# High-risk gestational trophoblastic neoplasia (FIGO score 7 or more, including ultra-high-risk)

Source: https://onco.cc/cancers/high-risk-gtn/  
OnCo record `high-risk-gtn` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

High-risk gestational trophoblastic neoplasia is the aggressive form of this pregnancy-related cancer, usually choriocarcinoma that has spread to the lungs, liver or brain and produces very high hCG. It is treated with the multi-drug EMA-CO regimen, started gently in the sickest women to avoid early deaths, and most are cured; resistant disease gets platinum regimens, immunotherapy or surgery.

## Summary

High-risk gestational trophoblastic neoplasia, a FIGO 2000 score of 7 or more, is usually gestational choriocarcinoma, a tumour of syncytiotrophoblast and cytotrophoblast that follows a molar, term, miscarried or ectopic pregnancy and spreads through the blood to the lungs, vagina, liver and brain; it bleeds readily and produces enormous amounts of hCG. Choriocarcinoma after a term pregnancy is often diagnosed late because nobody suspects it, and any woman of reproductive age with unexplained metastases should have an hCG measured. Multi-agent chemotherapy became standard in the 1980s when Kenneth Bagshawe's group at Charing Cross developed EMA-CO (etoposide, methotrexate and actinomycin D alternating weekly with cyclophosphamide and vincristine), which cures more than nine in ten women with high-risk disease and remains the first-line regimen in the NCCN and FIGO guidelines.

The main causes of death are early haemorrhage and organ failure in women with very high tumour burden, and late resistance. For ultra-high-risk disease (score 13 or more, or liver or brain metastases) the Charing Cross and Sheffield centres showed that starting with one or two cycles of low-dose etoposide and cisplatin before EMA-CO prevents the early deaths caused by tumour breakdown and haemorrhage, and brain metastases are treated with higher-dose intrathecal or systemic methotrexate with or without radiotherapy or surgery. Women whose hCG plateaus on EMA-CO switch to EP-EMA (etoposide and cisplatin alternating with EMA) or to TP/TE (paclitaxel with cisplatin alternating with paclitaxel and etoposide), which cure most of the remainder; hysterectomy, lung resection or excision of a resistant focus localised by PET can remove the last chemoresistant deposit, and high-dose chemotherapy with autologous stem cell rescue has cured a few. Because trophoblast expresses PD-L1, pembrolizumab produced durable remissions in women with multiply resistant disease in the first case series (Lancet 2017), and avelumab and pembrolizumab are now tested as salvage and as first-line partners. hCG follow-up runs for at least a year, often longer, before pregnancy is allowed, and late effects of etoposide, including a small excess of leukaemia, are monitored.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: High-risk GTN; Metastatic gestational choriocarcinoma; Ultra-high-risk gestational trophoblastic neoplasia (score 13 or more); Choriocarcinoma after term pregnancy
- Tags: subtype-page; gynaecologic
- Group: gynaecologic
- Burden: A minority of gestational trophoblastic neoplasia, often choriocarcinoma after a non-molar pregnancy with metastases to lung, liver or brain and very high hCG; cure rates still exceed nine in ten with multi-agent chemotherapy.
- Subtypes: High-risk gestational choriocarcinoma with lung metastases (FIGO score 7 to 12); Ultra-high-risk gestational trophoblastic neoplasia (score 13 or more; induction low-dose etoposide-cisplatin); Gestational trophoblastic neoplasia with liver metastases; Gestational trophoblastic neoplasia with brain metastases (high-dose methotrexate, radiotherapy or surgery); Choriocarcinoma after term pregnancy or miscarriage (late diagnosis); EMA-CO-resistant gestational trophoblastic neoplasia (EP-EMA, TP/TE, pembrolizumab, surgery)
- Biomarkers: Serum hCG (very high; response and surveillance); FIGO 2000 score (7 or more high risk; 13 or more ultra-high risk); Sites of metastasis on CT, MRI of brain and pelvic ultrasound (liver and brain define ultra-high risk); Cerebrospinal fluid to serum hCG ratio (brain involvement); Genotyping to confirm gestational origin and identify the causative pregnancy; PD-L1 expression (universal; checkpoint inhibitor rationale)

