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Choriocarcinoma is a malignant trophoblastic tumour usually of placental origin. It is characterized by early metastasis to the brain and lungs. With early detection, it has a better prognosis with treatment. We report a case of 18 years female at 26 weeks of gestation in her third pregnancy who had a history of treatment for metastatic gestational trophoblastic neoplasm with chemotherapy and radiotherapy two years back. Therefore, she was managed as a case of recurrent choriocarcinoma with brain metastasis with chemotherapy (etoposide and cisplatin with etoposide, methotrexate, and dactinomycin) and was responsive. Her symptoms resolved and β-human chorionic gonadotropin dropped to normal value (<2.39 mIU/ml) which has shown that timely diagnosis and management can be vital for the successful treatment of brain metastasis., Keywords: chemotherapy; choriocarcinoma; metastasis; recurrence.

Background: Although most patients at high risk of Gestational Trophoblastic Neoplasia (GTN) respond to standard treatments, there is a group of patients that will die because of it. The use of new single or combination drugs in this population has become a priority., Case Report: We present the case of a relapsed high risk choriocarcinoma patient who did not respond to several chemotherapy treatments nor to PET guided salvage surgery. Because of treatment toxicity, the patient was started on Capecitabine, with which she achieved total remission, still present after 15 months of starting treatment., Conclusions: The use of Capecitabine and the multidisciplinary management of this population should be taken into account for patients at high risk of relapsing to EP/EMA because of its efficacy and little toxicity.

Objective: Hydatidiform mole can be classified by histopathologic characteristics and by genetic constitutions and most complete moles are diploid, whereas most partial moles are triploid. We investigated the concordance between these two classifications, characterized moles with conflicting classifications, and compared the ability of the two classifications to discriminate between patients with and without a substantial risk of persistent trophoblastic disease., Methods: 294 cases of consecutively collected hydropic placentas clinically suspected of hydatidiform mole made the basis of this retrospective study. We determined the ploidy and reviewed the original histopathologic material in all cases. Data on possible chemotherapy were collected for each patient., Results: 270 of the conceptuses were histopathologically classified as hydatidiform mole. Among the 24 conceptuses classified as non-molar miscarriage, 20 were triploids, 2 were diploid androgenetic and 2 were diploid biparental. In 23% of the conceptuses, the histopathologic and genetic classifications were conflicting. 5% of the patients with hydropic placentas classified as partial mole encountered persistent trophoblastic disease; however, the genome was diploid in all these moles. None of 131 patients with a triploid hydropic gestation encountered persistent trophoblastic disease., Conclusion: As full concordance between the histopathologic and the genetic classifications was not found, we believe that features beyond the genetic constitution influence the development of morphologic features in hydatidiform moles. We recommend that gestations suspected of hydatidiform mole are subjected to histopathologic examination. If hydatidiform change and trophoblastic hyperplasia are identified, the ploidy should be used to identify patients with a high risk of persistent trophoblastic disease.

Objective: To investigate the indication of lung lobectomy in patients of malignant trophoblastic tumor with lung metastasis., Methods: Data on a total of 629 cases of malignant trophoblastic tumor of stage III-IV in Peking Union Medical College Hospital from 1990 to 2003 were reviewed. Ninety-five cases including those that underwent lung lobectomy and cases with normal level of serum human chorionic gonadotropin-beta subunit (beta-hCG, < 2 IU/L) and residual pulmonary nodules after chemotherapy were selected and studied., Results: Lung lobectomies were performed on six cases of invasive mole with lung metastasis and the pathological results were all necrotic nodules;another 35 cases of invasive mole with normal level of serum beta-hCG but residual pulmonary nodules after chemotherapy have been followed up for 6 months to 11 years and all were stable of diseases (SD). Lung lobectomies were performed on 29 cases of choriocarcinoma with lung metastasis. Among them, there were 17 cases whose pathological results were hemorrhage and necrotic tissue without trophoblastic cells (negative pathological results), while trophoblastic cells could still be detected in 12 cases of resected lung specimens (positive pathological results). Twenty-five cases of choriocarcinoma with normal serum beta-hCG but residual pulmonary nodules after chemotherapy were followed up, five cases had progress of disease (PD) and 20 were SD. There were no significant differences of age, stage and the last pregnancy between the positive and negative pathological results, SD and PD groups, respectively. However, the number of chemotherapeutic courses for decreasing beta-hCG from 10 IU/L to 2 IU/L and the total courses in the group of positive pathological results and PD group were significantly more than that of negative pathological results group and SD group (P = 0.01, P = 0.001)., Conclusions: For invasive mole, lung metastasis can be successfully treated by chemotherapy alone. Patients with residual pulmonary nodules but normal serum beta-hCG after chemotherapy can be followed up and spared lung lobectomy. For choriocarcinoma, slowly decreasing of beta-hCG from 10 IU/L to 2 IU/L is a high risk for chemoresistance, and it is an indication for thoracotomy. Progression of disease after multiple chemotherapy courses should be treated with lung lobectomy.

