Initial Management of High-risk Gestational Trophoblastic Neoplasia

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Ini titi al al manag em ement of hi gh gh- ri ri sk sk g es estati on onal tr op ophobl as asti c neopl as asi a

Official Official reprint reprint from from UpToDate ® www.uptodate.com   ©2015 UpToDate®

Initial management of high-risk gestational trophoblastic neoplasia Authors Ross S Berkowitz, MD Donald Peter Goldstein, MD Neil S Horowitz, MD

Section Editor  Barbara Goff, MD

Deputy Editors Don S Dizon, MD, FACP Sandy J Falk, MD, FACOG

 All topics topics are are upda updated ted as new new evide evidence nce become becomes s availa available ble and and our our peer review process  process   is complete. Literature review cur rent rent through: Jan 2015. | This topic last l ast updated: Jan 06, 2015. INTRODUCTION  INTRODUCTION  — Gestational trophoblastic disease (GTD) defines a group of conditions that arise from an aberrant fertilization event. When GTD recurs or there is evidence of metastatic disease, it is called gestational trophoblastic neoplasia (GTN) and comprises four subtypes of disease: ● Invasive mole ● Choriocarcinoma ● Placental site  site  trophoblastic tumor (PSTT) ● Epithelioid trophoblastic tumor (ETT) The initial treatment treatment of high-risk GTN is discussed here. The pathol ogy, epidemiology, clinical manifestations, and staging of of GTD are discussed separ ately.   In addition, the management of low-risk and recurrent GTN are also discussed discuss ed separately. ● (See "H "Hydatidiform ydatidiform mole: Epidemiology, clinical features, and   diagnosis".) ● (See "Gestational trophoblastic disease: Pathology" .) ● (See "Hydatidiform mole: Management".) Management" .) ● (See "Initial management of low-risk gestational trophoblastic neoplasia" .) DEFINITION OF HIGH-RISK DISEASE  DISEASE  — High-risk gestational trophoblastic neoplasia (GTN) is characterized by the International Federation of Gynecology and Obstetrics (FIGO) stage and the World Health Organization (WHO) risk score (table (table 1) 1) (see "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification", section on 'Staging and risk assessment' ): ● Stage IV disease ● Stages II and III with risk score >6 Of note, the WHO Prognostic Prognostic Scoring System is not applicable to patients with placental site trophoblastic tumor tumor (PSTT) or epithelioid epithel ioid trophoblastic trophoblastic tumor (ETT), (ETT), and those  those  patients are not categorized categorized as either low risk or high high risk. risk. They are, however, st aged based on the FIGO Stage. Stag e. The management management of these patients is discussed below. (See 'Placental site or epithelioid trophoblastic tumor'  tumor'   below.) APPROACH TO TREATMENT  TREATMENT  — Gestational trophoblastic neoplasia (GTN) is uniquely sensitive to chemotherapy, which is the major  treatment   modality for patients with high-risk disease. The exception to this is women with placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT), in which case, the primary treatment may be a combination of surgery and chemotherapy, primarily because PSTT and ETT are relatively resistant to chemotherapy as compared with choriocarcinoma and invasive mole. Regardless, in the treatment of high-risk GTN, other modalities such as surgery and radiation therapy (RT) may be indicated in addition to chemotherapy. For patients in whom combination chemotherapy is indicated, treatment may result in ovarian insufficiency. Therefore, we advocate for the use of oral contraceptives to suppress the pituitary glands' production of      luteinizing hormone which aims to protect the ovaries from the toxicity of chemotherapy and also suppress the production of human chorionic gonadotropin (hCG), which in our clinical experience, could falsely suggest the http://www http://www.uptod .uptodate.com ate.com/contents/initi /contents/initi al-man al- management-of-hi agement-of-hig g h-ris h-r isk k-g estational- trophoblastic -neoplasia?top -neoplasi a?topic icKey Key=ON =ON C%2F96232&elapsed C%2F96232&elapsedTi TimeMs= meMs=0&sou… 0&sou… 1/13

