Combinations of anti-cancer drugs to treat high-risk cancers arising from the placenta, known as high-risk gestational trophoblastic neoplasia (GTN)

GTN is a cancer that most often arises after a molar pregnancy but can arise after any type of pregnancy. Molar pregnancies occur due to abnormal growth of placental tissue that is usually benign and treated by evacuation of the womb (D&C). However, in less than 10% of molar pregnancies in the UK, the growth remains after D&C and transforms into a cancer (GTN) that needs treatment with anti-cancer drugs (chemotherapy). GTN can be low-risk or high-risk. Anti-cancer drugs are very effective, especially in low-risk GTN, which is usually cured with single-drug treatment. However, high-risk GTN needs to be treated with combinations of anti-cancer drugs for the best effect. These drugs can produce toxic side effects that are more likely to occur when used in combination with each other. The most commonly administered drug combination is abbreviated as EMA/CO, which stands for Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide and Oncovin® (vincristine), but several other combinations are also in use.

We undertook this review to try to determine which combination/s of drugs are the most effective for the first-line drug treatment of high-risk GTN, and with the least side effects. We found only one small, older study that compared a drug combination abbreviated as CHAMOCA with one called MAC. The CHAMOCA regimen, which is no longer recommended for GTN treatment, was found to be extremely toxic to the blood and bone marrow, with no greater effect against the cancer than the MAC regimen. Based on the available evidence, it is currently not possible to determine whether EMA/CO is the most effective and least toxic drug combination as no high-quality studies have been conducted comparing this combination with other combinations. GTN is a rare cancer and so studies in this field are difficult to conduct, therefore researchers need to collaborate in order to produce the necessary high-quality evidence.

Authors' conclusions: 

CHAMOCA is not recommended for GTN treatment as it is more toxic and not more effective than MAC. EMA/CO is currently the most widely used first-line combination chemotherapy for high-risk GTN, although this regimen has not been rigorously compared to other combinations such as MAC or FAV in RCTs. Other regimens may be associated with less acute toxicity than EMA/CO; however, proper evaluation of these combinations in high-quality RCTs that include long-term surveillance for secondary cancers is required. We acknowledge that, given the low incidence of GTN, RCTs in this field are difficult to conduct, hence multicentre collaboration is necessary.

Read the full abstract...

This is an update of the original review that was published in The Cochrane Database of Systematic Reviews, 2009, Issue 2. Gestational trophoblastic neoplasia (GTN) are malignant disorders of the placenta that include invasive hydatidiform mole, choriocarcinoma, placental-site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). Choriocarcinoma and invasive hydatidiform mole respond well to chemotherapy: low-risk tumours are treated with single-agent chemotherapy (e.g. methotrexate or actinomycin D), whereas high-risk tumours are treated with combination chemotherapy (e.g. EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine)). Various drug combinations may be used for high-risk tumours; however, the comparative efficacy and safety of these regimens is not clear.


To determine the efficacy and safety of combination chemotherapy in treating high-risk GTN.

Search strategy: 

For the original review, we searched the Cochrane Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 2, 2008), MEDLINE, EMBASE and CBM in May 2008. For the updated review, we searched Cochrane Group Specialised Register, CENTRAL, MEDLINE and EMBASE to September 2012 and on 1 June 2015. In addition, we searched online clinical trial registries for ongoing trials.

Selection criteria: 

Randomised controlled trials (RCTs) and quasi-RCTs comparing first-line combination chemotherapy interventions in women with high-risk GTN.

Data collection and analysis: 

Two review authors independently collected data using a data extraction form. Meta-analysis could not be performed as we included only one study.

Main results: 

We included one RCT of 42 women with high-risk GTN who were randomised to MAC (methotrexate, actinomycin D and chlorambucil) or the modified CHAMOCA regimen (cyclophosphamide, hydroxyurea, actinomycin D, methotrexate, doxorubicin, melphalan and vincristine). There were no statistically significant differences in efficacy of the two regimens; however women in the MAC group experienced statistically significantly less toxicity overall and less haematological toxicity than women in the CHAMOCA group. During the study period, six women in the CHAMOCA group died compared with one in the MAC group. This study was stopped early due to unacceptable levels of toxicity in the CHAMOCA group. We identified no RCTs comparing EMA/CO with MAC or other chemotherapy regimens.