L. Holden

PURPOSE: To evaluate the results of etoposide, methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine (EMA/CO) chemotherapy in women with high-risk gestational trophoblastic tumors (GTT) and to document the middle- and long-term toxicity of the regimen. PATIENTS AND METHODS: A total of 272 consecutive women with high-risk GTT, including 121 previously treated patients, were treated with weekly EMA/CO. The median follow-up duration is 4.5 years (range, 1 to 16). RESULTS: The cumulative 5-year survival rate is 86.2% (95% confidence interval, 81.9% to 90.5%). No deaths from GTT have occurred later than 2 years after the end [corrected] of EMA/CO. In a multivariate model, adverse prognostic factors were the presence of liver metastases (P < .0001), interval from antecedent pregnancy (P < .0001), brain metastases (P = .0008), and term delivery of antecedent pregnancy (P = .045). There were 11 (4%) early deaths, while 213 patients (78%) achieved a complete remission. Forty-seven (17%) developed drug resistance to EMA/CO, of whom 33 (70%) were salvaged by further cisplatin-based chemotherapy and surgery. Two women developed acute myeloid leukemia, two cervical malignancy, and one gastric adenocarcinoma after EMA/CO. More than half (56%) of the women who had fertility-conserving surgery and who have been in remission at least 2 years have become pregnant since the completion of EMA/CO, with 112 live births, including three infants with congenital abnormalities. CONCLUSION: EMA/CO is an effective and well-tolerated regimen for high-risk GTT. More than half of the women will retain their fertility; however, there is a small but significant risk of second malignancy.

PURPOSE: We have simplified the treatment of gestational trophoblastic disease (GTD) in order to reduce the number of patients exposed to potentially carcinogenic chemotherapy. Patients who score 0 to 8 on the Charing Cross scoring system are classified as low-risk and receive methotrexate (MTX) and folinic acid (FA), whereas those who score higher than 8 are classified as high-risk and receive the etoposide, methotrexate, and dactinomycin (EMA)/cyclophosphamide and vincristine (CO) regimen. PATIENTS AND METHODS: Between 1992 and 2000, 485 women with GTD were commenced on MTX/FA at Charing Cross Hospital, London, United Kingdom. If patients developed MTX resistance or toxicity, treatment was altered according to the level of beta human chorionic gonadotropin (hCG). If serum hCG was < or = 100 IU/L, patients received dactinomycin; if hCG was greater than 100 IU/L, patients received EMA/CO. RESULTS: The median duration of follow-up was 4.7 years. Overall survival was 100% and the relapse rate was 3.3% (16 of 485 patients). hCG values normalized in 324 (66.8%) of 485 patients with MTX alone, whereas 161 (33.2%) of 485 patients required a change in treatment, 11 because of MTX toxicity and 150 because of MTX resistance. Sixty-seven patients changed to dactinomycin, of whom 58 achieved normal hCG values, and nine required third-line chemotherapy with EMA/CO. hCG values normalized in 93 (98.9%) of 94 patients who changed directly to EMA/CO from MTX. CONCLUSION: Single-agent dactinomycin has activity in patients with low-risk GTD who develop MTX resistance and whose hCG is low. Simplifying the stratification of GTD into two classes (low- and high-risk) does not compromise overall outcome and may reduce the risk of second tumors.

PURPOSE: To evaluate the results of etoposide, cisplatin/etoposide, methotrexate, and actinomycin D (EP/EMA) chemotherapy in patients with gestational trophoblastic tumors (GTTs), who have relapsed after or who have become refractory to EMA/cyclophosphamide and vincristine (CO) chemotherapy, and in patients presenting with metastatic placental site trophoblastic tumors (PSTTs). PATIENTS AND METHODS: We have treated a total of 34 patients with GTT and eight patients with metastatic PSTT with the EP/EMA chemotherapy schedule. RESULTS: Twenty-two patients received EP/EMA because of apparent drug resistance to EMA/CO, and because the human chorionic gonadotropin (hCG) was near normal, they were not assessable for response. Twenty-one of these patients (95%) are alive and in remission. In the group where the hCG was high enough to confirm a response (greater than one log fall in hCG) to EP/EMA, all 12 patients responded and nine of these patients (75%) are alive and in remission. We have treated three patients with PSTT where the interval from antecedent pregnancy was less than 2 years, and all patients (100%) are alive and in remission. We have treated five patients where the interval from antecedent pregnancy was greater than 2 years and one fifth (20%) remain in remission. The survival for patients with GTT is 30 (88%) out of 34 patients and four (50%) out of eight patients for PSTT, giving an overall survival for these two cohorts of 34 (81%) out of 42 patients. The toxicity of this schedule is significant, with grade 3 or 4 toxicity (National Cancer Institute common toxicity criteria) recorded in hemoglobin (21%), WBC (68%), and platelets (40%). The role of surgery in this group of patients is important and contributed to sustained remission in five patients (23%) and possibly helped an additional seven patients (32%). CONCLUSION: EP/EMA is an effective but moderately toxic regimen for patients with high-risk GTT who become refractory to or relapse from EMA/CO chemotherapy. Also, EP/EMA clearly has activity in patients with metastatic PSTT.