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Ini ti al manag ement of hi gh- ri sk g estati onal tr ophobl asti c neopl asi a

presence of active disease if not suppressed [ 1]. (See "Fertility preservation in patients undergoing gonadotoxic treatment or gonadal resection", section on 'Gonadal suppression'   and"Hydatidiform mole: Management", section on 'Contraception'.) Chemotherapy  — Patients with high-risk GTN are likely to develop drug resistance if single-agent therapy is administered. Therefore, these patients are commonly treated with multi-agent regimens. Evidence of the greater likelihood of resistance to single-agent chemotherapy comes from a retrospective study that included over 300 patients treated for nonmetastatic GTN [ 2]. Although all patients were cured, 27 of 253 patients (11 percent) initially treated with methotrexate  (MTX) developed resistance. In this series, only six patients experienced a relapse after obtaining a remission; of these, five patients had a choriocarcinoma. Our preferred regimen for these patients is etoposide, MTX, plus actinomycin D (ActD) alternating with cyclophosphamide  andvincristine  (EMA-CO) because it results in complete response rates between 71 and 78 percent and long-term survival rates of 85 to 94 percent [ 3-11]. However, a 2012 Cochrane review has found that regimens that incorporate etoposide and cisplatin  are effective options, though the lack of randomized trials prevented an analysis to define the optimal regimen [ 12]. EMA-CO  — EMA-CO has emerged as the regimen of choice for initial treatment of high-risk GTN. This is predominantly based on retrospective data that consistently show it is active in high-risk GTN and is associated with a low toxicity profile [12,13]. The components of this regimen are [ 11]: ● Etoposide  – 100 mg/m2 IV over 30 minutes on days 1 and 2 ● MTX – 100 mg/m 2 IV bolus followed by 200 mg/m 2IV over 12 hours on day 1 ●  ActD – 0.5 mg IV bolus on days 1 and 2 ● Leucovorin  calcium – 15 mg orally every 12 hours for four doses, starting 24 hours after start of MTX ● Cyclophosphamide  – 600 mg/m2 IV on day 8 ● Vincristine  – 1.0 mg/m2 IV on day 8  Although EMA-CO is the most widely used regimen, there have been no randomized trials to demonstrate that it should be the preferred regimen. However, compared with other combination regimens, it appears to be as effective (if not more so) and better tolerated. This was shown in one report that included over 200 women with high-risk GTN treated with [ 13]: ● MTX plus ActD and folinic acid (MA, administered between 1971 and 1995) ● MTX, ActD, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine  (CHAMOCA, administered between 1982 and 1995) ● MTX, ActD, and chlorambucil  (MAC, administered between 1971 and 1982) ● EMA-CO (administered between 1985 and 1995) Of these four regimens, EMA-CO resulted in [ 13]: ● The highest remission rate (91 percent) compared with MA, CHAMOCA, and MAC (63, 76, and 68 percent, respectively) and required the fewest number of courses to attain remission ● The lowest mortality rate (9 percent versus 37, 22, and 33 percent, respectively) In a 2012 systematic review, the administration of EMA-CO was associated with primary remission rates ranging from 54 to 91 percent of patients [ 12]. These data support the use of EMA-CO as a primary treatment for high-risk GTN. Administration  — Treatment with EMA-CO should be administered every two to three weeks. Although a treatment delay or dose reduction may be required due to side effects, these should be avoided as both have http://www.uptodate.com/contents/initi al-management-of-high-risk-g estational-trophoblastic-neoplasia?topicKey=ON C%2F96232&elapsedTimeMs=0&sou… 2/13

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Ini ti al manag ement of hi gh- ri sk g estati onal tr ophobl asti c neopl asi a

