Clinical assessment of EMA/CO induced DNA damage in peripheral blood lymphocytes of high-risk gestational trophoblastic tumor patients.

From 1989 to 1994, Etoposide, Methotrexate, Actinomycin-D, Cyclophosphamide, Vincristine, Folic acid (EMA/CO) regimen was administered to seven patients with high-risk gestational tumours according to the Bagshawe 1976 criteria. Peripheral blood lymphocytes were obtained from two of these seven high-risk gestational trophoblastic patients receiving the EMA/CO regimen, and damage levels of DNA during chemotherapy were assessed using SCGE (single cell gel electrophoresis) assay. Additionally, the efficacy, toxicity and clinical results of EMA/CO regimen were evaluated in patients with high-risk gestational trophoblastic tumours. Fever (71.4%), leukopenia (57%), increase in transaminase concentrations (57%), trombocytopenia (57%), and anemia (57%) were among the most frequent side-effects of the EMA/CO regimen. All these toxic effects were reversible and there was no need to stop the therapy. EMA/CO is highly effective in patients with high-risk gestational trophoblastic disease and its toxicity is predictable and reversible. Because of chemotherapy, DNA damage that is shown in peripheral blood lymphocytes, increases at the 8th day of the EMA/CO regimen. When DNA damage is higher in patients, the course of chemotherapy per each patient is shortened. When DNA damage is higher in the patients, the multisystem effects due to toxicity are more significant. The SCGE assay has many possibilities in such research and has proved to be a relatively simple, quick and sensitive technique.

Gestational trophoblastic disease: does central nervous system chemoprophylaxis have a role?

In the UK there are standardized surveillance procedures for gestational trophoblastic disease. However, there are differences in practice between the two treatment centres in terms of definition of persistent gestational trophoblastic disease, prognostic risk assessment and chemotherapeutic regimens. The role of prophylactic chemotherapy for cerebral micrometastatic disease in persistent gestational trophoblastic disease is unclear. We have analysed the outcome of 69 patients with lung metastases who elsewhere might have received prophylactic intrathecal chemotherapy. Of the 69 patients, 67 received intravenous chemotherapy only. The other two patients had cerebral metastases at presentation. One patient who received only intravenous chemotherapy subsequently developed a cerebral metastasis, but this patient's initial treatment was compromised by non-compliance. This experience supports our current policy of not treating patients with pulmonary metastases, without clinical evidence of central nervous system (CNS) involvement, with prophylactic intrathecal therapy.

Gestational trophoblastic disease.

BACKGROUND: Gestational trophoblastic disease consists of a group of interrelated diseases, including molar pregnancy, placental site trophoblastic tumor, and choriocarcinoma. METHODS: Advances in the diagnosis and management of gestational trophoblastic diseases over the past 5 years were reviewed. RESULTS: Molar pregnancy is now categorized as complete or partial on the basis of gross and microscopic histopathologic and karyotypic findings. Early detection of persistent gestational trophoblastic tumor (GTT) depends on careful postmolar gonadotropin follow-up and consideration of the diagnosis for any woman of reproductive age with unexplained gynecologic and/or systemic symptoms. Triple therapy with methotrexate, actinomycin D, and cyclophosphamide was once the preferred treatment for patients with high risk metastatic GTT but induced remission in only about 50%. Treatment with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine is now the preferred regimen for treatment of high risk metastatic GTT and has been shown to induce remission in about 70% of patients. CONCLUSIONS: Important advances have been made in the diagnosis and treatment of patients with gestational trophoblastic disease, and patients can be reassured that they can anticipate normal reproductive functioning.

Effects of prophylactic chemotherapy for postmolar trophoblastic disease in patients with complete hydatidiform mole.

An analysis of 233 patients with complete hydatidiform mole admitted to Hacettepe University Hospital between 1964 and 1988 has been carried out. Methotrexate was administered prophylactically to 19 of 120 low-risk and to 52 of 113 high-risk patients. The difference in the incidence of postmolar gestational trophoblastic disease between prophylactically untreated and treated groups of either low-risk (13.9% versus 5.3%, P greater than 0.01) or high-risk (26.2% versus 25.0%, P greater than 0.01) patients was found to be statistically insignificant. Drug toxicity and mortality rates were 16.9% and 2.8%, respectively. It is concluded that prophylactic chemotherapy is not highly effective in the prophylaxis of postmolar gestational trophoblastic disease. Strict follow-up through sensitive betahuman chorionic gonadotropin assays should be the standard management of postmolar patients.

[Therapeutic and preventive care of trophoblastic disease in Czechoslovakia]. / Lécebne preventivní péce u trofoblastické nemoci v CSSR.

The authors list units of trophoblastic disease and its classification used and elaborated in the Centre for trophoblastic disease. The authors submit detailed information on the organization of diagnostic and therapeutic and preventive care of patients with trophoblastic disease in the CSSR. The authors draw attention to the establishment of a Centre for trophoblastic diseases (CTN) with the statute of a reference department. Reasons for its legalization are given. Its function and structure are described.

