DACTINOMYCIN BETTER THAN METHOTRAXATE IN LOW RISK TROPHOBLASTIC DISEASE?

February 1, 2011 — Cancers that arise from products of conception in the uterus, known collectively as gestational trophoblastic neoplasia (GTN), are rare but highly curable.
Low-risk GTN, which includes hydatidiform moles that have undergone malignant transformation and choriocarcinomas, has a high cure rate and there are many effective single-drug chemotherapy regimens. However, there is no consensus on which is the best drug and regimen to use.
The choice of drug and regimen is highly institution-specific, according to a group of gynecologic oncologists, led by Raymond Osborne, MD, FRCSC, MBA, from the Odette Cancer Center in Toronto, Ontario, Canada.
There is a historic preference for methotrexate, but they report a new phase 3 trial in which methotrexate was bested by dactinomycin.
The study is published online January 24 in the Journal of Clinical Oncology.
It involved 216 women with low-risk GTN who were enrolled over a period of 8 years, and compared 2 commonly used single-drug regimens.
Dr. Osborne and colleagues report that biweekly dactinomycin had a significantly higher complete response rate than a weekly intramuscular (IM) methotrexate regimen (70% vs 53%; P = .01); adverse effects were relatively modest with both regimens.
However, an accompanying editorial says this study "does not change standard practice at this time."
Most treating physicians will continue to use single-agent methotrexate, and will reserve dactinomycin for cases of methotrexate resistance or toxicity, writes editorialist Carol Aghajanian, MD, from the Memorial Sloan-Kettering Cancer Center in New York City.
But both the researchers and the editorialist agree that further trials exploring the dactinomycin regimen in this setting are warranted.
Definitions Were Changed
One of the issues with this particular study, according to Dr. Aghajanian, is that the definitions for GTN were changed while it was underway.
The study accrued patients between 1999 and 2007, but in 2002 the definitions of GTN were changed by the International Federation of Gynecology and Obstetrics (FIGO). The investigators chose not to change the definitions in their trial for logistical reasons, but because the criteria they were using are significantly different from current FIGO definitions, extrapolating from this study to clinical practice is "difficult," Dr. Aghajanian writes.
Another point is that dactinomycin is a vesicant — it can cause blisters — which makes administration more challenging and local tissue injury a possibility, she notes.
Furthermore, long-term safety data have not been compiled for dactinomycin, as they have for methotrexate, and the long-term safety and reproductive data from this study are not yet mature.
"Minimizing both long- and short-term toxicity is paramount in low-risk GTN," Dr. Aghajanian notes, because the cure rate is high (nearly 100%) and these women usually hope to have further pregnancies.
Further Testing Is Warranted
In the trial, IM methotrexate was used at a dose of 30 mg/m² once a week.
The regimen of dactinomycin that was shown to be superior was an intravenous (IV) dose of 1.25 mg/m² every 2 weeks. With this administration schedule, it is "relatively easy to administer and has a low toxicity profile," the researchers explain.
Dr. Osborne and colleagues say that further comparison of this biweekly dactinomycin regimen with other methotrexate regimens is warranted.
The editorialist agrees, and suggests that future trials should test it against IV or IM methotrexate 0.4 mg/kg given for 5 days and against the 8-day alternating methotrexate/leucovorin regimen (where IM methotrexate 1 mg/kg is given on days 1, 3, 5, and 7 and leucovorin 15 mg is given orally on days 2, 4, 6, and 8).
The authors have disclosed no relevant financial relationships.
J Clin Oncol. Published online January 24, 2011.