Objective: To assess malignant trophoblastic neoplasia with the standards of the clinical stage and prognostic factor scoring system., Methods: Through assessing the high-risk factors except clinical stages for 223 patients before treatment according to International Federation of Gynecology and Obstetrics (FIGO) scoring system published in 2000, appropriate treatments were selected for the different patients., Results: Forty-three of 78 cases of choriocarcinomas were with high-risk factors, the other 35 cases were with low-risk factors; 7 of 145 cases of invasive moles were with high-risk factors and the others were with low-risk factors. The primary chemotherapy principle was that one agent was used for those patients with low-risk factors and two or multiple-agents were used for those patients with high-risk factors. Among all patients, the one-year, three-year and five-year survival rates were 98.6%, 98.1% and 97.1% respectively. No patient died of drug toxicity or complication., Conclusion: Selection of treatment approaches according to the prognostic assessment of malignant trophoblastic neoplasia could lead to promising survival rate with no uncurable complication and toxic effects.

Neutral endopeptidase 24.11 (NEP) is known to regulate cellular functions by degrading several bioactive peptides, such as gonadotropin-releasing hormone (GnRH). The present study was performed to clarify the mechanisms of NEP expression by GnRH in human choriocarcinoma (BeWo) cells. GnRH increased NEP expression and enzyme activity in a dose- and time-dependent manner in BeWo cells. The phosphorylation levels of protein kinase C (PKC) delta, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK1 and 2) were enhanced after 10 min exposure of 10(-6)m GnRH. The effect of GnRH on both NEP expression and enzyme activity was completely inhibited by inhibitors of PKC, PKC delta, and p38MAPK. Cell number was reduced by 54.4 per cent of the control by culture with 10(-6)m GnRH for 24 h. However, phosphoramidon, a NEP specific inhibitor, inhibited antiproliferative effect of GnRH and reverted to the control level. In conclusion, GnRH induces NEP expression by PKC delta and p38MAPK, and increased NEP expression may be involved in antiproliferative effect in BeWo cells.

Background: Post-termchoriocarcinoma is a rare complication of pregnancy. The presence of epithelioid trophoblastic elements may lead to the persistence of locally invasive disease which is unresponsive to multiagent chemotherapy. Relapse is associated with an estimated mortality rate of 30%., Case: We present a case of Stage IC post-term choriocarcinoma and epithelioid trophoblastic tumor. While the metastatic sites in the lungs responded to multiagent chemotherapy, a hysterectomy was required to treat persistent disease in the uterus. The patient relapsed within 4 months of completion of chemotherapy. Relapse was treated with high-dose chemotherapy with peripheral stem cell support. The patient is alive with no evidence of disease 23 months posttransplant., Conclusions: The application of multimodality treatment and high-dose chemotherapy resulted in a successful outcome for this patient, indicating a potential role for high-dose therapy in patients who suffer a relapse of choriocarcinoma.

Objective: The aim of this study was to evaluate clinical manifestations, management options, and prognosis for women presenting with gestational trophoblastic tumors with vaginal metastasis., Method: Fifty-one patients with vaginal metastases were analyzed retrospectively between January 1985 and September 2000. Vaginal metastasis were documented by physical examination and tissue biopsy., Results: The incidence of vaginal metastasis in choriocarcinoma and invasive mole was 8.6 and 4.1%, respectively. The metastatic tumors were mostly located in the anterior wall of the lower part of vagina. Eighteen patients presented with hemorrhage and rupture. All patients were treated with 5-Fu combined chemotherapy. Vaginal packing was employed to stop bleeding in 16 patients. Three of them received selective angiographic embolization. Vaginal tumors disappeared after chemotherapy. Forty-four patients with complete remission were followed up periodically without evidence of recurrence., Conclusions: Large or multiple vaginal metastases place the patients at high risk for significant hemorrhage. 5-Fu combined chemotherapy is still a reliable method for treating vaginal metastases. Angiographic embolization is emerging as a successful procedure to control the severe hemorrhage of vaginal tumors.