been associated with less than optimal outcomes. Treatment should be continued until the hCG level becomes undetectable and remains undetectable for three consecutive weeks. Finally, we administer at least three courses of EMA-CO after the patient achieves undetectable hCG levels as consolidation therapy to reduce the risk of relapse, which is supported by the limited data. (See "Initial management of low-risk gestational trophoblastic neoplasia", section on 'Consolidation therapy'.) The Charing Cross Group has reported the use of induction low-dose etoposide  (100 mg/m2 ) andcisplatin (20 mg/m2) on days 1 and 2 every seven days in selected patients with high tumor burden. This has almost completely eliminated early mortality from respiratory compromise and hemorrhage. They also report a 94 percent remission rate with EMA-CO by carefully excluding non-gestational tumors using genetic analysis [ 14]. Patients with brain metastases  — For patients with brain metastases, a neurosurgical consult should be obtained prior to treatment. These patients are at risk for complications directly related to their brain metastases or as a consequence of treatment, which may require urgent or emergent treatment (eg, craniotomy for    intracerebral bleeding). For these patients, we administer a modification of systemic EMA-CO that uses a higher MTX dose (1000 mg/m 2 over 24 hours) than what is routinely administered [ 15]. The higher dose of      parenteral MTX allows for adequate levels of MTX within the cerebrospinal fluid (CSF) [ 15-18]. In addition, these patients should receive dexamethasone  to decreasecerebral edema; however, prophylactic anti-epileptic drugs are generally not recommended in most patients, provided there is no history of an antecedent seizure. (See "Seizures in patients with primary and metastatic brain tumors" .)  A typical regimen is as follows [18]: ● Etoposide  – 100 mg/m2 IV over 60 minutes on days 1 and 2 ● MTX – 1000 mg/m 2IV over 24 hours on day 1 ●  ActD – 0.5 mg IV bolus on days 1 and 2 ● Leucovorin  calcium – 30 mg intramuscular (IM) or orally every 12 hours for three days, starting 32 hours after treatment with MTX ● Cyclophosphamide  – 600 mg/m2 IV on day 8 ● Vincristine  – 1.0 mg/m2 IV on day 8 Finally, these patients should be closely followed during treatment, which can be done using serial imaging. Role for intrathecal therapy  — The need for intrathecal (IT) therapy in these patients is controversial [16,18-20], and its use alongside high-dose EMA-CO is based on institutional preferences. If administered, MTX is given as a 12.5 mg dose IT on day 8, followed by leucovorin  calcium 15 mg at 24 and 36 hours. However, one small study that included 15 patients treated with EMA-CO plus IT MTX reported that 87 percent (13 patients) achieved a sustained remission without the use of whole-brain irradiation [ 18]. Concomitant whole-brain radiation therapy  — At the New England Trophoblastic Disease Center    (NETDC), we administer cranial RT (20 to 30 Gy in 2 Gy daily fractions) concurrently with high-dose MTX chemotherapy. As with the role of IT MTX, the role of cranial RT is also controversial. In addition to shrinking the brain metastases, concomitant cranial irradiation increases the MTX concentration within the central nervous system (CNS) [21] and reduces the risk of cerebral hemorrhage prior to eradication of tumor, and may improve survival [22,23]. However, the use of concurrent MTX and cranial irradiation also increased the likelihood of      treatment-related toxicity, especially leukoencephalopathy. (See "Delayed complications of cranial irradiation", section on 'Neurocognitive effects'.) Cisplatin-containing regimens  — In some centers, a modified EMA-CO regimen that incorporates cisplatin  is preferentially administered to patients with a risk score >12. The most commonly used combination replaces vincristine  andcyclophosphamide  (used in EMA-CO) withetoposide  and cisplatin on day 8 (EMA-EP). EMA-EP alone or in combination with surgery induced complete remission in 16 (76 percent) of 21 patients with EMA-CO resistance [5]. http://www.uptodate.com/contents/initi al-management-of-high-risk-g estational-trophoblastic-neoplasia?topicKey=ON C%2F96232&elapsedTimeMs=0&sou… 3/13

