It is well known that antecedent term delivery and metastasis to sites other than the lungs and vagina are high risk factors for patients with gestational trophoblastic neoplasia. Here we report on a patient with choriocarcinoma who presented with brain and lung metastases after term delivery and was treated by EMA-CO chemotherapy. A 31-year-old woman delivered a healthy infant at term. Frequent episodes of hemoptysis occurred beginning 3 weeks after the delivery. On admission to our hospital, she had lesions in the uterus, lungs and brain as well as motor aphasia and hemiplagia. The pretreatment beta-hCG level was 21,000 ng/ml and the WHO score was 16 (high-risk group). The EMA-CO regimen was administrated as first-line chemotherapy and the patient achieved complete remission after 7 courses. Treatment was terminated after 11 courses and maintained with etoposide (25 mg/day) for 6 months. The patient has remained in complete remission for more than 16 years without other adjuvant therapies. We believe that EMA-CO can currently be considered the regimen of first choice for most high-risk patients with gestational trophoblastic neoplasia in view of its effectiveness and excellent tolerability.</p

Hiramatsu, Yuji

Ishida, Makoto

Masuyama, Hisashi

Murakami, Kazuharu

Sakurai, Masaru

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 59, Issue 5 2005 Article 9OCTOBER 2005Term delivery choriocarcinoma patient withbrain and lung metastases successfully treatedby etoposide, methotrexate, actomycin D,cyclophosphamide and vincristine (EMA-CO)chemotherapy.Yuji Hiramatsu∗ Hisashi Masuyama† Makoto Ishida‡Kazuharu Murakami∗∗ Masaru Sakurai††∗Okayama University,†Okayama University,‡&#xFEFF;Hiroshima Red Cro Hospital & Atomic-bomb Survivors Hospital,∗∗&#xFEFF;Tamashima Central Hospital,††Tamashima Central Hospital,Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Term delivery choriocarcinoma patient withbrain and lung metastases successfully treatedby etoposide, methotrexate, actomycin D,cyclophosphamide and vincristine (EMA-CO)chemotherapy.∗Yuji Hiramatsu, Hisashi Masuyama, Makoto Ishida, Kazuharu Murakami, andMasaru SakuraiAbstractIt is well known that antecedent term delivery and metastasis to sites other than the lungsand vagina are high risk factors for patients with gestational trophoblastic neoplasia. Here wereport on a patient with choriocarcinoma who presented with brain and lung metastases after termdelivery and was treated by EMA-CO chemotherapy. A 31-year-old woman delivered a healthyinfant at term. Frequent episodes of hemoptysis occurred beginning 3 weeks after the delivery. Onadmission to our hospital, she had lesions in the uterus, lungs and brain as well as motor aphasiaand hemiplagia. The pretreatment beta-hCG level was 21,000 ng/ml and the WHO score was 16(high-risk group). The EMA-CO regimen was administrated as first-line chemotherapy and thepatient achieved complete remission after 7 courses. Treatment was terminated after 11 coursesand maintained with etoposide (25 mg/day) for 6 months. The patient has remained in completeremission for more than 16 years without other adjuvant therapies. We believe that EMA-CO cancurrently be considered the regimen of first choice for most high-risk patients with gestationaltrophoblastic neoplasia in view of its effectiveness and excellent tolerability.KEYWORDS: choriocarcinoma, term delivery, EMA-CO chemotherapy, metastasis∗PMID: 16286962 [PubMed - indexed for MEDLINE]Copyright (C) OKAYAMA UNIVERSITY MEDICAL SCHOOL Term Delivery Choriocarcinoma Patient with Brain and Lung Metastases Successfully Treated by Etoposide,Methotrexate, Actomycin D, Cyclophosphamide and Vincristine (EMA-CO)Chemotherapy Yuji Hiramatsu??, Hisashi Masuyama?, Makoto Ishida?,Kazuharu Murakami?, and Masaru Sakurai??Department of Obstetrics& Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan,?Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima 730-0052, Japan, and?Tamashima Central Hospital, Kurashiki, Okayama 713-8122, Japan It is well known that antecedent term delivery and metastasis to sites other than the lungs and vagina are high risk factors for patients with gestational trophoblastic neoplasia. Here we report on a patient with choriocarcinoma who presented with brain and lung metastases after term delivery and was treated by EMA-CO chemotherapy. A 31-year-old woman delivered a healthy infant at term. Frequent episodes of hemoptysis occurred beginning 3 weeks after the delivery. On admission to our hospital, she had lesions in the uterus, lungs and brain as well as motor aphasia and hemiplagia. The pretreatmentβ-hCG level was 21,000 ng/ml and the WHO score was 16(high-risk group). The EMA-CO regimen was administrated as ﬁrst-line chemotherapy and the patient achieved complete remission after 7 courses. Treatment was terminated after 11 courses and maintained with etoposide (25 mg/day) for 6 months. The patient has remained in complete remission for more than 16 years without other adjuvant therapies. We believe that EMA-CO can currently be considered the regimen of ﬁrst choice for most high-risk patients with gestational trophoblastic neoplasia in view of its eﬀectiveness and excellent tolerability.Key words:choriocarcinoma, term delivery, EMA-CO chemotherapy, metastasis R ecently, gestational trophoblastic neoplasia has become the most curable of gynecological malig-nancies for several reasons. DiSaia and Cresman［1］summarized these reasons as follows:1) a sensitive marker is produced by the tumor i.e., human chorionic gonadotropin (hCG), and the amount of hormone produced is directly related to the number of viable tumor cells;2) this tumor is extremely sensitive to various chemotherapy agents;3)risk factors for recurrence are known, allowing treatment to be individualized;and 4)the aggressive use of multiple treatment modalities, such as single-and multiple-agent chemotherapy regimens,radiation, and surgery.Nevertheless, the failure rate among “high-risk”patients is still too high despite the use of aggressive multi-drug regimens［2-4］. These patients usually have Received March 24,2005;accepted May 11,2005.?Corresponding author.Phone:＋81-86-235-7317;Fax:＋81-86-225-9570 E-mail:kiki1063＠cc.okayama-u.ac.jp(Y.Hiramatsu)http://www.lib.okayama-u.ac.jp/www/acta/Acta Med. Okayama, 2005 Vol. 59 , No. 5, pp. 235-238 Case Report Copyright?ｃ2005by Okayama University Medical School.1Hiramatsu et al.: Term delivery choriocarcinoma patient with brain and lungProduced by The Berkeley Electronic Press, 2005multiple metastases(including brain and liver), high hCG levels, and term delivery.Here, we report a case of choriocarcinoma presenting after term delivery with more than 16 years of survival in complete remission. The patient initially had lung and brain metastases with motor aphasia and hemiplagia, and was treated by etoposide, methotrexate, actomycin D,cyclophosphamide and vincristine(EMA-CO)regimen.Case Report A 31-year-old woman(gravida 3, para 2)who had no history of chorionic disease delivered a 3,265 g male infant on August 8, 1988. The placenta was macroscopically normal. The patient continued to have daily slight vaginal bleeding after delivery and frequently episodes of hemoptysis which began at the end of August. A physi-cian detected coin lesions in both lungs by radiographic examination. She had generalized convulsions on Septem-ber 30. A computed tomographic(CT)scan of the brain revealed a lesion in the left frontal lobe;motor aphasia subsequently developed. Further examination revealed that the urinary hCG level was over 300,000 IU/l and the serum hCG level was 497,000 IU/l. The patient was referred to the Okayama University Hospital for further examination and treatment.On admission, physical examination revealed right hemiplagia, motor aphasia, and genital bleeding, and the uterus was the size of a 10-week pregnancy. The pretreat-ment serum hCG level was 866,000 IU/l, the serumβ-hCG level was 21,000 IU/l, and the urinary hCG level was 512,000 IU/l. Ultrasonographic examination detect-ed an intrauterine mass of 6 cm in diameter(Fig. 1). A chest X-ray(Fig. 2A)and thoracic CT scan detected scattered metastatic lesions in the bilateral lungs, and the brain CT examination revealed a large metastasis in the left frontal lobe(Fig. 2B). According to the modiﬁcation of Bagshawe’s scoring system by the World Health Organization(WHO)the patient scored 16, placing her in the high risk group(≧8)and the FIGO stage was IVa.Therefore, the EMA-CO regimen of Bagshawe(Table 1)［5］was used as ﬁrst-line chemotherapy for this patient.With the ﬁrst course of treatment, the patient suﬀered nausea, vomiting, and myelosupression. However, few Hiramatsu et al. Acta Med. Okayama Vol. 59 , No. 5 236 Fig.1  Ultrasonography at admission. Longitudinal