Objective: The aim of this study was to explore the risk of pregnancy of patients who conceived within 1 year after successful chemotherapy for gestational trophoblastic tumor (GTT)., Methods: From 1966 to 1996, 22 patients who conceived within 1 year after chemotherapy were followed up and analyzed retrospectively., Results: Among 22 patients, 9 had term deliveries and 1 had a premature birth, 6 had induced abortion at the patient's request, and 6 had therapeutic abortion because of various indications such as repeated hydatidiform mole (1 case), intrauterine death (1 case), inevitable abortion (1 case), and threatened abortion (3 cases). The fetal loss rate was 27.1% (6/22). The incidence rate of gestational trophoblastic disease (GTD) was 9.1% (2/22). The incidence rate of GTT was 4.5% (1/22). The average interval between completion of chemotherapy and pregnancy was 10.25 months in the group of term pregnancies and 5.86 months in that of fetal loss (P < 0.05), indicating that the longer the interval, the lesser the risk of GTD., Conclusion: The results suggest that contraception for 1 year is necessary in patients with GTT after successful chemotherapy. However, in the case of a patient who conceives within 1 year, it is not necessary to terminate pregnancy, but the pregnancy must be carefully watched., (Copyright 2001 Academic Press.)

Between 1986-1998 in University Oncology Gynecology Department in Poznan, Poland were treated 23 women with choriocarcinoma. Despite of intensive chemotherapy 3 women were dead. In the report we present the history of this choriocarcinomas making effect to answer why our therapy was ineffective.

Objective: To determine the effect of chemotherapy on patients who wished to conceive after successful treatment of gestational trophoblastic disease. Patients-During a 12-year period (1984-1995), 90 patients with gestational trophoblastic tumor at Jordan University Hospital received repeated courses of chemotherapy; 85 patients are in continued remission (42 invasive mole and 43 choriocarcinoma). Fifty-five patients wished to conceive. Main outcome measures-Pregnancy, live births., Results: Forty-two patients (76%) achieved pregnancy, resulting in 20 pregnancies and 94 viable babies., Conclusions: Chemotherapy is very effective in the cure of gestational trophoblastic tumors. Return of fertility compares favorably with the general population of the same reproductive age. There appears to be no increase in fetal congenital malformations.

Objective: To determine the risk of pregnancy for patients who conceive within one year after successful chemotherapy for gestational trophoblastic tumor (GTT)., Methods: We followed up and analysed retrospectively 22 patients who conceived within one year after receiving chemotherapy for GTT from 1966 through 1996., Results: Of 22 patients, 9 had term delivery, 1 had premature birth, 6 requested induced abortion, and 6 experienced therapeutic abortion because of repeated hydatidiform mole (1 patient), intrauterine death (1), inevitable abortion (1), or threatened abortion (3). The fetal wastage rate was 27.3% (6/22). The incidence of gestational trophoblastic disease (GTD), including hydatidiform mole, was 9.1% (2/22). The incidence of GTT was 4.5%. The average interval between completion of chemotherapy and pregnancy was 9.78 months in the group of term pregnancy and 6.50 months in the group of fetal wastage (P < 0.05)., Conclusions: Patients conceiving within one year after successful chemotherapy for GTT are at higher risk for recurrence of GTD and fetal wastage. Therefore, patients with preserved fertility should practice contraception for at least one year after chemotherapy to get better pregnancy outcome.

We report a patient who developed metastatic gestational choriocarcinoma following delivery of a normal, healthy child that, however, was anemic and required blood transfusion. The patient developed secondary postpartum hemorrhage over a period of several weeks and required curettage and myometrial contractants to control the bleeding. At the time of diagnosis the patient had extensive pulmonary metastases and ultrasound showed full penetration of the myometrium by tumor. Immediately following the second course of chemotherapy with etoposide, methotrexate, and actinomycin D, alternating with cyclophosphamide and vincristine, the patient developed sepsis associated with a uteroperitoneal fistula and required hysterectomy. The sepsis was associated with disseminated intravascular coagulopathy and adult respiratory distress syndrome. However, the patient's tumor was exquisitely sensitive to chemotherapy and with good intensive care unit support and chemotherapy the survived without residual scar except for the loss of reproductive function. There are two lessons to be learned from these events: (1) The syndrome of secondary postpartum hemorrhage with a fetus that is anemic spells a diagnosis of choriocarcinoma; and (2) color Doppler flow vaginal ultrasound performed at the time of presentation of trophoblastic tumors may be useful to show full penetration of the myometrium by tumor which may be a warning of possible scar rupture in a subsequent pregnancy.

