Practical management of gestational trophoblastic disease

ONCOLOGY UPDATE

PRACTICAL MANAGEMENT OF GESTATIONAL TROPHOBLASTIC DISEASE Frank D. Cirisano, Jr., MD and John T. Soper, MD

Gestational trophoblastic disease (GTD) represents a spectrum of tumors that arise from the fetal chorion during pregnancy, including benign partial and complete hydatidiform moles, persistent invasive or metastatic moles, placental-site trophoblastic tumors, and gestational choriocarcinomas. Gestational trophoblastic diseases all exhibit proliferation of both cytotrophoblast and syncytiotrophoblast cells, with the exception of placental-site tumor, which is derived from the intermediate trophoblast cells. Practical management of these tumors begins with preoperative evaluation and screening for metastatic disease followed by uterine evacuation or hysterectomy. Postmolar GTD includes local noninvasive proliferation of molar tissue, invasive mole, or gestational choriocarcinoma. The management of malignant GTD may be directed from three classification systems developed to predict patient prognosis and guide the decision for either single or multiagent chemotherapy. These systems assess clinical risk factors in addition to sites of metastatic disease. Treatment with aggressive multiagent chemotherapy and individualized multimodality therapy is warranted in these extremely highrisk patients. After remission, patients should be followed closely for 1 year and periodically thereFrom Gynecologic Oncology Associates, Inc., Miami, Florida, and the Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina.

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after. Pregnancy is deferred and contraception instituted for 1 year to prevent disruption of serum human chorionic gonadotropin surveillance. (Prim Care Update Ob/ Gyns 1999;6:75– 81. © 1999 Elsevier Science Inc. All rights reserved.)

Trophoblastic cells are derived from the outer cell mass of the preimplantation embryo. They normally produce human chorionic gonadotropin (hCG), which maintains early pregnancy. The absence of Human Leukocyte Antigen and type A, type B, type O blood type antigen expression allows normal trophoblast to escape from maternal immunologic rejection. These tissues may continuously embolize from endometrial sinuses into the maternal venous system even in normal pregnancy. These properties of normal trophoblastic function are exaggerated in all forms of gestational trophoblastic disease with the exception of placental-site tumors, as discussed below.

Spectrum of GTD COMPLETE HYDATIDIFORM MOLE A complete mole is characterized by paternally derived diploid genotype (diandric diploidy). Most frequently, a fertilized egg loses the maternal complement and the paternal haploid set is reduplicated resulting in a 46,XX chromosomal complement. Approximately 5% of complete moles appear to arise from

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dispermic fertilization of an empty egg resulting in either a 46,XY or 46,XX paternally derived genotype.1 Diandric diploidy yielding 46,YY chromosomal complement has not been clinically recognized.1 Fetal tissues are absent, having resorbed prior to establishment of fetal cardiovascular development, explaining an absence of fetal vessels. Histologic features include diffuse hyperplasia of both cytotrophoblast and syncytiotrophoblast tissues, and edema of chorionic villi, which manifests grossly as grape-like tissue. The incidence of complete moles is estimated to range between 0.26 and 2.1 per 1,000 pregnancies, with the highest incidence occurring in the Asian populations.2 Increasing risk has also been reported at the extremes of reproductive age below 15 years and above 45 years2 compared with expected risk in women between the ages of 25 and 29. Paternal age above 45 is also associated with an elevated risk.3

INVASIVE HYDATIDIFORM MOLE Invasive hydatidiform moles invade beyond the normal placentation site into the myometrium and may result in uterine subinvolution, rupture, or intraperitoneal hemorrhage. Venous metastases are uncommon but may occur most frequently to the lower genital tract and lungs. Although invasive moles may spontaneously regress, chemotherapy is instituted for most patients with a rising postevacuation hCG without distinguishing between complete moles with inva-

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sive component and those with choriocarcinoma.1

PARTIAL HYDATIDIFORM MOLE Partial moles are characterized by triploidy that incorporates an extra haploid paternal chromosomal complement (diandric triploidy). Dispermic fertilization of an egg with retention of the maternal haploid complement results in either 69,XXX or 69,XYY genotype.1 The fetus typically survives beyond 8 weeks’ gestation. Fetal vessels are identifiable in placental tissue, which is characterized by focal hydropic villi with trophoblastic hyperplasia. As hydropic changes may not be detected in aborted fetuses, the epidemiology of partial moles is difficult to characterize. In contrast to complete moles, there is no maternal or paternal age-associated risk associated with partial hydatidiform moles.3