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While no randomized trials compared EMA-CO with cisplatin-containing regimens, a retrospective study evaluated outcomes among 83 patients treated with cisplatin-containing treatment and 103 patients treated with EMA-CO [24]. Compared with EMA-CO, incorporation of cisplatin was associated with: ●  A slightly lower remission rate (85 versus 92 percent, respectively) ●  A lower number of cycles to achieve a normal hCG level (three versus five courses) ● More toxicity, including fever, nephropathy, nausea, and diarrhea APE  — Given the activity ofcisplatin  for GTN, one group reported their experience using ActD, cisplatin, and etoposide  (APE) for high-risk GTN that included 59 patients (out of a total of 96) who were treated with this regimen as initial therapy between 1985 and 2013 [ 25]. Patients with brain metastases or placental site trophoblastic tumors (PSTT) were excluded from treatment. The overall remission rate for these patients was 95 percent. One patient required treatment discontinuation after four cycles due to grade 2 ototoxicity. The final two had refractory disease to this regimen, but all three entered remission with second-line EMA-CO therapy. The five-year disease-free survival rate was 98 percent. Surgery  — Approximately 50 percent of patients with high-risk, metastatic GTN will require adjuvant surgery to achieve cure, even in the presence of multi-organ involvement [ 26-39]. As an example, in one study of 50 patients with high-risk, metastatic GTN treated with EMA-CO between 1986 and 2005, among 24 patients who underwent a total of 28 surgical procedures, the cure rate was 87.5 percent. These procedures included hysterectomy, pulmonary resection, uterine wedge resection, small bowel resection, and selective uterine artery embolization [33]. Surgery is generally performed to resect foci of chemotherapy-resistant disease or to control complications such as bleeding or infection. PLACENTAL SITE OR EPITHELIOID TROPHOBLASTIC TUMOR  — Although universally accepted guidelines are not available, patients with placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT) should be treated with a combination of surgery and chemotherapy. Multi-agent regimens are usually administered, including etoposide, methotrexate  (MTX), plus actinomycin D (ActD) alternating with cyclophosphamide  andvincristine  (EMA-CO) [40] or EMA plus etoposide and cisplatin  (EMA-EP) [41]. There are no prospective data to inform whether one or the other is the preferred regimen. (See "Management of      resistant or recurrent gestational trophoblastic neoplasia", section on 'High-risk gestational trophoblastic neoplasia'.) Unfortunately, patients with metastatic disease have a poor prognosis and a high fatality rate [ 42-44]. In a 2012 review of the literature that reported on the deaths from gestational trophoblastic neoplasia (GTN), 30 percent had placental site trophoblastic tumors (PSTT) [ 44]. In addition, one single-institution series of 18 patients with PSTT reported that five of six who had extrauterine disease ultimately died despite the administration of multiagent chemotherapy [ 43]. Survival with PSTT is strongly related to the number of years since the antecedent pregnancy. Papadopoulos et al, reporting on 34 patients, found that while all 27 patients diagnosed within four    years of the antecedent pregnancy survived, all seven patients died when the antecedent pregnancy was more than four years [42]. MONITORING DURING TREATMENT  — As with women who are treated for low-risk gestational trophoblastic neoplasia (GTN), all women with high-risk GTN should be monitored with serial measurements of serum human chorionic gonadotropin (hCG) at the start of treatment and then at weekly intervals during therapy. This and other considerations for patients during treatment are discussed separately. (See "Initial management of lowrisk gestational trophoblastic neoplasia", section on 'Monitoring during treatment' .) The approximate biologic half-life of hCG is 1.5 to 3 days, and serum levels should fall exponentially (by at least one log within 18 days). A slower rate of decline suggests the possibility of chemoresistance, although there is no consensus or clear guideline as to the optimal cutoff for determining chemoresistance or the management of      patients with a slower than expected tumor marker decline [ 45-47]. Definition of remission  — Remission is achieved when the quantitative hCG level becomes undetectable for    three consecutive weeks. Given the sensitivity of this tumor marker, no imaging is required if levels are consistent with remission because abnormalities on imaging can persist despite the attainment of undetectable http://www.uptodate.com/contents/initi al-management-of-high-risk-g estational-trophoblastic-neoplasia?topicKey=ON C%2F96232&elapsedTimeMs=0&sou… 4/13

