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After the diagnosis has been confirmed, blood type, hematocrit, and thyroid, liver, and renal function tests should be obtained. A chest radiograph can rule out metastasis to the lungs. Subsequently, the molar pregnancy should be terminated. Suction curettage under general anesthesia is the method of choice once the patient is deemed stable. This can be safely accomplished even when the uterus is the size of a 28-week gestation. Local or regional anesthesia may be an option for the stable, cooperative patient with a small uterus. Intravenous oxytocin should be administered after dilation of the cervix but before the start of evacuation and may be continued, if necessary, for 24 hours post-evacuation. Tissue should be submitted for pathologic study. Blood loss usually is moderate, but precautions should be taken for the possibility of hemorrhage requiring a transfusion. When a large hydatidiform mole (>12 weeks in size) is evacuated by suction curettage, a laparotomy setup should be readily available, as hysterotomy, hysterectomy, or bilateral hypogastric artery ligation may be necessary if perforation or hemorrhage occurs. After the completion of the evacuation, all Rh-negative patients should receive Rh immune globulin.
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Hysterectomy continues to remain an option for good surgical candidates not desirous of future pregnancy and for older women (who are more likely to develop malignant sequelae). If theca lutein cysts are encountered at laparotomy, the ovaries should remain intact, as regression to normal size will occur with diminishing hCG titers. Surgical treatment of these cysts is indicated only if rupture, torsion, or hemorrhage occurs or if the enlarged ovaries become infected.
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It is important to note that hysterectomy does not eliminate the need for careful postsurgical surveillance with hCG testing, although the likelihood of metastatic disease following hysterectomy for gestational trophoblastic disease decreases from 20 to 3.5%. Current recommendations restrict hysterotomy to cases complicated by hemorrhage. Medical induction of labor with prostaglandins, oxytocin, or intra-amniotic instillation of prostaglandin or hypertonic solutions is no longer an acceptable method for evacuation of a molar pregnancy.
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Prophylactic Chemotherapy
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Controversy surrounds the use of prophylactic chemotherapy (with methotrexate or dactinomycin) after a complete molar pregnancy. Several studies indicate that the incidence of postmolar gestational trophoblastic neoplasia may be decreased with prophylactic chemotherapy. However, further studies are required to determine whether the potential side effects warrant such treatment in noncompliant patients and in those at high risk for persistent gestational trophoblastic disease (age >35 years, history of prior molar pregnancy, trophoblastic hyperplasia).
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Despite earlier diagnosis of molar pregnancies, the incidence of persistent gestational trophoblastic disease has not decreased. Three-fourths of patients with malignant nonmetastatic trophoblastic disease and half of patients with malignant metastatic disease develop these tumors following a hydatidiform mole. In the remainder, disease arises subsequent to a term pregnancy, abortion, or ectopic pregnancy. Several clinical features of hydatidiform moles are recognized as having a high association with malignant trophoblastic neoplasia. In general, at diagnosis, the larger the uterus and the higher the hCG titer, the greater the risk for malignant gestational trophoblastic disease. The combination of theca lutein cysts and uterine size excessive for gestational age is associated with an extremely high risk of malignant sequelae. Pathologic specimens with marked nuclear atypia, necrosis, hemorrhage, or trophoblastic proliferation may also increase the risk of persistent disease.
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Regardless of the method of termination (suction curettage or hysterectomy) or presence of high-risk features, close monitoring with serial hCG titers is essential for every patient, as the incidence of malignant sequelae approaches 20–30%. After evacuation of the molar pregnancy, the patient should undergo serial hCG determinations, beginning within 48 hours after evacuation and then at weekly intervals until hCG values decline to undetectable levels (<5 mIU per milliliter) on three successive assays. If titer remission occurs spontaneously within 14 weeks and without a titer plateau, the hCG titer should then be repeated monthly for at least 6 months to 1 year before the patient is released from close medical supervision. Thereafter, the patient may enter into a routine gynecologic care program.
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A gynecologic examination should be done 1 week after evacuation, at which time blood may be taken for the hCG titer. Estimates of uterine size, presence of adnexal masses (theca lutein cysts) and presence of vulvar, vaginal, or cervical lesions should be noted. Unless symptoms develop, the examination may be repeated at 4-week intervals throughout the observation period. If pre-evacuation chest radiography has revealed pulmonary metastases, chest radiographs should be repeated at 4-week intervals until spontaneous remission is confirmed, then at 3-month intervals during the remainder of the surveillance period.
