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First-line chemotherapy in low-risk gestational trophoblastic neoplasia

  • Review
  • Intervention




This is an update of a Cochrane review that was first published in Issue 1, 2009. Gestational trophoblastic neoplasia (GTN) is a rare but curable disease arising in the fetal chorion during pregnancy. Most women with low-risk GTN will be cured by evacuation of the uterus with or without single-agent chemotherapy. However, chemotherapy regimens vary between treatment centres worldwide and the comparable benefits and risks of these different regimens are unclear.


To determine the efficacy and safety of first-line chemotherapy in the treatment of low-risk GTN.

Search methods

In September 2008, we electronically searched the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL Issue 3, 2008), MEDLINE and EMBASE. In addition, we searched online trial registers, conference proceedings and reference lists of identified studies. We re-ran these searches in February 2012 for this updated review.

Selection criteria

For the original review, we included randomised controlled trials (RCTs), quasi-RCTs and non-RCTs that compared first-line chemotherapy for the treatment of low-risk GTN. For this updated version of the review, we included only RCTs.

Data collection and analysis

Two review authors independently assessed studies for inclusion and extracted data to a pre-designed data extraction form. Meta-analysis was performed by pooling the risk ratio (RR) of individual trials.

Main results

We included five moderate to high quality RCTs (517 women) in the updated review. These studies all compared methotrexate with dactinomycin. Three studies compared weekly intramuscular (IM) methotrexate with bi-weekly pulsed intravenous (IV) dactinomycin (393 women), one study compared five-day IM methotrexate with bi-weekly pulsed IV dactinomycin (75 women) and one study compared eight-day IM methotrexate-folinic acid (MTX-FA) with five-day IV dactinomycin (49 women).

Overall, dactinomycin was associated with significantly higher rates of primary cure than methotrexate (five studies, 513 women; RR 0.64, 95% Confidence Interval (CI) 0.54 to 0.76). Methotrexate was associated with significantly more treatment failure than dactinomycin (five studies, 513 women; RR 3.81, 95% CI 1.64 to 8.86). We consider this evidence to be of a moderate quality.

There was no significant difference between the two groups with respect to nausea (four studies, 466 women; RR 0.61, 95% CI 0.29 to 1.26) or any of the other individual side-effects reported, although data for all of these outcomes were insufficient and too heterogeneous to be conclusive. No severe adverse effects (SAEs) occurred in either group in three out of the five included studies and there was no significant difference in SAEs between the groups overall (five studies, 515 women; RR 0.35, 95% CI 0.08 to 1.66; I² = 60%), however, there was a trend towards fewer SAEs in the methotrexate group. We considered this evidence to be of a low quality due to substantial heterogeneity and low consistency in the occurrence/reporting of SAEs between trials.

Authors' conclusions

Dactinomycin is more likely to achieve a primary cure in women with low-risk GTN, and less likely to result in treatment failure, compared with methotrexate. There is limited evidence relating to side-effects, however, the pulsed dactinomycin regimen does not appear to be associated with significantly more side-effects than the low-dose methotrexate regimen and therefore should compare favourably to the five- and eight-day methotrexate regimens in this regard.

We consider pulsed dactinomycin to have a better cure rate than, and a side-effect profile at least equivalent to, methotrexate when used for first-line treatment of low-risk GTN. Data from a large ongoing trial of pulsed dactinomycin compared with five- and eight-day methotrexate regimens is likely to have an important impact on our confidence in these findings.

Plain language summary

First-line treatment with anti-cancer drugs for low risk gestational trophoblastic neoplasia

Gestational trophoblastic neoplasia (GTN) is a rare but curable disease whereby a malignant tumour develops in the womb after a normal or molar pregnancy (where tissue develops in the womb instead of a baby). Women with GTN are classified as having low- or high-risk GTN using a specific scoring system. Virtually all women with low-risk GTN are cured by treatment with chemotherapy (anti-cancer drugs) after undergoing dilatation and curettage (D&C) of the womb. Methotrexate and dactinomycin are the two most commonly used drugs for first-line treatment of low-risk GTN, although methotrexate is favoured in Europe and North America. Sometimes the first-line treatment fails to cure the disease or has side-effects that require it be discontinued, and a secondary treatment has to be used. If methotrexate is the first drug used, dactinomycin is usually the secondary treatment, and vice versa. We undertook this review as it was not clear which drug, if any, was more likely to cure low-risk disease in the first instance. Furthermore, it was not clear which, if any, caused more side-effects.

This review included five studies of moderate to high quality comparing three different treatment regimens of dactinomycin and methotrexate that differed by drug dose and dosing frequency. Overall, and for each treatment regimen compared, dactinomycin was much more likely to achieve a cure in the first instance than methotrexate, and much less likely to fail.

More evidence is needed on the relative side-effects of these drugs for low-risk GTN. The most commonly experienced side-effects in both groups were nausea, fatigue and anaemia. Overall, side-effects were relatively mild in both groups but there was a trend to more severe side-effects in women treated with dactinomycin, especially with the five-day treatment. Since pulsed dactinomycin achieved similar rates of cure to higher doses of dactinomycin but with milder side-effects, pulsed dactinomycin is preferable to the five-day dactinomycin regimen for first-line treatment of GTN. In addition, since the side-effects are modest and comparable to 'low-dose' methotrexate, we consider pulsed dactinomycin to be at least as good as methotrexate (low-and higher dose regimens), the more commonly used drug, for first-line treatment of low-risk GTN.

A large trial is underway, comparing the more conventional five- and eight-day methotrexate treatment schedules with pulsed dactinomycin, that will add to this body of evidence and may change our conclusions.