NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Gestational Trophoblastic
Neoplasia
Version 1.2021 — February 02, 2021

NCCN.org

Continue

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

*Nadeem R. Abu-Rustum, MD Ω/Chair Peter Frederick, MD Ω Steven W. Remmenga, MD Ω

Memorial Sloan Kettering Cancer Center Roswell Park Cancer Institute Fred & Pamela Buffett Cancer Center
*Catheryn M. Yashar, MD §/Vice Chair David K. Gaffney, MD, PhD § R. Kevin Reynolds, MD Ω
UC San Diego Moores Cancer Center Huntsman Cancer Institute University of Michigan
Kristin Bradley, MD § at the University of Utah Rogel Cancer Center
University of Wisconsin Robert Giuntoli II, MD Ω Ritu Salani, MD, MBA Ω
Carbone Cancer Center Abramson Cancer Center at UCLA Jonsson Comprehensive Cancer Center
Susana M. Campos, MD, MPH, MS † the University of Pennsylvania Rachel Sisodia, MD Ω
Dana-Farber/Brigham and Women’s Ernest Han, MD, PhD Ω Massachusetts General Hospital
Cancer Center City of Hope Cancer Center
Hye Sook Chon, MD Ω National Medical Center Pamela Soliman, MD, MPH Ω
Moffitt Cancer Center Warner K. Huh, MD Ω The University of Texas MD Anderson Cancer Center
Christina Chu, MD Ω O'Neal Comprehensive Edward Tanner, MD Ω
Fox Chase Cancer Center Cancer Center at UAB Robert H. Lurie Comprehensive
Lani Clinton, MD, PhD ≠ Jayanthi Lea, MD Ω Cancer Center of Northwestern University
Duke Cancer Institute UT Southwestern Simmons Todd Tillmanns, MD Ω
Comprehensive Cancer Center St. Jude Children’s Research Hospital/
David Cohn, MD Ω
The Ohio State University Andrea Mariani, MD Ω The University of Tennessee Health Science Center
Comprehensive Cancer Center - Mayo Clinic Cancer Center Stefanie Ueda, MD Ω
James Cancer Hospital and David Mutch, MD Ω UCSF Helen Diller Family
Solove Research Institute Siteman Cancer Center at Barnes- Comprehensive Cancer Center
Marta Ann Crispens, MD Ω Jewish Hospital and Washington Renata Urban, MD Ω
Vanderbilt-Ingram Cancer Center University School of Medicine Fred Hutchinson Cancer Research Center/
Shari Damast, MD § Christa Nagel, MD Ω Seattle Cancer Care Alliance
Yale Cancer Center/ Case Comprehensive Cancer Center/ Stephanie L. Wethington, MD, MSc Ω
Smilow Cancer Hospital University Hospitals Seidman Cancer The Sidney Kimmel Comprehensive
Center and Cleveland Clinic Taussig Cancer Center at Johns Hopkins
Elisabeth Diver, MD Ω Cancer Institute
Stanford Cancer Institute Emily Wyse ¥
Larissa Nekhlyudov, MD, MPH Þ Patient Advocate
Christine M. Fisher, MD, MPH § Dana-Farber/Brigham and Women’s
University of Colorado Cancer Center Cancer Center NCCN
Nicole McMillian, MS
Angela Motter, PhD
Continue Ω Gynecologic oncology § Radiotherapy/Radiation
Þ Internal medicine oncology
† Medical oncology *Discussion Section Writing
≠ Pathology Committee
NCCN Guidelines Panel Disclosures ¥ Patient advocacy
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

Gestational Trophoblastic Neoplasia Subcommittee

David Mutch, MD Ω/Lead
Siteman Cancer Center at Barnes-Jewish Hospital
and Washington University School of Medicine
Elisabeth Diver, MD Ω
Stanford Cancer Institute
R. Kevin Reynolds, MD Ω
University of Michigan Rogel Cancer Center

NCCN Guidelines Panel Disclosures Continue Ω Gynecologic oncology

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

NCCN Gestational Trophoblastic Neoplasia Panel Members

Clinical Trials: NCCN believes that
NCCN GTN Subcommittee Members
the best management for any patient
Summary of the Guidelines Updates with cancer is in a clinical trial.
Participation in clinical trials is
Hydatidiform Mole (Noninvasive) especially encouraged.
Workup, Initial Treatment, Monitoring, Findings and Additional Evaluation (HM-1)
To find clinical trials online at NCCN
Persistent Post-molar GTN, Treatment (HM-2) Member Institutions, click here:
nccn.org/clinical_trials/member_
Gestational Trophoblastic Neoplasia (GTN) institutions.aspx.
Workup (GTN-1)
NCCN Categories of Evidence and
Primary Treatment for Low-Risk GTN (GTN-2)
Consensus: All recommendations
Treatment for Persistent GTN (GTN-3) are category 2A unless otherwise
Primary Treatment for High-Risk GTN (GTN-4) indicated.
Primary Treatment for Intermediate Trophoblastic Tumor: PSTT and ETT (GTN-5)
See NCCN Categories of Evidence
and Consensus.
Principles of Pathology (GTN-A)
Systemic Therapy for GTN (GTN-B) NCCN Categories of Preference:
Principles of Gynecologic Survivorship (GTN-C) All recommendations are considered
appropriate.
Staging (ST-1) See NCCN Categories of Preference.

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2021.
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

Updates in Version 1.2021 of the NCCN Guidelines for Gestational Trophoblastic Neoplasia from Version 3.2020 include:
General
• Principles of Gynecologic Survivorship: This is a new section that discusses the physical and psychosocial effects of gynecologic cancers
as well as clinical approaches to managing them. (GTN-C).
• Section title changed to Principles of Systemic therapy for GTN. (GTN-B)
Hydatidiform Mole (Noninvasive)
HM-1 HM-2
• Monitoring: Contraception (oral contraceptives preferred) added as • Staging
a recommendation. First bullet: H&P revised to include pelvic exam.
• Findings and Additional Evaluation: New bullet added: Determine FIGO stage and prognostic score.
Top pathway; After "Normal hCG levels for 3 consecutive assays": • Treatment
Revised, hCG assay twice in 3-month intervals hCG assay every 3 No extrauterine disease: Single-agent systemic therapy as in
months for 6 months GTN-2 added as an option.
Bottom pathway: hCG levels indicate postmolar gestational Extrauterine disease: A new bifurcation was added for
trophoblastic neoplasia (GTN) revised to Persistent hCG elevation Low-risk GTN: (<7 prognostic score) (See GTN-2) and High-risk
(plateau or rise). GTN: ≥7 prognostic score or Stage IV (See GTN-4). Previously
◊ After Persistent hCG elevation (plateau or rise), revised to chemotherapy on GTN-1 was recommended.
Persistent post-molar gestational trophoblastic neoplasia (GTN). • Monitoring for No extrauterine disease: After "hCG assay every 2
• Footnote a revised: If chest x-ray positive for metastases, then weeks until 3 consecutive normal assays, followed by monthly for
perform chest/abdomen/pelvis CT and brain MRI and manage as 6 months" recommendation clarified as Persistent hCG elevation
GTN after initial uterine evacuation. (plateau or rise)
• Footnote d revised: Hysterectomy with salpingectomy may be • Footnote g is new: See FIGO Staging System for GTN (ST-1) and
considered as initial treatment for hydatidiform mole in patients who Prognostic Scoring Index for GTN (ST-2).
are older or do not wish to preserve fertility. • Footnote removed from this page: See Principles of Systemic
• Footnote e revised: A formal follow-up program allows for early Therapy (GTN-B) for specific recommendations.
detection of GTN and limits exposure to combination chemotherapy
(Sita-Lumsden A, et al. Br J Cancer 2012;107:1810-1814). See
Principles of Pathology (GTN-A).
• Footnote f added to page: Oral contraceptive pills are preferred
because they suppress endogenous luteinizing hormone (LH)/
follicle-stimulating hormone (FSH), which may interfere with hCG
measurement at low levels.

Continue

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
UPDATES
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

Gestational Trophoblastic Neoplasia (GTN) checked during a chemotherapy cycle; they should only be checked
GTN-1 at the start of each cycle.
• Findings; Middle pathway: Revised, High-risk GTN: FIGO stages II–III
and ≥7 prognostic score or Stage IV. (Also for GTN-4) GTN-4 High-risk GTN
• Footnote c revised: "... consider possibility of luteinizing hormone • New page title added: Primary Treatment for High-Risk GTN.
(LH) crossover or phantom hCG. Consult with..." • Treatment; EMA/CO; If brain metastases: Revised, Increase
methotrexate dose and folinic acid leucovorin dose.
GTN-2 Low-risk GTN • Footnote q revised: Increase the methotrexate infusion dose in the
• New page title added: Primary Treatment for Low-Risk GTN EMA/CO protocol to 1000 mg/m2 and give folinic acid 30 mg every
• Response Assessment 12 hours for 3 days starting 32 hours after the infusion begins. For
Top pathway; Normal hCG level: Revised, Continue systemic dosing modifications for brain metastases, See Systemic Therapy for
therapy for 2 2–3 treatment cycles (4 weeks total) past hCG GTN (GTN-B 2 of 6).
normalization.
Bottom pathway; Poor response to initial therapy: Revised, "... for GTN-5 Intermediate trophoblastic tumor: PSTT and ETT
3 treatment cycles (6 weeks total) or hCG level rises (>10% change) • New page title added: Primary Treatment for PSTT and ETT.
for 2 treatment cycles (4 weeks total)." • Metastatic pathway; Chemotherapy with a platinum/etoposide-
• Follow-up/Surveillance: Second bullet revised, Contraception (oral containing regimen,...: Bullet removed, "Use granulocyte colony-
contraceptives pills preferred). stimulating factor (G-CSF) with chemotherapy regimens (See
• Footnote i revised: Regimens are continued until 2 2–3 full cycle(s) NCCN Guidelines for Hematopoietic Growth Factors)." This
past normalization of the hCG. recommendation can be found on GTN-B.
• Footnote l revised: hCG plateau during treatment can be defined as a
<10% decrease in hCG over 2 3 treatment cycles (4 weeks total).

GTN-3
• New page title added: Primary Treatment for Persistent GTN
• Top pathway
Revised, Good response to initial therapy followed by hCG level
plateau or re-elevation (hCG <300).
• Bottom pathway
Revised, Good response to initial therapy followed by rapid rise in
hCG level (hCG ≥ 300) or Poor response to initial therapy
• Response Assessment
The recommendation for Normal hCG levels was revised: Continue
systemic therapy for 2 2-3 treatment cycles past normalization.
hCG level plateaus: The "weeks" timeframes for the treatment
cycles were removed (ie "4 weeks total" and "2 weeks total").
• Footnote removed: hCG level plateaus (<10% change) for 2 treatment
cycles (4 weeks total) or hCG level rises (>10% change) for 1
treatment cycle (2 weeks total).
• Footnote removed: Do not start a cycle of methotrexate or
dactinomycin if the WBC was <3.0 or the ANC was <1.5 or if there was Continue
persistent mucositis >grade 1. CBC and chemistries should not be
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
UPDATES
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

Hydatidiform Mole (Noninvasive) and GTN

GTN-B Systemic Therapy for GTN
• The dosing and Comments/Considerations throughout this section were extensively revised.
• Footnote b is new: Round filgrastim dose to the nearest vial size by institution-defined weight limits.

4 of 6
• The "TIP: Paclitaxel, Ifosfamide, Cisplatin" regimen under "Other Recommended Regimens" was moved from page 5 of 6 to page 4 of 6 to
clarify that only TIP is recommended for High-Risk GTN: Therapy for Methotrexate-Resistant GTN .
• Footnote d regarding VIP is new: For dosing references, See page TEST-E from the NCCN Guidelines for Testicular Cancer.
• Footnote e regarding TIP is new: For dosing references, See page TEST-F from the NCCN Guidelines Testicular Cancer.

5 of 6
• Page title revised: High-Risk GTN: Therapy for Methotrexate-Resistant GTN Additional agents/regimens shown to have some activity in treating
multiagent chemotherapy-resistant GTN.
• Usefule in Certain Circumstances:
PD-1/PD-L1 inhibitors: Dosing was added for avelumab, Avelumab 800 mg IV every 2 weeks

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Hydatidiform Mole (Noninvasive) Discussion

WORKUP INITIAL TREATMENT MONITORINGe FINDINGS AND ADDITIONAL

EVALUATION

• H&P hCG assay

• Pelvic ultrasound Normal hCG levels
every 3
• Chest x-raya for 3 consecutive
months for 6
• Quantitative • H&P 1 month assays
months
human chorionic after initial
gonadotropin (hCG) Suction dilation treatment
assay and curettage • hCG assay
Complete
• CBC differential and (D&C), preferably every 1–2
or partial
platelet count under ultrasound weeks until
hydatidiform
• Liver/renal/thyroid guidanceb,c normalized
mole Persistent
function tests/ or • Contraception
chemistry profile Hysterectomy (oral post-molar
• Blood type and with contraceptives Persistent hCG gestational
screen salpingectomyd preferred)f elevation trophoblastic
Administer Rho(D) (plateau or rise) neoplasia
immune globulin if (GTN)
Rh negative (See HM-2)

aIf chest x-ray positive for metastases, then perform chest/abdomen/pelvis CT and brain MRI and manage as GTN after initial uterine evacuation.
bUse largest curette feasible. Sharp curettage after suction. Use uterotonic drugs after initiating evacuation of uterus. Oxytocin receptors may be absent.
cProphylactic chemotherapy with methotrexate or dactinomycin may be considered at the time of evacuation of a hydatidiform mole in patients at high riskfor post-molar
GTN (age >40 years, hCG >100,000 mIU/mL, excessive uterine enlargement, and theca lutein cysts >6 cm) when hCG follow-up is unavailable or unreliable (Wang Q,
et al. Cochrane Database Sust Rev 2017;9:CD007289).
dHysterectomy with salpingectomy may be considered as initial treatment for hydatidiform mole in patients who do not wish to preserve fertility.
eA formal follow-up program allows for early detection of GTN and limits exposure to combination chemotherapy (Sita-Lumsden A, et al. Br J Cancer 2012;107:1810-
1814). See Principles of Pathology (GTN-A).
fOral contraceptive pills are preferred because they suppress endogenous luteinizing hormone (LH)/follicle-stimulating hormone (FSH), which may interfere with hCG
measurement at low levels.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
HM-1
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Hydatidiform Mole (Noninvasive) Discussion

FINDINGS STAGING TREATMENT MONITORING

Consider repeat hCG levels normalize

D&C hCG assay
or every 2
Single-agent weeks until 3
systemic consecutive
No extrauterine
therapy as in normal
One or more of the disease
GTN-2 assays,
following indicating or followed by
post-molar GTN: • H&P (including Hysterectomy monthly for 6
• hCG levels plateau pelvic exam) with months
for 4 consecutive • Doppler pelvic salpingectomy
values over ultrasoundh Persistent
Chemotherapy
3 weeks • Chest x-rayi hCG elevation
as in GTN-3
• hCG levels rise • Determine (plateau or rise)
≥10% for 3 values Low-risk GTN:
FIGO stage
over 2 weeks (<7 prognostic score)j
and prognostic
(See GTN-2)
• hCG persistence scorej
6 months after molar
evacuation Extrauterine
disease

High-risk GTN:
≥7 prognostic scorej or
Histopathologic Stage IV (See GTN-4)
diagnosis of
choriocarcinomag
(See GTN-1)
and/or
Presence of
metastatic disease

gSee Principles of Pathology (GTN-A).

hDoppler pelvic ultrasound to confirm absence of pregnancy, measure uterine size, and determine volume and vasculature of tumor within the uterus.
if the chest x-ray is normal, no further imaging is indicated before commencing treatment. If the chest x-ray shows metastases, CT scan of the abdomen/pelvis and MRI
of the brain are indicated.
jSee FIGO Staging System for GTN (ST-1) and Prognostic Scoring Index for GTN (ST-2).