lower abdomi-nal ultrasonographic examination showed an intrauterine mass about 6 cm in diameter with mixed echogenecity.Fig.2  Chest X-ray ﬁlm and brain CT scan at admission. There is a large mass around the right hilar region and multiple coin lesions in the lung ﬁelds (A). A large metastatic lesion is seen in the left frontal lobe(B).2Acta Medica Okayama, Vol. 59 [2005], Iss. 5, Art. 9http://escholarship.lib.okayama-u.ac.jp/amo/vol59/iss5/9side eﬀects were noted after the ﬁrst course and the tumors rapidly became smaller. Approximately 4 months after commencing chemotherapy, the patient achieved complete remission, as determined by 3 negative weeklyβ-hCG assays. At this time, she had received 7 courses of EMA-CO chemotherapy. Five consolidation courses were performed after complete remission and treatment was terminated after a total 11 courses (6 months after presentation). The chest X-ray and brain CT scan obtained after 10 courses are shown in Fig. 3. After 11 courses of EMA-CO chemotherapy, the patient was maintained with etoposide (25 mg/day) for 6 months.The patient has now been in complete remission for more than 16 years.Discussion Choriocarcinoma is one of the most rapidly invasive and widely metastasizing malignancies, and its incidence is 1 per 150,000-160,000 normal pregnancies. The prognosis for patients with metastatic choriocarcinoma following term gestation is generally poor［3］. The more extensive spread of disease and the decreased responsive-ness to chemotherapy following term gestation are pos-tulated to be due to a change in the host immune response and/or a delayed diagnosis. Although vaginal bleeding is the most common presenting symptom of this carcinoma,it can occur at any time during pregnancy and the puerperium for a variety of reasons. Thus, the disease is generally widely disseminated at the time of diagnosis,and there is with a large tumor volume and a markedly elevated hCG titer.There are several factors that adversely inﬂuence the response to treatment in patients with metastatic chor-iocarcinoma. Lurain et al.［3］proposed the following 6 High-risk Choriocarcinoma after Term Delivery October 2005 Table 1  EMA-CO Regimen Course 1(EMA)Day 1  Etoposide;100 mg/m?, i.v. infusion in 200 ml of saline over 30 min Actinomycin D;0.5 mg, i.v. push Methotrexate;100 mg/m?, i.v. push followed by a 200 mg/m?, i.v, infusion over 12 h Day 2  Etoposide;100 mg/m?, i.v. infusion in 200 ml of saline over 30 min Actinomycin D;0.5 mg, i.v. push Folic acid;15 mg, i.m. or orally every 12 h for 4 days beginning 24 h after start Course 2(CO)Day 8  Vincristine;1.0 mg/m?, i.v. push Cytoxan;600 mg/m?, i.v. in saline This regimen consists of 2 courses:1)course 1 is given on days 1 and 2, 2)course 2 is given on day 8. These courses can usually be given on day 1 and 2, 8, 15 and 16, 22 etc., and the intervals should not be extended without course.Fig.3  The X-ray and brain CT scan after 10 courses of EMA-CO chemotherapy. The X-ray(A)shows only atelectasis of the right lung because of long-term drainage removing ﬂuid due to tumor necrosis.No metastatic lesions were found at this time. The brain CT scan(B)shows a very small left frontal lesion and that appears to be calciﬁcated.2373Hiramatsu et al.: Term delivery choriocarcinoma patient with brain and lungProduced by The Berkeley Electronic Press, 2005 prognostic factors from a literature review:1) a clinicopathological diagnosis of choriocarcinoma;2)more than 4 months from the antecedent pregnancy to treat-ment;3)a pretreatment hCG titer＞100,000 IU/L;4)metastasis to sites other than the lungs and vagina;5)antecedent term gestation;and 6)previous failed therapy.It has also been reported that patients with metastatic high-risk gestational trophoblastic disease following term pregnancy have a 50.0 remission rate(11/22)compared to a 75.0  remission rate (18/24) for women with metastatic choriocarcinoma following other types of preg-nancy［3］.The number of high-risk factors present had a very signiﬁcant eﬀect on the response to treatment. If there were only 1 or 2 of the high-risk factors outlined above,the survival rate was 74 , in contrast to only 27  for patients with 3 or 4 factors［3］. The patient in this case had 3 high-risk factors and thus presented a very high-risk case, but she has survived for more than 16 years in complete remission.Several multi-drug chemotherapy schedules have been reported, including MAC(methotraxate, actinomycin D,and cyclophosphamide), CHAMOCA, and EMA-CO［5］. The cure rate achieved with the MAC regimen was reported to be 51  for primary treatment and 30  for secondary treatment［3］. The CHAMOCA regimen was reported to produce complete clinical remission in patients who were resistant to MAC therapy, but it is a highly toxic protocol. Bolis et al.