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© 2000 American Society for Clinical Oncology Etoposide and Cisplatin/Etoposide, Methotrexate, and Actinomycin D (EMA) Chemotherapy for Patients With High-Risk Gestational Trophoblastic Tumors Refractory to EMA/Cyclophosphamide and Vincristine Chemotherapy and Patients Presenting With Metastatic Placental Site Trophoblastic TumorsFrom the Department of Medical Oncology, Charing Cross Hospital, London, United Kingdom. Address reprint requests to E.S. Newlands, Department of Medical Oncology, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF, United Kingdom; email e.newlands{at}ic.ac.uk
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.
SURVIVAL OF PATIENTS with gestational trophoblastic tumors (GTTs) is now generally very good provided these patients are treated in centers that are experienced in the management of this disease. The overall survival of patients who need chemotherapy in most centers is in the range of 95% to 97%. GTTs range from patients with low-risk disease who can be cured in most cases with methotrexate and folinic acid to patients with much more aggressive tumors and high-risk disease who need combination chemotherapy from the outset. Over the last 20 years, etoposide, methotrexate, and actinomycin D (EMA)/cyclophosphamide and vincristine (CO) chemotherapy has become established as the treatment of choice for patients with high-risk disease. Bower et al1 recently reported results in 272 consecutive patients treated with this schedule, and the cumulative 5-year survival rate was 86.2%. No deaths from GTT occurred more than 2 years after the start of EMA/CO chemotherapy. However, in a multivariate model, adverse prognostic factors that were identified 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). An unusual feature of patients with GTT is their ability to be salvaged after failure of their primary therapy. In this report, there were 47 patients who developed drug resistance to EMA/CO, but 33 (70%) were salvaged by further chemotherapy (usually etoposide, cisplatin [EP]/EMA) and/or surgery. Of note in this report, more than half of the women (56%) who had fertility-conserving surgery and who had been in remission for at least 2 years had become pregnant since completing EMA/CO chemotherapy. There were 112 live births, which included three infants with congenital abnormalities. Placental site trophoblastic tumor (PSTT) is a rare variant of trophoblastic tumor with mainly cytotrophoblastic differentiation and relatively little human chorionic gonadotropin (hCG) production. These tumors can occur after both complete hydatidiform moles and normal biparental pregnancies.2 They have different clinical behavior to typical choriocarcinoma in that they commonly infiltrate locally and can spread via the lymphatics. The treatment of choice for patients with disease localized to the uterus is hysterectomy.3 Here we report in detail our results with the EP/EMA schedule of chemotherapy in patients with relapse or refractory GTT after EMA/CO chemotherapy and in patients with PSTT.
Between 1980 and December 1997, we treated 42 women with high-risk GTT that have either become refractory to or relapsed after EMA/CO chemotherapy, including eight patients with PSTT where the EP/EMA chemotherapy was their primary chemotherapy. The EP/EMA schedule is listed in Table 1, and patient characteristics are listed in Table 2.
If total WBC < 2,000 x 109/L or platelets < 75,000 x 109/L, treatment was delayed until recovery above these figures. If creatinine or blood urea increased to > 1.5 times the upper limit of normal, the EDTA clearance was repeated, and the dose of cisplatin was reduced by the same percentage as the reduction in EDTA from baseline. If patients developed mucositis from methotrexate, the dose of folinic acid was doubled both in dose and duration before considering reduction in the dose of methotrexate. Granulocyte colony-stimulating factor (G-CSF) was given for 3 or 4 days between courses if at any time the total WBC decreased below 2,000 x 109/L at the time the next course of chemotherapy was due. Surgery was performed on 17 patients, for a total of 22 operations. The impact of surgery on the patients’ outcome was retrospectively analyzed using the effect of the operation on the hCG estimations, which were done twice weekly. We defined an operation as (1) therapeutic when the hCG clearly decreased in the postoperative period and achieved normal values combined with EP/EMA chemotherapy; (2) not assessable usually where the hCG was near the normal range and the time of surgery and the impact of the operation on patient outcome was not clear; and (3) not effective where, at best, there was a transient decrease in hCG followed by progressively increasing values or no decrease at all.