GESTATIONAL CHORIOCARCINOMA Gestational choriocarcinoma can spontaneously arise from placental tissue or result from malignant transformation from molar tissue. Choriocarcinoma is characterized by malignant proliferation of syncytiotrophoblast and cytotrophoblast tissues. Histologically, these tumors appear as solid sheets of cells without chorionic villi. When villous structures are identified in a primary or metastatic site, the histologic diagnosis is invasive mole, not choriocarcinoma. The absence of ABO and HLA antigens allows early hematogenous dissemination.1 Rapid tumor growth may result in necrosis and hemorrhage at metastatic sites, and the disease progresses rapidly in the absence of treatment. Reported incidence rates vary from 1 in 24,096 to 1 in 40,650 pregnancies with a two-fold increased risk for non-Caucasians compared with Caucasians.4 Older patients are also at increased risk, 76

with an 8.6-fold risk elevation for women older than 40 years. The greatest risk factor for gestational choriocarcinoma is prior hydatidiform mole, with between 1,000- to 2,000-fold increase when compared to prior term pregnancy.1

PLACENTAL SITE TROPHOBLASTIC TUMOR Placental-site trophoblastic tumors (PSTT) warrant special attention, given the variation from other forms of GTD. They arise from intermediate cytotrophoblasts at the implantation site following any type of antecedent pregnancy.1 In contrast to other forms of GTD, PSTT have no syncytiotrophoblasts and secrete a scant amount of hCG in relation to tumor volume.5 Human placental lactogen (hPL) may be elaborated by individual tumors and, if elevated, serial measurements of serum hPL may serve as a tumor marker.5 Histologic findings vary and include benign trophoblastic proliferation of the placental site, locally invasive placental-site tumor, and malignant placental-site site tumor.

Management of Hydatidiform Mole The management of partial and complete hydatidiform moles involves primary evacuation of the uterus followed by postevacuation hCG monitoring for persistent or progressive disease. Partial hydatidiform moles usually present as missed or threatened spontaneous abortion.3 The majority have relatively low pre-evacuation hCG levels when compared to complete moles. This is consistent with the focal hydropic changes in villi, only modest increase in trophoblast mass, and the absence of theca lutein cysts in most cases. The risk for invasive or persistent disease is less than 5% following evacuation of partial moles and is usually non-

metastatic. The histologic diagnosis of choriocarcinoma is also rare in these patients. In complete moles, hydropic changes and trophoblastic proliferation are diffuse. Uterine enlargement beyond that expected for gestational age occurs in over 50% of patients. Complete moles are associated with vaginal bleeding (97%), theca lutein cysts (25–50%), preeclampsia (25%–27%), hyperemesis (25%), and clinical hyperthyroidism (7%–10%). 1 Approximately 20% of patients with complete moles will require further treatment following evacuation for invasive or persistent mole (66%– 75%) or gestational choriocarcinoma (25%–33%). Overall, metastatic disease is found in 2%– 4% of these patients.1

EVACUATION The preoperative evacuation for the patient with a molar gestation involves a baseline ultrasound to confirm the diagnosis, screening for metastatic disease, and stabilizing the patient for surgery. Following a complete physical examination, preoperative studies should include a baseline serum hCG level, complete blood count, chemistry panel including liver enzymes, blood urea nitrogen and creatinine, thyroid function tests, and chest X-ray to screen for metastases and medical complications of molar pregnancy. Tremor and tachycardia reflective of clinical hyperthyroidism are noted in 10% of patients with complete moles.6 b-Adrenergic blockers are indicated preoperatively in these patients to prevent thyroid storm, which may be caused by the stress of surgery or intubation. Preoperative anemia should be corrected. Blood pressure should be stabilized in the event of pregnancyinduced hypertension or hyperthyroidism. Pulmonary complications occur in approximately 25% of patients Prim Care Update Ob/Gyns

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with uterine sizes greater than 14 –16 weeks’ gestation.7 Central venous access is indicated in these patients to allow central venous pressure monitoring and rapid blood product or fluid resuscitation. A baseline arterial blood gas should also be performed, given the increased risk for respiratory insufficiency due to preeclampsia, iatrogenic fluid overload, trophoblastic deportation or metastases, highoutput congestive heart failure caused by anemia, or hyperthyroidism.

