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Using the FIGO 2000 scoring system, each patient is considered individually and treated by a multidisciplinary team. Figure 34-9 outlines the general diagnostic and therapeutic approaches used at the University of Texas MD Anderson Cancer Center.
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Hydatidiform mole is curable. The treatment is mainly surgical (53), but optimal management is dependent on the desire to preserve reproductive capability. All patients are evaluated for any medical condition secondary to the mole and treated appropriately before surgery. Most patients are of reproductive age, wish to maintain fertility, and are treated with suction dilation and curettage, often with ultrasound guidance to remove all molar tissue and avoid uterine perforation (1,53). The procedure has less than a 1% incidence of mortality (15). If the uterus is greater than 16 weeks in size, there is a risk of pulmonary embolization of molar tissue, and care in a referral center is warranted (2). Depending on the trophoblastic elements, the amount of bleeding can vary. Oxytocin is often infused immediately prior to surgery to limit the volume of blood lost, although caution is necessary in patients with medical complications due to the risk of hyponatremia and fluid overload (54). Specimens from surgery are sent for pathologic evaluation. Labor induction and hysterectomy are not recommended due to the increased incidence of post-molar GTN requiring chemotherapy (38). Patients maintaining fertility should be counseled with regard to the possibility of another molar pregnancy and of malignant transformation. Patients with partial moles should be given anti-D immunoglobulin prophylaxis.
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In the rare patient who has completed childbearing and no longer desires fertility, hysterectomy to remove the uterus with the mole intact is reasonable. The ovaries may be preserved, even in the setting of theca lutein cysts. After hysterectomy, patients must be followed with hCG levels.
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Postsurgical Care and Indications for Chemotherapy
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After primary surgical treatment, all patients undergo weekly serum β-hCG tests until the level returns to normal on three consecutive assays (ie, 3 consecutive weeks). Three consecutive normal β-hCG levels define complete remission.
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Urine pregnancy tests alone are considered inadequate for monitoring. The level of β-hCG typically normalizes within 8 weeks, but this may take up to 14 to 16 weeks in 20% of patients. In patients with complete moles, the β-hCG should be checked monthly for 6 months. Patients with partial moles have less than 1 in 3,000 risk of subsequent GTD, but rates in the literature range up to 6% (2,3). Although international guidelines do not require follow-up serum hCG testing, this is still performed at our institution (2,6).
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Contraception should be used for 6 months, but no increased risk of recurrent molar pregnancy has been demonstrated in the 6-month period (2). Because luteinizing hormone (LH) interferes with the detection of β-hCG at low levels, the use of oral contraceptives may be useful, because they suppress endogenous LH. Historically, oral contraceptive use prior to normalization of hCG was linked to GTD, but modern oral contraceptives do not appear to pose this risk (2,6).
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Eighty percent of patients need no further treatment (4,55). The other 20% who develop malignant sequelae are treated as appropriate for their status, as either low- or high-risk patients as defined by the FIGO 2000 criteria (see Table 34-5) (15). These patients are considered to have malignant GTN rather than molar pregnancies. The initial pathologic results of the previous gestation were complete mole in 78%, partial mole in 9%, and choriocarcinoma in 8% (15). Of these patients, 81% had low-risk disease, 18% had high-risk disease, and 1% had PSTT. Risk factors include a preevacuation hCG level >100,000 IU/L, excessive uterine growth, theca lutein cysts over 6 cm in diameter, and age over 40 years (56,57). These patients are identified through the following events (2,3,49):
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Rising or plateaued β-hCG level for 2 weeks measured over three separate intervals
Tissue diagnosis of choriocarcinoma
Evidence of metastatic disease
Elevation of β-hCG level after a normal result
Postevacuation bleeding not due to retained tissues
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An elevated but falling hCG 6 months after molar evacuation does not mandate chemotherapy because hCG levels eventually normalize in patients (58). However, a serum hCG level greater than 20,000 IU/L more than 4 weeks after evacuation prompts chemotherapy because of the risk of uterine perforation and hemorrhage (1,2). Patients who receive treatment for molar pregnancy are encouraged to use effective contraception with hormonal or barrier methods during the 6-month interval of β-hCG follow-up. Intrauterine devices are not used because of the potential for uterine perforation. It is essential to exclude a new pregnancy in a patient under surveillance, rather than assume GTD. This is done by correlating the rise in β-hCG levels and ultrasonic findings based on the hCG level.