［6］reported that the overall response rate of EMA-CO was 86  with 81  of subjects surviving a median observation time of 32 months, while the survival rate of high-risk patients was 88  with 76  having no evidence of disease. In addi-tion, they reported that the remission rate for second-line treatment by the EMA-CO regimen was 64 , which is higher than the rates achieved using other regimens such as MAC or CHAMOCA.The toxicity of EMA-CO regimen is acceptable and less than that of the CHAMOCA or MAC regimens.Our patient was treated with only EMA-CO therapy and maintenance etoposide. Etoposide shows promise not only as ﬁrst-line therapy, but also in treating patients who have become resistant to conventional therapy［1］.Recently, it was reported that taxanes have also been eﬀective with relapsed high-risk trophoblastic disease［7,8］.In gestational trophoblastic disease, it is necessary to continue treatment even after a negative hCG titer is achieved. As is well known, a minimum of 10?viable tumor cells are necessary to produce a detectableβ-hCG titer, so most authors advocate at least three consolida-tion courses. Moreover, relapse sometimes occurs after several years of complete remission. The likelihood of relapse depends on individual risk factors;however, the overall relapse rate for EMA-CO therapy was reported to be 11  by Newland et al.［4］and 19.0  by Bolis et al.［6］.Accordingly, adjuvant therapy is given to most high-risk patients. Cerebral metastasis may be treated simulta-neously with whole-brain irradiation of 30 to 40 Gy,while hysterectomy and thoracotomy are used for the excision of resistant tumor foci［1, 3］.It is well known that secondary chemotherapy yields poor results in patients with gestational trophoblastic disease［3］, so is very important to choose the most eﬀective regimen for treating high risk metastatic chor-iocarcinoma from the start. We believe that currently the EMA-CO regimen should be considered the ﬁrst-line for most high-risk patients with gestational trophoblastic disease in view of the good response rate it has achieved and its excellent tolerability.References 1. DiSaia PJ and Cresman WT:Gestational trophoblastic neoplasma;in Clinical Gynecologic Oncology, 4 th Ed, Mosby Year Book, St. Louis(1993)pp 210-237.2. Begent RH and Bagshawe KD:The management of high-risk chor-iocarcinoma. Semin Oncol(1982)9:198-207.3. Lurain JR and Brewer JI:Treatment of high-risk gestational trophob-lastic disease with methotrexate, actinomycin D, and cyclophos-phamide chemotherapy. Obstet Gynecol(1985)65:830-836.4. Newlands ES, Bagshawe KD, Begent RH, Rustin GJ, Holden L and Dent J:Developments in chemotherapy for medium-and high-risk patients with gestational trophoblastic tumors (1979-1984). Br J Obstet Gynecol(1986)93:63-69.5. Bagshawe KD:Treatment of high-risk choriocarcinoma. J Reprod Med(1984)29:813-820.6. Bolis G, Bonazzi C, Landoni F, Mangili G, Vergadoro F, Zanaboni F and Mangioni C:EMA/CO regimen in high-risk gestational trophoblas-tic tumor(GTT). Gynecol Oncol(1988)31:439-444.7. Joshua AM, Carter JR and Beale P:The use of taxanes in choriocar-cinoma;a case report and review of the literature. Gynecol Oncol(2004)94:581-583.8. Osborne R, Covens A, Merchandani DE and Gerulath A:Successful salvage of relapsed high-risk gestational trophoblastic neoplasia patients using a novel paclitaxel-containing doublet. J Reprod Med(2004)49:655-661.Hiramatsu et al. Acta Med. Okayama Vol. 59 , No. 5 2384Acta Medica Okayama, Vol. 59 [2005], Iss. 5, Art. 9http://escholarship.lib.okayama-u.ac.jp/amo/vol59/iss5/9

Term delivery choriocarcinoma patient with brain and lung metastases successfully treated by etoposide, methotrexate, actomycin D, cyclophosphamide and vincristine (EMA-CO) chemotherapy.

Term delivery choriocarcinoma patient with brain and lung metastases successfully treated by etoposide, methotrexate, actomycin D, cyclophosphamide and vincristine (EMA-CO) chemotherapy.

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