SUCTION CURETTAGE After induction of anesthesia, the cervix is dilated to accommodate a 12–14 mm cannula, which is introduced to the mid to lower third of the endometrial cavity. The uterus is not sounded because of the increased risk of perforation. Oxytocin infusion is started after cervical dilation and continued postoperatively for 24 hours or until bleeding is minimal. The suction and sharp curettage specimens are submitted separately as the sharp curettings are more likely to contain invasive molar tissue or choriocarcinoma.

COMPLICATIONS OF MANAGEMENT Perforation may occur at the time of suction dilation and curettage for hydatidiform mole because of operative technique or deep myometrial penetration by tumor. Laparoscopy or laparotomy should then be performed to evaluate for injury to adjacent structures and secure hemostasis at the uterine perforation site. Molar pregnancy may occur in a twin pregnancy with an estimated frequency of 1 in 22,000 to 1 in 100,000 pregnancies.9 If suspected, a thorough obstetric ultrasound is indicated to rule out fetal malformations and characterize the placenta, along with chromosomal analysis by amniocentesis. In the presence of normal findings, it has been suggested that patients may be followed to term and delivered vaginally with close postpartum serum hCG surveillance. In this situation, a patient would need to be managed jointly by subspecialists in maternal-fetal medicine and gynecologic oncology. These patients may have an increased risk for malignant GTD, requiring chemotherapy.9

HYSTERECTOMY The risk for persistent or invasive mole and choriocarcinoma may be reduced from approximately 20% to 3.5% in patients evacuated by hysterectomy rather than dilation and curettage.6 Total abdominal hysterectomy is performed with the mole in situ. The adnexa are not removed unless the patient is perimenopausal because the risk for ovarian metastases is rare and most ovarian masses are theca lutein cysts. Theca lutein cysts regress spontaneously with a mean interval of 8 weeks, and need not be either decompressed or removed in the absence of torsion or rupture with bleeding. These complications occur in only 3% of patients with theca lutein cysts.8 Volume 6, Number 3, 1999

RISK FACTORS FOR POSTMOLAR GTD AND CHEMOPROPHYLAXIS Postmolar gestational trophoblastic disease includes local noninvasive proliferation of molar tissue, invasive mole, or gestational choriocarcinoma. Approximately 3%– 4% of patients with partial moles will experience postmolar GTD, compared with 20% with complete moles.10 Persistent or invasive moles comprise 70%–90% of postmolar GTD, whereas 10%–30% will have choriocarcinoma.6 Risk factors include the presence of clinically detectable theca lutein cysts, uterine enlargement beyond dates, and hCG levels above 1,000,000 mIU/mL.2 Additional clinical risk factors include pulmonary complications during

evacuation, eclampsia, uterine subinvolution, and hemorrhage following evacuation; however, these high-risk clinical characteristics predict only 15% of patients that will develop postmolar GTD.10 Routine prophylactic chemotherapy is not currently recommended.

SURVEILLANCE AND PREGNANCY AFTER MOLAR EVACUATION A baseline serum hCG level should be obtained within 48 hours of molar evacuation and followed weekly until normal. Levels should then be followed every 1–2 months for 3– 6 months for patients with partial moles and 6 –12 months for patients with complete moles, given the risk for malignant sequelae. Contraception is indicated during surveillance to avoid confusion caused by elevated hCG from intercurrent pregnancy. Oral contraceptives remain one of the safest and most effective means of contraception and may be recommended with no apparent increase in risk for postmolar GTD.1 Criteria for the diagnosis of postmolar GTD include progressive rise in hCG levels; plateau of hCG levels for 3– 4 consecutive weeks (6 10% change); histologic evidence of invasive mole, choriocarcinoma or placental-site tumor; or evidence of metastatic disease.1 The reported risk for subsequent partial or complete molar pregnancy is between 1% and 2%, increasing to 28% after a second mole.11 After a single molar pregnancy, the patient may be reassured regarding the likelihood of a normal outcome in subsequent pregnancies, though early ultrasound is indicated and placental products should be histologically evaluated at delivery or evacuation. An hCG level 6 weeks after delivery is also prudent to exclude the rare occurrence of choriocarcinoma. 77

CIRISANO AND SOPER Table 1. FIGO Staging of Gestational Trophoblastic Disease Stage Stage I. Stage II. Stage III.

