Regular articleTreatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy☆☆
Introduction
Since Hertz and colleagues at the National Cancer Institute (NCI) first demonstrated the efficacy of chemotherapy in the treatment of metastatic gestational trophoblastic disease over 40 years ago, the cure rate for these tumors has steadily increased and now exceeds 90% [1]. Cure is currently anticipated in all patients with nonmetastatic and low-risk metastatic disease; however, approximately 20% of patients with high-risk metastatic disease will still fail treatment and die. This emphasizes the necessity to select high-risk patients correctly for aggressive multimodality therapy. The early NCI investigators recognized that the outcome of therapy depended to a large extent on the duration of disease, height of the pretreatment human chorionic gonadotropin (hCG) level, the presence or the absence of brain or liver metastases, and expertise in the use of chemotherapy [2], [3].
Patients with high-risk metastatic disease are now treated with initial combination, rather than single-agent, chemotherapy with or without adjuvant radiotherapy or surgery. The benefit of this approach was first noted at the John I. Brewer Trophoblastic Disease Center in 1968. Patients with high-risk disease who were initially treated with the triple-chemotherapy regimen of methotrexate, actinomycin D, and cyclophosphamide or chlorambucil (MAC) had a survival rate of 65%, whereas the survival rate for similar patients who were treated initially with a single agent followed by MAC as secondary therapy was 39% [4]. Others subsequently confirmed the value of initial combination chemotherapy with MAC for treatment of patients with high-risk metastatic gestational trophoblastic disease [5], [6], [7], [8].
After the discovery in the early 1980s that etoposide was a very effective chemotherapeutic agent for gestational trophoblastic neoplasia, Newlands et al. formulated the EMA-CO regimen, employing etoposide, high-dose methotrexate with folinic acid rescue, actinomycin D, cyclophosphamide, and vincristine [9]. Since then, complete response rates and long-term survival rates of over 80% have been reported by several groups [10], [11], [12], [13], [14], [15]. In 1992 we reported our initial results of the first 12 patients with high-risk metastatic trophoblastic tumors treated primarily with EMA-CO at the Brewer Center between 1986 and 1991 [11]. The objective of the present study was to update our experience, evaluating the efficacy, toxicity, and survival of patients with high-risk gestational trophoblastic neoplasia treated with the EMA-CO regimen.
Section snippets
Materials and methods
From 1986 to 2001, 45 patients with high-risk gestational trophoblastic neoplasia were prospectively treated with EMA-CO chemotherapy (Table 1). Twenty-five patients were treated primarily with the EMA-CO regimen because of the presence of one or more high-risk factors: (1) an immediate pretreatment serum β-hCG level in excess of 40,000 mIU/mL (12); (2) duration of disease greater than 4 months from antecedent pregnancy event to treatment (14); (3) metastases to sites other than the lungs and
Results
The results of treatment for all 45 patients with high-risk gestational trophoblastic neoplasia who received EMA-CO at the Brewer Center from 1986 to 2001 are presented in Table 2. The overall survival was 91%, with a median follow-up of 36 months. Survival was 92% for the 25 patients who received EMA-CO as primary therapy and 90% for the 20 patients who were treated secondarily with EMA-CO after primary failure with single agents. Of the entire 45 patients treated with EMA-CO, 32 (71%) had a
Discussion
Patients with high-risk gestational trophoblastic neoplasia (any NCI poor prognosis factor, FIGO Stage IV, WHO score >7, or prior unsuccessful single-agent chemotherapy) should be treated with multiagent chemotherapy, employing etoposide, high-dose methotrexate with folinic acid, and actinomycin D, with or without adjuvant radiotherapy or surgery. The EMA-CO protocol formulated by the Charing Cross Hospital—London group is currently the most common chemotherapy regimen used to treat high-risk
References (22)
- et al.
Five years experience with chemotherapy of meta-static choriocarcinoma and related tumors in women
Am J Obstet Gynecol
(1961) - et al.
Sequential use of methotrexate and actinomycin D in the treatment of metastatic choriocarcinoma and related trophoblastic diseases in women
Am J Obstet Gynecol
(1965) - et al.
Gestational trophoblastic diseaseA comparative study of the results of therapy in patients with invasive mole and with choriocarcinoma
Am J Obstet Gynecol
(1971) - et al.
Treatment of metastatic trophoblastic diseasegood and poor prognosis
Am J Obstet Gynecol
(1973) - et al.
Modified triple chemotherapy in the management of high-risk metastatic gestational trophoblastic tumors
Gynecol Oncol
(1984) - et al.
EMA/CO regimen in high-risk gestational trophoblastic tumors
Gynecol Oncol
(1988) - et al.
Risk factors for the prediction of treatment failure in gestational trophoblastic tumors treated with EMA/CO regimen
Gynecol Oncol
(1998) - et al.
The management of gestational trophoblastic tumors with etoposide, methotrexate, and actinomycin D
Gynecol Oncol
(1997) - et al.
Combination chemotherapy with methotrexate, etoposide, and actinomycin D for high-risk gestational trophoblastic tumors
Gynecol Oncol
(2000) - et al.
Uterine arteriovenous malformationsprimary treatment with therapeutic embolization
J Vasc Intervent Radiol
(1991)
Treatment of metastatic gestational trophoblastic tumors
Cited by (86)
EMACO for treatment of gestational trophoblastic neoplasia: A multinational multicenter study
2023, Gynecologic OncologyOther rare uterine cancers: neuroendocrine tumors, yolk sac tumors, choriocarcinoma
2023, Diagnosis and Treatment of Rare Gynecologic CancersSurveillance for gestational trophoblastic neoplasia following molar pregnancy: a cost-effectiveness analysis
2021, American Journal of Obstetrics and GynecologyTreatment of high-risk gestational trophoblastic neoplasia and chemoresistance/relapsed disease
2021, Best Practice and Research: Clinical Obstetrics and GynaecologyEMA vs EMACO in the treatment of gestational trophoblastic neoplasia
2020, Gynecologic OncologyCitation Excerpt :Remission rates of 63.3%, 67.5%, 76.2% and 90.6% and number of chemotherapy cycles to remission of 10.0 ± 4.0, 10.7 ± 4.3, 9.1 ± 3.9 and 8.5 ± 2.2 courses were reported for MFA (methotrexate, folinic acid, and actinomycin-D), MAC (methotrexate, actinomycin-D, and cyclophosphamide), and CHAMOCA (cyclophosphamide, hydroxyurea, doxorubicin, actinomycin-D, methotrexate, melphalan, and vincristine), and EMACO, respectively [26]. Additional studies further supported the effectiveness of EMACO with remission rates ranging from 72 to 92% and overall survival rates from 86 to 99% [10–16]. Four studies, however, have reported comparable remission rates in patients receiving EMA: 89.7% from the United States, 74.4% from Japan, 75.5% from England, and 96% from South Korea [17–20].
Gestational trophoblast disease: clinical presentation and treatment
2019, Diagnostic HistopathologyCitation Excerpt :Historical data from treatment prior to the introduction of multiagent chemotherapy demonstrated that less than one-third of high-risk patients would be cured with single-agent therapy.33 The introduction of combination chemotherapy treatments in the 1970s transformed this situation, and modern data indicate a cure rate for high-risk patients of 85–94% using EMA/CO chemotherapy.4,34–36 This combination delivers a dose-intense treatment with the five chemotherapy agents, delivered in two groups 1 week apart as shown in Table 4.
- ☆
This study was presented at the XIth World Congress on Gestational Trophoblastic Diseases, Santa Fe, New Mexico, USA, October 27–31, 2001.