Elsevier

Gynecologic Oncology

Volume 91, Issue 3, December 2003, Pages 552-557
Gynecologic Oncology

Regular article
Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy☆

https://doi.org/10.1016/j.ygyno.2003.08.028Get rights and content

Abstract

Objective

The objective of the study was to evaluate the efficacy and toxicity of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine (EMA-CO) chemotherapy for the treatment of high-risk gestational trophoblastic neoplasia.

Methods

Forty-five patients with high-risk gestational trophoblastic tumors received 257 EMA-CO treatment cycles between 1986 and 2001. Twenty-five were treated primarily with EMA-CO because of the presence of one or more high-risk factors and 20 were treated with EMA-CO secondarily after failure of single-agent chemotherapy. Patients who had incomplete responses or developed resistance to EMA-CO were treated with drug combinations employing cisplatin and etoposide with or without bleomycin or ifosfamide. Adjuvant surgery and radiotherapy were used in selected patients. Survival, clinical response, and toxicity were analyzed retrospectively.

Results

The overall survival rates was 91% (41/45); survival rates were 92% (23/25) for primary treatment and 90% (18/20) for secondary treatment with EMA-CO. Of the 45 patients treated with EMA-CO, 32 (71%) had a complete clinical response, 9 (20%) developed resistance but were subsequently placed into remission with cisplatin-based chemotherapy, and 4 (9%) died of widespread metastatic disease. Clinical complete response to EMA-CO was significantly influenced by duration of disease from antecedent pregnancy to treatment (<6 months, 84%, vs >6 months, 43%), metastatic site (lung and pelvis, 73%, vs other, 40%), and WHO score (≤7, 96%, vs >7, 36%). The EMA-CO chemotherapy regimen produced no life-threatening toxicity, caused grade 3–4 hematologic toxicity in 1.6% of cycles, and was associated with neutropenia necessitating a 1-week delay in treatment in only 13.5% of cycles.

Conclusions

EMA-CO chemotherapy is a well-tolerated and highly effective treatment for high-risk gestational trophoblastic neoplasia, yielding a 71% complete response rate and a 91% survival rate in this series.

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

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    Treatment of metastatic gestational trophoblastic tumors

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      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].

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      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.

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    This study was presented at the XIth World Congress on Gestational Trophoblastic Diseases, Santa Fe, New Mexico, USA, October 27–31, 2001.

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