PURPOSE: No increase in second tumor incidence was found in a previous analysis of women treated with chemotherapy for gestational trophoblastic tumors (GTT). More patient years at risk enabled a further analysis of the risk of second tumors to be performed in the 1,377 women treated in this until up to 1990. PATIENTS AND METHODS: Health questionnaires were returned on 93.3% of patients who successfully completed chemotherapy and were living in the United Kingdom. The remainder were flagged for death or developing further cancers by the Office of Population Census and Surveys and by the Thames Cancer Registry. Incidence density analysis was performed based on 15,279 person-years of observation available. Standardized incidence ratio (SIR) was used to estimate the relative risk (RR) of second tumors associated with the treatment. To calculate the expected number, the actual incidence rates observed by the Thames Cancer Registry during the same calendar period of observation were used. RESULTS: An overall 50% excess of risk (RR = 1.5; 95% confidence interval [CI], 1.1 to 2.1; P < .011) was observed: there were 37 second tumors, when 24.5 were expected. For specific second tumors, the risk was significantly increased for myeloid leukemia (RR = 16.6; 95% CI, 5.4 to 38.9), colon (RR = 4.6; 95% CI, 1.5 to 10.7), and breast cancer when the survival exceeded 25 years (RR = 5.8; 95% CI, 1.2 to 16.9). The risk was not significantly increased among the 554 women receiving single-agent therapy (RR = 1.3; 95% CI, 0.6 to 2.1). Leukemias only developed in patients receiving etoposide plus other cytotoxic drugs. CONCLUSION: This study suggests that there is a slight increased risk of second tumors after sequential or combination chemotherapy for GTT. This has become apparent since the introduction of etoposide and longer follow-up.

OBJECTIVE: To assess the efficacy, toxicity and survival in patients with high risk GTT treated with the EMA/CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine/oncovine). DESIGN: Open non-randomized study of 148 consecutive patients referred to the Charing Cross Hospital between 1979 and 1989. SETTING: Trophoblastic disease centre in a London teaching hospital. SUBJECTS: 148 consecutive patients with high risk GTT were treated with the EMA/CO regimen. 76 patients had received no prior chemotherapy and 72 had received prior chemotherapy. MAIN OUTCOME MEASURES: Survival, causes of treatment failure and toxicity were analysed. RESULTS: Of 76 patients who had received no prior chemotherapy, 62 (82%) are in remission; an overall survival of 85% for the 148 patients. Ten of the 76 patients without prior chemotherapy died from extensive disease within 3 weeks of starting chemotherapy. The complete and partial response rates to EMA/CO chemotherapy were 80% and 18% respectively. The addition of cisplatin salvaged 9 of 11 (82%) who developed drug resistance and did not require surgery. Salvage surgery alone resulted in 7 of 8 (87%) having complete remissions. Relapse after EMA/CO chemotherapy is uncommon (5.4%) but survival is still relatively good with further chemotherapy and/or surgery with 6 (75%) of 8 patients obtaining a further sustained remission. Complications from EMA/CO chemotherapy are acceptable with myelosuppression being dose-limiting. Late sequelae are uncommon: menstruation usually returns with a few months, and no fetal abnormalities have been recorded in subsequent pregnancies. One patient developed what we presume to be a therapy-induced acute myeloid leukaemia. CONCLUSION: At present EMA/CO chemotherapy is our treatment of choice for patients with high risk GTT. Its toxicity is predictable and reversible. In patients developing drug resistance, salvage surgery is important. Future developments may include further dose intensification with the addition of haemopoietic growth factors, earlier diagnosis and the separation of gestational from non-gestational trophoblastic tumours.