[Principles of prevention, early diagnosis, treatment and after-care of gestational trophoblastic tumors]. / Grundsätze zur Prophylaxe, Früherfassung, Behandlung und Nachsorge von gestationsbedingten Trophoblasttumoren.

Principles for prophylaxis, early diagnosis, therapy and after-care of gestation-caused trophoblast tumors are discussed. With this basis interdisciplinarily co-ordinated recommendations are given for therapy and after-care, which have been elaborated by a group of specialists.

Serum methotrexate and human chorionic gonadotropin concentrations during five-day chemotherapy for low-risk metastatic gestational trophoblastic neoplasia.

A recent report of serum methotrexate (MTX) levels measured during treatment of gestational trophoblastic neoplasia (GTN) led us to determine MTX and human chorionic gonadotropin (beta-hCG) levels in a patient with low-risk metastatic GTN with a pulmonary metastasis. Peak MTX concentrations exceeded 10(-6) mol/l considered by many investigators to be within the therapeutic range against many human tumors. Serum beta-hCG levels did not decline during MTX administration; however, after 5 days of MTX a steep dose-response curve was observed which continued during 5 courses of chemotherapy.

Dietary factors and risk of trophoblastic disease.

The risk of gestational trophoblastic disease in relation to frequency of consumption of selected dietary items was evaluated with data from a case-control study conducted in Northern Italy on 148 women with histologically confirmed gestational trophoblastic disease and two control groups, one consisting of 372 obstetric control subjects and one consisting of 406 patients in the hospital for acute, nonobstetric, nongynecologic conditions. Patients with gestational trophoblastic disease tended to consume several foods less frequently, including the major sources of vitamin A and animal protein in the Italian diet. Relative risk estimates were significantly below unity in both control groups for green vegetable, carrot, liver, and cheese consumption and in the obstetric control group only for milk, meat, eggs, fresh fruit, and fish. Inverse relationships emerged between the risk of gestational trophoblastic disease and beta-carotene or retinol intake index. The trend of decreasing risk with increasing intake was significant for beta-carotene consumption. The present findings confirm that various aspects of diet may influence the risk of gestational trophoblastic disease. However, the limitation of available evidence still introduces serious uncertainties in the interpretation of these findings and suggests the potential importance of further epidemiologic and biochemical research to obtain more precise definition of specific dietary correlates of gestational trophoblastic disease.

Subsequent pregnancy outcome in patients with molar pregnancy and gestational trophoblastic tumors.

Subsequent pregnancy outcome was reviewed in patients with complete and partial mole and persistent gestational trophoblastic tumors who were treated at the New England Trophoblastic Disease Center between Jun 1, 1965, and Dec 31, 1986. In general, these patients can be reassured that they can anticipate a normal reproductive outcome in the future.

Prophylactic chemotherapy for hydatidiform mole. Five to 15 years follow-up.

The effectiveness of the prophylactic chemotherapy was evaluated in 420 patients with molar pregnancy. All patients were followed for 5 to 15 years after the evacuation. Twenty-two (7.5%) of 293 patients with prophylactic chemotherapy and 23 (18.1%) of 127 patients without prophylactic chemotherapy (control) developed secondary trophoblastic disease. The prophylactic chemotherapy could reduce the occurrence of secondary trophoblastic disease. In these secondary trophoblastic diseases, 5 (22.7%) of 22 patients in the prophylactic chemotherapy group and 5 (21.7%) of 23 in the control had metastatic trophoblastic disease. Choriocarcinoma after the molar pregnancy developed in two patients (0.7%) of the prophylactic chemotherapy group and two (1.6%) of the control. Prophylactic chemotherapy did not eliminate the occurrence of choriocarcinoma. The complication of the prophylactic chemotherapy was seen in 27.3% of the patients. Neither severe complication nor death were related to the toxicity.

Effects of prophylactic chemotherapy for persistent trophoblastic disease in patients with complete hydatidiform mole.

Seventy-one patients with complete hydatidiform mole were prospectively randomized into two groups: one group (39 patients) was treated with a single course of methotrexate and citrovorum factor rescue as chemoprophylaxis; the other group (32 patients) was not treated. After molar evacuation, four patients from the treated group (10.3%) and ten patients from the untreated group (31.3%) developed persistent trophoblastic disease. The time interval from evacuation of the mole to diagnosis of persistent trophoblastic disease was longer in the treated group than in the untreated group (9.5 +/- 2.4 weeks versus 5.1 +/- 1.6 weeks, P less than .05). Among high-risk patients, there was a lower incidence of persistent trophoblastic disease in the treated group than in the untreated group (14.3 versus 47.4%, P less than .05). Among low-risk patients there was no difference between the groups (5.6 versus 7.7%, P greater than .05). All 14 patients with persistent trophoblastic disease achieved complete remission with therapeutic chemotherapy. More courses of chemotherapy were required until complete remission in the treated group than in the untreated group (2.5 +/- 0.5 versus 1.4 +/- 0.5, P less than .005). These findings suggest that even though chemoprophylaxis reduces the incidence of persistent trophoblastic disease in patients at high risk, it increases tumor resistance and morbidity. Although prophylactic chemotherapy with methotrexate and citrovorum factor rescue may be helpful for high-risk patients who cannot be followed or whose compliance is in question, careful follow-up remains the most important way to identify patients who should receive chemotherapy.