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hCG levels, representing fibrosis rather than active tumor. Persistent or progressive disease   — The French Trophoblastic Disease Reference Center in Lyon defines chemotherapy resistance as an increase or a plateau in two consecutive hCG values over a two-week interval [48]. As described above, other generally accepted criteria include detection of new metastases [ 49]. For    patients who appear to have persistent disease, surgery may be a curative option. The approach to patients who experience disease progression is discussed separately. (See "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification" .) PROGNOSIS  — The overall cure rate for patients with high-risk gestational trophoblastic neoplasia (GTN) (stage II to III) ranges between 95 and 100 percent [ 50]. At the New England Trophoblastic Disease Center (NETDC), we treated 90 patients between July 1965 and December 2013, of whom 77.8 percent had a sustained complete remission with primary chemotherapy (table 2). As depicted in the table, of those who developed resistance, second-line therapy ultimately resulted in sustained remission in 85 percent of patients. Overall, 87 (96.7 percent) of 90 patients with high-risk stage II and III GTN achieved complete remission. For patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV high-risk GTN, the prognosis is not as good, though complete remission can be expected in 60 to 70 percent of patients [ 50]. Much of this success is due to the use of combination chemotherapy. After combination chemotherapy was introduced as primary treatment in this group, the survival rate dramatically improved. Since the introduction of      intensive primary combination chemotherapy with adjunctive surgery and radiation therapy (RT), survival at the NETDC increased from 30 to 84 percent ( table 3) [26]. Prognostic factors  — For patients with high-risk GTN, long-term survival appeared to be associated with variables related to disease extent [ 51]: ● In the presence of liver metastases, only 27 percent were alive ● If brain metastases were present, the survival rate was 70 percent ● If both were present, only 10 percent were alive Data from the Charing Cross Hospital indicate that survival with hepatic metastases appears to have improved over time. Excluding early deaths (within four weeks of presentation) and two deaths unrelated to GTN, the cause-specific survival in 25 patients was 68 percent [ 52,53]. POSTTREATMENT SURVEILLANCE  — After remission is achieved, serum human chorionic gonadotropin (hCG) should be measured monthly until there have been undetectable hCG levels for 12 months [ 54,55]. The follow-up of patients treated for high-risk gestational trophoblastic neoplasia (GTN) is similar to that of      women treated for low-risk GTN and includes considerations of contraception and the timing of subsequent pregnancies. These issues are discussed separately. (See "Initial management of low-risk gestational trophoblastic neoplasia", section on 'Posttreatment surveillance'   and"Initial management of low-risk gestational trophoblastic neoplasia", section on 'Fertility and pregnancy' .) Uterine arteriovenous malformation  — Patients treated for GTN that invaded the myometrium (both low-risk and high-risk) are at risk of developing a uterine artery malformation (also known as an arteriovenous fistula), which can persist for months or years after remission is achieved. A fistula may remain asymptomatic and undiagnosed or may present with menorrhagia. The presence of an arteriovenous malformation has also been associated with recurrent miscarriage. (See "Differential diagnosis of genital tract bleeding in women", section on 'Arteriovenous malformation'.) The diagnosis is made with the use of color Doppler transabdominal or endovaginal ultrasonography. Selective pelvic arteriography clearly identifies the abnormal vascular malformation and helps in evaluating possible treatment modalities. If symptomatic, treatment consists of hysterectomy or, when preservation of reproductive function is desired, treatment consists of selective uterine artery embolization [ 56-58]. DIAGNOSIS OF RECURRENT OR RESISTANT DISEASE  — Patients whose human chorionic gonadotropin (hCG) level re-elevates after becoming undetectable for three consecutive weeks are considered to have recurrent  disease. In contrast, patients whose hCG level remains elevated despite treatment are considered to http://www.uptodate.com/contents/initi al-management-of-high-risk-g estational-trophoblastic-neoplasia?topicKey=ON C%2F96232&elapsedTimeMs=0&sou… 5/13

