Low-Risk Gestational Trophoblastic Neoplasia (FIGO Score 0–6) Treatment
There is no consensus on the best chemotherapy regimen for initial management of low-risk gestational trophoblastic neoplasia (GTN), and first-line regimens vary by geography and institutional preference. Most regimens have not been compared head-to-head, and the level of evidence for efficacy is often limited to 3iiDii except as noted below. Even if there are differences in initial remission rate among the regimens, salvage with alternate regimens is very effective, and the ultimate cure rates are generally 99% or more. The initial regimen is generally given until a normal beta human chorionic gonadotropin (beta-hCG) (for the institution) is achieved and sustained for 3 consecutive weeks (or at least for one treatment cycle beyond normalization of the beta-hCG). A salvage regimen is instituted if any of the following occur:
- A plateau of the beta-hCG for 3 weeks (defined as a beta-hCG decrease of 10% or less for 3 consecutive weeks).
- A rise in beta-hCG of greater than 20% for 2 consecutive weeks.
- Metastases appear.
The use of chemotherapy in the first-line management of low-risk GTN has been assessed in a Cochrane Collaboration systematic review. In that systematic review, four randomized controlled trials were identified.[2-5]
- Biweekly (pulsed) dactinomycin (1.25 mg/m2 intravenously [IV]) .
- Weekly intramuscular methotrexate (30 mg/m2).
These three trials included a total of 392 patients. All three trials showed better primary complete response (CR) rates without the need for additional salvage therapy associated with pulsed dactinomycin (relative risk [RR] of cure, 3.00; 95% confidence interval [CI], 1.10–8.17), even though the magnitude of benefit showed substantial heterogeneity (I2 statistic = 79%).[3-5][Level of evidence: 1iiDii] Fewer courses of therapy were needed to achieve CR and cure with dactinomycin treatment. As expected, salvage chemotherapy was nearly uniformly successful, because almost all low-risk GTN patients are ultimately cured, irrespective of the initial chemotherapeutic regimen. There were no statistically significant differences in most toxicities, including the following:
- Nausea and vomiting.
- Hematologic toxicity.
- Hepatic toxicity.
There was a statistically significant increase in dermatologic toxicity, including alopecia, associated with dactinomycin. However, in the largest study, there was statistically significantly more low-grade gastrointestinal toxicity, grade 2 nausea, grade 1 to 2 vomiting, and grades 1 to 3 neutropenia in the dactinomycin group. In that study, choriocarcinoma patients and patients with a risk score of 5 to 6 had a worse CR rate to initial treatment with single-agent therapy, and methotrexate was virtually ineffective.
The fourth randomized trial was a very small study of 45 patients and compared a 5-day regimen of dactinomycin (10 μg/kg) with an 8-day regimen of methotrexate (1 mg/kg) and folinic acid (0.1 mg/kg) on alternate days. There was a statistically significant decrease in risk of failure to achieve primary cure without the need for salvage therapy in the dactinomycin arm (RR, 0.57; 95% CI, 0.40–0.81).[Level of evidence: 1iiDii] There was less alopecia associated with methotrexate but more hepatic toxicity.
The Cochrane systematic review also summarized the evidence from four nonrandomized trials, but comparisons across studies are difficult. The regimens evaluated in those studies are included in the lists below.[Level of evidence: 3iiDii]
Commonly used treatment regimens include the following:
- The 8-day Charing Cross regimen. Methotrexate (50 mg intramuscularly [IM] on days 1, 3, 5, and 7) and folinic acid (7.5 mg orally on days 2, 4, 6, and 8). This may be the most common regimen worldwide,[1,6] but it has not been directly compared with other regimens.
- Biweekly pulsed dactinomycin (1.25 mg/m2 intravenously [IV]).
- Weekly methotrexate (30 mg/m2 IM). Efficacy of this regimen appears to be low for choriocarcinoma and for patients with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) risk scores of 5 to 6.
Other regimens in less-common use include the following:
- An 8-day regimen of methotrexate (1 mg/kg IM days 1, 3, 5, and 7) and folinic acid (0.1 mg/kg IM days 2, 4, 6, and 8).
- Methotrexate 20 mg/m2 IM days 1 to5, repeated every 14 days.
- Dactinomycin 12 μg/kg/day IV days 1 to 5, repeated every 2 to 3 weeks. This regimen has fallen out of favor because of substantial alopecia and nausea.
- Methotrexate 20 mg IM daily, days 1 to 5; and dactinomycin 500 μg IV daily, days 1 to 5, repeated every 14 days.
- Dactinomycin 10 μg/kg/day, days 1 to 5, repeated every 2 weeks.
- Methotrexate 0.4 mg/kg/day IM daily on days 1 to 5, repeated after 7 days.
- Etoposide 100 mg/m2/day IV on days 1 to 5, or 250 mg/m2 IV on days 1 and 3, at 10-day intervals.
The unusual patient with a tumor that becomes refractory to single-agent chemotherapy is treated with one of the combination regimens described below for high-risk GTN. (Refer to the High-Risk Gestational Trophoblastic Neoplasia (FIGO Score ≥7) Treatment section of this summary for more information.)Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with low risk metastatic gestational trophoblastic tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
- Alazzam M, Tidy J, Hancock BW, et al.: First line chemotherapy in low risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev (1): CD007102, 2009. [PUBMED Abstract]
- Lertkhachonsuk AA, Israngura N, Wilailak S, et al.: Actinomycin d versus methotrexate-folinic acid as the treatment of stage I, low-risk gestational trophoblastic neoplasia: a randomized controlled trial. Int J Gynecol Cancer 19 (5): 985-8, 2009. [PUBMED Abstract]
- Gilani MM, Yarandi F, Eftekhar Z, et al.: Comparison of pulse methotrexate and pulse dactinomycin in the treatment of low-risk gestational trophoblastic neoplasia. Aust N Z J Obstet Gynaecol 45 (2): 161-4, 2005. [PUBMED Abstract]
- Yarandi F, Eftekhar Z, Shojaei H, et al.: Pulse methotrexate versus pulse actinomycin D in the treatment of low-risk gestational trophoblastic neoplasia. Int J Gynaecol Obstet 103 (1): 33-7, 2008. [PUBMED Abstract]
- Osborne RJ, Filiaci V, Schink JC, et al.: Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin Oncol 29 (7): 825-31, 2011. [PUBMED Abstract]
- Khan F, Everard J, Ahmed S, et al.: Low-risk persistent gestational trophoblastic disease treated with low-dose methotrexate: efficacy, acute and long-term effects. Br J Cancer 89 (12): 2197-201, 2003. [PUBMED Abstract]
- Hitchins RN, Holden L, Newlands ES, et al.: Single agent etoposide in gestational trophoblastic tumours. Experience at Charing Cross Hospital 1978-1987. Eur J Cancer Clin Oncol 24 (6): 1041-6, 1988. [PUBMED Abstract]