[Screening in gynecologic oncology]. / Screening in der gynäkologischen Onkologie.

Practical value of screening depends on various characteristics of cancers themselves, suitable tests and programs being able to cover a sufficient part of the population. Cancers favourable for screening are those with a high prevalence in the population screened, a detectable preclinical stage and better treatment results if detected by screening than detected by symptoms. Suitable screening tests have to be highly sensitive and specific, simple, cheap and without any risk. Before the widespread application of a screening program as a public health measure scientific basis and rational organization should be well known and the benefit has to be evident. Cytological screening is the most effective measure in cervical cancer control. Screening also promises a reduction in mortality from breast cancer, but further evaluation is necessary before decisions can be made about the application as a public health measure. Selective screening is probably connected with an improved health care for high risk persons of endometrial cancer. Follow up with HCG-RIA after hydatidiform mole improves early detection and prognosis of trophoblastic neoplasias significantly.

Management of gestational trophoblastic disease: results of a cooperative study.

Three hundred fifty-four evaluable cases of hydatidiform mole diagnosed from 1970 to 1979 in 10 regional hospitals in Lombardy are analyzed in the present report. Twenty-six (7.3%) of the patients developed persistent trophoblastic disease. Younger (less than 20 years) and older (40 years or more) age at diagnosis, a large-for-dates uterus, and ovarian enlargement were associated with an increased risk of developing persistent trophoblastic disease. Twenty-three (9%) cases of persistent trophoblastic disease were observed among 250 women not prophylactically treated, but only in 3 (3%) among 104 who received prophylactic chemotherapy. High-risk groups are defined and the role of prophylactic chemotherapy is discussed.

[Studies on the viability of trophoblast after termination of various kinds of pregnancies (author's transl)].

Although normal value of hCG (LH level) does not necessarily indicate eradication of viable trophoblast, its confirmation has been demonstrated as a clinically useful guide for the probable prevention of choriocarcinoma after hydatidiform mole by Takeuchi et al. Choriocarcinoma preceded by other pregnancies than hydatidiform mole which has the highest risk for choriocarcinoma has drawn more attention than before in connection with the decrease of postmolar choriocarcinoma. So that I have studied the regression rate of urinary gonadotropin (hCG) after the termination of various kinds of pregnancies. In 2,433 cases of induced abortion, 695 cases of spontaneous abortion, 1,724 cases of term delivery and 43 cases of hydatidiform mole, their urinary hCG were determined to the level of physiological range of LH. The rate of hCG regression was in the order of term delivery, spontaneous abortion, induced abortion and hydatidiform mole. The younger was the gestational age of trophoblast, the slower was the regression of hCG. At one month after the termination of pregnancy, 80.1%, 11%, 0.3%, 8% and 4.1%, and at two month 55.8%, 1.6%, 0.5%, 4% and 0.5% for hydatidiform mole, induced abortion of less than 12 week of gestation, spontaneous abortion of less than 12 week of gestation, spontaneous abortion of between 13 and 20 week of gestation respectively still showed abnormal hCG value. One percent of induced abortion at 5 month, 4% of spontaneous abortion at 3 month, 0.3% of term delivery at 4 month still maintained abnormal titer. No malignant sequelae in patients under the investigation have ever been observed in the follow up period between 3 and 8 years.

PIP: Although normal values of human chorionic gonadotropin (hCG), luteinizing hormone (LH) level does not necessarily indicate eradication of a viable trophoblast, its confirmation has been demonstrated as a clinically useful guide for the probable prevention of choriocarcinoma after hydatidiform mole by Takeuchi et al. Choriocarcinoma preceded by other pregnancies than hydatidiform mole which has the highest risk for choriocarcinoma has drawn more attention than before in connection with the decrease of postmolar choriocarcinoma. Therefore, the author studied the regression rate of urinary gonadotropin hCG after the termination of various kinds of pregnancies. In 2433 cases of induced abortion, 695 cases of spontaneous abortion, 1724 cases of term delivery, and 43 cases of hydatidiform mole, their urinary hCG were determined to the level of physiological range of LH. The rate of hCG regression was in the order of term delivery, spontaneous abortion, induced abortion, and hydatidiform mole. The younger was the gestational age of trophoblast, the slower was the regression of hCG. At 1 month after pregnancy termination, 80.1%, 11%, 0.3%, 8%, and 4.1%, and at 2 months, 55.8%, 1.6%, 0.5%, 4%, and 0.5% for hydatidiform mole, induced abortion of less than 12 weeks gestation, sportaneous abortion of less than 12 weeks gestation, spontaneous abortion between weeks 13-20 showed continued abnormal hCG values. 1% of induced abortions at 5 months, 4% of spontaneous abortions at 3 months, 0.3% of term deliveries at 4 months still maintained abnormal titers. No malignant sequelae in patients under investigation have been observed during the 3-8 year follow-up period. (author's modified)