• © 2011 by American Society of Clinical Oncology

Treatment of Low-Risk Gestational Trophoblastic Neoplasia

Gestational trophoblastic disease (GTD) spans a heterogeneous spectrum of diseases that arise in the fetal chorion during pregnancy. Included in this definition are hydatidiform moles (partial and complete), choriocarcinoma, placental site trophoblastic tumors (PSTTs), and epithelioid trophoblastic tumors (ETTs).

Hydatidiform moles are benign processes with malignant potential. Malignant transformation occurs in 15% to 20% of complete hydatiform moles (CHMs) and less than 5% of partial hydatiform moles (PHMs). In fact, malignant transformation is so rare in PHMs that if one is contemplating treatment for this diagnosis, it is prudent to confirm the pathologic diagnosis, to rule out a false-positive human chorionic gonadotropin (hCG) test, and to make sure that the patient has not had an incomplete evacuation before proceeding. In the current era of early detection of pregnancy, it can be difficult to distinguish early CHMs from PHMs histologically. Complete and partial hydatiform moles can be distinguished by performing a p57 immunostain.¹ Lack of nuclear p57 staining in villous stromal cells and cytotrophoblasts confirms diagnosis of CHMs (as opposed to hydropic abortion or PHMs). CHMs are entirely androgenic, whereas the p57 gene is paternally imprinted and maternally expressed.

According to current International Federation of Gynecology and Obstetrics (FIGO) classification,² hydatiform moles are considered to have undergone malignant transformation and therefore meet the definition of gestational trophoblastic neoplasm (GTN) if after evacuation there are four values or more indicating an hCG plateau during a period of at least 3 weeks; a rise of hCG of 10% or greater for three values or more during a period of at least 2 weeks; or persistence of hCG 6 months after mole evacuation. Only hydatiform moles that meet the definition of GTN are subject to staging and risk scoring. GTN is a term used for hydatiform moles that have undergone malignant transformation; this term is also used for all choriocarcinomas, including PSTTs and ETTs. PSTTs and ETTs are not subject to staging or risk scoring systems and need to be considered separately. Thus, in considering treatment of low-risk GTN, one is referring to hydatiform moles that have undergone malignant transformation (often referred to as persistence) and choriocarcinomas, which receive a low risk score.

The most recently published FIGO staging and classification systems are detailed in Tables 1 and 2.³ Use of the FIGO staging system is essential for determining initial therapy for patients with GTN to ensure the best possible outcomes with the least morbidity.

In this issue of Journal of Clinical Oncology, Osborne et al⁴ report the results of a randomized phase III trial performed by the Gynecologic Oncology Group of weekly methotrexate versus pulsed dactinomycin for low-risk GTN. The study accrued patients between 1999 and 2007. In 2002, the FIGO definitions for GTN changed, as did the staging and classification system. The investigators chose not to adapt the new definitions for GTN for logistical reasons. They did extend the acceptance of patients with risk scores from 0 to 4 (June 1999 to June 2002) to 0 to 6 (July 2002 to February 2007), and of the 216 evaluable patients, 17 (7.9%) had a risk score 5 to 6. The GTN definitions used in the study (< 10% decrease in hCG in three consecutive weekly values; > 20% sustained rise in hCG over two consecutive weekly values; persistently elevated hCG more than 4 months after initial evacuation; histologically proven nonmetastatic choriocarcinoma; histologically proven metastatic choriocarcinoma if the metastatic site[s] is one [or more] of the following: vagina, parametrium, or lung [if no lung lesion is > 2 cm]) are significantly different than the current FIGO definitions, making application of the study results to current practice difficult.

Several different outpatient chemotherapy regimens have been used to treat low-risk GTN (Table 3). The variability in primary response rates probably, at least in part, represents differences in drug dosages, schedules, routes of administration, and length of therapy delivered after normalization of hCG, as well as patient selection criteria. Chemotherapy is delivered until hCG values have returned to normal and then at least one cycle is given after the first normal hCG value (practice standards and regimens vary with respect to the amount of therapy delivered after the first normal hCG value, with a range of one to three cycles delivered after the first normal hCG). In general, the weekly intramuscular or intermittent continuous intravenous infusion methotrexate regimens are considered less effective than the daily ×5 days methotrexate or 8-day alternating methotrexate/leucovorin regimens. The inadequacy of the weekly intramuscular methotrexate regimen, especially in patients with a risk score of 5 to 6 and with the histologic diagnosis of choriocarcinoma, was confirmed by the current study. Dactinomycin, when given daily for 5 days, is probably an acceptable alternative to methotrexate in terms of efficacy, although it has a higher adverse effect profile (largely myelosuppression, nausea, and alopecia) and therefore has most often been used as a secondary therapy for patients who develop methotrexate resistance or toxicity. Dactinomycin given biweekly, as in the study by Osborne et al,⁴ is much more tolerable. However, dactinomycin is a vesicant, making administration more challenging and local tissue injury a possibility. Furthermore, long-term safety data have not been compiled for dactinomycin as it has been for methotrexate. For example, it has been shown that exposure to combination chemotherapy, but not single-agent methotrexate, increases the risk of developing second tumors.¹⁰ In addition, combination chemotherapy, more than single-agent methotrexate, increases the risk of early menopause.¹¹ Long-term safety and reproductive data is not yet mature with respect to the current study. Minimizing both long- and short-term toxicity is paramount in low-risk gestational trophoblastic neoplasm, for which the cure rate is high (nearly 100%) and patients are often desirous of future childbearing.

The study by Osborne et al⁴ does not change standard practice at this time. Most treating physicians will continue to use single-agent methotrexate, giving it daily for a period of 5 days or via the 8-day alternating methotrexate/leucovorin regimen, and will reserve the use of dactinomycin given daily for 5 days for methotrexate resistance or toxicity. Future randomized trials of biweekly dactinomycin compared with the daily ×5 days methotrexate and the 8-day alternating methotrexate/leucovorin regimens are warranted. These studies should include long-term follow-up for second tumors and reproductive outcomes and careful assessment of short-term toxicities such as alopecia.