioid trophoblastic tumours and follow-up.


      Between 40 and 65 EOTTD members from 17 European countries and 7 non-European countries attended the clinical workshops held on 6 occasions. Flow diagrams for patient management were composed to display minimum and best practice for most treatment situations. New agreed definitions of recurrence and chemotherapy resistance were formulated.


      Despite the many differences between and within the participating countries, an important step in uniform treatment of GTD and GTN within Europe was made by the Clinical Working Party of the EOTTD. This is an example on how guidelines and harmonisation can be achieved within international networks.

      Graphical abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Eysbouts Y.K.
        • Bulten J.
        • Ottevanger P.B.
        • Thomas C.M.
        • Ten Kate-Booij M.J.
        • van Herwaarden A.E.
        • et al.
        Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.
        Gynecol Oncol. 2016; 140: 70-75
        • Joneborg U.
        • Folkvaljon Y.
        • Papadogiannakis N.
        • Lambe M.
        • Marions L.
        Temporal trends in incidence and outcome of hydatidiform mole: a retrospective cohort study.
        Acta Oncol. 2018; 57: 1094-1099
        • Savage P.
        • Williams J.
        • Wong S.L.
        • Short D.
        • Casalboni S.
        • Catalano K.
        • et al.
        The demographics of molar pregnancies in England and Wales from 2000-2009.
        J Reprod Med. 2010; 55: 341-345
        • Moliner A.M.
        Creating a European Union framework for actions in the field of rare diseases.
        Adv Exp Med Biol. 2010; 686: 457-473
        • Elias K.M.
        • Berkowitz R.S.
        • Horowitz N.S.
        State-of-the-Art workup and initial management of newly diagnosed molar pregnancy and postmolar gestational trophoblastic neoplasia.
        J Natl Compr Canc Netw. 2019; 17: 1396-1401
        • Ngan H.Y.S.
        • Seckl M.J.
        • Berkowitz R.S.
        • Xiang Y.
        • Golfier F.
        • Sekharan P.K.
        • Lurain J.R.
        • Massuger L.
        Update on the diagnosis and management of gestational trophoblastic disease.
        Int J Gynaecol Obstet. 2018; 143: 79-85
        • Ronnett B.M.
        Hydatidiform moles: ancillary techniques to refine diagnosis.
        Arch Pathol Lab Med. 2018; 142: 1485-1502
        • RCOG
        Management of gestational trophoblastic neoplasia, guideline no 38.
        2010 (Available from:)
        • Ngan H.Y.
        • Bender H.
        • Benedet J.L.
        • Jones H.
        • Montruccoli G.C.
        • Pecorelli S.
        • et al.
        Gestational trophoblastic neoplasia, FIGO 2000 staging and classification.
        Int J Gynaecol Obstet. 2003; 83: 175-177
        • Golfier F.
        • Clerc J.
        • Hajri T.
        • Massardier J.
        • Frappart L.
        • Duvillard P.
        • et al.
        Contribution of referent pathologists to the quality of trophoblastic diseases diagnosis.
        Hum Reprod. 2011; 26: 2651-2657
        • Osborne R.J.
        • Filiaci V.L.
        • Schink J.C.
        • Mannel R.S.
        • Behbakht K.
        • Hoffman J.S.
        • et al.
        Second curettage for low-risk nonmetastatic gestational trophoblastic neoplasia.
        Obstet Gynecol. 2016; 128: 535-542
        • Pezeshki M.
        • Hancock B.W.
        • Silcocks P.
        • Everard J.E.
        • Coleman J.
        • Gillespie A.M.
        • et al.
        The role of repeat uterine evacuation in the management of persistent gestational trophoblastic disease.
        Gynecol Oncol. 2004; 95: 423-429
        • Savage P.
        • Seckl M.J.
        The role of repeat uterine evacuation in trophoblast disease.
        Gynecol Oncol. 2005; 99 (reply 252-3): 251-252
        • Schlaerth J.B.
        • Morrow C.P.
        • Kletzky O.A.
        • Nalick R.H.
        • D'Ablaing G.A.
        Prognostic characteristics of serum human chorionic gonadotropin titer regression following molar pregnancy.
        Obstet Gynecol. 1981; 58: 478-482
        • van Trommel N.E.
        • Massuger L.F.
        • Verheijen R.H.
        • Sweep F.C.
        • Thomas C.M.
        The curative effect of a second curettage in persistent trophoblastic disease: a retrospective cohort survey.