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Prophylactic Chemotherapy
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Prophylactic adjuvant chemotherapy after molar evacuation is controversial and usually not advised. The postevacuation risk of developing GTN is 15% to 20% after complete mole and 0.5% to 1% after partial mole. In one study, administering dactinomycin intravenously for 5 days starting 3 days after molar evacuation reduced the risk of GTN to 3% to 8% (59). However, such prophylaxis exposes approximately 80% of women to unnecessary chemotherapy and its attendant side effects, as the hCG levels would have been expected to decline without chemotherapy. Additionally, surveillance is still required after chemotherapy, and unnecessary chemotherapy may induce drug resistance (60). Because the vast majority of patients with GTN are detected and cured with hCG surveillance and directed chemotherapy without prophylaxis, prophylactic chemotherapy has not improved survival. Thus, the benefit of prophylaxis is outweighed by the risk, except in unique circumstances where compliant patient follow-up is not possible (2,61).
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A minority of patients who have undergone removal of a complete hydatidiform mole may develop the unusual complication of intermediate trophoblastic disease (19). They usually present with vaginal bleeding and a slightly elevated β-hCG titer. Examination of the uterus may reveal multiple nodules involving the endometrium and myometrium. Surgical intervention is warranted because progressive disease tends to develop, and the disease does not readily respond to chemotherapy.
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Malignant Gestational Trophoblastic Disease
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For malignant GTD, the treatment depends on the cell type, stage, level of serum β-hCG, duration of the disease, specific sites of metastases, and extent of prior treatment. Patients should be stratified for risk prior to initiating a treatment plan. The FIGO 2000 system incorporating the modified WHO scoring system is the most commonly used risk stratification system (see Table 34-4) (47,48,49). A score of 0 to 6 indicates a low risk of developing resistance to single-agent chemotherapy; a score over 6 indicates a high risk of resistance to single-agent chemotherapy and mandates combination chemotherapy.
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To assign a risk category and stage, patients must undergo history, physical, and directed imaging. Patients who are detected early by hCG monitoring are evaluated by history, examination, serum hCG, pelvic ultrasound (excludes pregnancy, measures uterine size, and excludes pelvic extension), and chest x-ray. If the chest x-ray suggests lung metastasis, a chest CT may be ordered, but only lesions visible on chest x-ray should be scored (2,49). If a patient is found to have lung metastasis, an MRI of the brain is obtained to exclude brain metastasis (6). If a patient has choriocarcinoma or suspected GTN following a nonmolar pregnancy, imaging should include a CT of the chest and abdomen, MRI of the brain and pelvis, and a pelvic ultrasound to evaluate for metastases to the lung, liver, pelvis, and brain (2). Positron emission tomography (PET)/CT may be useful in imaging patients with recurrent disease prior to consideration of surgical resection (6). Lumbar puncture to measure the CSF:serum hCG ratio is of historical interest but is not routinely used since the advent of MRI.
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Low-Risk Disease, Nonmetastatic
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Hysterectomy is the treatment of choice for patients who do not wish to maintain fertility. Posthysterectomy chemotherapy may be considered but is not routine. The rationale behind chemotherapy is to reduce the likelihood of disseminating viable tumor cells at surgery and during the immediate postoperative period as well as to eliminate any occult metastases. Outcomes data are not convincing. Patients who wish to retain fertility should receive chemotherapy as primary treatment for low-risk disease. Each patient must be stratified for risk prior to initiating chemotherapy.
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Acceptable chemotherapy regimens are listed in Table 34-6. Either methotrexate, with or without folinic acid rescue, or dactinomycin is acceptable with the schedules as outlined. The differences in inclusion criteria in studies comparing these regimens make determining superiority of one regimen over another difficult, although dactinomycin may result in superior outcomes. The only published randomized trial compared low-dose methotrexate (30 mg/m2) with dactinomycin and found dactinomycin to be superior (62). Advocates of methotrexate cite less toxicity, no hair loss, less nausea, less vomiting, and less myelosuppression. Advocates of dactinomycin cite the above trial and less frequent infusion schedule (2). An ongoing trial conducted by the Gynecologic Oncology Group compares pulsed dactinomycin with intravenous methotrexate. Regardless, patient outcome for low-risk nonmetastatic GTN is cure.