## Standard of care

- Staging: hCG, chest CT, brain MRI, abdominal imaging, pelvic Doppler ultrasound and FIGO scoring; genotyping where the antecedent pregnancy is unclear. ([CT (computed tomography)](https://onco.cc/technologies/ct/), [MRI](https://onco.cc/technologies/mri/), [Ultrasound](https://onco.cc/technologies/ultrasound/), [Tumour markers (CEA, LDH, chromogranin, thyroglobulin)](https://onco.cc/terms/tumour-markers/), [Disease-specific staging and risk systems (FIGO, Ann Arbor, IPI, R-ISS, ELN, IMDC)](https://onco.cc/terms/staging-systems/))
- High-risk disease, first line: EMA-CO (etoposide, methotrexate, actinomycin D alternating with cyclophosphamide and vincristine) until hCG normalises plus at least three consolidation cycles. ([Etoposide](https://onco.cc/drugs/etoposide/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Dactinomycin (actinomycin D)](https://onco.cc/drugs/dactinomycin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Vincristine](https://onco.cc/drugs/vincristine/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/))
- Ultra-high-risk disease: Induction low-dose etoposide and cisplatin for one to three cycles before EMA-CO to prevent early death from haemorrhage and organ failure. ([Etoposide](https://onco.cc/drugs/etoposide/), [Cisplatin](https://onco.cc/drugs/cisplatin/))
- Brain metastases: High-dose systemic and intrathecal methotrexate within EMA-CO, with whole-brain or stereotactic radiotherapy or craniotomy for bleeding or single lesions. ([Methotrexate](https://onco.cc/drugs/methotrexate/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/))
- Resistant or relapsed disease: EP-EMA or TP/TE; resection of a resistant focus (hysterectomy, lung wedge); pembrolizumab or avelumab; high-dose chemotherapy with autologous rescue in exceptional cases. ([Etoposide](https://onco.cc/drugs/etoposide/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Avelumab](https://onco.cc/drugs/avelumab/), [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [PET/CT](https://onco.cc/technologies/pet-ct/))

## State of the art

- EMA-CO cures more than nine in ten women with high-risk disease.
- Low-dose induction chemotherapy has largely eliminated early deaths in ultra-high-risk disease.
- PD-1 and PD-L1 antibodies rescue women with multiply resistant disease.

## Open problems

- EMA-CO has never been tested against any other regimen in a randomised trial.
- Late diagnosis of choriocarcinoma after term pregnancy still costs lives.
- Etoposide raises the long-term risk of leukaemia and its dose cannot easily be reduced.
- Where checkpoint inhibitors belong in the sequence is being worked out from small series.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Choriocarcinoma
- FIGO cancer report: gestational trophoblastic disease (2021): https://doi.org/10.1002/ijgo.13877
- NCCN Gestational Trophoblastic Neoplasia: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1489
- Wikipedia: https://en.wikipedia.org/wiki/Choriocarcinoma

## Connected records

- cancers: [Gestational trophoblastic neoplasia](https://onco.cc/cancers/gestational-trophoblastic/), [Low-risk gestational trophoblastic neoplasia (FIGO score 0 to 6)](https://onco.cc/cancers/low-risk-gtn/), [Non-seminomatous germ cell tumour](https://onco.cc/cancers/non-seminoma/), [Placental-site trophoblastic tumour and epithelioid trophoblastic tumour](https://onco.cc/cancers/placental-site-trophoblastic-tumour/)
- technologies: [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [CT (computed tomography)](https://onco.cc/technologies/ct/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [MRI](https://onco.cc/technologies/mri/), [PET/CT](https://onco.cc/technologies/pet-ct/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Serum tumour markers: proper use and misuse](https://onco.cc/technologies/serum-tumour-markers/), [Ultrasound](https://onco.cc/technologies/ultrasound/)
- targets: [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Avelumab](https://onco.cc/drugs/avelumab/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Dactinomycin (actinomycin D)](https://onco.cc/drugs/dactinomycin/), [Etoposide](https://onco.cc/drugs/etoposide/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Vincristine](https://onco.cc/drugs/vincristine/)
- terms: [Disease-specific staging and risk systems (FIGO, Ann Arbor, IPI, R-ISS, ELN, IMDC)](https://onco.cc/terms/staging-systems/), [Tumour markers (CEA, LDH, chromogranin, thyroglobulin)](https://onco.cc/terms/tumour-markers/)
- key papers: [EMA/CO for high-risk gestational trophoblastic tumours: results from a cohort of 272 patients](https://onco.cc/key-papers/paper-bower-ema-co-high-risk-gtn-charing-cross-jco-1997/), [FIGO Cancer Report 2021: diagnosis and management of gestational trophoblastic disease](https://onco.cc/key-papers/paper-figo-cancer-report-gestational-trophoblastic-disease-ijgo-2021/), [FIGO staging for gestational trophoblastic neoplasia 2000](https://onco.cc/key-papers/paper-figo-2000-staging-gestational-trophoblastic-neoplasia-ijgo-2002/)

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