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
HM-2
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

WORKUPa FINDINGSg TREATMENT

(unless previously done)
Low-risk GTN
(See GTN-2)
(<7 prognostic score)e

• H&P
• Repeat CBC differential and platelet count
• Repeat liver/renal/thyroid function tests/chemistry profile
• Imaging
High-risk GTN:
Chest/abdominal/pelvic CT scan with contrastb
≥7 prognostic scoree
◊ Brain MRI (preferred) or CT with contrast if (See GTN-4)
or
pulmonary metastasis
Stage IV
Pelvic ultrasound or MRI
• hCG assayc,d
• Determine FIGO stage and prognostic scoree
• Histopathologic assessmentf
Intermediate
trophoblastic tumorh
• Placental site
trophoblastic tumor
(See GTN-5)
(PSTT)
• Epithelioid
trophoblastic tumor
(ETT)

aIf visible lesions are seen in lower genital tract, do NOT biopsy due to risk of hemorrhage.
bIf contrast is contraindicated, other imaging techniques such as MRI may be considered.
cIf hCG is elevated with no evidence of disease on imaging, consider possibility of LH crossover or phantom hCG. Consult with laboratory medicine/pathology to test for
phantom hCG with serial dilution study or comparison of serum to urine hCG.
dIf hCG is elevated, but hyperglycosylated hCG is normal, quiescent GTN may be diagnosed and not treated.
eSee FIGO Staging System for GTN (ST-1) and Prognostic Scoring Index for GTN (ST-2).
fSee Principles of Pathology (GTN-A).
gConsider consultation with a clinician or center with expertise in management of gestational trophoblastic diseases.
hPrognostic scoring is not valid for intermediate tumors.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
GTN-1
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

PRIMARY TREATMENT FOR LOW-RISK GTN

DIAGNOSIS TREATMENT MONITORING DURING RESPONSE ASSESSMENT FOLLOW-UP/
TREATMENT SURVEILLANCEm

Normal hCG level • hCG assay every month

• Continue systemic for 12 months
therapy for 2–3 treatment • Contraception
cycles past hCG (oral contraceptives
normalization preferred)n
Followed by
hCG level plateaul

Single-agent
Low-risk GTN hCG assay every 2 Good
systemic therapy
confirmed weeks, at the start response
optionsi,j,k
(<7 prognostic of each treatment to initial
• Methotrexate
score) cycle therapy
• Dactinomycin
Followed by Response
rapid rise in hCG level assessment
(>10% change) (See GTN-3)

Poor response to initial therapy:

hCG level plateaus (<10% change)
for 3 treatment cycles
or
hCG level rises (>10% change)
for 2 treatment cycles
iRegimens are continued until 2–3 full cycle(s) past normalization of the hCG.
jHysterectomy with salpingectomy may be considered if there is localized disease
in the uterus and where fertility preservation is not desired. Leave ovaries in situ, even
in presence of theca lutein cysts.
kSee Systemic Therapy for GTN (GTN-B) for specific recommendations.
lhCG plateau during treatment can be defined as a <10% decrease in hCG over 3 treatment cycles.
mSee Principles of Gynecologic Survivorship (GTN-C).
nOral contraceptive pills are preferred because they suppress endogenous LH/FSH, which may interfere with hCG measurement at low levels.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
GTN-2
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

TREATMENT FOR PERSISTENT GTN

TREATMENTg MONITORING RESPONSE ADDITIONAL
DURING ASSESSMENTo TREATMENT
TREATMENTm Normal hCG levels
Change to single agent not • Continue systemic therapy for 2–3
Good response used in first-line therapyk treatment cycles past normalization
to initial therapy • Methotrexate hCG assay every 2
followed by hCG • Dactinomycin weeks, at the start of
level plateau or and each treatment cycle hCG level
re-elevation Consider hysterectomy plateaus Repeat workup to
(hCG <300) with salpingectomyj (<10% change) for check for metastasis
2 treatment cycles and
or Transition to
hCG level rises combination therapy:
(>10% change) for EMA/COk
1 treatment cycle

Normal hCG levels

Good response Change from single-agent systemic • Continue systemic therapy for 2–3
to initial therapy therapy to combination EMA/COk treatment cycles past normalization
followed by rapid and hCG assay every 2 Administer
rise in hCG level Repeat workup to check for metastasis weeks, at the start of hCG level etoposide/
(hCG ≥ 300) and each treatment cycle plateaus platinum-based
or Consider hysterectomy (<10% change) for regimensk and
Poor response to with salpingectomyj 2 treatment cycles consider surgical
initial therapy or resection if feasible
hCG level rises as per Additional
(>10% change) for Treatment for High-
1 treatment cycle Risk GTN (See
GTN-4 and GTN-B)

gConsider consultation with a clinician or center with expertise in management of kSee Systemic Therapy for GTN (GTN-B) for specific recommendations.
gestational trophoblastic diseases. mSee Principles of Gynecologic Survivorship (GTN-C).
jHysterectomy with salpingectomy may be considered if there is localized disease oPost-treatment imaging is not recommended for follow-up after hCG normalization
in the uterus and where fertility preservation is not desired. Leave ovaries in situ, in patients with post-molar GTN or choriocarcinoma, where hCG is a reliable
even in presence of theca lutein cysts. tumor marker.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
GTN-3
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

PRIMARY TREATMENT FOR HIGH-RISK GTN

DIAGNOSIS TREATMENTg MONITORING RESPONSE ADDITIONAL TREATMENT
DURING ASSESSMENTo
TREATMENT m

Normal hCG
levels: Continue
hCG assay every
systemic therapy
month for 12 months
regimen for 2–3
EMA/COk cycles
• If brain metastases:
Increase methotrexate dose and
leucovorin dosep
High-risk GTN Consider brain radiotherapy: Good response
confirmed: ◊ Stereotactic brain radiotherapy hCG assay followed by hCG
≥7 Prognostic score ± intrathecal methotrexate every 2 plateau at low
or or weeks levels EMA/EP or
Stage IVe ◊ Whole brain radiation during EP/EMAk
(30 Gy in 15 fractions [2.0 Gy/fx]) treatment Relapse from
• If extensive metastatic disease with remission
prognostic score >12:e
Consider induction low-dose EP, as Chemotherapy:
noted in GTN-B, for 1–3 cycles prior Etoposide/platinum-based
to starting EMA/CO regimens with bleomycin,
Incomplete
ifosfamide, or paclitaxelk,q
response to
and
treatment
Consider resection for
chemotherapy-resistant
eSee FIGO Staging System for GTN (ST-1) and Prognostic Scoring Index for GTN disease, if feasibler
(ST-2).
gConsider consultation with a clinician or center with expertise in management of
gestational trophoblastic diseases. pFor dosing modifications for brain metastases, See Systemic Therapy for GTN
kSee Systemic Therapy for GTN (GTN-B) for specific recommendations. (GTN-B 2 of 6).
mSee Principles of Gynecologic Survivorship (GTN-C). qAlso see Additional Agents Shown to Have Some Activity in Treating Multiagent
oPost-treatment imaging is not recommended for follow-up after hCG normalization Chemotherapy-Resistant GTN (GTN-B 5 of 6).
in patients with post-molar GTN or choriocarcinoma, where hCG is a reliable rConsider surgery, especially hysterectomy with salpingectomy and pulmonary
tumor marker. resection, for chemotherapy-resistant disease.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
GTN-4
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

PRIMARY TREATMENT FOR PSTT AND ETT

DIAGNOSIS TREATMENTg MONITORING AND
SURVEILLANCEm,v
• Interval from index
pregnancy <2 years
• Superficial invasion
• No necrosis hCG monitoring
Hysterectomy If recurrence
• Mitotic count or
with or
Nonmetastatic ≤5/10 HPFs Surveillance
salpingectomy progression:
(Stage I) with imagingv,w
± pelvic lymph Consider Systemic
• Interval from index if hCG is not a
node biopsyt systemic therapyk
pregnancy ≥2 years reliable marker
therapy,k
• Deep invasion
as per
• Necrosis
Intermediate metastatic
• Mitotic count
trophoblastic disease
>5/10 HPFs
tumor confirmedf pathway
• PSTTs If recurrence
• ETT or
progression:
Systemic
Hysterectomy with salpingectomy, excision of metastatic hCG monitoring
therapyk
disease if feasible or
or
and Surveillance
Metastatic Best
Chemotherapy with a platinum/etoposide-containing with imagingv,w
supportive
regimen, such as EMA/EP, EP/EMA, or other regimens if hCG is not a
care (See
such as TP/TE, BEP, VIP, or ICEk,u reliable marker
NCCN
fSee Principles of Pathology (GTN-A).
Guidelines
gConsider consultation with a clinician or center with expertise in management of gestational trophoblastic diseases. for Palliative
kSee Systemic Therapy for GTN (GTN-B) for specific recommendations. Care)
mSee Principles of Gynecologic Survivorship (GTN-C).
sReported poor prognostic factors in PSTT are high miotic rates (>5/10 high-power fields [HPFs]), deep myometrial invasion, extensive coagulative necrosis,
lymphovascular space invasion (LVSI), and interval since last pregnancy >2 years. (Baergen RN, et al. Gynecol Oncol 2006;100:511-520.)
tThe incidence of pelvic lymph node metastasis in PSTT/ETT is estimated to be between 5% and 15% in clinical stage I tumors. Therefore, pelvic lymph node biopsy
should be considered at the time of hysterectomy with salpingectomy, especially with large, deeply invasive tumors.
uAlso see Additional Agents Shown to Have Some Activity in Treating Multiagent Chemotherapy-Resistant GTN (See GTN-B 6 of 6).
vPost-treatment imaging is indicated for follow-up after treatment of PSTT and ETT, where hCG is a less reliable tumor marker.
wConsider PET/CT for follow-up at the completion of chemotherapy and then every 6–12 months for 2–3 years.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
GTN-5
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

PRINCIPLES OF PATHOLOGY
Procedure
• D&C
• Hysterectomy
• Pelvic exenteration
• Other
Pathologic Diagnosis of Benign, Noninvasive Hydatidiform Mole2

Gross Chorionic Villi Trophoblastic Cytologic Villous Stroma p57 IHC DNA
Examination Hyperplasia Atypia Genotyping
Complete Mole Diffuse hydropic Diffusely Marked, often May be marked Marked edema Absent nuclear Diploid
villi; fetus absent enlarged circumferential with cisterns staining in diandric
and trophoblast cytotrophoblasts genome
inclusions; blood and villous stromal
vessels absent; cells
nucleated red blood
cells (RBCs) absent
Partial Mole Patchy hydropic Dual population Mild Mild May have cisterns; Nuclear staining Triploid
villi; fetal tissue of villi composed trophoblastic present in diandric-
may be present of enlarged pseudoinclusions; cytotrophoblasts monogynic
villi and small, blood vessels and villous stromal genome
fibrotic villi present; nucleated cells
RBCs present

• Report histologic type only.

• If myometrial or vascular invasion is present (ie, invasive mole), use pathologic assessment for malignant GTN below.

Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
GTN-A
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
1 OF 2
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

PRINCIPLES OF PATHOLOGY
Pathologic Assessment for Malignant Gestational Trophoblastic Tumora
• Tumor site (ie, uterine corpus, cervix, other, cannot be determined)
• Tumor size (measured in cm)
• Histologic type
Hydatidiform mole, invasive
Choriocarcinoma
Placental site trophoblastic tumor
Epithelioid trophoblastic tumor
Malignant trophoblastic tumor, type cannot be determined
• Tissue/organ involvement (list all organs submitted for evaluation involved by tumor)
• Specimen margin status (where applicable; when negative, may also include closest margin and distance to closest margin)
• Lymphovascular space invasion

Immunohistochemical Markers for Differential Diagnosis of GTN1,2,3

Mel-CAM (CD146) hPL β-HCG p63 Cyclin E Ki-67

PSTT + + _ _ >10%

ETT _ _ _ + >50% >10%

Choriocarcinoma +/- + + _ High,

usually >90%
Mel-CAM: melanoma cell adhesion molecule; hPL: human placental lactogen; β-HCG: beta-human chorionic gonadotropin
Footnotes
aBenign trophoblastic tumors/lesions (ie, exaggerated placental site, placental site nodule) are benign and should NOT be reported using these principles.

