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

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.