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Response to treatment is determined by monitoring serum β-hCG levels every 1 to 2 weeks during treatment (2). Persistent elevation over three consecutive samples or an increase in titer of β-hCG over two consecutive samples over more than 2 weeks indicates disease resistant to first-line therapy and requires restaging (2). Phantom hCG syndrome must be excluded in the setting of low-level persistent positive results. Assuming this represents a true result, if the tumor is still limited to the uterus and the patient is older than 40 years and/or has no wish to retain fertility, hysterectomy is offered. If the patient prefers to retain fertility and belongs to the low-risk category, she can be treated with other chemotherapy. Patients who are initially treated with methotrexate but fail with hCG levels less than 300 IU/L can often be cured with dactinomycin administered as a single agent. Patients with higher levels of hCG should be treated with combination EMA-CO chemotherapy (etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine) (2,6). Despite a high rate of resistance to first-line chemotherapy, a cure rate of almost 100% is achieved with combination chemotherapy. In the rare instances of tumor resistance to combination chemotherapy in a patient who wishes to retain fertility, localized resection should be offered after careful evaluation by perioperative MRI, ultrasonography, and/or arteriography.
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Once the serum hCG has normalized, three additional treatments of chemotherapy past normal are administered to minimize the chance of recurrence (2). A comparison of two versus three cycles of methotrexate past normalization of hCG level showed a doubling in recurrence rates in patients receiving only two consolidation courses, so it is important to administer three cycles past titer normalization (63).
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Low-Risk Disease, Metastatic
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More than 50 years ago, metastatic GTD was not curable. Since then, treatments have improved such that the cure rate now exceeds 90% (5). This success is the result of a combination of factors:
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The discovery that these tumors are chemosensitive
The ability to diagnose and monitor therapy by using β-hCG levels
Identification of prognostic factors
Use of combination therapy
Referral of patients to specialized centers for treatment
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Patients with metastatic low-risk disease as determined by the WHO prognostic scoring system have a high potential for cure with chemotherapy alone (1,2). Single-agent chemotherapy with methotrexate or dactinomycin is indicated as in low risk nonmetastatic disease (see Table 34-6). Complete response occurs in 90% of patients with low-risk disease, with little short- or long-term toxicity (64). In patients who fail single-agent therapy with methotrexate and have hCG levels less than 300 IU/L, dactinomycin can still result in cure (6). Patients who fail single-agent chemotherapy are still cured with combination regimens (64).
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Patients in whom treatment does not produce a complete response may have undetected metastatic disease. Mutch et al reported that at least 40% of patients with a negative chest radiograph result will have a positive chest CT scan and may be at higher risk of resistance to single-agent therapy (65). The cure rate for patients with low-risk disease is essentially 100% (2,6).
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High-risk disease is not likely to be cured by single-agent chemotherapy, and patients with high-risk disease are at the highest risk of treatment failure. These patients should be treated with combination chemotherapy, most commonly EMA-CO (Table 34-7) (1,2,5). The ACE regimen (dactinomycin, cisplatin, and etoposide) has recently been reported to have outstanding efficacy but is not yet regarded as standard of care for upfront high-risk disease (66).
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Historically, a combination of MAC (methotrexate, dactinomycin, and cyclophosphamide) was used, producing cure rates of 63% to 80% (67). In intermediate- or high-risk GTT, MAC is most effective when used as initial chemotherapy (65% survival) rather than second-line treatment (39% survival) following failed single-agent therapy (67).
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An older regimen, CHAMOCA (cyclophosphamide, hydroxyurea, dactinomycin, methotrexate with leucovorin rescue, vincristine, cyclophosphamide, and doxorubicin), resulted in a remission rate of 82%, but this regimen was inferior to MAC in terms of toxicity and efficacy and is not used in current practice (68).
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Because etoposide was identified to have activity against trophoblastic disease, Bagshawe developed the EMA-CO regimen and reported a survival rate of 83% in patients with high-risk choriocarcinoma (69). The efficacy of this combination has been confirmed and this remains the preferred regimen for high-risk GTT (70,71,72). It is generally well tolerated. Toxicity includes alopecia, mild anemia, neutropenia, and stomatitis. Reproductive function is preserved in 75% of patients. In patients with significant tumor volume, rapid tumor necrosis may result in hemorrhage, and consideration may be given to lower dose induction therapy. After normalization of hCG, three additional consolidation cycles (6 weeks) of EMA-CO are administered (2).
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Metastases Requiring Special Care
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In the setting of high-risk disease and bulky tumor in areas susceptible to massive hemorrhage or worsening organ failure, consideration may be given to induction chemotherapy followed by full-dose combination chemotherapy. Patients with massive pulmonary or liver metastases or brain metastases may benefit from a 25% dose reduction for the first two cycles, with monitoring in an intensive care unit setting until the disease shrinks enough to allow full-dose chemotherapy with less significant risk of hemorrhage. An alternative strategy is to use low-dose etoposide 100 mg/m2 and cisplatin 20 mg/m2 on days 1 and 2 every week up to three times prior to initiating standard EMA-CO. Additionally, consideration can be given to using EMA-EP (EMA with etoposide and cisplatin) rather than EMA-CO in patients with the worst prognosis, namely with liver and brain metastases.