References
1College of American Pathologists: Protocol for the Examination of Specimens From Patients With Primary Gestational Trophoblastic Malignancy. 2017. Available at:
https://documents.cap.org/protocols/cp-trophoblast-17protocol-4000.pdf.
2Kurman RJ, Carcangiu ML, Herrington CS, et al. WHO Classification of Tumours of Female Reproductive Organs, Fourth Edition. Vol. 6; 2014:155-168.
3Chi DS, Berchuck A, Dizon DS, et al. Table 26.2: Immunohistochemical Markers for Differential Diagnosis of GTD. Principles and Practice of Gynecologic Oncology
2017:745.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
GTN-A
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
2 OF 2
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

SYSTEMIC THERAPY FOR GTN

Regimens for Low-Risk GTN
Preferred Regimens Comments/Considerations
Methotrexate • A multiday methotrexate regimen is typically
0.4 mg/kg/day (max 25 mg/day) IV (preferred) or IM daily x 5 days; used as first-line therapy for low-risk GTN. Due
Repeat every 14 days to its toxicity profile, 5-day dactinomycin has
(category 1) most often been used as secondary therapy for
patients with methotrexate toxicity or effusions
OR contradicting the use of methotrexate.

1 mg/kg IM every other day x 4 days (Days 1, 3, 5, and 7) NOT RECOMMENDED

Alternating every other day with leucovorin 0.1 mg/kg rounded up • Methotrexate 30–50 mg/m2 IM weekly
to the nearest 5-mg dose increment or 15 mg PO (preferred) or OR Methotrexate infusion
IM 30 hours after each methotrexate dose on Days 2, 4, 6, and 8; (eg, 300 mg/m2 over 12 hours/leucovorin) due to
Repeat every 14 days lesser efficacy.
(category 1)
Dactinomycin • Dactinomycin pulse regimen should not be used
10–12 mcg/kg (or 0.5 mg flat dose) IV daily x 5 days; as secondary therapy for methotrexate-resistant
Repeat every 14 days disease nor as primary therapy in patients with
(category 1) choriocarcinoma.

OR

1.25 mg/m2 (max 2 mg) IV pulse;

Repeat every 14 days
(category 1)

Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
GTN-B
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
1 OF 6
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

SYSTEMIC THERAPY FOR GTN

High-Risk GTN: Primary Therapy Optionsa
Preferred Regimens Comments/Considerations
EMA/CO: Etoposide, Methotrexate, Dactinomycin/Cyclophosphamide, Vincristine • Consider low-dose induction chemotherapy with
(Repeat every 2 weeks until hCG normalizes, then continue for an additional 6–8 etoposide 100 mg/m2/day IV and cisplatin 20 mg/m2/day
weeks) IV on Days 1 and 2 every 7 days for 1–3 courses prior
• Etoposide 100 mg/m2/day IV on Days 1 and 2 to starting EMA/CO in patients with widely metastatic
• Dactinomycin 0.5 mg IV push on Days 1 and 2 disease (prognostic score >12) who are at significant
• Methotrexate 300 mg/m2 IV infusion over 12 hours on Day 1 risk for pulmonary, intraperitoneal, or intracranial
• Leucovorin 15 mg PO (preferred) or IM every 12 hours for 4 doses hemorrhage.
starting 24 hours after the start of methotrexate infusion • For secondary prophylaxis of neutropenic fever, or for
• Cyclophosphamide 600 mg/m2 IV on Day 8 treatment delay: Filgrastim, 5 mcg/kg 3–4 days/wk [ie, on
• Vincristine 1 mg/m2 (maximum of 2 mg) IV over 5–10 minutes on Day 8 days 4–6(7) and 10–12(13)] of each EMA/CO cycle.b
• For patients with brain metastases, increase the
methotrexate infusion dose in the EMA/CO protocol to
1000 mg/m2 and extend the infusion from 12 to 24 hours;
give leucovorin 15 mg PO every 6 hours for 12 doses
starting 32 hours after the start of the methotrexate
infusion.

aUsegranulocyte colony-stimulating factor (G-CSF) as primary prophylaxis with etoposide/cisplatin or etoposide/carboplatin-based regimens. See NCCN Guidelines for
Hematopoietic Growth Factors.
bRound filgrastim dose to the nearest vial size by institution-defined weight limits.

Note: All recommendations are category 2A unless otherwise indicated. Continued

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
GTN-B
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
2 OF 6
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

SYSTEMIC THERAPY FOR GTN

High-Risk GTN: Primary Therapy Optionsa – Continued
For highest-risk patients, consider: EMA/EP or EP/EMA
• EMA/EP (or EP/EMA) regimen is considered the most appropriate therapy for patients who have responded to EMA/CO but have plateauing
low hCG levels or have developed re-elevation of hCG levels after a complete response to EMA/CO.
Preferred Regimens Comments/Considerations
EMA/EP: Etoposide, Methotrexate, Dactinomycin/Etoposide, Cisplatin c • Consider low-dose induction chemotherapy with
(Repeat every 2 weeks alternating EMA with EP weekly through 6–8 weeks etoposide 100 mg/m2/day IV and cisplatin 20 mg/m2/day IV
post-serologic remission) on Days 1 and 2 every 7 days for 1–3 courses prior
• Etoposide 100 mg/m2/day IV on Day 1 to starting EMA/EP or EP/EMA in patients with widely
• Methotrexate 300 mg/m2 IV infusion over 12 hours on Day 1 metastatic disease (prognostic score >12) who are at
Leucovorin 15 mg PO (preferred) or IM every 12 hours for 4 doses significant risk for pulmonary, intraperitoneal, or intracranial
beginning 24 hours after the start of the methotrexate infusion hemorrhage.
• Dactinomycin 0.5 mg IV push on Day 1 • For patients with brain metastases, increase the
methotrexate infusion dose in the EP/EMA or EMA/EP
• Etoposide 150 mg/m2 IV on Day 8 protocol to 1000 mg/m2 and extend the infusion from
2
• Cisplatin 75 mg/m IV on Day 8 12 to 24 hours; give leucovorin 15 mg PO every
• Filgrastim 5 mcg/kg SC on Days 9–14b 6 hours for 12 doses starting 32 hours after the start of the
EP/EMA: Etoposide, Cisplatin/Etoposide, Methotrexate, Dactinomycin c methotrexate infusion.
(Repeat every 2 weeks alternating EP with EMA weekly through 6–8 weeks
post-serologic remission)
• Etoposide 150 mg/m2 on Day 1
• Cisplatin 75 mg/m2 IV on Day 1

• Etoposide 100 mg/m2 IV on Day 8

• Methotrexate 300 mg/m2 IV infusion over 12 hours on Day 8
Leucovorin 15 mg PO (preferred) or IM every 12 hours for 4 doses
beginning 24 hours after the start of the methotrexate infusion
• Dactinomycin 0.5 mg IV on Day 8
• Filgrastim 5 mcg/kg SC on Days 3–6 and 10–13b

aUse G-CSF as primary prophylaxis with etoposide/cisplatin or etoposide/carboplatin-based regimens. See NCCN Guidelines for Hematopoietic Growth Factors.
bRound filgrastim dose to the nearest vial size by institution-defined weight limits.
cDosing schedules also apply to the Intermediate Trophoblastic Tumor (PSTT and ETT) regimens listed on GTN-B 6 of 6.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
GTN-B
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
3 OF 6
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

SYSTEMIC THERAPY FOR GTN

High-Risk GTN: Therapy for Methotrexate-Resistant GTNa
Preferred Regimens
TP/TE: Paclitaxel, Cisplatin/Paclitaxel, Etoposide (Repeat every 2 weeks)c VIP: Etoposide, Ifosfamide, Cisplatin (Repeat every 3 weeks)c,d
• Paclitaxel 135 mg/m2 IV infusion on Day 1 • Etoposide 75 mg/m2/day IV on Days 1–5
• Cisplatin 75 mg/m2 IV on Day 1 • Ifosfamide 1200 mg/m2/day IV on Days 1–5 with mesna
protection
Alternating every 2 weeks with: Mesna 120 mg/m2/day IV bolus 15 minutes prior to ifosfamide,
• Paclitaxel 135 mg/m2 IV infusion on Day 15 then 1200 mg/m2/day IV infusion over 12 hours after
• Etoposide 150 mg/m2 IV on Day 15 ifosfamide dose on Days 1–5
• Pegfilgrastim 6 mg SC on Days 2 and 16 • Cisplatin 20 mg/m2/day IV on Days 1–5
• Pegfilgrastim 6 mg SC on Day 5;
OR Filgrastim 5 mcg/kg SC on Days 6–14b
BEP: Bleomycin, Etoposide, Cisplatin (Repeat every 3 weeks)c,d ICE: Ifosfamide, Carboplatin, Etoposide (Repeat every 3 weeks)c
• Bleomycin 30 units IV weekly on Days 1, 8, and 15 or Days 2, 9, and 16 • Ifosfamide 1.2 g/m2/day IV on Days 1–3 with mesna protection
• Etoposide 100 mg/m2/day IV on Days 1–5 Mesna 120 mg/m2/day IV bolus 15 minutes prior to ifosfamide,
• Cisplatin 20 mg/m2/day IV on Days 1–5 then 1200 mg/m2/day IV infusion over 12 hours
• Pegfilgrastim 6 mg SC on Day 8; after ifosfamide dose on Days 1–3
OR Filgrastim 5 mcg/kg SC on Days 6–14b • Carboplatin AUC 4 IV on Day 1
• Etoposide 75 mg/m2/day IV on Days 1–3
Comments/Considerations • Pegfilgrastim 6 mg SC on Day 4;
• Lifetime dose of bleomycin should not exceed 270 units. OR Filgrastim 300 mcg SC on Days 6–14
• Pulmonary function testing should be performed prior to initiation of
therapy and every fourth dose thereafter.

Other Recommended Regimens

TIP: Paclitaxel, Ifosfamide, Cisplatin (Repeat every 3 weeks)e
• Paclitaxel 250 mg/m2 IV on Day 1
• Ifosfamide 1500 mg/m2/day IV on Days 2–5 with mesna protection
Mesna 300 mg/m2 IV 15 minutes prior to ifosfamide, then at 4 hours and 8 hours from the start of each ifosfamide dose on Days 2–5
• Cisplatin 25 mg/m2/day IV on Days 2–5
aUse G-CSF as primary prophylaxis with etoposide/cisplatin or etoposide/carboplatin-based regimens. See NCCN Guidelines for Hematopoietic Growth Factors.
bRound filgrastim dose to the nearest vial size by institution-defined weight limits.
cDosing schedules also apply to the Intermediate Trophoblastic Tumor (PSTT and ETT) regimens listed on GTN-B 6 of 6.
dFor dosing references, see page TEST-E in the NCCN Guidelines for Testicular Cancer.
eFor dosing references, see page TEST-F in the NCCN Guidelines for Testicular Cancer.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
GTN-B
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
4 OF 6
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

SYSTEMIC THERAPY FOR GTN

High-Risk GTN:
Additional Agents/Regimens Shown to Have Some Activity in Treating Multiagent Chemotherapy-Resistant GTNc,f

Useful in Certain Circumstances

• PD-1/PD-L1 inhibitors
(eg, pembrolizumab, nivolumab, avelumab)g
Pembrolizumab 200 mg IV every 3 weeks or 400 mg IV every 6 weeks
Nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks
Avelumab 800 mg IV every 2 weeks

• 5-fluorouracil–based regimens
5-fluorouracil 1200 mg/m2/day continuous infusion over 3 days

• Capecitabine-based regimens (repeat cycle every 3 weeks)

Capecitabine 1250 mg/m2 PO twice daily for 2 weeks on and 1 week off

• Gemcitabine ± carboplatin (Repeat every 3 weeks)

Gemcitabine 600–1000 mg/m2/day IV on Days 1 and 8 depending on the patient's bone marrow reserves.
Carboplatin AUC 4 or 5 IV on Day 1

• Gemcitabine ± cisplatin (Repeat every 4 weeks)

Gemcitabine 600–800 mg/m2/day IV on Days 1, 8, and 15
Cisplatin 25–30 mg/m2/day IV on Days 1, 8, and 15, repeat every 4 weeks

• High-dose chemotherapy with peripheral stem cell transplanth

cDosing schedules also apply to the Intermediate Trophoblastic Tumor (PSTT and ETT) regimens listed on GTN-B 6 of 6.
fRecommend referral to center that specializes in the treatment of GTN.
gSee NCCN Guidelines for Management of Immunotherapy-Related Toxicities.
hGiven on clinical trial protocol.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
GTN-B
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
5 OF 6
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

SYSTEMIC THERAPY FOR GTN

Intermediate Trophoblastic Tumor (PSTT and ETT)a,i,j

Preferred Regimensg Other Recommended Regimensg Useful in Certain Circumstancesg

• EMA/EP: Etoposide, methotrexate, • TP/TE: Paclitaxel, cisplatin/paclitaxel, Additional agents/regimens shown to have some activity
dactinomycin/etoposide, cisplatin etoposide in treating multiagent chemotherapy-resistant GTN:
• EP/EMA: Etoposide, cisplatin/etoposide, • BEP: Bleomycin, etoposide, cisplatin • PD-1/PD-L1 inhibitors
methotrexate, dactinomycin • VIP: Etoposide, ifosfamide, cisplatin (eg, pembrolizumab, nivolumab, avelumab)g
• ICE: Ifosfamide, carboplatin, • 5-fluorouracil–based regimens
etoposide • Capecitabine-based regimens
• Gemcitabine ± carboplatin
• Gemcitabine ± cisplatin
• High-dose chemotherapy with peripheral stem cell
transplanth

aUse G-CSF as primary prophylaxis with etoposide/cisplatin or etoposide/carboplatin-based regimens. See NCCN Guidelines for Hematopoietic Growth Factors.
gSee NCCN Guidelines for Management of Immunotherapy-Related Toxicities.
hGiven on clinical trial protocol.
iIf feasible, perform hysterectomy with salpingectomy and excision of metastatic disease.
jFor dosing schedules, see High-Risk GTN sections GTN-B 3 of 6, GTN-B 4 of 6, and GTN-B 5 of 6.

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
GTN-B
Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
6 OF 6
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

PRINCIPLES OF GYNECOLOGIC SURVIVORSHIP

Physical Effects
• Gynecologic cancer treatment typically involves surgery, chemotherapy, hormone therapy, radiation therapy, and/or immunotherapy. These
treatments cause acute, short-term, and long-term toxicities.
• Surgical approaches may be extensive and pose risks such as adhesion formation, which may cause pain and may contribute to small
bowel obstruction, urinary or gastrointestinal complications (eg, incontinence, diarrhea), pelvic floor dysfunction (manifested by a variety of
urinary, bowel, and/or sexual effects), and lymphedema.
• Chemotherapy agents vary, though commonly used regimens may pose a significant risk of neurotoxicity, cardiac toxicity, development of
hematologic cancers, and cognitive dysfunction.
• Long-term estrogen deprivation may cause symptoms such as hot flashes, vaginal dryness, and bone loss.
• Radiation therapy may cause long-term complications (eg, fibrosis, vulvovaginal atrophy) and may predispose patients to secondary
cancers of the subcutaneous tissue, and/or underlying organs that are proximal to the radiation field.
• Immunotherapy use is emerging, and to date, long-term effects of these treatments are unknown.