Strictly confined to uterine corpus Disease extension beyond uterus, limited to genital tract Extension to lungs with or without genital tract involvement All other metastases

Stage IV. Substage A. No risk factors B. One risk factor C. Both risk factors Risk factors 1. Pretherapy serum hCG .100,000 mIU/mL 2. Duration of disease .6 months

FIGO, International Federation of Gynecology and Obstetrics; hCG, human chorionic gonadotropin. Data from Creasman WT.12

Management of Malignant GTD The management of malignant GTD may be directed from three classification systems, which were developed to predict patient prognosis and guide the decision to institute either single agent or multiagent chemotherapy. The International Federation of Gynecology and Obstetrics (FIGO) staging for GTD (Table 1) divides patients by site of disease extension and clinical risk factors.12 The World Health Organization (WHO) prognostic index score for GTD (Table 2) tabulates a total score based on the presence of

individual risk factors.13 Patients with total WHO prognostic index score 0 – 4 are considered low risk, those with 5–7 intermediate, and those with scores greater than 8 are considered high risk. The Clinical Classification System for malignant GTD divides patients into three categories: nonmetastatic; goodprognosis metastatic; and poorprognosis metastatic based on the presence or absence of risk factors for failure of initial single-agent therapy (Table 3).14 –16 In retrospectively reviewing 385 patients presenting for primary therapy and 69 patients presenting for secondary therapy at the Southeastern Regional Trophoblastic Disease Center, all systems identified low-risk patients with the same efficiency.10 The FIGO or WHO systems might prove beneficial should chemotherapy regimens of intermediate intensity become standardized for intermediate risk patients (WHO score of 5–7). The authors use the Clinical Classification System because it is simpler to employ when making decisions regarding primary therapy.

THERAPY FOR NONMETASTATIC GTD A variety of methotrexate regimens have been used to treat patients with nonmetastatic GTD (Table 4) with comparable remission rates of 74%– 89%.1 To date, no regimen has proven superior in randomized

Table 3. Clinical Classification of Malignant Gestational Trophoblastic Disease (GTD) I. Nonmetastatic GTD: no evidence of disease outside uterus; not assigned to prognostic category II. Metastatic GTD: any metastases A. Good-prognosis mestastatic GTD 1. Short duration (,4 mo from antecedent pregnancy) 2. Low serum hCG level (,40,000 mIU/mL) 3. No brain or liver metastases 4. No prior chemotherapy 5. No antecedent term pregnancy B. Poor-prognosis metastatic GTD 1. Long duration (.4 months from antecedent pregnancy) 2. High pretreatment hCG level (.40,000 mIU/mL) 3. Brain or liver metastases 4. Antecedent term pregnancy 5. Prior chemotherapy hCG, human chorionic gonadotropin. Data from Hammond et al,14 Hammond et al,15 and Soper et al.16

trials. Based on convenience of scheduling and toxicity, the authors use the weekly intramuscular methotrexate regimen. Dactinomycin is most often reserved as salvage therapy for patients with nonmetastatic GTD because of gastrointestinal toxicity, alopecia, and potential for extravasation injury.1 Because of similar toxicity and remission rates, the authors prefer the intravenous bolus regimen to the 5-day infusion (Table 4). Both 5-fluorouracil and etoposide

Table 2. WHO Prognostic Score Index for Gestational Trophoblastic Disease Prognostic factors

0

1

2

4

Age (y) Interval* hCG ABO Groups (female X male) Largest tumor size (including uterine) Metastatic site Number of metastases Prior chemotherapy

#35 ,4 mo ,103 — — — — —

.35 4–6 mo 103–104 OXA 3–5 cm spleen/kidney 1–4 —

— 7–12 mo 104–105 B .5 cm liver/gastrointest 4–8 single drug

— .12 mo .105 — — brain .8 two or more

Total score: 0 – 4 5 low risk; 5–7 5 intermediate risk; $8 5 high risk. * Interval from antecedent pregnancy to start of chemotherapy. WHO, World Health Organization; hCG, human chorionic gonadotropin. Data from the World Health Organization.13