Chemotherapy may induce acute ovarian failure, but in women who retain gonadal function throughout chemotherapy, the late effects upon ovarian function are unknown. A retrospective controlled survey was performed to ascertain whether chemotherapy for gestational trophoblastic tumours (GTT) results in premature menopause. Questionnaires were sent to 1,489 women diagnosed between 1971 and 1990 with GTT, including 1089 who had received chemotherapy and 400 who had not received chemotherapy (controls). Responses were obtained from 972 chemotherapy-treated patients and 327 controls. 124 women were not evaluable for menopause date as they had undergone hysterectomy as part of the treatment for GTT or had developed permanent amenorrhoea during chemotherapy. Overall, 172 women reported that they were postmenopausal, including 157 women who had received chemotherapy. The median age at menopause for the evaluable population was 50 years (range 25-56 years). The age at menopause was significantly earlier in the treated arm (median 50, range 25-56 years) than in the controls (median 53, range 40-57 years) (logrank test chi 2 = 12.6, P = 0.0004). Menopause occurred significantly earlier in women treated with combination chemotherapy (median 49, range 25-56 years) compared with single agent methotrexate (median 51, range 25-56 years) (logrank test chi 2 = 8.3, P = 0.004). However, the age at completion of chemotherapy in the treated arm did not influence the age of menopause (proportional Hazards chi 2 = 1.99, P = 0.16). Chemotherapy for GTT induces menopause 3 years earlier than it occurs in women with GTT who do not receive chemotherapy. Although the difference is statistically significant, the magnitude is modest and most women can be reassured that neither fertility nor postmenopausal osteoporosis will be greatly affected.

The author engaged in the registration work and the clinical studies of trophoblastic disease over 20 years at Niigata University in Niigata prefecture, before transferring to University of the Ryukyus in Okinawa prefecture in 1992. In this paper, the following four topics are reviewed and discussed. 1) the registration data of trophoblastic disease in Niigata prefecture, 2) the treatment results of gestational chorio-carcinoma at the Niigata University Hospital, 3) a trial administration of Gn-RH analogue in patients with gestational choriocarcinoma to suppress secretion of hCG-like substance (hLS) which might cross-react anti-hCG antibodies in hCG immunoassay system, 4) the two rare cases of extrauterine gestational choriocarcinoma who were presented to the Ryukyus University Hospital.

Paclitaxel has been reported to inhibit proliferation and to promote differentiation of choriocarcinoma cells. We report a case of a patient with high risk trophoblastic disease who had remission with paclitaxel. The mechanisms of paclitaxel resistance are reviewed.

Although beta human chorionic gonadotrophin (beta-HCG) is a clinically-useful tumour marker in gestational trophoblastic neoplasia, there is limited information on how serum beta HCG regresses in molar pregnancy and choriocarcinoma during chemotherapy. The study included 41 patients who had been treated by single- and multidrug regimens, and decay curves for regression of beta HCG in the circulation in these patients were fitted to the data. Thirty-three patients achieved a biochemical remission ('cured') by first-line chemotherapy; this gave an overall efficacy rate of 80%. The beta HCG decay curves convey useful information of the chemosensitivity of the tumour, and may assist in determining the time required for treatment and earlier change in treatment for the chemoresistant tumour.

Objective: Evaluation of the treatment of patients with gestational trophoblastic disease., Setting: Academic Medical Centre, Amsterdam., Design: Descriptive., Method: Clinical data from all patients treated between 1983 and 1992 were collected., Results: Thirty-one patients were treated in this period. Eighteen patients had persistent trophoblast after a molar pregnancy, 7 had choriocarcinoma after a normal pregnancy and in 6 patients the obstetrical history was unclear. The initial treatment strategy was chosen on the basis of prognostic factors; low-risk patients received mono-chemotherapy (Methotrexate) and high-risk patients were treated with polychemotherapy (EMA/CO). In 15 cases adjuvant therapy was necessary. Complete remission was achieved in 29 patients, 2 patients died. The adverse effects of the chemotherapy were generally mild., Conclusion: Persistent trophoblastic disease has an unpredictable presentation and course. Therefore treatment should preferably be given in a reference centre.