Psychosocial Effects
• Psychosocial effects after cancer may include psychological (eg, depression, anxiety, fear of recurrence, altered body image), financial (eg,
return to work, insurance concerns), and interpersonal (eg, relationships, sexuality, intimacy) effects.

Clinical Approach
• All gynecologic cancer survivors should receive regular general medical care that focuses on chronic disease management, monitoring of
cardiovascular risk factors, recommended vaccinations, and encouraging adoption of a healthy lifestyle.
• In order to assess the late and long-term effects of gynecologic cancers, clinicians should comprehensively document the patient’s history,
conduct a thorough physical examination, and conduct necessary imaging and/or laboratory testing. All women, whether sexually active
or not, should be asked about genitourinary symptoms, including vulvovaginal dryness. Referral to appropriate specialty providers (eg,
physical therapy, pelvic floor therapy, sexual therapy, psychotherapy) is recommended. As most treatments for gynecologic cancers will
cause sexual dysfunction, early menopause, and infertility, special attention to the resultant medical and psychosocial implications is
needed.
• Post-radiation use of vaginal dilators and moisturizers is recommended.
• Communication and coordination with all clinicians involved in the care of survivors, including primary care clinicians, is critical. Providing
cancer survivors with a summary of their treatment and recommendations for follow-up is recommended.

Additional Guidance
• See NCCN Guidelines for Distress Management
• See NCCN Guidelines for Smoking Cessation
• See NCCN Guidelines for Survivorship

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
GTN-C
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

FIGO STAGING SYSTEM FOR GTNa

Stage Criteria
I Tumor confined to uterus
II Tumor extends to other genital structures (ovary, tube, vagina, broad
ligaments) by metastasis or direct extension
III Lung metastasis
IV All other distant metastases

Continued

aUsed with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth
Edition (2017) published by Springer International Publishing.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
ST-1
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

PROGNOSTIC SCORING INDEX FOR GTNa

Prognostic factor Risk score
0 1 2 4
Age (years) <40 ≥40 -- --

Antecedent pregnancy Hydatidiform mole Abortion Term pregnancy --

Interval from index pregnancy (months) <4 4-6 7-12 >12
Pretreatment hCG (IU/L) <103 103 to <104 104 to 105 ≥105
Largest tumor size, including uterus (cm) <3 3-5 >5
Site of metastases Lung Spleen, kidney Gastrointestinal tract Brain, liver

Number of metastases identified 0 1-4 5-8 >8

Previous failed chemotherapy -- -- Single drug Two or more drugs
Total score -- -- -- --

• The total score for a patient is obtained by adding the individual scores for each prognostic factor.
• FIGO Prognostic Score
Low risk: <7
High risk: ≥7

aUsed with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth
Edition (2017) published by Springer International Publishing.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
ST-2
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021 NCCN Guidelines Index

Table of Contents
Gestational Trophoblastic Neoplasia Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

Version 1.2021, 02/02/21 © 2021 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
CAT-1
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

Discussion This discussion corresponds to the NCCN Guidelines for Gestational Trophoblastic Neoplasia. Last updated: May 6, 2019.

Table of Contents

Overview ......................................................................................... MS-2 High-Risk GTN ............................................................................ MS-7

Types of Gestational Trophoblastic Disease .................................... MS-2 Primary Chemotherapy ............................................................ MS-7

Hydatidiform Mole ........................................................................... MS-3 Induction Chemotherapy for Ultra-High-Risk Disease ............ MS-8

Presentation and Workup ............................................................. MS-3 Management of CNS Metastases ......................................... MS-8

Treatment .................................................................................... MS-3 Adjuvant Surgery ..................................................................... MS-8

Follow-up ..................................................................................... MS-4 Salvage Chemotherapy ............................................................ MS-8

Post-Molar GTN ........................................................................... MS-4 Additional Agents/Regimens with Potential Activity in Treatment-
Resistant GTN ...................................................................... MS-9
Gestational Trophoblastic Neoplasia ................................................ MS-4
Intermediate Trophoblastic Tumors ............................................. MS-9
Presentation and Workup ............................................................. MS-4
Treatment Approach .............................................................. MS-10
Low-Risk GTN ............................................................................. MS-5
References ................................................................................... MS-11
First-line Therapy...................................................................... MS-5

Second-line Therapy................................................................. MS-6

Multiagent Therapy ................................................................... MS-7

MS-1
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

Overview chromosome duplication; or 2) via dispermy. Partial HMs can contain fetal
Gestational trophoblastic disease (GTD) refers to a group of benign and tissue, but complete moles do not.
malignant tumors that develop in the uterus from placental tissue.
Post-molar GTN, which includes invasive mole and choriocarcinoma,
Pathogenesis of GTD is unique in that maternal tumors arise from
develops in about 15% to 20% of complete moles, but in only 1% to 5% of
gestational tissue that can have locally invasive or metastatic potential.
partial moles.2,3,6,7 The reported incidence of GTN after molar pregnancy is
Historical data on incidence of GTD varies widely by region, with higher
18% to 29%.2,3,8,9 This rate appears to be stable despite the progressively
incidence reported in Asia compared with Europe and North America.
earlier diagnosis of complete HM.9 Invasive moles arise from extension of
These differences are thought to be due at least in part to varying
HM into the myometrium via tissue or venous channels. Approximately
diagnostic criteria, reporting practices, quality of epidemiologic data, and
15% of invasive moles metastasize to the lung or vagina. Persistent
diet and nutrition. In the United States, the reported incidence of GTD is
elevated human chorionic gonadotropin (hCG) after evacuation of a molar
approximately one out of every 1000 pregnancies.1-3
pregnancy most often leads to the diagnosis of invasive mole.2
The most common form of GTD is hydatidiform mole (HM), also known as Choriocarcinoma develops from villous trophoblast. Features of these
molar pregnancy. HMs are considered a benign, premalignant disease. malignant epithelial tumors include abnormal trophoblastic hyperplasia
Malignant forms of GTD are collectively referred to as gestational and anaplasia, hCG production, absence of chorionic villi, hemorrhage,
trophoblastic neoplasia (GTN), and include invasive mole, and necrosis.2,3 Choriocarcinoma has been reported to occur with different
choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid types of pregnancy events, including HM (50%), term or preterm gestation
trophoblastic tumor (ETT). HM encompasses about 80% of all GTD, (25%), and tubal pregnancy or abortion (25%). Approximately 2% to 3% of
invasive moles account for 15%, and choriocarcinoma and other rarer HMs progress to choriocarcinoma.
types of GTN comprise the remaining 5%.4 Cure rates are approaching
The intermediate trophoblastic tumors (ITT), including PSTT and ETT, are
100%, and treatment typically allows for fertility preservation.4,5
rare subtypes of GTN with an incidence of about 1 in 100,000
pregnancies, representing approximately 1% of all GTN cases.10 Most
Types of Gestational Trophoblastic Disease
PSTTs follow nonmolar gestations and present months to years after the
HM occurs as a result of abnormal fertilization and is characterized as
antecedent pregnancy. Less often, PSTT develops after evacuation of
complete or partial based on differences in morphology, karyotype, and
HM.4 PSTT arises from interstitial trophoblast at the placental implantation
malignant potential. The majority of complete moles (80%) occur as a
site and consists predominately of mononuclear intermediate trophoblast
result of abnormal fertilization of an ovum lacking nuclear DNA, and have
without chorionic villi, infiltrating in sheets or cords between myometrial
two identical paternal chromosome complements derived from duplication
fibers. It is associated with less vascular invasion, necrosis, and
of the haploid genome of a single sperm. The remaining 20% occur as a
hemorrhage than choriocarcinoma.
result of dispermy (fertilization by two sperm). Partial moles occur when an
ovum retains its nucleus and abnormal fertilization occurs in one of two ETT is a rare variant of PSTT that simulates carcinoma. Based on
ways: 1) fertilization by a single sperm with subsequent paternal morphologic and histochemical features, it appears to develop from
MS-2
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

neoplastic transformation of chorionic-type intermediate trophoblast. ETT The NCCN Panel recommends workup of patients with HM to include
typically presents years after term delivery. history and physical; pelvic ultrasound; quantitative hCG assay; complete
blood count (CBC) with platelets; liver, renal, and thyroid function tests; as
Hydatidiform Mole well as blood type and screen. Recommended imaging also includes chest
Presentation and Workup x-ray.
Patients with HM commonly present with vaginal bleeding, typically around
Treatment
6 to 16 weeks of gestation. Due to widespread ultrasound screening
during early pregnancy and accurate hCG testing, most cases of HM are Initial treatment of HM in women who wish to preserve fertility is suction
detected prior to the onset of additional signs such as uterine enlargement dilation and curettage (D&C), preferably performed under ultrasound
beyond that expected for gestation date, pre-eclampsia, hyperemesis, guidance to reduce the risk of uterine perforation.8,12 Rho(D)
anemia, and theca lutein ovarian cysts.2-4 Partial HMs tend to grow more immunoglobulin should be administered at the time of evacuation to
slowly and may present later in the first or early second trimester, often patients with Rh-negative blood types.8 To reduce the risk of heavy
with symptoms of incomplete or missed abortion and diagnosis made bleeding, uterotonic agents (eg, methylergonovine and/or prostaglandins)
upon histologic examination of the curettage specimen.2,3 should be administered during the procedure and continued for several
hours postoperatively.2,13 For women who are older or do not wish to
Initial determination of suspected HM is often made based on ultrasound preserve fertility, hysterectomy can be considered as an alternative.14
findings in combination with clinical symptoms and hCG levels. Due to Histopathologic review and possible genetic testing confirm the diagnosis.
hyperplastic trophoblastic cells in complete HM, many patients will have
marked elevations in hCG, at times greater than 100,000 IU/L. However, Prophylactic chemotherapy at the time of uterine evacuation is
such elevations in hCG are observed in less than 10% of patients with controversial and may reduce the incidence of post-molar GTN by 3% to
partial HM. Characteristic ultrasound findings of complete HM include 8%. A Cochrane database review (3 randomized controlled trials [RCTs], n
enlarged uterus with a heterogenous mass (ie, snowstorm appearance). = 613) did not conclude sufficient evidence for standard administration of
Hydropic/swollen chorionic villi lead to the appearance of small cystic prophylactic chemotherapy to prevent post-molar GTN; however, evidence
spaces, creating a vesicular pattern. However, these characteristics may was suggestive that prophylactic chemotherapy may reduce the risk of
not be readily observed with the diagnosis of HM early in the first progression to GTN among women with complete HM at high risk for
trimester. As molar pregnancy advances, these cystic spaces become malignant transformation.15 The NCCN Guidelines state that prophylactic
larger and more numerous. Features that may be noted on ultrasound methotrexate or dactinomycin can be considered for patients deemed at
imaging of partial HM include focal cystic spaces within the placenta, high risk for post-molar GTN. Risk factors for post-molar GTN include age
gestational sac that is empty or elongated along the transverse axis, >40 years, hCG levels in excess of 100,000 mIU/mL, excessive uterine
and/or fetal anomalies or fetal demise.2-4,8,11 enlargement, and/or theca lutein cysts larger than 6 cm.2,8,15,16

MS-3
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

Follow-up • hCG levels plateau for 4 consecutive values over ≥3 weeks

Follow-up with hCG monitoring is essential following initial treatment of • hCG levels rise ≥10% for 3 values over ≥2 weeks
HM to ensure that hCG levels return to normal. The hCG molecules • hCG persistence 6 months or more after molar evacuation
associated with GTD are more heterogenous and degraded than those
Assessment and staging of the post-molar GTN should include history and
associated with normal pregnancy.2,17 Therefore, monitoring should be
physical examination, Doppler pelvic ultrasound, and chest x-ray to assess
performed with a quantitative assay capable of detecting all forms of hCG,
for metastatic disease. Doppler pelvic ultrasound is used to confirm the
including beta-hCG, core hCG, nicked-free beta, beta core, and
absence of pregnancy, measure uterine size, and to delineate the volume
hyperglycosylated forms.4,18,19 Post-molar GTN develops in about 15% to
and vasculature of the tumor. If chest x-ray reveals no evidence of
20% of complete moles, but in only 0.1% to 5% of partial moles.
metastatic disease, no further imaging is recommended prior to treatment.
Therefore, careful monitoring can facilitate early detection of persistent
GTN. Risk of recurrence is low (<2%) following a single molar pregnancy, Repeat D&C or hysterectomy can be considered for persistent post-molar
but increases significantly for women who experience one or more GTN.24-26 An observational study conducted over a period of 10 years
recurrences.2,3,6,12,13,20 examined 544 women who underwent second uterine evacuation for
persistent GTD.26 Following repeat curettage, 68% had no further
Once normalized, recurrent elevation of hCG has been reported in less
evidence of disease or chemotherapy requirements. However,
than 1% of patients.20,21 The occurrence of GTN following hCG
chemotherapy requirement was more likely for patients with a histologic
normalization is rare after the recommended 6 months of post-
confirmation of persistent trophoblastic disease and for urinary hCG levels
normalization hCG monitoring.22 A recent study showed that patients with
in excess of 1500 IU/L at time of second evacuation.26 Several groups
complete HM who normalized beyond 56 days post uterine evacuation
have discussed the optimal characteristics of candidates for repeat uterine
had a 3.8-fold higher risk of developing post-molar GTN.20
evacuation.26-30
The NCCN Panel recommends hCG assay monitoring every one to two
Repeat surgical treatment should be followed by hCG monitoring every 2
weeks until levels have normalized, defined in the guidelines as 3
weeks until the patient has 3 consecutive normal assays, with monthly
consecutive normal assays. Following initial normalization, hCG should be
hCG monitoring for an additional 6 months. For evidence of metastatic
measured twice in 3-month intervals to ensure levels remain normal. If
disease, histopathologic diagnosis of choriocarcinoma, or persistent hCG
hCG levels remain elevated, treat per the post-molar GTN algorithm.
elevation (ie, plateau or rise), follow recommendations for staging and
Post-Molar GTN treatment in the algorithms for GTN.