Survival Cumulative overall survival of all patients was 34 (81%) out of 42 patients. There were two different subgroups of patients with GTT (excluding PSTT) in this study. The first subgroup consisted of 22 patients whose hCG had seemed to plateau on EMA/CO chemotherapy, with their hCG sufficiently close enough to the normal range to make it impossible to evaluate response. Twenty-one (95%) of these 22 patients are alive and in remission. The second subgroup consisted of 12 patients who had become resistant to or relapsed after EMA/CO, where the hCG was sufficiently high enough to define response as a greater than one log fall in response to EP/EMA chemotherapy, and 100% of the patients responded. Nine of these patients (75%) are alive and in remission. All three patients who relapsed after EMA/CO are in remission. Overall, 30 (88%) out of 34 patients with GTT, who developed resistance to EMA/CO chemotherapy, are alive and in remission (Fig 1A).
The optimum chemotherapy for patients with metastatic PSTT has yet to be determined because this variant of trophoblastic disease is rare and has rather variable chemosensitivity. We have previously shown that the survival of patients with PSTT is closely related to the interval from the last known antecedent pregnancy. The outlook for patients whose last known pregnancy is less than 2 years before they present with their PSTT is generally good, whereas the outlook for those presenting with metastatic disease more than 2 years from the last known pregnancy is bad.3 Using the EP/EMA schedule of chemotherapy as primary treatment for eight patients with PSTT, four (50%) of the eight patients are alive and in remission (Fig 1B). When expressed in terms of the interval from the last known pregnancy, three (100%) of the three patients whose interval from the last known pregnancy was less than 2 years are alive and in remission in contrast with one fifth of the patients (20%) whose interval from the last known pregnancy was greater than 2 years. The clinical impression is that cisplatin should be included in the initial treatment of patients with PSTT. Seventeen patients underwent a total of 22 operations (Table 3). The timing of surgery in relation to EP/EMA chemotherapy was before chemotherapy (six surgeries), during chemotherapy (six surgeries), and after chemotherapy (10 surgeries). The effect of surgery was assessed as clearly therapeutic in five patients (23%) and not assessable in seven patients (32%), as analyzed by the response of the serum hCG and patient outcome. In 10 patients (45%) surgery had no significant impact on the disease or patient outcome on the basis of the failure of serum hCG to decrease postoperatively.
Toxicity The EP/EMA schedule is moderately toxic to administer. There are inherent problems in administering weekly chemotherapy that combines a renally excreted drug, methotrexate, with a potentially nephrotoxic drug, cisplatin. The myelosuppression is cumulative in some patients, necessitating the use of G-CSF and, with thrombocytopenia, delays in chemotherapy. Myelosuppression caused delays in chemotherapy in 37 patients (88%) and dose reductions in 16 patients (38%). Thirteen patients (31%) required G-CSF. Initially, we used a 2-day EMA (etoposide and actinomycin D repeated on day 2) schedule, and this required delays in chemotherapy in most cases; reducing EMA to 1 day is easier to manage and induces fewer treatment delays. The main hematologic and renal toxicities seen with the EP/EMA schedule are listed in Table 4.