This is the first report on the ATP cell viability assay as a chemosensitivity test system for gestational trophoblastic neoplasms (GTN). We obtained chemosensitivity profiles in two established trophoblastic cell lines and four fresh tumors. Ten drugs were tested in vitro in the two cell lines JAR and JEG-3. The IC50 values of the 10 chemotherapeutic agents tested were very similar for both cell lines. The three most active drugs in these cell lines were VP-16, paclitaxel and vincristine. This is the first report on the activity of paclitaxel in trophoblastic cell lines. We furthermore evaluated this assay for chemosensitivity testing in four fresh malignant GTN tumors: one placental site trophoblastic tumor, one chorocarcinoma and two invasive moles. The placental site trophoblastic tumor specimen revealed to be rather chemoresistant in vitro whereas the other three tumors were chemosensitive. From our cell line data we conclude that the ATP cell viability assay is a practicable assay for chemosensitivity testing of GTN cell lines and gives repeatable results. However, the value of this assay for fresh GTN chemosensitivity testing needs to be defined.

EMA/CO (etoposide-methotrexate-actinomycin D and Cytoxan-Oncovin) is an effective and well-tolerated chemotherapy regimen for the treatment of high-risk gestational trophoblastic disease. However, it is associated with significant neutropenia often requiring dose reductions and treatment delays. We describe the use of granulocyte colony-stimulating factor (G-CSF) in three patients in order to maintain the treatment schedule. A subcutaneous injection of 5 micrograms/kg/day was administered on Days 3-6 and 9-14 of each chemotherapy cycle. No patients had any adverse effects and all received full chemotherapy doses without any treatment delay. The addition of G-CSF to the EMA/CO regimen may benefit patients by achieving dose intensity in the treatment of high-risk gestational trophoblastic disease.

Interleukin 1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were assayed by 125I immunoradiometric assay in sera of 42 cases of vesicular mole (VM), 24 cases of choriocarcinoma and 23 normal pregnant women at their first trimester (controls). According to pathologic diagnosis and serial serum hCG beta assays, the cases with VM and choriocarcinoma were subdivided into remission and progressive tumor groups. The progressive tumor groups--both VM and choriocarcinoma--showed marked elevations of serum IL-1 beta, IL-6 and TNF alpha. For choriocarcinoma in remission this elevation was considerably less pronounced. The VM cases in remission had only a slight increase of the mean serum IL-6 value and none of the cases had elevated IL-1 beta or TNF values. These results may indicate that serum IL-1 beta and TNF-alpha assays are valuable biomarkers in the differential diagnosis of gestational trophoblastic disease (GTD). Moreover, normal values of these cytokines may rule out high-risk GTD, whereas markedly elevated values may indicate poor prognosis.

The paper reports on clinical experiences of treatment of 58 patients with Gestational Trophoblastic Tumors (GTT), collected between 1978 and 1991. According to the Bagshawe-Score, 29 patients were at low-risk, 10 patients were assigned to the high-risk category. Among 29 metastatic cases, 5 patients had brain metastasis. In 33 patients, treatment started from the time of diagnosis. In 25 cases, treatment was initiated at other hospitals and patients were referred only after various unsatisfactory treatment measures. Low-risk patients were mainly subjected to methotrexate and folinic acid. Patients at medium-risk received a sequential chemotherapy. In high-risk patients we preferred the CHA-MOCA- or the EMA/CO-regimen. Treatment was successful in 91.4% of patients including all cases of low- and medium-risk. Five patients with brain metastases received systemic chemotherapy combined with intrathecal application of methotrexate and radiotherapy. Three of them could be cured. Patients taken from other hospitals more often underwent primary hysterectomies prior to systemic chemotherapy (40% versus 3%) and more often developed drug resistant tumors due to inadequate primary treatment. Five patients (8.6%) died from their disease, but only one of them received primary treatment in our department. Thus, the outcome (1/33 compared to 4/25) was significantly better for patients treated primarily at specialized centers.

Surgery combined with chemotherapy was applied in 34 out of 178 patients (19.1%) with GTD during treatment at the Institute of Oncology in Warsaw in the years 1977-1989. This mode of treatment was used twice as often in patients with MTD (Metastatic Tumour Disease) (31.6%) than in those with NMTD (Non Metastatic Tumour Disease) (14.2%). All 34 patients, who were operated on, had hysterectomy and 3 of them thoracotomy also. The most common indication for surgery was the chemoresistance of the disease, which had been stated in 53% of all treated surgically. All the patients with NMTD and those with good prognosis MTD, treated by combination of chemotherapy and surgery were cured, which confirms the efficacy of adjuvant surgery in these groups of patients. The role of surgery in patients with high-risk MTD is limited because of disseminated disease, frequently seen in this group.