Post-molar GTN is typically diagnosed by hCG surveillance. The NCCN Gestational Trophoblastic Neoplasia
Guidelines use the FIGO staging criteria for post-molar GTN as meeting
Presentation and Workup
one of more of the following criteria after treatment for HM, as indicated by
The presentation of GTN can vary depending upon the antecedent
hCG monitoring:23
pregnancy event and disease type and extent. Post-molar GTN, including
MS-4
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

invasive mole or choriocarcinoma, can be associated with irregular pregnancy, pretreatment hCG, largest tumor size (including the uterus),
bleeding after initial treatment for molar pregnancy, an enlarged and site and number of metastases, and previous chemotherapy regimens that
irregular uterus, and bilateral ovarian enlargement. However, these signs were unsuccessful. The sum of individual scores denotes the FIGO
may be absent in patients with choriocarcinoma associated with normal, prognostic score of low-risk GTN (<7) or high-risk GTN (≥7).23,34,37 This
non-molar pregnancies. Trophoblastic tumors have fragile vessels and as prognostic scoring system is not valid for the ITTs ETT and PSTT.10
a result, metastatic lesions are often hemorrhagic. In addition to bleeding,
metastatic lesions may be associated with neurologic or pulmonary Low-Risk GTN
symptoms. ETT and PSTT typically present with irregular uterine bleeding First-line Therapy
arising after some time has passed from a previous pregnancy.2,3,31 Low-risk GTN encompasses cases with a FIGO prognostic score of six or
less. Standard front-line treatment for low-risk GTN is single-agent
Workup for GTN includes history and physical examination and metastatic chemotherapy using methotrexate or dactinomycin. Numerous studies
imaging workup, to include chest/abdominal/pelvic CT scan with contrast have evaluated these agents, but differences in inclusion criteria and
(or MRI if contrast is contraindicated) as well as brain MRI (preferred) or dosage regimens have made it challenging to determine a superior
brain CT if pulmonary metastasis. Visible lesions in the lower genital tract regimen. While some consider methotrexate to have a more favorable
should not be biopsied due to hemorrhage risk. Additionally, the NCCN adverse effect profile, dactinomycin may achieve similar or better efficacy
Panel recommends repeat CBC differential with platelets; liver, renal, and with a less-frequent infusion schedule.4,18,37-39 A 2016 Cochrane Database
thyroid function testing; and hCG assay. If hCG is elevated with no review of RCTs in low-risk GTN showed with moderate-certainty evidence
evidence of disease on imaging, consider the possibility of phantom that first-line methotrexate may be more likely to fail than dactinomycin
hCG.32 Elevated hCG with normal hyperglycosylated hCG may indicate (risk ratio [RR], 3.55; 95% confidence interval [CI], 1.81–6.95; 6 trials, 577
quiescent GTN not requiring immediate/further treatment.33 participants; I(2) = 61%).39 Similarly, the authors concluded that
dactinomycin is more likely to lead to a primary cure than methotrexate
Based on these findings, the GTN should be staged and scored according
(RR, 0.65; 95% CI, 0.57–0.75; six trials, 577 participants; I(2) = 26%).39
to the current FIGO staging and prognostic scoring system.23,34 GTN
However, 55% of the data came from trials of weekly IM methotrexate,
staging is based on tumor location and extent: stage I disease is uterine-
which seems to be less effective than the 5- or 8-day methotrexate
confined, stage II involves direct extension or metastasis to other genital
regimens. A now closed for lack of accrual phase III RCT (NCT01535053)
structures, stage III disease is determined by lung metastasis, and stage
comparing pulse dactinomycin to multiday methotrexate regimens noted
IV disease includes non-pulmonary distant metastasis. The current FIGO
primary remission rates of 75% for pulse dactinomycin versus 88.5% for
prognostic scoring system was adapted from the WHO classification,
the multiday methotrexate regimens (5-day > 8-day). Overall quality-of-life
which incorporated prognostic factors from Bagshawe’s scoring
scores were similar. Alopecia was more common with dactinomycin,
system.35,36 FIGO prognostic scoring is based on individual risk factors that
mucositis was more common with the methotrexate regimens, and no
have been shown to be predictive of GTN that is resistant to single-agent
patient required multiagent chemotherapy or salvage surgery to reach
chemotherapy, such as age, antecedent pregnancy, interval from index
remission.40
MS-5
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

Currently supported regimens of dactinomycin include a 5-day regimen 3 additional treatment cycles past normalization to minimize the risk of
(10–12 mcg/kg or flat 0.5 mg dose IV, repeated every 2 weeks) or a recurrence.3,5,18 Surveillance should include monthly hCG for 1 year, along
dactinomycin pulse regimen (1.25 mg/m2, IV, repeated every 2 weeks).18 with contraception (oral contraception preferred). Chemotherapy
Primary remission rates for initial treatment with 5-day dactinomycin range resistance is indicated by a plateau in hCG over 3 consecutive cycles or a
from 77% to 94%, and for pulse dactinomycin, from 69% to 90%.37 For rise in hCG over 2 consecutive cycles.4,38 Second-line chemotherapy is
methotrexate, currently supported regimens include 5-day methotrexate then indicated.
(0.4 mg/kg IV or IM daily x 5 days, repeated every 2 weeks) or an 8-day
Second-line Therapy
regimen of methotrexate alternating with leucovorin rescue (1.0–1.5 mg/kg
Currently, there are no RCT data on second-line therapy for low-risk GTN,
IM, every other day x 4 days, alternating with leucovorin, 15 mg PO,
but general evidence and consensus supports a change to the alternative
repeated every 2 weeks).18 Primary remission rates for multiday
single-agent chemotherapy for patients who have had a good initial
methotrexate regimens range from 87% to 93% for the 5-day protocol, and
from 74% to 93% for 8-day methotrexate with leucovorin rescue.37 response to chemotherapy but experience hCG plateau, or for patients
who experience toxicity that limits the dose or frequency of treatment.4,18,46
Methotrexate regimens that are no longer recommended due to lesser Adjuvant hysterectomy and salpingectomy can be considered for patients
efficacy include weekly IM methotrexate (30–50 mg/m2) and pulse-dose IV with localized disease in the uterus for whom fertility preservation is not
infusion methotrexate.37,41,42 Although weekly IM methotrexate was desired. The ovaries are left in situ, even in the presence of theca lutein
successful in 70% of patients with a prognostic score of 0–1, the success cysts.
rate fell to 40% and 12% with a prognostic score of 2–4 and 5–6,
respectively.4,41 In a large case series (n = 618), 8-day methotrexate was Second-line dactinomycin is considered to have an acceptable response
rate in patients with low levels of hCG, but multiagent chemotherapy may
comparatively more successful when analyzed by prognostic score
be favored in the second-line setting for patients whose hCG exceeds a
subgrouping.43
given threshold.43,47,48 The hCG threshold for considering dactinomycin
The guidelines note that a multiday methotrexate regimen is typically used versus multiagent regimens has been debated and revised over
as first-line therapy in low-risk GTN due to its generally favorable toxicity time.3,18,43,48,49
profile. Dactinomycin is often used as a secondary therapy for patients
Dactinomycin has been associated with complete response rate of
with methotrexate toxicity or effusions contradicting the use of
approximately 75% in large case series of patients with methotrexate-
methotrexate. Alternative single-agent options for treatment of low-risk
resistant GTN.50,51 A retrospective review of 358 patients with low-risk GTN
GTN that are primarily used in Asia include etoposide and
fluorouracil.37,44,45 identified 68 patients who were determined to have resistant disease after
a 5-day methotrexate regimen (n = 68). The complete response rate to
NCCN Panel consensus recommendations for monitoring of secondary dactinomycin was 75%, and all patients who required third-line
chemotherapy response is hCG assay at least every one to two weeks.38 multiagent chemotherapy with or without surgery achieved permanent
Upon hCG normalization, continuation of therapy is recommended for 2 to remission. Clinicopathologic diagnosis of choriocarcinoma (vs. post-molar
MS-6
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

GTN) was significantly associated with resistance to secondary outcomes include liver and brain metastases, particularly if co-occurring.
dactinomycin.50 In a recent retrospective review of 877 patients with GTN However, the prognosis for these patients has improved over time.54-56
initially treated with 8-day methotrexate, 103 patients required second-line
therapy and were placed on a 5-day dactinomycin protocol.51 Complete Primary Chemotherapy

response to second-line dactinomycin was observed among 75.7% (n = EMA/CO, in which EMA and CO are given on alternate weeks, is the most
78). Among the 25 patients who required third-line treatment for resistant commonly used initial regimen for high-risk disease. Based on existing
disease or relapse, overall survival was 100%.51 evidence, this regimen is thought to provide the best combination of
efficacy with acceptable toxicity for treating patients with high-risk GTN.
Multiagent Therapy Multiple groups have confirmed the efficacy of EMA/CO, reporting
For disease that is resistant to single-agent chemotherapy, repeat disease complete response rates of 62% to 78% and long-term survival rates of
workup for metastasis and transition to combination chemotherapy. The 85% to 94%.52,53,57-64
following criteria warrant a switch to a multiagent regimen: poor response
to initial therapy, significant elevation in hCG level, development of Reports of other regimens that have been used in first-line treatment of
metastasis, or resistance to sequential single-agent chemotherapy high-risk GTN include:
regimens.3,5 The most commonly used regimen in this setting is EMA/CO
• EMA/EP (etoposide, methotrexate, dactinomycin alternating with
(etoposide, methotrexate, and dactinomycin alternating with
etoposide and cisplatin)65,66 or EP/EMA (etoposide and cisplatin
cyclophosphamide and vincristine).43,46,52 The use of EMA/CO in this
alternating with etoposide, methotrexate, and dactinomycin)67
setting is based upon its efficacy in managing high-risk GTN.53 Cure rates
• MEA (methotrexate, etoposide, dactinomycin) 68
with EMA/CO approach 100% even in the presence of relapsed/resistant
• MAC (methotrexate, dactinomycin, and chlorambucil)69
low-risk GTN.3,5,52 For persistent or recurrent disease after EMA/CO
• FA (5-FU and dactinomycin)70
combination therapy, treat per the high-risk GTN algorithm with
• MEF (methotrexate, etoposide, and 5-FU)71
etoposide/platinum-based regimens and surgical resection as feasible.
• CHAMOCA (methotrexate, dactinomycin, cyclophosphamide,
High-Risk GTN doxorubicin, melphalan, hydroxyurea, and vincristine)69

High-risk GTN is defined as FIGO stages II-III disease with a prognostic Due to the lack of RCTs in this setting, systematic reviews have been
score ≥7, or FIGO stage IV disease.23,34 High-risk disease is relatively rare unable to draw conclusions regarding a superior combination regimen for
among patients with post-molar GTN, estimated at only 6% (39/618) in a primary treatment of high-risk GTN.46,72 EMA/EP (or EP/EMA) is highly
large case series.43 High-risk GTN should be treated with multiagent active and considered by some to be superior to EMA/CO for ultra-high-
chemotherapy. Adjuvant surgery or radiation therapy may be included. risk disease; however, its use as standard initial therapy is limited by
With a multimodal approach, cure rates have reached approximately 90%, increased toxicity and inability to provide adequate salvage chemotherapy
including almost all patients with only lung/vaginal metastases and 70% if required for persistent/recurrent disease.4,67
for patients with stage IV disease.5 Factors associated with poorer

MS-7
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

Induction Chemotherapy for Ultra-High-Risk Disease depending on the patient’s symptoms as well as number, size, and
Patients with widespread metastatic GTN, as evidenced by prognostic location of brain lesions.55,75,76,78,80-83
score greater than 12, have a poorer prognosis.73,74 Initiation of standard
Adjuvant Surgery
combination chemotherapy in these patients can lead to tumor collapse
Adjuvant surgical procedures for chemotherapy-resistant disease may be
with hemorrhage, metabolic acidosis, septicemia, and/or multiple organ
required to manage high-risk disease. Select patients with isolated
failure, resulting in the potential for early death (ie, within 4 weeks).18,52,74
disease may be candidates for surgical resection, especially for isolated
Efforts to improve outcomes for this ultra-high-risk population have
disease in the uterus or lungs.84-86 PET/CT imaging may be useful for
included induction chemotherapy with etoposide and cisplatin prior to
detecting isolated metastatic sites that are amenable to targeted surgery.87
initiating EMA/CO.52,74 In a case series of 140 patients with high-risk GTN,
Additionally, interventional procedures to prevent or control hemorrhage
33 patients who were determined to have large disease burden (ie, ultra-
are important components in the management of high-risk GTN.4 Selective
high-risk GTN) received low-dose induction chemotherapy with
arterial embolization can be used to manage bleeding from the
etoposide/cisplatin prior to EMA/CO therapy (etoposide 100 mg/m² IV and
uterus/vagina or other tumor sites.88-90 In one case series, nearly 50% of
cisplatin 20mg/m² IV on days 1 and 2, every seven days for 1-3 courses).
patients with high-risk disease underwent some form of surgical procedure
Overall survival and early death rate were 94.3% and 0.7%, respectively,
during the course of treatment in order to effect cure.91
for the high-risk GTN cohort, representing a considerable improvement
over outcomes reported for an earlier cohort who did not receive induction Salvage Chemotherapy
chemotherapy.52 Despite the use of multiagent primary therapy, approximately 30% to 40%
of high-risk patients will have an incomplete response to first-line therapy
Management of CNS Metastases
or experience relapse from remission.92,93 Most of these patients have
Additional treatment considerations are recommended for patients with
multiple metastases to sites other than the lung and vagina and many will
central nervous system (CNS) metastases, who may require emergency
have received inadequate initial therapy.94,95 Salvage chemotherapy with
intervention to manage intracranial bleeding or elevated intracranial
drug regimens employing etoposide and a platinum agent, often combined
pressure.4,75 Rates of CNS metastases are low with post-molar GTN, but
with surgical resection of persistent tumor, will result in cure of about 80%
approximately 20% of patients with choriocarcinoma have CNS
to 90% of patients with high-risk disease.96
involvement.75 In addition to systemic combination chemotherapy,
additional treatment modalities may be employed, including whole brain The EMA/EP or EP/EMA regimens are considered the most appropriate
irradiation, stereotactic radiosurgery, and/or craniotomy with surgical therapy for patients who have responded to EMA/CO but have plateauing
excision.4,55,76-79 Additionally, EMA/CO should be modified to include high- low hCG levels or have developed re-elevation of hCG after a complete
dose methotrexate dose (1 g/m2) or the addition of intrathecal response to EMA/CO.97,98 The rate of complete response/remission with
methotrexate to encourage sufficient blood brain barrier penetration.18,78 EMA/EP for disease resistant to EMA/CO has been reported between
Reported cure rates with brain metastases range from 50% to 80%, 75% and 85%.63,97-100