        Gynecol Oncol. 2005; 99: 6-13
        • Seckl M.J.
        • Sebire N.J.
        • Fisher R.A.
        • Golfier F.
        • Massuger L.
        • Sessa C.
        • et al.
        Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2013; 24: vi39-vi50
        • Mapelli P.
        • Mangili G.
        • Picchio M.
        • Gentile C.
        • Rabaiotti E.
        • Giorgione V.
        • et al.
        Role of 18F-FDG PET in the management of gestational trophoblastic neoplasia.
        Eur J Nucl Med Mol Imag. 2013; 40: 505-513
        • Chalouhi G.E.
        • Golfier F.
        • Soignon P.
        • Massardier J.
        • Guastalla J.P.
        • Trillet-Lenoir V.
        • et al.
        Methotrexate for 2000 FIGO low-risk gestational trophoblastic neoplasia patients: efficacy and toxicity.
        Am J Obstet Gynecol. 2009; 200: 643 e1-6
        • Sita-Lumsden A.
        • Short D.
        • Lindsay I.
        • Sebire N.J.
        • Adjogatse D.
        • Seckl M.J.
        • et al.
        Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000-2009.
        Br J Cancer. 2012; 107: 1810-1814
        • Lawrie T.A.
        • Alazzam M.
        • Tidy J.
        • Hancock B.W.
        • Osborne R.
        First-line chemotherapy in low-risk gestational trophoblastic neoplasia.
        Cochrane Database Syst Rev. 2016; : Cd007102
        • Li J.
        • Li S.
        • Yu H.
        • Wang J.
        • Xu C.
        • Lu X.
        The efficacy and safety of first-line single-agent chemotherapy regimens in low-risk gestational trophoblastic neoplasia: a network meta-analysis.
        Gynecol Oncol. 2018; 148: 247-253
        • Li L.
        • Wan X.
        • Feng F.
        • Ren T.
        • Yang J.
        • Zhao J.
        • et al.
        Pulse actinomycin D as first-line treatment of low-risk post-molar non-choriocarcinoma gestational trophoblastic neoplasia.
        BMC Cancer. 2018; 18: 585
        • Yarandi F.
        • Mousavi A.
        • Abbaslu F.
        • Aminimoghaddam S.
        • Nekuie S.
        • Adabi K.
        • et al.
        Five-day intravascular methotrexate versus biweekly actinomycin-D in the treatment of low-risk gestational trophoblastic neoplasia: a clinical randomized trial.
        Int J Gynecol Cancer. 2016; 26: 971-976
        • Bolze P.A.
        • Mathe M.
        • Hajri T.
        • You B.
        • Dabi Y.
        • Schott A.M.
        • et al.
        First-line hysterectomy for women with low-risk non-metastatic gestational trophoblastic neoplasia no longer wishing to conceive.
        Gynecol Oncol. 2018; 150: 282-287
        • Ahamed E.
        • Short D.
        • North B.
        • Savage P.M.
        • Seckl M.J.
        Survival of women with gestational trophoblastic neoplasia and liver metastases: is it improving?.
        J Reprod Med. 2012; 57: 262-269
        • 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.
        J Clin Oncol. 2013; 31: 280-286
        • Balachandran K.
        • Salawu A.
        • Ghorani E.
        • Kaur B.
        • Sebire N.J.
        • Short D.
        • 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.
        Gynecol Oncol. 2019;
        • 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.
        Eur J Cancer. 2019; 109: 162-171
        • Froeling F.E.M.
        • Ramaswami R.
        • Papanastasopoulos P.
        • Kaur B.
        • Sebire N.J.
        • Short D.
        • et al.
        Intensified therapies improve survival and identification of novel prognostic factors for placental-site and epithelioid trophoblastic tumours.
        Br J Cancer. 2019; 120: 587-594
        • 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.
        Lancet. 2017; 390: 2343-2345
        • Frijstein M.M.
        • Lok C.A.R.
        • Coulter J.
        • van Trommel N.E.
        • Ten Kate-Booij M.J.
        • Golfier F.
        • et al.
        Is there uniformity in definitions and treatment of gestational trophoblastic disease in Europe?.
        Int J Gynecol Cancer. 2019; 29: 108-112
        • Bolze P.A.
        • Attia J.
        • Massardier J.
        • Seckl M.J.
        • Massuger L.
        • van Trommel N.
        • et al.
        Formalised consensus of the European Organisation for Treatment of Trophoblastic Diseases on management of gestational trophoblastic diseases.
        Eur J Cancer. 2015; 51: 1725-1731