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GESTATIONAL TROPHOBLASTIC DISEASE Table 4. Treatment Regimens for Nonmetastatic Gestational Trophoblastic Disease Regimen

Complete Response Rate

Methotrexate oral 5 d Methotrexate IM 5 d Weekly IM methotrexate Methotrexate/folinic acid Dactinomycin 1.25 mg/m2 bolus Dactinomycin 9–13 mg/kg/d 3 5 d infusion Etoposide 200 mg/m2 po 3 5 d oral

87% 74%–92% 74% 74%–90% 80%–94% 77%–84% 98%

IM, intramuscularly; po, orally. Data from Hancock, et al.1

have activity in the treatment of patients with GTD but are not attractive for management of patients with nonmetastatic GTD because of a higher incidence of toxicity than the methotrexate or dactinomycin regimens. The role for primary hysterectomy must not be overlooked in patients with nonmetastatic GTD who desire sterilization, because hysterectomy during the first cycle of chemotherapy may reduce the amount of chemotherapy needed to achieve remission and salvage patients refractory to primary chemotherapy.14

MANAGEMENT OF LOW-RISK/ GOOD-PROGNOSIS METASTATIC GTD Women with low-risk metastatic GTD have a 50%– 60% complete remission rate when treated initially with either methotrexate or dactinomycin for 5-day cycles.1 Patients who fail the initial regimen are usually salvaged with the other. While infusional 5-fluorouracil and oral etoposide have been used in these patients with comparable success, they remain second-line therapies because of toxicity. Multiagent chemotherapy is indicated after failing two single-agent regimens. Chemotherapy is continued for 1–2 cycles beyond a negative hCG level. It has been suggested that primary hysterectomy with chemotherapy can be offered to low-risk Volume 6, Number 3, 1999

metastatic GTD patients who do not wish to preserve fertility, as this reduces the total number of cycles to achieve remission, and 13% of these patients may ultimately require hysterectomy to achieve sustained remission.14

MANAGEMENT OF HIGH-RISK/ POOR-PROGNOSIS METASTATIC GTD Multiagent primary chemotherapy is indicated in all patients with high-risk metastatic GTD. Sustained remission is achieved in 63%– 80% of those treated with methotrexate 0.3 mg per kg intramuscularly, dactinomycin 8 –10 mg per kg intravenously and chlorambucil 0.2 mg per kg orally or cyclophosphamide 250 mg intramuscularly (MAC) each given daily for 5 days every 2–3 weeks.15 In a randomized Gynecologic Oncology Group trial, the MAC regimen achieved a 73% remission rate when compared with an alternative 8-drug schedule (CHAMOMA) of methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine, which had a 65% remission rate and higher toxicity.17 A third combination regimen of alternating cycles of etoposidemethotrexate-dactinomycin and cyclophosphamide-vincristine (EMA-CO, Table 5) has been used in high-risk patients with 75%– 85% complete response rates in patients

receiving primary therapy and a 69% salvage rate for previously treated patients, with comparable toxicity to MAC.18 The EMA-CO regimen includes administration of intrathecal methotrexate, though this is often omitted because therapeutic levels of methotrexate have been reported in the cerebrospinal fluid after moderate dose infusion, consistent with the drug’s known pharmacodynamic tendency to accumulate in the third space.19 More recently, cisplatin (80 mg per m2)etoposide (100 mg per m2) have been used in place of cyclophosphamide-vincristine in small series of high-risk metastatic GTD patients. Reported success rates using EMA“EP” are 82%–100% in small numbers of patients.1 Further study is needed comparing this regimen to EMA-CO. Currently, EMA-CO appears to offer the most favorable response rate and toxicity profile and is currently the first-line combination regimen that the authors use in high-risk patients. MULTIMODALITY THERAPY. Approximately 30% of women with poorprognosis metastatic GTD will undergo surgery for removal of primary tumor or metastases, or for the management of metastatic complications, such as hemorrhage or infection.14 Single-agent chemotherapy is often administered as an “umbrella” to protect against metastases at the time of resection. Pulmonary wedge resection is the most commonly used procedure for excision of drug-resistant metastatic disease, with an up to 93% success rate.20 Primary hepatic involvement has been reported in 2%– 8% of patients with metastatic GTD and is associated with 40%–50% survival rates.16 Individualized treatment options include combination chemotherapy, whole-liver irradiation with 2,000 cGy, hepatic artery chemotherapy infusion, and local resection. These lesions tend to be 79