MS-8
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

Additional drug combinations containing etoposide and a platinum agent Pembrolizumab is a monoclonal antibody that inhibits programmed cell
have been effective in patients who have developed disease resistant to death protein 1 (PD-1), which functions as a checkpoint protein for
methotrexate-containing regimens. These include TP/TE (paclitaxel and regulation of various immune cells, including T cells with potential
cisplatin alternating weekly with paclitaxel and etoposide), BEP antitumor activity.113-115 Programmed death ligand 1 (PD-L1) is strongly
(bleomycin, etoposide, and cisplatin), VIP (etoposide, ifosfamide, and expressed by GTN.116,117 Outcomes were recently reported for 4 patients
cisplatin), and ICE (ifosfamide, carboplatin, and etoposide).46,96,99,101,102 with drug-resistant GTN who received pembrolizumab, including 2 cases
Additionally, TIP (paclitaxel, ifosfamide, and cisplatin) has been used as a of metastatic choriocarcinoma and 2 cases of metastatic PSTT or mixed
salvage chemotherapy regimen in germ cell tumors, including those with PSTT/ETT.118 All patients had tumors with high levels of PD-L1
choriocarcinoma components.103-106 expression. Durable response to pembrolizumab was observed in three of
the four cases. The patient whose disease did not respond to
These etoposide-platinum containing regimens require the use of pembrolizumab had strong PD-L1 tumor expression but an absence of
granulocyte colony-stimulating factor (G-CSF) support to prevent tumor-infiltrating lymphocytes.118
neutropenic complications and treatment delays.96,101,107 The overall
success of salvage therapy in this group of patients is about 80%. Factors Gemcitabine, capecitabine, and fluorouracil may also have potential for
associated with worse survival outcomes include high hCG at the start of treating GTN in this setting. Limited data have suggested activity of
salvage therapy, greater number of metastatic sites, metastases to sites gemcitabine, administered with or without a platinum agent.119 Additional
other than the lung and vagina (stage IV), and FIGO score >12. support for the potential activity of these regimens in GTN can be found in
the data for treating germ cell tumors. Successful use of capecitabine as
Additional Agents/Regimens with Potential Activity in Treatment- single-agent salvage chemotherapy has been reported.120,121 Groups in
Resistant GTN
Asia have also reported on fluorouracil, primarily in combination with
Several additional treatment regimens have been shown to have some dactinomycin.70
activity when treating resistant GTN, including high-dose chemotherapy
(HDC) with peripheral stem cell transplant, immunotherapy, and other Intermediate Trophoblastic Tumors
chemotherapy regimens. For a subset of patients with resistant disease Whereas molar pregnancies and choriocarcinoma are derived from villous
despite multidrug chemotherapy, HDC with autologous stem cell support trophoblast (ie, cytotrophoblast and syncytiotrophoblast), ITTs (including
has been reported to produce sustained complete responses.108-112 A PSTT and ETT) develop from extravillous trophoblast (ie, intermediate
retrospective study of 32 patients with refractory choriocarcinoma or poor- trophoblast). ITTs comprise approximately 1% of GTN cases, and as such,
prognosis PSTT/ETT who underwent HDC with peripheral blood stem cell their biologic behavior and treatment are less well established. These
support reported a sustained complete response in 7 patients, with 13 of tumors typically develop months to years following normal pregnancies,
32 patients remaining disease free at the time of analysis following HDC but can occur after any pregnancy event. A recent series of 62 cases of
with or without additional therapy.110 ITT suggested that interval between antecedent pregnancy and disease
onset may be longer for ETT than PSTT.122

MS-9
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

PSTT and ETT are generally slow-growing tumors that can metastasize The most important prognostic factors include advanced disease stage
months or years after the initial primary has developed and often present and interval from last known pregnancy event of ≥48 months.124,127,128,134
with abnormal uterine bleeding or amenorrhea. The vast majority of ITTs Additional risk factors associated with less favorable outcomes are
secrete hCG, but at significantly lower levels compared with other types of advancing age, deep myometrial invasion, tumor necrosis, large tumor
GTN. As such, hCG is a less reliable tumor marker for these subtypes of size, and mitotic index.10,128,135
GTN. At diagnosis, metastases are noted in 30% to 50% of cases, most
commonly to the lungs. Unlike other GTNs, these have a greater Treatment Approach

propensity for lymphatic spread. Data are currently being collected in a ITTs are relatively chemoresistant and thus follow a somewhat different
global database of PSTTs and ETTs through the efforts of the treatment paradigm than invasive mole and choriocarcinoma, with surgical
International Society for the Study of Trophoblastic Disease (ISSTD).10,123- intervention playing a more critical role. Treatment of PSTT and ETT is
128 determined mainly based on presence or absence of metastatic disease
with some consideration given to high-risk factors. Hysterectomy with
ITTs can be differentiated from other types of GTN via their lymph node dissection is the recommended treatment for localized
histopathologic characteristics.10 In PSTT, immunohistochemical (IHC) disease. Metastasectomy should be employed for isolated distant disease,
staining reveals the diffuse presence of cytokeratin, Mel-CAM, and human especially in the lungs. Chemotherapy is given to patients with metastatic
placental lactogen (hPL), whereas hCG staining is only focal. Cytogenetic disease and should be considered for patients with nonmetastatic disease
studies have revealed that PSTTs are more often diploid than aneuploid.129 who have any of the adverse prognostic factors noted above.136
Serum hPL measurements are not clinically useful in monitoring disease
course or guiding clinical management.126,127,130,131 ETT is distinguished Although the optimal chemotherapy regimen for PSTT and ETT remains to
from PSTT by its smaller, fairly monomorphic cells and a nested, nodular, be defined, the current clinical impression is that a platinum/etoposide-
well-circumscribed growth pattern. IHC reveals strong expression of p63, containing regimen, such as EMA/EP or TP/TE, is the treatment of choice.
but only focal to weak expression of Mel-CAM and hPL.132 It frequently The survival rate is approximately 100% for nonmetastatic disease and
involves the lower uterine segment and endocervix, and because of its 50% to 60% for metastatic disease. Increased use of platinum-based and
epithelioid histologic appearance and expression of p63 and cytokeratins, HDCT over time has led to improved overall survival for the subset of
ETT can be confused with squamous cell carcinoma.10,132,133 patients with ITT who have an overall poor prognosis (ie, interval ≥48
months from last known pregnancy event).124,126-128
Due to the rarity of these tumors, generally small cohort sizes preclude
rigorous statistical analysis of risk factors in ITT. The FIGO prognostic
scoring system for GTN does not correlate well with outcomes in PSTT
and ETT.10 Based on findings from the largest existing database, PSTT
and ETT accounted for 125 of 54,743 cases of GTD (0.23%), with post-
treatment 5- and 10-year survival estimates of 80% and 75%, respectively.

MS-10
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

References Center over the past three decades: does early diagnosis alter risk for
gestational trophoblastic neoplasia? Gynecol Oncol 2015;138:46-49.
1. Altieri A, Franceschi S, Ferlay J, et al. Epidemiology and aetiology of Available at: https://www.ncbi.nlm.nih.gov/pubmed/25969351.
gestational trophoblastic diseases. Lancet Oncol 2003;4:670-678.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/14602247. 10. Horowitz NS, Goldstein DP, Berkowitz RS. Placental site trophoblastic
tumors and epithelioid trophoblastic tumors: Biology, natural history, and
2. Lurain JR. Gestational trophoblastic disease I: epidemiology, pathology, treatment modalities. Gynecol Oncol 2017;144:208-214. Available at:
clinical presentation and diagnosis of gestational trophoblastic disease, https://www.ncbi.nlm.nih.gov/pubmed/27789086.
and management of hydatidiform mole. Am J Obstet Gynecol
2010;203:531-539. Available at: 11. Shaaban AM, Rezvani M, Haroun RR, et al. Gestational Trophoblastic
https://www.ncbi.nlm.nih.gov/pubmed/20728069. Disease: Clinical and Imaging Features. Radiographics 2017;37:681-700.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28287945.
3. Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease.
Lancet 2010;376:717-729. Available at: 12. Hancock BW, Tidy JA. Current management of molar pregnancy. J
https://www.ncbi.nlm.nih.gov/pubmed/20673583. Reprod Med 2002;47:347-354. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12063873.
4. Brown J, Naumann RW, Seckl MJ, Schink J. 15years of progress in
gestational trophoblastic disease: Scoring, standardization, and salvage. 13. Ngan HY, Seckl MJ, Berkowitz RS, et al. Update on the diagnosis and
Gynecol Oncol 2017;144:200-207. Available at: management of gestational trophoblastic disease. Int J Gynaecol Obstet
https://www.ncbi.nlm.nih.gov/pubmed/27743739. 2015;131 Suppl 2:S123-126. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26433668.
5. Lurain JR. Gestational trophoblastic disease II: classification and
management of gestational trophoblastic neoplasia. Am J Obstet Gynecol 14. Zhao P, Lu Y, Huang W, et al. Total hysterectomy versus uterine
2011;204:11-18. Available at: evacuation for preventing post-molar gestational trophoblastic neoplasia in
https://www.ncbi.nlm.nih.gov/pubmed/20739008. patients who are at least 40 years old: a systematic review and meta-
analysis. BMC Cancer 2019;19:13. Available at:
6. Berkowitz RS, Goldstein DP. Current advances in the management of https://www.ncbi.nlm.nih.gov/pubmed/30612545.
gestational trophoblastic disease. Gynecol Oncol 2013;128:3-5. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/22846466. 15. Wang Q, Fu J, Hu L, et al. Prophylactic chemotherapy for hydatidiform
mole to prevent gestational trophoblastic neoplasia. Cochrane Database
7. Berkowitz RS, Goldstein DP. Chorionic tumors. N Engl J Med Syst Rev 2017;9:CD007289. Available at:
1996;335:1740-1748. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28892119.
https://www.ncbi.nlm.nih.gov/pubmed/8929267.
16. Berkowitz RS, Goldstein DP. Gestational trophoblastic disease.
8. Berkowitz RS, Goldstein DP. Clinical practice. Molar pregnancy. N Engl Cancer 1995;76:2079-2085. Available at:
J Med 2009;360:1639-1645. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8635004.
https://www.ncbi.nlm.nih.gov/pubmed/19369669.

9. Sun SY, Melamed A, Goldstein DP, et al. Changing presentation of

complete hydatidiform mole at the New England Trophoblastic Disease
MS-11
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

17. Cole LA. Human chorionic gonadotropin and associated molecules. 25. Doll KM, Soper JT. The role of surgery in the management of
Expert Rev Mol Diagn 2009;9:51-73. Available at: gestational trophoblastic neoplasia. Obstet Gynecol Surv 2013;68:533-
https://www.ncbi.nlm.nih.gov/pubmed/19099349. 542. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23803756.

18. Ngan HYS, Seckl MJ, Berkowitz RS, et al. Update on the diagnosis 26. Pezeshki M, Hancock BW, Silcocks P, et al. The role of repeat uterine
and management of gestational trophoblastic disease. Int J Gynaecol evacuation in the management of persistent gestational trophoblastic
Obstet 2018;143 Suppl 2:79-85. Available at: disease. Gynecol Oncol 2004;95:423-429. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30306586. https://www.ncbi.nlm.nih.gov/pubmed/15581942.

19. Muller CY, Cole LA. The quagmire of hCG and hCG testing in 27. Garner EI, Feltmate CM, Goldstein DP, Berkowitz RS. The curative
gynecologic oncology. Gynecol Oncol 2009;112:663-672. Available at: effect of a second curettage in persistent trophoblastic disease: a
https://www.ncbi.nlm.nih.gov/pubmed/19007977. retrospective cohort survey. Gynecol Oncol 2005;99:3-5. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16139344.
20. Coyle C, Short D, Jackson L, et al. What is the optimal duration of
human chorionic gonadotrophin surveillance following evacuation of a 28. van Trommel NE, Thomas CM, Massuger LF, Sweep FC. Second
molar pregnancy? A retrospective analysis on over 20,000 consecutive curettage in persistent trophoblastic disease (PTD): the need for univocal
patients. Gynecol Oncol 2018;148:254-257. Available at: definition of PTD. Gynecol Oncol 2005;99:250-251; author reply 251.
https://www.ncbi.nlm.nih.gov/pubmed/29229282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16224821.

21. Schmitt C, Doret M, Massardier J, et al. Risk of gestational 29. Osborne RJ, Filiaci VL, Schink JC, et al. Second Curettage for Low-
trophoblastic neoplasia after hCG normalisation according to hydatidiform Risk Nonmetastatic Gestational Trophoblastic Neoplasia. Obstet Gynecol
mole type. Gynecol Oncol 2013;130:86-89. Available at: 2016;128:535-542. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23523617. https://www.ncbi.nlm.nih.gov/pubmed/27500329.

22. Braga A, Maesta I, Matos M, et al. Gestational trophoblastic neoplasia 30. Savage P, Seckl MJ. The role of repeat uterine evacuation in
after spontaneous human chorionic gonadotropin normalization following trophoblast disease. Gynecol Oncol 2005;99:251-252; author reply 252-
molar pregnancy evacuation. Gynecol Oncol 2015;139:283-287. Available 253. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16137746.
at: https://www.ncbi.nlm.nih.gov/pubmed/26383828.
31. May T, Goldstein DP, Berkowitz RS. Current chemotherapeutic
23. Committee FO. FIGO staging for gestational trophoblastic neoplasia management of patients with gestational trophoblastic neoplasia.
2000. FIGO Oncology Committee. Int J Gynaecol Obstet 2002;77:285- Chemother Res Pract 2011;2011:806256. Available at:
287. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12065144. https://www.ncbi.nlm.nih.gov/pubmed/22312558.