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have resistant  disease. Despite the success of combination chemotherapy, patients treated for high-risk gestational trophoblastic neoplasia (GTN) have an 8 to 10 percent risk of recurrence, dependent on stage and risk score [59]. This is often detected by a re-elevation in the quantitative serum hCG levels after three consecutive weeks of undetectable quantitative hCG levels. The approach to patients with recurrent or resistant disease is discussed separately. (See "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification" .) SUMMARY AND RECOMMENDATIONS ● Gestational trophoblastic neoplasia (GTN) is characterized by the International Federation of Gynecology and Obstetrics (FIGO) stage and the World Health Organization (WHO) risk score ( table 1). Patients are defined as having high-risk GTN if they have stage IV disease or stage II to III disease with a risk score >6. (See 'Definition of high-risk disease'  above.) ● The WHO Prognostic Scoring System is not applicable to patients with placental site trophoblastic tumor    (PSTT) or epithelioid trophoblastic tumor (ETT). Therefore, patients with these subtypes of GTN are not categorized as either low risk or high risk. They should be characterized by their FIGO Stage. (See 'Definition of high-risk disease'  above.) ● GTN is uniquely sensitive to chemotherapy, which is the major treatment modality for patients with highrisk disease. The exception to this is women with PSTT or ETT, in which case, the primary treatment may be a combination of surgery and chemotherapy, primarily because PSTT and ETT are relatively resistant to chemotherapy as compared with choriocarcinoma and invasive mole. (See 'Approach to treatment'  above.) ● For patients with high-risk GTN, we recommend multi-agent chemotherapy rather than single-agent therapy (Grade 1B). We suggest a combination of etoposide, methotrexate  (MTX), plus actinomycin D (ActD) alternating with cyclophosphamide  andvincristine  (EMA-CO) (Grade 2C). (See 'EMA-CO'  above.) ● For patients with high-risk GTN and brain metastases, a neurosurgical consult should be obtained prior to treatment. We suggest EMA-CO as the primary systemic treatment, using a higher MTX dose (1000 mg/m2 over 24 hours) than what is routinely administered otherwise (Grade 2C). We also suggest cranial radiation therapy (RT) for these patients ( Grade 2C). However, for patients who do not wish to proceed with cranial RT, we suggest additional chemotherapy using intrathecal MTX ( Grade 2C). (See 'Patients with brain metastases'  above.) ●  Approximately 50 percent of patients with high-risk, metastatic GTN will require adjuvant surgery to achieve cure, even in the presence of multi-organ involvement. (See 'Surgery'  above.) ●  Although universally accepted guidelines are not available, for patients with PSTT or ETT, we suggest a combination of surgery and chemotherapy ( Grade 2C). Multi-agent regimens are usually administered, including EMA-CO or EMA plus etoposide  andcisplatin  (EMA-EP). There are no prospective data to inform whether one or the other is the preferred regimen, and a choice between them is based on institutional preferences. (See 'Placental site or epithelioid trophoblastic tumor'   above.) ●  As with women who are treated for low-risk GTN, all women with high-risk GTN should be monitored with serial measurements of serum human chorionic gonadotropin (hCG) at the start of treatment and then at weekly intervals during therapy. (See 'Monitoring during treatment'  above.) ● The overall cure rate for patients with high-risk GTN (stage II to III) ranges between 95 and 100 percent. The extent of disease is a prognostic factor among these patients. (See 'Prognosis'  above.) ●  After remission is achieved, serum hCG should be measured monthly until monitoring has shown one year   of normal hCG levels. (See 'Posttreatment surveillance'  above.) Use of UpToDate is subject to the Subscription and License Agreement . REFERENCES

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Initial management of high-ri sk gestational trophoblastic neoplasia