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Effective contraceptive measures should be implemented and maintained throughout the period of surveillance. Studies have not shown an increased risk of persistent gestational trophoblastic neoplasia after a molar pregnancy with the use of oral contraceptives. Therefore, they remain the most widely used method of birth control. A patient who has entered into spontaneous remission with negative titers, examinations, and chest radiographs for 6 months to 1 year and who is desirous of becoming pregnant may terminate contraceptive practices. Successful pregnancy is the norm, and complications are similar to those of the general population.
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Therapy for persistent gestational trophoblastic neoplasia after evacuation of a hydatidiform mole is usually instituted because of an abnormal hCG regression curve. The most critical period of observation is the first 4 to 6 weeks post-evacuation. Although the hCG titer usually returns to normal by 1–2 weeks after evacuation of a hydatidiform mole, it should normalize in most women by the eighth week.
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Approximately 70% of patients achieve a normal hCG level within 8 weeks of evacuation. Very few patients whose hCG titers normalize during this interval will require future treatment. In the past, therapy for persistent disease was initiated for the 30% of women whose hCG titer remained elevated at or beyond 8 weeks post-termination. However, current data suggest that half of these patients will demonstrate a continuous decline in titers and ultimately achieve normal hCG levels without further treatment. The remaining half will experience a rising or plateauing titer with histologic evidence of an invasive mole or choriocarcinoma.
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Delayed postevacuation bleeding is uncommon after a molar pregnancy and signifies the presence of an invasive mole or choriocarcinoma. It is invariably attended by an enlarging uterus and an abnormal hCG regression pattern. In some cases, curettage is effective in stopping the bleeding, although little intracavitary tissue will be present in most of these cases. The mainstay of treatment is chemotherapy.
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Malignant Gestational Trophoblastic Neoplasia
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According to the 2002 criteria established by the International Federation of Gynecology and Obstetrics (FIGO), malignant gestational trophoblastic neoplasia may be diagnosed in the setting of (1) a rise in hCG levels of 10% or greater for ≥3 values over 2 weeks; (2) a plateau in ≥4 hCG values over 3 successive weeks; (3) hCG levels elevated at 6 months postevacuation; or (4) a tissue diagnosis of choriocarcinoma.
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Once the diagnosis of malignant trophoblastic disease is suspected or established, an accurate history and physical examination are crucial. Most patients will have an enlarged uterus as well as ovarian enlargement caused by theca lutein cysts. Sites of metastasis must be sought, especially in the lower genital tract. A chest radiograph can diagnose lung metastases, although a chest computerized tomography (CT) will miss fewer pulmonary metastatic lesions. Liver metastases may be diagnosed with ultrasonography or CT scan. Brain metastases are best evaluated with a CT scan or magnetic resonance imaging (MRI). The ratio of serum hCG values to the concentration of hCG in cerebrospinal fluid (normal >60:1) may also prove helpful. Baseline hematologic counts, coagulation studies, and hepatic and renal function tests are critical in later assessing the risk of drug toxicity. After all sites of metastases have been identified and the patient's desires for preservation of reproductive function are determined, specific therapy should be initiated.
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Nonmetastatic Malignant Gestational Trophoblastic Disease
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Trophoblastic disease confined to the uterus is the most common malignant lesion seen in gestational trophoblastic neoplasia. The diagnosis is usually made during the postmolar surveillance period. Therapy for patients with nonmetastatic malignant trophoblastic disease includes (1) single-agent chemotherapy or (2) combination chemotherapy and hysterectomy, with surgery performed on the third day of drug therapy for patients who do not wish to preserve reproductive function.
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Table 51–2 summarizes the recommended chemotherapeutic regimens available for nonmetastatic gestational trophoblastic neoplasia. Single-agent chemotherapy using methotrexate or dactinomycin has demonstrated clear-cut superiority over other protocols. A randomized trial conducted by the Gynecologic Oncology Group concluded that biweekly IV dactinomycin 1.25 mg/m2 achieved a higher complete response rate as compared to weekly IM methotrexate 30 mg/m2. The methotrexate dose used in this trial, however, was lower than the weekly dose of 50 mg/m2 given typically to most low-risk patients and may have accounted for the superiority of the dactinomycin. Therefore, the regimen of choice in this group of patients has yet to be determined.