The management of patients with GTT should take place in specialist centers because the disease is rare and usually curable. Patients with low-risk disease can frequently be cured with methotrexate and folinic acid chemotherapy. This treatment has the advantage of having no known carcinogenic potential for inducing second tumors after long follow-up.4 Patients with high-risk disease or patients who have become resistant to methotrexate and folinic acid need combination chemotherapy. The EMA/CO schedule of chemotherapy, or one of its minor variants, is extensively used worldwide in this category of patient, and approximately 86% of patients treated with this schedule will achieve sustained long-term remission.1 Menstruation usually returns within 2 to 6 months after completing EMA/CO chemotherapy, provided patients are less than 40 years old. However, EMA/CO chemotherapy and its similar variants do carry a small risk of second tumor induction, and clearly, only women with high-risk disease should be exposed to this type of chemotherapy.4 In addition, combination chemotherapy will bring forward the age of menopause from 52 to 53 years in patients with molar pregnancies not receiving chemotherapy to 47 years in patients receiving combination chemotherapy.5 We have felt that the results with EMA/CO are sufficiently good, the toxicity profile well tolerated, and the ease of administration of this treatment for it to remain first line therapy for most patients with high-risk disease with GTT. The toxicity profile for EP/EMA reported here in detail for the first time confirms that this is not an easy schedule of chemotherapy to administer. Because cisplatin is the main active agent6 not included in the EMA/CO schedule, it is rational to include it in a salvage schedule in patients whose disease has become resistant to EMA/CO. Separating the nephrotoxic agent cisplatin (in EP) from the renally excreted drug methotrexate (in EMA) reduces the inherent problems involved in combining these agents in the same schedule. It is widely recognized that there are a series of adverse prognostic variables in terms of survival for patients with high-risk GTT. These include brain and liver metastases, interval from antecedent pregnancy greater than 12 months, and antecedent term delivery. A case could be made for using EP/EMA as the primary treatment in patients with particularly high-risk disease, and this would certainly include patients with established liver metastases. Our initial experience in patients with metastatic PSTT presenting less than 2 years from their last known pregnancy are one group of patients who may gain from starting their therapy with EP/EMA. This limited experience needs to be enlarged. Patients presenting with metastatic PSTT seem to fall into two groups, those whose interval from the last known antecedent pregnancy is less than 2 years and those whose interval is greater than or equal to 2 years. In the small number of patients that have been treated with the EP/EMA schedule, it seems that patients with metastatic disease whose interval from the last antecedent pregnancy is less than 2 years will respond well and remain in remission. Clearly, patients presenting with metastatic disease and an interval of greater than 2 years need novel alternative therapies. Comparing these results with the earlier patients with PSTT who were treated with the EMA/CO schedule, the survival was 13 (76%) out of 17 patients. The four deaths were in patients whose interval from the antecedent pregnancy was greater than 2 years. In those patients whose hCG was high enough to assess response to EMA/CO, five (42%) out of 12 patients responded, and hysterectomy was the critical factor in achieving complete remission in six (86%) out of seven patients who failed to respond to EMA/CO. Surgery clearly has a role in patients whose disease has relapsed or has demonstrated evidence of drug resistance (normally to the EMA/CO schedule). Twice-weekly serum hCG estimations provide a sensitive monitor of the impact of each therapy used, and combining the hCG response with the patient outcome retrospectively, we identified that in five patients (23%) the surgery clearly contributed to a sustained remission (Table 3). However, in seven patients (32%) the effect of surgery could not be clearly assessed and in 10 patients (45%) did not contribute to outcome. It is possible that selection of sites for surgery could be made more precise by introducing 18F-fluorodeoxyglucose positron emission tomography scanning7,8 or 131I-anti-hCG scanning9 as a routine preoperatively. Although almost half the patients did not clearly benefit from the operation, we would like to emphasize the importance of salvage surgery in this group of patients. Our results are in agreement with other series of patients whose surgery clearly played a significant role in achieving complete remissions in selected patients.10-13 With the excellent outcome for the majority of patients with GTT, only a small number of patients become available for the evaluation of new treatments. A number of new anticancer agents have not yet been fully evaluated in the management of GTT, including paclitaxel, docetaxel, gemcitabine, and temozolomide. Paclitaxel has been shown to have activity in patients with germ cell tumors that have failed prior therapy.14 There are preliminary case reports using paclitaxel in GTT; Jones et al15 reported two patients with GTT who responded to paclitaxel therapy, and one of these two patients remains alive and in remission. In a further report from the M.D. Anderson Cancer Center, a patient receiving high-dose paclitaxel (250 mg/m2 repeated every 3 weeks) remains in remission.16 The use of high-dose chemotherapy with autologous bone marrow support has so far not been fully evaluated in patients with GTT. Up to now, the occasional patient treated with high-dose chemotherapy has usually had multiple prior forms of chemotherapy, and clearly patient selection is important because it is widely recognized that patients with completely refractory disease to standard therapy will do poorly on high-dose chemotherapy. We know from experience in patients with refractory germ cell tumors that patients whose disease is still sensitive to standard agents, usually including cisplatin, are the patients that stay in remission.17 There have been two case reports of sustained remissions in patients with GTT given high-dose chemotherapy; one patient was treated with cyclophosphamide, etoposide, and melphalan, and the other patient was treated with ifosfamide, carboplatin, and etoposide.18,19 The results presented here show that the EP/EMA schedule is a highly effective salvage regimen when combined with surgery in selected cases in patients with GTT whose disease is refractory to or who have relapsed after EMA/CO chemotherapy. EP/EMA chemotherapy should also be considered in the primary treatment of patients with metastatic PSTT.