The haemodynamics of the uterine arteries and myometrium were assessed using Doppler ultrasound in forty consecutive patients requiring treatment for invasive mole and choriocarcinoma. The investigations were performed prior to the commencement of chemotherapy and the subjects followed prospectively. The Doppler waveforms from the uterine arteries were analysed using the pulsatility index. It was found that patients with a pulsatility index of 1.1 or less were significantly more likely to develop drug resistance than those with a higher value (P < 0.04). There was no significant association between the pulsatility index and metastatic disease or uterine bleeding. Five out of eight patients who developed drug resistance could have avoided initial inadequate treatment if the Doppler findings were included in the scoring system for selecting chemotherapy for these tumours. It can be concluded that assessment of the uterine arteries using the pulsatility index prior to the treatment of patients with invasive mole and choriocarcinoma is of help in predicting those who will develop drug resistance.

Objective: We attempted to evaluate the use of ifosfamide either alone or in combination in patients with refractory malignant gestational trophoblastic disease., Study Design: Our study comprised, in part, a phase II multiinstitutional trial of ifosfamide in refractory gynecologic malignancies and, in part, a review of institutional experience with ifosfamide in combination chemotherapy., Results: Single-agent ifosfamide produced a significant response in titer in one of two patients with refractory choriocarcinoma. Ifosfamide with etoposide and cisplatin (also known as VIP) resulted in significant response in human chorionic gonadotropin titers in three patients with highly refractory metastatic gestational trophoblastic disease and one cure in this group of patients., Conclusion: Ifosfamide has activity in refractory choriocarcinoma and, when combined with etoposide and cisplatin (VIP), may be curative.

All 1391 patients treated for gestational trophoblastic tumors (invasive mole and choriocarcinoma) at the John I. Brewer Trophoblastic Disease Center of Northwestern University between 1969 (when use of combination chemotherapy for initial treatment of high-risk disease came into general use) and 1988 were evaluated. Univariate and multivariate analyses were used to determine the relative importance of prognostic factors with respect to survival. The overall cure rate was 93% (363/391): 100% for 223 patients with nonmetastatic disease and 83% for 168 patients with metastatic disease. The only patients who died had a clinicopathologic diagnosis of metastatic choriocarcinoma. In addition to presence of metastasis (83% vs 100%, p less than 0.0001) and diagnosis of choriocarcinoma (67% vs 100%, p less than 0.0001), number of metastases (47% if greater than 8 vs 92% if less than or equal to 8, p less than 0.0001), metastases to sites other than the lung or vagina (52% vs 91%, p = 0.0002), and previous failed chemotherapy (46% vs 84%, p = 0.0014) demonstrated independent significant effects on survival in patients with metastatic disease. A Brewer score, based on our multivariate analysis of survival in patients with metastatic disease, provided predictability of outcome (likelihood ratio chi 2 statistic, chi 2 = 49.8) comparable to that with the World Health Organization score (chi 2 = 45.3), both of which, in turn, were better predictors than either the traditional Hammond clinical classification system (chi 2 = 34.4) or the International Federation of Gynecology and Obstetrics stage (chi 2 = 22.9).

This study investigates the physicochemical characteristics of human chorionic gonadotropin (hCG) in gestational trophoblastic disease (GTD), with special reference to the clinical course of chemotherapy and prognosis. In gel high performance liquid chromatography (HPLC), the hCG molecules from normal pregnancy and from the hydatidiform mole had the same molecular form as standard purified hCG, whereas hCG from choriocarcinoma was inconsistent in molecular form, containing molecules which are smaller, the same or larger than those of standard purified hCG. In two fatal choriocarcinoma patients, large hCG and large hCG alpha were found in the urine samples collected within one month prior to death. In a chromatofocusing study, the chromatofocusing pattern of hCG from GTD was acidic and similar to that of early pregnancy. The chromatofocusing patterns did not alter or were altered only slightly during the course of chemotherapy. In a Concanavalin A-Sepharose (Con A) chromatography study, the Con A binding shifted from low to high binding in patients with GTD who were responsive to chemotherapy. In summary, the molecular form, electric charge and Con A binding of hydatidiform mole hCG are similar to those of early pregnancy hCG and standard purified hCG, whereas the molecular form and Con A binding of choriocarcinoma are different from those of early pregnancy hCG and standard purified hCG. The presence of smaller or larger molecular forms of hCG may be an ominous sign, whereas the presence of high Con A binding may be a favorable sign. The chromatofocusing pattern seems to be unrelated to the clinical course of chemotherapy.