24. Eysbouts YK, Massuger L, IntHout J, et al. The added value of 32. Rotmensch S, Cole LA. False diagnosis and needless therapy of
hysterectomy in the management of gestational trophoblastic neoplasia. presumed malignant disease in women with false-positive human
Gynecol Oncol 2017;145:536-542. Available at: chorionic gonadotropin concentrations. Lancet 2000;355:712-715.
https://www.ncbi.nlm.nih.gov/pubmed/28390821. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10703803.

MS-12
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

33. Cole LA, Muller CY. Hyperglycosylated hCG in the management of Trophoblastic Diseases; September 21-24, 2017; Amsterdam, The
quiescent and chemorefractory gestational trophoblastic diseases. Netherlands.
Gynecol Oncol 2010;116:3-9. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19822356. 41. Osborne RJ, Filiaci V, Schink JC, et al. Phase III trial of weekly
methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic
34. Ngan HY, Bender H, Benedet JL, et al. Gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin Oncol 2011;29:825-
neoplasia, FIGO 2000 staging and classification. Int J Gynaecol Obstet 831. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21263100.
2003;83 Suppl 1:175-177. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/14763174. 42. Kohorn EI. Is lack of response to single-agent chemotherapy in
gestational trophoblastic disease associated with dose scheduling or
35. Gestational trophoblastic diseases. Report of a WHO Scientific Group. chemotherapy resistance? Gynecol Oncol 2002;85:36-39. Available at:
World Health Organ Tech Rep Ser 1983;692:7-81. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11925117.
https://www.ncbi.nlm.nih.gov/pubmed/6318459.
43. Sita-Lumsden A, Short D, Lindsay I, et al. Treatment outcomes for 618
36. Bagshawe KD. Risk and prognostic factors in trophoblastic neoplasia. women with gestational trophoblastic tumours following a molar pregnancy
Cancer 1976;38:1373-1385. Available at: at the Charing Cross Hospital, 2000-2009. Br J Cancer 2012;107:1810-
https://www.ncbi.nlm.nih.gov/pubmed/182354. 1814. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23059744.

37. Goldstein DP, Berkowitz RS, Horowitz NS. Optimal management of 44. Hitchins RN, Holden L, Newlands ES, et al. Single agent etoposide in
low-risk gestational trophoblastic neoplasia. Expert Rev Anticancer Ther gestational trophoblastic tumours. Experience at Charing Cross Hospital
2015;15:1293-1304. Available at: 1978-1987. Eur J Cancer Clin Oncol 1988;24:1041-1046. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26517533. https://www.ncbi.nlm.nih.gov/pubmed/2842160.

38. Mangili G, Lorusso D, Brown J, et al. Trophoblastic disease review for 45. Sung HC, Wu PC, Yang HY. Reevaluation of 5-fluorouracil as a single
diagnosis and management: a joint report from the International Society therapeutic agent for gestational trophoblastic neoplasms. Am J Obstet
for the Study of Trophoblastic Disease, European Organisation for the Gynecol 1984;150:69-75. Available at:
Treatment of Trophoblastic Disease, and the Gynecologic Cancer https://www.ncbi.nlm.nih.gov/pubmed/6089563.
InterGroup. Int J Gynecol Cancer 2014;24:S109-116. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25341573. 46. Alazzam M, Tidy J, Osborne R, et al. Chemotherapy for resistant or
recurrent gestational trophoblastic neoplasia. Cochrane Database Syst
39. Lawrie TA, Alazzam M, Tidy J, et al. First-line chemotherapy in low- Rev 2016:CD008891. Available at:
risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev https://www.ncbi.nlm.nih.gov/pubmed/26760424.
2016:CD007102. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27281496. 47. Covens A, Filiaci VL, Burger RA, et al. Phase II trial of pulse
dactinomycin as salvage therapy for failed low-risk gestational
40. Schink JC, Filiaci V, Huang H, al. e. A phase III randomized trial of trophoblastic neoplasia: a Gynecologic Oncology Group study. Cancer
pulse actinomycin-D versus multi-day methotrexate for the treatment of 2006;107:1280-1286. Available at:
low risk gestational trophoblastic neoplasia [abstract]. Presented at the https://www.ncbi.nlm.nih.gov/pubmed/16900525.
XIX World Congress of the International Society for the Study of
MS-13
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

48. McNeish IA, Strickland S, Holden L, et al. Low-risk persistent Reprod Med 2002;47:465-471. Available at:
gestational trophoblastic disease: outcome after initial treatment with low- https://www.ncbi.nlm.nih.gov/pubmed/12092015.
dose methotrexate and folinic acid from 1992 to 2000. J Clin Oncol
2002;20:1838-1844. Available at: 56. Crawford RA, Newlands E, Rustin GJ, et al. Gestational trophoblastic
https://www.ncbi.nlm.nih.gov/pubmed/11919242. disease with liver metastases: the Charing Cross experience. Br J Obstet
Gynaecol 1997;104:105-109. Available at:
49. McGrath S, Short D, Harvey R, et al. The management and outcome https://www.ncbi.nlm.nih.gov/pubmed/8988707.
of women with post-hydatidiform mole 'low-risk' gestational trophoblastic
neoplasia, but hCG levels in excess of 100 000 IU l(-1). Br J Cancer 57. Newlands ES, Bagshawe KD, Begent RH, et al. Results with the
2010;102:810-814. Available at: EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide,
https://www.ncbi.nlm.nih.gov/pubmed/20160727. vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to
1989. Br J Obstet Gynaecol 1991;98:550-557. Available at:
50. Lurain JR, Chapman-Davis E, Hoekstra AV, Schink JC. Actinomycin D https://www.ncbi.nlm.nih.gov/pubmed/1651757.
for methotrexate-failed low-risk gestational trophoblastic neoplasia. J
Reprod Med 2012;57:283-287. Available at: 58. Bolis G, Bonazzi C, Landoni F, et al. EMA/CO regimen in high-risk
https://www.ncbi.nlm.nih.gov/pubmed/22838241. gestational trophoblastic tumor (GTT). Gynecol Oncol 1988;31:439-444.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/2846414.
51. Prouvot C, Golfier F, Massardier J, et al. Efficacy and Safety of
Second-Line 5-Day Dactinomycin in Case of Methotrexate Failure for 59. Kim SJ, Bae SN, Kim JH, et al. Risk factors for the prediction of
Gestational Trophoblastic Neoplasia. Int J Gynecol Cancer 2018;28:1038- treatment failure in gestational trophoblastic tumors treated with EMA/CO
1044. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29629964. regimen. Gynecol Oncol 1998;71:247-253. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/9826467.
52. Alifrangis C, Agarwal R, Short D, et al. EMA/CO for high-risk
gestational trophoblastic neoplasia: good outcomes with induction low- 60. Matsui H, Suzuka K, Iitsuka Y, et al. Combination chemotherapy with
dose etoposide-cisplatin and genetic analysis. J Clin Oncol 2013;31:280- methotrexate, etoposide, and actinomycin D for high-risk gestational
286. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23233709. trophoblastic tumors. Gynecol Oncol 2000;78:28-31. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10873405.
53. Lurain JR, Singh DK, Schink JC. Primary treatment of metastatic high-
risk gestational trophoblastic neoplasia with EMA-CO chemotherapy. J 61. Escobar PF, Lurain JR, Singh DK, et al. Treatment of high-risk
Reprod Med 2006;51:767-772. Available at: gestational trophoblastic neoplasia with etoposide, methotrexate,
https://www.ncbi.nlm.nih.gov/pubmed/17086804. actinomycin D, cyclophosphamide, and vincristine chemotherapy. Gynecol
Oncol 2003;91:552-557. Available at:
54. Ahamed E, Short D, North B, et al. Survival of women with gestational https://www.ncbi.nlm.nih.gov/pubmed/14675675.
trophoblastic neoplasia and liver metastases: is it improving? J Reprod
Med 2012;57:262-269. Available at: 62. Turan T, Karacay O, Tulunay G, et al. Results with EMA/CO
https://www.ncbi.nlm.nih.gov/pubmed/22696824. (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine)
chemotherapy in gestational trophoblastic neoplasia. Int J Gynecol Cancer
55. Newlands ES, Holden L, Seckl MJ, et al. Management of brain 2006;16:1432-1438. Available at:
metastases in patients with high-risk gestational trophoblastic tumors. J https://www.ncbi.nlm.nih.gov/pubmed/16803542.
MS-14
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

63. Lu WG, Ye F, Shen YM, et al. EMA-CO chemotherapy for high-risk trophoblastic disease: a Gynecologic Oncology Group study. Obstet
gestational trophoblastic neoplasia: a clinical analysis of 54 patients. Int J Gynecol 1989;73:357-362. Available at:
Gynecol Cancer 2008;18:357-362. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2536911.
https://www.ncbi.nlm.nih.gov/pubmed/17711444.
70. Zhao Y, Zhang W, Duan W. Management of gestational trophoblastic
64. Cagayan MS. High-risk metastatic gestational trophoblastic neoplasia. neoplasia with 5-fluorouracil and actinomycin D in northern China. J
Primary management with EMA-CO (etoposide, methotrexate, Reprod Med 2009;54:88-94. Available at:
actinomycin D, cyclophosphamide and vincristine) chemotherapy. J https://www.ncbi.nlm.nih.gov/pubmed/19301571.
Reprod Med 2012;57:231-236. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22696818. 71. Wang S, An R, Han X, et al. Combination chemotherapy with 5-
fluorouracil, methotrexate and etoposide for patients with high-risk
65. Cyriac S, Rajendranath R, Sridevi V, Sagar TG. Etoposide, cisplatin- gestational trophoblastic tumors: a report based on our 11-year clinical
etoposide, methotrexate, actinomycin-D as primary treatment for experiences. Gynecol Oncol 2006;103:1105-1108. Available at:
management of very-high-risk gestational trophoblastic neoplasia. Int J https://www.ncbi.nlm.nih.gov/pubmed/16870237.
Gynaecol Obstet 2011;115:37-39. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21802685. 72. Deng L, Yan X, Zhang J, Wu T. Combination chemotherapy for high-
risk gestational trophoblastic tumour. Cochrane Database Syst Rev
66. Ghaemmaghami F, Modares M, Arab M, et al. EMA-EP regimen, as 2009:CD005196. Available at:
firstline multiple agent chemotherapy in high-risk GTT patients (stage II- https://www.ncbi.nlm.nih.gov/pubmed/19370618.
IV). Int J Gynecol Cancer 2004;14:360-365. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15086738. 73. Kong Y, Yang J, Jiang F, et al. Clinical characteristics and prognosis of
ultra high-risk gestational trophoblastic neoplasia patients: A retrospective
67. Han SN, Amant F, Leunen K, et al. EP-EMA regimen (etoposide and cohort study. Gynecol Oncol 2017;146:81-86. Available at:
cisplatin with etoposide, methotrexate, and dactinomycin) in a series of 18 https://www.ncbi.nlm.nih.gov/pubmed/28461032.
women with gestational trophoblastic neoplasia. Int J Gynecol Cancer
2012;22:875-880. Available at: 74. Bolze PA, Riedl C, Massardier J, et al. Mortality rate of gestational
https://www.ncbi.nlm.nih.gov/pubmed/22635033. trophoblastic neoplasia with a FIGO score of >/=13. Am J Obstet Gynecol
2016;214:390 e391-398. Available at:
68. Dobson LS, Lorigan PC, Coleman RE, Hancock BW. Persistent https://www.ncbi.nlm.nih.gov/pubmed/26433171.
gestational trophoblastic disease: results of MEA (methotrexate, etoposide
and dactinomycin) as first-line chemotherapy in high risk disease and EA 75. Savage P, Kelpanides I, Tuthill M, et al. Brain metastases in
(etoposide and dactinomycin) as second-line therapy for low risk disease. gestational trophoblast neoplasia: an update on incidence, management
Br J Cancer 2000;82:1547-1552. Available at: and outcome. Gynecol Oncol 2015;137:73-76. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10789722. https://www.ncbi.nlm.nih.gov/pubmed/25598530.

69. Curry SL, Blessing JA, DiSaia PJ, et al. A prospective randomized 76. Gavanier D, Leport H, Massardier J, et al. Gestational trophoblastic
comparison of methotrexate, dactinomycin, and chlorambucil versus neoplasia with brain metastasis at initial presentation: a retrospective
methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, study. Int J Clin Oncol 2019;24:153-160. Available at:
hydroxyurea, and vincristine in "poor prognosis" metastatic gestational https://www.ncbi.nlm.nih.gov/pubmed/30242539.
MS-15
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

77. Piura E, Piura B. Brain metastases from gestational trophoblastic 85. Fleming EL, Garrett L, Growdon WB, et al. The changing role of
neoplasia: review of pertinent literature. Eur J Gynaecol Oncol thoracotomy in gestational trophoblastic neoplasia at the New England
2014;35:359-367. Available at: Trophoblastic Disease Center. J Reprod Med 2008;53:493-498. Available
https://www.ncbi.nlm.nih.gov/pubmed/25118474. at: https://www.ncbi.nlm.nih.gov/pubmed/18720924.

78. Neubauer NL, Latif N, Kalakota K, et al. Brain metastasis in gestational 86. Kanis MJ, Lurain JR. Pulmonary Resection in the Management of
trophoblastic neoplasia: an update. J Reprod Med 2012;57:288-292. High-Risk Gestational Trophoblastic Neoplasia. Int J Gynecol Cancer
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22838242. 2016;26:796-800. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26905332.
79. Soper JT, Spillman M, Sampson JH, et al. High-risk gestational
trophoblastic neoplasia with brain metastases: individualized 87. Mapelli P, Mangili G, Picchio M, et al. Role of 18F-FDG PET in the
multidisciplinary therapy in the management of four patients. Gynecol management of gestational trophoblastic neoplasia. Eur J Nucl Med Mol
Oncol 2007;104:691-694. Available at: Imaging 2013;40:505-513. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17137617. https://www.ncbi.nlm.nih.gov/pubmed/23314259.