CIRISANO AND SOPER Table 5. EMA-CO Chemotherapy for High-Risk Gestational Trophoblastic Disease Course A Day 1 Dactinomycin Etoposide Methotrexate* Day 2 Dactinomycin Etoposide Folinic acid Course B Day 8† Vincristine Cyclophosphamide Day 15 Recycle course A

500 100 100 200

mg mg/m2 mg/m2 mg/m2

IV IV IV IV

bolus infusion over 30 min bolus infusion over 12 h

500 mg 100 mg/m2 15 mg

IV bolus IV infusion over 30 min IM/po q 6 h 3 4 doses begin 12 h after methotrexate infusion complete

1.0 mg/m2 600 mg/m2

IV bolus IV infusion

* Increased to 1 g/m2 as 24-hour infusion for patients with CNS metastases. Folinic acid increased to 15 mg IM/po q 8 hours 3 9 doses beginning 12 hours after methotrexate infusion completed. † Patients with CNS metastases or high-risk WHO score often receive 12.5 mg methotrexate by intrathecal injection. EMA-CO, etoposide-methotrexate-dactinomycin and cyclophoshamide-vincristine; IV, intravenous; IM, intramuscular; po, orally. Data from Hancock et al.1

highly vascularized with the potential for liver rupture and intraabdominal hemorrhage. When brain metastases occur, they may be managed using multiagent chemotherapy comprised of high-dose intravenous methotrexate (1 g per m2) infusions and intrathecal methotrexate incorporated into the EMA-CO regimen, with reported success rates of 67%– 69%.21 Alternatively, whole-brain irradiation to 3,000 cGy combined with MAC chemotherapy has similar success rates of 70%– 89%.16 The authors have concerns regarding long-term neurologic function in patients who receive concurrent moderate-to-high-dose methotrexate infusions and central nervous system irradiation, and currently use a modification of the EMA-CO regimen.

MONITORING AND RECURRENCE FOLLOWING TREATMENT FOR MALIGNANT GTD Weekly serum hCG levels are followed in patients receiving chemo80

therapy for malignant GTD. Both nonmetastatic and low-risk metastatic tumors generally clear hCG in a log-linear fashion. Relative tumor resistance is considered when regression is less than 25% or when a rise occurs, and alternative chemotherapy should be instituted. Remission is defined as three normal hCG levels within a 2-week period. At our institution, patients with nonmetastatic or metastatic lowrisk disease receive one or two additional cycles and those with high-risk receive three or more maintenance cycles, depending on total treatment interval required to achieve remission. Recurrence risk ranges from ,5% for patients with nonmetastatic or low-risk metastatic disease up to 20% for those with high-risk disease.22 Approximately 80% of recurrences are within the first year and 95% by 18 months.22 After remission, patients are monitored for the first 3 months at 2-week intervals, and monthly thereafter for 1 year. Because the risk of recurrence is low after 1 year, the authors follow hCG levels every

6 months for at least 5 years. The risk for subsequent recurrence after a second remission is 50%, indicating the need for even closer longterm surveillance. Pregnancy should be deferred for at least 1 year to prevent disruption of hCG surveillance. The majority of pregnancies following treatment for GTD have a favorable outcome without an increased risk of congenital malformations.1 Because of the increased risk for repeat molar gestation (1%–2%), these patients warrant early ultrasound to confirm fetal viability and placental appearance, chest X-ray to rule out occult metastases, histologic evaluation of the placenta at delivery to exclude choriocarcinoma, and follow-up serum hCG 6 – 8 weeks after delivery to rule out recurrent malignant GTD. Unlike the risk for repeat molar gestation, a second gestational choriocarcinoma following successful treatment of choriocarcinoma arising from a normal pregnancy has not been reported.1

PLACENTAL-SITE TUMORS These tumors typically have only a small proportion of syncytiotrophoblastic tissue and may produce only low levels of hCG or none at all. The intermediate cytotrophoblasts may produce hPL, which serves as a more reliable tumor marker.1 Unlike other forms of GTD, placentalsite tumors are less sensitive to chemotherapy, warranting earlier surgical intervention. Benign proliferations may be managed successfully with uterine curettage. After a negative metastatic workup, locally invasive tumors are best managed with hysterectomy, although hysterotomy and uterine reconstruction has been reported with subsequent term pregnancy by cesarean section.5 Combination chemotherapy is indicated for metastatic disease, with limited data supporting the use of EMA-CO.2 Prim Care Update Ob/Gyns