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Significant vaginal hemorrhage should prompt resuscitative transfusion but is expected to resolve within 3 to 4 days. Additional strategies for management may include embolization, hysterectomy, and arterial ligation. Nearly all patients experiencing hemorrhage can be expected to survive with appropriate resuscitation and management (73). Twenty-five percent of patients with high-risk disease do not attain complete remission, in which case salvage chemotherapy is administered.
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Pulmonary metastases can be extensive and may cause respiratory failure and death (74). Some factors that predict a worse outcome or early death from respiratory compromise include cyanosis, pulmonary hypertension, dyspnea, anemia, tachycardia, extensive (>50%) lung opacification, mediastinal involvement, bilateral pleural effusion, and a high WHO prognostic score (75,76). In patients with extensive pulmonary metastases, reduced doses of initial chemotherapy have been suggested to abate the risk of respiratory failure, although this strategy does not protect completely against pulmonary failure and death (75,76).
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Central Nervous System Metastases
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Like pulmonary metastases, CNS metastases pose a significant threat. Although clinically apparent in only 7% to 28% of patients with choriocarcinoma, CNS involvement is found in as many as 40% of patients on postmortem examination. Multimodality therapy seems to be optimal, yielding a remission rate of 50% (7 of 14 patients) with disease-free intervals of 12 to 120 months.
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Athanassiou et al reported that 8.8% of 782 patients had CNS metastases (41). The overall survival rate of patients who had CNS metastases at diagnosis was 80%. The overall survival of patients who developed CNS metastases after initial diagnosis and treatment was only 25%. Two other studies found similar outcomes and concluded that CNS prophylaxis may improve prognosis (77,78). However, Gillespie et al showed no benefit of CNS prophylaxis in 69 patients with lung metastases (79). We do not advocate CNS prophylaxis in the absence of definite CNS disease.
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Patients with known CNS disease benefit from chemotherapy and whole-brain irradiation. In a retrospective analysis of 70 patients, half died before therapy was initiated. Of the remaining patients, 24% of those given chemotherapy alone survived, but 50% of patients given concurrent chemotherapy plus whole-brain irradiation achieved long-term remission and none died of CNS disease (80).
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When patients present with CNS metastases, primary treatment of the brain with surgical resection or radiotherapy prior to EMA-CO chemotherapy is indicated to decrease the risk of hemorrhage. Surgical resection is appropriate only for patients with solitary metastasis. Surgical decompression should be considered for patients who have symptoms of raised intracranial pressure (81).
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The optimal dose of radiation appears to be 30 Gy. Patients with less than 25 Gy had a lower cure rate (80). The local control rate was 91% if >22 Gy was administered but 24% if <22 Gy was administered (82). For CNS disease, it is prudent to administer 30 Gy over 10 fractions initiated simultaneously with the start of chemotherapy. Stereotactic radiotherapy or gamma-knife treatment has been advocated at the end of chemotherapy to treat any residual unresectable lesions as an alternative to whole-brain radiation, due to the toxicity and limited evidence of improvement with whole-brain irradiation (6).
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The EMA-CO chemotherapy regimen should be administered following surgery or radiation (83). The dose of methotrexate is escalated to 1,000 mg/m2. Intrathecal methotrexate 12.5 mg may be given with the CO component of EMA-CO or with whole-brain radiotherapy (20-30 Gy in two daily fractions) concurrent with chemotherapy (6,84). Extracranial sites of metastases at the time of CNS metastasis are common. Overall survival in patients with CNS metastases is 67% (83).
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Patients in First Remission
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Patients in first remission thought to have a high risk of recurrence are observed closely with serum β-hCG levels and posttherapy baseline radiologic imaging. For patients who had lung metastases, a repeat high-resolution CT scan at the end of chemotherapy serves as a baseline for follow-up. Many patients who have had lung metastases have residual nodules in the lung field on CT scans or chest x-ray, signifying fibrous scar tissue. For patients who had brain metastases, an MRI of the head would be obtained. Likewise, for patients who had liver metastases, a CT scan of the liver would be obtained. If the uterus is in place and was a site of previous disease, consideration is also given to baseline MRI of the uterus. The rationale is that modest increases in the β-hCG level, signifying relapse, may be accompanied by subtle changes in “sterile” lesions noted on earlier images. This finding raises the issue of surgical resection of a chemotherapy-resistant site. If the imaging obtained after chemotherapy reveals suspicious nodules or masses and the β-hCG level is normal, a baseline PET-CT scan is sometimes obtained to serve as a baseline. If the β-hCG level rises during follow-up, a PET-CT scan would help identify active disease.