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Treatment failure or intolerable side effects should result in administration of the alternative agent or regimen. Each treatment cycle should be repeated as soon as normal tissues (bone marrow and gastrointestinal mucosa) have recovered, with a minimum 7-day window between the last day of one course and the first day of the next course. Overall, the complete response rate to single-agent therapy ranges from 60 to 98%, with salvage rates approaching 100%. Methotrexate is contraindicated in the presence of hepatocellular disease or when renal function is impaired.
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During treatment, weekly quantitative hCG titers and complete blood counts should be obtained. Before each course of therapy, liver and renal function assessments should be assessed. At least 1 additional course of drug therapy should be given after attainment of the first normal hCG value. The number of treatment cycles necessary to induce remission is proportionate to the magnitude of the hCG concentration at the start of therapy. An average of 3 or 4 courses of single-agent therapy is usually required. After remission has been induced and treatment is completed, hCG assays should be obtained monthly for 1 year.
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Metastatic Gestational Trophoblastic Disease
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Treatment in metastatic disease uses either single-agent chemotherapy (Table 51–2) or multiagent chemotherapy in cases in which resistance to a single agent is anticipated. Several systems have been developed to determine at onset which patients will require more aggressive therapy. The National Cancer Institute system is used in the United States to determine whether the patient will have a good or poor prognosis in response to single-agent chemotherapy (Table 51–3).
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Table 51–4 highlights the World Health Organization (WHO) scoring system in which patients are categorized into low- or high-risk groups based on risk factors such as age, type of antecedent pregnancy, interval from antecedent pregnancy to initiation of chemotherapy, pretreatment hCG level, size of largest tumor, site of metastases, number of metastases, and prior chemotherapy. A total score of 0–6 is considered low risk and a total score ≥7 is categorized as high risk.
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The revised 2002 FIGO staging system combines the use of both anatomic and nonanatomic factors (Table 51–5). A patient is assigned a stage based on the anatomic location of disease and given a risk factor score based on the WHO prognostic scoring system. The goal of the revised FIGO staging is to improve the assessment and clinical management of patients and to unify staging to allow for international comparisons in treatment success.
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a. Good-Prognosis Patients
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Based on the clinical classification of malignant disease, patients can be expected to respond satisfactorily to single-agent chemotherapy if (1) metastases are confined to the lungs or pelvis, (2) serum hCG levels are below 40,000 mIU/mL at the onset of treatment, and (3) therapy is started within 4 months of apparent onset of disease. The most common site of metastasis in gestational trophoblastic disease is the lungs. When a patient develops pulmonary metastasis with elevation of the hCG titer, choriocarcinoma is a more likely cause than metastatic invasive mole, although the latter can also metastasize to the lungs.
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The advantage of single-agent chemotherapy over multiagent therapy lies in its more favorable toxicity profile, with fewer total side effects, and a lower likelihood that these effects would be irreversible. It is important to keep in mind that despite the "good-prognosis" designation of low-risk disease, failure of drug therapy does occur in 10% of cases. Therefore, meticulous care by a knowledgeable physician such as a gynecologic oncologist is necessary for optimal outcomes.
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In good-prognosis patients, single-agent chemotherapy (Table 51–2) with methotrexate is considered the drug of choice. Ideally, the 5-day treatment course is given every other week, as the possibility of tumor regrowth increases with treatment gaps >2 weeks. Once negative titers have been achieved, an additional course is administered before beginning the period of surveillance. In cases in which resistance to methotrexate occurs, as manifested by rising or plateauing titers or by the development of new metastases, or cases in which negative titers are not achieved by the fifth course of methotrexate, the patient should be given dactinomycin. Dactinomycin should also be the agent of choice for patients who experience severe side effects with methotrexate.