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References 1. Hancock BW, Newlands ES, Berkowitz RS. Gestational trophoblastic disease, 1st ed. New York: Chaman & Hall Medical, 1997. 2. Bagshawe KD, Dent J, Webb J. Hydatidiform mole in England and Wales 1973–1983. Lancet 1986;2: 673. 3. Parazzini F, LaVecchia C, Pampallona S. Parental age and risk of complete and partial hydatidiform mole. Br J Obstet Gynaecol 1986;93: 582. 4. Brinton LA, Braken MB, Connelly RR. Choriocarcinoma incidence in the United States. Am J Epidemiol 1986;123:1094. 5. Leiserowitz GS, Webb MJ. Treatment of placental site trophoblastic tumor with hysterotomy and uterine reconstruction. Obstet Gynecol 1996;88:696. 6. Curry SL, Hammond CG, Tyrey L, et al. Hydatidiform mole: diagnosis, management, and long-term follow up of 347 patients. Obstet Gynecol 1975;45:1. 7. Twiggs LB, Okagaki T, Phillips GC, et al. Trophoblastic pseudotumor: evidence of malignant disease potential. Gynecol Oncol 1981;12:238. 8. Montz FJ, Schlaerth JB, Morrow CP. The natural history of theca lutein cysts. Obstet Gynecol 1988;72:247. 9. Stellar MA, Genest DR, Bernstein MR, et al. Natural history of twin pregnancy with complete hydatidiform mole and coexistent fetus. Obstet Gynecol 1994;83:35.

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10. Soper JT, Evans AC, Conoway MR, et al. Evaluation of prognostic factors and staging in gestational trophoblastic tumors. Obstet Gynecol 1994;84:969. 11. Sand PK, Lurain JR, Brewer JI. Repeat gestational trophoblastic disease. Obstet Gynecol 1984;63:140. 12. Creasman WT. Revision in classification by International Federation of Gynecology and Obstetrics. Am J Obstet Gynecol 1992:351–359. 13. World Health Organization Scientific Group on Gestational Trophoblastic Disease. Technical report series No. 692. Geneva: World Health Organization, 1983. 14. Hammond CB, Weed JC Jr, Currie JL. The role of operation in the current therapy of gestational trophoblastic disease. Am J Obstet Gynecol 1980;136:844. 15. Hammond CB, Borchert LG, Tyrey L, et al. Treatment of metastatic trophoblastic disease: good and poor prognosis. Am J Obstet Gynecol 1973;115:4. 16. Soper JT, Clarke-Pearson DL, Hammond CB. Metastatic gestational trophoblastic disease: prognostic factors in previously untreated patients. Obstet Gynecol 1988;71:338. 17. Curry SL, Blessing JA, DiSaia PJ, et al. A prospective, randomized comparison of methotrexate, dactinomycin, and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine in “poor prognosis” metastatic

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19.

20.

21.

22.

gestational trophoblastic disease: a Gynecologic Oncology Group study. Obstet Gynecol 1989;73:357. Bower M, Newlands ES, Holden L, Short D, et al. EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol 1997;15:2636 – 43. Elit L, Covens A, Osborne R, et al. High-dose methotrexate for gestational trophoblastic disease. Gynecol Oncol 1994;54:282. Tomoda Y, Arii Y, Kaseki S, et al. Surgical indications for resection in pulmonary metastasis of choriocarcinoma. Cancer 1980;46:2723. Newlands ES, Bagshwawe KD, Begent RH, Rustin GJ, Holden L. Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high-risk gestational trophoblastic tumors. Br J Obstet Gynaecol 1991;98:550 –552. Mutch DG, Soper JT, Babcock CS, et al. Recurrent gestational trophoblastic disease: experience of the Southeastern Regional Trophoblastic Disease Center. Cancer 1990;66: 978.

Address correspondence and reprint requests to Frank D. Cirisano, Jr, MD, Gynecologic Oncology Associates, Inc., 1295 N.W. 14th Street, Suite H, Miami, FL 33125.

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