Twenty-eight patients with "poor prognosis" metastatic gestational trophoblastic disease were treated during a 17-year period. The primary treatment was combination chemotherapy with methotrexate, actinomycin D, and chlorambucil (MAC). Patients who failed to respond to this regimen were treated secondarily with other combinations. Adjuvant surgery and radiotherapy were used in selected cases. The overall remission rate was 89% (25 of 28): 71% for first-line treatment with MAC (20 of 28) and 62% for second-line treatment (five of eight). The response rate to MAC correlated well with the patient's score (modified World Health Organization [WHO] scoring system--1983). Seventeen patients treated with MAC had scores less than 12, and all of them achieved remission. Of 11 patients having scores of 12 or more, only three achieved remission with MAC (27%). Of the eight who did not, five achieved remission with other combinations (62%) and three died. No patient died because of chemotherapy toxicity. The WHO scoring system is a good index to select high-risk patients who need primary chemotherapy more aggressive than MAC.

From 1976 to 1988, 320 patients with gestational trophoblastic disease were treated in the Department of Obstetrics and Gynaecology, University of Hong Kong. Eighteen patients had vaginal metastases. The clinical features and behaviour of the disease were analysed. The prognosis depends mainly on the extent of the disease. Similar favourable response to chemotherapy was observed in low-risk patients with vaginal metastases.

Forty-nine women who had received chemotherapy for gestational trophoblastic disease subsequently became pregnant a total of 65 times. Of these 65 pregnancies, 42 (64.7%) terminated in term births, 4 (6.1%) in premature births, 1 (1.5%) in stillbirth, 8 (2.3%) in spontaneous abortion and 7 (10.8%) in elective abortion, while 3 patients (4.6%) had repeat molar pregnancies. No congenital malformations or obstetric complications were observed. Treatment of gestational trophoblastic disease with chemotherapy is compatible with the preservation of fertility and is not associated with any increase in congenital fetal malformations.

The experience of the Southern Regional Trophoblastic Disease Center includes 222 patients who were referred from January 1972 to October 1977. The initial tissue diagnosis was hydatidiform mole in 212 patients and choriocarcinoma in ten. There was spontaneous remission of 142 (69%) of the moles and one of the choriocarcinomas, and 77 patients developed persistent trophoblastic disease. Of these, 58 had no evidence of metastasis, and all achieved remission with single-drug therapy. Nineteen patients developed metastases; 13 were in the "good prognosis" category, and all achieved remission with single-drug therapy. Five (83%) of the six patients with metastases in the "poor prognosis" group achieved remission with triple chemotherapy; one died of her disease.

We investigated the incidence of second tumors after cytotoxic chemotherapy in 457 long-term survivors treated for choriocarcinoma or an invasive mole between 1958 and 1978. Treatment was given according to regular intermittent schedules and over a mean period of four months, with no maintenance. Methotrexate was given to all but two patients, and 261 (57 per cent) also received other cytotoxic drugs, most commonly dactinomycin, vincristine, cyclophosphamide, mercaptopurine, and 6-azauridine. After a mean period of 7.8 years since the beginning of treatment and a total of 3522 patient-years of risk, second neoplasms had developed in only two women (acute leukemia in one and carcinoma of the breast in the other). This figure is less than the number of cases of cancer that would have been expected (3.5) in this group and suggests that the use of methotrexate as chemotherapy for choriocarcinoma is not carcinogenic in the medium term.

Virtually 100% of patients with nonmetastatic and low-risk metastatic trophoblastic tumors are now curable by only conventional chemotherapeutic agents such as methotrexate, actinomycin D, or their combination with or without other agents. However, approximately 30% of high-risk patients with metastatic trophoblastic tumors are resistant to conventional chemotherapy. All of the high-risk patients resistant to chemotherapy are those with metastatic choriocarcinoma. Thus, the efficacy of multidrug chemotherapy and combination chemotherapy of cisplatin or VP16-213 with other agents is now being examined.

Radioimmunoassays and bioassays based on the reactions of the native molecule of human chorionic gonadotropin (HCG) fail to differentiate HCG from pituitary luteinizing hormone (LH). An assay based on the beta-subunit of HCG which detects HCG exclusively has been used in our laboratory to monitor patients undergoing chemotherapy for gestational trophoblastic disease (GTD). We have been able to differentiate minimal, persisting tumor activity from normal levels of pituitary gonadotropins and have based therapy on these findings. Alternatively, treatment has been terminated when HCG is no longer detectable in the serum. Tumor activity has been detected in the beta-subunit assay at a time when biologic activity in the urine indicated remission.