24. Lybol C, Thomas CM, Blanken EA, et al. Comparing cisplatin-based combination chemotherapy with EMA/CO chemotherapy for the treatment of high risk gestational trophoblastic neoplasia. Eur J Cancer    2013; 49:860. 25. Even C, Pautier P, Duvillard P, et al. Actinomycin D, cisplatin, and etoposide regimen is associated with almost universal cure in patients with high-risk gestational trophoblastic neoplasia. Eur J Cancer 2014; 50:2082. 26. Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic diseases. Gynecol Oncol 2009; 112:654. 27. Tomoda Y, Arii Y, Kaseki S, et al. Surgical indications for resection in pulmonary metastasis of      choriocarcinoma. Cancer 1980; 46:2723. 28. Fleming EL, Garrett L, Growdon WB, et al. The changing role of thoracotomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center. J Reprod Med 2008; 53:493. 29. Jones WB, Romain K, Erlandson RA, et al. Thoracotomy in the management of gestational choriocarcinoma. A clinicopathologic study. Cancer 1993; 72:2175. 30. Hoekstra AV, Lurain JR, Rademaker AW, Schink JC. Gestational trophoblastic neoplasia: treatment outcomes. Obstet Gynecol 2008; 112:251. 31.  Alazzam M, Hancock BW, Tidy J. Role of hysterectomy in managing persistent gestational trophoblastic disease. J Reprod Med 2008; 53:519. 32. Doumplis D, Al-Khatib K, Sieunarine K, et al. A review of the management by hysterectomy of 25 cases of gestational trophoblastic tumours from March 1993 to January 2006. BJOG 2007; 114:1168. 33. Lurain JR, Singh DK, Schink JC. Role of surgery in the management of high-risk gestational trophoblastic neoplasia. J Reprod Med 2006; 51:773. 34. Pisal N, North C, Tidy J, Hancock B. Role of hysterectomy in management of gestational trophoblastic disease. Gynecol Oncol 2002; 87:190. 35. Xu LT, Sun CF, Wang YE, Song HZ. Resection of pulmonary metastatic choriocarcinoma in 43 drugresistant patients. Ann Thorac Surg 1985; 39:257. 36. Wang YA, Song HZ, Xia ZF, Sun CF. Drug resistant pulmonary choriocarcinoma metastasis treated by lobectomy: report of 29 cases. Chin Med J (Engl) 1980; 93:758. 37. Cagayan MS, Magallanes MS. The role of adjuvant surgery in the management of gestational trophoblastic neoplasia. J Reprod Med 2008; 53:513. 38. Soper JT. Role of surgery and radiation therapy in the management of gestational trophoblastic disease. Best Pract Res Clin Obstet Gynaecol 2003; 17:943. 39. Clark RM, Nevadunsky NS, Ghosh S, et al. The evolving role of hysterectomy in gestational trophoblastic neoplasia at the New England Trophoblastic Disease Center. J Reprod Med 2010; 55:194. 40. Newlands ES, Mulholland PJ, Holden L, et al. Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumors. J Clin Oncol 2000; 18:854. 41. Newlands ES, Bower M, Fisher RA, Paradinas FJ. Management of placental site trophoblastic tumors. J Reprod Med 1998; 43:53. 42. Papadopoulos AJ, Foskett M, Seckl MJ, et al. Twenty-five years' clinical experience with placental site trophoblastic tumors. J Reprod Med 2002; 47:460. 43. Hyman DM, Bakios L, Gualtiere G, et al. Placental site trophoblastic tumor: analysis of presentation, treatment, and outcome. Gynecol Oncol 2013; 129:58. 44. Kingdon SJ, Coleman RE, Ellis L, Hancock BW. Deaths from gestational trophoblastic neoplasia: any lessons to be learned? J Reprod Med 2012; 57:293. 45. van Trommel NE, Massuger LF, Schijf CP, et al. Early identification of resistance to first-line single-agent methotrexate in patients with persistent trophoblastic disease. J Clin Oncol 2006; 24:52. 46. You B, Pollet-Villard M, Fronton L, et al. Predictive values of hCG clearance for risk of methotrexate resistance in low-risk gestational trophoblastic neoplasias. Ann Oncol 2010; 21:1643. 47. Kerkmeijer LG, Thomas CM, Harvey R, et al. External validation of serum hCG cutoff levels for prediction of resistance to single-agent chemotherapy in patients with persistent trophoblastic disease. Br J Cancer    http://www.uptodate.com/contents/initi al-management-of-high-risk-g estational-trophoblastic-neoplasia?topicKey=ON C%2F96232&elapsedTimeMs=0&sou… 8/13