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One-quarter of patients with high-risk metastatic disease do not achieve complete remission with EMA-CO or experience relapse later. These patients require identification of chemotherapy-resistant sites for possible surgical resection and salvage therapy with alternative platinum-based regimens. These regimens may include EMA-EP (omitting day 2 etoposide and dactinomycin and alternating weekly with etoposide and cisplatin); TE/TP (paclitaxel and etoposide alternating weekly with paclitaxel and cisplatin); ACE (dactinomycin, cisplatin, and etoposide); VIP (etoposide, ifosfamide, and cisplatin); BEP (bleomycin, etoposide, and cisplatin); cisplatin, vincristine, and methotrexate; PVB (cisplatin, vinblastine, and bleomycin); PEBA (cisplatin, etoposide, bleomycin, and doxorubicin); and ICE (high-dose ifosfamide, carboplatin, and etoposide) (2,5,66,85,86,87,88,89,90,91,92,93,94,95). Response rates range from 20% to 75%. The most commonly used regimens are EMA-EP, which is toxic but results in a cure rate greater than 75%, and TE/TP, which may be equally efficacious and less toxic (2).
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Cure can also be achieved with surgery in a subset of chemoresistant patients who have one to three disease sites after combination chemotherapy. In this setting, PET-CT may be useful to detect metastatic sites (6,96). Total or radical hysterectomy to remove the disease, with or without adnexectomy and lymphadenectomy, can be curative in 90% of patients with primary drug-resistant and relapsed GTN (97,98).
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Patients who fail these approaches may be candidates for high-dose chemotherapy. Limited outcomes data exist, but reports suggest that high-dose chemotherapy alone combined with surgical resection may lead to salvage in one-third of patients. The most common regimen is CarbopEC-T (carboplatin, etoposide, cyclophosphamide, and paclitaxel) (2,6).
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Placental Site Trophoblastic Tumor
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Originally known as trophoblastic pseudotumor, these tumors have been designated as PSTT to better reflect their malignant potential. The median age at diagnosis is 33 years (range, 18-47 years). The most common presenting symptoms are irregular vaginal bleeding, amenorrhea, and a pelvic mass (17). The median interval from antecedent pregnancy is 3.4 years. These tumors present with lung metastases in 10% to 20% of cases, and 10% of patients develop metastases during the follow-up interval (17).
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The FIGO scoring is not used to determine the treatment of PSTT (2). Hysterectomy is the preferred treatment for nonmetastatic disease, which is highly curable. Postoperative chemotherapy is indicated for patients with certain risk factors, including metastatic disease, mitotic index, hCG level, and time from antecedent pregnancy. The latter is the most prognostic factor (2). The long-term survival rate of patients presenting with PSTT within 4 years of antecedent pregnancy was 98%, compared with 100% mortality for patients presenting with PSTT more than 4 years after antecedent pregnancy, but these findings have been inconsistent (14,17).
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The general strategy is to perform hysterectomy for patients with nonmetastatic disease who present less than 4 years after antecedent pregnancy. Premenopausal patients with limited disease may preserve their ovaries, and lymphadenectomy is of limited utility (17). Patients with metastatic disease at presentation receive EMA-EP (2,14,94,99,100) and, upon response, undergo resection of residual disease sites and hysterectomy. Recurrent disease not amenable to surgical resection may require radiation or combination chemotherapy with EMA-CO (94,99). Patients who present more than 4 years after antecedent pregnancy have poor survival and should be considered for clinical trials or high-dose chemotherapy, even when the disease appears to be localized (1,2,7). Patients with limited disease who desire fertility may be considered for focal uterine resection with or without chemotherapy, but this is investigational (1,2).
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Placental site trophoblastic tumor produces β-hCG inconsistently, so the serum β-hCG level is not uniformly helpful in diagnosis, treatment, or follow-up (17,64). Placental site trophoblastic tumor is less responsive to chemotherapy than choriocarcinoma, but chemotherapy remains effective in many patients, and the prognosis depends on the extent of disease at presentation (2,17). The overall mortality rate of PSTT is 16% to 21% (3). The median overall survival is 86 months; 88% of patients with early-stage disease and 11% of patients with advanced-stage disease were without evidence of disease 28 months after diagnosis (17).
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Epithelioid Trophoblastic Tumor
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This rare disease entity appears to be distinct from PSTT but is treated in a similar fashion. The International Society for the Study of Trophoblastic Disease database is collecting information on both of these tumor entities and will inform future treatment decisions (2).