Advances in the management of gestational trophoblastic tumor have been made during the last three decades. Individualization of the therapy is one of the major advances. A number of risk factors has proved to predict accurately the prognosis of each patient. A few systems were currently in use, but difficult in putting them to practical use in the different geographical areas. At National Taiwan University Hospital from 1965 to 1979, 65 patients treated by chemotherapy were analyzed with respect of various prognostic factors. The score was assigned according to the mortality rate of each item to each prognostic factor, and thus established a scoring system which is suitable for the use in Taiwan. After establishment of our scoring system, 51 patients from 1980 to 1986 were treated according to the system and the appropriate therapeutic regimens. The outcome of these patients and toxicity of the different therapeutic regimens are presented.

Etoposide (VP16) levels were determined by high-performance liquid chromatography assay in plasma, urine, and surgical specimens of patients with choriocarcinoma undergoing surgery after a dose of 100 or 200 mg/m2 given as a 1-hour infusion. The drug disappeared from plasma biexponentially, with a terminal half-life of 4.1 +/- 0.4 hours, an apparent volume of distribution of 9 +/- 1.1 L/m2, and clearance of 21.5 +/- 3.1 ml/minute/m2. Fifty and 740 minutes after the end of VP16 infusion, the drug concentrations in myometrial carcinoma or in normal myometrium were approximately 40%-50% of those in plasma; 25-180 minutes after the end of drug infusion, the concentrations of VP16 in lung metastases amounted to 19%-43% of those in plasma, whereas in normal lung, the concentrations of VP16 were 38%-61% of those in plasma. In subcutaneous tissue, VP16 levels were much lower than in plasma (about 5%-27%). About 50% of VP16 was eliminated in the urine as unchanged drug, glucuronide, or sulfate.

Two treatment regimens for nonmetastatic gestational trophoblastic disease are compared in this retrospective study. The course of 39 patients with nonmetastatic gestational trophoblastic disease treated with methotrexate alone is contrasted to that of 29 patients with nonmetastatic gestational trophoblastic disease who were treated with methotrexate alternated with folinic acid. Of those patients initially treated with methotrexate alone, 7.7% developed methotrexate-resistant disease and required a change in chemotherapy for induction of remission. In contrast, 27.5% of patients initially treated with methotrexate and folinic acid developed methotrexate-resistant disease and required a change in chemotherapy to achieve remission. Ultimately, remission was achieved in all patients. Methotrexate as single-agent chemotherapy was found to be consistently more toxic than methotrexate alternated with folinic acid. It is concluded that methotrexate with folinic acid at the dosage used in this study, while less toxic than methotrexate alone, is less effective than methotrexate alone in the induction of remission of nonmetastatic gestational trophoblastic disease.

Methotrexate and folinic acid was administered as primary therapy in 185 patients with gestational trophoblastic disease between 1974 and 1984. Methotrexate and folinic acid induced complete remission in 147 (90.2%) of 163 patients with nonmetastatic disease and in 15 (68.2%) of 22 patients with low-risk metastatic disease. Sustained remission was achieved in 132 (81.5%) patients following only one course of chemotherapy. All patients with methotrexate resistance subsequently achieved remission with Actinomycin D or combination chemotherapy. Methotrexate when administered with folinic acid was associated with granulocytopenia, thrombocytopenia, and hepatotoxicity in 11 (5.9%), 3 (1.6%), and 26 (14.1%) patients, respectively. The human chorionic gonadotropin (hCG) regression curve served as a reliable guide for the administration of chemotherapy and enabled the attainment of a high remission rate while limiting chemotherapy exposure. Methotrexate and folinic acid achieves an excellent therapeutic outcome with limited chemotherapy exposure and effectively limits systemic toxicity.

The excretion pattern of human chorionic gonadotropin (hCG) or luteinizing hormone (LH) was observed in the urine of 77 patients with trophoblastic neoplasia, 109 with complete remission from trophoblastic neoplasia, and 94 with no trophoblastic neoplasia, when the anti-beta-subunit hCG system radioimmunoassay (anti-beta-subunit RIA), which specifically measured hCG was used. The sensitivity of anti-beta-subunit RIA was limited to urinary hCG 16 mIL/ml from the specificity of the anti-beta-subunit serum. Luteinizing hormone in the urine of patients with complete remission and in normal menstrual, postmenopausal, and castrated women was less than 16 mIU/ml in most cases. The excretion pattern of urinary hCG in the patients undergoing treatment for trophoblastic neoplasia was more clearly comprehended with the anti-beta-subunit RIA as compared with the anti-hCH RIA. The criteria for judgment of complete remission were that the hCG value dropped to less than 16 mIU/ml and that cellular response was not observed at least in the last two courses.