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2009; 100:979. 48. Golfier F, Labrousse C, Frappart L, et al. [Evaluation of treatment relating to gestational trophoblastic tumor registered to the French Trophoblastic Disease Reference Center (TDRC) in Lyon from 1999 to 2005]. Gynecol Obstet Fertil 2007; 35:205. 49. McNeish IA, Strickland S, Holden L, et al. Low-risk persistent gestational trophoblastic disease: outcome after initial treatment with low-dose methotrexate and folinic acid from 1992 to 2000. J Clin Oncol 2002; 20:1838. 50. Lurain JR. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol 2011; 204:11. 51. Lurain JR, Schink JC. Importance of salvage therapy in the management of high-risk gestational trophoblastic neoplasia. J Reprod Med 2012; 57:219. 52. Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010; 376:717. 53.  Ahamed E, Short D, North B, et al. Survival of women with gestational trophoblastic neoplasia and liver   metastases: is it improving? J Reprod Med 2012; 57:262. 54. Committee on Practice Bulletins-Gynecology, American College of Obstetricians and Gynecologists.  ACOG Practice Bulletin #53. Diagnosis and treatment of gestational trophoblastic disease. Obstet Gynecol 2004; 103:1365. 55. Society of Gynecologic Oncologists Clinical Practice Guidelines. Practice guidelines: gestational trophoblastic disease. Oncology (Williston Park) 1998; 12:455. 56. Lim AK, Agarwal R, Seckl MJ, et al. Embolization of bleeding residual uterine vascular malformations in patients with treated gestational trophoblastic tumors. Radiology 2002; 222:640. 57. Yang JJ, Xiang Y, Wan XR, Yang XY. Diagnosis and management of uterine arteriovenous fistulas with massive vaginal bleeding. Int J Gynaecol Obstet 2005; 89:114. 58. McGrath S, Harding V, Lim AK, et al. Embolization of uterine arteriovenous malformations in patients with gestational trophoblastic tumors: a review of patients at Charing Cross Hospital, 2000-2009. J Reprod Med 2012; 57:319. 59. Goldstein DP, Zanten-Przybysz IV, Bernstein MR, Berkowitz RS. Revised FIGO staging system for    gestational trophoblastic tumors. Recommendations regarding therapy. J Reprod Med 1998; 43:37. Topic 96232 Version 1.0

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GRAPHICS

FIGO Staging of Gestational Trophoblastic Neoplasia (GTN) and modified WHO Prognostic Scoring System as adapted by FIGO

Stage

Disease confined to the

I

uterus

Stage

GTN extends outside of 

II

Risk factor

Score 0

1

2

4

Age (years)

12

III

with

(months)*

or without genital tract involvement Stage

All other metastatic sites

IV

Pretreatment

12 10 5

10 5

(mIU/mL) 8

–

–

Single

≥2

drug

drugs

(including The stage should be followed

10 3 to

3 to 4 cm

uterus) Site of 

Lung

metastases Number of  metastases Prior failed chemotherapy

FIGO: International Federation of Gynecology and Obstetrics; WHO: World Health Organization; hCG: human chorionic gonadotropin. * Interval (in months) between end of antecedent pregnancy and start of chemotherapy. Original figure modified for this publication. Berkowitz RS, Goldstein DP. Current management of  gestational trophoblastic diseases. Gynecol Oncol 2009; 112:654. Table used with the permission of  Elsevier Inc. All rights reserved. Graphic 98185 Version 2.0

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Results of chemotherapy in 90 patients with high-risk stage II and III gestational trophoblastic neoplasia (GTN) (New England Trophoblastic Disease Center, July 1965 to December 2013) Stage

Treatment

II

Number of  patients

Remissions (%)

16

16 (100)

Primary

11

11 (68.9)

Second-line

5

5 (31.1)

74

71 (95.9)

Primary

59

59 (79.7)

Second-line

15

12 (16.3)

90

87 (96.7)

Primary

70

70 (77.8)

Second-line

20

17 (18.9)

III

Total

Graphic 98248 Version 1.0

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Results of chemotherapy in 39 patients with stage IV gestational trophoblastic neoplasia (New England Trophoblastic Disease Center, July 1965 to December 2013) Time period

Total number of  patients

Remissions (%)

1965 to 1975

20

6 (30)

1976 to 2013

19

16 (84)

Graphic 98252 Version 1.0

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Disclosures Ross S Ber kow itz, MD Nothing to disclose. Donald Peter Goldstein, MD Nothing to disclose. Neil S Horowitz, MD Nothing to disclose. Barbara Goff, MD Nothing to disclose. Don S Dizon, MD, FACP Employee of UpToDate, Inc. Sandy J Falk, MD, FACOG Employee of UpToDate, Inc. Contributor disclosures are review ed for c onflicts of interest by the editorial group. When found, these are address ed by vetting through a multi-level review process , and through requirements f or    references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Disclosures:

Conflict of intere st policy

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