80. Rustin GJ, Newlands ES, Begent RH, et al. Weekly alternating 88. Lim AK, Agarwal R, Seckl MJ, et al. Embolization of bleeding residual
etoposide, methotrexate, and actinomycin/vincristine and uterine vascular malformations in patients with treated gestational
cyclophosphamide chemotherapy for the treatment of CNS metastases of trophoblastic tumors. Radiology 2002;222:640-644. Available at:
choriocarcinoma. J Clin Oncol 1989;7:900-903. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11867779.
https://www.ncbi.nlm.nih.gov/pubmed/2472471.
89. Tse KY, Chan KK, Tam KF, Ngan HY. 20-year experience of
81. Evans AC, Jr., Soper JT, Clarke-Pearson DL, et al. Gestational managing profuse bleeding in gestational trophoblastic disease. J Reprod
trophoblastic disease metastatic to the central nervous system. Gynecol Med 2007;52:397-401. Available at:
Oncol 1995;59:226-230. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17583238.
https://www.ncbi.nlm.nih.gov/pubmed/7590478.
90. McGrath S, Harding V, Lim AK, et al. Embolization of uterine
82. Small W, Jr., Lurain JR, Shetty RM, et al. Gestational trophoblastic arteriovenous malformations in patients with gestational trophoblastic
disease metastatic to the brain. Radiology 1996;200:277-280. Available at: tumors: a review of patients at Charing Cross Hospital, 2000-2009. J
https://www.ncbi.nlm.nih.gov/pubmed/8657926. Reprod Med 2012;57:319-324. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22838248.
83. Bakri Y, Berkowitz RS, Goldstein DP, et al. Brain metastases of
gestational trophoblastic tumor. J Reprod Med 1994;39:179-184. Available 91. Lurain JR, Singh DK, Schink JC. Role of surgery in the management
at: https://www.ncbi.nlm.nih.gov/pubmed/7518516. of high-risk gestational trophoblastic neoplasia. J Reprod Med
2006;51:773-776. Available at:
84. Alazzam M, Hancock BW, Tidy J. Role of hysterectomy in managing https://www.ncbi.nlm.nih.gov/pubmed/17086805.
persistent gestational trophoblastic disease. J Reprod Med 2008;53:519-
524. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18720927. 92. Powles T, Savage PM, Stebbing J, et al. A comparison of patients with
relapsed and chemo-refractory gestational trophoblastic neoplasia. Br J

MS-16
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

Cancer 2007;96:732-737. Available at: 99. Arpitha A, Pallavi VR, Bafna UD, et al. Role of salvage therapy in
https://www.ncbi.nlm.nih.gov/pubmed/17299394. chemo resistant or recurrent high-risk gestational trophoblastic neoplasm.
Int J Gynecol Cancer 2019;29:547-553. Available at:
93. Hoekstra AV, Lurain JR, Rademaker AW, Schink JC. Gestational https://www.ncbi.nlm.nih.gov/pubmed/30700567.
trophoblastic neoplasia: treatment outcomes. Obstet Gynecol
2008;112:251-258. Available at: 100. Lurain JR, Singh DK, Schink JC. Management of metastatic high-risk
https://www.ncbi.nlm.nih.gov/pubmed/18669719. gestational trophoblastic neoplasia: FIGO stages II-IV: risk factor score >
or = 7. J Reprod Med 2010;55:199-207. Available at:
94. Lurain JR, Casanova LA, Miller DS, Rademaker AW. Prognostic https://www.ncbi.nlm.nih.gov/pubmed/20626175.
factors in gestational trophoblastic tumors: a proposed new scoring
system based on multivariate analysis. Am J Obstet Gynecol 101. Wang J, Short D, Sebire NJ, et al. Salvage chemotherapy of relapsed
1991;164:611-616. Available at: or high-risk gestational trophoblastic neoplasia (GTN) with
https://www.ncbi.nlm.nih.gov/pubmed/1847005. paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE). Ann
Oncol 2008;19:1578-1583. Available at:
95. Lurain JR, Hoekstra AV, Schink JC. Results of treatment of patients https://www.ncbi.nlm.nih.gov/pubmed/18453518.
with gestational trophoblastic neoplasia referred to the Brewer
Trophoblastic Disease Center after failure of treatment elsewhere (1979- 102. Essel KG, Bruegl A, Gershenson DM, et al. Salvage chemotherapy
2006). J Reprod Med 2008;53:535-540. Available at: for gestational trophoblastic neoplasia: Utility or futility? Gynecol Oncol
https://www.ncbi.nlm.nih.gov/pubmed/18720930. 2017;146:74-80. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28473205.
96. Lurain JR, Schink JC. Importance of salvage therapy in the
management of high-risk gestational trophoblastic neoplasia. J Reprod 103. Feldman DR, Hu J, Dorff TB, et al. Paclitaxel, Ifosfamide, and
Med 2012;57:219-224. Available at: Cisplatin Efficacy for First-Line Treatment of Patients With Intermediate- or
https://www.ncbi.nlm.nih.gov/pubmed/22696816. Poor-Risk Germ Cell Tumors. J Clin Oncol 2016;34:2478-2483. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/27185842.
97. Newlands ES, Mulholland PJ, Holden L, et al. Etoposide and
cisplatin/etoposide, methotrexate, and actinomycin D (EMA) 104. Mardiak J, Rejlekova K, Mego M, et al. Determination of efficacy of
chemotherapy for patients with high-risk gestational trophoblastic tumors TIP combination (paclitaxel, ifosfamide, cisplatin) as first salvage therapy
refractory to EMA/cyclophosphamide and vincristine chemotherapy and for patients with relapsed germ cell tumors in a poor prognosis group.
patients presenting with metastatic placental site trophoblastic tumors. J 2009;27:e16049-e16049. Available at:
Clin Oncol 2000;18:854-859. Available at: http://ascopubs.org/doi/abs/10.1200/jco.2009.27.15_suppl.e16049.
https://www.ncbi.nlm.nih.gov/pubmed/10673528.
105. Kondagunta GV, Bacik J, Donadio A, et al. Combination of paclitaxel,
98. Mao Y, Wan X, Lv W, Xie X. Relapsed or refractory gestational ifosfamide, and cisplatin is an effective second-line therapy for patients
trophoblastic neoplasia treated with the etoposide and cisplatin/etoposide, with relapsed testicular germ cell tumors. J Clin Oncol 2005;23:6549-6555.
methotrexate, and actinomycin D (EP-EMA) regimen. Int J Gynaecol Available at: https://www.ncbi.nlm.nih.gov/pubmed/16170162.
Obstet 2007;98:44-47. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17481633. 106. Motzer RJ, Sheinfeld J, Mazumdar M, et al. Paclitaxel, ifosfamide,
and cisplatin second-line therapy for patients with relapsed testicular germ
MS-17
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

cell cancer. J Clin Oncol 2000;18:2413-2418. Available at: 114. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation
https://www.ncbi.nlm.nih.gov/pubmed/10856101. immunotherapy--inhibiting programmed death-ligand 1 and programmed
death-1. Clin Cancer Res 2012;18:6580-6587. Available at:
107. Lurain JR, Nejad B. Secondary chemotherapy for high-risk https://www.ncbi.nlm.nih.gov/pubmed/23087408.
gestational trophoblastic neoplasia. Gynecol Oncol 2005;97:618-623.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15863169. 115. Wherry EJ. T cell exhaustion. Nat Immunol 2011;12:492-499.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/21739672.
108. Benigno BB. High-dose chemotherapy with autologous stem cell
support as salvage therapy in recurrent gestational trophoblastic disease. 116. Bolze PA, Patrier S, Massardier J, et al. PD-L1 Expression in
Int J Gynecol Cancer 2013;23:1331-1333. Available at: Premalignant and Malignant Trophoblasts From Gestational Trophoblastic
https://www.ncbi.nlm.nih.gov/pubmed/23970157. Diseases Is Ubiquitous and Independent of Clinical Outcomes. Int J
Gynecol Cancer 2017;27:554-561. Available at:
109. El-Helw LM, Seckl MJ, Haynes R, et al. High-dose chemotherapy and https://www.ncbi.nlm.nih.gov/pubmed/28060141.
peripheral blood stem cell support in refractory gestational trophoblastic
neoplasia. Br J Cancer 2005;93:620-621. Available at: 117. Veras E, Kurman RJ, Wang TL, Shih IM. PD-L1 Expression in
https://www.ncbi.nlm.nih.gov/pubmed/16222307. Human Placentas and Gestational Trophoblastic Diseases. Int J Gynecol
Pathol 2017;36:146-153. Available at:
110. Frijstein MM, Lok CAR, Short D, et al. The results of treatment with https://www.ncbi.nlm.nih.gov/pubmed/27362903.
high-dose chemotherapy and peripheral blood stem cell support for
gestational trophoblastic neoplasia. Eur J Cancer 2019;109:162-171. 118. Ghorani E, Kaur B, Fisher RA, et al. Pembrolizumab is effective for
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30731277. drug-resistant gestational trophoblastic neoplasia. Lancet 2017;390:2343-
2345. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29185430.
111. van Besien K, Verschraegen C, Mehra R, et al. Complete remission
of refractory gestational trophoblastic disease with brain metastases 119. Pandian Z, Seckl MJ, Smith R, Lees DA. Gestational
treated with multicycle ifosfamide, carboplatin, and etoposide (ICE) and choriocarcinoma: an unusual presentation with response to gemcitabine
stem cell rescue. Gynecol Oncol 1997;65:366-369. Available at: and surgery. BJOG 2004;111:382-384. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/9159354. https://www.ncbi.nlm.nih.gov/pubmed/15008778.

112. Yamamoto E, Niimi K, Fujikake K, et al. High-dose chemotherapy 120. Bianconi MI, Otero S, Storino C, Jankilevich G. Role of Capecitabine
with autologous peripheral blood stem cell transplantation for in the Management of Gestational Trophoblastic Neoplasia: A Drug for
choriocarcinoma: A case report and literature review. Mol Clin Oncol Two Settings. J Reprod Med 2017;62:250-256. Available at:
2016;5:660-664. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30027717.
https://www.ncbi.nlm.nih.gov/pubmed/27900108.
121. Bianconi M, Jankilevich G, Otero S, et al. Successful salvage of a
113. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, relapsed high risk gestational trophoblastic neoplasia patient using
Differences, and Implications of Their Inhibition. Am J Clin Oncol capecitabine. Gynecol Oncol 2007;106:268-271. Available at:
2016;39:98-106. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17493670.
https://www.ncbi.nlm.nih.gov/pubmed/26558876.

MS-18
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
Printed by Roshni Sethia on 3/4/2021 4:30:17 PM. For personal use only. Not approved for distribution. Copyright © 2021 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 1.2021

Gestational Trophoblastic Neoplasia

122. Zhang Y, Zhang S, Huang W, et al. Intermediate trophoblastic tumor: 2006;100:511-520. Available at:
the clinical analysis of 62 cases and prognostic factors. Arch Gynecol https://www.ncbi.nlm.nih.gov/pubmed/16246400.
Obstet 2019. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30607597. 130. Papadopoulos AJ, Foskett M, Seckl MJ, et al. Twenty-five years'
clinical experience with placental site trophoblastic tumors. J Reprod Med
123. Lan C, Li Y, He J, Liu J. Placental site trophoblastic tumor: lymphatic 2002;47:460-464. Available at:
spread and possible target markers. Gynecol Oncol 2010;116:430-437. https://www.ncbi.nlm.nih.gov/pubmed/12092014.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19910023.
131. Hassadia A, Gillespie A, Tidy J, et al. Placental site trophoblastic
124. Frijstein MM, Lok CAR, van Trommel NE, et al. Management and tumour: clinical features and management. Gynecol Oncol 2005;99:603-
prognostic factors of epithelioid trophoblastic tumors: Results from the 607. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16085293.
International Society for the Study of Trophoblastic Diseases database.
Gynecol Oncol 2019;152:361-367. Available at: 132. Shih IM, Kurman RJ. Epithelioid trophoblastic tumor: a neoplasm
https://www.ncbi.nlm.nih.gov/pubmed/30473257. distinct from choriocarcinoma and placental site trophoblastic tumor
simulating carcinoma. Am J Surg Pathol 1998;22:1393-1403. Available at:
125. Kurman RJ, Shih Ie M. Discovery of a cell: reflections on the https://www.ncbi.nlm.nih.gov/pubmed/9808132.
checkered history of intermediate trophoblast and update on its nature and
pathologic manifestations. Int J Gynecol Pathol 2014;33:339-347. 133. Allison KH, Love JE, Garcia RL. Epithelioid trophoblastic tumor:
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24901393. review of a rare neoplasm of the chorionic-type intermediate trophoblast.
Arch Pathol Lab Med 2006;130:1875-1877. Available at:
126. Schmid P, Nagai Y, Agarwal R, et al. Prognostic markers and long- https://www.ncbi.nlm.nih.gov/pubmed/17149967.
term outcome of placental-site trophoblastic tumours: a retrospective
observational study. Lancet 2009;374:48-55. Available at: 134. Yang J, Zong L, Wang J, et al. Epithelioid Trophoblastic Tumors:
https://www.ncbi.nlm.nih.gov/pubmed/19552948. Treatments, Outcomes, and Potential Therapeutic Targets. J Cancer
2019;10:11-19. Available at:
127. Zhao J, Lv WG, Feng FZ, et al. Placental site trophoblastic tumor: A https://www.ncbi.nlm.nih.gov/pubmed/30662520.
review of 108 cases and their implications for prognosis and treatment.
Gynecol Oncol 2016;142:102-108. Available at: 135. Hancock B, Froeling FEM, Ramaswami R, et al. The ISSTD global
https://www.ncbi.nlm.nih.gov/pubmed/27168005. placental site and epithelioid trophoblastic tumor (PSTT/ETT) database –
an analysis of 326 patients. ISSTD XVIIIWorld Congress on Gestational
128. Froeling FEM, Ramaswami R, Papanastasopoulos P, et al. Trophoblastic Disease. Bali, Indonesia; 2015.
Intensified therapies improve survival and identification of novel prognostic
factors for placental-site and epithelioid trophoblastic tumours. Br J Cancer 136. Sobecki-Rausch J, Winder A, Maniar KP, et al. Surgery and
2019;120:587-594. Available at: Platinum/Etoposide-Based Chemotherapy for the Treatment of Epithelioid
https://www.ncbi.nlm.nih.gov/pubmed/30792530. Trophoblastic Tumor. Int J Gynecol Cancer 2018;28:1117-1122. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/29757875.
129. Baergen RN, Rutgers JL, Young RH, et al. Placental site
trophoblastic tumor: A study of 55 cases and review of the literature
emphasizing factors of prognostic significance. Gynecol Oncol
MS-19
Version 1.2021 © 2020 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.