The Choriocarcinoma Service is funded by the National Specialist Commissioning Advisory Group of the Department of Health, London, United Kingdom.
1. Bower M, Newlands ES, Holden L, et al: EMA/CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide, vincristine) for high-risk gestational trophoblastic tumours: Results from a cohort of 272 patients. J Clin Oncol 15:2636-2643, 1997 2. Fisher RA, Paradinas FJ, Newlands ES, et al: Genetic evidence that placental site trophoblastic tumours can originate from a hydatidiform mole or a normal conceptus. Br J Cancer 65:355-358, 1992[Medline] 3. Bower M, Paradinas FJ, Fisher RA, et al: Placental site trophoblastic tumour: Molecular analysis and clinical experience. Clin Cancer Res 2:897-902, 1996[Abstract] 4. Rustin GJS, Newlands ES, Lutz J-M, et al: Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumours (GTT) increases the incidence of second tumours. Clin Oncol 14:2769-2773, 1996 5. Bower M, Rustin GJS, Newlands ES, et al: Chemotherapy for gestational trophoblastic tumours hastens menopause by 3 years. Cancer 34:1204-1207, 1998 6. Newlands ES: New chemotherapeutic agents in the management of gestational trophoblastic disease. Semin Oncol 9:239-243, 1982[Medline] 7. Lewis P, Griffin S, Marsden P, et al: Whole-body 18F-fluorodeoxyglucose positron emission tomography in preoperative evaluation of lung cancer. Lancet 344:1265-1266, 1994[Medline]
8.
Frohlich A, Diederichs CG, Staib L, et al: Detection of liver metastases from pancreatic cancer using FDG PET. J Nucl Med 40:250-255, 1999 9. Begent RHJ, Bagshawe KD, Green AJ, et al: The clinical value of imaging with antibody to human chorionic gonadotrophin in the detection of residual choriocarcinoma. Br J Cancer 55:657-660, 1987[Medline] 10. Mutch DG, Soper JT, Babcock CJ: Recurrent gestational trophoblastic disease. Cancer 66:978-982, 1990[Medline] 11. Soper JT: Surgical therapy for gestational trophoblastic disease. J Reprod Med 39:168-174, 1994[Medline] 12. Jones WB, Wolchok J, Lewis JL Jr: The role of surgery in the management of gestational trophoblastic disease. Int J Gynaecol Cancer 6:261-266, 1996 13. Lurain JR: Management of high-risk gestational trophoblastic disease. J Reprod Med 43:44-52, 1998 [Medline] 14. Motzer RJ, Bajorin DF, Schwartz LH, et al: Phase II trial of paclitaxel shows antitumor activity in patients with previously treated germ cell tumors. J Clin Oncol 21:2277-2283, 1994 15. Jones WB, Schneider J, Shapiro F, et al: Treatment of resistant gestational choriocarcinoma with Taxol: A report of two cases. Gynecol Oncol 61:126-130, 1996[Medline] 16. Termrungruanglert W, Kudelka AP, Piamsomboon S, et al: Remission of refractory gestational trophoblastic disease with high dose paclitaxel. Anticancer Drugs 7:503-506, 1996[Medline] 17. Beyer J, Kramar A, Mandanas R, et al: High-dose chemotherapy as salvage treatment in germ cell tumours: A multivariate analysis of prognostic variables. Oncol 14:2638-2645, 1996 18. Giacolone PL, Benos P, Donnadio D, et al: High-dose chemotherapy with autologous bone marrow transplantation for refractory metastatic gestational trophoblastic disease. Gynecol Oncol 58:383-385, 1995[Medline] 19. van Besien K, Verschraegen C, Mehra R, et al: Complete remission of refractory gestational trophoblastic disease with brain metastases treated with multicycle ifosfamide, carboplatin and etoposide (ICE) and stem cell rescue. Gynecol Oncol 65:366-369, 1997[Medline] Submitted June 4, 1999; accepted October 29, 1999. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