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B. Poor-Prognosis Patients
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Poor-prognosis patients, based on the Clinical Classification of Malignant Disease, are those with any of the following risk factors: (1) serum hCG titers >40,000 mIU/mL at the onset of treatment, (2) diagnosis of disease more than 4 months after molar pregnancy, (3) brain or liver metastases, (4) prior unsuccessful chemotherapy, or (5) onset after term gestation. These patients respond poorly (<40% response rate) to single-agent therapy. A poor response is also seen in patients with advanced revised FIGO stages and WHO scores ≥7. These patients present a serious challenge to the clinician, as many have been previously treated with chemotherapy, have developed resistance to key agents, and/or have accumulated considerable toxicity with depleted bone marrow reserves. In fact, prior unsuccessful chemotherapy is considered to be one of the worst prognostic factors.
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Generally, poor-prognosis patients are managed by a gynecologic oncologist and may require prolonged hospitalization and multiple courses of chemotherapy. They often need multispeciality care and other life-support measures, including hyperalimentation, antibiotics, and transfusions to correct the effects of marrow depression.
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Central nervous system involvement, particularly brain metastases with focal neurologic signs, commonly occurs with choriocarcinoma. Because patients with brain or liver metastases are at high risk of sudden death from hemorrhagic lesions, it is standard practice to institute whole-brain or whole-liver irradiation concomitantly with combination chemotherapy. Uncertainty remains regarding whether radiation therapy exerts its beneficial effects by destroying tumor in combination with drug therapy or by preventing fatal hemorrhage and thus keeping the patient alive until remission with chemotherapy has been achieved. For acute bleeding episodes, surgical intervention or angiographic embolization should be considered.
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Cerebral metastases are treated over a 2-week period with radiation given at a dosage of 3 Gy daily, 5 days a week, to a total organ dose of 30 Gy. Whole-liver irradiation is usually accomplished over 10 days to attain a 20-Gy whole-organ dose given at a rate of 2 Gy daily, 5 days a week. Other treatment options include selective hepatic artery chemotherapy infusion.
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Previously, patients with poor prognosis or high-risk gestational trophoblastic neoplasia were treated with methotrexate, dactinomycin, and chlorambucil or cyclophosphamide and the modified Bagshawe protocol (cyclophosphamide, hydroxyurea, methotrexate, vincristine, cyclophosphamide, and dactinomycin). Currently, etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine (EMACO) chemotherapy (Table 51–6) repeated every 2 weeks provides the best response rate (approximately 80%) with the lowest side-effect profile. Monitoring for drug toxicity is the same as that in single-agent therapy but with higher vigilance due to the possibility of combined toxicity.
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Treatment of malignant trophoblastic disease must be continued with repeated courses of combination chemotherapy until hCG titers return to undetectable levels (<5 mIU/mL). Complete remission is documented only after 3 consecutive weekly normal hCG titers have been achieved. It is recommended that all high-risk patients receive at least 3 courses of multiagent chemotherapy after hCG titers have returned to normal. After remission is achieved, follow-up is the same as for hydatidiform moles and metastatic good-prognosis disease.
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Salvage therapy for disease not responsive to EMACO substitutes cisplatin and etoposide for cyclophosphamide and vincristine (EP-EMA) (Table 51–6). Close monitoring of renal function is required because of nephrotoxicity secondary to cisplatin and renally excreted methotrexate. Other treatment options include paclitaxel, topotecan, and high-dose chemotherapy with autologous bone marrow transplantation. As stated previously, chemotherapy should be continued for at least 3 cycles after a negative hCG is achieved. In resistant cases, adjunctive measures along with chemotherapy may include hysterectomy, resection of metastatic tumors, or irradiation of unresectable lesions.
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During and after treatment, a thorough discussion about birth control and reproductive options is of utmost importance. Oral contraceptive pills should be used if not contraindicated. Contraceptive efforts should be continued for at least 1 year after remission.
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Placental-Site Trophoblastic Tumor
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As treatment of PSTT is generally resistant to chemotherapy, hysterectomy is the recommended route of treatment. Partial uterine resection involving the tumor is possible if the patient desires future fertility. Chemotherapy is indicated in cases of metastatic disease. EP-EMA is the preferred regimen over EMACO, with paclitaxel and topotecan used when resistance develops. The greatest adverse outcomes are associated with an interval of >2 years from the antecedent pregnancy to diagnosis.